CN117105927A - PROTAC compound based on EGFR allosteric site and application thereof - Google Patents

PROTAC compound based on EGFR allosteric site and application thereof Download PDF

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CN117105927A
CN117105927A CN202311005106.6A CN202311005106A CN117105927A CN 117105927 A CN117105927 A CN 117105927A CN 202311005106 A CN202311005106 A CN 202311005106A CN 117105927 A CN117105927 A CN 117105927A
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acid
cancer
compound
egfr
pharmaceutically acceptable
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石巧娟
龚晓猛
黄文海
闵敬丽
蒋莉莉
王尊元
曾申昕
潘有禄
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Hangzhou Medical College
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Hangzhou Medical College
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Abstract

The invention discloses an EGFR-based allosteric site PROTAC compound shown in the following formulas I, II and III and pharmaceutically acceptable salts and hydrates thereof. The invention also discloses a preparation method of the compound and application of the compound and a pharmaceutical composition in preparing medicines for preventing or/and treating cancers. The compound can induce EGFR degradation with less dosage, and can reduce toxic and side effects on human bodies; the EGFR can also show excellent EGFR protein degradation effect and anticancer activity, has better anticancer effect than EGFR inhibitors, can be used for preventing or/and treating various cancers, and has great application prospect in the field of medicines.

Description

PROTAC compound based on EGFR allosteric site and application thereof
Technical Field
The invention relates to the field of synthesis of pharmaceutical compounds, in particular to a PROTAC compound based on EGFR allosteric sites and application thereof.
Background
Protein degradation targeting chimeras (Proteolysis Targeting Chimeras, PROTAC) are a currently developing and relatively mature technology for targeted protein degradation, which degrades target proteins (Protein of Interest, POI) via UPS. PROTAC is a heterobifunctional molecule, one end of which is a ligand of POI, and the other end of which is a ligand of E3 ligase, and the two ligands are connected through a linker (linker). When PROTAC enters the cell, the POI may be tethered to a specific E3 ligase subunit, forming a POI-PROTAC-E3 ternary complex and triggering K48 ubiquitination, resulting in its subsequent degradation by the proteasome. Theoretically, the PROTAC needs to be bound to the pathogenic protein only briefly (not for a long time), and the protein can be released by labeling with ubiquitination, so that the PROTAC acts like a catalyst and can be recycled, and the PROTAC needs to have a small concentration in cells.
There are 600 more known E3 ligases, but there are four main types of E3 ligases currently used in the protoc technology: von Hippel-Lindau (VHL), cereblon (CRBN), murine Double Mimute (MDM 2) and Cellular inhibitors of apoptosis proteins (cIAP 1).
EGFR (epidermal growth factor receptor, abbreviated as EGFR, erbB-1 or HER 1) is one of the members of the epidermal growth factor receptor (HER) family, which includes HER1 (ErbB 1, EGFR), HER2 (ErbB 2, NEU), HER3 (ErbB 3) and HER4 (ErbB 4), and the HER family plays an important regulatory role in cell physiology. EGFR is widely distributed on the surfaces of mammalian epithelial cells, fibroblasts, glial cells, keratinocytes and the like, and EGFR signaling pathways play an important role in physiological processes such as growth, proliferation, differentiation and the like of cells.
Studies have shown that: there is a high or abnormal expression of EGFR in many solid tumors, which is associated with inhibition of proliferation, angiogenesis, tumor invasion, metastasis and apoptosis of tumor cells. The possible mechanisms are as follows: high expression of EGFR leads to an enhancement of downstream signaling; increased expression of mutant EGFR receptors or ligands results in sustained activation of EGFR; the effect of the autocrine loop is enhanced; disruption of receptor down-regulation mechanisms; activation of abnormal signaling pathways, and the like. The overexpression of EGFR plays an important role in the evolution of malignant tumors, and EGFR is over-expressed in tissues such as glial cells, kidney cancer, lung cancer, prostate cancer, pancreatic cancer, breast cancer and the like, so that the EGFR has become an effective anti-tumor target.
Currently, a number of EGFR tyrosine kinase inhibitors (tyrosine kinase inhibitors, TKIs) have been marketed for the treatment of a variety of cancers, which can be divided into three generations: the first generation is a single-target reversible EGFR targeted tyrosine kinase inhibitor, is effective on 19 exon deletion mutation (EGFR 19 Del/Delins) and 21 exon 858 codon missense mutation (EGFR 21L 858R), and represents medicines including gefitinib (Iressa), erlotinib and icotinib; the second generation is an irreversible covalent inhibitor of EGFR and other ErbB tyrosine kinase receptor family members, effective against EGFR-typical sensitive mutations (EGFR 19 Del/Delins, 21L 858R) and "moderately sensitive" mutations (G719X, S768I, L861Q) as well as some rare mutations, representing drugs afatinib, dacatinib, lapatinib; the third generation of EGFR sensitive mutation and T790M drug-resistant mutation are targeted simultaneously, and the EGFR sensitive mutation and T790M drug-resistant mutation can effectively penetrate the blood brain barrier, have remarkable brain transfer effect, and represent the drugs including the Ornitinib and the domestic Amitinib.
However, after 8-13 months of EGFR-TKIs treatment, almost all patients inevitably develop acquired resistance, reducing the anti-tumor effect of EGFR-TKIs.
The fourth generation EGFR inhibitor EAI045 binds to the allosteric site of EGFR instead of the ATP binding site, so amino acid mutations in the ATP binding site have less effect on the binding of EAI045 to EGFR, and the literature has also demonstrated that EAI045 has better binding capacity to EGFR wild type as well as common mutants, but the problem of mutation resistance of small molecule EGFR inhibitors is not yet fully solved.
Disclosure of Invention
The invention aims to provide a PROTAC compound based on EGFR allosteric sites and application thereof, and the compound not only has excellent EGFR protein degradation and anticancer activity, but also can reduce toxic and side effects on human bodies, and can be used for preparing antitumor drugs.
Another object of the present invention is to provide the use of the above-mentioned compounds or pharmaceutically acceptable salts and hydrates thereof for the preparation of a medicament for the prevention or/and treatment of cancer.
In order to achieve the above object, the present invention provides a compound having the following formulas I, ii, iii or pharmaceutically acceptable salts and hydrates thereof:
wherein, the compound n of the formula I is an integer of 1-7, and m is an integer of 1-2; the compound n of the formula II is an integer of 1-2; the compound n of formula III is an integer from 1 to 7, and m is an integer from 1 to 2.
According to the invention, a protein degradation targeting complex (PROTACs) dual-function small molecule is prepared by connecting an EGFR small molecule inhibitor and a CRBN protein ligand or a VHL protein ligand in an E3 ubiquitin ligase complex through a connecting chain, and EGFR protein degradation can be selectively induced through ubiquitination marking, so that the EGFR protein degradation targeting complex has good anti-tumor activity.
Preferably, the compounds of formula i are more active when they are rigid chains, more preferably m=1; the compound n of the formula II is an integer of 1-2; the compound n of formula III is an integer from 1 to 7, and m is an integer from 1 to 2. n is an integer of 1 to 7, more preferably an integer of 2 to 5, and the preferred compounds have better EGFR degradation induction and anti-tumor activity.
The invention also includes stereoisomers of the compounds of formula (I, II, III). All stereoisomers of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers, and mixtures thereof (e.g., racemates), are included within the scope of the present invention.
The invention also includes tautomers of the compounds of formula (I, II, III). The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconverted via a low energy barrier.
The invention also includes prodrugs of derivatives of formula (I, ii, iii), which may themselves have a relatively weak or even no activity, but which are converted to the corresponding biologically active form under physiological conditions (e.g. by metabolism, solvolysis or otherwise) after administration.
Pharmaceutically acceptable salts include: addition salts with hydrochloric acid, hydroolfactory acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, tea disulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid or benzoic acid; and hydrochloric acid, hydroolfactory acid, sulfuric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, trifluoroacetic acid, maleic acid, benzenesulfonic acid or patonic acid.
The flexible chain compound of formula I is prepared by the following reaction scheme:
the rigid chain compound of formula I is prepared by the following reaction scheme:
the compound of formula II is prepared by the following reaction scheme:
the flexible chain compound of formula III is prepared by the following reaction scheme:
the rigid chain compound of formula III is prepared by the following reaction scheme:
a pharmaceutical composition comprising a compound of formula (I, ii, iii) or pharmaceutically acceptable salts and hydrates thereof, and a pharmaceutically acceptable excipient.
Wherein the compound of the formulas (I, II and III) or pharmaceutically acceptable salts and hydrates thereof are used as active ingredients and are mixed with pharmaceutically acceptable excipients to prepare a pharmaceutical composition, and the excipients are diluents, auxiliary agents or carriers used in the pharmaceutical field.
A clinically acceptable dosage form is prepared by adding pharmaceutically acceptable auxiliary materials into a pharmaceutical composition, wherein the dosage form is injection, tablet or capsule.
A pharmaceutical composition comprising a compound of formula (I, ii, iii) or pharmaceutically acceptable salts and hydrates thereof, and a different anti-neoplastic agent. The compound or the pharmaceutically acceptable salt, hydrate and prodrug thereof can be used as an anti-tumor agent singly or in combination with different anti-tumor agents for treating and preventing tumors.
The invention also discloses application of the compounds shown in the formulas (I, II and III) or pharmaceutically acceptable salts and hydrates thereof in preparing medicines for preventing or/and treating cancers.
The cancer is multiple myeloma, gastric cancer, lung cancer, breast cancer, esophageal cancer, colon cancer, medulloblastoma, acute myelogenous leukemia, chronic leukemia, prostatic cancer, hepatoma, renal cytoma, cervical cancer, skin cancer, ovarian cancer, colon cancer, glioma, thyroid cancer or pancreatic cancer.
The invention has the beneficial effects that:
the invention gives up a small molecule inhibitor mode of inhibiting EGFR by occupying an ATP binding site of driving (EGFR), and solves the drug resistance problem caused by mutation of amino acid residues of the ATP binding site of EGFR by exposing an allosteric site outside an EGFR dimer and triggering event-driven (event-driving) by PROTAC to degrade EGFR.
The bi-functional small molecules of the formulas (I, II and III) can carry out ubiquitination marking on EGFR, can induce protein degradation with less dosage, and the process is similar to catalytic reaction, does not need equimolar amount of medicine, and can reduce toxic and side effects on human bodies;
the in-vitro anti-tumor activity test and the in-vitro EGFR protein degradation activity test show that the bifunctional small molecules shown in the formulas (I, II and III) have excellent EGFR protein degradation effect and anti-cancer activity, the anti-cancer effect is superior to that of EGFR inhibitors, and the bifunctional small molecules can be used for preparing medicines for preventing or/and treating various cancers and have great application prospects in the medicine field.
Detailed Description
The examples and preparations provided below further illustrate and exemplify the compounds of the invention and methods of preparing the same. It should be understood that the scope of the following examples and preparations is not intended to limit the scope of the present invention in any way. The starting materials of the present invention may be obtained commercially or prepared by methods known in the art.
The structure of the compound is changed into a nuclear magnetic resonance structure 1 H-NMR) and High Resolution Mass Spectrometry (HRMS), the NMR measurement was performed by an ACF-400BRUK nuclear magnetic resonance apparatus, and the measurement solvent was deuterated chloroform (CDC 1) 3 ) Or deuterated dimethyl sulfoxide (DMSO-D) 6 ) TMS is an internal standard. Column chromatography adopts 200-300 mesh silica gel.
Example 1:
preparation of methyl 2- (6-bromo-1-oxoisoindolin-2-yl) -2-phenylacetate:
2.80g (13.92 mmol) of methyl 2-amino-2-phenylacetate and 3.90g (12.66 mmol) of methyl 5-bromo-2-bromomethylbenzoate are weighed out in 60mL of DMF and DIPEA (6.60 mL,37.98 mmol) is added dropwise at 0deg.C. After the completion of the dropwise addition, the mixture was stirred at 80℃for 12 hours, and the reaction was completed by TLC. The reaction solution was cooled to room temperature, quenched with 50mL of water, extracted with saturated brine (300 mL) and ethyl acetate (100 mL. Times.3), and the organic phases were combined and washed with saturated brine (250 mL. Times.3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and weighed to give 3.28g of brown oily liquid 1a in a yield of about 72%.
(2) Preparation of 2- (6-bromo-1-oxoisoindol-2-yl) -2-phenylacetic acid:
intermediate 1a (3.20 g,8.89 mmol) was dissolved in THF/MeOH/H 2 A mixed solution of O (1:1:1) (30 mL) and lithium hydroxide (2.65 g,63.30 mmol) were added. After stirring for 2h, the reaction was complete by TLC. To the reaction solution was added 30mL of water, and extracted with ethyl acetate (50 ml×2) to remove unhydrolyzed reactants. The aqueous phase was adjusted to pH 1-2 with concentrated HCl, a white solid precipitated and extracted with ethyl acetate (150 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 2.74g of white solid 1b in a yield of about 87%. 1 H NMR(500MHz,DMSO-d 6 )δ7.87(d,J＝1.9Hz,1H),7.79(dd,J＝8.1,1.9Hz,1H),7.53(d,J＝8.1Hz,1H),7.49-7.39(m,5H),5.98(s,1H),4.61(d,J＝17.8Hz,1H),3.90(d,J＝17.8Hz,1H).
(3) Preparation of 2- (6-bromo-1-oxoisoindol-2-yl) -2-phenyl-N- (thiazol-2-yl) acetamide:
intermediate 1b (2.00 g,5.78 mmol), 2-aminothiazole (1.10 g,11.55 mmol) and HATU (4.40 g,11.55 mmol) was dissolved in 30mL of DMF, DIPEA (4.00 mL,23.12 mmol) was added, after stirring at 45℃for 8h, the reaction was detected by TLC, 30mL of water was added to the reaction solution for quenching, and then extracted with saturated brine (200 mL) and ethyl acetate (100 mL. Times.3), and the organic phases were combined and washed with saturated brine (250 mL. Times.3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, sand-making, column chromatography to give crude product, and finally recrystallisation with ethyl acetate/petroleum ether system to give 1.55g of white solid 1c in a yield of about 63%. 1 H NMR(400MHz,Chloroform-d)δ7.88(d,J＝1.8Hz,1H),7.80(dd,J＝8.1,1.9Hz,1H),7.55(d,J＝8.2Hz,1H),7.50(t,J＝3.1Hz,1H),7.48-7.43(m,2H),7.38(dd,J＝6.4,1.8Hz,2H),7.29(d,J＝3.6Hz,1H),6.29(s,1H),4.73(d,J＝17.9Hz,1H),3.96(d,J＝17.9Hz,1H). 13 C NMR(101MHz,Chloroform-d)δ173.39,171.55,162.59,146.75,143.15,139.75,139.40,138.85,134.36,134.05,131.29,130.79,126.32,119.37,63.47,53.73.
(4) Preparation of 2- (1-oxo-6- (6- (piperazin-1-yl) pyridin-3-yl) isoindol-2-yl) -2-phenyl-N- (thiazol-2-yl) acetamide:
the reaction solvent was first deoxygenated by passing nitrogen gas through it, intermediate 1c (520 mg,1.21 mmol) and (6- (piperazin-1-yl) pyridin-3-yl) boric acid (440 mg,1.81 mmol) were placed in a lock tube and 2N Na was added 2 CO 3 (3 mL,6.00 mmol) and 1, 4-dioxane (12 mL), were preheated at 100deg.C for 20min, then Pd (dppf) Cl was added 2 (53 mg,0.07 mmol) and X-phos (52 mg,0.11 mmol). After stirring at 100℃for 8h, the reaction was allowed to cool to room temperature and was detected by TLC to be complete. The reaction was diluted with dichloromethane and filtered through celite, and the filtrate was extracted with dichloromethane (80 ml×3) and water (200 mL). The organic phases were combined and washed with saturated brine (200 mL. Times.1), dried over anhydrous sodium sulfate, filtered, concentrated, and sand-packed to give 292mg of a brown solid JBJ-07-149 in about 47% yield. 1 H NMR(400MHz,DMSO-d 6 )δ8.50(d,J＝2.6Hz,1H),7.96-7.84(m,3H),7.61(d,J＝8.0Hz,1H),7.46(ddd,J＝17.1,7.6,4.4Hz,4H),7.41-7.36(m,2H),7.27(d,J＝3.6Hz,1H),6.90(d,J＝8.9Hz,1H),6.32(s,1H),4.78(d,J＝17.6Hz,1H),3.99(d,J＝17.6Hz,1H),3.49(d,J＝5.1Hz,4H),2.82(t,J＝5.1Hz,4H). 13 C NMR(101MHz,DMSO-d 6 )δ168.99,168.18,159.05,158.22,146.18,141.11,138.26,138.24,136.41,135.01,132.71,129.86,129.57,129.27,129.19,124.74,124.38,120.00,114.46,107.38,58.74,48.90,45.79,45.52.
(5) Preparation of tert-butyl (4- (5-bromopentanamide) phenyl) carbamate:
313mg (1.73 mmol) of 5-bromopentanoic acid was weighed into a single-necked round bottom flask, 20mL of anhydrous methylene chloride was added to dissolve, then 712mg (1.87 mmol) of HATU was sequentially added, DIPEA (476. Mu.L, 2.88 mmol) was refluxed for 15min at 45℃and finally tert-butyl (4-aminophenyl) carbamate (300 mg,1.44 mmol) was added to reflux and reacted overnight, the completion of the reaction was detected by TLC the next day, 20mL of water was added to the reaction solution, and then extracted with water (100 mL) and methylene chloride (50 mL. Times.3), and the organic phases were combined and washed with saturated brine (100 mL. Times.1). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and sand-made, and column chromatography gave 320mg of pink flocculent solid 1d in about 60% yield. 1 H NMR(500MHz,DMSO-d6)δ9.82(s,1H),9.23(s,1H),7.49-7.30(m,4H),3.66(t,J＝6.3Hz,2H),2.31(t,J＝7.2Hz,2H),1.80-1.65(m,4H),1.46(s,9H).
(6) Preparation of tert-butyl (4- (5- (4- (3-oxo-2- (2-oxo-1-phenyl-2- (thiazol-2-ylamino) ethyl) isoindol-5-yl) pyridin-2-yl) piperazin-1-yl) pentanamido) phenyl) carbamate:
100mg (0.19 mmol) of JBJ-07-149 and 1d 73mg (0.19 mmol) of intermediate were weighed into a single-necked round bottom flask, dissolved in 10mL of DMF, then added with DIPEA (83. Mu.L, 0.50 mmol), reacted overnight at 75℃and the reaction was detected by TLC the next day to be complete, quenched by adding 20mL of water to the reaction solution, extracted with saturated brine (80 mL) and dichloromethane (40 mL. Times.3), and the organic phases were combined and washed with saturated brine (100 mL. Times.3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and sand-packed, and column chromatography gave 117mg of yellow oil 1g in about 75% yield.
(7) Preparation of N- (4-aminophenyl) -5- (4- (5- (3-oxo-2- (2-oxo-1-phenyl-2- (thiazol-2-ylamino) ethyl) isoindol-5-yl) pyridin-2-yl) piperazin-1-yl) pentanamide:
1g of intermediate (110 mg, 0.14 mol) was weighed and placed in a single-necked round bottom flask, 2mL of methylene chloride was added for dissolution, then 1.5mL of 2N HCl-EA solution was added dropwise, an off-white solid was precipitated, after stirring at room temperature for 3 hours, the reaction was complete by TLC detection, saturated sodium carbonate solution was added dropwise to adjust pH to 8-9, then water (80 mL) and methylene chloride (30 mL. Times.3) were added for extraction, and the organic phases were combined and washed with saturated brine (100 mL. Times.1). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 77mg of yellow solid 1j in about 80% yield.
50mg (0.071 mmol) of intermediate 1j and 68mg (0.36 mmol) of 3-bromopiperidine-2, 6-dione are weighed into a single-necked round bottom flask, 5mL of DMF is added for dissolution, then DIPEA (71. Mu.L, 0.43 mol) is added, the reaction is allowed to react overnight at 90℃and the reaction solution is black, the basic reaction is detected by TLC, 5mL of water is added to the reaction solution for quenching, then saturated brine (40 mL) and dichloromethane (20 mL. Times.3) are used for extraction, and the organic phases are combined and washed with saturated brine (40 mL. Times.3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and sand-packed, and column chromatography gave 28mg of brown solid I-1 in about 50% yield.
The specific structure of the obtained N- (4- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) -5- (4- (5- (3-oxo-2- (2-oxo-1-phenyl-2- (thiazol-2-ylamino) ethyl) isoindolin-5-yl) pyridin-2-yl) piperazin-1-yl) pentanamide is as follows:
1 H NMR(500MHz,DMSO-d 6 )δ10.79(s,1H),δ9.55(s,1H),δ8.51(d,J＝2.6Hz,1H),7.96-7.90(m,2H),7.87(dd,J＝7.9,1.8Hz,1H),7.62(d,J＝8.1Hz,1H),7.51-7.43(m,5H),7.41-7.38(m,2H),7.32-7.28(m,2H),6.93(d,J＝9.0Hz,1H),6.65-6.59(m,1H),6.33(s,1H),4.78(d,J＝17.6Hz,1H),4.27(ddd,J＝11.7,7.1,4.8Hz,1H),4.00(d,J＝17.6Hz,1H),3.57(m,8H),2.74(ddd,J＝17.4,11.9,5.3Hz,1H),2.36-2.26(m,2H),2.11(dq,J＝13.4,4.8Hz,1H),1.88(ddd,J＝17.0,11.9,5.6Hz,1H),1.64-1.48(m,4H),1.32-1.18(m,4H). 13 C NMR(126MHz,Chloroform-d)δ174.26,173.63,170.87,168.92,168.26,158.97,158.22,146.16,144.61,141.48,139.67,137.45,134.34,133.14,129.99,129.78,129.66,129.34,124.89,124,69,121.36,119.32,114.81,112.95,107.53,57.95,57.61,53.65,52.98,49.28,44.93,36.37,30.85,29.94,28.41,25.34.MS(ESI):Calcd for C 44 H 45 N 9 O 5 S[M+H] + 812.34,found 812.42.
example 2
The specific preparation method is the same as in example 1 to prepare N- (4- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) -8- (4- (5- (3-oxo-2- (2-oxo-1-phenyl-2- (thiazol-2-ylamino) ethyl) isoindolin-5-yl) pyridin-2-yl) piperazin-1-yl) octanamide, which has the following structure:
1 H NMR(500MHz,DMSO-d6)δ10.79(s,1H),9.52(s,1H),8.50(d,J＝2.7Hz,1H),7.95-7.89(m,2H),7.87(dd,J＝7.9,1.8Hz,1H),7.61(d,J＝8.1Hz,1H),7.51-7.41(m,5H),7.40-7.37(m,2H),7.31-7.28(m,2H),6.91(d,J＝9.1Hz,1H),6.64-6.61(m,1H),6.34(s,1H),4.78(d,J＝17.7Hz,1H),4.27(ddd,J＝11.8,7.2,4.8Hz,1H),4.00(d,J＝17.7Hz,1H),3.55(m,6H),2.74(ddd,J＝17.4,12.0,5.4Hz,1H),2.58(dt,J＝17.3,4.2Hz,1H),2.34(m,3H),2.23(t,J＝7.5Hz,2H),2.11(dq,J＝13.6,5.1Hz,1H),1.86(qd,J＝12.2,4.7Hz,1H),1.52(dt,J＝51.3,7.0Hz,4H),1.33(d,J＝25.7Hz,8H). 13 C NMR(126MHz,DMSO-d6)δ174.21,173.59,170.81,168.88,168.20,158.85,157.95,146.19,144.34,141.14,138.28,136.44,134.92,132.70,129.90,129.69,129.58,129.26,124.73,124.56,121.17,120.06,114.54,113.05,107.47,58.69,58.24,53.21,52.91,48.90,44.96,36.69,31.20,29.16,27.25,26.47,25.71,25.19.MS(ESI):Calcd for C 47 H 51 N 9 O 5 S[M+H]+854.38,found854.51.
example 3
The specific preparation was the same as in example 1 to give N- (4- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) -10- (4- (5- (3-oxo-2- (2-oxo-1-phenyl-2- (thiazol-2-ylamino) ethyl) isoindolin-5-yl) pyridin-2-yl) piperazin-1-yl) decanoamide:
1 H NMR(400MHz,DMSO-d 6 )δ10.79(s,1H),9.50(d,J＝1.5Hz,1H),8.50(d,J＝2.6Hz,1H),7.93-7.89(m,2H),7.85(dt,J＝8.0,1.4Hz,1H),7.60(d,J＝8.0Hz,1H),7.51-7.36(m,7H),7.33-7.25(m,3H),6.90(d,J＝9.1Hz,1H),6.66-6.58(m,2H),6.34(d,J＝1.4Hz,1H),4.78(d,J＝17.6Hz,1H),4.26(ddd,J＝11.8,7.3,4.8Hz,1H),3.99(d,J＝17.7Hz,1H),3.72-3.48(m,6H),2.74(ddd,J＝17.4,12.0,5.4Hz,1H),2.63-2.55(m,1H),2.39-2.27(m,2H),2.22(t,J＝7.4Hz,2H),2.11(dq,J＝13.6,4.7Hz,1H),1.85(qd,J＝12.2,4.7Hz,1H),1.50(dt,J＝42.8,7.3Hz,4H),1.32-1.21(m,12H). 13 C NMR(101MHz,DMSO-d 6 )δ174.29,173.66,170.85,168.96,168.26,158.90,158.03,146.26,144.40,141.20,138.29,136.50,135.00,132.77,129.96,129.76,129.65,129.33,124.79,124.63,121.22,120.13,114.61,113.11,107.53,58.74,58.33,53.26,52.96,48.96,45.00,36.77,31.27,29.45,29.33,29.23,27.41,26.57,25.82,25.25.MS(ESI):Calcd for C 49 H 55 N 9 O 5 S[M+H] + 882.41,found 882.67.
example 4
(1) Preparation of (1- (4-nitrophenyl) azetidin-3-yl) methanol:
2.00g (14.17 mmol) of p-fluoronitrobenzene and 2.63g (21.26 mmol) of 3-methylazetidine hydrochloride are weighed and placed in a round bottom flask, 30mL of DMF is added for dissolution, 5.88g (42.52 mmol) of potassium carbonate is finally added for reaction at 70 ℃ for 3 hours, the reaction is detected to be complete by TLC, water quenching is carried out on the reaction solution, saturated saline (200 mL) and ethyl acetate (100 mL multiplied by 3) are added for extraction, the organic phases are combined, the saturated saline (200 mL multiplied by 3) is used for washing, anhydrous sodium sulfate is used for drying, the crude product is obtained by reduced pressure distillation, finally, the crude product is recrystallized by an ethyl acetate petroleum ether system, and 2.75g of orange yellow solid is obtained by filtration, wherein the yield is about 93%. 1 H NMR(400MHz,DMSO-d 6 )δ8.06-7.96(m,2H),6.43-6.35(m,2H),4.88(s,1H),4.07-3.98(m,2H),3.76(dd,J＝8.7,5.3Hz,2H),3.58(d,J＝6.1Hz,2H),2.85(tp,J＝8.2,5.8Hz,1H). 13 C NMR(101MHz,DMSO-d 6 )δ155.04,136.34,126.38,109.62,62.77,53.66,31.55.
(2) Preparation of 1- (4-nitrophenyl) azetidine-3-carbaldehyde:
2.44mL (3.66 g,28.82 mmol) of oxalyl chloride was measured, placed in a three-necked flask, diluted with 6mL of DCM, the reaction flask was moved to-78deg.C, 4.09mL (4.50 g,57.63 mmol) of DMSO was measured, diluted with 15mL of DCM, and then slowly injected into the reaction flask with a syringe, after 15min, 1.5g of intermediate 1m (7.20 mmol) was dissolved with 60mL of DCM and slowly injected into the reaction flask with a syringe, after 30min 10.41mL (7.29 g,72.04 mmol) of TEA was added, and the reaction flask was moved to room temperature. The reaction was complete by TLC. The reaction mixture was quenched with water, extracted with 200mL of water and dichloromethane (100 mL. Times.3), the organic phases combined, washed once with saturated brine (200 mL), dried over anhydrous sodium sulfate, and distilled under reduced pressure to give crude product as yellow oily liquid 1o which was directly transferred to the next step.
(3) Preparation of 3- (dimethoxymethyl) -1- (4-nitrophenyl) azetidine:
all intermediate 1o was put into a round bottom flask, 50mL of methanol was added for ultrasonic dissolution, then 4.11mL (3.82 g,36.02 mmol) of trimethyl orthoformate and 248mg (1.44 mmol) of p-toluenesulfonic acid were added, and the reaction was refluxed overnight at 67℃and detected by TLC the next day to be complete. The reaction solution is directly subjected to dry sample column chromatography to obtain a crude product, and finally, the crude product is recrystallized by an ethyl acetate petroleum ether system to obtain 1.67g of yellow powder solid 1q, wherein the total yield of the two steps is about 69%.
(4) Preparation of 4- (3- (dimethoxymethyl) azetidin-1-yl) aniline:
500mg (1.98 mmol) of intermediate 1q and 100mg of Pd/C (10%) were weighed in sequence, placed in a round bottom flask, dissolved by adding 50mL of methanol, replaced with hydrogen for three times, reacted overnight at room temperature, the yellow of the reaction liquid disappeared the next day, and the reaction was completed by TLC detection. The reaction was filtered through celite to remove Pd/C, then dry column chromatography to give 420mg of a brown oily liquid 1s (room temperature cure) in about 95% yield.
(5) Preparation of 3- ((4- (3- (dimethoxymethyl) azetidin-1-yl) phenyl) amino) piperidine-2, 6-dione:
500mg (2.25 mmol) of the intermediate 1s, 648mg (3.37 mmol) of 3-bromopiperidine-2, 6-dione are weighed in sequence, placed in a round bottom flask, 25mL of DMF is added for dissolution, 1.12mL (6.75 mmol) of DIPEA is added, the reaction is carried out for 4h at 50 ℃, the solution turns black, and the reaction is completed through TLC detection. The reaction mixture was quenched with water, extracted with water (200 mL) and ethyl acetate (100 mL. Times.3), the organic phases were combined, washed 3 times with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and dry-stirred column chromatography gave 511mg of a black solid 1u in a yield of about 68%. 1 H NMR(400MHz,DMSO-d 6 )δ10.77(s,1H),6.60(d,J＝8.4Hz,2H),6.31(d,J＝8.4Hz,2H),4.59(d,J＝7.2Hz,1H),4.15(dd,J＝11.1,4.8Hz,1H),3.73(t,J＝7.5Hz,2H),3.47(t,J＝6.5Hz,2H),3.26(s,6H),2.61-2.54(m,1H),2.08(dq,J＝9.6,4.8Hz,2H),1.82(qd,J＝11.8,4.7Hz,2H). 13 C NMR(101MHz,DMSO-d6)δ174.45,173.65,144.77,139.65,114.53,113.24,105.76,54.42,53.82,53.65,32.44,31.08,25.29.
(6) Preparation of 1- (4- ((2, 6-dioxohesperidin-3-yl) amino) phenyl) azetidine-3-carbaldehyde:
weigh intermediate 1u 200mg (0.60 mmol) in round bottom flask, add 8mL THF to dissolve, add 8mL 3M H dropwise with stirring 2 SO 4 (40 eq) the solution turned green, then the reaction was warmed to 50 ℃, and after 0.5h, the reaction was complete by TLC. Saturated NaHCO is added dropwise into the reaction solution 3 The pH was adjusted to 7-8, water (50 mL) and methylene chloride (30 mL. Times.3) were added to the mixture to extract, the organic phases were combined, washed 1 time with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and dry-mixed column chromatographed to give 138mg of a dark green solid 1w in about 80% yield.
Finally, 50mg (0.17 mmol) of intermediate 1w is weighed in turn, and then, JBJ-07-149 mg (0.12 mmol) is placed in a round bottom flask, 6mL of reaction solvent (DCM: meOH=1:1) is added for dissolution, 1 drop of glacial acetic acid is added dropwise for catalysis, and NaBH (OAc) is added after 20min 3 133mg (0.63 mmol) were reacted overnight at room temperature. The next day TLC detection, there was a small amount of remaining starting material. The reaction mixture was quenched with water, extracted with water (40 mL) and dichloromethane (30 mL. Times.3), the organic phases combined, washed 1 time with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and dry-stirred column chromatography to give 32mg of black solid I-4 in about 34% yield.
The obtained 2- (6- (6- (4- (1- (4- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) azetidin-3-yl) methyl) piperazin-1-yl) pyridin-3-yl) -1-oxoisoindol-2-yl) -2-phenyl-N- (thiazol-2-yl) acetamide (i-4) has the following specific structure:
1 H NMR(400MHz,DMSO-d 6 )δ10.77(s,1H),8.50(d,J＝2.5Hz,1H),7.90(dd,J＝7.7,2.1Hz,2H),7.85(dd,J＝8.0,1.8Hz,1H),7.59(d,J＝8.1Hz,1H),7.50-7.37(m,6H),7.27(d,J＝3.6Hz,1H),6.89(d,J＝8.9Hz,1H),6.60(d,J＝8.4Hz,2H),6.34(s,1H),6.27(d,J＝8.4Hz,2H),4.78(d,J＝17.6Hz,1H),4.14(dt,J＝10.1,4.4Hz,1H),3.99(d,J＝17.6Hz,1H),3.80(t,J＝7.2Hz,2H),3.53(t,J＝4.9Hz,4H),3.31(t,J＝6.4Hz,2H),2.87(h,J＝6.9Hz,1H),2.72(ddd,J＝17.2,11.6,5.3Hz,1H),2.57(tt,J＝8.8,4.6Hz,3H),2.46(t,J＝5.1Hz,4H),2.15-1.76(m,2H). 13 C NMR(101MHz,DMSO-d 6 )δ174.57,173.72,168.97,168.28,158.91,158.04,146.27,145.16,141.19,140.20,138.36,138.30,136.49,134.98,132.76,130.18,129.95,129.65,129.33,124.79,124.58,120.12,114.67,114.61,113.00,107.52,62.66,58.75,57.57,53.99,53.04,48.96,45.08,31.13,28.16,25.44.MS(ESI):Calcd for C 43 H 43 N 9 O 4 S[M+H] + 782.33,found 782.54.
example 5
The specific preparation method is the same as in example 3 to prepare 2- (6- (6- (4- (1- (4- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperidin-4-yl) methyl) piperazin-1-yl) pyridin-3-yl) -1-oxoisoindol-2-yl) -2-phenyl-N- (thiazol-2-yl) acetamide, which has the following structure:
1 H NMR(400MHz,Chloroform-d)δ8.96(s,1H),8.47(d,J＝2.5Hz,1H),8.17-8.05(m,1H),7.83-7.63(m,2H),7.56(d,J＝3.6Hz,1H),7.50-7.33(m,6H),7.00(d,J＝3.6Hz,1H),6.90(d,J＝8.4Hz,2H),6.78-6.62(m,4H),5.02(d,J＝17.2Hz,1H),4.15(d,J＝17.2Hz,1H),3.98(dd,J＝12.3,4.8Hz,1H),3.61(t,J＝5.1Hz,4H),3.54-3.44(m,2H),2.88-2.45(m,10H),2.29(d,J＝7.1Hz,2H),1.94-1.84(m,3H),1.48-1.35(m,2H). 13 C NMR(101MHz,DMSO-d 6 )δ174.47,173.70,168.96,168.26,158.89,158.02,146.28,141.22,138.30,136.55,134.98,132.77,129.98,129.66,129.33,125.43,124.82,124.65,120.13,118.98,116.31,114.63,114.09,107.55,58.75,55.45,53.60,53.38,51.51,48.97,45.03,31.18,29.56,27.08,25.37.MS(ESI):Calcd for C 45 H 47 N 9 O 4 S[M+H] + 810.36,found 810.56.
example 6
(1) Preparation of 2- (1-oxo-6- (6- (4- (pyrrolidin-3-ylmethyl) piperazin-1-yl) pyridin-3-yl) isoindol-2-yl) -2-phenyl-N- (thiazol-2-yl) acetamide:
150mg (0.74 mmol) of 1-Boc-3-pyrrolidine formaldehyde is weighed in sequence, JBJ-07-149 mg (0.25 mmol) is placed in a round bottom flask, 8mL of 1, 2-dichloroethane is added for dissolution, 1 drop of glacial acetic acid is added dropwise for catalysis, and NaBH (OAc) is added after 20min 3 155mg (0.74 mmol), and reacted overnight at room temperature. The next day TLC detection, reaction was complete. The reaction mixture was quenched with water, extracted with water (40 mL) and dichloromethane (30 mL. Times.3), the organic phases combined, washed 1 time with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and dry-stirred column chromatography gave 164mg of a white solid in about 95% yield. The resulting product was dissolved in 3mL of ethyl acetate, then 2mL of 2N HCl-EA solution was added dropwise, a white solid was precipitated, and after stirring at room temperature for 3 hours, the reaction was complete by TLC, saturated sodium carbonate solution was added dropwise to adjust pH to 8-9, extraction was performed with water (60 mL) and dichloromethane (30 mL. Times.3), and the organic phases were combined and washed with saturated brine (100 mL. Times.1). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 124mg of white solid 2a in about 88% yield. 1 H NMR(500MHz,DMSO-d 6 )δ8.50(d,J＝2.6Hz,1H),7.93(dd,J＝8.8,2.6Hz,1H),7.85(d,J＝8.1Hz,1H),7.61(d,J＝7.9Hz,1H),7.43(t,J＝7.2Hz,2H),7.41-7.34(m,4H),7.08(s,1H),6.92(d,J＝8.9Hz,1H),6.24(s,1H),4.91(d,J＝17.9Hz,1H),4.07-3.95(m,2H),3.69-3.47(m,8H)3.12-2.76(m,4H),1.85(s,1H),1.40(s,1H),1.24(d,J＝13.7Hz,2H),1.18(t,J＝7.1Hz,1H).
Finally, 50mg (0.084 mmol) of intermediate 2a and 23mg (0.093 mmol) of 5-fluoro thalidomide were weighed in order, placed in a round bottom flask, dissolved in 5mL of DMSO, followed by DIPEA (54 mg,0.42 mmol) and reacted at 75℃for 3h. After 3h the reaction was complete by TLC. The reaction mixture was quenched with water, extracted with water (50 mL) and ethyl acetate (30 mL. Times.3), the organic phases were combined, washed with saturated brine (60 mL. Times.3), dried over anhydrous sodium sulfate, filtered, concentrated, and dry-stirred column chromatography gave 68mg of yellow powdered solid II-1 in about 95% yield.
The obtained 2- (6- (6- (4- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) pyrrolidin-3-yl) methyl) piperazin-1-yl) pyridin-3-yl) -1-oxoisoinden-2-yl) -2-phenyl-N- (thiazol-2-yl) acetamide (II-1) has the following specific structure
1 H NMR(400MHz,Chloroform-d)δ9.14(s,1H),8.48(d,J＝2.5Hz,1H),8.13(s,1H),7.78(dd,J＝8.7,2.6Hz,1H),7.67(dd,J＝11.6,8.1Hz,2H),7.56(d,J＝3.6Hz,1H),7.49-7.29(m,7H),6.98(dd,J＝15.8,2.9Hz,2H),6.78-6.62(m,3H),5.04(d,J＝17.3Hz,1H),4.94(dt,J＝12.5,7.0Hz,1H),4.14(d,J＝17.4Hz,1H),3.61(dt,J＝17.2,6.1Hz,5H),3.22(dd,J＝10.1,6.9Hz,1H),2.90-2.43(m,8H),2.18(ddd,J＝44.0,10.9,6.2Hz,2H),1.43-1.32(m,3H). 13 C NMR(101MHz,DMSO-d 6 )δ173.37,170.72,168.96,168.26,167.78,158.84,158.02,152.35,146.28,141.20,138.28,136.52,134.99,134.53,132.77,129.95,129.65,129.33,125.48,124.79,120.13,116.04,115.76,114.60,107.54,105.99,58.74,53.19,52.68,49.21,48.95,47.72,31.83,31.67,31.54,29.78,29.55,22.80.MS(ESI):Calcd for C 46 H 43 N 9 O 6 S[M+H] + 850.32,found 850.41.
Example 7
The specific preparation method is the same as in example 6 to prepare 2- (6- (6- (4- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) pyrrolidin-3-yl) methyl) piperazin-1-yl) pyridin-3-yl) -1-oxoisoquinolin-2-yl) -2-phenyl-N- (thiazol-2-yl) acetamide (II-2) which has the following structure:
1 H NMR(500MHz,DMSO-d 6 )δδ12.73(s,1H),11.09(s,1H),8.50(d,J＝2.5Hz,1H),7.95-7.89(m,2H),7.85(dd,J＝7.9,1.8Hz,1H),7.60(d,J＝8.1Hz,1H),7.54(dd,J＝8.7,7.0Hz,1H),7.50(t,J＝3.3Hz,1H),7.48-7.45(m,2H),7.45-7.42(m,1H),7.42-7.38(m,2H),7.28(d,J＝3.6Hz,1H),7.11(dd,J＝6.9,2.4Hz,1H),7.07(dd,J＝8.8,2.1Hz,1H),6.90(d,J＝9.0Hz,1H),6.35(s,1H),5.08(dd,J＝12.9,5.4Hz,1H),4.79(d,J＝17.7Hz,1H),3.99(d,J＝17.6Hz,1H),3.69-3.47(m,8H),2.88(ddd,J＝17.2,13.9,5.5Hz,1H),2.62-2.53(m,3H),2.48(d,J＝8.0Hz,2H),2.37(d,J＝6.7Hz,2H),2.04(ddt,J＝26.0,9.6,4.8Hz,2H),1.72-1.61(m,1H),1.24-1.17(m,2H). 13 C NMR(126MHz,DMSO-d 6 )δ173.30,170.58,168.89,168.18,167.62,167.58,167.00,158.84,157.96,146.44,141.10,138.23,136.39,135.24,134.93,134.44,132.69,129.85,129.58,129.26,129.22,124.70,124.46,121.71,120.04,114.54,111.80,110.40,107.40,79.65,61.31,58.67,56.07,53.32,51.20,49.21,48.88,36.10,31.46,29.50,22.63.MS(ESI):Calcd for C 46 H 43 N 9 O 6 S[M+H] + 850.32,found 850.48.
example 8
The specific preparation method is the same as in example 6 to prepare 2- (6- (6- (4- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) piperazin-1-yl) pyridin-3-yl) -1-oxoisoinden-2-yl) -2-phenyl-N- (thiazol-2-yl) acetamide (II-3) having the following structure:
1 H NMR(400MHz,Chloroform-d)δ9.71(d,J＝31.6Hz,1H),8.48(d,J＝2.5Hz,1H),8.12(s,1H),7.76(dd,J＝8.8,2.5Hz,1H),7.67(dd,J＝8.6,5.9Hz,2H),7.56(d,J＝3.6Hz,1H),7.42(dd,J＝7.3,2.9Hz,3H),7.37-7.31(m,3H),7.29(d,J＝2.3Hz,1H),7.07-7.01(m,1H),6.99(d,J＝3.6Hz,1H),6.71(d,J＝5.9Hz,2H),5.04(d,J＝17.5Hz,1H),4.93(dd,J＝11.9,5.3Hz,1H),4.13(d,J＝17.4Hz,1H),3.61(t,J＝5.0Hz,4H),2.96(t,J＝12.4Hz,2H),2.84-2.72(m,2H),2.56(t,J＝4.9Hz,4H),2.27(d,J＝6.7Hz,2H),2.16-1.99(m,2H),1.89(t,J＝17.3Hz,3H),1.41-1.29(m,3H). 13 C NMR(101MHz,Chloroform-d)δ172.09,172.04,169.08,168.95,168.14,167.96,167.36,158.81,158.71,155.39,146.26,140.60,139.30,138.51,137.42,136.20,134.39,134.17,132.38,129.74,129.22,129.00,128.76,125.44,125.13,123.37,121.43,118.46,117.72,114.11,113.80,108.61,106.90,77.32,64.30,58.23,53.39,49.09,48.23,33.84,30.11,28.96,22.71.MS(ESI):Calcd for C 47 H 45 N 9 O 6 S[M+H] + 864.33,found 864.54.
example 9
The specific preparation method is the same as in example 6 to prepare 2- (6- (6- (4- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) piperidin-4-yl) methyl) piperazin-1-yl) pyridin-3-yl) -1-oxoisoinden-2-yl) -2-phenyl-N- (thiazol-2-yl) acetamide (II-4) having the following structure:
1 H NMR(400MHz,Chloroform-d)δ9.58(s,1H),8.46(d,J＝2.4Hz,1H),8.10(s,1H),7.75(dd,J＝8.7,2.6Hz,1H),7.66(d,J＝8.0Hz,1H),7.57-7.46(m,2H),7.44-7.36(m,3H),7.36-7.28(m,4H),7.15(d,J＝8.5Hz,1H),6.97(d,J＝3.5Hz,1H),6.70(d,J＝9.8Hz,2H),5.01(d,J＝17.4Hz,1H),4.94(dd,J＝12.1,5.5Hz,1H),4.10(dd,J＝15.3,7.2Hz,1H),3.73(t,J＝9.7Hz,2H),3.59(d,J＝5.2Hz,4H),2.80(dddd,J＝32.0,20.1,10.9,6.5Hz,4H),2.55(d,J＝5.2Hz,4H),2.30(d,J＝6.8Hz,2H),2.07(dt,J＝10.3,5.6Hz,1H),1.97-1.82(m,2H),1.81-1.69(m,1H),1.54-1.28(m,3H). 13 C NMR(101MHz,Chloroform-d)δ171.98,168.97,168.90,167.98,167.50,166.71,158.83,158.75,150.88,146.26,140.58,138.54,137.35,136.20,135.47,134.14,132.38,129.74,129.21,129.00,128.78,125.09,123.66,123.36,121.42,117.13,115.23,113.79,106.91,77.32,64.52,60.45,58.27,53.41,51.92,51.64,49.09,48.24,45.11,32.94,31.43,30.96,29.71,29.67,22.70.MS(ESI):Calcd for C 47 H 45 N 9 O 6 S[M+H] + 864.33,found 864.48.
example 10
Sequentially, 50mg (0.098 mmol) of JBJ-07-149 and 56mg (0.15 mmol) of HATU were weighed into a round bottom flask, 7mL of DMF was added for dissolution, 81. Mu.L (0.49 mmol) of DIPEA was then added, stirring was carried out at 40℃for 15min, then 45mg (0.12 mmol) of intermediate 2C was added, reaction was carried out at 40℃overnight, and completion of the reaction was detected by TLC the next day. The reaction mixture was quenched with water, extracted with water (50 mL) and ethyl acetate (30 mL. Times.3), the organic phases combined, washed with saturated sodium carbonate solution (60 mL. Times.1), and then with saturated brine (60 mL. Times.3), dried over anhydrous sodium sulfate, filtered, concentrated, and dry-stirred column chromatography to give 65mg of yellow powdered solid II-5 in about 76% yield.
The prepared 2- (6- (6- (4- (3- ((3- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) prop-2-yn-1-yl) oxy) propionyl) piperazin-1-yl) pyridin-3-yl) -1-oxoisoinden-2-yl) -2-phenyl-N- (thiazol-2-yl) acetamide (II-5) has the following structure:
1 H NMR(400MHz,Chloroform-d)δ9.56(d,J＝33.5Hz,1H),8.49(s,1H),8.14(s,1H),7.89(s,1H),7.84-7.72(m,3H),7.68(d,J＝8.0Hz,1H),7.54(d,J＝3.6Hz,1H),7.42(d,J＝7.0Hz,3H),7.34(t,J＝4.9Hz,3H),6.99(d,J＝3.6Hz,1H),6.76-6.61(m,2H),5.09-4.90(m,2H),4.43(s,2H),3.96(t,J＝6.4Hz,2H),3.86-3.49(m,8H),2.91-2.64(m,5H),2.20-2.08(m,1H). 13 C NMR(101MHz,Chloroform-d)δ171.91,171.80,169.48,168.94,168.45,168.39,167.95,167.89,166.62,166.54,158.64,158.30,146.26,140.74,138.27,137.54,137.43,136.46,134.13,132.41,131.93,130.69,129.77,129.22,129.01,128.77,126.68,125.76,123.75,123.38,121.60,113.82,106.99,90.23,84.50,66.83,66.77,60.44,59.09,58.25,49.46,48.23,45.47,45.14,41.31,33.62,31.39,29.71,22.57,21.10.MS(ESI):Calcd for C 47 H 40 N 8 O 8 S[M+H] + 877.28,found 877.41.
example 11
(1) Preparation of 2- (1-oxo-6- (6- (4- (prop-2-yn-1-yl) piperazin-1-yl) pyridin-3-yl) isoindol-2-yl) -2-phenyl-N- (thiazol-2-yl) acetamide:
JBJ-07-149 mg (0.39 mmol) was weighed and dissolved in 10mL DMF, 42mg (0.35 mmol) of 3-bromopropyl was added, and finally 194. Mu.L (1.18 mmol) of DIPEA was added, and the mixture was stirred at room temperature for 3 hours, and the reaction was completed by TLC detection. To the reaction solution was added 10mL of water for quenching, followed by extraction with saturated brine (60 mL) and dichloromethane (50 mL. Times.3), and the organic phases were combined and washed with saturated brine (50 mL. Times.3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and dry-loaded column chromatography to give 80mg of brown solid 3a in a yield of about 37%. 1 H NMR(400MHz,DMSO-d 6 )δ12.74(s,1H),8.50(d,J＝2.6Hz,1H),7.96-7.85(m,3H),7.61(d,J＝8.0Hz,1H),7.49-7.37(m,6H),7.28(d,J＝3.6Hz,1H),6.94(d,J＝8.9Hz,1H),6.33(s,1H),4.77(d,J＝17.5Hz,1H),3.99(d,J＝17.5Hz,1H),3.57(t,J＝5.0Hz,4H),3.34(d,J＝2.4Hz,2H),3.20(d,J＝2.4Hz,1H),2.55(t,J＝5.0Hz,4H). 13 C NMR(101MHz,DMSO-d 6 )δ168.89,168.19,158.81,146.20,141.15,138.20,136.49,134.90,132.69,129.91,129.59,129.27,124.75,124.56,120.06,114.57,107.55,79.58,76.49,58.68,51.34,48.91,46.51,44.94.
(2) 20mg (0.036 mmol) of intermediate 3a, 21mg (0.036 mmol) of intermediate 3b, 1.2mg (0.0073 mmol) of copper sulfate, 3mg (0.015 mmol) of sodium ascorbate were weighed and placed in a three-necked flask, N 2 Protection was then followed by addition of t-butanol (2 mL) and water (2 mL) using a syringe, sonicated for 5min, then moved to 60℃and heated for 1h, and reacted at room temperature for 16h. The reaction was complete by TLC. Concentrating the reaction solution under reduced pressure to dry, adding 1, 4-dioxane for dissolving, and performing dry sample mixing column chromatography to obtain 40mg pale yellowThe yield of color solid III-1 was about 98%.
To obtain (2S, 4R) -1- ((2S) -3, 3-dimethyl-2- (2- (4- (3-oxo-2- (2-oxo-1-phenyl-2- (thiazol-2-ylamino) ethyl) isoindolin-5-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-1-yl) ethoxy) acetamido-4-hydroxy-N- (4- (4- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (III-1) with the following structure:
1 H NMR(400MHz,Chloroform-d)δ8.65(s,1H),8.37(s,1H),8.02(d,J＝24.6Hz,2H),7.79(s,1H),7.69(d,J＝8.8Hz,1H),7.63(d,J＝7.9Hz,1H),7.51-7.37(m,5H),7.34(d,J＝7.4Hz,3H),7.28(d,J＝5.0Hz,5H),7.03-6.94(m,1H),6.84-6.58(m,2H),5.07(dd,J＝17.5,11.0Hz,1H),4.84(t,J＝7.8Hz,1H),4.67(d,J＝9.2Hz,1H),4.55(s,3H),4.50-4.32(m,3H),4.16(dd,J＝17.2,3.5Hz,1H),4.11-4.00(m,2H),3.94(d,J＝14.4Hz,1H),3.83(d,J＝20.0Hz,4H),3.76-3.69(m,2H),3.58(s,4H),2.67(s,4H),2.45(s,3H),2.29(d,J＝44.5Hz,3H),1.00(s,9H). 13 C NMR(101MHz,Chloroform-d)δ171.67,171.08,169.02,168.16,162.59,158.41,152.03,150.46,146.21,140.79,139.44,138.49,137.54,136.40,134.28,132.34,130.72,129.97,129.37,129.14,128.80,128.76,128.04,125.63,123.51,121.38,114.41,107.20,70.14,69.49,67.07,59.23,58.26,58.12,57.35,57.13,52.02,50.22,48.45,44.43,43.10,37.36,35.99,26.55,14.22.MS(ESI):Calcd for C 57 H 63 N 13 O 7 S 2 [M+H] + 1106.45,found 1106.75.
example 12
The specific preparation method is the same as in example 11 to prepare (2S, 4 r) -1- ((2S) -2- (tert-butyl) -4-oxo-14- (4- (5- (3-oxo-2- (2-oxo-1-phenyl-2- (thiazol-2-ylamino) ethyl) isoindolin-5-yl) pyridin-2-yl) piperazin-1-yl) methyl) -1H-1,2, 3-triazol-1-yl) -6,9, 12-triazol-3-azatetradecyl) -4-hydroxy-N- (4- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (iii-2) having the following structure:
1 H NMR(400MHz,Chloroform-d)δ8.69(s,1H),8.43(s,1H),8.05(s,2H),7.73(d,J＝8.2Hz,2H),7.66(d,J＝8.0Hz,2H),7.42(d,J＝7.1Hz,5H),7.33(d,J＝12.4Hz,6H),7.06-6.91(m,1H),6.70(s,1H),5.04(dd,J＝18.1,4.4Hz,1H),4.73(s,1H),4.63(d,J＝8.9Hz,1H),4.53(s,4H),4.36(d,J＝14.1Hz,2H),4.04-3.96(m,2H),3.94-3.82(m,3H),3.71(s,10H),3.66-3.50(m,10H),2.69(s,3H),2.45(d,J＝31.5Hz,4H),0.98(s,9H). 13 C NMR(101MHz,Chloroform-d)δ171.41,171.05,170.26,169.11,168.00,162.59,158.42,152.05,150.43,146.34,140.78,139.42,138.46,137.58,136.46,134.09,132.41,130.80,129.99,129.49,129.40,129.20,128.89,128.15,125.84,123.52,121.54,114.47,107.23,71.03,70.63,70.51,70.20,69.97,69.43,69.26,68.27,67.18,58.95,58.51,57.18,56.97,52.46,48.40,44.49,43.18,36.81,26.52,14.22.MS(ESI):Calcd for C 61 H 71 N 13 O 9 S 2 [M+H] + 1194.49,found 1194.79.
example 13
The specific preparation method is the same as in example 11 to prepare (2S, 4 r) -1- ((2S) -2- (tert-butyl) -4-oxo-17- (4- (5- (3-oxo-2- (2-oxo-1-phenyl-2- (thiazol-2-ylamino) ethyl) isoindol-5-yl) pyridin-2-yl) piperazin-1-yl) methyl) -1H-1,2, 3-triazol-1-yl) -6,9,12, 15-tetraoxa-3-azepinyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) tetrahydropyrrole-2-carboxamide having the following structure:
1 H NMR(400MHz,Chloroform-d)δ8.67(s,1H),8.42(s,1H),8.02(s,1H),7.85(s,2H),7.76-7.68(m,2H),7.65(d,J＝7.8Hz,1H),7.56(d,J＝7.9Hz,1H),7.47(d,J＝12.7Hz,2H),7.41(d,J＝6.7Hz,3H),7.34(d,J＝6.4Hz,3H),7.29(s,2H),7.05-6.92(m,1H),6.74-6.67(m,1H),5.30(s,1H),5.04(dd,J＝17.2,9.3Hz,1H),4.81-4.73(m,1H),4.61(t,J＝6.9Hz,2H),4.55(s,2H),4.45(q,J＝7.8,6.6Hz,1H),4.37(s,1H),4.06(d,J＝11.0Hz,1H),3.98(s,2H),3.86(s,5H),3.77-3.39(m,4H),2.78(s,3H),2.47(s,3H),2.42-2.33(m,1H),2.22(d,J＝9.4Hz,1H),0.98(s,9H). 13 C NMR(101MHz,Chloroform-d)δ171.49,171.12,170.43,168.07,162.59,158.25,152.07,150.51,146.25,140.81,139.42,138.39,137.57,136.44,134.15,132.36,130.73,129.98,129.43,129.36,129.16,128.84,128.05,125.78,123.53,121.43,114.52,107.29,70.97,70.55,70.44,70.28,70.18,69.89,69.34,69.28,68.38,67.24,59.05,58.23,57.14,52.07,50.42,48.47,44.15,43.16,36.91,26.53,14.22.MS(ESI):Calcd for C 63 H 75 N 13 O 10 S 2 [M+H] + 1238.53,found 1238.74.
example 14
(1) Preparation of (2S, 4 r) -1- ((S) -2- (2-chloroacetamido) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide:
VHLL-1 580mg (1.16 mmol) was weighed into a three-necked flask, N 2 The protection was carried out by adding 15mL of methylene chloride by syringe, then adding 768. Mu.L (4.64 mmol) of DIPEA, and finally adding 100. Mu.L (1.22 mmol) of chloroacetyl chloride under ice bath, and after 20min the reaction flask was moved to room temperature for reaction overnight. The next day TLC was used to detect completion of the reaction, 10mL of water was added to the reaction mixture, followed by extraction with water (150 mL) and dichloromethane (70 mL. Times.3), and the organic phases were combined and washed with saturated brine (50 mL. Times.1). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and dry column chromatography to give 452mg of white solid 3e in a yield of about 80%. 1 H NMR(400MHz,DMSO-d 6 )δ8.99(s,1H),8.64(t,J＝6.1Hz,1H),8.34(d,J＝9.4Hz,1H),7.41(q,J＝8.3Hz,4H),4.55(d,J＝9.3Hz,1H),4.49-4.40(m,2H),4.36(dt,J＝4.3,2.1Hz,1H),4.27-4.14(m,3H),3.70-3.60(m,2H),2.45(s,2H),2.06(dd,J＝13.0,7.7Hz,1H),1.90(ddd,J＝13.0,8.9,4.5Hz,1H),0.95(s,9H). 13 C NMR(101MHz,DMSO-d 6 )δ172.34,169.44,166.20,151.98,148.19,139.95,131.63,130.11,129.12,127.86,69.34,59.22,57.28,57.07,42.94,42.11,38.42,36.17,26.68,16.42.
(2) Intermediate 2a 60mg (0.10 mmol), intermediate 3e 77mg (0.15 mmol) and potassium carbonate 42mg (0.30 mmol) were weighed out sequentially, placed in a round bottom flask, dissolved in 5mL DMF and reacted overnight at room temperature, the next day TLC detection reaction was complete. The reaction mixture was quenched with water, extracted with water (50 mL) and ethyl acetate (30 mL. Times.3), the organic phases combined, washed with saturated sodium carbonate solution (60 mL. Times.1), and then with saturated brine (60 mL. Times.3), dried over anhydrous sodium sulfate, filtered, concentrated, and dry-stirred column chromatography to give 27mg of white solid III-4 in about 26% yield.
The prepared (2S, 4R) -1- ((2S) -3, 3-dimethyl-2- (2- (3- (5- (3-oxo-2- (2-oxo-1-phenyl-2- (thiazol-2-ylamino) ethyl) isoindol-5-yl) pyridin-2-yl) piperazin-1-yl) methyl) pyrrolidin-1-yl) acetamido) butyryl) -4-hydroxy-N- (4- (4- (-4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (III-4) has the following structure:
/>
1 H NMR(400MHz,Chloroform-d)δ8.65(t,J＝1.9Hz,1H),8.41(s,1H),8.07-8.03(m,1H),7.91(s,1H),7.68(dd,J＝33.0,8.5Hz,3H),7.50(dd,J＝10.9,3.7Hz,1H),7.41(tt,J＝5.2,1.9Hz,3H),7.36-7.29(m,7H),6.98(dd,J＝6.3,3.6Hz,1H),6.79-6.63(m,2H),5.06(dd,J＝17.6,6.6Hz,1H),4.83-4.72(m,1H),4.52(q,J＝16.0,12.7Hz,3H),4.35(d,J＝15.2Hz,1H),4.14(d,J＝17.5Hz,2H),3.65(d,J＝10.4Hz,1H),3.55(s,4H),2.52-2.27(m,10H),2.22-2.08(m,1H),1.98(s,1H),1.28(t,J＝3.6Hz,2H),0.98(s,9H). 13 C NMR(101MHz,Chloroform-d)δ171.52,171.27,169.12,169.01,168.13,158.49,150.43,148.47,146.29,140.71,138.58,138.34,137.63,136.31,134.26,132.37,131.73,130.85,129.91,129.49,129.36,129.12,128.81,128.73,128.11,123.47,121.44,113.95,107.06,70.21,63.25,59.25,58.81,58.22,57.34,57.01,54.19,53.04,48.42,45.16,43.22,35.16,32.01,29.79,29.59,26.61,26.57,16.15.MS(ESI):Calcd for C 57 H 65 N 11 O 6 S 2 [M+H] + 1064.47,found 1064.83.
example 15
The specific preparation method is the same as in example 14 to prepare (2S, 4 r) -1- ((2S) -3, 3-dimethyl-2- (2- (4- (5- (3-oxo-2- (2-oxo-1-phenyl-2- (thiazol-2-ylamino) ethyl) isoindol-5-yl) pyridin-2-yl) piperazin-1-yl) methyl) piperidin-1-yl) acetamido) butyryl) -4-hydroxy-N- (4- (4- (-4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (iii-5) having the following structure:
1 H NMR(400MHz,Chloroform-d)δ8.66(s,1H),8.45(t,J＝1.9Hz,1H),8.06(d,J＝1.6Hz,1H),7.98(d,J＝8.7Hz,1H),7.73(dt,J＝9.1,2.7Hz,1H),7.69-7.62(m,2H),7.50(dd,J＝6.4,3.6Hz,1H),7.43-7.37(m,3H),7.32(d,J＝8.8Hz,7H),6.97(t,J＝3.7Hz,1H),6.73(d,J＝15.0Hz,1H),6.69(d,J＝9.0Hz,1H),5.06(dd,J＝17.5,7.5Hz,1H),4.77(t,J＝7.9Hz,1H),4.50(dt,J＝11.3,4.0Hz,3H),4.35(dd,J＝15.1,5.4Hz,1H),4.17-4.08(m,2H),3.69-3.61(m,1H),3.57(t,J＝5.1Hz,4H),2.90(s,2H),2.82(d,J＝10.3Hz,1H),2.79-2.72(m,1H),2.48(d,J＝6.1Hz,8H),2.24-2.03(m,5H),1.75(dd,J＝25.1,12.3Hz,2H),1.18(d,J＝13.1Hz,3H),0.96(s,9H). 13 C NMR(101MHz,Chloroform-d)δ171.41,171.20,168.05,158.81,158.53,158.46,150.37,148.38,146.28,140.60,138.59,138.24,137.56,136.17,134.28,134.22,132.29,131.68,130.75,129.83,129.42,129.26,129.01,128.71,128.64,128.04,125.06,123.38,121.36,113.84,106.85,70.09,64.53,61.45,58.73,58.11,58.00,57.22,56.88,54.14,53.37,48.30,45.10,43.17,36.32,35.03,32.52,31.12,29.71,26.50,16.07.MS(ESI):Calcd for C 58 H 67 N 11 O 6 S 2 [M+H] + 1078.48,found 1078.82.
EXAMPLE 16 preparation of hydrochloric acid
Taking the compound III-4 obtained in example 14 as an example, the compound III-4 is dissolved in ethyl acetate, HCl gas is introduced to be saturated, and the mixture is placed in an ice bath to precipitate a solid, namely hydrochloride of the compound III-4.
Application example: EGFR protein degradation Activity assay
Corresponding cells after drug intervention are collected, washed 2 times with precooled PBS, PMSF and PIPA lysate are mixed in a ratio of 1:100, cells are lysed on ice for 20min,4 ℃ and 12000r/min are centrifuged for 20min, the supernatant, namely the total protein of the cells, is taken, protein quantity is detected by BCA method, and the protein is denatured for 5min at 100 ℃ after being diluted by 5 x protein loading buffer. Proteins were separated by SDS-PAGE, transferred to membrane, blocked for 2 hours and incubated overnight at 4 ℃. TBST was washed and the secondary antibody was incubated at 1:1000 for 2 hours, and developed on X-ray film after chemiluminescence, and the results are shown in Table 1 and Table 2.
TABLE 1
TABLE 2
As can be seen from Table 1, compound III-4 vs EGFR WT And EGFR (epidermal growth factor receptor) Del19 All have good degradation activity, and EGFR in H1299 cells can be enabled at the concentration of 0.1 mu M WT About 76% degradation of EGFR in PC-9 cells Del19 Degradation is about 72%.
As can be seen from Table 2, compounds II-3 and II-5 pair EGFR in H1975 cells L858R/T790M Has better degradation activity, can degrade about 60% at the concentration of 0.1 mu M, and the degradation effect is kept unchanged at the high concentration of 1 mu M.

Claims (7)

1. An EGFR allosteric site-based PROTAC compound is characterized by comprising a compound shown in formulas I, II and III and pharmaceutically acceptable salts thereof:
wherein, the compound n of the formula I is an integer of 1-7, and m is an integer of 1-2;
the compound n of the formula II is an integer of 1-2;
the compound n of formula III is an integer from 1 to 7, and m is an integer from 1 to 2.
2. The EGFR allosteric site based PROTAC class compound of claim 1 wherein said pharmaceutically acceptable salt comprises: addition salts with hydrochloric acid, hydroolfactory acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, tea disulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid or benzoic acid; and hydrochloric acid, hydroolfactory acid, sulfuric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, trifluoroacetic acid, maleic acid, benzenesulfonic acid or patonic acid.
3. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
4. A formulation of a pharmaceutical composition according to claim 3, wherein the pharmaceutical composition is formulated into a clinically acceptable dosage form by adding pharmaceutically acceptable excipients.
5. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a different anti-cancer agent.
6. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention or/and treatment of cancer.
7. The use according to claim 6, wherein the cancer is multiple myeloma, gastric cancer, lung cancer, breast cancer, esophageal cancer, colon cancer, medulloblastoma, acute myelogenous leukemia, chronic leukemia, prostate cancer, hepatoma, renal cytoma, cervical cancer, skin cancer, ovarian cancer, colon cancer, glioma, thyroid cancer or pancreatic cancer.
CN202311005106.6A 2023-08-10 2023-08-10 PROTAC compound based on EGFR allosteric site and application thereof Pending CN117105927A (en)

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