CN116102537A - Quinolinone derivative and preparation method and application thereof - Google Patents
Quinolinone derivative and preparation method and application thereof Download PDFInfo
- Publication number
- CN116102537A CN116102537A CN202211407887.7A CN202211407887A CN116102537A CN 116102537 A CN116102537 A CN 116102537A CN 202211407887 A CN202211407887 A CN 202211407887A CN 116102537 A CN116102537 A CN 116102537A
- Authority
- CN
- China
- Prior art keywords
- compound
- quinolinone derivative
- methyl
- pharmaceutically acceptable
- solvate
- 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.)
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- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical class C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title description 8
- 201000008827 tuberculosis Diseases 0.000 claims abstract description 21
- 230000001355 anti-mycobacterial effect Effects 0.000 claims abstract description 11
- 239000002532 enzyme inhibitor Substances 0.000 claims abstract description 8
- 229940125532 enzyme inhibitor Drugs 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 235
- 238000006243 chemical reaction Methods 0.000 claims description 69
- -1 methoxy, hydroxy Chemical group 0.000 claims description 63
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 29
- 239000003814 drug Substances 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 24
- 229940079593 drug Drugs 0.000 claims description 21
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 18
- 239000012453 solvate Substances 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 229910052731 fluorine Inorganic materials 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 13
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 11
- 241000187479 Mycobacterium tuberculosis Species 0.000 claims description 11
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 5
- 201000009671 multidrug-resistant tuberculosis Diseases 0.000 claims description 5
- 125000004011 3 membered carbocyclic group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 3
- 208000015355 drug-resistant tuberculosis Diseases 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 2
- 229940126062 Compound A Drugs 0.000 claims description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000002194 synthesizing effect Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 20
- 230000002365 anti-tubercular Effects 0.000 abstract description 9
- 231100001159 controllable toxicity Toxicity 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 description 61
- 238000001308 synthesis method Methods 0.000 description 51
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- 239000000543 intermediate Substances 0.000 description 48
- 239000007787 solid Substances 0.000 description 44
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 35
- 239000000243 solution Substances 0.000 description 30
- 238000004896 high resolution mass spectrometry Methods 0.000 description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 239000000706 filtrate Substances 0.000 description 22
- 239000012074 organic phase Substances 0.000 description 22
- 239000011734 sodium Substances 0.000 description 21
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 19
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 17
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
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- 125000000753 cycloalkyl group Chemical group 0.000 description 9
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 238000010790 dilution Methods 0.000 description 8
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
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- 125000003367 polycyclic group Chemical group 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 241001049988 Mycobacterium tuberculosis H37Ra Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000012258 culturing Methods 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 231100000517 death Toxicity 0.000 description 3
- 125000001183 hydrocarbyl group Chemical group 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- FFRYUAVNPBUEIC-UHFFFAOYSA-N quinoxalin-2-ol Chemical compound C1=CC=CC2=NC(O)=CN=C21 FFRYUAVNPBUEIC-UHFFFAOYSA-N 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- PTTUMBGORBMNBN-UHFFFAOYSA-N 1,2,3-trifluoro-5-nitrobenzene Chemical compound [O-][N+](=O)C1=CC(F)=C(F)C(F)=C1 PTTUMBGORBMNBN-UHFFFAOYSA-N 0.000 description 2
- KOFLVDBWRHFSAB-UHFFFAOYSA-N 1,2,4,5-tetrahydro-1-(phenylmethyl)-5,9b(1',2')-benzeno-9bh-benz(g)indol-3(3ah)-one Chemical compound C1C(C=2C3=CC=CC=2)C2=CC=CC=C2C23C1C(=O)CN2CC1=CC=CC=C1 KOFLVDBWRHFSAB-UHFFFAOYSA-N 0.000 description 2
- KYFXPHPBTUJULU-UHFFFAOYSA-N 2-(2-methoxyanilino)-2-(2-phenylmethoxyphenyl)acetonitrile Chemical compound COC1=CC=CC=C1NC(C#N)C1=CC=CC=C1OCC1=CC=CC=C1 KYFXPHPBTUJULU-UHFFFAOYSA-N 0.000 description 2
- UOXJNGFFPMOZDM-UHFFFAOYSA-N 2-[di(propan-2-yl)amino]ethylsulfanyl-methylphosphinic acid Chemical compound CC(C)N(C(C)C)CCSP(C)(O)=O UOXJNGFFPMOZDM-UHFFFAOYSA-N 0.000 description 2
- OCKWONYIDVFISR-UHFFFAOYSA-N 3,4,5-trifluoropyridine Chemical compound FC1=CN=CC(F)=C1F OCKWONYIDVFISR-UHFFFAOYSA-N 0.000 description 2
- WPDAWFCZGSQOPZ-UHFFFAOYSA-N 4-(2-bromoethyl)oxane Chemical compound BrCCC1CCOCC1 WPDAWFCZGSQOPZ-UHFFFAOYSA-N 0.000 description 2
- FJXJAAFKONAPKR-UHFFFAOYSA-N 4-methoxy-2-nitrobenzo[e][1]benzofuran Chemical compound COC1=CC2=CC=CC=C2C2=C1OC([N+]([O-])=O)=C2 FJXJAAFKONAPKR-UHFFFAOYSA-N 0.000 description 2
- NYIVWTWKIQOBKO-UHFFFAOYSA-N 4-phenanthren-3-ylbutanoic acid Chemical compound C1=CC=C2C3=CC(CCCC(=O)O)=CC=C3C=CC2=C1 NYIVWTWKIQOBKO-UHFFFAOYSA-N 0.000 description 2
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- SFHYNDMGZXWXBU-LIMNOBDPSA-N 6-amino-2-[[(e)-(3-formylphenyl)methylideneamino]carbamoylamino]-1,3-dioxobenzo[de]isoquinoline-5,8-disulfonic acid Chemical compound O=C1C(C2=3)=CC(S(O)(=O)=O)=CC=3C(N)=C(S(O)(=O)=O)C=C2C(=O)N1NC(=O)N\N=C\C1=CC=CC(C=O)=C1 SFHYNDMGZXWXBU-LIMNOBDPSA-N 0.000 description 2
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- ZCJKTGPZLLGECQ-UHFFFAOYSA-N 4-chloro-2,6-difluorobenzoic acid Chemical compound OC(=O)C1=C(F)C=C(Cl)C=C1F ZCJKTGPZLLGECQ-UHFFFAOYSA-N 0.000 description 1
- XUHYQIQIENDJER-BYPYZUCNSA-N 5-[(2s)-pyrrolidin-2-yl]-2h-tetrazole Chemical compound C1CCN[C@@H]1C1=NNN=N1 XUHYQIQIENDJER-BYPYZUCNSA-N 0.000 description 1
- UTTJAIFHRUAFED-UHFFFAOYSA-N 5-hydroxy-3,4-dihydro-2(1h)-quinolinone Chemical compound N1C(=O)CCC2=C1C=CC=C2O UTTJAIFHRUAFED-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- CFCWRLAINATSJN-UHFFFAOYSA-N 8-fluoro-4-hydroxy-1h-quinolin-2-one Chemical compound C1=CC=C2C(O)=CC(=O)NC2=C1F CFCWRLAINATSJN-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- RVHMNSYRSSOONW-UHFFFAOYSA-N FC=1C=CC(=C2CCC(NC=12)=O)OCC1(CCNCC1)O Chemical compound FC=1C=CC(=C2CCC(NC=12)=O)OCC1(CCNCC1)O RVHMNSYRSSOONW-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 241001646725 Mycobacterium tuberculosis H37Rv Species 0.000 description 1
- 108700035964 Mycobacterium tuberculosis HsaD Proteins 0.000 description 1
- LWLSVNFEVKJDBZ-UHFFFAOYSA-N N-[4-(trifluoromethoxy)phenyl]-4-[[3-[5-(trifluoromethyl)pyridin-2-yl]oxyphenyl]methyl]piperidine-1-carboxamide Chemical compound FC(OC1=CC=C(C=C1)NC(=O)N1CCC(CC1)CC1=CC(=CC=C1)OC1=NC=C(C=C1)C(F)(F)F)(F)F LWLSVNFEVKJDBZ-UHFFFAOYSA-N 0.000 description 1
- NSGDYZCDUPSTQT-UHFFFAOYSA-N N-[5-bromo-1-[(4-fluorophenyl)methyl]-4-methyl-2-oxopyridin-3-yl]cycloheptanecarboxamide Chemical compound Cc1c(Br)cn(Cc2ccc(F)cc2)c(=O)c1NC(=O)C1CCCCCC1 NSGDYZCDUPSTQT-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000008043 acidic salts Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- JIMXXGFJRDUSRO-UHFFFAOYSA-N adamantane-1-carboxylic acid Chemical compound C1C(C2)CC3CC2CC1(C(=O)O)C3 JIMXXGFJRDUSRO-UHFFFAOYSA-N 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000005210 alkyl ammonium group Chemical group 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 1
- 229940101006 anhydrous sodium sulfite Drugs 0.000 description 1
- 229940124976 antitubercular drug Drugs 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- AQNQQHJNRPDOQV-UHFFFAOYSA-N bromocyclohexane Chemical compound BrC1CCCCC1 AQNQQHJNRPDOQV-UHFFFAOYSA-N 0.000 description 1
- BRTFVKHPEHKBQF-UHFFFAOYSA-N bromocyclopentane Chemical compound BrC1CCCC1 BRTFVKHPEHKBQF-UHFFFAOYSA-N 0.000 description 1
- WEDIIKBPDQQQJU-UHFFFAOYSA-N butane-1-sulfonyl chloride Chemical compound CCCCS(Cl)(=O)=O WEDIIKBPDQQQJU-UHFFFAOYSA-N 0.000 description 1
- WKIXWKIEOCQGAF-UHFFFAOYSA-N butane-2-sulfonyl chloride Chemical compound CCC(C)S(Cl)(=O)=O WKIXWKIEOCQGAF-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- DVECBJCOGJRVPX-UHFFFAOYSA-N butyryl chloride Chemical compound CCCC(Cl)=O DVECBJCOGJRVPX-UHFFFAOYSA-N 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 230000036978 cell physiology Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229910000365 copper sulfate Inorganic materials 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229960000285 ethambutol Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229960003350 isoniazid Drugs 0.000 description 1
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- NCBZRJODKRCREW-UHFFFAOYSA-N m-anisidine Chemical compound COC1=CC=CC(N)=C1 NCBZRJODKRCREW-UHFFFAOYSA-N 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- QLNWXBAGRTUKKI-UHFFFAOYSA-N metacetamol Chemical compound CC(=O)NC1=CC=CC(O)=C1 QLNWXBAGRTUKKI-UHFFFAOYSA-N 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- BIWOSRSKDCZIFM-UHFFFAOYSA-N piperidin-3-ol Chemical compound OC1CCCNC1 BIWOSRSKDCZIFM-UHFFFAOYSA-N 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- KPBSJEBFALFJTO-UHFFFAOYSA-N propane-1-sulfonyl chloride Chemical compound CCCS(Cl)(=O)=O KPBSJEBFALFJTO-UHFFFAOYSA-N 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960005206 pyrazinamide Drugs 0.000 description 1
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 description 1
- 229960001225 rifampicin Drugs 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 1
- 230000008791 toxic response Effects 0.000 description 1
- 239000000814 tuberculostatic agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- A61P31/06—Antibacterial agents for tuberculosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/48—Oxygen atoms attached in position 4 having an acyclic carbon atom attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pulmonology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a quinolinone derivative, which has a structure shown in a formula I. It has excellent anti-Mycobacterium tuberculosis activity as a componentThe novel DprE1 enzyme inhibitor has controllable toxicity, excellent antitubercular activity and pharmacokinetic property and good clinical application prospect.
Description
Technical Field
The invention belongs to the field of chemical medicines, and particularly relates to a quinolinone derivative, a preparation method and application thereof.
Background
Tuberculosis is a chronic infectious disease caused by mycobacterium tuberculosis infection, and is one of ten global fatal diseases. Wherein one-fourth of tuberculosis deaths are caused by drug resistant tuberculosis. To date, the treatment of drug-sensitive tuberculosis has remained along with four drugs in the 70 s of the last century: isoniazid, rifampicin, pyrazinamide and ethambutol. The approval of bedaquiline and delaimab for sale by FDA and EMA in europe has been made in the united states since 2012, but currently being controversial, and not yet used as first-line antitubercular drugs due to the undefined toxic response and efficacy of bedaquiline and delaimab. Therefore, the development of anti-mycobacterium tuberculosis drugs having novel chemical structures and modes of action is considered as an important research direction at present.
Mycobacterium tuberculosis has a characteristic, complex cell wall structure, and involves a variety of functions related to cell physiology and pathogenesis. Whereas the unique DprE1 key enzyme within mycobacteria is associated with mycobacterium tuberculosis cell wall biosynthesis, it is critical for mycobacterium tuberculosis survival. The inhibitors of the DprE1 enzyme found in the past few years (e.g., BTZ and OPC-167832) have been found to be able to cause mycobacterial death by covalent or non-covalent binding to the DprE1 enzyme. These compounds all show antitubercular efficacy, providing strong evidence for the design of DprE1 enzyme inhibitors and treatment of tuberculosis.
However, the properties such as antitubercular activity of the existing DprE1 enzyme inhibitor still need to be further improved, and further research on quinolinone compounds with controllable toxicity, better antitubercular activity, better pharmacokinetic properties and better application prospects is expected to obtain better clinical treatment effects, so that the quinolinone compounds have important significance.
Disclosure of Invention
The purpose of the present invention is to provide a novel DprE1 enzyme inhibitor having excellent antitubercular activity.
The invention provides quinolinone derivatives shown in a formula I or pharmaceutically acceptable salts and solvates thereof:
Wherein ring A is aryl, aromatic heterocyclic group or aromatic heterocyclic group; l is O or NR 7 The method comprises the steps of carrying out a first treatment on the surface of the L ', L' are each independently selected from none, CO, SO 2 NH or (CH) 2 ) m M is an integer of 1 to 3; m is M 1 、M 2 Each independently selected from N or CH;
R 1 、R 2 、R 3 are independently selected from H, halogen, C1-C3 alkoxy, hydroxy, -NR 11 R 12 Or R is 2 、R 3 Connecting to form a 3-7 membered ring; r is R 11 Is H or C1-C3 alkyl, R 12 Is C1-C3 alkyl or-CO-R 13 ，R 13 A C1-C3 alkyl group substituted or unsubstituted with halogen;
R 4 is-H or-OH;
R 5 、R 6 are independently selected from-H, -Boc, bridged cyclic hydrocarbon radicals, R a 、R b 、R c Substituted or unsubstituted aryl, halogen substituted or unsubstituted aromatic heterocyclic radical, R d Substituted or unsubstituted C1-C4 alkyl, C3-C6 cycloalkyl or
t is an integer of 1 to 3;
wherein R is a 、R b 、R c Are independently selected from halogen, nitro,
Wherein R 'and R' are each independently selected from:H、-CO-R s or-SO 2 -R s The method comprises the steps of carrying out a first treatment on the surface of the R' "is-O-R s Or->
R s 、R p 、R q Independently selected from H, C C3 alkyl, or R p 、R q Connected into a ring;
R d halogen, halogen substituted or unsubstituted C1-C3 alkyl, C3-C6 cycloalkyl or C3-C6 heterocycloalkyl;
R 7 is C1-C3 alkyl.
Further, the ring A is
Further, R is as described above 1 、R 2 、R 3 Are independently selected from H, F, methoxy, hydroxy, -NR 11 R 12 Or R is 1 、R 2 Connecting to form a three-membered ring; r is R 11 Is H or methyl, R 12 Is methyl or-CO-R 13 ，R 13 1 to 3F substituted or unsubstituted methyl groups.
Further, R is as described above 1 H, F or methoxy, R 2 Is H or-NR 11 R 12 ，R 3 Is H, or R 2 And R is 3 To form a saturated 3-membered carbocyclic ring; r is R 11 Is H or methyl, R 12 Is methyl or-CO-R 13 ，R 13 Is methyl or-CF 3 。
Furthermore, the quinolinone derivative has a structure shown in formula II-A:
preferably, R 1 Is H or F, R 2 Is H and R 3 Is H, or R 2 、R 3 And linked to form a saturated 3-membered carbocyclic ring.
Furthermore, the quinolinone derivative has a structure shown in formula II-B:
wherein R is 3 Is H;
preferably, R 1 Is H or F, R 2 is-NR 11 R 12 ；R 11 Is H or methyl, R 12 Is methyl or-CO-R 13 ，R 13 Is methyl or-CF 3 。
Furthermore, the quinolinone derivative has a structure shown in formula II-C or formula II-D:
wherein R is 2 And R is 3 All are H;
preferably, R 1 H, F or methoxy.
Furthermore, the quinolinone derivative has a structure shown in formula II-E or formula II-F:
wherein R is 1 、R 2 、R 3 All are H.
Further, the above L is O or N-CH 3 。
Further, the L' is CO or SO 2 NH or CH 2 。
Further, the above L' is none.
Further, go upM is as follows 1 And M 2 At least one of which is CH.
Further, M is as described above 1 Is CH, M 2 Is N.
Further, M is as described above 1 Is CH, M 2 CH.
Further, M is as described above 1 Is N, M 2 CH.
Further, R is as described above 5 is-H or R a 、R b 、R c Substituted aryl.
Further, R is as described above a 、R b 、R c Is halogen.
Further, R is as described above a 、R b 、R c Each independently selected from F or Cl; preferably, R a 、R b Is F, R c Is Cl.
Further, R is as described above 5 is-H or
Further, R is as described above 6 is-H, -Boc, polycyclic bridged cyclic hydrocarbon radical, R a 、R b 、R c Substituted aryl, two F-substituted azaaromatic heterocyclic groups, R d Substituted or unsubstituted C1-C4 alkyl, C5-C6 cycloalkyl or
t is an integer of 1 to 2.
Further, R is as described above a 、R b Is F, R c Selected from Cl, nitro,
Wherein R 'and R' are each independently selected from: H. -CO-R s or-SO 2 -R s The method comprises the steps of carrying out a first treatment on the surface of the R' "is-O-R s Or->
R s 、R p 、R q Respectively and independently selectFrom H, methyl, or R p 、R q Are connected into a three-membered ring;
the R is d Is Cl, F substituted or unsubstituted C1-C3 alkyl, C3-C6 cycloalkyl or C6 heterocycloalkyl, wherein the heteroatom of the heterocycloalkyl is N and/or O.
Further, R is as described above 6 The method comprises the following steps: -H, -Boc,
Further, the quinolinone derivative has a structure represented by formula III-A or formula III-B:
furthermore, the quinolinone derivative has the following structure:
Further, the quinolinone derivative has a structure represented by formula III-C:
furthermore, the quinolinone derivative has the following structure:
further, the quinolinone derivative has a structure represented by the formula III-D:
furthermore, the quinolinone derivative has the following structure:
the invention also provides a synthesis method of the quinolinone derivative, which comprises the following steps: reacting the compound A with the compound B for 4-8 hours at 70-90 ℃ under the action of inorganic alkali to obtain a compound shown in a formula I;
the reaction formula is as follows:
wherein R is 0 is-OH or-NH-R 7 。
The invention also provides application of the quinolinone derivative or pharmaceutically acceptable salt or solvate thereof as a DprE1 enzyme inhibitor.
The invention also provides application of the quinolinone derivative or pharmaceutically acceptable salt or solvate thereof in preparing a medicament for treating tuberculosis, preferably, the tuberculosis is drug-resistant tuberculosis.
Further, the above-mentioned drug is an anti-mycobacterium tuberculosis drug, preferably, the mycobacterium tuberculosis is drug-resistant mycobacterium tuberculosis.
The invention has the beneficial effects that: the compound has excellent anti-mycobacterium tuberculosis activity, is used as a novel DprE1 enzyme inhibitor, has controllable toxicity, excellent anti-tuberculosis activity and pharmacokinetic property, and has very good clinical application prospect.
In the present invention, "substituted" means that 1, 2 or more hydrogen atoms in a molecule are replaced by other different atoms or molecules, including 1, 2 or more substitutions on a co-or an ectopic atom in the molecule.
In the present invention, the minimum and maximum values of the carbon atom content in the hydrocarbon group are represented by a prefix, and for example, the C1 to C6 alkyl group or the C1 to C6 alkyl group means a C1, C2, C3, C4, C5, C6 alkyl group, that is, a straight-chain or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, hexyl, and the like. Similarly, C1-C6 alkoxy refers to C1, C2, C3, C4, C5, C6 alkoxy.
In the present invention, "salts" are acidic and/or basic salts formed with inorganic and/or organic acids and/or bases of a compound or stereoisomers thereof, and also include zwitterionic salts (inner salts), and also include quaternary ammonium salts, such as alkylammonium salts. These salts may be obtained directly in the final isolation and purification of the compounds. Or by mixing the compound, or a stereoisomer thereof, with a suitable amount (e.g., equivalent) of an acid or base. These salts may be obtained by precipitation in solution and collected by filtration, or recovered after evaporation of the solvent, or by lyophilization after reaction in an aqueous medium. The salts of the present invention may be metal ion salts (sodium, potassium, etc.) of the compound as the hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoric, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate salts.
In the present invention, "solvate thereof" means a compound forms a solvate with a solvent, wherein the solvent includes (but is not limited to): water, ethanol, methanol, isopropanol, propylene glycol, tetrahydrofuran, and dichloromethane.
In the present invention, "pharmaceutically acceptable" means that the carrier, cargo, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients comprising the pharmaceutical dosage form, and physiologically compatible with the recipient.
"halogen" is fluorine, chlorine, bromine or iodine.
"alkyl" is a hydrocarbon radical containing few hydrogen atoms in the alkane molecule, e.g. methyl-CH 3 ethyl-CH 3 CH 2 Propyl, isopropyl, etc.
"aryl" refers to an all-carbon monocyclic or fused polycyclic group having a conjugated pi-electron system, e.g., phenyl, naphthyl.
"aromatic heterocyclic" refers to a single ring or fused multiple rings containing one to more heteroatoms with conjugated pi-electron systems. Containing at least one ring heteroatom selected from N, O or S, the remaining ring atoms being C, and having a fully conjugated pi-electron system. Such as a benzopyrazinyl group.
"aromatic heterocyclic group" refers to a group formed by the aryl or aromatic heterocyclic group described above sharing two adjacent carbon atoms or heteroatoms with another cyclic structure.
"heterocycle" refers to a saturated or unsaturated cyclic hydrocarbon, which may be monocyclic or polycyclic, and which carries at least one ring heteroatom (including but not limited to O, S or N) with the remainder being C. For example, a "3-to 8-membered heterocyclic ring" refers to a heterocyclic ring having 3 to 8 total carbon atoms and heteroatoms.
"cycloalkyl" refers to a saturated cyclic hydrocarbon substituent; the cyclic hydrocarbon may be a single ring or multiple rings. For example, "3-8 membered cycloalkyl" refers to cycloalkyl groups having 3 to 8 carbon atoms.
"heterocycloalkyl" refers to a saturated cyclic hydrocarbon substituent; the cyclic hydrocarbon may be monocyclic or polycyclic and carry at least one ring heteroatom (including but not limited to O, S or N). For example, "3-to 8-membered heterocyclic group" means a heterocyclic group having 3 to 8 total carbon atoms and hetero atoms.
"bridged ring hydrocarbons" can be divided into bicyclic bridged ring hydrocarbons and polycyclic bridged ring hydrocarbons. Bicyclic bridged ring hydrocarbons are composed of two alicyclic rings sharing more than two carbon atoms; polycyclic bridged ring hydrocarbons are composed of three or more alicyclic rings sharing two or more carbon atoms. "bridged cyclic hydrocarbon" is a hydrocarbon group in which one hydrogen atom is eliminated from the molecule of the bridged cyclic hydrocarbon; the "polycyclic hydrocarbon group" is a hydrocarbon group in which one hydrogen atom is omitted from the molecule of the polycyclic hydrocarbon.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Detailed Description
The raw materials and equipment used in the invention are all known products and are obtained by purchasing commercial products.
Example 1,
Compound A1 5- ((1- (4-chloro-2, 6-difluorophenyl) -4-hydroxypiperidin-4-yl) methoxy) -3, 4-dihydroquinolin-2 (1H) -one
The synthetic route for compound A1 is as follows:
the first step:
250mL of dry tetrahydrofuran was added to a three-necked flask, and raw material 1 (28.23 g,200 mmol) and raw material 2 (35.56 g,240 mmol) were dissolved therein, and the mixed system was cooled to 0℃with an ice-salt bath. 110mL of a sodium hexamethyldisilazide solution having a concentration of 2mol/L was slowly dropped into the constant pressure dropping funnel. The reaction was exothermic and the dropping rate was controlled to maintain the reaction temperature at 0-2 ℃. After the dripping is finished, the reaction mixture is kept at 0 ℃ and stirred for 10min, then the ice salt bath is removed, the temperature of the ice salt bath is naturally raised to room temperature, and the reaction mixture is stirred at the room temperature for 3h. TLC monitored the completion of the reaction, the reaction was swirled under reduced pressure to remove most of the solvent, ice water was added to the obtained residue, saturated aqueous citric acid solution was slowly added to carefully adjust the system to neutrality, and after three extractions with dichloromethane were performed, the organic phases were combined and washed with water and saturated brine in this order. The organic phase was separated and dried over anhydrous sodium sulfate, suction filtered and spin-dried, and purified by column chromatography to give the target intermediate 3.2g (yield 84%) as a pale yellow oil.
And a second step of:
into a two-necked flask, 135mL of concentrated sulfuric acid was added, and the sulfuric acid was cooled to 0℃with an ice-salt bath. Intermediate 3 (43.0 g,167 mmol) was dissolved in 40mL of methylene chloride, the resulting solution was slowly added dropwise to the above sulfuric acid solution via a dropping funnel over a period of 30min, and the dropping speed was controlled so that the reaction solution temperature was maintained at 0-5 ℃. After the dripping is finished, the reaction mixture is kept at 0 ℃ and stirred for 10min, then the ice salt bath is removed, the temperature of the ice salt bath is naturally raised to room temperature, and the reaction mixture is stirred at the room temperature for 2h. TLC monitored the completion of the reaction, the reaction was swirled off the vast majority of the low boiling solvent dichloromethane at 30 ℃ under reduced pressure, and the resulting residue was added to crushed ice. The mixture was stirred, the solid was allowed to precipitate in a large amount, the precipitate was allowed to stand for 20min, and the solid was filtered off with a separator funnel. The solids were transferred to a beaker and washed thoroughly with water, and the filter cake was brought to near pale yellow to off-white when the filtrate pH was near 7. The cake was taken out and dried in a vacuum oven with phosphorus pentoxide to give 28.7g (yield: 89%) of intermediate 4 as a pale yellow solid.
And a third step of:
intermediate 4.0 g was dissolved in 100mL of glacial acetic acid, and 4.6g of 10% palladium on carbon was added thereto after stirring and dissolution. After 5 times of nitrogen substitution, hydrogen substitution is carried out again, and the mixture is heated to 110 ℃ in a hydrogen atmosphere to react for 3d. After the TLC detection reaction is finished, the acetic acid solvent is distilled off under reduced pressure, the reaction system is diluted by PE: EA=2:1, diatomite is used for suction filtration, and sodium bicarbonate or sodium carbonate aqueous solution is added after the filtrate is dried in a spinning way to adjust the pH of the system to be about 7. The mixture is sonicated for 10min, the filter cake is filtered off with suction and washed with water several times. The filter cake was filtered off with suction and dried, and then rinsed several times with DCM to give a filtrate. The filtrate was dried by spin-drying and separated by silica gel column chromatography to give intermediate 5.6 g, yield 92.9%.
Fourth step:
21.0g of intermediate 5 was weighed, dissolved in 300mL of dry dichloromethane, cooled to-15℃in a cold bath at-30℃and 400mL of BBr was slowly added dropwise under these conditions 3 . The dropping speed is controlled to keep the system temperature below-10 ℃. After the addition, the stirring is carried out for 30min at low temperature, the cold bath is removed, the reaction system is naturally warmed to room temperature, and the stirring is carried out for 3h. TLC monitoring showed complete reaction, the system was spun down at room temperature under reduced pressure to remove solvent and low boilers, the residue was added to 200mL of crushed ice and stirred until the crushed ice was completely dissolved. Dichloromethane was added for extraction and the solution was separated. The aqueous phase was extracted three more times with dichloromethane and the organic phases were combined and washed with water, saturated brine. The organic phase was separated and dried over anhydrous sodium sulfate, suction filtered and spin-dried to give a filtrate, which was purified by column chromatography to give 6.2g of a white solid intermediate in 83% yield.
Fifth step:
intermediate 6 (100 mg,0.55 mmol) was dissolved in 6mL anhydrous DMF, anhydrous potassium carbonate (114 mg, 0.8235 mmol) was added, and after stirring at room temperature for 5min, raw material 7 (171 mg,0.66 mmol) was slowly added and the temperature was raised to 80℃for reaction for 6h. TLC monitoring reaction completion, cooling the reaction liquid to room temperature, adding a proper amount of ice water, extracting with ethyl acetate three times, combining organic phases, washing with water, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, and further separating with a silica gel chromatographic column to obtain the target compound A1, wherein the yield is 10 percent, and the pale yellow solid is 24 mg. 1 H NMR(400MHz,DMSO-d 6 )δ10.00(s,1H),7.34–7.19(m,2H),7.00(t,J＝9.7Hz,1H),6.58(dd,J＝9.1,3.7Hz,1H),4.69(s,1H),3.77(s,2H),3.38(m,J＝10.5,9.1,4.6Hz,2H),3.03–2.87(m,4H),2.46(s,2H),1.79(dt,J＝12.3,6.4Hz,2H),1.63(d,J＝12.9Hz,2H).HR-MS:m/z 463.1015(M+Na) + .
EXAMPLE 2,
Compound A2 5- ((1- (4-chloro-2, 6-difluorophenyl) -4-hydroxypiperidin-4-yl) methoxy) -3, 4-dihydroquinolin-2 (1H) -one
Referring to the synthesis method of the compound A1, the raw material 1 is changed into 3-methoxy aniline to obtain the compound A2, which is a white solid with a yield of 15%. 1 H NMR(400MHz,DMSO-d 6 )δ10.01(s,1H),7.26(d,J＝8.8Hz,2H),7.07(t,J＝8.1Hz,1H),6.59(d,J＝8.2Hz,1H),6.48(d,J＝7.9Hz,1H),4.69(s,1H),3.78(s,2H),3.36(d,J＝12.0Hz,2H),2.97(d,J＝11.7Hz,2H),2.87(t,J＝7.7Hz,2H),2.42(dd,J＝8.4,6.9Hz,2H),1.81(dt,J＝12.4,6.4Hz,2H),1.63(d,J＝12.8Hz,2H).HR-MS:m/z 445.1107(M+Na) + .
EXAMPLE 3,
Compound A3 4- ((1- (4-chloro-2, 6-difluorophenyl) -4-hydroxypiperidin-4-yl) methoxy) quinolin-2 (1H) -one
The compound A3 is obtained by taking 4-hydroxyquinoline-2 (1H) -ketone and a raw material 7 as raw materials and referring to a fifth step of a synthesis method of the compound A1, and the yield is 20 percent. 1 H NMR(400MHz,DMSO-d 6 )δ11.33(s,1H),7.95(d,J＝8.1Hz,1H),7.51(t,J＝7.6Hz,1H),7.28(d,J＝8.7Hz,2H),7.18(t,J＝7.7Hz,1H),5.87(s,1H),4.89(s,1H),3.95(s,2H),3.41(d,J＝11.4Hz,2H),3.01(d,J＝11.5Hz,2H),1.87–1.66(m,4H).HR-MS:m/z443.0947(M+Na) + .
EXAMPLE 4,
Compound A4 4- ((1- (4-chloro-2, 6-difluorophenyl) -4-hydroxypiperidin-4-yl) methoxy) -8-fluoroquinolin-2 (1H) -one
8-fluoro-4-hydroxyquinolin-2 (1H) -one and 7 are used as raw materialsReferring to the fifth synthesis method of the compound A1, the compound A4 is obtained as a pale yellow solid with a yield of 18%. 1 H NMR(400MHz,DMSO-d 6 )δ11.38(s,1H),7.79(d,J＝8.1Hz,1H),7.44(dd,J＝11.1,8.0Hz,1H),7.28(d,J＝8.8Hz,2H),7.18(td,J＝8.1,4.9Hz,1H),4.92(s,1H),3.97(s,2H),3.00(d,J＝11.5Hz,2H),2.00(q,J＝7.3Hz,2H),1.76(q,J＝13.3,12.0Hz,4H).
EXAMPLE 5,
Compound A5N- (3- ((1- (4-chloro-2, 6-difluorophenyl) -4-hydroxypiperidin-4-yl) methoxy) phenyl) -2, 2-trifluoro-N-methylacetamide
The compound A5 is obtained by referring to a fifth step of the synthesis method of the compound A1 by taking 2, 2-trifluoro-N- (3-hydroxyphenyl) -N-methylacetamide and 7 as raw materials, and the yield is 15.3 percent. 1 H NMR(400MHz,DMSO-d 6 )δ7.38(t,J＝8.1Hz,1H),7.30–7.21(m,2H),7.13–7.03(m,2H),6.98(d,J＝7.9Hz,1H),4.75(s,1H),3.83(s,2H),3.40(s,3H),3.29(s,2H),2.98(dd,J＝9.8,5.3Hz,2H),1.80(dt,J＝12.4,6.2Hz,2H),1.63(d,J＝12.8Hz,2H).
EXAMPLE 6,
Compound A6 1- (4-chloro-2, 6-difluorophenyl) -4- ((3- (methylamino) phenoxy) methyl) piperidin-4-ol
Compound A5 (23 mg,0.048 mmol) was dissolved in tetrahydrofuran, and an aqueous solution (1 mL) of sodium hydroxide (8 mg,0.19 mmol) was added thereto to react at room temperature for 8 hours. TLC was used to monitor completion of the reaction, a proper amount of water was added, extraction was performed three times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure, followed by separation with a silica gel column chromatography to give the objective compound A6 as a white solid (8 mg) in 43% yield. 1 H NMR(400MHz,DMSO-d 6 )δ7.37–7.19(m,2H),6.96(t,J＝8.0Hz,1H),6.13(dd,J＝8.1,2.2Hz,2H),6.09(t,J＝2.2Hz,1H),5.59(q,J＝5.1Hz,1H),4.63(s,1H),3.70(s,2H),3.38(d,J＝10.9Hz,2H),2.96(d,J＝11.5Hz,2H),2.65(d,J＝5.0Hz,3H),1.80(m,J＝12.6,4.6Hz,2H),1.58(d,J＝12.9Hz,2H).HR-MS:m/z 405.1157(M+Na) + .
EXAMPLE 7,
Compound A7N- (3- ((1- (4-chloro-2, 6-difluorophenyl) -4-hydroxypiperidin-4-yl) methoxy) phenyl) -1- (difluoro-l 3-methyl) -l 2-fluorocarboxamide
The compound A7 is obtained by taking 2, 2-trifluoro-N- (3-hydroxyphenyl) acetamide and 7 as raw materials and referring to a fifth synthesis method of the compound A1, and the yield is 18 percent. 1 H NMR(400MHz,DMSO-d 6 )δ11.21(s,1H),7.36(t,J＝2.2Hz,1H),7.34–7.23(m,4H),6.84(dd,J＝8.0,2.4Hz,1H),4.73(s,1H),3.79(s,2H),2.97(d,J＝11.5Hz,2H),1.80(m,J＝12.7,4.6Hz,2H),1.62(d,J＝12.9Hz,2H),1.24(d,J＝7.9Hz,2H).HR-MS:m/z 487.0815(M+Na) + .
EXAMPLE 8,
Compound A8N- (3- ((1- (4-chloro-2, 6-difluorophenyl) -4-hydroxypiperidin-4-yl) methoxy) phenyl) acetamide
N- (3-hydroxyphenyl) acetamide and 7 are used as raw materials, and the compound A8 is obtained by referring to a fifth step of the synthesis method of the compound A1, and the yield is 18 percent. 1 H NMR(400MHz,DMSO-d 6 )δ9.89(s,1H),7.35(t,J＝2.2Hz,1H),7.26(d,J＝8.9Hz,2H),7.17(t,J＝8.1Hz,1H),7.06(d,J＝8.1Hz,1H),6.63(dd,J＝8.1,2.4Hz,1H),4.70(s,1H),3.74(s,2H),3.38(d,J＝11.5Hz,2H),2.96(d,J＝11.6Hz,2H),2.03(s,3H),1.79(dt,J＝12.4,6.4Hz,2H),1.60(d,J＝12.9Hz,2H).
EXAMPLE 9,
Compound A9 1- (4-chloro-2, 6-difluorophenyl) -4- ((quinoxalin-5-yloxy) methyl) piperidin-4-ol
The quinoxaline-5-alcohol and 7 are used as raw materials, and the compound A9 is obtained by referring to a fifth step of synthesis method of the compound A1, and the yield is 12 percent. 1 H NMR(400MHz,DMSO-d 6 )δ8.95(q,J＝1.9Hz,2H),7.77(t,J＝8.2Hz,1H),7.65(d,J＝8.4Hz,1H),7.34(d,J＝7.8Hz,1H),7.28(d,J＝8.9Hz,2H),4.80(d,J＝7.6Hz,1H),4.04(s,2H),3.42(t,J＝10.8Hz,2H),3.01(d,J＝11.5Hz,2H),1.99(m,J＝12.5,4.8Hz,2H),1.70(d,J＝12.8Hz,2H).HR-MS:m/z 428.0948(M+Na) + .
EXAMPLE 10,
A10 1- (4-chloro-2, 6-difluorophenyl) -4- ((quinoxalin-2-yloxy) methyl) piperidin-4-ol
The compound A10 is obtained by taking 2-hydroxyquinoxaline and 7 as raw materials and referring to a fifth step of synthesis method of the compound A1, and the yield is 15 percent. 1 H NMR(400MHz,DMSO-d 6 )δ8.26(s,1H),7.92(d,J＝8.6Hz,1H),7.81(dd,J＝7.9,1.5Hz,1H),7.61(m,J＝8.7,7.2,1.6Hz,1H),7.40–7.34(m,1H),7.29–7.21(m,2H),4.74(s,1H),4.31(s,2H),3.25(t,J＝11.4Hz,2H),2.93(d,J＝11.5Hz,2H),1.79(m,J＝12.7,4.4Hz,2H),1.61(d,J＝13.1Hz,2H).HR-MS:m/z 428.0951(M+Na) + .
EXAMPLE 11,
Compound A11- (4-chloro-2, 6-difluorophenyl) -4- ((7-methoxy-1, 5-naphthyridin-4-yl) oxy) methyl) piperidin-4-ol
Taking 7-methoxy-1, 5 naphthyridine-4-alcohol and 7 as raw materials, referring to a fifth step of the compound A1, obtaining a compound A11, light yellowSolid, yield 15%. 1 H NMR(400MHz,DMSO-d 6 )δ8.36(d,J＝1.7Hz,1H),7.87(d,J＝7.8Hz,1H),7.77(d,J＝2.4Hz,1H),7.31–7.20(m,2H),6.13(d,J＝7.8Hz,1H),4.83(s,1H),4.28(s,2H),3.98(d,J＝1.2Hz,3H),3.27(d,J＝3.4Hz,2H),2.93(d,J＝11.7Hz,2H),1.81(dd,J＝13.0,8.6Hz,2H),1.48(d,J＝12.6Hz,2H).HR-MS:m/z 436.1234(M+H) + .
EXAMPLE 12,
Compound A12- (4-chloro-2, 6-difluorophenyl) -4- ((3-hydroxyphenyl) (methyl) amino) methyl) piperidin-4-ol
The 3-hydroxy-N-methylaniline and 7 are used as raw materials, and the compound A12 is obtained by referring to the fifth step of the synthesis method of the compound A1, so that the yield of the compound A12 is 10 percent. 1 H NMR(400MHz,DMSO-d 6 )δ8.92(s,1H),7.24(d,J＝9.0Hz,2H),6.90(t,J＝8.1Hz,1H),6.27–6.22(m,1H),6.20(d,J＝2.3Hz,1H),6.02(dd,J＝7.8,2.0Hz,1H),4.43(s,1H),3.24(s,2H),2.93(s,3H),2.89(d,J＝12.0Hz,4H),1.71–1.60(m,2H),1.53(d,J＝12.7Hz,2H).HR-MS:405.1158(M+Na) + .
EXAMPLE 13,
Compound A13 5- ((1- (4-chloro-2, 6-difluorophenyl) -3-hydroxypiperidin-3-yl) methoxy) -3, 4-dihydroquinolin-2 (1H) -one
The synthesis procedure for compound a13 was as follows:
raw material 8 (100 mg,0.614 mmol) was dissolved in 6mL of anhydrous DMF, anhydrous potassium carbonate (127 mg,0.921 mmol) was added, and after stirring at room temperature for 5min, raw material 9 (191 mg,0.7368 mmol) was slowly added and the temperature was raised to 80℃for reaction for 6h. The reaction was monitored by TLC to be complete,the reaction solution was cooled to room temperature, an appropriate amount of ice water was added, extraction was performed three times with ethyl acetate, the organic phases were combined, washed with water, then with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure, and further, the objective compound a13 was isolated as a pale yellow solid 42mg with a silica gel column chromatography in 16% yield. 1 H NMR(400MHz,DMSO-d 6 )δ10.00(s,1H),7.30–7.21(m,2H),7.05(t,J＝8.1Hz,1H),6.57(d,J＝8.3Hz,1H),6.47(d,J＝7.9Hz,1H),4.78(s,1H),3.98(s,2H),3.22(d,J＝11.8Hz,1H),3.03(d,J＝5.6Hz,2H),2.94(d,J＝11.8Hz,1H),2.87–2.75(m,2H),2.38(m,J＝7.7,2.2Hz,2H),1.96–1.87(m,1H),1.77(s,1H),1.63–1.46(m,2H).HR-MS:m/z 445.1109(M+Na) + .
EXAMPLE 14,
Compound A14 1- (4-chloro-2, 6-difluorophenyl) -3- ((quinoxalin-5-yloxy) methyl) piperidin-3-ol
The quinoxaline-5-alcohol and 9 are used as raw materials, and the compound A14 is obtained by referring to a synthesis method of the compound A13, and is a pale yellow solid with the yield of 10%. 1 H NMR(400MHz,DMSO-d 6 )δ8.93(d,J＝1.8Hz,1H),8.89(d,J＝1.9Hz,1H),7.75(t,J＝8.2Hz,1H),7.62(dd,J＝8.4,1.1Hz,1H),7.31(dd,J＝7.9,1.2Hz,1H),7.23–7.14(m,2H),4.87(s,1H),4.26(s,2H),3.37(d,J＝11.9Hz,1H),3.05(d,J＝4.8Hz,2H),3.02(d,J＝11.6Hz,1H),2.14–2.05(m,1H),1.87–1.77(m,1H),1.68–1.51(m,2H).HR-MS:m/z:428.0948(M+Na) + .
EXAMPLE 15,
Compound A15 1- (4-chloro-2, 6-difluorophenyl) -3- ((quinoxalin-2-yloxy) methyl) piperidin-3-ol
2-hydroxyquinoxaline and 9 are used as raw materials, and the compound A15 is obtained by referring to a synthesis method of the compound A13, and is a pale yellow solid with a yield of 13%. 1 H NMR(400MHz,DMSO-d 6 )δ8.59(s,1H),8.01(dd,J＝8.2,1.4Hz,1H),7.83(dd,J＝8.3,1.4Hz,1H),7.75(ddd,J＝8.3,6.9,1.5Hz,1H),7.64(ddd,J＝8.3,7.0,1.5Hz,1H),7.27–7.18(m,2H),4.95(s,1H),4.55(s,2H),3.26(d,J＝11.8Hz,1H),3.06(s,2H),2.98(d,J＝11.8Hz,1H),1.97(d,J＝12.9Hz,1H),1.83–1.73(m,1H),1.63(td,J＝8.7,4.2Hz,1H),1.59–1.48(m,1H).
EXAMPLE 16,
Compound A16 1- (4-chloro-2, 6-difluorophenyl) -3- ((7-methoxy-1, 5-naphthyridin-4-yl) oxy) methyl) piperidin-3-ol
The 7-methoxy-1, 5 naphthyridine-4-alcohol and 9 are used as raw materials, and the compound A16 is obtained by referring to the synthesis method of the compound A13, so that the yield is 17 percent. 1 H NMR(400MHz,DMSO-d 6 )δ8.36(d,J＝2.0Hz,1H),7.87(d,J＝7.8Hz,1H),7.77(d,J＝2.5Hz,1H),7.31–7.17(m,2H),6.13(d,J＝7.8Hz,1H),4.83(s,1H),4.28(s,2H),3.98(d,J＝1.2Hz,3H),3.26(d,J＝12.7Hz,2H),2.93(d,J＝11.7Hz,2H),1.81(dd,J＝13.1,8.6Hz,2H),1.48(d,J＝12.6Hz,2H).
EXAMPLE 17,
Compound A17 5- ((4- ((4-chloro-2, 6-difluorophenyl) amino) -1-hydroxycyclohexyl) methoxy) -8-fluoro-3, 4-dihydroquinolin-2 (1H) -one
The synthesis procedure for compound a17 was as follows:
intermediate 6 (100 mg,0.55 mmol) was dissolved in 6mL anhydrous DMF, anhydrous potassium carbonate (114 mg, 0.8235 mmol) was added, and after stirring at room temperature for 5min, raw material 10 (181 mg,0.66 mmol) was slowly added and the temperature was raised to 80℃for reaction for 6h. The reaction was monitored by TLC to be complete,the reaction solution was cooled to room temperature, a proper amount of ice water was added, extraction was performed three times with ethyl acetate, the organic phases were combined, washed with water, then with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure, and further, the target compound a17 was isolated as a pale yellow solid with a yield of 10% by using a silica gel column. 1 H NMR(400MHz,DMSO-d 6 )δ9.98(s,1H),7.36(d,J＝7.2Hz,2H),6.98(t,J＝9.7Hz,1H),6.53(dd,J＝9.1,3.8Hz,1H),5.76(s,1H),4.46(s,1H),3.67(s,2H),3.57(s,2H),2.88(t,J＝7.6Hz,2H),2.44(t,J＝7.7Hz,2H),2.43–2.31(m,2H),1.66(t,J＝12.4Hz,2H),1.51(d,J＝12.9Hz,2H).HR-MS:m/z 455.1342(M+H) + .
EXAMPLE 18,
Compound A18- ((4- ((4-chloro-2, 6-difluorophenyl) amino) -1-hydroxycyclohexyl) methoxy) quinolin-2 (1H) -one
The 4-hydroxyquinoline-2 (1H) -ketone and 10 are taken as raw materials, and the compound A18 is obtained by referring to a synthesis method of the compound A17, so that the yield is 12 percent. 1 H NMR(400MHz,DMSO-d 6 )δ7.84–7.79(m,1H),7.25(t,J＝7.8Hz,1H),7.16(d,J＝8.0Hz,2H),6.76(d,J＝8.4Hz,1H),6.62(s,2H),6.54(t,J＝7.5Hz,1H),4.70(d,J＝7.9Hz,1H),4.56(s,1H),3.99(s,2H),3.76(m,1H),1.65(m,5H),1.43(m,2H).
EXAMPLE 19,
Compound A19 4, - ((4-chloro-2, 6-difluorophenyl) amino) -1- ((quinoxalin-5-yloxy) methyl) cyclohexan-1-ol
The quinoxaline-5-alcohol and 10 are used as raw materials, and the compound A19 is obtained by referring to a synthesis method of the compound A17, and is a pale yellow solid with the yield of 11%. 1 H NMR(400MHz,DMSO-d 6 )δ9.00–8.86(m,2H),7.76(t,J＝8.1Hz,1H),7.64(d,J＝8.4Hz,1H),7.30(d,J＝7.8Hz,1H),7.18(d,J＝8.1Hz,2H),4.78–4.68(m,1H),4.58(s,1H),3.97(s,2H),3.60–3.37(m,1H),1.71(p,J＝12.5,12.0Hz,7H).HR-MS:m/z 442.1101(M+Na) + .
EXAMPLE 20,
Compound A20- ((4-chloro-2, 6-difluorophenyl) amino) -1- ((quinoxalin-2-yloxy) methyl) cyclohexan-1-ol
2-hydroxyquinoxaline and 10 are used as raw materials, and the compound A20 is obtained by referring to a synthesis method of the compound A17, and is a pale yellow solid with the yield of 10%. 1 H NMR(400MHz,DMSO-d 6 )δ8.61(s,1H),8.01(d,J＝8.2Hz,1H),7.84(dd,J＝8.5,1.5Hz,1H),7.79–7.73(m,1H),7.64(m,J＝8.4,6.9,1.5Hz,1H),7.23–7.13(m,2H),4.77–4.65(m,1H),4.59(s,1H),4.25(s,2H),1.71(t,J＝11.8Hz,6H),1.56(d,J＝12.5Hz,2H).HR-MS:m/z 442.1180(M+Na) + .
EXAMPLE 21,
Compound B1 8-fluoro-5- ((4-hydroxypiperidin-4-yl) methoxy) -3, 4-dihydroquinolin-2 (1H) -one
The synthesis procedure for compound B1 is as follows:
the first step:
intermediate 6 (0.1 g,0.55 mmol) and anhydrous potassium carbonate (0.092 g,0.66 mmol) were dissolved in 4mL DMF and after half an hour of stirring, starting material 11 (0.14 g,0.66 mmol) was added and the reaction was allowed to react at 80℃for 6-8h after completion of the reaction. The reaction was stopped, water was added to the reaction solution, and extraction was performed with ethyl acetate. Drying, drying under reduced pressure, concentrating the organic phase, and separating by silica gel column chromatography. Intermediate 12, 100mg, was obtained in 46% yield.
And a second step of:
intermediate 12 (50 mg,0.275 mmol) was dissolved in methanol, 5mL of concentrated hydrochloric acid was added, and the reaction was completed after 2 hours at room temperature. The reaction mixture was dried by distillation under reduced pressure, a small amount of alkaline water was added thereto, and extraction was performed with ethyl acetate. Drying, concentrating the organic phase under reduced pressure, and separating by silica gel column chromatography to obtain compound B1. A7 (Compound F1) was obtained in a yield of 90% as a white solid (36 mg). 1 H NMR(400MHz,DMSO-d 6 )δ10.03(s,1H),7.07–6.96(m,1H),6.58(dd,J＝9.1,3.7Hz,1H),5.17(s,1H),3.77(s,2H),3.18(t,J＝4.7Hz,2H),3.15–3.07(m,2H),2.91(t,J＝7.6Hz,2H),2.48(s,2H),1.92(m,J＝13.6,4.7Hz,2H),1.69(d,J＝13.9Hz,2H).HR-MS:m/z295.1459(M+H) + .
EXAMPLE 22,
Compound B2 5- ((1- (2, 6-difluoro-4-nitrophenyl) -4-hydroxypiperidin-4-yl) methoxy) -8-fluoro-3, 4-dihydroquinolin-2 (1H) -one
Compound B1 (300 mg,1.02 mmol) was dissolved in 10mL of anhydrous DMF, DIEA (337. Mu.L, 2.04 mmol) was added, and after stirring at room temperature for 5min, 1,2, 3-trifluoro-5-nitrobenzene (143. Mu.L, 1.224 mmol) was slowly added, and the temperature was raised to 55℃and the reaction was continued for 10h. TLC monitoring reaction completion, cooling the reaction solution to room temperature, adding a proper amount of ice water, extracting with ethyl acetate three times, combining organic phases, washing with water, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, and further separating with a silica gel chromatographic column to obtain the target compound B2, 280mg of yellow solid, wherein the yield is 60.8%. 1 H NMR(400MHz,DMSO-d 6 )δ10.00(s,1H),8.06–7.72(m,2H),7.01(t,J＝9.7Hz,1H),6.59(dd,J＝9.1,3.8Hz,1H),4.82(s,1H),3.78(s,2H),3.51(t,J＝12.0Hz,2H),3.34(s,2H),2.91(t,J＝7.5Hz,2H),2.50–2.41(m,2H),1.83(m,J＝12.7,4.5Hz,2H),1.67(d,J＝13.0Hz,2H).HR-MS:m/z 474.1257(M+Na) + .
EXAMPLE 23,
Compound B3 5- ((1- (4-amino-2, 6-difluorophenyl) -4-hydroxypiperidin-4-yl) methoxy) -8-fluoro-3, 4-dihydroquinolin-2 (1H) -one
Compound B2 (75 mg,0.17 mmol) was dissolved in 10mL of methanol, 10% palladium on carbon (19 mg,0.017 mmol) was added, suction filtration was performed under reduced pressure, the reaction system was replaced with hydrogen gas three times, and the reaction was carried out at room temperature under a hydrogen gas atmosphere for 4 hours. TLC monitoring reaction completion, reaction liquid was filtered through celite to remove palladium carbon, filter cake was rinsed three times with methanol, filtrate was concentrated to dryness under reduced pressure, finally compound B3 was separated by silica gel column chromatography, 50mg of white solid was obtained, yield 71%. 1 H NMR(400MHz,DMSO-d 6 )δ7.00(t,J＝9.7Hz,1H),6.58(dd,J＝9.1,3.8Hz,1H),6.20–6.06(m,2H),5.39(s,2H),4.56(s,1H),3.75(s,2H),3.28(d,J＝11.5Hz,2H),2.92(t,J＝7.6Hz,2H),2.77–2.67(m,2H),2.51–2.42(m,2H),1.75(dt,J＝12.1,6.3Hz,2H),1.59(d,J＝12.7Hz,2H).HR-MS:m/z 444.1499(M+Na) + .
EXAMPLE 24,
Compound B4N- (3, 5-difluoro-4- (4- ((8-fluoro-2-oxo-1, 2,3, 4-tetrahydroquinolin-5-yl) oxy) methyl) -4-hydroxypiperidin-1-yl) phenyl) acetamide
Compound B3 (15 mg,0.036 mmol) was dissolved in 5mL of dichloromethane, triethylamine (10. Mu.L, 0.07 mmol) was added, stirred at 0deg.C for 2min, acetyl chloride (4. Mu.L, 0.04 mmol) was slowly added dropwise, stirring was continued at 0deg.C for 30min, and then naturally warmed to room temperature for further reaction for 2h. TLC monitoring reaction completion, vacuum concentrating and spin-drying the reaction liquid, separating by silica gel chromatographic column to obtain compound B4, 19mg white solid, yield 33%. 1 H NMR(400MHz,DMSO-d 6 )δ10.13(s,1H),10.00(s,1H),7.43–7.18(m,2H),7.00(t,J＝9.7Hz,1H),6.58(dd,J＝9.1,3.7Hz,1H),4.65(s,1H),3.76(s,2H),3.37(d,J＝12.2Hz,2H),2.97–2.83(m,4H),2.49–2.44(m,2H),2.03(s,3H),1.80(m,J＝12.5,4.5Hz,2H),1.62(d,J＝12.7Hz,2H).
EXAMPLE 25,
Compound B5N- (3, 5-difluoro-4- (4- ((8-fluoro-2-oxo-1, 2,3, 4-tetrahydroquinolin-5-yl) oxy) methyl) -4-hydroxypiperidin-1-yl) phenyl) -N- (methylsulfonyl) methanesulfonamide
The compound B5 is obtained as a white solid with a yield of 63% by taking the compound B3 and methanesulfonyl chloride as raw materials and referring to the synthesis method of the compound B4. 1 H NMR(400MHz,DMSO-d 6 )δ10.00(s,1H),7.38(d,J＝9.4Hz,2H),7.01(t,J＝9.7Hz,1H),6.59(dd,J＝9.1,3.7Hz,1H),4.74(s,1H),3.78(s,2H),3.54(s,6H),3.43(t,J＝11.7Hz,2H),3.11(d,J＝11.7Hz,2H),2.92(t,J＝7.7Hz,2H),2.46(d,J＝10.9Hz,2H),1.90–1.76(m,2H),1.65(d,J＝12.9Hz,2H).
EXAMPLE 26,
Compound B6 5- ((1- (3, 5-difluoropyridin-4-yl) -4-hydroxypiperidin-4-yl) methoxy) -8-fluoro-3, 4-dihydroquinolin-2 (1H) -one
The compound B1 and 3,4, 5-trifluoropyridine are used as raw materials, and the compound B6 is obtained by referring to a synthesis method of the compound B2, so that the yield is 40 percent. 1 H NMR(400MHz,Chloroform-d)δ8.18–8.08(m,2H),7.62(s,1H),6.93(t,J＝9.4Hz,1H),6.48(dd,J＝9.1,3.9Hz,1H),3.85(s,2H),3.66–3.53(m,2H),3.45(d,J＝12.9Hz,2H),3.01(t,J＝7.7Hz,2H),2.66(dd,J＝8.4,6.9Hz,2H),2.14(s,1H),1.95–1.80(m,4H).HR-MS:m/z 430.1355(M+Na) + .
EXAMPLE 27,
Compound B7, 5-difluoro-4- (4- ((8-fluoro-2-oxo-1, 2,3, 4-tetrahydroquinolin-5-yl) oxy) methyl) -4-hydroxypiperidin-1-yl) benzoic acid methyl ester
The compound B7 is obtained by taking the compound B1 and 3,4, 5-trifluoro methyl benzoate as raw materials and referring to a synthesis method of the compound B2, and the yield is 20 percent. 1 H NMR(400MHz,Chloroform-d)δ7.58(s,1H),7.55–7.47(m,2H),6.93(t,J＝9.4Hz,1H),6.49(dd,J＝9.1,3.9Hz,1H),3.89(s,3H),3.85(s,2H),3.56(t,J＝11.7Hz,2H),3.29(d,J＝12.5Hz,2H),3.02(t,J＝7.7Hz,2H),2.66(dd,J＝8.4,6.9Hz,2H),2.14(s,1H),1.95–1.78(m,4H).HR-MS:m/z 487.1452(M+Na) + .
EXAMPLE 28,
Compound B8 8-fluoro-5- ((4-hydroxy-1-isobutylpiperidin-4-yl) methoxy) -3, 4-dihydroquinolin-2 (1H) -one
Compound B1 (100 mg,0.34 mmol) was dissolved in 4mL of anhydrous DMF, DIEA (222 mg,0.68 mmol) was added, and after stirring at room temperature for 5min bromoisobutane (45. Mu.L, 0.408 mmol) was added, the temperature was immediately raised to 65℃and the reaction was continued for 4h. TLC monitoring reaction completion, cooling the reaction liquid to room temperature, adding a proper amount of ice water, extracting with ethyl acetate three times, combining organic phases, washing with water, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, and further separating with a silica gel chromatographic column to obtain the target compound B8, wherein the yield is 18 percent, and the white solid is 21 mg. 1 H NMR(400MHz,DMSO-d 6 )δ10.00(s,1H),7.01(t,J＝9.7Hz,1H),6.59(dd,J＝9.1,3.7Hz,1H),4.74(s,1H),3.78(s,2H),3.54(s,6H),3.11(d,J＝11.7Hz,2H),2.92(t,J＝7.7Hz,2H),2.45(s,2H),1.88–1.76(m,1H),1.65(d,J＝12.9Hz,2H),1.25(d,J＝8.8Hz,6H).
EXAMPLE 29,
Compound B9 8-fluoro-5- ((4-hydroxy-1- (pentan-3-yl) piperidin-4-yl) methoxy) -3, 4-dihydroquinolin-2 (1H) -one
With compounds B1 and 3-bromoPentane is used as a raw material, and the compound B9 is obtained by referring to a synthesis method of the compound B8, and is white solid with the yield of 19%. 1 H NMR(400MHz,Chloroform-d)δ7.57(s,1H),6.92(t,J＝9.4Hz,1H),6.46(dd,J＝9.1,3.9Hz,1H),5.30(s,1H),4.66(p,J＝6.1Hz,1H),4.01(d,J＝13.2Hz,2H),3.80(s,2H),3.27(t,J＝12.8Hz,2H),3.04–2.88(m,2H),2.64(dd,J＝8.4,7.0Hz,2H),2.04(s,1H),1.74(d,J＝13.3Hz,2H),1.62–1.50(m,4H),1.36–1.19(m,2H),0.90(t,J＝7.4Hz,6H).
EXAMPLE 30,
Compound B10- ((1-cyclopentyl-4-hydroxypiperidin-4-yl) methoxy) -8-fluoro-3, 4-dihydroquinolin-2 (1H) -one
Compound B10 was obtained as a white solid in 21% yield by referring to the synthesis method of compound B8 using compound B1 and bromocyclopentane as raw materials. 1 H NMR(400MHz,Chloroform-d)δ7.61(s,1H),6.84(t,J＝9.4Hz,1H),6.38(dd,J＝9.1,3.9Hz,1H),5.05(tt,J＝6.1,2.7Hz,1H),3.89(s,2H),3.72(s,2H),3.17(t,J＝12.4Hz,2H),2.92(t,J＝7.6Hz,2H),2.57(t,J＝7.7Hz,2H),2.16–1.91(m,1H),1.78(m,J＝16.1,5.3Hz,2H),1.71–1.48(m,8H),1.20(d,J＝11.7Hz,2H).
EXAMPLE 31,
Compound B11- ((1-cyclohexyl-4-hydroxypiperidin-4-yl) methoxy) -8-fluoro-3, 4-dihydroquinolin-2 (1H) -one
The compound B11 is obtained by taking the compound B1 and bromocyclohexane as raw materials and referring to a synthesis method of the compound B8, and the yield is 18 percent. 1 H NMR(400MHz,Chloroform-d)δ7.57(s,1H),6.92(t,J＝9.4Hz,1H),6.46(dd,J＝9.1,3.9Hz,1H),5.30(s,1H),4.66(h,J＝5.8,5.4Hz,1H),4.01(d,J＝13.1Hz,2H),3.80(s,2H),3.27(t,J＝12.8Hz,2H),2.99(t,J＝7.7Hz,2H),2.64(dd,J＝8.4,7.0Hz,2H),2.04(s,1H),1.74(d,J＝13.3Hz,2H),1.61–1.51(m,4H),0.90(t,J＝7.4Hz,8H).
EXAMPLE 32,
Compound B12-fluoro-5- ((4-hydroxy-1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) piperidin-4-yl) methoxy) -3, 4-dihydroquinolin-2 (1H) -one
The compound B12 is obtained by taking the compounds B1 and 4- (2-bromoethyl) tetrahydro-2H-pyran as raw materials and referring to a synthesis method of the compound B8, and the yield is 16 percent. 1 H NMR(400MHz,DMSO-d 6 )δ10.00(s,1H),6.99(t,J＝9.7Hz,1H),6.55(dd,J＝9.1,3.7Hz,1H),4.54(s,1H),3.81(dd,J＝10.9,4.2Hz,2H),3.70(s,2H),3.30–3.20(m,3H),2.90(t,J＝7.6Hz,2H),2.76–2.53(m,4H),2.47–2.29(m,5H),1.70(d,J＝12.9Hz,2H),1.63–1.50(m,3H),1.40(s,1H),1.24(s,1H),1.15(tt,J＝12.1,6.3Hz,2H).HR-MS:m/z 407.2339(M+H) + .
EXAMPLE 33,
Compound B13-fluoro-5- ((4-hydroxy-1- (2-morpholinoethyl) piperidin-4-yl) methoxy) -3, 4-dihydroquinolin-2 (1H) -one
The compound B13 is obtained as white solid with the yield of 12% by taking the compounds B1 and 4- (2-bromoethyl) morpholine as raw materials and referring to the synthesis method of the compound B8. 1 H NMR(400MHz,Chloroform-d)δ7.61(s,1H),6.92(t,J＝9.4Hz,1H),6.45(dd,J＝9.1,3.9Hz,1H),3.87(s,2H),3.78–3.68(m,6H),3.67–3.62(m,1H),3.48(d,J＝11.2Hz,2H),3.15–3.06(m,1H),2.99(dd,J＝8.5,7.0Hz,2H),2.86(t,J＝6.2Hz,2H),2.64(dd,J＝8.5,6.9Hz,2H),2.61–2.52(m,4H),2.38(s,2H),1.91(d,J＝14.2Hz,2H).HR-MS:m/z 408.2292(M+H) + .
EXAMPLE 34,
Compound B14 5- ((1- (4-chloro-2, 6-difluorobenzyl) -4-hydroxypiperidin-4-yl) methoxy) -8-fluoro-3, 4-dihydroquinolin-2 (1H) -one
The compound B14 is obtained by taking the compound B1 and 4-chloro-2, 6-difluorobenzyl bromide as raw materials and referring to a synthesis method of the compound B8, and the yield is 7 percent. 1 H NMR(400MHz,DMSO-d 6 )δ9.98(s,1H),7.23–7.11(m,2H),6.99(t,J＝9.7Hz,1H),6.54(dd,J＝9.1,3.8Hz,1H),4.47(s,1H),3.68(s,2H),2.90(t,J＝7.6Hz,2H),2.57(d,J＝4.1Hz,1H),2.46(dd,J＝8.5,6.9Hz,2H),1.67(t,J＝8.4Hz,6H),1.50(q,J＝12.2,11.1Hz,1H).HR-MS:m/z 477.1189(M+Na) + .
Example 35,
Compound B15- ((1- (4-chloro-2, 6-difluorobenzoyl) -4-hydroxypiperidin-4-yl) methoxy) -8-fluoro-3, 4-dihydroquinolin-2 (1H) -one
4-chloro-2, 6-difluorobenzoic acid (25. Mu.L, 0.21 mmol) was dissolved in 8mL of anhydrous DMF, DIEA (75. Mu.L, 0.42 mmol), HATU (88 mg,0.231 mmol) were added sequentially, stirred at ambient temperature for 10min, then Compound B1 (74 mg,0.252 mmol) was added and the reaction was continued at ambient temperature for 2h. TLC monitoring the reaction completion, adding a proper amount of water, extracting with ethyl acetate three times, combining the organic phases, washing with water, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, further separating with a silica gel chromatographic column to obtain the target compound B15, 62mg of white solid, yield 64%. 1 H NMR(400MHz,Chloroform-d)δ7.62(s,1H),7.01(m,J＝7.2,6.2,2.2Hz,2H),6.92(t,J＝9.4Hz,1H),6.45(dd,J＝9.1,3.9Hz,1H),4.66(dt,J＝13.4,3.3Hz,1H),3.93–3.71(m,2H),3.56(m,J＝12.9,3.3Hz,1H),3.39(d,J＝13.5Hz,1H),3.30(m,J＝12.9,3.3Hz,1H),2.98(t,J＝7.7Hz,2H),2.64(t,J＝7.7Hz,2H),2.19(s,1H),1.89(dd,J＝13.7,2.9Hz,1H),1.82–1.73(m,2H),1.72–1.65(m,1H).HR-MS:m/z 491.0961(M+Na) + .
EXAMPLE 36,
Compound B16 5- ((1- ((3 r,5r,7 r) -adamantane-1-carbonyl) -4-hydroxypiperidin-4-yl) methoxy) -8-fluoro-3, 4-dihydroquinolin-2 (1H) -one
The compound B16 is obtained by taking adamantanecarboxylic acid and the compound B1 as raw materials and referring to a synthesis method of the compound B15, and the yield is 58 percent. 1 H NMR(400MHz,Chloroform-d)δ7.67(s,1H),6.92(t,J＝9.4Hz,1H),6.45(dd,J＝9.1,3.9Hz,1H),4.44–4.25(m,2H),3.79(s,2H),3.29(t,J＝12.7Hz,2H),2.99(dd,J＝8.4,6.9Hz,2H),2.65(dd,J＝8.5,6.9Hz,2H),2.08–1.98(m,9H),1.98–1.90(m,1H),1.78(d,J＝13.2Hz,5H),1.65(dt,J＝13.1,6.6Hz,4H).
EXAMPLE 37,
The compound C1N- (5- (((3R, 4R) -1- (4-chloro-2, 6-difluorophenyl) -3, 4-dihydroxypiperidin-4-yl) methoxy) -2-fluorophenyl) -1- (difluoro-l 3-methyl) -l 2-fluorocarboxamide
The synthetic route for compound C1 is as follows:
the first step:
raw material 13 (48 g,195.40 mmol), (S) -5- (pyrrolidin-2-yl) -1H-tetrazole (5.44 g,39.08 mmol) and anhydrous sodium acetate (3.21 g,39.08 mmol) were dissolved in 200mL anhydrous DMF and cooled to-40℃N 2 A solution of 3/4 nitronitrobenzene (20.93 g,195.40 mmol) in DMF (300 mL) was added under protection, the reaction system was taken under N 2 The reaction is carried out for 4 hours at the temperature of minus 30 ℃ under protection. Then adding the rest 1/4 nitrobenzene, and N at-30 to-40 DEG C 2 The reaction was continued for 6h under protection. Adding saturated ammonium chloride aqueous solution, extracting with methyl tert-butyl ether twice, mixing organic phases, washing with saturated saline solution, and noDrying with sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain a reaction intermediate. The reaction intermediate was dissolved in methanol (240 mL), the reaction system was cooled to-10℃and anhydrous copper sulfate (15.59 g,97.70 mmol) was added thereto, followed by further reaction for 2 hours. TLC was used to monitor completion of the reaction, the reaction mixture was diluted with a suitable amount of water, extracted three times with methyl tert-butyl ether, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure, followed by separation through a silica gel column to give intermediate 14, 13.1g of a brown oil, yield 26%.
And a second step of:
intermediate 14 (12 g,45.86 mmol) and trimethylsulfoxide iodide (13.12 g,59.62 mmol) were dissolved in dimethyl sulfoxide (145 mL), N 2 Sodium tert-butoxide (5.73 g,59.62 mmol) was added under protection and stirred at ambient temperature for 20min. TLC monitoring reaction completion, adding appropriate amount of water, extracting with ethyl acetate three times, combining organic phases, washing with water, washing with saturated saline water, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, further separating the racemate compound with a silica gel chromatographic column, separating the racemate compound with a chiral column to obtain intermediate 15,3.6g of yellow solid with a yield of 29%.
And a third step of:
raw material 16 (60 mg,0.27 mmol) was dissolved in 5mL anhydrous DMF, anhydrous potassium carbonate (75 mg,0.54 mmol) was added, and after stirring at room temperature for 5min intermediate 15 (82 mg,0.297 mmol) was slowly added and the temperature was raised to 80℃for reaction for 6h. TLC monitoring reaction completion, cooling the reaction solution to room temperature, adding an appropriate amount of ice water, extracting with ethyl acetate three times, combining organic phases, washing with water, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, further separating with a silica gel chromatographic column to obtain the target compound C1, 10mg brown oily substance, yield 7%. 1 H NMR(400MHz,DMSO-d 6 )δ8.93(s,1H),7.31–7.21(m,2H),6.77(dd,J＝11.8,8.6Hz,1H),6.23(dd,J＝7.7,2.8Hz,1H),5.88(dt,J＝8.6,3.2Hz,1H),5.07–4.83(m,2H),4.36(s,1H),3.64–3.49(m,1H),3.31–3.19(m,2H),3.18–3.09(m,2H),2.94(dd,J＝11.0,5.0Hz,1H),2.84(d,J＝11.6Hz,1H).HR-MS:m/z425.0871(M-C 2 F 3 O) + .
EXAMPLE 38,
Compound C2N- (3- (((3R, 4R) -1- (4-chloro-2, 6-difluorophenyl) -3, 4-dihydroxypiperidin-4-yl) methoxy) phenyl) -1- (difluoro-l 3-methyl) -l 2-fluorocarboxamide
The compound C2 is obtained by a third step of synthesis method of the compound C1 by taking 2, 2-trifluoro-N- (3-hydroxyphenyl) acetamide and an intermediate 15 as raw materials, and the yield is 8 percent. 1 H NMR(400MHz,DMSO-d6)δ8.87(s,1H),7.25(d,J＝8.8Hz,2H),6.81(t,J＝8.0Hz,1H),6.13(d,J＝2.1Hz,1H),6.08(d,J＝2.3Hz,1H),5.94(dd,J＝7.9,2.1Hz,1H),5.22(t,J＝6.0Hz,1H),4.74(s,1H),4.23(s,1H),3.58(s,1H),3.31–3.21(m,1H),3.16(t,J＝10.0Hz,2H),3.01(dd,J＝13.0,5.2Hz,1H),2.93(d,J＝7.9Hz,1H),2.84(d,J＝11.0Hz,1H).
EXAMPLE 39,
Compound C3 5- ((3R, 4R) -1- (4-chloro-2, 6-difluorophenyl) -3, 4-dihydroxypiperidin-4-yl) methoxy) -3, 4-dihydroquinolin-2 (1H) -one
The compound C3, white solid is obtained by referring to a third step of the synthesis method of the compound C1 by taking 5-hydroxy-3, 4-dihydroquinolin-2 (1H) -one and an intermediate 15 as raw materials, wherein the yield is 20%. 1 H NMR(400MHz,DMSO-d 6 )δ10.02(s,1H),7.31–7.23(m,2H),7.08(t,J＝8.1Hz,1H),6.59(d,J＝8.3Hz,1H),6.49(d,J＝8.0Hz,1H),4.86(d,J＝6.4Hz,1H),4.51(s,1H),4.04(d,J＝8.8Hz,1H),3.75(dt,J＝11.0,5.6Hz,1H),3.68(d,J＝8.8Hz,1H),3.39–3.31(m,1H),3.21(t,J＝10.7Hz,1H),2.97(dd,J＝11.0,5.1Hz,1H),2.92–2.80(m,3H),2.43(t,J＝7.7Hz,2H),1.92(m,J＝13.0,4.8Hz,1H),1.74–1.59(m,1H).、
EXAMPLE 40,
Compound C4 7- ((3R, 4R) -1- (4-chloro-2, 6-difluorophenyl) -3, 4-dihydroxypiperidin-4-yl) methoxy) -4-fluoro-1, 1a,3,7 b-tetrahydro-2H-cyclopropa [ C ] quinolin-2-one
With 4-fluoro-7-hydroxy-1, 1a,3,7 b-tetrahydro-2H-cyclopropa [ c ]]Quinoline-2-one and intermediate 15 are used as raw materials, and the compound C4 is obtained by referring to a third step of synthesis method of the compound C1, and is a pale yellow solid with the yield of 20%. 1 H NMR(400MHz,DMSO-d 6 )δ9.76(s,1H),7.31–7.23(m,2H),7.02–6.94(m,1H),6.57(m,J＝9.3,5.9,3.8Hz,1H),4.87(dd,J＝11.7,6.5Hz,1H),4.54(d,J＝4.5Hz,1H),4.07(t,J＝8.3Hz,1H),3.81–3.69(m,2H),3.35(d,J＝11.6Hz,1H),3.26–3.17(m,1H),2.96(dd,J＝11.0,5.1Hz,1H),2.90(d,J＝8.3Hz,1H),2.78–2.67(m,1H),2.04(dt,J＝8.3,4.4Hz,1H),1.99–1.86(m,1H),1.73(dd,J＝19.4,13.5Hz,1H),1.65(m,J＝9.2,4.3Hz,1H),0.57(p,J＝4.5Hz,1H).HR-MS:m/z 491.0961(M+Na) + .
EXAMPLE 41,
Compound D1 tert-butyl (4R) -4- ((8-fluoro-2-oxo-1, 2,3, 4-tetrahydroquinolin-5-yl) oxy) methyl) -3, 4-dihydroxypiperidine-1-carboxylate
The synthetic route for compound D1 is as follows:
the first step:
raw material 17 (1 g,4.69 mmol) was dissolved in toluene (15 mL), triethylamine (716. Mu.L, 5.16 mmol) was added at room temperature, followed by slow dropwise addition of sulfoxide chloride (375. Mu.L, 5.16 mmol), stirring was continued at room temperature for 5min, and then the temperature was raised to 40℃for reaction 30min. TLC monitored the reaction was complete, ice water was added to the reaction solution, extraction was performed three times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to afford crude intermediate 18, which was used directly in the next reaction without further purification.
And a second step of:
intermediate 6 (412 mg,2.265 mmol) was dissolved in anhydrous DMF (15 mL), anhydrous potassium carbonate (785 mg,5.67 mmol) was added, and after stirring at room temperature for 5min intermediate 18 (4.69 mmol) was added and immediately warmed to 80℃for 4h. TLC monitored the reaction to completion, cooled the reaction to room temperature, added with an appropriate amount of ice water, extracted three times with ethyl acetate, combined with the organic phases, washed with water, then with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and further separated with a silica gel column to give intermediate 19, 731mg of a white solid in 86% yield.
And a third step of:
AD-mix beta (935 mg,1.2 mmol) and methanesulfonamide (77 mg,0.8 mmol) were added sequentially to a mixed solution of water (10 mL) and tert-butanol (10 mL), stirred at room temperature for 10min, cooled to 0℃and then added with intermediate 19 (300 mg,0.8 mmol) and reacted at 0℃for 15h. TLC monitoring the reaction completion, adding anhydrous sodium sulfite (504 mg,4 mmol), stirring at normal temperature for 30min, adding water for dilution, extracting with ethyl acetate three times, combining organic phases, washing with 1M NaOH, washing with water, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, further separating with silica gel chromatographic column to obtain compound D1, 189mg of white solid with a yield of 58%. 1 H NMR(400MHz,Chloroform-d)δ7.65(s,1H),6.91(t,J＝9.4Hz,1H),6.48(dd,J＝9.1,3.9Hz,1H),4.20–3.72(m,4H),3.19–3.03(m,1H),2.95(t,J＝7.7Hz,3H),2.63(q,J＝8.0,7.1Hz,3H),1.66(s,2H),1.47(s,9H).
EXAMPLE 42,
Compound D2 5- ((3R, 4R) -1- (2, 6-difluoro-4-nitrophenyl) -3, 4-dihydroxypiperidin-4-yl) methoxy) -8-fluoro-3, 4-dihydroquinolin-2 (1H) -one
The synthesis procedure for compound D2 was as follows:
the first step:
compound D1 (335 mg,0.82 mmol) was dissolved in dichloromethane (8 mL), trifluoroacetic acid (2 mL) was added, and the reaction was stirred at room temperature for 4h. After the TLC monitoring, the reaction solution was concentrated to dryness under reduced pressure at 40℃and dissolved with an appropriate amount of dichloromethane, concentrated to dryness under reduced pressure, and the operation was repeated 3 times to obtain the crude product intermediate 20, which was directly used for the next reaction without further purification.
And a second step of:
intermediate 20 (300 mg,0.97 mmol) was dissolved in 10mL anhydrous DMF, DIEA (344. Mu.L, 1.94 mmol) was added, and after stirring at room temperature for 5min 1,2, 3-trifluoro-5-nitrobenzene (starting material 21) (136. Mu.L, 1.164 mmol) was slowly added and the temperature was raised to 55deg.C and the reaction continued for 10h. TLC monitoring reaction completion, cooling the reaction solution to room temperature, adding an appropriate amount of ice water, extracting with ethyl acetate three times, combining organic phases, washing with water, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, further separating with a silica gel chromatographic column to obtain the target compound D2, 220mg of yellow solid, and the yield is 50%. 1 H NMR(400MHz,DMSO-d 6 )δ10.01(s,1H),8.06–7.92(m,2H),7.02(t,J＝9.7Hz,1H),6.58(dd,J＝9.1,3.7Hz,1H),5.01(d,J＝6.3Hz,1H),4.66(s,1H),4.04(d,J＝8.8Hz,1H),3.76(dt,J＝8.8,6.5Hz,1H),3.70(d,J＝8.8Hz,1H),3.45(t,J＝12.3Hz,1H),3.26(d,J＝17.0Hz,2H),2.87(m,J＝7.6,4.6Hz,2H),2.50–2.42(m,3H),1.94(m,J＝13.2,4.8Hz,1H),1.78–1.69(m,1H).
EXAMPLE 43,
Compound D3 5- ((3R, 4R) -1- (4-amino-2, 6-difluorophenyl) -3, 4-dihydroxypiperidin-4-yl) methoxy) -8-fluoro-3, 4-dihydroquinolin-2 (1H) -one
The compound D2 is used as a raw material, and the compound D3 is obtained by referring to a synthesis method of the compound B3, so that a white solid is obtained, and the yield is 60%. 1 H NMR(400MHz,DMSO-d 6 )δ10.00(s,1H),7.01(t,J＝9.7Hz,1H),6.57(dd,J＝9.1,3.7Hz,1H),6.14(d,J＝11.5Hz,2H),5.41(s,2H),4.69(d,J＝6.5Hz,1H),4.36(s,1H),3.99(d,J＝8.7Hz,1H),3.68(m,J＝9.9,9.0,4.8Hz,2H),3.31–3.21(m,1H),3.15(t,J＝10.4Hz,1H),2.93–2.86(m,1H),2.71(dd,J＝10.4,5.1Hz,1H),2.47(d,J＝7.8Hz,4H),1.85(dt,J＝12.8,6.9Hz,1H).
EXAMPLE 44,
Compound D4N- (3, 5-difluoro-4- ((3R, 4R) -4- ((8-fluoro-2-oxo-1, 2,3, 4-tetrahydroquinolin-5-yl) oxy) methyl) -3, 4-dihydroxypiperidin-1-yl) phenyl) acetamide
The compound D3 is used as a raw material, and the compound D4 is obtained by referring to a synthesis method of the compound B4, so that the yield of the white solid is 65%. 1 H NMR(400MHz,DMSO-d 6 )δ10.13(s,1H),10.01(s,1H),7.24(d,J＝11.3Hz,2H),7.02(t,J＝9.7Hz,1H),6.58(dd,J＝9.1,3.8Hz,1H),4.80(d,J＝6.5Hz,1H),4.46(s,1H),4.01(d,J＝8.8Hz,1H),3.78–3.65(m,2H),3.20(t,J＝10.5Hz,1H),2.89(dd,J＝7.5,5.1Hz,2H),2.80(d,J＝11.0Hz,1H),2.47(d,J＝7.9Hz,4H),2.03(s,3H),1.95–1.85(m,1H).
EXAMPLE 45,
Compound D5 5- ((3R, 4R) -1- (3, 5-difluoropyridin-4-yl) -3, 4-dihydroxypiperidin-4-yl) methoxy) -8-fluoro-3, 4-dihydroquinolin-2 (1H) -one
The intermediate 20 and 3,4, 5-trifluoropyridine are used as raw materials, and the compound D5 is obtained by referring to a second step of synthesis method of the compound D2, and the yield is 25 percent. 1 H NMR(400MHz,DMSO-d 6 )δ10.01(s,1H),8.26(s,2H),7.02(t,J＝9.7Hz,1H),6.58(dd,J＝9.1,3.7Hz,1H),5.76(s,1H),4.99(d,J＝6.3Hz,1H),4.64(s,1H),4.03(d,J＝8.8Hz,1H),3.76(dd,J＝10.6,5.4Hz,1H),3.69(d,J＝8.8Hz,1H),3.41(t,J＝12.3Hz,1H),3.27(d,J＝11.0Hz,1H),2.87(m,J＝7.6,4.6Hz,2H),2.46(t,J＝7.7Hz,2H),1.92(m,J＝13.0,4.7Hz,1H).HR-MS:m/z 424.1486(M+H) + .
EXAMPLE 46,
Compound D6, 5-difluoro-4- ((3R, 4R) -4- ((8-fluoro-2-oxo-1, 2,3, 4-tetrahydroquinolin-5-yl) oxy) methyl) -3, 4-dihydroxypiperidin-1-yl) benzoic acid methyl ester
The intermediate 20 and 3,4, 5-trifluoro methyl benzoate are used as raw materials, and the compound D6 is obtained by referring to a second step of synthesis method of the compound D2, and the yield is 32 percent. 1 H NMR(400MHz,DMSO-d 6 )δ10.01(s,1H),7.52(d,J＝9.2Hz,2H),7.02(t,J＝9.8Hz,1H),6.68–6.49(m,1H),4.94(d,J＝6.2Hz,1H),4.59(s,1H),4.03(d,J＝8.8Hz,1H),3.83(s,3H),3.75(s,1H),3.68(d,J＝8.6Hz,1H),3.21–3.09(m,1H),2.87(d,J＝7.5Hz,2H),2.50–2.41(m,4H),1.93(t,J＝12.8Hz,1H).
EXAMPLE 47,
Compound D7, 5-difluoro-4- ((3R, 4R) -4- ((8-fluoro-2-oxo-1, 2,3, 4-tetrahydroquinolin-5-yl) oxy) methyl) -3, 4-dihydroxypiperidin-1-yl) -N-methylbenzamide
The synthesis procedure for compound D7 was as follows:
the first step:
compound D6 (200 mg,0.42 mmol) was dissolved in methanol (10 mL), naOH (84 mg,2.1 mmol) was weighed and dissolved in 1mL of water, followed by dropwise addition to the reaction solution, and the temperature was raised to 60℃for reaction for 3 hours. TLC monitored the reaction was complete, the reaction was cooled to room temperature, acidified with 2M hydrochloric acid to pH 5-6 and concentrated to dryness under reduced pressure. Dissolving with a proper amount of mixed solvent of dichloromethane/methanol (10/1), filtering to remove generated NaCl, concentrating the filtrate under reduced pressure, and spin-drying to obtain a crude product intermediate 21, which is directly used for the next reaction without further purification.
And a second step of:
intermediate 21 (0.1 mmol) was dissolved in DMF and DIEA (71. Mu.L, 0.4 mmol), HATU (42 mg.0.11 mmol) and methylamine hydrochloride (10 mg,0.12 mmol) were added sequentially under stirring at normal temperature and reacted for 2h at normal temperature. TLC was used to monitor completion of the reaction, a proper amount of water was added, extraction was performed three times with ethyl acetate, the organic phases were combined, washed with water, then with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure, followed by separation with a silica gel column to give the objective compound D7, 15mg of a white solid in 31% yield. 1 H NMR(400MHz,DMSO-d 6 )δ10.01(s,1H),8.45(q,J＝4.5Hz,1H),7.54–7.45(m,2H),7.02(t,J＝9.7Hz,1H),6.58(dd,J＝9.1,3.7Hz,1H),4.90(s,1H),4.56(s,1H),4.03(d,J＝8.8Hz,1H),3.75(dd,J＝10.4,5.1Hz,1H),3.68(d,J＝8.8Hz,1H),3.24(t,J＝11.1Hz,1H),3.17(s,2H),3.08(dd,J＝28.7,8.6Hz,1H),2.89(m,J＝7.9,7.5,4.8Hz,2H),2.76(d,J＝4.4Hz,2H),2.46(d,J＝7.7Hz,2H),1.93(m,J＝13.1,4.8Hz,1H),1.70(d,J＝13.7Hz,1H).
EXAMPLE 48,
Compound D8, 5-difluoro-4- ((3R, 4R) -4- ((8-fluoro-2-oxo-1, 2,3, 4-tetrahydroquinolin-5-yl) oxy) methyl) -3, 4-dihydroxypiperidin-1-yl) -N-isopropylbenzamide
The intermediate 21 and isopropylamine are used as raw materials, and the compound D8 is obtained by referring to a second step of synthesis method of the compound D7, and is white solid with the yield of 42%. 1 H NMR(400MHz,Chloroform-d)δ8.03(s,2H),7.58(s,1H),7.30–7.27(m,1H),6.93(t,J＝9.3Hz,1H),6.52(dd,J＝9.0,3.9Hz,1H),5.83(s,1H),4.25(d,J＝7.6Hz,1H),4.08–3.95(m,3H),3.54–3.40(m,1H),3.34(d,J＝8.6Hz,2H),3.16(d,J＝12.1Hz,1H),2.97(s,4H),2.89(s,4H),2.69–2.61(m,2H),1.97(d,J＝11.9Hz,2H).
EXAMPLE 49,
Compound D9N-cyclopropyl-3, 5-difluoro-4- ((3R, 4R) -4- ((8-fluoro-2-oxo-1, 2,3, 4-tetrahydroquinolin-5-yl) oxy) methyl) -3, 4-dihydroxypiperidin-1-yl) benzamide
The intermediate 21 and cyclopropylamine are used as raw materials, and the compound D9 is obtained by referring to a second step of synthesis method of the compound D7, and is white solid with the yield of 55%. 1 H NMR(400MHz,DMSO-d 6 )δ10.01(s,1H),8.40(d,J＝4.2Hz,1H),7.50(d,J＝10.0Hz,2H),7.02(t,J＝9.7Hz,1H),6.58(dd,J＝9.1,3.8Hz,1H),4.90(d,J＝6.4Hz,1H),4.55(s,1H),4.09(q,J＝5.2Hz,1H),4.03(d,J＝8.8Hz,1H),3.75(dt,J＝11.1,5.6Hz,1H),3.68(d,J＝8.8Hz,1H),3.24(t,J＝10.9Hz,1H),3.17(d,J＝5.3Hz,2H),3.13–3.00(m,2H),2.88(dd,J＝7.5,4.4Hz,1H),2.82(m,J＝7.8,3.8Hz,1H),2.46(d,J＝7.6Hz,1H),1.93(m,J＝13.0,4.7Hz,1H),1.70(d,J＝13.5Hz,1H),0.69(m,J＝7.1,4.7Hz,2H),0.57–0.49(m,2H).
EXAMPLE 50,
Compound D10- ((3R, 4R) -3, 4-dihydroxy-1-propionylpiperidin-4-yl) methoxy) -8-fluoro-3, 4-dihydroquinolin-2 (1H) -one
The intermediate 20 and propionyl chloride are used as raw materials, and the compound D10 is obtained by referring to the synthesis method of the compound B4, and is white solid with the yield of 30%. 1 H NMR(400MHz,Chloroform-d)δ7.59(s,1H),6.92(t,J＝9.7Hz,1H),6.49(dd,J＝9.1,3.9Hz,1H),4.69–4.32(m,1H),4.02–3.87(m,2H),3.79(d,J＝12.4Hz,1H),3.67(d,J＝13.5Hz,1H),3.47–3.19(m,1H),2.94(td,J＝7.6,3.0Hz,2H),2.88–2.69(m,2H),2.67–2.57(m,2H),2.47–2.31(m,2H),1.91(t,J＝12.4Hz,1H),1.73(ddd,J＝20.4,13.2,5.3Hz,1H),1.16(td,J＝7.4,4.4Hz,3H).
EXAMPLE 51,
Compound D11 5- (((3R, 4R) -1-butyryl-3, 4-dihydroxypiperidin-4-yl) methoxy) -8-fluoro-3, 4-dihydroquinolin-2 (1H) -one
The intermediate 20 and butyryl chloride are used as raw materials, and the compound D11 is obtained by referring to a synthesis method of the compound B4, and is white solid with the yield of 25%. 1 H NMR(400MHz,Chloroform-d)δ7.66(s,1H),6.91(td,J＝9.4,2.4Hz,1H),6.49(dd,J＝9.1,3.9Hz,1H),4.65–4.34(m,1H),4.02–3.86(m,2H),3.80(d,J＝12.6Hz,1H),3.68(d,J＝13.6Hz,1H),3.51–3.37(m,1H),3.26(dd,J＝12.9,10.4Hz,1H),2.93(td,J＝7.5,4.1Hz,2H),2.81(dd,J＝10.2,5.9Hz,1H),2.61(q,J＝7.5Hz,2H),2.34(ddt,J＝10.0,7.1,3.9Hz,2H),1.90(t,J＝13.2Hz,1H),1.66(dt,J＝14.7,6.0Hz,2H),0.97(td,J＝7.4,4.8Hz,3H).
EXAMPLE 52,
Compound D12 5- (((3R, 4R) -1- (2-cyclopropylacetyl) -3, 4-dihydroxypiperidin-4-yl) methoxy) -8-fluoro-3, 4-dihydroquinolin-2 (1H) -one
The intermediate 20 and 2-cyclopropyl acetyl chloride are used as raw materials, and the compound D12 is obtained by referring to a synthesis method of the compound B4, and the yield is 32 percent. 1 H NMR(400MHz,Chloroform-d)δ7.61(s,1H),6.97–6.85(m,1H),6.49(dd,J＝9.1,3.9Hz,1H),4.72–4.34(m,1H),4.01–3.87(m,2H),3.86–3.60(m,2H),3.49–3.20(m,1H),2.94(td,J＝7.6,3.4Hz,2H),2.89–2.71(m,2H),2.62(q,J＝7.4Hz,2H),2.37–2.26(m,2H),1.91(dd,J＝16.4,4.7Hz,1H),1.75(td,J＝13.2,6.9Hz,1H),1.04(d,J＝7.3Hz,1H),0.57(d,J＝7.9Hz,2H),0.19(h,J＝4.7Hz,2H).
EXAMPLE 53,
Compound D13 5- (((3R, 4R) -1- (2-cyclohexylacetyl) -3, 4-dihydroxypiperidin-4-yl) methoxy) -8-fluoro-3, 4-dihydroquinolin-2 (1H) -one
The intermediate 20 and 2-cyclohexyl acetyl chloride are used as raw materials, and the compound D13 is obtained by referring to a synthesis method of the compound B4, and the yield is 22 percent. 1 H NMR(400MHz,Chloroform-d)δ7.62(s,1H),6.92(td,J＝9.5,2.5Hz,1H),6.48(dd,J＝9.1,3.9Hz,1H),4.70–4.35(m,1H),4.01–3.85(m,2H),3.85–3.64(m,2H),3.51–3.18(m,1H),2.93(q,J＝7.3Hz,2H),2.87–2.67(m,2H),2.62(q,J＝7.9Hz,2H),2.25(dd,J＝9.3,6.8Hz,2H),1.89(dd,J＝12.2,9.2Hz,1H),1.81–1.67(m,5H),1.34–1.09(m,5H),1.06–0.85(m,2H).
EXAMPLE 54,
Compound D14 5- ((3R, 4R) -1- (3- ((difluoro-l 3-methyl) -l 2-fluorenyl) propionyl) -3, 4-dihydroxypiperidin-4-yl) methoxy) -8-fluoro-3, 4-dihydroquinolin-2 (1H) -one
The intermediate 20 and 4, 4-trifluoro-butyryl chloride are used as raw materials, and the compound D14 is obtained by referring to the synthesis method of the compound B4, and the yield is 13 percent. 1 H NMR(400MHz,DMSO-d6)δ10.00(s,1H),7.01(t,J＝9.7Hz,1H),6.56(dd,J＝9.1,3.7Hz,1H),5.05(s,1H),4.71(s,1H),4.27(dd,J＝12.0,5.1Hz,1H),4.21–4.09(m,1H),4.06–3.97(m,1H),3.67(t,J＝8.5Hz,2H),3.62–3.46(m,2H),2.98–2.79(m,2H),2.75–2.53(m,2H),2.44(t,J＝7.5Hz,2H),2.38–2.25(m,2H),1.80–1.58(m,2H).
EXAMPLE 55,
Compound D15 5- (((3R, 4R) -3, 4-dihydroxy-1- (propylsulfonyl) piperidin-4-yl) methoxy) -8-fluoro-3, 4-dihydroquinolin-2 (1H) -one
The intermediate 20 and propyl sulfonyl chloride are used as raw materials, and the compound D15 is obtained by referring to a synthesis method of the compound B4, and is white solid with the yield of 28%. 1 H NMR(400MHz,DMSO-d 6 )δ10.01(s,1H),7.01(t,J＝9.7Hz,1H),6.55(dd,J＝9.1,3.8Hz,1H),5.11(d,J＝6.0Hz,1H),4.70(s,1H),4.02(d,J＝8.8Hz,1H),3.67(dd,J＝14.0,7.2Hz,2H),3.47–3.36(m,2H),3.04(m,J＝8.8,7.7,5.0Hz,3H),2.94–2.81(m,3H),2.46(d,J＝15.5Hz,2H),1.81(dd,J＝12.9,4.7Hz,1H),1.74–1.63(m,3H),1.00(t,J＝7.4Hz,2H).HR-MS:439.1315(M+Na) + .
EXAMPLE 56,
Compound D16 5- (((3R, 4R) -1- (2-cyclopentylethyl) -3, 4-dihydroxypiperidin-4-yl) methoxy) -8-fluoro-3, 4-dihydroquinolin-2 (1H) -one
The intermediate 20 and 2-cyclopentyl bromoethane are used as raw materials, and the compound D16 is obtained by referring to the synthesis method of the compound B8, and the yield is 32%. 1 H NMR(400MHz,Chloroform-d)δ7.58(s,1H),6.91(t,J＝9.4Hz,1H),6.49(dd,J＝9.1,3.9Hz,1H),4.03–3.86(m,3H),2.98(td,J＝7.7,4.5Hz,2H),2.82(dd,J＝11.0,4.4Hz,1H),2.61(q,J＝6.6,5.5Hz,3H),2.46–2.36(m,2),2.33(t,J＝10.1Hz,1H),1.88–1.81(m,2H),1.74(dt,J＝14.3,8.9Hz,4),1.66–1.56(m,2),1.56–1.44(m,4H),1.15–1.02(m,2H).
EXAMPLE 57,
Compound D17 5- (((3R, 4R) -1- (2-cyclohexylethyl) -3, 4-dihydroxypiperidin-4-yl) methoxy) -8-fluoro-3, 4-dihydroquinolin-2 (1H) -one
The intermediate 20 and 2-cyclohexyl bromoethane are used as raw materials, and the compound D17 is obtained by referring to a synthesis method of the compound B8, and is white solid with the yield of 37%. 1 H NMR(400MHz,DMSO-d 6 )δ10.00(s,1H),7.00(dd,J＝10.4,9.0Hz,1H),6.54(dd,J＝9.1,3.8Hz,1H),4.60(d,J＝6.7Hz,1H),4.22(s,1H),3.94(d,J＝8.8Hz,1H),3.60(t,J＝7.9Hz,2H),2.86(m,J＝7.6,4.0Hz,2H),2.73–2.61(m,1H),2.46(t,J＝7.7Hz,2H),2.32(dd,J＝10.0,5.7Hz,2H),2.26–2.11(m,1H),2.08(t,J＝10.3Hz,1H),1.76(m,J＝13.1,4.4Hz,1H),1.72–1.52(m,6H),1.32(q,J＝7.3Hz,2H),1.28–1.04(m,4H),0.89(q,J＝10.8,9.7Hz,2H).HR-MS:m/z 421.2498(M+H) + .
EXAMPLE 58,
Compound D18 5- (((3R, 4R) -3, 4-dihydroxy-1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) piperidin-4-yl) methoxy) -8-fluoro-3, 4-dihydroquinolin-2 (1H) -one
The intermediate 20 and 4- (2-bromoethyl) tetrahydro-2H-pyran are used as raw materials, and the compound D18 is obtained by referring to the synthesis method of the compound B8, and the yield is 26 percent. 1 H NMR(400MHz,DMSO-d 6 )δ10.00(s,1H),7.00(t,J＝9.7Hz,1H),6.54(dd,J＝9.1,3.7Hz,1H),4.64(s,1H),4.27(s,1H),3.95(d,J＝8.7Hz,1H),3.86–3.74(m,2H),3.70–3.54(m,3H),3.26(m,J＝11.8,2.1Hz,2H),2.86(m,J＝7.6,4.0Hz,2H),2.74–2.55(m,1H),2.49–2.31(m,4H),2.18(d,J＝37.9Hz,1H),1.78(t,J＝12.9Hz,1H),1.63–1.32(m,6H),1.17(m,J＝16.2,6.7,4.5Hz,3H).HR-MS:m/z423.2296(M+H) + .
EXAMPLE 59,
Compound D19 5- (((3R, 4R) -3, 4-dihydroxy-1- (2-methoxyethyl) piperidin-4-yl) methoxy) -8-fluoro-3, 4-dihydroquinolin-2 (1H) -one
The intermediate 20 and 1-bromo-2-methoxyethane are used as raw materials, and the compound D19 is obtained by referring to a synthesis method of the compound B8, and the yield is 10%. 1 H NMR(400MHz,Chloroform-d)δ7.56(s,1H),6.91(t,J＝9.4Hz,1H),6.49(dd,J＝9.1,3.9Hz,1H),4.07–3.79(m,3H),3.53(t,J＝5.5Hz,2H),3.36(s,3H),2.98(td,J＝7.7,4.3Hz,2H),2.90(dd,J＝10.6,4.3Hz,1H),2.74–2.58(m,5),2.50–2.41(m,1H),2.37(t,J＝10.2Hz,1H),1.86(dd,J＝6.8,4.4Hz,2H).
EXAMPLE 60,
Compound D20- ((3R, 4R) -3, 4-dihydroxy-1- (2- (2-methoxyethoxy) ethyl) piperidin-4-yl) methoxy) -8-fluoro-3, 4-dihydroquinolin-2 (1H) -one
The intermediate 20 and 1-bromo-2- (2-methoxyethoxy) ethane are used as raw materials, and the compound D20 is obtained by referring to a synthesis method of the compound B8, and the yield is 10%. 1 H NMR(400MHz,Chloroform-d)δ7.59(s,1H),6.91(t,J＝9.4Hz,1H),6.49(dd,J＝9.1,3.9Hz,1H),4.02–3.89(m,3H),3.67–3.59(m,4H),3.58–3.53(m,2H),3.39(s,3H),2.99(td,J＝7.6,3.5Hz,2H),2.90(dd,J＝11.1,4.3Hz,1H),2.70(t,J＝5.7Hz,2H),2.62(t,J＝7.7Hz,2H),2.56–2.49(m,1),2.44(t,J＝10.1Hz,1H),1.87(q,J＝4.4Hz,3H).
Example 61,
Compound D21 5- ((3R, 4R) -1- (2-cyclopentylacetyl) -3, 4-dihydroxypiperidin-4-yl) methoxy) -8-fluoro-3, 4-dihydroquinolin-2 (1H) -one
The intermediate 20 and 2-cyclopentyl acetyl chloride are used as raw materials, and the compound D21 is obtained by referring to a synthesis method of the compound B4, and is white solid with the yield of 48%. 1 H NMR(400MHz,Chloroform-d)δ7.59(s,1H),6.90(t,J＝9.5Hz,1H),6.45(dt,J＝9.0,4.4Hz,1H),5.80(d,J＝25.9Hz,1H),4.41(s,2H),4.13(s,1H),4.02(d,J＝3.5Hz,1H),3.76(t,J＝5.7Hz,1H),3.61(t,J＝5.7Hz,1H),3.06–2.93(m,2H),2.64(dd,J＝8.4,6.9Hz,2H),2.38(dd,J＝15.4,7.2Hz,2H),2.26(td,J＝17.3,16.3,8.6Hz,3H),1.86(q,J＝8.5,7.2Hz,2H),1.64–1.47(m,4H),1.17(td,J＝13.3,10.4,6.3Hz,2H).
Example 62,
Compound D22- ((3R, 4R) -1- (butylsulfonyl) -3, 4-dihydroxypiperidin-4-yl) methoxy) -8-fluoro-3, 4-dihydroquinolin-2 (1H) -one
The intermediate 20 and butyl sulfonyl chloride are used as raw materials, and the compound D22 is obtained by referring to a synthesis method of the compound B4, and is white solid with the yield of 62%. 1 H NMR(400MHz,Chloroform-d)δ7.60(s,1H),6.92(t,J＝9.4Hz,1H),6.49(dd,J＝9.1,3.9Hz,1H),4.03–3.90(m,3H),3.78(ddd,J＝11.7,5.4,1.9Hz,1H),3.68–3.60(m,1H),3.16(ddd,J＝12.2,10.3,4.8Hz,1H),3.03–2.89(m,5H),2.72(d,J＝5.9Hz,1H),2.68–2.58(m,3H),1.98–1.90(m,2H),1.87–1.76(m,2H),1.47(h,J＝7.4Hz,2H),0.97(t,J＝7.4Hz,3H).
EXAMPLE 63,
Compound D23 5- ((3R, 4R) -1- ((3-chloropropyl) sulfonyl) -3, 4-dihydroxypiperidin-4-yl) methoxy) -8-fluoro-3, 4-dihydroquinolin-2 (1H) -one
The intermediate 20 and 3-chloropropane sulfonyl chloride are used as raw materials, and the compound D23 is obtained by referring to a synthesis method of the compound B4, and the yield is 44%. 1 H NMR(400MHz,DMSO-d 6 )δ10.00(s,1H),7.01(dd,J＝10.4,9.0Hz,1H),6.54(dd,J＝9.1,3.8Hz,1H),5.12(d,J＝6.0Hz,1H),4.73(d,J＝1.0Hz,1H),4.01(d,J＝8.8Hz,1H),3.75(t,J＝6.5Hz,2H),3.70–3.61(m,2H),3.43(dd,J＝11.1,5.7Hz,2H),3.23–3.15(m,2H),3.12–3.00(m,1H),2.95–2.81(m,3H),2.45(t,J＝7.6Hz,2H),2.18–2.04(m,2H),1.83(td,J＝13.3,4.8Hz,1H),1.71(d,J＝13.9Hz,1H).
EXAMPLE 64,
Compound D24 5- ((3R, 4R) -1- (sec-butylsulfonyl) -3, 4-dihydroxypiperidin-4-yl) methoxy) -8-fluoro-3, 4-dihydroquinolin-2 (1H) -one
The intermediate 20 and sec-butylsulfonyl chloride are used as raw materials, and the compound D24 is obtained by referring to a synthesis method of the compound B4, and is white solid with the yield of 49%. 1 H NMR(400MHz,DMSO-d 6 )δ10.00(s,1H),7.01(dd,J＝10.4,9.1Hz,1H),6.55(dd,J＝9.1,3.8Hz,1H),5.08(dd,J＝6.0,1.1Hz,1H),4.68(d,J＝1.1Hz,1H),4.00(d,J＝8.8Hz,1H),3.62(dd,J＝14.3,6.9Hz,2H),3.47(dt,J＝13.0,6.8Hz,2H),3.18–3.05(m,2H),2.96(td,J＝11.2,5.2Hz,1H),2.86(td,J＝7.6,3.9Hz,2H),2.45(t,J＝7.7Hz,2H),1.92–1.72(m,2H),1.67(d,J＝13.7Hz,1H),1.42(ddd,J＝13.8,9.2,7.3Hz,1H),1.20(d,J＝6.8Hz,3H),0.95(t,J＝7.5Hz,3H).
Example 65,
Compound D25 5- ((3R, 4R) -3, 4-dihydroxy-1- ((3, 3-trifluoropropyl) sulfonyl) piperidin-4-yl) methoxy) -8-fluoro-3, 4-dihydroquinolin-2 (1H) -one
The intermediate 20 and 3, 3-trifluoropropane-1-sulfonyl chloride are used as raw materials, and the compound D25 is obtained by referring to the synthesis method of the compound B4, and is a white solid with the yield of 66%. 1 H NMR(400MHz,DMSO-d 6 )δ10.01(s,1H),7.01(dd,J＝10.5,9.1Hz,1H),6.55(dd,J＝9.1,3.7Hz,1H),5.12(d,J＝6.0Hz,1H),4.72(d,J＝1.0Hz,1H),4.01(d,J＝8.8Hz,1H),3.72–3.60(m,2H),3.45(dd,J＝11.0,5.4Hz,2H),3.35(dd,J＝6.9,4.2Hz,2H),3.16–3.07(m,1H),2.97(t,J＝11.0Hz,1H),2.86(td,J＝7.6,4.0Hz,2H),2.75–2.63(m,2H),2.45(t,J＝7.6Hz,2H),1.83(td,J＝13.1,4.7Hz,1H),1.74–1.65(m,1H).
The following experiments prove the beneficial effects of the invention.
Experimental example 1 in vitro test of anti-Mycobacterium tuberculosis Activity of Compounds
1. Test of in vitro anti-Mycobacterium tuberculosis H37Ra Activity of Compounds
The H37Ra (ATCC 25177) strain is added into 7H9+ADN culture medium, and shake-cultured at 160rpm for 2 weeks to grow to logarithmic phase, and the bacterial liquid is diluted to 1X 10 5 CFAbout U/mL for standby. The compound to be tested is fully dissolved in DMSO to prepare a high concentration solution of 10mg/mL, and the solution is preserved at the temperature of 2-8 ℃. The bacterial liquid is diluted to 10-50 mug/mL for sampling, the sample is added according to two compound multiple holes, 8-10 concentration gradients (2-time gradient dilution) are sequentially added into a 96-well plate, an equivalent blank DMSO solution is used as a blank control, the bacterial liquid without adding medicine is used as a growth control, and the volume of each hole is 200 mu L. 5% CO after finishing the plate addition 2 And (3) standing and culturing at 37 ℃ for 5 days, checking the growth condition of the tubercle bacillus, adding 1% of Resazurin solution into a growth control hole for culturing overnight, observing whether the color is changed from blue to red, adding 1% of Resazurin solution into all the rest holes for culturing overnight, and measuring the fluorescence value at 540/590nm by using a PE Envision multifunctional microplate analyzer. The lowest drug concentration corresponding to the strain mortality rate of more than 90% measured by fluorescence absorption is the MIC value of the compound on H37Ra, and the calculation formula is as follows: mortality = 1- (test Kong Yingguang value-blank fluorescence value)/(growth control fluorescence value-blank fluorescence value).
The inhibitory activity of the compounds against Mycobacterium tuberculosis H37Ra is shown in Table 1:
results of Table 1 Compounds against Mycobacterium tuberculosis H37Ra Activity
Note that: MIC < 0.001. Mu.M; b, MIC is less than or equal to 0.001 mu M and less than or equal to 0.01 mu M; c, MIC is less than or equal to 0.01 mu M and less than or equal to 0.1 mu M; d, MIC is less than or equal to 0.1 mu M and less than or equal to 1 mu M; e, MIC is more than or equal to 1 mu M.
The results in Table 1 show that most of the compounds have a significant inhibitory activity against Mycobacterium tuberculosis H37Ra in vitro. Wherein, the antibacterial activity of C3, C4, D2 and D17 is equivalent to that of positive control OPC-167832, and the MIC value is lower than 0.001 mu M, and the antibacterial activity is obvious.
2. In vitro test of anti-mycobacterium tuberculosis H37Rv Activity of Compounds
Compound solution preparation: the test compound will begin at 64 μg/mL. The compound was dissolved in DMSO at a concentration of 2048. Mu.g/mL as a frozen stock (-80 ℃). 100. Mu.L of stock solution was added to 700. Mu.L of 7H9 w/o Tween for 8-fold dilution to give 800. Mu.L of 256. Mu.g/mL solution for well plate setting.
96 well plate arrangement: the medium was 7h9, od600=0.001 type medium, 100 μl of test compound or positive control was added in duplicate to each of the two columns (four times for duplicate). 100. Mu.L from column 2 to column 3 was taken and mixed well as double serial dilutions were made and mixed thoroughly by blowing up and down 8 times. Serial dilutions were made to column 11 and the last 100 μl of solution was discarded. After the addition, the culture was carried out under sealed conditions at 37℃for 7 days. The concentration of drug corresponding to strain death was measured for 90% or more, and MIC values were recorded.
The inhibitory activity of the main compounds against mycobacterium tuberculosis H37Rv is shown in table 2:
table 2 results of anti-Mycobacterium tuberculosis H37Rv Activity
Note that: MIC < 0.1. Mu.M; b, MIC is less than or equal to 0.1 mu M and less than or equal to 1 mu M; c, MIC is more than or equal to 1 mu M.
The results in Table 2 show that, for the more optimal compounds with anti-Mycobacterium tuberculosis H37Ra activity, the in vitro anti-Mycobacterium tuberculosis H37Rv activity is consistent with that of the positive compounds, and all the compounds exhibit excellent anti-tuberculosis activity.
3. Test of in vitro anti-drug resistant Mycobacterium tuberculosis (MDR-TB and XDR-TB) Activity test dosing of Compounds:
test compound: preparing stock mother solution by completely dissolving DMSO, filtering and sterilizing, and then serial diluting with tubercle bacillus Middlebrook 7H9 culture solution, adding 96-well culture plate with 100 μl/well before use, wherein the final concentration of the drug is: 1. Mu.g/mL, 0.5. Mu.g/mL, 0.25. Mu.g/mL, 0.125. Mu.g/mL, 0.0625. Mu.g/mL, 0.03125. Mu.g/mL, 0.0156. Mu.g/mL, 0.0078. Mu.g/mL, 0.0039. Mu.g/mL, 0.00019. Mu.g/mL, 0.0001. Mu.g/mL.
Control: the solvent DMSO was added at the same concentration as the highest concentration of the test drug.
Tuberculosis bacteria: MDR/XDR strain (Y117, Y16)
Taking passagesStrains in 1-2 log phase, millbase to od600=1.0 (about 5×10) 6 CFU/mL) was diluted to 200. Mu.L in 10mL of the culture medium, and 100. Mu.L/well (about 10) 4 CFU/well) was added to the culture plate; the control group was added with an equivalent amount of the test compound (D100), 1/10 amount of the bacteria (D10) and 1/100 amount of the bacteria (D1).
And (3) observing results:
at 37℃for 14 days, the colony growth of each group was observed, and the minimum concentration of the aseptically grown drug group was used as the MIC value of the test compound for the strain.
The inhibitory activities of the main compounds on drug-resistant Mycobacterium tuberculosis MDR-TB (Y117) and XDR-TB (Y16) are shown in Table 3:
Table 3 results of the Activity of the Compounds against drug-resistant Mycobacterium tuberculosis Y117 and Y16
Note that: a is MIC 100 <0.01μg/mL；B:0.01μg/mL≤MIC 100 <0.05μg/mL；C:0.05μg/mL≤MIC 100 <0.1μg/mL；D:MIC 100 ≥0.1μg/mL
The results show that the compounds C4 and D17 have remarkable bactericidal activity on clinically isolated mycobacterium tuberculosis and have good clinical application value.
Experimental example 2, compound solubility test
Experimental procedure
1. Preparing pure water
2. Sample preparation: to 792. Mu.L of water were added 8. Mu.L of a control solution at a concentration of 10mM and a stock solution of the test compound.
3. The sample tube was shaken at room temperature for 1h (1000 rpm).
4. Preparation of standard yeast
4.1 preparation of 300. Mu.M labelling solution (SS): to 194. Mu.L of MeOH/ACN (4/1) solution was added 6. Mu.L of 10mM compound.
4.2A standard curve was prepared in MeOH/ACN (4/1) solution.
5. The sample was subjected to centrifugation (10 min-12000 rpm) to precipitate undissolved particles. And the supernatant was transferred to a new sample bottle.
6. Diluting the supernatant 10-fold and 100-fold with water
10. Mu.L of the supernatant was added to 90. Mu.L of water, and 10-fold dilution was performed.
10. Mu.L of the supernatant was added to 990. Mu.L of water and 100-fold dilution was performed.
Sample preparation for LC-MS/MS
mu.L of the sample (no dilution, 10-fold dilution and 100-fold dilution) and the standard curve sample were added to 95. Mu.L CAN for loading analysis.
The solubility data of the main compounds are shown in table 4.
Table 4 compound solubility
The results show that compared with a positive control, the solubility of the compounds D17 and D24 is obviously improved, which indicates that the compounds possibly have better drug generation properties and have potential clinical application value.
In conclusion, the invention provides a novel quinolinone derivative which has excellent antitubercular mycobacteria activity, is used as a novel DprE1 enzyme inhibitor, has controllable toxicity, excellent antitubercular activity and pharmacokinetic properties, and has very good clinical application prospect.
Claims (13)
1. Quinolinone derivatives represented by formula I or pharmaceutically acceptable salts or solvates thereof:
wherein ring A is aryl, aromatic heterocyclic group or aromatic heterocyclic group; l isO or NR 7 The method comprises the steps of carrying out a first treatment on the surface of the L ', L' are each independently selected from none, CO, SO 2 NH or (CH) 2 ) m M is an integer of 1 to 3; m is M 1 、M 2 Each independently selected from N or CH;
R 1 、R 2 、R 3 are independently selected from H, halogen, C1-C3 alkoxy, hydroxy, -NR 11 R 12 Or R is 2 、R 3 Connecting to form a 3-7 membered ring; r is R 11 Is H or C1-C3 alkyl, R 12 Is C1-C3 alkyl or-CO-R 13 ，R 13 A C1-C3 alkyl group substituted or unsubstituted with halogen;
R 4 is-H or-OH;
R 5 、R 6 are independently selected from-H, -Boc, bridged cyclic hydrocarbon radicals, R a 、R b 、R c Substituted or unsubstituted aryl, halogen substituted or unsubstituted aromatic heterocyclic radical, R d Substituted or unsubstituted C1-C4 alkyl, C3-C6 cycloalkyl or
t is an integer of 1 to 3;
wherein R is a 、R b 、R c Are independently selected from halogen, nitro,
Wherein R 'and R' are each independently selected from: H. -CO-R s or-SO 2 -R s The method comprises the steps of carrying out a first treatment on the surface of the R' "is-O-R s Or->
R s 、R p 、R q Independently selected from H, C C3 alkyl, or R p 、R q Connected into a ring;
R d halogen, halogen substituted or unsubstituted C1-C3 alkyl, C3-C6 cycloalkyl or C3-C6 heterocycloalkyl;
R 7 is C1-C3 alkyl.
2. The quinolinone derivative or pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein ring a is
3. The quinolinone derivative or pharmaceutically acceptable salt or solvate thereof according to claim 1 or 2, wherein R 1 、R 2 、R 3 Are independently selected from H, F, methoxy, hydroxy, -NR 11 R 12 Or R is 1 、R 2 Connecting to form a three-membered ring; r is R 11 Is H or methyl, R 12 Is methyl or-CO-R 13 ，R 13 1 to 3F substituted or unsubstituted methyl groups.
4. A quinolinone derivative or a pharmaceutically acceptable salt or solvate thereof as claimed in claim 3 wherein R 1 H, F or methoxy, R 2 Is H or-NR 11 R 12 ，R 3 Is H, or R 2 And R is 3 To form a saturated 3-membered carbocyclic ring; r is R 11 Is H or methyl, R 12 Is methyl or-CO-R 13 ，R 13 Is methyl or-CF 3 。
5. The quinolinone derivative or pharmaceutically acceptable salt or solvate thereof according to claim 4, wherein the quinolinone derivative has a structure according to formula II-a:
preferably, R 1 Is H or F, R 2 Is H and R 3 Is H, or R 2 、R 3 And linked to form a saturated 3-membered carbocyclic ring.
6. The quinolinone derivative or pharmaceutically acceptable salt or solvate thereof according to claim 4, wherein the quinolinone derivative has a structure according to formula II-B:
wherein R is 3 Is H;
preferably, R 1 Is H or F, R 2 is-NR 11 R 12 ；R 11 Is H or methyl, R 12 Is methyl or-CO-R 13 ，R 13 Is methyl or-CF 3 。
7. The quinolinone derivative or pharmaceutically acceptable salt or solvate thereof according to claim 4, wherein the quinolinone derivative has a structure of formula II-C or formula II-D:
wherein R is 2 And R is 3 All are H;
preferably, R 1 H, F or methoxy.
8. The quinolinone derivative or pharmaceutically acceptable salt or solvate thereof according to claim 4, wherein the quinolinone derivative has a structure according to formula II-E or formula II-F:
wherein R is 1 、R 2 、R 3 All are H.
9. The quinolinone derivative or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-8, wherein the quinolinone derivative has a structure of formula III-a, formula III-B formula III-C or formula III-D:
10. The quinolinone derivative or pharmaceutically acceptable salt or solvate thereof according to claim 9, wherein the quinolinone derivative has the structure:
11. the method for synthesizing a quinolinone derivative or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 10, comprising the steps of: reacting the compound A with the compound B for 4-8 hours at 70-90 ℃ under the action of inorganic alkali to obtain a compound shown in a formula I;
the reaction formula is as follows:
wherein R is 0 is-OH or-NH-R 7 。
12. Use of a quinolinone derivative or a pharmaceutically acceptable salt or solvate thereof as claimed in any one of claims 1 to 11 as a DprE1 enzyme inhibitor.
13. Use of a quinolinone derivative or a pharmaceutically acceptable salt or solvate thereof as claimed in any one of claims 1 to 11 in the manufacture of a medicament for the treatment of tuberculosis; preferably, the drug is an anti-mycobacterium tuberculosis drug; more preferably, the drug for treating tuberculosis is a drug for treating drug-resistant tuberculosis, and the mycobacterium tuberculosis is drug-resistant mycobacterium tuberculosis.
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