CN117510484A - mIDH1/NAMPT双靶点抑制剂及其应用 - Google Patents
mIDH1/NAMPT双靶点抑制剂及其应用 Download PDFInfo
- Publication number
- CN117510484A CN117510484A CN202311494330.6A CN202311494330A CN117510484A CN 117510484 A CN117510484 A CN 117510484A CN 202311494330 A CN202311494330 A CN 202311494330A CN 117510484 A CN117510484 A CN 117510484A
- Authority
- CN
- China
- Prior art keywords
- compound
- ring
- cancer
- synthesis
- mmol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000003112 inhibitor Substances 0.000 title claims abstract description 44
- 102000015532 Nicotinamide phosphoribosyltransferase Human genes 0.000 title claims abstract 14
- 108010064862 Nicotinamide phosphoribosyltransferase Proteins 0.000 title claims abstract 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 325
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 42
- 239000003814 drug Substances 0.000 claims abstract description 18
- 239000002904 solvent Substances 0.000 claims abstract description 13
- 201000010099 disease Diseases 0.000 claims abstract description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 239000000651 prodrug Substances 0.000 claims abstract description 7
- 229940002612 prodrug Drugs 0.000 claims abstract description 7
- 206010005003 Bladder cancer Diseases 0.000 claims abstract description 3
- 206010005949 Bone cancer Diseases 0.000 claims abstract description 3
- 208000018084 Bone neoplasm Diseases 0.000 claims abstract description 3
- 208000003174 Brain Neoplasms Diseases 0.000 claims abstract description 3
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 3
- 208000005016 Intestinal Neoplasms Diseases 0.000 claims abstract description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 3
- 208000034578 Multiple myelomas Diseases 0.000 claims abstract description 3
- 206010033128 Ovarian cancer Diseases 0.000 claims abstract description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 claims abstract description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims abstract description 3
- 206010035226 Plasma cell myeloma Diseases 0.000 claims abstract description 3
- 206010060862 Prostate cancer Diseases 0.000 claims abstract description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims abstract description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 claims abstract description 3
- 208000024313 Testicular Neoplasms Diseases 0.000 claims abstract description 3
- 206010057644 Testis cancer Diseases 0.000 claims abstract description 3
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims abstract description 3
- 206010017758 gastric cancer Diseases 0.000 claims abstract description 3
- 201000010536 head and neck cancer Diseases 0.000 claims abstract description 3
- 208000014829 head and neck neoplasm Diseases 0.000 claims abstract description 3
- 201000002313 intestinal cancer Diseases 0.000 claims abstract description 3
- 208000032839 leukemia Diseases 0.000 claims abstract description 3
- 201000007270 liver cancer Diseases 0.000 claims abstract description 3
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 3
- 201000005202 lung cancer Diseases 0.000 claims abstract description 3
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims abstract description 3
- 201000004228 ovarian endometrial cancer Diseases 0.000 claims abstract description 3
- 201000002528 pancreatic cancer Diseases 0.000 claims abstract description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 claims abstract description 3
- 201000011549 stomach cancer Diseases 0.000 claims abstract description 3
- 201000003120 testicular cancer Diseases 0.000 claims abstract description 3
- 201000005112 urinary bladder cancer Diseases 0.000 claims abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 46
- 229920006395 saturated elastomer Polymers 0.000 claims description 37
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 33
- 125000000623 heterocyclic group Chemical group 0.000 claims description 30
- -1 amino, hydroxyl Chemical group 0.000 claims description 23
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
- 229910052757 nitrogen Inorganic materials 0.000 claims description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 19
- 150000002367 halogens Chemical class 0.000 claims description 19
- 150000001336 alkenes Chemical class 0.000 claims description 15
- 150000001408 amides Chemical class 0.000 claims description 15
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 13
- 101100344720 Caenorhabditis elegans mdh-1 gene Proteins 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 125000005842 heteroatom Chemical group 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 239000011593 sulfur Substances 0.000 claims description 8
- 201000011510 cancer Diseases 0.000 claims description 7
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 6
- 150000001555 benzenes Chemical group 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- MEAAWTRWNWSLPF-UHFFFAOYSA-N 2-phenoxypyridine Chemical group C=1C=CC=NC=1OC1=CC=CC=C1 MEAAWTRWNWSLPF-UHFFFAOYSA-N 0.000 claims description 3
- 125000004399 C1-C4 alkenyl group Chemical group 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 125000004450 alkenylene group Chemical group 0.000 claims description 3
- 150000001345 alkine derivatives Chemical class 0.000 claims description 3
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- 125000003368 amide group Chemical group 0.000 claims description 3
- 125000005605 benzo group Chemical group 0.000 claims description 3
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 230000009977 dual effect Effects 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 230000001404 mediated effect Effects 0.000 claims description 3
- 229960005141 piperazine Drugs 0.000 claims description 3
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 229960001948 caffeine Drugs 0.000 claims 1
- 239000012453 solvate Substances 0.000 claims 1
- RYYVLZVUVIJVGH-UHFFFAOYSA-N trimethylxanthine Natural products CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 18
- 229940079593 drug Drugs 0.000 abstract description 13
- 230000008499 blood brain barrier function Effects 0.000 abstract description 8
- 210000001218 blood-brain barrier Anatomy 0.000 abstract description 8
- 230000007547 defect Effects 0.000 abstract description 3
- 230000035755 proliferation Effects 0.000 abstract description 3
- 206010059866 Drug resistance Diseases 0.000 abstract description 2
- 231100000053 low toxicity Toxicity 0.000 abstract description 2
- 230000003211 malignant effect Effects 0.000 abstract description 2
- 239000012466 permeate Substances 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 description 172
- 238000003786 synthesis reaction Methods 0.000 description 172
- 239000007787 solid Substances 0.000 description 81
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 69
- 238000006243 chemical reaction Methods 0.000 description 52
- 239000000243 solution Substances 0.000 description 50
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
- 239000012074 organic phase Substances 0.000 description 25
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 23
- 239000000843 powder Substances 0.000 description 21
- 239000000203 mixture Substances 0.000 description 19
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
- 238000003818 flash chromatography Methods 0.000 description 17
- VUVORVXMOLQFMO-ONEGZZNKSA-N (e)-3-pyridin-3-ylprop-2-enoic acid Chemical compound OC(=O)\C=C\C1=CC=CN=C1 VUVORVXMOLQFMO-ONEGZZNKSA-N 0.000 description 16
- 241001465754 Metazoa Species 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 16
- 210000004027 cell Anatomy 0.000 description 15
- 238000001308 synthesis method Methods 0.000 description 14
- 238000003756 stirring Methods 0.000 description 13
- TWYYFYNJOJGNFP-CUXYNZQBSA-N (2s,4r,5s,6s)-2-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-2-carbamoyl-4-[[(e,4s,6s)-4,6-dimethyloct-2-enoyl]oxymethyl]-5-hydroxy-1,3-dioxane-4,5,6-tricarboxylic acid Chemical compound O1[C@H](C(O)=O)[C@](C(O)=O)(O)[C@](COC(=O)/C=C/[C@@H](C)C[C@@H](C)CC)(C(O)=O)O[C@]1(C(N)=O)CCC(=C)[C@@H](OC(C)=O)[C@H](C)CC1=CC=CC=C1 TWYYFYNJOJGNFP-CUXYNZQBSA-N 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 238000000034 method Methods 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- 108090000790 Enzymes Proteins 0.000 description 10
- 102000004190 Enzymes Human genes 0.000 description 10
- 241000699660 Mus musculus Species 0.000 description 10
- 238000012544 monitoring process Methods 0.000 description 10
- 238000011580 nude mouse model Methods 0.000 description 10
- 102200069690 rs121913500 Human genes 0.000 description 10
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 9
- KPBNHDGDUADAGP-VAWYXSNFSA-N FK-866 Chemical compound C=1C=CN=CC=1/C=C/C(=O)NCCCCC(CC1)CCN1C(=O)C1=CC=CC=C1 KPBNHDGDUADAGP-VAWYXSNFSA-N 0.000 description 9
- 239000004698 Polyethylene Substances 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
- DCGDPJCUIKLTDU-SUNYJGFJSA-N (4r)-4-[(1s)-1-fluoroethyl]-3-[2-[[(1s)-1-[4-methyl-5-[2-(trifluoromethyl)pyridin-4-yl]pyridin-2-yl]ethyl]amino]pyrimidin-4-yl]-1,3-oxazolidin-2-one Chemical compound C[C@H](F)[C@H]1COC(=O)N1C1=CC=NC(N[C@@H](C)C=2N=CC(=C(C)C=2)C=2C=C(N=CC=2)C(F)(F)F)=N1 DCGDPJCUIKLTDU-SUNYJGFJSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 102100039905 Isocitrate dehydrogenase [NADP] cytoplasmic Human genes 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 238000011065 in-situ storage Methods 0.000 description 7
- 230000004083 survival effect Effects 0.000 description 7
- WLWNRAWQDZRXMB-YLFCFFPRSA-N (2r,3r,4r,5s)-n,3,4,5-tetrahydroxy-1-(4-phenoxyphenyl)sulfonylpiperidine-2-carboxamide Chemical compound ONC(=O)[C@H]1[C@@H](O)[C@H](O)[C@@H](O)CN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 WLWNRAWQDZRXMB-YLFCFFPRSA-N 0.000 description 6
- 101001042041 Bos taurus Isocitrate dehydrogenase [NAD] subunit beta, mitochondrial Proteins 0.000 description 6
- 101000960234 Homo sapiens Isocitrate dehydrogenase [NADP] cytoplasmic Proteins 0.000 description 6
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000000890 drug combination Substances 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 239000011259 mixed solution Substances 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- QVHJQCGUWFKTSE-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound OC(=O)C(C)NC(=O)OC(C)(C)C QVHJQCGUWFKTSE-UHFFFAOYSA-N 0.000 description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 4
- LJIOTBMDLVHTBO-CUYJMHBOSA-N (2s)-2-amino-n-[(1r,2r)-1-cyano-2-[4-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]phenyl]cyclopropyl]butanamide Chemical compound CC[C@H](N)C(=O)N[C@]1(C#N)C[C@@H]1C1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)N2CCN(C)CC2)C=C1 LJIOTBMDLVHTBO-CUYJMHBOSA-N 0.000 description 4
- VUDZSIYXZUYWSC-DBRKOABJSA-N (4r)-1-[(2r,4r,5r)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one Chemical compound FC1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N[C@H](O)CC1 VUDZSIYXZUYWSC-DBRKOABJSA-N 0.000 description 4
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 description 4
- KPGXRSRHYNQIFN-UHFFFAOYSA-L 2-oxoglutarate(2-) Chemical compound [O-]C(=O)CCC(=O)C([O-])=O KPGXRSRHYNQIFN-UHFFFAOYSA-L 0.000 description 4
- RXCVUHMIWHRLDF-HXUWFJFHSA-N 5,8-dichloro-2-[(4-methoxy-6-methyl-2-oxo-1H-pyridin-3-yl)methyl]-7-[(R)-methoxy(oxetan-3-yl)methyl]-3,4-dihydroisoquinolin-1-one Chemical compound ClC1=C2CCN(C(C2=C(C(=C1)[C@@H](C1COC1)OC)Cl)=O)CC=1C(NC(=CC=1OC)C)=O RXCVUHMIWHRLDF-HXUWFJFHSA-N 0.000 description 4
- QCMHGCDOZLWPOT-FMNCTDSISA-N COC1=C(CC[C@@H]2CCC3=C(C2)C=CC(=C3)[C@H]2CC[C@](N)(CO)C2)C=CC=C1 Chemical compound COC1=C(CC[C@@H]2CCC3=C(C2)C=CC(=C3)[C@H]2CC[C@](N)(CO)C2)C=CC=C1 QCMHGCDOZLWPOT-FMNCTDSISA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 4
- 239000007853 buffer solution Substances 0.000 description 4
- 238000006911 enzymatic reaction Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 239000012452 mother liquor Substances 0.000 description 4
- 230000001575 pathological effect Effects 0.000 description 4
- 102200069708 rs121913499 Human genes 0.000 description 4
- 239000011550 stock solution Substances 0.000 description 4
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 4
- MSSQOQPKGAMUSY-LEAFIULHSA-N 2-[1-[2-[(4r,6s)-8-chloro-6-(2,3-dimethoxyphenyl)-4,6-dihydropyrrolo[1,2-a][4,1]benzoxazepin-4-yl]acetyl]piperidin-4-yl]acetic acid Chemical compound COC1=CC=CC([C@@H]2C3=CC(Cl)=CC=C3N3C=CC=C3[C@@H](CC(=O)N3CCC(CC(O)=O)CC3)O2)=C1OC MSSQOQPKGAMUSY-LEAFIULHSA-N 0.000 description 3
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 3
- HWXBTNAVRSUOJR-UHFFFAOYSA-N 2-hydroxyglutaric acid Chemical compound OC(=O)C(O)CCC(O)=O HWXBTNAVRSUOJR-UHFFFAOYSA-N 0.000 description 3
- MBEPWLCDXKKANL-UHFFFAOYSA-N 2-pyridin-3-yloxyacetic acid Chemical compound OC(=O)COC1=CC=CN=C1 MBEPWLCDXKKANL-UHFFFAOYSA-N 0.000 description 3
- HNFMVVHMKGFCMB-UHFFFAOYSA-N 3-[3-[4-(1-aminocyclobutyl)phenyl]-5-phenylimidazo[4,5-b]pyridin-2-yl]pyridin-2-amine Chemical compound NC1=NC=CC=C1C1=NC2=CC=C(C=3C=CC=CC=3)N=C2N1C1=CC=C(C2(N)CCC2)C=C1 HNFMVVHMKGFCMB-UHFFFAOYSA-N 0.000 description 3
- ZDHQVQVNOIWLNX-UHFFFAOYSA-N 5-(7-chloro-10h-benzo[1,2]cyclohepta[2,4-c][1,3]thiazol-10-yl)-1-methyl-4-sulfanylidenepyrimidin-2-one Chemical compound S=C1NC(=O)N(C)C=C1C1C2=CC=C(Cl)C=C2C=CC2=C1N=CS2 ZDHQVQVNOIWLNX-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 241000283690 Bos taurus Species 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- 239000007821 HATU Substances 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 201000007983 brain glioma Diseases 0.000 description 3
- 210000005013 brain tissue Anatomy 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 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
- 229940125876 compound 15a Drugs 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 230000005284 excitation Effects 0.000 description 3
- 210000002216 heart Anatomy 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 235000005152 nicotinamide Nutrition 0.000 description 3
- 239000011570 nicotinamide Substances 0.000 description 3
- 229960003966 nicotinamide Drugs 0.000 description 3
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 3
- 230000035515 penetration Effects 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 210000000952 spleen Anatomy 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- JQSHBVHOMNKWFT-DTORHVGOSA-N varenicline Chemical compound C12=CC3=NC=CN=C3C=C2[C@H]2C[C@@H]1CNC2 JQSHBVHOMNKWFT-DTORHVGOSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- AEVBPXDFDKBGLT-YOUFYPILSA-N (2s,3s,4r,5r)-n-[2-[4-(diethoxyphosphorylmethyl)anilino]-2-oxoethyl]-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolane-2-carboxamide Chemical compound C1=CC(CP(=O)(OCC)OCC)=CC=C1NC(=O)CNC(=O)[C@@H]1[C@@H](O)[C@@H](O)[C@H](N2C(NC(=O)C=C2)=O)O1 AEVBPXDFDKBGLT-YOUFYPILSA-N 0.000 description 2
- YBUPWRYTXGAWJX-RXMQYKEDSA-N (4s)-4-propan-2-yl-1,3-oxazolidin-2-one Chemical compound CC(C)[C@H]1COC(=O)N1 YBUPWRYTXGAWJX-RXMQYKEDSA-N 0.000 description 2
- WIKBZUXHNPONPP-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoro-2-iodo-2-(trifluoromethyl)propane Chemical compound FC(F)(F)C(I)(C(F)(F)F)C(F)(F)F WIKBZUXHNPONPP-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- JWOHBPPVVDQMKB-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-4-carboxylic acid Chemical group CC(C)(C)OC(=O)N1CCC(C(O)=O)CC1 JWOHBPPVVDQMKB-UHFFFAOYSA-N 0.000 description 2
- HRMRQBJUFWFQLX-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-3-carboxylic acid Chemical group CC(C)(C)OC(=O)N1CCC(C(O)=O)C1 HRMRQBJUFWFQLX-UHFFFAOYSA-N 0.000 description 2
- BTTNYQZNBZNDOR-UHFFFAOYSA-N 2,4-dichloropyrimidine Chemical compound ClC1=CC=NC(Cl)=N1 BTTNYQZNBZNDOR-UHFFFAOYSA-N 0.000 description 2
- NTCXGMREWSJCRG-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonyl]pentanoic acid Chemical compound CCCC(C(O)=O)C(=O)OC(C)(C)C NTCXGMREWSJCRG-UHFFFAOYSA-N 0.000 description 2
- VRPJIFMKZZEXLR-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical group CC(C)(C)OC(=O)NCC(O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 description 2
- CFWRDBDJAOHXSH-SECBINFHSA-N 2-azaniumylethyl [(2r)-2,3-diacetyloxypropyl] phosphate Chemical compound CC(=O)OC[C@@H](OC(C)=O)COP(O)(=O)OCCN CFWRDBDJAOHXSH-SECBINFHSA-N 0.000 description 2
- HCLQARMRCPEALF-DNQXCXABSA-N 3-[[(2r)-2-[(1r)-2-[[1-(1-benzothiophen-2-yl)-2-methylpropan-2-yl]amino]-1-hydroxyethyl]pyrrolidin-1-yl]methyl]benzonitrile Chemical compound C([C@@H]1[C@H](O)CNC(C)(CC=2SC3=CC=CC=C3C=2)C)CCN1CC1=CC=CC(C#N)=C1 HCLQARMRCPEALF-DNQXCXABSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- KCBAMQOKOLXLOX-BSZYMOERSA-N CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O Chemical compound CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O KCBAMQOKOLXLOX-BSZYMOERSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 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
- 108010075869 Isocitrate Dehydrogenase Proteins 0.000 description 2
- 102000012011 Isocitrate Dehydrogenase Human genes 0.000 description 2
- 101710102690 Isocitrate dehydrogenase [NADP] cytoplasmic Proteins 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical group C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- PLXBWHJQWKZRKG-UHFFFAOYSA-N Resazurin Chemical compound C1=CC(=O)C=C2OC3=CC(O)=CC=C3[N+]([O-])=C21 PLXBWHJQWKZRKG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- NPUXORBZRBIOMQ-RUZDIDTESA-N [(2R)-1-[[4-[[3-(benzenesulfonylmethyl)-5-methylphenoxy]methyl]phenyl]methyl]-2-pyrrolidinyl]methanol Chemical compound C=1C(OCC=2C=CC(CN3[C@H](CCC3)CO)=CC=2)=CC(C)=CC=1CS(=O)(=O)C1=CC=CC=C1 NPUXORBZRBIOMQ-RUZDIDTESA-N 0.000 description 2
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 229940125833 compound 23 Drugs 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- SNRUBQQJIBEYMU-UHFFFAOYSA-N dodecane Chemical compound CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000003304 gavage Methods 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 description 2
- ODBLHEXUDAPZAU-UHFFFAOYSA-N isocitric acid Chemical compound OC(=O)C(O)C(C(O)=O)CC(O)=O ODBLHEXUDAPZAU-UHFFFAOYSA-N 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- YRCHYHRCBXNYNU-UHFFFAOYSA-N n-[[3-fluoro-4-[2-[5-[(2-methoxyethylamino)methyl]pyridin-2-yl]thieno[3,2-b]pyridin-7-yl]oxyphenyl]carbamothioyl]-2-(4-fluorophenyl)acetamide Chemical compound N1=CC(CNCCOC)=CC=C1C1=CC2=NC=CC(OC=3C(=CC(NC(=S)NC(=O)CC=4C=CC(F)=CC=4)=CC=3)F)=C2S1 YRCHYHRCBXNYNU-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000002360 preparation method Methods 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
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229930195734 saturated hydrocarbon Natural products 0.000 description 2
- 239000012086 standard solution Substances 0.000 description 2
- 239000012089 stop solution Substances 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 230000004580 weight loss Effects 0.000 description 2
- 239000012224 working solution Substances 0.000 description 2
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 2
- SOZMSEPDYJGBEK-LURJTMIESA-N (1s)-1-(4-bromophenyl)ethanamine Chemical compound C[C@H](N)C1=CC=C(Br)C=C1 SOZMSEPDYJGBEK-LURJTMIESA-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
- 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
- ITOFPJRDSCGOSA-KZLRUDJFSA-N (2s)-2-[[(4r)-4-[(3r,5r,8r,9s,10s,13r,14s,17r)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H](CC[C@]13C)[C@@H]2[C@@H]3CC[C@@H]1[C@H](C)CCC(=O)N[C@H](C(O)=O)CC1=CNC2=CC=CC=C12 ITOFPJRDSCGOSA-KZLRUDJFSA-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
- 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
- NSFJAFZHYOAMHL-UHFFFAOYSA-N (4-nitrophenyl)boronic acid Chemical compound OB(O)C1=CC=C([N+]([O-])=O)C=C1 NSFJAFZHYOAMHL-UHFFFAOYSA-N 0.000 description 1
- QDMNNMIOWVJVLY-MRVPVSSYSA-N (4s)-4-phenyl-1,3-oxazolidin-2-one Chemical compound C1OC(=O)N[C@H]1C1=CC=CC=C1 QDMNNMIOWVJVLY-MRVPVSSYSA-N 0.000 description 1
- UVNPEUJXKZFWSJ-LMTQTHQJSA-N (R)-N-[(4S)-8-[6-amino-5-[(3,3-difluoro-2-oxo-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]pyrazin-2-yl]-2-oxa-8-azaspiro[4.5]decan-4-yl]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@@](=O)N[C@@H]1COCC11CCN(CC1)c1cnc(Sc2ccnc3NC(=O)C(F)(F)c23)c(N)n1 UVNPEUJXKZFWSJ-LMTQTHQJSA-N 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
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- IDZRAUUUHXQGKC-UHFFFAOYSA-N 1-(5-bromopyridin-2-yl)ethanone Chemical compound CC(=O)C1=CC=C(Br)C=N1 IDZRAUUUHXQGKC-UHFFFAOYSA-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
- WGMHMVLZFAJNOT-UHFFFAOYSA-N 1-ethoxyethylideneazanium;chloride Chemical compound [Cl-].CCOC(C)=[NH2+] WGMHMVLZFAJNOT-UHFFFAOYSA-N 0.000 description 1
- SINFYKZXNIJIEU-UHFFFAOYSA-N 1h-pyrrolo[2,3-b]pyridine-5-carboxylic acid Chemical compound OC(=O)C1=CN=C2NC=CC2=C1 SINFYKZXNIJIEU-UHFFFAOYSA-N 0.000 description 1
- GHXBPCSSQOKKGB-UHFFFAOYSA-N 2,4-dichloro-7h-pyrrolo[2,3-d]pyrimidine Chemical compound ClC1=NC(Cl)=C2C=CNC2=N1 GHXBPCSSQOKKGB-UHFFFAOYSA-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
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 description 1
- CESUXLKAADQNTB-ZETCQYMHSA-N 2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@@](N)=O CESUXLKAADQNTB-ZETCQYMHSA-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
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- 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 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
- RAEVOBPXEHVUFY-LURJTMIESA-N 4187-53-5 Chemical compound C[C@H](N)C1=CC=C([N+]([O-])=O)C=C1 RAEVOBPXEHVUFY-LURJTMIESA-N 0.000 description 1
- PQGCEDQWHSBAJP-TXICZTDVSA-N 5-O-phosphono-alpha-D-ribofuranosyl diphosphate Chemical compound O[C@H]1[C@@H](O)[C@@H](O[P@](O)(=O)OP(O)(O)=O)O[C@@H]1COP(O)(O)=O PQGCEDQWHSBAJP-TXICZTDVSA-N 0.000 description 1
- VKLKXFOZNHEBSW-UHFFFAOYSA-N 5-[[3-[(4-morpholin-4-ylbenzoyl)amino]phenyl]methoxy]pyridine-3-carboxamide Chemical compound O1CCN(CC1)C1=CC=C(C(=O)NC=2C=C(COC=3C=NC=C(C(=O)N)C=3)C=CC=2)C=C1 VKLKXFOZNHEBSW-UHFFFAOYSA-N 0.000 description 1
- ZQVLPMNLLKGGIU-UHFFFAOYSA-N 5-bromopyridine-2-carbaldehyde Chemical compound BrC1=CC=C(C=O)N=C1 ZQVLPMNLLKGGIU-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 238000011729 BALB/c nude mouse Methods 0.000 description 1
- LSPHULWDVZXLIL-UHFFFAOYSA-N Camphoric acid Natural products CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 1
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-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
- 101000960235 Dictyostelium discoideum Isocitrate dehydrogenase [NADP] cytoplasmic Proteins 0.000 description 1
- 101710177984 Isocitrate dehydrogenase [NADP] Proteins 0.000 description 1
- 101710175291 Isocitrate dehydrogenase [NADP], mitochondrial Proteins 0.000 description 1
- 101710157228 Isoepoxydon dehydrogenase patN Proteins 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- MDXGYYOJGPFFJL-QMMMGPOBSA-N N(alpha)-t-butoxycarbonyl-L-leucine Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)OC(C)(C)C MDXGYYOJGPFFJL-QMMMGPOBSA-N 0.000 description 1
- NUGPIZCTELGDOS-QHCPKHFHSA-N N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclopentanecarboxamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CC[C@@H](C=1C=NC=CC=1)NC(=O)C1CCCC1)C NUGPIZCTELGDOS-QHCPKHFHSA-N 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- JLEBZPBDRKPWTD-TURQNECASA-O N-ribosylnicotinamide Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](CO)O2)O)=C1 JLEBZPBDRKPWTD-TURQNECASA-O 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
- 101800000628 PDH precursor-related peptide Proteins 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- SIOXPEMLGUPBBT-UHFFFAOYSA-N Picolinic acid Natural products OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 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
- 102000004357 Transferases Human genes 0.000 description 1
- 108090000992 Transferases Proteins 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- WREOTYWODABZMH-DTZQCDIJSA-N [[(2r,3s,4r,5r)-3,4-dihydroxy-5-[2-oxo-4-(2-phenylethoxyamino)pyrimidin-1-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N(C=C\1)C(=O)NC/1=N\OCCC1=CC=CC=C1 WREOTYWODABZMH-DTZQCDIJSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 150000001294 alanine derivatives Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 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
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000001348 anti-glioma Effects 0.000 description 1
- 235000003704 aspartic acid Nutrition 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
- 230000004888 barrier function Effects 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- LSPHULWDVZXLIL-QUBYGPBYSA-N camphoric acid Chemical compound CC1(C)[C@H](C(O)=O)CC[C@]1(C)C(O)=O LSPHULWDVZXLIL-QUBYGPBYSA-N 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940125904 compound 1 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
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 231100000371 dose-limiting toxicity Toxicity 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229940100242 glycol stearate Drugs 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002632 lipids 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
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- YGBMCLDVRUGXOV-UHFFFAOYSA-N n-[6-[6-chloro-5-[(4-fluorophenyl)sulfonylamino]pyridin-3-yl]-1,3-benzothiazol-2-yl]acetamide Chemical compound C1=C2SC(NC(=O)C)=NC2=CC=C1C(C=1)=CN=C(Cl)C=1NS(=O)(=O)C1=CC=C(F)C=C1 YGBMCLDVRUGXOV-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000018791 negative regulation of catalytic activity Effects 0.000 description 1
- 235000020956 nicotinamide riboside Nutrition 0.000 description 1
- 239000011618 nicotinamide riboside Substances 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 231100000590 oncogenic Toxicity 0.000 description 1
- 230000002246 oncogenic effect Effects 0.000 description 1
- 238000005895 oxidative decarboxylation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229950010131 puromycin Drugs 0.000 description 1
- NIPZZXUFJPQHNH-UHFFFAOYSA-N pyrazine-2-carboxylic acid Chemical compound OC(=O)C1=CN=CC=N1 NIPZZXUFJPQHNH-UHFFFAOYSA-N 0.000 description 1
- HDOUGSFASVGDCS-UHFFFAOYSA-N pyridin-3-ylmethanamine Chemical compound NCC1=CC=CN=C1 HDOUGSFASVGDCS-UHFFFAOYSA-N 0.000 description 1
- WFLNXIGGSFCTBB-UHFFFAOYSA-N pyridine-2-carboxylic acid Chemical compound N1=C(C=CC=C1)C(=O)O.N1=C(C=CC=C1)C(=O)O.N1=C(C=CC=C1)C(=O)O WFLNXIGGSFCTBB-UHFFFAOYSA-N 0.000 description 1
- IIVUJUOJERNGQX-UHFFFAOYSA-N pyrimidine-5-carboxylic acid Chemical compound OC(=O)C1=CN=CN=C1 IIVUJUOJERNGQX-UHFFFAOYSA-N 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 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 1
- 210000005084 renal tissue Anatomy 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- XZPVPNZTYPUODG-UHFFFAOYSA-M sodium;chloride;dihydrate Chemical class O.O.[Na+].[Cl-] XZPVPNZTYPUODG-UHFFFAOYSA-M 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- MXSNQMUVXLVDHI-UHFFFAOYSA-N tert-butyl n-butylcarbamate Chemical group CCCCNC(=O)OC(C)(C)C MXSNQMUVXLVDHI-UHFFFAOYSA-N 0.000 description 1
- USFPINLPPFWTJW-UHFFFAOYSA-N tetraphenylphosphonium Chemical compound C1=CC=CC=C1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 USFPINLPPFWTJW-UHFFFAOYSA-N 0.000 description 1
- 238000009210 therapy by ultrasound Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000004102 tricarboxylic acid cycle Effects 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种mIDH1/NAMPT双靶点抑制剂，选自结构如式I或式Ⅱ所示的化合物或其药学上可接受的盐、外消旋体、立体异构体、前药或溶剂化合物。本发明双靶点抑制剂能有效克服单一型mIDH1抑制剂和单一型NAMPT抑制剂对实体瘤疗效差的缺点，能抑制肿瘤的恶性增殖，治疗效果好、毒性低、不易产生耐药性且可透过血脑屏障，可用于制备治疗癌症或肿瘤相关疾病药物，所述的癌症或肿瘤相关疾病包括多发性骨髓瘤、白血病、乳腺癌、前列腺癌、肺癌、肝癌、胃癌、骨癌、脑癌、头颈癌、肠癌、胰腺癌、膀胱癌、睾丸癌、卵巢癌以及子宫内膜癌。
Description
技术领域
本发明属于药物化学领域，涉及一类mIDH1/NAMPT双靶点抑制剂及其应用。
背景技术
异柠檬酸脱氢酶(isocitrate dehydrogenase,IDH)是参与三羧酸循环的关键代谢酶，野生型蛋白质催化异柠檬酸氧化脱羧为α-酮戊二酸(α-KG)，同时生成CO2和NADPH。研究者已经在多种癌症类型中鉴别出IDH1突变(主要存在于细胞质)，突变常发生于IDH1的第132位，突变的IDH1(mIDH1)获得了新的催化活性，将α-KG进一步转化为2-羟基戊二酸(2-HG)，同时将NADPH氧化为NADP+。2-HG是致癌代谢物，大量累积会诱发肿瘤的发生、发展。因此，选择性的抑制mIDH1是治疗癌症的一个安全有效的治疗策略。目前，选择性mIDH1抑制剂艾伏尼布(AG-120)和奥卢他昔尼(FT-2102)已经被FDA批准用于急性髓系白血病(AML)的治疗。然而，现有mIDH1抑制剂对实体瘤的治疗效果较差，且对mIDH1抑制剂的耐药性已经出现并且日益严重。
烟酰胺磷酸核糖转移酶(NAMPT)布于细胞质，是NAD+补救合成途径中的关键限速酶，在肿瘤中高表达，为肿瘤持续提供生长所必需的NAD+，与肿瘤生长密切相关。因此，选择性的抑制NAMPT也是治疗癌症的有效策略。然而，NAMPT抑制剂作为单一药物治疗实体瘤和血液瘤的临床试验结果显示，其剂量限制毒性会导致抗肿瘤效果不佳，目前还没有一款选择性的NAMPT抑制剂被FDA批准用于癌症的治疗。
基于以上研究现状，需要具有同时抑制mIDH1和NAMPT的小分子抑制剂用于治疗各种癌症。
发明内容
本发明的目的是提供一种能透脑的且能有效解决单一型mIDH1抑制剂和单一型NAMPT抑制剂对实体瘤疗效差等缺点的双靶点抑制剂。
本发明的目的是通过以下技术方案实现的：
作为本发明的其中一个技术方案，mIDH1/NAMPT双靶点抑制剂，选自结构如式I所示的化合物或其药学上可接受的盐、外消旋体、立体异构体、前药或溶剂化合物：
其中，环A选自取代或未取代的6元饱和或不饱和杂环、苯环并5元饱和或不饱和杂环或5-6元饱和或不饱和杂环并5-6元饱和或不饱和杂环；5-6元饱和或不饱和杂环的取代基为卤素、氨基、羟基、羧基、氰基、烯烃、酰胺中的至少一种；6元饱和或不饱和杂环、苯环并5元饱和或不饱和杂环、5-6元饱和或不饱和杂环并5-6元饱和或不饱和杂环中的杂原子选自氧原子、氮原子；
X选自直链或支链的亚烷基链、1,4-哌嗪亚基或1,3-吡咯烷亚基；X可被以下基团中的一个、多个或任意组合中断一或多次：-O-、-CONH-、NHCO-、-NHCONH-、-NH-、-S-、亚烯基，X的氢可被以下一个或多个基团取代：卤素、氨基、羟基、羧基、酰胺、氰基、烯烃、炔烃、C1-C4烷氧基、C1-C6烷基；
L选自共价键、取代或未取代的苯环、5-6元杂环或C1-C4烯基、C1-C4烷氧基、C1-C4酰胺基；苯环的取代基为卤素、氨基、羟基、羧基、氰基、烯烃、酰胺中的至少一种；
环B选自取代或未取代的苯环、5-6元饱和或不饱和杂环；苯环的取代基为卤素、氨基、羟基、羧基、氰基、烯烃、酰胺中的至少一种；5-6元饱和或不饱和杂环中含有1-2个杂原子，杂原子选自氧原子、氮原子；
R4选自氢或C1-C4烷基；
R5选自卤素、C1-C4烷基、取代或未取代苯基、羟基或叔丁氧基，苯环的取代基为卤素、氨基、羟基、羧基、氰基、烯烃、酰胺中的至少一种；
或R4与R5组合构成苯环。
优选地，结构如式I所示的化合物中，环A选自：
X选自： m＝0-8的整数，具体的，m＝0、1、2、3、4、5、6、7、8；n＝0-8的整数，具体的，n＝0、1、2、3、4、5、6、7、8；p＝0-8的整数，具体的，p＝0、1、2、3、4、5、6、7、8，优选为1-4的整数；
更优选地，结构如式I所示的化合物中，L选自苯环苯氧基吡啶环/>嘧啶环/>或共价键；
环B选自苯环吡啶环/>嘧啶环/>或咪唑环
R4选自氢或甲基；
R5选自F、甲基、苯基、羟基或叔丁氧基；
或R4与R5组合构成苯环。
结构如式I所示的化合物中，环A选自：
X选自：m＝0/>n＝0/>
L选自苯环；
环B选自苯环或吡啶环；
R4选自甲基；
R5选自F、甲基、苯基、羟基或叔丁氧基；
或R4与R5组合构成苯环。
作为本发明的进一步优选方案，mIDH1/NAMPT双靶点抑制剂，选自结构如式Ia、Ib、Ic所示的化合物或其药学上可接受的盐、外消旋体、立体异构体、前药或溶剂化合物：
其中，环A、X、L、环B、R4、R5和结构如式I所示的化合物相同。
作为本发明的其中另一个技术方案，mIDH1/NAMPT双靶点抑制剂，选自结构如式Ⅱ所示的化合物或其药学上可接受的盐、外消旋体、立体异构体、前药或溶剂化合物：
其中，环A选自取代或未取代的6元饱和或不饱和杂环、苯环并5元饱和或不饱和杂环或5-6元饱和或不饱和杂环并5-6元饱和或不饱和杂环；5-6元饱和或不饱和杂环的取代基为卤素、氨基、羟基、羧基、氰基、烯烃、酰胺中的至少一种；6元饱和或不饱和杂环、苯环并5元饱和或不饱和杂环、5-6元饱和或不饱和杂环并5-6元饱和或不饱和杂环中的杂原子选自氧原子、氮原子；
X选自直链或支链的亚烷基链、1,4-哌嗪亚基或1,3-吡咯烷亚基；X可被以下基团中的一个、多个或任意组合中断一或多次：-O-、-CONH-、NHCO-、-NHCONH-、-NH-、-S-、亚烯基，X的氢可被以下一个或多个基团取代：卤素、氨基、羟基、羧基、酰胺、氰基、烯烃、炔烃、C1-C4烷氧基、C1-C6烷基；
L选自共价键、取代或未取代的苯环、5-6元杂环或C1-C4烯基、C1-C4烷氧基、C1-C4酰胺基；苯环的取代基为卤素、氨基、羟基、羧基、氰基、烯烃、酰胺中的至少一种；
环B选自取代或未取代的苯环、5-6元饱和或不饱和杂环；苯环的取代基为卤素、氨基、羟基、羧基、氰基、烯烃、酰胺中的至少一种；5-6元饱和或不饱和杂环中含有1-2个杂原子，杂原子选自氧原子、氮原子；
R1选自硫、-NH-、-N(CH3)-或-CH-；
R2选自氮或-CH-；
R3选自硫或-CH-；
R4选自氢或C1-C4烷基；
R5选自卤素、C1-C4烷基、取代或未取代苯基、羟基或叔丁氧基，苯环的取代基为卤素、氨基、羟基、羧基、氰基、烯烃、酰胺中的至少一种；
或R4与R5组合构成苯环。
优选地，结构如式Ⅱ所示的化合物中，环A选自：
X选自： m＝0-8的整数；n＝0-8的整数；p＝0-8的整数；
L选自苯环、苯氧基、吡啶环、嘧啶环或共价键；
环B选自苯环、吡啶环、嘧啶环或咪唑环；
R1选自硫、-NH-、-N(CH3)-或-CH-；
R2选自氮或-CH-；
R3选自硫或-CH-；
R4选自氢或甲基；
R5选自F、甲基、苯基、羟基或叔丁氧基；
或R4与R5组合构成苯环。
更优选地，结构如式Ⅱ所示的化合物中，环A选自：
X选自：m＝0-8的整数；n＝0-8的整数；p＝0-8的整数；
L选自苯环；
环B选自苯环、吡啶环或嘧啶环；
R1选自硫，R2选自-CH-，R3选自-CH-；或R1选自-CH-，R2选自-CH-，R3选自S；或R1选自-NH-，R2选自-CH-，R3选自-CH-；
R4选自甲基；
R5选自甲基。
最优选地，结构如式Ⅱ所示的化合物中，环A选自：
X选自：n＝0；
L选自苯环；
环B选自苯环、吡啶环或嘧啶环；
R1选自-NH-，R2选自-CH-，R3选自-CH-；
R4选自甲基；
R5选自甲基。
作为本发明的进一步优选方案，mIDH1/NAMPT双靶点抑制剂，选自结构如式Ⅱa所示的化合物或其药学上可接受的盐、外消旋体、立体异构体、前药或溶剂化合物：
其中，环A、X、L、环B、R1、R2、R3、R4、R5和结构如式Ⅱ所示的化合物相同。
具体的，mIDH1/NAMPT双靶点抑制剂，选自结构如下所示的化合物：
/>
药学上可接受的盐为式I、式Ⅱ所示的化合物的酸加成盐，用于成盐的酸包括无机酸、有机酸；所述的无机酸包括：盐酸、硫酸、磷酸、甲磺酸；所述的有机酸包括：乙酸、三氯乙酸、丙酸、丁酸、马来酸、对甲苯磺酸、苹果酸、丙二酸、肉桂酸、柠檬酸、富马酸、樟脑酸、二葡糖酸、天冬氨酸、酒石酸。
本发明的另一目的在于提供一种药物组合物，含有所述的mIDH1/NAMPT双靶点抑制剂和与药学上可接受的载体。
药学上可接受的载体指的是对有机体不引起明显的刺激性和不干扰所给予化合物的生物活性和性质的赋形剂或稀释剂。
本发明式I和式Ⅱ所示的化合物具有mIDH1/NAMPT双重抑制活性，能有效克服单一型mIDH1抑制剂和单一型NAMPT抑制剂对实体瘤疗效差的缺点，能抑制癌症的恶性增殖，治疗效果好、毒性低、不易产生耐药性，且本发明化合物可透过血脑屏障，因此本发明化合物可以制备成mIDH1/NAMPT双重抑制剂，可用于制备治疗癌症或肿瘤相关疾病药物。
本发明的另一目的在于提供所述的mIDH1/NAMPT双靶点抑制剂在制备与mIDH1和/或NAMPT介导的疾病药物的应用。
所述的mIDH1和/或NAMPT介导的疾病为癌症或肿瘤相关疾病。
本发明的另一个目的是提供所述的mIDH1/NAMPT双靶点抑制剂在制备治疗癌症或肿瘤相关疾病药物的应用。
癌症或肿瘤相关疾病包括但不限于多发性骨髓瘤、白血病、乳腺癌、前列腺癌、肺癌、肝癌、胃癌、骨癌、脑癌、头颈癌、肠癌、胰腺癌、膀胱癌、睾丸癌、卵巢癌以及子宫内膜癌等。
本发明中的术语除特别说明外，一般具有如下的含义。
Me为甲基，Et为乙基，Boc为叔丁氧羰基。
术语“烷基”表示具有所述数目之碳原子的直链或支链饱和烃基。
术语“C1-C4烷基”指具有1-4个碳原子的直链或支链饱和烃基。C1-C4烷基包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基。
术语“烷氧基”表示O-烷基。术语“C1-C4烷氧基”指具有O-C1-C4烷基。
术语“卤素”为氟、氯、溴或碘。优选为氟、氯、溴。
附图说明
图1为给药7天后ICR小鼠的心、肝、脾、肺、肾组织H&E染色病理切片。
图2为给药后原位移植瘤裸鼠的体重变化曲线。
图3为给药后原位移植瘤裸鼠脑组织荧光成像结果。
图4为给药后原位移植瘤裸鼠脑组织荧光强度统计。
图5为给药后原位移植瘤裸鼠的生存曲线。
图6为给药后原位移植瘤裸鼠脑组织病理切片图。
具体实施方式
以下实施例用于更好地理解本发明的技术方案，但并不限定本发明。
实施例中的实验方法，如无特殊说明，均为常规方法。
实施例中所用的试验材料，如无特殊说明，均为自商店购买得到的常规生化试剂。
实施例1
化合物1a的合成：
将2,4-二氯嘧啶(8.00g，53.70mmol)与(S)-4-异丙基-噁唑烷-2-酮(6.93g，53.70mmol)溶于40mL无水DMF中，在冰浴搅拌下，缓慢滴加60％NaH-矿物油(2.60g，64.45mmol)的无水DMF混悬液(20mL)，滴加完毕，冰浴下继续搅拌约1小时，撤去冰浴，继续反应1小时，TLC监测反应结束，向反应液中缓慢加入200mL冰水，伴随大量白色固体析出，加入100mL乙酸乙酯溶解固体，用乙酸乙酯萃取混合溶液三次，每次200mL，合并有机相，并依次用水洗涤两次(每次150mL)、饱和氯化钠水溶液洗涤两次(每次150mL)。有机相经无水硫酸钠干燥后减压浓缩，经快速柱层析(PE:EA＝15:1,v:v)分离，得到8.16g化合物1a，白色固体产物，收率：62.6％。1H NMR(500MHz,CDCl3-d)δ8.52(d,J＝5.8Hz,1H),8.23(d,J＝5.8Hz,1H),4.94-4.77(m,1H),4.50-4.26(m,2H),2.72-2.55(m,1H),1.04(d,J＝7.0Hz,3H),0.93(d,J＝6.7Hz,3H)。
化合物2a的合成：
将化合物1a(300mg，1.24mmol)、(S)-1-(4-硝基苯基)-乙-1-胺(247.5mg，1.49mmol)、Pd2(dba)3(22.76mg，0.025mmol)、BINAP(77.37，0.124mmol)和碳酸钾(346mg，2.48mmol)溶于20mL甲苯中，氮气保护下加热至90℃，回流反应16h，TLC监测反应结束后，向反应液中加入50mL水，室温搅拌10min，用乙酸乙酯萃取三次，每次50mL，合并有机相。有机相分别用水、饱和碳酸氢钠和饱和食盐水各洗涤一次，每次30mL，无水硫酸钠干燥，经快速柱层析(PE:EA＝2:1,v:v)分离得到247mg化合物2a，淡黄色固体，收率53.6％。1H NMR(300MHz,DMSO-d6)δ8.14(d,J＝5.6Hz,1H),7.58(s,1H),7.18(d,J＝5.6Hz,1H),6.99(d,J＝8.0Hz,2H),6.52-6.43(m,2H),4.86(m,1H),4.67(dt,J＝7.5,3.5Hz,1H),4.44-4.27(m,2H),2.08(s,1H),1.36(d,J＝7.0Hz,3H),0.86-0.55(m,6H).
化合物3a的合成：
称取氯化铵(216mg,4.04mmol)和还原性铁粉(226mg,4.04mmol)于50mL三颈烧瓶中，加入10mL丙酮和5mL水，氮气保护，加热至80℃，回流反应0.5h，向混合溶液中缓慢注入5mL化合物2a(300mg,0.81mmol)的丙酮溶液，滴加完毕后，继续80℃搅拌3h；TLC监测反应结束后，冷却，硅藻土抽滤，滤液减压浓缩，浓缩后的物质溶于约100mL乙酸乙酯，分别用水和饱和食盐水各洗三次，无水硫酸钠干燥，减压浓缩，得到化合物3a，橙黄色固体，直接用于下一步。
化合物4a的合成：
将化合物3a(200mg，0.586mmol)、Boc-丙氨酸(133mg，0.703mmol)和DIPEA(0.194mL，1.17mmol)溶于3mL无水DMF中，冰浴下搅拌10min，再缓慢加入HATU(334mg,0.879mmol)，加毕，恢复室温搅拌4h，TLC监测至反应终点；搅拌下，将反应液倒入50mL冰水中，用乙酸乙酯萃取三次，合并有机相，有机相依次用水、饱和碳酸氢钠以及饱和食盐水各洗一次，每次20mL，再经无水硫酸钠干燥，减压浓缩，经快速柱层析(PE:EA＝2:1,v:v)分离得到256mg化合物4a，淡黄色固体，收率85.3％。1H NMR(300MHz,CDCl3)δ8.16(d,J＝5.9Hz,1H),7.83(s,1H),7.53-7.46(m,3H),7.26(s,1H),5.20(s,1H),5.01(s,1H),4.68-4.54(m,1H),4.37-4.16(m,2H),3.51(q,J＝6.1Hz,2H),2.62(t,J＝6.0Hz,2H),2.48-2.00(m,1H),1.54(d,J＝6.9Hz,3H),1.45(s,9H),0.84-0.60(m,6H)。
化合物I-8的合成：
将化合物4a(300mg，0.585mmol)置于50mL茄型瓶中，冰浴搅拌下，缓慢逐滴加入3mL 4M的盐酸EA，滴加完毕后，继续冰浴搅拌约5h，TLC监测至反应终点；抽滤，得到195mg盐酸盐白色固体粉末；将反式-3-(3-吡啶基)丙烯酸(78mg，0.522mmol)、盐酸盐固体粉末和DIPEA(0.43ml,2.61mmol)溶于3mL无水DMF中，冰浴下搅拌15min，再缓慢加入HATU(248mg，0.653mmol)，恢复至室温搅拌4h，TLC监测反应结束；将反应液倒入30mL冰水中，用乙酸乙酯萃取三次，合并有机相，并依次用水、饱和碳酸氢钠以及饱和食盐水各洗一次，每次30mL，无水硫酸钠干燥，减压浓缩，经快速柱层析(DCM:MeOH＝40:1,v:v)分离得到98mg化合物I-8，淡黄色固体，收率41.5％。1H NMR(300MHz,CDCl3)δ8.64(d,J＝38.6Hz,2H),8.23-8.04(m,2H),7.78(d,J＝7.9Hz,1H),7.63-7.44(m,4H),7.26(s,1H),6.89(s,1H),6.51(d,J＝15.7Hz,1H),5.02-5.00(m,1H),4.63-4.60(m,1H),4.33-4.21(m,2H),3.77-3.70(m,2H),2.73(m,2H),2.48-2.34(m,1H),1.46(d,J＝9.0Hz,3H),0.70(dd,J＝24.0,6.0Hz,6H)。13CNMR(75MHz,DMSO-d6)δ170.51,164.47,161.00,158.75,156.69,154.36,149.98,148.97,140.47,137.48,135.13,133.82,130.67,125.74,124.21,123.87,118.98,97.44,62.72,57.86,49.56,40.08,38.34,33.77,26.89,17.69,13.73。ESI-HRMS m/z:544.2666[M+H]+。
实施例2
化合物5a的合成：
化合物5a的合成方法参考化合物4a的合成，仅将Boc-丙氨酸替换为Boc-甘氨酸，投入化合物3a(200mg,0.586mmol)和Boc-甘氨酸(123mg,0.703mmol)，得到249mg化合物5a，淡黄色固体，收率85.3％。1H NMR(300MHz,DMSO-d6)δ9.75(s,1H),8.16(d,J＝5.6Hz,1H),7.70-7.55(m,1H),7.47(d,J＝8.3Hz,2H),7.31-7.23(m,2H),7.20(d,J＝5.6Hz,1H),6.95(d,J＝7.7Hz,1H),4.97(s,1H),4.64(dq,J＝8.3,4.3,3.6Hz,1H),4.33(tdd,J＝12.4,8.8,3.2Hz,2H),3.70(d,J＝6.1Hz,2H),2.04(m,1H),1.42(d,J＝6.9Hz,3H),1.40(s,9H),0.80-0.50(m,6H)。
化合物I-10的合成：
化合物I-10的合成方法参考化合物I-8的合成，仅将化合物4a替换为化合物5a，投入化合物5a(200mg，0.401mmol)和反式-3-(3-吡啶基)丙烯酸(62mg，0.415mmol)，得到91mg化合物I-10，白色固体，收率52.5％。1H NMR(300MHz,DMSO-d6)δ9.97(s,1H),8.79(d,J＝2.2Hz,1H),8.58(dd,J＝4.7,1.6Hz,1H),8.44(t,J＝5.8Hz,1H),8.17(d,J＝5.8Hz,1H),8.03(dt,J＝8.0,1.9Hz,1H),7.77(s,1H),7.50(ddd,J＝12.8,6.7,4.3Hz,4H),7.25(dd,J＝12.3,7.0Hz,3H),6.91(d,J＝15.9Hz,1H),4.99(s,2H),4.64(dt,J＝7.8,3.4Hz,1H),4.42-4.25(m,2H),4.04(d,J＝5.8Hz,2H),1.97(d,J＝15.3Hz,1H),1.43(d,J＝7.0Hz,3H),0.67(d,J＝56.5Hz,6H)。13C NMR(75MHz,DMSO-d6)δ167.31,164.82,160.38,157.86,156.98,154.30,149.78,148.78,140.56,137.10,135.54,134.24,130.75,125.82,124.03,123.99,119.09,97.41,62.79,57.93,49.65,42.76,28.94,26.91,23.19,17.68,13.73。ESI-HRMS m/z:530.2508[M+H]+。
实施例3
化合物6a的合成：
化合物6a的合成方法参考化合物4a的合成，仅将Boc-丙氨酸替换为Boc-丁氨酸，投入化合物3a(200mg，0.586mmol)和Boc-丁氨酸(143mg，0.703mmol)，得到273mg化合物6a，淡黄色固体，收率88.6％。1H NMR(300MHz,CDCl3)δ8.83(s,1H),8.15(d,J＝5.8Hz,1H),7.56(d,J＝8.1Hz,2H),7.45(d,J＝5.8Hz,1H),7.26(s,1H),6.06-5.78(m,1H),4.83(t,J＝6.5Hz,1H),4.62(dt,J＝7.6,3.4Hz,1H),4.35-4.19(m,2H),3.26(d,J＝6.2Hz,2H),2.43-2.36(m,2H),2.07(s,1H),1.88(dd,J＝7.5,4.8Hz,2H),1.54(d,J＝6.9Hz,3H),1.47(s,9H),0.72(dd,J＝19.9,7.0Hz,6H)。
化合物I-11的合成：
化合物I-11的合成方法参考化合物I-8的合成，仅将化合物4a替换为化合物6a，投入化合物6a(200mg，0.380mmol)和反式-3-(3-吡啶基)丙烯酸(58mg，0.390mmol)，得到89mg化合物I-11，白色固体，收率49.2％。1H NMR(300MHz,DMSO-d6)δ9.84(s,1H),8.75(s,1H),8.55(d,J＝4.8Hz,1H),8.19(d,J＝22.3Hz,2H),7.97(d,J＝8.0Hz,1H),7.73(s,1H),7.46(t,J＝9.1Hz,4H),7.21(dd,J＝11.7,6.6Hz,3H),6.72(d,J＝15.9Hz,1H),4.93(s,1H),4.62(s,1H),4.33(d,J＝12.4Hz,2H),3.28-3.11(m,2H),2.33(t,J＝7.5Hz,2H),1.97-1.67(m,3H),1.40(d,J＝7.0Hz,3H),0.79(d,J＝42.7Hz,6H)。13C NMR(75MHz,DMSO-d6)δ170.51,164.47,161.00,158.75,156.71,149.98,148.97,140.47,137.48,135.13,133.82,130.67,125.74,124.21,123.87,118.98,97.44,62.72,57.86,49.60,38.34,33.77,26.89,25.19,23.27,17.69,13.72。ESI-HRMS m/z:558.2827[M+H]+。
实施例4
化合物7a的合成：
化合物7a的合成方法同化合物4a，仅将Boc-丙氨酸替换为Boc-戊氨酸，投入化合物3a(200mg，0.586mmol)和Boc-戊氨酸(153mg，0.703mmol)，得到283mg化合物7a，淡黄色固体，收率89.2％。1H NMR(300MHz,DMSO-d6)δ9.72(s,1H),8.16(d,J＝5.6Hz,1H),7.60(s,1H),7.50-7.39(m,2H),7.30-7.13(m,3H),6.72(s,1H),4.96(s,1H),4.68-4.58(m,1H),4.40-4.25(m,2H),2.98-2.87(m,2H),2.27(t,J＝7.3Hz,2H),2.09(s,1H),1.61-1.49(m,2H),1.41(d,J＝7.0Hz,3H),1.37(s,9H),1.28-1.23(m,2H),0.66(d,J＝56.7Hz,6H)。
化合物I-12的合成：
化合物I-12的合成方法同化合物I-8，仅将化合物4a替换为化合物7a，投入化合物7a(200mg，0.370mmol)和反-3(3-吡啶基)丙烯酸(56mg，0.378mmol)，得到73mg化合物I-12，白色固体，收率46.3％。1H NMR(300MHz,DMSO-d6)δ9.82(d,J＝6.8Hz,1H),8.76(s,1H),8.56(d,J＝4.8Hz,1H),8.19(q,J＝7.0,6.3Hz,2H),8.00(d,J＝8.0Hz,1H),7.85(d,J＝22.3Hz,1H),7.58-7.38(m,4H),7.34-7.08(m,3H),6.84-6.63(m,1H),4.95(s,1H),4.62(s,1H),4.34(d,J＝10.7Hz,2H),3.21(q,J＝6.4Hz,2H),2.31(t,J＝7.4Hz,2H),2.29-2.09(m,1H),1.64-1.49(m,4H),1.24(s,3H),0.73-0.50(m,6H)。13C NMR(75MHz,DMSO-d6)δ198.55,197.56,172.58,164.01,161.01,158.73,156.70,154.35,149.98,149.40,140.59,137.86,137.48,134.36,130.92,125.72,123.67,120.57,119.04,97.41,62.71,57.85,49.60,44.59,42.59,41.23,29.22,28.21,26.88,23.23,17.68,13.72。ESI-HRMS m/z:572.2976[M+H]+。
实施例5
化合物8a的合成：
化合物8a的合成方法同化合物4a，仅将Boc-丙氨酸替换为1-Boc-4-哌啶甲酸，投入化合物3a(200mg，0.586mmol)和1-Boc-4-哌啶甲酸(161mg，0.703mmol)，得到289mg化合物8a，淡黄色固体，收率89.1％。1H NMR(300MHz,CDCl3)δ8.15(d,J＝5.8Hz,1H),7.50-7.43(m,3H),7.36(s,1H),7.26(s,1H),5.71(s,1H),5.09-4.94(m,1H),4.61(dd,J＝8.0,3.9Hz,1H),4.40-4.05(m,6H),2.48-2.30(m,1H),1.90(d,J＝13.0Hz,2H),1.74(qd,J＝12.3,4.5Hz,2H),1.53(d,J＝7.1Hz,3H),1.48(s,9H),0.72(dd,J＝19.1,6.9Hz,6H)。
化合物I-13的合成：
化合物I-13的合成方法同化合物I-8，仅将化合物4a替换为化合物8a，投入化合物8a(200mg，0.362mmol)和反-3-(3-吡啶基)丙烯酸(55mg，0.369mmol)，得到75mg化合物I-13，白色固体，收率47.6％。1H NMR(300MHz,DMSO-d6)δ9.80(s,1H),8.88(s,1H),8.66-8.46(m,1H),8.17(t,J＝6.8Hz,2H),7.76-7.31(m,6H),7.22(dd,J＝13.9,6.9Hz,3H),4.96(s,1H),4.63(d,J＝7.6Hz,1H),4.54-4.19(m,4H),3.30(s,2H),3.18(s,1H),2.82-2.44(m,3H),1.86(d,J＝13.1Hz,2H),1.42(d,J＝7.0Hz,3H),0.66(d,J＝56.0Hz,6H)。13C NMR(75MHz,DMSO-d6)δ170.85,164.33,160.23,157.64,157.03,154.30,149.57,148.58,140.13,137.58,134.88,134.23,130.86,125.68,124.47,124.02,118.95,97.42,62.78,57.93,49.67,38.42,35.91,31.47,29.38,28.93,28.66,26.89,22.67,17.67,13.71。ESI-HRMS m/z:584.2983[M+H]+。
实施例6
化合物9a的合成：
化合物9a的合成方法参考化合物4a的合成，仅将Boc-丙氨酸替换为1-Boc-吡咯烷-3-甲酸，投入化合物3a(200mg，0.586mmol)和1-Boc-吡咯烷-3-甲酸(151mg，0.703mmol)，得到273mg淡黄色固体9a，收率86.7％。1H NMR(300MHz,DMSO-d6)δ7.92(d,J＝5.8Hz,1H),7.32-7.12(m,3H),7.04(s,1H),7.02(s,1H),4.77(s,1H),4.44-4.29(m,1H),4.14-3.79(m,2H),3.59-3.00(m,4H),2.75(d,J＝10.1Hz,1H),1.94(m,2H),1.68(s,1H),1.29(d,J＝6.9Hz,3H),1.23(s,9H).0.83(dd,J＝17.3,5.6Hz,6H)。
化合物I-14的合成：
化合物I-14的合成方法参考化合物I-8的合成，仅将化合物4a替换为化合物9a，投入化合物9a(200mg，0.371mmol)和反-3-(3-吡啶基)丙烯酸(57mg，0.380mmol)，得到74mg化合物I-14，白色固体，收率47.2％。1H NMR(500MHz,DMSO-d6)δ10.06(d,J＝18.0Hz,1H),8.90(s,1H),8.57(td,J＝4.8,1.6Hz,1H),8.22-8.18(m,2H),7.79(s,1H),7.55-7.50(m,3H),7.46(td,J＝7.4,4.7Hz,1H),7.27(d,J＝8.0Hz,2H),7.22(d,J＝6.0Hz,1H),7.18(s,1H),4.96(s,1H),4.64(s,1H),4.38-4.32(m,2H),4.01-3.98(m,1H),3.90-3.81(m,1H),3.78-3.70(m,1H),3.66-3.55(m,1H),3.29-3.16(m,1H),2.28-2.14(m,2H),1.43(d,J＝7.0Hz,3H),0.63(d,J＝6.0Hz,6H)。13C NMR(75MHz,DMSO-d6)δ170.79,170.40,163.06,160.86,158.54,156.76,154.34,149.97,149.33,140.77,137.23,136.93,134.50,130.82,125.78,123.75,121.90,121.78,119.15,97.43,62.73,57.87,49.60,48.65,48.46,45.76,45.39,44.56,42.66,39.50,29.47,28.08,26.90,23.24,17.68,13.73。ESI-HRMS m/z:570.2818[M+H]+。
实施例7
化合物14a的合成：
将(S)-(-)-1-(4-溴苯)乙胺(4g，20mmol)、4-硝基苯基硼酸(3.68g，22mmol)、四三苯基磷钯(1.1g，1mmol)、碳酸铯(13.04g，40mmol)依次溶于20mL水和100mL 1,4-二氧六环的混合溶剂中，氮气保护下加热至90℃反应4h，TLC监测反应，反应结束后，待反应液降温至室温，减压浓缩除去1,4-二氧六环，加入150mL乙酸乙酯和100mL水溶解稀释浓缩液并转移至分液漏斗，用乙酸乙酯萃取三次，每次200mL，合并有机相；有机相依次用2mol/L的氢氧化钠水溶液、水、饱和食盐水各洗涤1次，每次150mL，有机相经无水硫酸钠干燥后减压浓缩，得到5g化合物14a粗品，黄色固体，无需进一步纯化，直接用于下一步反应。1H NMR(400MHz,CDCl3)δ8.29(d,J＝8.8Hz,2H),7.73(d,J＝8.8Hz,2H),7.60(d,J＝8.3Hz,2H),7.49(d,J＝8.2Hz,2H),4.21(q,J＝6.6Hz,1H),1.43(d,J＝6.6Hz,3H)。
化合物15a的合成：
将化合物14a(1.50g，6.19mmol)、化合物1a(1.5g,6.19mmol)和DIPEA(4g，31mmol)溶于5mL DMSO中，氮气保护下加热至110℃反应16h，TLC监测反应，反应结束后，反应液冷却至室温，加入50mL乙酸乙酯和50mL水，室温搅拌10min，乙酸乙酯萃取2次，每次50mL，合并有机相，有机相依次用水和饱和氯化钠水溶液各洗涤1次，每次50mL，无水硫酸钠干燥，最后经快速柱层析(PE:EA＝5:1,v:v)得到1.14g化合物15a，黄色固体，收率41.2％。1H NMR(500MHz,DMSO-d6)δ8.31(d,J＝8.6Hz,2H),8.21(s,1H),7.94(d,J＝8.6Hz,2H),7.74(d,J＝8.1Hz,2H),7.63(d,J＝7.0Hz,2H),7.59(d,J＝2.8Hz,1H),7.23(d,J＝5.6Hz,1H),5.04(s,1H),4.60(s,1H),4.32(d,J＝29.0Hz,2H),1.72(s,1H),1.49(d,J＝7.0Hz,3H),0.65(s,3H),0.45(s,3H)。
化合物16a的合成：
化合物16a的合成步骤参考化合物3a的合成，投入化合物15a(600mg，1.34mmol)、还原性铁粉(374mg，6.70mmol)和氯化铵(358mg，6.70mmol)得到512mg化合物16a，黄色固体，收率91.3％。
化合物I-16的合成：
化合物I-16的合成步骤参考化合物4a的合成，投入化合物16a(150mg，0.36mmol)和咪唑并[1,2-a]吡啶-6-甲酸(88mg,0.54mmol)，得到68mg化合物I-16，白色固体，收率33.6％。1H NMR(400MHz,DMSO-d6)δ10.56(s,1H),9.39(s,1H),8.33-7.71(m,8H),7.60(d,J＝27.3Hz,4H),7.36(s,2H),7.18(s,1H),4.97(s,1H),4.58(s,1H),4.28(d,J＝22.9Hz,2H),1.74(s,1H),1.43(s,3H),0.63(d,J＝2.48MHz,3H),0.43(d,J＝1.68MHz,3H)。13C NMR(100MHz,DMSO-d6)δ163.08,161.38,159.07,157.37,154.95,151.69,147.91,145.53,142.78,138.48,136.32,130.33,129.85,128.16,127.31,126.73,123.06,121.32,115.96,114.62,63.32,58.48,55.45,27.41,23.89,18.35,14.24。ESI-HRMS m/z:562.2566[M+H]+。
实施例8
化合物I-17的合成：
化合物I-17的合成方法参考化合物4a的合成，投入化合物16a(200mg，0.48mmol)和反式-3-(3-吡啶基)丙烯酸(108mg，0.72mmol)，得到112mg化合物I-17，淡黄色固体粉末，收率42.6％。1H NMR(300MHz,DMSO-d6)δ10.39(s,1H),8.84(s,1H),8.59(d,J＝3.7Hz,1H),8.18(d,J＝4.7Hz,1H),8.06(d,J＝7.9Hz,1H),7.85(d,J＝8.4Hz,1H),7.79(d,J＝8.4Hz,2H),7.68(s,1H),7.60(dd,J＝13.9,8.3Hz,4H),7.49(dd,J＝7.8,4.9Hz,1H),7.39(d,J＝6.5Hz,2H),7.21(d,J＝5.6Hz,1H),6.96(d,J＝15.8Hz,1H),5.01(s,1H),4.62(s,1H),4.33(d,J＝10.1Hz,2H),1.77(s,1H),1.47(d,J＝6.9Hz,3H),0.67(s,3H),0.46(s,3H)。13C NMR(150MHz,DMSO-d6)δ175.00,163.56,161.63,159.48,157.18,154.89,150.88,149.77,145.43,138.85,138.29,137.38,135.71,134.60,131.01,127.34,126.60,124.64,124.53,120.15,97.85,79.02,63.20,58.37,50.39,29.51,18.29。ESI-HRMS m/z:549.2609[M+H]+。
实施例9
化合物I-18的合成：
化合物I-18的合成方法参考化合物4a的合成，投入化合物16a(150mg，0.36mmol)和3-吡啶氧基乙酸(83mg，0.54mmol)得到81mg化合物I-18，白色固体，收率40.9％。1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),8.44(s,1H),8.25-8.02(d,2H),7.80(s,1H),7.66(d,J＝8.3Hz,2H),7.54(dd,J＝15.5,8.2Hz,4H),7.39-7.31(m,4H),7.16(d,J＝5.3Hz,1H),4.96(s,1H),4.78(s,2H),4.56(s,1H),4.26(d,J＝22.0Hz,2H),1.67(s,1H),1.42(d,J＝6.7Hz,3H),0.61(s,3H),0.41(s,3H)。13C NMR(100MHz,DMSO-d6)δ166.66,161.65,155.64,154.96,154.73,153.05,142.80,138.55,138.27,138.08,136.00,127.31,126.68,124.69,121.83,120.62,67.64,63.29,58.44,54.13,27.41,23.96,18.61,18.34,17.26,14.17。ESI-HRMSm/z:553.2561[M+H]+。
实施例10
化合物I-19的合成：
化合物I-19的合成方法参考化合物4a的合成，投入化合物16a(150mg，0.36mmol)和7-氮杂吲哚-5-羧酸(88mg，0.54mmol)，得到79mg化合物I-19，淡黄色固体，收率39.1％。1H NMR(400MHz,DMSO-d6)δ11.96(s,1H),10.33(s,1H),8.81(d,J＝1.9Hz,1H),8.57-8.53(m,1H),8.19-8.08(m,1H),7.85(d,J＝8.6Hz,2H),7.57(dd,J＝16.1,8.5Hz,6H),7.35(d,J＝4.9Hz,2H),7.17(d,J＝5.5Hz,1H),6.66-6.50(m,1H),4.97(s,1H),4.57(s,1H),4.28(d,J＝19.9Hz,2H),1.77(s,1H),1.43(d,J＝6.9Hz,3H),0.63(s,3H),0.43(s,3H)。13C NMR(100MHz,DMSO-d6)δ165.84,154.99,150.20,143.39,139.21,138.41,136.78,135.67,128.60,128.34,127.14,126.65,124.70,123.18,121.12,119.21,101.55,97.99,63.29,58.45,46.03,29.57,27.41,23.97,18.35,14.24,9.14。ESI-HRMS m/z:562.2561[M+H]+。
实施例11
化合物I-20的合成：
化合物I-20的合成方法参考化合物4a的合成，投入化合物16a(150mg，0.36mmol)和1H-吡唑[3,4-b]嘧啶-5-羧酸(88mg，0.54mmol)，得到55mg化合物I-20，淡黄色固体，收率27.3％。1H NMR(500MHz,CDCl3)δ9.36(s,1H),8.69(s,1H),8.44(d,J＝21.75Hz,1H),8.34(d,J＝21.2Hz,1H),8.26(s,1H),7.73(d,J＝14.45Hz,2H),7.61(d,J＝9.7Hz,2H),7.56-7.50(m,4H),7.46(m,2H),7.24(s,1H),6.98(d,J＝9.4Hz,1H),5.07(s,1H),4.57(s,1H),4.20-4.29(m,2H),1.87(s,1H),1.58(d,J＝9.5Hz,3H),0.85(s,3H),0.62(s,3H)。13C NMR(100MHz,DMSO-d6)δ161.07,158.84,157.51,157.38,154.82,144.84,144.21,143.29,139.03,138.75,138.14,133.09,132.24,128.67,126.37,125.49,123.55,122.99,109.64,106.39,99.56,63.01,58.59,50.78,31.59,27.45,18.29。ESI-HRMS m/z:562.2495[M+H]+。
实施例12
化合物I-21的合成：
将N,N'-羰基二咪唑(350mg，2.16mmol)和三乙胺(200μL，1.44mmol)溶于4mL无水四氢呋喃中，在氮气保护和冰浴条件下，缓慢滴加化合物16a(300mg，0.72mmol)的无水四氢呋喃溶液，滴毕，继续搅拌2h，TLC监测至化合物16a反应完全。滴加3-氨甲基吡啶(94mg，0.86mmol)的四氢呋喃溶液，氮气保护下加热至60℃，反应5h，反应液冷却至室温，减压浓缩除去溶剂，得到黄色油状液体。将黄色油状液体溶于100mL乙酸乙酯中，依次用100mL水和100mL饱和氯化钠水溶液洗涤一次，无水硫酸钠干燥；经快速柱层析(DCM:CH3OH＝50:1,v:v)得到53mg化合物I-21，黄色固体，收率13.4％。1H NMR(400MHz,DMSO-d6)δ8.13(s,1H),7.76(s,1H),7.64-7.54(m,3H),7.52(dd,J＝6.6,2.5Hz,2H),7.38(d,J＝8.1Hz,2H),7.25(d,J＝8.3Hz,4H),7.15(d,J＝5.6Hz,2H),6.58(d,J＝8.4Hz,2H),5.12(s,2H),5.02-4.87(m,1H),4.57(s,1H),4.37-4.17(m,2H),1.76(s,1H),1.40(d,J＝6.9Hz,3H),0.63(s,3H),0.42(s,3H)。13C NMR(100MHz,DMSO-d6)δ161.69,157.30,154.97,148.69,143.88,139.44,133.78,132.77,132.57,132.07,131.98,129.35,129.24,128.07,127.55,126.49,126.39,125.74,114.73,97.88,63.29,58.45,50.35,27.40,23.97,18.33,14.23。ESI-HRMS m/z:552.2692[M+H]+。
实施例13
路线一：
化合物19a的合成：
将5-溴-2-吡啶甲醛(4g，21.4mmol)和(S)-(-)-叔丁基亚磺酰胺(3.9g，28.8mmol)溶于180mL1,2-二氯乙烷中，加入碳酸铯(21g，64.6mmol)，氮气保护下升温至80℃反应5h；TLC监测反应结束后，停止加热，向反应液中滴加60mL饱和氯化铵溶液，搅拌10分钟后，转移至分液漏斗，加入400mL二氯甲烷、240mL饱和氯化铵溶液和100mL水，充分振摇后分液，收集有机相并减压浓缩除去溶剂，经快速柱层析(PE:EA＝8:1,v:v)分离得5.6g化合物19a，白色固体，收率90％。1H NMR(400MHz,CDCl3)δ8.82(dd,J＝2.3,0.9Hz,1H),8.67(s,1H),7.95(qd,J＝8.4,1.5Hz,2H),1.30(s,9H)。
化合物20a的合成：
将化合物19a(5.6g，19.36mmol)溶于230mL二氯甲烷中，氮气置换后降温至-78℃，缓慢滴加50mL浓度为1mol/的甲基溴化镁的四氢呋喃溶液，滴毕，继续-78℃反应4h；TLC监测反应结束后，向反应液中分批加入300mL饱和氯化铵溶液淬灭反应，用二氯甲烷萃取2次，每次200mL，合并有机相，用200mL饱和食盐水洗涤1次，再经无水硫酸钠干燥后减压浓缩，经快速柱层析(PE:EA＝2:1,v:v)分离得到4.91g化合物20a，白色固体，收率84％。1H NMR(400MHz,CDCl3)δ8.62(d,J＝2.3Hz,1H),7.80(dt,J＝8.4,1.9Hz,1H),7.23(d,J＝8.3Hz,1H),4.62(d,J＝6.0Hz,1H),4.59-4.53(m,1H),1.51(dd,J＝6.8,1.2Hz,3H),1.27(d,J＝1.3Hz,9H)。
化合物21a的合成：
化合物21a的合成方法参考化合物14a的合成，投入化合物20a(4.9g，16.12mmol)和4-硝基苯基硼酸(2.96g，17.73mmol)得到4.9g化合物21a，黄色固体，收率88％。1H NMR(400MHz,CDCl3)δ8.83(dt,J＝2.3,1.0Hz,1H),8.41-8.31(m,2H),7.92(dd,J＝8.1,2.4Hz,1H),7.78-7.72(m,2H),7.46(d,J＝8.0Hz,1H),4.79(d,J＝6.2Hz,1H),4.68(p,J＝6.5Hz,1H),1.58(d,J＝6.7Hz,3H),1.30(d,J＝0.9Hz,9H)。
化合物22a的合成：
将4.9g化合物21a溶于甲醇和盐酸的混合体系中(甲醇40mL，浓盐酸25mL)，室温搅拌6小时；TLC监测反应结束后，减压浓缩除去反应液中的甲醇，加入20mL水稀释剩余物，缓慢滴加2mol/L的氢氧化钠溶液调节pH至10，用二氯甲烷萃取3次，每次200mL，合并有机相并减压浓缩，经快速柱层析(DCM:MeOH＝20:1,v:v)分离得到3.16g化合物22a，黄色固体，收率92％。1H NMR(400MHz,DMSO-d6)δ8.91(dd,J＝2.4,0.8Hz,1H),8.39-8.29(m,2H),8.18(dd,J＝8.2,2.4Hz,1H),8.07-7.99(m,2H),7.64(d,J＝8.2Hz,1H),4.08(q,J＝6.7Hz,1H),2.09(s,2H),1.32(d,J＝6.7Hz,3H)。
化合物23a的合成：
化合物23a的合成方法参考化合物15a的合成，投入化合物22a(0.6g，2.468mmol)和化合物1a(0.59g，2.468mmol)，得到635mg化合物23a，黄色固体，收率57.3％。ESI-MS m/z:449.2。
化合物24a的合成：
化合物24a的合成方法参考化合物3a的合成，投入化合物23a(250mg，0.56mmol)、还原性铁粉(155mg，2.79mmol)和氯化铵(149mg，2.79mmol)，得到240mg化合物24a，黄色固体，收率95.3％。
化合物I-24的合成：
化合物I-24的合成方法参考化合物4a的合成，投入化合物24a(200mg，0.48mmol)和反式-3-(3-吡啶基)丙烯酸(106mg，0,72mmol)，得到120mg化合物I-24，黄色固体，收率48.0％。1H NMR(600MHz,DMSO-d6)δ10.44(s,1H),8.85(d,J＝2.3Hz,1H),8.82(d,J＝2.3Hz,1H),8.60(dd,J＝4.8,1.6Hz,1H),8.23(s,1H),8.08(dt,J＝8.0,2.0Hz,1H),8.01(d,J＝8.3Hz,1H),7.97-7.88(m,1H),7.84(d,J＝8.6Hz,2H),7.71-7.65(m,3H),7.51(dd,J＝7.9,4.7Hz,1H),7.35(d,J＝8.0Hz,1H),7.26(d,J＝5.7Hz,1H),6.96(d,J＝15.8Hz,1H),5.01(s,1H),4.49(s,1H),4.36-4.19(m,2H),1.52(d,J＝7.2Hz,3H),0.95(d,J＝7.0Hz,1H),0.53(s,3H),0.42(s,3H)。13C NMR(126MHz,DMSO-d6)δ163.10,160.68,158.22,156.88,154.28,151.04,150.15,149.03,146.33,146.06,138.96,136.90,134.35,134.28,133.13,131.93,130.52,128.77,127.02,124.11,124.05,120.64,119.77,62.72,57.86,51.83,48.51,39.94,39.77,39.61,39.44,39.27,39.11,38.94,26.78,21.43,17.68,13.59。ESI-HRMS m/z:550.2555[M+H]+。
路线二：
化合物25a的合成：
化合物25a的合成方法参考化合物14a的合成，投入2-乙酰基-5-溴吡啶(2g，10mmol)、4-硝基苯硼酸(1.83g，11mmol)、四三苯基磷钯(0.57g，0.5mmol)和碳酸铯(6.5g，20mmol)，得2.5g化合物25a粗品，黄色固体。ESI-MS m/z:243.1[M+H]+。
化合物26a的合成：
将化合物25a(3g，12.38mmol)、乙酸铵(14.3g，185.77mmol)、氰基硼氢化钠(3.11g，49.54mmol)，溶于50mL无水乙醇中，氮气保护下加热至120℃，回流反应10min，TLC监测反应结束后，反应液降至室温，减压浓缩除去溶剂；加入100mL乙酸乙酯和50mL水溶解，调节pH值为10左右，室温搅拌15min，乙酸乙酯萃取3次，每次120mL。有机相合并后依次使用水、饱和氯化钠水溶液洗涤1次，每次60mL，无水硫酸钠干燥后经快速柱层析(DCM:MeOH＝15:1,v:v)分离，得到1.7g化合物26a，黄色固体，产率56.67％。1H NMR(400MHz,CDCl3)δ8.82(d,J＝2.0Hz,1H),8.35(d,J＝8.7Hz,2H),7.92(dd,J＝8.1,2.3Hz,1H),7.74(d,J＝8.7Hz,2H),7.47(d,J＝8.1Hz,1H),4.32(q,J＝6.7Hz,1H),1.52(d,J＝6.7Hz,3H)。
化合物23a的合成：
将化合物26a(0.6g，2.468mmol)、化合物1a(0.59g,2.468mmol)和DIPEA(1.6g，12.34mmol)溶于15mL DMSO中，氮气保护下加热至110℃，反应16h；反应液降至室温，加入50mL乙酸乙酯和50mL水，室温搅拌10min，乙酸乙酯萃取3次，每次100mL，合并有机相，依次用水和饱和氯化钠水溶液洗涤1次，每次50mL，向有机相中加入无水硫酸钠干燥，经快速柱层析(PE:EA＝5:1,v:v)手性拆分得到200mg化合物23a，黄色固体，收率18％。
实施例14
化合物I-25的合成：
化合物I-25的合成方法参考化合物4a的合成，投入化合物24a(176mg，0.42mmol)和咪唑并[1,2-a]吡啶-6-甲酸(102mg，0.63mmol)，得到198mg化合物I-25，黄色固体，收率89.6％。1H NMR(300MHz,DMSO-d6)δ10.49(s,1H),9.29(s,1H),8.83(d,J＝2.3Hz,1H),8.23(d,J＝4.0Hz,1H),8.13(s,1H),8.01(dd,J＝8.2,2.4Hz,1H),7.90(d,J＝8.7Hz,2H),7.80-7.67(m,6H),7.34(d,J＝7.0Hz,1H),7.24(d,J＝5.7Hz,1H),4.99(s,1H),4.49(s,1H),4.37-4.17(m,2H),1.52(d,J＝7.1Hz,3H),1.24(d,J＝5.2Hz,1H),0.53(s,3H),0.42(s,3H)。13C NMR(126MHz,DMSO-d6)δ165.87,163.37,161.18,158.92,156.67,154.32,151.00,146.53,144.34,138.73,134.04,132.95,132.37,131.17,128.96,128.75,126.83,123.55,120.75,120.27,118.82,115.92,114.41,62.69,57.82,54.81,51.91,39.96,39.79,39.62,39.46,39.29,39.12,38.96,26.78,21.46,17.69,13.59。ESI-HRMS m/z:563.2521[M+H]+。
实施例15
化合物I-26的合成：
化合物I-26的合成方法参考化合物4a的合成，投入化合物24a(150mg，0.36mmol)和3-吡啶氧基乙酸(83mg，0.54mmol)，得到118mg化合物I-26，淡黄色固体，收率65％。1HNMR(500MHz,DMSO-d6)δ10.30(s,1H),8.80(s,1H),8.40(d,J＝3.0Hz,1H),8.27-8.19(m,2H),7.99(dd,J＝8.3,2.4Hz,1H),7.84(s,1H),7.80-7.74(m,2H),7.68(d,J＝8.4Hz,2H),7.48-7.43(m,1H),7.38(dd,J＝8.5,4.6Hz,1H),7.25(d,J＝5.6Hz,1H),4.99(s,1H),4.85(s,2H),4.48(s,1H),4.38-4.17(m,2H),1.52(d,J＝7.2Hz,3H),0.51(s,3H),0.41(s,3H)。13C NMR(126MHz,DMSO-d6)δ166.74,163.55,161.76,159.52,157.17,154.87,154.65,147.10,142.78,138.67,138.53,134.68,133.44,132.86,127.46,124.61,121.72,120.69,119.32,67.57,63.21,55.39,40.59,40.50,40.42,40.33,40.26,40.17,40.00,39.83,39.67,39.50,22.03,18.26,14.11。ESI-HRMS m/z:554.2518[M+H]+。
实施例16
化合物I-34的合成：
化合物I-34的合成方法参考化合物4a的合成，投入化合物16a(200mg，0.48mmol)和烟酸(88.46mg，0.72mmol)，得到167mg化合物I-34，淡黄色固体粉末，收率66.8％。1H NMR(500MHz,DMSO-d6)δ10.85(s,1H),9.33(d,J＝1.5Hz,1H),8.95(d,J＝2.4Hz,1H),8.83(t,J＝2.0Hz,1H),8.39(s,1H),8.27-8.13(m,2H),8.00(d,J＝8.4Hz,2H),7.65(dd,J＝17.0,8.1Hz,4H),7.39(dd,J＝19.1,7.1Hz,3H),5.08(s,1H),4.64(s,1H),4.36(d,J＝13.8Hz,2H),1.78(s,1H),1.51(d,J＝7.0Hz,3H),0.70(s,3H),0.49(s,3H)。13C NMR(126MHz,DMSO-d6)δ164.52,161.64,159.45,159.33,157.22,154.89,152.61,149.16,145.48,138.58,138.23,136.11,135.95,131.05,127.16,126.64,126.57,126.54,123.99,121.15,58.38,55.38,40.59,40.50,40.42,40.33,40.16,40.00,39.83,39.66,39.50,27.34,23.87,18.29,14.15。ESI-HRMS m/z:523.2463[M+H]+。
实施例17
化合物I-35的合成：
化合物I-35的合成方法参考化合物4a的合成，投入化合物16a(240mg，0.57mol)和2-甲酸吡嗪(106mg，0.86mmol)，得到240mg化合物I-35，淡黄色固体，收率80％。1H NMR(500MHz,DMSO-d6)δ10.52(s,1H),9.13(d,J＝2.3Hz,1H),8.82-8.74(m,1H),8.31(dt,J＝8.0,2.0Hz,1H),8.19(s,1H),7.86(d,J＝8.3Hz,2H),7.65(d,J＝8.3Hz,2H),7.62-7.57(m,3H),7.39(d,J＝7.8Hz,2H),7.21(d,J＝5.7Hz,1H),5.00(s,1H),4.61(s,1H),4.42-4.23(m,2H),1.77(s,1H),1.47(d,J＝7.0Hz,3H),0.67(s,3H),0.46(s,3H)。13C NMR(126MHz,DMSO-d6)δ165.06,162.17,158.67,158.31,158.20,154.88,154.66,148.21,145.51,144.55,144.34,143.71,138.54,137.99,136.26,127.20,126.81,126.55,121.41,58.73,54.08,40.49,40.41,40.32,40.15,39.99,39.82,39.65,39.49,27.42,23.58,18.54,17.18。ESI-HRMS m/z:524.2412[M+H]+。
实施例18
化合物I-36的合成：
化合物I-36的合成方法参考化合物4a的合成，投入化合物16a(200mg，0.48mol)和呋喃[3,2-b]吡啶-2-羧酸(116mg，0.72mmol)，得到77mg化合物I-36，白色固体，收率28.5％。1H NMR(500MHz,DMSO-d6)δ10.63(s,1H),8.19(s,1H),7.96-7.90(m,2H),7.84(d,J＝7.9Hz,1H),7.80(s,1H),7.74(d,J＝8.4Hz,1H),7.65(d,J＝8.3Hz,2H),7.60(d,J＝8.0Hz,2H),7.54-7.49(m,1H),7.38(t,J＝7.5Hz,3H),7.22(d,J＝5.7Hz,1H),5.01(s,1H),4.61(s,1H),4.41-4.21(m,2H),1.77(s,1H),1.47(d,J＝7.1Hz,3H),0.67(s,3H),0.47(s,3H)。13C NMR(126MHz,DMSO-d6)δ162.77,161.58,159.42,157.10,154.95,149.26,145.50,138.24,138.10,136.22,131.99,131.92,129.27,127.66,127.63,127.18,126.66,124.35,123.41,121.33,112.43,111.22,58.38,54.07,40.59,40.50,40.42,40.33,40.16,39.99,39.83,39.66,39.49,27.34,23.89,18.55,18.28。ESI-HRMS m/z:562.2455[M+H]+。
实施例19
化合物10a的合成：
化合物10a的合成方法参考化合物1a的合成，投入化合物2,4-二氯嘧啶(1.00g,6.71mmol)和(S)-4-苯基-噁唑烷-2-酮(927mg,6.71mmol)，得到860mg化合物10a，白色固体，收率85.9％。ESI-HRMS m/z:276.0508[M+H]+。
化合物I-37的合成：
化合物I-37的合成参考化合物I-17的合成路线，最终投入化合物40a(70mg，0.155mol)和反式-3-(3-吡啶基)丙烯酸(34mg,0.23mmol)，得到36mg化合物I-37，黄色固体，收率46％。1H NMR(600MHz,DMSO-d6)δ10.39(s,1H),8.85(d,J＝2.3Hz,1H),8.60(dd,J＝4.8,1.6Hz,1H),8.19-8.12(m,1H),8.06(dt,J＝8.1,1.9Hz,1H),7.80(d,J＝8.2Hz,2H),7.71-7.58(m,4H),7.50(dd,J＝7.9,4.7Hz,1H),7.47-7.13(m,9H),7.05(s,1H),6.96(d,J＝15.8Hz,1H),5.89(s,1H),4.94(s,1H),4.84(t,J＝8.5Hz,1H),4.22(s,1H),1.41(d,J＝6.9Hz,3H)。13C NMR(101MHz,DMSO-d6)δ167.76,163.64,161.50,157.09,154.94,150.94,149.82,141.15,140.95,138.94,138.34,137.44,135.72,135.10,134.68,131.10,129.35,128.24,127.40,127.07,126.52,124.74,124.60,124.44,121.86,120.23,71.05,57.52,40.69,40.48,40.28,40.07,39.86,39.65,39.44,23.09。ESI-HRMS m/z:583.2454[M+H]+。
实施例20
化合物I-40的合成：
化合物I-40的合成方法参考化合物I-24的合成路线二，投入化合物46a(150mg，0.33mmol)得174mg化合物I-40，淡黄色固体粉末，收率95％。1H NMR(300MHz,DMSO-d6)δ10.34(s,1H),9.06(d,J＝1.8Hz,2H),8.39(d,J＝2.9Hz,1H),8.22(dd,J＝4.6,1.4Hz,1H),8.19(d,J＝1.5Hz,1H),7.79(d,J＝3.3Hz,4H),7.74(s,1H),7.48-7.42(m,1H),7.37(dd,J＝8.5,4.5Hz,1H),7.23(d,J＝5.8Hz,1H),5.13-4.92(m,1H),4.85(s,2H),4.55-4.08(m,3H),2.55(s,1H),1.55(t,J＝7.7Hz,3H),0.96(d,J＝7.0Hz,2H),0.76(d,J＝6.9Hz,2H),0.46(d,J＝31.3Hz,2H)。13C NMR(126MHz,DMSO-d6)δ166.84,155.02,154.97,154.85,154.65,142.71,139.35,138.44,129.48,127.66,127.53,124.64,121.85,120.73,120.65,67.58,63.33,58.60,21.07,18.24,18.12,14.41。ESI-HRMS m/z:577.2277[M+Na]+。
实施例21
化合物I-41的合成：
化合物I-41的合成方法参考化合物I-37的合成，投入化合物49a(250mg，0.5mmol)，得200mg淡黄色固体I-37，收率86％。1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),8.83(d,J＝2.2Hz,1H),8.59(dd,J＝4.8,1.6Hz,1H),8.22(s,1H),8.05(dt,J＝8.1,2.0Hz,1H),7.87(s,1H),7.81-7.59(m,4H),7.49(dd,J＝8.0,4.8Hz,2H),7.42(s,4H),7.20(d,J＝6.7Hz,4H),6.94(d,J＝15.9Hz,2H),5.15(s,1H),4.99(tt,J＝8.0,3.0Hz,1H),4.38(t,J＝8.5Hz,1H),4.16(s,1H),3.28-2.93(m,1H),2.68(s,1H),1.51(d,J＝7.0Hz,3H)。13C NMR(101MHz,DMSO-d6)δ163.54,161.77,159.48,157.27,154.37,150.87,149.76,145.20,138.80,138.38,137.37,136.27,135.66,134.61,131.01,129.84,128.77,127.32,127.08,126.68,124.63,124.52,120.02,97.91,66.31,36.39,31.44,23.74。ESI-HRMS m/z:597.2603[M+H]+。
实施例22
化合物I-42的合成：
化合物I-42的合成方法参考化合物I-41的合成，投入化合物49a(250mg,0.5mmol)，得230mg化合物I-42，白色固体，收率76％。1H NMR(300MHz,DMSO-d6)δ10.20(s,1H),8.38(d,J＝2.9Hz,1H),8.21(dd,J＝4.5,1.4Hz,2H),7.90(s,1H),7.64(s,3H),7.45(dd,J＝2.9,1.4Hz,2H),7.43-7.39(m,3H),7.36(dd,J＝8.6,4.7Hz,2H),7.20(d,J＝5.8Hz,4H),6.90(s,1H),5.14(s,1H),4.98(tt,J＝7.7,2.9Hz,1H),4.82(s,2H),4.38(t,J＝8.5Hz,1H),4.15(s,1H),3.11(s,1H),2.65(s,1H),1.50(d,J＝7.0Hz,3H)。13C NMR(126MHz,DMSO-d6)δ166.57,161.78,157.28,154.65,154.37,145.23,142.76,138.53,138.31,137.97,136.28,135.91,128.77,127.22,127.08,126.70,124.59,121.73,120.42,67.59,66.32,55.38,23.67。ESI-HRMS m/z:601.2555[M+H]+。
实施例23
化合物I-43的合成：
化合物I-43的合成方法参考I-41的合成，投入化合物49a(250mg,0.5mmol)，得220mg化合物I-43，白色固体，收率73％。1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),9.28(s,1H),8.23(s,1H),8.13(s,1H),7.91(s,1H),7.77(d,J＝9.4Hz,3H),7.73-7.66(m,2H),7.43(s,5H),7.20(d,J＝5.9Hz,5H),6.91(s,1H),5.26-5.07(m,1H),5.00(dq,J＝8.1,4.6,3.7Hz,1H),4.38(t,J＝8.5Hz,1H),4.17(d,J＝13.1Hz,1H),3.18(s,1H),2.68(s,1H),1.52(d,J＝7.0Hz,3H)。13C NMR(126MHz,DMSO-d6)δ163.84,161.79,157.29,154.38,145.25,145.01,138.62,138.36,136.29,135.96,134.85,129.88,129.42,128.78,127.16,126.72,123.89,121.03,120.73,116.56,114.89,66.32,55.38,23.68。ESI-HRMS m/z:610.2552[M+H]+。
实施例24
化合物51a的合成：
参考专利WO 2014/141104 Al合成化合物51a。
化合物I-44的合成：
将铁粉(168mg,3mmol)和氯化铵(161mg,3mmol)溶于4mL水和10mL丙酮中，氮气保护，加热至70℃回流反应30min。将化合物53a(302mg,0.6mmol)溶于10mL丙酮并注入到反应液中，继续反应6h后停止加热，冷却至室温，反应液经硅藻土抽滤，并用50mL二氯甲烷淋洗滤饼，滤液减压浓缩后溶于100mL二氯甲烷中，依次用水和饱和食盐水水洗涤1次，每次50mL。有机相经减压浓缩除去溶剂后溶于6mL无水DMF，向其中加入DIPEA(194mg,1.5mmol)、反式-3-(3-吡啶基)丙烯酸(112mg，0.75mmol)，冰浴下搅拌10分钟后加入HATU(381mg，1mmol)，10分钟后移除冰浴，室温反应4小时。TLC监测反应结束后，向反应液中加入10mL冰水淬灭反应，再加入10mL乙酸乙酯搅拌10分钟后加入100mL乙酸乙酯溶解并转移混合液至分液漏斗，依次用水、饱和碳酸氢钠、饱和食盐水洗涤一次，每次30mL，有机相经无水硫酸钠干燥后减压浓缩，经快速柱层析(DCM:MeOH＝80:1到DCM:MeOH＝40:1,v:v)得到220mg化合物I-44，淡黄色固体，收率60％。1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),8.84(d,J＝2.2Hz,1H),8.60(dd,J＝4.7,1.6Hz,1H),8.20(d,J＝5.7Hz,1H),8.06(dt,J＝8.0,2.0Hz,1H),7.79(d,J＝8.7Hz,2H),7.69-7.58(m,5H),7.49(dd,J＝8.0,4.8Hz,1H),7.45(d,J＝8.4Hz,2H),7.24(d,J＝5.7Hz,1H),6.95(d,J＝15.8Hz,1H),5.33-5.21(m,1H),4.75-4.67(m,1H),4.46-4.37(m,2H),4.27(s,1H),1.52(d,J＝6.9Hz,3H),1.07(s,9H),0.90-0.79(m,3H)。13CNMR(101MHz,DMSO-d6)δ163.56,157.61,155.04,150.89,149.78,138.93,138.49,137.39,135.53,134.60,131.00,127.37,127.05,126.61,124.63,124.54,120.13,74.00,64.66,63.63,56.96,55.39,28.51,16.20。ESI-HRMS m/z:607.3024[M+H]+。
实施例25
化合物I-45的合成：
化合物I-45的合成方法参考化合物I-44的合成，将其中的反式-3-(3-吡啶基)丙烯酸替换为3-吡啶氧基乙酸(115mg,0.75mmol)，得230mg化合物I-45，淡黄色固体粉末，收率62％。1H NMR(400MHz,DMSO-d6)δ10.25(s,1H),8.39(d,J＝2.9Hz,1H),8.24-8.15(m,2H),7.72(d,J＝8.8Hz,2H),7.65-7.56(m,4H),7.44(d,J＝8.8Hz,3H),7.37(dd,J＝8.4,4.5Hz,1H),7.24(d,J＝5.6Hz,1H),5.26(s,1H),4.83(s,2H),4.71(dt,J＝7.2,4.9Hz,1H),4.50-4.36(m,2H),4.26(s,1H),1.52(d,J＝6.9Hz,3H),1.31-0.92(m,9H),0.84(s,3H)。13C NMR(126MHz,DMSO-d6)δ166.61,155.04,154.65,142.77,138.53,138.42,138.10,135.77,127.27,127.04,126.63,124.59,121.73,120.54,74.00,67.59,64.69,63.64,56.98,28.52,16.21。ESI-HRMS m/z:611.2974[M+H]+。
实施例26
化合物I-46的合成：
化合物I-46的合成方法参考化合物I-44的合成，将其中的反式-3-(3-吡啶基)丙烯酸替换为咪唑并[1,2-a]吡啶-6-甲酸(122mg，0.75mmol)，得到215mg化合物I-46，淡黄色固体粉末，收率61％。1H NMR(400MHz,DMSO-d6)δ10.46(s,1H),9.29(s,1H),8.20(d,J＝5.7Hz,1H),8.13(s,1H),7.86(d,J＝8.7Hz,2H),7.78(dd,J＝9.5,1.8Hz,1H),7.74-7.59(m,6H),7.46(d,J＝8.2Hz,2H),7.24(d,J＝5.7Hz,1H),5.28(s,1H),4.77-4.65(m,1H),4.53-4.36(m,2H),4.27(s,1H),1.53(d,J＝6.9Hz,3H),1.06(s,9H),0.85(d,J＝5.7Hz,3H)。13C NMR(101MHz,DMSO-d6)δ163.91,157.61,155.05,145.09,138.76,138.46,135.80,135.06,129.42,127.20,127.06,126.65,123.73,121.13,120.64,116.65,114.87,74.00,64.67,63.64,56.97,55.39,28.51,16.20。ESI-HRMS m/z:620.2969[M+H]+。
实施例27
化合物I-47的合成：
将化合物I-44(150mg，0.247mmol)溶于1mL无水二氯甲烷中，加入2mL三氟乙酸，室温搅拌16小时。TLC监测反应结束后，向反应液中加入10mL乙酸乙酯，剧烈搅拌下缓慢滴加饱和碳酸氢钠溶液，直至没有气泡产生。用50mL乙酸乙酯萃取，有机相依次用饱和碳酸氢钠溶液、饱和食盐水洗涤一次，每次各20mL。有机相经无水硫酸钠干燥后减压浓缩，经快速柱层析(DCM:MeOH＝50:1-20:1,v:v)得到125mg化合物I-47，黄色固体，收率92％。1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),8.84(d,J＝2.2Hz,1H),8.60(dd,J＝4.8,1.6Hz,1H),8.15(d,J＝5.6Hz,1H),8.06(d,J＝8.1Hz,1H),7.89(s,1H),7.79(d,J＝8.7Hz,2H),7.69-7.56(m,5H),7.49(dt,J＝10.0,5.1Hz,3H),7.17(d,J＝5.5Hz,1H),6.96(d,J＝15.8Hz,1H),5.17-4.95(m,2H),4.84-4.75(m,1H),4.51-4.35(m,2H),4.03(s,1H),1.47(d,J＝7.0Hz,3H),0.65(s,3H)。13C NMR(126MHz,DMSO-d6)δ163.57,157.40,155.01,150.87,149.75,145.31,138.86,138.44,137.37,135.75,134.61,131.03,127.40,127.02,126.63,124.68,124.52,120.14,64.06,63.73,57.46,50.13,23.52。ESI-HRMS m/z:551.2398[M+H]+。
实施例28
化合物I-48的合成：
化合物I-48的合成方法参考化合物I-47的合成，将其中的化合物I-44替换为化合物I-45(151mg，0.247mmol)，得到126mg化合物I-48，白色固体粉末，收率92％。1H NMR(400MHz,DMSO-d6)δ10.22(s,1H),8.39(d,J＝2.9Hz,1H),8.22(dd,J＝4.5,1.3Hz,1H),8.15(d,J＝5.7Hz,1H),7.85(s,1H),7.71(d,J＝8.7Hz,2H),7.65-7.55(m,4H),7.51-7.41(m,3H),7.37(dd,J＝8.4,4.6Hz,1H),7.17(d,J＝5.7Hz,1H),5.10(s,1H),4.98(s,1H),4.83(s,2H),4.79(ddd,J＝8.5,4.0,2.8Hz,1H),4.49-4.37(m,2H),4.03(s,1H),1.47(d,J＝7.0Hz,3H),0.65(s,3H)。13C NMR(126MHz,DMSO-d6)δ166.60,161.59,155.00,154.65,145.36,142.76,138.53,138.36,138.03,135.98,127.30,127.01,126.64,124.60,121.73,120.52,67.60,64.04,63.72,57.45,50.12,23.52。ESI-HRMS m/z:555.2346[M+H]+。
实施例29
化合物I-49的合成：
化合物I-49的合成方法参考化合物I-47的合成，将其中的化合物I-44替换为化合物I-46(153mg，0.247mmol)，得到127mg化合物I-49，白色固体粉末，收率92％。1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),9.28(s,1H),8.21-8.08(m,2H),7.85(d,J＝8.7Hz,2H),7.77(dd,J＝9.5,1.8Hz,1H),7.73-7.64(m,4H),7.61(d,J＝8.1Hz,2H),7.48(d,J＝7.9Hz,2H),7.18(d,J＝5.7Hz,1H),5.11(s,1H),4.99(s,1H),4.83-4.76(m,1H),4.47(dd,J＝9.0,2.8Hz,1H),4.41(t,J＝8.7Hz,1H),3.98(d,J＝56.8Hz,1H),1.48(d,J＝7.0Hz,3H),0.67(s,3H)。13C NMR(126MHz,DMSO-d6)δ163.91,157.39,155.01,145.36,145.10,138.68,138.40,136.03,135.04,129.40,127.24,127.03,126.66,123.75,121.14,120.68,116.64,114.86,64.06,63.73,57.46,50.13,49.08,23.52。ESI-HRMS m/z:564.2349[M+H]+。
实施例30
化合物55a的合成：
参考专利WO 2014/141104 Al合成化合物55a。
化合物I-50的合成：
化合物I-50的合成方法参考化合物I-44的合成，投入化合物57a(160mg，0.35mmol)，得到170mg化合物I-50，淡黄色固体，收率86％。1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),8.83(d,J＝2.2Hz,1H),8.59(dd,J＝4.8,1.6Hz,1H),8.21(s,1H),8.05(d,J＝8.1Hz,1H),7.92(s,1H),7.81-7.75(m,2H),7.68-7.57(m,5H),7.49(dd,J＝8.0,4.8Hz,1H),7.38(d,J＝7.7Hz,2H),7.22(d,J＝5.6Hz,1H),6.95(d,J＝15.8Hz,1H),4.96(s,1H),4.73(dd,J＝30.0,8.1Hz,1H),4.38(d,J＝49.4Hz,3H),1.46(d,J＝7.0Hz,3H),1.24(d,J＝6.7Hz,1H),1.08(d,J＝23.6Hz,2H)。13C NMR(126MHz,DMSO-d6)δ163.57,161.51,159.68,154.51,150.87,149.76,138.90,138.31,137.38,135.56,134.61,131.02,127.34,126.66,126.37,124.66,124.52,120.17,97.50,89.01,87.65,62.29,50.33,23.99,16.79,16.63。ESI-HRMS m/z:575.2173[M+Na]+。
实施例31
化合物I-51的合成：
化合物I-51的合成方法参考化合物I-45的合成，投入化合物57a(160mg，0.35mmol)，得到188mg化合物I-51，淡黄色固体，收率97％。1H NMR(400MHz,DMSO-d6)δ10.22(s,1H),8.38(d,J＝3.0Hz,1H),8.21(d,J＝4.4Hz,2H),7.91(s,1H),7.71(d,J＝8.5Hz,2H),7.65-7.55(m,4H),7.46-7.32(m,4H),7.22(d,J＝5.6Hz,1H),4.96(s,1H),4.82(s,2H),4.72(dd,J＝30.6,7.7Hz,1H),4.38(d,J＝49.9Hz,3H),1.45(d,J＝7.0Hz,3H),1.07(d,J＝25.0Hz,3H)。13C NMR(126MHz,DMSO-d6)δ166.61,161.52,159.69,156.91,154.65,154.51,145.36,142.77,138.53,138.23,138.08,135.79,127.25,126.68,126.36,124.59,121.72,120.55,97.49,67.59,62.27,55.38,50.33,23.99,16.79,16.62。ESI-HRMS m/z:579.2120[M+Na]+。
实施例32
化合物I-52的合成：
化合物I-52的合成方法参考化合物I-46的合成，投入化合物57a(50mg，0.35mmol)，得到55mg化合物I-52，淡黄色固体，收率88％。1H NMR(400MHz,DMSO-d6)δ10.46(s,1H),9.29(s,1H),8.22(s,1H),8.13(s,1H),7.96(s,1H),7.86(d,J＝8.8Hz,2H),7.78(dd,J＝9.5,1.8Hz,1H),7.73-7.70(m,1H),7.69(s,1H),7.66(s,1H),7.64(d,J＝7.9Hz,2H),7.49-7.34(m,2H),7.23(d,J＝5.6Hz,1H),5.05(d,J＝58.8Hz,1H),4.73(dd,J＝30.5,8.4Hz,1H),4.45(s,2H),4.26(d,J＝56.6Hz,1H),1.46(d,J＝7.0Hz,3H),1.24(s,1H),1.10(d,J＝23.3Hz,2H)。13C NMR(126MHz,DMSO-d6)δ163.84,154.52,144.90,138.72,138.28,135.86,134.60,129.49,127.18,126.70,126.37,124.11,121.17,120.85,116.47,114.94,97.51,62.29,55.38,23.99,16.80,16.63。ESI-HRMS m/z:566.2305[M+H]+。
实施例33
/>
化合物I-53的合成：
化合物I-53的合成方法参考I-44的合成，投入化合物59a(333mg，0.66mmol)，得到360mg化合物I-53，淡黄色固体粉末，收率90％。1H NMR(400MHz,DMSO-d6)δ10.45(s,1H),8.84(dd,J＝8.7,2.3Hz,2H),8.60(dd,J＝4.7,1.6Hz,1H),8.22(d,J＝5.1Hz,1H),8.10-7.98(m,2H),7.84(d,J＝8.5Hz,2H),7.79-7.67(m,3H),7.65(s,1H),7.53-7.42(m,2H),7.26(d,J＝5.7Hz,1H),6.96(d,J＝15.9Hz,1H),5.29(s,1H),4.68(s,1H),4.43(s,2H),4.28(s,1H),1.56(d,J＝7.0Hz,3H),1.06(s,9H),0.77(s,3H)。13C NMR(126MHz,DMSO-d6)δ163.67,161.94,159.42,157.63,155.04,150.90,149.76,146.86,139.56,137.54,134.82,134.63,133.86,132.44,130.99,127.62,124.58,124.52,120.29,98.30,74.04,64.60,63.62,57.09,55.37,51.34,28.69,28.49,16.07。ESI-HRMS m/z:608.2968[M+H]+。
实施例34
化合物I-54的合成：
化合物I-54的合成方法参考化合物I-45的合成，投入化合物59a(333mg，0.66mmol)，得到380mg化合物I-54，白色固体粉末，收率94％。1H NMR(400MHz,DMSO-d6)δ10.29(s,1H),8.81(d,J＝2.4Hz,1H),8.39(d,J＝3.0Hz,1H),8.22(d,J＝4.8Hz,2H),8.03(dd,J＝8.3,2.4Hz,1H),7.76(d,J＝8.4Hz,2H),7.69(d,J＝8.4Hz,2H),7.44(d,J＝8.5Hz,2H),7.37(dd,J＝8.5,4.6Hz,1H),7.26(d,J＝5.7Hz,1H),5.28(s,1H),4.84(s,2H),4.67(d,J＝8.8Hz,1H),4.42(s,2H),4.27(s,1H),1.55(d,J＝7.0Hz,3H),1.05(s,9H),0.77(s,3H)。13C NMR(101MHz,DMSO-d6)δ166.74,162.02,157.62,155.04,154.63,146.88,142.76,138.74,138.51,134.86,133.77,132.67,127.54,124.60,121.71,120.64,98.27,74.04,67.55,64.58,63.61,57.06,51.34,28.47,16.07。ESI-HRMS m/z:612.2926[M+H]+。
实施例35
化合物I-55的合成：
化合物I-55的合成方法参考化合物I-46的合成，投入化合物59a(333mg，0.66mmol)，得到350mg化合物I-55，白色固体粉末，收率86％。1H NMR(400MHz,DMSO-d6)δ10.50(s,1H),9.29(s,1H),8.85(d,J＝2.3Hz,1H),8.23(d,J＝6.1Hz,1H),8.13(s,1H),8.07(dd,J＝8.2,2.4Hz,1H),7.91(d,J＝8.7Hz,2H),7.81-7.67(m,5H),7.46(d,J＝8.2Hz,1H),7.26(d,J＝5.7Hz,1H),5.29(s,1H),4.68(dt,J＝7.9,4.6Hz,1H),4.42(d,J＝4.0Hz,2H),4.29(s,1H),1.56(d,J＝7.0Hz,3H),1.06(s,9H),0.78(s,3H)。13C NMR(126MHz,DMSO-d6)δ164.00,162.01,157.64,155.04,146.90,145.10,139.41,135.06,134.86,133.82,132.73,129.46,127.46,123.72,121.26,120.60,116.66,114.87,74.05,64.62,63.62,57.09,51.36,28.50,16.08。ESI-HRMS m/z:621.2928[M+H]+。
实施例36
化合物I-56的合成：
化合物I-56的合成方法参考化合物I-47的合成，投入化合物I-53(260mg，0.42mmol)，得到200mg化合物I-56，淡黄色固体粉末，收率86％。1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),8.83(dd,J＝15.3,2.3Hz,2H),8.60(dd,J＝4.8,1.6Hz,1H),8.18(s,1H),8.06(d,J＝8.1Hz,1H),8.00(dd,J＝8.2,2.4Hz,1H),7.84(d,J＝8.7Hz,2H),7.79-7.62(m,4H),7.50(dd,J＝8.0,4.8Hz,1H),7.43(d,J＝8.2Hz,1H),7.30-7.15(m,1H),6.96(d,J＝15.8Hz,1H),5.12(t,J＝1.6Hz,1H),4.79(d,J＝55.5Hz,2H),4.41(s,2H),3.77(s,1H),1.51(d,J＝7.0Hz,3H),0.91(t,J＝7.4Hz,1H),0.55(s,2H)。13C NMR(126MHz,DMSO-d6)δ163.66,162.81,157.52,155.03,150.88,149.75,146.97,139.50,137.52,134.78,134.64,133.78,131.00,129.13,127.66,124.60,124.53,120.26,65.49,64.11,63.82,57.50,51.90,30.47,19.12,14.01。ESI-HRMS m/z:552.2347[M+H]+。
实施例37
化合物I-57的合成：
化合物I-57的合成方法参考化合物I-47的合成，投入化合物I-54(280mg，0.46mmol)得到220mg化合物I-57，白色固体，收率87％。1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),8.81(d,J＝2.3Hz,1H),8.41(d,J＝2.9Hz,1H),8.24(d,J＝4.6Hz,1H),8.19(s,1H),8.03(dd,J＝8.2,2.4Hz,1H),7.98-7.81(m,1H),7.80-7.66(m,4H),7.52-7.38(m,3H),7.24(d,J＝5.8Hz,1H),5.14(d,J＝13.5Hz,1H),4.86(s,4H),4.41(s,2H),3.75(s,1H),1.52(d,J＝7.0Hz,3H),0.97(d,J＝6.1Hz,1H),0.56(s,2H)。13C NMR(101MHz,DMSO-d6)δ166.70,162.49,157.71,154.98,154.78,146.66,142.32,138.78,138.05,135.26,133.90,132.65,127.62,124.82,122.31,120.59,67.55,64.07,63.88,57.52,51.79,21.94。ESI-HRMS m/z:556.2294[M+H]+。
实施例38
/>
化合物I-58的合成：
化合物I-58的合成方法参考化合物I-47的合成，投入化合物I-55(240mg，0.42mmol)，得到200mg化合物I-58，白色固体粉末，收率90％。1H NMR(400MHz,DMSO-d6)δ10.50(s,1H),9.29(t,J＝1.4Hz,1H),8.83(d,J＝2.4Hz,1H),8.18(s,1H),8.15-8.10(m,1H),8.02(dd,J＝8.2,2.4Hz,1H),7.90(d,J＝8.7Hz,2H),7.79(d,J＝1.8Hz,1H),7.78-7.74(m,2H),7.74-7.65(m,3H),7.44(d,J＝8.0Hz,1H),7.21(s,1H),5.13(d,J＝10.6Hz,1H),4.87(s,1H),4.72(s,1H),4.41(s,2H),3.78(s,1H),1.52(d,J＝7.0Hz,3H),1.07-0.90(m,1H),0.56(s,2H)。13C NMR(126MHz,DMSO-d6)δ164.00,162.91,155.04,147.04,145.10,139.33,135.05,134.79,133.73,129.46,127.50,123.74,121.24,120.61,120.35,116.66,114.87,64.11,63.82,57.50,55.37,51.92,21.98。ESI-HRMS m/z:565.2298[M+H]+。
实施例39
化合物I-59的合成：
化合物I-59的合成方法参考化合物I-50的合成，投入化合物61a(135mg,0.30mmol)，得到150mg化合物I-59，淡黄色固体粉末，收率90％。1H NMR(400MHz,DMSO-d6)δ10.45(s,1H),8.84(dd,J＝4.8,2.2Hz,2H),8.60(dd,J＝4.8,1.6Hz,1H),8.26(d,J＝5.6Hz,1H),8.10-8.00(m,2H),7.96(d,J＝7.2Hz,1H),7.88-7.80(m,2H),7.77-7.62(m,3H),7.50(dd,J＝7.9,4.8Hz,1H),7.41-7.34(m,1H),7.25(d,J＝5.6Hz,1H),6.96(d,J＝15.8Hz,1H),4.97(s,1H),4.66(d,J＝31.2Hz,1H),4.42(s,2H),4.37-4.15(m,1H),1.51(d,J＝7.1Hz,3H),1.23(s,1H),1.01(dd,J＝23.8,6.4Hz,2H)。13C NMR(126MHz,DMSO-d6)δ163.67,159.74,154.47,150.89,149.76,147.02,139.54,137.53,134.86,134.64,133.67,132.45,131.00,127.58,124.59,124.52,120.31,89.08,87.72,62.33,22.01,16.85,16.68。ESI-HRMS m/z:554.2303[M+H]+。
实施例40
化合物I-60的合成：
化合物I-60的合成方法参考化合物I-51的合成，投入化合物61a(135mg，0.30mmol)，得到160mg化合物I-60，白色固体，收率95％。1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),8.82(s,1H),8.39(d,J＝3.0Hz,1H),8.23(dd,J＝14.1,5.1Hz,2H),7.99(dd,J＝31.1,7.4Hz,2H),7.85-7.62(m,4H),7.44(dd,J＝8.5,3.0Hz,1H),7.37(dd,J＝8.4,4.3Hz,2H),7.24(d,J＝5.7Hz,1H),4.97(s,1H),4.84(s,2H),4.65(d,J＝30.6Hz,1H),4.41(d,J＝8.0Hz,2H),4.36-4.12(m,1H),1.50(d,J＝7.1Hz,3H),1.24(s,1H),1.00(dd,J＝24.1,6.3Hz,2H)。13C NMR(101MHz,DMSO-d6)δ166.74,163.59,159.78,156.85,154.63,154.47,147.04,142.76,138.73,138.51,134.90,133.57,132.67,127.49,124.61,121.71,120.66,119.29,97.61,89.25,67.54,62.32,57.75,52.50,22.02,16.87,16.66。ESI-HRMS m/z:558.2250[M+H]+。
实施例41
化合物I-61的合成：
化合物I-61的合成方法参考化合物I-52的合成，投入化合物61a(135mg，0.30mmol)，得到150mg化合物I-61，白色固体，收率88％。1H NMR(400MHz,DMSO-d6)δ10.51(s,1H),9.34-9.26(m,1H),8.86(d,J＝2.4Hz,1H),8.26(d,J＝5.6Hz,1H),8.14(s,1H),8.06(d,J＝8.3Hz,1H),7.96(d,J＝7.3Hz,1H),7.93-7.85(m,2H),7.83-7.63(m,5H),7.45-7.35(m,1H),7.25(d,J＝5.7Hz,1H),4.98(s,1H),4.66(d,J＝31.4Hz,1H),4.42(d,J＝8.1Hz,2H),4.30(d,J＝53.0Hz,1H),1.51(d,J＝7.1Hz,3H),1.24(d,J＝6.9Hz,1H),1.02(dd,J＝24.2,6.3Hz,2H)。13C NMR(126MHz,DMSO-d6)δ163.97,154.48,147.06,145.00,139.37,134.90,134.83,133.63,132.75,129.49,127.42,123.92,121.28,120.71,119.34,116.57,114.92,97.64,89.10,87.74,62.35,57.76,55.36,52.51,22.02,16.85,16.69。ESI-HRMS m/z:567.2255[M+H]+。
实施例42
化合物I-62的合成：
化合物I-62的合成步骤参考化合物I-15，投入化合物66a(200mg，0.352mmol)和反式-3-(3-吡啶基)丙烯酸(53mg，0.357mmol)，得到86mg化合物I-62，白色固体，收率49.8％。1H NMR(300MHz,DMSO-d6)δ9.89(s,1H),8.74(d,J＝2.2Hz,1H),8.54(d,J＝4.8Hz,1H),8.27(t,J＝5.8Hz,1H),8.14(d,J＝5.6Hz,1H),7.95(d,J＝8.0Hz,1H),7.64(s,1H),7.58-7.37(m,4H),7.29(d,J＝8.2Hz,2H),7.10(d,J＝5.6Hz,1H),6.75(d,J＝15.9Hz,1H),5.03(s,1H),4.79(s,1H),4.52(t,J＝8.9Hz,1H),4.32(s,1H),3.46(q,J＝6.4Hz,2H),2.55(d,J＝6.9Hz,2H),1.44(d,J＝6.9Hz,3H),1.24(m,1H),0.61(s,6H)。13C NMR(75MHz,DMSO-d6)δ169.10,164.53,159.11,154.39,152.06,150.00,148.99,140.78,138.19,137.40,135.17,133.81,130.64,125.79,124.15,123.85,121.80,118.97,118.96,110.75,63.70,58.89,54.83,49.92,39.79,36.16,35.25,27.14,23.24,17.21,14.14。ESI-HRMS m/z:600.2383[M+H]+。
实施例43
化合物I-63的合成：
化合物I-63的合成步骤参考化合物I-16的合成，投入化合物68a(150mg，0.32mmol)和反-3-(3-吡啶基)丙烯酸(71mg，0.48mol)得到54mg化合物I-63，淡黄色固体粉末，收率27.3％。1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.79(s,1H),8.55(s,1H),8.11(s,1H),8.00(d,J＝7.3Hz,1H),7.74(d,J＝7.2Hz,3H),7.66-7.34(m,8H),7.07(d,J＝4.7Hz,1H),6.93(d,J＝14.9Hz,1H),5.07(s,1H),4.74(s,1H),4.47(s,1H),4.29(s,1H),2.99(s,1H),1.45(d,J＝5.6Hz,3H),0.71(s,3H),0.49(s,3H)。13C NMR(100MHz,DMSO-d6)δ163.63,159.70,155.92,155.00,152.69,150.95,149.83,138.92,138.36,137.39,135.76,134.66,131.09,127.38,126.70,124.76,124.59,122.37,120.20,111.41,64.31,59.50,59.46,55.45,46.12,27.71,23.92,17.83,14.70。ESI-HRMS m/z:605.2337[M+H]+。
实施例44
化合物I-64的合成：
化合物I-64的合成步骤参考化合物I-16的合成，投入化合物68a(150mg，0.32mmol)和咪唑并[1,2-a]吡啶-6-甲酸(77mg，0.48mmol)，得到71mg固体化合物I-64，收率36.3％。1H NMR(400MHz,DMSO-d6)δ10.38(s,1H),9.23(s,1H),8.11(d,J＝5.5Hz,1H),8.08(s,1H),7.81(s,1H),7.67-7.64(m,5H),7.59(d,J＝8.6Hz,2H),7.55(d,J＝8.2Hz,2H),7.41(d,J＝7.4Hz,2H),7.08(d,J＝5.5Hz,1H),5.05(s,1H),4.72(s,1H),4.47(s,1H),4.28(s,1H),1.45(d,J＝7.0Hz,3H),1.19(s,1H),0.61(s,3H),0.46(s,3H)。13C NMR(100MHz,DMSO-d6)δ163.98,159.76,157.45,155.01,154.45,152.68,145.16,144.65,138.72,138.30,136.05,135.31,135.14,129.46,127.23,126.74,123.77,121.19,120.71,116.73,114.93,111.41,64.31,59.47,55.46,27.70,17.83,14.68。ESI-HRMS m/z:618.2291[M+H]+。
实施例45
化合物I-71的合成：
化合物I-71的合成步骤参考化合物I-17的合成，投入化合物71a(130mg，0.274mmol)和反-3-(3-吡啶基)丙烯酸(61.4mg，0.412mol)，得到106mg化合物I-71，淡黄色固体粉末，收率63％。1H NMR(300MHz,DMSO-d6)δ10.38(s,1H),8.84(d,J＝2.2Hz,1H),8.59(dd,J＝4.8,1.6Hz,1H),8.16(d,J＝5.6Hz,1H),8.05(dt,J＝7.7,1.8Hz,1H),7.78(d,J＝8.6Hz,3H),7.67(s,1H),7.63-7.55(m,4H),7.49(dd,J＝7.9,4.8Hz,1H),7.44(d,J＝7.9Hz,2H),7.12(d,J＝5.6Hz,1H),6.95(d,J＝15.8Hz,1H),5.10(s,1H),4.78(s,1H),4.52(t,J＝9.1Hz,1H),4.32(s,1H),1.49(d,J＝7.1Hz,3H),1.25(d,J＝4.5Hz,1H),0.50(s,6H)。13C NMR(101MHz,DMSO-d6)δ163.62,159.76,155.01,152.69,150.94,149.89,149.82,139.07,138.97,138.89,138.35,137.43,135.77,134.67,131.08,127.38,126.81,126.70,126.59,124.73,124.59,122.40,120.21,111.41,64.31,59.46,40.69,40.48,40.27,40.06,39.85,39.64,39.43,27.71,17.82,14.70。ESI-HRMS m/z:605.2337[M+H]+。
实施例46
化合物I-72的合成：
化合物I-72的合成步骤参考I-16的合成，投入化合物71a(300mg，0.63mmol)和咪唑并[1,2-a]吡啶-6-甲酸(154mg，0.95mmol)，得到226mg化合物I-72，白色固体，收率76.3％。1H NMR(300MHz,DMSO-d6)δ10.56(s,1H),9.38(s,1H),8.78(dd,J＝4.4,1.4Hz,1H),8.55(dd,J＝8.4,1.4Hz,1H),8.28-8.24(m,1H),8.16(d,J＝5.6Hz,1H),8.01(dd,J＝9.5,1.8Hz,1H),7.93(d,J＝1.6Hz,1H),7.84(d,J＝8.8Hz,3H),7.67-7.58(m,4H),7.53(dd,J＝8.4,4.4Hz,1H),7.45(d,J＝7.9Hz,2H),7.12(d,J＝5.6Hz,1H),5.10(s,1H),4.77(s,1H),4.52(t,J＝8.6Hz,1H),4.33(s,1H),1.50(d,J＝7.0Hz,3H),1.24(d,J＝5.1Hz,1H),0.50(s,6H)。13C NMR(101MHz,DMSO-d6)δ163.30,159.74,155.01,152.71,151.66,143.39,140.15,138.51,138.26,136.26,135.17,132.21,131.19,130.09,129.39,127.27,127.03,126.75,122.46,121.27,115.69,115.45,115.15,111.42,64.31,59.47,40.67,40.46,40.26,40.05,39.84,39.63,39.42,27.72,17.83,14.71。ESI-HRMS m/z:618.2293[M+H]+。
实施例47
化合物I-73的合成：
化合物I-73的合成方法参考化合物I-24的合成，投入化合物73a(150mg，0.32mmol)和反-3-(3-吡啶基)丙烯酸(71mg，0.48mol)，得到140mg化合物I-73，淡黄色固体粉末，收率60.94％。1H NMR(300MHz,DMSO-d6)δ10.43(s,1H),8.83(dd,J＝9.9,2.3Hz,2H),8.60(dd,J＝4.8,1.6Hz,1H),8.17(d,J＝5.8Hz,1H),8.06(dt,J＝8.1,1.9Hz,1H),7.97(dd,J＝8.2,2.4Hz,1H),7.82(d,J＝8.7Hz,2H),7.74-7.60(m,4H),7.49(dd,J＝8.0,4.8Hz,1H),7.41(d,J＝8.3Hz,1H),7.14(d,J＝5.5Hz,1H),6.95(d,J＝15.8Hz,1H),5.11(s,1H),4.63(s,1H),4.54-4.24(m,2H),1.53(d,J＝7.1Hz,3H),1.24(d,J＝4.9Hz,1H),0.42(s,6H)。13C NMR(126MHz,DMSO-d6)δ163.10,159.18,154.37,152.08,150.97,150.34,149.20,146.47,138.90,138.37,136.96,134.15,134.07,133.03,132.04,130.44,128.74,126.98,124.03,123.96,121.79,120.60,119.74,63.64,58.85,54.81,39.96,39.79,39.63,39.46,39.29,39.13,38.96,27.04,21.56,17.25,14.02。ESI-HRMS m/z:606.2288[M+H]+。
实施例48
化合物I-74的合成：
化合物I-74的合成方法参考化合物I-24的合成，投入化合物71a(179mg，0.38mmol)和咪唑并[1,2-a]吡啶-6-甲酸(92mg，0.57mmol)，得到130mg化合物I-74，白色固体，收率66.3％。1H NMR(300MHz,DMSO-d6)δ10.48(s,1H),9.28(t,J＝1.4Hz,1H),8.83(d,J＝2.3Hz,1H),8.20-8.11(m,2H),8.00(dd,J＝8.2,2.4Hz,1H),7.89(d,J＝8.7Hz,2H),7.78-7.72(m,3H),7.71(d,J＝1.3Hz,2H),7.68(dt,J＝3.3,1.3Hz,1H),7.42(d,J＝7.5Hz,1H),7.15(d,J＝5.5Hz,1H),5.12(s,1H),4.73-4.44(m,2H),4.29(s,1H),1.54(d,J＝7.1Hz,3H),1.24(d,J＝4.8Hz,1H),0.43(s,6H)。13C NMR(126MHz,DMSO-d6)δ167.27,163.44,159.18,154.36,152.07,146.50,144.55,138.74,134.52,134.18,132.98,132.32,131.54,131.34,128.88,128.60,126.82,123.13,120.70,120.44,120.04,116.11,114.30,63.64,58.85,54.81,52.50,39.95,39.79,39.62,39.45,39.29,39.12,38.95,21.57,17.25,14.04。ESI-HRMS m/z:619.2222[M+H]+。
实施例49
化合物81a的合成：
将2,4-二氯-7H-吡咯并[2,3-d]嘧啶(5.0g，26.60mmol)与对甲苯磺酰氯(5.58g，29.26mmol)溶于25mL无水DMF中，置于冰浴下搅拌5分钟，再缓慢滴加60％NaH(1.17g，29.26mmol)的DMF(10mL)混悬液，滴加结束后，将混合溶液转移至室温搅拌2h。TLC监测反应结束后，向反应液中加入100mL乙酸乙酯，再加入100ml冰水淬灭反应，剧烈搅拌10分钟，用300mL乙酸乙酯萃取，有机相依次用水洗涤2次(每次100ml)、100mL饱和碳酸氢钠溶液洗涤1次、300mL饱和氯化钠水溶液洗涤1次，有机相经无水硫酸钠干燥后减压浓缩，经快速柱层析(PE:EA＝4:1,v:v)分离，得到化合物81a 6.35g，白色固体，收率70.1％。1H NMR(400MHz,CDCl3)δ8.15-8.08(m,2H),7.75(d,J＝4.0Hz,1H),7.39-7.33(m,2H),6.68(d,J＝4.0Hz,1H),2.43(s,3H)。
化合物82a的合成：
将化合物81a(4.0g，11.66mmol)、(S)-(-)-4-异丙基-2-噁唑烷酮(1.51g，11.66mmol)、磷酸钾(4.95g,23.32mmol)、Xantphos Pd-G3(333mg，0.35mmol)溶于115mL甲苯中，氮气保护下升温至80℃回流反应4h。TLC监测反应结束后。将反应液用300mL乙酸乙酯稀释转移至分液漏斗中，依次用水洗涤2次(每次150mL)、300mL饱和氯化钠水溶液洗涤1次，有机相经无水硫酸钠干燥后减压浓缩，经快速柱层析(PE:EA＝6:1,v:v)分离，得到1.73g化合物82a，白色固体，收率34.2％。1H NMR(400MHz,CDCl3)δ8.19-8.11(m,2H),7.66(d,J＝4.1Hz,1H),7.41-7.35(m,2H),7.09(d,J＝4.1Hz,1H),4.98(ddd,J＝9.1,5.3,4.0Hz,1H),4.49(t,J＝8.9Hz,1H),4.36(dd,J＝9.0,5.2Hz,1H),2.45(s,3H),1.30-1.25(m,1H),0.95(d,J＝7.1Hz,3H),0.83(d,J＝6.9Hz,3H)。
化合物85a的合成：
化合物85a的合成同化合物I-17，得180mg化合物85a，黄色固体，收率53％。1H NMR(500MHz,CDCl3)δ9.81(s,1H),8.60-8.53(m,3H),8.40(s,1H),7.85-7.79(m,3H),7.76-7.69(m,4H),7.65(s,1H),7.65-7.55(m,3H),7.58-7.52(m,3H),7.53(s,1H),7.44(dd,J＝8.0,5.0Hz,1H),7.37-7.31(m,3H),7.27(dq,J＝7.6,1.1Hz,3H),7.21(s,1H),6.88(s,1H),4.86(d,J＝1.5Hz,1H),4.47(s,1H),4.26(s,1H),4.11(s,1H),2.41(t,J＝1.0Hz,4H),2.28(s,1H),1.60(s,3H),1.03(s,3H),0.98(s,3H)。
化合物I-79的合成：
将化合物85a(90mg，0.12mmol)溶于2mL四氢呋喃中，氮气保护下升温至60℃，向溶液中注射2mL1mol/L的四丁基氟化铵的四氢呋喃溶液，反应16小时。TLC监测反应结束后，停止加热，用45mL乙酸乙酯稀释反应液，依次用饱和氯化铵溶液、水、饱和食盐水各洗涤2次，每次30mL。有机相经无水硫酸钠干燥后减压浓缩，经快速柱层析(DCM:MeOH＝50:1-25:1,v:v)分离，得到50mg化合物I-79，淡黄色固体，收率70％。1H NMR(400MHz,DMSO-d6)δ11.20(s,1H),10.41(d,J＝8.1Hz,1H),8.84(d,J＝2.3Hz,1H),8.59(dd,J＝4.7,1.6Hz,1H),8.05(dt,J＝8.1,2.0Hz,1H),7.78(d,J＝8.4Hz,2H),7.69-7.58(m,3H),7.55(d,J＝8.3Hz,2H),7.49(dd,J＝8.0,4.7Hz,1H),7.43(d,J＝8.0Hz,2H),7.25(d,J＝8.1Hz,1H),7.01-6.87(m,2H),6.35(dd,J＝3.6,2.0Hz,1H),5.15-5.01(m,1H),4.74(s,1H),4.46(t,J＝8.9Hz,1H),4.27(s,1H),1.96(d,J＝32.0Hz,1H),1.47(d,J＝7.1Hz,3H),1.17(t,J＝7.3Hz,6H)。13CNMR(126MHz,DMSO-d6)δ163.59,158.03,156.31,150.84,149.75,138.85,138.14,137.23,135.75,134.58,131.06,127.27,126.69,126.52,124.80,124.51,121.18,120.14,102.63,102.24,63.64,59.16,45.95,27.81,23.90,17.82,14.60,9.12。ESI-HRMS m/z:610.2534[M+H]+。
实施例50
化合物I-80的合成：
化合物I-80的合成方法参考化合物I-79的合成，得到90mg化合物I-80，白色固体，收率76％。1H NMR(400MHz,DMSO-d6)δ11.20(s,1H),10.27(s,1H),8.38(d,J＝3.0Hz,1H),8.21(d,J＝4.6Hz,1H),7.70(d,J＝8.5Hz,2H),7.64-7.48(m,4H),7.47-7.39(m,3H),7.36(dd,J＝8.4,4.5Hz,1H),7.25(d,J＝8.1Hz,1H),6.92(d,J＝4.0Hz,1H),6.35(d,J＝3.6Hz,1H),5.13-5.01(m,1H),4.83(s,2H),4.73(s,1H),4.46(t,J＝9.0Hz,1H),4.27(d,J＝7.9Hz,1H),1.89(d,J＝88.0Hz,1H),1.47(d,J＝7.0Hz,3H),1.38-1.11(m,6H).13C NMR(101MHz,DMSO-d6)δ166.61,158.02,156.29,154.89,154.65,149.83,142.72,138.50,138.01,135.98,127.20,126.68,126.55,124.60,121.67,121.20,120.50,102.62,102.23,67.52,63.61,59.14,45.89,27.77,23.92,17.81,14.57,9.06。ESI-HRMS m/z:592.2663[M+H]+。
实施例51
化合物86a的合成：
将化合物45a(600mg，2.46mmol)、化合物82a(1.07g，2.46mmol)和DIPEA(2.2g，17.22mmol)溶于3mL DMSO中，氮气保护下加热至110℃回流反应16h。TLC监测反应结束后，将反应液用200mL乙酸乙酯稀释并转移至分液漏斗中，依次用100mL水洗涤2次(每次50mL)，200mL饱和氯化钠溶液洗涤1次，有机相经无水硫酸钠干燥后减压浓缩至干。经快速柱层析(DCM:EA＝40:1,v:v)手性拆分，得到254mg化合物86a，黄色固体，收率16.0％。1H NMR(300MHz,DMSO-d6)δ9.23(d,J＝14.2Hz,2H),8.36(d,J＝8.2Hz,2H),8.03(d,J＝67.0Hz,5H),7.48(s,1H),7.28(d,J＝18.8Hz,2H),6.66(d,J＝4.1Hz,1H),4.99(d,J＝109.0Hz,2H),4.43(d,J＝35.7Hz,2H),2.39(d,J＝10.3Hz,3H),2.22(s,1H),1.62(d,J＝7.1Hz,3H),0.99-0.78(m,3H),0.38(s,3H)。
化合物I-81的合成：
化合物I-81的合成方法同化合物I-79，得到56mg化合物I-81，淡黄色固体，收率80％。1H NMR(300MHz,DMSO-d6)δ11.27(s,1H),10.49(s,1H),9.08(s,2H),8.85(d,J＝2.2Hz,1H),8.60(dd,J＝4.8,1.6Hz,1H),8.06(d,J＝8.1Hz,1H),7.92-7.75(m,4H),7.67(d,J＝15.8Hz,1H),7.50(dd,J＝8.0,4.8Hz,1H),7.04-6.86(m,3H),6.45(dd,J＝3.7,1.9Hz,1H),5.18(t,J＝7.2Hz,1H),4.70(s,1H),4.44(t,J＝8.8Hz,1H),4.33(dd,J＝9.0,4.8Hz,1H),2.41(td,J＝7.0,3.8Hz,1H),1.56(d,J＝6.9Hz,3H),0.91(d,J＝7.0Hz,3H),0.77(d,J＝6.8Hz,3H)。13C NMR(101MHz,DMSO-d6)δ170.91,163.74,157.82,156.23,154.97,154.83,150.93,149.79,140.13,137.68,134.67,130.96,130.89,129.26,127.74,124.56,124.47,121.00,120.28,102.53,102.11,63.66,59.54,28.27,21.55,17.93,14.78。ESI-HRMS m/z:612.2434[M+H]+。
实施例52
化合物I-82的合成：
化合物I-82的合成方法参考化合物I-81的合成，得到58mg化合物I-82，淡黄色固体，收率80％。1H NMR(300MHz,DMSO-d6)δ11.27(s,1H),10.34(s,1H),9.07(s,2H),8.39(dd,J＝2.9,0.7Hz,1H),8.22(dd,J＝4.5,1.4Hz,1H),7.79(s,4H),7.45(ddd,J＝8.5,2.9,1.4Hz,1H),7.37(ddd,J＝8.5,4.6,0.8Hz,1H),7.01-6.83(m,2H),6.45(dd,J＝3.7,1.9Hz,1H),5.28-5.09(m,1H),4.85(s,2H),4.70(s,1H),4.44(t,J＝8.8Hz,1H),4.33(dd,J＝8.9,4.8Hz,1H),2.41(td,J＝7.0,3.7Hz,1H),1.55(d,J＝7.0Hz,3H),0.90(d,J＝7.0Hz,3H),0.77(d,J＝6.9Hz,3H).13C NMR(101MHz,DMSO-d6)δ170.96,166.84,157.81,156.22,154.99,154.83,154.64,149.91,142.71,139.33,138.44,129.49,127.65,124.64,121.80,121.00,120.63,102.53,102.11,67.53,63.66,59.54,28.27,21.55,17.92,14.78。ESI-HRMS m/z:616.2385[M+H]+。
实施例53
一、化合物对mIDH1活性抑制效果的测定
(一)、IDH1-R132H/R132C
将待测化合物溶解在DMSO中配制成浓度为10mM的母液，并用DMSO梯度稀释至待测浓度。
缓冲液配方：150mM NaCl,20mM Tris-HCl pH 7.5,10mM MgC12,0.05％BSA。
底物混合物：缓冲液配制的20μM NADPH和5mMα-酮戊二酸的混合溶液。
终止液：缓冲液配制的36μg/mL心肌黄酶和30mM刃天青的混合溶液。
在384孔板中加入1μL DMSO溶解的待测化合物和39μL用缓冲液稀释的IDH1-R132H/IDH1-R132C酶，酶的终浓度为0.125μg/mL，于室温下孵育1h。添加10μL底物混合物使反应体系为50μL，启动反应，并在室温下孵育1.5h；添加25μL终止液，并在室温下孵育10min以结束反应。在激发波长和发射波长分别为544nm和590nm(Ex/Em＝544/590nm)的条件下读取荧光强度(Fluorescence Intensity,FI)。酶活抑制程度越大，荧光信号越强。不加IDH-R132H/IDH-R132C的孔荧光信号最强，将此记为FImax，溶剂对照孔(只含缓冲液和DMSO)的荧光信号最弱，记为FImin，而加入化合物的孔荧光信号理论上在FImin与FImax之间，记为FIx，酶活抑制率计算公式为：
酶抑制率(％)＝[1-(FImax-FIx/FImax-FImin)]×100％
数据处理均采用GraphPad Prism软件计算分析求得。
(二)、IDH1-WT(野生型IDH1)
将测试化合物溶解在DMSO中配制成浓度为10mM的母液，并用DMSO梯度稀释至待测浓度。
缓冲液配方：150mM NaCl,20mM Tris-HCl pH 7.5,10mM MgC12,0.05％BSA。
底物混合物：缓冲液配制的0.35mM异柠檬酸盐、100μg/mL心肌黄酶和200μM刃天青的混合溶液。
在384孔板中加入1μL DMSO溶解的待测化合物和39μL用缓冲液稀释的IDH1-WT酶，其中含有62.5μM NADP+和2.5mMβ-巯基乙醇，酶的终浓度为0.02μg/mL。该混合物在室温下孵育1h；然后，加入10μL底物混合物使反应体系为50μL，开始反应，在室温下反应30min，加入25μL 6％的十二烷基硫酸钠(SDS)溶液停止反应。在激发波长和发射波长分别为544nm和590nm的条件下读取荧光强度。
(三)实验结果
表1.化合物对mIDH1和IDH1-WT抑制活性的IC50(nM)
结果显示，大部分化合物对IDH1-R132H具有良好的活性，优于IDH1-R132C，且对正常IDH1(IDH1-WT)无明显抑制，说明化合物可能对IDH1-R132H突变的肿瘤具有良好的抑制活性且抑制效果要优于IDH1-R132C突变的肿瘤，具有良好的选择性。
二、化合物对NAMPT活性抑制效果的测定
(一)、实验方法
酶反应体系：25μL，其中各种组分的终浓度为：50mM Tris-HCl(pH7.5)、0.02％BSA、12mM MgCl2、2mM ATP、0.4mM PRPP、2mM DTT、2μg/mL NAMPT、0.2μM NAM、DMSO和倍比稀释的化合物。
先将0.5μLDMSO溶解的不同浓度的化合物溶液加到96孔板中，再加入20μL上述酶反应混合溶液(除底物之外的酶反应组分)，于室温孵育5min后，加入4.5μL底物烟酰胺(NAM)水溶液以启动反应，37℃反应15min后，于95℃加热1min终止酶反应；反应液在冰上冷却后，依次加入10μL 20％苯乙酮(DMSO溶解)和2M KOH，涡旋混合仪上混匀后于0℃作用2min，加入45μL 88％甲酸，37℃孵育10min；使用酶标仪测定激发波长382nm、发射波长445nm处的荧光值，绘制荧光与抑制剂浓度的曲线，求得IC50值。
(二)、实验结果
表2.化合物对NAMPT抑制活性的IC50(nM)
由表1和表2可见，本发明部分化合物对mIDH1/NAMPT具有非常良好的抑制活性和对正常IDH1的选择性，尤其是化合物I-16、I-17、I-18、I-26、I-37、I-41、I-42、I-43、I-44、I-45、I-46、I-47、I-48、I-49、I-50、I-51、I-52、I-59、I-60、I-61、I-79、I-80、I-81、I-82对mIDH1/NAMPT的抑制活性更为突出。
三、测定化合物的透血脑屏障能力
实验步骤：
1.溶液配制
20％的牛脑磷脂(PBL)-十二烷溶液：配制体积分数为20％的牛脑磷脂(PBL)-十二烷溶液，超声至完全溶解。用十二烷将20％的牛脑磷脂-十二烷溶液稀释至2％。
化合物母液浓度：称取一定量的化合物，配制成浓度为5mg/mL或摩尔浓度为10mM的母液，备用。
化合物储备液制备：取10μL化合物母液，用含20％乙腈的pH 7.4PBS稀释100倍，制成二次储备溶液(最终浓度为50μg/mL)；
2.实验操作
(1)待测药物标准曲线的绘制
将浓度为5mg/mL的一级母液(阳性对照，阴性对照和化合物)倍半稀释成浓度为1.67、0.56、0.18、0.062、0.021、0.0068、0mg/mL的标准溶液，用高效液相色谱分别测定其峰面积，以峰面积对化合物的质量浓度做标准曲线。分析样品在0～1.67mg/mL范围内是否具有良好的线性关系。
(2)化合物透血脑屏障能力的测定
(a)润板：贴壁加50-100μL 70％乙醇，润湿96孔滤板，30s后吸出，加入100μL PBS洗涤，重复2遍，第二遍吸净所有PBS。
(b)包被：取4-5μL超声后的PBL-十二烷溶液(2％)加到受体板的滤膜上并加入150或200μL pH7.4的PBS缓冲液；
(c)添加300μL测试化合物至供体板中；
(d)测试化合物从供体孔通过脂质膜扩散到受体孔中。静置6或18h，发生渗透。受体、供体和参考孔中的药物浓度使用HPLC法测定。计算化合物的有效渗透率(Pe，cm/s)。
Pe＝-(218.3/t)*log[1-2CA(t)/CD(t0)]×10-6(cm/s)
其中，CA(t)为t时接收板中药物溶液的浓度(mg/L或摩尔浓度)；CD(t0)为供给板中溶液的初始浓度(mg/L或摩尔浓度)；t为孵育时间(s)
表3.化合物透血脑屏障能力
注：a CNS+表示高渗透，CNS-表示低渗透。
由此可见，化合物I-51具有高效穿透血脑屏障的能力。发明人同样考察了其余51个化合物，也具备穿透血脑屏障的能力。而FK866不具备穿透血脑屏障的能力，AG-120穿透血脑屏障的能力较差。
综合考虑化合物的酶活性、选择性、溶解性及透血脑屏障能力后，挑选化合物I-51进行进一步的细胞实验及体内活性评估。
四、测定化合物对细胞活性影响
将U87 MG细胞或U87 MGIDH1-R132H细胞在T125瓶中生长，U87 MG细胞采用含有10％FBS、l x霉素/链霉素的DMEM培养基，U87 MGIDH1-R132H细胞采用含有10％ FBS、l x青霉素/链霉素、1μL/mL嘌呤霉素的DMEM培养基。待细胞长至80％时，用胰蛋白酶消化收集后，得到U87MG或U87 MGIDH1-R132H细胞悬浮液(含10％ FBS的DMEM)，以100μL/孔播种到96孔白色底板中，密度为5000个细胞/孔，37℃、5％的CO2中孵育过夜，第二天添加以梯度稀释的100μL待测化合物到每孔中，DMSO的终浓度为0.2％。然后将96孔板置于培养箱中72h，再每孔加入10μLCCK8溶液并将96孔板置于培养箱中4h。用酶标仪测定450nm处的吸光度(OD)。实验结果如下：
表4.化合物对细胞活性的影响
注：阳性药AG-120和IDH-305为mIDH1抑制剂、阳性药FK866为NAMPT抑制剂。两药联用组为mIDH1抑制剂和NAMPT抑制剂摩尔比为1:1的组合。
结果见表4，表明化合物I-51能明显抑制U87 MGIDH1-R132H细胞的增殖，且作用72h后的抑制效果优于阳性药组和药物联用组。
五、测定化合物的急性毒性
受试动物：ICR小鼠(江苏华创信诺医药科技有限公司)；18-22g；雄性；共44只。
受试样品：化合物I-51、IDH-305、FK866。
化合物I-51、IDH-305、FK866溶解在DMSO中，加入和DMSO等量的HS(聚乙二醇硬脂酸酯)和PEG-400助溶，再用生理盐水稀释，三者均通过尾静脉注射，给药剂量均为400mg/kg，单次给药后，观察动物状态。各组小鼠给药后12个小时之内，动物未见异常。给药24个小时内未见动物死亡，给药第7天后动物未见死亡。未见其他明显异常。于第7天取心、肝、脾、肺、肾等组织进行H&E染色观察病理切片(图1)，各组织细胞形态良好。小鼠静脉给予400mg/kg受试药物均未见毒性反应，说明化合物I-51的安全性良好。
六、化合物药代动力学参数
受试动物：SD大鼠(180-200g，雄性)，购自江苏华创信诺医药科技有限公司。
受试样品：化合物I-51。
实验步骤：对SD大鼠静脉注射化合物I-51(1mg/kg)，灌胃给予化合物I-51(10mg/kg)，在给药2min(灌胃时无该时间点)、5min、15min、0.5h、1h、2h、4h、6h、8h、12h和24h采集眼眶静脉血液，制备血浆，采用LC-MS/MS检测化合物浓度，考察其血浆清除率CL、消除半衰期T1/2、峰时间Tmax、峰浓度Cmax、药时曲线下面积AUC、表观分布容积Vss、相对生物利用度F等药代参数。
测定方法：用95％乙腈溶解化合物I-51得到系列浓度的工作溶液。向10μL空白SD大鼠血浆中添加10μL工作溶液(1、2、5、10、50、100、500、1000、5000、10000ng/mL)以达到总体积为20μL 1×10000ng/mL浓度的化合物I-51校准标准液。将20μL标准品、20μL未知样品(10μL未知样品血浆和10μL 95％乙腈)分别添加到200μL乙腈中以沉淀蛋白质；然后将样品震荡涡旋30s，再在4℃、18000rpm下离心10min，取10μL上清液注入LC-MS/MS系统进行定量分析。
化合物I-51的药代动力学参数(PK Parameter)如表5。
表5.化合物I-51的药代动力学参数
注：iv：静脉注射；po：口服；CL：表观清除率；T1/2：半衰期；AUC0-t：从给药开始到最后一个点(24小时的)的药时曲线下面积；AUC0-∞：从给药开始到理论外推无穷远的时间的药时曲线下面积；Tmax：达峰时间；Cmax：达峰浓度；F：相对生物利用度。
七、化合物抗脑胶质瘤活性测定
受试样品：化合物I-51、阳性药(mIDH1抑制剂IDH305、NAMPT抑制剂FK866)。
实验方法：取对数生长期的人脑胶质瘤U87 MGIDH1-R132H细胞接种于44只BALB/c裸小鼠的前囟中点前1.0mm，矢状缝向右旁开2.5mm处，进针深度为3.0mm，每只小鼠的细胞接种量为1×105个。用小动物成像仪挑选生长状态良好且肿瘤大小均一的荷瘤裸鼠44只，分成7组，除模型对照组为8只荷瘤裸鼠，其余6组每组6只，即(1)模型对照组(给予等量溶媒，溶媒：DMSO、HS、PEG-400和生理盐水体积比1:1:1:8的混合溶剂)；(2)FK866组(给药量为单次30mg/kg，ip，bid)；(3)IDH305组(给药量为单次300mg/kg，po，bid)；(4)药物联用组(给药量为单次30mg/kg FK866+300mg/kg IDH305，bid)；(5)化合物I-51低剂量组(给药量为单次10mg/kg，iv，bid)；(6)化合物I-51中剂量组(给药量为单次20mg/kg，iv，bid)。(7)化合物I-51高剂量组(给药量为单次40mg/kg，iv，bid)。每隔一天称量裸鼠体重，给药35天后安乐处死裸鼠，手术剥离动物全脑、心、肝、脾、肺、肾等。
实验结果显示：模型对照组动物在13天左右全部死亡，体重明显降低(图2)；单一药物组(FK866组、IDH305组)能够延长动物生存期，中位存活期分别为17天和23.5天，缓解动物体重降低；与FK866组相比，药物联用组能显著延长动物生存期(26.5天)(**P<0.01)，与IDH305组相比，药物联用组的动物生存期无显著性差异；不同剂量下化合物I-51均能缓解动物体重的降低，显著延长动物生存期，低、中、高剂量组小鼠的动物生存期分别为25.5、30.5和34天(**P<0.01)，并呈浓度依懒性地抑制肿瘤生长(图3、图4、图5)。在20mg/kg和40mg/kg剂量下，化合物I-51明显优于药物联用组的治疗效果(**P<0.01)，同时H&E染色病理切片结果显示肿瘤细胞明显减少(图6)。因此，化合物I-51对人脑胶质瘤细胞U87 MGIDH1 -R132H裸小鼠原位移植瘤生长有显著的抑制作用，并且化合物I-51中、高剂量组(20mg/kg和40mg/kg)对人脑胶质瘤细胞U87 MGIDH1-R132H原位移植瘤裸鼠抗肿瘤活性明显强于单一阳性药组及药物联用组。
Claims (10)
1.mIDH1/NAMPT双靶点抑制剂，其特征在于：选自结构如式I所示的化合物或其药学上可接受的盐、外消旋体、立体异构体、前药或溶剂化合物：
其中，环A选自取代或未取代的6元饱和或不饱和杂环、苯环并5元饱和或不饱和杂环或5-6元饱和或不饱和杂环并5-6元饱和或不饱和杂环；5-6元饱和或不饱和杂环的取代基为卤素、氨基、羟基、羧基、氰基、烯烃、酰胺中的至少一种；6元饱和或不饱和杂环、苯环并5元饱和或不饱和杂环、5-6元饱和或不饱和杂环并5-6元饱和或不饱和杂环中的杂原子选自氧原子、氮原子；
X选自直链或支链的亚烷基链、1,4-哌嗪亚基或1,3-吡咯烷亚基；X可被以下基团中的一个、多个或任意组合中断一或多次：-O-、-CONH-、NHCO-、-NHCONH-、-NH-、-S-、亚烯基，X的氢可被以下一个或多个基团取代：卤素、氨基、羟基、羧基、酰胺、氰基、烯烃、炔烃、C1-C4烷氧基、C1-C6烷基；
L选自共价键、取代或未取代的苯环、5-6元杂环或C1-C4烯基、C1-C4烷氧基、C1-C4酰胺基；苯环的取代基为卤素、氨基、羟基、羧基、氰基、烯烃、酰胺中的至少一种；
环B选自取代或未取代的苯环、5-6元饱和或不饱和杂环；苯环的取代基为卤素、氨基、羟基、羧基、氰基、烯烃、酰胺中的至少一种；5-6元饱和或不饱和杂环中含有1-2个杂原子，杂原子选自氧原子、氮原子；
R4选自氢或C1-C4烷基；
R5选自卤素、C1-C4烷基、取代或未取代苯基、羟基或叔丁氧基，苯环的取代基为卤素、氨基、羟基、羧基、氰基、烯烃、酰胺中的至少一种；
或R4与R5组合构成苯环。
2.根据权利要求1所述的mIDH1/NAMPT双靶点抑制剂，其特征在于：结构如式I所示的化合物中，环A选自：
X选自： m＝0-8的整数；n＝0-8的整数；p＝0-8的整数；
L选自苯环、苯氧基、吡啶环、嘧啶环或共价键；
环B选自苯环、吡啶环、嘧啶环或咪唑环；
R4选自氢或甲基；
R5选自氟、甲基、苯基、羟基或叔丁氧基；
或R4与R5组合构成苯环。
3.根据权利要求2所述的mIDH1/NAMPT双靶点抑制剂，其特征在于：结构如式I所示的化合物中，环A选自：
X选自：m＝0；n＝0；
L选自苯环；
环B选自苯环或吡啶环；
R4选自甲基；
R5选自F、甲基、苯基、羟基或叔丁氧基；
或R4与R5组合构成苯环。
4.mIDH1/NAMPT双靶点抑制剂，其特征在于：选自结构如式Ⅱ所示的化合物或其药学上可接受的盐、外消旋体、立体异构体、前药或溶剂化合物：
其中，环A选自：
X选自： m＝0-8的整数；n＝0-8的整数；p＝0-8的整数；
L选自苯环、苯氧基、吡啶环、嘧啶环或共价键；
环B选自苯环、吡啶环、嘧啶环或咪唑环；
R1选自硫、-NH-、-N(CH3)-或-CH-；
R2选自氮或-CH-；
R3选自硫或-CH-；
R4选自氢或甲基；
R5选自F、甲基、苯基、羟基或叔丁氧基；
或R4与R5组合构成苯环。
5.根据权利要求4所述的mIDH1/NAMPT双靶点抑制剂，其特征在于：结构如式Ⅱ所示的化合物中，环A选自：
X选自：m＝0-8的整数；n＝0-8的整数；p＝0-8的整数；
L选自苯环；
环B选自苯环、吡啶环或嘧啶环；
R1选自硫，R2选自-CH-，R3选自-CH-；或R1选自-CH-，R2选自-CH-，R3选自S；或R1选自-NH-，R2选自-CH-，R3选自-CH-；
R4选自甲基；
R5选自甲基。
6.根据权利要求4所述的mIDH1/NAMPT双靶点抑制剂，其特征在于：结构如式Ⅱ所示的化合物中，环A选自：
X选自：n＝0；
L选自苯环；
环B选自苯环、吡啶环或嘧啶环；
R1选自-NH-，R2选自-CH-，R3选自-CH-；
R4选自甲基；
R5选自甲基。
7.mIDH1/NAMPT双靶点抑制剂，其特征在于：选自结构如下所示的化合物或其药学上可接受的盐、外消旋体、立体异构体、前药或溶剂化合物：
8.一种药物组合物，其特征在于：含有权利要求1-7任一项所述的mIDH1/NAMPT双靶点抑制剂和与药学上可接受的载体。
9.权利要求1-7任一项所述的mIDH1/NAMPT双靶点抑制剂在制备与mIDH1和/或NAMPT介导的疾病药物的应用。
10.权利要求1-7任一项所述的mIDH1/NAMPT双靶点抑制剂在制备治疗癌症或肿瘤相关疾病药物的应用；所述的癌症或肿瘤相关疾病包括多发性骨髓瘤、白血病、乳腺癌、前列腺癌、肺癌、肝癌、胃癌、骨癌、脑癌、头颈癌、肠癌、胰腺癌、膀胱癌、睾丸癌、卵巢癌、子宫内膜癌。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311494330.6A CN117510484A (zh) | 2023-11-10 | 2023-11-10 | mIDH1/NAMPT双靶点抑制剂及其应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311494330.6A CN117510484A (zh) | 2023-11-10 | 2023-11-10 | mIDH1/NAMPT双靶点抑制剂及其应用 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117510484A true CN117510484A (zh) | 2024-02-06 |
Family
ID=89750843
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311494330.6A Pending CN117510484A (zh) | 2023-11-10 | 2023-11-10 | mIDH1/NAMPT双靶点抑制剂及其应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117510484A (zh) |
-
2023
- 2023-11-10 CN CN202311494330.6A patent/CN117510484A/zh active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2020343671C1 (en) | RIP1 inhibitory compounds and methods for making and using the same | |
| JP2023126907A (ja) | Ｒｈｏ－関連プロテインキナーゼ阻害剤、それを含む医薬組成物並びにその調製方法及び使用 | |
| CN111362967B (zh) | 苯并氧杂二氮杂十四碳烯衍生物及其用途 | |
| WO2020156285A1 (zh) | 一种苯并吡啶酮杂环化合物及其用途 | |
| JP2021523226A (ja) | Ｒｉｐ１阻害剤化合物並びにそれを製造及び使用するための方法 | |
| CN117715915A (zh) | 作为kras g12d抑制剂的杂环化合物 | |
| JP2020509017A (ja) | 新規イソインドリン誘導体、その医薬組成物および使用 | |
| CN112424185A (zh) | 含苯环的化合物、其制备方法及应用 | |
| US11414390B2 (en) | Cycloolefin substituted heteroaromatic compounds and their use | |
| EP4234548A1 (en) | Substituted benzo or pyridopyrimidine amine inhibitor, preparation method therefor, and application thereof | |
| CN112300153A (zh) | 一种杂环化合物、药物组合物和用途 | |
| CN112292374A (zh) | 一种新型磷酸肌醇3-激酶抑制剂及其制备方法和用途 | |
| JP7201800B2 (ja) | Ｆｌｔ３およびａｘｌの阻害剤としての３，９－ジアザスピロ［５，５］ウンデカン系化合物 | |
| EP3865487A1 (en) | Aromatic ring-linked dioxane-quinazoline or -quinoline compounds, compositions and use thereof | |
| TW202024037A (zh) | 用於治療特定白血病之化合物 | |
| CN117510484A (zh) | mIDH1/NAMPT双靶点抑制剂及其应用 | |
| CN111087408A (zh) | 一种大环结构的idh2突变体抑制剂及其医药用途 | |
| KR101872264B1 (ko) | 신규한 유형의 시티딘 유도체 이량체 및 그의 용도 | |
| CA3188173A1 (en) | Novel compound, and pharmaceutical composition for preventing or treating resistant cancer, comprising same | |
| IL298103A (en) | Converted tricyclic amides, their analogs, and methods of using them | |
| TWI804016B (zh) | 一種噻吩並嘧啶類化合物、包含其藥物組合物及其應用 | |
| CN112209933B (zh) | 含有4-氮杂螺庚烷的btk抑制剂 | |
| WO2022171018A1 (zh) | 取代苯并或吡啶并嘧啶胺类抑制剂及其制备方法和应用 | |
| WO2023151513A1 (en) | Conjugates of chemotherapy agents and tissue-binding small molecules, compositions and methods thereof | |
| CN115536699A (zh) | 一种新型EGFR-TKIs、制备方法、药物组合物及其应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |