US20180339983A1 - Biaryl monobactam compounds and methods of use thereof for the treatment of bacterial infections - Google Patents
Biaryl monobactam compounds and methods of use thereof for the treatment of bacterial infections Download PDFInfo
- Publication number
- US20180339983A1 US20180339983A1 US15/775,487 US201615775487A US2018339983A1 US 20180339983 A1 US20180339983 A1 US 20180339983A1 US 201615775487 A US201615775487 A US 201615775487A US 2018339983 A1 US2018339983 A1 US 2018339983A1
- Authority
- US
- United States
- Prior art keywords
- alkyl
- tert
- mmol
- amino
- optionally substituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 238000000034 method Methods 0.000 title claims abstract description 131
- -1 Biaryl monobactam compounds Chemical class 0.000 title claims abstract description 77
- 208000035143 Bacterial infection Diseases 0.000 title claims abstract description 20
- 208000022362 bacterial infectious disease Diseases 0.000 title claims abstract description 20
- 238000011282 treatment Methods 0.000 title claims description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 481
- 150000003839 salts Chemical class 0.000 claims abstract description 192
- 239000003937 drug carrier Substances 0.000 claims abstract description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 85
- 229910052717 sulfur Inorganic materials 0.000 claims description 59
- 125000002950 monocyclic group Chemical group 0.000 claims description 57
- 229910052760 oxygen Inorganic materials 0.000 claims description 57
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 51
- 229910052739 hydrogen Inorganic materials 0.000 claims description 48
- 239000001257 hydrogen Substances 0.000 claims description 48
- 229910052736 halogen Chemical group 0.000 claims description 42
- 150000002367 halogens Chemical group 0.000 claims description 42
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 38
- 125000006413 ring segment Chemical group 0.000 claims description 36
- 125000003118 aryl group Chemical group 0.000 claims description 33
- 125000000217 alkyl group Chemical group 0.000 claims description 32
- 125000001424 substituent group Chemical group 0.000 claims description 28
- 229920006395 saturated elastomer Polymers 0.000 claims description 27
- 125000005842 heteroatom Chemical group 0.000 claims description 26
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 25
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 23
- 125000002947 alkylene group Chemical group 0.000 claims description 23
- 239000003781 beta lactamase inhibitor Substances 0.000 claims description 23
- 229940126813 beta-lactamase inhibitor Drugs 0.000 claims description 23
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 23
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 claims description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 20
- 150000002431 hydrogen Chemical group 0.000 claims description 17
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 16
- 235000019000 fluorine Nutrition 0.000 claims description 15
- 125000001153 fluoro group Chemical group F* 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 13
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 11
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 8
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 claims description 7
- SMOBCLHAZXOKDQ-ZJUUUORDSA-N [(2s,5r)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl] hydrogen sulfate Chemical compound O=C([C@H]1N2C[C@@](CC1)(N(C2=O)OS(O)(=O)=O)[H])NC1CCNCC1 SMOBCLHAZXOKDQ-ZJUUUORDSA-N 0.000 claims description 7
- HZZVJAQRINQKSD-PBFISZAISA-N clavulanic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 claims description 7
- 229950011310 relebactam Drugs 0.000 claims description 7
- 125000004429 atom Chemical group 0.000 claims description 6
- 229960002379 avibactam Drugs 0.000 claims description 6
- 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 claims description 6
- 229960003324 clavulanic acid Drugs 0.000 claims description 6
- FKENQMMABCRJMK-RITPCOANSA-N sulbactam Chemical compound O=S1(=O)C(C)(C)[C@H](C(O)=O)N2C(=O)C[C@H]21 FKENQMMABCRJMK-RITPCOANSA-N 0.000 claims description 6
- 229960005256 sulbactam Drugs 0.000 claims description 6
- LPQZKKCYTLCDGQ-WEDXCCLWSA-N tazobactam Chemical compound C([C@]1(C)S([C@H]2N(C(C2)=O)[C@H]1C(O)=O)(=O)=O)N1C=CN=N1 LPQZKKCYTLCDGQ-WEDXCCLWSA-N 0.000 claims description 6
- 229960003865 tazobactam Drugs 0.000 claims description 6
- 241000589516 Pseudomonas Species 0.000 claims description 3
- 241000588748 Klebsiella Species 0.000 claims description 2
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 2
- 241000588923 Citrobacter Species 0.000 claims 1
- 241000588914 Enterobacter Species 0.000 claims 1
- 241000588722 Escherichia Species 0.000 claims 1
- 241000588771 Morganella <proteobacterium> Species 0.000 claims 1
- 241000607720 Serratia Species 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 182
- 229960003644 aztreonam Drugs 0.000 abstract description 8
- 239000003782 beta lactam antibiotic agent Substances 0.000 abstract description 7
- 239000002132 β-lactam antibiotic Substances 0.000 abstract description 7
- 229940124586 β-lactam antibiotics Drugs 0.000 abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 367
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 249
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 218
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 217
- 239000000243 solution Substances 0.000 description 181
- 235000019439 ethyl acetate Nutrition 0.000 description 175
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 165
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 131
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 104
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 100
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 95
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 90
- 238000006243 chemical reaction Methods 0.000 description 86
- 239000011541 reaction mixture Substances 0.000 description 83
- 239000000741 silica gel Substances 0.000 description 78
- 229910002027 silica gel Inorganic materials 0.000 description 78
- 229960001866 silicon dioxide Drugs 0.000 description 78
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 76
- 239000012044 organic layer Substances 0.000 description 65
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 62
- 239000000543 intermediate Substances 0.000 description 61
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 60
- 238000005160 1H NMR spectroscopy Methods 0.000 description 58
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 57
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 56
- 239000012267 brine Substances 0.000 description 54
- 238000004440 column chromatography Methods 0.000 description 48
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 47
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 45
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 45
- 239000000706 filtrate Substances 0.000 description 40
- 239000002904 solvent Substances 0.000 description 39
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 34
- 229910052938 sodium sulfate Inorganic materials 0.000 description 33
- 239000007832 Na2SO4 Substances 0.000 description 32
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 31
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 26
- 239000003153 chemical reaction reagent Substances 0.000 description 25
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 25
- 229910052737 gold Inorganic materials 0.000 description 25
- 239000010931 gold Substances 0.000 description 25
- 239000010410 layer Substances 0.000 description 25
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 24
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 24
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 23
- 239000000377 silicon dioxide Substances 0.000 description 23
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 22
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 22
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 22
- 229910052681 coesite Inorganic materials 0.000 description 20
- 229910052906 cristobalite Inorganic materials 0.000 description 20
- 229910052682 stishovite Inorganic materials 0.000 description 20
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 20
- 229910052905 tridymite Inorganic materials 0.000 description 20
- 102000006635 beta-lactamase Human genes 0.000 description 19
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 19
- 239000003480 eluent Substances 0.000 description 19
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 19
- 241000894006 Bacteria Species 0.000 description 18
- 230000001580 bacterial effect Effects 0.000 description 17
- LZWLLMFYVGUUAL-UHFFFAOYSA-L ditert-butyl(cyclopenta-1,3-dien-1-yl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.CC(C)(C)P(C(C)(C)C)C1=CC=C[CH-]1.CC(C)(C)P(C(C)(C)C)C1=CC=C[CH-]1 LZWLLMFYVGUUAL-UHFFFAOYSA-L 0.000 description 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 17
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 16
- 239000003814 drug Substances 0.000 description 16
- 238000000746 purification Methods 0.000 description 16
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 16
- 239000007787 solid Substances 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 14
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 14
- 229910000024 caesium carbonate Inorganic materials 0.000 description 14
- 125000001072 heteroaryl group Chemical group 0.000 description 14
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 14
- 235000019260 propionic acid Nutrition 0.000 description 14
- 230000002829 reductive effect Effects 0.000 description 14
- 239000011734 sodium Substances 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 13
- 239000003242 anti bacterial agent Substances 0.000 description 13
- 125000004567 azetidin-3-yl group Chemical group N1CC(C1)* 0.000 description 13
- 239000012071 phase Substances 0.000 description 13
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 13
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- 208000015181 infectious disease Diseases 0.000 description 12
- 108060004734 metallo-beta-lactamase Proteins 0.000 description 12
- 102000020235 metallo-beta-lactamase Human genes 0.000 description 12
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 12
- DPZMUWXOAMOYDT-UHFFFAOYSA-N tert-butyl oxirane-2-carboxylate Chemical compound CC(C)(C)OC(=O)C1CO1 DPZMUWXOAMOYDT-UHFFFAOYSA-N 0.000 description 12
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 12
- 150000003952 β-lactams Chemical class 0.000 description 12
- 125000002619 bicyclic group Chemical group 0.000 description 11
- 125000004122 cyclic group Chemical group 0.000 description 11
- 229910000027 potassium carbonate Inorganic materials 0.000 description 11
- 0 *C(*)([C@@]1NC(C(C2=NC(N)=S*2)=NO**I**N)=O)N(*IS(O)(=O)=O)C1=O Chemical compound *C(*)([C@@]1NC(C(C2=NC(N)=S*2)=NO**I**N)=O)N(*IS(O)(=O)=O)C1=O 0.000 description 10
- 108020004256 Beta-lactamase Proteins 0.000 description 10
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 10
- 229940088710 antibiotic agent Drugs 0.000 description 10
- 230000003115 biocidal effect Effects 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- 230000002401 inhibitory effect Effects 0.000 description 10
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 10
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 10
- 229910000160 potassium phosphate Inorganic materials 0.000 description 10
- 235000011009 potassium phosphates Nutrition 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 235000017557 sodium bicarbonate Nutrition 0.000 description 10
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 10
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 9
- GZFGOTFRPZRKDS-UHFFFAOYSA-N 4-bromophenol Chemical compound OC1=CC=C(Br)C=C1 GZFGOTFRPZRKDS-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 108090000204 Dipeptidase 1 Proteins 0.000 description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 9
- CDGJTKZKKHLQQN-GSVOUGTGSA-N [(3s)-3-amino-2,2-dimethyl-4-oxoazetidin-1-yl] hydrogen sulfate Chemical compound CC1(C)[C@H](N)C(=O)N1OS(O)(=O)=O CDGJTKZKKHLQQN-GSVOUGTGSA-N 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 9
- WZPBZJONDBGPKJ-VEHQQRBSSA-N aztreonam Chemical compound O=C1N(S([O-])(=O)=O)[C@@H](C)[C@@H]1NC(=O)C(=N/OC(C)(C)C(O)=O)\C1=CSC([NH3+])=N1 WZPBZJONDBGPKJ-VEHQQRBSSA-N 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 235000019253 formic acid Nutrition 0.000 description 9
- 238000002953 preparative HPLC Methods 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 8
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 description 8
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 239000003426 co-catalyst Substances 0.000 description 8
- 239000002808 molecular sieve Substances 0.000 description 8
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 8
- 238000000926 separation method Methods 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 8
- OSPRIEIOIUDYFI-UHFFFAOYSA-N tert-butyl N-[3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCN1C=C(C=N1)B1OC(C)(C)C(C)(C)O1 OSPRIEIOIUDYFI-UHFFFAOYSA-N 0.000 description 8
- 229940086542 triethylamine Drugs 0.000 description 8
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 7
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 7
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 7
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- SILRCLUGLHJTDD-QPXSJBHFSA-N [(3S)-3-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-[(1S)-1-carboxy-2-[4-[1-[(2R)-2,3-diaminopropyl]-2-methylpyrazol-2-ium-4-yl]-3-fluorophenoxy]ethoxy]iminoacetyl]amino]-2,2-dimethyl-4-oxoazetidin-1-yl] sulfate Chemical compound S(=O)(=O)(ON1C([C@@H](C1=O)NC(\C(=N/O[C@@H](COC1=CC(=C(C=C1)C=1C=[N+](N(C=1)C[C@@H](CN)N)C)F)C(=O)O)\C=1N=C(SC=1)N)=O)(C)C)[O-] SILRCLUGLHJTDD-QPXSJBHFSA-N 0.000 description 1
- PPDUTBRQFHNSGF-UJSDCABASA-N [(3S)-3-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-[(1S)-1-carboxy-2-[4-[6-(1,3-diaminopropan-2-ylamino)-1-methylpyridin-1-ium-3-yl]phenoxy]ethoxy]iminoacetyl]amino]-2,2-dimethyl-4-oxoazetidin-1-yl] sulfate Chemical compound S(=O)(=O)(ON1C([C@@H](C1=O)NC(\C(=N/O[C@@H](COC1=CC=C(C=C1)C=1C=[N+](C(=CC=1)NC(CN)CN)C)C(=O)O)\C=1N=C(SC=1)N)=O)(C)C)[O-] PPDUTBRQFHNSGF-UJSDCABASA-N 0.000 description 1
- UEFCWYSCDKAJNF-DDXMEKHPSA-N [(3S)-3-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-[(1S)-2-[4-[1,2-bis(3-aminopropyl)pyrazol-2-ium-4-yl]phenoxy]-1-carboxyethoxy]iminoacetyl]amino]-2,2-dimethyl-4-oxoazetidin-1-yl] sulfate Chemical compound S(=O)(=O)(ON1C([C@@H](C1=O)NC(\C(=N/O[C@@H](COC1=CC=C(C=C1)C=1C=[N+](N(C=1)CCCN)CCCN)C(=O)O)\C=1N=C(SC=1)N)=O)(C)C)[O-] UEFCWYSCDKAJNF-DDXMEKHPSA-N 0.000 description 1
- RZQRGRNGJLIXNZ-GPLOAZAPSA-N [(3S)-3-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-[(1S)-2-[4-[2-(azetidin-3-ylmethylamino)-1-methylpyridin-1-ium-4-yl]phenoxy]-1-carboxyethoxy]iminoacetyl]amino]-2,2-dimethyl-4-oxoazetidin-1-yl] sulfate Chemical compound S(=O)(=O)(ON1C([C@@H](C1=O)NC(\C(=N/O[C@@H](COC1=CC=C(C=C1)C1=CC(=[N+](C=C1)C)NCC1CNC1)C(=O)O)\C=1N=C(SC=1)N)=O)(C)C)[O-] RZQRGRNGJLIXNZ-GPLOAZAPSA-N 0.000 description 1
- JDMZZHNMMUXZEM-XJTJISGASA-N [(3S)-3-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-[(1S)-2-[6-[3-(azetidin-3-ylmethyl)imidazol-3-ium-1-yl]pyridin-3-yl]oxy-1-carboxyethoxy]iminoacetyl]amino]-2,2-dimethyl-4-oxoazetidin-1-yl] sulfate Chemical compound S(=O)(=O)(ON1C([C@@H](C1=O)NC(\C(=N/O[C@@H](COC=1C=NC(=CC=1)N1C=[N+](C=C1)CC1CNC1)C(=O)O)\C=1N=C(SC=1)N)=O)(C)C)[O-] JDMZZHNMMUXZEM-XJTJISGASA-N 0.000 description 1
- QENCWLSYVCXHAZ-UPKWXMMBSA-N [(3S)-3-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-[(1S)-2-[6-[[1-(azetidin-3-ylmethyl)pyridin-1-ium-4-yl]amino]pyridin-3-yl]oxy-1-carboxyethoxy]iminoacetyl]amino]-2,2-dimethyl-4-oxoazetidin-1-yl] sulfate Chemical compound S(=O)(=O)(ON1C([C@@H](C1=O)NC(\C(=N/O[C@@H](COC=1C=NC(=CC=1)NC1=CC=[N+](C=C1)CC1CNC1)C(=O)O)\C=1N=C(SC=1)N)=O)(C)C)[O-] QENCWLSYVCXHAZ-UPKWXMMBSA-N 0.000 description 1
- JVEGBIPXHACLIX-ZTSWXMPZSA-N [(3S)-3-[[(2Z)-2-(2-amino-5-chloro-1,3-thiazol-4-yl)-2-[(1S)-2-[4-[6-(2-aminoethylamino)-1-methylpyridin-1-ium-3-yl]phenoxy]-1-carboxyethoxy]iminoacetyl]amino]-2,2-dimethyl-4-oxoazetidin-1-yl] sulfate Chemical compound S(=O)(=O)(ON1C([C@@H](C1=O)NC(\C(=N/O[C@@H](COC1=CC=C(C=C1)C=1C=[N+](C(=CC=1)NCCN)C)C(=O)O)\C=1N=C(SC=1Cl)N)=O)(C)C)[O-] JVEGBIPXHACLIX-ZTSWXMPZSA-N 0.000 description 1
- FBXSQTIURKVXCM-KUWBHHGFSA-N [(3S)-3-[[(2Z)-2-[(1S)-2-[2-[3-(3-aminopropyl)imidazol-3-ium-1-yl]pyrimidin-5-yl]oxy-1-carboxyethoxy]imino-2-(2-amino-1,3-thiazol-4-yl)acetyl]amino]-2,2-dimethyl-4-oxoazetidin-1-yl] sulfate Chemical compound S(=O)(=O)(ON1C([C@@H](C1=O)NC(\C(\C=1N=C(SC=1)N)=N/O[C@@H](COC=1C=NC(=NC=1)N1C=[N+](C=C1)CCCN)C(=O)O)=O)(C)C)[O-] FBXSQTIURKVXCM-KUWBHHGFSA-N 0.000 description 1
- ZVOBXJVAYUXFHC-COADASIMSA-N [(3S)-3-[[(2Z)-2-[(1S)-2-[4-[1-(2-aminoethyl)-2-(3-aminopropyl)pyrazol-2-ium-4-yl]phenoxy]-1-carboxyethoxy]imino-2-(2-amino-1,3-thiazol-4-yl)acetyl]amino]-2,2-dimethyl-4-oxoazetidin-1-yl] sulfate Chemical compound S(=O)(=O)(ON1C([C@@H](C1=O)NC(\C(\C=1N=C(SC=1)N)=N/O[C@@H](COC1=CC=C(C=C1)C=1C=[N+](N(C=1)CCCN)CCN)C(=O)O)=O)(C)C)[O-] ZVOBXJVAYUXFHC-COADASIMSA-N 0.000 description 1
- ALDDIRYWGOLCTP-VSZOASKFSA-N [(3S)-3-[[(2Z)-2-[(1S)-2-[4-[1-(3-aminopropyl)-2-(azetidin-3-ylmethyl)pyrazol-2-ium-4-yl]phenoxy]-1-carboxyethoxy]imino-2-(2-amino-1,3-thiazol-4-yl)acetyl]amino]-2,2-dimethyl-4-oxoazetidin-1-yl] sulfate Chemical compound S(=O)(=O)(ON1C([C@@H](C1=O)NC(\C(\C=1N=C(SC=1)N)=N/O[C@@H](COC1=CC=C(C=C1)C=1C=[N+](N(C=1)CCCN)CC1CNC1)C(=O)O)=O)(C)C)[O-] ALDDIRYWGOLCTP-VSZOASKFSA-N 0.000 description 1
- WSQJBRIUQKAMEU-NQYCYQSHSA-N [(3S)-3-[[(2Z)-2-[(1S)-2-[4-[1-(3-aminopropyl)-2-methylpyrazol-2-ium-4-yl]-3-chlorophenoxy]-1-carboxyethoxy]imino-2-(2-amino-1,3-thiazol-4-yl)acetyl]amino]-2,2-dimethyl-4-oxoazetidin-1-yl] sulfate Chemical compound S(=O)(=O)(ON1C([C@@H](C1=O)NC(\C(\C=1N=C(SC=1)N)=N/O[C@@H](COC1=CC(=C(C=C1)C=1C=[N+](N(C=1)CCCN)C)Cl)C(=O)O)=O)(C)C)[O-] WSQJBRIUQKAMEU-NQYCYQSHSA-N 0.000 description 1
- ZDJOXQHDSRKXHY-ASBANEHBSA-N [(3S)-3-[[(2Z)-2-[(1S)-2-[4-[2-(2-aminoethylamino)-1-(azetidin-3-ylmethyl)pyrimidin-1-ium-5-yl]phenoxy]-1-carboxyethoxy]imino-2-(2-amino-1,3-thiazol-4-yl)acetyl]amino]-2,2-dimethyl-4-oxoazetidin-1-yl] sulfate Chemical compound S(=O)(=O)(ON1C([C@@H](C1=O)NC(\C(\C=1N=C(SC=1)N)=N/O[C@@H](COC1=CC=C(C=C1)C=1C=NC(=[N+](C=1)CC1CNC1)NCCN)C(=O)O)=O)(C)C)[O-] ZDJOXQHDSRKXHY-ASBANEHBSA-N 0.000 description 1
- AVHUBNHCZUUEKM-UCOJPOCPSA-N [(3S)-3-[[(2Z)-2-[(1S)-2-[4-[2-(2-aminoethylamino)-1-methylpyrimidin-1-ium-5-yl]phenoxy]-1-carboxyethoxy]imino-2-(2-amino-1,3-thiazol-4-yl)acetyl]amino]-2,2-dimethyl-4-oxoazetidin-1-yl] sulfate Chemical compound S(=O)(=O)(ON1C([C@@H](C1=O)NC(\C(\C=1N=C(SC=1)N)=N/O[C@@H](COC1=CC=C(C=C1)C=1C=NC(=[N+](C=1)C)NCCN)C(=O)O)=O)(C)C)[O-] AVHUBNHCZUUEKM-UCOJPOCPSA-N 0.000 description 1
- SCTJRBLNSVHIRS-RNQBPFNISA-N [(3S)-3-[[(2Z)-2-[(1S)-2-[4-[2-(3-aminopropylamino)-1-methylpyridin-1-ium-4-yl]phenoxy]-1-carboxyethoxy]imino-2-(2-amino-1,3-thiazol-4-yl)acetyl]amino]-2,2-dimethyl-4-oxoazetidin-1-yl] sulfate Chemical compound S(=O)(=O)(ON1C([C@@H](C1=O)NC(\C(\C=1N=C(SC=1)N)=N/O[C@@H](COC1=CC=C(C=C1)C1=CC(=[N+](C=C1)C)NCCCN)C(=O)O)=O)(C)C)[O-] SCTJRBLNSVHIRS-RNQBPFNISA-N 0.000 description 1
- HKXCQKRWBDJMFJ-UCOJPOCPSA-N [(3S)-3-[[(2Z)-2-[(1S)-2-[4-[3-amino-1-(3-aminopropyl)-2-methylpyrazol-1-ium-4-yl]-3-fluorophenoxy]-1-carboxyethoxy]imino-2-(2-amino-1,3-thiazol-4-yl)acetyl]amino]-2,2-dimethyl-4-oxoazetidin-1-yl] sulfate Chemical compound Cn1c(N)c(c[n+]1CCCN)-c1ccc(OC[C@H](O\N=C(/C(=O)N[C@@H]2C(=O)N(OS([O-])(=O)=O)C2(C)C)c2csc(N)n2)C(O)=O)cc1F HKXCQKRWBDJMFJ-UCOJPOCPSA-N 0.000 description 1
- SIOCGFROYKXLIR-YYWXNABISA-N [(3S)-3-[[(2Z)-2-[(1S)-2-[4-[3-amino-1-(3-aminopropyl)-2-methylpyrazol-1-ium-4-yl]phenoxy]-1-carboxyethoxy]imino-2-(2-amino-5-chloro-1,3-thiazol-4-yl)acetyl]amino]-2,2-dimethyl-4-oxoazetidin-1-yl] sulfate Chemical compound S(=O)(=O)(ON1C([C@@H](C1=O)NC(\C(\C=1N=C(SC=1Cl)N)=N/O[C@@H](COC1=CC=C(C=C1)C=1C(=[N+](N(C=1)CCCN)C)N)C(=O)O)=O)(C)C)[O-] SIOCGFROYKXLIR-YYWXNABISA-N 0.000 description 1
- SOQNCCWGVSJNKA-WWZQITJSSA-N [(3S)-3-[[(2Z)-2-[(1S)-2-[4-[3-amino-2-(3-aminopropyl)-1-methylpyrazol-1-ium-4-yl]phenoxy]-1-carboxyethoxy]imino-2-(2-amino-1,3-thiazol-4-yl)acetyl]amino]-2,2-dimethyl-4-oxoazetidin-1-yl] sulfate Chemical compound S(=O)(=O)(ON1C([C@@H](C1=O)NC(\C(\C=1N=C(SC=1)N)=N/O[C@@H](COC1=CC=C(C=C1)C=1C=[N+](N(C=1N)CCCN)C)C(=O)O)=O)(C)C)[O-] SOQNCCWGVSJNKA-WWZQITJSSA-N 0.000 description 1
- XBOADYOVSULTNB-COADASIMSA-N [(3S)-3-[[(2Z)-2-[(1S)-2-[4-[5-(2-aminoethylamino)-1-methylpyridin-1-ium-2-yl]phenoxy]-1-carboxyethoxy]imino-2-(2-amino-1,3-thiazol-4-yl)acetyl]amino]-2,2-dimethyl-4-oxoazetidin-1-yl] sulfate Chemical compound S(=O)(=O)(ON1C([C@@H](C1=O)NC(\C(\C=1N=C(SC=1)N)=N/O[C@@H](COC1=CC=C(C=C1)C1=[N+](C=C(C=C1)NCCN)C)C(=O)O)=O)(C)C)[O-] XBOADYOVSULTNB-COADASIMSA-N 0.000 description 1
- OCTOGHFVVNHADK-ZGBKVAEISA-N [(3S)-3-[[(2Z)-2-[(1S)-2-[4-[6-(2-aminoethylamino)-1-(azetidin-3-ylmethyl)pyridin-1-ium-3-yl]phenoxy]-1-carboxyethoxy]imino-2-(2-amino-1,3-thiazol-4-yl)acetyl]amino]-2,2-dimethyl-4-oxoazetidin-1-yl] sulfate Chemical compound S(=O)(=O)(ON1C([C@@H](C1=O)NC(\C(\C=1N=C(SC=1)N)=N/O[C@@H](COC1=CC=C(C=C1)C=1C=[N+](C(=CC=1)NCCN)CC1CNC1)C(=O)O)=O)(C)C)[O-] OCTOGHFVVNHADK-ZGBKVAEISA-N 0.000 description 1
- CBCAUQMDRJQWRK-SOKZPXHTSA-N [(3S)-3-[[(2Z)-2-[(1S)-2-[4-[6-(2-aminoethylamino)-1-methylpyridin-1-ium-3-yl]phenoxy]-1-carboxyethoxy]imino-2-(2-amino-1,3-thiazol-4-yl)acetyl]amino]-2,2-dimethyl-4-oxoazetidin-1-yl] sulfate Chemical compound S(=O)(=O)(ON1C([C@@H](C1=O)NC(\C(\C=1N=C(SC=1)N)=N/O[C@@H](COC1=CC=C(C=C1)C=1C=[N+](C(=CC=1)NCCN)C)C(=O)O)=O)(C)C)[O-] CBCAUQMDRJQWRK-SOKZPXHTSA-N 0.000 description 1
- FVXBXUSXDAGGEW-DDXMEKHPSA-N [(3S)-3-[[(2Z)-2-[(1S)-2-[4-[6-[(2-aminoethylamino)methyl]-1-methylpyridin-1-ium-3-yl]phenoxy]-1-carboxyethoxy]imino-2-(2-amino-1,3-thiazol-4-yl)acetyl]amino]-2,2-dimethyl-4-oxoazetidin-1-yl] sulfate Chemical compound S(=O)(=O)(ON1C([C@@H](C1=O)NC(\C(\C=1N=C(SC=1)N)=N/O[C@@H](COC1=CC=C(C=C1)C=1C=[N+](C(=CC=1)CNCCN)C)C(=O)O)=O)(C)C)[O-] FVXBXUSXDAGGEW-DDXMEKHPSA-N 0.000 description 1
- NILNNHZBISCOIS-ZUHFZGFMSA-N [(3S)-3-[[(2Z)-2-[(1S)-2-[6-[1-(3-aminopropyl)-2-methylpyrazol-2-ium-4-yl]pyridazin-3-yl]oxy-1-carboxyethoxy]imino-2-(2-amino-1,3-thiazol-4-yl)acetyl]amino]-2,2-dimethyl-4-oxoazetidin-1-yl] sulfate Chemical compound S(=O)(=O)(ON1C([C@@H](C1=O)NC(\C(\C=1N=C(SC=1)N)=N/O[C@@H](COC=1N=NC(=CC=1)C=1C=[N+](N(C=1)CCCN)C)C(=O)O)=O)(C)C)[O-] NILNNHZBISCOIS-ZUHFZGFMSA-N 0.000 description 1
- DTHDXPYXTXOBGA-TUVMUKFFSA-N [(3S)-3-[[(2Z)-2-[(1S)-2-[6-[3-(3-aminopropyl)imidazol-3-ium-1-yl]pyridin-3-yl]oxy-1-carboxyethoxy]imino-2-(2-amino-1,3-thiazol-4-yl)acetyl]amino]-2,2-dimethyl-4-oxoazetidin-1-yl] sulfate Chemical compound S(=O)(=O)(ON1C([C@@H](C1=O)NC(\C(\C=1N=C(SC=1)N)=N/O[C@@H](COC=1C=NC(=CC=1)N1C=[N+](C=C1)CCCN)C(=O)O)=O)(C)C)[O-] DTHDXPYXTXOBGA-TUVMUKFFSA-N 0.000 description 1
- FUUGPMXTLAJOST-ATNCVIMFSA-N [(3S)-3-[[(2Z)-2-[(2S)-1-[4-[1-(3-aminopropyl)-2-methylpyrazol-2-ium-4-yl]-3-fluorophenoxy]-2-carboxypropan-2-yl]oxyimino-2-(2-amino-1,3-thiazol-4-yl)acetyl]amino]-2,2-dimethyl-4-oxoazetidin-1-yl] sulfate Chemical compound S(=O)(=O)(ON1C([C@@H](C1=O)NC(\C(\C=1N=C(SC=1)N)=N/O[C@](COC1=CC(=C(C=C1)C=1C=[N+](N(C=1)CCCN)C)F)(C)C(=O)O)=O)(C)C)[O-] FUUGPMXTLAJOST-ATNCVIMFSA-N 0.000 description 1
- FSIQEWQYYRNGRM-QVVYNQDHSA-N [(3S)-3-[[(2Z)-2-[(2S)-1-[4-[1-(3-aminopropyl)-2-methylpyrazol-2-ium-4-yl]phenoxy]-2-carboxypropan-2-yl]oxyimino-2-(2-amino-1,3-thiazol-4-yl)acetyl]amino]-2,2-dimethyl-4-oxoazetidin-1-yl] sulfate Chemical compound S(=O)(=O)(ON1C([C@@H](C1=O)NC(\C(\C=1N=C(SC=1)N)=N/O[C@](COC1=CC=C(C=C1)C=1C=[N+](N(C=1)CCCN)C)(C)C(=O)O)=O)(C)C)[O-] FSIQEWQYYRNGRM-QVVYNQDHSA-N 0.000 description 1
- PHAXQXQYUHUTRW-OALKUNGNSA-N [(3S)-3-[[(2Z)-2-[(2S)-1-[4-[6-(2-aminoethylamino)-1-methylpyridin-1-ium-3-yl]phenoxy]-2-carboxypropan-2-yl]oxyimino-2-(2-amino-1,3-thiazol-4-yl)acetyl]amino]-2,2-dimethyl-4-oxoazetidin-1-yl] sulfate Chemical compound S(=O)(=O)(ON1C([C@@H](C1=O)NC(\C(\C=1N=C(SC=1)N)=N/O[C@](COC1=CC=C(C=C1)C=1C=[N+](C(=CC=1)NCCN)C)(C)C(=O)O)=O)(C)C)[O-] PHAXQXQYUHUTRW-OALKUNGNSA-N 0.000 description 1
- XOIVFPXRMXQVJT-CKWMZHOLSA-N [(3S)-3-[[(2Z)-2-[(2S)-1-[6-[3-(3-aminopropyl)imidazol-3-ium-1-yl]pyridin-3-yl]oxy-2-carboxypropan-2-yl]oxyimino-2-(2-amino-1,3-thiazol-4-yl)acetyl]amino]-2,2-dimethyl-4-oxoazetidin-1-yl] sulfate Chemical compound C[C@@](COc1ccc(nc1)-n1cc[n+](CCCN)c1)(O\N=C(/C(=O)N[C@@H]1C(=O)N(OS([O-])(=O)=O)C1(C)C)c1csc(N)n1)C(O)=O XOIVFPXRMXQVJT-CKWMZHOLSA-N 0.000 description 1
- VNSDJTRALGQKJH-IYPSOCABSA-N [(3S)-3-[[(2Z)-2-[(2S)-3-[4-[1-(3-aminopropyl)-2-methylpyrazol-2-ium-4-yl]phenoxy]-1-methoxy-1-oxopropan-2-yl]oxyimino-2-(2-amino-1,3-thiazol-4-yl)acetyl]amino]-2,2-dimethyl-4-oxoazetidin-1-yl] sulfate Chemical compound S(=O)(=O)(ON1C([C@@H](C1=O)NC(\C(\C=1N=C(SC=1)N)=N/O[C@H](C(=O)OC)COC1=CC=C(C=C1)C=1C=[N+](N(C=1)CCCN)C)=O)(C)C)[O-] VNSDJTRALGQKJH-IYPSOCABSA-N 0.000 description 1
- VNBITECPPDPIAS-NMJWXOLTSA-N [(3S)-3-[[(2Z)-2-[2-[4-[1-(3-aminopropyl)-2-methylpyrazol-2-ium-4-yl]phenoxy]-1-phosphonoethoxy]imino-2-(2-amino-1,3-thiazol-4-yl)acetyl]amino]-2,2-dimethyl-4-oxoazetidin-1-yl] sulfate Chemical compound S(=O)(=O)(ON1C([C@@H](C1=O)NC(\C(\C=1N=C(SC=1)N)=N/OC(COC1=CC=C(C=C1)C=1C=[N+](N(C=1)CCCN)C)P(=O)(O)O)=O)(C)C)[O-] VNBITECPPDPIAS-NMJWXOLTSA-N 0.000 description 1
- RNVYQYLELCKWAN-RXMQYKEDSA-N [(4r)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol Chemical compound CC1(C)OC[C@@H](CO)O1 RNVYQYLELCKWAN-RXMQYKEDSA-N 0.000 description 1
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 1
- FZKHVWYNJCXNKV-UHFFFAOYSA-N [Si](C)(C)(C(C)(C)C)OC(C(=O)OC(C)(C)C)COC=1C=NC(=CC=1)NC1=CC=NC=C1 Chemical compound [Si](C)(C)(C(C)(C)C)OC(C(=O)OC(C)(C)C)COC=1C=NC(=CC=1)NC1=CC=NC=C1 FZKHVWYNJCXNKV-UHFFFAOYSA-N 0.000 description 1
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- POHWAQLZBIMPRN-UHFFFAOYSA-N tert-butyl n-(3-aminopropyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCCN POHWAQLZBIMPRN-UHFFFAOYSA-N 0.000 description 1
- XCAQIUOFDMREBA-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonyl]carbamate Chemical compound CC(C)(C)OC(=O)NC(=O)OC(C)(C)C XCAQIUOFDMREBA-UHFFFAOYSA-N 0.000 description 1
- AHDIBLCWWYDXII-UHFFFAOYSA-N tert-butyl n-[2-(hydroxymethyl)-3-[(2-methylpropan-2-yl)oxycarbonylamino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCC(CO)CNC(=O)OC(C)(C)C AHDIBLCWWYDXII-UHFFFAOYSA-N 0.000 description 1
- SOBBHYDDNWGZCN-UHFFFAOYSA-N tert-butyl n-[2-[(5-bromopyrimidin-2-yl)amino]ethyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCNC1=NC=C(Br)C=N1 SOBBHYDDNWGZCN-UHFFFAOYSA-N 0.000 description 1
- PZSPXAMRSRUYNR-UHFFFAOYSA-N tert-butyl n-[3-(5-bromopyridin-2-yl)prop-2-ynyl]carbamate Chemical compound CC(C)(C)OC(=O)NCC#CC1=CC=C(Br)C=N1 PZSPXAMRSRUYNR-UHFFFAOYSA-N 0.000 description 1
- DSPYCWLYGXGJNJ-UHFFFAOYSA-N tert-butyl n-prop-2-ynylcarbamate Chemical compound CC(C)(C)OC(=O)NCC#C DSPYCWLYGXGJNJ-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000000165 tricyclic carbocycle group Chemical group 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 230000036642 wellbeing Effects 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 238000002424 x-ray crystallography Methods 0.000 description 1
- 150000003954 δ-lactams Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/433—Thidiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
- C07C53/15—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen containing halogen
- C07C53/16—Halogenated acetic acids
- C07C53/18—Halogenated acetic acids containing fluorine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
- A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- This invention relates to novel biaryl monobactam compounds, processes for their preparation and their use as therapeutic agents. More particularly, the invention relates to biaryl monobactam compounds and their use as antibiotic agents for the treatment of bacterial infections.
- ⁇ -lactams are the most widely used antibiotics for treatment of serious bacterial infections. These include carbapenems, cephalosporins, penicillins, and monobactams. As has been observed for other antibiotic classes, resistance to ⁇ -lactams has emerged. For most Gram-negative bacteria, this resistance is primarily driven by the expression of ⁇ -lactamases, enzymes that hydrolyze ⁇ -lactam compounds. There are 4 different classes of ⁇ -lactamases (A, B, C, and D) capable of hydrolyzing overlapping but distinct subsets of ⁇ -lactams (Drawz and Bonomo, Clin. Micro. Rev., 2010, 23:160-201).
- MBLs metallo ⁇ -lactamases
- Aztreonam a monobactam
- aztreonam has poor activity against Pseudomonas and Acinetobacter strains.
- monobactams are inherently resistant to hydrolysis by MBLs, several companies have begun developing novel monobactam compounds for the treatment of infections caused by Gram-negative bacteria.
- Monobactam compounds comprising a siderophore moiety are disclosed in WO 2007/065288, WO2012/073138 , J. Medicinal Chemistry 56: 5541-5552 (2013), and Bioorganic and Medicinal Chemistry Letters 22:5989 (2012).
- U.S. Patent Application Publication No. US 2014/0275007 discloses oxamazin monobactams and their use as antibacterial agents
- U.S. Patent Application Publication No. US 2015/0266867 also discloses novel monobactam compounds for the use as antibacterial agents
- International Patent Application Publication No. WO 2013/110643 discloses novel amidine substituted monobactam derivatives and their use as antimicrobial reagents.
- the invention relates to the design and synthesis of a series of bi-aryl monobactam analogs, a novel class of highly potent antibiotics effective against a broad range of Gram-negative bacteria.
- These compounds and their pharmaceutically acceptable salts may be useful as therapeutic agents for clinical treatment of various infections caused by Gram-negative bacteria, including strains that are multidrug resistant.
- the compounds can be used alone or in combination with a suitable ⁇ -lactamase inhibitor. More particularly, the present invention includes compounds of Formula I:
- W is a bond or O
- R X and R Z are independently hydrogen, —SC 1 -C 3 alkyl, C 1 -C 3 alkyl, —(C 1 -C 3 alkylene) n OC 1 -C 3 alkyl, or —(C 1 -C 3 alkylene) n NC 1 -C 3 alkyl, wherein the —SC 1 -C 3 alkyl, the C 1 -C 3 alkyl, the —(C 1 -C 3 alkylene) n OC 1 -C 3 alkyl and the —(C 1 -C 3 alkylene) n NC 1 -C 3 alkyl are optionally substituted with one to seven fluorines;
- R X and R Z together with the carbon to which they are attached, form a monocyclic C 4 -C 7 cycloalkyl or a monocyclic C 4 -C 7 heterocycloalkyl with 1, 2, or 3 heteroatom ring atoms independently selected from N, O and S, wherein said C 4 -C 7 cycloalkyl and said C 4 -C 7 heterocycloalkyl are optionally substituted with one to three substituents independently selected from —F, —OH and —OC 1 -C 3 alkyl;
- X is N or CR 1 ;
- R 1 is hydrogen, C 1 -C 3 alkyl, or halogen; wherein said C 1 -C 3 alkyl is optionally substituted with one to three R a ;
- each occurrence of R a is independently hydrogen, halogen, C 1 -C 3 alkyl, —NR c R d or —OR e ;
- Z is C 1 -C 3 alkylene, optionally substituted with one to three R b ;
- each occurrence of R b is independently —C 1 -C 8 alkyl, —C 3 -C 7 cycloalkyl, —C(O)OR e , —C(O)NR c R d , tetrazolyl, oxadiazolonyl, HetA, AryA, —S(O) m R e , —S(O) m NR c R d , or —P(O)(R e ) p wherein said —C 1 -C 8 alkyl and said —C 3 -C 7 cycloalkyl are optionally substituted with one to three R a ;
- HetA is a 4- to 6-membered saturated or monounsaturated monocyclic ring with 1, 2, or 3 heteroatom ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with one to four R 4 ;
- AryA is a 5- to 6-membered monocyclic aromatic ring with 0, 1, 2, or 3 ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with one to four R 4 ;
- Y is a bond, O, NR 2 , S, or CH 2 ;
- R 2 is hydrogen, —C 1 -C 3 alkyl, —C(O)R e —C(O)NR c R d , —S(O) m R e , or —S(O) m NR c R d wherein said —C 1 -C 3 alkyl is optionally substituted with one to three R a ;
- a 1 is AryA
- a 2 is —(CH 2 ) n N(R 3 ) 2 —, C 3 -C 7 cycloalkyl, AryC or HetC, wherein said C 3 -C 7 cycloalkyl is optionally substituted with one to four R 4 ;
- AryC is a 5- to 6-membered monocyclic aromatic ring with 0, 1, 2, or 3 ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with one to four R 4 ;
- HetC is a 4- to 7-membered saturated or monounsaturated monocyclic ring with 1, 2, or 3 heteroatom ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with one to four R 4 ;
- each occurrence of R 4 is independently: —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, —C 2 -C 8 alkynyl, halogen, —OR e , —S(O) m R e , —S(O) m NR c R d , —C(O)R e , —OC(O)R e , —C(O)OR e , —CN, —C(O)NR c R d , —NR c R d , —(CH 2 ) n NR c R d ; —NR c C(O)R e , —NR c C(O)OR e , —NR c C(O)NR c R d , —NR c S(O) m R e , ⁇ NH, —CF 3 , —OCF 3 , —OCHF 2 ,
- HetB is a 3- to 6-membered saturated or monounsaturated monocyclic ring with 1, 2, or 3 heteroatom ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with one to three R a ;
- Q is a bond, CH 2 , O, S, —(CH 2 ) n NR 3 —, or —NR 3 (CH 2 ) n —, wherein each CH 2 is unsubstituted or substituted with one to two substituents selected from halogen, —C 1 -C 6 alkyl, OR e and —(CH 2 ) n NR c R d ;
- R 3 is hydrogen or —C 1 -C 3 alkyl, wherein said —C 1 -C 3 alkyl is optionally substituted with one to three R a ;
- M is R 5 , —NHR 5 , —N(R 5 ) 2 , —OR 5 , —(CH 2 ) n R 5 , —C(O)R 5 , —C(NH)R 5 , or —S(O) m R 5 ;
- R 5 is H, C 2 -C 10 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl-C 3 -C 7 cycloalkyl, HetB, AryB, or —NH(C 1 -C 6 alkyl), wherein said C 1 -C 6 alkyl, said C 2 -C 10 alkyl and said C 3 -C 7 cycloalkyl are optionally substituted with one to four R 6 ;
- AryB is a 5- to 6-membered monocyclic aromatic ring with 0, 1, 2, or 3 ring atoms independently selected from N, O and S, optionally substituted with one to four R 4 ;
- each occurrence of R 6 is independently selected from the group consisting of: halogen, —OR e , —S(O) m R e , —S(O) m NR c R d , —C(O)R e , —OC(O)R e —C(O)OR e , —CN, —C(O)NR c R d , —C(NH)NR c R d , —N c R d , —(CH 2 ) n NR c R d , —N(R c )(C(O)R e ), —N(R c )(C(O)OR e ), —N(R c )(C(O)NR c R d ), —N(R c )(S(O) m R e ), and HetB;
- each occurrence of R e is independently: hydrogen, —C 1 -C 10 alkyl, —C 2 -C 10 alkenyl, —OH, —OC 1 -C 4 alkyl, —C 3 -C 6 cycloalkyl, —C 1 -C 10 alkylene-C 3 -C 6 cycloalkyl, HetB, —C 1 -C 10 alkylene-HetB, AryB, —C 1 -C 10 alkylene-AryB, or —C 1 -C 10 alkylene-HetB; wherein each R e is optionally substituted with one to three R h ;
- each occurrence of R f is independently: halogen, —C 1 -C 10 alkyl, —OH, —OC 1 -C 4 alkyl, —S(O) m C 1 -C 4 alkyl, —CN, —CF 3 , —OCHF 2 , —OCF 3 , or NH 2 , wherein said —C 1 -C 10 alkyl is optionally substituted with one to three substituents independently selected from: —OH, halogen, cyano, and —S(O) 2 CH 3 ;
- each occurrence of R g is independently: hydrogen, —C(O)R e , and —C 1 -C 10 alkyl, wherein said —C 1 -C 10 alkyl is optionally substituted with one to five fluorines;
- each occurrence of R h is independently: halogen, —C 1 -C 10 alkyl, —OH, —OC 1 -C 4 alkyl, —S(O) m C 1 -C 4 alkyl, —CN, —CF 3 , —OCHF 2 , or —OCF 3 ; wherein said —C 1 -C 10 alkyl is optionally substituted with one to three substituents independently selected from: —OH, halogen, cyano, or —S(O) 2 CH 3 ;
- each n is independently 0, 1, 2, 3 or 4;
- each m is independently 0, 1 or 2
- each p is independently 1 or 2.
- the present invention also includes compounds of Formula I:
- W is a bond or O
- R X and R Z are independently hydrogen, —SC 1 -C 3 alkyl, C 1 -C 3 alkyl, —(C 1 -C 3 alkylene) n OC 1 -C 3 alkyl, or —(C 1 -C 3 alkylene) n NC 1 -C 3 alkyl, wherein the —SC 1 -C 3 alkyl, the C 1 -C 3 alkyl, the —(C 1 -C 3 alkylene) n OC 1 -C 3 alkyl and the —(C 1 -C 3 alkylene) n NC 1 -C 3 alkyl are optionally substituted with one to seven fluorines;
- R X and R Z together with the carbon to which they are attached, form a monocyclic C 4 -C 7 cycloalkyl or a monocyclic C 4 -C 7 heterocycloalkyl with 1, 2, or 3 heteroatom ring atoms independently selected from N, O and S, wherein said C 4 -C 7 cycloalkyl and said C 4 -C 7 heterocycloalkyl are optionally substituted with one to three substituents independently selected from —F, —OH and —OC 1 -C 3 alkyl;
- X is N or CR 1 ;
- R 1 is hydrogen, C 1 -C 3 alkyl, or halogen; wherein said C 1 -C 3 alkyl is optionally substituted with one to three R a ;
- each occurrence of R a is independently hydrogen, halogen, C 1 -C 3 alkyl, —NR c R d or —OR e ;
- Z is C 1 -C 3 alkylene, optionally substituted with one to three R b ;
- each occurrence of R b is independently —C 1 -C 8 alkyl, —C 3 -C 7 cycloalkyl, —C(O)OR e , —C(O)NR c R d , tetrazolyl, oxadiazolonyl, HetA, AryA, —S(O) m R e , —S(O) m NR c R d , or —P(O)(R e ) p wherein said —C 1 -C 8 alkyl and said —C 3 -C 7 cycloalkyl are optionally substituted with one to three R a ;
- HetA is a 4- to 6-membered saturated or monounsaturated monocyclic ring with 1, 2, or 3 heteroatom ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with one to four R 4 ;
- AryA is a 5- to 6-membered monocyclic aromatic ring with 0, 1, 2, or 3 ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with one to four R 4 ;
- Y is a bond, O, NR 2 , S, or CH 2 ;
- R 2 is hydrogen, —C 1 -C 3 alkyl, —C(O)R e , —C(O)NR c R d , —S(O) m R e , or —S(O) m NR c R d wherein said —C 1 -C 3 alkyl is optionally substituted with one to three R a ;
- a 1 is AryA
- a 2 is C 3 -C 7 cycloalkyl, AryC or HetC, wherein said C 3 -C 7 cycloalkyl is optionally substituted with one to four R 4 ;
- AryC is a 5- to 6-membered monocyclic aromatic ring with 0, 1, 2, or 3 ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with one to four R 4 ;
- HetC is a 4- to 7-membered saturated or monounsaturated monocyclic ring with 1, 2, or 3 heteroatom ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with one to four R 4 ;
- each occurrence of R 4 is independently: —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, —C 2 -C 8 alkynyl, halogen, —OR e , —S(O) m R e , —S(O) m NR c R d , —C(O)R e , —OC(O)R e —C(O)OR e , —CN, —C(O)NR c R d , —NR c R d , —NR c C(O)R e , —NR c C(O)OR e , —NR c C(O)NR c R d , —NR c S(O) m R e , ⁇ NH, —CF 3 , —OCF 3 , —OCHF 2 , —C 3 -C 6 cycloalkyl, —O—C 3
- HetB is a 3- to 6-membered saturated or monounsaturated monocyclic ring with 1, 2, or 3 heteroatom ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with one to three R a ;
- Q is a bond, CH 2 , O, S, —(CH 2 ) n NR 3 —, or —NR 3 (CH 2 ) n —;
- R 3 is hydrogen or —C 1 -C 3 alkyl, wherein said —C 1 -C 3 alkyl is optionally substituted with one to three R a ;
- M is R 5 , —NR 5 , —OR 5 , —(CH 2 ) n R 5 , —C(O)R 5 , —CH(NH)R 5 , or —S(O) m R 5 ;
- R 5 is C 2 -C 10 alkyl, C 3 -C 7 cycloalkyl, HetB, or AryB, wherein said C 2 -C 10 alkyl and said C 3 -C 7 cycloalkyl are optionally substituted with one to four R 6 ;
- AryB is a 5- to 6-membered monocyclic aromatic ring with 0, 1, 2, or 3 ring atoms independently selected from N, O and S, optionally substituted with one to four R 4 ;
- each occurrence of R 6 is independently selected from the group consisting of: halogen, —OR e , —S(O) m R e , —S(O) m NR c R d , —C(O)R e , —OC(O)R e —C(O)OR e , —CN, —C(O)NR c R d , —C(NH)NR c R d , —NR c R d , —N(R c )(C(O)R e ), —N(R c )(C(O)OR e ), —N(R c )(C(O)NR c R d ), and —N(R c )(S(O) m R e );
- each occurrence of R c and R d is independently: hydrogen, —C 1 -C 10 alkyl, —C 2 -C 10 alkenyl, —C 3 -C 6 cycloalkyl, —C 1 -C 10 alkylene-C 3 -C 6 cycloalkyl, HetA, —C 1 -C 10 alkylene-HetB, AryB, —C 1 -C 10 alkylene-AryB, and —C 1 -C 10 alkylene-HetB, or, alternatively, R c and R d together with the nitrogen atom to which they are attached, form a 4- to 7-membered cycloheteroalkyl optionally containing one to two additional heteroatoms independently selected from O, S and —NR g , and wherein each R c and R d is optionally substituted with one to three R f ;
- each occurrence of R e is independently: hydrogen, —C 1 -C 10 alkyl, —C 2 -C 10 alkenyl, —OH, —OC 1 -C 4 alkyl, —C 3 -C 6 cycloalkyl, —C 1 -C 10 alkylene-C 3 -C 6 cycloalkyl, HetB, —C 1 -C 10 alkylene-HetB, AryB, —C 1 -C 10 alkylene-AryB, or —C 1 -C 10 alkylene-HetB; wherein each R e is optionally substituted with one to three R h ;
- each occurrence of R f is independently: halogen, —C 1 -C 10 alkyl, —OH, —OC 1 -C 4 alkyl, —S(O) m C 1 -C 4 alkyl, —CN, —CF 3 , —OCHF 2 , or —OCF 3 ; wherein said —C 1 -C 10 alkyl is optionally substituted with one to three substituents independently selected from: —OH, halogen, cyano, and —S(O) 2 CH 3 ;
- each occurrence of R g is independently: hydrogen, —C(O)R e , and —C 1 -C 10 alkyl, wherein said —C 1 -C 10 alkyl is optionally substituted with one to five fluorines;
- each occurrence of R h is independently: halogen, —C 1 -C 10 alkyl, —OH, —OC 1 -C 4 alkyl, —S(O) m C 1 -C 4 alkyl, —CN, —CF 3 , —OCHF 2 , or —OCF 3 ; wherein said —C 1 -C 10 alkyl is optionally substituted with one to three substituents independently selected from: —OH, halogen, cyano, or —S(O) 2 CH 3 ;
- each n is independently 0, 1, 2, 3 or 4;
- each m is independently 0, 1 or 2
- each p is independently 1 or 2.
- the present invention also relates to a pharmaceutical composition for treating a bacterial infection in a subject, including infection with multidrug resistant Gram-negative bacterial strains, comprising a biaryl monobactam compound of the invention and a pharmaceutically acceptable carrier, diluent or excipient.
- the Compounds of Formula (I) (also referred to herein as the “biaryl monobactam compounds”) and pharmaceutically acceptable salts thereof can be useful, for example, for inhibiting the growth of Gram-negative bacterial strains, including but not limited to, Pseudomonas and Acinetobacter strains, and/or for treating or preventing the clinical manifestations thereof in a patient.
- the present invention is also directed to methods of treating Gram-negative bacterial infections in a subject in need of treatment thereof, comprising administering to the subject an effective amount of a biaryl monobactam compound of the invention.
- the method includes administration of a beta lactamase inhibitor compound.
- the invention relates to novel biaryl monobactam analogs, a class of highly potent antibiotics effective against a broad range of Gram-negative bacteria. These compounds have utility as therapeutic agents for clinical treatment of various infections caused by Gram-negative bacteria, including strains that are multidrug resistant, and for the treatment or prevention of the clinical pathologies associated therewith.
- each variable including those of Formulas I, II-1, II-2, II-3, III-1, III-2, and III-3, and the various embodiments thereof, each variable is selected independently of the others unless otherwise indicated.
- the present invention encompasses all compounds of Formulas I, II-1, II-2, II-3, III-1, III-2, and III-3, and the various embodiments thereof, for example, any solvates, hydrates, stereoisomers, and tautomers of said compounds and of any pharmaceutically acceptable salts thereof.
- the present invention includes compounds of Formula I:
- a first embodiment of the invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X, Y, Z, A 1 , Q, A 2 , M, W, R X and R z are as defined in Formula I in the Summary of the Invention.
- a second embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is a bond, and all other variables are as defined in Embodiment E1.
- a third embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is O, and all other variables are as defined in Embodiment E1.
- a fourth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is N, and all other variables are as defined in Embodiment E1.
- a fifth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is CR 1 , and R 1 is hydrogen, halogen or C 1 -C 3 alkyl optionally substituted with one to three R a , and all other variables are as defined in Embodiment E1.
- R 1 is hydrogen
- R 1 is halogen
- R 1 is chlorine
- R 1 is fluorine
- R 1 is C 1 -C 3 alkyl optionally substituted with one to three R a , wherein each occurrence of R a is independently hydrogen, halogen, C 1 -C 3 alkyl, —NR c R d or —OR e .
- a sixth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is C 1 -C 3 alkylene optionally substituted with one to three R b , wherein each occurrence of R b is independently hydrogen, C 1 -C 8 alkyl, C 3 -C 7 cycloalkyl, —C(O)OR e , —C(O)NR c R d , tetrazolyl, oxadiazolonyl, HetA, AryA, —S(O) m R e , —S(O) m NR c R d , or —P(O)(R e ) p , wherein said C 1 -C 8 alkyl and said
- Z is C 1 -C 3 alkylene substituted with one occurrence of R b .
- Z is C 1 -C 3 alkylene substituted with two occurrences of R b .
- Z is C 1 -C 3 alkylene substituted with three occurrences of R b .
- a seventh embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is C 1 -C 3 alkylene substituted with —C(O)OR e ; and all other variables are as defined in Embodiment E1.
- An eighth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is C 1 -C 3 alkylene substituted with —C(O)OH; and all other variables are as defined in Embodiment E1.
- a ninth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is C 1 -C 3 alkylene substituted with tetrazolyl; and all other variables are as defined in Embodiment E1.
- a tenth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is C 1 -C 3 alkylene substituted with C 1 -C 8 alkyl, optionally substituted with one to three R a , and all other variables are as defined in Embodiment E1.
- An eleventh embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is C 1 -C 3 alkylene substituted with methyl; and all other variables are as defined in Embodiment E1.
- a twelfth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is C 1 -C 3 alkylene substituted with methyl and —C(O)OH; and all other variables are as defined in Embodiment E1.
- a thirteenth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is —CH(C(O)OH)CH 2 — and all other variables are as defined in Embodiment E1.
- a fourteenth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is C 1 -C 3 alkylene substituted with oxadiazolonyl, and all other variables are as defined in Embodiment E1.
- a fifteenth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is a bond, and all other variables are as defined in Embodiment E1.
- a sixteenth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is O, and all other variables are as defined in Embodiment E1.
- a seventeenth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is NR 2 , and all other variables are as defined in Embodiment E1.
- R 2 is hydrogen. In another sub-embodiment of Embodiment E17, R 2 is C 1 -C 3 alkyl optionally substituted with one to three R a . In a further sub-embodiment of Embodiment E17, R 2 is C(O)R e . In yet another sub-embodiment of Embodiment E17, R 2 is —C(O)NR c R d . In still another sub-embodiment of Embodiment E17, R 2 is —S(O) m R e . In a further sub-embodiment of Embodiment E17, R 2 is —S(O) m NR c R d .
- An eighteenth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is S, and all other variables are as defined in Embodiment E1.
- An nineteenth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is CH 2 , and all other variables are as defined in Embodiment E1.
- a twentieth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 a 5- to 6-membered monocyclic aromatic ring with 0, 1, 2, or 3 ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with one to four R 4 , and all other variables are as defined in Embodiment E1.
- a twenty-first embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is a 5-membered monocyclic aromatic ring with 0, 1, 2, or 3 ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with one to four R 4 , and all other variables are as defined in Embodiment E1.
- a twenty-second embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is a 6-membered monocyclic aromatic ring with 0, 1, 2, or 3 ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with one to four R 4 , and all other variables are as defined in Embodiment E1.
- a 1 has 1 ring atoms independently selected from N, N as a quaternary salt, O and S. In a further sub-embodiment of Embodiment E21 or E22, A 1 has 2 ring atoms independently selected from N, N as a quaternary salt, 0 and S. In another sub-embodiment of Embodiment E21 or E22, A 1 has 2 ring atoms independently selected from N, N as a quaternary salt, O and S. In yet another sub-embodiment of Embodiment E21 or E22, A 1 has 3 ring atoms independently selected from N, N as a quaternary salt, O and S.
- a twenty-third embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is an 6-membered monocyclic aromatic ring, optionally substituted with one to four R 4 , and all other variables are as defined in Embodiment E1.
- a twenty-fourth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is an unsubstituted 6-membered monocyclic aromatic ring, and all other variables are as defined in Embodiment E1.
- a twenty-fifth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is:
- a twenty-sixth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is a bond, and all other variables are as defined in Embodiment E1.
- a twenty-seventh embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is CH 2 , and all other variables are as defined in Embodiment E1.
- a twenty-eighth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is O, and all other variables are as defined in Embodiment E1.
- a twenty-ninth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is S, and all other variables are as defined in Embodiment E1.
- a thirtieth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is —(CH 2 ) n NR 3 —, and all other variables are as defined in Embodiment E1.
- a thirty-first embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is —NR 3 (CH 2 ) n —, and all other variables are as defined in Embodiment E1.
- a thirty-second embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is NH, and all other variables are as defined in Embodiment E1.
- a thirty-third embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is N(C 1 -C 3 alkyl) optionally substituted with one to three R a , and all other variables are as defined in Embodiment E1.
- a thirty-fourth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is C 3 -C 7 cycloalkyl optionally substituted with one to four R 4 ; and all other variables are as defined in Embodiment E1.
- a thirty-fifth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is AryC; and all other variables are as defined in Embodiment E1.
- a thirty-sixth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is a 5-membered monocyclic aromatic ring with 0, 1, 2, or 3 ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with one to four R 4 ; and all other variables are as defined in Embodiment E1.
- a thirty-seventh embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is a 6-membered monocyclic aromatic ring with 0, 1, 2, or 3 ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with one to four R 4 , and all other variables are as defined in Embodiment E1.
- a thirty-eighth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is HetC; and all other variables are as defined in Embodiment E1.
- a thirty-ninth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is a 4- to 7-membered saturated or monounsaturated monocyclic ring with 1 heteroatom ring atom selected from N, N as a quaternary salt, O and S, optionally substituted with one to four R 4 ; and all other variables are as defined in Embodiment E1.
- a fortieth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is a 4- to 7-membered saturated or monounsaturated monocyclic ring with 2 heteroatom ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with one to four R 4 ; and all other variables are as defined in Embodiment E1.
- a forty-first embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is a 4- to 7-membered saturated or monounsaturated monocyclic ring with 3 heteroatom ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with one to four R 4 ; and all other variables are as defined in Embodiment E1.
- a 2 is unsubstituted. In other sub-embodiments, A 2 is substituted with one R 4 . In further sub-embodiments A 2 is substituted with two R 4 . In additional sub-embodiments, A 2 is substituted with three R 4 . In still further sub-embodiments, A 2 is substituted with four R 4 .
- a 2 is substituted with methyl. In additional sub-embodiments, A 2 is substituted with —NH 2 . In further sub-embodiments, A 2 is substituted with ⁇ NH. In other sub-embodiments, A 2 is substituted with one to four substitutents selected from: ⁇ NH, —NH 2 , and —CH 3 .
- a forty-second embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is:
- a forty-third embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is:
- a forty-fourth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is:
- a forty-fifth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is:
- a forty-sixth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is:
- a forty-seventh embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is:
- a forty-eighth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is:
- a forty-ninth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is:
- a fiftieth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is:
- a fifty-first embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is:
- a fifty-second embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is:
- a fifty-third embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is:
- a fifty-fourth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is:
- a fifty-fifth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is:
- a fifty-sixth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is:
- a fifty-seventh embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is:
- a fifty-eighth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is:
- a fifty-ninth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is defined in any of Embodiments E34-E58, M is R 5 , and all other variables are as defined in Embodiment E1.
- a sixtieth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is defined in any of Embodiments E34-E58, M is C 2 -C 10 alkyl optionally substituted with one to four R 6 , and all other variables are as defined in Embodiment E1.
- a sixty-first embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is defined in any of Embodiments E34-E58, M is C 3 -C 7 cycloalkyl optionally substituted with one to four R 6 , and all other variables are as defined in Embodiment E1.
- a sixty-second embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is defined in any of Embodiments E34-E58, M is HetB, and all other variables are as defined in Embodiment E1.
- a sixty-third embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is defined in any of Embodiments E34-E58, M is AryB, and all other variables are as defined in Embodiment E1.
- a sixty-fourth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is defined in any of Embodiments E34-E58, M is —NR 5 , and all other variables are as defined in Embodiment E1.
- a sixty-fifth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is defined in any of Embodiments E34-E58, M is —OR 5 , and all other variables are as defined in Embodiment E1.
- a sixty-sixth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is defined in any of Embodiments E34-E58, M is —(CH 2 ) n R 5 , and all other variables are as defined in Embodiment E1.
- a sixty-seventh embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is defined in any of Embodiments E34-E58, M is —C(O)R 5 , and all other variables are as defined in Embodiment E1.
- a sixty-eighth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is defined in any of Embodiments E34-E58, M is —CH(NH)R 5 , and all other variables are as defined in Embodiment E1.
- a sixty-ninth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is defined in any of Embodiments E34-E58, M is —S(O) m R 5 and all other variables are as defined in Embodiment E1.
- a seventieth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is defined in any of Embodiments E34-E58, M is —(CH 2 ) 3 NH 2 , and all other variables are as defined in Embodiment E1.
- a seventy-first embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is defined in any of Embodiments E34-E58, M is —(CH 2 ) 1-2 HetB, and all other variables are as defined in Embodiment E1.
- a seventy-second embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is defined in any of Embodiments E34-E58, M is —CH 2 AryB, and all other variables are as defined in Embodiment E1.
- a seventy-third embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is defined in any of Embodiments E34-E58, M is defined in any of Embodiments E59-E72, R X and R Z are methyl, and all other variables are as defined in Embodiment E1.
- a seventy-fourth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is defined in any of Embodiments E34-E58, M is defined in any of Embodiments E59-E72, R X is hydrogen and R Z is methyl, and all other variables are as defined in Embodiment E1.
- a seventy-fifth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is defined in any of Embodiments E34-E58, M is defined in any of Embodiments E59-E72, one of R X and R Z is SCH 3 , and all other variables are as defined in Embodiment E1.
- a seventy-sixth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is defined in any of Embodiments E34-E58, M is defined in any of Embodiments E59-E72, one of R X and R Z is SC 1 -C 3 alkyl, optionally substituted with one to seven fluorines, and all other variables are as defined in Embodiment E1.
- a seventy-seventh embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is defined in any of Embodiments E34-E58, M is defined in any of Embodiments E59-E72, one of R X and R Z is SCH 3 , optionally substituted with one to three fluorines, and all other variables are as defined in Embodiment E1.
- a seventy-eighth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is defined in any of Embodiments E34-E58, M is defined in any of Embodiments E59-E72, one of R X and R Z is C 1 -C 3 alkyl, optionally substituted with one to seven fluorines, and all other variables are as defined in Embodiment E1.
- a seventy-ninth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is defined in any of Embodiments E34-E58, M is defined in any of Embodiments E59-E72, one of R X and R Z is (C 1 -C 3 alkylene) n OC 1 -C 3 alkyl, optionally substituted with one to seven fluorines, and all other variables are as defined in Embodiment E1.
- An eightieth embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is defined in any of Embodiments E34-E58, M is defined in any of Embodiments E59-E72, one of R X and R Z is (C 1 -C 3 alkylene) n NC 1 -C 3 alkyl, optionally substituted with one to seven fluorines, and all other variables are as defined in Embodiment E1.
- An eighty-first embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A 1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A 2 is defined in any of Embodiments E34-E58, M is defined in any of Embodiments E59-E72, R X and R Z , together with the carbon to which they are attached, come together to form a monocyclic C 4 -C 7 cycloalkyl or a monocyclic C 4 -C 7 heterocycloalkyl with 1, 2, or 3 heteroatom ring atom
- An eighty-second embodiment is a compound of Formula II-1, II-2, II-3, III-1, III-2, or III-3, or a pharmaceutically acceptable salt thereof,
- X is defined in any of Embodiments E1, E4, E Embodiment 5-A, E5-B, E5-C, E5-D, or E5-E;
- a 1 is defined in any of Embodiments E1, E20-E25;
- a 2 is defined in any of Embodiments E1, E34-E58;
- M is defined in any of Embodiments E1, E59-E72;
- R X and R are defined in any of Embodiments E1, E73-E81;
- R b1 , R b2 , and R b3 are independently hydrogen, C 1 -C 8 alkyl, C 3 -C 7 cycloalkyl, —C(O)OR e , —C(O)NR c R d , tetrazolyl, oxadiazolonyl, HetA, AryA, —S(O) m R e , —S(O) m NR c R d
- An eighty-third embodiment is a compound of Formula II-1, II-2, II-3, III-1, III-2, or III-3, or a pharmaceutically acceptable salt thereof, wherein R b1 and R b2 are independently hydrogen, C 1 -C 3 alkyl, tetrazolyl, oxadiazolonyl or —C(O)OR e ; and R b3 is hydrogen, and all other variables are as defined in Embodiment E82.
- An eighty-fourth embodiment is a compound having the structure:
- each occurrence of R 4 is independently: —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, —C 2 -C 8 alkynyl, halogen, —OR e —S(O) m R e , —S(O) m NR c R d , —C(O)R e , —OC(O)R e , —C(O)OR e , —CN, —C(O)NR c R d , —NR c R d , —(CH 2 )NR c R d ; —NR c C(O)R e , —NR c C(O)OR e , —NR c C(O)NR c R d , —NR c S(O) m R e , ⁇ NH, —CF 3 , —OCF 3 , —OCHF 2 ,
- R 5 is C 2 -C 10 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl-C 3 -C 7 cycloalkyl, HetB, AryB, or —NH(C 1 -C 6 alkyl), wherein said C 1 -C 6 alkyl, said C 2 -C 10 alkyl and said C 3 -C 7 cycloalkyl are optionally substituted with one to four R 6 .
- a pharmaceutical composition comprising an effective amount of a compound of Formula I, II-1, II-2, II-3, III-1, III-2, or III-3, as defined herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
- a pharmaceutical composition comprising (i) a compound of Formula I, II-1, II-2, II-3, III-1, III-2, and III-3, or a pharmaceutically acceptable salt thereof, and (ii) a second compound, wherein the second compound is an beta-lactamase inhibitor compound, wherein the compound of Formula I, II-1, II-2, II-3, III-1, III-2, and III-3, and the second compound are each employed in an amount that renders the combination effective for treating or preventing bacterial infection.
- a method for treating a bacterial infection in a subject which comprises administering to a subject in need of such treatment an effective amount of a compound of Formula I, II-1, II-2, II-3, III-1, III-2, or III-3, or a pharmaceutically acceptable salt thereof.
- a method for preventing and/or treating a bacterial infection which comprises administering to a subject in need of such treatment a pharmaceutical composition comprising an effective amount of a compound of Formula I, II-1, II-2, II-3, III-1, III-2, and II-3, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
- a method for treating a bacterial infection which comprises administering to a subject in need of such treatment a therapeutically effective amount of the composition of (a), (b), (c), (d), or (e).
- the present invention also includes a compound of Formula I, II-1, II-2, II-3, III-1, II-2, or III-3, or a pharmaceutically acceptable salt thereof, (i) for use in, (ii) for use as a medicament for, or (iii) for use in the preparation (or manufacture) of a medicament for, medicine or treating bacterial infection, including infection with a multidrug resistant bacterial strain.
- the compounds of the present invention can optionally be employed in combination with one or more second therapeutic agents including relebactam, tazobactam, clavulanic acid, sulbactam, and avibactam.
- Additional embodiments of the invention include the pharmaceutical compositions, combinations and methods set forth in (a)-(j) above and the uses set forth in the preceding paragraph, wherein the compound of the present invention employed therein is a compound of one of the embodiments, sub-embodiments, classes or sub-classes described above.
- the compound may optionally be used in the form of a pharmaceutically acceptable salt in these embodiments.
- each embodiment may be combined with one or more other embodiments, to the extent that such a combination provides a stable compound or salt and is consistent with the description of the embodiments. It is further to be understood that the embodiments of compositions and methods provided as (a) through (j) above are understood to include all embodiments of the compounds and/or salts, including such embodiments as result from combinations of embodiments.
- Additional embodiments of the present invention include each of the pharmaceutical compositions, combinations, methods and uses set forth in the preceding paragraphs, wherein the compound of the present invention or its salt employed therein is substantially pure.
- a pharmaceutical composition comprising a compound of Formula I, II-1, II-2, II-3, III-1, III-2, or III-3 or its salt and a pharmaceutically acceptable carrier and optionally one or more excipients
- substantially pure is in reference to a compound of Formula I, II-1, II-2, II-3, III-1, III-2, or III-3 or its salt per se; i.e., the purity of this active ingredient in the composition.
- ⁇ -lactamase inhibitor refers to a compound which is capable of inhibiting enzyme activity from ⁇ -lactamases.
- inhibiting ⁇ -lactamase activity means inhibiting the activity of a class A, C, and/or D ⁇ -lactamase.
- inhibition at a 50% inhibitory concentration is preferably achieved at or below about 100 micrograms/mL, or at or below about 50 micrograms/mL, or at or below about 25 micrograms/mL.
- class A”, “class B”, “class C”, and “class D” ⁇ -lactamases are understood by those skilled in the art and are described in S. G. Waley, ⁇ -lactamase: mechanisms of action, in The Chemistry of ⁇ -Lactams, M. I. Page, Ed.; Chapman and Hall, London, (1992) 198-228.
- metallo- ⁇ -lactamase denotes a metalloprotein capable of inactivating a ⁇ -lactam antibiotic.
- the ⁇ -lactamase can be an enzyme which catalyzes the hydrolysis of the ⁇ -lactam ring of a ⁇ -lactam antibiotic.
- microbial metallo- ⁇ -lactamases can be, for example, a zinc metallo- ⁇ -lactamase.
- ⁇ -Lactamases of interest include those disclosed in, e.g., S. G. Waley, ⁇ -lactamase: mechanisms of action, in The Chemistry of ⁇ -Lactams, M. I.
- ⁇ -Lactamases of particular interest herein include metallo- ⁇ -lactamases of Escherichia coli (such as New Delhi Metallo- ⁇ -lactamase, NDM), Serratia marcescens (such as IMP), and Klebsiella spp. (such as Verona integron-encoded metallo- ⁇ -lactamase, VIM).). Additional metallo- ⁇ -lactamases of interest herein include SPM-, GIM-, SIM-, KHM-, AIM-, DIM-, SMB-, TMB-, and FIM-type enzymes.
- antibiotic refers to a compound or composition which decreases the viability of a microorganism, or which inhibits the growth or proliferation of a microorganism.
- the phrase “inhibits the growth or proliferation” means increasing the generation time (i.e., the time required for the bacterial cell to divide or for the population to double) by at least about 2-fold.
- Preferred antibiotics are those which can increase the generation time by at least about 10-fold or more (e.g., at least about 100-fold or even indefinitely, as in total cell death).
- an antibiotic is further intended to include an antimicrobial, bacteriostatic, or bactericidal agent. Examples of antibiotics include penicillins, cephalosporins and carbapenems.
- ⁇ -lactam antibiotic refers to a compound with antibiotic properties that contains a ⁇ -lactam functionality.
- Non-limiting examples of ⁇ -lactam antibiotics include penicillins, cephalosporins, penems, carbapenems, and monobactams.
- the term “about”, when modifying the quantity (e.g., kg, L, or equivalents) of a substance or composition, or the value of a physical property, or the value of a parameter characterizing a process step (e.g., the temperature at which a process step is conducted), or the like refers to variation in the numerical quantity that can occur, for example, through typical measuring, handling and sampling procedures involved in the preparation, characterization and/or use of the substance or composition; through inadvertent error in these procedures; through differences in the manufacture, source, or purity of the ingredients employed to make or use the compositions or carry out the procedures; and the like.
- “about” can mean a variation of ⁇ 0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 2.0, 3.0, 4.0, or 5.0 of the appropriate unit. In certain embodiments, “about” can mean a variation of ⁇ 1%, 2%, 3%, 4%, 5%, 10%, or 20%.
- Another embodiment of the present invention is a compound of Formula I, II-1, II-2, II-3, III-1, III-2, or III-3, or a pharmaceutically acceptable salt thereof, as originally defined or as defined in any of the foregoing embodiments, sub-embodiments, aspects, classes or sub-classes, wherein the compound or its salt is in a substantially pure form.
- substantially pure means suitably at least about 60 wt. %, typically at least about 70 wt. %, preferably at least about 80 wt. %, more preferably at least about 90 wt. % (e.g., from about 90 wt. % to about 99 wt. %), even more preferably at least about 95 wt.
- % (e.g., from about 95 wt. % to about 99 wt. %, or from about 98 wt. % to 100 wt. %), and most preferably at least about 99 wt. % (e.g., 100 wt. %) of a product containing a compound of Formula I, II-1, II-2, II-3, III-1, III-2, or III-3 or its salt (e.g., the product isolated from a reaction mixture affording the compound or salt) consists of the compound or salt.
- the level of purity of the compounds and salts can be determined using a standard method of analysis such as thin layer chromatography, gel electrophoresis, high performance liquid chromatography, and/or mass spectrometry.
- a compound or salt of 100% purity is one which is free of detectable impurities as determined by a standard method of analysis.
- a substantially pure compound can be either a substantially pure mixture of the stereoisomers or a substantially pure individual diastereomer or enantiomer unless expressly depicted otherwise.
- the present invention encompasses all stereoisomeric forms of the compounds of Formula I, II-1, II-2, II-3, III-1, III-2, and III-3. Unless a specific stereochemistry is indicated, the present invention is meant to comprehend all such isomeric forms of these compounds. Centers of asymmetry that are present in the compounds of Formula I, II-1, II-2, II-3, III-1, III-2, and III-3 can all independently of one another have (R) configuration or (S) configuration.
- the invention includes all possible enantiomers and diastereomers and mixtures of two or more stereoisomers, for example mixtures of enantiomers and/or diastereomers, in all ratios.
- enantiomers are a subject of the invention in enantiomerically pure form, both as levorotatory and as dextrorotatory antipodes, in the form of racemates and in the form of mixtures of the two enantiomers in all ratios.
- the invention includes both the cis form and the trans form as well as mixtures of these forms in all ratios.
- the preparation of individual stereoisomers can be carried out, if desired, by separation of a mixture by customary methods, for example by chromatography or crystallization, by the use of stereochemically uniform starting materials for the synthesis or by stereoselective synthesis.
- a derivatization can be carried out before a separation of stereoisomers.
- the separation of a mixture of stereoisomers can be carried out at an intermediate step during the synthesis of a compound of Formula I, II-1, II-2, II-3, III-1, II-2, and III-3 or it can be done on a final racemic product.
- Absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing a stereogenic center of known configuration. Where compounds of this invention are capable of tautomerization, all individual tautomers as well as mixtures thereof are included in the scope of this invention.
- the present invention includes all such isomers, as well as salts, solvates (including hydrates) and solvated salts of such racemates, enantiomers, diastereomers and tautomers and mixtures thereof.
- Alkyl means saturated carbon chains which may be linear or branched or combinations thereof, unless the carbon chain is defined otherwise.
- alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like.
- Alkylene refers to an alkyl group, as defined above, wherein one of the alkyl group's hydrogen atoms has been replaced with a bond.
- alkylene groups include —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, —CH(CH 3 )CH 2 CH 2 —, —CH(CH 3 )— and —CH 2 CH(CH 3 )CH 2 —.
- an alkylene group has from 1 to about 6 carbon atoms.
- an alkylene group has from 1 to about 3 carbon atoms.
- an alkylene group is branched.
- an alkylene group is linear.
- an alkylene group is —CH 2 —.
- C 1 -C 6 alkylene refers to an alkylene group having from 1 to 6 carbon atoms.
- Alkenyl means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched, or combinations thereof, unless otherwise defined. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like.
- Alkynyl means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched, or combinations thereof, unless otherwise defined. Examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like.
- “Aromatic ring system” or “aromatic” in reference to a ring means monocyclic, bicyclic or tricyclic aromatic ring or ring system containing 5-14 ring atoms, wherein at least one of the rings is aromatic.
- the term may be used to describe a saturated or monounsaturated carbocyclic ring fused to an aryl group.
- a 5-7-membered cycloalkyl can be fused through two adjacent ring atoms to a 5-6-membered heteroaryl containing 1, 2, or 3 heteroatom ring atoms selected from N, O, and S.
- a heteromonocyclic ring is fused through two ring atoms to a phenyl or 5-6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S.
- the N can be in the form of quaternary amine.
- an N ring atom can be in the form of an N-oxide.
- Aryl means a monocyclic, bicyclic or tricyclic carbocyclic aromatic ring or ring system containing 6-14 carbon atoms, wherein at least one of the rings is aromatic.
- aryl include phenyl and naphthyl. In one embodiment of the present invention, aryl is phenyl.
- Cycloalkyl means a saturated monocyclic, bicyclic or bridged carbocyclic ring, having a specified number of carbon atoms.
- Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, indanyl, and the like.
- cycloalkyl is selected from: cyclopropane, cyclobutane, cyclopentane, and cyclohexane.
- Cycloalkenyl means a nonaromatic monocyclic or bicyclic carbocylic ring containing at least one double bond.
- Examples of cycloalkenyl include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooxtenyl and the like.
- heterocycloalkyl refers to a non-aromatic saturated monocyclic or multicyclic ring system comprising 3 to 11 ring atoms, wherein from 1 to 4 of the ring atoms are independently N, NH, S (including SO and SO 2 ) and O, and the remainder of the ring atoms are carbon atoms.
- a heterocycloalkyl group can be joined via a ring carbon or ring nitrogen atom (if present). Where the ring or ring system contains one or more N atoms, the N can be in the form of quaternary amine.
- a heterocycloalkyl group is monocyclic and has from about 3 to about 7 ring atoms.
- a heterocycloalkyl group is monocyclic has from about 4 to about 7 ring atoms. In another embodiment, a heterocycloalkyl group is bicyclic and has from about 7 to about 11 ring atoms. When a heterocycloalkyl contains two rings, the rings may be fused or spirocyclic. In still another embodiment, a heterocycloalkyl group is monocyclic and has 5 or 6 ring atoms. In one embodiment, a heterocycloalkyl group is monocyclic. In another embodiment, a heterocycloalkyl group is bicyclic. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
- Any —NH group in a heterocycloalkyl ring may exist protected such as, for example, as an —N(BOC), —N(Cbz), —N(Tos) group and the like; such protected heterocycloalkyl groups are considered part of this invention.
- a heterocycloalkyl group can be optionally substituted by one or more “ring system substituents” which may be the same or different, and are as defined herein below.
- the nitrogen or sulfur atom of the heterocycloalkyl (if present) can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
- Non-limiting examples of monocyclic heterocycloalkyl rings include oxetanyl, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, delta-lactam, delta-lactone, silacyclopentane, silapyrrolidine and the like, and all isomers thereof.
- “Drug resistant” means, in connection with a Gram-negative bacterial strain, a strain which is no longer susceptible to at least one previously effective drug; which has developed the ability to withstand antibiotic attack by at least one previously effective drug.
- “Multi-drug resistant” means a strain that is no longer susceptible to two or more previously effective drugs; which has developed the ability to withstand antibiotic attack by two or more previously effective drugs.
- a drug resistant strain may relay that ability to withstand to its progeny. Said resistance may be due to random genetic mutations in the bacterial cell that alters its sensitivity to a single drug or to different drugs.
- Heterocycloalkenyl means a nonaromatic monocyclic, bicyclic or bridged carbocyclic ring or ring system containing at least one double bond and containing at least one heteroatom selected from N, NH, S and O.
- Heteroaryl means monocyclic, bicyclic or tricyclic ring or ring system containing 5-14 carbon atoms and containing at least one ring heteroatom selected from N, NH, S (including SO and SO 2 ) and O, wherein at least one of the heteroatom containing rings is aromatic. In the case of a heteroaryl ring system where one or more of the rings are saturated and contain one or more N atoms, the N can be in the form of quaternary amine. In one embodiment, a heteroaryl group has 5 to 10 ring atoms. In another embodiment, a heteroaryl group is monocyclic and has 5 or 6 ring atoms. In another embodiment, a heteroaryl group is bicyclic.
- a heteroaryl group can be optionally substituted by one or more ring system substituents which may be the same or different. Any nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide.
- heteroaryl also encompasses a heteroaryl group, as defined above, which is fused to a benzene ring.
- heteroaryl examples include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzopyrazolyl, benzofuranyl, benzothiophenyl (including S-oxide and dioxide), benzotriazolyl, furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl, quinazolinyl, dibenzofuranyl, and the like.
- heteroaryl is selected from: pyridine, pyrimidine, thiazole, benzimidazole, benzthiazole, benzoxazole, and benzisoxazole.
- heteroaryl is pyridine. Examples of bicyclic rings include:
- Heterocycle means a monocyclic or bicyclic saturated, partially unsaturated, or unsaturated ring system containing 5-10 atoms and containing at least one ring heteroatom selected from N, S and O. In select embodiments, the ring system contains 1-4 heteroatoms selected from N, S and O. When a heterocycle contains two rings, the rings may be fused, bridged or spirocyclic. Examples of monocyclic heterocycle rings include piperazine, piperidine, and morpholine. Examples of bicyclic heterocycle rings include 1,4-diazabicyclo[2,2,2]octane and 2,6-diazaspiroheptane.
- Halogen includes fluorine, chlorine, bromine and iodine.
- Oxo means an oxygen atom connected to another atom by a double bond and is can be represented “ ⁇ O”.
- any variable e.g., R 1 , R a , etc.
- its definition on each occurrence is independent of its definition at every other occurrence.
- combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
- a squiggly line across a bond in a substituent variable represents the point of attachment.
- a “stable” compound is a compound which can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic administration to a subject).
- the compounds of the present invention are limited to stable compounds embraced by Formula I, II-1, II-2, II-3, III-1, III-2, and III-3.
- substituted shall be deemed to include multiple degrees of substitution by a named substitutent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different. When a group, e.g., C 1 -C 8 alkyl, is indicated as being substituted, such substitutions can also occur where such group is part of a larger substituent, e.g., —C 1 -C 6 alkyl-C 3 -C 7 cycloalkyl and —C 1 -C 8 alkyl-aryl.
- the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
- the present invention is meant to include all suitable isotopic variations of the compounds of Formula I, II-1, II-2, II-3, III-1, III-2, and III-3.
- different isotopic forms of hydrogen (H) include protium (1H) and deuterium ( 2 H or D). Protium is the predominant hydrogen isotope found in nature.
- Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
- Isotopically-enriched compounds within Formula I, II-1, II-2, II-3, III-1, III-2, and III-3 can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
- any of the various cyclic rings and ring systems described herein may be attached to the rest of the compound at any ring atom (i.e., any carbon atom or any heteroatom) provided that a stable compound results.
- a heteroaromatic ring described as containing from “1 to 4 heteroatoms” means the ring can contain 1, 2, 3 or 4 heteroatoms. It is also to be understood that any range cited herein includes within its scope all of the sub-ranges within that range.
- a heterocyclic ring described as containing from “1 to 4 heteroatoms” is intended to include as aspects thereof, heterocyclic rings containing 2 to 4 heteroatoms, 3 or 4 heteroatoms, 1 to 3 heteroatoms, 2 or 3 heteroatoms, 1 or 2 heteroatoms, 1 heteroatom, 2 heteroatoms, 3 heteroatoms, and 4 heteroatoms.
- C 1 -C 6 when used with a chain means that the chain can contain 1, 2, 3, 4, 5 or 6 carbon atoms. It also includes all ranges contained therein including C 1 -C 5 , C 1 -C 4 , C 1 -C 3 , C 1 -C 2 , C 2 -C 6 , C 3 -C 6 , C 4 -C 6 , C 5 -C 6 , and all other possible combinations.
- the compounds of the present invention have at least one asymmetric center and can have one or more additional centers as a result of the presence of certain substituents and/or substituent patterns. Accordingly, compounds of the invention can occur as mixtures of stereoisomers, or as individual diastereomers, or enantiomers. All isomeric forms of these compounds, whether individually or in mixtures, are within the scope of the present invention.
- compound refers to the free compound and, to the extent they are stable, any hydrate or solvate thereof.
- a hydrate is the compound complexed with water
- a solvate is the compound complexed with an organic solvent.
- the compounds of the present invention can be employed in the form of pharmaceutically acceptable salts. It will be understood that, as used herein, the compounds of the instant invention can also include the pharmaceutically acceptable salts, and also salts that are not pharmaceutically acceptable when they are used as precursors to the free compounds or their pharmaceutically acceptable salts or in other synthetic manipulations.
- pharmaceutically acceptable salt refers to a salt which possesses the effectiveness of the parent compound and which is not biologically or otherwise undesirable (e.g., is neither toxic nor otherwise deleterious to the recipient thereof).
- pharmaceutically acceptable salt refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds encompassed within the term “pharmaceutically acceptable salt” refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid.
- Representative salts of basic compounds of the present invention include, but are not limited to, the following: acetate, ascorbate, adipate, alginate, aspirate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, clavulanate, citrate, cyclopentane propionate, diethylacetic, digluconate, dihydrochloride, dodecylsulfanate, edetate, edisylate, estolate, esylate, ethanesulfonate, formic, fumarate, gluceptate, glucoheptanoate, gluconate, glutamate, glycerophosphate, glycollylarsanilate, hemisulfate, heptanoate, hexanoate, hexyl
- suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
- Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, dicyclohexyl amines and basic ion-exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
- the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
- lower alkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides
- dialkyl sulfates like dimethyl, diethyl, dibutyl
- diamyl sulfates long chain halides
- salts can be obtained by known methods, for example, by mixing a compound of the present invention with an equivalent amount and a solution containing a desired acid, base, or the like, and then collecting the desired salt by filtering the salt or distilling off the solvent.
- the compounds of the present invention and salts thereof may form solvates with a solvent such as water, ethanol, or glycerol.
- the compounds of the present invention may form an acid addition salt and a salt with a base at the same time according to the type of substituent of the side chain.
- the compound of the invention can also be employed in the form of a prodrug. Any prodrug precursor known in the art can be used to form a prodrug of the invention.
- the hydrogen in —COOH in formula I can be replaced with any the following groups: C 1-6 alkyl, C 3-6 cycloalkyl, —C 1-6 alkylene-C 3-6 cycloalkyl, C 3-7 cycloheteroalkyl, —C 1-6 alkylene-C 3-7 cycloheteroalkyl, aryl, —C 1-10 alkylene-aryl, heteroaryl, and —C 1-10 alkylene-heteroaryl.
- the C 1-6 alkyl, C 3-6 cycloalkyl, or C 3-7 cycloheteroalkyl can be substituted.
- each aryl and heteroaryl can be substituted.
- the present invention includes pharmaceutical compositions comprising a compound of Formula I of the present invention, optionally one other active components (e.g., a ⁇ -lactamase inhibitor), and a pharmaceutically acceptable carrier.
- active components e.g., a ⁇ -lactamase inhibitor
- pharmaceutically acceptable carrier is meant that the ingredients of the pharmaceutical composition must be compatible with each other, do not interfere with the effectiveness of the active ingredient(s), and are not deleterious (e.g., toxic) to the recipient thereof.
- compositions according to the invention may, in addition to the inhibitor, contain diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art.
- the present invention includes a method for treating a bacterial infection which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound of Formula I, II-1, II-2, II-3, III-1, III-2, and III-3, or a pharmaceutically acceptable salt thereof, optionally in combination with a ⁇ -lactamase inhibitor.
- subject or, alternatively, “patient” as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
- administration and variants thereof (e.g., “administering” a compound) in reference to a compound of Formula I, II-1, II-2, II-3, III-1, III-2, and III-3 mean providing the compound, or a pharmaceutically acceptable salt thereof, to the individual in need of treatment.
- a compound or a salt thereof is provided in combination with one or more other active agents (e.g., a ⁇ -lactamase inhibitor)
- “administration” and its variants are each understood to include provision of the compound or its salt and the other agents at the same time or at different times.
- the agents of a combination are administered at the same time, they can be administered together in a single composition or they can be administered separately.
- a “combination” of active agents can be a single composition containing all of the active agents or multiple compositions each containing one or more of the active agents.
- a combination can be either a single composition comprising both agents or two separate compositions each comprising one of the agents; in the case of three active agents a combination can be either a single composition comprising all three agents, three separate compositions each comprising one of the agents, or two compositions one of which comprises two of the agents and the other comprises the third agent; and so forth.
- compositions and combinations of the present invention are suitably administered in effective amounts.
- effective amount means the amount of active compound sufficient to inhibit bacterial growth and thereby elicit the response being sought (i.e., an “inhibition effective amount”) in a cell, tissue, system, animal or human.
- the effective amount is a “therapeutically effective amount” for the alleviation of the symptoms of the disease or condition being treated (e.g., the healing of conditions associated with bacterial infection, and/or bacterial drug resistance).
- the effective amount is a “prophylactically effective amount” for prophylaxis of the symptoms of the disease or condition being prevented.
- compositions of the present invention are suitably parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, intraocular, or intrarectal, wherein the composition is suitably formulated for administration by the selected route using formulation methods well known in the art, including, for example, the methods for preparing and administering formulations described in chapters 39, 41, 42, 44 and 45 in Remington—The Science and Practice of Pharmacy, 21 st edition, 2006.
- compounds of the invention are administered intravenously in a hospital setting.
- administration is oral in the form of a tablet or capsule or the like.
- a therapeutic composition When administered systemically, a therapeutic composition is for example, suitably administered at a sufficient dosage to attain a blood level of inhibitor of at least about 1 microgram/mL, and in additional embodiment at least about 10 micrograms/mL, and at least about 25 micrograms/mL. For localized administration, much lower concentrations than this may be effective, and much higher concentrations may be tolerated.
- Intravenous administration of a compound of the invention can be conducted by reconstituting a powdered form of the compound with an acceptable solvent.
- suitable solvents include, for example, saline solutions (e.g., 0.9% Sodium Chloride Injection) and sterile water (e.g., Sterile Water for Injection, Bacteriostatic Water for Injection with methylparaben and propylparaben, or Bacteriostatic Water for Injection with 0.9% benzyl alcohol).
- the powdered form of the compound can be obtained by gamma-irradiation of the compound or by lyophilization of a solution of the compound, after which the powder can be stored (e.g., in a sealed vial) at or below room temperature until it is reconstituted.
- the concentration of the compound in the reconstituted IV solution can be, for example, in a range of from about 0.1 mg/mL to about 20 mg/mL.
- the present invention also includes a method for inhibiting bacterial growth which comprises administering to a bacterial cell culture, or to a bacterially infected cell culture, tissue, or organism, an inhibition effective amount of a compound of Formula I, II-1, II-2, II-3, III-1, III-2, and III-3.
- Additional embodiments of the invention include the bacterial growth inhibiting method just described, wherein the compound of the present invention employed therein is a compound of one of the embodiments, sub-embodiments or classes described above. The compound may optionally be used in the form of a pharmaceutically acceptable salt in these embodiments.
- the method can involve administration of a compound of Formula I, II-1, II-2, II-3, III-1, III-2, and III-3 to an experimental cell culture in vitro to prevent the growth of ⁇ -lactam resistant bacteria.
- the method can alternatively involve administration of a compound of Formula I to an animal, including a human, to prevent the growth of ⁇ -lactam resistant bacteria in vivo.
- the compound of Formula I, II-1, II-2, II-3, III-1, III-2, and III-3 is typically co-administered with a ⁇ -lactamase inhibitor.
- the methods of the presently disclosed subject matter are useful for treating these conditions in that they inhibit the onset, growth, or spread of the condition, cause regression of the condition, cure the condition, or otherwise improve the general well-being of a subject afflicted with, or at risk of, contracting the condition.
- the terms “treat”, “treating”, and grammatical variations thereof, as well as the phrase “method of treating”, are meant to encompass any desired therapeutic intervention, including but not limited to a method for treating an existing infection in a subject, and a method for the prophylaxis (i.e., preventing) of infection, such as in a subject that has been exposed to a microbe as disclosed herein or that has an expectation of being exposed to a microbe as disclosed herein.
- Compounds of the invention can be employed for the treatment, prophylaxis or inhibition of bacterial growth or infections due to bacteria that are resistant to ⁇ -lactam antibiotics. More particularly, the bacteria can be metallo- ⁇ -lactamase positive strains that are highly resistant to ⁇ -lactam antibiotics.
- the terms “slightly resistant” and “highly resistant” are well-understood by those of ordinary skill in the art (see, e.g., Payne et al., Antimicrobial Agents and Chemotherapy 38:767-772 (1994); Hanaki et al., Antimicrobial Agents and Chemotherapy 30:11.20-11.26 (1995)).
- bacterial strains which are highly resistant to imipenem are those against which the MIC of imipenem is >16 ⁇ g/mL, and bacterial strains which are slightly resistant to imipenem are those against which the MIC of imipenem is >4 ⁇ g/mL.
- ⁇ -lactamase inhibitors can be used in combination with a ⁇ -lactamase inhibitor for the treatment of infections caused by ⁇ -lactamase producing strains, in addition to those infections which are subsumed within the antibacterial spectrum of the antibiotic agent.
- ⁇ -lactamase producing bacteria are Pseudomonas aeruginosa, Pseudomonas putida, Enterobacter cloacae, Klebsiella pneumoniae, Klebsiella oxytoca, Escherichia coli, Serratia marcescens, Enterobacter aerogenes, Enterobacter asburiae, Citrobacter freundii, Proteus mirabilis, Morganella morganii, Providencia rettgeri, Stenotrophomonas maltophilia and Acinetobacter baumannii.
- a compound of Formula I, II-1, II-2, II-3, III-1, III-2, and III-3 in admixture or conjunction with a ⁇ -lactamase inhibitor, or a prodrug thereof. It is advantageous to use a compound of Formula I in combination with a class A and C ⁇ -lactamase inhibitor because of the class B ⁇ -lactamase resistant properties of the compounds. It is also advantageous to use a compound of Formula I in combination with one or more Class A, C, or D ⁇ -lactamase inhibitors to further limit ⁇ -lactam susceptability. As already noted, the compound of Formula I and the ⁇ -lactamase inhibitor can be administered separately (at the same time or as different times) or in the form of a single composition containing both active ingredients.
- Relebactam, tazobactam, clavulanic acid, sulbactam, avibactam and other ⁇ -lactamase and metallo- ⁇ -lactamase inhibitors suitable for use in the present invention include those known to show inhibitory activity to ⁇ -lactamases.
- the ⁇ -lactam intermediate can be either purchased from commercial sources or synthesized following the scheme below, which shows the synthesis of ⁇ -lactam analogs wherein Rx and Rz come together to form a 4-membered spirocyclic ring.
- the synthetic scheme has been discussed in detail in the literature. (See EP 0229012). This amine can be converted to the final monobactam compounds with a similar procedure demonstrated in the following Examples.
- Step A ethyl 2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoacetate
- Step B 2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoacetic acid
- Step A tert-butyl (3-methyl-1,2,4-thiadiazol-5-yl)carbamate
- Step B 2-(5-((tert-butoxycarbonyl)amino)-1,2,4-thiadiazol-3-yl)acetic acid
- the resulting solution was extracted with 640 mL of ethyl acetate and the aqueous layers were combined.
- the pH value of the solution was adjusted to 2 with HCl (2M mol/L).
- the resulting solution was extracted with 2.5 L of ethyl acetate and the organic layers were combined.
- the resulting mixture was washed with 2000 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum, which resulted in the title compound.
- Step C 2-(5-((tert-Butoxycarbonyl)amino)-1,2,4-thiadiazol-3-yl)-2-oxoacetic acid
- Step A tert-butyl 3-((6-bromopyridin-3-yl)oxy)-2-hydroxypropanoate
- Step B tert-butyl 3-((6-bromopyridin-3-yl)oxy)-2-((tert-butyldimethyl-silyl)oxy)propanoate
- Step B tert-butyl 3-(4-bromophenoxy)-2-hydroxy-2-methylpropanoate
- Step D tert-butyl 2-(aminooxy)-3-(4-bromophenoxy)-2-methylpropanoate
- Step B (R)-3-(4-bromo-3-fluorophenoxy)-2-methylpropane-1,2-diol
- AD-mix ⁇ (12 g, 0.035 mmol of osmium) was added to a suspension of 1-bromo-2-fluoro-4-((2-methyl-allyl)oxy)benzene (2.1 g, 8.5 mmol) in tert-butanol (41 mL) and water (41 mL). The reaction was stirred at rt for 4 h, then partitioned between EtOAc and water. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO 4 ), filtered and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel (0-100% EtOAc in hexanes as eluent) to give the title compound. LC-MS [M+H]: m/z 279.0.
- Step D tert-butyl (S)-3-(4-bromo-3-fluorophenoxy)-2-hydroxy-2-methylpropanoate
- Step E tert-butyl (S)-2-(aminooxy)-3-(4-bromo-3-fluorophenoxy)-2-methylpropanoate
- Trimethylsilyldiazomethane (2.2 mL of a 2.0 M solution in hexanes, 4.41 mmol) was added to a (1:1) mixture of DCM:CH 3 OH (2 mL). The resulting mixture was added to a stirred solution of (R)-3-(4-bromophenoxy)-2-hydroxypropanoic acid (288 mg, 1.10 mmol) in (1:1) DCM:CH 3 OH (10 mL). The reaction mixture was stirred at rt for 30 min. Then the reaction was concentrated in vacuo to give the title compound, which was used without further purification. LC-MS [M+H]: m/z 275.2.
- Step A tert-butyl 3-fluoro-3-((tosyloxy)methyl)azetidine-1-carboxylate
- p-Toluenesulfonyl chloride (1.02 g, 5.32 mmol) was added to a stirred solution of tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylate (993 mg, 4.84 mmol) and triethylamine (742 ⁇ L, 5.32 mmol) in DCM (20 mL) at 0° C. The reaction mixture was allowed to warm to rt, then additional triethylamine (337 ⁇ L, 2.66 mmol) was added.
- Step B tert-butyl 3-((4-bromo-1H-pyrazol-1-yl)methyl)-3-fluoroazetidine-1-carboxylate
- Step B tert-butyl (2-((5-bromopyridin-2-yl)amino)ethyl)carbamate
- Step A tert-butyl (3-((6-chloropyridazin-3-yl)amino)propyl)carbamate
- Step A 3-((tert-butoxycarbonyl)amino)-2-fluoropropyl 4-methyl benzenesulfonate
- Step B tert-butyl (3-(4-bromo-1H-pyrazol-1-yl)-2-fluoropropyl)carbamate
- Step B 2-(3-(1-trityl-1H-imidazol-4-yl)propyl)isoindoline-1,3-dione
- Step D tert-butyl (3-(1-trityl-1H-imidazol-4-yl)propyl)carbamate
- Step E tert-butyl (3-(1H-imidazol-4-yl)propyl)carbamate
- Step A tert-butyl N-[(2S)-2,3-dihydroxypropyl]carbamate
- Step B tert-butyl (S)-(2,3-bis((tert-butyldimethylsilyl)oxy)propyl)carbamate
- tert-butyl N-[(2S)-2,3-dihydroxypropyl]carbamate (20 g, 105 mmol, 1 eq) in N,N-dimethylformamide (200 mL), and imidazole (32 g, 470 mmol, 4.50 equiv).
- tert-butyl(chloro)dimethylsilane (40.8 g, 271 mmol, 2.6 eq) was added in several batches at 0° C. The reaction was stirred overnight at room temperature, and then diluted with ethyl acetate (500 mL).
- Step C tert-butyl (S)-(2-((tert-butyldimethylsilyl)oxy)-3-hydroxypropyl)carbamate
- Step D (S)-3-((tert-butoxycarbonyl)amino)-2-((tert-butyldimethylsilyl)oxy)propyl methanesulfonate
- Step E tert-butyl (S)-(3-bromo-2-((tert-butyldimethylsilyl)oxy)propyl)carbamate
- Step F tert-butyl (S)-(3-(4-bromo-1H-pyrazol-1-yl)-2-((tertbutyldimethylsilyl)oxy)-propyl)carbamate
- Step A tert-Butyl (3-(4-bromo-1H-pyrazol-1-yl)propyl)carbamate
- Step B tert-Butyl (R)-3-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)phenoxy)-2-hydroxypropanoate
- Step C tert-Butyl (S)-3-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)phenoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)propanoate
- Step D (S)-4-(4-(3-(tert-Butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium
- Step E (S)-4-(4-(2-(Aminooxy)-3-(tert-butoxy)-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium
- Step F (S,Z)-4-(4-(3-(tert-Butoxy)-2-((((2-((tert-butoxycarbonyl)amino)-thiazol-4-yl)(carboxy)methylene)amino)oxy)-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium
- Step G (S)-3-((Z)-2-((((S)-1-(tert-Butoxy)-3-(4-(1-(3-((tert-butoxycarbonyl)amino)propy)-2-methyl-1H-pyrazol-2-ium-4-yl)phenoxy)-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate
- Step H Mono(4-(4-((S)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-carboxyethoxy)phenyl)-1-(3-ammoniopropyl)-2-methyl-1H-pyrazol-2-ium) mono(2,2,2-trifluoroacetate)
- Step A tert-Butyl (3-(4-bromo-1H-imidazol-1-yl)propyl)carbamate
- Step B tert-Butyl (R)-3-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-imidazol-4-yl)phenoxy)-2-hydroxypropanoate
- Step C tert-Butyl (S)-3-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-imidazol-4-yl)phenoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)propanoate
- Step D (S)-4-(4-(3-(tert-Butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-3-methyl-1H-imidazol-3-ium iodide
- Step E (S)-4-(4-(2-(Aminooxy)-3-(tert-butoxy)-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-3-methyl-1H-imidazol-3-ium iodide
- Step F (S,Z)-4-(4-(3-(tert-butoxy)-2-((((2-((tert-butoxycarbonyl)amino)-thiazol-4-yl)(carboxy)methylene)amino)oxy)-3-oxopropoxy)phenyl)-1-(3-((tert-butoxy-carbonyl)amino)propyl)-3-methyl-1H-imidazol-3-ium iodide
- Step G (S)-3-((Z)-2-((((S)-1-(tert-Butoxy)-3-(4-(1-(3-((tert-butoxycarbonyl)amino)propy)-3-methyl-1H-imidazol-3-ium-4-yl)phenoxy)-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate
- Step H Mono(4-(4-((S)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-carboxyethoxy)phen)-1-(3-ammoniopropyl)-3-methyl-1H-imidazol-3-ium) mono(2,2,2-trifluoroacetate)
- Example 3 was synthesized and characterized by LC/MS.
- Step A tert-Butyl (3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propyl)carbamate
- Step C tert-Butyl (3-(4-(4-(2-bromoethoxy)phenyl)-1H-pyrazol-1-yl)propyl)carbamate
- the mixture was degassed via a stream of nitrogen gas for approximately 5 minutes, at which point, the vial was sealed and heated in a microwave reactor to 120° C. for 20 minutes. After cooling to room temperature, the mixture was filtered through a pad of CeliteTM (diatomaceous earth), and the solid layer was rinsed with EtOAc. The combined organics were concentrated, and the resulting crude residue was purified by column chromatography on silica gel (0-60% EtOAc:hexanes as eluent) to afford the title compound. LC-MS [M+Na] + : m/z 446.3.
- Step D tert-Butyl (3-(4-(4-(2-((1,3-dioxoisoindolin-2-yl)oxy)ethoxy)phenyl)-1H-pyrazol-1-yl)propyl)carbamate
- N-Hydroxyphthalimide (185 mg, 1.13 mmol) was added to a stirred solution of tert-butyl (3-(4-(4-(2-bromoethoxy)phenyl)-1H-pyrazol-1-yl)propyl)carbamate (320 mg, 0.754 mmol) and DBU (138 mg, 0.905 mmol) in DMF (3.8 mL), and the resulting mixture was heated to 50° C. After 16 hours, the reaction mixture was cooled to room temperature and EDC (117 mg, 0.754 mmol) was added. After stirring at room temperature for 30 minutes, the reaction mixture was partitioned between EtOAc and water.
- Step A tert-Butyl (S)-2-(aminooxy)-3-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-imidazol-4-yl)phenoxy)propanoate
- Step B (S,Z)-2-(((1-(tert-Butoxy)-3-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-imidazol-4-yl)phenoxy)-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)-amino)thiazol-4-yl)acetic acid
- Step C tert-Butyl (S)-3-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-imidazol-4-yl)phenoxy)-2-((((Z)-1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoate
- Step D (S)-3-(4-(1-(3-Aminopropyl)-1H-imidazol-4-yl)phenoxy)-2-(((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid
- Step A (S,Z)-4-(4-(3-(tert-Butoxy)-2-((((2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)(carboxy)methylene)amino)oxy)-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)-amino)propyl)-2-methyl-1H-pyrazol-2-ium iodide
- Step B (S)-3-((Z)-2-((((S)-1-(tert-Butoxy)-3-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium-4-yl)phenoxy)-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate
- Step C (S)-3-((Z)-2-(2-Amino-5-chlorothiazol-4-yl)-2-(((S)-2-(4-(1-(3-aminopropyl)-2-methyl-1H-pyrazol-2-ium-4-yl)phenoxy)-1-carboxyethoxy)imino)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate
- Step A (S,Z)-4-(4-(3-(tert-Butoxy)-2-((((5-((tert-butoxycarbonyl)amino)-1,2,4-thiadiazol-3-yl)(carboxy)methylene)amino)oxy)-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)-amino)propyl)-2-methyl-1H-pyrazol-2-ium iodide
- Step B (S)-3-((Z)-2-((((S)-1-(tert-Butoxy)-3-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium-4-yl)phenoxy)-1-oxopropan-2-yl)oxy)imino)-2-(5-((tert-butoxycarbonyl)amino)-1,2,4-thiadiazol-3-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate
- Step C (S)-3-((Z)-2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(((S)-2-(4-(1-(3-aminopropyl)-2-methyl-1H-pyrazol-2-ium-4-yl)phenoxy)-1-carboxyethoxy)imino)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate
- Example 13 was synthesized and characterized by LC/MS.
- Exam- LCMS ple Name Structure [M + 1] 13 3-(4-(5-((S)-2-((((Z)-1-(2- aminothiazol-4-yl)-2-(((S)- 2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3- yl)amino)-2-oxo- ethylidene)amino)oxy)-2- carboxyethoxy)pyridin-2- yl)-1H-pyrazol-1-yl)propan- 1-aminium 2,2,2- trifluoroacetate 668.24
- Step A tert-butyl (R)-2-hydroxy-3-(4-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)phenoxy)propanoate
- Step B tert-butyl (S)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-(4-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)phenoxy)propanoate
- Step C (S)-4-(2-(4-(4-(3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)-phenyl)-1H-pyrazol-1-yl)ethyl)-4-methylmorpholin-4-ium iodide
- Step D (S)-4-(2-(4-(4-(2-(aminooxy)-3-(tert-butoxy)-3-oxopropoxy)phenyl)-1H-pyrazol-1-yl)ethyl)-4-methylmorpholin-4-ium iodide
- Step E (S,Z)-4-(2-(4-(4-(3-(tert-butoxy)-2-((((2-((tert-butoxycarbonyl)amino)thiazol-4-yl)(carboxy)methylene)amino)oxy)-3-oxopropoxy)phenyl)-1H-pyrazol-1-yl)ethyl)-4-methylmorpholin-4-ium iodide
- Step F 4-(2-(4-(4-((S)-3-(tert-butoxy)-2-((((Z)-1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-3-oxopropoxy)phenyl)-1H-pyrazol-1-yl)ethyl)-4-methylmorpholin-4-ium iodide
- Step G (S)-3-((Z)-2-(2-aminothiazol-4-yl)-2-(((S)-1-carboxy-2-(4-(1-(2-(4-methyl-morpholino-4-ium)ethyl)-1H-pyrazol-4-yl)phenoxy)ethoxy)imino)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate
- Step A tert-butyl (3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propyl)carbamate
- Step B tert-butyl 3-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)phenoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-2-methylpropanoate
- Step C tert-butyl 3-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)phenoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-2-methylpropanoate
- Step D 4-(4-(3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-2-methyl-3-oxopropoxy)-phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium iodide
- Step E (Z)-4-(4-(3-(tert-butoxy)-2-((((2-((tert-butoxycarbonyl)amino)thiazol-4-yl)(carboxy)methylene)amino)oxy)-2-methyl-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium iodide
- Step F 4-(4-(3-(tert-butoxy)-2-((((Z)-1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((2R,3S)-2-methyl-4-oxo-1-sulfoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methyl-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium
- Step G (S)-3-((Z)-2-((((S)-1-(4-(1-(3-aminopropyl)-2-methyl-1H-pyrazol-2-ium-4-yl)phenoxy)-2-carboxypropan-2-yl)oxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate compound with 2,2,2-trifluoroacetic acid (1:1)
- Step A tert-butyl (R)-3-(4-bromo-3-fluorophenoxy)-2-hydroxypropanoate
- Step B tert-butyl (R)-3-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)-3-fluorophenoxy)-2-hydroxypropanoate
- Step C tert-butyl (S)-3-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)-3-fluorophenoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)propanoate
- Step D (S)-4-(4-(3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)-2-fluorophenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium iodide
- Step E (S,Z)-4-(4-(3-(tert-butoxy)-2-((((2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-(carboxy)methylene)amino)oxy)-3-oxopropoxy)-2-fluorophenyl)-1-(3-((tert-butoxy-carbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium iodide
- Step F 4-(4-((S)-3-(tert-butoxy)-2-((((Z)-1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-3-oxopropoxy)-2-fluorophenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium
- Step G (S)-3-((Z)-2-(((S)-2-(4-(1-(3-aminopropyl)-2-methyl-1H-pyrazol-2-ium-4-yl)-3-fluorophenoxy)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate compound with formic acid (1:1)
- Step A 4-(4-(3-(tert-butoxy)-2-((((Z)-1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((2R,3S)-2-methyl-4-oxo-1-sulfoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methyl-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium
- Step B (2R,3S)-3-((Z)-2-((((S)-1-(4-(1-(3-aminopropyl)-2-methyl-1H-pyrazol-2-ium-4-yl)phenoxy)-2-carboxypropan-2-yl)oxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2-methyl-4-oxoazetidine-1-sulfonate compound with 2,2,2-trifluoroacetic acid (1:1)
- Step A tert-butyl 3-((6-bromopyridin-3-yl)oxy)-2-hydroxypropanoate
- Example 26 (S)-3-((Z)-2-(((S)-2-((6-(1-(3-aminopropyl)-1H-pyrazol-4-yl)-1-methylpyridin-1-ium-3-yl)oxy)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate compound with 2,2,2-trifluoroacetic acid (1:1) was prepared from tert-butyl 3-((6-bromopyridin-3-yl)oxy)-2-hydroxypropanoate by 6 steps. The procedures of the six steps were same as in step B, C, D, E, F, G of Example 2. LC-MS [M] + : m/z 682.20
- Step A tert-Butyl (3-(3-amino-4-bromo-1H-pyrazol-1-yl)propyl)carbamate
- Step B tert-Butyl (S)-3-(4-(3-amino-1-(3-((tert-butoxycarbonyl)amino)-propyl)-1H-pyrazol-4-yl)phenoxy)-2-((tert-butyldimethylsilyl)oxy)propanoate
- Step C tert-Butyl 3-(4-(3-(((allyloxy)carbonyl)amino)-1-(3-((tert-butoxycarbonyl)amino) propyl)-1H-pyrazol-4-yl)phenoxy)-2-((tert-butyldimethylsilyl)oxy)propanoate
- Step D tert-Butyl 3-(4-(3-(((allyloxy)carbonyl)amino)-1-(3-((tert-butoxycarbonyl)-amino)propyl)-1H-pyrazol-4-yl)phenoxy)-2-hydroxypropanoate
- Step E tert-Butyl 3-(4-(3-(((allyloxy)carbonyl)amino)-1-(3-((tert-butoxycarbonyl)-amino)propy)-1H-pyrazol-4-yl)phenoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)propanoate
- Step F tert-Butyl 3-(4-(3-(((allyloxy)carbonyl)amino)-1-(3-((tert-butoxycarbonyl)-amino)propyl)-1H-pyrazol-4-yl)phenoxy)-2-(aminooxy)propanoate
- Step G (Z)-2-(((3-(4-(3-(((Allyloxy)carbonyl)amino)-1-(3-((tert-butoxycarbonyl)amino)-propyl)-1H-pyrazol-4-yl)phenoxy)-1-(tert-butoxy)-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid
- Step H tert-Butyl 3-(4-(3-(((allyloxy)carbonyl)amino)-1-(3-((tert-butoxycarbonyl)amino)-propyl)-1H-pyrazol-4-yl)phenoxy)-2-(((Z)-1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2 oxoethylidene)amino)oxy)-propanoate
- Step I tert-Butyl 3-(4-(3-amino-1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)phenoxy)-2-(((Z)-1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoate
- Step J (S)-3-(4-(3-Amino-1-(3-aminopropyl)-1H-pyrazol-4-yl)phenoxy)-2-(((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid
- Step A (S)-3-(((Allyloxy)carbonyl)amino)-4-(4-(3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium iodide
- Step B (R)-3-(4-bromophenoxy)-2-hydroxypropanoic acid
- Step D (R)-3-(4-bromophenoxy)-2-((tert-butyldimethylsilyl)oxy)-propanamide
- Step E (S)-3-(4-bromophenoxy)-2-((tert-butyldimethylsilyl)oxy)-propanenitrile
- Step F (S)-5-(2-(4-bromophenoxy)-1-((tert-butyldimethylsilyl)oxy)ethyl)-2H-tetrazole
- Step G (S)-5-(2-(4-bromophenoxy)-1-((tert-butyldimethylsilyl)oxy)ethyl)-2-(4-methoxybenzyl)-2H-tetrazole
- Step H (S)-tert-butyl (3-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)ethoxy)phenyl)-1H-pyrazol-1-yl)propyl)carbamate
- Step I (S)-tert-butyl (3-(4-(4-(2-hydroxy-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)ethoxy)phenyl)-1H-pyrazol-1-yl)propyl)carbamate
- Step J (R)-tert-butyl (3-(4-(4-(2-((1,3-dioxoisoindolin-2-yl)oxy)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)ethoxy)phenyl)-1H-pyrazol-1-yl)propyl)carbamate
- Step K (R)-1-(3-((tert-butoxycarbonyl)amino)propyl)-4-(4-(2-((1,3-dioxoisoindolin-2-yl)oxy)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)ethoxy)phenyl)-2-methyl-1H-pyrazol-2-ium iodide
- Step L (R)-4-(4-(2-(aminooxy)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)ethoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium
- Step M (R,Z)-1-(3-((tert-butoxycarbonyl)amino)propyl)-4-(4-(2-((((2-((tert-butoxy-carbonyl)amino)thiazol-4-yl)(carboxy)methylene)amino)oxy)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)ethoxy)phenyl)-2-methyl-1H-pyrazol-2-ium
- Step N (R,Z)-4-(4-(2-((((2-aminothiazol-4-yl)(carboxy)methylene)-amino)oxy)-2-(2H-tetrazol-5-yl)ethoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium
- Step O (S)-3-((Z)-2-(2-aminothiazol-4-yl)-2-(((R)-2-(4-(1-(3-((tert-butoxycarbonyl)-amino)propyl)-2-methyl-1H-pyrazol-2-ium-4-yl)phenoxy)-1-(2H-tetrazol-5-yl)ethoxy)-imino)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate
- Step P 1-(3-aminopropyl)-4-(4-((R)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-(2H-tetrazol-5-yl)ethoxy)phenyl)-2-methyl-1H-pyrazol-2-ium 2,2,2-trifluoroacetate
- Step A 4-(4-((R)-2-(((Z)-(1-(2-aminothiazol-4-yl)-2-(((2S,3S)-2-methyl-4-oxo-1-sulfoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-(2H-tetrazol-5-yl)ethoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium
- Step B 1-(3-aminopropyl)-4-(4-((R)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-2-methyl-4-oxo-1-sulfoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-(2H-tetrazol-5-yl)ethoxy)phenyl)-2-methyl-1H-pyrazol-2-ium 2,2,2-trifluoroacetate
- Step A tert-butyl (3-(2-nitro-1H-imidazol-1-yl)propyl)carbamate
- Step B tert-butyl (3-(4-bromo-2-nitro-1H-imidazol-1-yl)propyl)carbamate
- Step C (R)-tert-butyl 3-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-2-nitro-1H-imidazol-4-yl)phenoxy)-2-hydroxypropanoate
- Step D (R)-tert-butyl 3-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-2-nitro-1H-imidazol-4-yl)phenoxy)-2-((tert-butyldimethylsilyl)oxy)propanoate
- Step E (R)-tert-butyl 3-(4-(2-amino-1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-imidazol-4-yl)phenoxy)-2-((tert-butyldimethylsilyl)oxy)propanoate
- Step F (R)-tert-butyl 3-(4-(2-(bis(tert-butoxycarbonyl)amino)-1-(3-((tert-butoxycarbonyl)-amino)propyl)-1H-imidazol-4-yl)phenoxy)-2-((tert-butyldimethylsilyl)oxy)propanoate
- Step G (R)-tert-butyl 3-(4-(2-(bis(tert-butoxycarbonyl)amino)-1-(3-((tert-butoxy-carbonyl)amino)propyl)-1H-imidazol-4-yl)phenoxy)-2-hydroxypropanoate
- Step H (S)-tert-butyl 3-(4-(2-(bis(tert-butoxycarbonyl)amino)-1-(3-((tert-butoxy-carbonyl)amino)propyl)-1H-imidazol-4-yl)phenoxy)-2-((1,3-dioxoisoindolin-2-yl)-oxy)propanoate
- Step I (S)-tert-butyl 2-(aminooxy)-3-(4-(2-(bis(tert-butoxycarbonyl)amino)-1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-imidazol-4-yl)phenoxy)propanoate
- Step J (S,Z)-2-(((3-(4-(2-(bis(tert-butoxycarbonyl)amino)-1-(3-((tert-butoxycarbonyl)-amino)propyl)-1H-imidazol-4-yl)phenoxy)-1-(tert-butoxy)-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid
- Step K (S)-tert-butyl 3-(4-(2-(bis(tert-butoxycarbonyl)amino)-1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-imidazol-4-yl)phenoxy)-2-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoate
- Step L 3-(2-amino-4-(4-((S)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-carboxyethoxy)phenyl)-1H-imidazol-1-yl)propan-1-aminium 2,2,2-trifluoroacetate
- Step A (S,E)-tert-butyl 3-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-4-yl)phenoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)propanoate
- Step B (S,E)-tert-butyl 2-(aminooxy)-3-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-4-yl)phenoxy)propanoate
- Step C (Z)-2-((((S)-1-(tert-butoxy)-3-(4-((E)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-4-yl)phenoxy)-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid
- Step D (S)-tert-butyl 3-(4-((E)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-4-yl)phenoxy)-2-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoate
- Step E 3-(4-(4-((S)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-carboxyethoxy)phenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)propan-1-aminium 2,2,2-trifluoroacetate
- Step A tert-butyl 2-(tert-butyldimethylsilyl)oxy)-3-(6-(pyridin-4-ylamino)pyridin-3-yl)oxy)propanoate
- Step B tert-butyl 3-((6-((tert-butoxycarbonyl)(pyridin-4-yl)amino)pyridin-3-yl)oxy)-2-((tert-butyl dimethylsilyl)oxy)propanoate
- Step C tert-butyl 3-((6-((tert-butoxycarbonyl)(pyridin-4-yl)amino)pyridin-3-yl)oxy)-2-hydroxypropanoate
- Step D tert-butyl 3-((6-((tert-butoxycarbonyl)(pyridin-4-yl)amino)pyridin-3-yl)oxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)propanoate
- Step E 4-((5-(3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)pyridin-2-yl)(tert-butoxycarbonyl)amino)-1-(3-((tert-butoxycarbonyl)amino)propyl)pyridin-1-ium
- Step F 4-((5-(2-(aminooxy)-3-(tert-butoxy)-3-oxopropoxy)pyridin-2-yl)(tert-butoxy-carbonyl)amino)-1-(3-((tert-butoxycarbonyl)amino)propyl)pyridin-1-ium
- Step G (Z)-4-((5-(3-(tert-butoxy)-2-((((2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-(carboxy)methylene)amino)oxy)-3-oxopropoxy)pyridin-2-yl)(tert-butoxycarbonyl)amino)-1-(3-((tert-butoxycarbonyl)amino)propyl)pyridin-1-ium
- Step H 4-((5-(3-(tert-butoxy)-2-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-3-oxopropoxy)pyridin-2-yl)(tert-butoxycarbonyl)amino)-1-(3-((tert-butoxycarbonyl)amino)-propyl)pyridin-1-ium
- Step K 1-(3-aminopropyl)-4-((5-((S)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-carboxyethoxy)-pyridin-2-yl)amino)pyridin-1-ium 2,2,2-trifluoroacetate
- Step A tert-butyl 2-((tert-butyldimethylsilyl)oxy)-3-((6-(pyridin-4-yloxy)pyridin-3-yl)oxy)propanoate
- Step B tert-butyl 2-hydroxy-3-((6-(pyridin-4-yloxy)pyridin-3-yl)oxy)propanoate
- Step C tert-butyl 2-((1,3-dioxoisoindolin-2-yl)oxy)-3-((6-(pyridin-4-yloxy)pyridin-3-yl)oxy)propanoate
- Step D 4-((5-(3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)pyridin-2-yl)oxy)-1-(3-((tert-butoxycarbonyl)amino)propyl)pyridin-1-ium
- Step E (Z)-4-((5-(3-(tert-butoxy)-2-((((2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-(carboxy)methylene)amino)oxy)-3-oxopropoxy)pyridin-2-yl)oxy)-1-(3-((tert-butoxy-carbonyl)amino)propyl)pyridin-1-ium
- Step F 4-((5-(3-(tert-butoxy)-2-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-3-oxopropoxy)pyridin-2-yl)oxy)-1-(3-((tert-butoxycarbonyl)amino)propyl)pyridin-1-ium
- Step G 1-(3-aminopropyl)-4-((5-((S)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-carboxyethoxy)-pyridin-2-yl)oxy)pyridin-1-ium 2,2,2-trifluoroacetate
- 6-Bromopyridin-3-ol (700 mg, 4.02 mmol), 2-chloroethanol (972 mg, 12.1 mmol), and K 2 CO 3 (1.39 g, 10.1 mmol), were combined and suspended in acetonitrile (18 mL). A stream of N 2 gas was bubbled through a septum into the solution for 10 minutes and the resultant solution was heated at 80° C. for 18 hours. After standing at ambient temperature for two days, the mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by silica gel column chromatography (24 g column) using a gradient of 0-100% EtOAc/Hexanes as eluent to provide the title compound.
- Step B 2-bromo-5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridine
- Step C 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-(1H-imidazol-1-yl)pyridine
- Step D 2-((6-(1H-imidazol-1-yl)pyridin-3-yl)oxy)ethan-1-ol
- Step E 2-(2-((6-(1H-imidazol-1-yl)pyridin-3-yl)oxy)ethoxy)isoindoline-1,3-dione
- Step F 3-(3-((tert-butoxycarbonyl)amino)propyl)-1-(5-(2-((1,3-dioxoisoindolin-2-yl)oxy)ethoxy)pyridin-2-yl)-1H-imidazol-3-ium
- Step G 1-(5-(2-(aminooxy)ethoxy)pyridin-2-yl)-3-(3-((tert-butoxycarbonyl)amino)propyl)-1H-imidazol-3-ium
- Step H (Z)-3-(3-((tert-butoxycarbonyl)amino)propyl)-1-(5-(2-((((2-((tert-butoxycarbonyl)amino)thiazol-4-yl)(carboxy)methylene)amino)oxy)ethoxy)pyridin-2-yl)-1H-imidazol-3-ium
- Step I (S,Z)-3-(3-((tert-butoxycarbonyl)amino)propyl)-1-(5-(2-(((1-(2-((tert-butoxy-carbonyl)amino)thiazol-4-yl)-2-((2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)ethoxy)pyridin-2-yl)-1H-imidazol-3-ium
- Step J (S,Z)-3-(2-((2-((6-(3-(3-aminopropyl)-1H-imidazol-3-ium-1-yl)pyridin-3-yl)oxy)ethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate 2,2,2-trifluoroacetate
- Ethyl oxirane-2-carboxylate (1.47 g, 12.6 mmol) was suspended in MTBE (25 mL) and 6-bromopyridin-3-ol (1.0 g, 5.75 mmol) and 4 ⁇ molecular sieves (2 g) were added.
- Intermediate 2 (0.482 g, 0.575 mmol) was added and the resultant mixture stirred at ambient temperature for 3 days. Solids were removed by filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (40 g column) using a gradient of 0-60% EtOAc/Hexanes as eluent to provide the title compound.
- Step B (R)-3-((6-bromopyridin-3-yl)oxy)-2-hydroxypropanoic acid
- Step C tert-butyl (R)-3-((6-bromopyridin-3-yl)oxy)-2-hydroxypropanoate
- Step D tert-butyl (R)-3-((6-bromopyridin-3-yl)oxy)-2-((tert-butyldimethylsilyl)oxy)-propanoate
- Step E tert-butyl (R)-3-((6-(1H-imidazol-1-yl)pyridin-3-yl)oxy)-2-((tert-butyl dimethylsilyl)oxy)propanoate
- Step F tert-butyl (R)-3-((6-(1H-imidazol-1-yl)pyridin-3-yl)oxy)-2-hydroxypropanoate
- Step G tert-butyl (S)-3-((6-(1H-imidazol-1-yl)pyridin-3-yl)oxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)propanoate
- Step H (S)-3-(3-aminopropyl)-1-(5-(3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)pyridin-2-yl)-1H-imidazol-3-ium
- Step I (S)-1-(5-(3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)pyridin-2-yl)-3-(3-((tert-butoxycarbonyl)amino)propyl)-1H-imidazol-3-ium
- Step J (S)-1-(5-(2-(aminooxy)-3-(tert-butoxy)-3-oxopropoxy)pyridin-2-yl)-3-(3-((tert-butoxycarbonyl)amino)propyl)-1H-imidazol-3-ium
- Step K (S,Z)-1-(5-(3-(tert-butoxy)-2-((((2-((tert-butoxycarbonyl)amino)thiazol-4-yl)(carboxy)methylene)amino)oxy)-3-oxopropoxy)pyridin-2-yl)-3-(3-((tert-butoxy-carbonyl)amino)propyl)-1H-imidazol-3-ium
- Step L 1-(5-((S)-3-(tert-butoxy)-2-(((Z)-1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-3-oxopropoxy)pyridin-2-yl)-3-(3-((tert-butoxycarbonyl)amino)propyl)-1H-imidazol-3-ium
- Step M (S)-3-((Z)-2-(((S)-2-((6-(3-(3-aminopropyl)-1H-imidazol-3-ium-1-yl)pyridin-3-yl)oxy)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate compound with 2,2,2-trifluoroacetic acid (1:1)
- Step A tert-butyl (3-(2-nitro-1H-imidazol-1-yl)propyl)carbamate
- Step B tert-butyl (3-(2-amino-1H-imidazol-1-yl)propyl)carbamate
- Step C tert-butyl 3-((6-((1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-imidazol-2-yl)amino)pyridin-3-yl)oxy)-2-((tert-butyldimethylsilyl)oxy)propanoate
- Step D tert-butyl 3-((6-((1-(3-(bis(tert-butoxycarbonyl)amino)propyl)-1H-imidazol-2-yl)(tert-butoxycarbonyl)amino)pyridin-3-yl)oxy)-2-((tert-butyldimethylsilyl)oxy)propanoate
- Step E tert-butyl 3-((6-((1-(3-(bis(tert-butoxycarbonyl)amino)propyl)-1H-imidazol-2-yl)(tert-butoxycarbonyl)amino)pyridin-3-yl)oxy)-2-hydroxypropanoate
- step E tert-butyl 3-((6-((1-(3-(bis(tert-butoxycarbonyl)amino)propyl)-1H-imidazol-2-yl)(tert-butoxycarbonyl)amino)pyridin-3-yl)oxy)-2-hydroxypropanoate) was converted to C37A and C37B as TFA salts following a similar procedure from step C, step E to step H in Example 1.
- Compound 37A 3-(2-((5-((S)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-carb oxyethoxy)pyridin-2-yl)amino)-1H-imidazol-1-yl)propan-1-aminium 2,2,2-trifluoroacetate.
- Step A tert-butyl (R)-3-(4-bromo-3-chlorophenoxy)-2-hydroxypropanoate
- Step B tert-butyl (R)-3-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)-3-chlorophenoxy)-2-hydroxypropanoate
- Step C tert-butyl (S)-3-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)-3-chlorophenoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)propanoate
- Step D (S)-4-(4-(3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)-2-chlorophenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium iodide
- Step E (S,Z)-4-(4-(3-(tert-butoxy)-2-((((2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-(carboxy)methylene)amino)oxy)-3-oxopropoxy)-2-chlorophenyl)-1-(3-((tert-butoxy-carbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium iodide
- Step F 4-(4-((S)-3-(tert-butoxy)-2-((((Z)-1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-3-oxopropoxy)-2-chlorophenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium
- Step G (S)-3-((Z)-2-(((S)-2-(4-(1-(3-aminopropyl)-2-methyl-1H-pyrazol-2-ium-4-yl)-3-chlorophenoxy)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate
- Step A tert-butyl (3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propyl)carbamate
- Step B tert-butyl 3-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)-phenoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-2-methylpropanoate
- Step C tert-butyl 3-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)phenoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-2-methylpropanoate
- Step D 4-(4-(3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-2-methyl-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium iodide
- Step E (Z)-4-(4-(3-(tert-butoxy)-2-((((2-((tert-butoxycarbonyl)amino)thiazol-4-yl)(carboxy)methylene)amino)oxy)-2-methyl-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium iodide
- Step F 4-(4-(3-(tert-butoxy)-2-((((Z)-1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-sulfoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methyl-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium
- Step G (S)-3-((Z)-2-((((S)-1-(4-(1-(3-aminopropyl)-2-methyl-1H-pyrazol-2-ium-4-yl)phenoxy)-2-carboxypropan-2-yl)oxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate
- Step D tert-butyl (3-(4-(4-(2-(dimethoxyphosphoryl)-2-hydroxyethoxy)phenyl)-1H-pyrazol-1-yl)propyl)carbamate
- Step E tert-butyl (3-(4-(4-(2-(dimethoxyphosphoryl)-2-((1,3-dioxoisoindolin-2-yl)oxy)-ethoxy)phenyl)-1H-pyrazol-1-yl)propyl)carbamate
- Step F 1-(3-((tert-butoxycarbonyl)amino)propyl)-4-(4-(2-(dimethoxyphosphoryl)-2-((1,3-dioxoisoindolin-2-yl)oxy)ethoxy)phenyl)-2-methyl-1H-pyrazol-2-ium trifluoromethanesulfonate
- Methyl trifluoromethanesulfonate (0.069 ml, 0.63 mmol) was added to a stirred, cooled 0° C. mixture of tert-butyl (3-(4-(4-(2-(dimethoxyphosphoryl)-2-((1,3-dioxoisoindolin-2-yl)oxy)ethoxy)phenyl)-1H-pyrazol-1-yl)propyl)carbamate (370 mg, 0.60 mmol) in CH 3 CN. The mixture was stirred at 0° C. for 10 min, at RT overnight, and then concentrated. The resulting residue was purified by column chromatography on silica gel, eluting with CH 2 Cl 2 /MeOH (100-80%) to give the title compound. LC-MS [M] + : m/z 629.33
- Step G 1-(3-aminopropyl)-4-(4-(2-((1,3-dioxoisoindolin-2-yl)oxy)-2-phosphonoethoxy)-phenyl)-2-methyl-1H-pyrazol-2-ium trifluoromethanesulfonate
- Step H 1-(3-((tert-butoxycarbonyl)amino)propyl)-4-(4-(2-((1,3-dioxoisoindolin-2-yl)oxy)-2-phosphonoethoxy)phenyl)-2-methyl-1H-pyrazol-2-ium
- Triethylamine (0.31 ml, 2.2 mmol) was added to a stirred, cooled room temperature mixture of 1-(3-aminopropyl)-4-(4-(2-((1,3-dioxoisoindolin-2-yl)oxy)-2-phosphonoethoxy)phenyl)-2-methyl-1H-pyrazol-2-ium trifluoromethanesulfonate (0.28 g, 0.56 mmol), and di-tert-butyl dicarbonate (0.24 g, 1.12 mmol) in DMF. The reaction mixture was stirred at room temperature overnight. The mixture was purified by preparative HPLC reverse phase (C-18), eluting with 0.05% TFA in CH 3 CN/water (2-100%) to give title compound.
- LC-MS [M] + m/z 601.32
- Step I 1-(3-((tert-butoxycarbonyl)amino)propyl)-4-(4-(2-((((Z)-1-(2-((tert-butoxycarbonyl)-amino)thiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxo-ethylidene)amino)oxy)-2-phosphonoethoxy)phenyl)-2-methyl-1H-pyrazol-2-ium
- Step J (3S)-3-((Z)-2-((2-(4-(1-(3-aminopropyl)-2-methyl-1H-pyrazol-2-ium-4-yl)phenoxy)-1-phosphonoethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate
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EP4007759A4 (en) * | 2020-08-06 | 2024-04-10 | Ningxia Academy of Agriculture and Forestry Sciences | BETA-LACTAM COMPOUNDS, THEIR PREPARATION AND THEIR USE AS ANTIBACTERIAL AGENTS |
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PL2790681T5 (pl) | 2011-11-18 | 2024-02-05 | Regeneron Pharmaceuticals, Inc. | Sposób otrzymywania farmaceutycznej postaci użytkowej o przedłużonym uwalnianiu zawierającej mikrocząstki białkowe powlekane polimerem z wykorzystaniem suszenia rozpyłowego |
MX2017016424A (es) | 2015-06-15 | 2019-08-01 | Nmd Pharma Aps | Compuestos para su uso en el tratamiento de trastornos neuromusculares. |
RU2746129C2 (ru) | 2015-12-15 | 2021-04-07 | Мерк Шарп И Доум Корп. | Биарильные монобактамные соединения и способы их применения для лечения бактериальных инфекций |
EP3691639B1 (en) | 2017-10-02 | 2023-11-15 | Merck Sharp & Dohme LLC | Chromane monobactam compounds for the treatment of bacterial infections |
US11591284B2 (en) | 2017-12-14 | 2023-02-28 | Nmd Pharma A/S | Compounds for the treatment of neuromuscular disorders |
US11730714B2 (en) | 2017-12-14 | 2023-08-22 | Nmd Pharma A/S | Compounds for the treatment of neuromuscular disorders |
US11147788B2 (en) | 2017-12-14 | 2021-10-19 | Nmd Pharma A/S | Compounds for the treatment of neuromuscular disorders |
US10385028B2 (en) | 2017-12-14 | 2019-08-20 | Nmd Pharma A/S | Compounds for the treatment of neuromuscular disorders |
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CN111511737B (zh) * | 2018-01-29 | 2022-10-18 | 南京明德新药研发有限公司 | 用于治疗细菌感染的单环β-内酰胺化合物 |
WO2020048828A1 (en) | 2018-09-03 | 2020-03-12 | Bayer Pharma Aktiengesellschaft | 5-heteroaryl-3,9-diazaspiro[5.5]undecane compounds |
WO2020048827A1 (en) | 2018-09-03 | 2020-03-12 | Bayer Aktiengesellschaft | 1, 3, 9-triazaspiro[5.5] undecan-2-one compounds |
US20220002288A1 (en) * | 2018-11-13 | 2022-01-06 | Nanjing Sanhome Pharmaceutical Co., Ltd. | Monobactam compounds and use therefor |
CA3121202A1 (en) | 2018-11-30 | 2020-06-04 | Nuvation Bio Inc. | Pyrrole and pyrazole compounds and methods of use thereof |
CN111303144B (zh) * | 2019-12-13 | 2020-11-27 | 苏州信诺维医药科技有限公司 | 一种治疗细菌感染的化合物 |
EP4079305A4 (en) * | 2019-12-19 | 2024-01-10 | Shenzhen Optimum Biological Technology Co., Ltd | APPLICATION OF A COMPOUND IN THE PREPARATION OF DRUG |
CN112661667B (zh) * | 2020-12-28 | 2023-02-03 | 浦拉司科技(上海)有限责任公司 | 一种三氟乙脒的制备方法 |
CN115463219A (zh) * | 2021-11-09 | 2022-12-13 | 中国医学科学院医药生物技术研究所 | 包含β-内酰胺类化合物的药物组合物及其用途 |
IL312841A (en) | 2021-11-18 | 2024-07-01 | Merck Sharp & Dohme Llc | CHROMANE AMIDINE MONOBACTAM ANTIBIOTICS |
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RU2746129C2 (ru) | 2015-12-15 | 2021-04-07 | Мерк Шарп И Доум Корп. | Биарильные монобактамные соединения и способы их применения для лечения бактериальных инфекций |
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WO2017106064A1 (en) | 2017-06-22 |
AU2016371600A1 (en) | 2018-05-10 |
BR112018010962A8 (pt) | 2023-04-11 |
EP3390357A1 (en) | 2018-10-24 |
US11230543B2 (en) | 2022-01-25 |
MA44083A (fr) | 2021-06-02 |
BR112018010962A2 (pt) | 2018-12-04 |
JP7184646B2 (ja) | 2022-12-06 |
US20200361928A1 (en) | 2020-11-19 |
RU2018123484A (ru) | 2020-01-17 |
CN108368040A (zh) | 2018-08-03 |
EP3978472A1 (en) | 2022-04-06 |
KR20180093925A (ko) | 2018-08-22 |
MX2018005382A (es) | 2018-08-16 |
CN108368040B (zh) | 2024-08-23 |
AU2016371600B2 (en) | 2021-02-18 |
RU2746129C2 (ru) | 2021-04-07 |
RU2018123484A3 (pt) | 2020-03-26 |
JP2018537483A (ja) | 2018-12-20 |
EP3390357B1 (en) | 2021-11-10 |
CA3008006A1 (en) | 2017-06-22 |
CA3008006C (en) | 2024-04-09 |
EP3390357A4 (en) | 2019-06-12 |
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