CN114514233A - 用于单酰基甘油脂肪酶(magl)的荧光探针 - Google Patents
用于单酰基甘油脂肪酶(magl)的荧光探针 Download PDFInfo
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- CN114514233A CN114514233A CN202080066086.1A CN202080066086A CN114514233A CN 114514233 A CN114514233 A CN 114514233A CN 202080066086 A CN202080066086 A CN 202080066086A CN 114514233 A CN114514233 A CN 114514233A
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- China
- Prior art keywords
- phenyl
- carbonyl
- methyl
- oxo
- hexahydropyrido
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- 102000005398 Monoacylglycerol Lipase Human genes 0.000 title claims abstract description 73
- 108020002334 Monoacylglycerol lipase Proteins 0.000 title claims abstract description 73
- 239000007850 fluorescent dye Substances 0.000 title claims abstract description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 169
- 238000000034 method Methods 0.000 claims abstract description 82
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 100
- -1 (tert-butyl 2- (3- ((1- ((4aR, 8aS) -3-oxooctahydro-2H-pyrido [4, 3-b ] [1, 4] oxazin-6-carbonyl) piperidin-4-ylidene) (phenyl) methyl) phenoxy) ethyl) carbamate Chemical compound 0.000 claims description 80
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 72
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 55
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 47
- 150000003839 salts Chemical class 0.000 claims description 45
- 238000006243 chemical reaction Methods 0.000 claims description 34
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 33
- PCBZRNYXXCIELG-WYFCWLEVSA-N COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 Chemical compound COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 PCBZRNYXXCIELG-WYFCWLEVSA-N 0.000 claims description 29
- 125000005647 linker group Chemical group 0.000 claims description 29
- 125000006239 protecting group Chemical group 0.000 claims description 29
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 26
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 25
- 150000001412 amines Chemical class 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- 239000004202 carbamide Substances 0.000 claims description 14
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 14
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims description 14
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 13
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 229940080818 propionamide Drugs 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 230000008569 process Effects 0.000 claims description 11
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims description 7
- 241000124008 Mammalia Species 0.000 claims description 7
- 238000002059 diagnostic imaging Methods 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- CPDAYCDBCSPKNF-UHFFFAOYSA-N 4a,5,6,7,8,8a-hexahydro-4h-pyrido[4,3-b][1,4]oxazin-3-one Chemical compound C1CNCC2NC(=O)COC21 CPDAYCDBCSPKNF-UHFFFAOYSA-N 0.000 claims description 6
- AFLJOVJELTZNRF-PXJZQJOASA-N O1N=C2C(=N1)C(NCCOC1=CC(=CC=C1)/C(=C\1/CCN(CC/1)C(=O)N1CC[C@H]3[C@@H](C1)NC(=O)CO3)/C1=CC=CC=C1)=CC=C2N(=O)=O Chemical compound O1N=C2C(=N1)C(NCCOC1=CC(=CC=C1)/C(=C\1/CCN(CC/1)C(=O)N1CC[C@H]3[C@@H](C1)NC(=O)CO3)/C1=CC=CC=C1)=CC=C2N(=O)=O AFLJOVJELTZNRF-PXJZQJOASA-N 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- 239000000203 mixture Substances 0.000 abstract description 25
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 38
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 31
- 239000000543 intermediate Substances 0.000 description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- XBXCNNQPRYLIDE-UHFFFAOYSA-M n-tert-butylcarbamate Chemical compound CC(C)(C)NC([O-])=O XBXCNNQPRYLIDE-UHFFFAOYSA-M 0.000 description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- QUPDWYMUPZLYJZ-UHFFFAOYSA-N ethyl Chemical compound C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 description 19
- KHUXNRRPPZOJPT-UHFFFAOYSA-N phenoxy radical Chemical compound O=C1C=C[CH]C=C1 KHUXNRRPPZOJPT-UHFFFAOYSA-N 0.000 description 19
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 18
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 17
- 239000002904 solvent Substances 0.000 description 17
- 235000019439 ethyl acetate Nutrition 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- 239000003921 oil Substances 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 12
- 239000006260 foam Substances 0.000 description 12
- 239000002585 base Substances 0.000 description 11
- 239000010410 layer Substances 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- 125000000217 alkyl group Chemical group 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- 239000000460 chlorine Substances 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- RCRCTBLIHCHWDZ-UHFFFAOYSA-N 2-Arachidonoyl Glycerol Chemical compound CCCCCC=CCC=CCC=CCC=CCCCC(=O)OC(CO)CO RCRCTBLIHCHWDZ-UHFFFAOYSA-N 0.000 description 8
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 8
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 8
- 238000003556 assay Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 7
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 229910052731 fluorine Inorganic materials 0.000 description 7
- 239000011737 fluorine Substances 0.000 description 7
- 125000005843 halogen group Chemical group 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- 239000000523 sample Substances 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 7
- VOLGAXAGEUPBDM-UHFFFAOYSA-N $l^{1}-oxidanylethane Chemical compound CC[O] VOLGAXAGEUPBDM-UHFFFAOYSA-N 0.000 description 6
- YGNSGMAPLOVGIU-UHFFFAOYSA-N 3-[2-[(2-methylpropan-2-yl)oxycarbonylamino]ethoxy]propanoic acid Chemical compound CC(C)(C)OC(=O)NCCOCCC(O)=O YGNSGMAPLOVGIU-UHFFFAOYSA-N 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- XISPDFMAOWZEQG-UHFFFAOYSA-N 4h-1,4-oxazin-3-one Chemical compound O=C1COC=CN1 XISPDFMAOWZEQG-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 230000000670 limiting effect Effects 0.000 description 6
- 235000019260 propionic acid Nutrition 0.000 description 6
- 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 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 5
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 5
- 239000007832 Na2SO4 Substances 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 239000012230 colorless oil Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 238000003818 flash chromatography Methods 0.000 description 5
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 5
- 239000011736 potassium bicarbonate Substances 0.000 description 5
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
- CFXIZQUUKBAVOZ-SDVJBAMBSA-N (4aR,8aS)-6-[4-[[3-(2-aminoethoxy)phenyl]-phenylmethyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one Chemical compound NCCOc1cccc(c1)C(C1CCN(CC1)C(=O)N1CC[C@@H]2OCC(=O)N[C@@H]2C1)c1ccccc1 CFXIZQUUKBAVOZ-SDVJBAMBSA-N 0.000 description 4
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 4
- FBXGQDUVJBKEAJ-UHFFFAOYSA-N 4h-oxazin-3-one Chemical compound O=C1CC=CON1 FBXGQDUVJBKEAJ-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- 229940114079 arachidonic acid Drugs 0.000 description 4
- 235000021342 arachidonic acid Nutrition 0.000 description 4
- 238000004296 chiral HPLC Methods 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 4
- 238000012632 fluorescent imaging Methods 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Substances [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 239000000126 substance Chemical group 0.000 description 4
- 238000004808 supercritical fluid chromatography Methods 0.000 description 4
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 4
- LOVPHSMOAVXQIH-UHFFFAOYSA-M (4-nitrophenyl) carbonate Chemical compound [O-]C(=O)OC1=CC=C([N+]([O-])=O)C=C1 LOVPHSMOAVXQIH-UHFFFAOYSA-M 0.000 description 3
- YZXBAPSDXZZRGB-PNXWREOESA-N (5z,8z,11z,14z)-2,2,3,3,4,4,5,6-octadeuterioicosa-5,8,11,14-tetraenoic acid Chemical compound OC(=O)C([2H])([2H])C([2H])([2H])C([2H])([2H])C(/[2H])=C(/[2H])C\C=C/C\C=C/C\C=C/CCCCC YZXBAPSDXZZRGB-PNXWREOESA-N 0.000 description 3
- XEKAWZARUWARND-UHFFFAOYSA-N 6h-oxazin-3-one Chemical compound O=C1NOCC=C1 XEKAWZARUWARND-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 239000007821 HATU Substances 0.000 description 3
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 3
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 125000004438 haloalkoxy group Chemical group 0.000 description 3
- 125000001188 haloalkyl group Chemical group 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- PAQZWJGSJMLPMG-UHFFFAOYSA-N propylphosphonic anhydride Substances CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 3
- 230000009257 reactivity Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
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- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- KVKFRMCSXWQSNT-UHFFFAOYSA-N n,n'-dimethylethane-1,2-diamine Chemical compound CNCCNC KVKFRMCSXWQSNT-UHFFFAOYSA-N 0.000 description 1
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- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- 239000003208 petroleum Substances 0.000 description 1
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- 239000010452 phosphate Substances 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
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- 238000000746 purification Methods 0.000 description 1
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- 239000012857 radioactive material Substances 0.000 description 1
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- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
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- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- WGRULTCAYDOGQK-UHFFFAOYSA-M sodium;sodium;hydroxide Chemical compound [OH-].[Na].[Na+] WGRULTCAYDOGQK-UHFFFAOYSA-M 0.000 description 1
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical group COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ITLCXSHKUNNAHG-UHFFFAOYSA-N tert-butyl 4-benzoylpiperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C(=O)C1=CC=CC=C1 ITLCXSHKUNNAHG-UHFFFAOYSA-N 0.000 description 1
- PQRSEALCCLJIHJ-UHFFFAOYSA-N tert-butyl n-[2-(4-bromophenoxy)ethyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCOC1=CC=C(Br)C=C1 PQRSEALCCLJIHJ-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- PHCBRBWANGJMHS-UHFFFAOYSA-J tetrasodium;disulfate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O PHCBRBWANGJMHS-UHFFFAOYSA-J 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
Classifications
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- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
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- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
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- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
- C07F7/0816—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring said ring comprising Si as a ring atom
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- C09B23/04—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups one >CH- group, e.g. cyanines, isocyanines, pseudocyanines
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- C09B23/08—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups more than three >CH- groups, e.g. polycarbocyanines
- C09B23/083—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups more than three >CH- groups, e.g. polycarbocyanines five >CH- groups
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- C09B23/08—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups more than three >CH- groups, e.g. polycarbocyanines
- C09B23/086—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups more than three >CH- groups, e.g. polycarbocyanines more than five >CH- groups
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- G01N21/64—Fluorescence; Phosphorescence
- G01N21/6486—Measuring fluorescence of biological material, e.g. DNA, RNA, cells
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- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
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Abstract
本发明提供了具有通式(I)的荧光探针,其中X、Y、L和R1至R4如本文所述;包括所述化合物的组合物;制备所述化合物的方法;以及使用所述化合物的方法。所述化合物可用作用于单酰基甘油脂肪酶(MAGL)的荧光探针。
Description
技术领域
本发明涉及可用作用于单酰基甘油脂肪酶(MAGL)的荧光探针的有机化合物。
背景技术
荧光成像探针已成为研究定位(例如健康和疾病状态中的表达水平和蛋白质分布,活细胞中蛋白质的结构、动力学和功能)的高分辨率工具(L.A.Stoddart,L.E.Kilpatrick,S.J.Briddon,S.J.Hill,Neuropharmacology 2015,98,48-57)。此类探针可以例如使用共聚焦活细胞成像应用于流式细胞术荧光活化细胞分选(FACS)实验或细胞运输研究。此外,荧光成像探针允许以高时空精度实时监测配体-受体相互作用和蛋白质可视化(A.J.Vemall,S.J.Hill,B.Kellam,Br.J.Pharmacol.2014,171,1073-1084;C.Iliopoulos-Tsoutsouvas,R.N.Kulkarni,A.Makriyannis,S.P.Nikas,ExpertOpin.Drug Discov.2018,13,933-947)。另外,此类探针提供了以高通量方式生成平衡和动力学结合数据的潜力,而无需使用例如时间分辨荧光共振能量转移(TR-FRET)处理放射性物质。荧光成像探针还可用于支持将临床前药理学动物数据转化为临床药理学动物数据,并可应用于人类的剂量选择。它们可以例如经由产生全血中的离体定量受体结合数据用作靶标接合的标志物。根据各自的应用,荧光成像探针需要匹配特定的标准,包括对各自靶标的亲和力、选择性和特异性、有利的光物理特性以及在不同技术和细胞类型中的适用性。
发明内容
在第一方面(A1),本发明提供式(I)化合物
或其药用盐,其中X、Y、L和R1至R4如本文所定义。
在另一方面,本发明提供了一种生产如本文所述的式(I)化合物的方法,该方法包括:
(a)使第一胺4a,5,6,7,8,8a-六氢-4H-吡啶并[4,3-b][1,4]噁嗪-3-酮(2),
与第二胺1,其中R2、R3、R4、L和PG如本文所定义,
在碱和脲形成剂存在下
反应以形成式3化合物,其中R2、R3、R4、L和PG如本文所定义
(b)使第一胺4a,5,6,7,8,8a-六氢-4H-吡啶并[4,3-b][1,4]噁嗪-3-酮(2),
与第二胺1a(其中R1、R2、R3、R4和L如本文所定义)
在碱和脲形成剂存在下
进行反应以形成所述式(I)化合物。
在另一方面,本发明提供了根据本文所述的方法制造的如本文所述的式(I)化合物。
在另一方面,本发明提供了化合物,其选自:
N-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-(2-氨基乙氧基)丙酰胺;
N-[2-[3-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基氨基]-3-氧代-丙氧基]乙基]氨基甲酸叔丁酯;
N-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-(2-氨基乙氧基)乙氧基]丙酰胺;
N-[2-[2-[3-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基氨基]-3-氧代-丙氧基]乙氧基]乙基]氨基甲酸叔丁酯;
(4aR,8aS)-6-[4-[[3-(2-氨基乙氧基)苯基]-苯基-甲基]哌啶-1-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮;
N-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]氨基甲酸叔丁酯;
N-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-[2-(2-氨基乙氧基)乙氧基]乙氧基]丙酰胺;和
N-[2-[2-[2-[3-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基氨基]-3-氧代-丙氧基]乙氧基]乙氧基]乙基]氨基甲酸叔丁酯;
以及其用于制备本发明的荧光探针的用途。
在另一方面,本发明提供了研究单酰基甘油脂肪酶(MAGL)占用的方法,该方法包括使MAGL与本文所述的式(I)化合物接触。
在另一方面,本发明提供了哺乳动物中单酰基甘油脂肪酶(MAGL)的诊断成像的方法,该方法包括使MAGL与本文所述的式(I)化合物接触。
在另一方面,本发明提供了产生单酰基甘油脂肪酶(MAGL)平衡和动力学结合数据的方法,该方法包括使MAGL与本文所述的式(I)化合物接触。
具体实施方式
定义
结合本发明的特定方面、实施方案或实施例描述的特征、整数、特性、化合物、化学部分或基团应理解为适用于本文所述的任何其他方面、实施方案或实施例,除非与其不相容。本说明书(包括任何所附权利要求、摘要和附图)中所公开的所有特征和/或由此公开的任何方法或过程的所有步骤可以任何组合进行组合,除了这些特征和/或步骤中的至少一些互相排斥的组合之外。本发明不限于任何前述实施方案的细节。本发明扩展到本说明书(包括任何所附权利要求、摘要和附图)中所公开的特征的任何新颖特征或任何新颖组合,或者扩展到由此公开的任何方法或过程的步骤的任何新颖步骤或任何新颖组合。
术语“烷基”是指含有1至12个碳原子的单价或多价(例如,单价或二价)直链或支链饱和烃基。在一些优选实施例中,烷基基团含有1至6个碳原子,例如1、2、3、4、5或6个碳原子(“C1-C6-烷基”)。在其他实施例中,烷基基团含有1个至3个碳原子,例如1个、2个或3个碳原子。烷基的一些非限制性实例包括甲基、乙基、丙基、2-丙基(异丙基)、正丁基、异丁基、仲丁基、叔丁基和2,2-二甲基丙基。烷基的特别优选但非限制性实例是甲基。
术语“烷氧基”是指经由氧原子附接到母体分子部分上的如前所定义的烷基基团。除非另外指明,否则烷氧基基团含有1至12个碳原子。在一些优选实施例中,烷氧基基团含有1至6个碳原子(“C1-C6-烷氧基”)。在其他实施例中,烷氧基基团含有1至4个碳原子。在其他实施例中,烷氧基基团含有1至3个碳原子。烷氧基基团的一些非限制性实例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基和叔丁氧基。烷氧基的特别优选但非限制性实例是甲氧基。
术语“卤素”或“卤代”是指氟(F)、氯(C1)、溴(Br)或碘(I)。优选地,术语“卤素”或“卤代”是指氟(F)、氯(Cl)或溴(Br)。“卤素”或“卤代”的特别优选但非限制性实例是氟(F)和氯(Cl)。
术语“卤代烷基”是指其中烷基基团的至少一个氢原子已被卤素原子、优选氟代替的烷基基团。优选地,“卤代烷基”是指其中烷基基团的1、2或3个氢原子已被卤素原子、最优选氟代替的烷基基团。卤代烷基的特别优选但非限制性的实例是三氟甲基和三氟乙基。
术语“卤代烷氧基”是指其中烷氧基基团的至少一个氢原子已被卤素原子、优选氟代替的烷氧基基团。优选地,“卤代烷氧基”是指其中烷氧基基团的1、2或3个氢原子已被卤素原子、最优选氟代替的烷氧基基团。卤代烷氧基的一个特别优选但非限制性的实例为三氟甲氧基(-OCF3)。
术语“药用盐”是指保留游离碱或游离酸的生物效果和性质的那些盐,这些盐在生物学或其他方面不是不合需要的。这些盐用无机酸诸如盐酸、氢溴酸、硫酸、硝酸、磷酸等(特别是盐酸)和有机酸诸如乙酸、丙酸、乙醇酸、丙酮酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲基磺酸、乙基磺酸、对甲苯磺酸、水杨酸、N-乙酰基半胱氨酸等形成。此外,这些盐可通过将无机碱或有机碱加入游离酸中来制备。衍生自无机碱的盐包括但不限于钠、钾、锂、铵、钙、镁盐等。衍生自有机碱的盐包括但不限于以下各项的盐:伯胺、仲胺和叔胺、取代胺(包括天然存在的取代胺)、环胺和碱性离子交换树脂(诸如异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、赖氨酸、精氨酸、N-乙基哌啶、哌啶、聚亚胺树脂等)。式(I)化合物的特定药用盐为盐酸盐。
如本文所用,术语“保护基”(PG)表示选择性封闭多功能化合物中的反应位点以便在合成化学中通常与之相关的另一未保护的反应位点上选择性发生化学反应的基团。保护基可在适当的点被去除。示例性保护基团是氨基保护基团、羧基保护基团或羟基保护基团。特定的保护基团是叔丁氧基羰基(Boc)、苄氧基羰基(Cbz)、芴基甲氧基羰基(Fmoc)和苄基(Bn)。进一步特定的保护基团是叔丁氧基羰基(Boc)和芴基甲氧基羰基(Fmoc)。更特定的保护基团是叔丁氧基羰基(Boc)。示例性保护基团及其在有机合成中的应用在例如T.W.Greene和P.G.M.Wutts,“Protective Groups in Organic Chemistry”,第5版,2014,John Wiley&Sons,N.Y中描述。
如本文所用,术语“脲形成剂”是指能够使得第一胺转化为物质的化合物,该物质可与第二胺反应,从而形成脲类衍生物。脲形成剂的非限制性实例包括双(三氯甲基)碳酸酯、光气、氯甲酸三氯甲酯、(4-硝基苯基)碳酸酯和1,1′-羰基二咪唑。脲形成剂如G.Sartori等人(Green Chemistry 2000,2,140)所述,该文献以引用方式并入本文。
式(I)的化合物可以含有若干不对称中心,并且可以以光学纯对映体、对映体的混合物(例如外消旋体)、光学纯非对映体、非对映体的混合物、非对映外消旋体或非对映外消旋体的混合物存在。
根据Cahn-Ingold-Prelog惯例,非对称碳原子可以是“R”或“S”构型。
缩写“MAGL”是指单酰基甘油脂肪酶。术语“MAGL”和“单酰基甘油脂肪酶”在本文中可互换使用。
本发明的化合物
在第一方面(A1),本发明提供式(I)化合物
或其药用盐,其中:
L为连接基;
R1为荧光标记;
R2、R3和R4各自独立地选自氢、卤素、C1-C6-烷基、卤代-C1-C6-烷基、C1-C6-烷氧基和卤代-C1-C6-烷氧基;并且
X和Y均为CH;或者
X和Y一起形成双键(C=C)。
在一个实施例中,所述式(I)化合物为式(Ia)化合物,
其中L和R1至R4如本文所定义。
本发明还提供了本发明第一方面(A1)的以下列举的实施例(E):
E1.根据A1所述的式(I)化合物或其药用盐,其中
L为连接基,其选自
其中
n在每次出现时独立地为选自1、2、3、4、5、6和7的整数;
波形线指示与R1的连接点;并且
星号指示与式(I)其余部分的连接点;
R1为荧光标记,其选自
其中波形线指示与连接基L的连接点;
R2、R3和R4各自独立地选自氢、卤素、C1-C6-烷基、卤代-C1-C6-烷基、C1-C6-烷氧基和卤代-C1-C6-烷氧基;并且
X和Y均为CH;或者
X和Y一起形成双键(C=C)。
E2.根据A1所述的式(I)化合物或其药用盐,其中所述连接基L选自
其中
n在每次出现时独立地为选自1、2、3、4、5、6和7的整数;
波形线指示与荧光标记R1的连接点;并且
星号指示与式(I)其余部分的连接点。
E3.根据A1和E1所述的式(I)化合物或其药用盐,其中所述连接基L选自
其中
n在每次出现时独立地为选自1、2、3、4、5、6和7的整数;
波形线指示与荧光标记R1的连接点;并且
星号指示与式(I)其余部分的连接点。
E4.根据A1和E1所述的式(I)化合物或其药用盐,其中所述连接基L选自
其中
n在每次出现时独立地为选自1、2和3的整数;
波形线指示与荧光标记R1的连接点;并且
星号指示与式(I)其余部分的连接点。
E5.根据A1和E1所述的式(I)化合物或其药用盐,其中所述连接基L选自
其中
n在每次出现时独立地为选自1、2和3的整数;
波形线指示与荧光标记R1的连接点;并且
星号指示与式(I)其余部分的连接点。
E6.根据A1和E1所述的式(I)化合物或其药用盐,其中所述连接基L选自
其中
波形线指示与荧光标记R1的连接点;并且
星号指示与式(I)其余部分的连接点。
E7.根据A1和E1所述的式(I)化合物或其药用盐,其中所述连接基L选自
其中
波形线指示与荧光标记R1的连接点;并且
星号指示与式(I)其余部分的连接点。
E8.根据A1和E2至E7中任一项所述的式(I)化合物或其药用盐,其中所述荧光标记R1选自
其中波形线指示与连接基L的连接点。
E9.根据A1和E1至E7中任一项所述的式(I)化合物或其药用盐,其中所述荧光标记R1选自
E10.根据A1和E1至E7中任一项所述的式(I)化合物或其药用盐,其中所述荧光标记R1选自
E11.根据A1和E1至E10中任一项所述的式(I)化合物或其药用盐,其中R2为氢。
E12.根据A1和E1至E11中任一项所述的式(I)化合物或其药用盐,其中R3为氢。
E13.根据A1和E1至E12中任一项所述的式(I)化合物或其药用盐,其中R4为氢。
E14.根据A1所述的式(I)化合物或其药用盐,其中所述式(I)化合物为式(II)化合物:
其中所述连接基L选自
其中
n在每次出现时独立地为选自1、2和3的整数;
波形线指示与荧光标记R1的连接点;并且
星号指示与式(I)其余部分的连接点;
并且其中所述荧光标记R1选自
其中波形线指示与连接基L的连接点。
E15.根据A1所述的式(I)化合物或其药用盐,其中所述式(I)化合物为式(II)或(III)化合物:
其中所述连接基L选自
其中
n在每次出现时独立地为选自1、2和3的整数;
波形线指示与荧光标记R1的连接点;并且
星号指示与式(I)其余部分的连接点;
并且其中所述荧光标记R1选自
其中波形线指示与连接基L的连接点。
E16.根据A1所述的式(I)化合物或其药用盐,其中所述式(I)化合物为式(II)化合物:
其中所述连接基L选自
其中
n在每次出现时独立地为选自1、2和3的整数;
波形线指示与荧光标记R1的连接点;并且
星号指示与式(I)其余部分的连接点;
并且其中所述荧光标记R1选自
其中波形线指示与连接基L的连接点。
E17.根据A1所述的式(I)化合物或其药用盐,其中所述式(I)化合物为式(II)或(III)化合物:
其中所述连接基L选自
其中
波形线指示与荧光标记R1的连接点;并且
星号指示与式(I)其余部分的连接点;
并且其中所述荧光标记R1选自
其中波形线指示与连接基L的连接点。
E18.根据权利要求A1和E1至E17中任一项所述的式(I)化合物或其药用盐,其中所述式(I)化合物选自:
N-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-[(4-硝基-2,1,3-苯并噁二唑-7-基)氨基]乙氧基]丙酰胺;
N-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-[(4-硝基-2,1,3-苯并噁二唑-7-基)氨基]乙氧基]丙酰胺;
N-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-[2-[(4-硝基-2,1,3-苯并噁二唑-7-基)氨基]乙氧基]乙氧基]丙酰胺;
N-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-[2-[(4-硝基-2,1,3-苯并噁二唑-7-基)氨基]乙氧基]乙氧基]丙酰胺;
N-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-[2-[(4-硝基-2,1,3-苯并噁二唑-7-基)氨基]乙氧基]乙氧基]丙酰胺;
N-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-[(4-硝基-2,1,3-苯并噁二唑-7-基)氨基]乙氧基]丙酰胺;
N-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]14-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-[2-[2-[(4-硝基-2,1,3-苯并噁二唑-7-基)氨基]乙氧基]乙氧基]乙氧基]丙酰胺;
N-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-[2-[2-[(4-硝基-2,1,3-苯并噁二唑-7-基)氨基]乙氧基]乙氧基]乙氧基]丙酰胺;
N-[2-[3-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基氨基]-3-氧代-丙氧基]乙基]-3-[2,2-二氟-12-(1H-吡咯-2-基)-3-氮杂-1-氮鎓-2-甲硼烷负离子杂三环[7.3.0.03,7]十二碳-1(12),4,6,8,10-五烯-4-基]丙酰胺;和
(4aR,8aS)-6-(4-((3-(2-((7-硝基苯并[c][1,2,5]噁二唑-4-基)氨基)乙氧基)苯基)(苯基)亚甲基)哌啶-1-羰基)六氢-2H-吡啶并[4,3-b][1,4]噁嗪-3(4H)-酮。
E19.根据权利要求A1和E1至E17中任一项所述的式(I)化合物或其药用盐,其中所述式(I)化合物选自:
N-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-[2-[(4-硝基-2,1,3-苯并噁二唑-7-基)氨基]乙氧基]乙氧基]丙酰胺;
N-[2-[3-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基氨基]-3-氧代-丙氧基]乙基]-3-[2,2-二氟-12-(1H-吡咯-2-基)-3-氮杂-1-氮鎓-2-甲硼烷负离子杂三环[7.3.0.03,7]十二碳-1(12),4,6,8,10-五烯-4-基]丙酰胺。
E20.根据权利要求A1和E1至E17中任一项所述的式(I)化合物或其药用盐,其中所述式(I)化合物选自:
N-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-[2-[(4-硝基-2,1,3-苯并噁二唑-7-基)氨基]乙氧基]乙氧基]丙酰胺;
N-[2-[3-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基氨基]-3-氧代-丙氧基]乙基]-3-[2,2-二氟-12-(1H-吡咯-2-基)-3-氮杂-1-氮鎓-2-甲硼烷负离子杂三环[7.3.0.03,7]十二碳-1(12),4,6,8,10-五烯-4-基]丙酰胺;和
(4aR,8aS)-6-(4-((3-(2-((7-硝基苯并[c][1,2,5]噁二唑-4-基)氨基)乙氧基)苯基)(苯基)亚甲基)哌啶-1-羰基)六氢-2H-吡啶并[4,3-b][1,4]噁嗪-3(4H)-酮。
本发明还涉及可用于生产本发明的荧光探针的合成中间体(即未标记的化合物)。
列举的实施例21至23提供了此类合成中间体的优选实例。
E21.一种化合物,其选自:
N-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-(2-氨基乙氧基)丙酰胺;
N-[2-[3-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基氨基]-3-氧代-丙氧基]乙基]氨基甲酸叔丁酯;
N-[2-[2-[3-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基氨基]-3-氧代-丙氧基]乙氧基]乙基]氨基甲酸叔丁酯;
(4aR,8aS)-6-[4-[[3-(2-氨基乙氧基)苯基]-苯基-甲基]哌啶-1-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮;
N-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]氨基甲酸叔丁酯;
N-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-[2-(2-氨基乙氧基)乙氧基]乙氧基]丙酰胺;
N-[2-[2-[2-[3-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基氨基]-3-氧代-丙氧基]乙氧基]乙氧基]乙基]氨基甲酸叔丁酯;和
N-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-(2-氨基乙氧基)乙氧基]丙酰胺。
E22.一种化合物,其选自:
N-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-(2-氨基乙氧基)丙酰胺;
N-[2-[3-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基氨基]-3-氧代-丙氧基]乙基]氨基甲酸叔丁酯;
N-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-(2-氨基乙氧基)乙氧基]丙酰胺;
N-[2-[2-[3-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基氨基]-3-氧代-丙氧基]乙氧基]乙基]氨基甲酸叔丁酯;
(4aR,8aS)-6-[4-[[3-(2-氨基乙氧基)苯基]-苯基-甲基]哌啶-1-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮;
N-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]氨基甲酸叔丁酯;
N-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-[2-(2-氨基乙氧基)乙氧基]乙氧基]丙酰胺;
N-[2-[2-[2-[3-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基氨基]-3-氧代-丙氧基]乙氧基]乙氧基]乙基]氨基甲酸叔丁酯;
(2-(3-((1-((4aR,8aS)-3-氧代八氢-2H-此啶并[4,3-b][1,4]噁嗪-6-羰基)哌啶-4-亚基)(苯基)甲基)苯氧基)乙基)氨基甲酸叔丁酯;
(2-(4-((1-((4aR,8aS)-3-氧代八氢-2H-吡啶并[4,3-b][1,4]噁嗪-6-羰基)哌啶-4-亚基)(苯基)甲基)苯氧基)乙基)氨基甲酸叔丁酯;
N-[3-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶亚基]-苯基-甲基]苯基]丙-2-炔基]氨基甲酸叔丁酯;
N-[3-[4-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶亚基]-苯基-甲基]苯基]丙-2-炔基]氨基甲酸叔丁酯;
N-[(E)-3-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶亚基]-苯基-甲基]苯基]烯丙基]氨基甲酸叔丁酯;
N-[(E)-3-[4-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶亚基]-苯基-甲基]苯基]烯丙基]氨基甲酸叔丁酯;
N-[2-[3-[(SR)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]氨基甲酸叔丁酯;
N-[2-[4-[(SR)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]氨基甲酸叔丁酯;
N-[3-[3-[(SR)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯基]丙基]氨基甲酸叔丁酯:
N-[3-[4-[(SR)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯基]丙基]氨基甲酸叔丁酯;
N-[3-[4-[(SR)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯基]丙-2-炔基]氨基甲酸叔丁酯;
N-[3-[3-[(SR)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯基]丙-2-炔基]氨基甲酸叔丁酯;
N-[(E)-3-[4-[(SR)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯基]烯丙基]氨基甲酸叔丁酯;
N-[(E)-3-[3-[(SR)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并
[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯基]烯丙基]氨基甲酸叔丁酯;
N-[2-[3-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶亚基]-苯基-甲基]苯氧基]乙基氨基]-3-氧代-丙氧基]乙基]氨基甲酸叔丁酯;
N-[3-[4-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶亚基]-苯基-甲基]苯基]丙基]氨基甲酸叔丁酯;
N-[3-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶亚基]-苯基-甲基]苯基]丙基]氨基甲酸叔丁酯。
E23.一种化合物,其选自:
N-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-(2-氨基乙氧基)丙酰胺;
N-[2-[3-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基氨基]-3-氧代-丙氧基]乙基]氨基甲酸叔丁酯;
N-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-(2-氨基乙氧基)乙氧基]丙酰胺;
N-[2-[2-[3-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基氨基]-3-氧代-丙氧基]乙氧基]乙基]氨基甲酸叔丁酯;
(4aR,8aS)-6-[4-[[3-(2-氨基乙氧基)苯基]-苯基-甲基]哌啶-1-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮;
N-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]氨基甲酸叔丁酯;
N-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-[2-(2-氨基乙氧基)乙氧基]乙氧基]丙酰胺;
N-[2-[2-[2-[3-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基氨基]-3-氧代-丙氧基]乙氧基]乙氧基]乙基]氨基甲酸叔丁酯;
(2-(3-((1-((4aR,8aS)-3-氧代八氢-2H-吡啶并[4,3-b][1,4]噁嗪-6-羰基)哌啶-4-亚基)(苯基)甲基)苯氧基)乙基)氨基甲酸叔丁酯;和
(2-(4-((1-((4aR,8aS)-3-氧代八氢-2H-吡啶并[4,3-b][1,4]噁嗪-6-羰基)哌啶-4-亚基)(苯基)甲基)苯氧基)乙基)氨基甲酸叔丁酯。
E24.根据E21-E23中任一项所述的化合物用于制备根据A1和E1至E20中任一项所述的式(I)的荧光探针的用途。
在特定实施例中,本发明提供了如本文所述的式(I)化合物的药用盐。在另一个特定实施例中,本发明提供了如本文所述的式(I)化合物作为游离碱。
制造过程
本发明的式(I)化合物的制备可按照顺序或并发合成路线进行。本发明的合成如以下总体方案所示。执行反应和纯化所得产物所需的技能对于本领域的技术人员是已知的。除非指明是相反情况,否则以下方法说明中所用的取代基和指数具有本文所提供的含义。
如果起始物质、中间体或式(I)化合物之一含有一种或多种在一个或多个反应步骤的反应条件下不稳定或具有反应性的官能团,则可以在关键步骤之前应用本领域中众所周知的方法引入适当的保护基(如以下文献所述:T.W.Greene和P.G.M.Wutts,“ProtectiveGroups in Organic Chemistry”,第5版,2014年,John Wiley&Sons,N.Y.)。此类保护基可在合成的后期使用文献中所述的标准方法去除。
如果起始物质或中间体含有立体异构中心,则可能获得呈非对映异构体或对映异构体的混合物形式的式(I)的化合物,其可以通过本领域中众所周知的方法(例如,手性HPLC、手性SFC或手性结晶)进行分离。外消旋化合物可例如通过非对映体盐分离为相应的对应体,其通过用光学纯的酸进行结晶,或通过使用手性吸附剂或手性洗脱剂的特定色谱法分离对映体。同样可分离含有立体异构中心的起始物质和中间体,以提供非对映异构体/对映异构体富集的起始物质和中间体。在式(I)化合物的合成中使用此类非对映异构体/对映异构体富集的起始物质和中间体通常将得到相应的非对映异构体/对映异构体富集的式(I)化合物。
本领域的技术人员将认识到,在式(I)化合物的合成中(如果不希望如此)将应用“正交保护基策略”,其允许每次裂解多个保护基而不影响分子中的其他保护基。正交保护的原理是本领域中众所周知的,并且也已经见诸文献报道(例如,Barany和R.B.Merrifield,J.Am.Chem.Soc.1977,99,7363;H.Waldmann等人,Angew.Chem.Int.Ed.Engl.1996,35,2056)。
本领域的技术人员将认识到,反应顺序可根据中间体的反应性和性质而变化。
更详细地,式(I)化合物可以通过下面给出的方法、通过实例中给出的方法或通过类似方法来制备。各个反应步骤的适当反应条件是本领域技术人员已知的。同样,有关文献中报道的影响所述反应的反应条件,参见例如:Comprehensive OrganicTransformations:A Guide to Functional Group Preparations,2nd Edition,RichardC.Larock.John Wiley&Sons,New York,NY.1999。在存在或不存在溶剂的情况下进行反应都很方便。对所用溶剂的性质没有特别的限制,只要它对反应或所涉及的试剂没有不利影响并且至少在一定程度上可以溶解试剂即可。所描述的反应可以在很宽的温度范围内发生,并且精确的反应温度对于本发明不是关键的。可以方便地在-78℃至回流的温度范围内进行所描述的反应。反应所需的时间还可在很大范围内变化,这取决于许多因素,特别是反应温度和试剂的性质。然而,0.5小时至几天的时间通常将足以产生所描述的中间体和化合物。反应顺序不限于方案中显示的反应顺序,而是取决于起始物质及其相应的反应性,可以自由地改变反应步骤的顺序。
如果起始原料或中间体无法商购获得,或者其合成未见诸文献报道,则可以采用类似于接近的类似物的现有制备方法或按照实验部分的概述进行制备。
以下缩写用于本文本:
AcOH=乙酸,ACN=乙腈,Boc=叔丁氧羰基,CAS RN=化学文摘登记号,Cbz=苄氧羰基,Cs2CO3=碳酸铯,CO=一氧化碳,CuCl=氯化亚铜(I),CuCN=氰化亚铜(I),CuI=碘化亚铜(I),DMAP=4-二甲基氨基吡啶,DME=二甲氧基乙烷,DMEDA=N,N’-二甲基乙二胺,DMF=N,N-二甲基甲酰胺,DIPEA=N,N-二异丙基乙胺,dppf=1,1-双(二苯基膦基)二茂铁,EDC.HCl=N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐,EI=电子轰击,ESI=电喷雾电离,EtOAc=乙酸乙酯,EtOH=乙醇,h=小时,FA=甲酸,H2O=水,H2SO4=硫酸,Hal=卤素,HATU=1-[双(二甲氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓-3-氧化物六氟磷酸盐,HBTU=O-苯并三唑-N,N,N’,N’-四甲基-脲鎓-六氟-磷酸盐,HCl=氯化氢,HOBt=1-羟基-1H-苯并三唑;HPLC=高效液相层析,iPrMgCl=异丙基氯化镁,I2=碘,IPA=2-丙醇,(Ir[dF(CF3)ppy]2(dtbpy))PF6=[4,4′-双(1,1-二甲基乙基)-2,2′-联吡啶-N1,N1′]双[3,5-二氟-2-[5-(三氟甲基)-2-吡啶基-N]苯基-C]铱(III)六氟磷酸盐,ISP=离子喷雾正(模式),ISN=离子喷雾负(模式),K2CO3=碳酸钾,KHCO3=碳酸氢钾,KI=碘化钾,KOH=氢氧化钾,K3PO4=磷酸三钾,LiAlH4或LAH=氢化铝锂,LiHMDS=双(三甲基甲硅烷基)酰胺锂,LiOH=氢氧化锂,MgSO4=硫酸镁,min=分钟,mL=毫升,MPLC=中压液相层析,MS=质谱,NaH=氢化钠,NaHCO3=碳酸氢钠,NaNO2=亚硝酸钠,NaOH=氢氧化钠,Na2CO3=碳酸钠,Na2SO4=硫酸钠,Na2S2O3=硫代硫酸钠,NBS=N-溴代琥珀酰亚胺,nBuLi=正丁基锂,NEt3=三乙胺(TEA),NH4Cl=氯化铵,NiCl2 glyme=氯化镍(II)乙二醇二甲基醚络合物,NMP=N-甲基-2-吡咯烷酮,OAc=乙酰氧基,T3P=丙基膦酸酐,P2O5=五氧化二磷,PE=石油醚,PG=保护基团,Pd-C=钯碳,PdCl2(dppf)-CH2Cl2=1,1′-双(二苯基膦基)二茂铁-二氯化钯(II)二氯甲烷络合物,Pd2(dba)3=三(二亚苄基丙酮)二钯(0),Pd(OAc)2=乙酸钯(II),Pd(OH)2=氢氧化钯,Pd(PPh3)4=四(三苯基膦)钯(0),PTSA=对甲苯磺酸,R=任何基团,RT=室温,SFC=超临界流体色谱,S-PHOS=2-二环己基膦基-2′,6′-二甲氧基联苯,T3P=丙基磷酸酐,TBAI=碘化四丁基铵,TEA=三乙胺,TFA=三氟乙酸,THF=四氢呋喃,TMEDA=N,N,N′,N′-四甲基乙二胺,ZnCl2=氯化锌,Xantphos=4,5-双(二苯基膦基)-9,9-二甲基氧杂蒽。
其中L、n、R1、R2、R3和R4如本文所述的式I化合物可按照类似于文献所述的方法和/或如方案1中所述合成。
方案1
因此,在脲形成剂诸如双(三氯甲基)碳酸酯的存在下,用合适的碱和溶剂诸如DCM中的碳酸氢钠,使4a,5,6,7,8,8a-六氢-4H-吡啶并[4,3-b][1,4]噁嗪-3-酮2与中间体1反应,得到式3化合物(步骤a)。进一步的,脲形成剂包括但不限于光气、氯甲酸三氯甲酸酯、(4-硝基苯基)碳酸酯或1,1′-羰基二咪唑。文献中广泛描述了此类反应以及这些试利的使用(例如,G.Sartori等人,Green Chemistry 2000,2,140)。本领域的技术人员将认识到,由于中间形成的氨基甲酰氯的反应性和稳定性以及为避免通过以下方式形成不希望的对称脲副产物,添加试剂的顺序在此类反应中可能很重要。哌啶衍生物1带有合适的保护基团“PG”,例如Cbz或Boc保护基团。哌啶1和4a,5,6,7,8,8a-六氢-4H-吡啶并[4,3-b][1,4]噁嗪-3-酮2可商购获得,或者可根据文献报道的方法或如下所述的方法制备。
应用本领域中已知的方法去除中间体3中的保护基团(例如,在0℃至室温之间的温度下,使用TFA在DCM溶液中去除Boc基;在合适的溶剂诸如MeOH、EtOH、EtOAc或它们的混合物中存在合适的催化剂诸如活性炭负载的Pd或Pd(OH)2的情况下使用氢气去除Cbz基团;以及例如以下文献所述:T.W.Greene和P.G.M.Wutts,“Protective Groups in OrganicChemistry”,Wuts,第4版,2006年,Wiley N.Y.),以提供式Ia分子(步骤b)。
胺Ia与含有羧酸部分的荧光标记反应得到式Ib(R1=荧光标记)的化合物(步骤 c)。这种类型的酰胺偶联通过使用已知的偶联试剂(例如DCC、HATU、EDCI、HOBt、TBTU、T3P等)之一和碱(如Huenig碱、三乙胺或DMAP),在合适的溶剂(如N,N-二甲基甲酰胺、DMA、DCM或二噁烷)中,优选在0℃至室温之间来完成。为了形成带有硝基苯并呋喃染料的最终分子Ib,胺Ia可以与用4-氯-7-硝基苯-2-氧杂-1,3-二唑(CAS RN 10199-89-0)例如在碱(例如N,N-二异丙基乙胺)存在下在溶剂(如MeOH)中优选在环境温度进行亲核芳香族取代反应(步骤c)。
任选地,哌啶衍生物1(其中“PG”为荧光标记或叔丁氧基羰基)可以根据步骤a直接转化为式(Ib)化合物。在“PG”为叔丁氧基羰基的情况下,可以获得带有R1等同于叔丁氧基羰基的式(Ib)的最终分子。
4a,5,6,7,8,8a-六氢-4H-吡啶并[4,3-b][1,4]噁嗪-3-酮2可以例如方案2中所述和/或类似于文献中描述的方法合成。
方案2
因此,其中“PG”表示合适的保护基团诸如Cbz或Boc保护基团的3-氨基哌啶-4-醇衍生物3可例如用酰氯4进行酰化(使用在合适的溶剂诸如THF、水、丙酮或它们的混合物中的合适的碱诸如碳酸钠或碳酸钾、氢氧化钠或乙酸钠),其中“LG”表示合适的离去基团(例如,Cl或Br),以提供中间体5(步骤a)。中间体4可商购获得,或者可根据文献报道的方法制备。
可使用本领域中众所周知的方法将中间体5环化为中间体6,例如通过THF中的氢化钠或IPA和水中的叔丁醇钾处理5(步骤b)。此类反应如文献中所述(例如,Z.Rafinski等人,J.Org.Chem.2015,80,7468;S.Dugar等人,Synthesis 2015,47(5),712;WO2005/066187)。
应用本领域中已知的方法去除中间体6中的保护基团(例如,在0℃至室温之间的温度下,使用TFA在DCM溶液中去除Boc基;在合适的溶剂诸如MeOH、EtOH、EtOAc或它们的混合物中存在合适的催化剂诸如活性炭负载的Pd或Pd(OH)2的情况下使用氢气去除Cbz基团;以及例如以下文献所述:T.W.Greene和P.G.M.Wutts,“Protective Groups in OrganicChemistry”,第4版,2006年,Wiley N.Y.),以提供中间体2(步骤c)。
中间体2可作为非对映体和对映体的混合物获得,或作为单一立体异构体获得,这取决于合成中采用的是外消旋混合物还是顺式或反式3-氨基哌啶-4-醇衍生物3的光学纯形式。中间体3可商购获得,且其合成已描述于文献中(例如WO2005/066187;WO2011/0059118;WO2016/185279)。光学纯顺式构型的中间体2可例如使用本领域已知的方法(例如通过非对映体盐结晶或通过手性色谱法)手性分离可商购获得的外消旋-(4aR,8aS)-4a,5,6,7,8,8a-六氢-4H-吡啶并[4,3-b][1,4]噁嗪-3-酮(任选地呈盐的形式,例如盐酸盐)来获得。
1型中间体可以通过多种条件(这可以通过方案3中所概述的一般合成程序所示例的)制备。
方案3
可以例如使用NH2NHT在溶剂(如1,4-二噁烷)中优选通过加热至80℃使式7的酮反应为N-甲苯磺酰基腙8(步骤a)。在进一步的步骤,使式8的N-甲苯磺酰基腙与芳基卤化物9(其中X1选自由以下项组成的组:Cl、Br和I)在催化系统存在下反应得到结构10的中间体(步骤b)。用于这样的转化的合适的催化系统由例如[Pd(PPPh3)2Cl2]组成但不限于[Pd(PPPh3)2Cl2]在LiOtBu存在下在溶剂(例如1,4-二噁烷)中在温度80℃进行。使用催化剂(例如Pd(OH)2或Pd/C,优选在溶剂(如THF、MeOH、EtOH、EtOAc或其混合物)中(优选在THF中)的Pd/C)在约室温和在例如氢的大气压下进行烯烃10的多相催化加氢得到11型中间体(步骤 c)。使用酸性条件(例如二噁烷中的4M HCl)在溶剂(如DCM中的MeOH或优选TFA)在约室温切割中间体11的BOC基团得到1型中间体(步骤d)。
酮7和芳基卤化物9可商购获得,或者可以根据本领域技术人员已知的方法合成。
在一方面,本发明提供了制备本文所述的式(I)化合物的方法,该方法包括:
(a)使第一胺4a,5,6,7,8,8a-六氢-4H-吡啶并[4,3-b][1,4]噁嗪-3-酮(2),
与第二胺1,其中R2、R3、R4、L和PG如本文所定义,
在碱和脲形成剂存在下
反应以形成式3化合物,其中R2、R3、R4、L和PG如本文所定义
(b)使第一胺4a,5,6,7,8,8a-六氢-4H-吡啶并[4,3-b][1,4]噁嗪-3-酮(2),
与第二胺1a(其中R1、R2、R3、R4和L如本文所定义)
在碱和脲形成剂存在下
进行反应以形成所述式(I)化合物。
在一个实施例中,提供了一种根据本发明所述的方法,其中所述碱为碳酸氢钠。
在一个实施例中,提供了一种根据本发明所述的方法,其中所述脲形成剂选自双(三氯甲基)碳酸酯、光气、氯甲酸三氯甲酯、(4-硝基苯基)碳酸酯和1,1′-羰基二咪唑,优选地其中所述脲形成剂为双(三氯甲基)碳酸酯。
在一个实施例中,提供了根据本发明的方法,其中所述保护基团“PG”为Cbz或Boc保护基团。
在一个方面,本发明提供了一种如本文所述的式(I)化合物,该化合物根据本文所述的方法中的任一方法进行制备。
MAGL抑制活性
通过在天然底物2-花生四烯酰甘油(2-AG)水解得到花生四烯酸后测定酶促活性,分析化合物对MAGL的抑制活性,然后可进行质谱分析。该测定在在后文缩写为“2-AG测定”。
2-AG测定在384孔测定板(PP,Greiner目录号784201)中进行,总体积为20μL。在聚丙烯板中,利用3倍稀释步骤在100%DMSO(VWR Chemicals 23500.297)中制备化合物稀释液,以使测定的最终浓度范围为12.5μM至0.8pM。将0.25μL化合物稀释液(100%DMSO)加入9μL MAGL的测定缓冲液(50mM TRIS(GIBCO,15567-027)、1mM EDTA(Fluka,03690-100mL)和0.01%(v/v)Tween)中。振摇后,将板在室温下孵育15min。加入10μL 2-花生四烯酰甘油的测定缓冲液溶液,以开始反应。该测定中的最终浓度为50pM MAGL和8μM 2-花生四烯酰甘油。振摇并在RT孵育30min后,加入40μL含4μM d8-花生四烯酸的ACN淬灭反应。利用在线SPE系统(Agilent Rapidfire)与三重四极杆质谱仪(Agilent 6460)偶联跟踪花生四烯酸的含量。在ACN/水液体设置中,使用C18 SPE小柱(G9205A)。质谱仪在负电喷雾模式下操作,花生四烯酸的质量离子对为303.1→259.1,d8-花生四烯酸的质量离子对为311.1→267.0。基于[花生四烯酸/d8-花生四烯酸]的强度比计算化合物的活性。
表1
在一个方面,本发明提供了如本文所述的式(I)化合物及其药用盐或酯,其中所述式(I)化合物及其药用盐或酯具有低于25μM、优选低于10μM、更优选地低于5μM的MAGL抑制IC50,该IC50值在本文所述的MAGL测定中测得。
在一个实施例中,如本文所述的式(I)化合物及其药用盐或酯的IC50(MAGL抑制)值介于0.000001μM和25μM之间,特定化合物具有介于0.000005μM和10μM之间的IC50值,更特定的化合物具有介于0.00005μM和5μM之间的IC50值,该IC50值在本文所述的MAGL测定中测得。
使用本发明的化合物
式(I)化合物是对于MAGL具有高亲和力的荧光成像探针。因此,它们可以用作研究定位(例如健康和疾病状态中的表达水平和蛋白质分布,活细胞中MAGL的结构、动力学和功能)的高分辨率工具。它们也可以例如使用共聚焦活细胞成像应用于流式细胞术荧光活化细胞分选(FACS)实验或细胞运输研究。
在一方面,本发明提供了如本文所述的式(I)化合物,用于单酰基甘油脂肪酶(MAGL)的占用研究。
在另一方面,本发明提供了化合物如本文所述的式(I)化合物,用于哺乳动物中单酰基甘油脂肪酶(MAGL)的诊断成像。
在另一方面,本发明提供了如本文所述的式(I)化合物,用于产生单酰基甘油脂肪酶(MAGL)平衡和动力学结合数据。
在另一方面,本发明提供了在单酰基甘油脂肪酶(MAGL)的占用研究中使用如本文所述的式(I)化合物。
在另一方面,本发明提供了在哺乳动物中单酰基甘油脂肪酶(MAGL)的诊断成像中使用本文所述的式(I)化合物。
在另一方面,本发明提供了为了产生单酰基甘油脂肪酶(MAGL)平衡和动力学结合数据使用如本文所述的式(I)化合物。
在另一方面,本发明提供了研究单酰基甘油脂肪酶(MAGL)占用的方法,该方法包括使MAGL与本文所述的式(I)化合物接触。
在另一方面,本发明提供了哺乳动物中单酰基甘油脂肪酶(MAGL)的诊断成像的方法,该方法包括使MAGL与本文所述的式(I)化合物接触。
在另一方面,本发明提供了产生单酰基甘油脂肪酶(MAGL)平衡和动力学结合数据的方法,该方法包括使MAGL与本文所述的式(I)化合物接触。
实例
通过参考以下实例将更全面地理解本发明。然而,权利要求不应被解释为限于实例的范围。
在作为对映体的混合物获得制备实施例的情况下,可以通过本文所述的方法或通过本领域技术人员已知的方法(诸如手性色谱(例如,手性SFC)或结晶)分离纯对映体。
如果没有另行说明,则在氩气氛下制备所有反应实施例和中间体。
实例1
3-(2-(2-(2-((7-硝基苯并[c][1,2,5]噁二唑-4-基)氨基)乙氧基)乙氧基)乙氧基)-N-(2-(3-((1-((4aR,8aS)-3-氧代八氢-2H-吡啶并[4,3-b][1,4]噁嗪-6-羰基)哌啶-4-基)(苯基)甲基)苯氧基)乙基)丙酰胺
步骤a)(Z)-4-(苯基(2-甲苯磺酰基亚肼基)甲基)哌啶-1-甲酸苄酯
将4-甲苯磺酰肼(1.54g,8.29mmol;CAS RN 1576-35-8)和4-苯甲酰哌啶-1-甲酸叔丁酯(2.0g,6.91mmol;CAS RN 922504-27-6)的1,4-二噁烷(150mL)溶液在100℃搅拌16小时。添加EtOAc和H2O水。分离各层并将有机层经Na2SO4干燥。在减压下除去溶剂,并将粗品通过快速色谱法(ISCO硅胶,25g柱,庚烷AcOEt 0-30)纯化以得到标题化合物(3.55g,定量),其为淡棕色油状物。LC-HRMS(ESI):492.1945([M+H]+)。
步骤b)4-((3-(2-((叔丁氧羰基)氨基)乙氧基)苯基)(苯基)亚甲基)哌啶-1-甲酸苄酯
将(Z)-4-(苯基(2-甲苯磺酰基亚肼基)甲基)哌啶-1-甲酸苄酯(1g,2.03mmol)、双(三苯基膦)氯化钯(II)(143mg,203μmol)、叔丁醇锂(246mg,3.05mmol)和N-Boc-2-(3-溴苯氧基)乙胺(772mg,2.44mmol;CAS RN 1098107-26-6)在1,4-二噁烷(3mL)中的混合物在80℃搅拌14小时。添加EtOAc和H2O水。分离各层并将有机层经Na2SO4干燥。在减压下除去溶剂,并将粗品通过快速色谱法(ISCO硅胶,80g柱,庚烷AcOEt0-30)纯化以得到标题化合物(280mg,22%),其为淡黄色泡沫。LC-HRMS(ESI):443.2309([M-Boc+H]+)。
步骤c)(2-(3-(苯基(哌啶-4-基)甲基)苯氧基)乙基)氨基甲酸叔丁酯
在高压釜中将Pd+Pt/C(2.5%+2.5%,7.01g)添加至4-((3-(2-((叔丁氧羰基)氨基)乙氧基)苯基)(苯基)亚甲基)哌啶-1-甲酸苄酯(4.8g,8.85mmol)在甲醇(240mL)和AcOH(4.8mL)中的溶液中。反应容器用氢气吹扫三次。将混合物在50℃和50巴氢气压力下搅拌18小时。滤出催化剂并用甲醇洗涤。将滤液在真空中浓缩以得到标题化合物(3.386g,93%),其为无色固体。LC-HRMS(ESI):411.2644([M+H]+)。
步骤d)(+)-顺式-4a,5,6,7,8,8a-六氢-4H-吡啶并[4,3-b][1,4]噁嗪-3-酮
利用制备型手性HPLC(ReprosilChiral NR色谱柱)将外消旋-(4aR,8aS)-六氢-2H-吡啶并[4,3-b][1,4]噁嗪-3(4H)-酮二盐酸盐的对映体(500mg,2.18mmol,ChemBridgeCorporation)分离,其中使用EtOH(包含0.05%NH4OAc)∶正庚烷(30∶70)的等度混合物。
第一个洗脱的对映体:(+)-顺式-4a,5,6,7,8,8a-六氢-4H-吡啶并[4,3-b][1,4]噁嗪-3-酮。黄色固体(0.150g;44.0%)。MS(ESI):m/z=157.1[M+H]+。
第二个洗脱的对映体:(-)-顺式-4a,5,6,7,8,8a-六氢-4H-吡啶并[4,3-b][1,4]噁嗪-3-酮。黄色固体(0.152g;44.6%)。MS(ESI):m/z=157.1[M+H]+。
步骤e)(2-(3-((1-((4aR,8aS)-3-氧代八氢-2H-吡啶并[4,3-b][1,4]噁嗪-6-羰基)哌啶-4-基)(苯基)甲基)苯氧基)乙基)氨基甲酸叔丁酯
将(+)-顺式-4a,5,6,7,8,8a-六氢-4H-吡啶并[4,3-b][1,4]噁嗪-3-酮(295mg,1.1mmol)和碳酸氢钠(368mg,4.38mmol)在DCM(13mL)中的混合物冷却至0℃。添加三光气(228mg,767μmol)并将混合物在环境温度搅拌14小时并再次冷却至0℃。添加(2-(3-(苯基(哌啶-4-基)甲基)苯氧基)乙基)氨基甲酸叔丁酯(450mg,1.1mmol)和DIPEA(567mg,766μL,4.38mmol)。将悬浮液在环境温度搅拌2小时。添加EtOAc和H2O水。分离各层并将有机层经Na2SO4干燥。在减压下除去溶剂,并将粗产物通过制备型HPLC纯化以得到标题化合物(392mg,60%),其为灰白色泡沫。MS(ESI):m/z=493.4([M-Boc+H]+)。
步骤f)(4aR,8aS)-6-(4-((3-(2-氨基乙氧基)苯基)(苯基)甲基)哌啶-1-羰基)六氢-2H-吡啶并[4,3-b][1,4]噁嗪-3(4H)-酮
将TFA(274mg,185μL,2.4mmol)添加至(2-(3-((1-((4aR,8aS)-3-氧代八氢-2H-吡啶并[4,3-b][1,4]噁嗪-6-羰基)哌啶-4-基)(苯基)甲基)苯氧基)乙基)氨基甲酸叔丁酯(178mg,300μmol)的DCM(2.49mL)溶液。将反应混合物在环境温度搅拌3小时。添加乙酸乙酯和KHCO3水溶液。分离各层。将水层用乙酸乙酯萃取。将合并的有机相经硫酸钠干燥并在减压下干燥以得到标题化合物(178mg,定量),其为淡黄色泡沫,其不经进一步纯化即可用于下一步。LC-HRMS(ESI):493.2813([M+H]+)。
步骤g)(12-氧代-15-(3-((1-((4aR,8aS)-3-氧代八氢-2H-吡啶并[4,3-b][1,4]噁嗪-6-羰基)哌啶-4-基)(苯基)甲基)苯氧基)-3,6,9-三氧杂-13-氮杂十五烷基)氨基甲酸叔丁酯
将DIPEA(52.5mg,70.9μL,406μmol)添加至(4aR,8aS)-6-(4-((3-(2-氨基乙氧基)苯基)(苯基)甲基)哌啶-1-羰基)六氢-2H-吡啶并[4,3-b][1,4]噁嗪-3(4H)-酮(50mg,101μmol)、3-[2-[2-[2-(叔丁氧羰基氨基)乙氧基]乙氧基]乙氧基]丙酸(33mg,101μmol;CAS RN1347750-75-7)和HATU(43mg,112μmol)在DMF(338μL)中的混合物中。将混合物在环境温度搅拌18h。添加乙酸乙酯和KHCO3水溶液。分离各层。将有机层用水洗涤并经硫酸钠干燥。除去溶剂提供粗产物,将其通过快速色谱法(ISCO硅胶,12g柱,庚烷EtOAc 0%-70%和DCMMeOH 0%-10%)纯化以得到标题化合物(36mg,48%),其为无色固体。LC-HRMS(ESI):796.4494([M+H]+)。
步骤h)3-(2-(2-(2-氨基乙氧基)乙氧基)乙氧基)-N-(2-(3-((1-((4aR,8aS)-3-氧代八氢-2H-吡啶并[4,3-b][1,4]噁嗪-6-羰基)哌啶-4-基)(苯基)甲基)苯氧基)乙基)丙酰胺
将TFA(51mg,34.4μL,446μmol)添加至(12-氧代-15-(3-((1-((4aR,8aS)-3-氧代八氢-2H-吡啶并[4,3-b][1,4]噁嗪-6-羰基)哌啶-4-基)(苯基)甲基)苯氧基)-3,6,9-三氧杂-13-氮杂十五烷基)氨基甲酸叔丁酯(74mg,56μmol)的CH2Cl2(21μL)溶液。将反应混合物在环境温度搅拌3小时。添加乙酸乙酯和KHCO3水溶液。分离各层。将水层用乙酸乙酯萃取。将合并的有机相经硫酸钠干燥并在减压下干燥以得到标题化合物(36mg,48%),其为淡黄色泡沫。LC-HRMS(ESI):696.3963([M+H]+)。
步骤i)3-(2-(2-(2-((7-硝基苯并[c][1,2,5]噁二唑-4-基)氨基)乙氧基)乙氧基)乙氧基)-N-(2-(3-((1-((4aR,8aS)-3-氧代八氢-2H-吡啶并[4,3-b][1,4]噁嗪-6-羰基)哌啶-4-基)(苯基)甲基)苯氧基)乙基)丙酰胺
将4-氯-7-硝基苯-2-氧杂-1,3-二唑(2.8mg,14μmol;CAS RN 10199-89-0)和N,N-二异丙基乙胺(1.9mg,2.5μL,14μmol)添加至3-(2-(2-(2-氨基乙氧基)乙氧基)乙氧基)-N-(2-(3-((1-((4aR,8aS)-3-氧代八氢-2H-吡啶并[4,3-b][1,4]噁嗪-6-羰基)哌啶-4-基)(苯基)甲基)苯氧基)乙基)丙酰胺(10mg,14.4μmol)的MeOH(240μL)溶液。将反应混合物在环境温度搅拌14h并倒入乙酸乙酯/水中。分离各层。将有机层经硫酸钠干燥并蒸发至干燥。将粗物质通过快速色谱法(ISCO硅胶,25g柱,DCM MeOH 0-40%)纯化以得到标题化合物(5mg,34%),其为橙色固体。LC-HRMS(ESI):859.3985([M+H]+)。
实例2
3-(2-((7-硝基苯并[c][1,2,5]噁二唑-4-基)氨基)乙氧基)-N-(2-(3-((1-((4aR,8aS)-3-氧代八氢-2H-吡啶并[4,3-b][1,4]噁嗪-6-羰基)哌啶-4-基)(苯基)甲基)苯氧基)乙基)丙酰胺
步骤a)(2-(3-氧代-3-((2-(3-((1-((4aR,8aS)-3-氧代八氢-2H-吡啶并[4,3-b][1,4]噁嗪-6-羰基)哌啶-4-基)(苯基)甲基)苯氧基)乙基)氨基)丙氧基)乙基)氨基甲酸叔丁酯
类似于实例1g)中所述的程序,将(4aR,8aS)-6-(4-((3-(2-氨基乙氧基)苯基)(苯基)甲基)哌啶-1-羰基)六氢-2H-吡啶并[4,3-b][1,4]噁嗪-3(4H)-酮(实例1f)用3-[2-(叔丁氧羰基氨基)乙氧基]丙酸(CAS RN 1260092-44-1)缩合以得到标题化合物,其为无色油状物。
步骤b)3-(2-氨基乙氧基)-N-(2-(3-((1-((4aR,8aS)-3-氧代八氢-2H-吡啶并[4,3-b][1,4]噁嗪-6-羰基)哌啶-4-基)(苯基)甲基)苯氧基)乙基)丙酰胺
类似于实例1h)中所述的程序,将(2-(3-氧代-3-((2-(3-((1-((4aR,8aS)-3-氧代八氢-2H-吡啶并[4,3-b][1,4]噁嗪-6-羰基)哌啶-4-基)(苯基)甲基)苯氧基)乙基)氨基)丙氧基)乙基)氨基甲酸叔丁酯用TFA脱保护以得到标题化合物,其为灰白色固体。LC-HRMS(ESI):608.3437([M+H]+)。
步骤c)3-(2-((7-硝基苯并[c][1,2,5]噁二唑-4-基)氨基)乙氧基)-N-(2-(3-((1-((4aR,8aS)-3-氧代八氢-2H-吡啶并[4,3-b][1,4]噁嗪-6-羰基)哌啶-4-基)(苯基)甲基)苯氧基)乙基)丙酰胺
类似于实例1i)中所述的程序,使3-(2-氨基乙氧基)-N-(2-(3-((1-((4aR,8aS)-3-氧代八氢-2H-吡啶并[4,3-b][1,4]噁嗪-6-羰基)哌啶-4-基)(苯基)甲基)苯氧基)乙基)丙酰胺与4-氯-7-硝基苯-2-氧杂-1,3-二唑反应以得到标题化合物,其为橙色固体。LC-HRMS(ESI):770.3461([M+H]+)。
实例3
3-(2-(2-((7-硝基苯并[c][1,2,5]噁二唑-4-基)氨基)乙氧基)乙氧基)-N-(2-(3-((1-((4aR,8aS)-3-氧代八氢-2H-吡啶并[4,3-b][1,4]噁嗪-6-羰基)哌啶-4-基)(苯基)甲基)苯氧基)乙基)丙酰胺
步骤a)(2-(2-(3-氧代-3-((2-(3-((1-((4aR,8aS)-3-氧代八氢-2H-吡啶并[4,3-b][1,4]噁嗪-6-羰基)哌啶-4-基)(苯基)甲基)苯氧基)乙基)氨基)丙氧基)乙氧基)乙基)氨基甲酸叔丁酯
类似于实例1g)中所述的程序,将(4aR,8aS)-6-(4-((3-(2-氨基乙氧基)苯基)(苯基)甲基)哌啶-1-羰基)六氢-2H-吡啶并[4,3-b][1,4]噁嗪-3(4H)-酮(实例1f)用3-[2-[2-(叔丁氧羰基氨基)乙氧基]乙氧基]丙酸(CAS RN 1365655-91-9)缩合以得到标题化合物,其为无色油状物。LC-HRMS(ESI):774.4065([M+Na]+)。
步骤b)3-(2-(2-氨基乙氧基)乙氧基)-N-(2-(3-((1-((4aR,8aS)-3-氧代八氢-2H-吡啶并[4,3-b][1,4]噁嗪-6-羰基)哌啶-4-基)(苯基)甲基)苯氧基)乙基)丙酰胺
类似于实例1h)中所述的程序,将(2-(2-(3-氧代-3-((2-(3-((1-((4aR,8aS)-3-氧代八氢-2H-吡啶并[4,3-b][1,4]噁嗪-6-羰基)哌啶-4-基)(苯基)甲基)苯氧基)乙基)氨基)丙氧基)乙氧基)乙基)氨基甲酸叔丁酯用TFA脱保护以得到标题化合物,其为灰白色固体。LC-HRMS(ESI):652.3702([M+H]+)。
步骤c)3-(2-(2-((7-硝基苯并[c][1,2,5]噁二唑-4-基)氨基)乙氧基)乙氧基)-N-(2-(3-((1-((4aR,8aS)-3-氧代八氢-2H-吡啶并[4,3-b][1,4]噁嗪-6-羰基)哌啶-4-基)(苯基)甲基)苯氧基)乙基)丙酰胺
类似于实例1i)中所述的程序,使3-(2-(2-氨基乙氧基)乙氧基)-N-(2-(3-((1-((4aR,8aS)-3-氧代八氢-2H-吡啶并[4,3-b][1,4]噁嗪-6-羰基)哌啶-4-基)(苯基)甲基)苯氧基)乙基)丙酰胺与4-氯-7-硝基苯-2-氧杂-1,3-二唑反应以得到标题化合物,其为橙色固体。LC-HRMS(ESI):814.3638([M+H]+)。
实例4
N-[2-[3-[(R或S)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]氨基甲酸叔丁酯
步骤a)N-[2-[3-[(R或S)-苯基(4-哌啶基)甲基]苯氧基]乙基]氨基甲酸叔丁酯
通过制备型手性HPLC分离外消旋-(2-(3-(苯基(哌啶-4-基)甲基)苯氧基)乙基)氨基甲酸叔丁酯的对映体(实例1c)。
第一个洗脱的对映体:(-)-N-[2-[3-[(R或S)-苯基(4-哌啶基)甲基]苯氧基]乙基]氨基甲酸叔丁酯。白色泡沫。LC-HRMS(ESI):411.2648([M+H]+)。
第二个洗脱的对映体:(+)-N-[2-[3-[(S或R)-苯基(4-哌啶基)甲基]苯氧基]乙基]氨基甲酸叔丁酯。白色泡沫。LC-HRMS(ESI):411.2649([M+H]+)。
步骤b)N-[2-[3-[(R或S)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]氨基甲酸叔丁酯
类似于实例1e)中所述的程序,使(+)-顺式-4a,5,6,7,8,8a-六氢-4H-吡啶并[4,3-b][1,4]噁嗪-3-酮(实例1d)与N-[2-[3-[(R或S)-苯基(4-哌啶基)甲基]苯氧基]乙基]氨基甲酸叔丁酯反应以得到标题化合物,其为无色油状物。LC-HRMS(ESI):593.3335([M+H]+)。
实例5
N-[2-[3-[(S或R)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]氨基甲酸叔丁酯
步骤a)N-[2-[3-[(S或R)-苯基(4-哌啶基)甲基]苯氧基]乙基]氨基甲酸叔丁酯
通过制备型手性HPLC分离外消旋-(2-(3-(苯基(哌啶-4-基)甲基)苯氧基)乙基)氨基甲酸叔丁酯的对映体(实例1c)。
第一个洗脱的对映体:(-)-N-[2-[3-[(R或S)-苯基(4-哌啶基)甲基]苯氧基]乙基]氨基甲酸叔丁酯。白色泡沫。LC-HRMS(ESI):411.2648([M+H]+)。
第二个洗脱的对映体:(+)-N-[2-[3-[(S或R)-苯基(4-哌啶基)甲基]苯氧基]乙基]氨基甲酸叔丁酯。白色泡沫。LC-HRMS(ESI):411.2649([M+H]+)。
步骤b)N-[2-[3-[(S或R)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]氨基甲酸叔丁酯类似于实例1e)中所述的程序,使(+)-顺式-4a,5,6,7,8,8a-六氢-4H-吡啶并[4,3-b][1,4]噁嗪-3-酮(实例1d)与N-[2-[3-[(S或R)-苯基(4-哌啶基)甲基]苯氧基]乙基]氨基甲酸叔丁酯反应以得到标题化合物,其为灰白色泡沫。LC-HRMS(ESI):593.3336([M+H]+)。
实例6
(4aR,8aS)-6-[4-[(S或R)-[3-(2-氨基乙氧基)苯基]-苯基-甲基]哌啶-1-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮
类似于实例1f)中所述的程序,将N-[2-[3-[(S或R)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]氨基甲酸叔丁酯(实例5b)用TFA脱保护以得到标题化合物,其为黄色油状物。LC-HRMS(ESI):493.2815([M+H]+)。
实例7
(4aR,8aS)-6-[4-[(R或S)-[3-(2-氨基乙氧基)苯基]-苯基-甲基]哌啶-1-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮
类似于实例1f)中所述的程序,将N-[2-[3-[(R或S)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]氨基甲酸叔丁酯(实例4b)用TFA脱保护以得到标题化合物,其为黄色油状物。LC-HRMS(ESI):493.2815([M+H]+)。
实例8
N-[2-[2-[3-[2-[3-[(S或R)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基氨基]-3-氧代-丙氧基]乙氧基]乙基]氨基甲酸叔丁酯
类似于实例1g)中所述的程序,将(4aR,8aS)-6-[4-[(S或R)-[3-(2-氨基乙氧基)苯基]-苯基-甲基]哌啶-1-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮(实例6)用3-[2-[2-(叔丁氧羰基氨基)乙氧基]乙氧基]丙酸(CAS RN 1365655-91-9)缩合以得到标题化合物,其为白色粉末。LC-HRMS(ESI):752.4237([M+H]+)。
实例9
N-[2-[2-[3-[2-[3-[(R或S)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基氨基]-3-氧代-丙氧基]乙氧基]乙基]氨基甲酸叔丁酯
类似于实例1g)中所述的程序,将(4aR,8aS)-6-[4-[(R或S)-[3-(2-氨基乙氧基)苯基]-苯基-甲基]哌啶-1-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮(实例7)用3-[2-[2-(叔丁氧羰基氨基)乙氧基]乙氧基]丙酸(CAS RN 1365655-91-9)缩合以得到标题化合物,其为白色粉末。LC-HRMS(ESI):752.4236([M+H]+)。
实例10
N-[2-[3-[(R或S)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-(2-氨基乙氧基)乙氧基]丙酰胺
类似于实例1h)中所述的程序,将N-[2-[2-[3-[2-[3-[(R或S)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基氨基]-3-氧代-丙氧基]乙氧基]乙基]氨基甲酸叔丁酯(实例9)用TFA脱保护以得到标题化合物,其为淡黄色油状物。LC-HRMS(ESI):652.3703([M+H]+)。
实例11
N-[2-[3-[(S或R)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-(2-氨基乙氧基)乙氧基]丙酰胺
类似于实例1h)中所述的程序,将N-[2-[2-[3-[2-[3-[(S或R)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基氨基]-3-氧代-丙氧基]乙氧基]乙基]氨基甲酸叔丁酯(实例8)用TFA脱保护以得到标题化合物,其为淡黄色油状物。LC-HRMS(ESI):652.3705([M+H]+)。
实例12
N-[2-[3-[(S或R)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-[2-[(4-硝基-2,1,3-苯并噁二唑-7-基)氨基]乙氧基]乙氧基]丙酰胺
类似于实例1i)中所述的程序,使N-[2-[3-[(S或R)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-(2-氨基乙氧基)乙氧基]丙酰胺(实例11)与4-氯-7-硝基苯-2-氧杂-1,3-二唑反应以得到标题化合物,其为黄色固体。LC-HRMS(ESI):813.3573([M-H]-)。
实例13
N-[2-[3-[(R或S)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-[2-[(4-硝基-2,1,3-苯并噁二唑-7-基)氨基]乙氧基]乙氧基]丙酰胺
类似于实例1i)中所述的程序,使N-[2-[3-[(R或S)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-(2-氨基乙氧基)乙氧基]丙酰胺(实例10)与4-氯-7-硝基苯-2-氧杂-1,3-二唑反应以得到标题化合物,其为黄色固体。LC-HRMS(ESI):813.3571([M-H]-)。
实例14
N-[2-[3-[2-[3-[(S或R)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基氨基]-3-氧代-丙氧基]乙基]氨基甲酸叔丁酯
类似于实例1g)中所述的程序,将(4aR,8aS)-6-[4-[(S或R)-[3-(2-氨基乙氧基)苯基]-苯基-甲基]哌啶-1-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮(实例6)用3-[2-(叔丁氧羰基氨基)乙氧基]丙酸(CAS RN 1260092-44-1)缩合以得到标题化合物,其为无色油状物。LC-HRMS(ESI):708.3957([M+H]+)。
实例15
N-[2-[3-[2-[3-[(R或S)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基氨基]-3-氧代-丙氧基]乙基]氨基甲酸叔丁酯
类似于实例1g)中所述的程序,将(4aR,8aS)-6-[4-[(R或S)-[3-(2-氨基乙氧基)苯基]-苯基-甲基]哌啶-1-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮(实例7)用3-[2-(叔丁氧羰基氨基)乙氧基]丙酸(CAS RN 1260092-44-1)缩合以得到标题化合物,其为无色油状物。LC-HRMS(ESI):708.3957([M+H]+)。
实例16
N-[2-[3-[(R或S)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-(2-氨基乙氧基)丙酰胺
类似于实例1h)中所述的程序,将N-[2-[3-[2-[3-[(R或S)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基氨基]-3-氧代-丙氧基]乙基]氨基甲酸叔丁酯(实例15)用TFA脱保护以得到标题化合物,其为淡黄色油状物。LC-HRMS(ESI):608.3442([M+H]+)。
实例17
N-[2-[3-[(S或R)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-[(4-硝基-2,1,3-苯并噁二唑-7-基)氨基]乙氧基]丙酰胺
步骤a)N-[2-[3-[(S或R)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-(2-氨基乙氧基)丙酰胺
类似于实例1h)中所述的程序,将N-[2-[3-[2-[3-[(S或R)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基氨基]-3-氧代-丙氧基]乙基]氨基甲酸叔丁酯(实例14)用TFA脱保护以得到标题化合物,其为淡黄色油状物。LC-HRMS(ESI):608.3441([M+H]+)。
步骤b)N-[2-[3-[(S或R)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-[(4-硝基-2,1,3-苯并噁二唑-7-基)氨基]乙氧基]丙酰胺
类似于实例1i)中所述的程序,使N-[2-[3-[(R或S)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-(2-氨基乙氧基)丙酰胺与4-氯-7-硝基苯-2-氧杂-1,3-二唑反应以得到标题化合物,其为黄色固体。LC-HRMS(ESI):771.3464([M+H]+)。
实例18
N-[2-[3-[(R或S)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-[(4-硝基-2,1,3-苯并噁二唑-7-基)氨基]乙氧基]丙酰胺
类似于实例1i)中所述的程序,使N-[2-[3-[(R或S)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-(2-氨基乙氧基)丙酰胺(实例16)与4-氯-7-硝基苯-2-氧杂-1,3-二唑反应以得到标题化合物,其为黄色固体。LC-HRMS(ESI):771.3464([M+H]+)。
实例19
N-[2-[2-[2-[3-[2-[3-[(S或R)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基氨基]-3-氧代-丙氧基]乙氧基]乙氧基]乙基]氨基甲酸叔丁酯
类似于实例1g)中所述的程序,将(4aR,8aS)-6-[4-[(S或R)-[3-(2-氨基乙氧基)苯基]-苯基-甲基]哌啶-1-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮(实例7)用3-[2-[2-[2-(叔丁氧羰基氨基)乙氧基]乙氧基]乙氧基]丙酸(CAS RN 1347750-75-7)缩合以得到标题化合物,其为棕色油状物。LC-HRMS(ESI):796.4466([M+H]+)。
实例20
N-[2-[3-[(S或R)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-[2-(2-氨基乙氧基)乙氧基]乙氧基]丙酰胺
类似于实例1h)中所述的程序,将N-[2-[2-[2-[3-[2-[3-[(S或R)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基氨基]-3-氧代-丙氧基]乙氧基]乙氧基]乙基]氨基甲酸叔丁酯(实例19)用TFA脱保护以得到标题化合物,其为黄色油状物。LC-HRMS(ESI):696.3961([M+H]+)。
实例21
N-[2-[3-[2-[3-[(S或R)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基氨基]-3-氧代-丙氧基]乙基]-3-[2,2-二氟-12-(1H-吡咯-2-基)-3-氮杂-1-氮鎓-2-甲硼烷负离子杂三环[7.3.0.03,7]十二碳-1(12),4,6,8,10-五烯-4-基]丙酰胺
在室温向3-(2-氨基乙氧基)-N-(2-(3-((S)-(1-((4aR,8aS)-3-氧代八氢-2H-吡啶并[4,3-b][1,4]噁嗪-6-羰基)哌啶-4-基)(苯基)甲基)苯氧基)乙基)丙酰胺(实例17a,3.4mg,5.6μmol)在DMF(0.5mL)中的搅拌溶液中添加7-(3-((2,5-二氧代吡咯烷-1-基)氧基)-3-氧代丙基)-5,5-二氟-3-(1H-吡咯-2-基)-5H-514-二吡咯并[1,2-c:2′,1′-f][1,3,2]二氮杂硼烷-4-鎓(2mg,4.7μmol;CAS RN 201998-61-0),随后添加DIPEA(18mg,2.4μL,14.1μmol)。14小时后添加DIPEA(3.0mg,4.1μL,23.5μmol)并混合物在室温再搅拌24小时。添加乙腈(0.1mL)并将粗反应混合物通过制备型HPLC纯化以得到标题化合物,其为紫色泡沫。LC-HRMS(ESI):919.452([M+H]+)。
实例22
N-[2-[3-[(S或R)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-[2-[2-[(4-硝基-2,1,3-苯并噁二唑-7-基)氨基]乙氧基]乙氧基]乙氧基]丙酰胺
类似于实例1i)中所述的程序,使N-[2-[3-[(S或R)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-[2-(2-氨基乙氧基)乙氧基]乙氧基]丙酰胺(实例20)与4-氯-7-硝基苯-2-氧杂-1,3-二唑反应以得到标题化合物,其为黄色泡沫。LC-HRMS(ESI):859.3996([M+H]+)
实例23
(2-(3-((1-((4aR,8aS)-3-氧代八氢-2H-吡啶并[4,3-b][1,4]噁嗪-6-羰基)哌啶-4-亚基)(苯基)甲基)苯氧基)乙基)氨基甲酸叔丁酯
步骤a)(2-(3-(苯基(哌啶-4-亚基)甲基)苯氧基)乙基)氨基甲酸叔丁酯
将Pd/C 10%(10%,10mg)添加至4-((3-(2-((叔丁氧羰基)氨基)乙氧基)苯基)(苯基)亚甲基)哌啶-1-甲酸苄酯(110mg,0.2mmol)的乙醇(10mL)溶液。将反应容器用氢气吹扫。将混合物在室温在1atm氢气压力下搅拌5小时。通过硅藻土短塞滤出催化剂并用乙醇洗涤。将滤液在真空中浓缩以得到标题化合物(81mg,定量),其为黄色油状物。粗品的NMR显示了所需的产物。
步骤b)(2-(3-((1-(3-氧代八氢-2H-吡啶并[4,3-b][1,4]噁嗪-6-羰基)哌啶-4-亚基)(苯基)甲基)苯氧基)乙基)氨基甲酸叔丁酯
将(+)-顺式-4a,5,6,7,8,8a-六氢-4H-吡啶并[4,3-b][1,4]噁嗪-3-酮(呈与手性助剂的混合物)(MW=744g/mol,201mg,0.27mmol)和碳酸氢钠(92mg,1.1mmol)在DCM(4mL)中的混合物冷却至0℃。添加三光气(57mg,191μmol)并将混合物在环境温度搅拌14小时并再次冷却至0℃。添加(2-(3-(苯基(哌啶-4-亚基)甲基)苯氧基)乙基)氨基甲酸叔丁酯(115mg,0.27mmol)和DIPEA(142mg,191μL,1.1mmol)。将悬浮液在环境温度搅拌2小时。添加EtOAc和H2O水。分离各层并将有机层经Na2SO4干燥。在减压下除去溶剂并将粗品提供柱色谱法(SiO2,在环己烷中的30%至100%的EtOAc,然后是在DCM中的0%至10%的MeOH)纯化以得到标题化合物(50mg,32%),其为白色油状物。LC-HRMS(ESI):m/z=591.3172([M+H]+)。
实例24
(4aR,8aS)-6-(4-((3-(2-((7-硝基苯并[c][1,2,5]噁二唑-4-基)氨基)乙氧基)苯基)(苯基)亚甲基)哌啶-1-羰基)六氢-2H-吡啶并[4,3-b][1,4]噁嗪-3(4H)-酮
步骤a)(4aR,8aS)-6-(4-((3-(2-氨基乙氧基)苯基)(苯基)亚甲基)哌啶-1-羰基)六氢-2H-吡啶并[4,3-b][1,4]噁嗪-3(4H)-酮
类似于实例1h)中所述的程序,将(2-(3-((1-(3-氧代八氢-2H-吡啶并[4,3-b][1,4]噁嗪-6-羰基)哌啶-4-亚基)(苯基)甲基)苯氧基)乙基)氨基甲酸叔丁酯用TFA脱保护以得到标题化合物,其为灰白色固体。LCMS(ESI):491.1([M+H]+)。
步骤b)3-(2-(2-(2-((7-硝基苯并[c][1,2,5]噁二唑-4-基)氨基)乙氧基)乙氧基)乙氧基)-N-(2-(3-((1-((4aR,8aS)-3-氧代八氢-2H-吡啶并[4,3-b][1,4]噁嗪-6-羰基)哌啶-4-基)(苯基)甲基)苯氧基)乙基)丙酰胺
类似于实例1i)中所述的程序,使3-(2-氨基乙氧基)-N-(2-(3-((1-((4aR,8aS)-3-氧代八氢-2H-吡啶并[4,3-b][1,4]噁嗪-6-羰基)哌啶-4-基)(苯基)甲基)苯氧基)乙基)丙酰胺与4-氯-7-硝基苯-2-氧杂-1,3-二唑反应以得到标题化合物,其为橙色固体。LC-HRMS(ESI):654.2675([M+H]+)。
实例25
(2-(4-((1-((4aR,8aS)-3-氧代八氢-2H-吡啶并[4,3-b][1,4]噁嗪-6-羰基)哌啶-4-亚基)(苯基)甲基)苯氧基)乙基)氨基甲酸叔丁酯
步骤a)4-((4-(2-((叔丁氧羰基)氨基)乙氧基)苯基)(苯基)亚甲基)哌啶-1-甲酸苄酯
将(Z)-4-(苯基(2-甲苯磺酰基亚肼基)甲基)哌啶-1-甲酸苄酯(200mg,0.4mmol)、四(三苯基膦)钯(0)(46mg,40μmol)、叔丁醇锂(48mg,0.6mmol)和N-Boc-2-(4-溴苯氧基)乙胺(200mg,0.6mmol)在1,4-二噁烷(8mL)中的混合物在80℃搅拌14小时。添加EtOAc和H2O水。分离各层并将有机层经Na2SO4干燥。在减压下除去溶剂,并将粗品通过快速色谱法(SiO2,15g柱,环己烷EtOAc 0-30%)纯化以得到标题化合物(52mg,25%),其为淡黄色泡沫。LCMS(ESI):565.1([M+Na]+)。
步骤b)(4aR,8aS)-6-(4-((4-(2-氨基乙氧基)苯基)(苯基)亚甲基)哌啶-1-羰基)六氢-2H-吡啶并[4,3-b][1,4]噁嗪-3(4H)-酮
类似于实例23a)中所述的程序,将4-((4-(2-((叔丁氧羰基)氨基)乙氧基)苯基)(苯基)亚甲基)哌啶-1-甲酸苄酯用Pd/C和氢脱保护以得到标题化合物,其为棕色油状物。LCMS(ESI):409.1([M+H]+)。
步骤c、)(2-(4-((1-((4aR,8aS)-3-氧代八氢-2H-吡啶并[4,3-b][1,4]噁嗪-6-羰基)哌啶-4-亚基)(苯基)甲基)苯氧基)乙基)氨基甲酸叔丁酯
类似于实例23b)中所述的程序,(4aR,8aS)-6-(4-((4-(2-氨基乙氧基)苯基)(苯基)亚甲基)哌啶-1-羰基)六氢-2H-吡啶并[4,3-b][1,4]噁嗪-3(4H)-酮与(+)-顺式-4a,5,6,7,8,8a-六氢-4H-吡啶并[4,3-b][1,4]噁嗪-3-酮利用三光气形成脲以得到标题化合物,其为透明油状物。LC-HRMS(ESI):591.3168([M+H]+)。
可以类似于实例1至25制备以下实例。
实例26
N-[3-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶亚基]-苯基-甲基]苯基]丙-2-炔基]氨基甲酸叔丁酯
实例27
N-[3-[4-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶亚基]-苯基-甲基]苯基]丙-2-炔基]氨基甲酸叔丁酯
实例28
N-[(E)-3-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶亚基]-苯基-甲基]苯基]烯丙基]氨基甲酸叔丁酯
实例29
N-[(E)-3-[4-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶亚基]-苯基-甲基]苯基]烯丙基]氨基甲酸叔丁酯
实例30
N-[2-[3-[(SR)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]氨基甲酸叔丁酯
实例31
N-[2-[4-[(SR)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]氨基甲酸叔丁酯
实例32
N-[3-[3-[(SR)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯基]丙基]氨基甲酸叔丁酯
实例33
N-[3-[4-[(SR)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯基]丙基]氨基甲酸叔丁酯
实例34
N-[3-[4-[(SR)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯基]丙-2-炔基]氨基甲酸叔丁酯
实例35
N-[3-[3-[(SR)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯基]丙-2-炔基]氨基甲酸叔丁酯
实例36
N-[(E)-3-[4-[(SR)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯基]烯丙基]氨基甲酸叔丁酯
实例37
N-[(E)-3-[3-[(SR)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯基]烯丙基]氨基甲酸叔丁酯
实例38
N-[2-[3-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶亚基]-苯基-甲基]苯氧基]乙基氨基]-3-氧代-丙氧基]乙基]氨基甲酸叔丁酯
实例39
N-[3-[4-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶亚基]-苯基-甲基]苯基]丙基]氨基甲酸叔丁酯
实例40
N-[3-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶亚基]-苯基-甲基]苯基]丙基]氨基甲酸叔丁酯
Claims (25)
5.根据权利要求1至4中任一项所述的式(I)化合物或其药用盐,其中R2为氢。
6.根据权利要求1至5中任一项所述的式(I)化合物或其药用盐,其中R3为氢。
7.根据权利要求1至6中任一项所述的式(I)化合物或其药用盐,其中R4为氢。
10.根据权利要求1至9中任一项所述的式(I)化合物或其药用盐,其中所述式(I)化合物选自:
N-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-[(4-硝基-2,1,3-苯并噁二唑-7-基)氨基]乙氧基]丙酰胺;
N-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-[(4-硝基-2,1,3-苯并噁二唑-7-基)氨基]乙氧基]丙酰胺;
N-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-[2-[(4-硝基-2,1,3-苯并噁二唑-7-基)氨基]乙氧基]乙氧基]丙酰胺;
N-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-[2-[(4-硝基-2,1,3-苯并噁二唑-7-基)氨基]乙氧基]乙氧基]丙酰胺;
N-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-[2-[(4-硝基-2,1,3-苯并噁二唑-7-基)氨基]乙氧基]乙氧基]丙酰胺;
N-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-[(4-硝基-2,1,3-苯并噁二唑-7-基)氨基]乙氧基]丙酰胺;
N-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-[2-[2-[(4-硝基-2,1,3-苯并噁二唑-7-基)氨基]乙氧基]乙氧基]乙氧基]丙酰胺;
N-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-[2-[2-[(4-硝基-2,1,3-苯并噁二唑-7-基)氨基]乙氧基]乙氧基]乙氧基]丙酰胺;
N-[2-[3-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基氨基]-3-氧代-丙氧基]乙基]-3-[2,2-二氟-12-(1H-吡咯-2-基)-3-氮杂-1-氮鎓-2-甲硼烷负离子杂三环[7.3.0.03,7]十二碳-1(12),4,6,8,10-五烯-4-基]丙酰胺;和
(4aR,8aS)-6-(4-((3-(2-((7-硝基苯并[c][1,2,5]噁二唑-4-基)氨基)乙氧基)苯基)(苯基)亚甲基)哌啶-1-羰基)六氢-2H-吡啶并[4,3-b][1,4]噁嗪-3(4H)-酮。
11.根据权利要求10所述的式(I)化合物或其药用盐,其中所述式(I)化合物选自:
N-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-[2-[(4-硝基-2,1,3-苯并噁二唑-7-基)氨基]乙氧基]乙氧基]丙酰胺;
N-[2-[3-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基氨基]-3-氧代-丙氧基]乙基]-3-[2,2-二氟-12-(1H-吡咯-2-基)-3-氮杂-1-氮鎓-2-甲硼烷负离子杂三环[7.3.0.03,7]十二碳-1(12),4,6,8,10-五烯-4-基]丙酰胺;和
(4aR,8aS)-6-(4-((3-(2-((7-硝基苯并[c][1,2,5]噁二唑-4-基)氨基)乙氧基)苯基)(苯基)亚甲基)哌啶-1-羰基)六氢-2H-吡啶并[4,3-b][1,4]噁嗪-3(4H)-酮。
12.一种化合物,其选自:
N-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-(2-氨基乙氧基)丙酰胺;
N-[2-[2-[3-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基氨基]-3-氧代-丙氧基]乙氧基]乙基]氨基甲酸叔丁酯;
N-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]氨基甲酸叔丁酯;
N-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-[2-(2-氨基乙氧基)乙氧基]乙氧基]丙酰胺;
N-[2-[2-[2-[3-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基氨基]-3-氧代-丙氧基]乙氧基]乙氧基]乙基]氨基甲酸叔丁酯;
N-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]-3-[2-(2-氨基乙氧基)乙氧基]丙酰胺;
(2-(3-((1-((4aR,8aS)-3-氧代八氢-2H-吡啶并[4,3-b][1,4]噁嗪-6-羰基)哌啶-4-亚基)(苯基)甲基)苯氧基)乙基)氨基甲酸叔丁酯;
(2-(4-((1-((4aR,8aS)-3-氧代八氢-2H-吡啶并[4,3-b][1,4]噁嗪-6-羰基)哌啶-4-亚基)(苯基)甲基)苯氧基)乙基)氨基甲酸叔丁酯;
N-[3-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶亚基]-苯基-甲基]苯基]丙-2-炔基]氨基甲酸叔丁酯;
N-[3-[4-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶亚基]-苯基-甲基]苯基]丙-2-炔基]氨基甲酸叔丁酯;
N-[(E)-3-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶亚基]-苯基-甲基]苯基]烯丙基]氨基甲酸叔丁酯;
N-[(E)-3-[4-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶亚基]-苯基-甲基]苯基]烯丙基]氨基甲酸叔丁酯;
N-[2-[3-[(SR)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]氨基甲酸叔丁酯;
N-[2-[4-[(SR)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯氧基]乙基]氨基甲酸叔丁酯;
N-[3-[3-[(SR)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯基]丙基]氨基甲酸叔丁酯;
N-[3-[4-[(SR)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯基]丙基]氨基甲酸叔丁酯;
N-[3-[4-[(SR)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯基]丙-2-炔基]氨基甲酸叔丁酯;
N-[3-[3-[(SR)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯基]丙-2-炔基]氨基甲酸叔丁酯;
N-[(E)-3-[4-[(SR)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯基]烯丙基]氨基甲酸叔丁酯;
N-[(E)-3-[3-[(SR)-[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶基]-苯基-甲基]苯基]烯丙基]氨基甲酸叔丁酯;
N-[2-[3-[2-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶亚基]-苯基-甲基]苯氧基]乙基氨基]-3-氧代-丙氧基]乙基]氨基甲酸叔丁酯;
N-[3-[4-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶亚基]-苯基-甲基]苯基]丙基]氨基甲酸叔丁酯;
N-[3-[3-[[1-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-4-哌啶亚基]-苯基-甲基]苯基]丙基]氨基甲酸叔丁酯。
13.根据权利要求12所述的化合物用于制备根据权利要求1至11中任一项所述的化合物的用途。
14.一种制备根据权利要求1至11中任一项所述的式(I)化合物的方法,所述方法包括:
(a)在碱和脲形成剂存在下,使第一胺4a,5,6,7,8,8a-六氢-4H-吡啶并[4,3-b][1,4]噁嗪-3-酮(2),
与第二胺1,其中R2、R3、R4和L如权利要求1至11中任一项所定义,并且PG为合适的保护基团,
进行反应以形成式3化合物,其中R2、R3、R4和L如权利要求1至11中任一项所定义,并且PG为合适的保护基团
(b)在碱和脲形成剂存在下,使第一胺4a,5,6,7,8,8a-六氢-4H-吡啶并[4,3-b][1,4]噁嗪-3-酮(2),
与第二胺1a,其中R1、R2、R3、R4和L如权利要求1至11中任一项所定义,
进行反应以形成所述式(I)化合物。
15.根据权利要求1至11中任一项所述的式(I)化合物,其根据权利要求14所述的方法制备。
16.根据权利要求1至11中任一项所述的式(I)化合物,其用于单酰基甘油脂肪酶(MAGL)占用研究。
17.根据权利要求1至11中任一项所述的式(I)化合物,其用于哺乳动物中单酰基甘油脂肪酶(MAGL)的诊断成像。
18.根据权利要求1至11中任一项所述的式(I)化合物,其用于产生单酰基甘油脂肪酶(MAGL)平衡和动力学结合数据。
19.根据权利要求1至11中任一项所述的式(I)化合物在单酰基甘油脂肪酶(MAGL)占用研究中的用途。
20.根据权利要求1至11中任一项所述的式(I)化合物在哺乳动物中单酰基甘油脂肪酶(MAGL)的诊断成像中的用途。
21.根据权利要求1至11中任一项所述的式(I)化合物用于产生单酰基甘油脂肪酶(MAGL)平衡和动力学结合数据的用途。
22.一种研究单酰基甘油脂肪酶(MAGL)占用的方法,所述方法包括使MAGL与根据权利要求1至11中任一项所述的式(I)化合物接触。
23.一种在哺乳动物中单酰基甘油脂肪酶(MAGL)的诊断成像的方法,所述方法包括使MAGL与根据权利要求1至11中任一项所述的式(I)化合物接触。
24.一种产生单酰基甘油脂肪酶(MAGL)平衡和动力学结合数据的方法,所述方法包括使MAGL与根据权利要求1至11中任一项所述的式(I)化合物接触。
25.如前所述的本发明。
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WO2020035424A1 (en) | 2018-08-13 | 2020-02-20 | F. Hoffmann-La Roche Ag | New heterocyclic compounds as monoacylglycerol lipase inhibitors |
KR20220062515A (ko) | 2019-09-12 | 2022-05-17 | 에프. 호프만-라 로슈 아게 | Magl 억제제로서 4,4a,5,7,8,8a-헥사피리도[4,3-b][1,4]옥사진-3-온 화합물 |
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WO2023247666A1 (en) * | 2022-06-24 | 2023-12-28 | F. Hoffmann-La Roche Ag | Fluorescent probes for magl |
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