CN113365631A - 布鲁顿酪氨酸激酶抑制剂 - Google Patents
布鲁顿酪氨酸激酶抑制剂 Download PDFInfo
- Publication number
- CN113365631A CN113365631A CN202080009929.4A CN202080009929A CN113365631A CN 113365631 A CN113365631 A CN 113365631A CN 202080009929 A CN202080009929 A CN 202080009929A CN 113365631 A CN113365631 A CN 113365631A
- Authority
- CN
- China
- Prior art keywords
- substituted
- amino
- methoxy
- pyrazin
- imidazo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 108010029445 Agammaglobulinaemia Tyrosine Kinase Proteins 0.000 title abstract description 20
- 102000001714 Agammaglobulinaemia Tyrosine Kinase Human genes 0.000 title abstract 3
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 title description 4
- 239000005483 tyrosine kinase inhibitor Substances 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims description 75
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 125000001072 heteroaryl group Chemical group 0.000 claims description 18
- -1 Amino Chemical group 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 235000019000 fluorine Nutrition 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 229920006395 saturated elastomer Polymers 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 10
- 125000005842 heteroatom Chemical group 0.000 claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 10
- 229910052717 sulfur Chemical group 0.000 claims description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 9
- 125000001153 fluoro group Chemical group F* 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 239000001301 oxygen Chemical group 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 8
- 239000011593 sulfur Chemical group 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- ZIJOFEBTDYXAFM-UHFFFAOYSA-N 3-[8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl]cyclohexan-1-ol Chemical compound C1CC(C=2N3C=CN=C(N)C3=C(N=2)C2=CC=C(OC3=CC=CC=C3)C=C2)CC(O)C1 ZIJOFEBTDYXAFM-UHFFFAOYSA-N 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 125000002619 bicyclic group Chemical group 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- FYSIUWYMRNTZJV-UHFFFAOYSA-N 4-[8-amino-1-[4-(2-fluoro-3-methoxyphenoxy)phenyl]imidazo[1,5-a]pyrazin-3-yl]cyclohexan-1-ol Chemical compound NC=1C=2N(C=CN=1)C(=NC=2C1=CC=C(C=C1)OC1=C(C(=CC=C1)OC)F)C1CCC(CC1)O FYSIUWYMRNTZJV-UHFFFAOYSA-N 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 2
- 125000006717 (C3-C10) cycloalkenyl group Chemical group 0.000 claims description 2
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 2
- 125000006584 (C3-C10) heterocycloalkyl group Chemical group 0.000 claims description 2
- MOAQKNRITNVWBX-UHFFFAOYSA-N 1-cyclopentyl-7-methoxy-3-(4-phenoxyphenyl)pyrazolo[4,3-c]pyridin-4-amine Chemical compound COC1=CN=C(C2=C1N(N=C2C3=CC=C(C=C3)OC4=CC=CC=C4)C5CCCC5)N MOAQKNRITNVWBX-UHFFFAOYSA-N 0.000 claims description 2
- JZMZEFYRNDUCRR-UHFFFAOYSA-N 3-[4-amino-3-[4-(2-fluoro-3-methoxyphenoxy)phenyl]-7-methoxypyrazolo[4,3-c]pyridin-1-yl]cyclohexan-1-ol Chemical compound NC1=NC=C(C2=C1C(=NN2C1CC(CCC1)O)C1=CC=C(C=C1)OC1=C(C(=CC=C1)OC)F)OC JZMZEFYRNDUCRR-UHFFFAOYSA-N 0.000 claims description 2
- IVVYQXFUTYLAJX-UHFFFAOYSA-N 3-[4-amino-7-methoxy-3-(4-phenoxyphenyl)pyrazolo[4,3-c]pyridin-1-yl]cyclohexan-1-ol Chemical compound NC1=NC=C(C2=C1C(=NN2C1CC(CCC1)O)C1=CC=C(C=C1)OC1=CC=CC=C1)OC IVVYQXFUTYLAJX-UHFFFAOYSA-N 0.000 claims description 2
- DFEQLGLCMYCEQB-UHFFFAOYSA-N 3-[8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl]cyclohexane-1-carboxylic acid Chemical compound Nc1nccn2c(nc(-c3ccc(Oc4ccccc4)cc3)c12)C1CCCC(C1)C(O)=O DFEQLGLCMYCEQB-UHFFFAOYSA-N 0.000 claims description 2
- OSMRDXXWHZQZLK-UHFFFAOYSA-N 3-[8-amino-1-[4-(2-fluoro-3-methoxyphenoxy)phenyl]imidazo[1,5-a]pyrazin-3-yl]cyclohexan-1-ol Chemical compound NC=1C=2N(C=CN=1)C(=NC=2C1=CC=C(C=C1)OC1=C(C(=CC=C1)OC)F)C1CC(CCC1)O OSMRDXXWHZQZLK-UHFFFAOYSA-N 0.000 claims description 2
- YBHAUIKQCNELHB-UHFFFAOYSA-N 3-[8-amino-5-ethoxy-1-[4-(2-fluoro-3-methoxyphenoxy)phenyl]imidazo[1,5-a]pyrazin-3-yl]cyclohexan-1-ol Chemical compound CCOC1=CN=C(C2=C(N=C(N12)C3CCCC(C3)O)C4=CC=C(C=C4)OC5=CC=CC(=C5F)OC)N YBHAUIKQCNELHB-UHFFFAOYSA-N 0.000 claims description 2
- VVHHSJBSPSEWPF-UHFFFAOYSA-N 3-cyclohexyl-5-ethoxy-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-8-amine Chemical compound C1(CCCCC1)C1=NC(=C2N1C(=CN=C2N)OCC)C1=CC=C(C=C1)OC1=CC=CC=C1 VVHHSJBSPSEWPF-UHFFFAOYSA-N 0.000 claims description 2
- RBDXGFOIETZYRC-UHFFFAOYSA-N 3-cyclopentyl-5-ethoxy-1-[4-(2-fluoro-3-methoxyphenoxy)phenyl]imidazo[1,5-a]pyrazin-8-amine Chemical compound CCOC1=CN=C(C2=C(N=C(N12)C3CCCC3)C4=CC=C(C=C4)OC5=CC=CC(=C5F)OC)N RBDXGFOIETZYRC-UHFFFAOYSA-N 0.000 claims description 2
- RWPJLXJODMTMCD-UHFFFAOYSA-N 4-[4-amino-3-[4-(2-fluoro-3-methoxyphenoxy)phenyl]-7-methoxypyrazolo[4,3-c]pyridin-1-yl]cyclohexan-1-ol Chemical compound NC1=NC=C(C2=C1C(=NN2C1CCC(CC1)O)C1=CC=C(C=C1)OC1=C(C(=CC=C1)OC)F)OC RWPJLXJODMTMCD-UHFFFAOYSA-N 0.000 claims description 2
- LBVPQYSWRVMGPY-UHFFFAOYSA-N 4-[4-amino-7-methoxy-3-(4-phenoxyphenyl)pyrazolo[4,3-c]pyridin-1-yl]cyclohexan-1-ol Chemical compound NC1=NC=C(C2=C1C(=NN2C1CCC(CC1)O)C1=CC=C(C=C1)OC1=CC=CC=C1)OC LBVPQYSWRVMGPY-UHFFFAOYSA-N 0.000 claims description 2
- WJGFPHMEXYHRPL-UHFFFAOYSA-N 4-[8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl]cyclohexan-1-ol Chemical compound C1CC(CCC1C2=NC(=C3N2C=CN=C3N)C4=CC=C(C=C4)OC5=CC=CC=C5)O WJGFPHMEXYHRPL-UHFFFAOYSA-N 0.000 claims description 2
- ZGDMPGSXFASYEV-UHFFFAOYSA-N 4-[8-amino-1-[4-(3-chloro-2-fluorophenoxy)phenyl]imidazo[1,5-a]pyrazin-3-yl]cyclohexan-1-ol Chemical compound NC=1C=2N(C=CN=1)C(=NC=2C1=CC=C(C=C1)OC1=C(C(=CC=C1)Cl)F)C1CCC(CC1)O ZGDMPGSXFASYEV-UHFFFAOYSA-N 0.000 claims description 2
- HBNBERGKAOESDA-UHFFFAOYSA-N 4-[8-amino-1-[4-(3-chlorophenoxy)phenyl]imidazo[1,5-a]pyrazin-3-yl]cyclohexan-1-ol Chemical compound NC=1C=2N(C=CN=1)C(=NC=2C1=CC=C(C=C1)OC1=CC(=CC=C1)Cl)C1CCC(CC1)O HBNBERGKAOESDA-UHFFFAOYSA-N 0.000 claims description 2
- NQRGTVLUNYVKML-UHFFFAOYSA-N 4-[8-amino-1-[4-(3-methoxy-2-methylphenoxy)phenyl]imidazo[1,5-a]pyrazin-3-yl]cyclohexan-1-ol Chemical compound NC=1C=2N(C=CN=1)C(=NC=2C1=CC=C(C=C1)OC1=C(C(=CC=C1)OC)C)C1CCC(CC1)O NQRGTVLUNYVKML-UHFFFAOYSA-N 0.000 claims description 2
- RSBVDSARXOEXPC-UHFFFAOYSA-N 4-[8-amino-1-[4-(3-methylphenoxy)phenyl]imidazo[1,5-a]pyrazin-3-yl]cyclohexan-1-ol Chemical compound CC1=CC(=CC=C1)OC2=CC=C(C=C2)C3=C4C(=NC=CN4C(=N3)C5CCC(CC5)O)N RSBVDSARXOEXPC-UHFFFAOYSA-N 0.000 claims description 2
- IABSEKDJBHSTHR-UHFFFAOYSA-N 4-[8-amino-5-ethoxy-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl]cyclohexan-1-ol Chemical compound CCOC1=CN=C(C2=C(N=C(N12)C3CCC(CC3)O)C4=CC=C(C=C4)OC5=CC=CC=C5)N IABSEKDJBHSTHR-UHFFFAOYSA-N 0.000 claims description 2
- CLZLFBNKJMLXAN-UHFFFAOYSA-N 4-[8-amino-5-ethoxy-1-[4-(2-fluoro-3-methoxyphenoxy)phenyl]imidazo[1,5-a]pyrazin-3-yl]cyclohexan-1-ol Chemical compound CCOC1=CN=C(C2=C(N=C(N12)C3CCC(CC3)O)C4=CC=C(C=C4)OC5=CC=CC(=C5F)OC)N CLZLFBNKJMLXAN-UHFFFAOYSA-N 0.000 claims description 2
- ILIROAJJZQATOU-UHFFFAOYSA-N 5-ethoxy-3-(oxan-4-yl)-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-8-amine Chemical compound CCOC1=CN=C(C2=C(N=C(N12)C3CCOCC3)C4=CC=C(C=C4)OC5=CC=CC=C5)N ILIROAJJZQATOU-UHFFFAOYSA-N 0.000 claims description 2
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000002837 carbocyclic group Chemical group 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- FPIQZBQZKBKLEI-UHFFFAOYSA-N ethyl 1-[[2-chloroethyl(nitroso)carbamoyl]amino]cyclohexane-1-carboxylate Chemical compound ClCCN(N=O)C(=O)NC1(C(=O)OCC)CCCCC1 FPIQZBQZKBKLEI-UHFFFAOYSA-N 0.000 claims description 2
- GCHCFWATRJAINH-UHFFFAOYSA-N ethyl 4-[8-amino-1-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]imidazo[1,5-a]pyrazin-3-yl]cyclohexane-1-carboxylate Chemical compound CCOC(=O)C1CCC(CC1)C2=NC(=C3N2C=CN=C3N)C4=CC=C(C=C4)CNC(=O)C5=CC=CC=C5OC GCHCFWATRJAINH-UHFFFAOYSA-N 0.000 claims description 2
- 125000004366 heterocycloalkenyl group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 4
- 239000003112 inhibitor Substances 0.000 abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 31
- 239000000203 mixture Substances 0.000 description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 17
- 102100029823 Tyrosine-protein kinase BTK Human genes 0.000 description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 238000000034 method Methods 0.000 description 15
- 239000000126 substance Substances 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 14
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 12
- 239000012267 brine Substances 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- 229940124291 BTK inhibitor Drugs 0.000 description 9
- 239000007832 Na2SO4 Substances 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 125000004429 atom Chemical group 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 7
- 238000001819 mass spectrum Methods 0.000 description 7
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical class OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- XLBDVRHCZOATJY-UHFFFAOYSA-N 3-chloro-n-methylpyrazin-2-amine;hydrochloride Chemical compound Cl.CNC1=NC=CN=C1Cl XLBDVRHCZOATJY-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 235000019439 ethyl acetate Nutrition 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000012746 preparative thin layer chromatography Methods 0.000 description 5
- 229940002612 prodrug Drugs 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000010189 synthetic method Methods 0.000 description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 210000003719 b-lymphocyte Anatomy 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000000132 electrospray ionisation Methods 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- HPGREQYQDSTKIR-UHFFFAOYSA-N 4-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)cyclohexan-1-ol Chemical compound N=1C(Br)=C2C(N)=NC=CN2C=1C1CCC(O)CC1 HPGREQYQDSTKIR-UHFFFAOYSA-N 0.000 description 3
- 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 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- 239000007821 HATU Substances 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 210000003630 histaminocyte Anatomy 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 3
- 238000000021 kinase assay Methods 0.000 description 3
- 238000004020 luminiscence type Methods 0.000 description 3
- 230000035772 mutation Effects 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 3
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- DIDOWRPUZQMBJJ-UHFFFAOYSA-N 3-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)cyclohexan-1-ol Chemical compound C1C(C=2N3C=CN=C(N)C3=C(N=2)Br)CC(O)CC1 DIDOWRPUZQMBJJ-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
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Classifications
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- 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
- C07D471/04—Ortho-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
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- 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
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Health & Medical Sciences (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
Abstract
具有下式(I)或(II)的布鲁顿酪氨酸激酶(BTK)抑制剂。
Description
本申请要求于2019年1月18日提交的美国临时申请第62/794,284号的优先权,其通过引用的方式并入本文以用于所有目的,如同在本文中充分阐述一样。
技术领域
本文描述了布鲁顿酪氨酸激酶抑制剂、制备此类抑制剂的方法和含有此类抑制剂的药物组合物。
背景技术
布鲁顿酪氨酸激酶(BTK)在B细胞的信号转导中起重要作用,并且是有助于B细胞存活、分化、增殖和活化的因子。目前,需要有治疗B细胞或肥大细胞参与的疾病的方法。众所周知,BTK还参与肥大细胞活化并且与血小板的生理功能有关。因此,BTK抑制剂可有效治疗B细胞或肥大细胞参与的疾病,例如过敏性疾病、自身免疫性疾病、炎性疾病、血栓栓塞性疾病和癌症。
发明内容
在一个方面,本发明公开了具有以下结构的式(I)、式(II)化合物、其异构体、其互变异构体、其药学上可接受的溶剂化物或其药学上可接受的前药:
A、B、G和D各自独立地为N或CR1,条件是仅A、B、G和D中的一个或两个可为N;
R1为氢、烷基、-OR1A、氨基、-OH、-CN、-NHOH、-NR1AR1B或-CONH2;
R2独立地为氢、卤素、-CZ3、-CHZ2、-CH2Z、-OCZ3、-OCH2Z、-OCHZ2、-CN、-SOnNR2AR2B、-NHC(O)NR2AR2B、-N(O)n、-NR2AR2B、-C(O)R2A、-C(O)-OR2A、-C(O)NR2AR2B、-SOnR2A、-OR2A、-NR2CSO2R2B、-NR2CC(O)R2A、-NR2CC(O)OR2A、-NR2AOR2B、取代或未取代的烷基其任选地被一至五个氟取代、取代或未取代的杂烷基其任选地被一至五个氟取代、取代或未取代的环烷基其任选地被一至五个氟取代、取代或未取代的杂环烷基其任选地被一至五个氟取代、取代或未取代的芳基、或取代或未取代的杂芳基,其中两个相邻的R2取代基可任选地连接以形成取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或取代或未取代的杂芳基,并且y为0-5的整数;
M为取代或未取代的C1-6烷基、取代或未取代的C3-10环烷基、取代或未取代的C3-10环烯基、取代或未取代的3-10元杂环烷基、取代或未取代的3-10元杂环烯基和5-10元杂芳基,其中M被取代时,其含有1-9个取代基,所述取代基在每次出现时独立地选自卤素、-OR2A、-NR2AR2B、=O、-CN、-C(O)OR2A、-OC(O)R2A、-C(O)NR2AR2B、-NR2CC(O)R2A、C1-6烷基、C1-6卤代烷基;被-OR2A取代的C1-6烷基;任选地被一至五个氟取代的C3-8环烷基、-SO2R2A、SO3R2A、C(O)R2A和3-8元杂环基;
-X-E为下列情况之一:(1)X为O、-OCR2AR2B-、-CR2AR2BO-、-S(O)-、-S(O)2-、-CR2AR2B-、-CR2AR2BNR2C(C=O)-、-CR2AR2B(C=O)NR2C-、-(C=O)NR2CCR2AR2B-、-NR2C(C=O)CR2AR2B-或键;并且E为氢、被一至五个R3取代基取代的芳基或杂芳基、或3-7元饱和或部分不饱和碳环、8-10元双环饱和或部分不饱和芳基环、具有1-4个独立地选自氮、氧或硫的杂原子的5-6元单环杂芳基环、具有1-3个独立地选自氮、氧或硫的杂原子的4-7元饱和或部分不饱和杂环、具有1-5个独立地选自氮、氧或硫的杂原子的7-10元双环饱和或部分不饱和杂环或具有1-5个独立地选自氮、氧或硫的杂原子的8-10元双环杂芳基环;或(2)-X-E为氢、卤素、-OR2A、-O(CH2)1-4R2A、-CN、-NO2;
R1A、R1B、R2A、R2B和R2C各自独立地为氢、-CZ3、-CN、-COOH、-CONH2、-CHZ2、-CH2Z、取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或取代或未取代的杂芳基,其中与同一氮原子相连的R1A和R1B取代基可任选地连接以形成取代或未取代的杂环烷基或取代或未取代的杂芳基,并且与同一氮原子相连的R2A和R1B可任选地连接以形成取代或未取代的杂环烷基或取代或未取代的杂芳基;
Z独立地为-F、-Cl、-Br或-I;并且
n独立地为1-2的整数。
在另一个方面,R2为H、F、Cl、OCH3、CH3,并且y为1或2。
在另一个方面,A为CR1,并且B、G和D中的一个为N。
在另一个方面,A为C-H或C-NH2。
在另一个方面,B为N,并且G和D为C-H。
在另一个方面,B为N,G为C-H,并且D为CR1。
在另一个方面,该化合物选自3-[8-氨基-1-(4-苯氧基-苯基)-咪唑并[1,5-a]吡嗪-3-基]-环己醇,
4-{8-氨基-1-[4-(2-氟-3-甲氧基-苯氧基)-苯基]-咪唑并[1,5-a]吡嗪-3-基}-环己醇,
N-{4-[1-(3-羟基-环己基)-1H-吡唑并[4,3-c]吡啶-3-基]-苄基}-2-甲氧基-苯甲酰胺,
(3-{8-氨基-1-[4-(2-氟-3-甲氧基-苯氧基)-苯基]-咪唑并[1,5-a]吡嗪-3-基}-环己醇,
4-[8-氨基-1-(4-苯氧基-苯基)-咪唑并[1,5-a]吡嗪-3-基]-环己醇,
4-{8-氨基-1-[4-(3-氯-2-氟-苯氧基)-苯基]-咪唑并[1,5-a]吡嗪-3-基}-环己醇,
4-{8-氨基-1-[4-(3-氯-苯氧基)-苯基]-咪唑并[1,5-a]吡嗪-3-基}-环己醇,
4-[8-氨基-1-(4-间甲苯氧基-苯基)-咪唑并[1,5-a]吡嗪-3-基]-环己醇,
4-{8-氨基-1-[4-(3-甲氧基-2-甲基-苯氧基)-苯基]-咪唑并[1,5-a]吡嗪-3-基}-环己醇,
N-{4-[1-(4-羟基-环己基)-1H-吡唑并[4,3-c]吡啶-3-基]-苄基}-2-甲氧基-苯甲酰胺,
N-{4-[8-氨基-3-(4-羟基-环己基)-咪唑并[1,5-a]吡嗪-1-基]-苄基}-2-甲氧基-苯甲酰胺,
N-{4-[8-氨基-3-(3-羟基-环己基)-咪唑并[1,5-a]吡嗪-1-基]-苄基}-2-甲氧基-苯甲酰胺,
N-[4-(8-氨基-3-环戊基-咪唑并[1,5-a]吡嗪-1-基)-苄基]-2-甲氧基-苯甲酰胺,
N-[4-(1-环戊基-1H-吡唑并[4,3-c]吡啶-3-基)-苄基]-2-甲氧基-苯甲酰胺,
3-[4-氨基-7-甲氧基-3-(4-苯氧基-苯基)-吡唑并[4,3-c]吡啶-1-基]-环己醇,
4-[4-氨基-7-甲氧基-3-(4-苯氧基-苯基)-吡唑并[4,3-c]吡啶-1-基]-环己醇,
3-{4-氨基-3-[4-(2-氟-3-甲氧基-苯氧基)-苯基]-7-甲氧基-吡唑并[4,3-c]吡啶-1-基}-环己醇,
4-{4-氨基-3-[4-(2-氟-3-甲氧基-苯氧基)-苯基]-7-甲氧基-吡唑并[4,3-c]吡啶-1-基}-环己醇,
1-环戊基-7-甲氧基-3-(4-苯氧基-苯基)-1H-吡唑并[4,3-c]吡啶-4-基胺,
3-{8-氨基-5-乙氧基-1-[4-(2-氟-3-甲氧基-苯氧基)-苯基]-咪唑并[1,5-a]吡嗪-3-基}-环己醇,
4-{8-氨基-5-乙氧基-1-[4-(2-氟-3-甲氧基-苯氧基)-苯基]-咪唑并[1,5-a]吡嗪-3-基}-环己醇、
4-[8-氨基-5-乙氧基-1-(4-苯氧基-苯基)-咪唑并[1,5-a]吡嗪-3-基]-环己醇,
3-环己基-5-乙氧基-1-(4-苯氧基-苯基)-咪唑并[1,5-a]吡嗪-8-基胺,
3-环戊基-5-乙氧基-1-[4-(2-氟-3-甲氧基-苯氧基)-苯基]-咪唑并[1,5-a]吡嗪-8-基胺,
N-{4-[8-氨基-5-乙氧基-3-(4-羟基-环己基)-咪唑并[1,5-a]吡嗪-1-基]-苄基}-2-甲氧基-苯甲酰胺,
N-[4-(8-氨基-3-环己基-5-乙氧基-咪唑并[1,5-a]吡嗪-1-基)-苄基]-2-甲氧基-苯甲酰胺,
N-[4-(8-氨基-3-环戊基-5-乙氧基-咪唑并[1,5-a]吡嗪-1-基)-苄基]-2-甲氧基-苯甲酰胺,
5-乙氧基-1-(4-苯氧基-苯基)-3-(四氢吡喃-4-基)-咪唑并[1,5-a]吡嗪-8-基胺,
3-[8-氨基-1-(4-苯氧基-苯基)-咪唑并[1,5-a]吡嗪-3-基]-环己烷甲酸,
4-(8-氨基-1-{4-[(2-甲氧基-苯甲酰基氨基)-甲基]-苯基}-咪唑并[1,5-a]吡嗪-3-基)-环己烷甲酸乙酯和,
N-{4-[8-氨基-3-(4-甲氧基-环己基)-咪唑并[1,5-a]吡嗪-1-基]-苄基}-2-甲氧基-苯甲酰胺。
具体实施方式
本文所述的方法包括向有需要的受试者施用含有治疗有效量的一种或多种本文所述的BTK抑制剂化合物的组合物。
前药是指将这种前药施用于哺乳动物受试者时,在体内释放式(I)或(II)活性母体药物的任何化合物。式I或(II)化合物的前药通过修饰式I或(II)化合物中存在的官能团,使得修饰物可在体内裂解以释放母体化合物来制备。前药可通过修饰化合物中存在的官能团,使得修饰物在常规操作中或在体内裂解为母体化合物来制备。
互变异构体是指通过分子的一个原子的质子转移到另一个原子的现象产生的化合物。互变异构体还指处于平衡状态并且易于从一种异构形式转化为另一种异构形式的两种或更多种结构异构体中的一种结构异构体。本领域普通技术人员将认识到,可能有其他互变异构环原子排列。这些化合物的所有此类异构形式明确地包括在本公开中。
异构体是指具有相同分子式但原子键合的性质或顺序或者原子在空间中的排列不同的化合物。原子在空间中的排列不同的异构体称为立体异构体。不互为镜像的立体异构体称为非对映异构体,彼此不重合的镜像的立体异构体称为对映异构体。当化合物具有不对称中心时,例如,其与四个不同的基团连接时,可能有一对对映异构体。手性化合物可以单独的对映异构体或其混合物的形式存在。除非另有说明,否则本说明书旨在包括单独的立体异构体以及混合物。
本公开的某些化合物可以非溶剂化形式以及溶剂化形式(包括水合形式)存在。溶剂化物是指溶剂分子与式I或式(II)化合物结合形成的复合物。溶剂可为有机化合物、无机化合物或它们的混合物。
药学上可接受的盐是指在医学判断范围内适用于与人和低等动物的组织接触而无过度的毒性、刺激、过敏反应等,并且与合理的利益/风险比相称的盐。这些盐可在本发明化合物的最终分离和纯化过程中获得,或者通过使游离碱官能团与合适的无机酸诸如盐酸、磷酸或硫酸反应,或与有机酸诸如抗坏血酸、柠檬酸、酒石酸、乳酸、马来酸、丙二酸、富马酸、羟基乙酸、琥珀酸、丙酸、乙酸、甲磺酸等反应而单独获得。酸官能团可与有机或无机碱如氢氧化钠、氢氧化钾或氢氧化锂反应。
治疗有效量是指本发明化合物或组合物有效抑制布鲁顿酪氨酸激酶并因此产生所需治疗效果的量。
如本文所用,术语烷基是指具有在指定范围内的碳原子数的一价直链或支链饱和脂族烃基。例如,C1-6烷基是指所有己烷基和戊烷基异构体以及正丁基、异丁基、仲丁基和叔丁基、正丙基和异丙基、乙基和甲基中的任一者。烷基还包括一个或多个氢被氘置换的饱和脂族烃基,例如CD3。
术语支链烷基是指如上所定义的但不包括在指定范围内的直链烷基的烷基。如本文所定义,支链烷基包括通过仲碳或叔碳与化合物的其余部分连接的烷基。例如,异丙基为支链烷基。
术语环烷基是指具有在指定范围内的碳原子数的烷烃的任何单环。例如,C3-6环烷基是指环丙基、环丁基、环戊基和环己基。
术语卤素是指氟、氯、溴和碘(或者称为氟基、氯基、溴基和碘基)。
术语卤代烷基是指氢原子中的一个或多个氢原子被卤素(即F、Cl、Br和/或I)置换的如上定义的烷基。例如,C1-6卤代烷基是指具有一个或多个卤素取代基的如上定义的C1至C6直链或支链烷基。术语氟烷基具有类似的含义,但卤素取代基仅限于氟。合适的氟烷基包括(CH2)0-4CF3系列。
术语C(O)或CO是指羰基。术语S(O)2或SO2是指磺酰基。术语S(O)或SO是指亚磺酰基。
术语芳基是指苯基、萘基、四氢萘基、茚基、二氢茚基等。特别感兴趣的芳基为苯基。
术语杂芳基是指(i)含有1-4个独立地选自N、O和S的杂原子的5元或6元杂芳环,或(ii)为选自喹啉基、异喹啉基和喹喔啉基的杂双环。合适的5元和6元杂芳环包括,例如吡啶基、吡咯基、吡嗪基、嘧啶基、哒嗪基、三嗪基、噻吩基、呋喃基、咪唑基、吡唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、噁三唑基、噻唑基、异噻唑基和噻二唑基。一类感兴趣的杂芳基由(i)含有1-3个独立地选自N、O和S的杂原子的5元和6元杂芳环,和(ii)选自喹啉基、异喹啉基和喹喔啉基的杂双环组成。特别感兴趣的杂芳基为吡咯基、咪唑基、吡啶基、吡嗪基、喹啉基、异喹啉基和喹喔啉基。
本发明范围内的4元至7元饱和杂环的示例包括,例如氮杂环丁基、哌啶基、吗啉基、硫代吗啉基、噻唑烷基、异噻唑烷基、噁唑烷基、异噁唑烷基、吡咯烷基、咪唑烷基、哌嗪基、四氢呋喃基、四氢噻吩基、吡唑烷基、六氢嘧啶基、噻嗪烷基、硫氮杂环庚烷基、氮杂环庚烷基、二氮杂环庚烷基、四氢吡喃基、四氢噻喃基和二噁烷基。本发明范围内的4元至7元不饱和杂环的示例包括与上句所列的饱和杂环对应的单不饱和杂环,其中单键被双键置换(例如,碳-碳单键被碳-碳双键置换)。
应理解,上文所列的具体环不是对可用于本发明的环的限制。这些环仅为代表性的。
制备本发明化合物的合成方法在以下方案、方法和实施例中说明。起始原料为市售的,或可根据本领域已知的步骤或如本文所述的方法来制备。本发明化合物通过下面所示的具体实施例来说明。然而,这些具体的实施例不应被解释为形成被认为是本发明的唯一种类。这些实施例进一步说明了制备本发明化合物的细节。本领域技术人员将易于理解,条件和工艺中的已知变化可用于制备此类化合物。
不可逆和可逆的BTK抑制剂靶向BTK的半胱氨酸残基C481。用依鲁替尼(ibrutinib)治疗后,一些患者出现了耐药性。已经报道了BTK内的突变,例如C481S、C481Y、C481R、C481F。随着时间的推移,耐药性将随着临床试验外的临床应用的拓展而增加。
本发明提供了可具有不同结合模式的式(I)、式(II)的BTK抑制剂化合物。具体而言,式(I)、式(II)的BTK抑制剂化合物对BTK具有良好活性,也可有效抑制BTK突变。例如,这些化合物可有效抑制C481 BTK突变。
式(I)或(II)的BTK抑制剂化合物可通过有机化学领域公知的方法来制备。用于合成这些化合物的起始原料可为合成的或从商业来源获得,诸如但不限于中国化工公司或西格玛奥德里奇生化科技(密苏里州圣路易斯)中国公司。本文所述的化合物和具有不同取代基的其他相关化合物任选地使用诸如March,ADVANCED ORGANIC CHEMISTRY,第4版,(Wiley,1992年);Carey和Sundberg,ADVANCED ORGANIC CHEMISTRY,第4版,A和B卷(Plenum,2000年,2001年);Fieser and Fieser’s Reagents for Organic Synthesis,第1-17卷(John Wiley and Sons,1991年);Rodd's Chemistry of Carbon Compounds,第1-5卷和增刊(Elsevier Science Publishers,1989年);Organic Reactions,第1-40卷(JohnWiley and Sons,1991年)和Larock's Comprehensive Organic Transformations(VCHPublishers Inc.,1989年)中所述的技术和材料来合成。本文所述的化合物的其他合成方法可参见国际申请公开WO 2013/010868A1,Liu,J.等人,ACS Medicinal ChemistryLetters,第10卷(2016年)第198-203页。本申请中使用的化学术语的定义可参见这些参考文献(如果本文未另外定义)。可使用下列合成方法作为指导。
在合成工序期间,可能需要和/或期望保护任何相关分子上的敏感或反应性基团。这是通过常规的保护基团,诸如T.W Greene和P.G.M.Wutts“Protective Groups inOrganic Synthesis”,第3版,John Wiley and Sons,1999年中所述的保护基团来实现的。使用本领域公知的方法在恰当的后续阶段任选地除去保护基团。任选地分离并纯化反应产物。如有需要,可使用常规技术,但不限于过滤、蒸馏结晶、层析等。使用常规手段(包括物理常数和光谱数据)任选地表征此类材料。
本文所述的化合物可具有一个或多个立体中心,并且每个中心可以R或S构型存在。本文提供的化合物包括所有非对映异构体、对映异构体和差向异构体形式以及它们的适当混合物。
式I的BTK抑制剂化合物可为例如咪唑并[1,5-a]吡嗪衍生物。具体而言,式(I)的BTK抑制剂化合物可为,例如化合物E或G,其中A、B、D、G和M具有先前定义的含义,并且R为制备化合物E和G的合成方法的非限制性示例可通过方案一中所示的一般合成路线制备。
方案一
参考方案一,不同的胺(A)可通过芳族腈的氢化获得,然后可在碱诸如TEA、DIPEA、DMAP的存在下,在溶剂诸如DMF、THF或DCM中与适当的胺保护的氨基酸反应,并与不同的偶联剂诸如PyBOP、TBTU、EDCI或HATU反应以形成中间体B。可使用缩合试剂如POCl3,在加热条件下环化B以提供关键中间体C,随后在适当温度下使用溴或N-溴代琥珀酰亚胺在溶剂如DCM或DMF中可实现溴化以获得化合物D,然后与适当取代的苯基硼酸(也可使用相应的硼酸酯)直接反应,得到所需化合物E。如果A为化合物D的C-Cl,则其可在NH3的条件下在110℃的PrOH中转化为化合物F,然后与适当取代的苯基硼酸(也可使用相应的硼酸酯)直接偶联,得到所需化合物G。
下文的方案二示出了用于制备本发明化合物J的一般合成路线。中间体H可通过基本上类似于国际专利公开WO 2017127371中所述的方法获得。吲唑上的1-氮与MOH通过Mitsunobu反应或与MOTs通过置换进行偶联反应得到中间体I,然后使用适当取代的苯基硼酸(也可以使用相应的硼酸酯)通过金属催化剂偶联反应衍生,得到所需化合物J。
本发明还包括与本文所述的化合物相同,但一个或多个原子被原子质量或质量数与通常在自然界中发现的原子质量或质量数不同的原子置换的同位素标记的本发明化合物。可掺入本发明化合物中的同位素的示例包括氢、碳、氮、氧、磷、氟和氯的同位素,诸如分别为2H、3H、13C、14C、15N、17O、18O、31P、32P、35S、18F和36Cl。
某些同位素标记的式(I)或(II)化合物(例如用3H和14C标记的化合物)可用于化合物和/或底物组织分布测定。氚代和碳-14同位素由于其易于制备和可检测性而是特别优选的。此外,用较重同位素(诸如氘)进行的取代可会因更大的代谢稳定性(例如,增加的体内半衰期或降低的剂量要求)而带来某些治疗优点,因此在一些情况下可能是优选的。同位素标记的式I化合物通常可通过与下文方案和/或实施例中公开的步骤类似的步骤,通过用适当的同位素标记的试剂取代非同位素标记的试剂来制备。
一般实验条件:制备薄层层析(Prep-TLC)在20cm×20cm板(500微米厚硅胶)上进行。硅胶层析在Biotage Horizon快速层析系统上进行。1H NMR谱在Bruker Ascend TM 400光谱仪上在400MHz、298K下记录,化学位移以参考氘代溶剂的残余质子信号的百万分之一(ppm)给出:CHCl3在δ=7.26ppm处,CH3OH或CH3OD在δ=3.30ppm处。LCMS谱在AgilentTechnologies 1260Infinity或6120四极质谱仪上采集。LC的流动相为乙腈(A)和含有0.01%甲酸的水(B),使用SBC18 50mm×4.6mm×2.7μm毛细管柱,洗脱液梯度为在6.0min内5%-95%A、在5.0min内60%-95%A、在5.0min内80%-100%A以及在10min内85%-100%A。质谱(MS)通过电喷雾离子化质谱(ESI)测定。除非另有说明,否则所有温度均为摄氏度。
分析性HPLC质谱条件:
LC1:柱:SB-C18 50mm×4.6mm×2.7μm;温度:50℃;洗脱液:在6min内5:95v/v乙腈/水+0.01%甲酸;流速:1.5mL/min,进样量5μL;检测:PDA,200nm-600nm;MS:质量范围150amu-750amu;正离子电喷雾电离。
LC2:柱:SB-C18 50mm×4.6mm×2.7μm;温度:50℃;洗脱液:在3.00min内5:95至95:5v/v乙腈/水+0.05%TFA;流速:1.5mL/min,进样量5μL;检测:PDA,200nm-600nm;MS:质量范围150amu-750amu;正离子电喷雾电离。
LC3:柱:SB-C18 50mm×4.6mm×2.7μm;温度:50℃;洗脱液:在3.75min内10:90至98:2v/v乙腈/水+0.05%TFA;流速:1.0mL/min,进样量10μL;检测:PDA,200nm-600nm;MS:质量范围150amu-750amu;正离子电喷雾电离。
缩写词表:
AcOH=乙酸;Alk=烷基;Ar=芳基;Boc=叔丁氧基羰基;bs=宽单峰;CH2Cl2=二氯甲烷;d=双重峰;dd=双二重峰;DBU=1,8-二氮杂双环-[5.4.0]十一碳-7-烯;DCM=二氯甲烷;DEAD=偶氮二甲酸二乙酯;DMF=N,N-二甲基甲酰胺;DMSO=二甲亚砜;EA=乙酸乙酯;ESI=电喷雾电离;Et=乙基;EtOAc=乙酸乙酯;EtOH=乙醇;h=小时;HOAc=乙酸;LiOH=氢氧化锂;m=多重峰;Me=甲基;MeCN=乙腈;MeOH=甲醇;MgSO4=硫酸镁;min=分钟;MS=质谱;NaCl=氯化钠;NaOH=氢氧化钠;Na2SO4=硫酸钠;NMR=核磁共振波谱分析;PE=石油醚;PG=保护基团;Ph=苯基;rt=室温;s=单峰;t=三重峰;TFA=三氟乙酸;THF=四氢呋喃;Ts=对甲苯磺酰基(甲苯磺酰基)。
本发明化合物可按照下文详述的一般方法制备。在某些实施方案中,本文提供了制备本文所述的酪氨酸激酶抑制剂化合物的方法。在某些实施方案中,本文所述的化合物使用以下合成方案合成。在其他实施方案中,化合物使用与下文所述的方法类似的方法通过使用适当的替代起始原料合成。所有关键中间体都根据以下方法制备。
实施例1
3-[8-氨基-1-(4-苯氧基-苯基)-咪唑并[1,5-a]吡嗪-3-基]-环己醇
反应方案
步骤1:N-((3-氯吡嗪-2-基)甲基)-3-羟基环己烷甲酰胺(2)
向(3-氯吡嗪-2-基)甲胺盐酸盐(1)(1.25g,6.94mmol)和3-羟基环己烷羧酸(1g,6.94mmol)的DCM(20mL)混合物中加入TEA(2.8g,27.76mmol)和HATU(3.2g,8.32mmol),并在室温下搅拌1小时。将反应混合物倒入水中,用EA萃取。有机相用盐水洗涤,Na2SO4干燥,过滤,滤液浓缩。残余物通过柱层析(DCM/MeOH=30/1)纯化得到2(410mg,21.9%)。1H NMR(400MHz,CDCl3):δ8.45(s,1H),8.33(s,1H),6.83(br,1H),4.69(d,J=4.4Hz,2H),2.71-2.78(m,1H),1.69-1.95(m,5H),1.60-1.65(m,2H),1.25-1.40(m,3H);
化学式:C12H16ClN3O2;分子量:269.73;LCMS:(ES+):m/z 270.1[M+1]+,tR=1.36min。步骤2:乙酸3-(((3-氯吡嗪-2-基)甲基)氨基甲酰基)环己酯(3)
将2(360mg,1.33mmol)和Ac2O(2.7g,26.60mmol)的吡啶(20mL)混合物在室温下搅拌18小时。反应混合物浓缩,残余物通过制备TLC(DCM/MeOH=15/1)纯化得到3(210mg,50.6%)。化学式:C14H18ClN3O3;分子量:311.77;LCMS:(ES+):m/z 312.1,314.1[M+1]+,tR=3.26min。
步骤3:乙酸3-(8-氯咪唑并[1,5-a]吡嗪-3-基)环己酯(4)
向3(210mg,0.67mmol)和DMF(49mg,0.67mmol)的ACN(10mL)混合物中加入POCl3(410mg,2.68mmol),并在室温下搅拌3小时。反应混合物用饱和NaHCO3淬灭至pH=10,用EA萃取。有机相用盐水洗涤,Na2SO4干燥,过滤,滤液浓缩得到4(180mg,91.4%)。1H NMR(400MHz,CDCl3):δ7.79(s,1H),7.61(d,J=4.8Hz,1H),7.33(d,J=4.8Hz,1H),5.28(m,1H),2.08-2.15(m,4H),1.88-2.04(m,4H),1.62-1.82(m,4H);化学式:C14H16ClN3O2;分子量:293.75;LCMS:(ES+):m/z 294.1,296.1[M+1]+,tR=3.73min。
步骤4:乙酸3-(1-溴-8-氯咪唑并[1,5-a]吡嗪-3-基)环己酯(5)
向4(180mg,0.61mmol)的THF(10mL)混合物中加入NBS(109mg,0.61mmol),并在室温下搅拌1小时。反应混合物用水淬灭,用EA萃取。有机相用盐水洗涤,Na2SO4干燥,过滤,滤液浓缩,残余物通过制备TLC(DCM/MeOH=15/1)纯化得到5(205mg,89.5%);化学式:C14H15BrClN3O2;分子量:372.65;LCMS:(ES+):m/z 372.0,374.0[M+1]+,tR=4.32min。
步骤5:3-(8-氨基-1-溴咪唑并[1,5-a]吡嗪-3-基)环己醇(6)
将5(205mg,0.55mmol)的85%的NH3(5mL)和i-PrOH(5mL)混合物加热至110℃,并搅拌6小时,然后冷却至室温。反应混合物浓缩,残余物溶于EA,用盐水洗涤,Na2SO4干燥,过滤,滤液浓缩得到6(145mg,84.8%)。化学式:C12H15BrN4O;分子量:311.18;LCMS:(ES+):m/z311,313[M+1]+,tR=2.39min。
步骤6:3-(8-氨基-1-(4-苯氧基苯基)咪唑并[1,5-a]吡嗪-3-基)环己醇(7)
将6(70mg,0.23mmol)、(4-苯氧基苯基)硼酸(96mg,0.45mmol)、Pd(dppf)Cl2·CH2Cl2(19mg,0.023mmol)和K2CO3(62mg,0.45mmol)的二氧六环(10mL)和水(2mL)混合物加热至100℃,并在N2条件下搅拌5小时,然后冷却至室温。反应混合物过滤,滤液浓缩。残余物通过制备HPLC纯化得到7(30mg,32.6%)。1H NMR(400MHz,d3-MeOD):δ7.59-7.61(m,3H),7.41(t,J=7.6Hz,2H),7.17(d,J=7.6Hz,1H),7.13(d,J=7.6Hz,2H),7.09(d,J=7.6Hz,2H),6.99(d,J=4.8Hz,1H),4.22(m,1H),3.54-3.60(m,1H),1.91-2.04(m,4H),1.74-1.82(m,2H),1.59-1.71(m,2H);化学式:C24H24N4O2;分子量:400.48;LCMS:(ES+):m/z 401.2[M+1]+,tR=3.22min。
实施例2
4-{8-氨基-1-[4-(2-氟-3-甲氧基-苯氧基)-苯基]-咪唑并[1,5-a]吡嗪-3-基}-环己醇
反应方案
步骤1:乙酸4-(((3-氯吡嗪-2-基)甲基)氨基甲酰基)环己酯(2)
在0℃下,向4-乙酰氧基环己烷-1-羧酸(207mg,1.11mmol)、(3-氯吡嗪-2-基)甲胺盐酸盐(1)(200mg,1.11mmol)、HATU(422mg,1.11mmol)的DCM(10mL)混合物中滴加TEA(449mg,4.44mmol)。30分钟后,将混合物在室温下搅拌1小时。反应混合物用水(20mL)淬灭,用DCM(20mL)萃取三次。合并的有机相用5%Na2CO3(30mL)、盐水(50mL)洗涤,无水硫酸钠干燥并过滤。滤液真空浓缩,并通过硅胶柱层析(DCM/MeOH=200:1-50:1)纯化得到产物2(246mg,收率71%)。1H-NMR(400MHz,CDCl3):δ8.46(d,J=2.3Hz,1H),8.34(d,J=2.3Hz,1H),6.84(s,1H),4.77–4.63(m,3H),2.80(s,1H),2.39–2.20(m,1H),2.14–2.08(m,1H),2.06(d,J=9.8Hz,5H),2.00–1.90(m,1H),1.87–1.77(m,1H),1.60(dd,J=12.6,8.1Hz,1H),1.44(dd,J=19.0,8.2Hz,1H)。
步骤2:乙酸4-(8-氯咪唑并[1,5-a]吡嗪-3-基)环己酯(3)
在冰水浴下,向2(246mg,0.79mmol)的MeCN(20mL)溶液和DMF(57mg,0.79mmol)中滴加POCl3(483mg,3.15mmol)。将反应混合物在室温下搅拌2小时。将反应混合物倒入pH=10的冰(20g)和氨水(10mL)的混合物中。混合物用DCM(30mL)萃取三次,合并的有机相用饱和NaHCO3(50mL)、水(50mL)和盐水(50mL)洗涤,Na2SO4干燥。除去溶剂得到粗品3(230mg,收率95%)。化学式:C14H16ClN3O2;分子量:293.8。LCMS:(ES+):m/z 294.1,296.2[M+1]+,tR=1.98min。
步骤3:乙酸4-(1-溴-8-氯咪唑并[1,5-a]吡嗪-3-基)环己酯(4)
在0℃下,向3(230mg,0.78mmol)的THF(10mL)溶液中加入NBS(137mg,0.78mmol)。将混合物在25℃下搅拌0.5小时,然后用水(50mL)稀释混合物溶液,用EA(30mL)萃取三次。有机相用碳酸氢钠(20mL)、水(20mL)和盐水(20mL)洗涤,Na2SO4干燥。通过旋转蒸发除去溶剂,并通过硅胶柱层析(DCM/MeOH=100:1)纯化得到4(265mg,收率91%)。1HNMR(400MHz,CDCl3):δ7.59(dd,J=5.0,2.2Hz,1H),7.29(d,J=5.0Hz,1H),4.89–4.70(m,1H),3.05–2.86(m,1H),2.24–2.13(m,2H),2.04(d,J=6.3Hz,4H),1.91(d,J=14.0Hz,1H),1.87–1.78(m,1H),1.77–1.63(m,1H),1.52(dt,J=24.0,6.5Hz,2H)。化学式:C14H15BrClN3O2;分子量:372.6;LCMS:(ES+):m/z 374.0[M+1]+,tR=2.30min。
步骤4:4-(8-氨基-1-溴咪唑并[1,5-a]吡嗪-3-基)环己-1-醇(5)
在封管中向4(265mg,0.71mmol)的异丙醇(5mL)溶液中加入氨水溶液(5.0mL),并将混合物在80℃搅拌5小时。将混合物溶液蒸干,用乙酸乙酯(50mL)稀释。有机相用水(20mL)和盐水(20mL)洗涤,Na2SO4干燥。除去溶剂得到粗品5(160mg,收率72%)。化学式:C12H15BrN4O;分子量:311.2;LCMS:(ES+):m/z 313.1,[M+1]+,tR=1.15min。
步骤5:4-(8-氨基-1-(4-(2-氟-3-甲氧基苯氧基)苯基)咪唑并[1,5-a]吡嗪-3-基)环己-1-醇(6)
将5(90mg,0.29mmol)、(4-(2-氟-3-甲氧基苯氧基)苯基)-硼酸(189mg,0.72mmol)、PdCl2(dppf)(42mg,0.058mmol)和碳酸钾(80mg,0.58mmol)的混合物在二氧六环(5.0mL)和水(1.0mL)中混合。将反应混合物在Ar条件下回流搅拌4小时。然后将混合物冷却至室温,过滤,用EA(20mL)洗涤三次。有机相用水(20mL)和盐水(20mL)洗涤,Na2SO4干燥。除去溶剂,用制备TLC(50:1)纯化得到6(20mg,收率20%)。1HNMR(400MHz,MeOD-d3):δ7.82(d,J=6.0Hz,1H),7.64(d,J=8.7Hz,2H),7.15(dd,J=14.0,5.3Hz,3H),7.05–6.94(m,2H),6.80(dd,J=11.1,4.1Hz,1H),3.71–3.60(m,1H),3.22–3.10(m,1H),2.14–2.00(m,4H),1.82(dt,J=13.7,6.9Hz,2H),1.57–1.44(m,2H)。化学式:C25H25FN4O3;分子量:448.5;LCMS:(ES+):m/z 449.3[M+1]+,tR=1.68min。
实施例3
N-{4-[1-(3-羟基-环己基)-1H-吡唑并[4,3-c]吡啶-3-基]-苄基}-2-甲氧基-苯甲酰胺
反应方案
步骤1:N-(4-(1H-吡唑并[4,3-c]吡啶-3-基)苄基)-2-甲氧基苯甲酰胺(3):
将2(228mg,0.77mmol)、2-甲氧基-N-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄基)苯甲酰胺(1,620mg,1.69mmol)、PdCl2(dppf)(56mg,0.077mmol)和碳酸钾(212mg,1.54mmol)的混合物在二氧六环(10mL)和水(2.0mL)中混合。将反应混合物在Ar条件下回流搅拌8小时。然后将混合物冷却至室温,过滤,用EA(20mL)洗涤三次。有机相用水(20mL)和盐水(20mL)洗涤,Na2SO4干燥。除去溶剂,用制备TLC纯化得到3(50mg,收率18%)。1H NMR(400MHz,CDCl3):δ10.86(s,1H),9.39(s,1H),8.47(d,J=5.4Hz,1H),8.40–8.26(m,2H),7.98(d,J=7.6Hz,2H),7.54(d,J=7.8Hz,2H),7.48(t,J=7.6Hz,1H),7.42(d,J=5.5Hz,1H),7.12(t,J=7.6Hz,1H),7.00(d,J=8.4Hz,1H),4.79(d,J=5.5Hz,2H),3.96(s,3H)。
化学式:C21H18N4O2;分子量:358.4;LC-MS:(ES+):m/z 359.2[M+H]+。tR=1.52min。
步骤2:N-(4-(1-(3-羟基环己基)-1H-吡唑并[4,3-c]吡啶-3-基)苄基)-2-甲氧基苯甲酰胺(4):
将3(50mg,0.14mmol)、3-羟基环己基-4-甲基苯-磺酸酯(76mg,0.28mmol)和Cs2CO3(132mg,0.40mmol)的DMF(5.0mL)混合物在80℃搅拌过夜。然后将混合物冷却至室温,并用水(10mL)淬灭。混合物用乙酸乙酯(20mL)萃取三次。合并的有机相用盐水(20mL)洗涤,无水硫酸钠干燥。过滤后,滤液减压浓缩,用制备TLC纯化得到4(6.0mg,收率2.8%)。1H NMR(400MHz,MeOD):δ9.29(s,1H),8.35(d,J=6.2Hz,1H),8.00(d,J=8.2Hz,2H),7.92(dd,J=7.7,1.7Hz,1H),7.71(d,J=6.1Hz,1H),7.56(d,J=8.1Hz,2H),7.54-7.47(m,1H),7.16(d,J=8.4Hz,1H),7.07(t,J=7.5Hz,1H),4.71(s,2H),3.98(s,3H),3.89-3.75(m,1H),2.31(d,J=11.6Hz,1H),2.02(ddd,J=19.4,18.2,7.5Hz,5H),1.67-1.51(m,1H),1.43-1.32(m,1H)。化学式:C27H28N4O3,分子量:456.5。LC-MS:(ES+):m/z 457.2[M+H]+。tR=1.62min。
实施例4至31按照上述实施例1至3的步骤制备:
BTK激酶测定
使用BTK激酶系统(Promega;目录号:V2941)和ADP-GloTM激酶测定试剂盒(Promega;目录号:V9101)进行BTK测定。使用384孔测定板(Corning;目录号:3570)在5μL的反应体积中进行测量。将6ng BTK酶、抑制剂或1%DMSO、1μg聚(Glu4,Tyr1)肽和50μM ATP在由40mM Tris-Cl(pH 7.5)、20mM MgCl2、0.1mg/mL BSA、50μM DTT和2mM MnCl2组成的反应缓冲液中温育一小时。按照ADP-GloTM激酶检测试剂盒中所述,使用5μL ADP-GloTM试剂和10μL激酶检测试剂来检测ADP。使用多功能酶标仪(多标记读板仪,Perkin Elmer)记录发光。发光信号与反应缓冲液中ADP量之间呈线性关系。对于每种化合物,在各种化合物浓度下测量酶活性,在不存在抑制剂的情况下进行阴性对照反应,重复三次,并且使用六组无酶对照来确定基线发光水平。生成量效曲线以确定BTK活性的IC50所需的浓度。
实施例32
下表示出了本发明所选化合物在BTK抑制测定中的活性。化合物编号对应上表中的化合物编号。活性表示为“A”的化合物的IC50≤10nM;活性表示为“B”的化合物的IC50为10nM-100nM;活性表示为“C”的化合物的IC50为100nM-1000nM;活性表示为“D”的化合物的IC50为1000nM-10000nM;活性表示为“E”的化合物的IC50≥10000nM。
Claims (10)
1.一种具有以下结构的式(I)或(II)的化合物、其异构体、其互变异构体、其药学上可接受的溶剂化物或其药学上可接受的前药:
其中:
A、B、G和D各自独立地为N或CR1,条件是仅A、B、G和D中的一个或两个可为N;
R1为氢、烷基、-OR1A、氨基、-OH、-CN、-NHOH、-NR1AR1B或-CONH2;
R2独立地为氢、卤素、-CZ3、-CHZ2、-CH2Z、-OCZ3、-OCH2Z、-OCHZ2、-CN、-SOnNR2AR2B、-NHC(O)NR2AR2B、-N(O)n、-NR2AR2B、-C(O)R2A、-C(O)-OR2A、-C(O)NR2AR2B、-SOnR2A、-OR2A、-NR2CSO2R2B、-NR2CC(O)R2A、-NR2CC(O)OR2A、-NR2AOR2B、取代或未取代的烷基其任选地被一至五个氟取代、取代或未取代的杂烷基其任选地被一至五个氟取代、取代或未取代的环烷基其任选地被一至五个氟取代、取代或未取代的杂环烷基其任选地被一至五个氟取代、取代或未取代的芳基、或取代或未取代的杂芳基,其中两个相邻的R2取代基可任选地连接以形成取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基或取代或未取代的杂芳基,并且y为0-5的整数;
M为取代或未取代的C1-6烷基、取代或未取代的C3-10环烷基、取代或未取代的C3-10环烯基、取代或未取代的3-10元杂环烷基、取代或未取代的3-10元杂环烯基和5-10元杂芳基,其中当M被取代时,其含有1-9个取代基,所述取代基在每次出现时独立地选自卤素、-OR2A、-NR2AR2B、=O、-CN、-C(O)OR2A、-OC(O)R2A、-C(O)NR2AR2B、-NR2CC(O)R2A、C1-6烷基、C1-6卤代烷基、被-OR2A取代的C1-6烷基、任选地被一至五个氟取代的C3-8环烷基、-SO2R2A、SO3R2A、C(O)R2A和3-8元杂环基;
-X-E为下列情况之一:(1)X为O、-OCR2AR2B-、-CR2AR2BO-、-S(O)-、-S(O)2-、-CR2AR2B-、-CR2AR2BNR2C(C=O)-、-CR2AR2B(C=O)NR2C-、-(C=O)NR2CCR2AR2B-、-NR2C(C=O)CR2AR2B-或键;并且E为氢、被一至五个R3取代基取代的芳基或杂芳基、或3-7元饱和或部分不饱和碳环、8-10元双环饱和或部分不饱和芳基环、具有1-4个独立地选自氮、氧或硫的杂原子的5-6元单环杂芳基环、具有1-3个独立地选自氮、氧或硫的杂原子的4-7元饱和或部分不饱和杂环、具有1-5个独立地选自氮、氧或硫的杂原子的7-10元双环饱和或部分不饱和杂环、或具有1-5个独立地选自氮、氧或硫的杂原子的8-10元双环杂芳基环;或(2)-X-E为氢、卤素、-OR2A、-O(CH2)1-4R2A、-CN、-NO2;
R1A、R1B、R2A、R2B和R2C各自独立地为氢、-CZ3、-CN、-COOH、-CONH2、-CHZ2、-CH2Z、取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、或取代或未取代的杂芳基,其中与同一氮原子相连的R1A和R1B取代基可任选地连接以形成取代或未取代的杂环烷基或取代或未取代的杂芳基,并且与同一氮原子相连的R2A和R2B取代基可任选地连接以形成取代或未取代的杂环烷基或取代或未取代的杂芳基;
Z独立地为-F、-Cl、-Br或-I;并且
n独立地为1-2的整数。
4.根据权利要求1所述的化合物,其中R2为H、F、Cl、OCH3、CH3,并且y为1或2。
5.根据权利要求1所述的化合物,其中A为CR1,并且B、G和D中的一个为N。
6.根据权利要求5所述的化合物,其中A为C-H或C-NH2。
7.根据权利要求6所述的化合物,其中B为N,并且G和D为C-H。
8.根据权利要求6所述的化合物,其中B为N,G为C-H,并且D为CR1。
10.根据权利要求1所述的化合物,其中所述化合物选自3-[8-氨基-1-(4-苯氧基-苯基)-咪唑并[1,5-a]吡嗪-3-基]-环己醇,
4-{8-氨基-1-[4-(2-氟-3-甲氧基-苯氧基)-苯基]-咪唑并[1,5-a]吡嗪-3-基}-环己醇,
N-{4-[1-(3-羟基-环己基)-1H-吡唑并[4,3-c]吡啶-3-基]-苄基}-2-甲氧基-苯甲酰胺,
(3-{8-氨基-1-[4-(2-氟-3-甲氧基-苯氧基)-苯基]-咪唑并[1,5-a]吡嗪-3-基}-环己醇,
4-[8-氨基-1-(4-苯氧基-苯基)-咪唑并[1,5-a]吡嗪-3-基]-环己醇,
4-{8-氨基-1-[4-(3-氯-2-氟-苯氧基)-苯基]-咪唑并[1,5-a]吡嗪-3-基}-环己醇,
4-{8-氨基-1-[4-(3-氯-苯氧基)-苯基]-咪唑并[1,5-a]吡嗪-3-基}-环己醇,
4-[8-氨基-1-(4-间甲苯氧基-苯基)-咪唑并[1,5-a]吡嗪-3-基]-环己醇,
4-{8-氨基-1-[4-(3-甲氧基-2-甲基-苯氧基)-苯基]-咪唑并[1,5-a]吡嗪-3-基}-环己醇,
N-{4-[1-(4-羟基-环己基)-1H-吡唑并[4,3-c]吡啶-3-基]-苄基}-2-甲氧基-苯甲酰胺,
N-{4-[8-氨基-3-(4-羟基-环己基)-咪唑并[1,5-a]吡嗪-1-基]-苄基}-2-甲氧基-苯甲酰胺,
N-{4-[8-氨基-3-(3-羟基-环己基)-咪唑并[1,5-a]吡嗪-1-基]-苄基}-2-甲氧基-苯甲酰胺,
N-[4-(8-氨基-3-环戊基-咪唑并[1,5-a]吡嗪-1-基)-苄基]-2-甲氧基-苯甲酰胺,
N-[4-(1-环戊基-1H-吡唑并[4,3-c]吡啶-3-基)-苄基]-2-甲氧基-苯甲酰胺,
3-[4-氨基-7-甲氧基-3-(4-苯氧基-苯基)-吡唑并[4,3-c]吡啶-1-基]-环己醇,
4-[4-氨基-7-甲氧基-3-(4-苯氧基-苯基)-吡唑并[4,3-c]吡啶-1-基]-环己醇,
3-{4-氨基-3-[4-(2-氟-3-甲氧基-苯氧基)-苯基]-7-甲氧基-吡唑并[4,3-c]吡啶-1-基}-环己醇,
4-{4-氨基-3-[4-(2-氟-3-甲氧基-苯氧基)-苯基]-7-甲氧基-吡唑并[4,3-c]吡啶-1-基}-环己醇,
1-环戊基-7-甲氧基-3-(4-苯氧基-苯基)-1H-吡唑并[4,3-c]吡啶-4-基胺,
3-{8-氨基-5-乙氧基-1-[4-(2-氟-3-甲氧基-苯氧基)-苯基]-咪唑并[1,5-a]吡嗪-3-基}-环己醇,
4-{8-氨基-5-乙氧基-1-[4-(2-氟-3-甲氧基-苯氧基)-苯基]-咪唑并[1,5-a]吡嗪-3-基}-环己醇,
4-[8-氨基-5-乙氧基-1-(4-苯氧基-苯基)-咪唑并[1,5-a]吡嗪-3-基]-环己醇,
3-环己基-5-乙氧基-1-(4-苯氧基-苯基)-咪唑并[1,5-a]吡嗪-8-基胺,
3-环戊基-5-乙氧基-1-[4-(2-氟-3-甲氧基-苯氧基)-苯基]-咪唑并[1,5-a]吡嗪-8-基胺,
N-{4-[8-氨基-5-乙氧基-3-(4-羟基-环己基)-咪唑并[1,5-a]吡嗪-1-基]-苄基}-2-甲氧基-苯甲酰胺,
N-[4-(8-氨基-3-环己基-5-乙氧基-咪唑并[1,5-a]吡嗪-1-基)-苄基]-2-甲氧基-苯甲酰胺,
N-[4-(8-氨基-3-环戊基-5-乙氧基-咪唑并[1,5-a]吡嗪-1-基)-苄基]-2-甲氧基-苯甲酰胺,
5-乙氧基-1-(4-苯氧基-苯基)-3-(四氢吡喃-4-基)-咪唑并[1,5-a]吡嗪-8-基胺,
3-[8-氨基-1-(4-苯氧基-苯基)-咪唑并[1,5-a]吡嗪-3-基]-环己烷甲酸,
4-(8-氨基-1-{4-[(2-甲氧基-苯甲酰基氨基)-甲基]-苯基}-咪唑并[1,5-a]吡嗪-3-基)-环己烷甲酸乙酯和,
N-{4-[8-氨基-3-(4-甲氧基-环己基)-咪唑并[1,5-a]吡嗪-1-基]-苄基}-2-甲氧基-苯甲酰胺。
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CN115443277A (zh) * | 2020-03-12 | 2022-12-06 | 重庆复尚源创医药技术有限公司 | 作为激酶抑制剂的化合物 |
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KR20210136995A (ko) | 2021-11-17 |
EP3911326A1 (en) | 2021-11-24 |
US20220064162A1 (en) | 2022-03-03 |
CA3126940A1 (en) | 2020-07-23 |
AU2020207953A1 (en) | 2021-08-26 |
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WO2020150681A1 (en) | 2020-07-23 |
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