CN114907317B - Pyrazole-vinyl-isonicotinic acid derivative and preparation method and application thereof - Google Patents
Pyrazole-vinyl-isonicotinic acid derivative and preparation method and application thereof Download PDFInfo
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- CN114907317B CN114907317B CN202210621385.8A CN202210621385A CN114907317B CN 114907317 B CN114907317 B CN 114907317B CN 202210621385 A CN202210621385 A CN 202210621385A CN 114907317 B CN114907317 B CN 114907317B
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- isonicotinic acid
- pyrazole
- dimethylformamide
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- -1 Pyrazole-vinyl-isonicotinic acid derivative Chemical class 0.000 title claims abstract description 63
- 238000002360 preparation method Methods 0.000 title claims abstract description 36
- 150000001875 compounds Chemical class 0.000 claims abstract description 67
- 101001088883 Homo sapiens Lysine-specific demethylase 5B Proteins 0.000 claims abstract description 19
- 102100033247 Lysine-specific demethylase 5B Human genes 0.000 claims abstract description 17
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N Vilsmeier-Haack reagent Natural products CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 50
- 238000006243 chemical reaction Methods 0.000 claims description 15
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 14
- 206010028980 Neoplasm Diseases 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 10
- 229940126062 Compound A Drugs 0.000 claims description 9
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- PMDHIMMPXRSDML-UHFFFAOYSA-N 2-methylpyridine-4-carboxylic acid Chemical compound CC1=CC(C(O)=O)=CC=N1 PMDHIMMPXRSDML-UHFFFAOYSA-N 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 3
- 229960000583 acetic acid Drugs 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 206010017758 gastric cancer Diseases 0.000 claims description 3
- 239000012362 glacial acetic acid Substances 0.000 claims description 3
- 201000011549 stomach cancer Diseases 0.000 claims description 3
- 238000011282 treatment Methods 0.000 claims description 3
- 239000005051 trimethylchlorosilane Substances 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- HPARLNRMYDSBNO-UHFFFAOYSA-N 1,4-benzodioxine Chemical group C1=CC=C2OC=COC2=C1 HPARLNRMYDSBNO-UHFFFAOYSA-N 0.000 claims 1
- 230000005764 inhibitory process Effects 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 6
- 239000003112 inhibitor Substances 0.000 abstract description 5
- 239000002246 antineoplastic agent Substances 0.000 abstract description 4
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical class OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 abstract description 4
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 3
- 108090000790 Enzymes Proteins 0.000 abstract description 2
- 102000004190 Enzymes Human genes 0.000 abstract description 2
- 238000006000 Knoevenagel condensation reaction Methods 0.000 abstract description 2
- 238000005874 Vilsmeier-Haack formylation reaction Methods 0.000 abstract description 2
- 150000007514 bases Chemical class 0.000 abstract description 2
- 238000003379 elimination reaction Methods 0.000 abstract description 2
- 150000002611 lead compounds Chemical group 0.000 abstract description 2
- 230000000269 nucleophilic effect Effects 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 42
- 239000007787 solid Substances 0.000 description 25
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 21
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 10
- 239000000243 solution Substances 0.000 description 7
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 5
- 229940067157 phenylhydrazine Drugs 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 4
- 239000004472 Lysine Substances 0.000 description 4
- 230000011987 methylation Effects 0.000 description 4
- 238000007069 methylation reaction Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 108010033040 Histones Proteins 0.000 description 3
- 101000615488 Homo sapiens Methyl-CpG-binding domain protein 2 Proteins 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 102100021299 Methyl-CpG-binding domain protein 2 Human genes 0.000 description 3
- 230000014509 gene expression Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- OTDDCLPBNWLJLH-UHFFFAOYSA-N 1,3-diphenylpyrazole-4-carboxylic acid Chemical compound OC(=O)C1=CN(C=2C=CC=CC=2)N=C1C1=CC=CC=C1 OTDDCLPBNWLJLH-UHFFFAOYSA-N 0.000 description 2
- ISDBWOPVZKNQDW-UHFFFAOYSA-N 4-phenylbenzaldehyde Chemical compound C1=CC(C=O)=CC=C1C1=CC=CC=C1 ISDBWOPVZKNQDW-UHFFFAOYSA-N 0.000 description 2
- VGXRQCOVGLGFIM-UHFFFAOYSA-N 7-oxo-5-phenyl-6-propan-2-yl-1H-pyrazolo[1,5-a]pyrimidine-3-carbonitrile Chemical compound N1=C2C(C#N)=CNN2C(=O)C(C(C)C)=C1C1=CC=CC=C1 VGXRQCOVGLGFIM-UHFFFAOYSA-N 0.000 description 2
- 108010074870 Histone Demethylases Proteins 0.000 description 2
- 102000008157 Histone Demethylases Human genes 0.000 description 2
- 102000006947 Histones Human genes 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000011242 molecular targeted therapy Methods 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 2
- FXLOVSHXALFLKQ-UHFFFAOYSA-N p-tolualdehyde Chemical compound CC1=CC=C(C=O)C=C1 FXLOVSHXALFLKQ-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- NRESDXFFSNBDGP-UHFFFAOYSA-N (4-bromophenyl)hydrazine Chemical compound NNC1=CC=C(Br)C=C1 NRESDXFFSNBDGP-UHFFFAOYSA-N 0.000 description 1
- YMMCBGIHBVKZGD-UHFFFAOYSA-N (4-fluorophenyl)methylhydrazine Chemical compound NNCC1=CC=C(F)C=C1 YMMCBGIHBVKZGD-UHFFFAOYSA-N 0.000 description 1
- PVRSIFAEUCUJPK-UHFFFAOYSA-N (4-methoxyphenyl)hydrazine Chemical compound COC1=CC=C(NN)C=C1 PVRSIFAEUCUJPK-UHFFFAOYSA-N 0.000 description 1
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 description 1
- CWKXDPPQCVWXAG-UHFFFAOYSA-N 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde Chemical compound O1CCOC2=CC(C=O)=CC=C21 CWKXDPPQCVWXAG-UHFFFAOYSA-N 0.000 description 1
- WCGPCBACLBHDCI-UHFFFAOYSA-N 2,4-difluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C(F)=C1 WCGPCBACLBHDCI-UHFFFAOYSA-N 0.000 description 1
- VVVOJODFBWBNBI-UHFFFAOYSA-N 2,5-difluorobenzaldehyde Chemical compound FC1=CC=C(F)C(C=O)=C1 VVVOJODFBWBNBI-UHFFFAOYSA-N 0.000 description 1
- ZWDVQMVZZYIAHO-UHFFFAOYSA-N 2-fluorobenzaldehyde Chemical compound FC1=CC=CC=C1C=O ZWDVQMVZZYIAHO-UHFFFAOYSA-N 0.000 description 1
- 239000001431 2-methylbenzaldehyde Substances 0.000 description 1
- LCRCBXLHWTVPEQ-UHFFFAOYSA-N 2-phenylbenzaldehyde Chemical compound O=CC1=CC=CC=C1C1=CC=CC=C1 LCRCBXLHWTVPEQ-UHFFFAOYSA-N 0.000 description 1
- PIKNVEVCWAAOMJ-UHFFFAOYSA-N 3-fluorobenzaldehyde Chemical compound FC1=CC=CC(C=O)=C1 PIKNVEVCWAAOMJ-UHFFFAOYSA-N 0.000 description 1
- ZRYZBQLXDKPBDU-UHFFFAOYSA-N 4-bromobenzaldehyde Chemical compound BrC1=CC=C(C=O)C=C1 ZRYZBQLXDKPBDU-UHFFFAOYSA-N 0.000 description 1
- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 0.000 description 1
- XXNOGQJZAOXWAQ-UHFFFAOYSA-N 4-chlorophenylhydrazine Chemical compound NNC1=CC=C(Cl)C=C1 XXNOGQJZAOXWAQ-UHFFFAOYSA-N 0.000 description 1
- BXRFQSNOROATLV-UHFFFAOYSA-N 4-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=C(C=O)C=C1 BXRFQSNOROATLV-UHFFFAOYSA-N 0.000 description 1
- QPVQVIZTBJOFLW-UHFFFAOYSA-N CC(C=C1)=CCC1(C=O)OCC1=CC=CC=C1 Chemical compound CC(C=C1)=CCC1(C=O)OCC1=CC=CC=C1 QPVQVIZTBJOFLW-UHFFFAOYSA-N 0.000 description 1
- AEHQAPXJHVTFBL-UHFFFAOYSA-N CC1(CC=C(C=C1)S(=O)(=O)C)C=O Chemical compound CC1(CC=C(C=C1)S(=O)(=O)C)C=O AEHQAPXJHVTFBL-UHFFFAOYSA-N 0.000 description 1
- 206010048723 Multiple-drug resistance Diseases 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000000928 benzodioxinyl group Chemical group O1C(=COC2=C1C=CC=C2)* 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 230000009400 cancer invasion Effects 0.000 description 1
- 238000002659 cell therapy Methods 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000006565 epigenetic process Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- QJZUKDFHGGYHMC-UHFFFAOYSA-N pyridine-3-carbaldehyde Chemical compound O=CC1=CC=CN=C1 QJZUKDFHGGYHMC-UHFFFAOYSA-N 0.000 description 1
- BGUWFUQJCDRPTL-UHFFFAOYSA-N pyridine-4-carbaldehyde Chemical compound O=CC1=CC=NC=C1 BGUWFUQJCDRPTL-UHFFFAOYSA-N 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 238000010583 slow cooling Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000003041 virtual screening Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a pyrazole-vinyl-isonicotinic acid derivative which has remarkable biological inhibition activity on KDM5B, can be used for preparing and researching and developing a novel KDM5B inhibitor, enriches the variety of isonicotinic acid derivatives, and lays a foundation for developing a drug for inhibiting KDM 5B. The invention takes basic compounds such as aromatic ring aldehydes and the like as raw materials, and is prepared by nucleophilic addition-elimination, vilsmeier-Haack reaction and Knoevenagel condensation reaction, and the preparation method is simple, mild in condition and high in yield. The compound has nanomolar inhibition on KDM5B on enzyme level, provides a lead compound structure for further researching anti-cancer drugs for inhibiting KDM5B, and has better application prospect.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and relates to a pyrazole-vinyl-isonicotinic acid derivative, and a preparation method and application thereof.
Background
Cancer has developed into a public health problem that severely threatens the health of the general public, placing a heavy burden on the home and society, and its morbidity and mortality are still increasing. Cancer treatment comprises surgery, radiotherapy, chemotherapy, molecular targeted therapy, tumor immunotherapy, cell therapy and the like, wherein the molecular targeted therapy drug can specifically inhibit a regulatory factor related to tumor growth or inhibit microenvironment conducive to cancer growth or survival, and the like, so that tumor growth, invasion and metastasis are inhibited or blocked, and the safety is higher than that of the traditional chemotherapy drug. Therefore, the targeted anticancer therapeutic drug with good design and research and development effects and small side effects has urgency and necessity.
Methylation modification of histones is a reversible epigenetic process, mainly occurring on tail lysine and arginine residues, with a broad range of biological functions. The university of harvard Shi Yang professor task group discovered for the first time that lysine-specific demethylase 1 (lysine specific demethylase, lsd 1) was present, confirming that histone methylation is a reversible process. Later, there are several subject groups reporting the family of histone demethylases, jumonji C (JMjC). With the continuous and intensive research, the unknown problems in the methylation modification process of histones are gradually revealed. The apparent regulatory histone lysine demethylase KDM5B (lysine-specific demethylase B, KDM 5B), also called plu-1 or JARID1B, belongs to one member of the (JMjjc-KDMS) subfamily of JMJD, can remove the methylation state of H3K4Me2/3, regulates the transcription and expression of genes, and is closely related to the occurrence and development of diseases such as cancer, immunity, chemotherapy multiple drug resistance and the like. According to the related research report, KDM5B is over-expressed in various solid tumors such as prostate, gastric cancer, breast cancer, ovarian cancer, liver cancer and the like and leukemia, and the over-expression level is related to the worsening degree of the cancer and the poor prognosis. A great deal of evidence shows that KDM5B is a potential oncogene, and the reduction or knockout of the expression level of KDM5B can obviously inhibit the tumor bioactivity such as tumor metastasis and invasion, and the anti-tumor drug targeting KDM5B provides a new opportunity for cancer treatment.
In recent years, KDM5 inhibitors of various structural frameworks have been discovered by computer-aided technology (high throughput virtual screening, HTS) in combination with corresponding drug design approaches, some of which (CPI-455, EPT 103182) have entered preclinical studies, but currently no drug is marketed, and most of which are still in early stages of research. Therefore, it is of great importance to develop KDM5B inhibitors with high potency, low toxicity, high selectivity and good pharmacokinetic parameters.
Disclosure of Invention
In order to overcome the deficiencies of the prior art, one of the objects of the present invention is to provide a pyrazole-vinyl-isonicotinic acid derivative which has a good inhibitory effect on HDM5B, IC 50 On the order of micrometers, shows good inhibitory activity.
It is a second object of the present invention to provide a process for the preparation of pyrazole-vinyl-isonicotinic acid derivatives.
The invention further aims to provide application of the pyrazole-vinyl-isonicotinic acid derivative in preparing medicines for inhibiting KDM 5B.
One of the purposes of the invention is realized by adopting the following technical scheme:
pyrazole-vinyl-isonicotinic acid derivative with structural formula I
Wherein R is 1 Selected from phenyl, substituted phenyl, N-containing six membered heterocyclyl, benzodioxinyl;
R 2 selected from phenyl and substituted phenyl.
Further, the substituent of the substituted phenyl is C1-C6 saturated alkyl, C1-C6 saturated alkoxy, halogen, nitro, C1-C6 saturated alkylsulfonyl and phenyl.
Further, the R 1 Selected from the group consisting of
R 2 Selected from the group consisting of
The second purpose of the invention is realized by adopting the following technical scheme:
a process for the preparation of pyrazole-vinyl-isonicotinic acid derivatives comprising the steps of:
(1) Adding absolute ethyl alcohol into the compound A, then adding the compound B and a catalyst into the compound A, and stirring the mixture at room temperature for reaction to obtain a compound C;
(2) First, vilsmeier-Haack reagent was prepared: dropwise adding phosphorus oxychloride into N, N-dimethylformamide under ice bath condition, and stirring at room temperature to obtain a mixture; dissolving the compound C obtained in the step (1) in N, N-dimethylformamide, dropwise adding the N-dimethylformamide into the mixture in ice bath, and stirring for reaction to obtain a compound D;
(3) And (3) mixing the compound D obtained in the step (2) with 2-methyliisonicotinic acid, N-dimethylformamide and a catalyst, and stirring for reaction to obtain a compound I.
Further, the catalyst in the step (1) is glacial acetic acid, the adding molar ratio of the compound A to the compound B is 1:1, and the adding ratio of the compound A to the absolute ethyl alcohol is 1g:10-20mL.
Further, the addition mole ratio of the compound C to phosphorus oxychloride and N, N-dimethylformamide in the Vilsmeier-Haack reagent in the step (2) is 1:5:10;
when the compound C is dissolved in N, N-dimethylformamide, the adding ratio of the compound C to the N, N-dimethylformamide is 1g:10mL.
Further, the catalyst in the step (3) is trimethylchlorosilane;
the addition molar ratio of the compound D to the 2-methylisonicotinic acid is 1:1.
The third purpose of the invention is realized by adopting the following technical scheme:
use of pyrazole-vinyl-isonicotinic acid derivatives for the preparation of a medicament for inhibiting KDM 5B.
Further, the derivative is used for preparing medicines for treating tumors with high KDM5B expression.
Further, the tumor is gastric cancer, breast cancer or prostate cancer.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides a pyrazole-vinyl-isonicotinic acid derivative which has obvious biological inhibition activity on KDM5B, can be used for preparing and researching and developing a novel KDM5B inhibitor, enriches the variety of isonicotinic acid derivatives, and lays a foundation for developing a drug for inhibiting KDM 5B. The invention takes basic compounds such as aromatic ring aldehydes and the like as raw materials, and is prepared by nucleophilic addition-elimination, vilsmeier-Haack reaction and Knoevenagel condensation reaction, and the preparation method is simple, mild in condition and high in yield. The compound has nanomolar inhibition on KDM5B on enzyme level, provides a lead compound structure for further researching anti-cancer drugs for inhibiting KDM5B, and has better application prospect.
Detailed Description
The present invention will be further described with reference to the following specific embodiments, and it should be noted that, on the premise of no conflict, new embodiments may be formed by any combination of the embodiments or technical features described below.
Example 1
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-1, wherein R 1 Is that
R 2 Is->
The preparation process is as follows:
(1) Benzaldehyde (compound A,1g,8.32 mmol) is taken in a 50mL flask, 20mL of absolute ethyl alcohol is added, phenylhydrazine (compound B,900.07mg,8.32 mmol) and glacial acetic acid (0.05 mL, equivalent weight is 0.05) are added, and reflux reaction is carried out for 1h under stirring at room temperature; after the reaction, most of the organic solvent was removed by rotary evaporation under reduced pressure, a large amount of solid was precipitated by slow cooling, and the mixture was suction-filtered to obtain (E) -1-phenyl-2- (1-phenylethynyl) hydrazine (compound C,1.2g,5.71 mmol) as a white solid, with a yield of 68%. Because the product is unstable, it needs to be rapidly taken to the next step.
(2) First, vilsmeier-Haack reagent was prepared: preparation N, N-dimethylformamide (4.17 g,57.07 mmol) was weighed into a 100mL flask, phosphorus oxychloride (4.37 g,28.53 mmol) was added dropwise under ice bath and stirred at room temperature for 40min (molar ratio of addition of compound C to phosphorus oxychloride to N, N-dimethylformamide was 1:5:10). Then, compound C (1.2 g,5.71 mmol) obtained in the step (1) is weighed and dissolved in 5mL of N, N-dimethylformamide, the obtained compound C is dropwise added into the prepared Vilsmeier-Haack reagent in an ice bath, the reaction is carried out for 5H under the condition of stirring at 85 ℃, 200mL of ice water is added after the TLC monitoring reaction is finished, KOH alkaline aqueous solution is added to adjust the pH to be neutral (pH is 6-7), and white solid 1, 3-diphenyl-1H-pyrazole-4-carboxylic acid (compound D,994mg,3.99 mmol) is obtained through full ultrasonic filtration and suction filtration, and the yield is 70%.
Analytical data for the product are as follows: 1 H NMR(600MHz,DMSO-d 6 ,ppm)δ12.55(s,1H,-COOH),9.07(s,1H,Ar-H),8.02–7.95(m,2H,Ar-H),7.87–7.80(m,2H,Ar-H),7.54(t,J＝8.0Hz,2H,Ar-H),7.48–7.41(m,3H,Ar-H),7.39(t,J＝7.4Hz,1H,Ar-H).
(3) 1, 3-diphenyl-1H-pyrazole-4-carboxylic acid (compound D,900mg,3.68 mmol) prepared in the step (2), 2-methyliisonicotinic acid (497.11 mg,3.68 mmol), trimethylchlorosilane (3 mL, equivalent of 0.05) solvent N, N-dimethylformamide (15 mL) were added to the Schlenk tube and mixed, stirred at 120℃for 24 hours, after completion of the TCL monitoring reaction, water was added first for 100-200mL, followed by ultrasonic filtration, suction filtration and drying to obtain a crude product, which was separated by silica gel column chromatography, and dichloromethane/methanol (V: V=10:1) was eluted to obtain compound I-1 (1.04 g,2.87 mmol) ((E) -2- (2- (1, 3-diphenyl-1H-pyrazol-4-yl) vinyl) isonicotinic acid) as a yellow solid in 78% yield.
1 H NMR(600MHz,DMSO-d 6 ,ppm)δ13.67(s,1H,-COOH),9.12(s,1H,Ar-H),8.73(d,J＝4.7Hz,1H,Ar-H),7.95(d,J＝7.8Hz,2H,Ar-H),7.79(s,1H,Ar-H),7.71(s,1H,Ar-H),7.68(d,J＝16.7Hz,2H,Ar-H),7.70(d,J＝15.9Hz,1H,-CH＝C-),7.68(d,J＝16.7Hz,2H,Ar-H),7.64(d,J＝4.5Hz,1H,Ar-H),7.57(dd,J＝11.4,7.2Hz,4H,Ar-H),7.49(t,J＝7.3Hz,1H,Ar-H),7.38(t,J＝7.3Hz,1H,Ar-H),7.33(d,J＝15.9Hz,1H,-CH＝C-) 13 C NMR(100MHz,DMSO-d 6 ,ppm)δ166.16,156.09,151.43,150.60,139.19,138.91,132.56,129.61,128.78,128.35,128.25,127.46,126.84,126.68,122.83,120.81,120.75,118.96,118.45.
Example 2
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-2, wherein R 1 Is that
R 2 Is that
The preparation process is as follows:
this embodiment differs from embodiment 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 4-pyridinecarboxaldehyde to give compound (E) -2- (2- (1-phenyl-3- (pyridin-4-yl) -1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 64% yield.
1 H NMR(400MHz,DMSO-d 6 ,ppm)δ9.23(s,1H,Ar-H),8.85(d,J＝6.3Hz,2H,Ar-H),8.77(d,J＝4.9Hz,1H,Ar-H),8.00(s,1H,Ar-H),7.98(s,1H,Ar-H),7.97(s,1H,Ar-H),7.96(s,1H,Ar-H),7.89(s,1H,Ar-H),7.77(d,J＝15.9Hz,1H,-C＝CH-),7.68(dd,J＝4.9,1.4Hz,1H,Ar-H),7.60(t,J＝8.0Hz,2H,Ar-H),7.46–7.39(m,1H,-C＝CH-,1H,Ar-H). 13 C NMR(100MHz,DMSO-d 6 )δ166.58,156.23,151.02,147.78,147.68,143.51,139.56,139.34,130.19,129.68,128.56,127.84,123.72,122.30,121.68,121.57,120.80,119.27,34.46.
Example 3
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-3, wherein R 1 Is that
R 2 Is that
The preparation process is as follows:
this embodiment differs from embodiment 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 3-pyridinecarboxaldehyde to give compound (E) -2- (2- (1-phenyl-3- (pyridin-3-yl) -1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 68% yield.
1 H NMR(600MHz,DMSO-d 6 ,ppm)δ9.21(s,1H,Ar-H),9.04(s,1H,Ar-H),8.80(d,J＝4.6Hz,1H,Ar-H),8.75(d,J＝4.8Hz,1H,Ar-H),8.40(d,J＝7.5Hz,1H,Ar-H),7.98(d,J＝7.9Hz,2H,Ar-H),7.89(s,1H,Ar-H),7.85–7.79(m,1H,Ar-H),7.70(d,J＝16.1Hz,1H,-CH＝C-),7.68(d,J＝5.0Hz,1H,Ar-H),7.59(t,J＝7.8Hz,2H,Ar-H),7.41(t,J＝7.3Hz,1H,Ar-H),7.37(d,J＝15.9Hz,1H,-CH＝C-). 13 C NMR(100MHz,DMSO-d 6 ,ppm)δ166.45,155.98,150.38,147.48,146.18,145.45,139.98,139.38,130.39,130.17,128.39,128.18,127.66,126.06,123.09,121.69,120.08,119.15.
Example 4
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-4, wherein R 1 Is that
R 2 Is that
The preparation process is as follows:
this embodiment differs from embodiment 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 4-methylbenzaldehyde to give compound (E) -2- (2- (1-phenyl-3- (tolyl) -1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 63% yield.
1 H NMR(600MHz,DMSO-d 6 ,ppm)δ13.71(s,1H,-COOH),9.11(s,1H,Ar-H),8.73(d,J＝4.9Hz,1H,Ar-H),7.94(d,J＝8.0Hz,2H,Ar-H),7.82(s,1H,Ar-H),7.69(d,J＝16.0Hz,1H,-CH＝C-),7.66(d,J＝4.9Hz,1H,Ar-H),7.57(dd,J＝18.5,7.9Hz,4H,Ar-H),7.37(t,J＝7.3Hz,3H,Ar-H),7.32(d,J＝15.9Hz,1H,-CH＝C-),2.40(s,3H,-CH 3 ). 13 C NMR(100MHz,DMSO-d 6 ,ppm)δ165.93,155.63,151.56,149.78,139.57,139.18,137.81,129.61,129.35,128.17,126.93,126.66,126.37,123.92,121.04,120.98,118.79,118.44,20.86.
Example 5
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-5, wherein R 1 Is that
R 2 Is->
The preparation process is as follows:
this embodiment differs from embodiment 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 2-fluorobenzaldehyde to give compound (E) -2- (2- (3- (2-fluorophenyl) -1-phenyl-1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 71% yield.
1 H NMR(600MHz,DMSO-d 6 ,ppm)δ13.65(s,1H,-COOH),9.17(s,1H,Ar-H),8.67(d,J＝4.9Hz,1H,Ar-H),7.91(d,J＝7.7Hz,2H,Ar-H),7.71(s,1H,Ar-H),7.69–7.64(m,1H,Ar-H),7.62(dd,J＝4.9,1.3Hz,1H,Ar-H),7.57(t,J＝8.0Hz,2H,Ar-H),7.40(t,J＝7.4Hz,1H,Ar-H),7.37–7.31(m,1H,-C＝CH-,1H,Ar-H),7.16(d,J＝16.0Hz,1H,-C＝CH-). 13 C NMR(100MHz,DMSO-d 6 )δ166.70,160.65(dd,J＝248.6,6.7Hz),156.21,151.04,141.02,139.83,139.50,132.43(t,J＝10.2Hz),130.20,127.71,127.53,127.20,122.38,121.58,121.50,121.29,119.05,112.67(d,J＝13.2Hz),112.60,112.54,110.16(t,J＝20.0Hz).
Example 6
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-6, wherein R 1 Is that
R 2 Is that
Its preparation process is as followsThe following steps:
this embodiment differs from embodiment 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 3-fluorobenzaldehyde to give compound (E) -2- (2- (3- (3-fluorophenyl) -1-phenyl-1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 61% yield.
1 H NMR(400MHz,DMSO-d 6 ,ppm)δ9.16(s,1H),8.68(d,J＝4.9Hz,1H),7.94(d,J＝7.7Hz,2H),7.74(s,1H),7.67–7.62(m,2H),7.58(t,J＝8.0Hz,3H),7.46(d,J＝9.9Hz,1H),7.44–7.42(m,1H),7.42–7.36(m,2H),7.24(d,J＝16.0Hz,1H). 13 C NMR(101MHz,DMSO-d 6 )δ166.93,159.92(d,J＝246.9Hz),156.32,150.93,147.22,139.62,132.32,132.29,131.56(d,J＝8.1Hz),130.15,127.61,127.34,126.98,125.32(d,J＝3.4Hz),122.92(d,J＝3.5Hz),121.45,121.27,120.76(t,J＝7.5Hz),119.00,116.70,116.48.
Example 7
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-7, wherein R 1 Is that
R 2 Is that
The preparation process is as follows:
this embodiment differs from embodiment 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 4-fluorobenzaldehyde to give compound (E) -2- (2- (3- (4-fluorophenyl) -1-phenyl-1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 65% yield.
1 H NMR(600MHz,DMSO--d 6 ,ppm)δ13.69(s,1H，-COOH),9.11(s,1H,Ar-H),8.72(d,J＝4.9Hz,1H,Ar-H),7.95(s,1H,Ar-H),7.94(s,1H,Ar-H),7.79(s,1H,Ar-H),7.74(q,J＝8.4,5.6Hz,2H,Ar-H),7.65(d,J＝8.4Hz,1H,Ar-H),7.63(s,1H,Ar-H),7.57(t,J＝7.9Hz,2H,Ar-H),7.41(d,J＝8.8Hz,1H,-CH＝C-),7.38(q,J＝8.9,5.4Hz,2H,Ar-H),7.32(d,J＝15.9Hz,1H,-CH＝C-). 13 C NMR(150MHz,DMSO-d 6 ,ppm)δ166.16,162.95,161.33,155.94,150.47,150.36,139.09,130.26,130.20,129.55,128.99,128.97,127.69,126.89,126.66,122.49,120.82,120.70,118.87,118.40,115.77,115.63.
Example 8
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-8, wherein R 1 Is that
R 2 Is that
The preparation process is as follows:
this embodiment differs from embodiment 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 4-chlorobenzaldehyde to give compound (E) -2- (2- (3- (4-chlorophenyl) -1-phenyl-1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 65% yield.
1 H NMR(600MHz,DMSO-d 6 ,ppm)δ13.66(s,1H,-COOH),9.14(s,1H,Ar-H),8.74(s,1H,Ar-H),8.50(s,1H,Ar-H),7.95(d,J＝7.1Hz,2H,Ar-H),7.81(s,1H,Ar-H),7.73(d,J＝7.2Hz,2H,Ar-H),7.64(m,1H-CH＝C-1H and Ar-H 2H),7.57(s,2H,Ar-H),7.39(s,1H,Ar-H),7.34(d,J＝15.9Hz,1H,-CH＝C-). 13 C NMR(100MHz,DMSO-d 6 ,ppm)δ166.64,156.49,151.08,150.60,139.58,139.43,133.65,131.88,130.40,130.14,129.39,128.34,127.63,127.31,122.99,121.42,121.35,119.54,118.98.
Example 9
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-9, wherein R 1 Is that
R 2 Is that
The preparation process is as follows:
this embodiment differs from embodiment 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 4-bromobenzaldehyde to give compound (E) -2- (2- (3- (4-bromophenyl) -1-phenyl-1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 77% yield.
1 H NMR(600MHz,DMSO-d 6 ,ppm)δ9.12(s,1H),Ar-H,8.71(d,J＝4.4Hz,1H,Ar-H),7.95(d,J＝7.7Hz,2H,Ar-H),7.81(s,1H,Ar-H),7.76(d,J＝8.0Hz,2H,Ar-H),7.70–7.61(m,4H),7.57(t,J＝7.5Hz,2H,Ar-H),7.38(t,J＝7.1Hz,1H,Ar-H),7.32(d,J＝15.9Hz,1H,-CH＝C-). 13 C NMR(100MHz,DMSO-d 6 ,ppm)δ167.01,156.33,150.92,150.62,140.66,139.59,132.30,132.26,130.67,130.13,128.54,127.56,127.29,122.74,122.28,121.53,121.43,119.57,118.98.
Example 10
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-10, wherein R 1 Is that
R 2 Is that
The preparation process is as follows:
this embodiment differs from embodiment 1 in that: the 4-methoxybenzaldehyde of example 1, step (1), gave the compound (E) -2- (2- (3- (4-methoxyphenyl) -1-phenyl-1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 66% yield.
1 H NMR(600MHz,DMSO-d 6 ,ppm)δ13.65(s,1H,-COOH),9.09(s,1H,Ar-H),8.72(d,J＝4.9Hz,1H,Ar-H),7.93(d,J＝7.9Hz,2H,Ar-H),7.78(s,1H,Ar-H),7.66(d,J＝15.9Hz,1H,-CH＝C-),7.63(d,J＝2.5Hz,2H,Ar-H),7.62(s,1H,Ar-H),7.56(t,J＝7.9Hz,2H,Ar-H),7.36(t,J＝7.4Hz,1H,Ar-H),7.31(d,J＝15.9Hz,1H,-CH＝C-),7.12(d,J＝8.6Hz,2H,Ar-H),3.84(s,3H,-OCH 3 ). 13 C NMR(100MHz,DMSO-d 6 ,ppm)δ166.69,159.91,156.64,151.80,151.08,139.71,139.45,130.09,130.01,127.71,127.17,127.03,125.40,123.51,121.27,121.22,119.23,118.84,114.74,55.70.
Example 11
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-11, wherein R 1 Is that
R 2 Is that
The preparation process is as follows:
this embodiment differs from embodiment 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 4-nitrobenzaldehyde to give compound (E) -2- (2- (3- (4-nitrophenyl) -1-phenyl-1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 78% yield.
1 H NMR(600MHz,DMSO-d 6 ,ppm)δ9.20(s,1H,Ar-H),8.71(d,J＝4.1Hz,1H,Ar-H),8.41(d,J＝8.4Hz,2H,Ar-H),8.01(d,J＝8.4Hz,2H,Ar-H),7.98(d,J＝7.9Hz,2H,Ar-H),7.85(s,1H,Ar-H),7.69(d,J＝16.0Hz,1H,-CH＝C-),7.66(d,J＝4.3Hz,1H,Ar-H),7.59(t,J＝7.6Hz,2H,Ar-H),7.41(t,J＝7.3Hz,1H,Ar-H),7.37(d,J＝15.9Hz,1H,-CH＝C-). 13 C NMR(100MHz,DMSO-d 6 ,ppm)δ155.61,150.32,148.90,147.04,139.06,138.97,129.67,129.07,128.96,127.60,127.11,124.10,121.68,121.25,121.07,119.78,118.66.
Example 12
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-12, wherein R 1 Is that
R 2 Is that
The preparation process is as follows: />
This embodiment differs from embodiment 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 1-methyl-4 (methylsulfonyl) benzaldehyde to give compound (E) -2- (2- (3- (4- (methylsulfonyl) phenyl) -1-phenyl-1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 69% yield.
1 H NMR(600MHz,DMSO-d 6 ,ppm)δ9.20(s,1H,Ar-H),8.76(d,J＝4.2Hz,1H,Ar-H),8.11(d,J＝7.6Hz,2H,Ar-H),8.01(d,J＝7.7Hz,2H,Ar-H),7.98(d,J＝7.5Hz,2H,Ar-H),7.94(s,1H,Ar-H),7.77(d,J＝15.9Hz,1H,-CH＝C-),7.72(d,J＝3.2Hz,1H,Ar-H),7.59(t,J＝6.8Hz,2H,Ar-H),7.42(s,1H,Ar-H),7.40(d,J＝10.0Hz,1H,-CH＝C-),3.31(s,3H,-CH 3 ). 13 C NMR(100MHz,DMSO-d 6 ,ppm)δ166.23,155.48,150.14,149.58,140.83,140.70,139.45,137.80,130.17,129.42,128.19,128.06,127.60,127.17,124.43,122.10,121.90,119.83,119.16,44.01.
Example 13
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-13, wherein R 1 Is that
R 2 Is->
The preparation process is as follows:
this embodiment differs from embodiment 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 4-phenylbenzaldehyde to give compound (E) -2- (2- (3- ([ 1,1' -diphenyl ] -4-yl) -1-phenyl-1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 59% yield.
1 H NMR(400MHz,DMSO-d 6 ,ppm)δ9.16(s,1H),8.75(d,J＝4.9Hz,1H),7.98(d,J＝8.0Hz,2H),7.90(s,1H),7.87(d,J＝8.2Hz,2H),7.84–7.76(m,5H),7.70(d,J＝4.5Hz,1H),7.58(t,J＝7.7Hz,2H),7.51(t,J＝7.5Hz,2H),7.44–7.36(m,3H). 13 C NMR(100MHz,DMSO-d 6 )δ165.93,155.57,151.01,149.76,140.00,139.64,139.48,139.15,131.56,129.64,129.00,128.74,127.68,127.13,127.03,126.78,126.66,123.84,121.19,121.07,119.02,118.50.
Example 14
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-14, wherein R 1 Is that
R 2 Is->
The preparation process is as follows:
this embodiment differs from embodiment 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 1- (benzyloxy) -4-methylbenzaldehyde to give compound (E) -2- (2- (3- (4- (benzyloxy) phenyl) -1-phenyl-1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 62% yield.
1 H NMR(600MHz,DMSO-d 6 ,ppm)δ9.10(s,1H,Ar-H),8.75(d,J＝4.4Hz,1H,Ar-H),7.94(d,J＝7.6Hz,2H,Ar-H),7.90(s,1H,Ar-H),7.73(d,J＝16.2Hz,1H,-CH＝C-and 1H,Ar-H),7.64(d,J＝7.9Hz,2H,Ar-H),7.56(t,J＝7.2Hz,2H,Ar-H),7.50(d,J＝7.0Hz,2H,Ar-H),7.42(t,J＝7.1Hz,2H,Ar-H),7.40–7.35(m,2H,Ar-H),7.33(d,J＝16.1Hz,1H,-CH＝C-),7.20(d,J＝8.0Hz,2H,Ar-H),5.20(s,2H,-CH 2 -). 13 C NMR(100MHz,DMSO-d 6 ,ppm)δ166.01,159.08,155.12,151.95,148.60,141.44,139.60,137.41,130.11,128.94,128.37,128.22,127.70,127.20,126.41,125.41,124.90,122.30,121.88,118.99,118.93,115.60,69.79.
Example 15
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-15, wherein R 1 Is that
R 2 Is that
The preparation process is as follows:
this embodiment differs from embodiment 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 2, 4-difluorobenzaldehyde to give compound (E) -2- (2- (3- (2, 4-difluorophenyl) -1-phenyl-1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 64% yield.
1 H NMR(400MHz,DMSO-d 6 ,ppm)δ9.15(s,1H,Ar-H),8.66(d,J＝4.9Hz,1H,Ar-H),7.94(s,1H,Ar-H),7.92(s,1H,Ar-H),7.75(s,1H,Ar-H),7.69(td,J＝8.5,6.7Hz,1H,Ar-H),7.62(dd,J＝4.9,1.4Hz,1H,Ar-H),7.57(t,J＝8.0Hz,2H,Ar-H),7.54–7.48(m,1H,Ar-H),7.45–7.36(m,1H,-C＝CH-,1H,Ar-H),7.29(td,J＝8.4,2.1Hz,1H),7.22(d,J＝16.0Hz,1H,-C＝CH-). 13 C NMR(100MHz,DMSO-d 6 )δ167.22,162.89(dd,J＝304.0,12.3Hz),160.42(dd,J＝305.3,12.3Hz),161.38(d,J＝12.6Hz),158.90(d,J＝12.5Hz),156.18,150.79,146.34,141.47,139.59,133.50(dd,J＝9.9,4.6Hz),130.15,127.91,127.37,127.07,122.56(d,J＝3.0Hz),121.57,121.37,120.78,119.02,117.40(q,J＝15.3,3.7Hz),112.64(dd,J＝21.4,3.5Hz),105.17(t,J＝26.1Hz).
Example 16
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-16, wherein R 1 Is that
R 2 Is that
The preparation process is as follows:
this embodiment differs from embodiment 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 2, 5-difluorobenzaldehyde to give compound (E) -2- (2- (3- (2, 6-difluorophenyl) -1-phenyl-1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 72% yield.
1 H NMR(600MHz,DMSO-d 6 ,ppm)δ13.72(s,1H,-COOH),9.13(s,1H,Ar-H),8.73(d,J＝4.9Hz,1H,Ar-H),7.96(d,J＝7.7Hz,2H,Ar-H),7.81(s,1H,Ar-H),7.68(d,J＝15.9Hz,1H,-C＝CH-),7.65(dd,J＝4.9,1.3Hz,1H,Ar-H),7.64–7.59(m,1H,Ar-H),7.57(t,J＝8.0Hz,2H,Ar-H),7.55(d,J＝7.7Hz,1H,-C＝CH-),7.53–7.50(m,1H,Ar-H),7.39(t,J＝7.4Hz,1H,Ar-H),7.34(d,J＝4.5Hz,1H,Ar-H),7.33–7.31(m,1H,Ar-H). 13 C NMR(101MHz,DMSO-d 6 )δ166.84,162.77(d,J＝243.8Hz)156.40,151.01,150.43,150.41,140.11,139.58,135.38(d,J＝8.2Hz),131.39(d,J＝8.5Hz),130.12,128.54,127.58,127.34,124.84(d,J＝2.6Hz),122.78,121.48,121.40,119.64,119.03,115.67(d,J＝21.0Hz),115.19(d,J＝22.3Hz).
Example 17
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-17, wherein R 1 Is that
R 2 Is that
The preparation process is as follows:
this embodiment differs from embodiment 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to biphenyl formaldehyde to give compound (E) -2- (2- (3- (naphthalen-2-yl) -1-phenyl-1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 65% yield.
1 H NMR(600MHz,DMSO-d 6 ,ppm)δ9.18(s,1H,Ar-H),8.69(d,J＝4.5Hz,1H,Ar-H),8.24(s,1H,Ar-H),8.10(d,J＝8.4Hz,1H,Ar-H),8.06(s,1H,Ar-H),8.00(d,J＝8.4Hz,3H,Ar-H),7.87(d,J＝8.2Hz,1H,Ar-H),7.80(s,1H,Ar-H),7.76(d,J＝16.0Hz,1H,-C＝CH-),7.63(d,J＝4.6Hz,1H,Ar-H),7.59(t,J＝7.2Hz,4H,Ar-H),7.42–7.38(m,1H,Ar-H),7.36(d,J＝15.9Hz,1H,-C＝CH-). 13 C NMR(101MHz,DMSO-d 6 )δ166.88,156.49,151.83,150.96,139.71,133.42,133.08,130.60,130.13,128.80,128.71,128.27,128.15,127.72,127.48,127.21,127.10,127.05,126.69,123.21,121.42,121.36,119.81,118.98,60.23,56.50,21.22,19.02,14.54.
Example 18
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-18, wherein R 1 Is that
R 2 Is that
The preparation process is as follows:
this embodiment differs from embodiment 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-carbaldehyde to give compound (E) -2- (2- (3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -1-phenyl-1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 77% yield.
1 H NMR(600MHz,DMSO-d 6 ,ppm)δ13.75(s,1H,-COOH),9.07(s,1H,Ar-H),8.73(d,J＝4.5Hz,1H,Ar-H),7.93(d,J＝7.8Hz,2H,Ar-H),7.78(s,1H,Ar-H),7.65(m,1H,-CH＝C-,1H,Ar-H),7.56(t,J＝7.6Hz,2H,Ar-H),7.36(t,J＝7.2Hz,1H,Ar-H),7.31(d,J＝15.9Hz,1H,-CH＝C-),7.16(d,J＝8.0Hz,2H,Ar-H),7.03(d,J＝7.9Hz,1H,Ar-H),4.32(s,4H,-CH 2 ). 13 C NMR(100MHz,DMSO-d 6 ,ppm)δ166.76,156.55,151.41,151.06,144.24,143.94,139.79,139.68,130.09,127.87,127.19,127.07,126.21,123.31,121.77,121.33,119.26,118.86,117.94,117.16,64.67,64.62.
Example 19
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-19, wherein R 1 Is that
R 2 Is that
The preparation process is as follows:
this embodiment differs from embodiment 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 4-fluorobenzaldehyde and phenylhydrazine was adjusted to 4-fluorobenzylhydrazine to give the compound (E) -2- (2- (1, 3-bis (4-fluorophenyl) -1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 64% yield.
1 H NMR(600MHz,DMSO-d 6 ,ppm)δ13.69(s,1H,-COOH),9.10(s,1H,Ar-H),8.72(d,J＝4.7Hz,1H,Ar-H),7.98(q,J＝8.4,4.5Hz,2H,Ar-H),7.79(s,1H,Ar-H),7.76–7.70(m,2H,Ar-H),7.65(s,1H,Ar-H),7.63(d,J＝9.8Hz,1H,-CH＝C-),7.48–7.35(m,4H,Ar-H),7.30(d,J＝15.9Hz,1H,-CH＝C-). 13 C NMR(100MHz,DMSO-d 6 ,ppm)δ166.27,162.57(d,J＝170.6Hz),160.98,159.30,155.96,150.48(d,J＝9.2Hz),139.31,135.74(d,J＝2.5Hz),130.32,130.24,128.94(d,J＝3.1Hz),127.76,127.15,122.48,120.90,120.78,120.55,120.46,118.95,116.48,116.25,115.87,115.66.
Example 20
Pyrazole-vinyl-isonicotinic acid derivative, and preparation method thereofI-20 wherein R 1 Is that
R 2 Is that
The preparation process is as follows:
this embodiment differs from embodiment 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 4-fluorobenzaldehyde and phenylhydrazine was adjusted to 4-chlorophenylhydrazine to give compound (E) -2- (2- (1- (4-chlorophenyl) -3- (4-fluorophenyl) -1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 69% yield.
1 H NMR(600MHz,DMSO-d 6 ,ppm)δ13.72(s,1H),9.14(s,1H),8.72(d,J＝4.7Hz,1H),7.97(d,J＝8.7Hz,2H),7.80(s,1H),7.77–7.71(m,2H),7.67–7.60(m,4H),7.40(t,J＝8.7Hz,2H),7.31(d,J＝15.9Hz,1H). 13 C NMR(100MHz,DMSO-d 6 ,ppm)δ166.71,163.96,161.51,156.42,151.15,151.05,139.64,138.42,131.26,130.83,130.75,130.02,129.33,129.30,128.41,127.55,122.86,121.43,121.31,120.47,119.70,116.38,116.16.
Example 21
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-21, wherein R 1 Is that
R 2 Is that
The preparation process is as follows: />
This embodiment differs from embodiment 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 4-fluorobenzaldehyde and phenylhydrazine was adjusted to 4-bromophenylhydrazine to give compound (E) -2- (2- (1- (4-bromophenyl) -3- (4-fluorophenyl) -1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 75% yield.
1 H NMR(600MHz,DMSO-d 6 ,ppm)δ9.14(s,1H,Ar-H),8.69(d,J＝4.3Hz,1H,Ar-H),7.91(d,J＝8.4Hz,2H,Ar-H),7.79(s,1H,Ar-H),7.78–7.70(m,4H,Ar-H),7.63(s,1H,Ar-H),7.61(d,J＝15.8Hz,1H,-CH＝C-),7.39(t,J＝8.5Hz,2H,Ar-H),7.29(d,J＝15.8Hz,1H,-CH＝C-). 13 C NMR(100MHz,DMSO-d 6 ,ppm)δ167.14,163.95,161.51,156.21,151.15,150.85,141.12,138.82,132.92,130.83,130.74,129.34,129.31,128.64,127.47,122.57,121.58,121.44,120.76,119.78,119.49,116.38,116.17.
Example 22
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-22, wherein R 1 Is that
R 2 Is that
The preparation process is as follows:
this embodiment differs from embodiment 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 4-fluorobenzaldehyde and phenylhydrazine was adjusted to 4-methoxyphenylhydrazine to give compound (E) -2- (2- (3- (4-fluorophenyl) -1- (4-methoxyphenyl) -1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 67% yield.
1 H NMR(600MHz,DMSO-d6,ppm)δ8.98(s,1H,Ar-H),8.60(d,J＝3.9Hz,1H,Ar-H),7.85(d,J＝8.4Hz,2H,Ar-H),7.78(s,1H,Ar-H),7.71(d,J＝5.8Hz,2H,Ar-H),7.61(d,J＝3.8Hz,1H,Ar-H),7.58(d,J＝16.1Hz,1H,-C＝CH-),7.38(t,J＝8.4Hz,2H,Ar-H),7.24(d,J＝15.9Hz,1H,-C＝CH-),7.11(d,J＝8.4Hz,2H,Ar-H),3.82(s,3H,-CH3). 13 C NMR(100MHz,DMSO-d6,ppm)δ163.81,161.37,158.45,155.99,150.40,150.36,133.31,130.77,130.69,129.74,129.71,128.44,127.06,122.39,121.76,121.61,120.52,119.11,116.33,116.12,115.15,55.95.
Experimental example 1
KDM5B inhibition Activity assay
Detection of 1.1KDM5B Activity inhibition
(1) 1 XAssaybuffer is configured.
(2) Concentration gradient configuration of the compound: the initial concentration of the test compound was 25 μm, diluted 3-fold, and divided into 10 concentrations, each concentration being a single well test. The initial concentration of the positive control compound CPI-455 test was 1. Mu.M, diluted 3-fold, and equally divided into 10 concentrations, each concentration was set up for the multiplex well test. The solution was diluted to a corresponding 1000-fold final concentration in 384-well Source plates and then transferred with Echo550 to the 384-well reaction plates for assay. Min and Max wells were shifted to 10nL of 100% DMSO.
(3) A2 Xenzyme solution was prepared from the 1 Xreaction solution.
(4) A2X substrate mixed solution was prepared from the 1X reaction solution.
(5) Add 5. Mu.L of 2 Xenzyme solution to each well; mu.L of 1 Xreaction solution was added to Min wells, centrifuged at 1000rpm for 1Min and incubated at room temperature for 15 Min.
(6) mu.L of the 2 Xsubstrate mixed solution was added to each well of the reaction plate, and the reaction was initiated, centrifuged at 1000rpm for 1min and incubated at room temperature for 30min.
(7) mu.L of the detection solution was added to each well, centrifuged at 1000rpm for 1min, and incubated at room temperature for 60 min.
(8) Signal Intiness (665 nm)/Intiness (615 nm) was read using EnVision.
The data analysis was performed according to the following formula:
fitting dose-response curve: the X axis is the log value of the concentration, the Y axis is the percent inhibition rate, and the analysis software GraphPad Prism5 log (inhibitor) vs. response-Variable slope fit quantitative response curve is adopted, so that the IC of the compound on protein binding inhibition is obtained 50 Values.
1.2 experimental results
The experimental results are shown in the following table:
TABLE 1
As can be seen from Table 1, the compounds of the general formula I have a remarkable inhibitory activity on histone demethylase KDM5B, and the compounds I-1, I-3, I-5, I-6, I-7, I-9, I-10, I-19, I-22 have IC 50 <10 mu M of IC in which compounds I-7, I-10 50 Down to nanomolar levels. Surface the compound with the structural general formula I has remarkable inhibition activity on histone demethylase 5B.
The above embodiments are only preferred embodiments of the present invention, and the scope of the present invention is not limited thereto, but any insubstantial changes and substitutions made by those skilled in the art on the basis of the present invention are intended to be within the scope of the present invention as claimed.
Claims (9)
1. A pyrazole-vinyl-isonicotinic acid derivative is characterized by having a structural general formula I
Wherein when R is 1 Selected from phenyl, substituted phenyl,
R in the case of benzodioxin group 2 Selected from phenyl, substituted phenyl;
when R is 1 Selected from the group consisting of
When R is 2 Selected from the group consisting of substitutionA phenyl group;
the substituent of the substituted phenyl is C1-C6 saturated alkyl, C1-C6 saturated alkoxy, halogen, nitro, C1-C6 saturated alkylsulfonyl and phenyl.
2. The pyrazole-vinyl-isonicotinic acid derivative according to claim 1, wherein R 1 Selected from the group consisting of
R 2 Selected from the group consisting of
3. Process for the preparation of pyrazole-vinyl-isonicotinic acid derivatives according to any of claims 1 to 2, characterized in that it comprises the following steps:
(1) Adding absolute ethyl alcohol into the compound A, then adding the compound B and a catalyst into the compound A, and stirring the mixture at room temperature for reaction to obtain a compound C;
(2) First, vilsmeier-Haack reagent was prepared: dropwise adding phosphorus oxychloride into N, N-dimethylformamide under ice bath condition, and stirring at room temperature to obtain a mixture; dissolving the compound C obtained in the step (1) in N, N-dimethylformamide, dropwise adding the N-dimethylformamide into the mixture in ice bath, and stirring for reaction to obtain a compound D;
(3) And (3) mixing the compound D obtained in the step (2) with 2-methyliisonicotinic acid, N-dimethylformamide and a catalyst, and stirring for reaction to obtain a compound I.
4. The method for producing pyrazole-vinyl-isonicotinic acid derivative according to claim 3, wherein the catalyst in the step (1) is glacial acetic acid, the addition molar ratio of the compound A to the compound B is 1:1, and the addition ratio of the compound A to the absolute ethyl alcohol is 1g:10-20mL.
5. The method for producing pyrazole-vinyl-isonicotinic acid derivative according to claim 3, wherein the addition molar ratio of compound C to phosphorus oxychloride, N-dimethylformamide in the Vilsmeier-Haack reagent of step (2) is 1:5:10;
when the compound C is dissolved in N, N-dimethylformamide, the adding ratio of the compound C to the N, N-dimethylformamide is 1g:10mL.
6. The process for the preparation of pyrazole-vinyl-isonicotinic acid derivatives according to claim 3, wherein the catalyst in step (3) is trimethylchlorosilane;
the addition molar ratio of the compound D to the 2-methylisonicotinic acid is 1:1.
7. Use of a pyrazole-vinyl-isonicotinic acid derivative according to any of claims 1 to 2, for the preparation of a medicament for inhibiting KDM 5B.
8. The use according to claim 7, wherein said derivative is used for the preparation of a medicament for the treatment of tumors in which KDM5B is highly expressed.
9. The use of claim 8, wherein the tumor is gastric cancer, breast cancer or prostate cancer.
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