CN112920130A - Triazole compound, preparation method and application thereof in preparation of cancer prevention and treatment drugs - Google Patents
Triazole compound, preparation method and application thereof in preparation of cancer prevention and treatment drugs Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
- C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention provides a compound shown as a formula (I) or a pharmaceutically acceptable salt thereof:
wherein Ar is selected from any one of substituted aromatic ring groups or substituted aromatic heterocyclic groups; r1Any one of H, alkane, aryl, CF3 and alkyl tertiary amine structure; r2Any one of halogen structures such as H, alkane, aryl, CF3, F, Cl, Br and the like; r3And R4Is selected from any one of H, alkane, aryl, cyclic and substituted cyclic structure. The compound or the pharmaceutically acceptable salt thereof has the effect of efficiently and reversibly inhibiting the activity of LSD1 protease, and is expected to relieve the toxic and side effects of the medicine.
Description
Technical Field
The invention belongs to the field of chemical drugs, and particularly relates to a triazole compound, a preparation method and application thereof in preparation of anti-cancer drugs.
Background
Epigenetics is a new subject arising in the post-genome era and is a concept corresponding to genetics. Genetics refers to changes in gene expression levels, such as gene mutations, gene heterozygous losses, microsatellite instability, and the like, caused by changes in gene sequences; epigenetics, on the other hand, is a discipline for studying heritable phenotypic changes resulting from changes in gene expression without changes in genomic DNA sequences, and is a branching discipline of genetics. Major studies in epigenetics include DNA methylation, histone modification, chromatin remodeling, noncoding RNA regulation, genomic imprinting, pseudogenes, RNA splicing, RNA editing, RNA interference, X chromatin inactivation, introns, riboswitches, etc. Epigenetics has led to the recognition that modifications including DNA methylation, histone modification, chromatin remodeling, and non-coding RNA regulation can also record genetic information, and that many epigenetic changes are reversible, and research into epigenetic modifications and regulation has become a hotspot and frontier in life sciences.
Recent studies have found that epigenetics leads to persistent changes in gene expression, which is an important mechanism for disease development. Epigenetics is closely related to the occurrence and development of many diseases, including tumors, diabetes, neuropsychiatric diseases, autoimmune diseases, aging, senile diseases, etc., and has become a hot point of research in recent years. With the continuous and intensive research on epigenetics, human beings have intensively understood the control mechanisms of epigenetics, such as DNA methylation, histone modification, non-coding RNA and chromosome remodeling, and the action mechanism of epigenetics is also proved.
Chemical modification refers to the phenomenon of a change in the covalent structure of a protein or nucleic acid by the introduction or removal of chemical groups. Chemical modification modulation differs from allosteric modulation in that it affects enzyme activity by causing changes in the covalent bonds of enzyme molecules, changes in chemical structure. Chemical modification of an enzyme is catalyzed by another enzyme and is another important means of rapid regulation in vivo. The chemical modification includes phosphorylation and dephosphorylation, acetylation and deacetylation, methylation and demethylation, adenylation and deadenylation, -SH and-S-S-interconversion, etc., wherein phosphorylation and dephosphorylation, methylation and demethylation are the most important and common.
In 2004, the first histone lysine-specific demethylase 1(LSD1) was discovered by the shiver medical institute. The subject group first identified histone methylation as a dynamic equilibrium process, a reversible histone modification. This discovery provides a new idea for the action mechanism of histone modification and the corresponding drug research. LSD1 is a Flavin Adenine Dinucleotide (FAD) -dependent demethylase that specifically removes monomethylated and dimethylated groups at the H3K4 and H3K9 sites. LSD1 is involved in regulating receptor-mediated gene transcription and maintaining chromatin activity and inactivity, so as to regulate the interaction between histone and other proteins and influence the activation, inhibition and chromosome inactivation of gene transcription, and is known as "switch" of gene in deep cell. The functional imbalance of LSD1 can cause the change of a plurality of important life phenomena, which is the first real histone lysine demethylase, so that the realization that histone methylation is a dynamic equilibrium process, the biological processes such as activation and inhibition of gene transcription are dynamically regulated through the interaction of histone methyltransferase and demethylase, the histone methylation is redefined, and a new way is provided for further and deeply researching histone modification and related drugs.
Studies have demonstrated that LSD1 exerts its biological functions not only by demethylation of histones, but also by demethylation of non-histones p53 and Dnmt 1. The biological effects of LSD1 are mainly manifested by regulation of sex hormone receptor-mediated gene transcription, regulation of tumor cell proliferation, apoptosis and metastasis, and regulation of embryonic development, mitosis, etc. The RNA interference technology and the small molecule LSD1 inhibitor are utilized to regulate the expression quantity and activity of LSD1, so that the proliferation, metastasis and invasion of tumor cells can be controlled. Meanwhile, the LSD1 is highly expressed in various tumors and is closely related to breast cancer, prostate cancer, ovarian cancer, bladder cancer, liver cancer, taste cancer, lung cancer, neuroblastoma, leukemia and the like, and an anti-tumor treatment scheme targeting the LSD1 shows higher selectivity and lower toxic and side effects. Therefore, LSD1 may be a new target for epigenetic antitumor drugs.
A number of highly potent inhibitors of LSD1 were developed for the treatment of malignant tumors. However, these inhibitors are basically covalently bound to the drug and will intercalate into the DNA, so the toxic side effects of the drug are greater.
Disclosure of Invention
In view of the above, the present invention provides a triazole compound, a preparation method thereof, and an application thereof in preparing a medicament for preventing and treating cancer, aiming at overcoming the defects in the prior art.
In order to achieve the purpose, the technical scheme of the invention is realized as follows:
a compound of formula (I) or a pharmaceutically acceptable salt thereof:
in the formula (I), Ar is selected from any one of a substituted aromatic ring group or a substituted aromatic heterocyclic group;
R1any one of H, alkane, aryl, CF3 and alkyl tertiary amine structure;
R2any one of halogen structures such as H, alkane, aryl, CF3, F, Cl, Br and the like;
R3and R4Is selected from any one of H, alkane, aryl, cyclic and substituted cyclic structure.
Preferably, the compound is selected from any one of the following compounds 1 to 18:
the invention also provides a preparation method of the compound or the pharmaceutically acceptable salt thereof, and the synthetic route is as follows:
the pharmaceutical composition of the compound and the pharmaceutically acceptable salt thereof comprises one or more pharmaceutically acceptable excipients, and the dosage form of the pharmaceutical composition is any pharmaceutically acceptable dosage form.
The invention also provides application of the compound, the pharmaceutically acceptable salt and the pharmaceutical composition thereof in preparing medicaments for treating and/or preventing cancers.
Preferably, the cancer is a related cancer having an abnormality of histone demethylase (LSD 1).
Preferably, the cancer is breast cancer, prostate cancer, ovarian cancer, bladder cancer, liver cancer, taste cancer, lung cancer, neuroblastoma or leukemia.
The invention also provides application of the compound, the pharmaceutically acceptable salt and the pharmaceutical composition thereof in preparation of reversible LSD1 inhibitors.
Compared with the prior art, the invention has the following advantages:
the compound or the pharmaceutically acceptable salt thereof has the effect of efficiently and reversibly inhibiting the activity of LSD1 protease, and is expected to relieve the toxic and side effects of the medicine.
Detailed Description
Unless defined otherwise, technical terms used in the following examples have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention belongs. The test reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the experimental methods are conventional methods unless otherwise specified.
The invention will be described in detail with reference to the following examples.
Example 1: preparation of Compound 1
The preparation method comprises the following steps:
1) preparation of Compound (1-1):
4-Ethynylbenzoic acid (438mg, 3.00mmol) was dissolved in DMF (15mL), EDCI (863mg, 1.50mmol), HOBt (486mg, 1.20mmol), DIPEA (1.16g, 9.00mmol) N-methylpiperazine (300mg, 3mmol) were added, and the reaction was carried out at room temperature for 8 hours. The reaction mixture was washed with saturated brine, extracted with ethyl acetate, dried and concentrated, and purified by column chromatography (dichloromethane: methanol: 20:1) to give compound 1-1 (white solid, 554mg, 81%).
The results of nuclear magnetic testing of compound 1-1 are:
1HNMR(400MHz,CDCl3)δ7.51(d,J＝8.3Hz,1H),7.35(d,J＝8.3Hz,1H),3.78(s,1H),3.40(s,1H),3.14(s,1H),2.47(s,1H),2.30(s,2H).δ13C NMR(100MHz,CDCl3)δ169.6,136.0,132.3,127.2,123.7,82.9,78.8,55.3,54.8,47.7,42.2.HRMS(ESI)calculated for C14H16N2NaO+:251.1160,found 251.1162.
2) preparation of Compound (1-2)
5-bromo-2-methoxybenzyl alcohol (434mg, 2.00mmol) was added to dry THF (3.50mL), diphenyl phosphorazidate (660mg, 2.4mmol) was added, 1, 8-diazabicycloundecen-7-ene (329. mu.L, 2.20mmol) was slowly added dropwise under ice bath, and after completion, the reaction was allowed to proceed overnight at room temperature. The reaction mixture was washed with 5% diluted hydrochloric acid solution, extracted with ethyl acetate, dried and concentrated, and purified by column chromatography (dichloromethane: methanol: 15:1) to give compound 1-2 (colorless oil, 349mg, 72%).
The results of nuclear magnetic testing of compounds 1-2 are:
1HNMR(400MHz,CDCl3)δ7.50–7.30(m,2H),6.77(d,J＝8.6Hz,1H),4.31(s,2H),3.83(s,3H).13C NMR(100MHz,CDCl3)δ156.6,132.4,132.2,126.1,55.6,49.5.HRMS(ESI)calculated for C8H8BrN3NaO+:263.9748,found 263.9751.
3) preparation of Compound 1
Compound 1-1(228mg, 1.00mmol), compound 1-2(266mg, 1.10mmol) was added to THF (4.00mL), H2Adding CuSO into O (4.00mL) respectively4·5 H2O (12mg, 0.05mmol), sodium ascorbate (20mg, 0.1mmol), reacted at room temperature for 1 h. Reacting the reaction solution with H2Wash with O, extract with ethyl acetate, dry concentrate the organic phase, and purify by column chromatography (dichloromethane: methanol 20:1) to give compound 1 (white solid, 372mg, 79%).
The nuclear magnetic test results for compound 1 were:
1HNMR(400MHz,CDCl3)δ8.09–7.70(m,3H),7.45(d,J＝8.1Hz,1H),7.41(dd,J＝8.8,2.5Hz,1H),7.35–7.28(m,1H),6.80(d,J＝8.7Hz,1H),5.53(s,2H),3.85(s,3H),3.80(s,2H),3.47(s,2H),2.56–2.44(m,4H),2.32(s,3H).13C NMR(100MHz,CDCl3)δ169.8,156.1,146.8,135.1,132.9,132.6,131.9,127.6,125.5,124.9,120.4,112.8,112.5,55.8,55.1,54.6,48.5,47.6,46.0,42.0.HRMS(ESI)
calculated for C22H24BrN5NaO2 +:492.1011,found 492.1013.
example 2: preparation of Compound 2
The preparation method comprises the following steps:
1) preparation of Compound (2-1):
the preparation method comprises the following steps: similar to the production method of the compound 1-1, except that one of the raw materials used is 5- (piperazin-1-yl) pyrimidine, and N-methylpiperazine in the production method of the compound (1-1) was replaced by equimolar amounts.
The results of nuclear magnetic testing of compound 2-1 are:
1H NMR(400MHz,CDCl3)δ8.29(d,J＝4.9Hz,2H),7.52(d,J＝7.9Hz,2H),7.37(d,J＝8.0Hz,2H),6.51(t,J＝4.8Hz,1H),4.03–3.66(m,6H),3.54–3.38(m,2H),3.16(s,1H).13C NMR(100MHz,CDCl3)δ169.8,161.5,157.8,135.8,132.3,127.2,123.8,110.6,82.8,79.0,47.5,44.0,43.5,42.2.HRMS(ESI)calculated for C17H16N4NaO+:315.1222,found 315.1224。
2) preparation of compound 2:
the preparation method comprises the following steps: similar to the preparation method of compound 1, except that one of the starting materials used was compound 2-1, instead of 1-1 in the preparation method of compound 1, equimolar.
The nuclear magnetic test results for compound 2 were:
1H NMR(400MHz,DMSO-d6)δ8.64(s,1H),8.38(dd,J＝4.8,0.7Hz,2H),7.95(d,J＝8.1Hz,2H),7.64–7.46(m,3H),7.38(d,J＝2.5Hz,1H),7.05(d,J＝8.8Hz,1H),6.67(t,J＝4.7Hz,1H),5.59(s,2H),3.82(s,3H),3.74(d,J＝32.0Hz,4H),3.46(s,2H).13C NMR(100MHz,DMSO-d6)δ169.4,161.5,158.5,156.8,146.1,135.5,133.0,132.6,132.3,128.3,126.3,125.6,122.9,114.1,112.2,111.0,56.5,48.5,43.9,43.6,41.9.HRMS(ESI)calculated for C8H8BrN3NaO+:556.1073,found 556.1075.
example 3: preparation of Compound 3
The preparation method comprises the following steps: similar to the production method of compound 1, except that one of the raw materials used is compound 2-1, instead of N-methylpiperazine in the production method of compound (1-1) in equimolar amounts; one of the raw materials used, methoxy dimethyl benzyl alcohol, was substituted equimolar to 5-bromo-2-methoxy benzyl alcohol in the preparation method of compound (1-2).
The nuclear magnetic test results for compound 3 were:
1H NMR(400MHz,CDCl3)δ8.30(d,J＝4.7Hz,2H),7.86(d,J＝8.0Hz,2H),7.73(s,1H),7.47(d,J＝8.0Hz,2H),7.31(td,J＝7.9,1.7Hz,1H),7.20(dd,J＝7.7,1.6Hz,1H),6.89-6.97(m,2H),6.52(t,J＝4.7Hz,1H),6.22(q,J＝7.1Hz,1H),3.82(s,9H),3.51(s,2H),1.97(d,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ170.4,161.6,157.8,156.4,146.3,134.8,132.6,129.8,128.1,127.8,126.9,125.7,121.0,119.5,110.9,110.6,55.6,54.6,47.6,44.1,43.6,42.2,20.4.HRMS(ESI)
calculated for C26H27N7NaO2 +:492.2124,found 492.2127.
example 4: preparation of Compound 4
The preparation method comprises the following steps: similar to the production method of compound 1, except that one of the raw materials used is compound 2-1, instead of N-methylpiperazine in the production method of compound (1-1) in equimolar amounts; one of the raw materials used was 2-methoxybenzyl alcohol, which was equimolar in place of 5-bromo-2-methoxybenzyl alcohol in the preparation method of compound (1-2).
The nuclear magnetic test results for compound 4 were:
1H NMR(400MHz,CDCl3)δ8.35(dt,J＝11.7,5.5Hz,2H),8.01–7.84(m,2H),7.85–7.72(m,1H),7.59–7.44(m,2H),7.46–7.35(m,1H),7.35–7.19(m,1H),6.98(td,J＝12.2,11.7,7.1Hz,2H),6.71–6.49(m,1H),5.63(dd,J＝11.7,6.4Hz,2H),4.09–3.70(m,9H),3.64–3.39(m,2H).13C NMR(100MHz,CDCl3)δ170.4,161.6,157.9,157.3,146.9,134.9,132.5,130.6,130.5,127.9,125.8,122.9,121.1,120.3,110.9,110.6,55.7,49.4,47.7,44.1,43.6,42.3.HRMS(ESI)calculated for C25H25N7NaO2 +:478.1967,found 478.1969.
example 5: preparation of Compound 5
The preparation method comprises the following steps: similar to the production method of compound 1, except that morpholine, which is one of the starting materials, was used in place of N-methylpiperazine in the production method of compound (1-1) in an equimolar amount.
The nuclear magnetic test results for compound 5 were:
1H NMR(400MHz,DMSO-d6)δ8.63(s,1H),7.92(d,J＝8.0Hz,2H),7.54(dd,J＝8.8,2.5Hz,1H),7.47(d,J＝8.2Hz,2H),7.37(d,J＝2.5Hz,1H),7.05(d,J＝8.8Hz,1H),5.58(s,2H),3.81(s,3H),3.60(s,6H),3.36(s,2H).13C NMR(100MHz,DMSO-d6)δ168.8,156.4,145.6,134.8,132.6,132.2,131.9,127.8,125.8,125.1,122.4,113.7,111.8,66.1,56.0,55.0,48.0.HRMS(ESI)calculated for C21H21BrN4NaO3+:479.0695,found 479.0697。
example 6: preparation of Compound 6
The preparation method comprises the following steps: similar to the production method of compound 1, except that one of the raw materials used is compound 2-1, instead of N-methylpiperazine in the production method of compound (1-1) in equimolar amounts; 3-chlorobenzyl alcohol, equimolar to 5-bromo-2-methoxybenzyl alcohol in the preparation process of the compound (1-2).
The nuclear magnetic test results for compound 6 were:
1H NMR(400MHz,CDCl3)δ8.30(d,J＝4.7Hz,2H),7.85(d,J＝8.0Hz,2H),7.77(s,1H),7.47(d,J＝8.1Hz,2H),7.34–7.27(m,2H),7.24–7.03(m,1H),6.53(t,J＝4.7Hz,1H),5.54(s,2H),3.86(d,J＝34.5Hz,6H),3.51(s,2H).13C NMR(100MHz,CDCl3)δ170.2,161.5,157.8,147.5,136.5,135.2,132.0,130.5,129.1,128.1,126.1,125.8,120.1,110.6,53.6,47.6,44.0,43.6,42.2.HRMS(ESI)calculated for C24H22ClN7NaO+:482.1472,found 482.1474。
example 7: preparation of Compound 7
The preparation method comprises the following steps:
1) preparation of Compound (7-1):
methyl 3-bromo-5-iodobenzoate (500mg, 1.47mmol), trimethylethynylsilicon (159mg, 1.62mmol), Pd (PPh)3)2Cl2(227mg, 0.324mmol), CuI (31mg, 0.162mmol), TEA (984mg, 9.72mmol) were added to THF (10mL) and reacted at room temperature for 5h under Ar. The reaction mixture was washed with saturated brine, extracted with ethyl acetate, and the organic phase was concentrated by drying to give compound 7-1 (colorless oil, 352mg, 77%) without further purification.
2) Preparation of Compound (7-2):
compound 7-1(460mg, 1.48mmol) was added to THF (13mL), TBAF (0.12mL, 0.44mmol) was added dropwise, and the reaction was allowed to proceed at room temperature for 1 h. The reaction mixture was washed with water, extracted with ethyl acetate, dried, concentrated and purified by column chromatography (petroleum ether: ethyl acetate 150:1) to give compound 7-2 (colorless oil, 254.75mg, 72%).
The results of nuclear magnetic testing of compound 7-2 are:
1H NMR(400MHz,CDCl3)δ8.12(s,1H),8.05(s,1H),7.77(s,1H),3.91(s,3H),3.17(s,1H).13C NMR(100MHz,CDCl3)δ165.1,138.9,132.9,132.1,131.9,124.4,122.3,81.2,79.7,52.7.HRMS(ESI)calculated for C10H7BrNaO2 +:260.9527,found 260.9529。
3) preparation of Compound (7-3):
compound 7-2(296mg, 1.24mmol) was added to THF/H2To O (12mL/4mL), LiOH (89mg, 3.72mmol) was added under ice-cooling, and the reaction was carried out at room temperature for 3 hours. The reaction mixture was washed with 1N diluted hydrochloric acid solution, extracted with ethyl acetate, and the organic phase was concentrated by drying to give compound 7-3 (pale yellow solid, 248mg, 89%).
The results of nuclear magnetic testing of compound (7-2) were:
1HNMR(400MHz,DMSO-d6)δ13.62(s,1H),8.04(t,J＝1.6Hz,1H),7.96(d,J＝1.6Hz,1H),7.92(s,1H),4.48(s,1H).13C NMR(100MHz,DMSO-d6)δ165.1,138.3,132.8,131.7,124.7,100.0,83.9,81.5.HRMS(ESI)calculated for C9H5BrNaO2 +:246.9371,found 246.9373.
4) preparation of Compound (7-4):
similar to the production method of the compound 1-1, except that one of the starting materials (7-3) used was equimolar in place of the 4-ethynylbenzoic acid in the production method of the compound (1-1); 5- (piperazin-1-yl) pyrimidine, one of the starting materials used, was substituted equimolar to N-methylpiperazine in the preparation method of the compound (1-1).
The results of nuclear magnetic testing of compound (7-4) were:
1HNMR(400MHz,CDCl3)δ8.30(d,J＝4.8Hz,2H),7.66(t,J＝1.7Hz,1H),7.53(t,J＝1.7Hz,1H),7.44(t,J＝1.4Hz,1H),3.84(d,J＝41.6Hz,6H),3.44(s,2H),3.18(s,1H).13C NMR(100MHz,CDCl3)δ167.9,161.5,157.8,137.5,136.0,130.5,129.2,124.5,122.5,110.7,81.2,79.8,47.5,44.0,43.5,42.2.HRMS(ESI)calculated for C17H15BrN4NaO+:393.0327,found 393.0329.
5) preparation of Compound (7-5):
similar to the preparation method of the compound (1-2), except that methoxy dimethyl benzyl alcohol, which is one of the starting materials, was used in place of 5-bromo-2-methoxy benzyl alcohol in the preparation method of the compound (1-2) in an equimolar amount.
The results of nuclear magnetic testing of compounds 7-5 are:
1H NMR(400MHz,CDCl3)δ8.30(d,J＝4.8Hz,2H),7.66(t,J＝1.7Hz,1H),7.53(t,J＝1.7Hz,1H),7.44(t,J＝1.4Hz,1H),3.84(d,J＝41.6Hz,6H),3.44(s,2H),3.18(s,1H).13C NMR(100MHz,CDCl3)δ156.5,129.2,129.1,126.6,120.8,110.6,55.4,55.0,20.2.HRMS(ESI)calculated for C9H11N3NaO+:200.0800,found 200.0802。
6) preparation of compound 7:
similar to the preparation method of the compound 1, except that 7 to 5 of one of the raw materials is used in place of 1 to 2 in the preparation method of the compound 1 in an equimolar manner; one of the starting materials used was 7-4, equimolar instead of 1-1 in the preparation method of compound 1.
The nuclear magnetic test results for compound 7 were:
1H NMR(400MHz,CDCl3)δ8.32(d,J＝4.7Hz,2H),8.04(d,J＝1.7Hz,1H),7.78(d,J＝1.6Hz,1H),7.68(d,J＝1.5Hz,1H),7.48(d,J＝1.7Hz,1H),7.33(dd,J＝8.7,7.0Hz,1H),7.23(dd,J＝7.8,1.8Hz,1H),6.98(t,J＝7.5Hz,1H),6.92(d,J＝8.3Hz,1H),6.55(td,J＝4.8,1.5Hz,1H),6.22(q,J＝7.1Hz,1H),4.01–3.76(m,9H),3.51(s,2H),1.98(d,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ168.8,161.6,157.9,156.6,145.0,138.0,133.5,130.1,129.9,129.2,127.7,127.0,123.2,123.0,121.1,119.8,111.0,110.7,55.7,54.7,47.7,44.1,43.6,42.3,20.4.HRMS(ESI)calculated for C26H26BrN7NaO2 +:570.1229,found570.1231。
example 8: preparation of Compound 8
Compound 7(40mg,0.073mmol), phenylboronic acid (10mg,0.080mmol), Pd (PPh)3)4(8mg,0.0073mmol), sodium carbonate (15mg,0.146mmol) was added to 1, 4-dioxane (1.00mL), H2In O (0.50mL), the mixture is protected by Ar and reacted for 5h at 80 ℃. Reacting the reaction solution with H2Washing with O, extracting with ethyl acetate, drying, concentrating, and purifying by column chromatography (petroleum ether: ethyl acetate: 1:5) to obtain compound 8 (white solid 33mg, 83%).
The nuclear magnetic test results for compound 8 were:
1HNMR(400MHz,CDCl3)δ8.32(d,J＝4.8Hz,2H),8.16(t,J＝1.7Hz,1H),7.80(t,J＝1.6Hz,1H),7.74(s,1H),7.68–7.59(m,2H),7.57(t,J＝1.7Hz,1H),7.51–7.41(m,2H),7.41–7.29(m,2H),7.23(dd,J＝7.6,1.7Hz,1H),6.98(td,J＝7.6,1.0Hz,1H),6.92(dd,J＝8.2,1.0Hz,1H),6.54(t,J＝4.8Hz,1H),6.25(q,J＝7.0Hz,1H),3.92(d,J＝26.7Hz,4H),3.84(s,5H),3.58(s,2H),1.99(d,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ170.3,161.6,157.9,156.5,146.3,142.3,140.0,136.8,132.1,130.0,129.0,128.0,127.3,127.0,125.8,125.1,123.7,121.1,119.6,55.6,54.6,47.7,44.2,43.7,20.45.HRMS(ESI)calculated for C32H31N7NaO2 +:568.2437,found 568.2439。
example 9: preparation of Compound 9
The preparation method comprises the following steps:
1) preparation of Compound (9-1):
2' -hydroxyacetophenone (1.50g, 11.0mmol) was added to dry THF (20mL) and NaBH was added slowly under ice bath4(208mg, 5.50mmol) and reacted at room temperature for 5 h. Adding H to the reaction solution2The reaction was quenched with O (2mL), washed with water, extracted with ethyl acetate, and the organic phase was concentrated by drying to give compound 9-1 (colorless oil, 1.29g, 85%) without further purification.
2) Preparation of Compound (9-2):
compound 9-1(570mg, 4.12mmol), azidotrimethylsilane (713mg, 6.19mmol), copper trifluoromethanesulfonate (74mg, 0.21mmol) were added to dry dichloromethane (8mL) and reacted at room temperature for 5 h. The reaction was washed with water, extracted with ethyl acetate, and the organic phase was concentrated by drying to give compound 9-2 (colorless oil, 0.48g, 71%) without further purification.
The results of nuclear magnetic testing of compound 9-2 are:
1H NMR(400MHz,CDCl3)δ8.16(s,1H),7.25–7.11(m,1H),6.98(dd,J＝7.8,1.7Hz,1H),6.85(ddt,J＝6.5,3.5,1.8Hz,2H),5.02(q,J＝6.6Hz,1H),3.34(s,1H),1.55(d,J＝6.6Hz,3H).13C NMR(100MHz,CDCl3)δ155.1,128.9,128.7,126.6,120.1,117.0,71.3,23.4.HRMS(ESI)calculated for C8H9N3NaO+:186.0643,found 186.0645。
3) preparation of compound 9:
the preparation method comprises the following steps: similarly to the production method of compound 1, one of the raw materials used is compound 2-1, instead of N-methylpiperazine in the production method of compound (1-1) in an equimolar amount; compound 9-2, equimolar instead of 1-2 in the preparation of compound 1.
The nuclear magnetic test result of compound 9 was:
1H NMR(400MHz,CDCl3)δ9.17(s,1H),8.31(d,J＝4.8Hz,2H),7.82(s,1H),7.77(d,J＝8.2Hz,2H),7.42(d,J＝8.2Hz,2H),7.20(dd,J＝7.7,1.6Hz,1H),7.11(td,J＝7.7,1.7Hz,1H),6.95–6.85(m,1H),6.82(td,J＝7.5,1.2Hz,1H),6.54(t,J＝4.8Hz,1H),6.14(q,J＝7.1Hz,1H),3.84(dd,J＝40.8,19.3Hz,6H),3.51(s,2H),1.99(d,J＝7.2Hz,1H).13C NMR(100MHz,CDCl3)δ170.8,161.5,157.9,154.6,146.1,134.4,132.6,129.9,127.9,127.3,126.1,125.8,120.2,116.5,110.7,55.7,47.7,44.1,43.7,42.5,19.9.HRMS(ESI)calculated for C25H25N7NaO2 +:478.1967,found 478.1969。
example 10: preparation of Compound 10
The preparation method comprises the following steps: similar to the production method of compound 9, 2-hydroxybenzyl alcohol, which is one of the starting materials, was used in place of 9-1 in the production method of compound (9-2) in an equimolar amount; compound 2-1, equimolar instead of 9-1, in the preparation process of Compound (9-2).
The nuclear magnetic test results for compound 10 were:
1H NMR(400MHz,CDCl3)δ9.41(s,1H),8.33(s,2H),7.88(d,J＝3.4Hz,1H),7.79(dd,J＝8.3,3.2Hz,2H),7.46(dd,J＝8.5,3.2Hz,2H),7.30–7.21(m,1H),7.21–7.09(m,1H),6.93(dd,J＝8.5,3.1Hz,1H),6.89–6.75(m,1H),6.56(d,J＝4.5Hz,1H),5.54(d,J＝3.4Hz,2H),4.16–3.68(m,7H),3.54(s,2H).δ.13C NMR(100MHz,CDCl3)δ170.9,161.4,157.8,155.3,134.2,132.6,127.8,125.7,121.2，121.1,120.2,116.3,110.7,49.9,47.7,43.5,42.4,29.7.HRMS(ESI)calculated for C25H25N7NaO2 +:478.1967,found 478.1969。
example 11: preparation of Compound 11
The preparation method comprises the following steps: similar to the preparation method of compound 9, 2- (1-hydroxyethyl) -4-chlorobenzyl alcohol, one of the starting materials, was used in place of 9-1 in the preparation method of compound (9-2) in an equimolar amount.
The nuclear magnetic test results for compound 11 were:
1H NMR(400MHz,CDCl3)δ9.41(s,1H),8.33(dd,J＝4.8,1.1Hz,2H),7.82(d,J＝1.1Hz,1H),7.81–7.64(m,2H),7.48–7.31(m,2H),7.23–7.12(m,1H),7.06(ddd,J＝8.6,2.5,1.0Hz,1H),6.82(dd,J＝8.7,1.0Hz,1H),6.56(td,J＝4.8,1.0Hz,1H),6.06(q,J＝7.1Hz,1H),4.43–3.76(m,6H),3.53(s,2H),1.97(d,J＝7.3Hz,3H).13C NMR(100MHz,CDCl3)δ171.0,161.5,157.9,153.4,146.1,134.4,132.5,129.7,127.9,127.6,127.2,125.9,124.9,120.1,118.0,110.8,55.4,47.8,44.1,43.4,42.5,19.61.HRMS(ESI)calculated for C25H24ClN7NaO2 +:512.1578,found 512.1580。
example 12: preparation of Compound 12
The preparation method comprises the following steps: similar to the preparation method of compound 9, 2- (1-hydroxyethyl) -4-chlorobenzyl alcohol, one of the starting materials, was used in place of 9-1 in the preparation method of compound (9-2) in an equimolar amount.
The results of nuclear magnetic testing of compound 12 are:
1H NMR(400MHz,CDCl3)δ7.83(d,J＝1.9Hz,1H),7.74(dd,J＝8.3,2.0Hz,2H),7.36(dd,J＝8.3,2.1Hz,2H),7.18(d,J＝2.4Hz,1H),7.05(d,J＝8.6Hz,1H),6.76(dd,J＝8.6,2.1Hz,1H),6.10(tt,J＝7.2,3.6Hz,1H),3.79(s,2H),3.41(s,2H),2.51(s,2H),2.40–2.29(m,5H),1.96(dd,J＝7.1,2.1Hz,3H).13C NMR(100MHz,CDCl3)δ170.5,153.5,146.1,134.5,132.3,127.8,127.2,125.8,124.6,120.1,117.6,55.2,54.6,47.6,45.9,42.1,19.7.HRMS(ESI)calculated for C22H24ClN5NaO2 +:448.1516,found 448.1518.
example 13: preparation of Compound 13
The preparation method comprises the following steps: similar to the preparation of Compound 9, one of the starting materials used was
1-1, equimolar substitution for 2-1 in the preparation of compound 9.
The nuclear magnetic test results for compound 8 were:
1H NMR(400MHz,CDCl3)δ8.84(s,1H),8.00(d,J＝1.8Hz,1H),7.83(s,1H),7.69(d,J＝1.5Hz,1H),7.41(d,J＝1.7Hz,1H),7.24(d,J＝1.6Hz,1H),7.16(td,J＝7.7,1.6Hz,1H),6.87(t,J＝7.5Hz,1H),6.81(d,J＝8.0Hz,1H),6.13(q,J＝7.1Hz,1H),3.75(s,2H),3.41(s,2H),2.48(s,2H),2.32(s,5H),1.99(d,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ168.6,154.5,144.9,137.7,133.3,130.1,129.8,129.2,127.5,125.9,123.2,122.9,120.5,120.2,116.6,55.7,55.2,54.6,47.6,46.0,42.1,19.9.HRMS(ESI)calculated for C22H25N5NaO2 +:414.1906,found 414.1908.
example 14: preparation of Compound 14
The preparation method comprises the following steps: similar to the production method of compound 9, 2-hydroxybenzyl alcohol, which is one of the starting materials, was used in place of 9-1 in the production method of compound (9-2) in an equimolar amount; compound 1-1, equimolar instead of 2-1 in the preparation of compound 8.
The nuclear magnetic test results for compound 14 were:
1H NMR(400MHz,CDCl3)δ9.60(s,1H),7.85(s,1H),7.75(d,J＝7.9Hz,2H),7.40(d,J＝7.9Hz,2H),7.25(s,1H),7.20–7.13(m,1H),6.87(d,J＝8.1Hz,1H),6.82(t,J＝7.5Hz,1H),5.52(s,2H),3.83(s,2H),3.44(s,2H),2.53(s,2H),2.33(s,5H).13C NMR(100MHz,CDCl3)δ170.5,155.5,146.6,134.4,132.6,131.0,130.6,127.8,125.7,121.4,120.9,120.2,116.3,55.2,54.7,50.0,47.7,46.0,42.3.HRMS(ESI)calculated for C21H23N5NaO2 +:400.1749,found 400.1751。
example 15: preparation of Compound 15
The preparation method comprises the following steps: similar to the preparation of compound 9, except that one of the starting materials used was 2- (1-hydroxyethyl) -4-chlorobenzyl alcohol, equimolar to the 9-1 in the preparation of compound (9-2).
The nuclear magnetic test results for compound 15 were:
1H NMR(400MHz,CDCl3)δ9.30(s,1H),8.30(dd,J＝4.8,1.2Hz,2H),7.97(t,J＝1.6Hz,1H),7.83(d,J＝1.2Hz,1H),7.77(t,J＝1.4Hz,1H),7.45(q,J＝1.5Hz,1H),7.14(dd,J＝2.7,1.1Hz,1H),7.05(ddd,J＝8.6,2.6,1.2Hz,1H),6.81(dd,J＝8.6,1.2Hz,1H),6.55(td,J＝4.8,1.2Hz,1H),6.07(q,J＝7.0Hz,1H),4.03–3.69(m,6H),3.51(s,2H),1.92(d,J＝7.1Hz,3H).13CNMR(100MHz,CDCl3)δ161.4,157.8,153.1,144.7,137.4,133.1,130.0,129.6,129.2,127.4,127.1,124.9,123.1,122.9,120.4,117.7,110.8,55.1,47.7,44.0,43.4,42.4,19.7.HRMS(ESI)calculated for C25H23BrClN7NaO2 +:590.0683,found 590.0685。
example 16: preparation of Compound 16
The preparation method comprises the following steps: similar to the production method of compound 9, except that (14-1) was used as one of the starting materials in place of compound (2-1) in the production method of compound 8 in an equimolar amount.
The nuclear magnetic test results for compound 16 were:
1H NMR(400MHz,CDCl3)δ7.97(d,J＝1.9Hz,1H),7.83(s,1H),7.69(s,1H),7.40(d,J＝1.9Hz,1H),7.25–7.21(m,1H),7.14(td,J＝7.7,1.5Hz,1H),6.86(t,J＝7.6Hz,1H),6.81(d,J＝8.0Hz,1H),6.13(q,J＝7.1Hz,1H),3.75(s,2H),3.42(s,2H),2.51(s,2H),2.33(d,J＝18.0Hz,5H),1.97(d,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ168.6,154.5,144.9,137.7,133.3,130.1,129.8,127.5,125.9,123.2,122.9,120.5,120.2,116.6,55.8,55.2,54.6,47.6,46.0,42.1,19.9.HRMS(ESI)calculated for C22H24BrN5NaO2 +:492.1011,found 492.1013。
example 17: preparation of Compound 17
The preparation method comprises the following steps: similar to the preparation of compound 9, except that one of the starting materials used was 2- (1-hydroxyethyl) -4-chlorobenzyl alcohol, equimolar to the 9-1 in the preparation of compound (9-2).
The nuclear magnetic test result of compound 17 was:
1H NMR(400MHz,DMSO-d6)δ10.27(s,1H),8.91(s,1H),8.15(d,J＝1.8Hz,1H),7.87(s,1H),7.51(d,J＝1.7Hz,1H),7.21(dd,J＝8.6,2.6Hz,1H),7.10(d,J＝2.7Hz,1H),6.88(d,J＝8.6Hz,1H),6.13(q,J＝7.0Hz,1H),3.62(s,2H),3.36(s,2H),2.32(d,J＝42.1Hz,4H),2.19(s,3H),1.86(d,J＝7.1Hz,3H).13C NMR(100MHz,DMSO-d6)δ167.0,153.3,144.0,138.9,133.3,129.0,128.6,128.4,128.3,126.4,122.7,122.3,122.2,121.9,54.6,54.0,47.0,45.6,41.4,20.0.HRMS(ESI)calculated for C22H23BrClN5NaO2 +:526.0621,found 526.0623。
example 18: preparation of Compound 18
The preparation method comprises the following steps: similar to the preparation of compound 9, except that one of the starting materials used was 2- (1-hydroxyethyl) -4-chlorobenzyl alcohol, equimolar to the 9-1 in the preparation of compound (9-2).
The nuclear magnetic test results for compound 16 were:
1H NMR(400MHz,CDCl3)δ8.78(s,1H),8.31(d,J＝4.8Hz,2H),7.99(d,J＝1.8Hz,1H),7.79(s,1H),7.75(d,J＝1.6Hz,1H),7.45(d,J＝1.8Hz,1H),7.17(dd,J＝7.7,1.6Hz,1H),7.12(td,J＝7.7,1.6Hz,1H),6.54(t,J＝4.8Hz,1H),6.12(q,J＝7.0Hz,1H),4.07–3.68(m,6H),3.49(s,2H),1.95(d,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ169.1,157.9,154.4,144.7,137.5,133.3,130.1,130.0,129.2,127.3,125.9,123.2,123.0,120.4,116.5,110.8,55.6,47.7,44.1,43.5,42.4,19.9.HRMS(ESI)calculated for C25H24BrN7NaO2 +:556.1073,found 556.1075。
example 19: enzyme activity assay
Enzyme Activity test Using a Kit of Cayman LSD 1(LSD1 inhibition Screening Assay Kit, Item No.700120, available from Cayman Chemical Company, Annrbor, Mich.), the compounds of examples 1-18 above were tested and the results are shown in the following table:
| compound (I) | LSD1 enzyme activity IC50/nM |
| 1 | 1210 |
| 2 | 982 |
| 3 | 312 |
| 4 | 893 |
| 5 | 1343 |
| 6 | 572 |
| 7 | 191 |
| 8 | 89 |
| 9 | 216 |
| 10 | 349 |
| 11 | 114 |
| 12 | 342 |
| 13 | 410 |
| 14 | 2342 |
| 15 | 118 |
| 16 | 457 |
| 17 | 216 |
| 18 | 302 |
As can be seen from the data in the table above, the compounds 1 to 18 of the invention have high and reversible LSD1 protease activity inhibition effect, and are expected to relieve the toxic and side effects of the medicine.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and should not be taken as limiting the invention, so that any modifications, equivalents, improvements and the like, which are within the spirit and principle of the present invention, should be included in the scope of the present invention.
Claims (8)
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
in the formula (I), Ar is selected from any one of a substituted aromatic ring group or a substituted aromatic heterocyclic group;
R1any one of H, alkane, aryl, CF3 and alkyl tertiary amine structure;
R2any one of halogen structures such as H, alkane, aryl, CF3, F, Cl, Br and the like;
R3and R4Is taken fromH. Any one of alkane, aryl, cyclic and substituted cyclic structures.
2. The compound of claim 1, wherein: the compound is selected from any one of the following compounds 1-18:
3. a process for preparing a compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: the synthetic route of the compound is as follows:
4. a pharmaceutical composition comprising a compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein: the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients, and the dosage form of the pharmaceutical composition is any pharmaceutically acceptable dosage form.
5. Use of a compound according to any one of claims 1 to 3, a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 4 for the manufacture of a medicament for the treatment and/or prevention of cancer.
6. Use according to claim 5, characterized in that: the cancer is a related cancer with histone demethylase abnormalities.
7. Use according to claim 5, characterized in that: the cancer is breast cancer, prostate cancer, ovarian cancer, bladder cancer, liver cancer, taste cancer, lung cancer, neuroblastoma or leukemia.
8. Use of a compound of any one of claims 1-3, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 4 for the preparation of a medicament that is a reversible LSD1 inhibitor.
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