CN114008037A - 作为kras g12c抑制剂的杂环化合物 - Google Patents
作为kras g12c抑制剂的杂环化合物 Download PDFInfo
- Publication number
- CN114008037A CN114008037A CN202080045105.2A CN202080045105A CN114008037A CN 114008037 A CN114008037 A CN 114008037A CN 202080045105 A CN202080045105 A CN 202080045105A CN 114008037 A CN114008037 A CN 114008037A
- Authority
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- China
- Prior art keywords
- alkyl
- radical
- group
- alkylene
- isopropyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 102200006538 rs121913530 Human genes 0.000 title claims abstract description 20
- 239000003112 inhibitor Substances 0.000 title abstract description 13
- 150000002391 heterocyclic compounds Chemical class 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 109
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- -1 -C(s) - Chemical group 0.000 claims description 169
- 150000003254 radicals Chemical class 0.000 claims description 80
- 238000000034 method Methods 0.000 claims description 52
- 125000004432 carbon atom Chemical group C* 0.000 claims description 40
- 229910052736 halogen Inorganic materials 0.000 claims description 31
- 150000002367 halogens Chemical class 0.000 claims description 31
- 239000001257 hydrogen Substances 0.000 claims description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims description 30
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 27
- 125000003118 aryl group Chemical group 0.000 claims description 22
- 125000001072 heteroaryl group Chemical group 0.000 claims description 21
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 14
- 206010028980 Neoplasm Diseases 0.000 claims description 12
- 201000011510 cancer Diseases 0.000 claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
- 229910052701 rubidium Inorganic materials 0.000 claims description 10
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 125000006716 (C1-C6) heteroalkyl group Chemical group 0.000 claims description 5
- 125000002837 carbocyclic group Chemical group 0.000 claims description 4
- 239000012038 nucleophile Substances 0.000 claims description 4
- 229910052721 tungsten Inorganic materials 0.000 claims description 4
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 3
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 3
- 230000002401 inhibitory effect Effects 0.000 claims description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 3
- 201000002528 pancreatic cancer Diseases 0.000 claims description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 3
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 125000003566 oxetanyl group Chemical group 0.000 claims description 2
- 125000004043 oxo group Chemical group O=* 0.000 claims description 2
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 claims description 2
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims 1
- 239000002246 antineoplastic agent Substances 0.000 claims 1
- 230000003287 optical effect Effects 0.000 abstract description 2
- 125000000524 functional group Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 224
- 239000000047 product Substances 0.000 description 184
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 105
- 239000007787 solid Substances 0.000 description 95
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 91
- 239000000243 solution Substances 0.000 description 83
- 235000019439 ethyl acetate Nutrition 0.000 description 78
- 238000003756 stirring Methods 0.000 description 73
- 239000000203 mixture Substances 0.000 description 65
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 64
- 239000011541 reaction mixture Substances 0.000 description 63
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 61
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 54
- 239000007832 Na2SO4 Substances 0.000 description 48
- 239000012267 brine Substances 0.000 description 48
- 229910052938 sodium sulfate Inorganic materials 0.000 description 48
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 48
- 239000012044 organic layer Substances 0.000 description 45
- 238000001035 drying Methods 0.000 description 42
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 40
- 238000001914 filtration Methods 0.000 description 39
- 238000005160 1H NMR spectroscopy Methods 0.000 description 37
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 32
- 239000004305 biphenyl Substances 0.000 description 29
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 28
- 238000010898 silica gel chromatography Methods 0.000 description 28
- 125000000217 alkyl group Chemical group 0.000 description 26
- 239000000543 intermediate Substances 0.000 description 24
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 23
- 239000012300 argon atmosphere Substances 0.000 description 22
- 238000006243 chemical reaction Methods 0.000 description 22
- 239000003921 oil Substances 0.000 description 21
- 235000019198 oils Nutrition 0.000 description 21
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 238000013507 mapping Methods 0.000 description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 17
- 238000012746 preparative thin layer chromatography Methods 0.000 description 17
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 230000035772 mutation Effects 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- 239000004698 Polyethylene Substances 0.000 description 14
- 238000010828 elution Methods 0.000 description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 11
- 239000003814 drug Substances 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 238000009472 formulation Methods 0.000 description 10
- 125000001424 substituent group Chemical group 0.000 description 10
- ZVYNUGSPFZCYEV-UHFFFAOYSA-N 2,6-dichloro-5-fluoropyridine-3-carboxamide Chemical compound NC(=O)C1=CC(F)=C(Cl)N=C1Cl ZVYNUGSPFZCYEV-UHFFFAOYSA-N 0.000 description 9
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 125000002947 alkylene group Chemical group 0.000 description 9
- 229910052786 argon Inorganic materials 0.000 description 9
- 125000002619 bicyclic group Chemical group 0.000 description 9
- 125000005843 halogen group Chemical group 0.000 description 9
- 125000004404 heteroalkyl group Chemical group 0.000 description 9
- 239000000651 prodrug Substances 0.000 description 9
- 229940002612 prodrug Drugs 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 8
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 8
- 125000002252 acyl group Chemical group 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 8
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 235000019260 propionic acid Nutrition 0.000 description 8
- 229910052717 sulfur Inorganic materials 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
- XCUAIINAJCDIPM-XVFCMESISA-N N(4)-hydroxycytidine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=NO)C=C1 XCUAIINAJCDIPM-XVFCMESISA-N 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 125000005842 heteroatom Chemical group 0.000 description 7
- 229910052760 oxygen Inorganic materials 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- 235000014113 dietary fatty acids Nutrition 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 239000000194 fatty acid Substances 0.000 description 6
- 229930195729 fatty acid Natural products 0.000 description 6
- 239000011259 mixed solution Substances 0.000 description 6
- 125000002950 monocyclic group Chemical group 0.000 description 6
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- 239000003765 sweetening agent Substances 0.000 description 6
- JAELLLITIZHOGQ-UHFFFAOYSA-N tert-butyl propanoate Chemical compound CCC(=O)OC(C)(C)C JAELLLITIZHOGQ-UHFFFAOYSA-N 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 5
- 125000000304 alkynyl group Chemical group 0.000 description 5
- 239000007859 condensation product Substances 0.000 description 5
- 150000004665 fatty acids Chemical class 0.000 description 5
- 239000000796 flavoring agent Substances 0.000 description 5
- 235000003599 food sweetener Nutrition 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- 229940124597 therapeutic agent Drugs 0.000 description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 4
- 229910019213 POCl3 Inorganic materials 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 239000007900 aqueous suspension Substances 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 230000000903 blocking effect Effects 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 239000002270 dispersing agent Substances 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 4
- 125000001188 haloalkyl group Chemical group 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- 230000036961 partial effect Effects 0.000 description 4
- 239000002953 phosphate buffered saline Substances 0.000 description 4
- 239000011148 porous material Substances 0.000 description 4
- 235000011056 potassium acetate Nutrition 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 229910052702 rhenium Inorganic materials 0.000 description 4
- 239000000375 suspending agent Substances 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 239000000080 wetting agent Substances 0.000 description 4
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 4
- CUYKNJBYIJFRCU-UHFFFAOYSA-N 3-aminopyridine Chemical compound NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 3
- 239000004471 Glycine Substances 0.000 description 3
- LOXDYFFNULDIMW-UHFFFAOYSA-N IC1=C(C(=NC=C1)C(C)C)N Chemical compound IC1=C(C(=NC=C1)C(C)C)N LOXDYFFNULDIMW-UHFFFAOYSA-N 0.000 description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 229920001213 Polysorbate 20 Polymers 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
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- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- YGNLUSPBKVKNCY-JTQLQIEISA-N tert-butyl (2S)-2-methyl-4-prop-2-enoylpiperazine-1-carboxylate Chemical compound C(C=C)(=O)N1C[C@@H](N(CC1)C(=O)OC(C)(C)C)C YGNLUSPBKVKNCY-JTQLQIEISA-N 0.000 description 1
- DATRVIMZZZVHMP-QMMMGPOBSA-N tert-butyl (2s)-2-methylpiperazine-1-carboxylate Chemical compound C[C@H]1CNCCN1C(=O)OC(C)(C)C DATRVIMZZZVHMP-QMMMGPOBSA-N 0.000 description 1
- YXIMCNGUIIEJMO-UHFFFAOYSA-N tert-butyl 2-sulfanylacetate Chemical compound CC(C)(C)OC(=O)CS YXIMCNGUIIEJMO-UHFFFAOYSA-N 0.000 description 1
- KBUYNGNZKTXFCX-UHFFFAOYSA-N tert-butyl 3-[2-[(2,6-dichloro-5-fluoropyridine-3-carbonyl)carbamoylamino]-N-[(2-methylpropan-2-yl)oxycarbonyl]-3-propan-2-ylanilino]propanoate Chemical compound CC(C)C1=CC=CC(N(CCC(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=C1NC(NC(C(C=C(C(Cl)=N1)F)=C1Cl)=O)=O KBUYNGNZKTXFCX-UHFFFAOYSA-N 0.000 description 1
- DOMTZTVJNZKUNX-UHFFFAOYSA-N tert-butyl 3-aminopropanoate;hydrochloride Chemical compound Cl.CC(C)(C)OC(=O)CCN DOMTZTVJNZKUNX-UHFFFAOYSA-N 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- WHAFDJWJDDPMDO-UHFFFAOYSA-N trimethyl(phenyl)phosphanium Chemical compound C[P+](C)(C)C1=CC=CC=C1 WHAFDJWJDDPMDO-UHFFFAOYSA-N 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P35/00—Antineoplastic agents
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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- C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
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Abstract
本发明提供了作为KRAS G12C抑制剂的杂环化合物,具体包括通式I至XI所描述的化合物以及其所有立体异构体、旋光异构体、构形异构体和药学上可以接受的盐。通式中所有官能团有详细的定义。
Description
技术领域
本发明涉及KRAS G12C突变抑制剂杂环化合物,以及含有这些化合物的组合物,旨在用于治疗与KRAS G12C相关的包含癌症在内的各种疾病。
背景技术
大鼠肉瘤(RAS)蛋白是一种小型的、膜结合的鸟嘌呤核苷酸结合蛋白;它们可作为分子开关在活性GTP结合和非活性GDP结合构象之间循环。共有三种主要的RAS蛋白亚型:KRAS、NRAS以及HRAS。它们在调节细胞增殖、分化和存活过程中起着至关重要的作用。主要RAS蛋白亚型出现的过度激活突变是癌症中最常见的病变之一,而KRAS突变目前在人类癌症中最为常见。此种大多数突变已被证明会导致活性GTP结合数量的增加,从而诱发致癌性转化。KRAS中最常见的致癌突变位点是G12残基,而G12C突变(甘氨酸-12突变为半胱氨酸)是该残基的常见突变之一。约有14%的肺腺癌和1%-4%的胰腺癌以及结直肠癌病例中发现存在KRAS G12C突变。考虑到KRAS G12C突变在人类癌症中起到的作用和出现频率,针对以KRAS G12C突变为主要特征的癌症患者研发全新药物治疗方案的需求就显得极为迫切。
发明内容
本发明描述了KRAS G12C突变抑制剂。本发明进一步描述了包括KRAS G12C抑制剂在内的药物制剂。
一方面,本发明的特征在于它是一种通式I中的所示化合物或其药学上可接受的盐:
式中,
Q表示能够与亲核试剂形成共价键的部分,示例性Q的优选结构如下所示:
X表示N、C、CR3或者CF;R3表示H、-CN或者C1-6烷基;
-L-表示单键、双键、-NH-或者-N(C1-6烷基)-;
Ra、Rb和Rc各自独立地表示H、卤素、取代或未取代的C1-4烷基、取代或未取代的C1-4环烷基或氰基;或者Rc可以与Het-1的碳原子连接形成双环。
Het-1选自以下双环和三环部分:
Re与Rd独立地选自氢、卤素;
R1和R2独立地选自氢、卤素、氰基、C1-6烷氧基、羟基、C(O)NH2、C(O)NHC1-6烷基、C(O)N(C1-6烷基)2、C1-6烷基磺酰、S(O)2NH2、S(O)2NHC1-6烷基、NHC(O)NH2、NHC(O)NHC1-6烷基、C1-6烷基、NHC(O)OC1-6烷基、C(O)-C1-6烷基、-C(O)C1-6烷基、C1-6杂烷基、杂环基或杂环基烷基;或者R1和R2与它们所连接的碳原子可以形成一个三到六元的碳环。
Het-2选自以下杂环:
R3和R6各自独立地表示H、OH、C1-6烷基、C3-10环烷基、C3-10杂环烷基、C1-6卤代烷基、C1-6烷氧基、NH-C1-6烷基、N(C1-6烷基)2、CN或卤素;
R4表示氢、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C3-8环烷基、C2-4烯基、C2-4炔基、芳基或者杂芳基;
R5表示卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、OH、OR’、N(R’)2、C2-4烯基、C2-4炔基、C0-3亚烷基-C3-8环烷基、C0-3亚烷基-C3-8卤代环烷基、芳基或杂芳基、C0-3亚烷基-C6-14芳基或C0-3亚烷基-C2-14杂芳基,R’各自独立地表示H、C1-6烷基、C1-6卤代烷基、C3-8环烷基、C2-4烯基、C2-4炔基、芳基或者杂芳基;或者两个R’取代基与它们所连接的氮原子一起形成含有O、S或NR’的3-8元碳环或3-8元杂环;
R7表示C1-8烷基、C0-3亚烷基-C6-14芳基、C0-3亚烷基-C2-14杂芳基、C0-3亚烷基-C3-10环烷基、C0-3亚烷基-C2-10杂环烷基、C1-6烷氧基、O-C0-3亚烷基-C6-14芳基、O-C0-3亚烷基-C3-14杂芳基、O-C0-3亚烷基-C1-10环烷基、O-C0-3亚烷基-C2-14杂环烷基、NH-C1-8烷基、N(C1-8烷基)2、NH-C0-3亚烷基-C6-14芳基、NH-C0-3亚烷基-C2-14杂芳基、NH-C0-3亚烷基-C1-10环烷基、NH-C0-3亚烷基-C2-14杂环烷基、卤素、-CN或C1-6亚烷基-胺;
R8表示H、OH、C1-6烷基、C1-6环烷基、C1-6卤代烷基、C1-6卤代环烷基、C1-6烷氧基、NH-C1-6烷基、N(C1-6烷基)2或CN;
L1表示一个化学键、O、S或NR11;
L2表示一个化学键、-C(O)-或C1-3亚烷基;
R9表示氢、C1-8烷基、羟基C1-8烷基、二羟基C1-8烷基、C1-8烷基-NH-C1-8烷基、C1-8烷基-N(C1-8烷基)2、-C1-4亚烷基-NR11R12、C2-10杂环基、C2-10杂环基烷基、C6-14芳基、C2-14杂芳基或C3-14杂芳基烷基,其中R9可以被一个或多个R13选择性取代;
R9-L1-也可以不存在;
R10表示氢、C3-10环烷基、C3-10杂环基、C6-14芳基、C7-20芳烷基或C3-14杂芳基,其中C3-10环烷基、C3-10杂环基、C6-14芳基、C7-20芳烷基或C3-14杂芳基可以被一个或多个R5或R6选择性取代;
R3、R4、R5、R6、R7、R8、R9和R10各自独立地被一个或多个以下组分选择性取代:卤素、氰基、C1-6烷氧基、羟基、氨基、C(O)NH2、C(O)NHC1-6烷基、C(O)NHC3-6环烷基、C(O)N(C1-6烷基)2、SC1-6烷基、S(O)C1-6烷基、S(O)2C1-6烷基、SC3-6环烷基、S(O)C3-6环烷基、S(O)2C1-6环烷基、S(O)2NH2、S(O)2NHC1-6烷基、S(O)2NHC3-6烷基、NHC(O)NH2、NHC(O)NHC1-6烷基、NHC(O)NHC1-6环烷基、C1-6烷基、C3-6环烷基、NHC(O)OC1-6烷基、C(O)-C1-6环烷基、C(O)C1-6烷基氨基、C1-6杂烷基、P(O)(C1-6烷基)2、杂环基或杂环基烷基;
R5和R7上的取代基可通过碳碳键、碳碳双键、碳氮键、酰胺键、醚键、酯键和硫醚键连接形成大环;
R11表示H或者C1-3烷基;R12独立地表示氢、酰基、C1-8烷基、C1-8卤代烷基或C1-8羟烷基;
R13独立地表示氢、氧、酰基、羟基、C1-8羟烷基、氰基、卤素、C1-8烷基、芳烷基、C1-8卤代烷基、C1-8杂烷基、C1-10环烷基、C1-10杂环基烷基、C1-8烷氧基、N(C1-8烷基)2、C1-8烷基-N(C1-8烷基)2或-Cl-4亚烷基-NR11R12,其中Cl-8烷基可以由从R1或C1-8环烷基中选择的一个或两个取代基进行选择性取代;
每个烷基、烯基、炔基、环烷基、芳基、杂芳基均可被定义部分中所定义的取代基取代。
另一方面,本发明提供了一种通式II中的化合物或其药学上可接受的盐:
式中,
R3、R4、R5和R7的定义如上所示;
Q选自以下部分:
Ra、Rb和Rc的定义如上所示;
R1和R2的定义如上所示;
Re与Rd独立地选自氢、卤素;
Ra和Rb的定义如上所示。
另一方面,本发明提供了一种通式III中的化合物或其药学上可接受的盐:
式中,
R3、R4和R5的定义如上所示;
Q选自以下部分:
Ra、Rb和Rc的定义如上所示;
R1和R2的定义如上所示;
Re与Rd独立地选自氢、卤素;
Ra和Rb的定义如上所示;
Z和Y各自独立地表示N或者CR3;
W表示N或者CR6;
R6的定义如上所示;
R13和R14独立地表示支链或直链C1-6烷基、支链或直链C1-6烯基、C3-6环烷基、C3-6杂环基、-SC1-6烷基、-S(O)C1-6烷基、-S(O)2C1-6烷基、-P(O)(C1-6烷基)2、-OC1-6烷基、-OC3-6杂环基、-OC3-6环基、-SC3-6杂环基、-SC3-6环基,条件是R13和R14不同时为支链或直链C1-6烷基、C3-6环烷基。
一方面,本发明的特征在于它是一种通式IV中的化合物或其药学上可接受的盐:
式中,
Q和R7的定义如上所示;
R1和R2的定义如上所示;
n和m独立地表示0、1、2、3、4和5;
R3、R4、R5和R6的定义如上所示。
一方面,本发明提供了一种通式V中的化合物或其药学上可接受的盐:
式中,
Q和R7的定义如上所示;
R1和R2的定义如上所示;
n和m独立地表示0、1、2、3、4或者5;
R3、R4、R5和R6的定义如上所示。
一方面,本发明提供了一种通式VI中的化合物或其药学上可接受的盐:
式中,
Q的定义如上所示;
Z、Y、R1、R2、R3、R4和R5的定义如上所示;
W表示N或者CR6;
R6的定义如上所示;
n和m独立地表示0、1、2、3、4或者5;
Re与Rd独立地选自氢、卤素;
Ra和Rb的定义如上所示;
R3、R4和R5的定义如上所示;
R15表示支链或直链C1-6烷基、C3-6环烷基、C3-6杂环基、-SC1-6烷基、-OC1-6烷基、-OC3-6杂环基、-OC3-6环基、-SC3-6杂环基或-SC3-6环基;
R16表示-S(O)C1-6烷基、-S(O)2C1-6烷基、-S(O)2NHC1-6烷基、-S(O)2N(C1-6烷基)2、-P(O)(C1-6烷基)2。
一方面,本发明提供了一种通式VII中的化合物或其药学上可接受的盐:
式中,
Q的定义如上所示;
Z、Y、R1、R2、R3和R4的定义如上所示;
W表示N或者CR6;
R6的定义如上所示;
n和m独立地表示0、1、2、3、4或者5;
R17和R18独立地选自由以下组分组成的基团:卤素、支链或者直链C1-6烷基、C3-6环烷基、C3-6杂环基、-SC1-6烷基、-OC1-6烷基、-OC3-6杂环基、-OC3-6环基、-SC3-6杂环、-SC3-6环基、-S(O)C1-6烷基、-S(O)2C1-6烷基、-S(O)2NHC1-6烷基、-S(O)2N(C1-6烷基)2以及-P(O)(C1-6烷基)2;
L3选自由以下组分组成的基团:-(CH2)qC(O)-、-O(CH2)qC(O)-、-NR19(CH2)qNR20-、-(CH2)qNR20-、-O(CH2)qO-、-(CH2)qC(O)NR19-、-O(CH2)qC(O)NR19-、-S(CH2)qC(O)-、-S(CH2)qC(O)-;-O(CH2)qC(O)NR19-、-O(CH2)qCNR19-、-S(CH2)qO-、-O(CH2)qS-、-S(CH2)qS-、-NR19(CH2)qC(O)N20-、-NR19(CH2)qC-、–NR19(CH2)qO-、-OC(O)(CH2)q-、-OC(O)(CH2)q-、-O(O)(CH2)qS-、-(CH2)tCH=CH(CH2)r-、-O(CH2)qCH=CH(CH2)r-、-O(CH2)qCH=CH(CH2)rO-、-OCH2)qCH=CH(CH2)rO-、-S(CH2)qCH=CH(CH2)r-、-(CH2)qCH=CH(CH2)rS-、-O(CH2)qCH=CH(CH2)rS-、-S(CH2)qCH=CH(CH2)rO-、-C(CH2)qS(CH2)r-以及-C(CH2)qO(CH2)r-;
q和r在1到6之间独立选定;最好是q和r各自独立地表示1、2、3、4、5或6;
R19和R20独立地选自氢、C1-6烷基、C3-6环烷基;
Re与Rd独立地选自氢、卤素;
Ra和Rb的定义如上所示。
一方面,本发明提供了一种通式VIIA中的化合物或其药学上可接受的盐:
式中,
R1和R2独立地选自氢、卤素、C0-6亚烷基-CN、C0-6亚烷基-R19R20、C1-6烷氧基、羟基、C0-6亚烷基-C(O)NH2、C0-6亚烷基-C(O)NHC1-6烷基、C0-6亚烷基-C(O)N(C1-6烷基)2、C0-6亚烷基-S(O)2-C1-6烷基、C0-6亚烷基-S(O)2NH2、C0-6亚烷基-S(O)2NHC1-6烷基、C0-6亚烷基-S(O)2N(C1-6烷基)2、C0-6亚烷基-NHC(O)NH2、C0-6亚烷基-NHC(O)NHC1-6烷基、C0-6亚烷基-NR19C(O)N(C1-6烷基)2、C1-6烷基、C0-6亚烷基-NHC(O)OC1-6烷基、C0-6亚烷基-C(O)-C1-6烷基、C1-6杂烷基、C0-6亚烷基-杂环基或C0-6亚烷基-杂环基烷基;或者R1和R2与它们所连接的碳原子可以形成一个三到六元的碳环;
Z和Y独立地表示N或者CR3;
W表示N或者CR6;
W1表示N或者CR3;
W2表示N或者CR4;
Z1、Z2、Z3、Z4和Z5独立地表示N或CR18;
R3、R4和R6独立地表示H、OH、CN或卤素、C1-6烷基、C3-10环烷基、C3-10杂烷基、C3-10杂环烷基、C1-6卤代烷基、C1-6烷氧基、NH-C1-6烷基、N(C1-6烷基)2、C3-8环烷基、C2-4烯基、C2-4炔基、C2-6杂环基、芳基或杂芳基;
R17和R18独立地选自卤素、CN、支链或者直链C1-6烷基、C3-6环烷基、C3-6杂环基、-SC1-6烷基、-OC1-6烷基、-OC3-6杂环基、-OC3-6环基、NH-C1-6烷基、N(C1-6烷基)2、-SC3-6杂环基、-SC3-6环基、-S(O)C1-6烷基、-S(O)2C1-6烷基、-S(O)2NH2、-S(O)2NHC1-6烷基、-S(O)2N(C1-6烷基)2、-P(O)(C1-6烷基)2、C2-6杂环基、C6-10芳基或C1-5杂芳基;
L3选自-(CH2)q、-(CH2)qC(O)-、-O(CH2)qC(O)-、-NR19(CH2)qNR20-、-(CH2)qNR20-、-O(CH2)qO-、-(CH2)qC(O)NR19-、-(CH2)qC(S)NR19-、-(CH2)qCHCF3NR19-、-(CH2)qNR19C(O)-、(CH2)qNR19CHCF3-、-C(O)NR19(CH2)q-、-CHCF3NR19(CH2)q-、-C(S)NR19(CH2)q-、-O(CH2)qC(O)NR19-、-O(CH2)qC(S)NR19-、-S(O)v(CH2)qC(O)-、-O(CH2)qC(O)NR19-、-NR19C(O)(CH2)qC(O)NR20-、-C(O)NR19(CH2)qC(O)NR20-、-C(O)NR19(CH2)qNR20C(O)-、-NR19C(O)(CH2)qNR20C(O)-、O(CH2)qCNR19-、-S(O)v(CH2)qO-、-O(CH2)qS(O)v-、-S(O)v(CH2)q-、-(CH2)qS(O)v-、-S(O)v(CH2)qS(O)v-、-NR19(CH2)qC(O)NR20-、-NR19(CH2)q-、-NR19C(O)(CH2)q-、–NR19CHCF3(CH2)q-、–NR19(CH2)qO-、-(CH2)rOC(O)(CH2)q-、-OC(O)(CH2)q-、-OC(O)(CH2)qS(O)v-、-(CH2)qCH=CH(CH2)r-、-NR19(CH2)qCH=CH(CH2)r-、NR19C(O)(CH2)qCH=CH(CH2)r-、-(CH2)qCH=CH(CH2)rC(O)NR20-、-(CH2)qNR19C(O)NR20(CH2)r-、-(CH2)qNR19C(S)NR20(CH2)r-、-(CH2)qNR19S(O)2NR20(CH2)r-、-(CH2)qS(O)v(CH2)r-、-(CH2)qS(O)2NR20(CH2)r-、-(CH2)qNR19S(O)v(CH2)r-、-(CH2)qSS(CH2)r-、-(CH2)qS(CH2)r-、-(CH2)qO(CH2)r-、-(CH2)qNR19(CH2)r-、-(CH2)qC≡C(CH2)r-、-O(CH2)qCH=CH(CH2)r-、-O(CH2)qCH≡CH(CH2)r-、-(CH2)qCH=CH(CH2)rO-、-(CH2)qCH≡CH(CH2)rO-、-O(CH2)qCH=CH(CH2)rO-、-O(CH2)qCH≡CH(CH2)rO-、-S(O)v(CH2)qCH=CH(CH2)r-、S(O)v(CH2)qCH≡CH(CH2)r-、-(CH2)qCH=CH(CH2)rS(O)v-、(CH2)qCH≡CH(CH2)rS(O)v-、-O(CH2)qCH=CH(CH2)rS(O)v-、-O(CH2)qCH≡CH(CH2)rS(O)v-、-S(O)v(CH2)qCH=CH(CH2)rO-、S(O)v(CH2)qCH≡CH(CH2)rO-、-C(CH2)qS(CH2)r-、-C(CH2)qO(CH2)r-、-C(O)NR19S(O)2(CH2)q-或者-(CH2)qS(O)2NR19C(O)-;或者L3表示L4-L5-L6;
L4和L6独立地选自-(CH2)q-、-O(CH2)q-、-S(CH2)q-、-NR19(CH2)q-、-(CH2)qNR20-、-(CH2)qO-、-(CH2)qS-、-(CH2)qC(O)-、-C(O)(CH2)q-、-(CH2)qC(O)NR19-、-NR19(C(O)(CH2)q-、-(CH2)qCH=CH(CH2)r-、-O(CH2)qCH=CH(CH2)r-、-(CH2)qCH=CH(CH2)rO-、-S(CH2)qCH=CH(CH2)r-、-(CH2)qCH=CH(CH2)rS-、-O(CH2)qCH=CH(CH2)rS-或-S(CH2)qCH=CH(CH2)rO-;
L5表示C2-6杂环基、C6-10芳基或C1-9杂芳基;
L3、L4、L5和L6中的每个氧代基团可独立地被硫羰基、-C(S)-、氧杂环丁烷基或亚胺基、-C(=NR19)-取代;
q和r在0到10之间独立选定;最好是q和r各自独立地表示0、1、2、3、4、5、6、7、8、9或10;
v是0、1或者2;
R19和R20独立地选自氢、C1-6烷基、C3-10杂烷基、C3-6环烷基、C6-10芳基或C1-5杂芳基、C2-6杂环基;或者R19和R20可以连接成一个环;
Q表示能够与亲核试剂形成共价键的部分,示例性Q的优选结构如下所示:
Ra、Rb和Rc各自独立地表示H、卤素、取代或未取代的C1-4烷基、取代或未取代的C1-4环烷基、C3-10杂烷基或氰基。
Re和Rd独立地选自氢、卤素、C1-6烷基、卤化C1-6烷基、CN。
另一方面,本发明提供了一种通式VIIB中的化合物或其药学上可接受的盐:
式中,
R17、Z、Z5、W、W1、W2和L3的定义如上所示;
L6选自-(CH2)q-、-(CH2)qC(O)-、-O(CH2)qC(O)-、-NR19(CH2)qNR20-、-(CH2)qNR20-、-O(CH2)qO-、-(CH2)qC(O)NR19-、-(CH2)qNR19C(O)-、-C(O)NR19(CH2)q-、-O(CH2)qC(O)NR19-、-S(O)v(CH2)qC(O)-、-O(CH2)qC(O)NR19-、-NR19C(O)(CH2)qC(O)NR20-、-C(O)NR19(CH2)qC(O)NR20-、-C(O)NR19(CH2)qNR20C(O)-、-NR19C(O)(CH2)qNR20C(O)-、O(CH2)qCNR19-、-S(O)v(CH2)qO-、-O(CH2)qS(O)v-、-S(O)v(CH2)qS(O)v-、-NR19(CH2)qC(O)NR20-、-NR19(CH2)q-、-NR19C(O)(CH2)q-、-NR19(CH2)qO-、-OC(O)(CH2)q-、-O(O)(CH2)q-、-O(O)(CH2)qS(O)v-、-(CH2)qCH=CH(CH2)r-、-NR19(CH2)qCH=CH(CH2)r-、NR19C(O)(CH2)qCH=CH(CH2)r-、-(CH2)qCH=CH(CH2)rC(O)NR20-、-(CH2)qC≡C(CH2)r-、-O(CH2)qCH=CH(CH2)r-、-O(CH2)qCH≡CH(CH2)r-、-(CH2)qCH=CH(CH2)rO-、-(CH2)qCH≡CH(CH2)rO-、-O(CH2)qCH=CH(CH2)rO-、-O(CH2)qCH≡CH(CH2)rO-、-S(O)v(CH2)qCH=CH(CH2)r-、S(O)v(CH2)qCH≡CH(CH2)r-、-(CH2)qCH=CH(CH2)rS(O)v-、(CH2)qCH≡CH(CH2)rS(O)v-、-O(CH2)qCH=CH(CH2)rS(O)v-、-O(CH2)qCH≡CH(CH2)rS(O)v-、-S(O)v(CH2)qCH=CH(CH2)rO-、S(O)v(CH2)qCH≡CH(CH2)rO-、-C(CH2)qS(CH2)r-以及C(CH2)qO(CH2)r-;
q和r在0到10之间独立选定;最好是q和r各自独立地表示0、1、2、3、4、5、6、7、8、9或10;
v是0、1或者2;
L3和L6也可以不存在;
另一方面,本发明的特征在于它是一种通式VIIC中的化合物或其药学上可接受的盐:
另一方面,本发明提供了一种通式VIII中的化合物或其药学上可接受的盐:
式中,
Q、L1、L2、R9和R7的定义如上所示;
Ra、Rb、Re和Rd的定义如上所示。
另一方面,本发明提供了一种通式IX中的化合物或其药学上可接受的盐:
式中,
Q、n、m、L1、L2、R1、R2、R9和R10的定义如上所示;
Ra、Rb、Re和Rd的定义如上所示。
另一方面,本发明提供了一种通式X中的化合物或其药学上可接受的盐:
式中,
Q、n、m、L1、L2、R1、R2、R9和R10的定义如上所示;
L4表示-CR21R22-、-(CR21R22)2-、O、S、NR21、NC(O)NR21或NS(O)2NR21R22;
R21和R22独立地选自由以下组分组成的基团:氢、C1-6烷基以及C3-6环烷基;
Ra、Rb、Re和Rd的定义如上所示。
另一方面,本发明提供了一种通式XI中的化合物或其药学上可接受的盐:
式中,
Q、n、m、L1、L2、R1、R2、R9和R10的定义如上所示;
L4表示-CR21R22-、-(CR21R22)2-、O、S、NR21、NC(O)NR21或NS(O)2NR21R22;
R21和R22独立地选自氢、C1-6烷基、C3-6环烷基;
Ra、Rb、Re和Rd的定义如上所示。
在一些实施例中,本发明还提供了上述分子式I至分子式XI的任何化合物的立体异构体、对映体、阻转异构体,或者药学上可接受的盐。
在一些实施例中,分子式I至分子式XI的化合物选自其立体异构体、对映体或阻转异构体或药学上可接受的盐。
在一些实施例中,分子式I至分子式XI的化合物或其立体异构体、对映体或阻转异构体或药学上可接受的盐选自以下化合物:
另一方面,本发明提供了一种药物组合物,其中包含本文公开的药学上可接受的载体和化合物,或者药学上可接受的载体。
另一方面,本发明提供了一种针对由KRAS G12C突变所诱发疾病的治疗方法。该方法包括向受试者施用有效治疗用量的本文公开化合物。另一方面,本发明的特征在于它是一种通过向受试者施用有效治疗用量的本文公开化合物来治疗以下任一病症的方法:胰腺癌、结直肠癌、肝细胞癌、乳腺癌、卵巢癌、肺癌、肝癌、肉瘤或任何其他形式的癌症。
本发明包括上文和下文所述实施例的所有可能组合。
具体实施方式
定义
除非另有说明,否则术语“烷基”本身或作为另一取代基的一部分是指具有指定碳原子数(即:C1-10是指1至10个碳)的直链(即非支链)或支链或环状烃基或其组合,可以是完全饱和的、单不饱和的或多不饱和的,并且可以包括二价基团和多价基团。饱和烃基的实施例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、环己基、(环己基)甲基、环丙基甲基等基团、正戊基、正己基、正庚基、正辛基等物质的同系物和异构体。不饱和烷基是指具有一个或多个双键或三键的烷基。不饱和烷基的实施例包括但不限于乙烯基、2-丙烯基、丁烯基、2-异戊烯基、2-(丁二烯基)、2,4-戊二烯基、3-(1,4-戊二烯基)、乙炔基、1-丙炔基和3-丙炔基、3-丁炔基以及高级同系物和异构体。仅限于烃基的烷基称为“高烷基”。所述烷基可选择性地被一个或多个卤素原子取代。
术语“卤代烷基”是指上述定义的烷基,其中一个或多个氢原子已被卤素原子取代。
术语“亚烷基”本身或作为另一取代基的一部分是指衍生自烷基的二价基团,实施例包括但不限于-CH2CH2CH2CH2-、-CH2CH=CHCH2-、-CH2C≡CCH2-、-CH2CH2CH(CH2CH2CH3)CH2-。通常,烷基(或亚烷基)基团具有1至24个碳原子,本发明中首选那些具有10个或以下碳原子的基团。“低级烷基”或“低级亚烷基”是短链烷基或亚烷基,通常具有八个或以下碳原子。所述亚烷基的氢原子可选择性地被一个或多个卤素原子取代。
术语“炔基”是指含有至少一个碳碳三键的碳链,可以是直链或支链或其组合。炔基的实施例包括乙炔基、炔丙基、3-甲基-1-戊炔基、2-庚炔基等。所述炔基可选择性地被一个或多个卤素原子取代。
术语“环烷基”是指单环或双环饱和碳环,每个碳环具有3至10个碳原子。环烷基的“稠合类似物”是指与芳基或杂芳基稠合的单环,其中联结点位于非芳族部分。环烷基及其稠合类似物的实施例包括环丙基、环丁基、环戊基、环己基、环庚基、四氢萘基、十氢萘基、茚满基等。所述环烷基可选择性地被一个或多个卤素原子取代。
术语“烷氧基”是指具有所示碳原子数的直链或支链烷氧基。C1-6烷氧基的实施例包括甲氧基、乙氧基、丙氧基、异丙氧基等。
除非另有说明,术语“杂烷基”本身或与另一术语组合是指稳定的直链或支链或环状烃基,或其组合,由至少一个碳原子以及至少一个选自O、N、P、Si和S组成基团的杂原子组成;其中氮、磷和硫原子可选择性地被氧化,而氮杂原子可选择性地被季铵化。杂原子O、N、P、S以及Si可以位于杂烷基的任何内部位置,或者位于烷基与分子的其余部分连接的位置。实施例包括但不限于-CH2-CH2-O-CH3、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-CH2-S-CH2-CH3、-CH2-CH2、-S(O)-CH3、-CH2-CH2-S(O)2-CH3、-CH=CH-O-CH3、-Si(CH3)3、-CH2-CH=N-OCH3、-CH=CH-N(CH3)-CH3、-O-CH3、-O-CH2-CH3和-CN。多至两个或三个杂原子可以是连续的,例如-CH2-NH-OCH3和-CH2-O-Si(CH3)3。类似地,术语“亚杂烷基”本身或作为另一取代基的一部分是指衍生自杂烷基的二价基团,实施例包括但不限于-CH2-CH2-S-CH2-CH2-和-CH2-S-CH2-CH2-NH-CH2-。对于亚杂烷基,杂原子也可占据链末端中的一个或两个(例如亚烷基氧代、亚烷基二氧代、亚烷基氨基、亚烷基二氨基等)。更进一步,对于亚烷基和亚杂烷基连接基团,其中连接基团的分子式书写方向并不暗示连接基团的取向。例如,分子式-C(O)OR'-表示-C(O)OR'-和-R'OC(O)-。如上所述,本文所用的杂烷基还包括通过杂原子连接到分子其余部分的那些基团,例如-C(O)R'、-C(O)NR'、-NR'R"、-OR'、-SR'及/或-SO2R'。在列举“杂烷基”,随后列举特定的杂烷基(如-NR'R"等)时,应理解术语“杂烷基”和-NR'R"不是多余的或相互排斥的。相反,为了增加清晰度,还列举了特定的杂烷基。因此,术语“杂烷基”在本文中不应解释为排除特定的杂烷基,例如-NR'R"等。
术语“环烷氧基”是指上述定义的与氧原子键合的环烷基,如环丙基氧基。
术语“卤代烷氧基”是指上述定义的烷氧基,其中一个或多个氢原子已被卤素原子取代。
术语“芳基”是指仅含碳原子的单环或双环芳族环。芳基的“稠合类似物”是指与单环环烷基或单环杂环基稠合的芳基,联结点在芳族部分上。芳基及其稠合类似物的实施例包括苯基、萘基、茚满基、茚基、四氢萘基、2,3-二氢苯并呋喃基、二氢苯并吡喃基、1,4-苯并二恶烷基等。
术语“杂芳基”是指含有至少一个(例如1、2或3)选自N、O和S的杂原子的单环或双环芳族环,每个环含有5至6个原子。杂芳基的“稠合类似物”是指与单环环烷基或单环杂环基稠合的杂芳基,联结点在芳族部分上。杂芳基的实施例包括吡咯基、异恶唑基、异噻唑基、吡唑基、吡啶基、恶唑基、恶二唑基、噻二唑基、噻唑基、咪唑基、三唑基、四唑基、呋喃基、三嗪基、噻吩基、嘧啶基、哒嗪基、吡嗪基、苯并恶唑基、苯并噻唑基、苯并咪唑基、苯并呋喃基、苯并噻吩基、呋喃(2,3-b)吡啶基、喹啉基、吲哚基、异喹啉基等。
定义中所述烷基、芳基和所述杂芳基是未取代基团或被选自取代基团中的至少一个取代基取代。
所述取代基选自由卤素原子组成的基团、羟基、具有1-4个碳原子的烷基、具有1-4个碳原子的烷氧基、具有1-4个碳原子的卤代烷基、具有1-4个碳原子的卤代烷氧基、氰基、具有2-6个碳原子的炔基、具有1-5个碳原子的烷酰基、具有3-7个环原子的环烷基、杂芳基、芳基、具有7-10个碳原子的芳烷氧基、芳基羰基;两个邻近的-x基团可选择性地连接在一起形成具有3或4个碳原子的亚烷基或亚烯基链、氨基羰基、具有2至5个碳原子的烯基、具有1至4个碳原子的烷硫基、氨基亚磺酰基、氨基磺酰基、羟基、-SF5、具有1-4个碳原子的羟烷基、硝基、氨基、羧基、具有2-5个碳原子的烷氧羰基、具有1-4个碳原子的烷氧烷基、具有1-4个碳原子的烷酰基氨基、具有1-4个碳原子的烷基磺酰基、具有1-6个碳原子的烷酰基(烷基)氨基、在烷酰基和烷基部分均具有1至6个碳原子的烷酰基氨基烷基、在烷酰基和每个烷基部分均具有1-6个碳原子的烷酰基(烷基)氨基烷基、具有1-4个碳原子的烷基磺酰基氨基、具有1-6个碳原子的单或二烷基氨基羰基、具有1-6个碳原子的单或二烷基氨基磺酰基、具有1至4个碳原子的氨基烷基、具有1至6个碳原子的单或二烷基氨基、在每个烷基部分中具有1-6个碳原子的单或二烷基氨基烷基、具有7-10个碳原子的芳烷基、在烷基部分中具有1-4个碳原子的杂芳基烷基、在烷氧基部分中具有1-4个碳原子的杂芳基烷氧基以及具有1-4个碳原子的烷基磺酰基氨基;
术语“杂环基”是指含有至少一个选自N、S和O杂原子的单环或双环饱和环,每个环具有3-10个原子,其中联结点可以是碳或氮。杂环基的“稠合类似物”是指与芳基或杂芳基稠合的单环杂环,其中联结点位于非芳族部分。“杂环基”及其稠合类似物的实施例包括吡咯烷基、哌啶基、哌嗪基、咪唑烷基、2,3-二氢呋喃(2,3-b)吡啶基、苯并恶嗪基、四氢喹啉基、四氢异喹啉基、二氢吲哚基等。该术语还包括非芳族的部分不饱和单环,如通过氮连接的2-或4-吡啶酮或N-取代-(1H,3H)-嘧啶-2,4-二酮(N-取代尿嘧啶)。
除非另有说明,否则术语“卤素”(halo或halogen)本身或作为另一取代基的一部分是指氟、氯、溴或碘原子。此外,术语“卤代烷基”(haloalkyl或halogenated alkyl)包括单卤代烷基和多卤代烷基。例如,术语“卤代(C1-C4)烷基”包括但不限于三氟甲基、2,2,2-三氟乙基、4-氯丁基、3-溴丙基等。
“前药”是指在体内转化为母体药物的化合物。因为在某些情况下,前药可能比母体药物更容易给药;因此,前药通常是有用的。例如,前药可以通过口服给药获得生物利用度,而母体药物则不然。与母体药物相比,前药还可以在药物组合物中改善溶解度。前药的实施例包括但不限于分子式I中的任何化合物。该化合物以酯(“前药”)的形式给药,促进其在细胞膜中的传输,而原药的水溶性不利于该传输运动;但一旦进入有利水溶性的细胞内,该化合物就被代谢水解为活性实体羧酸。前药实施例还包括键合到酸基上的短肽(多氨基酸),其中肽经代谢,释放出活性部分。
光学异构体-非对映异构体-阻转异构体-几何异构体-互变异构体:
通式I至通式XI的任何化合物可能包含一个或多个不对称中心/单键旋转受阻,因此可能以外消旋体和外消旋混合物、单一对映体、单一阻转异构体、非对映体混合物和单个非对映体的形式出现。本发明旨在包含分子式I至分子式XI的化合物的所有这些异构体形式。
本文所述的部分化合物含有烯属双键,除非另有说明,否则包括E形和Z形几何异构体。
部分通式I至分子式XI的化合物可能含有一个或更多环状环系统,因此可能以cis-和trans-异构体的形式存在。本发明旨在包括所有此类cis和trans-异构体。
本文所述的一些化合物可以存在不同的氢联结点,称为互变异构体,例如酮及其烯醇式,就被称为酮-烯醇互变异构体。分子式I至分子式XI化合物涵盖各个互变异构体及其混合物。
分子式I至分子式XI化合物可通过例如HPLC或从合适的溶剂(如MeOH或EtOAc或其混合物)中分步结晶,分离成非对映异构的成对对映体。这样得到的成对对映体可以通过常规方法分离成单独的立体异构体,例如通过使用光学活性胺或酸作为拆分剂或在手性HPLC柱上进行分离。
或者,通式I至通式XI化合物的任何对映体也可通过使用光学纯原始材料或已知构型试剂的立体专一性合成获得。
稳定同位素标记类似物:
通式I至通式XI化合物中的一个或以上质子可被氘原子取代,从而生成具有改进药理活性的氘化类似物。
盐及其制剂
本文所述化合物可用作游离碱或盐。
术语“药学上可接受的盐”是指从药学上可接受的无毒碱或酸(包括无机或有机碱和无机或有机酸)中制备的盐。衍生自无机碱的盐包括铝、铵、钙、铜、铁、亚铁、锂、镁、锰盐、锰、钾、钠、锌等;其中具体首选的是铵盐、钙盐、镁盐、钾盐和钠盐。衍生自药学上可接受的有机无毒碱的盐包括伯胺、仲胺和叔胺、取代胺(包括天然存在的取代胺)、环胺和碱性离子交换树脂(例如精氨酸、甜菜碱、咖啡碱、胆碱、N,N'-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基乙醇胺、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡糖胺、葡糖胺、组氨酸、羟胺、异丙胺、赖氨酸、甲基葡糖胺、吗啉、哌嗪、哌啶、聚胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等)的盐。
当本发明的化合物为碱性,盐可以从药学上可接受的无毒酸中制备,包括无机酸和有机酸。此类酸包括乙酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、富马酸、葡萄糖酸、谷氨酸、氢溴酸、盐酸、羟基乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、粘酸、硝酸、磷酸、泛酸、硫酸、磷酸、琥珀酸、酒石酸、对甲苯磺酸等。具体首选的是柠檬酸、氢溴酸、盐酸、马来酸、磷酸、硫酸和酒石酸。
应当理解,如本文所用,凡提述分子式I化合物均包括药学上可接受的盐。
口服制剂可以是硬胶胶囊,其中活性成分与惰性固体稀释剂(如碳酸钙、磷酸钙或高岭土混合),也可以是软胶胶囊,其中活性成分与水或油介质(例如花生油、液体石蜡或橄榄油)混合。
水悬浮液包含与适合制备水悬浮液的赋形剂混合的活性物质。此类赋形剂属于悬浮剂,例如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、海藻酸钠、聚乙烯基吡咯烷酮、黄蓍胶和阿拉伯树胶;分散剂或润湿剂可以是天然存在的磷脂(例如卵磷脂)或环氧烷与脂肪酸的缩合产物(例如脂肪酸聚氧乙烯酯),或环氧乙烷与长链脂肪醇的缩合产物(例如heptadecaethylene-oxycetanol),或环氧乙烷与衍生自脂肪酸和己糖醇的偏酯的缩合产物(例如聚氧乙烯山梨醇单油酸酯),或环氧乙烷与衍生自脂肪酸和己糖醇酐的偏酯的缩合产物(例如聚乙烯山梨醇单油酸酯)。水悬浮液还包含一种或多种防腐剂(例如乙基或正丙基、对羟苯甲酸)、一种或多种着色剂、一种或多种调味剂,以及一种或多种甜味剂(例如蔗糖、糖精或阿斯巴甜)。
油状悬浮液可以通过将活性成分悬浮在植物油(例如花生油、橄榄油、芝麻油或椰子油)中,或者悬浮在矿物油(例如液体石蜡)进行配制。油状悬浮液可能含有增稠剂,例如蜂蜡、硬石蜡或鲸蜡醇。也可添加上述甜味剂和调味剂,产生可口的口服制剂。这些组合物可通过添加抗氧化剂保存,例如抗坏血酸。
通过加水制备水悬浮液的飞散性粉末和颗粒可用作分散剂或湿润剂、悬浮剂和一种或多种防腐剂混合物中的活性成分。适用的分散剂或润湿剂和悬浮剂已经在上文中有所示例。此外,也可能存在其他赋形剂,例如甜味剂、调味剂和着色剂,
本发明的药物组合物也可以是水包油乳剂的形式。油相可以是植物油(例如橄榄油或花生油)或矿物油(例如液体石蜡)或其混合物。适用的乳化剂可以是天然存在的磷脂(例如大豆、卵磷脂)、衍生自脂肪酸和己糖醇酸酐的酯或偏酯(例如失水山梨醇单油酸酯),以及偏酯与环氧乙烷的缩合产物(例如聚氧乙烯失水山梨醇单油酸酯)。乳剂也可以含有甜味剂和调味剂。
糖浆和酏剂可使用甜味剂例如甘油、丙二醇、山梨醇或蔗糖进行配制。此类制剂还可能含有镇痛剂、防腐剂以及调味料和着色剂。药物组合物可以是无菌可注射的含水或含油悬浮液的形式。该悬浮液可以根据已知技术使用上述适当的分散剂或润湿剂和悬浮剂进行配制。无菌可注射制剂也可以是不经肠道的可接受的无毒稀释剂或溶剂中的无菌可注射溶液或悬浮液,例如在1,3-丁二醇中的溶液。可使用的可接受载体和溶剂包括水、林格氏溶液和等渗氯化钠溶液。此外,无菌固定油通常用作溶剂或悬浮介质。对此,任一温和固定油,包括合成单甘油酯或二甘油酯都可使用。另外脂肪酸如油酸也可用于制备注射剂。
本发明的化合物也可以鼻腔给药或通过吸入给药,通常通过干粉吸入器以干粉形式(或者单独作为混合物例如与乳糖的干共混物,或者作为混合组分颗粒,例如与磷脂,例如磷脂酰胆碱混合)给药或通过加压容器、泵、喷射器、喷雾器(首选使用电流体力学产生细雾的I型喷雾器)或雾化器以气溶胶喷雾的形式给药,可选择使用或不使用合适的推进剂,例如1,1,1,2-四氟乙烷或1,1,1,2,3,3,3-七氟丙烷。对于鼻腔给药,粉末可包含生物粘合剂,例如壳聚糖或环糊精。
本发明化合物的溶液或悬浮液可置于加压容器、泵、喷射器、雾化器或喷雾器中,所述溶液或悬浮液实施例包括乙醇、含水乙醇或用于分散、增溶或延长活性物质释放的适当替代剂,作为溶剂的推进剂和选配的表面活性剂,例如山梨糖醇三油酸酯、油酸或低聚乳酸。
在用于干粉或悬浮液制剂前,药物产品被微细化至适于通过吸入递送的尺寸(通常小于5μm)。
可采用适当的粉碎方法完成这一操作,例如螺旋喷射研磨、流化床喷射研磨、超临界流体处理,形成纳米颗粒、实现高压均质化或喷雾干燥。
用于吸入器或注入器的胶囊(例如由明胶或HPMC制成)、起泡剂和药筒可以配制成包含本发明化合物的粉末混合物、适当的粉末基料如乳糖或淀粉以及性能改性剂如L-亮氨酸、甘露醇或硬脂酸镁。乳糖可以是无水乳糖或一水合物的形式;但优选后者。其他合适的赋形剂包括右旋糖酐、葡萄糖、麦芽糖、山梨醇、木糖醇、果糖、蔗糖和海藻糖。
对于通过电流体力学产生细雾的雾化器,其使用的适当溶液制剂每次致动含有1mg至20mg本发明化合物,且致动体积的变化范围为1L至100L。典型制剂可包括分子通式I至XI所示的化合物、丙二醇、无菌水、乙醇和氯化钠。一些替代溶剂例如甘油和聚乙二醇可用来代替丙二醇。
适当的香料(如薄荷醇和左旋甲氧苄醇)或甜味剂(如糖精或糖精钠)均可添加到本发明中用于吸入/鼻腔给药的制剂中。
可以使用例如聚乳酸-羟基乙酸共聚物(PGLA)等物质将用于吸入/鼻腔给药的制剂配制为速释和/或缓释制剂。缓释制剂包括迟释、持续释放、脉冲释放、控释、定向释放、程序释放。
如使用干粉吸入器和气雾剂,剂量单位通过输送定量的阀门确定。根据本发明的情况,使用单位通常设计成施用定量剂量或含有1fig至10mg分子式I至XI化合物的“泡剂”。总日剂量通常在1lag至10mg,可以单次给药,或者更常见的是全天分次给药。
通式I至XI化合物也可以栓剂的形式进行直肠给药。这些组合物可通过将药物与合适的无刺激性赋形剂混合进行制备;其中赋形剂在常温下为固体,但在直肠温度下为液体。因此将在直肠中熔化,释放药物。这类赋形剂材料为可可脂和聚乙二醇。
对于局部用药含有通式I至通式XI化合物的乳膏、软膏、胶冻、溶液或悬浮液等也是可使用的。(就本申请而言,局部应用应包括漱口药和漱口剂。)
每天每公斤体重施用约0.01mg至140mg的剂量水平可有效治疗上述疾病,或者每位患者每天施用约0.5mg至7g的剂量。例如,通过每天每公斤体重施用约0.01至50mg的化合物,或者每位患者每天约0.5mg至3.5g的剂量,可能有效地治疗病症;但优选每位患者每天施用2.5mg至1g的化合物。
对于可与载体材料结合产生单一剂型的活性成分,其用量根据所治疗的宿主和特定的给药方式而变化。例如,用于人口服给药的制剂可包含0.5mg至5g与载体材料适当且适用量混合的活性剂,该载体材料的量可为全量组成的5%至95%左右。剂量单位形式通常包含约1mg至500mg的活性成分;一般的活性成分含量为25mg、50mg、100mg、200mg、300mg、400mg、500mg、600mg、800mg或1000mg。
但应当理解的是,特定患者的特定剂量水平取决于多种因素,包括年龄、体重、整体健康状况、性别、饮食情况、给药时间、给药途径、排泄速率、药物组合以及正在接受治疗的特定疾病的严重程度。
适应症
本发明化合物可用于治疗由KRAS G12C突变诱发的疾病以及任何形式的癌症。
联合靶向治疗
本文件披露的KRAS G12C突变抑制剂的施用可与其他癌症治疗方法结合使用。例如,抑制剂可与外科治疗、放射或其他治疗剂(例如抗体、其他激酶抑制剂、靶向治疗、丝裂原活化蛋白(MAP)激酶信号通路抑制剂或化学疗法)结合施用。抑制剂也可以与RNAi疗法、反义疗法或免疫疗法联合施用。本文所述KRAS G12C突变抑制剂可与一种、两种或多种其他治疗剂联合使用。在下文概述的实施例中,应理解,“第二治疗剂”还包括除KRAS G12C突变抑制剂之外的一种以上的治疗剂。例如,本文公开的化合物可与诸如索拉非尼、PD-1抗体或PD-L1抗体等试剂联合使用。本文所述KRAS G12C突变抑制剂可与一种、两种或多种其他治疗剂一起施用。
合成
本发明化合物可按以下合成方案制备:
反应式1
反应式2
反应式3
反应式4
反应式5
反应式6
反应式7
反应式8
反应式9
反应式10
生物活性评价
三维增殖实验:NCI-H358(H358,KRAS G12C)和LS513(KRAS G12D)癌细胞系从ATCC(美国标准生物品收藏中心,弗吉尼亚州)获得。将细胞接种于96孔球状基面板(CORNING公司,纽约),使用含有10%FBS的RPMI-1640培养基。将化合物(11个点稀释)和二甲基亚砜(DMSO)注入孔中,在37℃条件下与细胞共同培养4天。然后使用CellTiter-GloCellTiter-Glo(Promega公司,威斯康星州)检测细胞活力。化合物的半数抑制率浓度(IC50)值被确定为与DMSO处理后细胞相比抑制50%细胞活力的浓度(A:IC50<0.1μM;B:IC50在0.1μM和1μM之间;C:IC50在1μM和10μM之间;D:>10μM;ND:不确定)。
磷酸化激活ERK(pERK)实验:在复合处理前16小时将NCI-H358细胞接种在含有RPMI-1640培养基与10%FBS的96孔培养板(Greiner公司)中。将化合物连续稀释后加入培养孔中,在37℃条件下培养3小时。处理后,在室温条件下用3.7%的甲醛(VWR公司)固定细胞20分钟,然后在-20℃条件下用冰冷甲醇进行渗透20分钟。然后倒出甲醇,替换成添加有0.05%Tween-20表面活性剂的(PBS磷酸盐缓冲液)封闭缓冲液(LiCOR公司),并在室温条件下温和摇动培养1小时。然后用含有pERK1/2抗体(Cell Signaling公司)的封闭缓冲液替换上述封闭缓冲液,并在4℃条件下温和摇动过夜。使用1x PBS(磷酸盐缓冲液)+0.1%Tween-20对培养板冲洗5次。然后添加含有LiCOR IRDye 680RD二级抗体(LiCOR公司)的封闭缓冲液,并在室温条件下轻轻摇动培养1小时。用1x PBS+0.1%Tween-20冲洗培养板5次后,使用CLARIOstar读板器(BMG LABTECH公司)读板。半数抑制率浓度(IC50)值被确定为与DMSO处理后细胞相比抑制50%荧光信号的浓度(A:IC50<0.1μM;B:IC50在0.1μM和1μM之间;C:IC50在1μM和10μM之间;D:>10μM;ND:不确定)。
实施例IC50
下列缩写具有所示含义。CIP:2-氯-1,3-二甲基咪唑六氟磷酸盐;EA:乙酸乙酯;DBU:1,8-二氮杂二环[5.4.0]十一碳-7-烯;DIBAL:氢化二异丁基铝;DIPEA:二异丙基乙胺;DMAP:N,N-二甲基氨基吡啶;DME:1,2-二甲氧基乙烷;DMF:N,N-二甲基甲酰胺;dmpe:1,2-双(二甲基膦)乙烷;DMSO:二甲基亚砜;dppb:1,4-双(二苯基膦)丁烷;dppe:1,2-双(二苯基膦)乙烷;dppf:1,1’-双(二苯基膦)二茂铁;dppm:1,1’-双(二苯基膦)甲烷;DIAD:偶氮二甲酸二异丙酯;EDCI:1-(3-二甲基氨基丙基)-3-乙基碳二亚胺;HATU:2-(7-氮苯并三氮唑)-1,1,3,3-四甲基脲六氟磷酸酯;HMPA:六甲基磷酰胺;IPA:异丙醇;LDA:二异丙基氨基锂;LHMDS:双(六甲基二硅基)氨基锂;LAH:氢化铝锂;NCS:N-氯代琥珀酰亚胺;PE:石油醚;PyBOP:苯并三唑-1-基氧三吡咯烷基六氟磷酸盐;TDA:三(2-(2-甲氧乙氧基)乙基)胺;DCM:二氯甲烷;TEA:三乙胺;TFA:三氟乙酸;THF:四氢呋喃;NCS:N-氯代琥珀酰亚胺;NMM:N-甲基吗啉;NMP:N-甲基吡咯烷酮;NMM:N-甲基吗啉;NMI:M-甲基咪唑;PPh3:三苯基膦,RT或rt表示室温;STAB:三乙酰氧基硼氢化钠;TCFH:氯-N,N,N’,N’-四甲基甲脒六氟磷酸盐;T3P:丙基膦酸酐。
采用沃特世micromass ZQ 4000(MAA050型)作为质量检测器、沃特世2487UV为检测器,在沃特世HPLC 2790上进行HPLC-MS分析。使用的分析柱为飞诺美OOB-4605-E0(5U-XB-C18-100A、50x4.6mm)。流动相为洗脱剂A(水、0.05%TFA)和洗脱剂B(CH3CN、0.05%TFA),洗脱速度为1mL/min。起始条件为90%A作用1分钟,然后90%A在5分钟内直链下降到10%A,再在1分钟内从10%A回升到90%A。总运行时间为7分钟。
参考以下实例,更容易理解本发明的内容,给出这些实施例是为了说明本发明而不是限制其范围。
实施例1
(S)-24-(4-丙烯酰基-2-甲基哌嗪-1-基)-26,36-二氟-12-异丙基-21,22-二氢-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶杂-1(3,4)-吡啶杂-3(1,2)-苯杂环七蕃-22,5-二酮((S)-24-(4-Acryloyl-2-methylpiperazin-1-yl)-26,36-difluoro-12-isopropyl-21,22-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphane-22,5-dione)
步骤1(E)-3-(3-氨基-2-异丙基吡啶-4-基)丙烯酸叔丁酯(tert-butyl(E)-3-(3-amino-2-isopropylpyridin-4-yl)acrylate)
在氩气保护环境下,将Pd(OAc)2(58mg,0.26mmol)添加到4-碘代-2-异丙基吡啶-3-胺(690mg,2.63mmol)、丙烯酸叔丁酯(505mg,3.95mmol)、三甲苯基膦(79mg,0.26mmol)和三乙胺(399mg,3.95mmol)溶于DMF(10ml)得到的搅拌溶液中。将所得混合物在100℃条件下搅拌3小时,得到黑色悬浮液。然后加入水(20mL)和乙酸乙酯(50mL)。用盐水洗涤有机层、用Na2SO4干燥,然后过滤、浓缩。残余物经硅胶层析法(PE:EtOAc=1:1)纯化后得到600mg黄色固态目标产物。MS(ES+):262.8[M+1]+。
步骤2 3-(3-氨基-2-异丙基吡啶-4-基)丙酸叔丁酯(tert-butyl 3-(3-amino-2-isopropylpyridin-4-yl)propanoate)
在室温搅拌条件下,将10%Pd/C(100mg)添加到(E)-3-(3-氨基-2-异丙基吡啶-4-基)丙烯酸叔丁酯(600mg,2.3mmol)的甲醇溶液(10ml)中。用氢气置换反应容器三次,所得混合物在30℃条件下搅拌16小时。然后将混合物过滤,并将滤液进行浓缩,得到黄色油状目标产物。MS(ES+):264.8[M+1]+。
步骤3 3-(3-(3-(2,6-二氯-5-氟烟酰基)脲基-2-异丙基吡啶-4-基)丙酸叔丁酯(tert-butyl 3-(3-(3-(2,6-dichloro-5-fluoronicotinoyl)ureido)-2-isopropylpyridin-4-yl)propanoate)
在氩气保护,将乙二酰氯(192mg,1.49mmol)添加到2,6-二氯-5-氟烟酰胺(157mg,0.754mmol)的四氢呋喃(THF)溶液(5mL)中,室温条件下搅拌。将所得混合物在80℃条件下搅拌1小时后,减压除去溶剂。然后用的四氢呋喃(5mL)稀释残余物,并在0℃条件下逐滴加入到步骤2产物的搅拌溶液(100mg,0.378mmol)中。在0℃条件下搅拌1小时后,用水淬灭反应混合物,并用乙酸乙酯萃取。用盐水洗涤有机层、用Na2SO4干燥,然后过滤、浓缩。用制备薄层色谱纯化残余物(PE:EtOAc=1:1)纯化后得到168mg白色固态目标产物。MS(ES+):499.0[M+1]+。
步骤4 3-(3-(7-氯-6-氟-4-羟基-2-氧代吡啶并[2,3-d]嘧啶-1(2H)-基)-2-异丙基吡啶基-4-基)丙酸叔丁酯(tert-butyl 3-(3-(7-chloro-6-fluoro-4-hydroxy-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-isopropylpyridin-4-yl)propanoate)
在室温搅拌以及氩气保护环境下,将六甲基二硅基氨基钾(KHMDS,1.0M)(3.5mL,3.49mmol)加入步骤3产物(791mg,1.58mmol)的四氢呋喃(12mL)溶液中。在室温条件下搅拌1小时后,用水淬灭反应,并用乙酸乙酯萃取。有机层用盐水洗涤、用Na2SO4干燥,然后过滤并浓缩、干燥,得到671mg白色固态纯产物。MS(ES+):463.0[M+1]+。
步骤5 3-(3-(7-(2-氨基-6-氟苯基)-6-氟-4-羟基-2-氧代吡啶并[2,3-d]嘧啶-1(2H)-基)-2-异丙基吡啶-4-基)丙酸叔丁酯(tert-butyl 3-(3-(7-(2-amino-6-fluorophenyl)-6-fluoro-4-hydroxy-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-isopropylpyridin-4-yl)propanoate)
在室温搅拌以及氩气保护环境下,将Pd(dppf)Cl2.DCM(37mg,0.045mmol)加入步骤4产物(210mg,0.453mmol)、3-氟-2-(4,4,5,5-四甲基-1,3,2-二氧苯并呋喃-2-基)苯胺(215mg,0.907mmol)和乙酸钾(134mg,1.36mmol)的二氧六环(6mL)和水(2滴)的溶液中。在80℃条件下搅拌1.5小时后得到黑色溶液,反应混合物加入水后使用乙酸乙酯萃取。有机层用盐水洗涤、用Na2SO4干燥,然后过滤、浓缩。残余物经硅胶层析法(PE:EtOAc=1:2)纯化后得到229mg白色固体目标产物。MS(ES+):537.8[M+1]+。
步骤6 3-(3-(7-(2-氨基-6-氟苯基)-6-氟-4-羟基-2-氧代吡啶并[2,3-d]嘧啶-1(2H)-基)-2-异丙基吡啶-4-基)丙酸(3-(3-(7-(2-amino-6-fluorophenyl)-6-fluoro-4-hydroxy-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-isopropylpyridin-4-yl)propanoic acid)
在室温搅拌以及氩气保护环境下,将三氟乙酸(1mL)加入步骤5产物(229mg,0.426mmol)的二氯甲烷溶液(3mL)中。在25℃条件下搅拌3小时后,将反应混合物浓缩至干燥状态,得到360mg黄色油状目标产物。MS(ES+):482.0[M+1]+。
步骤7 26,36-二氟-24-羟基-12-异丙基-21,22-二氢-4-氮-杂2(1,7)-吡啶并[2,3-d]嘧啶杂-1(3,4)-吡啶杂-3(1,2)-苯杂环七蕃-22,5-二酮(26,36-difluoro-24-hydroxy-12-isopropyl-21,22-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphane-22,5-dione)
在室温搅拌以及氩气保护环境下,将TCFH(628mg,3.74mmol)加入步骤6产物(360mg,0.74mmol)和NMI(920mg,14.5mmol)的DMF(20mL)的溶液中。在25℃条件下将所得混合物搅拌1小时,然后用水淬灭后通过乙酸乙酯进行萃取。用盐水洗涤有机层、用Na2SO4干燥,然后过滤、浓缩。残余物经硅胶层析(DCM:MeOH=10:1)纯化后得160mg黄色固态目标产物。MS(ES+):463.8[M+1]+
步骤8 tert-butyl(S)-4-(26,36-二氟-12-异丙基-22,5-二氧代-21,22-二氢-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶杂-1(3,4)-吡啶杂-3(1,2)-苯杂环七蕃-24-基)-3-甲基哌嗪-1-甲酸叔丁酯(tert-butyl(S)-4-(26,36-difluoro-12-isopropyl-22,5-dioxo-21,22-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphane-24-yl)-3-methylpiperazine-1-carboxylate)
在室温搅拌以及氩气保护环境下,将POCl3(318mg,2.06mmol)加入步骤8产物(160mg,0.344mmol)和DIPEA(446mg,3.44mmol)溶于CH3CN(3mL)溶液中。在80℃条件下将所得混合物搅拌1小时,然后浓缩至干燥。将残余物溶于3mL的DMF中,所得溶液在室温以及氩气保护环境下用二异丙基乙胺(DIPEA)(244mg,1.9mmol)和叔丁基(S)-3-甲基哌嗪-1-羧酸盐(140mg,0.68mmol)进行处理。在25℃条件下搅拌2小时后,用水淬灭反应混合物,并用乙酸乙酯萃取。用盐水洗涤有机层、用Na2SO4干燥,然后过滤、浓缩。用制备薄层色谱纯化残余物(EtOAc:MeOH=15:1)纯化后得33mg黄色固态目标产物。MS(ES+):646.0[M+1]+。
步骤9(S)-24-(4-丙烯酰基-2-甲基哌嗪-1-基)-26,36-二氟-12-异丙基-21,22-二氢-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶-1(3,4)-吡啶杂-3(1,2)-苯杂环七蕃-22,5-二酮((S)-24-(4-acryloyl-2-methylpiperazin-1-yl)-26,36-difluoro-12-isopropyl-21,22-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphane-22,5-dione)
在室温搅拌条件以及氩气保护环境下,将三氟乙酸(TFA,0.5ml)加入步骤8产物(30mg,0.046mmol)的二氯甲烷(2mL)溶液中。在25℃条件下搅拌1小时后,将混合物浓缩至干燥,然后用2mL二氯甲烷(DCM)稀释。在室温条件以及氩气保护环境下用二异丙基乙胺(DIPEA)(24mg,0.186mmol)和丙烯酰氯(5mg,0.046mmol)处理所得溶液。在25℃条件下将所得混合物搅拌0.5小时,然后用水淬灭反应混合物,并用乙酸乙酯萃取。用盐水洗涤有机层、用Na2SO4干燥,然后过滤、浓缩。用制备薄层色谱纯化残余物(EtOAc:MeOH=15:1)纯化后得5.5mg黄色固态目标产物。MS(ES+):600.0[M+1]+。
1HNMR图谱:(400MHz,CD3OD)δ8.43(d,1H),8.24~8.21(m,1H),7.42~7.33(m,2H),7.00~6.96(m,2H),6.92~6.90(m,1H),6.2(d,1H),5.72(d,1H),5.22(m,1H),3.98(m,3H),3.52~3.51(m,1H),2.9(m,1H),2.74~2.67(m,2H),2.35(m,1H),2.14~2.06(m,1H),1.9(m,1H),1.3~1.1(m,6H),0.36~0.25(m,2H).
实施例2
(S)-24-(4-丙烯酰基-2-甲基哌嗪-1-基)-26,36-二氟-12-异丙基-21,22-二氢-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶杂-1(3,4)-吡啶杂-3(1,2)-苯杂环七蕃-22-酮((S)-24-(4-acryloyl-2-methylpiperazin-1-yl)-26,36-difluoro-12-isopropyl-21,22-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphan-22-one)
步骤1 26,36-二氟-24-羟基-12-异丙基-21,22-二氢-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶杂-1(3,4)-吡啶杂-3(1,2)-苯杂环七蕃-22-酮(26,36-difluoro-24-hydroxy-12-isopropyl-21,22-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphan-22-one)
在0℃搅拌以及氩气保护环境下,将硼烷-甲基硫醚络合物(10.0M,5.78ml,5.78mmol)加入实施例1步骤7产物(6.7g,14.5mmol)的1,2-二甲氧基乙烷(140ml)溶液中。在45℃条件下反应混合物搅拌2小时后,在0℃条件下用甲醇淬灭。搅拌2小时后,加水并用乙酸乙酯萃取反应混合物。用盐水洗涤有机层、用Na2SO4干燥,然后过滤、浓缩。残余物经硅胶层析(EA:PE=4:1)纯化,得到3.5g纯产物。MS(ES+):450.0[M+1]+。
步骤2(S)-4-(26,36-二氟-12-异丙基-22-氧代-21,22-二氢-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶杂-1(3,4)-吡啶杂-3(1,2)-苯杂环七蕃-24-基)-3-甲基哌嗪-1-甲酸叔丁酯(tert-butyl(S)-4-(26,36-difluoro-12-isopropyl-22-oxo-21,22-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphane-24-yl)-3-methylpiperazine-1-carboxylate)
在室温搅拌以及氩气保护环境下,将(4.09g,26.7mmol)POCl3加入(2g,4.3mmol)步骤1产物和DIPEA(5.74g,44.5mmol)的CH3CN(20mLl)溶液中。在80℃条件下将混合物搅拌0.5小时,然后浓缩至干燥。将残余物溶于20ml的DMF中,所得溶液在0℃条件下加入二异丙基乙胺(DIPEA)(2.87mg,22.3mmol)和(S)-3-甲基哌嗪-1-羧酸叔丁基酯(1.78g,8.9mmol)。在0℃条件下搅拌5分钟后,用水淬灭反应混合物,并用乙酸乙酯萃取。用盐水洗涤有机层、用Na2SO4干燥,然后过滤、浓缩。残余物经硅胶层析(EtOAc:MeOH=15:1)纯化后得1.54mg黄色固体目标产物。MS(ES+):632.0[M+1]+.
步骤3(S)-24-(4-丙烯酰基-2-甲基哌嗪-1-基)-26,36-二氟-12-异丙基-21,22-二氢-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶-1(3,4)-吡啶杂-3(1,2)-苯杂环七蕃-22-酮((S)-24-(4-acryloyl-2-methylpiperazin-1-yl)-26,36-difluoro-12-isopropyl-21,22-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphan-22-one)
在室温搅拌以及氩气保护环境下,将三氟乙酸(20mL)加入步骤2产物(2mg,3.17mmol)的二氯甲烷(20mL)溶液中。在室温条件下将所得混合物搅拌0.5小时,然后浓缩至干燥。将残余物溶于40ml二氯甲烷中,所得溶液在0℃条件下加入二异丙基乙胺(4.1g,31.7mmol)和丙烯酰氯(240mg,2.69mmol)。在0℃条件下搅拌5分钟后,反应完成,用水淬灭反应混合物,并用乙酸乙酯萃取。用盐水洗涤有机层、用Na2SO4干燥,然后过滤、浓缩。残余物经硅胶层析(EtOAc:MeOH=15:1)纯化后得1.38mg黄色固态目标产物。MS(ES+):586.0[M+1]+
1HNMR图谱:(400MHz,CDCl3)δ8.62(d,1H),7.85(dd,1H),7.25-7.21(m,2H),6.59-6.40(m,3H),5.84(d,1H),5.36(m,1H),4.8-3.2(m,7H),3.32(d,1H),3.1-2.79(m,3H),2.38-2.0(m,3H),1.63-1.52(m,3H),1.47-1.25(m,5H),1.03-0.78(d,3H).
实施例2A和2B
实施例2A:保留时间:4.6min,MS(ESI,m/e):586[M+1]+.
1H NMR(400MHz,DMSO-d6)δ8.47(d,J=5.0Hz,1H),8.25(d,J=9.6Hz,1H),7.39–7.22(m,2H),6.87(m,1H),6.69(d,J=8.2Hz,1H),6.62–6.53(t,1H),6.21(d,J=16.5Hz,1H),5.78(d,J=10.7Hz,1H),4.84(m,2H),4.51(d,J=13.9Hz,1H),4.33-3.98(m,3H),3.57(m,2H),3.31–3.11(m,2H),2.80(m,2H),2.42(m,1H),2.20(m,1H),2.04–1.84(m,1H),1.43–1.20(m,3H),1.08(d,J=6.4Hz,3H),0.88(d,J=6.7Hz,3H).
实施例2B:保留时间:5.7min,MS(ESI,m/e):586[M+1]+.
1H NMR(400MHz,DMSO-d6)δ8.47(m,2H),7.38–7.22(m,2H),6.89(m,1H),6.69(d,J=8.2Hz,1H),6.63–6.51(t,1H),6.23(m,1H),5.78(d,J=10.3Hz,1H),5.13(s,1H),4.80(d,J=6.6Hz,1H),4.31-3.70(m,6H),3.23(m,1H),2.93(m,1H),2.80(m,2H),2.60-2.44(m,1H),2.18(m,1H),1.90(m,1H),1.29–1.18(m,3H),1.12(d,J=7.0Hz,3H),0.87(d,J=6.6Hz,3H).
实施例3
(S)-2-(1-丙烯酰基-4-(26,36-二氟-12-异丙基-22,5-二氧代-21,22-二氢-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶杂-1(3,4)-吡啶杂-3(1,2)-苯杂环七蕃-24-基)哌嗪-2-基)乙腈((S)-2-(1-acryloyl-4-(26,36-difluoro-12-isopropyl-22,5-dioxo-21,22-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphane-24-yl)piperazin-2-yl)acetonitrile)
步骤1 benzyl(S)-4-(1-(4-(3-(叔丁氧基)-3-丙酰基)-2-异丙基吡啶-3-基)-7-氯-6-氟-2-氧代-1,2-吡啶并[2,3-d]嘧啶-4-基)-2-(氰甲基)哌嗪-1-甲酸苄酯(benzyl(S)-4-(1-(4-(3-(tert-butoxy)-3-oxopropyl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate)
起始于实施例1步骤4的产物(150mg,0.325mmol)和(S)-2-(氰基甲基)哌嗪-1-甲酸苄酯盐酸盐(192mg,0.649mmol),按照实施例1步骤8中描述的条件获得目标产物(256mg)。MS(ESI+):703.9[M+H]+
步骤2(2S)-4-(7-(2-氨基-6-氟苯基)-1-(4-(3-(叔丁氧基)-3-丙酰基)-2-异丙基吡啶-3-基)-6-氟-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2-(氰甲基)哌嗪-1-甲酸苄酯(benzyl(2S)-4-(7-(2-amino-6-fluorophenyl)-1-(4-(3-(tert-butoxy)-3-oxopropyl)-2-isopropylpyridin-3-yl)-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate)
起始于步骤1的产物(217mg,0.308mmol)、3-氟-2-(4,4,5,5-四甲基-1,3,2-二氧苯并呋喃-2-基)苯胺(146mg,0.616mmol)后,按照实施例1步骤5中所述条件获得黄色固态目标产物(158mg)。MS(ESI+):779.0[M+H]+。
步骤3 3-(3-(7-(2-氨基-6-氟苯基)-4-((S)-4-((苄氧基)碳酰基)-3-(氰甲基)哌嗪-1-基)-6-氟-2-氧代吡啶并[2,3-d]嘧啶-1(2H)-基)-2-异丙基吡啶-4-基)丙酸(3-(3-(7-(2-amino-6-fluorophenyl)-4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-6-fluoro-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-isopropylpyridin-4-yl)propanoic acid)
起始于步骤2的产物(158mg,0.203mmol)后,按照实施例1步骤6中所述条件获得黄色固态目标产物(152mg)。MS(ESI+):722.9[M+H]+.
步骤4(S)-2-(氰甲基)-4-(26,36-二氟-12-异丙基-22,5-二氧代-21,22-二氢-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶杂-1(3,4)-吡啶杂-3(1,2)-苯杂环七蕃-24-基)哌嗪-1-甲酸苄酯(benzyl(S)-2-(cyanomethyl)-4-(26,36-difluoro-12-isopropyl-22,5-dioxo-21,22-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphane-24-yl)piperazine-1-carboxylate)
起始于步骤3的产物(152mg,0.211mmol),按照实施例1步骤7中所述条件获得黄色固态目标产物(96mg)。MS(ES+):704.9[M+H]+.
步骤5(S)-2-(4-(26,36-二氟-12-异丙基-22,5-二氧代-21,22-二氢-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶杂-1(3,4)-吡啶杂-3(1,2)-苯杂环七蕃-24-基)哌嗪-2-基)乙腈((S)-2-(4-(26,36-difluoro-12-isopropyl-22,5-dioxo-21,22-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphane-24-yl)piperazin-2-yl)acetonitrile)
在室温搅拌条件下,将10%Pd/C(70mg)加入步骤4产物(70mg,0.099mmol)的甲醇(4ml)溶液中。将所得混合物在30℃以及氢气保护环境下搅拌1.5h后,将反应混合物过滤并浓缩,得到黄色固态目标产物(48mg)。MS(ES+):570.9[M+H]+.
步骤6(S)-2-(1-丙烯酰基-4-(26,36-二氟-12-异丙基-22,5-二氧代-21,22-二氢-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶杂-1(3,4)-吡啶杂-3(1,2)-苯杂环七蕃-24-基)哌嗪-2-基)乙腈((S)-2-(1-acryloyl-4-(26,36-difluoro-12-isopropyl-22,5-dioxo-21,22-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphane-24-yl)piperazin-2-yl)acetonitrile)
在5~10℃搅拌条件下,将丙烯酰氯(8mg,0.084mmol)加入步骤7产物(48mg,0.084mmol)及二异丙基乙胺(44mg,0.341mmol)的二氯甲烷(1mL)溶液中。在室温条件下搅拌1小时后,用水淬灭反应混合物,并用乙酸乙酯萃取。用盐水洗涤有机层、用Na2SO4干燥,然后过滤、浓缩。用制备薄层色谱纯化残余物(EtOAc:MeOH=10:1)纯化后得9mg黄色固态目标产物。MS(ES+):625.0[M+H]+.
1HNMR图谱:(400MHz,CDCl3)δ8.92(s,1H),8.54-8.53(d,J=4.4Hz,1H),7.99~7.96(m,1H),7.52~7.21(m,3H),7.01(m,1H),6.62(m,1H),6.48(m,1H),5.90-5.88(d,J=11.2Hz,1H),5.0~3.7(m,7H),3.0~2.8(m,5H),2.61(m,1H),2.33(m,1H),1.32~1.25(m,3H),1.08~1.06(m,3H).
实施例4
(S)-24-(4-丙烯酰基-2-甲基哌嗪-1-基)-26,36-二氟-12-异丙基-4-甲基-21,22-二氢-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶杂-1(3,4)-吡啶杂-3(1,2)-苯杂环七蕃-22-酮((S)-24-(4-acryloyl-2-methylpiperazin-1-yl)-26,36-difluoro-12-isopropyl-4-methyl-21,22-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphan-22-one)
在室温搅拌条件下,将CH3I(42mg,0.299mmol)加入实施例2(50mg,0.085mmol)和Cs2CO3(111mg,0.342mmol)的DMF(2ml)溶液中。在40℃条件下搅拌5小时后,用水处理反应混合物,并用乙酸乙酯萃取。用盐水洗涤有机层、用Na2SO4干燥,然后过滤、浓缩。用制备薄层色谱纯化残余物(EA:MeOH=15:1)纯化后得15mg黄色固体目标产物。MS(ES+):599.9[M+1]+。
1HNMR图谱:(400MHz,CDCl3)δ8.54-8.53(d,J=4Hz,1H),7.88-7.76(m,1H),7.40-7.26(q,1H),7.09-7.05(m,2H),6.93-6.89(t,1H),6.65(s,1H),6.44-6.39(d,J=20Hz,1H),5.83-5.80(d,J=12Hz,1H),5.51-4.57(m,2H),4.28-3.17(m,4H),2.95-2.86(m,3H),2.66-2.63(d,J=12Hz,1H),2.48-2.42(m,5H),1.89(s,1H),1.46-1.44(d,J=8Hz,2H),1.38-1.22(t,5H),1.15-0.86(m,3H).
实施例5
(S)-24-(4-丙烯酰基-2-甲基哌嗪-1-基)-26,36-二氟-12-异丙基-21,22-二氢-4,6-二氮杂-2(1,7)-吡啶并[2,3-d]嘧啶杂-1(3,4)-吡啶杂-3(1,2)-苯杂环八蕃-22,5-二酮((S)-24-(4-acryloyl-2-methylpiperazin-1-yl)-26,36-difluoro-12-isopropyl-21,22-dihydro-4,6-diaza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacyclooctaphane-22,5-dione)
步骤1 26,36-二氟-12-异丙基-21,22,23,24-四氢-4,6-二氮杂-2(1,7)-吡啶并[2,3-d]嘧啶杂-1(3,4)-吡啶杂-3(1,2)-苯杂环八蕃-22,24,5-三酮(26,36-difluoro-12-isopropyl-21,22,23,24-tetrahydro-4,6-diaza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacyclooctaphane-22,24,5-trione)
在搅拌条件下,将叠氮磷酸二苯酯(701.76mg,2.55mmol)加入实施例1步骤6的产物(408mg,0.85mmol)和三乙醇胺(TEA)(430.06mg,4.25mmol)的甲苯(15ml)溶液中。在75℃条件下将混合物搅拌1小时后,加入水(5mL)和乙酸乙酯(3mL)。将混合物搅拌0.5小时,过滤收集所得固体并干燥,得到180mg的黄色固体目标产物。MS(ES+):478.9[M+1]+。
步骤2(S)-24-(4-丙烯酰基-2-甲基哌嗪-1-基)-26,36-二氟-12-异丙基-21,22-二氢-4,6-二氮杂-2(1,7)-吡啶并[2,3-d]嘧啶杂-1(3,4)-吡啶杂-3(1,2)-苯杂环八蕃-22,5-二酮((S)-24-(4-acryloyl-2-methylpiperazin-1-yl)-26,36-difluoro-12-isopropyl-21,22-dihydro-4,6-diaza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacyclooctaphane-22,5-dione)
起始于步骤1的产物,按照实施例1中的步骤8和步骤9所述反应条件得到黄色固体目标产物。MS(ES+):614.9[M+1]+
1HNMR图谱:(400MHz,CDCl3)δ11.23(s,1H),8.59(s,1H),7.89(s,1H),7.43(s,1H),7.19(s,1H),7.03(s,1H),6.63(s,1H),6.44-6.40(d,J=16,1H),5.84-5.81(d,J=12,1H),4.77(s,2H),4.12-3.75(m,2H),3.65(m,2H),3.22(m,2H),2.66(m,1H),1.43(m,5H),1.32(m,3H),1.02(m,3H).
实施例6A和6B
26,36-二氟-24-((2S,5R)-4-(2-氟丙烯酰基)-2,5-二甲基哌嗪-1-yl)-12-异丙基-21,22-二氢-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶杂-1(3,4)-吡啶杂-3(1,2)-苯杂环七蕃-22-酮(26,36-difluoro-24-((2S,5R)-4-(2-fluoroacryloyl)-2,5-dimethylpiperazin-1-yl)-12-isopropyl-21,22-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphan-22-one)
步骤1(2R,5S)-4-(26,36-二氟-12-异丙基-22-氧代-21,22-二氢-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶杂-1(3,4)-吡啶杂-3(1,2)-苯杂环七蕃-24-基)-2,5-二甲基哌嗪-1-甲酸叔丁酯(tert-butyl(2R,5S)-4-(26,36-difluoro-12-isopropyl-22-oxo-21,22-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphane-24-yl)-2,5-dimethylpiperazine-1-carboxylate)
在搅拌条件下,将二异丙基乙胺(345mg,2.7mmol)和POCl3(414mg,2.7mmol)加入实施例2步骤1产物(120mg,0.27mmol)的CH3CN(18ml)溶液中。在80℃条件下搅拌混合物1h。将反应混合物减压浓缩,残余物溶解于(1ml)DMF中。所得溶液在0℃条件下用DIEA(172mg,1.4mmol)和(2R,5S)-2,5-二甲基哌嗪-1-甲酸叔丁酯((2R,5S)-tert-butyl 2,5-dimethylpiperazine-1-carboxylate)(64mg,0.3mmol)进行处理。在0℃条件下搅拌10分钟后,用水淬灭反应混合物,并用乙酸乙酯萃取。有机层用盐水洗涤、用Na2SO4干燥,然后过滤并浓缩,得到182mg黄色固体目标化合物。MS(ES+):645.9[M+1]+
步骤2 24-((2S,5R)-2,5-二甲基哌嗪-1-基)-26,36-二氟-12-异丙基-21,22-二氢-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶杂-1(3,4)-吡啶杂-3(1,2)-苯杂环庚烷-22-酮(24-((2S,5R)-2,5-dimethylpiperazin-1-yl)-26,36-difluoro-12-isopropyl-21,22-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphan-22-one)
再搅拌条件下,将三氟乙酸(1ml)加入步骤1步产物(182mg,0.28mmol)的二氯甲烷(1ml)溶液中。在室温搅拌1小时后,将反应混合物浓缩,用NaHCO3(水溶液)碱化至pH为7-8,然后使用乙酸乙酯进行萃取。有机层用盐水洗涤、用Na2SO4干燥,然后过滤并浓缩,得到141mg黄色固体目标化合物。MS(ES+):545.9[M+1]+.
步骤3 26,36-二氟-24-((2S,5R)-4-(2-丙烯酰基)-2,5-二甲基哌嗪-1-基)-12-异丙基-21,22-二氢-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶杂-1(3,4)-吡啶杂-3(1,2)-苯杂环七蕃-22-酮(26,36-difluoro-24-((2S,5R)-4-(2-fluoroacryloyl)-2,5-dimethylpiperazin-1-yl)-12-isopropyl-21,22-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphan-22-one)
将2-氟丙基-2-烯酸(2-fluoroprop-2-enoic acid)(9.37mg,0.1mmol)、二异丙基乙胺(84mg,0.65mmol)和丙基膦酸酐(T3P)(124mg,0.39mmol)加入步骤2产物(70mg,0.13mmol)的二氯甲烷(3ml)溶液中。在室温条件下搅拌10分钟后用(15ml)饱和NaHCO3水溶液淬灭反应物,然后使用二氯甲烷萃取。用盐水洗涤有机层、用Na2SO4干燥,然后过滤、浓缩。用制备薄层色谱(甲醇/乙酸乙酯=5%)纯化残余物,得到15.5mg的黄色固体实施例6A(快速洗脱),MS(ES+):617.9[M+1]+,以及15.2mg的黄色固体实施例6B(慢速洗脱),MS(ES+):617.9[M+1]+。
1HNMR图谱(实施例6A):(400MHz,CDCl3)δ8.47-8.46(d,J=4Hz,2H),7.34-7.26(m,2H),6.72-6.54(m,2H),5.37-5.32(m,2H),4.87-4.88(m,2H),4.75-4.25(m,1H),4.12-4.01(m,2H),3.78-3.63(m,1H),3.17(s,1H),2.84(m,1H),2.76-2.73(m,1H),2.45(m,1H),2.12-1.93(m,2H),1.27-1.09(m,10H),0.84-0.82(d,J=8Hz,3H).
1HNMR图谱(实施例6B):(400MHz,CDCl3)δ8.47-8.45(d,J=4Hz,1H),8.11(m,1H),7.33-7.24(m,2H),6.71-6.55(m,2H),5.37-5.32(d,J=20Hz,2H),4.88-4.61(m,3H),4.52-4.11(m,1H),3.88-3.46(m,2H),3.25(m,1H),2.89-2.73(m,2H),2.57(m,1H),2.18-1.91(m,2H),1.50-1.48(d,J=8Hz,2H),1.38-1.25(m,4H),1.08-1.06(d,J=8Hz,3H),0.93-0.91(d,J=8Hz,3H).
实施例7A和7B
24-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-26,36-二氟-12-异丙基-21,22-二氢-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶杂-1(3,4)-吡啶杂-3(1,2)-苯杂环七蕃-22-酮(24-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-26,36-difluoro-12-isopropyl-21,22-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphan-22-one)
在搅拌条件下,将T3P(0.123g,0.385mmol)加入实施例6A和6B步骤2产物(0.07g,0.128mmol)、丙烯酸(0.007g,0.103mmol)和二异丙基乙胺(0.083g,0.642mmol)的二氯甲烷(3ml)溶液中。在室温以及氩气保护环境下搅拌0.5小时后,用NaHCO3(水溶液)淬灭反应物并用二氯甲烷萃取,之后通过盐水洗涤有机层并用Na2SO4干燥,过滤后浓缩。用制备薄层色谱纯化残余物(MeOH:EA=7.5%),得到9.8mg的黄色固态示例7A产物(快速洗脱),MS(ES+):599.9[M+1]+,以及9.8mg的黄色固态实施例7B(慢速洗脱),MS(ES+):599.9[M+1]+.
1HNMR图谱(实施例7A):(400MHz,CDCl3)δ8.49(m,2H),7.34-7.26(m,1H),6.86-6.70(m,2H),6.59-6.55(m,1H),6.22-6.17(m,1H),5.77-5.74(m,1H),4.97-4.87(m,2H),4.75-4.25(m,1H),4.07-3.86(m,4H),2.84-2.66(m,3H),2.13-1.78(m,3H),1.36-1.24(d,2H),1.18(d,1H),1.17-1.06(m,3H),0.88-0.78(d,4H).
1HNMR图谱(实施例7B):(400MHz,CDCl3)δ8.46-8.45(d,J=4Hz,1H),8.12-8.06(m,1H),7.33-7.26(m,2H),6.87-6.55(m,3H),6.21-6.16(m,1H),5.78-5.75(m,1H),4.89-4.47(m,4H),4.27-3.56(m,3H),2.84-2.78(m,2H),2.46-1.87(m,2H),1.48-1.45(m,3H),1.32-1.28(m,3H),1.10-1.06(m,3H),0.92-0.78(m,3H).
实施例8
(S)-24-(4-丙烯酰基-2-甲基哌嗪-1-yl)-26,36-二氟-12-异丙基-21,22-二氢-8-硫杂-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶杂-1(3,4)-吡啶杂-3(1,2)-苯杂环八蕃-22-酮((S)-24-(4-acryloyl-2-methylpiperazin-1-yl)-26,36-difluoro-12-isopropyl-21,22-dihydro-8-thia-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacyclooctaphan-22-one)
步骤1 3-(3-氨基-2-异丁基吡啶-4-基硫)丙酸甲酯(methyl 3-(3-amino-2-isopropylpyridin-4-ylthio)propanoate)
在80℃条件以及氩气保护环境下,将4-碘代-2-异丙基吡啶-3-胺(625mg,2.385mmol)、3-巯基丙酸甲酯(716mg,5.964mmol)、二异丙基乙胺(1.231g,9.542mmol)、Pd2(dba)3(437mg,0.477mmol)和Xantphos(552mg,0.954mmol)的1,4-二氧六环(15ml)混合物搅拌2小时。用水淬灭反应混合物并用乙酸乙酯进行萃取。用盐水洗涤有机层、用Na2SO4干燥,然后过滤、浓缩。残余物经硅胶层析(EA:PE=1:1)纯化后得到582mg黄色固体目标产物。MS(ES+):255[M+1]+.
步骤2 3-(3-(3-(2,6-二氯-5-氟烟碱酰基)脲)-2-异丙基吡啶-4-基硫代)丙酸甲酯(methyl 3-(3-(3-(2,6-dichloro-5-fluoronicotinoyl)ureido)-2-isopropylpyridin-4-ylthio)propanoate)
起始于2,6-二氯-5-氟烟酰胺和步骤1产物,按照实施例1步骤3中所述步骤获得黄色固体目标产物。MS(ES+):489[M+1]+
步骤3 3-(3-(7-氯-6-氟-4-羟基-2-氧代吡啶并[2,3-d]嘧啶-1(2H)-基)-2-异丙基吡啶-4-基硫)丙酸甲酯(methyl 3-(3-(7-chloro-6-fluoro-4-hydroxy-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-isopropylpyridin-4-ylthio)propanoate)
在室温搅拌条件下将步骤2产物(900mg,1.844mmol)和K2CO3(509mg,3.689mmol)的DMF(15ml)混合物搅拌18小时。加入水然后用乙酸乙酯萃取混合物。有机层用盐水洗涤、用Na2SO4干燥,然后过滤并浓缩,得到804mg黄色固体目标产物。MS(ES+):453[M+1]+.
步骤4 3-(3-(7-(2-氨基-6-氟苯基)-6-氟-2,4-二氧代-3,4-二氢吡啶并[2,3-d]嘧啶-1(2H)-基)-2-异丙基吡啶-4-基硫)丙酸甲酯(methyl 3-(3-(7-(2-amino-6-fluorophenyl)-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-2-isopropylpyridin-4-ylthio)propanoate)
起始于步骤3产物和3-氟-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯胺(3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline)后,按照实施例1步骤5中所述步骤获得黄色固态目标产物。MS(ES+):527.8[M+1]+
步骤5 3-(3-(7-(2-胺基-6-氟苯基)-6-氟-2,4-二氧代-3,4-二氢吡啶并[2,3-d]嘧啶-1(2H)-基)-2-异丙基吡啶-4-基硫代)丙酸(3-(3-(7-(2-amino-6-fluorophenyl)-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-2-isopropylpyridin-4-ylthio)propanoic acid)
将步骤4产物(300mg,28.8mmol)溶于6N HCl/四氢呋喃(30ml/5ml)后得到的混合物在室温条件下搅拌过夜。用NaHCO3(水溶液)调节反应混合物的pH至5-6,并用乙酸乙酯萃取。有机层用盐水洗涤、用Na2SO4干燥,然后过滤并浓缩,得到360mg棕色固态目标产物。MS(ES+):513.8[M+1]+.
步骤6 26,36-二氟-12-异丙基-21,22,23,24-四氢-8-硫杂-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶杂-1(3,4)-吡啶杂-3(1,2)-苯杂环八蕃-22,24,5-三酮(26,36-difluoro-12-isopropyl-21,22,23,24-tetrahydro-8-thia-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacyclooctaphane-22,24,5-trione)
在室温搅拌以及氩气保护环境下,将溶于乙酸乙酯(50%质量百分比,2.2g,3.5mmol)的丙基膦酸酐加入步骤5产物(360mg,0.70mmol)的四氢呋喃(12ml)溶液中。在55℃条件下,搅拌反应混合物过夜。用NaHCO3(水溶液)调节反应混合物的pH至5-6,并用乙酸乙酯萃取。用盐水洗涤有机层、用Na2SO4干燥,然后过滤、浓缩。用制备薄层色谱纯化残余物(EA:MeOH=15:1)后得130mg黄色固体目标产物。MS(ES+):495.8[M+1]+
步骤7 26,36-二氟-12-异丙基-21,22,23,24-四氢-8-硫杂-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶杂-1(3,4)-吡啶杂-3(1,2)-苯杂环八蕃-22,24-二酮(26,36-difluoro-12-isopropyl-21,22,23,24-tetrahydro-8-thia-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacyclooctaphane-22,24-dione)
在0℃搅拌以及氩气保护环境下,将溶于四氢呋喃(1.0M,1.3ml,1.3mmol)的硼烷四氢呋喃络合物加入步骤6产物(130mg,0.26mmol)的四氢呋喃(7ml)溶液中。室温搅拌1小时后,在氩气保护以及0℃条件下,额外加入溶于四氢呋喃(1.0M,0.8ml,0.8mmol)的硼烷四氢呋喃络合物。在室温条件下将混合物再搅拌1小时,然后用水淬灭后通过乙酸乙酯进行萃取。用盐水洗涤有机层、用Na2SO4干燥,然后过滤、浓缩。用制备薄层色谱纯化残余物(EA:MeOH=15:1)纯化后得69mg白色固体目标产物。MS(ES+):481.9[M+1]+。
步骤8(S)-4-(26,36-二氟-12-异丙基-22-氧代-21,22-二氢-8-硫杂-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶杂-1(3,4)-吡啶杂-3(1,2)-苯杂环八蕃-24-基)-3-甲基哌嗪-1-甲酸叔丁酯(tert-butyl(S)-4-(26,36-difluoro-12-isopropyl-22-oxo-21,22-dihydro-8-thia-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacyclooctaphane-24-yl)-3-methylpiperazine-1-carboxylate)
得到步骤7产物和(S)-3-甲基哌嗪-1-甲酸叔丁酯后,按照实施例2步骤2中所述步骤获得黄色固体目标产物。MS(ES+):663.8[M+1]+。
步骤9(S)-24-(4-丙烯酰基-2-甲基哌嗪-1-基)-26,36-二氟-12-异丙基-21,22-二氢-8-硫杂-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶杂-1(3,4)-吡啶杂-3(1,2)-苯杂环八蕃-22-酮((S)-24-(4-acryloyl-2-methylpiperazin-1-yl)-26,36-difluoro-12-isopropyl-21,22-dihydro-8-thia-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacyclooctaphan-22-one)
起始与步骤8的产物,按照实施例2中的步骤3所述步骤得到黄色固态目标产物。MS(ES+):617.8[M+1]+.
1HNMR图谱:(400MHz,CDCl3)δ8.53-8.52(d,J=4Hz,1H),7.83(m,1H),7.26-7.21(m,1H),7.15-7.13(d,J=8Hz,1H),6.64(s,2H),6.42-6.38(m,3H),5.82-5.80(d,J=8Hz,1H),4.98-4.41(m,2H),4.38-3.61(m,3H),3.47-3.32(m,3H),3.14-3.02(m,3H),2.78(m,1H),2.22(m,1H),2.07-1.68(m,3H),1.64-1.55(m,2H),1.39-1.37(d,J=8Hz,2H),1.01-0.99(d,J=8Hz,3H).
实施例9
(S)-24-(4-丙烯酰基-2-甲基哌嗪-1-基)-26,36-二氟12-异丙基-21,22-二氢-7-硫杂-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶杂-1(3,4)-吡啶杂-3(1,2)-苯杂环七蕃-22-酮((S)-24-(4-acryloyl-2-methylpiperazin-1-yl)-26,36-difluoro-12-isopropyl-21,22-dihydro-7-thia-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphan-22-one)
步骤1 2-异丙基-4-((4-甲氧基苯基)硫)吡啶-3-胺(2-isopropyl-4-((4-methoxybenzyl)thio)pyridin-3-amine)
将4-碘代-2-异丙基吡啶-3-胺(4-iodo-2-isopropylpyridin-3-amine)(320mg,1.2mmol)、(4-甲氧基苯基)甲硫醇((4-methoxyphenyl)methanethiol)(376mg,2.4mmol)、二异丙基乙胺(630mg,4.9mmol)、Xantphos(283mg,0.49mmol)和Pd2(dba)3(224mg,0.24mmol)溶于二氧六环(10mL)中得到的混合液在90℃条件下搅拌2小时。在室温条件下用水淬灭反应物并用乙酸乙酯萃取。用盐水洗涤有机层、用Na2SO4干燥,然后过滤、浓缩。残余物经硅胶层析法(PE:EA=5:1)纯化后得到382mg黄色固体目标产物。MS(ES+):288.8[M+1]+。
步骤2 7-氯-6-氟-4-羟基-1-(2-异丙基-4-((4-甲氧基苯基)硫代)吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮(7-chloro-6-fluoro-4-hydroxy-1-(2-isopropyl-4-((4-methoxybenzyl)thio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one)
起始于步骤1产物和2,6-二氯-5-氟烟酰胺(2,6-dichloro-5-fluoronicotinamide),按照实施例1步骤3和步骤4所述程序获得白色固体目标产物。MS(ES+):486.9[M+1]+。
步骤3 2-((3-(7-氯-6-氟-4-羟基-2-氧代吡啶并[2,3-d]嘧啶-1(2H)-基)-2-异丙基吡啶-4-基)硫代)乙酸叔丁酯(tert-butyl 2-((3-(7-chloro-6-fluoro-4-hydroxy-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-isopropylpyridin-4-yl)thio)acetate)
在室温搅拌以及氩气保护环境下,将三氟甲磺酸酐(620.7mg,2.2mmol,溶于1ml的三氟乙酸中)加入步骤2产物(538mg,1.1mmol)的三氟乙酸(12ml)溶液中。在80℃条件下将所得混合物搅拌2.5小时,然后浓缩至干燥。将残余物溶于DMF(12ml),所得溶液用TEA(2.0g,19.8mmol)和溴乙酸叔丁酯(171.6mg,0.88mmol,溶于1mlDMF中)进行处理。搅拌30分钟后,加水并用乙酸乙酯萃取混合物。用盐水洗涤有机层、用Na2SO4干燥,然后过滤、浓缩。残余物经硅胶层析法(PE:EA=1:1)纯化后得到144mg黄色固体目标产物。MS(ES+):480.9[M+1]+。
步骤4 26,36-二氟-24-羟基-12-异丙基-21,22-二氢-7-硫杂-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶杂-1(3,4)-吡啶杂-3(1,2)-苯杂环八蕃-22,5-二酮(26,36-difluoro-24-hydroxy-12-isopropyl-21,22-dihydro-7-thia-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphane-22,5-dione)
起始于步骤3产物和3-氟-2-(四甲基-1,3,2-二氧苯并呋喃-2-基)苯胺,按照实施例1步骤5、步骤6和步骤7中所述步骤获得白色固体目标产物。MS(ES+):481.8[M+1]+。
步骤5(S)-24-(4-丙烯酰基-2-甲基哌嗪-1-基)-26,36-二氟-12-异丙基-21,22-二氢-7-硫杂-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶杂-1(3,4)-吡啶杂-3(1,2)-苯杂环七蕃-22-酮((S)-24-(4-acryloyl-2-methylpiperazin-1-yl)-26,36-difluoro-12-isopropyl-21,22-dihydro-7-thia-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphan-22-one)
起始于步骤4的产物,按照实施例8中的步骤7、步骤8和步骤9所述步骤得到黄色固态目标产物。MS(ES+):604.1[M+1]+.
1HNMR图谱:(400MHz,DMSO-d6)δ8.54-8.50(m,1H),8.48-8.47(d,J=4Hz,1H),8.34-8.32(m,1H),7.62-7.60(m,1H),7.46-7.42(m,1H),7.35-7.25(m,2H),6.88-6.84(m,1H),6.70-6.68(m,1H),6.65-6.60(t,1H),6.23-6.19(d,J=16Hz,1H),5.79-5.76(m,1H),4.24(m,1H),4.31-4.20(m,1H),3.99-3.95(m,2H),3.63-3.60(m,2H),3.01-2.93(m,3H),2.91-2.80(m,1H),2.57-2.54(m,1H),1.43(m,1H),1.24(m,3H),1.16-1.13(m,2H),1.12-1.11(m,3H),0.91-0.89(d,J=8Hz,3H).
实施例10
(S)-24-(4-丙烯酰基-2-甲基哌嗪-1-基)-36-氯-26-氟-12-异丙基-21,22-二氢-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶杂-1(3,4)-吡啶杂-3(1,2)-苯杂环七蕃-22-酮((S)-24-(4-acryloyl-2-methylpiperazin-1-yl)-36-chloro-26-fluoro-12-isopropyl-21,22-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphan-22-one)
步骤1 3-氯-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯胺(3-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline)
在105℃搅拌以及氩气保护环境下,将2-溴-3-氯苯胺(10g,48.43mmol)、4,4,5,5-四甲基-2-(四甲基-1,3,2-二氧杂硼烷-2-基)-1,3,2-二氧杂硼烷(15.99g,62.96mmol)、乙酸钾(14.26g,145.29mmol)和[1,1'-双(二苯基膦)二茂铁]二氯钯(II)(3.54g,4.84mmol)的1,4-二氧六环(150ml)混合物搅拌14小时。然后将混合物冷却至室温并通过助滤硅藻土层过滤,使用乙酸乙酯清洗滤饼。用盐水洗涤滤液,用Na2SO4干燥,过滤并浓缩后得到17.51g黑色油状粗产物。
步骤2 3-(3-(7-(2-氨基-6-氯苯基)-6-氟-2,4-二氧代-3,4-二氢吡啶并[2,3-d]嘧啶-1(2H)-基)-2-异丙基吡啶-4-基)丙酸叔丁酯(tert-butyl 3-(3-(7-(2-amino-6-chlorophenyl)-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-2-isopropylpyridin-4-yl)propanoate)
在搅拌条件下,将[1,1’-双(二苯基膦)二茂铁]二氯钯(II)合二氯甲烷(0.18g,0.22mmol)和H2O(1mL)的混合物加入实施例1步骤4产物和乙酸钾(0.64g,6.48mmol)的1,4-二氧六环(40mL)溶液中。将所得混合物在80℃以及氢气保护环境下搅拌2h。加入水然后用乙酸乙酯萃取反应混合物。用盐水洗涤有机层、用Na2SO4干燥,然后过滤、浓缩。残余物经硅胶层析(EA:PE=1:1)纯化后得到2.39g黄色固体目标产物。MS(ES+):553.8[M+1]+.
步骤3 3-(3-(7-(2-氨基-6-氯苯基)-6-氟-2,4-二氧代-3,4-二氢吡啶并[2,3-d]嘧啶-1(2H)-基)-2-异丙基吡啶-4-基)丙酸(3-(3-(7-(2-amino-6-chlorophenyl)-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-2-isopropylpyridin-4-yl)propanoic acid)
将步骤2产物(600mg,1.085mmol)溶于三氟乙酸(6mL)得到的混合液在室温条件下搅拌0.5小时。将反应混合物浓缩至干燥,得到859mg的棕色油状目标产物。MS(ES+):497.8[M+1]+。
步骤4 36-氯-26-氟-12-异丙基l-21,22,23,24-四氢-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶杂-1(3,4)-吡啶杂-3(1,2)-苯杂环七蕃-22,24,5-三酮(36-chloro-26-fluoro-12-isopropyl-21,22,23,24-tetrahydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphane-22,24,5-trione)
在室温搅拌以及氩气保护环境下,将T3P(3.78g,5.93mmol)加入步骤3产物(590mg,1.18mmol)的二氯乙烷(30mL)溶液中。在50℃条件下搅拌1h后,用饱和的NaHCO3(水溶液)淬灭反应,然后使用乙酸乙酯进行萃取。用盐水洗涤有机层、用Na2SO4干燥,然后过滤、浓缩。残余物经硅胶层析(MeOH/EA=2%)纯化后得到165mg黄色固体目标产物。MS(ES+):479.8[M+1]+。
步骤5 36-氯-26-氟-12-异丙基-21,22,23,24-四氢-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶杂-1(3,4)-吡啶杂-3(1,2)-苯杂环七蕃-22,24-二酮(36-chloro-26-fluoro-12-isopropyl-21,22,23,24-tetrahydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphane-22,24-dione)
起始于步骤4的产物,按照实施例2中的步骤1所述反应条件得到黄色固体目标化合物。MS(ES+):465.8[M+1]+。
步骤6(S)-24-(4-丙烯酰基-2-甲基哌嗪-1-基)-36-氯-26-氟-12-异丙基-21,22-二氢-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶杂-1(3,4)-吡啶杂-3(1,2)-苯杂环七蕃-22-酮((S)-24-(4-acryloyl-2-methylpiperazin-1-yl)-36-chloro-26-fluoro-12-isopropyl-21,22-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphan-22-one)
起始于5的产物,按照实施例2中的步骤2和步骤3所述步骤得到黄色固态目标产物。MS(ES+):601.8[M+1]+.
1HNMR图谱:(400MHz,CDCl3)δ8.58-8.57(d,J=4Hz,1H),7.93-7.87(m,1H),7.26-7.15(m,2H),6.88-6.86(d,J=8Hz,1H),6.73-6.71(d,J=8Hz,1H),6.60(s,1H),6.44-6.40(m,1H),5.84-5.81(d,J=12Hz,1H),5.46-5.30(m,1H),4.78-4.23(m,4H),3.85-3.39(m,3H),2.91-2.71(m,3H),2.30-1.94(m,2H),1.68-1.58(m,3H),1.39-1.37(d,J=8Hz,2H),1.29-1.26(m,3H),1.06-1.04(d,J=8Hz,3H).
实施例11
(S)-26,36-二氟-24-(4-(2-氟丙烯酰基)-2-甲基哌嗪-1-基)-12-异丙基-21,22-二氢-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶杂-1(3,4)-吡啶杂-3(1,2)-苯杂环七蕃-22-酮((S)-26,36-difluoro-24-(4-(2-fluoroacryloyl)-2-methylpiperazin-1-yl)-12-isopropyl-21,22-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphan-22-one)
起始于实施例2步骤2产物和2-氟丙烯酸,按照实施例6A和6B步骤2及步骤3中所述反应条件获得黄色固态目标化合物。MS(ES+):603.9[M+1]+.
1HNMR图谱:(400MHz,DMSO-d6)δ8.47-8.45(m,2H),7.73-7.25(m,2H),6.70-6.55(m,2H),5.41-5.36(m,3H),4.8-4.79(m,1H),4.50-3.45(m,6H),2.80-2.78(m,2H),2.51-2.44(m,2H),2.23-2.22(m,1H),1.98-1.88(m,1H),1.40-0.08(m,11H).
实施例12
(S)-4-乙酰基-24-(4-丙烯酰基-2-甲基哌嗪-1-基)-26,36-二氟-12-异丙基-21,22-二氢-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶杂-1(3,4)-吡啶杂-3(1,2)-苯杂环七蕃-22-酮
((S)-4-acetyl-24-(4-acryloyl-2-methylpiperazin-1-yl)-26,36-difluoro-12-isopropyl-21,22-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphan-22-one)
在室温搅拌条件下,将乙酰氯(17.6mg,0.22mmol)加入实施例2(50mg,0.085mmol)和二异丙基乙胺(58mg,0.45mmol)的二氯甲烷(2mL)溶液中。在40℃条件下搅拌2小时后,用饱和NaHCO3(水溶液)淬灭反应,并用乙酸乙酯萃取。用盐水洗涤有机层、用Na2SO4干燥,然后过滤、浓缩。用制备薄层色谱纯化残余物(EA:MeOH=5:1)纯化后得到21mg黄色固态目标产物。MS(ES+):627.9[M+1]+.
1HNMR图谱:(400MHz,CDCl3)δ8.49-8.48(d,J=4Hz,1H),7.88-7.83(t,1H),7.47(q,1H),7.18(t,1H),6.99(t,2H),6.62(s,1H),6.43(d,1H),5.84-5.81(d,J=12Hz,1H),5.13-4.37(m,2H),4.26-3.28(m,5H),3.26-2.66(m,3H),2.65-2.36(m,2H),2.04(s,1H),1.43-1.41(d,J=8Hz,2H),1.31-1.18(m,8H),1.01-0.99(d,J=8Hz,3H).
实施例13
((S)-24-(4-丙烯酰基-2-甲基哌嗪-1-基)-26,36-二氟-12-异丙基-22-氧代-21,22-二氢-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶杂-1(3,4)-吡啶杂-3(1,2)-苯杂环七蕃-4-N,N-二甲基甲酰胺
((S)-24-(4-acryloyl-2-methylpiperazin-1-yl)-26,36-difluoro-12-isopropyl-N,N-dimethyl-22-oxo-21,22-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphane-4-carboxamide)
在搅拌条件下,将二甲基氨基甲酰氯(18mg,0.171mmol)、二异丙基乙胺(33mg,0.256mmol)和二甲基氨基吡啶(10mg,0.085mmol)加入实施例2(50mg,0.085mmol)的二氯乙烷(3mL)溶液中。在80℃条件下将所得混合物搅拌过夜,然后用水淬灭,并用乙酸乙酯萃取。用盐水洗涤有机层、用Na2SO4干燥,然后过滤、浓缩。用制备薄层色谱纯化残余物(MeOH/EA=1:9),得到24.5mg黄色固体目标产物。MS(ES+):656.9[M+1]+.
1HNMR图谱:(400MHz,CDCl3)δ8.52(s,1H),7.88-7.86(d,J=8Hz,1H),7.36(s,1H),7.21(s,1H),7.07-7.05(d,J=8Hz,2H),6.64-6.63(d,J=4Hz,1H),6.44-6.40(d,J=16Hz,1H),5.84-5.81(m,1H),4.82-4.80(m,1H),4.78-3.56(m,4H),3.20(s,1H),2.89(s,1H),2.80-2.76(d,J=16Hz,2H),2.49(s,3H),1.46(m,3H),1.40-1.25(m,9H),1.08-0.97(m,5H).
实施例14
(S)-24-(4-丙烯酰基-2-甲基哌嗪-1-基)-26,36-二氟-12-异丙基-4-烟碱酰基-21,22-二氢-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶杂-1(3,4)-吡啶杂-3(1,2)-苯杂环七蕃-22-酮((S)-24-(4-acryloyl-2-methylpiperazin-1-yl)-26,36-difluoro-12-isopropyl-4-nicotinoyl-21,22-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphan-22-one)
在室温搅拌条件下,将吡啶-3-羧酸(29mg,0.239mmol)、2-氯-1,3-二甲基咪唑六氟磷酸盐(99mg,0.359mmol)和二异丙基乙胺(46mg,0.359mmol)加入实施例2(35mg,0.060mmol)溶于N-甲基吡咯烷酮(NMP)(3mL)得到的搅拌溶液中。在80℃条件下搅拌过夜后,用水淬灭反应混合物,并用乙酸乙酯萃取。用盐水洗涤有机层、用Na2SO4干燥,然后过滤、浓缩。用制备薄层色谱纯化残余物(MeOH/EA=1:9),得到5.8mg黄色固态目标产物。MS(ES+):690.8[M+1]+.
1HNMR图谱:(400MHz,CDCl3)δ8.52-8.48(m,2H),8.34(s,1H),7.90-7.85(m,1H),7.44-7.42(d,J=8Hz,1H),7.11(s,1H),7.07-7.03(m,3H),6.78(s,1H),6.68(s,1H),6.62-6.58(m,1H),6.44-6.40(d,J=16Hz,1H),5.85-5.82(d,J=12Hz,1H),5.34-4.81(m,1H),4.81-4.16(m,2H),4.11-3.93(m,3H),3.75-3.32(m,3H),2.81-2.64(m,3H),2.29-2.02(m,2H),1.15-0.73(m,9H).
实施例15
(S)-24-(4-丙烯酰基-2-甲基哌嗪-1-基)-26,36-二氟-4-(2-羟基-2-甲基丙酰基)-12-异丙基-21,22-二氢-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶杂-1(3,4)-吡啶杂-3(1,2)-苯杂环七蕃-22-酮((S)-24-(4-acryloyl-2-methylpiperazin-1-yl)-26,36-difluoro-4-(2-hydroxy-2-methylpropanoyl)-12-isopropyl-21,22-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphan-22-one)
在室温搅拌条件下,将CIP(45.6mg,0.164mmol)添加到实施例2(40mg,0.0816mmol)、2-羟基-2-甲基丙酸(25.6mg,0.245mmol)和二异丙基乙胺(8064mg,0.49mmol)的N-甲基吡咯烷酮(2mL)溶液中。在50℃条件下将所得混合物搅拌4小时,然后用水淬灭。然后用乙酸乙酯萃取反应混合物。用盐水洗涤有机层、用Na2SO4干燥,然后过滤、浓缩。用制备薄层色谱纯化残余物(EA:MeOH=5:1)后得到9mg黄色固体目标产物。MS(ES+):671.8[M+1]+.
1HNMR图谱:(400MHz,CDCl3)δ8.52-8.50(d,J=8Hz,1H),7.85(m,1H),7.44(m,1H),7.20(m,1H),7.16-7.04(m,2H),6.62-6.55(dd,1H),6.44-6.39(d,J=20Hz,1H),5.82-5.74(m,1H),4.74(s,1H),4.55-4.15(m,1H),4.03-3.82(m,1H),3.82-3.48(m,2H),3.49(s,1H),2.82(m,1H),2.54-2.37(m,2H),1.81(s,1H),1.65(s,1H),1.54-1.41(m,8H),0.99-0.97(d,J=8Hz,3H),0.90-0.76(m,8H)。
实施例16
(S)-24-(4-丙烯酰基-2-甲基哌嗪-1-基)-26,36-二氟-12-异丙基-4-甲基-21,22-二氢-4,6-二氮杂-2(1,7)-吡啶并[2,3-d]嘧啶-1(3,4)-吡啶-3(1,2)-苯杂环八蕃-22,5-二酮
((S)-24-(4-acryloyl-2-methylpiperazin-1-yl)-26,36-difluoro-12-isopropyl-4-methyl-21,22-dihydro-4,6-diaza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacyclooctaphane-22,5-dione)
在搅拌下,将碘甲烷(48.0mg,0.336mmol)添加到实施例5产物(5.2mg,0.007mmol)和碳酸铯(27.5mg,0.084mmol)的DMF(0.9ml)溶液混合物中。在室温条件下,将混合溶液搅拌过夜,然后用水淬灭并用乙酸乙酯萃取。有机层用盐水洗涤、Na2SO4干燥,然后过滤并浓缩,得到3.7mg黄色固态目标产物。MS(ES+):628.8[M+1]+。
1HNMR图谱:(400MHz,CDCl3)δ8.57-8.56(d,J=4Hz,1H),7.85-7.83(d,J=8Hz,1H),7.52(m,1H),7.16-7.11(m,3H),6.65(s,1H),6.44-6.40(m,1H),5.84-5.81(d,J=12Hz,1H),5.36-5.33(m,1H),4.78-4.46(m,3H),4.21(m,1H),4.01-3.64(m,1H),3.58-3.20(m,1H),3.12(m,4H),2.85(m,1H),2.62(m,1H),2.21(m,1H),2.01(m,1H),1.47-1.41(m,3H),1.29-1.25(m,4H),1.01(m,3H)。
实施例17
(S)-24-(4-丙烯酰基-2-甲基哌嗪-1-基)-26,36-二氟-16-异丙基-21,22-二氢-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶-1,3(1,2)-二苯杂环七蕃-22-酮
((S)-24-(4-acryloyl-2-methylpiperazin-1-yl)-26,36-difluoro-16-isopropyl-21,22-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacycloheptaphan-22-one)
步骤1 2-溴-6-异丙基苯胺
将溴代丁二酰亚胺(1.31g,7.4mmol)一次性添加到2-异丙基苯胺(1.00g,7.4mmol)的苯(40.0mL)溶液中。室温下搅拌过夜后。在减压条件下,推算出反应混合物的体积减少了四分之一,并过滤掉固体物质。浓缩滤液,加入戊烷和冰块,再加入0.4mL乙酸酐。大约15分钟后,过滤掉固体物质。从滤液中分离出戊烷溶液,用NH4OH清洗,并浓缩。在83℃、0.2mmHg下蒸馏残余物,得到目标化合物(600.0mg)。
1H NMR(400MHz,DMSO-d6):δ7.22(d,1H),7.04(d,1H),6.53-6.49(t,1H),4.98(s,2H),3.07-3.03(m,1H),6.15(d,6H)。
步骤2(E)-3-(2-氨基-3-异丙基苯基)丙烯酸叔丁酯
将2-溴-6-异丙基苯胺(50.0mg,4.70mmol)、丙烯酸叔丁酯(59.6mg,0.467mmol)、K2CO3(64.0mg,0.46mmol)、Pd(OAc)2(10.0mg,0.045mmol)和三邻甲苯膦(28.0mg,0.093mmol)溶于DMF(15mL)中,在100℃以及氩气保护环境下,持续加热2小时。用水淬灭反应混合物,并用乙酸乙酯(10mL×2)萃取。用Na2SO4干燥合并有机相,并浓缩。经硅胶层析纯化残余物,用乙酸乙酯/己烷(0-10%)进行梯度洗脱,得到40mg目标化合物。MS(ESI+):262.1[M+1]+。
1H NMR(400MHz,DMSO-d6):δ7.86(d,1H),7.27(d,1H),7.07(d,1H),6.58-6.54(t,1H),6.21(d,1H),5.23(s,2H),3.06-3.00(m,1H),1.48(s,9H),1.13(d,6H)。
步骤3(E)-3-(2-(3-(2,6-二氯-5-氟烟酰基)脲基)-3-异丙基苯基)丙烯酸叔丁酯
得到2,6-二氯-5-氟烟酰胺和步骤2产物后,按照实施例1步骤3中所述步骤获得黄色固态目标产物。MS(ESI+):496.1[M+1]+。
1H NMR(400MHz,DMSO-d6):δ11.37(s,1H),9.60(s,1H),8.52(d,1H),7.72-7.66(m,2H),7.44(d,1H),7.38-7.34(t,1H),6.47(d,1H),3.31-3.12(m,1H),1.47(s,9H),1.17(d,6H)。
步骤4(E)-3-(2-(7-氯-6-氟-2,4-二氧代-3,4-二羟基吡啶并[2,3-d]嘧啶-1(2H)-基)-3-异丙基苯基)丙烯酸叔丁酯
得到步骤3的产物后,按照实施例8中的步骤3所述步骤得到黄色固态目标产物。
1HNMR(400MHz,CDCl3):δ8.55(s,1H),8.24(d,1H),7.64-7.62(dd,1H),7.55-7.50(m,2H),7.25(d,1H),6.36(d,1H),2.58-2.54(m,1H),1.45(s,9H),1.18(d,3H),1.07(d,3H)。
步骤5 2-氟-6-硝基苯基三氟甲磺酸酯
在0℃条件下冷却后,将吡啶(6.15mL,76.43mmol)和Tf2O(12.86mL,76.43mmol)添加到2-氟-6-硝基苯酚(10.0g,63.69mmol)的二氯甲烷(200.0mL)溶液中。搅拌2小时后,用NaHCO3(水溶液)淬灭反应混合物,并用二氯甲烷萃取。用1N盐酸溶液洗涤二氯甲烷层,在MgSO4干燥并浓缩,得到目标化合物的粗产物(17.0g)。
1HNMR(400MHz,CDCl3):δ8.00-7.97(m,1H),7.64-7.54(m,2H)。
步骤6 2-(2-氟-6-硝基苯基)-4,4,5,5-四甲基-1,3,2-二氧硼戊环
将双(频哪醇合)二硼(381.0mg,1.50mmol)、乙酸钾(295.0mg,3.0mmol)和Pd(dppf)Cl2(82.0mg,0.1mmol)以及4滴水加入步骤5产物(290.0mg,1.0mmol)的二氧六环(3.0mL)溶液中。80℃条件下搅拌2.5小时后,使用助滤硅藻土层过滤反应混合物。浓缩滤液,经硅胶层析纯化残余物,用乙酸乙酯/己烷(0-20%)进行梯度洗脱,得到目标化合物(250.0mg)。
1HNMR(400MHz,CDCl3):δ8.03(d,1H),7.56-7.50(m,1H),7.39-7.35(t,1H),1.45(s,12H)。
步骤7 3-氟-2-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯胺
在氮气环境下,将10%Pd/C(992mg,0.93mmol)添加到2-(2-氟-6-硝基苯基)-4,4,5,5-四甲基-1,3,2-二氧硼戊环(2.49g,9.32mmol)的乙酸乙酯(40mL)溶液中。然后在室温氢气环境下,搅拌混合溶液16.5小时。使用助滤硅藻土层过滤反应混合物,然后用乙酸乙酯洗涤助滤硅藻土层。浓缩滤液,得到目标化合物(2.2g)。MS(ESI+):238.1[M+1]+.
步骤8(E)-3-(2-(7-(2-氨基-6-氟苯基)-6-氟-2,4-二氧代-3,4-二羟基吡啶并[2,3-d]嘧啶-1(2H)-基)-3-异丙基苯基)丙烯酸叔丁酯
在氩气保护环境下,将K2CO3(60.0mg,0.436mmol)和Pd(dppf)Cl2(18.0mg,0.022mmol)加入步骤4产物(100.0mg,0.218mmol)和步骤7产物(155.0mg,0.654mmol)的二氧六环(3.0mL)溶液。在80℃条件下搅拌2小时后,用水(10mL)淬灭反应混合物,并用乙酸乙酯(10mLx 2)萃取。用Na2SO4干燥合成的萃取物,过滤并浓缩。经硅胶层析纯化残余物,用乙酸乙酯/己烷(0-20%)进行梯度洗脱,得到目标化合物(120mg)。MS(ESI+):479.1[M-55]+。
步骤9
3-(2-(7-(2-氨基-6-氟苯基)-6-氟-2,4-二氧代-3,4-二羟基吡啶并[2,3-d]嘧啶-1(2H)-基)-3-异丙基苯基)丙酸叔丁酯
将Pd/C(24mg,0.023mmol)加入步骤8产物(120.0mg,0.225mmol)溶于甲醇(5mL)和7M NH3/MeOH(0.05mL)得到的溶液中。在室温条件下,搅拌混合溶液2小时,再使用助滤硅藻土层过滤,然后浓缩滤液,得到目标化合物(118.0mg)。MS(ESI+):481.1[M-55]+。
步骤10
3-(2-(7-(2-氨基-6-氟苯基)-6-氟-2,4-二氧代-3,4-二羟基吡啶并[2,3-d]嘧啶-1(2H)-基)-3-异丙基苯基)丙酸
在0℃条件下,将步骤9产物(118.0mg,0.22mmol)添加到4N盐酸溶液/二氧六环溶液(4.0mL)中。0℃条件下搅拌10分钟后,室温下静止反应混合物2小时。将反应混合物浓缩至干燥,得到目标化合物的粗产物(100.0mg)。MS(ESI+):481.1[M+1]+。
步骤11
26,36-二氟-16-异丙基-21,22,23,24-四氢-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶-1,3(1,2)-二苯杂环七蕃-22,24,5-三酮(26,36-difluoro-16-isopropyl-21,22,23,24-tetrahydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacycloheptaphane-22,24,5-trione)
得到步骤10的产物后,按照实施例1中的步骤7所述步骤得到黄色固态目标产物。MS(ESI+):463.1[M+1]+。
步骤12
26,36-二氟-16-异丙基-21,22,23,24-四氢-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶-1,3(1,2)-二苯杂环七蕃-22,24-二酮(26,36-difluoro-16-isopropyl-21,22,23,24-tetrahydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacycloheptaphane-22,24-dione)
得到步骤11的产物后,按照实施例2中的步骤1所述步骤得到黄色固态目标产物。MS(ESI+):449.1[M+1]+。
步骤13
(S)-24-(4-丙烯酰基-2-甲基哌嗪-1-基)-26,36-二氟-16-异丙基-21,22-二氢-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶-1,3(1,2)-二苯杂环七蕃-22-酮((S)-24-(4-acryloyl-2-methylpiperazin-1-yl)-26,36-difluoro-16-isopropyl-21,22-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacycloheptaphan-22-one)
在室温以及氩气保护环境下,将POCl3(20mg,0.134mmol)加入步骤12产物(10.0mg,0.022mmol)和二异丙基乙胺(28.4mg,0.22mmol)的CH3CN溶液(1.0ml)中。在80℃条件下搅拌1小时后,将反应混合物浓缩至干燥。将残余物溶于DMF(1.0mL)溶液中,然后加入二异丙基乙胺(28.4mg,0.22mmol)和中间体2(13.0mg,0.044mmol)。室温搅拌过夜后,加入乙酸乙酯(10mL),用水(8mL x 3)、盐水(8mL x 2)洗涤乙酸乙酯层,然后用Na2SO4干燥,并浓缩。经硅胶层析纯化残余物,用甲醇/二氯甲烷(0-5%)进行梯度洗脱,得到6.0mg目标化合物。MS(ESI+):585.1[M+1]+.
1HNMR(400MHz,CDCl3):δ7.88-7.81(m,1H),7.41-7.37(t,1H),7.29-7.20(m,3H),7.69-7.59(m,1H),6.55-6.47(m,2H),6.43-6.39(m,1H),5.82(d,1H),4.87-4.73(m,1H),4.68-4.56(m,1H),4.18-4.13(m,1H),3.97-3.87(m,1H),3.78-3.68(m,1H),3.56-3.36(m,1H),3.30-3.23(m,1H),3.00-2.94(m,1H),2.88-2.84(m,1H),2.67-2.61(m,1H),2.41-2.31(m,2H),2.03-1.99(m,2H),1.23-1.22(m,3H),1.21-1.20(m,3H),0.95-0.94(m,3H)。
实施例18
(S)-24-(4-丙烯酰基-2-甲基哌嗪-1-基)-26,36-二氟-16-异丙基-21,22-二氢-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶-1,3(1,2)-二苯杂环七蕃-22,5-二酮((S)-24-(4-acryloyl-2-methylpiperazin-1-yl)-26,36-difluoro-16-isopropyl-21,22-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacycloheptaphan-22,5-dione)
得到实施例17步骤11的产物和中间体2后,按照实施例17步骤13中所述步骤获得黄色固态目标产物。MS(ESI+):599.1[M+1]+。
1HNMR(400MHz,CDCl3):δ7.89-7.80(m,1H),7.73-7.70(m,1H),7.53-7.33(m,4H),7.16-7.10(m,1H),7.03-6.97(m,1H),6.86-6.77(m,1H),6.69-6.51(m,1H),6.45-6.38(m,1H),5.84-5.81(m,1H),4.33-3.98(m,4H),3.77-3.60(m,2H),3.09-2.98(m,1H),2.93-2.85(m,1H),2.82-2.76(m,1H),2.63-2.57(m,1H),2.37-2.33(m,1H),2.22-2.20(m,1H),1.22-1.06(m,6H),0.90-0.89(m,3H).
实施例19
(S)-24-(4-丙烯酰基-2-甲基哌嗪-1-基)-26,36-二氟-16-异丙基-4-甲基-21,22-二氢-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶-1,3(1,2)-二苯杂环七蕃-22-酮((S)-24-(4-acryloyl-2-methylpiperazin-1-yl)-26,36-difluoro-16-isopropyl-4-methyl--21,22-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacycloheptaphan-22-one)
将K2CO3(11.8mg,0.086mmol)和CH3I(18.2mg,0.13mmol)添加到实施例17产物(25mg,0.043mmol)的DMF(1.0mL)溶液中。在40℃条件下,搅拌反应混合物3小时,再加入CH3I(36.4mg,0.26mmol),然后在室温条件下将反应混合物搅拌过夜。加入(5mL)水然后用乙酸乙酯(10mL)萃取混合物。用水(5mL x 3)、盐水(5mL)洗涤有机层,用Na2SO4干燥,并过滤。浓缩滤液,经硅胶层析纯化残余物,用甲醇/二氯甲烷(0-3%)进行梯度洗脱,得到目标化合物(10mg,得率39%)。MS(ESI+):599.1[M+1]+。
1HNMR(400MHz,CDCl3):δ7.75-7.73(m,1H),7.34-26(m,3H),7.14-7.12(m,1H),7.02-7.00(m,1H),6.88-6.83(m,1H),6.68-6.54(m,1H),6.41(d,1H),5.81(d,1H),5.40-5.33(m,1H),4.90-4.75(m,1H),4.68-4.50(m,1H),4.19-4.14(m,1H),3.98-3.86(m,1H),3.81-3.71(m,1H),3.59-3.50(m,1H),3.46-3.38(m,1H),3.26-3.12(m,1H),3.06-3.00(m,1H),2.81-2.74(m,1H),2.59-2.54(m,1H),2.44-2.42(m,4H),1.94-1.85(m,1H),1.25-1.23(m,3H),0.98-0.96(m,3H)。
实施例20
24-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-26,36-二氟-16-异丙基-21,22-二氢-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶-1,3(1,2)-二苯杂环七蕃-22-酮24-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-26,36-difluoro-16-isopropyl-21,22-dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacycloheptaphan-22-one
步骤1
24-((2S,5R)-(4-(3-氯丙酰基)-2,5-二甲基哌嗪-1-基)-26,36-二氟-16-异丙基-21,22-二氢-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶-1,3(1,2)-二苯杂环七蕃-22-酮
得到实施例17步骤12的产物(25mg)和中间体4(46mg)后,按照实施例17步骤13中所述步骤获得黄色固态目标产物。MS(ESI+):635.1[M+1]+.
步骤2
24-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-26,36-二氟-16-异丙基-21,22-二氢-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶-1,3(1,2)-二苯杂环七蕃-22-酮
将三乙胺(112.7mg)加入步骤1产物(20mg)溶于乙腈(1.0mL)得到的溶液中。在80℃条件下搅拌12小时后,用乙酸乙酯(10mL)稀释反应混合物,然后用水(8mL x 2)、盐水(8mL)洗涤,并用Na2SO4干燥。浓缩溶液,得到目标化合物(20mg)。MS(ESI+):599.1[M+1]+。
实施例20A和20B
采用硅胶层析法分离实施例20(约20mg),经硅胶层析纯化残余物,用甲醇/二氯甲烷(0-5%)进行梯度洗脱,得到黄色固态实施例20A(8mg,快速洗脱)和实施例20B(7.0mg,缓慢洗脱)。
实施例20A:1HNMR(400MHz,CDCl3):δ7.83-7.78(m,1H),7.41-7.38(m,1H),7.28-7.20(m,3H),6.61-6.47(m,3H),6.44-6.35(t,1H),5.81-5.78(m,1H),5.12-5.10(m,1H),5.01-4.97(m,1H),4.41-4.30(m,1H),4.15-4.08(m,1H),4.00-3.00(m,2H),3.72-3.64(m,1H),3.32-3.29(m,1H),3.01-2.96(m,1H),2.89-2.82(m,1H),2.66-2.58(m,1H),2.44-2.32(m,2H),2.02-1.99(m,1H),1.40-1.39(m,3H),1.22-1.17(m,6H),0.91-0.89(m,3H)。
MS(ESI+):599.1[M+1]+。
实施例20B:1HNMR(400MHz,CDCl3):δ7.89-7.82(m,1H),7.40-7.36(m,1H),7.28-7.19(m,3H),6.66-6.55(m,1H),6.53-6.40(m,3H),5.83-5.78(m,1H),5.20-5.13(m,1H),4.94-4.88(m,1H),4.80-4.74(m,1H),4.54-4.46(m,1H),4.44-4.39(m,1H),3.74-3.63(m,2H),3.58-3.53(m,1H),3.31-3.26(m,1H),3.22-3.19(m,1H),3.00-2.95(m,1H),2.89-2.84(m,1H),2.64-2.58(m,1H),2.38-2.33(m,1H),2.00-1.97(m,1H),1.64-1.62(m,3H),1.50-1.48(m,3H),1.22-1.17(m,3H),1.00-0.96(m,3H)。
MS(ESI+):599.1[M+1]+。
实施例21
(S)-24-(4-丙烯酰基-2-甲基哌嗪-1-基)-26,36-二氟-16-异丙基-21,22-二氢-4,8-二氮杂-2(1,7)-吡啶并[2,3-d]嘧啶-1,3(1,2)-二苯杂环七蕃-22,5-二酮((S)-24-(4-acryloyl-2-methylpiperazin-1-yl)-26,36-difluoro-16-isopropyl-21,22-dihydro-4,8-diaza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacyclooctaphane-22,5-dione)
步骤1 3-((3-溴-2-硝基苯基)氨基)丙酸叔丁酯
在80℃条件下,搅拌1-溴-3-氟-2-硝基苯(0.6918g,3.145mmol)、3-氨基丙酸叔丁酯盐酸盐(0.6436g,3.543mmol)和二异丙基乙胺(1.55mL,9.38mmol)的15mL DMA溶液,持续23小时。加水(80mL),并用乙酸乙酯(4x20mL)萃取混合物。用水(3x20mL)、盐水洗涤合并的有机层,然后用Na2SO4干燥、过滤、浓缩,得到黄色油状目标化合物(1.0g)。
1HNMR(400MHz,CDCl3)δ7.15(t,J=8.2Hz,1H),6.96(dd,J=7.8,0.9Hz,1H),6.77(d,J=8.4Hz,1H),5.84(s,1H),3.46(dd,J=12.3,6.3Hz,2H),2.55(t,J=6.5Hz,2H),1.47(s,9H)。
步骤2 3-((3-溴-2-硝基苯基)(叔丁氧羰基)氨基)丙酸叔丁酯
在室温条件下,将二碳酸二叔丁酯(1.20mL,5.22mmol)添加到步骤1产物(0.4405g,1.276mmol)、4-二甲基氨基吡啶(0.1614g,1.321mmol)和二异丙基乙胺(0.86mL,5.22mmol)的5mL干DMF溶液中。在80℃条件下,搅拌反应混合物23小时。加水(80mL),并用乙酸乙酯(4x20mL)萃取反应混合物。用水(3x20mL)、盐水洗涤合并的有机层,然后用Na2SO4干燥、过滤、浓缩。残余物经硅胶层析(洗脱剂:乙酸乙酯:己烷/0:100至10:90),得到棕色油状目标化合物(0.3688g)。MS(ESI+):467.1,469.1[M+23]+。
步骤3 3-((叔丁氧羰基)(2-硝基-3-(丙-1-烯-2-基)苯基)氨基)丙酸叔丁酯
在80℃的氩气保护环境下,将步骤2产物(0.36g,1.04mmol)、异丙烯硼酸频哪醇酯(0.45mL,2.39mmol)、四(三苯基膦)钯(0.0956g,0.0827mmol)和K2CO3(0.4138g,2.994mmol)加入到20mL 1,4-二氧六环与4mL水中,将反应混合物搅拌3小时。加入20mL乙酸乙酯和20mL盐水。用Na2SO4干燥有机层,过滤、浓缩,然后采用硅胶层析法提纯,再用石油醚/乙酸乙酯(100:0至90:10)进行梯度洗脱,得到红色油状目标化合物(0.2838g)。MS(ESI+):429.2[M+23]+。
步骤4 3-((2-氨基-3-异丙基苯基)(叔丁氧羰基)氨基)丙酸叔丁酯
在室温条件下,使用氢气球,将步骤3产物(0.28g,0.69mmol)和10%Pd/C(0.164g,0.155mmol)溶于25mL乙酸乙酯,搅拌1小时,使用助滤硅藻土层过滤反应混合物,并将滤液进行浓缩。将残余物溶于20mL甲醇中,然后用兰尼镍(3.1g)进行处理。在30℃条件下,使用氢气球,搅拌反应混合物2小时。使用助滤硅藻土层过滤反应混合物,并将滤液进行浓缩,得到无色油状目标化合物(0.2514g)。MS(ESI+):379.2[M+1]+。
步骤5
3-((叔丁氧羰基)(2-(3-(2,6-二氯-5-氟烟酰基)脲基)-3-异丙基苯基)氨基)丙酸叔丁酯
得到2,6-二氯-5-氟烟酰胺(3.67g)和步骤4产物(3.58g)后,按照实施例1步骤3中所述步骤获得白色固态目标产物(3.8g)。MS(ESI+):611.2[M-1]+。
步骤6
3-((叔丁氧羰基)(2-(7-氯-6-氟-2,4-二氧代-3,4-二羟基吡啶并[2,3-d]嘧啶-1(2H)-基)-3-异丙基苯基)氨基)丙酸叔丁酯
得到2,6-二氯-5-氟烟酰胺(3.67g)和步骤5产物(3.35g)后,按照实施例8步骤3中所述步骤获得白色固态目标产物(1.94g)。MS(ESI+):575.1[M-1]+。
步骤7
3-((2-(7-氯-6-氟-2,4-二氧代-3,4-二羟基吡啶并[2,3-d]嘧啶-1(2H)-基)-3-异丙基苯基)氨基)丙酸
在室温条件下,搅拌步骤6产物(0.8295g,1.437mmol)溶于三氟乙酸(10.0mL)和二氯甲烷(10mL)得到的溶液,持续5小时。加入甲苯(10mL),浓缩混合物,得到灰色固态目标化合物(0.80g)。MS(ESI+):421.1[M+1]+.
步骤8
3-((2-(7-(2-氨基-6-氟苯基)-6-氟-2,4-二氧代-3,4-二羟基吡啶并[2,3-d]嘧啶-1(2H)-基)-3-异丙基苯基)氨基)丙酸
得到步骤7产物(0.6g)和3-氟-2-(4,4,5,5-四甲基-1,3,2-二氧苯并呋喃-2-基)苯胺(0.50g)后,按照实施例17步骤8中所述步骤获得白色固态目标产物(0.66g)。MS(ESI+):496.2[M+1]+。
步骤9
26,36-二氟-16-异丙基-21,22,23,24-四氢-4,8-二氮杂-2(1,7)-吡啶并[2,3-d]嘧啶-1,3(1,2)-二苯杂环八蕃-22,24,5-三酮
得到步骤8产物(0.24g)后,按照实施例1步骤7所述步骤得到灰色固态目标产物(0.11g)。MS(ESI+):632.0[M+1]+.
步骤10
(S)-24-(4-丙烯酰基-2-甲基哌嗪-1-基)-26,36-二氟-16-异丙基-21,22-二氢-4,8-二氮杂-2(1,7)-吡啶并[2,3-d]嘧啶-1,3(1,2)-二苯杂环八蕃-22,5-二酮
得到步骤9的产物(44mg)和中间体1(69mg)后,按照实施例17步骤13中所述步骤得到白色固态目标产物(12mg),但粗产物采用反相硅胶柱层析法(C-18,粒径:40μm,孔径分布:),用CH3CN/H2O(10-80%)进行洗脱。MS(ESI+):614.3[M+1]+.
实施例22
(S)-24-(4-丙烯酰基-2-甲基哌嗪-1-基)-26,36-二氟-16-异丙基-21,22-二氢-4,8-二氮杂-2(1,7)-吡啶并[2,3-d]嘧啶-1,3(1,2)-二苯杂环八蕃-22-酮
((S)-24-(4-acryloyl-2-methylpiperazin-1-yl)-26,36-difluoro-16-isopropyl-21,22-dihydro-4,8-diaza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacyclooctaphan-22-one)
步骤1
26,36-二氟-16-异丙基-21,22,23,24-四氢-4,8-二氮杂-2(1,7)-吡啶并[2,3-d]嘧啶-1,3(1,2)-二苯杂环八蕃-22,24-二酮
得到实施例21步骤9的产物(190mg)后,按照实施例1步骤7中所述步骤获得黄色固态目标产物(70mg)。MS(ESI+):464.2[M+1]+。
步骤2
(S)-24-(4-丙烯酰基-2-甲基哌嗪-1-基)-26,36-二氟-16-异丙基-21,22-二氢-4,8-二氮杂-2(1,7)-吡啶并[2,3-d]嘧啶-1,3(1,2)-二苯杂环八蕃-22-酮
得到步骤1的产物(50mg)和中间体1(101mg)后,按照实施例17步骤13中所述步骤得到白色固态目标产物(2.3mg),但粗产物采用反相硅胶柱层析法(C-18,粒径:40μm,孔径分布:),用CH3CN/H2O(10-80%)进行洗脱。MS(ESI+):600.3[M+1]+.
实施例23A和23B
24-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-26,36-二氟-16-异丙基-21,22-二氢-4,8-二氮杂-2(1,7)-吡啶并[2,3-d]嘧啶-1,3(1,2)-二苯杂环八蕃-22-酮(24-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-26,36-difluoro-16-isopropyl-21,22-dihydro-4,8-diaza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacyclooctaphan-22-one)
将POCl3(0.0800mL,0.858mmol)添加到实施例22步骤1产物(0.0598g,0.125mmol)和二异丙基乙胺(0.22mL,1.26mmol)的5mL干乙腈溶液中。在回流下搅拌反应混合物1小时。蒸发掉乙腈后,将中间体3(0.0738g,0.262mmol)和二异丙基乙胺(0.24mL,1.38mmol)的5mL干乙腈溶液加入到残余物中。搅拌反应混合物1小时,然后浓缩。采用硅胶层析法,首先用二氯甲烷/甲醇己烷(100:0-90:10)洗脱,然后采用反相硅胶柱层析法(C-18,粒径:40μm,孔径分布:)用CH3CN/H2O(10-80%)进行洗脱,得到黄色固态实施例23A(0.0070g,快速洗脱)和实施例23B(0.0074g,缓慢洗脱)。MS(ESI+):614.3[M+1]+.
实施例24A和24B
24-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-26,36-二氟-16-异丙基-21,22-二氢-4,8-二氮杂-2(1,7)-吡啶并[2,3-d]嘧啶-1,3(1,2)-二苯杂环八蕃-22,5-二酮(24-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-26,36-difluoro-16-isopropyl-21,22-dihydro-4,8-diaza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacyclooctaphane-22,5-dione)
将POCl3(0.0600mL,0.644mmol)添加到实施例21步骤9产物(0.0470g,0.0984mmol)和二异丙基乙胺(0.18mL,1.03mmol)的5mL干乙腈溶液中。在回流下搅拌反应混合物1小时。蒸发掉乙腈后,将中间体3(0.0744g,0.264mmol)和二异丙基乙胺(0.22mL,1.26mmol)的5mL干乙腈溶液加入到残余物中。搅拌反应混合物1小时,然后浓缩。采用硅胶层析法,首先用二氯甲烷/甲醇己烷(100:0-90:10)洗脱,然后采用逆相管柱层析法(C-18,粒径:40μm,孔径分布:)用CH3CN/H2O(10-80%)进行洗脱,得到黄色固态实施例24A(0.0012g,快速洗脱)和实施例24B(0.0018g,缓慢洗脱)。MS(ESI+):628.3[M+1]+.
实施例25
(S)-24-(4-丙烯酰基-2-甲基哌嗪-1-基)-26,36-二氟-16-异丙基-21,22-二氢-4,7-二氮杂-2(1,7)-吡啶并[2,3-d]嘧啶-1,3(1,2)-二苯杂环七蕃-22,5-二酮((S)-24-(4-acryloyl-2-methylpiperazin-1-yl)-26,36-difluoro-16-isopropyl-21,22-dihydro-4,7-diaza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacycloheptaphane-22,5-dione)
步骤1N-(3-溴-2-硝基苯基)-N-(叔丁氧羰基)甘氨酸叔丁酯
在氮气环境下,将NaH(2.03g,50.7mmol)分批加入冰浴后的3-溴-2-硝基苯胺(5g,23.0mmol)的干四氢呋喃(100mL)预冷溶液中。0℃条件下搅拌0.5小时后,加入Boc2O(6.42mL,27.7mmol),再搅拌2小时。然后,加入BrCH2CO2 t-Bu(4.07mL,27.7mmol),在室温条件下,搅拌反应混合物过夜。将反应混合物倒入饱和的氯化铵水溶液(100/100mL)中,用乙酸乙酯萃取(80mLx 3)。浓缩合成的萃取物,并采用硅胶层析法(石油醚/乙酸乙酯:100/0-95/5)提纯,得到黄色油状目标化合物(6.664g)。MS(ESI):275.0/277.0[M+H-异丁烯-Boc]+.
1HNMR(400MHz,CDCl3)δ7.74-7.66(m,1H),7.62(dd,J=8.2,1.2Hz,1H),7.42-7.32(m,1H),4.52(d,J=17.2Hz,1H),3.60(d,J=17.2Hz,1H),1.51-1.43(m,13H),1.34(s,6H).
步骤2 N-(叔丁氧羰基)-N-(2-硝基-3-(丙-1-烯-2-基)苯基)甘氨酸叔丁酯
得到步骤1产物(6.66g)后,按照实施例21步骤3所述步骤得到浅黄色油状目标产物(4.26g)。MS(ESI):237.1[M+H-异丁烯-Boc]+.
1HNMR(400MHz,CDCl3)δ7.65-7.56(m,1H),7.48-7.39(m,1H),7.29-7.24(m,1H),5.22-5.16(m,1H),4.99(s,1H),4.55(d,J=17.7Hz,1H),3.65(d,J=17.7Hz,1H),2.08(s,3H),1.52-1.44(m,13H),1.33(s,6H).
步骤3
N-(2-氨基-3-异丙基苯基)-N-(叔丁氧羰基)甘氨酸叔丁酯
在氮气环境下,将7M溶于甲醇(0.5mL)的氨和10%Pd/C(1.2g,1.13mmol)加入步骤2产物(4.45g,11.3mmol)溶于甲醇(50mL)得到的溶液中。在室温H2环境下,搅拌混合物11.5h。用助滤硅藻土层过滤反应混合物,然后用乙酸乙酯洗涤助滤硅藻土层。浓缩滤液,得到淡黄色油状目标化合物(4.27g)。MS(ESI):265.2[M+H]+.
步骤4
N-(叔丁氧羰基)-N-(2-(3-(2,6-二氯-5-氟烟酰基)脲基)-3-异丙基苯基)甘氨酸叔丁酯(tert-butyl N-(tert-butoxycarbonyl)-N-(2-(3-(2,6-dichloro-5-fluoronicotinoyl)ureido)-3-isopropylphenyl)glycinate)
得到2,6-二氯-5-氟烟酰胺(2.34g)和步骤3产物(3.31g)后,按照实施例1步骤3中所述步骤获得白色固态目标产物(4.71g)。MS(ESI):597.0[M-H]-.
步骤5
N-((叔丁氧羰基)-N-(2-(7-氯-6-氟-2,4-二氧代-3,4-二羟基吡啶并[2,3-d]嘧啶-1(2H)-基)-3-异丙基苯基)甘氨酸叔丁酯
得到步骤4产物(4.21g)后,按照实施例8步骤3所述步骤得到白色固态目标产物(2.73g)。MS(ESI):564.2[M+H]+.
步骤6
(2-(7-氯-6-氟-2,4-二氧代-3,4-二羟基吡啶并[2,3-d]嘧啶-1(2H)-基)-3-异丙基苯基)甘氨酸
将三氟乙酸(4ml)加入步骤5步产物(600mg,1.07mmol)的二氯甲烷(6ml)溶液中。室温下搅拌16小时后,加入4mL1,4-二氧六环,然后浓缩溶液,得到棕色油状物供下一步使用,无需进一步提纯。MS(ESI):407.1[M+H]+.
步骤7
(2-(7-(2-氨基-6-氟苯基)-6-氟-2,4-二氧代-3,4-二羟基吡啶并[2,3-d]嘧啶-1(2H)-基)-3-异丙基苯基)甘氨酸
得到步骤6产物(505.5mg)和3-氟-2-(4,4,5,5-四甲基-1,3,2-二氧苯并呋喃-2-基)苯胺(736.5mg)后,按照实施例17步骤8中所述步骤获得白色固态目标产物(637mg)。MS(ESI):482.1[M+H]+.
步骤8
26,36-二氟-16-异丙基-21,22,23,24-四氢-4,7-二氮杂-2(1,7)-吡啶并[2,3-d]嘧啶-1,3(1,2)-二苯杂环七蕃-22,24,5-三酮
将吡啶(320μL,3.97mmol)加入步骤7产物(637mg,1.32mmol)的干乙腈(10mL)浑浊溶液中。再加入N-甲基咪唑(320μL,3.97mmol),随后加入干DMF(10mL)和TCFH(562.5mg,1.98mmol)。搅拌11小时后,将反应混合物倒入0.5N盐酸溶液(12mL),用乙酸乙酯(15mL x4)萃取。用盐水(5mL x 2)洗涤有机相,水相用乙酸乙酯(5mLx2)萃取。浓缩合成的有机相,采用硅胶层析法提纯残余物(石油醚/乙酸乙酯:100/0至50/50),得到黄色固态目标产物(200mg)。MS(ESI):464.1[M+H]+.
步骤9
(S)-24-(4-丙烯酰基-2-甲基哌嗪-1-基)-26,36-二氟-16-异丙基-21,22-二氢-4,7-二氮杂-2(1,7)-吡啶并[2,3-d]嘧啶-1,3(1,2)-二苯杂环七蕃-22,5-二酮
得到步骤8的产物(60mg)和中间体2(69mg)后,按照实施例17步骤13中所述步骤获得白色固态目标产物(2.14mg)。MS(ESI):600.3[M+H]+.
实施例26
24-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-26,36-二氟-16-异丙基-21,22-二氢-4,7-二氮杂-2(1,7)-吡啶并[2,3-d]嘧啶-1,3(1,2)-二苯杂环七蕃-22,5-二酮(24-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-26,36-difluoro-16-isopropyl-21,22-dihydro-4,7-diaza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacycloheptaphane-22,5-dione)
得到步骤8的产物(55mg)和中间体3(133mg)后,按照实施例17步骤13中所述步骤获得黄色固态目标产物(7.8g)。MS(ESI):614.3[M+H]+.
实施例27A和27B
24-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-26,36-二氟-16-异丙基-21,22-二氢-4,7-二氮杂-2(1,7)-吡啶并[2,3-d]嘧啶-1,3(1,2)-二苯杂环七蕃-22-酮(24-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-26,36-difluoro-16-isopropyl-21,22-dihydro-4,7-diaza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacycloheptaphan-22-one)
步骤1
26,36-二氟-16-异丙基-21,22,23,24-四氢-4,7-二氮杂-2(1,7)-吡啶并[2,3-d]嘧啶-1,3(1,2)-二苯杂环七蕃-22,24-二酮
得到实施例25步骤8的产物(100mg)和后,按照实施例1步骤7中所述步骤获得黄色固态目标产物(16mg)。MS(ESI):450.1[M+H]+.
步骤2
24-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-26,36-二氟-16-异丙基-21,22-二氢-4,7-二氮杂-2(1,7)-吡啶并[2,3-d]嘧啶-1,3(1,2)-二苯杂环七蕃-22-酮
在氩气环境下,将二异丙基乙胺(74μL,0.44mmol)和POCl3(25μL,0.27mmol)加入步骤1产物(20mg,0.04mmol)的干乙腈(2mL)溶液中。80℃条件下搅拌1小时后,浓缩反应混合物。向残余物中加入DIEA(74μL,0.44mmol),并加入1-((2R,5S)-2,5-二甲基哌嗪-1-基)丙-2-烯-1-酮(中间体3,75mg,30%纯度,0.13mmol)的干DMF(1.0mL)溶液。在室温条件下搅拌1.5小时后,将反应混合物倒入水中(5mL),用乙酸乙酯(5mL×4)萃取。用饱和的氯化铵水溶液(3ml)洗涤合成的萃取物,并浓缩,再采用硅胶层析法(石油醚/乙酸乙酯:80/20-0/100;DCM/EtOAc:90/10-20/80;DCM/MeOH:100/0-92/8),提纯残余物,从而得到黄色固态实施例27A(快速洗脱)(5.4mg)以及实施例27A与实施例27B的混合物(缓慢洗脱)。用制备薄层色谱(石油醚∶乙酸乙酯=1:5,洗脱两次)进一步提纯混合物,得到另外1.0mg实施例27A和黄色固态实施例27B(5.6mg)。MS(ESI):600.3[M+H]+.
实施例27A:1HNMR(400MHz,CDCl3)δ7.83-7.73(m,1H),7.31-7.26(m,1H),7.26-7.19(m,1H),6.81(dd,J=17.4,7.9Hz,2H),6.66-6.54(m,1H),6.54-6.45(m,2H),6.44-6.34(m,1H),5.84-5.75(m,1H),5.38-5.27(m,1H),5.14(brs,1H),5.04-4.94(m,1H),4.40-4.27(m,1H),4.14-4.06(m,1H),4.04-3.97(m,1H),3.97-3.89(m,1H),3.84(d,J=12.6Hz,1H),3.71-3.61(m,1H),3.33-3.18(m,2H),3.18-3.08(m,1H),2.70-2.58(m,1H),1.39(d,J=6.8Hz,2H),1.37-1.24(m,4H),1.21(d,J=6.8Hz,2H),1.16(d,J=6.8Hz,2H),0.84(d,J=6.8Hz,2H).
实施例27B:1HNMR(400MHz,CDCl3)δ7.82(dd,J=19.6,9.2Hz,1H),7.30-7.27(m,1H),7.25-7.19(m,1H),6.88-6.74(m,2H),6.67(dd,J=16.9,10.9Hz,1H),6.59-6.34(m,3H),5.87-5.75(m,1H),5.21-5.12(m,1H),4.98(d,J=14.5Hz,1H),4.90-4.71(m,1H),4.61-4.48(m,1H),4.45-4.36(m,1H),3.92-3.81(m,1H),3.79-3.53(m,3H),3.33-3.06(m,3H),2.67-2.56(m,1H),1.64(d,J=6.8Hz,1H),1.56-1.41(m,7H),1.20(d,J=6.8Hz,2H),0.99-0.89(m,2H).
实施例28
(S)-24-(4-丙烯酰基-2-甲基哌嗪-1-基)-26,36-二氟-16-异丙基-8-甲基-21,22-二氢-4,8-二氮杂-2(1,7)-吡啶并[2,3-d]嘧啶-1,3(1,2)-二苯杂环八蕃-22-酮((S)-24-(4-acryloyl-2-methylpiperazin-1-yl)-26,36-difluoro-16-isopropyl-8-methyl-21,22-dihydro-4,8-diaza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacyclooctaphan-22-one)
步骤1
3-((3-溴-2-硝基苯基)(甲基)氨基)丙酸乙酯
得到3-(甲基氨基)丙酸乙酯和1-溴-3-氟-2-硝基苯后,按照实施例21步骤1中所述步骤得到黄色油状目标产物。MS:(ESI+):353.7[M+23]+.
步骤2
3-(甲基(2-硝基-3-(丙-1-烯-2-基)苯基)氨基)丙酸乙酯
得到步骤1的产物和异丙烯硼酸频哪醇酯后,按照实施例21步骤3中所述步骤获得黄色固态目标产物。MS:(ESI+):293.1[M+1]+.
步骤3
3-((2-氨基-3-异丙基苯基)(甲基)氨基)丙酸乙酯
得到步骤2产物后,按照实施例21步骤4所述步骤得到油状目标产物。MS:(ESI+):265.1[M+1]+。
步骤4
3-((2-(3-(2,6-二氯-5-氟烟酰基)脲基)-3-异丙基苯基)(甲基)氨基)丙酸乙酯
得到步骤3的产物后,按照实施例21中的步骤5所述步骤得到黄色固态目标产物。MS:(ESI+):499.1[M+1]+。
步骤5
3-((2-(7-氯-6-氟-2,4-二氧代-3,4-二羟基吡啶并[2,3-d]嘧啶-1(2H)-yl)-3-异丙基苯基)(甲基)氨基)丙酸乙酯
得到2,6-二氯-5-氟烟酰胺(2.45g)后,按照实施例8步骤3中所述步骤获得棕色固态目标产物(1.19g)。MS:(ESI+):463.2[M+1]+。
步骤6
3-((2-(7-(2-氨基-6-氟苯基)-6-氟-2,4-二氧代-3,4-二羟基吡啶并[2,3-d]嘧啶-1(2H)-yl)-3-异丙基苯基)(甲基)氨基)丙酸乙酯
得到步骤5产物(0.67g)和3-氟-2-(4,4,5,5-四甲基-1,3,2-二氧苯并呋喃-2-基)苯胺(0.75g)后,按照实施例17步骤8中所述步骤获得棕色固态目标产物(0.53g)。MS:(ESI+):538.2[M+1]+.
步骤7
3-((2-(7-(2-氨基-6-氟苯基)-6-氟-2,4-二氧代-3,4-二羟基吡啶并[2,3-d]嘧啶-1(2H)-yl)-3-异丙基苯基)(甲基)氨基)丙酸
将氢氧化锂(141mg)溶于水(2.5mL)加入到步骤6产物(420mg)的四氢呋喃(2.5mL)溶液中。室温下搅拌2小时后,将反应混合物浓缩至干燥,然后用水溶解(10mL),再用Et2O(2mL×5)洗涤。用1N盐酸溶液将水相酸化至pH=7,然后减压浓缩至干燥。残余物与甲苯(2mLx3)共沸蒸发,得到目标化合物—锂盐(400mg,黄色固态)。MS:(ESI+):510.2[M+1]+.
步骤8
26,36-二氟-16-异丙基-8-甲基-21,22,23,24-四氢-4,8-二氮杂-2(1,7)-吡啶并[2,3-d]嘧啶-1,3(1,2)-二苯杂环八蕃-22,24,5-三酮
得到步骤7产物(0.20g)后,按照实施例1步骤7所述步骤得到黄色固态目标产物(0.14g)。MS:(ESI+):492.2[M+1]+。
步骤9
26,36-二氟-16-异丙基-8-甲基-21,22,23,24-四氢-4,8-二氮杂-2(1,7)-吡啶并[2,3-d]嘧啶-1,3(1,2)-二苯杂环八蕃-22,24-二酮
得到步骤8产物(10mg)后,按照实施例2步骤1所述步骤得到黄色固态目标产物(13g,粗)。MS:(ESI+):478.1[M+1]+。
步骤10
(S)-24-(4-丙烯酰基-2-甲基哌嗪-1-基)-26,36-二氟-16-异丙基-8-甲基-21,22-二氢-4,8-二氮杂-2(1,7)-吡啶并[2,3-d]嘧啶-1,3(1,2)-二苯杂环八蕃-22-酮
得到步骤9的产物(10mg)和中间体2(47mg)后,按照实施例17步骤13中所述步骤获得棕色固态目标产物(3.23mg)。MS(ESI+):614.3[M+1]+.
实施例29
(S)-24-(4-丙烯酰基-2-甲基哌嗪-1-基)-26,36-二氟-16-异丙基-8-甲基-21,22-二氢-4,8-二氮杂-2(1,7)-吡啶并[2,3-d]嘧啶-1,3(1,2)-二苯杂环八蕃-22,5-二酮
((S)-24-(4-acryloyl-2-methylpiperazin-1-yl)-26,36-difluoro-16-isopropyl-8-methyl-21,22-dihydro-4,8-diaza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacyclooctaphane-22,5-dione)
得到实施例28步骤8的产物(15mg)和中间体2(30mg)后,按照实施例17步骤13中所述步骤获得黄色固态目标产物(0.85mg)。MS(ESI+):628.3[M+1]+.
实施例30
24-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-26,36-二氟-16-异丙基-8-甲基-21,22-二氢-4,8-二氮杂-2(1,7)-吡啶并[2,3-d]嘧啶-1,3(1,2)-二苯杂环八蕃-22,5-二酮
(24-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-26,36-difluoro-16-isopropyl-8-methyl-21,22-dihydro-4,8-diaza-2(1,7)-pyrido[2,3-d]pyrimidina-1,3(1,2)-dibenzenacyclooctaphane-22,5-dione)
得到实施例28步骤8的产物(40mg)和中间体3(245mg)后,按照实施例17步骤13所述步骤得到白色固态目标产物(12mg),但粗产物的提纯采用了C-18逆相管柱层析法,使用0.1%甲酸水溶液/乙腈(100%-0%)进行梯度洗脱,得到白色固态目标化合物(2.9mg;产率:5.68%)。MS(ESI+):642.3[M+1]+.
实施例31
(S)-24-(4-丙烯酰基-2-甲基哌嗪-1-基)-26,36-二氟-12-异丙基-4-甲基-21,22-二氢-7-硫杂-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶-1(3,4)-吡啶-3(1,2)-苯杂环七蕃-22-酮
((S)-24-(4-acryloyl-2-methylpiperazin-1-yl)-26,36-difluoro-12-isopropyl-4-methyl-21,22-dihydro-7-thia-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphan-22-one)
步骤1 2-巯基乙酸叔丁酯
在室温条件下,将2-溴乙酸叔丁酯(20g,0.10mol)和硫代乙酸钾(18g,0.16mol)的乙醇(200ml)溶液持续搅拌16小时。用2N氢氧化钠溶液(205ml)处理反应混合物,并搅拌1小时。用1N盐酸溶液将混合溶液的pH值调节至7,再用乙酸乙酯萃取反应混合物。用盐水洗涤有机层,用无水Na2SO4干燥、过滤并浓缩,得到8.5g棕色油状粗产物供下一步使用,无需进一步提纯。
步骤2 2-((3-氨基-2-异丙基吡啶-4-基)巯基)乙酸叔丁酯
将含有中间体5(6.25g,23.86mmol)、2-巯基乙酸叔丁酯(8.84g,59.64mmol)、二异丙基乙胺(12.31g,95.42mmol)、Pd2(dba)3(4.37g,4.77mmol)和二甲基氧杂蒽(5.52g,9.54mmol)的1,4-二氧六环(30ml)混合溶液加热至90℃,并在氩气保护环境下搅拌2小时。反应完成后,将混合物冷却至室温,用水淬灭,再用乙酸乙酯萃取。用盐水洗涤有机层、用无水Na2SO4干燥,然后过滤、浓缩。残余物经硅胶层析法(PE:EA=2:1)纯化后得到4.6g黄色固态纯产物。MS(ES+):283[M+1]+
步骤3
2-((3-(3-(2,6-二氯-5-氟烟酰基)脲基)-2-异丙基吡啶-4-基)巯基)乙酸叔丁酯
得到2,6-二氯-5-氟烟酰胺(6.67g)和步骤2产物(4.5g)后,按照实施例1步骤3中所述步骤获得黄色固态目标产物(3.1g)。MS(ES+):517[M+1]+.
步骤4
2-((3-(7-氯-6-氟-4-羟基-2-氧代吡啶并[2,3-d]嘧啶-1(2H)-基)-2-异丙基吡啶-4-基)巯基)乙酸叔丁酯
得到步骤3产物(3.0g)后,按照实施例8步骤3所述步骤得到白色固态目标产物(2.1g)。MS(ES+):481[M+1]+.
步骤5
2-((3-(7-(2-氨基-6-氟苯基)-6-氟-4-羟基-2-氧代吡啶并[2,3-d]嘧啶-1(2H)-基)-2-异丙基吡啶-4-基)巯基)乙酸叔丁酯
得到步骤4产物(700mg)和3-氟-2-(4,4,5,5-四甲基-1,3,2-二氧苯并呋喃-2-基)苯胺(3.45g)后,按照实施例17步骤8中所述步骤获得白色固态目标产物(575mg)。MS(ES+):556[M+1]+.
步骤6
26,36-二氟-24-羟基-12-异丙基-21,22-二氢-7-硫杂-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶-1(3,4)-吡啶-3(1,2)-苯杂环七蕃-22,5-二酮
在室温条件下,向步骤5产物(240mg,0.43mmol)的(3ml)二氯甲烷溶液中添加(3ml)三氟乙酸(TFA)。在室温条件下将所得混合物搅拌1小时,然后浓缩。将残余物溶于DMF(60ml)中。在室温以及氩气保护环境下,加入N-甲基咪唑(532mg,6.49mmol)和TCFH(393mg,1.30mmol)。在室温条件下将所得混合物搅拌1小时,然后用水淬灭后通过乙酸乙酯进行萃取。用盐水洗涤有机层、用无水Na2SO4干燥,然后过滤、浓缩。用制备薄层色谱纯化残余物(PE:EA=1:1)纯化后得到92mg黄色固态目标产物。MS(ES+):482[M+1]+.
步骤7
26,36-二氟-24-羟基-12-异丙基-21,22-二氢-7-硫杂-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶-1(3,4)-吡啶-3(1,2)-苯杂环七蕃-22-酮
在0℃以及氩气保护环境下,将硼烷四氢呋喃络合物(1M,0.6ml,0.57mmol)加入步骤6产物(92mg,0.19mmol)的四氢呋喃(1ml)溶液中。在室温以及氩气保护环境下将所得反应混合物搅拌1小时,然后用水淬灭后通过乙酸乙酯进行萃取。用盐水洗涤有机层、用无水Na2SO4干燥,然后过滤、浓缩。用制备薄层色谱纯化残余物(PE:EA=2:1)纯化后得到57mg黄色固态目标产物。MS(ES+):468[M+1]+.
步骤8
(S)-24-(4-丙烯酰基-2-甲基哌嗪-1-基)-26,36-二氟-12-异丙基-21,22-二氢-7-硫杂-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶-1(3,4)-吡啶-3(1,2)-苯杂环七蕃-22-酮
得到步骤7的产物(57mg)和中间体2(79mg)后,按照实施例17步骤8中所述步骤获得黄色固态目标产物(37mg)。MS(ES+):604[M+1]+.
步骤9
(S)-24-(4-丙烯酰基-2-甲基哌嗪-1-基)-26,36-二氟-12-异丙基-4-甲基-21,22-二氢-7-硫杂-4-氮杂-2(1,7)-吡啶并[2,3-d]嘧啶-1(3,4)-吡啶-3(1,2)-苯杂环七蕃-22-酮
在室温条件搅拌下,将甲醛(30%)(5ml)和三乙酰氧基硼氢化钠(121mg,0.60mmol)加入步骤8产物(35mg,0.06mmol)的四氢呋喃(1ml)溶液中。搅拌1小时后,用水淬灭混合物,并用乙酸乙酯萃取。用盐水洗涤有机层、用无水Na2SO4干燥,然后过滤、浓缩。用制备薄层色谱纯化残余物(乙酸乙酯),得到17mg黄色固态目标产物。MS(ES+):618[M+1]+.
中间体的合成
中间体1
(S)-1-(3-甲基哌嗪-1-基)丙-2-烯-1-酮三氟乙酸盐
步骤1(S)-4-丙烯酰基-2-甲基哌嗪-1-甲酸叔丁酯
在0℃、搅拌下,在15分钟内将丙烯酰氯(2.10mL,25.8mmol)加入(S)-2-甲基哌嗪-1-甲酸叔丁酯(4.7971g,23.952mmol)和三乙胺(8.0mL,57.4mmol)的二氯甲烷(80mL)的溶液中。然后,用20mL水处理反应混合物,并用200mL乙酸乙酯萃取。用60mL2N盐酸溶液(水溶液)和5x50mL水、盐水洗涤有机层,并用Na2SO4干燥。将溶液过滤后,浓缩,得到浅黄色油状目标化合物。MS(ESI+):277.1[M+23]+.
步骤2(S)-1-(3-甲基哌嗪-1-基)丙-2-烯-1-酮三氟乙酸盐
,将含有(S)-4-丙烯酰-2-甲基哌嗪-1-甲酸叔丁酯(3.57g,14.0mmol)和三氟乙酸(8.0mL,107.7mmol)的二氯甲烷(20mL)溶液在室温条件下搅拌5小时。然后加入20mL甲苯。将反应混合物浓缩得到浅色油状目标化合物(4.24g)。MS(ESI+):155.1[M+1]+.
中间体2
(S)-1-(3-甲基哌嗪-1-基)丙-2-烯-1-酮
将中间体1(4.24g)粗产物溶于25mL氢氧化钠(水溶液)(2.67g氢氧化钠)。加入10g氯化钠,使反应混合物达到饱和,再用3x30mL二氯甲烷进行萃取。用Na2SO4干燥合成的有机层,并浓缩,得到中间体2(2.3g)。MS(ESI+):155.1[M+1]+.
中间体3
1-((2R,5S)-2,5-二甲基哌嗪-1-基)丙-2-烯-1-酮三氟乙酸盐
步骤1(2S,5R)-4-丙烯酰-2,5-二甲基哌嗪-1-甲酸叔丁酯
在0℃、搅拌下,将丙烯酰氯(1.70mL,20.9mmol)加入到(2S,5R)-2,5-二甲基哌嗪-1-甲酸叔丁酯(3.83g,17.9mmol)和三乙胺(5.2mL,37.3mmol)的二氯甲烷(30mL)溶液中。在0℃条件下搅拌15分钟后,加水(10mL),然后在室温条件下搅拌反应混合物1小时。用50mL乙酸乙酯萃取混合物,用20mL2N盐酸溶液(水溶液)、2x20mL0.2M盐酸溶液(水溶液)、2x20mL水、盐水洗涤有机层,然后用Na2SO4干燥。将溶液过滤后,浓缩,得到浅色油状目标化合物。MS(ESI+):291.1[M+23]+。
步骤2 1-((2R,5S)-2,5-二甲基哌嗪-1-基)丙-2-烯-1-酮三氟乙酸盐
在室温、搅拌下,将步骤1产物(3.85g,14.3mmol)溶于三氟乙酸(10.0mL,134.6mmol)和二氯甲烷(40mL)中,持续1小时。加入甲苯(40mL),并蒸发反应混合物,得到浅黄色油状目标化合物(4.0g)。MS(ESI+):169.2[M+1]+。
中间体4
3-氯-1-((2R,5S)-2,5-二甲基哌嗪-1-基)丙-1-酮盐酸盐
将步骤1中间体3的产物(200.0mg,0.746mmol)加入4N盐酸溶液/二氧六环溶液(1.0mL)中。在室温条件下搅拌1小时后,将反应混合物浓缩至干燥,得到目标化合物(150mg)。MS(ESI+):205.1[M+1]+.
1H NMR(400MHz,DMSO-d6):δ3.82-3.79(m,2H),.60-3.57(m,4H),3.45-3.35(m,2H),2.99-2.95(m,1H),2.82-2.75(m,1H),1.29-1.21(m,6H).
中间体5
4-碘-2-异丙基吡啶-3-胺
步骤1 2,4-二氯吡啶-3-胺
在室温、搅拌下,将铁粉(140g,2.49mol)加入2,4-二氯-3-硝基吡啶(150g,0.78摩尔)的醋酸(750ml)溶液中。40℃条件下搅拌3小时后,用Na2CO3(aq.)将反应混合物的pH值调节至8~9,并用乙酸乙酯萃取。有机层用盐水洗涤,在无水Na2SO4干燥,过滤并浓缩,得到120g的粗制目标产物,为棕色固态。MS(ES+):162.9[M+1]+。
步骤2 4-氯-2-(丙-1-烯-2-基)吡啶-3-胺
在室温以及氩气保护环境下,将Pd(dppf)Cl2.DCM(32g,0.039mol)加入2,4-二氯吡啶-3-胺(85g,0.52mol)、异丙烯基硼酸频哪醇酯(115g,0.68mol)、K3PO4(287g,1.36mol)的四氢呋喃(1.7升)/水(340ml)的溶液中。在75℃条件下将混合物搅拌7小时,然后用水淬灭后通过乙酸乙酯进行萃取。用盐水洗涤有机层、用无水Na2SO4干燥,然后过滤、浓缩。残余物经硅胶层析法(PE:EA=2:1)纯化后得到84mg白色固态目标产物。MS(ES+):168.9[M+1]+。
步骤3 4-碘-2-异丙基吡啶-3-胺
将4-氯-2-(丙-1-烯-2-基)吡啶-3-胺(84g,0.5mol)溶于HI(水溶液,55-58%,1.26L)得到的混合溶液在120℃氩气保护环境下搅拌过夜。然后,用Na2CO3(水溶液)调节反应混合物的pH至9-10,并用乙酸乙酯萃取。用NaHSO3(水溶液)和盐水洗涤有机层,用无水Na2SO4干燥、过滤并浓缩,得到90g棕色油状粗产物供下一步使用,无需进一步提纯。MS(ES+):262.8[M+1]+。
本申请中提及的文献均作为参考文献纳入本文,单独引证归并。此外,应理解,在阅读上述指导后,本领域技术人员可对本发明作出任何修改和变更。任何此类更改和变更也属于所附权利要求所定义的范围。
Claims (10)
1.一种通式VII中的化合物或其药学上可接受的盐,
式中,
Q表示能够与亲核试剂形成共价键的部分,Q的优选结构如下所示:
Ra、Rb和Rc各自独立地选自以下基团:H、卤素、取代或未取代的C1-4烷基、取代或未取代的C3-4环烷基或氰基;
R1和R2各自独立地选自以下基团:氢、卤素、氰基、C1-6烷氧基、羟基、C(O)NH2、C(O)NHC1-6烷基、C(O)N(C1-6烷基)2、C1-6烷基磺酰基、S(O)2NH2、S(O)2NH1-6烷基、NHC(O)NH2、NHC(O)NHC1-6烷基、C1-6烷基、NHC(O)OC1-6烷基、C(O)-C1-6烷基、-C(O)C1-6烷基、C1-6杂烷基、杂环基以及杂环基烷基;或者R1和R2与它们所连接的碳原子可以形成一个三到六元的碳环;
R3和R6各自独立地选自以下基团:H、OH、C1-6烷基、C3-10环烷基、C3-10杂环烷基、C1-6卤代烷基、C1-6烷氧基、NH-C1-6烷基、N(C1-6烷基)2、CN以及卤素;
R4选自以下基团:氢、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C3-8环烷基、C2-4烯基、C2-4炔基、芳基以及杂芳基;
Z和Y各自独立地表示N或者CR3;
W表示N或者CR6;
n和m各自独立地表示0、1、2、3、4或者5;
R17和R18各自独立地选自以下基团:卤素、支链或者直链C1-6烷基、C3-6环烷基、C3-6杂环基、-SC1-6烷基、-OC1-6烷基、-OC3-6杂环基、-OC3-6环基、-SC3-6杂环基、-SC3-6环基、-S(O)C1-6烷基、-S(O)2C1-6烷基、-S(O)2NHC1-6烷基、-S(O)2N(C1-6烷基)2以及-P(O)(C1-6烷基)2;
L3选自以下基团:-(CH2)qC(O)-、-O(CH2)qC(O)-、-NR19(CH2)qNR20-、-(CH2)qNR20-、-O(CH2)qO-、-(CH2)qC(O)NR19-、-O(CH2)qC(O)NR19-、-S(CH2)qC(O)-、-S(CH2)qC(O)-;-O(CH2)qC(O)NR19-、-O(CH2)qCNR19-、-S(CH2)qO-、-O(CH2)qS-、-S(CH2)qS-、-NR19(CH2)qC(O)N20-、-NR19(CH2)qC-、–NR19(CH2)qO-、-O(O)(CH2)q-、-O(O)(CH2)q-、-O(CH2)qS-、-(CH2)tCH=CH(CH2)r-、-O(CH2)qCH=CH(CH2)r-、-O(CH2)qCH=CH(CH2)rO-、-O(CH2)qCH=CH(CH2)rO-、-S(CH2)qCH=CH(CH2)r-、-(CH2)qCH=CH(CH2)rS-、-O(CH2)qCH=CH(CH2)rS-、-S(CH2)qCH=CH(CH2)rO-、-C(CH2)qS(CH2)r-以及-C(CH2)qO(CH2)r-;
q和r各自独立地为1至6的整数;
R19和R20各自独立地选自以下基团:氢、C1-6烷基以及C3-6环烷基。
2.一种通式VIIA中的化合物或其药学上可接受的盐:
式中,
R1和R2独立地选自以下基团:氢、卤素、C0-6亚烷基-CN、C0-6亚烷基-R19R20、C1-6烷氧基、羟基、C0-6亚烷基-C(O)NH2、C0-6亚烷基-C(O)NHC1-6烷基、C0-6亚烷基-C(O)N(C1-6烷基)2、C0-6亚烷基-S(O)2-C1-6烷基、C0-6亚烷基-S(O)2NH2、C0-6亚烷基-S(O)2NHC1-6烷基、C0-6亚烷基-S(O)2N(C1-6烷基)2、C0-6亚烷基-NHC(O)NH2、C0-6亚烷基-NHC(O)NHC1-6烷基、C0-6亚烷基-NR19C(O)N(C1-6烷基)2、C1-6烷基、C0-6亚烷基-NHC(O)OC1-6烷基、C0-6亚烷基-C(O)-C1-6烷基、C1-6杂烷基、C0-6亚烷基-杂环基以及C0-6亚烷基-杂环基烷基;或者R1和R2与它们所连接的碳原子可以形成一个三到六元的碳环;
Z和Y各自独立地表示N或者CR3;
W表示N或者CR6;
W1表示N或者CR3;
W2表示N或者CR4;
Z1、Z2、Z3、Z4和Z5各自独立地表示N或CR18;
R3、R4和R6各自独立地选自以下基团:H、OH、CN或卤素、C1-6烷基、C3-10环烷基、C3-10杂烷基、C3-10杂环烷基、C1-6卤代烷基、C1-6烷氧基、NH-C1-6烷基、N(C1-6烷基)2、C3-8环烷基、C2-4烯基、C2-4炔基、C2-6杂环基、芳基和杂芳基;
R17和R18各自独立地选自以下基团:卤素、CN、支链或者直链C1-6烷基、C3-6环烷基、C3-6杂环基、-SC1-6烷基、-OC1-6烷基、-OC3-6杂环基、-OC3-6环基、NH-C1-6烷基、N(C1-6烷基)2、-SC3-6杂环基、-SC3-6环基、-S(O)C1-6烷基、-S(O)2C1-6烷基、-S(O)2NH2、-S(O)2NHC1-6烷基、-S(O)2N(C1-6烷基)2、-P(O)(C1-6烷基)2、C2-6杂环基、C6-10芳基和C1-5杂芳基;
L3选自以下基团:-(CH2)q、-(CH2)qC(O)-、-O(CH2)qC(O)-、-NR19(CH2)qNR20-、-(CH2)qNR20-、-O(CH2)qO-、-(CH2)qC(O)NR19-、-(CH2)qC(S)NR19-、-(CH2)qCHCF3NR19-、-(CH2)qNR19C(O)-、(CH2)qNR19CHCF3-、-C(O)NR19(CH2)q-、-CHCF3NR19(CH2)q-、-C(S)NR19(CH2)q-、-O(CH2)qC(O)NR19-、-O(CH2)qC(S)NR19-、-S(O)v(CH2)qC(O)-、-O(CH2)qC(O)NR19-、-NR19C(O)(CH2)qC(O)NR20-、-C(O)NR19(CH2)qC(O)NR20-、-C(O)NR19(CH2)qNR20C(O)-、-NR19C(O)(CH2)qNR20C(O)-、O(CH2)qCNR19-、-S(O)v(CH2)qO-、-O(CH2)qS(O)v-、-S(O)v(CH2)q-、-(CH2)qS(O)v-、-S(O)v(CH2)qS(O)v-、-NR19(CH2)qC(O)NR20-、-NR19(CH2)q-、-NR19C(O)(CH2)q-、–NR19CHCF3(CH2)q-、–NR19(CH2)qO-、-(CH2)rOC(O)(CH2)q-、-OC(O)(CH2)q-、-OC(O)(CH2)qS(O)v-、-(CH2)qCH=CH(CH2)r、-NR19(CH2)qCH=CH(CH2)r-、NR19C(O)(CH2)qCH=CH(CH2)r-、-(CH2)qCH=CH(CH2)rC(O)NR20-、-(CH2)qNR19C(O)NR20(CH2)r-、-(CH2)qNR19C(S)NR20(CH2)r-、-(CH2)qNR19S(O)2NR20(CH2)r-、-(CH2)qS(O)v(CH2)r-、-(CH2)qS(O)2NR20(CH2)r-、-(CH2)qNR19S(O)v(CH2)r-、-(CH2)qSS(CH2)r-、-(CH2)qS(CH2)r-、-(CH2)qO(CH2)r-、-(CH2)qNR19(CH2)r-、-(CH2)qC≡C(CH2)r-、-O(CH2)qCH=CH(CH2)r-、-O(CH2)qCH≡CH(CH2)r-、-(CH2)qCH≡CH(CH2)rO-、-O(CH2)qCH=CH(CH2)rO-、-O(CH2)qCH≡CH(CH2)rO-、-S(O)v(CH2)qCH=CH(CH2)r-、S(O)v(CH2)qCH≡CH(CH2)r-、-(CH2)qCH=CH(CH2)rS(O)v-、(CH2)qCH≡CH(CH2)rS(O)v-、-O(CH2)qCH=CH(CH2)rS(O)v-、-O(CH2)qCH≡CH(CH2)rS(O)v-、-S(O)v(CH2)qCH=CH(CH2)rO-、S(O)v(CH2)qCH≡CH(CH2)rO-、-C(CH2)qS(CH2)r-、-C(CH2)qO(CH2)r-、-C(O)NR19S(O)2(CH2)q-和-(CH2)qS(O)2NR19C(O)-;或者L3表示L4-L5-L6;
L4和L6各自独立地选自以下基团:-(CH2)q-、-O(CH2)q-、-S(CH2)q-、-NR19(CH2)q-、-(CH2)qNR20-、-(CH2)qO-、-(CH2)qS-、-(CH2)qC(O)-、-C(O)(CH2)q-、-(CH2)qC(O)NR19-、-NR19C(O)(CH2)q-、-(CH2)qCH=CH(CH2)r-、-O(CH2)qCH=CH(CH2)r-、-(CH2)qCH=CH(CH2)rO-、-S(CH2)qCH=CH(CH2)r-、-(CH2)qCH=CH(CH2)rS-、-O(CH2)qCH=CH(CH2)rS-以及-S(CH2)qCH=CH(CH2)rO-;
L5表示C2-6杂环基、C6-10芳基或C1-9杂芳基;
L3、L4、L5和L6中的每个氧代基团可独立地被硫羰基、-C(S)-、氧杂环丁烷基或亚胺基、-C(=NR19)-选择性取代;
q和r各自独立地为0至10的整数;
v是0、1或者2;
R19和R20各自独立地选自以下基团:氢、C1-6烷基、C3-10杂烷基、C3-6环烷基、C6-10芳基或C1-5杂芳基和C2-6杂环基;或者R19和R20可以连接成一个环;
Q表示能够与亲核试剂形成共价键的部分,Q的优选结构如下所示:
Ra、Rb和Rc各自独立地表示H、卤素、取代或未取代的C1-4烷基、取代或未取代的C1-4环烷基、C3-10杂烷基或氰基;Rb和Rc可以连接成一个环;
Re和Rd各自独立地选自以下基团:氢、卤素、C1-6烷基、卤化C1-6烷基、CN。
3.一种通式VIIB中的化合物或其药学上可接受的盐,
式中,
R17、Z、Z5、W、W1、W2和Y的定义如上所示;
L6选自由以下组分组成的基团:-(CH2)q-、-(CH2)qC(O)-、-O(CH2)qC(O)-、-NR19(CH2)qNR20-、-(CH2)qNR20-、-O(CH2)qO-、-(CH2)qC(O)NR19-、-(CH2)qNR19C(O)-、-C(O)NR19(CH2)q-、-O(CH2)qC(O)NR19-、-S(O)v(CH2)qC(O)-、-O(CH2)qC(O)NR19-、-NR19C(O)(CH2)qC(O)NR20-、-C(O)NR19(CH2)qC(O)NR20-、-C(O)NR19(CH2)qNR20C(O)-、-NR19C(O)(CH2)qNR20C(O)-、O(CH2)qCNR19-、-S(O)v(CH2)qO-、-O(CH2)qS(O)v-、-S(O)v(CH2)qS(O)v-、-NR19(CH2)qC(O)NR20-、-NR19(CH2)q-、-NR19C(O)(CH2)q-、-NR19(CH2)qO-、-O(O)(CH2)q-、-O(O)(CH2)q-、-O(O)(CH2)qS(O)v-、-NR19(CH2)qCH=CH(CH2)r-、NR19C(O)(CH2)qCH=CH(CH2)r-、-(CH2)qCH=CH(CH2)rC(O)NR20-、-(CH2)qC≡C(CH2)r-、-O(CH2)qCH=CH(CH2)r-、-O(CH2)qCH≡CH(CH2)r-、-(CH2)qCH≡CH(CH2)rO-、-O(CH2)qCH=CH(CH2)rO-、-O(CH2)qCH≡CH(CH2)rO-、-S(O)v(CH2)qCH=CH(CH2)r-、S(O)v(CH2)qCH≡CH(CH2)r-、-(CH2)qCH=CH(CH2)rS(O)v-、(CH2)qCH≡CH(CH2)rS(O)v-、-O(CH2)qCH=CH(CH2)rS(O)v-、-O(CH2)qCH≡CH(CH2)rS(O)v-、-S(O)v(CH2)qCH=CH(CH2)rO-、S(O)v(CH2)qCH≡CH(CH2)rO-、-C(CH2)qS(CH2)r-以及C(CH2)qO(CH2)r-;或L6也可以不存在;
q和r在0到10之间独立选定的整数;
v是0、1或者2;
6.根据权利要求1至5所述的以药学上可接受的盐和药学上可接受的赋形剂形式出现的任何化合物。
7.一种抑制细胞中KRAS G12C且治疗KRAS G12C诱发疾病的方法。
8.一种包括按治疗有效用量向受试者施用权利要求1至5所述的任何化合物治疗受试者癌症的方法。
9.根据权利要求8所述的方法,其中癌症指肺癌、胰腺癌和结肠直肠癌。
10.一种按治疗有效用量向受试者施用权利要求1至6所述的任何化合物与其它任何治疗有效量的抗癌药物联用治疗受试者癌症的方法。
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WO2020259513A1 (en) | 2020-12-30 |
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EP3990448A1 (en) | 2022-05-04 |
CA3144548A1 (en) | 2020-12-30 |
AU2020308353B9 (en) | 2024-01-25 |
JP2022539341A (ja) | 2022-09-08 |
EP3990448A4 (en) | 2023-08-02 |
US20220153741A1 (en) | 2022-05-19 |
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