WO2023207949A1 - 并环类化合物及其应用 - Google Patents
并环类化合物及其应用 Download PDFInfo
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- WO2023207949A1 WO2023207949A1 PCT/CN2023/090502 CN2023090502W WO2023207949A1 WO 2023207949 A1 WO2023207949 A1 WO 2023207949A1 CN 2023090502 W CN2023090502 W CN 2023090502W WO 2023207949 A1 WO2023207949 A1 WO 2023207949A1
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- WIPO (PCT)
- Prior art keywords
- group
- compound
- alkyl
- pain
- trifluoromethyl
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 165
- 208000002193 Pain Diseases 0.000 claims abstract description 53
- 230000036407 pain Effects 0.000 claims abstract description 48
- 101000654356 Homo sapiens Sodium channel protein type 10 subunit alpha Proteins 0.000 claims abstract description 32
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- 102100031374 Sodium channel protein type 10 subunit alpha Human genes 0.000 claims abstract description 22
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- 201000010099 disease Diseases 0.000 claims abstract description 8
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- 238000002360 preparation method Methods 0.000 claims description 184
- -1 amino, carboxyl Chemical group 0.000 claims description 144
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 79
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- 125000005842 heteroatom Chemical group 0.000 claims description 39
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 38
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- 229910052736 halogen Inorganic materials 0.000 claims description 36
- 150000002367 halogens Chemical class 0.000 claims description 36
- 229910052717 sulfur Inorganic materials 0.000 claims description 35
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 33
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 29
- 125000002887 hydroxy group Chemical class [H]O* 0.000 claims description 24
- 125000000623 heterocyclic group Chemical group 0.000 claims description 21
- 150000001768 cations Chemical class 0.000 claims description 16
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- 229940002612 prodrug Drugs 0.000 claims description 14
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- 125000006714 (C3-C10) heterocyclyl group Chemical group 0.000 claims description 12
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 125000003277 amino group Chemical class 0.000 claims description 8
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 125000004093 cyano group Chemical class *C#N 0.000 claims description 8
- 125000004043 oxo group Chemical group O=* 0.000 claims description 8
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- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
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- 206010036376 Postherpetic Neuralgia Diseases 0.000 claims description 3
- 229910052805 deuterium Inorganic materials 0.000 claims description 3
- 239000000835 fiber Substances 0.000 claims description 3
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000002757 morpholinyl group Chemical group 0.000 claims description 3
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 2
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 2
- 208000004998 Abdominal Pain Diseases 0.000 claims description 2
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 2
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- 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 2
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- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 2
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- 229910001413 alkali metal ion Inorganic materials 0.000 claims description 2
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 2
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- 229940079593 drug Drugs 0.000 abstract description 10
- 230000002401 inhibitory effect Effects 0.000 abstract description 3
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- 239000000243 solution Substances 0.000 description 161
- 238000005481 NMR spectroscopy Methods 0.000 description 125
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- 239000012074 organic phase Substances 0.000 description 47
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- 238000003756 stirring Methods 0.000 description 37
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- 239000008346 aqueous phase Substances 0.000 description 33
- JPVKCHIPRSQDKL-UHFFFAOYSA-N 3-aminobenzenesulfonamide Chemical compound NC1=CC=CC(S(N)(=O)=O)=C1 JPVKCHIPRSQDKL-UHFFFAOYSA-N 0.000 description 32
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 25
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- 238000004949 mass spectrometry Methods 0.000 description 24
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 1
- 230000003238 somatosensory effect Effects 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- LSOZALWRNWQPLK-UHFFFAOYSA-N tert-butyl n-[(3-aminophenyl)methyl]carbamate Chemical compound CC(C)(C)OC(=O)NCC1=CC=CC(N)=C1 LSOZALWRNWQPLK-UHFFFAOYSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- 208000004371 toothache Diseases 0.000 description 1
- XPDWGBQVDMORPB-UHFFFAOYSA-N trifluoromethane acid Natural products FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 210000003901 trigeminal nerve Anatomy 0.000 description 1
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/18—Sulfonamides
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- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
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- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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- A—HUMAN NECESSITIES
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/4035—Isoindoles, e.g. phthalimide
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- A—HUMAN NECESSITIES
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- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/423—Oxazoles condensed with carbocyclic rings
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
- C07C311/46—Y being a hydrogen or a carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C381/00—Compounds containing carbon and sulfur and having functional groups not covered by groups C07C301/00 - C07C337/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
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- 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
- C07D405/02—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 two hetero rings
- C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
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- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
Definitions
- the third object of the present invention is to provide a method of using the paracyclic compound or pharmaceutical composition in preparing Nav1.8 inhibitors or preparing drugs for treating, preventing or controlling diseases or symptoms related to Nav1.8 channels. application.
- the A ring is a benzene ring, a pyridine ring, a thiophene ring, a furan ring, or a pyrrolidine ring.
- the A ring is a benzene ring or a pyridine ring;
- R 2a , R 2b and R 2c are each independently selected from hydrogen atom, halogen, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C6 alkoxy group, hydroxyl, cyano group, amino group, nitro group , C3-C8 cycloalkyloxy, C3-C8 cycloalkyl and 3-10 membered heterocyclyl containing 1-4 heteroatoms selected from N, O and S; the substituted substituent is selected from From halogen, C1-C6 alkyl, hydroxyl, C3-C8 cycloalkyl and 3-10 membered heterocyclyl containing 1-4 heteroatoms selected from N, O and S;
- the compound of Formula I is selected from the following compounds of Formula III:
- the compound of Formula I is selected from the following compounds of Formula V:
- halogen may be fluorine, chlorine, bromine or iodine.
- deuterated C1-C6 alkyl group means that one or more hydrogens of a C1-C6 alkyl group as defined above are replaced by deuterium.
- the fourth step is the preparation of 2-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-4-(trifluoromethyl)benzoic acid 1e
- the first step is the preparation of 2-(7-fluorochroman-4-yl)-4-(trifluoromethyl)benzoic acid methyl ester 11a
- N-(3-cyanophenyl)-2-(7-fluorochroman-4-yl)-4-(trifluoromethyl)benzamide 16a (98 mg, 0.22 mmol) was dissolved in To 5 mL of 4N hydrogen chloride-1,4-dioxane solution, add ethanol (0.26 mL), seal, and stir at 0-5°C for 24 hours. The reaction mixture was concentrated under reduced pressure, 7M ammonia-methanol solution (10 mL) and ammonium chloride (24 mg, 0.44 mmol) were added to the concentrate, and the reaction was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (MeOH:DCM; 1:30 to 1:10) to obtain compound 16 (61 mg) (white solid), yield: 59.93%.
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了一种式I所述的并环类化合物及其应用。本发明的并环类化合物具有Nav1.8选择性抑制活性,可作为Nav抑制剂及用于制备治疗和/或减轻疼痛和疼痛相关疾病的药物。
Description
优先权信息
本发明请求于2022年4月25日向中国国家知识产权局提交的、申请号为2022104406606、发明名称为“并环类化合物及其应用”的中国专利申请的优先权,并且其全部内容通过引用结合在本发明中。
本发明涉及医药技术领域,尤其是涉及一类并环类化合物及其作为Nav抑制剂的应用和其在制备治疗和/或减轻疼痛和疼痛相关疾病的药物中的应用。
疼痛是临床上最常见的症状之一,伤害感受性疼痛是任何破坏性或潜在的有害刺激所致,神经病理性疼痛是躯体感觉神经系统的损伤或疾病所导致的疼痛。当神经元正常结构被破坏,可产生痛觉超敏或缺失症状。机体感知疼痛是伤害性刺激产生并在神经元间传递的过程,钠离子通道活性是神经元传导兴奋刺激的重要因素,钠离子通道受损易导致神经元损伤,从而出现疼痛感知紊乱。
钠离子通道是由内在膜蛋白形成的离子通道,可以让钠离子通过细胞膜,由α亚基(孔道组成蛋白)和β亚基(调节蛋白)组成,其中电压门控型钠离子通道(voltage-gated sodium channels,VGSCs)根据α亚基的不同分为9种亚型,分别为Nav1.1~1.9[Genome Biol,2003,4(3):2071-2077.]。根据对河豚毒素(TTX)的敏感性,VGSCs家族可以分为两大类:河豚毒素敏感型(TTX-S)和河豚毒素抵抗型(TTX-R),其中VGSCs亚型Nav1.1、Nav1.2、Nav1.3、Nav1.4、Nav1.6、Nav1.7属于TTX-S,Nav1.5、Nav1.8、Nav1.9属于TTX-R[Neuron,2000,26(1):13–25.]。
Nav1.8属于TTX-R型,编码基因为位于人类染色体3p21-22区域的SCN10A。Nav1.8蛋白由α、β亚基组成,α亚基是主要的功能单位。每个α亚基由4个同源结构域围成一个中心,形成Nav1.8的中央孔,每个结构域含6个α螺旋穿膜结构(S1~S6),其中保守的S4是钠离子通道的电压感受器。β亚基主要有4个亚型β1~β4,在人类中主要是β1和β3,对α在细胞膜的定位和稳定性起辅助作用,同时也参与了α亚基的失活和电压敏感性[J Biol Chem,2004,279:24826~24833]。Nav1.8主要表达于外周感觉神经元,如背根神经节(dorsal root ganglion,DRG)神经元,该钠通道的激活阈值高,主要介导动作电位的上升支,即钠离子的内流[J Neuro physiol,2001,86:629~640]。Nav1.8在慢性疼痛中具有非常重要的作用。在角叉菜胶诱发的炎症痛模型中,Nav1.8的mRNA及其对应的TTX-R电流都有明显的升高[Neuroreport,1998,9,967~972]。完全弗氏佐剂(complete Freund's adjuvant,CFA)注射能使三叉神经中的Nav1.8的mRNA增加2.5倍[J pain,2008,9:522~531]。注射Nav1.8反义核苷酸,能阻滞CFA所致的自发痛和痛觉过敏,减少了机械痛敏[Pain,2006,123:75~82.]。在一些慢性神经病理疼痛模型中,DRG中的Nav1.8表达均明显上调,而高选择性的Nav1.8阻滞剂能够阻滞机械痛觉过敏[Proc Natl Acad Sci USA,2007,104:8520~8525;Neuropharmacology,2010,59:201~207.]。根据一系列研究表明,Nav1.8是高选择性的疼痛治疗靶点,Nav1.8选择性抑制剂有望成为治疗于炎性疼痛、神经疼痛、手术后疼痛和癌痛等多种疼痛类型的新型疗法。
由于大部分电压门控钠离子通道亚型之间相对保守,缺乏选择性的疗法可能会造成严重的副作用。Navl.8主要分布在外周神经系统,所以选择性地抑制Navl.8有望有效地减少副作用。因此,在临床应用中,有必要开发高活性、高选择性的Navl.8抑制剂。
有鉴于此,特提出本发明。
发明内容
本发明的目的之一在于提供一种并环类化合物。
本发明的目的之二在于提供一种包含所述并环类化合物的药物组合物。
本发明的目的之三在于提供一种所述并环类化合物或药物组合物在制备Nav1.8抑制剂或制备用于治疗、预防或控制与Nav1.8通道相关的疾病或症状的药物中的应用。
为了实现本发明的上述目的,特采用以下技术方案:
本发明一方面提供了一种式I化合物,或其前体药物、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其可药用的盐,
其中:
A环选自C6-C12芳基、含有1-4个选自N、O和S中的杂原子的5-10元杂芳基、C3-C8环烷基和含有1-4个选自N、O和S中的杂原子的3-10元杂环基;
优选地,A环为苯环、吡啶环、噻吩环、呋喃环、吡咯烷环,特别地,A环为苯环或吡啶环;
(R1)m表示m个R1取代,m为0、1、2、3、4或5,优选为0、1或2;
R1各自独立地选自氢原子、卤素、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、羟基取代的C1-C6烷氧基、羟基、C1-C6羟烷基、氰基、氨基(-NH2)、C1-C6烷基氨基、硝基、脒基、-C(=NOH)NH2、羧基、氧代(=O)、硫代(=S)、-NHSO2NH2、-SO2Me、-CH2ORe、-SO2N(Rf)2、-CON(Rf)2、C3-C8环烷基、含有1-4个选自N、O和S中的杂原子的3-10元杂环基和含有1-4个选自N、O和S中的杂原子的杂环基取代的C1-C6烷基,特别地,R1各自独立地选自氢原子、卤素、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、羟基、C1-C6羟烷基、氰基、氨基(-NH2)、硝基、脒基、羧基、氧代(=O)、硫代(=S)、-NHSO2NH2、-SO2Me、-CH2ORe、-SO2N(Rf)2、-CON(Rf)2、C3-C8环烷基、含有1-4个选自N、O和S中的杂原子的3-10元杂环基和含有1-4个选自N、O和S中的杂原子的杂环基取代的C1-C6烷基;
Re选自氢原子、C1-C6烷基、-C(O)R7、-S(O)2OH、-S(O)2O-Q+、-PO(OH)2、-PO(OH)O-Q+和-PO(O-)2W2+;
Rf各自独立地选自氢原子、C1-C6烷基、C3-C8环烷基、脒基,特别地,Rf各自独立地选自氢原子、C1-C6烷基、C3-C8环烷基;
Q+为药学上可接受的单价阳离子;W2+为药学上可接受的二价阳离子;
R7选自取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C2-C6烯基、羧基和-C(O)O-M+,所述取代的取代基选自羟基、氨基、羧基和-C(O)O-M+中的一个或多个;M+为药学上可接受的单价阳离子;
优选地,R1各自独立地选自氢原子、卤素、C1-C6烷基、脒基、氧代(=O)、-
SO2NH2、-SO2NHCH3-、-NHSO2NH2、吗啉基、-CONH2、-CH2OPO(OH)2、硝基、羟基、羧基、C1-C3烷基氨基、二羟基丙氧基、-C(=NOH)NH2、特别地,R1各自独立地选自氢原子、卤素、C1-C6烷基、脒基、氧代(=O)、-SO2NH2、-SO2NHCH3-、-NHSO2NH2、吗啉基、-CONH2、-CH2OPO(OH)2和硝基;
或者,相邻的两个R1和与其相连的A环一起形成未取代的或被1-4个取代基取代的苯并[5-6元杂环],所述取代基选自卤素、氨基(-NH2)、羟基、巯基、氧代(=O)、硫代(=S)、C1-C6烷基;所述5-6元杂环含有1至3个选自N、O、S的杂原子;
优选地,苯并[5-6元杂环]选自:
特别是选自:
n为0或1,优选为0;
X为N原子或C-R2c;
优选地,X为C-R2c;更优选为-CH-;
R2a、R2b和R2c各自独立地选自氢原子、卤素、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、羟基、氰基、氨基、硝基、C3-C8环烷基氧基、C3-C8环烷基和含有1-4个选自N、O和S中的杂原子的3-10元杂环基;所述的取代的取代基选自卤素、C1-C6烷基、羟基、C3-C8环烷基和含有1-4个选自N、O和S中的杂原子的3-10元杂环基;
优选地,R2a、R2b和R2c各自独立地选自氢原子、卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6羟烷基;
优选地,R2a为卤素、C1-C6烷基或卤代C1-C6烷基,R2b为氢原子、卤素或卤代C1-C6烷基,R2c为氢原子或卤素;
R3a、R3b、R3c和R3d各自独立地选自氢原子、卤素、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、羟基、氰基、氨基、硝基、C3-C8环烷基氧基、C3-C8环烷基和含有1-4个选自N、O和S中的杂原子的3-10元杂环基;所述的取代的取代基选自卤素、氘、C1-C6烷基、羟基、C3-C8环烷基和含有1-4个选自N、O和S中的杂原子的3-10元杂环基;
优选地,R3a、R3b、R3c和R3d各自独立地选自卤素、C1-C6烷基、卤代C1-C6烷基、氘代C1-C6烷基、氘代C1-C6烷氧基、C1-C6羟烷基;优选为卤素;
Y为O、S、CRcRd或NRc;
优选地,Y为O、CRcRd或NRc;
Rc和Rd各自独立地选自氢原子、C1-C6烷基、羟基、C3-C8环烷基和含有1-4个选自N、O和S中的杂原子的3-10元杂环基;优选地,Rc和Rd各自独立地选自氢原子、C1-C6
烷基、C3-C8环烷基;
或者Rc和Rd和与其相连的碳原子形成C3-C8环烷基或含有1-4个选自N、O和S中的杂原子的3-10元杂环基;优选形成C3-C8环烷基;
R4a、R4b、R4c和R4d各自独立地选自氢原子、C1-C6烷基、羟基、C3-C8环烷基和含有1-4个选自N、O和S中的杂原子的3-10元杂环基;
或者R4a和R4b与其相连的碳原子形成C3-C8环烷基或含有1-4个选自N、O和S中的杂原子的3-10元杂环基;
或者R4c和R4d与其相连的碳原子形成C3-C8环烷基或含有1-4个选自N、O和S中的杂原子的3-10元杂环基;
优选地,R4a和R4b各自独立地选自氢原子、C1-C6烷基、C3-C8环烷基;
优选地,R4c和R4d各自独立地选自氢原子、C1-C6烷基、C3-C8环烷基;或者R4c和R4d与其相连的碳原子形成C3-C8环烷基;
o为0、1或2,优选为0或1,更优选为1。
在一些实施方式中,式I化合物选自如下式II化合物:
其中,R2a、R2b、R2c、X、R3a、R3b、R3c、R3d、Y、R4a、R4b、R4c、R4d、o的定义与前述相同;
R5a、R5b和R5c各自独立地选自氢原子、卤素、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、C3-C6环烷基;
R6选自氢原子、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、羟基、C1-C6羟烷基、氰基、氨基、硝基、-CH2ORe、C3-C8环烷基和含有1-4个选自N、O和S中的杂原子的3-10元杂环基;优选为氢原子或-CH2ORe;
Re选自氢原子、C1-C6烷基、-C(O)R7、-S(O)2OH、-S(O)2O-Q+、-PO(OH)2、-PO(OH)O-Q+和-PO(O-)2W2+;
Q+为药学上可接受的单价阳离子;W2+为药学上可接受的二价阳离子;
R7选自取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C2-C6烯基、羧基和-C(O)O-M+,所述取代的取代基选自羟基、氨基、羧基和-C(O)O-M+中的一个或多个;M+为药学上可接受的单价阳离子;
优选地,Q+和M+相同或不同,且各自独立地选自季铵盐离子和碱金属离子,优选为Na+或K+;W2+为碱土金属离子,优选为Mg2+或Ca2+。
在一些实施方式中,式I化合物选自如下式III化合物:
其中,R2a、R2b、R2c、X、R3a、R3b、R3c、R3d、Y、R4a、R4b、R4c、R4d、o的定义与前述相同,R5a、R5b和R5c的定义与式II相同。
R5d选自氢原子、卤素、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、C3-C6环烷基。
在一些实施方式中,式I化合物选自如下式IV化合物:
其中,R2a、R2b、R2c、X、R3a、R3b、R3c、R3d、Y、R4a、R4b、R4c、R4d、o、R5a、R5b、R5c、R5d的定义与式III相同。
在一些实施方式中,式I化合物选自如下式V化合物:
其中,R2a、R2b、R2c、X、R3b、Y、R4a、R4b、R4c、R4d、o、n、A环、R1、m的定义与式I相同。
在一些优选实施方式中,式I化合物选自下列化合物:
本发明中的术语定义如下:
所述“卤素”可以为氟、氯、溴或碘。
所述“C1-C6烷基”是指具有1-6个碳原子的链状烷基;其具体实例可以包括甲基、乙基、丙基、正丙基、异丙基、丁基、正丁基、异丁基、叔丁基、1-甲基-丁基、1-乙基-丁基、戊基、正戊基、异戊基、新戊基、叔戊基、己基、正己基、1-甲基戊基、2-甲基戊基、4-甲基-2-戊基、3,3-二甲基丁基、2-乙基丁基以及类似基团,但不限于此。
所述“氘代C1-C6烷基”是指如上所定义的C1-C6烷基的一个或多个氢被氘取代。
所述“卤代C1-C6烷基”是指如上所定义的C1-C6烷基的一个或多个氢被卤素取代。
所述“C1-C6羟烷基”是指如上所定义的C1-C6烷基的一个或多个氢被羟基取代。
所述“C2-C6烯基”是指直链或支链的含有2-6个碳原子,至少有一个碳碳双键的基团;其具体实例可以包括乙烯基、丙烯基、2-丙烯基、(E)-2-丁烯基、(Z)-2-丁烯基、(E)-2-甲基-2-丁烯基、(Z)-2-甲基-2-丁烯基、2,3-二甲基-2-丁烯基、(Z)-2-戊烯基、(E)-1-戊烯基、(E)-2-戊烯基、(Z)-2-己烯基、(E)-1-己烯基、(Z)-1-己烯基、(E)-2-己烯基、(Z)-3-己烯基、(E)-3-己烯基、(E)-1,3-己二烯基、4-甲基-3-戊烯基或降冰片烯。
所述“C1-C6烷氧基”是指RO-基团,其中R为如上所述的C1-C6烷基。烷氧基的具体实例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、仲丁氧基、正戊氧基、异戊氧基、新戊氧基、正己氧基、异己氧基、3-甲基戊氧基、3,3-二甲基丁氧基、2-乙基丁氧基等。
所述“卤代C1-C6烷氧基”是指如上所述的烷氧基的至少一个氢被卤素取代得到的基团;
其具体实例包括三氟甲氧基等。
所述“氘代C1-C6烷氧基”是指RO-基团,其中R为如上所述的氘代C1-C6烷基。
所述“C3-C8环烷基”是指包含3-12个碳原子的完全饱和的环状烃类化合物基团,其具体实例包括环丙基、环丁基、环戊基、环己基。
所述“C3-C8环烷基氧基”是指RO-基团,其中R为如上所述的C3-C8环烷基。
所述“3-10元杂环基”是指环上含有1至4个选自氮、氧、硫中的杂原子的3-10元环烷基团,其具体实例包括哌嗪、哌啶、吗啉等。
所述“C6-C12芳基”是指具有6至12个碳原子的单环或多环芳基;其具体实例包括苯基、萘基。
所述“5-10元芳杂基”是指环上含有1至4个选自氮、氧、硫中的杂原子的5-10元芳香基团,其具体实例包括吡啶、哒嗪、嘧啶等。
“可药用盐”包括所述式I化合物与酸或碱形成的盐;所述酸包括无机酸、有机酸;优选地,所述无机酸包括盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸、碳酸;优选地,所述有机酸包括甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、柠檬酸、枸橼酸、酒石酸、苦味酸、甲磺酸、乙磺酸、对甲苯磺酸、谷氨酸、双羟萘酸;所述碱包括钠、钾、钙、铝、锂和铵的氢氧化物、碳酸盐、碳酸氢盐等。
“药学上可接受的单价阳离子”包括碱金属阳离子、铵阳离子和季铵盐阳离子,例如Li+、Na+、K+、NH4
+。
“药学上可接受的二价阳离子”包括碱土金属阳离子和氨基酸阳离子,例如Ca+、Mg+、精氨酸的二价离子。药学上可接受的二价阳离子(W2+)可以被两个药学上可接受的单价阳离子(Q+)替换。
本申请所涉及的化合物及其前体药物、可药用盐可具有异构体或消旋体,例如光学异构体(包括非对映异构体和对映异构体)、阻转异构体、几何异构体(顺反异构体)、构象异构体、互变异构体以及它们的混合物等,但不限于此。这些异构体也包含在本发明的权利要求所限定的范围中。
本发明另一方面提供了一种药物组合物,其包括选自式I化合物、其前体药物、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体和其可药用的盐中的一种或多种,以及药学上可接受的辅料。
本发明再一方面提供了式I化合物或其前体药物、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其可药用的盐在制备Nav1.8抑制剂或用于治疗和/或减轻疼痛和疼痛相关疾病的药物中的应用。
所述疼痛和疼痛相关疾病包括但不限于伤害性疼痛、炎性疼痛(包括但不限于类风湿性关节炎疼痛或外阴痛)、神经性疼痛(包括但不限于疱疹后神经疼,特发性小纤维神经疼)、肌肉骨骼疼(包括但不限于骨关节炎疼、背痛、冷痛、烧伤疼痛或牙痛)、术后疼痛(包括但不限于拇囊炎切除术后疼痛、腹壁成形术疼痛等)和内状疼痛、功能性疼痛、肌肉或骨骼损伤相关疼痛、盆腔痛、腹腔痛、胸腔痛、腰骶神经痛、术前疼痛、术间疼痛、术后疼痛、肠痛(包括但不限于炎性肠病疼痛、克罗恩病疼痛或间质性膀胱炎)、急性或慢性疼痛、偏头痛、三叉神经痛、胰腺炎、肾绞痛、癌症痛、化学或药物疗法导致的疼痛、糖尿病神经痛、带状疱疹后神经痛、背部疼痛、幻肢痛、坐骨神经痛、小纤维神经痛、红斑性肢痛症等。
本发明具有以下有益效果:
本发明结构的并环类化合物较现有结构具有更优的Nav1.8选择性抑制活性和药物代谢动力学性质,作为Nav1.8抑制剂可用于治疗或减轻与疼痛或疼痛相关的疾病,具有重要的临床应用价值。
在上文中已经详细地描述了本发明,但是上述实施方式本质上仅是例示性,且并不欲限制本发明。此外,本文并不受前述现有技术或发明内容或以下实施例中所描述的任何理论的限制。
下面结合实施例对本发明作进一步的说明,需要说明的是,提供以下实施例仅出于说明目的并不构成对本发明要求保护范围的限制。
除特殊说明外,在实施例中所采用的原料、试剂、方法等均为本领域常规的原料、试剂、方法。
本发明中,室温指环境温度,为10℃-35℃。过夜是指8-15小时。回流是指常压下溶剂回流温度。
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD),内标为四甲基硅烷(TMS)。MS的测定用Finnigan LCQ/Deca(ESI)质谱仪。高效液相色谱法(HPLC)分析使用Gilson-215高压液相色谱仪。
薄层层析硅胶板使用烟台黄海HSGF 254或青岛GF 254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.2mm,薄层层析分离纯化产品采用的规格是0.4mm-0.5mm。硅胶柱色谱法一般使用烟台黄海硅胶200-300目硅胶为载体。
实施例中的反应进程的监测采用薄层色谱法(TLC),反应所使用的展开剂,纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括二氯甲烷/甲醇体系和石油醚/乙酸乙酯体系,溶剂的体积比根据化合物的极性不同而进行调节,也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成,或可购买自上海皓鸿生物医药科技有限公司、毕得医药等公司。实施例中无特殊说明,反应均能够在氩气氛或氮气氛围下进行。
实施例1 2-(5-氟-2,3-二氢-1H-茚-1-基)-N-(3-氨磺酰苯基)-4-(三氟甲基)苯甲酰胺1的制备
第一步N'-(5-氟-2,3-二氢-1H-茚-1-亚基)-4-甲苯磺酰肼1b的制备
将对甲苯磺酰肼(6.73g,39.96mmol)悬浮于甲醇溶液中,加热至60℃,直到对甲苯磺酰肼完全溶解。慢慢向混合物中加入5-氟-1-茚酮1a(5.00g,33.30mmol,上海皓鸿生物医药科技有限公司)。3小时后,产生沉淀物,将沉淀物过滤,用甲醇淋洗。在真空中干燥沉淀物,得到化合物1b(8.00g)(白色固体),产率:75.46%。1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),7.81(d,J=8.2Hz,2H),7.49(dd,J=8.5,5.5Hz,1H),7.39(d,J=8.1Hz,2H),7.19(d,J=9.1Hz,1H),7.08(t,J=8.8Hz,1H),3.03–2.95(m,2H),2.76(dd,J=7.6,5.2Hz,2H),2.36(s,3H).
第二步2-(6-氟-1H-茚-3-基)-4-(三氟甲基)苯甲酸甲酯1c的制备
向N'-(5-氟-2,3-二氢-1H-茚-1-亚基)-4-甲苯磺酰肼1b(2.00g,6.28mmol),[1,1'-
双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(205.38mg,0.25mol),碳酸钠(1.07g,10.06mmol)和1,4-二氧六环/水(4:1)(60mL)的混合物中加入2-溴-4-三氟甲基苯甲酸甲酯(1.42g,5.03mmol,上海皓鸿生物医药科技有限公司)。氩气保护,将反应混合物在90℃下搅拌10h。冷却,反应液减压浓缩,加入70mL水和70mL乙酸乙酯,均匀混合,静置分层。水相用乙酸乙酯萃取(70mL×3)。合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩。用硅胶柱色谱法(EA:PE;1:25至1:15)纯化,得到化合物1c(1.58g)(无色油状物),产率:74.79%。1H NMR(400MHz,Chloroform-d)δ8.04(d,J=7.9Hz,1H),7.71(d,J=8.9Hz,2H),7.26–7.22(m,1H),6.97(d,J=1.8Hz,1H),6.95(d,J=1.3Hz,1H),6.51(t,J=2.1Hz,1H),3.60(s,3H),3.56(d,J=1.5Hz,2H).
第三步2-(5-氟-2,3-二氢-1H-茚-1-基)-4-(三氟甲基)苯甲酸甲酯1d的制备
将2-(6-氟-1H-茚-3-基)-4-(三氟甲基)苯甲酸甲酯1c(1g,5.68mmol)、10%Pd-C催化剂(200mg)和乙醇(30mL)的混合物在氢气下60℃搅拌30h。过滤出催化剂后,蒸发滤液。用硅胶柱色谱法(EA:PE;1:25至1:15)纯化,得到化合物1d(840mg)(无色油状物),产率:83.50%。1H NMR(400MHz,Chloroform-d)δ7.93(d,J=8.2Hz,1H),7.53(d,J=8.2Hz,1H),7.33(s,1H),7.00(d,J=8.7Hz,1H),6.91–6.78(m,2H),5.13(t,J=8.1Hz,1H),3.94(s,3H),3.10–2.91(m,2H),2.86–2.71(m,1H),2.12–1.97(m,1H).
第四步2-(5-氟-2,3-二氢-1H-茚-1-基)-4-(三氟甲基)苯甲酸1e的制备
将2-(5-氟-2,3-二氢-1H-茚-1-基)-4-(三氟甲基)苯甲酸甲酯1d(800mg,2.36mmol)溶于四氢呋喃(20ml)中,加入氢氧化钠(189mg,4.72mmol)的水溶液(5mL)。反应混合物在室温下搅拌12小时。反应液减压浓缩至剩余少部分水溶液,加20mL水,用2M的盐酸水溶液调节pH至2,有固体析出,将固体过滤,并于真空中干燥。得到化合物1e(670mg)(淡黄色固体),产率:87.37%。1H NMR(400MHz,Chloroform-d)δ8.10(d,J=8.0Hz,1H),7.56(d,J=8.0Hz,1H),7.34(s,1H),7.00(d,J=8.7Hz,1H),6.85(d,J=6.9Hz,2H),5.31(t,J=7.9Hz,1H),3.00(qd,J=16.1,10.0Hz,2H),2.86–2.73(m,1H),2.02(dq,J=17.0,8.5Hz,1H).
第五步2-(5-氟-2,3-二氢-1H-茚-1-基)-4-(三氟甲基)苯甲酰氯1f的制备
将2-(5-氟-2,3-二氢-1H-茚-1-基)-4-(三氟甲基)苯甲酸1e(100mg,0.31mmol)溶于无水二氯甲烷(4mL)中,置于冰浴,滴加草酰氯(0.32mL,3.70mmol),加毕,继续搅拌3小时。反应液浓缩,得到化合物1f(106mg),产品不经纯化直接用于下一步反应。
第六步2-(5-氟-2,3-二氢-1H-茚-1-基)-N-(3-氨磺酰苯基)-4-(三氟甲基)苯甲酰胺1的制备
将间氨基苯磺酰胺(64mg,0.37mmol,毕得医药)溶于无水四氢呋喃中,加入N,N-二异丙基乙胺(DIEA,0.102mL,0.62mmol)置于冰浴,滴加2-(6-氟-1,2,3,4-四氢萘-1-基)-4(三氟甲基)苯甲酰氯1f(106mg,0.31mmol)的无水二氯甲烷溶液,加毕,转移至室温反应过夜。反应液浓缩,加入20mL水和20mL乙酸乙酯,均匀混合,静置分层。水相用乙酸乙酯萃取(1 5mL×3)。合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩。用硅胶柱色谱法(MeOH:DCM;1:80至1:50)纯化,得到化合物1(91mg)(白色固体),产率:61.49%。1H NMR(400MHz,Methanol-d4)δ8.20(s,1H),7.88–7.77(m,1H),7.73(d,J=8.0Hz,1H),7.67(d,J=8.1Hz,1H),7.63(d,J=8.2Hz,1H),7.51(t,J=8.0Hz,1H),7.34(s,1H),7.03(d,J=9.0Hz,1H),6.96(dd,J=8.2,5.3Hz,1H),6.87(td,J=8.9,2.3Hz,1H),4.75(t,J=8.1Hz,1H),3.14–2.90(m,2H),2.80–2.66(m,1H),2.23–2.07(m,1H).
实施例2 2-(5-氟-2,3-二氢-1H-茚-1-基)-N-((2-吗啉吡啶-3-基)甲基)-4-(三氟甲基)苯甲酰胺2的制备
采用实施例1的合成路线,将第六步原料间氨基苯磺酰胺替换为[2-(4-吗啉)-3-吡啶]甲胺制得化合物2(57mg)。MS m/z(ESI):500.18[M+l]+。
实施例3 2-(5-氟-2,3-二氢-1H-茚-1-基)-N-(2-氧代-1,2-二氢吡啶-4-基)-4-(三氟甲基)苯甲酰胺3的制备
第一步2-(5-氟-2,3-二氢-1H-茚-1-基)-N-(2-甲氧基吡啶-4-基)-4-(三氟甲基)苯甲酰胺3a的制备
将4-氨基-2-甲氧基吡啶(46mg,0.37mmol,毕得医药)溶于无水四氢呋喃中,加入N,N-二异丙基乙胺(102μL,0.62mmol),置于冰浴,滴加2-(6-氟-1,2,3,4-四氢萘-1-基)-4(三氟甲基)苯甲酰氯1f(106mg,0.31mmol)的无水二氯甲烷溶液,加毕,转移至室温搅拌过夜。反应液浓缩,加入20mL水和20mL乙酸乙酯,均匀混合,静置分层。水相用乙酸乙酯萃取(10mL×3)。合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩。用硅胶柱色谱法(MeOH:DCM;1:120至1:70)纯化,得到化合物3a(101mg)(白色固体),产率:75.87%。MS m/z(ESI):431.13[M+l]+。
第二步化合物3的制备
将2-(5-氟-2,3-二氢-1H-茚-1-基)-N-(2-甲氧基吡啶-4-基)-4-(三氟甲基)苯甲酰胺3a(101mg,0.25mmol,溶于冰醋酸(2mL)中,加入2mL 33%的氢溴酸的醋酸溶液,加热至90℃回流,反应过夜。反应液浓缩,倾入20mL饱和碳酸氢钠溶液中,充分搅拌,直至气泡消失。水相用乙酸乙酯萃取(10mL×3)。合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩。用硅胶柱色谱法(MeOH:DCM;1:50至1:30)纯化,得到化合物3(59mg)(白色固体),产率:60.38%。1H NMR(400MHz,DMSO-d6)δ11.32(s,1H),10.74(s,1H),7.75(s,2H),7.33(d,J=6.5Hz,2H),7.14(d,J=8.8Hz,1H),6.94(dt,J=14.2,8.5Hz,2H),6.83(s,1H),6.44(d,J=6.1Hz,1H),4.59(t,J=8.1Hz,1H),3.08–2.87(m,2H),2.65–2.55(m,1H),2.17–2.04(m,1H).
实施例4 2-(6-氟-2,3-二氢-1H-茚-1-基)-N-(2-氧代-1,2-二氢吡啶-4-基)-4-(三氟甲基)苯甲酰胺4的制备
采用实施例1合成路线的第一步到第五步反应,将起始原料5-氟-1-茚酮替换为6-氟-
1-茚酮,得到酰氯中间体,并继续采用实施例3的合成路线制得化合物4(38mg)。MS m/z(ESI):417.18[M+l]+。
实施例5 2-(6-氟-1,2,3,4-四氢萘-1-基)-N-(3-氨磺酰苯基)-4-(三氟甲基)苯甲酰胺5的制备
第一步N'-(6-氟-1,2,3,4-四氢萘-1-亚基)-4-甲苯磺酰肼5b的制备
将对甲苯磺酰肼(6.73g,36.11mmol)悬浮于甲醇溶液中,加热至60℃,直到对甲苯磺酰肼完全溶解。慢慢向混合物中加入6-氟-3,4-二氢-2H-1-萘酮5a(5.00g,30.09mmol,上海皓鸿生物医药科技有限公司)。3小时后,产生沉淀物,将沉淀物过滤,用甲醇淋洗。在真空中干燥沉淀物。得到化合物5b(9.60g)(白色固体),产率:95.41%。1H NMR(400MHz,Chloroform-d)δ7.96(dd,J=8.7,6.1Hz,1H),7.92(d,J=8.1Hz,2H),7.72(s,1H),7.33(d,J=8.0Hz,2H),6.89(td,J=8.6,2.1Hz,1H),6.78(d,J=9.1Hz,1H),2.74–2.65(m,2H),2.46(t,J=6.5Hz,2H),2.42(s,3H),1.95–1.81(m,2H).
第二步2-(6-氟-1,2,3,4-四氢萘-1-基)-4(三氟甲基)苯甲酸甲酯5c的制备
向N'-(6-氟-1,2,3,4-四氢萘-1-亚基)-4-甲苯磺酰肼5b(3.00g,8.97mmol),[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(306mg,0.375mol),碳酸钠(1.59g,14.98mmol)和1,4-二氧六环/水(4:1,40mL)的混合物中加入2-溴-4-三氟甲基苯甲酸甲酯(2.12g,7.49mmol,上海皓鸿生物医药科技有限公司)。氩气保护,将反应混合物在90℃下搅拌10h。冷却,反应液减压浓缩,加入50mL水和50mL乙酸乙酯,均匀混合,静置分层。水相用乙酸乙酯萃取(10mL×3)。合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩。用硅胶柱色谱法(EA:PE;1:20至1:10)纯化,得到化合物5c(2.02g)(黄色固体),产率:76.69%。1H NMR(400MHz,Chloroform-d)δ7.96(d,J=8.1Hz,1H),7.67(d,J=8.2Hz,1H),7.61(s,1H),6.92(d,J=9.0Hz,1H),6.73(td,J=8.5,2.2Hz,1H),6.53(dd,J=8.3,5.8Hz,1H),5.99(t,J=4.5Hz,1H),3.54(s,3H),3.00–2.75(m,2H),2.50–2.35(m,2H).
第三步2-(6-氟-1,2,3,4-四氢萘-1-基)-4(三氟甲基)苯甲酸甲酯5d的制备
将2-(6-氟-1,2,3,4-四氢萘-1-基)-4(三氟甲基)苯甲酸甲酯5c(2g,5.68mmol)、10%Pd-C催化剂(400mg)和乙醇(60mL)的混合物在氢气下60℃搅拌30h。过滤出催化剂后,蒸发滤液。用硅胶柱色谱法(EA:PE;1:20至1:15)纯化,得到化合物5d(1.70g)(白色固体),产率:84.52%。1H NMR(400MHz,Chloroform-d)δ8.08(d,J=8.2Hz,1H),7.55(d,J=8.4Hz,1H),7.23(s,1H),6.86(dd,J=9.5,2.1Hz,1H),6.75(td,J=8.4,2.4Hz,1H),6.71–6.64(m,1H),5.13(t,J=6.1Hz,1H),3.73(s,3H),2.95(dt,J=13.0,6.6Hz,1H),2.89–2.80(m,1H),2.28(dt,J=9.6,6.3Hz,1H),1.95–1.73(m,3H).
第四步2-(6-氟-1,2,3,4-四氢萘-1-基)-4(三氟甲基)苯甲酸5e的制备
将2-(6-氟-1,2,3,4-四氢萘-1-基)-4(三氟甲基)苯甲酸甲酯5d(1.7g,4.83mmol)
溶于四氢呋喃(28ml)中,加入氢氧化钠(386mg,9.65mmol)的水溶液(7mL)。反应混合物在室温下搅拌6小时。反应液减压浓缩至剩余少部分水溶液,加20mL水,用2M的盐酸水溶液调节pH至2,有固体析出,将固体过滤,并于真空中干燥。得到化合物5e(1.4g)(黄色固体),产率:85.75%。MS m/z(ESI):337.08[M-l]-.
第五步2-(6-氟-1,2,3,4-四氢萘-1-基)-4(三氟甲基)苯甲酰氯5f的制备
将2-(6-氟-1,2,3,4-四氢萘-1-基)-4(三氟甲基)苯甲酸5e(100mg,0.29mmol)溶于无水二氯甲烷(4ml)中,置于冰浴,滴加草酰氯(0.30mL,3.55mmol),加毕,继续搅拌3小时。反应液浓缩,得到化合物5f(105mg),产品不经纯化直接用于下一步反应。
第六步2-(6-氟-1,2,3,4-四氢萘-1-基)-N-(3-氨磺酰苯基)-4-(三氟甲基)苯甲酰胺5的制备
将间氨基苯磺酰胺(61mg,0.35mmol,毕得医药)溶于无水四氢呋喃中,加入DIEA(98μL,0.59mmol),置于冰浴,滴加2-(6-氟-1,2,3,4-四氢萘-1-基)-4(三氟甲基)苯甲酰氯5f(105mg,0.29mmol)的无水二氯甲烷溶液,加毕,转移至室温反应2小时。反应液浓缩,加入20mL水和20mL乙酸乙酯,均匀混合,静置分层。水相用乙酸乙酯萃取(10mL×3)。合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩。用硅胶柱色谱法(MeOH:DCM;1:100至1:50)纯化,得到化合物5(105mg)(白色固体),产率:72.55%。1H NMR(400MHz,Methanol-d4)δ8.35(s,1H),7.80(d,J=7.6Hz,1H),7.73–7.60(m,3H),7.53(t,J=7.9Hz,1H),7.22(s,1H),6.84(t,J=8.6Hz,2H),6.77(t,J=8.2Hz,1H),4.56(t,J=6.2Hz,1H),3.01–2.89(m,1H),2.87–2.75(m,1H),2.31–2.16(m,1H),2.02–1.82(m,2H),1.81–1.64(m,1H).
实施例6 2-(6-氟-1,2,3,4-四氢萘-1-基)-N-(2-氧代-1,2-二氢吡啶-4-基)-4-(三氟甲基)苯甲酰胺6的制备
第一步2-(6-氟-1,2,3,4-四氢萘-1-基)-N-(2-甲氧基吡啶-4-基)-4-(三氟甲基)苯甲酰胺6a的制备
将4-氨基-2-甲氧基吡啶(44mg,0.35mmol,毕得医药)溶于无水四氢呋喃中,加入DIEA(98μL,0.59mmol),置于冰浴,滴加2-(6-氟-1,2,3,4-四氢萘-1-基)-4(三氟甲基)苯甲酰氯5f(105mg,0.29mmol)的无水二氯甲烷溶液,加毕,转移至室温搅拌过夜。反应液浓缩,加入20mL水和20mL乙酸乙酯,均匀混合,静置分层。水相用乙酸乙酯萃取(10mL×3)。合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩。用硅胶柱色谱法(MeOH:DCM;1:100至1:50)纯化,得到化合物6a(109mg)(白色固体),产率:83.32%。MS m/z(ESI):445.15[M+l]+.
第二步2-(6-氟-1,2,3,4-四氢萘-1-基)-N-(2-氧代-1,2-二氢吡啶-4-基)-4-(三氟甲基)苯甲酰胺6的制备
将2-(6-氟-1,2,3,4-四氢萘-1-基)-N-(2-甲氧基吡啶-4-基)-4-(三氟甲基)苯甲酰胺6a(109mg,0.25mmol,溶于冰醋酸(2mL)中,加入2mL 33%的氢溴酸的醋酸溶液,加热至90℃回流,反应过夜。反应液浓缩,倾入20mL饱和碳酸氢钠溶液中,充分搅拌,直至气泡消失。水相用乙酸乙酯萃取(10mL×3)。合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩。用硅胶柱色谱法(MeOH:DCM;1:50至1:30)纯化,得到化合物6(89mg)(白色固体),产率:84.31%。1H NMR(400MHz,DMSO-d6)δ
11.31(s,1H),10.71(s,1H),7.73(s,2H),7.32(d,J=7.2Hz,1H),7.23(s,1H),6.96(d,J=9.8Hz,1H),6.89(t,J=8.6Hz,1H),6.81(s,1H),6.80–6.74(m,1H),6.41(d,J=7.1Hz,1H),4.37(t,J=7.1Hz,1H),2.99–2.87(m,1H),2.82–2.71(m,1H),2.18–2.07(m,1H),1.93–1.76(m,2H),1.73–1.58(m,1H).
实施例7 2-(6-氟-1,2,3,4-四氢萘-1-基)-N-(3-(氨磺酰氨基)苯基)-4-(三氟甲基)苯甲酰胺7的制备
采用实施例5的合成路线,将第六步原料间氨基苯磺酰胺替换为N-(3-氨基苯基)磺胺制得化合物7(46mg)。1H NMR(400MHz,DMSO-d6)δ10.67(s,1H),9.52(s,1H),7.71(s,2H),7.58(s,1H),7.34(d,J=8.1Hz,1H),7.23(t,J=8.1Hz,1H),7.18(s,1H),7.05(s,2H),7.02–6.94(m,2H),6.90(td,J=8.6,2.5Hz,1H),6.85–6.79(m,1H),4.42(t,J=7.1Hz,1H),3.01–2.88(m,1H),2.77(dd,J=16.4,8.5Hz,1H),1.93–1.75(m,2H),1.71–1.55(m,1H).
实施例8 2-(6-氟-1,2,3,4-四氢萘-1-基)-N-(3-(N-甲基氨磺酰)苯基)-4-(三氟甲基)苯甲酰胺8的制备
采用实施例5的合成路线,将第六步原料间氨基苯磺酰胺替换为N-甲基-3-氨基苯磺酰胺制得化合物8(53mg)。1H NMR(400MHz,DMSO-d6)δ10.97(s,1H),8.32(s,1H),7.84(d,J=8.1Hz,1H),7.76(q,J=8.1Hz,2H),7.58(t,J=7.9Hz,1H),7.52(q,J=4.8Hz,2H),7.25(s,1H),6.96(dd,J=9.9,2.3Hz,1H),6.89(td,J=8.6,2.5Hz,1H),6.84–6.75(m,1H),4.44(t,J=7.2Hz,1H),2.94(ddd,J=15.3,8.8,6.0Hz,1H),2.77(dt,J=16.7,4.4Hz,1H),2.44(d,J=4.9Hz,3H),2.20–2.09(m,1H),1.96–1.74(m,2H),1.73–1.59(m,1H).
实施例9 2-(7-氟苯并二氢吡喃-4-基)-N-(3-氨磺酰苯基)-4-(三氟甲基)苯甲酰胺9的制备
第一步N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼9b的制备
将对甲苯磺酰肼(6.73g,36.11mmol)悬浮于甲醇溶液中,加热至60℃,直到对甲
苯磺酰肼完全溶解。慢慢向混合物中加入7-氟-4-二氢色原酮9a(5.00g,30.09mmol,上海皓鸿生物医药科技有限公司)。3小时后,产生沉淀物,将沉淀物过滤,用甲醇淋洗。在真空中干燥沉淀物,得到化合物9b(9.60g)(白色固体),产率:95.41%。1H NMR(400MHz,Chloroform-d)δ7.90(d,J=7.7Hz,2H),7.87(d,J=8.8Hz,1H),7.54(s,1H),7.34(d,J=8.0Hz,2H),6.67(t,J=7.7Hz,1H),6.56(d,J=9.4Hz,1H),4.24(t,J=5.9Hz,2H),2.65(t,J=5.9Hz,2H),2.43(s,3H).
第二步2-(7-氟-2H-苯并吡喃-4-基)-4(三氟甲基)苯甲酸甲酯9c的制备
向N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼9b(3.00g,8.97mmol),[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(306mg,0.375mol),碳酸钠(1.59g,14.98mmol)和1,4-二氧六环/水(4:1)(40mL)的混合物中加入2-溴-4-三氟甲基苯甲酸甲酯(2.12g,7.49mmol,上海皓鸿生物医药科技有限公司)。氩气保护,将反应混合物在90℃下搅拌10h。冷却,反应液减压浓缩,加入50mL水和50mL乙酸乙酯,均匀混合,静置分层。水相用乙酸乙酯萃取(10mL×3)。合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩。用硅胶柱色谱法(EA:PE;1:20至1:10)纯化,得到化合物9c(2.0 2g)(黄色固体),产率:76.69%。1H NMR(400MHz,Chloroform-d)δ8.02(d,J=8.1Hz,1H),7.71(d,J=8.1Hz,1H),7.60(s,1H),6.68–6.58(m,1H),6.50(d,J=7.5Hz,2H),5.69(t,J=3.8Hz,1H),4.90(dd,J=14.2,3.4Hz,2H),3.63(s,3H).
第三步2-(7-氟-2H-苯并吡喃-4-基)-4(三氟甲基)苯甲酸9d的制备
将2-(7-氟-2H-苯并吡喃-4-基)-4(三氟甲基)苯甲酸甲酯9c(1.7g,4.80mmol)溶于四氢呋喃(28ml)中,加入氢氧化钠(386mg,9.65mmol)的水溶液(7mL)。反应混合物在室温下搅拌6小时。反应液减压浓缩至剩余少部分水溶液,加20mL水,用2M的盐酸水溶液调节pH至2,有固体析出,将固体过滤,并于真空中干燥。得到化合物9d(1.4g)(黄色固体),产率:85.75%。1H NMR(400MHz,Chloroform-d)δ8.12(d,J=8.1Hz,1H),7.74(d,J=8.1Hz,1H),7.59(s,1H),6.60(d,J=9.7Hz,1H),6.47(d,J=7.3Hz,2H),5.65(t,J=3.6Hz,1H),4.89(d,J=3.6Hz,2H).
第四步2-(7-氟-2H-苯并吡喃-4-基)-4(三氟甲基)苯甲酰氯9e的制备
将2-(7-氟-2H-苯并吡喃-4-基)-4(三氟甲基)苯甲酸9d(100mg,0.29mmol)溶于无水二氯甲烷(4ml)中,置于冰浴,滴加草酰氯(0.30mL,3.55mmol),加毕,继续搅拌3小时。反应液浓缩,得到化合物9e(105mg),产品不经纯化直接用于下一步反应。
第五步2-(7-氟-2H-苯并吡喃-4-基)-N-(3-氨磺酰苯基)-4-(三氟甲基)苯甲酰胺9f的制备
将间氨基苯磺酰胺(60mg,0.35mmol,毕得医药)溶于无水四氢呋喃中,加入DIEA(97μL,0.58mmol),置于冰浴,滴加2-(7-氟-2H-苯并吡喃-4-基-4-基)-4(三氟甲基)苯甲酰氯9e(105mg,0.29mmol)的无水二氯甲烷溶液,加毕,转移至室温反应2小时。反应液浓缩,加入20mL水和20mL乙酸乙酯,均匀混合,静置分层。水相用乙酸乙酯萃取(10mL×3)。合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩。用硅胶柱色谱法(MeOH:DCM;1:100至1:50)纯化,得到化合物9f(105mg)(白色固体),产率:72.55%。1H NMR(400MHz,Methanol-d4)δ8.05(t,J=1.8Hz,1H),7.87(s,1H),7.71(s,1H),7.64(d,J=7.8Hz,1H),7.53(d,J=8.9Hz,1H),7.45(t,J=7.9Hz,1H),6.73(dd,J=9.3,6.3Hz,1H),6.53(ddd,J=9.1,5.4,2.5Hz,2H),5.94(t,J=3.9Hz,1H),4.87–4.80(m,2H).
第六步2-(7-氟苯并二氢吡喃-4-基)-N-(3-氨磺酰苯基)-4-(三氟甲基)苯甲酰胺9的制备
将2-(7-氟-2H-苯并吡喃-4-基)-N-(3-氨磺酰苯基)-4-(三氟甲基)苯甲酰胺9f(100mg,5.68mmol)、10%Pd-C催化剂(20mg)和乙醇(8mL)的混合物在氢气下60℃搅拌30h。过滤出催化剂后,蒸干滤液。用硅胶柱色谱法(EA:PE;1:20至1:15)纯
化,得到化合物9(82mg)(白色固体),产率:81.67%。1H NMR(400MHz,Methanol-d4)δ8.36(t,J=1.7Hz,1H),7.85–7.80(m,1H),7.75(d,J=8.0Hz,1H),7.70(s,1H),7.68(s,1H),7.54(t,J=8.0Hz,1H),7.29(s,1H),6.88–6.70(m,1H),6.65–6.48(m,2H),4.65(t,J=6.9Hz,1H),4.27–4.04(m,2H),2.45–2.31(m,1H),2.26–2.14(m,1H).
实施例10 2-(7-氟苯并二氢吡喃-4-基)-N-((2-吗啉吡啶-3-基)甲基)-4-(三氟甲基)苯甲酰胺10的制备
采用实施例9的合成路线,将第五步原料间氨基苯磺酰胺替换为[2-(4-吗啉)-3-吡啶]甲胺制得化合物10(26mg)。1H NMR(400MHz,Methanol-d4)δ8.20(d,J=3.7Hz,1H),7.78(d,J=7.0Hz,1H),7.66(d,J=9.6Hz,2H),7.28(d,J=18.9Hz,1H),7.11–7.02(m,1H),6.79–6.72(m,1H),6.62–6.51(m,2H),4.62(t,J=4.7Hz,1H),4.29–4.18(m,1H),4.17–4.07(m,1H),3.89–3.81(m,4H),3.15–3.07(m,4H),2.35–2.21(m,1H),2.23–2.08(m,1H).实施例11 2-(7-氟苯并二氢吡喃-4-基)-N-(2-氧代-1,2-二氢吡啶-4-基)-4-(三氟甲基)苯甲酰胺11的制备
第一步2-(7-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酸甲酯11a的制备
将2-(7-氟-2H-苯并吡喃-4-基)-4(三氟甲基)苯甲酸甲酯9c(500mg,1.42mmol)、10%Pd-C催化剂(100mg)和乙醇(50mL)的混合物在氢气下60℃搅拌30h。过滤出催化剂后,蒸发滤液。用硅胶柱色谱法(EA:PE;1:40至1:20)纯化,得到化合物11a(458mg)(白色油状物),产率:91.08%。1H NMR(400MHz,Chloroform-d)δ8.00(d,J=8.1Hz,1H),7.57(d,J=8.2Hz,1H),7.29(s,1H),6.72–6.66(m,1H),6.63(dd,J=10.2,2.5Hz,1H),6.55(td,J=8.4,2.6Hz,1H),5.06(t,J=6.7Hz,1H),4.20(t,J=5.3Hz,2H),2.49–2.35(m,1H),2.16–2.03(m,1H).
第二步2-(7-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酸11b的制备
将2-(7-氟苯并二氢吡喃-4-基)-4(三氟甲基)苯甲酸甲酯11a(400mg,1.13mmol)溶于四氢呋喃(12ml)中,加入氢氧化钠(90mg,2.26mmol)的水溶液(3mL)。反应混合物在室温下搅拌过夜。反应液减压浓缩至剩余少部分水溶液,加20mL水,用2M的盐酸水溶液调节pH至2,有固体析出,将固体过滤,并于真空中干燥。得到化合物11b(308mg)(淡黄色固体),产率:80.17%。1H NMR(400MHz,Chloroform-d)δ8.15(d,J=8.1Hz,1H),7.60(d,J=8.4Hz,1H),7.30(s,1H),6.71–6.66(m,1H),6.63(dd,J=10.2,
2.5Hz,1H),6.55(td,J=8.3,2.5Hz,1H),5.20(t,J=6.6Hz,1H),4.19(dt,J=6.0,3.2Hz,2H),2.49–2.37(m,1H),2.15–2.01(m,1H).
第三步2-(7-氟苯并二氢吡喃-4-基)-4(三氟甲基)苯甲酰氯11c的制备
将2-(7-氟苯并二氢吡喃-4-基)-4(三氟甲基)苯甲酸11b(100mg,0.29mmol)溶于无水二氯甲烷(4ml)中,置于冰浴,滴加草酰氯(0.30mL,3.53mmol),加毕,继续搅拌3小时。反应液浓缩,得到化合物11c(105mg),产品不经纯化直接用于下一步反应。
第四步2-(7-氟苯并二氢吡喃-4-基)-N-(2-甲氧基吡啶-4-基)-4-(三氟甲基)苯甲酰胺11d的制备
将4-氨基-2-甲氧基吡啶(44mg,0.35mmol,毕得医药)溶于无水四氢呋喃中,加入DIEA(97μL,0.59mmol),置于冰浴,滴加2-(7-氟苯并二氢吡喃-4-基)-4(三氟甲基)苯甲酰氯11c(105mg,0.29mmol)的无水二氯甲烷溶液,加毕,转移至室温搅拌过夜。反应液浓缩,加入20mL水和20mL乙酸乙酯,均匀混合,静置分层。水相用乙酸乙酯萃取(10mL×3)。合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩。用硅胶柱色谱法(MeOH:DCM;1:100至1:50)纯化,得到化合物11d(91mg)(白色固体),产率:73.12%。
第五步2-(7-氟苯并二氢吡喃-4-基)-N-(2-氧代-1,2-二氢吡啶-4-基)-4-(三氟甲基)苯甲酰胺11的制备
将2-(7-氟苯并二氢吡喃-4-基)-N-(2-甲氧基吡啶-4-基)-4-(三氟甲基)苯甲酰胺11d(91mg,0.25mmol,溶于冰醋酸(2mL)中,加入33%的氢溴酸的醋酸溶液(2mL),加热至90℃回流,反应过夜。反应液浓缩,倾入20mL饱和碳酸氢钠溶液中,充分搅拌,直至气泡消失。水相用乙酸乙酯萃取(10mL×3)。合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩。用硅胶柱色谱法(MeOH:DCM;1:50至1:30)纯化,得到化合物11(59mg)(白色固体),产率:66.94%。1H NMR(400MHz,Methanol-d4)δ7.74–7.66(m,2H),7.40(d,J=7.2Hz,1H),7.31(s,1H),7.04(d,J=1.9Hz,1H),6.81–6.71(m,2H),6.59–6.49(m,2H),4.59(t,J=7.1Hz,1H),4.28–4.05(m,2H),2.41–2.26(m,1H),2.27–2.12(m,1H).
实施例12 2-(7-氟苯并二氢吡喃-4-基)-N-(3-(氨磺酰氨基)苯基)-4-(三氟甲基)苯甲酰胺12的制备
采用实施例9的合成路线,将第五步原料间氨基苯磺酰胺替换为N-(3-氨基苯基)磺胺制得化合物12(31mg)。1H NMR(400MHz,DMSO-d6)δ10.69(s,1H),9.53(s,1H),7.76(s,2H),7.57(s,1H),7.36(d,J=8.3Hz,1H),7.29–7.20(m,2H),7.05(s,2H),6.99(d,J=8.4Hz,1H),6.85–6.78(m,1H),6.68(ddd,J=15.6,9.5,2.5Hz,2H),4.53(t,J=7.0Hz,1H),4.23–4.06(m,2H),2.27(dt,J=9.3,4.8Hz,1H),2.16(dq,J=13.2,7.7,7.0Hz,1H).
实施例13 2-(7-氟苯并二氢吡喃-4-基)-N-(3-(N-甲基氨磺酰)苯基)-4-(三氟甲基)苯甲酰胺13的制备
采用实施例9的合成路线,将第五步原料间氨基苯磺酰胺替换为N-甲基-3-氨基苯磺酰胺制得化合物13(53mg)。1H NMR(400MHz,DMSO-d6)δ11.00(s,1H),8.33(s,1H),7.94–7.75(m,3H),7.59(t,J=7.9Hz,1H),7.53(d,J=9.2Hz,2H),7.32(s,1H),6.80(t,J=7.6Hz,1H),6.71–6.64(m,2H),4.57(t,J=7.1Hz,1H),4.24–4.13(m,2H),2.45(d,J=4.9Hz,3H),2.33–2.14(m,2H).
实施例14 2-(7-氟苯并二氢吡喃-4-基)-N-(2-氧代吲哚-5-基)-4-(三氟甲基)苯甲酰胺14的制备
采用实施例11的合成路线的第一步到第四步反应,将第四步原料4-氨基-2-甲氧基吡啶替换为5-氨基-1,3-二氢吲哚-2-酮制得化合物14(31mg)。1H NMR(400MHz,Methanol-d4)δ7.69(q,J=8.2Hz,2H),7.53(s,1H),7.27(s,1H),7.22(d,J=8.0Hz,1H),7.12(dd,J=8.1,1.5Hz,1H),6.86–6.77(m,1H),6.57(ddd,J=13.1,7.4,4.1Hz,2H),4.63(t,J=6.8Hz,1H),4.25–4.10(m,2H),3.50(s,2H),2.41–2.31(m,1H),2.24–2.13(m,1H).
实施例15 2-(7-氟苯并二氢吡喃-4-基)-N-(2-氧代-2,3-二氢苯并[d]恶唑-6-基)-4-(三氟甲基)苯甲酰胺15的制备
采用实施例11的合成路线的第一步到第四步反应,将第四步原料4-氨基-2-甲氧基吡啶替换为6-氨基-2-苯并噁唑酮制得化合物15(45mg)。1H NMR(400MHz,DMSO-d6)δ11.61(bs,1H),10.72(s,1H),7.80–7.74(m,3H),7.37(dd,J=8.4,1.7Hz,1H),7.28(s,1H),7.07(d,J=8.4Hz,1H),6.82–6.76(m,1H),6.66(qd,J=9.3,8.4,2.5Hz,2H),4.54(t,J=7.0Hz,1H),4.18(t,J=4.9Hz,2H),2.33–2.10(m,2H).
实施例16 N-(3-氨基甲酰苯基)-2-(7-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酰胺16的制备
第一步N-(3-氰基苯基)-2-(7-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酰胺16a的制备
将2-(7-氟苯并二氢吡喃-4-基)-4(三氟甲基)苯甲酸11b(100mg,0.29mmol)与间氨基苯甲腈(42mg,0.35mmol)溶于吡啶中(0.5mL),冰浴下滴加三氯氧磷(55μL,0.58mmol)。加毕,室温搅拌2小时。反应液减压浓缩,加入15mL水和15mL乙酸乙酯,均匀混合,静置分层。水相用乙酸乙酯萃取(10mL×3)。合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩。用硅胶柱色谱法(MeOH:DCM;1:100至1:50)纯化,得到化合物16a(98mg)(白色固体),产率:75.72%。1H NMR(400MHz,Chloroform-d)δ8.05(s,1H),8.04(s,1H),7.78(d,J=8.0Hz,1H),7.65(d,J=8.0Hz,1H),7.60(d,J=8.0Hz,1H),7.48(t,J=7.9Hz,1H),7.42(d,J=7.6Hz,1H),7.36(s,1H),6.71–6.66(m,1H),6.57(dd,J=10.1,2.0Hz,1H),6.49(td,J=8.3,2.2Hz,1H),4.64(t,J=7.2Hz,1H),4.25(dt,J=9.0,4.2Hz,1H),4.16(t,J=9.1Hz,1H),2.44–2.32(m,1H),2.24–2.14(m,1H).
第二步N-(3-氨基甲酰苯基)-2-(7-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酰胺16的制备
将N-(3-氰基苯基)-2-(7-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酰胺16a(98mg,0.22mmol)溶于5mL的4N氯化氢-1,4-二氧六环溶液,加入乙醇(0.26mL),密封,0-5℃下搅拌24小时。反应混合物减压浓缩,浓缩物中加入7M氨-甲醇溶液(10mL)和氯化铵(24mg,0.44mmol),室温下搅拌反应过夜。反应液减压浓缩,用硅胶柱色谱法(MeOH:DCM;1:30至1:10)纯化,得到化合物16(61mg)(白色固体),产率:59.93%。
MS m/z(ESI):458.30[M+l]+.
实施例17 N-(3-氨甲酰苯基)-2-(7-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酰胺17的制备
采用实施例11的合成路线的第一步到第四步反应,将第四步原料4-氨基-2-甲氧基吡啶替换为3-氨基苯甲酰胺制得化合物17(50mg)。1H NMR(400MHz,Methanol-d4)δ8.17(s,1H),7.86(d,J=8.2Hz,1H),7.74(d,J=8.0Hz,1H),7.68(d,J=8.2Hz,1H),7.65(d,J=7.8Hz,1H),7.46(t,J=7.9Hz,1H),7.28(s,1H),6.82(t,J=7.4Hz,1H),6.57(d,J=10.5Hz,2H),4.66(t,J=6.9Hz,1H),4.25–4.08(m,2H),2.42–2.32(m,1H),2.24–2.14(m,1H).实施例18 2-(7-氟苯并二氢吡喃-4-基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺18的制备
第一步N-(6-氯哒嗪-4-基)-2-(7-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酰胺18a的制备
将4氨基-6-氯哒嗪(46mg,0.35mmol,韶远科技(上海)有限公司)溶于无水四氢呋喃中(3mL),冰浴冷却,加入氢化钠(23mg,0.58mmol,60%纯度),反应30分钟。滴加2-(7-氟
苯并二氢吡喃-4-基)-4(三氟甲基)苯甲酰氯11c(105mg,0.29mmol)的无水四氢呋喃溶液,氩气保护,室温反应过夜。加入20mL水和20mL乙酸乙酯,均匀混合,静置分层。水相用乙酸乙酯萃取(10mL×3)。合并有机相,用无水硫酸钠干燥,减压浓缩,制得粗品化合物18a(67mg),产物不经纯化,直接用于下一步反应。MS m/z(ESI):452.20[M+l]+.
第二步2-(7-氟苯并二氢吡喃-4-基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺18的制备
将上步所得粗品化合物18a(67mg,0.15mmol)溶于乙酸(5mL),加入乙酸钾(87mg,0.89mmol),130℃反应2小时。反应液减压浓缩,倾入20mL饱和碳酸氢钠溶液中,充分搅拌,直至气泡消失。水相用乙酸乙酯萃取(10mL×3)。合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩。用硅胶柱色谱法(MeOH:DCM;1:40至1:20)纯化,得到化合物18(29mg)(白色固体),产率:45.13%。1H NMR(600MHz,Chloroform-d)δ12.25(s,1H),9.82(s,1H),8.14(s,1H),7.62(d,J=7.8Hz,1H),7.49(d,J=8.0Hz,1H),7.32–7.18(m,2H),6.62(t,J=7.5Hz,1H),6.50(dd,J=10.0,2.2Hz,2H),6.44–6.39(m,1H),4.56(t,J=6.8Hz,1H),4.19–4.13(m,1H),4.07(t,J=7.3Hz,1H),2.34–2.20(m,2H),2.14–2.02(m,2H).
实施例19 5-氯-2-(6-氟-1,2,3,4-四氢萘-1-基)-N-(3-氨磺酰苯基)-4-(三氟甲基)苯甲酰胺胺19的制备
第一步5-氨基-2-溴-4-(三氟甲基)苯甲酸甲酯19b的制备
将3-氨基-4-三氟甲基苯甲酸甲酯19a(5g,22.81mmol)溶于DMF(100mL)中。在0℃条件下,分批加入N-溴代丁二酰亚胺(4.87g,27.38mmol),加毕,将混合物在室温下搅拌70分钟。加入200mL水和200mL乙酸乙酯,均匀混合,静置分层。水相用乙酸乙酯萃取(100mL×3)。合并有机相,用饱和氯化钠溶液洗涤3次,无水硫酸钠干燥,过滤,滤液浓缩。用硅胶柱色谱法(EA:PE;1:50至1:30)纯化,得到化合物19b(5.20g)(白色固体),产率:76.47%。1H NMR(400MHz,Chloroform-d)δ7.67(s,1H),7.14(s,1H),4.30(s,2H),3.93(s,3H).
第二步5-氨基-2-(6-氟-3,4-二氢萘-1-基)-4-(三氟甲基)苯甲酸甲酯19c的制备
向N'-(6-氟-1,2,3,4-四氢萘-1-亚基)-4-甲苯磺酰肼5b(5.35g,16.10mmol),[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(548mg,0.67mmol),碳酸钠(1.85g,26.84mmol)和1,4-二氧六环/水(4:1)(60mL)的混合物中加入5-氨基-2-溴-4-(三氟甲基)苯甲酸甲酯19b(4.00g,13.42mmol)。氩气保护,将反应混合物在90℃下搅拌10h。冷却,反应液减压浓缩,加入70mL水和70mL乙酸乙酯,均匀混合,静置分层。水相用乙酸乙酯萃取(40mL×3)。合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩。用硅胶柱色谱法(EA:PE;1:20至1:10)纯化,得到化合物19c(3.55g)(无色油状物),产率:72.41%。1H NMR(400MHz,Chloroform-d)δ7.39(s,1H),7.23(s,1H),6.89(dd,J=9.1,2.6Hz,1H),6.72(td,J=8.6,2.7Hz,1H),6.60(dd,J=8.5,5.8Hz,1H),5.92(t,J=4.6Hz,1H),3.48(s,3H),2.80–2.86(s,2H),2.42–2.30(m,2H).
第三步5-氨基-2-(6-氟-1,2,3,4-四氢萘-1-基)-4-(三氟甲基)苯甲酸甲酯19d的制备
将5-氨基-2-(6-氟-3,4-二氢萘-1-基)-4-(三氟甲基)苯甲酸甲酯19c(3.00g,8.21mmol)、10%Pd-C催化剂(600mg)和乙醇(80mL)的混合物在氢气下60℃搅拌30h。过滤出催化剂后,蒸发滤液。用硅胶柱色谱法(EA:PE;1:20至1:15)纯化,得到化合物19d(2.75g)(白色固体),产率:91.16%。1H NMR(400MHz,Chloroform-d)δ7.17(s,1H),6.99(s,1H),6.82(d,J=9.4Hz,1H),6.74(d,J=1.6Hz,1H),6.72(d,J=1.7Hz,1H),4.72(t,J=6.4Hz,1H),3.85(s,3H),2.91(ddd,J=16.9,8.5,5.6Hz,1H),2.80(dt,J=16.9,5.4Hz,1H),2.21–2.12(m,1H),1.91–1.82(m,1H),1.82–1.70(m,2H).
第四步5-氯-2-(6-氟-1,2,3,4-四氢萘-1-基)-4-(三氟甲基)苯甲酸甲酯19e的制备
将CuCl2(1.46g,10.89mmol)溶于无水乙腈(60mL)中,氮气保护下,室温中加入亚硝基叔丁酯(0.97mL,8.97mmol),随后在65℃下剧烈搅拌至黑绿色悬浮液。缓慢滴加5-氨基-2-(6-氟-1,2,3,4-四氢萘-1-基)-4-(三氟甲基)苯甲酸甲酯19d(2g,5.44mmol)的无水乙腈溶液。加毕,继续搅拌30分钟后,移至室温搅拌过夜。加入100mL水和100mL乙酸乙酯,均匀混合,静置分层。水相用乙酸乙酯萃取(70mL×3)。合并有机相,用饱和氯化钠溶液洗涤3次,无水硫酸钠干燥,过滤,滤液浓缩。用硅胶柱色谱法(EA:PE;1:60至1:30)纯化,得到化合物19e(1.40g)(无色油状物),产率:66.48%。1H NMR(400MHz,Chloroform-d)δ7.94(s,1H),7.28(s,1H),6.85(dd,J=9.6,2.4Hz,1H),6.75(td,J=8.4,2.6Hz,1H),6.67(dd,J=8.4,5.9Hz,1H),4.94(t,J=6.4Hz,1H),3.92(s,3H),2.95(dd,J=16.3,7.8Hz,1H),2.83(dt,J=16.3,4.5Hz,1H),2.31–2.18(m,1H),1.88(dq,J=14.3,7.2Hz,1H),1.82–1.73(m,2H).
第五步5-氯-2-(6-氟-1,2,3,4-四氢萘-1-基)-4-(三氟甲基)苯甲酸19f的制备
将5-氨基-2-(6-氟-1,2,3,4-四氢萘-1-基)-4-(三氟甲基)苯甲酸甲酯19e(1.4g,3.62mmol)溶于四氢呋喃(32ml)中,加入氢氧化钠(290mg,7.24mmol)的水溶液(5mL)。反应混合物在60℃下搅拌6小时。反应液减压浓缩至剩余少部分水溶液,加20mL水,用2M的盐酸水溶液调节pH至2,有固体析出,将固体过滤,并于真空中干燥。得到化合物19f(690mg)(白色固体),产率:51.14%。MS m/z(ESI):371.00[M-l]-.
第六步5-氯-2-(6-氟-1,2,3,4-四氢萘-1-基)-4-(三氟甲基)苯甲酰氯19g的制备
将5-氯-2-(6-氟-1,2,3,4-四氢萘-1-基)-4-(三氟甲基)苯甲酸19f(100mg,0.27mmol)溶于无水二氯甲烷(4ml)中,置于冰浴,滴加草酰氯(0.27mL,3.22mmol),加毕,继续搅拌3小时。反应液浓缩,得到化合物19g(105mg),产品不经纯化直接用于下一步反应。
第七步5-氯-2-(6-氟-1,2,3,4-四氢萘-1-基)-N-(3-氨磺酰苯基)-4-(三氟甲基)苯甲酰胺19的制备
将间氨基苯磺酰胺(55mg,0.32mmol,毕得医药)溶于无水四氢呋喃中,加入DIEA(89μL,0.54mmol),置于冰浴,滴加5-氯-2-(6-氟-1,2,3,4-四氢萘-1-基)-4-(三氟甲基)苯甲酰氯19g(105mg,0.27mmol)的无水二氯甲烷溶液,加毕,转移至室温反应2小时。反应液浓缩,加入20mL水和20mL乙酸乙酯,均匀混合,静置分层。水相用乙酸乙酯萃取(10mL×3)。合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩。用硅胶柱色谱法(MeOH:DCM;1:100至1:50)纯化,得到化合物19(82mg)(白色固体),产率:58.53%。1H NMR(400MHz,Chloroform-d)δ8.47(s,1H),8.04(s,1H),7.88(d,J=8.1Hz,1H),7.59(s,1H),7.57(d,J=8.1Hz,1H),7.43(t,J=8.0Hz,1H),7.32(s,1H),6.79–6.73(m,1H),6.71–6.62(m,2H),5.39(s,2H),4.50–4.43(m,2H),2.93–2.81(m,2H),2.74(dt,J=16.8,4.5Hz,2H),2.16(tt,J=13.9,6.0Hz,2H),1.85–1.76(m,2H),1.73–1.63(m,1H).
实施例20 5-氯-2-(6-氟-1,2,3,4-四氢萘-1-基)-N-(2-氧代-1,2-二氢吡啶-4-基)-4-(三氟甲基)苯甲酰胺20的制备
采用实施例19的合成路线,将第七步原料间氨基苯磺酰胺替换为4-氨基-2-甲氧基吡啶,得到甲氧基吡啶中间体,并继续采用实施例3的合成路线的第二步制得化合物20(39mg)。1H NMR(400MHz,Chloroform-d)δ9.05(s,1H),7.58(s,1H),7.28(s,1H),7.24(d,J=7.2Hz,1H),6.81–6.74(m,2H),6.70(d,J=1.6Hz,1H),6.68(d,J=1.7Hz,2H),4.44(t,J=7.5Hz,1H),2.92–2.80(m,1H),2.80–2.69(m,1H),2.24–2.11(m,1H),1.90–1.75(m,2H),1.75–1.64(m,1H).
实施例21 5-氯-2-(7-氟苯并二氢吡喃-4-基)-N-(3-氨磺酰苯基)-4-(三氟甲基)苯甲酰胺21的制备
采用实施例19的合成路线,将第二步原料N'-(6-氟-1,2,3,4-四氢萘-1-亚基)-4-甲苯磺酰肼替换为N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼制得化合物21(39mg)。1H NMR(400MHz,Chloroform-d)δ8.59(s,1H),8.06(s,1H),7.93(d,J=7.7Hz,1H),7.64(s,1H),7.55(d,J=7.6Hz,1H),7.43(t,J=7.8Hz,1H),7.37(s,1H),6.65(t,J=7.4Hz,1H),6.50(dd,J=10.1,2.2Hz,1H),6.47–6.40(m,1H),5.40(s,2H),4.55(t,J=7.1Hz,1H),4.22–4.14(m,1H),4.08(t,J=9.4Hz,1H),2.33–2.25(m,1H),2.19–2.08(m,1H).
实施例22 5-氯-2-(7-氟苯并二氢吡喃-4-基)-N-(2-氧代-1,2-二氢吡啶-4-基)-4-(三氟甲基)苯甲酰胺22的制备
采用实施例19的合成路线,将第二步原料N'-(6-氟-1,2,3,4-四氢萘-1-亚基)-4-甲苯磺酰肼替换为N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼,将第七步原料间氨基苯磺酰胺替换为4-氨基-2-甲氧基吡啶,得到甲氧基吡啶中间体,并继续采用实施例3的合成路线的第二步制得化合物22(39mg)。1H NMR(400MHz,Chloroform-d)δ9.53(s,1H),7.61(s,1H),7.32(s,1H),7.23(d,J=7.1Hz,1H),6.80(d,J=6.7Hz,1H),6.75(s,1H),6.68–6.60(m,1H),6.52(dd,J=10.1,2.5Hz,1H),6.45(td,J=8.3,2.5Hz,1H),4.52(t,J=7.2Hz,1H),4.21–4.14(m,1H),4.09(q,J=7.1Hz,2H),2.35–2.23(m,1H),2.15–2.03(m,1H),2.02(s,1H).
实施例23 5-氯-2-(7-氟苯并二氢吡喃-4-基)-N-(3-氧异喹啉-5-基)-4-(三氟甲基)苯甲酰胺23的制备
采用实施例19的合成路线,将第二步原料N'-(6-氟-1,2,3,4-四氢萘-1-亚基)-4-甲苯磺酰肼替换为N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼,将第七步原料间氨基苯磺酰胺替换为6-氨基-异吲哚啉-1-酮制得化合物23(38mg)。1H NMR(400MHz,Chloroform-d)δ9.14(s,1H),8.67(s,1H),8.17(s,1H),8.12(d,J=8.2Hz,1H),7.70(s,1H),7.56(d,J=8.3Hz,1H),7.40(s,1H),6.71–6.60(m,1H),6.55(dd,J=10.1,2.4Hz,1H),6.48(td,J=8.3,2.4Hz,1H),4.71(s,2H),4.63(t,J=7.1Hz,1H),4.27–4.20(m,1H),4.14(t,J=9.0Hz,1H),2.38(dd,J=11.5,5.7Hz,1H),2.24–2.10(m,1H).
实施例24 N-(3-氨基甲酰苯基)-5-氯-2-(7-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酰胺24的制备
采用实施例19的合成路线,将第二步原料N'-(6-氟-1,2,3,4-四氢萘-1-亚基)-4-甲苯磺酰肼替换为N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼,将第七步原料间氨基苯磺酰胺替换为间氨基苯甲腈,得到苯甲腈中间体,并继续采用实施例16的合成路线的第二步反应制得化合物24(45mg)。MS m/z(ESI):492.34[M+l]+.
实施例25 N-(3-氨甲酰苯基)-5-氯-2-(7-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酰胺25的制备
采用实施例19的合成路线,将第二步原料N'-(6-氟-1,2,3,4-四氢萘-1-亚基)-4-甲苯磺酰肼替换为N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼,将第七步原料间氨基苯磺酰胺替换为间氨基苯甲酰胺制得化合物25(38mg)。1H NMR(400MHz,Methanol-d4)δ8.17(s,1H),7.86–7.82(m,1H),7.81(s,1H),7.64(d,J=7.7Hz,1H),7.45(t,J=7.9Hz,1H),7.36(s,1H),6.80(dd,J=8.9,6.7Hz,1H),6.58–6.51(m,2H),4.62(t,J=7.0Hz,1H),4.21–4.12(m,2H),2.39–2.28(m,1H),2.24–2.11(m,1H).
实施例26 5-氯-2-(7-氟苯并二氢吡喃-4-基)-4-甲基-N-(2-氧代-1,2-二氢吡啶-4-基)苯甲酰胺26的制备
第一步2-溴-4-甲基-5-硝基苯甲酸甲酯26b的制备
将化合物2-溴-4-甲基苯甲酸甲酯26a(5g,21.83mmol,毕得医药)在浓硫酸(25mL)中溶解中。在0℃条件下,加入硝酸钾(2.21g,21.83mmol)的硫酸溶液(10mL)。在0℃下搅拌1.5小时后,将反应混合物倒入400mL冰水中。过滤收集沉淀物,并用大量水冲洗。得到化合物26b(4.20g)(白色固体),产率:70.21%。1H NMR(400MHz,Chloroform-d)δ8.49(s,1H),7.70(s,1H),3.96(s,3H),2.63(s,3H).
第二步2-(7-氟苯并二氢吡喃-4-基)-4-甲基-5-硝基苯甲酸甲酯26c的制备
向N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼9b(2.93g,8.76mmol),[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(298mg,0.37mmol),碳酸钠(1.55g,14.60mmol)和1,4-二氧六环/水(4:1)(50mL)的混合物中加入2-溴-4-甲基-5-硝基苯甲酸甲酯26b(2.00g,7.30mmol)。氩气保护,将反应混合物在90℃下搅拌10h。冷却,反应液减压浓缩,加入50mL水和50mL乙酸乙酯,均匀混合,静置分层。水相用乙酸乙酯萃取(50mL×3)。合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩。用硅胶柱色谱法(EA:PE;1:30至1:15)纯化,得到化合物26c(1.95g)(无色油状物),产率:77.84%。1H NMR(400MHz,Chloroform-d)δ8.58(s,1H),7.32(s,1H),6.61(dd,J=9.8,2.2Hz,1H),6.52–6.38(m,2H),5.65(t,J=3.8Hz,1H),5.03–4.78(m,2H),3.66(s,3H),2.67(s,3H).
第三步5-氨基-2-(7-氟苯并二氢吡喃-4-基)-4-甲基苯甲酸甲酯26d的制备
将2-(7-氟苯并二氢吡喃-4-基)-4-甲基-5-硝基苯甲酸甲酯26c(1.90g,5.53mmol)、10%Pd-C催化剂(380mg)和乙醇(40mL)的混合物在氢气下60℃搅拌30h。过滤出催化剂后,蒸发滤液。用硅胶柱色谱法(EA:PE;1:20至1:15)纯化,得到化合物26d(1.54g)(无色油状物),产率:88.24%。1H NMR(400MHz,Chloroform-d)δ7.23(s,1H),6.74(ddd,J=8.6,6.7,1.0Hz,1H),6.63(s,1H),6.57(dd,J=10.3,2.6Hz,1H),6.50(td,J=8.4,2.6Hz,1H),4.94(t,J=6.4Hz,1H),4.16(ddd,J=5.9,4.0,1.2Hz,2H),3.87(s,3H),2.39–2.27(m,1H),2.07(s,3H),2.06–1.97(m,1H).
第四步5-氯-2-(7-氟苯并二氢吡喃-4-基)-4-甲基苯甲酸甲酯26e的制备
将CuCl2(1.02g,7.61mmol)溶于无水乙腈(50mL)中,氮气保护下,室温中加入亚硝基叔丁酯(0.85mL,7.14mmol),随后在65℃下剧烈搅拌至黑绿色悬浮液。缓慢滴加5-氨基-2-(7-氟苯并二氢吡喃-4-基)-4-甲基苯甲酸甲酯26d(1.5g,4.76mmol)的无水乙腈溶液。加毕,继续搅拌30分钟后,移至室温搅拌过夜。加入70mL水和70mL乙酸乙酯,均匀混合,静置分层。水相用乙酸乙酯萃取(50mL×3)。合并有机相,用饱和氯化钠溶液洗涤3次,无水硫酸钠干燥,过滤,滤液浓缩。用硅胶柱色谱法(EA:PE;1:70至1:40)纯化,得到化合物26e(969mg)(无色油状物),产率:60.85%。1H NMR(400MHz,Chloroform-d)δ7.92(s,1H),6.83(s,1H),6.73–6.66(m,1H),6.60(dd,J=10.3,2.6Hz,1H),6.52(td,J=8.4,2.6Hz,1H),5.06(t,J=6.4Hz,1H),4.16(ddd,J=6.2,3.8,1.8Hz,2H),3.90(s,3H),2.41–2.32(m,1H),2.29(s,3H),2.05–1.94(m,1H).
第五步5-氯-2-(7-氟苯并二氢吡喃-4-基)-4-甲基苯甲酸26f的制备
将5-氯-2-(7-氟苯并二氢吡喃-4-基)-4-甲基苯甲酸甲酯26e(960mg,2.87mmol)溶于四氢呋喃(24ml)中,加入氢氧化钠(229mg,5.74mmol)的水溶液(6mL)。反应混合物在70℃下搅拌过夜。反应液减压浓缩至剩余少部分水溶液,加15mL水,用2M的盐酸水溶液调节pH至2,有固体析出,将固体过滤,并于真空中干燥。得到化合物26f(525mg)(白色固体),产率:57.08%。MS m/z(ESI):319.20[M-l]-.
第六步5-氯-2-(7-氟苯并二氢吡喃-4-基)-4-甲基苯甲酰氯26g的制备
将5-氯-2-(7-氟苯并二氢吡喃-4-基)-4-甲基苯甲酸26f(100mg,0.31mmol)溶于无水二氯甲烷(4ml)中,置于冰浴,滴加草酰氯(0.39mL,4.68mmol),加毕,继续搅拌6小时。反应液浓缩,得到化合物26g(106mg),产品不经纯化直接用于下一步反应。
第七步5-氯-2-(7-氟苯并二氢吡喃-4-基)-4-甲基-N-(2-氧代-1,2-二氢吡啶-4-基)苯甲酰胺26的制备
将4-氨基-2-甲氧基吡啶(47mg,0.38mmol,毕得医药)溶于无水四氢呋喃中,加入N,N-二异丙基乙胺(102μL mL,0.62mmol),置于冰浴,滴加5-氯-2-(7-氟苯并二氢吡喃-4-基)-4-甲基苯甲酰氯26g(106mg,0.31mmol)的无水二氯甲烷溶液,加毕,转移至室温搅拌过夜。反应液浓缩,加入20mL水和20mL乙酸乙酯,均匀混合,静置分层。水相用乙酸乙酯萃取(10mL×3)。合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩。残余物不经进一步纯化,溶于冰醋酸(2mL)中,加入33%的氢溴酸的醋酸溶液(2mL),加热至90℃回流,反应过夜。反应液浓缩,倾入20mL饱和碳酸氢钠溶液中,充分搅拌,直至气泡消失。水相用乙酸乙酯萃取(10mL×3)。合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩。用硅胶柱色谱法(MeOH:DCM;1:40至1:30)纯化,得到化合物26(69mg)(白色固体),产率:53.48%。1H NMR(400MHz,Chloroform-d)δ9.12(s,1H),7.46(s,1H),7.23(d,J=7.0Hz,1H),6.90(d,J=7.0Hz,1H),6.85(s,1H),6.70(s,1H),6.68–6.60(m,1H),6.51(dd,J=10.1,2.4Hz,1H),6.42(td,J=8.3,2.3Hz,1H),4.54(t,J=6.7Hz,1H),4.11(dt,J=18.9,7.4Hz,2H),2.28(dd,J=13.6,7.7Hz,1H),2.23(s,3H),2.05(d,J=10.2Hz,1H).
实施例27 2-氟-6-(7-氟苯并二氢吡喃-4-基)-N-(2-氧代-1,2-二氢吡啶-4-基)-3-(三氟甲基)苯甲酰胺27的制备
第一步2-氟-6-(7-氟-2H-苯并吡喃-4-基)-3-(三氟甲基)苯甲酸甲酯27b的制备
向N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼9b(3.00g,8.97mmol),[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(293mg,0.359mol),碳酸钠(1.59g,14.98mmol)和1,4-二氧六环/水(4:1)(40mL)的混合物中加入6-溴-2-氟-3-(三氟甲基)苯甲酸甲酯27a(2.16g,7.18mmol)。氩气保护,将反应混合物在90℃下搅拌10h。冷却,反应液减压浓缩,加入50mL水和50mL乙酸乙酯,均匀混合,静置分层。水相
用乙酸乙酯萃取(10mL×3)。合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩。用硅胶柱色谱法(EA:PE;1:20至1:10)纯化,得到化合物27b(2.45g)(无色油状物),产率:73.75%。1H NMR(400MHz,Chloroform-d)δ7.72(t,J=7.6Hz,1H),7.21(d,J=8.0Hz,1H),6.70–6.58(m,2H),6.54(td,J=8.4,2.5Hz,1H),5.73(t,J=3.9Hz,1H),4.86(d,J=3.8Hz,2H),3.67(s,3H).
第二步 化合物27的制备
采用实施例11的合成路线,将第一步原料化合物9c替换为化合物27b制得化合物27(31mg)。MS m/z(ESI):451.34[M+l]+.
实施例28 2-氟-6-(7-氟苯并二氢吡喃-4-基)-N-(3-氨磺酰苯基)-3-(三氟甲基)苯甲酰胺28的制备
采用实施例27的合成路线,将原料4-氨基-2-甲氧基吡啶替换为间氨基苯磺酰胺制得化合物28(38mg)。1H NMR(400MHz,DMSO-d6)δ11.30(s,1H),8.34(t,J=1.9Hz,1H),7.93–7.75(m,2H),7.71–7.53(m,2H),7.45(s,2H),7.08(d,J=8.3Hz,1H),6.88(t,J=7.5Hz,1H),6.77–6.62(m,2H),4.38(t,J=7.1Hz,1H),4.21(t,J=4.4Hz,2H),2.30(dq,J=15.1,5.6,5.1Hz,1H),2.19–2.07(m,1H).
实施例29 N-(3-氨甲酰苯基)-2-氟-6-(7-氟苯并二氢吡喃-4-基)-3-(三氟甲基)苯甲酰胺29的制备
采用实施例27的合成路线,将原料4-氨基-2-甲氧基吡啶替换为间氨基苯甲酰胺制得化合物29(31mg)。1H NMR(400MHz,Chloroform-d)δ9.64(s,1H),8.21(dt,J=6.7,2.5Hz,1H),8.07(d,J=1.9Hz,1H),7.56(t,J=7.7Hz,1H),7.45–7.34(m,2H),6.93(d,J=8.2Hz,1H),6.72(dd,J=8.6,6.4Hz,1H),6.53(dd,J=10.1,2.6Hz,1H),6.41(td,J=8.3,2.6Hz,1H),6.34(s,1H),5.32(s,1H),4.47(t,J=7.0Hz,1H),4.16(ddd,J=10.1,6.4,3.3Hz,1H),4.08(ddd,J=11.2,8.3,2.9Hz,1H),2.39–2.28(m,1H),2.17–2.08(m,1H).
实施例30 2-(7-氟-2,2-二甲基苯并二氢吡喃--4-基)-N-(2-氧代-1,2-二氢吡啶-4-基)-4-(三氟甲基)苯甲酰胺30的制备
第一步7-氟-2,2-二甲基苯并二氢吡喃-4-酮30b的制备
将4-氟-2-羟基苯乙酮30a(2g,12.98mmol)溶于乙醇(30mL),加入丙酮(9.55mL,129.8mmol)和吡咯烷(3.17mL,25.95mmol),并在80℃下加热反应6小时。TLC监测反应完成后,浓缩反应混合物。浓缩物用二氯甲烷重新溶解,依次用1M HCl水溶液,NaCl溶液洗涤。无水硫酸钠干燥,过滤,滤液浓缩。用硅胶柱色谱法(EA:PE;1:15至1:4)纯化,得到化合物30b(1.90g)(无色油状物),产率:75.40%。1H NMR(400MHz,Chloroform-d)δ7.79(dd,J=8.8,6.7Hz,1H),6.61(td,J=8.5,2.4Hz,1H),6.53(dd,J=10.1,2.4Hz,1H),2.64(s,2H),1.39(s,6H).
第二步N'-(7-氟-2,2-二甲基苯并二氢吡喃-4-亚基)-4-甲基苯磺酰肼30c的制备
将对甲苯磺酰肼(1.58g,8.50mmol)悬浮于甲醇溶液中,滴加冰醋酸(0.5mL),再向混合物中加入30b(1.50g,7.72mmol),加热至70℃反应过夜。反应混合物冷却至室温后产生大量沉淀物。将沉淀物过滤,用甲醇淋洗。在真空中干燥沉淀物。得到化合物30c(2.34g)(白色固体),产率:83.59%。1H NMR(400MHz,Chloroform-d)δ7.90(d,J=8.4Hz,2H),7.85–7.77(m,2H),7.34(d,J=8.1Hz,2H),6.61(td,J=8.5,2.5Hz,1H),6.50(dd,J=9.9,2.5Hz,1H),2.56(s,2H),2.43(s,3H),1.33(s,6H).
第三步2-(7-氟-2,2-二甲基-2H-苯并吡喃-4-基)-4-(三氟甲基)苯甲酸甲酯30d的制备
向化合物30c(768mg,2.12mmol),[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(72mg,0.11mol),碳酸钠(373mg,4.24mmol)和1,4-二氧六环/水(4:1)(16mL)的混合物中加入2-溴-4-(三氟甲基)苯甲酸甲酯(500mg,1.77mmol)。氩气保护,将反应混合物在85℃下搅拌16h。冷却,反应液减压浓缩,加入30mL水和30mL乙酸乙酯,均匀混合,静置分层。水相用乙酸乙酯萃取(20mL×3)。合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩。用硅胶柱色谱法(EA:PE;1:40至1:20)纯化,得到化合物30d(623mg)(无色油状物),产率:92.72%。1H NMR(400MHz,Chloroform-d)δ8.00(d,J=8.1Hz,1H),7.77–7.63(m,1H),7.55(d,J=1.9Hz,1H),6.61(dd,J=10.0,2.4Hz,1H),6.55–6.42(m,2H),5.46(s,1H),3.65(s,3H),1.51(s,6H).
第四步 化合物30的制备
采用实施例11的合成路线,将第一步原料化合物9c替换为化合物30d制得化合物30(31mg)1H NMR(400MHz,Chloroform-d)δ7.55(d,J=8.0Hz,1H),7.52–7.45(m,1H),7.36(s,1H),7.24(d,J=7.2Hz,1H),6.82(d,J=7.1Hz,1H),6.71(s,1H),6.57(dd,J=8.6,6.5Hz,1H),6.51(dd,J=10.3,2.6Hz,1H),6.41(td,J=8.3,2.6Hz,1H),4.49(dd,J=12.2,6.1Hz,1H),2.23(dd,J=13.5,6.0Hz,1H),1.91(t,J=12.9Hz,1H),1.41(s,3H),1.25(s,3H).
实施例31 4-(5-氯-2-(7-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酰胺基)吡啶酰胺31的制备
采用实施例19的合成路线,将第二步原料N'-(6-氟-1,2,3,4-四氢萘-1-亚基)-4-甲苯
磺酰肼替换为N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼,将第七步原料间氨基苯磺酰胺替换为4-氨基吡啶-2-甲酰胺制得化合物31(34mg)。1H NMR(400MHz,Methanol-d4)δ8.53(d,J=5.5Hz,1H),8.29(d,J=2.2Hz,1H),7.93(dd,J=5.5,2.2Hz,1H),7.85(s,1H),7.41(s,1H),6.78(dd,J=9.5,6.3Hz,1H),6.59–6.46(m,2H),4.60(t,J=7.3Hz,1H),4.21(ddd,J=11.3,5.9,3.5Hz,1H),4.13(ddd,J=11.4,8.7,2.8Hz,1H),2.39–2.27(m,1H),2.29–2.16(m,1H).
实施例32 N-(3-氨基甲酰-4-氟苯基)-2-氟-6-(7-氟苯并二氢吡喃-4-基)-3-(三氟甲基)苯甲酰胺32的制备
第一步2-氟-6-(7-氟苯并二氢吡喃-4-基)-3-(三氟甲基)苯甲酸甲酯32a的制备
将2-氟-6-(7-氟-2H-苯并吡喃-4-基)-3(三氟甲基)苯甲酸甲酯27b(500mg,1.35mmol)、10%Pd-C催化剂(100mg)和乙醇(50mL)的混合物在氢气下60℃搅拌30h。过滤出催化剂后,蒸干滤液。用硅胶柱色谱法(EA:PE;1:40至1:20)纯化,得到化合物32a(420mg)(无色油状物),产率:83.55%。1H NMR(600MHz,Chloroform-d)δ7.56(t,J=7.7Hz,1H),6.90(d,J=8.3Hz,1H),6.72(ddd,J=8.7,6.4,1.0Hz,1H),6.60(dd,J=10.2,2.6Hz,1H),6.55(td,J=8.3,2.6Hz,1H),4.35(t,J=6.9Hz,1H),4.22–4.11(m,2H),3.95(s,3H),2.39–2.28(m,1H),2.16–2.04(m,1H).
第二步2-氟-6-(7-氟苯并二氢吡喃-4-基)-3-(三氟甲基)苯甲酸32b的制备
将化合物32a(400mg,1.07mmol)溶于四氢呋喃(20ml)中,加入氢氧化钠(86mg,2.15mmol)的水溶液(5mL)。反应混合物在室温下搅拌过夜。反应液减压浓缩至剩余少部分水溶液,再加20mL水,用2M的盐酸水溶液调节pH至2,有固体析出,过滤,并于真空中干燥。得到化合物32b(353mg)(淡黄色固体),产率:91.71%。
MS m/z(ESI):356.86[M-l]-。
第三步N-(3-氰基-4-氟苯基)-2-氟-6-(7-氟苯并二氢吡喃-4-基)-3-(三氟甲基)苯甲酰胺32c的制备
将化合物32b(100mg,279.12μmol)溶于无水二氯甲烷(4ml)中,置于冰浴,滴加草酰氯(0.29mL,3.35mmol),加毕,继续搅拌3小时。反应液浓缩,得到的酰氯备用。将3-氰基-4-氟苯胺(57mg,418.69μmol,毕得医药)溶于无水四氢呋喃中,加入DIEA(92μL,0.56mmol),置于冰浴,滴加制备好的酰氯的无水二氯甲烷溶液,加毕,转移至室温搅拌过夜。反应液浓缩,加入20mL水和20mL乙酸乙酯,均匀混合,静置分层。水相用乙酸乙酯萃取(10mL×3)。合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩。用硅胶柱色谱法(MeOH:DCM;1:100至1:50)纯化,得到化合物32c(106mg)(白色固体),产率:79.72%。1H NMR(400MHz,Chloroform-d)δ8.05
(dd,J=5.4,2.7Hz,1H),7.91(s,1H),7.77(ddd,J=9.1,4.5,2.8Hz,1H),7.62(t,J=7.8Hz,1H),7.25(d,J=5.8Hz,1H),7.01(d,J=8.3Hz,1H),6.71(dd,J=8.5,6.4Hz,1H),6.58(dd,J=10.1,2.6Hz,1H),6.53(td,J=8.3,2.6Hz,1H),4.50(t,J=7.1Hz,1H),4.27–4.11(m,2H),2.45–2.33(m,1H),2.25–2.13(m,1H).
第四步2-氟-N-(4-氟-3-(N'-羟基氨基甲酰)苯基)-6-(7-氟苯并二氢吡喃-4-基)-3-(三氟甲基)苯甲酰胺32d的制备
将化合物32c(100mg,209.92μmol)溶于95%乙醇(3mL)中,加入盐酸羟胺(28mg,419.84μmol)和Et3N(56μL,419.84μmol),反应混合物在80℃下搅拌4小时。将混合物冷却至环境温度。反应液浓缩,加入20mL水和20mL乙酸乙酯,均匀混合,静置分层。水相用乙酸乙酯萃取(10mL×3)。合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩得32d粗产物,不经进一步纯化,直接用于下一步。
第五步2-氟-N-(3-氨基甲酰-4-氟苯基)-6-(7-氟苯并二氢吡喃-4-基)-3-(三氟甲基)苯甲酰胺32的制备
将上一步化合物32d的粗产物溶解在乙酸(1ml)中。向混合物中加入乙酰氯(16.4μL,230.91μmol)。反应混合物在室温下搅拌30分钟。向混合物中加入PdCl2(3.72mg,20.99μmol)和三乙基硅烷(43.6μL,272.89μmol)。反应混合物在70-75℃下继续搅拌2小时。TLC监测反应完毕后,反应液减压浓缩,倾入20mL的饱和碳酸氢钠溶液中,充分搅拌,直至气泡消失。水相用乙酸乙酯萃取(10mL×3)。合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩。用硅胶柱色谱法(MeOH:DCM;1:15至1:10)纯化,得到化合物32(59mg)(白色固体),产率:60.38%。
MS m/z(ESI):494.27[M+l]+。
实施例33 N-(3-氨基甲酰-4-氟苯基)-5-氯-2-(7-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酰胺33的制备
采用实施例19的合成路线的第一步到第五步,将第二步原料N'-(6-氟-1,2,3,4-四氢萘-1-亚基)-4-甲苯磺酰肼替换为N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼,再采用实施例32的合成路线的第三步到第五步制得化合物33(38mg)。
MS m/z(ESI):510.28[M+l]+。
实施例34(4-(5-氯-2-(7-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酰胺基)-2-氧代吡啶-1(2H)-基)甲基磷酸二氢酯34的制备
第一步5-氯-N-(1-(氯甲基)-2-氧代-1,2-二氢吡啶-4-基)-2-(7-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酰34a的制备
将化合物22(200mg,0.43mmol)溶于N,N-二甲基甲酰胺(0.2mL)和无水二氯甲烷(2.4mL)中,加入氯甲酸氯甲酯(114μL,1.29mmol),氮气保护,室温搅拌反应4小时,用乙酸乙酯(20mL)稀释反应液,分别用饱和碳酸氢钠溶液(10mL×3)和饱和氯化钠溶液(10mL×3)洗涤有机相,用无水硫酸钠干燥,过滤,减压浓缩得34a(190mg),其不经进一步纯化可直接用于下一步反应。
第二步(4-(5-氯-2-(7-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酰胺基)-2-氧代吡啶-1(2H)-基)甲基二叔丁基磷酸酯34b的制备
将化合物34a(190mg,0.37mmol)溶于N,N-二甲基甲酰胺(4mL)中,加入磷酸二叔丁酯钾盐(185mg,0.74mmol,上海毕得医药有限公司)和四丁基碘化铵(13.7mg,0.037mmol,上海毕得医药有限公司),升温至70℃搅拌反应4小时,用乙酸乙酯(20mL)稀释反应液,分别用饱和碳酸氢钠溶液(10mL×3)和饱和氯化钠溶液(10mL×3)洗涤有机相,用无水硫酸钠干燥,过滤,减压浓缩得34b(260mg),其不经进一步纯化可直接用于下一步反应。MS m/z(ESI):689.34[M+l]+。
第三步4-(5-氯-2-(7-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酰胺基)-2-氧代吡啶-1(2H)-基)甲基磷酸二氢酯34的制备
将化合物34b(260mg,0.38mmol)溶于乙腈(3mL)、乙酸(3mL)和水(3mL)混合溶剂中,加热至70℃搅拌反应3小时。反应完毕后,减压浓缩,用乙腈打浆,过滤,有那个乙腈洗涤,干燥,得到化合物34(110mg)。MS m/z(ESI):577.13[M+l]+。
实施例35 N-(3-氨基甲酰-4-氯苯基)-5-氯-2-(7-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酰胺35的制备
采用实施例19的合成路线的第一步到第五步,将第二步原料N'-(6-氟-1,2,3,4-四氢萘-1-亚基)-4-甲苯磺酰肼替换为N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼,再采用实施例32的合成路线的第三步到第五步,将第三步原料3-氰基-4-氟苯胺替换为3-氰基-4-氯苯胺制得化合物35(18mg)。1H NMR(500MHz,Methanol-d4)δ7.84(d,J=2.6Hz,1H),7.81(s,1H),7.70(dd,J=8.8,2.6Hz,1H),7.46(d,J=8.8Hz,1H),7.38(s,1H),6.84–6.74(m,
1H),6.59–6.52(m,2H),4.60(t,J=7.1Hz,2H),4.25–4.17(m,1H),4.18–4.10(m,2H),2.39–2.28(m,2H),2.25–2.15(m,1H).
实施例36 5-氯-2-(7-氟苯并二氢吡喃-4-基)-N-(2-氧代-1,2-二氢吡啶-4-基)苯甲酰胺36的制备
采用实施例19的合成路线,以第二步起始,将原料5-氨基-2-溴-4-(三氟甲基)苯甲酸甲酯替换为5-氨基-2-溴苯甲酸甲酯,并将原料N'-(6-氟-1,2,3,4-四氢萘-1-亚基)-4-甲苯磺酰肼替换为N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼,将第七步原料间氨基苯磺酰胺替换为4-氨基-2-甲氧基吡啶,得到甲氧基吡啶中间体,并继续采用实施例3的合成路线的第二步制得化合物36(58mg)。1H NMR(600MHz,Methanol-d4)δ7.55(d,J=2.3Hz,1H),7.43–7.37(m,2H),7.03(dd,J=5.3,3.2Hz,2H),6.80–6.76(m,1H),6.75(dd,J=7.2,2.1Hz,1H),6.55–6.49(m,2H),4.51(dd,J=7.9,6.2Hz,1H),4.21(ddd,J=11.2,6.5,3.3Hz,1H),4.13(ddd,J=11.2,8.5,2.8Hz,1H),2.35–2.26(m,1H),2.20–2.10(m,1H).
实施例37 N-(3-氨基甲酰苯基)-5-氯-6-(7-氟苯并二氢吡喃-4-基)苯甲酰胺37的制备
采用实施例19的合成路线,以第二步起始,将原料5-氨基-2-溴-4-(三氟甲基)苯甲酸甲酯替换为5-氨基-2-溴苯甲酸甲酯,并将原料N'-(6-氟-1,2,3,4-四氢萘-1-亚基)-4-甲苯磺酰肼替换为N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼,将第七步原料间氨基苯磺酰胺替换为间氨基苯甲酰胺制得化合物37。1H NMR(500MHz,Methanol-d4)δ8.16(t,J=1.9Hz,1H),7.85(ddd,J=8.1,2.2,1.0Hz,1H),7.64(dt,J=7.8,1.4Hz,1H),7.57(d,J=2.2Hz,1H),7.46(t,J=7.9Hz,1H),7.40(dd,J=8.4,2.3Hz,1H),7.02(d,J=8.5Hz,1H),6.85–6.79(m,1H),6.56–6.49(m,2H),4.57(t,J=6.9Hz,1H),4.21(ddd,J=11.2,6.6,3.3Hz,1H),4.13(ddd,J=11.1,8.3,2.8Hz,1H),2.37–2.28(m,1H),2.21–2.10(m,1H).
实施例38 N-(3-氨基甲酰苯基)-2-氟-6-(7-氟苯并二氢吡喃-4-基)苯甲酰胺38的制备
采用实施例29的合成方法,将原料6-溴-2-氟-3-(三氟甲基)苯甲酸甲酯替换为2-溴-6-氟苯甲酸甲酯制得化合物38。1H NMR(600MHz,Methanol-d4)δ8.15(t,J=2.0Hz,1H),7.86(ddd,J=8.1,2.2,1.0Hz,1H),7.65(ddd,J=7.7,1.8,1.0Hz,1H),7.46(t,J=7.9Hz,1H),7.39(td,J=8.1,5.9Hz,1H),7.12(t,J=8.7Hz,1H),6.88(dd,J=9.2,6.6Hz,1H),6.83(d,J=7.9Hz,1H),6.55–6.50(m,2H),4.41(t,J=6.9Hz,1H),4.23(ddd,J=11.3,6.7,3.2Hz,1H),
4.13(ddd,J=11.1,8.3,2.8Hz,1H),2.37–2.26(m,1H),2.23–2.13(m,1H)。
实施例39 N-(3-氨基甲酰苯基)-5-氟-2-(7-氟苯并二氢吡喃-4-基)苯甲酰胺39的制备
采用实施例29的合成方法,将原料6-溴-2-氟-3-(三氟甲基)苯甲酸甲酯替换为2-溴-5-氟苯甲酸甲酯制得化合物39。1H NMR(500MHz,Methanol-d4)δ8.16(t,J=2.0Hz,1H),7.85(ddd,J=8.1,2.2,1.0Hz,1H),7.64(dt,J=7.9,1.3Hz,1H),7.46(t,J=7.9Hz,1H),7.32(dd,J=8.7,2.8Hz,1H),7.15(td,J=8.5,2.8Hz,1H),7.04(dd,J=8.8,5.4Hz,1H),6.86–6.79(m,1H),6.55–6.49(m,2H),4.57(t,J=6.9Hz,1H),4.21(ddd,J=11.2,6.6,3.3Hz,1H),4.13(ddd,J=11.2,8.3,2.8Hz,1H),2.36–2.27(m,1H),2.19–2.11(m,1H).
实施例40 N-(3-氨基甲酰苯基)-4,5-氟-2-(7-氟苯并二氢吡喃-4-基)苯甲酰胺40的制备
采用实施例29的合成方法,将原料6-溴-2-氟-3-(三氟甲基)苯甲酸甲酯替换为2-溴-4,5-二氟苯甲酸甲酯制得化合物40。1H NMR(500MHz,Methanol-d4)δ8.15(t,J=1.9Hz,1H),7.84(ddd,J=8.1,2.3,1.0Hz,1H),7.64(dt,J=7.8,1.4Hz,1H),7.54(dd,J=10.5,7.9Hz,1H),7.46(t,J=7.9Hz,1H),6.89(dd,J=11.9,7.7Hz,1H),6.83(dd,J=9.5,6.4Hz,1H),6.59–6.51(m,2H),4.61(t,J=7.0Hz,1H),4.21(ddd,J=11.2,6.4,3.3Hz,1H),4.14(ddd,J=11.2,8.5,2.8Hz,1H),2.40–2.28(m,2H),2.22–2.09(m,1H).
实施例41 N-(3-(氨基甲基)苯基)-5-氯-2-(7-氟苯并二氢吡喃-4-基)-4-三氟甲基苯甲酰胺41的制备
第一步(3-(5-氯-2-(7-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酰胺)氨基甲酸叔丁酯41b的制备
化合物5-氯-2-(7-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酸41a的制备采用实施例19的第一步到第五步的方法,将第二步的原料N'-(6-氟-1,2,3,4-四氢萘-1-亚基)-4-甲苯磺酰肼替换为N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼制得化合物41a。
将化合物41a(100mg,226.87μmol)溶于无水二氯甲烷(4ml)中,置于冰浴,滴加草酰氯(0.23mL,2.67mmol),加毕,继续搅拌3小时。反应液浓缩,得到的酰氯备用。将(3-氨基苄基)氨基甲酸叔丁酯(71mg,320.24μmo)溶于无水四氢呋喃中,加入DIEA(93μL,0.53mmol),置于冰浴,滴加制备好的酰氯的无水二氯甲烷溶液,加毕,转移
至室温搅拌过夜。反应液浓缩,加入20mL水和20mL乙酸乙酯,均匀混合,静置分层。水相用乙酸乙酯萃取(10mL×3)。合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩。用硅胶柱色谱法(MeOH:DCM;1:100至1:50)纯化,得到化合物41b(98mg)(白色固体),产率:63.42%。1H NMR(400MHz,Chloroform-d)δ8.02(s,1H),7.64(s,1H),7.55–7.45(m,2H),7.37(s,1H),7.32(t,J=7.9Hz,1H),7.09(d,J=7.7Hz,1H),6.72–6.63(m,1H),6.58(dd,J=10.1,2.6Hz,1H),6.51(td,J=8.4,2.7Hz,1H),4.98(t,J=6.0Hz,1H),4.64(t,J=7.3Hz,1H),4.28(d,J=6.1Hz,2H),4.25–4.17(m,1H),4.14(ddd,J=11.3,8.6,2.6Hz,1H),2.42–2.29(m,1H),2.21–2.08(m,1H),1.60–1.14(m,9H).
第二步N-(3-(氨基甲基)苯基)-5-氯-2-(7-氟苯并二氢吡喃-4-基)-4-三氟甲基苯甲酰胺41的制备
将化合物41b(98mg)溶于2mL二氯甲烷中,加入2mL的4N氯化氢-1,4-二氧六环溶液。反应混合物在室温下搅拌3小时。反应液减压浓缩,用二氯甲烷溶解,加入氨气甲醇溶液中和,减压浓缩。用硅胶柱色谱法(MeOH:DCM;1:40至1:20)纯化,得到化合物41(39mg)(白色固体),产率:48.12%。
实施例42 N-(3-(氨基甲基)-4-氟苯基)-5-氯-2-(7-氟苯并吡喃-4-基)-4-三氟甲基苯甲酰胺42的制备
化合物5-氯-N-(3-氰基-4-氟苯基)-2-(7-氟苯并二氢吡喃-4-基)-4-三氟甲基苯甲酰胺42a的制备采用实施例32的第三步方法,将化合物2-氟-6-(7-氟苯并二氢吡喃-4-基)-3-(三氟甲基)苯甲酸32b替换为化合物5-氯-2-(7-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酸41a制得化合物42a。
将化合物42a(100mg,202.91μmol)溶于乙醇(4ml)中,置于冰浴,氮气保护,依次加入NiCl2·6H2O(53mg,223.20μmol),NaBH4(23mg,608.73μmol)。加毕,室温搅拌过夜。TLC监测反应完成后,将反应液减压浓缩,乙酸乙酯稀释后用2N HCl溶液洗涤,再用饱和碳酸氢钠溶液调节pH~9,水相用乙酸乙酯萃取(10mL×3)。合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩。用硅胶柱色谱法(MeOH:DCM;1:40至1:20)纯化,得到化合物42(32mg)(白色固体),产率:31.74%。MS m/z(ESI):497.18[M+l]+。
实施例43 5-氯-N-(2-((R)-2,3-二羟基丙氧基)吡啶-4-基)-2-(7-氟苯并吡喃-4-基)-4-三氟甲基苯甲酰胺43的制备
第一步5-氯-N-(2-(((S)-2,2-二甲基-1,3-二氧戊环-4-基)甲氧基)吡啶-4-基)-2-(7-氟苯并二氢吡喃-4)-三氟甲基苯甲酰胺43c的制备
化合物5-氯-2-(7-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酰氯43a的制备采用实施例19的第一步到第六步的方法,将第二步的原料N'-(6-氟-1,2,3,4-四氢萘-1-亚基)-4-甲苯磺酰肼替换为N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼制得化合物43a。
将化合物43b(62mg,274.70μmol)溶于无水四氢呋喃中,加入DIEA(80μL,0.48mmol),置于冰浴,滴加现制备的43a(90mg,228.92μmol)的无水二氯甲烷溶液,加毕,转移至室温搅拌过夜。反应液浓缩,加入20mL水和20mL乙酸乙酯,均匀混合,静置分层。水相用乙酸乙酯萃取(10mL×3)。合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩。用硅胶柱色谱法(MeOH:DCM;1:200至1:150)纯化,得到化合物43c(114mg)(白色固体),产率:85.72%。1H NMR(400MHz,Chloroform-d)δ8.03(dd,J=5.9,2.3Hz,1H),7.64(s,1H),7.38(s,1H),7.17(s,1H),7.04–6.95(m,1H),6.63(t,J=7.5Hz,1H),6.56(dd,J=10.1,2.5Hz,1H),6.49(td,J=8.4,2.6Hz,1H),4.58(t,J=7.3Hz,1H),4.46(td,J=6.4,4.9Hz,1H),4.41–4.28(m,2H),4.21(ddd,J=11.1,5.6,3.5Hz,1H),4.18–4.08(m,2H),3.83(dd,J=8.4,6.2Hz,1H),2.41–2.28(m,1H),2.18–2.05(m,1H),1.42(s,3H),1.35(s,3H).
第二步5-氯-N-(2-((R)-2,3-二羟基丙氧基)吡啶-4-基)-2-(7-氟苯并吡喃-4-基)-4-三氟甲基苯甲酰胺43的制备
将化合物43c(100mg,202.91μmol)溶于2mL二氯甲烷中,加入2mL的4N氯化氢-1,4-二氧六环溶液。反应混合物在室温下搅拌1小时。反应液减压蒸干后加水,碳酸钠调pH至碱性,乙酸乙酯萃取(10mL×3),合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩。用硅胶柱色谱法(MeOH:DCM;1:40至1:20)纯化,得到化合物43(69mg)(白色固体),产率:74.11%。1H NMR(500MHz,Methanol-d4)δ8.02(d,J=5.8Hz,1H),7.82(s,1H),7.40(s,1H),7.29(d,J=1.8Hz,1H),7.17(dd,J=5.8,1.8Hz,1H),6.83–6.74(m,1H),6.58–6.52(m,2H),4.58(t,J=7.2Hz,1H),4.35(dd,J=11.0,4.4Hz,1H),4.28(dd,J=10.9,6.0Hz,1H),4.21(ddd,J=11.3,6.0,3.4Hz,1H),4.14(ddd,J=11.3,8.7,2.7Hz,1H),4.02–3.93(m,1H),3.71–3.59(m,2H),2.39–2.30(m,1H),2.25–2.15(m,1H).
实施例44 N-(3-(氨基甲酰氨基)-4-氟苯基)-5-氯-2-(7-氟苯并吡喃-4-基)-4-三氟甲基苯甲酰胺44的制备
第一步5-(5-氯-2-(7-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酰胺)-2-氟苯甲酸甲酯44b的制备
将2-氟-5-氨基苯甲酸甲酯(46mg,274.70μmol)溶于无水四氢呋喃中,加入DIEA(80μL,0.48mmol),置于冰浴,滴加预先制备的化合物43a(90mg,228.92μmol)的无水二氯甲烷溶液,加毕,转移至室温搅拌过夜。反应液浓缩,加入20mL水和20mL乙酸乙酯,均匀混合,静置分层。水相用乙酸乙酯萃取(10mL×3)。合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩。用硅胶柱色谱法(MeOH:DCM;1:200至1:150)纯化,得到化合物44b(110mg)(白色固体),产率:91.38%。1H NMR(400MHz,Chloroform-d)δ7.99(dd,J=6.1,2.8Hz,1H),7.97–7.90(m,2H),7.66(s,1H),7.40(s,1H),7.16(dd,J=10.0,9.0Hz,1H),6.66(dd,J=8.6,6.4Hz,1H),6.58(dd,J=10.1,2.6Hz,
1H),6.51(td,J=8.3,2.6Hz,1H),4.65–4.56(m,1H),4.23(ddd,J=11.2,5.7,3.5Hz,1H),4.15(ddd,J=11.5,9.1,2.7Hz,1H),3.88(s,3H),2.42–2.31(m,1H),2.22–2.11(m,1H).
第二步5-(5-氯-2-(7-氟苯并吡喃-4-基)-4-三氟甲基苯甲酰胺)-2-氟苯甲酸44c的制备
将化合物44b(100mg,190.17μmol)溶于甲醇(8ml)中,加入氢氧化钠(30mg,760.66μmol)的水溶液(2mL)。反应混合物在室温下搅拌过夜。反应液减压浓缩至剩余少部分水溶液,加20mL水,用2M的盐酸水溶液调节pH至2,有固体析出,将固体过滤,并于真空中干燥。得到化合物44c(90mg)(淡黄色固体),产率:92.47%。MS m/z(ESI):510.09[M-l]-。
第三步N-(3-(氨基甲酰氨基)-4-氟苯基)-5-氯-2-(7-氟苯并吡喃-4-基)-4-三氟甲基苯甲酰胺44的制备
将化合物44c(50mg,97.69μmol)溶于四氢呋喃溶液中,加入CDI(16mg,97.69μmol),反应混合物在室温下搅拌1小时,依次加入DIEA(68μL,0.39mmol)和盐酸胍(19mg,195.38μmol)。将反应混合物升温至50℃搅拌过夜。反应液浓缩,加入20mL水和20mL乙酸乙酯,均匀混合,静置分层。水相用乙酸乙酯萃取(10mL×3)。合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩。用硅胶柱色谱法(MeOH:DCM;1:150至1:100)纯化,得到化合物44(26mg)(白色固体),产率:48.14%。1H NMR(400MHz,Chloroform-d)δ8.22(brs,1H),8.08(dd,J=6.4,2.8Hz,1H),7.87(dt,J=7.7,3.5Hz,1H),7.65(s,1H),7.38(s,1H),7.10(dd,J=10.6,8.9Hz,1H),6.68–6.62(m,1H),6.56(dd,J=10.1,2.6Hz,1H),6.49(td,J=8.3,2.6Hz,1H),4.61(t,J=7.3Hz,1H),4.26–4.17(m,1H),4.17–4.11(m,1H),2.40–2.29(m,1H),2.21–2.08(m,1H).
实施例45 2-(5-氯-2-(7-氟苯并二氢吡喃-4-基)-4-三氟甲基苯甲酰胺)噻吩-3-甲酰胺45的制备
采用实施例19的合成路线,将第二步原料N'-(6-氟-1,2,3,4-四氢萘-1-亚基)-4-甲苯磺酰肼替换为N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼,将第七步原料间氨基苯磺酰胺替换为2-氨基噻吩-3-甲酰胺制得化合物45(39mg)。1H NMR(500MHz,Methanol-d4)δ7.89(s,1H),7.43(s,1H),7.36(d,J=5.8Hz,1H),6.99(d,J=5.9Hz,1H),6.77(dd,J=8.1,6.7Hz,1H),6.56–6.49(m,2H),4.74(t,J=7.1Hz,1H),4.20(ddd,J=11.3,6.1,3.4Hz,1H),4.13(ddd,J=11.3,8.7,2.7Hz,1H),2.42–2.33(m,1H),2.23–2.13(m,1H).
实施例46 5-(5-氯-2-(7-氟苯并二氢吡喃-4-基)-4-三氟甲基苯甲酰胺)噻吩-3-甲酰胺46的制备
采用实施例19的合成路线,将第二步原料N'-(6-氟-1,2,3,4-四氢萘-1-亚基)-4-甲苯磺酰肼替换为N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼,将第七步原料间氨基苯磺酰胺替换为2-氨基噻吩-4-甲酰胺制得化合物46(31mg)1H NMR(500MHz,Methanol-d4)δ7.83(s,1H),7.67(d,J=1.7Hz,1H),7.38(s,1H),7.18(d,J=1.7Hz,1H),6.79–6.74(m,
1H),6.58–6.53(m,2H),4.61(t,J=7.1Hz,1H),4.24–4.16(m,1H),4.17–4.12(m,1H),2.40–2.30(m,1H),2.22–2.11(m,1H).
实施例47 5-(5-氯-2-(7-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酰胺基)呋喃-3-羧酸47的制备
采用实施例19的合成路线,将第二步原料N'-(6-氟-1,2,3,4-四氢萘-1-亚基)-4-甲苯磺酰肼替换为N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼,将第七步原料间氨基苯磺酰胺替换为5-氨基呋喃-3-羧酸甲酯,再经过一步酯水解制得化合物47(29mg)。1H NMR(600MHz,Methanol-d4)δ7.83(s,1H),7.38(s,1H),7.26(d,J=3.6Hz,1H),6.78(dd,J=9.0,6.4Hz,1H),6.60(d,J=3.6Hz,1H),6.59–6.52(m,2H),4.61(t,J=7.2Hz,1H),4.20(ddd,J=11.1,6.1,3.4Hz,1H),4.14(ddd,J=11.3,8.6,2.7Hz,1H),2.39–2.31(m,1H),2.21–2.14(m,1H).
实施例48 5-氯-N-(1,3-二氧代异吲哚啉-5-基)-2-(7-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酰胺48的制备
采用实施例19的合成路线,将第二步原料N'-(6-氟-1,2,3,4-四氢萘-1-亚基)-4-甲苯磺酰肼替换为N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼,将第七步原料间氨基苯磺酰胺替换为4-氨基邻苯二甲酰亚胺制得化合物48(37mg)。1H NMR(600MHz,Chloroform-d)δ8.61(s,1H),8.42(s,1H),8.13(s,1H),8.06(d,J=8.2Hz,1H),7.80(d,J=8.1Hz,1H),7.73(s,1H),7.42(s,1H),6.71–6.64(m,1H),6.55(dd,J=10.2,2.6Hz,1H),6.49(td,J=8.4,2.6Hz,1H),4.63(t,J=7.4Hz,1H),4.25(dt,J=9.5,4.2Hz,1H),4.19–4.12(m,1H),2.42–2.36(m,1H),2.23–2.14(m,1H).
实施例49 5-氯-2-(7-氟苯并二氢吡喃-4-基)-N-(5-氧代吡咯烷-3-基)-4-(三氟甲基)苯甲酰胺49的制备
将化合物41a(50mg,133.43μmol)溶于四氢呋喃溶液中,依次加入DIEA(46μL,0.27mmol)和HATU(76mg,200.15μmol)。反应混合物在室温下搅拌15分钟,加入4-氨基吡咯烷-2-酮盐酸盐(20mg,146.78μmol),继续搅拌反应5小时。向反应体系中
加入20mL水,乙酸乙酯萃取(10mL×3)。合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩。用硅胶柱色谱法(MeOH:DCM;1:150至1:100)纯化,得到化合物49(51mg)(白色固体),产率:83.67%。1H NMR(400MHz,Chloroform-d)δ7.58(s,1H),7.45(t,J=5.9Hz,1H),7.36(s,1H),6.66(td,J=7.5,6.4,1.9Hz,1H),6.61(dd,J=10.1,2.6Hz,1H),6.52(td,J=8.3,2.6Hz,1H),6.23(d,J=5.7Hz,1H),4.82–4.70(m,1H),4.65–4.55(m,1H),4.25(ddd,J=10.2,4.8,3.0Hz,1H),4.17(ddd,J=11.4,9.0,2.7Hz,1H),3.87–3.78(m,1H),3.36(ddd,J=25.6,10.6,2.6Hz,1H),2.74(dd,J=17.4,8.0Hz,1H),2.41–2.24(m,2H),2.25–2.09(m,1H).
实施例50 N-(3-氨基甲酰基苯基)-5-氯-2-(8-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酰胺50的制备
采用实施例25的合成路线,将原料N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼替换为N'-(8-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼制得化合物50(61mg)。1H NMR(600MHz,Methanol-d4)δ8.16(t,J=2.0Hz,1H),7.85–7.83(m,1H),7.82(s,1H),7.64(dt,J=7.7,1.3Hz,1H),7.44(t,J=7.9Hz,1H),7.37(s,1H),6.95–6.87(m,1H),6.77–6.70(m,1H),6.60(d,J=7.8Hz,1H),4.69(dd,J=8.2,6.3Hz,1H),4.27(ddd,J=11.1,6.1,3.3Hz,1H),4.18(ddd,J=11.3,8.9,2.7Hz,1H),2.46–2.33(m,1H),2.28–2.17(m,1H).
实施例51 5-氯-2-(8-氟苯并二氢吡喃-4-基)-N-(2-氧代-1,2-二氢吡啶-4-基)-4-(三氟甲基)苯甲酰胺51的制备
采用实施例22的合成路线,将原料N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼替换为N'-(8-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼制得化合物51(57mg)。1H NMR(600MHz,Methanol-d4)δ7.81(s,1H),7.44–7.32(m,2H),7.00(d,J=2.1Hz,1H),6.92(dd,J=11.0,8.0Hz,1H),6.73(ddd,J=10.0,7.7,3.5Hz,2H),6.57(d,J=7.9Hz,1H),4.63(t,J=7.3Hz,1H),4.29(ddd,J=11.0,5.8,3.4Hz,1H),4.18(ddd,J=11.4,9.1,2.6Hz,1H),2.42–2.33(m,1H),2.29–2.20(m,1H).
实施例52 N-(3-氨基甲酰基苯基)-5-氯-2-(7,8-二氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酰52的制备
采用实施例25的合成路线,将原料N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼替换为N'-(7,8-二氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼制得化合物52(47mg)。1H NMR(600MHz,Methanol-d4)δ8.14(t,J=2.0Hz,1H),7.84(d,J=9.0Hz,2H),7.65(d,J=
7.8Hz,1H),7.46(t,J=8.0Hz,1H),7.41(s,1H),6.67(td,J=9.4,7.0Hz,1H),6.59(t,J=7.1Hz,1H),4.65(t,J=7.3Hz,1H),4.33(ddd,J=11.3,5.8,3.4Hz,1H),4.26–4.20(m,1H),2.43–2.35(m,1H),2.32–2.22(m,1H).
实施例53 5-氯-2-(7,8-二氟苯并二氢吡喃-4-基)-N-(2-氧代-1,2-二氢吡啶-4-基)-4-(三氟甲基)苯甲酰胺53的制备
采用实施例22的合成路线,将原料N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼替换为N'-(7,8-二氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼制得化合物53(39mg)。1H NMR(600MHz,Methanol-d4)δ7.81(s,1H),7.45(s,1H),7.40(d,J=7.2Hz,1H),6.98(d,J=2.1Hz,1H),6.70(dd,J=7.2,2.1Hz,1H),6.65(td,J=9.4,7.0Hz,1H),6.54(dd,J=8.6,6.1Hz,1H),4.59(t,J=7.5Hz,1H),4.33(ddd,J=11.2,5.5,3.5Hz,1H),4.21(ddd,J=11.5,9.2,2.6Hz,1H),2.40–2.32(m,1H),2.33–2.24(m,1H).
实施例54 N-(3-氨基甲酰基苯基)-5-氯-2-(6-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酰54的制备
采用实施例25的合成路线,将原料N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼替换为N'-(6-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼制得化合物54(64mg)。1H NMR(600MHz,Chloroform-d)δ9.33(brs,1H),8.23–8.06(m,2H),7.72(s,1H),7.50–7.34(m,2H),6.85–6.69(m,2H),6.43(d,J=9.3Hz,1H),6.21(brs,1H),5.50(brs,1H),4.64(t,J=7.5Hz,1H),4.29–4.16(m,1H),4.16–4.04(m,1H),2.42–2.32(m,1H),2.20–2.10(m,1H).
实施例55 5-氯-2-(6-氟苯并二氢吡喃-4-基)-N-(2-氧代-1,2-二氢吡啶-4-基)-4-(三氟甲基)苯甲酰胺55的制备
采用实施例22的合成路线,将原料N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼替换为N'-(6-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼制得化合物55(49mg)。1H NMR(600MHz,Chloroform-d)δ11.94(brs,1H),9.58(brs,1H),7.63(s,1H),7.33(s,1H),7.22(d,J=7.2Hz,1H),6.88–6.80(m,1H),6.76(d,J=5.9Hz,2H),6.71(s,1H),6.44–6.36(m,1H),4.55(t,J=7.5Hz,1H),4.19(dt,J=9.7,4.0Hz,1H),4.06(t,J=9.8Hz,1H),2.37–2.26(m,1H),2.13–2.05(m,1H).
实施例56 N-(3-氨基甲酰基-4-氟苯基)-5-氯-2-(7-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酰胺56的制备
采用实施例25的合成路线,将原料间氨基苯甲酰胺替换为5-氨基-2-氟苯甲酰胺制得化合物56(48mg)。1H NMR(600MHz,Methanol-d4)δ8.07(dd,J=6.5,2.8Hz,1H),7.88(ddd,J=9.0,4.4,2.8Hz,1H),7.81(s,1H),7.37(s,1H),7.22(dd,J=10.5,8.9Hz,1H),6.83–6.76(m,1H),6.59–6.51(m,2H),4.61(t,J=7.1Hz,1H),4.20(ddd,J=11.3,6.1,3.4Hz,1H),4.14(ddd,J=11.3,8.7,2.7Hz,1H),2.40–2.30(m,1H),2.23–2.14(m,1H).
实施例57 N-(3-氨基甲酰基-4-氟苯基)-5-氯-2-(8-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酰胺57的制备
采用实施例25的合成路线,将原料N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼替换为N'-(8-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼,再将原料间氨基苯甲酰胺替换为5-氨基-2-氟苯甲酰胺制得化合物57(58mg)。1H NMR(400MHz,Chloroform-d)δ9.84(s,1H),8.56(ddd,J=9.2,4.5,2.9Hz,1H),8.19(dd,J=6.7,2.9Hz,1H),7.77(s,1H),7.40(s,1H),7.21(dd,J=11.4,9.0Hz,1H),6.98–6.87(m,1H),6.80–6.71(m,1H),6.66(td,J=7.9,4.9Hz,1H),6.49(d,J=7.9Hz,1H),5.12(s,1H),4.71(dd,J=8.4,6.2Hz,1H),4.32(ddd,J=11.3,5.9,3.4Hz,1H),4.21(ddd,J=11.4,9.0,2.6Hz,1H),2.49–2.34(m,1H),2.27–2.12(m,1H).
实施例58 N-(3-氨基甲酰基-4-氟苯基)-5-氯-2-(6-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酰胺58的制备
采用实施例25的合成路线,将原料N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼替换为N'-(6-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼,再将原料间氨基苯甲酰胺替换为5-氨基-2-氟苯甲酰胺制得化合物58(53mg)。1H NMR(600MHz,Chloroform-d)δ10.00(brs,1H),8.54(dt,J=8.4,3.4Hz,1H),8.13(s,1H),7.76(s,1H),7.38(s,1H),7.17(dd,J=11.4,9.0Hz,1H),6.81–6.68(m,3H),6.42(d,J=9.0Hz,1H),5.23(brs,1H),4.63(t,J=7.5Hz,1H),4.22(ddd,J=11.2,5.6,3.5Hz,1H),4.10(td,J=10.1,9.4,2.8Hz,1H),2.48–2.35(m,1H),2.22–2.10(m,1H).
实施例59 N-(4-羰基苯基)-5-氯-2-(7-氟苯并二氢-4-基)-4-(三氟甲基)苯甲酰胺59的制备
采用实施例25的合成路线,将原料间氨基苯甲酰胺替换为对氨基苯甲酰胺制得化合物59(43mg)。1H NMR(600MHz,Methanol-d4)δ7.93–7.86(m,2H),7.82(s,1H),7.79–7.76(m,2H),7.38(s,1H),6.80(dd,J=9.5,6.5Hz,1H),6.58–6.53(m,2H),4.61(t,J=7.1Hz,1H),4.20(ddd,J=11.4,6.2,3.4Hz,1H),4.14(ddd,J=11.3,8.6,2.8Hz,1H),2.39–2.31(m,1H),2.24–2.15(m,1H).
实施例60 N-(4-氨基-3-氟苯基)-5-氯-2-(7-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酰胺60的制备
采用实施例25的合成路线,将原料间氨基苯甲酰胺替换为4-氨基-2-氟制得化合物60(63mg)。1H NMR(600MHz,Methanol-d4)δ7.84(t,J=8.5Hz,1H),7.82(s,1H),7.80(dd,J=13.7,2.1Hz,1H),7.43–7.38(m,2H),6.81–6.76(m,1H),6.57–6.52(m,2H),4.60(t,J=7.2Hz,1H),4.21(ddd,J=11.3,6.1,3.4Hz,1H),4.14(ddd,J=11.4,8.8,2.7Hz,1H),2.39–2.31(m,1H),2.25–2.16(m,1H).
实施例61N-(4-氨基-3-氟苯基)-5-氯-2-(8-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酰胺61的制备
采用实施例25的合成路线,将原料N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼替换为N'-(8-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼,再将原料间氨基苯甲酰胺替换为4-氨基-2-氟苯甲酰胺制得化合物61(68mg)。1H NMR(600MHz,Methanol-d4)δ7.86–7.83(m,2H),7.80(dd,J=13.7,2.0Hz,1H),7.43–7.40(m,2H),6.94–6.89(m,1H),6.74(td,J=8.0,4.8Hz,1H),6.59(dd,J=7.9,1.4Hz,1H),4.71–4.60(m,1H),4.30(ddd,J=11.5,5.9,3.4Hz,1H),4.20(ddd,J=11.4,9.0,2.6Hz,1H),2.47–2.34(m,1H),2.31–2.22(m,1H).
实施例62 N-(4-氨基-3-氟苯基)-5-氯-2-(6-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酰胺62的制备
采用实施例25的合成路线,将原料N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼替换为N'-(6-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼,再将原料间氨基苯甲酰胺替换为4-氨基-2-氟苯甲酰胺制得化合物62(58mg)。1H NMR(600MHz,Methanol-d4)δ7.87–7.83(m,2H),7.80(dd,J=13.6,2.0Hz,1H),7.43–7.40(m,2H),6.86–6.79(m,2H),6.54(dd,J=9.2,2.9Hz,1H),4.62(dd,J=8.5,6.4Hz,1H),4.22(ddd,J=11.3,5.8,3.4Hz,1H),4.11(ddd,J=11.4,9.2,2.7Hz,1H),2.39–2.31(m,1H),2.26–2.16(m,1H).
实施例63 N-(4-氨基-3-氯苯基)-5-氯-2-(7-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酰胺63的制备
采用实施例25的合成路线,将原料间氨基苯甲酰胺替换为4-氨基-2-氯苯甲酰胺制得化合物63(64mg)。1H NMR(600MHz,Chloroform-d)δ7.98(d,J=2.0Hz,1H),7.91(brs,1H),7.70–7.64(m,2H),7.54(dd,J=8.5,2.0Hz,1H),7.46(s,1H),6.68(dd,J=8.5,6.4Hz,1H),6.60(dd,J=10.1,2.6Hz,1H),6.55(td,J=8.3,2.6Hz,1H),4.60(dd,J=8.7,6.4Hz,1H),4.28(ddd,J=11.2,5.6,3.5Hz,1H),4.18(ddd,J=11.5,9.3,2.5Hz,1H),2.43–2.35(m,1H),2.25–2.15(m,1H).
实施例64 N-(3-氨基甲酰基-4-氯苯基)-5-氯-2-(7-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酰胺64的制备
采用实施例25的合成路线,将原料间氨基苯甲酰胺替换为5-氨基-2-氯苯甲酰胺制得化合物64(55mg)。1H NMR(600MHz,Methanol-d4)δ7.88(d,J=2.6Hz,1H),7.82(s,1H),7.72(dd,J=8.7,2.6Hz,1H),7.45(d,J=8.8Hz,1H),7.38(s,1H),6.79(dd,J=8.3,6.5Hz,1H),6.59–6.53(m,2H),4.60(t,J=7.2Hz,1H),4.21(ddd,J=11.3,6.2,3.4Hz,1H),4.14(ddd,J=11.3,8.6,2.7Hz,1H),2.38–2.31(m,1H),2.23–2.14(m,1H).
实施例65 N-(3-氨基甲酰基-4-溴苯基)-5-氯-2-(7-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酰胺65的制备
采用实施例25的合成路线,将原料间氨基苯甲酰胺替换为5-氨基-2-溴苯甲酰胺制得化合物65(59mg)。1H NMR(500MHz,Methanol-d4)δ7.85(d,J=2.4Hz,1H),7.81(s,1H),7.66–7.58(m,2H),7.37(s,1H),6.82–6.76(m,1H),6.59–6.52(m,2H),4.60(t,J=7.1Hz,1H),4.20(ddd,J=11.3,6.1,3.4Hz,1H),4.14(ddd,J=11.3,8.6,2.8Hz,1H),2.39–2.30(m,1H),2.23–2.13(m,1H).
实施例66 5-氯-2-(8-氟苯并二氢吡喃-4-基)-N-(3-氨磺基苯基)-4-(三氟甲基)苯甲酰胺66的制备
采用实施例19的合成路线,将第二步原料N'-(6-氟-1,2,3,4-四氢萘-1-亚基)-4-甲苯磺酰肼替换为N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼制得化合物66(51mg)。1H NMR(600MHz,Methanol-d4)δ8.35(s,1H),7.83(d,J=8.2Hz,1H),7.75–7.68(m,2H),7.55(t,J=8.0Hz,1H),7.06(d,J=8.3Hz,1H),6.92(dd,J=10.9,8.2Hz,1H),6.75(td,J=8.0,4.7Hz,1H),6.65(d,J=7.9Hz,1H),4.52(t,J=7.1Hz,1H),4.31(ddd,J=10.4,6.6,3.2Hz,1H),4.20(ddd,J=11.2,8.2,2.6Hz,1H),2.40(ddt,J=13.9,6.6,3.2Hz,1H),2.25(dtd,J=11.8,8.3,3.0Hz,1H).
实施例67 N-(3-氨基甲酰基-4-氟苯基)-2-氟-6-(7-氟苯并二氢吡喃-4-基)-3-(三氟甲基)苯甲酰胺
采用实施例27的合成路线,将原料4-氨基-2-甲氧基吡啶替换为5-氨基-2-氟苯甲酰胺制得化合物67(31mg)。1H NMR(600MHz,Methanol-d4)δ8.10(dd,J=6.5,2.8Hz,1H),7.92(dt,J=7.7,3.5Hz,1H),7.73(t,J=7.8Hz,1H),7.27(t,J=9.7Hz,1H),7.06(d,J=8.3Hz,1H),6.86(dd,J=9.5,6.3Hz,1H),6.66–6.50(m,2H),4.47(t,J=7.1Hz,1H),4.26(ddd,J=10.4,6.6,3.2Hz,1H),4.20–4.13(m,1H),2.41–2.33(m,1H),2.27–2.17(m,1H).
实施例68 2-氟-6-(8-氟b苯并二氢吡喃-4-基)-4-甲氧基-N-(3-氨磺酰基苯基)-3-(三氟甲基)苯甲酰胺68的制备
采用实施例27的合成路线,将原料6-溴-2-氟-3-(三氟甲基)苯甲酸甲酯替换为6-溴-2-氟-4-甲氧基-3-(三氟甲基)苯甲酸乙酯(合成参照WO 2019/014352),将原料N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼替换为N'-(8-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼,将原料4-氨基-2-甲氧基吡啶替换为间氨基苯磺酰胺制得化合物68(27mg)。1H NMR(600MHz,Methanol-d4)δ8.31(s,1H),7.80(d,J=8.1Hz,1H),7.69(d,J=7.8Hz,1H),7.53(t,J=8.0Hz,1H),6.95–6.85(m,1H),6.77(td,J=8.0,4.7Hz,1H),6.68(d,J=7.9Hz,1H),6.61(s,1H),4.53(t,J=7.4Hz,1H),4.39–4.32(m,1H),4.23–4.14(m,1H),3.77(s,3H),2.43–2.35(m,1H),2.37–2.28(m,1H).
实施例69 N-(3-氨基甲酰基-4-氟苯基)-2-氟-6-(8-氟苯并二氢吡喃-4-基)-4-甲氧基-3-(三氟甲基)苯甲酰胺69的制备
采用实施例68的合成路线,将原料间氨基苯磺酰胺替换为5-氨基-2-氟苯甲酰胺制得化合物69(30mg)。1H NMR(600MHz,Methanol-d4)δ8.04(dd,J=6.5,2.8Hz,1H),7.88(dt,J=7.9,3.6Hz,1H),7.23(t,J=9.7Hz,1H),6.96–6.89(m,1H),6.77(td,J=8.0,4.6Hz,1H),6.68(d,J=7.9Hz,1H),6.60(s,1H),4.52(t,J=7.4Hz,1H),4.38–4.31(m,1H),4.22–4.16(m,1H),2.42–2.35(m,1H),2.36–2.27(m,1H).
实施例70 5-氯-2-(7-(三氟甲氧基)苯并二氢吡喃-4-基)-N-(3-氨磺基苯基)-4-(三氟甲基)苯甲酰胺70的制备
采用实施例19的合成路线,将第二步原料N'-(6-氟-1,2,3,4-四氢萘-1-亚基)-4-甲苯磺酰肼替换为N'-(7-(三氟甲氧基)苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼制得化合物70(17mg)。1H NMR(600MHz,Chloroform-d)δ8.47(s,1H),8.09(s,1H),7.97(d,J=8.2Hz,1H),7.67(s,1H),7.61(d,J=7.8Hz,1H),7.48(t,J=8.0Hz,1H),7.40(s,1H),6.78–6.65(m,2H),6.60(d,J=8.5Hz,1H),5.21(s,1H),4.61(dd,J=8.8,6.2Hz,1H),4.24(dt,J=11.1,4.2Hz,1H),4.18–4.07(m,1H),2.40–2.27(m,1H),2.24–2.12(m,1H).
实施例71 5-氯-2-(7-(三氟甲基)苯并二氢吡喃-4-基)-N-(3-氨磺基苯基)-4-(三氟甲基)苯甲酰胺71的制备
采用实施例19的合成路线,将第二步原料N'-(6-氟-1,2,3,4-四氢萘-1-亚基)-4-甲苯磺酰肼替换为N'-(7-(三氟甲基)苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼制得化合物71
(47mg)。1H NMR(600MHz,Methanol-d4)δ8.33(t,J=1.9Hz,1H),7.87(s,1H),7.77(d,J=8.1Hz,1H),7.69(d,J=7.8Hz,1H),7.52(t,J=8.0Hz,1H),7.41(s,1H),7.11–7.03(m,2H),6.99(d,J=8.1Hz,1H),4.72(t,J=7.6Hz,1H),4.30(dt,J=9.7,4.6Hz,1H),4.25–4.17(m,1H),2.44–2.35(m,1H),2.33–2.26(m,1H).
实施例72 N-(3-氨基甲酰基-4-氟苯基)-5-氯-2-(7-(三氟甲基)苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酰72的制备
采用实施例19的合成路线,将第二步原料N'-(6-氟-1,2,3,4-四氢萘-1-亚基)-4-甲苯磺酰肼替换为N'-(7-(三氟甲基)苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼,将第七步原料间氨基苯磺酰胺替换为5-氨基-2-氟苯甲酰胺制得化合物72(41mg)。1H NMR(600MHz,Chloroform-d)δ9.84(s,1H),8.54(dt,J=8.1,3.6Hz,1H),8.21(dd,J=6.8,2.8Hz,1H),7.81(s,1H),7.44(s,1H),7.22(dd,J=11.3,9.0Hz,1H),7.11(s,1H),6.95(d,J=8.1Hz,1H),6.85(d,J=8.1Hz,1H),6.81–6.75(m,1H),5.13(s,1H),4.72(t,J=7.6Hz,1H),4.32(dt,J=11.6,4.2Hz,1H),4.27–4.16(m,1H),2.47–2.37(m,1H),2.36–2.25(m,1H).
实施例73 5-氯-2-(7-(三氟甲基)苯并二氢吡喃-4-基)-N-(2-氧代-1,2-二氢吡啶-4-基)-4-(三氟甲基)苯甲酰胺73的制备
采用实施例19的合成路线,将第二步原料N'-(6-氟-1,2,3,4-四氢萘-1-亚基)-4-甲苯磺酰肼替换为N'-(7-(三氟甲基)苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼,将第七步原料间氨基苯磺酰胺替换为4-氨基-2-甲氧基吡啶,得到甲氧基吡啶中间体,并继续采用实施例3的合成路线的第二步制得化合物73(44mg)。1H NMR(600MHz,Chloroform-d)δ11.95(brs,1H),9.25(brs,1H),7.64(s,1H),7.34(s,1H),7.23(d,J=7.2Hz,1H),7.08(s,1H),6.96(d,J=8.1Hz,1H),6.82(d,J=8.1Hz,1H),6.77(d,J=7.1Hz,1H),6.73(s,1H),4.61(t,J=7.7Hz,1H),4.27(dt,J=9.2,4.1Hz,1H),4.21–4.09(m,1H),2.41–2.29(m,1H),2.25–2.11(m,1H).
实施例74 2-氟-N-(3-氨磺酰基苯基)-3-(三氟甲基)-6-(7-(三氟甲基)苯并二氢吡喃-4-基)苯甲酰胺74的制备
采用实施例27的合成路线,将原料N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼替换为N'-(7-(三氟甲基)苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼,将原料4-氨基-2-甲氧基
吡啶替换为间氨基苯磺酰胺制得化合物74(46mg)。1H NMR(600MHz,Methanol-d4)δ8.36(d,J=2.4Hz,1H),7.79(d,J=8.1Hz,1H),7.74(t,J=7.8Hz,1H),7.71(d,J=7.8Hz,1H),7.55(t,J=8.0Hz,1H),7.12–7.00(m,4H),4.56(t,J=7.2Hz,1H),4.32(ddd,J=10.2,6.2,3.5Hz,1H),4.25–4.17(m,1H),2.44–2.35(m,1H),2.34–2.24(m,1H).
实施例75 N-(3-氨基-4-氟苯基)-2-氟-3-(三氟甲基)-6-(7-(三氟甲基)苯并二氢吡喃-4-基)苯甲酰胺75的制备
采用实施例27的合成路线,将原料N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼替换为N'-(7-(三氟甲基)苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼,将原料4-氨基-2-甲氧基吡啶替换为5-氨基-2-氟苯甲酰胺制得化合物75(37mg)。1H NMR(600MHz,Methanol-d4)δ8.07(dd,J=6.5,2.8Hz,1H),7.89(dt,J=7.9,3.5Hz,1H),7.73(t,J=7.8Hz,1H),7.23(t,J=9.7Hz,1H),7.09–7.00(m,5H),4.55(t,J=7.3Hz,1H),4.31(ddd,J=10.2,6.2,3.5Hz,1H),4.21(ddd,J=11.3,8.6,2.7Hz,1H),2.42–2.35(m,1H),2.33–2.25(m,1H).
实施例76 2-氟-N-(2-羟基吡啶-4-基)-3-(三氟甲基)-6-(7-(三氟甲基)苯并二氢吡喃-4-基)苯甲酰胺76的制备
采用实施例27的合成路线,将原料N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼替换为N'-(7-(三氟甲基)苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼制得化合物76(21mg)。1H NMR(600MHz,Methanol-d4)δ7.75(t,J=7.8Hz,1H),7.39(d,J=7.2Hz,1H),7.12(d,J=8.3Hz,1H),7.08–7.02(m,2H),7.00(d,J=8.0Hz,1H),6.96(s,1H),6.66(d,J=7.2Hz,1H),4.52(t,J=7.5Hz,1H),4.32(dt,J=10.0,4.5Hz,1H),4.23–4.16(m,1H),2.42–2.24(m,2H).
实施例77 2-氟-N-(3-氨磺酰基苯基)-3-(三氟甲基)-6-(8-氟苯并二氢吡喃-4-基)苯甲酰胺77的制备
采用实施例27的合成路线,将原料N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼替换为N'-(8-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼,将原料4-氨基-2-甲氧基吡啶替换为间氨基苯磺酰胺制得化合物77(59mg)。1H NMR(600MHz,Methanol-d4)δ8.35(s,1H),7.83(d,J=8.2Hz,1H),7.75–7.68(m,4H),7.55(t,J=8.0Hz,1H),7.06(d,J=8.3Hz,1H),6.92(dd,J=10.9,8.2Hz,1H),6.75(td,J=8.0,4.7Hz,1H),6.65(d,J=7.9Hz,1H),4.52(t,J=7.1Hz,1H),4.31(ddd,J=10.4,6.6,3.2Hz,1H),4.20(ddd,J=11.2,8.2,2.6Hz,1H),2.44–
2.36(m,2H),2.30–2.21(m,2H).
实施例78 N-(3-氨基-4-氟苯基)-2-氟-3-(三氟甲基)-6-(8-氟苯并二氢吡喃-4-基)苯甲酰胺78的制备
采用实施例27的合成路线,将原料N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼替换为N'-(8-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼,将原料4-氨基-2-甲氧基吡啶替换为5-氨基-2-氟苯甲酰胺制得化合物78(47mg)。1H NMR(400MHz,Chloroform-d)δ10.01(s,1H),8.59(ddd,J=9.0,4.5,2.8Hz,1H),8.12(dd,J=6.7,2.9Hz,1H),7.61(t,J=7.7Hz,1H),7.20(dd,J=11.4,9.0Hz,1H),6.98(d,J=8.2Hz,1H),6.91(ddd,J=10.4,8.0,1.6Hz,1H),6.73–6.61(m,2H),6.56(dd,J=7.6,1.4Hz,1H),5.02(s,1H),4.54(t,J=7.0Hz,1H),4.29(ddd,J=11.3,6.5,3.3Hz,1H),4.19(ddd,J=11.2,8.3,2.8Hz,1H),2.49–2.37(m,1H),2.27–2.14(m,1H).
实施例79 2-氟-N-(2-羟基吡啶-4-基)-3-(三氟甲基)-6-(8-氟苯并二氢吡喃-4-基)苯甲酰胺79的制备
采用实施例27的合成路线,将原料N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼替换为N'-(7-(三氟甲基)苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼制得化合物79(25mg)。1H NMR(600MHz,Methanol-d4)δ7.73(t,J=7.8Hz,1H),7.42(d,J=7.2Hz,1H),7.08(d,J=8.3Hz,1H),6.99(d,J=2.1Hz,1H),6.94–6.90(m,1H),6.77–6.68(m,2H),6.61(d,J=7.8Hz,1H),4.47(t,J=7.2Hz,1H),4.31(ddd,J=10.3,6.3,3.4Hz,1H),4.22–4.15(m,1H),2.41–2.34(m,1H),2.30–2.20(m,1H).
实施例80 N-(3-氨基甲酰基-4-氟苯基)-5-氯-2-(7,8-二氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酰80的制备
采用实施例19的合成路线,将第二步原料N'-(6-氟-1,2,3,4-四氢萘-1-亚基)-4-甲苯磺酰肼替换为N'-(7,8-二氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼,将第七步原料间氨基苯磺酰胺替换为5-氨基-2-氟苯甲酰胺制得化合物80(37mg)。1H NMR(600MHz,Chloroform-d)δ9.61(s,1H),8.51(dt,J=8.2,3.6Hz,1H),8.18(dd,J=6.9,2.8Hz,1H),7.77(s,1H),7.39(s,1H),7.25–7.19(m,1H),6.76(d,J=12.5Hz,1H),6.56(q,J=8.5Hz,1H),6.45(t,J=7.4Hz,1H),5.19(s,1H),4.67(t,J=7.4Hz,1H),4.37–4.30(m,1H),4.25–4.18(m,1H),2.44–2.37(m,1H),2.24–2.15(m,1H).
实施例81 N-(3-氨基-4-氟苯基)-2-氟-3-(三氟甲基)-6-(8-氟苯并二氢吡喃-4-基)苯甲
酰胺81的制备
采用实施例27的合成路线,将原料N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼替换为N'-(7,8-二氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼,将原料4-氨基-2-甲氧基吡啶替换为5-氨基-2-氟苯甲酰胺制得化合物81(36mg)。1H NMR(500MHz,Methanol-d4)δ8.07(dd,J=6.4,2.8Hz,1H),7.91(ddd,J=9.0,4.3,2.8Hz,1H),7.72(t,J=7.9Hz,1H),7.25(dd,J=10.5,8.9Hz,1H),7.06(d,J=8.3Hz,1H),6.73–6.59(m,2H),4.48(t,J=7.1Hz,1H),4.34(ddd,J=11.3,6.4,3.3Hz,1H),4.23(ddd,J=11.2,8.5,2.8Hz,1H),2.43–2.33(m,1H),2.31–2.20(m,1H).
实施例82 2-氟-N-(3-氨磺酰基苯基)-3-(三氟甲基)-6-(7,8-二氟苯并二氢吡喃-4-基)苯甲酰胺82的制备
采用实施例27的合成路线,将原料N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼替换为N'-(7,8-二氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼,将原料4-氨基-2-甲氧基吡啶替换为间氨基苯磺酰胺制得化合物82(66mg)。1H NMR(600MHz,Methanol-d4)δ8.35(d,J=2.2Hz,1H),7.84–7.78(m,1H),7.72(dd,J=17.6,8.2Hz,2H),7.55(t,J=8.0Hz,1H),7.07(d,J=8.3Hz,1H),6.72–6.65(m,1H),6.63(t,J=7.4Hz,1H),4.49(t,J=7.1Hz,1H),4.34(ddd,J=10.4,6.5,3.4Hz,1H),4.23(ddd,J=11.6,8.4,2.6Hz,1H),2.43–2.35(m,1H),2.30–2.22(m,1H).
实施例83 N-(3-氨基-4-氟苯基)-2-氟-3-(三氟甲基)-6-(6-(三氟甲氧基)苯并二氢吡喃-4-基)苯甲酰胺83的制备
采用实施例27的合成路线,将原料N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼替换为N'-(6-(三氟甲氧基)苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼,将原料4-氨基-2-甲氧基吡啶替换为5-氨基-2-氟苯甲酰胺制得化合物83(38mg)。1H NMR(600MHz,Chloroform-d)δ9.99(s,1H),8.58(dt,J=8.1,3.5Hz,1H),8.15(dd,J=6.7,2.8Hz,1H),7.63(t,J=7.6Hz,1H),7.26(d,J=1.3Hz,1H),7.20(dd,J=11.4,9.0Hz,1H),6.97(d,J=8.4Hz,2H),6.85(d,J=9.0Hz,1H),6.70–6.63(m,2H),4.84(s,1H),4.53(t,J=7.1Hz,1H),4.22(ddd,J=10.3,6.5,3.3Hz,1H),4.17–4.10(m,1H),2.45–2.38(m,1H),2.21–2.14(m,1H).
实施例84 2-氟-N-(3-氨磺酰基苯基)-3-(三氟甲基)-6-(6-(三氟甲氧基)苯并二氢吡
喃-4-基)苯甲酰胺84的制备
采用实施例27的合成路线,将原料N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼替换为N'-(6-(三氟甲氧基)苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼,将原料4-氨基-2-甲氧基吡啶替换为间氨基苯磺酰胺制得化合物84(40mg)。1H NMR(600MHz,Methanol-d4)δ8.38(d,J=2.4Hz,1H),7.80(d,J=8.1Hz,1H),7.77–7.69(m,2H),7.56(t,J=8.0Hz,1H),7.08–7.00(m,2H),6.90(d,J=9.0Hz,1H),6.84–6.79(m,1H),4.52(t,J=7.0Hz,1H),4.26(ddd,J=10.6,6.6,3.2Hz,1H),4.20–4.14(m,1H),2.43–2.34(m,1H),2.25–2.16(m,1H).
实施例85 N-(3-氨基-4-氟苯基)-2-氟-3-(三氟甲基)-6-(7-(三氟甲氧基)苯并二氢吡喃-4-基)苯甲酰胺85的制备
采用实施例27的合成路线,将原料N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼替换为N'-(7-(三氟甲氧基)苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼,将原料4-氨基-2-甲氧基吡啶替换为5-氨基-2-氟苯甲酰胺制得化合物85(34mg)。1H NMR(500MHz,Methanol-d4)δ8.08(dd,J=6.4,2.8Hz,1H),7.91(ddd,J=8.9,4.3,2.8Hz,1H),7.73(t,J=7.8Hz,1H),7.24(dd,J=10.5,8.9Hz,1H),7.06(d,J=8.3Hz,1H),6.93(dd,J=8.2,1.1Hz,1H),6.76–6.67(m,2H),4.49(t,J=7.1Hz,1H),4.28(ddd,J=11.3,6.3,3.4Hz,1H),4.18(ddd,J=11.4,8.6,2.8Hz,1H),2.42–2.32(m,1H),2.29–2.17(m,1H).
实施例86 2-氟-N-(3-氨磺酰基苯基)-3-(三氟甲基)-6-(7-(三氟甲氧基)苯并二氢吡喃-4-基)苯甲酰胺86的制备
采用实施例27的合成路线,将原料N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼替换为N'-(7-(三氟甲氧基)苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼,将原料4-氨基-2-甲氧基吡啶替换为5-氨基-2-氟苯甲酰胺制得化合物86(73mg)。1H NMR(600MHz,Methanol-d4)δ8.36(t,J=2.0Hz,1H),7.81(dd,J=8.1,2.2Hz,1H),7.76–7.68(m,2H),7.55(t,J=8.0Hz,1H),7.06(d,J=8.3Hz,1H),6.93(d,J=8.2Hz,1H),6.74–6.70(m,2H),4.50(t,J=7.1Hz,1H),4.28(ddd,J=11.2,6.3,3.3Hz,1H),4.18(ddd,J=11.3,8.6,2.7Hz,1H),2.42–2.34(m,1H),2.29–2.20(m,1H).
实施例87 N-(3-氨基-4-氟苯基)-2-氟-3-(三氟甲基)-6-(7-氯苯并二氢吡喃-4-基)苯甲
酰胺87的制备
采用实施例19的合成路线,将第二步原料N'-(6-氟-1,2,3,4-四氢萘-1-亚基)-4-甲苯磺酰肼替换为N'-(7-氯苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼,将第七步原料间氨基苯磺酰胺替换为5-氨基-2-氟苯甲酰胺制得化合物87(22mg)。MS m/z(ESI):525.20[M-l]-。实施例88 2-氟-N-(3-氨磺酰基苯基)-3-(三氟甲基)-6-(7-氯苯并二氢吡喃-4-基)苯甲酰胺88的制备
采用实施例19的合成路线,将第二步原料N'-(6-氟-1,2,3,4-四氢萘-1-亚基)-4-甲苯磺酰肼替换为N'-(7-氯苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼制得化合物88(19mg)。MS m/z(ESI):545.40[M+l]+。
实施例89 5-氯-2-(7-氟苯并二氢吡喃-4-基)-N-(2-氨磺基吡啶-4-基)-4-(三氟甲基)苯甲酰胺89的制备
第一步5-氯-2-(7-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酰胺89a的制备
将化合物41a(100mg,226.87μmol)溶于无水二氯甲烷(4ml)中,置于冰浴,滴加草酰氯(0.23mL,2.67mmol),加毕,继续搅拌3小时。反应液浓缩,得到的酰氯备
用。将装有乙酸乙酯(2mL)和氨水(2mL)的混合溶液的反应瓶置于冰浴,滴加制备好的酰氯的无水二氯甲烷溶液,加毕,转移至室温搅拌1小时。向反应体系中加入水,用乙酸乙酯萃取,均匀混合,静置分层。分离有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩。用硅胶柱色谱法(MeOH:DCM;1:100至1:50)纯化,得到化合物89a(89mg)(白色固体),产率:89.23%。1H NMR(500MHz,Chloroform-d)δ7.61(s,1H),7.33(s,1H),6.65(ddd,J=8.5,6.5,1.0Hz,1H),6.60(dd,J=10.1,2.6Hz,1H),6.53(td,J=8.3,2.6Hz,1H),6.27(brs,1H),5.93(brs,1H),4.22(ddd,J=11.3,6.0,3.5Hz,1H),4.16(ddd,J=11.4,8.8,2.8Hz,1H),2.40–2.31(m,1H),2.15–2.05(m,1H).
第二步2-(苄硫基)-4-碘吡啶89c的制备
将苄硫醇(2.78g,22.42mmol)溶于干燥的四氢呋喃溶液中,在0℃搅拌条件下分批次加入氢化钠(897mg,22.42mmol,60%),将混合物在0℃下搅拌1小时。在0℃搅拌条件下向混合物中逐滴添加化合物2氟4碘吡啶89b(5g,22.42mmol)的四氢呋喃溶液。将所得混合物在室温搅拌12h,反应毕,置于冰浴中,加水淬灭并用乙酸乙酯萃取。分离有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩。用硅胶柱色谱法(EA:PE;1:100至1:70)纯化,得到化合物89c(7.05g)(无色油状物),产率:96.10%。
第三步4-碘吡啶-2-磺酰氯89d的制备
将化合物2-(苄硫基)-4-碘吡啶89c(5g,15.28mmol)溶于二氯甲烷(60mL)中,加入冰醋酸(8.6mL)和水(17mL)。在0℃搅拌条件下,加入1,3-二氯-5,5-二甲基海因(9.03g,45.85mmol)。将混合物在室温下搅拌10小时,反应毕用水淬灭并用DCM萃取。将合并的有机层用碳酸氢钠洗涤,经无水硫酸镁干燥,过滤并减压浓缩,残余物用三倍体积的PE研磨并过滤,得到化合物89d(3.10g)(黄色固体),产率:66.84%。
第四步N,N-双(2,4-二甲氧基苄基)-4-碘吡啶-2-磺酰胺89e的制备
将化合物4碘吡啶2磺酰氯89d(3g,9.88mmol)溶于二氯甲烷,氮气保护下,加入DIEA(4.3mL,24.71mmol),然后分批次加入双(2,4二甲氧基苄基)胺(2.82g,8.90mmol)。将混合物在20℃下搅拌1.5h,反应毕用水稀释,并用二氯甲烷萃取。分离有机层,无水硫酸钠干燥,过滤,滤液浓缩。用硅胶柱色谱法(MeOH:DCM;1:200至1:150)纯化,得到化合物89e(3.09g)(白色固体),产率:53.49%。1H NMR(400MHz,Chloroform-d)δ8.19(d,J=5.0Hz,1H),7.83(d,J=1.5Hz,1H),7.66(dd,J=5.0,1.6Hz,1H),7.24(d,J=8.3Hz,2H),6.40(dd,J=8.3,2.4Hz,2H),6.22(d,J=2.4Hz,2H),4.56(s,4H),3.79(s,6H),3.63(s,6H).
第五步N-(2-(N,N-双(2,4-二甲氧基苄基)氨磺酰基)吡啶-4-基)-5-氯-2-(7-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酰胺89f的制备
向N,N-双(2,4-二甲氧基苄基)-4-碘吡啶-2-磺酰胺89e(169mg,288.98μmol),三(二亚苄基丙酮)二钯(22.05mg,24.08μmol),Xantphos(20.90mg,36.12μmol),碳酸铯(66mg,481.63μmol)和1,4-二氧六环(60mL)的混合物中加入5-氯-2-(7-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酰胺89a(90mg,240.81μmol)。氩气保护,将反应混合物在110℃下搅拌1.5小时。冷却,反应液减压浓缩,加入20mL水和20mL乙酸乙酯,均匀混合,静置分层。水相用乙酸乙酯萃取(10mL×3)。合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩。用硅胶柱色谱法(MeOH:DCM;1:80至1:40)纯化,得到化合物89f(149mg)(白色固体),产率:74.52%。MS m/z(ESI):831.20[M+l]+
第六步5-氯-2-(7-氟苯并二氢吡喃-4-基)-N-(2-氨磺基吡啶-4-基)-4-(三氟甲基)苯甲酰胺89的制备
将化合物89f(140mg,168.63μmol)溶于二氯甲烷(2mL)中,冰浴下滴加三氟乙酸(2mL),滴加完毕,室温下反应4小时。TLC监测反应完毕后,将反应液倒入冰水中,用二氯甲烷萃取,合并有机相,有机相再用饱和碳酸氢钠溶液洗涤。无水硫酸钠干
燥,过滤,滤液浓缩,所得残渣用二氯甲烷重结晶,得到化合物89(81mg)(白色固体),产率:90.65%。1H NMR(500MHz,Methanol-d4)δ8.56(d,J=5.5Hz,1H),8.35(d,J=1.8Hz,1H),7.86(s,1H),7.83(dd,J=5.5,2.1Hz,1H),7.43(s,1H),6.82–6.73(m,1H),6.57–6.49(m,2H),4.64–4.56(m,1H),4.22(ddd,J=11.3,5.9,3.5Hz,1H),4.13(ddd,J=11.4,8.9,2.7Hz,1H),2.39–2.30(m,1H),2.27–2.19(m,1H).
实施例90 2-氟-N-(2-氨磺基吡啶-4-基)-6-(7-(三氟甲氧基)苯并二氢吡喃-4-基)-3-(三氟甲基)苯甲酰胺90的制备
采用实施例27的合成路线,将原料N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼替换为N'-(7-(三氟甲氧基)苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼,得到中间体2-氟-6-(7-(三氟甲氧基)苯并二氢吡喃-4-基)-3-(三氟甲基)苯甲酸后,再采用实施例89的合成路线制得化合物90(77mg)。1H NMR(500MHz,Methanol-d4)δ8.58(d,J=5.5Hz,1H),8.34(d,J=2.0Hz,1H),7.83(dd,J=5.5,2.1Hz,1H),7.76(t,J=7.9Hz,1H),7.11(d,J=8.3Hz,1H),6.91–6.88(m,1H),6.73–6.67(m,2H),4.48(dd,J=8.1,6.4Hz,1H),4.28(ddd,J=11.3,6.0,3.4Hz,1H),4.17(ddd,J=11.4,8.7,2.8Hz,1H),2.40–2.31(m,1H),2.32–2.21(m,1H).
实施例91 2-氟-N-(2-氨磺基吡啶-4-基)-6-(7-(三氟甲基)苯并二氢吡喃-4-基)-3-(三氟甲基)苯甲酰胺91的制备
采用实施例27的合成路线,将原料N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼替换为N'-(7-(三氟甲基)苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼,得到中间体2-氟-6-(7-(三氟甲基)苯并二氢吡喃-4-基)-3-(三氟甲基)苯甲酸后,再采用实施例89的合成路线制得化合物91(92mg)。1H NMR(500MHz,Methanol-d4)δ8.57(d,J=5.5Hz,1H),8.33(d,J=2.0Hz,1H),7.80(dd,J=5.5,2.1Hz,1H),7.76(t,J=7.9Hz,1H),7.12(d,J=8.3Hz,1H),7.06–6.98(m,3H),4.54(t,J=7.4Hz,1H),4.32(ddd,J=11.3,5.8,3.6Hz,1H),4.19(ddd,J=11.5,8.7,2.9Hz,1H),2.42–2.27(m,2H).
实施例92 2-氟-N-(2-氨磺基吡啶-4-基)-6-(7,8-二氟苯并二氢吡喃-4-基)-3-(三氟甲基)苯甲酰胺92的制备
采用实施例27的合成路线,将原料N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼替
换为N'-(7,8-二氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼,得到中间体2-氟-6-(7,8-二氟苯并二氢吡喃-4-基)-3-(三氟甲基)苯甲酸后,再采用实施例89的合成路线制得化合物92(69mg)。1H NMR(500MHz,Methanol-d4)δ8.59(d,J=5.5Hz,1H),8.32(d,J=2.0Hz,1H),7.85(dd,J=5.5,2.1Hz,1H),7.76(t,J=7.9Hz,1H),7.12(d,J=8.2Hz,1H),6.70–6.56(m,2H),4.48(t,J=7.2Hz,1H),4.34(ddd,J=11.3,6.2,3.4Hz,1H),4.21(ddd,J=11.3,8.7,2.8Hz,1H),2.42–2.32(m,1H),2.33–2.22(m,1H).
实施例93 5-氯-N-(4-氟-3-(N'-羟基氨基甲酰)苯基)-2-(7-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酰胺93的制备
采用实施例32的合成路线的第三步和第四步,将化合物2-氟-6-(7-氟苯并二氢吡喃-4-基)-3-(三氟甲基)苯甲酸32b替换为化合物5-氯-2-(7-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酸41a制得化合物93(57mg)。1H NMR(500MHz,Methanol-d4)δ7.84–7.80(m,2H),7.78(ddd,J=8.9,4.4,2.8Hz,1H),7.36(s,1H),7.18(dd,J=10.1,8.9Hz,1H),6.83–6.77(m,1H),6.60–6.52(m,2H),4.63–4.58(m,1H),4.20(ddd,J=11.3,6.1,3.5Hz,1H),4.15(ddd,J=11.3,8.5,2.8Hz,1H),2.40–2.30(m,1H),2.23–2.12(m,1H).
实施例94 2-氟-N-(4-氟-3-(N'-羟基氨基甲酰)苯基)-6-(7-(三氟甲基)苯并二氢吡喃-4-基)-3-(三氟甲基)苯甲酰胺94的制备
采用实施例27的合成路线的第一步,将原料N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼替换为N'-(7-(三氟甲氧基)苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼,再采用实施例32的合成路线的第一步到第四步的方法制得化合物94(27mg)。1H NMR(500MHz,Methanol-d4)δ7.84(dd,J=6.3,2.7Hz,1H),7.80(ddd,J=8.9,4.4,2.8Hz,1H),7.72(t,J=7.9Hz,1H),7.20(dd,J=10.0,8.9Hz,1H),7.04(d,J=8.3Hz,1H),6.92(dd,J=8.3,0.8Hz,1H),6.75–6.69(m,2H),4.51–4.46(m,1H),4.27(ddd,J=11.3,6.4,3.4Hz,1H),4.18(ddd,J=11.3,8.5,2.8Hz,1H),2.42–2.32(m,1H),2.27–2.15(m,1H).
实施例95 2-氟-N-(4-氟-3-(N'-羟基氨基甲酰)苯基)-6-(7,8-二氟苯并二氢吡喃-4-基)-3-(三氟甲基)苯甲酰胺95的制备
采用实施例27的合成路线的第一步,将原料N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯
磺酰肼替换为N'-(7,8-二氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼,再采用实施例32的合成路线的第一步到第四步的方法制得化合物95(29mg)。1H NMR(500MHz,Methanol-d4)δ7.83(dd,J=6.2,2.7Hz,1H),7.79(ddd,J=8.9,4.4,2.8Hz,1H),7.72(t,J=7.8Hz,1H),7.20(dd,J=10.1,8.9Hz,1H),7.05(d,J=8.2Hz,1H),6.72–6.65(m,1H),6.65–6.60(m,1H),4.48(t,J=7.0Hz,1H),4.34(ddd,J=11.2,6.4,3.3Hz,1H),4.23(ddd,J=11.3,8.5,2.8Hz,1H),2.43–2.33(m,1H),2.29–2.21(m,1H).
实施例96 5-氯-N-(4-溴-3-(N'-羟基氨基甲酰)苯基)-2-(7-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酰胺96的制备
采用实施例32的合成路线的第三步和第四步,将化合物2-氟-6-(7-氟苯并二氢吡喃-4-基)-3-(三氟甲基)苯甲酸32b替换为化合物5-氯-2-(7-氟苯并二氢吡喃-4-基)-4-(三氟甲基)苯甲酸41a,将化合物3-氰基-4-氟苯胺替换为3-氰基-4-溴苯胺制得化合物96(16mg)。1H NMR(600MHz,Methanol-d4)δ7.82(s,1H),7.76(d,J=2.6Hz,1H),7.70(dd,J=8.7,2.6Hz,1H),7.61(d,J=8.8Hz,1H),7.36(s,1H),6.79(dd,J=8.1,6.7Hz,1H),6.61–6.53(m,2H),4.59(t,J=7.1Hz,1H),4.20(ddd,J=11.2,6.2,3.4Hz,1H),4.14(ddd,J=11.4,8.7,2.7Hz,1H),2.38–2.30(m,1H),2.22–2.13(m,1H).
实施例97 2-氟-6-(8-氟-7-(三氟甲氧基)苯并二氢吡喃-4-基)-N-(3-氨磺基苯基)-3-(三氟甲基)苯甲酰胺97的制备
第一步(2-氟-3-(三氟甲氧基)苯基)硼酸97b的制备
将化合物2-氟三氟甲氧基苯97a(5.00g,27.76mmol)溶于干燥的四氢呋喃(70mL)中,室温下加入硼酸三异丙酯(5.74g,30.54mmol),反应液冷却至-70℃,氮气保
护,向反应液中滴加LDA(2M,15.28mL,30.54mmol)。滴毕,反应液缓慢升至室温,加入稀盐酸淬灭反应,用乙酸乙酯萃取,分离有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩,得到化合物97b(5.1g)(棕黄色液体),产率:82.04%。产品不经纯化直接用于下一步反应。
第二步2-氟-3-(三氟甲氧基)苯酚97c的制备
将化合物(2-氟-3-(三氟甲氧基)苯基)硼酸97b(5.00g,22.33mmol)溶于乙醚(60mL)中,冰水浴冷却。向反应液中滴加双氧水(60mL,30%),滴毕,反应液室温搅拌过夜。反应毕,向反应体系中加水,用乙醚萃取3次,合并有机相,水洗,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩,得到化合物97c(4.05g)(淡黄色液体),产率:92.49%。1H NMR(400MHz,Chloroform-d)δ7.01(td,J=8.2,1.8Hz,1H),6.95(ddd,J=8.5,7.3,1.9Hz,1H),6.85(ddt,J=8.3,6.7,1.6Hz,1H),6.00(brs,1H).
第三步2-氟-1-(丙-2-炔-1-氧基)-3-(三氟甲氧基)苯97d的制备
将化合物2-氟-3-(三氟甲氧基)苯酚97c(4.00g,20.40mmol)溶于乙腈(60mL),加入碳酸钾(3.66g,26.52mmol),0℃下滴加溴丙炔(2.43g,20.40mmol),滴毕,室温搅拌过夜。反应毕,向反应体系中加水,用乙醚萃取3次,合并有机相,水洗,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩,得到化合物97d(4.45g)(无色液体),产率:93.17%。1H NMR(400MHz,Chloroform-d)δ7.11–7.04(m,2H),7.01–6.91(m,1H),4.79(d,J=2.4Hz,2H),2.56(t,J=2.4Hz,1H).
第四步1-((3-氯丙基-2-炔-1-基)氧基)-2-氟-3-(三氟甲氧基)苯97e的制备
将化合物2-氟-1-(丙-2-炔-1-氧基)-3-(三氟甲氧基)苯97d(4.40g,18.79mmol)溶于乙腈(60mL),加入N-氯代丁二酰亚胺(5.02g,37.58mmol)和硝酸银(0.96g,5.64mmol),氩气保护下,像反应混合物中加入四丁基氟化铵(2.95g,11.27mmol),反应混合物在室温下搅拌过夜。过滤除去银盐,滤液减压浓缩,向残余物中加水,用乙醚萃取2次,合并有有机相,用弱酸洗涤2次,再用饱和碳酸氢钠溶液洗涤2次,无水硫酸钠干燥,过滤,滤液浓缩,得到化合物97e(1.08g)(无色液体),产率:20.41%。产品不经纯化直接用于下一步反应。
第五步8-氟-7-(三氟甲氧基)苯并二氢吡喃-4-酮97f的制备
将化合物1-((3-氯丙基-2-炔-1-基)氧基)-2-氟-3-(三氟甲氧基)苯97e(1.00g,3.72mmol)滴加到0℃下的浓盐酸(20mL)中,0℃下搅拌1小时。将反应液缓慢滴加到大量冰水中,用乙醚萃取2次,合并有有机相,用饱和碳酸氢钠溶液洗涤2次,无水硫酸钠干燥,过滤,滤液浓缩,用硅胶柱色谱法(EA:PE;1:20至1:10)纯化,得到化合物97f(205mg)(白色固体),产率:22.01%。1H NMR(400MHz,Chloroform-d)δ7.70(dd,J=8.9,2.2Hz,1H),6.95(ddd,J=8.9,6.2,1.5Hz,1H),4.67(dd,J=6.9,6.0Hz,2H),2.87(dd,J=6.9,6.0Hz,2H).
第六步N'-(8-氟-7-(三氟甲氧基)苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼97g的制备
将对甲苯磺酰肼(179mg,0.96μmol)悬浮于甲醇溶液中,加热至60℃,直到对甲苯磺酰肼完全溶解。慢慢向混合物中加入化合物8-氟-7-(三氟甲氧基)苯并二氢吡喃-4-酮97f(200mg,0.80μmol)。继续搅拌6小时,反应液冷却后产生沉淀物,将沉淀物过滤,用甲醇淋洗。在真空中干燥沉淀物,得到化合物97g(321mg)(白色固体),产率:95.97%。MS m/z(ESI):419.20[M+l]+.
再采用实施例27的合成路线,将原料N'-(7-氟苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼替换为化合物N'-(8-氟-7-(三氟甲氧基)苯并二氢吡喃-4-亚基)-4-甲苯磺酰肼97g,制得化合物97(29mg)。1H NMR(500MHz,Methanol-d4)δ8.36(t,J=2.0Hz,1H),7.82(ddd,J=8.1,2.2,1.0Hz,1H),7.75(t,J=7.9Hz,1H),7.71(dt,J=7.9,1.4Hz,1H),7.55(t,J=8.0Hz,1H),7.08(d,J=8.2Hz,1H),6.82(t,J=7.8Hz,1H),6.72(ddd,J=8.8,2.1,0.9Hz,1H),4.54(dd,J=7.8,6.4Hz,1H),4.37(ddd,J=11.3,6.2,3.4Hz,1H),4.27(ddd,J=11.3,8.6,2.8Hz,1H),2.46–2.36(m,1H),2.34–2.24(m,1H).
实施例98 N-(3-氨基-4-氟苯基)-2-氟-6-(8-氟-7-(三氟甲氧基)苯并二氢吡喃-4-基)-3-(三氟甲基)苯甲酰胺98的制备
采用实施例97的合成路线,将原料间氨基苯磺酰胺替换为5-氨基-2-氟苯甲酰胺原料制得化合物98(35mg)。1H NMR(600MHz,Methanol-d4)δ8.08(dd,J=6.6,2.7Hz,1H),7.91(dt,J=7.9,3.5Hz,1H),7.74(t,J=7.8Hz,1H),7.24(t,J=9.7Hz,1H),7.08(d,J=8.3Hz,1H),6.81(t,J=7.7Hz,1H),6.72(d,J=8.8Hz,1H),4.53(t,J=7.1Hz,1H),4.37(ddd,J=10.2,6.2,3.5Hz,1H),4.29–4.22(m,1H),2.44–2.36(m,1H),2.34–2.25(m,1H).
生物部分测试:
测试例1、本发明化合物对钠离子通道1.8(Navl.8)的阻滞活性
1.检测方法:全细胞手动膜片钳技术检测化合物对电压门控Nav1.8通道电流的影响
2.检测化合物的配制和分析
阴性对照:含0.5%DMSO的电生理细胞外液
测试化合物:称量一定质量的化合物用DMSO溶解,配制20mM的DMSO母液。测试当天,将20mM的化合物母液用细胞外液梯度稀释至需要检测的最终浓度,保证测试药物溶液中的DMSO含量不超过0.5%,此浓度的DMSO对检测的Nav1.8通道电流没有影响。例如配制100nM和1μM化合物溶液,其梯度稀释方法如下:先吸取5μL DMSO母液加入到10mL的细胞外液中,溶解均匀,得到10μM的化合物溶液;再吸取1mL的10μM的化合物,加入到9mL的细胞外液中,溶解均匀,得到1μM的化合物溶液;再吸取1mL的1μM的化合物,加入到9mL的细胞外液中,溶解均匀,得到100nM的化合物溶液。本实验的所有阳性对照使用VX-150原型药作为阳性对照药物,其半数抑制浓度为33.45±0.86nM,与原文献报道结果一致。本实验使用的阴性对照为含有0.5%DMSO的细胞外液,给药10分钟后通道的电流变化值≤5%。
3.细胞培养
Nav1.8细胞株:稳定表达人源Nav1.8钠通道的HEK293(Flp-In T-Rex-293)细胞,编码基因信息如下:NM_001293306.2。
培养和传代条件与方法:细胞株培养在37℃、5%CO2的恒温培养箱中。Nav1.8稳转株用含10%无四环素的胎牛血清(HyClone公司)和100μg/mL Hygromycin B的DMEM(Gibco公司)高糖的完全培养基培养。实验前一天细胞生长到90%左右密度时消化传代,首先吸去培养基,用37℃预热的磷酸缓冲液(PBS)洗涤细胞,弃掉PBS缓冲液后,加入胰酶消化后转移至离心管中,800rpm离心3分钟,弃去上清,加入含1μg/mL Doxcycline的完全培养基重悬,传代至6孔板中,诱导培养20小时后,分离传代至用多聚赖氨酸包被的盖玻片中继续培养1-2小时后,用于电生理记录实验。
4.电生理实验
在室温(23~25℃)下用全细胞电压钳技术记录Nav1.8钠通道电流。
全细胞电压钳记录实验采用Axon patch 700B膜片钳放大器(Molecular Devices公司),数模转换器为Digidata 1440A(Molecular Devices公司),玻璃微电极由玻璃电极毛胚(World Precision Instrunents公司)经拉制仪(P97,Sutter公司)拉制而成,灌注电极内液后的尖端电阻为1.5-2.5MΩ左右,将玻璃微电极插入放大器探头即可连接至膜片钳放大器。钳制电压和数据记录由pClamp 10软件(Molecular Devices公司)通过电脑控制和
记录,采样频率为20kHz,滤波频率为2kHz。
电生理实验用细胞外液和细胞内液:
细胞外液配方(mM):140NaCl,3KCl,1CaCl2,1MgCl2,10HEPES and 20Glucose,用NaOH调节pH至7.3。
细胞内液配方(mM):140CsF,10NaCl,10HEPES,1.1EGTA and 20Glucose,用CsOH调节pH至7.3。
电生理刺激方案:得到全细胞记录(达到高阻抗的GΩ封接条件)后,在-80mV下钳制电压下等待4-5分钟至电极内液与细胞内液平衡,然后开始电生理记录。电流刺激和化合物活性检测方案:细胞钳制在-80mV,给予时长20ms,+10mV的去极化电压刺激,再复极化到-80mV,刺激频率为0.5Hz。确定Nav1.8钠通道电流稳定后(约1分钟)开始给药过程,至细胞电流不再变化为止(化合物抑制达到稳态)。化合物每个浓度至少测试3个细胞(n≥3)。所有检测化合物后给予单浓度100nM VX-150作阳性对照。
5.数据分析
数据采集分析处理采用pClamp10(Molecular Devices公司)GraphPad Prism 5(GraphPad Software公司)和Excel(Microsoft公司)软件。化合物对电流的影响用以下公式计算:
抑制率(%)=[1-加药后电流的大小(IDrug)/加药前电流的大小(IControl)]×100。
表1.本发明部分化合物在100nM浓度下对Nav1.8通道的阻滞活性
表2本发明部分化合物在30nM浓度下对Nav1.8通道的阻滞活性
表3本发明部分化合物在10nM浓度下对Nav1.8通道的阻滞活性
表4本发明部分化合物在1nM浓度下对Nav1.8通道的阻滞活性
测试例2、本发明化合物的药代动力学测试
1.实验动物
健康ICR小鼠,雄性,体重18–20g,数量6只为一组。
2.实验药品
本发明中实施例9、实施例21、实施例22化合物和对照化合物VX-150(根据专利WO2014120808合成得到)。
3.药物配制
称取一定量药物,按照给药途径的不同,用不同溶媒配制。灌胃给药溶媒:0.5%MC;静脉给药溶媒:5%DMSO+10%Solutol+10%乙醇+75%Saline。
4.给药
ICR小鼠在给药前禁食12小时,自由饮水。静脉给药剂量为2mg/kg,灌胃给药剂量为10mg/kg。
5.采样与测定
静脉给药后0.083、0.5、1.0、3.0、5.0和8.0h,灌胃给药后0.5、1.0、3.0、5.0、8.0和24h;在以上设定时间点经小鼠尾静脉取静脉全血10μL,置已加入30μL 0.1M柠檬酸三钠试管中于–20℃冰箱中冷冻;取血浆样品10μL(从冰箱-80℃中取出样品,室温自然溶化后涡旋30秒)至1.5mL离心管中,加入100μL内标溶液(D5&D8 100ng/mL乙腈溶液),涡旋60秒后离心3分钟(离心力12000rpm);取上清液100μL移至装有等体积水的96孔进样板上,振荡混匀后LC-MS/MS进样分析。
6.药物代谢动力学参数结果
本发明化合物及对照化合物的药代动力学参数见下表3。
表3本发明实施例9、21、22和对照化合物的药代动力学参数
结论:上述研究结果表明,本发明化合物在小鼠体内具有明显优于对照化合物的药物代谢动力学性质。
以上各实施例仅用以举例说明本发明的技术方案,而非对其限制。尽管参照前述各实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解:在没有脱离本发明权利要求所限定的精神和实质的范围内,可以对前述各实施例所记载的技术方案进行修改,或者对其中部分或者全部技术特征进行等同替换;而这些修改或者替换仍然在本发明权利要求所限定的范围内。
Claims (10)
- 一种式I化合物,或其前体药物、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其可药用的盐,
其中:A环选自C6-C12芳基、含有1-4个选自N、O和S中的杂原子的5-10元杂芳基、C3-C8环烷基和含有1-4个选自N、O和S中的杂原子的3-10元杂环基;(R1)m表示m个R1取代,m为0、1、2、3、4或5,优选为0、1或2;R1各自独立地选自氢原子、卤素、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、羟基取代的C1-C6烷氧基、羟基、C1-C6羟烷基、氰基、氨基(-NH2)、C1-C6烷基氨基、硝基、脒基、-C(=NOH)NH2、羧基、氧代(=O)、硫代(=S)、-NHSO2NH2、-SO2Me、-CH2ORe、-SO2N(Rf)2、-CON(Rf)2、C3-C8环烷基、含有1-4个选自N、O和S中的杂原子的3-10元杂环基和含有1-4个选自N、O和S中的杂原子的杂环基取代的C1-C6烷基;Re选自氢原子、C1-C6烷基、-C(O)R7、-S(O)2OH、-S(O)2O-Q+、-PO(OH)2、-PO(OH)O-Q+和-PO(O-)2W2+;Rf各自独立地选自氢原子、C1-C6烷基、C3-C8环烷基、脒基;Q+为药学上可接受的单价阳离子;W2+为药学上可接受的二价阳离子;R7选自取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C2-C6烯基、羧基和-C(O)O-M+,所述取代的取代基选自羟基、氨基、羧基和-C(O)O-M+中的一个或多个;M+为药学上可接受的单价阳离子;或者,相邻的两个R1和与其相连的A环一起形成未取代的或被1-4个取代基取代的苯并[5-6元杂环],所述取代基选自卤素、氨基(-NH2)、羟基、巯基、氧代(=O)、硫代(=S)、C1-C6烷基;所述5-6元杂环含有1至3个选自N、O、S的杂原子;优选地,苯并[5-6元杂环]选自:n为0或1,优选为0;X为N原子或C-R2c;优选地,X为C-R2c;更优选为-CH-;R2a、R2b和R2c各自独立地选自氢原子、卤素、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、羟基、氰基、氨基、硝基、C3-C8环烷基氧基、C3-C8环烷基和含有1-4个选自N、O和S中的杂原子的3-10元杂环基;所述的取代的取代基选自卤素、C1-C6烷基、羟基、C3-C8环烷基和含有1-4个选自N、O和S中的杂原子的3-10元杂环基;R3a、R3b、R3c和R3d各自独立地选自氢原子、卤素、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、羟基、氰基、氨基、硝基、C3-C8环烷基氧基、C3-C8环烷基和含有1-4个选自N、O和S中的杂原子的3-10元杂环基;所述的取代的取代基选自卤素、氘、C1-C6烷基、羟基、C3-C8环烷基和含有1-4个选自N、O和S中的杂原子的3-10元杂环基;Y为O、S、CRcRd或NRc;优选地,Y为O、CRcRd或NRc;Rc和Rd各自独立地选自氢原子、C1-C6烷基、羟基、C3-C8环烷基和含有1-4个选自N、O和S中的杂原子的3-10元杂环基;优选地,Rc和Rd各自独立地选自氢原子、C1-C6烷基、C3-C8环烷基;或者Rc和Rd和与其相连的碳原子形成C3-C8环烷基或含有1-4个选自N、O和S中的杂原子的3-10元杂环基;优选形成C3-C8环烷基;R4a、R4b、R4c和R4d各自独立地选自氢原子、C1-C6烷基、羟基、C3-C8环烷基和含有1-4个选自N、O和S中的杂原子的3-10元杂环基;或者R4a和R4b与其相连的碳原子形成C3-C8环烷基或含有1-4个选自N、O和S中的杂原子的3-10元杂环基;或者R4c和R4d与其相连的碳原子形成C3-C8环烷基或含有1-4个选自N、O和S中的杂原子的3-10元杂环基;o为0、1或2,优选为0或1,更优选为1。 - 根据权利要求1所述的式I化合物,或其前体药物、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其可药用的盐,其中,A环为苯环、吡啶环、噻吩环、呋喃环或吡咯烷环;优选地,R1各自独立地选自氢原子、卤素、C1-C6烷基、脒基、氧代(=O)、-SO2NH2、-SO2NHCH3-、-NHSO2NH2、吗啉基、-CONH2、-CH2OPO(OH)2、硝基、羟基、羧基、C1-C3烷基氨基、二羟基丙氧基、-C(=NOH)NH2、优选地,R2a、R2b和R2c各自独立地选自氢原子、卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6羟烷基;优选地,R2a为卤素、C1-C6烷基或卤代C1-C6烷基,R2b为氢原子、卤素或卤代C1-C6烷基,R2c为氢原子或卤素;优选地,R3a、R3b、R3c和R3d各自独立地选自卤素、C1-C6烷基、卤代C1-C6烷基、氘代C1-C6烷基、氘代C1-C6烷氧基、C1-C6羟烷基;优选为卤素;优选地,R4a和R4b各自独立地选自氢原子、C1-C6烷基、C3-C8环烷基;优选地,R4c和R4d各自独立地选自氢原子、C1-C6烷基、C3-C8环烷基;或者R4c和R4d与其相连的碳原子形成C3-C8环烷基。
- 根据权利要求1或2所述的式I化合物,或其前体药物、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其可药用的盐,其中,式I化合物选自如下式II化合物:
其中,R2a、R2b、R2c、X、R3a、R3b、R3c、R3d、Y、R4a、R4b、R4c、R4d、o的定义同相应权利要求;R5a、R5b和R5c各自独立地选自氢原子、卤素、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、C3-C6环烷基;R6选自氢原子、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、羟基、C1-C6羟烷基、氰基、氨基、硝基、-CH2ORe、C3-C8环烷基和含有1-4个选自N、O和S中的杂原子的3-10元杂环基;优选为氢原子或-CH2ORe;Re选自氢原子、C1-C6烷基、-C(O)R7、-S(O)2OH、-S(O)2O-Q+、-PO(OH)2、-PO(OH)O-Q+和-PO(O-)2W2+;Q+为药学上可接受的单价阳离子;W2+为药学上可接受的二价阳离子;R7选自取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C2-C6烯基、羧基和-C(O)O-M+,所述取代的取代基选自羟基、氨基、羧基和-C(O)O-M+中的一个或多个;M+为药学上可接受的单价阳离子;优选地,Q+和M+相同或不同,且各自独立地选自季铵盐离子和碱金属离子,优选为Na+或K+;W2+为碱土金属离子,优选为Mg2+或Ca2+。 - 根据权利要求1或2所述的式I化合物,或其前体药物、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其可药用的盐,其中,式I化合物选自如下式III化合物:
其中,R2a、R2b、R2c、X、R3a、R3b、R3c、R3d、Y、R4a、R4b、R4c、R4d、o的定义同相应权利要求,R5a、R5b、R5c和R5d各自独立地选自氢原子、卤素、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、C3-C6环烷基。 - 根据权利要求1或2所述的式I化合物,或其前体药物、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其可药用的盐,其中,式I化合物选自如下式IV化合物:
其中,R2a、R2b、R2c、X、R3a、R3b、R3c、R3d、Y、R4a、R4b、R4c、R4d、o的定义同相应权利要求,R5a、R5b、R5c和R5d各自独立地选自氢原子、卤素、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、C3-C6环烷基。 - 根据权利要求1或2所述的式I化合物,或其前体药物、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其可药用的盐,其中,式I化合物选自如下式V 化合物:
其中,R2a、R2b、R2c、X、R3b、Y、R4a、R4b、R4c、R4d、o、n、A环、R1、m的定义同相应权利要求。 - 根据权利要求1所述的式I化合物,或其前体药物、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其可药用的盐,其中,式I化合物选自下列化合物:
- 一种药物组合物,其包括选自权利要求1-7任一项所述的化合物、其前体药物、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体和其可药用的盐中的一种或多种以及任选的药学上可接受的辅料。
- 权利要求1-7任一项所述的化合物或其前体药物、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其可药用的盐或权利要求8所述的药物组合物在制备Nav1.8抑制剂中的用途。
- 权利要求1-7任一项所述的化合物或其前体药物、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其可药用的盐或权利要求8所述的药物组合物在制备用于治疗和/或减轻疼痛和疼痛相关疾病的药物中的用途;所述疼痛和疼痛相关疾病包括伤害性疼痛、炎性疼痛、神经性疼痛、肌肉骨骼疼、术后疼痛和内状疼痛、功能性疼痛、肌肉或骨骼损伤相关疼痛、盆腔痛、腹腔痛、胸腔痛、腰骶神经痛、术前疼痛、术间疼痛、术后疼痛、肠痛、急性或慢性疼痛、偏头痛、三叉神经痛、胰腺炎、肾绞痛、癌症痛、化学或药物疗法导致的疼痛、糖尿病神经痛、带状疱疹后神经痛、背部疼痛、幻肢痛、坐骨神经痛、小纤维神经痛、红斑性肢痛症。
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