CN114057743A - Process for preparing imidazotriazine and pyrrolopyrimidine derivatives as inhibitors of KRAS G12C - Google Patents
Process for preparing imidazotriazine and pyrrolopyrimidine derivatives as inhibitors of KRAS G12C Download PDFInfo
- Publication number
- CN114057743A CN114057743A CN202010778338.5A CN202010778338A CN114057743A CN 114057743 A CN114057743 A CN 114057743A CN 202010778338 A CN202010778338 A CN 202010778338A CN 114057743 A CN114057743 A CN 114057743A
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- CN
- China
- Prior art keywords
- methylpyrrolidin
- methoxy
- imidazo
- heterocyclyl
- cycloalkyl
- 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.)
- Pending
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- 102200006538 rs121913530 Human genes 0.000 title abstract description 17
- 239000003112 inhibitor Substances 0.000 title abstract description 11
- XZLIYCQRASOFQM-UHFFFAOYSA-N 5h-imidazo[4,5-d]triazine Chemical compound N1=NC=C2NC=NC2=N1 XZLIYCQRASOFQM-UHFFFAOYSA-N 0.000 title abstract description 4
- 150000004944 pyrrolopyrimidines Chemical class 0.000 title abstract description 4
- 238000004519 manufacturing process Methods 0.000 title description 13
- 238000000034 method Methods 0.000 claims abstract description 17
- 239000000203 mixture Substances 0.000 claims description 75
- 150000001875 compounds Chemical class 0.000 claims description 62
- -1 said-NRbRcCycloalkyl Chemical group 0.000 claims description 45
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 40
- 125000003118 aryl group Chemical group 0.000 claims description 30
- 125000001072 heteroaryl group Chemical group 0.000 claims description 30
- 125000000623 heterocyclic group Chemical group 0.000 claims description 30
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 29
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 25
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 25
- 229910052736 halogen Inorganic materials 0.000 claims description 22
- 150000002367 halogens Chemical class 0.000 claims description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 20
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 20
- 239000003153 chemical reaction reagent Substances 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 229910019213 POCl3 Inorganic materials 0.000 claims description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 12
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 12
- 150000002431 hydrogen Chemical class 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 8
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 8
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 8
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 8
- 125000004043 oxo group Chemical group O=* 0.000 claims description 8
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims description 8
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 229910052783 alkali metal Inorganic materials 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 6
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 6
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 6
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 6
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 6
- 238000006467 substitution reaction Methods 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 5
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 5
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical compound CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 claims description 4
- 229910015845 BBr3 Inorganic materials 0.000 claims description 4
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 150000001298 alcohols Chemical class 0.000 claims description 4
- 229910000102 alkali metal hydride Inorganic materials 0.000 claims description 4
- 150000008046 alkali metal hydrides Chemical class 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Substances BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 4
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 claims description 4
- 238000010511 deprotection reaction Methods 0.000 claims description 4
- 229910052805 deuterium Inorganic materials 0.000 claims description 4
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 claims description 4
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical class [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 claims description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 4
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 claims description 4
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N methylimidazole Natural products CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 claims description 4
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 239000012312 sodium hydride Substances 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 3
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 229910006124 SOCl2 Inorganic materials 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 2
- 125000001033 ether group Chemical group 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- 229910000103 lithium hydride Inorganic materials 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 2
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 229910052701 rubidium Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- LFQULJPVXNYWAG-UHFFFAOYSA-N sodium;phenylmethanolate Chemical compound [Na]OCC1=CC=CC=C1 LFQULJPVXNYWAG-UHFFFAOYSA-N 0.000 claims description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- CRUISIDZTHMGJT-UHFFFAOYSA-L zinc;dichloride;hydrochloride Chemical compound Cl.[Cl-].[Cl-].[Zn+2] CRUISIDZTHMGJT-UHFFFAOYSA-L 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims 1
- 125000006239 protecting group Chemical group 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 10
- 201000011510 cancer Diseases 0.000 abstract description 4
- 150000003839 salts Chemical class 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 55
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 45
- 229910052938 sodium sulfate Inorganic materials 0.000 description 29
- 238000006243 chemical reaction Methods 0.000 description 27
- 239000007832 Na2SO4 Substances 0.000 description 26
- 239000000047 product Substances 0.000 description 26
- 239000012267 brine Substances 0.000 description 24
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 24
- 235000019439 ethyl acetate Nutrition 0.000 description 22
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 20
- 239000012044 organic layer Substances 0.000 description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 238000012746 preparative thin layer chromatography Methods 0.000 description 18
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 16
- 239000000460 chlorine Substances 0.000 description 16
- 102000016914 ras Proteins Human genes 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 15
- 238000000746 purification Methods 0.000 description 15
- 229920006395 saturated elastomer Polymers 0.000 description 14
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 239000002904 solvent Substances 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 7
- 102100030708 GTPase KRas Human genes 0.000 description 6
- 101000584612 Homo sapiens GTPase KRas Proteins 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 5
- QSKMFYCQRQLYMF-ZDUSSCGKSA-N benzyl (2S)-2-(cyanomethyl)piperazine-1-carboxylate Chemical compound C(#N)C[C@@H]1N(CCNC1)C(=O)OCC1=CC=CC=C1 QSKMFYCQRQLYMF-ZDUSSCGKSA-N 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- UVNXNSUKKOLFBM-UHFFFAOYSA-N imidazo[2,1-b][1,3,4]thiadiazole Chemical compound N1=CSC2=NC=CN21 UVNXNSUKKOLFBM-UHFFFAOYSA-N 0.000 description 5
- 230000035772 mutation Effects 0.000 description 5
- 239000012074 organic phase Substances 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
- OTFBOTDTDPMZPW-JTQLQIEISA-N CC(C)(C)OC1=NC(OC[C@H]2N(C)CCC2)=NN2C1=NC=C2Br Chemical compound CC(C)(C)OC1=NC(OC[C@H]2N(C)CCC2)=NN2C1=NC=C2Br OTFBOTDTDPMZPW-JTQLQIEISA-N 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 206010069755 K-ras gene mutation Diseases 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 102100029974 GTPase HRas Human genes 0.000 description 3
- 102100039788 GTPase NRas Human genes 0.000 description 3
- 101000584633 Homo sapiens GTPase HRas Proteins 0.000 description 3
- 101000744505 Homo sapiens GTPase NRas Proteins 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108010014186 ras Proteins Proteins 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 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 2
- FYADHXFMURLYQI-UHFFFAOYSA-N 1,2,4-triazine Chemical compound C1=CN=NC=N1 FYADHXFMURLYQI-UHFFFAOYSA-N 0.000 description 2
- SQAINHDHICKHLX-UHFFFAOYSA-N 1-naphthaldehyde Chemical compound C1=CC=C2C(C=O)=CC=CC2=C1 SQAINHDHICKHLX-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- XWISIRUFGYQLSR-UHFFFAOYSA-N 7-bromo-2,4-dichloroimidazo[2,1-f][1,2,4]triazine Chemical compound N1=C(Cl)N=C(Cl)C2=NC=C(Br)N21 XWISIRUFGYQLSR-UHFFFAOYSA-N 0.000 description 2
- AFKUTLXBFSRDQD-UHFFFAOYSA-N 7-bromo-2-chloro-4-[(2-methylpropan-2-yl)oxy]imidazo[2,1-f][1,2,4]triazine Chemical compound BrC1=CN=C2C(=NC(=NN21)Cl)OC(C)(C)C AFKUTLXBFSRDQD-UHFFFAOYSA-N 0.000 description 2
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
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- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Disclosed herein are methods of making G12C inhibitors of imidazotriazines and pyrrolopyrimidine derivatives, or stereoisomers thereof or pharmaceutically acceptable salts thereof, for use as G12C inhibitors for the treatment of cancer.
Description
Technical Field
Disclosed herein are methods of making G12C inhibitors of imidazotriazines and pyrrolopyrimidine derivatives, or stereoisomers thereof or pharmaceutically acceptable salts thereof, for use as G12C inhibitors for the treatment of cancer.
Background
RAS is one of the most well-known oncogenes. In humans, three RAS genes (HRAS, KRAS and NRAS) encode four highly homologous RAS proteins (HRAS, KRAS-4A, KRAS-4B and NRAS). RAS proteins are small gtpases that act as binary molecular switches, involved in extracellular growth and differentiation signaling.
RAS typically cycles between a GDP-bound "off state and a GTP-bound" on "state. This cycle is regulated by several factors. Guanine nucleotide exchange factor (GEF), including SOS1 and SOS2, promotes the exchange and formation of GTP-bound RAS. At the same time, GTPase Activating Proteins (GAPs), such as NF-1, promote GTP hydrolysis, thus returning RAS to a GDP-binding inactive state (Kessler et al, PNAS, 2019, 116 (32): 15823-15829). Once bound to GTP, RAS initiates conformational changes in two specific regions, Switch 1 and Switch 2, allowing binding and activation of downstream effector proteins to initiate cascades of intracellular signaling pathways. These effectors include the RAF-MEK-ERK and PI3K-AKT-mTOR pathways, both of which play important roles in regulating cell proliferation, differentiation and survival (Cox et al, Nature Reviews Drug Discovery,2014,13: 828-.
RAS mutations have been identified in about 30% of human tumors. These mutations often occur as single base missense mutations in codons 12, 13, or 61, resulting in stabilization of the activated GTP-bound RAS form and constitutive activation of RAS downstream signaling pathways. KRAS is the most common mutant RAS in cancer, accounting for 85% of all RAS-driven cancers, followed by NRAS (12%) and HRAS (3%). KRAS mutations have been detected in approximately 95% of pancreatic ductal adenocarcinomas, 50% of colorectal adenocarcinomas, and 30% of lung adenocarcinomas. Most KRAS mutations occur at residue 12, and the mutation types differ among different cancers. In colon and pancreatic cancers, the predominant KRAS mutation is G12D (glycine to lysine), while in non-small cell lung cancer (NSCLC), almost half of the KRAS mutations are G12C (glycine to cysteine) (Cox et al, Nature Reviews Drug Discovery,2014,13: 828-.
RAS has long been considered as a therapeutic target for many cancers based on its critical role in cellular proliferation and its high mutation rate in human cancers. However, despite decades of research efforts, no anti-RAS small molecule has yet been clinically approved. The main reason is the lack of a pharmacologically acceptable pocket on the surface of the RAS (Papke et al, Science,2017,355: 1158-. Recently, more and more studies have shown that RAS may be pharmacotherapeutically treated with small molecules. Several inhibitors that directly target KRAS G12C are under investigation (Patriceli et al, Cancer Discovery,2016,6 (3); 316-29) (Fell et al, ACS Med. chem. Lett.2018,9,12, 1230-1234).
Small molecule selective inhibitors of KRAS are being developed to prevent or treat disease, for example, WO2015/054572a1 provides compounds with activity as inhibitors of G12C mutant RAS protein. WO2016/164675A1 and WO2017/015562A1 disclose substituted quinazoline compounds as KRAS G12C inhibitors. WO2014/152588a1, WO2016/049524a1, WO2016/168540a1, WO2017/058728a1, WO2017/058792a1, WO2017/058805a1, WO2017/058915a1, WO2017/087528a1, WO2018/064510a1, WO2018/068017a1, WO2018/119183a2, WO2018/206539a1, WO2018/218069a1, WO2019/051291a1, WO2019/055540a1, WO2019/137985a1, WO2019/141250a1, WO2019/150305a1, WO2019/155399a1, WO2019/213516a1, WO2019/213526a 213526, WO2019/213526a 362020, WO2019/213526a 213526/362020, WO 20172 a 213526/362020, WO2019/213526a 362020/213526 a 362020.
Therefore, there is still a great need for new inhibitors of selectively targeting mutant KRAS with high efficiency and safety and methods for their preparation. Continued efforts to develop KRAS G12C inhibitors will suggest new therapeutic modalities for KRAS G12C driven cancers.
Disclosure of Invention
The present invention relates to the following aspects:
item 1. a process for the preparation of a compound of formula (I),
L1and L2Each independently selected from the group consisting of a single bond, -CO-NH-, -NH-CO-, -O-, -NRa-、-NRa(CH2)m-、-(CH2)m-、-O-(CH2)m-、-O-CH(Ra)-、-CH(Ra)-、-CH(Ra)(CH2)m-、-(CH2)m-O-；
R1Selected from cycloalkyl, heterocyclyl, aryl,Or heteroaryl, said cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with at least one R6Substituent (e.g., - (R)6)q1When q1 is greater than 1, each R6Are the same or different substituents);
R2is selected from-NRbRcCycloalkyl, heterocyclyl, aryl, heteroaryl, said-NRbRcCycloalkyl, heterocyclyl, aryl, heteroaryl optionally substituted with at least one R6Substituent (e.g., - (R)6)q2When q2 is greater than 1, each R6Are the same or different substituents);
R6is selected from-C1-8Alkyl, halogen, hydroxy, oxo, -C1-8Alkoxy, -NRbRcCycloalkyl, heterocyclyl, aryl, or heteroaryl, said-C1-8Alkyl, -C1-8Alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with at least one halogen, hydroxy, amino, CN, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
or when R is6When attached to two adjacent atoms of the ring, two R6Taken together with the carbon atom to which they are attached to form a 5-8 membered ring, said 5-8 membered ring containing 0, 1 or 2 heteroatoms selected from N, O or optionally oxidized S; r3Selected from hydrogen, halogen, -C1-8Alkyl, -C2-8Alkenyl, -C2-8Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, said-C1-8Alkyl, -C2-8Alkenyl, -C2-8Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with halogen, hydroxy, -C1-8Alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl;
R4is selected from
R5Selected from hydrogen, halogen, -C1-8Alkyl, -C2-8Alkenyl, -C2-8Alkynyl, oxo, -NRbRc、-(CH2)m-C(O)-NRdReCycloalkyl, heterocyclyl, aryl, heteroaryl or- (CH)2)m-CN；
Each Ra、RbAnd RcEach independently selected from hydrogen, deuterium, cyano, halogen, hydroxy, -C1-8Alkoxy, -C1-8Alkyl, -C2-8Alkenyl, -C2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NRdReor-CO-NRdResaid-C1-8Alkoxy, -C1-8Alkyl, -C2-8Alkenyl, -C2-8Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with RfIs substituted, or
(RaAnd Rb)、(RaAnd Rc)、(RbAnd Rc) With the atoms to which they are attached form a 4-6 membered ring, said 4-6 membered ring optionally substituted with at least 1RgSubstitution;
each RfSelected from halogen, hydroxy, oxo, -C1-8Alkoxy, -NRdRe、-CO-NRdRe、-NRd-CO-ReCycloalkyl, heterocyclyl, aryl or heteroaryl, said-C1-8Alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted by halogen, hydroxy or-C1-4Alkyl substitution;
Rd、Reand RgEach independently selected from hydrogen, deuterium, halogen, oxo, or-C1-8Alkyl radical of formula (I), said1-8Alkyl is optionally substituted by at least one halogen, oxo, -CF3or-COCH3Substitution;
PR1selected from ether protecting groups, ester protecting groups, carbamate protecting groups, preferably neopentyl, tert-butyl, benzyl, acetyl, propionyl, pivaloyl, Boc, Cbz, more preferably tert-butyl;
PR2selected from Boc or Cbz;
p is independently selected from 0, 1,2, 3 or 4;
q1 and q2 are independently selected from 0, 1,2, 3, 4, 5, 6, 7 or 8;
each m and n is independently selected from 0, 1,2, 3, 4, 5 or 6.
Item 2. the production method according to item 1, characterized in that:
the reagent used in step 1 is selected from NBS and Br2。
Item 3. the production method according to item 1, characterized in that:
the reagents used in step 2 and step 7 are respectively and independently selected from phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, Lucas reagent, mixture of concentrated hydrochloric acid and anhydrous zinc chloride, Vilesnier-Haack reagent, thionyl chloride, sulfuryl chloride and chlorine gas, preferably POCl3、PCl5、SOCl2More preferably POCl3。
Item 4. the production method according to item 1, characterized in that:
the reagent used in step 3 is selected from alkali metal salts of alcohols, preferably sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium tert-butoxide, sodium benzylate, potassium benzylate, lithium benzylate, more preferably lithium tert-butoxide.
Item 5. the production method according to item 1, wherein:
the reagent used in step 4 is selected from the group consisting of alkali metal hydrides, alkali metal salts, alkyllithium compounds and aminolithium compounds, preferably sodium hydride, potassium hydride, lithium hydride, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, n-butyllithium, sec-butyllithium, tert-butyllithium, diisopropylaminolithium and hexamethyldisilaaminolithium, and more preferably sodium hydride.
Item 6. the production method according to item 1, characterized in that:
the reagent used in step 5 is selected from alkali metal salts of alcohols, alkyllithium compounds and aminolithium compounds, preferably sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, n-butyllithium, sec-butyllithium, tert-butyllithium, diisopropylaminolithium and hexamethyldisilazane, and more preferably n-butyllithium.
Item 7. the production method according to item 1, characterized in that:
the deprotection conditions in the step 6 and the step 9 are respectively and independently selected from catalytic hydrogenation or acidic deprotection, preferably trifluoroacetic acid and triethylsilane combined, BBr3Pd/C in combination with hydrogen, trifluoroacetic acid, hydrochloric acid, Pd/C in combination with cyclohexadiene, more preferably trifluoroacetic acid in combination with triethylsilane, BBr3Pd/C in combination with hydrogen.
The production method according to item 1, characterized in that:
the reagent used in step 8 is selected from nitrogen-containing organic bases, preferably triethylamine, diethylamine, diisopropylethylamine, pyridine, methylimidazole, piperidine, morpholine, indoline, quinoline, isoquinoline, dimethylaminopyridine, more preferably triethylamine, diethylamine, diisopropylethylamine, dimethylaminopyridine, and even more preferably diisopropylethylamine.
Item 9. the production method according to item 1, characterized in that:
the reagent used in step 9 is selected from inorganic bases, nitrogen-containing organic bases, and alkali metal hydrides, preferably sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, diethylamine, diisopropylethylamine, pyridine, methylimidazole, piperidine, morpholine, indoline, quinoline, isoquinoline, and dimethylaminopyridine, and more preferably sodium bicarbonate.
Item 10. the production method according to item 1, characterized in that:
L1selected from the group consisting of single bond, -CO-, - (CH)2)m-、-CH(Ra)-、-CH(Ra)(CH2)m-、-(CH2)m-O-, further preferably selected from- (CH)2)m-、-CH(Ra) -; and/or
L2Selected from single bond, -O- (CH)2)m-、-O-CH(Ra)-、-O-CH(Ra)-(CH2)m-; and/or
R1Is selected from
And/or
R2Is selected from
-NRbRc、
And/or
R3Selected from hydrogen, halogen or-C1-8An alkyl group; and/or
R3' is selected from hydrogen, -C1-8Alkyl, -C2-8Alkenyl or-C2-8An alkynyl group; and/or
R4Is selected from
And/or
R5Selected from hydrogen, -CH3、-C2H5、-C3H7、-C4H9、-C5H11、-(CH2)m-C(O)-NRdRe、-(CH2)m-CN。
Item 11. the production method according to item 1, wherein:
R1is selected from
R2Is selected from
(e.g. in
)、
(e.g. in
)、
Item 12. the production method according to item 1, wherein:
a compound of the formula (I) or (II) is
Examples
The following examples are intended to be illustrative only and should not be construed as being limiting in any way. Unless otherwise indicated, the experimental procedures in the following examples are conventional. Unless otherwise indicated, reagents and materials are commercially available. All solvents and chemicals used were of analytical grade or chemical purity. The solvent is redistilled before use. The anhydrous solvents were prepared according to standard or reference methods. Silica gel for column chromatography (100-; unless otherwise stated, all silica gels were eluted with petroleum ether (60-90 ℃ C.)/ethyl acetate (v/v) and developed with iodine or phosphomolybdic acid in ethanol. Unless otherwise stated, all extraction solvents were passed over anhydrous Na2SO4And (5) drying. Recording on a Bruck-400 NMR spectrometer with TMS (tetramethylsilane) as internal standard1H NMR spectrum. LC/MS data were recorded by using an Agilent1100 high performance liquid chromatography-ion trap mass spectrometer (LC-MSD trap) equipped with Diode Array Detector (DAD) and ion trap (ESI source) detecting at 214nm and 254 nm. All names of compounds except the reagent are
And (4) generating.
In the following examples, the following abbreviations are used:
ac acetyl group
AcOH acetic acid
Aq aqueous
Brine saturated aqueous sodium chloride solution
Bn benzyl group
Boc tert-butyloxycarbonyl group
Cbz benzyloxycarbonyl
DMF N, N-dimethylformamide
Dppf 1,1' -bis (diphenylphosphino) ferrocene
DBU 1, 8-diazabicyclo [5.4.0] undec-7-ene
DCE 1, 2-dichloroethane
DCM dichloromethane
DIEA or DIPEA N, N-diisopropylethylamine
DMAP 4-N, N-dimethylaminopyridine
DMF N, N-dimethylformamide
DMSO dimethyl sulfoxide
EA or EtOAc ethyl acetate
eq equivalent weight
g
h or hr
HCl hydrochloric acid
HPLC high performance liquid chromatography
IPA 2-propanol
i-PrOH Isopropanol
mg of
mL of
Mmol millimole
MeCN acetonitrile
MeOH methanol
Min minute
MS or MS Mass Spectrometry
NMR nuclear magnetic resonance
Pd/C palladium on carbon
PE Petroleum Ether
PMB 4-methoxybenzyl
PPA polyphosphoric acid
Rt., RT., or rt. Room temperature
Ru-Phos/Ru-PHOS 2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1' -biphenyl
SEM 2-Trimethylsilylethoxymethoxy
TBSCl tert-butyldimethylsilyl chloride
TEA Triethanolamine
TFA trifluoroacetic acid
THF tetrahydrofuran
THP tetrahydropyrans
TLC thin layer chromatography
Synthetic example 3: compound a 3: 2- ((S) -1-acryloyl-4- (7- (3-methoxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
Step A: 7-Bromoimidazo [2,1-f ] [1,2,4] triazine-2, 4(1H,3H) -dione
To imidazo [2,1-f at a temperature below 25 ℃][1,2,4]Triazine-2, 4(1H,3H) -dione (30g, 0.20mol) in H2NBS (24.6g, 0.14mol) was added in portions to a solution in O (1.2L). The mixture was stirred at room temperature for 1 h. The mixture was filtered. The filtrate was concentrated to remove the solvent. The resulting residue and the previous filter cake were combined and washed in MeOH (20V) and then MeOH: H2Slurried in O (1:1, 20V) to give the product (30.4g, 94%). MS M/e 231(M +1)+。
And B: 7-bromo-2, 4-dichloroimidazo [2,1-f ] [1,2,4] triazine
The 350ml sealed tube is filled with 7-bromoimidazo [2,1-f ]][1,2,4]Triazine-2, 4(1H,3H) -dione (10g, 43mmol), triethylamine hydrochloride (12g, 88mmol) and POCl3(100 ml). The mixture was stirred at 120 ℃ overnight. The mixture was concentrated to remove POCl3. The residue was diluted with EA (200ml) and saturated NaHCO3 (aq) was added dropwise at below 20 ℃ until pH was above 7. The solution was separated. Subjecting the organic layer to H2O washing with Na2SO4Dried, filtered and concentrated. The resulting residue was purified by column chromatography with 0-20% EA in PE to give the product (8.5g, 73%). MS M/e 267(M +1)+。
And C: (S) -4- (7-bromo-2-chloroimidazo [2,1-f ] [1,2,4] triazin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester
(S) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester hydrochloride (974mg, 3.29mmol) was added to 7-bromo-2, 4-dichloroimidazo [2, 1-f)][1,2,4]Triazine (1g, 3.76mmol), DIEA (1.2g, 9.3mmol) in THF (10 ml). The reaction was then stirred at rt for 2 h. The reaction mixture was diluted in water and extracted with DCM. The combined organic extracts were washed with saturated aqueous NaCl and Na2SO4Dried and concentrated. The crude product was purified by silica gel column chromatography (EA: PE ═ 1:2) to obtain the objective compound (1.4g, 86.8%).1H NMR(400MHz,CDCl3)δ7.55(s,1H),7.44–7.32(m,5H),6.03(s,1H),5.24–5.14(m,2H),4.75(s,2H),4.27(s,1H),3.67–3.16(m,3H),2.83–2.58(m,2H)ppm,MS:M/e 490(M+1)+。
Step D: (S) -4- (7-bromo-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester
To a solution of NaH (74mg, 1.84mmol, 60%) in THF (5mL) was added (S) - (1-methylpyrrolidin-2-yl) methanol (169mg, 1.47mmol) at 0 ℃. After 30min, a solution of the product of step A (600mg, 1.23mmol) in THF (5mL) was added. The reaction was then stirred at 60 ℃ overnight. The mixture was cooled to rt, diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, over Na2SO4Dried, filtered and concentrated. The residue was purified by combi flash to give the objective compound (180mg, 26%). MS M/e 569(M +1)+。
Step E: (S) -benzyl 2- (cyanomethyl) -4- (7- (3-methoxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazine-1-carboxylate
The flask was charged with Pd (dppf) Cl2(12.4mg, 0.017mmol), the product of step B (100mg, 0.17mmol), (3-methoxynaphthalen-1-yl) boronic acid (38mg, 0.19mmol), Na2CO3(22mg, 0.2mmol), dioxane (3ml) and H2O (0.3 ml). The resulting mixture was stirred at 90 ℃ for 4h, then cooled to room temperature. The reaction was quenched with water, extracted with EtOAc, washed with brine and Na2SO4Dried, filtered and concentrated. The residue was purified by combi flash to give the objective compound (90mg, 79%). MS M/e 647(M +1)+。
Step F: 2- ((S) -4- (7- (3-methoxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
BBr is heated at-10 deg.C3(1M in DCM, 0.61mL) was added dropwise to a mixture of the product of step C (160mg, 0.25mmol) in DCM (2 mL). The reaction was stirred at-10 ℃ for 1 hour. The mixture was filtered and the filter cake was dried by oven. The filter cake (20mg, crude) was used in the next step without further purification. MS M/e 513(M +1)+。
Step G: 2- ((S) -1-acryloyl-4- (7- (3-methoxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
To the product of step D (20mg, crude) in CH at 0 deg.C3Saturated NaHCO was added to the mixture in CN (1mL)3(0.5mL) followed by addition of acryloyl chloride (4mg) in CH3CN (0.3 mL). The resulting mixture was stirred at room temperature for 30 min. The reaction was diluted with water, extracted with EA, washed with brine, and taken over Na2SO4Drying and filteringAnd concentrated. The residue was purified by preparative TLC to give the title compound (1.7mg, 10% over two steps).1H NMR(400MHz,DMSO-d6)δ7.93(d,J＝8.2Hz,1H),7.83(s,1H),7.61–7.48(m,3H),7.34(s,2H),6.93–6.85(m,1H),6.23(d,J＝16.6Hz,1H),5.82(d,J＝10.4Hz,1H),5.03(m,2H),4.17(s,2H),3.88(s,3H),3.67–3.44(m,5H),3.17–2.76(m,6H),2.07–1.38(m,6H)ppm。MS:M/e 567(M+1)+。
Example 4: compound a 4: 2- ((S) -1-acryloyl-4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-ylmethyl) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
Step A: 7-bromo-4- (tert-butoxy) -2-chloroimidazo [2,1-f ] [1,2,4] triazine
To 7-bromo-2, 4-dichloroimidazo [2,1-f][1,2,4]To a solution of triazine (0.53g, 2mmol) in THF (6mL) was added t-BuOLi (176mg, 2.2mmol) portionwise. The mixture was then stirred at room temperature for 0.4 h. The residue was purified by combi flash to give the title compound (400mg, 66%).1H NMR(400MHz,CDCl3)δ7.67(s,1H),1.78(s,9H)ppm。
And B: (S) -7-bromo-4- (tert-butoxy) -2- ((1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazine
To a solution of NaH (448mg, 11.2mmol, 60%) in THF (10mL) was added (S) - (1-methylpyrrolidin-2-yl) methanol (0.7g, 6.15mmol) at 0 deg.C. After 30min, a solution of the product of step A (1.6g, 5.6mmol) in THF (5mL) was added. The reaction was then stirred at 60 ℃ for 1 h. The mixture was cooled to room temperature, diluted with water (30mL) and extracted with EtOAc (60mL × 2). The combined organic layers were washed with brine, over Na2SO4Dried, filtered and concentrated. Purifying the residue by combi flash to obtainTo the title compound (0.7g, 33%). MS M/e 384(M +1)+。
And C: (4- (tert-butoxy) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-7-yl) (naphthalen-1-yl) methanol
To a solution of the product of step B (250mg, 0.7mmol) in THF (10mL) was added dropwise n-butyllithium (0.6mL, 0.96mmol, 1.6M in hexanes) maintaining the temperature between-75 and-65 ℃. After 30min, a mixture of 1-naphthaldehyde (120mg, 0.77mmol) in THF (2mL) was added dropwise. The resulting mixture was stirred at-70 ℃ for 1h, then warmed to room temperature for 1 h. Reacting with saturated NH4Quench Cl solution, extract with EtOAc (60mL x 2), wash with brine, and Na2SO4Dried, filtered and concentrated. The residue was purified by combi flash to give the objective compound (230mg, 71%). MS M/e 462(M +1)+。
Step D: (S) -2- ((1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-ylmethyl) imidazo [2,1-f ] [1,2,4] triazin-4-ol
To a mixture of the product of step C (230mg, 0.5mmol) in DCM (4mL) was added TFA (2mL) and Et3SiH (2 mL). The reaction was heated at 25 ℃ overnight. The mixture was concentrated to dryness and the residue was used in the next step without further purification. MS M/e 390(M +1)+。
Step E: (S) -benzyl 2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-ylmethyl) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazine-1-carboxylate
To the residue of step D (200mg, crude) in toluene (10mL) was added POCl3(465mg, 3mmol) and DIEA (258mg, 2 mmol). The resulting mixture was stirred at 100 ℃ overnight. The mixture was concentrated to dryness and treated with THF (15 mL). DIEA (258mg, 2mmol) and benzyl (S) -2- (cyanomethyl) piperazine-1-carboxylate (130mg, 0.5mmol) were then added and the reaction stirred at room temperature for 3 hours. The reaction was quenched with saturated water and extracted with EtOAc (80 mL). The organic layer was washed with brine, over Na2SO4Dried, filtered and concentrated. The residue was purified by combi flash to give the title compound (100mg, 32%, over two steps). MS M/e 631(M +1)+。
Step F: 2- ((S) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-ylmethyl) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
To a mixture of the product of step E (50mg, 0.079mmol) in EtOH/THF (2.5mL/2.5mL) was added Pd/C (30mg, 10% Pd). The reaction was carried out at room temperature under H2Stirring for 8h under balloon. The mixture was filtered and the solid was washed with THF (5 mL). The filtrate was concentrated to dryness (50mg) and the residue was used in the next step without further purification. MS M/e 497(M +1)+。
Step G: 2- ((S) -1-acryloyl-4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-ylmethyl) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
To the product of step F (50mg, crude) in CH at 0 deg.C3Saturated NaHCO was added to the mixture in CN (3mL)3(0.5mL) then acryloyl chloride (6mg, 0.1mmol) in CH was added3CN (0.3 mL). The resulting mixture was stirred at room temperature for 30 min. The reaction was diluted with water and extracted with EA (60 mL). Will be provided withThe organic layer was washed with brine, over Na2SO4Dried, filtered and concentrated. The residue was purified by preparative TLC to give the title compound (4mg, 10% over two steps).1HNMR(400MHz,DMSO-d6)δ8.21(d,J＝7.6Hz,1H),7.95(d,J＝8.0Hz,1H),7.83(d,J＝8.0Hz,1H),7.62–7.49(m,2H),7.48–7.38(m,2H),7.34(s,1H),7.00–6.75(m,1H),6.19(d,J＝16.4Hz,1H),5.78(d,J＝10.8Hz,1H),5.19–4.75(m,2H),4.64(s,2H),4.57–4.08(m,3H),3.57–3.02(m,5H),2.89–2.67(m,2H),2.53-2.47(m,5H),2.16–1.90(m,1H),1.86–1.57(m,3H)ppm。MS:M/e551(M+1)+。
Example 5: compound a 5: 2- ((S) -1-acryloyl-4- (7- ((3-hydroxynaphthalen-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
Step A: 4-Formylnaphthalen-2-yl pivalate
To a solution of 3-hydroxy-1-naphthaldehyde (0.86g, 5mmol) in THF (10mL) was added pyridine (790mg, 10mmol), followed by dropwise addition of pivaloyl chloride (720mg, 6 mmol). The mixture was then stirred at room temperature for 16 h. The reaction was quenched with water, extracted with EtOAc (60mL x 2), washed with brine, and washed with Na2SO4Dried, filtered and concentrated. The residue was purified by combi flash to give the title compound (620mg, 48%). MS M/e 257(M +1)+。
And B: 4- ((4- (tert-butoxy) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-7-yl) (hydroxy) methyl) naphthalen-2-yl pivalate
To (S) -7-bromo-4- (tert-butoxy) -2- ((1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f][1,2,4]Solution of triazine (383mg, 1mmol) in THF (6mL) was added n-butyl drop wiseLithium (1mL, 1.6mmol) maintained at a temperature between-75 and-65 ℃. After 30min, a mixture of the product of step A (307mg, 1.2mmol) in THF (1mL) was added dropwise. The resulting mixture was stirred at-70 ℃ for 1h, then warmed to room temperature for 3 h. Reacting with saturated NH4Quench Cl solution, extract with EtOAc (60mL x 2), wash with brine, and Na2SO4Dried, filtered and concentrated. The residue was purified by combi flash to give the title compound (340mg, 60%). MS M/e 562(M +1)+。
And C: (S) -4- ((4-hydroxy-2- ((1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-7-yl) methyl) naphthalen-2-yl pivalate
To a mixture of the product of step B (340mg, 0.6mmol) in DCM (8mL) was added TFA (2mL) and Et3SiH (4 mL). The reaction was heated at 40 ℃ overnight. The mixture was concentrated to dryness and the residue was used in the next step without further purification. MS M/e 490(M +1)+。
Step D: benzyl (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- ((3- (pivaloyloxy) naphthalen-1-yl) methyl) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazine-1-carboxylate
To the residue of step C (crude) in toluene (10mL) was added POCl3(567mg, 3.6mmol) and DIEA (314mg, 2.44 mmol). The resulting mixture was stirred at 100 ℃ overnight. The mixture was concentrated to dryness and treated with THF (10 mL). DIEA (619mg, 4.8mmol) and benzyl (S) -2- (cyanomethyl) piperazine-1-carboxylate (155mg, 0.6mmol) were then added and the reaction stirred at rt for 16 h. The reaction was quenched with saturated water, extracted with EtOAc (60mL), washed with brine, and washed with Na2SO4Dried, filtered and concentrated. Passing the residue through combi fPurification by lash gave the title compound (130mg, 29% over two steps). MS M/e 731(M +1)+。
Step E: 4- ((4- ((S) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-7-yl) methyl) naphthalen-2-yl pivalate
To a mixture of the product of step D (130mg, 0.178mmol) in EtOH/THF (6mL/6mL) was added Pd/C (100mg, 10% Pd). The reaction was carried out at room temperature under H2Stirring for 16h (under balloon). The mixture was filtered and the solid was washed with DCM/MeOH (5mL/5 mL). The filtrate was concentrated to dryness (100mg) and the residue was used in the next step without further purification. MS M/e 597(M +1)+。
Step F: 4- ((4- ((S) -4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-7-yl) methyl) naphthalen-2-yl pivalate
To 4- ((4- ((S) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2, 1-f) at 0 deg.C][1,2,4]Triazin-7-yl) methyl) naphthalen-2-yl pivalate (40mg, crude) in CH3Saturated NaHCO was added to the mixture in CN (2mL)3(1mL) then acryloyl chloride (6.6mg, 0.1mmol) in CH was added3CN (0.5 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction was diluted with water and extracted with EA. The organic layer was washed with brine, over MgSO4Dried, filtered and concentrated. The residue was purified by preparative TLC to give 50mg of the objective compound. MS M/e 651(M +1)+。
Step G: 2- ((S) -1-acryloyl-4- (7- ((3-hydroxynaphthalen-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
To a mixture of the product of step F (50mg) in THF (2mL) was added NaOH (2M, 1 mL). The reaction was stirred at room temperature for 2 hours. Adjusting the pH of the mixture to
And the residue was extracted with EA. The combined organic layers were washed with brine, over Na2SO4Dried and concentrated. The residue was purified by preparative TLC to give the title compound (8mg, 18%). 1H NMR (400MHz, DMSO-d6) δ 8.08(d, J ═ 8.2Hz,1H),7.70(d, J ═ 8.1Hz,1H),7.54-7.40(m,2H),7.32(s,1H),7.05(s,1H), 6.96-6.83 (m,2H),6.20(d, J ═ 16.5Hz,1H),5.81(d, J ═ 10.2Hz,1H),4.89-5.06(m,2H),4.58(s,5H),4.16(s,1H),3.33-3.50(m,4H),2.70-3.07(m,8H),2.10(s,1H),1.51-1.74(m,3H), ppm. MS M/e 567(M +1)+。
Example 6: compound a 6: 2- ((S) -1-acryloyl-4- (7- ((8-chloronaphthalen-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
Step A: (4- (tert-butoxy) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-7-yl) (8-chloronaphthalen-1-yl) methanol
To (S) -7-bromo-4- (tert-butoxy) -2- ((1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f][1,2,4]To a solution of triazine (383mg, 1mmol) in THF (10mL) was added dropwise n-butyllithium (1mL, 1.6mmol) maintaining the temperature between-75 and-65 ℃. After 30min, a mixture of 8-chloro-1-naphthaldehyde (200mg, 1.1mmol) in THF (2mL) was added dropwise. The resulting mixture was stirred at-70 ℃ for 1h, then warmed to room temperature for 16 h. Reacting with saturated NH4Aqueous Cl solution and EtOAc (50 mL. times.2) extraction. The combined organic layers were washed with brine, over Na2SO4Dried, filtered and concentrated. The residue was purified by combi flash to give the objective compound (400mg, 80%). MS M/e 496(M +1)+。
And B: (S) -7- ((8-chloronaphthalen-1-yl) methyl) -2- ((1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-ol
To a mixture of the product of step A (400mg, 0.8mmol) in DCM (4mL) was added TFA (4mL) and Et3SiH (4 mL). The reaction was stirred at 25 ℃ overnight. The mixture was concentrated to dryness and the residue was used in the next step without further purification. MS M/e 424(M +1)+。
And C: (S) -benzyl 4- (7- ((8-chloronaphthalen-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate
To the above residue (crude) of step B in toluene (8mL) was added POCl3(1g, 6.5mmol) and DIEA (428mg, 3.23 mmol). The resulting mixture was stirred at 100 ℃ overnight. The mixture was concentrated to dryness and treated with THF (15 mL). DIEA (825mg, 6.4mmol) and benzyl (S) -2- (cyanomethyl) piperazine-1-carboxylate (209mg, 0.8mmol) were then added and the reaction stirred at room temperature for 3 hours. The reaction was quenched with water and extracted with EtOAc (80 mL). The organic layer was washed with brine, over Na2SO4Dried, filtered and concentrated. The residue was purified by combi flash to give the title compound (40mg, 6% over two steps). MS M/e 665(M +1)+。
Step D: 2- ((S) -4- (7- ((8-chloronaphthalen-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
To a mixture of the product of step C (30mg, 0.05mmol) in DCM (5mL) at-70 deg.C was added 1N BBr in DCM3(0.1mL, 0.1 mmol). The reaction was slowly warmed to room temperature for 2 hours. Add another 1N BBr in DCM3(0.1mL, 0.1mmol) and stirred overnight. The reaction was diluted with water and extracted with DCM (60 mL). The organic layer was washed with brine, over Na2SO4Dried, filtered and concentrated to give the title compound (20mg, crude) which was used in the next step without further purification. MS M/e 531(M +1)+。
Step E: 2- ((S) -1-acryloyl-4- (7- ((8-chloronaphthalen-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
To the product of step D (20mg, crude) in CH at 0 deg.C3Saturated NaHCO was added to the mixture in CN (4mL)3(0.3mL) followed by addition of acryloyl chloride (6mg, 0.1mmol) in CH3CN (0.3 mL). The resulting mixture was stirred at room temperature for 30 min. The reaction was diluted with water and extracted with EA (60 mL). The organic layer was washed with brine, over Na2SO4Dried, filtered and concentrated. The residue was purified by preparative TLC to give the title compound (0.4mg, 1.3% over two steps).1HNMR(400MHz,CD3OD)δ7.94–7.86(m,2H),7.60–7.35(m,4H),6.90–6.75(m,2H),6.24–6.22(m,1H),5.90–5.76(m,1H),5.69(dd,J＝3.6Hz,8.8Hz 1H),5.25–4.95(m,4H),4.65–4.55(m,1H),4.40–4.26(m,2H),4.25–4.10(m,1H),3.70–3.55(m,1H),3.14–3.04(m,2H),2.95–2.70(m,3H),2.48(s,3H),2.42–2.30(m,1H),2.13–1.98(m,1H),1.86–1.65(m,3H)ppm。MS:M/e 586(M+1)+。
Example 7: compound a 07: 2- ((S) -1-acryloyl-4- (7- ((8-methylnaphthalen-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
Step A: (4- (tert-butoxy) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-7-yl) (8-methylnaphthalen-1-yl) methanol
To (S) -7-bromo-4- (tert-butoxy) -2- ((1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f][1,2,4]To a solution of triazine (550mg, 1.43mmol) in THF (10mL) was added dropwise n-butyllithium (1.43mL, 1.6mmol) maintaining the temperature between-75 and-65 ℃. After 30min, a mixture of 8-methyl-1-naphthaldehyde (294mg, 1.72mmol) in THF (2mL) was added dropwise. The resulting mixture was stirred at-70 ℃ for 1h, then warmed to room temperature for 16 h. Reacting with saturated NH4Aqueous Cl was quenched and extracted with EtOAc (50mL × 2). The combined organic layers were washed with brine, over Na2SO4Dried, filtered and concentrated. The residue was purified by combi flash to give the objective compound (340mg, 50%). MS M/e 476(M +1)+。
And B: (S) -7- ((8-methylnaphthalen-1-yl) methyl) -2- ((1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-ol
To a mixture of the product of step A (340mg, 0.715mmol) in DCM (4mL) was added TFA (4mL) and Et3SiH (4 mL). The reaction was heated at 25 ℃ for 3 hours. The mixture was concentrated to dryness and the residue was used in the next step without further purification. MS M/e 404(M +1)+。
And C: (S) -benzyl 2- (cyanomethyl) -4- (7- ((8-methylnaphthalen-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazine-1-carboxylate
To the residue of step B (crude) in toluene (8mL) was added POCl3(868mg, 5.6mmol) and DIEA (360mg, 2.8 mmol). The resulting mixture was stirred at 100 ℃ overnight. The mixture was concentrated to dryness and treated with THF (15 mL). DIEA (720mg, 5.6mmol) and benzyl (S) -2- (cyanomethyl) piperazine-1-carboxylate (217mg, 0.84mmol) were then added and the reaction stirred at room temperature for 2 hours. The reaction was quenched with water and extracted with EtOAc (60mL × 2). The combined organic layers were washed with brine, over Na2SO4Dried, filtered and concentrated. The residue was purified by combi flash to give the title compound (120mg, 26% over two steps). MS M/e 645(M +1)+。
Step D: 2- ((S) -4- (7- ((8-methylnaphthalen-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
To a mixture of the product of step C (120mg, 0.186mmol) in EtOH/THF (5mL/5mL) was added Pd/C (80mg, 10% Pd). The reaction was carried out at room temperature under H2Stirring for 16h (under balloon). The suspension was filtered and the solid was washed with MeOH (5 mL). The filtrate was concentrated to dryness (90mg) and the residue was used in the next step without further purification. MS M/e 511(M +1)+。
Step E: 2- ((S) -1-acryloyl-4- (7- ((8-methylnaphthalen-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
At 0 deg.CProduct of D (90mg, crude) in CH3Saturated NaHCO was added to the mixture in CN (4mL)3(0.5mL) then acryloyl chloride (16mg, 0.17mmol) in CH was added3CN (0.3 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction was diluted with water and extracted with EA (60mL × 2). The combined organic phases were washed with brine, over Na2SO4Dried, filtered and concentrated. The residue was purified by preparative TLC to give the title compound (25mg, 24% over two steps).1HNMR(400MHz,DMSO-d6)δ7.90–7.76(m,2H),7.44–7.31(m,2H),7.32–7.23(m,2H),6.95–6.75(m,2H),6.19(d,J＝17.6Hz 1H),5.78(dd,J＝10.8Hz 1H),5.15–4.83(m,2H),4.78(s,2H),4.55–3.94(m,3H),3.90–3.40(m,2H),3.15–2.85(m,5H),2.76–2.71(m,4H),2.31(s,3H),2.24–2.10(m,1H),1.96–1.83(m,1H),1.80–1.50(m,3H)ppm。MS:M/e 565(M+1)+。
Example 8: compound A8: 2- ((S) -1-acryloyl-4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-2-ylmethyl) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
Step A: (4- (tert-butoxy) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-7-yl) (naphthalen-2-yl) methanol
To (S) -7-bromo-4- (tert-butoxy) -2- ((1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f][1,2,4]To a solution of triazine (383mg, 1mmol) in THF (10mL) was added dropwise n-butyllithium (1mL, 1.6mmol) maintaining the temperature between-75 and-65 ℃. After 30min, a mixture of 2-naphthaldehyde (170mg, 1.1mmol) in THF (2mL) was added dropwise. The resulting mixture was stirred at-70 ℃ for 1h, then warmed to room temperature for 1 h. Reacting with saturated NH4Aqueous Cl was quenched and extracted with EtOAc (60mL × 2). The combined organic layers were washed with brine, over Na2SO4Dried, filtered and concentrated. The residue was purified by combi flash to give the target compound (150mg, 32%). MS M/e 462(M +1)+。
And B: (S) -2- ((1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-2-ylmethyl) imidazo [2,1-f ] [1,2,4] triazin-4-ol
To a mixture of the product of step A (150mg, 0.32mmol) in DCM (2mL) was added TFA (2mL) and Et3SiH (2 mL). The reaction was stirred at 25 ℃ for 5 hours. The mixture was concentrated to dryness and the residue was used in the next step without further purification. MS M/e 390(M +1)+。
And C: (S) -benzyl 2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-2-ylmethyl) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazine-1-carboxylate
To POCl3To the residue of step B above (200mg, crude) (4mL) was added triethylamine hydrochloride (137mg, 1 mmol). The resulting mixture was stirred in a sealed tube at 120 ℃ overnight. The mixture was concentrated to dryness and treated with THF (6 mL). DIEA (340mg, 2.64mmol) and benzyl (S) -2- (cyanomethyl) piperazine-1-carboxylate (85mg, 0.33mmol) were then added and the reaction stirred at room temperature for 3 hours. The reaction was quenched with water and extracted with EtOAc (60mL × 2). The combined organic layers were washed with brine, over Na2SO4Dried, filtered and concentrated. The residue was purified by combi flash to give the title compound (60mg, 29% over two steps). MS M/e 631(M +1)+。
Step D: 2- ((S) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-2-ylmethyl) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
To a mixture of the product of step C (60mg, 0.095mmol) in EtOH/THF (3mL/3mL) was added Pd/C (50mg, 10% Pd). The reaction was carried out at room temperature under H2Stir overnight (balloon). The mixture was filtered and the solid was washed with DCM/MeOH (20mL/1 mL). The filtrate was concentrated to dryness (40mg) and the residue was used in the next step without further purification. MS M/e 497(M +1)+。
Step E: 2- ((S) -1-acryloyl-4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-2-ylmethyl) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
To the product of step D (40mg, crude) in CH at 0 deg.C3Saturated NaHCO was added to the mixture in CN (5mL)3(0.5mL) then acryloyl chloride (9mg, 0.1mmol) in CH was added3CN (0.3 mL). The resulting mixture was stirred at room temperature for 30 min. The reaction was diluted with water and extracted with EA (60 mL). The organic layer was washed with brine, over Na2SO4Dried, filtered and concentrated. The residue was purified by preparative TLC to give the title compound (8mg, 15% over two steps).1HNMR(400MHz,DMSO-d6)δ7.92–7.70(m,4H),7.54–7.33(m,4H),6.90–6.79(m,1H),6.17(d,J＝16.4Hz,1H),5.76(d,J＝9.6Hz,1H),5.15–4.75(m,2H),4.65–4.39(m,1H),4.33(s,2H),4.26–3.77(m,3H),3.54–3.36(m,2H),3.19–2.67(m,6H),2.28(s,3H),2.16-2.04(m,1H),1.95–1.76(m,1H),1.74–1.50(m,2H)ppm。MS:M/e 551(M+1)+。
Example 9: compound a 09: 2- ((S) -1-acryloyl-4- (7- ((2, 3-dihydrobenzofuran-4-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
Step A: 7-bromo-4- (tert-butoxy) -2-chloroimidazo [2,1-f ] [1,2,4] triazine
To 7-bromo-2, 4-dichloroimidazo [2,1-f][1,2,4]Triazine (2g, 7.5mmol) was added portionwise to a cooled solution at 0 ℃ in THF (20mL) tert-butyllithium (660mg, 8.3 mmol). After the addition, the reaction mixture was stirred at room temperature for 30 minutes. The solution was quenched with ice water and extracted with EA. The organic layer was washed with brine, over Na2SO4Dried, filtered and concentrated. The crude product was purified by Combi Flash (PE: EA ═ 9:1) to give the product (1.4g, 64%). MS: M/e 305(M +1) +
And B: (S) -7-bromo-4- (tert-butoxy) -2- ((1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazine
NaH (276mg, 6.9mmol) was added to a solution of (S) - (1-methylpyrrolidin-2-yl) methanol (637mg, 5.5mmol) in THF (20 mL). After stirring at room temperature for 30 minutes, 7-bromo-4- (tert-butoxy) -2-chloroimidazo [2,1-f ] in THF (5mL) is added dropwise][1,2,4]Triazine (1.4g, 4.6 mmol). The resulting mixture was transferred to a 60 ℃ oil bath and stirred at 60 ℃ for 30 minutes. The solution is treated with NH4The Cl solution (5mL) was quenched and extracted with EA (15 mL). The organic layer was dried, concentrated and passed through Combi Flash (DCM: NH)3Purification (7M in methanol) 20:1) gave the product (0.9g, 51%).1H NMR(400MHz,DMSO-d6)δ7.73(s,1H),4.29-4.33(m,1H),4.19-4.15(m,1H),2.95(d,J＝8.0Hz,1H),2.66-2.63(m,1H),2.38(s,3H),2.19-2.14(m,1H),1.95-1.91(m,1H),1.69(s,9H),1.68-1.62(m,3H)ppm。MS:M/e 384(M+1)+
And C: (4- (tert-butoxy) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-7-yl) (2, 3-dihydrobenzofuran-4-yl) methanol
To (S) -7-bromo-4- (tert-butoxy) -2- ((1)-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f][1,2,4]Triazine (300mg, 0.78mmol) in THF (5mL) at-78 deg.C cooled solution was added dropwise n-butyllithium (1.6M in n-hexane, 0.7mL, 1.12 mmol). After stirring for 30min, 2, 3-dihydrobenzofuran-4-carbaldehyde (139mg, 0.9mmol) in THF (3mL) was added dropwise. The resulting mixture was gradually stirred to room temperature overnight. The solution is treated with NH4The Cl solution (5mL) was quenched and extracted with EA (15 mL). The organic layer was dried, concentrated and passed through Combi Flash (DCM: NH)3Purification (7M in methanol) to 100:3) afforded the product (290mg, 82%). MS: M/e 454(M +1) +
Step D: (S) -7- ((2, 3-dihydrobenzofuran-4-yl) methyl) -2- ((1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-ol
Adding Et3SiH (2mL) and TFA (2mL) was added to (4- (tert-butoxy) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f][1,2,4]Triazin-7-yl) (2, 3-dihydrobenzofuran-4-yl) methanol (290mg, 0.6mmol) in DCM (2 mL). The solution was stirred at room temperature for 6 hours and then heated at 40 ℃ overnight. The solvent was evaporated under an oil pump and then co-distilled with toluene. The crude product was used directly in the next step (240mg, crude). MS M/e 382(M +1)+
Step E: (S) -4-chloro-7- ((2, 3-dihydrobenzofuran-4-yl) methyl) -2- ((1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazine
Will contain (S) -7- ((2, 3-dihydrobenzofuran-4-yl) methyl) -2- ((1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f][1,2,4]Triazin-4-ol (190mg, 0.5mmol), Et3HCl (138mg, 1mmol) and POCl3A sealed tube (8mL) was heated at 120 ℃ overnight. After cooling, the solvent was evaporated under an oil pump and co-distilled with toluene to giveTo the crude product, it was used directly in the next step (200mg, crude). MS M/e 400(M +1)+。
Step F: benzyl (S) -2- (cyanomethyl) -4- (7- ((2, 3-dihydrobenzofuran-4-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazine-1-carboxylate
(S) -benzyl 2- (cyanomethyl) piperazine-1-carboxylate (208mg, 0.8mmol) was added to (S) -4-chloro-7- ((2, 3-dihydrobenzofuran-4-yl) methyl) -2- ((1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f][1,2,4]Triazine (200mg, 0.52mmol) in THF (20mL) was added followed by DIEA (520mg, 4 mmol). The reaction mixture was stirred at room temperature for 1 hour. Water (10mL) was added to the solution and extracted with EA (15 mL). Subjecting the organic layer to Na2SO4Dried, concentrated and passed through Combi Flash (DCM: NH)3Purification (7M in MeOH) ═ 100:7) afforded the product (150mg, 48%). MS M/e 623(M +1)+。
Step G: 2- ((S) -4- (7- ((2, 3-dihydrobenzofuran-4-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
Reacting (S) -2- (cyanomethyl) -4- (7- ((2, 3-dihydrobenzofuran-4-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2, 1-f)][1,2,4]Triazin-4-yl) piperazine-1-carboxylic acid benzyl ester (75mg, 0.12mmol) and a solution of Pd/C (wet, 10%, 50mg) in THF/EtOH (2mL/2mL) in H2Stir under balloon at room temperature overnight. The catalyst was filtered and the filtrate was concentrated to give the crude product, which was used as is (55mg, crude). MS M/e 489(M +1)+
Step H: 2- ((S) -1-acryloyl-4- (7- ((2, 3-dihydrobenzofuran-4-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
NaHCO is added3The solution (saturated, 0.5mL) was added to 2- ((S) -4- (7- ((2, 3-dihydrobenzofuran-4-yl) methyl) 2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f][1,2,4]Triazin-4-yl) piperazin-2-yl) acetonitrile (30mg, crude) in CH3CN (5mL), followed by acryloyl chloride (7mg, 0.07 mmol). The reaction mixture was stirred at room temperature for 1 hour. The solution was evaporated, water (4mL) was added, and extracted with EA (8 mL). The organic layer was dried, concentrated and purified by preparative TLC (DCM: NH)3(7M in MeOH) ═ 10:1), yielding the product (6mg, 18%).1H NMR(400MHz,CD3OD)δ7.31(s,1H),7.00(t,J＝8.0Hz,1H),6.82(br.s,1H),6.67(d,J＝8.0Hz,1H),6.59(d,J＝8.0Hz,1H),6.28(d,J＝16.0Hz,1H),5.83(d,J＝8.0Hz,1H),5.12(br.s,1H),4.59(s,2H),4.51(t,J＝8.0Hz,2H),4.40(br.s,2H),4.35-4.29(m,2H),4.15(s,2H),3.63-3.48(m,2H),3.24(s,1H),3.14(d,J＝8.0Hz,2H),3.02(s,1H),2.88(s,2H),2.61(s,3H),2.19-2.00(m,2H),1.87-1.60(m,3H)ppm。MS:M/e 543(M+1)+。
Example 10: compound a 10: 2- ((S) -1-acryloyl-4- (7- ((4-methoxynaphthalen-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
Step A: (4- (tert-butoxy) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-7-yl) (4-methoxynaphthalen-1-yl) methanol
To (S) -7-bromo-4- (tert-butoxy) -2- ((1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f][1,2,4]To a solution of triazine (383mg, 1mmol) in THF (5mL) was added dropwise n-butyllithium (0.94mL, 1.5mmol) maintaining the temperature at-75 to-65 deg.CAnd (3) removing the solvent. After 30min, a mixture of 4-methoxy-1-naphthaldehyde (223.2mg, 1.2mmol) in THF (5mL) was added dropwise. The resulting mixture was stirred at-70 ℃ for 1h, then warmed to room temperature for 1 h. Reacting with saturated NH4The Cl solution was quenched and extracted with EtOAc. The organic layer was washed with brine, over Na2SO4Dried, filtered and concentrated. The residue was purified by combi flash to give the title compound (320mg, 65%). MS M/e 492(M +1)+。
And B: (S) -7- ((4-Methylnaphthalen-1-yl) methyl) -2- ((1-Methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-ol
To a mixture of the product of step A (250mg) in DCE (2mL) was added TFA (2mL) and Et3SiH (2 mL). The reaction was stirred at 25 ℃ overnight. The mixture was concentrated to dryness. The residue was used directly in the next step without further purification. MS M/e 420(M +1)+。
And C: (S) -benzyl 2- (cyanomethyl) -4- (7- ((4-methoxynaphthalen-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazine-1-carboxylate
To POCl3To the residue of step B above (200mg, crude) (3mL) was added triethylamine hydrochloride (204mg, 1.5 mmol). The resulting mixture was stirred at 120 ℃ overnight. The mixture was concentrated to dryness and treated with THF (5 mL). DIEA (177mg, 1.5mmol) and benzyl (S) -2- (cyanomethyl) piperazine-1-carboxylate (130mg, 0.5mmol) were then added and the reaction stirred at room temperature for 2 hours. The reaction was quenched with water and extracted with EtOAc (80 mL). The organic layer was washed with brine, over Na2SO4Dried, filtered and concentrated. The residue was purified by combi flash to give the title compound (75mg, 24% over two steps).MS:M/e 661(M+1)+。
Step D: 2- ((S) -4- (7- ((4-methoxynaphthalen-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
To a mixture of the product of step C (60mg) in EtOH/THF (2mL/2mL) was added Pd/C (10mg, 10% Pd). The reaction was carried out at room temperature under H2Stirring for 8h under balloon. The mixture was filtered and the solid was washed with THF (5 mL). The filtrate was concentrated to dryness (40mg) and the residue was used in the next step without further purification. MS M/e 527(M +1)+。
Step E: 2- ((S) -1-acryloyl-4- (7- ((4-methoxynaphthalen-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
To the product of step D (40mg, crude) in CH at 0 deg.C3Saturated NaHCO was added to the mixture in CN (2mL)3(0.5mL) then acryloyl chloride (8mg, 0.1mmol) in CH was added3CN (0.3 mL). The resulting mixture was stirred at room temperature for 30 min. The reaction was diluted with water and extracted with EA (60 mL). The organic layer was washed with brine, over Na2SO4Dried, filtered and concentrated. The residue was purified by preparative TLC to give the title compound (2.17mg, 10% over two steps). 1H NMR (400MHz, DMSO-d6) δ 8.19(d, J ═ 7.5Hz,1H),8.10(d, J ═ 9.0Hz,1H), 7.58-7.45 (m,2H),7.34(d, J ═ 7.6Hz,1H),7.25(s,1H),6.89(d, J ═ 7.8Hz,2H),6.18(d, J ═ 16.4Hz,1H),5.77(d, J ═ 10.3Hz,1H),4.85(s,2H),4.52(s,2H),4.24(s,1H),4.10(s,1H),3.94(s,3H),3.30(s,3H),2.94(s,5H),2.31(s,4H), 2.91(s,1H), 1.67(s, 1H), 1H, 67(s, 67 ppm). MS M/e 581(M +1)+。
Example 11: compound a 11: 2- ((S) -1-acryloyl-4- (7- (2-chloro-6-fluorobenzyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
Step A: (4- (tert-butoxy) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-7-yl) (2-chloro-6-fluorophenyl) methanol
To (S) -7-bromo-4- (tert-butoxy) -2- ((1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f][1,2,4]To a solution of triazine (300mg, 0.78mmol) in THF (8mL) was added dropwise n-butyllithium (1.6M, 0.69mL, 1.1mmol) maintaining the temperature between-75 and-65 ℃. After 1h, a suspension of 2-chloro-6-fluorobenzaldehyde (148mg, 0.93mmol) in THF (2mL) was added dropwise. The resulting mixture was stirred at-70 ℃ for 2h and then allowed to warm to room temperature overnight. Reacting with saturated NH4Aqueous Cl was quenched and extracted with EtOAc (20mL X3). The combined organic phases were washed with brine, over Na2SO4Dried, filtered and concentrated. The residue was purified by preparative TLC to give the target compound (150mg, 41.5%). MS M/e 464(M +1)+。
And B: (S) -7- (2-chloro-6-fluorobenzyl) -2- ((1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-ol
To a solution of the product of step A (150mg, 0.323mmol) in DCM (5mL) was added TFA (5mL) and Et3SiH (5 mL). The reaction mixture was stirred at 40 ℃ overnight. The mixture was concentrated in vacuo. Adding NaHCO to the residue3The solution (1M, 10mL) was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The residue was purified by preparative TLC to give the title product (180mg, 100%). MS M/e392(M +1)+。
And C: (S) -4-chloro-7- (2-chloro-6-fluorobenzyl) -2- ((1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazine
To (S) -7- (2-chloro-6-fluorobenzyl) -2- ((1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f][1,2,4]Triazin-4-ol (180mg, 0.46mmol) in POCl3To the solution (10mL) was added triethylamine hydrochloride (137mg, 1 mmol). The mixture was sealed and stirred at 110 ℃ overnight. The mixture was cooled to room temperature and concentrated in vacuo. The residue was used directly in the next step. MS M/e 410(M +1)+。
Step D: 2- ((S) -4- (7- (2-chloro-6-fluorobenzyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
To the product of step C in acetonitrile (10mL) was slowly added a solution of (S) -2- (piperazin-2-yl) acetonitrile (125mg, 1mmol) and DIEA (258mg, 2mmol) in acetonitrile (2 mL). The mixture was stirred at room temperature for 2 h. The mixture was used directly in the next step. MS M/e 499(M +1)+。
Step E: 2- ((S) -1-acryloyl-4- (7- (2-chloro-6-fluorobenzyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
Addition of NaHCO to the mixture from step D3Solution (1M, 10 mL). Acryloyl chloride (90mg, 0.1mol) was slowly added to the mixture. The reaction was stirred at rt for 2 h. The resulting mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. Purified by preparative TLC to giveThe title product (1.1mg, 0.4%, by three step) 1H NMR (400MHz, DMSO-d6) δ 7.33(br.s,2H),7.16(br.s,2H),6.85(s,1H),6.28(d, J ═ 16.4Hz,1H),5.83(d, J ═ 9.6Hz,1H),4.75(s,1H),4.53(d, J ═ 7.3Hz,1H),4.37(s,2H),4.15(s,1H),3.88(s,1H),3.71(s,1H), 3.58-3.49 (m,1H),3.13(s,1H),3.06(s,3H),2.89(s,1H), 2.83-2.74 (m,3H),2.41(s,1H),2.19(s,1H), 2.06 (s,3H),2.89(s,1H), 2.83-2.74 (m, 3H). MS M/e 553(M +1)+。
Example 12: compound a 12: 2- ((S) -1-acryloyl-4- (7- (2-chlorobenzyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
Step A: (4- (tert-butoxy) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-7-yl) (2-chlorophenyl) methanol
To (S) -7-bromo-4- (tert-butoxy) -2- ((1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f][1,2,4]A solution of triazine (383mg, 1mmol) in THF (8mL) was added dropwise with a solution of n-butyllithium (1.6M, 0.94mL, 1.5mmol) maintaining the temperature between-75 and-65 ℃. After 1h, a suspension of 2-chlorobenzaldehyde (168mg, 1.2mmol) in THF (2mL) was added dropwise. The resulting mixture was stirred at-70 ℃ for 2h and then allowed to warm to room temperature overnight. Reacting with saturated NH4Aqueous Cl was quenched and extracted with EtOAc (20mL X3). The combined organic phases were washed with brine, over Na2SO4Dried, filtered and concentrated. The residue was purified by preparative TLC to give the title compound (420mg, 94.3%). MS M/e 446(M +1)+。
And B: (S) -7- (2-chlorobenzyl) -2- ((1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-ol
To (4- (tert-butoxy) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazoleAnd [2,1-f ]][1,2,4]Triazin-7-yl) (2-chlorophenyl) methanol (420mg, 0.94mmol) in DCM (10mL) was added TFA (5mL) and Et3SiH (5 mL). The reaction mixture was stirred at 40 ℃ overnight. The mixture was concentrated in vacuo. Adding NaHCO to the residue3The solution (1M, 10mL) was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The residue was purified by preparative TLC to give the title product (200mg, 56.8%). MS M/e374(M +1)+。
And C: (S) -4-chloro-7- (2-chlorobenzyl) -2- ((1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazine
To (S) -7- (2-chlorobenzyl) -2- ((1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f][1,2,4]Triazin-4-ol (130mg, 0.35mmol) in POCl3To the solution (5mL) was added triethylamine hydrochloride (137mg, 1 mmol). The mixture was sealed and stirred at 110 ℃ overnight. The mixture was cooled to room temperature and concentrated in vacuo. The residue was used directly in the next step. MS M/e392(M +1)+。
Step D: 2- ((S) -4- (7- (2-chlorobenzyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
To the product of step C in acetonitrile (10mL) was slowly added a solution of (S) -2- (piperazin-2-yl) acetonitrile (125mg, 1mmol) and DIEA (258mg, 2mmol) in acetonitrile (2 mL). The mixture was stirred at room temperature for 2 h. The mixture was used directly in the next step. MS: M/e 481(M +1)+。
Step E: 2- ((S) -1-acryloyl-4- (7- (2-chlorobenzyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
Addition of NaHCO to the mixture of products of step D3Solution (1M, 10 mL). Acryloyl chloride (90mg, 0.1mol) was slowly added to the mixture. The reaction was stirred at rt for 2 h. The resulting mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The residue was purified by preparative TLC to give the title product (3.2mg, 1.7% over three steps). 1H NMR (400MHz, DMSO-d6) δ 7.42(d, J ═ 7.2Hz,1H),7.32(s,1H),7.25(d, J ═ 4.3Hz,3H),6.82(s,1H),6.29(d, J ═ 16.5Hz,1H),5.83(d, J ═ 10.4Hz,1H),4.72(s,1H),4.50(dd, J ═ 12.2,7.3Hz,1H),4.34(s,2H),4.18(s,1H),3.84(s,1H),3.69(s,1H), 3.26-3.15 (m,3H),3.03(s,3H),2.90(s,1H),2.79(s,2H),2.36(s,1H),2.19(s,1H),2.05(s, 1H), 1H (m, 1H). MS M/e 536(M +1)+。
Example 13: compound a 13: 2- ((S) -1-acryloyl-4- (7- ((2, 3-dihydrobenzofuran-7-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
Step A: (4- (tert-butoxy) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-7-yl) (2, 3-dihydrobenzofuran-7-yl) methanol
To (S) -7-bromo-4- (tert-butoxy) -2- ((1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f][1,2,4]Triazine (300mg, 0.78mmol) in THF (8mL) at-78 deg.C cooled solution was added dropwise n-butyllithium (1.6M in n-hexane, 0.7mL, 1.2 mmol). After stirring for 30min, 2, 3-dihydrobenzofuran-7-carbaldehyde (139mg, 0.9mmol) in THF (1mL) was added dropwise. The resulting mixture was gradually stirred to room temperature overnight. The solution is treated with NH4The Cl solution (5mL) was quenched and extracted with EA (15 mL). The organic layer was dried, concentrated and passed through Combiflash (DCM: NH)3MeOH ═ 4%) purification to give the product (2)80mg，79％)。MS:M/e 454(M+1)+。
And B: (S) -7- ((2, 3-dihydrobenzofuran-7-yl) methyl) -2- ((1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-ol
Adding Et3SiH (2mL) and TFA (2mL) was added to (4- (tert-butoxy) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f][1,2,4]Triazin-7-yl) (2, 3-dihydrobenzofuran-7-yl) methanol (280mg, 0.6mmol) in DCM (2 mL). The solution was heated at 40 ℃ overnight. The solvent was evaporated under an oil pump and then co-distilled with toluene. The crude product was used directly in the next step (235mg, crude). MS M/e 382(M +1)+。
And C: (S) -4-chloro-7- ((2, 3-dihydrobenzofuran-7-yl) methyl) -2- ((1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazine
Will contain (S) -7- ((2, 3-dihydrobenzofuran-7-yl) methyl) -2- ((1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f][1,2,4]Triazin-4-ol (235mg, 0.6mmol), Et3HCl (106mg, 1.2mmol) and POCl3A sealed tube (5mL) was heated at 120 ℃ overnight. After cooling, the solvent was evaporated under an oil pump and co-distilled with toluene to give the crude product, which was used directly in the next step (240mg, crude). MS M/e 400(M +1)+。
Step D: benzyl (S) -2- (cyanomethyl) -4- (7- ((2, 3-dihydrobenzofuran-7-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazine-1-carboxylate
(S) -benzyl 2- (cyanomethyl) piperazine-1-carboxylate (259mg, 1.0mmol) was added to (S) -4-chloro-7- ((2, 3-dihydrobenzofuran-7-yl) methyl) -2- ((1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f][1,2,4]Triazine (190mg, 0.5mmol) in THF (10mL) was added followed by DIEA (516mg, 4 mmol). The reaction mixture was stirred at room temperature for 1 hour. The solution was quenched with water (5mL) and extracted with EA (10 mL). Subjecting the organic layer to Na2SO4Dried, concentrated and passed through Combiflash (DCM: NH)3Purification (7M in MeOH) ═ 10:1) afforded the product (100mg, 34%). MS M/e 623(M +1)+。
Step E: 2- ((S) -4- (7- ((2, 3-dihydrobenzofuran-7-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
Reacting (S) -2- (cyanomethyl) -4- (7- ((2, 3-dihydrobenzofuran-7-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2, 1-f)][1,2,4]Triazin-4-yl) piperazine-1-carboxylic acid benzyl ester (100mg, 0.16mmol) and Pd/C (wet, 10%, 100mg) suspension in THF/EtOH (4mL/4mL) in H2Stir under balloon at room temperature overnight. The catalyst was filtered and the filtrate was concentrated to give the crude product, which was used directly (60mg, 76%). MS M/e 489(M +1)+
Step F: 2- ((S) -1-acryloyl-4- (7- ((2, 3-dihydrobenzofuran-7-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
NaHCO is added3The solution (saturated, 0.5mL) was added to 2- ((S) -4- (7- ((2, 3-dihydrobenzofuran-7-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f][1,2,4]Triazin-4-yl) piperazin-2-yl) acetonitrile (60mg, 0.12mmol) in CH3To a solution of CN (5mL) was added acryloyl chloride (17mg, 0.18 mmol). The reaction mixture was stirred at room temperature for 1 hour. The solution was evaporated, water (4mL) was added, and extracted with EA (10 mL). The organic layer was dried, concentrated and purified by preparative TLC (DCM: NH)3(7M in MeOH) ═ 9:1), yielding the product (6mg, 9%).1H NMR(400MHz,CD3OD)δ7.25(s,1H),7.08(t,J＝8.0Hz,1H),6.93(d,J＝8.0Hz,1H),6.81(br.s,1H),6.73(t,J＝8.0Hz,1H),6.28(d,J＝16.0Hz,1H),5.83(d,J＝12.0Hz,1H),5.12(br.s,1H),4.59-4.51(m,3H),4.37(s,2H),4.10(s,3H),3.6-3.47(m,2H),3.22-3.18(m,4H),2.87(s,3H),2.56(s,3H),2.50(s,1H),2.12-2.10(m,1H),1.87-1.78(m,4H)ppm。MS:M/e 543(M+1)+
Example 14: compound a 14: 2- ((S) -1-acryloyl-4- (2- (((S) -4, 4-difluoro-1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-ylmethyl) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
Step A: (S) -7-bromo-4- (tert-butoxy) -2- ((4, 4-difluoro-1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazine
To a solution of (S) - (4, 4-difluoro-1-methylpyrrolidin-2-yl) methanol (500mg, 3.3mmol) in THF (5mL) at 0 deg.C was added NaH (264mg, 60%, 6.6mmol) and the mixture was stirred for 5 min. Then 7-bromo-4- (tert-butoxy) -2-chloroimidazo [2,1-f ] is added][1,2,4]A solution of triazine (1.0g, 3.3mmol) in THF (5mL) and the resulting mixture was stirred at 60 ℃ for 1 hour. The mixture was cooled and then poured into H2O (20 mL). The mixture was extracted with EA (20mL x 3). The combined organic phases were washed with brine (20 mL. times.3) and Na2SO4Dried and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (825mg, yield: 60%). MS M/e 420(M +1)+。
And B: (4- (tert-butoxy) -2- (((S) -4, 4-difluoro-1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-7-yl) (naphthalen-1-yl) methanol
In N2To (S) -7-bromo-4- (tert-butoxy) -2- ((4, 4-difluoro-1-methylpyrrolidin-2-yl) methoxy) imidazo [2, 1-f) in an atmosphere at-78 deg.C][1,2,4]To a solution of triazine (825mg, 1.97mmol) in THF (5mL) was added n-butyllithium (1.6M, 2.5mL, 4.0 mmol). The mixture was stirred at-78 ℃ for 30 min. A solution of 1-naphthaldehyde (624mg, 4.0mmol) in THF (4mL) was then added to the system at-78 ℃. The reaction was stirred for 30min, then warmed to room temperature and stirred for 30 min. The reaction mixture was quenched with saturated NH at room temperature4Cl (20mL) was quenched and extracted with EA (20 mL. times.2). The combined organic phases were washed with brine (20 mL. times.3) and Na2SO4Dried and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (590mg, yield: 61%). MS M/e 498(M +1)+。
And C: (S) -2- ((4, 4-difluoro-1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-ylmethyl) imidazo [2,1-f ] [1,2,4] triazin-4-ol
To (4- (tert-butoxy) -2- (((S) -4, 4-difluoro-1-methylpyrrolidin-2-yl) methoxy) imidazo [2, 1-f) in TFA (5mL)][1,2,4]Triazin-7-yl) (naphthalen-1-yl) methanol (590mg, 1.19mmol) Et was added3SiH (5mL), and the mixture was stirred at 40 ℃ for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was treated with HCl (5mL, 4M) and extracted with DCM (5mL × 3). The aqueous layer was basified to pH-10 with NaOH (4M) and extracted with DCM/IPA (5:1, 10mL x 5). The combined organic phases were washed with brine (20 mL. times.3) and Na2SO4Dried, concentrated and purified by column chromatography to give the title compound (350mg, yield: 69%). MS M/e 426(M +1)+。
Step D: (S) -4-chloro-2- ((4, 4-difluoro-1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-ylmethyl) imidazo [2,1-f ] [1,2,4] triazine
Reacting (S) -2- ((4, 4-difluoro-1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-ylmethyl) imidazo [2,1-f][1,2,4]Triazin-4-ol (120mg, 0.28mmol) and Et3NHCl (500mg, 3.6mmol) in POCl3The mixture in (5mL) was stirred at 100 ℃ for 16 hours. The mixture was concentrated and diluted with 5mL of THF and the resulting mixture was used directly in the next step. MS M/e 444(M +1)+。
Step E: 2- ((S) -4- (2- (((S) -4, 4-difluoro-1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-ylmethyl) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
To (S) -4-chloro-2- ((4, 4-difluoro-1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-ylmethyl) imidazo [2, 1-f) at room temperature][1,2,4]To a solution of triazine in THF (5mL) was added DIEA (500mg, 3.87mmol) followed by a solution of (S) -2- (piperazin-2-yl) acetonitrile (71mg, 0.568mmol) in DCM (1.5 mL). The resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated and diluted with DCM (20 mL). The mixture was washed with brine (10 mL. times.2) over Na2SO4Dried, concentrated, and purified by preparative HPLC to give the title compound (55mg, yield: 30%, over two steps). MS M/e533(M +1)+。
Step F: 2- ((S) -1-acryloyl-4- (2- (((S) -4, 4-difluoro-1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-ylmethyl) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
To a mixture of 2- ((S) -4- (2- (((S) -4,4-difluoro-1-methylpyrrolidin-2-yl) methoxy) -7- (naphthalen-1-ylmethyl) imidazo [2,1-f][1,2,4]Triazin-4-yl) piperazin-2-yl) acetonitrile (55mg, 0.085mmol) and NaHCO3/H2To a mixture of O (200mg, 1mL) in MeCN (1mL) was added dropwise a solution of acryloyl chloride (25mg, 0.27mmol) in MeCN (1 mL). The resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with 10mL EA and washed with brine (5mL x 3). The combined organic phases are passed over Na2SO4Dried, concentrated and purified by preparative TLC (PE/EA ═ 1:2) to give the title compound (18mg, yield: 27%).1H NMR(400MHz,DMSO-d6)δ8.19(d,J＝7.2Hz,1H),7.92(d,J＝8.8Hz,1H),7.81(d,J＝7.2Hz,1H),7.58–7.46(m,2H),7.46–7.34(m,2H),7.28(s,1H),6.80(dd,J＝16.4,10.4Hz,1H),6.15(d,J＝16.4Hz,1H),5.74(d,J＝10.4Hz,1H),5.46–4.77(m,2H),4.63(s,2H),4.40–4.03(m,3H),3.84–3.46(m,1H),3.47–3.17(m,3H),3.04–2.55(m,5H),2.46–2.37(m,1H),2.32(s,3H),2.25-2.05(m,1H)ppm。MS:M/e 587(M+1)+。
Example 15: compound a 15: 2- ((S) -4- (7- ((1H-indazol-4-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) -1-acryloylpiperazin-2-yl) acetonitrile
Step A: 4- ((4- (tert-butoxy) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-7-yl) (hydroxy) methyl) -1H-indazole-1-carboxylic acid tert-butyl ester
To (S) -7-bromo-4- (tert-butoxy) -2- ((1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f][1,2,4]Triazine (300mg, 0.78mmol) in THF (8mL) at-78 deg.C cooled solution was added dropwise n-butyllithium (1.6M in n-hexane, 0.7mL, 1.2 mmol). After stirring for 30min, tert-butyl 4-formyl-1H-indazole-1-carboxylate (231mg, 0.9mmol) in THF (2mL) was added dropwise. The resulting mixture was gradually stirred to room temperature overnight. The solution is treated with NH4The Cl solution (5mL) was quenched and extracted with EA (15 mL). The organic layer was dried, concentrated and passed through CombiFlash (ii)DCM:NH3Purification (7M in MeOH) ═ 10:1) afforded the product (230mg, 53%). MS M/e 552(M +1)+。
And B: (S) -7- ((1H-indazol-4-yl) methyl) -2- ((1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-ol
Adding Et3SiH (2mL) and TFA (2mL) was added to 4- ((4- (tert-butoxy) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2, 1-f)][1,2,4]A solution of triazin-7-yl) (hydroxy) methyl) -1H-indazole-1-carboxylic acid tert-butyl ester (230mg, 0.4mmol) in DCM (2 mL). The solution was heated at 80 ℃ overnight. The solvent was evaporated under an oil pump and then azeotroped with toluene. The crude product was used directly in the next step (160mg, crude). MS M/e 380(M +1)+。
And C: (S) -7- ((1H-indazol-4-yl) methyl) -4-chloro-2- ((1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazine
Will contain (S) -7- ((1H-indazol-4-yl) methyl) -2- ((1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f][1,2,4]Triazin-4-ol (160mg, 0.4mmol), Et3HCl (222mg, 1.6mmol) and POCl3A sealed tube (8mL) was heated at 120 ℃ overnight. After cooling, the solvent was evaporated under an oil pump and co-distilled with toluene to give the crude product, which was used directly in the next step (160mg, crude). MS M/e398(M +1)+。
Step D: (S) -4- (7- ((1H-indazol-4-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester
(S) -benzyl 2- (cyanomethyl) piperazine-1-carboxylate (207mg, 0.8mmol) was added to (S) -7- ((1H-indazol-4-yl) methyl) -4-chloro-2- ((1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f][1,2,4]Triazine (160mg, 0.4mmol) in THF (10mL) was added followed by DIEA (413mg, 3.2 mmol). The reaction mixture was stirred at room temperature for 1 hour. Water (5mL) was added to the solution, and extracted with EA (10 mL). Subjecting the organic layer to Na2SO4Dried, concentrated and passed through Combiflash (DCM: NH)3Purification (7M in MeOH) ═ 20:3) afforded the product (80mg, 32%). MS M/e 621(M +1)+。
Step E: 4- ((4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-7-yl) methyl) -1H-indazole-1-carboxylic acid tert-butyl ester
Will (Boc)2O (34mg, 0.16mmol) was added to (S) -4- (7- ((1H-indazol-4-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f][1,2,4]Triazin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester (80mg, 0.13mmol), DMAP (2mg), and triethylamine (20mg, 0.2mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 2 hours, then concentrated and purified by CombiFlash (DCM: MeOH ═ 8%) to give the product (35mg, 38%) MS: M/e 721(M +1)+。
Step F: 4- ((4- ((S) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-7-yl) methyl) -1H-indazole-1-carboxylic acid tert-butyl ester
Reacting 4- ((4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2, 1-f)][1,2,4]Triazin-7-yl) methyl) -1H-indazole-1-carboxylic acid tert-butyl esterA solution of butyl ester (35mg, 0.05mmol) and Pd/C (wet, 10%, 23mg) in THF/EtOH (3mL/3mL) in H2Stir under balloon at room temperature overnight. The catalyst was filtered off and the filtrate was concentrated to give the crude product, which was used as such (20mg, 71%). MS M/e 587(M +1)+。
Step G: 4- ((4- ((S) -4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-7-yl) methyl) -1H-indazole-1-carboxylic acid tert-butyl ester
NaHCO is added3The solution (saturated, 0.3mL) was added to 4- ((4- ((S) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2, 1-f)][1,2,4]Triazin-7-yl) methyl) -1H-indazole-1-carboxylic acid tert-butyl ester (20mg, 0.03mmol) in CH3CN (3mL), followed by addition of acryloyl chloride (5mg, 0.06 mmol). The reaction mixture was stirred at room temperature for 1 hour. The solution was evaporated, water (2mL) was added, and extracted with EA (5 mL). The organic layer was dried, concentrated and used directly in the next step (20mg, crude). MS M/e 641(M +1)+。
Step H: 2- ((S) -4- (7- ((1H-indazol-4-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) -1-acryloylpiperazin-2-yl) acetonitrile
TFA (0.2mL) was added to 4- ((4- ((S) -4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2, 1-f)][1,2,4]A solution of triazin-7-yl) methyl) -1H-indazole-1-carboxylic acid tert-butyl ester (20mg, 0.03mmol) in DCM (3 mL). After stirring at room temperature for 1 hour, water was added to the solution, extracted with DCM and NaHCO3And (4) washing the solution. The organic layer was dried, concentrated and purified by preparative TLC (DCM: NH)3(7M in MeOH) ═ 10:1),the product was obtained (6mg, 38%).1H NMR(400MHz,CD3OD)δ8.12(s,1H),7.45(s,1H),7.42(d,J＝8.0Hz,1H),7.30(t,J＝8.0Hz,1H),6.97(d,J＝8.0Hz,1H),6.81(br.s,1H),6.28(d,J＝16.0Hz,1H),5.83(d,J＝8.0Hz,1H),5.09(s,1H),4.62(s,1H),4.57(s,3H),4.42-4.37(m,1H),4.15(s,1H),3.78-3.48(m,5H),3.20(s,2H),2.97(s,3H),2.91-2.85(m,2H),2.28-1.94(m,4H)ppm。MS:M/e541(M+1)+。
Example 18: compound a 18: 2- ((S) -1-acryloyl-4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (2- (trifluoromethyl) benzyl) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
Step A: (4- (tert-butoxy) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-7-yl) (2- (trifluoromethyl) phenyl) methanol
To (S) -7-bromo-4- (tert-butoxy) -2- ((1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f][1,2,4]A solution of triazine (200mg, 0.5mmol) in THF (8mL) was added dropwise a solution of n-butyllithium (1.6M, 0.77mL, 1mmol) maintaining the temperature between-75 and-65 ℃. After 1h, a suspension of 2- (trifluoromethyl) benzaldehyde (174mg, 1mmol) in THF (2mL) was added dropwise. The resulting mixture was stirred at-70 ℃ for 2h and then allowed to warm to room temperature overnight. Reacting with saturated NH4Aqueous Cl was quenched and extracted with EtOAc (20mL X3). The combined organic layers were washed with brine, over Na2SO4Dried, filtered and concentrated. The residue was purified by preparative TLC to give the target compound (210mg, 87.8%). MS M/e 480(M +1)+。
And B: (S) -2- ((1-methylpyrrolidin-2-yl) methoxy) -7- (2- (trifluoromethyl) benzyl) imidazo [2,1-f ] [1,2,4] triazin-4-ol
To (4- (tert-butoxy)) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f][1,2,4]To a solution of triazin-7-yl) (2- (trifluoromethyl) phenyl) methanol (310mg, 0.67mmol) in DCM (10mL) was added TFA (5mL) and Et3SiH (5 mL). The reaction mixture was stirred at 40 ℃ overnight. The mixture was concentrated in vacuo. Adding NaHCO to the residue3The solution (1M, 10mL) was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. Purification by preparative TLC gave the title product (200mg, 65.7%). MS M/e 408(M +1)+。
And C: (S) -4-chloro-2- ((1-methylpyrrolidin-2-yl) methoxy) -7- (2- (trifluoromethyl) benzyl) imidazo [2,1-f ] [1,2,4] triazine
To (S) -2- ((1-methylpyrrolidin-2-yl) methoxy) -7- (2- (trifluoromethyl) benzyl) imidazo [2, 1-f)][1,2,4]Triazin-4-ol (200mg, 0.49mmol) in POCl3To the solution (5mL) was added triethylamine hydrochloride (137mg, 1 mmol). The mixture was sealed and stirred at 110 ℃ overnight. The mixture was cooled to room temperature and concentrated in vacuo. The residue was used directly in the next step. MS M/e 426(M +1)+。
Step D: 2- ((S) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (2- (trifluoromethyl) benzyl) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
To the product of step C in acetonitrile (10mL) was slowly added a solution of (S) -2- (piperazin-2-yl) acetonitrile (125mg, 1mmol) and DIEA (258mg, 2mmol) in acetonitrile (2 mL). The mixture was stirred at room temperature for 2 h. The mixture was used directly in the next step. MS M/e515(M +1)+。
Step E: 2- ((S) -1-acryloyl-4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7- (2- (trifluoromethyl) benzyl) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
Addition of NaHCO to the mixture of products of step D3Solution (1M, 10 mL). Acryloyl chloride (90mg, 0.1mol) was slowly added to the mixture. The reaction was stirred at rt for 2 h. The resulting mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. Purification by preparative TLC gave the title product (1.2mg, 0.43% in three steps) 1H NMR (400MHz, CD3OD) δ 7.74(d, J ═ 7.7Hz,1H),7.52(t, J ═ 7.2Hz,1H),7.44(t, J ═ 7.3Hz,1H),7.28(d, J ═ 7.3Hz,1H),7.24(s,1H),6.82(s,1H),6.29(d, J ═ 16.7, 1H),5.84(d, J ═ 10.1Hz,1H),5.34(s,1H),5.10(s,1H),4.69(s,1H), 4.51-4.44 (m,1H),4.42(s,2H),3.82(s,1H), 3.70H (m, 3.70H), 3.3.3H (s,1H), 3.93 (m,1H), 3.3.1H), 3.93 (m,2H, 1H), 3.3.3.1H), 3.3.3.3.1H, 1H), 3.3.93 (m,1H), 3.3.3.1H). MS M/e 569(M +1)+。
Example 19: compound a 19: 2- ((S) -1-acryloyl-4- (7- ((4-hydroxynaphthalen-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
Step A: 2- ((S) -4- (7- ((4-hydroxynaphthalen-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
Reacting (S) -2- (cyanomethyl) -4- (7- ((4-methoxynaphthalen-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2, 1-f)][1,2,4]Triazin-4-yl) piperazine-1-carboxylic acid benzyl ester (50mg, 0.075mmol) was dissolved in DCM (3ml) and BBr was added3(1M in DCM, 2.3ml, 2.27 mmol). The mixture was stirred at room temperature for 2 hours. The reaction was concentrated to dryness (40mg) and the residue was used in the next step without further purification. MS M/e 513(M +1)+。
And B: 2- ((S) -1-acryloyl-4- (7- ((4-hydroxynaphthalen-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
To the product of step A (100mg, crude) in CH at 0 deg.C3Saturated NaHCO was added to the mixture in CN (2mL)3(1mL) then acryloyl chloride (20mg, 0.22mmol) in CH was added3CN (0.5 mL). The resulting mixture was stirred at room temperature for 30 min. The reaction was diluted with water and extracted with EA (60 mL). The organic layer was washed with brine, over Na2SO4Dried, filtered and concentrated. The residue was purified by preparative TLC to give the title compound (1.9mg, 10% over two steps).1H NMR(400MHz,DMSO-d6)δ10.08(s,1H),9.71(s,1H),8.18(d,J＝8.0Hz,1H),8.04(d,J＝8.0Hz,1H),7.51–5.40(m,2H),7.29(s,1H),7.20(d,J＝7.4Hz,1H),6.83–6.51(m,2H),6.20(d,J＝16.6Hz,1H),5.79(d,J＝10.1Hz,1H),5.07–4.98(m,2H),4.68–4.54(m,1H),4.50(s,3H),4.10(s,1H),3.79(s,2H),3.10–3.01(m,4H),2.92(d,J＝3.2Hz,6H),2.20(s,1H),2.05–1.89(m,3H)ppm。MS:M/e 567(M+1)+。
Example 20: compound a 20: 2- ((S) -1-acryloyl-4- (7- (2-fluoro-6-hydroxybenzyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
Step A: (2- (benzyloxy) -6-fluorophenyl) (4- (tert-butoxy) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-7-yl) methanol
To (S) -7-bromo-4- (tert-butoxy) -2- ((1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f][1,2,4]To a solution of triazine (383mg, 1mmol) in THF (10mL) was added dropwise n-butyllithium (1mL,1.6mmol) at a temperature of between-75 and-65 ℃. After 30min, a mixture of 2- (benzyloxy) -6-fluorobenzaldehyde (276mg, 1.2mmol) in THF (2mL) was added dropwise. The resulting mixture was stirred at-70 ℃ for 1h, then warmed to room temperature for 16 h. Reacting with saturated NH4Aqueous Cl was quenched and extracted with EtOAc (50mL × 2). The combined organic layers were washed with brine, over Na2SO4Dried, filtered and concentrated. The residue was purified by combi flash to give the objective compound (320mg, 63%). MS M/e 536(M +1)+。
And B: (S) -7- (2- (benzyloxy) -6-fluorobenzyl) -2- ((1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-ol
To a mixture of the product of step A (320mg) in DCE (3mL) was added TFA (3mL) and Et3SiH (3 mL). The reaction was stirred at 25 ℃ overnight. The mixture was concentrated to dryness and the residue was used in the next step without further purification. MS M/e 464(M +1)+。
And C: (S) -7- (2- (benzyloxy) -6-fluorobenzyl) -4-chloro-2- ((1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazine
Dissolve the product of step B (120mg, 0.26mmol) in POCl3To (2ml) was then added triethylamine hydrochloride (106mg, 0.78 mmol). The reaction was heated at 100 ℃ overnight. The mixture was concentrated to dryness and the residue was used directly in the next step without further purification (100mg, crude). MS M/e482(M +1)+。
Step D: (S) -4- (7- (2- (benzyloxy) -6-fluorobenzyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester
The product of step C (100mg, 0.21mmol) was dissolved in THF (3ml) then DIEA (81mg, 0.63mmol) and benzyl (S) -2- (cyanomethyl) piperazine-1-carboxylate (59mg, 0.23mmol) were added and the reaction stirred at room temperature for 3 hours. The reaction was quenched with saturated water and extracted with EtOAc (80 mL). The organic layer was washed with brine, over Na2SO4Dried, filtered and concentrated. The residue was purified by combi flash to give the title compound (40mg, 10% over two steps). MS M/e 705(M +1)+。
Step E: 2- ((S) -4- (7- (2-fluoro-6-hydroxybenzyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
The product of step D (40mg) was dissolved in a mixture of EtOH (2mL) and THF (2mL) followed by addition of Pd/C (10mg, 10%). The reaction mixture was hydrogenated at a balloon, stirred overnight, and filtered through a pad of celite. The filtrate was evaporated to give the title compound (40mg, crude) which was used in the next step without further purification. MS M/e 481(M +1)+。
Step F: 2- ((S) -1-acryloyl-4- (7- (2-fluoro-6-hydroxybenzyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
To the product of step E (50mg, crude) in CH at 0 deg.C3Saturated NaHCO was added to the mixture in CN (1mL)3(1mL) then acryloyl chloride (10mg, 0.1mmol) in CH was added3CN (0.3 mL). The resulting mixture was stirred at room temperature for 30 min. The reaction was diluted with water and extracted with EA (60 mL). Will be organicThe layers were washed with brine, over Na2SO4Dried, filtered and concentrated. The residue was purified by preparative TLC to give the title compound (0.5mg, 3% over two steps). 1H NMR (400MHz, cd3od) δ 7.20-7.04 (m,2H),6.80(s,1H), 6.69-6.53 (m,2H),6.28(d, J ═ 17.3Hz,1H),5.83(d, J ═ 10.3Hz,1H),5.09(s,1H),4.80(s,2H), 4.54-4.49 (m,1H),4.17(s,3H), 3.96-3.87 (m,1H), 3.84-3.74 (m,1H),3.53-3.48(m,2H), 3.29-3.17 (m,2H),3.08(s,3H), 2.88-2.65 (m,3H),2.47-2.40(m,1H),2.21-2.08(m, 3H). MS M/e 535(M +1)+。
Example 21: compound a 21: 2- ((S) -1-acryloyl-4- (7- ((2-hydroxynaphthalen-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
Step A: (4- (tert-butoxy) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-7-yl) (2-methoxynaphthalen-1-yl) methanol
To (S) -7-bromo-4- (tert-butoxy) -2- ((1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f][1,2,4]To a solution of triazine (383mg, 1mmol) in THF (10mL) was added dropwise n-butyllithium (1mL, 1.6mmol) maintaining the temperature between-75 and-65 ℃. After 30min, a mixture of 2-methoxy-1-naphthaldehyde (223mg, 1.2mmol) in THF (2mL) was added dropwise. The resulting mixture was stirred at-70 ℃ for 1h, then warmed to room temperature for 16 h. Reacting with saturated NH4Aqueous Cl was quenched and extracted with EtOAc (50mL × 2). The combined organic layers were washed with brine, over Na2SO4Dried, filtered and concentrated. The residue was purified by combi flash to give the title compound (340mg, 69%). MS M/e 492(M +1)+。
And B: (S) -7- ((2-Methylnaphthalen-1-yl) methyl) -2- ((1-Methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-ol
To a mixture of the product of step A (340mg, 0.8mmol) in DCE (3mL) was added TFA (3mL) and Et3SiH (3 mL). The reaction was heated at 25 ℃ overnight. The mixture was concentrated to dryness and the residue was used in the next step without further purification. MS M/e 420(M +1)+。
And C: (S) -benzyl 2- (cyanomethyl) -4- (7- ((2-methoxynaphthalen-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazine-1-carboxylate
To POCl3To the residue of step B (300mg, crude) (4mL) was added triethylamine hydrochloride (292mg, 2.15 mmol). The resulting mixture was stirred at 100 ℃ overnight. The mixture was concentrated to dryness and treated with THF (15 mL). DIEA (387mg, 2.04mmol) and benzyl (S) -2- (cyanomethyl) piperazine-1-carboxylate (194mg, 0.75mmol) were then added and the reaction stirred at room temperature for 2 hours. The reaction was quenched with water and extracted with EtOAc (80 mL). The organic layer was washed with brine, over Na2SO4Dried, filtered and concentrated. The residue was purified by combi flash to give the title compound (130mg, 27% over two steps). MS M/e 661(M +1)+。
Step D: 2- ((S) -4- (7- ((2-hydroxynaphthalen-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
To a mixture of the product of step C (30mg, 0.05mmol) in DCM (3mL) at room temperature was added 1N BBr in DCM3(0.5mL, 0.5 mmol). The reaction was stirred at room temperature for 2 hours. The reaction was filtered and the filter cake was washed with MTBE to give the title compound (20mg, crude) which was used without further work-upThe product can be directly used in the next step after one-step purification. MS M/e 513(M +1)+。
Step E: 2- ((S) -1-acryloyl-4- (7- ((2-hydroxynaphthalen-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) imidazo [2,1-f ] [1,2,4] triazin-4-yl) piperazin-2-yl) acetonitrile
To the product of step D (20mg, crude) in CH at 0 deg.C3Saturated NaHCO was added to the mixture in CN (1mL)3(0.5mL) then acryloyl chloride (6mg, 0.1mmol) in CH was added3CN (0.3 mL). The resulting mixture was stirred at room temperature for 30 min. The reaction was diluted with water and extracted with EA. The organic layer was washed with brine, over Na2SO4Dried, filtered and concentrated. The residue was purified by preparative TLC to give the title compound (2.25mg, 10% over two steps). 1H NMR (400MHz, DMSO-d6) δ 10.01(s,1H),7.95(d, J ═ 7.8Hz,1H),7.87(d, J ═ 7.8Hz,1H),7.80(d, J ═ 8.7Hz,1H),7.47(t, J ═ 7.3Hz,1H),7.34(d, J ═ 6.9Hz,3H),6.71-6.91(m,2H),6.24(d, J ═ 16.5Hz,1H),5.84(d, J ═ 9.7Hz,1H), 5.19-4.85 (m,2H),4.80-4.71(m,2H),4.55(s,2H),4.18(s,1H),3.92(s,1H),3.67(s, 3.67, 1H), 3.83 (s,2H), 3.18 (s,2H), 3.07(m, 2H), 3.3.3.3.83 (m,2H), 3.3.3.3.3.3H). MS M/e 567(M +1)+。
Biochemical function assay
His-tagged KRAS (aa 1-169) G12C, C51S, C80L, C118S were expressed, purified, and internally loaded with GDP. All protein and substrate solutions were in a solution containing 25mM HEPES pH7.5, 10mM MgCl2And 0.01% Triton X-100 in assay buffer. Purified GDP-loaded KRAS (aa 1-169) G12C, C51S, C80L, C118S protein was preincubated with serially diluted compounds at 24 ℃ for 3 hours. Purified SOS1(aa 564-1049) protein, GTP S (Sigma) and GST-cRaf RBD (aa 1-149) were then added to each well and incubated at 24 ℃ for a further 3 hours. This addition initiated a nucleotide exchange reaction and the conversion of inactive GDP-loaded KRAS G12C to active GTP S KRAS G12C binding to GST-cRaf RBD. After incubation, Mab anti-6 HIS-Tb cryptate (Cisbio) and Mab anti-GST-XL 665(Cisbio) were added and incubated for a further 3 hours at 24 ℃. The binding interaction between active GTP S KRAS G12C and GST-cRaf RBD brings Tb and XL665 into close proximity, thereby increasing the FRET signal (Ex337nm, Em665nm/620 nm). The percent inhibition of the nucleotide exchange reaction in the presence of an increase in compound concentration was calculated based on the ratio of the fluorescence at 665nm to 620nm detected on a BMG PHERAStar FSX instrument. IC50 values were calculated for each compound by fitting the data to a four parameter logistic model by Dotmatics.
Table 1: compound A series
| Compound numbering | IC50(nmol) | Compound numbering | IC50(nmol) |
| A4 | 46.7 | A5 | 29 |
| A6 | 100 | A7 | 47.8 |
| A8 | 7700 | A9 | 1060 |
| A10 | 187 | A11 | 215 |
| A12 | 217 | A13 | 101 |
| A14 | 506 | A15 | 1180 |
| A18 | 235 | A19 | 9.6 |
| A20 | 19.1 | A21 | 20.8 |
Claims (12)
1. A preparation method of a compound shown as a formula (I),
L1and L2Each independently selected from the group consisting of a single bond, -CO-NH-、-NH-CO-、-O-、-NRa-、-NRa(CH2)m-、-(CH2)m-、-O-(CH2)m-、-O-CH(Ra)-、-CH(Ra)-、-CH(Ra)(CH2)m-、-(CH2)m-O-；
R1Selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl, said cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with at least one R6Substituent (e.g., - (R)6)q1When q1 is greater than 1, each R6Are the same or different substituents);
R2is selected from-NRbRcCycloalkyl, heterocyclyl, aryl, heteroaryl, said-NRbRcCycloalkyl, heterocyclyl, aryl, heteroaryl optionally substituted with at least one R6Substituent (e.g., - (R)6)q2When q2 is greater than 1, each R6Are the same or different substituents);
R6is selected from-C1-8Alkyl, halogen, hydroxy, oxo, -C1-8Alkoxy, -NRbRcCycloalkyl, heterocyclyl, aryl, or heteroaryl, said-C1-8Alkyl, -C1-8Alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with at least one halogen, hydroxy, amino, CN, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or when R is6When attached to two adjacent atoms of the ring, two R6Taken together with the carbon atom to which they are attached to form a 5-8 membered ring, said 5-8 membered ring containing 0, 1 or 2 heteroatoms selected from N, O or optionally oxidized S; r3Selected from hydrogen, halogen, -C1-8Alkyl, -C2-8Alkenyl, -C2-8Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, said-C1-8Alkyl, -C2-8Alkenyl, -C2-8Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with halogen, hydroxy, -C1-8Alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl;
R4is selected from
R5Selected from hydrogen, halogen, -C1-8Alkyl, -C2-8Alkenyl, -C2-8Alkynyl, oxo, -NRbRc、-(CH2)m-C(O)-NRdReCycloalkyl, heterocyclyl, aryl, heteroaryl or- (CH)2)m-CN；
Each Ra、RbAnd RcEach independently selected from hydrogen, deuterium, cyano, halogen, hydroxy, -C1-8Alkoxy, -C1-8Alkyl, -C2-8Alkenyl, -C2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NRdReor-CO-NRdResaid-C1-8Alkoxy, -C1-8Alkyl, -C2-8Alkenyl, -C2-8Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with RfIs substituted, or
(RaAnd Rb)、(RaAnd Rc)、(RbAnd Rc) With the atoms to which they are attached form a 4-6 membered ring, said 4-6 membered ring optionally substituted with at least 1RgSubstitution;
each RfSelected from halogen, hydroxy, oxo, -C1-8Alkoxy, -NRdRe、-CO-NRdRe、-NRd-CO-ReCycloalkyl, heterocyclyl, aryl or heteroaryl, said-C1-8Alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted by halogen, hydroxy or-C1-4Alkyl substitution;
Rd、Reand RgEach independently selected from hydrogen, deuterium, halogen, oxo, or-C1-8Alkyl radical of formula (I), said1-8Alkyl is optionally substituted by at least one halogen, oxo, -CF3or-COCH3Substitution;
PR1selected from ether protecting groups, ester protecting groups, carbamatesA protecting group, preferably neopentyl, tert-butyl, benzyl, acetyl, propionyl, pivaloyl, Boc, Cbz, more preferably tert-butyl;
PR2selected from Boc or Cbz;
p is independently selected from 0, 1,2, 3 or 4;
q1 and q2 are independently selected from 0, 1,2, 3, 4, 5, 6, 7 or 8;
each m and n is independently selected from 0, 1,2, 3, 4, 5 or 6.
2. The method of claim 1, wherein:
the reagent used in step 1 is selected from NBS and Br2。
3. The method of claim 1, wherein:
the reagents used in step 2 and step 7 are respectively and independently selected from phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, Lucas reagent, mixture of concentrated hydrochloric acid and anhydrous zinc chloride, Vilesnier-Haack reagent, thionyl chloride, sulfuryl chloride and chlorine gas, preferably POCl3、PCl5、SOCl2More preferably POCl3。
4. The method of claim 1, wherein:
the reagent used in step 3 is selected from alkali metal salts of alcohols, preferably sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium tert-butoxide, sodium benzylate, potassium benzylate, lithium benzylate, more preferably lithium tert-butoxide.
5. The method of claim 1, wherein:
the reagent used in step 4 is selected from the group consisting of alkali metal hydrides, alkali metal salts, alkyllithium compounds and aminolithium compounds, preferably sodium hydride, potassium hydride, lithium hydride, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, n-butyllithium, sec-butyllithium, tert-butyllithium, diisopropylaminolithium and hexamethyldisilaaminolithium, and more preferably sodium hydride.
6. The method of claim 1, wherein:
the reagent used in step 5 is selected from alkali metal salts of alcohols, alkyllithium compounds and aminolithium compounds, preferably sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, n-butyllithium, sec-butyllithium, tert-butyllithium, diisopropylaminolithium and hexamethyldisilazane, and more preferably n-butyllithium.
7. The method of claim 1, wherein:
the deprotection conditions in the step 6 and the step 9 are respectively and independently selected from catalytic hydrogenation or acidic deprotection, preferably trifluoroacetic acid and triethylsilane combined, BBr3Pd/C in combination with hydrogen, trifluoroacetic acid, hydrochloric acid, Pd/C in combination with cyclohexadiene, more preferably trifluoroacetic acid in combination with triethylsilane, BBr3Pd/C in combination with hydrogen.
8. The method of claim 1, wherein:
the reagent used in step 8 is selected from nitrogen-containing organic bases, preferably triethylamine, diethylamine, diisopropylethylamine, pyridine, methylimidazole, piperidine, morpholine, indoline, quinoline, isoquinoline, dimethylaminopyridine, more preferably triethylamine, diethylamine, diisopropylethylamine, dimethylaminopyridine, and even more preferably diisopropylethylamine.
9. The method of claim 1, wherein:
the reagent used in step 9 is selected from inorganic bases, nitrogen-containing organic bases, and alkali metal hydrides, preferably sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, diethylamine, diisopropylethylamine, pyridine, methylimidazole, piperidine, morpholine, indoline, quinoline, isoquinoline, and dimethylaminopyridine, and more preferably sodium bicarbonate.
10. The method of claim 1, wherein:
L1selected from the group consisting of single bond, -CO-, - (CH)2)m-、-CH(Ra)-、-CH(Ra)(CH2)m-、-(CH2)m-O-, further preferably selected from- (CH)2)m-、-CH(Ra) -; and/or
L2Selected from single bond, -O- (CH)2)m-、-O-CH(Ra)-、-O-CH(Ra)-(CH2)m-; and/or
R1Is selected from
And/or
R2Is selected from
-NRbRc、
And/or
R3Selected from hydrogen, halogen or-C1-8An alkyl group; and/or
R3' is selected from hydrogen, -C1-8Alkyl, -C2-8Alkenyl or-C2-8An alkynyl group; and/or
R4Is selected from
And/or
R5Selected from hydrogen, -CH3、-C2H5、-C3H7、-C4H9、-C5H11、-(CH2)m-C(O)-NRdRe、-(CH2)m-CN。
11. The method of claim 1, wherein:
R1is selected from
R2Is selected from
(e.g. in
)、
(e.g. in
)、
12. The method of claim 1, wherein:
a compound of the formula (I) or (II) is
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