WO2022199589A1 - 嘧啶衍生物 - Google Patents
嘧啶衍生物 Download PDFInfo
- Publication number
- WO2022199589A1 WO2022199589A1 PCT/CN2022/082343 CN2022082343W WO2022199589A1 WO 2022199589 A1 WO2022199589 A1 WO 2022199589A1 CN 2022082343 W CN2022082343 W CN 2022082343W WO 2022199589 A1 WO2022199589 A1 WO 2022199589A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- phenyl
- pharmaceutically acceptable
- methoxy
- chloro
- compound
- Prior art date
Links
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 title abstract description 3
- 150000003230 pyrimidines Chemical class 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 86
- 150000003839 salts Chemical class 0.000 claims abstract description 55
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 41
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 36
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 32
- 125000000217 alkyl group Chemical group 0.000 claims description 28
- 229910052794 bromium Inorganic materials 0.000 claims description 28
- 229910052801 chlorine Inorganic materials 0.000 claims description 28
- 125000005842 heteroatom Chemical group 0.000 claims description 28
- 229910052740 iodine Inorganic materials 0.000 claims description 28
- 229910052731 fluorine Inorganic materials 0.000 claims description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 21
- 229910052736 halogen Inorganic materials 0.000 claims description 20
- 150000002367 halogens Chemical class 0.000 claims description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims description 17
- 229910052717 sulfur Inorganic materials 0.000 claims description 15
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 125000004076 pyridyl group Chemical group 0.000 claims description 9
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 8
- 125000006716 (C1-C6) heteroalkyl group Chemical group 0.000 claims description 7
- 125000002757 morpholinyl group Chemical group 0.000 claims description 7
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 7
- 238000006467 substitution reaction Methods 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 125000004193 piperazinyl group Chemical group 0.000 claims description 5
- 125000003386 piperidinyl group Chemical group 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 4
- 125000004455 (C1-C3) alkylthio group Chemical group 0.000 claims description 4
- 125000000335 thiazolyl group Chemical group 0.000 claims description 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 3
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims description 3
- 108010081348 HRT1 protein Hairy Proteins 0.000 claims description 3
- 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 claims description 3
- VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 3
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 3
- 125000002971 oxazolyl group Chemical group 0.000 claims description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 2
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 claims 1
- 238000003419 tautomerization reaction Methods 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 8
- 201000010099 disease Diseases 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 6
- -1 inorganic acid salts Chemical class 0.000 description 224
- 238000005481 NMR spectroscopy Methods 0.000 description 113
- 238000000034 method Methods 0.000 description 97
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 82
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 71
- 238000006243 chemical reaction Methods 0.000 description 64
- 239000000243 solution Substances 0.000 description 63
- 239000007787 solid Substances 0.000 description 41
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 32
- 235000019439 ethyl acetate Nutrition 0.000 description 28
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- 125000001424 substituent group Chemical group 0.000 description 20
- 101000941879 Homo sapiens Leucine-rich repeat serine/threonine-protein kinase 2 Proteins 0.000 description 19
- 150000001412 amines Chemical class 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- 102100032693 Leucine-rich repeat serine/threonine-protein kinase 2 Human genes 0.000 description 17
- 239000012043 crude product Substances 0.000 description 17
- 239000003921 oil Substances 0.000 description 17
- UJTLJYUBCUVDIX-UHFFFAOYSA-N 4-(4-methoxy-2-nitrophenyl)morpholine Chemical compound [O-][N+](=O)C1=CC(OC)=CC=C1N1CCOCC1 UJTLJYUBCUVDIX-UHFFFAOYSA-N 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- 239000000706 filtrate Substances 0.000 description 16
- 239000000203 mixture Substances 0.000 description 16
- YAAWASYJIRZXSZ-UHFFFAOYSA-N pyrimidine-2,4-diamine Chemical compound NC1=CC=NC(N)=N1 YAAWASYJIRZXSZ-UHFFFAOYSA-N 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 125000003118 aryl group Chemical group 0.000 description 15
- 239000000460 chlorine Substances 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 239000002585 base Substances 0.000 description 14
- 239000002253 acid Substances 0.000 description 13
- 125000004429 atom Chemical group 0.000 description 13
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 12
- 125000000623 heterocyclic group Chemical group 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 125000001183 hydrocarbyl group Chemical group 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 125000006239 protecting group Chemical group 0.000 description 9
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 125000001072 heteroaryl group Chemical group 0.000 description 8
- 230000004770 neurodegeneration Effects 0.000 description 8
- 208000015122 neurodegenerative disease Diseases 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 8
- 125000000524 functional group Chemical group 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 description 7
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
- KCOBIBRGPCFIGF-UHFFFAOYSA-N 1-bromo-4-methoxy-2-nitrobenzene Chemical compound COC1=CC=C(Br)C([N+]([O-])=O)=C1 KCOBIBRGPCFIGF-UHFFFAOYSA-N 0.000 description 6
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 125000004122 cyclic group Chemical group 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 230000035772 mutation Effects 0.000 description 6
- 238000012746 preparative thin layer chromatography Methods 0.000 description 6
- 108090000765 processed proteins & peptides Proteins 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 125000004434 sulfur atom Chemical group 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 5
- 125000003342 alkenyl group Chemical group 0.000 description 5
- 125000000304 alkynyl group Chemical group 0.000 description 5
- 239000012298 atmosphere Substances 0.000 description 5
- 229960003638 dopamine Drugs 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 5
- 125000004353 pyrazol-1-yl group Chemical group [H]C1=NN(*)C([H])=C1[H] 0.000 description 5
- 150000003254 radicals Chemical class 0.000 description 5
- XIKUAKVCJMVXCI-UHFFFAOYSA-N 2,5-dichloro-n-(2-dimethylphosphorylphenyl)pyrimidin-4-amine Chemical compound CP(C)(=O)C1=CC=CC=C1NC1=NC(Cl)=NC=C1Cl XIKUAKVCJMVXCI-UHFFFAOYSA-N 0.000 description 4
- PLEJCMKVJYUUBA-UHFFFAOYSA-N 2-fluoro-4-methoxy-1-nitrobenzene Chemical compound COC1=CC=C([N+]([O-])=O)C(F)=C1 PLEJCMKVJYUUBA-UHFFFAOYSA-N 0.000 description 4
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 4
- OYSJXTOZCXRLDI-UHFFFAOYSA-N 3-methoxy-5-morpholin-4-ylaniline Chemical compound COC1=CC(N)=CC(N2CCOCC2)=C1 OYSJXTOZCXRLDI-UHFFFAOYSA-N 0.000 description 4
- BECJQIPSWDVBPG-UHFFFAOYSA-N 5-methoxy-2-morpholin-4-ylaniline Chemical compound NC1=CC(OC)=CC=C1N1CCOCC1 BECJQIPSWDVBPG-UHFFFAOYSA-N 0.000 description 4
- CZRAMOZWAQDBOH-UHFFFAOYSA-N COC(C=C1)=CC=C1NC(N=C1NC(C=CC=C2)=C2P(C)(C)=O)=NC=C1Cl Chemical compound COC(C=C1)=CC=C1NC(N=C1NC(C=CC=C2)=C2P(C)(C)=O)=NC=C1Cl CZRAMOZWAQDBOH-UHFFFAOYSA-N 0.000 description 4
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 125000002619 bicyclic group Chemical group 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 125000000392 cycloalkenyl group Chemical group 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- 229940098779 methanesulfonic acid Drugs 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- 125000004430 oxygen atom Chemical group O* 0.000 description 4
- 125000003367 polycyclic group Chemical group 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- VWYWLAMDXYCVKQ-UHFFFAOYSA-N (2-dimethylphosphorylphenyl)methanamine Chemical compound CP(C)(C1=C(CN)C=CC=C1)=O VWYWLAMDXYCVKQ-UHFFFAOYSA-N 0.000 description 3
- KRZHNWCGVABBQS-UHFFFAOYSA-N (3-methoxy-4-nitrophenyl)-morpholin-4-ylmethanone Chemical compound C1=C([N+]([O-])=O)C(OC)=CC(C(=O)N2CCOCC2)=C1 KRZHNWCGVABBQS-UHFFFAOYSA-N 0.000 description 3
- GPRUBQPFDXFIJN-UHFFFAOYSA-N (4-amino-3-methoxyphenyl)-morpholin-4-ylmethanone Chemical compound C1=C(N)C(OC)=CC(C(=O)N2CCOCC2)=C1 GPRUBQPFDXFIJN-UHFFFAOYSA-N 0.000 description 3
- FZZMTSNZRBFGGU-UHFFFAOYSA-N 2-chloro-7-fluoroquinazolin-4-amine Chemical compound FC1=CC=C2C(N)=NC(Cl)=NC2=C1 FZZMTSNZRBFGGU-UHFFFAOYSA-N 0.000 description 3
- DHHGHQKIKXKQGJ-UHFFFAOYSA-N 2-dimethylphosphorylaniline Chemical compound CP(C)(=O)C1=CC=CC=C1N DHHGHQKIKXKQGJ-UHFFFAOYSA-N 0.000 description 3
- ZSVQXYLKROOGIU-UHFFFAOYSA-N 2-dimethylphosphorylbenzonitrile Chemical compound CP(C)(C(C=CC=C1)=C1C#N)=O ZSVQXYLKROOGIU-UHFFFAOYSA-N 0.000 description 3
- MTEIMCRMZXDKKN-UHFFFAOYSA-N 2-methoxy-1-n-(2-methoxyethyl)-1-n-methylbenzene-1,4-diamine Chemical compound COCCN(C)C1=CC=C(N)C=C1OC MTEIMCRMZXDKKN-UHFFFAOYSA-N 0.000 description 3
- QAJAXOPOSLBUDC-UHFFFAOYSA-N 2-methyl-1,3-dihydroisoindol-5-amine Chemical compound C1=C(N)C=C2CN(C)CC2=C1 QAJAXOPOSLBUDC-UHFFFAOYSA-N 0.000 description 3
- BRTDKJDVVFXVQK-UHFFFAOYSA-N 3-methoxy-4-morpholin-4-ylaniline Chemical compound COC1=CC(N)=CC=C1N1CCOCC1 BRTDKJDVVFXVQK-UHFFFAOYSA-N 0.000 description 3
- KORWLDQABONDQH-UHFFFAOYSA-N 4-(2-methoxy-4-nitrophenyl)morpholine Chemical compound COC1=CC([N+]([O-])=O)=CC=C1N1CCOCC1 KORWLDQABONDQH-UHFFFAOYSA-N 0.000 description 3
- LYFCUCBHLVLGSR-UHFFFAOYSA-N 4-bromo-1-(3-nitrophenyl)pyrazole Chemical compound [O-][N+](=O)C1=CC=CC(N2N=CC(Br)=C2)=C1 LYFCUCBHLVLGSR-UHFFFAOYSA-N 0.000 description 3
- FJCKBSTUEJMTOO-UHFFFAOYSA-N 4-methoxy-3-morpholin-4-ylaniline Chemical compound COC1=CC=C(N)C=C1N1CCOCC1 FJCKBSTUEJMTOO-UHFFFAOYSA-N 0.000 description 3
- YYDYAQAVAHKFJO-UHFFFAOYSA-N 5-methoxy-2,3-dihydro-1h-indole Chemical compound COC1=CC=C2NCCC2=C1 YYDYAQAVAHKFJO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEUXMJMQUYZAER-UHFFFAOYSA-N CN(CCOC)C(C=C(C=C1)NC(N=C2NC(C=CC=C3)=C3P(C)(C)=O)=NC=C2Cl)=C1OC Chemical compound CN(CCOC)C(C=C(C=C1)NC(N=C2NC(C=CC=C3)=C3P(C)(C)=O)=NC=C2Cl)=C1OC XEUXMJMQUYZAER-UHFFFAOYSA-N 0.000 description 3
- FUKUDAJILQHMEZ-UHFFFAOYSA-N CN(CCOC)C(C=CC(OC)=C1)=C1NC(N=C1NC(C=CC=C2)=C2P(C)(C)=O)=NC=C1Cl Chemical compound CN(CCOC)C(C=CC(OC)=C1)=C1NC(N=C1NC(C=CC=C2)=C2P(C)(C)=O)=NC=C1Cl FUKUDAJILQHMEZ-UHFFFAOYSA-N 0.000 description 3
- BAXGQDKFTOVUPU-UHFFFAOYSA-N CN(CCOC)C1=CC(NC(N=C2NC(C=CC=C3)=C3P(C)(C)=O)=NC=C2Cl)=CC(OC)=C1 Chemical compound CN(CCOC)C1=CC(NC(N=C2NC(C=CC=C3)=C3P(C)(C)=O)=NC=C2Cl)=CC(OC)=C1 BAXGQDKFTOVUPU-UHFFFAOYSA-N 0.000 description 3
- WHQITHUUXVJUSQ-UHFFFAOYSA-N COC(C=C1)=CC(N2CCOCC2)=C1NC(N=C1NC(C=CC=C2)=C2P(C)(C)=O)=NC=C1Cl Chemical compound COC(C=C1)=CC(N2CCOCC2)=C1NC(N=C1NC(C=CC=C2)=C2P(C)(C)=O)=NC=C1Cl WHQITHUUXVJUSQ-UHFFFAOYSA-N 0.000 description 3
- ONXALUNCAFZERA-UHFFFAOYSA-N COC1=CC(N2CCOCC2)=CC(NC(N=C2NC(C=CC=C3)=C3P(C)(C)=O)=NC=C2Cl)=C1 Chemical compound COC1=CC(N2CCOCC2)=CC(NC(N=C2NC(C=CC=C3)=C3P(C)(C)=O)=NC=C2Cl)=C1 ONXALUNCAFZERA-UHFFFAOYSA-N 0.000 description 3
- FVTGOAWCOBPHKJ-UHFFFAOYSA-N COC1=CC=CC(NC(N=C2NC(C=CC=C3)=C3P(C)(C)=O)=NC=C2Cl)=C1N1CCOCC1 Chemical compound COC1=CC=CC(NC(N=C2NC(C=CC=C3)=C3P(C)(C)=O)=NC=C2Cl)=C1N1CCOCC1 FVTGOAWCOBPHKJ-UHFFFAOYSA-N 0.000 description 3
- LILWBGFNPJSZRO-UHFFFAOYSA-N CP(C)(C1=C(CNC2=NC(Cl)=NC=C2Cl)C=CC=C1)=O Chemical compound CP(C)(C1=C(CNC2=NC(Cl)=NC=C2Cl)C=CC=C1)=O LILWBGFNPJSZRO-UHFFFAOYSA-N 0.000 description 3
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 3
- 102220577899 Leucine-rich repeat serine/threonine-protein kinase 2_G2019S_mutation Human genes 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229910052796 boron Inorganic materials 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- WQAWEUZTDVWTDB-UHFFFAOYSA-N dimethyl(oxo)phosphanium Chemical compound C[P+](C)=O WQAWEUZTDVWTDB-UHFFFAOYSA-N 0.000 description 3
- 229940093915 gynecological organic acid Drugs 0.000 description 3
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical compound C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical group CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 2
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- GIKMWFAAEIACRF-UHFFFAOYSA-N 2,4,5-trichloropyrimidine Chemical compound ClC1=NC=C(Cl)C(Cl)=N1 GIKMWFAAEIACRF-UHFFFAOYSA-N 0.000 description 2
- JMUDXQVNBZCQRF-UHFFFAOYSA-N 2-bromo-1-methoxy-4-nitrobenzene Chemical group COC1=CC=C([N+]([O-])=O)C=C1Br JMUDXQVNBZCQRF-UHFFFAOYSA-N 0.000 description 2
- SMVGKYGHORARFC-UHFFFAOYSA-N 2-chloro-N-(2-dimethylphosphorylphenyl)-5-(trifluoromethyl)pyrimidin-4-amine Chemical compound ClC1=NC=C(C(=N1)NC1=C(C=CC=C1)P(C)(C)=O)C(F)(F)F SMVGKYGHORARFC-UHFFFAOYSA-N 0.000 description 2
- FNVCHOKFWYQJJR-UHFFFAOYSA-N 2-chloro-N-(2-dimethylphosphorylphenyl)-5-fluoropyrimidin-4-amine Chemical compound N1=C(N=CC(=C1NC1=C(C=CC=C1)P(=O)(C)C)F)Cl FNVCHOKFWYQJJR-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- CUYKNJBYIJFRCU-UHFFFAOYSA-N 3-aminopyridine Chemical compound NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N 3H-indole Chemical compound C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 2
- VJJMMWWNJQLQDM-UHFFFAOYSA-N 4-(2-methoxy-5-nitrophenyl)morpholine Chemical compound COC1=CC=C([N+]([O-])=O)C=C1N1CCOCC1 VJJMMWWNJQLQDM-UHFFFAOYSA-N 0.000 description 2
- GZAHFOQPNREFCZ-UHFFFAOYSA-N 4-(2-methoxy-6-nitrophenyl)morpholine Chemical compound COC1=CC=CC([N+]([O-])=O)=C1N1CCOCC1 GZAHFOQPNREFCZ-UHFFFAOYSA-N 0.000 description 2
- FQSSTTVXBFMHJK-UHFFFAOYSA-N 4-(3-methoxy-5-nitrophenyl)morpholine Chemical compound [O-][N+](=O)C1=CC(OC)=CC(N2CCOCC2)=C1 FQSSTTVXBFMHJK-UHFFFAOYSA-N 0.000 description 2
- RNMOZCXLJVXTKP-UHFFFAOYSA-N 4-(5-methoxy-2-nitrophenyl)morpholine Chemical compound COC1=CC=C([N+]([O-])=O)C(N2CCOCC2)=C1 RNMOZCXLJVXTKP-UHFFFAOYSA-N 0.000 description 2
- JZJKYYMACBPTDC-UHFFFAOYSA-N 4-bromo-1-(4-nitrophenyl)pyrazole Chemical compound C1=CC([N+](=O)[O-])=CC=C1N1N=CC(Br)=C1 JZJKYYMACBPTDC-UHFFFAOYSA-N 0.000 description 2
- JDXRMEMHYIYRAN-UHFFFAOYSA-N 4-methoxy-2-morpholin-4-ylaniline Chemical compound COC1=CC=C(N)C(N2CCOCC2)=C1 JDXRMEMHYIYRAN-UHFFFAOYSA-N 0.000 description 2
- VRJHQPZVIGNGMX-UHFFFAOYSA-N 4-piperidinone Chemical compound O=C1CCNCC1 VRJHQPZVIGNGMX-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- HOLCXFFUQHFRHC-UHFFFAOYSA-N CN(C)S(C(C=C1)=CC=C1NC(N=C1NC(C=CC=C2)=C2P(C)(C)=O)=NC=C1Cl)(=O)=O Chemical compound CN(C)S(C(C=C1)=CC=C1NC(N=C1NC(C=CC=C2)=C2P(C)(C)=O)=NC=C1Cl)(=O)=O HOLCXFFUQHFRHC-UHFFFAOYSA-N 0.000 description 2
- JLEMGLAOWIQWPQ-UHFFFAOYSA-N CN(CC1)CCN1C(N=C1)=CC=C1NC1=CN(C(C=C2)=CC=C2N)N=C1 Chemical compound CN(CC1)CCN1C(N=C1)=CC=C1NC1=CN(C(C=C2)=CC=C2N)N=C1 JLEMGLAOWIQWPQ-UHFFFAOYSA-N 0.000 description 2
- BNQOYAZKKZTHTL-UHFFFAOYSA-N CN(CC1)CCN1C(N=C1)=CC=C1NC1=CN(C(C=C2)=CC=C2[N+]([O-])=O)N=C1 Chemical compound CN(CC1)CCN1C(N=C1)=CC=C1NC1=CN(C(C=C2)=CC=C2[N+]([O-])=O)N=C1 BNQOYAZKKZTHTL-UHFFFAOYSA-N 0.000 description 2
- IOUKZMYYOYZERV-UHFFFAOYSA-N COC(C=C1)=CC=C1NC1=NC=C(C(F)(F)F)C(NC(C=CC=C2)=C2P(C)(C)=O)=N1 Chemical compound COC(C=C1)=CC=C1NC1=NC=C(C(F)(F)F)C(NC(C=CC=C2)=C2P(C)(C)=O)=N1 IOUKZMYYOYZERV-UHFFFAOYSA-N 0.000 description 2
- AFLFOPBUNCLAOM-UHFFFAOYSA-N COC(C=CC(NC(N=C1NC(C=CC=C2)=C2P(C)(C)=O)=NC=C1Cl)=C1)=C1N1CCOCC1 Chemical compound COC(C=CC(NC(N=C1NC(C=CC=C2)=C2P(C)(C)=O)=NC=C1Cl)=C1)=C1N1CCOCC1 AFLFOPBUNCLAOM-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 229940124786 LRRK2 inhibitor Drugs 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 125000006242 amine protecting group Chemical group 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 125000005002 aryl methyl group Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 2
- 238000001212 derivatisation Methods 0.000 description 2
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 229960001484 edetic acid Drugs 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 125000001188 haloalkyl group Chemical group 0.000 description 2
- 125000004366 heterocycloalkenyl group Chemical group 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 102000056111 human LRRK2 Human genes 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 229940043355 kinase inhibitor Drugs 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 125000005647 linker group Chemical group 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 2
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 2
- RLKHFSNWQCZBDC-UHFFFAOYSA-N n-(benzenesulfonyl)-n-fluorobenzenesulfonamide Chemical compound C=1C=CC=CC=1S(=O)(=O)N(F)S(=O)(=O)C1=CC=CC=C1 RLKHFSNWQCZBDC-UHFFFAOYSA-N 0.000 description 2
- 125000000740 n-pentyl group Chemical class [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 2
- RDOWQLZANAYVLL-UHFFFAOYSA-N phenanthridine Chemical compound C1=CC=C2C3=CC=CC=C3C=NC2=C1 RDOWQLZANAYVLL-UHFFFAOYSA-N 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229930195734 saturated hydrocarbon Natural products 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 2
- TYFQFVWCELRYAO-UHFFFAOYSA-N suberic acid Chemical compound OC(=O)CCCCCCC(O)=O TYFQFVWCELRYAO-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 2
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 1
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 1
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- GCTFTMWXZFLTRR-GFCCVEGCSA-N (2r)-2-amino-n-[3-(difluoromethoxy)-4-(1,3-oxazol-5-yl)phenyl]-4-methylpentanamide Chemical compound FC(F)OC1=CC(NC(=O)[C@H](N)CC(C)C)=CC=C1C1=CN=CO1 GCTFTMWXZFLTRR-GFCCVEGCSA-N 0.000 description 1
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 1
- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 description 1
- VIJSPAIQWVPKQZ-BLECARSGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O VIJSPAIQWVPKQZ-BLECARSGSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 1
- STKNXTNVBKLVRQ-UHFFFAOYSA-N (3-aminophenyl)methanesulfonamide Chemical group NC1=CC=CC(CS(N)(=O)=O)=C1 STKNXTNVBKLVRQ-UHFFFAOYSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 1
- OOKAZRDERJMRCJ-KOUAFAAESA-N (3r)-7-[(1s,2s,4ar,6s,8s)-2,6-dimethyl-8-[(2s)-2-methylbutanoyl]oxy-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl]-3-hydroxy-5-oxoheptanoic acid Chemical compound C1=C[C@H](C)[C@H](CCC(=O)C[C@@H](O)CC(O)=O)C2[C@@H](OC(=O)[C@@H](C)CC)C[C@@H](C)C[C@@H]21 OOKAZRDERJMRCJ-KOUAFAAESA-N 0.000 description 1
- AVAWMINJNRAQFS-ZCFIWIBFSA-N (3r)-n,n-dimethylpyrrolidin-3-amine Chemical group CN(C)[C@@H]1CCNC1 AVAWMINJNRAQFS-ZCFIWIBFSA-N 0.000 description 1
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 1
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 1
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 description 1
- STPKWKPURVSAJF-LJEWAXOPSA-N (4r,5r)-5-[4-[[4-(1-aza-4-azoniabicyclo[2.2.2]octan-4-ylmethyl)phenyl]methoxy]phenyl]-3,3-dibutyl-7-(dimethylamino)-1,1-dioxo-4,5-dihydro-2h-1$l^{6}-benzothiepin-4-ol Chemical compound O[C@H]1C(CCCC)(CCCC)CS(=O)(=O)C2=CC=C(N(C)C)C=C2[C@H]1C(C=C1)=CC=C1OCC(C=C1)=CC=C1C[N+]1(CC2)CCN2CC1 STPKWKPURVSAJF-LJEWAXOPSA-N 0.000 description 1
- VUEGYUOUAAVYAS-JGGQBBKZSA-N (6ar,9s,10ar)-9-(dimethylsulfamoylamino)-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline Chemical compound C1=CC([C@H]2C[C@@H](CN(C)[C@@H]2C2)NS(=O)(=O)N(C)C)=C3C2=CNC3=C1 VUEGYUOUAAVYAS-JGGQBBKZSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- DEVSOMFAQLZNKR-RJRFIUFISA-N (z)-3-[3-[3,5-bis(trifluoromethyl)phenyl]-1,2,4-triazol-1-yl]-n'-pyrazin-2-ylprop-2-enehydrazide Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(C2=NN(\C=C/C(=O)NNC=3N=CC=NC=3)C=N2)=C1 DEVSOMFAQLZNKR-RJRFIUFISA-N 0.000 description 1
- KRUCRVZSHWOMHC-UHFFFAOYSA-N 1,1-dioxo-1-benzothiophen-6-amine Chemical group NC1=CC=C2C=CS(=O)(=O)C2=C1 KRUCRVZSHWOMHC-UHFFFAOYSA-N 0.000 description 1
- 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 description 1
- 125000004511 1,2,3-thiadiazolyl group Chemical group 0.000 description 1
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 1
- ARCACZWMYGILNI-UHFFFAOYSA-N 1,2,3-trifluoro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C(F)=C1F ARCACZWMYGILNI-UHFFFAOYSA-N 0.000 description 1
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 description 1
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 1
- 125000004506 1,2,5-oxadiazolyl group Chemical group 0.000 description 1
- 125000004517 1,2,5-thiadiazolyl group Chemical group 0.000 description 1
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 description 1
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 description 1
- KQMXPHISFRKBJP-UHFFFAOYSA-N 1,3-benzodioxol-4-amine Chemical group NC1=CC=CC2=C1OCO2 KQMXPHISFRKBJP-UHFFFAOYSA-N 0.000 description 1
- XGNXYCFREOZBOL-UHFFFAOYSA-N 1,3-benzodioxol-5-amine Chemical group NC1=CC=C2OCOC2=C1 XGNXYCFREOZBOL-UHFFFAOYSA-N 0.000 description 1
- IAWQUHCVFXQBMC-UHFFFAOYSA-N 1,3-benzoxazol-5-amine Chemical group NC1=CC=C2OC=NC2=C1 IAWQUHCVFXQBMC-UHFFFAOYSA-N 0.000 description 1
- DJMOXMNDXFFONV-UHFFFAOYSA-N 1,3-dimethyl-7-[2-(n-methylanilino)ethyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCN(C)C1=CC=CC=C1 DJMOXMNDXFFONV-UHFFFAOYSA-N 0.000 description 1
- KKHFRAFPESRGGD-UHFFFAOYSA-N 1,3-dimethyl-7-[3-(n-methylanilino)propyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCCN(C)C1=CC=CC=C1 KKHFRAFPESRGGD-UHFFFAOYSA-N 0.000 description 1
- LKFXYYLRIUSARI-UHFFFAOYSA-N 1,3-thiazol-5-amine Chemical compound NC1=CN=CS1 LKFXYYLRIUSARI-UHFFFAOYSA-N 0.000 description 1
- LUKSDHOQKVTGGT-UHFFFAOYSA-N 1-(3-amino-4-fluorophenyl)ethanone Chemical group CC(=O)C1=CC=C(F)C(N)=C1 LUKSDHOQKVTGGT-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 1
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- FRJNKYGTHPUSJR-UHFFFAOYSA-N 1-benzothiophene 1,1-dioxide Chemical compound C1=CC=C2S(=O)(=O)C=CC2=C1 FRJNKYGTHPUSJR-UHFFFAOYSA-N 0.000 description 1
- MEQKSFQEPDRNEQ-UHFFFAOYSA-N 1-bromo-3-methoxy-5-nitrobenzene Chemical group COC1=CC(Br)=CC([N+]([O-])=O)=C1 MEQKSFQEPDRNEQ-UHFFFAOYSA-N 0.000 description 1
- JXIJUAWSDBACEB-UHFFFAOYSA-N 1-chloro-2-methoxy-4-nitrobenzene Chemical compound COC1=CC([N+]([O-])=O)=CC=C1Cl JXIJUAWSDBACEB-UHFFFAOYSA-N 0.000 description 1
- LDMOEFOXLIZJOW-UHFFFAOYSA-N 1-dodecanesulfonic acid Chemical compound CCCCCCCCCCCCS(O)(=O)=O LDMOEFOXLIZJOW-UHFFFAOYSA-N 0.000 description 1
- ZRIKJXDEJYMBEJ-UHFFFAOYSA-N 1-fluoro-4-methoxy-2-nitrobenzene Chemical compound COC1=CC=C(F)C([N+]([O-])=O)=C1 ZRIKJXDEJYMBEJ-UHFFFAOYSA-N 0.000 description 1
- WFQDTOYDVUWQMS-UHFFFAOYSA-N 1-fluoro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C=C1 WFQDTOYDVUWQMS-UHFFFAOYSA-N 0.000 description 1
- YTKNUPJYGSOVLV-UHFFFAOYSA-N 1-methylindazol-6-amine Chemical group C1=C(N)C=C2N(C)N=CC2=C1 YTKNUPJYGSOVLV-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 description 1
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 description 1
- 125000005955 1H-indazolyl group Chemical group 0.000 description 1
- UTQNKKSJPHTPBS-UHFFFAOYSA-N 2,2,2-trichloroethanone Chemical group ClC(Cl)(Cl)[C]=O UTQNKKSJPHTPBS-UHFFFAOYSA-N 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- CVYQRDKVWVBOFP-UHFFFAOYSA-N 2,2-difluoro-1,3-benzodioxol-5-amine Chemical group NC1=CC=C2OC(F)(F)OC2=C1 CVYQRDKVWVBOFP-UHFFFAOYSA-N 0.000 description 1
- JVJUKIGIRZNFFY-UHFFFAOYSA-N 2,3-dihydro-1h-isoindol-4-amine Chemical group NC1=CC=CC2=C1CNC2 JVJUKIGIRZNFFY-UHFFFAOYSA-N 0.000 description 1
- VEPOHXYIFQMVHW-XOZOLZJESA-N 2,3-dihydroxybutanedioic acid (2S,3S)-3,4-dimethyl-2-phenylmorpholine Chemical compound OC(C(O)C(O)=O)C(O)=O.C[C@H]1[C@@H](OCCN1C)c1ccccc1 VEPOHXYIFQMVHW-XOZOLZJESA-N 0.000 description 1
- WHPFEQUEHBULBW-UHFFFAOYSA-N 2,4-dichloro-5-fluoropyrimidine Chemical compound FC1=CN=C(Cl)N=C1Cl WHPFEQUEHBULBW-UHFFFAOYSA-N 0.000 description 1
- GEQNZVKIDIPGCO-UHFFFAOYSA-N 2,4-dimethoxyaniline Chemical group COC1=CC=C(N)C(OC)=C1 GEQNZVKIDIPGCO-UHFFFAOYSA-N 0.000 description 1
- FQMZXMVHHKXGTM-UHFFFAOYSA-N 2-(1-adamantyl)-n-[2-[2-(2-hydroxyethylamino)ethylamino]quinolin-5-yl]acetamide Chemical compound C1C(C2)CC(C3)CC2CC13CC(=O)NC1=CC=CC2=NC(NCCNCCO)=CC=C21 FQMZXMVHHKXGTM-UHFFFAOYSA-N 0.000 description 1
- CGNAIUUCOVWLLL-UHFFFAOYSA-N 2-(difluoromethoxy)aniline Chemical compound NC1=CC=CC=C1OC(F)F CGNAIUUCOVWLLL-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 description 1
- FMKGJQHNYMWDFJ-CVEARBPZSA-N 2-[[4-(2,2-difluoropropoxy)pyrimidin-5-yl]methylamino]-4-[[(1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl]amino]pyrimidine-5-carbonitrile Chemical compound FC(COC1=NC=NC=C1CNC1=NC=C(C(=N1)N[C@H]1CC([C@H](CC1)O)(C)C)C#N)(C)F FMKGJQHNYMWDFJ-CVEARBPZSA-N 0.000 description 1
- VVCMGAUPZIKYTH-VGHSCWAPSA-N 2-acetyloxybenzoic acid;[(2s,3r)-4-(dimethylamino)-3-methyl-1,2-diphenylbutan-2-yl] propanoate;1,3,7-trimethylpurine-2,6-dione Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O.CN1C(=O)N(C)C(=O)C2=C1N=CN2C.C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 VVCMGAUPZIKYTH-VGHSCWAPSA-N 0.000 description 1
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- NPRYCHLHHVWLQZ-TURQNECASA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynylpurin-8-one Chemical compound NC1=NC=C2N(C(N(C2=N1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C NPRYCHLHHVWLQZ-TURQNECASA-N 0.000 description 1
- 125000004174 2-benzimidazolyl group Chemical group [H]N1C(*)=NC2=C([H])C([H])=C([H])C([H])=C12 0.000 description 1
- KCFDURKFXBLIAY-UHFFFAOYSA-N 2-bromo-1-methoxy-3-nitrobenzene Chemical group COC1=CC=CC([N+]([O-])=O)=C1Br KCFDURKFXBLIAY-UHFFFAOYSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- UBPDKIDWEADHPP-UHFFFAOYSA-N 2-iodoaniline Chemical compound NC1=CC=CC=C1I UBPDKIDWEADHPP-UHFFFAOYSA-N 0.000 description 1
- JDDAFHUEOVUDFJ-UHFFFAOYSA-N 2-iodobenzonitrile Chemical compound IC1=CC=CC=C1C#N JDDAFHUEOVUDFJ-UHFFFAOYSA-N 0.000 description 1
- LFOIDLOIBZFWDO-UHFFFAOYSA-N 2-methoxy-6-[6-methoxy-4-[(3-phenylmethoxyphenyl)methoxy]-1-benzofuran-2-yl]imidazo[2,1-b][1,3,4]thiadiazole Chemical compound N1=C2SC(OC)=NN2C=C1C(OC1=CC(OC)=C2)=CC1=C2OCC(C=1)=CC=CC=1OCC1=CC=CC=C1 LFOIDLOIBZFWDO-UHFFFAOYSA-N 0.000 description 1
- KOHBEDRJXKOYHL-UHFFFAOYSA-N 2-methoxy-n-methylethanamine Chemical group CNCCOC KOHBEDRJXKOYHL-UHFFFAOYSA-N 0.000 description 1
- GPWQHYMVUZYWIK-UHFFFAOYSA-N 2-methyl-1,3-benzothiazol-5-amine Chemical group NC1=CC=C2SC(C)=NC2=C1 GPWQHYMVUZYWIK-UHFFFAOYSA-N 0.000 description 1
- GDIRRUCMINBFNR-UHFFFAOYSA-N 2-n,2-n-dimethyl-3h-benzimidazole-2,5-diamine Chemical group C1=C(N)C=C2NC(N(C)C)=NC2=C1 GDIRRUCMINBFNR-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- LGDHZCLREKIGKJ-UHFFFAOYSA-N 3,4-dimethoxyaniline Chemical group COC1=CC=C(N)C=C1OC LGDHZCLREKIGKJ-UHFFFAOYSA-N 0.000 description 1
- WNRGWPVJGDABME-UHFFFAOYSA-N 3,5-Dimethoxyaniline Chemical group COC1=CC(N)=CC(OC)=C1 WNRGWPVJGDABME-UHFFFAOYSA-N 0.000 description 1
- RNNUSMIPHMAFKN-UHFFFAOYSA-N 3-(2-methoxyethoxy)aniline Chemical group COCCOC1=CC=CC(N)=C1 RNNUSMIPHMAFKN-UHFFFAOYSA-N 0.000 description 1
- CPHZPWZSSBCSAH-UHFFFAOYSA-N 3-(2-methyl-1,3-thiazol-4-yl)aniline Chemical group S1C(C)=NC(C=2C=C(N)C=CC=2)=C1 CPHZPWZSSBCSAH-UHFFFAOYSA-N 0.000 description 1
- DMWKPJRZFGLSAX-UHFFFAOYSA-N 3-(2-methylpyrimidin-4-yl)aniline Chemical group CC1=NC=CC(C=2C=C(N)C=CC=2)=N1 DMWKPJRZFGLSAX-UHFFFAOYSA-N 0.000 description 1
- KFOWCFUJSYGZMB-UHFFFAOYSA-N 3-(2-morpholin-4-ylethoxy)aniline Chemical group NC1=CC=CC(OCCN2CCOCC2)=C1 KFOWCFUJSYGZMB-UHFFFAOYSA-N 0.000 description 1
- SADHVOSOZBAAGL-UHFFFAOYSA-N 3-(trifluoromethoxy)aniline Chemical group NC1=CC=CC(OC(F)(F)F)=C1 SADHVOSOZBAAGL-UHFFFAOYSA-N 0.000 description 1
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
- OCLILGBSWCUZDJ-UHFFFAOYSA-N 3-[2-(4-methylpiperazin-1-yl)ethoxy]aniline Chemical group C1CN(C)CCN1CCOC1=CC=CC(N)=C1 OCLILGBSWCUZDJ-UHFFFAOYSA-N 0.000 description 1
- WFMRAKZOFYATRY-UHFFFAOYSA-N 3-[2-(dimethylamino)ethoxy]-4-methoxyaniline Chemical group COC1=CC=C(N)C=C1OCCN(C)C WFMRAKZOFYATRY-UHFFFAOYSA-N 0.000 description 1
- BMBSJDSXSMKTNV-UHFFFAOYSA-N 3-[2-(dimethylamino)ethoxy]aniline Chemical group CN(C)CCOC1=CC=CC(N)=C1 BMBSJDSXSMKTNV-UHFFFAOYSA-N 0.000 description 1
- LHMQDVIHBXWNII-UHFFFAOYSA-N 3-amino-4-methoxy-n-phenylbenzamide Chemical group C1=C(N)C(OC)=CC=C1C(=O)NC1=CC=CC=C1 LHMQDVIHBXWNII-UHFFFAOYSA-N 0.000 description 1
- INCJNDAQNPWMPZ-UHFFFAOYSA-N 3-amino-4-methoxybenzamide Chemical group COC1=CC=C(C(N)=O)C=C1N INCJNDAQNPWMPZ-UHFFFAOYSA-N 0.000 description 1
- APIVVDFBBPFBDZ-UHFFFAOYSA-N 3-amino-n,n-dimethylbenzenesulfonamide Chemical group CN(C)S(=O)(=O)C1=CC=CC(N)=C1 APIVVDFBBPFBDZ-UHFFFAOYSA-N 0.000 description 1
- PYDQTASEULDNRL-UHFFFAOYSA-N 3-amino-n-methylbenzamide Chemical group CNC(=O)C1=CC=CC(N)=C1 PYDQTASEULDNRL-UHFFFAOYSA-N 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- PWURRRRGLCVBMX-UHFFFAOYSA-N 3-methoxy-4-nitrobenzoic acid Chemical compound COC1=CC(C(O)=O)=CC=C1[N+]([O-])=O PWURRRRGLCVBMX-UHFFFAOYSA-N 0.000 description 1
- NCBZRJODKRCREW-KWCOIAHCSA-N 3-methoxyaniline Chemical group COC1=CC=C[11C](N)=C1 NCBZRJODKRCREW-KWCOIAHCSA-N 0.000 description 1
- XOVUFGGDEAHJLB-UHFFFAOYSA-N 3-piperidin-4-ylaniline Chemical group NC1=CC=CC(C2CCNCC2)=C1 XOVUFGGDEAHJLB-UHFFFAOYSA-N 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- LGBFKALRQPQBJJ-UHFFFAOYSA-N 4-(2-methoxyethyl)aniline Chemical group COCCC1=CC=C(N)C=C1 LGBFKALRQPQBJJ-UHFFFAOYSA-N 0.000 description 1
- PODGLCSJCBYFGC-UHFFFAOYSA-N 4-[2-(4-methylpiperazin-1-yl)ethoxy]aniline Chemical group C1CN(C)CCN1CCOC1=CC=C(N)C=C1 PODGLCSJCBYFGC-UHFFFAOYSA-N 0.000 description 1
- CCCVQPGAXZNTIL-UHFFFAOYSA-N 4-[2-(dimethylamino)ethoxy]aniline Chemical group CN(C)CCOC1=CC=C(N)C=C1 CCCVQPGAXZNTIL-UHFFFAOYSA-N 0.000 description 1
- WYFCZWSWFGJODV-MIANJLSGSA-N 4-[[(1s)-2-[(e)-3-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]prop-2-enoyl]-5-(4-methyl-2-oxopiperazin-1-yl)-3,4-dihydro-1h-isoquinoline-1-carbonyl]amino]benzoic acid Chemical compound O=C1CN(C)CCN1C1=CC=CC2=C1CCN(C(=O)\C=C\C=1C(=CC=C(Cl)C=1F)N1N=NN=C1)[C@@H]2C(=O)NC1=CC=C(C(O)=O)C=C1 WYFCZWSWFGJODV-MIANJLSGSA-N 0.000 description 1
- QEPGWLBMAAEBCP-UHFFFAOYSA-N 4-amino-n,n-dimethylbenzamide Chemical group CN(C)C(=O)C1=CC=C(N)C=C1 QEPGWLBMAAEBCP-UHFFFAOYSA-N 0.000 description 1
- BABGMPQXLCJMSK-UHFFFAOYSA-N 4-amino-n,n-dimethylbenzenesulfonamide Chemical group CN(C)S(=O)(=O)C1=CC=C(N)C=C1 BABGMPQXLCJMSK-UHFFFAOYSA-N 0.000 description 1
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 1
- HUDPLKWXRLNSPC-UHFFFAOYSA-N 4-aminophthalhydrazide Chemical group O=C1NNC(=O)C=2C1=CC(N)=CC=2 HUDPLKWXRLNSPC-UHFFFAOYSA-N 0.000 description 1
- GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical compound C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 description 1
- WVGCPEDBFHEHEZ-UHFFFAOYSA-N 4-bromo-1h-pyrazole Chemical compound BrC=1C=NNC=1 WVGCPEDBFHEHEZ-UHFFFAOYSA-N 0.000 description 1
- PXACTUVBBMDKRW-UHFFFAOYSA-N 4-bromobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Br)C=C1 PXACTUVBBMDKRW-UHFFFAOYSA-N 0.000 description 1
- NGRRREPRVBZRID-UHFFFAOYSA-N 4-methoxy-3-(4-methylpiperazin-1-yl)aniline Chemical group COC1=CC=C(N)C=C1N1CCN(C)CC1 NGRRREPRVBZRID-UHFFFAOYSA-N 0.000 description 1
- CQJCPOVTPNWVBW-UHFFFAOYSA-N 4-methoxy-3-(trifluoromethyl)aniline Chemical group COC1=CC=C(N)C=C1C(F)(F)F CQJCPOVTPNWVBW-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical group [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 description 1
- WCIGMFCFPXZRMQ-UHFFFAOYSA-N 5-(2-fluoropyridin-4-yl)-2-phenylmethoxy-n-pyridin-3-ylbenzamide Chemical compound C1=NC(F)=CC(C=2C=C(C(OCC=3C=CC=CC=3)=CC=2)C(=O)NC=2C=NC=CC=2)=C1 WCIGMFCFPXZRMQ-UHFFFAOYSA-N 0.000 description 1
- KMEBUNSLFRQSEM-UHFFFAOYSA-N 5-amino-2-methylisoindole-1,3-dione Chemical compound C1=C(N)C=C2C(=O)N(C)C(=O)C2=C1 KMEBUNSLFRQSEM-UHFFFAOYSA-N 0.000 description 1
- XFJBGINZIMNZBW-CRAIPNDOSA-N 5-chloro-2-[4-[(1r,2s)-2-[2-(5-methylsulfonylpyridin-2-yl)oxyethyl]cyclopropyl]piperidin-1-yl]pyrimidine Chemical compound N1=CC(S(=O)(=O)C)=CC=C1OCC[C@H]1[C@@H](C2CCN(CC2)C=2N=CC(Cl)=CN=2)C1 XFJBGINZIMNZBW-CRAIPNDOSA-N 0.000 description 1
- DWAQDRSOVMLGRQ-UHFFFAOYSA-N 5-methoxyindole Chemical compound COC1=CC=C2NC=CC2=C1 DWAQDRSOVMLGRQ-UHFFFAOYSA-N 0.000 description 1
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 description 1
- RSIWALKZYXPAGW-NSHDSACASA-N 6-(3-fluorophenyl)-3-methyl-7-[(1s)-1-(7h-purin-6-ylamino)ethyl]-[1,3]thiazolo[3,2-a]pyrimidin-5-one Chemical compound C=1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)N=C2SC=C(C)N2C(=O)C=1C1=CC=CC(F)=C1 RSIWALKZYXPAGW-NSHDSACASA-N 0.000 description 1
- HCCNBKFJYUWLEX-UHFFFAOYSA-N 7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)-3-(pyrazin-2-ylmethylamino)pyrido[3,4-b]pyrazin-2-one Chemical compound O=C1N(CCOCCC)C2=CC(C=3C=NC(OC)=CC=3)=NC=C2N=C1NCC1=CN=CC=N1 HCCNBKFJYUWLEX-UHFFFAOYSA-N 0.000 description 1
- JPARDNRMCTVFJO-UHFFFAOYSA-N 7-amino-2-methyl-3h-isoindol-1-one Chemical group C1=CC(N)=C2C(=O)N(C)CC2=C1 JPARDNRMCTVFJO-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- JQUCWIWWWKZNCS-LESHARBVSA-N C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F Chemical compound C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F JQUCWIWWWKZNCS-LESHARBVSA-N 0.000 description 1
- OJRUSAPKCPIVBY-KQYNXXCUSA-N C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N Chemical compound C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N OJRUSAPKCPIVBY-KQYNXXCUSA-N 0.000 description 1
- WLIWXKXTZRGUDP-UHFFFAOYSA-N CNCC(N)OC Chemical group CNCC(N)OC WLIWXKXTZRGUDP-UHFFFAOYSA-N 0.000 description 1
- CZJVIAFNNPBBJK-UHFFFAOYSA-N COC(C=C(C=C1)C(N2CCOCC2)=O)=C1NC(N=C1NC(C=CC=C2)=C2P(C)(C)=O)=NC=C1Cl Chemical compound COC(C=C(C=C1)C(N2CCOCC2)=O)=C1NC(N=C1NC(C=CC=C2)=C2P(C)(C)=O)=NC=C1Cl CZJVIAFNNPBBJK-UHFFFAOYSA-N 0.000 description 1
- BORBTDOBNANCBN-UHFFFAOYSA-N COC(C=C1)=C(C(F)(F)F)C=C1NC(N=C1NC(C=CC=C2)=C2P(C)(C)=O)=NC=C1Cl Chemical compound COC(C=C1)=C(C(F)(F)F)C=C1NC(N=C1NC(C=CC=C2)=C2P(C)(C)=O)=NC=C1Cl BORBTDOBNANCBN-UHFFFAOYSA-N 0.000 description 1
- MSACNODAXJVUDF-UHFFFAOYSA-N CP(C)[O] Chemical compound CP(C)[O] MSACNODAXJVUDF-UHFFFAOYSA-N 0.000 description 1
- PKMUHQIDVVOXHQ-HXUWFJFHSA-N C[C@H](C1=CC(C2=CC=C(CNC3CCCC3)S2)=CC=C1)NC(C1=C(C)C=CC(NC2CNC2)=C1)=O Chemical compound C[C@H](C1=CC(C2=CC=C(CNC3CCCC3)S2)=CC=C1)NC(C1=C(C)C=CC(NC2CNC2)=C1)=O PKMUHQIDVVOXHQ-HXUWFJFHSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 229940126639 Compound 33 Drugs 0.000 description 1
- 229940127007 Compound 39 Drugs 0.000 description 1
- YPZMPEPLWKRVLD-PJEQPVAWSA-N D-Glycero-D-gulo-Heptose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)C=O YPZMPEPLWKRVLD-PJEQPVAWSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- RRSNDVCODIMOFX-MPKOGUQCSA-N Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O Chemical compound Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O RRSNDVCODIMOFX-MPKOGUQCSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical group NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 108010020246 Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Proteins 0.000 description 1
- 102000009784 Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Human genes 0.000 description 1
- 102220579336 Leucine-rich repeat serine/threonine-protein kinase 2_R1441G_mutation Human genes 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000034819 Mobility Limitation Diseases 0.000 description 1
- FFDGPVCHZBVARC-UHFFFAOYSA-N N,N-dimethylglycine Chemical compound CN(C)CC(O)=O FFDGPVCHZBVARC-UHFFFAOYSA-N 0.000 description 1
- LVDRREOUMKACNJ-BKMJKUGQSA-N N-[(2R,3S)-2-(4-chlorophenyl)-1-(1,4-dimethyl-2-oxoquinolin-7-yl)-6-oxopiperidin-3-yl]-2-methylpropane-1-sulfonamide Chemical compound CC(C)CS(=O)(=O)N[C@H]1CCC(=O)N([C@@H]1c1ccc(Cl)cc1)c1ccc2c(C)cc(=O)n(C)c2c1 LVDRREOUMKACNJ-BKMJKUGQSA-N 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- QOVYHDHLFPKQQG-NDEPHWFRSA-N N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O Chemical compound N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O QOVYHDHLFPKQQG-NDEPHWFRSA-N 0.000 description 1
- PCKPVGOLPKLUHR-UHFFFAOYSA-N OH-Indolxyl Natural products C1=CC=C2C(O)=CNC2=C1 PCKPVGOLPKLUHR-UHFFFAOYSA-N 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 1
- SPXSEZMVRJLHQG-XMMPIXPASA-N [(2R)-1-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol Chemical compound C(C1=CC=CC=C1)OC=1C=C(OCC2=CC=C(CN3[C@H](CCC3)CO)C=C2)C=CC=1 SPXSEZMVRJLHQG-XMMPIXPASA-N 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- PSLUFJFHTBIXMW-WYEYVKMPSA-N [(3r,4ar,5s,6s,6as,10s,10ar,10bs)-3-ethenyl-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-6-(2-pyridin-2-ylethylcarbamoyloxy)-5,6,6a,8,9,10-hexahydro-2h-benzo[f]chromen-5-yl] acetate Chemical compound O([C@@H]1[C@@H]([C@]2(O[C@](C)(CC(=O)[C@]2(O)[C@@]2(C)[C@@H](O)CCC(C)(C)[C@@H]21)C=C)C)OC(=O)C)C(=O)NCCC1=CC=CC=N1 PSLUFJFHTBIXMW-WYEYVKMPSA-N 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- BBAWTPDTGRXPDG-UHFFFAOYSA-N [1,3]thiazolo[4,5-b]pyridine Chemical compound C1=CC=C2SC=NC2=N1 BBAWTPDTGRXPDG-UHFFFAOYSA-N 0.000 description 1
- PNDPGZBMCMUPRI-XXSWNUTMSA-N [125I][125I] Chemical compound [125I][125I] PNDPGZBMCMUPRI-XXSWNUTMSA-N 0.000 description 1
- HUEKBQXFNHWTQQ-UHFFFAOYSA-N [4-[[5-chloro-4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-methoxyphenyl]-morpholin-4-ylmethanone Chemical compound ClC1=CNC=2N=C(N=C(C=21)NC)NC1=C(C=C(C=C1)C(=O)N1CCOCC1)OC HUEKBQXFNHWTQQ-UHFFFAOYSA-N 0.000 description 1
- CKUAXEQHGKSLHN-UHFFFAOYSA-N [C].[N] Chemical group [C].[N] CKUAXEQHGKSLHN-UHFFFAOYSA-N 0.000 description 1
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
- VYTBPJNGNGMRFH-UHFFFAOYSA-N acetic acid;azane Chemical compound N.N.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O VYTBPJNGNGMRFH-UHFFFAOYSA-N 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 102000003802 alpha-Synuclein Human genes 0.000 description 1
- 108090000185 alpha-Synuclein Proteins 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical group 0.000 description 1
- 125000005101 aryl methoxy carbonyl group Chemical group 0.000 description 1
- 125000005110 aryl thio group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 1
- 231100000871 behavioral problem Toxicity 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 1
- 238000002306 biochemical method Methods 0.000 description 1
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001735 carboxylic acids Chemical group 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- QZHPTGXQGDFGEN-UHFFFAOYSA-N chromene Chemical compound C1=CC=C2C=C[CH]OC2=C1 QZHPTGXQGDFGEN-UHFFFAOYSA-N 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 231100000870 cognitive problem Toxicity 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940127204 compound 29 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125877 compound 31 Drugs 0.000 description 1
- 229940125878 compound 36 Drugs 0.000 description 1
- 229940125807 compound 37 Drugs 0.000 description 1
- 229940127573 compound 38 Drugs 0.000 description 1
- 229940126540 compound 41 Drugs 0.000 description 1
- 229940125936 compound 42 Drugs 0.000 description 1
- 229940125844 compound 46 Drugs 0.000 description 1
- 229940127271 compound 49 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 229940126545 compound 53 Drugs 0.000 description 1
- 229940127113 compound 57 Drugs 0.000 description 1
- 229940125900 compound 59 Drugs 0.000 description 1
- 229940126179 compound 72 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- XSYZCZPCBXYQTE-UHFFFAOYSA-N cyclodecylcyclodecane Chemical compound C1CCCCCCCCC1C1CCCCCCCCC1 XSYZCZPCBXYQTE-UHFFFAOYSA-N 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- NLUNLVTVUDIHFE-UHFFFAOYSA-N cyclooctylcyclooctane Chemical compound C1CCCCCCC1C1CCCCCCC1 NLUNLVTVUDIHFE-UHFFFAOYSA-N 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- 239000013024 dilution buffer Substances 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
- 210000005064 dopaminergic neuron Anatomy 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- BJXYHBKEQFQVES-NWDGAFQWSA-N enpatoran Chemical compound N[C@H]1CN(C[C@H](C1)C(F)(F)F)C1=C2C=CC=NC2=C(C=C1)C#N BJXYHBKEQFQVES-NWDGAFQWSA-N 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 229910052732 germanium Inorganic materials 0.000 description 1
- GNPVGFCGXDBREM-UHFFFAOYSA-N germanium atom Chemical compound [Ge] GNPVGFCGXDBREM-UHFFFAOYSA-N 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 229940089468 hydroxyethylpiperazine ethane sulfonic acid Drugs 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000004926 indolenyl group Chemical group 0.000 description 1
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229940044173 iodine-125 Drugs 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 150000002576 ketones Chemical group 0.000 description 1
- TYQCGQRIZGCHNB-JLAZNSOCSA-N l-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 210000004558 lewy body Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- RENRQMCACQEWFC-UGKGYDQZSA-N lnp023 Chemical compound C1([C@H]2N(CC=3C=4C=CNC=4C(C)=CC=3OC)CC[C@@H](C2)OCC)=CC=C(C(O)=O)C=C1 RENRQMCACQEWFC-UGKGYDQZSA-N 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 description 1
- ZBELDPMWYXDLNY-UHFFFAOYSA-N methyl 9-(4-bromo-2-fluoroanilino)-[1,3]thiazolo[5,4-f]quinazoline-2-carboximidate Chemical compound C12=C3SC(C(=N)OC)=NC3=CC=C2N=CN=C1NC1=CC=C(Br)C=C1F ZBELDPMWYXDLNY-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 125000006682 monohaloalkyl group Chemical group 0.000 description 1
- 125000004572 morpholin-3-yl group Chemical group N1C(COCC1)* 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- 125000003136 n-heptyl group Chemical class [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical class C(CCCCC)* 0.000 description 1
- NXPPAOGUKPJVDI-UHFFFAOYSA-N naphthalene-1,2-diol Chemical compound C1=CC=CC2=C(O)C(O)=CC=C21 NXPPAOGUKPJVDI-UHFFFAOYSA-N 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 125000004930 octahydroisoquinolinyl group Chemical group C1(NCCC2CCCC=C12)* 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- QNNHQVPFZIFNFK-UHFFFAOYSA-N oxazolo[4,5-b]pyridine Chemical compound C1=CC=C2OC=NC2=N1 QNNHQVPFZIFNFK-UHFFFAOYSA-N 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 229950000688 phenothiazine Drugs 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 229960004838 phosphoric acid Drugs 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 125000006684 polyhaloalkyl group Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000004317 sodium nitrate Substances 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 150000003413 spiro compounds Chemical class 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000003523 substantia nigra Anatomy 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000006253 t-butylcarbonyl group Chemical group [H]C([H])([H])C(C(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000001648 tannin Substances 0.000 description 1
- 235000018553 tannin Nutrition 0.000 description 1
- 229920001864 tannin Polymers 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000004496 thiazol-5-yl group Chemical group S1C=NC=C1* 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000005309 thioalkoxy group Chemical group 0.000 description 1
- 238000002877 time resolved fluorescence resonance energy transfer Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
Definitions
- the present invention relates to a series of pyrimidine derivatives and their applications in preparing medicines for treating related diseases, and specifically discloses a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and their applications in preparing medicines for treating relative diseases.
- LRRK2 kinase Mutation and overexpression of LRRK2 kinase have increasingly been shown to be fundamental factors in the induction of neurodegenerative diseases, characterized by selective degeneration and cell death of dopaminergic neurons in the substantia nigra. Affects 1% of the population over the age of 65, with hereditary patients accounting for 5-10% of the affected population. In the early stages of the disease, the most obvious symptoms are shaking, slow movement and difficulty walking. Cognitive and behavioral problems also develop later in life, and dementia is often seen later in life.
- LRRK2 leucine-rich repeat kinase 2
- NM_198578.2 The NCBI engagement sequence for human LRRK2 mRNA is NM_198578.2.
- Evidence shows that LRRK2 phosphorylates ⁇ -synuclein at serine-129 and that this phosphorylated form constitutes an important part of Lewy bodies.
- single nucleotide polypeptides in the functional domain of LRRK2 have been shown to cause common and sporadic neurodegenerative diseases.
- LRRK2 mutations have identified more than 20 LRRK2 mutations in families with late-onset neurodegenerative disease.
- the G2019S mutation co-segregates with autosomal dominant and it causes approximately 6% of familial cases and 3% of sporadic cases in Europe.
- the G2019S mutation occurs in the highly conserved kinase domain, so the G2019S mutation may have an effect on kinase activity.
- amino acid substitutions at another residue, R1441 have also been implicated in neurodegenerative diseases and have been shown to increase LRRK2 kinase activity.
- the present invention aims to invent a compound that can highly inhibit LRRK2 kinase, thereby further inventing a drug that can well treat neurodegenerative diseases.
- the present invention provides compounds of formula (I), pharmaceutically acceptable salts thereof and tautomers thereof,
- W is selected from
- L is selected from a single bond and -CH 2 -;
- R 1 and R 2 are each independently selected from H, F, Cl, Br, I, OH, CN, NH 2 and COOH, or each independently selected from: C 1 optionally substituted with 1, 2 or 3 Rs -6 alkyl, C 1-6 heteroalkyl, 4-6 membered heterocycloalkyl and R a -L 1 -, and R 1 and R 2 are not selected from:
- R a is selected from H, phenyl, 5-6 membered heteroaryl, C 4-6 cycloalkyl and 4-6 membered heterocycloalkyl;
- R 1 and R 2 are linked together, building blocks is selected from optionally substituted with 1, 2 or 3 R
- R 1 with connected together, structural units Selected from optionally substituted with 1, 2 or 3 Rs:
- R 3 is selected from F, Cl, Br, I, OH, CN, CF 3 and NH 2 ;
- R 4 are each independently selected from H, F, Cl, Br and I;
- R 5 and R 6 are independently selected from H, halogen, OH, CN, NH 2 , NO 2 , COOH and R b -L 2 -L 3 -L 4 -, or are independently selected from optionally 2 or 3 R-substituted: C 1-6 alkyl, C 1-6 heteroalkyl, C 4-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl , and R 5 and R 6 are not selected from optionally substituted by 1, 2 or 3 halogens
- R b is selected from H, halogen, OH, CN, NH 2 , NO 2 , COOH, or optionally substituted with 1 , 2 or 3 Rs: C 1-6 alkyl, C 1-6 heteroalkyl , C 4-6 cycloalkyl, 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl;
- R 5 and R 6 are linked together, building blocks is selected to form an optionally substituted with 1, 2 or 3 Rs:
- R 7 is selected from H, halogen, OH, CN, NH 2 , NO 2 , COOH, or from: NH 2 and C 1-3 alkyl optionally substituted with 1, 2 or 3 Rs;
- R 8 is selected from F, Cl, Br, I, OH, CN and NH 2 ;
- R is selected from halogen, OH, CN, NH2 , COOH, or selected from: C1-3 alkyl and C1-3 heteroalkyl optionally substituted with 1, 2 or 3 R';
- R' is selected from F, Cl, Br, I, OH, CN, NH2 , COOH, Me, Et, CF3 , CHF2 , CH2F , NHCH3 and N( CH3 ) 2 ;
- the number of heteroatoms or heteroatomic groups is independently selected from 1, 2 or 3, respectively.
- R is selected from F, Cl, Br, I, OH, CN, NH and COOH, or from : Me, Et, Other variables are as defined in the present invention.
- the above R is selected from F, Cl, Br, I, OH, CN, NH2 , -N( CH3 ) 2 , COOH, Me, Et, CF3 , CHF2 , CH2F , Other variables are as defined in the present invention.
- the above Ra is selected from H, phenyl and 6-membered heterocycloalkyl, and other variables are as defined herein.
- the above Ra is selected from H, phenyl and morpholinyl, and other variables are as defined in the present invention
- Ra is selected from H
- Other variables are as defined in the present invention.
- Ra-L 1 - is selected from optionally substituted with 1, 2 or 3 Rs:
- Other variables are as defined in the present invention.
- R 1 and R 2 are independently selected from H, F, Cl, Br, I, OH, CN, NH 2 and COOH, or are independently selected from optionally 1, 2 Or 3 R-substituted: C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 alkylamino, N,N'-di(C 1-2 alkyl ) amino- and 5-6 membered heterocycloalkyl, other variables are as defined in the present invention.
- R 1 and R 2 are independently selected from H, F, Cl, Br, I, OH, CN, NH 2 , COOH, or independently selected from optionally 1, 2 Or 3 R substituted: Me, Other variables are as defined in the present invention;
- R 1 and R 2 are independently selected from H, F, Cl, Br, I, OH, CN, NH 2 , COOH, CF 3 , Other variables are as defined in the present invention.
- R 1 and R 2 are linked together, the structural unit selected from Other variables are as defined in the present invention.
- Rb is selected from H halogen, OH, CN, NH2 , NO2 and COOH, or selected from optionally substituted with 1, 2 or 3 Rs: C1-3 alkylamino, C 1-3 alkoxy, C 1-3 alkylthio, N,N'-bis(C 1-2 alkyl)amino, pyrrolidinyl, morpholinyl, piperazinyl, pyridyl and pyrimidinyl, Other variables are as defined in the present invention.
- Rb is selected from H halogen, OH, CN, NH2 , NO2 and COOH, or selected from optionally substituted with 1, 2 or 3 Rs:
- Other variables are as defined in the present invention.
- R b is selected from the group consisting of: H, halogen, OH, CN, NH 2 , NO 2 , COOH, Other variables are as defined in the present invention.
- R b -L 2 -L 3 -L 4 - is selected from:
- Other variables are as defined in the present invention.
- R 5 and R 6 are independently selected from H, halogen, OH, CN, NH 2 , NO 2 and COOH, or independently selected from optionally 1, 2 or 3 R substituted: C1-3 heteroalkyl, thiazolyl, pyrimidinyl, pyridyl, thienyl, piperidinyl, morpholinyl and piperazinyl, other variables are as defined in the present invention.
- R 5 and R 6 are each independently selected from H, F, Cl, Br, I, OH, CN, NH 2 , NO 2 and COOH, or independently selected from optionally 1, 2 or 3 R substitutions: Other variables are as defined in the present invention.
- R 5 and R 6 are independently selected from H, F, Cl, Br, I, OH, CN, NH 2 , NO 2 , COOH, Other variables are as defined in the present invention.
- R7 is selected from H, or optionally substituted with 1, 2 or 3 Rs: NH2 and CH3 , other variables are as defined herein.
- R 7 is selected from H, -N(CH 3 ) 2 and CH 3 , and other variables are as defined in the present invention.
- R 5 and R 6 are linked together, the structural unit Selected from: Other variables are as defined in the present invention.
- the above-mentioned compounds are selected from
- R 1 , R 2 , R 3 and R 4 are as defined in the present invention.
- the present invention also provides compounds, pharmaceutically acceptable salts or tautomers thereof, selected from the group consisting of:
- the above-mentioned compound, a pharmaceutically acceptable salt thereof, or a tautomer thereof is selected from the group consisting of:
- the present invention also provides the use of the above compounds, their pharmaceutically acceptable salts and their tautomers in preparing medicines related to LRRK2 kinase inhibitors.
- salts refers to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases.
- base addition salts can be obtained by contacting the neutral forms of such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent.
- Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
- acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
- Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acids; also include salts of amino acids such as arginine, etc.
- inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate,
- Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts.
- the neutral form of the compound is regenerated by contacting the salt with a base or acid in a conventional manner and isolating the parent compound.
- the parent form of a compound differs from its various salt forms by certain physical properties, such as solubility in polar solvents.
- pharmaceutically acceptable salts pertain to derivatives of compounds of the present invention wherein the parent compound is modified by salt formation with an acid or salt formation with a base.
- pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like.
- Pharmaceutically acceptable salts include conventional nontoxic salts or quaternary ammonium salts of the parent compound, such as those formed from nontoxic inorganic or organic acids.
- non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxy, hydroxynaphthalene, isethionic acid, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid, phosphoric
- the pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
- the compounds provided herein also exist in prodrug forms.
- Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the present invention.
- prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.
- Certain compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the present invention.
- the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
- the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to within the scope of the present invention.
- Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
- Optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
- a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art
- the diastereoisomers were resolved and the pure enantiomers recovered.
- separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).
- the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
- compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
- active ingredient refers to a chemical entity that is effective in treating the target disorder, disease or condition.
- substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable of.
- optionally substituted means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically achievable basis.
- any variable eg, R
- its definition in each case is independent.
- the group may optionally be substituted with up to two Rs, with independent options for R in each case.
- combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
- linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
- substituent When a substituent is vacant, it means that the substituent does not exist. For example, when X in AX is vacant, it means that the structure is actually A. When a substituent's bond can be cross-linked to two atoms on a ring, the substituent can bond to any atom on the ring. When a listed substituent does not indicate through which atom it is attached to a compound included in the general formula but not specifically mentioned, such substituent may be bonded through any of its atoms. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds. For example, structural unit Indicates that it can be substituted at any position on cyclohexyl or cyclohexadiene.
- ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl, or heteroaryl. So-called rings include monocyclic, bicyclic, spirocyclic, paracyclic or bridged rings.
- the number of atoms in a ring is generally defined as the number of ring members, eg, "5-7 membered ring” means 5-7 atoms arranged around it. Unless otherwise specified, the ring optionally contains 1 to 3 heteroatoms.
- 5-7 membered ring includes, for example, phenyl, pyridine, and piperidinyl; on the other hand, the term “5-7 membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but does not include phenyl.
- ring also includes ring systems containing at least one ring, wherein each "ring" independently meets the above definition.
- heterocycle or “heterocyclyl” means a stable heteroatom or heteroatom-containing monocyclic, bicyclic, or tricyclic ring, which may be saturated, partially unsaturated, or unsaturated ( aromatic), which contain carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a benzene ring to form a bicyclic ring.
- Nitrogen and sulfur heteroatoms can optionally be oxidized (ie, NO and S(O)p, where p is 1 or 2).
- Nitrogen atoms can be substituted or unsubstituted (ie, N or NR, where R is H or other substituents already defined herein).
- the heterocycle can be attached to any heteroatom or pendant carbon atom to form a stable structure.
- the heterocycles described herein may undergo substitution at the carbon or nitrogen positions if the resulting compound is stable.
- the nitrogen atoms in the heterocycle are optionally quaternized.
- a preferred solution is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred solution is that the total number of S and O atoms in the heterocycle does not exceed 1.
- aromatic heterocyclic group or “heteroaryl” means an aromatic ring of a stable 5, 6, 7 membered monocyclic or bicyclic or 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.
- Nitrogen atoms can be substituted or unsubstituted (ie, N or NR, where R is H or other substituents already defined herein).
- Nitrogen and sulfur heteroatoms can optionally be oxidized (ie, NO and S(O)p, where p is 1 or 2). Notably, the total number of S and O atoms on the aromatic heterocycle does not exceed 1.
- Bridged rings are also included in the definition of heterocycle.
- a bridged ring is formed when one or more atoms (ie, C, O, N, or S) link two non-adjacent carbon or nitrogen atoms.
- Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a triple ring. In bridged rings, substituents on the ring may also appear on the bridge.
- heterocyclic compounds include, but are not limited to: acridinyl, azacinyl, benzimidazolyl, benzofuranyl, benzomercaptofuranyl, benzomercaptophenyl, benzoxazolyl, benzoxanyl oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, Carboline, chromanyl, chromene, cinnolinyldecahydroquinolyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] tetrahydrofuranyl, furanyl, furanyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl
- hydrocarbyl or its subordinate concepts (such as alkyl, alkenyl, alkynyl, aryl, etc.) by itself or as part of another substituent means straight chain, branched chain or cyclic Hydrocarbon radicals or combinations thereof, can be fully saturated (such as alkyl), mono- or polyunsaturated (such as alkenyl, alkynyl, aryl), can be mono- or polysubstituted, and can be monovalent (such as methyl), divalent (such as methylene), or polyvalent (such as methine), and may include divalent or polyvalent radicals with the specified number of carbon atoms (such as C1 -C12 for 1 to 12 carbons) , C 1-12 is selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 ; C 3-12 is selected from C 3 , C4
- Hydrocarbyl includes but is not limited to aliphatic hydrocarbon groups and aromatic hydrocarbon groups
- the aliphatic hydrocarbon groups include chain and cyclic groups, specifically including but not limited to alkyl, alkenyl, and alkynyl groups
- the aromatic hydrocarbon groups include but are not limited to 6-12 membered aromatic hydrocarbon groups, such as benzene, naphthalene, etc.
- the term “hydrocarbyl” refers to straight or branched chain radicals or combinations thereof, which may be fully saturated, mono- or polyunsaturated, and may include divalent and polyvalent radicals.
- saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl) Methyl, cyclopropylmethyl, and homologues or isomers of n-pentyl, n-hexyl, n-heptyl, n-octyl and other atomic groups.
- Unsaturated hydrocarbon groups have one or more double or triple bonds, examples of which include but are not limited to vinyl, 2-propenyl, butenyl, crotyl, 2-prenyl, 2-(butadienyl) , 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers body.
- heterohydrocarbyl or its subordinate concepts (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.) by itself or in combination with another term means a stable straight, branched chain A cyclic or cyclic hydrocarbon radical or a combination thereof, consisting of a certain number of carbon atoms and at least one heteroatom.
- heteroalkyl by itself or in combination with another term refers to a stable straight chain, branched chain hydrocarbon radical or combination thereof, consisting of a certain number of carbon atoms and at least one heteroatom.
- the heteroatoms are selected from B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized.
- a heteroatom or heteroatom group can be located at any internal position within a heterohydrocarbyl group, including where the hydrocarbyl group is attached to the rest of the molecule, but the terms "alkoxy,”"alkylamino,” and “alkylthio" (or thioalkoxy) ) is a conventional expression referring to those alkyl groups attached to the rest of the molecule through an oxygen, amino or sulfur atom, respectively.
- Up to two heteroatoms may be consecutive, eg -CH2 -NH- OCH3 .
- cycloalkyl refers to any one of the groups listed above.
- heterocycloalkyl or subordinate concepts thereof (such as aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl , heterocycloalkynyl, etc.) by themselves or in combination with other terms represent cyclized “hydrocarbyl”, “heterohydrocarbyl”, respectively.
- a heteroatom may occupy the position at which the heterocycle is attached to the remainder of the molecule.
- cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
- heterocyclyl groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuranindol-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
- alkyl is used to denote a straight or branched chain saturated hydrocarbon group, which may be monosubstituted (eg -CH2F ) or polysubstituted (eg -CF3 ), may be monovalent (eg methyl), divalent (eg methylene), or polyvalent (eg methine).
- alkyl groups examples include methyl (Me), ethyl (Et), propyl (eg, n-propyl and isopropyl), butyl (eg, n-butyl, isobutyl, s-butyl) , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl) and the like.
- alkenyl refers to an alkyl group having one or more carbon-carbon double bonds at any position in the chain, which may be mono- or poly-substituted, and may be mono-, di-, or polyvalent.
- alkenyl groups include vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexamadienyl, and the like.
- alkynyl refers to an alkyl group having one or more carbon-carbon triple bonds at any point in the chain, which may be mono- or polysubstituted, and may be mono-, di-, or polyvalent.
- alkynyl groups include ethynyl, propynyl, butynyl, pentynyl and the like.
- cycloalkyl includes any stable cyclic or polycyclic hydrocarbon group, any carbon atom is saturated, may be mono- or polysubstituted, and may be monovalent, divalent or polyvalent.
- examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclodecane, and the like.
- cycloalkenyl includes any stable cyclic or polycyclic hydrocarbon group containing one or more unsaturated carbon-carbon double bonds at any position on the ring, which may be mono- or polysubstituted, It can be one price, two price or multiple price.
- examples of such cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and the like.
- a cycloalkynyl group includes any stable cyclic or polycyclic hydrocarbon group containing one or more carbon-carbon triple bonds at any position on the ring, which may be mono- or polysubstituted, and which may be a price, double price or multiple price.
- halogen or “halogen” by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
- haloalkyl is intended to include monohaloalkyl and polyhaloalkyl.
- halo( C1 - C4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like Wait.
- examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
- Alkoxy represents the above-mentioned alkyl groups having the specified number of carbon atoms attached through an oxygen bridge, and unless otherwise specified, C 1-6 alkoxy includes C 1 , C 2 , C 3 , C 4 , C 5 and C 6 of the alkoxy. Examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, and S- pentoxy.
- aryl refers to a polyunsaturated aromatic hydrocarbon substituent, which may be mono- or polysubstituted, monovalent, divalent or polyvalent, which may be monocyclic or polycyclic (such as 1 to 3 rings; at least one of which is aromatic), fused together or covalently linked.
- heteroaryl refers to an aryl group (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatoms are selected from B, N, O, and S, wherein nitrogen and sulfur atoms are optionally oxidized, and nitrogen atoms are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
- Non-limiting examples of aryl or heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrrolyl oxazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl azolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thiophene base, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-
- aryl when used in conjunction with other terms (eg, aryloxy, arylthio, aralkyl) includes aryl and heteroaryl rings as defined above.
- aralkyl is intended to include those radicals in which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, etc.), including wherein a carbon atom (eg, methylene) has been replaced by, for example, oxygen Atoms are substituted for those alkyl groups such as phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like.
- leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, affinity substitution reaction).
- representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters, etc.; acyloxy, such as acetoxy, trifluoroacetoxy, and the like.
- protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
- amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
- Representative amino protecting groups include, but are not limited to: formyl; acyl groups, such as alkanoyl groups (eg, acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl groups, such as tert-butoxycarbonyl (Boc) ; Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); Arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
- hydroxy protecting group refers to a protecting group suitable for preventing hydroxyl side reactions.
- Representative hydroxy protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (eg acetyl); arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
- alkyl groups such as methyl, ethyl and tert-butyl
- acyl groups such as alkanoyl (eg acetyl)
- arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenyl
- the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
- aq stands for water
- HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate
- EDC represents N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
- m-CPBA 3-chloroperoxybenzoic acid
- eq represents equivalent, equivalent
- CDI represents Carbonyldiimidazole
- DCM for dichloromethane
- PE for petroleum ether
- DIAD diisopropyl azodicarboxylate
- DMF N,N-dimethylformamide
- DMSO dimethyl sulfoxide
- EtOAc for ethyl acetate Ester
- EtOH for ethanol
- MeOH for methanol
- CBz benzyloxycarbonyl
- the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction method (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuK ⁇ radiation, and the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
- SXRD single crystal X-ray diffraction method
- the cultured single crystal is collected by Bruker D8 venture diffractometer
- the light source is CuK ⁇ radiation
- the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
- the compound diethyl phosphonate (20.00 g, 144.82 mmol, 18.69 mL) was slowly added dropwise to a solution of methylmagnesium bromide (3.0 M tetrahydrofuran solution, 160.00 mL, 480 mmol) in tetrahydrofuran (300 mL), and the mixture was controlled
- the inner temperature is lower than 10°C. The temperature was slowly raised to room temperature and stirred for 5 hours.
- the mixture was filtered and concentrated, the resulting residue was diluted with aqueous hydrochloric acid (1 N, 80 mL), the pH was adjusted to about 2, and the resulting mixture was filtered.
- the filtrate was extracted with dichloromethane (100 mL ⁇ 2), the aqueous layer was separated, and the pH was adjusted to about 9 with aqueous sodium bicarbonate solution, then extracted with dichloromethane (200 mL ⁇ 2).
- the organic layer was dried over anhydrous sodium sulfate and concentrated to dryness.
- reaction solution was concentrated under reduced pressure, and the residue was separated and purified by high performance liquid chromatography to obtain (2-((5-chloro-2-((4-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl ) dimethylphosphine oxide (27.0 mg), yield: 42%.
- Lithium aluminum tetrahydride (198.14 mg, 5.22 mmol) was dissolved in tetrahydrofuran (10 mL), and then 5-amino-2-methyl-isoindoline-1,3-dione was added to the reaction solution at 10 degrees Celsius (400 mg, 2.27 mmol) in tetrahydrofuran (10 mL). The reaction solution was stirred at 80°C for 3 hours.
- 2-Dimethylphosphoryl benzonitrile (70.0 mg, 0.391 mmol) was dissolved in methanol (10 mL), and wet palladium on carbon (10%, 20 mg) was added to the reaction solution.
- the reaction solution was reacted under a hydrogen (50 psi) atmosphere at 20°C for 16 hours.
- the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow solid, which was rinsed with a small amount of ethyl acetate to obtain the crude product 2-dimethylphosphorylbenzylamine (70.0 mg, yellow solid).
- reaction solution was concentrated, separated and purified by thin layer chromatography (15/1 dichloromethane/methanol) to obtain 2,5-dichloro-N-[(2-dimethylphosphorylphenyl)methyl]pyrimidine-4- Amine (0.1 g, yellow solid, yield: 66%).
- reaction solution was concentrated under reduced pressure, and the residue was separated and purified by high performance liquid chromatography to obtain 1-[6-[[5-chloro-4-[(2-dimethylphosphorylphenyl)methylamino]pyrimidin-2-yl ]Amino]-5-methoxy-indoline-1-yl]-2-(dimethylamino)acetyl (40.00 mg), yield: 23%.
- Reaction solution 10mM hydroxyethylpiperazineethanesulfonic acid (PH7.5); 2mM magnesium chloride; 0.5mM ethylene glycol diethyl ether diaminetetraacetic acid; 0.002% polyoxyethylene fatty alcohol ether; 1mM dithiothreitol and 1% DMSO;
- LRRK2 Recombinant Human Protein express recombinant full-length human LRRK2 Protein in insect Sf9 cells with baculovirus using GST tag;.
- Substrate 0.4uM Fluorescein-ERM (LRRKtide)peptide; 57uM ATP.
- HTRF Homogeneous time-resolved fluorescence
- Test sample (compound prepared in each example) LRRK2 kinase inhibitory activity Compound 1 +++ Compound 2 +++ Compound 3 +++ Compound 4 +++ Compound 5 +++ Compound 6 +++ Compound 7 +++ Compound 8 +++ Compound 9 +++ Compound 10 +++ Compound 11 +++ Compound 12 +++ Compound 13 +++ Compound 14 +++ Compound 15 +++ Compound 16 +++ Compound 17 +++ Compound 18 +++ Compound 19 +++ Compound 20 +++ Compound 21 +++ Compound 22 +++ Compound 23 +++ Compound 24 +++ Compound 25 +++ Compound 26 +++ Compound 27 +++ Compound 28 +++ Compound 29 +++ Compound 30 +++ Compound 31 + Compound 32 + Compound 33 ++ Compound 34 +++ Compound 35 +++ Compound 36 +++ Compound 37 ++
- the compounds of the present invention have significant and even unexpected LRRK2 kinase inhibitory activity.
Abstract
一系列嘧啶衍生物及其在制备治疗相关疾病药物中的应用,具体公开了式(I)所示化合物或其药学上可接受的盐及其在制备治疗相关疾病药物中的应用。
Description
本申请主张如下优先权:
PCT/CN2021/082459,申请日2021年03月23日。
本发明涉及一系列嘧啶衍生物及其在制备治疗相关疾病药物中的应用,具体公开了式(I)所示化合物或其药学上可接受的盐及其在制备治疗相关疾病药物中的应用。
LRRK2激酶的突变及过表达越来越多地被证明是诱发神经退行性疾病的根本因素,以黑质区中多巴胺能神经元的选择性变性和细胞死亡为主要特征。影响着1%的65岁以上的人群,其中遗传性患者占发病人群的5-10%。该疾病的早期,最明显的症状表现为摇动,活动缓慢和行走困难。后期还会出现认知和行为问题,晚期通常会出现痴呆。
越来越多的证据显示富含亮氨酸重复序列的激酶2(LRRK2)突变与神经退行性疾病有不可分割的联系,LRRK2是一种在催化磷酸化和GTP-GDP水解中涉及的2527氨基酸蛋白。人类LRRK2mRNA的NCBI参与序列是NM_198578.2。证据显示,LRRK2在丝氨酸-129处磷酸化a-突触核蛋白,并且这一磷酸化形式构成路易体的重要部分。另外,已经显示LRRK2的功能结构域中的单核苷酸多肽性引起常见性且散发性神经退行性疾病。目前为止,研究人员已经在患有迟发型神经退行性疾病的家族中识别了超过20个LRRK2突变。例如G2019S突变与常染色体显性共分离,并且其在欧洲导致约6%的家庭性病例和3%散发性病例。G2019S突变发生在高度保守的激酶结构域,因此G2019S突变可能对激酶活性有影响。此外,在另一残基R1441上的氨基酸取代也与神经退行性疾病有关,并且显示提高了LRRK2激酶的活性。在转基因小鼠模型中的突变体LRRK2蛋白R1441G的过度表达与多巴胺释放减少有关,显示LRRK2抑制剂也能积极地调节多巴胺的释放并且在治疗以及多巴胺释放减少有关,显示LRRK2抑制剂也能积极地调节多巴胺的释放并且在治疗以降低的多巴胺水平为特征的疾病中具有潜在效用。相关的数据进一步显示了LRRK2激酶活性抑制剂也可用于治疗相关的神经变性疾病。
因此,开发有效的LRRK2激酶以及突变的LRRK2激酶的抑制剂成为目前治疗神经退行性疾病的一条重要的途径。本发明旨在发明一种可以高度对LRRK2激酶抑制的化合物,从而进一步发明可以很好的治疗神经退行性疾病的药物。
ACS Med.Chem.Lett.2015,6,584-589公开了化合物JH-II-127,属于LRRK2激酶抑制剂,其结构式如式(III)所示:
发明内容
本发明提供式(I)化合物、其药学上可接受的盐及其互变异构体,
其中,
L选自单键和-CH
2-;
R
1和R
2分别独立地选自H、F、Cl、Br、I、OH、CN、NH
2和COOH,或分别独立地选自任选被1、2或3个R取代的:C
1-6烷基、C
1-6杂烷基、4~6元杂环烷基和R
a-L
1-,且R
1、R
2不选自:
R
a选自H、苯基、5~6元杂芳基、C
4-6环烷基和4~6元杂环烷基;
L
1选自-C(=O)-、-C(=O)NH-、-S(=O)-、-S(=O)
2-、-CH
2-和-CH
2CH
2-;
R
3选自F、Cl、Br、I、OH、CN、CF
3和NH
2;
R
4分别独立地选自H、F、Cl、Br和I;
R
5和R
6分别独立地选自H、卤素、OH、CN、NH
2、NO
2、COOH和R
b-L
2-L
3-L
4-,或分别独立地选自任选被1、2或3个R取代的:C
1-6烷基、C
1-6杂烷基、C
4-6环烷基、4~6元杂环烷基、苯基和5~6元杂芳基,且R
5和R
6不选自任选被1、2或3个卤素取代的
R
b选自H、卤素、OH、CN、NH
2、NO
2、COOH,或选自任选被1、2或3个R取代的:C
1-6烷基、C
1-
6杂烷基、C
4-6环烷基、4~6元杂环烷基和5~6元杂芳基;
L
2、L
3和L
4分别独立地选自单键、O、S、NH、-C(=O)-、-C(=O)NH-、-S(=O)-、-S(=O)
2-、-(CH
2)
1-3-、苯基、5~6元杂芳基和4~6元杂环烷基,且L
2、L
3和L
4不同时选自单键;
R
7选自H、卤素、OH、CN、NH
2、NO
2、COOH,或选自任选被1、2或3个R取代的:NH
2和C
1-3烷基;
R
8选自F、Cl、Br、I、OH、CN和NH
2;
R选自卤素、OH、CN、NH
2、COOH,或选自任选被1、2或3个R’取代的:C
1-3烷基和C
1-3杂烷基;
R’选自F、Cl、Br、I、OH、CN、NH
2、COOH、Me、Et、CF
3、CHF
2、CH
2F、NHCH
3和N(CH
3)
2;
所述C
1-6杂烷基、C
1-3杂烷基、4~6元杂环烷基和5~6元杂芳基之杂原子或杂原子团,选自-C(=O)NH-、-NH-、-C(=NH)-、-S(=O)
2NH-、-S(=O)NH-、-N=、-O-、-S-、-O-N=、-C(=O)O-、-C(=O)-、-S(=O)-、 -S(=O)
2-和-NHC(=O)NH-;
以上任何一种情况下,杂原子或杂原子团的数目分别独立地选自1、2或3。
在本发明的一些方案中,上述R选自F、Cl、Br、I、OH、CN、NH
2和COOH,或选自任选被1、2或3个R’取代的:C
1-3烷基、C
1-3烷氧基和C
1-3烷基-C(=O)-,其他变量如本发明所定义;
在本发明的一些方案中,上述Ra选自H、苯基和6元杂环烷基,其他变量如本发明所定义。
在本发明的一些方案中,上述Ra选自H、苯基和吗啉基,其他变量如本发明所定义;
在本发明的一些方案中,上述R
1和R
2分别独立地选自H、F、Cl、Br、I、OH、CN、NH
2和COOH,或分别独立地选自任选被1、2或3个R取代的:C
1-3烷基、C
1-3烷氧基、C
1-3烷硫基、C
1-3烷氨基、N,N’-二(C
1-2烷基)氨基-和5~6元杂环烷基,其他变量如本发明所定义。
在本发明的一些方案中,上述Rb选自H卤素、OH、CN、NH
2、NO
2和COOH,或选自任选被1、2或3个R取代的:C
1-3烷氨基、C
1-3烷氧基、C
1-3烷硫基、N,N’-二(C
1-2烷基)氨基、吡咯烷基、吗啉基、哌嗪基、吡啶基和嘧啶基,其他变量如本发明所定义。
在本发明的一些方案中,上述L
2、L
3和L
4分别独立地选自:单键、O、S、NH、-C(=O)-、-C(=O)NH-、 -S(=O)-、-S(=O)
2-、-CH
2-、-CH
2CH
2-、苯基、吡啶基、吡唑基、咪唑基、吡啶基、嘧啶基、噻吩基、恶唑基、噻唑基、异恶唑基和异噻唑基,其他变量如本发明所定义。
在本发明的一些方案中,上述L
2、L
3和L
4分别独立地选自:单键、O、S、NH、-C(=O)-、-C(=O)NH-、-S(=O)-、-S(=O)
2-、-CH
2-、-CH
2CH
2-、
其他变量如本发明所定义。
在本发明的一些方案中,上述R
5和R
6分别独立地选自H、卤素、OH、CN、NH
2、NO
2和COOH,或分别独立地选自任选被1、2或3个R取代的:C
1-3杂烷基、噻唑基、嘧啶基、吡啶基、噻吩基、哌啶基、吗啉基和哌嗪基,其他变量如本发明所定义。
在本发明的一些方案中,上述R
7选自H,或选自任选被1、2或3个R取代的:NH
2和CH
3,其他变量如本发明所定义。
在本发明的一些方案中,上述R
7选自H、-N(CH
3)
2和CH
3,其他变量如本发明所定义。
在本发明的一些方案中,上述化合物选自
R
1、R
2、R
3和R
4如本发明所定义。
本发明还提供化合物、其药学上可接受的盐或其互变异构体,其选自:
在本发明的一些方案中,上述化合物、其药学上可接受的盐或其互变异构体,其选自:
本发明还提供了上述化合物、其药学上可接受的盐及其互变异构体在制备LRRK2激酶抑制剂相关药物中的应用。
相关定义
除非另有说明,本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的,而应该按照普通的含义去理解。当本文中出现商品名时,意在指代其对应的商品或其活性成分。这里所采用的术语“药学上可接受的”,是针对那些化合物、材料、组合物和/或剂型而言,它们在可靠的医学判断的范围之内,适用于与人类和动物的组织接触使用,而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症,与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐,由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐,所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸,碳酸氢根,磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等;以及有机酸盐,所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸;还包括氨基酸(如精氨酸等)的盐,以及如葡糖醛酸等有机酸的盐(参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977))。本发明的某些特定的化合物含有碱性和酸性的官能团,从而可以被转换成任一碱或酸加成盐。
优选地,以常规方式使盐与碱或酸接触,再分离母体化合物,由此再生化合物的中性形式。化合物的母体形式与其各种盐的形式的不同之处在于某些物理性质,例如在极性溶剂中的溶解度不同。
本文所用的“药学上可接受的盐”属于本发明化合物的衍生物,其中,通过与酸成盐或与碱成盐的方式修饰所述母体化合物。药学上可接受的盐的实例包括但不限于:碱基比如胺的无机酸或有机酸盐、酸根比如羧酸的碱金属或有机盐等等。药学上可接受的盐包括常规的无毒性的盐或母体化合物的季铵盐,例如无毒的无机酸或有机酸所形成的盐。常规的无毒性的盐包括但不限于那些衍生自无机酸和有机酸的盐,所述的无机酸或有机酸选自2-乙酰氧基苯甲酸、2-羟基乙磺酸、乙酸、抗坏血酸、苯磺酸、苯甲酸、碳酸氢根、碳酸、柠檬酸、依地酸、乙烷二磺酸、乙烷磺酸、富马酸、葡庚糖、葡糖酸、谷氨酸、 乙醇酸、氢溴酸、盐酸、氢碘酸盐、羟基、羟萘、羟乙磺酸、乳酸、乳糖、十二烷基磺酸、马来酸、苹果酸、扁桃酸、甲烷磺酸、硝酸、草酸、双羟萘酸、泛酸、苯乙酸、磷酸、多聚半乳糖醛、丙酸、水杨酸、硬脂酸、亚乙酸、琥珀酸、氨基磺酸、对氨基苯磺酸、硫酸、单宁、酒石酸和对甲苯磺酸。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下,这样的盐的制备方法是:在水或有机溶剂或两者的混合物中,经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地,优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。
除了盐的形式,本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外,前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在,包括水合物形式。一般而言,溶剂化形式与非溶剂化的形式相当,都包含在本发明的范围之内。
本发明的某些化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、非对映异构体、几何异构体和单个的异构体都包括在本发明的范围之内。
除非另有说明,用楔形键和虚线键
表示一个立体中心的绝对构型,用
表示一个立体中心的相对构型。当本文所述化合物含有烯属双键或其它几何不对称中心,除非另有规定,它们包括E、Z几何异构体。同样地,所有的互变异构形式均包括在本发明的范围之内。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物,包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体,及其外消旋混合物和其他混合物,例如对映异构体或非对映体富集的混合物,所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物,均包括在本发明的范围之内。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体,可以通过不对称合成或者具有手性助剂的衍生作用来制备,其中将所得非对映体混合物分离,并且辅助基团裂开以提供纯的所需对映异构体。或者,当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时,与适当的光学活性的酸或碱形成非对映异构体的盐,然后通过本领域所公知的常规方法进行非对映异构体拆分,然后回收得到纯的对映体。此外,对映异构体和非对映异构体的分离通常是通过使用色谱法完成的,所述色谱法采用手性固定相,并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如,可用放射性同位素标记化合物,比如氚(
3H),碘-125(
125I)或C-14(
14C)。本发明的化合物的所有同位素组成的变换,无论放射性与否,都包括在本发明的范围之内。
术语“活性成分”、“治疗剂”,“活性物质”或“活性剂”是指一种化学实体,它可以有效地治疗目标紊乱、疾病或病症。
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的,并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代,可以包括重氢和氢的变体,只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为酮基(即=O)时,意味着两个氢原子被取代。酮取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代,也可以不被取代,除非另有规定,取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时,其在每一种情况下的定义都是独立的。因此,例如,如果一个基团被0-2个R所取代,则所述基团可以任选地至多被两个R所取代,并且每种情况下的R都有独立的选项。此外,取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时,比如-(CRR)
0-,表示该连接基团为单键。
当其中一个变量选自单键时,表示其连接的两个基团直接相连,比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时,表示该取代基是不存在的,比如A-X中X为空缺时表示该结构实际上是A。当一个取代基的键可以交叉连接到一个环上的两个原子时,这种取代基可以与这个环上的任意原子相键合。当所列举的取代基中没有指明其通过哪一个原子连接到化学结构通式中包括但未具体提及的化合物时,这种取代基可以通过其任何原子相键合。取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。例如,结构单元
表示其可在环己基或者环己二烯上的任意一个位置发生取代。
除非另有规定,术语“杂”表示杂原子或杂原子团(即含有杂原子的原子团),包括碳(C)和氢(H)以外的原子以及含有这些杂原子的原子团,例如包括氧(O)、氮(N)、硫(S)、硅(Si)、锗(Ge)、铝(Al)、硼(B)、-O-、-S-、=O、=S、-C(=O)O-、-C(=O)-、-C(=S)-、-S(=O)、-S(=O)
2-,以及任选被取代的-C(=O)N(H)-、-N(H)-、-C(=NH)-、-S(=O)
2N(H)-或-S(=O)N(H)-。
除非另有规定,“环”表示被取代或未被取代的环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所谓的环包括单环、联环、螺环、并环或桥环。环上原子的数目通常被定义为环的元数,例如,“5~7元环”是指环绕排列5~7个原子。除非另有规定,该环任选地包含1~3个杂原子。因此,“5~7元环”包括例如苯基、吡啶和哌啶基;另一方面,术语“5~7元杂环烷基环”包括吡啶基和哌啶基,但不包括苯基。术语“环”还包括含有至少一个环的环系,其中的每一个“环”均独立地符合上述定义。
除非另有规定,术语“杂环”或“杂环基”意指稳定的含杂原子或杂原子团的单环、双环或三环,它们可以是饱和的、部分不饱和的或不饱和的(芳族的),它们包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子,其中上述任意杂环可以稠合到一个苯环上形成双环。氮和硫杂原子可任选被氧化(即NO和S(O)p,p是1或2)。氮原子可以是被取代的或未取代的(即N或NR,其中R是H或本文已经定义过的其他取代基)。该杂环可以附着到任何杂原子或碳原子的侧基上从而形成稳定的结构。如果产生的化合物是稳定的,本文所述的杂环可以发生碳位或氮位上的取代。杂环中的氮原子任选地被季铵化。一个优选方案是,当杂环中S及O原子的总数超过1时,这些杂原子彼此不相邻。另一个优选方案是,杂环中S及O原子的总数不超过1。如本文所用,术语“芳族杂环基团”或“杂芳基”意指稳定 的5、6、7元单环或双环或7、8、9或10元双环杂环基的芳香环,它包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子。氮原子可以是被取代的或未取代的(即N或NR,其中R是H或本文已经定义过的其他取代基)。氮和硫杂原子可任选被氧化(即NO和S(O)p,p是1或2)。值得注意的是,芳香杂环上S和O原子的总数不超过1。桥环也包含在杂环的定义中。当一个或多个原子(即C、O、N或S)连接两个不相邻的碳原子或氮原子时形成桥环。优选的桥环包括但不限于:一个碳原子、两个碳原子、一个氮原子、两个氮原子和一个碳-氮基。值得注意的是,一个桥总是将单环转换成三环。桥环中,环上的取代基也可以出现在桥上。
杂环化合物的实例包括但不限于:吖啶基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并巯基呋喃基、苯并巯基苯基、苯并恶唑基、苯并恶唑啉基、苯并噻唑基、苯并***基、苯并四唑基、苯并异恶唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、苯并二氢吡喃基、色烯、噌啉基十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、吲哚烯基、二氢吲哚基、中氮茚基、吲哚基、3H-吲哚基、异苯并呋喃基、异吲哚基、异二氢吲哚基、异喹啉基、异噻唑基、异恶唑基、亚甲二氧基苯基、吗啉基、萘啶基,八氢异喹啉基、恶二唑基、1,2,3-恶二唑基、1,2,4-恶二唑基、1,2,5-恶二唑基、1,3,4-恶二唑基、恶唑烷基、恶唑基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪、吩噻嗪、苯并黄嘌呤基、酚恶嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并恶唑、吡啶并咪唑、吡啶并噻唑、吡啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、四唑基,6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、异噻唑基噻吩基、噻吩并恶唑基、噻吩并噻唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-***基、1,2,4-***基、1,2,5-***基、1,3,4-***基和呫吨基。还包括稠环和螺环化合物。
除非另有规定,术语“烃基”或者其下位概念(比如烷基、烯基、炔基、芳基等等)本身或者作为另一取代基的一部分表示直链的、支链的或环状的烃原子团或其组合,可以是完全饱和的(如烷基)、单元或多元不饱和的(如烯基、炔基、芳基),可以是单取代或多取代的,可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基),可以包括二价或多价原子团,具有指定数量的碳原子(如C
1-C
12表示1至12个碳,C
1-12选自C
1、C
2、C
3、C
4、C
5、C
6、C
7、C
8、C
9、C
10、C
11和C
12;C
3-12选自C
3、C
4、C
5、C
6、C
7、C
8、C
9、C
10、C
11和C
12。)。“烃基”包括但不限于脂肪烃基和芳香烃基,所述脂肪烃基包括链状和环状,具体包括但不限于烷基、烯基、炔基,所述芳香烃基包括但不限于6-12元的芳香烃基,例如苯、萘等。在一些实施例中,术语“烃基”表示直链的或支链的原子团或它们的组合,可以是完全饱和的、单元或多元不饱和的,可以包括二价和多价原子团。饱和烃原子团的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、异丁基、环己基、(环己基)甲基、环丙基甲基,以及正戊基、正己基、正庚基、正辛基等原子团的同系物或异构体。不饱和烃基具有一个或多个双键或三键,其实例包括但不限于乙烯基、2-丙烯基、丁烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2,4-戊二烯基、3-(1,4-戊二烯基)、乙炔基、1-和3-丙炔基,3-丁炔基,以及更高级的同系物和异构体。
除非另有规定,术语“杂烃基”或者其下位概念(比如杂烷基、杂烯基、杂炔基、杂芳基等等)本身或者与另一术语联合表示稳定的直链的、支链的或环状的烃原子团或其组合,有一定数目的碳原子和至少一个杂原子组成。在一些实施例中,术语“杂烷基”本身或者与另一术语联合表示稳定的直链的、支链的烃原子团或其组合物,有一定数目的碳原子和至少一个杂原子组成。在一个典型实施例中,杂原子选自B、O、N和S,其中氮和硫原子任选地被氧化,氮杂原子任选地被季铵化。杂原子或杂原子团可以位于杂烃基的任何内部位置,包括该烃基附着于分子其余部分的位置,但术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)属于惯用表达,是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烷基基团。实例包括但不限于-CH
2-CH
2-O-CH
3、-CH
2-CH
2-NH-CH
3、-CH
2-CH
2-N(CH
3)-CH
3、-CH
2-S-CH
2-CH
3、-CH
2-CH
2、-S(O)-CH
3、-CH
2-CH
2-S(O)
2-CH
3、-CH=CH-O-CH
3、-CH
2-CH=N-OCH
3和–CH=CH-N(CH
3)-CH
3。至多两个杂原子可以是连续的,例如-CH
2-NH-OCH
3。
除非另有规定,术语“环烃基”、“杂环烃基”或者其下位概念(比如芳基、杂芳基、环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基等等)本身或与其他术语联合分别表示环化的“烃基”、“杂烃基”。此外,就杂烃基或杂环烃基(比如杂烷基、杂环烷基)而言,杂原子可以占据该杂环附着于分子其余部分的位置。环烃基的实例包括但不限于环戊基、环己基、1-环己烯基、3-环己烯基、环庚基等。杂环基的非限制性实例包括1-(1,2,5,6-四氢吡啶基)、1-哌啶基、2-哌啶基,3-哌啶基、4-吗啉基、3-吗啉基、四氢呋喃-2-基、四氢呋喃吲哚-3-基、四氢噻吩-2-基、四氢噻吩-3-基,1-哌嗪基和2-哌嗪基。
除非另有规定,术语“烷基”用于表示直链或支链的饱和烃基,可以是单取代(如-CH
2F)或多取代的(如-CF
3),可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。烷基的例子包括甲基(Me),乙基(Et),丙基(如,n-丙基和异丙基),丁基(如,n-丁基,异丁基,s-丁基,t-丁基),戊基(如,n-戊基,异戊基,新戊基)等。
除非另有规定,“烯基”指在链的任何位点上具有一个或多个碳碳双键的烷基,可以是单取代或多取代的,可以是一价、二价或者多价。烯基的例子包括乙烯基,丙烯基,丁烯基,戊烯基,己烯基,丁间二烯基,戊间二烯基,己间二烯基等。
除非另有规定,“炔基”指在链的任何位点上具有一个或多个碳碳三键的烷基,可以是单取代或多取代的,可以是一价、二价或者多价。炔基的例子包括乙炔基,丙炔基,丁炔基,戊炔基等。
除非另有规定,环烷基包括任何稳定的环状或多环烃基,任何碳原子都是饱和的,可以是单取代或多取代的,可以是一价、二价或者多价。这些环烷基的实例包括,但不限于,环丙基、降冰片烷基、[2.2.2]二环辛烷、[4.4.0]二环癸烷等。
除非另有规定,环烯基包括任何稳定的环状或多环烃基,该烃基在环的任何位点含有一个或多个不饱和的碳-碳双键,可以是单取代或多取代的,可以是一价、二价或者多价。这些环烯基的实例包括,但不限于,环戊烯基、环己烯基等。
除非另有规定,环炔基包括任何稳定的环状或多环烃基,该烃基在环的任何位点含有一个或多个碳-碳三键,可以是单取代或多取代的,可以是一价、二价或者多价。
除非另有规定,术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。此外,术语“卤代烷基”意在包括单卤代烷基和多卤代烷基。例如,术语“卤代(C
1-C
4)烷基”意在包括但 不仅限于三氟甲基、2,2,2-三氟乙基、4-氯丁基和3-溴丙基等等。除非另有规定,卤代烷基的实例包括但不仅限于:三氟甲基、三氯甲基、五氟乙基,和五氯乙基。
“烷氧基”代表通过氧桥连接的具有特定数目碳原子的上述烷基,除非另有规定,C
1-6烷氧基包括C
1、C
2、C
3、C
4、C
5和C
6的烷氧基。烷氧基的例子包括但不限于:甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基和S-戊氧基。除非另有规定,术语“芳基”表示多不饱和的芳族烃取代基,可以是单取代或多取代的,可以是一价、二价或者多价,它可以是单环或多环(比如1至3个环;其中至少一个环是芳族的),它们稠合在一起或共价连接。术语“杂芳基”是指含有一至四个杂原子的芳基(或环)。在一个示范性实例中,杂原子选自B、N、O和S,其中氮和硫原子任选地被氧化,氮原子任选地被季铵化。杂芳基可通过杂原子连接到分子的其余部分。芳基或杂芳基的非限制性实施例包括苯基、1-萘基、2-萘基、4-联苯基、1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-恶唑基、4-恶唑基、2-苯基-4-恶唑基、5-恶唑基、3-异恶唑基、4-异恶唑基、5-异恶唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯并噻唑基、嘌呤基、2-苯并咪唑基、5-吲哚基、1-异喹啉基、5-异喹啉基、2-喹喔啉基、5-喹喔啉基、3-喹啉基和6-喹啉基。上述任意一个芳基和杂芳基环系的取代基选自下文所述的可接受的取代基。
除非另有规定,芳基在与其他术语联合使用时(例如芳氧基、芳硫基、芳烷基)包括如上定义的芳基和杂芳基环。因此,术语“芳烷基”意在包括芳基附着于烷基的那些原子团(例如苄基、苯乙基、吡啶基甲基等),包括其中碳原子(如亚甲基)已经被例如氧原子代替的那些烷基,例如苯氧基甲基、2-吡啶氧甲基3-(1-萘氧基)丙基等。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如,代表性的离去基团包括三氟甲磺酸酯;氯、溴、碘;磺酸酯基,如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等;酰氧基,如乙酰氧基、三氟乙酰氧基等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于:甲酰基;酰基,例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基);烷氧基羰基,如叔丁氧基羰基(Boc);芳基甲氧羰基,如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc);芳基甲基,如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基;甲硅烷基,如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于:烷基,如甲基、乙基和叔丁基;酰基,例如链烷酰基(如乙酰基);芳基甲基,如苄基(Bn),对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基,DPM);甲硅烷基,如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备,包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式,优选的实施方式包括但不限于本发明的实施例。
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词:aq代表水;HATU代表O-(7-氮杂苯 并***-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐;EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐;m-CPBA代表3-氯过氧苯甲酸;eq代表当量、等量;CDI代表羰基二咪唑;DCM代表二氯甲烷;PE代表石油醚;DIAD代表偶氮二羧酸二异丙酯;DMF代表N,N-二甲基甲酰胺;DMSO代表二甲亚砜;EtOAc代表乙酸乙酯;EtOH代表乙醇;MeOH代表甲醇;CBz代表苄氧羰基,是一种胺保护基团;BOC代表叔丁基羰基是一种胺保护基团;HOAc代表乙酸;NaCNBH
3代表氰基硼氢化钠;r.t.代表室温;O/N代表过夜;THF代表四氢呋喃;Boc
2O代表二-叔丁基二碳酸酯;TFA代表三氟乙酸;DIPEA代表二异丙基乙基胺;SOCl
2代表氯化亚砜;CS
2代表二硫化碳;TsOH代表对甲苯磺酸;NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺;NCS代表1-氯吡咯烷-2,5-二酮;n-Bu
4NF代表氟化四丁基铵;iPrOH代表2-丙醇;mp代表熔点;LDA代表二异丙基胺基锂。
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构,如果本发明涉及化合物的绝对构型,则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD),把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据,光源为CuKα辐射,扫描方式:
扫描,收集相关数据后,进一步采用直接法(Shelxs97)解析晶体结构,便可以确证绝对构型。
下面通过实施例对本发明进行详细描述,但并不意味着对本发明任何不利限制。
实施例1
(2-((5-氯-2-((4-甲氧基苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧化膦
第一步
二甲基氧膦
0℃条件下,向甲基溴化镁(3.0M四氢呋喃溶液,160.00mL,480mmol)的四氢呋喃溶液(300mL)中缓慢滴加化合物膦酸二乙酯(20.00g,144.82mmol,18.69mL),控制内温低于10℃。缓慢升温至室温搅拌5小时。反应结束,将反应液置于冰浴中依次加入饱和碳酸氢钠溶液40mL和乙醇160mL,有大量白色固体析出,过滤除去白色固体,滤液浓缩至40mL并加入150mL甲苯,浓缩后,加入二氯甲烷130mL,乙醇13mL,搅拌1小时,过滤,滤液浓缩得到粗品直接用于下一步化合物二甲基氧膦(45.00g,无色油 状)。
1H NMR:(400MHz,CDCl
3)δ1.59(dd,J=3.6,14.4Hz,6H).
第二步
(2-氨基苯基)二甲基氧化膦
将2-碘苯胺溶液(12.50g,57.07mmol)和二甲基氧化膦(5.35g,68.49mmol),K
3PO
4(14.54g,68.49mmol),4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(660.44mg,1.14mmol)和醋酸钯(256.26mg,1.14mmol)置于DMF(80mL)中,反应混合物在氮气保护下,加热至150℃并搅拌16小时。将混合物过滤并浓缩,将所得残余物用盐酸水溶液(1N,80mL)稀释,调节pH值至大约2,将所得混合物过滤。滤液用二氯甲烷(100mL×2)萃取,将水层分离出来,并且用碳酸氢钠水溶液将pH值调节至约9,然后用二氯甲烷(200mL×2)萃取。有机层用无水硫酸钠干燥并浓缩至干。将粗产物通过重结晶(石油醚:乙酸乙酯=5:1)纯化,得(2-氨基苯基)二甲基氧化膦(6.00g,白色固体),产率:62.15%。
1H NMR:(400MHz,CDCl
3):δ7.20(m,1H),7.04(m,1H),6.69-6.58(m,2H),5.35(br s,2H),1.75(s,3H),1.71(s,3H).
MS-ESI计算值[M+H]
+170,实测值170.1。
第三步
(2-((2,5-二氯嘧啶-4-基)氨基)苯基)二甲基氧化膦
在16℃下,向(2-氨基苯基)二甲基氧化膦(2.50g,14.8mmol)和2,4,5-三氯嘧啶(2.85g,15.5mmol)的DMF(20mL)混合物中,加入DI石油醚A(3.82g,29.6mmol)。然后将反应混合物加热至70℃并搅拌16小时。将反应混合物用水(50mL)稀释,并用乙酸乙酯(40mL×3)萃取。将合并的有机相用饱和盐水(20mL×2)洗涤,无水硫酸钠干燥,过滤并真空浓缩。粗产物在乙醇中重结晶,得(2-((2,5-二氯嘧啶-4-基)氨基)苯基)二甲基氧化膦(3.20g,白色固体),产率:68.4%。
1H NMR:(400MHz,CD
3OD)δ8.50(m,1H),8.35-8.28(m,1H),7.69-7.59(m,2H),7.36-7.28(m,1H),1.91(s,3H),1.88(s,3H).
MS-ESI计算值[M+H]
+316;317;318,实测值316;317;318。
第四步
(2-((5-氯-2-((4-甲氧基苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧化膦
将(2-((2,5-二氯嘧啶-4-基)氨基)苯基)二甲基氧化膦(50.0mg,0.158mmol)溶于叔丁醇(5mL)中,然后向反应液加入4-甲氧基苯胺(23.4mg,0.190mmol)和甲烷磺酸(45.6mg,0.475mmol)。反应液在90℃,搅拌12小时。反应液减压浓缩,剩余物经高效液相色谱法分离纯化得到(2-((5-氯-2-((4-甲氧基苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧化膦(27.0mg),产率:42%。
1H NMR:(400MHz,CDCl
3)δ12.41(s,1H),10.42(s,1H),8.45-8.42(m,1H),7.80(s,1H),7.43-7.40(m,2H),7.37-7.34(m,2H),7.29-7.27(m,1H),6.92-6.89(m,2H),3.85(s,3H),1.88-1.85(m,6H)。
MS-ESI计算值[M+H]
+403和405,实测值403和405。
实施例2
5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-甲氧基-3-(三氟甲基)苯基]嘧啶-2,4-二胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为4-甲氧基-3-(三氟甲基)苯胺,得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-甲氧基-3-(三氟甲基)苯基]嘧啶-2,4-二胺(36.00mg),产率:42%。
1H NMR:(400MHz,CD3OD)δ8.18-8.15(m,2H),7.70-7.65(m,2H),7.61-7.58(m,1H),7.46(br.s.,1H),7.40-7.37(m,1H),7.24-7.22(m,1H),3.95(s,3H),1.89(s,3H),1.86(s,3H).
MS-ESI计算值[M+H]
+471和473,实测值471和473。
实施例3
5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-(2-甲基噻唑-4-基)苯基]嘧啶-2,4-二胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为3-(2-甲基噻唑-4-基)苯胺,得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-(2-甲基噻唑-4-基)苯基]嘧啶-2,4-二胺(30.00mg),产率:37%。
1H NMR:(400MHz,CD
3OD)δ8.26(s,1H),8.17-8.16(m,1H),8.04-8.01(m,2H),7.76-7.74(m,1H),7.69-7.65(m,1H),7.57-7.55(m,2H),7.30-7.29(m,2H),2.99(s,3H),1.90(s,3H),1.87(s,3H).
MS-ESI计算值[M+H]
+470和472,实测值470和472。
实施例4
3-[[5-氯-4-(2-二甲基磷酰基苯胺)嘧啶-2-基]氨基]-4-甲氧基-本甲酰胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为3-氨基-4-甲氧基-本甲酰胺,得到3-[[5-氯-4-(2-二甲基磷酰基苯胺)嘧啶-2-基]氨基]-4-甲氧基-本甲酰胺(23.00mg),产率:27%。
1H NMR:(400MHz,CD
3OD)δ8.24-8.19(m,2H),8.01(s,1H),7.92-7.90(m,1H),7.67-7.62(m,1H),7.50-7.45(m,1H),7.37-7.34(m,1H),7.24-7.22(m,1H),3.94(s,3H),1.90(s,3H),1.86(s,3H).
MS-ESI计算值[M+H]
+446和448,实测值446和448。
实施例5
3-[[5-氯-4-(2-二甲基磷酰基苯胺)嘧啶-2-基]氨基]-N-甲基-本甲酰胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为3-氨基-N-甲基-苯甲酰胺,得到3-[[5-氯-4-(2-二甲基磷酰基苯胺)嘧啶-2-基]氨基]-N-甲基-本甲酰胺(31.00mg),产率:35%。
1H NMR:(400MHz,CD
3OD)δ8.23(s,1H),8.15(br.s.,1H),7.88(s,1H),7.72-7.65(m,2H),7.57-7.55(m,1H),7.50-7.46(m,2H),7.40-7.37(m,1H),2.91(s,3H),1.90-1.86(m,6H).
MS-ESI计算值[M+H]
+430和432,实测值430和432。
实施例6
5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-(1-哌啶甲基)苯基]嘧啶-2,4-二胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为3-(1-哌啶甲基)苯胺,得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-(1-哌啶甲基)苯基]嘧啶-2,4-二胺(31.00mg),产率:32%。
1H NMR:(400MHz,CD
3OD)δ8.24(s,1H),8.20(br.s.,1H),7.76-7.70(m,1H),7.63(s,1H),7.59-7.54(m,2H),7.51-7.50(m,2H),7.47-7.43(m,1H),4.29(s,2H),3.43-3.41(d,J=12.0Hz,2H),2.98(t,J=12.0Hz,2H),1.90-1.87(m,6H),1.86-1.82(m,5H),1.55-1.45(m,1H).
MS-ESI计算值[M+H]
+470和472,实测值470和472。
实施例7
5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-(2-甲基嘧啶-4-基)苯基]嘧啶-2,4-二胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为3-(2-甲基嘧啶-4-基)苯胺,得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-(2-甲基嘧啶-4-基)苯基]嘧啶-2,4-二胺(42.00mg,),产率:53%。
1H NMR:(400MHz,CD
3OD)δ9.02(br.s.,1H),8.46(br.s.,1H),8.37(br.s.,1H),8.32-8.27(m,2H),8.17(br.s.,1H),7.79-7.78(m,1H),7.68-7.66(m,2H),7.32(br.s.,2H),2.92(br.s.,3H),1.89(s,3H),1.86(s,3H).
MS-ESI计算值[M+H]
+465和467,实测值465和467。
实施例8
[3-[[5-氯-4-(2-二甲基磷酰基苯胺基)嘧啶-2-基]胺]苯基]甲磺酰胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为3-氨基苄磺酰胺,得到[3-[[5-氯-4-(2-二甲基磷酰基苯胺基)嘧啶-2-基]胺]苯基]甲磺酰胺(20.0mg),产率:3.2%。
1H NMR:(400MHz,CD
3OD)δ8.17-8.12(m,2H),7.76-7.71(m,1H),7.62-7.58(m,1H),7.48-7.40(m,4H),7.36(br.s.,1H),4.26(s,2H),1.90-1.87(m,6H).
MS-ESI计算值[M+H]
+466和468,实测值466和468。
实施例9
1-[3-[[5-氯-4-(2-二甲基磷酰基苯胺基)嘧啶-2-基]胺]-4-氟-苯基]乙酮
根据实施例1中第四步方法,将对甲氧基苯胺替换为1-(3-氨基-4-氟-苯基)乙酮,得到1-[3-[[5-氯-4-(2-二甲基磷酰基苯胺基)嘧啶-2-基]胺]-4-氟-苯基]乙酮(39.0mg),产率:43%。
1H NMR:(400MHz,CD3OD)δ8.26(s,1H),8.17-8.14(m,1H),8.07-8.03(m,2H),7.67-7.61(m,1H),7.45-7.40(m,1H),7.33(br.s.,2H),2.54(s,3H),1.89(s,3H),1.86(s,3H).
MS-ESI计算值[M+H]
+433和435,实测值433和435。
实施例10
3-[[5-氯-4-(2-二甲基磷酰基苯胺)嘧啶-2-基]氨基]-4-甲氧基-N-苯基-苯甲酰胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为3-氨基-4-甲氧基-N-苯基-苯甲酰胺,得到3-[[5-氯-4-(2-二甲基磷酰基苯胺)嘧啶-2-基]氨基]-4-甲氧基-N-苯基-苯甲酰胺(32.0mg),产率:38%。
1H NMR:(400MHz,CD
3OD)δ8.21-8.16(m,3H),7.93-7.91(m,1H),7.66(d,J=8.0Hz,2H),7.57-7.52(m,1H),7.41-7.35(m,3H),7.26(d,J=8.5Hz,1H),7.18-7.15(m,2H),3.98(s,3H),1.87(s,3H),1.84(s,3H).
MS-ESI计算值[M+H]
+522和524,实测值522和524。
实施例11
5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-[2-(2-哌啶基)乙基]苯基]嘧啶-2,4-二胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为3-[2-(2-哌啶基)乙基]苯胺,得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-[2-(2-哌啶基)乙基]苯基]嘧啶-2,4-二胺(20.0mg),产率:26%。
1H NMR:(400MHz,CD
3OD)δ8.72-8.71(m,1H),8.55-8.50(m,1H),8.23-8.19(m,2H),7.97-7.91(m,2H),7.74-7.68(m,1H),7.55-7.51(m,1H),7.43-7.39(m,1H),7.33-7.31(m,3H),7.18-7.17(m,1H),3.41-3.37(m,2H),3.16-3.12(m,2H),1.90(s,3H),1.86(s,3H).
MS-ESI计算值[M+H]
+478和480,实测值478和480。
实施例12
1-[3-[[5-氯-4-(2-二甲基磷酰基苯胺基)嘧啶-2-基]胺]苯基]乙酮
根据实施例1中第四步方法,将对甲氧基苯胺替换为1-(3-苯胺)乙酮,得到1-[3-[[5-氯-4-(2-二甲基磷酰基苯胺基)嘧啶-2-基]胺]苯基]乙酮(25.0mg),产率:29%。
1H NMR:(400MHz,CD
3OD)δ8.21(s,1H),8.15(br.s.,1H),7.99(s,1H),7.93-7.91(m,1H),7.70-7.64(m,2H),7.56-7.52(m,1H),7.43-7.40(m,2H),2.55(s,3H),1.89(s,3H),1.86(s,3H).
MS-ESI计算值[M+H]
+415和417,实测值415和417。
实施例13
5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-(4-哌啶基)苯基]嘧啶-2,4-二胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为3-(4-哌啶基)苯胺,得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-(4-哌啶基)苯基]嘧啶-2,4-二胺(25.0mg,),产率:33%。
1H NMR:(400MHz,CD3OD)δ8.88-8.87(m,2H),8.31(d,J=8.0Hz,2H),8.25(s,1H),8.15(br.s.,1H),8.08(s,1H),7.85(d,J=8.0Hz,1H),7.73-7.71(m,1H),7.67-7.62(m,2H),7.35-7.31(m,1H),7.27-7.23(m,1H),1.89(s,3H),1.85(s,3H).
MS-ESI计算值[M+H]
+450和452,实测值450和452。
实施例14
3-((5-氯-4-((2-(二甲基磷酰基)苯基)氨基)嘧啶-2-基)氨基)-N,N-二甲基苯磺酰胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为3-氨基-N,N-二甲基苯磺酰胺,得到3-((5-氯-4-((2-(二甲基磷酰基)苯基)氨基)嘧啶-2-基)氨基)-N,N-二甲基苯磺酰胺(26.0mg),产率:34%。
1H NMR:(400MHz,CD
3OD)δ8.37-8.36(m,1H),8.21(s,1H),7.95-7.91(m,2H),7.63-7.61(m,2H),7.51-7.48(m,2H),7.36-7.35(m,1H),2.69(s,6H),1.90-1.86(m,6H).
MS-ESI计算值[M+H]
+480和482,实测值480和482。
实施例15
4-((5-氯-4-((2-(二甲基磷酰基)苯基)氨基)嘧啶-2-基)氨基)-N,N-二甲基苯磺酰胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为4-氨基-N,N-二甲基苯磺酰胺,得到4-((5-氯-4-((2-(二甲基磷酰基)苯基)氨基)嘧啶-2-基)氨基)-N,N-二甲基苯磺酰胺(12.0mg),产率:16%。
1H NMR:(400MHz,CD
3OD)δ8.43-8.40(m,1H),8.21(s,1H),7.86-7.83(m,2H),7.70-7.62(m,2H),7.60-7.59(m,2H),7.36-7.35(m,1H),2.68(s,6H),1.89-1.85(m,6H).
MS-ESI计算值[M+H]
+480和482,实测值480和482。
实施例16
(2-((5-氯-2-((3-甲氧基苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧化膦
根据实施例1中第四步方法,将对甲氧基苯胺替换为3-甲氧基苯胺,得到(2-((5-氯-2-((3-甲氧基苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧化膦(21.0mg),产率:33%。
1H NMR:(400MHz,CD
3OD)δ8.35-8.34(m,1H),8.15(s,1H),7.73-7.71(m,1H),7.57-7.56(m,1H),7.43-7.42(m,1H),7.36-7.34(m,1H),7.03(s,1H),6.99-6.97(m,1H),6.93-6.92(m,1H),3.79(s,3H),1.92-1.88(m,6H).
MS-ESI计算值[M+H]
+403和405,实测值403和405。
实施例17
3-((5-氯-4-((2-(二甲基磷酰基)苯基)氨基)嘧啶-2-基)氨基)-N,N-二甲基苯甲酰胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为3-氨基-N,N-二甲基苯甲酰,得到3-((5-氯-4-((2-(二甲基磷酰基)苯基)氨基)嘧啶-2-基)氨基)-N,N-二甲基苯甲酰胺(11.0mg),产率:16%。
1H NMR:(400MHz,CD
3OD)δ8.41-8.38(m,1H),8.15(s,1H),7.79(s,1H),7.61-7.57(m,3H),7.34-7.30(m,2H),7.02-7.00(m,1H),3.10(s,3H),2.96(s,3H),1.89-1.85(m,6H).
MS-ESI计算值[M+H]
+444和446,实测值444和446
实施例18
4-((5-氯-4-((2-(二甲基磷酰基)苯基)氨基)嘧啶-2-基)氨基)-N,N-二甲基苯甲酰胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为4-氨基-N,N-二甲基苯甲酰胺,得到4-((5-氯-4-((2-(二甲基磷酰基)苯基)氨基)嘧啶-2-基)氨基)-N,N-二甲基苯甲酰胺(16.0mg),产率:23%。
1H NMR:(400MHz,CD
3OD)δ8.45-8.42(m,1H),8.16(s,1H),7.79(s,1H),7.69-7.62(m,4H),7.34-7.32(m,3H),3.10(s,6H),1.89-1.85(m,6H).
MS-ESI计算值[M+H]
+444和446,实测值444和446
实施例19
(4-((5-氯-4-((2-(二甲基磷酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)(吗啉代)甲酮
第一步
(3-甲氧基-4-硝基苯基)(吗啉代)甲酮
将3-甲氧基-4-硝基苯甲酸(2.00g,10.2mmol)溶于无水二氯甲烷(30mL)中,向反应液中加入***啉(1.06g,12.2mmol),1-羟基苯并***(2.74g,20.3mmol),1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(3.89g,20.3mmol)和N,N-二异丙基乙基胺(2.62g,20.3mmol)。反应液在25℃,搅拌12小时。反应液加入水(40mL),滤液用乙酸乙酯(50mL×3)萃取。合并有机相,用饱和食盐水洗涤(40mL×3),无水硫酸钠干燥,过滤,滤液减压浓缩,剩余物用硅胶柱色谱法分离纯化(1:1石油醚/乙酸乙酯)分离纯化得到(3-甲氧基 -4-硝基苯基)(吗啉代)甲酮(1.80g,无色油状物),产率:67%。
1H NMR:(400MHz,DMSO-d6)δ7.96-7.93(m,1H),7.38(s,1H),7.14-7.12(m,1H),3.96(s,3H),3.67-3.56(m,6H),3.36-3.31(m,2H).
第二步
(4-氨基-3-甲氧基苯基)(吗啉代)甲酮
将(3-甲氧基-4-硝基苯基)(吗啉代)甲酮(1.80g,6.76mmol)溶于甲醇(50mL)中,向反应液中加入干钯碳(10%,200mg)。反应液在25℃氢气(15psi)氛围下反应12小时。反应液过滤,滤液减压浓缩得到(4-氨基-3-甲氧基苯基)(吗啉代)甲酮(1.40g,白色固体),产率:88%。
1H NMR:(400MHz,DMSO-d6)δ8.86(s,1H),8.82-8.80(m,1H),6.63-6.61(m,1H),5.16(s,2H),3.78(s,3H),3.60-3.58(m,4H),3.52-3.49(m,4H).
MS-ESI计算值[M+H]
+237,实测值237
第三步
(4-((5-氯-4-((2-(二甲基磷酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)(吗啉代)甲酮
根据实施例1中第四步方法,将对甲氧基苯胺替换为(4-氨基-3-甲氧基苯基)(吗啉代)甲酮,得到(4-((5-氯-4-((2-(二甲基磷酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)(吗啉代)甲酮(25.0mg),产率:30%。
1H NMR:(400MHz,CDCl
3)δ12.39(s,1H),10.22(s,1H),8.39-8.37(m,1H),7.90-7.89(m,2H),7.50-7.48(m,1H),7.39-7.29(m,2H),7.04(s,1H),6.95-6.93(m,1H),3.95(s,3H),3.77-3.70(m,8H),1.88-1.80(m,6H).
MS-ESI计算值[M+H]
+516和518,实测值516和518。
实施例20
5-氯-N2-(3,4-二甲氧基苯基)-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为3,4-二甲氧基苯胺,得到5-氯-N2-(3,4-二甲氧基苯基)-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺(27.0mg),产率:36%。
1H NMR:(400MHz,CD
3OD)δ8.39(br.s,1H),8.10(br.s,1H),7.72-7.70(m,1H),7.52(br.s,1H),7.44-7.38(m,1H),7.07-7.01(m,2H),6.98-6.94(m,1H),3.89(s,3H),3.78(br.s,3H),1.93(s,3H),1.89(s,3H).
MS-ESI计算值[M+H]
+433和435,实测值433和435。
实施例21
5-氯-N2-(2,4-二甲氧基苯基)-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为2,4-二甲氧基苯胺,得到5-氯-N2-(2,4-二甲氧基苯基)-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺(20.0mg),产率:27%。
1H NMR:(400MHz, CD
3OD)δ8.39(br.s,1H),8.07(br.s,1H),7.72-7.70(m,1H),7.56(br.s,1H),7.43-7.39(m,1H),7.33(d,J=7.6Hz,1H),6.73(d,J=2.4Hz,1H),6.59(d,J=7.6Hz,1H),3.87(s,3H),3.86(s,3H),1.93(s,3H),1.89(s,3H).
MS-ESI计算值[M+H]
+433和435,实测值433和435。
实施例22
5-氯-N2-(3,5-二甲氧基苯基)-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为3,5-二甲氧基苯胺,得到5-氯-N2-(3,5-二甲氧基苯基)-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺(35.0mg),产率:47%。
1H NMR:(400MHz,CD
3OD)δ8.39(s,1H),8.13(s,1H),7.75-7.67(m,1H),7.57-7.55(m,1H),7.45-7.39(m,1H),6.60(s,2H),6.48(s,1H),3.78(s,6H),1.92(s,3H),1.89(s,3H).
MS-ESI计算值[M+H]
+433和435,实测值433和435。
实施例23
N2-[3-(三氟甲氧基)苯基]-5-氯-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为3-三氟甲氧基苯胺,得到N2-[3-(三氟甲氧基)苯基]-5-氯-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺(18.0mg),产率:23%。
1H NMR:(400MHz,CD
3OD)δ8.22(s,1H),8.19-8.15(m,1H),7.73-7.71(m,1H),7.58-7.56(m,1H),7.49(s,1H),7.45-7.38(m,3H),7.09-7.07(m,1H),1.88(s,3H),1.85(s,3H).
MS-ESI计算值[M+H]
+457和459,实测值457和459。
实施例24
5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-(2-甲氧基乙基)苯基]嘧啶-2,4-二胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为4-(2-甲氧基乙基)苯胺,得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-(2-甲氧基乙基)苯基]嘧啶-2,4-二胺(23.0mg),产率:30%。
1H NMR:(400MHz,CD
3OD)δ8.35(br.s,1H),8.10(br.s,1H),7.70-7.66(m,1H),7.54(br.s,1H),7.44-7.38(m,1H),7.33(d,J=8.8Hz, 2H),7.04(d,J=8.0Hz,2H),4.20-4.15(m,2H),3.81-3.77(m,2H),3.46(s,3H),1.92(s,3H),1.89(s,3H).
MS-ESI计算值[M+H]
+447和449,实测值447和449。
实施例25
5-氯-N2-[4-[2-(二甲基氨基)乙基]苯基]-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为4-(2-(二甲基氨基)乙氧基)苯胺,得到5-氯-N2-[4-[2-(二甲基氨基)乙基]苯基]-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺(25.0mg),产率:32%。
1H NMR:(400MHz,CD
3OD)δ8.31(br.s,1H),8.15(br.s,1H),7.73-7.68(m,1H),7.57(br.s,1H),7.46-7.42(m,1H),7.42-7.38(m,2H),7.13-7.11(m,2H),4.46-4.39(m,2H),3.70-3.63(m,2H),3.03(s,6H),1.92(s,3H),1.88(s,3H).
MS-ESI计算值[M+H]
+460和462,实测值460和462。
实施例26
5-氯-N2-[3-[2-(二甲基氨基)乙基]-4-甲氧基-苯基]-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为3-(2-(二甲氨基)乙氧基)-4-甲氧基苯胺,得到5-氯-N2-[3-[2-(二甲基氨基)乙基]-4-甲氧基-苯基]-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺(33.0mg),产率:35%。
1H NMR:(400MHz,CD
3OD)δ8.36(br.s,1H),8.14(s,1H),7.69-7.65(m,1H),7.54-7.50(m,1H),7.43-7.36(m,1H),7.19-7.13(m,2H),7.09-7.03(m,1H),4.29-4.25(m,2H),3.93(s,3H),3.60-3.56(m,2H),3.03(s,6H),1.91(s,3H),1.88(s,3H).
MS-ESI计算值[M+H]
+490和492,实测值490和492。
实施例27
5-氯-N2-[3-[2-(二甲基氨基)乙基]苯基]-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为3-(2-(二甲基氨基)乙氧基)苯胺,得到5-氯-N2-[3-[2-(二甲基氨基)乙基]苯基]-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺(18.0mg),产率:20%。
1H NMR: (400MHz,CD
3OD)δ8.42(br.s,1H),8.19-8.15(m,1H),7.68-7.66(m,1H),7.58-7.56(m,1H),7.37(br.s,1H),7.32-7.15(m,3H),6.78-6.75(m,1H),4.33-4.29(m,2H),3.62-3.57(m,2H),2.99(s,6H),1.91(s,3H),1.87(s,3H).
MS-ESI计算值[M+H]
+460和462,实测值460和462。
实施例28
5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-(2-甲氧基乙基)苯基]嘧啶-2,4-二胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为3-(2-甲氧基乙氧基)苯胺,得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-(2-甲氧基乙基)苯基]嘧啶-2,4-二胺(25.0mg),产率:33%。
1H NMR:(400MHz,CD
3OD)δ8.33(br.s,1H),8.17(s,1H),7.71-7.70(m,1H),7.60-7.58(m,1H),7.47-7.40(m,1H),7.34-7.32(m,1H),7.08(s,1H),6.95-6.94(m,2H),4.12-4.06(m,2H),3.77-3.73(m,2H),3.44(s,3H),1.92(s,3H),1.89(s,3H).
MS-ESI计算值[M+H]
+447和449,实测值447和449。
实施例29
5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-甲氧基-3-(4-甲基哌嗪-1-基)苯基]嘧啶-2,4-二胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为4-甲氧基-3-(4-甲基哌嗪-1-基)苯胺,得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-甲氧基-3-(4-甲基哌嗪-1-基)苯基]嘧啶-2,4-二胺(24.0mg),产率:30%。
1H NMR:(400MHz,CD
3OD)δ8.47-8.44(m,1H),8.05(s,1H),7.59-7.56(m,1H),7.50-7.47(m,1H),7.25-7.24(m,2H),7.06(s,1H),6.84(d,J=9.2Hz,1H),3.86(s,3H),3.02(br.s.,4H),2.60(br.s.,4H),2.35(s,3H),1.88(s,3H),1.85(s,3H).
MS-ESI计算值[M+H]
+501和503,实测值501和503。
实施例30
5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-(2-***啉基乙基)苯基]嘧啶-2,4-二胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为3-(2-吗啉代乙氧基)苯胺,得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-(2-***啉基乙基)苯基]嘧啶-2,4-二胺(6.0mg),产率:8%。
1H NMR:(400MHz,CD3OD)δ8.52-8.48(m,1H),8.12(s,1H),7.67-7.55(m,2H),7.32-7.24(m,2H),7.18-7.08(m,2H),6.64-6.56(m,1H),4.08(t,J=5.6Hz,2H),3.74-3.70(m,4H),2.79(t,J=5.6Hz,2H),2.63-2.56(m,4H),1.89(s,3H),1.86(s,3H).
MS-ESI计算值[M+H]
+502和504,实测值502和504。
实施例31
5-氯-N4-(2-二甲基磷酰基苯基)-N2-(5-甲氧基-2-***啉基-苯基)嘧啶-2,4-二胺
第一步
4-(4-甲氧基-2-硝基-苯基)***啉
将1-溴-4-甲氧基-2-硝基苯(400.0mg,1.72mmol)溶于无水二氧六环(4mL)中,向反应液中加入***啉(150.2mg,1.72mmol),碳酸铯(1.12g,3.45mmol),醋酸钯(19.4mg,86.2umol)和4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(99.8mg,172.4umol),反应液在100℃,搅拌3小时。反应完全,反应液冷至室温,加入水(5mL),用乙酸乙酯(20mL×3)萃取。合并有机相,用饱和食盐水洗涤(15mL×3),无水硫酸钠干燥,过滤,滤液减压浓缩,剩余物用制备薄层色谱法板分离纯化(10:1石油醚/乙酸乙酯,Rf=0.12)分离纯化得到4-(4-甲氧基-2-硝基-苯基)***啉(210mg,黄色固体),产率:41%。
1H NMR:(400MHz,CD
3OD)δ7.40-7.35(m,1H),7.29(d,J=2.8Hz,1H),7.19(dd,J=2.8,8.8Hz,1H),3.86-3.83(m,3H),3.81-3.76(m,4H),3.01-2.93(m,4H).
MS-ESI计算值[M+H]
+239,实测值239。
第二步
5-甲氧基-2-***啉基-苯胺
将4-(4-甲氧基-2-硝基-苯基)***啉(100.0mg,0.462mmol)溶于乙酸乙酯(15mL)中,向反应液中加入湿钯碳(40.0mg,10%纯度),反应液在氢气(50psi)氛围,20℃下,搅拌5小时。反应完全,过滤,滤液减压浓缩得到5-甲氧基-2-***啉基-苯胺(100mg,黄色固体)。
1H NMR:(400MHz,CD
3OD)δ6.94(d,J=8.4Hz,1H),6.38(d,J=2.8Hz,1H),6.27(dd,J=2.8,8.4Hz,1H),3.85-3.81(m,4H),3.72(s,3H),2.85-2.81(m,4H).
第三步
5-氯-N4-(2-二甲基磷酰基苯基)-N2-(5-甲氧基-2-***啉基-苯基)嘧啶-2,4-二胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为5-甲氧基-2-吗啉代苯胺,得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-(5-甲氧基-2-***啉基-苯基)嘧啶-2,4-二胺(15.0mg),产率:18%。
1H NMR:(400MHz,CD
3OD)δ8.31(s,2H),7.74(dd,J=7.6,13.6Hz,1H),7.63(t,J=7.2Hz,1H),7.51-7.42(m,1H),7.39-7.22(m,2H),6.90(d,J=8.4Hz,1H),3.87-3.81(m,4H),3.72(s,3H),2.99(br.s.,4H),1.92(s,3H),1.89(s,3H).
MS-ESI计算值[M+H]
+488和490,实测值488和490。
实施例32
5-氯-N4-(2-二甲基磷酰基苯基)-N2-(4-甲氧基-2-***啉基-苯基)嘧啶-2,4-二胺
第一步
4-(5-甲氧基-2-硝基-苯基)***啉
将2-氟-4-甲氧基-1-硝基苯(400.0mg,2.34mmol)溶于无水二甲基亚砜(4mL)中,向反应液中加入***啉(203.9mg,2.34mmol)和碳酸钾(646.8mg,4.68mmol),反应液在100℃,搅1小时。液相色谱和反应完全后。反应液冷至室温,加入水(5mL),滤液用乙酸乙酯(20mL×3)萃取。合并有机相,用饱和食盐水洗涤(15mL×3),无水硫酸钠干燥,过滤,滤液减压浓缩得到4-(5-甲氧基-2-硝基-苯基)***啉(520mg)。
1H NMR:(400MHz,CD3OD)δ7.94(d,J=8.8Hz,1H),6.69-6.62(m,2H),3.88(s,3H),3.83-3.78(m,4H),3.08-3.00(m,4H).
MS-ESI计算值[M+H]
+239,实测值239。
第二步
5-甲氧基-2-***啉基-苯胺
根据实施例31中第二步方法,将4-(4-甲氧基-2-硝基-苯基)***啉替换为4-(5-甲氧基-2-硝基-苯基)***啉,得到4-甲氧基-2-***啉基-苯胺(420mg,黄色固体)。
1H NMR:(400MHz,CDCl
3)δ6.71(d,J=8.4Hz,1H),6.64(d,J=2.8Hz,1H),6.55(dd,J=2.8,8.4Hz,1H),3.88-3.84(m,4H),3.76(s,3H),3.42(br.s.,2H),2.95-2.91(m,4H).
第三步
5-氯-N4-(2-二甲基磷酰基苯基)-N2-(4-甲氧基-2-***啉基-苯基)嘧啶-2,4-二胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为4-甲氧基-2-吗啉代苯胺,得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-(4-甲氧基-2-***啉基-苯基)嘧啶-2,4-二胺(11.0mg),产率:14%。
1H NMR:(400MHz,CD
3OD)δ8.39-8.37(m,1H),8.09(s,1H),7.81(d,J=8.8Hz,1H),7.67-7.60(m,1H),7.55-7.54(m,1H),7.33-7.26(m,1H),6.76(s,1H),6.58-6.55(m,1H),3.86-3.82(m,4H),3.80(s,3H),2.91-2.87(m,4H),1.88(s,3H),1.85(s,3H).
MS-ESI计算值[M+H]
+488和490,实测值488和490。
实施例33
5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-甲氧基-2-[2-甲氧基乙基(甲基)氨基]苯基]嘧啶-2,4-二胺
第一步
5-甲氧基-N-(2-甲氧基乙基)-N-甲基-2-硝基-苯胺
根据实施例32中第一步方法,将***啉替换为N-甲基-2-甲氧基乙胺,得到5-甲氧基-N-(2-甲氧基乙基)-N-甲基-2-硝基-苯胺(512mg,黄色油状物),粗品直接用于下一步。
1H NMR:(400MHz,CDCl
3)δ7.87(d,J=9.2Hz,1H),6.59(d,J=2.4Hz,1H),6.41(dd,J=2.4,9.2Hz,1H),3.87(s,3H),3.63-3.61(m,2H),3.39-3.36(m,2H),3.36(s,3H),2.92(s,3H).
MS-ESI计算值[M+H]
+241,实测值241。
第二步
4-甲氧基-N2-(2-甲氧基乙基)-N2-甲基-苯-1,2-二胺
根据实施例31中第二步方法,将4-(4-甲氧基-2-硝基-苯基)***啉替换为5-甲氧基-N-(2-甲氧基乙基)-N-甲基-2-硝基-苯胺,得到4-甲氧基-N2-(2-甲氧基乙基)-N2-甲基-苯-1,2-二胺(400mg,黄色油状物),粗品直接用于下一步。
MS-ESI计算值[M+H]
+211,实测值211。
第三步
根据实施例1中第四步方法,将对甲氧基苯胺替换为5-甲氧基N1-(2-甲氧基乙基)-N1甲基苯-1,2-二胺,得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-甲氧基-2-[2-甲氧基乙基(甲基)氨基]苯基]嘧啶-2,4-二胺(29.0mg),产率:37%。
1H NMR:(400MHz,CD
3OD)δ8.39-8.37(dd,J=4.4,8.4Hz,1H),8.08(s,1H),7.88(d,J=8.8Hz,1H),7.69-7.61(m,1H),7.58(t,J=8.0Hz,1H),7.34-7.27(m,1H),6.80(d,J=2.8Hz,1H),6.57(dd,J=2.8,8.8Hz,1H),3.79(s,3H),3.45(t,J=5.6Hz,2H),3.28(s,3H),3.04(t,J=5.6Hz,2H),2.72(s,3H),1.88(s,3H),1.85(s,3H).
MS-ESI计算值[M+H]
+490和492,实测值490和492。
实施例34
5-氯-N4-(2-二甲基磷酰基苯基)-N2-(4-甲氧基-3-***啉基-苯基)嘧啶-2,4-二胺
第一步
4-(2-甲氧基-5-硝基-苯基)***啉
根据实施例31中第一步方法,将1-溴-4-甲氧基-2-硝基苯替换为2-溴-1-甲氧基-4-硝基苯,得到4-(2-甲氧基-5-硝基-苯基)***啉(130mg,黄色固体),产率:28%。
1H NMR:(400MHz,CD
3OD)δ7.99(dd,J=2.8,8.8Hz,1H),7.80(d,J=2.8Hz,1H),7.13(d,J=8.8Hz,1H),4.00(s,3H),3.89-3.83(m,4H),3.15-3.05(m,4H).MS-ESI计算值[M+H]
+239,实测值239。
第二步
4-甲氧基-3-***啉基-苯胺
根据实施例31中第二步方法,将4-(4-甲氧基-2-硝基-苯基)***啉替换为4-(2-甲氧基-5-硝基-苯基)***啉,得到4-甲氧基-3-***啉基-苯胺(110mg,黄色固体),粗品直接用于下一步。
1H NMR:(400MHz,CDCl
3)δ6.73-6.68(m,1H),6.39-6.32(m,2H),3.90-3.87(m,4H),3.80(s,3H),3.45(br.s.,2H),3.08-3.02(m,4H).
MS-ESI计算值[M+H]
+209,实测值209。
第三步
根据实施例1中第四步方法,将对甲氧基苯胺替换为4-甲氧基-3-吗啉代苯胺得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-(4-甲氧基-3-***啉基-苯基)嘧啶-2,4-二胺(24.0mg),产率:29%。
1H NMR:(400MHz,CD
3OD)δ8.24(s,1H),8.16(br.s.,1H),7.82(d,J=2.4Hz,1H),7.76-7.69(m,1H),7.64(dd,J=2.4,8.8Hz,1H),7.56(t,J=7.6Hz,1H),7.48-7.42(m,1H),7.39(d,J=8.8Hz,1H),4.13(br.s.,2H),4.11(s,3H),4.10(br.s.,2H),3.66(br.s.,4H),1.93(s,3H),1.89(s,3H).
MS-ESI计算值[M+H]
+488和490,实测值488和490。
实施例35
5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-甲氧基-3-[2-甲氧基乙基(甲基)氨基]苯基]嘧啶-2,4-二胺
第一步
2-甲氧基-N-(2-甲氧基乙基)-N-甲基-5-硝基-苯胺
根据实施例31中第一步方法,将1-溴-4-甲氧基-2-硝基苯和***啉替换为2-溴-1-甲氧基-4-硝基苯和N-甲基-2-甲氧基乙胺,得到2-甲氧基-N-(2-甲氧基乙基)-N-甲基-5-硝基-苯胺(90mg,黄色固体),产率:22%。
1H NMR:(400MHz,CD
3OD)δ7.92-7.87(m,1H),7.78(d,J=2.8Hz,1H),7.10-7.06(m,1H),3.98(s,3H),3.61-3.57(m,2H),3.37-3.34(m,2H),3.32(br.s.,3H),2.92(s,3H).
MS-ESI计算值[M+H]
+241,实测值241。
第二步
4-甲氧基-N3-(2-甲氧基乙基)-N3-甲基-苯-1,3-二胺
根据实施例31中第二步方法,将4-(4-甲氧基-2-硝基-苯基)***啉替换为2-甲氧基-N-(2-甲氧基乙基)-N- 甲基-5-硝基-苯胺,得到4-甲氧基-N3-(2-甲氧基乙基)-N3-甲基-苯-1,3-二胺(100mg,黄色油状物),粗品直接用于下一步。
1H NMR:(400MHz,CDCl
3)δ6.69(d,J=8.4Hz,1H),6.47(br.s.,1H),6.35(d,J=8.8Hz,1H),3.80(s,3H),3.59-3.51(m,2H),3.41-3.34(m,2H),3.33(s,3H),2.89(s,3H).
第三步
5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-甲氧基-3-[2-甲氧基乙基(甲基)氨基]苯基]嘧啶-2,4-二胺根据实施例1中第四步方法,将对甲氧基苯胺替换为6-甲氧基N1-(2-甲氧基乙基)-N1甲基苯-1,3-二胺,得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-甲氧基-3-[2-甲氧基乙基(甲基)氨基]苯基]嘧啶-2,4-二胺(18.0mg),产率:21%。
1H NMR:(400MHz,CD
3OD)δ8.22(s,1H),8.15(br.s.,1H),7.74-7.64(m,3H),7.56-7.49(m,1H),7.44-7.36(m,2H),4.08(s,3H),3.81-3.74(m,2H),3.50-3.34(m,2H),3.24(s,3H),3.22(s,3H),1.90(s,3H),1.86(s,3H).
MS-ESI计算值[M+H]
+490和492,实测值490和492。
实施例36
5-氯-N4-(2-二甲基磷酰基苯基)-N2-(3-甲氧基-5-***啉基-苯基)嘧啶-2,4-二胺
第一步
4-(3-甲氧基-5-硝基-苯基)***啉
根据实施例31中第一步方法,将1-溴-4-甲氧基-2-硝基苯替换为1-溴-3-甲氧基-5-硝基苯,得到4-(3-甲氧基-5-硝基-苯基)***啉(115mg,黄色固体),产率:28%。
1H NMR:(400MHz,CD
3OD)δ7.41(t,J=2.0Hz,1H),7.23(t,J=2.0Hz,1H),6.84(t,J=2.0Hz,1H),3.87(s,3H),3.87-3.83(m,4H),3.26-3.22(m,4H).
MS-ESI计算值[M+H]
+239,实测值239。
第二步
3-甲氧基-5-***啉基-苯胺
根据实施例31中第二步方法,将4-(4-甲氧基-2-硝基-苯基)***啉替换为4-(3-甲氧基-5-硝基-苯基)***啉,得到3-甲氧基-5-***啉基-苯胺(100mg,黄色油状物),粗品直接用于下一步。
1H NMR:(400MHz,CDCl
3)δ5.94-5.91(m,1H),5.88(t,J=2.0Hz,1H),5.84(t,J=2.0Hz,1H),3.86-3.81(m,4H),3.76(s,3H),3.64(br.s.,2H),3.14-3.10(m,4H).
MS-ESI计算值[M+H]
+241,实测值241。
第三步
5-氯-N4-(2-二甲基磷酰基苯基)-N2-(3-甲氧基-5-***啉基-苯基)嘧啶-2,4-二胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为3-甲氧基-5-吗啉代苯胺,得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-(3-甲氧基-5-***啉基-苯基)嘧啶-2,4-二胺(22.0mg),产率:25%。
1H NMR:(400MHz, CDCl
3)δ12.56(br.s.,1H),11.40(br.s.,1H),8.41(br.s.,1H),7.90(s,1H),7.80(br.s.,1H),7.55(br.s.,2H),7.42-7.33(m,2H),7.06(br.s.,1H),4.32(br.s.,4H),3.87(s,3H),3.50(br.s.,4H),1.92(s,3H),1.89(s,3H).
MS-ESI计算值[M+H]
+488和490,实测值488和490。
实施例37
5-氯-N4-(2-二甲基磷酰基苯基)-N2-(3-甲氧基-2-***啉基-苯基)嘧啶-2,4-二胺
第一步
4-(2-甲氧基-6-硝基-苯基)***啉
根据实施例31中第一步方法,将1-溴-4-甲氧基-2-硝基苯替换为2-溴-1-甲氧基-3-硝基苯,得到4-(2-甲氧基-6-硝基-苯基)***啉(73.0mg,黄色固体),产率:18%。
1H NMR:(400MHz,CD
3OD)δ6.02-5.97(m,1H),5.93-5.89(m,1H),5.82(dd,J=1.2,8.0Hz,1H),2.63(s,3H),2.40(t,J=4.4Hz,4H),1.80(br.s.,4H).
MS-ESI计算值[M+H]
+239,实测值239。
第二步
3-甲氧基-5-***啉基-苯胺
根据实施例31中第二步方法,将4-(4-甲氧基-2-硝基-苯基)***啉替换为4-(2-甲氧基-6-硝基-苯基)***啉,得到3-甲氧基-2-***啉基-苯胺(90.0mg,黄色油状物),粗品直接用于下一步。
1H NMR:(400MHz,CDCl3)
1H NMR:(400MHz,CDCl
3)δ6.94(t,J=8.4Hz,1H),6.40(dd,J=1.2,8.0Hz,1H),6.28(dd,J=1.2,8.4Hz,1H),4.29(br.s.,2H),3.94-3.87(m,2H),3.88-3.82(m,1H),3.80(s,3H),3.73-3.55(m,5H).
MS-ESI计算值[M+H]
+241,实测值241。
第三步
5-氯-N4-(2-二甲基磷酰基苯基)-N2-(3-甲氧基-2-***啉基-苯基)嘧啶-2,4-二胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为3-甲氧基-2-吗啉代苯胺,得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-(3-甲氧基-2-***啉基-苯基)嘧啶-2,4-二胺(8.0mg),产率:10%。
1H NMR:(400MHz,CD
3OD)δ8.37(s,1H),8.16(dd,J=4.0,8.0Hz,1H),7.80(dd,J=7.6,13.6Hz,1H),7.70(t,J=8.0Hz,1H),7.57-7.52(m,1H),7.40(d,J=8.4Hz,1H),7.04(t,J=8.4Hz,1H),6.89(d,J=8.4Hz,1H),3.89(s,3H),3.36-3.34(m,4H),3.83(br.s.,4H),1.90(s,3H),1.87(s,3H).
MS-ESI计算值[M+H]
+488和490,实测值488和490。
实施例38
5-氯-N4-(2-二甲基磷酰基苯基)-N2-[5-甲氧基-2-[2-甲氧基乙基(甲基)氨基]苯基]嘧啶-2,4-二胺
第一步
4-甲氧基-N-(2-甲氧基乙基)-N-甲基-2-硝基-苯胺
根据实施例32中第一步方法,将***啉和2-氟-4-甲氧基-1-硝基苯替换为1-氟-4-甲氧基-2-硝基苯和N-甲基-2-甲氧基乙胺,得到4-甲氧基-N-(2-甲氧基乙基)-N-甲基-2-硝基-苯胺(500mg,黄色油状物),粗品直接用于下一步。
1H NMR:(400MHz,CDCl
3)δ7.23-7.18(m,2H),7.05(dd,J=2.8,8.8Hz,1H),3.81(s,3H),3.54-3.49(m,2H),3.32(s,3H),3.22(t,J=6.0Hz,2H),2.83(s,3H).
MS-ESI计算值[M+H]
+241,实测值241。
第二步
4-甲氧基-N1-(2-甲氧基乙基)-N1-甲基-苯-1,2-二胺
根据实施例31中第二步方法,将4-(4-甲氧基-2-硝基-苯基)***啉替换为4-甲氧基-N-(2-甲氧基乙基)-N-甲基-2-硝基-苯胺,得到4-甲氧基-N1-(2-甲氧基乙基)-N1-甲基-苯-1,2-二胺(440mg,黄色油状物),粗品直接用于下一步。
1H NMR:(400MHz,CDCl
3)δ6.97(d,J=8.4Hz,1H),6.30-6.24(m,2H),4.28(br.s.,2H),3.75(s,3H),3.45(t,J=5.6Hz,2H),3.37(s,3H),2.98(t,J=5.6Hz,2H),2.69(s,3H).
MS-ESI计算值[M+H]
+243,实测值243。
第三步
5-氯-N4-(2-二甲基磷酰基苯基)-N2-[5-甲氧基-2-[2-甲氧基乙基(甲基)氨基]苯基]嘧啶-2,4-二胺根据实施例1中第四步方法,将对甲氧基苯胺替换为4-甲氧基N
1-(2-甲氧基乙基)-N
1甲基苯-1,2-二胺,得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[5-甲氧基-2-[2-甲氧基乙基(甲基)氨基]苯基]嘧啶-2,4-二胺(5.0mg),产率:6%。
1H NMR:(400MHz,CDCl
3)δ8.76-8.69(m,2H),8.15(s,1H),8.10(d,J=2.8Hz,1H),7.58(t,J=8.0Hz,1H),7.35-7.27(m,1H),7.16-7.10(m,3H),6.49(dd,J=2.8,8.4Hz,1H),3.70(s,3H),3.42(t,J=5.6Hz,2H),3.32(s,3H),3.01(t,J=5.6Hz,2H),2.70(s,3H),1.86(s,3H),1.83(s,3H).
MS-ESI计算值[M+H]
+490和492,实测值490和492。
实施例39
5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-甲氧基-5-[2-甲氧基乙基(甲基)氨基]苯基]嘧啶-2,4-二胺
第一步
3-甲氧基-N-(2-甲氧基乙基)-N-甲基-5-硝基-苯胺
根据实施例31中第一步方法,将1-溴-4-甲氧基-2-硝基苯和***啉替换为1-溴-3-甲氧基-5-硝基苯N-甲基-2-甲氧基乙胺,得到3-甲氧基-N-(2-甲氧基乙基)-N-甲基-5-硝基-苯胺(176mg,黄色油状物),产率:42%。
1H NMR:(400MHz,CD
3OD)δ7.20(t,J=2.0Hz,1H),7.05(t,J=2.0Hz,1H),6.59(t,J=2.0Hz,1H),3.85(s,3H),3.60(s,4H),3.36(s,3H),3.04(s,3H).
MS-ESI计算值[M+H]
+241,实测值241。
第二步
5-甲氧基-N1-(2-甲氧基乙基)-N1-甲基-苯-1,3-二胺
根据实施例31中第二步方法,将4-(4-甲氧基-2-硝基-苯基)***啉替换为4-甲氧基-N-(2-甲氧基乙基)-N-甲基-2-硝基-苯胺,得到5-甲氧基-N1-(2-甲氧基乙基)-N1-甲基-苯-1,3-二胺(180mg,黄色油状物),粗品直接用于下一步。
1H NMR:(400MHz,CD
3OD)δ5.77-5.75(m,1H),5.72-5.69(m,2H),3.76(s,3H),3.57-3.54(m,2H),3.48-3.44(m,2H),3.36(s,3H),2.94(s,3H).
MS-ESI计算值[M+H]
+243,实测值243。
第三步
5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-甲氧基-5-[2-甲氧基乙基(甲基)氨基]苯基]嘧啶-2,4-二胺根据实施例1中第四步方法,将对甲氧基苯胺替换为5-甲氧基N
1-(2-甲氧基乙基)-N
1甲基苯-1,3-二胺,得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-甲氧基-5-[2-甲氧基乙基(甲基)氨基]苯基]嘧啶-2,4-二胺(18.0mg),产率:21%。
1H NMR:(400MHz,D
2O)δ8.08(s,1H),7.65-7.60(m,1H),7.60-7.56(m,1H),7.48(t,J=7.6Hz,1H),7.45-7.39(m,1H),7.05(s,1H),6.89(d,J=10.4Hz,2H),3.64(s,3H),3.55(d,J=4.8Hz,2H),3.23(br.s.,2H),3.11(s,3H),3.07(s,3H),1.72(s,3H),1.68(s,3H).
MS-ESI计算值[M+H]
+490和492,实测值490和492。
实施例40
5-氯-N4-(2-二甲基偶磷酰基苯基)-N2-(3-甲氧基-4-***啉-苯基)嘧啶-2,4-二氨基
第一步
4-(2-甲氧基-4-硝基-苯基)***啉
将1-氯-2-甲氧基-4-硝基-苯(500mg,2.67mmol)和***啉(697.83mg,8.01mmol)的混合物加热至120℃搅拌15小时。向混合物中加入水(15mL),并用乙酸乙酯(15mL×3)萃取。合并有机相,无水硫酸钠干燥,过滤蒸干。得到的粗品用制备薄层色谱法(石油醚:乙酸乙酯=4:1,Rf=0.4)分离纯化得到4-(2-甲氧基-4-硝基-苯基)***啉(290mg,黄色油状),产率:46%。
1H NMR:(400MHz,CDCl
3)δ7.81(dd,J=2.4,8.8Hz,1H),7.66(d,J=2.4Hz,1H),6.82(d,J=8.8Hz,1H),3.89(s,3H),3.85-3.79(m,4H),3.21-3.13(m,4H).
第二步
4-(2-甲氧基-4-氨基-苯基)***啉
将4-(2-甲氧基-4-硝基-苯基)***啉(290mg,1.22mmol)溶于乙酸乙酯(10mL)中,向反应液中加入湿钯碳(50.0mg,10%纯度),反应液在氢气(50psi)氛围,20℃下,搅拌6小时。反应完全。反应液 过滤,滤液减压浓缩得到4-(2-甲氧基-4-氨基-苯基)***啉(290.0mg,红色油状物),粗品不经纯化直接用于下一步。
1H NMR:(400MHz,CDCl3)δ7.19(s,1H),6.75–6.65(m,1H),6.21(s,1H),3.86-3.77(m,4H),3.75(s,3H),3.00-2.79(m,4H).
第三步
根据实施例1中第四步方法,将对甲氧基苯胺替换为4-(2-甲氧基-4-氨基-苯基)***啉,得到5-氯-N4-(2-二甲基偶磷酰基苯基)-N2-(3-甲氧基-4-***啉-苯基)嘧啶-2,4-二氨基(46.0mg),产率:54%。
1H NMR:(400MHz,CD
3OD)δ8.31(s,1H),8.25-8.12(m,1H),7.82-7.70(m,2H),7.70-7.60(m,1H),7.55-7.46(m,1H),7.42(d,J=1.6Hz,1H),7.27(dd,J=2.0,8.8Hz,1H),4.16(br t,J=4.4Hz,4H),3.87(s,3H),3.80(br s,4H),1.92(s,3H),1.88(s,3H).
MS-ESI计算值[M+H]
+488和490,实测值488和490。
实施例41
5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-甲氧基-4-[2-甲氧乙基(甲基)氨基]苯基]嘧啶-2,4-二胺
第一步
2-甲氧基-N-(2-甲氧乙基)-N-甲基-4-硝基-苯胺
根据实施例32中第一步方法,将***啉替换为2-甲氧基-N-甲基-乙二胺,得到2-甲氧基-N-(2-甲氧乙基)-N-甲基-4-硝基-苯胺(170mg,黄色油状),产率:27%。
1H NMR:(400MHz,CDCl
3)δ7.79(dd,J=2.4,8.8Hz,1H),7.62(d,J=2.4Hz,1H),6.74(d,J=8.8Hz,1H),3.85(s,3H),3.59-3.45(m,4H),3.26(s,3H),2.96(s,3H)。
第二步
2-甲氧基-N1-(2-甲氧乙基)-N1-甲基-苯-1,4-二胺
根据实施例31中第二步方法,将4-(4-甲氧基-2-硝基-苯基)***啉替换为2-甲氧基-N-(2-甲氧乙基)-N-甲基-4-硝基-苯胺得到2-甲氧基-N1-(2-甲氧乙基)-N1-甲基-苯-1,4-二胺(160mg,红色油状)粗品不经纯化直接用于下一步。
1H NMR:(400MHz,CDCl
3)δ6.77(d,J=8.0Hz,1H),6.24-6.10(m,2H),3.74(s,3H),3.43(t,J=6.0Hz,2H),3.25(s,3H),3.07(t,J=6.0Hz,2H),2.71(s,3H).
第三步
5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-甲氧基-4-[2-甲氧乙基(甲基)氨基]苯基]嘧啶-2,4-二胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为2-甲氧基-N1-(2-甲氧乙基)-N1-甲基-苯-1,4-二胺,得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-甲氧基-4-[2-甲氧乙基(甲基)氨基]苯基]嘧啶-2,4-二胺(27.0mg),产率:31%。
1H NMR:(400MHz,CD
3OD)δ8.32(s,1H),8.22-8.13(m,1H),7.80-7.70(m,1H),7.68-7.56(m,2H),7.54-7.45(m,1H),7.44-7.35(m,1H),7.31-7.23(m,1H),3.86(s,5H),3.37(s,2H),3.29(s,3H),1.92(s,3H),1.89(s,3H).
MS-ESI计算值[M+H]
+490和492,实测值490和492。
实施例42
5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-甲氧基-2-[2-甲氧乙基(甲基)胺]苯基]嘧啶-2,4-二胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为3-甲氧基-N2-(2-甲氧乙基)-N2-甲基-苯-1,2-二氨基得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-甲氧基-2-[2-甲氧乙基(甲基)胺]苯基]嘧啶-2,4-二胺(7.00mg),产率:9%。
1H NMR:(400MHz,CD
3OD)δ8.36(s,1H),7.88(br s,1H),7.75-7.58(m,2H),7.44-7.27(m,4H),4.05(s,3H),3.97-3.57(m,2H),3.51-3.34(m,2H),3.11(s,6H),1.90(s,3H),1.87(s,3H)。
MS-ESI计算值[M+H]
+490和492,实测值490和492。
实施例43
5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-[2-(4-甲基哌嗪-1-基)乙氧基]苯基]嘧啶-2,4-二胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为3-[2-(4-甲基哌嗪-1-基)乙氧基]苯胺得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-[2-(4-甲基哌嗪-1-基)乙氧基]苯基]嘧啶-2,4-二胺(16.0mg)产率:20%。
1H NMR:(400MHz,CD
3OD)δ8.54-8.48(m,1H),8.12(s,1H),7.67-7.56(m,2H),7.31-7.24(m,2H),7.17-7.08(m,2H),6.63-6.58(m,1H),4.07(t,J=5.6Hz,2H),2.82(t,J=5.6Hz,2H),2.76-2.41(m,8H),2.33(s,3H),1.89(s,3H),1.86(s,3H)。
MS-ESI计算值[M+H]
+515和517,实测值515和517。
实施例44
5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-[2-(4甲基哌嗪-1-基)乙氧基]苯基]嘧啶-2,4-二胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为4-[2-(4-甲基哌嗪-1-基)乙氧基]苯胺得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-[2-(4甲基哌嗪-1-基)乙氧基]苯基]嘧啶-2,4-二胺(35.0mg),产率:40%。
1H NMR:(400MHz,CD
3OD)δ8.32(s,1H),8.14(s,1H),7.76-7.66(m,1H),7.60(s,1H),7.47-7.42(m,1H),7.41-7.36(m,2H),7.18-7.08(m,2H),4.55-4.48(m,2H),3.93-3.56(m,10H),3.06(s,3H),1.91(s,3H),1.88(s,3H)。MS-ESI计算值[M+H]
+515和517,实测值515和517。
实施例45
5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-[4-[2-甲氧乙基(甲基)胺]吡唑-1-基]苯基]嘧啶-2,4-二胺
第一步
4-溴-1-(4-硝基苯)吡唑
根据实施例32中第一步方法,将***啉和2-氟-4-甲氧基-1-硝基苯替换为对氟硝基苯和4-溴吡唑,得到4-溴-1-(4-硝基苯)吡唑(15.0g,黄色固体),产率:79%。1H NMR:(400MHz,CDCl
3)δ8.35(d,J=9.2Hz,2H),8.06(s,1H),7.84(d,J=9.2Hz,2H),7.75(s,1H)。
MS-ESI计算值[M+H]
+268和270,实测值268和270。
第二步
N-(2-甲氧乙基)-N-甲基-1-(4-硝基苯)吡唑-4-氨基
将4-溴-1-(4-硝基苯)吡唑(200mg,1.00eq),2-甲氧基-N-甲基-二乙胺(200mg,2.24mmol),和叔丁基醇钠(71.7mg,746umol)溶于四氢呋喃(3.00mL)中,在氮气保护下向反应液中加入甲烷磺酸(2-二-叔丁基膦基-2',4',6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯-2-基)钯(II)(30.0mg,37.3umol),于80℃下搅拌反应16小时。反应液过滤蒸干,用制备薄层色谱法(二氯甲烷:甲醇=10:1)纯化得到N-(2-甲氧乙基)-N-甲基-1-(4-硝基苯)吡唑-4-氨基(122mg,黄色固体),产率:59%。1H NMR:(400MHz,CDCl
3)δ8.33-8.26(m,2H),7.81-7.73(m,2H),7.49(s,1H),7.34(d,J=0.8Hz,1H),3.58(t,J=5.6Hz,2H),3.38(s,3H),3.34-3.28(m,2H),2.88(s,3H).
MS-ESI计算值[M+H]
+277,实测值277。
第三步
1-(4-氨基苯)-N-(2-甲氧乙基)-N-甲基-吡唑-4-胺
根据实施例31中第二步方法,将4-(4-甲氧基-2-硝基-苯基)***啉替换为N-(2-甲氧乙基)-N-甲基-1-(4-硝基苯)吡唑-4-氨基得到1-(4-氨基苯)-N-(2-甲氧乙基)-N-甲基-吡唑-4-胺(110mg,黄色固体),粗品不经纯化直接用于下一步。
1H NMR:(400MHz,CDCl3)δ7.43-7.40(m,1H),7.40-7.37(m,1H),7.33(d,J=0.8Hz,1H),7.26(d,J=0.8Hz,1H),6.75-6.73(m,1H),6.72-6.70(m,1H),3.58(t,J=5.8Hz,2H),3.41-3.36(m,3H),3.24(t,J=5.8Hz,2H),2.82(s,3H)。
第四步
根据实施例1中第四步方法,将对甲氧基苯胺替换为1-(4-氨基苯)-N-(2-甲氧乙基)-N-甲基-吡唑-4-胺,得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-[4-[2-甲氧乙基(甲基)胺]吡唑-1-基]苯基]嘧啶-2,4-二胺(58.0mg),产率:42%。
1H NMR:(400MHz,CD
3OD)δ8.89(s,1H),8.25(s,2H),8.06(s,1H),7.90-7.82(m,2H),7.79-7.71(m,1H),7.65-7.58(m,3H),7.51-7.44(m,1H),3.89-3.82(m,2H),3.67-3.60(m,2H),3.44(s,3H),3.42(s,3H),1.91(s,3H),1.88(s,3H).
MS-ESI计算值[M+H]
+526和528,实测值526和528。
实施例46
5-氯-N2-[4-[4-[(3R)-3-(二甲氨基)吡咯烷-1-基]吡唑-1-基]苯基]-N4-(2-二甲基磷酰基苯基)嘧啶-2,4-二胺
第一步
(3R)-N,N-二甲基-1-[1-(4-硝基苯)吡唑-4-基]吡咯烷-3-胺
根据实施例45中第二步方法,将2-甲氧基-N-甲基-二乙胺替换为(3R)-N,N-二甲基吡唑-3-胺得到(3R)-N,N-二甲基-1-[1-(4-硝基苯)吡唑-4-基]吡咯烷-3-胺(72.0mg,黄色固体),产率:32%。1H NMR:(400MHz,CDCl3)δ8.33-8.26(m,2H),7.80-7.74(m,2H),7.42(s,1H),7.28(s,1H),3.38-3.21(m,3H),3.09(t,J=8.0Hz,1H),2.98-2.88(m,1H),2.32(s,6H),2.25-2.14(m,1H),2.10-1.90(m,1H)。
MS-ESI计算值[M+H]
+302,实测值302。
第二步
(3R)-1-[1-(4-苯胺基)吡唑-4-基]-N,N-二甲基-吡咯烷-3-胺
根据实施例31中第二步方法,将4-(4-甲氧基-2-硝基-苯基)***啉替换为(3R)-N,N-二甲基-1-[1-(4-硝基苯)吡唑-4-基]吡咯烷-3-胺得到(3R)-1-[1-(4-苯胺基)吡唑-4-基]-N,N-二甲基-吡咯烷-3-胺(60.0mg,黄色油状),产率:87%。
1H NMR:(400MHz,CDCl
3)δ7.43-7.41(m,1H),7.40-7.38(m,1H),7.26(d,J=0.8Hz,1H),7.19(d,J=0.8Hz,1H),6.75-6.72(m,1H),6.72-6.70(m,1H),3.31(dd,J=7.2,8.0Hz,1H),3.25-3.18(m,2H),3.02(t,J=8.0Hz,1H),2.96-2.86(m,1H),2.30(s,6H),2.22-2.12(m,1H),1.98-1.85(m,1H).
MS-ESI计算值[M+H]
+272,实测值272。
第三步
5-氯-N2-[4-[4-[(3R)-3-(二甲氨基)吡咯烷-1-基]吡唑-1-基]苯基]-N4-(2-二甲基磷酰基苯基)嘧啶-2,4-二胺根据实施例1中第四步方法,将对甲氧基苯胺替换为(3R)-1-[1-(4-苯胺基)吡唑-4-基]-N,N-二甲基-吡咯烷-3-胺,得到5-氯-N2-[4-[4-[(3R)-3-(二甲氨基)吡咯烷-1-基]吡唑-1-基]苯基]-N4-(2-二甲基磷酰基苯基)嘧啶-2,4-二胺(12.0mg)产率:18%。
1H NMR:(400MHz,DMSO-d
6)δ7.99(s,1H),7.85-7.79(m,1H),7.71(s,1H),7.58-7.40(m,5H),7.35-7.26(m,3H),3.93-3.85(m,1H),3.36-3.24(m,3H),3.04-2.97(m,1H),2.76(d,J=2.3Hz,6H),2.42-2.30(m,1H),2.10-2.01(m,1H),1.68(s,3H),1.65(s,3H)。
MS-ESI计算值[M+H]
+551和553,实测值551和553。
实施例47
5-氯-N2-[4-[4-[(3S)-3-(二甲氨基)吡咯烷-1-基]吡唑-1-基]苯基]-N4-(2-二甲基磷酰基苯基)嘧啶-2,4-二胺
第一步
(3S)-N,N-二甲基-1-[1-(4-硝基苯)吡唑-4-基]吡咯烷-3-胺
根据实施例45中第二步方法,将2-甲氧基-N-甲基-二乙胺替换为(3S)-N,N-二甲基吡唑-3-胺得到(3S)-N,N-二甲基-1-[1-(4-硝基苯)吡唑-4-基]吡咯烷-3-胺(100mg,黄色固体),产率:44%。1H NMR:(400MHz,CDCl
3)δ8.32-8.27(m,2H),7.79-7.75(m,2H),7.42(s,1H),7.29(s,1H),3.36-3.24(m,3H),3.09(t,J=8.0Hz,1H),2.98-2.90(m,1H),2.32(s,6H),2.25-2.16(m,1H),1.99-1.92(m,1H).
MS-ESI计算值[M+H]
+302,实测值302。
第二步
(3S)-1-[1-(4-苯胺基)吡唑-4-基]-N,N-二甲基-吡咯烷-3-胺
根据实施例31中第二步方法,将4-(4-甲氧基-2-硝基-苯基)***啉替换为(3S)-N,N-二甲基-1-[1-(4-硝基苯)吡唑-4-基]吡咯烷-3-胺得到(3S)-1-[1-(4-苯胺基)吡唑-4-基]-N,N-二甲基-吡咯烷-3-胺(65.0mg,黄色固体),粗品。
1H NMR:(400MHz,CDCl
3)δ7.43-7.41(m,1H),7.41-7.38(m,1H),7.26(d,J=0.8Hz,1H),7.19(d,J=0.8Hz,1H),6.75-6.73(m,1H),6.72-6.70(m,1H),3.31(dd,J=7.2,8.0Hz,1H),3.25-3.19(m,2H),3.02(t,J=8.0Hz,1H),2.96-2.86(m,1H),2.30(s,6H),2.21-2.12(m,1H),1.98-1.85(m,1H).
MS-ESI计算值[M+H]
+272,实测值272。
第三步
5-氯-N2-[4-[4-[(3S)-3-(二甲氨基)吡咯烷-1-基]吡唑-1-基]苯基]-N4-(2-二甲基磷酰基苯基)嘧啶-2,4-二胺根据实施例1中第四步方法,将对甲氧基苯胺替换为(3S)-1-[1-(4-苯胺基)吡唑-4-基]-N,N-二甲基-吡咯烷-3-胺的得到5-氯-N2-[4-[4-[(3S)-3-(二甲氨基)吡咯烷-1-基]吡唑-1-基]苯基]-N4-(2-二甲基磷酰基苯基)嘧啶-2,4-二胺(36.0mg),产率:52%。
1H NMR:(400MHz,D
2O)δ7.90(s,1H),7.63-7.58(m,1H),7.57-7.49(m,2H),7.41-7.34(m,2H),7.32-7.27(m,1H),7.22-7.17(m,2H),7.15-7.09(m,2H),4.00-3.89(m,1H),3.41-3.28(m,3H),3.10-2.98(m,1H),2.85(d,J=2.8Hz,6H),2.49-2.37(m,1H),2.15-2.08(m,1H),1.69(s,3H),1.66(s,3H)。
MS-ESI计算值[M+H]
+551和553,实测值551和553。
实施例48
第一步
根据实施例45中第二步方法,将2-甲氧基-N-甲基-二乙胺替换为1-甲基哌嗪得到1-甲基-4-[1-(3-硝基苯)吡唑-4-基]哌嗪(98.0mg,黄色固体),产率:46%。1H NMR:(400MHz,CDCl
3)δ8.38(t,J=2.4Hz,1H),8.01-7.94(m,2H),7.52(t,J=8.4Hz,1H),7.45(s,1H),7.41(s,1H),3.07-2.98(m,4H),2.60-2.47(m,4H),2.30(s,3H).
MS-ESI计算值[M+H]
+288,实测值288。
第二步
4-[4-(4-甲基哌嗪-1-基)吡唑-1-基]苯胺
根据实施例31中第二步方法,将4-(4-甲氧基-2-硝基-苯基)***啉替换为1-甲基-4-[1-(3-硝基苯)吡唑-4-基]哌嗪得到4-[4-(4-甲基哌嗪-1-基)吡唑-1-基]苯胺(90.00mg,黄色油状),粗品。
1H NMR:(400MHz,CDCl
3)δ7.43-7.37(m,3H),7.33(d,J=0.8Hz,1H),6.73(s,1H),6.71(s,1H),3.09-3.00(m,4H),2.64-2.55(m,4H),2.35(s,3H)。
MS-ESI计算值[M+H]
+258,实测值258。
第三步
根据实施例1中第四步方法,将对甲氧基苯胺替换为4-[4-(4-甲基哌嗪-1-基)吡唑-1-基]苯胺5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-[4-(4-甲基哌嗪-1-基)吡唑-1-基]苯基]嘧啶-2,4-二胺(50.0mg),产率:49%。
1H NMR:(400MHz,D
2O)δ7.87(s,1H),7.67(s,1H),7.61-7.55(m,1H),7.53-7.45(m,2H),7.32-7.22(m,2H),7.18-7.05(m,4H),3.53(t,J=14.4Hz,4H),3.25-3.14(m,2H),3.03-2.91(m,2H),2.87(s,3H),1.69(s,3H),1.65(s,3H).
MS-ESI计算值[M+H]
+537和539,实测值537和539。
实施例49
5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-(4-***啉吡唑-1-基)苯基]嘧啶-2,4-二胺
第一步
4-[1-(4-硝基苯)吡唑-4-基]***啉
根据实施例45中第二步方法,将2-甲氧基-N-甲基-二乙胺替换为***啉得到4-[1-(4-硝基苯)吡唑-4-基]***啉(102mg,黄色固体),产率:50%。1H NMR:(400MHz,CDCl
3)δ8.35-8.28(m,2H),7.82-7.77(m,2H),7.57(s,1H),7.48(d,J=0.8Hz,1H),3.93-3.82(m,4H),3.06-3.03(m,4H)。
MS-ESI计算值[M+H]
+275,实测值275。
第二步
4-(4-***啉吡唑-1-基)苯胺
根据实施例31中第二步方法,将4-(4-甲氧基-2-硝基-苯基)***啉替换为4-[1-(4-硝基苯)吡唑-4-基]***啉得到4-(4-***啉吡唑-1-基)苯胺(80.0mg,黄色固体),产率:90%。
1H NMR:(400MHz,CDCl
3)δ7.45 7.38(m,3H),7.34(s,1H),6.73(d,J=8.8Hz,2H),3.92-3.80(m,4H),3.04-2.94(m,4H)。
MS-ESI计算值[M+H]
+245,实测值245。
第三步
5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-(4-***啉吡唑-1-基)苯基]嘧啶-2,4-二胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为4-(4-***啉吡唑-1-基)苯胺得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-(4-***啉吡唑-1-基)苯基]嘧啶-2,4-二胺(36.0mg),产率:39%。
1H NMR:(400MHz,CD
3OD)δ8.50(s,1H),8.29-8.20(m,2H),7.92(s,1H),7.81(d,J=8.8Hz,2H),7.77-7.69(m,1H),7.64-7.54(m,3H),7.49-7.42(m,1H),4.06-3.98(m,4H),3.54-3.47(m,4H),1.91(s,3H),1.88(s,3H)。
MS-ESI计算值[M+H]
+524和526,实测值524和526。
实施例50
5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-[4-[[6-(4-甲基哌嗪-1-基)-3-吡啶]胺]吡唑-1-基]苯基]嘧啶-2,4-胺
第一步
6-(4-甲基哌嗪-1-基)-N-[1-(4-硝基苯)吡唑-4-基]吡啶-3-胺
根据实施例45中第二步方法,将2-甲氧基-N-甲基-二乙胺替换为6-(4-甲基哌嗪-1-基)吡啶-3-氨基得到6-(4-甲基哌嗪-1-基)-N-[1-(4-硝基苯)吡唑-4-基]吡啶-3-胺(222mg,黄色固体),产率:78%。1H NMR:(400MHz,CDCl
3)δ8.24(d,J=8.4Hz,2H),7.96(d,J=2.8Hz,1H),7.74-7.67(m,3H),7.56(s,1H),7.19-7.16(m,1H),6.60(d,J=8.8Hz,1H),3.45-3.39(m,4H),2.51-2.48(m,4H),2.31-2.27(m,3H)。
MS-ESI计算值[M+H]
+380,实测值380。
第二步
N-[1-(4-氨基苯)吡唑-4-基]-6-(4-甲基哌嗪-1-基)吡啶-3-胺
根据实施例31中第二步方法,将4-(4-甲氧基-2-硝基-苯基)***啉替换为6-(4-甲基哌嗪-1-基)-N-[1-(4-硝基苯)吡唑-4-基]吡啶-3-胺得到N-[1-(4-氨基苯)吡唑-4-基]-6-(4-甲基哌嗪-1-基)吡啶-3-胺(200mg,浅黄色固体),产率:99%。
1H NMR:(400MHz,CDCl
3)δ7.96(d,J=2.8Hz,1H),7.64(s,1H),7.52(s,1H),7.44-7.37(m,2H),7.17(dd,J=3.0,8.8Hz,1H),6.77-6.70(m,2H),6.63(d,J=8.8Hz,1H),3.50-3.41(m,4H),2.59-2.53(m,4H),2.35(s,3H).
MS-ESI计算值[M+H]
+350,实测值350。
第三步
5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-[4-[[6-(4-甲基哌嗪-1-基)-3-吡啶]胺]吡唑-1-基]苯基]嘧啶-2,4-胺根据实施例1中第四步方法,将对甲氧基苯胺替换为N-[1-(4-氨基苯)吡唑-4-基]-6-(4-甲基哌嗪-1-基)吡啶-3-胺得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[4-[4-[[6-(4-甲基哌嗪-1-基)-3-吡啶]胺]吡唑-1-基]苯基]嘧啶-2,4-胺(52.0mg),产率:27%。
1H NMR:(400MHz,CD
3OD)δ8.39(s,1H),8.31-8.20(m,2H),7.98-7.92(m,1H),7.84(d,J=8.8Hz,2H),7.78-7.69(m,2H),7.66-7.59(m,2H),7.58-7.53(m,2H),7.52-7.43(m,2H),4.35-4.24(m,2H),3.79-3.69(m,2H),3.68-3.57(m,2H),3.43-3.34(m,2H),3.03(s,3H),1.92(s,3H),1.88(s,3H).
MS-ESI计算值[M+H]
+629和631,实测值629和631。
实施例51
5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-[4-(4-甲基哌嗪-1-基)吡唑-1-基]苯基]嘧啶-2,4-二胺
第一步
4-溴-1-(3-硝基苯基)吡唑
根据实施例32中第一步方法,将***啉和2-氟-4-甲氧基-1-硝基苯替换为三氟硝基苯得到4-溴-1-(3-硝基苯基)吡唑(8.00g,黄色固体),产率:84%。1H NMR:(400MHz,CDCl
3)δ8.51(t,J=2.0Hz,1H),8.19-8.13(m,1H),8.05-8.01(m,2H),7.72(s,1H),7.65(t,J=8.4Hz,1H)
第二步
1-甲基-4-[1-(3-硝基苯基)吡唑-4-基]哌嗪
根据实施例45中第二步方法,将2-甲氧基-N-甲基-二乙胺替换为4-溴-1-(3-硝基苯基)吡唑得到1-甲基-4-[1-(3-硝基苯基)吡唑-4-基]哌嗪(98.0mg,黄色固体),产率:46%。1H NMR:(400MHz,CDCl
3)δ8.38(t,J=2.4Hz,1H),8.01-7.94(m,2H),7.52(t,J=8.4Hz,1H),7.45(s,1H),7.41(s,1H),3.07- 2.98(m,4H),2.60-2.47(m,4H),2.30(s,3H)。
第三步
3-[4-(4-甲基哌嗪-1-基)吡唑-1-基]苯胺
根据实施例31中第二步方法,将4-(4-甲氧基-2-硝基-苯基)***啉替换为1-甲基-4-[1-(3-硝基苯基)吡唑-4-基]哌嗪得到3-[4-(4-甲基哌嗪-1-基)吡唑-1-基]苯胺(50.0mg,白色固体),产率:57%。
1H NMR:(400MHz,CDCl
3)δ7.35(d,J=7.6Hz,2H),7.11(t,J=8.0Hz,1H),6.98-6.93(m,1H),6.89-6.82(m,1H),6.52-6.46(m,1H),3.03-2.93(m,4H),2.57-2.48(m,4H),2.28(s,3H)。
第四步
5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-[4-(4-甲基哌嗪-1-基)吡唑-1-基]苯基]嘧啶-2,4-二胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为3-[4-(4-甲基哌嗪-1-基)吡唑-1-基]苯胺得到5-氯-N4-(2-二甲基磷酰基苯基)-N2-[3-[4-(4-甲基哌嗪-1-基)吡唑-1-基]苯基]嘧啶-2,4-二胺(75.0mg)产率:67%。
1H NMR:(400MHz,CD
3OD)δ8.23(s,2H),7.99(s,1H),7.89-7.87(m,1H),7.71-7.61(m,3H),7.51(t,J=8.0Hz,1H),7.33-7.22(m,3H),3.73-3.59(m,4H),3.37(s,2H),3.09-2.96(m,5H),1.91(s,3H),1.87(s,3H)。
MS-ESI计算值[M+H]
+538和540,实测值538和540。
实施例52
5-氯-N2-[3-[4-[(3R)-3-(二甲胺基)吡咯烷-1-基]吡唑-1-基]苯基]-N4-(2-二甲基磷酰基苯基)嘧啶-2,4-二胺
第一步
(3R)-N,N-二甲基-1-[1-(3-硝基苯)吡唑-4-基]吡咯烷-3-胺
参照实施例1第二步将甲基哌嗪替换为(3R)-N,N-二甲基吡咯烷-3-胺,得到(3R)-N,N-二甲基-1-[1-(3-硝基苯)吡唑-4-基]吡咯烷-3-胺(33.0mg,黄色固体),产率:15%。1H NMR:(400MHz,CDCl
3)δ8.29(t,J=2.0Hz,1H),7.88(dd,J=2.0,8.0Hz,2H),7.44-7.39(m,1H),7.23-7.10(m,3H),3.23-3.07(m,3H),2.94(t,J=8.0Hz,1H),2.84-2.76(m,1H),2.19-2.14(m,6H)。
第二步
(3R)-1-[1-(3-胺基苯基)吡唑-4-基]-N,N-二甲基-吡咯烷-3-胺
根据实施例31中第二步方法,将4-(4-甲氧基-2-硝基-苯基)***啉替换为(3R)-N,N-二甲基-1-[1-(3-硝基苯)吡唑-4-基]吡咯烷-3-胺得到(3R)-1-[1-(3-胺基苯基)吡唑-4-基]-N,N-二甲基-吡咯烷-3-胺(30.0mg,白色固体,粗品)。
第三步
5-氯-N2-[3-[4-[(3R)-3-(二甲胺基)吡咯烷-1-基]吡唑-1-基]苯基]-N4-(2-二甲基磷酰基苯基)嘧啶-2,4-二胺 根据实施例1中第四步方法,将对甲氧基苯胺替换为(3R)-1-[1-(3-胺基苯基)吡唑-4-基]-N,N-二甲基-吡咯烷-3-胺得到5-氯-N2-[3-[4-[(3R)-3-(二甲胺基)吡咯烷-1-基]吡唑-1-基]苯基]-N4-(2-二甲基磷酰基苯基)嘧啶-2,4-二胺(19.0mg),产率:29%。
1H NMR:(400MHz,CD
3OD)δ8.32-8.08(m,3H),7.91(s,1H),7.72-7.63(m,3H),7.51(t,J=8.4Hz,1H),7.35-7.17(m,3H),4.26-4.14(m,1H),3.85-3.74(m,1H),3.73-3.62(m,2H),3.42-3.34(m,1H),2.68-2.56(m,1H),2.48-2.35(m,1H),1.92(s,3H),1.88(s,3H).
MS-ESI计算值[M+H]
+551和553,实测值551和553。
实施例53
N4-(2-二甲基磷酰基苯基)-N2-(4-甲氧基苯基)-5-(三氟甲基)嘧啶-2,4-二胺
第一步
N-[2-(1-氨基-1-甲基-乙基)苯基]-2,5-二氯-嘧啶-4-胺
将2-(二氟甲氧基)苯胺(100mg,0.591mmol)和2,4-二氯嘧啶-5-(三氟甲基)嘧啶(128.3mg,0.591mmol)溶于二甲基甲酰胺(2mL)中,然后向反应液加入二异丙基乙胺(229mg,1.77mmol)。反应液在30℃,搅拌16小时。液相色谱和反应完全后。反应液冷至室温,加入水(10mL),滤液用乙酸乙酯(20mL×3)萃取。合并有机相,用饱和食盐水洗涤(15mL×3),无水硫酸钠干燥,过滤,滤液减压浓缩,剩余物用制备薄层色谱法纯化(乙酸乙酯,Rf=0.20)分离纯化得到混合物2-氯-N-(2-二甲基磷酰基苯基)-5-(三氟甲基)嘧啶-4-胺(50.0mg,黄色固体),产率:24%。
1H NMR:(400MHz,CD
3OD)δ8.72(s,1H),8.49(m,1H),7.66-7.74(m,1H),7.60-7.65(m,1H),7.26-7.33(m,1H),1.91(s,3H),1.87(s,3H).
MS-ESI计算值[M+H]
+350和352,实测值350和352。
第二步
根据实施例1中第四步方法,将(2-((2,5-二氯嘧啶-4-基)氨基)苯基)二甲基氧化膦替换为2-氯-N-(2-二甲基磷酰基苯基)-5-(三氟甲基)嘧啶-4-胺,得到N4-(2-二甲基磷酰基苯基)-N2-(4-甲氧基苯基)-5-(三氟甲基)嘧啶-2,4-二胺(6.00mg),产率:10%。
1H NMR:(400MHz,CD
3OD)δ8.45(s,1H),7.82(d,J=3.6Hz,1H),7.61(dd,J=4.4,9.2Hz,1H),7.31(d,J=8.8Hz,4H),7.01(d,J=8.8Hz,2H),3.88(s,3H),1.88(s,3H),1.84(s,3H).
MS-ESI计算值[M+H]
+437和439,实测值437和439。
实施例54
2-(二甲基氨基)-1-[6-[[4-(2-二甲基磷酰基苯氨基)-5-氟-嘧啶-2-基]氨基]-5-甲氧基-吲哚-1-基]乙酮
第一步
2-氯-N-(2-二甲基磷酰基苯基)-5-氟-嘧啶-4-胺
将2-二甲基磷酰基苯胺(200mg,1.18mmol)溶于二甲基甲酰胺(4mL)中,然后在10摄氏度下向反应液中加入2,4-二氯-5-氟-嘧啶(197mg,1.18mmol)和碳酸钾(490mg,3.55mmol)。反应液在60℃,搅拌16小时。液相色谱和反应完全后。反应液用饱和氯化铵(10mL)淬灭,乙酸乙酯(20mL×3)萃取,合并有机相后用饱和食盐水洗(10mL×2),无水硫酸钠干燥、过滤、浓缩后用制备TLC板(乙酸乙酯/甲醇=10:1,Rf=0.26)分离纯化得到2-氯-N-(2-二甲基磷酰基苯基)-5-氟-嘧啶-4-胺(55mg,黄色固体),产率:15.5%。
1H NMR:(400MHz,CD3OD)δ8.63(m,1H),8.22(m,1H),7.70-7.58(m,2H),7.34-7.26(m,1H),1.92(s,3H),1.89(s,3H).
MS-ESI计算值[M+H]
+300和302,实测值300和302。
第二步
2-(二甲基氨基)-1-[6-[[4-(2-二甲基磷酰基苯氨基)-5-氟-嘧啶-2-基]氨基]-5-甲氧基-吲哚-1-基]乙酮根据实施例1中第四步方法,将对甲氧基苯胺替换为1-(6-氨基-5-甲氧基吲哚-1-基)-2-(甲基氨基)乙酮,得到2-(二甲基氨基)-1-[6-[[4-(2-二甲基磷酰基苯氨基)-5-氟-嘧啶-2-基]氨基]-5-甲氧基-吲哚-1-基]乙酮(22.0mg),产率:19.1%。
1H NMR:(400MHz,CD
3OD)δ8.48(d,J=7.6Hz,1H),8.31(s,1H),8.04(d,J=4.8Hz,1H),7.67(dd,J=7.6,13.8Hz,1H),7.48(t,J=8.0Hz,1H),7.38-7.32(m,1H),7.17(s,1H),4.34(s,2H),4.15(t,J=8.4Hz,2H),3.87(s,3H),3.40-3.37(m,2H),3.00(s,6H),1.94(s,3H),1.91(s,3H).
MS-ESI计算值[M+H]
+513,实测值513。
实施例55
1-[6-[[5-氯-4-(2-二甲基磷酰基苯胺)嘧啶-2-基]氨基]-5-甲氧基-二氢吲哚-1-基]-2-(二甲氨基)乙酰基
第一步
5-甲氧基二氢吲哚
0℃下向5-甲氧基吲哚(40.00g,0.272mol)的乙酸(200mL)溶液中分批加入氰基硼氢化钠(34.16g,0.544mol),并在20℃下搅拌4小时,反应完全后,向反应液中加入20%的氢氧化钠溶液调节pH至13,然后向其中加入乙酸乙酯(300mL),分液,水相用乙酸乙酯(300.00mL×2)萃取,合并有机相经无水硫酸钠干燥、过滤、减压浓缩,再经色谱硅胶柱(0-25%乙酸乙酯/石油醚)分离纯化得到5-甲氧基二氢吲哚(25.00g,淡黄色油状物),产率:62%。
1H NMR:(400MHz,CDCl
3)δ6.77(s,1H),6.61-6.60(m,2H),3.76(s,3H),3.54(t,J=8.0Hz,2H),3.02(t,J=8.0Hz,2H).
第二步
2-(二甲氨基)-1-(5-甲氧基二氢吲哚-1-基)乙酰基(盐酸盐)
室温条件下,向5-甲氧基二氢吲哚(25.00g,0.168mol)的二氯甲烷(500mL)溶液中加入2-二甲胺乙酸(25.92g,0.251mol),PyBOP(139.52g,0.268mol)和二异丙基乙胺(64.97g,0.503mol)并在20℃下搅拌10小时,反应完全后,向反应液中加入2N的盐酸(120mL),并搅拌30分钟(pH=3),此时析出大量的白色固体,过滤,干燥得2-(二甲氨基)-1-(5-甲氧基二氢吲哚-1-基)乙酰基(盐酸盐)(40.00g,白色固体),产率:88%。
1H NMR:(400MHz,CDCl
3)δ8.06-8.03(m,1H),6.87(s,1H),6.76-6.75(m,1H),4.26(s,2H),4.08-4.04(m,2H),3.78(s,3H),3.26-3.22(m,2H),3.01(s,6H).
第三步
2-(二甲氨基)-1-(5-甲氧基-6-硝基-二氢吲哚-1-基)乙酰基
0℃下向硝酸钠(13.81g,0.163mol)的三氟乙酸(100mL)溶液中加入2-(二甲氨基)-1-(5-甲氧基二氢吲哚-1-基)乙酰基(盐酸盐)(40.00g,0.148mol)的三氟乙酸(100mL)溶液,并在0℃下搅拌1.5小时,反应完全后,向反应液中加入2N的氢氧化钠溶液调节pH至11(过程中保证温度在10℃以下),此时析出大量的黄色固体,过滤,干燥得2-(二甲氨基)-1-(5-甲氧基-6-硝基-二氢吲哚-1-基)乙酰基(36.00g,黄色固体),产率:87%。
1H NMR:(400MHz,CDCl
3)δ8.70(s,1H),6.93(s,1H),4.26(t,J=8.0Hz,2H),3.93(s,3H),3.26(t,J=8.0Hz,2H),3.20(s,2H),2.37(s,6H).
第四步
1-(6-氨基-5-甲氧基-二氢吲哚-1-基)-2-(二甲氨基)乙酰基
将2-(二甲氨基)-1-(5-甲氧基-6-硝基-二氢吲哚-1-基)乙酰基(5.00g,17.90mmol)溶于乙酸乙酯(100mL)和甲醇(15mL)中,向反应液中加入湿钯碳(10%,600mg)。反应液在20℃氢气(50psi)氛围下反应4小时。反应液过滤,滤液减压浓缩得到黄色固体,用少量乙酸乙酯冲洗,得到1-(6-氨基-5-甲氧基-二氢吲哚-1-基)-2-(二甲氨基)乙酰基(2.50g,淡黄色固体),产率:56%。
1H NMR:(400MHz,CDCl
3)δ7.68(s,1H),6.62(s,1H),4.01(t,J=8.0Hz,2H),3.79(s,3H),3.17(s,2H),3.06(t,J=8.0Hz,2H),2.36(s,6H).
第五步
1-[6-[[5-氯-4-(2-二甲基磷酰基苯胺)嘧啶-2-基]氨基]-5-甲氧基-二氢吲哚-1-基]-2-(二甲氨基)乙酰基根据实施例1中第四步方法,将对甲氧基苯胺替换为1-(6-氨基-5-甲氧基-二氢吲哚-1-基)-2-(二甲氨基)乙酰基,得到1-[6-[[5-氯-4-(2-二甲基磷酰基苯胺)嘧啶-2-基]氨基]-5-甲氧基-二氢吲哚-1-基]-2-(二甲氨基)乙酰基(45.00mg),产率:13%。
1H NMR:(400MHz,CD
3OD)δ8.33-8.29(m,1H),8.20(s,1H),8.11(s, 1H),7.68-7.63(m,1H),7.46-7.42(m,1H),7.38-7.34(m,1H),7.16(s,1H),4.34(s,2H),4.14(t,J=8.0Hz,2H),3.85(s,3H),3.36(t,J=8.0Hz,2H),2.99(s,6H),1.92(s,3H),1.88(s,3H).
MS-ESI计算值[M+H]
+529;531,实测值529;531。
实施例56
5-[[5-氯-4-(2-二甲基磷酰基苯胺)嘧啶-2-基]氨基]-6-甲基-1,3-二氢苯并咪唑-2-羰基
根据实施例1中第四步方法,将对甲氧基苯胺替换为5-氨基-6-甲基-1,3-二氢苯并咪唑-2-羰基,得到5-[[5-氯-4-(2-二甲基磷酰基苯胺)嘧啶-2-基]氨基]-6-甲基-1,3-二氢苯并咪唑-2-羰基(7.00mg),产率:7.2%。
1H NMR:(400MHz,CD3OD)δ8.21-7.78(m,2H),7.76-7.69(m,2H),7.37(br.s.,1H),7.06-7.04(m,2H),2.28(s,3H),1.90-1.87(m,6H).
MS-ESI计算值[M+H]
+443和445,实测值443和445。
实施例57
6-[[5-氯-4-(2-二甲基磷酰基苯胺)嘧啶-2-基]氨基]-2,3-二氢酞嗪-1,4-二羰基
根据实施例1中第四步方法,将对甲氧基苯胺替换为6-氨基-2,3-二氢酞嗪-1,4-二酮,得到6-[[5-氯-4-(2-二甲基磷酰基苯胺)嘧啶-2-基]氨基]-2,3-二氢酞嗪-1,4-二羰基(3.60mg),产率:3.8%。
1H NMR:(400MHz,CD
3OD)δ8.29(s,1H),8.15-8.09(m,3H),7.95-7.92(m,1H),7.72-7.67(m,1H),7.55-7.52(m,1H),7.44-7.40(m,1H),1.89(s,3H),1.86(s,3H).
MS-ESI计算值[M+H]
+457和459,实测值457和459。
实施例58
N5-[5-氯-4-(2-二甲基磷酰基苯胺)嘧啶-2-基]-N,N-二甲基-1氢-苯并咪唑-2,5-二胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为N,N-二甲基-1H-苯并咪唑-2,5-二胺,得到N5-[5-氯-4-(2-二甲基磷酰基苯胺)嘧啶-2-基]-N,N-二甲基-1氢-苯并咪唑-2,5-二胺(14.00mg,),产率:12%。
1H NMR:(400MHz,CD
3OD)::δ8.01(s,1H),7.79(br.s.,1H),7.61-7.59(m,1H),7.45-7.34(m,2H),7.21- 7.18(m,2H),7.13-7.11(m,1H),3.20(s,6H),1.78(s,3H),1.74(s,3H).
MS-ESI计算值[M+H]
+456;458,实测值456;458。
实施例59
4-[[5-氯-4-(2-二甲基磷酰基苯胺)嘧啶-2-基]氨基]异吲哚啉
根据实施例1中第四步方法,将对甲氧基苯胺替换为4-氨基异吲哚啉,得到4-[[5-氯-4-(2-二甲基磷酰基苯胺)嘧啶-2-基]氨基]异吲哚啉(17.0mg),产率:19%。
1H NMR:(400MHz,CD
3OD)δ8.21(s,1H),7.93(br.s.,1H),7.82-7.80(m,1H),7.68-7.59(m,3H),7.34-7.33(m,2H),4.38(s,2H),1.86(s,3H),1.83(s,3H).
MS-ESI计算值[M+H]
+428和430,实测值428和430。
实施例60
6-((5-氯-4-((2-(二甲基磷酰基)苯基)氨基)嘧啶-2-基)氨基)苯并[b]噻吩-1,1-二氧化物
根据实施例1中第四步方法,将对甲氧基苯胺替换为6-氨基苯并[b]噻吩-1,1-二氧化物,得到6-((5-氯-4-((2-(二甲基磷酰基)苯基)氨基)嘧啶-2-基)氨基)苯并[b]噻吩-1,1-二氧化物(20.0mg),产率:27%。
1H NMR:(400MHz,CD
3OD)δ8.29(s,1H),8.11-8.10(m,1H),7.98(s,1H),7.74-7.71(m,2H),7.60-7.57(m,1H),7.49-7.45(m,3H),7.01-6.99(m,1H),1.91-1.88(m,6H).
MS-ESI计算值[M+H]
+461和463,实测值461和463。
实施例61
(2-((5-氯-2-((2-甲基苯并[d]噻唑-5-基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧化膦
根据实施例1中第四步方法,将对甲氧基苯胺替换为2-甲基苯并[d]噻唑-5-胺,得到(2-((5-氯-2-((2-甲基苯并[d]噻唑-5-基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧化膦(30.0mg),产率:43%。
1H NMR:(400MHz,CD
3OD)δ8.31(s,1H),8.17-8.15(m,2H),8.05(s,1H),7.78-7.69(m,2H),7.48-7.43(m,2H),3.11(s,3H),1.92-1.88(m,6H).
MS-ESI计算值[M+H]
+444和446,实测值444和446。
实施例62
(2-((5-氯-2-((1-甲基-1H-吲唑-6-基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧化膦2-甲基苯并[d]噻唑-5-胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为1-甲基-1H-吲唑-6-胺,得到(2-((5-氯-2-((1-甲基-1H-吲唑-6-基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧化膦2-甲基苯并[d]噻唑-5-胺(21.0mg),产率:31%。
1H NMR:(400MHz,CD
3OD)δ8.28-8.27(m,1H),8.22(s,1H),8.11(s,1H),7.86-7.84(m,1H),7.73-7.68(m,2H),7.40-7.38(m,2H),7.23-7.21(m,1H),3.97(s,3H),1.92-1.88(m,6H).
MS-ESI计算值[M+H]
+427和429,实测值427和429。
实施例63
5-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-2-甲基异-1-酮
根据实施例1中第四步方法,将对甲氧基苯胺替换为5-氨基-2-甲基异-1-酮,得到5-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-2-甲基异-1-酮(25.0mg),产率:29%。
1HNMR:(400MHz,CD
3OD)δ8.38-8.35(m,1H),8.18(s,1H),7.96(s,1H),7.72-7.65(m,2H),7.60-7.55(m,2H),7.40-7.39(m,1H),4.38(s,2H),3.20(s,3H),1.88(s,3H),1.84(s,3H).
MS-ESI计算值[M+H]
+442和444,实测值442和444。
实施例64
5-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-2-甲基异-1-酮
根据实施例1中第四步方法,将对甲氧基苯胺替换为6-氨基-2-甲基异-1-酮,得到5-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-2-甲基异-1-酮(25.0mg),产率:29%。
1HNMR:(400MHz,DMSO-d6)δ11.23(s,1H),9.62(s,1H),8.63(s,1H),8.25(s,1H),8.02-8.01(m,1H),7.82-7.81(m,1H),7.80-7.79(m,1H),7.61-7.57(m,1H),7.55-7.43(m,1H),7.19-7.17(m,1H),4.39(s,2H),3.07(s,3H),1.80(s,3H),1.77(s,3H).
MS-ESI计算值[M+H]
+442和444,实测值442和444。
实施例65
4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-2-甲基异-1-酮
根据实施例1中第四步方法,将对甲氧基苯胺替换为4-氨基-2-甲基异-1-酮,得到4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-2-甲基异-1-酮(25.0mg),产率:29%。
1HNMR:(400MHz,CD
3OD)δ8.16-8.15(m,1H),8.10(s,1H),7.75-7.73(m,1H),7.57-7.55(m,2H),7.47-7.43(m,1H),7.29-7.28(m,1H),7.20-7.19(m,1H),4.40(s,2H),3.04(s,3H),1.85(s,3H),1.82(s,3H).
MS-ESI计算值[M+H]
+442和444,实测值442和444。
实施例67
5-氯-N4-(2-甲基磷酰基苯基)-N2-(2-甲基异吲哚啉-5-基)嘧啶-2,4-二胺
第一步
2-甲基异吲哚啉-5-胺
将四氢铝锂(198.14mg,5.22mmol)溶于四氢呋喃(10mL)中,然后在10摄氏度下向反应液中加入5-氨基-2-甲基-异吲哚啉-1,3-二酮(400mg,2.27mmol)的四氢呋喃(10mL)。反应液在80℃,搅拌3小时。反应完全后,在冰浴条件下,向反应液中缓慢的依次加入水(0.2mL),15%NaOH水溶液(0.2mL)和水(0.6mL),室温搅拌30分钟后过滤,滤液减压浓缩后用制备薄层色谱法分离纯化(乙酸乙酯,Rf=0.1)分离纯化得到2-甲基异吲哚啉-5胺(100mg,黄色油状物),产率:30%。
1H NMR:(400MHz,CD
3OD)δ6.97(d,J=8.0Hz,1H),6.66-6.59(m,2H),3.82(d,J=8.0Hz,4H),2.57(s,3H).
MS-ESI计算值[M+H]
+149,实测值149。
第二步
5-氯-N4-(2-甲基磷酰基苯基)-N2-(2-甲基异吲哚啉-5-基)嘧啶-2,4-二胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为2-甲基异吲哚啉-5-胺,得到5-氯-N4-(2-甲基磷酰基苯基)-N2-(2-甲基异吲哚啉-5-基)嘧啶-2,4-二胺(12.0mg),产率:16%。
1H NMR:(400MHz,CD3OD)δ8.25(s,1H),8.16(br.s,1H),7.78(dd,J=7.6Hz,1H),7.69(t,J=7.6Hz,1H),7.56-7.43(m,4H),4.85-4.82(m,2H),4.58-4.44(m,2H),3.17(s,3H),1.90(s,3H),1.87(s,3H).
MS-ESI计算值[M+H]
+428和430,实测值428和430。
实施例68
(2-((5-氯-2-((4-甲氧基苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧化膦
根据实施例1中第四步方法,将对甲氧基苯胺替换为7-氨基—2,3-二氢-2-甲基-1H-异吲哚-1-酮,得到7-[[5-氯-4-(2-二甲基膦酰基苯胺基)嘧啶-2-基]氨基]-2-甲基-异吲哚-1-酮(33.0mg),产率:43%。
1H NMR:(400MHz,CD
3OD)δ8.36(s,1H),8.07(br.s,1H),7.86-7.79(m,2H),7.72(t,J=7.8Hz,1H),7.57(t,J=6.8Hz,1H),7.35-7.31(m,1H),7.29-7.25(m,1H),4.48(s,2H),3.17(s,3H),1.89(s,3H),1.86(s,3H).
MS-ESI计算值[M+H]
+442和444,实测值442和444。
实施例69
N2-(1,3-苯并二氧戊环-5-基)-5-氯-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为苯并[d][1,3]二氧杂环戊烯-5-胺,得到N2-(1,3-苯并二氧戊环-5-基)-5-氯-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺(26.0mg),产率:36%。
1H NMR:(400MHz,CD
3OD)δ8.37(br.s,1H),8.10(br.s,1H),7.70(dd,J=7.6,14.0Hz,1H),7.59(br.s,1H),7.45-7.39(m,1H),6.97(s,1H),6.92-6.88(m,1H),6.87-6.83(m,1H),6.05(s,2H),1.92(s,3H),1.89(s,3H).MS-ESI计算值[M+H]
+417和419,实测值417和419。
实施例70
5-氯-N2-(2,3-二氢-1,4-苯并二氧杂苯-6-基)-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为2,3-二氢苯并[b][1,4]二氧杂环己烯-6-胺,得到5-氯-N2-(2,3-二氢-1,4-苯并二氧杂苯-6-基)-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺(21.0mg),产率:28%。
1H NMR:(400MHz,CD
3OD)δ8.38(br.s,1H),8.09(br.s,1H),7.73-7.67(m,1H),7.58-7.57(t,J=7.2Hz,1H),7.45-7.39(m,1H),6.97(d,J=2.4Hz,1H),6.93-6.87(m,1H),6.86-6.82(m,1H),4.29(s,4H),1.92(s,3H),1.89(s,3H).
MS-ESI计算值[M+H]
+431和433,实测值431和433。
实施例71
5-氯-N2-(2,2-二氟-1,3-苯并二氧戊环-5-基)-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-胺,得到5-氯-N2-(2,2-二氟-1,3-苯并二氧戊环-5-基)-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺(10.0mg),产率:36%。
1H NMR:(400MHz,CD3OD)δ8.38-8.36(m,1H),8.13(s,1H),7.70-7.67(m,3H),7.33-7.32(m,1H),7.15-7.13(m,1H),,7.08-7.04(m,1H),1.88(s,3H),1.85(s,3H).
MS-ESI计算值[M+H]
+453和455,实测值453和455。
实施例72
N2-(1,3-苯并二氧戊环-4-基)-5-氯-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为苯并[d][1,3]二氧杂环戊烯-4-胺,得到N2-(1,3-苯并二氧戊环-4-基)-5-氯-N4-(2-二甲基膦酰基苯胺基)嘧啶-2,4-二胺(20.0mg),产率:28%。
1H NMR:(400MHz,CD
3OD)δ8.37(br.s,1H),8.17(s,1H),7.71-7.68(m,1H),7.53(br.s,1H),7.44-7.34(m,1H),6.98-6.86(m,3H),5.98(s,2H),1.92(s,3H),1.89(s,3H).
MS-ESI计算值[M+H]
+417和419,实测值417和419。
实施例73
N2-(1,3-苯并噁唑-5-基)-5-氯-N4-(2-二甲基磷酰基苯基)嘧啶-2,4-二胺
根据实施例1中第四步方法,将对甲氧基苯胺替换为苯并[d]恶唑-5-胺,得到N2-(1,3-苯并噁唑-5-基)-5-氯-N4-(2-二甲基磷酰基苯基)嘧啶-2,4-二胺(9.0mg),产率:14%。
1H NMR:(400MHz,CD
3OD)δ8.51-8.48(m,1H),8.44(s,1H),8.15-8.04(m,2H),7.65-7.58(m,1H),7.57-7.52(m,3H),7.30-7.23(m,1H),1.89(s,3H),1.85(s,3H).
MS-ESI计算值[M+H]
+414和416,实测值414和416。
实施例74
1-[6-[[5-氯-4-[(2-二甲基磷酰基苯基)甲氨基]嘧啶-2-基]氨基]-5-甲氧基-二氢吲哚-1-基]-2-(二甲氨基)乙酰基
第一步
2-二甲基磷酰基苯腈
氮气条件下,将2-碘苯氰(300.0mg,1.31mmol)溶于无水二氧六环(5mL)中,向反应液中加入二甲基氧化磷(102.24mg,1.31mmol),碳酸铯(0.854g,2.62mmol),4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(7.6mg,0.013mmol)和三(二亚苄基丙酮)二钯(12.0mg,0.013mmol),反应液在90℃下搅拌12小时。反应完全后,过滤,减压浓缩,向其中加入10mL水和10mL乙酸乙酯,水相经乙酸乙酯(10mL×3)萃取,有机相经无水硫酸钠干燥、过滤、减压浓缩后,将反应液浓缩,经硅胶柱色谱法(20-50%乙酸乙酯/石油醚)分离纯化得到2-二甲基磷酰基苯腈(90.0mg,白色固体),产率:38%。
1H NMR:(400MHz,CDCl3)δ8.34-8.29(m,1H),7.83-7.79(m,2H),7.69-7.66(m,1H),1.99(s,3H),1.95(s,3H).
第二步
2-二甲基磷酰基苄胺
将2-二甲基磷酰基苯腈(70.0mg,0.391mmol)溶于甲醇(10mL)中,向反应液中加入湿钯碳(10%,20mg)。反应液在20℃氢气(50psi)氛围下反应16小时。反应液过滤,滤液减压浓缩得到黄色固体,用少量乙酸乙酯冲洗,得到粗产物2-二甲基磷酰基苄胺(70.0mg,黄色固体)。
MS-ESI计算值[M+H]
+184,实测值184。
第三步
2,5-二氯-N-[(2-二甲基磷酰基苯基)甲基]嘧啶-4-胺
室温条件下,向2,4,5-三氯嘧啶(0.105g,0.573mmol)的二氯甲烷(8mL)溶液中加入2-二甲基磷酰基苄胺(0.07g,0.382mmol)和三乙胺(0.097g,0.955mmol)并在20℃下搅拌16小时,反应完全后,用二氯甲烷(10.00mL×3)萃取,有机相经无水硫酸钠干燥、过滤、减压浓缩后,将反应液浓缩,经薄层色谱法(15/1二氯甲烷/甲醇)分离纯化得到2,5-二氯-N-[(2-二甲基磷酰基苯基)甲基]嘧啶-4-胺(0.1g,黄色固体,产率:66%)。
1H NMR:(400MHz,CDCl3)δ8.26-8.23(m,1H),7.93(s,1H),7.75-7.72(m,1H),7.55-7.52(m,1H),7.44-7.39(m,2H),4.97-4.95(m,2H),1.87(s,3H),1.84(s,3H).
第四步
1-[6-[[5-氯-4-[(2-二甲基磷酰基苯基)甲氨基]嘧啶-2-基]氨基]-5-甲氧基-二氢吲哚-1-基]-2-(二甲氨基)乙酰基
将1-(6-氨基-5-甲氧基-吲哚-1-基)-2-(二甲氨基)乙酰基(75.51mg,0.303mmol)溶于叔丁醇(5mL)中,然后向反应液加入2,5-二氯-N-[(2-二甲基磷酰基苯基)甲基]嘧啶-4-胺(100.00mg,0.303mmol)和甲烷磺酸(87.33mg,0.909mmol)。反应液在90℃条件下搅拌16小时。反应液减压浓缩,剩余物经高效液相色谱法分离纯化得到1-[6-[[5-氯-4-[(2-二甲基磷酰基苯基)甲氨基]嘧啶-2-基]氨基]-5-甲氧基-二氢吲哚-1-基]-2-(二甲氨基)乙酰基(40.00mg),产率:23%。
1H NMR:(400MHz,CD
3OD)δ8.91(br.s.,1H),8.01(s,1H),7.68-7.65(m,1H),7.46(s,3H),7.16(s,1H),5.25(s,2H),4.33(s,2H),4.17-4.12(m,2H),3.91(s,3H),3.35-3.33(m,2H),2.93(s,6H),1.94(s,3H),1.91(s,3H).
MS-ESI计算值[M+H]
+543和545,实测值543和545。
实验例1:体外评价LRRK2激酶抑制活性
实验目的:通过均相时间分辨荧光检测磷酸化Fluorescein-ERM(LRRKtide)peptide的磷酸基团与
Tb-pERM(pLRRKtide)Antibody抗体结合后产生的能量信号转移(520nM/485nM荧光信号比值)。计算待测化合物的LRRK2激酶抑制IC
50值。
实验材料:
1.反应溶液:10mM羟乙基哌嗪乙磺酸(PH7.5);2mM氯化镁;0.5mM乙二醇二***二胺四乙酸;0.002%聚氧乙烯脂肪醇醚;1mM二硫苏糖醇和1%DMSO;
2.检测溶液:TR-FRET Dilution Buffer;
3.LRRK2 Recombinant Human Protein:使用GST标签用杆状病毒在昆虫Sf9细胞中表达重组全长人LRRK2 Protein;.
4.底物:0.4uM Fluorescein-ERM(LRRKtide)peptide;57uM ATP。
检测方法:
均相时间分辨荧光技术(HTRF);
实验操作:
1.通过Echo550非接触式纳升级声波移液***加入待测化合物的DMSO溶液;
2.用新鲜制备的反应溶液配置酶和多肽混合溶液,加入到反应孔穴中,室温下预温育20分钟;
3.加入57uM ATP引发反应,室温反应90分钟;
4.加入检测***(Fluorescein-ERM(LRRKtide)peptide多肽,
Tb-pERM(pLRRKtide)Antibody抗体及10mM乙二胺四乙酸),室温反应60分钟,用Em/Ex 520/485检测荧光信号;
5.通过信号比值计算相对DMSO空白的相对酶活性抑制,利用软件XLfit5拟合曲线计算IC
50值。 实验结果:
表1-LRRK2磷酸二酯酶抑制活性测试结果
供试品(各实施例所制得的化合物) | LRRK2激酶抑制活性 |
化合物1 | +++ |
化合物2 | +++ |
化合物3 | +++ |
化合物4 | +++ |
化合物5 | +++ |
化合物6 | +++ |
化合物7 | +++ |
化合物8 | +++ |
化合物9 | +++ |
化合物10 | +++ |
化合物11 | +++ |
化合物12 | +++ |
化合物13 | +++ |
化合物14 | +++ |
化合物15 | +++ |
化合物16 | +++ |
化合物17 | +++ |
化合物18 | +++ |
化合物19 | +++ |
化合物20 | +++ |
化合物21 | +++ |
化合物22 | +++ |
化合物23 | +++ |
化合物24 | +++ |
化合物25 | +++ |
化合物26 | +++ |
化合物27 | +++ |
化合物28 | +++ |
化合物29 | +++ |
化合物30 | +++ |
化合物31 | + |
化合物32 | + |
化合物33 | ++ |
化合物34 | +++ |
化合物35 | +++ |
化合物36 | +++ |
化合物37 | ++ |
化合物38 | + |
化合物39 | +++ |
化合物40 | +++ |
化合物41 | +++ |
化合物42 | + |
化合物43 | +++ |
化合物44 | +++ |
化合物45 | +++ |
化合物46 | +++ |
化合物47 | +++ |
化合物48 | +++ |
化合物49 | +++ |
化合物50 | +++ |
化合物51 | +++ |
化合物52 | +++ |
化合物53 | +++ |
化合物54 | ++ |
化合物55 | +++ |
化合物56 | +++ |
化合物57 | +++ |
化合物58 | +++ |
化合物59 | +++ |
化合物60 | +++ |
化合物61 | +++ |
化合物62 | +++ |
化合物63 | +++ |
化合物64 | +++ |
化合物65 | +++ |
化合物67 | +++ |
化合物68 | ++ |
化合物69 | +++ |
化合物70 | +++ |
化合物71 | ++ |
化合物72 | +++ |
化合物73 | +++ |
化合物74 | + |
注:100nM≦“+”<1000nM;10nM≦“++”<100nM;1nM≦“+++”<10nM;
结论:本发明化合物具有显著甚至意料不到的LRRK2激酶抑制活性。
Claims (24)
- 式(Ⅰ)所示化合物、其药学上可接受的盐,其中,L选自单键和-CH 2-;R 1和R 2分别独立地选自H、F、Cl、Br、I、OH、CN、NH 2和COOH,或分别独立地选自任选被1、2或3个R取代的:C 1-6烷基、C 1-6杂烷基、4~6元杂环烷基和R a-L 1-,且R 1、R 2不选自:R a选自H、苯基、5~6元杂芳基、C 4-6环烷基和4~6元杂环烷基;L 1选自-C(=O)-、-C(=O)NH-、-S(=O)-、-S(=O) 2-、-CH 2-和-CH 2CH 2-;R 3选自F、Cl、Br、I、OH、CN、CF 3和NH 2;R 4分别独立地分别独立地选自H、F、Cl、Br和I;R 5和R 6分别独立地选自H、卤素、OH、CN、NH 2、NO 2、COOH和R b-L 2-L 3-L 4-,或分别独立地选自任选被1、2或3个R取代的:C 1-6烷基、C 1-6杂烷基、C 4-6环烷基、4~6元杂环烷基、苯基和5~6元杂芳基,且R 5和R 6不选自任选被1、2或3个卤素取代的R b选自H、卤素、OH、CN、NH 2、NO 2、COOH,或选自任选被1、2或3个R取代的:C 1-6烷基、C 1- 6杂烷基、C 4-6环烷基、4~6元杂环烷基和5~6元杂芳基;L 2、L 3和L 4分别独立地选自单键、O、S、NH、-C(=O)-、-C(=O)NH-、-S(=O)-、-S(=O) 2-、-(CH 2) 1-3-、苯基、5~6元杂芳基和4~6元杂环烷基,且L 2、L 3和L 4不同时选自单键;R 7选自H、卤素、OH、CN、NH 2、NO 2和COOH,或选自任选被1、2或3个R取代的:NH 2和C 1-3烷基;R 8选自F、Cl、Br、I、OH、CN和NH 2;R选自卤素、OH、CN、NH 2、COOH,或选自任选被1、2或3个R’取代的:C 1-3烷基和C 1-3杂烷基;R’选自F、Cl、Br、I、OH、CN、NH 2、COOH、Me、Et、CF 3、CHF 2、CH 2F、NHCH 3和N(CH 3) 2;所述C 1-6杂烷基、C 1-3杂烷基、4~6元杂环烷基和5~6元杂芳基之杂原子或杂原子团,选自-C(=O)NH-、-NH-、-C(=NH)-、-S(=O) 2NH-、-S(=O)NH-、-N=、-O-、-S-、-O-N=、-C(=O)O-、-C(=O)-、-S(=O)-、 -S(=O) 2-和-NHC(=O)NH-;以上任何一种情况下,杂原子或杂原子团的数目分别独立地选自1、2或3。
- 根据权利要求1或2所述化合物、其药学上可接受的盐及其互变异构体,其中,Ra选自H、苯基和6元杂环烷基。
- 根据权利要求1或2所述化合物、其药学上可接受的盐及其互变异构体,其中,R 1和R 2分别独立地选自H、F、Cl、Br、I、OH、CN、NH 2和COOH,或分别独立地选自任选被1、2或3个R取代的:C 1-3烷基、C 1-3烷氧基、C 1-3烷硫基、C 1-3烷氨基、N,N’-二(C 1-2烷基)氨基-和5~6元杂环烷基。
- 根据权利要求1或2所述化合物、其药学上可接受的盐及其互变异构体,其中,Rb选自H、卤素、OH、CN、NH 2、NO 2和COOH,或选自任选被1、2或3个R取代的:C 1-3烷氨基、C 1-3烷氧基、C 1-3烷硫基、N,N’-二(C 1-2烷基)氨基、吡咯烷基、吗啉基、哌嗪基、吡啶基和嘧啶基。
- 根据权利要求1或2所述化合物、其药学上可接受的盐及其互变异构体,其中,L 2、L 3和L 4分别独立地选自:单键、O、S、NH、-C(=O)-、-C(=O)NH-、-S(=O)-、-S(=O) 2-、-CH 2-、-CH 2CH 2-、苯基、吡 啶基、吡唑基、咪唑基、吡啶基、嘧啶基、噻吩基、恶唑基、噻唑基、异恶唑基和异噻唑基。
- 根据权利要求1或2所述化合物、其药学上可接受的盐及其互变异构体,其中,R 5和R 6分别独立地选自H、卤素、OH、CN、NH 2、NO 2和COOH,或分别独立地选自任选被1、2或3个R取代的:C 1- 3杂烷基、噻唑基、嘧啶基、吡啶基、噻吩基、哌啶基、吗啉基和哌嗪基。
- 根据权利要求19所述化合物、其药学上可接受的盐及其互变异构体,其中,R 7选自H、-N(CH 3) 2、和CH 3。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CNPCT/CN2021/082459 | 2021-03-23 | ||
CN2021082459 | 2021-03-23 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2022199589A1 true WO2022199589A1 (zh) | 2022-09-29 |
Family
ID=83396314
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2022/082343 WO2022199589A1 (zh) | 2021-03-23 | 2022-03-22 | 嘧啶衍生物 |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2022199589A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN116870016A (zh) * | 2022-12-01 | 2023-10-13 | 希格生科(深圳)有限公司 | 杂芳环化合物及其医药用途 |
Citations (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102105150A (zh) * | 2008-05-21 | 2011-06-22 | 阿里亚德医药股份有限公司 | 用作激酶抑制剂的磷衍生物 |
WO2012151561A1 (en) * | 2011-05-04 | 2012-11-08 | Ariad Pharmaceuticals, Inc. | Compounds for inhibiting cell proliferation in egfr-driven cancers |
CN103153064A (zh) * | 2010-10-14 | 2013-06-12 | 阿里亚德医药股份有限公司 | 抑制egfr导致的癌症中细胞增殖的方法 |
US20140066406A1 (en) * | 2008-05-21 | 2014-03-06 | Ariad Pharmaceuticals, Inc. | Phosphorus Derivatives as Kinase Inhibitors |
CN106699810A (zh) * | 2015-11-17 | 2017-05-24 | 清华大学 | 一种含氮杂环化合物及其制备方法与在抑制激酶活性中的应用 |
WO2017086829A1 (ru) * | 2015-11-19 | 2017-05-26 | Закрытое акционерное общество "Р-Фарм" (ЗАО "Р-Фарм") | Дихлорацетаты замещенных n4-[2-(диметилфосфиноил) фенил]-n2-(2-метокси-4-пиперидин-1-илфенил)-5-хлорпиримидин-2,4-диаминов в качестве модуляторов alk и egfr, предназначенных для лечения рака |
WO2018102366A1 (en) * | 2016-11-30 | 2018-06-07 | Ariad Pharmaceuticals, Inc. | Anilinopyrimidines as haematopoietic progenitor kinase 1 (hpk1) inhibitors |
CN109071512A (zh) * | 2016-02-03 | 2018-12-21 | 重庆复创医药研究有限公司 | 作为激酶抑制剂的含磷化合物 |
WO2019120121A1 (zh) * | 2017-12-21 | 2019-06-27 | 深圳市塔吉瑞生物医药有限公司 | 用于抑制激酶活性的二苯氨基嘧啶类化合物 |
CN110467638A (zh) * | 2018-05-09 | 2019-11-19 | 北京赛特明强医药科技有限公司 | 一种含有间氯苯胺类取代基的双氨基氯代嘧啶类化合物、制备方法及其应用 |
CN110467637A (zh) * | 2018-05-09 | 2019-11-19 | 北京赛特明强医药科技有限公司 | 一种含有氧化膦类取代苯胺的双氨基氯代嘧啶类化合物、制备方法及其应用 |
CN111718325A (zh) * | 2019-03-22 | 2020-09-29 | 烟台药物研究所 | 一种2,4,5-取代嘧啶类化合物及其制备方法和应用 |
WO2020200191A1 (en) * | 2019-04-04 | 2020-10-08 | Betta Pharmaceuticals Co., Ltd | Egfr inhibitors, compositions and methods there of |
WO2020249048A1 (zh) * | 2019-06-12 | 2020-12-17 | 上海科技大学 | Alk蛋白调节剂及其抗肿瘤应用 |
WO2021125803A1 (ko) * | 2019-12-16 | 2021-06-24 | 한국화학연구원 | 신규한 피리미딘 유도체 및 이의 용도 |
WO2021190417A1 (zh) * | 2020-03-23 | 2021-09-30 | 齐鲁制药有限公司 | 新型氨基嘧啶类egfr抑制剂 |
-
2022
- 2022-03-22 WO PCT/CN2022/082343 patent/WO2022199589A1/zh unknown
Patent Citations (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102105150A (zh) * | 2008-05-21 | 2011-06-22 | 阿里亚德医药股份有限公司 | 用作激酶抑制剂的磷衍生物 |
US20140066406A1 (en) * | 2008-05-21 | 2014-03-06 | Ariad Pharmaceuticals, Inc. | Phosphorus Derivatives as Kinase Inhibitors |
CN103153064A (zh) * | 2010-10-14 | 2013-06-12 | 阿里亚德医药股份有限公司 | 抑制egfr导致的癌症中细胞增殖的方法 |
WO2012151561A1 (en) * | 2011-05-04 | 2012-11-08 | Ariad Pharmaceuticals, Inc. | Compounds for inhibiting cell proliferation in egfr-driven cancers |
CN106699810A (zh) * | 2015-11-17 | 2017-05-24 | 清华大学 | 一种含氮杂环化合物及其制备方法与在抑制激酶活性中的应用 |
WO2017086829A1 (ru) * | 2015-11-19 | 2017-05-26 | Закрытое акционерное общество "Р-Фарм" (ЗАО "Р-Фарм") | Дихлорацетаты замещенных n4-[2-(диметилфосфиноил) фенил]-n2-(2-метокси-4-пиперидин-1-илфенил)-5-хлорпиримидин-2,4-диаминов в качестве модуляторов alk и egfr, предназначенных для лечения рака |
CN109071512A (zh) * | 2016-02-03 | 2018-12-21 | 重庆复创医药研究有限公司 | 作为激酶抑制剂的含磷化合物 |
WO2018102366A1 (en) * | 2016-11-30 | 2018-06-07 | Ariad Pharmaceuticals, Inc. | Anilinopyrimidines as haematopoietic progenitor kinase 1 (hpk1) inhibitors |
WO2019120121A1 (zh) * | 2017-12-21 | 2019-06-27 | 深圳市塔吉瑞生物医药有限公司 | 用于抑制激酶活性的二苯氨基嘧啶类化合物 |
CN110467638A (zh) * | 2018-05-09 | 2019-11-19 | 北京赛特明强医药科技有限公司 | 一种含有间氯苯胺类取代基的双氨基氯代嘧啶类化合物、制备方法及其应用 |
CN110467637A (zh) * | 2018-05-09 | 2019-11-19 | 北京赛特明强医药科技有限公司 | 一种含有氧化膦类取代苯胺的双氨基氯代嘧啶类化合物、制备方法及其应用 |
CN111718325A (zh) * | 2019-03-22 | 2020-09-29 | 烟台药物研究所 | 一种2,4,5-取代嘧啶类化合物及其制备方法和应用 |
WO2020200191A1 (en) * | 2019-04-04 | 2020-10-08 | Betta Pharmaceuticals Co., Ltd | Egfr inhibitors, compositions and methods there of |
WO2020249048A1 (zh) * | 2019-06-12 | 2020-12-17 | 上海科技大学 | Alk蛋白调节剂及其抗肿瘤应用 |
WO2021125803A1 (ko) * | 2019-12-16 | 2021-06-24 | 한국화학연구원 | 신규한 피리미딘 유도체 및 이의 용도 |
WO2021190417A1 (zh) * | 2020-03-23 | 2021-09-30 | 齐鲁制药有限公司 | 新型氨基嘧啶类egfr抑制剂 |
Non-Patent Citations (2)
Title |
---|
CHEN, YONGFEI ET AL.: "Discovery of N-(5-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methyl-1, 4-diazepan-1-yl)phenyl)acrylamide (CHMFL-ALK/EGFR-050) as a potent ALK/EGFR dual kinase inhibitor capable of overcoming a variety of ALK/EGFR associated drug resistant mutants in NSCLC", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 139, 31 December 2017 (2017-12-31), pages 674 - 697, XP055600563, DOI: 10.1016/j.ejmech.2017.08.035 * |
HUANG, WEISHENG ET AL.: "Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase", JOURNAL OF MEDICINAL CHEMISTRY, vol. 59, no. 10, 31 December 2016 (2016-12-31), pages 4948 - 4964, XP055480025, DOI: 10.1021/acs.jmedchem.6b00306 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN116870016A (zh) * | 2022-12-01 | 2023-10-13 | 希格生科(深圳)有限公司 | 杂芳环化合物及其医药用途 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6754505B2 (ja) | Ask1阻害剤、その調製方法および使用 | |
KR102457933B1 (ko) | Rock의 억제제로서의 트리아졸론 및 테트라졸론 | |
AU2011205485B2 (en) | Compounds and methods | |
WO2017024968A1 (zh) | 作为fgfr和vegfr抑制剂的乙烯基化合物 | |
CA2674875A1 (en) | Purine derivatives | |
CA2683624A1 (en) | Pharmaceutical compounds | |
JP2018531218A6 (ja) | Fgfr及びvegfr阻害剤であるビニル化合物 | |
JP6836693B2 (ja) | A2a受容体アンタゴニストとしての縮合環誘導体 | |
WO2019034075A1 (zh) | Fgfr和egfr抑制剂 | |
JP2017519821A (ja) | PI3K阻害剤としてのピリド[1,2−a]ピリミドン類似体 | |
MXPA06009193A (es) | Procedimiento para la preparacion de compuestos triazol sustituidos. | |
JP6774578B2 (ja) | Mek阻害剤としてのクマリン環系化合物およびその応用。 | |
CA2351526A1 (en) | Indole derivatives and their use as serotonin receptor ligands | |
JP7050054B2 (ja) | Pde4阻害剤としての縮合環系化合物 | |
WO2022199589A1 (zh) | 嘧啶衍生物 | |
WO2019242689A1 (zh) | 一种氰基取代吡啶及氰基取代嘧啶类化合物、制备方法及其应用 | |
CA2581492A1 (en) | Indol derivatives as inhibitors of soluble adenylyl cyclase | |
WO2018127207A1 (zh) | 噻唑衍生物及其应用 | |
JP7044754B2 (ja) | Crth2阻害剤としてのインドール誘導体 | |
CA2255165A1 (en) | Benzothiophene derivatives useful in therapy | |
WO2023070114A2 (en) | Reversible lysine covalent modifiers of egfr and uses thereof | |
WO2018090973A1 (zh) | Fgfr4抑制剂及其制备方法和应用 | |
JP4834441B2 (ja) | ピリミジニルアルキルチオ基を有する新規環式化合物 | |
WO2016169514A1 (zh) | 咪唑类化合物 | |
RU2331638C2 (ru) | 2-тиозамещенные производные имидазола и их применение в фармацевтике |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 22774245 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |