WO2019080723A1 - Polysubstituted pyridone derivative, preparation method therefor and medical use thereof - Google Patents
Polysubstituted pyridone derivative, preparation method therefor and medical use thereofInfo
- Publication number
- WO2019080723A1 WO2019080723A1 PCT/CN2018/109969 CN2018109969W WO2019080723A1 WO 2019080723 A1 WO2019080723 A1 WO 2019080723A1 CN 2018109969 W CN2018109969 W CN 2018109969W WO 2019080723 A1 WO2019080723 A1 WO 2019080723A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- cycloalkyl
- alkyl
- cancer
- aryl
- Prior art date
Links
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 title claims abstract description 10
- 238000002360 preparation method Methods 0.000 title abstract description 302
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 41
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 25
- 238000011282 treatment Methods 0.000 claims abstract description 22
- 239000003112 inhibitor Substances 0.000 claims abstract description 8
- -1 amino, nitro, cyano, hydroxy, decyl Chemical group 0.000 claims description 229
- 125000000623 heterocyclic group Chemical group 0.000 claims description 210
- 125000000217 alkyl group Chemical group 0.000 claims description 174
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 174
- 239000000203 mixture Substances 0.000 claims description 174
- 125000003118 aryl group Chemical group 0.000 claims description 168
- 125000001072 heteroaryl group Chemical group 0.000 claims description 164
- 150000001875 compounds Chemical class 0.000 claims description 156
- 229910052736 halogen Inorganic materials 0.000 claims description 97
- 150000002367 halogens Chemical group 0.000 claims description 96
- 125000003545 alkoxy group Chemical group 0.000 claims description 85
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 79
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 75
- 125000004043 oxo group Chemical group O=* 0.000 claims description 70
- 150000002148 esters Chemical group 0.000 claims description 64
- 125000000304 alkynyl group Chemical group 0.000 claims description 61
- 150000003839 salts Chemical class 0.000 claims description 61
- 125000003342 alkenyl group Chemical group 0.000 claims description 54
- 229910052757 nitrogen Inorganic materials 0.000 claims description 53
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 48
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 37
- 229910052739 hydrogen Inorganic materials 0.000 claims description 34
- 239000001257 hydrogen Substances 0.000 claims description 34
- 229910020008 S(O) Inorganic materials 0.000 claims description 29
- 201000011510 cancer Diseases 0.000 claims description 24
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 24
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 22
- 125000004185 ester group Chemical group 0.000 claims description 22
- 201000005202 lung cancer Diseases 0.000 claims description 22
- 208000020816 lung neoplasm Diseases 0.000 claims description 22
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 22
- 201000005787 hematologic cancer Diseases 0.000 claims description 21
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 claims description 21
- 206010006187 Breast cancer Diseases 0.000 claims description 20
- 208000026310 Breast neoplasm Diseases 0.000 claims description 20
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 20
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 20
- 206010017758 gastric cancer Diseases 0.000 claims description 20
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 20
- 201000002528 pancreatic cancer Diseases 0.000 claims description 20
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 20
- 201000011549 stomach cancer Diseases 0.000 claims description 20
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 19
- 239000003814 drug Substances 0.000 claims description 17
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 17
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 16
- 239000004480 active ingredient Substances 0.000 claims description 15
- 125000005842 heteroatom Chemical group 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 12
- 229910052721 tungsten Inorganic materials 0.000 claims description 11
- 229910052720 vanadium Inorganic materials 0.000 claims description 11
- 206010005003 Bladder cancer Diseases 0.000 claims description 10
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 10
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 10
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 10
- 208000005016 Intestinal Neoplasms Diseases 0.000 claims description 10
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 10
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 claims description 10
- 206010061306 Nasopharyngeal cancer Diseases 0.000 claims description 10
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 10
- 206010033128 Ovarian cancer Diseases 0.000 claims description 10
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 10
- 206010060862 Prostate cancer Diseases 0.000 claims description 10
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 10
- 208000015634 Rectal Neoplasms Diseases 0.000 claims description 10
- 206010038389 Renal cancer Diseases 0.000 claims description 10
- 206010039491 Sarcoma Diseases 0.000 claims description 10
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 10
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 10
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 10
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 10
- 201000010881 cervical cancer Diseases 0.000 claims description 10
- 229940079593 drug Drugs 0.000 claims description 10
- 201000004101 esophageal cancer Diseases 0.000 claims description 10
- 201000010536 head and neck cancer Diseases 0.000 claims description 10
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 10
- 201000002313 intestinal cancer Diseases 0.000 claims description 10
- 201000010982 kidney cancer Diseases 0.000 claims description 10
- 201000007270 liver cancer Diseases 0.000 claims description 10
- 208000014018 liver neoplasm Diseases 0.000 claims description 10
- 206010038038 rectal cancer Diseases 0.000 claims description 10
- 201000001275 rectum cancer Diseases 0.000 claims description 10
- 201000000849 skin cancer Diseases 0.000 claims description 10
- 201000002510 thyroid cancer Diseases 0.000 claims description 10
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 10
- 238000007112 amidation reaction Methods 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 150000001412 amines Chemical class 0.000 claims description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 239000001301 oxygen Substances 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 6
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 5
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 5
- 230000009471 action Effects 0.000 claims description 5
- 125000004429 atom Chemical group 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 5
- 238000010931 ester hydrolysis Methods 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 238000005809 transesterification reaction Methods 0.000 claims description 3
- XOJVVFBFDXDTEG-UHFFFAOYSA-N pristane Chemical compound CC(C)CCCC(C)CCCC(C)CCCC(C)C XOJVVFBFDXDTEG-UHFFFAOYSA-N 0.000 claims 2
- 125000005843 halogen group Chemical group 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 355
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 219
- 239000007787 solid Substances 0.000 description 217
- 238000006243 chemical reaction Methods 0.000 description 180
- 235000019439 ethyl acetate Nutrition 0.000 description 169
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 163
- 210000004027 cell Anatomy 0.000 description 95
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 92
- 238000005481 NMR spectroscopy Methods 0.000 description 92
- 238000000034 method Methods 0.000 description 80
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 68
- 239000000543 intermediate Substances 0.000 description 62
- 239000011541 reaction mixture Substances 0.000 description 57
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 50
- 238000010898 silica gel chromatography Methods 0.000 description 49
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 47
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 47
- 239000012267 brine Substances 0.000 description 46
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 42
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 40
- 239000000243 solution Substances 0.000 description 40
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 38
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 38
- 230000002829 reductive effect Effects 0.000 description 36
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 35
- 239000012044 organic layer Substances 0.000 description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- 238000012360 testing method Methods 0.000 description 29
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 27
- 239000003480 eluent Substances 0.000 description 27
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 26
- 235000019270 ammonium chloride Nutrition 0.000 description 25
- 239000000706 filtrate Substances 0.000 description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 23
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 21
- 239000003921 oil Substances 0.000 description 20
- 235000019198 oils Nutrition 0.000 description 20
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 20
- 229910000027 potassium carbonate Inorganic materials 0.000 description 20
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 19
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 19
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 19
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 19
- 230000005764 inhibitory process Effects 0.000 description 18
- SIDZXXQYQLBOHZ-UHFFFAOYSA-N 4-(6,7-dimethoxyquinolin-4-yl)oxy-3-fluoroaniline Chemical compound C=12C=C(OC)C(OC)=CC2=NC=CC=1OC1=CC=C(N)C=C1F SIDZXXQYQLBOHZ-UHFFFAOYSA-N 0.000 description 17
- RNIVGJYWHHSMKA-UHFFFAOYSA-N diethyl 4-oxopyran-2,5-dicarboxylate Chemical compound CCOC(=O)C1=CC(=O)C(C(=O)OCC)=CO1 RNIVGJYWHHSMKA-UHFFFAOYSA-N 0.000 description 17
- 239000002609 medium Substances 0.000 description 17
- 239000012074 organic phase Substances 0.000 description 17
- 238000003756 stirring Methods 0.000 description 17
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 17
- 230000000694 effects Effects 0.000 description 16
- MKJMTKSTMONLDG-UHFFFAOYSA-N 4H-pyrido[1,2-a]pyrazine-8-carboxamide Chemical compound C1=C2N(CC=N1)C=CC(=C2)C(=O)N MKJMTKSTMONLDG-UHFFFAOYSA-N 0.000 description 15
- BFICLMNNLSXLES-UHFFFAOYSA-N 6-ethoxycarbonyl-5-(4-fluorophenyl)-1-methyl-4-oxopyridine-3-carboxylic acid Chemical compound C(C)OC(=O)C1=C(C(C(=CN1C)C(=O)O)=O)C1=CC=C(C=C1)F BFICLMNNLSXLES-UHFFFAOYSA-N 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 15
- 239000007821 HATU Substances 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 14
- 238000000746 purification Methods 0.000 description 14
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 13
- 238000004587 chromatography analysis Methods 0.000 description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 13
- 125000006413 ring segment Chemical group 0.000 description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000012091 fetal bovine serum Substances 0.000 description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- ORPHLVJBJOCHBR-UHFFFAOYSA-N 403-19-0 Chemical compound OC1=CC=C([N+]([O-])=O)C=C1F ORPHLVJBJOCHBR-UHFFFAOYSA-N 0.000 description 11
- 125000002619 bicyclic group Chemical group 0.000 description 11
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- 238000004113 cell culture Methods 0.000 description 11
- 239000003153 chemical reaction reagent Substances 0.000 description 11
- 230000002401 inhibitory effect Effects 0.000 description 11
- QOLGFNPPWLWYKB-UHFFFAOYSA-N 10-(4-fluorophenyl)-8,11-dioxo-4-oxa-1,7-diazatricyclo[7.4.0.03,7]trideca-9,12-diene-12-carboxylic acid Chemical compound C1COC2N1C(=O)C3=C(C(=O)C(=CN3C2)C(=O)O)C4=CC=C(C=C4)F QOLGFNPPWLWYKB-UHFFFAOYSA-N 0.000 description 10
- RUDFGVCQAZXNAJ-UHFFFAOYSA-N 3-(4-amino-2-fluorophenyl)-5-(3,4-dimethoxyphenyl)pyridin-2-amine Chemical compound C1=C(OC)C(OC)=CC=C1C1=CN=C(N)C(C=2C(=CC(N)=CC=2)F)=C1 RUDFGVCQAZXNAJ-UHFFFAOYSA-N 0.000 description 10
- LBUNNMJLXWQQBY-UHFFFAOYSA-N 4-fluorophenylboronic acid Chemical compound OB(O)C1=CC=C(F)C=C1 LBUNNMJLXWQQBY-UHFFFAOYSA-N 0.000 description 10
- 229910052799 carbon Inorganic materials 0.000 description 10
- 125000003367 polycyclic group Chemical group 0.000 description 10
- 238000002953 preparative HPLC Methods 0.000 description 10
- IQKDEFQVYLYAHD-UHFFFAOYSA-N 5-oxo-4-oxa-1,7-diazatricyclo[7.4.0.03,7]trideca-9,12-diene-12-carboxamide Chemical compound C1C2OC(=O)CN2CC2=CCC(C(=O)N)=CN21 IQKDEFQVYLYAHD-UHFFFAOYSA-N 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
- 150000001408 amides Chemical class 0.000 description 9
- 239000006285 cell suspension Substances 0.000 description 9
- 230000003833 cell viability Effects 0.000 description 9
- 238000012054 celltiter-glo Methods 0.000 description 9
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 9
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 9
- DNUTZBZXLPWRJG-UHFFFAOYSA-N 1-Piperidine carboxylic acid Chemical compound OC(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-N 0.000 description 8
- SBAUKJHVFYEIPL-UHFFFAOYSA-N 11-(6-methylpyridin-3-yl)-9,12-dioxo-4-oxa-1,8-diazatricyclo[8.4.0.03,8]tetradeca-10,13-diene-13-carboxylic acid Chemical compound CC1=CC=C(C=N1)C=1C(C(=CN2CC3OCCCN3C(C21)=O)C(=O)O)=O SBAUKJHVFYEIPL-UHFFFAOYSA-N 0.000 description 8
- NKTWEFPOIPLNLR-UHFFFAOYSA-N 3-(4-amino-2-fluorophenyl)-5-(1-ethylpyrazol-4-yl)pyridin-2-amine Chemical compound NC1=CC(=C(C=C1)C=1C(=NC=C(C=1)C=1C=NN(C=1)CC)N)F NKTWEFPOIPLNLR-UHFFFAOYSA-N 0.000 description 8
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 8
- XOYMXSWONJKENU-UHFFFAOYSA-N 6-(6,7-dimethoxyquinolin-4-yl)oxypyridazin-3-amine Chemical compound COc1cc2nccc(Oc3ccc(N)nn3)c2cc1OC XOYMXSWONJKENU-UHFFFAOYSA-N 0.000 description 8
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 8
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 8
- WQZLUEWLCVCNGV-UHFFFAOYSA-N N-[4-[2-amino-5-(1-piperidin-4-ylpyrazol-4-yl)pyridin-3-yl]-3-fluorophenyl]-6-(azetidine-1-carbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxopyridine-3-carboxamide Chemical compound NC1=NC=C(C=C1C1=C(C=C(C=C1)NC(=O)C1=CN(C(=C(C1=O)C1=CC=C(C=C1)F)C(=O)N1CCC1)C)F)C=1C=NN(C1)C1CCNCC1 WQZLUEWLCVCNGV-UHFFFAOYSA-N 0.000 description 8
- 125000003282 alkyl amino group Chemical group 0.000 description 8
- 150000004982 aromatic amines Chemical class 0.000 description 8
- 230000008878 coupling Effects 0.000 description 8
- 238000010168 coupling process Methods 0.000 description 8
- 238000005859 coupling reaction Methods 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 125000005366 cycloalkylthio group Chemical group 0.000 description 8
- SNRCKKQHDUIRIY-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron(2+) Chemical compound [Fe+2].ClCCl.Cl[Pd]Cl.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 SNRCKKQHDUIRIY-UHFFFAOYSA-L 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 8
- 238000004949 mass spectrometry Methods 0.000 description 8
- 102000005962 receptors Human genes 0.000 description 8
- 108020003175 receptors Proteins 0.000 description 8
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 7
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 7
- VZJWVVVRPJDHSZ-UHFFFAOYSA-N 3-fluoro-4-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]oxyaniline Chemical compound C=12C=C(OC)C(OCCOC)=CC2=NC=NC=1OC1=CC=C(N)C=C1F VZJWVVVRPJDHSZ-UHFFFAOYSA-N 0.000 description 7
- IACVKAWALUBODZ-UHFFFAOYSA-N 4-[2-(4-bromo-2-methoxyphenoxy)ethoxymethyl]-2,2-dimethyl-1,3-dioxolane Chemical compound CC1(OCC(O1)COCCOC2=C(C=C(C=C2)Br)OC)C IACVKAWALUBODZ-UHFFFAOYSA-N 0.000 description 7
- FZRBMKFTDBVGRU-UHFFFAOYSA-N B(C1=CC(=CN=C1N)Br)(O)O Chemical compound B(C1=CC(=CN=C1N)Br)(O)O FZRBMKFTDBVGRU-UHFFFAOYSA-N 0.000 description 7
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- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
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- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
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- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/69—Two or more oxygen atoms
-
- 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
Definitions
- the present invention relates to a polysubstituted pyridone derivative, a process for the preparation thereof, a pharmaceutical composition containing the same, and its use as an Axl/c-MET inhibitor, particularly in the treatment of cancer.
- Receptor tyrosine kinases are multidomain transmembrane proteins that function as sensors for extracellular receptor ligands in cells. When the ligand binds to the receptor, the receptor is dimerized on the surface of the cell membrane and activates the kinase domain within the membrane, resulting in phosphorylation of tyrosine and further activation of a cascade of signaling pathways downstream. To date, nearly 60 receptor tyrosine kinases have been found in the human genome, which extensively regulate the cellular metabolic processes, including survival, growth, differentiation, proliferation, adhesion, and death.
- the TAM family of receptor tyrosine kinases has three members, Axl, Mer, and Tyro-3, which regulate a variety of cytological responses including cell survival, differentiation, migration, and adhesion. Studies have shown that the signaling of receptor TAM also controls vascular smooth muscle homeostasis, platelet function, microthrombus stability and erythrocyte formation. The receptor TAM also plays a key role in immunity and inflammation. It promotes phagocytosis of apoptotic cells and stimulates the differentiation of NK cells.
- Axl is a member of the TAM family of receptor tyrosine kinases. Among the three members, Axl and Tyro-3 have the most similar gene structure, while Axl and Mer have the most similar tyrosine kinase domain amino acid sequence.
- Axl is an important regulator of cell survival, proliferation, aggregation, migration and adhesion. Axl is widely expressed in cells and organs such as monocytes, macrophages, platelets, endothelial cells, cerebellum, heart, skeletal muscle, liver and kidney. In the study of many cancer cells, the Axl gene in hematopoietic cells, mesenchymal cells and endothelial cells is overexpressed or ectopically expressed. Overexpression of Axl is particularly prominent in all types of leukemia and most solid tumors. Moreover, Axl is more highly expressed in metastatic or malignant tumors than normal tissues or primary tumors, and its high expression is closely related to poor clinical treatment.
- Axl is involved in drug resistance caused by different mechanisms in a variety of tumor cells, and overexpression of Axl kinase has become an important marker of cancer drug resistance in cancer patients. Inhibition of Axl receptor tyrosine kinase can reduce the activation of pro-survival signals of tumor cells, block tumor invasion, and increase the sensitivity of targeted drug therapy and chemoradiotherapy. Therefore, Axl is an effective target for cancer treatment.
- tyrosine kinase inhibitors such as Cabozinidinib, Foretinib, Merestinib, Crizotinib, etc.
- Cabozinidinib Foretinib
- Merestinib Merestinib
- Crizotinib etc.
- Axl kinase inhibitor activity they are multi-target molecules, Not selective.
- BGB324 The only clinical candidate for Axl selectivity in the world is BGB324, which is undergoing multiple clinical phase II trials. Therefore, there is currently no new drug for Axl inhibitors for patients.
- c-MET is a member of the transmembrane tyrosine kinase receptor (RTKs) family with autonomous phosphorylation activity.
- the c-MET receptor contains a tyrosine residue that regulates the activity of the enzyme in the tyrosine kinase catalytic domain of the cell, forming a docking site for several signaling proteins, which in turn leads to a biological response.
- c-MET was first isolated from cell lines derived from human osteosarcoma, primarily on epithelial cells. During embryonic development and adulthood, many organ epithelial cells express c-MET receptors on the surface, including liver, pancreas, prostate, kidney, muscle, and bone marrow.
- HGF is the only ligand for c-MET.
- c-MET When c-MET binds to it, it triggers receptor dimerization, thereby activating tyrosine kinase in the c-MET cytoplasmic protein kinase domain, causing autophosphorylation of c-MET carboxy terminal tyrosine (Tyrl349, Tyrl356) Chemical.
- c-MET activates the recruitment of the adaptor proteins Gabl and Grb2, activates Shp2, Ras and ERK/MAPK, and multiple effector proteins in the cytoplasm are recruited to the phosphorylated carboxy terminus and rapidly phosphorylated, resulting in activation of multiple signaling pathways within the cell, such as PI3K/AKT, Ras-Rac/Rho, MAPK and STAT3 pathways promote various biological functions such as cell deformation, proliferation, anti-apoptosis, cell separation, exercise and invasion.
- the normal HGF/c-MET signaling pathway participates in various physiological processes in different cells and different stages of cell differentiation, such as controlling cell migration during embryonic development and repairing after tissue damage.
- abnormal c-MET disorders include overexpression, sustained activation of constituent kinases, gene amplification, by HGF paracrine and autocrine activation, c-MET mutations, and subsequent changes.
- Abnormal HGF/c-MET signaling pathway plays a very important role in tumorigenesis and can induce tumor growth, invasion, drug resistance and survival. Therefore, effective inhibition of HGF/c-MET signaling pathways in tumor cells will have a significant effect on a variety of cancers.
- the present inventors have developed new AxL/c-MET inhibitors. It can be used alone or in combination with other active drugs, providing a broad prospect for the treatment of cancer.
- the inventors have deliberately studied and designed a series of polysubstituted pyridone derivatives, and intensive studies have shown that such compounds can be used as effective Axl/c-MET inhibitors. It can be used alone or in combination with other active drugs for the treatment of cancer, in particular solid tumors or hematological tumors with high expression of Axl/c-MET.
- the present invention relates to a compound of the formula (I) or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable form thereof salt,
- W and V are each independently selected from CH, CF or N;
- R a is selected from -OR 1 , -SR 1 or -NR 1 R 2 ;
- R 1 and R 2 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl And a heterocyclic group, an aryl group and a heteroaryl group are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl Substituting one or more groups of a heterocyclic group, an aryl group, or a heteroaryl group;
- R a is -NR 1 R 2
- R 1 and R 2 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic ring, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano Substituting one or more groups of a group, a hydroxyl group, a thiol group, a carboxyl group, an ester group, an oxo group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group;
- R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic
- the base and heteroaryl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituting one or more groups of a heteroaryl group;
- R a is -NR 1 R 2
- R 1 and R 2 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic ring
- R 3 is bonded to the nitrogen-containing heterocyclic ring to further form a fused heterocyclic ring
- said nitrogen heterocycle is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, thiol, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, Substituting one or more groups of a heteroaryl group;
- R 4 is selected from an aryl group, a heteroaryl group or an alkynyl group, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, thiol, carboxyl, ester, Substituting one or more groups of oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;
- R 4 when R 4 is aryl or heteroaryl, R a is bonded to R 4 to form a heterocyclic ring fused to R 4 , which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, Substituting one or more groups of a hydroxyl group, a mercapto group, a carboxyl group, an ester group, an oxo group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;
- R 5 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or OR 6 , said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, The aryl and heteroaryl are optionally further substituted with one or more groups selected from the group Q;
- Q is selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;
- the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl group is optionally further selected from the group consisting of halogen, nitro, cyano, hydroxy, decyl, oxo, alkyl, cycloalkyl, Heterocyclyl, aryl, heteroaryl, -OR b , -O(CH 2 ) m OR b , -OC(O)R b , -C(O)OR b , -C(O)NR b R c , -NHC(O)R b , -S(O)R b , -S(O) 2 R b ,
- R 6 is selected from the group consisting of alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl; said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl Further selected from the group consisting of halogen, nitro, cyano, hydroxy, decyl, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR b , -O(CH 2 ) m OR b , -OC(O)R b , -C(O)OR b , -C(O)NR b R c , -NHC(O)R b , -S(O)R b , -S(O) 2 R b , -S(O)NR b R c , -NR b R c , -NR b R c , -NR b R
- R b and R c are each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl And the heteroaryl group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituting one or more groups of a heteroaryl group;
- R b and R c together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, decyl Substituting one or more groups of a carboxyl group, an ester group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;
- R 7 is selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl
- the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, thiol, carboxy, ester, and oxygen. Substituting one or more groups of a substituent, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;
- n is an integer from 1 to 6;
- n is an integer from 1 to 4.
- each H atom of the compound of formula (I) may optionally be independently replaced by a D atom.
- the compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer thereof, a diastereomer thereof, Or a mixture thereof, or a pharmaceutically acceptable salt thereof,
- R a is selected from -NR 1 R 2 ;
- R 1 and R 2 are as defined by the formula (I).
- the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof in another preferred embodiment of the invention, or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof,
- R 1 and R 2 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl And a heterocyclic group, an aryl group and a heteroaryl group are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl Substituting one or more groups of a heterocyclic group, an aryl group, or a heteroaryl group;
- R a is -NR 1 R 2
- R 1 and R 2 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic ring, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano Substituting one or more groups of a group, a hydroxyl group, a thiol group, a carboxyl group, an ester group, an oxo group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group;
- the nitrogen-containing heterocyclic ring is preferably a 4- to 7-membered nitrogen-containing heterocyclic ring, more preferably the following heterocyclic ring:
- R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic
- the base and heteroaryl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituting one or more groups of a heteroaryl group.
- the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof in another preferred embodiment of the invention, or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof,
- R a is selected from -NR 1 R 2 ;
- R 1 or R 2 is bonded to R 3 to form a nitrogen-containing heterocyclic ring fused to a pyridone ring, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, Substituting one or more groups of a carboxyl group, an ester group, an oxo group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;
- R 1 and R 2 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl And a heterocyclic group, an aryl group and a heteroaryl group are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl Substituting one or more groups of a heterocyclic group, an aryl group, or a heteroaryl group;
- R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic
- the base and heteroaryl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituting one or more groups of a heteroaryl group;
- the nitrogen-containing heterocyclic ring fused to the pyridone ring is preferably a 6- or 12-membered nitrogen-containing heterocyclic ring, more preferably the following nitrogen-containing heterocyclic ring:
- the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof in another preferred embodiment of the invention, or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof,
- R a is selected from -NR 1 R 2 ;
- R 1 and R 2 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic ring, and R 3 is bonded to the nitrogen-containing heterocyclic ring to further form a fused heterocyclic ring, which is optionally further selected from the group consisting of halogen, amino, Substituting one or more groups of nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;
- R 1 and R 2 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl And a heterocyclic group, an aryl group and a heteroaryl group are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl Substituting one or more groups of a heterocyclic group, an aryl group, or a heteroaryl group;
- R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic
- the base and heteroaryl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituting one or more groups of a heteroaryl group;
- the fused heterocyclic ring is preferably a 10-12 membered fused heterocyclic ring, more preferably:
- the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (II) or a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a form of the mixture, or a pharmaceutically acceptable salt thereof,
- Y is selected from CH or N;
- q is an integer from 1 to 4.
- W, V, R a , R 3 , R 4 , R 7 , Q, n are as defined in the general formula (I).
- the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof in another preferred embodiment of the invention, or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof,
- R 4 is selected from 5- to 6-membered aryl or heteroaryl, or alkynyl, and the aryl, heteroaryl, alkynyl group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, Substituting one or more groups of a carboxyl group, an ester group, an oxo group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;
- the aryl, heteroaryl, alkynyl group is preferably:
- the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (III) or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a form of the mixture, or a pharmaceutically acceptable salt thereof,
- Y is selected from CH or N;
- R 8 is selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
- p is an integer from 1 to 4.
- q is an integer from 1 to 4.
- W, V, R a , R 3 , R 7 , Q, n are as defined in the general formula (I).
- the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (IV) or a mesogen, racemate, enantiomer, diastereomer thereof, or a form of the mixture, or a pharmaceutically acceptable salt thereof,
- Y is selected from CH or N;
- R 8 is selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
- Q is selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;
- the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl group is optionally further selected from the group consisting of halogen, nitro, cyano, hydroxy, decyl, oxo, alkyl, cycloalkyl, Heterocyclyl, aryl, heteroaryl, -OR b , -O(CH 2 ) m OR b , -OC(O)R b , -C(O)OR b , -C(O)NR b R c , -NHC(O)R b , -S(O)R b , -S(O) 2 R b ,
- Q' is selected from -NR b R c ;
- R b and R c are each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl And the heteroaryl group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituting one or more groups of a heteroaryl group;
- R b and R c together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, decyl Substituting one or more groups of a carboxyl group, an ester group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;
- p is an integer from 1 to 4.
- W, V, R a , R 3 , R 7 , m, n are as defined in the general formula (I).
- the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof in another preferred embodiment of the invention, or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof,
- Q is selected from aryl or heteroaryl; the aryl or heteroaryl is optionally further selected from the group consisting of halogen, alkyl, cycloalkyl, heterocyclyl, -OR b , -O(CH 2 ) m OR b Substituted by one or more groups;
- R b is selected from the group consisting of hydrogen, alkyl and cycloalkyl, wherein the alkyl and cycloalkyl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo. Substituting one or more groups of a cycloalkyl group or a heterocyclic group;
- n 1 to 6.
- the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof in another preferred embodiment of the invention, or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof,
- R a is selected from -NR 1 R 2 ;
- R 1 or R 2 is bonded to R 4 to form a heterocyclic ring fused to R 4 , preferably a 6-membered heterocyclic ring, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy Substituting one or more groups of an ester group, an oxo group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;
- R 1 and R 2 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl And a heterocyclic group, an aryl group and a heteroaryl group are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl Substituting one or more groups of a heterocyclic group, an aryl group, or a heteroaryl group;
- R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic
- the base and heteroaryl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituting one or more groups of a heteroaryl group.
- the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof in another preferred embodiment of the invention, or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof,
- R 5 is OR 6 or SR 6 ;
- R 6 is as defined in the general formula (I);
- the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof in another preferred embodiment of the invention, or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof,
- R 6 is selected from the group consisting of aryl and heteroaryl; the aryl and heteroaryl are optionally further selected from the group consisting of halogen, hydroxy, thiol, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, hetero Substituting one or more groups of aryl, -OR b , -O(CH 2 ) m OR b , -NR b R c ;
- R b and R c are each independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, wherein the alkyl, cycloalkyl, optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl Substituting one or more groups of a carboxyl group, an ester group, an oxo group, a cycloalkyl group, or a heterocyclic group;
- R b and R c together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, decyl Substituting one or more groups of a carboxyl group, an ester group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;
- n 1 to 6.
- the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof in another preferred embodiment of the invention, or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof,
- R 7 is selected from the group consisting of hydrogen, halogen, alkyl, and the alkyl group is optionally further substituted with one or more halogens;
- n 1 or 2.
- the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof in another preferred embodiment of the invention, or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof,
- R 5 is the following group:
- Exemplary compounds of the invention include, but are not limited to, the following compounds:
- Another aspect of the invention provides a compound of the formula (I) or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or A method for preparing a medicinal salt, comprising the steps of:
- NR 3 -6-(ethoxycarbonyl)-5-R 4 -4-oxo-1,4-dihydropyridine-3-arylamide (Ig) is first subjected to ester hydrolysis, and then to R 1 R 2 NH is subjected to amidation reaction to obtain a compound of the formula (I) via a two-step process;
- R a is selected from -OR 1 when 1 or -SR
- the NR 3 -6-(ethoxycarbonyl)-5-R 4 -4-oxo-1,4-dihydropyridine-3-arylamide (Ig) is first subjected to ester hydrolysis to obtain the acid (Ig'). Further reacting with an alcohol or a thiol under the action of EDCI to obtain a compound of the formula (I);
- R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , W, V, n are as defined in the formula (I).
- the invention further provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer thereof, a diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
- the pharmaceutical composition may further comprise another therapeutically active ingredient, preferably another therapeutically active ingredient, preferably a rectal cancer, an intestinal cancer, a pancreatic cancer, a breast cancer, a prostate cancer, Esophageal cancer, gastric cancer, blood cancer, lung cancer, liver cancer, thyroid cancer, sarcoma, brain cancer, skin cancer, head and neck cancer, nasopharyngeal cancer, ovarian cancer, cervical cancer, bladder cancer and kidney cancer, more preferably blood cancer, lung cancer, breast cancer, Pancreatic cancer and stomach cancer.
- another therapeutically active ingredient preferably another therapeutically active ingredient, preferably a rectal cancer, an intestinal cancer, a pancreatic cancer, a breast cancer, a prostate cancer, Esophageal cancer, gastric cancer, blood cancer, lung cancer, liver cancer, thyroid cancer, sarcoma, brain cancer, skin cancer, head and neck cancer, nasopharyngeal cancer, ovarian cancer, cervical cancer, bladder cancer and kidney cancer, more preferably blood cancer, lung cancer, breast cancer, Pan
- the present invention also relates to a process for the preparation of the above composition, which comprises the compound of the formula (I) or a racemate, a racemate, an enantiomer thereof, a diastereomer thereof, Or a mixture thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, is admixed with a pharmaceutically acceptable carrier, diluent or excipient.
- the invention further provides a compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for use in the preparation of an Axl/c-MET inhibitor.
- the invention further provides a compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for use in the manufacture of a medicament for treating cancer.
- the cancer is preferably rectal cancer, intestinal cancer, pancreatic cancer, breast cancer, prostate cancer, esophageal cancer, gastric cancer, blood cancer, lung cancer, liver cancer, thyroid cancer, sarcoma, brain cancer, skin cancer, head and neck cancer, nasopharyngeal cancer, ovarian cancer.
- cervical cancer, bladder cancer and kidney cancer more preferably blood cancer, lung cancer, breast cancer, pancreatic cancer and gastric cancer.
- the cancer is preferably rectal cancer, intestinal cancer, pancreatic cancer, breast cancer, prostate cancer, esophageal cancer, gastric cancer, blood cancer, lung cancer, liver cancer, thyroid cancer, sarcoma, brain cancer, skin cancer, head and neck cancer, nasopharyngeal cancer, Ovarian cancer, cervical cancer, bladder cancer, and kidney cancer, and more preferably, blood cancer, lung cancer, breast cancer, pancreatic cancer, and stomach cancer.
- the invention further provides a compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as an Axl/c-MET inhibitor.
- the invention further provides a compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as a medicament for treating cancer;
- the cancer is preferably rectal cancer, intestinal cancer, pancreatic cancer, breast cancer, prostate cancer, esophageal cancer, gastric cancer, blood cancer, Lung cancer, liver cancer, thyroid cancer, sarcoma, brain cancer, skin cancer, head and neck cancer, nasopharyngeal cancer, ovarian cancer, cervical cancer, bladder cancer, and kidney cancer, and more preferably, blood cancer, lung cancer, breast cancer, pancreatic cancer, and stomach cancer.
- the cancer is preferably rectal cancer, intestinal cancer, pancreatic cancer, breast cancer, prostate cancer, esophageal cancer, gastric cancer, blood cancer, lung cancer, liver cancer, thyroid cancer, sarcoma, brain cancer, skin cancer, head and neck cancer, nasopharyngeal Cancer, ovarian cancer, cervical cancer, bladder cancer, and kidney cancer, and more preferably, blood cancer, lung cancer, breast cancer, pancreatic cancer, and stomach cancer.
- a method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) according to the invention or a mesogen, racemate, enantiomer thereof a form, a mixture of diastereomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, preferably a rectal cancer, an intestinal cancer, a pancreatic cancer, a breast cancer, a prostate cancer, an esophageal cancer , gastric cancer, blood cancer, lung cancer, liver cancer, thyroid cancer, sarcoma, brain cancer, skin cancer, head and neck cancer, nasopharyngeal cancer, ovarian cancer, cervical cancer, bladder cancer and kidney cancer, more preferably blood cancer, lung cancer, breast cancer, pancreatic cancer And stomach cancer.
- a rectal cancer an intestinal cancer, a pancreatic cancer, a breast cancer, a prostate cancer, an esophageal cancer , gastric cancer, blood cancer, lung cancer
- a method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) according to the invention or a mesogen, racemate, enantiomer thereof , a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition therewith, and another therapeutically active ingredient, wherein the other therapeutically active ingredient
- the cancer is preferably rectal cancer, intestinal cancer, pancreatic cancer, breast cancer, prostate cancer, esophageal cancer, gastric cancer, blood cancer, lung cancer, liver cancer, thyroid cancer, sarcoma, brain cancer , skin cancer, head and neck cancer, nasopharyngeal cancer, ovarian cancer, cervical cancer, bladder cancer and kidney cancer, more preferably blood cancer, lung cancer, breast cancer, pancreatic cancer and gastric cancer.
- the compound of the formula (I) of the present invention can form a pharmaceutically acceptable acid addition salt with an acid according to a conventional method in the art to which the present invention pertains.
- the acid includes inorganic acids and organic acids, and acceptable inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.
- Acceptable organic acids include methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, Naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, and the like.
- the compound of the formula (I) of the present invention can form a pharmaceutically acceptable base addition salt with a base according to a conventional method in the art to which the present invention pertains.
- the base includes an inorganic base and an organic base, and acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, etc., and acceptable inorganic bases include aluminum hydroxide and hydroxide. Calcium, potassium hydroxide, sodium carbonate and sodium hydroxide.
- the pharmaceutical composition of the present invention includes any one or more of the compounds of the present invention (or a pharmaceutically acceptable salt, solvate, hydrate, prodrug or derivative thereof) and optionally a pharmaceutically acceptable Carrier. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents. Alternatively, the compounds of the invention may be administered to a patient in need thereof in combination with one or more other therapeutic agents. It will also be understood that certain compounds of the invention may exist in free form or, where appropriate, in the form of their pharmaceutically acceptable salts for therapeutic use.
- the pharmaceutical compositions of the present invention also include a pharmaceutically acceptable carrier.
- the carrier includes any or all solvents, diluents, or other liquid carriers, dispersion or suspending adjuvants, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricating agents Agents, etc., which are adjusted to the particular dosage form desired.
- Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers for formulating pharmaceutical compositions, as well as known techniques for their preparation.
- any conventional carrier medium is contemplated to be within the scope of the invention unless it is incompatible with the compounds of the invention, for example, by producing any undesirable biological effects or interacting in a deleterious manner with any other component of the pharmaceutical composition.
- materials that can be used as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl Cellulose and cellulose acetate; powdered tragacanth; maltose; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and Soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide
- the compounds of the invention can be administered to a patient by a variety of routes of administration. These routes of administration include, but are not limited to, oral, sublingual, subcutaneous, intravenous, nasal, topical, dermal, intraperitoneal, intramuscular, pulmonary, and the like.
- compositions containing the active ingredient may be in the form of solids, semi-solids, liquids and aerosols, for example, tablets, granules, capsules, powders, liquids, suspensions, suppositories, and the like. It can also be administered in a sustained release manner, for example, by a long-acting injection, an osmotic pump, a pill, a patch, or the like.
- Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
- the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier, such as a) filler or filler, such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) viscous Mixtures such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, c) humectants such as glycerin, d) disintegrants such as agar, calcium carbonate, potato or tapioca starch , alginic acid, certain silicates and sodium carbonate, e) solution retarding agents, such as paraffin, f) absorption accelerators, such as quaternary ammonium compounds, g) wetting agents, such as cetyl alcohol and mono-hard Glycerol, h) absorbents such as kaolin and bentonite,
- Solid compositions of a similar type may also be employed as fillers in filling soft or hard gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycols.
- the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells (e.g., enteric coatings and other coatings well known in the pharmaceutical formulation art). It may optionally comprise an opacifying agent, and may also be a composition which is released only, or preferably in certain parts of the intestinal tract, optionally releasing the active ingredient in a delayed manner.
- coatings and shells e.g., enteric coatings and other coatings well known in the pharmaceutical formulation art.
- It may optionally comprise an opacifying agent, and may also be a composition which is released only, or preferably in certain parts of the intestinal tract, optionally releasing the active ingredient in a delayed manner.
- useful embedding compositions include polymeric materials and waxes.
- Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
- the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzoic acid Benzyl ester, propylene glycol, 1,3-butanediol, dimethylformamide, oil (especially cottonseed, groundnut (peanut), corn, germ, olive, ramie and sesame oil), glycerin, tetrahydrofurfuryl alcohol, Polyethylene glycol and sorbitan fatty acid esters, and mixtures thereof.
- the oral compositions may also include adjuvants such
- Injectable preparations may be formulated in accordance with the prior art using suitable dispersion or wetting agents and suspensions.
- the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol.
- Acceptable carriers or solvents include water, Ringer's solution, and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspension.
- any bland fixed oil may be employed, including the prepared mono or diglycerides.
- fatty acids such as oleic acid find use in the preparation of injectables.
- the injectable preparation may be sterile, for example, by filtration through a bacteria-resistance filter, or by adding a bactericidal agent in the form of a sterile solid composition before use, which may be dissolved or dispersed in sterile water or other In bacteria injectable medium.
- compositions for rectal or vaginal administration are preferably suppositories which can be prepared by admixing a compound of the present invention with a suitable non- irritating excipient or carrier (for example, cocoa butter, polyethylene glycol or suppository wax) in the environment It is a solid at temperature and is a liquid at body temperature, thus melting and releasing the active compound in the rectum or vaginal cavity.
- a suitable non- irritating excipient or carrier for example, cocoa butter, polyethylene glycol or suppository wax
- the dosage of the drug to be administered depends on a variety of factors including, but not limited to, the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the conduct of the patient, the patient Diet, time of administration, mode of administration, rate of excretion, combination of drugs, and the like.
- the optimal mode of treatment such as the mode of treatment, the daily amount of the compound of the formula, or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment regimens.
- the compounds or pharmaceutical compositions of the invention may be formulated and used in combination therapy, i.e., the compounds and pharmaceutical compositions may be formulated simultaneously, prior or subsequently with one or more other desired therapies or procedures. Apply.
- the particular combination of treatments (therapies or procedures) employed in the combination regimen will take into account the compatibility of the desired therapy and/or procedure, as well as the desired therapeutic effect to be achieved.
- alkyl refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 12 carbon atoms, more preferably from 1 to 6 carbons.
- the alkyl group of the atom is a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 12 carbon atoms, more preferably from 1 to 6 carbons.
- Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 - dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -methylhexyl, 3-methylhexyl, 4-methylhexyl,
- lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl and the like.
- the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from the group consisting of an alkane Base, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, naphthenic An oxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
- an alkane Base alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, hetero
- alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3- Butyl group and the like.
- the alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio group.
- alkynyl refers to an alkyl radical as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, propynyl, butynyl and the like.
- the alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio group.
- cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. One carbon atom.
- Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
- a polycycloalkyl group includes a spiro ring, a fused ring, and a cycloalkyl group.
- spirocycloalkyl refers to a polycyclic group that shares a carbon atom (referred to as a spiro atom) between 5 to 20 members of a single ring, which may contain one or more double bonds, but none of the rings have a fully conjugated ⁇ electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
- the spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the rings.
- spirocycloalkyl groups include:
- fused cycloalkyl refers to 5 to 20 members, and each ring in the system shares an all-carbon polycyclic group of an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
- fused cycloalkyl groups include:
- bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have complete Conjugate ⁇ -electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring.
- bridged cycloalkyl groups include:
- the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Base, benzocycloheptyl and the like.
- the cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
- heterocyclyl or “heterocycle” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more ring atoms are selected from the group consisting of nitrogen and oxygen. Or a hetero atom of S(O) m (where m is an integer of 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
- ring atoms Preferably comprising from 3 to 12 ring atoms, wherein from 1 to 4 are heteroatoms; most preferably from 3 to 8 ring atoms, wherein from 1 to 3 are heteroatoms; most preferably from 5 to 7 ring atoms, wherein 1 to 2 or 1 to 3 are heteroatoms.
- monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine.
- the group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl and the like are preferably 1, 2, 5-oxadiazolyl, pyranyl or morpholinyl.
- Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
- spiroheterocyclyl or “spiroheterocycle” refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between 5 to 20 members of a single ring, wherein one or more ring atoms are selected from nitrogen. a hetero atom of oxygen or S(O) m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
- the spiroheterocyclyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of shared spiro atoms between the ring and the ring, and is preferably a monospiroheterocyclic group and a dispiroheterocyclic group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospiroheterocyclic group.
- Non-limiting examples of spiroheterocyclyl groups include:
- fused heterocyclic refers to 5 to 20 members, each ring of the system sharing an adjacent pair of atomic polycyclic heterocyclic groups with one or more of the other rings in the system, one or more A ring may contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system in which one or more ring atoms are selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2) a hetero atom, the remaining ring atoms being carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
- fused heterocyclic groups include:
- bridge heterocyclyl or “bridge heterocycle” refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms which are not directly bonded, which may contain one or more double bonds, but None of the rings have a fully conjugated ⁇ -electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
- bridge heterocyclic groups include:
- the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples of which include:
- the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
- aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms) having a conjugated ⁇ -electron system, preferably 6 to 10 members, such as benzene. Base and naphthyl. More preferred is phenyl.
- the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include:
- the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle An alkylthio group, a carboxyl group or a carboxylate group.
- heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen.
- the heteroaryl group is preferably 5 to 10 members, and has 1 to 3 hetero atoms; more preferably 5 or 6 members, and 1 to 2 hetero atoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyridyl An oxazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more selective Pyrazolyl or thiazolyl.
- the heteroaryl ring may be fused to an aryl, hetero
- the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.
- alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
- alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
- the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.
- haloalkyl refers to an alkyl group substituted by one or more halogens, wherein alkyl is as defined above.
- haloalkoxy refers to an alkoxy group substituted by one or more halogens, wherein alkoxy is as defined above.
- hydroxyalkyl refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
- hydroxy refers to an -OH group.
- halogen means fluoro, chloro, bromo or iodo.
- amino means -NH 2.
- cyano refers to -CN.
- nitro refers to -NO 2 .
- mercapto refers to -SH.
- ester group refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
- acyl refers to a compound containing a -C(O)R group, wherein R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.
- sulfonic acid group refers to -S(O) 2 OH.
- sulfonate group refers to -S (O) 2 O (alkyl), or -S (O) 2 O (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
- heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
- Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
- “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
- the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
- “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention which is safe and effective for use in a mammal and which possesses the desired biological activity.
- the present invention adopts the following technical solutions.
- Step 1 Ethyl acetoacetate and N,N-dimethylformamide dimethyl acetal are directly condensed at room temperature to obtain (Z)-2-((dimethylamino)methylene)-3- Ethyl oxobutyrate (Ia);
- Step 2 (Z)-2-((Dimethylamino)methylene)-3-oxobutanoate ethyl ester (Ia) is reacted with strong sodium hydride in anhydrous tetrahydrofuran to form an enol sodium salt intermediate And then undergoing a cyclization reaction with diethyl oxalate to obtain diethyl 4-oxo-4H-pyran-2,5-dicarboxylate (Ib);
- Step 3 Diethyl 4-oxo-4H-pyran-2,5-dicarboxylate (Ib) and amine (R 3 NH 2 ) are subjected to an addition-condensation reaction to obtain NR 3 -4-oxo- Diethyl 1,4-dihydropyridine-2,5-dicarboxylate (Ic);
- Step 4 NR 3 -1-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (Ic) is brominated by N-bromosuccinimide (NBS). NR 3 -3-bromo-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (Id) was obtained.
- Step 5 NR 3 -3-bromo-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (Id) and the corresponding boric acid by Suzuki coupling reaction (potassium carbonate as a base, Pd(dppf)Cl 2 is a catalyst, dioxane/water is a mixed solvent, and the reaction temperature is 80 ° C), and NR 3 -3-R 4 -4-oxo-1,4-dihydropyridine-2 is obtained.
- 5-dicarboxylic acid diethyl ester (Ie) 5-dicarboxylic acid diethyl ester (Ie);
- Step 6 Selective hydrolysis of NR 3 -3-R 4 -4-oxo-1,4-dihydropyridine-2,5-dicarboxylate diethyl ester (Ie) under the action of sodium hydroxide to obtain NR 3-6- (ethoxycarbonyl) -5-R 4 -4- oxo-1,4-dihydropyridine-3-carboxylic acid (the If);
- Step 7 NR 3 -6-(ethoxycarbonyl)-5-R 4 -4-oxo-1,4-dihydropyridine-3-carboxylic acid (If) with aromatic amine (Ih) via HATU and N , N-diisopropylethylamine (DIPEA) was subjected to amidation to give NR 3 -6-(ethoxycarbonyl)-5-R 4 -4-oxo-1,4-dihydropyridine-3- Aromatic amide (Ig);
- Step 8 NR 3 -6-(ethoxycarbonyl)-5-R 4 -4-oxo-1,4-dihydropyridine-3-arylamide (Ig) can be directly amine with R 1 R 2 NH Transesterification to obtain a compound of the formula (I); or a two-step process of amidation with a pre-ester group followed by amidation with R 1 R 2 NH to give a compound of the formula (I).
- R a is selected from -OR 1 or -SR 1 when, (I) a compound of formula 2 was prepared according to the following scheme:
- Step 1 Alkaline hydrolysis of ester groups by NaOH with NR 3 -6-(ethoxycarbonyl)-5-R 4 -4-oxo-1,4-dihydropyridine-3-aramidamide (Ig) NR 3 -6-carboxy-5-R 4 -4-oxo-1,4-dihydropyridine-3-aryl amic acid (Ig');
- Step 2 NR 3 -6-carboxy-5-R 4 -4-oxo-1,4-dihydropyridine-3-aryl amic acid (Ig') is reacted with an alcohol or a thiol under the action of EDCI. a compound of formula (I).
- Step 1 NR 3 -3-bromo-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (Id) and substituted aryl boronic acid in Pd(dppf)Cl 2 and Suzuki coupling under the action of K 2 CO 3 , while the substituent amino group, hydroxyl group or sulfhydryl group on the aryl group is cyclized with the ortho ester group to obtain cyclized NR 3 -4-oxo-1,4-di Hydropyridine-5-carboxylate ethyl ester (Ii);
- Step 2 Cyclized NR 3 -4-oxo-1,4-dihydropyridine-5-carboxylate ethyl ester (Ii) is hydrolyzed under basic conditions (NaOH) to give cyclized NR 3 -4-oxyl Des-1,4-dihydropyridin-5-carboxylic acid (Ij);
- Step 3 Cyclization of NR 3 -4-oxo-1,4-dihydropyridine-5-carboxylic acid (Ij) with aromatic amine (Ih) via HATU and N,N-diisopropylethylamine (DIPEA) The amidation reaction is carried out to obtain a compound of the formula (I').
- Step 1 Diethyl 4-oxo-4H-pyran-2,5-dicarboxylate (Ib) with an amino group (-NH 2 ) at one end and an amine with PG-X by addition-condensation Reaction to give N-substituted-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (Ik);
- Step 2 N-substituted 4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (Ik) is deprotected and then cyclized with an ortho ester group to obtain a cyclization reaction.
- Step 3 Cyclization of ethyl 4-oxo-1,4-dihydropyridine-5-carboxylate (Il) by bromination of NBS to give cyclized 3-bromo-4-oxo-1,4-di Hydropyridine-5-formic acid ethyl ester (Im);
- Step 4 Cyclization of ethyl 3-bromo-4-oxo-1,4-dihydropyridine-5-carboxylate (Im) with the corresponding boronic acid by Suzuki coupling reaction (potassium carbonate as base, Pd(dppf)Cl 2 is a catalyst, dioxane/water is a mixed solvent, and the reaction temperature is 80 ° C) to obtain a cyclized 3-R 4 -4-oxo-1,4-dihydropyridine-5-carboxylic acid ethyl ester (In );
- Step 5 The cyclized 3-R 4 -4-oxo-1,4-dihydropyridine-5-carboxylic acid ethyl ester intermediate (In) is hydrolyzed under basic conditions (NaOH) to give a cyclized 3- R 4 -4-oxo-1,4-dihydropyridine-5-carboxylic acid intermediate (Io);
- Step 6 Cyclized 3-R 4 -4-oxo-1,4-dihydropyridine-5-carboxylic acid intermediate (Io) with aromatic amine (Ih) via HATU and N,N-diisopropyl B
- the amine (DIPEA) is subjected to an amidation reaction to give a compound of the formula (I").
- Step 1 Diethyl 4-oxo-4H-pyran-2,5-dicarboxylate (Ib) and aminoacetaldehyde dimethylacetal are obtained by addition-condensation reaction to obtain 1-(2,2-dimethoxy Ethyl ethyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (Ip);
- Step 2 1-(2,2-Dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (Ip) with amino alcohol, amino mercaptan Or the diamine is first subjected to a aldehyde condensation reaction of methanol, and then cyclized with an ortho ester group to obtain a fused ring of ethyl 4-oxo-1,4-dihydropyridine-5-carboxylate (Iq);
- Step 3 The fused ring of ethyl 4-oxo-1,4-dihydropyridine-5-carboxylate (Iq) is brominated by NBS to give the cyclized 3-bromo-4-oxo-1,4-di Hydropyridine-5-formic acid ethyl ester (Ir);
- Step 4 3-bromo-4-oxo-1,4-dihydropyridine-5-carboxylic acid ethyl ester (Ir) and the corresponding boronic acid by Suzuki coupling reaction (potassium carbonate as base, Pd(dppf)Cl 2 as catalyst , dioxane / water is a mixed solvent, the reaction temperature is 80 ° C), to give 3-R 4 -4-oxo-1,4-dihydropyridine-5-carboxylic acid ethyl ester (Is);
- Step 5 Ethyl 3-R 4 -4-oxo-1,4-dihydropyridine-5-carboxylate (Is) is hydrolyzed under basic conditions (NaOH) to give cyclized 3-R 4 -4- Oxo-1,4-dihydropyridine-5-carboxylic acid (It);
- Step 6 Cyclized 3-R 4 -4-oxo-1,4-dihydropyridine-5-carboxylic acid (It) with aromatic amine (Ih) via HATU and N,N-diisopropylethylamine ( DIPEA) is subjected to an amidation reaction to give a compound of the formula (I"').
- R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , W, V, n are as defined in the formula (I).
- Figure 1 Growth curve of tumor volume in treated and control mice in the EBC-1 non-small cell lung cancer model.
- Figure 2 Plot of body weight versus treatment time in treatment and control mice in the EBC-1 non-small cell lung cancer model.
- the compounds of the present invention are prepared using convenient starting materials and common preparatory procedures.
- the present invention provides typical or propensating reaction conditions such as reaction temperature, time, solvent, pressure, molar ratio of reactants. However, other reaction conditions can be adopted unless otherwise stated. Optimization conditions may vary with the use of a particular reactant or solvent, but under normal circumstances, the reaction optimization steps and conditions can be determined.
- protecting groups may be used in the present invention to protect certain functional groups from unwanted reactions.
- protecting groups suitable for the various functional groups and their protection or deprotection conditions are well known to those skilled in the art. For example, T. W. Greene and G. M. Wuts, "Protective Groups in Organic Preparation” (3rd edition, Wiley, New York, 1999, and references cited in the book) describe in detail the protection or deprotection of a large number of protecting groups.
- the separation and purification of the compounds and intermediates are carried out according to specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin layer chromatography, preparative high performance liquid chromatography or a mixture of the above methods.
- the specific method of use can be referred to the examples described in the present invention.
- other similar separation and purification methods can be employed. It can be characterized using conventional methods, including physical constants and spectral data.
- the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
- NMR nuclear magnetic resonance
- MS mass spectrometry
- the NMR shift is given in units of 10 -6 (ppm).
- the NMR was determined by using a Brukerdps300 type nuclear magnetic instrument.
- the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was tetramethyl. Silane (TMS).
- the MS was measured using an ACQUITY H-Class UPLC mass spectrometer (QDa Detector) (manufacturer: Waters).
- the liquid phase was prepared using a Waters 2545 High Performance Liquid Chromatograph (Waters 2489 UV/visible Detector, 2767 Sample MGR, Unitary C18, 5 ⁇ m 20 mm x 250 mm) (manufacturer: Waters)
- Thin layer chromatography silica gel plate uses Qingdao Ocean Chemical GF254 silica gel plate.
- the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm.
- the specification for thin layer chromatography separation and purification is 0.4mm ⁇ 0.5. Mm.
- the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from Netcom Mall, Beijing Coupling, Sigma, Belling, Yi Shiming, Shanghai Shuya, Shanghai Inoke, An Nike Chemical, Shanghai Bi De and other companies.
- the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
- An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
- the reaction solvent, organic solvent or inert solvent is each expressed as a solvent which does not participate in the reaction under the described reaction conditions, and includes, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform.
- THF tetrahydrofuran
- DMF dimethylformamide
- NMP nitrogen-methylpyrrolidone
- pyridine pyridine
- the chemical reactions described in the present invention are generally carried out under normal pressure.
- the reaction temperature is between -78 ° C and 200 ° C.
- the reaction time and conditions are, for example, one atmosphere, between -78 ° C and 200 ° C, and completed in about 1 to 24 hours. If the reaction is overnight, the reaction time is generally 16 hours. There is no particular description in the examples, and the reaction temperature is room temperature and is 20 ° C to 30 ° C.
- the progress of the reaction in the examples was monitored by thin layer chromatography (TLC).
- TLC thin layer chromatography
- the system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And the ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted depending on the polarity of the compound.
- the column chromatography eluent system and the thin layer chromatography developer system include: A: dichloromethane and methanol systems, B: n-hexane and ethyl acetate systems, C: petroleum ether and acetic acid
- A dichloromethane and methanol systems
- B n-hexane and ethyl acetate systems
- C petroleum ether and acetic acid
- the volume ratio of the solvent is adjusted depending on the polarity of the compound, and a small amount of an alkaline or acidic reagent such as triethylamine or acetic acid may be added for adjustment.
- ⁇ M micromolar
- DIPEA diisopropylethylamine
- IC 50 concentration that inhibits 50% activity
- NBS N-bromosuccinimide
- PE petroleum ether
- TBDPS tert-butyldiphenyl silicon
- Step 1 Preparation of ethyl (Z)-2-((dimethylamino)methylene)-3-oxobutanoate (a1)
- Step 4 Preparation of 3-bromo-1-methyl-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (a4)
- Step 5 Preparation of diethyl 3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate (a5)
- Step 6 Preparation of 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (a)
- 5-(4-fluorophenyl)-4 was obtained in the same manner as in Preparation Example 1, except that (tetrahydro-2H-pyran-4-yl)methanamine (Shanghai Pide) was used instead of the aqueous methylamine solution.
- -oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid (c) (white solid, four-step yield: 36.8%)
- Step 2 Preparation of 1-(3-aminopropyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid ethyl ester hydrochloride (d2)
- Step 4 10-Bromo-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane- Preparation of 8-carboxylic acid ethyl ester (d4)
- Step 5 10-(4-Fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4] Preparation of azacycloheptane-8-carboxylic acid ethyl ester (d5)
- 1,3-Diamino-2-hydroxypropane (4 g, 44.4 mmol) and imidazole (6.1 g, 88.8 mmol) were added to a round bottom flask containing DMF (30 mL) at room temperature.
- the mixture was cooled to 0 ° C, and a solution of TBDPSCl in DMF (30 mL, 88.8 mmol) was slowly added dropwise. After the addition was completed, the temperature was raised to room temperature and stirred overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut 12.4 g, yellow oil, yield 85.1%).
- Step 2 4-((tert-Butyldiphenylsilyl)oxy)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2- Preparation of a][1,4]diazepane-8-carboxylic acid ethyl ester (f2)
- Step 3 10-Bromo-4-((tert-butyldiphenylsilyl)oxy)-1,9-dioxo-1,2,3,4,5,9-hexahydropyridyl[ Preparation of 1,2-a][1,4]diazepane-8-carboxylic acid ethyl ester (f3)
- Step 4 4-((tert-Butyldiphenylsilyl)oxy)-10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9 -Preparation of ethyl hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylate (f4)
- Step 5 10-(4-Fluorophenyl)-4-hydroxy-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1 , 4] Preparation of diazepane-8-carboxylic acid (f)
- Step 1 1 - ((1-(tert-Butoxycarbonyl)piperidin-2-yl)methyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester ( Preparation of g1)
- Step 3 Preparation of 3-bromo-4-oxo-1-(piperidin-2-ylmethyl)-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester hydrochloride (g3)
- Step 4 1-Bromo-2,12-dioxo-2,6,6a,7,8,9,10,12-octahydrodipyrido[1,2-a:1',2'-d Preparation of pyrazine-3-carboxylic acid ethyl ester (g4)
- Step 5 1-(4-Fluorophenyl)-2,12-dioxo-2,6,6a,7,8,9,10,12-octahydrodipyrido[1,2-a:1 Preparation of ',2'-d]pyrazine-3-carboxylic acid ethyl ester (g5)
- Step 6 1-(4-Fluorophenyl)-2,12-dioxo-2,6,6a,7,8,9,10,12-octahydrodipyrido[1,2-a:1 Preparation of ',2'-d]pyrazine-3-carboxylic acid (g)
- Morpholine-3-carboxylic acid (3.0 g, 22.9 mmol) and potassium carbonate (15.8 g, 114.4 mmol) were added to a round bottom flask containing acetone (20 mL) and water (10 mL). Boc 2 O (7.5 g, 34.4 mmol) was slowly added dropwise with stirring, and the mixture was stirred at this temperature overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc : 34.1%).
- Step 2 Preparation of 3-carbamoylmorpholine-4-carboxylic acid tert-butyl ester (j1-2)
- Step 3 Preparation of 3-(aminomethyl)morpholine-4-carboxylic acid tert-butyl ester (j1)
- PREPARATIVE EXAMPLE 10 7-(4-Fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4 ,5]Preparation of pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (intermediate k)
- Step 2 Preparation of 3-bromo-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (k2)
- Step 4 7-(4-Fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5
- pyrazino[2,1-B][1,3]oxazine-9-carboxylic acid ethyl ester k4
- Step 5 7-(4-Fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5
- PREPARATIVE EXAMPLE 12 7-(6-Methylpyridin-3-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1', Preparation of 2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (intermediate m)
- PREPARATIVE EXAMPLE 13 7-(5-Methylthiophen-2-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1', Preparation of 2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (intermediate n)
- PREPARATIVE EXAMPLE 16 (3R)-6-(4-Fluorophenyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazole[ Preparation of 3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (intermediate q)
- PREPARATIVE EXAMPLE 17 (3S)-6-(4-Fluorophenyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazole[ Preparation of 3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (intermediate r)
- PREPARATIVE EXAMPLE 18 (4R)-7-(4-Fluorophenyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyridine And [1', 2': 4,5] Preparation of pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (intermediate s)
- Step 2 Preparation of tert-butyl 4-(4-(6-amino-5-bromopyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (u2)
- Step 1 Preparation of 4-((4-bromo-2-methoxyphenoxy)methyl)-2,2-dimethyl-1,3-dioxolan (bb1)
- 3-(4-Bromo-2-methoxyphenoxy)propane-1,2-diol (2.1 g, 7.58 mmol) was added sequentially to a reaction flask containing 1,2-dibromoethane (30 mL). Tetrabutylammonium bromide (488 mg, 1.52 mmol) and 50% (w/w) sodium hydroxide solution (30 mL). After heating the mixture to 55 ° C and stirring for 6 hours, additional 1,2-dibromoethane (30 mL) and 50% (w/w) sodium hydroxide solution (30 mL) were added and stirring was continued at this temperature overnight. .
- reaction solution was cooled to room temperature, it was diluted with water and extracted with dichloromethane (100 mL x 3), and the organic phase was combined. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography (EtOAc:EtOAc: Dioxane (1.7 g, yellow solid, yield: 73.9%).
- Step 4 2-(4-((1,4-Dioxa-2-yl)methoxy)-3-methoxyphenyl)-4,4,5,5-tetramethyl-1, Preparation of 3,2-dioxaborane (bb4)
- Step 6 5-(4-((1,4-Dioxa-2-yl)methoxy)-3-methoxyphenyl)-3-(4-amino-2-fluorophenyl)pyridine
- Step 2 4-((2-(4-Bromo-2-methoxyphenoxy)ethoxy)methyl)-2,2-dimethyl-1,3-dioxolane (cc) Preparation
- Step 1 Preparation of 4-(2-(4-bromo-2-methoxyphenoxy)ethyl)morpholine (ee1-1)
- Step 2 4-(2-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy) Preparation of ethyl)ethyl)morpholine (ee1)
- Step 1 4-(((2,2-Dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl)amino)-2-methoxybenzene Preparation of methyl formate (hh1)
- Methyl 4-amino-2-methoxybenzoate (5 g, 27.6 mmol) was added to a reaction flask containing isopropyl alcohol (100 mL) at room temperature. The mixture was warmed to 50 ° C and stirred for 10 minutes, then added 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (Shanghai Bi De , 5.13 g, 27.6 mmol). The mixture was further heated to 80 ° C and stirred for 1 hour.
- Step 3 Preparation of 4-(2-fluoro-4-nitrophenoxy)-6-methoxy-7-(2-methoxyethoxy)quinazoline (oo3)
- Step 4 Preparation of 3-fluoro-4-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)oxy)phenylamine (oo)
- PREPARATIVE EXAMPLE 42 4-(2-((4-(4-Amino-2-fluorophenoxy)-6-methoxyquinazolin-7-yl)oxy)ethyl)piperazine-1 -Preparation of tert-butyl formate (intermediate qq)
- Step 1 5-((4-(2-Amino-5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyridine-3- Ethyl 3-fluorophenyl)carbamoyl)-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylate (1a)
- Step 2 5-((4-(2-Amino-5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyridine-3- Of 3-(fluorophenyl)carbamoyl)-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid (1b)
- Step 3 4-(4-(6-Amino-5-(4-(6-carbamoyl-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-di) Preparation of tert-butyl ester (1c) of hydropyridine-3-carboxamido)-2-fluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate
- Step 4 N 5 -(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl) Preparation of -3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (1)
- Example 2 The same procedure as in Example 1 was carried out except that 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4- Dihydropyridine-3-carboxylic acid (c) in place of 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3- Carboxylic acid (a) to give N 5 -(4-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3 -fluorophenyl)-3-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2 , 5-dimethylformamide (7) (white solid, four-step yield: 11.2%).
- Step 1 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (9a) preparation
- Step 4 5-((4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)carbamoyl)-3-bromo-4-oxo
- Step 5 5-((4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)carbamoyl)-4-oxo-1-( Preparation of ethyl (tetrahydro-2H-pyran-4-yl)methyl)-3-(p-tolyl)-1,4-dihydropyridine-2-carboxylate (9e)
- Step 6 5-((4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)carbamoyl)-4-oxo-1-( Preparation of (tetrahydro-2H-pyran-4-yl)methyl)-3-(p-tolyl)-1,4-dihydropyridine-2-carboxylic acid (9f)
- Step 7 N 5 -(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)-N 2 -methyl-4-oxo-1
- Step 7 N 5 -(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)-N 2 -methyl-4-oxo-1
- Example 10 N 5 -(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-3-fluorophenyl)-3-(4-fluorobenzene Of 1-(1-isopropyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (10)
- Example 10 The same procedure as in Example 10 was employed except that 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-
- the carboxylic acid (a) is substituted for 5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (b) to obtain N 5 -(4- (2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-3-fluorophenyl)-3-(4-fluorophenyl)-1-methyl-4- Oxo-1,4-dihydropyridine-2,5-dimethylformamide (11) (white solid, three-step yield: 18.8%).
- Example 11 The same procedure as in Example 11 was employed except that 3-(4-amino-2-fluorophenyl)-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-2-amine (v) was used. Instead of 3-(4-amino-2-fluorophenyl)-5-(3,4-dimethoxyphenyl)pyridin-2-amine (x), N 5 -(4-(2-amino) was obtained.
- Example 13 N 5 -(4-(2-Amino-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-3-(4 Of -fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (13)
- Example 14 N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl) -10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9 hexahydropyrido[1,2- ⁇ ][1,4]diazepine Preparation of heptane-8-carboxamide (14)
- Step 1 4-(4-(6-Amino-5-(2-fluoro-4-(10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5 ,9-Hexidopyrido[1,2- ⁇ ][1,4]diazepane-8-formylamino)phenyl)pyridin-3-yl)-1H-pyrazol-1-yl
- piperidine-1-carboxylic acid tert-butyl ester 14a
- Step 2 N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)- 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2- ⁇ ][1,4]diazepine
- Example 14 The same procedure as in Example 14 was employed except that 4-(4-(6-amino-5-(4-amino-2,5-difluorophenyl)pyridin-3-yl)-1H-pyrazole-1 was used.
- Example 16 N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl) -7-(4-fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-pyrido[1',2':4,5]pyridyl Preparation of oxazolo[2,1-C][1,4]oxazine-9-carboxamide (16)
- Example 14 The same procedure as in Example 14 was carried out except that 7-(4-fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-pyrido[1] was used.
- Example 14 The same procedure as in Example 14 was carried out except that 7-(4-fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1] was used.
- Example 14 The same procedure as in Example 14 was carried out except that 6,8-dioxy-7-(p-tolyl)-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2 was used.
- Example 20 N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl) -10-(4-fluorophenyl)-4-hydroxy-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2- ⁇ ][1,4 Preparation of diazepane-8-carboxamide (20)
- Example 14 The same procedure as in Example 14 was carried out except that 10-(4-fluorophenyl)-4-hydroxy-1,9-dioxo-1,2,3,4,5,9-hexahydropyridyl[ 1,2-a][1,4]diazepane-8-carboxylic acid (f) instead of 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4 ,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylic acid (d), to give N-(4-(2-amino-5-( 1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-10-(4-fluorophenyl)-4-hydroxy-1, 9-dioxo 1,2,3,4,5,9 hexahydropyrido[1,2- ⁇ ][1,4]diazepane
- Example 14 The same procedure as in Example 14 was employed except that (4R)-7-(4-fluorophenyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a- Hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (s) in place of 10-(4-fluorobenzene) -1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylic acid ( d), (4R)-N-(4-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3 -fluorophenyl)-7-(4-fluorophenyl)-4-methyl-6,8-dioxo-3,4,6,8,12
- Example 23 N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl) -6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2- d] Preparation of pyrazine-8-carboxamide (23)
- Example 14 The same procedure as in Example 14 was carried out except that 6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazole [3,2 -a]pyrido[1,2-d]pyrazine-8-carboxylic acid (o) instead of 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5 , 9-hexahydropyrido[1,2-a][1,4]diazepan-8-carboxylic acid (d), to obtain N-(4-(2-amino-5-(1-) (piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-(4-fluorophenyl)-5,7-dioxo- 2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido
- Example 24 (3R)-N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3- Fluorophenyl)-6-(4-fluorophenyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazole[3,2- Preparation of a] pyrido[1,2-d]pyrazine-8-carboxamide (24)
- Example 25 N-(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-3-fluorophenyl)-6-(4-fluorophenyl) )-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide Preparation of (25)
- Example 23 The same procedure as in Example 23 was carried out except that 3-(4-amino-2-fluorophenyl)-5-(3,4-dimethoxyphenyl)pyridin-2-amine (x) was used instead of 4- (4-(6-Amino-5-(4-amino-2-fluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (u), Preparation of N-(4-(2-amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-3-fluorophenyl)-6-(4-fluorophenyl)- 5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (25 (white solid, one step yield: 40.2%).
- Example 26 N-(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-3-fluorophenyl)-10-(4-fluorophenyl) -1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2- ⁇ ][1,4]diazepane-8-carboxamide ( Preparation of 26)
- Example 27 N-(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)-1,9-dioxo-10-(pair Of -tolyl)-1,2,3,4,5,9-hexahydropyrido[1,2- ⁇ ][1,4]diazepane-8-carboxamide (27)
- Example 19 The same procedure as in Example 19 was carried out except that 3-(4-amino-2-methylphenyl)-5-(3,4-dimethoxyphenyl)pyridin-2-amine (aa) was used instead of 4-( 4-(6-Amino-5-(4-amino-2-fluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (u), made N-(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)-1,9-dioxo-10-(p-tolyl) -1,2,3,4,5,9-hexahydropyrido[1,2- ⁇ ][1,4]diazepane-8-carboxamide (27) (white solid, one step Rate: 37.9%).
- Example 27 The same procedure as in Example 27 was employed except that (3R)-6-(4-fluorophenyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a- Instead of 1,9-dioxo-10-(p-tolyl)-1, hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (q) 2,3,4,5,9-Hexidopyrido[1,2-a][1,4]diazepane-8-carboxylic acid (e), (3R)-N-(4) -(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)-6-(4-fluorophenyl)-3-methyl-5,7-di Oxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8
- Example 28 The same procedure as in Example 28 was employed except that (3S)-6-(4-fluorophenyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a- Hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (r) in place of 1,9-dioxo-10-(p-tolyl)-1, 2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylic acid (e), (3S)-N-(4) -(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)-6-(4-fluorophenyl)-3-methyl-5,7-di Oxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8
- Example 30 N-(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-2,5-difluorophenyl)-6-(4- Fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8 - Preparation of formamide (30)
- Step 1 Preparation of 3-(4-amino-2,5-difluorophenyl)-5-(3,4-dimethoxyphenyl)pyridin-2-amine (Intermediate 30a)
- 3-bromo-5-(3,4-dimethoxyphenyl)pyridine was added to a reaction flask containing (10 mL) a mixture of 1,4-dioxane and water (4:1) at room temperature.
- 2-Amine prepared according to Example 30 of WO2013115280, page 130) (500 mg, 1.62 mmol), 4-amino-2,5-difluorophenylboronic acid pinacol ester (619 mg, 2.43 mmol), potassium carbonate (671 mg, 4.86 mmol), Pd(dppf)Cl 2 .DCM (130 mg, 0.16 mmol). Sealed, replaced with nitrogen three times, heated to 90 ° C and stirred overnight.
- Step 2 N-(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-2,5-difluorophenyl)-6-(4-fluoro Phenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8- Preparation of formamide (30)
- Example 31 N-(4-(2-Amino-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-(4- Fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8 - Preparation of formamide (31)
- Example 30 The same procedure as in Example 30 was employed except that 3-(4-amino-2-fluorophenyl)-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-2-amine (v) Instead of 3-(4-amino-2,5-difluorophenyl)-5-(3,4-dimethoxyphenyl)pyridin-2-amine (30a), N-(4-(2) was obtained.
- Example 31 The same procedure as in Example 31 was carried out except that 10-(4-fluorophenyl)-4-hydroxy-1,9-dioxo-1,2,3,4,5,9-hexahydropyridyl[ 1,2-a][1,4]diazepane-8-carboxylic acid (f) in place of 6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7 ,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (o), N-(4-(2-amino-5) -(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-10-(4-fluorophenyl)-4-hydroxy-1-,9-di Oxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepan
- Example 35 N-(4-(2-Amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)phenyl -1,9-dioxo-10-(p-tolyl)-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazacyclocycle Preparation of heptane-8-carboxamide (35)
- Example 36 N-(4-(2-Amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3 -fluorophenyl)-1,9-dioxo-10-(p-tolyl)-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4] Preparation of diazepane-8-carboxamide (36)
- Example 37 N-(4-(2-Amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3 -fluorophenyl)-7-(6-methylpyridin-3-yl)-6,8-dioxo 3,4,6,8,12,12a-hexahydro-2H-pyrido[1', Preparation of 2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide (37)
- Example 36 The same procedure as in Example 36 was employed except that 7-(6-methylpyridin-3-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H- Pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (m) instead of 1,9-dioxo-10-(pair Tolyl-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylic acid (e), to give N- (4-(2-Amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)- 7-(6-Methylpyridin-3-yl)-6,8-dioxo-3,4,6,8,12,12a-hex
- Example 14 The same procedure as in Example 14 was employed except that 3-(4-amino-2-fluorophenyl)-5-(3-methoxy-4-(2-morpholinoethoxy)phenyl)pyridine- 2-amine (ee) instead of 4-(4-(6-amino-5-(4-amino-2-fluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1 - tert-butyl formate (u) to give N-(4-(2-amino-5-(3-methoxy-4-(2-morpholinoethoxy)phenyl)pyridin-3-yl) 3-fluorophenyl)-10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][ 1,4]diazepane-8-carboxamide (38) (white solid, one step yield: 21.3%).
- Example 39 N-(4-(2-Amino-5-(3-methoxy-4-(2-morpholinoethoxy)phenyl)pyridin-3-yl)-3-fluorophenyl) -7-(5-methylthiophen-2-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4 ,5]Preparation of pyrazino[2,1-b][1,3]oxazine-9-carboxamide (39)
- Example 38 The same procedure as in Example 38 was employed except for 7-(5-methylthiophen-2-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyridine.
- Example 40 N-(4-(5-(4-(2-((1,4-dioxo)-2-yl)methoxy)ethoxy)-3-methoxyphenyl)- 2-amino-pyridin-3-yl)-3-fluorophenyl)-6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydro Preparation of oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (40)
- Example 38 The same procedure as in Example 38 was carried out except that 6-(4-methylphenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a ] Pyrido[1,2-d]pyrazine-8-carboxylic acid (p) in place of 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9 -Hexidopyrido[1,2-a][1,4]diazepan-8-carboxylic acid (d) to give N-(4-(2-amino-5-(3-methoxy) 4-(2-morpholinoethoxy)phenyl)pyridin-3-yl)-3-fluorophenyl)-5,7-dioxo-6-(p-tolyl)-2,3, 5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazin
- Example 42 N-(4-(5-(4-(4-1,4-dioxan-2-yl)methoxy)-3-methoxyphenyl)-2-amino-pyridine-3 -yl)-3-fluorophenyl)-6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazole[3,2 -a]Preparation of pyrido[1,2-d]pyrazine-8-carboxamide (42)
- Example 41 The same procedure as in Example 41 was carried out except that 6,8-dioxo-7-(p-tolyl)-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2 ':4,5]pyrazine[2,1-b][1,3]oxazine-9-carboxylic acid (l) instead of 6-(4-methylphenyl)-5,7-dioxo-2, 3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (p) to give N-(4-( 2-Amino-5-(3-methoxy-4-(2-morpholinoethoxy)phenyl)pyridin-3-yl)-3-fluorophenyl)-6,8-dioxo-7 -(p-tolyl)-3,4,6,8,12,12a-hexahydro-2H-pyrido
- Example 44 N-(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)-1,5-dioxo-4-(( Preparation of tetrahydro-2H-pyran-4-yl)methyl)-1,4,5,6-tetrahydrobenzo[f][1,7]naphthyridin-2-carboxamide (44)
- Step 1 N-(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)-1,5-dioxo-4-((four Preparation of hydrogen-2H-pyran-4-yl)methyl)-1,4,5,6-tetrahydrobenzo[f][1,7]naphthyridin-2-carboxamide (44)
- Step 2 5-((4-(2-Amino-5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyridine-3- 3-fluorophenyl)carbamoyl)-3-bromo-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine
- ethyl-2-carboxylate 45b
- Step 3 4-(4-(6-Amino-5-(2-fluoro-4-(8-fluoro-1,5-dioxo-4-((tetrahydro-2H-pyran-4-yl)) [Methyl)-1,4,5,6-tetrahydrobenzo[f][1,7]naphthyridin-2-carboxamido)phenyl)pyridin-3-yl)-1H-pyrazole- Preparation of tert-butyl ester of 1-yl) piperidine-1-carboxylate (45c)
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Abstract
The present invention relates to a polysubstituted pyridone derivative, a preparation method therefor and a medical use thereof. In particular, involved are a polysubstituted pyridone derivative as shown in general formula (I), a preparation method therefor, a pharmaceutical composition containing the derivative, and the use of same as an Axl/c-MET inhibitor in the treatment of cancers, wherein the definitions of each group in general formula (I) are the same as those in the description.
Description
本发明涉及一种多取代吡啶酮类衍生物,其制备方法,含有其的药物组合物,以及其作为Axl/c-MET抑制剂的用途,特别是在治疗癌症中的用途。The present invention relates to a polysubstituted pyridone derivative, a process for the preparation thereof, a pharmaceutical composition containing the same, and its use as an Axl/c-MET inhibitor, particularly in the treatment of cancer.
受体酪氨酸激酶(RTKs)为多域的跨膜蛋白,其功能为细胞的膜外受体配体的传感器。当配体与受体的结合时,诱导受体在细胞膜表面二聚并激活膜内的激酶域,从而导致酪氨酸的磷酸化以及进一步激活下游一连串的信号传导通路。到目前为止,在人体基因库找到了近60个受体酪氨酸激酶,它们广泛地调节着细胞的新陈代谢过程,包括存活、生长、分化、增殖、粘连和死亡。Receptor tyrosine kinases (RTKs) are multidomain transmembrane proteins that function as sensors for extracellular receptor ligands in cells. When the ligand binds to the receptor, the receptor is dimerized on the surface of the cell membrane and activates the kinase domain within the membrane, resulting in phosphorylation of tyrosine and further activation of a cascade of signaling pathways downstream. To date, nearly 60 receptor tyrosine kinases have been found in the human genome, which extensively regulate the cellular metabolic processes, including survival, growth, differentiation, proliferation, adhesion, and death.
受体酪氨酸激酶的TAM家族有三个成员Axl、Mer和Tyro-3,调控着包括细胞生存、诱导分化、移动和黏粘等在内的各种细胞学反应。研究表明,受体TAM的信号传递也控制着血管平滑肌稳态、血小板功能、微血栓稳定性及红血球形成等。受体TAM还在免疫和炎症方面发挥着关键作用。它促进凋亡细胞的吞噬,刺激NK细胞的诱导分化。The TAM family of receptor tyrosine kinases has three members, Axl, Mer, and Tyro-3, which regulate a variety of cytological responses including cell survival, differentiation, migration, and adhesion. Studies have shown that the signaling of receptor TAM also controls vascular smooth muscle homeostasis, platelet function, microthrombus stability and erythrocyte formation. The receptor TAM also plays a key role in immunity and inflammation. It promotes phagocytosis of apoptotic cells and stimulates the differentiation of NK cells.
Axl是受体酪氨酸激酶的TAM家族的一员。三个成员之间,Axl和Tyro-3具有最为相似的基因结构,而Axl和Mer具有最为相似的酪氨酸激酶域氨基酸序列。Axl是细胞存活、增殖、聚集、迁移和黏附的重要调节器。Axl在单核细胞、巨噬细胞、血小板、内皮细胞、小脑、心脏、骨骼肌、肝脏和肾脏等细胞及器官中都有广泛表达。在对许多癌细胞的研究中发现,造血细胞、间质细胞和内皮细胞中的Axl基因都存在着超表达或异位表达现象。各类白血病和多数的实体瘤中,Axl的过度表达现象尤为突出。不仅如此,相对于正常的组织或者初期肿瘤,Axl在转移的或恶性肿瘤中的表达更高,其高表达与临床治疗不佳密切相关。Axl is a member of the TAM family of receptor tyrosine kinases. Among the three members, Axl and Tyro-3 have the most similar gene structure, while Axl and Mer have the most similar tyrosine kinase domain amino acid sequence. Axl is an important regulator of cell survival, proliferation, aggregation, migration and adhesion. Axl is widely expressed in cells and organs such as monocytes, macrophages, platelets, endothelial cells, cerebellum, heart, skeletal muscle, liver and kidney. In the study of many cancer cells, the Axl gene in hematopoietic cells, mesenchymal cells and endothelial cells is overexpressed or ectopically expressed. Overexpression of Axl is particularly prominent in all types of leukemia and most solid tumors. Moreover, Axl is more highly expressed in metastatic or malignant tumors than normal tissues or primary tumors, and its high expression is closely related to poor clinical treatment.
越来越多的证据表明,Axl在多种肿瘤细胞中参与由不同机制造成的耐药性,Axl激酶的超表达已经成为癌症患者呈现治疗耐药性的一个重要标志。通过对Axl受体酪氨酸激酶的抑制可以降低肿瘤细胞的促存活信号的活化,阻滞肿瘤的侵袭,增加靶向药物治疗和放化疗敏感度。因此,Axl为癌症治疗的有效靶点。A growing body of evidence suggests that Axl is involved in drug resistance caused by different mechanisms in a variety of tumor cells, and overexpression of Axl kinase has become an important marker of cancer drug resistance in cancer patients. Inhibition of Axl receptor tyrosine kinase can reduce the activation of pro-survival signals of tumor cells, block tumor invasion, and increase the sensitivity of targeted drug therapy and chemoradiotherapy. Therefore, Axl is an effective target for cancer treatment.
虽然几个替尼类酪氨酸激酶抑制剂,如卡博替尼(Cabozantinib)、Foretinib、Merestinib、克里唑替尼(Crizotinib)等含有Axl激酶抑制剂活性,但它们为多靶点分子,不具有选择性。全球唯一一个Axl选择性的临床候选药物是BGB324,正在进行多个临床二期试验。因此,目前还没有Axl抑制剂新药供患者使用。Although several tyrosine kinase inhibitors, such as Cabozinidinib, Foretinib, Merestinib, Crizotinib, etc., contain Axl kinase inhibitor activity, they are multi-target molecules, Not selective. The only clinical candidate for Axl selectivity in the world is BGB324, which is undergoing multiple clinical phase II trials. Therefore, there is currently no new drug for Axl inhibitors for patients.
c-MET是一类具有自主磷酸化活性的跨膜酪氨酸激酶受体(RTKs)家族成员。c-MET受体在细胞含一个酪氨酸激酶催化域,有4个关键的调节酶活性的酪氨酸残基,形成几个信号传导蛋白的停泊位点,进而导致生物应答。c-MET最先是从 人骨肉瘤衍生出的细胞系中分离出来的,主要是在上皮细胞上表达。在胚胎发育和成年时期,很多器官上皮细胞表面表达c-MET受体,包括肝、胰腺、前列腺、肾脏、肌肉和骨髓。c-MET is a member of the transmembrane tyrosine kinase receptor (RTKs) family with autonomous phosphorylation activity. The c-MET receptor contains a tyrosine residue that regulates the activity of the enzyme in the tyrosine kinase catalytic domain of the cell, forming a docking site for several signaling proteins, which in turn leads to a biological response. c-MET was first isolated from cell lines derived from human osteosarcoma, primarily on epithelial cells. During embryonic development and adulthood, many organ epithelial cells express c-MET receptors on the surface, including liver, pancreas, prostate, kidney, muscle, and bone marrow.
HGF是c-MET的唯一配体。当c-MET与其结合后,触发受体二聚化,从而激活c-MET胞质内蛋白激酶结构域中酪氨酸激酶,引起c-MET羧基末端酪氨酸(Tyrl349、Tyrl356)的自身磷酸化。c-MET激活招募衔接蛋白Gabl和Grb2,激活Shp2、Ras和ERK/MAPK,细胞质中的多种效应蛋白募集到磷酸化的羧基末端并被快速磷酸化,导致激活细胞内多种信号通路,如PI3K/AKT、Ras-Rac/Rho、MAPK及STAT3通路等,促进细胞变形、增殖、抗凋亡、细胞分离、运动和侵袭等多种生物学功能。HGF is the only ligand for c-MET. When c-MET binds to it, it triggers receptor dimerization, thereby activating tyrosine kinase in the c-MET cytoplasmic protein kinase domain, causing autophosphorylation of c-MET carboxy terminal tyrosine (Tyrl349, Tyrl356) Chemical. c-MET activates the recruitment of the adaptor proteins Gabl and Grb2, activates Shp2, Ras and ERK/MAPK, and multiple effector proteins in the cytoplasm are recruited to the phosphorylated carboxy terminus and rapidly phosphorylated, resulting in activation of multiple signaling pathways within the cell, such as PI3K/AKT, Ras-Rac/Rho, MAPK and STAT3 pathways promote various biological functions such as cell deformation, proliferation, anti-apoptosis, cell separation, exercise and invasion.
正常的HGF/c-MET信号通路在不同细胞以及细胞不同分化阶段参与多种生理过程,如胚胎发育过程中控制细胞的迁移,组织损伤后的修复等。但异常的c-MET失调包含过度表达、组成激酶持续激活、基因扩增、通过HGF旁分泌和自分泌激活、c-MET突变以及后继的改变等。异常的HGF/c-MET信号通路在肿瘤发生发展中起非常重要作用,能诱导肿瘤的生长、侵袭、耐药和存活。因此,有效地抑制肿瘤细胞中HGF/c-MET信号通路将会对多种癌症产生显著疗效。The normal HGF/c-MET signaling pathway participates in various physiological processes in different cells and different stages of cell differentiation, such as controlling cell migration during embryonic development and repairing after tissue damage. However, abnormal c-MET disorders include overexpression, sustained activation of constituent kinases, gene amplification, by HGF paracrine and autocrine activation, c-MET mutations, and subsequent changes. Abnormal HGF/c-MET signaling pathway plays a very important role in tumorigenesis and can induce tumor growth, invasion, drug resistance and survival. Therefore, effective inhibition of HGF/c-MET signaling pathways in tumor cells will have a significant effect on a variety of cancers.
因此,本发明研究开发了新的AxL/c-MET抑制剂。其可以单独使用或与其它活性药物联合使用,为癌症的治疗提供广阔的前景。Therefore, the present inventors have developed new AxL/c-MET inhibitors. It can be used alone or in combination with other active drugs, providing a broad prospect for the treatment of cancer.
发明内容Summary of the invention
本发明人经过潜心研究,设计合成了一系列多取代吡啶酮类衍生物,对其进行深入研究的结果显示,该类化合物能够作为有效的Axl/c-MET抑制剂。其可以单独使用或与其它活性药物联合使用,用于治疗癌症,特别是Axl/c-MET高表达的实体瘤或血液肿瘤。The inventors have deliberately studied and designed a series of polysubstituted pyridone derivatives, and intensive studies have shown that such compounds can be used as effective Axl/c-MET inhibitors. It can be used alone or in combination with other active drugs for the treatment of cancer, in particular solid tumors or hematological tumors with high expression of Axl/c-MET.
因此,本发明涉及一种式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,Accordingly, the present invention relates to a compound of the formula (I) or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable form thereof salt,
其中,among them,
W和V各自独立地选自CH、CF或N;W and V are each independently selected from CH, CF or N;
R
a选自-OR
1、-SR
1或-NR
1R
2;
R a is selected from -OR 1 , -SR 1 or -NR 1 R 2 ;
R
1和R
2各自独立地选自氢、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基,所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选 自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代;
R 1 and R 2 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl And a heterocyclic group, an aryl group and a heteroaryl group are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl Substituting one or more groups of a heterocyclic group, an aryl group, or a heteroaryl group;
或者,当R
a为-NR
1R
2时,R
1和R
2与其相连的氮原子一起形成含氮杂环,所述含氮杂环任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代;
Alternatively, when R a is -NR 1 R 2 , R 1 and R 2 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic ring, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano Substituting one or more groups of a group, a hydroxyl group, a thiol group, a carboxyl group, an ester group, an oxo group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group;
R
3选自氢、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基,所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代;
R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic The base and heteroaryl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituting one or more groups of a heteroaryl group;
或者,R
a与R
3连同与R
a相连的羰基和与R
3相连的氮原子一起形成与吡啶酮环稠合的杂环,所述杂环任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代;
Alternatively, R a and R 3 together with a carbonyl group attached to R a and a nitrogen atom bonded to R 3 form a heterocyclic ring fused to a pyridone ring, which is optionally further selected from the group consisting of halogen, amino, and nitro Substituting one or more groups of cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;
或者,当R
a为-NR
1R
2时,R
1和R
2与其相连的氮原子一起形成含氮杂环,并且R
3与该含氮杂环相连进一步形成稠合杂环,所述含氮杂环任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代;
Alternatively, when R a is -NR 1 R 2 , R 1 and R 2 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic ring, and R 3 is bonded to the nitrogen-containing heterocyclic ring to further form a fused heterocyclic ring, said The nitrogen heterocycle is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, thiol, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, Substituting one or more groups of a heteroaryl group;
R
4选自芳基、杂芳基或炔基,所述芳基、杂芳基或炔基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代;
R 4 is selected from an aryl group, a heteroaryl group or an alkynyl group, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, thiol, carboxyl, ester, Substituting one or more groups of oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;
或者,当R
4为芳基或杂芳基时,R
a与R
4相连形成与R
4稠合的杂环,所述杂环任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代;
Alternatively, when R 4 is aryl or heteroaryl, R a is bonded to R 4 to form a heterocyclic ring fused to R 4 , which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, Substituting one or more groups of a hydroxyl group, a mercapto group, a carboxyl group, an ester group, an oxo group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;
R
5选自烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基或OR
6,所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自基团Q的一个或多个基团取代;
R 5 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or OR 6 , said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, The aryl and heteroaryl are optionally further substituted with one or more groups selected from the group Q;
Q选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基;所述烷基、烷氧基、环烷基、杂环基、芳基、杂芳基任选进一步被选自卤素、硝基、氰基、羟基、巯基、氧代基、烷基、环烷基、杂环基、芳基、杂芳基、-OR
b、-O(CH
2)
mOR
b、-OC(O)R
b、-C(O)OR
b、-C(O)NR
bR
c、-NHC(O)R
b、-S(O)R
b、-S(O)
2R
b、-S(O)NR
bR
c、-NR
bR
c、-S(O)
2NR
bR
c、-NHS(O)R
b、-NHS(O)
2R
b的一个或多个基团取代;
Q is selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl; The alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl group is optionally further selected from the group consisting of halogen, nitro, cyano, hydroxy, decyl, oxo, alkyl, cycloalkyl, Heterocyclyl, aryl, heteroaryl, -OR b , -O(CH 2 ) m OR b , -OC(O)R b , -C(O)OR b , -C(O)NR b R c , -NHC(O)R b , -S(O)R b , -S(O) 2 R b , -S(O)NR b R c , -NR b R c , -S(O) 2 NR b Substituting one or more groups of R c , -NHS(O)R b , -NHS(O) 2 R b ;
R
6选自烷基、烷氧基、环烷基、杂环基、芳基、杂芳基;所述烷基、烷氧基、环烷基、杂环基、芳基、杂芳基任选进一步被选自卤素、硝基、氰基、羟基、巯基、氧代基、烷基、环烷基、杂环基、芳基、杂芳基、-OR
b、-O(CH
2)
mOR
b、-OC(O)R
b、-C(O)OR
b、-C(O)NR
bR
c、-NHC(O)R
b、-S(O)R
b、-S(O)
2R
b、-S(O)NR
bR
c、-NR
bR
c、 -S(O)
2NR
bR
c、-NHS(O)R
b、-NHS(O)
2R
b的一个或多个基团取代;
R 6 is selected from the group consisting of alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl; said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl Further selected from the group consisting of halogen, nitro, cyano, hydroxy, decyl, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR b , -O(CH 2 ) m OR b , -OC(O)R b , -C(O)OR b , -C(O)NR b R c , -NHC(O)R b , -S(O)R b , -S(O) 2 R b , -S(O)NR b R c , -NR b R c , -S(O) 2 NR b R c , -NHS(O)R b , -NHS(O) 2 R b Substituting multiple groups;
R
b和R
c各自独立地选自氢、卤素、羟基、烷基、环烷基、杂环基、芳基、杂芳基,其中所述烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代;
R b and R c are each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl And the heteroaryl group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituting one or more groups of a heteroaryl group;
或者R
b和R
c与他们连接的氮原子一起形成含氮杂环基,所述含氮杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代;
Or R b and R c together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, decyl Substituting one or more groups of a carboxyl group, an ester group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;
R
7选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基;所述烷基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代;
R 7 is selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl The alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, thiol, carboxy, ester, and oxygen. Substituting one or more groups of a substituent, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;
m为1至6的整数;m is an integer from 1 to 6;
n为1至4的整数;n is an integer from 1 to 4;
其中,通式(I)化合物中的每一个H原子可以任选独立地被D原子替代。Wherein each H atom of the compound of formula (I) may optionally be independently replaced by a D atom.
在本发明一个优选的实施方案中,根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,In a preferred embodiment of the invention, the compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer thereof, a diastereomer thereof, Or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中,among them,
R
a选自-NR
1R
2;
R a is selected from -NR 1 R 2 ;
R
1和R
2通式(I)所定义。
R 1 and R 2 are as defined by the formula (I).
在本发明另一个优选的实施方案中,根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,In another preferred embodiment of the invention, the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中,among them,
R
1和R
2各自独立地选自氢、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基,所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代;
R 1 and R 2 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl And a heterocyclic group, an aryl group and a heteroaryl group are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl Substituting one or more groups of a heterocyclic group, an aryl group, or a heteroaryl group;
或者,当R
a为-NR
1R
2时,R
1和R
2与其相连的氮原子一起形成含氮杂环,所述含氮杂环任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代;
Alternatively, when R a is -NR 1 R 2 , R 1 and R 2 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic ring, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano Substituting one or more groups of a group, a hydroxyl group, a thiol group, a carboxyl group, an ester group, an oxo group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group;
所述含氮杂环优选4至7元含氮杂环,更优选以下杂环:The nitrogen-containing heterocyclic ring is preferably a 4- to 7-membered nitrogen-containing heterocyclic ring, more preferably the following heterocyclic ring:
R
3选自氢、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基,所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代。
R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic The base and heteroaryl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituting one or more groups of a heteroaryl group.
在本发明另一个优选的实施方案中,根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,In another preferred embodiment of the invention, the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中,among them,
R
a选自-NR
1R
2;
R a is selected from -NR 1 R 2 ;
其中,R
1或R
2与R
3相连形成与吡啶酮环稠合的含氮杂环,所述含氮杂环任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代;
Wherein R 1 or R 2 is bonded to R 3 to form a nitrogen-containing heterocyclic ring fused to a pyridone ring, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, Substituting one or more groups of a carboxyl group, an ester group, an oxo group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;
R
1和R
2各自独立地选自氢、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基,所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代;
R 1 and R 2 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl And a heterocyclic group, an aryl group and a heteroaryl group are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl Substituting one or more groups of a heterocyclic group, an aryl group, or a heteroaryl group;
R
3选自氢、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基,所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代;
R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic The base and heteroaryl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituting one or more groups of a heteroaryl group;
所述与吡啶酮环稠合的含氮杂环优选6或12元含氮杂环,更优选以下含氮杂环:The nitrogen-containing heterocyclic ring fused to the pyridone ring is preferably a 6- or 12-membered nitrogen-containing heterocyclic ring, more preferably the following nitrogen-containing heterocyclic ring:
在本发明另一个优选的实施方案中,根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或 其可药用盐,In another preferred embodiment of the invention, the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中,among them,
R
a选自-NR
1R
2;
R a is selected from -NR 1 R 2 ;
R
1和R
2与其相连的氮原子一起形成含氮杂环,并且R
3与该含氮杂环相连进一步形成稠合杂环,所述稠合杂环任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代;
R 1 and R 2 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic ring, and R 3 is bonded to the nitrogen-containing heterocyclic ring to further form a fused heterocyclic ring, which is optionally further selected from the group consisting of halogen, amino, Substituting one or more groups of nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;
R
1和R
2各自独立地选自氢、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基,所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代;
R 1 and R 2 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl And a heterocyclic group, an aryl group and a heteroaryl group are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl Substituting one or more groups of a heterocyclic group, an aryl group, or a heteroaryl group;
R
3选自氢、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基,所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代;
R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic The base and heteroaryl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituting one or more groups of a heteroaryl group;
所述稠合杂环优选10-12元稠合杂环,更优选:The fused heterocyclic ring is preferably a 10-12 membered fused heterocyclic ring, more preferably:
在本发明另一个优选的实施方案中,根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,其为通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,In another preferred embodiment of the invention, the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (II) or a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a form of the mixture, or a pharmaceutically acceptable salt thereof,
其中,among them,
Y选自CH或N;Y is selected from CH or N;
q为1至4的整数;q is an integer from 1 to 4;
W、V、R
a、R
3、R
4、R
7、Q、n如通式(I)所定义。
W, V, R a , R 3 , R 4 , R 7 , Q, n are as defined in the general formula (I).
在本发明另一个优选的实施方案中,根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,In another preferred embodiment of the invention, the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中,among them,
R
4选自5~6元芳基或杂芳基、或炔基,所述芳基、杂芳基、炔基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代;
R 4 is selected from 5- to 6-membered aryl or heteroaryl, or alkynyl, and the aryl, heteroaryl, alkynyl group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, Substituting one or more groups of a carboxyl group, an ester group, an oxo group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;
所述芳基、杂芳基、炔基优选:The aryl, heteroaryl, alkynyl group is preferably:
在本发明另一个优选的实施方案中,根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,其为通式(III)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,In another preferred embodiment of the invention, the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (III) or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a form of the mixture, or a pharmaceutically acceptable salt thereof,
其中,among them,
Y选自CH或N;Y is selected from CH or N;
R
8选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基;
R 8 is selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
p为1至4的整数;p is an integer from 1 to 4;
q为1至4的整数;q is an integer from 1 to 4;
W、V、R
a、R
3、R
7、Q、n如通式(I)所定义。
W, V, R a , R 3 , R 7 , Q, n are as defined in the general formula (I).
在本发明另一个优选的实施方案中,根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,其为通式(IV)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,In another preferred embodiment of the invention, the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (IV) or a mesogen, racemate, enantiomer, diastereomer thereof, or a form of the mixture, or a pharmaceutically acceptable salt thereof,
其中,among them,
Y选自CH或N;Y is selected from CH or N;
R
8选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基;
R 8 is selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
Q选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基;所述烷基、烷氧基、环烷基、杂环基、芳基、杂芳基任选进一步被选自卤素、硝基、氰基、羟基、巯基、氧代基、烷基、环烷基、杂环基、芳基、杂芳基、-OR
b、-O(CH
2)
mOR
b、-OC(O)R
b、-C(O)OR
b、-C(O)NR
bR
c、-NHC(O)R
b、-S(O)R
b、-S(O)
2R
b、-S(O)NR
bR
c、-NR
bR
c、-S(O)
2NR
bR
c、-NHS(O)R
b、-NHS(O)
2R
b的一个或多个基团取代;
Q is selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl; The alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl group is optionally further selected from the group consisting of halogen, nitro, cyano, hydroxy, decyl, oxo, alkyl, cycloalkyl, Heterocyclyl, aryl, heteroaryl, -OR b , -O(CH 2 ) m OR b , -OC(O)R b , -C(O)OR b , -C(O)NR b R c , -NHC(O)R b , -S(O)R b , -S(O) 2 R b , -S(O)NR b R c , -NR b R c , -S(O) 2 NR b Substituting one or more groups of R c , -NHS(O)R b , -NHS(O) 2 R b ;
Q’选自-NR
bR
c;
Q' is selected from -NR b R c ;
R
b和R
c各自独立地选自氢、卤素、羟基、烷基、环烷基、杂环基、芳基、杂芳基,其中所述烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代;
R b and R c are each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl And the heteroaryl group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituting one or more groups of a heteroaryl group;
或者R
b和R
c与他们连接的氮原子一起形成含氮杂环基,所述含氮杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代;
Or R b and R c together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, decyl Substituting one or more groups of a carboxyl group, an ester group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;
p为1至4的整数;p is an integer from 1 to 4;
W、V、R
a、R
3、R
7、m、n如通式(I)所定义。
W, V, R a , R 3 , R 7 , m, n are as defined in the general formula (I).
在本发明另一个优选的实施方案中,根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,In another preferred embodiment of the invention, the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中,among them,
Q选自芳基或杂芳基;所述芳基或杂芳基任选进一步被选自卤素、烷基、环烷 基、杂环基、-OR
b、-O(CH
2)
mOR
b的一个或多个基团取代;
Q is selected from aryl or heteroaryl; the aryl or heteroaryl is optionally further selected from the group consisting of halogen, alkyl, cycloalkyl, heterocyclyl, -OR b , -O(CH 2 ) m OR b Substituted by one or more groups;
R
b选自氢、烷基和环烷基,其中所述烷基和环烷基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、环烷基、杂环基的一个或多个基团取代;
R b is selected from the group consisting of hydrogen, alkyl and cycloalkyl, wherein the alkyl and cycloalkyl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo. Substituting one or more groups of a cycloalkyl group or a heterocyclic group;
m为1至6的整数。m is an integer from 1 to 6.
在本发明另一个优选的实施方案中,根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,In another preferred embodiment of the invention, the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中,among them,
R
a选自-NR
1R
2;
R a is selected from -NR 1 R 2 ;
R
1或R
2与R
4相连形成与R
4稠合的杂环,优选6元杂环,所述杂环任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代;
R 1 or R 2 is bonded to R 4 to form a heterocyclic ring fused to R 4 , preferably a 6-membered heterocyclic ring, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy Substituting one or more groups of an ester group, an oxo group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;
R
1和R
2各自独立地选自氢、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基,所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代;
R 1 and R 2 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl And a heterocyclic group, an aryl group and a heteroaryl group are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl Substituting one or more groups of a heterocyclic group, an aryl group, or a heteroaryl group;
R
3选自氢、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基,所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代。
R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic The base and heteroaryl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituting one or more groups of a heteroaryl group.
在本发明另一个优选的实施方案中,根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,In another preferred embodiment of the invention, the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中,among them,
R
5为OR
6或SR
6;
R 5 is OR 6 or SR 6 ;
R
6如通式(I)所定义;
R 6 is as defined in the general formula (I);
在本发明另一个优选的实施方案中,根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,In another preferred embodiment of the invention, the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中,among them,
R
6选自芳基和杂芳基;所述芳基和杂芳基任选进一步被选自卤素、羟基、巯基、氧代基、烷基、环烷基、杂环基、芳基、杂芳基、-OR
b、-O(CH
2)
mOR
b、-NR
bR
c的一个或多个基团取代;
R 6 is selected from the group consisting of aryl and heteroaryl; the aryl and heteroaryl are optionally further selected from the group consisting of halogen, hydroxy, thiol, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, hetero Substituting one or more groups of aryl, -OR b , -O(CH 2 ) m OR b , -NR b R c ;
R
b和R
c各自独立地选自氢、卤素、烷基、环烷基,其中所述烷基、环烷基、任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、 环烷基、杂环基的一个或多个基团取代;
R b and R c are each independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, wherein the alkyl, cycloalkyl, optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl Substituting one or more groups of a carboxyl group, an ester group, an oxo group, a cycloalkyl group, or a heterocyclic group;
或者R
b和R
c与他们连接的氮原子一起形成含氮杂环基,所述含氮杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代;
Or R b and R c together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, decyl Substituting one or more groups of a carboxyl group, an ester group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;
m为1至6的整数。m is an integer from 1 to 6.
在本发明另一个优选的实施方案中,根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,In another preferred embodiment of the invention, the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中,among them,
R
7选自氢、卤素、烷基,所述烷基任选进一步被一个或多个卤素取代;
R 7 is selected from the group consisting of hydrogen, halogen, alkyl, and the alkyl group is optionally further substituted with one or more halogens;
n为1或2。n is 1 or 2.
在本发明另一个优选的实施方案中,根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,In another preferred embodiment of the invention, the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中,among them,
R
5为下列基团:
R 5 is the following group:
本发明典型的化合物包括但不限于以下化合物:Exemplary compounds of the invention include, but are not limited to, the following compounds:
或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐。Or a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
本发明另一方面提供一种通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的制备方法,其包含以下步骤:Another aspect of the invention provides a compound of the formula (I) or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or A method for preparing a medicinal salt, comprising the steps of:
当R
a选自-NR
1R
2时,
When R a is selected when R 2 -NR 1,
将N-R
3-6-(乙氧基羰基)-5-R
4-4-氧代-1,4-二氢吡啶-3-芳酰胺(Ig)直接与R
1R
2NH进行胺酯交换反应,得到通式(I)化合物;
Amine transesterification of NR 3 -6-(ethoxycarbonyl)-5-R 4 -4-oxo-1,4-dihydropyridine-3-arylamide (Ig) directly with R 1 R 2 NH To obtain a compound of the formula (I);
或者将N-R
3-6-(乙氧基羰基)-5-R
4-4-氧代-1,4-二氢吡啶-3-芳酰胺(Ig)先进行酯基水解,再与R
1R
2NH进行酰胺化反应,经由两步过程得到通式(I)化合物;
Or NR 3 -6-(ethoxycarbonyl)-5-R 4 -4-oxo-1,4-dihydropyridine-3-arylamide (Ig) is first subjected to ester hydrolysis, and then to R 1 R 2 NH is subjected to amidation reaction to obtain a compound of the formula (I) via a two-step process;
当R
a选自-OR
1或-SR
1时,
When R a is selected from -OR 1 when 1 or -SR,
将N-R
3-6-(乙氧基羰基)-5-R
4-4-氧代-1,4-二氢吡啶-3-芳酰胺(Ig)先进行酯基水解,所得酸(Ig’)再在EDCI的作用下与醇或硫醇反应得到通式(I)化合物;
The NR 3 -6-(ethoxycarbonyl)-5-R 4 -4-oxo-1,4-dihydropyridine-3-arylamide (Ig) is first subjected to ester hydrolysis to obtain the acid (Ig'). Further reacting with an alcohol or a thiol under the action of EDCI to obtain a compound of the formula (I);
其中,R
1、R
2、R
3、R
4、R
5、R
7、W、V、n如通式(I)所定义。
Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , W, V, n are as defined in the formula (I).
本发明进一步提供一种药物组合物,其含有根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,以及一种或多种药学上可接受的载体、稀释剂或赋形剂。所述药物组合物还可以进一步含有另一种治疗活性成分,所述另一种治疗活性成分优选为治疗癌症的药物,所述癌症优选直肠癌、肠癌、胰腺癌、乳腺癌、前列腺癌、食道癌、胃癌、血癌、肺癌、肝癌、甲状腺癌、肉瘤、脑癌、皮肤癌、头颈癌、鼻咽癌、卵巢癌、宫颈癌、膀胱癌和肾癌,更优选血癌、肺癌、乳腺癌、胰腺癌和胃癌。The invention further provides a pharmaceutical composition comprising a compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer thereof, a diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients. The pharmaceutical composition may further comprise another therapeutically active ingredient, preferably another therapeutically active ingredient, preferably a rectal cancer, an intestinal cancer, a pancreatic cancer, a breast cancer, a prostate cancer, Esophageal cancer, gastric cancer, blood cancer, lung cancer, liver cancer, thyroid cancer, sarcoma, brain cancer, skin cancer, head and neck cancer, nasopharyngeal cancer, ovarian cancer, cervical cancer, bladder cancer and kidney cancer, more preferably blood cancer, lung cancer, breast cancer, Pancreatic cancer and stomach cancer.
本发明还涉及一种制备上述组合物的方法,其包括将通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐与药学上可接受的载体、稀释剂或赋形剂相混合。The present invention also relates to a process for the preparation of the above composition, which comprises the compound of the formula (I) or a racemate, a racemate, an enantiomer thereof, a diastereomer thereof, Or a mixture thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, is admixed with a pharmaceutically acceptable carrier, diluent or excipient.
本发明进一步提供一种根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,或含有其的药物组合物在制备Axl/c-MET抑制剂中的用途。The invention further provides a compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for use in the preparation of an Axl/c-MET inhibitor.
本发明进一步提供一种根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,或含有其的药物组合物在制备治疗癌症的药物中的用途。所述癌症优选直肠癌、肠癌、胰腺癌、乳腺癌、前列腺癌、食道癌、胃癌、血癌、肺癌、肝癌、甲状腺癌、肉瘤、脑癌、皮肤癌、头颈癌、鼻咽癌、卵巢癌、宫颈癌、膀胱癌和肾癌, 更优选血癌、肺癌、乳腺癌、胰腺癌和胃癌。The invention further provides a compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for use in the manufacture of a medicament for treating cancer. The cancer is preferably rectal cancer, intestinal cancer, pancreatic cancer, breast cancer, prostate cancer, esophageal cancer, gastric cancer, blood cancer, lung cancer, liver cancer, thyroid cancer, sarcoma, brain cancer, skin cancer, head and neck cancer, nasopharyngeal cancer, ovarian cancer. , cervical cancer, bladder cancer and kidney cancer, more preferably blood cancer, lung cancer, breast cancer, pancreatic cancer and gastric cancer.
本发明另一方面提供根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐与另一种治疗活性成分联合,在制备治疗癌症的药物中的用途,其中所述另一种治疗活性成分与通式(I)所示的化合物同时、分开或相继使用;所述癌症优选直肠癌、肠癌、胰腺癌、乳腺癌、前列腺癌、食道癌、胃癌、血癌、肺癌、肝癌、甲状腺癌、肉瘤、脑癌、皮肤癌、头颈癌、鼻咽癌、卵巢癌、宫颈癌、膀胱癌和肾癌,更优选血癌、肺癌、乳腺癌、胰腺癌和胃癌。According to a further aspect of the invention there is provided a compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Or a pharmaceutically acceptable salt thereof, in combination with another therapeutically active ingredient, for use in the manufacture of a medicament for the treatment of cancer, wherein the other therapeutically active ingredient is simultaneously, separately or sequentially with the compound of formula (I) The cancer is preferably rectal cancer, intestinal cancer, pancreatic cancer, breast cancer, prostate cancer, esophageal cancer, gastric cancer, blood cancer, lung cancer, liver cancer, thyroid cancer, sarcoma, brain cancer, skin cancer, head and neck cancer, nasopharyngeal cancer, Ovarian cancer, cervical cancer, bladder cancer, and kidney cancer, and more preferably, blood cancer, lung cancer, breast cancer, pancreatic cancer, and stomach cancer.
本发明进一步提供一种根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,或含有其的药物组合物,其用作Axl/c-MET抑制剂。The invention further provides a compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as an Axl/c-MET inhibitor.
本发明进一步提供一种根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,或含有其的药物组合物,其用作治疗癌症的药物;所述癌症优选直肠癌、肠癌、胰腺癌、乳腺癌、前列腺癌、食道癌、胃癌、血癌、肺癌、肝癌、甲状腺癌、肉瘤、脑癌、皮肤癌、头颈癌、鼻咽癌、卵巢癌、宫颈癌、膀胱癌和肾癌,更优选血癌、肺癌、乳腺癌、胰腺癌和胃癌。The invention further provides a compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as a medicament for treating cancer; the cancer is preferably rectal cancer, intestinal cancer, pancreatic cancer, breast cancer, prostate cancer, esophageal cancer, gastric cancer, blood cancer, Lung cancer, liver cancer, thyroid cancer, sarcoma, brain cancer, skin cancer, head and neck cancer, nasopharyngeal cancer, ovarian cancer, cervical cancer, bladder cancer, and kidney cancer, and more preferably, blood cancer, lung cancer, breast cancer, pancreatic cancer, and stomach cancer.
本发明另一方面提供根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,或含有其的药物组合物,其用于与另一种治疗活性成分联合,其中所述另一种治疗活性成分与通式(I)所示的化合物同时、分开或相继使用;所述癌症优选直肠癌、肠癌、胰腺癌、乳腺癌、前列腺癌、食道癌、胃癌、血癌、肺癌、肝癌、甲状腺癌、肉瘤、脑癌、皮肤癌、头颈癌、鼻咽癌、卵巢癌、宫颈癌、膀胱癌和肾癌,更优选血癌、肺癌、乳腺癌、胰腺癌和胃癌。According to a further aspect of the invention there is provided a compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same, for use in combination with another therapeutically active ingredient, wherein the other therapeutically active ingredient is simultaneously and separately separated from the compound of formula (I) Or used sequentially; the cancer is preferably rectal cancer, intestinal cancer, pancreatic cancer, breast cancer, prostate cancer, esophageal cancer, gastric cancer, blood cancer, lung cancer, liver cancer, thyroid cancer, sarcoma, brain cancer, skin cancer, head and neck cancer, nasopharyngeal Cancer, ovarian cancer, cervical cancer, bladder cancer, and kidney cancer, and more preferably, blood cancer, lung cancer, breast cancer, pancreatic cancer, and stomach cancer.
一种治疗癌症的方法,其包含向有需要的患者施用治疗有效量的根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,或含有其的药物组合物,所述癌症优选直肠癌、肠癌、胰腺癌、乳腺癌、前列腺癌、食道癌、胃癌、血癌、肺癌、肝癌、甲状腺癌、肉瘤、脑癌、皮肤癌、头颈癌、鼻咽癌、卵巢癌、宫颈癌、膀胱癌和肾癌,更优选血癌、肺癌、乳腺癌、胰腺癌和胃癌。A method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) according to the invention or a mesogen, racemate, enantiomer thereof a form, a mixture of diastereomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, preferably a rectal cancer, an intestinal cancer, a pancreatic cancer, a breast cancer, a prostate cancer, an esophageal cancer , gastric cancer, blood cancer, lung cancer, liver cancer, thyroid cancer, sarcoma, brain cancer, skin cancer, head and neck cancer, nasopharyngeal cancer, ovarian cancer, cervical cancer, bladder cancer and kidney cancer, more preferably blood cancer, lung cancer, breast cancer, pancreatic cancer And stomach cancer.
一种治疗癌症的方法,其包含向有需要的患者施用治疗有效量的根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,或含有其的药物组合物,与另一种治疗活性成分,其中所述另一种治疗活性成分与通式(I)所示的化合物同时、分开或相继使用;所述癌症优选直肠癌、肠癌、胰腺癌、乳腺癌、前列腺癌、食道癌、胃癌、血癌、肺癌、肝癌、甲状腺癌、肉瘤、脑癌、皮肤癌、头颈癌、鼻咽癌、 卵巢癌、宫颈癌、膀胱癌和肾癌,更优选血癌、肺癌、乳腺癌、胰腺癌和胃癌。A method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) according to the invention or a mesogen, racemate, enantiomer thereof , a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition therewith, and another therapeutically active ingredient, wherein the other therapeutically active ingredient The compounds shown in I) are used simultaneously, separately or sequentially; the cancer is preferably rectal cancer, intestinal cancer, pancreatic cancer, breast cancer, prostate cancer, esophageal cancer, gastric cancer, blood cancer, lung cancer, liver cancer, thyroid cancer, sarcoma, brain cancer , skin cancer, head and neck cancer, nasopharyngeal cancer, ovarian cancer, cervical cancer, bladder cancer and kidney cancer, more preferably blood cancer, lung cancer, breast cancer, pancreatic cancer and gastric cancer.
按照本发明所属领域的常规方法,本发明通式(I)所示的化合物可以与酸生成药学上可接受的酸式加成盐。所述酸包括无机酸和有机酸,可以接受的无机酸包括盐酸、氢溴酸、硫酸、磷酸等,可以接受的有机酸包括甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、三氟乙酸、马来酸、柠檬酸、富马酸、草酸、酒石酸、苯甲酸等。The compound of the formula (I) of the present invention can form a pharmaceutically acceptable acid addition salt with an acid according to a conventional method in the art to which the present invention pertains. The acid includes inorganic acids and organic acids, and acceptable inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc. Acceptable organic acids include methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, Naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, and the like.
按照本发明所属领域的常规方法,本发明通式(I)所示的化合物可以与碱生成药学上可接受的碱式加成盐。所述碱包括无机碱和有机碱,可接受的有机碱包括二乙醇胺、乙醇胺、N-甲基葡糖胺、三乙醇胺、氨丁三醇等,可接受的无机碱包括氢氧化铝、氢氧化钙、氢氧化钾、碳酸钠和氢氧化钠等。The compound of the formula (I) of the present invention can form a pharmaceutically acceptable base addition salt with a base according to a conventional method in the art to which the present invention pertains. The base includes an inorganic base and an organic base, and acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, etc., and acceptable inorganic bases include aluminum hydroxide and hydroxide. Calcium, potassium hydroxide, sodium carbonate and sodium hydroxide.
本发明的药物组合物包括任意一种或更多种本发明所述的化合物(或其可药用盐、溶剂化物、水合物、前药或衍生物)以及任选地包括药学上可接受的载体。在某些实施方案中,这些组合物任选地还包括一种或多种其他治疗药物。可选地,本发明的化合物可联合一种或多种其他治疗药物,向有此需求的患者施用。还要理解的是,本发明的某些化合物可以以游离的形式,或适当时,以其可药用盐的形式存在以用于治疗。The pharmaceutical composition of the present invention includes any one or more of the compounds of the present invention (or a pharmaceutically acceptable salt, solvate, hydrate, prodrug or derivative thereof) and optionally a pharmaceutically acceptable Carrier. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents. Alternatively, the compounds of the invention may be administered to a patient in need thereof in combination with one or more other therapeutic agents. It will also be understood that certain compounds of the invention may exist in free form or, where appropriate, in the form of their pharmaceutically acceptable salts for therapeutic use.
如上所述,本发明的药物组合物还包括药学上可接受的载体。在本文中,所述载体包括任何或所有溶剂、稀释剂、或其他液体载体、分散或悬浮辅助剂、表面活性剂、等渗剂、增稠或乳化剂、防腐剂、固体粘合剂、润滑剂等,其调整为所需的特定剂量形式。Remington’s Pharmaceutical Sciences,Sixteenth Edition,E.W.Martin(Mack Publishing Co.,Easton,Pa.,1980)公开了各种用于配制药物组合物的载体,以及用于其制备的已知技术。除非任何常规载体介质与本发明的化合物不相容,例如通过产生任何不期望的生物作用或者和药物组合物的任何其他成分以有害的方式相互作用,否则其用途预计属于本发明范围内。可以作为药学上可接受的载体的材料的一些示例包括但不限于:糖例如乳糖、葡萄糖和蔗糖;淀粉例如玉米淀粉和马铃薯淀粉;纤维素及其衍生物例如羧甲基纤维素钠、乙基纤维素和醋酸纤维素;粉状西黄蓍胶;麦芽糖;明胶;滑石粉;赋形剂如可可脂和栓剂蜡;油例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油;二元醇类例如丙二醇;酯例如油酸乙酯和月桂酸乙酯;琼脂;缓冲剂例如氢氧化镁和氢氧化铝;褐藻酸;无热原的水;等渗盐水;林格溶液(Ringer’s solution);乙醇和磷酸盐缓冲溶液;以及其他无毒可相容的润滑剂例如十二烷基硫酸钠和硬脂酸镁;以及根据配制者的判断,组合物中还可存在着色剂、释放剂、包衣剂、甜味剂、调味剂和芳香剂、防腐剂和抗氧化剂。As stated above, the pharmaceutical compositions of the present invention also include a pharmaceutically acceptable carrier. As used herein, the carrier includes any or all solvents, diluents, or other liquid carriers, dispersion or suspending adjuvants, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricating agents Agents, etc., which are adjusted to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers for formulating pharmaceutical compositions, as well as known techniques for their preparation. The use of any conventional carrier medium is contemplated to be within the scope of the invention unless it is incompatible with the compounds of the invention, for example, by producing any undesirable biological effects or interacting in a deleterious manner with any other component of the pharmaceutical composition. Some examples of materials that can be used as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl Cellulose and cellulose acetate; powdered tragacanth; maltose; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and Soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol and phosphate buffer solutions; and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate; and, depending on the formulator's judgment, coloring may also be present in the composition. Agents, release agents, coating agents, sweeteners, flavoring and fragrances, preservatives and antioxidants.
本发明化合物可以通过各种给药途径施用于患者。这些给药途径包括但不限于:口服、舌下含服、皮下注射、静脉注射、滴鼻、表面涂抹、皮渗透、腹腔内给药、肌肉注射、肺部给药等。The compounds of the invention can be administered to a patient by a variety of routes of administration. These routes of administration include, but are not limited to, oral, sublingual, subcutaneous, intravenous, nasal, topical, dermal, intraperitoneal, intramuscular, pulmonary, and the like.
含活性成分的药物组合物可以为固体、半固体、液体和气雾剂的形式,例如,片剂、颗粒剂、胶囊、粉末剂、液体、混悬剂、栓剂等。也可以缓释的方式例如通过长效注射剂、渗透泵、药丸、贴剂等方式给药。The pharmaceutical compositions containing the active ingredient may be in the form of solids, semi-solids, liquids and aerosols, for example, tablets, granules, capsules, powders, liquids, suspensions, suppositories, and the like. It can also be administered in a sustained release manner, for example, by a long-acting injection, an osmotic pump, a pill, a patch, or the like.
用于口服施用的固体剂型包括胶囊、片剂、丸剂、粉剂和颗粒剂。在这样的固体剂型中,活性化合物和至少一种惰性可药用赋形剂或载体相混合,例如a)填料或填充剂,例如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸,b)粘合剂,例如羧甲基纤维素、海藻酸盐/酯、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯树胶,c)保湿剂例如甘油,d)崩解剂,例如琼脂、碳酸钙、马铃薯或木薯淀粉、褐藻酸、某些硅酸盐和碳酸钠,e)溶液阻滞剂(solutionretardingagent),例如石蜡,f)吸收加速剂,例如季铵盐化合物,g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯,h)吸收剂,例如高岭土和膨润土,以及i)润滑剂,例如滑石粉、硬脂酸钙、硬脂酸镁,固体聚乙二醇、十二烷基硫酸钠,及其混合物。在胶囊、片剂和丸剂的情况下,所述剂型还可包括缓冲剂。Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier, such as a) filler or filler, such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) viscous Mixtures such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, c) humectants such as glycerin, d) disintegrants such as agar, calcium carbonate, potato or tapioca starch , alginic acid, certain silicates and sodium carbonate, e) solution retarding agents, such as paraffin, f) absorption accelerators, such as quaternary ammonium compounds, g) wetting agents, such as cetyl alcohol and mono-hard Glycerol, h) absorbents such as kaolin and bentonite, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixture. In the case of capsules, tablets, and pills, the dosage form can also include a buffer.
相似类型的固体组合物也可作为填充剂用于填充软或硬明胶胶囊,其使用例如乳糖以及高分子量聚乙二醇的赋形剂。可将片剂、糖衣剂(dragee)、胶囊剂、丸剂和颗粒剂的固体剂型制备成具有包衣和壳层(shell)(例如肠溶衣以及药物制剂领域公知的其他包衣)。其可任选包含遮光剂(opacifying agent),还可以是仅在或优选在肠道中的某些部分释放,任选地以延迟的方式释放所述活性成分的组合物。可用的包埋组合物的示例包括高分子物质和蜡。Solid compositions of a similar type may also be employed as fillers in filling soft or hard gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycols. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells (e.g., enteric coatings and other coatings well known in the pharmaceutical formulation art). It may optionally comprise an opacifying agent, and may also be a composition which is released only, or preferably in certain parts of the intestinal tract, optionally releasing the active ingredient in a delayed manner. Examples of useful embedding compositions include polymeric materials and waxes.
用于口服施用的液体剂型包括但不限于可药用乳剂、微乳剂、溶液剂、混悬剂、糖浆剂和酏剂。除了活性化合物,液体剂型还可以包含现有技术中常用的惰性稀释剂,例如水或其他溶剂,增溶剂和乳化剂例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油(尤其是棉籽、落花生(花生)、玉米、胚芽、橄榄、蓖麻和芝麻的油)、甘油、四氢糠醇、聚乙二醇和山梨聚糖脂肪酸酯,及其混合物。除了惰性稀释剂,口服组合物也可包括佐剂(adjuvant),例如润湿剂、乳化和混悬剂、甜味剂、调味剂和芳香剂。Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzoic acid Benzyl ester, propylene glycol, 1,3-butanediol, dimethylformamide, oil (especially cottonseed, groundnut (peanut), corn, germ, olive, ramie and sesame oil), glycerin, tetrahydrofurfuryl alcohol, Polyethylene glycol and sorbitan fatty acid esters, and mixtures thereof. Besides inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
可注射制剂,例如,根据现有技术可以使用适当的分散或润湿剂和混悬剂配制无菌可注射水性或油性混悬液。所述无菌可注射制剂也可以是在无毒肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液、混悬液或乳液,例如,1,3-丁二醇中的溶液。可接受的载体或溶剂包括水、林格溶液、和等渗氯化钠溶液。此外,无菌、固定油常规用作溶剂或混悬基质。出于此目的,可以使用任何温和的固定油,包括制备的单甘油酯或甘油二酯。此外,脂肪酸例如油酸可用于注射物的制备。可注射制剂可以是无菌的,例如,通过细菌-阻留过滤器进行过滤,或通过使用前以无菌固体组合物的形式加入杀菌剂,其可以溶于或分散于无菌水或其他无菌可注射介质中。Injectable preparations, for example, may be formulated in accordance with the prior art using suitable dispersion or wetting agents and suspensions. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Acceptable carriers or solvents include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspension. For this purpose any bland fixed oil may be employed, including the prepared mono or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. The injectable preparation may be sterile, for example, by filtration through a bacteria-resistance filter, or by adding a bactericidal agent in the form of a sterile solid composition before use, which may be dissolved or dispersed in sterile water or other In bacteria injectable medium.
用于直肠或阴道施用的组合物优选栓剂,可以通过将本发明化合物和合适的 非刺激性赋形剂或载体(例如,可可脂、聚乙二醇或栓剂蜡)混合来制备,其在环境温度下是固体,在体温下是液体,因此在直肠或阴道腔中融化并释放活性化合物。Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by admixing a compound of the present invention with a suitable non- irritating excipient or carrier (for example, cocoa butter, polyethylene glycol or suppository wax) in the environment It is a solid at temperature and is a liquid at body temperature, thus melting and releasing the active compound in the rectum or vaginal cavity.
本领域技术人员熟知,药物的给药剂量依赖于多种因素,包括但并非限定于以下因素:所用特定化合物的活性、病人的年龄、病人的体重、病人的健康状况、病人的行被、病人的饮食、给药时间、给药方式、排泄的速率、药物的组合等。另外,最佳的治疗方式如治疗的模式、通式化合物的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。It is well known to those skilled in the art that the dosage of the drug to be administered depends on a variety of factors including, but not limited to, the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the conduct of the patient, the patient Diet, time of administration, mode of administration, rate of excretion, combination of drugs, and the like. In addition, the optimal mode of treatment, such as the mode of treatment, the daily amount of the compound of the formula, or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment regimens.
还要理解的是,可以配制本发明的化合物或药物组合物,并用于联合治疗,即化合物和药物组合物可以与同一种或多种其他期望的疗法或医疗程序同时、在先或随后配制或施用。以组合方案采用的具体治疗组合(疗法或程序)将考虑到所需的疗法和/或程序的相容性,以及要达到的理想治疗作用。It will also be understood that the compounds or pharmaceutical compositions of the invention may be formulated and used in combination therapy, i.e., the compounds and pharmaceutical compositions may be formulated simultaneously, prior or subsequently with one or more other desired therapies or procedures. Apply. The particular combination of treatments (therapies or procedures) employed in the combination regimen will take into account the compatibility of the desired therapy and/or procedure, as well as the desired therapeutic effect to be achieved.
发明的详细说明Detailed description of the invention
除非有相反陈述,在说明书和权利要求书中使用的术语具有下述含义。Terms used in the specification and claims have the following meanings unless stated to the contrary.
术语“烷基”指饱和脂肪族烃基团,其为包含1至20个碳原子的直链或支链基团,优选含有1至12个碳原子的烷基,更优选含有1至6个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基,及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基,非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的,当被取代时,取代基可以在任何可使用的连接点上被取代,所述取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基 或羧酸酯基。The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 12 carbon atoms, more preferably from 1 to 6 carbons. The alkyl group of the atom. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 - dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2 , 5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-B Hexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-decyl, 2-methyl-2-ethylhexyl, 2-methyl-3-B Hexyl group, 2,2- Diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from the group consisting of an alkane Base, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, naphthenic An oxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
术语“烯基”指由至少两个碳原子和至少一个碳-碳双键组成的如上定义的烷基,例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。烯基可以是取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3- Butyl group and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio group.
术语“炔基”指由至少两个碳原子和至少一个碳-碳三键组成的如上定义的烷基,例如乙炔基、丙炔基、丁炔基等。炔基可以是取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。The term "alkynyl" refers to an alkyl radical as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, propynyl, butynyl and the like. The alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio group.
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基,环烷基环包含3至20个碳原子,优选包含3至12个碳原子,更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等;多环环烷基包括螺环、稠环和桥环的环烷基。The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. One carbon atom. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene A polycycloalkyl group includes a spiro ring, a fused ring, and a cycloalkyl group.
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团,其可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统。优选为6至14元,更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基,优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括:The term "spirocycloalkyl" refers to a polycyclic group that shares a carbon atom (referred to as a spiro atom) between 5 to 20 members of a single ring, which may contain one or more double bonds, but none of the rings have a fully conjugated π electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members. The spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the rings. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:
术语“稠环烷基”指5至20元,系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团,其中一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基,优选为双环或三环,更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括:The term "fused cycloalkyl" refers to 5 to 20 members, and each ring in the system shares an all-carbon polycyclic group of an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic or tricyclic ring, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group. Non-limiting examples of fused cycloalkyl groups include:
术语“桥环烷基”指5至20元,任意两个环共用两个不直接连接的碳原子的全碳多环基团,其可以含有一个或多个双键,但没有一个环具有完全共轭的π电 子系统。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基,优选为双环、三环或四环,更有选为双环或三环。桥环烷基的非限制性实例包括:The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have complete Conjugate π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring. Non-limiting examples of bridged cycloalkyl groups include:
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上,其中与母体结构连接在一起的环为环烷基,非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Base, benzocycloheptyl and the like. The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
术语“杂环基”或“杂环”指饱和或部分不饱和单环或多环环状烃取代基,其包含3至20个环原子,其中一个或多个环原子为选自氮、氧或S(O)
m(其中m是整数0至2)的杂原子,但不包括-O-O-、-O-S-或-S-S-的环部分,其余环原子为碳。优选包含3至12个环原子,其中1~4个是杂原子;最优选包含3至8个环原子,其中1~3个是杂原子;最优选包含5至7个环原子,其中1~2或1~3个是杂原子。单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基等,优选1、2、5-噁二唑基、吡喃基或吗啉基。多环杂环基包括螺环、稠环和桥环的杂环基。
The term "heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more ring atoms are selected from the group consisting of nitrogen and oxygen. Or a hetero atom of S(O) m (where m is an integer of 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. Preferably comprising from 3 to 12 ring atoms, wherein from 1 to 4 are heteroatoms; most preferably from 3 to 8 ring atoms, wherein from 1 to 3 are heteroatoms; most preferably from 5 to 7 ring atoms, wherein 1 to 2 or 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine. The group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl and the like are preferably 1, 2, 5-oxadiazolyl, pyranyl or morpholinyl. Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
术语“螺杂环基”或“螺杂环”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团,其中一个或多个环原子为选自氮、氧或S(O)
m(其中m是整数0至2)的杂原子,其余环原子为碳。其可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统。优选为6至14元,更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基,优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括:
The term "spiroheterocyclyl" or "spiroheterocycle" refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between 5 to 20 members of a single ring, wherein one or more ring atoms are selected from nitrogen. a hetero atom of oxygen or S(O) m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. The spiroheterocyclyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of shared spiro atoms between the ring and the ring, and is preferably a monospiroheterocyclic group and a dispiroheterocyclic group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospiroheterocyclic group. Non-limiting examples of spiroheterocyclyl groups include:
术语“稠杂环基”或“稠合杂环”指5至20元,系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团,一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统,其中一个或多个环原子为选自 氮、氧或S(O)
m(其中m是整数0至2)的杂原子,其余环原子为碳。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基,优选为双环或三环,更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括:
The term "fused heterocyclic" or "fused heterocyclic" refers to 5 to 20 members, each ring of the system sharing an adjacent pair of atomic polycyclic heterocyclic groups with one or more of the other rings in the system, one or more A ring may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system in which one or more ring atoms are selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2) a hetero atom, the remaining ring atoms being carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic ring, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:
术语“桥杂环基”或“桥杂环”指5至14元,任意两个环共用两个不直接连接的原子的多环杂环基团,其可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统,其中一个或多个环原子为选自氮、氧或S(O)
m(其中m是整数0至2)的杂原子,其余环原子为碳。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基,优选为双环、三环或四环,更有选为双环或三环。桥杂环基的非限制性实例包括:
The term "bridge heterocyclyl" or "bridge heterocycle" refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms which are not directly bonded, which may contain one or more double bonds, but None of the rings have a fully conjugated π-electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring. Non-limiting examples of bridge heterocyclic groups include:
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上,其中与母体结构连接在一起的环为杂环基,其非限制性实例包括:The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples of which include:
杂环基可以是任选取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团,优选为6至10元,例如苯基和萘基。更优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为芳基环,其非限制性实例包括:The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms) having a conjugated π-electron system, preferably 6 to 10 members, such as benzene. Base and naphthyl. More preferred is phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include:
芳基可以是取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle An alkylthio group, a carboxyl group or a carboxylate group.
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系,其中杂原子选自氧、硫和氮。杂芳基优选为5至10元,含1至3个杂原子;更优选为5元或6元,含1至2个杂原子;优选例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等,优选为咪唑基、噻唑基、吡唑基或嘧啶基、噻唑基;更有选吡唑基或噻唑基。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环,其非限制性实例包括:The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 10 members, and has 1 to 3 hetero atoms; more preferably 5 or 6 members, and 1 to 2 hetero atoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyridyl An oxazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more selective Pyrazolyl or thiazolyl. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples of which include:
杂芳基可以是任选取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基),其中烷基的定义如上所述。烷氧基的非限制性实例包括:甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.
术语“卤代烷基”指被一个或多个卤素取代的烷基,其中烷基如上所定义。The term "haloalkyl" refers to an alkyl group substituted by one or more halogens, wherein alkyl is as defined above.
术语“卤代烷氧基”指被一个或多个卤素取代的烷氧基,其中烷氧基如上所定义。The term "haloalkoxy" refers to an alkoxy group substituted by one or more halogens, wherein alkoxy is as defined above.
术语“羟烷基”指被羟基取代的烷基,其中烷基如上所定义。The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
术语“羟基”指-OH基团。The term "hydroxy" refers to an -OH group.
术语“卤素”指氟、氯、溴或碘。The term "halogen" means fluoro, chloro, bromo or iodo.
术语“氨基”指-NH
2。
The term "amino" means -NH 2.
术语“氰基”指-CN。The term "cyano" refers to -CN.
术语“硝基”指-NO
2。
The term "nitro" refers to -NO 2 .
术语“氧代基”指=O。The term "oxo" refers to =0.
术语“羧基”指-C(O)OH。The term "carboxy" refers to -C(O)OH.
术语“巯基”指-SH。The term "mercapto" refers to -SH.
术语“酯基”指-C(O)O(烷基)或-C(O)O(环烷基),其中烷基和环烷基如上所定义。The term "ester group" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
术语“酰基”指含有-C(O)R基团的化合物,其中R为烷基、环烷基、杂环基、芳基、杂芳基。The term "acyl" refers to a compound containing a -C(O)R group, wherein R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.
术语“磺酸基”指-S(O)
2OH。
The term "sulfonic acid group" refers to -S(O) 2 OH.
术语“磺酸酯基”指-S(O)
2O(烷基)或-S(O)
2O(环烷基),其中烷基和环烷基如上所定义。
The term "sulfonate group" refers to -S (O) 2 O (alkyl), or -S (O) 2 O (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生,该说明包括该事件或环境发生或不发生的场合。例如,“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在,该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。"Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group. .
“取代的”指基团中的一个或多个氢原子,优选为最多5个,更优选为1~3个氢原子彼此独立地被相应数目的取代基取代。不言而喻,取代基仅处在它们的可能的化学位置,本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如,具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。"Substituted" refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物,以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药,利于活性成分的吸收进而发挥生物活性。"Pharmaceutical composition" means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients. The purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
“可药用盐”是指本发明化合物的盐,这类盐用于哺乳动物体内时具有安全性和有效性,且具有应有的生物活性。"Pharmaceutically acceptable salt" refers to a salt of a compound of the invention which is safe and effective for use in a mammal and which possesses the desired biological activity.
本发明化合物的合成方法Method for synthesizing the compound of the present invention
为了完成本发明的目的,本发明采用如下技术方案。In order to accomplish the object of the present invention, the present invention adopts the following technical solutions.
本发明通式(I)化合物的一般制备方法如下所述。The general preparation method of the compound of the formula (I) of the present invention is as follows.
当R
a为-NR
1R
2时,按照如下方案1制备通式(I)化合物:
When R a is -NR 1 R 2 , the compound of the formula (I) is prepared according to the following scheme 1:
方案1plan 1
步骤1:乙酰乙酸乙酯与N,N-二甲基甲酰胺二甲基缩醛在室温条件下直接缩合,得到(Z)-2-((二甲基氨基)亚甲基)-3-氧代丁酸乙酯(Ia);Step 1: Ethyl acetoacetate and N,N-dimethylformamide dimethyl acetal are directly condensed at room temperature to obtain (Z)-2-((dimethylamino)methylene)-3- Ethyl oxobutyrate (Ia);
步骤2:(Z)-2-((二甲基氨基)亚甲基)-3-氧代丁酸乙酯(Ia)在无水四氢呋喃中与强碱氢化钠作用形成烯醇钠盐中间体,然后与草酸二乙酯发生环化反应,得到4-氧代-4H-吡喃-2,5-二羧酸二乙酯(Ib);Step 2: (Z)-2-((Dimethylamino)methylene)-3-oxobutanoate ethyl ester (Ia) is reacted with strong sodium hydride in anhydrous tetrahydrofuran to form an enol sodium salt intermediate And then undergoing a cyclization reaction with diethyl oxalate to obtain diethyl 4-oxo-4H-pyran-2,5-dicarboxylate (Ib);
步骤3:4-氧代-4H-吡喃-2,5-二羧酸二乙酯(Ib)与胺(R
3NH
2)通过加成-缩合反应,得到N-R
3-4-氧代-1,4-二氢吡啶-2,5-二羧酸二乙酯(Ic);
Step 3: Diethyl 4-oxo-4H-pyran-2,5-dicarboxylate (Ib) and amine (R 3 NH 2 ) are subjected to an addition-condensation reaction to obtain NR 3 -4-oxo- Diethyl 1,4-dihydropyridine-2,5-dicarboxylate (Ic);
步骤4:N-R
3-1-4-氧代-1,4-二氢吡啶-2,5-二羧酸二乙酯(Ic)被N-溴代丁二酰亚胺(NBS)溴代,得到N-R
3-3-溴-4-氧代-1,4-二氢吡啶-2,5-二羧酸二乙酯(Id)。
Step 4: NR 3 -1-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (Ic) is brominated by N-bromosuccinimide (NBS). NR 3 -3-bromo-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (Id) was obtained.
步骤5:N-R
3-3-溴-4-氧代-1,4-二氢吡啶-2,5-二羧酸二乙酯(Id)与相应硼酸通过Suzuki偶联反应(碳酸钾为碱、Pd(dppf)Cl
2为催化剂、二氧六环/水为混合溶剂,反应温度为80℃),得到N-R
3-3-R
4-4-氧代-1,4-二氢吡啶-2,5-二羧酸二乙酯(Ie);
Step 5: NR 3 -3-bromo-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (Id) and the corresponding boric acid by Suzuki coupling reaction (potassium carbonate as a base, Pd(dppf)Cl 2 is a catalyst, dioxane/water is a mixed solvent, and the reaction temperature is 80 ° C), and NR 3 -3-R 4 -4-oxo-1,4-dihydropyridine-2 is obtained. 5-dicarboxylic acid diethyl ester (Ie);
步骤6:N-R
3-3-R
4-4-氧代-1,4-二氢吡啶-2,5-二羧酸二乙酯(Ie)在氢氧化钠作用下进行选择性水解,得到N-R
3-6-(乙氧基羰基)-5-R
4-4-氧代-1,4-二氢吡啶-3-羧酸(If);
Step 6: Selective hydrolysis of NR 3 -3-R 4 -4-oxo-1,4-dihydropyridine-2,5-dicarboxylate diethyl ester (Ie) under the action of sodium hydroxide to obtain NR 3-6- (ethoxycarbonyl) -5-R 4 -4- oxo-1,4-dihydropyridine-3-carboxylic acid (the If);
步骤7:N-R
3-6-(乙氧基羰基)-5-R
4-4-氧代-1,4-二氢吡啶-3-羧酸(If)与芳香胺(Ih)通过HATU和N,N-二异丙基乙胺(DIPEA)进行酰胺化反应,得到N-R
3-6-(乙 氧基羰基)-5-R
4-4-氧代-1,4-二氢吡啶-3-芳酰胺(Ig);
Step 7: NR 3 -6-(ethoxycarbonyl)-5-R 4 -4-oxo-1,4-dihydropyridine-3-carboxylic acid (If) with aromatic amine (Ih) via HATU and N , N-diisopropylethylamine (DIPEA) was subjected to amidation to give NR 3 -6-(ethoxycarbonyl)-5-R 4 -4-oxo-1,4-dihydropyridine-3- Aromatic amide (Ig);
步骤8:N-R
3-6-(乙氧基羰基)-5-R
4-4-氧代-1,4-二氢吡啶-3-芳酰胺(Ig)可直接与R
1R
2NH进行胺酯交换,获得通式(I)化合物;或者经先酯基水解,再与R
1R
2NH进行酰胺化反应的两步过程得到通式(I)化合物。
Step 8: NR 3 -6-(ethoxycarbonyl)-5-R 4 -4-oxo-1,4-dihydropyridine-3-arylamide (Ig) can be directly amine with R 1 R 2 NH Transesterification to obtain a compound of the formula (I); or a two-step process of amidation with a pre-ester group followed by amidation with R 1 R 2 NH to give a compound of the formula (I).
R
a选自-OR
1或-SR
1时,按照如下方案2制备通式(I)化合物:
R a is selected from -OR 1 or -SR 1 when, (I) a compound of formula 2 was prepared according to the following scheme:
方案2Scenario 2
步骤1:将N-R
3-6-(乙氧基羰基)-5-R
4-4-氧代-1,4-二氢吡啶-3-芳酰胺(Ig)通过NaOH进行酯基的碱性水解,得到N-R
3-6-羧基-5-R
4-4-氧代-1,4-二氢吡啶-3-芳酰胺酸(Ig’);
Step 1: Alkaline hydrolysis of ester groups by NaOH with NR 3 -6-(ethoxycarbonyl)-5-R 4 -4-oxo-1,4-dihydropyridine-3-aramidamide (Ig) NR 3 -6-carboxy-5-R 4 -4-oxo-1,4-dihydropyridine-3-aryl amic acid (Ig');
步骤2:N-R
3-6-羧基-5-R
4-4-氧代-1,4-二氢吡啶-3-芳酰胺酸(Ig’)在EDCI的作用下与醇或硫醇反应得到通式(I)化合物。
Step 2: NR 3 -6-carboxy-5-R 4 -4-oxo-1,4-dihydropyridine-3-aryl amic acid (Ig') is reacted with an alcohol or a thiol under the action of EDCI. a compound of formula (I).
当R
4与R
1或R
2以及其相连的氮原子或氧原子或硫原子一起形成杂环时,进一步通过如下方案3制备通式化合物:
When R 4 forms a heterocyclic ring with R 1 or R 2 together with a nitrogen atom or an oxygen atom or a sulfur atom to which it is bonded, the compound of the formula is further prepared by the following scheme 3:
方案3Option 3
步骤1:N-R
3-3-溴-4-氧代-1,4-二氢吡啶-2,5-二羧酸二乙酯(Id)与取代的芳基 硼酸在Pd(dppf)Cl
2和K
2CO
3的作用下进行Suzuki偶联,同时芳基上取代基氨基、羟基或巯基与邻位的酯基发生环化反应得到环化的N-R
3-4-氧代-1,4-二氢吡啶-5-羧酸乙酯(Ii);
Step 1: NR 3 -3-bromo-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (Id) and substituted aryl boronic acid in Pd(dppf)Cl 2 and Suzuki coupling under the action of K 2 CO 3 , while the substituent amino group, hydroxyl group or sulfhydryl group on the aryl group is cyclized with the ortho ester group to obtain cyclized NR 3 -4-oxo-1,4-di Hydropyridine-5-carboxylate ethyl ester (Ii);
步骤2:环化的N-R
3-4-氧代-1,4-二氢吡啶-5-羧酸乙酯(Ii)在碱性条件下(NaOH)水解得到环化的N-R
3-4-氧代-1,4-二氢吡啶-5-甲酸(Ij);
Step 2: Cyclized NR 3 -4-oxo-1,4-dihydropyridine-5-carboxylate ethyl ester (Ii) is hydrolyzed under basic conditions (NaOH) to give cyclized NR 3 -4-oxyl Des-1,4-dihydropyridin-5-carboxylic acid (Ij);
步骤3:环化的N-R
3-4-氧代-1,4-二氢吡啶-5-甲酸(Ij)与芳香胺(Ih)通过HATU和N,N-二异丙基乙胺(DIPEA)进行酰胺化反应,得到通式(I’)化合物。
Step 3: Cyclization of NR 3 -4-oxo-1,4-dihydropyridine-5-carboxylic acid (Ij) with aromatic amine (Ih) via HATU and N,N-diisopropylethylamine (DIPEA) The amidation reaction is carried out to obtain a compound of the formula (I').
当R
1或R
2与R
3以及其相连的氮原子或氧原子或硫原子一起形成杂环时,进一步通过如下方案4制备通式化合物:
When R 1 or R 2 forms a heterocyclic ring with R 3 and the nitrogen or oxygen atom or sulfur atom to which it is attached, the compound of the formula is further prepared by the following scheme 4:
方案4 Option 4
步骤1:4-氧代-4H-吡喃-2,5-二羧酸二乙酯(Ib)与一端带有氨基(-NH
2)而另一带有PG-X的胺通过加成-缩合反应得到N-取代-4-氧代-1,4-二氢吡啶-2,5-二羧酸二乙酯(Ik);
Step 1: Diethyl 4-oxo-4H-pyran-2,5-dicarboxylate (Ib) with an amino group (-NH 2 ) at one end and an amine with PG-X by addition-condensation Reaction to give N-substituted-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (Ik);
步骤2:N-取代-4-氧代-1,4-二氢吡啶-2,5-二羧酸二乙酯(Ik)通过脱保护后再与邻位的酯基进行环化反应,得到环化的4-氧代-1,4-二氢吡啶-5-甲酸乙酯(Il);Step 2: N-substituted 4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (Ik) is deprotected and then cyclized with an ortho ester group to obtain a cyclization reaction. Cyclolated ethyl 4-oxo-1,4-dihydropyridine-5-carboxylate (Il);
步骤3:环化的4-氧代-1,4-二氢吡啶-5-甲酸乙酯(Il)通过NBS溴代反应得到环化的3-溴-4-氧代-1,4-二氢吡啶-5-甲酸乙酯(Im);Step 3: Cyclization of ethyl 4-oxo-1,4-dihydropyridine-5-carboxylate (Il) by bromination of NBS to give cyclized 3-bromo-4-oxo-1,4-di Hydropyridine-5-formic acid ethyl ester (Im);
步骤4:环化的3-溴-4-氧代-1,4-二氢吡啶-5-甲酸乙酯(Im)与相应硼酸通过Suzuki偶联反应(碳酸钾为碱、Pd(dppf)Cl
2为催化剂、二氧六环/水为混合溶剂,反应温度为80℃),得到环化的3-R
4-4-氧代-1,4-二氢吡啶-5-甲酸乙酯(In);
Step 4: Cyclization of ethyl 3-bromo-4-oxo-1,4-dihydropyridine-5-carboxylate (Im) with the corresponding boronic acid by Suzuki coupling reaction (potassium carbonate as base, Pd(dppf)Cl 2 is a catalyst, dioxane/water is a mixed solvent, and the reaction temperature is 80 ° C) to obtain a cyclized 3-R 4 -4-oxo-1,4-dihydropyridine-5-carboxylic acid ethyl ester (In );
步骤5:环化的3-R
4-4-氧代-1,4-二氢吡啶-5-羧酸乙酯中间体(In)在碱性条件 下(NaOH)水解得到环化的3-R
4-4-氧代-1,4-二氢吡啶-5-甲酸中间体(Io);
Step 5: The cyclized 3-R 4 -4-oxo-1,4-dihydropyridine-5-carboxylic acid ethyl ester intermediate (In) is hydrolyzed under basic conditions (NaOH) to give a cyclized 3- R 4 -4-oxo-1,4-dihydropyridine-5-carboxylic acid intermediate (Io);
步骤6:环化的3-R
4-4-氧代-1,4-二氢吡啶-5-甲酸中间体(Io)与芳香胺(Ih)通过HATU和N,N-二异丙基乙胺(DIPEA)进行酰胺化反应,得到通式(I”)化合物。
Step 6: Cyclized 3-R 4 -4-oxo-1,4-dihydropyridine-5-carboxylic acid intermediate (Io) with aromatic amine (Ih) via HATU and N,N-diisopropyl B The amine (DIPEA) is subjected to an amidation reaction to give a compound of the formula (I").
当R
a为-NR
1R
2,R
1和R
2与其相连的氮原子一起形成含氮杂环,并且R
3与该含氮杂环以及其相连的氮原子一起进一步形成稠合杂环时,进一步通过如下方案5制备通式化合物:
When R a is -NR 1 R 2 , R 1 and R 2 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic ring, and R 3 together with the nitrogen-containing heterocyclic ring and the nitrogen atom to which it is bonded further form a fused heterocyclic ring Further preparing a compound of the formula by the following scheme 5:
方案5Option 5
步骤1:4-氧代-4H-吡喃-2,5-二羧酸二乙酯(Ib)与氨基乙醛缩二甲醇通过加成-缩合反应得到1-(2,2-二甲氧基乙基)-4-氧代-1,4-二氢吡啶-2,5-二甲酸二乙酯(Ip);Step 1: Diethyl 4-oxo-4H-pyran-2,5-dicarboxylate (Ib) and aminoacetaldehyde dimethylacetal are obtained by addition-condensation reaction to obtain 1-(2,2-dimethoxy Ethyl ethyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (Ip);
步骤2:1-(2,2-二甲氧基乙基)-4-氧代-1,4-二氢吡啶-2,5-二甲酸二乙酯(Ip)与氨基醇、氨基硫醇或二胺先通过甲醇的醛缩置换反应,再与邻位的酯基环化,得到稠环的4-氧代-1,4-二氢吡啶-5-甲酸乙酯(Iq);Step 2: 1-(2,2-Dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (Ip) with amino alcohol, amino mercaptan Or the diamine is first subjected to a aldehyde condensation reaction of methanol, and then cyclized with an ortho ester group to obtain a fused ring of ethyl 4-oxo-1,4-dihydropyridine-5-carboxylate (Iq);
步骤3:稠环的4-氧代-1,4-二氢吡啶-5-甲酸乙酯(Iq)通过NBS溴代反应得到环化的3-溴-4-氧代-1,4-二氢吡啶-5-甲酸乙酯(Ir);Step 3: The fused ring of ethyl 4-oxo-1,4-dihydropyridine-5-carboxylate (Iq) is brominated by NBS to give the cyclized 3-bromo-4-oxo-1,4-di Hydropyridine-5-formic acid ethyl ester (Ir);
步骤4:3-溴-4-氧代-1,4-二氢吡啶-5-甲酸乙酯(Ir)与相应硼酸通过Suzuki偶联反应(碳酸钾为碱、Pd(dppf)Cl
2为催化剂、二氧六环/水为混合溶剂,反应温度为80℃),得到3-R
4-4-氧代-1,4-二氢吡啶-5-甲酸乙酯(Is);
Step 4: 3-bromo-4-oxo-1,4-dihydropyridine-5-carboxylic acid ethyl ester (Ir) and the corresponding boronic acid by Suzuki coupling reaction (potassium carbonate as base, Pd(dppf)Cl 2 as catalyst , dioxane / water is a mixed solvent, the reaction temperature is 80 ° C), to give 3-R 4 -4-oxo-1,4-dihydropyridine-5-carboxylic acid ethyl ester (Is);
步骤5:3-R
4-4-氧代-1,4-二氢吡啶-5-羧酸乙酯(Is)在碱性条件下(NaOH)水解得到环化的3-R
4-4-氧代-1,4-二氢吡啶-5-甲酸(It);
Step 5: Ethyl 3-R 4 -4-oxo-1,4-dihydropyridine-5-carboxylate (Is) is hydrolyzed under basic conditions (NaOH) to give cyclized 3-R 4 -4- Oxo-1,4-dihydropyridine-5-carboxylic acid (It);
步骤6:环化的3-R
4-4-氧代-1,4-二氢吡啶-5-甲酸(It)与芳香胺(Ih)通过HATU和N,N-二异丙基乙胺(DIPEA)进行酰胺化反应,得到通式(I”’)化合物。
Step 6: Cyclized 3-R 4 -4-oxo-1,4-dihydropyridine-5-carboxylic acid (It) with aromatic amine (Ih) via HATU and N,N-diisopropylethylamine ( DIPEA) is subjected to an amidation reaction to give a compound of the formula (I"').
其中,R
1、R
2、R
3、R
4、R
5、R
7、W、V、n如通式(I)中所定义。
Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , W, V, n are as defined in the formula (I).
图1.EBC-1非小细胞肺癌模型中治疗组和对照组小鼠肿瘤体积的生长变化曲线图。Figure 1. Growth curve of tumor volume in treated and control mice in the EBC-1 non-small cell lung cancer model.
图2.EBC-1非小细胞肺癌模型中治疗组和对照组小鼠体重随治疗时间的变化曲线图。Figure 2. Plot of body weight versus treatment time in treatment and control mice in the EBC-1 non-small cell lung cancer model.
进一步通过实施例来理解本发明的化合物及其制备,这些实施例说明了一些制备或使用所述化合物的方法。然而,要理解的是,这些实施例不限制本发明。现在已知的或进一步开发的本发明的变化被认为落入本文中描述的和要求保护的本发明范围之内。The compounds of the invention and their preparation are further understood by the examples which illustrate some methods of preparing or using the compounds. However, it is to be understood that these examples do not limit the invention. Variations of the invention now known or further developed are considered to be within the scope of the invention as described and claimed herein.
本发明化合物是利用便利的起始原料和通用的制备步骤来完成制备的。本发明给出了典型的或倾向性的反应条件,诸如反应温度、时间、溶剂、压力、反应物的摩尔比。但是除非特殊说明,其他反应条件也能采纳。优化条件可能随着具体的反应物或溶剂的使用而改变,但在通常情况下,反应优化步骤和条件都能得到确定。The compounds of the present invention are prepared using convenient starting materials and common preparatory procedures. The present invention provides typical or propensating reaction conditions such as reaction temperature, time, solvent, pressure, molar ratio of reactants. However, other reaction conditions can be adopted unless otherwise stated. Optimization conditions may vary with the use of a particular reactant or solvent, but under normal circumstances, the reaction optimization steps and conditions can be determined.
另外,本发明中可能用到了一些保护基团来保护某些官能团避免不必要的反应。适宜于各种官能团的保护基以及它们的保护或脱保护条件已经为本领域技术人员广泛熟知。例如T.W.Greene和G.M.Wuts的《有机制备中的保护基团》(第3版,Wiley,New York,1999和书中的引用文献)详细描述了大量的保护基团的保护或脱保护。In addition, some protecting groups may be used in the present invention to protect certain functional groups from unwanted reactions. Protecting groups suitable for the various functional groups and their protection or deprotection conditions are well known to those skilled in the art. For example, T. W. Greene and G. M. Wuts, "Protective Groups in Organic Preparation" (3rd edition, Wiley, New York, 1999, and references cited in the book) describe in detail the protection or deprotection of a large number of protecting groups.
化合物和中间体的分离和纯化依据具体的需求采取适当的方法和步骤,例如过滤、萃取、蒸馏、结晶、柱层析、制备薄层板色谱、制备高效液相色谱或上述方法的混合使用。其具体使用方法可参阅本发明描述的实例。当然,其他类似的分离和纯化手段也是可以采用的。可以使用常规方法(包括物理常数和波谱数据)对其进行表征。The separation and purification of the compounds and intermediates are carried out according to specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin layer chromatography, preparative high performance liquid chromatography or a mixture of the above methods. The specific method of use can be referred to the examples described in the present invention. Of course, other similar separation and purification methods can be employed. It can be characterized using conventional methods, including physical constants and spectral data.
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移以10
-6(ppm)的单位给出。NMR的测定是用Brukerdps300型核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d
6),氘代氯仿(CDCl
3),氘代甲醇(CD
3OD),内标为四甲基硅烷(TMS)。
The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). The NMR shift is given in units of 10 -6 (ppm). The NMR was determined by using a Brukerdps300 type nuclear magnetic instrument. The solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was tetramethyl. Silane (TMS).
MS的测定用ACQUITY H-Class UPLC质谱仪(QDa Detector)(生产商:Waters)。The MS was measured using an ACQUITY H-Class UPLC mass spectrometer (QDa Detector) (manufacturer: Waters).
制备液相使用Waters 2545高效液相色谱仪(Waters 2489UV/visible Detector, 2767Sample MGR,Unitary C18,5μm 20mm x250mm)(生产商:Waters)The liquid phase was prepared using a Waters 2545 High Performance Liquid Chromatograph (Waters 2489 UV/visible Detector, 2767 Sample MGR, Unitary C18, 5 μm 20 mm x 250 mm) (manufacturer: Waters)
微波反应使用Initiator+EU型微波反应器(生产商:Biotage)Microwave reaction using Initiator + EU type microwave reactor (manufacturer: Biotage)
薄层层析硅胶板使用青岛海洋化工GF254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。Thin layer chromatography silica gel plate uses Qingdao Ocean Chemical GF254 silica gel plate. The specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm~0.2mm. The specification for thin layer chromatography separation and purification is 0.4mm~0.5. Mm.
柱层析一般使用青岛海洋硅胶100~200目、200~300目硅胶为载体。Column chromatography generally uses Qingdao Ocean Silicone 100-200 mesh and 200-300 mesh silica gel as carriers.
本发明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,或可购买自网化商城、北京偶合、Sigma、百灵威、易世明、上海书亚、上海伊诺凯、安耐吉化学,上海毕得等公司。The known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from Netcom Mall, Beijing Coupling, Sigma, Belling, Yi Shiming, Shanghai Shuya, Shanghai Inoke, An Nike Chemical, Shanghai Bi De and other companies.
实施例中无特殊说明,反应能够均在氩气氛或氮气氛下进行。Unless otherwise specified in the examples, the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
反应溶剂,有机溶剂或惰性溶剂各自表述为使用的该溶剂在所描述的反应条件下不参与反应,包括,如苯、甲苯、乙腈、四氢呋喃(THF)、二甲基甲酰胺(DMF)、氯仿、二氯甲烷、乙醚、甲醇、氮-甲基吡咯碄酮(NMP)、吡啶等。实施例中无特殊说明,溶液是指水溶液。The reaction solvent, organic solvent or inert solvent is each expressed as a solvent which does not participate in the reaction under the described reaction conditions, and includes, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform. Methylene chloride, diethyl ether, methanol, nitrogen-methylpyrrolidone (NMP), pyridine, and the like. Unless otherwise stated in the examples, the solution means an aqueous solution.
本发明中所描述的化学反应一般在常压下进行。反应温度在-78℃至200℃之间。反应时间和条件为,例如,一个大气压下,-78℃至200℃之间,大约1至24小时内完成。如果反应过夜,则反应时间一般为16小时。实施例中无特殊说明,反应的温度为室温,为20℃~30℃。The chemical reactions described in the present invention are generally carried out under normal pressure. The reaction temperature is between -78 ° C and 200 ° C. The reaction time and conditions are, for example, one atmosphere, between -78 ° C and 200 ° C, and completed in about 1 to 24 hours. If the reaction is overnight, the reaction time is generally 16 hours. There is no particular description in the examples, and the reaction temperature is room temperature and is 20 ° C to 30 ° C.
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的体系有:A:二氯甲烷和甲醇体系,B:正己烷和乙酸乙酯体系,C:石油醚和乙酸乙酯体系,D:丙酮,溶剂的体积比根据化合物的极性不同而进行调节。The progress of the reaction in the examples was monitored by thin layer chromatography (TLC). The system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And the ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted depending on the polarity of the compound.
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:A:二氯甲烷和甲醇体系,B:正己烷和乙酸乙酯体系,C:石油醚和乙酸乙酯体系,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。Purification Compounds The column chromatography eluent system and the thin layer chromatography developer system include: A: dichloromethane and methanol systems, B: n-hexane and ethyl acetate systems, C: petroleum ether and acetic acid In the ester system, the volume ratio of the solvent is adjusted depending on the polarity of the compound, and a small amount of an alkaline or acidic reagent such as triethylamine or acetic acid may be added for adjustment.
除非另行定义,文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those skilled in the art. In addition, any methods and materials similar or equivalent to those described may be employed in the methods of the invention.
缩略语Abbreviations
μL=微升;μL=microliter;
μM=微摩尔;μM=micromolar;
NMR=核磁共振;NMR = nuclear magnetic resonance;
Boc=叔丁氧基羰基Boc=tert-butoxycarbonyl
br=宽峰Br=wide peak
d=双峰d=double peak
δ=化学位移δ=chemical shift
℃=摄氏度°C=degree Celsius
dd=双双峰Dd=double peak
DIPEA=二异丙基乙基胺DIPEA=diisopropylethylamine
DMF=N,N-二甲基甲酰胺DMF=N,N-dimethylformamide
DMSO=二甲亚砜DMSO = dimethyl sulfoxide
DCM=二氯甲烷DCM = dichloromethane
EA=乙酸乙酯EA=ethyl acetate
HPLC=高效液相HPLC = high performance liquid phase
Hz=赫兹Hz=hertz
IC
50=抑制50%活性的浓度
IC 50 = concentration that inhibits 50% activity
J=偶合常数(Hz)J = coupling constant (Hz)
m=多重峰m=multiple peak
M+H
+=母体化合物质量+一质子
M+H + = parent compound mass + one proton
mg=毫克Mg=mg
mL=毫升mL=ml
mmol=毫摩尔Mmmol = millimolar
MS=质谱MS=MS
nM=纳摩尔nM=Namol
NBS=N-溴代琥珀酰亚胺NBS=N-bromosuccinimide
PE=石油醚PE = petroleum ether
ppm=每百万分Ppm = per million points
s=单峰s=single peak
t=三重峰t=triple peak
TEA=三乙胺TEA = triethylamine
TBDPS=叔丁基二苯基硅TBDPS=tert-butyldiphenyl silicon
TFA=三氟乙酸TFA = trifluoroacetic acid
THF=四氢呋喃THF = tetrahydrofuran
制备实施例1:6-(乙氧基羰基)-5-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-3-羧酸(中间体a)的制备PREPARATIVE EXAMPLE 1: 6-(Ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (intermediate a Preparation
步骤1:(Z)-2-((二甲基氨基)亚甲基)-3-氧代丁酸乙酯(a1)的制备Step 1: Preparation of ethyl (Z)-2-((dimethylamino)methylene)-3-oxobutanoate (a1)
于0℃,将乙酰乙酸乙酯(18g,138.31mmol)加入到含有N,N-二甲基甲酰胺二甲基缩醛(16.48g,138.31mmol)的反应瓶中。反应混合液升至室温继续搅拌12小时,待反应完全后,将反应液减压浓缩,得到(Z)-2-((二甲基氨基)亚甲基)-3-氧代丁酸乙酯。(26.5g,红色油状物,收率:100%)。Ethyl acetoacetate (18 g, 138.31 mmol) was added to a reaction flask containing N,N-dimethylformamide dimethyl acetal (16.48 g, 138.31 mmol) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirring was continued for 12 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give ethyl (Z)-2-((dimethylamino)methylene)-3-oxobutanoate. . (26.5 g, red oil, yield: 100%).
LC-MS(ESI):m/z 186.2[M+H
+]。
LC-MS (ESI): m / z 186.2 [M + H +].
步骤2:4-氧代-4H-吡喃-2,5-二羧酸二乙酯(a2)的制备Step 2: Preparation of diethyl 4-oxo-4H-pyran-2,5-dicarboxylate (a2)
在含有无水四氢呋喃(25mL)的反应瓶中加入(Z)-2-((二甲基氨基)亚甲基)-3-氧代丁酸乙酯(2.2g,11.89mmol)。将反应液冷却至0℃,搅拌下缓慢加入氢化钠(618mg,15.46mmol,60%),加毕,继续搅拌30分钟。再加入草酸二乙酯(1.91g,13.08mmol),加毕,加热至回流并继续搅拌2小时。待反应完全后冷却至室温,用1N的稀盐酸淬灭,反应液用乙酸乙酯萃取(60mLx3),合并有机相。将有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱液为PE:EA/2:1),得到4-氧代-4H-吡喃-2,5-二羧酸二乙酯(2.0g,乳白色固体,收率:70.1%)。Ethyl (Z)-2-((dimethylamino)methylene)-3-oxobutanoate (2.2 g, 11.89 mmol) was added to a reaction flask containing anhydrous tetrahydrofuran (25 mL). The reaction solution was cooled to 0 ° C, and sodium hydride (618 mg, 15.46 mmol, 60%) was slowly added with stirring, and the mixture was stirred for 30 minutes. Additional diethyl oxalate (1.91 g, 13.08 mmol) was added, added, heated to reflux and stirring was continued for 2 h. After completion of the reaction, the mixture was cooled to room temperature, and then diluted with EtOAc EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography (eluent: EtOAc: EtOAc: EtOAc) Solid, yield: 70.1%).
LC-MS(ESI):m/z 241.1[M+H
+]。
LC-MS (ESI): m / z 241.1 [M + H +].
步骤3:1-甲基-4-氧代-1,4-二氢吡啶-2,5-二羧酸二乙酯(a3)的制备Step 3: Preparation of diethyl 1-methyl-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate (a3)
在含有乙醇(40mL)的反应瓶中加入4-氧代-4H-吡喃-2,5-二羧酸二乙酯(4.5g,18.75mmol),将混合物冷却至0℃,搅拌下滴加甲胺水溶液(3.14mL,22.50mmol,33%),加毕,升至室温并继续搅拌1小时。待反应完全后,将反应液减压浓缩,残余物用乙酸乙酯萃取(40mLx3),合并有机相。将有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱液为DCM:CH
3OH/10:1),得到1-甲基-4-氧代-1,4-二氢吡啶-2,5-二羧酸二乙酯(4.0g,黄色固体,收率:84.0%)。
To a reaction flask containing ethanol (40 mL) was added 4-oxo-4H-pyran-2,5-dicarboxylic acid diethyl ester (4.5 g, 18.75 mmol), and the mixture was cooled to 0 ° C and then added dropwise with stirring. Aqueous methylamine (3.14 mL, 22.50 mmol, 33%) was added and then warmed to room temperature and stirring was continued for one hour. After the reaction was completed, the reaction mixture was evaporated. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by chromatography chromatography (eluent DCM: CH 3 OH / 10: 1) by silica gel column chromatography to give methyl-4-oxo-1,4-dihydro-pyridine-2,5- Diethyl carboxylate (4.0 g, yellow solid, yield: 84.0%).
LC-MS(ESI):m/z 253.3[M+H
+]。
LC-MS (ESI): m / z 253.3 [M + H +].
步骤4:3-溴-1-甲基-4-氧代-1,4-二氢吡啶-2,5-二羧酸二乙酯(a4)的制备Step 4: Preparation of 3-bromo-1-methyl-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (a4)
在含有DMF(40mL)的反应瓶中加入1-甲基-4-氧代-1,4-二氢吡啶-2,5-二羧酸二乙酯(4g,15.81mmol)和N-溴代丁二酰亚胺(NBS)(5.63g,31.62mmol)。将混合物升温至80℃并搅拌3小时。待反应完全后,将反应液减压浓缩,残余物用饱和硫代硫酸钠水溶液淬灭,乙酸乙酯萃取(40mL×3),合并有机相。将有机相用饱和的食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱液为DCM:CH
3OH/10:1),得到3-溴-1-甲基-4-氧代-1,4-二氢吡啶-2,5-二羧酸二乙酯(3.8g,黄色固体,收率:72.4%)。
Add 1-methyl-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (4 g, 15.81 mmol) and N-bromo in a reaction flask containing DMF (40 mL) Succinimide (NBS) (5.63 g, 31.62 mmol). The mixture was warmed to 80 ° C and stirred for 3 hours. After the reaction was completed, the mixture was evaporated. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by chromatography on silica gel column chromatography (eluent DCM: CH 3 OH / 10: 1), to give 3-bromo-1-methyl-4-oxo-1,4-dihydro-2 , diethyl 5-dicarboxylate (3.8 g, yellow solid, yield: 72.4%).
LC-MS(ESI):m/z 332.1/334.1[M+H
+]。
LC-MS (ESI): m / z 332.1 / 334.1 [M + H +].
步骤5:3-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-2,5-二羧酸二乙酯(a5)的制备Step 5: Preparation of diethyl 3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate (a5)
于室温,在含有(50mL)1,4-二氧六环和水混合液(4:1)的反应瓶中加入3-溴-1-甲基-4-氧代-1,4-二氢吡啶-2,5-二羧酸二乙酯(3.8g,11.44mmol)、对氟苯硼酸(1.92g,13.73mmol)、碳酸钾(4.74g,34.32mmol)、Pd(dppf)Cl
2.DCM(934mg,1.14mmol)。密封,氮气置换三次,加热至80℃搅拌1.5小时。待反应液冷却至室温后,过滤,滤液用水(50mL)稀释,乙酸乙酯萃取(50mL×3),合并有机相。将有机相用饱和的食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱液为DCM:CH
3OH/10:1),得到3-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-2,5-二羧酸二乙酯(3.2g,黄色固体,收率:80.6%)。
3-bromo-1-methyl-4-oxo-1,4-dihydrogen was added to the reaction flask containing (50 mL) of a mixture of 1,4-dioxane and water (4:1) at room temperature. Diethyl pyridine-2,5-dicarboxylate (3.8 g, 11.44 mmol), p-fluorophenylboronic acid (1.92 g, 13.73 mmol), potassium carbonate (4.74 g, 34.32 mmol), Pd(dppf)Cl 2 .DCM (934 mg, 1.14 mmol). Sealed, replaced with nitrogen three times, heated to 80 ° C and stirred for 1.5 hours. After the reaction mixture was cooled to room temperature, it was filtered, and the filtrate was diluted with water (50mL), ethyl acetate (50mL×3), and the organic phase was combined. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by chromatography on silica gel column chromatography (eluent DCM: CH 3 OH / 10: 1), to give 3- (4-fluorophenyl) -1-methyl-4-oxo-1,4 Dihydropyridine-2,5-dicarboxylic acid diethyl ester (3.2 g, yellow solid, yield: 80.6%).
LC-MS(ESI):m/z 347.3[M+H
+]。
LC-MS (ESI): m / z 347.3 [M + H +].
步骤6:6-(乙氧基羰基)-5-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-3-羧酸(a)的制备Step 6: Preparation of 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (a)
在含有(40mL)乙醇的反应瓶中加入3-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-2,5-二羧酸二乙酯(3.2g,9.22mmol)。将反应液冷却至0℃,搅拌下滴加氢氧化钠水溶液(10mL,11.06mmol),加毕升至室温并继续搅拌1小时。待反应完全后,将反应液冷却至0℃,用1N的盐酸调节pH~3,有白色固体析出,继续搅拌30分钟。过滤,收集固体6-(乙氧基羰基)-5-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-3-羧酸(a)(2.3g,白色固体,收率:78.1%)。3-(4-Fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester was added to a reaction flask containing (40 mL) of ethanol ( 3.2 g, 9.22 mmol). The reaction solution was cooled to 0 ° C, and aqueous sodium hydroxide (10 mL, 11.06 mmol) After the reaction was completed, the reaction mixture was cooled to 0 ° C, pH was adjusted to 3 with 1N hydrochloric acid, and a white solid was precipitated and stirring was continued for 30 minutes. Filtration and collection of solid 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (a) (2.3 g, white solid, yield: 78.1%).
LC-MS(ESI):m/z 320.1[M+H
+]。
LC-MS (ESI): m / z 320.1 [M + H +].
制备实施例2:5-(4-氟苯基)-1-异丙基-4-氧代-1,4-二氢吡啶-3-甲酸(中间体b)、5-(4-氟苯基)-1-环丙基-4-氧代-1,4-二氢吡啶-3-甲酸(中间体b1)、5-(4-氟苯基)-1-环丁基-4-氧代-1,4-二氢吡啶-3-甲酸(中间体b2)和5-(4-氟苯基)-1-叔丁基-4-氧代-1,4-二氢吡啶-3-甲酸(中间体b3)的制备Preparation Example 2: 5-(4-Fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (intermediate b), 5-(4-fluorobenzene) -1 -cyclopropyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (intermediate b1), 5-(4-fluorophenyl)-1-cyclobutyl-4-oxo Des-1,4-dihydropyridine-3-carboxylic acid (intermediate b2) and 5-(4-fluorophenyl)-1-tert-butyl-4-oxo-1,4-dihydropyridine-3- Preparation of formic acid (intermediate b3)
采用与制备实施例1相同的方法,除了分别用异丙胺、环丙胺、环丁胺和叔丁胺代替甲胺水溶液,分别制得:In the same manner as in Preparation Example 1, except that isopropylamine, cyclopropylamine, cyclobutylamine and t-butylamine were respectively used in place of the aqueous methylamine solution, respectively:
5-(4-氟苯基)-1-异丙基-4-氧代-1,4-二氢吡啶-3-甲酸(b)(灰色固体,四步收率:38.3%);LC-MS(ESI):m/z 348.3[M+H
+]。
5-(4-Fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (b) (gray solid, four-step yield: 38.3%); MS (ESI): m/z 348.3 [M+H + ].
5-(4-氟苯基)-1-环丙基-4-氧代-1,4-二氢吡啶-3-甲酸(b1)(灰色固体,四步收率:70.8%);LC-MS(ESI):m/z 346.3[M+H
+]。
5-(4-Fluorophenyl)-1-cyclopropyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (b1) (gray solid, four-step yield: 70.8%); MS (ESI): m / z 346.3 [m + H +].
5-(4-氟苯基)-1-环丁基-4-氧代-1,4-二氢吡啶-3-甲酸(b2)(灰色固体,四步收率:80.9%);LC-MS(ESI):m/z 360.1[M+H
+]。
5-(4-Fluorophenyl)-1-cyclobutyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (b2) (gray solid, four-step yield: 80.9%); MS (ESI): m / z 360.1 [m + H +].
5-(4-氟苯基)-1-叔丁基-4-氧代-1,4-二氢吡啶-3-甲酸(b3)(灰色固体,四步收率:4.1%);LC-MS(ESI):m/z 362.1[M+H
+]。
5-(4-Fluorophenyl)-1-tert-butyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (b3) (gray solid, four-step yield: 4.1%); MS (ESI): m / z 362.1 [m + H +].
制备实施例3:5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸(中间体c)的制备Preparation Example 3: 5-(4-Fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3- Preparation of formic acid (intermediate c)
采用与制备实施例1相同的方法,除了用(四氢-2H-吡喃-4-基)甲胺(上海毕得)代替甲胺水溶液,制得5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸(c)(白色固体,四步收率:36.8%)5-(4-fluorophenyl)-4 was obtained in the same manner as in Preparation Example 1, except that (tetrahydro-2H-pyran-4-yl)methanamine (Shanghai Pide) was used instead of the aqueous methylamine solution. -oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid (c) (white solid, four-step yield: 36.8%)
LC-MS(ESI):m/z 403.3[M+H
+]。
LC-MS (ESI): m / z 403.3 [M + H +].
制备实施例4:10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸(中间体d)的制备Preparation Example 4: 10-(4-Fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4 Preparation of diazepane-8-carboxylic acid (intermediate d)
步骤1:1-(3-((叔丁氧基羰基)氨基)丙基)-4-氧代-1,4-二氢吡啶-2,5-二羧酸二乙酯(d1)的制备Step 1:1-(Preparation of 3-((tert-Butoxycarbonyl)amino)propyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (d1)
室温下,在含有乙醇(50mL)的圆底烧瓶中加入4-氧-4氢-吡喃-2,5-二甲酸乙酯(a2)(3.0g,12.5mmol)和N-叔丁氧羰基-1,3-丙二胺(2.2g,12.6mmol)。将混合物升温至60℃并搅拌4小时,待反应完全后,将反应液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为MeOH:DCM=1:10),得到1-(3-((叔丁氧羰基)氨基)丙基)-4-氧-1,4-二氢吡啶-2,5-二甲酸乙酯(2.5g,黄色油状物,收率:50%)。Add 4-oxo-4hydro-pyran-2,5-dicarboxylate (a2) (3.0 g, 12.5 mmol) and N-tert-butoxycarbonyl to a round bottom flask containing ethanol (50 mL) at room temperature. - 1,3-propanediamine (2.2 g, 12.6 mmol). The mixture was warmed to 60 ° C and stirred for 4 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc Ethyl dihydropyridine-2,5-dicarboxylate (2.5 g, yellow oil, yield: 50%).
LC-MS(ESI):m/z 397.2[M+H
+]。
LC-MS (ESI): m / z 397.2 [M + H +].
步骤2:1-(3-氨丙基)-4-氧-1,4-二氢吡啶-2,5-二甲酸乙酯盐酸盐(d2)的制备Step 2: Preparation of 1-(3-aminopropyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid ethyl ester hydrochloride (d2)
在含有二氯甲烷(10mL)的反应瓶中加入1-(3-((叔丁氧羰基)氨基)丙基)-4-氧-1,4-二氢吡啶-2,5-二甲酸乙酯(2.5g,6.3mmol)和盐酸二氧六环(10mL,4M)。于室温搅拌30分钟后,将反应液减压浓缩,得到粗产品1-(3-氨丙基)-4-氧-1,4-二氢吡啶-2,5-二甲酸乙酯盐酸盐(2.0g,白色固体,收率:95%)。其未经纯化直接用于下一步反应。Add 1-(3-((tert-butoxycarbonyl)amino)propyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate B to a reaction flask containing dichloromethane (10 mL) Ester (2.5 g, 6.3 mmol) and dioxane hydrochloride (10 mL, 4M). After stirring at room temperature for 30 minutes, the reaction mixture was evaporated. (2.0 g, white solid, yield: 95%). It was used directly in the next reaction without purification.
LC-MS(ESI):m/z 297.2[M+H
+]。
LC-MS (ESI): m / z 297.2 [M + H +].
步骤3:1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸乙 酯(d3)的制备Step 3: 1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylic acid Preparation of ester (d3)
于室温,在含有乙醇(20mL)的圆底烧瓶中加入1-(3-氨丙基)-4-氧-1,4-二氢吡啶-2,5-二甲酸乙酯盐酸盐(2.0g,6.0mmol)和三乙胺(1.0g,12.1mmol)。将混合物升温至80℃并搅拌2小时,待反应完全后,将反应液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为MeOH:DCM=1:10),得到1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸乙酯(1.5g,黄色油状物,收率:99%)。Add 1-(3-aminopropyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid ethyl ester hydrochloride (2.0) in a round bottom flask containing ethanol (20 mL) at room temperature. g, 6.0 mmol) and triethylamine (1.0 g, 12.1 mmol). The mixture was warmed to 80 ° C and stirred for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc:EtOAc:EtOAc: 1,2-a][1,4]Diazepane-8-carboxylic acid ethyl ester (1.5 g, yellow oil, yield: 99%).
LC-MS(ESI):m/z 251.2[M+H
+]。
LC-MS (ESI): m / z 251.2 [M + H +].
步骤4:10-溴-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-羧酸乙酯(d4)的制备Step 4: 10-Bromo-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane- Preparation of 8-carboxylic acid ethyl ester (d4)
于室温,在含有DMF(15mL)的圆底烧瓶中加入1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸乙酯(1.5g,5.98mmol),搅拌下滴加液溴(0.62mL,11.96mmol),加毕,搅拌过夜。待反应完全后,将反应液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为MeOH:DCM=1:10),得到10-溴-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸乙酯(1.1g,黄色固体,收率:55.7%)。Add 1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4 to a round bottom flask containing DMF (15 mL) at room temperature. Ethyl diazepane-8-carboxylate (1.5 g, 5.98 mmol) was added dropwise with stirring EtOAc (EtOAc,EtOAc. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: MeOH: EtOAc: : : : : : : : : : : : : : : : : : : : : : : : Ethyl pyrido[1,2-a][1,4]diazepane-8-carboxylate (1.1 g, yellow solid, yield: 55.7%).
LC-MS(ESI):m/z 329.1/331.1[M+H
+]。
LC-MS (ESI): m / z 329.1 / 331.1 [M + H +].
步骤5:10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-羧酸乙酯(d5)的制备Step 5: 10-(4-Fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4] Preparation of azacycloheptane-8-carboxylic acid ethyl ester (d5)
于室温,在含有乙腈(12mL)和水(3mL)的圆底烧瓶中加入10-溴-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸乙酯(1.1g,3.32mmol)、4-氟苯硼酸(693mg,4.98mmol)、碳酸钾(1.37g,9.96mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(270mg,0.33mmol)。密封,氮气置换三次,加热至80℃搅拌4小时。待反应液冷却至室温后,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为MeOH:DCM=1:10),得到10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-羧酸乙酯(800mg,白色固体,收率:69.8%)。Add 10-bromo-1,9-dioxo-1,2,3,4,5,9-hexahydropyridyl[1] to a round bottom flask containing acetonitrile (12 mL) and water (3 mL) at room temperature. , 2-a][1,4]Diazepane-8-carboxylic acid ethyl ester (1.1 g, 3.32 mmol), 4-fluorophenylboronic acid (693 mg, 4.98 mmol), potassium carbonate (1.37 g, 9.96 mmol) And [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (270 mg, 0.33 mmol). Sealed, replaced with nitrogen three times, heated to 80 ° C and stirred for 4 hours. After the reaction liquid was cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut elut Ethyl 5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylate (800 mg, white solid, yield: 69.8%).
LC-MS(ESI):m/z 345.2[M+H
+]。
LC-MS (ESI): m / z 345.2 [M + H +].
步骤6:10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸(d)的制备Step 6: 10-(4-Fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4] Preparation of azepane-8-carboxylic acid (d)
于室温,在含有乙醇(8mL)和水(2mL)的圆底烧瓶中加入10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-羧酸乙酯(800mg,mmol)和一水合氢氧化锂(160mg,3.48mmol)。将混合物升温至60℃并搅拌4h。待反应完全后,将反应液减压浓缩,得到粗产品10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸(800mg,淡黄色固体,收率:100%)。其未经纯化直接用于下一步反应。Add 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9- to a round bottom flask containing ethanol (8 mL) and water (2 mL) at room temperature. Ethyl hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylate (800 mg, mmol) and lithium hydroxide monohydrate (160 mg, 3.48 mmol). The mixture was warmed to 60 ° C and stirred for 4 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give the crude product 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyridine [ 1,2-a][1,4]diazepane-8-carboxylic acid (800 mg, pale yellow solid, yield: 100%). It was used directly in the next reaction without purification.
LC-MS(ESI):m/z 317.1[M+H
+]。
LC-MS (ESI): m / z 317.1 [M + H +].
制备实施例5:1,9-二氧代-10-(对甲苯基)-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸(中间体e)的制备Preparation Example 5: 1,9-dioxo-10-(p-tolyl)-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4] Preparation of azepane-8-carboxylic acid (intermediate e)
采用与制备实施例4相同的方法,除了用4-甲基苯硼酸(上海毕得)代替4-氟苯硼酸,制得1,9-二氧代-10-(对甲苯基)-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸(e)(灰色固体,两步收率:64.3%)。In the same manner as in Preparation Example 4, except that 4-methylbenzeneboronic acid (Shanghai Pide) was used instead of 4-fluorophenylboronic acid, 1,9-dioxo-10-(p-tolyl)-1 was obtained. 2,3,4,5,9-Hexidopyrido[1,2-a][1,4]diazepane-8-carboxylic acid (e) (gray solid, two-step yield: 64.3% ).
LC-MS(ESI):m/z 313.2[M+H
+]。
LC-MS (ESI): m / z 313.2 [M + H +].
制备实施例6:10-(4-氟苯基)-4-羟基-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸(中间体f)的制备Preparation Example 6: 10-(4-Fluorophenyl)-4-hydroxy-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a] Preparation of [1,4]diazepane-8-carboxylic acid (intermediate f)
步骤1:2-((叔丁基二苯基硅烷基)氧基)丙烷-1,3-二胺(f1)的制备Step 1: Preparation of 2-((tert-butyldiphenylsilyl)oxy)propane-1,3-diamine (f1)
于室温,在含有DMF(30mL)的圆底烧瓶中加入1,3-二氨基-2-羟基丙烷(4g,44.4mmol)和咪唑(6.1g,88.8mmol)。将混合物冷却至0℃,缓慢滴加TBDPSCl的DMF溶液(30mL,88.8mmol)。加毕,升温至室温并搅拌过夜。待反应完全后,将反应液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为MeOH:DCM=1:10),得到2-((叔丁基二苯基硅烷基)氧基)丙烷-1,3-二胺(12.4g,黄色油状物,收率85.1%)。1,3-Diamino-2-hydroxypropane (4 g, 44.4 mmol) and imidazole (6.1 g, 88.8 mmol) were added to a round bottom flask containing DMF (30 mL) at room temperature. The mixture was cooled to 0 ° C, and a solution of TBDPSCl in DMF (30 mL, 88.8 mmol) was slowly added dropwise. After the addition was completed, the temperature was raised to room temperature and stirred overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut 12.4 g, yellow oil, yield 85.1%).
LC-MS(ESI):m/z 329.3[M+H
+]。
LC-MS (ESI): m / z 329.3 [M + H +].
步骤2:4-((叔丁基二苯基甲硅烷基)氧基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸乙酯(f2)的制备Step 2: 4-((tert-Butyldiphenylsilyl)oxy)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2- Preparation of a][1,4]diazepane-8-carboxylic acid ethyl ester (f2)
于室温,在含有乙醇(10mL)的圆底烧瓶中加入4-氧代-4H-吡喃-2,5-二羧酸二乙酯(a2)(370mg,1.54mmol),2-((叔丁基二苯基硅烷基)氧基)丙烷-1,3-二胺(608mg,1.85mmol)和三乙胺(1.2g,9.24mmol)。将混合物升温至80℃并搅拌4小时,待反应完全后,将反应液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为MeOH:DCM=1:10),得到4-((叔丁基二苯基甲硅烷基)氧基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸乙酯(350mg,黄色油状物,收率:53.2%)。To a round bottom flask containing ethanol (10 mL) was added 4-oxo-4H-pyran-2,5-dicarboxylic acid diethyl ester (a2) (370 mg, 1.54 mmol), 2- ((un) Butyldiphenylsilyl)oxy)propane-1,3-diamine (608 mg, 1.85 mmol) and triethylamine (1.2 g, 9.24 mmol). The mixture was warmed to 80 ° C and stirred for 4 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc:EtOAc:EtOAc: -1,2,3,4,5,9-Hexidopyrido[1,2-a][1,4]diazepane-8-carboxylic acid ethyl ester (350 mg, yellow oil, yield : 53.2%).
LC-MS(ESI):m/z 505.2[M+H
+]。
LC-MS (ESI): m / z 505.2 [M + H +].
步骤3:10-溴-4-((叔丁基二苯基甲硅烷基)氧基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸乙酯(f3)制备Step 3: 10-Bromo-4-((tert-butyldiphenylsilyl)oxy)-1,9-dioxo-1,2,3,4,5,9-hexahydropyridyl[ Preparation of 1,2-a][1,4]diazepane-8-carboxylic acid ethyl ester (f3)
于室温,在含有DMF(5mL)的圆底烧瓶中加入4-((叔丁基二苯基甲硅烷基)氧基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸乙酯(250 mg,0.49mmol),搅拌下滴加液溴(0.04ml,1.5mmol)。加毕,搅拌过夜,待反应完全后,将反应液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为MeOH:DCM=1:10),得到10-溴-4-((叔丁基二苯基甲硅烷基)氧基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸乙酯(200mg,黄色油状物,收率:69.0%)。4-((tert-Butyldiphenylsilyl)oxy)-1,9-dioxo-1,2,3,4,5 was added to a round bottom flask containing DMF (5 mL) at room temperature. , 9-Hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylic acid ethyl ester (250 mg, 0.49 mmol), bromine (0.04 ml, 1.5) Mm). After the addition was completed, the mixture was stirred overnight, and after the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting elut elut elut elut -Ethoxy-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylic acid ethyl ester (200 mg, yellow oil Yield: 69.0%).
LC-MS(ESI):m/z 583.2/585.2[M+H
+]。
LC-MS (ESI): m / z 583.2 / 585.2 [M + H +].
步骤4:4-((叔丁基二苯基甲硅烷基)氧基)-10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-羧酸乙酯(f4)的制备Step 4: 4-((tert-Butyldiphenylsilyl)oxy)-10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9 -Preparation of ethyl hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylate (f4)
于室温,在含有乙腈(4mL)和水(1mL)的圆底烧瓶中加入10-溴-4-((叔丁基二苯基甲硅烷基)氧基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸乙酯(270mg,0.46mmol)、对氟苯硼酸(100mg,0.70mmol)、碳酸钾(200mg,1.38mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(40mg,0.05mmol)。密封,氮气置换三次,加热至80℃搅拌4小时。待反应液冷却至室温后,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为MeOH:DCM=1:10),得到4-((叔丁基二苯基甲硅烷基)氧基)-10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-羧酸乙酯(200mg,白色固体,收率:73.2%)。Add 10-bromo-4-((tert-butyldiphenylsilyl)oxy)-1,9-dioxo- in a round bottom flask containing acetonitrile (4 mL) and water (1 mL) at room temperature. 1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylic acid ethyl ester (270 mg, 0.46 mmol), p-fluorobenzene Boric acid (100 mg, 0.70 mmol), potassium carbonate (200 mg, 1.38 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (40 mg, 0.05 mmol) . Sealed, replaced with nitrogen three times, heated to 80 ° C and stirred for 4 hours. After the reaction liquid was cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc 1,1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepan-8-carboxylic acid Ethyl ester (200 mg, white solid, yield: 73.2%).
LC-MS(ESI):m/z 599.3[M+H
+]。
LC-MS (ESI): m / z 599.3 [M + H +].
步骤5:10-(4-氟苯基)-4-羟基-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸(f)的制备Step 5: 10-(4-Fluorophenyl)-4-hydroxy-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1 , 4] Preparation of diazepane-8-carboxylic acid (f)
于室温,在含有乙醇(mL)和水(mL)的圆底烧瓶中加入4-((叔丁基二苯基甲硅烷基)氧基)-10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-羧酸乙酯(200mg,0.33mmol)和一水合氢氧化锂(10mg,0.37mmol)。将混合物升温至60℃并搅拌4小时。待反应完全后,将反应液减压浓缩,得到粗产品10-(4-氟苯基)-4-羟基-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸(190mg,淡黄色固体,收率:100%)。其未经纯化直接用于下一步反应。4-((tert-Butyldiphenylsilyl)oxy)-10-(4-fluorophenyl)-1 was added to a round bottom flask containing ethanol (mL) and water (mL) at room temperature. Ethyl 9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylate (200 mg, 0.33 mmol) and lithium hydroxide monohydrate (10 mg, 0.37 mmol). The mixture was warmed to 60 ° C and stirred for 4 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give the crude product 10-(4-fluorophenyl)-4-hydroxy-1,9-dioxo-1,2,3,4,5,9- Hydropyrido[1,2-a][1,4]diazepane-8-carboxylic acid (190 mg, pale yellow solid, yield: 100%). It was used directly in the next reaction without purification.
LC-MS(ESI):m/z 333.2[M+H
+]。
LC-MS (ESI): m / z 333.2 [M + H +].
制备实施例7:1-(4-氟苯基)-2,12-二氧代-2,6,6a,7,8,9,10,12-八氢二吡啶并[1,2-a:1',2'-d]吡嗪-3-甲酸(中间体g)的制备Preparation Example 7: 1-(4-Fluorophenyl)-2,12-dioxo-2,6,6a,7,8,9,10,12-octahydrodipyrido[1,2-a Preparation of :1',2'-d]pyrazine-3-carboxylic acid (intermediate g)
步骤1:1-((1-(叔丁氧基羰基)哌啶-2-基)甲基)-4-氧代-1,4-二氢吡啶-2,5-二甲酸二乙酯(g1)的制备Step 1: 1 - ((1-(tert-Butoxycarbonyl)piperidin-2-yl)methyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester ( Preparation of g1)
于室温,在含有乙醇(20mL)的圆底烧瓶中加入4-氧代-4H-吡喃-2,5-二羧酸二乙酯(a2)(1.5g,6.25mmol)和1-叔丁氧羰基-2-氨甲基哌啶(1.68g,7.50mmol)。将混合物升温至60℃并搅拌4小时,待反应完全后,减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为MeOH:DCM=1:10),得到1-((1-(叔丁氧基羰基)哌啶-2-基)甲基)-4-氧代-1,4-二氢吡啶-2,5-二甲酸二乙酯(2.4g,黄色油状物,收率:88.4%)。Add 4-oxo-4H-pyran-2,5-dicarboxylic acid diethyl ester (a2) (1.5 g, 6.25 mmol) and 1-tert-butyl at room temperature in a round bottom flask containing ethanol (20 mL). Oxycarbonyl-2-aminomethylpiperidine (1.68 g, 7.50 mmol). The mixture was warmed to 60 ° C and stirred for 4 hours. After the reaction was completed, concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc elut elut elut elut - Oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (2.4 g, yellow oil, yield: 88.4%).
LC-MS(ESI):m/z 437.4[M+H
+]。
LC-MS (ESI): m / z 437.4 [M + H +].
步骤2:3-溴-1-(1-(叔丁氧羰基)哌啶-2-基)甲基)-4-氧代-1,4-二氢吡啶-2,5-二甲酸二乙酯(g2)的制备Step 2: 3-Bromo-1-(1-(tert-butoxycarbonyl)piperidin-2-yl)methyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl Preparation of ester (g2)
于室温,在含有DMF(25mL)的圆底烧瓶中加入1-((1-(叔丁氧基羰基)哌啶-2-基)甲基)-4-氧代-1,4-二氢吡啶-2,5-二甲酸二乙酯(2.4g,5.50mmol)和NBS(1.96g,10.99mmol)并搅拌过夜。待反应完全后,将反应液减压浓缩,残余物通过硅胶柱层析色谱法纯化(洗脱剂为MeOH:DCM=1:10),得到3-溴-1-(1-(叔丁氧羰基)哌啶-2-基)甲基)-4-氧代-1,4-二氢吡啶-2,5-二甲酸二乙酯(2.3g,黄色油状物,收率:80.0%)Add 1-((1-(tert-butoxycarbonyl)piperidin-2-yl)methyl)-4-oxo-1,4-dihydrogen to a round bottom flask containing DMF (25 mL) at rt. Diethyl pyridine-2,5-dicarboxylate (2.4 g, 5.50 mmol) and NBS (1.96 g, 10.9 mmol) were stirred overnight. After the reaction mixture was completed, the reaction mixture was evaporated to dryness mjjjjjjjjjjjjjjjj Carbonyl)piperidin-2-yl)methyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (2.3 g, yellow oil, yield: 80.0%)
LC-MS(ESI):m/z 515.2/517.2[M+H
+]。
LC-MS (ESI): m / z 515.2 / 517.2 [M + H +].
步骤3:3-溴-4-氧代-1-(哌啶-2-基甲基)-1,4-二氢吡啶-2,5-二甲酸二乙酯盐酸盐(g3)的制备Step 3: Preparation of 3-bromo-4-oxo-1-(piperidin-2-ylmethyl)-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester hydrochloride (g3)
于室温,在含有二氯甲烷(20mL)的反应瓶中加入3-溴-1-(1-(叔丁氧羰基)哌啶-2-基)甲基)-4-氧代-1,4-二氢吡啶-2,5-二甲酸二乙酯(2.3g,4.4mmol)和盐酸二氧六环(10mL,4M),并搅拌30分钟。待反应完全后,将反应液减压浓缩,得到粗产品3-溴-4-氧代-1-(哌啶-2-基甲基)-1,4-二氢吡啶-2,5-二甲酸二乙酯盐酸盐(2.0g,白 色固体,收率:100%),其未经纯化直接用于下一步反应。3-bromo-1-(1-(tert-butoxycarbonyl)piperidin-2-yl)methyl)-4-oxo-1,4 was added to a reaction flask containing dichloromethane (20 mL) at room temperature. Dihydropyridine-2,5-dicarboxylic acid diethyl ester (2.3 g, 4.4 mmol) and dioxane hydrochloride (10 mL, 4 M) were stirred for 30 min. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give the crude product 3-bromo-4-oxo-1-(piperidin-2-ylmethyl)-1,4-dihydropyridine-2,5- Diethyl formate hydrochloride (2.0 g, white solid, yield: 100%) was used for the next step without purification.
LC-MS(ESI):m/z 415.2/417.2[M+H
+]。
LC-MS (ESI): m / z 415.2 / 417.2 [M + H +].
步骤4:1-溴-2,12-二氧代-2,6,6a,7,8,9,10,12-八氢二吡啶并[1,2-a:1',2'-d]吡嗪-3-甲酸乙酯(g4)的制备Step 4: 1-Bromo-2,12-dioxo-2,6,6a,7,8,9,10,12-octahydrodipyrido[1,2-a:1',2'-d Preparation of pyrazine-3-carboxylic acid ethyl ester (g4)
于室温,在含有DMF(20mL)和水(10mL)的反应瓶中加入3-溴-4-氧代-1-(哌啶-2-基甲基)-1,4-二氢吡啶-2,5-二甲酸二乙酯盐酸盐(2.0g,4.3mmol)和NaHCO
3(2.16g,25.75mmol),并搅拌,30分钟。待反应完全后,反应液用二氯甲烷萃取(30mL×3),合并有机相。将有机相减压浓缩,得到粗产品1-溴-2,12-二氧代-2,6,6a,7,8,9,10,12-八氢二吡啶并[1,2-a:1',2'-d]吡嗪-3-甲酸乙酯(1.2g,白色固体,收率:75.8%)。其未经纯化直接用于下一步反应。
Add 3-bromo-4-oxo-1-(piperidin-2-ylmethyl)-1,4-dihydropyridine-2 to a reaction vial containing DMF (20 mL) and water (10 mL). , 5-dicarboxylic acid diethyl ester hydrochloride (2.0g, 4.3mmol) and NaHCO 3 (2.16g, 25.75mmol), and stirred for 30 minutes. After the reaction was completed, the reaction mixture was extracted with dichloromethane (30 mL×3), and the organic phase was combined. The organic phase was concentrated under reduced pressure to give the crude product 1-bromo-2,12-dioxo-2,6,6a,7,8,9,10,12-octahydrodipyrido[1,2-a: 1 ',2'-d]pyrazine-3-carboxylic acid ethyl ester (1.2 g, white solid, yield: 75.8%). It was used directly in the next reaction without purification.
LC-MS(ESI):m/z 369.1/371.1[M+H
+]。
LC-MS (ESI): m / z 369.1 / 371.1 [M + H +].
步骤5:1-(4-氟苯基)-2,12-二氧代-2,6,6a,7,8,9,10,12-八氢二吡啶并[1,2-a:1',2'-d]吡嗪-3-甲酸乙酯(g5)的制备Step 5: 1-(4-Fluorophenyl)-2,12-dioxo-2,6,6a,7,8,9,10,12-octahydrodipyrido[1,2-a:1 Preparation of ',2'-d]pyrazine-3-carboxylic acid ethyl ester (g5)
于室温,在含有乙腈(12mL)和水(3mL)的圆底烧瓶中加入1-溴-2,12-二氧代-2,6,6a,7,8,9,10,12-八氢二吡啶并[1,2-a:1',2'-d]吡嗪-3-甲酸乙酯(1.2g,3.3mmol)、对氟苯硼酸(670mg,4.79mmol)、碳酸钾(1.32g,9.57mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(233mg,mmol)。密封,氮气置换三次,加热至80℃,搅拌4小时。待反应液冷却至室温后,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为MeOH:DCM=1:10),得到1-(4-氟苯基)-2,12-二氧代-2,6,6a,7,8,9,10,12-八氢二吡啶并[1,2-a:1',2'-d]吡嗪-3-甲酸乙酯(890mg,白色固体,收率:70.2%)。Add 1-bromo-2,12-dioxo-2,6,6a,7,8,9,10,12-octahydrogen to a round bottom flask containing acetonitrile (12 mL) and water (3 mL) at rt. Dipyrido[1,2-a:1',2'-d]pyrazine-3-carboxylic acid ethyl ester (1.2 g, 3.3 mmol), p-fluorophenylboronic acid (670 mg, 4.79 mmol), potassium carbonate (1.32 g) , 9.57 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (233 mg, mmol). Sealed, replaced with nitrogen three times, heated to 80 ° C, and stirred for 4 hours. After the reaction liquid was cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut elut , 8, 9, 10, 12-octahydrodipyrido[1,2-a:1',2'-d]pyrazine-3-carboxylic acid ethyl ester (890 mg, white solid, yield: 70.2%).
LC-MS(ESI):m/z 385.2[M+H
+]。
LC-MS (ESI): m / z 385.2 [M + H +].
步骤6:1-(4-氟苯基)-2,12-二氧代-2,6,6a,7,8,9,10,12-八氢二吡啶并[1,2-a:1',2'-d]吡嗪-3-甲酸(g)的制备Step 6: 1-(4-Fluorophenyl)-2,12-dioxo-2,6,6a,7,8,9,10,12-octahydrodipyrido[1,2-a:1 Preparation of ',2'-d]pyrazine-3-carboxylic acid (g)
于室温,在含有乙醇(8mL)和水(2mL)的圆底烧瓶中加入1-(4-氟苯基)-2,12-二氧代-2,6,6a,7,8,9,10,12-八氢二吡啶并[1,2-a:1',2'-d]吡嗪-3-甲酸乙酯(800mg,2.08mmol)和一水合氢氧化锂(91mg,2.2mmol)。将混合物升温至60℃,并搅拌4小时。待反应完全后,减压浓缩,得到粗产品1-(4-氟苯基)-2,12-二氧代-2,6,6a,7,8,9,10,12-八氢二吡啶并[1,2-a:1',2'-d]吡嗪-3-甲酸(800mg,淡黄色固体,收率:100%)。其未经纯化直接用于下一步反应。Add 1-(4-fluorophenyl)-2,12-dioxo-2,6,6a,7,8,9 to a round bottom flask containing ethanol (8 mL) and water (2 mL) at room temperature. 10,12-octahydrodipyrido[1,2-a:1',2'-d]pyrazine-3-carboxylic acid ethyl ester (800 mg, 2.08 mmol) and lithium hydroxide monohydrate (91 mg, 2.2 mmol) . The mixture was warmed to 60 ° C and stirred for 4 hours. After the reaction was completed, it was concentrated under reduced pressure to give crude product 1-(4-fluorophenyl)-2,12-dioxo-2,6,6a,7,8,9,10,12-octahydrodipyridine. And [1,2-a:1',2'-d]pyrazine-3-carboxylic acid (800 mg, pale yellow solid, yield: 100%). It was used directly in the next reaction without purification.
LC-MS(ESI):m/z 357.2[M+H
+]。
LC-MS (ESI): m / z 357.2 [M + H +].
制备实施例8:6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢-1H-吡啶并[1,2-a]吡咯并[1,2-D]吡嗪-8-羧酸(中间体h)的制备PREPARATIVE EXAMPLE 8: 6-(4-Fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydro-1H-pyrido[1,2-a]pyrrole And [1,2-D]pyrazine-8-carboxylic acid (intermediate h) preparation
采用与制备实施例7相同的方法,除了用2-(氨基甲基)吡咯烷-1-羧酸叔丁酯(上海安耐吉)代替1-叔丁氧羰基-2-氨甲基哌啶,制得6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢-1H-吡啶并[1,2-a]吡咯并[1,2-D]吡嗪-8-羧酸(h)(灰色固体,六步收率21.5%)。In the same manner as in Preparation Example 7, except that 2-(aminomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (Shanghai Angji) was used instead of 1-tert-butoxycarbonyl-2-aminomethylpiperidine. , 6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydro-1H-pyrido[1,2-a]pyrrolo[ 1,2-D]pyrazine-8-carboxylic acid (h) (grey solid, 21.5% yield in six steps).
LC-MS(ESI):m/z 343.2[M+H
+]。
LC-MS (ESI): m / z 343.2 [M + H +].
制备实施例9:7-(4-氟苯基)-6,8-二氧代-3,4,6,8,12,12a-六氢-1H-吡啶并[1',2':4,5]吡嗪并[2,1-c][1,4]恶嗪-9-甲酸(中间体j)的制备Preparation Example 9: 7-(4-Fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-pyrido[1',2':4 ,5]Preparation of pyrazino[2,1-c][1,4]oxazine-9-carboxylic acid (intermediate j)
步骤1:4-(叔丁氧羰基)吗啉-3-羧酸(j1-1)的制备Step 1: Preparation of 4-(tert-butoxycarbonyl)morpholine-3-carboxylic acid (j1-1)
于室温,在含有丙酮(20mL)和水(10mL)的圆底烧瓶中加入吗啉-3-羧酸(3.0g,22.9mmol)和碳酸钾(15.8g,114.4mmol)。搅拌下缓慢滴加Boc
2O(7.5g,34.4mmol),加毕,于该温度继续搅拌过夜。待反应完全后,将反应液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为MeOH:DCM=1:5),得到4-(叔丁氧羰基)吗啉-3-羧酸(1.8g,黄色油状物,收率:34.1%)。
Morpholine-3-carboxylic acid (3.0 g, 22.9 mmol) and potassium carbonate (15.8 g, 114.4 mmol) were added to a round bottom flask containing acetone (20 mL) and water (10 mL). Boc 2 O (7.5 g, 34.4 mmol) was slowly added dropwise with stirring, and the mixture was stirred at this temperature overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc : 34.1%).
LC-MS(ESI):m/z 232.1[M+H
+]。
LC-MS (ESI): m / z 232.1 [M + H +].
步骤2:3-氨基甲酰基吗啉-4-羧酸叔丁酯(j1-2)的制备Step 2: Preparation of 3-carbamoylmorpholine-4-carboxylic acid tert-butyl ester (j1-2)
于室温,在含有DMF(40mL)的圆底烧瓶中加入4-(叔丁氧羰基)吗啉-3-羧酸(1.8g,7.78mmol)、氯化铵(1.26g,23.3mmol)、HOBT(3.15g,23.3mmol)、EDCI(2.24g,11.67mmol)和DIPEA(4.52g,35.01mmol)。将混合物于该温度搅拌过夜。待反应完全后,将反应液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为MeOH:DCM=1:10),得到3-氨基甲酰基吗啉-4-羧酸叔丁酯(380mg,黄色油状物,收率:21.1%)。4-(tert-Butoxycarbonyl)morpholine-3-carboxylic acid (1.8 g, 7.78 mmol), ammonium chloride (1.26 g, 23.3 mmol), HOBT was added to a round bottom flask containing DMF (40 mL) at room temperature. (3.15 g, 23.3 mmol), EDCI (2.24 g, 11.67 mmol) and DIPEA (4.52 g, 35.01 mmol). The mixture was stirred at this temperature overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjjj 21.1%).
LC-MS(ESI):m/z 231.1[M+H
+]。
LC-MS (ESI): m / z 231.1 [M + H +].
步骤3:3-(氨基甲基)吗啉-4-羧酸叔丁酯(j1)的制备Step 3: Preparation of 3-(aminomethyl)morpholine-4-carboxylic acid tert-butyl ester (j1)
于室温,在含有THF(4mL)的圆底烧瓶中加入3-氨基甲酰基吗啉-4-羧酸叔丁酯(380mg,1.65mmol)和硼烷的THF溶液(1.7mL,4.95mmol)。将混合物加热至回流并搅拌6小时。待反应完全后,将反应液冷却至室温,然后缓慢滴加甲醇淬灭反应。将反应液减压浓缩,残余物通过硅胶柱层析色谱法纯化(洗脱剂为MeOH:DCM=1:10),得到3-(氨基甲基)吗啉-4-羧酸叔丁酯(300mg,黄色油状物,收率:84.1%)。A solution of 3-carbamoylmorpholine-4-carboxylic acid tert-butyl ester (380 mg, 1.65 mmol) and borane in THF (1.7 mL, 4.95 mmol) was obtained from THF (4 mL). The mixture was heated to reflux and stirred for 6 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and then the reaction was quenched by dropwise addition of methanol. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjj 300 mg, yellow oil, yield: 84.1%).
LC-MS(ESI):m/z 217.1[M+H
+]。
LC-MS (ESI): m / z 217.1 [M + H +].
其余步骤采用与制备实施例7相同的方法,除了用3-(氨基甲基)吗啉-4-羧酸叔丁酯(j1)代替1-叔丁氧羰基-2-氨甲基哌啶,制得7-(4-氟苯基)-6,8-二氧代-3,4,6,8,12,12a-六氢-1H-吡啶并[1',2':4,5]吡嗪并[2,1-c][1,4]恶嗪-9-甲酸(j)(灰色固体,六步收率18.3%)。The remaining steps were carried out in the same manner as in Preparation Example 7, except that 3-(aminomethyl)morpholine-4-carboxylic acid tert-butyl ester (j1) was used instead of 1-tert-butoxycarbonyl-2-aminomethylpiperidine. 7-(4-Fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-pyrido[1',2':4,5] Pyrazino[2,1-c][1,4]oxazine-9-carboxylic acid (j) (grey solid, yield of 18.3% in six steps).
LC-MS(ESI):m/z 359.4[M+H
+]。
LC-MS (ESI): m / z 359.4 [M + H +].
制备实施例10:7-(4-氟苯基)-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酸(中间体k)的制备PREPARATIVE EXAMPLE 10: 7-(4-Fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4 ,5]Preparation of pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (intermediate k)
步骤1:1-(2,2-二甲氧基乙基)-4-氧代-1,4-二氢吡啶-2,5-二甲酸二乙酯(k1)的制备Preparation of Step 1:1-(2,2-Dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (k1)
于室温,在含有乙醇(50mL)的圆底烧瓶中加入4-氧代-4H-吡喃-2,5-二羧酸二乙酯(a2)(5g,20.8mmol)和氨基乙醛缩二甲醇(3.3g,31.39mmol)。将混合物升 温至80℃并搅拌4小时。待反应完全后,减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为MeOH:CM=1:10),得到1-(2,2-二甲氧基乙基)-4-氧代-1,4-二氢吡啶-2,5-二甲酸二乙酯(3.4g,黄色油状物,收率:50.0%)。Add 4-oxo-4H-pyran-2,5-dicarboxylic acid diethyl ester (a2) (5 g, 20.8 mmol) and aminoacetaldehyde in a round bottom flask containing ethanol (50 mL) at room temperature. Methanol (3.3 g, 31.39 mmol). The mixture was warmed to 80 ° C and stirred for 4 hours. After the reaction was completed, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc:EtOAc: Dihydropyridine-2,5-dicarboxylic acid diethyl ester (3.4 g, yellow oil, yield: 50.0%).
LC-MS(ESI):m/z 382.3[M+H
+]。
LC-MS (ESI): m / z 382.3 [M + H +].
步骤2:3-溴-1-(2,2-二甲氧基乙基)-4-氧代-1,4-二氢吡啶-2,5-二羧酸二乙酯(k2)的制备Step 2: Preparation of 3-bromo-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (k2)
于室温,在含有DMF(100mL)的圆底烧瓶中加入1-(2,2-二甲氧基乙基)-4-氧代-1,4-二氢吡啶-2,5-二甲酸二乙酯(10g,30.55mmol)和NBS(6.0g,33.7mmol)。将混合物于该温度搅拌过夜。待反应完全后,将反应液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为MeOH:DCM=1:10),得到3-溴-1-(2,2-二甲氧基乙基)-4-氧代-1,4-二氢吡啶-2,5-二羧酸二乙酯(8.8g,黄色油状物,收率:71.1%)。Add 1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid to a round bottom flask containing DMF (100 mL) at room temperature. Ethyl ester (10 g, 30.55 mmol) and NBS (6.0 g, 33.7 mmol). The mixture was stirred at this temperature overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc elut elut elut elut Diethyl 4-dihydropyridine-2,5-dicarboxylate (8.8 g, yellow oil, yield: 71.1%).
LC-MS(ESI):m/z 406.1/408.1[M+H
+]。
LC-MS (ESI): m / z 406.1 / 408.1 [M + H +].
步骤3:7-溴-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-羧酸乙酯(k3)的制备Step 3: 7-Bromo-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazine[2 ,1-b][1,3] Preparation of Oxazine-9-carboxylic Acid Ethyl Ester (k3)
于室温,在含有乙腈(80mL)的圆底烧瓶中加入3-溴-1-(2,2-二甲氧基乙基)-4-氧代-1,4-二氢吡啶-2,5-二羧酸二乙酯(6.0g,14.78mmol)、乙酸(24mL)和甲磺酸(8mL)。将混合物升温至70℃并搅拌4小时。待反应液冷却至室温后,加入三乙胺(25mL)和3-氨基丙-1-醇(2.7g,35.95mmol),加热至回流并搅拌过夜。待反应完全后,将反应液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为MeOH:CM=1:10),得到7-溴-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-羧酸乙酯(3.6g,黄色油状物,收率:65.8%)。3-bromo-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2,5 was added to a round bottom flask containing acetonitrile (80 mL) at room temperature. Diethyldicarboxylate (6.0 g, 14.78 mmol), acetic acid (24 mL) and methanesulfonic acid (8 mL). The mixture was warmed to 70 ° C and stirred for 4 hours. After the reaction liquid was cooled to room temperature, triethylamine (25 mL) and 3-aminopropan-1-ol (2.7 g, 35.95 mmol) were added, and the mixture was heated to reflux and stirred overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: MeOH: MeOH = 1:10) to give 7-bromo-6,8-dioxo-3,4,6,8,12,12a-s Hydrogen-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid ethyl ester (3.6g, yellow oil, Rate: 65.8%).
LC-MS(ESI):m/z 371.1/373.1[M+H
+]。
LC-MS (ESI): m / z 371.1 / 373.1 [M + H +].
步骤4:7-(4-氟苯基)-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-B][1,3]恶嗪-9-羧酸乙酯(k4)的制备Step 4: 7-(4-Fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5 Preparation of pyrazino[2,1-B][1,3]oxazine-9-carboxylic acid ethyl ester (k4)
于室温,在含有乙腈(8mL)和水(2mL)的圆底烧瓶中加入7-溴-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-羧酸乙酯(800mg,2.2mmol)、4-氟苯硼酸(452mg,3.2mmol)、碳酸钾(900mg,6.6mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(176mg,0.22mmol)。密封,氮气置换三次,加热至80℃搅拌4小时。待反应液冷却至室温后,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为MeOH:DCM=1:10),得到7-(4-氟苯基)-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-羧酸乙酯(830mg,白色固体,收率:97.7%)。Add 7-bromo-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyridine to a round bottom flask containing acetonitrile (8 mL) and water (2 mL) at room temperature And [1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid ethyl ester (800 mg, 2.2 mmol), 4-fluorophenylboronic acid (452 mg) , 3.2 mmol), potassium carbonate (900 mg, 6.6 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (176 mg, 0.22 mmol). Sealed, replaced with nitrogen three times, heated to 80 ° C and stirred for 4 hours. After the reaction liquid was cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut , 12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid ethyl ester (830 mg, White solid, yield: 97.7%).
LC-MS(ESI):m/z 387.2[M+H
+]。
LC-MS (ESI): m / z 387.2 [M + H +].
步骤5:7-(4-氟苯基)-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酸(k)的制备Step 5: 7-(4-Fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5 Preparation of pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (k)
于室温,在含有乙醇(10mL)和水(2mL)的圆底烧瓶中加入7-(4-氟苯基)-6,8- 二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-羧酸乙酯(830mg,2.15mmol)和一水合氢氧化锂(128mg,2.80mmol)。将混合物升温至60℃并搅拌4小时。待反应完全后,将反应液减压浓缩,得到粗产品7-(4-氟苯基)-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酸(中间体k)(830mg,淡黄色固体,收率:100.0%)。其未经纯化直接用于下一步反应。Add 7-(4-fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a- to a round bottom flask containing ethanol (10 mL) and water (2 mL) at room temperature. Hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid ethyl ester (830 mg, 2.15 mmol) and one Lithium hydroxide hydrate (128 mg, 2.80 mmol). The mixture was warmed to 60 ° C and stirred for 4 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give crude product 7-(4-fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H- Pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (intermediate k) (830 mg, pale yellow solid, yield: 100.0 %). It was used directly in the next reaction without purification.
LC-MS(ESI):m/z 359.4M+H
+]。
LC-MS (ESI): m / z 359.4M + H +].
制备实施例11:6,8-二氧代-7-(对甲苯基)-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酸(中间体l)的制备PREPARATIVE EXAMPLE 11: 6,8-Dioxo-7-(p-tolyl)-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5 Preparation of pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (intermediate l)
采用与制备实施例10相同的方法,除了用4-甲基苯硼酸代替4-氟苯硼酸,制得6,8-二氧代-7-(对甲苯基)-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酸(l)(灰色固体,两步步收率70.3%)。In the same manner as in Preparation Example 10, except that 4-methylbenzeneboronic acid was used in place of 4-fluorophenylboronic acid, 6,8-dioxo-7-(p-tolyl)-3,4,6,8 was obtained. ,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (l) (grey solid , two-step yield 70.3%).
LC-MS(ESI):m/z 355.2[M+H
+]。
LC-MS (ESI): m / z 355.2 [M + H +].
制备实施例12:7-(6-甲基吡啶-3-基)-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酸(中间体m)的制备PREPARATIVE EXAMPLE 12: 7-(6-Methylpyridin-3-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1', Preparation of 2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (intermediate m)
采用与制备实施例10相同的方法,除了用(6-甲基吡啶-3-基)硼酸代替4-氟苯硼酸,制得7-(6-甲基吡啶-3-基)-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酸(m)(灰色固体,两步收率:36.2%)。In the same manner as in Preparation Example 10, except that (6-methylpyridin-3-yl)boronic acid was used instead of 4-fluorophenylboronic acid, 7-(6-methylpyridin-3-yl)-6,8 was obtained. -dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3] Oxazine-9-carboxylic acid (m) (grey solid, two-step yield: 36.2%).
LC-MS(ESI):m/z 356.2[M+H
+]。
LC-MS (ESI): m / z 356.2 [M + H +].
制备实施例13:7-(5-甲基噻吩-2-基)-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酸(中间体n)的制备PREPARATIVE EXAMPLE 13: 7-(5-Methylthiophen-2-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1', Preparation of 2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (intermediate n)
采用与制备实施例10相同的方法,除了用(5-甲基噻吩-2-基)硼酸代替4-氟苯硼酸,制得7-(5-甲基噻吩-2-基)-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酸(n)(灰色固体,两步收率:26.5%)。In the same manner as in Preparation Example 10 except that (5-methylthiophen-2-yl)boronic acid was used instead of 4-fluorophenylboronic acid, 7-(5-methylthiophen-2-yl)-6,8 was obtained. -dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3] Oxazine-9-carboxylic acid (n) (grey solid, two-step yield: 26.5%).
LC-MS(ESI):m/z 361.2[M+H
+]。
LC-MS (ESI): m / z 361.2 [M + H +].
制备实施例14:6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-羧酸(中间体o)的制备PREPARATIVE EXAMPLE 14: 6-(4-Fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyridinium[ Preparation of 1,2-d]pyrazine-8-carboxylic acid (intermediate o)
采用与制备实施例10相同的方法,除了用2-氨基乙-1-醇代替3-氨基丙-1-醇,制得6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-羧酸(o)(灰色固体,三步收率:53.2%)。In the same manner as in Preparation Example 10 except that 2-aminoethyl-1-ol was used in place of 3-aminopropan-1-ol, 6-(4-fluorophenyl)-5,7-dioxo- 2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (o) (gray solid, three-step Rate: 53.2%).
LC-MS(ESI):m/z 345.1[M+H
+]。
LC-MS (ESI): m / z 345.1 [M + H +].
制备实施例15:6-(4-甲苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-羧酸(中间体p)的制备PREPARATIVE EXAMPLE 15: 6-(4-Tolyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyridin[1] ,2-d]Preparation of pyrazine-8-carboxylic acid (intermediate p)
采用与制备实施例14相同的方法,除了用4-甲基苯硼酸代替4-氟苯硼酸,制得6-(4-甲苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-羧酸(p)(灰色固体,两步收率:73.5%)。In the same manner as in Preparation Example 14, except that 4-methylbenzeneboronic acid was used in place of 4-fluorophenylboronic acid, 6-(4-methylphenyl)-5,7-dioxo-2,3,5 was obtained. 7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (p) (grey solid, two-step yield: 73.5%).
LC-MS(ESI):m/z 341.1[M+H
+]。
LC-MS (ESI): m / z 341.1 [M + H +].
制备实施例16:(3R)-6-(4-氟苯基)-3-甲基-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-羧酸(中间体q)的制备PREPARATIVE EXAMPLE 16: (3R)-6-(4-Fluorophenyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazole[ Preparation of 3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (intermediate q)
采用与制备实施例10相同的方法,除了用(R)-2-氨基丙-1-醇代替3-氨基丙-1- 醇,制得(3R)-6-(4-氟苯基)-3-甲基-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-羧酸(q)(灰色固体,三步收率:54.2%)。In the same manner as in Preparation Example 10, except that (R)-2-aminopropan-1-ol was used in place of 3-aminopropan-1-ol, (3R)-6-(4-fluorophenyl)- 3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8 - Carboxylic acid (q) (grey solid, three-step yield: 54.2%).
LC-MS(ESI):m/z 359.2[M+H
+]。
LC-MS (ESI): m / z 359.2 [M + H +].
制备实施例17:(3S)-6-(4-氟苯基)-3-甲基-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-羧酸(中间体r)的制备PREPARATIVE EXAMPLE 17: (3S)-6-(4-Fluorophenyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazole[ Preparation of 3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (intermediate r)
采用与制备实施例10相同的方法,除了用(S)-2-氨基丙-1-醇代替3-氨基丙-1-醇,制得(3S)-6-(4-氟苯基)-3-甲基-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-羧酸(r)(灰色固体,三步收率:51.7%)。In the same manner as in Preparation Example 10, except that (S)-2-aminopropan-1-ol was used instead of 3-aminopropan-1-ol, (3S)-6-(4-fluorophenyl)- 3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8 - Carboxylic acid (r) (grey solid, three-step yield: 51.7%).
LC-MS(ESI):m/z 359.2[M+H
+]。
LC-MS (ESI): m / z 359.2 [M + H +].
制备实施例18:(4R)-7-(4-氟苯基)-4-甲基-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酸(中间体s)的制备PREPARATIVE EXAMPLE 18: (4R)-7-(4-Fluorophenyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyridine And [1', 2': 4,5] Preparation of pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (intermediate s)
采用与制备实施例10相同的方法,除了用(R)-3-氨基丁-1-醇代替3-氨基丙-1-醇,制得(4R)-7-(4-氟苯基)-4-甲基-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酸(s)(灰色固体,三步收率:49.1%)。In the same manner as in Preparation Example 10, except that (R)-3-aminobutan-1-ol was used instead of 3-aminopropan-1-ol, (4R)-7-(4-fluorophenyl)- 4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazine[2,1 -b][1,3]oxazine-9-carboxylic acid (s) (gray solid, three-step yield: 49.1%).
LC-MS(ESI):m/z 373.2[M+H
+]。
LC-MS (ESI): m / z 373.2 [M + H +].
制备实施例19:9-(4-氟苯基)-1,8-二氧代-1,3,4,8-四氢-2H-吡啶并[1,2-a]吡嗪-7-羧酸(中间体t)的制备PREPARATIVE EXAMPLE 19: 9-(4-Fluorophenyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7- Preparation of carboxylic acid (intermediate t)
采用与制备实施例4相同的方法,除了用N-叔丁氧羰基-1,2-乙二胺代替N-叔丁氧羰基-1,3-丙二胺,制得9-(4-氟苯基)-1,8-二氧代-1,3,4,8-四氢-2H-吡啶并[1,2-a] 吡嗪-7-羧酸(t)(灰色固体,六步收率:38.7%)。In the same manner as in Preparation Example 4, except that N-tert-butoxycarbonyl-1,2-ethanediamine was used instead of N-tert-butoxycarbonyl-1,3-propanediamine to obtain 9-(4-fluoro Phenyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxylic acid (t) (gray solid, six steps) Yield: 38.7%).
LC-MS(ESI):m/z 303.2[M+H
+]。
LC-MS (ESI): m / z 303.2 [M + H +].
制备实施例20:4-(4-(6-氨基-5-(4-氨基-2-氟苯基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(中间体u)的制备PREPARATIVE EXAMPLE 20: 4-(4-(6-Amino-5-(4-amino-2-fluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid Preparation of tert-butyl ester (intermediate u)
步骤1:3-溴-5-碘吡啶-2-胺(u1)的制备Step 1: Preparation of 3-bromo-5-iodopyridin-2-amine (u1)
在含有乙腈(100mL)的反应瓶中加入5-碘吡啶-2-胺(5.0g,22.73mmol)和NBS(4.0g,22.73mmol)。将反应混合物于50℃搅拌12小时,然后冷却至室温,过滤,减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱液为PE:EA/20:1),得到3-溴-5-碘吡啶-2-胺(2.5g,黄色固体,收率:36.8%)。5-iodopyridin-2-amine (5.0 g, 22.73 mmol) and NBS (4.0 g, 22.73 mmol) were added to a reaction flask containing acetonitrile (100 mL). The reaction mixture was stirred at 50 <0>C for 12 h then cooled to EtOAc. The residue was purified by EtOAc EtOAcjjjjjjj .
LC-MS(ESI):m/z 299.3/301.3[M+H
+]。
LC-MS (ESI): m / z 299.3 / 301.3 [M + H +].
步骤2:4-(4-(6-氨基-5-溴吡啶-3-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(u2)的制备Step 2: Preparation of tert-butyl 4-(4-(6-amino-5-bromopyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (u2)
于室温,在含有(50mL)甲苯、乙醇和水的混合液(2:2:1)的反应瓶中加入3-溴-5-碘吡啶-2-胺(2.5g,8.36mmol)、4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(北京偶合,3.78g,10.03mmol)、碳酸钠(2.66g,25.08mmol)、Pd(PPh
3)
4(483mg,0.42mmol)。密封,氮气置换三次,加热至80℃并搅拌1.5小时。待反应完全后,过滤,滤液用水(50mL)稀释,乙酸乙酯萃取(50mL×3),合并有机相。将有机相用饱和的食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱液为PE:EA/1:1),得到4-(4-(6-氨基-5-溴吡啶-3-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(2.8g,黄色固体,收率:79.4%)。
3-bromo-5-iodopyridin-2-amine (2.5 g, 8.36 mmol), 4- in a reaction flask containing (50 mL) a mixture of toluene, ethanol and water (2:2:1) at room temperature (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-Butyl ester (Beijing coupling, 3.78 g, 10.03 mmol), sodium carbonate (2.66 g, 25.08 mmol), Pd(PPh 3 ) 4 (483 mg, 0.42 mmol). Sealed, replaced with nitrogen three times, heated to 80 ° C and stirred for 1.5 hours. After the reaction was completed, it was filtered, and the filtrate was diluted with water (50mL), ethyl acetate (50mL × 3), and the organic phase was combined. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography (eluent: EtOAc/EtOAc) to afford 4-(4-(6-amino-5-bromopyridin-3-yl)-1H-pyrazole- Tert-butyl ester of 1-yl)piperidine-1-carboxylate (2.8 g, yellow solid, yield: 79.4%).
LC-MS(ESI):m/z 422.2/424.3[M+H
+]。
LC-MS (ESI): m / z 422.2 / 424.3 [M + H +].
步骤3:4-(4-(6-氨基-5-(4-氨基-2-氟苯基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(u)的制备Step 3: 4-(4-(6-Amino-5-(4-amino-2-fluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl Preparation of ester (u)
于室温,在含有(40mL)1,4-二氧六环和水的混合液(4:1)的反应瓶中加入4-(4-(6-氨基-5-溴吡啶-3-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(2.8g,6.64mmol)、4-氨基-2-氟苯硼酸频那醇酯(上海毕得,1.88g,7.96mmol)、碳酸钾(2.75g,19.92mmol)、Pd(dppf)Cl
2.DCM(538mg,0.66mmol)。密封,氮气置换三次,加热至90℃并搅拌过夜。待反应完全后,过滤,滤液用水(50mL)稀释,乙酸乙酯萃取(50mL×3),合并有机相。将有机相用饱和的食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱液为PE:EA/1:2),得到4-(4-(6-氨基-5-(4-氨基-2-氟苯基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(中间体u)(2.3g,黄色固体,收率:77.1%)。
4-(4-(6-Amino-5-bromopyridin-3-yl) was added to a reaction flask containing (40 mL) a mixture of 1,4-dioxane and water (4:1) at room temperature. -1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (2.8 g, 6.64 mmol), 4-amino-2-fluorobenzeneboronic acid pinacol ester (Shanghai Bide, 1.88 g, 7.96 mmol) ), potassium carbonate (2.75 g, 19.92 mmol), Pd(dppf)Cl 2 .DCM (538 mg, 0.66 mmol). Sealed, replaced with nitrogen three times, heated to 90 ° C and stirred overnight. After the reaction was completed, it was filtered, and the filtrate was diluted with water (50mL), ethyl acetate (50mL × 3), and the organic phase was combined. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography (EtOAc:EtOAc:EtOAc: Tert-butyl 3-methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (intermediate u) (2.3 g, yellow solid, yield: 77.1%).
LC-MS(ESI):m/z 453.4[M+H
+]。
LC-MS (ESI): m / z 453.4 [M + H +].
制备实施例21:3-(4-氨基-2-氟苯基)-5-(1-乙基-1H-吡唑-4-基)吡啶-2-胺(中间体v)的制备PREPARATIVE EXAMPLE 21 Preparation of 3-(4-Amino-2-fluorophenyl)-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-2-amine (Intermediate v)
采用与制备实施例20相同的方法,除了用1-乙基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡唑(北京偶合)代替4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯,制得3-(4-氨基-2-氟苯基)-5-(1-乙基-1H-吡唑-4-基)吡啶-2-胺(v)(黄色固体,两步收率:68.8%)。The same procedure as in Preparation Example 20 was employed except that 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H was used. -pyrazole (Beijing coupling) instead of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole- tert-Butyl 1-phenyl)piperidine-1-carboxylate to give 3-(4-amino-2-fluorophenyl)-5-(1-ethyl-1H-pyrazol-4-yl)pyridine-2 - Amine (v) (yellow solid, two-step yield: 68.8%).
LC-MS(ESI):m/z 298.3[M+H
+]。
LC-MS (ESI): m / z 298.3 [M + H +].
制备实施例22:3-(4-氨基-2-氟苯基)-5-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)吡啶-2-胺(中间体w)的制备PREPARATIVE EXAMPLE 22: 3-(4-Amino-2-fluorophenyl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridine-2 - Preparation of an amine (intermediate w)
采用与制备实施例20相同的方法,除了用1-(四氢-2H-吡喃-4-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡唑(北京偶合)代替4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯,制得3-(4-氨基-2-氟苯基)-5-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)吡啶-2-胺(w)(黄色固体,两步收率:72.3%)。The same procedure as in Preparation Example 20 was employed except that 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-di was used. Oxaborane-2-yl)-1H-pyrazole (Beijing coupling) instead of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) Tert-butyl ester of 2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate to give 3-(4-amino-2-fluorophenyl)-5-(1-(tetrahydro-) 2H-Pyr-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine (w) (yellow solid, two-step yield: 72.3%).
LC-MS(ESI):m/z 354.3[M+H
+]。
LC-MS (ESI): m / z 354.3 [M + H +].
制备实施例23:3-(4-氨基-2-氟苯基)-5-(3,4-二甲氧基苯基)吡啶-2-胺(中间体x)的制备Preparation Example 23: Preparation of 3-(4-amino-2-fluorophenyl)-5-(3,4-dimethoxyphenyl)pyridin-2-amine (Intermediate x)
采用与制备实施例20相同的方法,除了用(3,4-二甲氧基苯基)硼酸(北京偶合)代替4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯,制得3-(4-氨基-2-氟苯基)-5-(3,4-二甲氧基苯基)吡啶-2-胺(x)(黄色固体,两步收率:79.1%)。The same procedure as in Preparation Example 20 was carried out except that (3,4-dimethoxyphenyl)boronic acid (Beijing coupling) was used instead of 4-(4-(4,4,5,5-tetramethyl-1, Tert-butyl 3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate to give 3-(4-amino-2-fluorophenyl) -5-(3,4-Dimethoxyphenyl)pyridin-2-amine (x) (yellow solid, two-step yield: 79.1%).
LC-MS(ESI):m/z 340.2[M+H
+]。
LC-MS (ESI): m / z 340.2 [M + H +].
制备实施例24:4-(4-(6-氨基-5-(4-氨基-2,5-二氟苯基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(中间体y)的制备Preparation Example 24: 4-(4-(6-Amino-5-(4-amino-2,5-difluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine- Preparation of 1-butylic acid tert-butyl ester (intermediate y)
采用与制备实施例20相同的方法,除了用4-氨基-2,5-二氟苯硼酸频那醇酯(上海毕得)代替4-氨基-2-氟苯硼酸频那醇酯,制得4-(4-(6-氨基-5-(4-氨基-2,5-二氟苯基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(y)(黄色固体,一步收率:63.4%)。Prepared in the same manner as in Preparation Example 20 except that 4-amino-2,5-difluorophenylboronic acid pinacol ester (Shanghai Bied) was used instead of 4-amino-2-fluorophenylboronic acid pinacol ester. 4-(4-(6-Amino-5-(4-amino-2,5-difluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl Ester (y) (yellow solid, one step yield: 63.4%).
LC-MS(ESI):m/z 471.4[M+H
+]。
LC-MS (ESI): m / z 471.4 [M + H +].
制备实施例25:3-(4-氨基苯基)-5-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)吡啶-2-胺(中间体z)的制备Preparation Example 25: 3-(4-Aminophenyl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine (middle Preparation of body z)
采用与制备实施例22相同的方法,除了用4-氨基苯硼酸频那醇酯(北京偶合)代替4-氨基-2-氟苯硼酸频那醇酯,制得3-(4-氨基苯基)-5-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)吡啶-2-胺(z)(黄色固体,两步收率:72.3%)。In the same manner as in Preparation Example 22, except that 4-aminophenylboronic acid pinacol ester (Beijing coupling) was used instead of 4-amino-2-fluorophenylboronic acid pinacol ester to obtain 3-(4-aminophenyl). -5-(4-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine (z) (yellow solid, two-step yield: 72.3%) .
LC-MS(ESI):m/z 336.3[M+H
+]。
LC-MS (ESI): m / z 336.3 [M + H +].
制备实施例26:3-(4-氨基苯基)-5-(3,4-二甲氧基苯基)吡啶-2-胺(中间体aa)的制备PREPARATIVE EXAMPLE 26 Preparation of 3-(4-Aminophenyl)-5-(3,4-dimethoxyphenyl)pyridin-2-amine (Intermediate aa)
采用与制备实施例23相同的方法,除了用4-氨基苯硼酸频那醇酯(北京偶合)代替4-氨基-2-氟苯硼酸频那醇酯,制得3-(4-氨基苯基)-5-(3,4-二甲氧基苯基)吡啶-2-胺(aa)(黄色固体,两步收率:79.1%)。In the same manner as in Preparation Example 23, except that 4-aminophenylboronic acid pinacol ester (Beijing coupling) was used instead of 4-amino-2-fluorophenylboronic acid pinacol ester to obtain 3-(4-aminophenyl). -5-(3,4-Dimethoxyphenyl)pyridin-2-amine (aa) (yellow solid, two-step yield: 79.1%).
LC-MS(ESI):m/z 322.4[M+H
+]。
LC-MS (ESI): m / z 322.4 [M + H +].
制备实施例28:5-(4-((1,4-二恶烷-2-基)甲氧基)-3-甲氧基苯基)-3-(4-氨基-2-氟苯基)吡啶-2-胺(中间体bb)的制备Preparation Example 28: 5-(4-((1,4-dioxan-2-yl)methoxy)-3-methoxyphenyl)-3-(4-amino-2-fluorophenyl) Preparation of pyridin-2-amine (intermediate bb)
步骤1:4-((4-溴-2-甲氧基苯氧基)甲基)-2,2-二甲基-1,3-二氧戊环(bb1)的制备Step 1: Preparation of 4-((4-bromo-2-methoxyphenoxy)methyl)-2,2-dimethyl-1,3-dioxolan (bb1)
于室温,在含有无水四氢呋喃溶液(25mL)的反应瓶中加入4-溴-2-甲氧基苯酚(2g,9.85mmol)、丙酮缩甘油(1.95g,14.77mmol)、三苯基膦(3.1g,11.82mmol)和偶氮二甲酸二异丙酯(2.39g,11.82mmol)。密封,氮气置换三次,将混合物加热回流搅拌过夜。待反应液冷却至室温后,加入饱和氯化铵水溶液淬灭反应,用二氯甲烷萃取(30mL×3),合并有机相。有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱液为 PE:EA/10:1),得到4-((4-溴-2-甲氧基苯氧基)甲基)-2,2-二甲基-1,3-二氧戊环(2.5g,黄色油状物,收率:80.1%)。4-bromo-2-methoxyphenol (2 g, 9.85 mmol), acetone glycerol (1.95 g, 14.77 mmol), triphenylphosphine (diphenylphosphine) was added to a reaction flask containing anhydrous tetrahydrofuran solution (25 mL) at room temperature. 3.1 g, 11.82 mmol) and diisopropyl azodicarboxylate (2.39 g, 11.82 mmol). It was sealed, replaced with nitrogen three times, and the mixture was stirred and stirred under reflux overnight. After the reaction mixture was cooled to room temperature, the reaction was quenched with saturated aqueous ammonium chloride, and extracted with dichloromethane (30mL×3). The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography (eluent: EtOAc: 1:1) to give 4-((4-bromo-2-methoxyphenoxy)methyl)-2,2- Dimethyl-1,3-dioxolane (2.5 g, yellow oil, yield: 80.1%).
步骤2:3-(4-溴-2-甲氧基苯氧基)丙烷-1,2-二醇(bb2)的制备Step 2: Preparation of 3-(4-bromo-2-methoxyphenoxy)propane-1,2-diol (bb2)
在含有乙酸(15mL)和水(15mL)的反应瓶中加入4-((4-溴-2-甲氧基苯氧基)甲基)-2,2-二甲基-1,3-二氧戊环(2.5g,7.88mmol)。将混合物加热至60℃搅拌30分钟。待反应完全后,将反应液减压浓缩,残余物加入乙酸乙酯稀释。有机相依次用饱和的碳酸氢钠溶液和饱和的食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱液为DCM:MeOH/10:1),得到3-(4-溴-2-甲氧基苯氧基)丙烷-1,2-二醇。(2.1g,黄色油状物,收率:96.3%)。Add 4-((4-bromo-2-methoxyphenoxy)methyl)-2,2-dimethyl-1,3-di in a reaction flask containing acetic acid (15 mL) and water (15 mL) Oxolane (2.5 g, 7.88 mmol). The mixture was heated to 60 ° C and stirred for 30 minutes. After the reaction was completed, the reaction mixture was concentrated under reduced vacuo. The organic layer was washed with aq. The residue was purified by silica gel column chromatography eluting elut elut elut (2.1 g, yellow oil, yield: 96.3%).
LC-MS(ESI):m/z 277.1/279.1[M+H
+]。
LC-MS (ESI): m / z 277.1 / 279.1 [M + H +].
步骤3:2-((4-溴-2-甲氧基苯氧基)甲基)-1,4-二恶烷(bb3)的制备Step 3: Preparation of 2-((4-bromo-2-methoxyphenoxy)methyl)-1,4-dioxane (bb3)
在含有1,2-二溴乙烷(30mL)的反应瓶中依次加入3-(4-溴-2-甲氧基苯氧基)丙烷-1,2-二醇(2.1g,7.58mmol)、四丁基溴化铵(488mg,1.52mmol)和50%(w/w)的氢氧化钠溶液(30mL)。将混合物加热至55℃并搅拌6小时后,再补加1,2-二溴乙烷(30mL)和50%(w/w)的氢氧化钠溶液(30mL),并在该温度继续搅拌过夜。待反应液冷却至室温后,加水稀释并用二氯甲烷萃取(100mL x 3),合并有机相。有机相用饱和的食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱液为PE:EA/2:1),得到2-((4-溴-2-甲氧基苯氧基)甲基)-1,4-二恶烷(1.7g,黄色的固体,收率:73.9%)。3-(4-Bromo-2-methoxyphenoxy)propane-1,2-diol (2.1 g, 7.58 mmol) was added sequentially to a reaction flask containing 1,2-dibromoethane (30 mL). Tetrabutylammonium bromide (488 mg, 1.52 mmol) and 50% (w/w) sodium hydroxide solution (30 mL). After heating the mixture to 55 ° C and stirring for 6 hours, additional 1,2-dibromoethane (30 mL) and 50% (w/w) sodium hydroxide solution (30 mL) were added and stirring was continued at this temperature overnight. . After the reaction solution was cooled to room temperature, it was diluted with water and extracted with dichloromethane (100 mL x 3), and the organic phase was combined. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography (EtOAc:EtOAc: Dioxane (1.7 g, yellow solid, yield: 73.9%).
LC-MS(ESI):m/z 303.1/305.1[M+H
+]。
LC-MS (ESI): m / z 303.1 / 305.1 [M + H +].
步骤4:2-(4-((1,4-二恶烷-2-基)甲氧基)-3-甲氧基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(bb4)的制备Step 4: 2-(4-((1,4-Dioxa-2-yl)methoxy)-3-methoxyphenyl)-4,4,5,5-tetramethyl-1, Preparation of 3,2-dioxaborane (bb4)
于室温,在含有1,4-二氧六环(30mL)和水(7.5mL)的反应瓶中加入2-((4-溴-2-甲氧基苯氧基)甲基)-1,4-二恶烷(1.7g,5.6mmol)、联硼酸频那醇酯(2.8g,11.2mmol)、乙酸钠(1.37mg,16.8mmol)和Pd(dppf)Cl
2(457mg,0.56mmol)。密封,氮气置换三次,加热至90℃并搅拌2小时。待反应液冷却至室温后,加入乙酸乙酯稀释,有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱液为PE:EA/2:1),得到2-(4-((1,4-二恶烷-2-基)甲氧基)-3-甲氧基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷。(1.83g,淡黄色油状物,收率:93.3%)。
2-((4-Bromo-2-methoxyphenoxy)methyl)-1 was added to a reaction flask containing 1,4-dioxane (30 mL) and water (7.5 mL) at room temperature. 1,4-dioxane (1.7g, 5.6mmol), with boronic acid pinacol ester (2.8g, 11.2mmol), sodium acetate (1.37mg, 16.8mmol) and Pd (dppf) Cl 2 (457mg , 0.56mmol). Sealed, replaced with nitrogen three times, heated to 90 ° C and stirred for 2 hours. After the reaction mixture was cooled to room temperature, diluted with ethyl acetate. The residue was purified by silica gel column chromatography (eluent: EtOAc: EtOAc: EtOAc) -Methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane. (1.83 g, pale yellow oil, yield: 93.3%).
LC-MS(ESI):m/z 351.2[M/M+H
+]。
LC-MS (ESI): m / z 351.2 [M / M + H +].
步骤5:3-(4-氨基-2-氟苯基)-5-溴吡啶-2-胺(bb5)的制备Step 5: Preparation of 3-(4-amino-2-fluorophenyl)-5-bromopyridin-2-amine (bb5)
于室温,在含有1,4-二氧六环(10mL)和水(2.5mL)的反应瓶中加入5-溴-3-碘吡啶-2-胺(1g,3.36mmol)、4-氨基-2-氟苯硼酸频那醇酯(954mg,4.03mmol)、碳酸钾(1.39g,10.06mmol)和Pd(PPh
3)
4(392mg,0.34mmol)。密封,氮气置换三次,加热至80℃并搅拌1小时。待反应液冷却到室温后,加入乙酸乙酯稀释。有机相 用饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱液为DCM:MeOH/10:1),得到3-(4-氨基-2-氟苯基)-5-溴吡啶-2-胺(880mg,黄色固体,收率:92.8%)。
Add 5-bromo-3-iodopyridin-2-amine (1 g, 3.36 mmol), 4-amino- to a reaction flask containing 1,4-dioxane (10 mL) and water (2.5 mL) at room temperature. 2-fluorophenyl boronic acid pinacol ester (954mg, 4.03mmol), potassium carbonate (1.39g, 10.06mmol) and Pd (PPh 3) 4 (392mg , 0.34mmol). Sealed, replaced with nitrogen three times, heated to 80 ° C and stirred for 1 hour. After the reaction solution was cooled to room temperature, it was diluted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by EtOAc EtOAcjjjjjjj Yellow solid, yield: 92.8%).
LC-MS(ESI):m/z282.0/284.0[M+H
+]。
LC-MS (ESI): m / z282.0 / 284.0 [M + H +].
步骤6:5-(4-((1,4-二恶烷-2-基)甲氧基)-3-甲氧基苯基)-3-(4-氨基-2-氟苯基)吡啶-2-胺(bb)的制备Step 6: 5-(4-((1,4-Dioxa-2-yl)methoxy)-3-methoxyphenyl)-3-(4-amino-2-fluorophenyl)pyridine Preparation of 2-amine (bb)
于室温,在含有1,4-二氧六环(6mL)和水(1.5mL)的反应瓶中加入3-(4-氨基-2-氟苯基)-5-溴吡啶-2-胺(bb5)(250mg,0.88mmol)、2-(4-((1,4-二恶烷-2-基)甲氧基)-3-甲氧基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(bb4)(371mg,1.06mmol)、碳酸铯(860mg,2.64mmol)和Pd(PPh
3)
4(104mg,0.09mmol)。密封,氮气置换三次,加热至90℃并搅拌过夜。待反应液冷却至室温后,加入乙酸乙酯稀释。有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱液为DCM:MeOH/4:1),得到5-(4-((1,4-二恶烷-2-基)甲氧基)-3-甲氧基苯基)-3-(4-氨基-2-氟苯基)吡啶-2-胺(bb)(140mg,黄色固体,收率:37.1%)。
3-(4-Amino-2-fluorophenyl)-5-bromopyridin-2-amine was added to a reaction flask containing 1,4-dioxane (6 mL) and water (1.5 mL) at room temperature. Bb5) (250 mg, 0.88 mmol), 2-(4-((1,4-dioxan-2-yl)methoxy)-3-methoxyphenyl)-4,4,5,5- Tetramethyl-1,3,2-dioxaborane (bb4) (371 mg, 1.06 mmol), cesium carbonate (860 mg, 2.64 mmol), and Pd(PPh 3 ) 4 (104 mg, 0.09 mmol). Sealed, replaced with nitrogen three times, heated to 90 ° C and stirred overnight. After the reaction solution was cooled to room temperature, it was diluted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by EtOAc EtOAc EtOAc elut elut elut elut -Methoxyphenyl)-3-(4-amino-2-fluorophenyl)pyridin-2-amine (bb) (140 mg, yellow solid, yield: 37.1%).
LC-MS(ESI):m/z 426.3[M+H
+]。
LC-MS (ESI): m / z 426.3 [M + H +].
制备实施例28:4-((2-(4-溴-2-甲氧基苯氧基)乙氧基)甲基)-2,2-二甲基-1,3-二氧戊环(中间体cc)的制备Preparation Example 28: 4-((2-(4-Bromo-2-methoxyphenoxy)ethoxy)methyl)-2,2-dimethyl-1,3-dioxolan ( Preparation of intermediate cc)
步骤1:2-(4-溴-2-甲氧基苯氧基)乙-1-醇(cc1)的制备Step 1: Preparation of 2-(4-bromo-2-methoxyphenoxy)ethan-1-ol (cc1)
在含有DMF(60mL)的反应瓶中加入4-溴-2-甲氧基苯酚(5g,24.63mmol)、2-溴乙醇(6.15g,49.26mmol)和碳酸钾(10.19g,73.89mmol)。将混合物加热至110℃并搅拌20小时,待反应液冷至室温后,加入乙酸乙酯稀释,有机相依次用水和饱和的食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱液为PE:EA/1:1),得到2-(4-溴-2-甲氧基苯氧基)乙-1-醇(5.8g,无色的油状物,收率:95.4%)。4-bromo-2-methoxyphenol (5 g, 24.63 mmol), 2-bromoethanol (6.15 g, 49.26 mmol) and potassium carbonate (10.19 g, 73.89 mmol) were added to a reaction flask containing DMF (60 mL). The mixture was heated to 110 ° C and stirred for 20 hours. After the reaction mixture was cooled to room temperature, ethyl acetate was evaporated and evaporated. The residue was purified by silica gel column chromatography (EtOAc: EtOAc/EtOAc) Colorless oil, yield: 95.4%).
LC-MS(ESI):m/z 246.0/248.0[M+H
+]。
LC-MS (ESI): m / z 246.0 / 248.0 [M + H +].
步骤2:4-((2-(4-溴-2-甲氧基苯氧基)乙氧基)甲基)-2,2-二甲基-1,3-二氧戊环(cc)的制备Step 2: 4-((2-(4-Bromo-2-methoxyphenoxy)ethoxy)methyl)-2,2-dimethyl-1,3-dioxolane (cc) Preparation
在含有无水四氢呋喃(60mL)的反应瓶中加入2-(4-溴-2-甲氧基苯氧基)乙-1-醇(5.5g,22.3mmol)。将混合物冷却至0℃,加入氢化钠(3.56g,89.2mmol,60%) 并搅拌30分钟,然后再加入对甲基苯磺酸-2,2-二甲基-1,3-二氧戊环基-4-甲酯的四氢呋喃溶液(8.3g,29mmol)。将反应液升温至室温并搅拌3小时,待反应完成后,加水淬灭,用乙酸乙酯(80mLx3)萃取,合并有机相用。有机相用饱和的食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱液为PE:EA/1:1),得到4-((2-(4-溴-2-甲氧基苯氧基)乙氧基)甲基)-2,2-二甲基-1,3-二氧戊环(cc)(4.6g,无色的油状物,收率:57.2%)。2-(4-Bromo-2-methoxyphenoxy)ethan-1-ol (5.5 g, 22.3 mmol) was added to a reaction flask containing anhydrous tetrahydrofuran (60 mL). The mixture was cooled to 0 ° C, sodium hydride (3.56 g, 89.2 mmol, 60%) was added and stirred for 30 minutes, then 2,2-dimethyl-1,3-dioxo-p-toluenesulfonate was added. A solution of the cyclo-4-methyl ester in tetrahydrofuran (8.3 g, 29 mmol). The reaction mixture was warmed to room temperature and stirred for 3 hr. After the reaction was completed, water was evaporated, and ethyl acetate (80 mL×3). The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography (eluent: EtOAc / 1:1) to give 4-((2-(4-bromo-2-methoxyphenoxy)ethoxy) 2,2-Dimethyl-1,3-dioxolane (cc) (4.6 g, colorless oil, yield: 57.2%).
LC-MS(ESI):m/z 361.1/363.0[M/M+H
+]。
LC-MS (ESI): m / z 361.1 / 363.0 [M / M + H +].
制备实施例29:5-(4-(2-((1,4-二恶烷-2-基)甲氧基)乙氧基)-3-甲氧基苯基)-3-(4-氨基-2-氟苯基)吡啶-2-胺(中间体dd)的制备Preparation Example 29: 5-(4-(2-((1,4-dioxan-2-yl)methoxy)ethoxy)-3-methoxyphenyl)-3-(4- Preparation of amino-2-fluorophenyl)pyridin-2-amine (intermediate dd)
采用与制备实施例27相同的方法,除了用4-((2-(4-溴-2-甲氧基苯氧基)乙氧基)甲基)-2,2-二甲基-1,3-二氧戊环(cc)代替4-((4-溴-2-甲氧基苯氧基)甲基)-2,2-二甲基-1,3-二氧戊环(bb1),制得5-(4-(2-((1,4-二恶烷-2-基)甲氧基)乙氧基)-3-甲氧基苯基)-3-(4-氨基-2-氟苯基)吡啶-2-胺(dd)(黄色固体,四步收率:33.8%)。In the same manner as in Preparation Example 27 except that 4-((2-(4-bromo-2-methoxyphenoxy)ethoxy)methyl)-2,2-dimethyl-1, 3-Dioxolane (cc) instead of 4-((4-bromo-2-methoxyphenoxy)methyl)-2,2-dimethyl-1,3-dioxolane (bb1) To give 5-(4-(2-((1,4-dioxan-2-yl)methoxy)ethoxy)-3-methoxyphenyl)-3-(4-amino-) 2-fluorophenyl)pyridin-2-amine (dd) (yellow solid, four-step yield: 33.8%).
LC-MS(ESI):m/z 470.4[M+H
+]。
LC-MS (ESI): m / z 470.4 [M + H +].
制备实施例30:3-(4-氨基-2-氟苯基)-5-(3-甲氧基-4-(2-吗啉乙氧基)苯基)吡啶-2-胺(中间体ee)的制备PREPARATIVE EXAMPLE 30: 3-(4-Amino-2-fluorophenyl)-5-(3-methoxy-4-(2-morpholinoethoxy)phenyl)pyridin-2-amine (Intermediate Preparation of ee)
步骤1:4-(2-(4-溴-2-甲氧基苯氧基)乙基)吗啉(ee1-1)的制备Step 1: Preparation of 4-(2-(4-bromo-2-methoxyphenoxy)ethyl)morpholine (ee1-1)
在含有DMF(20mL)的反应瓶中加入4-溴-2-甲氧基苯酚(6.5g,32.34mmol)、4-(2-氯乙基)吗啉(5.3g,35.57mmol)、碳酸钾(11.2g,80.85mmol)。将混合物升温至80℃并搅拌12小时。待反应液冷却至室温,加入乙酸乙酯稀释,用乙酸乙酯(30mL x2)萃取,合并有机相。有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱液为DCM:MeOH/10:1),得到4-(2-(4-溴-2-甲氧基苯氧基)乙基)吗啉(8.9g,黄色固体,收率:88.2%)。4-bromo-2-methoxyphenol (6.5 g, 32.34 mmol), 4-(2-chloroethyl)morpholine (5.3 g, 35.57 mmol), potassium carbonate were added to a reaction flask containing DMF (20 mL). (11.2 g, 80.85 mmol). The mixture was warmed to 80 ° C and stirred for 12 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate and ethyl acetate (30 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by EtOAcqqq elut elut elut elut elut 8.9 g, yellow solid, yield: 88.2%).
LC-MS(ESI):m/z 316.1/318.2[M+H
+]。
LC-MS (ESI): m / z 316.1 / 318.2 [M + H +].
步骤2:4-(2-(2-甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯氧基)乙基)吗啉(ee1)的制备Step 2: 4-(2-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy) Preparation of ethyl)ethyl)morpholine (ee1)
于室温,在含有1,4-二氧六环(12mL)和水(3mL)的反应瓶中加入4-(2-(4-溴-2-甲氧基苯氧基)乙基)吗啉(1g,3.16mmol)、联硼酸频那醇酯(1.22g,4.75mmol)、乙酸钠(1.29g,9.48mmol)和Pd(dppf)Cl
2.DCM(261mg,0.32mmol)。密封,氮气置换三次,加热至95℃并搅拌12小时。反应液冷却至室温后,加入乙酸乙酯稀释,用乙酸乙酯(30mL x2)萃取,合并有机相。有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,残余物通过硅胶柱层析色谱法纯化(洗脱液为DCM:MeOH/10:1),得到4-(2-(2-甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯氧基)乙基)吗啉(ee1)(700mg,黄色固体,收率:60.99%)。
4-(2-(4-Bromo-2-methoxyphenoxy)ethyl)morpholine was added to a reaction flask containing 1,4-dioxane (12 mL) and water (3 mL) at room temperature (1 g, 3.16 mmol), pinacol borate (1.22 g, 4.75 mmol), sodium acetate (1.29 g, 9.48 mmol) and Pd(dppf)Cl 2 .DCM (261 mg, 0.32 mmol). Sealed, replaced with nitrogen three times, heated to 95 ° C and stirred for 12 hours. After the reaction mixture was cooled to room temperature, diluted with ethyl acetate and ethyl acetate (30 mL, The organic phase was washed with brine, dried over anhydrous sodium sulfate -(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)morpholine (ee1) (700 mg, yellow solid, yield: 60.99%).
LC-MS(ESI):m/z363.4[M+H
+]
LC-MS (ESI): m/z 363.4 [M+H + ]
其余步骤采用与制备实施例20相同的方法,除了4-(2-(2-甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯氧基)乙基)吗啉(ee1)用代替4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯,制得3-(4-氨基-2-氟苯基)-5-(3-甲氧基-4-(2-吗啉乙氧基)苯基)吡啶-2-胺(中间体L1)(黄色固体,两步收率:58.9%)。The remaining steps were carried out in the same manner as in Preparation Example 20 except that 4-(2-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) Instead of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclo), cyclopentan-2-yl)phenoxy)ethyl)morpholine (ee1) tert-Butyl pentrol-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate to give 3-(4-amino-2-fluorophenyl)-5-(3-methyl Oxy-4-(2-morpholinoethoxy)phenyl)pyridin-2-amine (Intermediate L1) (yellow solid, two-step yield: 58.9%).
LC-MS(ESI):m/z 438.4[M+H
+]。
LC-MS (ESI): m / z 438.4 [M + H +].
制备实施例31:4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯胺(中间体ff)的制备PREPARATIVE EXAMPLE 31 Preparation of 4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluoroaniline (Intermediate ff)
步骤1:4-(2-氟-4-硝基苯氧基)-6,7-二甲氧基喹啉(ff1)的制备Step 1: Preparation of 4-(2-fluoro-4-nitrophenoxy)-6,7-dimethoxyquinoline (ff1)
于室温,在含有二苯醚(38mL)的反应瓶中加入4-氯-6,7-二甲氧基喹啉(2.0g,8.94mmol)和2-氟-4-硝基苯酚(2.81g,17.88mmol)。将混合物升温至140℃并搅拌10小时,待反应液冷却至室温后,有米白色固体析出。将反应液过滤,滤饼用乙醚洗涤,收集固体得到4-(2-氟-4-硝基苯氧基)-6,7-二甲氧基喹啉(ff1)(3.0g,米白色固体,收率:97.55%)。4-Chloro-6,7-dimethoxyquinoline (2.0 g, 8.94 mmol) and 2-fluoro-4-nitrophenol (2.81 g) were added to a reaction flask containing diphenyl ether (38 mL) at room temperature. , 17.88 mmol). The mixture was heated to 140 ° C and stirred for 10 hours. After the reaction mixture was cooled to room temperature, a white solid was precipitated. The reaction solution was filtered, and the filter cake was washed with diethyl ether. The solid was collected to give 4-(2-fluoro-4-nitrophenoxy)-6,7-dimethoxyquinoline (ff1) (3.0 g, white solid , yield: 97.55%).
LC-MS(ESI):m/z 345.2[M+H
+]。
LC-MS (ESI): m / z 345.2 [M + H +].
步骤2:4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯胺(ff)的制备Step 2: Preparation of 4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluoroaniline (ff)
于室温,在含有乙醇(30mL)和水(10mL)的反应瓶中加入4-(2-氟-4-硝基苯氧 基)-6,7-二甲氧基喹啉(3.0g,8.72mmol)、铁粉(2.44g,43.6mmol)和氯化铵(4.67g,87.2mmol)。将混合物升温至80℃并搅拌1小时,待反应液冷却至室温后,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱液为DCM:MeOH/5:1),得到4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯胺(ff)(2.6g,灰色固体,收率:95.0%)。4-(2-Fluoro-4-nitrophenoxy)-6,7-dimethoxyquinoline (3.0 g, 8.72) was added to a reaction flask containing ethanol (30 mL) and water (10 mL) at room temperature. Methyl), iron powder (2.44 g, 43.6 mmol) and ammonium chloride (4.67 g, 87.2 mmol). The mixture was warmed to 80 ° C and stirred for 1 hour. After the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was purified by EtOAc EtOAc EtOAc elut elut elut elut Fluoroaniline (ff) (2.6 g, gray solid, yield: 95.0%).
LC-MS(ESI):m/z315.2[M+H
+]。
LC-MS (ESI): m / z315.2 [M + H +].
制备实施例32:6-((6,7-二甲氧基喹啉-4-基)氧基)哒嗪-3-胺(中间体gg)的制备Preparation Example 32: Preparation of 6-((6,7-dimethoxyquinolin-4-yl)oxy)pyridazin-3-amine (Intermediate gg)
步骤1:4-((6-氯哒嗪-3-基)氧基)-6,7-二甲氧基喹啉(gg1)的制备Step 1: Preparation of 4-((6-chloropyridazin-3-yl)oxy)-6,7-dimethoxyquinoline (gg1)
于室温,在含有DMF(100mL)的反应瓶中加入6,7-二甲氧基喹啉-4-醇(500mg,2.44mmol)、3,6-二氯哒嗪(436mg,2.92mmol)和碳酸钾(1.0g,3.0mmol)。将混合物升温至140℃并搅拌2小时。待反应液冷却至室温后,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱液为PE:EA/1:3),得到4-((6-氯哒嗪-3-基)氧基)-6,7-二甲氧基喹啉(gg1)(137mg,白色固体,收率:17.6%)。Add 6,7-dimethoxyquinolin-4-ol (500 mg, 2.44 mmol), 3,6-dichloropyridazine (436 mg, 2.92 mmol) and a reaction flask containing DMF (100 mL) at room temperature. Potassium carbonate (1.0 g, 3.0 mmol). The mixture was warmed to 140 ° C and stirred for 2 hours. After the reaction liquid was cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: EtOAc/EtOAc: EtOAc) Base quinoline (gg1) (137 mg, white solid, yield: 17.6%).
LC-MS(ESI):m/z 318.0/320.1[M+H
+]。
LC-MS (ESI): m / z 318.0 / 320.1 [M + H +].
步骤2:N-(2,4-二甲氧基苄基)-6-((6,7-二甲基喹啉-4-基)氧基)哒嗪-3-胺(gg2)的制备Step 2: Preparation of N-(2,4-dimethoxybenzyl)-6-((6,7-dimethylquinolin-4-yl)oxy)pyridazin-3-amine (gg2)
于室温,在含有甲苯(15mL)的微波管中加入4-((6-氯哒嗪-3-基)氧基)-6,7-二甲氧基喹啉(1.0g,3.14mmol)、(2,4-二甲氧基苯基)甲胺(10.5g,62.9mmol)、碳酸铯(3.1g,9.43mmol)、Pd
2(dba)
3(576mg,0.63)和xantphose(728mg,1.26mmol)。密封,氮气置换三次,置于微波反应器中升温至130℃并搅拌1小时。待反应液冷却至室温后,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱液为DCM:MeOH/10:1),得到N-(2,4-二甲氧基苄基)-6-((6,7-二甲基喹啉-4-基)氧基)哒嗪-3-胺(700mg,白色固体,收率:49.8%)。
4-((6-chloropyridazin-3-yl)oxy)-6,7-dimethoxyquinoline (1.0 g, 3.14 mmol) was added to a microwave tube containing toluene (15 mL) at room temperature. (2,4-Dimethoxyphenyl)methylamine (10.5 g, 62.9 mmol), cesium carbonate (3.1 g, 9.43 mmol), Pd 2 (dba) 3 (576 mg, 0.63) and xantphose (728 mg, 1.26 mmol) ). It was sealed, replaced with nitrogen three times, placed in a microwave reactor and warmed to 130 ° C and stirred for 1 hour. After the reaction liquid was cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut elut Benzyl quinolin-4-yl)oxy)pyridazin-3-amine (700 mg, white solid, yield: 49.8%).
LC-MS(ESI):m/z 449.2[M+H
+]。
LC-MS (ESI): m / z 449.2 [M + H +].
步骤3:6-((6,7-二甲氧基喹啉-4-基)氧基)哒嗪-3-胺(gg)的制备Step 3: Preparation of 6-((6,7-dimethoxyquinolin-4-yl)oxy)pyridazin-3-amine (gg)
在含有三氟乙酸(10mL)的反应瓶中加入N-(2,4-二甲氧基苄基)-6-((6,7-二甲基喹啉-4-基)氧基)哒嗪-3-胺(700mg,1.56mmol)。将混合物于室温搅拌7小时。待反应完全后,将反应液减压浓缩。残余物用二氯甲烷稀释,有机相依次用饱和碳酸氢钠水溶液和饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱液为DCM:MeOH/4:1),得到6-((6,7-二甲氧基喹啉-4-基)氧基)哒嗪-3-胺(gg)(400mg,白色固体,收率:86.0%)。Add N-(2,4-dimethoxybenzyl)-6-((6,7-dimethylquinolin-4-yl)oxy)anthracene to a reaction flask containing trifluoroacetic acid (10 mL) Pyrazin-3-amine (700 mg, 1.56 mmol). The mixture was stirred at room temperature for 7 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was diluted with methylene chloride. The residue was purified by EtOAc EtOAc EtOAcEtOAc 3-amine (gg) (400 mg, white solid, yield: 86.0%).
LC-MS(ESI):m/z 299.2[M+H
+]。
LC-MS (ESI): m / z 299.2 [M + H +].
制备实施例33:4-(4-氨基-2-氟苯氧基)-7-甲氧基喹啉-6-甲酰胺(中间体hh)的制备Preparation example 33: Preparation of 4-(4-amino-2-fluorophenoxy)-7-methoxyquinolin-6-carboxamide (intermediate hh)
步骤1:4-((((2,2-二甲基-4,6-二氧代-1,3-二恶烷-5-亚基)甲基)氨基)-2-甲氧基苯甲酸甲酯(hh1)的制备Step 1: 4-(((2,2-Dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl)amino)-2-methoxybenzene Preparation of methyl formate (hh1)
于室温,在含有异丙醇(100mL)的反应瓶中加入4-氨基-2-甲氧基苯甲酸甲酯(5g,27.6mmol)。将混合物升温至50℃并搅拌10分钟,再加入5-(甲氧基亚甲基)-2,2-二甲基-1,3-二恶烷-4,6-二酮(上海毕得,5.13g,27.6mmol)。将混合物继续升温至 80℃并搅拌1小时。待反应液冷却至室温,过滤,收集固体,得到4-((((2,2-二甲基-4,6-二氧代-1,3-二恶烷-5-亚基)甲基)氨基)-2-甲氧基苯甲酸甲酯(8g,棕色固体,收率:86.5%)。Methyl 4-amino-2-methoxybenzoate (5 g, 27.6 mmol) was added to a reaction flask containing isopropyl alcohol (100 mL) at room temperature. The mixture was warmed to 50 ° C and stirred for 10 minutes, then added 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (Shanghai Bi De , 5.13 g, 27.6 mmol). The mixture was further heated to 80 ° C and stirred for 1 hour. The reaction solution was cooled to room temperature, filtered, and the solid was collected to give 4-((((2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-yl))methyl Methyl amino)-2-methoxybenzoate (8 g, brown solid, yield: 86.5%).
LC-MS(ESI):m/z 336.3[M+H
+]。
LC-MS (ESI): m / z 336.3 [M + H +].
步骤2:4-羟基-7-甲氧基喹啉-6-羧酸甲酯(hh2)的制备Step 2: Preparation of methyl 4-hydroxy-7-methoxyquinoline-6-carboxylate (hh2)
于室温,在含有二苯醚(100mL)的反应瓶中加入4-((((2,2-二甲基-4,6-二氧代-1,3-二恶烷-5-亚基)甲基)氨基)-2-甲氧基苯甲酸甲酯(8g,23.9mmol)。将混合物升温至200℃并搅拌8小时,待反应液冷却至室温,过滤,收集固体,得到4-羟基-7-甲氧基喹啉-6-羧酸甲酯(5.2g,棕色固体,收率:93.4%)。Add 4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-)ylene to the reaction flask containing diphenyl ether (100 mL) at room temperature Methyl)amino)-2-methoxybenzoic acid methyl ester (8 g, 23.9 mmol). The mixture was warmed to 200 ° C and stirred for 8 hours. The reaction mixture was cooled to room temperature, filtered, and solid was collected to give 4-hydroxyl. Methyl-7-methoxyquinoline-6-carboxylate (5.2 g, brown solid, yield: 93.4%).
LC-MS(ESI):m/z 234.1[M+H
+]。
LC-MS (ESI): m / z 234.1 [M + H +].
步骤3:4-氯-7-甲氧基喹啉-6-羧酸甲酯(hh3)的制备Step 3: Preparation of methyl 4-chloro-7-methoxyquinoline-6-carboxylate (hh3)
于室温,在含有二氯亚砜(20mL)的反应瓶中加入4-羟基-7-甲氧基喹啉-6-羧酸甲酯(1g,4.29mmol)和DMF(0.1mL)。将混合物加热至回流并搅拌3小时,待反应液冷却至室温后,减压浓缩。残余物于二氯甲烷(30mL)稀释,有机相依次用饱和碳酸氢钠水溶液和饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。得到粗产品4-氯-7-甲氧基喹啉-6-羧酸甲酯(1.0g,棕色固体,收率:92.8%)。Methyl 4-hydroxy-7-methoxyquinoline-6-carboxylate (1 g, 4.29 mmol) and DMF (0.1 mL) were added to a reaction flask containing thionyl chloride (20 mL). The mixture was heated to reflux and stirred for 3 hours. After the reaction mixture was cooled to room temperature, concentrated. The residue was diluted with methylene chloride (30 mL). The crude product 4-chloro-7-methoxyquinoline-6-carboxylic acid methyl ester (1.0 g, brown solid, yield: 92.8%) was obtained.
LC-MS(ESI):m/z 237.1/239.1[M+H
+]。
LC-MS (ESI): m / z 237.1 / 239.1 [M + H +].
步骤4:4-氯-7-甲氧基喹啉-6-甲酰胺(hh4)的制备Step 4: Preparation of 4-chloro-7-methoxyquinolin-6-carboxamide (hh4)
于室温,在含有THF(10mL)的反应瓶中加入4-氯-7-甲氧基喹啉-6-羧酸甲酯(1g,3.98mmol)和氨水(33.0%,5mL)。密封,将混合物加热至80℃并搅拌过夜,待反应液冷却至室温后,过滤,收集固体,得到4-氯-7-甲氧基喹啉-6-甲酰胺(600mg,棕色固体,收率:63.9%)。Methyl 4-chloro-7-methoxyquinoline-6-carboxylate (1 g, 3.98 mmol) and aqueous ammonia (33.0%, 5 mL) were added to a reaction flask containing THF (10 mL). The mixture was heated to 80 ° C and stirred overnight. After the reaction mixture was cooled to room temperature, filtered, and the solid was collected to give 4-chloro-7-methoxyquinoline-6-carboxamide (600 mg, brown solid, yield : 63.9%).
LC-MS(ESI):m/z 236.2/238.2[M+H
+]。
LC-MS (ESI): m / z 236.2 / 238.2 [M + H +].
步骤5:4-(2-氟-4-硝基苯氧基)-7-甲氧基喹啉-6-甲酰胺(hh5)的制备Step 5: Preparation of 4-(2-fluoro-4-nitrophenoxy)-7-methoxyquinolin-6-carboxamide (hh5)
于室温,在含有二苯醚(10mL)的反应瓶中加入4-氯-7-甲氧基喹啉-6-甲酰胺(600mg,2.39mmol)和2-氟-4-硝基苯酚(750mg,4.78mmol)。将混合物升温至140℃并搅拌10小时,待反应液冷却至室温后,有米白色固体析出。将反应液过滤,收集固体,得到4-(2-氟-4-硝基苯氧基)-7-甲氧基喹啉-6-甲酰胺(800mg,米白色固体,收率:93.7%)。4-Chloro-7-methoxyquinoline-6-carboxamide (600 mg, 2.39 mmol) and 2-fluoro-4-nitrophenol (750 mg) were added to a reaction flask containing diphenyl ether (10 mL) at room temperature. , 4.78 mmol). The mixture was heated to 140 ° C and stirred for 10 hours. After the reaction mixture was cooled to room temperature, a white solid was precipitated. The reaction mixture was filtered, and the solid was evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj .
LC-MS(ESI):m/z 358.2[M+H
+]。
LC-MS (ESI): m / z 358.2 [M + H +].
步骤6:4-(4-氨基-2-氟苯氧基)-7-甲氧基喹啉-6-甲酰胺(hh)的制备Step 6: Preparation of 4-(4-amino-2-fluorophenoxy)-7-methoxyquinolin-6-carboxamide (hh)
于室温,在含有乙醇(15mL)和水(5mL)的反应瓶中加入4-(2-氟-4-硝基苯氧基)-7-甲氧基喹啉-6-甲酰胺(800mg,2.24mmol)、铁粉(627mg,11.2mmol)和氯化铵(1.3g,22.7mmol)。将混合物升温至80℃并搅拌1小时,待反应液冷却至室温后,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱液为DCM:MeOH/5:1),得到4-(4-氨基-2-氟苯氧基)-7-甲氧基喹啉-6-甲酰胺(600mg, 灰色固体,收率:81.7%)。Add 4-(2-fluoro-4-nitrophenoxy)-7-methoxyquinoline-6-carboxamide (800 mg, in a reaction flask containing ethanol (15 mL) and water (5 mL) at room temperature. 2.24 mmol), iron powder (627 mg, 11.2 mmol) and ammonium chloride (1.3 g, 22.7 mmol). The mixture was warmed to 80 ° C and stirred for 1 hour. After the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was purified by EtOAc EtOAc EtOAc EtOAc elut elut Formamide (600 mg, gray solid, yield: 81.7%).
LC-MS(ESI):m/z 328.3[M+H
+]。
LC-MS (ESI): m / z 328.3 [M + H +].
制备实施例34:4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯胺(中间体ii)的制备Preparation Example 34: Preparation of 4-((1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)phenylamine (Intermediate ii)
步骤1:4-(4-硝基苯氧基)-1H-吡咯并[2,3-b]吡啶(ii1)的制备Step 1: Preparation of 4-(4-nitrophenoxy)-1H-pyrrolo[2,3-b]pyridine (ii1)
在含有NMP(10mL)的反应瓶中加入4-氯-7-氮杂吲哚(500mg,3.28mmol)、4-硝基苯酚(638mg,4.58mmol)和DIPEA(1.27g,9.83mmol)。将混合物加热至200℃并搅拌3小时,待反应液冷却至室温后,加入乙酸乙酯稀释,有机相用饱和的食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱液为DCM:MeOH/10:1),得到4-(4-硝基苯氧基)-1H-吡咯并[2,3-b]吡啶(300mg,黄色固体,收率:35.8%)。4-Chloro-7-azaindole (500 mg, 3.28 mmol), 4-nitrophenol (638 mg, 4.58 mmol) and DIPEA (1.27 g, 9.83 mmol) were added to a reaction flask containing NMP (10 mL). The mixture was heated to 200 ° C and stirred for 3 hours. After the reaction mixture was cooled to room temperature, ethyl acetate was evaporated and evaporated. The residue was purified by EtOAcqqq elut elut elut elut elut elut 300 mg, yellow solid, yield: 35.8%).
LC-MS(ESI):m/z 256.2[M+H
+]。
LC-MS (ESI): m / z 256.2 [M + H +].
步骤2:4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯胺(ii)的制备Step 2: Preparation of 4-((1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)phenylamine (ii)
在含有甲醇(4mL)和四氢呋喃(4mL)的反应瓶中加入4-(4-硝基苯氧基)-1H-吡咯并[2,3-b]吡啶(300mg,1.17mmol)、锌粉(230mg,3.52mmol)和氯化铵(625mg,11.7mmol)。将混合物于室温搅拌过夜,反应完全后,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱液为DCM:MeOH/10:1)得到4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯胺(80mg,黄色固体,收率:30.4%)。Add 4-(4-nitrophenoxy)-1H-pyrrolo[2,3-b]pyridine (300 mg, 1.17 mmol), zinc powder to a reaction flask containing methanol (4 mL) and tetrahydrofuran (4 mL). 230 mg, 3.52 mmol) and ammonium chloride (625 mg, 11.7 mmol). The mixture was stirred at room temperature overnight. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut elut 80 mg, yellow solid, yield: 30.4%).
LC-MS(ESI):m/z 226.1[M+H
+]。
LC-MS (ESI): m / z 226.1 [M + H +].
制备实施例35:4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)-3-氟苯胺(中间体jj)的制备PREPARATIVE EXAMPLE 35 Preparation of 4-((1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)-3-fluoroaniline (Intermediate jj)
采用与制备实施例36相同的方法,除了用2-氟4-硝基苯酚代替4-硝基苯酚,制得4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)-3-氟苯胺(黄色固体,两步收率:23.5%)。4-((1H-pyrrolo[2,3-b]pyridin-4-yl) was obtained in the same manner as in Preparation Example 36 except that 2-fluoro 4-nitrophenol was used instead of 4-nitrophenol. Oxy)-3-fluoroaniline (yellow solid, two-step yield: 23.5%).
LC-MS(ESI):m/z 244.2[M+H
+]。
LC-MS (ESI): m / z 244.2 [M + H +].
制备实施例36:4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯胺(中间体kk)的制备PREPARATIVE EXAMPLE 36 Preparation of 4-((6,7-Dimethoxyquinazolin-4-yl)oxy)-3-fluoroaniline (Intermediate kk)
采用与制备实施例31相同的方法,除了用4-氯-6,7-二甲氧基喹唑啉代替4-氯-6,7-二甲氧基喹啉,制得4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯胺(黄色固体,两步收率:88.6%)。4- (6) was obtained in the same manner as in Preparation Example 31 except that 4-chloro-6,7-dimethoxyquinazoline was used instead of 4-chloro-6,7-dimethoxyquinoline. , 7-Dimethoxyquinazolin-4-yl)oxy)-3-fluoroaniline (yellow solid, two-step yield: 88.6%).
LC-MS(ESI):m/z 306.3[M+H
+]。
LC-MS (ESI): m / z 306.3 [M + H +].
制备实施例37:4-((6,7-二甲氧基喹唑啉-4-基)氧基)苯胺(中间体ll)的制备PREPARATIVE EXAMPLE 37 Preparation of 4-((6,7-Dimethoxyquinazolin-4-yl)oxy)phenylamine (Intermediate 11)
采用与制备实施例36相同的方法,除了用4-硝基苯酚代替2-氟4-硝基苯酚,制得4-((6,7-二甲氧基喹唑啉-4-基)氧基)苯胺(黄色固体,两步收率:85.7%)。In the same manner as in Preparation Example 36, except that 4-nitrophenol was used instead of 2-fluoro-4-nitrophenol, 4-((6,7-dimethoxyquinazolin-4-yl)oxy was obtained. Aniline (yellow solid, two-step yield: 85.7%).
LC-MS(ESI):m/z 298.3[M+H
+]。
LC-MS (ESI): m / z 298.3 [M + H +].
制备实施例38:4-(4-氨基-2-氟苯氧基)吡啶-2-胺(中间体mm)的制备Preparation Example 38: Preparation of 4-(4-amino-2-fluorophenoxy)pyridin-2-amine (Intermediate mm)
采用与制备实施例31相同的方法,除了用4-氯吡啶-2-胺代替4-氯-6,7-二甲氧基喹啉,制得4-(4-氨基-2-氟苯氧基)吡啶-2-胺(黄色固体,两步收率:43.5%)。In the same manner as in Preparation Example 31, except that 4-chloropyridin-2-amine was used instead of 4-chloro-6,7-dimethoxyquinoline, 4-(4-amino-2-fluorophenoxyl) was obtained. Pyridin-2-amine (yellow solid, two-step yield: 43.5%).
LC-MS(ESI):m/z 220.2[M+H
+]。
LC-MS (ESI): m / z 220.2 [M + H +].
制备实施例39:4-(4-氨基-2-苯氧基)吡啶-2-胺(中间体nn)的制备PREPARATIVE EXAMPLE 39 Preparation of 4-(4-Amino-2-phenoxy)pyridin-2-amine (Intermediate nn)
采用与制备实施例38相同的方法,除了用4-硝基苯酚代替2-氟-4-硝基苯酚,制得4-(4-氨基-2-苯氧基)吡啶-2-胺(黄色固体,两步收率:39.5%)。In the same manner as in Preparation Example 38 except that 4-nitrophenol was used instead of 2-fluoro-4-nitrophenol, 4-(4-amino-2-phenoxy)pyridin-2-amine (yellow) was obtained. Solid, two-step yield: 39.5%).
LC-MS(ESI):m/z 202.1[M+H
+]。
LC-MS (ESI): m / z 202.1 [M + H +].
制备实施例40:3-氟-4-((6-甲氧基-7-(2-甲氧基乙氧基)喹唑啉-4-基)氧基)苯胺(中间体oo)的制备PREPARATIVE EXAMPLE 40: Preparation of 3-fluoro-4-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)oxy)phenylamine (Intermediate oo)
步骤1:7-(苄氧基)-4-(2-氟-4-硝基苯氧基)-6-甲氧基喹唑啉(oo1)的制备Step 1: Preparation of 7-(benzyloxy)-4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinazoline (oo1)
在含有NMP(35mL)的反应瓶中加入7-(苄氧基)-4-氯-6-甲氧基喹唑啉(2g,6.65mmol)、2-氟-4-硝基苯酚(1.57mg,9.98mmol)和DIPEA(2.6g,20.0mmol)。将混合物加热至180℃并搅拌4小时,待反应液冷却至室温后,加入乙酸乙酯稀释,有机相用饱和的食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱液为DCM:MeOH/20:1),得到7-(苄氧基)-4-(2-氟-4-硝基苯氧基)-6-甲氧基喹唑啉(2.1g,黄色固体,收率:76.5%)。Add 7-(benzyloxy)-4-chloro-6-methoxyquinazoline (2 g, 6.65 mmol), 2-fluoro-4-nitrophenol (1.57 mg) to a reaction flask containing NMP (35 mL). , 9.98 mmol) and DIPEA (2.6 g, 20.0 mmol). The mixture was heated to 180 ° C and stirred for 4 hours. After the reaction mixture was cooled to room temperature, ethyl acetate was evaporated and evaporated. The residue was purified by EtOAc EtOAc EtOAc elut elut elut elut elut -Methoxyquinazoline (2.1 g, yellow solid, yield: 76.5%).
LC-MS(ESI):m/z 422.2[M+H
+]。
LC-MS (ESI): m / z 422.2 [M + H +].
步骤2:4-(2-氟-4-硝基苯基)-6-甲基喹唑啉-7-醇(oo2)的制备Step 2: Preparation of 4-(2-fluoro-4-nitrophenyl)-6-methylquinazolin-7-ol (oo2)
在含有三氟乙酸(25mL)的反应瓶中加入7-(苄氧基)-4-(2-氟-4-硝基苯氧基)-6-甲氧基喹唑啉(2.1g,4.99mmol)。将混合物于室温搅拌过夜,待反应完全后,将反应液减压浓缩。残余物用二氯甲烷稀释,有机相依次用饱和碳酸氢钠水溶液和饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱液为DCM:MeOH/5:1),得到4-(2-氟-4-硝基苯基)-6-甲基喹唑啉-7-醇(1.4g,白色固体,收率:91.6%)。Add 7-(benzyloxy)-4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinazoline (2.1 g, 4.99) to a reaction flask containing trifluoroacetic acid (25 mL). Mm). The mixture was stirred at room temperature overnight, and after the reaction was completed, the mixture was concentrated. The residue was diluted with methylene chloride. The residue was purified by EtOAc EtOAc EtOAc elut elut elut elut Alcohol (1.4 g, white solid, yield: 91.6%).
LC-MS(ESI):m/z 332.2[M+H
+]。
LC-MS (ESI): m / z 332.2 [M + H +].
步骤3:4-(2-氟-4-硝基苯氧基)-6-甲氧基-7-(2-甲氧基乙氧基)喹唑啉(oo3)的制备Step 3: Preparation of 4-(2-fluoro-4-nitrophenoxy)-6-methoxy-7-(2-methoxyethoxy)quinazoline (oo3)
在含有DMF(8mL)的反应瓶中加入4-(2-氟-4-硝基苯基)-6-甲基喹唑啉-7-醇 (350mg,1.13mmol)、1-溴-2-甲氧基乙烷(235mg,1.69mmol)、碳酸钾(400mg,2.81mmol)。将混合物升温至80℃并搅拌12小时,待反应液冷却至室温,加入乙酸乙酯稀释,用乙酸乙酯(15mL x3)萃取,合并有机相。有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱液为DCM:MeOH/10:1),得到4-(2-氟-4-硝基苯氧基)-6-甲氧基-7-(2-甲氧基乙氧基)喹唑啉(340mg,黄色固体,收率:77.3%)。Add 4-(2-fluoro-4-nitrophenyl)-6-methylquinazolin-7-ol (350 mg, 1.13 mmol), 1-bromo-2- in a reaction flask containing DMF (8 mL) Methoxyethane (235 mg, 1.69 mmol), potassium carbonate (400 mg, 2.81 mmol). The mixture was warmed to 80 ° C and stirred for 12 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and extracted with ethyl acetate (15 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by EtOAc EtOAc EtOAc EtOAc(EtOAc 2-methoxyethoxy)quinazoline (340 mg, yellow solid, yield: 77.3%).
LC-MS(ESI):m/z 390.3[M+H
+]。
LC-MS (ESI): m / z 390.3 [M + H +].
步骤4:3-氟-4-((6-甲氧基-7-(2-甲氧基乙氧基)喹唑啉-4-基)氧基)苯胺(oo)的制备Step 4: Preparation of 3-fluoro-4-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)oxy)phenylamine (oo)
于室温,在含有乙醇(30mL)和水(10mL)的反应瓶中加入4-(2-氟-4-硝基苯氧基)-6-甲氧基-7-(2-甲氧基乙氧基)喹唑啉(340mg,0.87mmol)、铁粉(243mg,4.35mmol)和氯化铵(460mg,8.7mmol)。将混合物升温至80℃并搅拌1小时,待反应液冷却至室温后,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱液为DCM:MeOH/5:1),得到3-氟-4-((6-甲氧基-7-(2-甲氧基乙氧基)喹唑啉-4-基)氧基)苯胺(280mg,灰色固体,收率:89.7%)。4-(2-Fluoro-4-nitrophenoxy)-6-methoxy-7-(2-methoxyB) was added to a reaction flask containing ethanol (30 mL) and water (10 mL) at room temperature Oxy) quinazoline (340 mg, 0.87 mmol), iron powder (243 mg, 4.35 mmol) and ammonium chloride (460 mg, 8.7 mmol). The mixture was warmed to 80 ° C and stirred for 1 hour. After the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was purified by EtOAc EtOAc EtOAc elut elut elut elut Quinazolin-4-yl)oxy)aniline (280 mg, gray solid, yield: 89.7%).
LC-MS(ESI):m/z 360.2[M+H
+]。
LC-MS (ESI): m / z 360.2 [M + H +].
制备实施例41:4-((6-甲氧基-7-(2-甲氧基乙氧基)喹唑啉-4-基)氧基)苯胺(中间体pp)PREPARATIVE EXAMPLE 41: 4-((6-Methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)oxy)phenylamine (Intermediate pp)
采用与制备实施例40相同的方法,除了用4-硝基苯酚代替2-氟-4-硝基苯酚,制得4-((6-甲氧基-7-(2-甲氧基乙氧基)喹唑啉-4-基)氧基)苯胺(黄色固体,四步收率:27.8%)。In the same manner as in Preparation Example 40, except that 4-nitrophenol was used instead of 2-fluoro-4-nitrophenol, 4-((6-methoxy-7-(2-methoxyethoxy) was obtained. Base quinazolin-4-yl)oxy)aniline (yellow solid, four-step yield: 27.8%).
LC-MS(ESI):m/z 342.3[M+H
+]。
LC-MS (ESI): m / z 342.3 [M + H +].
制备实施例42:4-(2-((4-(4-氨基-2-氟苯氧基)-6-甲氧基喹唑啉-7-基)氧基)乙基)哌嗪-1-甲酸叔丁酯(中间体qq)的制备PREPARATIVE EXAMPLE 42: 4-(2-((4-(4-Amino-2-fluorophenoxy)-6-methoxyquinazolin-7-yl)oxy)ethyl)piperazine-1 -Preparation of tert-butyl formate (intermediate qq)
采用与制备实施例40相同的方法,除了用4-(2-氯乙基)哌嗪-1-羧酸叔丁酯代 替1-溴-2-甲氧基乙烷,制得4-(2-((4-(4-氨基-2-氟苯氧基)-6-甲氧基喹唑啉-7-基)氧基)乙基)哌嗪-1-甲酸叔丁酯(黄色固体,两步收率:63.7%)。4-(2) was obtained in the same manner as in Preparation Example 40 except that 1-(2-chloroethyl)piperazine-1-carboxylic acid tert-butyl ester was used instead of 1-bromo-2-methoxyethane. -((4-(4-Amino-2-fluorophenoxy)-6-methoxyquinazolin-7-yl)oxy)ethyl)piperazine-1-carboxylic acid tert-butyl ester (yellow solid, Two-step yield: 63.7%).
LC-MS(ESI):m/z 514.4[M+H
+]。
LC-MS (ESI): m / z 514.4 [M + H +].
制备实施例43:4-(2-((4-(4-氨基苯氧基)-6-甲氧基喹唑啉-7-基)氧基)乙基)哌嗪-1-甲酸叔丁酯(中间体rr)的制备PREPARATIVE EXAMPLE 43: 4-(2-((4-(4-Aminophenoxy)-6-methoxyquinazolin-7-yl)oxy)ethyl)piperazine-1-carboxylic acid tert-butyl Preparation of ester (intermediate rr)
采用与制备实施例42相同的方法,除了用4-硝基苯酚代替2-氟-4-硝基苯酚,制得4-(2-((4-(4-氨基苯氧基)-6-甲氧基喹唑啉-7-基)氧基)乙基)哌嗪-1-甲酸叔丁酯(黄色固体,四步收率:23.4%)。In the same manner as in Preparation Example 42, except that 4-nitrophenol was used in place of 2-fluoro-4-nitrophenol, 4-(2-(4-(4-aminophenoxy)-6-) was obtained. Tert-Butyl methoxyquinazolin-7-yl)oxy)ethyl)piperazine-1-carboxylate (yellow solid, four-step yield: 23.4%).
LC-MS(ESI):m/z 496.4[M+H
+]。
LC-MS (ESI): m / z 496.4 [M + H +].
制备实施例44:4-((6-甲氧基-7-(2-吗啉乙氧基)喹唑啉-4-基)氧基)苯胺(中间体ss)的制备PREPARATIVE EXAMPLE 44: Preparation of 4-((6-Methoxy-7-(2-morpholinoethoxy)quinazolin-4-yl)oxy)phenylamine (Intermediate ss)
采用与制备实施例43相同的方法,除了用4-(2-氯乙基)吗啉代替4-(2-氯乙基)哌嗪-1-羧酸叔丁酯,制得4-((6-甲氧基-7-(2-吗啉代乙氧基)喹唑啉-4-基)氧基)苯胺(黄色固体,两步收率:70.2%)。In the same manner as in Preparation Example 43, except that 4-(2-chloroethyl)morpholine was used instead of 4-(2-chloroethyl)piperazine-1-carboxylic acid tert-butyl ester to give 4-(( 6-Methoxy-7-(2-morpholinoethoxy)quinazolin-4-yl)oxy)phenylamine (yellow solid, two-step yield: 70.2%).
LC-MS(ESI):m/z 394.3[M+H
+]。
LC-MS (ESI): m / z 394.3 [M + H +].
制备实施例45:3-氟-4-((6-甲氧基-7-(2-吗啉乙氧基)喹唑啉-4-基)氧基)苯胺(tt)的制备Preparation Example 45: Preparation of 3-fluoro-4-((6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-yl)oxy)aniline (tt)
采用与制备实施例42相同的方法,除了用4-(2-氯乙基)吗啉代替4-(2-氯乙基)哌嗪-1-羧酸叔丁酯,制得3-氟-4-((6-甲氧基-7-(2-吗啉乙氧基)喹唑啉-4-基)氧基)苯胺(黄色固体,两步收率:63.2%)。In the same manner as in Preparation Example 42, except that 4-(2-chloroethyl)morpholine was used instead of 4-(2-chloroethyl)piperazine-1-carboxylic acid tert-butyl ester to give 3-fluoro- 4-((6-Methoxy-7-(2-morpholinoethoxy)quinazolin-4-yl)oxy)phenylamine (yellow solid, two-step yield: 63.2%).
LC-MS(ESI):m/z 415.3[M+H
+]。
LC-MS (ESI): m / z 415.3 [M + H +].
实施例1:N
5-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-3-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-2,5-二甲酰胺(1)的制备
Example 1: N 5 -(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl Preparation of 3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (1)
步骤1:5-((4-(2-氨基-5-(1-(1-(叔丁氧基羰基)哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)氨基甲酰基)-3-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-2-羧酸乙酯(1a)的制备Step 1: 5-((4-(2-Amino-5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyridine-3- Ethyl 3-fluorophenyl)carbamoyl)-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylate (1a Preparation
在含有DMF(10mL)的反应瓶中加入6-(乙氧基羰基)-5-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-3-羧酸(a)(150mg,0.47mmol)、4-(4-(6-氨基-5-(4-氨基-2-氟苯基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(u)(235mg,0.52mmol)、HATU(268mg,0.705mmol)和DIPEA(182mg,1.41mmol)。将混合物于室温搅拌30分钟,待反应完全后,加入饱和的碳酸氢钠溶液淬灭,用乙酸乙酯萃取(30mLx3),合并有机相。将有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,残余物通过硅胶柱层析色谱法纯化(洗脱剂为MeOH:DCM=1:20),得到5-((4-(2-氨基-5-(1-(1-(叔丁氧基羰基)哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)氨基甲酰基)-3-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-2-羧酸乙酯(1a)(230mg,黄色固体, 收率:65.0%)。Add 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3- to a reaction flask containing DMF (10 mL) Carboxylic acid (a) (150 mg, 0.47 mmol), 4-(4-(6-amino-5-(4-amino-2-fluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl Piperidine-1-carboxylic acid tert-butyl ester (u) (235 mg, 0.52 mmol), HATU (268 mg, 0.705 mmol) and DIPEA (182 mg, 1.41 mmol). The mixture was stirred at room temperature for 30 minutes. After the reaction was completed, EtOAc (EtOAc) The organic phase was washed with brine, dried over anhydrous sodium sulfate (4-(2-Amino-5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluoro Ethyl phenyl)carbamoyl)-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylate (1a) (230 mg, yellow solid , yield: 65.0%).
LC-MS(ESI):m/z 754.4[M+H
+]。
LC-MS (ESI): m / z 754.4 [M + H +].
步骤2:5-((4-(2-氨基-5-(1-(1-(叔丁氧基羰基)哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)氨基甲酰基)-3-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-2-甲酸(1b)的制备Step 2: 5-((4-(2-Amino-5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyridine-3- Of 3-(fluorophenyl)carbamoyl)-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid (1b)
于室温,在含有乙醇(8mL)的反应瓶中加入5-((4-(2-氨基-5-(1-(1-(叔丁氧基羰基)哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)氨基甲酰基)-3-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-2-羧酸乙酯(230mg,0.31mmol)、氢氧化锂一水合物(17mg,0.40mmol)和水(2mL)。将混合物升温至70℃并搅拌2小时,待反应完全后,减压浓缩得到粗产品5-((4-(2-氨基-5-(1-(1-(叔丁氧基羰基)哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)氨基甲酰基)-3-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-2-甲酸(1b)(220mg,灰色固体,收率:100%)。其未经纯化直接用于下一步反应。Add 5-((4-(2-amino)-5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-) to a reaction flask containing ethanol (8 mL) at room temperature Pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)carbamoyl)-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-di Ethyl hydropyridine-2-carboxylate (230 mg, 0.31 mmol), lithium hydroxide monohydrate (17 mg, 0.40 mmol) and water (2 mL). The mixture was warmed to 70 ° C and stirred for 2 hours. After the reaction was completed, concentrated under reduced pressure to give crude 5--(4-(2-amino-5-(1-(1-(t-butoxycarbonyl))piperidine. 4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)carbamoyl)-3-(4-fluorophenyl)-1-methyl-4- Oxo-1,4-dihydropyridine-2-carboxylic acid (1b) (220 mg, gray solid, yield: 100%). It was used directly in the next reaction without purification.
LC-MS(ESI):m/z 726.3[M+H
+]。
LC-MS (ESI): m / z 726.3 [M + H +].
步骤3:4-(4-(6-氨基-5-(4-(6-氨基甲酰基-5-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-3-甲酰胺基)-2-氟苯基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯(1c)的制备Step 3: 4-(4-(6-Amino-5-(4-(6-carbamoyl-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-di) Preparation of tert-butyl ester (1c) of hydropyridine-3-carboxamido)-2-fluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate
在含有DMF(3mL)的反应瓶中加入5-((4-(2-氨基-5-(1-(1-(叔丁氧基羰基)哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)氨基甲酰基)-3-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-2-甲酸(70mg,0.10mmol)、氯化铵(26mg,0.5mmol)、三吡咯烷基溴化磷六氟磷酸盐(93mg,0.2mmol)和DIPEA(52mg,0.4mmol)。将混合物于室温搅拌2小时后,加入饱和的碳酸氢钠水溶液淬灭,乙酸乙酯萃取(10mL×3),合并有机相。将有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为MeOH:DCM=1:10),得到4-(4-(6-氨基-5-(4-(6-氨基甲酰基-5-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-3-甲酰胺基)-2-氟苯基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯(1c)(30mg,黄色固体,收率:42.9%)In a reaction flask containing DMF (3 mL) was added 5-((4-(2-amino-5-(1-(1-(tert-butoxycarbonyl))piperidin-4-yl)-1H-pyrazole- 4-yl)pyridin-3-yl)-3-fluorophenyl)carbamoyl)-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine- 2-carboxylic acid (70 mg, 0.10 mmol), ammonium chloride (26 mg, 0.5 mmol), tripyrrolidinylphosphonium bromide (93 mg, 0.2 mmol) and DIPEA (52 mg, 0.4 mmol). After the mixture was stirred at room temperature for 2 hr, EtOAc (EtOAc m. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography eluting elut elut elut elut elut elut 4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxamido)-2-fluorophenyl)pyridin-3-yl)-1H-pyrazole- Tert-butyl ester of 1-yl)piperidine-1-carboxylate (1c) (30 mg, yellow solid, yield: 42.9%)
LC-MS(ESI):m/z725.3[M+H
+]。
LC-MS (ESI): m / z725.3 [M + H +].
步骤4:N
5-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-3-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-2,5-二甲酰胺(1)的制备
Step 4: N 5 -(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl) Preparation of -3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (1)
在含有DCM(3mL)的反应瓶中加入4-(4-(6-氨基-5-(4-(6-氨基甲酰基-5-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-3-甲酰胺基)-2-氟苯基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯(30mg,0.04mmol)和盐酸的1,4-二氧六环溶液(1.5mL,4M)。将混合物于室温搅拌1小时后,减压浓缩。残余物通过制备HPLC纯化(C18,乙腈/水(0.1%甲酸):10%~100%),得到N
5-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-3-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-2,5-二甲酰胺(1)(10mg,白色固体,41.7%)。
Add 4-(4-(6-amino-5-(4-(6-carbamoyl-5-(4-fluorophenyl))-1-methyl-4-) to a reaction flask containing DCM (3 mL) Oxo-1,4-dihydropyridine-3-carboxamido)-2-fluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (30 mg, 0.04 mmol) and a solution of 1,4-dioxane hydrochloride (1.5 mL, 4M). The mixture was stirred at room temperature for 1 hour and then concentrated. The residue was purified by preparative HPLC (C18, EtOAc/water (0.1% EtOAc): 10% to 100%) to afford N 5 -(4-(2-amino-5-(1-(piperidin-4-yl)) -1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydrogen Pyridine-2,5-dimethylformamide (1) (10 mg, white solid, 41.7%).
LC-MS(ESI):m/z 625.3[M+H
+]。
LC-MS (ESI): m / z 625.3 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.95(s,1H),8.82(s,1H),8.33(s,1H),8.27–8.20(m,2H),8.14(s,1H),8.02(s,1H),7.89(dd,J=12.3,2.0Hz,1H),7.81(s,1H),7.54(d,J=2.4Hz,1H),7.43(dd,J=8.4,2.0Hz,1H),7.39–7.31(m,3H),7.27–7.21(m,2H),5.53(s,2H),4.29–4.22(m,1H),3.87(s,3H),3.16(d,J=12.7Hz,2H),2.81–2.72(m,2H),2.05(d,J=12.1Hz,2H),1.91(tt,J=12.3,6.2Hz,2H)。
1 H NMR (400MHz, DMSO- d 6) δ12.95 (s, 1H), 8.82 (s, 1H), 8.33 (s, 1H), 8.27-8.20 (m, 2H), 8.14 (s, 1H), 8.02 (s, 1H), 7.89 (dd, J = 12.3, 2.0 Hz, 1H), 7.81 (s, 1H), 7.54 (d, J = 2.4 Hz, 1H), 7.43 (dd, J = 8.4, 2.0 Hz) , 1H), 7.39–7.31 (m, 3H), 7.27–7.21 (m, 2H), 5.53 (s, 2H), 4.29–4.22 (m, 1H), 3.87 (s, 3H), 3.16 (d, J) =12.7 Hz, 2H), 2.81 - 2.72 (m, 2H), 2.05 (d, J = 12.1 Hz, 2H), 1.91 (tt, J = 12.3, 6.2 Hz, 2H).
实施例2:N
5-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-3-(4-氟苯基)-N
2,1二甲基-4-氧代-1,4-二氢吡啶-2,5-二甲酰胺(2)的制备
Example 2: N 5 -(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl Preparation of 3-(4-fluorophenyl)-N 2 ,1 -dimethyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (2)
采用与实施例1相同的方法,除了用甲胺盐酸盐代替氯化铵,制得N
5-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-3-(4-氟苯基)-N
2,1二甲基-4-氧代-1,4-二氢吡啶-2,5-二甲酰胺(2)(白色固体,两步收率:22.3%)。
In the same manner as in Example 1, except that methylamine hydrochloride was used instead of ammonium chloride, N 5 -(4-(2-amino-5-(1-(piperidin-4-yl)-1H-) was obtained. Pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-3-(4-fluorophenyl)-N 2 ,1 dimethyl-4-oxo-1,4-dihydro Pyridine-2,5-dimethylformamide (2) (white solid, two-step yield: 22.3%).
LC-MS(ESI):m/z 639.3[M+H
+]。
LC-MS (ESI): m / z 639.3 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.94(s,1H),8.82(d,J=6.9Hz,1H),8.73(q,J=4.8Hz,1H),8.31(s,1H),8.26(d,J=2.3Hz,1H),8.14(s,1H),7.94–7.88(m,1H),7.83(d,J=5.0Hz,1H),7.55(d,J=2.5Hz,1H),7.49–7.28(m,4H),7.24(t,J=8.8Hz,2H),5.54(s,2H),4.25–4.30(m,4H),3.82(s,3H),3.18(d,J=11.9Hz,2H),2.79(t,J=12.2Hz,2H),2.14–1.86(m,4H)。
1 H NMR (400MHz, DMSO- d 6) δ12.94 (s, 1H), 8.82 (d, J = 6.9Hz, 1H), 8.73 (q, J = 4.8Hz, 1H), 8.31 (s, 1H) , 8.26 (d, J = 2.3 Hz, 1H), 8.14 (s, 1H), 7.94 - 7.88 (m, 1H), 7.83 (d, J = 5.0 Hz, 1H), 7.55 (d, J = 2.5 Hz, 1H), 7.49–7.28 (m, 4H), 7.24 (t, J=8.8 Hz, 2H), 5.54 (s, 2H), 4.25–4.30 (m, 4H), 3.82 (s, 3H), 3.18 (d) , J = 11.9 Hz, 2H), 2.79 (t, J = 12.2 Hz, 2H), 2.14 - 1.86 (m, 4H).
实施例3:N
5-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-N
2-环丙基-3-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-2,5-二甲酰胺(3)的制备
Example 3: N 5 -(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl Preparation of -N 2 -cyclopropyl-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (3)
采用与实施例1相同的方法,除了用环丙基胺代替氯化铵,制得N
5-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-N
2-环丙基-3-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-2,5-二甲酰胺(3)(白色固体,两步收率:25.6%)。
In the same manner as in Example 1, except that a cyclopropylamine was used in place of ammonium chloride, N 5 -(4-(2-amino-5-(1-(piperidin-4-yl)-1H-pyridyl) was obtained. Zin-4-yl)pyridin-3-yl)-3-fluorophenyl)-N 2 -cyclopropyl-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4 - Dihydropyridine-2,5-dimethylformamide (3) (white solid, two-step yield: 25.6%).
LC-MS(ESI):m/z 665.3[M+H
+]。
LC-MS (ESI): m / z 665.3 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.93(s,1H),8.89–8.80(m,2H),8.33(s,1H), 8.26(d,J=2.2Hz,1H),8.15(s,1H),7.89(d,J=11.9Hz,1H),7.83(d,J=4.5Hz,1H),7.55(d,J=2.2Hz,1H),7.47–7.32(m,2H),7.27(p,J=8.6Hz,4H),5.54(s,2H),4.28(d,J=11.3Hz,2H),3.20(d,J=12.0Hz,2H),2.82(t,J=12.2Hz,2H),2.09(d,J=13.8Hz,2H),1.96(p,J=11.9,10.4Hz,2H),0.54(d,J=7.2Hz,2H),0.01(d,J=7.3Hz,2H)。
1 H NMR (400MHz, DMSO- d 6) δ12.93 (s, 1H), 8.89-8.80 (m, 2H), 8.33 (s, 1H), 8.26 (d, J = 2.2Hz, 1H), 8.15 ( s, 1H), 7.89 (d, J = 11.9 Hz, 1H), 7.83 (d, J = 4.5 Hz, 1H), 7.55 (d, J = 2.2 Hz, 1H), 7.47 - 7.32 (m, 2H), 7.27 (p, J = 8.6 Hz, 4H), 5.54 (s, 2H), 4.28 (d, J = 11.3 Hz, 2H), 3.20 (d, J = 12.0 Hz, 2H), 2.82 (t, J = 12.2) Hz, 2H), 2.09 (d, J = 13.8 Hz, 2H), 1.96 (p, J = 11.9, 10.4 Hz, 2H), 0.54 (d, J = 7.2 Hz, 2H), 0.01 (d, J = 7.3 Hz, 2H).
实施例4:N-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-5-(4-氟苯基)-1-甲基-6-(吗啉-4-羰基)-4-氧代-1,4-二氢吡啶-3-甲酰胺(4)的制备Example 4: N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl) Preparation of 5-(4-fluorophenyl)-1-methyl-6-(morpholin-4-carbonyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (4)
采用与实施例1相同的方法,除了用吗啉代替氯化铵,制得N-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-5-(4-氟苯基)-1-甲基-6-(吗啉-4-羰基)-4-氧代-1,4-二氢吡啶-3-甲酰胺(4)(白色固体,两步收率:28.6%)。In the same manner as in Example 1, except that morpholine was used instead of ammonium chloride, N-(4-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazole-4) was obtained. -yl)pyridin-3-yl)-3-fluorophenyl)-5-(4-fluorophenyl)-1-methyl-6-(morpholin-4-carbonyl)-4-oxo-1, 4-Dihydropyridine-3-carboxamide (4) (white solid, two-step yield: 28.6%).
LC-MS(ESI):m/z 695.4[M+H
+]。
LC-MS (ESI): m / z 695.4 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.91(s,1H),8.83(d,J=6.9Hz,1H),8.32(s,1H),8.26(d,J=2.3Hz,1H),8.15(s,1H),7.90(dd,J=12.3,2.0Hz,1H),7.83(d,J=4.6Hz,1H),7.56(d,J=2.3Hz,1H),7.47–7.26(m,6H),5.55(s,2H),4.30(td,J=11.0,5.3Hz,1H),3.81(s,3H),3.59–3.54(m,2H),3.43–3.30(m,4H),3.23–3.17(m,2H),3.01(dd,J=18.4,8.9Hz,2H),2.84–2.79(m,2H),2.13–1.93(m,4H)。
1 H NMR (400MHz, DMSO- d 6) δ12.91 (s, 1H), 8.83 (d, J = 6.9Hz, 1H), 8.32 (s, 1H), 8.26 (d, J = 2.3Hz, 1H) , 8.15 (s, 1H), 7.90 (dd, J = 12.3, 2.0 Hz, 1H), 7.83 (d, J = 4.6 Hz, 1H), 7.56 (d, J = 2.3 Hz, 1H), 7.47 - 7.26 ( m,6H),5.55(s,2H),4.30(td,J=11.0,5.3Hz,1H),3.81(s,3H),3.59–3.54(m,2H),3.43–3.30(m,4H) , 3.23 - 3.17 (m, 2H), 3.01 (dd, J = 18.4, 8.9 Hz, 2H), 2.84 - 2.79 (m, 2H), 2.13 - 1.93 (m, 4H).
实施例5:N-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-6-(氮杂环丁烷-1-羰基)-5-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-3-甲酰胺(5)的制备Example 5: N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl) -6-(azetidin-1-carbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide (5) Preparation
采用与实施例1相同的方法,除了用氮杂环丁烷盐酸盐代替氯化铵,制得N-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-6-(氮杂环丁烷-1-羰基)-5-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-3-甲酰胺(5)(白色固体,两步收率:24.1%)。In the same manner as in Example 1, except that aziridine hydrochloride was used instead of ammonium chloride, N-(4-(2-amino-5-(1-(piperidin-4-yl)-) was obtained. 1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-(azetidin-1-carbonyl)-5-(4-fluorophenyl)-1-methyl 4-Oxo-1,4-dihydropyridine-3-carboxamide (5) (white solid, two-step yield: 24.1%).
LC-MS(ESI):m/z 665.3[M+H
+]。
LC-MS (ESI): m / z 665.3 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.89(s,1H),8.82(d,J=7.1Hz,1H),8.32(s,1H),8.26(d,J=2.3Hz,1H),8.14(s,1H),7.89(dd,J=12.2,1.9Hz,1H),7.83(d,J=4.9Hz,1H),7.55(d,J=2.3Hz,1H),7.50–7.14(m,6H),5.55(s,2H),4.33–4.23(m,1H),3.98(dd,J=9.2,6.6Hz,2H),3.85(s,3H),3.50(d,J=6.8Hz,2H),3.18(d,J=12.3Hz,2H),2.79(t,J=12.0Hz,2H),2.18–1.84(m,6H)。
1 H NMR (400MHz, DMSO- d 6) δ12.89 (s, 1H), 8.82 (d, J = 7.1Hz, 1H), 8.32 (s, 1H), 8.26 (d, J = 2.3Hz, 1H) , 8.14 (s, 1H), 7.89 (dd, J = 12.2, 1.9 Hz, 1H), 7.83 (d, J = 4.9 Hz, 1H), 7.55 (d, J = 2.3 Hz, 1H), 7.50 - 7.14 ( m,6H),5.55(s,2H),4.33–4.23(m,1H),3.98(dd,J=9.2,6.6Hz,2H),3.85(s,3H),3.50(d,J=6.8Hz , 2H), 3.18 (d, J = 12.3 Hz, 2H), 2.79 (t, J = 12.0 Hz, 2H), 2.18 - 1.84 (m, 6H).
实施例6:N
5-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-3-(4-氟苯基)-1-异丙基-4-氧代-1,4-二氢吡啶-2,5-二甲酰胺(6)的制备
Example 6: N 5 -(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl Preparation of 3-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (6)
采用与实施例1相同的方法,除了用5-(4-氟苯基)-1-异丙基-4-氧代-1,4-二氢吡啶-3-甲酸(b)代替6-(乙氧基羰基)-5-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-3-羧酸(a),制得N
5-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-3-(4-氟苯基)-1-异丙基-4-氧代-1,4-二氢吡啶-2,5-二甲酰胺(6)(白色固体,四步收率:13.5%)。
In the same manner as in Example 1, except that 5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (b) was used instead of 6-( Ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (a) to give N 5 -(4- (2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-3-(4-fluorophenyl) 1-isopropyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (6) (white solid, four-step yield: 13.5%).
LC-MS(ESI):m/z 663.4[M+H
+]。
LC-MS (ESI): m / z 663.4 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.95(s,1H),8.77(s,1H),8.31(d,J=2.9Hz,2H),8.26(d,J=2.3Hz,1H),8.14(s,1H),8.04(s,1H),7.90(dd,J=12.3,2.0Hz,1H),7.81(s,1H),7.55(d,J=2.4Hz,1H),7.43(dd,J=8.4,2.0Hz,1H),7.36(ddd,J=10.1,5.9,2.9Hz,3H),7.24(t,J=9.0Hz,2H),5.54(s,2H),4.51(q,J=6.6Hz,1H),4.23-4.29(m,1H),3.16(d,J=12.5Hz,2H),2.82–2.74(m,2H),2.05(d,J=11.9Hz,2H),1.96–1.86(m,2H),1.56(d,J=6.6Hz,6H)。
1 H NMR (400MHz, DMSO- d 6) δ12.95 (s, 1H), 8.77 (s, 1H), 8.31 (d, J = 2.9Hz, 2H), 8.26 (d, J = 2.3Hz, 1H) , 8.14 (s, 1H), 8.04 (s, 1H), 7.90 (dd, J = 12.3, 2.0 Hz, 1H), 7.81 (s, 1H), 7.55 (d, J = 2.4 Hz, 1H), 7.43 ( Dd, J = 8.4, 2.0 Hz, 1H), 7.36 (ddd, J = 10.1, 5.9, 2.9 Hz, 3H), 7.24 (t, J = 9.0 Hz, 2H), 5.54 (s, 2H), 4.51 (q) , J = 6.6 Hz, 1H), 4.23-4.29 (m, 1H), 3.16 (d, J = 12.5 Hz, 2H), 2.82 - 2.74 (m, 2H), 2.05 (d, J = 11.9 Hz, 2H) , 1.96–1.86 (m, 2H), 1.56 (d, J = 6.6 Hz, 6H).
实施例7:N
5-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-3-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-2,5-二甲酰胺(7)的制备
Example 7: N 5 -(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl )-3-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2,5-di Preparation of formamide (7)
采用与实施例1相同的方法,除了用5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸(c)代替6-(乙氧基羰基)-5-(4-氟苯基)-1-甲基-4-氧代 -1,4-二氢吡啶-3-羧酸(a),制得N
5-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-3-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-2,5-二甲酰胺(7)(白色固体,四步收率:11.2%)。
The same procedure as in Example 1 was carried out except that 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4- Dihydropyridine-3-carboxylic acid (c) in place of 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3- Carboxylic acid (a) to give N 5 -(4-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3 -fluorophenyl)-3-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2 , 5-dimethylformamide (7) (white solid, four-step yield: 11.2%).
LC-MS(ESI):m/z 709.4[M+H
+]。
LC-MS (ESI): m / z 709.4 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.90(s,1H),8.78(d,J=6.9Hz,1H),8.27–8.24(m,2H),8.14(s,1H),8.00(s,1H),7.92–7.80(m,2H),7.55(d,J=2.4Hz,1H),7.45–7.19(m,7H),5.54(s,2H),4.29(q,J=13.1,11.2Hz,1H),3.94–3.86(m,2H),3.28–3.08(m,5H),2.79(t,J=12.1Hz,2H),2.49(s,4H),2.07(d,J=13.2Hz,2H),1.51–1.28(m,4H)。
1 H NMR (400MHz, DMSO- d 6) δ12.90 (s, 1H), 8.78 (d, J = 6.9Hz, 1H), 8.27-8.24 (m, 2H), 8.14 (s, 1H), 8.00 ( s, 1H), 7.92 - 7.80 (m, 2H), 7.55 (d, J = 2.4 Hz, 1H), 7.45 - 7.19 (m, 7H), 5.54 (s, 2H), 4.29 (q, J = 13.1, 11.2 Hz, 1H), 3.94–3.86 (m, 2H), 3.28–3.08 (m, 5H), 2.79 (t, J = 12.1 Hz, 2H), 2.49 (s, 4H), 2.07 (d, J = 13.2) Hz, 2H), 1.51–1.28 (m, 4H).
实施例8:N
5-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-3-(4-氟苯基)-N
2-甲基-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-2,5-二甲酰胺(8)的制备
Example 8: N 5 -(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl )-3-(4-fluorophenyl)-N 2 -methyl-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine Preparation of -2,5-dimethylformamide (8)
采用与实施例7相同的方法,除了用甲胺盐酸盐代替氯化铵,制得N
5-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-3-(4-氟苯基)-N
2-甲基-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-2,5-二甲酰胺(8)(白色固体,两步收率:22.3%)。
In the same manner as in Example 7, except that methylamine hydrochloride was used instead of ammonium chloride, N 5 -(4-(2-amino-5-(1-(piperidin-4-yl)-1H-) was obtained. Pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-3-(4-fluorophenyl)-N 2 -methyl-4-oxo-1-((tetrahydro-2H) -pyran-4-yl)methyl)-1,4-dihydropyridine-2,5-dimethylformamide (8) (white solid, two-step yield: 22.3%).
LC-MS(ESI):m/z 723.4[M+H
+]。
LC-MS (ESI): m / z 723.4 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.90(s,1H),8.88–8.67(m,2H),8.38–8.23(m,2H),8.15(s,1H),7.95–7.74(m,2H),7.56(d,J=2.4Hz,1H),7.49–7.15(m,6H),5.55(s,2H),4.33–4.20(m,1H),4.07(d,J=7.3Hz,2H),3.94–3.82(m,2H),3.35–3.10(m,4H),2.84–2.73(m,2H),2.48(d,J=4.8Hz,4H),2.15–1.86(m,5H),1.46(d,J=12.4Hz,2H),1.31(dd,J=12.2,4.2Hz,1H)。
1 H NMR (400 MHz, DMSO-d 6 ) δ 12.90 (s, 1H), 8.88 - 8.67 (m, 2H), 8.38 - 8.23 (m, 2H), 8.15 (s, 1H), 7.95 - 7.74 (m) , 2H), 7.56 (d, J = 2.4 Hz, 1H), 7.49 - 7.15 (m, 6H), 5.55 (s, 2H), 4.33 - 4.20 (m, 1H), 4.07 (d, J = 7.3 Hz, 2H), 3.94–3.82 (m, 2H), 3.35–3.10 (m, 4H), 2.84–2.73 (m, 2H), 2.48 (d, J = 4.8 Hz, 4H), 2.15–1.86 (m, 5H) , 1.46 (d, J = 12.4 Hz, 2H), 1.31 (dd, J = 12.2, 4.2 Hz, 1H).
实施例9:N
5-(4-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)苯基)-N
2-甲基-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-3-(对甲苯基)-1,4-二氢吡啶-2,5-二甲酰胺(9)的制备
Example 9: N 5 -(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)-N 2 -methyl-4-oxo- Preparation of 1-((tetrahydro-2H-pyran-4-yl)methyl)-3-(p-tolyl)-1,4-dihydropyridine-2,5-dimethylamide (9)
步骤1:4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-2,5-二羧酸二乙酯(9a)的制备Step 1: 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (9a) preparation
于室温,在含有乙醇(4mL)的圆底烧瓶中加入4-氧-4氢-吡喃-2,5-二甲酸乙酯(a2)(300mg,1.25mmol)和(四氢-2H-吡喃-4-基)甲胺(173mg,1.5mmol)。将混合物升温至80℃并搅拌2小时,待反应完全后,将反应液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为MeOH:DCM=1:20),得到4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-2,5-二羧酸二乙酯(9a)(300mg,黄色固体,收率:71.2%)。Add 4-oxo-4hydro-pyran-2,5-dicarboxylate (a2) (300 mg, 1.25 mmol) and (tetrahydro-2H-pyridyl) to a round bottom flask containing ethanol (4 mL) at room temperature. Methyl-4-yl)methylamine (173 mg, 1.5 mmol). The mixture was warmed to 80 ° C and stirred for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut Diethyl 1,4-dihydropyridine-2,5-dicarboxylate (9a) (300 mg, yellow solid, yield: 71.2%).
LC-MS(ESI):m/z 338.3[M+H
+]。
LC-MS (ESI): m / z 338.3 [M + H +].
步骤2:3-溴-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-2,5-二羧酸二乙酯(9b)的制备Step 2: 3-Bromo-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester Preparation of (9b)
在含有DMF(5mL)的反应瓶中加入4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-2,5-二羧酸二乙酯(9a)(300mg,0.89mmol)和N-溴代丁二酰亚胺(317mg,1.78mmol)。将混合物升温至80℃并搅拌3小时,待反应完全后,将反应液减压浓 缩,残余物用饱和硫代硫酸钠水溶液淬灭,乙酸乙酯萃取(10mL×3),合并有机相。将有机相用饱和的食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱液为DCM:CH
3OH/10:1),得到3-溴-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-2,5-二羧酸二乙酯(9b)(320mg,黄色固体,收率:86.0%)。
Add 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2,5-dicarboxyl to a reaction vial containing DMF (5 mL) Diethyl acid (9a) (300 mg, 0.89 mmol) and N-bromosuccinimide (317 mg, 1.78 mmol). The mixture was warmed to 80 ° C and stirred for 3 hours. After the reaction was completed, the mixture was evaporated. The organic phase was washed with brine brine, dried over anhydrous The residue was purified by chromatography on silica gel column chromatography (eluent DCM: CH 3 OH / 10: 1), to give 3-bromo-4-oxo-1 - ((tetrahydro-pyran-4 -2H- Methyl)-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (9b) (320 mg, yellow solid, yield: 86.0%).
LC-MS(ESI):m/z 416.2/418.2[M+H
+]。
LC-MS (ESI): m / z 416.2 / 418.2 [M + H +].
步骤3:5-溴-6-(乙氧基羰基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸(9c)的制备Step 3: 5-Bromo-6-(ethoxycarbonyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3 - Preparation of formic acid (9c)
在含有(9mL)乙醇的反应瓶中加入3-溴-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-2,5-二羧酸二乙酯(9b)(1.0g,2.39mmol)。将反应液冷却至0℃,搅拌下滴加氢氧化钠水溶液(3mL,2.87mmol),加毕升至室温并继续搅拌1小时。待反应完全后,将反应液冷却至0℃,用1N的盐酸调节pH~3,有白色固体析出,继续搅拌30分钟。过滤,收集固体,得到5-溴-6-(乙氧基羰基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸(9c)(600mg,白色固体,收率:64.4%)。3-bromo-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2 was added to a reaction flask containing (9 mL) of ethanol. Diethyl 5-dicarboxylate (9b) (1.0 g, 2.39 mmol). The reaction solution was cooled to 0 ° C, and aqueous sodium hydroxide (3 mL, 2.87 mmol) was added dropwise with stirring, and the mixture was warmed to room temperature and stirring was continued for 1 hour. After the reaction was completed, the reaction mixture was cooled to 0 ° C, pH was adjusted to 3 with 1N hydrochloric acid, and a white solid was precipitated and stirring was continued for 30 minutes. Filtration and collection of the solid to give 5-bromo-6-(ethoxycarbonyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydro Pyridine-3-carboxylic acid (9c) (600 mg, white solid, yield: 64.4%).
LC-MS(ESI):m/z 304.1/306.1[M+H
+]。
LC-MS (ESI): m / z 304.1 / 306.1 [M + H +].
步骤4:5-((4-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)苯基)氨基甲酰基)-3-溴-4-氧代-1-((四氢-2H-吡喃-2-基)-4-基)甲基)-1,4-二氢吡啶-2-羧酸乙酯(9d)的制备Step 4: 5-((4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)carbamoyl)-3-bromo-4-oxo Preparation of ethyl 1-((tetrahydro-2H-pyran-2-yl)-4-yl)methyl)-1,4-dihydropyridine-2-carboxylate (9d)
在含有DMF(10mL)的反应瓶中加入5-溴-6-(乙氧基羰基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸(9c)(100mg,0.26mmol)、3-(4-氨基-2-甲苯基)-5-(3,4-二甲氧基苯基)吡啶-2-胺(aa)(99mg,0.31mmol)、HATU(146mg,0.39mmol)和DIPEA(99mg,0.77mmol)。将混合物于室温搅拌30分钟,待反应完全后,加入饱和的碳酸氢钠溶液淬灭,用乙酸乙酯萃取(30mLx3),合并有机相。将有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,残余物通过硅胶柱层析色谱法纯化(洗脱剂为MeOH:DCM=1:20),得到5-((4-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)苯基)氨基甲酰基)-3-溴-4-氧代-1-((四氢-2H-吡喃-2-基)-4-基)甲基)-1,4-二氢吡啶-2-羧酸乙酯(9d)(160mg,黄色固体,收率:89.1%)。Add 5-bromo-6-(ethoxycarbonyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1 to a reaction vial containing DMF (10 mL) , 4-dihydropyridine-3-carboxylic acid (9c) (100 mg, 0.26 mmol), 3-(4-amino-2-methylphenyl)-5-(3,4-dimethoxyphenyl)pyridine-2 -Amine (aa) (99 mg, 0.31 mmol), HATU (146 mg, 0.39 mmol) and DIPEA (99 mg, 0.77 mmol). The mixture was stirred at room temperature for 30 minutes. After the reaction was completed, EtOAc (EtOAc) The organic phase was washed with brine, dried over anhydrous sodium sulfate (4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)carbamoyl)-3-bromo-4-oxo-1-((four Ethyl 2-H-pyran-2-yl)-4-yl)methyl)-1,4-dihydropyridine-2-carboxylate (9d) (160 mg,yield:yield: 89.1%).
LC-MS(ESI),m/z 691.3/693.4[M/M+H
+]。
LC-MS (ESI), m / z 691.3 / 693.4 [M / M + H +].
步骤5:5-((4-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)苯基)氨基甲酰基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-3-(对甲苯基)-1,4-二氢吡啶-2-羧酸乙酯(9e)的制备Step 5: 5-((4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)carbamoyl)-4-oxo-1-( Preparation of ethyl (tetrahydro-2H-pyran-4-yl)methyl)-3-(p-tolyl)-1,4-dihydropyridine-2-carboxylate (9e)
于室温,在含有(5mL)1,4-二氧六环和水混合液(4:1)的反应瓶中加入5-((4-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)苯基)氨基甲酰基)-3-溴-4-氧代-1-((四氢-2H-吡喃-2-基)-4-基)甲基)-1,4-二氢吡啶-2-羧酸乙酯(9d)(120mg,0.17mmol)、对甲基苯硼酸(35mg,0.25mmol)、碳酸钾(70mg,0.51mmol)、Pd(dppf)Cl
2.DCM(14mg,0.017mmol)。密封,氮气置换三次,加热至80℃搅拌1.5小时。待反应液冷却至室温后,过滤,滤液用水(10mL)稀释,乙酸乙酯萃取(15mL×3),合并有机相。将有机相用饱和的食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通 过硅胶柱层析色谱法纯化(洗脱液为DCM:CH
3OH/10:1),得到5-((4-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)苯基)氨基甲酰基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-3-(对甲苯基)-1,4-二氢吡啶-2-羧酸乙酯(9e)(100mg,黄色固体,收率:83.4%)。
Add 5-((4-(2-amino-5-(3,4-dimethyl)) to the reaction flask containing (5 mL) 1,4-dioxane and water mixture (4:1) at room temperature Oxyphenyl)pyridin-3-yl)phenyl)carbamoyl)-3-bromo-4-oxo-1-((tetrahydro-2H-pyran-2-yl)-4-yl)- Ethyl 4-1,4-dihydropyridine-2-carboxylic acid ethyl ester (9d) (120 mg, 0.17 mmol), p-methylphenylboronic acid (35 mg, 0.25 mmol), potassium carbonate (70 mg, 0.51 mmol), Pd ( Dppf) Cl 2 .DCM (14 mg, 0.017 mmol). Sealed, replaced with nitrogen three times, heated to 80 ° C and stirred for 1.5 hours. After the reaction mixture was cooled to room temperature, it was filtered, and the filtrate was diluted with water (10 mL), and ethyl acetate (15 mL×3). The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography (eluent DCM: CH 3 OH / 10: 1), to give 5 - ((4- (2-amino-5- (3,4-dimethoxybenzene Pyridin-3-yl)phenyl)carbamoyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-3-(p-tolyl)-1 Ethyl 4-dihydropyridine-2-carboxylate (9e) (100 mg, yellow solid, yield: 83.4%).
LC-MS(ESI),m/z 703.4[M/M+H
+]。
LC-MS (ESI), m / z 703.4 [M / M + H +].
步骤6:5-((4-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)苯基)氨基甲酰基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-3-(对甲苯基)-1,4-二氢吡啶-2-甲酸(9f)的制备Step 6: 5-((4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)carbamoyl)-4-oxo-1-( Preparation of (tetrahydro-2H-pyran-4-yl)methyl)-3-(p-tolyl)-1,4-dihydropyridine-2-carboxylic acid (9f)
于室温,在含有乙醇(2mL)的反应瓶中加入5-((4-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)苯基)氨基甲酰基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-3-(对甲苯基)-1,4-二氢吡啶-2-羧酸乙酯(9e)(100mg,0.14mmol)、氢氧化锂一水合物(10mg,0.21mmol)和水(0.5mL)。将反应液升温至70℃并搅拌2小时,待反应完全后,减压浓缩得到粗产品5-((4-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)苯基)氨基甲酰基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-3-(对甲苯基)-1,4-二氢吡啶-2-甲酸(9f)(100mg,灰色固体,收率:100%)。其未经纯化直接用于下一步反应。Add 5-((4-(2-amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)carbamate to a reaction flask containing ethanol (2 mL) at room temperature Acyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-3-(p-tolyl)-1,4-dihydropyridine-2-carboxylic acid ethyl ester (9e) (100 mg, 0.14 mmol), lithium hydroxide monohydrate (10 mg, 0.21 mmol) and water (0.5 mL). The reaction solution was warmed to 70 ° C and stirred for 2 hours. After the reaction was completed, concentrated under reduced pressure to give the crude product 5-((4-(2-amino-5-(3,4-dimethoxyphenyl)pyridine) 3-yl)phenyl)carbamoyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-3-(p-tolyl)-1,4-di Hydropyridine-2-carboxylic acid (9f) (100 mg, gray solid, yield: 100%). It was used directly in the next reaction without purification.
LC-MS(ESI),m/z 675.4[M/M+H
+]。
LC-MS (ESI), m / z 675.4 [M / M + H +].
步骤7:N
5-(4-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)苯基)-N
2-甲基-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-3-(对甲苯基)-1,4-二氢吡啶-2,5-二甲酰胺(9)的制备
Step 7: N 5 -(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)-N 2 -methyl-4-oxo-1 Preparation of ((tetrahydro-2H-pyran-4-yl)methyl)-3-(p-tolyl)-1,4-dihydropyridine-2,5-dimethylformamide (9)
于室温,在含有DMF(3mL)的圆底烧瓶中加入5-((4-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)苯基)氨基甲酰基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-3-(对甲苯基)-1,4-二氢吡啶-2-甲酸(9f)(50mg,0.074mmol)、甲胺盐酸盐(14mg,0.22mmol)、HOBT(30mg,0.22mmol)、EDCI(42mg,0.22mmol)和DIPEA(57mg,0.44mmol)。将混合物于该温度搅拌过夜,待反应完全后,将反应液减压浓缩。残余物通过制备HPLC纯化(C18,乙腈/水(0.1%甲酸):10%~100%),得到N
5-(4-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)苯基)-N
2-甲基-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-3-(对甲苯基)-1,4-二氢吡啶-2,5-二甲酰胺(9)(6mg,白色固体,收率:11.2%)。
Add 5-((4-(2-amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)amino) to a round bottom flask containing DMF (3 mL) at room temperature Formyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-3-(p-tolyl)-1,4-dihydropyridine-2-carboxylic acid (9f (50 mg, 0.074 mmol), methylamine hydrochloride (14 mg, 0.22 mmol), HOBT (30 mg, 0.22 mmol), EDCI (42 mg, 0.22 mmol) and DIPEA (57 mg, 0.44 mmol). The mixture was stirred at this temperature overnight, and after the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, EtOAc/water (0.1% EtOAc): 10% to 100%) to afford N 5 -(2-(2-amino-5-(3,4-dimethoxyphenyl) Pyridin-3-yl)phenyl)-N 2 -methyl-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-3-(p-tolyl)- 1,4-Dihydropyridine-2,5-dimethylformamide (9) (6 mg, white solid, yield: 11.2%).
LC-MS(ESI),m/z 688.4[M/M+H
+]。
LC-MS (ESI), m / z 688.4 [M / M + H +].
1H NMR(400MHz,DMSO-d
6)δ8.76(s,1H),8.25(d,J=2.3Hz,1H),7.80(d,J=8.3Hz,2H),7.60(d,J=2.4Hz,1H),7.53(d,J=8.3Hz,2H),7.19(s,6H),6.99(d,J=8.3Hz,1H),5.66(s,2H),4.05(d,J=7.4Hz,2H),3.87(d,J=10.6Hz,2H),3.83(s,3H),3.77(s,3H),3.24(s,1H),2.47(d,J=4.6Hz,3H),2.35(s,3H),1.46(d,J=13.2Hz,2H)。
1 H NMR (400MHz, DMSO- d 6) δ8.76 (s, 1H), 8.25 (d, J = 2.3Hz, 1H), 7.80 (d, J = 8.3Hz, 2H), 7.60 (d, J = 2.4 Hz, 1H), 7.53 (d, J = 8.3 Hz, 2H), 7.19 (s, 6H), 6.99 (d, J = 8.3 Hz, 1H), 5.66 (s, 2H), 4.05 (d, J = 7.4 Hz, 2H), 3.87 (d, J = 10.6 Hz, 2H), 3.83 (s, 3H), 3.77 (s, 3H), 3.24 (s, 1H), 2.47 (d, J = 4.6 Hz, 3H) , 2.35 (s, 3H), 1.46 (d, J = 13.2 Hz, 2H).
实施例10:N
5-(4-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)-3-氟苯基)-3-(4-氟苯基)-1-异丙基-4-氧代-1,4-二氢吡啶-2,5-二甲酰胺(10)的制备
Example 10: N 5 -(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-3-fluorophenyl)-3-(4-fluorobenzene Of 1-(1-isopropyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (10)
采用与实施例6相同的方法,除了用3-(4-氨基-2-氟苯基)-5-(3,4-二甲氧基苯基)吡啶-2-胺(x)代替4-(4-(6-氨基-5-(4-氨基-2-氟苯基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(u),制得N
5-(4-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)-3-氟苯基)-3-(4-氟苯基)-1-异丙基-4-氧代-1,4-二氢吡啶-2,5-二甲酰胺(10)(白色固体,三步收率:17.5%)。
In the same manner as in Example 6, except that 3-(4-amino-2-fluorophenyl)-5-(3,4-dimethoxyphenyl)pyridin-2-amine (x) was used instead of 4- (4-(6-Amino-5-(4-amino-2-fluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (u), Preparation of N 5 -(4-(2-amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-3-fluorophenyl)-3-(4-fluorophenyl) 1-Isopropyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (10) (white solid, three-step yield: 17.5%).
LC-MS(ESI),m/z 640.4[M/M+H
+]。
LC-MS (ESI), m / z 640.4 [M / M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.95(s,1H),8.77(s,1H),8.29(d,J=2.4Hz,2H),8.04(s,1H),7.91(dd,J=12.5,1.8Hz,1H),7.60(d,J=2.4Hz,1H),7.52–7.32(m,4H),7.29–7.18(m,2H),7.18–7.06(m,2H),6.98(d,J=8.4Hz,1H),5.66(s,2H),4.50(p,J=6.6Hz,1H),3.79(d,J=20.5Hz,6H),1.56(d,J=6.6Hz,6H)。
1 H NMR (400 MHz, DMSO-d 6 ) δ 12.95 (s, 1H), 8.77 (s, 1H), 8.29 (d, J = 2.4 Hz, 2H), 8.04 (s, 1H), 7.91 (dd, J=12.5, 1.8 Hz, 1H), 7.60 (d, J=2.4 Hz, 1H), 7.52–7.32 (m, 4H), 7.29–7.18 (m, 2H), 7.18–7.06 (m, 2H), 6.98 (d, J = 8.4 Hz, 1H), 5.66 (s, 2H), 4.50 (p, J = 6.6 Hz, 1H), 3.79 (d, J = 20.5 Hz, 6H), 1.56 (d, J = 6.6 Hz) , 6H).
实施例11:N
5-(4-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)-3-氟苯基)-3-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-2,5-二甲酰胺(11)的制备
Example 11: N 5 -(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-3-fluorophenyl)-3-(4-fluorobenzene Of 1-methyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (11)
采用与实施例10相同的方法,除了用6-(乙氧基羰基)-5-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-3-羧酸(a)代替5-(4-氟苯基)-1-异丙基-4-氧代-1,4-二氢吡啶-3-甲酸(b),制得N
5-(4-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)-3-氟苯基)-3-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-2,5-二甲酰胺(11)(白色固体,三步收率:18.8%)。
The same procedure as in Example 10 was employed except that 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3- The carboxylic acid (a) is substituted for 5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (b) to obtain N 5 -(4- (2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-3-fluorophenyl)-3-(4-fluorophenyl)-1-methyl-4- Oxo-1,4-dihydropyridine-2,5-dimethylformamide (11) (white solid, three-step yield: 18.8%).
LC-MS(ESI),m/z 612.3[M/M+H
+]。
LC-MS (ESI), m / z 612.3 [M / M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.95(s,1H),8.83(s,1H),8.29(d,J=2.4Hz,1H),8.22(s,1H),8.02(s,1H),7.89(dd,J=12.4,1.8Hz,1H),7.59(d,J=2.4Hz,1H),7.52–7.32(m,4H),7.28–7.20(m,2H),7.17–7.08(m,2H),6.98(d,J=8.4Hz,1H),5.66(s,2H),3.87(s,3H),3.79(d,J=20.5Hz,6H)。
1 H NMR (400MHz, DMSO- d 6) δ12.95 (s, 1H), 8.83 (s, 1H), 8.29 (d, J = 2.4Hz, 1H), 8.22 (s, 1H), 8.02 (s, 1H), 7.89 (dd, J = 12.4, 1.8 Hz, 1H), 7.59 (d, J = 2.4 Hz, 1H), 7.52 - 7.32 (m, 4H), 7.28 - 7.20 (m, 2H), 7.17 - 7.08 (m, 2H), 6.98 (d, J = 8.4 Hz, 1H), 5.66 (s, 2H), 3.87 (s, 3H), 3.79 (d, J = 20.5 Hz, 6H).
实施例12:N
5-(4-(2-氨基-5-(1-乙基-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-3-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-2,5-二甲酰胺(12)的制备
Example 12: N 5 -(4-(2-Amino-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-3-(4 Of -fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (12)
采用与实施例11相同的方法,除了用3-(4-氨基-2-氟苯基)-5-(1-乙基-1H-吡唑-4-基)吡啶-2-胺(v)代替3-(4-氨基-2-氟苯基)-5-(3,4-二甲氧基苯基)吡啶-2-胺(x),制得N
5-(4-(2-氨基-5-(1-乙基-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-3-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-2,5-二甲酰胺(12)(白色固体,三步收率:20.6%)。
The same procedure as in Example 11 was employed except that 3-(4-amino-2-fluorophenyl)-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-2-amine (v) was used. Instead of 3-(4-amino-2-fluorophenyl)-5-(3,4-dimethoxyphenyl)pyridin-2-amine (x), N 5 -(4-(2-amino) was obtained. -5-(1-ethyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-3-(4-fluorophenyl)-1-methyl-4-oxo代-1,4-Dihydropyridine-2,5-dimethylformamide (12) (white solid, three-step yield: 20.6%).
LC-MS(ESI),m/z 570.4[M/M+H
+]。
LC-MS (ESI), m / z 570.4 [M / M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.95(s,1H),8.83(s,1H),8.23(dd,J=6.6,2.2Hz,2H),8.09(s,1H),8.02(s,1H),7.89(dd,J=12.3,2.0Hz,1H),7.77(s,1H),7.51(d,J=2.3Hz,1H),7.42(dd,J=8.4,2.0Hz,1H),7.39–7.31(m,3H),7.28–7.21(m,2H),5.53(s,2H),4.11(q,J=7.3Hz,2H),3.87(s,3H),1.38(t,J=7.3Hz,3H)。
1 H NMR (400MHz, DMSO- d 6) δ12.95 (s, 1H), 8.83 (s, 1H), 8.23 (dd, J = 6.6,2.2Hz, 2H), 8.09 (s, 1H), 8.02 ( s, 1H), 7.89 (dd, J = 12.3, 2.0 Hz, 1H), 7.77 (s, 1H), 7.51 (d, J = 2.3 Hz, 1H), 7.42 (dd, J = 8.4, 2.0 Hz, 1H) ), 7.39 - 7.31 (m, 3H), 7.28 - 7.21 (m, 2H), 5.53 (s, 2H), 4.11 (q, J = 7.3 Hz, 2H), 3.87 (s, 3H), 1.38 (t, J = 7.3 Hz, 3H).
实施例13:N
5-(4-(2-氨基-5-(1-乙基-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-3-(4-氟苯基)-1-异丙基-4-氧代-1,4-二氢吡啶-2,5-二甲酰胺(13)的制备
Example 13: N 5 -(4-(2-Amino-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-3-(4 Of -fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (13)
采用与实施例12相同的方法,除了用5-(4-氟苯基)-1-异丙基-4-氧代-1,4-二氢吡啶-3-甲酸(b)代替6-(乙氧基羰基)-5-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-3-羧酸(a),制得N
5-(4-(2-氨基-5-(1-乙基-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-3-(4-氟苯基)-1-异丙基-4-氧代-1,4-二氢吡啶-2,5-二甲酰胺(13)(白色固体,三步收率:22.4%)。
In the same manner as in Example 12 except that 5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (b) was used instead of 6-( Ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (a) to give N 5 -(4- (2-Amino-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl 4-Oxo-1,4-dihydropyridine-2,5-dimethylformamide (13) (white solid, three-step yield: 22.4%).
LC-MS(ESI),m/z 598.3[M/M+H
+]。
LC-MS (ESI), m / z 598.3 [M / M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.95(s,1H),8.77(s,1H),8.41–8.21(m,2H),8.06(d,J=18.2Hz,2H),7.90(dd,J=12.3,2.0Hz,1H),7.78(s,1H),7.52(d,J=2.3Hz,1H),7.47–7.20(m,5H),5.53(s,2H),4.50(p,J=6.6Hz,1H),4.11(q,J=7.2Hz,2H),1.77–1.16(m,9H)。
1 H NMR (400 MHz, DMSO-d 6 ) δ 12.95 (s, 1H), 8.77 (s, 1H), 8.41 - 8.21 (m, 2H), 8.06 (d, J = 18.2 Hz, 2H), 7.90 ( Dd, J = 12.3, 2.0 Hz, 1H), 7.78 (s, 1H), 7.52 (d, J = 2.3 Hz, 1H), 7.47 - 7.20 (m, 5H), 5.53 (s, 2H), 4.50 (p , J = 6.6 Hz, 1H), 4.11 (q, J = 7.2 Hz, 2H), 1.77 - 1.16 (m, 9H).
实施例14:N-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9六氢吡啶并[1,2-α][1,4]二氮杂环庚烷-8-甲酰胺(14)的制备Example 14: N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl) -10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9 hexahydropyrido[1,2-α][1,4]diazepine Preparation of heptane-8-carboxamide (14)
步骤1:4-(4-(6-氨基-5-(2-氟-4-(10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-α][1,4]二氮杂环庚烷-8-甲酰氨基)苯基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯(14a)的制备Step 1: 4-(4-(6-Amino-5-(2-fluoro-4-(10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5 ,9-Hexidopyrido[1,2-α][1,4]diazepane-8-formylamino)phenyl)pyridin-3-yl)-1H-pyrazol-1-yl Preparation of piperidine-1-carboxylic acid tert-butyl ester (14a)
在含有DMF(4mL)的反应瓶中加入10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸(d)(45mg,0.14mmol)、4-(4-(6-氨基-5-(4-氨基-2-氟苯基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(u)(50mg,0.11mmol)、HATU(63mg,0.17mmol)和DIPEA(43mg,0.33mmol)。将混合物于室温搅拌30分钟,待反应完全后,加入饱和的碳酸氢钠溶液淬灭,用乙酸乙酯萃取(10mLx3),合并有机相。将有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为MeOH:CM=1:20),得到4-(4-(6-氨基-5-(2-氟-4-(10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-α][1,4]二氮杂环庚烷-8-甲酰氨基)苯基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯(中间体14a)(40mg,黄色固体,收率:48.2%)。Add 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2- to a reaction flask containing DMF (4 mL). a][1,4]diazepane-8-carboxylic acid (d) (45 mg, 0.14 mmol), 4-(4-(6-amino-5-(4-amino-2-fluorophenyl)) tert-Butyl pyridine-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (u) (50 mg, 0.11 mmol), HATU (63 mg, 0.17 mmol) and DIPEA (43 mg, 0.33 mmol) . The mixture was stirred at room temperature for 30 minutes. After the reaction was completed, EtOAc (EtOAc) The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography (eluent: MeOH: MeOH = 1: 20) to afford 4-(4-(6-amino-5-(2-fluoro-4-(10-(4-) Fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-α][1,4]diazepan-8- Formylamino)phenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (Intermediate 14a) (40 mg, yellow solid, yield: 48.2%) .
LC-MS(ESI):m/z 751.3[M/M+H
+]。
LC-MS (ESI): m / z 751.3 [M / M + H +].
步骤2:N-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-α][1,4]二氮杂环庚烷-8-甲酰胺(14)的制备Step 2: N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)- 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-α][1,4]diazepine Preparation of heptane-8-carboxamide (14)
在含有DCM(3mL)的反应瓶中加入4-(4-(6-氨基-5-(2-氟-4-(10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-α][1,4]二氮杂环庚烷-8-甲酰氨基)苯基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯(14a)(40mg,0.05mmol)和盐酸的1,4-二氧六 环溶液(1.5mL,4M)。将混合物于室温搅拌1小时后,减压浓缩。残余物通过制备HPLC纯化(C18,乙腈/水(0.1%甲酸):10%~100%),得到N-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-α][1,4]二氮杂环庚烷-8-甲酰胺(14)(11mg,白色固体,31.9%)。Add 4-(4-(6-amino-5-(2-fluoro-4-(10-(4-fluorophenyl)-1,9-dioxo-1) to a reaction flask containing DCM (3 mL) , 2,3,4,5,9-hexahydropyrido[1,2-α][1,4]diazepane-8-carboxamido)phenyl)pyridin-3-yl)- 1H-Pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (14a) (40 mg, 0.05 mmol) and 1,4-dioxane hydrochloride (1.5 mL, 4M). The mixture was stirred at room temperature for 1 hour and then concentrated. The residue was purified by preparative HPLC (C18, EtOAc/EtOAc (EtOAc:EtOAc:EtOAc:EtOAc) 1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5 , 9-Hexidopyrido[1,2-α][1,4]diazepane-8-carboxamide (14) (11 mg, white solid, 31.9%).
LC-MS(ESI):m/z 651.4[M/M+H
+]。
LC-MS (ESI): m / z 651.4 [M / M + H +].
1H NMR(400MHz,DMSO-d
6)δ13.01(s,1H),8.97(s,1H),8.86(s,1H),8.70(t,J=6.6Hz,2H),8.31(d,J=2.2Hz,1H),8.25(s,1H),8.01–7.91(m,2H),7.83(s,1H),7.51–7.38(m,2H),7.36–7.18(m,4H),6.40(s,2H),4.66(d,J=12.3Hz,1H),4.53–4.42(m,1H),4.05(d,J=15.9Hz,1H),3.40(s,2H),3.09(d,J=11.6Hz,2H),2.27–1.98(m,6H),1.24(s,2H)。
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.01 (s, 1H), 8.97 (s, 1H), 8.86 (s, 1H), 8.70 (t, J = 6.6 Hz, 2H), 8.31 (d, J=2.2 Hz, 1H), 8.25 (s, 1H), 8.01–7.91 (m, 2H), 7.83 (s, 1H), 7.51–7.38 (m, 2H), 7.36–7.18 (m, 4H), 6.40 (s, 2H), 4.66 (d, J = 12.3 Hz, 1H), 4.53 - 4.42 (m, 1H), 4.05 (d, J = 15.9 Hz, 1H), 3.40 (s, 2H), 3.09 (d, J = 11.6 Hz, 2H), 2.27 - 1.98 (m, 6H), 1.24 (s, 2H).
实施例15:N-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-2,5-二氟苯基)-10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-α][1,4]二氮杂环庚烷-8-甲酰胺(15)的制备Example 15: N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-2,5-difluoro Phenyl)-10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-α][1,4] Preparation of diazepane-8-carboxamide (15)
采用与实施例14相同的方法,除了用4-(4-(6-氨基-5-(4-氨基-2,5-二氟苯基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(y)代替4-(4-(6-氨基-5-(4-氨基-2-氟苯基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(u),制得N-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-2,5-二氟苯基)-10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-α][1,4]二氮杂环庚烷-8-甲酰胺(15)(白色固体,两步收率:36.3%)。The same procedure as in Example 14 was employed except that 4-(4-(6-amino-5-(4-amino-2,5-difluorophenyl)pyridin-3-yl)-1H-pyrazole-1 was used. -yl)piperidine-1-carboxylic acid tert-butyl ester (y) in place of 4-(4-(6-amino-5-(4-amino-2-fluorophenyl)pyridin-3-yl)-1H-pyrazole -1-yl)piperidine-1-carboxylic acid tert-butyl ester (u) to give N-(4-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazole-4) -yl)pyridin-3-yl)-2,5-difluorophenyl)-10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9- Hexahydropyrido[1,2-α][1,4]diazepane-8-carboxamide (15) (white solid, two-step yield: 36.3%).
LC-MS(ESI):m/z 669.4[M/M+H
+]。
LC-MS (ESI): m / z 669.4 [M / M + H +].
1H NMR(400MHz,DMSO-d
6)δ13.24(s,1H),8.88(s,1H),8.68(s,1H),8.51–8.39(m,1H),8.28(s,1H),8.15(s,1H),7.86(s,1H),7.58(s,1H),7.37(d,J=6.7Hz,1H),7.35–7.15(m,4H),5.71(s,2H),4.73–4.35(m,3H),4.12–4.00(m,1H),3.65–3.36(m,4H),3.05(s,2H),2.18(s,6H)。
1 H NMR (400MHz, DMSO- d 6) δ13.24 (s, 1H), 8.88 (s, 1H), 8.68 (s, 1H), 8.51-8.39 (m, 1H), 8.28 (s, 1H), 8.15(s,1H), 7.86(s,1H), 7.58(s,1H), 7.37(d,J=6.7Hz,1H),7.35–7.15(m,4H),5.71(s,2H),4.73 – 4.35 (m, 3H), 4.12–4.00 (m, 1H), 3.65–3.36 (m, 4H), 3.05 (s, 2H), 2.18 (s, 6H).
实施例16:N-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-7-(4-氟苯基)-6,8-二氧代-3,4,6,8,12,12a-六氢-1H-吡啶并[1',2':4,5]吡嗪并[2,1-C][1,4]恶嗪-9-甲酰胺(16)的制备Example 16: N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl) -7-(4-fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-pyrido[1',2':4,5]pyridyl Preparation of oxazolo[2,1-C][1,4]oxazine-9-carboxamide (16)
采用与实施例14相同的方法,除了用7-(4-氟苯基)-6,8-二氧代-3,4,6,8,12,12a-六氢-1H-吡啶并[1',2':4,5]吡嗪并[2,1-c][1,4]恶嗪-9-甲酸(j)代替10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸(d),制得N-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-7-(4-氟苯基)-6,8-二氧代-3,4,6,8,12,12a-六氢-1H-吡啶并[1',2':4,5]吡嗪并[2,1-C][1,4]恶嗪-9-甲酰胺(16)(白色固体,两步收率:26.7%)。The same procedure as in Example 14 was carried out except that 7-(4-fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-pyrido[1] was used. ',2':4,5]pyrazine[2,1-c][1,4]oxazine-9-carboxylic acid (j) instead of 10-(4-fluorophenyl)-1,9-dioxo Generation of 1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylic acid (d) to give N-(4 -(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-7-(4-fluorobenzene ,6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-pyrido[1',2':4,5]pyrazino[2,1-C [1,4]oxazine-9-carboxamide (16) (white solid, two-step yield: 26.7%).
LC-MS(ESI):m/z 693.4[M/M+H
+]。
LC-MS (ESI): m / z 693.4 [M / M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.87(s,1H),8.95–8.86(m,1H),8.78(s,2H),8.26(s,2H),7.95(s,3H),7.48(s,1H),7.42(d,J=8.2Hz,1H),7.16(s,2H),6.75–6.52(m,2H),4.65(s,1H),4.52–4.44(m,1H),4.13(d,J=6.6Hz,2H),3.97(s,3H),3.46(s,2H),3.31–3.28(m,2H),3.13–3.06(m,2H),2.94–2.80(m,2H),2.20(s,4H)。
1 H NMR (400 MHz, DMSO-d 6 ) δ 12.87 (s, 1H), 8.95 - 8.86 (m, 1H), 8.78 (s, 2H), 8.26 (s, 2H), 7.95 (s, 3H), 7.48(s,1H), 7.42 (d, J=8.2Hz, 1H), 7.16(s,2H), 6.75–6.52(m,2H), 4.65(s,1H),4.52–4.44(m,1H) , 4.13 (d, J = 6.6 Hz, 2H), 3.97 (s, 3H), 3.46 (s, 2H), 3.31 - 3.28 (m, 2H), 3.13 - 3.06 (m, 2H), 2.94 - 2.80 (m , 2H), 2.20 (s, 4H).
实施例17:N-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-7-(4-氟苯基)-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酰胺(17)的制备Example 17: N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl) -7-(4-fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyridyl Preparation of oxazolo[2,1-b][1,3]oxazine-9-carboxamide (17)
采用与实施例14相同的方法,除了用7-(4-氟苯基)-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酸(k)代替10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸(d),制得N-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-7-(4-氟苯基)-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酰胺(17)(白色固体,两步收率:29.3%)。The same procedure as in Example 14 was carried out except that 7-(4-fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1] was used. ',2':4,5]pyrazine[2,1-b][1,3]oxazine-9-carboxylic acid (k) instead of 10-(4-fluorophenyl)-1,9-dioxo Generation of 1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylic acid (d) to give N-(4 -(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-7-(4-fluorobenzene ,6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b [1,3]oxazine-9-carboxamide (17) (white solid, two-step yield: 29.3%).
LC-MS(ESI):m/z 693.4[M/M+H
+]。
LC-MS (ESI): m / z 693.4 [M / M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.79(s,1H),9.12(s,1H),8.92(s,1H),8.32–8.17(m,2H),7.98–7.89(m,2H),7.79(s,1H),7.53–7.34(m,2H),7.18(t,J=8.9Hz,2H),7.11(dd,J=8.7,5.8Hz,2H),6.30(s,2H),5.30(t,J=4.0Hz,1H),4.73–4.50(m,2H),4.46(dq,J=10.1,5.2,4.2Hz,1H),4.23(dd,J=13.2,4.4Hz,1H),4.14–3.96(m, 1H),3.88(td,J=11.7,2.8Hz,1H),3.16–3.04(m,3H),2.50(s,1H),2.38–1.83(m,4H),1.75–1.62(m,1H),1.58(d,J=13.1Hz,1H),1.31–1.14(m,1H)。
1H NMR (400MHz, DMSO-d 6 ) δ 12.79 (s, 1H), 9.12 (s, 1H), 8.92 (s, 1H), 8.32–8.17 (m, 2H), 7.98–7.89 (m, 2H) , 7.79 (s, 1H), 7.53 - 7.34 (m, 2H), 7.18 (t, J = 8.9 Hz, 2H), 7.11 (dd, J = 8.7, 5.8 Hz, 2H), 6.30 (s, 2H), 5.30 (t, J = 4.0 Hz, 1H), 4.73 - 4.50 (m, 2H), 4.46 (dq, J = 10.1, 5.2, 4.2 Hz, 1H), 4.23 (dd, J = 13.2, 4.4 Hz, 1H) , 4.14–3.96 (m, 1H), 3.88 (td, J=11.7, 2.8 Hz, 1H), 3.16–3.04 (m, 3H), 2.50 (s, 1H), 2.38–1.83 (m, 4H), 1.75 –1.62 (m, 1H), 1.58 (d, J = 13.1 Hz, 1H), 1.31 - 1.14 (m, 1H).
实施例18:N-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-6,8-二氧代-7-(对甲苯基)-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酰胺(18)的制备Example 18: N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl) -6,8-dioxo-7-(p-tolyl)-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazine Preparation of [2,1-b][1,3]oxazine-9-carboxamide (18)
采用与实施例14相同的方法,除了用6,8-二氧-7-(对甲苯基)-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酸(l)代替10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸(d),制得N-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-6,8-二氧代-7-(对甲苯基)-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酰胺(18)(白色固体,两步收率:19.8%)。The same procedure as in Example 14 was carried out except that 6,8-dioxy-7-(p-tolyl)-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2 was used. ':4,5]pyrazine[2,1-b][1,3]oxazine-9-carboxylic acid (l) instead of 10-(4-fluorophenyl)-1,9-dioxo-1 , 2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepan-8-carboxylic acid (d), N-(4-(2) -amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6,8-dioxo-7- (p-tolyl)-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazine[2,1-b][1,3 Oxazine-9-carboxamide (18) (white solid, two-step yield: 19.8%).
LC-MS(ESI):m/z 689.3[M/M+H
+]。
LC-MS (ESI): m / z 689.3 [M / M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.82(s,1H),8.89(s,1H),8.25(d,J=2.3Hz,1H),8.14(s,1H),7.92–7.73(m,2H),7.54(d,J=2.3Hz,1H),7.48–7.30(m,2H),7.15(d,J=7.9Hz,2H),6.95(s,2H),5.54(s,2H),5.28(t,J=4.0Hz,1H),4.72–4.43(m,2H),4.31–4.02(m,3H),3.91–3.80(m,1H),3.09(d,J=11.6Hz,3H),2.72–2.60(m,2H),2.51(s,2H),2.36(s,3H),2.01(d,J=11.9Hz,2H),1.84(qd,J=12.1,4.0Hz,2H),1.73–1.49(m,1H)。
1 H NMR (400 MHz, DMSO-d 6 ) δ 12.82 (s, 1H), 8.89 (s, 1H), 8.25 (d, J = 2.3 Hz, 1H), 8.14 (s, 1H), 7.92 - 7.73 ( m, 2H), 7.54 (d, J = 2.3 Hz, 1H), 7.48 - 7.30 (m, 2H), 7.15 (d, J = 7.9 Hz, 2H), 6.95 (s, 2H), 5.54 (s, 2H) ), 5.28 (t, J = 4.0 Hz, 1H), 4.72 - 4.43 (m, 2H), 4.31 - 4.02 (m, 3H), 3.91 - 3.80 (m, 1H), 3.09 (d, J = 11.6 Hz, 3H), 2.72–2.60 (m, 2H), 2.51 (s, 2H), 2.36 (s, 3H), 2.01 (d, J = 11.9 Hz, 2H), 1.84 (qd, J = 12.1, 4.0 Hz, 2H) ), 1.73–1.49 (m, 1H).
实施例19:N-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-1,9-二氧代-10-(对甲苯基)-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酰胺(19)的制备Example 19: N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl) -1,9-dioxo-10-(p-tolyl)-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepine Preparation of alkane-8-carboxamide (19)
采用与实施例14相同的方法,除了用1,9-二氧代-10-(对甲苯基)-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸(e)代替10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸(d),制得N-(4-(2-氨基 -5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-1,9-二氧代-10-(对甲苯基)-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酰胺(19)(白色固体,两步收率:26.4%)。The same procedure as in Example 14 was carried out except that 1,9-dioxo-10-(p-tolyl)-1,2,3,4,5,9-hexahydropyrido[1,2-a] was used. [1,4]diazepane-8-carboxylic acid (e) instead of 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexa Hydrogen pyrido[1,2-a][1,4]diazepane-8-carboxylic acid (d) to give N-(4-(2-amino-5-(1-(piperidine)- 4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-1,9-dioxo-10-(p-tolyl)-1,2,3, 4,5,9-Hexidopyrido[1,2-a][1,4]diazepane-8-carboxamide (19) (white solid, two-step yield: 26.4%).
LC-MS(ESI):m/z 647.3[M/M+H
+]。
LC-MS (ESI): m / z 647.3 [M / M + H +].
1H NMR(400MHz,DMSO-d
6)δ13.03(s,1H),8.84(s,1H),8.61(s,1H),8.32(s,1H),8.26(s,1H),8.14(s,1H),7.89(d,J=12.7Hz,1H),7.82(s,1H),7.56(s,1H),7.39(dt,J=16.4,8.3Hz,2H),7.16(dd,J=19.3,7.9Hz,4H),5.55(s,2H),4.63(s,1H),4.26(s,2H),4.05(s,2H),3.16(d,J=11.4Hz,2H),2.77(s,2H),2.34(s,3H),2.23–1.84(m,6H)。
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.0.3 (s, 1H), 8.84 (s, 1H), 8.61 (s, 1H), 8.32 (s, 1H), 8.26 (s, 1H), 8.14 ( s, 1H), 7.89 (d, J = 12.7 Hz, 1H), 7.82 (s, 1H), 7.56 (s, 1H), 7.39 (dt, J = 16.4, 8.3 Hz, 2H), 7.16 (dd, J =19.3, 7.9 Hz, 4H), 5.55 (s, 2H), 4.63 (s, 1H), 4.26 (s, 2H), 4.05 (s, 2H), 3.16 (d, J = 11.4 Hz, 2H), 2.77 (s, 2H), 2.34 (s, 3H), 2.23 - 1.84 (m, 6H).
实施例20:N-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-10-(4-氟苯基)-4-羟基-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-α][1,4]二氮杂环庚烷-8-甲酰胺(20)的制备Example 20: N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl) -10-(4-fluorophenyl)-4-hydroxy-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-α][1,4 Preparation of diazepane-8-carboxamide (20)
采用与实施例14相同的方法,除了用10-(4-氟苯基)-4-羟基-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸(f)代替10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸(d),制得N-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-10-(4-氟苯基)-4-羟基-1,9-二氧代1,2,3,4,5,9六氢吡啶并[1,2-α][1,4]二氮杂环庚烷-8-甲酰胺(20)(白色固体,两步收率:12.4%)。The same procedure as in Example 14 was carried out except that 10-(4-fluorophenyl)-4-hydroxy-1,9-dioxo-1,2,3,4,5,9-hexahydropyridyl[ 1,2-a][1,4]diazepane-8-carboxylic acid (f) instead of 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4 ,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylic acid (d), to give N-(4-(2-amino-5-( 1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-10-(4-fluorophenyl)-4-hydroxy-1, 9-dioxo 1,2,3,4,5,9 hexahydropyrido[1,2-α][1,4]diazepane-8-carboxamide (20) (white solid, Two-step yield: 12.4%).
LC-MS(ESI):m/z 667.3[M/M+H
+]。
LC-MS (ESI): m / z 667.3 [M / M + H +].
1H NMR(400MHz,DMSO-d
6)δ13.09–12.99(m,1H),9.01–8.86(m,2H),8.85–8.77(m,1H),8.38(s,1H),8.30–8.18(m,1H),8.05(s,2H),7.58–7.44(m,2H),7.22(s,4H),5.83–5.59(m,2H),5.39–5.23(m,1H),4.58–4.41(m,2H),4.34–4.24(m,2H),3.13–3.06(m,2H),2.96–2.86(m,1H),2.34–2.10(m,4H),0.84–0.71(m,4H)。
1 H NMR (400MHz, DMSO- d 6) δ13.09-12.99 (m, 1H), 9.01-8.86 (m, 2H), 8.85-8.77 (m, 1H), 8.38 (s, 1H), 8.30-8.18 (m, 1H), 8.05 (s, 2H), 7.58–7.44 (m, 2H), 7.22 (s, 4H), 5.83–5.59 (m, 2H), 5.39–5.23 (m, 1H), 4.58–4.41 (m, 2H), 4.34–4.24 (m, 2H), 3.13–3.06 (m, 2H), 2.96–2.86 (m, 1H), 2.34–2.10 (m, 4H), 0.84–0.71 (m, 4H) .
实施例21:(4R)-N-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-7-(4-氟苯基)-4-甲基-6,8-二氧代-3,4,6,8,12,12a六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酰胺(21)的制备Example 21: (4R)-N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3- Fluorophenyl)-7-(4-fluorophenyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a hexahydro-2H-pyrido[1', Preparation of 2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide (21)
采用与实施例14相同的方法,除了用(4R)-7-(4-氟苯基)-4-甲基-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酸(s)代替10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸(d),制得(4R)-N-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-7-(4-氟苯基)-4-甲基-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酰胺(21)(白色固体,两步收率:12.4%)。The same procedure as in Example 14 was employed except that (4R)-7-(4-fluorophenyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a- Hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (s) in place of 10-(4-fluorobenzene) -1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylic acid ( d), (4R)-N-(4-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3 -fluorophenyl)-7-(4-fluorophenyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1 ', 2': 4,5] pyrazino[2,1-b][1,3]oxazine-9-carboxamide (21) (white solid, two-step yield: 12.4%).
LC-MS(ESI):m/z 707.3[M/M+H
+]。
LC-MS (ESI): m / z 707.3 [M / M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.78(s,1H),8.91(s,1H),8.31(s,1H),8.26(s,1H),8.14(s,1H),7.90(d,J=12.5Hz,1H),7.82(s,1H),7.55(s,1H),7.45(d,J=8.7Hz,1H),7.37(d,J=8.4Hz,1H),7.17(s,3H),5.55(s,2H),5.46(s,1H),4.73(d,J=10.3Hz,1H),4.52(d,J=25.2Hz,2H),4.31–4.23(m,1H),3.99(s,1H),3.18(s,2H),2.78(s,2H),1.98(d,J=49.3Hz,6H),1.22(d,J=6.8Hz,3H)。
1 H NMR (400MHz, DMSO- d 6) δ12.78 (s, 1H), 8.91 (s, 1H), 8.31 (s, 1H), 8.26 (s, 1H), 8.14 (s, 1H), 7.90 ( d, J = 12.5 Hz, 1H), 7.82 (s, 1H), 7.55 (s, 1H), 7.45 (d, J = 8.7 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.17 ( s, 3H), 5.55 (s, 2H), 5.46 (s, 1H), 4.73 (d, J = 10.3 Hz, 1H), 4.52 (d, J = 25.2 Hz, 2H), 4.31 - 4.23 (m, 1H) ), 3.99 (s, 1H), 3.18 (s, 2H), 2.78 (s, 2H), 1.98 (d, J = 49.3 Hz, 6H), 1.22 (d, J = 6.8 Hz, 3H).
实施例22:N-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-9-(4-氟苯基)-1,8-二氧代-1,3,4,8-四氢-2H-吡啶并[1,2-a]吡嗪-7-甲酰胺(22)的制备Example 22: N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl) -9-(4-Fluorophenyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide (22 Preparation
采用与实施例14相同的方法,除了用9-(4-氟苯基)-1,8-二氧代-1,3,4,8-四氢-2H-吡啶并[1,2-a]吡嗪-7-羧酸(t)代替10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸(d),制得N-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-9-(4-氟苯基)-1,8-二氧代1,3,4,8-四氢-2H-吡啶并[1,2-a]吡嗪-7-甲酰胺(22)(白色固体,两步收率:36.8%)。The same procedure as in Example 14 was carried out except that 9-(4-fluorophenyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a was used. Pyrazin-7-carboxylic acid (t) in place of 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyridyl[1,2 -a][1,4]diazepan-8-carboxylic acid (d) to give N-(4-(2-amino-5-(1-(piperidin-4-yl)-1H-) Pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-9-(4-fluorophenyl)-1,8-dioxo 1,3,4,8-tetrahydro-2H - Pyrido[1,2-a]pyrazine-7-carboxamide (22) (white solid, two-step yield: 36.8%).
LC-MS(ESI):m/z 637.3[M/M+H
+]。
LC-MS (ESI): m / z 637.3 [M / M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.93(s,1H),8.86(s,1H),8.77(s,1H),8.28(d,J=18.0Hz,2H),8.15(s,1H),7.90(d,J=12.3Hz,1H),7.82(s,1H),7.55(s,1H),7.49–7.33(m,2H),7.26–7.07(m,4H),5.55(s,2H),4.46(s,2H),4.27(s,1H),3.61(s,2H),3.47–3.40(m,1H),3.18(d,J=12.2Hz,2H),2.80(d,J=12.0Hz,2H),1.99(d,J=49.9Hz,4H)。
1 H NMR (400MHz, DMSO- d 6) δ12.93 (s, 1H), 8.86 (s, 1H), 8.77 (s, 1H), 8.28 (d, J = 18.0Hz, 2H), 8.15 (s, 1H), 7.90 (d, J = 12.3 Hz, 1H), 7.82 (s, 1H), 7.55 (s, 1H), 7.49 - 7.33 (m, 2H), 7.26 - 7.07 (m, 4H), 5.55 (s , 2H), 4.46 (s, 2H), 4.27 (s, 1H), 3.61 (s, 2H), 3.47 - 3.40 (m, 1H), 3.18 (d, J = 12.2 Hz, 2H), 2.80 (d, J = 12.0 Hz, 2H), 1.99 (d, J = 49.9 Hz, 4H).
实施例23:N-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-甲酰胺(23)的制备Example 23: N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl) -6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2- d] Preparation of pyrazine-8-carboxamide (23)
采用与实施例14相同的方法,除了用6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-羧酸(o)代替10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸(d),制得N-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-甲酰胺(23)(白色固体,两步收率:22.8%)。The same procedure as in Example 14 was carried out except that 6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazole [3,2 -a]pyrido[1,2-d]pyrazine-8-carboxylic acid (o) instead of 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5 , 9-hexahydropyrido[1,2-a][1,4]diazepan-8-carboxylic acid (d), to obtain N-(4-(2-amino-5-(1-) (piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-(4-fluorophenyl)-5,7-dioxo- 2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (23) (white solid, two-step Rate: 22.8%).
LC-MS(ESI):m/z 679.3[M/M+H
+]。
LC-MS (ESI): m / z 679.3 [M / M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.78(s,1H),8.88(s,1H),8.37–8.23(m,2H),8.15(s,1H),7.96–7.76(m,2H),7.56(s,1H),7.53–7.34(m,2H),7.20(s,3H),5.56(s,2H),4.96(d,J=8.9Hz,1H),4.33(dd,J=18.0,9.7Hz,2H),4.16(dd,J=14.1,8.1Hz,2H),3.74–3.61(m,2H),3.50–3.40(m,2H),3.20(d,J=12.5Hz,2H),2.82(t,J=11.2Hz,2H),2.18–1.87(m,4H)。
1 H NMR (400MHz, DMSO- d 6) δ12.78 (s, 1H), 8.88 (s, 1H), 8.37-8.23 (m, 2H), 8.15 (s, 1H), 7.96-7.76 (m, 2H ), 7.56 (s, 1H), 7.53 - 7.34 (m, 2H), 7.20 (s, 3H), 5.56 (s, 2H), 4.96 (d, J = 8.9 Hz, 1H), 4.33 (dd, J = 18.0, 9.7 Hz, 2H), 4.16 (dd, J = 14.1, 8.1 Hz, 2H), 3.74 - 3.61 (m, 2H), 3.50 - 3.40 (m, 2H), 3.20 (d, J = 12.5 Hz, 2H) ), 2.82 (t, J = 11.2 Hz, 2H), 2.18 - 1.87 (m, 4H).
实施例24:(3R)-N-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-6-(4-氟苯基)-3-甲基-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-甲酰胺(24)的制备Example 24: (3R)-N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3- Fluorophenyl)-6-(4-fluorophenyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazole[3,2- Preparation of a] pyrido[1,2-d]pyrazine-8-carboxamide (24)
采用与实施例14相同的方法,除了用(3R)-6-(4-氟苯基)-3-甲基-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-羧酸(q)代替10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸(d),制得(3R)-N-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-6-(4-氟苯基)-3-甲基-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-甲酰胺(24)(白色固体,两步收率:20.5%)。The same procedure as in Example 14 was employed except that (3R)-6-(4-fluorophenyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a- Hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (q) in place of 10-(4-fluorophenyl)-1,9-dioxo- 1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylic acid (d), (3R)-N- (4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-(4- Fluorophenyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d Pyrazine-8-carboxamide (24) (white solid, two-step yield: 20.5%).
LC-MS(ESI):m/z 693.4[M/M+H
+]。
LC-MS (ESI): m / z 693.4 [M / M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.78(s,1H),8.88(s,1H),8.37–8.23(m,2H),8.15(s,1H),7.96–7.76(m,2H),7.56(s,1H),7.53–7.34(m,2H),7.20(s,3H),5.56(s,2H),4.96(d,J=8.9Hz,1H),4.33(dd,J=18.0,9.7Hz,2H),4.16(dd,J=14.1,8.1Hz,2H),3.74–3.61(m,2H),3.50–3.40(m,1H),3.20(d,J=12.5Hz,2H),2.82(t,J=11.2Hz,2H),2.18–1.87(m,4H),1.21(t,J=9.9Hz,3H)。
1 H NMR (400MHz, DMSO- d 6) δ12.78 (s, 1H), 8.88 (s, 1H), 8.37-8.23 (m, 2H), 8.15 (s, 1H), 7.96-7.76 (m, 2H ), 7.56 (s, 1H), 7.53 - 7.34 (m, 2H), 7.20 (s, 3H), 5.56 (s, 2H), 4.96 (d, J = 8.9 Hz, 1H), 4.33 (dd, J = 18.0, 9.7 Hz, 2H), 4.16 (dd, J = 14.1, 8.1 Hz, 2H), 3.74 - 3.61 (m, 2H), 3.50 - 3.40 (m, 1H), 3.20 (d, J = 12.5 Hz, 2H) ), 2.82 (t, J = 11.2 Hz, 2H), 2.18 - 1.87 (m, 4H), 1.21 (t, J = 9.9 Hz, 3H).
实施例25:N-(4-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)-3-氟苯基)-6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-甲酰胺(25)的制备Example 25: N-(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-3-fluorophenyl)-6-(4-fluorophenyl) )-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide Preparation of (25)
采用与实施例23相同的方法,除了用3-(4-氨基-2-氟苯基)-5-(3,4-二甲氧基苯基)吡啶-2-胺(x)代替4-(4-(6-氨基-5-(4-氨基-2-氟苯基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(u),制得N-(4-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)-3-氟苯基)-6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-甲酰胺(25)(白色固体,一步收率:40.2%)。The same procedure as in Example 23 was carried out except that 3-(4-amino-2-fluorophenyl)-5-(3,4-dimethoxyphenyl)pyridin-2-amine (x) was used instead of 4- (4-(6-Amino-5-(4-amino-2-fluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (u), Preparation of N-(4-(2-amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-3-fluorophenyl)-6-(4-fluorophenyl)- 5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (25 (white solid, one step yield: 40.2%).
LC-MS(ESI):m/z 666.2[M/M+H
+]。
LC-MS (ESI): m / z 666.2 [M / M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.76(s,1H),8.87(d,J=9.0Hz,1H),8.29(d,J=2.4Hz,1H),7.89(dd,J=12.2,2.0Hz,1H),7.60(d,J=2.4Hz,1H),7.49–7.38(m,2H),7.28–7.02(m,6H),6.97(d,J=8.4Hz,1H),5.66(s,2H),5.46(dd,J=10.0,3.5Hz,1H),4.97(dt,J=12.4,3.4Hz,1H),4.27–4.12(m,2H),4.08–3.98(m,1H),3.85–3.74(m,6H),3.67(dt,J=11.2,7.4Hz,1H),3.47(dd,J=6.7,4.2Hz,1H)。
1 H NMR (400MHz, DMSO- d 6) δ12.76 (s, 1H), 8.87 (d, J = 9.0Hz, 1H), 8.29 (d, J = 2.4Hz, 1H), 7.89 (dd, J = 12.2, 2.0 Hz, 1H), 7.60 (d, J = 2.4 Hz, 1H), 7.49 - 7.38 (m, 2H), 7.28 - 7.02 (m, 6H), 6.97 (d, J = 8.4 Hz, 1H), 5.66(s, 2H), 5.46 (dd, J = 10.0, 3.5 Hz, 1H), 4.97 (dt, J = 12.4, 3.4 Hz, 1H), 4.27 - 4.12 (m, 2H), 4.08 - 3.98 (m, 1H), 3.85 - 3.74 (m, 6H), 3.67 (dt, J = 11.2, 7.4 Hz, 1H), 3.47 (dd, J = 6.7, 4.2 Hz, 1H).
实施例26:N-(4-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)-3-氟苯基)-10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-α][1,4]二氮杂环庚烷-8-甲酰胺(26)的制备Example 26: N-(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-3-fluorophenyl)-10-(4-fluorophenyl) -1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-α][1,4]diazepane-8-carboxamide ( Preparation of 26)
采用与实施例14相同的方法,除了用3-(4-氨基-2-氟苯基)-5-(3,4-二甲氧基苯基)吡啶-2-胺(x)代替4-(4-(6-氨基-5-(4-氨基-2-氟苯基)吡啶-3-基)-1H-吡唑-1-基)哌 啶-1-甲酸叔丁酯(u),制得N-(4-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)-3-氟苯基)-10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-α][1,4]二氮杂环庚烷-8-甲酰胺(26)(白色固体,一步收率:43.2%)。The same procedure as in Example 14 was carried out except that 3-(4-amino-2-fluorophenyl)-5-(3,4-dimethoxyphenyl)pyridin-2-amine (x) was used instead of 4- (4-(6-Amino-5-(4-amino-2-fluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (u), Preparation of N-(4-(2-amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-3-fluorophenyl)-10-(4-fluorophenyl)- 1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-α][1,4]diazepane-8-carboxamide (26) (white solid, one step yield: 43.2%).
LC-MS(ESI):m/z 638.4[M/M+H
+]。
LC-MS (ESI): m / z 638.4 [M / M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.95(s,1H),8.85(s,1H),8.67(t,J=6.5Hz,1H),8.29(d,J=2.4Hz,1H),7.89(dd,J=12.3,1.8Hz,1H),7.60(d,J=2.4Hz,1H),7.51–7.39(m,2H),7.29(ddd,J=9.0,5.7,2.7Hz,2H),7.25–7.05(m,4H),6.98(d,J=8.3Hz,1H),5.66(s,2H),4.65(d,J=9.9Hz,1H),4.06(s,1H),3.79(d,J=20.3Hz,6H),2.09(d,J=47.6Hz,4H)。
1 H NMR (400MHz, DMSO- d 6) δ12.95 (s, 1H), 8.85 (s, 1H), 8.67 (t, J = 6.5Hz, 1H), 8.29 (d, J = 2.4Hz, 1H) , 7.89 (dd, J = 12.3, 1.8 Hz, 1H), 7.60 (d, J = 2.4 Hz, 1H), 7.51 - 7.39 (m, 2H), 7.29 (ddd, J = 9.0, 5.7, 2.7 Hz, 2H ), 7.25 - 7.05 (m, 4H), 6.98 (d, J = 8.3 Hz, 1H), 5.66 (s, 2H), 4.65 (d, J = 9.9 Hz, 1H), 4.06 (s, 1H), 3.79 (d, J = 20.3 Hz, 6H), 2.09 (d, J = 47.6 Hz, 4H).
实施例27:N-(4-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)苯基)-1,9-二氧代-10-(对-甲苯基)-1,2,3,4,5,9-六氢吡啶并[1,2-α][1,4]二氮杂环庚烷-8-甲酰胺(27)的制备Example 27: N-(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)-1,9-dioxo-10-(pair Of -tolyl)-1,2,3,4,5,9-hexahydropyrido[1,2-α][1,4]diazepane-8-carboxamide (27)
采用与实施例19相同的方法,除了用3-(4-氨基-2-甲苯基)-5-(3,4-二甲氧基苯基)吡啶-2-胺(aa)代替4-(4-(6-氨基-5-(4-氨基-2-氟苯基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(u),制得N-(4-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)苯基)-1,9-二氧代-10-(对-甲苯基)-1,2,3,4,5,9-六氢吡啶并[1,2-α][1,4]二氮杂环庚烷-8-甲酰胺(27)(白色固体,一步收率:37.9%)。The same procedure as in Example 19 was carried out except that 3-(4-amino-2-methylphenyl)-5-(3,4-dimethoxyphenyl)pyridin-2-amine (aa) was used instead of 4-( 4-(6-Amino-5-(4-amino-2-fluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (u), made N-(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)-1,9-dioxo-10-(p-tolyl) -1,2,3,4,5,9-hexahydropyrido[1,2-α][1,4]diazepane-8-carboxamide (27) (white solid, one step Rate: 37.9%).
LC-MS(ESI):m/z 616.4[M/M+H
+]。
LC-MS (ESI): m / z 616.4 [M / M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.88(s,1H),8.82(s,1H),8.60(s,1H),8.25(d,J=2.1Hz,1H),7.80(d,J=8.4Hz,2H),7.61(s,1H),7.53(d,J=8.4Hz,2H),7.19–7.13(m,4H),6.99(d,J=8.3Hz,1H),5.67(s,2H),4.63(s,1H),4.14–3.98(m,1H),3.80(d,J=22.3Hz,6H),2.34(s,3H),2.02(s,2H)。
1 H NMR (400MHz, DMSO- d 6) δ12.88 (s, 1H), 8.82 (s, 1H), 8.60 (s, 1H), 8.25 (d, J = 2.1Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.61 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.19 - 7.13 (m, 4H), 6.99 (d, J = 8.3 Hz, 1H), 5.67 ( s, 2H), 4.63 (s, 1H), 4.14 - 3.98 (m, 1H), 3.80 (d, J = 22.3 Hz, 6H), 2.34 (s, 3H), 2.02 (s, 2H).
实施例28:(3R)-N-(4-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)苯基)-6-(4-氟苯基)-3-甲基-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-甲酰胺(28)的制备Example 28: (3R)-N-(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)-6-(4-fluorophenyl) )-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine Preparation of -8-carboxamide (28)
采用与实施例27相同的方法,除了用(3R)-6-(4-氟苯基)-3-甲基-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-羧酸(q)代替1,9-二氧代-10-(对甲苯基)-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸(e),制得(3R)-N-(4-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)苯基)-6-(4-氟苯基)-3-甲基-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-甲酰胺(28)(白色固体,一步收率:26.8%)。The same procedure as in Example 27 was employed except that (3R)-6-(4-fluorophenyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a- Instead of 1,9-dioxo-10-(p-tolyl)-1, hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (q) 2,3,4,5,9-Hexidopyrido[1,2-a][1,4]diazepane-8-carboxylic acid (e), (3R)-N-(4) -(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)-6-(4-fluorophenyl)-3-methyl-5,7-di Oxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (28) (white solid, One step yield: 26.8%).
LC-MS(ESI):m/z 662.3[M/M+H
+]。
LC-MS (ESI): m / z 662.3 [M / M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.64(s,1H),8.87(s,1H),8.33(d,J=58.4Hz,2H),7.81(d,J=8.2Hz,2H),7.67–7.37(m,3H),7.41–6.95(m,6H),5.66(s,2H),5.55(d,J=6.6Hz,1H),4.95(d,J=9.2Hz,1H),4.40–4.30(m,1H),4.15(t,J=10.6Hz,2H),3.80(d,J=22.0Hz,6H),3.70–3.61(m,1H),1.21(t,J=10.0Hz,3H)。
1 H NMR (400MHz, DMSO- d 6) δ12.64 (s, 1H), 8.87 (s, 1H), 8.33 (d, J = 58.4Hz, 2H), 7.81 (d, J = 8.2Hz, 2H) , 7.67–7.37 (m, 3H), 7.41–6.95 (m, 6H), 5.66 (s, 2H), 5.55 (d, J = 6.6 Hz, 1H), 4.95 (d, J = 9.2 Hz, 1H), 4.40–4.30 (m, 1H), 4.15 (t, J = 10.6 Hz, 2H), 3.80 (d, J = 22.0 Hz, 6H), 3.70–3.61 (m, 1H), 1.21 (t, J = 10.0 Hz) , 3H).
实施例29:(3S)-N-(4-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)苯基)-6-(4-氟苯基)-3-甲基-5,7-二氧代2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-甲酰胺(29)的制备Example 29: (3S)-N-(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)-6-(4-fluorophenyl) )-3-methyl-5,7-dioxo 2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine- Preparation of 8-formamide (29)
采用与实施例28相同的方法,除了用(3S)-6-(4-氟苯基)-3-甲基-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-羧酸(r)代替1,9-二氧代-10-(对甲苯基)-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸(e),制得(3S)-N-(4-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)苯基)-6-(4-氟苯基)-3-甲基-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-甲酰胺(29)(白色固体,一步收率:25.3%)。The same procedure as in Example 28 was employed except that (3S)-6-(4-fluorophenyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a- Hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (r) in place of 1,9-dioxo-10-(p-tolyl)-1, 2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylic acid (e), (3S)-N-(4) -(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)-6-(4-fluorophenyl)-3-methyl-5,7-di Oxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (29) (white solid, One step yield: 25.3%).
LC-MS(ESI):m/z 662.3[M/M+H
+]。
LC-MS (ESI): m / z 662.3 [M / M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.64(s,1H),8.87(s,1H),8.25(s,2H),7.81(d,J=8.4Hz,2H),7.65–7.48(m,3H),7.36–7.08(m,5H),6.99(d,J=8.4Hz,1H),5.66(s,2H),5.55(d,J=6.5Hz,1H),4.95(d,J=8.9Hz,1H),4.40–4.25(m,1H),4.25–4.05(m,2H),3.80(d,J=22.0Hz,6H),3.71–3.58(m,1H),1.20(d,J=6.2Hz,3H)。
1 H NMR (400MHz, DMSO- d 6) δ12.64 (s, 1H), 8.87 (s, 1H), 8.25 (s, 2H), 7.81 (d, J = 8.4Hz, 2H), 7.65-7.48 ( m, 3H), 7.36 - 7.08 (m, 5H), 6.99 (d, J = 8.4 Hz, 1H), 5.66 (s, 2H), 5.55 (d, J = 6.5 Hz, 1H), 4.95 (d, J = 8.9 Hz, 1H), 4.40 - 4.25 (m, 1H), 4.25 - 4.05 (m, 2H), 3.80 (d, J = 22.0 Hz, 6H), 3.71 - 3.58 (m, 1H), 1.20 (d, J = 6.2 Hz, 3H).
实施例30:N-(4-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)-2,5-二氟苯基)-6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-甲酰胺(30)的制备Example 30: N-(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-2,5-difluorophenyl)-6-(4- Fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8 - Preparation of formamide (30)
步骤1:3-(4-氨基-2,5-二氟苯基)-5-(3,4-二甲氧基苯基)吡啶-2-胺(中间体30a)的制备Step 1: Preparation of 3-(4-amino-2,5-difluorophenyl)-5-(3,4-dimethoxyphenyl)pyridin-2-amine (Intermediate 30a)
于室温,在含有(10mL)1,4-二氧六环和水的混合液(4:1)的反应瓶中加入3-溴-5-(3,4-二甲氧基苯基)吡啶-2-胺(参照WO2013115280第130页实施例30制备)(500mg,1.62mmol)、4-氨基-2,5-二氟苯硼酸频那醇酯(619mg,2.43mmol)、碳酸钾(671mg,4.86mmol)、Pd(dppf)Cl
2.DCM(130mg,0.16mmol)。密封,氮气置换三次,加热至90℃并搅拌过夜。待反应完全后,过滤,滤液用水(20mL)稀释,乙酸乙酯萃取(20mL×3),合并有机相。将有机相用饱和的食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱液为PE:EA/1:2),得到3-(4-氨基-2,5-二氟苯基)-5-(3,4-二甲氧基苯基)吡啶-2-胺(中间体30a)(400mg,黄色固体,收率:69.1%)。
3-bromo-5-(3,4-dimethoxyphenyl)pyridine was added to a reaction flask containing (10 mL) a mixture of 1,4-dioxane and water (4:1) at room temperature. 2-Amine (prepared according to Example 30 of WO2013115280, page 130) (500 mg, 1.62 mmol), 4-amino-2,5-difluorophenylboronic acid pinacol ester (619 mg, 2.43 mmol), potassium carbonate (671 mg, 4.86 mmol), Pd(dppf)Cl 2 .DCM (130 mg, 0.16 mmol). Sealed, replaced with nitrogen three times, heated to 90 ° C and stirred overnight. After the reaction was completed, it was filtered, and the filtrate was diluted with water (20mL), ethyl acetate (20mL × 3), and the organic phase was combined. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography (eluent: EtOAc/EtOAc: EtOAc) Methoxyphenyl)pyridin-2-amine (Intermediate 30a) (400 mg, yellow solid, yield: 69.1%).
LC-MS(ESI):m/z358.2[M/M+H
+]
LC-MS (ESI): m/z 358.2 [M/M+H + ]
步骤2:N-(4-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)-2,5-二氟苯基)-6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-甲酰胺(30)的制备Step 2: N-(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-2,5-difluorophenyl)-6-(4-fluoro Phenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8- Preparation of formamide (30)
在含有DMF(4mL)的反应瓶中加入6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-羧酸(o)(45mg,0.13mmol)、3-(4-氨基-2,5-二氟苯基)-5-(3,4-二甲氧基苯基)吡啶-2-胺(30a)(57mg,0.16mmol)、HATU(63mg, 0.17mmol)和DIPEA(50mg,0.33mmol)。将混合物于室温搅拌30分钟,待反应完全后,加入饱和的碳酸氢钠溶液淬灭,用乙酸乙酯萃取(10mLx3),合并有机相。将有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,残余物通过制备HPLC纯化(C18,乙腈/水(0.1%甲酸):10%~100%),得到N-(4-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)-2,5-二氟苯基)-6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-甲酰胺(30)(16mg,白色固体,收率:18.0%)。Add 6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazole [3,2] to a reaction flask containing DMF (4 mL). -a] Pyrido[1,2-d]pyrazine-8-carboxylic acid (o) (45 mg, 0.13 mmol), 3-(4-amino-2,5-difluorophenyl)-5-(3 4-Dimethoxyphenyl)pyridin-2-amine (30a) (57 mg, 0.16 mmol), HATU (63 mg, 0.17 mmol) and DIPEA (50 mg, 0.33 mmol). The mixture was stirred at room temperature for 30 minutes. After the reaction was completed, EtOAc (EtOAc) The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated,,,,,,,,,,,, (4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-2,5-difluorophenyl)-6-(4-fluorophenyl)-5 ,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (30) (16 mg, white solid, yield: 18.0%).
LC-MS(ESI):m/z 684.2[M/M+H
+]。
LC-MS (ESI): m / z 684.2 [M / M + H +].
1H NMR(400MHz,DMSO-d
6)δ13.06(s,1H),8.91(s,1H),8.44(dd,J=11.6,6.5Hz,1H),8.30(d,J=2.4Hz,1H),7.63(d,J=2.5Hz,1H),7.44(dd,J=11.1,6.7Hz,1H),7.33–7.03(m,6H),6.98(d,J=8.4Hz,1H),5.80(s,2H),5.46(dd,J=10.0,3.6Hz,1H),4.99(dd,J=12.4,3.7Hz,1H),4.26–4.13(m,2H),4.03(q,J=7.6Hz,1H),3.81(s,3H),3.76(s,3H),3.67(dt,J=11.0,7.4Hz,1H),3.46(td,J=6.7,3.3Hz,1H)。
1 H NMR (400MHz, DMSO- d 6) δ13.06 (s, 1H), 8.91 (s, 1H), 8.44 (dd, J = 11.6,6.5Hz, 1H), 8.30 (d, J = 2.4Hz, 1H), 7.63 (d, J = 2.5 Hz, 1H), 7.44 (dd, J = 11.1, 6.7 Hz, 1H), 7.33 - 7.03 (m, 6H), 6.98 (d, J = 8.4 Hz, 1H), 5.80(s, 2H), 5.46 (dd, J = 10.0, 3.6 Hz, 1H), 4.99 (dd, J = 12.4, 3.7 Hz, 1H), 4.26 - 4.13 (m, 2H), 4.03 (q, J = 7.6 Hz, 1H), 3.81 (s, 3H), 3.76 (s, 3H), 3.67 (dt, J = 11.0, 7.4 Hz, 1H), 3.46 (td, J = 6.7, 3.3 Hz, 1H).
实施例31:N-(4-(2-氨基-5-(1-乙基-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-甲酰胺(31)的制备Example 31: N-(4-(2-Amino-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-(4- Fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8 - Preparation of formamide (31)
采用与实施例30相同的方法,除了用3-(4-氨基-2-氟苯基)-5-(1-乙基-1H-吡唑-4-基)吡啶-2-胺(v)代替3-(4-氨基-2,5-二氟苯基)-5-(3,4-二甲氧基苯基)吡啶-2-胺(30a),制得N-(4-(2-氨基-5-(1-乙基-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-甲酰胺(31)(白色固体,一步收率:31.2%)。The same procedure as in Example 30 was employed except that 3-(4-amino-2-fluorophenyl)-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-2-amine (v) Instead of 3-(4-amino-2,5-difluorophenyl)-5-(3,4-dimethoxyphenyl)pyridin-2-amine (30a), N-(4-(2) was obtained. -amino-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-(4-fluorophenyl)-5,7-dioxo Generation-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (31) (white solid, one step Yield: 31.2%).
LC-MS(ESI):m/z 624.3[M/M+H
+]。
LC-MS (ESI): m / z 624.3 [M / M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.76(s,1H),8.88(s,1H),8.24(d,J=2.3Hz,1H),8.08(s,1H),7.89(dd,J=12.3,2.1Hz,1H),7.77(s,1H),7.51(d,J=2.4Hz,1H),7.45(dd,J=8.4,2.1Hz,1H),7.37(t,J=8.4Hz,1H),7.19(s,4H),5.53(s,2H),5.46(dd,J=10.0,3.6Hz,1H),4.98(dd,J=12.4,3.7Hz,1H),4.32–3.97(m,5H),3.67(dt,J=11.0,7.3Hz,1H),3.46(ddd,J=11.0,6.7,4.1Hz,1H),1.38(t,J=7.3Hz,3H)。
1 H NMR (400MHz, DMSO- d 6) δ12.76 (s, 1H), 8.88 (s, 1H), 8.24 (d, J = 2.3Hz, 1H), 8.08 (s, 1H), 7.89 (dd, J = 12.3, 2.1 Hz, 1H), 7.77 (s, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7.45 (dd, J = 8.4, 2.1 Hz, 1H), 7.37 (t, J = 8.4) Hz, 1H), 7.19 (s, 4H), 5.53 (s, 2H), 5.46 (dd, J = 10.0, 3.6 Hz, 1H), 4.98 (dd, J = 12.4, 3.7 Hz, 1H), 4.32 - 3.97 (m, 5H), 3.67 (dt, J = 11.0, 7.3 Hz, 1H), 3.46 (ddd, J = 11.0, 6.7, 4.1 Hz, 1H), 1.38 (t, J = 7.3 Hz, 3H).
实施例32:N-(4-(2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-1,9-二氧代-10-(对甲苯基)-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酰胺(32)的制备Example 32: N-(4-(2-Amino-5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-1,9-di Oxo-10-(p-tolyl)-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxamide Preparation of (32)
采用与实施例31相同的方法,除了用1,9-二氧代-10-(对甲苯基)-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸(e)代替6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-羧酸(o),制得N-(4-(2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-1,9-二氧代-10-(对甲苯基)-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酰胺(32)(白色固体,一步收率:33.7%)。The same procedure as in Example 31 was employed except that 1,9-dioxo-10-(p-tolyl)-1,2,3,4,5,9-hexahydropyrido[1,2-a] was used. [1,4]diazepane-8-carboxylic acid (e) in place of 6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-six N-(4-(2-amino-5-(1-methyl)-hydrocarbazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (o) -1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-1,9-dioxo-10-(p-tolyl)-1,2,3,4,5, 9-Hexidopyrido[1,2-a][1,4]diazepane-8-carboxamide (32) (white solid, one step yield: 33.7%).
LC-MS(ESI):m/z 592.3[M/M+H
+]。
LC-MS (ESI): m / z 592.3 [M / M + H +].
1H NMR(400MHz,DMSO-d
6)δ13.03(s,1H),8.84(s,1H),8.61(s,1H),8.24(s,1H),8.10(s,1H),7.89(d,J=12.2Hz,1H),7.79(s,1H),7.54(s,1H),7.40(dt,J=16.3,8.2Hz,2H),7.16(dd,J=19.1,7.9Hz,4H),5.58(s,2H),4.63(s,1H),4.11(dd,J=14.5,7.3Hz,2H),3.34(s,2H),2.97(s,1H),2.34(s,3H),2.10(d,J=47.9Hz,2H),1.39(t,J=7.3Hz,3H)。
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.03 (s, 1H), 8.84 (s, 1H), 8.61 (s, 1H), 8.24 (s, 1H), 8.10 (s, 1H), 7.89 ( d, J = 12.2 Hz, 1H), 7.79 (s, 1H), 7.54 (s, 1H), 7.40 (dt, J = 16.3, 8.2 Hz, 2H), 7.16 (dd, J = 19.1, 7.9 Hz, 4H) ), 5.58 (s, 2H), 4.63 (s, 1H), 4.11 (dd, J = 14.5, 7.3 Hz, 2H), 3.34 (s, 2H), 2.97 (s, 1H), 2.34 (s, 3H) , 2.10 (d, J = 47.9 Hz, 2H), 1.39 (t, J = 7.3 Hz, 3H).
实施例33:N-(4-(2-氨基-5-(1-乙基-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-6,8-二氧代-7-(对甲苯基)-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酰胺(33)的制备Example 33: N-(4-(2-Amino-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6,8-di Oxo-7-(p-tolyl)-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b Preparation of [1,3]oxazine-9-carboxamide (33)
采用与实施例31相同的方法,除了用6,8-二氧代-7-(对甲苯基)-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酸(l)代替6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-羧酸(o),制得N-(4-(2-氨基-5-(1-乙基-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-6,8-二氧代-7-(对甲苯基)-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酰胺(33)(白色固体,一步收率:26.7%)。The same procedure as in Example 31 was employed except that 6,8-dioxo-7-(p-tolyl)-3,4,6,8,12,12a-hexahydro-2H-pyrido[1', 2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (l) instead of 6-(4-fluorophenyl)-5,7-dioxo- 2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (o), N-(4) -(2-Amino-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6,8-dioxo-7-(p-toluene -3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine -9-carboxamide (33) (white solid, one step yield: 26.7%).
LC-MS(ESI):m/z 634.2[M/M+H
+]。
LC-MS (ESI): m / z 634.2 [M / M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.82(s,1H),8.89(s,1H),8.24(d,J=2.3Hz,1H),8.09(s,1H),7.88(dd,J=12.3,1.9Hz,1H),7.78(s,1H),7.52(d,J=2.3Hz,1H),7.49–7.29(m,2H),7.15(d,J=7.9Hz,2H),6.96(d,J=6.2Hz,2H),5.54(s,2H),5.34–5.24(m,1H),4.74–4.52(m,2H),4.27–4.17(m,1H),4.15–4.02(m,3H),3.87(dd,J=12.9,10.1Hz,1H),3.09(dd,J=12.6,3.5Hz,1H),2.36(s,3H),1.78–1.47(m, 1H),1.38(t,J=7.2Hz,3H),1.32–1.17(m,1H)。
1 H NMR (400MHz, DMSO- d 6) δ12.82 (s, 1H), 8.89 (s, 1H), 8.24 (d, J = 2.3Hz, 1H), 8.09 (s, 1H), 7.88 (dd, J = 12.3, 1.9 Hz, 1H), 7.78 (s, 1H), 7.52 (d, J = 2.3 Hz, 1H), 7.49 - 7.29 (m, 2H), 7.15 (d, J = 7.9 Hz, 2H), 6.96 (d, J = 6.2 Hz, 2H), 5.54 (s, 2H), 5.34 - 5.24 (m, 1H), 4.74 - 4.52 (m, 2H), 4.27 - 4.17 (m, 1H), 4.15 - 4.02 ( m,3H), 3.87 (dd, J = 12.9, 10.1 Hz, 1H), 3.09 (dd, J = 12.6, 3.5 Hz, 1H), 2.36 (s, 3H), 1.78 - 1.47 (m, 1H), 1.38 (t, J = 7.2 Hz, 3H), 1.32 - 1.17 (m, 1H).
实施例34:N-(4-(2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-10-(4-氟苯基)-4-羟基-1-,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酰胺(34)的制备Example 34: N-(4-(2-Amino-5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-10-(4- Fluorophenyl)-4-hydroxy-1-,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepine Preparation of heptane-8-carboxamide (34)
采用与实施例31相同的方法,除了用10-(4-氟苯基)-4-羟基-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸(f)代替6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-羧酸(o),制得N-(4-(2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-10-(4-氟苯基)-4-羟基-1-,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酰胺(34)(白色固体,一步收率:18.9%)。The same procedure as in Example 31 was carried out except that 10-(4-fluorophenyl)-4-hydroxy-1,9-dioxo-1,2,3,4,5,9-hexahydropyridyl[ 1,2-a][1,4]diazepane-8-carboxylic acid (f) in place of 6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7 ,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (o), N-(4-(2-amino-5) -(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-10-(4-fluorophenyl)-4-hydroxy-1-,9-di Oxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxamide (34) (white solid, one step Yield: 18.9%).
LC-MS(ESI):m/z 612.3[M/M+H
+]。
LC-MS (ESI): m / z 612.3 [M / M + H +].
1H NMR(400MHz,DMSO-d
6)δ13.00(s,1H),8.88(s,1H),8.73(d,J=26.7Hz,2H),8.26(d,J=6.6Hz,2H),7.97(dd,J=29.7,17.5Hz,3H),7.55–7.42(m,2H),7.34–7.19(m,4H),7.16–6.85(m,2H),5.74–5.63(m,1H),4.76–4.61(m,1H),4.41(s,1H),4.29(d,J=13.2Hz,2H),4.13(q,J=7.3Hz,2H),2.90(s,1H),1.39(t,J=7.2Hz,3H)。
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.00 (s, 1H), 8.88 (s, 1H), 8.73 (d, J = 26.7 Hz, 2H), 8.26 (d, J = 6.6 Hz, 2H) , 7.97 (dd, J = 29.7, 17.5 Hz, 3H), 7.55 - 7.42 (m, 2H), 7.34 - 7.19 (m, 4H), 7.16 - 6.85 (m, 2H), 5.74 - 5.63 (m, 1H) , 4.76–4.61 (m, 1H), 4.41 (s, 1H), 4.29 (d, J = 13.2 Hz, 2H), 4.13 (q, J = 7.3 Hz, 2H), 2.90 (s, 1H), 1.39 ( t, J = 7.2 Hz, 3H).
实施例35:N-(4-(2-氨基-5-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)吡啶-3-基)苯基)-1,9-二氧代-10-(对甲苯基)-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酰胺(35)的制备Example 35: N-(4-(2-Amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)phenyl -1,9-dioxo-10-(p-tolyl)-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazacyclocycle Preparation of heptane-8-carboxamide (35)
采用与实施例32相同的方法,除了用3-(4-氨基苯基)-5-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)吡啶-2-胺(z)代替3-(4-氨基-2-氟苯基)-5-(1-乙基-1H-吡唑-4-基)吡啶-2-胺(v),制得N-(4-(2-氨基-5-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)吡啶-3-基)苯基)-1,9-二氧代-10-(对甲苯基)-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酰胺(35)(白色固体,一步收率:23.8%)。The same procedure as in Example 32 was employed except that 3-(4-aminophenyl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridine was used. 2-Amine (z) in place of 3-(4-amino-2-fluorophenyl)-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-2-amine (v), N-(4-(2-Amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)phenyl)-1, 9-dioxo-10-(p-tolyl)-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepan-8 - Formamide (35) (white solid, one step yield: 23.8%).
LC-MS(ESI):m/z 630.4[M/M+H
+]。
LC-MS (ESI): m / z 630.4 [M / M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.88(s,1H),8.82(s,1H),8.60(s,1H),8.27–8.19(m,3H),7.88–7.75(m,3H),7.58(s,1H),7.49(d,J=8.3Hz,2H),7.16(dd,J=18.6,7.9Hz,4H),5.55(s,2H),4.63(s,1H),4.37(s,1H),4.05(s,1H),3.96(d,J=11.4Hz,2H),3.48(t,J=10.5Hz,3H),3.34(s,1H),2.34(s,3H),2.17–1.89(m,6H)。
1 H NMR (400MHz, DMSO- d 6) δ12.88 (s, 1H), 8.82 (s, 1H), 8.60 (s, 1H), 8.27-8.19 (m, 3H), 7.88-7.75 (m, 3H ), 7.58 (s, 1H), 7.49 (d, J = 8.3 Hz, 2H), 7.16 (dd, J = 18.6, 7.9 Hz, 4H), 5.55 (s, 2H), 4.63 (s, 1H), 4.37 (s, 1H), 4.05 (s, 1H), 3.96 (d, J = 11.4 Hz, 2H), 3.48 (t, J = 10.5 Hz, 3H), 3.34 (s, 1H), 2.34 (s, 3H) , 2.17–1.89 (m, 6H).
实施例36:N-(4-(2-氨基-5-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-1,9-二氧代-10-(对甲苯基)-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酰胺(36)的制备Example 36: N-(4-(2-Amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3 -fluorophenyl)-1,9-dioxo-10-(p-tolyl)-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4] Preparation of diazepane-8-carboxamide (36)
采用与实施例35相同的方法,除了用3-(4-氨基-2-氟苯基)-5-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)吡啶-2-胺(w)代替3-(4-氨基-2-甲苯基)-5-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)吡啶-2-胺(z),制得N-(4-(2-氨基-5-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-1,9-二氧代-10-(对甲苯基)-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酰胺(36)(白色固体,一步收率:28.7%)。The same procedure as in Example 35 was employed except that 3-(4-amino-2-fluorophenyl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4 was used. -yl)pyridin-2-amine (w) instead of 3-(4-amino-2-methylphenyl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4 -yl)pyridin-2-amine (z) to give N-(4-(2-amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4- Pyridin-3-yl)-3-fluorophenyl)-1,9-dioxo-10-(p-tolyl)-1,2,3,4,5,9-hexahydropyridyl[1 , 2-a][1,4]diazepane-8-carboxamide (36) (white solid, one step yield: 28.7%).
LC-MS(ESI):m/z 648.4[M/M+H
+]。
LC-MS (ESI): m / z 648.4 [M / M + H +].
1H NMR(400MHz,DMSO-d
6)δ13.03(s,1H),8.84(s,1H),8.61(s,1H),8.26(s,1H),8.18(s,1H),7.89(d,J=12.1Hz,1H),7.82(s,1H),7.56(s,1H),7.48–7.33(m,2H),7.16(dd,J=19.2,7.9Hz,4H),5.55(s,2H),4.71–4.60(m,1H),4.36(s,1H),4.11–4.01(m,1H),3.96(d,J=11.7Hz,2H),3.47(t,J=10.3Hz,4H),2.34(s,3H),2.20–1.89(m,6H)。
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.0.3 (s, 1H), 8.84 (s, 1H), 8.61 (s, 1H), 8.26 (s, 1H), 8.18 (s, 1H), 7.89 ( d, J = 12.1 Hz, 1H), 7.82 (s, 1H), 7.56 (s, 1H), 7.48 - 7.33 (m, 2H), 7.16 (dd, J = 19.2, 7.9 Hz, 4H), 5.55 (s , 2H), 4.71 - 4.60 (m, 1H), 4.36 (s, 1H), 4.11 - 4.01 (m, 1H), 3.96 (d, J = 11.7 Hz, 2H), 3.47 (t, J = 10.3 Hz, 4H), 2.34 (s, 3H), 2.20–1.89 (m, 6H).
实施例37:N-(4-(2-氨基-5-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-7-(6-甲基吡啶-3-基)-6,8-二氧代3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酰胺(37)的制备Example 37: N-(4-(2-Amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3 -fluorophenyl)-7-(6-methylpyridin-3-yl)-6,8-dioxo 3,4,6,8,12,12a-hexahydro-2H-pyrido[1', Preparation of 2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide (37)
采用与实施例36相同的方法,除了用7-(6-甲基吡啶-3-基)-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酸(m)代替1,9-二氧代-10-(对甲苯基)-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸(e),制得N-(4-(2-氨基-5-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯 基)-7-(6-甲基吡啶-3-基)-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酰胺(37)(白色固体,一步收率:19.4%)。The same procedure as in Example 36 was employed except that 7-(6-methylpyridin-3-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H- Pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (m) instead of 1,9-dioxo-10-(pair Tolyl-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylic acid (e), to give N- (4-(2-Amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)- 7-(6-Methylpyridin-3-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4, 5] Pyrazino[2,1-b][1,3]oxazine-9-carboxamide (37) (white solid, one step yield: 19.4%).
LC-MS(ESI):m/z 691.4[M/M+H
+]。
LC-MS (ESI): m / z 691.4 [M / M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.71(s,1H),8.93(s,1H),8.30–8.03(m,3H),7.94–7.70(m,2H),7.54(d,J=2.3Hz,1H),7.48–7.33(m,3H),7.25(d,J=7.9Hz,1H),5.55(s,2H),5.30(s,1H),4.74–4.52(m,2H),4.43–4.15(m,2H),4.05(d,J=16.4Hz,1H),4.01–3.77(m,3H),3.47(td,J=11.5,2.6Hz,5H),3.17–3.00(m,1H),2.15–1.76(m,4H),1.76–1.49(m,2H)。
1 H NMR (400MHz, DMSO- d 6) δ12.71 (s, 1H), 8.93 (s, 1H), 8.30-8.03 (m, 3H), 7.94-7.70 (m, 2H), 7.54 (d, J =2.3Hz,1H), 7.48–7.33(m,3H), 7.25(d,J=7.9Hz,1H),5.55(s,2H),5.30(s,1H),4.74–4.52(m,2H) , 4.43–4.15 (m, 2H), 4.05 (d, J = 16.4 Hz, 1H), 4.01–3.77 (m, 3H), 3.47 (td, J=11.5, 2.6 Hz, 5H), 3.17–3.00 (m) , 1H), 2.15–1.76 (m, 4H), 1.76–1.49 (m, 2H).
实施例38:N-(4-(2-氨基-5-(3-甲氧基-4-(2-吗啉乙氧基)苯基)吡啶-3-基)-3-氟苯基)-10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酰胺(38)的制备Example 38: N-(4-(2-Amino-5-(3-methoxy-4-(2-morpholinoethoxy)phenyl)pyridin-3-yl)-3-fluorophenyl) -10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepine Preparation of cycloheptane-8-carboxamide (38)
采用与实施例14相同的方法,除了用3-(4-氨基-2-氟苯基)-5-(3-甲氧基-4-(2-吗啉乙氧基)苯基)吡啶-2-胺(ee)代替4-(4-(6-氨基-5-(4-氨基-2-氟苯基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(u),制得N-(4-(2-氨基-5-(3-甲氧基-4-(2-吗啉乙氧基)苯基)吡啶-3-基)-3-氟苯基)-10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酰胺(38)(白色固体,一步收率:21.3%)。The same procedure as in Example 14 was employed except that 3-(4-amino-2-fluorophenyl)-5-(3-methoxy-4-(2-morpholinoethoxy)phenyl)pyridine- 2-amine (ee) instead of 4-(4-(6-amino-5-(4-amino-2-fluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1 - tert-butyl formate (u) to give N-(4-(2-amino-5-(3-methoxy-4-(2-morpholinoethoxy)phenyl)pyridin-3-yl) 3-fluorophenyl)-10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][ 1,4]diazepane-8-carboxamide (38) (white solid, one step yield: 21.3%).
LC-MS(ESI):m/z 737.3[M/M+H
+]。
LC-MS (ESI): m / z 737.3 [M / M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.99(s,1H),8.86(s,1H),8.69(s,1H),8.34(s,1H),7.92(d,J=12.3Hz,1H),7.74(s,1H),7.44(q,J=8.7,8.3Hz,2H),7.25(ddd,J=27.1,16.2,8.5Hz,6H),7.10(d,J=8.3Hz,1H),6.05(s,2H),4.66(d,J=11.9Hz,1H),4.35(s,2H),4.06(s,1H),3.86(s,7H),3.47(s,6H),2.10(d,J=48.5Hz,4H)。
1 H NMR (400MHz, DMSO- d 6) δ12.99 (s, 1H), 8.86 (s, 1H), 8.69 (s, 1H), 8.34 (s, 1H), 7.92 (d, J = 12.3Hz, 1H), 7.74 (s, 1H), 7.44 (q, J = 8.7, 8.3 Hz, 2H), 7.25 (ddd, J = 27.1, 16.2, 8.5 Hz, 6H), 7.10 (d, J = 8.3 Hz, 1H) ), 6.05 (s, 2H), 4.66 (d, J = 11.9 Hz, 1H), 4.35 (s, 2H), 4.06 (s, 1H), 3.86 (s, 7H), 3.47 (s, 6H), 2.10 (d, J = 48.5 Hz, 4H).
实施例39:N-(4-(2-氨基-5-(3-甲氧基-4-(2-吗啉乙氧基)苯基)吡啶-3-基)-3-氟苯基)-7-(5-甲基噻吩-2-基)-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酰胺(39)的制备Example 39: N-(4-(2-Amino-5-(3-methoxy-4-(2-morpholinoethoxy)phenyl)pyridin-3-yl)-3-fluorophenyl) -7-(5-methylthiophen-2-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4 ,5]Preparation of pyrazino[2,1-b][1,3]oxazine-9-carboxamide (39)
采用与实施例38相同的方法,除了7-(5-甲基噻吩-2-基)-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酸(n)代替 10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸(d),制得N-(4-(2-氨基-5-(3-甲氧基-4-(2-吗啉代乙氧基)苯基)吡啶-3-基)-3-氟苯基)-7-(5-甲基噻吩-2-基)-6,8-二氧代-3,4,6,8,12,12a六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酰胺(39)(白色固体,一步收率:17.5%)。The same procedure as in Example 38 was employed except for 7-(5-methylthiophen-2-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyridine. And [1',2':4,5]pyrazine[2,1-b][1,3]oxazine-9-carboxylic acid (n) instead of 10-(4-fluorophenyl)-1,9 -Dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylic acid (d), N -(4-(2-Amino-5-(3-methoxy-4-(2-morpholinoethoxy)phenyl)pyridin-3-yl)-3-fluorophenyl)-7-( 5-methylthiophen-2-yl)-6,8-dioxo-3,4,6,8,12,12a hexahydro-2H-pyrido[1',2':4,5]pyrazine And [2,1-b][1,3]oxazine-9-carboxamide (39) (white solid, one step yield: 17.5%).
LC-MS(ESI):m/z 781.3[M/M+H
+]。
LC-MS (ESI): m / z 781.3 [M / M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.73(s,1H),8.87(s,1H),8.30(d,J=2.4Hz,1H),7.90(d,J=11.7Hz,1H),7.60(d,J=2.4Hz,1H),7.51–7.33(m,2H),7.21–6.94(m,3H),6.74(d,J=3.5Hz,1H),6.60(d,J=3.5Hz,1H),5.68(s,2H),5.29(t,J=4.0Hz,1H),4.63(ddd,J=45.8,14.0,4.0Hz,2H),4.28(d,J=13.3Hz,1H),4.08(t,J=5.9Hz,3H),3.82(s,3H),3.58(t,J=4.7Hz,4H),3.34(s,9H),2.69(t,J=5.9Hz,2H),1.79–1.55(m,2H)。
1 H NMR (400MHz, DMSO- d 6) δ12.73 (s, 1H), 8.87 (s, 1H), 8.30 (d, J = 2.4Hz, 1H), 7.90 (d, J = 11.7Hz, 1H) , 7.60 (d, J = 2.4 Hz, 1H), 7.51 - 7.33 (m, 2H), 7.21 - 6.94 (m, 3H), 6.74 (d, J = 3.5 Hz, 1H), 6.60 (d, J = 3.5) Hz, 1H), 5.68 (s, 2H), 5.29 (t, J = 4.0 Hz, 1H), 4.63 (ddd, J = 45.8, 14.0, 4.0 Hz, 2H), 4.28 (d, J = 13.3 Hz, 1H) ), 4.08 (t, J = 5.9 Hz, 3H), 3.82 (s, 3H), 3.58 (t, J = 4.7 Hz, 4H), 3.34 (s, 9H), 2.69 (t, J = 5.9 Hz, 2H) ), 1.79–1.55 (m, 2H).
实施例40:N-(4-(5-(4-(2-((1,4-二恶烷-2-基)甲氧基)乙氧基)-3-甲氧基苯基)-2-氨基-吡啶-3-基)-3-氟苯基)-6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢唑并唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-甲酰胺(40)的制备Example 40: N-(4-(5-(4-(2-((1,4-dioxo)-2-yl)methoxy)ethoxy)-3-methoxyphenyl)- 2-amino-pyridin-3-yl)-3-fluorophenyl)-6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydro Preparation of oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (40)
采用与实施例30相同的方法,除了5-(4-(2-((1,4-二恶烷-2-基)甲氧基)乙氧基)-3-甲氧基苯基)-3-(4-氨基-2-氟苯基)吡啶-2-胺(dd)代替3-(4-氨基-2,5-二氟苯基)-5-(3,4-二甲氧基苯基)吡啶-2-胺(30a),制得N-(4-(5-(4-(2-((1,4-二恶烷-2-基)甲氧基)乙氧基)-3-甲氧基苯基)-2-氨基-吡啶-3-基)-3-氟苯基)-6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢唑并唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-甲酰胺(40)(白色固体,一步收率:26.7%)。In the same manner as in Example 30 except that 5-(4-(2-((1,4-dioxo-2-yl)methoxy)ethoxy)-3-methoxyphenyl)- 3-(4-Amino-2-fluorophenyl)pyridin-2-amine (dd) instead of 3-(4-amino-2,5-difluorophenyl)-5-(3,4-dimethoxy Phenyl)pyridin-2-amine (30a) to give N-(4-(5-(4-(2-(4-1,4-dioxan-2-yl)methoxy)ethoxy) 3-methoxyphenyl)-2-amino-pyridin-3-yl)-3-fluorophenyl)-6-(4-fluorophenyl)-5,7-dioxo-2,3, 5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (40) (white solid, one step yield: 26.7% ).
LC-MS(ESI):m/z 796.4[M/M+H
+]。
LC-MS (ESI): m / z 796.4 [M / M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.76(s,1H),8.89(s,1H),8.29(d,J=2.4Hz,1H),7.89(dd,J=12.3,2.0Hz,1H),7.60(d,J=2.4Hz,1H),7.48–7.37(m,2H),7.33–7.03(m,6H),6.98(d,J=8.4Hz,1H),5.66(s,2H),5.46(dd,J=10.0,3.6Hz,1H),4.98(dd,J=12.4,3.6Hz,1H),4.28–3.96(m,5H),3.82(s,3H),3.77–3.38(m,13H)。
1 H NMR (400 MHz, DMSO-d 6 ) δ 12.76 (s, 1H), 8.89 (s, 1H), 8.29 (d, J = 2.4 Hz, 1H), 7.89 (dd, J = 12.3, 2.0 Hz, 1H), 7.60 (d, J = 2.4 Hz, 1H), 7.48 - 7.37 (m, 2H), 7.33 - 7.03 (m, 6H), 6.98 (d, J = 8.4 Hz, 1H), 5.66 (s, 2H) ), 5.46 (dd, J = 10.0, 3.6 Hz, 1H), 4.98 (dd, J = 12.4, 3.6 Hz, 1H), 4.28 - 3.96 (m, 5H), 3.82 (s, 3H), 3.77 - 3.38 ( m, 13H).
实施例41:N-(4-(2-氨基-5-(3-甲氧基-4-(2-吗啉乙氧基)苯基)吡啶-3-基)-3-氟苯基)-5,7-二氧代-6-(对甲苯基)-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-甲酰胺(41)的制备Example 41: N-(4-(2-Amino-5-(3-methoxy-4-(2-morpholinoethoxy)phenyl)pyridin-3-yl)-3-fluorophenyl) -5,7-dioxo-6-(p-tolyl)-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d] Preparation of pyrazine-8-carboxamide (41)
采用与实施例38相同的方法,除了6-(4-甲苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-羧酸(p)代替10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸(d),制得N-(4-(2-氨基-5-(3-甲氧基-4-(2-吗啉乙氧基)苯基)吡啶-3-基)-3-氟苯基)-5,7-二氧代-6-(对甲苯基)-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-甲酰胺(41)(白色固体,一步收率:19.4%)。The same procedure as in Example 38 was carried out except that 6-(4-methylphenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a ] Pyrido[1,2-d]pyrazine-8-carboxylic acid (p) in place of 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9 -Hexidopyrido[1,2-a][1,4]diazepan-8-carboxylic acid (d) to give N-(4-(2-amino-5-(3-methoxy) 4-(2-morpholinoethoxy)phenyl)pyridin-3-yl)-3-fluorophenyl)-5,7-dioxo-6-(p-tolyl)-2,3, 5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (41) (white solid, one step yield: 19.4%) .
LC-MS(ESI):m/z 761.4[M/M+H
+]。
LC-MS (ESI): m / z 761.4 [M / M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.84(s,1H),8.87(s,1H),8.41–8.14(m,2H),7.89(d,J=12.5Hz,1H),7.60(s,1H),7.53–7.36(m,2H),7.22–6.93(m,6H),5.67(s,2H),5.47(d,J=6.6Hz,1H),4.97(d,J=8.9Hz,1H),4.28–3.97(m,5H),3.82(s,3H),3.72–3.53(m,5H),3.45(s,2H),2.69(t,J=5.9Hz,2H),2.35(s,3H)。
1 H NMR (400MHz, DMSO- d 6) δ12.84 (s, 1H), 8.87 (s, 1H), 8.41-8.14 (m, 2H), 7.89 (d, J = 12.5Hz, 1H), 7.60 ( s, 1H), 7.53–7.36 (m, 2H), 7.22–6.93 (m, 6H), 5.67 (s, 2H), 5.47 (d, J = 6.6 Hz, 1H), 4.97 (d, J = 8.9 Hz) , 1H), 4.28–3.97 (m, 5H), 3.82 (s, 3H), 3.72–3.53 (m, 5H), 3.45 (s, 2H), 2.69 (t, J = 5.9 Hz, 2H), 2.35 ( s, 3H).
实施例42:N-(4-(5-(4-((1,4-二恶烷-2-基)甲氧基)-3-甲氧基苯基)-2-氨基-吡啶-3-基)-3-氟苯基)-6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-甲酰胺(42)的制备Example 42: N-(4-(5-(4-(4-1,4-dioxan-2-yl)methoxy)-3-methoxyphenyl)-2-amino-pyridine-3 -yl)-3-fluorophenyl)-6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazole[3,2 -a]Preparation of pyrido[1,2-d]pyrazine-8-carboxamide (42)
采用与实施例30相同的方法,除了5-(4-((1,4-二恶烷-2-基)甲氧基)-3-甲氧基苯基)-3-(4-氨基-2-氟苯基)吡啶-2-胺(bb)代替3-(4-氨基-2,5-二氟苯基)-5-(3,4-二甲氧基苯基)吡啶-2-胺(30a),制得N-(4-(5-(4-((1,4-二恶烷-2-基)甲氧基)-3-甲氧基苯基)-2-氨基-吡啶-3-基)-3-氟苯基)-6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-甲酰胺(42)(白色固体,一步收率:30.2%)。In the same manner as in Example 30 except that 5-(4-((1,4-dioxan-2-yl)methoxy)-3-methoxyphenyl)-3-(4-amino- 2-fluorophenyl)pyridin-2-amine (bb) in place of 3-(4-amino-2,5-difluorophenyl)-5-(3,4-dimethoxyphenyl)pyridine-2- Amine (30a) to give N-(4-(5-(4-(4-1,4-dioxan-2-yl)methoxy)-3-methoxyphenyl)-2-amino- Pyridin-3-yl)-3-fluorophenyl)-6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazole[ 3,2-a] Pyrido[1,2-d]pyrazine-8-carboxamide (42) (white solid, one step yield: 30.2%).
LC-MS(ESI):m/z 752.4[M/M+H
+]。
LC-MS (ESI): m / z 752.4 [M / M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.76(s,1H),8.89(s,1H),8.29(d,J=2.4Hz,1H),7.89(dd,J=12.3,2.0Hz,1H),7.60(d,J=2.4Hz,1H),7.50–7.35(m,2H),7.34–7.02(m,6H),6.98(d,J=8.4Hz,1H),5.67(s,2H),5.46(dd,J=10.0,3.6Hz,1H),4.98(dd,J=12.3,3.6Hz,1H),4.26–4.11(m,2H),4.08–3.40(m,15H)。
1 H NMR (400 MHz, DMSO-d 6 ) δ 12.76 (s, 1H), 8.89 (s, 1H), 8.29 (d, J = 2.4 Hz, 1H), 7.89 (dd, J = 12.3, 2.0 Hz, 1H), 7.60 (d, J = 2.4 Hz, 1H), 7.50 - 7.35 (m, 2H), 7.34 - 7.02 (m, 6H), 6.98 (d, J = 8.4 Hz, 1H), 5.67 (s, 2H) ), 5.46 (dd, J = 10.0, 3.6 Hz, 1H), 4.98 (dd, J = 12.3, 3.6 Hz, 1H), 4.26 - 4.11 (m, 2H), 4.08 - 3.40 (m, 15H).
实施例43:N-(4-(2-氨基-5-(3-甲氧基-4-(2-吗啉乙氧基)苯基)吡啶-3-基)-3-氟苯 基)-6,8-二氧代-7-(对甲苯基)-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酰胺(43)的制备Example 43: N-(4-(2-Amino-5-(3-methoxy-4-(2-morpholinoethoxy)phenyl)pyridin-3-yl)-3-fluorophenyl) -6,8-dioxo-7-(p-tolyl)-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazine Preparation of [2,1-b][1,3]oxazine-9-carboxamide (43)
采用与实施例41相同的方法,除了6,8-二氧代-7-(对甲苯基)-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酸(l)代替6-(4-甲苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-羧酸(p),制得N-(4-(2-氨基-5-(3-甲氧基-4-(2-吗啉乙氧基)苯基)吡啶-3-基)-3-氟苯基)-6,8-二氧代-7-(对甲苯基)-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酰胺(43)(白色固体,一步收率:22.7%)。The same procedure as in Example 41 was carried out except that 6,8-dioxo-7-(p-tolyl)-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2 ':4,5]pyrazine[2,1-b][1,3]oxazine-9-carboxylic acid (l) instead of 6-(4-methylphenyl)-5,7-dioxo-2, 3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (p) to give N-(4-( 2-Amino-5-(3-methoxy-4-(2-morpholinoethoxy)phenyl)pyridin-3-yl)-3-fluorophenyl)-6,8-dioxo-7 -(p-tolyl)-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1, 3] Oxazine-9-carboxamide (43) (white solid, one step yield: 22.7%).
LC-MS(ESI):m/z 775.4[M/M+H
+]。
LC-MS (ESI): m / z 775.4 [M / M + H +].
实施例44:N-(4-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)苯基)-1,5-二氧代-4-((四氢-2H-吡喃-4-基)甲基)-1,4,5,6-四氢苯并[f][1,7]萘啶-2-甲酰胺(44)的制备Example 44: N-(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)-1,5-dioxo-4-(( Preparation of tetrahydro-2H-pyran-4-yl)methyl)-1,4,5,6-tetrahydrobenzo[f][1,7]naphthyridin-2-carboxamide (44)
步骤1:N-(4-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)苯基)-1,5-二氧代-4-((四氢-2H-吡喃-4-基)甲基)-1,4,5,6-四氢苯并[f][1,7]萘啶-2-甲酰胺(44)的制备Step 1: N-(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)-1,5-dioxo-4-((four Preparation of hydrogen-2H-pyran-4-yl)methyl)-1,4,5,6-tetrahydrobenzo[f][1,7]naphthyridin-2-carboxamide (44)
于室温,在含有(2.5mL)1,4-二氧六环和水混合液(4:1)的反应瓶中加入5-((4-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)苯基)氨基甲酰基)-3-溴-4-氧代-1-((四氢-2H-吡喃-2-基)-4-基)甲基)-1,4-二氢吡啶-2-羧酸乙酯(9d)(60mg,0.09mmol)、(2-氨基苯基)硼酸(18mg,0.14mmol)、碳酸钾(35mg,0.26mmol)、Pd(dppf)Cl
2.DCM(8mg,0.01mmol)。密封,氮气置换三次,加热至80℃搅拌1.5小时。待反应液冷却至室温后,过滤,滤液用水(10mL)稀释,乙酸乙酯萃取(15mL×3),合并有机相。将有机相用饱和的食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩。残余物通过制备 HPLC纯化(C18,乙腈/水(0.1%甲酸):10%~100%),得到N-(4-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)苯基)-1,5-二氧代-4-((四氢-2H-吡喃-4-基)甲基)-1,4,5,6-四氢苯并[f][1,7]萘啶-2-甲酰胺(15mg,白色固体,收率:25.3%)。
Add 5-((4-(2-amino-5-(3,4-)) to the reaction flask containing (2.5 mL) 1,4-dioxane and water mixture (4:1) at room temperature. Methoxyphenyl)pyridin-3-yl)phenyl)carbamoyl)-3-bromo-4-oxo-1-((tetrahydro-2H-pyran-2-yl)-4-yl) Methyl)-1,4-dihydropyridine-2-carboxylic acid ethyl ester (9d) (60 mg, 0.09 mmol), (2-aminophenyl)boronic acid (18 mg, 0.14 mmol), potassium carbonate (35 mg, 0.26 mmol) ), Pd(dppf)Cl 2 .DCM (8 mg, 0.01 mmol). Sealed, replaced with nitrogen three times, heated to 80 ° C and stirred for 1.5 hours. After the reaction mixture was cooled to room temperature, it was filtered, and the filtrate was diluted with water (10 mL), and ethyl acetate (15 mL×3). The organic phase was washed with brine brine, dried over anhydrous The residue was purified by preparative HPLC (C18, EtOAc/EtOAc (EtOAc:EtOAc:EtOAc:EtOAc) Pyridin-3-yl)phenyl)-1,5-dioxo-4-((tetrahydro-2H-pyran-4-yl)methyl)-1,4,5,6-tetrahydrobenzo [f][1,7]naphthyridine-2-carboxamide (15 mg, white solid, yield: 25.3%).
LC-MS(ESI):m/z 658.4[M/M+H
+]。
LC-MS (ESI): m / z 658.4 [M / M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.67(s,1H),12.48(s,1H),9.91(d,J=8.6Hz,1H),8.90(s,1H),8.27(d,J=2.4Hz,1H),7.90(d,J=8.4Hz,2H),7.70–7.52(m,4H),7.45(d,J=8.2Hz,1H),7.35(t,J=7.6Hz,1H),7.21(d,J=2.1Hz,1H),7.16(dd,J=8.3,2.1Hz,1H),7.00(d,J=8.4Hz,1H),5.69(s,2H),5.03(d,J=7.0Hz,2H),3.81(d,J=24.0Hz,7H),3.24–3.18(m,2H),2.07(s,2H),1.48–1.30(m,4H)。
1 H NMR (400MHz, DMSO- d 6) δ12.67 (s, 1H), 12.48 (s, 1H), 9.91 (d, J = 8.6Hz, 1H), 8.90 (s, 1H), 8.27 (d, J = 2.4 Hz, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.70 - 7.52 (m, 4H), 7.45 (d, J = 8.2 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.21 (d, J = 2.1 Hz, 1H), 7.16 (dd, J = 8.3, 2.1 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 5.69 (s, 2H), 5.03 ( d, J = 7.0 Hz, 2H), 3.81 (d, J = 24.0 Hz, 7H), 3.24 - 3.18 (m, 2H), 2.07 (s, 2H), 1.48 - 1.30 (m, 4H).
实施例45:N-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-8-氟-1,5-二氧代-4-((四氢-2H-吡喃-4-基)甲基)-1,4,5,6-四氢苯并[f][1,7]萘啶-2-甲酰胺(45)的制备Example 45: N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl) -8-fluoro-1,5-dioxo-4-((tetrahydro-2H-pyran-4-yl)methyl)-1,4,5,6-tetrahydrobenzo[f][1 , 7] Preparation of naphthyridine-2-carboxamide (45)
步骤1:5-溴-6-(乙氧基羰基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸(45a)的制备Step 1: 5-Bromo-6-(ethoxycarbonyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3 - Preparation of formic acid (45a)
在含有(9mL)乙醇的反应瓶中加入3-溴-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-2,5-二羧酸二乙酯(9b,1.0g,2.39mmol)。将反应液冷却至0℃,搅拌下滴加氢氧化钠水溶液(3mL,2.87mmol),加毕升至室温并继续搅拌1小时。待反应完全后,将反应液冷却至0℃,用1N的盐酸调节pH~3,有白色固体析出,继续搅拌30分钟。过滤,收集固体,得到5-溴-6-(乙氧基羰基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸(600mg,白色固体,收率:64.4%)。3-bromo-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2 was added to a reaction flask containing (9 mL) of ethanol. Diethyl 5-dicarboxylate (9b, 1.0 g, 2.39 mmol). The reaction solution was cooled to 0 ° C, and aqueous sodium hydroxide (3 mL, 2.87 mmol) was added dropwise with stirring, and the mixture was warmed to room temperature and stirring was continued for 1 hour. After the reaction was completed, the reaction mixture was cooled to 0 ° C, pH was adjusted to 3 with 1N hydrochloric acid, and a white solid was precipitated and stirring was continued for 30 minutes. Filtration and collection of the solid to give 5-bromo-6-(ethoxycarbonyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydro Pyridine-3-carboxylic acid (600 mg, white solid, yield: 64.4%).
LC-MS(ESI):m/z 388.0[M/M+H
+]。
LC-MS (ESI): m / z 388.0 [M / M + H +].
步骤2:5-((4-(2-氨基-5-(1-(1-(叔丁氧基羰基)哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)氨基甲酰基)-3-溴-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-2-羧酸乙酯(45b)的制备Step 2: 5-((4-(2-Amino-5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyridine-3- 3-fluorophenyl)carbamoyl)-3-bromo-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine Preparation of ethyl-2-carboxylate (45b)
在含有DMF(10mL)的反应瓶中加入5-溴-6-(乙氧基羰基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸(45a)(100mg,0.26mmol)、4-(4-(6-氨基-5-(4-氨基-2-氟苯基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(u)(140mg,0.31mmol)、HATU(146mg,0.39mmol)和DIPEA(99mg,0.77mmol)。将混合物于室温搅拌30分钟,待反应完全后,加入饱和的碳酸氢钠溶液淬灭,用乙酸乙酯萃取(30mLx3),合并有机相。将有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为MeOH:DCM=1:20),得到5-((4-(2-氨基-5-(1-(1-(叔丁氧基羰基)哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)氨基甲酰基)-3-溴-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-2-羧酸乙酯(170mg,黄色固体,收率:79.6%)。Add 5-bromo-6-(ethoxycarbonyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1 to a reaction vial containing DMF (10 mL) , 4-dihydropyridine-3-carboxylic acid (45a) (100 mg, 0.26 mmol), 4-(4-(6-amino-5-(4-amino-2-fluorophenyl)pyridin-3-yl)- tert-Butyl 1H-pyrazol-1-yl)piperidine-1-carboxylate (u) (140 mg, 0.31 mmol), HATU (146 mg, 0.39 mmol) and DIPEA (99 mg, 0.77 mmol). The mixture was stirred at room temperature for 30 minutes. After the reaction was completed, EtOAc (EtOAc) The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography eluting elut elut elut eluting elut Piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)carbamoyl)-3-bromo-4-oxo-1-(four Ethyl hydrogen-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2-carboxylate (170 mg, yellow solid, yield: 79.6%).
LC-MS(ESI):m/z 822.3/824.2[M/M+H
+]。
LC-MS (ESI): m / z 822.3 / 824.2 [M / M + H +].
步骤3:4-(4-(6-氨基-5-(2-氟-4-(8-氟-1,5-二氧代-4-((四氢-2H-吡喃-4-基)甲基)-1,4,5,6-四氢苯并[f]的[1,7]萘啶-2-甲酰氨基)苯基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯(45c)的制备Step 3: 4-(4-(6-Amino-5-(2-fluoro-4-(8-fluoro-1,5-dioxo-4-((tetrahydro-2H-pyran-4-yl)) [Methyl)-1,4,5,6-tetrahydrobenzo[f][1,7]naphthyridin-2-carboxamido)phenyl)pyridin-3-yl)-1H-pyrazole- Preparation of tert-butyl ester of 1-yl) piperidine-1-carboxylate (45c)
于室温,在含有(5mL)1,4-二氧六环和水混合液(4:1)的反应瓶中加入5-((4-(2-氨基-5-(1-(1-(叔丁氧基羰基)哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)氨基甲酰基)-3-溴-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-2-羧酸乙酯(45b)(170mg,0.20mmol)、2-氨基-4-氟苯硼酸(46.5mg,0.30mmol)、碳酸钾(83mg,0.60mmol)、Pd(dppf)Cl
2.DCM(16mg,0.02mmol)。密封,氮气置换三次,加热至80℃搅拌1.5小时。待反应液冷却至室温后,过滤,滤液用水(10mL)稀释,乙酸乙酯萃取(15mL×3),合并有机相。将有机相用饱和的食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱液为DCM:CH
3OH/10:1),得到4-(4-(6-氨基-5-(2-氟-4-(8-氟-1,5-二氧代-4-((四氢-2H-吡喃-4-基)甲基)-1,4,5,6-四氢苯并[f]的[1,7]萘啶-2-甲酰氨基)苯基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯(45c)(100mg,黄色固体,收率:62.0%)。
Add 5-((4-(2-amino-5-(1-(1-)) to the reaction flask containing (5 mL) 1,4-dioxane and water mixture (4:1) at room temperature. tert-Butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)carbamoyl)-3-bromo-4-oxo- Ethyl 1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2-carboxylate (45b) (170 mg, 0.20 mmol), 2-amino-4- fluorobenzene boronic acid (46.5mg, 0.30mmol), potassium carbonate (83mg, 0.60mmol), Pd ( dppf) Cl 2 .DCM (16mg, 0.02mmol). Sealed, replaced with nitrogen three times, heated to 80 ° C and stirred for 1.5 hours. After the reaction mixture was cooled to room temperature, it was filtered, and the filtrate was diluted with water (10 mL), and ethyl acetate (15 mL×3). The organic phase was washed with brine brine, dried over anhydrous The residue was purified by chromatography on silica gel column chromatography (eluent DCM: CH 3 OH / 10: 1), to give 4- (4- (6-amino-5- (2-fluoro-4- (8-fluoro [1,7] of -1,5-dioxo-4-((tetrahydro-2H-pyran-4-yl)methyl)-1,4,5,6-tetrahydrobenzo[f] Naphthyridine-2-carboxamido)phenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (45c) (100 mg, yellow solid, yield: 62.0%).
LC-MS(ESI):m/z 807.4[M/M+H
+]。
LC-MS (ESI): m / z 807.4 [M / M + H +].
步骤4:N-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-8-氟-1,5--二氧代-4-((四氢-2H-吡喃-4-基)甲基)-1,4,5,6-四氢苯并[f][1,7]萘啶-2-甲酰胺(45)的制备Step 4: N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)- 8-fluoro-1,5--dioxo-4-((tetrahydro-2H-pyran-4-yl)methyl)-1,4,5,6-tetrahydrobenzo[f][1 , 7] Preparation of naphthyridine-2-carboxamide (45)
在含有DCM(3mL)的反应瓶中加入4-(4-(6-氨基-5-(2-氟-4-(8-氟-1,5-二氧代-4-((四氢-2H-吡喃-4-基)甲基)-1,4,5,6-四氢苯并[f]的[1,7]萘啶-2-甲酰氨基)苯基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯(45c)(50mg,0.06mmol)和盐酸的1,4- 二氧六环溶液(1.5mL,4M)。将混合物于室温搅拌1小时后,减压浓缩。残余物通过制备HPLC纯化(C18,乙腈/水(0.1%甲酸):10%~100%),得到N-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-8-氟-1,5--二氧代-4-((四氢-2H-吡喃-4-基)甲基)-1,4,5,6-四氢苯并[f][1,7]萘啶-2-甲酰胺(45)(15mg,白色固体,35.4%)。In a reaction flask containing DCM (3 mL) was added 4-(4-(6-amino-5-(2-fluoro-4-(8-fluoro-1,5-dioxo-4-((tetrahydro-)- [1,7]naphthyridin-2-carboxamido)phenyl)pyridine-3-(2H-pyran-4-yl)methyl)-1,4,5,6-tetrahydrobenzo[f] tert-Butyl ester of -1H-pyrazol-1-yl)piperidine-l-carboxylate (45c) (50 mg, 0.06 mmol) and 1,4-dioxane hydrochloride (1.5 mL, 4M). The mixture was stirred at room temperature for 1 hour and then concentrated. The residue was purified by preparative HPLC (C18, EtOAc/EtOAc (EtOAc:EtOAc:EtOAc:EtOAc) 1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-8-fluoro-1,5--dioxo-4-((tetrahydro-2H-pyran-4- Methyl)-1,4,5,6-tetrahydrobenzo[f][1,7]naphthyridin-2-carboxamide (45) (15 mg, white solid, 35.4%).
LC-MS(ESI):m/z 707.4[M/M+H
+]。
LC-MS (ESI): m / z 707.4 [M / M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.73(s,1H),9.99(dd,J=9.3,6.5Hz,1H),8.91(s,1H),8.38(s,1H),8.28(d,J=2.3Hz,1H),8.16(s,1H),7.97(dd,J=12.2,2.0Hz,1H),7.83(s,1H),7.62–7.49(m,2H),7.42(t,J=8.4Hz,1H),7.22(ddt,J=12.5,6.6,2.8Hz,2H),5.57(s,2H),5.00(d,J=7.0Hz,2H),4.28–4.15(m,1H),3.87–3.79(m,2H),3.26–3.06(m,4H),2.71(t,J=12.2Hz,2H),2.11–1.79(m,6H),1.38(q,J=12.6Hz,4H)。
1 H NMR (400MHz, DMSO- d 6) δ12.73 (s, 1H), 9.99 (dd, J = 9.3,6.5Hz, 1H), 8.91 (s, 1H), 8.38 (s, 1H), 8.28 ( d, J = 2.3 Hz, 1H), 8.16 (s, 1H), 7.97 (dd, J = 12.2, 2.0 Hz, 1H), 7.83 (s, 1H), 7.62 - 7.49 (m, 2H), 7.42 (t , J = 8.4 Hz, 1H), 7.22 (ddt, J = 12.5, 6.6, 2.8 Hz, 2H), 5.57 (s, 2H), 5.00 (d, J = 7.0 Hz, 2H), 4.28 - 4.15 (m, 1H), 3.87–3.79 (m, 2H), 3.26–3.06 (m, 4H), 2.71 (t, J = 12.2 Hz, 2H), 2.11–1.79 (m, 6H), 1.38 (q, J = 12.6 Hz) , 4H).
实施例46:N-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-8-氟-4-甲基-1,5-二氧代-1,4,5,6-四氢苯并[f][1,7]萘啶-2-甲酰胺(46)的制备Example 46: N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl) Preparation of 8-fluoro-4-methyl-1,5-dioxo-1,4,5,6-tetrahydrobenzo[f][1,7]naphthyridine-2-carboxamide (46)
采用与实施例45相同的方法,除了用3-溴-1-甲基-4-氧代-1,4-二氢吡啶-2,5-二羧酸二乙酯(a4)代替3-溴-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-2,5-二羧酸二乙酯(9b),制得N-(4-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-8-氟-4-甲基-1,5-二氧代-1,4,5,6-四氢苯并[f][1,7]萘啶-2-甲酰胺(46)(白色固体,四步收率:7.3%)。In the same manner as in Example 45, except that 3-bromo-1-methyl-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (a4) was used instead of 3-bromo. 4-Oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (9b), obtained N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-8-fluoro 4-methyl-1,5-dioxo-1,4,5,6-tetrahydrobenzo[f][1,7]naphthyridin-2-carboxamide (46) (white solid, four steps Yield: 7.3%).
LC-MS(ESI):m/z 623.3[M/M+H
+]。
LC-MS (ESI): m / z 623.3 [M / M + H +].
实施例47:N
5-(6-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)哒嗪-3-基)-3-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-2,5-二甲酰胺(47)的制备
Example 47: N 5 -(6-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)pyridazin-3-yl )-3-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2,5-di Preparation of formamide (47)
步骤1:5-((6-溴哒嗪-3-基)氨基甲酰基)-3-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)二氢吡啶-2-羧酸乙酯(47a)的制备Step 1: 5-((6-Bromopyridazin-3-yl)carbamoyl)-3-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4) Of ethyl-methyl)dihydropyridine-2-carboxylate (47a)
在含有DMF(20mL)的反应瓶中加入5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸(c)(1.28g,3.2mmol)、6-溴哒嗪-3-胺(660mg,3.8mmol)、HATU(2.4g,6.3mmol)和DIPEA(1.63g,12.6mmol)。将混合物于室温搅拌24小时,待反应完全后,加入饱和的碳酸氢钠溶液淬灭,用乙酸乙酯萃取(30mLx3),合并有机相。将有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为MeOH:DCM=1:10),得到5-((6-溴哒嗪-3-基)氨基甲酰基)-3-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)二氢吡啶-2-羧酸乙酯(中间体47a)(1.3g,黄色油状物,收率:72.8%)。Add 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4- to a reaction flask containing DMF (20 mL) Dihydropyridine-3-carboxylic acid (c) (1.28 g, 3.2 mmol), 6-bromopyridazin-3-amine (660 mg, 3.8 mmol), HATU (2.4 g, 6.3 mmol) and DIPEA (1.63 g, 12.6 mmol) ). The mixture was stirred at room temperature for 24 hours. After the reaction was completed, EtOAc (EtOAc) The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography eluting elut elut elut elut elut Ethyl phenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)dihydropyridine-2-carboxylate (Intermediate 47a) (1.3 g, yellow oil , yield: 72.8%).
LC-MS(ESI):m/z 559.1/561.1[M/M+H
+]。
LC-MS (ESI): m / z 559.1 / 561.1 [M / M + H +].
步骤2:5-((6-溴哒嗪-3-基)氨基甲酰基)-3-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-2-羧酸(47b)的制备Step 2: 5-((6-Bromopyridazin-3-yl)carbamoyl)-3-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4) Of -yl)methyl)-1,4-dihydropyridine-2-carboxylic acid (47b)
于室温,在含有叔丁醇(40mL)的反应瓶中加入5-((6-溴哒嗪-3-基)氨基甲酰基)-3-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)二氢吡啶-2-羧酸乙酯(47a)(1.3g,2.3mmol)、氢氧化锂一水合物(387mg,6.9mmol)和水(0.5mL)。将混合物升温至60℃并搅拌3小时,待反应完全后,减压浓缩除去叔丁醇(25mL)。残余物用1M的盐酸溶液酸化至pH 2-3,过滤,收集固体,得到5-((6-溴哒嗪-3-基)氨基甲酰基)-3-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-2-羧酸(47b)(700mg,白色固体,收率:57.1%)。Add 5-((6-bromopyridazin-3-yl)carbamoyl)-3-(4-fluorophenyl)-4-oxo- in a reaction vial containing tert-butanol (40 mL) at room temperature. Ethyl 1-((tetrahydro-2H-pyran-4-yl)methyl)dihydropyridine-2-carboxylate (47a) (1.3 g, 2.3 mmol), lithium hydroxide monohydrate (387 mg, 6.9 Methyl) and water (0.5 mL). The mixture was warmed to 60 ° C and stirred for 3 hours. After the reaction was completed, then concentrated under reduced pressure to remove t-butanol (25 mL). The residue was acidified to pH 2-3 with 1M aqueous hydrochloric acid, filtered, and then evaporated to give 5-((6-bromopyrazin-3-yl)carbamoyl)-3-(4-fluorophenyl)-4 -oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2-carboxylic acid (47b) (700 mg, white solid, yield: 57.1% ).
LC-MS(ESI):m/z 531.1/533.1[M/M+H
+]。
LC-MS (ESI): m / z 531.1 / 533.1 [M / M + H +].
步骤3:N
5-(6-溴哒嗪-3-基)-3-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-2,5-二甲酰胺(47c)的制备
Step 3: N 5 -(6-Bromopyridazin-3-yl)-3-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)- Preparation of 1,4-dihydropyridine-2,5-dimethylformamide (47c)
在含有DMF(5mL)的反应瓶中加入5-((6-溴哒嗪-3-基)氨基甲酰基)-3-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-2-羧酸(300mg,0.56mmol)、氯化铵(91mg,1.69mmol)、三吡咯烷基溴化磷六氟磷酸盐(394mg,0.85mmol)和DIPEA(364mg,2.82mmol)。将混合物于室温搅拌2小时后,加入饱和的碳酸氢钠水溶液淬灭,乙酸乙酯萃取(10mL×3),合并有机相。将有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为MeOH:DCM=1:10),得到N
5-(6-溴哒嗪-3-基)-3-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-2,5-二甲酰胺(240mg,黄色固体,收率:80.0%)。
Add 5-((6-bromopyridazin-3-yl)carbamoyl)-3-(4-fluorophenyl)-4-oxo-1-(4) to a reaction vial containing DMF (5 mL) Hydrogen-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2-carboxylic acid (300 mg, 0.56 mmol), ammonium chloride (91 mg, 1.69 mmol), tripyrrolidinyl bromide Phosphorus hexafluorophosphate (394 mg, 0.85 mmol) and DIPEA (364 mg, 2.82 mmol). After the mixture was stirred at room temperature for 2 hr, EtOAc (EtOAc m. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by chromatography on silica gel column chromatography (eluent MeOH: DCM = 1: 10) , to give N 5 - (6- bromo-3-yl) -3- (4-fluorophenyl) - 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2,5-dimethylformamide (240 mg, yellow solid, yield: 80.0 %).
LC-MS(ESI):m/z 530.1/532.1[M/M+H
+]。
LC-MS (ESI): m / z 530.1 / 532.1 [M / M + H +].
步骤4:(2-氨基-5-溴吡啶-3-基)硼酸(47d)的制备Step 4: Preparation of (2-amino-5-bromopyridin-3-yl)boronic acid (47d)
于室温,在含有(25mL)1,4-二氧六环的反应瓶中加入2-氨基-3-碘-5-溴吡啶(2.5g,8.36mmol)、联硼酸频那醇脂(3.2g,12.5mmol)、乙酸钾(2.46g,25.0mmol)、Pd
2(dba)
3(1.53g,1.67mmol)和三环己基膦(234mg,0.83mmol)。密封,氮气置换三次,加热至90℃搅拌过夜。待反应液冷却至室温后,过滤,滤液用水(30mL)稀释,乙酸乙酯萃取(30mL×3),合并有机相。将有机相用饱和的食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱液为DCM:CH
3OH/10:1),得到(2-氨基-5-溴吡啶-3-基)硼酸(47d)(1.5g,黄色固体,收率:83.4%)。
2-Amino-3-iodo-5-bromopyridine (2.5 g, 8.36 mmol) and diboronic acid pinacol (3.2 g) were added to a reaction flask containing (25 mL) 1,4-dioxane at room temperature. 12.5 mmol), potassium acetate (2.46 g, 25.0 mmol), Pd 2 (dba) 3 (1.53 g, 1.67 mmol) and tricyclohexylphosphine (234 mg, 0.83 mmol). Sealed, replaced with nitrogen three times, heated to 90 ° C and stirred overnight. After the reaction mixture was cooled to room temperature, it was filtered, and the filtrate was diluted with water (30mL), ethyl acetate (30mL×3), and the organic phase was combined. The organic phase was washed with brine brine, dried over anhydrous The residue was purified by chromatography on a silica gel column chromatography (eluent DCM: CH 3 OH / 10: 1), to give (2-amino-5-bromo-3-yl) boronic acid (47d) (1.5g, yellow Solid, yield: 83.4%).
LC-MS(ESI):m/z 217.0/219.0[M/M+H
+]。
LC-MS (ESI): m / z 217.0 / 219.0 [M / M + H +].
步骤5:N
5-(6-(2-氨基-5-溴吡啶-3-基)哒嗪-3-基)-3-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-2,5-二甲酰胺(47e)的制备
Step 5: N 5 -(6-(2-Amino-5-bromopyridin-3-yl)pyridazin-3-yl)-3-(4-fluorophenyl)-4-oxo-1-(( Preparation of tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2,5-dimethylformamide (47e)
于室温,在含有(5mL)DMF和水的混合液(4:1)的反应瓶中加入(2-氨基-5-溴吡啶-3-基)硼酸(47d)(245mg,1.13mmol)、N
5-(6-溴哒嗪-3-基)-3-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-2,5二甲酰胺(47c)(240mg,0.45mmol)、碳酸钠(144mg,1.35mmol)和Pd(PPh
3)
4(104mg,0.09mmol)。密封,氮气置换三次,在微波反应器中加热至80℃搅拌20分钟。待反应液冷却至室温后,过滤,滤液用水(15mL)稀释,乙酸乙酯萃取(15mL×3),合并有机相。将有机相用饱和的食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱液为DCM:CH
3OH/5:1),得到N
5-(6-(2-氨基-5-溴吡啶-3-基)哒嗪-3-基)-3-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-2,5-二甲酰胺(47e)(90mg,黄色固体,收率:32.0%)。
(2-Amino-5-bromopyridin-3-yl)boronic acid (47d) (245 mg, 1.13 mmol), N was added to a reaction flask containing (5 mL) mixture of DMF and water (4:1) at room temperature. 5- (6-Bromopyridazin-3-yl)-3-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1 , 4-dihydro-pyridine-2,5-dicarboxamide (47c) (240mg, 0.45mmol) , sodium carbonate (144mg, 1.35mmol), and Pd (PPh 3) 4 (104mg , 0.09mmol). The mixture was sealed three times with nitrogen and heated to 80 ° C in a microwave reactor for 20 minutes. After the reaction mixture was cooled to room temperature, it was filtered, and the filtrate was diluted with water (15 mL) and ethyl acetate (15 mL×3). The organic phase was washed with brine brine, dried over anhydrous The residue was purified by chromatography on silica gel column chromatography (eluent DCM: CH 3 OH / 5: 1), to give N 5 - (6- (2- amino-5-bromo-3-yl) pyridazine - 3-yl)-3-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2, 5-Dimethylamide (47e) (90 mg, yellow solid, yield: 32.0%).
LC-MS(ESI):m/z 622.2/624.2[M/M+H
+]。
LC-MS (ESI): m / z 622.2 / 624.2 [M / M + H +].
步骤6:4-(4-(6-氨基-5-(6-(6-氨基甲酰基-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡 喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺基)哒嗪-3-基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯(47f)的制备Step 6: 4-(4-(6-Amino-5-(6-(6-carbamoyl-5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-py)喃-4-yl)methyl)-1,4-dihydropyridine-3-carboxamido)pyridazin-3-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine- Preparation of 1-carboxylic acid tert-butyl ester (47f)
于室温,在含有(2.5mL)1-4-二氧六环和水的混合液(4:1)的反应瓶中加入N
5-(6-(2-氨基-5-溴吡啶-3-基)哒嗪-3-基)-3-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-2,5-二甲酰胺(中间体47e)(90mg,0.14mmol)、4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(136mg,0.36mmol)、碳酸铯(140mg,0.14mmol)和Pd(dppf)Cl
2.DCM(24mg,0.03mmol)。密封,氮气置换三次,在微波反应器中加热至80℃搅拌40分钟。待反应液冷却至室温后,过滤,滤液用水(10mL)稀释,乙酸乙酯萃取(10mL×3),合并有机相。将有机相用饱和的食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱液为DCM:CH
3OH/5:1),得到4-(4-(6-氨基-5-(6-(6-氨基甲酰基-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺基)哒嗪-3-基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯(中间体47f)(76mg,黄色固体,收率:66.6%)。
Add N 5 -(6-(2-amino-5-bromopyridine-3-) to a reaction flask containing (2.5 mL) a mixture of 1-4-dioxane and water (4:1) at room temperature. Pyridazine-3-yl)-3-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-di Hydropyridine-2,5-dimethylformamide (intermediate 47e) (90 mg, 0.14 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclohexane) tert-Butyl pentrol-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (136 mg, 0.36 mmol), cesium carbonate (140 mg, 0.14 mmol) and Pd(dppf)Cl 2 . DCM (24 mg, 0.03 mmol). The mixture was sealed three times with nitrogen and heated to 80 ° C in a microwave reactor for 40 minutes. After the reaction mixture was cooled to room temperature, it was filtered, and the filtrate was diluted with water (10 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by chromatography on silica gel column chromatography (eluent DCM: CH 3 OH / 5: 1), to give 4- (4- (6-amino-5- (6- (6-carbamoyl- -(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamido)pyridazine tert-Butyl -3-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Intermediate 47f) (76 mg, yellow solid, yield: 66.6%).
LC-MS(ESI):m/z 793.4[M+H
+]。
LC-MS (ESI): m / z 793.4 [M + H +].
步骤7:N
5-(6-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)哒嗪-3-基)-3-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-2,5-二甲酰胺(47)的制备
Step 7: N 5 -(6-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)pyridazin-3-yl) -3-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2,5-dimethyl Preparation of amide (47)
在含有DCM(3mL)的反应瓶中加入4-(4-(6-氨基-5-(6-(6-氨基甲酰基-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺基)哒嗪-3-基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯(47f)(76mg,0.095mmol)和盐酸的1,4-二氧六环溶液(1.5mL,4M)。将混合物于室温搅拌1小时后,减压浓缩。残余物通过制备HPLC纯化(C18,乙腈/水(0.1%甲酸):10%~100%),得到N
5-(6-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)哒嗪-3-基)-3-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-2,5-二甲酰胺(47)(15.7mg,白色固体,23.8%)。
Add 4-(4-(6-amino-5-(6-(6-carbamoyl-5-(4-fluorophenyl)-4-oxo-1-) to a reaction flask containing DCM (3 mL) ((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamido)pyridazin-3-yl)pyridin-3-yl)-1H-pyrazole tert-Butyl ester of 1-yl)piperidine-l-carboxylate (47f) (76 mg, 0.095 mmol) and 1,4-dioxane hydrochloride (1.5 mL, 4M). The mixture was stirred at room temperature for 1 hour and then concentrated. The residue was purified by preparative HPLC (C18, acetonitrile / water (0.1% formic acid): 10% to 100%) to yield N 5 - (6- (2- amino-5- (l- (piperidin-4-yl) -1H-pyrazol-4-yl)pyridin-3-yl)pyridazin-3-yl)-3-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran) 4-yl)methyl)-1,4-dihydropyridine-2,5-dimethylformamide (47) (15.7 mg, white solid, 23.8%).
LC-MS(ESI):m/z 693.4[M+H
+]。
LC-MS (ESI): m / z 693.4 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ13.57(s,1H),8.84(s,1H),8.63(d,J=9.5Hz,1H),8.48(d,J=9.6Hz,1H),8.42–8.18(m,5H),8.01(s,1H),7.94(d,J=0.7Hz,1H),7.37(dt,J=8.3,4.2Hz,4H),7.29–7.15(m,2H),4.58–4.21(m,1H),4.13(d,J=7.4Hz,2H),4.01–3.77(m,2H),3.40–2.99(m,4H),2.92–2.66(m,2H),2.24–2.03(m,3H),1.95(dt,J=12.9,9.3Hz,2H),1.47(d,J=12.3Hz,2H),1.34(qd,J=12.1,4.4Hz,2H)。
1 H NMR (400MHz, DMSO- d 6) δ13.57 (s, 1H), 8.84 (s, 1H), 8.63 (d, J = 9.5Hz, 1H), 8.48 (d, J = 9.6Hz, 1H) , 8.42–8.18 (m, 5H), 8.01 (s, 1H), 7.94 (d, J = 0.7 Hz, 1H), 7.37 (dt, J = 8.3, 4.2 Hz, 4H), 7.29–7.15 (m, 2H) ), 4.58–4.21 (m, 1H), 4.13 (d, J=7.4 Hz, 2H), 4.01–3.77 (m, 2H), 3.40–2.99 (m, 4H), 2.92–2.66 (m, 2H), 2.24 - 2.03 (m, 3H), 1.95 (dt, J = 12.9, 9.3 Hz, 2H), 1.47 (d, J = 12.3 Hz, 2H), 1.34 (qd, J = 12.1, 4.4 Hz, 2H).
实施例48:N
5-(6-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)哒嗪-3-基)-3-(4-氟苯基)-N
2-甲基-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-2,5-二甲酰胺(48)的制备
Example 48: N 5 -(6-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)pyridazin-3-yl )-3-(4-fluorophenyl)-N 2 -methyl-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine Preparation of -2,5-dimethylformamide (48)
采用与实施例47相同的方法,除了用甲胺盐酸盐代替氯化铵,制得N
5-(6-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)哒嗪-3-基)-3-(4-氟苯基)-N
2-甲基-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-2,5-二甲酰胺(48)(白色固体,四步收率:10.2%)。
In the same manner as in Example 47, except that methylamine hydrochloride was used instead of ammonium chloride, N 5 -(6-(2-amino-5-(1-(piperidin-4-yl)-1H-) was obtained. Pyrazol-4-yl)pyridin-3-yl)pyridazin-3-yl)-3-(4-fluorophenyl)-N 2 -methyl-4-oxo-1-((tetrahydro-2H) -pyran-4-yl)methyl)-1,4-dihydropyridine-2,5-dimethylformamide (48) (white solid, four-step yield: 10.2%).
LC-MS(ESI):m/z 707.4[M+H
+]。
LC-MS (ESI): m / z 707.4 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ13.56(s,1H),8.84(s,1H),8.75(q,J=4.7Hz,1H),8.63(d,J=9.5Hz,1H),8.48(d,J=9.6Hz,1H),8.42–8.25(m,2H),8.29–8.16(m,2H),7.93(s,1H),7.35(td,J=5.6,2.4Hz,4H),7.28–7.09(m,2H),4.08(d,J=7.3Hz,2H),3.92–3.81(m,2H),3.28–3.12(m,4H),2.80(t,J=12.0Hz,2H),2.50–2.45(m,5H),2.09(d,J=13.2Hz,3H),1.99–1.90(m,1H),1.52–1.15(m,4H)。
1 H NMR (400MHz, DMSO- d 6) δ13.56 (s, 1H), 8.84 (s, 1H), 8.75 (q, J = 4.7Hz, 1H), 8.63 (d, J = 9.5Hz, 1H) , 8.48 (d, J = 9.6 Hz, 1H), 8.42 - 8.25 (m, 2H), 8.29 - 8.16 (m, 2H), 7.93 (s, 1H), 7.35 (td, J = 5.6, 2.4 Hz, 4H ), 7.28–7.09 (m, 2H), 4.08 (d, J = 7.3 Hz, 2H), 3.92–3.81 (m, 2H), 3.28–3.12 (m, 4H), 2.80 (t, J = 12.0 Hz, 2H), 2.50 - 2.45 (m, 5H), 2.09 (d, J = 13.2 Hz, 3H), 1.99 - 1.90 (m, 1H), 1.52 - 1.15 (m, 4H).
实施例49:N
5-(6-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)哒嗪-3-基)-3-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-2,5-二甲酰胺(49)的制备
Example 49: N 5 -(6-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)pyridazin-3-yl Preparation of 3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (49)
采用与实施例47相同的方法,除了用6-(乙氧基羰基)-5-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-3-羧酸(a)代替5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸(c),制得N
5-(6-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)哒嗪-3-基)-3-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-2,5-二甲酰胺(49)(白色固体,六步收率:3.1%)。
The same procedure as in Example 47 was employed except that 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3- Carboxylic acid (a) in place of 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3 -carboxylic acid (c) to give N 5 -(6-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)pyridazine 3-yl)-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (49) (white solid, six steps Yield: 3.1%).
LC-MS(ESI):m/z 609.4[M+H
+]。
LC-MS (ESI): m / z 609.4 [M + H +].
实施例50:5-((6-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)哒嗪-3-基)吡啶-3-基)氨基甲酰基)-3-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-2-羧酸乙酯(50)的制备Example 50: 5-((6-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridazin-3-yl)pyridin-3-yl Preparation of ethyl carbamoyl)-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylate (50)
采用与实施例47相同的方法,除了用6-(乙氧基羰基)-5-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-3-羧酸(a)代替5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸(c),制得5-((6-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)哒嗪-3-基)吡啶-3-基)氨基甲酰基)-3-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-2-羧酸乙酯(50)(白色固体,5步收率:6.3%)。The same procedure as in Example 47 was employed except that 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3- Carboxylic acid (a) in place of 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3 -carboxylic acid (c) to give 5-((6-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridazin-3-yl)pyridine -3-yl)carbamoyl)-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid ethyl ester (50) (white solid , 5 steps yield: 6.3%).
LC-MS(ESI):m/z 638.4[M+H
+]。
LC-MS (ESI): m / z 638.4 [M + H +].
实施例51:N-(6-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)哒嗪-3-基)-6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-甲酰胺(51)的制备Example 51: N-(6-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)pyridazin-3-yl) -6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2- d] Preparation of pyrazine-8-carboxamide (51)
步骤1:N-(6-溴哒嗪-3-基)-6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-D]吡嗪-8-甲酰胺(51a)的制备Step 1: N-(6-Bromopyridazin-3-yl)-6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrocaine Preparation of oxazo[3,2-a]pyrido[1,2-D]pyrazine-8-carboxamide (51a)
在含有DMF(3mL)的反应瓶中加入6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-羧酸(o)(80mg,0.24mmol)、6-溴哒嗪-3-胺(80mg,0.48mmol)、HATU(176mg,0.48mmol)和DIPEA(120mg,0.96mmol)。将混合物于室温搅拌12小时,待反应完全后,加入饱和的碳酸氢钠溶液淬灭,用乙酸乙酯萃取(10mLx3),合并有机相。将有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为MeOH:DCM=1:10),得到N-(6-溴哒嗪-3-基)-6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-D]吡嗪-8-甲酰胺(51a)(70mg,黄色油状物,收率:58.1%)。Add 6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazole [3,2] to a reaction flask containing DMF (3 mL). -a] Pyrido[1,2-d]pyrazine-8-carboxylic acid (o) (80 mg, 0.24 mmol), 6-bromopyridazin-3-amine (80 mg, 0.48 mmol), HATU (176 mg, 0.48) Methyl) and DIPEA (120 mg, 0.96 mmol). The mixture was stirred at room temperature for 12 hr. EtOAc (EtOAc) The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography eluting elut elut elut elut elut ,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-D]pyrazine-8-carboxamide (51a) (70 mg, yellow oil, yield: 58.1%).
LC-MS(ESI):m/z 500.0/502.0[M+H
+]。
LC-MS (ESI): m / z 500.0 / 502.0 [M + H +].
步骤2:N-(6-(2-氨基-5-溴吡啶-3-基)哒嗪-3-基)-6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-甲酰胺(51b)的制备Step 2: N-(6-(2-Amino-5-bromopyridin-3-yl)pyridazin-3-yl)-6-(4-fluorophenyl)-5,7-dioxo-2, Preparation of 3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (51b)
于室温,在含有(2.5mL)DMF和水的混合液(4:1)的反应瓶中加入(2-氨基-5-溴吡啶-3-基)硼酸(47d)(61mg,0.28mmol)、N-(6-溴哒嗪-3-基)-6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-D]吡嗪-8-甲酰胺(51a)(70mg,0.14mmol)、碳酸钠(45mg,0.42mmol)和Pd(PPh
3)
4(16mg,0.01mmol)。密封,氮气置换三次,在微波反应器中加热至80℃搅拌20分钟。待反应液冷却至室温后,过滤,滤液用水(10mL)稀释,乙酸乙酯萃取(10mL×3),合并有机相。将有机相用饱和的食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱液为DCM:CH
3OH/5:1),得到N-(6-(2-氨基-5-溴吡啶-3-基)哒嗪-3-基)-6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-甲酰胺(51b)(30mg,黄色固体,收率:36.2%)。
(2-Amino-5-bromopyridin-3-yl)boronic acid (47d) (61 mg, 0.28 mmol) was added to a reaction flask containing (2.5 mL) a mixture of DMF and water (4:1). N-(6-Bromopyridazin-3-yl)-6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazole[ 3,2-a]pyrido[1,2-D]pyrazine-8-carboxamide (51a) (70 mg, 0.14 mmol), sodium carbonate (45 mg, 0.42 mmol) and Pd(PPh 3 ) 4 (16 mg, 0.01 mmol). The mixture was sealed three times with nitrogen and heated to 80 ° C in a microwave reactor for 20 minutes. After the reaction mixture was cooled to room temperature, it was filtered, and the filtrate was diluted with water (10 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by chromatography on silica gel column chromatography (eluent DCM: CH 3 OH / 5: 1), to give N- (6- (2- amino-5-bromo-3-yl) pyridazin-3 -yl)-6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyridin[1 , 2-d] pyrazine-8-carboxamide (51b) (30 mg, yellow solid, yield: 36.2%).
LC-MS(ESI):m/z 592.1/594.1[M+H
+]。
LC-MS (ESI): m / z 592.1 / 594.1 [M + H +].
步骤3:4-(4-(6-氨基-5-(6-(6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-D]吡嗪-8-甲酰胺基)哒嗪-3-基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯(51c)的制备Step 3: 4-(4-(6-Amino-5-(6-(6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-six Hydrocarbazolo[3,2-a]pyrido[1,2-D]pyrazine-8-carboxamido)pyridazin-3-yl)pyridin-3-yl)-1H-pyrazole-1- Preparation of tert-butyl ester of piperidine-1-carboxylate (51c)
于室温,在含有(2.5mL)1-4-二氧六环和水的混合液(4:1)的反应瓶中加入N-(6-(2-氨基-5-溴吡啶-3-基)哒嗪-3-基)-6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-甲酰胺(51b)(30mg,0.05mmol)、4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(25mg,0.06mmol)、碳酸铯(50mg,0.15mmol)和Pd(dppf)Cl
2.DCM(5mg,0.005mmol)。密封,氮气置换三次,在微波反应器中加热至80℃搅拌40分钟。待反应液冷却至室温后,过滤,滤液用水(10mL)稀释,乙酸乙酯萃取(10mL×3),合并有机相。将有机相用饱和的食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过硅胶柱 层析色谱法纯化(洗脱液为DCM:CH
3OH/5:1),得到4-(4-(6-氨基-5-(6-(6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-D]吡嗪-8-甲酰胺基)哒嗪-3-基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯(51c)(10mg,黄色固体,收率:26.3%)。
Add N-(6-(2-amino-5-bromopyridin-3-yl) to a reaction flask containing (2.5 mL) a mixture of 1-4-dioxane and water (4:1) at room temperature. Pyridazin-3-yl)-6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazole [3,2-a Pyrido[1,2-d]pyrazine-8-carboxamide (51b) (30 mg, 0.05 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2) -Dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (25 mg, 0.06 mmol), cesium carbonate (50 mg, 0.15 mmol) and Pd ( Dppf) Cl 2 .DCM (5 mg, 0.005 mmol). The mixture was sealed three times with nitrogen and heated to 80 ° C in a microwave reactor for 40 minutes. After the reaction mixture was cooled to room temperature, it was filtered, and the filtrate was diluted with water (10 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by chromatography on silica gel column chromatography (eluent DCM: CH 3 OH / 5: 1), to give 4- (4- (6-amino-5- (6- (6- (4-Fluorophenyl -5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-D]pyrazine-8- Amido)pyridazin-3-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (51c) (10 mg, yellow solid, yield: 26.3% ).
LC-MS(ESI):m/z 763.4[M+H
+]。
LC-MS (ESI): m / z 763.4 [M + H +].
步骤4:N-(6-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)哒嗪-3-基)-6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-甲酰胺(51)的制备Step 4: N-(6-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)pyridazin-3-yl)- 6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d Preparation of pyrazine-8-carboxamide (51)
在含有DCM(3mL)的反应瓶中加入4-(4-(6-氨基-5-(6-(6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-D]吡嗪-8-甲酰氨基)哒嗪-3-基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯(51c)(10mg,0.01mmol)和盐酸的1,4-二氧六环溶液(1.5mL,4M)。将混合物于室温搅拌1小时后,减压浓缩。残余物通过制备HPLC纯化(C18,乙腈/水(0.1%甲酸):10%~100%),得到N-(6-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)哒嗪-3-基)-6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-甲酰胺(51)(2.3mg,白色固体,34.7%)。Add 4-(4-(6-amino-5-(6-(6-(4-fluorophenyl)-5,7-dioxo-2,3,5) to a reaction flask containing DCM (3 mL) ,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-D]pyrazine-8-carboxamido)pyridazin-3-yl)pyridin-3-yl) -1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (51c) (10 mg, 0.01 mmol) and 1,4-dioxane hydrochloride (1.5 mL, 4M). The mixture was stirred at room temperature for 1 hour and then concentrated. The residue was purified by preparative HPLC (C18, EtOAc/EtOAc (EtOAc:EtOAc:EtOAc:EtOAc) 1H-pyrazol-4-yl)pyridin-3-yl)pyridazin-3-yl)-6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11 , 11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (51) (2.3 mg, white solid, 34.7%).
LC-MS(ESI):m/z 663.3[M+H
+]。
LC-MS (ESI): m / z 663.3 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ13.60–13.51(m,1H),9.33–9.25(m,1H),9.03–8.98(m,1H),8.95(s,1H),8.87–8.78(m,1H),8.76–8.66(m,1H),8.64–8.54(m,2H),8.45(s,2H),8.08(s,2H),7.18(d,J=7.5Hz,3H),5.54–5.46(m,1H),5.36–5.26(m,1H),5.05–4.98(m,1H),4.60–4.48(m,2H),4.27–4.17(m,2H),4.11–4.01(m,2H),3.86–3.80(m,1H),3.19–3.06(m,3H),2.30–2.11(m,4H)。
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.60 - 13.51 (m, 1H), 9.33 - 9.25 (m, 1H), 9.03 - 8.98 (m, 1H), 8.95 (s, 1H), 8.87 - 8.78 (m, 1H), 8.76–8.66 (m, 1H), 8.64–8.54 (m, 2H), 8.45 (s, 2H), 8.08 (s, 2H), 7.18 (d, J = 7.5 Hz, 3H), 5.54–5.46 (m, 1H), 5.36–5.26 (m, 1H), 5.05–4.98 (m, 1H), 4.60–4.48 (m, 2H), 4.27–4.17 (m, 2H), 4.11–4.01 (m) , 2H), 3.86–3.80 (m, 1H), 3.19–3.06 (m, 3H), 2.30–2.11 (m, 4H).
实施例52:N-(6-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)哒嗪-3-基)-10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酰胺(52)的制备Example 52: N-(6-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)pyridazin-3-yl) -10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepine Preparation of cycloheptane-8-carboxamide (52)
采用与实施例51相同的方法,除了用10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸(d)代替6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-羧酸(o),制得N-(6-(2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)哒嗪-3-基)-10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酰胺(52)(白色固体,4步收率:4.3%)。The same procedure as in Example 51 was employed except that 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2- a][1,4]diazepane-8-carboxylic acid (d) instead of 6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a - hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (o) to give N-(6-(2-amino-5-(1-) (piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)pyridazin-3-yl)-10-(4-fluorophenyl)-1,9-dioxo- 1,2,3,4,5,9-Hexidopyrido[1,2-a][1,4]diazepane-8-carboxamide (52) (white solid, 4-step yield :4.3%).
LC-MS(ESI):m/z 635.4[M+H
+]。
LC-MS (ESI): m / z 635.4 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ13.62(s,1H),8.90(s,1H),8.70(s,1H),8.62(d,J=9.5Hz,1H),8.45(d,J=9.7Hz,1H),8.37(d,J=2.2Hz,1H),8.30(s,1H),8.25–8.18(m,2H),7.92(s,1H),7.31(dd,J=8.5,5.6Hz,3H),7.22(t,J=9.0Hz,2H),4.65(s,1H),4.27(s,1H),4.07(s,1H),3.34(s,2H),3.16(d,J=12.6Hz,2H),2.75(t,J=11.1Hz,2H),1.98(dd,J=67.0,10.3Hz,6H)。
1 H NMR (400MHz, DMSO- d 6) δ13.62 (s, 1H), 8.90 (s, 1H), 8.70 (s, 1H), 8.62 (d, J = 9.5Hz, 1H), 8.45 (d, J = 9.7 Hz, 1H), 8.37 (d, J = 2.2 Hz, 1H), 8.30 (s, 1H), 8.25 - 8.18 (m, 2H), 7.92 (s, 1H), 7.31 (dd, J = 8.5 , 5.6 Hz, 3H), 7.22 (t, J = 9.0 Hz, 2H), 4.65 (s, 1H), 4.27 (s, 1H), 4.07 (s, 1H), 3.34 (s, 2H), 3.16 (d) , J = 12.6 Hz, 2H), 2.75 (t, J = 11.1 Hz, 2H), 1.98 (dd, J = 67.0, 10.3 Hz, 6H).
实施例53:N-(6-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)哒嗪-3-基)-10-(4-氟苯基)-1,9-二氧代-1,2-,3,4,5,9-六氢吡啶并[1,2-D][1,4]二氮杂环庚烷-8-甲酰胺(53)的制备Example 53: N-(6-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)pyridazin-3-yl)-10-(4-fluorophenyl) -1,9-dioxo-1,2-,3,4,5,9-hexahydropyrido[1,2-D][1,4]diazepane-8-carboxamide Preparation of (53)
采用与实施例52相同的方法,除了用3,4-二甲氧基苯硼酸代替4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯,制得N-(6-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)哒嗪-3-基)-10-(4-氟苯基)-1,9-二氧代-1,2-,3,4,5,9-六氢吡啶并[1,2-D][1,4]二氮杂环庚烷-8-甲酰胺(53)(白色固体,三步收率:7.8%)。The same procedure as in Example 52 was employed except that 3,4-dimethoxyphenylboronic acid was used in place of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclo). tert-Butyl pentrol-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate to give N-(6-(2-amino-5-(3,4-dimethoxy) Phenyl) pyridin-3-yl)pyridazin-3-yl)-10-(4-fluorophenyl)-1,9-dioxo-1,2-,3,4,5,9-six Hydropyrido[1,2-D][1,4]diazepane-8-carboxamide (53) (white solid, three-step yield: 7.8%).
LC-MS(ESI):m/z 622.3[M+H
+]。
LC-MS (ESI): m / z 622.3 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.78(s,1H),8.62(s,1H),8.50(s,1H),8.35(d,J=2.1Hz,1H),7.82(d,J=8.4Hz,2H),7.62(s,1H),7.55(d,J=8.4Hz,2H),7.18–7.12(m,2H),6.95(d,J=8.3Hz,2H),5.68(s,2H),4.53(s,2H),4.15–3.99(m,2H),3.77(d,J=22.3Hz,6H),2.12(s,2H)。
1 H NMR (400MHz, DMSO- d 6) δ12.78 (s, 1H), 8.62 (s, 1H), 8.50 (s, 1H), 8.35 (d, J = 2.1Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.62 (s, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.18 - 7.12 (m, 2H), 6.95 (d, J = 8.3 Hz, 2H), 5.68 ( s, 2H), 4.53 (s, 2H), 4.15 - 3.99 (m, 2H), 3.77 (d, J = 22.3 Hz, 6H), 2.12 (s, 2H).
实施例54:N-(6-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)哒嗪-3-基)-1-(4-氟苯基)-2,12-二氧代-2,6,6a,7,8,9,10,12-八氢二吡啶并[1,2-a:1',2'-d]吡嗪-3-甲酰胺(54)的制备Example 54: N-(6-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)pyridazin-3-yl)-1-(4-fluorophenyl) -2,12-dioxo-2,6,6a,7,8,9,10,12-octahydrodipyrido[1,2-a:1',2'-d]pyrazine-3 -formamide (54) preparation
采用与实施例53相同的方法,除了用1-(4-氟苯基)-2,12-二氧代-2,6,6a,7,8,9,10,12-八氢二吡啶并[1,2-a:1',2'-d]吡嗪-3-甲酸(g)代替10-(4-氟苯 基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸(d),制得N-(6-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)哒嗪-3-基)-1-(4-氟苯基)-2,12-二氧代-2,6,6a,7,8,9,10,12-八氢二吡啶并[1,2-a:1',2'-d]吡嗪-3-甲酰胺(54)(白色固体,三步收率:6.5%)。The same procedure as in Example 53 was carried out except that 1-(4-fluorophenyl)-2,12-dioxo-2,6,6a,7,8,9,10,12-octahydrodipyridine was used. [1,2-a:1',2'-d]pyrazine-3-carboxylic acid (g) instead of 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4 ,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylic acid (d), to give N-(6-(2-amino-5-( 3,4-Dimethoxyphenyl)pyridin-3-yl)pyridazin-3-yl)-1-(4-fluorophenyl)-2,12-dioxo-2,6,6a,7 ,8,9,10,12-octahydrodipyrido[1,2-a:1',2'-d]pyrazine-3-carboxamide (54) (white solid, three-step yield: 6.5%) ).
LC-MS(ESI):m/z 662.3[M+H
+]。
LC-MS (ESI): m / z 662.3 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.69(s,1H),8.82(s,1H),8.43(d,J=58.4Hz,2H),7.86(d,J=8.2Hz,2H),7.77–7.30(m,3H),7.21–6.98(m,4H),5.68(s,2H),4.30–4.21(m,1H),4.13(t,J=10.6Hz,2H),3.70(d,J=22.0Hz,6H),3.60–3.51(m,2H),1.29-1.15(t,J=10.0Hz,6H)。
1 H NMR (400MHz, DMSO- d 6) δ12.69 (s, 1H), 8.82 (s, 1H), 8.43 (d, J = 58.4Hz, 2H), 7.86 (d, J = 8.2Hz, 2H) , 7.77–7.30 (m, 3H), 7.21–6.98 (m, 4H), 5.68 (s, 2H), 4.30–4.21 (m, 1H), 4.13 (t, J = 10.6 Hz, 2H), 3.70 (d) , J = 22.0 Hz, 6H), 3.60 - 3.51 (m, 2H), 1.29 - 1.15 (t, J = 10.0 Hz, 6H).
实施例55:N-(6-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)哒嗪-3-基)-7-(4-氟苯基)-6,8-二氧代-3,4-,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酰胺(55)的制备Example 55: N-(6-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)pyridazin-3-yl)-7-(4-fluorophenyl )-6,8-dioxo-3,4-,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b Preparation of [1,3]oxazine-9-carboxamide (55)
采用与实施例53相同的方法,除了用7-(4-氟苯基)-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酸(k)代替10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸(d),制得N-(6-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)哒嗪-3-基)-7-(4-氟苯基)-6,8-二氧代-3,4-,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酰胺(55)(白色固体,三步收率:9.3%)。The same procedure as in Example 53 was carried out except that 7-(4-fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1] was used. ',2':4,5]pyrazine[2,1-b][1,3]oxazine-9-carboxylic acid (k) instead of 10-(4-fluorophenyl)-1,9-dioxo Generation of 1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylic acid (d) to give N-(6 -(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)pyridazin-3-yl)-7-(4-fluorophenyl)-6,8-dioxo Generation-3,4-,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine -9-carboxamide (55) (white solid, three-step yield: 9.3%).
LC-MS(ESI):m/z 664.3[M+H
+]。
LC-MS (ESI): m / z 664.3 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.74(s,1H),8.89(s,1H),8.36(d,J=58.4Hz,2H),7.83(d,J=8.2Hz,2H),7.67–7.36(m,3H),7.40–6.94(m,4H),5.68(s,2H),5.57(d,J=6.6Hz,1H),4.96(d,J=9.2Hz,1H),4.41–4.33(m,1H),4.17(t,J=10.6Hz,2H),3.81(d,J=22.0Hz,6H),3.71–3.66(m,2H),1.20(t,J=10.0Hz,2H)。
1 H NMR (400MHz, DMSO- d 6) δ12.74 (s, 1H), 8.89 (s, 1H), 8.36 (d, J = 58.4Hz, 2H), 7.83 (d, J = 8.2Hz, 2H) , 7.67–7.36 (m, 3H), 7.40–6.94 (m, 4H), 5.68 (s, 2H), 5.57 (d, J = 6.6 Hz, 1H), 4.96 (d, J = 9.2 Hz, 1H), 4.41–4.33(m,1H), 4.17(t,J=10.6Hz,2H),3.81(d,J=22.0Hz,6H),3.71–3.66(m,2H),1.20(t,J=10.0Hz , 2H).
实施例56:N-(6-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)哒嗪-3-基)-6-(4-氟苯基)-5,7-二氧代-1,2,3,4-5,7,11,11a六氢-1H-吡啶并[1,2-a]吡咯并[1,2-D]吡嗪-8-甲酰胺(56)的制备Example 56: N-(6-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)pyridazin-3-yl)-6-(4-fluorophenyl -5,7-dioxo-1,2,3,4-5,7,11,11a hexahydro-1H-pyrido[1,2-a]pyrrolo[1,2-D]pyrazine Preparation of -8-formamide (56)
采用与实施例53相同的方法,除了用6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢-1H-吡啶并[1,2-a]吡咯并[1,2-D]吡嗪-8-羧酸(h)代替10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸(d),制得N-(6-(2-氨基-5-(3,4-二甲氧基苯基)吡啶-3-基)哒嗪-3-基)-6-(4-氟苯基)-5,7-二氧代-1,2,3,4-5,7,11,11a-六氢-1H-吡啶并[1,2-a]吡咯并[1,2-D]吡嗪-8-甲酰胺(56)(白色固体,三步收率:6.1%)。The same procedure as in Example 53 was employed except that 6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydro-1H-pyrido[1] was used. ,2-a]pyrrolo[1,2-D]pyrazine-8-carboxylic acid (h) instead of 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4 ,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylic acid (d), to give N-(6-(2-amino-5-( 3,4-Dimethoxyphenyl)pyridin-3-yl)pyridazin-3-yl)-6-(4-fluorophenyl)-5,7-dioxo-1,2,3,4 -5,7,11,11a-hexahydro-1H-pyrido[1,2-a]pyrrolo[1,2-D]pyrazine-8-carboxamide (56) (white solid, three-step yield : 6.1%).
LC-MS(ESI):m/z 648.3[M+H
+]。
LC-MS (ESI): m / z 648.3 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.61(s,1H),8.88(s,1H),8.43(d,J=58.4Hz,2H),7.72(d,J=8.2Hz,2H),7.69–7.36(m,3H),7.30–6.85(m,4H),5.66(s,2H),4.40–4.30(m,1H),4.15(t,J=10.6Hz,2H),3.80(d,J=22.0Hz,6H),3.70–3.61(m,2H),1.21(t,J=10.0Hz,4H)。
1 H NMR (400MHz, DMSO- d 6) δ12.61 (s, 1H), 8.88 (s, 1H), 8.43 (d, J = 58.4Hz, 2H), 7.72 (d, J = 8.2Hz, 2H) , 7.69–7.36 (m, 3H), 7.30–6.85 (m, 4H), 5.66 (s, 2H), 4.40–4.30 (m, 1H), 4.15 (t, J = 10.6 Hz, 2H), 3.80 (d) , J = 22.0 Hz, 6H), 3.70 - 3.61 (m, 2H), 1.21 (t, J = 10.0 Hz, 4H).
实施例57:N-(2'-氨基-5'-(3,4-二甲氧基苯基)-[3,3'-联吡啶]-6-基)-7-(6-甲基吡啶-3-基)-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酰胺(57)的制备Example 57: N-(2'-Amino-5'-(3,4-dimethoxyphenyl)-[3,3'-bipyridyl]-6-yl)-7-(6-methyl Pyridin-3-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazine[2 , 1-b][1,3] Preparation of Oxazine-9-carboxamide (57)
采用与实施例53相同的方法,除了用7-(6-甲基吡啶-3-基)-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酸(m)和2-氨基-5溴吡啶分别代替10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸(d)和2-氨基-5-溴哒嗪,制得N-(2'-氨基-5'-(3,4-二甲氧基苯基)-[3,3'-联吡啶]-6-基)-7-(6-甲基吡啶-3-基)-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酰胺(57)(白色固体,三步收率:9.7%)。The same procedure as in Example 53 was employed except that 7-(6-methylpyridin-3-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H- Pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (m) and 2-amino-5bromopyridine are substituted for 10-( 4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane- 8-carboxylic acid (d) and 2-amino-5-bromopyridazine to obtain N-(2'-amino-5'-(3,4-dimethoxyphenyl)-[3,3'-linked Pyridyl]-6-yl)-7-(6-methylpyridin-3-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyridinium[ 1', 2': 4,5] pyrazino[2,1-b][1,3]oxazine-9-carboxamide (57) (white solid, three-step yield: 9.7%).
LC-MS(ESI):m/z 660.3[M+H
+]。
LC-MS (ESI): m / z 660.3 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.84(s,1H),8.95(s,1H),8.46(d,J=2.3Hz,1H),8.37(d,J=8.6Hz,1H),8.29(d,J=2.4Hz,1H),8.12(s,1H),8.00(dd,J=8.6,2.4Hz,1H),7.66(d,J=2.4Hz,1H),7.42(d,J=7.9Hz,1H),7.26(d,J=7.9Hz,1H),7.20(d,J=2.1Hz,1H),7.16(dd,J=8.3,2.1Hz,1H),6.99(d,J=8.4Hz,1H),5.83(s, 2H),5.32(d,J=11.4Hz,1H),4.75–4.55(m,2H),4.24(d,J=13.3Hz,1H),4.07(s,1H),3.87(t,J=11.8Hz,1H),3.80(d,J=21.9Hz,6H),3.25–2.97(m,1H),2.52(s,3H),1.79–1.53(m,2H)。
1 H NMR (400MHz, DMSO- d 6) δ12.84 (s, 1H), 8.95 (s, 1H), 8.46 (d, J = 2.3Hz, 1H), 8.37 (d, J = 8.6Hz, 1H) , 8.29 (d, J = 2.4 Hz, 1H), 8.12 (s, 1H), 8.00 (dd, J = 8.6, 2.4 Hz, 1H), 7.66 (d, J = 2.4 Hz, 1H), 7.42 (d, J = 7.9 Hz, 1H), 7.26 (d, J = 7.9 Hz, 1H), 7.20 (d, J = 2.1 Hz, 1H), 7.16 (dd, J = 8.3, 2.1 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 5.83 (s, 2H), 5.32 (d, J = 11.4 Hz, 1H), 4.75 - 4.55 (m, 2H), 4.24 (d, J = 13.3 Hz, 1H), 4.07 ( s, 1H), 3.87 (t, J = 11.8 Hz, 1H), 3.80 (d, J = 21.9 Hz, 6H), 3.25 - 2.97 (m, 1H), 2.52 (s, 3H), 1.79 - 1.53 (m , 2H).
实施例58:N
5-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)-3-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-2,5-二甲酰胺(58)的制备
Example 58: N 5 -(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1- Preparation of methyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (58)
步骤1:5-((4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)氨基甲酰基)-3-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-2-羧酸乙酯(中间体58a)的制备Step 1: 5-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)carbamoyl)-3-(4-fluorophenyl) Preparation of ethyl 1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylate (intermediate 58a)
在含有DMF(30mL)的反应瓶中加入6-(乙氧基羰基)-5-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-3-羧酸(a)(800mg,2.51mmol)、4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯胺(ff)(790mg,2.51mmol)、HATU(1.43g,3.77mmol)和DIPEA(973mg,7.53mmol)。将混合物于室温搅拌30分钟,待反应完全后,加入饱和的碳酸氢钠溶液淬灭,用乙酸乙酯萃取(30mLx3),合并有机相。将有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为MeOH:CM=1:20),得到5-((4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)氨基甲酰基)-3-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-2-羧酸乙酯(58a)(1.4g,黄色固体,收率:90.4%)。Add 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3- to a reaction flask containing DMF (30 mL) Carboxylic acid (a) (800 mg, 2.51 mmol), 4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluoroaniline (ff) (790 mg, 2.51 mmol), HATU (1.43 g, 3.77 mmol) and DIPEA (973 mg, 7.53 mmol). The mixture was stirred at room temperature for 30 minutes. After the reaction was completed, EtOAc (EtOAc) The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography (eluent: MeOH: MeOH = 1:1) to give 5-((6,7-dimethoxyquinolin-4-yl)oxy. Ethyl 3-fluorophenyl)carbamoyl)-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylate (58a) (1.4 g, yellow solid, yield: 90.4%).
LC-MS(ESI):m/z 616.3[M+H
+]。
LC-MS (ESI): m / z 616.3 [M + H +].
步骤2:5-((4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)氨基甲酰基)-3-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-2-羧酸(58b)的制备。Step 2: 5-((4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)carbamoyl)-3-(4-fluorophenyl) Preparation of 1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid (58b).
于室温,在含有乙醇(16mL)的反应瓶中加入5-((4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)氨基甲酰基)-3-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-2-羧酸乙酯(1.4g,2.27mmol)、氢氧化锂一水合物(150mg,3.57mmol)和水(4mL)。将混合物升温至70℃并搅拌2小时,待反应完全后,减压浓缩,得到粗产品5-((4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)氨基甲酰基)-3-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-2-羧酸(58b)(1.4g,灰色固体,收率:100%)。其未经纯化直接用于下一步反应。Add 5-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)carbamoyl) to a reaction flask containing ethanol (16 mL) at room temperature Ethyl 3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylate (1.4 g, 2.27 mmol), lithium hydroxide monohydrate (150 mg, 3.57 mmol) and water (4 mL). The mixture was warmed to 70 ° C and stirred for 2 hours. After the reaction was completed, concentrated under reduced pressure to give crude 5-((4-((6,7-dimethoxyquinolin-4-yl)oxy)- 3-fluorophenyl)carbamoyl)-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid (58b) (1.4 g, Gray solid, yield: 100%). It was used directly in the next reaction without purification.
LC-MS(ESI):m/z 588.3[M+H
+]。
LC-MS (ESI): m / z 588.3 [M + H +].
步骤3:N
5-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)-3-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶2.5-甲酰胺(58)的制备
Step 3: N 5 -(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-methyl Preparation of keto-4-oxo-1,4-dihydropyridine 2.5-carboxamide (58)
在含有DMF(3mL)的反应瓶中加入5-((4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)氨基甲酰基)-3-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-2-羧酸(70mg,0.12mmol)、氯化铵(26mg,0.48mmol)、三吡咯烷基溴化鏻六氟磷酸盐(84mg,0.18mmol)和DIPEA(62mg,0.48mmol)。将混合物于室温搅拌2小时后,加入饱和的碳酸氢钠水溶液淬灭,乙酸乙酯萃取(10mL×3),合并有机相。将有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过制备HPLC纯化(C18,乙腈/水(0.1%甲酸):10%~100%),得到N
5-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)-3-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶2.5-甲酰胺(58b)(30mg,白色固体,42.9%)。
Add 5-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)carbamoyl)-3 to a reaction flask containing DMF (3 mL) -(4-Fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid (70 mg, 0.12 mmol), ammonium chloride (26 mg, 0.48 mmol), tripyrrole Alkyl bromide hexafluorophosphate (84 mg, 0.18 mmol) and DIPEA (62 mg, 0.48 mmol). After the mixture was stirred at room temperature for 2 hr, EtOAc (EtOAc m. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by preparative HPLC (C18, acetonitrile / water (0.1% formic acid): 10% to 100%) to afford N 5 - (4 - (( 6,7- dimethoxy-quinolin-4-yl) oxy 3-fluorophenyl)-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine 2.5-carboxamide (58b) (30 mg, white solid, 42.9%).
LC-MS(ESI):m/z 587.3[M+H
+]。
LC-MS (ESI): m / z 587.3 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.99(s,1H),8.83(s,1H),8.49(d,J=5.2Hz,1H),8.24(s,1H),8.05(dd,J=13.0,2.4Hz,2H),7.57–7.49(m,2H),7.48–7.41(m,2H),7.35(dd,J=8.5,5.7Hz,2H),7.25(t,J=8.8Hz,2H),6.49(d,J=5.2Hz,1H),3.96(s,6H),3.88(s,3H)。
1 H NMR (400MHz, DMSO- d 6) δ12.99 (s, 1H), 8.83 (s, 1H), 8.49 (d, J = 5.2Hz, 1H), 8.24 (s, 1H), 8.05 (dd, J = 13.0, 2.4 Hz, 2H), 7.57 - 7.49 (m, 2H), 7.48 - 7.41 (m, 2H), 7.35 (dd, J = 8.5, 5.7 Hz, 2H), 7.25 (t, J = 8.8 Hz) , 2H), 6.49 (d, J = 5.2 Hz, 1H), 3.96 (s, 6H), 3.88 (s, 3H).
实施例59:N
5-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)-3-(4-氟苯基)-N
2-1-二甲基-4-氧代-1,4-二氢吡啶-2,5-二甲酰胺(59)的制备
Example 59: N 5 -(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-N 2 Preparation of 1-dimethyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (59)
采用与实施例58相同的方法,除了用甲胺盐酸盐代替氯化铵,制得N
5-(4-((6,7- 二甲氧基喹啉-4-基)氧基)-3-氟苯基)-3-(4-氟苯基)-N
2-1-二甲基-4-氧代-1,4-二氢吡啶-2,5-二甲酰胺(59)(白色固体,一步收率:23.7%)。
In the same manner as in Example 58, except that methylamine hydrochloride was used in place of ammonium chloride, N 5 -(4-((6,7-dimethoxyquinolin-4-yl)oxy)- 3-fluorophenyl)-3-(4-fluorophenyl)-N 2 -1-dimethyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (59) White solid, one step yield: 23.7%).
LC-MS(ESI):m/z 601.3[M+H
+]。
LC-MS (ESI): m / z 601.3 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.98(s,1H),8.83(s,1H),8.73(q,J=4.7Hz,1H),8.49(d,J=5.2Hz,1H),8.05(dd,J=12.8,2.3Hz,1H),7.58–7.40(m,4H),7.38–7.18(m,4H),6.49(d,J=5.2Hz,1H),3.96(s,6H),3.83(s,3H),2.52(s,3H)。
1 H NMR (400MHz, DMSO- d 6) δ12.98 (s, 1H), 8.83 (s, 1H), 8.73 (q, J = 4.7Hz, 1H), 8.49 (d, J = 5.2Hz, 1H) , 8.05 (dd, J = 12.8, 2.3 Hz, 1H), 7.58 - 7.40 (m, 4H), 7.38 - 7.18 (m, 4H), 6.49 (d, J = 5.2 Hz, 1H), 3.96 (s, 6H) ), 3.83 (s, 3H), 2.52 (s, 3H).
实施例60:6-(氮杂环丁烷-1-甲酰基)-N-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)-5-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-3-甲酰胺(60)的制备Example 60: 6-(Azetidine-1-formyl)-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl Preparation of 5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide (60)
采用与实施例58相同的方法,除了用氮杂环丁烷盐酸盐代替氯化铵,制得N
6-(氮杂环丁烷-1-甲酰基)-N-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)-5-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-3-甲酰胺(60)(白色固体,一步收率:32.6%)。
In the same manner as in Example 58, except that azaetidine hydrochloride was used in place of ammonium chloride, N 6 -(azetidin-1-yl)-N-(4-((6) was obtained. ,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-di Hydropyridine-3-carboxamide (60) (white solid, one step yield: 32.6%).
LC-MS(ESI):m/z 627.4[M+H
+]。
LC-MS (ESI): m / z 627.4 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.91(s,1H),8.82(s,1H),8.49(d,J=5.2Hz,1H),8.05(dd,J=12.8,2.3Hz,1H),7.57–7.38(m,6H),7.31(t,J=8.7Hz,2H),6.50(d,J=5.2Hz,1H),4.01(d,J=9.6Hz,1H),3.96(s,6H),3.86(s,3H),3.58–3.49(m,2H),2.15(d,J=9.6Hz,1H),2.08–1.94(m,1H),1.85(d,J=10.6Hz,1H)。
1 H NMR (400 MHz, DMSO-d 6 ) δ 12.91 (s, 1H), 8.82 (s, 1H), 8.49 (d, J = 5.2 Hz, 1H), 8.05 (dd, J = 12.8, 2.3 Hz, 1H), 7.57–7.38 (m, 6H), 7.31 (t, J = 8.7 Hz, 2H), 6.50 (d, J = 5.2 Hz, 1H), 4.01 (d, J = 9.6 Hz, 1H), 3.96 ( s,6H),3.86(s,3H),3.58–3.49(m,2H), 2.15(d,J=9.6Hz,1H),2.08–1.94(m,1H),1.85(d,J=10.6Hz , 1H).
实施例61:N-环丙基-N
5-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)-3-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-2-5-二甲酰胺(61)的制备
Example 61: N-cyclopropyl-N 5 -(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluoro Preparation of Phenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2-5-dimethylamide (61)
采用与实施例58相同的方法,除了用环丙基胺代替氯化铵,制得N-环丙基-N
5-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)-3-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-2,5-二甲酰胺(61)(白色固体,一步收率:27.8%)。
N-cyclopropyl-N 5 -(4-((6,7-dimethoxyquinolin-4-yl) was obtained in the same manner as in Example 58 except that instead of ammonium chloride. )oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2,5-dimethylamide (61) (white solid, one step yield: 27.8%).
LC-MS(ESI):m/z 627.4[M+H
+]。
LC-MS (ESI): m / z 627.4 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.96(s,1H),8.83(d,J=3.5Hz,2H),8.49(d,J=5.2Hz,1H),8.05(dd,J=12.8,2.3Hz,1H),7.56–7.41(m,4H),7.33–7.21(m, 4H),6.48(d,J=5.3Hz,1H),3.96(s,6H),3.85(s,3H),2.01(q,J=7.3Hz,1H),0.54(d,J=7.3Hz,2H),0.03(d,J=6.9Hz,2H)。
1 H NMR (400 MHz, DMSO-d 6 ) δ 12.96 (s, 1H), 8.83 (d, J = 3.5 Hz, 2H), 8.49 (d, J = 5.2 Hz, 1H), 8.05 (dd, J = 12.8, 2.3 Hz, 1H), 7.56–7.41 (m, 4H), 7.33–7.21 (m, 4H), 6.48 (d, J=5.3 Hz, 1H), 3.96 (s, 6H), 3.85 (s, 3H) ), 2.01 (q, J = 7.3 Hz, 1H), 0.54 (d, J = 7.3 Hz, 2H), 0.03 (d, J = 6.9 Hz, 2H).
实施例62:N-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)-5-(4-氟苯基)-1-甲基-6-(吗啉-4-甲酰基)-4-氧代-1,4-二氢吡啶-3-甲酰胺(62)的制备Example 62: N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-(4-fluorophenyl)-1-methyl Preparation of keto-6-(morpholine-4-formyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (62)
采用与实施例58相同的方法,除了用吗啉胺代替氯化铵,制得N-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)-5-(4-氟苯基)-1-甲基-6-(吗啉-4-甲酰基)-4-氧代-1,4-二氢吡啶-3-甲酰胺(62)(白色固体,一步收率:30.4%)。In the same manner as in Example 58, except that morpholino was used in place of ammonium chloride, N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorol was obtained. Phenyl)-5-(4-fluorophenyl)-1-methyl-6-(morpholine-4-formyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (62 ) (white solid, one step yield: 30.4%).
LC-MS(ESI):m/z 657.4[M+H
+]。
LC-MS (ESI): m / z 657.4 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.94(s,1H),8.84(s,1H),8.49(d,J=5.2Hz,1H),8.05(dd,J=12.9,2.3Hz,1H),7.57–7.27(m,8H),6.50(d,J=5.2Hz,1H),3.96(s,6H),3.81(s,3H),3.56(dd,J=10.9,5.2Hz,2H),3.32–3.26(m,2H),3.07–2.76(m,4H)。
1 H NMR (400MHz, DMSO- d 6) δ12.94 (s, 1H), 8.84 (s, 1H), 8.49 (d, J = 5.2Hz, 1H), 8.05 (dd, J = 12.9,2.3Hz, 1H), 7.57–7.27 (m, 8H), 6.50 (d, J=5.2 Hz, 1H), 3.96 (s, 6H), 3.81 (s, 3H), 3.56 (dd, J = 10.9, 5.2 Hz, 2H) ), 3.32–3.26 (m, 2H), 3.07–2.76 (m, 4H).
实施例63:N
5-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)-3-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-2,5-二羧酰胺(63)的制备
Example 63: N 5 -(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-4- Preparation of oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2,5-dicarboxamide (63)
采用与实施例58相同的方法,除了用5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸(c)代替6-(乙氧基羰基)-5-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-3-羧酸(a),制得N
5-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)-3-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-2,5-二羧酰胺(63)(白色固体,三步收率:24.5%)。
The same procedure as in Example 58 was employed except that 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4- Dihydropyridine-3-carboxylic acid (c) in place of 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3- Carboxylic acid (a) to give N 5 -(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl) 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2,5-dicarboxamide (63) (white solid, three Step yield: 24.5%).
LC-MS(ESI):m/z 671.3[M+H
+]。
LC-MS (ESI): m / z 671.3 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.93(s,1H),8.78(s,1H),8.48(d,J=5.2Hz,1H),8.27(d,J=14.5Hz,1H),8.15–7.90(m,2H),7.55–7.30(m,6H),7.24(t,J=8.9Hz,2H),6.48(d,J=5.2Hz,1H),4.12(d,J=7.3Hz,2H),3.95(d,J=1.6Hz,6H),3.88(dd,J=11.7,3.8Hz,2H),3.21(s,1H),2.49(s,2H),1.49–1.28(m,4H)。
1 H NMR (400MHz, DMSO- d 6) δ12.93 (s, 1H), 8.78 (s, 1H), 8.48 (d, J = 5.2Hz, 1H), 8.27 (d, J = 14.5Hz, 1H) , 8.15–7.90 (m, 2H), 7.55–7.30 (m, 6H), 7.24 (t, J = 8.9 Hz, 2H), 6.48 (d, J = 5.2 Hz, 1H), 4.12 (d, J = 7.3) Hz, 2H), 3.95 (d, J = 1.6 Hz, 6H), 3.88 (dd, J = 11.7, 3.8 Hz, 2H), 3.21 (s, 1H), 2.49 (s, 2H), 1.49 - 1.28 (m) , 4H).
实施例64:N
5-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)-3-(4-氟苯基)-N
2-甲基-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-2,5-二甲酰胺(64)的制备
Example 64: N 5 -(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-N 2 -Methyl-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2,5-dimethylformamide (64)
采用与实施例63相同的方法,除了用甲胺盐酸盐代替氯化铵,制得N
5-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)-3-(4-氟苯基)-N
2-甲基-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-2,5-二甲酰胺(64)(白色固体,一步收率:30.2%)。
In the same manner as in Example 63, except that methylamine hydrochloride was used instead of ammonium chloride, N 5 -(4-((6,7-dimethoxyquinolin-4-yl)oxy)- 3-fluorophenyl)-3-(4-fluorophenyl)-N 2 -methyl-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1, 4-Dihydropyridine-2,5-dimethylformamide (64) (white solid, one step yield: 30.2%).
LC-MS(ESI):m/z 685.3[M+H
+]。
LC-MS (ESI): m / z 685.3 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.91(s,1H),8.78(s,1H),8.71(q,J=4.6Hz,1H),8.49(d,J=5.2Hz,1H),8.17–7.97(m,1H),7.59–7.18(m,8H),6.48(dd,J=5.3,1.1Hz,1H),4.07(d,J=7.2Hz,2H),3.95(d,J=1.6Hz,6H),3.90–3.81(m,2H),3.24(d,J=2.2Hz,1H),2.51(s,3H),2.48(d,J=4.7Hz,2H),1.54–1.17(m,4H)。
1 H NMR (400MHz, DMSO- d 6) δ12.91 (s, 1H), 8.78 (s, 1H), 8.71 (q, J = 4.6Hz, 1H), 8.49 (d, J = 5.2Hz, 1H) , 8.17–7.97 (m, 1H), 7.59–7.18 (m, 8H), 6.48 (dd, J=5.3, 1.1 Hz, 1H), 4.07 (d, J=7.2 Hz, 2H), 3.95 (d, J) =1.6 Hz,6H), 3.90–3.81 (m, 2H), 3.24 (d, J=2.2 Hz, 1H), 2.51 (s, 3H), 2.48 (d, J = 4.7 Hz, 2H), 1.54–1.17 (m, 4H).
实施例65:N
2-环丙基-N
5-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)-3-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-2,5-二甲酰胺(65)的制备
Example 65: N 2 -cyclopropyl-N 5 -(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-3-(4- Preparation of fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2,5-dimethylformamide (65)
采用与实施例63相同的方法,除了用环丙基胺代替氯化铵,制得N
2-环丙基-N
5-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)-3-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-2,5-二甲酰胺(65)(白色固体,一步收率:29.8%)。
In the same manner as in Example 63, except that cyclopropylamine was used in place of ammonium chloride, N 2 -cyclopropyl-N 5 -(4-((6,7-dimethoxyquinolin-4-) was obtained. (yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1, 4-Dihydropyridine-2,5-dimethylformamide (65) (white solid, one step yield: 29.8%).
LC-MS(ESI):m/z 711.4[M+H
+]。
LC-MS (ESI): m / z 711.4 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.90(s,1H),8.91–8.70(m,2H),8.48(d,J=5.2Hz,1H),8.05(dd,J=12.9,2.4Hz,1H),7.59–7.37(m,4H),7.35–7.13(m,4H),6.48(dd,J=5.2,1.1Hz,1H),4.09(d,J=7.3Hz,2H),4.05–3.77(m,8H),3.24(dd,J=12.6,10.4Hz,2H),2.50–2.40(m,3H),1.52–1.08(m,5H),0.53(d,J=7.2Hz,2H)。
1 H NMR (400MHz, DMSO- d 6) δ12.90 (s, 1H), 8.91-8.70 (m, 2H), 8.48 (d, J = 5.2Hz, 1H), 8.05 (dd, J = 12.9,2.4 Hz, 1H), 7.59–7.37 (m, 4H), 7.35–7.13 (m, 4H), 6.48 (dd, J=5.2, 1.1 Hz, 1H), 4.09 (d, J=7.3 Hz, 2H), 4.05 –3.77(m,8H), 3.24 (dd, J=12.6, 10.4 Hz, 2H), 2.50–2.40 (m, 3H), 1.52–1.08 (m, 5H), 0.53 (d, J=7.2 Hz, 2H) ).
实施例66:N
5-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)-3-(4-氟苯基)-1-异丙基-4-氧代-1,4-二氢吡啶-2,5-二甲酰胺(66)的制备
Example 66: N 5 -(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1- Preparation of isopropyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (66)
采用与实施例58相同的方法,除了用5-(4-氟苯基)-1-异丙基-4-氧代-1,4-二氢吡啶-3-甲酸(b)代替6-(乙氧基羰基)-5-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-3-羧酸(a),制得N
5-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)-3-(4-氟苯基)-1-异丙基-4-氧代-1,4-二氢吡啶-2,5-二甲酰胺(66)(白色固体,三步收率:23.4%)。
The same procedure as in Example 58 was employed except that 5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (b) was used instead of 6-( Ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (a) to give N 5 -(4- ((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-4-oxo-1 4-dihydropyridine-2,5-dimethylformamide (66) (white solid, three-step yield: 23.4%).
LC-MS(ESI):m/z 615.2[M+H
+]。
LC-MS (ESI): m / z 615.2 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.97(s,1H),8.77(s,1H),8.49(d,J=5.2Hz,1H),8.35–8.28(m,1H),8.06(dd,J=13.0,2.4Hz,2H),7.55–7.40(m,4H),7.35(ddd,J=8.7,5.6,2.6Hz,2H),7.29–7.20(m,2H),6.49(d,J=5.1Hz,1H),4.50(p,J=6.6Hz,1H),3.95(d,J=1.7Hz,6H),1.56(d,J=6.6Hz,6H)。
1 H NMR (400MHz, DMSO- d 6) δ12.97 (s, 1H), 8.77 (s, 1H), 8.49 (d, J = 5.2Hz, 1H), 8.35-8.28 (m, 1H), 8.06 ( Dd, J = 13.0, 2.4 Hz, 2H), 7.55 - 7.40 (m, 4H), 7.35 (ddd, J = 8.7, 5.6, 2.6 Hz, 2H), 7.29 - 7.20 (m, 2H), 6.49 (d, J = 5.1 Hz, 1H), 4.50 (p, J = 6.6 Hz, 1H), 3.95 (d, J = 1.7 Hz, 6H), 1.56 (d, J = 6.6 Hz, 6H).
实施例67:5-((6-((6,7-二甲氧基喹啉-4-基)氧基)哒嗪-3-基)氨基甲酰基)-3-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-2-羧酸乙酯(67)的制备Example 67: 5-((6-((6,7-Dimethoxyquinolin-4-yl)oxy)pyridazin-3-yl)carbamoyl)-3-(4-fluorophenyl) Preparation of ethyl 1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylate (67)
采用与实施例58中步骤1制备58a的方法相同,除了用6-((6,7-二甲氧基喹啉-4-基)氧基)哒嗪-3-胺(gg)代替4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯胺(ff),制得5-((6-((6,7-二甲氧基喹啉-4-基)氧基)哒嗪-3-基)氨基甲酰基)-3-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-2-羧酸乙酯(67)(白色固体,一步收率:21.1%)。The same procedure as in the preparation of 58a in Step 1 of Example 58 was used except that 6-((6,7-dimethoxyquinolin-4-yl)oxy)pyridazin-3-amine (gg) was used instead of 4- ((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluoroaniline (ff) to give 5-((6-(6,7-dimethoxyquinoline)- 4-yl)oxy)pyridazin-3-yl)carbamoyl)-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylate Ethyl acetate (67) (white solid, one step yield: 21.1%).
LC-MS(ESI):m/z 600.2[M+H
+]。
LC-MS (ESI): m / z 600.2 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ13.38(s,1H),8.87(s,1H),8.70(d,J=9.5Hz,1H),8.61(d,J=5.1Hz,1H),7.81(d,J=9.5Hz,1H),7.45(s,1H),7.40(s,1H),7.32–7.25(m,4H),7.01(d,J=5.1Hz,1H),4.12(q,J=7.1Hz,2H),3.96(s,3H),3.88(d,J=6.7Hz,6H),0.93(t,J=7.1Hz,3H)。
1 H NMR (400MHz, DMSO- d 6) δ13.38 (s, 1H), 8.87 (s, 1H), 8.70 (d, J = 9.5Hz, 1H), 8.61 (d, J = 5.1Hz, 1H) , 7.81 (d, J = 9.5 Hz, 1H), 7.45 (s, 1H), 7.40 (s, 1H), 7.32 - 7.25 (m, 4H), 7.01 (d, J = 5.1 Hz, 1H), 4.12 ( q, J = 7.1 Hz, 2H), 3.96 (s, 3H), 3.88 (d, J = 6.7 Hz, 6H), 0.93 (t, J = 7.1 Hz, 3H).
实施例68:N
5-(4-((6-氨基甲酰基-7甲氧基喹啉-4-基)氧基)-3-氟苯基)-3-(4-氟苯基)-1-异丙基-4-氧代-1,4-二氢吡啶-2,5-二甲酰胺(68)的制备
Example 68: N 5 -(4-((6-carbamoyl-7methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)- Preparation of 1-isopropyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (68)
采用与实施例66相同的方法,除了用4-(4-氨基-2-氟苯氧基)-7-甲氧基喹啉-6-甲酰胺(hh)代替4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯胺(ff),制得N
5-(4-((6-氨基甲酰基-7-甲氧基喹啉-4-基)氧基)-3-氟苯基)-3-(4-氟苯基)-1-异丙基-4-氧代-1,4-二氢吡啶-2,5-二甲酰胺(68)(白色固体,三步收率:30.2%)。
The same procedure as in Example 66 was employed except that 4-(4-amino-2-fluorophenoxy)-7-methoxyquinolin-6-carboxamide (hh) was used instead of 4-((6,7- Dimethoxyquinolin-4-yl)oxy)-3-fluoroaniline (ff) to give N 5 -(4-((6-carbamoyl-7-methoxyquinolin-4-yl) )oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-2,5-dimethylamide (68) ) (white solid, three-step yield: 30.2%).
LC-MS(ESI):m/z 628.2[M+H
+]。
LC-MS (ESI): m / z 628.2 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.99(s,1H),8.77(s,1H),8.68(t,J=2.6Hz,2H),8.31(s,1H),8.12–8.03(m,2H),7.91–7.84(m,1H),7.74(s,1H),7.56–7.46(m,3H),7.40–7.32(m,2H),7.28–7.21(m,2H),6.54(dd,J=5.2,1.2Hz,1H),4.50(q,J=6.6Hz,1H),4.04(s,3H),1.56(d,J=6.6Hz,6H)。
1 H NMR (400MHz, DMSO- d 6) δ12.99 (s, 1H), 8.77 (s, 1H), 8.68 (t, J = 2.6Hz, 2H), 8.31 (s, 1H), 8.12-8.03 ( m, 2H), 7.91–7.84 (m, 1H), 7.74 (s, 1H), 7.56–7.46 (m, 3H), 7.40–7.32 (m, 2H), 7.28–7.21 (m, 2H), 6.54 ( Dd, J = 5.2, 1.2 Hz, 1H), 4.50 (q, J = 6.6 Hz, 1H), 4.04 (s, 3H), 1.56 (d, J = 6.6 Hz, 6H).
实施例69:N-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)-10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酰胺(69)的制备Example 69: N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-10-(4-fluorophenyl)-1,9 -Preparation of dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxamide (69)
采用与实施例58相同的方法,除了10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸(d)代替6-(乙氧基羰基)-5-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-3-羧酸(a),制得N-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)-10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酰胺(69)(白色固体,一步收率:34.6%)。The same procedure as in Example 58 except that 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a was used. ][1,4]diazepane-8-carboxylic acid (d) instead of 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1 , 4-dihydropyridine-3-carboxylic acid (a), to give N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)- 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepine Heptane-8-carboxamide (69) (white solid, one step yield: 34.6%).
LC-MS(ESI):m/z 613.2[M+H
+]。
LC-MS (ESI): m / z 613.2 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ8.85(s,1H),8.68(t,J=6.6Hz,1H),8.48(d,J=5.2Hz,1H),8.04(dd,J=12.9,2.4Hz,1H),7.63–7.35(m,4H),7.25(dddd,J=30.7,8.9,6.2,1.9Hz,4H),6.49(dd,J=5.2,1.1Hz,1H),3.95(d,J=1.3Hz,6H),3.33(s,4H),2.09(d,J=45.0Hz,2H)。
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.85 (s, 1H), 8.68 (t, J = 6.6 Hz, 1H), 8.48 (d, J = 5.2 Hz, 1H), 8.04 (dd, J = 12.9, 2.4 Hz, 1H), 7.63 - 7.35 (m, 4H), 7.25 (dddd, J = 30.7, 8.9, 6.2, 1.9 Hz, 4H), 6.49 (dd, J = 5.2, 1.1 Hz, 1H), 3.95 (d, J = 1.3 Hz, 6H), 3.33 (s, 4H), 2.09 (d, J = 45.0 Hz, 2H).
实施例70:10-(4-氟苯基)-N-(4-((6-甲氧基-7-(2-吗啉乙基)喹唑啉-4-基)氧基)苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酰胺(70)的制备Example 70: 10-(4-Fluorophenyl)-N-(4-((6-methoxy-7-(2-morpholinethyl)quinazolin-4-yl)oxy)phenyl) -1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxamide ( Preparation of 70)
采用与实施例69相同的方法,除了4-((6-甲氧基-7-(2-吗啉乙氧基)喹唑啉-4-基)氧基)苯胺(ss)代替4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯胺(ff),制得10-(4-氟苯基)-N-(4-((6-甲氧基-7-(2-吗啉乙基)喹唑啉-4-基)氧基)苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酰胺(70)(白色固体,一步收率:26.7%)。In the same manner as in Example 69 except that 4-((6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-yl)oxy)phenylamine (ss) was used instead of 4-( (6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluoroaniline (ff) to give 10-(4-fluorophenyl)-N-(4-((6-A) Oxy-7-(2-morpholinoethyl)quinazolin-4-yl)oxy)phenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydro Pyrido[1,2-a][1,4]diazepane-8-carboxamide (70) (white solid, one step yield: 26.7%).
LC-MS(ESI):m/z 695.3[M+H
+]。
LC-MS (ESI): m / z 695.3 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.79(s,1H),8.83(s,1H),8.66(t,J=6.5Hz,1H),8.54(s,1H),7.82–7.77(m,2H),7.56(s,1H),7.42(s,1H),7.29(dq,J=8.0,2.7,2.2Hz,4H),7.21(t,J=9.0Hz,2H),4.70–4.60(m,1H),4.32(t,J=5.8Hz,2H),4.07(d,J=18.6Hz,1H),3.97(s,3H),3.62–3.57(m,4H),2.80(t,J=5.7Hz,2H),2.28–1.91(m,4H)。
1 H NMR (400MHz, DMSO- d 6) δ12.79 (s, 1H), 8.83 (s, 1H), 8.66 (t, J = 6.5Hz, 1H), 8.54 (s, 1H), 7.82-7.77 ( m, 2H), 7.56 (s, 1H), 7.42 (s, 1H), 7.29 (dq, J = 8.0, 2.7, 2.2 Hz, 4H), 7.21 (t, J = 9.0 Hz, 2H), 4.70 - 4.60 (m, 1H), 4.32 (t, J = 5.8 Hz, 2H), 4.07 (d, J = 18.6 Hz, 1H), 3.97 (s, 3H), 3.62 - 3.57 (m, 4H), 2.80 (t, J = 5.7 Hz, 2H), 2.28 - 1.91 (m, 4H).
实施例71:N-(6-((6,7-二甲氧基喹啉-4-基)氧基)哒嗪-3-基)-10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酰胺(71)的制备Example 71: N-(6-((6,7-Dimethoxyquinolin-4-yl)oxy)pyridazin-3-yl)-10-(4-fluorophenyl)-1,9 -Preparation of dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxamide (71)
采用与实施例69相同的方法,除了6-((6,7-二甲氧基喹啉-4-基)氧基)哒嗪-3-胺(gg)代替4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯胺(ff),制得N-(6-((6,7-二甲氧基喹啉-4-基)氧基)哒嗪-3-基)-10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酰胺(71)(白色固体,一步收率:15.6%)。In the same manner as in Example 69 except that 6-((6,7-dimethoxyquinolin-4-yl)oxy)pyridazin-3-amine (gg) was used instead of 4-((6,7-) Dimethoxyquinolin-4-yl)oxy)-3-fluoroaniline (ff) to give N-(6-(6,7-dimethoxyquinolin-4-yl)oxy) Pyridazin-3-yl)-10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][ 1,4]Diazepane-8-carboxamide (71) (white solid, one step yield: 15.6%).
LC-MS(ESI):m/z 597.3[M+H
+]。
LC-MS (ESI): m / z 597.3 [M + H +].
实施例72:N-(4-((2-氨基吡啶-4-基)氧基)苯基)-1,9-二氧代-10-(对甲苯基)-1,2,3,4,5,9-六氢吡啶并[1,2-A][1,4]二氮杂环庚烷-8-甲酰胺(72)的制备Example 72: N-(4-((2-Aminopyridin-4-yl)oxy)phenyl)-1,9-dioxo-10-(p-tolyl)-1,2,3,4 Of 5,9-hexahydropyrido[1,2-A][1,4]diazepane-8-carboxamide (72)
采用与实施例71相同的方法,除了1,9-二氧代-10-(对甲苯基)-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸(e)代替10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸(d),并且用4-(4-氨基-2-苯氧基)吡啶-2-胺(nn)分别和6-((6,7-二甲氧基喹啉-4-基)氧基)哒嗪-3-胺(gg),制得N-(4-((2-氨基吡啶-4-基)氧基)苯基)-1,9-二氧代-10-(对甲苯基)-1,2,3,4,5,9-六氢吡啶并[1,2-A][1,4]二氮杂环庚烷-8-甲酰胺(72)(白色固体,一步收率:2.7.1%)。The same procedure as in Example 71 was carried out except that 1,9-dioxo-10-(p-tolyl)-1,2,3,4,5,9-hexahydropyrido[1,2-a][ 1,4]Diazepane-8-carboxylic acid (e) instead of 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydro Pyrido[1,2-a][1,4]diazepane-8-carboxylic acid (d), and 4-(4-amino-2-phenoxy)pyridin-2-amine (nn ) and 6-((6,7-dimethoxyquinolin-4-yl)oxy)pyridazin-3-amine (gg), respectively, to obtain N-(4-((2-aminopyridine-4) -yl)oxy)phenyl)-1,9-dioxo-10-(p-tolyl)-1,2,3,4,5,9-hexahydropyrido[1,2-A][ 1,4]diazepane-8-carboxamide (72) (white solid, one step yield: 2.7.1%).
LC-MS(ESI):m/z 496.2[M+H
+]。
LC-MS (ESI): m / z 496.2 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.84(s,1H),8.81(s,1H),8.60(t,J=6.6Hz,1H),7.79(dd,J=15.6,7.3Hz,3H),7.25–7.06(m,6H),6.19(dd,J=6.0,2.2Hz,1H),6.06(s,2H),5.85(d,J=2.2Hz,1H),4.63(dd,J=14.4,6.1Hz,1H),4.04(s,1H),2.33(s,3H),2.15(s,1H),2.00-2.03(m,1H),1.09-1.24(m,1H),0.81-0.86(m,1H)。
1 H NMR (400MHz, DMSO- d 6) δ12.84 (s, 1H), 8.81 (s, 1H), 8.60 (t, J = 6.6Hz, 1H), 7.79 (dd, J = 15.6,7.3Hz, 3H), 7.25–7.06 (m, 6H), 6.19 (dd, J=6.0, 2.2 Hz, 1H), 6.06 (s, 2H), 5.85 (d, J=2.2 Hz, 1H), 4.63 (dd, J =14.4, 6.1 Hz, 1H), 4.04 (s, 1H), 2.33 (s, 3H), 2.15 (s, 1H), 2.00-2.03 (m, 1H), 1.09-1.24 (m, 1H), 0.81 0.86 (m, 1H).
实施例73:N-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)-6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-甲酰胺(73)的制备Example 73: N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-6-(4-fluorophenyl)-5,7 -Preparation of dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (73)
采用与实施例69相同的方法,除了6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-羧酸(o)代替10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸(d),制得N-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)-6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-甲酰胺(73)(白色固体,一步收率:40.3%)。The same procedure as in Example 69 was used except for 6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazole [3,2- a] pyrido[1,2-d]pyrazine-8-carboxylic acid (o) instead of 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5, 9-Hexidopyrido[1,2-a][1,4]diazepane-8-carboxylic acid (d) to give N-(4-((6,7-dimethoxyquine) Phenyl-4-yl)oxy)-3-fluorophenyl)-6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrocaine Zoxao[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (73) (white solid, one step yield: 40.3%).
LC-MS(ESI):m/z 641.3[M+H
+]。
LC-MS (ESI): m / z 641.3 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.80(s,1H),8.88(s,1H),8.48(d,J=5.3Hz,1H),8.04(dd,J=12.9,2.4Hz,1H),7.54(d,J=7.1Hz,2H),7.44(dd,J=16.1,7.0Hz,2H),7.19(s,4H),6.48(d,J=5.1Hz,1H),5.46(dd,J=10.0,3.5Hz,1H),4.99(d,J=8.9Hz,1H),4.28–4.10(m,2H),4.10–3.84(m,7H),3.67(dd,J=18.5,7.5Hz,1H),3.47(d,J=4.3Hz,1H)。
1 H NMR (400MHz, DMSO- d 6) δ12.80 (s, 1H), 8.88 (s, 1H), 8.48 (d, J = 5.3Hz, 1H), 8.04 (dd, J = 12.9,2.4Hz, 1H), 7.54 (d, J = 7.1 Hz, 2H), 7.44 (dd, J = 16.1, 7.0 Hz, 2H), 7.19 (s, 4H), 6.48 (d, J = 5.1 Hz, 1H), 5.46 ( Dd, J = 10.0, 3.5 Hz, 1H), 4.99 (d, J = 8.9 Hz, 1H), 4.28 - 4.10 (m, 2H), 4.10 - 3.84 (m, 7H), 3.67 (dd, J = 18.5, 7.5 Hz, 1H), 3.47 (d, J = 4.3 Hz, 1H).
实施例74:N-(4-((6-氨基甲酰基-7-甲氧基喹啉-4-基)氧基)-3-氟苯基)-6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-甲酰胺(74)的制备Example 74: N-(4-((6-carbamoyl-7-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-6-(4-fluorophenyl)- 5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (74 Preparation
采用与实施例73相同的方法,除了4-(4-氨基-2-氟苯氧基)-7-甲氧基喹啉-6-甲酰胺(hh)代替4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯胺(ff),制得N-(4-((6-氨基甲酰基-7-甲氧基喹啉-4-基)氧基)-3-氟苯基)-6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-甲酰胺(74)(白色固体,一步收率:32.6%)。In the same manner as in Example 73 except that 4-(4-amino-2-fluorophenoxy)-7-methoxyquinolin-6-carboxamide (hh) was used instead of 4-((6,7-di) Methoxyquinolin-4-yl)oxy)-3-fluoroaniline (ff), N-(4-((6-carbamoyl-7-methoxyquinolin-4-yl)oxy) 3-fluorophenyl)-6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazole[3,2- a] Pyrido[1,2-d]pyrazine-8-carboxamide (74) (white solid, one step yield: 32.6%).
LC-MS(ESI):m/z 654.3[M+H
+]。
LC-MS (ESI): m / z 654.3 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.81(s,1H),8.89(s,1H),8.68(d,J=4.9Hz,2H),8.06(dd,J=12.9,2.4Hz,1H),7.90–7.85(m,1H),7.74(s,1H),7.60–7.53(m,2H),7.48(t,J=8.8Hz,1H),7.19(s,4H),6.54(dd,J=5.2,1.1Hz,1H),5.46(dd,J=10.0,3.6Hz,1H),4.99(dd,J=12.3,3.7Hz,1H),4.25–4.19(m,1H),4.19–4.13(m,1H),4.04(s,4H),3.70–3.63(m,1H),3.49–3.43(m,1H)。
1 H NMR (400MHz, DMSO- d 6) δ12.81 (s, 1H), 8.89 (s, 1H), 8.68 (d, J = 4.9Hz, 2H), 8.06 (dd, J = 12.9,2.4Hz, 1H), 7.90–7.85 (m, 1H), 7.74 (s, 1H), 7.60–7.53 (m, 2H), 7.48 (t, J = 8.8 Hz, 1H), 7.19 (s, 4H), 6.54 (dd) , J = 5.2, 1.1 Hz, 1H), 5.46 (dd, J = 10.0, 3.6 Hz, 1H), 4.99 (dd, J = 12.3, 3.7 Hz, 1H), 4.25 - 4.19 (m, 1H), 4.19 - 4.13 (m, 1H), 4.04 (s, 4H), 3.70 - 3.63 (m, 1H), 3.49 - 3.43 (m, 1H).
实施例75:N-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)-7-(4-氟苯基)-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酰胺(75)的制备Example 75: N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-7-(4-fluorophenyl)-6,8 -dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3] Preparation of oxazine-9-carboxamide (75)
采用与实施例73相同的方法,除了7-(4-氟苯基)-6,8-二氧代3,4,6,8,12,12a六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酸(k)代替6-(4-氟苯基)-5,7-二氧代-2,3,5,7,11,11a-六氢恶唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-羧酸(o),制得N-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)-7-(4-氟苯基)-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酰胺(75)(白色固体,一步收率:40.2%)。The same procedure as in Example 73 was carried out except that 7-(4-fluorophenyl)-6,8-dioxo 3,4,6,8,12,12a hexahydro-2H-pyrido[1',2 ':4,5]pyrazine[2,1-b][1,3]oxazine-9-carboxylic acid (k) instead of 6-(4-fluorophenyl)-5,7-dioxo-2 , 3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (o), to obtain N-(4- ((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-7-(4-fluorophenyl)-6,8-dioxo-3,4, 6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide (75 (white solid, one step yield: 40.2%).
LC-MS(ESI):m/z 655.4[M+H
+]。
LC-MS (ESI): m / z 655.4 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.78(s,1H),8.90(s,1H),8.48(d,J=5.3Hz,1H),8.04(d,J=15.3Hz,1H),7.61–7.33(m,4H),7.29–6.98(m,4H),6.48(d,J=5.0Hz,1H),5.29(s,1H),4.65(d,J=32.4Hz,2H),4.14(d,J=58.2Hz,2H),3.95(d,J =1.5Hz,7H),3.10(s,1H),1.59(s,2H)。
1 H NMR (400MHz, DMSO- d 6) δ12.78 (s, 1H), 8.90 (s, 1H), 8.48 (d, J = 5.3Hz, 1H), 8.04 (d, J = 15.3Hz, 1H) , 7.61 - 7.33 (m, 4H), 7.29 - 6.98 (m, 4H), 6.48 (d, J = 5.0 Hz, 1H), 5.29 (s, 1H), 4.65 (d, J = 32.4 Hz, 2H), 4.14 (d, J = 58.2 Hz, 2H), 3.95 (d, J = 1.5 Hz, 7H), 3.10 (s, 1H), 1.59 (s, 2H).
实施例76:N-(3-氟-4-((6-甲氧基-7-(2-甲氧基乙氧基)喹唑啉-4-基)氧基)苯基)-7-(4-氟苯基)-6,8-二氧代-3,4-,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酰胺(76)的制备Example 76: N-(3-Fluoro-4-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)oxy)phenyl)-7- (4-fluorophenyl)-6,8-dioxo-3,4-,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazine Preparation of [2,1-b][1,3]oxazine-9-carboxamide (76)
采用与实施例75相同的方法,除了3-氟-4-((6-甲氧基-7-(2-甲氧基乙氧基)喹唑啉-4-基)氧基)苯胺(oo)代替4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯胺(ff),制得N-(3-氟-4-((6-甲氧基-7-(2-甲氧基乙氧基)喹唑啉-4-基)氧基)苯基)-7-(4-氟苯基)-6,8-二氧代-3,4-,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酰胺(76)(白色固体,一步收率:31.2%)。The same procedure as in Example 75 was employed except for 3-fluoro-4-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)oxy)phenylamine (o Instead of 4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluoroaniline (ff), N-(3-fluoro-4-((6-methoxy) 7-(2-methoxyethoxy)quinazolin-4-yl)oxy)phenyl)-7-(4-fluorophenyl)-6,8-dioxo-3,4 -,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide (76) (white solid, one step yield: 31.2%).
LC-MS(ESI):m/z 700.3[M+H
+]。
LC-MS (ESI): m / z 700.3 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.73(s,1H),8.90(s,1H),8.55(s,1H),7.98(dd,J=12.7,2.3Hz,1H),7.57(s,1H),7.52–7.37(m,3H),7.22–6.98(m,4H),5.29(t,J=4.1Hz,1H),4.64(ddd,J=44.4,14.1,4.1Hz,2H),4.39–4.15(m,3H),4.11–3.66(m,7H),3.35(s,3H),3.10(td,J=12.8,3.5Hz,1H),1.75–1.47(m,2H)。
1 H NMR (400MHz, DMSO- d 6) δ12.73 (s, 1H), 8.90 (s, 1H), 8.55 (s, 1H), 7.98 (dd, J = 12.7,2.3Hz, 1H), 7.57 ( s, 1H), 7.52–7.37 (m, 3H), 7.22–6.98 (m, 4H), 5.29 (t, J=4.1 Hz, 1H), 4.64 (ddd, J=44.4, 14.1, 4.1 Hz, 2H) , 4.39 - 4.15 (m, 3H), 4.11 - 3.66 (m, 7H), 3.35 (s, 3H), 3.10 (td, J = 12.8, 3.5 Hz, 1H), 1.75 - 1.47 (m, 2H).
实施例77:N-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)-3-氟苯基)-7-(4-氟苯基)-6,8-二氧代-3,4,6-,8,12,12a六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酰胺(77)的制备Example 77: N-(4-((1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)-3-fluorophenyl)-7-(4-fluorophenyl)-6 , 8-dioxo-3,4,6-,8,12,12a hexahydro-2H-pyrido[1',2':4,5]pyrazine[2,1-b][1, 3] Preparation of oxazine-9-carboxamide (77)
采用与实施例75相同的方法,除了4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)-3-氟苯胺(ii)代替3-氟-4-((6-甲氧基-7-(2-甲氧基乙氧基)喹唑啉-4-基)氧基)苯胺(oo),制得N-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)-3-氟苯基)-7-(4-氟苯基)-6,8-二氧代-3,4,6-,8,12,12a六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酰胺(77)(白色固体,一步收率:21.7%)。In the same manner as in Example 75 except that 4-((1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)-3-fluoroaniline (ii) was used instead of 3-fluoro-4-( (6-Methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)oxy)aniline (oo) to give N-(4-((1H-pyrrolo[2] ,3-b]pyridin-4-yl)oxy)-3-fluorophenyl)-7-(4-fluorophenyl)-6,8-dioxo-3,4,6-,8,12 , 12a hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide (77) (white solid, one step Yield: 21.7%).
LC-MS(ESI):m/z 584.3[M+H
+]。
LC-MS (ESI): m / z 584.3 [M + H +].
1H NMR(400MHz,DMSO-d6)δ12.74(s,1H),11.78(s,1H),8.90(s,1H),8.11 –7.95(m,2H),7.48(dt,J=8.9,1.7Hz,1H),7.39–7.30(m,2H),7.21–7.03(m,4H),6.38(d,J=5.4Hz,1H),6.25(dd,J=3.5,1.9Hz,1H),5.28(t,J=4.1Hz,1H),4.70(dd,J=14.1,3.7Hz,1H),4.59(dd,J=14.1,4.4Hz,1H),4.22(d,J=12.1Hz,1H),4.09–4.02(m,1H),3.86(td,J=11.7,2.8Hz,1H),3.10(td,J=12.8,3.5Hz,1H),1.68(dq,J=12.2,7.4,6.1Hz,1H),1.57(d,J=12.9Hz,1H)。1H NMR (400MHz, DMSO-d6) δ 12.74 (s, 1H), 11.78 (s, 1H), 8.90 (s, 1H), 8.11 - 7.95 (m, 2H), 7.48 (dt, J = 8.9, 1.7 Hz, 1H), 7.39 - 7.30 (m, 2H), 7.21 - 7.03 (m, 4H), 6.38 (d, J = 5.4 Hz, 1H), 6.25 (dd, J = 3.5, 1.9 Hz, 1H), 5.28 (t, J = 4.1 Hz, 1H), 4.70 (dd, J = 14.1, 3.7 Hz, 1H), 4.59 (dd, J = 14.1, 4.4 Hz, 1H), 4.22 (d, J = 12.1 Hz, 1H) , 4.09–4.02 (m, 1H), 3.86 (td, J=11.7, 2.8 Hz, 1H), 3.10 (td, J=12.8, 3.5 Hz, 1H), 1.68 (dq, J=12.2, 7.4, 6.1 Hz) , 1H), 1.57 (d, J = 12.9 Hz, 1H).
实施例78:10-(4-氟苯基)-N-(4-((6-甲氧基-7-(2-甲氧基乙氧基)喹唑啉-4-基)氧基)苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酰胺(78)的制备Example 78: 10-(4-Fluorophenyl)-N-(4-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)oxy) Phenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-A Preparation of amide (78)
采用与实施例69相同的方法,除了4-((6-甲氧基-7-(2-甲氧基乙氧基)喹唑啉-4-基)氧基)苯胺(pp)代替4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯胺(ff),制得10-(4-氟苯基)-N-(4-((6-甲氧基-7-(2-甲氧基乙氧基)喹唑啉-4-基)氧基)苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酰胺(78)(白色固体,一步收率:30.6%)。In the same manner as in Example 69, except that 4-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)oxy)phenylamine (pp) was used instead of 4- ((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluoroaniline (ff), 10-(4-fluorophenyl)-N-(4-((6-) Methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)oxy)phenyl)-1,9-dioxo-1,2,3,4,5,9 -Hexidopyrido[1,2-a][1,4]diazepane-8-carboxamide (78) (white solid, one step yield: 30.6%).
LC-MS(ESI):m/z 640.4[M+H
+]。
LC-MS (ESI): m / z 640.4 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.80(s,1H),8.84(s,1H),8.67(t,J=6.5Hz,1H),8.55(s,1H),7.80(d,J=8.6Hz,2H),7.58(s,1H),7.41(s,1H),7.30(dd,J=8.6,6.2Hz,4H),7.22(t,J=8.7Hz,2H),4.66(d,J=10.4Hz,1H),4.34(t,J=4.4Hz,2H),4.08(d,J=11.8Hz,1H),3.99(s,3H),3.84–3.74(m,2H),3.36(s,5H),2.16(s,1H),2.04(s,1H)。
1 H NMR (400MHz, DMSO- d 6) δ12.80 (s, 1H), 8.84 (s, 1H), 8.67 (t, J = 6.5Hz, 1H), 8.55 (s, 1H), 7.80 (d, J = 8.6 Hz, 2H), 7.58 (s, 1H), 7.41 (s, 1H), 7.30 (dd, J = 8.6, 6.2 Hz, 4H), 7.22 (t, J = 8.7 Hz, 2H), 4.66 ( d, J = 10.4 Hz, 1H), 4.34 (t, J = 4.4 Hz, 2H), 4.08 (d, J = 11.8 Hz, 1H), 3.99 (s, 3H), 3.84 - 3.74 (m, 2H), 3.36 (s, 5H), 2.16 (s, 1H), 2.04 (s, 1H).
实施例79:N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-7-(4-氟苯基)-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酰胺(79)的制备Example 79: N-(4-((6,7-Dimethoxyquinazolin-4-yl)oxy)-3-fluorophenyl)-7-(4-fluorophenyl)-6, 8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3 Preparation of Oxazine-9-carboxamide (79)
采用与实施例75相同的方法,除了4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯胺(kk)代替4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯胺(ff),制得N-(4-((6,7-二甲氧 基喹唑啉-4-基)氧基)-3-氟苯基)-7-(4-氟苯基)-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酰胺(79)(白色固体,一步收率:28.2%)。In the same manner as in Example 75, except for 4-((6,7-dimethoxyquinazolin-4-yl)oxy)-3-fluoroaniline (kk) instead of 4-((6,7-) Dimethoxyquinolin-4-yl)oxy)-3-fluoroaniline (ff) to give N-(4-((6,7-dimethoxyquinazolin-4-yl)oxy) )-3-fluorophenyl)-7-(4-fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1', 2': 4,5] pyrazino[2,1-b][1,3]oxazine-9-carboxamide (79) (white solid, one step yield: 28.2%).
LC-MS(ESI):m/z 656.4[M+H
+]。
LC-MS (ESI): m / z 656.4 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.73(s,1H),8.90(s,1H),8.56(s,1H),7.98(dd,J=12.7,2.3Hz,1H),7.57(s,1H),7.51–7.39(m,3H),7.21–7.07(m,4H),5.29(t,J=4.1Hz,1H),4.70(dd,J=14.1,3.7Hz,1H),4.59(dd,J=14.1,4.4Hz,1H),4.23(dd,J=13.7,4.4Hz,1H),4.07(dd,J=11.2,4.5Hz,1H),3.99(d,J=5.8Hz,6H),3.86(td,J=11.7,2.7Hz,1H),3.10(td,J=12.8,3.5Hz,1H),1.80–1.54(m,2H)。
1 H NMR (400MHz, DMSO- d 6) δ12.73 (s, 1H), 8.90 (s, 1H), 8.56 (s, 1H), 7.98 (dd, J = 12.7,2.3Hz, 1H), 7.57 ( s, 1H), 7.51–7.39 (m, 3H), 7.21–7.07 (m, 4H), 5.29 (t, J=4.1 Hz, 1H), 4.70 (dd, J=14.1, 3.7 Hz, 1H), 4.59 (dd, J = 14.1, 4.4 Hz, 1H), 4.23 (dd, J = 13.7, 4.4 Hz, 1H), 4.07 (dd, J = 11.2, 4.5 Hz, 1H), 3.99 (d, J = 5.8 Hz, 6H), 3.86 (td, J = 11.7, 2.7 Hz, 1H), 3.10 (td, J = 12.8, 3.5 Hz, 1H), 1.80 - 1.54 (m, 2H).
实施例80:N-3-氟-4-((6-甲氧基-7-(2-吗啉乙氧基)喹唑啉-4-基)氧基)苯基)-7-(4-氟苯基)-6,8-二氧代-3,4-6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酰胺(80)的制备Example 80: N-3-fluoro-4-((6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-yl)oxy)phenyl)-7-(4 -fluorophenyl)-6,8-dioxo-3,4-6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazine[2, Preparation of 1-b][1,3]oxazine-9-carboxamide (80)
采用与实施例75相同的方法,除了3-氟-4-((6-甲氧基-7-(2-吗啉乙氧基)喹唑啉-4-基)氧基)苯胺(tt)代替4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯胺(ff),制得N-3-氟-4-((6-甲氧基-7-(2-吗啉乙氧基)喹唑啉-4-基)氧基)苯基)-7-(4-氟苯基)-6,8-二氧代-3,4-6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酰胺(80)(白色固体,一步收率:24.7%)。The same procedure as in Example 75 was employed except that 3-fluoro-4-((6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-yl)oxy)aniline (tt) Instead of 4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluoroaniline (ff), N-3-fluoro-4-((6-methoxy)- 7-(2-morpholinoethoxy)quinazolin-4-yl)oxy)phenyl)-7-(4-fluorophenyl)-6,8-dioxo-3,4-6, 8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide (80) White solid, one step yield: 24.7%).
LC-MS(ESI):m/z 755.4[M+H
+]。
LC-MS (ESI): m / z 755.4 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.73(s,1H),8.90(s,1H),8.55(s,1H),7.98(dd,J=12.7,2.3Hz,1H),7.57(s,1H),7.53–7.37(m,3H),7.29–6.99(m,4H),5.29(t,J=4.0Hz,1H),4.73–4.52(m,2H),4.33(t,J=5.8Hz,2H),4.25–4.17(m,1H),4.11–4.02(m,1H),3.98(s,3H),3.93–3.77(m,1H),3.61–3.57(m,5H),3.11–2.99(m,1H),2.80(t,J=5.7Hz,2H),2.53(d,J=3.5Hz,3H),1.75–1.52(m,2H)。
1 H NMR (400MHz, DMSO- d 6) δ12.73 (s, 1H), 8.90 (s, 1H), 8.55 (s, 1H), 7.98 (dd, J = 12.7,2.3Hz, 1H), 7.57 ( s, 1H), 7.53–7.37 (m, 3H), 7.29–6.99 (m, 4H), 5.29 (t, J=4.0 Hz, 1H), 4.73–4.52 (m, 2H), 4.33 (t, J= 5.8 Hz, 2H), 4.25–4.17 (m, 1H), 4.11–4.02 (m, 1H), 3.98 (s, 3H), 3.93–3.77 (m, 1H), 3.61–3.57 (m, 5H), 3.11 – 2.99 (m, 1H), 2.80 (t, J = 5.7 Hz, 2H), 2.53 (d, J = 3.5 Hz, 3H), 1.75 - 1.52 (m, 2H).
实施例81:N-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)-9-(4-氟苯基)-1,8-二氧代-1,3,4,8-四氢-2H-吡啶并[1,2-a]吡嗪-7-甲酰胺(81)的制备Example 81: N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-9-(4-fluorophenyl)-1,8 -Preparation of dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxamide (81)
采用与实施例69相同的方法,除了9-(4-氟苯基)-1,8-二氧代-1,3,4,8-四氢-2H- 吡啶并[1,2-a]吡嗪-7-羧酸(t)代替10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸(d),制得N-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)-9-(4-氟苯基)-1,8-二氧代-1,3,4,8-四氢-2H-吡啶并[1,2-a]吡嗪-7-甲酰胺(81)(白色固体,一步收率:34.9%)。The same procedure as in Example 69 was carried out except that 9-(4-fluorophenyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a] Pyrazin-7-carboxylic acid (t) in place of 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2- a][1,4]diazepan-8-carboxylic acid (d) to obtain N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3 -fluorophenyl)-9-(4-fluorophenyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7 - Formamide (81) (white solid, one step yield: 34.9%).
LC-MS(ESI):m/z 599.3[M+H
+]。
LC-MS (ESI): m / z 599.3 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ13.01(s,1H),8.91(s,1H),8.81(s,1H),8.54(d,J=5.1Hz,1H),8.10(d,J=13.0Hz,1H),7.59(s,2H),7.53–7.45(m,2H),7.29–7.17(m,4H),6.55(d,J=5.1Hz,1H),4.52(s,2H),4.01(d,J=1.3Hz,6H),3.67(s,2H)。
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.01 (s, 1H), 8.91 (s, 1H), 8.81 (s, 1H), 8.54 (d, J = 5.1 Hz, 1H), 8.10 (d, J = 13.0 Hz, 1H), 7.59 (s, 2H), 7.53 - 7.45 (m, 2H), 7.29 - 7.17 (m, 4H), 6.55 (d, J = 5.1 Hz, 1H), 4.52 (s, 2H) ), 4.01 (d, J = 1.3 Hz, 6H), 3.67 (s, 2H).
实施例82:N-(4-((2-氨基吡啶-4-基)氧基)-3-氟苯基)-7-(4-氟苯基)-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酰胺(82)的制备Example 82: N-(4-((2-Aminopyridin-4-yl)oxy)-3-fluorophenyl)-7-(4-fluorophenyl)-6,8-dioxo-3 ,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-A Preparation of amide (82)
采用与实施例80相同的方法,除了4-(4-氨基-2-氟苯氧基)吡啶-2-胺(mm)代替4-((6-甲氧基-7-(2-吗啉乙氧基)喹唑啉-4-基)氧基)苯胺(ss),制得N-(4-((2-氨基吡啶-4-基)氧基)-3-氟苯基)-7-(4-氟苯基)-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酰胺(82)(白色固体,一步收率:30.8%)。In the same manner as in Example 80, except for 4-(4-amino-2-fluorophenoxy)pyridin-2-amine (mm) instead of 4-((6-methoxy-7-(2-morpholine) Ethoxy)quinazolin-4-yl)oxy)aniline (ss) to give N-(4-((2-aminopyridin-4-yl)oxy)-3-fluorophenyl)-7 -(4-fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazine [2,1-b][1,3]oxazine-9-carboxamide (82) (white solid, one step yield: 30.8%).
LC-MS(ESI):m/z 560.2[M+H
+]。
LC-MS (ESI): m / z 560.2 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.71(s,1H),8.89(s,1H),7.97(dd,J=12.9,2.5Hz,1H),7.79(d,J=5.9Hz,1H),7.46(dt,J=8.5,2.0Hz,1H),7.30(d,J=9.0Hz,1H),7.23–7.01(m,4H),6.16(dd,J=5.8,2.3Hz,1H),5.94(s,2H),5.79(d,J=2.3Hz,1H),5.28(t,J=4.0Hz,1H),4.69(dd,J=14.1,3.7Hz,1H),4.58(dd,J=14.1,4.4Hz,1H),4.27–4.18(m,1H),4.07(dd,J=11.1,4.5Hz,1H),3.86(td,J=11.8,2.7Hz,1H),3.10(td,J=12.7,3.5Hz,1H),1.68(d,J=10.9Hz,1H),1.57(d,J=13.3Hz,1H)。
1 H NMR (400MHz, DMSO- d 6) δ12.71 (s, 1H), 8.89 (s, 1H), 7.97 (dd, J = 12.9,2.5Hz, 1H), 7.79 (d, J = 5.9Hz, 1H), 7.46 (dt, J = 8.5, 2.0 Hz, 1H), 7.30 (d, J = 9.0 Hz, 1H), 7.23 - 7.01 (m, 4H), 6.16 (dd, J = 5.8, 2.3 Hz, 1H) ), 5.94 (s, 2H), 5.79 (d, J = 2.3 Hz, 1H), 5.28 (t, J = 4.0 Hz, 1H), 4.69 (dd, J = 14.1, 3.7 Hz, 1H), 4.58 (dd , J = 14.1, 4.4 Hz, 1H), 4.27 - 4.18 (m, 1H), 4.07 (dd, J = 11.1, 4.5 Hz, 1H), 3.86 (td, J = 11.8, 2.7 Hz, 1H), 3.10 ( Td, J = 12.7, 3.5 Hz, 1H), 1.68 (d, J = 10.9 Hz, 1H), 1.57 (d, J = 13.3 Hz, 1H).
实施例83:N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)苯基)-10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-α][1,4]二氮杂环庚烷-8-甲酰胺(83)的制备Example 83: N-(4-((6,7-Dimethoxyquinazolin-4-yl)oxy)phenyl)-10-(4-fluorophenyl)-1,9-dioxo Preparation of 1,3,3,4,5,9-hexahydropyrido[1,2-α][1,4]diazepane-8-carboxamide (83)
采用与实施例78相同的方法,除了4-((6,7-二甲氧基喹唑啉-4-基)氧基)苯胺(ll)代替4-((6-甲氧基-7-(2-甲氧基乙氧基)喹唑啉-4-基)氧基)苯胺(pp),制得N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)苯基)-10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-α][1,4]二氮杂环庚烷-8-甲酰胺(83)(白色固体,一步收率:29.4%)。In the same manner as in Example 78 except that 4-((6,7-dimethoxyquinazolin-4-yl)oxy)phenylamine (11) was used instead of 4-((6-methoxy-7-). (2-methoxyethoxy)quinazolin-4-yl)oxy)aniline (pp) to give N-(4-((6,7-dimethoxyquinazolin-4-yl) Oxy)phenyl)-10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-α][ 1,4]diazepane-8-carboxamide (83) (white solid, one step yield: 29.4%).
LC-MS(ESI):m/z 596.4[M+H
+]。
LC-MS (ESI): m / z 596.4 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.80(s,1H),8.85(s,1H),8.66(d,J=7.1Hz,1H),8.56(s,1H),7.80(d,J=8.6Hz,2H),7.57(s,1H),7.40(s,1H),7.31(d,J=8.4Hz,4H),7.22(t,J=8.7Hz,2H),4.66(d,J=13.3Hz,1H),4.07(s,1H),3.99(d,J=5.7Hz,6H),2.06(d,J=25.5Hz,4H)。
1 H NMR (400MHz, DMSO- d 6) δ12.80 (s, 1H), 8.85 (s, 1H), 8.66 (d, J = 7.1Hz, 1H), 8.56 (s, 1H), 7.80 (d, J = 8.6 Hz, 2H), 7.57 (s, 1H), 7.40 (s, 1H), 7.31 (d, J = 8.4 Hz, 4H), 7.22 (t, J = 8.7 Hz, 2H), 4.66 (d, J = 13.3 Hz, 1H), 4.07 (s, 1H), 3.99 (d, J = 5.7 Hz, 6H), 2.06 (d, J = 25.5 Hz, 4H).
实施例84:N-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-10-(4-氟苯基)-1,9-二氧代-1,2,3,4-,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酰胺(84)的制备Example 84: N-(4-((1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)phenyl)-10-(4-fluorophenyl)-1,9-di Preparation of oxo-1,2,3,4-,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxamide (84)
采用与实施例78相同的方法,除了4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯胺(ii)代替4-((6-甲氧基-7-(2-甲氧基乙氧基)喹唑啉-4-基)氧基)苯胺(pp),制得N-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-10-(4-氟苯基)-1,9-二氧代-1,2,3,4-,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酰胺(84)(白色固体,一步收率:26.7%)。In the same manner as in Example 78 except that 4-((1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)phenylamine (ii) was substituted for 4-((6-methoxy-7) -(2-methoxyethoxy)quinazolin-4-yl)oxy)aniline (pp) to give N-(4-((1H-pyrrolo[2,3-b]pyridine-4) -yl)oxy)phenyl)-10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4-,5,9-hexahydropyrido[1,2- a] [1,4]diazepane-8-carboxamide (84) (white solid, one step yield: 26.7%).
LC-MS(ESI):m/z 524.4[M+H
+]。
LC-MS (ESI): m / z 524.4 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.79(s,1H),11.74(s,1H),8.84(s,1H),8.67(t,J=6.6Hz,1H),8.09(d,J=5.4Hz,1H),7.79(d,J=8.7Hz,2H),7.36(t,J=3.0Hz,1H),7.29(dd,J=8.4,5.6Hz,2H),7.21(dd,J=10.7,8.7Hz,4H),6.43(d,J=5.5Hz,1H),6.22(t,J=2.7Hz,1H),4.65(d,J=11.7Hz,1H),4.05(d,J=11.7Hz,1H),3.34–3.40(m,1H),2.15(s,1H),2.06–1.97(m,1H)。
1 H NMR (400MHz, DMSO- d 6) δ12.79 (s, 1H), 11.74 (s, 1H), 8.84 (s, 1H), 8.67 (t, J = 6.6Hz, 1H), 8.09 (d, J = 5.4 Hz, 1H), 7.79 (d, J = 8.7 Hz, 2H), 7.36 (t, J = 3.0 Hz, 1H), 7.29 (dd, J = 8.4, 5.6 Hz, 2H), 7.21 (dd, J = 10.7, 8.7 Hz, 4H), 6.43 (d, J = 5.5 Hz, 1H), 6.22 (t, J = 2.7 Hz, 1H), 4.65 (d, J = 11.7 Hz, 1H), 4.05 (d, J = 11.7 Hz, 1H), 3.34 - 3.40 (m, 1H), 2.15 (s, 1H), 2.06 - 1.97 (m, 1H).
实施例85:N-(3-氟-4-((6-甲氧基-7-(2-(哌嗪-1-基)乙氧基)喹唑啉-4-基)氧基)苯基)-7-(4-氟苯基)-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并 [2,1-b][1,3]恶嗪-9-甲酰胺(85)的制备Example 85: N-(3-Fluoro-4-((6-methoxy-7-(2-(piperazin-1-yl)ethoxy)quinazolin-4-yl)oxy)benzene -7-(4-fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5 Preparation of pyrazino[2,1-b][1,3]oxazine-9-carboxamide (85)
步骤1:4-(2-((4-(2-氟-4-(7-(4-氟苯基)-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酰胺基)苯氧基)-6-甲氧基喹唑啉-7-基)氧基)乙基)哌嗪-1-甲酸叔丁酯(85a)的制备Step 1: 4-(2-((4-(2-fluoro-4-)-4-(4-fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a- Hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamido)phenoxy)-6- Preparation of tert-butyl oxyquinazolin-7-yl)oxy)ethyl)piperazine-1-carboxylate (85a)
在含有DMF(5mL)的反应瓶中加入4-(2-((4-(4-氨基-2-氟苯氧基)-6-甲氧基喹唑啉-7-基)氧基)乙基)哌嗪-1-甲酸叔丁酯(qq)(80mg,0.16mmol)、7-(4-氟苯基)-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酸(k)(57mg,0.16mmol)、HATU(91mg,0.24mmol)和DIPEA(62mg,0.48mmol)。将混合物于室温搅拌30分钟,待反应完全后,加入饱和的碳酸氢钠溶液淬灭,用乙酸乙酯萃取(10mLx3),合并有机相。将有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为MeOH:CM=1:10),得到4-(2-((4-(2-氟-4-(7-(4-氟苯基)-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酰胺基)苯氧基)-6-甲氧基喹唑啉-7-基)氧基)乙基)哌嗪-1-甲酸叔丁酯(85a)(80mg,黄色固体,收率:58.6%)。Add 4-(2-(4-(4-amino-2-fluorophenoxy)-6-methoxyquinazolin-7-yl)oxy)B to a reaction flask containing DMF (5 mL) Tert-butyl piperazine-1-carboxylate (qq) (80 mg, 0.16 mmol), 7-(4-fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a - hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (k) (57 mg, 0.16 mmol), HATU (91 mg, 0.24 mmol) and DIPEA (62 mg, 0.48 mmol). The mixture was stirred at room temperature for 30 minutes. After the reaction was completed, EtOAc (EtOAc) The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography (EtOAc:EtOAc: )-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b] [1,3]oxazine-9-carboxamido)phenoxy)-6-methoxyquinazolin-7-yl)oxy)ethyl)piperazine-1-carboxylic acid tert-butyl ester (85a) (80 mg, yellow solid, yield: 58.6%).
LC-MS(ESI):m/z 854.4[M/M+H
+]。
LC-MS (ESI): m / z 854.4 [M / M + H +].
步骤2:N-(3-氟-4-((6-甲氧基-7-(2-(哌嗪-1-基)乙氧基)喹唑啉-4-基)氧基)苯基)-7-(4-氟苯基)-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酰胺(85)的制备Step 2: N-(3-Fluoro-4-((6-methoxy-7-(2-(piperazin-1-yl)ethoxy)quinazolin-4-yl)oxy)phenyl) )-7-(4-fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5] Preparation of pyrazino[2,1-b][1,3]oxazine-9-carboxamide (85)
在含有DCM(3mL)的反应瓶中加入4-(2-((4-(2-氟-4-(7-(4-氟苯基)-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酰胺基)苯氧基)-6-甲氧基喹唑啉-7-基)氧基)乙基)哌嗪-1-甲酸叔丁酯(85a)(80mg,0.09mmol)和盐酸的1,4-二氧六环溶液(1.5mL,4M)。将混合物于室温搅拌1小时后,减压浓缩。残余物通过制备HPLC纯化(C18,乙腈/水(0.1%甲酸):10%~100%),得到N-(3-氟-4-((6-甲氧基-7-(2-(哌嗪-1-基)乙氧基)喹唑啉-4-基)氧基)苯基)-7-(4-氟苯基)-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酰胺(85)(16.8mg,白色固体,27.8%)。Add 4-(2-(4-)-fluoro-4-(7-(4-fluorophenyl)-6,8-dioxo-3,4 to a reaction flask containing DCM (3 mL). 6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide) Benzyloxy-6-methoxyquinazolin-7-yl)oxy)ethyl)piperazine-1-carboxylic acid tert-butyl ester (85a) (80 mg, 0.09 mmol) and 1,4-dihydrochloride Oxycyclohexane solution (1.5 mL, 4 M). The mixture was stirred at room temperature for 1 hour and then concentrated. The residue was purified by preparative HPLC (C18, EtOAc/EtOAc (EtOAc:EtOAc:EtOAc:EtOAc:EtOAc Pyrazin-1-yl)ethoxy)quinazolin-4-yl)oxy)phenyl)-7-(4-fluorophenyl)-6,8-dioxo-3,4,6,8 ,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide (85) (16.8 Mg, white solid, 27.8%).
LC-MS(ESI):m/z 754.4[M/M+H
+]。
LC-MS (ESI): m / z 754.4 [M / M + H +].
1H NMR(400MHz,DMSO-d
6)δ8.90(s,1H),8.55(s,1H),8.34(s,1H),7.98(dd,J=12.7,2.3Hz,1H),7.57(s,1H),7.52–7.39(m,3H),7.21–7.07(m,4H),5.29(t,J=4.0Hz,1H),4.72–4.57(m,2H),4.32(t,J=5.7Hz,2H),4.26–4.20(m,1H),4.06(d,J=4.4Hz,1H),3.98(s,3H),3.86(d,J=2.8Hz,1H),3.14–3.07(m,1H),2.83(dt,J=19.4,5.3Hz,6H),2.56(t,J=4.7Hz,4H),1.71–1.54(m,2H)。
1 H NMR (400MHz, DMSO- d 6) δ8.90 (s, 1H), 8.55 (s, 1H), 8.34 (s, 1H), 7.98 (dd, J = 12.7,2.3Hz, 1H), 7.57 ( s, 1H), 7.52–7.39 (m, 3H), 7.21–7.07 (m, 4H), 5.29 (t, J=4.0 Hz, 1H), 4.72–4.57 (m, 2H), 4.32 (t, J= 5.7 Hz, 2H), 4.26 - 4.20 (m, 1H), 4.06 (d, J = 4.4 Hz, 1H), 3.98 (s, 3H), 3.86 (d, J = 2.8 Hz, 1H), 3.14 - 3.07 ( m, 1H), 2.83 (dt, J = 19.4, 5.3 Hz, 6H), 2.56 (t, J = 4.7 Hz, 4H), 1.71 - 1.54 (m, 2H).
实施例86:N-(3-氟-4-((6-甲氧基-7-(2-(哌嗪-1-基)乙氧基)喹唑啉-4-基)氧基)苯基)-10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酰胺(86)的制备Example 86: N-(3-Fluoro-4-((6-methoxy-7-(2-(piperazin-1-yl)ethoxy)quinazolin-4-yl)oxy)benzene Base)-10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4] Preparation of azepane-8-carboxamide (86)
采用与实施例85相同的方法,除了10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸(d)代替7-(4-氟苯基)-6,8-二氧代3,4,6,8,12,12a六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]恶嗪-9-甲酸(k),制得N-(3-氟-4-((6-甲氧基-7-(2-(哌嗪-1-基)乙氧基)喹唑啉-4-基)氧基)苯基)-10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酰胺(86)(白色固体,两步收率:17.8%)。The same procedure as in Example 85 was employed except for 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a. ][1,4]diazepane-8-carboxylic acid (d) instead of 7-(4-fluorophenyl)-6,8-dioxo 3,4,6,8,12,12a hexahydro -2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (k) to give N-(3-fluoro- 4-((6-Methoxy-7-(2-(piperazin-1-yl)ethoxy)quinazolin-4-yl)oxy)phenyl)-10-(4-fluorophenyl) -1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxamide ( 86) (white solid, two-step yield: 17.8%).
LC-MS(ESI):m/z 712.4[M/M+H
+]。
LC-MS (ESI): m / z 712.4 [M / M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.96(s,1H),8.86(s,1H),8.69(t,J=6.6Hz,1H),8.57(s,1H),8.34(s,1H),8.06–7.94(m,1H),7.58(s,1H),7.52–7.42(m,3H),7.35–7.18(m,4H),4.66(d,J=12.0Hz,1H),4.33(t,J=5.7Hz,2H),4.06(s,1H),3.99(s,3H),3.33(s,2H),2.83(dt,J=15.8,5.3Hz,6H),2.56(s,4H),2.16(s,1H),2.09–1.99(m,1H)。
1 H NMR (400MHz, DMSO- d 6) δ12.96 (s, 1H), 8.86 (s, 1H), 8.69 (t, J = 6.6Hz, 1H), 8.57 (s, 1H), 8.34 (s, 1H), 8.06–7.94 (m, 1H), 7.58 (s, 1H), 7.52–7.42 (m, 3H), 7.35–7.18 (m, 4H), 4.66 (d, J=12.0 Hz, 1H), 4.33 (t, J = 5.7 Hz, 2H), 4.06 (s, 1H), 3.99 (s, 3H), 3.33 (s, 2H), 2.83 (dt, J = 15.8, 5.3 Hz, 6H), 2.56 (s, 4H), 2.16 (s, 1H), 2.09 - 1.99 (m, 1H).
实施例87:N-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)-8-氟-1,5-二氧代-4-((四氢-2H-吡喃-4-基)甲基)-1,4,5,6-四氢苯并[f][1,7]萘啶-2-甲酰胺(87)的制备Example 87: N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-8-fluoro-1,5-dioxo-4 -((tetrahydro-2H-pyran-4-yl)methyl)-1,4,5,6-tetrahydrobenzo[f][1,7]naphthyridin-2-carboxamide (87) preparation
步骤1:3-溴-5-((4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)氨甲酰基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-2-羧酸乙酯(87a)的制备Step 1: 3-Bromo-5-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)carbamoyl)-4-oxo- Preparation of ethyl 1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2-carboxylate (87a)
在含有DMF(5mL)的反应瓶中加入4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯胺(ff)(70mg,0.22mmol)、5-溴-6-(乙氧基羰基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸(45a)(85mg,0.22mmol)、HATU(125mg,0.33mmol)和DIPEA(85mg,0.66mmol)。将混合物于室温搅拌半小时,待反应完成后,加入饱和的碳酸氢钠溶液淬灭,用乙酸乙酯萃取(10mLx3),合并有机相。将有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为MeOH:CM=1:10),得到3-溴-5-((4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)氨甲酰基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-2-羧酸乙酯(87a)(120mg,黄色固体,收率:79.8%)。Add 4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluoroaniline (ff) (70 mg, 0.22 mmol), 5-- to a reaction flask containing DMF (5 mL) Bromo-6-(ethoxycarbonyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid (45a) (85 mg, 0.22 mmol), HATU (125 mg, 0.33 mmol) and DIPEA (85 mg, 0.66 mmol). The mixture was stirred at room temperature for half an hour. After the reaction was completed, EtOAc (EtOAc m. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography (EtOAc:EtOAc: Ethyl)-3-fluorophenyl)carbamoyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine- Ethyl 2-carboxylate (87a) (120 mg, yellow solid, yield: 79.8%).
LC-MS(ESI):m/z 683.2/684.2[M/M+H
+]。
LC-MS (ESI): m / z 683.2 / 684.2 [M / M + H +].
步骤2:N-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)-8-氟-1,5-二氧代-4-((四 氢-2H-吡喃-4-基)甲基)-1,4,5,6-四氢苯并[f][1,7]萘啶-2-甲酰胺(87)的制备Step 2: N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-8-fluoro-1,5-dioxo-4- Preparation of ((tetrahydro-2H-pyran-4-yl)methyl)-1,4,5,6-tetrahydrobenzo[f][1,7]naphthyridin-2-carboxamide (87)
于室温,在含有(2.5mL)1,4-二氧六环和水混合液(4:1)的反应瓶中加入3-溴-5-((4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)氨甲酰基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-2-羧酸乙酯(87a)(50mg,0.07mmol)、2-氨基-4-氟苯硼酸(17mg,0.11mmol)、碳酸钾(30mg,0.21mmol)、Pd(dppf)Cl
2.DCM(8mg,0.01mmol)。密封,氮气置换三次,加热至80℃搅拌1.5小时。待反应液冷却至室温后,过滤,滤液用水(10mL)稀释,乙酸乙酯萃取(15mL×3),合并有机相。将有机相用饱和的食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过HPLC纯化(C18,乙腈/水(0.1%甲酸):10%~100%),得到N-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)-8-氟-1,5-二氧代-4-((四氢-2H-吡喃-4-基)甲基)-1,4,5,6-四氢苯并[f][1,7]萘啶-2-甲酰胺(87)(15mg,黄色固体,收率:32.0%)。
Add 3-bromo-5-((4-((6,7-dimethoxy)) to the reaction flask containing (2.5 mL) 1,4-dioxane and water mixture (4:1) at room temperature. Benzyl quinolin-4-yl)oxy)-3-fluorophenyl)carbamoyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1, 4-Dihydropyridine-2-carboxylic acid ethyl ester (87a) (50 mg, 0.07 mmol), 2-amino-4-fluorobenzeneboronic acid (17 mg, 0.11 mmol), potassium carbonate (30 mg, 0.21 mmol), Pd (dppf) )Cl 2 .DCM (8 mg, 0.01 mmol). Sealed, replaced with nitrogen three times, heated to 80 ° C and stirred for 1.5 hours. After the reaction mixture was cooled to room temperature, it was filtered, and the filtrate was diluted with water (10 mL), and ethyl acetate (15 mL×3). The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by HPLC (C18, EtOAc/EtOAc (EtOAc:EtOAc:EtOAc:EtOAc: EtOAc 3-fluorophenyl)-8-fluoro-1,5-dioxo-4-((tetrahydro-2H-pyran-4-yl)methyl)-1,4,5,6-tetrahydro Benzo[f][1,7]naphthyridin-2-carboxamide (87) (15 mg, yellow solid, yield: 32.0%).
LC-MS(ESI):m/z 669.4[M/M+H
+]。
LC-MS (ESI): m / z 669.4 [M / M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.72(s,1H),12.57(s,1H),9.96(dd,J=9.4,6.5Hz,1H),8.88(s,1H),8.50(d,J=5.3Hz,1H),8.11(dd,J=12.8,2.4Hz,1H),7.60(dt,J=9.0,1.7Hz,1H),7.54(s,1H),7.49(t,J=8.9Hz,1H),7.42(s,1H),7.24–7.16(m,2H),6.51(dd,J=5.3,1.1Hz,1H),4.99(d,J=7.0Hz,2H),3.96(d,J=2.1Hz,6H),3.87–3.79(m,2H),3.22–3.17(m,2H),2.07(s,1H),1.44–1.31(m,4H)。
1 H NMR (400MHz, DMSO- d 6) δ12.72 (s, 1H), 12.57 (s, 1H), 9.96 (dd, J = 9.4,6.5Hz, 1H), 8.88 (s, 1H), 8.50 ( d, J = 5.3 Hz, 1H), 8.11 (dd, J = 12.8, 2.4 Hz, 1H), 7.60 (dt, J = 9.0, 1.7 Hz, 1H), 7.54 (s, 1H), 7.49 (t, J = 8.9 Hz, 1H), 7.42 (s, 1H), 7.24 - 7.16 (m, 2H), 6.51 (dd, J = 5.3, 1.1 Hz, 1H), 4.99 (d, J = 7.0 Hz, 2H), 3.96 (d, J = 2.1 Hz, 6H), 3.87 - 3.79 (m, 2H), 3.22 - 3.17 (m, 2H), 2.07 (s, 1H), 1.44 - 1.31 (m, 4H).
实施例88:N-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)-8-氟-4-甲基-1,5-二氧代-1,4,5,6-四氢苯并[F][1,7]萘啶-2-甲酰胺(88)的制备Example 88: N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-8-fluoro-4-methyl-1,5- Preparation of Dioxo-1,4,5,6-tetrahydrobenzo[F][1,7]naphthyridine-2-carboxamide (88)
采用与实施例87相同的方法,除了3-溴-1-甲基-4-氧代-1,4-二氢吡啶-2,5-二羧酸二乙酯(a4)代替5-溴-6-(乙氧基羰基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸(45a),制得N-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)-8-氟-4-甲基-1,5-二氧代-1,4,5,6-四氢苯并[F][1,7]萘啶-2-甲酰胺(88)(2.5mg,白色固体,两步收率:3.6%)。In the same manner as in Example 87, except that 3-bromo-1-methyl-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (a4) was used instead of 5-bromo- 6-(ethoxycarbonyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid (45a), made N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-8-fluoro-4-methyl-1,5-dioxo -1,4,5,6-Tetrahydrobenzo[F][1,7]naphthyridin-2-carboxamide (88) (2.5 mg, white solid, yield: 3.6%).
LC-MS(ESI):m/z 585.3[M/M+H
+]。
LC-MS (ESI): m / z 585.3 [M / M + H +].
实施例89:N-(3-氟-4-((3-苯基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-10-(4-氟苯基)-1,9-二氧代1,2,3,4,5,9六氢吡啶并[1,2-α][1,4]二氮杂环庚烷-8-甲酰胺(89)的制备Example 89: N-(3-Fluoro-4-((3-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)phenyl)-10-(4-fluoro Phenyl)-1,9-dioxo 1,2,3,4,5,9 hexahydropyrido[1,2-α][1,4]diazepane-8-carboxamide ( Preparation of 89)
步骤1:4-(2-氟-4-硝基苯氧基)-1H-吡咯并[2,3-b]吡啶(89a)的制备Step 1: Preparation of 4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo[2,3-b]pyridine (89a)
在含有NMP(15mL)的反应瓶中加入4-氯-7-氮杂吲哚(1.53g,10.03mmol)、2-氟-4-硝基苯酚(2.36g,15.04mmol)和DIPEA(3.9g,30.09mmol)。将混合物加热至200℃并搅拌3小时,待反应液冷却至室温后,加入乙酸乙酯稀释。有机相用饱和的食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱液为DCM:MeOH/10:1),得到4-(2-氟-4-硝基苯氧基)-1H-吡咯并[2,3-b]吡啶(89a)(1.0g,黄色固体,收率:36.4%)。4-Chloro-7-azaindole (1.53 g, 10.03 mmol), 2-fluoro-4-nitrophenol (2.36 g, 15.04 mmol) and DIPEA (3.9 g) were added to a reaction flask containing NMP (15 mL). , 30.09mmol). The mixture was heated to 200 ° C and stirred for 3 hours. After the reaction mixture was cooled to room temperature, diluted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by EtOAc EtOAc EtOAc elut elut elut elut b] Pyridine (89a) (1.0 g, yellow solid, yield: 36.4%).
LC-MS(ESI):m/z 274.1[M/M+H
+]。
LC-MS (ESI): m / z 274.1 [M / M + H +].
步骤2:4-(2-氟-4-硝基苯氧基)-3-碘-1H-吡咯并[2,3-b]吡啶(89b)的制备Step 2: Preparation of 4-(2-fluoro-4-nitrophenoxy)-3-iodo-1H-pyrrolo[2,3-b]pyridine (89b)
在含有DMF(15mL)的反应瓶中加入4-(2-氟-4-硝基苯氧基)-1H-吡咯并[2,3-b]吡啶(89a)(1.0g,3.65mmol)和N-碘代丁二酰亚胺(NIS)(985mg,4.38mmol)。将混合物升温至80℃并搅拌3小时。待反应完全后,将反应液减压浓缩,残余物用饱和硫代硫酸钠水溶液淬灭,乙酸乙酯萃取(40mL×3),合并有机相。将有机相用饱和的食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱液为DCM:CH
3OH/10:1),得到4-(2-氟-4-硝基苯氧基)-3-碘-1H-吡咯并[2,3-b]吡啶(89b)(940mg,黄色油状物,收率:64.7%)。
Add 4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo[2,3-b]pyridine (89a) (1.0 g, 3.65 mmol) to a reaction flask containing DMF (15 mL). N-iodosuccinimide (NIS) (985 mg, 4.38 mmol). The mixture was warmed to 80 ° C and stirred for 3 hours. After the reaction was completed, the mixture was evaporated. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by chromatography on silica gel column chromatography (eluent DCM: CH 3 OH / 10: 1), to give 4- (2-fluoro-4-nitrophenoxy) -3-iodo -1H- pyrrole And [2,3-b]pyridine (89b) (940 mg, yellow oil, yield: 64.7%).
LC-MS(ESI):m/z 400.0[M/M+H
+]。
LC-MS (ESI): m / z 400.0 [M / M + H +].
步骤3:4-(2-氟-4-硝基苯氧基)-3-碘-1H-吡咯并[2,3-b]吡啶-1-甲酸叔丁酯(89c)的制备Step 3: Preparation of 4-(2-fluoro-4-nitrophenoxy)-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (89c)
在含有DCM(15mL)的反应瓶中加入4-(2-氟-4-硝基苯氧基)-3-碘-1H-吡咯并[2,3-b]吡啶(89b)(940mg,2.37mmol)、Boc
2O(777mg,3.56mmol)、DMAP(43mg,0.15mmol)和三乙胺(919mg,7.11mmol)。将混合物于室温搅拌1.5小时。待反应完全后,将反应液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱液为PE:EA/5:1),得到4-(2-氟-4-硝基苯氧基)-3-碘-1H-吡咯并[2,3-b]吡啶-1-甲酸叔丁酯(89c)(620mg,黄色固体,收率:52.4%)。
Add 4-(2-fluoro-4-nitrophenoxy)-3-iodo-1H-pyrrolo[2,3-b]pyridine (89b) (940 mg, 2.37) to a reaction flask containing DCM (15 mL) Methyl), Boc 2 O (777 mg, 3.56 mmol), DMAP (43 mg, 0.15 mmol) and triethylamine (919 mg, 7.11 mmol). The mixture was stirred at room temperature for 1.5 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: EtOAc: EtOAc: EtOAc) 2,3-b]pyridine-1-carboxylic acid tert-butyl ester (89c) (620 mg, yellow solid, yield: 52.4%).
LC-MS(ESI):m/z 500.0[M/M+H
+]。
LC-MS (ESI): m / z 500.0 [M / M + H +].
步骤4:3-氟-4-((3-碘-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯胺(89d)的制备Step 4: Preparation of 3-fluoro-4-((3-iodo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)phenylamine (89d)
于室温,在含有乙醇(8mL)和水(2mL)的反应瓶中加入4-(2-氟-4-硝基苯氧基)-3-碘-1H-吡咯并[2,3-b]吡啶-1-甲酸叔丁酯(89c)(300mg,0.60mmol)、铁粉(168mg,3.0mmol)和氯化铵(321mg,6.0mmol)。将反应液升温至80℃并搅拌1小时,待反应液冷却至室温后,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱液为DCM:MeOH/5:1),得到3-氟-4-((3-碘-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯胺(89d)(100mg,黄色固体,收率:45.0%)。4-(2-Fluoro-4-nitrophenoxy)-3-iodo-1H-pyrrolo[2,3-b] was added to a reaction flask containing ethanol (8 mL) and water (2 mL) at room temperature. tert-Butyl pyridine-1-carboxylate (89c) (300 mg, 0.60 mmol), iron powder (168 mg, 3.0 mmol) and ammonium chloride (321 mg, 6.0 mmol). The reaction solution was warmed to 80 ° C and stirred for 1 hour. After the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut 4-yl)oxy)aniline (89d) (100 mg, yellow solid, yield: 45.0%).
LC-MS(ESI):m/z 370.0[M/M+H
+]。
LC-MS (ESI): m / z 370.0 [M / M + H +].
步骤5:N-(3-氟-4-((3-碘-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酰胺(89e)的制备Step 5: N-(3-Fluoro-4-((3-iodo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)phenyl)-10-(4-fluorophenyl) -1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxamide ( Preparation of 89e)
在含有DMF(5mL)的反应瓶中加入3-氟-4-((3-碘-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯胺(89d)(100mg,0.27mmol)、10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酸(d)(100mg,0.32mmol)、HATU(153mg,0.40mmol)和DIPEA(104mg,0.81mmol)。将混合物于室温搅拌30分钟,待反应完成后,加入饱和的碳酸氢钠溶液淬灭,用乙酸乙酯萃取(10mLx3),合并有机相。将有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂为MeOH:CM=1:10),得到N-(3-氟-4-((3-碘-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-10-(4-氟苯基)-1,9-二氧代1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酰胺(89e)(100mg,黄色固体,收率:53.9%)。In a reaction flask containing DMF (5 mL), 3-fluoro-4-((3-iodo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)aniline (89d) (100 mg, 0.27 mmol), 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4] Diazepane-8-carboxylic acid (d) (100 mg, 0.32 mmol), HATU (153 mg, 0.40 mmol) and DIPEA (104 mg, 0.81 mmol). The mixture was stirred at room temperature for 30 minutes. After the reaction was completed, EtOAc (EtOAc) The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography eluting elut elut elut eluting elut Pyridin-4-yl)oxy)phenyl)-10-(4-fluorophenyl)-1,9-dioxo 1,2,3,4,5,9-hexahydropyridyl[1, 2-a][1,4]diazepane-8-carboxamide (89e) (100 mg, yellow solid, yield: 53.9%).
LC-MS(ESI):m/z 668.1[M/M+H
+]。
LC-MS (ESI): m / z 668.1 [M / M + H +].
步骤6:4-(2-氟-4-(10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酰胺基)苯氧基)-3-碘-1H-吡咯并[2,3-b]吡啶-1-羧酸叔丁酯(89f)的制备Step 6: 4-(2-Fluoro-4-(10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyridyl[1, 2-a][1,4]diazepane-8-carboxamido)phenoxy)-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl Preparation of ester (89f)
在含有DCM(2mL)的反应瓶中加入N-(3-氟-4-((3-碘-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-10-(4-氟苯基)-1,9-二氧代1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂 环庚烷-8-甲酰胺(89e)(40mg,0.06mmol)、Boc
2O(20mg,0.09mmol)、DMAP(1mg,0.01mmol)和三乙胺(18mg,0.18mmol)。将混合物于该温度搅拌1.5小时。待反应完全后,将反应液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱液为PE:EA/5:1),得到4-(2-氟-4-(10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酰胺基)苯氧基)-3-碘-1H-吡咯并[2,3-b]吡啶-1-羧酸叔丁酯(89f)(30mg,白色固体,收率:63.5%)。
Add N-(3-fluoro-4-((3-iodo-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)phenyl)- in a reaction flask containing DCM (2 mL) 10-(4-fluorophenyl)-1,9-dioxo 1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepine Alkano-8-carboxamide (89e) (40 mg, 0.06 mmol), Boc 2 O (20 mg, 0.09 mmol), DMAP (1 mg, 0.01 mmol) and triethylamine (18 mg, 0.18 mmol). The mixture was stirred at this temperature for 1.5 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: EtOAc: EtOAc: EtOAc) Oxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepan-8-carboxamido)phenoxy)-3 - Iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (89f) (30 mg, white solid, yield: 63.5%).
LC-MS(ESI):m/z 768.1[M/M+H
+]。
LC-MS (ESI): m / z 768.1 [M / M + H +].
步骤7:N-(3-氟-4-((3-苯基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-10-(4-氟苯基)-1,9-二氧代1,2,3,4,5,9六氢吡啶并[1,2-α][1,4]二氮杂环庚烷-8-甲酰胺(89)的制备Step 7: N-(3-Fluoro-4-((3-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)phenyl)-10-(4-fluorobenzene) 1,1,9-dioxo 1,2,3,4,5,9 hexahydropyrido[1,2-α][1,4]diazepane-8-carboxamide (89 Preparation
于室温,在含有(3.3mL)乙醇、甲苯和水混合液(5:5:1)的反应瓶中加入4-(2-氟-4-(10-(4-氟苯基)-1,9-二氧代-1,2,3,4,5,9-六氢吡啶并[1,2-a][1,4]二氮杂环庚烷-8-甲酰氨基)苯氧基)-3-碘-1H-吡咯并[2,3-b]吡啶-1-羧酸叔丁酯(89f)(30mg,0.04mmol)、苯硼酸(6mg,0.06mmol)、碳酸钠(12mg,0.12mmol)、Pd(PPh
3)
2Cl
2(7mg,0.01mmol)。密封,氮气置换三次,加热至80℃搅拌1.5小时。待反应液冷却至室温后,过滤,滤液用水(10mL)稀释,乙酸乙酯萃取(15mL×3),合并有机相。将有机相用饱和的食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残余物通过HPLC纯化(C18,乙腈/水(0.1%甲酸):10%~100%),得到N-(3-氟-4-((3-苯基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-10-(4-氟苯基)-1,9-二氧代1,2,3,4,5,9六氢吡啶并[1,2-α][1,4]二氮杂环庚烷-8-甲酰胺(89)(6mg,白色固体,收率:24.3%)。
4-(2-Fluoro-4-(10-(4-fluorophenyl)-1) was added to a reaction flask containing (3.3 mL) a mixture of ethanol, toluene and water (5:5:1) at room temperature. 9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-formylamino)phenoxy -3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (89f) (30 mg, 0.04 mmol), phenylboronic acid (6 mg, 0.06 mmol), sodium carbonate (12 mg, 0.12 mmol), Pd(PPh 3 ) 2 Cl 2 (7 mg, 0.01 mmol). Sealed, replaced with nitrogen three times, heated to 80 ° C and stirred for 1.5 hours. After the reaction mixture was cooled to room temperature, it was filtered, and the filtrate was diluted with water (10 mL), and ethyl acetate (15 mL×3). The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by HPLC (C18, EtOAc/water (0.1% EtOAc): 10% to 100%) to afford N-(3-fluoro-4-((3-phenyl-1H-pyrrolo[2,3- b]pyridin-4-yl)oxy)phenyl)-10-(4-fluorophenyl)-1,9-dioxo 1,2,3,4,5,9 hexahydropyridyl[1, 2-α][1,4]diazepane-8-carboxamide (89) (6 mg, white solid, yield: 24.3%).
LC-MS(ESI):m/z 618.3[M/M+H
+]。
LC-MS (ESI): m / z 618.3 [M / M + H +].
实施例90:N
5-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)-3-(4-氟苯基)-1-环丙基-4-氧代-1,4-二氢吡啶-2.5-二甲酰胺(90)的制备
Example 90: N 5 -(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1- Preparation of cyclopropyl-4-oxo-1,4-dihydropyridine-2.5-dicarboxamide (90)
采用与实施例58相同的方法,除了用5-(4-氟苯基)-1-环丙基-4-氧代-1,4-二氢吡啶-3-甲酸(b1)代替6-(乙氧基羰基)-5-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-3-羧酸(a),制得N
5-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)-3-(4-氟苯基)-1-环丙基-4-氧代-1,4-二氢吡啶-2,5-二甲酰胺(90)(白色固体,三步收率:52%)。
The same procedure as in Example 58 was employed except that 5-(4-fluorophenyl)-1-cyclopropyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (b1) was used instead of 6-( Ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (a) to give N 5 -(4- ((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-cyclopropyl-4-oxo-1 4-dihydropyridine-2,5-dimethylformamide (90) (white solid, three-step yield: 52%).
LC-MS(ESI):m/z613.7[M+H
+]。
LC-MS (ESI): m / z613.7 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.83(s,1H),8.62(s,1H),8.48(d,J=5.2Hz,1H),8.12(s,1H),8.04(dd,J=12.9,2.4Hz,1H),7.97(s,1H),7.54–7.49(m,2H),7.47–7.40(m,2H),7.36–7.31(m,2H),7.28–7.22(m,2H),6.48(d,J=5.1Hz,1H),3.95(d,J=1.6Hz,6H),2.02–1.96(m,1H),1.26(s,2H),1.09(d,J=7.1Hz,2H)。
1 H NMR (400 MHz, DMSO-d 6 ) δ 12.83 (s, 1H), 8.62 (s, 1H), 8.48 (d, J = 5.2 Hz, 1H), 8.12 (s, 1H), 8.04 (dd, J = 12.9, 2.4 Hz, 1H), 7.97 (s, 1H), 7.54 - 7.49 (m, 2H), 7.47 - 7.40 (m, 2H), 7.36 - 7.31 (m, 2H), 7.28 - 7.22 (m, 2H), 6.48 (d, J = 5.1 Hz, 1H), 3.95 (d, J = 1.6 Hz, 6H), 2.02 - 1.96 (m, 1H), 1.26 (s, 2H), 1.09 (d, J = 7.1) Hz, 2H).
实施例91:N
5-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)-3-(4-氟苯基)-1-环丁基-4-氧代-1,4-二氢吡啶2.5-二甲酰胺(91)的制备
Example 91: N 5 -(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1- Preparation of cyclobutyl-4-oxo-1,4-dihydropyridine 2.5-dimethylformamide (91)
采用与实施例58相同的方法,除了用5-(4-氟苯基)-1-环丁基-4-氧代-1,4-二氢吡啶-3-甲酸(b2)代替6-(乙氧基羰基)-5-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-3-羧酸(a),制得N
5-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)-3-(4-氟苯基)-1-环丁基-4-氧代-1,4-二氢吡啶-2,5-二甲酰胺(91)(白色固体,三步收率:16.4%)。
The same procedure as in Example 58 was employed except that 5-(4-fluorophenyl)-1-cyclobutyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (b2) was used instead of 6-( Ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (a) to give N 5 -(4- ((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-cyclobutyl-4-oxo-1 4-dihydropyridine-2,5-dimethylformamide (91) (white solid, three-step yield: 16.4%).
LC-MS(ESI):m/z 627.3[M+H
+]。
LC-MS (ESI): m / z 627.3 [M + H +].
1HNMR(400MHz,DMSO-d
6)δ12.92(s,1H),8.78(s,1H),8.48(d,J=5.2Hz,1H),8.22(s,1H),8.06(dd,J=12.9,2.4Hz,1H),7.98(s,1H),7.51(d,J=13.1Hz,2H),7.48–7.39(m,2H),7.37–7.30(m,2H),7.28–7.18(m,2H),6.49(dd,J=5.2,1.0Hz,1H),4.80(t,J=8.2Hz,1H),3.95(d,J=1.5Hz,6H),2.69–2.52(m,2H),2.46–2.35(m,2H),1.86–1.71(m,2H)。
1 H NMR (400 MHz, DMSO-d 6 ) δ 12.92 (s, 1H), 8.78 (s, 1H), 8.48 (d, J = 5.2 Hz, 1H), 8.22 (s, 1H), 8.06 (dd, J = 12.9, 2.4 Hz, 1H), 7.98 (s, 1H), 7.51 (d, J = 13.1 Hz, 2H), 7.48 - 7.39 (m, 2H), 7.37 - 7.30 (m, 2H), 7.28 - 7.18 ( m, 2H), 6.49 (dd, J = 5.2, 1.0 Hz, 1H), 4.80 (t, J = 8.2 Hz, 1H), 3.95 (d, J = 1.5 Hz, 6H), 2.69 - 2.52 (m, 2H) ), 2.46–2.35 (m, 2H), 1.86–1.71 (m, 2H).
实施例92:1-(叔丁基)-5-(4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基甲酰基)-3-(4-氟苯基)-4-羰基-1,4-二氢吡啶-2-甲酸乙酯(92)的制备Example 92: 1-(tert-butyl)-5-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)carbamoyl)-3- Preparation of ethyl (4-fluorophenyl)-4-carbonyl-1,4-dihydropyridine-2-carboxylate (92)
采用与实施例58中合成58a相同的方法,除了用5-(4-氟苯基)-1-叔丁基-4-氧代-1,4-二氢吡啶-3-甲酸(b3)代替6-(乙氧基羰基)-5-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-3-羧酸(a),制得1-(叔丁基)-5-(4-((6,7-二甲氧基喹啉-4-基)氧)-3-氟苯基)氨基甲酰基)-3-(4-氟苯基)-4-羰基-1,4-二氢吡啶-2-甲酸乙酯(92)(白色固体,收率: 77.4%)。The same procedure as in the synthesis 58a of Example 58 was used except that 5-(4-fluorophenyl)-1-tert-butyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (b3) was used instead. 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (a) to give 1-( tert-Butyl)-5-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)carbamoyl)-3-(4-fluorophenyl) Ethyl 4-carbonyl-1,4-dihydropyridine-2-carboxylate (92) (white solid, yield: 77.4%).
LC-MS(ESI):m/z658.3[M+H
+]。
LC-MS (ESI): m / z658.3 [M + H +].
1HNMR(400MHz,DMSO-d
6)δ12.70(s,1H),8.99(s,1H),8.48(d,J=5.2Hz,1H),8.05(dd,J=12.9,2.4Hz,1H),7.58–7.39(m,4H),7.26(dt,J=11.4,7.5Hz,4H),6.49(dd,J=5.3,1.0Hz,1H),3.95(d,J=2.2Hz,6H),3.91(t,J=7.1Hz,2H),1.73(s,9H),0.83(t,J=7.1Hz,3H)。
1 H NMR (400 MHz, DMSO-d 6 ) δ 12.70 (s, 1H), 8.99 (s, 1H), 8.48 (d, J = 5.2 Hz, 1H), 8.05 (dd, J = 12.9, 2.4 Hz, 1H) ), 7.58–7.39 (m, 4H), 7.26 (dt, J = 11.4, 7.5 Hz, 4H), 6.49 (dd, J = 5.3, 1.0 Hz, 1H), 3.95 (d, J = 2.2 Hz, 6H) , 3.91 (t, J = 7.1 Hz, 2H), 1.73 (s, 9H), 0.83 (t, J = 7.1 Hz, 3H).
实施例93:N
5-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)-3-(4-氟苯基)-N
2-甲基-d
3-1-甲基-4-氧代-1,4-二氢吡啶-2,5-二甲酰胺(93)的制备
Example 93: N 5 -(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-N 2 -Preparation of methyl-d 3 -1-methyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (93)
采用与实施例58相同的方法,除了用氘代甲胺代替氯化铵,制得N
5-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)-3-(4-氟苯基)-N
2-甲基-d
3-1-甲基-4-氧代-1,4-二氢吡啶-2,5-二甲酰胺(93)(白色固体,40mg,收率:32%)。
N 5 -(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3 was obtained in the same manner as in Example 58 except that instead of ammonium chloride. -fluorophenyl)-3-(4-fluorophenyl)-N 2 -methyl-d 3 -1-methyl-4-oxo-1,4-dihydropyridine-2,5-diformamide (93) (white solid, 40 mg, yield: 32%).
LC-MS(ESI):m/z 604.26[M+H
+]。
LC-MS (ESI): m / z 604.26 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.97(s,1H)δ8.82(s,1H),8.69(s,1H),8.48(d,J=5.3Hz,1H),8.05(dd,J=13.0,2.4Hz,1H),7.56–7.40(m,4H),7.32(ddd,J=8.7,5.6,2.6Hz,2H),7.27–7.19(m,2H),6.48(dd,J=5.3,1.1Hz,1H),3.95(d,J=1.1Hz,6H),3.82(s,3H)。
1 H NMR (400MHz, DMSO- d 6) δ12.97 (s, 1H) δ8.82 (s, 1H), 8.69 (s, 1H), 8.48 (d, J = 5.3Hz, 1H), 8.05 (dd , J = 13.0, 2.4 Hz, 1H), 7.56 - 7.40 (m, 4H), 7.32 (ddd, J = 8.7, 5.6, 2.6 Hz, 2H), 7.27 - 7.19 (m, 2H), 6.48 (dd, J = 5.3, 1.1 Hz, 1H), 3.95 (d, J = 1.1 Hz, 6H), 3.82 (s, 3H).
实施例94:N
5-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)-3-(4-氟苯基)-1-异丙基-N
2-甲基-d
3-4-氧代-1,4-二氢吡-2,5-二甲酰胺(94)的制备
Example 94: N 5 -(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1- Preparation of isopropyl-N 2 -methyl-d 3 -4-oxo-1,4-dihydropyridin-2,5-dimethylformamide (94)
采用与实施例58相同的方法,除了用6-(乙氧基羰基)-5-(4-氟苯基)-1-异丙基-4-氧代-1,4-二氢吡啶-3-甲酸(b)代替6-(乙氧基羰基)-5-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-3-羧酸(a),以及用氘代甲胺代替氯化铵,制得N
5-(4-((6,7-二甲氧基 喹啉-4-基)氧基)-3-氟苯基)-3-(4-氟苯基)-1-异丙基-N
2-甲基-d
3-4-氧代-1,4-二氢吡-2,5-二甲酰胺(94)(白色固体,15mg,收率:38%)。
The same procedure as in Example 58 was employed except that 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3 was used. -carboxylic acid (b) in place of 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (a) And using m-methylamine instead of ammonium chloride to obtain N 5 -(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-3- (4-fluorophenyl)-1-isopropyl-N 2 -methyl-d 3 -4-oxo-1,4-dihydropyridin-2,5-dimethylformamide (94) (white solid, 15 mg, yield: 38%).
LC-MS(ESI):m/z 632.37[M+H
+]。
LC-MS (ESI): m / z 632.37 [M + H +].
1H NMR(400MHz,DMSO-d
6)δ12.95(s,1H),8.76(d,J=5.4Hz,2H),8.49(d,J=5.3Hz,1H),8.06(dd,J=12.9,2.4Hz,1H),7.54–7.40(m,4H),7.36–7.30(m,2H),7.27–7.20(m,2H),6.49(dd,J=5.3,1.1Hz,1H),4.40(q,J=6.6Hz,1H),3.95(d,J=1.7Hz,6H),1.53(d,J=6.6Hz,6H)。
1 H NMR (400 MHz, DMSO-d 6 ) δ 12.95 (s, 1H), 8.76 (d, J = 5.4 Hz, 2H), 8.49 (d, J = 5.3 Hz, 1H), 8.06 (dd, J = 12.9, 2.4 Hz, 1H), 7.54 - 7.40 (m, 4H), 7.36 - 7.30 (m, 2H), 7.27 - 7.20 (m, 2H), 6.49 (dd, J = 5.3, 1.1 Hz, 1H), 4.40 (q, J = 6.6 Hz, 1H), 3.95 (d, J = 1.7 Hz, 6H), 1.53 (d, J = 6.6 Hz, 6H).
实施例95:N
5-(4-(2-氨基-5-(1-乙基-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-3-(4-氟苯基)-1-异丙基-N
2=甲基-d3-4-氧代-1,4-二氢吡啶-2,5-二甲酰胺(95)的制备
Example 95: N 5 -(4-(2-Amino-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-3-(4 Of -fluorophenyl)-1-isopropyl-N 2 =methyl-d3-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (95)
采用与实施例12相同的方法,除了用氘代甲胺代替氯化铵,制得N
5-(4-(2-氨基-5-(1-乙基-1H-吡唑-4-基)吡啶-3-基)-3-氟苯基)-3-(4-氟苯基)-1-异丙基-N
2-甲基-d3-4-氧代-1,4-二氢吡啶-2,5-二甲酰胺(95)(白色固体,19毫克,收率:30%)
N 5 -(4-(2-amino-5-(1-ethyl-1H-pyrazol-4-yl)) was obtained in the same manner as in Example 12 except that instead of ammonium chloride. Pyridin-3-yl)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-N 2 -methyl-d3-4-oxo-1,4-dihydropyridine -2,5-dimethylformamide (95) (white solid, 19 mg, yield: 30%)
LC-MS(ESI):m/z 615.36[M+H
+]
LC-MS (ESI): m/z 615.36 [M+H + ]
1H NMR(400MHz,DMSO-d6)δ12.93(s,1H),8.77(s,1H),8.74(s,1H),8.24(d,J=2.4Hz,1H),8.10–8.07(m,1H),7.90(dd,J=12.3,2.0Hz,1H),7.78(d,J=0.8Hz,1H),7.52(d,J=2.3Hz,1H),7.43(dd,J=8.4,2.0Hz,1H),7.38(d,J=8.2Hz,1H),7.32(ddd,J=8.5,5.5,2.6Hz,2H),7.23(t,J=9.0Hz,2H),5.53(s,2H),4.39(p,J=6.6Hz,1H),4.11(q,J=7.3Hz,2H),1.53(d,J=6.6Hz,6H),1.38(t,J=7.3Hz,3H)。
1 H NMR (400MHz, DMSO- d6) δ12.93 (s, 1H), 8.77 (s, 1H), 8.74 (s, 1H), 8.24 (d, J = 2.4Hz, 1H), 8.10-8.07 (m , 1H), 7.90 (dd, J = 12.3, 2.0 Hz, 1H), 7.78 (d, J = 0.8 Hz, 1H), 7.52 (d, J = 2.3 Hz, 1H), 7.43 (dd, J = 8.4, 2.0 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.32 (ddd, J = 8.5, 5.5, 2.6 Hz, 2H), 7.23 (t, J = 9.0 Hz, 2H), 5.53 (s, 2H), 4.39 (p, J = 6.6 Hz, 1H), 4.11 (q, J = 7.3 Hz, 2H), 1.53 (d, J = 6.6 Hz, 6H), 1.38 (t, J = 7.3 Hz, 3H) .
生物学评价Biological evaluation
测试例1:激酶Axl和c-MET酶活性抑制(IC
50)评价实验
Test Example 1: c-MET kinase Axl and inhibition of enzyme activity (IC 50) evaluation test
本实验使用Mobility shift assay法,测试化合物在ATP浓度分别为相应激酶Km下的抑制活性。对照品为孢碱(staurosporine)和卡博替尼(Cabozantinib)。In this experiment, the Mobility shift assay was used to test the inhibitory activity of the compound at the ATP concentration of the corresponding kinase Km. The reference substance was staurosporine and cabozantinib.
测试化合物的浓度从10μM开始,10倍稀释。测试结果(IC
50)为两次独立实验的平均值。
The concentration of the test compound was started from 10 μM and diluted 10-fold. The test results (IC 50 ) are the average of two independent experiments.
实验耗材:Laboratory supplies:
激酶Axl(Carna,Cat.No.08-107,Lot.No.06CBS-3408)、激酶cMET(Carna,Cat.No.08-151,Lot.No.10CBS-1118M)、底物肽FAM-P2(GL Biochem,Cat.No.112394,Lot.No.P131014-XP112394)、底物肽FAM-P22(GL Biochem,Cat. No112393,Lot.No.P130408-ZB112393)、ATP(Sigma,Cat.No.A7699-1G,CAS No.987-65-5)、DMSO(Sigma,Cat.No.D2650,Lot.No.474382)、EDTA(Sigma,Cat.No.E5134,CAS No.60-00-4)、Brij-35、96孔板(Corning,Cat.No.3365,Lot.No.22008026)、384孔板(Corning,Cat.No.3573,Lot.No.12608008)、孢碱(Staurosporine)(MCE,Cat.No.HY-15141,Lot.No.19340),卡博替尼(越之康泰,参照专利WO 201101763A1合成)Kinase Axl (Carna, Cat. No. 08-107, Lot. No. 06 CBS-3408), kinase cMET (Carna, Cat. No. 08-151, Lot. No. 10 CBS-1118M), substrate peptide FAM-P2 (GL Biochem, Cat. No. 112394, Lot. No. P131014-XP112394), substrate peptide FAM-P22 (GL Biochem, Cat. No 112393, Lot. No. P130408-ZB112393), ATP (Sigma, Cat. No.) A7699-1G, CAS No. 987-65-5), DMSO (Sigma, Cat. No. D2650, Lot. No. 474382), EDTA (Sigma, Cat. No. E5134, CAS No. 60-00-4) , Brij-35, 96-well plates (Corning, Cat. No. 3365, Lot. No. 22008026), 384-well plates (Corning, Cat. No. 3573, Lot. No. 12608008), Staurosporine (MCE) , Cat. No. HY-15141, Lot. No. 19340), Cabotinib (City of Vietnam, synthesized by reference patent WO 201101763A1)
实验步骤:Experimental steps:
1)缓冲液配制:50mM HEPES,pH 7.5,0.00015%Brij-35。1) Buffer formulation: 50 mM HEPES, pH 7.5, 0.00015% Brij-35.
2)对照品卡博替尼和测试样品配制:将卡博替尼和本发明实施例化合物在100%DMSO中配制成梯度浓度,并用上述缓冲液稀释成10%DMSO,加入384孔板。例如,化合物起始浓度为10uM,则用100%DMSO配制成500uM,并梯度稀释10个浓度,再用缓冲液稀释10倍,配成含10%DMSO的化合物中间稀释体,转移5ul至384孔板。2) Control product cabozantini and test sample formulation: Cabbolinib and the compound of the present invention were formulated in a gradient concentration in 100% DMSO and diluted to 10% DMSO with the above buffer, and added to a 384-well plate. For example, when the initial concentration of the compound is 10 uM, it is made into 500 uM with 100% DMSO, and diluted in 10 concentrations, and then diluted 10-fold with buffer to prepare an intermediate dilution of the compound containing 10% DMSO, and transferred 5 ul to 384 wells. board.
3)将Axl和c-MET酶分别用以下缓冲液稀释成最佳浓度:50mM HEPES,pH 7.5,0.00015%Brij-35,2mM DTT。转移10ul至384孔板中,与化合物共孵育10-15分钟。3) Axl and c-METase were diluted to the optimal concentration with the following buffers: 50 mM HEPES, pH 7.5, 0.00015% Brij-35, 2 mM DTT. Transfer 10 ul to 384 well plates and incubate with compound for 10-15 minutes.
4)将底物用以下缓冲液稀释成最佳浓度:50mM HEPES,pH 7.5,0.00015%Brij-35,10mM MgCl
2,Km下的三磷酸腺苷。加入10ul至384孔板起始反应,并于28℃反应1小时。
4) The substrate was diluted to the optimal concentration with the following buffer: 50 mM HEPES, pH 7.5, 0.00015% Brij-35, 10 mM MgCl 2 , adenosine triphosphate at Km. The reaction was initiated by adding 10 ul to a 384-well plate and reacted at 28 ° C for 1 hour.
测试实验中各试剂的反应浓度如下表1所示。The reaction concentrations of the respective reagents in the test experiment are shown in Table 1 below.
表1Table 1
5)用Caliper Reader读取转化率,计算抑制率为两次测试平均值。5) The conversion rate was read with a Caliper Reader, and the inhibition rate was calculated as the average of the two tests.
6)用XL-fit软件拟合IC
50。
6) Fit the IC 50 with XL-fit software.
本发明化合物对Axl和c-MET激酶的抑制活性如下表2所示。The inhibitory activities of the compounds of the present invention against Axl and c-MET kinase are shown in Table 2 below.
表2:本发明化合物对激酶Axl和c-MET活性抑制的IC
50值
Table 2: IC 50 values of the compounds of the present invention and Axl kinase activity of c-MET inhibition
由上表2可知,本发明化合物能够有效地抑制Axl和MET激酶的活性。与阳性对照药物卡博替尼相比,部分发明化合物展现出更高的活性抑制能力。As apparent from the above Table 2, the compounds of the present invention are effective in inhibiting the activities of Axl and MET kinase. Some of the inventive compounds exhibited higher activity inhibition ability than the positive control drug cabozantinib.
测试例2:CellTiter-Glo(CTG)法测试本发明化合物在细胞系EBC-1上活性抑制能力Test Example 2: CellTiter-Glo (CTG) method for measuring the activity inhibition ability of the compound of the present invention on cell line EBC-1
实验试剂和耗材Experimental reagents and consumables
1)胎牛血清FBS(GBICO,Cat#10099-141,Lot#1828728)1) Fetal bovine serum FBS (GBICO, Cat#10099-141, Lot#1828728)
2)
Luminescent Cell Viability Assay(Promega,Cat#G7573,Lot#0000249676)
2) Luminescent Cell Viability Assay (Promega, Cat#G7573, Lot#0000249676)
4)MEM培养基(Hyclone,Cat#SH30024.01,Lot#AC10232463)4) MEM medium (Hyclone, Cat#SH30024.01, Lot#AC10232463)
5)NEAA(Gibco,Cat#11140-050,Lot#1872982)5) NEAA (Gibco, Cat#11140-050, Lot#1872982)
6)对照品:卡博替尼(越之康泰,参照专利WO201101763A1合成)6) Reference substance: cabozantini (Vietnamese, according to patent WO201101763A1 synthesis)
7)细胞7) Cells
细胞名称 细胞类型 培养基Cell name Cell type Medium
EBC-1 肺 MEM+0.01mM NEAA+10%FBSEBC-1 lung MEM+0.01mM NEAA+10%FBS
所选细胞置于37℃、5%CO
2、95%湿度条件下培养。
The selected cells were cultured at 37 ° C, 5% CO 2 , 95% humidity.
仪器instrument
1)多功能酶标仪,Molecular Devices,spectraMax M3。1) Multi-function microplate reader, Molecular Devices, spectraMax M3.
2)CO
2培养箱,Thermo Scientific,Model 311Series。
2) CO 2 incubator, Thermo Scientific, Model 311 Series.
3)生物安全柜,Dong Lian Ha Er,BSC-1100-L II A2。3) Biological safety cabinet, Dong Lian Ha Er, BSC-1100-L II A2.
4)倒置显微镜,Olympus,CKX41。4) Inverted microscope, Olympus, CKX41.
5)冰箱,海尔,BCD-190TMPK。5) Refrigerator, Haier, BCD-190TMPK.
细胞活力和IC
50测定
Cell viability and IC 50 determination
第一天:细胞培养和接种Day 1: Cell culture and inoculation
1)收获处于对数生长期的细胞并采用细胞计数仪进行细胞计数。用台盼蓝排 斥法检测细胞活力,确保细胞系活力在90%以上。1) Harvest cells in logarithmic growth phase and perform cell counting using a cell counter. Cell viability was measured by trypan blue exclusion to ensure cell viability was above 90%.
2)用完全培养液稀释调整细胞浓度,添加90μl细胞悬液至96孔板(第0天板和待测药板)中使细胞密度达到指定的浓度:700个/孔。2) Adjust the cell concentration by diluting with complete medium, and add 90 μl of the cell suspension to a 96-well plate (Day 0 plate and test plate) to bring the cell density to the specified concentration: 700 cells/well.
3)96孔板中的细胞置于37℃、5%CO
2、95%湿度条件下培养过夜。
3) Cells in 96-well plates were incubated overnight at 37 ° C, 5% CO 2 , 95% humidity.
第0天:T0读板Day 0: T0 reading board
4)向T0板中补入10μl培养液。4) 10 μl of the culture solution was added to the T0 plate.
5)融化CTG试剂(即
Luminescent Cell Viability Assay试剂,Promega,Cat#G7573)并平衡细胞板至室温30分钟。
5) Melting CTG reagents (ie Luminescent Cell Viability Assay Reagent, Promega, Cat# G7573) and equilibrate the cell plates to room temperature for 30 minutes.
6)每孔加入等体积的CTG溶液。6) Add an equal volume of CTG solution to each well.
7)在定轨摇床上振动2分钟使细胞裂解。7) The cells were lysed by shaking for 2 minutes on an orbital shaker.
8)将细胞板放置于室温10分钟以稳定冷光信号。8) Place the cell plate at room temperature for 10 minutes to stabilize the cold light signal.
9)用多功能酶标仪读取冷光值。9) Read the cold light value with a multi-function microplate reader.
第0天:加样Day 0: Dosing
10)样品稀释:将本发明化合物和对照品卡博替尼用DMSO溶解,进行梯度稀释,得到10倍溶液。10) Sample dilution: The compound of the present invention and the control product, cabozantinib, were dissolved in DMSO and subjected to gradient dilution to obtain a 10-fold solution.
11)加样:在已接种细胞的96孔板中每孔加入10μl药物溶液,每个细胞浓度设置三个复孔。被测化合物和对照品在细胞上的最高浓度为5μM,9个浓度,5倍稀释。11) Loading: 10 μl of the drug solution was added to each well of a 96-well plate in which cells were seeded, and three duplicate wells were set for each cell concentration. The highest concentration of the test compound and the control on the cells was 5 μM, 9 concentrations, and 5 fold dilution.
12)培养:将已加样的96孔板中的细胞置于37℃、5%CO
2、95%湿度条件下继续培养6天,分别进行CTG检测分析。
12) Culture: The cells in the 96-well plate that had been loaded were further cultured at 37 ° C, 5% CO 2 , 95% humidity for 6 days, and subjected to CTG detection analysis.
第6天:终点读板Day 6: End reading board
13)融化CTG试剂并平衡细胞板至室温30分钟。13) Melt the CTG reagent and equilibrate the cell plate to room temperature for 30 minutes.
14)每孔加入等体积的CTG溶液。14) Add an equal volume of CTG solution to each well.
15)在定轨摇床上振动2分钟使细胞裂解。15) The cells were lysed by shaking for 2 minutes on an orbital shaker.
16)将细胞板放置于室温10分钟以稳定冷光信号。16) Place the cell plate at room temperature for 10 minutes to stabilize the cold light signal.
17)用多功能酶标仪读取冷光值。17) Read the luminescence value with a multi-function microplate reader.
数据处理data processing
使用GraphPad Prism 7.0软件分析数据,利用非线性S曲线回归来拟合数据得出剂量-效应曲线,并由此计算IC
50值。
Data was analyzed using GraphPad Prism 7.0 software, using a nonlinear regression curve fit data S derived dose - response curves, IC50 values calculated therefrom IC.
细胞存活率(%)=(Lum
待测化合物-Lum
培养液对照)/(Lum
细胞对照-Lum
培养液对照)×100%
Cell viability (%) = (Lum test compound - Lum culture control ) / (Lum cell control - Lum culture control ) × 100%
本发明化合物在细胞系EBC-1上的活性抑制能力如下表3所示。The activity inhibitory ability of the compound of the present invention on the cell line EBC-1 is shown in Table 3 below.
表3:本发明化合物在细胞系EBC-1上活性抑制能力(IC
50值)
Table 3: Activity inhibition ability (IC 50 value) of the compound of the present invention on cell line EBC-1
由上表3可知,本发明化合物能够有效地抑制EBC-1细胞的活性。与阳性对照药物卡博替尼相比,本发明化合物展现出更强烈的抑制能力。同时由于EBC-1为c-MET驱动的肺癌细胞系,因此本发明化合物对EBC-1细胞活性进一步验证了它们对c-MET激酶靶点的抑制作用。As apparent from the above Table 3, the compound of the present invention can effectively inhibit the activity of EBC-1 cells. The compounds of the invention exhibited a more potent inhibitory capacity than the positive control drug cabozantinib. At the same time, since EBC-1 is a c-MET driven lung cancer cell line, the activity of the compounds of the present invention on EBC-1 cells further validates their inhibition of c-MET kinase targets.
测试例3:本发明化合物分别对细胞系NCI-H1299和A549中Axl磷酸化的抑 制作用Test Example 3: Inhibition of Axl phosphorylation in cell lines NCI-H1299 and A549 by the compounds of the present invention, respectively
NCI-H1299和A549均为Axl高表达的肺癌细胞系。通过Western blot法测试本发明化合物对NCI-H1299和A549的Axl(Tyr702)磷酸化的抑制作用(p-Axl)。NCI-H1299 and A549 are lung cancer cell lines with high expression of Axl. The inhibition of the phosphorylation of Axl (Tyr702) by NCI-H1299 and A549 by the compounds of the present invention (p-Axl) was tested by Western blot.
实验材料:Experimental Materials:
细胞株:Cell line:
肿瘤细胞在含有10%FBS的培养基中培养,置于37℃、5%CO2及95%湿度的培养箱中。所用血清购自GIBCO。Tumor cells were cultured in a medium containing 10% FBS and placed in an incubator at 37 ° C, 5% CO 2 and 95% humidity. The serum used was purchased from GIBCO.
实验试剂:Experimental reagents:
1.cOmplete,不含EDTA蛋白酶抑制剂混合物(EDTA-free Protease Inhibitor Cocktail)(Roche-4693132001,Sigma)1. cOmplete, EDTA-free Protease Inhibitor Cocktail (Roche-4693132001, Sigma)
2.PhosSTOPTM(Roche-4906845001,Sigma)2.PhosSTOPTM (Roche-4906845001, Sigma)
3.重组人Gas6蛋白(885-GSB-050,R&D)3. Recombinant human Gas6 protein (885-GSB-050, R&D)
4.Axl(C89E7)兔mAb(8661S,Cell Signaling Technology)4.Axl (C89E7) rabbit mAb (8661S, Cell Signaling Technology)
5.膦-Axl(Tyr702)(D12B2)兔mAb(5724S,Cell Signaling Technology)5. Phosphine-Axl (Tyr702) (D12B2) rabbit mAb (5724S, Cell Signaling Technology)
6.抗兔IgG,HRP-连接抗体(7074,Cell Signaling Technology)6. Anti-rabbit IgG, HRP-linked antibody (7074, Cell Signaling Technology)
7.台盼蓝染色液(0.4%)(C0040,Solarbio)7. Trypan blue staining solution (0.4%) (C0040, Solarbio)
8.RIPA细胞裂解和提取缓冲液(89901,Thermo);8. RIPA cell lysis and extraction buffer (89901, Thermo);
9.NuPAGE样品还原试剂(10×)(Thermo,Cat#NP0009);9. NuPAGE sample reduction reagent (10×) (Thermo, Cat#NP0009);
10.NuPAGE上样缓冲溶液(4×)(Thermo,Cat#NP0008)。10. NuPAGE loading buffer solution (4×) (Thermo, Cat# NP0008).
仪器设备:equipment:
1.CO2培养箱:Thermo Scientific,Model 311Series;1.CO2 incubator: Thermo Scientific, Model 311Series;
2.生物安全柜:Dong Lian Ha Er,BSC-1100-L II A2;2. Biological safety cabinet: Dong Lian Ha Er, BSC-1100-L II A2;
3.倒置显微镜:奥林巴斯,CKX41;3. Inverted microscope: Olympus, CKX41;
4.冰箱:海尔,BCD-190TMPK;4. Refrigerator: Haier, BCD-190TMPK;
5.Mini Gel Tank:A25977,Invitrogen;5.Mini Gel Tank: A25977, Invitrogen;
6.BlotTM2干式转渍系统(Dry Blotting System):IB21001,Invitrogen;6.BlotTM2 Dry Blotting System: IB21001, Invitrogen;
7.血球计数板:MH0096,美仑生物。7. Blood count board: MH0096, Meilun Biological.
实验方法:experimental method:
1.收集处于对数生长期的细胞并采用血球计数板(MH0096,美仑生物)进行细胞计数。用台盼蓝排除法检测细胞活力,确保用于实验的各细胞系活力均在90%以上。1. Collect cells in logarithmic growth phase and perform cell counting using a hemocytometer (MH0096, Meilun Bio). Cell viability was determined by trypan blue exclusion, ensuring that the viability of each cell line used in the experiment was above 90%.
2.用RPMI1640+10%FBS培养基稀释NCI-H1299细胞浓度至1×106个/ml,用F12K+10%FBS培养基稀释A549细胞浓度至1×106个/ml,。2. Dilute the concentration of NCI-H1299 cells to 1×10 6 cells/ml with RPMI1640+10% FBS medium, and dilute the A549 cell concentration to 1×10 6 cells/ml with F12K+10% FBS medium.
3.取1ml稀释的细胞悬浊液加入6孔板中。向含NCI-H1299细胞的孔中补加0.8ml的RPMI1640+10%FBS培养基,向含A549细胞的孔中补加0.8ml的F12K+10%FBS培养基。3. Add 1 ml of the diluted cell suspension to a 6-well plate. 0.8 ml of RPMI1640 + 10% FBS medium was added to the wells containing NCI-H1299 cells, and 0.8 ml of F12K + 10% FBS medium was added to the wells containing A549 cells.
4.待细胞贴壁24小时后,将培养基换为无血清培养基。4. After the cells were attached for 24 hours, the medium was changed to serum-free medium.
5. 24小时后,实验组加入200μL 10×浓度的待测化合物,使化合物终浓度为100nM。化合物稀释过程如下:5. After 24 hours, the experimental group was added with 200 μL of a 10× concentration of the test compound to give a final concentration of 100 nM. The compound dilution process is as follows:
a.将测试化合物配制成DMSO10mM储备液。a. The test compound was formulated into a DMSO 10 mM stock solution.
b.使用198μL的DMSO稀释2μL的10mM储备液至100μM工作液。b. Dilute 2 μL of 10 mM stock solution to 100 μM working solution using 198 μL of DMSO.
c.使用495μL的PBS稀释5μL的100μM工作液至1μM工作液。c. Dilute 5 μL of 100 μM working solution to 1 μM working solution using 495 μL of PBS.
d.实验组加入200μL 10×浓度的待测化合物,对照组中加入200μL的含1%DMSO的PBS。d. The experimental group was added with 200 μL of a 10× concentration of the test compound, and 200 μL of PBS containing 1% DMSO was added to the control group.
6.待化合物处理2小时后,加入确定浓度的Gas6(对NCI-H1299,Gas6浓度为100ng/ml;对A549,Gas6浓度为200ng/ml)。孵育时间:NCI-H1299:10min;A549:30min。6. After the compound was treated for 2 hours, a defined concentration of Gas6 (for NCI-H1299, Gas6 concentration of 100 ng/ml; for A549, Gas6 concentration of 200 ng/ml) was added. Incubation time: NCI-H1299: 10 min; A549: 30 min.
7.裂解细胞:7. Lysis cells:
a.弃细胞培养板中上清,PBS洗涤细胞一次。a. Discard the supernatant from the cell culture plate and wash the cells once with PBS.
b.每孔中加入100μL RIPA裂解液。b. Add 100 μL of RIPA lysate to each well.
c.冰浴30min。c. Ice bath for 30 min.
8.收取样品:8. Receive samples:
a.将裂解后的细胞转移至1.5mL EP管中,13000rpm转速下于4℃离心15min。a. The lysed cells were transferred to a 1.5 mL EP tube and centrifuged at 13,000 rpm for 15 min at 4 °C.
b.取65μL样品上清,与10μL NuPAGE样品还原试剂(10×)和25μL NuPAGE上样缓冲溶液(4×)混合均匀。b. Take 65 μL of the sample supernatant and mix well with 10 μL of NuPAGE sample reducing reagent (10×) and 25 μL of NuPAGE loading buffer solution (4×).
c.样品置于沸水浴10min,之后冰浴冷却,离心备用。c. The sample was placed in a boiling water bath for 10 min, then cooled in an ice bath and centrifuged for later use.
9.Western blot检测Axl、p-Axl(Tyr702)、GADPH表达水平:9. Western blot analysis of Axl, p-Axl (Tyr702), GADPH expression levels:
a.使用Quantity One软件读取各条带灰度值。a. Use the Quantity One software to read each strip of grayscale values.
b.p-Axl水平经Axl校准后,以对照组为1,计算各组抑制率。计算公式为:b. The p-Axl level was calibrated by Axl, and the control group was taken as 1, and the inhibition rate of each group was calculated. The calculation formula is:
化合物对p-Axl水平抑制率(%)=100-100*(实验组p-Axl体积/实验组Axl体积)/(对照组p-Axl体积/对照组Axl体积))。Compound inhibition rate (%) of p-Axl level = 100-100* (experimental group p-Axl volume / experimental group Axl volume) / (control group p-Axl volume / control group Axl volume)).
实验结果:Experimental results:
本发明化合物对细胞系NCI-H1299和A549中pAxl磷酸化的抑制作用如下表4所示。The inhibitory effects of the compounds of the present invention on pAxl phosphorylation in the cell lines NCI-H1299 and A549 are shown in Table 4 below.
表4:本发明化合物分别对细胞系NCI-H1299和A549中pAxl磷酸化抑制百分比Table 4: Percentage inhibition of pAxl phosphorylation in cell lines NCI-H1299 and A549, respectively, of the compounds of the invention
结论:由上表4可知,本发明化合物能够有效的抑制NCI-H1299和A549Axl(Tyr702)的磷酸化,抑制率高达百分之百。进一步验证了本发明化合物对Axl激酶活性的高度抑制作用。Conclusion: It can be seen from Table 4 above that the compound of the present invention can effectively inhibit the phosphorylation of NCI-H1299 and A549Axl (Tyr702), and the inhibition rate is as high as 100%. The high inhibitory effect of the compounds of the invention on Axl kinase activity was further verified.
测试例4:本发明化合物在Ba/F3Axl细胞上活性抑制能力Test Example 4: Activity inhibition ability of the compound of the present invention on Ba/F3Ax1 cells
试验方法:使用Promega公司的
Luminescent Cell Viability Assay试剂盒评估化合物对Ba/F3Axl细胞增殖的抑制活性。
Test method: using Promega The Luminescent Cell Viability Assay kit was used to evaluate the inhibitory activity of the compound on Ba/F3Axl cell proliferation.
仪器:Molecular Devices公司的Spectramax M3多功能酶标仪,Thermo Scientific公司的Model 311Series CO
2培养箱,Thermo Scientific公司的Model 1300Series A2生物安全柜,Olympus公司的CKX41SF倒置显微镜,Countstar公司的IC1000细胞计数仪,SIEMENS公司的KK25E76TI冰箱,其林贝尔公司的QB-9001微孔板快速振荡器。
Instruments: Molecular Devices' Spectramax M3 multi-function microplate reader, Thermo Scientific's Model 311Series CO 2 incubator, Thermo Scientific's Model 1300Series A2 biosafety cabinet, Olympus' CKX41SF inverted microscope, Countstar's IC1000 cell counter , SIEMENS KK25E76TI refrigerator, its Lin Bell company's QB-9001 microplate fast oscillator.
试验材料:胎牛血清FBS(Thermo Fisher公司,货号#10099-141,批号#1966174C),
荧光细胞存活测试试剂(Promega公司,货号#G7572,批号#0000310975),96孔透明平底黑壁细胞培养板(Thermo Fisher公司,货号#,批号#1207365),RPMI1640培养基(GE公司,货号#SH30809.01,批号#AD17321266),Murine IL-3(PeproTech公司,货号#213-13,批号#120948),rhGas6(R&D Systems公司,货号#885-GSB,批号#DFGX0417081),对照品bemcentinib(别名BGB324,上海毕得医药科技有限公司,货号#BD559084批号#AQU341),Ba/F3Axl细胞(由康源博创生物科技(北京)有限公司构建,完全培养基为RPMI1640+10%FBS+100ng/mL rhGas6,培养培养条件为37℃、5%CO2、95%湿度,生长倍增时间约为20小时,传代比例为1:10;参考Oncogene.2009; 28:3442–3455,Oncotarget.FASEB J.2017;31(4):1382–1397)。
Test material: fetal bovine serum FBS (Thermo Fisher, article number #10099-141, batch number #1966174C), Fluorescent cell survival test reagent (Promega, Cat. #G7572, Lot #0000310975), 96-well clear flat-bottomed black-wall cell culture plate (Thermo Fisher, Inc. ##207365), RPMI1640 medium (GE company, Cat. #SH30809 .01, Lot #AD17321266), Murine IL-3 (PeproTech, Cat. #213-13, Lot #120948), rhGas6 (R&D Systems, Inc. #885-GSB, Lot #DFGX0417081), reference bemcentinib (alias BGB324) , Shanghai Bi De Pharmaceutical Technology Co., Ltd., Item No. #BD559084 Batch #AQU341), Ba/F3Axl cells (constructed by Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd., complete medium is RPMI1640+10%FBS+100ng/mL rhGas6 The culture conditions were 37 ° C, 5% CO 2 , 95% humidity, the growth doubling time was about 20 hours, and the passage ratio was 1:10; refer to Oncogene.2009; 28:3442–3455, Oncotarget.FASEB J.2017; (4): 1382–1397).
试验步骤:复苏Ba/F3Axl细胞时,细胞冻存管于37℃水浴中快速摇动使其在1分钟内融解。取融解后的细胞悬液与含10%FBS的RPMI1640培养基混匀,1000转/分钟离心5分钟,弃上清。取5mL完全培养基重悬细胞沉淀,置于底面积25cm
2的细胞培养瓶中,放入37℃、95%湿度和5%CO
2的细胞培养箱中培养。细胞密度为2×106个活细胞/mL时进行细胞传代。细胞传代时,直接将旧细胞悬液吹打均匀后,保留1/10(即0.5mL)细胞悬液,加入4.5mL新的完全培养基,吹打均匀后,细胞瓶置于细胞培养瓶中继续培养。细胞汇合率再次达到2×106个活细胞/mL时进行细胞铺板。细胞铺板时,参照细胞传代方法,保留1/10(即0.5mL)细胞悬液继续培养,将剩余细胞悬液置于15mL离心管中,离心后弃上清,使用5mL完全培养基重悬细胞。用台盼蓝排斥法,使用Countstar公司的IC1000细胞计数仪检测细胞活力,确保细胞活力在90%以上。使用完全培养基配制密度为5.56×104个活细胞/mL的细胞悬液,加90μL细胞悬液至96孔细胞培养板中,使细胞培养板(第0天板和待测药板)中细胞密度为5000个活细胞/孔。设置不含细胞、不含化合物、只含完全培养基的对照组,设置不含化合物、含细胞的对照组。细胞板置于细胞培养箱中培养过夜。加化合物时,将本发明化合物和对照品bemcentinib用DMSO溶解,进行梯度稀释,得到10倍溶液。加10μL上述溶液至对应的细胞培养板中,使化合物起始浓度为100nM,相邻浓度稀释倍数为3.16倍,细胞培养板中DMSO含量为0.1%。细胞板置于细胞培养箱中继续培养72小时。检测时,融化CellTiter-Glo试剂(即
荧光细胞存活测试试剂,Promega公司,货号#G7572,批号#0000310975),并将细胞板移至室温平衡30分钟,加100μL的CellTiter-Glo至细胞板每个孔中,在其林贝尔公司的QB-9001微孔板快速振荡器上振动5分钟使细胞充分裂解,将细胞板放置于室温20分钟以稳定冷光信号,用Molecular Devices公司的Spectramax M3多功能酶标仪全波长扫描各孔的冷光值。
Test procedure: When the Ba/F3Axl cells were resuscitated, the cell cryotubes were rapidly shaken in a 37 ° C water bath to melt in 1 minute. The melted cell suspension was mixed with RPMI1640 medium containing 10% FBS, centrifuged at 1000 rpm for 5 minutes, and the supernatant was discarded. The cell pellet was resuspended in 5 mL of complete medium, placed in a cell culture flask having a bottom area of 25 cm 2 , and cultured in a cell incubator at 37 ° C, 95% humidity, and 5% CO 2 . Cell passage was performed at a cell density of 2 x 106 viable cells/mL. When the cells are passaged, the old cell suspension is directly blown evenly, and then 1/10 (ie, 0.5 mL) of the cell suspension is retained, 4.5 mL of new complete medium is added, and after being evenly blown, the cell bottle is placed in a cell culture flask and culture is continued. . Cell plating was performed when the cell confluence rate reached 2 x 106 viable cells/mL again. When the cells were plated, refer to the cell passage method, and retain 1/10 (ie 0.5 mL) cell suspension to continue the culture. Place the remaining cell suspension in a 15 mL centrifuge tube, discard the supernatant, and resuspend the cells in 5 mL of complete medium. . Using the trypan blue exclusion method, Countstar's IC1000 cell counter was used to measure cell viability to ensure cell viability was above 90%. A complete cell medium was used to prepare a cell suspension with a density of 5.56 x 104 viable cells/mL, and 90 μL of the cell suspension was added to a 96-well cell culture plate to prepare cells in the cell culture plate (Day 0 plate and test plate). The density is 5000 living cells/well. A control group containing no cells, no compound, and only complete medium was set, and a control group containing no compound and containing cells was set. The cell plates were placed in a cell culture incubator overnight. When a compound was added, the compound of the present invention and the control bemcentinib were dissolved in DMSO, and subjected to gradient dilution to obtain a 10-fold solution. 10 μL of the above solution was added to the corresponding cell culture plate so that the initial concentration of the compound was 100 nM, the dilution ratio of the adjacent concentration was 3.16 times, and the DMSO content in the cell culture plate was 0.1%. The cell plates were placed in a cell culture incubator for further 72 hours. Melt CellTiter-Glo reagent during testing (ie Fluorescent cell survival test reagent, Promega, Cat. #G7572, Lot #0000310975), and the cell plate was allowed to equilibrate to room temperature for 30 minutes, add 100 μL of CellTiter-Glo to each well of the cell plate, at its Linbell QB Vibrate for 5 minutes on a -9001 microplate fast shaker to allow the cells to fully lyse. Place the cell plate at room temperature for 20 minutes to stabilize the cold light signal. Scan the luminescence value of each well at full wavelength with Molecular Devices' Spectramax M3 multi-plate reader. .
受试样品:实施例化合物和bemcentinib(阳性对照化合物)Test sample: Example compound and bemcentinib (positive control compound)
数据分析:使用下列公式计算各浓度化合物作用下细胞存活率:Data analysis: Cell viability under various concentrations of compounds was calculated using the following formula:
细胞存活率(%)=(Lum待测药-Lum培养液对照)/(Lum细胞对照-Lum培养液对照)×100%,Cell viability (%) = (Lum test drug - Lum culture control) / (Lum cell control - Lum culture control) × 100%,
其中Lum指多功能酶标仪读出的待测药板各孔的冷光数值。Lum refers to the luminescence value of each hole of the test plate read by the multi-function microplate reader.
使用GraphPad Prism 7.0软件分析数据,利用非线性S曲线回归来拟合数据得出剂量-效应曲线,并由此计算IC
50值。
Data was analyzed using GraphPad Prism 7.0 software, using a nonlinear regression curve fit data S derived dose - response curves, IC50 values calculated therefrom IC.
实施例66和实施例93对Ba/F3Axl细胞增殖的抑制活性IC
50值分别为0.16nM和0.18nM。对照品bemcentinib对Ba/F3Axl细胞增殖的抑制活性IC
50值为26.9nM。本发明化合物表现出了与对照品更高的细胞增殖抑制活性。
Example 66 and Example 50 inhibiting activity IC 93 value pair of Ba / F3Axl cell proliferation embodiment of 0.16nM and 0.18nM respectively. Reference Sample bemcentinib of Ba / F3Axl cell proliferation inhibiting activity IC 50 value of 26.9nM. The compounds of the invention exhibit higher cell proliferation inhibitory activity than the control.
测试例5:本发明化合物在模型小鼠肿瘤细胞异位移植试验中的体内抗肿瘤活性测试Test Example 5: In vivo antitumor activity test of the compound of the present invention in model mouse tumor cell xenograft test
将人源非小细胞肺癌肿瘤细胞株EBC-1(ATCC)3×106个细胞接种于BALB/c-nude模型小鼠(北京维通达,雌性,10只)皮下。当肿瘤在小鼠皮下生长至107mm
3时,小鼠灌胃给予测试样品。
3×106 cells of human non-small cell lung cancer tumor cell line EBC-1 (ATCC) were inoculated subcutaneously into BALB/c-nude model mice (Beijing Vitonda, female, 10). When the tumor was grown subcutaneously to 107 mm 3 in mice, the mice were orally administered test samples.
将小鼠分为阴性溶媒对照组、本发明化合物组(实施例66)(100mg/kg)、每组5只。每天给药两次,持续四周。记录肿瘤生长体积。抗肿瘤疗效是基于治疗中肿瘤的生长曲线和相对肿瘤体积来评估。抑瘤率(TGI)通过以下公式计算:The mice were divided into a negative vehicle control group, a compound group of the present invention (Example 66) (100 mg/kg), and 5 mice each. It is administered twice daily for four weeks. The tumor growth volume was recorded. Antitumor efficacy is assessed based on the growth curve of the tumor in the treatment and relative tumor volume. The tumor inhibition rate (TGI) is calculated by the following formula:
相对肿瘤抑制率TGI(%):TGI=1-T/C(%)。T/C%为相对肿瘤增殖率,即在某一时间点,治疗组和对照组相对肿瘤体积或瘤重的百分比值。T和C分别为治疗组和对照组在某一特定时间点的相对肿瘤体积(RTV)。Relative tumor inhibition rate TGI (%): TGI = 1 - T / C (%). T/C% is the relative tumor proliferation rate, that is, the percentage of tumor volume or tumor weight relative to the treatment group and the control group at a certain time point. T and C are the relative tumor volumes (RTV) of the treatment group and the control group at a specific time point, respectively.
图1为EBC-1非小细胞肺癌模型中治疗组和对照组小鼠肿瘤体积的生长变化曲线图。图2为EBC-1非小细胞肺癌模型中治疗组和对照组小鼠体重随治疗时间的变化曲线图。由图1可知,本发明化合物能够有效地抑制肿瘤细胞在模型小鼠体内的生长,抑瘤率(TGI)高达98%。并且,如图2所示,荷瘤小鼠在实验过程中体重没有显著变化,显示本发明化合物具有良好的安全性和耐受性。Figure 1 is a graph showing the growth curve of tumor volume in a treatment group and a control group in an EBC-1 non-small cell lung cancer model. Figure 2 is a graph showing the changes in body weight of the treatment group and the control group as a function of treatment time in the EBC-1 non-small cell lung cancer model. As can be seen from Fig. 1, the compound of the present invention can effectively inhibit the growth of tumor cells in model mice, and the tumor inhibition rate (TGI) is as high as 98%. Also, as shown in Fig. 2, the tumor-bearing mice showed no significant change in body weight during the experiment, indicating that the compounds of the present invention have good safety and tolerability.
动物体内试验验证了本发明化合物高度抑制体内癌细胞生长,因此,本发明化合物在治疗与c-MET或Axl等癌驱动基因相关的疾病、特别是在治疗癌症方面,将会具有广阔的应用前景。In vivo experiments in animals have demonstrated that the compounds of the present invention highly inhibit the growth of cancer cells in vivo, and therefore, the compounds of the present invention have broad application prospects in the treatment of diseases associated with cancer-driven genes such as c-MET or Axl, particularly in the treatment of cancer. .
Claims (22)
- 一种通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,a compound of the formula (I) or a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof,其中,among them,W和V各自独立地选自CH、CF或N;W and V are each independently selected from CH, CF or N;R a选自-OR 1、-SR 1或-NR 1R 2; R a is selected from -OR 1 , -SR 1 or -NR 1 R 2 ;R 1和R 2各自独立地选自氢、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基,所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代; R 1 and R 2 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl And a heterocyclic group, an aryl group and a heteroaryl group are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl Substituting one or more groups of a heterocyclic group, an aryl group, or a heteroaryl group;或者,当R a为-NR 1R 2时,R 1和R 2与其相连的氮原子一起形成含氮杂环,所述含氮杂环任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代; Alternatively, when R a is -NR 1 R 2 , R 1 and R 2 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic ring, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano Substituting one or more groups of a group, a hydroxyl group, a thiol group, a carboxyl group, an ester group, an oxo group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group;R 3选自氢、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基,所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代; R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic The base and heteroaryl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituting one or more groups of a heteroaryl group;或者,R a与R 3连同与R a相连的羰基和与R 3相连的氮原子一起形成与吡啶酮环稠合的杂环,所述杂环任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代; Alternatively, R a and R 3 together with a carbonyl group attached to R a and a nitrogen atom bonded to R 3 form a heterocyclic ring fused to a pyridone ring, which is optionally further selected from the group consisting of halogen, amino, and nitro Substituting one or more groups of cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;或者,当R a为-NR 1R 2时,R 1和R 2与其相连的氮原子一起形成含氮杂环,并且R 3与该含氮杂环相连进一步形成稠合杂环,所述稠合杂环任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代; Alternatively, when R a is -NR 1 R 2 , R 1 and R 2 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic ring, and R 3 is bonded to the nitrogen-containing heterocyclic ring to further form a fused heterocyclic ring, said thick The heterocyclic ring is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, Substituting one or more groups of a heteroaryl group;R 4选自芳基、杂芳基或炔基,所述芳基、杂芳基或炔基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代; R 4 is selected from an aryl group, a heteroaryl group or an alkynyl group, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, thiol, carboxyl, ester, Substituting one or more groups of oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;或者,当R 4为芳基或杂芳基时,R a与R 4相连形成与R 4稠合的杂环,所述杂环任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、 烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代; Alternatively, when R 4 is aryl or heteroaryl, R a is bonded to R 4 to form a heterocyclic ring fused to R 4 , which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, Substituting one or more groups of a hydroxyl group, a mercapto group, a carboxyl group, an ester group, an oxo group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;R 5选自烷基、烯基、炔基、环烷基、杂环基、芳基、杂环芳基或OR 6,所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自基团Q的一个或多个基团取代; R 5 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heterocyclic aryl or OR 6 , said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic And an aryl group and a heteroaryl group are optionally further substituted with one or more groups selected from the group Q;Q选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基;所述烷基、烷氧基、环烷基、杂环基、芳基、杂芳基任选进一步被选自卤素、硝基、氰基、羟基、巯基、氧代基、烷基、环烷基、杂环基、芳基、杂芳基、-OR b、-O(CH 2) mOR b、-OC(O)R b、-C(O)OR b、-C(O)NR bR c、-NHC(O)R b、-S(O)R b、-S(O) 2R b、-S(O)NR bR c、-NR bR c、-S(O) 2NR bR c、-NHS(O)R b、-NHS(O) 2R b的一个或多个基团取代; Q is selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl; The alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl group is optionally further selected from the group consisting of halogen, nitro, cyano, hydroxy, decyl, oxo, alkyl, cycloalkyl, Heterocyclyl, aryl, heteroaryl, -OR b , -O(CH 2 ) m OR b , -OC(O)R b , -C(O)OR b , -C(O)NR b R c , -NHC(O)R b , -S(O)R b , -S(O) 2 R b , -S(O)NR b R c , -NR b R c , -S(O) 2 NR b Substituting one or more groups of R c , -NHS(O)R b , -NHS(O) 2 R b ;R 6选自烷基、烷氧基、环烷基、杂环基、芳基、杂芳基;所述烷基、烷氧基、环烷基、杂环基、芳基、杂芳基任选进一步被选自卤素、硝基、氰基、羟基、巯基、氧代基、烷基、环烷基、杂环基、芳基、杂芳基、-OR b、-O(CH 2) mOR b、-OC(O)R b、-C(O)OR b、-C(O)NR bR c、-NHC(O)R b、-S(O)R b、-S(O) 2R b、-S(O)NR bR c、-NR bR c、-S(O) 2NR bR c、-NHS(O)R b、-NHS(O) 2R b的一个或多个基团取代; R 6 is selected from the group consisting of alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl; said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl Further selected from the group consisting of halogen, nitro, cyano, hydroxy, decyl, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR b , -O(CH 2 ) m OR b , -OC(O)R b , -C(O)OR b , -C(O)NR b R c , -NHC(O)R b , -S(O)R b , -S(O) 2 R b , -S(O)NR b R c , -NR b R c , -S(O) 2 NR b R c , -NHS(O)R b , -NHS(O) 2 R b Substituting multiple groups;R b和R c各自独立地选自氢、卤素、羟基、烷基、环烷基、杂环基、芳基、杂芳基,其中所述烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代; R b and R c are each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl And the heteroaryl group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituting one or more groups of a heteroaryl group;或者R b和R c与他们连接的氮原子一起形成含氮杂环基,所述含氮杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代; Or R b and R c together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, decyl Substituting one or more groups of a carboxyl group, an ester group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;R 7选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基;所述烷基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代; R 7 is selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl The alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, thiol, carboxy, ester, and oxygen. Substituting one or more groups of a substituent, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;m为1至6的整数;m is an integer from 1 to 6;n为1至4的整数;n is an integer from 1 to 4;其中,通式(I)化合物中的每一个H原子可以任选独立地被D原子替代。Wherein each H atom of the compound of formula (I) may optionally be independently replaced by a D atom.
- 根据权利要求1所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,The compound of the formula (I) according to claim 1 or a mesogen, a racemate, an enantiomer, a diastereomer thereof, a mixture thereof, or a mixture thereof With salt,其中,among them,R a选自-NR 1R 2; R a is selected from -NR 1 R 2 ;R 1和R 2如权利要求1所定义。 R 1 and R 2 are as defined in claim 1.
- 根据权利要求1或2所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,The compound of the formula (I) according to claim 1 or 2, or a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or Medicinal salt,其中,among them,R 1和R 2各自独立地选自氢、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基,所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代; R 1 and R 2 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl And a heterocyclic group, an aryl group and a heteroaryl group are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl Substituting one or more groups of a heterocyclic group, an aryl group, or a heteroaryl group;或者,当R a为-NR 1R 2时,R 1和R 2与其相连的氮原子一起形成含氮杂环,所述含氮杂环任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代; Alternatively, when R a is -NR 1 R 2 , R 1 and R 2 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic ring, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano Substituting one or more groups of a group, a hydroxyl group, a thiol group, a carboxyl group, an ester group, an oxo group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group;R 3选自氢、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基,所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代。 R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic The base and heteroaryl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituting one or more groups of a heteroaryl group.
- 根据权利要求1所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,The compound of the formula (I) according to claim 1 or a mesogen, a racemate, an enantiomer, a diastereomer thereof, a mixture thereof, or a mixture thereof With salt,其中,among them,R a选自-NR 1R 2; R a is selected from -NR 1 R 2 ;其中,R 1或R 2与R 3相连形成与吡啶酮环稠合的含氮杂环,所述含氮杂环任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代; Wherein R 1 or R 2 is bonded to R 3 to form a nitrogen-containing heterocyclic ring fused to a pyridone ring, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, Substituting one or more groups of a carboxyl group, an ester group, an oxo group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;R 1和R 2各自独立地选自氢、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基,所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代; R 1 and R 2 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl And a heterocyclic group, an aryl group and a heteroaryl group are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl Substituting one or more groups of a heterocyclic group, an aryl group, or a heteroaryl group;R 3选自氢、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基,所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代。 R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic The base and heteroaryl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituting one or more groups of a heteroaryl group.
- 根据权利要求1所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,The compound of the formula (I) according to claim 1 or a mesogen, a racemate, an enantiomer, a diastereomer thereof, a mixture thereof, or a mixture thereof With salt,其中,among them,R a选自-NR 1R 2; R a is selected from -NR 1 R 2 ;R 1和R 2与其相连的氮原子一起形成含氮杂环,并且R 3与该含氮杂环相连进一步形成稠合杂环,所述稠合杂环任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代; R 1 and R 2 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic ring, and R 3 is bonded to the nitrogen-containing heterocyclic ring to further form a fused heterocyclic ring, which is optionally further selected from the group consisting of halogen, amino, Substituting one or more groups of nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;R 1和R 2各自独立地选自氢、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基,所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代; R 1 and R 2 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl And a heterocyclic group, an aryl group and a heteroaryl group are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl Substituting one or more groups of a heterocyclic group, an aryl group, or a heteroaryl group;R 3选自氢、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基,所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代。 R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic The base and heteroaryl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituting one or more groups of a heteroaryl group.
- 根据权利要求1至5中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,其为通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,The compound of the formula (I) according to any one of claims 1 to 5, or a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (II) or a meso form thereof, a racemate, an enantiomer, a diastereomer, or a mixture thereof, Or a pharmaceutically acceptable salt thereof,其中,among them,Y选自CH或N;Y is selected from CH or N;q为1至4的整数;q is an integer from 1 to 4;W、V、R a、R 3、R 4、R 7、Q、n如权利要求1所定义。 W, V, R a , R 3 , R 4 , R 7 , Q, n are as defined in claim 1.
- 根据权利要求1至6中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,The compound of the formula (I) according to any one of claims 1 to 6, or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof,其中,among them,R 4选自5~6元芳基或杂芳基、或炔基,所述芳基、杂芳基、炔基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代。 R 4 is selected from 5- to 6-membered aryl or heteroaryl, or alkynyl, and the aryl, heteroaryl, alkynyl group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, One or more groups of a carboxyl group, an ester group, an oxo group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group are substituted.
- 根据权利要求1至7中任一项所述的通式(I)所示的化合物或其内消旋体、 外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,其为通式(III)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,The compound of the formula (I) according to any one of claims 1 to 7, or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (III) or a mesogen, a racemate, an enantiomer, a diastereomer, or a mixture thereof, Or a pharmaceutically acceptable salt thereof,其中,among them,Y选自CH或N;Y is selected from CH or N;R 8选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基; R 8 is selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;p为1至4的整数;p is an integer from 1 to 4;q为1至4的整数;q is an integer from 1 to 4;W、V、R a、R 3、R 7、Q、n如权利要求1所定义。 W, V, R a , R 3 , R 7 , Q, n are as defined in claim 1.
- 根据权利要求1至8中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,其为通式(IV)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,The compound of the formula (I) according to any one of claims 1 to 8, or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (IV) or a meso form thereof, a racemate, an enantiomer, a diastereomer, or a mixture thereof, Or a pharmaceutically acceptable salt thereof,其中,among them,Y选自CH或N;Y is selected from CH or N;R 8选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基; R 8 is selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;Q选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基;所述烷基、烷氧基、环烷基、杂环基、 芳基、杂芳基任选进一步被选自卤素、硝基、氰基、羟基、巯基、氧代基、烷基、环烷基、杂环基、芳基、杂芳基、-OR b、-O(CH 2) mOR b、-OC(O)R b、-C(O)OR b、-C(O)NR bR c、-NHC(O)R b、-S(O)R b、-S(O) 2R b、-S(O)NR bR c、-NR bR c、-S(O) 2NR bR c、-NHS(O)R b、-NHS(O) 2R b的一个或多个基团取代; Q is selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl; The alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl group is optionally further selected from the group consisting of halogen, nitro, cyano, hydroxy, decyl, oxo, alkyl, cycloalkyl, Heterocyclyl, aryl, heteroaryl, -OR b , -O(CH 2 ) m OR b , -OC(O)R b , -C(O)OR b , -C(O)NR b R c , -NHC(O)R b , -S(O)R b , -S(O) 2 R b , -S(O)NR b R c , -NR b R c , -S(O) 2 NR b Substituting one or more groups of R c , -NHS(O)R b , -NHS(O) 2 R b ;Q’选自-NR bR c; Q' is selected from -NR b R c ;R b和R c各自独立地选自氢、卤素、羟基、烷基、环烷基、杂环基、芳基、杂芳基,其中所述烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代; R b and R c are each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl And the heteroaryl group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituting one or more groups of a heteroaryl group;或者R b和R c与他们连接的氮原子一起形成含氮杂环基,所述含氮杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代; Or R b and R c together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, decyl Substituting one or more groups of a carboxyl group, an ester group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;p为1至4的整数;p is an integer from 1 to 4;W、V、R a、R 3、R 7、m、n如权利要求1所定义。 W, V, R a , R 3 , R 7 , m, n are as defined in claim 1.
- 根据权利要求1至9中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,The compound of the formula (I) according to any one of claims 1 to 9, or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof,其中,among them,Q选自芳基或杂芳基;所述芳基或杂芳基任选进一步被选自卤素、烷基、环烷基、杂环基、-OR b、-O(CH 2) mOR b的一个或多个基团取代; Q is selected from aryl or heteroaryl; the aryl or heteroaryl is optionally further selected from the group consisting of halogen, alkyl, cycloalkyl, heterocyclyl, -OR b , -O(CH 2 ) m OR b Substituted by one or more groups;R b选自氢、烷基和环烷基,其中所述烷基和环烷基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、环烷基、杂环基的一个或多个基团取代; R b is selected from the group consisting of hydrogen, alkyl and cycloalkyl, wherein the alkyl and cycloalkyl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo. Substituting one or more groups of a cycloalkyl group or a heterocyclic group;m为1至6的整数。m is an integer from 1 to 6.
- 根据权利要求8至10中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,The compound of the formula (I) according to any one of claims 8 to 10, or a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof,其中,among them,R a选自-NR 1R 2; R a is selected from -NR 1 R 2 ;R 1或R 2与R 4相连形成与R 4稠合的杂环,所述杂环任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代; R 1 or R 2 is bonded to R 4 to form a heterocyclic ring fused to R 4 , which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo Substituting one or more groups of a group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;R 1和R 2各自独立地选自氢、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基,所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代; R 1 and R 2 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl And a heterocyclic group, an aryl group and a heteroaryl group are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl Substituting one or more groups of a heterocyclic group, an aryl group, or a heteroaryl group;R 3选自氢、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基,所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代。 R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic The base and heteroaryl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituting one or more groups of a heteroaryl group.
- 根据权利要求1至11中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,The compound of the formula (I) according to any one of claims 1 to 11, or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof,其中,among them,R 5为OR 6或SR 6; R 5 is OR 6 or SR 6 ;R 6如权利要求1所定义。 R 6 is as defined in claim 1.
- 根据权利要求12所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,The compound of the formula (I) according to claim 12, or a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable drug thereof With salt,其中,among them,R 6选自芳基和杂芳基;所述芳基和杂芳基任选进一步被选自卤素、羟基、巯基、氧代基、烷基、环烷基、杂环基、芳基、杂芳基、-OR b、-O(CH 2) mOR b、-NR bR c的一个或多个基团取代; R 6 is selected from the group consisting of aryl and heteroaryl; the aryl and heteroaryl are optionally further selected from the group consisting of halogen, hydroxy, thiol, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, hetero Substituting one or more groups of aryl, -OR b , -O(CH 2 ) m OR b , -NR b R c ;R b和R c各自独立地选自氢、卤素、烷基、环烷基,其中所述烷基、环烷基、任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、环烷基、杂环基的一个或多个基团取代; R b and R c are each independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, wherein the alkyl, cycloalkyl, optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl Substituting one or more groups of a carboxyl group, an ester group, an oxo group, a cycloalkyl group, or a heterocyclic group;或者R b和R c与他们连接的氮原子一起形成含氮杂环基,所述含氮杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代; Or R b and R c together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, decyl Substituting one or more groups of a carboxyl group, an ester group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;m为1至6的整数。m is an integer from 1 to 6.
- 根据权利要求1至13中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,The compound of the formula (I) according to any one of claims 1 to 13, or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof,其中,among them,R 7选自氢、卤素、烷基,所述烷基任选进一步被一个或多个卤素取代; R 7 is selected from the group consisting of hydrogen, halogen, alkyl, and the alkyl group is optionally further substituted with one or more halogens;n为1或2。n is 1 or 2.
- 根据权利要求1至14中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,其中,所述化合物选自:The compound of the formula (I) according to any one of claims 1 to 14, or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of
- 根据通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的制备方法,其包括以下步骤:a method for producing a compound represented by the formula (I) or a mesogen, a racemate, an enantiomer, a diastereomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, It includes the following steps:当R a选自-NR 1R 2时, When R a is selected when R 2 -NR 1,将N-R 3-6-(乙氧基羰基)-5-R 4-4-氧代-1,4-二氢吡啶-3-芳酰胺(Ig)直接与R 1R 2NH进行胺酯交换反应,得到通式(I)化合物; Amine transesterification of NR 3 -6-(ethoxycarbonyl)-5-R 4 -4-oxo-1,4-dihydropyridine-3-arylamide (Ig) directly with R 1 R 2 NH To obtain a compound of the formula (I);或者,将N-R 3-6-(乙氧基羰基)-5-R 4-4-氧代-1,4-二氢吡啶-3-芳酰胺(Ig)先进行酯基水解,再与R 1R 2NH进行酰胺化反应,经由两步得到通式(I)化合物; Alternatively, NR 3 -6-(ethoxycarbonyl)-5-R 4 -4-oxo-1,4-dihydropyridine-3-arylamide (Ig) is first subjected to ester hydrolysis, followed by R 1 R 2 NH is subjected to amidation reaction to obtain a compound of the formula (I) via two steps;当R a选自-OR 1或-SR 1时, When R a is selected from -OR 1 when 1 or -SR,将N-R 3-6-(乙氧基羰基)-5-R 4-4-氧代-1,4-二氢吡啶-3-芳酰胺(Ig)先进行酯基水解,所得酸(Ig’)再在EDCI的作用下与醇或硫醇反应得到通式(I)化合物; The NR 3 -6-(ethoxycarbonyl)-5-R 4 -4-oxo-1,4-dihydropyridine-3-arylamide (Ig) is first subjected to ester hydrolysis to obtain the acid (Ig'). Further reacting with an alcohol or a thiol under the action of EDCI to obtain a compound of the formula (I);其中,R 1、R 2、R 3、R 4、R 5、R 7、W、V、n如权利要求1所定义。 Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , W, V, n are as defined in claim 1.
- 一种药物组合物,其含有根据权利要求1至15中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐,以及一种或多种药学上可接受的载体、稀释剂或赋形剂。A pharmaceutical composition comprising the compound of the formula (I) according to any one of claims 1 to 15, or a mesogen, a racemate, an enantiomer thereof, a non-pair thereof An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
- 根据权利要求17所述的药物组合物,其进一步含有另一种治疗活性成分,所述另一种治疗活性成分优选为治疗癌症的药物,所述癌症优选直肠癌、肠癌、胰腺癌、乳腺癌、前列腺癌、食道癌、胃癌、血癌、肺癌、肝癌、甲状腺癌、肉瘤、脑癌、皮肤癌、头颈癌、鼻咽癌、卵巢癌、宫颈癌、膀胱癌和肾癌,更优选血癌、肺癌、乳腺癌、胰腺癌和胃癌。The pharmaceutical composition according to claim 17, which further comprises another therapeutically active ingredient, preferably another therapeutically active ingredient, which is preferably a drug for treating cancer, such as rectal cancer, intestinal cancer, pancreatic cancer, breast Cancer, prostate cancer, esophageal cancer, gastric cancer, blood cancer, lung cancer, liver cancer, thyroid cancer, sarcoma, brain cancer, skin cancer, head and neck cancer, nasopharyngeal cancer, ovarian cancer, cervical cancer, bladder cancer and kidney cancer, more preferably blood cancer, Lung cancer, breast cancer, pancreatic cancer and stomach cancer.
- 根据权利要求1至15中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或根据权利要求17或18所述的药物组合物在制备Axl/c-MET抑制剂中的用途。The compound of the formula (I) according to any one of claims 1 to 15, or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Use of a form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17 or 18, in the manufacture of an Axl/c-MET inhibitor.
- 根据权利要求1至15中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或根据权利要求17或18所述的药物组合物在制备治疗癌症的药物中的用途。The compound of the formula (I) according to any one of claims 1 to 15, or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Use of a form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17 or 18, for the manufacture of a medicament for the treatment of cancer.
- 根据权利要求20所述的用途,其中所述癌症优选直肠癌、肠癌、胰腺癌、乳腺癌、前列腺癌、食道癌、胃癌、血癌、肺癌、肝癌、甲状腺癌、肉瘤、脑癌、皮肤癌、头颈癌、鼻咽癌、卵巢癌、宫颈癌、膀胱癌和肾癌,更优选血癌、肺癌、乳腺癌、胰腺癌和胃癌。The use according to claim 20, wherein the cancer is preferably rectal cancer, intestinal cancer, pancreatic cancer, breast cancer, prostate cancer, esophageal cancer, gastric cancer, blood cancer, lung cancer, liver cancer, thyroid cancer, sarcoma, brain cancer, skin cancer , head and neck cancer, nasopharyngeal cancer, ovarian cancer, cervical cancer, bladder cancer and kidney cancer, more preferably blood cancer, lung cancer, breast cancer, pancreatic cancer and gastric cancer.
- 根据权利要求1至15中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐与另一种治疗活性成分联合,在制备治疗癌症的药物中的用途,其中所述另一种治疗活性成分与通式(I)所示的化合物同时、分开或相继使用;所述癌症直肠癌、肠癌、胰腺癌、乳腺癌、前列腺癌、食道癌、胃癌、血癌、肺癌、肝癌、甲状腺癌、肉瘤、脑癌、皮肤癌、头颈癌、鼻咽癌、卵巢癌、宫颈癌、膀胱癌和肾癌,更优选血癌、肺癌、乳腺癌、胰腺癌和胃癌。The compound of the formula (I) according to any one of claims 1 to 15, or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Use of a form, or a pharmaceutically acceptable salt thereof, in combination with another therapeutically active ingredient, in the manufacture of a medicament for the treatment of cancer, wherein the other therapeutically active ingredient is simultaneously, separately or separately from the compound of formula (I) Used sequentially; the cancer rectal cancer, intestinal cancer, pancreatic cancer, breast cancer, prostate cancer, esophageal cancer, gastric cancer, blood cancer, lung cancer, liver cancer, thyroid cancer, sarcoma, brain cancer, skin cancer, head and neck cancer, nasopharyngeal cancer, Ovarian cancer, cervical cancer, bladder cancer, and kidney cancer, and more preferably, blood cancer, lung cancer, breast cancer, pancreatic cancer, and stomach cancer.
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CN111233779A (en) * | 2020-04-02 | 2020-06-05 | 廖文英 | Preparation method of leflunomide |
WO2021057782A1 (en) * | 2019-09-24 | 2021-04-01 | 南京药捷安康生物科技有限公司 | Heterocyclic derivative and use thereof |
CN112625026A (en) * | 2019-09-24 | 2021-04-09 | 南京药捷安康生物科技有限公司 | Quinoline derivatives of TAM family kinase inhibitors |
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WO2021057782A1 (en) * | 2019-09-24 | 2021-04-01 | 南京药捷安康生物科技有限公司 | Heterocyclic derivative and use thereof |
CN112625027A (en) * | 2019-09-24 | 2021-04-09 | 南京药捷安康生物科技有限公司 | Heterocyclic derivatives and use thereof |
CN112625026A (en) * | 2019-09-24 | 2021-04-09 | 南京药捷安康生物科技有限公司 | Quinoline derivatives of TAM family kinase inhibitors |
CN112625026B (en) * | 2019-09-24 | 2022-09-09 | 药捷安康(南京)科技股份有限公司 | Quinoline derivatives of TAM family kinase inhibitors |
CN111233779A (en) * | 2020-04-02 | 2020-06-05 | 廖文英 | Preparation method of leflunomide |
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