KR20230011467A - Derivatives of Piperidinedione - Google Patents
Derivatives of Piperidinedione Download PDFInfo
- Publication number
- KR20230011467A KR20230011467A KR1020230004373A KR20230004373A KR20230011467A KR 20230011467 A KR20230011467 A KR 20230011467A KR 1020230004373 A KR1020230004373 A KR 1020230004373A KR 20230004373 A KR20230004373 A KR 20230004373A KR 20230011467 A KR20230011467 A KR 20230011467A
- Authority
- KR
- South Korea
- Prior art keywords
- methyl
- pyrimidin
- oxo
- benzyl
- compound
- Prior art date
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- 150000005458 piperidinediones Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 156
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 61
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 61
- -1 piperidinedione derivative compound Chemical class 0.000 claims abstract description 23
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 239000003446 ligand Substances 0.000 claims description 36
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 16
- KNCYXPMJDCCGSJ-UHFFFAOYSA-N piperidine-2,6-dione Chemical compound O=C1CCCC(=O)N1 KNCYXPMJDCCGSJ-UHFFFAOYSA-N 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 7
- 239000003112 inhibitor Substances 0.000 claims description 6
- QAVJNDSPSDYTMF-UHFFFAOYSA-N CC(C(C1=C2)=CC=C2N2CCC(COC3=CN=C(C4=CC=CC(CN(C(C=C5)=O)N=C5C5=CC=CC(C#N)=C5)=C4)N=C3)CC2)=NN(C(CCC(N2)=O)C2=O)C1=O Chemical compound CC(C(C1=C2)=CC=C2N2CCC(COC3=CN=C(C4=CC=CC(CN(C(C=C5)=O)N=C5C5=CC=CC(C#N)=C5)=C4)N=C3)CC2)=NN(C(CCC(N2)=O)C2=O)C1=O QAVJNDSPSDYTMF-UHFFFAOYSA-N 0.000 claims description 3
- ROODKQUYSNMHSP-UHFFFAOYSA-N CC(C1=CC(N2CCC(COC3=CN=C(C4=CC=CC(CN(C(C=C5)=O)N=C5C5=CC=CC(C#N)=C5)=C4)N=C3)CC2)=CC=C11)=NN(C(CCC(N2)=O)C2=O)C1=O Chemical compound CC(C1=CC(N2CCC(COC3=CN=C(C4=CC=CC(CN(C(C=C5)=O)N=C5C5=CC=CC(C#N)=C5)=C4)N=C3)CC2)=CC=C11)=NN(C(CCC(N2)=O)C2=O)C1=O ROODKQUYSNMHSP-UHFFFAOYSA-N 0.000 claims description 3
- DGYNXDZJUHDNMC-LUWJBUJKSA-N CN1N=CC(C2=CN=C3N(C[C@H](C4)OCCN4C(N=C4)=NC=C4C4=CC=C(CN(CC5)CCN5C(C=C5C(N6C(CCC(N7)=O)C7=O)=O)=CC=C5C6=O)C=C4)N=NC3=N2)=C1 Chemical compound CN1N=CC(C2=CN=C3N(C[C@H](C4)OCCN4C(N=C4)=NC=C4C4=CC=C(CN(CC5)CCN5C(C=C5C(N6C(CCC(N7)=O)C7=O)=O)=CC=C5C6=O)C=C4)N=NC3=N2)=C1 DGYNXDZJUHDNMC-LUWJBUJKSA-N 0.000 claims description 3
- SGXMBBRWPBXZFX-GYXLRUHFSA-N CN1N=CC(C2=CN=C3N(C[C@H](C4)OCCN4C(N=C4)=NC=C4C4=CC=C(CN(CC5)CCN5C(C=C5C=NN6C(CCC(N7)=O)C7=O)=CC=C5C6=O)C=C4)N=NC3=N2)=C1 Chemical compound CN1N=CC(C2=CN=C3N(C[C@H](C4)OCCN4C(N=C4)=NC=C4C4=CC=C(CN(CC5)CCN5C(C=C5C=NN6C(CCC(N7)=O)C7=O)=CC=C5C6=O)C=C4)N=NC3=N2)=C1 SGXMBBRWPBXZFX-GYXLRUHFSA-N 0.000 claims description 3
- QUVZSFHZGLBDRW-WXTKOERCSA-N CN1N=CC(C2=CN=C3N(C[C@H](C4)OCCN4C(N=C4)=NC=C4C4=CC=C(CN(CC5)CCN5C(C=CC=C5C(N6C(CCC(N7)=O)C7=O)=O)=C5C6=O)C=C4)N=NC3=N2)=C1 Chemical compound CN1N=CC(C2=CN=C3N(C[C@H](C4)OCCN4C(N=C4)=NC=C4C4=CC=C(CN(CC5)CCN5C(C=CC=C5C(N6C(CCC(N7)=O)C7=O)=O)=C5C6=O)C=C4)N=NC3=N2)=C1 QUVZSFHZGLBDRW-WXTKOERCSA-N 0.000 claims description 3
- WDJRGRQZTHRRKQ-PTYUOYDSSA-N CN1N=CC(C2=CN=C3N(C[C@H](C4)OCCN4C(N=C4)=NC=C4C4=CC=C(CN(CC5)CCN5C(C=CC=C5C=NN6C(CCC(N7)=O)C7=O)=C5C6=O)C=C4)N=NC3=N2)=C1 Chemical compound CN1N=CC(C2=CN=C3N(C[C@H](C4)OCCN4C(N=C4)=NC=C4C4=CC=C(CN(CC5)CCN5C(C=CC=C5C=NN6C(CCC(N7)=O)C7=O)=C5C6=O)C=C4)N=NC3=N2)=C1 WDJRGRQZTHRRKQ-PTYUOYDSSA-N 0.000 claims description 3
- NJWPXDDYWCUWCT-GYXLRUHFSA-N CN1N=CC(C2=CN=C3N(C[C@H](C4)OCCN4C(N=C4)=NC=C4C4=CC=C(CN(CC5)CCN5C5=CC=C(C=NN(C(CCC(N6)=O)C6=O)C6=O)C6=C5)C=C4)N=NC3=N2)=C1 Chemical compound CN1N=CC(C2=CN=C3N(C[C@H](C4)OCCN4C(N=C4)=NC=C4C4=CC=C(CN(CC5)CCN5C5=CC=C(C=NN(C(CCC(N6)=O)C6=O)C6=O)C6=C5)C=C4)N=NC3=N2)=C1 NJWPXDDYWCUWCT-GYXLRUHFSA-N 0.000 claims description 3
- BEANTDQXGFRSTC-UHFFFAOYSA-N N#CC1=CC(C(C=C2)=NN(CC3=CC(C(N=C4)=NC=C4OCC(CC4)CCN4C(C=C(C=NN(C(CCC(N4)=O)C4=O)C4=O)C4=C4)=C4F)=CC=C3)C2=O)=CC=C1 Chemical compound N#CC1=CC(C(C=C2)=NN(CC3=CC(C(N=C4)=NC=C4OCC(CC4)CCN4C(C=C(C=NN(C(CCC(N4)=O)C4=O)C4=O)C4=C4)=C4F)=CC=C3)C2=O)=CC=C1 BEANTDQXGFRSTC-UHFFFAOYSA-N 0.000 claims description 3
- BNMOTXPKPFTQEI-UHFFFAOYSA-N N#CC1=CC(C(C=C2)=NN(CC3=CC(C(N=C4)=NC=C4OCC(CC4)CCN4C(C=C4C(N5C(CCC(N6)=O)C6=O)=O)=CC=C4C5=O)=CC=C3)C2=O)=CC=C1 Chemical compound N#CC1=CC(C(C=C2)=NN(CC3=CC(C(N=C4)=NC=C4OCC(CC4)CCN4C(C=C4C(N5C(CCC(N6)=O)C6=O)=O)=CC=C4C5=O)=CC=C3)C2=O)=CC=C1 BNMOTXPKPFTQEI-UHFFFAOYSA-N 0.000 claims description 3
- DIJKKOLMQMXRHL-UHFFFAOYSA-N N#CC1=CC(C(C=C2)=NN(CC3=CC(C(N=C4)=NC=C4OCC(CC4)CCN4C(C=C4C=NN5C(CCC(N6)=O)C6=O)=CC=C4C5=O)=CC=C3)C2=O)=CC=C1 Chemical compound N#CC1=CC(C(C=C2)=NN(CC3=CC(C(N=C4)=NC=C4OCC(CC4)CCN4C(C=C4C=NN5C(CCC(N6)=O)C6=O)=CC=C4C5=O)=CC=C3)C2=O)=CC=C1 DIJKKOLMQMXRHL-UHFFFAOYSA-N 0.000 claims description 3
- SHQQVGUBXICIFZ-UHFFFAOYSA-N N#CC1=CC(C(C=C2)=NN(CC3=CC(C(N=C4)=NC=C4OCC(CC4)CCN4C(C=CC=C4C=NN5C(CCC(N6)=O)C6=O)=C4C5=O)=CC=C3)C2=O)=CC=C1 Chemical compound N#CC1=CC(C(C=C2)=NN(CC3=CC(C(N=C4)=NC=C4OCC(CC4)CCN4C(C=CC=C4C=NN5C(CCC(N6)=O)C6=O)=C4C5=O)=CC=C3)C2=O)=CC=C1 SHQQVGUBXICIFZ-UHFFFAOYSA-N 0.000 claims description 3
- YUVAEZSKFCKPKC-UHFFFAOYSA-N N#CC1=CC(C(C=C2)=NN(CC3=CC(C(N=C4)=NC=C4OCC(CC4)CCN4C4=C(C=NN(C(CCC(N5)=O)C5=O)C5=O)C5=CC=C4)=CC=C3)C2=O)=CC=C1 Chemical compound N#CC1=CC(C(C=C2)=NN(CC3=CC(C(N=C4)=NC=C4OCC(CC4)CCN4C4=C(C=NN(C(CCC(N5)=O)C5=O)C5=O)C5=CC=C4)=CC=C3)C2=O)=CC=C1 YUVAEZSKFCKPKC-UHFFFAOYSA-N 0.000 claims description 3
- ZIPGEFSAECNCTC-UHFFFAOYSA-N N#CC1=CC(C(C=C2)=NN(CC3=CC(C(N=C4)=NC=C4OCC(CC4)CCN4C4=CC=C(C=NN(C(CCC(N5)=O)C5=O)C5=O)C5=C4)=CC=C3)C2=O)=CC=C1 Chemical compound N#CC1=CC(C(C=C2)=NN(CC3=CC(C(N=C4)=NC=C4OCC(CC4)CCN4C4=CC=C(C=NN(C(CCC(N5)=O)C5=O)C5=O)C5=C4)=CC=C3)C2=O)=CC=C1 ZIPGEFSAECNCTC-UHFFFAOYSA-N 0.000 claims description 3
- 108010026668 snake venom protein C activator Proteins 0.000 abstract description 12
- 102000008022 Proto-Oncogene Proteins c-met Human genes 0.000 abstract description 9
- 108010089836 Proto-Oncogene Proteins c-met Proteins 0.000 abstract description 9
- 230000006806 disease prevention Effects 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 126
- 238000006243 chemical reaction Methods 0.000 description 94
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 81
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 72
- 239000000243 solution Substances 0.000 description 51
- 210000004027 cell Anatomy 0.000 description 45
- 238000002360 preparation method Methods 0.000 description 37
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- 239000011541 reaction mixture Substances 0.000 description 25
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 23
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 20
- 238000005481 NMR spectroscopy Methods 0.000 description 17
- 206010028980 Neoplasm Diseases 0.000 description 17
- 102000004190 Enzymes Human genes 0.000 description 15
- 108090000790 Enzymes Proteins 0.000 description 15
- 238000004440 column chromatography Methods 0.000 description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
- 239000013078 crystal Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- 208000005718 Stomach Neoplasms Diseases 0.000 description 11
- 238000001816 cooling Methods 0.000 description 11
- 206010017758 gastric cancer Diseases 0.000 description 11
- 201000011549 stomach cancer Diseases 0.000 description 11
- 201000011510 cancer Diseases 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- QSAJHBBRHWXBFE-UHFFFAOYSA-N 3-[6-oxo-1-[[3-[5-(piperidin-4-ylmethoxy)pyrimidin-2-yl]phenyl]methyl]pyridazin-3-yl]benzonitrile Chemical compound O=C1C=CC(C=2C=C(C=CC=2)C#N)=NN1CC(C=1)=CC=CC=1C(N=C1)=NC=C1OCC1CCNCC1 QSAJHBBRHWXBFE-UHFFFAOYSA-N 0.000 description 9
- 230000002401 inhibitory effect Effects 0.000 description 9
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Natural products C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000000376 reactant Substances 0.000 description 6
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- RYSICGXZRVMXDP-UHFFFAOYSA-N 3-bromopiperidine-2,6-dione Chemical compound BrC1CCC(=O)NC1=O RYSICGXZRVMXDP-UHFFFAOYSA-N 0.000 description 5
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 5
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- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 4
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- ZQFCTCYDRQFPBU-UHFFFAOYSA-N methyl 4-fluoro-2-methylbenzoate Chemical compound COC(=O)C1=CC=C(F)C=C1C ZQFCTCYDRQFPBU-UHFFFAOYSA-N 0.000 description 4
- 150000004682 monohydrates Chemical class 0.000 description 4
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 4
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- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- CNMOHEDUVVUVPP-UHFFFAOYSA-N piperidine-2,3-dione Chemical compound O=C1CCCNC1=O CNMOHEDUVVUVPP-UHFFFAOYSA-N 0.000 description 1
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- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
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- AHYMHWXQRWRBKT-UHFFFAOYSA-N tepotinib Chemical compound C1CN(C)CCC1COC1=CN=C(C=2C=C(CN3C(C=CC(=N3)C=3C=C(C=CC=3)C#N)=O)C=CC=2)N=C1 AHYMHWXQRWRBKT-UHFFFAOYSA-N 0.000 description 1
- 229950009455 tepotinib Drugs 0.000 description 1
- FJYBLMJHXRWDAQ-QMMMGPOBSA-N tert-butyl (2s)-2-(hydroxymethyl)morpholine-4-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCO[C@H](CO)C1 FJYBLMJHXRWDAQ-QMMMGPOBSA-N 0.000 description 1
- LOBHRXDXENCDIZ-AWEZNQCLSA-N tert-butyl (2s)-2-[(4-methylphenyl)sulfonyloxymethyl]morpholine-4-carboxylate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OC[C@H]1OCCN(C(=O)OC(C)(C)C)C1 LOBHRXDXENCDIZ-AWEZNQCLSA-N 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
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- A61K31/50—Pyridazines; Hydrogenated pyridazines
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61K31/5375—1,4-Oxazines, e.g. morpholine
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- C07D495/14—Ortho-condensed systems
Abstract
Description
본 발명은 피페리딘디온 유도체 화합물에 관한 것이다. 더욱 구체적으로, 본 발명은 표적단백질 리간드 및 E3 효소 리간드가 연결되어 있는 구조의 피페리딘디온 유도체 화합물에 관한 것이다.The present invention relates to piperidinedione derivative compounds. More specifically, the present invention relates to a piperidinedione derivative compound having a structure in which a target protein ligand and an E3 enzyme ligand are linked.
프로탁(PROTACs)은 프로테올리시스 타겟팅 키메라(PROteolysis TArgeting Chimeras)의 약자로서, 표적단백질(POI: protein of interest)의 분해를 유도하는 기술이다. 프로탁이라는 용어 대신에 TPD (표적 단백질 분해: Targeted Protein Degradation) 라는 용어가 사용되기도 한다.PROTACs, an abbreviation of PROteolysis TArgeting Chimeras, is a technology that induces the degradation of a target protein (POI: protein of interest). Instead of the term protac, the term TPD (Targeted Protein Degradation) is sometimes used.
프로탁은 표적단백질 리간드 및 E3 효소 리간드가 링커에 의하여 연결되어 있는 구조이다(도 1 참조). 표적단백질 리간드는 질병과 관련된 표적 단백질에 결합할 수 있는 구조이며, E3 효소 리간드는 E3 효소와 결합할 수 있는 구조이다.Protac is a structure in which a target protein ligand and an E3 enzyme ligand are connected by a linker (see FIG. 1). The target protein ligand is a structure that can bind to a target protein associated with a disease, and the E3 enzyme ligand is a structure that can bind to an E3 enzyme.
E3 효소(E3 리가아제)는 표적단백질에 유비퀴틴이라는 표지를 붙일 수 있고, 이러한 유비퀴틴 표지가 붙은 표적단백질은 프로테아좀에 의하여 분해된다.E3 enzyme (E3 ligase) can attach a label called ubiquitin to a target protein, and the target protein labeled with such ubiquitin is degraded by the proteasome.
프로탁 화합물의 표적단백질 리간드가 표적단백질에 결합한다면, 프로탁 화합물에 의하여 E3 효소가 표적단백질의 아주 가까운 거리에 위치하게 되며, 따라서 표적단백질이 프로테아좀에 의하여 제거될 수 있는 환경이 만들어지게 된다.If the target protein ligand of the Protac compound binds to the target protein, the E3 enzyme is located very close to the target protein by the Protac compound, thus creating an environment in which the target protein can be removed by the proteasome. do.
특히, 프로탁 화합물이 암세포의 증식에 관여하는 표적단백질에 결합한다면 해당 표적단백질의 분해를 유도하여 암 치료 효과를 거둘 수 있다.In particular, if the Protac compound binds to a target protein involved in the proliferation of cancer cells, it can achieve a cancer treatment effect by inducing degradation of the target protein.
본 발명은 표적단백질(특히 c-MET 단백질)의 분해 효과를 높여 TPD 용으로 사용될 수 있는 화합물을 제공하기 위한 것이다.The present invention is to provide a compound that can be used for TPD by increasing the decomposition effect of a target protein (particularly c-MET protein).
본 발명은 하기 화학식 1의 화합물 또는 이의 약학적으로 허용되는 염에 관한 것이다:The present invention relates to a compound of Formula 1 or a pharmaceutically acceptable salt thereof:
[화학식 1][Formula 1]
상기식에서,In the above formula,
Z는 표적단백질 리간드이고,Z is a target protein ligand;
Q1 내지 Q4는 각각 독립적으로 C-Z, C-H, C-Hal 또는 C≡N이되(여기에서, Hal은 할로겐이다), 단 Q1 내지 Q4 중 어느 하나는 C-Z이며,Q 1 to Q 4 are each independently CZ, CH, C-Hal or C≡N (here, Hal is a halogen), provided that any one of Q 1 to Q 4 is CZ;
R1은 수소, 할로겐, 니트로, 아미노, C1 내지 C6의 직쇄, 분지쇄 또는 사이클릭 알킬, 또는 할로겐으로 치환된 C1 내지 C6의 직쇄, 분지쇄 또는 사이클릭 알킬이다.R 1 is hydrogen, halogen, nitro, amino, C 1 to C 6 straight, branched or cyclic alkyl, or C 1 to C 6 straight, branched or cyclic alkyl substituted by halogen.
본 발명의 화합물에서 상기 R1은 수소, 할로겐, C1 내지 C4의 직쇄, 분지쇄 또는 사이클릭 알킬, 또는 할로겐으로 치환된 C1 내지 C4의 직쇄, 분지쇄 또는 사이클릭 알킬인 것이 바람직하다.In the compound of the present invention, R 1 is preferably hydrogen, halogen, C 1 to C 4 straight-chain, branched or cyclic alkyl, or halogen-substituted C 1 to C 4 straight-chain, branched or cyclic alkyl. Do.
본 발명의 화합물에서 상기 표적단백질 리간드로는 c_MET 억제제인 화합물이 사용될 수 있으며, 바람직하게는 하기 화합물로 이루어진 군으로부터 선택되는 화합물이 사용될 수 있다:In the compound of the present invention, a c_MET inhibitor compound may be used as the target protein ligand, and preferably a compound selected from the group consisting of the following compounds may be used:
또한, 본 발명은 하기 화학식 2의 화합물 또는 이의 약학적으로 허용되는 염에 관한 것이다:In addition, the present invention relates to a compound of Formula 2 or a pharmaceutically acceptable salt thereof:
[화학식 2][Formula 2]
상기식에서,In the above formula,
Y는 -C=O 또는 -CH2이고,Y is -C=0 or -CH 2 ;
Z는 표적단백질 리간드이며,Z is a target protein ligand,
Q1 내지 Q4는 각각 독립적으로 C-Z, C-H, C-Hal 또는 C≡N이되(여기에서, Hal은 할로겐이다), 단 Q1 내지 Q4 중 어느 하나는 C-Z이다.Q 1 to Q 4 are each independently CZ, CH, C-Hal or C≡N (here, Hal is a halogen), provided that any one of Q 1 to Q 4 is CZ.
본 발명의 화합물에서 상기 표적단백질 리간드로는 c-MET 억제제인 화합물이 사용될 수 있으며, 바람직하게는 하기 화합물로 이루어진 군으로부터 선택되는 화합물이 사용될 수 있다:In the compound of the present invention, a c-MET inhibitor compound may be used as the target protein ligand, and preferably a compound selected from the group consisting of the following compounds may be used:
본 발명에 따른 화합물은 바람직하게는 하기 화합물로 이루어진 군으로부터 선택되는 화합물 또는 이의 약학적으로 허용되는 염일 수 있다:The compound according to the present invention may preferably be a compound selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof:
또한, 본 발명에 따른 화합물은 바람직하게는 하기 화합물로 이루어진 군으로부터 선택되는 화합물 또는 이의 약학적으로 허용되는 염일 수 있다:In addition, the compound according to the present invention may preferably be a compound selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof:
3-(6-(4-(4-(2-((S)-2-((5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일)메틸)모르폴리노)피리미딘-5-일)벤질)피페라진-1-일)-1-옥소프탈라진-2(1H)-일)피페리딘-2,6-디온3-(6-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]tria zolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)-1-oxophthalazin-2(1H)-yl )piperidine-2,6-dione
3-(4-메틸-6-(4-(4-(2-((S)-2-((5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일)메틸)모르폴리노)피리미딘-5-일)벤질)피페라진-1-일)-1-옥소프탈라진-2(1H)-일)피페리딘-2,6-디온3-(4-methyl-6-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2 ,3] triazolo [4,5-b] pyrazin-1-yl) methyl) morpholino) pyrimidin-5-yl) benzyl) piperazin-1-yl) -1-oxophthalazin-2 ( 1H)-yl)piperidine-2,6-dione
3-(7-(4-(4-(2-((S)-2-((5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일)메틸)모르폴리노)피리미딘-5-일)벤질)피페라진-1-일)-1-옥소프탈라진-2(1H)-일)피페리딘-2,6-디온3-(7-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]tria zolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)-1-oxophthalazin-2(1H)-yl )piperidine-2,6-dione
3-(8-(4-(4-(2-((S)-2-((5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일)메틸)모르폴리노)피리미딘-5-일)벤질)피페라진-1-일)-1-옥소프탈라진-2(1H)-일)피페리딘-2,6-디온3-(8-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]tria zolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)-1-oxophthalazin-2(1H)-yl )piperidine-2,6-dione
3-(4-메틸-8-(4-(4-(2-((S)-2-((5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일)메틸)모르폴리노)피리미딘-5-일)벤질)피페라진-1-일)-1-옥소프탈라진-2(1H)-일)피페리딘-2,6-디온3-(4-methyl-8-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2 ,3] triazolo [4,5-b] pyrazin-1-yl) methyl) morpholino) pyrimidin-5-yl) benzyl) piperazin-1-yl) -1-oxophthalazin-2 ( 1H)-yl)piperidine-2,6-dione
3-(6-플루오로-7-(4-(4-(2-((S)-2-((5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일)메틸)모르폴리노)피리미딘-5-일)벤질)피페라진-1-일)-1-옥소프탈라진-2(1H)-일)피페리딘-2,6-디온3-(6-fluoro-7-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1, 2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)-1-oxophthalazin-2 (1H)-yl)piperidine-2,6-dione
2-(2,6-디옥소피페리딘-3-일)-4-(4-(4-(2-((S)-2-((5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일)메틸)모르폴리노)피리미딘-5-일)벤질)피페라진-1-일)이소인돌린-1,3-디온2-(2,6-dioxopiperidin-3-yl)-4-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazole-4 -yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl) isoindoline-1,3-dione
2-(2,6-디옥소피페리딘-3-일)-5-(4-(4-(2-((S)-2-((5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일)메틸)모르폴리노)피리미딘-5-일)벤질)피페라진-1-일)이소인돌린-1,3-디온2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazole-4 -yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl) isoindoline-1,3-dione
3-(1-(3-(5-((1-(2-(2,6-디옥소피페리딘-3-일)-1-옥소-1,2-디하이드로프탈라진-6-일)피페리딘-4-일)메톡시)피리미딘-2-일)벤질)-6-옥소-1,6-디하이드로피리다진-3-일)벤조니트릴3-(1-(3-(5-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl )piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile
3-(1-(3-(5-((1-(2-(2,6-디옥소피페리딘-3-일)-4-메틸-1-옥소-1,2-디하이드로프탈라진-6-일)피페리딘-4-일)메톡시)피리미딘-2-일)벤질)-6-옥소-1,6-디하이드로피리다진-3-일)벤조니트릴3-(1-(3-(5-((1-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazine -6-yl) piperidin-4-yl) methoxy) pyrimidin-2-yl) benzyl) -6-oxo-1,6-dihydropyridazin-3-yl) benzonitrile
3-(1-(3-(5-((1-(2-(2,6-디옥소피페리딘-3-일)-1-옥소-1,2-디하이드로프탈라진-5-일)피페리딘-4-일)메톡시)피리미딘-2-일)벤질)-6-옥소-1,6-디하이드로피리다진-3-일)벤조니트릴3-(1-(3-(5-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-5-yl )piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile
3-(1-(3-(5-((1-(3-(2,6-디옥소피페리딘-3-일)-4-옥소-3,4-디하이드로프탈라진-6-일)피페리딘-4-일)메톡시)피리미딘-2-일)벤질)-6-옥소-1,6-디하이드로피리다진-3-일)벤조니트릴3-(1-(3-(5-((1-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrophthalazin-6-yl )piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile
3-(1-(3-(5-((1-(3-(2,6-디옥소피페리딘-3-일)-4-옥소-3,4-디하이드로프탈라진-5-일)피페리딘-4-일)메톡시)피리미딘-2-일)벤질)-6-옥소-1,6-디하이드로피리다진-3-일)벤조니트릴3-(1-(3-(5-((1-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrophthalazin-5-yl )piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile
3-(1-(3-(5-((1-(3-(2,6-디옥소피페리딘-3-일)-1-메틸-4-옥소-3,4-디하이드로프탈라진-6-일)피페리딘-4-일)메톡시)피리미딘-2-일)벤질)-6-옥소-1,6-디하이드로피리다진-3-일)벤조니트릴3-(1-(3-(5-((1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrophthalazine -6-yl) piperidin-4-yl) methoxy) pyrimidin-2-yl) benzyl) -6-oxo-1,6-dihydropyridazin-3-yl) benzonitrile
3-(1-(3-(5-((1-(2-(2,6-디옥소피페리딘-3-일)-7-플루오로-1-옥소-1,2-디하이드로프탈라진-6-일)피페리딘-4-일)메톡시)피리미딘-2-일)벤질)-6-옥소-1,6-디하이드로피리다진-3-일)벤조니트릴3-(1-(3-(5-((1-(2-(2,6-dioxopiperidin-3-yl)-7-fluoro-1-oxo-1,2-dihydrophthala Zin-6-yl) piperidin-4-yl) methoxy) pyrimidin-2-yl) benzyl)-6-oxo-1,6-dihydropyridazin-3-yl) benzonitrile
3-(1-(3-(5-((1-(3-(2,6-디옥소피페리딘-3-일)-7-플루오로-4-옥소-3,4-디하이드로프탈라진-6-일)피페리딘-4-일)메톡시)피리미딘-2-일)벤질)-6-옥소-1,6-디하이드로피리다진-3-일)벤조니트릴3-(1-(3-(5-((1-(3-(2,6-dioxopiperidin-3-yl)-7-fluoro-4-oxo-3,4-dihydrophthala Zin-6-yl) piperidin-4-yl) methoxy) pyrimidin-2-yl) benzyl)-6-oxo-1,6-dihydropyridazin-3-yl) benzonitrile
3-(1-(3-(5-((1-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)피페리딘-4-일)메톡시)피리미딘-2-일)벤질)-6-옥소-1,6-디하이드로피리다진-3-일)벤조니트릴3-(1-(3-(5-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin- 4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile
3-(1-(3-(5-((1-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-5-일)피페리딘-4-일)메톡시)피리미딘-2-일)벤질)-6-옥소-1,6-디하이드로피리다진-3-일)벤조니트릴3-(1-(3-(5-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin- 4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile
본 발명에 따른 화합물은 표적단백질 리간드 및 E3 효소 리간드를 포함하는 화합물로서, 상기 표적단백질 리간드 및 E3 효소 리간드는 링커에 의하지 아니한 채 서로 직접 공유결합으로 연결되어 있으므로, 표적 단백질 분해를 위한 화합물로 유용하게 사용될 수 있다. 특히, 링커가 없이 표적 단백질 리간드 및 E3 효소 리간드가 직접 연결되어 있기 때문에, 화합물의 분자 크기를 최소화하여 물성을 우수하게 하고, 표적 단백질과 E3 리간드 사이의 단백질-단백질 상호작용을 극대화하여 효과적으로 표적단백질을 분해하는 것이 가능하다.The compound according to the present invention is a compound comprising a target protein ligand and an E3 enzyme ligand, and since the target protein ligand and E3 enzyme ligand are directly covalently linked to each other without using a linker, it is useful as a compound for target protein degradation. can be used In particular, since the target protein ligand and the E3 enzyme ligand are directly connected without a linker, the molecular size of the compound is minimized to improve physical properties, and the protein-protein interaction between the target protein and the E3 ligand is maximized to effectively target the protein. It is possible to decompose
본 발명에서 E3 효소 리간드로는 하기 화학식 3의 화합물과 같은 옥소프탈라진 피페리딘디온 유도체 또는 하기 화학식 4의 화합물과 같은 디옥소피페리딘 이소인돌린디온 유도체가 사용될 수 있다:In the present invention, as the E3 enzyme ligand, an oxophthalazine piperidinedione derivative such as the compound of Formula 3 or a dioxopiperidine isoindolinedione derivative such as the compound of Formula 4 below may be used:
[화학식 3][Formula 3]
상기식에서,In the above formula,
X는 할로겐 또는 시아노(-CN)이고,X is halogen or cyano (-CN);
Q1 내지 Q4는 각각 독립적으로 C-H 또는 C-X이며,Q 1 to Q 4 are each independently CH or CX;
R1은 수소, 할로겐, 니트로, 아미노, C1 내지 C6의 직쇄, 분지쇄 또는 사이클릭 알킬, 또는 할로겐으로 치환된 C1 내지 C6의 직쇄, 분지쇄 또는 사이클릭 알킬이다 (바람직하게는, 상기 R1은 수소, 할로겐, C1 내지 C4의 직쇄, 분지쇄 또는 사이클릭 알킬, 또는 할로겐으로 치환된 C1 내지 C4의 직쇄, 분지쇄 또는 사이클릭 알킬이다).R 1 is hydrogen, halogen, nitro, amino, C 1 to C 6 straight-chain, branched or cyclic alkyl, or C 1 to C 6 straight-chain, branched or cyclic alkyl substituted by halogen (preferably , Wherein R 1 is hydrogen, halogen, C 1 to C 4 straight-chain, branched or cyclic alkyl, or halogen-substituted C 1 to C 4 straight-chain, branched or cyclic alkyl).
[화학식 4][Formula 4]
상기식에서,In the above formula,
Y는 -C=O 또는 -CH2이고,Y is -C=0 or -CH 2 ;
X는 할로겐 또는 시아노(-CN)이고,X is halogen or cyano (-CN);
Q1 내지 Q4는 각각 독립적으로 C-H 또는 C-X이다.Q 1 to Q 4 are each independently CH or CX.
또한, 본 발명에 따른 피페리딘디온 유도체 화합물은 표적단백질 리간드로서, 핵 수용체(예를 들어, ER, AR, RAR 등), 단백질 키나제(예를 들어, Akt, c-Abl, BTK, anaplastic lymphoma kinase [ALK], CDK9, c-Met, RIPK2, DAPK1, PSD-95 등), 전사 조절에 관여하는 단백질(예를 들어, BRD4, Sirt2, HDAC6, TRIM24, IKZH1/3, Smad3 등), 조절 단백질(예를 들어, CRABP-I/II, TACC3, AHR, FKBP12, ERRα, SHP2, X-protein, PTPN11 등), 신경-퇴행성 관련 단백질(예를 들어, Huntingtin, Tau, a-synuclein, PSD-95 등), 세포 대사 효소(예를 들어, MetAP-2, DHODH), 융합 단백질(예를 들어, Alk-fusion, BCR-Abl, Brd-Nut, Ret-fusion, Halo Tags 등), 돌연변이 단백질(예를 들어, Braf mutant, EGFR mutant 및 deletion, Kras mutant, TP53 mutant 및 splicing varient 등), 비정상적 변형 단백질(예를 들어, EGFRdel19, P53 splicing varient, fusion proteins 등) 등을 표적단백질로 하는 화합물이 사용될 수 있으나, 바람직하게는 c-MET 단백질을 표적으로 하는 화합물이 표적단백질 리간드로 사용될 수 있다. 따라서, 본 발명에 따른 화합물은 c-MET 단백질과 관련있는 질병의 치료 또는 예방에 유용하게 사용될 수 있다.In addition, the piperidinedione derivative compound according to the present invention is a target protein ligand, nuclear receptor (e.g., ER, AR, RAR, etc.), protein kinase (e.g., Akt, c-Abl, BTK, anaplastic lymphoma kinase [ALK], CDK9, c-Met, RIPK2, DAPK1, PSD-95, etc.), proteins involved in transcriptional regulation (eg, BRD4, Sirt2, HDAC6, TRIM24, IKZH1/3, Smad3, etc.), regulatory proteins (e.g. CRABP-I/II, TACC3, AHR, FKBP12, ERRα, SHP2, X-protein, PTPN11, etc.), neurodegenerative related proteins (e.g. Huntingtin, Tau, a-synuclein, PSD-95 etc.), cellular metabolic enzymes (eg MetAP-2, DHODH), fusion proteins (eg Alk-fusion, BCR-Abl, Brd-Nut, Ret-fusion, Halo Tags, etc.), mutant proteins (eg Alk-fusion, BCR-Abl, Brd-Nut, Ret-fusion, Halo Tags, etc.) For example, compounds that target proteins such as Braf mutant, EGFR mutant and deletion, Kras mutant, TP53 mutant and splicing variant, etc.), abnormal modified protein (eg EGFRdel19, P53 splicing variant, fusion proteins, etc.) can be used. However, preferably, a compound targeting the c-MET protein may be used as the target protein ligand. Therefore, the compound according to the present invention can be usefully used for the treatment or prevention of diseases related to c-MET protein.
본 발명의 화합물에서 상기 표적단백질 리간드로는 c-MET 억제제인 화합물로서, 바람직하게는 하기 화합물로 이루어진 군으로부터 선택되는 화합물이 사용될 수 있다:In the compound of the present invention, the target protein ligand is a compound that is a c-MET inhibitor, preferably a compound selected from the group consisting of the following compounds:
본 발명에서 상기 표적단백질 리간드의 우측은, E3 효소 리간드인 상기 화학식 3 또는 4의 화학물에서 Q1 내지 Q4 중의 어느 하나의 탄소 원자에 공유결합할 수 있다. 이와 같이 표적단백질 리간드 및 E3 효소 리간드가 서로 공유결합하여 연결되는 부위는 공유결합 반응 과정 중에서 일부 치환기가 이탈될 수 있음을 통상의 기술자는 이해할 수 있을 것이다.In the present invention, the right side of the target protein ligand may covalently bind to any one carbon atom of Q1 to Q4 in the chemical compound of
본 발명의 화합물은 프로탁 화합물은 표적단백질(예를 들어, c-MET 단백질)결합하여 이를 분해할 수 있으므로, 표적단백질과 관련있는 질병의 치료 또는 예방에 유용하게 사용될 수 있다. 예를 들어, 본 발명의 화합물은 우수한 항암 효과를 가지며, 더 나아가서 c-MET 단백질의 분해를 유도하여 c-MET과 관련있는 질병에 대한 치료 효과를 나타낼 수 있다.Since the compound of the present invention can bind to and degrade a target protein (eg, c-MET protein), the protac compound can be usefully used for the treatment or prevention of diseases related to the target protein. For example, the compound of the present invention has an excellent anticancer effect, and further induces the degradation of c-MET protein to exhibit a therapeutic effect on diseases related to c-MET.
도 1은 표적단백질 리간드, 링커 및 E3 효소 리간드로 이루어지는 프로탁 화합물을 모식적으로 도시한 것이다.
도 2는 본 발명의 화합물의 MKN45 세포주에서의 단백질 분해 효과를 확인한 실험 결과를 나타낸 것이다.
도 3은 본 발명의 화합물의 SNU638, Hs746T, EBC-1 세포주에서의 단백질 분해 효과를 확인한 실험 결과를 나타낸 것이다.
도 4는 본 발명의 화합물의 MKN45 암세포 증식 억제 효과를 확인한 실험 결과를 나타낸 것이다.
도 5는 본 발명의 화합물의 SNU638, Hs746T, EBC-1 암세포 증식억제를 확인한 실험 결과를 나타낸 것이다.
도 6은 본 발명의 화합물의 정상 세포 증식 억제 효과 여부를 확인한 실험 결과를 나타낸 것이다.
도 7은 본 발명의 화합물의 농도 별 세포신호전달 억제 효과를 확인한 실험 결과를 나타낸 것이다.
도 8은 SNU638 세포에서 본 발명의 화합물의 시간별 세포신호전달 억제 효과를 확인한 실험 결과를 나타낸 것이다.
도 9는 SNU638 종양세포 이식 마우스에서 본 발명의 화합물의 복강투여에 의한 항암 효과를 확인한 실험 결과를 나타낸 것이다.
도 10은 SNU638 종양세포 이식 마우스에서 본 발명의 화합물의 경구투여에 의한 항암 효과를 확인한 실험 결과를 나타낸 것이다.1 schematically shows a protac compound consisting of a target protein ligand, a linker, and an E3 enzyme ligand.
Figure 2 shows the experimental results confirming the proteolytic effect of the compound of the present invention in the MKN45 cell line.
Figure 3 shows the experimental results confirming the proteolytic effect of the compound of the present invention in SNU638, Hs746T, EBC-1 cell lines.
Figure 4 shows the experimental results confirming the MKN45 cancer cell proliferation inhibitory effect of the compound of the present invention.
Figure 5 shows the experimental results confirming the inhibition of SNU638, Hs746T, EBC-1 cancer cell proliferation of the compound of the present invention.
Figure 6 shows the experimental results confirming whether or not the compound of the present invention has an inhibitory effect on normal cell proliferation.
Figure 7 shows the experimental results confirming the cell signaling inhibitory effect of each concentration of the compound of the present invention.
Figure 8 shows the experimental results confirming the cell signaling inhibitory effect over time of the compound of the present invention in SNU638 cells.
Figure 9 shows the experimental results confirming the anticancer effect by intraperitoneal administration of the compound of the present invention in mice transplanted with SNU638 tumor cells.
Figure 10 shows the experimental results confirming the anticancer effect by oral administration of the compound of the present invention in mice transplanted with SNU638 tumor cells.
이하, 본 발명의 이해를 돕기 위하여 본 발명을 실시예에 의거하여 상세하게 설명하기로 한다. 단, 하기의 실시예는 본 발명의 내용을 예시하는 것일 뿐, 본 발명의 사상이나 범위가 어떤 의미로든 하기 실시예에 의하여 한정되는 것은 아니다. 본 발명의 실시예는 당업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위하여 제공되는 것이다.Hereinafter, the present invention will be described in detail based on examples to aid understanding of the present invention. However, the following examples are merely illustrative of the contents of the present invention, and the spirit or scope of the present invention is not limited in any sense by the following examples. The embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.
실시예Example A: A: 옥소프탈라진일oxophthalazinyl 피페리딘디온piperidinedione 유도체 화합물의 제조 Preparation of derivative compounds
본 발명의 프로탁 화합물에서 E3 효소 리간드로 사용될 수 있는 화학식 1의 옥소프탈라진일 피페리딘디온(oxophthalazinyl piperidione) 화합물의 기본골격(scaffold)은 하기 반응식 1 또는 반응식 2의 반응 단계를 거쳐 제조할 수 있다:The scaffold of the oxophthalazinyl piperidione compound of
[반응식 1][Scheme 1]
[반응식 2][Scheme 2]
상기 반응식 1 또는 2에서, X는 수소, 할로겐 또는 시아노이다. 다만, 설명의 편의를 위하여, 상기 반응식에서는 화학식 1의 화합물 중 Q1 내지 Q4에서 탄소에 결합될 수 있는 치환기의 표시를 생략하였고, R1 치환기 중에서는 수소 또는 메틸과 같이 간단한 치환기만을 대표적으로 표시하였다.In
이하에서는, 화학식 1의 화합물의 구체적인 예를 실시예를 통하여 제조한다.Hereinafter, specific examples of the compound of
실시예 A1:Example A1:
화합물 의 제조compound manufacture of
A1-1) 메틸 2-플루오로-6-메틸벤조에이트 제조A1-1) Preparation of methyl 2-fluoro-6-methylbenzoate
실온에서, 아세톤 (200ml) 중의 2-플루오로-6-메틸벤조 산 (10g, 64.9 mmol) 용액에 K2CO3 (44.8g, 324 mmol)을 가하였다. 30분간 교반 후, 반응물에 요오드화 메탄 (46g, 324 mmol)을 가하고, 6시간 동안 60oC로 가열하였다. 냉각 후, 반응물을 여과하고, 감암 하에서 농축하였다. 생성물을 추가 정제없이 다음 반응에 사용하였다. (11.2g, 수율 103%) MS (ESI, m/z): [M+1]+ = [168.3].At room temperature, to a solution of 2-fluoro-6-methylbenzoic acid (10g, 64.9 mmol) in acetone (200ml) was added K 2 CO 3 (44.8g, 324 mmol). After stirring for 30 minutes, methane iodide (46g, 324 mmol) was added to the reaction mass and heated to 60 ° C. for 6 hours. After cooling, the reaction was filtered and concentrated in the dark. The product was used in the next reaction without further purification. (11.2 g, yield 103%) MS (ESI, m/z): [M+1] + = [168.3].
A1-2) 메틸 2-(브로모메틸)-6-플루오로벤조에이트 제조A1-2) Preparation of methyl 2-(bromomethyl)-6-fluorobenzoate
실온에서, ClCH2CH2Cl (250ml) 중의 메틸 2-플루오로-6-메틸벤조에이트 (21.2g, 126 mmol) 용액에 1-브로모피롤리딘-2,5-디온 (24.7g, 139mmol) 및 벤조일 벤젠카보퍼옥소에이트 (1.53g, 6.30mmol)을 순차적으로 가하였다. 반응물을 16시간 동안 가열 환류시켰다. 붉은 색이 사라지는 시점이 반응 완료 시점이다. 냉각 후, 반응물을 물로 세척하고, MgSO4로 건조시키고, 감압 농축시켰다. 조 생성물 을 추가 정제없이 다음 반응에 사용하였다. (35g, 수율 112%) MS (ESI, m/z): [M+1]+ = [245.9].1-Bromopyrrolidine-2,5-dione (24.7g, 139mmol) was added to a solution of methyl 2-fluoro-6-methylbenzoate (21.2g, 126 mmol) in ClCH 2 CH 2 Cl (250ml) at room temperature. and benzoylbenzenecarboperoxoate (1.53g, 6.30mmol) were sequentially added. The reaction was heated to reflux for 16 hours. The point at which the red color disappears is the completion point of the reaction. After cooling, the reaction was washed with water, dried over MgSO 4 and concentrated under reduced pressure. The crude product was used in the next reaction without further purification. (35 g, yield 112%) MS (ESI, m/z): [M+1] + = [245.9].
A1-3) 메틸 2-플루오로-6-포르밀벤조에이트 제조A1-3) Preparation of methyl 2-fluoro-6-formylbenzoate
실온에서, DCM (280ml) 중의 메틸 2-(브로모메틸)-6-플루오로벤조에이트 (35g, 142mmol) 용액에 NMO(24.9g, 212mmol)를 가하였다. 반응물을 4시간 동안 실온에서 교반하였다. DCM 층을 물(200ml)로 세척하고, MgSO4로 건조시키고, 감압 농축시켰다. 잔사를 컬럼 크로마토그래피로 정제하여, 표제 화합물을 흰색 고체로서 수득하였다. (11.52g, 수율 45%) MS (ESI, m/z): [M+1]+ = [183.1].At room temperature, to a solution of methyl 2-(bromomethyl)-6-fluorobenzoate (35 g, 142 mmol) in DCM (280 ml) was added NMO (24.9 g, 212 mmol). The reaction was stirred at room temperature for 4 hours. The DCM layer was washed with water (200ml), dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound as a white solid. (11.52 g, yield 45%) MS (ESI, m/z): [M+1] + = [183.1].
A1-4) 2-플루오로-6-포르밀벤조산 제조A1-4) Preparation of 2-fluoro-6-formylbenzoic acid
실온에서, THF (82ml) 중의 메틸 2-플루오로-6-포르밀벤조에이트 (11.5g, 63.2mmol) 용액에 리튬(+1) 하이드록사이드 (7.57g, 180mmol) 수용액(41ml)을 가하였다. 4시간 교반 후, 반응물을 감압 농축하여 THF를 건조시켰다. 0℃로 냉각시킨 후, 반응물을 1N HCl로 산성화시켜 pH를 4로 조정하였다. 반응물을 에틸 아세테이트 (100ml)로 2회 추출하였다. 결합한 에틸 아세테이트 층을 MgSO4로 건조시키고, 감압 농축시켜, 흰색 결정을 수득하였다(10.4g, 97.8%). MS (ESI, m/z): [M+1]+ = [168.8].At room temperature, to a solution of methyl 2-fluoro-6-formylbenzoate (11.5 g, 63.2 mmol) in THF (82 ml) was added lithium(+1) hydroxide (7.57 g, 180 mmol) aqueous solution (41 ml). . After stirring for 4 hours, the reactant was concentrated under reduced pressure to dry THF. After cooling to 0 °C, the reaction was acidified with 1N HCl to adjust the pH to 4. The reaction was extracted twice with ethyl acetate (100ml). The combined ethyl acetate layers were dried over MgSO 4 and concentrated under reduced pressure to obtain white crystals (10.4 g, 97.8%). MS (ESI, m/z): [M+1] + = [168.8].
A1-5) 8-플루오로프탈라진-1(2H)-온 제조A1-5) Preparation of 8-fluorophthalazin-1 (2H) -one
실온에서, 메탄올 (120ml) 중의 2-플루오로-6-포르밀벤조산 (10.4g, 61.9mmol) 용액에 NH2NH2 일수화물 (3.72mg, 61.9mmol)을 가하고, 16시간 동안 실온에서 교반하였다. 흰색 침전물을 여과하고, 메탄올로 세척하였다. 수득한 흰색 결정을 100ml의 에틸 아세테이트(EA)로 슬러리화하고, 여과하여 흰색 결정을 수득하였다(3.05g, 30%). MS (ESI, m/z): [M+1]+ = [164.8].At room temperature, to a solution of 2-fluoro-6-formylbenzoic acid (10.4g, 61.9mmol) in methanol (120ml) was added NH 2 NH 2 monohydrate (3.72mg, 61.9mmol) and stirred at room temperature for 16 hours. . The white precipitate was filtered off and washed with methanol. The obtained white crystals were slurried with 100 ml of ethyl acetate (EA) and filtered to obtain white crystals (3.05 g, 30%). MS (ESI, m/z): [M+1] + = [164.8].
A1-6) 3-(8-플루오로-1-옥소프탈라진-2(1H)-일)피페리딘-2,6-디온 제조A1-6) Preparation of 3-(8-fluoro-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione
0℃에서 DMF (5ml) 중의 8-플루오로프탈라진-1(2H)-온 (200mg, 1.22mmol) 용액에 NaH (60%, 53.6mg, 1.34mmol)을 가하고, 30분간 교반하였다. 이 용액에 3-브로모피페리딘-2,6-디온 (468mg, 2.44mmol)을 가하고 6시간 동안 교반하였다. 물로 반응을 종결시키고, 에틸 아세테이트 (20ml)로 2회 추출하였다. 결합한 에틸 아세테이트를 MgSO4로 건조시키고, 감압 농축시켰다. 잔사를 컬럼 크로마토그래피로 정제하여, 표제 화합물을 흰색 결정으로 수득하였다(70mg, 20.8%). MS (ESI, m/z): [M+1]+ = [276.1].To a solution of 8-fluorophthalazin-1(2H)-one (200mg, 1.22mmol) in DMF (5ml) at 0°C was added NaH (60%, 53.6mg, 1.34mmol) and stirred for 30 minutes. 3-bromopiperidine-2,6-dione (468mg, 2.44mmol) was added to the solution and stirred for 6 hours. The reaction was quenched with water and extracted twice with ethyl acetate (20ml). The combined ethyl acetate was dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound as white crystals (70 mg, 20.8%). MS (ESI, m/z): [M+1] + = [276.1].
실시예 A2:Example A2:
화합물 의 제조compound manufacture of
A2-1) 메틸 5-플루오로-6-메틸벤조에이트 제조A2-1) Preparation of methyl 5-fluoro-6-methylbenzoate
실온에서, 메탄올 (60ml) 중의 3-플루오로-2-메틸벤조 산 (10g, 64.9 mmol) 용액에 황산 (2ml)을 가하였다. 80oC로 가열하고, 밤새 교반하였다. 실온으로 냉각 후, 반응물을 증발시키고, NaHCO3 및 에틸아세테이트(EA)로 추출하였다. MgSO4로 건조시켰다. 조 생성물을 추가 정제없이 다음 반응에 사용하였다. (10.1g, 수율 92%) MS (ESI, m/z): [M+1]+ = [168.3].At room temperature, to a solution of 3-fluoro-2-methylbenzoic acid (10 g, 64.9 mmol) in methanol (60 ml) was added sulfuric acid (2 ml). Heated to 80 ° C and stirred overnight. After cooling to room temperature, the reaction was evaporated and extracted with NaHCO 3 and ethyl acetate (EA). Dried over MgSO 4 . The crude product was used in the next reaction without further purification. (10.1 g, yield 92%) MS (ESI, m/z): [M+1] + = [168.3].
A2-2) 메틸 2-(브로모메틸)-3-플루오로벤조에이트 제조A2-2) Preparation of methyl 2-(bromomethyl)-3-fluorobenzoate
실온에서, ClCH2CH2Cl (250ml) 중의 메틸 3-플루오로-2-메틸벤조에이트 (10g, 59.5mmol) 용액에 1-브로모피롤리딘-2,5-디온 (15.9g, 89.2mmol) 및 벤조일 벤젠카보퍼옥소에이트 (0.72g, 2.97mmol)을 순차적으로 가하였다. 반응물을 16시간 동안 가열 환류시켰다. 붉은 색이 사라지는 시점이 반응 완료 시점이다. 냉각 후, 반응물을 물로 세척하고, MgSO4로 건조시키고, 감압 농축시켰다. 조 생성물을 추가 정제없이 다음 반응에 사용하였다. (10.5g, 수율 71%) MS (ESI, m/z): [M+1]+ = [245.9].1-bromopyrrolidine-2,5-dione (15.9 g, 89.2 mmol) was added to a solution of methyl 3-fluoro-2-methylbenzoate (10 g, 59.5 mmol) in ClCH 2 CH 2 Cl (250 ml) at room temperature. and benzoylbenzenecarboperoxoate (0.72g, 2.97mmol) were sequentially added. The reaction was heated to reflux for 16 hours. The point at which the red color disappears is the completion point of the reaction. After cooling, the reaction was washed with water, dried over MgSO 4 and concentrated under reduced pressure. The crude product was used in the next reaction without further purification. (10.5 g, yield 71%) MS (ESI, m/z): [M+1] + = [245.9].
A2-3) 메틸 3-플루오로-2-포르밀벤조에이트 제조A2-3) Preparation of methyl 3-fluoro-2-formylbenzoate
실온에서, DCM (200ml) 중의 메틸 2-(브로모메틸)-3-플루오로벤조에이트 (10g, 40.5mmol) 용액에 NMO (10.4g, 89mmol), 4Å 분자체를 가하였다. 반응물을 4시간 동안 실온에서 교반하였다. DCM 층을 물(200ml)로 세척하고, MgSO4로 건조시키고, 감압 농축시켰다. 잔사를 컬럼 크로마토그래피로 정제하여, 표제 화합물을 수득하였다. (5.5g, 75%) MS (ESI, m/z): [M+1]+ = [183.1].To a solution of methyl 2-(bromomethyl)-3-fluorobenzoate (10 g, 40.5 mmol) in DCM (200 ml) was added NMO (10.4 g, 89 mmol), 4 Å molecular sieves at room temperature. The reaction was stirred at room temperature for 4 hours. The DCM layer was washed with water (200ml), dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound. (5.5 g, 75%) MS (ESI, m/z): [M+1] + = [183.1].
A2-4) 3-플루오로-2-포르밀벤조산 제조A2-4) Preparation of 3-fluoro-2-formylbenzoic acid
실온에서, THF (68ml) 중의 메틸 3-플루오로-2-포르밀벤조에이트 (2.5g, 13.7mmol) 용액에 리튬(+1) 하이드록사이드 일수화물 (2.88g, 68.6mmol) 수용액(41ml)을 가하였다. 4시간 교반 후, 반응물을 감압 농축하여 THF를 건조시켰다. 0℃로 냉각시킨 후, 반응물을 1N HCl로 산성화시켜 pH를 4로 조정하였다. 반응물을 에틸 아세테이트 (100ml)로 2회 추출하였다. 결합한 에틸 아세테이트 층을 MgSO4로 건조시키고, 감압 농축시켜, 흰색 결정을 수득하였다(2.5g, 108%). MS (ESI, m/z): [M+1]+ = [168.8].At room temperature, a solution of methyl 3-fluoro-2-formylbenzoate (2.5g, 13.7mmol) in THF (68ml) in aqueous solution of lithium(+1) hydroxide monohydrate (2.88g, 68.6mmol) (41ml) was added. After stirring for 4 hours, the reactant was concentrated under reduced pressure to dry THF. After cooling to 0 °C, the reaction was acidified with 1N HCl to adjust the pH to 4. The reaction was extracted twice with ethyl acetate (100ml). The combined ethyl acetate layers were dried over MgSO 4 and concentrated under reduced pressure to obtain white crystals (2.5 g, 108%). MS (ESI, m/z): [M+1] + = [168.8].
A2-5) 5-플루오로-1,2-디하이드로프탈라진-1-온 제조A2-5) Preparation of 5-fluoro-1,2-dihydrophthalazin-1-one
실온에서, THF:물=1:1 (70ml) 중의 3-플루오로-2-포르밀벤조산 (2.5g, 14.9mmol) 용액에 NH2NH2 일수화물 (1.22mg, 16.4mmol)을 가하고, 16시간 동안 교반하였다. 혼합물을 pH 4로 산성화하고, 고체를 헥산으로 여과하였다. 진공 건조시켜, 표제 화합물을 수득하였다(1.3g, 53%). MS (ESI, m/z): [M+1]+ = [165.3]To a solution of 3-fluoro-2-formylbenzoic acid (2.5g, 14.9mmol) in THF:water=1:1 (70ml) at room temperature, NH 2 NH 2 monohydrate (1.22mg, 16.4mmol) was added, and 16 Stir for an hour. The mixture was acidified to
A2-6) 3-(5-플루오로-1-옥소-1,2-디하이드로프탈라진-2-일)피페리딘-2,6-디온 제조A2-6) Preparation of 3-(5-fluoro-1-oxo-1,2-dihydrophthalazin-2-yl)piperidine-2,6-dione
0℃에서 DMF (10ml) 중의 5-플루오르-1,2-디하이드로로프탈라진-1-온 (300mg, 1.83mmol) 용액에 LDA (리튬 디이소프로필 아마이드, 2.19mmol)을 가하고, 30분간 교반하였다. 이 용액에 3-브로모피페리딘-2,6-디온 (526mg, 2.74mmol)을 가하고 6시간 동안 80℃에서 교반하였다. 반응이 완료되면, 반응물을 실온으로 냉각시키고, 물(100ml)에 붓고, 6N HCl로 pH를 3~4로 조정하고, 그 후 에틸 아세테이트로 추출하고, 이를 MgSO4로 건조시키고, 감압 농축시켰다. 생성물을 헥산으로 재결정하고, 진공 건조하여, 표제 화합물을 수득하였다. MS (ESI, m/z): [M+1]+ = [276.1].LDA (lithium diisopropyl amide, 2.19 mmol) was added to a solution of 5-fluoro-1,2-dihydrophthalazin-1-one (300 mg, 1.83 mmol) in DMF (10 ml) at 0 °C and stirred for 30 minutes. did 3-bromopiperidine-2,6-dione (526mg, 2.74mmol) was added to the solution and stirred at 80°C for 6 hours. Upon completion of the reaction, the reactant was cooled to room temperature, poured into water (100ml), the pH was adjusted to 3-4 with 6N HCl, then extracted with ethyl acetate, dried over MgSO 4 and concentrated under reduced pressure. The product was recrystallized from hexane and dried in vacuo to give the title compound. MS (ESI, m/z): [M+1] + = [276.1].
실시예 A3Example A3
화합물 의 제조compound manufacture of
A3-1) 메틸 4-플루오로-6-메틸벤조에이트 제조A3-1) Preparation of methyl 4-fluoro-6-methylbenzoate
실시예 A2-1의 제조방법에 준하여, 4-플루오로-2-메틸벤조산으로부터 메틸 4-플루오로-2-메틸벤조에이트를 제조하였다.According to the preparation method of Example A2-1, methyl 4-fluoro-2-methylbenzoate was prepared from 4-fluoro-2-methylbenzoic acid.
A3-2) 메틸 2-(브로모메틸)-4-플루오로벤조에이트 제조A3-2) Preparation of methyl 2-(bromomethyl)-4-fluorobenzoate
실온에서, ClCH2CH2Cl (100ml) 중의 메틸 4-플루오로-2-메틸벤조에이트 (20g, 119mmol) 용액에 1-브로모피롤리딘-2,5-디온 (31.8g, 178mmol) 및 벤조일 벤젠카보퍼옥소에이트 (1.92g, 5.95mmol)을 순차적으로 가하였다. 반응물을 3시간 동안 가열 환류시켰다. 붉은 색이 사라지는 시점이 반응 완료 시점이다. 냉각 후, 반응물을 물로 세척하고, MgSO4로 건조시키고, 감압 농축시켰다. 생성물을 MPLC (HX/EA EA 0 -> 5%)로 정제하였다(22g, 수율 75%). MS (ESI, m/z): [M+1]+ = [248.4].To a solution of methyl 4-fluoro-2-methylbenzoate (20 g, 119 mmol) in ClCH 2 CH 2 Cl (100 ml) at room temperature, 1-bromopyrrolidine-2,5-dione (31.8 g, 178 mmol) and benzoyl Benzenecarboperoxoate (1.92g, 5.95mmol) was added sequentially. The reaction was heated to reflux for 3 hours. The point at which the red color disappears is the completion point of the reaction. After cooling, the reaction was washed with water, dried over MgSO 4 and concentrated under reduced pressure. The product was purified by MPLC (HX/EA EA 0 -> 5%) (22 g, yield 75%). MS (ESI, m/z): [M+1] + = [248.4].
A3-3) 메틸 3-플루오로-2-포르밀벤조에이트 제조A3-3) Preparation of methyl 3-fluoro-2-formylbenzoate
실온에서, DCM (100ml) 중의 메틸 2-(브로모메틸)-4-플루오로벤조에이트 (22g, 89mmol) 용액에 NMO (15.6mg, 134mmol) 및 4Å 분자체를 순차적으로 가하였다. 반응물을 2시간 동안 실온에서 교반하였다. 분자체를 여과하고, DCM (50ml)로 세척하였다. DCM 층을 물(200ml)로 세척하고, MgSO4로 건조시키고, 감압 농축시켰다. 잔사를 컬럼 크로마토그래피로 정제하여, 표제 화합물을 흰색 고체로서 수득하였다. (12g, 73.98%) MS (ESI, m/z): [M+1]+ = [183.2].To a solution of methyl 2-(bromomethyl)-4-fluorobenzoate (22g, 89mmol) in DCM (100ml) at room temperature, NMO (15.6mg, 134mmol) and 4A molecular sieves were added sequentially. The reaction was stirred at room temperature for 2 hours. The molecular sieve was filtered and washed with DCM (50ml). The DCM layer was washed with water (200ml), dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound as a white solid. (12 g, 73.98%) MS (ESI, m/z): [M+1] + = [183.2].
A3-4) 4-플루오로-2-포르밀벤조산 제조A3-4) Preparation of 4-fluoro-2-formylbenzoic acid
실온에서, THF (50ml) 중의 메틸 4-플루오로-6-포르밀벤조에이트 (12g, 65.9mmol) 용액에 리튬(+1) 하이드록사이드 (13.8g, 329mmol) 수용액(50ml)을 가하였다. 2시간 교반 후, 반응물을 감압 농축하여 THF를 건조시켰다. 0℃로 냉각시킨 후, 반응물을 1N HCl로 산성화시켜 pH를 4로 조정하였다. 반응물을 에틸 아세테이트 (50ml)로 2회 추출하였다. 결합한 에틸 아세테이트 층을 MgSO4로 건조시키고, 감압 농축시켜, 흰색 결정을 수득하였다(10g, 90.3%). MS (ESI, m/z): [M+1]+ = [169.2].At room temperature, to a solution of methyl 4-fluoro-6-formylbenzoate (12 g, 65.9 mmol) in THF (50 ml) was added an aqueous solution of lithium(+1) hydroxide (13.8 g, 329 mmol) (50 ml). After stirring for 2 hours, the reaction mixture was concentrated under reduced pressure to dry THF. After cooling to 0 °C, the reaction was acidified with 1N HCl to adjust the pH to 4. The reaction was extracted twice with ethyl acetate (50ml). The combined ethyl acetate layer was dried over MgSO 4 and concentrated under reduced pressure to obtain white crystals (10 g, 90.3%). MS (ESI, m/z): [M+1] + = [169.2].
A3-5) 6-플루오로-1,2-디하이드로프탈라진-1-온 제조A3-5) Preparation of 6-fluoro-1,2-dihydrophthalazin-1-one
실온에서, 메탄올 (50ml) 중의 4-플루오로-2-포르밀벤조산 (6.78g, 40.3mmol) 용액에 NH2NH2 일수화물 (2.02g, 40.3mmol)을 가하였다. 30분간 교반 후, 반응물을 2시간 동안 80℃로 가열하였다. 반응물을 실온으로 냉각시키고, 감압 농축하였다. 잔사를 물(150ml)에 붓고, 에틸 아세테이트 (150ml)로 2회 추출하였다. 결합한 에틸 아세테이트 층을 MgSO4로 건조시키고, 감압 농축시켜, 흰색 결정을 수득하였다(5.5g, 83.07%). MS (ESI, m/z): [M+1]+ = [165.3].At room temperature, to a solution of 4-fluoro-2-formylbenzoic acid (6.78 g, 40.3 mmol) in methanol (50 ml) was added NH 2 NH 2 monohydrate (2.02 g, 40.3 mmol). After stirring for 30 minutes, the reaction was heated to 80 °C for 2 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was poured into water (150ml) and extracted twice with ethyl acetate (150ml). The combined ethyl acetate layer was dried over MgSO 4 and concentrated under reduced pressure to obtain white crystals (5.5 g, 83.07%). MS (ESI, m/z): [M+1] + = [165.3].
A3-6) 3-(6-플루오로-1-옥소프탈라진-2(1H)-일)피페리딘-2,6-디온 제조A3-6) Preparation of 3-(6-fluoro-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione
0℃에서 DMF (2ml) 중의 6-플루오르-1,2-디하이드로로프탈라진-1-온 (100mg, 0.609mmol) 용액에 소듐 2-메틸프로판-2-올레이트 (175mg, 0.914mmol)을 가하였다. 30분간 교반한 후, 3-브로모피페리딘-2,6-디온 (90mg, 0.471mmol)을 반응 혼합물에 가하고 6시간 동안 실온에서 교반하였다. 반응 혼합물에 물(20ml)을 붓고, 에틸 아세테이트(20ml)로 2회 추출하였다. 결합된 에틸 아세테이트를 MgSO4로 건조시키고, 감압 농축시켰다. 잔사를 크로마토그래피로 정제하여, 표제 화합물을 흰색 결정으로 수득하였다(110mg, 65.5%). MS (ESI, m/z): [M+1]+ = [276.6].Sodium 2-methylpropan-2-oleate (175 mg, 0.914 mmol) was added to a solution of 6-fluoro-1,2-dihydrophthalazin-1-one (100 mg, 0.609 mmol) in DMF (2 ml) at 0 °C. added After stirring for 30 minutes, 3-bromopiperidine-2,6-dione (90 mg, 0.471 mmol) was added to the reaction mixture and stirred at room temperature for 6 hours. Water (20ml) was poured into the reaction mixture and extracted twice with ethyl acetate (20ml). The combined ethyl acetate was dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by chromatography to give the title compound as white crystals (110 mg, 65.5%). MS (ESI, m/z): [M+1] + = [276.6].
실시예 A4Example A4
화합물 의 제조compound manufacture of
A4-1) 메틸 4-플루오로-6-메틸벤조에이트 제조A4-1) Preparation of methyl 4-fluoro-6-methylbenzoate
실시예 A2의 제조방법에 준하여, 5-플루오로-2-메틸벤조산으로부터 메틸 5-플루오로-2-메틸벤조에이트를 제조하였다.According to the preparation method of Example A2, methyl 5-fluoro-2-methylbenzoate was prepared from 5-fluoro-2-methylbenzoic acid.
A4-2) 메틸 2-(브로모메틸)-5-플루오로벤조에이트 제조A4-2) Preparation of methyl 2-(bromomethyl)-5-fluorobenzoate
실온에서, ClCH2CH2Cl (100ml) 중의 메틸 5-플루오로-2-메틸벤조에이트 (20g, 119mmol) 용액에 1-브로모피롤리딘-2,5-디온 (31.8g, 178mmol) 및 벤조일 벤젠카보퍼옥소에이트 (1.92g, 5.95mmol)을 순차적으로 가하였다. 반응물을 3시간 동안 가열 환류시켰다. 붉은 색이 사라지는 시점이 반응 완료 시점이다. 냉각 후, 반응물을 물로 세척하고, MgSO4로 건조시키고, 감압 농축시켰다. 생성물을 MPLC (HX/EA EA 0 -> 5%)로 정제하였다(29g, 수율 98.8%). MS (ESI, m/z): [M+1]+ = [248.4].To a solution of methyl 5-fluoro-2-methylbenzoate (20 g, 119 mmol) in ClCH 2 CH 2 Cl (100 ml) at room temperature, 1-bromopyrrolidine-2,5-dione (31.8 g, 178 mmol) and benzoyl Benzenecarboperoxoate (1.92g, 5.95mmol) was added sequentially. The reaction was heated to reflux for 3 hours. The point at which the red color disappears is the completion point of the reaction. After cooling, the reaction was washed with water, dried over MgSO 4 and concentrated under reduced pressure. The product was purified by MPLC (HX/EA EA 0 -> 5%) (29 g, yield 98.8%). MS (ESI, m/z): [M+1] + = [248.4].
A4-3) 메틸 5-플루오로-2-포르밀벤조에이트 제조A4-3) Preparation of methyl 5-fluoro-2-formylbenzoate
실온에서, DCM (100ml) 중의 메틸 2-(브로모메틸)-5-플루오로벤조에이트 (29g, 117mmol) 용액에 NMO (20.6mg, 176mmol) 및 4Å 분자체를 순차적으로 가하였다. 반응물을 2시간 동안 실온에서 교반하였다. 분자체를 여과하고, DCM (50ml)로 세척하였다. DCM 층을 물(200ml)로 세척하고, MgSO4로 건조시키고, 감압 농축시켰다. 잔사를 컬럼 크로마토그래피로 정제하여, 표제 화합물을 흰색 고체로서 수득하였다. (15g, 수율 70.16%) MS (ESI, m/z): [M+1]+ = [183.2].To a solution of methyl 2-(bromomethyl)-5-fluorobenzoate (29 g, 117 mmol) in DCM (100 ml) at room temperature, NMO (20.6 mg, 176 mmol) and 4A molecular sieves were added sequentially. The reaction was stirred at room temperature for 2 hours. The molecular sieve was filtered and washed with DCM (50ml). The DCM layer was washed with water (200ml), dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound as a white solid. (15 g, yield 70.16%) MS (ESI, m/z): [M+1] + = [183.2].
A4-4) 5-플루오로-2-포르밀벤조산 제조A4-4) Preparation of 5-fluoro-2-formylbenzoic acid
실온에서, THF (50ml) 중의 메틸 5-플루오로-2-포르밀벤조에이트 (15g, 82.3mmol) 용액에 리튬(+1) 하이드록사이드 (17.3g, 412mmol) 수용액(50ml)을 가하였다. 2시간 교반 후, 반응물을 감압 농축하여 THF를 건조시켰다. 0℃로 냉각시킨 후, 반응물을 1N HCl로 산성화시켜 pH를 4로 조정하였다. 반응물을 에틸 아세테이트 (50ml)로 2회 추출하였다. 결합한 에틸 아세테이트 층을 MgSO4로 건조시키고, 감압 농축시켜, 흰색 결정을 수득하였다(12g, 86.67%). MS (ESI, m/z): [M+1]+ = [169.2].At room temperature, to a solution of methyl 5-fluoro-2-formylbenzoate (15 g, 82.3 mmol) in THF (50 ml) was added lithium(+1) hydroxide (17.3 g, 412 mmol) aqueous solution (50 ml). After stirring for 2 hours, the reaction mixture was concentrated under reduced pressure to dry THF. After cooling to 0 °C, the reaction was acidified with 1N HCl to adjust the pH to 4. The reaction was extracted twice with ethyl acetate (50ml). The combined ethyl acetate layer was dried over MgSO 4 and concentrated under reduced pressure to obtain white crystals (12 g, 86.67%). MS (ESI, m/z): [M+1] + = [169.2].
A4-5) 7-플루오로-1,2-디하이드로프탈라진-1-온 제조A4-5) Preparation of 7-fluoro-1,2-dihydrophthalazin-1-one
실온에서, 메탄올 (50ml) 중의 5-플루오로-2-포르밀벤조산 (8.16g, 48.5mmol) 용액에 NH2NH2 일수화물 (3.74g, 74.8mmol)을 가하였다. 30분간 교반 후, 반응물을 2시간 동안 80℃로 가열하였다. 반응물을 실온으로 냉각시키고, 감압 농축하였다. 잔사를 물(150ml)에 붓고, 에틸 아세테이트 (150ml)로 2회 추출하였다. 결합한 에틸 아세테이트 층을 MgSO4로 건조시키고, 감압 농축시켜, 흰색 결정을 수득하였다(6.5g, 81.59%). MS (ESI, m/z): [M+1]+ = [165.3].At room temperature, to a solution of 5-fluoro-2-formylbenzoic acid (8.16g, 48.5mmol) in methanol (50ml) was added NH 2 NH 2 monohydrate (3.74g, 74.8mmol). After stirring for 30 minutes, the reaction was heated to 80 °C for 2 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was poured into water (150ml) and extracted twice with ethyl acetate (150ml). The combined ethyl acetate layer was dried over MgSO 4 and concentrated under reduced pressure to obtain white crystals (6.5 g, 81.59%). MS (ESI, m/z): [M+1] + = [165.3].
A4-6) 3-(7-플루오로-1-옥소프탈라진-2(1H)-일)피페리딘-2,6-디온 제조A4-6) Preparation of 3-(7-fluoro-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione
0℃에서 DMF (5ml) 중의 7-플루오르-1,2-디하이드로로프탈라진-1-온 (500mg, 3.05mmol) 용액에 소듐 2-메틸프로판-2-올레이트 (586mg, 6.09mmol)을 가하였다. 30분간 교반한 후, 3-브로모피페리딘-2,6-디온 (1.05mg, 5.48mmol)을 반응 혼합물에 가하고 6시간 동안 실온에서 교반하였다. 반응 혼합물을 물(50ml)에 붓고, 에틸 아세테이트(50ml)로 2회 추출하였다. 결합된 에틸 아세테이트를 MgSO4로 건조시키고, 감압 농축시켰다. 잔사를 컬럼 크로마토그래피로 정제하여, 표제 화합물을 흰색 결정으로 수득하였다(300mg, 35.78%). MS (ESI, m/z): [M+1]+ = [276.6].Sodium 2-methylpropan-2-oleate (586 mg, 6.09 mmol) was added to a solution of 7-fluoro-1,2-dihydrophthalazin-1-one (500 mg, 3.05 mmol) in DMF (5 ml) at 0 °C. added After stirring for 30 minutes, 3-bromopiperidine-2,6-dione (1.05mg, 5.48mmol) was added to the reaction mixture and stirred at room temperature for 6 hours. The reaction mixture was poured into water (50ml) and extracted twice with ethyl acetate (50ml). The combined ethyl acetate was dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound as white crystals (300 mg, 35.78%). MS (ESI, m/z): [M+1] + = [276.6].
실시예 A5Example A5
화합물 의 제조 (반응식 2에 준하여 제조함)compound Preparation of (prepared according to Scheme 2)
A5-1) 메틸 2-아세틸-6-플루오로벤조에이트 제조A5-1) Preparation of methyl 2-acetyl-6-fluorobenzoate
톨루엔 (20ml) 중의 메틸 2-아세틸-6-플루오로벤조에이트 (1.12g, 4.81mmol) 및 트리부틸(1-에톡시비닐)주석 (1.91g, 5.29mmol) 용액에 테트라키스(트리페닐포스핀)-팔라듐(0) (557mg, 0.48mmol)을 가하고, 100℃에서 16시간 동안 교반하였다. 냉각 후, 5ml의 1N-HCl을 가하고, 1시간 동안 교반하였다. 유기층을 MgSO4로 건조시키고, 감암 하에 농축하였다. 잔사를 실리카 컬럼 크로마토그래피로 정제하여, 표제 화합물을 황색 오일로서 수득하였다. (820mg, 수율 87%) MS (ESI, m/z): [M+1]+ = [196.8].To a solution of methyl 2-acetyl-6-fluorobenzoate (1.12 g, 4.81 mmol) and tributyl(1-ethoxyvinyl)tin (1.91 g, 5.29 mmol) in toluene (20 ml) was added tetrakis(triphenylphosphine). )-palladium(0) (557mg, 0.48mmol) was added and stirred at 100°C for 16 hours. After cooling, 5 ml of 1N-HCl was added and stirred for 1 hour. The organic layer was dried over MgSO 4 and concentrated in the dark. The residue was purified by silica column chromatography to give the title compound as a yellow oil. (820 mg, yield 87%) MS (ESI, m/z): [M+1] + = [196.8].
A5-2) 2-아세틸-6-플루오로벤조 산 제조A5-2) Preparation of 2-acetyl-6-fluorobenzoic acid
THF (20ml) 및 물 (10ml) 중의 메틸 2-아세틸-6-플루오로벤조에이트 (810mg, 4.13mmol) 용액에 LiOH (494mg, 20.6mmol)을 가하고, 실온에서 20시간 동안 교반하였다. 용액을 1N-HCl로 산성화시켜 pH가 약 3이 되도록 하였다. 100ml EA를 가하고, 유기층을 MgSO4로 건조시키고, 감압 농축하여 표제화합물을 수득하였다. (810mg 수율 108%) MS (ESI, m/z): [M+1]+ = [183.1].To a solution of methyl 2-acetyl-6-fluorobenzoate (810mg, 4.13mmol) in THF (20ml) and water (10ml) was added LiOH (494mg, 20.6mmol) and stirred at room temperature for 20 hours. The solution was acidified with 1N-HCl to a pH of about 3. After adding 100ml EA, the organic layer was dried over MgSO 4 and concentrated under reduced pressure to obtain the title compound. (810 mg yield 108%) MS (ESI, m/z): [M+1] + = [183.1].
A5-3) 8-플루오로-4-메틸프탈라진-1(2H)-온 제조A5-3) Preparation of 8-fluoro-4-methylphthalazin-1 (2H) -one
메탄올 (23ml) 중의 2-아세틸-6-플루오로벤조 산 (790mg, 4.34mmol) 용액에 히드라진 일수화물 (261mg, 5.20mmol)을 가하고, 16시간 동안 실온에서 교반하였다. 침전물을 여과하고, ACN (아세토니트릴)로 세척하여, 표제 화합물 을 흰색 고체로서 수득하였다. (612mg, 수율 79.2%) MS (ESI, m/z): [M+1]+ = [179.1].Hydrazine monohydrate (261 mg, 5.20 mmol) was added to a solution of 2-acetyl-6-fluorobenzoic acid (790 mg, 4.34 mmol) in methanol (23 ml) and stirred at room temperature for 16 hours. The precipitate was filtered and washed with ACN (acetonitrile) to give the title compound as a white solid. (612 mg, yield 79.2%) MS (ESI, m/z): [M+1] + = [179.1].
A5-4) 3-(8-플루오로-4-메틸-1-옥소프탈라진-2(1H)-일)피페리딘-2,6-디온 제조A5-4) Preparation of 3-(8-fluoro-4-methyl-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione
0℃에서 THF(30 ml) 중의 8-플루오로-4-메틸프탈라진-1(2H)-온(534 mg, 3 mmol) 용액에 1M-Lithium diisopropylamide (3.6 ml, 3.6 mmol)을 가하고, 20분간 교반하였다. 이 용액에 3-브로보피페리딘-2,6-디온(863 mg, 4.5 mmol)을 가하고 80℃에서 2시간 동안 교반하였다. 반응물을 감압 농축하여 건조시켰다. 물(10 ml)를 넣고 1시간 교반 후, 1N-HCl로 산성화시켜 pH를 4로 조정하였다. 침전물을 여과하고, 물로 세척하여, 표제 화합물을 흰색 고체로서 수득하였다(760 mg, 수율: 86.5 %). MS (ESI, m/z): [M+1]+ = [289.8].To a solution of 8-fluoro-4-methylphthalazin-1(2H)-one (534 mg, 3 mmol) in THF (30 ml) at 0°C was added 1M-Lithium diisopropylamide (3.6 ml, 3.6 mmol), Stir for 20 minutes. 3-brobopiperidine-2,6-dione (863 mg, 4.5 mmol) was added to the solution, and the mixture was stirred at 80°C for 2 hours. The reactant was concentrated under reduced pressure and dried. After adding water (10 ml) and stirring for 1 hour, the pH was adjusted to 4 by acidification with 1N-HCl. The precipitate was filtered and washed with water to give the title compound as a white solid (760 mg, yield: 86.5%). MS (ESI, m/z): [M+1] + = [289.8].
실시예 A6: 3-(6-브로모-1-옥소프탈라진-2(1H)-일)피페리딘-2,6-디온의 제조Example A6: Preparation of 3-(6-bromo-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione
A6-1) 5-브로모-3-하이드록시이소벤조푸란-1(3H)-온의 제조A6-1) Preparation of 5-bromo-3-hydroxyisobenzofuran-1 (3H) -one
200 ml 의 ClCH2CH2Cl 중의 5-브로모프탈라이드 (5.2 g, 24.4 mmol) 및 N-브로모숙신이미드 (5.6 g, 31.7 mmol) 혼합물에 AIBN (401 mg, 2.44 mmol)을 가하고, 8시간 동안 환류시켰다. 반응에 뒤이어 TLC를 진행하였다. 숙신이미드를 여과하고, 케이크를 ClCH2CH2Cl (50 mL)로 세척하였다. 용매를 진공에서 제거하여, 잔사 5.2g를 남기고, 여기에 50 ml 물을 가하였다. 혼합물을 4시간 동안 교반하면서 환류시키고, 혼합물을 냉각시키고, 생성물을 여과하고, 물로 중화 세척하고, 건조하여, 옅은 황백색의 결정을 수득하였다. (4.85g, 수율 86.7%)To a mixture of 5-bromophthalide (5.2 g, 24.4 mmol) and N-bromosuccinimide (5.6 g, 31.7 mmol) in 200 ml of ClCH 2 CH 2 Cl was added AIBN (401 mg, 2.44 mmol), Refluxed for 8 hours. The reaction was followed by TLC. The succinimide was filtered off and the cake was washed with ClCH 2 CH 2 Cl (50 mL). The solvent was removed in vacuo, leaving 5.2 g of a residue to which 50 ml water was added. The mixture was refluxed with stirring for 4 hours, the mixture was cooled, the product was filtered, neutral washed with water and dried to give pale off-white crystals. (4.85 g, yield 86.7%)
MS (ESI, m/z): [M+1]+ = [229.6] and [230.5]MS (ESI, m/z): [M+1] + = [229.6] and [230.5]
A6-2) 6-브로모프탈라진-1(2H)-온의 제조A6-2) Preparation of 6-bromophthalazin-1 (2H) -one
MeOH (50 mL) 중의 5-브로모-3-하이드록시-1,3-디하이드로-2-벤조푸란-1-온 (1.5g, 6.55 mmol) 용액에 NH2NH2 H2O (315 mg, 9.82 mmol)를 실온에서 가하고, 30분간 교반하였다. 반응을 5시간 동안 환류시켰다. 반응물을 실온으로 냉각시키고, 감압 농축하였다. 생성된 고체를 에틸 아세테이트로 분쇄(trituration)하여, 흰색 결정을 수득하였다. (1.31g, 5.82 mmol)To a solution of 5-bromo-3-hydroxy-1,3-dihydro-2-benzofuran-1-one (1.5 g, 6.55 mmol) in MeOH (50 mL) NH 2 NH 2 H 2 O (315 mg , 9.82 mmol) was added at room temperature and stirred for 30 minutes. The reaction was refluxed for 5 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. The resulting solid was triturated with ethyl acetate to give white crystals. (1.31 g, 5.82 mmol)
MS (ESI, m/z): [M+1]+ = [226.3].MS (ESI, m/z): [M+1] + = [226.3].
A6-3) 3-(6-브로모-1-옥소프탈라진-2(1H)-일)피페리딘-2,6-디온의 제조A6-3) Preparation of 3-(6-bromo-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione
THF (150 mL) 중의 6-브로모-1,2-디하이드로프탈라진-1-온 (1.31g, 5.82mmol) 현탁액에 1.0 M LDA (7.33 mL)을 0℃에서 적가하였다. 30분간 교반한 후, 3-브로모피페리딘-2,6-디온을 반응물에 일부분씩 가하였다. 반응물을 80℃로 가열하고, 2시간 동안 교반하였다. 반응이 종료되면, 반응물을 실온으로 냉각시키고, 물(100 ml)에 붓고, 6N HCl로 pH를 3~4로 조정하고, 에틸 아세테이트로 추출하고, 이를 MgSO4로 건조시키고, 감압 농축하였다. 생성된 고체를 여과하고, 에틸 아세테이트로 세척하여, 흰색 결정을 수득하였다.(1.73g, 5.15 mmol)To a suspension of 6-bromo-1,2-dihydrophthalazin-1-one (1.31 g, 5.82 mmol) in THF (150 mL) was added 1.0 M LDA (7.33 mL) dropwise at 0 °C. After stirring for 30 minutes, 3-bromopiperidine-2,6-dione was added portionwise to the reaction. The reaction was heated to 80 °C and stirred for 2 hours. Upon completion of the reaction, the reactant was cooled to room temperature, poured into water (100 ml), the pH was adjusted to 3-4 with 6N HCl, extracted with ethyl acetate, dried over MgSO 4 and concentrated under reduced pressure. The resulting solid was filtered and washed with ethyl acetate to give white crystals (1.73 g, 5.15 mmol).
MS (ESI, m/z): [M+1]+ = [337.2].MS (ESI, m/z): [M+1] + = [337.2].
[NMR] 1H NMR (400 MHz, DMSO-d6) δ11.08 (s, 1H), 8.45 (s, 1H), 8.28 (s, 1H), 8.18-8.16 (m, 1H), 8.06-8.04 (m, 1H), 5.84-5.80 (m, 1H), 2.93 - 2.90 (m, 1H), 2.65 - 2.54 (m, 2H), 2.15 - 2.12 (m, 1H).[NMR] 1H NMR (400 MHz, DMSO-d6) δ11.08 (s, 1H), 8.45 (s, 1H), 8.28 (s, 1H), 8.18-8.16 (m, 1H), 8.06-8.04 (m , 1H), 5.84-5.80 (m, 1H), 2.93 - 2.90 (m, 1H), 2.65 - 2.54 (m, 2H), 2.15 - 2.12 (m, 1H).
실시예 B : (2S)-2-{[5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일]메틸}-4-(5-{4-[(피페라진-1-일)메틸]페닐}피리미딘-2-일)모르폴린 합성Example B: (2S)-2-{[5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine-1 -yl]methyl}-4-(5-{4-[(piperazin-1-yl)methyl]phenyl}pyrimidin-2-yl)morpholine synthesis
하기 반응 공정을 거쳐서 하기 화학식의 c-MET 표적 단백질 리간드 화합물을 제조할 수 있다:A c-MET target protein ligand compound of the following formula can be prepared through the following reaction process:
Step 1) t-부틸 (2S)-2-{[(4-메틸벤젠술포닐)옥시]메틸}모르폴린-4-카복실레이트 합성Step 1) Synthesis of t-butyl (2S)-2-{[(4-methylbenzenesulfonyl)oxy]methyl}morpholine-4-carboxylate
DCM (500 ml) 중의 t-부틸 (2S)-2-(하이드록시메틸)모르폴린-4-카복실레이트 (10 g, 46 mmol) 용액에 4-메틸벤젠-1-술포닐 클로라이드 (9.65 g, 50.6 mmol), N,N-디메틸피리딘-4-아민(0.84 g, 6.9 mmol) 및 트리에틸아민 (3.0 당량)을 가하였다. 반응물을 2 시간 동안 실온에서 교반하였다. 반응 종료 후, 반응물을 물에 붓고, DCM으로 추출하고(2 회), MgSO4로 건조하고, 감압 하에서 농축하였다. 잔사를 헥산/에틸 아세테이트 (0~30%) 컬럼 크로마토그래피로 정제하여 표제 화합물 (17 g) 수득하였다.To a solution of t-butyl (2S)-2-(hydroxymethyl)morpholine-4-carboxylate (10 g, 46 mmol) in DCM (500 ml) was added 4-methylbenzene-1-sulfonyl chloride (9.65 g, 50.6 mmol), N,N-dimethylpyridin-4-amine (0.84 g, 6.9 mmol) and triethylamine (3.0 eq) were added. The reaction was stirred for 2 hours at room temperature. After completion of the reaction, the reactant was poured into water, extracted with DCM (twice), dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by hexane/ethyl acetate (0-30%) column chromatography to obtain the title compound (17 g).
MS (ESI, m/z): [M+H]+ = 372.4.MS (ESI, m/z): [M+H] + = 372.4.
Step 2) t-부틸 (2S)-2-(아지도메틸)모르폴린-4-카복실레이트 합성Step 2) Synthesis of t-butyl (2S)-2-(azidomethyl)morpholine-4-carboxylate
DMF (500 ml) 중의 t-부틸 (2S)-2-{[(4-메틸벤젠술포닐)옥시]메틸}모르폴린-4-카복실레이트 (17 g, 45.8 mmol) 용액에 소듐 아자이드 (12 g, 183 mmol), 소듐 아이오다이드 (1.03 g, 6.86 mmol)를 가하였다. 반응물을 12 시간 동안 70℃에서 교반하였다. 반응 종료 후, 반응물을 물에 붓고, 에틸 아세테이트으로 추출하고(2 회), MgSO4 상에서 건조시키고, 감압 하에서 농축하였다. 잔사를 헥산/에틸 아세테이트 (0~30%) 컬럼 크로마토그래피로 정제하여, 표제 화합물 (10.2 g)을 수득하였다.Sodium azide (12 g, 183 mmol) and sodium iodide (1.03 g, 6.86 mmol) were added. The reaction was stirred at 70° C. for 12 hours. After completion of the reaction, the reaction was poured into water, extracted with ethyl acetate (twice), dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by hexane/ethyl acetate (0-30%) column chromatography to give the title compound (10.2 g).
MS (ESI, m/z): [M+H]+ = 243.4.MS (ESI, m/z): [M+H] + = 243.4.
Step 3) t-부틸 (2R)-2-(아미노메틸)모르폴린-4-카복실레이트 합성Step 3) Synthesis of t-butyl (2R)-2-(aminomethyl)morpholine-4-carboxylate
MeOH (500 ml) 중의 t-부틸 (2S)-2-(아지도메틸)모르폴린-4-카복실레이트 (9.5 g, 39.2 mmol) 용액에 Pd/C (2 g, 5%)를 가하고, 이후 H2 (가스) 하에서 1시간 동안 반응시켰다. 반응 종료 후, 반응 혼합물을 셀라이트를 통하여 여과하고, 감압 하에서 농축하였다. 표제 화합물(8.4 g)을 추가 정제 없이 다음 반응에서 바로 사용하였다.To a solution of t-butyl (2S)-2-(azidomethyl)morpholine-4-carboxylate (9.5 g, 39.2 mmol) in MeOH (500 ml) was added Pd/C (2 g, 5%), then It was reacted for 1 hour under H 2 (gas). After completion of the reaction, the reaction mixture was filtered through celite and concentrated under reduced pressure. The title compound (8.4 g) was used directly in the next reaction without further purification.
MS (ESI, m/z): [M+H]+ = 217.4.MS (ESI, m/z): [M+H] + = 217.4.
Step 4) t-부틸 (2R)-2-{[(3-아미노-6-브로모피라진-2-일)아미노]메틸}모르폴린-4-카복실레이트 합성Step 4) Synthesis of t-butyl (2R)-2-{[(3-amino-6-bromopyrazin-2-yl)amino]methyl}morpholine-4-carboxylate
DMSO (300 ml) 중의 t-부틸 (2R)-2-(아미노메틸)모르폴린-4-카복실레이트 (8.4 g, 38.8 mmol) 및 3,5-디브로모피라진-2-아민 (11.8 g, 46.6 mmol) 용액에 트리에틸아민(3.0 당량)을 가하였다. 반응물을 12 시간 동안 150℃에서 교반하였다. 반응 종료 후, 반응물을 물에 붓고, 에틸 아세테이트로 추출하고(2 회), MgSO4 상에서 건조시키고, 감압 하에서 농축하였다. 잔사를 헥산/에틸 아세테이트(20~50%) 컬럼 크로마토그래피로 정제하여, 표제 화합물(8.5g)을 수득하였다.t-butyl (2R)-2-(aminomethyl)morpholine-4-carboxylate (8.4 g, 38.8 mmol) and 3,5-dibromopyrazin-2-amine (11.8 g, 46.6 mmol) was added triethylamine (3.0 equiv.). The reaction was stirred at 150 °C for 12 hours. After completion of the reaction, the reaction was poured into water, extracted with ethyl acetate (twice), dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by hexane/ethyl acetate (20-50%) column chromatography to give the title compound (8.5 g).
MS (ESI, m/z): [M+H]+ = 389.4.MS (ESI, m/z): [M+H] + = 389.4.
Step 5) t-부틸 (2S)-2-({5-브로모-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일}메틸)모르폴린-4-카복실레이트 합성Step 5) t-butyl (2S)-2-({5-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl}methyl)morpholine-4- carboxylate synthesis
DMF(300 ml) 중의 t-부틸 (2R)-2-{[(3-아미노-6-브로모피라진-2-일)아미노]메틸}모르폴린-4-카복실레이트 (8.4 g, 21.6 mmol) 용액에 이소아밀 니트라이트(isoamyl nitrite) (3.8 g, 32.5 mmol)를 가하였다. 반응물을 3 시간 동안 70℃에서 교반하였다. 반응 종료 후, 반응물을 물에 붓고, 에틸 아세테이트로 추출하고(2 회), MgSO4 상에서 건조시키고, 감압 하에서 농축하였다. 잔사를 헥산/에틸 아세테이트 (0~30%) 컬럼 크로마토그래피로 정제하여, 표제 화합물(7.5g)을 수득하였다.t-Butyl (2R)-2-{[(3-amino-6-bromopyrazin-2-yl)amino]methyl}morpholine-4-carboxylate (8.4 g, 21.6 mmol) in DMF (300 ml) To the solution was added isoamyl nitrite (3.8 g, 32.5 mmol). The reaction was stirred at 70 °C for 3 hours. After completion of the reaction, the reaction was poured into water, extracted with ethyl acetate (twice), dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by hexane/ethyl acetate (0-30%) column chromatography to give the title compound (7.5 g).
MS (ESI, m/z): [M+H]+ = 400.4.MS (ESI, m/z): [M+H] + = 400.4.
Step 6) t-부틸 (2S)-2-{[5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일]메틸}모르폴린-4-카복실레이트 합성Step 6) t-butyl (2S)-2-{[5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine Synthesis of -1-yl]methyl}morpholine-4-carboxylate
1,4-디옥산 (300 ml) 및 H2O (100 ml) 중의 t-부틸 (2S)-2-({5-브로모-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일}메틸)모르폴린-4-카복실레이트 (7.5 g, 18.8 mmol), 1-메틸-4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)-1H-피라졸 (4.7 g, 22.5 mmol) 및 세슘 카보네이트(18.4 g, 56.4 mmol) 용액에 Pd(dppf)Cl2 (0.7 g, 0.95 mmol)를 가하였다. 반응물을 2 시간 동안 80℃에서 교반하였다. 반응 종료 후, 반응물을 물에 붓고, 에틸 아세테이트로 추출하고(2 회), MgSO4 상에서 건조시키고, 감압 하에 농축하였다. 잔사를 헥산/에틸 아세테이트 (10~30%) 컬럼 크로마토그래피로로 정제하여, 표제 화합물(7.1 g)을 수득하였다.t-butyl (2S)-2-({5-bromo-1H-[1,2,3]triazolo[4,5 in 1,4-dioxane (300 ml) and H 2 O (100 ml) -b] pyrazin-1-yl} methyl) morpholine-4-carboxylate (7.5 g, 18.8 mmol), 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2- To a solution of dioxaborolan-2-yl)-1H-pyrazole (4.7 g, 22.5 mmol) and cesium carbonate (18.4 g, 56.4 mmol) was added Pd(dppf)Cl2 (0.7 g, 0.95 mmol). The reaction was stirred at 80° C. for 2 hours. After completion of the reaction, the reaction was poured into water, extracted with ethyl acetate (twice), dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by hexane/ethyl acetate (10-30%) column chromatography to give the title compound (7.1 g).
MS (ESI, m/z): [M+H]+ = 401.4.MS (ESI, m/z): [M+H] + = 401.4.
Step 7) (2S)-2-{[5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일]메틸}모르폴린 합성Step 7) (2S)-2-{[5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine-1- 1]methyl}morpholine synthesis
DCM (300 ml) 중의 t-부틸 (2S)-2-{[5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일]메틸}모르폴린-4-카복실레이트 (7.1 g, 17.7 mmol) 용액에 TFA (100 ml)를 가하였다. 반응물을 2 시간 동안 실온에서 교반하였다. 반응 종료 후, 반응 혼합물 감압 하에서 농축하였다. 표제 화합물(4.8 g)을 추가 정제 없이 다음 반응에 바로 사용하였다.t-Butyl (2S)-2-{[5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5- in DCM (300 ml) To a solution of b]pyrazin-1-yl]methyl}morpholine-4-carboxylate (7.1 g, 17.7 mmol) was added TFA (100 ml). The reaction was stirred for 2 hours at room temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The title compound (4.8 g) was used directly in the next reaction without further purification.
MS (ESI, m/z): [M+H]+ = 301.4.MS (ESI, m/z): [M+H] + = 301.4.
Step 8) (2S)-4-(5-브로모피리미딘-2-일)-2-{[5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일]메틸}모르폴린 합성Step 8) (2S)-4-(5-bromopyrimidin-2-yl)-2-{[5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2, Synthesis of 3]triazolo[4,5-b]pyrazin-1-yl]methyl}morpholine
EtOH(300 ml) 중의 (2S)-2-{[5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일]메틸}모르폴린 (4.8 g, 16 mmol) 및 5-브로모-2-클로로피리미딘 (4.64 g, 24 mmol) 용액에 에틸비스(프로판-2-일)아민 (3.0 당량)을 가하였다. 반응물을 9 시간 동안 50℃에서 교반하였다. 반응 종료 후, 반응 혼합물을 감압 하에서 농축하였다. 표제 화합물을 EtOH로 재결정하였다. 표제 화합물(5.5 g)을 추가 정제 없이 다음 반응에 바로 사용하였다.(2S)-2-{[5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine in EtOH (300 ml) To a solution of -1-yl]methyl}morpholine (4.8 g, 16 mmol) and 5-bromo-2-chloropyrimidine (4.64 g, 24 mmol) ethylbis(propan-2-yl)amine (3.0 eq.) was added. The reaction was stirred at 50° C. for 9 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The title compound was recrystallized from EtOH. The title compound (5.5 g) was used directly in the next reaction without further purification.
MS (ESI, m/z): [M+H]+ = 458.4.MS (ESI, m/z): [M+H] + = 458.4.
Step 9) 4-{2-[(2S)-2-{[5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일]메틸}모르폴린-4-일]피리미딘-5-일}벤즈알데하이드 합성Step 9) 4-{2-[(2S)-2-{[5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5- Synthesis of b]pyrazin-1-yl]methyl}morpholin-4-yl]pyrimidin-5-yl}benzaldehyde
1,4-디옥산 (150 ml) 및 H2O (50 ml) 중의 (2S)-4-(5-브로모피리미딘-2-일)-2-{[5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일]메틸}모르폴린 (5.5 g, 12 mmol), 4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)벤즈알데하이드 (4.2 g, 18 mmol), 세슘 카보네이트(8.31 g, 60.1 mmol) 용액에 Pd(dppf)Cl2 (1.8 g, 2.41 mmol)를 가하였다. 반응물을 2 시간 동안 90℃에서 교반하였다. 반응 종료 후, 반응물을 물에 붓고, 에틸 아세테이트로 추출하고(2 회), MgSO4 상에서 건조시키고, 감압 하에서 농축하였다. 잔사를 헥산/에틸 아세테이트 (30~50%) 컬럼 크로마토그래피로 정제하여, 표제 화합물(5 g)을 수득하였다.(2S)-4-(5-bromopyrimidin-2-yl)-2-{[5-(1-methyl-1H in 1,4-dioxane (150 ml) and H 2 O (50 ml) -Pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}morpholine (5.5 g, 12 mmol), 4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (4.2 g, 18 mmol), Pd(dppf)Cl2 in a solution of cesium carbonate (8.31 g, 60.1 mmol) (1.8 g, 2.41 mmol) was added. The reaction was stirred at 90° C. for 2 hours. After completion of the reaction, the reaction was poured into water, extracted with ethyl acetate (twice), dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by hexane/ethyl acetate (30-50%) column chromatography to obtain the title compound (5 g).
MS (ESI, m/z): [M+H]+ = 483.4.MS (ESI, m/z): [M+H] + = 483.4.
Step 10) t-부틸 4-[(4-{2-[(2S)-2-{[5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일]메틸}모르폴린-4-일]피리미딘-5-일}페닐l)메틸]피페라진-1-카복실레이트 합성Step 10) t-butyl 4-[(4-{2-[(2S)-2-{[5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3] Synthesis of triazolo[4,5-b]pyrazin-1-yl]methyl}morpholin-4-yl]pyrimidin-5-yl}phenyll)methyl]piperazine-1-carboxylate
DCM (250 ml) 중의 4-{2-[(2S)-2-{[5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일]메틸}모르폴린-4-일]피리미딘-5-일}벤즈알데하이드 (5 g, 10.4 mmol) 및 t-부틸 피페라진-1-카복실레이트 (4.8 g, 26 mmol) 용액에 소듐 트리아세톡시보로하이드라이드 (3.9 g, 18.7 mmol) 및 AcOH(1 ml)를 가하였다. 반응물을 18 시간 동안 실온에서 교반하였다. 반응 종료 후, 반응물을 물에 붓고, DCM으로 추출하고(2 회), MgSO4 상에서 건조시키고, 감압 하에서 농축하였다. 잔사를 디클로로메탄/메탄올 (0~10%) 컬럼 크로마토그래피로 정제하여, 표제 화합물(6.7g)을 수득하였다.4-{2-[(2S)-2-{[5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4 in DCM (250 ml) ,5-b]pyrazin-1-yl]methyl}morpholin-4-yl]pyrimidin-5-yl}benzaldehyde (5 g, 10.4 mmol) and t-butyl piperazine-1-carboxylate (4.8 g , 26 mmol) was added sodium triacetoxyborohydride (3.9 g, 18.7 mmol) and AcOH (1 ml). The reaction was stirred at room temperature for 18 hours. After completion of the reaction, the reaction was poured into water, extracted with DCM (twice), dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by dichloromethane/methanol (0-10%) column chromatography to obtain the title compound (6.7 g).
MS (ESI, m/z): [M+H]+ = 653.8.MS (ESI, m/z): [M+H] + = 653.8.
Step 11) (2S)-2-{[5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일]메틸}-4-(5-{4-[(피페라진-1-일)메틸]페닐}피리미딘-2-일)모르폴린 합성Step 11) (2S)-2-{[5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine-1- yl]methyl}-4-(5-{4-[(piperazin-1-yl)methyl]phenyl}pyrimidin-2-yl)morpholine synthesis
DCM (150 ml) 중의 t-부틸 4-[(4-{2-[(2S)-2-{[5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일]메틸}모르폴린-4-일]피리미딘-5-일}페닐l)메틸]피페라진-1-카복실레이트 (6.7 g, 10.3 mmol) 용액에 TFA (50 ml)를 가하였다. 반응물을 2 시간 동안 실온에서 교반하였다. 반응 종료 후, 반응 혼합물을 감압 하에서 농축하였다. 잔사를 디클로로메탄/메탄올 (0~10%) 컬럼 크로마토그래피로 정제하여, 표제 화합물(6.7g)을 수득하였다.t-Butyl 4-[(4-{2-[(2S)-2-{[5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2 in DCM (150 ml) ,3]triazolo[4,5-b]pyrazin-1-yl]methyl}morpholin-4-yl]pyrimidin-5-yl}phenyll)methyl]piperazine-1-carboxylate (6.7 g, 10.3 mmol) solution was added TFA (50 ml). The reaction was stirred for 2 hours at room temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by dichloromethane/methanol (0-10%) column chromatography to obtain the title compound (6.7 g).
MS (ESI, m/z): [M+H]+ = 553.6.MS (ESI, m/z): [M+H] + = 553.6.
실시예 C : TPD 용 화합물의 제조Example C: Preparation of compounds for TPD
실시예 1:Example 1:
3-(6-(4-(4-(2-((S)-2-((5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일)메틸)모르폴리노)피리미딘-5-일)벤질)피페라진-1-일)-1-옥소프탈라진-2(1H)-일)피페리딘-2,6-디온3-(6-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]tria zolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)-1-oxophthalazin-2(1H)-yl )piperidine-2,6-dione
NMP (N-메틸-2-피롤리돈) (3ml) 중의 3-(6-플루오로-1-옥소프탈라진-2(1H)-일)피페리딘-2,6-디온 (50 mg, 0.182 mmol) 및 (S)-2-((5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일)메틸)-4-(5-(4-(피페라진-1-일메틸)페닐)피리미딘-2-일)모르폴린 (100 mg, 0.182 mmol) 용액에 에틸비스(프로판-2-일)아민 (3.0 당량)을 반응 혼합물에 가하였다. 반응물을 24 시간 동안 130℃에서 교반하였다. 잔사를 MeOH/DCM (0~20%) MPLC(중압 액체 크로마토그래피)로 정제하여, 표제 화합물(70 mg)을 수득하였다.3-(6-fluoro-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (50 mg) in NMP (N-methyl-2-pyrrolidone) (3ml) , 0.182 mmol) and (S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine- 1-yl)methyl)-4-(5-(4-(piperazin-1-ylmethyl)phenyl)pyrimidin-2-yl)morpholine (100 mg, 0.182 mmol) in a solution -yl)amine (3.0 eq) was added to the reaction mixture. The reaction was stirred at 130° C. for 24 hours. The residue was purified by MeOH/DCM (0-20%) MPLC (Medium Pressure Liquid Chromatography) to give the title compound (70 mg).
MS (ESI, m/z): [M+H]+ = 808.8MS (ESI, m/z): [M+H] + = 808.8
1H NMR (500 MHz, DMSO-d 6 ) d ppm 11.01 (s, 1 H) 9.21 (s, 1 H) 8.72 - 8.80 (m, 2 H) 8.64 (s, 1 H) 8.31 (s, 1 H) 8.22 - 8.27 (m, 1 H) 8.05 (t, J=8.32 Hz, 1 H) 7.59 - 7.69 (m, 2 H) 7.46 - 7.54 (m, 1 H) 7.34 - 7.46 (m, 1 H) 7.26 (d, J=5.49 Hz, 1 H) 5.75 (d, J=6.87 Hz, 1 H) 4.86 - 5.00 (m, 3 H) 4.79 (d, J=10.68 Hz, 2 H) 4.73 (d, J=12.66 Hz, 2 H) 4.39 (d, J=12.51 Hz, 1 H) 4.22 (br. s., 1 H) 3.88 - 3.98 (m, 4 H) 3.64 (s, 1 H) 3.39 - 3.62 (m, 7 H) 3.07 - 3.17 (m, 2 H) 2.85 - 2.98 (m, 2 H) 2.14 - 2.21 (m, 2 H). 1 H NMR (500 MHz, DMSO-d 6 ) d ppm 11.01 (s, 1 H) 9.21 (s, 1 H) 8.72 - 8.80 (m, 2 H) 8.64 (s, 1 H) 8.31 (s, 1 H) ) 8.22 - 8.27 (m, 1 H) 8.05 (t, J=8.32 Hz, 1 H) 7.59 - 7.69 (m, 2 H) 7.46 - 7.54 (m, 1 H) 7.34 - 7.46 (m, 1 H) 7.26 (d, J=5.49 Hz, 1 H) 5.75 (d, J=6.87 Hz, 1 H) 4.86 - 5.00 (m, 3 H) 4.79 (d, J=10.68 Hz, 2 H) 4.73 (d, J= 12.66 Hz, 2 H) 4.39 (d, J=12.51 Hz, 1 H) 4.22 (br. s., 1 H) 3.88 - 3.98 (m, 4 H) 3.64 (s, 1 H) 3.39 - 3.62 (m, 7 H) 3.07 - 3.17 (m, 2 H) 2.85 - 2.98 (m, 2 H) 2.14 - 2.21 (m, 2 H).
실시예 2: Example 2:
3-(4-메틸-6-(4-(4-(2-((S)-2-((5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일)메틸)모르폴리노)피리미딘-5-일)벤질)피페라진-1-일)-1-옥소프탈라진-2(1H)-일)피페리딘-2,6-디온3-(4-methyl-6-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2 ,3] triazolo [4,5-b] pyrazin-1-yl) methyl) morpholino) pyrimidin-5-yl) benzyl) piperazin-1-yl) -1-oxophthalazin-2 ( 1H)-yl)piperidine-2,6-dione
NMP(3ml) 중의 3-(6-플루오로-4-메틸-1-옥소프탈라진-2(1H)-일)피페리딘-2,6-디온 (50 mg, 0.182 mmol) 및 (2S)-2-{[5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일]메틸}-4-(5-{4-[(피페라진-1-일)메틸]페닐}피리미딘-2-일)모르폴린 (100 mg, 0.182 mmol) 용액에 에틸비스(프로판-2-일)아민 (3.0 당량)을 반응 혼합물에 가하였다. 반응물을 24 시간 동안 130℃에서 교반하였다. 잔사를 MeOH/DCM (0~20%) MPLC로 정제하여, 표제 화합물(75 mg)을 수득하였다.3-(6-Fluoro-4-methyl-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (50 mg, 0.182 mmol) and (2S )-2-{[5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}- To a solution of 4-(5-{4-[(piperazin-1-yl)methyl]phenyl}pyrimidin-2-yl)morpholine (100 mg, 0.182 mmol) was added 3.0 eq) was added to the reaction mixture. The reaction was stirred at 130° C. for 24 hours. The residue was purified by MeOH/DCM (0-20%) MPLC to give the title compound (75 mg).
MS (ESI, m/z): [M+H]+ = 822.92MS (ESI, m/z): [M+H] + = 822.92
1H NMR (500 MHz, DMSO-d 6 ) d ppm 10.98 (s, 1 H) 9.21 (s, 2 H) 8.78 (s, 2 H) 8.65 (s, 2 H) 8.31 (s, 2 H) 7.86 - 8.03 (m, 1 H) 7.50 (d, J=8.70 Hz, 1 H) 4.86 - 4.99 (m, 3 H) 4.73 (d, J=12.05 Hz, 1 H) 4.39 (d, J=13.73 Hz, 1 H) 3.90 - 3.98 (m, 9 H) 3.36 - 3.54 (m, 11 H) 3.07 - 3.17 (m, 2 H) 2.53 - 2.66 (m, 6 H). 1 H NMR (500 MHz, DMSO-d 6 ) d ppm 10.98 (s, 1 H) 9.21 (s, 2 H) 8.78 (s, 2 H) 8.65 (s, 2 H) 8.31 (s, 2 H) 7.86 - 8.03 (m, 1 H) 7.50 (d, J=8.70 Hz, 1 H) 4.86 - 4.99 (m, 3 H) 4.73 (d, J=12.05 Hz, 1 H) 4.39 (d, J=13.73 Hz, 1 H) 3.90 - 3.98 (m, 9 H) 3.36 - 3.54 (m, 11 H) 3.07 - 3.17 (m, 2 H) 2.53 - 2.66 (m, 6 H).
실시예 3:Example 3:
3-(7-(4-(4-(2-((S)-2-((5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일)메틸)모르폴리노)피리미딘-5-일)벤질)피페라진-1-일)-1-옥소프탈라진-2(1H)-일)피페리딘-2,6-디온3-(7-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]tria zolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)-1-oxophthalazin-2(1H)-yl )piperidine-2,6-dione
NMP(3ml) 중의 3-(7-플루오로-1-옥소프탈라진-2(1H)-일)피페리딘-2,6-디온 (50 mg, 0.182 mmol) 및 (2S)-2-{[5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일]메틸}-4-(5-{4-[(피페라진-1-일)메틸]페닐}피리미딘-2-일)모르폴린 (100mg, 0.182 mmol) 용액에 에틸비스(프로판-2-일)아민 (3.0 당량)을 반응 혼합물에 가하였다. 반응물을 24 시간 동안 130℃에서 교반하였다. 잔사를 MeOH/DCM (0~20%) MPLC로 정제하여 표제 화합물(60 mg)을 수득하였다.3-(7-Fluoro-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (50 mg, 0.182 mmol) and (2S)-2- in NMP (3ml) {[5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}-4-(5 -{4-[(piperazin-1-yl)methyl]phenyl}pyrimidin-2-yl)morpholine (100mg, 0.182 mmol) reacted with ethylbis(propan-2-yl)amine (3.0 eq.) added to the mixture. The reaction was stirred at 130° C. for 24 hours. The residue was purified by MeOH/DCM (0-20%) MPLC to give the title compound (60 mg).
MS (ESI, m/z): [M+H]+ = 808.8MS (ESI, m/z): [M+H] + = 808.8
1H NMR (500 MHz, DMSO-d 6 ) d ppm 10.92 (s, 1 H) 9.21 (s, 2 H) 8.88 (s, 1 H) 8.73 - 8.78 (m, 1 H) 8.62 - 8.68 (m, 2 H) 8.29 - 8.35 (m, 2 H) 8.26 (d, J=5.95 Hz, 2 H) 7.91 - 8.00 (m, 1 H) 7.43 (d, J=8.09 Hz, 1 H) 4.81 - 4.99 (m, 2 H) 3.88 - 3.96 (m, 9 H) 3.41 - 3.51 (m, 1 H) 3.29 - 3.47 (m, 11 H) 3.06 - 3.18 (m, 2 H) 2.53 - 2.68 (m, 3 H). 1 H NMR (500 MHz, DMSO-d 6 ) d ppm 10.92 (s, 1 H) 9.21 (s, 2 H) 8.88 (s, 1 H) 8.73 - 8.78 (m, 1 H) 8.62 - 8.68 (m, 2 H) 8.29 - 8.35 (m, 2 H) 8.26 (d, J=5.95 Hz, 2 H) 7.91 - 8.00 (m, 1 H) 7.43 (d, J=8.09 Hz, 1 H) 4.81 - 4.99 (m , 2 H) 3.88 - 3.96 (m, 9 H) 3.41 - 3.51 (m, 1 H) 3.29 - 3.47 (m, 11 H) 3.06 - 3.18 (m, 2 H) 2.53 - 2.68 (m, 3 H).
실시예 4:Example 4:
3-(8-(4-(4-(2-((S)-2-((5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일)메틸)모르폴리노)피리미딘-5-일)벤질)피페라진-1-일)-1-옥소프탈라진-2(1H)-일)피페리딘-2,6-디온3-(8-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]tria zolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)-1-oxophthalazin-2(1H)-yl )piperidine-2,6-dione
NMP(3ml) 중의 3-(8-플루오로-1-옥소프탈라진-2(1H)-일)피페리딘-2,6-디온 (50 mg, 0.182 mmol) 및 (2S)-2-{[5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일]메틸}-4-(5-{4-[(피페라진-1-일)메틸]페닐}피리미딘-2-일)모르폴린 (100mg, 0.182 mmol) 용액에 에틸비스(프로판-2-일)아민 (3.0 당량)을 반응 혼합물에 가하였다. 반응물을 24 시간 동안 130℃에서 교반하였다. 잔사를 MeOH/DCM (0~20%) MPLC로 정제하여, 표제 화합물(53 mg)을 수득하였다.3-(8-fluoro-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (50 mg, 0.182 mmol) and (2S)-2- in NMP (3ml) {[5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}-4-(5 -{4-[(piperazin-1-yl)methyl]phenyl}pyrimidin-2-yl)morpholine (100mg, 0.182 mmol) reacted with ethylbis(propan-2-yl)amine (3.0 eq.) added to the mixture. The reaction was stirred at 130° C. for 24 hours. The residue was purified by MeOH/DCM (0-20%) MPLC to give the title compound (53 mg).
MS (ESI, m/z): [M+H]+ = 808.8MS (ESI, m/z): [M+H] + = 808.8
1H NMR (500 MHz, DMSO-d 6 ) d ppm 10.92 (s, 1 H) 9.14 (s, 1 H) 8.69 (s, 2 H) 8.57 (s, 1 H) 8.24 (s, 1 H) 8.21 (s, 1 H) 7.69 - 7.75 (m, 1 H) 7.56 (d, J=8.09 Hz, 2 H) 7.31 - 7.39 (m, 2 H) 7.26 (d, J=8.24 Hz, 1 H) 4.79 - 4.93 (m, 2 H) 4.66 (d, J=12.51 Hz, 1 H) 4.30 (br. s., 1 H) 3.82 - 3.90 (m, 4 H) 3.28 - 3.45 (m, 14 H) 2.99 - 3.10 (m, 3 H) 2.55 (br. s., 3 H). 1 H NMR (500 MHz, DMSO-d 6 ) d ppm 10.92 (s, 1 H) 9.14 (s, 1 H) 8.69 (s, 2 H) 8.57 (s, 1 H) 8.24 (s, 1 H) 8.21 (s, 1 H) 7.69 - 7.75 (m, 1 H) 7.56 (d, J=8.09 Hz, 2 H) 7.31 - 7.39 (m, 2 H) 7.26 (d, J=8.24 Hz, 1 H) 4.79 - 4.93 (m, 2 H) 4.66 (d, J=12.51 Hz, 1 H) 4.30 (br. s., 1 H) 3.82 - 3.90 (m, 4 H) 3.28 - 3.45 (m, 14 H) 2.99 - 3.10 (m, 3 H) 2.55 (br. s., 3 H).
실시예 5:Example 5:
3-(4-메틸-8-(4-(4-(2-((S)-2-((5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일)메틸)모르폴리노)피리미딘-5-일)벤질)피페라진-1-일)-1-옥소프탈라진-2(1H)-일)피페리딘-2,6-디온3-(4-methyl-8-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2 ,3] triazolo [4,5-b] pyrazin-1-yl) methyl) morpholino) pyrimidin-5-yl) benzyl) piperazin-1-yl) -1-oxophthalazin-2 ( 1H)-yl)piperidine-2,6-dione
NMP(3ml) 중의 3-(8-플루오로-4-메틸-1-옥소프탈라진-2(1H)-일)피페리딘-2,6-디온 (50 mg, 0.182 mmol) 및 (2S)-2-{[5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일]메틸}-4-(5-{4-[(피페라진-1-일)메틸]페닐}피리미딘-2-일)모르폴린 (100 mg, 0.182 mmol) 용액에 에틸비스(프로판-2-일)아민 (3.0 당량)을 반응 혼합물에 가하였다. 반응물을 24 시간 동안 130℃에서 교반하였다. 잔사를 MeOH/DCM (0~20%) MPLC로 정제하여, 표제 화합물(45 mg)을 수득하였다.3-(8-fluoro-4-methyl-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (50 mg, 0.182 mmol) and (2S )-2-{[5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}- To a solution of 4-(5-{4-[(piperazin-1-yl)methyl]phenyl}pyrimidin-2-yl)morpholine (100 mg, 0.182 mmol) was added 3.0 eq) was added to the reaction mixture. The reaction was stirred at 130° C. for 24 hours. The residue was purified by MeOH/DCM (0-20%) MPLC to give the title compound (45 mg).
MS (ESI, m/z): [M+H]+ = 822.92MS (ESI, m/z): [M+H] + = 822.92
1H NMR (500 MHz, DMSO-d 6 ) d ppm 10.92 (s, 1 H) 9.14 (s, 1 H) 8.74 (s, 2 H) 8.58 (s, 1 H) 8.24 (s, 1 H) 7.80 (t, J=8.09 Hz, 1 H) 7.73 (d, J=7.02 Hz, 1 H) 7.58 (br. s., 1 H) 7.48 (d, J=7.93 Hz, 1 H) 7.35 (d, J=8.39 Hz, 1 H) 4.79 - 4.93 (m, 2 H) 4.67 (d, J=12.82 Hz, 1 H) 4.33 (d, J=13.28 Hz, 1 H) 3.82 - 3.91 (m, 4 H) 3.29 - 3.47 (m, 14 H) 3.01 - 3.11 (m, 2 H) 2.78 - 2.90 (m, 1 H) 2.46 - 2.63 (m, 3 H) 2.43 (s, 3H). 1 H NMR (500 MHz, DMSO-d 6 ) d ppm 10.92 (s, 1 H) 9.14 (s, 1 H) 8.74 (s, 2 H) 8.58 (s, 1 H) 8.24 (s, 1 H) 7.80 (t, J=8.09 Hz, 1 H) 7.73 (d, J=7.02 Hz, 1 H) 7.58 (br. s., 1 H) 7.48 (d, J=7.93 Hz, 1 H) 7.35 (d, J =8.39 Hz, 1 H) 4.79 - 4.93 (m, 2 H) 4.67 (d, J=12.82 Hz, 1 H) 4.33 (d, J=13.28 Hz, 1 H) 3.82 - 3.91 (m, 4 H) 3.29 - 3.47 (m, 14 H) 3.01 - 3.11 (m, 2 H) 2.78 - 2.90 (m, 1 H) 2.46 - 2.63 (m, 3 H) 2.43 (s, 3H).
실시예 6:Example 6:
3-(6-플루오로-7-(4-(4-(2-((S)-2-((5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일)메틸)모르폴리노)피리미딘-5-일)벤질)피페라진-1-일)-1-옥소프탈라진-2(1H)-일)피페리딘-2,6-디온3-(6-fluoro-7-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1, 2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)-1-oxophthalazin-2 (1H)-yl)piperidine-2,6-dione
NMP(3ml) 중의 3-(6,7-디플루오로-1-옥소프탈라진-2(1H)-일)피페리딘-2,6-디온 (50mg, 0.182 mmol) 및 (2S)-2-{[5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일]메틸}-4-(5-{4-[(피페라진-1-일)메틸]페닐}피리미딘-2-일)모르폴린 (100 mg, 0.182 mmol) 용액에 에틸비스(프로판-2-일)아민 (3.0 당량)을 반응 혼합물에 가하였다. 반응물을 24 시간 동안 130℃에서 교반하였다. 잔사를 MeOH/DCM (0~20%) MPLC로 정제하여, 표제 화합물(50 mg)을 수득하였다.3-(6,7-difluoro-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (50 mg, 0.182 mmol) and (2S)- 2-{[5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}-4- Ethylbis(propan-2-yl)amine (3.0 equiv. ) was added to the reaction mixture. The reaction was stirred at 130° C. for 24 hours. The residue was purified by MeOH/DCM (0-20%) MPLC to give the title compound (50 mg).
MS (ESI, m/z): [M+H]+ = 826.82MS (ESI, m/z): [M+H] + = 826.82
1H NMR (500 MHz, DMSO-d 6 ) d ppm 10.98 (s, 1 H) 9.14 (s, 1 H) 8.74 (s, 2 H) 8.58 (s, 1 H) 8.26 - 8.35 (m, 1 H) 8.24 (s, 1 H) 7.81 - 7.91 (m, 1 H) 7.71 - 7.81 (m, 2 H) 7.67 (d, J=8.39 Hz, 1 H) 7.55 (br. s., 3 H) 5.72 (br. s., 1 H) 4.78 - 4.92 (m, 2 H) 4.67 (d, J=12.51 Hz, 1 H) 4.40 (br. s., 1 H) 4.33 (d, J=13.28 Hz, 1 H) 4.15 (br. s., 1 H) 3.79 - 3.92 (m, 4 H) 3.73 (br. s., 2 H) 3.39 - 3.51 (m, 3 H) 3.18 (br. s., 3 H) 3.01 - 3.13 (m, 3 H) 2.76 - 2.92 (m, 1 H) 2.45 - 2.59 (m, 3 H). 1 H NMR (500 MHz, DMSO-d 6 ) d ppm 10.98 (s, 1 H) 9.14 (s, 1 H) 8.74 (s, 2 H) 8.58 (s, 1 H) 8.26 - 8.35 (m, 1 H) ) 8.24 (s, 1 H) 7.81 - 7.91 (m, 1 H) 7.71 - 7.81 (m, 2 H) 7.67 (d, J=8.39 Hz, 1 H) 7.55 (br. s., 3 H) 5.72 ( br. s., 1 H) 4.78 - 4.92 (m, 2 H) 4.67 (d, J=12.51 Hz, 1 H) 4.40 (br. s., 1 H) 4.33 (d, J=13.28 Hz, 1 H) ) 4.15 (br. s., 1 H) 3.79 - 3.92 (m, 4 H) 3.73 (br. s., 2 H) 3.39 - 3.51 (m, 3 H) 3.18 (br. s., 3 H) 3.01 - 3.13 (m, 3 H) 2.76 - 2.92 (m, 1 H) 2.45 - 2.59 (m, 3 H).
실시예 7:Example 7:
2-(2,6-디옥소피페리딘-3-일)-4-(4-(4-(2-((S)-2-((5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일)메틸)모르폴리노)피리미딘-5-일)벤질)피페라진-1-일)이소인돌린-1,3-디온2-(2,6-dioxopiperidin-3-yl)-4-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazole-4 -yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl) isoindoline-1,3-dione
NMP(3ml) 중의 2-(2,6-디옥소피페리딘-3-일)-4-플루오로이소인돌린-1,3-디온 (50mg, 0.182 mmol) 및 (2S)-2-{[5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일]메틸}-4-(5-{4-[(피페라진-1-일)메틸]페닐}피리미딘-2-일)모르폴린 (100 mg, 0.182 mmol) 용액에 에틸비스(프로판-2-일)아민 (3.0 당량)을 반응 혼합물에 가하였다. 반응물을 24 시간 동안 130℃에서 교반하였다. 잔사를 MeOH/DCM (0~20%) MPLC로 정제하여, 표제 화합물(80 mg)을 수득하였다.2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (50mg, 0.182 mmol) and (2S)-2-{[5 in NMP (3ml) -(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}-4-(5-{4 To a solution of -[(piperazin-1-yl)methyl]phenyl}pyrimidin-2-yl)morpholine (100 mg, 0.182 mmol) was added ethylbis(propan-2-yl)amine (3.0 equiv) to the reaction mixture. added The reaction was stirred at 130° C. for 24 hours. The residue was purified by MeOH/DCM (0-20%) MPLC to give the title compound (80 mg).
MS (ESI, m/z): [M+H]+ = 809.82MS (ESI, m/z): [M+H] + = 809.82
1H NMR (500 MHz, DMSO-d 6 ) d ppm 11.03 (s, 1 H) 9.14 (s, 1 H) 8.70 (s, 2 H) 8.58 (s, 1 H) 8.24 (s, 1 H) 7.64 (t, J=7.63 Hz, 1 H) 7.58 (br. s., 1 H) 7.37 (br. s., 2 H) 7.23 - 7.34 (m, 2 H) 5.02 (dd, J=12.66, 5.34 Hz, 1 H) 4.78 - 4.96 (m, 2 H) 4.66 (d, J=12.51 Hz, 2 H) 4.32 (d, J=13.12 Hz, 1 H) 4.15 (br. s., 1 H) 3.80 - 3.92 (m, 4 H) 3.53 (br. s., 1 H) 3.37 - 3.49 (m, 2 H) 3.33 (br. s., 1 H) 2.98 - 3.13 (m, 2 H) 2.71 - 2.88 (m, 1 H) 2.46 - 2.65 (m, 5 H) 1.79 - 2.00 (m, 3 H) 1.68 (br. s., 1 H) 1.38 (br. s., 1 H). 1 H NMR (500 MHz, DMSO-d 6 ) d ppm 11.03 (s, 1 H) 9.14 (s, 1 H) 8.70 (s, 2 H) 8.58 (s, 1 H) 8.24 (s, 1 H) 7.64 (t, J=7.63 Hz, 1 H) 7.58 (br. s., 1 H) 7.37 (br. s., 2 H) 7.23 - 7.34 (m, 2 H) 5.02 (dd, J=12.66, 5.34 Hz , 1 H) 4.78 - 4.96 (m, 2 H) 4.66 (d, J=12.51 Hz, 2 H) 4.32 (d, J=13.12 Hz, 1 H) 4.15 (br. s., 1 H) 3.80 - 3.92 (m, 4 H) 3.53 (br. s., 1 H) 3.37 - 3.49 (m, 2 H) 3.33 (br. s., 1 H) 2.98 - 3.13 (m, 2 H) 2.71 - 2.88 (m, 1 H) 2.46 - 2.65 (m, 5 H) 1.79 - 2.00 (m, 3 H) 1.68 (br. s., 1 H) 1.38 (br. s., 1 H).
실시예 8:Example 8:
2-(2,6-디옥소피페리딘-3-일)-5-(4-(4-(2-((S)-2-((5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일)메틸)모르폴리노)피리미딘-5-일)벤질)피페라진-1-일)이소인돌린-1,3-디온2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazole-4 -yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl) isoindoline-1,3-dione
NMP(3ml) 중의 2-(2,6-디옥소피페리딘-3-일)-5-플루오로이소인돌린-1,3-디온 (50mg, 0.182 mmol) 및 (2S)-2-{[5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일]메틸}-4-(5-{4-[(피페라진-1-일)메틸]페닐}피리미딘-2-일)모르폴린 (100 mg, 0.182 mmol) 용액에 에틸비스(프로판-2-일)아민 (3.0 당량)을 반응 혼합물에 가하였다. 반응물을 24 시간 동안 130℃에서 교반하였다. 잔사를 MeOH/DCM (0~20%) MPLC로 정제하여, 표제 화합물(80 mg)을 수득하였다.2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (50mg, 0.182 mmol) and (2S)-2-{[5 in NMP (3ml) -(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}-4-(5-{4 To a solution of -[(piperazin-1-yl)methyl]phenyl}pyrimidin-2-yl)morpholine (100 mg, 0.182 mmol) was added ethylbis(propan-2-yl)amine (3.0 equiv) to the reaction mixture. added The reaction was stirred at 130° C. for 24 hours. The residue was purified by MeOH/DCM (0-20%) MPLC to give the title compound (80 mg).
MS (ESI, m/z): [M+H]+ = 809.82MS (ESI, m/z): [M+H] + = 809.82
1H NMR (500 MHz, DMSO-d 6 ) d ppm 11.02 (s, 1 H) 9.14 (s, 1 H) 8.63 - 8.71 (m, 1 H) 8.54 - 8.60 (m, 1 H) 8.24 (s, 1 H) 7.66 - 7.77 (m, 1 H) 7.62 (d, J=8.54 Hz, 1 H) 7.56 (br. s., 1 H) 7.37 (br. s., 1 H) 7.28 (br. s., 1 H) 7.19 (d, J=8.85 Hz, 1 H) 4.96 - 5.05 (m, 1 H) 4.78 - 4.93 (m, 2 H) 4.62 - 4.76 (m, 2 H) 4.32 (d, J=12.51 Hz, 1 H) 4.15 (br. s., 1 H) 3.79 - 3.90 (m, 4 H) 3.50 (br. s., 1 H) 3.31 - 3.48 (m, 3 H) 2.97 - 3.13 (m, 3 H) 2.80 (d, J=12.51 Hz, 2 H) 2.50 - 2.61 (m, 5 H) 1.77 - 1.96 (m, 3 H) 1.69 (br. s., 1 H) 1.38 (br. s., 1 H). 1 H NMR (500 MHz, DMSO-d 6 ) d ppm 11.02 (s, 1 H) 9.14 (s, 1 H) 8.63 - 8.71 (m, 1 H) 8.54 - 8.60 (m, 1 H) 8.24 (s, 1 H) 7.66 - 7.77 (m, 1 H) 7.62 (d, J=8.54 Hz, 1 H) 7.56 (br. s., 1 H) 7.37 (br. s., 1 H) 7.28 (br. s. , 1 H) 7.19 (d, J=8.85 Hz, 1 H) 4.96 - 5.05 (m, 1 H) 4.78 - 4.93 (m, 2 H) 4.62 - 4.76 (m, 2 H) 4.32 (d, J=12.51 Hz, 1 H) 4.15 (br. s., 1 H) 3.79 - 3.90 (m, 4 H) 3.50 (br. s., 1 H) 3.31 - 3.48 (m, 3 H) 2.97 - 3.13 (m, 3 H) 2.80 (d, J=12.51 Hz, 2 H) 2.50 - 2.61 (m, 5 H) 1.77 - 1.96 (m, 3 H) 1.69 (br. s., 1 H) 1.38 (br. s., 1 H).
실시예 9:Example 9:
3-(1-(3-(5-((1-(2-(2,6-디옥소피페리딘-3-일)-1-옥소-1,2-디하이드로프탈라진-6-일)피페리딘-4-일)메톡시)피리미딘-2-일)벤질)-6-옥소-1,6-디하이드로피리다진-3-일)벤조니트릴3-(1-(3-(5-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl )piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile
NMP(3ml) 중의 3-(6-플루오로-1-옥소-1,2-디하이드로프탈라진-2-일)피페리딘-2,6-디온 (50 mg, 0.182 mmol) 및 (3-(6-옥소-1-(3-(5-(피페리딘-4-일메톡시)피리미딘-2-일)벤질)-1,6-디하이드로피리다진-3-일)벤조니트릴 (120 mg, 0.182 mmol) 용액에 에틸비스(프로판-2-일)아민 (3.0 당량)을 반응 혼합물에 가하였다. 반응물을 24 시간 동안 130℃에서 교반하였다. 잔사를 MeOH/DCM (0~20%) MPLC로 정제하여, 표제 화합물(90 mg)을 수득하였다.3-(6-Fluoro-1-oxo-1,2-dihydrophthalazin-2-yl)piperidine-2,6-dione (50 mg, 0.182 mmol) and (3 -(6-oxo-1-(3-(5-(piperidin-4-ylmethoxy)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzonitrile ( 120mg, 0.182mmol) ethylbis(propan-2-yl)amine (3.0 equiv.) was added to the reaction mixture.The reaction was stirred for 24 hours at 130°C. The residue was obtained in MeOH/DCM (0-20% ) MPLC to give the title compound (90 mg).
MS (ESI, m/z): [M+H]+ =734.80MS (ESI, m/z): [M+H] + =734.80
1H NMR (500 MHz, DMSO-d 6 ) d ppm 10.93 (s, 1 H) 8.59 (s, 2 H) 8.31 (s, 2 H) 8.15 - 8.21 (m, 3 H) 8.11 (d, J=9.77 Hz, 1 H) 7.96 (d, J=9.00 Hz, 1 H) 7.87 (d, J=7.63 Hz, 1 H) 7.65 (t, J=7.86 Hz, 1 H) 7.37 - 7.51 (m, 3 H) 7.16 - 7.25 (m, 1 H) 7.10 (d, J=9.77 Hz, 1 H) 5.68 (dd, J=11.67, 5.11 Hz, 1 H) 5.38 (s, 2 H) 3.96 - 4.09 (m, 4 H) 2.77 - 3.00 (m, 3 H) 2.45 - 2.59 (m, 1 H) 2.07 (br. s., 1 H) 1.97 - 2.05 (m, 1 H) 1.84 (d, J=11.44 Hz, 2 H) 1.26 - 1.43 (m, 2 H). 1 H NMR (500 MHz, DMSO-d 6 ) d ppm 10.93 (s, 1 H) 8.59 (s, 2 H) 8.31 (s, 2 H) 8.15 - 8.21 (m, 3 H) 8.11 (d, J= 9.77 Hz, 1 H) 7.96 (d, J=9.00 Hz, 1 H) 7.87 (d, J=7.63 Hz, 1 H) 7.65 (t, J=7.86 Hz, 1 H) 7.37 - 7.51 (m, 3 H) ) 7.16 - 7.25 (m, 1 H) 7.10 (d, J=9.77 Hz, 1 H) 5.68 (dd, J=11.67, 5.11 Hz, 1 H) 5.38 (s, 2 H) 3.96 - 4.09 (m, 4 H) 2.77 - 3.00 (m, 3 H) 2.45 - 2.59 (m, 1 H) 2.07 (br. s., 1 H) 1.97 - 2.05 (m, 1 H) 1.84 (d, J=11.44 Hz, 2 H) ) 1.26 - 1.43 (m, 2 H).
실시예 10:Example 10:
3-(1-(3-(5-((1-(2-(2,6-디옥소피페리딘-3-일)-4-메틸-1-옥소-1,2-디하이드로프탈라진-6-일)피페리딘-4-일)메톡시)피리미딘-2-일)벤질)-6-옥소-1,6-디하이드로피리다진-3-일)벤조니트릴3-(1-(3-(5-((1-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazine -6-yl) piperidin-4-yl) methoxy) pyrimidin-2-yl) benzyl) -6-oxo-1,6-dihydropyridazin-3-yl) benzonitrile
NMP(3ml) 중의 3-(6-플루오로-4-메틸-1-옥소프탈라진-2(1H)-일)피페리딘-2,6-디온 (50 mg, 0.182 mmol) 및 (3-(6-옥소-1-(3-(5-(피페리딘-4-일메톡시)피리미딘-2-일)벤질)-1,6-디하이드로피리다진-3-일)벤조니트릴 (120 mg, 0.182 mmol) 용액에 에틸비스(프로판-2-일)아민 (3.0 당량)을 반응 혼합물에 가하였다. 반응물을 24 시간 동안 130℃에서 교반하였다. 잔사를 MeOH/DCM (0~20%) MPLC로 정제하여, 표제 화합물(70 mg)을 수득하였다.3-(6-Fluoro-4-methyl-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (50 mg, 0.182 mmol) and (3 -(6-oxo-1-(3-(5-(piperidin-4-ylmethoxy)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzonitrile ( 120mg, 0.182mmol) ethylbis(propan-2-yl)amine (3.0 equiv.) was added to the reaction mixture.The reaction was stirred for 24 hours at 130°C. The residue was obtained in MeOH/DCM (0-20% ) MPLC to give the title compound (70 mg).
MS (ESI, m/z): [M+H]+ = 748.81 1H NMR (500 MHz, DMSO-d 6 ) d ppm 10.91 (s, 1 H) 8.52 - 8.64 (m, 2 H) 8.25 - 8.34 (m, 2 H) 8.08 - 8.22 (m, 3 H) 7.99 (d, J=9.00 Hz, 1 H) 7.86 (d, J=7.63 Hz, 1 H) 7.65 (t, J=7.86 Hz, 1 H) 7.33 - 7.48 (m, 3 H) 7.09 (d, J=9.77 Hz, 1 H) 6.97 - 7.05 (m, 1 H) 5.57 - 5.67 (m, 1 H) 5.32 - 5.43 (m, 3 H) 4.00 - 4.13 (m, 4 H) 2.77 - 3.00 (m, 3 H) 2.40 - 2.60 (m, 5 H) 2.03 - 2.11 (m, 1 H) 1.94 - 2.03 (m, 1 H) 1.84 (d, J=11.44 Hz, 2 H) 1.36 (q, J=11.44 Hz, 2 H). MS (ESI, m/z): [M+H] + = 748.81 1 H NMR (500 MHz, DMSO-d 6 ) d ppm 10.91 (s, 1 H) 8.52 - 8.64 (m, 2 H) 8.25 - 8.34 (m, 2 H) 8.08 - 8.22 (m, 3 H) 7.99 (d, J=9.00 Hz, 1 H) 7.86 (d, J=7.63 Hz, 1 H) 7.65 (t, J=7.86 Hz, 1 H) ) 7.33 - 7.48 (m, 3 H) 7.09 (d, J=9.77 Hz, 1 H) 6.97 - 7.05 (m, 1 H) 5.57 - 5.67 (m, 1 H) 5.32 - 5.43 (m, 3 H) 4.00 - 4.13 (m, 4 H) 2.77 - 3.00 (m, 3 H) 2.40 - 2.60 (m, 5 H) 2.03 - 2.11 (m, 1 H) 1.94 - 2.03 (m, 1 H) 1.84 (d, J= 11.44 Hz, 2 H) 1.36 (q, J=11.44 Hz, 2 H).
실시예 11:Example 11:
3-(1-(3-(5-((1-(2-(2,6-디옥소피페리딘-3-일)-1-옥소-1,2-디하이드로프탈라진-5-일)피페리딘-4-일)메톡시)피리미딘-2-일)벤질)-6-옥소-1,6-디하이드로피리다진-3-일)벤조니트릴3-(1-(3-(5-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-5-yl )piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile
NMP(3ml) 중의 3-(5-플루오로-1-옥소프탈라진-2(1H)-일)피페리딘-2,6-디온 (50 mg, 0.182 mmol) 및 (3-(6-옥소-1-(3-(5-(피페리딘-4-일메톡시)피리미딘-2-일)벤질)-1,6-디하이드로피리다진-3-일)벤조니트릴 (120 m g, 0.182 mmol) 용액에 에틸비스(프로판-2-일)아민 (3.0 당량)을 반응 혼합물에 가하였다. 반응물을 24 시간 동안 130℃에서 교반하였다. 잔사를 MeOH/DCM (0~20%) MPLC로 정제하여, 표제 화합물(90 mg)을 수득하였다.3-(5-fluoro-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (50 mg, 0.182 mmol) and (3-(6- Oxo-1-(3-(5-(piperidin-4-ylmethoxy)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzonitrile (120 mg, 0.182 mmol) solution, ethylbis(propan-2-yl)amine (3.0 equivalent) was added to the reaction mixture.The reaction was stirred for 24 hours at 130° C. The residue was purified by MeOH/DCM (0-20%) MPLC This gave the title compound (90 mg).
MS (ESI, m/z): [M+H]+ =734.80MS (ESI, m/z): [M+H] + =734.80
1H NMR (500 MHz, DMSO-d 6 ) d ppm 10.99 (s, 1 H) 8.58 - 8.66 (m, 2 H) 8.29 - 8.38 (m, 3 H) 8.15 - 8.22 (m, 2 H) 8.11 (d, J=9.77 Hz, 1 H) 7.84 (d, J=7.93 Hz, 1 H) 7.87 (d, J=7.63 Hz, 1 H) 7.72 (t, J=7.86 Hz, 1 H) 7.65 (t, J=7.86 Hz, 1 H) 7.49 (d, J=7.93 Hz, 1 H) 7.38 - 7.44 (m, 2 H) 7.10 (d, J=9.77 Hz, 1 H) 5.74 (dd, J=11.52, 4.65 Hz, 1 H) 5.38 (s, 2 H) 4.10 (d, J=6.26 Hz, 2 H) 2.73 - 2.93 (m, 3 H) 2.45 - 2.60 (m, 3 H) 2.00 - 2.13 (m, 2 H) 1.85 - 1.99 (m, 4 H) 1.60 (q, J=11.29 Hz, 2 H). 1 H NMR (500 MHz, DMSO-d 6 ) d ppm 10.99 (s, 1 H) 8.58 - 8.66 (m, 2 H) 8.29 - 8.38 (m, 3 H) 8.15 - 8.22 (m, 2 H) 8.11 ( d, J=9.77 Hz, 1 H) 7.84 (d, J=7.93 Hz, 1 H) 7.87 (d, J=7.63 Hz, 1 H) 7.72 (t, J=7.86 Hz, 1 H) 7.65 (t, J=7.86 Hz, 1 H) 7.49 (d, J=7.93 Hz, 1 H) 7.38 - 7.44 (m, 2 H) 7.10 (d, J=9.77 Hz, 1 H) 5.74 (dd, J=11.52, 4.65 Hz, 1 H) 5.38 (s, 2 H) 4.10 (d, J=6.26 Hz, 2 H) 2.73 - 2.93 (m, 3 H) 2.45 - 2.60 (m, 3 H) 2.00 - 2.13 (m, 2 H) ) 1.85 - 1.99 (m, 4 H) 1.60 (q, J=11.29 Hz, 2 H).
실시예 12:Example 12:
3-(1-(3-(5-((1-(3-(2,6-디옥소피페리딘-3-일)-4-옥소-3,4-디하이드로프탈라진-6-일)피페리딘-4-일)메톡시)피리미딘-2-일)벤질)-6-옥소-1,6-디하이드로피리다진-3-일)벤조니트릴3-(1-(3-(5-((1-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrophthalazin-6-yl )piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile
NMP(3ml) 중의 3-(7-플루오로-1-옥소프탈라진-2(1H)-일)피페리딘-2,6-디온 (50 mg, 0.182 mmol) 및 (3-(6-옥소-1-(3-(5-(피페리딘-4-일메톡시)피리미딘-2-일)벤질)-1,6-디하이드로피리다진-3-일)벤조니트릴 (120 mg, 0.182 mmol) 용액에 에틸비스(프로판-2-일)아민 (3.0 당량)을 반응 혼합물에 가하였다. 반응물을 24 시간 동안 130℃에서 교반하였다. 잔사를 MeOH/DCM (0~20%) MPLC로 정제하여, 표제 화합물 (40 mg)을 수득하였다.3-(7-fluoro-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (50 mg, 0.182 mmol) and (3-(6- Oxo-1-(3-(5-(piperidin-4-ylmethoxy)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzonitrile (120 mg, 0.182 mmol) solution, ethylbis(propan-2-yl)amine (3.0 equivalent) was added to the reaction mixture.The reaction was stirred for 24 hours at 130° C. The residue was purified by MeOH/DCM (0-20%) MPLC This gave the title compound (40 mg).
MS (ESI, m/z): [M+H]+ =734.80MS (ESI, m/z): [M+H] + =734.80
1H NMR (500 MHz, DMSO-d 6 ) d ppm 10.94 (s, 1 H) 8.54 - 8.64 (m, 2 H) 8.31 (d, J=1.68 Hz, 2 H) 8.13 - 8.21 (m, 3 H) 8.11 (d, J=9.77 Hz, 1 H) 7.86 (d, J=7.78 Hz, 1 H) 7.70 (d, J=9.00 Hz, 1 H) 7.65 (t, J=7.86 Hz, 1 H) 7.56 (dd, J=9.00, 2.44 Hz, 1 H) 7.36 - 7.48 (m, 3 H) 7.09 (d, J=9.77 Hz, 1 H) 5.63 - 5.74 (m, 1 H) 5.38 (s, 2 H) 3.95 - 4.08 (m, 4 H) 2.78 - 2.97 (m, 3 H) 2.45 - 2.62 (m, 3 H) 1.98 - 2.12 (m, 2 H) 1.85 (d, J=11.44 Hz, 2 H) 1.35 (q, J=11.19 Hz, 2 H). 1 H NMR (500 MHz, DMSO-d 6 ) d ppm 10.94 (s, 1 H) 8.54 - 8.64 (m, 2 H) 8.31 (d, J=1.68 Hz, 2 H) 8.13 - 8.21 (m, 3 H) ) 8.11 (d, J=9.77 Hz, 1 H) 7.86 (d, J=7.78 Hz, 1 H) 7.70 (d, J=9.00 Hz, 1 H) 7.65 (t, J=7.86 Hz, 1 H) 7.56 (dd, J=9.00, 2.44 Hz, 1 H) 7.36 - 7.48 (m, 3 H) 7.09 (d, J=9.77 Hz, 1 H) 5.63 - 5.74 (m, 1 H) 5.38 (s, 2 H) 3.95 - 4.08 (m, 4 H) 2.78 - 2.97 (m, 3 H) 2.45 - 2.62 (m, 3 H) 1.98 - 2.12 (m, 2 H) 1.85 (d, J=11.44 Hz, 2 H) 1.35 ( q, J = 11.19 Hz, 2H).
실시예 13:Example 13:
3-(1-(3-(5-((1-(3-(2,6-디옥소피페리딘-3-일)-4-옥소-3,4-디하이드로프탈라진-5-일)피페리딘-4-일)메톡시)피리미딘-2-일)벤질)-6-옥소-1,6-디하이드로피리다진-3-일)벤조니트릴3-(1-(3-(5-((1-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrophthalazin-5-yl )piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile
NMP(3ml) 중의 3-(8-플루오로-1-옥소프탈라진-2(1H)-일)피페리딘-2,6-디온 (50 mg, 0.182 mmol) 및 (3-(6-옥소-1-(3-(5-(피페리딘-4-일메톡시)피리미딘-2-일)벤질)-1,6-디하이드로피리다진-3-일)벤조니트릴 (120 mg, 0.182 mmol) 용액에 에틸비스(프로판-2-일)아민 (3.0 당량)을 반응 혼합물에 가하였다. 반응물을 24 시간 동안 130℃에서 교반하였다. 잔사를 MeOH/DCM (0~20%) MPLC로 정제하여, 표제 화합물(40 mg)을 수득하였다.3-(8-fluoro-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (50 mg, 0.182 mmol) and (3-(6- Oxo-1-(3-(5-(piperidin-4-ylmethoxy)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzonitrile (120 mg, 0.182 mmol) solution, ethylbis(propan-2-yl)amine (3.0 equivalent) was added to the reaction mixture.The reaction was stirred for 24 hours at 130° C. The residue was purified by MeOH/DCM (0-20%) MPLC This gave the title compound (40 mg).
MS (ESI, m/z): [M+H]+ =734.80MS (ESI, m/z): [M+H] + =734.80
1H NMR (500 MHz, DMSO-d 6 ) d ppm10.93 (s, 1 H) 8.56 - 8.66 (m, 2 H) 8.32 (d, J=6.10 Hz, 2 H) 8.14 - 8.24 (m, 3 H) 8.11 (d, J=9.77 Hz, 1 H) 7.87 (d, J=7.63 Hz, 1 H) 7.72 (t, J=7.93 Hz, 1 H) 7.65 (t, J=7.86 Hz, 1 H) 7.37 - 7.47 (m, 2 H) 7.24 - 7.37 (m, 2 H) 7.10 (d, J=9.77 Hz, 1 H) 5.38 (s, 2 H) 4.08 (d, J=6.26 Hz, 2 H) 3.38 (d, J=9.77 Hz, 2 H) 2.79 - 2.92 (m, 1 H) 2.69 (q, J=10.58 Hz, 2 H) 2.45 - 2.60 (m, 4 H) 1.98 - 2.09 (m, 1 H) 1.90 (br. s., 1 H) 1.80 (br. s., 2 H) 1.52 - 1.68 (m, 2 H). 1 H NMR (500 MHz, DMSO-d 6 ) d ppm10.93 (s, 1 H) 8.56 - 8.66 (m, 2 H) 8.32 (d, J=6.10 Hz, 2 H) 8.14 - 8.24 (m, 3 H) 8.11 (d, J=9.77 Hz, 1 H) 7.87 (d, J=7.63 Hz, 1 H) 7.72 (t, J=7.93 Hz, 1 H) 7.65 (t, J=7.86 Hz, 1 H) 7.37 - 7.47 (m, 2 H) 7.24 - 7.37 (m, 2 H) 7.10 (d, J=9.77 Hz, 1 H) 5.38 (s, 2 H) 4.08 (d, J=6.26 Hz, 2 H) 3.38 (d, J=9.77 Hz, 2 H) 2.79 - 2.92 (m, 1 H) 2.69 (q, J=10.58 Hz, 2 H) 2.45 - 2.60 (m, 4 H) 1.98 - 2.09 (m, 1 H) 1.90 (br. s., 1 H) 1.80 (br. s., 2 H) 1.52 - 1.68 (m, 2 H).
실시예 14:Example 14:
3-(1-(3-(5-((1-(3-(2,6-디옥소피페리딘-3-일)-1-메틸-4-옥소-3,4-디하이드로프탈라진-6-일)피페리딘-4-일)메톡시)피리미딘-2-일)벤질)-6-옥소-1,6-디하이드로피리다진-3-일)벤조니트릴3-(1-(3-(5-((1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrophthalazine -6-yl) piperidin-4-yl) methoxy) pyrimidin-2-yl) benzyl) -6-oxo-1,6-dihydropyridazin-3-yl) benzonitrile
NMP(3ml) 중의 3-(7-플루오로-4-메틸-1-옥소프탈라진-2(1H)-일)피페리딘-2,6-디온 (50 mg, 0.182 mmol) 및 (3-(6-옥소-1-(3-(5-(피페리딘-4-일메톡시)피리미딘-2-일)벤질)-1,6-디하이드로피리다진-3-일)벤조니트릴 (120 mg, 0.182 mmol) 용액에 에틸비스(프로판-2-일)아민 (3.0 당량)을 반응 혼합물에 가하였다. 반응물을 24 시간 동안 130℃에서 교반하였다. 잔사를 MeOH/DCM (0~20%) MPLC로 정제하여, 표제 화합물(38 mg)을 수득하였다.3-(7-Fluoro-4-methyl-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (50 mg, 0.182 mmol) and (3 -(6-oxo-1-(3-(5-(piperidin-4-ylmethoxy)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzonitrile ( 120mg, 0.182mmol) ethylbis(propan-2-yl)amine (3.0 equiv.) was added to the reaction mixture.The reaction was stirred for 24 hours at 130°C. The residue was obtained in MeOH/DCM (0-20% ) MPLC to give the title compound (38 mg).
MS (ESI, m/z): [M+H]+ = 748.81MS (ESI, m/z): [M+H] + = 748.81
1H NMR (500 MHz, DMSO-d 6 ) d ppm 10.91 (s, 1 H) 8.59 (s, 2 H) 8.25 - 8.34 (m, 2 H) 8.13 - 8.21 (m, 2 H) 8.11 (d, J=9.77 Hz, 1 H) 7.86 (d, J=7.78 Hz, 1 H) 7.70 (d, J=9.00 Hz, 1 H) 7.65 (t, J=7.86 Hz, 1 H) 7.54 (dd, J=9.08, 2.37 Hz, 1 H) 7.47 (d, J=2.44 Hz, 1 H) 7.37 - 7.45 (m, 2 H) 7.10 (d, J=9.77 Hz, 1 H) 5.63 (d, J=6.10 Hz, 1 H) 5.38 (s, 2 H) 3.94 - 4.09 (m, 4 H) 2.77 - 3.00 (m, 3 H) 2.45 - 2.61 (m, 4 H) 2.39 (s, 3 H) 1.97 - 2.06 (m, 1 H) 1.85 (d, J=12.21 Hz, 2 H) 1.26 - 1.43 (m, 2 H). 1 H NMR (500 MHz, DMSO-d 6 ) d ppm 10.91 (s, 1 H) 8.59 (s, 2 H) 8.25 - 8.34 (m, 2 H) 8.13 - 8.21 (m, 2 H) 8.11 (d, J=9.77 Hz, 1 H) 7.86 (d, J=7.78 Hz, 1 H) 7.70 (d, J=9.00 Hz, 1 H) 7.65 (t, J=7.86 Hz, 1 H) 7.54 (dd, J= 9.08, 2.37 Hz, 1 H) 7.47 (d, J=2.44 Hz, 1 H) 7.37 - 7.45 (m, 2 H) 7.10 (d, J=9.77 Hz, 1 H) 5.63 (d, J=6.10 Hz, 1 H) 5.38 (s, 2 H) 3.94 - 4.09 (m, 4 H) 2.77 - 3.00 (m, 3 H) 2.45 - 2.61 (m, 4 H) 2.39 (s, 3 H) 1.97 - 2.06 (m, 1 H) 1.85 (d, J=12.21 Hz, 2 H) 1.26 - 1.43 (m, 2 H).
실시예 15:Example 15:
3-(1-(3-(5-((1-(2-(2,6-디옥소피페리딘-3-일)-7-플루오로-1-옥소-1,2-디하이드로프탈라진-6-일)피페리딘-4-일)메톡시)피리미딘-2-일)벤질)-6-옥소-1,6-디하이드로피리다진-3-일)벤조니트릴 및 3-(1-(3-(5-((1-(3-(2,6-디옥소피페리딘-3-일)-7-플루오로-4-옥소-3,4-디하이드로프탈라진-6-일)피페리딘-4-일)메톡시)피리미딘-2-일)벤질)-6-옥소-1,6-디하이드로피리다진-3-일)벤조니트릴)3-(1-(3-(5-((1-(2-(2,6-dioxopiperidin-3-yl)-7-fluoro-1-oxo-1,2-dihydrophthala Zin-6-yl) piperidin-4-yl) methoxy) pyrimidin-2-yl) benzyl)-6-oxo-1,6-dihydropyridazin-3-yl) benzonitrile and 3-( 1-(3-(5-((1-(3-(2,6-dioxopiperidin-3-yl)-7-fluoro-4-oxo-3,4-dihydrophthalazine-6 -yl)piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile)
NMP(3ml) 중의 3-(6,7-디플루오로-1-옥소프탈라진-2(1H)-일)피페리딘-2,6-디온 (50 mg, 0.182 mmol) 및 (3-(6-옥소-1-(3-(5-(피페리딘-4-일메톡시)피리미딘-2-일)벤질)-1,6-디하이드로피리다진-3-일)벤조니트릴 (120 mg, 0.182 mmol) 용액에 에틸비스(프로판-2-일)아민 (3.0 당량)을 반응 혼합물에 가하였다. 반응물을 24 시간 동안 130℃에서 교반하였다. 잔사를 MeOH/DCM (0~20%) MPLC로 정제하여, 표제 화합물(50 mg)을 수득하였다.3-(6,7-difluoro-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (50 mg, 0.182 mmol) and (3- (6-oxo-1- (3- (5- (piperidin-4-ylmethoxy) pyrimidin-2-yl) benzyl) -1,6-dihydropyridazin-3-yl) benzonitrile (120 mg, 0.182 mmol) solution of ethylbis(propan-2-yl)amine (3.0 equivalent) was added to the reaction mixture.The reaction was stirred for 24 hours at 130° C. The residue was dissolved in MeOH/DCM (0-20%) Purification by MPLC gave the title compound (50 mg).
MS (ESI, m/z): [M+H]+ = 752.78MS (ESI, m/z): [M+H] + = 752.78
실시예 16:Example 16:
3-(1-(3-(5-((1-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)피페리딘-4-일)메톡시)피리미딘-2-일)벤질)-6-옥소-1,6-디하이드로피리다진-3-일)벤조니트릴3-(1-(3-(5-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin- 4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile
NMP(3ml) 중의 2-(2,6-디옥소피페리딘-3-일)-4-플루오로이소인돌린-1,3-디온 (50 mg, 0.182 mmol) 및 (3-(6-옥소-1-(3-(5-(피페리딘-4-일메톡시)피리미딘-2-일)벤질)-1,6-디하이드로피리다진-3-일)벤조니트릴 (120 mg, 0.182 mmol) 용액에 에틸비스(프로판-2-일)아민 (3.0 당량)을 반응 혼합물에 가하였다. 반응물을 24 시간 동안 130℃에서 교반하였다. 잔사를 MeOH/DCM (0~20%) MPLC로 정제하여, 표제 화합물(80 mg)을 수득하였다.2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (50 mg, 0.182 mmol) and (3-(6-oxo- 1-(3-(5-(piperidin-4-ylmethoxy)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzonitrile (120 mg, 0.182 mmol) Ethylbis(propan-2-yl)amine (3.0 equivalent) was added to the reaction mixture to the solution.The reaction was stirred for 24 hours at 130° C. The residue was purified by MeOH/DCM (0-20%) MPLC, The title compound (80 mg) was obtained.
MS (ESI, m/z): [M+H]+ = 735.75MS (ESI, m/z): [M+H] + = 735.75
1H NMR (500 MHz, DMSO-d 6 ) d ppm 11.10 (s, 1 H) 8.68 (s, 2 H) 8.39 (d, J=5.95 Hz, 2 H) 8.22 - 8.28 (m, 2 H) 8.18 (d, J=9.77 Hz, 1 H) 7.94 (d, J=7.78 Hz, 1 H) 7.67 - 7.76 (m, 2 H) 7.46 - 7.52 (m, 2 H) 7.34 (d, J=7.17 Hz, 1 H) 7.37 (d, J=8.54 Hz, 1 H) 7.17 (d, J=9.77 Hz, 1 H) 5.45 (s, 2 H) 5.10 (dd, J=12.82, 5.49 Hz, 1 H) 4.15 (d, J=6.10 Hz, 2 H) 3.76 (d, J=11.60 Hz, 2 H) 3.31 (t, J=7.10 Hz, 1 H) 2.81 - 2.98 (m, 3 H) 2.70 (s, 2 H) 2.52 - 2.63 (m, 2 H) 2.00 - 2.08 (m, 1 H) 1.53 - 1.62 (m, 2 H). 1 H NMR (500 MHz, DMSO-d 6 ) d ppm 11.10 (s, 1 H) 8.68 (s, 2 H) 8.39 (d, J=5.95 Hz, 2 H) 8.22 - 8.28 (m, 2 H) 8.18 (d, J=9.77 Hz, 1 H) 7.94 (d, J=7.78 Hz, 1 H) 7.67 - 7.76 (m, 2 H) 7.46 - 7.52 (m, 2 H) 7.34 (d, J=7.17 Hz, 1 H) 7.37 (d, J=8.54 Hz, 1 H) 7.17 (d, J=9.77 Hz, 1 H) 5.45 (s, 2 H) 5.10 (dd, J=12.82, 5.49 Hz, 1 H) 4.15 ( d, J=6.10 Hz, 2 H) 3.76 (d, J=11.60 Hz, 2 H) 3.31 (t, J=7.10 Hz, 1 H) 2.81 - 2.98 (m, 3 H) 2.70 (s, 2 H) 2.52 - 2.63 (m, 2 H) 2.00 - 2.08 (m, 1 H) 1.53 - 1.62 (m, 2 H).
실시예 17:Example 17:
3-(1-(3-(5-((1-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-5-일)피페리딘-4-일)메톡시)피리미딘-2-일)벤질)-6-옥소-1,6-디하이드로피리다진-3-일)벤조니트릴3-(1-(3-(5-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin- 4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile
NMP(3ml) 중의 2-(2,6-디옥소피페리딘-3-일)-5-플루오로이소인돌린-1,3-디온 (50 mg, 0.182 mmol) 및 (3-(6-옥소-1-(3-(5-(피페리딘-4-일메톡시)피리미딘-2-일)벤질)-1,6-디하이드로피리다진-3-일)벤조니트릴 (120 mg, 0.182 mmol) 용액에 에틸비스(프로판-2-일)아민 (3.0 당량)을 반응 혼합물에 가하였다. 반응물을 24 시간 동안 130℃에서 교반하였다. 잔사를 MeOH/DCM (0~20%) MPLC로 정제하여, 표제 화합물(80 mg)을 수득하였다.2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (50 mg, 0.182 mmol) and (3-(6-oxo- 1-(3-(5-(piperidin-4-ylmethoxy)pyrimidin-2-yl)benzyl)-1,6-dihydropyridazin-3-yl)benzonitrile (120 mg, 0.182 mmol) Ethylbis(propan-2-yl)amine (3.0 equivalent) was added to the reaction mixture to the solution.The reaction was stirred for 24 hours at 130° C. The residue was purified by MeOH/DCM (0-20%) MPLC, The title compound (80 mg) was obtained.
MS (ESI, m/z): [M+H]+ = 735.75MS (ESI, m/z): [M+H] + = 735.75
1H NMR (500 MHz, DMSO-d 6 ) d ppm 11.02 (s, 1 H) 8.59 (s, 2 H) 8.31 (d, J=1.83 Hz, 2 H) 8.13 - 8.22 (m, 2 H) 8.11 (d, J=9.77 Hz, 1 H) 7.86 (d, J=7.78 Hz, 1 H) 7.65 (t, J=7.86 Hz, 1 H) 7.60 (d, J=8.54 Hz, 1 H) 7.37 - 7.45 (m, 2 H) 7.28 (s, 1 H) 7.19 (dd, J=8.70, 1.98 Hz, 1 H) 7.09 (d, J=9.61 Hz, 1 H) 5.38 (s, 2 H) 5.00 (dd, J=12.82, 5.34 Hz, 1 H) 3.98 - 4.07 (m, 4 H) 3.19 - 3.24 (m, 1 H) 2.96 (t, J=11.90 Hz, 2 H) 2.77 - 2.89 (m, 1 H) 2.63 (s, 2 H) 2.45 - 2.56 (m, 2 H) 1.90 - 2.01 (m, 1 H) 1.24 - 1.38 (m, 2 H). 1 H NMR (500 MHz, DMSO-d 6 ) d ppm 11.02 (s, 1 H) 8.59 (s, 2 H) 8.31 (d, J=1.83 Hz, 2 H) 8.13 - 8.22 (m, 2 H) 8.11 (d, J=9.77 Hz, 1 H) 7.86 (d, J=7.78 Hz, 1 H) 7.65 (t, J=7.86 Hz, 1 H) 7.60 (d, J=8.54 Hz, 1 H) 7.37 - 7.45 (m, 2 H) 7.28 (s, 1 H) 7.19 (dd, J=8.70, 1.98 Hz, 1 H) 7.09 (d, J=9.61 Hz, 1 H) 5.38 (s, 2 H) 5.00 (dd, J=12.82, 5.34 Hz, 1 H) 3.98 - 4.07 (m, 4 H) 3.19 - 3.24 (m, 1 H) 2.96 (t, J=11.90 Hz, 2 H) 2.77 - 2.89 (m, 1 H) 2.63 (s, 2 H) 2.45 - 2.56 (m, 2 H) 1.90 - 2.01 (m, 1 H) 1.24 - 1.38 (m, 2 H).
실험예Experimental example : :
실험예 1: 세포주 배양 및 화합물 처리Experimental Example 1: Cell line culture and compound treatment
c-MET 과발현 인간 위암 세포주 MKN45 및 SNU638을 10 % 소 태아 혈청(fetal bovine serum), 페니실린 (100U/ml) 및 스트렙토마이신 (100mg/ml)을 첨가한 RPMI 배지에서 배양하고, c-MET 엑손 14 결손(exon 14 skipping) 돌연변이 인간 위암 세포주 Hs746T는 DMEM 배지에서 배양하였다. c-MET 과발현 인간 폐암 세포주 EBC-1은 10 % fetal bovine serum, 페니실린 (100U/ml) 및 스트렙토마이신 (100mg/ml)을 첨가한 MEM 배지에서 배양하였다. 인간 폐조직에서 유래한 정상세포주 WI-38은 10 % fetal bovine serum, 페니실린 (100U/ml) 및 스트렙토마이신 (100mg/ml)을 첨가한 EMEM 배지에서 배양하였다.c-MET overexpressing human gastric cancer cell lines MKN45 and SNU638 were cultured in RPMI medium supplemented with 10% fetal bovine serum, penicillin (100 U/ml) and streptomycin (100 mg/ml), and c-
본 발명에 따라 합성된 화합물은 DMSO (dimethyl sulfoxide)에 용해시킨 10 mM의 원료용액으로 준비하였으며, 순차적으로 희석하여 처리하였다.The compound synthesized according to the present invention was prepared as a 10 mM raw material solution dissolved in dimethyl sulfoxide (DMSO), and was diluted and treated sequentially.
실험예 2: 본 발명의 화합물의 c-MET 단백질 분해능 평가Experimental Example 2: Evaluation of c-MET protein degrading ability of the compound of the present invention
세포에서 발현되는 c-MET에 대한 본 발명의 화합물의 분해능을 평가하기 위하여 세포들을 12 웰 플레이트(well plate)에서 2 × 105 세포/well의 농도로 분주한 뒤, 위암 세포주들은 시료를 24 시간 동안 처리하였고 폐암 세포주는 48시간동안 처리하였다.In order to evaluate the resolution of the compound of the present invention for c-MET expressed in cells, cells were dispensed at a concentration of 2 × 10 5 cells/well in a 12-well plate, and gastric cancer cell lines were sampled for 24 hours. and lung cancer cell lines were treated for 48 hours.
단백질 발현을 확인하기 위한 웨스턴 블롯 분석(western blotting assay)을 수행하기 위하여, 화합물이 처리된 세포에 프로테아제 억제제(protease inhibitor)가 첨가된 40 μL의 RIPA 버퍼(buffer)를 30분간 처리한 뒤, 얼음 위에서 스크래퍼를 이용하여 세포 용해물을 모으고, 4℃ 15,000 rpm에서 30분 동안 원심 분리하여, 단백질이 포함된 상층액을 얻었다.To perform a western blotting assay to confirm protein expression, compound-treated cells were treated with 40 μL of RIPA buffer to which protease inhibitors were added for 30 minutes, and then incubated on ice. The cell lysate was collected using a scraper from above, and centrifuged at 4° C. and 15,000 rpm for 30 minutes to obtain a protein-containing supernatant.
이후, 각 샘플 당 3 μg의 단백질을 사용하여 Simple Western Automated Western Blot System Abby 기기를 이용하여 단백질 발현을 측정하였다. SDS와 열에 의해 변성된(denaturation) 단백질을 분자량 별로 분리하여 모세관(capillary)에 부착한 뒤, 1차 항체인 anti-c-MET 또는 anti-GAPDH 항체와 반응시키고, 이후 HRP-conjugated 2차 항체에 반응시킨 뒤, 단백질 발현 신호(signal)를 compass software로 분석하였다.Then, protein expression was measured using the Simple Western Automated Western Blot System Abby device using 3 μg of protein per sample. SDS and heat-denatured proteins are separated by molecular weight, attached to a capillary, reacted with a primary antibody, anti-c-MET or anti-GAPDH antibody, and then with an HRP-conjugated secondary antibody. After reacting, protein expression signals were analyzed with compass software.
단백질의 발현은 GAPDH의 발현값을 기준으로 정규화 하였으며, 0.1% DMSO 담체(vehicle)를 처리한 샘플을 100% 기준으로 하여 각 샘플에서의 단백질 발현양을 백분율(%)로 측정하고, 화합물 처리에 의한 단백질 발현양의 변화로부터 DC50 (50 %의 단백질 발현 저해가 달성되는 화합물의 농도)를 계산하였다.Protein expression was normalized based on the expression value of GAPDH, and the protein expression amount in each sample was measured as a percentage (%) based on 100% of the sample treated with 0.1% DMSO vehicle, and the compound treatment DC 50 (the concentration of the compound at which 50% inhibition of protein expression is achieved) was calculated from the change in the amount of protein expression by .
그 결과를 표 1 내지 4 및 도 1과 2에 나타냈다.The results are shown in Tables 1 to 4 and FIGS. 1 and 2.
[표 1] 본 발명의 화합물의 MKN45 세포주에서의 DC50 및 IC50 [Table 1] DC 50 and IC 50 of compounds of the present invention in MKN45 cell line
[표 2] 본 발명의 화합물의 SNU638 세포주에서의 DC50 및 IC50 [Table 2] DC 50 and IC 50 in SNU638 cell line of the compounds of the present invention
[표 3] 본 발명의 화합물의 HS746T 세포주에서의 DC50 및 IC50 Table 3: DC 50 and IC 50 of the compounds of the present invention in HS746T cell line
[표 4] 본 발명의 화합물의 EBC-1 세포주에서의 DC50 및 IC50 [Table 4] DC 50 and IC 50 of compounds of the present invention in EBC-1 cell line
실험 결과, 위암 세포주 MKN45에서 대다수의 화합물들은 우수한 분해능을 나타냈으며, 특히 표 1 내지 4 및 도 1과 2의 결과에서 보이는 바와 같이 실험에 사용된 모든 위암세포주와 폐암 세포주에 대하여 본 발명의 화합물들은 c-MET 단백질을 효과적으로 분해하였다.As a result of the experiment, most of the compounds in the gastric cancer cell line MKN45 showed excellent resolution. In particular, as shown in the results of Tables 1 to 4 and FIGS. 1 and 2, the compounds of the present invention were used for all gastric cancer cell lines and lung cancer cell lines used in the experiment. c-MET protein was effectively degraded.
실험예 3: 본 발명의 화합물에 의한 암세포 항증식 활성 평가Experimental Example 3: Evaluation of cancer cell antiproliferative activity by the compound of the present invention
세포 성장에 대한 저해 활성을 관찰하기 위하여 세포들을 96 well plate에서 5,000 세포/well의 농도로 분주한 뒤, 다양한 농도로 준비된 본 발명의 화합물로 72 시간 동안 처리하였다. 세포의 생존율은, 미트콘드리아의 전자전달계에 존재하는 탈수소효소(dehydrogenase)와 반응하여 포르마잔(formazon)을 생성하는 WST-8 (water soluble tetrazolium salt) 시료를 well 당 10 ml 씩 첨가한 뒤, 2 시간 동안 배양하고, 450 nm에서 흡광도를 측정하여 얻은 값을 GraphicPad Prism 8.0 소프트웨어를 사용하여 계산하였다. IC50 값 (50 %의 세포 증식 억제를 달성하는 화합물의 농도)은 측정 결과의 평균값이다. 그 결과를 표 1 내지 4 및 도 3과 4에 나타내었다.In order to observe the inhibitory activity on cell growth, the cells were dispensed in a 96 well plate at a concentration of 5,000 cells/well, and then treated with the compound of the present invention prepared at various concentrations for 72 hours. Cell viability was measured by adding 10 ml of WST-8 (water soluble tetrazolium salt) sample per well, which reacts with dehydrogenase present in the mitochondrial electron transport system to produce formazan, After incubation for 2 hours, absorbance was measured at 450 nm and the obtained value was calculated using GraphicPad Prism 8.0 software. The IC 50 value (the concentration of the compound that achieves 50% inhibition of cell proliferation) is the average value of the measurement results. The results are shown in Tables 1 to 4 and FIGS. 3 and 4.
실험 결과에서 보여지는 바와 같이, 본 발명의 화합물들은 암세포의 증식을 억제하는 효과를 보였으며, 특히 c-MET을 효과적으로 분해하는 실시예 1, 2 및 10의 화합물들은 5 nM 미만의 저농도에서 위암 세포주 MKN45의 증식을 효과적으로 억제하였다(표 1 및 도 3 참조). 또한, 실시예 1, 2 및 10의 화합물들은 다른 위암 세포주인 SNU638 및 Hs746T와 폐암 세포주 EBC-1에서도 100 nM 미만의 농도에서 암세포의 증식을 효과적으로 억제하였다.As shown in the experimental results, the compounds of the present invention showed an effect of inhibiting the proliferation of cancer cells, and in particular, the compounds of Examples 1, 2 and 10, which effectively degrade c-MET, gastric cancer cell lines at low concentrations of less than 5 nM. Proliferation of MKN45 was effectively inhibited (see Table 1 and Figure 3). In addition, the compounds of Examples 1, 2 and 10 effectively inhibited the proliferation of cancer cells at a concentration of less than 100 nM in other gastric cancer cell lines, SNU638 and Hs746T, and lung cancer cell line EBC-1.
실험예 4: 본 발명의 화합물에 의한 정상세포 독성 평가Experimental Example 4: Evaluation of normal cell toxicity by the compound of the present invention
본 발명의 화합물의 처리에 의하여 정상 세포의 성장이 저해되는지 여부를 관찰하기 위하여, 정상 세포주 WI-38를 96 well plate에서 5,000 세포/well의 농도로 분주한 뒤, 다양한 농도로 준비된 본 발명의 화합물로 72 시간 동안 처리하였다. 세포의 생존율은 미트콘드리아에 전자전달계에 존재하는 dehydrogenase와 반응하여 포르마잔(formazon)을 생성하는 WST-8 (water soluble tetrazolium salt) 시료를 well 당 10 ml 씩 첨가한 뒤, 2 시간 동안 배양하고, 450 nm에서 흡광도를 측정하여 얻은 값을 GraphicPad Prism 8.0 소프트웨어를 사용하여 계산하였다. IC50 값 (50 %의 세포 증식 억제를 달성하는 화합물의 농도)은 측정 결과의 평균값이다. 그 결과를 표 5 및 도 5에 나타내었다.In order to observe whether the growth of normal cells is inhibited by the treatment of the compound of the present invention, the normal cell line WI-38 was dispensed at a concentration of 5,000 cells/well in a 96 well plate, and then the compound of the present invention prepared at various concentrations treated for 72 hours. Cell viability was measured by adding 10 ml of WST-8 (water soluble tetrazolium salt) sample per well, which reacts with dehydrogenase present in the electron transport system to mitochondria to produce formazan, and incubated for 2 hours. , the absorbance was measured at 450 nm and the value obtained was calculated using GraphicPad Prism 8.0 software. The IC 50 value (the concentration of the compound that achieves 50% inhibition of cell proliferation) is the average value of the measurement results. The results are shown in Table 5 and Figure 5.
[표 5] 본 발명의 화합물의 WI-38 세포주에서의 IC50 [Table 5] IC 50 of compounds of the present invention in WI-38 cell line
실험 결과, 본 발명의 화합물들은 정상 세포주의 증식에 영향을 주지 아니함을 확인하였다.As a result of the experiment, it was confirmed that the compounds of the present invention did not affect the proliferation of normal cell lines.
실험예 5: 본 발명의 화합물에 의한 c-MET 신호전달 억제 평가Experimental Example 5: Evaluation of inhibition of c-MET signaling by the compound of the present invention
본 발명의 화합물의 c-MET에 분해에 의한 암세포 성장 신호 억제 효과를 평가하기 위하여, 위암 세포주 SNU638을 6 well plate에서 5 × 105 세포/well의 농도로 분주한 뒤, 다양한 농도로 준비된 본 발명의 화합물로 24 시간 동안 처리하였다.In order to evaluate the effect of inhibiting cancer cell growth signal by degradation of the compound of the present invention to c-MET, the gastric cancer cell line SNU638 was dispensed in a 6 well plate at a concentration of 5 × 10 5 cells/well, and then prepared at various concentrations according to the present invention. was treated for 24 hours with the compound of
또한, 본 발명의 화합물에 의해 유도된 c-MET 단백질 분해에 의하여 암세포 성장 신호 전달 억제 효과가 얼마나 유지되는지 확인하기 위하여 시료를 30 nM의 농도로 처리한 후, 시간별로 세포를 확보하였다.In addition, in order to confirm how much the cancer cell growth signal transduction inhibitory effect is maintained by c-MET proteolysis induced by the compound of the present invention, the samples were treated at a concentration of 30 nM, and then cells were obtained over time.
단백질 발현을 확인하기 위한 western blotting assay를 수행하기 위하여, 화합물이 처리된 세포에 protease inhibitor가 첨가된 70 μL의 RIPA buffer를 30분간 처리한 뒤, 얼음 위에서 스크래퍼를 이용하여 세포 용해물을 모으고, 4℃ 15,000 rpm에서 30 분 동안 원심 분리하여 단백질이 포함된 상층액을 얻었다.To perform a western blotting assay to confirm protein expression, compound-treated cells were treated with 70 μL of RIPA buffer with protease inhibitors added for 30 minutes, then cell lysates were collected using a scraper on ice, and 4 A supernatant containing protein was obtained by centrifugation at 15,000 rpm for 30 minutes.
이후, 각 샘플 당 10 μg의 단백질을 사용하여 SDS-PAGE, 단백질의 막 전이(membrane transfer)를 수행하고, anti-phospho-c-MET, anti-phospho-ERK, anti-phospho-AKT, anti-c-MET, anti-ERK, anti-AKT 또는 anti-GAPDH 항체에 4℃에서 16 시간 동안 반응시키고, 2차 항체를 상온에서 1시간 동안 반응시킨 후, SuperSignal™ West Pico PLUS 화학 발광 기질(chemiluminescence substrate)과 이미지 분석기(analyzer)를 이용하여 단백질의 발현을 확인하였다. 그 결과를 도 6 및 도 7에 나타내었다.Thereafter, SDS-PAGE and membrane transfer of proteins were performed using 10 μg of protein for each sample, and anti-phospho-c-MET, anti-phospho-ERK, anti-phospho-AKT, anti- After reacting with c-MET, anti-ERK, anti-AKT or anti-GAPDH antibodies at 4°C for 16 hours, and reacting with secondary antibodies for 1 hour at room temperature, SuperSignal™ West Pico PLUS chemiluminescence substrate ) and an image analyzer were used to confirm protein expression. The results are shown in Figures 6 and 7.
도 6의 결과에서 보이는 바와 같이, 본 발명의 화합물은 대체적으로 처리 농도에 비례하여 c-MET에 의해 유도되는 암세포의 ERK와 AKT 신호의 활성화를 억제하였다. 또한, 도 7의 결과에서 보이는 바와 같이, 저분자 화합물 억제제(small inhibitor)인 테포티닙(Tepotinib)을 처리한 세포주에 비하여 암세포의 ERK와 AKT 신호전달 억제가 더 오랫동안 유지되는 것을 확인할 수 있었다.As shown in the results of FIG. 6 , the compounds of the present invention inhibited the activation of ERK and AKT signals in cancer cells induced by c-MET in proportion to the treatment concentration. In addition, as shown in the results of FIG. 7 , it was confirmed that inhibition of ERK and AKT signaling in cancer cells was maintained for a longer period of time compared to cell lines treated with a small molecule inhibitor, tepotinib.
실험예 6: 위암 세포가 이식된 동물모델에서의 본 발명의 화합물의 항암 활성 평가Experimental Example 6: Evaluation of anticancer activity of the compound of the present invention in an animal model transplanted with gastric cancer cells
본 발명의 화합물의 c-MET 분해에 의한 암세포 성장 억제 효과를 동물모델에서 평가하기 위하여 1 × 107 개의 위암 세포주 SNU638을 면역부전 마우스에 이식하여 일정한 크기의 종양을 형성시켰다.To evaluate the cancer cell growth inhibitory effect of the compound of the present invention by c-MET degradation in an animal model, 1 × 10 7 gastric cancer cell line SNU638 was transplanted into immunodeficient mice to form tumors of a certain size.
본 발명의 화합물의 항암활성을 평가하기 위하여, 위 마우스를 무작위로 그룹으로 나누고(각 군당 5마리씩 분배), 담체와 본 발명의 화합물을 복강투여(도 7) 및 경구투여(도 8)로 2 주간 매일 처리하고, 3일마다 마우스의 체중과 종양의 크기를 측정하였다.In order to evaluate the anticancer activity of the compound of the present invention, the stomach mice were randomly divided into groups (distributed 5 mice per group), and the carrier and the compound of the present invention were administered intraperitoneally (FIG. 7) and orally (FIG. 8). The treatment was performed every day for a week, and the body weight and tumor size of the mice were measured every 3 days.
실험이 종료된 이후, 종양을 적출하여 무게를 측정하였으며, 종양에서의 c-MET 단백질의 발현의 변화를 관찰하기 위하여 종양을 분쇄하여 단백질을 얻은 후, western blotting assay를 이용하여 확인하였다. 그 결과를 도 8 및 도 9에 각각 도시하였다.After the experiment was finished, the tumor was removed and weighed. In order to observe the change in c-MET protein expression in the tumor, the protein was obtained by crushing the tumor and confirmed using a western blotting assay. The results are shown in FIGS. 8 and 9 respectively.
실험 결과에서 확인할 수 있듯이, 화합물의 처리기간 동안 마우스의 체중변화는 거의 관찰되지 않았으며, 본 발명의 화합물을 복강투여 또는 경구투여로 처리한 경우 마우스에 이식된 인간 위암 세포주의 성장을 효과적으로 억제하고 종양의 사멸을 유도하였다.As can be seen from the experimental results, almost no change in the body weight of mice was observed during the treatment period of the compound, and when the compound of the present invention was administered intraperitoneally or orally, it effectively inhibited the growth of human gastric cancer cell lines transplanted into mice. Apoptosis of the tumor was induced.
또한, 도 8로부터 확인되는 바와 같이, 실험 종료 후 적출된 종양의 단백질 발현을 관찰하였을 때, 본 발명의 화합물을 처리한 그룹에서의 c-MET의 발현이 대조군에 비하여 확연히 낮음을 확인할 수 있었다.In addition, as confirmed from FIG. 8 , when the protein expression of the tumors extracted after the end of the experiment was observed, the expression of c-MET in the group treated with the compound of the present invention was significantly lower than that of the control group.
본 발명에 따른 화합물은 항암제로서 유용하게 사용될 수 있다.The compounds according to the present invention can be usefully used as anticancer agents.
Claims (9)
[화학식 1]
상기식에서,
Z는 표적단백질 리간드이고,
Q1 내지 Q4는 각각 독립적으로 C-Z, C-H, C-Hal 또는 C≡N이되(여기에서, Hal은 할로겐이다), 단 Q1 내지 Q4 중 어느 하나는 C-Z이며,
R1은 수소, 할로겐, 니트로, 아미노, C1 내지 C6의 직쇄, 분지쇄 또는 사이클릭 알킬, 또는 할로겐으로 치환된 C1 내지 C6의 직쇄, 분지쇄 또는 사이클릭 알킬이다.A compound of Formula 1 or a pharmaceutically acceptable salt thereof:
[Formula 1]
In the above formula,
Z is a target protein ligand;
Q 1 to Q 4 are each independently CZ, CH, C-Hal or C≡N (here, Hal is a halogen), provided that any one of Q 1 to Q 4 is CZ;
R 1 is hydrogen, halogen, nitro, amino, C 1 to C 6 straight, branched or cyclic alkyl, or C 1 to C 6 straight, branched or cyclic alkyl substituted by halogen.
The compound of claim 1, wherein the target protein ligand is selected from the group consisting of the following compounds:
[화학식 2]
상기식에서,
Y는 -C=O 또는 -CH2이고,
Z는 표적단백질 리간드이며,
Q1 내지 Q4는 각각 독립적으로 C-Z, C-H, C-Hal 또는 C≡N이되(여기에서, Hal은 할로겐이다), 단 Q1 내지 Q4 중 어느 하나는 C-Z이다.A compound of Formula 2 or a pharmaceutically acceptable salt thereof:
[Formula 2]
In the above formula,
Y is -C=0 or -CH 2 ;
Z is a target protein ligand,
Q 1 to Q 4 are each independently CZ, CH, C-Hal or C≡N (here, Hal is a halogen), provided that any one of Q 1 to Q 4 is CZ.
The compound according to claim 5, wherein the target protein ligand is selected from the group consisting of the following compounds:
A compound selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof:
3-(6-(4-(4-(2-((S)-2-((5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일)메틸)모르폴리노)피리미딘-5-일)벤질)피페라진-1-일)-1-옥소프탈라진-2(1H)-일)피페리딘-2,6-디온
3-(4-메틸-6-(4-(4-(2-((S)-2-((5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일)메틸)모르폴리노)피리미딘-5-일)벤질)피페라진-1-일)-1-옥소프탈라진-2(1H)-일)피페리딘-2,6-디온
3-(7-(4-(4-(2-((S)-2-((5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일)메틸)모르폴리노)피리미딘-5-일)벤질)피페라진-1-일)-1-옥소프탈라진-2(1H)-일)피페리딘-2,6-디온
3-(8-(4-(4-(2-((S)-2-((5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일)메틸)모르폴리노)피리미딘-5-일)벤질)피페라진-1-일)-1-옥소프탈라진-2(1H)-일)피페리딘-2,6-디온
3-(4-메틸-8-(4-(4-(2-((S)-2-((5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일)메틸)모르폴리노)피리미딘-5-일)벤질)피페라진-1-일)-1-옥소프탈라진-2(1H)-일)피페리딘-2,6-디온
3-(6-플루오로-7-(4-(4-(2-((S)-2-((5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일)메틸)모르폴리노)피리미딘-5-일)벤질)피페라진-1-일)-1-옥소프탈라진-2(1H)-일)피페리딘-2,6-디온
2-(2,6-디옥소피페리딘-3-일)-4-(4-(4-(2-((S)-2-((5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일)메틸)모르폴리노)피리미딘-5-일)벤질)피페라진-1-일)이소인돌린-1,3-디온
2-(2,6-디옥소피페리딘-3-일)-5-(4-(4-(2-((S)-2-((5-(1-메틸-1H-피라졸-4-일)-1H-[1,2,3]트리아졸로[4,5-b]피라진-1-일)메틸)모르폴리노)피리미딘-5-일)벤질)피페라진-1-일)이소인돌린-1,3-디온
3-(1-(3-(5-((1-(2-(2,6-디옥소피페리딘-3-일)-1-옥소-1,2-디하이드로프탈라진-6-일)피페리딘-4-일)메톡시)피리미딘-2-일)벤질)-6-옥소-1,6-디하이드로피리다진-3-일)벤조니트릴
3-(1-(3-(5-((1-(2-(2,6-디옥소피페리딘-3-일)-4-메틸-1-옥소-1,2-디하이드로프탈라진-6-일)피페리딘-4-일)메톡시)피리미딘-2-일)벤질)-6-옥소-1,6-디하이드로피리다진-3-일)벤조니트릴
3-(1-(3-(5-((1-(2-(2,6-디옥소피페리딘-3-일)-1-옥소-1,2-디하이드로프탈라진-5-일)피페리딘-4-일)메톡시)피리미딘-2-일)벤질)-6-옥소-1,6-디하이드로피리다진-3-일)벤조니트릴
3-(1-(3-(5-((1-(3-(2,6-디옥소피페리딘-3-일)-4-옥소-3,4-디하이드로프탈라진-6-일)피페리딘-4-일)메톡시)피리미딘-2-일)벤질)-6-옥소-1,6-디하이드로피리다진-3-일)벤조니트릴
3-(1-(3-(5-((1-(3-(2,6-디옥소피페리딘-3-일)-4-옥소-3,4-디하이드로프탈라진-5-일)피페리딘-4-일)메톡시)피리미딘-2-일)벤질)-6-옥소-1,6-디하이드로피리다진-3-일)벤조니트릴
3-(1-(3-(5-((1-(3-(2,6-디옥소피페리딘-3-일)-1-메틸-4-옥소-3,4-디하이드로프탈라진-6-일)피페리딘-4-일)메톡시)피리미딘-2-일)벤질)-6-옥소-1,6-디하이드로피리다진-3-일)벤조니트릴
3-(1-(3-(5-((1-(2-(2,6-디옥소피페리딘-3-일)-7-플루오로-1-옥소-1,2-디하이드로프탈라진-6-일)피페리딘-4-일)메톡시)피리미딘-2-일)벤질)-6-옥소-1,6-디하이드로피리다진-3-일)벤조니트릴
3-(1-(3-(5-((1-(3-(2,6-디옥소피페리딘-3-일)-7-플루오로-4-옥소-3,4-디하이드로프탈라진-6-일)피페리딘-4-일)메톡시)피리미딘-2-일)벤질)-6-옥소-1,6-디하이드로피리다진-3-일)벤조니트릴
3-(1-(3-(5-((1-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)피페리딘-4-일)메톡시)피리미딘-2-일)벤질)-6-옥소-1,6-디하이드로피리다진-3-일)벤조니트릴
3-(1-(3-(5-((1-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-5-일)피페리딘-4-일)메톡시)피리미딘-2-일)벤질)-6-옥소-1,6-디하이드로피리다진-3-일)벤조니트릴A compound selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof:
3-(6-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]tria zolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)-1-oxophthalazin-2(1H)-yl )piperidine-2,6-dione
3-(4-methyl-6-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2 ,3] triazolo [4,5-b] pyrazin-1-yl) methyl) morpholino) pyrimidin-5-yl) benzyl) piperazin-1-yl) -1-oxophthalazin-2 ( 1H)-yl)piperidine-2,6-dione
3-(7-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]tria zolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)-1-oxophthalazin-2(1H)-yl )piperidine-2,6-dione
3-(8-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]tria zolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)-1-oxophthalazin-2(1H)-yl )piperidine-2,6-dione
3-(4-methyl-8-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2 ,3] triazolo [4,5-b] pyrazin-1-yl) methyl) morpholino) pyrimidin-5-yl) benzyl) piperazin-1-yl) -1-oxophthalazin-2 ( 1H)-yl)piperidine-2,6-dione
3-(6-fluoro-7-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazol-4-yl)-1H-[1, 2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl)-1-oxophthalazin-2 (1H)-yl)piperidine-2,6-dione
2-(2,6-dioxopiperidin-3-yl)-4-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazole-4 -yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl) isoindoline-1,3-dione
2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(2-((S)-2-((5-(1-methyl-1H-pyrazole-4 -yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)benzyl)piperazin-1-yl) isoindoline-1,3-dione
3-(1-(3-(5-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl )piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile
3-(1-(3-(5-((1-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxo-1,2-dihydrophthalazine -6-yl) piperidin-4-yl) methoxy) pyrimidin-2-yl) benzyl) -6-oxo-1,6-dihydropyridazin-3-yl) benzonitrile
3-(1-(3-(5-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-5-yl )piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile
3-(1-(3-(5-((1-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrophthalazin-6-yl )piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile
3-(1-(3-(5-((1-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrophthalazin-5-yl )piperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile
3-(1-(3-(5-((1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-4-oxo-3,4-dihydrophthalazine -6-yl) piperidin-4-yl) methoxy) pyrimidin-2-yl) benzyl) -6-oxo-1,6-dihydropyridazin-3-yl) benzonitrile
3-(1-(3-(5-((1-(2-(2,6-dioxopiperidin-3-yl)-7-fluoro-1-oxo-1,2-dihydrophthala Zin-6-yl) piperidin-4-yl) methoxy) pyrimidin-2-yl) benzyl)-6-oxo-1,6-dihydropyridazin-3-yl) benzonitrile
3-(1-(3-(5-((1-(3-(2,6-dioxopiperidin-3-yl)-7-fluoro-4-oxo-3,4-dihydrophthala Zin-6-yl) piperidin-4-yl) methoxy) pyrimidin-2-yl) benzyl)-6-oxo-1,6-dihydropyridazin-3-yl) benzonitrile
3-(1-(3-(5-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin- 4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile
3-(1-(3-(5-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin- 4-yl)methoxy)pyrimidin-2-yl)benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile
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WO2010078897A1 (en) | 2009-01-08 | 2010-07-15 | Merck Patent Gmbh | Novel polymorphic forms of 3-(1-{3-[5-(1-methyl-piperidin-4ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride salt and processes of manufacturing thereof |
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