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WO2021175234A1 - Composé benzothiazole et son utilisation médicale - Google Patents

Composé benzothiazole et son utilisation médicale Download PDF

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WO2021175234A1
WO2021175234A1 PCT/CN2021/078798 CN2021078798W WO2021175234A1 WO 2021175234 A1 WO2021175234 A1 WO 2021175234A1 CN 2021078798 W CN2021078798 W CN 2021078798W WO 2021175234 A1 WO2021175234 A1 WO 2021175234A1
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compound
substituted
unsubstituted
dmso
nmr
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Chinese (zh)
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孙宏斌
陈彩萍
周鑫煜
刘胜杰
袁浩亮
温小安
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China Pharmaceutical University
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China Pharmaceutical University
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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
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to the field of medicinal chemistry, in particular to benzothiazole compounds and their use in pharmacy, in particular to benzothiazole compounds as USP7 C-terminal domain regulators and their use in the prevention and treatment of myelodysplastic syndromes and malignancies. Use in tumors, inflammations or autoimmune diseases.
  • Myelodysplastic syndrome is a group of heterogeneous myeloid clonal diseases originating from hematopoietic stem cells, characterized by abnormal differentiation and development of myeloid cells, manifested by ineffective hematopoiesis, refractory hematopoietic reduction, and hyperplasia. The risk is transformed into acute myeloid leukemia (AML).
  • AML acute myeloid leukemia
  • the main causes of death of patients are complications caused by the disease itself and death caused by conversion to AML (Cancer 2010, 16: 2174-2179). According to statistics, in the United States, the prevalence rate is about 0.004-0.005%, and the susceptible population is elderly men or those who have previously received chemotherapy (Blood 2008, 112: 45-52).
  • MDS is divided into two types: high-risk and low-risk.
  • the classification is based on the proportion of immature cells in the bone marrow and the analysis of mutant genes.
  • the International Prognostic Scoring System (IPSS) is used to score the test results, based on the proportion of bone marrow blasts, the number of blood cells, and the type of gene mutation (Am.J.Hematol.2014,89:98-108; Blood 1997,89 :2079-2088).
  • IIPSS International Prognostic Scoring System
  • Different types of MDS have different treatment goals.
  • the goal of treatment for low-risk MDS is to reduce the need for blood transfusion, delay the process of transforming AML, and increase survival, while the goal of treatment for high-risk MDS is to prolong survival.
  • DNMT1 DNA methyltransferase 1
  • DNMT1 DNA methyltransferase 1
  • the C-terminus mainly exerts its catalytic function of methylation, while the N-terminus mainly regulates the activity of the catalytic region through allosteric action, thereby controlling the interaction between DNMT1 and other proteins (Prog.Mol.Biol.Transl.Sci.2011, 101:221-254; Epigenetics 2012, 7:994-1007).
  • DNMT1 The basic function of DNMT1 is to methylate newly synthesized DNA in the S phase of the cell cycle (Nature 2007,447:396-398). In mammals, the time point of methylation is precise and fixed, while the human body controls the time point of methylation through regulation of the level of DNMT1 protein: regulation of a series of transcription and post-transcriptional modifications Down, the protein level of DNMT1 changes with changes in the cell cycle, reaching a peak in the early S phase, then decreasing and reaching the lowest point in the G1 phase (Sci.Signal. 2010, 3:ra80).
  • the protein level of DNMT1 is controlled by a variety of post-transcriptional modification methods: ubiquitination, acetylation (Sci.Signal.2011,4:pe3; Mol.Cell Biol.2011,31:4720-4734), methylation (Proc. Natl.Acad.Sci.USA 2009,106:5076-5081; Nat.Genet.2009,41:125-129; Nat.Struct.Mol.Biol.2011,18:42-48) and protein-protein interactions (such as And ⁇ -catenin) (Nucleus 2011, 2:392-402) can affect the level of DNMT1 protein.
  • DNMT1 DNMT1
  • ubiquitination directly mediates the degradation of DNMT1 protein and plays a vital role in its stability.
  • USP7 is a deubiquitinating enzyme, which is a kind of ubiquitin-specific proteases (USPs), which can efficiently hydrolyze the ubiquitin chain on the substrate protein and deubiquitinate the target substrate to stabilize it.
  • USP7 is a nuclear protein, which is mainly distributed in nuclear dots in the nucleus to perform its physiological functions.
  • USP7 structure is highly conserved (human and mouse USP7 structure homology is as high as 98.6%), composed of 1102 amino acids, and its relative molecular mass is about 135kDa (Cell 2009,138:389-403; Nat.Cell Biol. 2002, 4:106-110).
  • USP7 can be divided into N-terminal TRAF domain (residue 53-206), catalytic domain (residue 208-560) and C-terminal UBL domain (residue 564-1084) according to its amino acid sequence and function.
  • USP7 plays an important role in the protein stability, enzyme activity and target DNA recognition of DNMT1.
  • USP7 is the deubiquitinating enzyme of DNMT1. Its C-terminal UBL1-2 region has an acid pocket consisting of four amino acid residues Glu736, Asp758, Glu759 and Asp764 and the KG connecting region of DNMT1 (residue 1109-1119) Interaction (Nat.Commun.2015, 6:7023-7034), thereby deubiquitinating and stabilizing the DNMT1 protein.
  • USP7 plays an important role in the stability of DNMT1.
  • USP7 also It can regulate the enzymatic activity of DNMT1 through protein-protein interaction.
  • USP7 mediates the binding of DNMT1 to the target DNA.
  • DNMT1 itself does not recognize the target DNA sequence of hemimethylation. It needs to form a trimer complex with USP7 and UHRF1 before it can perform demethylation.
  • the N-terminal of USP7 is bound to UHRF1
  • the C-terminal of USP7 is bound to the N-terminal TS region of DNMT1
  • UHRF1 is bound to the N-terminal RFTS region of DNMT1.
  • the SDR region of UHRF1 can specifically recognize DNA hemimethylated CpG islands, and the DNMT1-UHRF1-USP7 complex is then pulled to the DNA target region to play a role (Nucleic Acids Res. 2011, 39: 8355-8365). Therefore, inhibiting DNMT1 by interfering with the interaction between the C-terminal domain of USP7 and DNMT1 is a potential treatment approach for diseases such as myelodysplastic syndrome and malignant tumors.
  • USP7 C-terminal regulator has potentially important medical value.
  • small molecule modulators of USP7 C-terminal protein It is of great significance to develop small molecule modulators of USP7 C-terminal domain with high activity and low toxic and side effects.
  • the present invention provides a class of benzothiazole compounds, which can be used as USP7 C-terminal regulators, or pharmaceutically acceptable salts or esters or solvates thereof. It has a strong binding force to the C-terminal protein of USP7, and can reduce the protein level of DNMT1 in tumor cells. It also has a significant anti-tumor cell proliferation effect. In addition, it can also inhibit the deubiquitination of NF ⁇ B by USP7.
  • the invention also provides preparation methods, pharmaceutical combinations and medical uses of the benzothiazole compounds and intermediates thereof.
  • X is methylene, carbonyl or sulfonyl
  • Y is hydrogen or XR 1 ;
  • R 1 and R 2 are each independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Substituted heterocycloalkyl, substituted or unsubstituted heterocycloalkenyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic aryl.
  • R 3 is hydrogen, hydroxyl, heterocyclyl, alkyl, NH 2 , NO 2 , COOH, CN, SH, CF 3 , SO 3 H, SO 2 CH 3 or halogen.
  • X is a methylene group, a carbonyl group or a sulfonyl group
  • Y is hydrogen or XR 1 ;
  • R 1 is a substituted alkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted benzyl group, a substituted or unsubstituted heteroarylmethyl group, a substituted or unsubstituted aryl group or a heteroaryl group;
  • R 2 is substituted and unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl
  • R 3 is hydrogen, a hydroxyl group or a heterocyclic group.
  • X is a sulfonyl group
  • Y is hydrogen or XR 1 ;
  • R 1 is a substituted alkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted benzyl group, a substituted or unsubstituted heteroarylmethyl group, a substituted or unsubstituted aryl group or a heteroaryl group;
  • R 2 is substituted or unsubstituted heterocycloalkyl
  • R 3 is hydrogen
  • the benzothiazole compound of the present invention is a compound represented by the following formula II or formula III or a pharmaceutically acceptable salt or solvate thereof:
  • Y is hydrogen or SO 2 R 1 ;
  • R 1 and R 2 are each independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Substituted heterocycloalkyl, substituted or unsubstituted heterocycloalkenyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic aryl.
  • the benzothiazole compound of the present invention is any one of the compounds in Table 1 or a pharmaceutically acceptable salt or ester or solvation thereof:
  • the present invention provides the use of benzothiazole compounds represented by formulas I to III or pharmaceutically acceptable salts or esters or solvates thereof in the preparation of USP7 C-terminal regulators.
  • the inventors discovered that the benzothiazole compounds represented by formulas I to III can bind to the C-terminal of USP and cause conformational changes at the C-terminal of USP. This is the first type of USP7 C-terminal small molecule regulators disclosed so far.
  • the present invention also provides the use of the benzothiazole compounds represented by formulas I to III or pharmaceutically acceptable salts or esters or solvates thereof in the preparation of prevention or treatment of inflammation, autoimmune diseases, myelodysplastic syndromes and malignant tumors. Use in medicine.
  • the inflammation and autoimmune diseases include but are not limited to: ulcerative colitis, Crohn's disease, systemic lupus erythematosus, rheumatoid arthritis, psoriasis, multiple sclerosis or Behçet's disease.
  • the tumor includes, but is not limited to: bone cancer, hematology cancer, nervous system cancer, gastrointestinal cancer, urinary system cancer, lung cancer, liver cancer or skin cancer.
  • the bone cancer includes, but is not limited to: bone-derived sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, Malignant giant cell tumor chordoma, osteochondroma (gu tube exogenous bone wart), benign chondroma, chondroblastoma, cartilage and tumor-like fibroma, osteoid osteoma, and giant cell tumor.
  • bone-derived sarcoma osteosarcoma
  • fibrosarcoma malignant fibrous histiocytoma
  • chondrosarcoma chondrosarcoma
  • Ewing's sarcoma malignant lymphoma
  • multiple myeloma Malignant giant cell tumor chordoma
  • osteochondroma gu tube exogenous bone
  • the hematological cancers include but are not limited to: acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, myelodysplastic disease, multiple myeloma and myelodysplastic syndrome, Hodge King's lymphoma (malignant lymphoma) and Waldenstrom's macroglobulinemia.
  • the nervous system cancers include, but are not limited to: meningeal cancer, such as meningiomas, meningiosarcoma, and glioma; brain cancers, such as astrocytoma, medulloblastoma, glioma, ependymoma, Germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, and congenital tumors; spinal cord tumors, such as fibroneuronoma, meningioma , Glioma and Sarcoma.
  • meningeal cancer such as meningiomas, meningiosarcoma, and glioma
  • brain cancers such as astrocytoma, medulloblastoma, glioma, ependymoma, Germ cell tumor (pineal tumor), glioblastoma multi
  • the gastrointestinal tumors include, but are not limited to: esophageal cancers, such as squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma; stomach cancers, such as tumors, lymphomas, and leiomyosarcomas; pancreatic cancer, such as ductal adenocarcinoma, insulinoma, Glucagonoma, gastrinoma, carcinoid tumor and vasoactive intestinal peptide tumor; small bowel cancer, such as adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma , Fibroneuronoma and fibroids; colorectal cancer, such as adenocarcinoma, tubular adenocarcinoma, villous adenoma, hamartoma, and leiomyoma.
  • the urinary system cancers include, but are not limited to: kidney cancer, such as adenocarcinoma, Wilms tumor (wilms tumor), lymphoma, and leukemia; bladder and urethral cancer, such as squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma ; Prostate cancer, such as adenocarcinoma and sarcoma; Testicular cancer, such as seminoma, teratoma, embryonic carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, gland Tumor-like tumors and lipomas.
  • kidney cancer such as adenocarcinoma, Wilms tumor (wilms tumor), lymphoma, and leukemia
  • bladder and urethral cancer such as squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma
  • Prostate cancer such as adenocar
  • the lung cancer includes, but is not limited to: bronchial carcinoma, such as squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, and adenocarcinoma; bronchioloalveolar carcinoma; bronchial adenoma; sarcoma; lymphoma; pulmonary chondroma Hamartoma and mesothelioma.
  • bronchial carcinoma such as squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, and adenocarcinoma
  • bronchioloalveolar carcinoma bronchial adenoma
  • sarcoma sarcoma
  • lymphoma pulmonary chondroma Hamartoma
  • mesothelioma mesothelioma.
  • the liver cancer includes but is not limited to: hepatocellular carcinoma, such as hepatocellular carcinoma; cholangiocarcinoma; hepato
  • the skin cancer includes but is not limited to: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis .
  • the compound of the present invention can be used in combination with one or more other types of drugs for the prevention or treatment of the above-mentioned diseases, including but not limited to the following combination drugs:
  • preventive or therapeutic drugs can be one or more anti-cancer drugs, including alkylating agents (such as cisplatin, cyclophosphamide, ifosfamide, melphalan, Chlorambucil, Bendamustine, Estramustine, Cetepa, Iminoquinone, Busulfan, Dibromomannitol, Cyclohexylnitrosene, Carmustine, Pyrimidine Nitrosourea, Methalin Nitrosourea, methazine, procarbazine, etc.), antimetabolites (such as fluorouracil, cytarabine, furfurouracil, difurfurouracil, mercaptopurine, sulfathioprine, azathioprine, thioguanine) , Methotrexate, methotrexate, etc.), anti-tumor antibiotics (such as mitomycin C, bleomycin
  • alkylating agents such as cisplatin,
  • the present invention also provides a pharmaceutical composition for preventing or treating inflammation, autoimmune diseases, myelodysplastic syndromes and tumors, which contains a therapeutically effective amount of any benzothiazole compound represented by formula I to III or its Pharmaceutically acceptable salts or solvates are used as active ingredients and pharmaceutically acceptable excipients.
  • the adjuvants that can be arbitrarily mixed can be changed according to the dosage form, administration form, etc.
  • the carrier includes but is not limited to excipients, binders, disintegrating agents, lubricants, flavoring agents, flavoring agents, coloring agents and sweetening agents.
  • the pharmaceutical composition can be in the form of conventional pharmaceutics such as ordinary tablets or capsules, sustained-release tablets or capsules, controlled-release tablets or capsules, granules, powders, syrups, oral liquids or injections.
  • the present invention has the following advantages:
  • the benzothiazole compound of the present invention or its pharmaceutically acceptable salt or ester or solvate has a strong binding force with the C-terminal protein of USP7, and is the first USP7 C-terminal small molecule regulator published so far It can reduce the protein level of DNMT1 in tumor cells and has a significant anti-tumor cell proliferation effect, so it can be used to prepare drugs for the prevention or treatment of myelodysplastic syndromes and malignant tumors.
  • the USP7 C-terminal small molecule regulator of the present invention can also block the binding of USP7 C-terminal to NF ⁇ B, inhibit the deubiquitination of NF ⁇ B, and has significant anti-inflammatory activity, so it can also be used for the preparation of anti-inflammatory drugs and treatments.
  • Drugs for autoimmune diseases can also block the binding of USP7 C-terminal to NF ⁇ B, inhibit the deubiquitination of NF ⁇ B, and has significant anti-inflammatory activity, so it can also be used for the preparation of anti-inflammatory drugs and treatments.
  • Drugs for autoimmune diseases Drugs for autoimmune diseases.
  • the benzothiazole compound of the present invention or its pharmaceutically acceptable salt or ester or solvate has good drug-forming properties in human liver microsomes, and can be absorbed orally with good drug-forming properties.
  • the benzothiazole compound of the present invention has simple structure, ingenious synthesis route design, cheap and readily available raw materials, safe and environmentally friendly synthesis process, and is easy to scale production.
  • Figure 1 is an X-ray co-crystal structure diagram of compound 25 and USP7 C-terminal protein
  • Figure 2 is a graph of the GST Pull-down experiment result of the compound's influence on the interaction between USP7 C-terminal protein and DNMT1;
  • Figure 3 is a Western Blot experimental result of compound 55 concentration-dependently reducing the level of DNMT1 in NB4 cells;
  • Figure 4 is a diagram showing the results of a Western Blot experiment in which compound 60 reduces the level of DNMT1 in NB4 cells in a concentration-dependent manner;
  • Figure 5 shows the effect of compound 55 on LPS-induced IL-1b and IL-6 expression on Raw264.7 cells.
  • Compound 1c (100mg, 0.39mmol) was added to dichloromethane (3mL) (suspension), followed by isonicotinic acid (52mg, 0.47mmol), 1-(3-dimethylaminopropyl)-3- Ethylcarbodiimide hydrochloride (96mg, 0.47mmol) and 4-dimethylaminopyridine (47mg, 0.47mmol) were stirred overnight at room temperature. A large amount of gray solids were observed to precipitate.
  • Ethyl p-fluorobenzoate (13a, 100mg, 0.59mmol) was dissolved in dry dimethyl sulfoxide (1mL), and 1-Boc-piperazine (13b, 121mg, 0.65mmol) and potassium carbonate (246mg , 1.78mmol), stirred at 120°C for 5h, TLC monitored the completion of the reaction and added saturated brine (5mL), extracted with ethyl acetate (5mL ⁇ 3).
  • Ethyl 5-chloromethyl-2-furancarboxylate (33f, 200mg, 1.06mmol) was dissolved in acetonitrile (10mL), followed by morpholine (55mg, 1.27mmol), potassium iodide (176mg, 1.27mmol) and potassium carbonate (212mg, 1.27mmol), stirred at room temperature for 7 hours.
  • the mother liquor after recrystallization was evaporated to remove the solvent under reduced pressure, ethyl acetate (30 mL) was added to the obtained solid to make a slurry, and a yellow solid (37b, 2.06 g) was obtained by suction filtration, which was combined with the solid obtained by recrystallization and put into the next step.
  • Ethyl acetate (100 mL) was added to the obtained solid to dissolve it, 15% sodium hydroxide solution was added dropwise to adjust the pH to 6-7, and then saturated sodium bicarbonate solution was used to adjust the pH to 7-8.
  • the ethyl acetate was evaporated under reduced pressure and then filtered with suction, the filter cake was collected and dried.
  • the filtrate was extracted with ethyl acetate (80mL ⁇ 3).
  • the ethyl acetate layer was washed with saturated brine and dried with anhydrous sodium sulfate for 0.5 hours.
  • the anhydrous sodium sulfate was removed by filtration and the solvent was evaporated under reduced pressure.
  • dichloromethane (3mL) to the reaction solution to dilute, transfer the reaction solution to a 15mL centrifuge tube, centrifuge at 2500rpm for 5 minutes, discard the supernatant, add dichloromethane (3mL), and continue centrifugation at 2500rpm for 5 minutes.
  • Dissolve compound 39c (1.78g, 7.10mmol) in dioxane (80mL), add solid sodium hydroxide (1.70g, 42.60mmol) under ice bath, add water (40mL) to the system, and stir under ice bath 30 minutes. After that, 5% sodium hypochlorite solution (29 mL, 42.60 mmol) was added dropwise to the system, and the mixture was stirred at room temperature overnight. After the reaction was monitored by TLC, the stirring was stopped, the solvent was evaporated under reduced pressure and water (10mL) was added, and the compound 39d (white solid, 1.44g, yield 91%) was obtained by suction filtration: 1 H NMR (500MHz, DMSO-d 6 ) ⁇ 7.
  • reaction solution was diluted with anhydrous dichloromethane (30mL), washed with 1N dilute hydrochloric acid (50mL), water (50mL ⁇ 2) and saturated brine (50mL) successively, dried with anhydrous sodium sulfate, filtered, and the filtrate Concentrate and recrystallize with ethyl acetate (10 mL) to obtain compound 1b (light yellow solid, 1.7 g, yield 73%).
  • the furoic acid was replaced with 1-Boc-4-piperidinecarboxylic acid to prepare the N-Boc precursor compound of compound 41 (dark green solid, 140 mg).
  • reaction solution was concentrated, ethyl acetate (30 mL) was added, neutralized with saturated sodium bicarbonate aqueous solution (30 mL), filtered under reduced pressure, and the filter cake was washed with water (30 mL) and ethyl acetate (10 mL) to obtain compound 55c (Brown solid, 1.05g, yield 94%).
  • the monomethyl isophthalate (56a, 500mg, 2.77mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 1023mg, 3.32mmol) and triethylamine (561mg, 5.54mmol) were sequentially added to N,N-dimethylformamide (6mL), stirred at room temperature and reacted for 1 hour, then 3-amino-1-propanesulfonic acid was added (579mg, 4.16mmol), continue to stir the reaction at room temperature.
  • Dissolve compound 57b (166mg, 0.54mmol) in a mixed solution of acetic acid (7.5mL) and water (2.5mL), add zinc powder (176mg, 2.7mmol), stir at room temperature until TLC detects the reaction is complete, add saturated carbonic acid first Sodium bicarbonate solution (15ml), then add solid sodium bicarbonate until no bubbles are generated.
  • Example 65 Referring to the synthesis procedure of Example 65, the raw material 65a was replaced with 1-tert-butoxycarbonyl-4-piperidineacetic acid to obtain intermediate 66a (white solid, 497 mg).
  • Example 65 Referring to the synthesis step of Example 65, the raw material 65a was replaced with Boc-glycine, and the 2-amino-6nitrobenzothiazole was replaced with 71e to obtain intermediate 71f (white solid, 240 mg, 85%).
  • Example 65 Referring to the synthetic route of Example 65, the raw material 65a was replaced with Boc-glycine, and 2-thiophenesulfonyl chloride was replaced with 1-methyl-1H-pyrazole-3-sulfonyl chloride to obtain intermediate 72a (yellow solid, 150 mg).
  • Example 80 Refer to the synthesis procedure of Example 80, replace 1-tert-butoxycarbonyl-4-piperidineacetic acid with tetrahydropyran-4-carboxylic acid, and replace 2-thiophenesulfonyl chloride with 3-(chlorosulfonyl)propionate methyl Ester to obtain compound 85 (white solid, 160 mg).
  • Example 85 tetrahydropyran-4-carboxylic acid was replaced with 1-methylpiperidine-4-carboxylic acid to obtain the methyl ester of compound 87.
  • compound 85 was replaced with the methyl ester of compound 87 to obtain compound 87 (white solid, 127 mg).
  • Example 2 Referring to the synthetic experimental procedure of Example 1, the furoyl chloride was replaced with acetyl chloride to prepare N-(6-aminobenzo[d]thiazol-2-yl)acetamide. Again referring to the synthetic experimental procedure in Example 23, p-nitrobenzoyl chloride was replaced with 2-thiophenesulfonyl chloride, and 1c was replaced with N-(6-aminobenzo[d]thiazol-2-yl)acetamide to obtain Compound 92 (white solid).
  • MST Micro thermophoresis
  • the MST method was used to determine the binding force of the compound to the C-terminal protein of USP7, and the respective equilibrium dissociation constants (K D ) were calculated.
  • the compound of the present invention (dissolved with dimethyl sulfoxide (DMSO) to prepare a mother liquor, dilute with Tris-HCl buffer to an appropriate concentration before use); USP7 C-terminal protein (10 ⁇ M); Microthermophoresis (NT.115) ; MST standard capillary; MST protein fluorescent labeling kit (NT-647); Tris-HCl buffer.
  • DMSO dimethyl sulfoxide
  • Table 1 shows the binding force (K D ) test results of some compounds with the C-terminal protein of USP7. Experimental results show that the compound of the present invention can bind to the C-terminal protein of USP7, and some compounds have strong affinity, and other compounds also have good affinity.
  • SPR Surface Plasmon Resonance
  • the SPR method was used to determine the binding force of the compound to the C-terminal protein of USP7, and the respective equilibrium dissociation constants (K D ) were calculated.
  • the compound of the present invention (dissolved in DMSO to prepare a mother liquor, diluted with PBST (pH 7.4, Tween 20 content 0.05%) buffer to an appropriate concentration before use); USP7 C-terminal protein (1mg/mL); Biacore T200(GE Healthcare); CM5 chip (GE Healthcare); Amino coupling kit (GE Healthcare); PBST buffer.
  • Table 2 shows the binding force (K D ) test results of some compounds with the C-terminal protein of USP7.
  • the experimental results show that the compound of the present invention can bind to the C-terminal protein of USP7, and some compounds have stronger affinity, and other compounds also have better affinity.
  • SPR Surface Plasmon Resonance
  • the surface plasmon resonance (SPR) method was used to determine the binding ability of the compound to the full-length USP7 protein and different domains to investigate whether the compound is specific to the C-terminal domain protein of USP7.
  • Example 96 Refer to the test method of Example 96 to replace the USP7 C-terminal protein with the USP7 full-length protein or proteins with different domains to perform the surface plasmon resonance (SPR) method to determine the binding force of the protein to the compound.
  • SPR surface plasmon resonance
  • Table 3 shows the binding ability test results of compounds 25, 55 and 60 with the full-length USP7 protein and different domains.
  • the experimental results show that compounds 25, 55 and 60 have strong specificity to the C-terminal domain protein of USP7. They do not bind to the N-terminal domain protein of USP7. Although they also bind to the catalytic domain protein of USP7, their affinity is not as good as With the C-terminal domain protein.
  • the binding of compound 55 to the C-terminal domain protein of USP7 is highly dependent on the C-terminal UB12 domain and amino acid sequence 666-723. When the UB12 domain or amino acid sequence 666-723 is missing, the binding force drops sharply; other compounds have a strong effect on the C-terminal structure of USP7 Domain proteins are also specific.
  • CTD ⁇ UBl2 is the USP7 C-terminal protein with the UBL2 domain deleted
  • CTD ⁇ 666-723 is the USP7 C-terminal protein with the amino acid sequence 666-723 deleted
  • ND means not tested.
  • Compound 25 binds to the UBL2 domain of the C-terminal protein of USP7, and the binding pocket is composed of key amino acid residues such as Asp666, Tyr706 and Arg723.
  • the sulfonyl group of compound 25 forms a hydrogen bond with the Asp666 residue of UBL2 of the USP7 C-terminal protein, and the amide group and thiazole ring form a hydrogen bond with Tyr706 residue.
  • the CellTiter-Glo method was used to evaluate the compound's inhibitory activity against tumor cell proliferation in vitro
  • the compound of the present invention (dissolved in DMSO to prepare a mother liquor, and dilute to an appropriate concentration with complete medium before use); CellTiter-Glo Luminescent cell viability detection kit (purchased from Promega); medium and fetal calf serum (purchased from Biological Industries) Company); 96-well cell culture plate (purchased from Thermo Fisher Scientific Company), EnSpire microplate reader (purchased from PerkinElmer Company).
  • Select cells with more than 90% viable cells for cell plating that is, add 100 ⁇ L of cell suspension to each well of a 96-well plate, including 2500 LNCaP cells per well, RS 4; 5000 cells per well for 11 cells, and MM.1S cells 16,500 cells per well, 2000 cells per well for NB4, MCF7, Huh7 and HCT-116 cells. Place the 96-well plate in a 37°C, 5% CO 2 incubator for 24 hours.
  • the 96-well plate was placed in a 37°C, 5% CO 2 incubator for continuous culture, in which LNCaP cells were cultured for 6 days, MM.1S cells were cultured for 5 days, RS 4;11, NB4, MCF7, Huh7 and HCT-116 cells Continue to cultivate for 3 days.
  • the compound 60 of the present invention has significant in vitro proliferation inhibitory activity against the above-mentioned various tumor cells, especially LNCaP, RS 4; 11, NB4. Some other compounds of the present invention also have an inhibitory effect on the growth of tumor cells. This result suggests that the compounds of the present invention can be used to prepare anti-tumor drugs.
  • the compound of the present invention (dissolved in DMSO to prepare a mother liquor, diluted with a complete medium to a concentration of 1 ⁇ M, 5 ⁇ M, 10 ⁇ M and 20 ⁇ M before use); modified RMPI-1640 medium and fetal calf serum (purchased from Biological Industries); 6 Well cell culture plate (purchased from NEST company).
  • compounds 55 and 60 decreased the DNMT1 level of NB4 cells in a concentration-dependent manner.
  • Other compounds of the present invention such as 25, 44, 56 have the same effect, indicating that the compound of the present invention inhibits the deubiquitination of DNMT1 by USP7 by interfering with the binding of USP7 C-terminal to DNMT1, thereby degrading DNMT1 ubiquitination Increase, and thus decrease the DNMT1 level.
  • the incubation system is incubated at 37°C for one hour. After adding NADPH solution, the timing starts. The reaction was terminated at each time point by adding the stop solution, and the sampling interval was 0, 5, 15, 30, and 60 minutes, a total of 5 points. NADPH was not added to the negative control, and the sampling time point was 0 to 60 minutes.
  • Ultra-high performance liquid chromatography system Waters, ACQUITY UPLC, including binary solvent manager (ACQUITY UPLC Binary Solvent Manager), sample manager (ACQUITY UPLC Sample Manager), high-throughput sample organizer (ACQUTIY UPLC Sample Organizer) ), high temperature column heater (ACQUITY UPLC Column Heater HT).
  • Binary solvent manager ACQUITY UPLC Binary Solvent Manager
  • sample manager ACQUITY UPLC Sample Manager
  • high-throughput sample organizer ACQUTIY UPLC Sample Organizer
  • ACQUITY UPLC Column Heater HT High temperature column heater
  • Mass spectrometer TQ 6500+, American Applied Biosystems
  • electrospray ion source (ESI) tandem quadrupole mass analyzer.
  • Micro analytical balance (XP26, METTLER TOLEDO Instruments (Shanghai) Co., Ltd.); vortex oscillator (SI-A256, Scientific Industries, Inc.; MULTI-TUBE VORTEXER, Fisher Scientific); small desktop high-speed refrigerated centrifuge (5417R, Eppendorf); ultrapure water machine (Millipore); pipette (Eppendorf).
  • the data processing system is Analyst software (American Applied Biosystems, software version number 1.6.3).
  • Methanol (Burdick & Jackson, HPLC), acetonitrile (Burdick & Jackson, HPLC), formic acid (J&K), water is ultrapure water.
  • Solvent 5% DMSO + 10% solutol + 85% saline.
  • mice Balb/C male mice, SPF grade.
  • mice were grouped according to Table 6 for experiment.
  • Blood was collected from the orbit. About 0.03 mL of each sample was collected. Heparin sodium was anticoagulated and placed on ice after collection.
  • Plasma samples were collected on ice and centrifuged to separate plasma within 1 hour (centrifugation conditions: 6800g, 6 minutes, 2-8°C). Plasma samples are stored in a -80°C refrigerator before analysis, and the plasma samples are analyzed by the analysis department of the laboratory using LC-MS/MS.
  • the blood sampling time points are as follows:
  • Oral group 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 24h after administration.
  • Intravenous group 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, 24h after administration.
  • A 0.1% formic acid aqueous solution
  • B 0.1% formic acid acetonitrile solution
  • column temperature 40°C
  • autosampler temperature 4°C
  • flow rate 0.6 ml/min
  • injection volume 2 ⁇ l.
  • Scan mode negative ion multi-reaction detection mode
  • ion source electrospray ion source
  • atomization mode electrospray
  • Q1 resolution Unit
  • Q3 resolution Unit
  • atomizing gas (Gas1) 50psi
  • auxiliary heater (Gas2 ) 50psi
  • Curtain Air (CUR) 40psi
  • Ion Source Voltage (IS) -450v
  • TEM Ion Source Temperature
  • Preparation of 400,000ng/mL working solution Take compound 55 stock solution and dilute it with methanol to a working solution with a concentration of 400,000ng/mL.
  • Preparation of standard curve and quality control samples Take a certain amount of 400,000ng/mL working solution and add it to a certain amount of blank plasma at a ratio of 1:39 to prepare a plasma sample with a concentration of 10,000ng/mL. Take 10000ng/mL plasma samples and dilute them to 5000, 1000, 500, 100, 50, 10, 5ng/mL standard curve samples and 4000, 800, 15ng/mL quality control samples with blank plasma.
  • Preparation of the internal standard working solution pipet a certain amount of tolbutamide internal standard stock solution with a concentration of 1018,000ng/mL into a certain volume of volumetric flask, dilute to the mark with methanol and mix well to obtain a concentration of 200ng /mL of internal standard working solution.
  • the non-compartmental model calculates the pharmacokinetic parameters AUC 0-t , AUC 0- ⁇ , MRT 0- ⁇ , C max , T max and T 1/2 of the test product respectively.
  • the bioavailability (F) will be calculated by the following formula.
  • mice pharmacokinetic data is shown in Table 7.
  • Table 7 The results show that compound 55 can be absorbed orally, and its oral bioavailability in mice is 19.54%.
  • the other compounds of the present invention can also be absorbed orally. This indicates that the benzothiazole compounds of the present invention have better drug-forming properties.
  • Raw264.7 cells (purchased from the Cell Bank of the Chinese Academy of Sciences) were cultured in DMEM medium containing 10% inactivated fetal bovine serum.
  • Raw264.7 was inoculated into a 12-well plate at 300,000 per well, and cultured adherently for 12 hours.
  • Compound 55 was prepared into a 10 mM stock solution with DMSO, and diluted sequentially with DMEM medium containing 10% inactivated fetal bovine serum to obtain a drug solution with a corresponding working concentration. The medium in the 12-well plate was discarded, and the medium containing the medicinal solution was added for pretreatment for 1 h.
  • the lipopolysaccharide (LPS) stock solution with a concentration of 1 mg/mL was diluted with culture medium to a 100 ng/mL culture medium solution, and the compound was diluted with the lipopolysaccharide-containing medium solution to the corresponding working concentration (0-20 ⁇ M).
  • the pretreated medium was discarded, the medium solution was added to the control wells, the 100ng/mL lipopolysaccharide medium solution was added to the positive wells, and the compound-containing lipopolysaccharide medium solution was added to the dosing wells. After stimulation for 1 hour, the culture medium was discarded, and the cells were frozen in a refrigerator at -80°C for subsequent testing.
  • compound 55 significantly inhibited LPS-induced IL-6 and IL-1b in a dose-dependent manner.
  • Other compounds of the present invention also have similar effects, indicating that the compound of the present invention has anti-inflammatory activity.
  • Example 60 The compound 60 (50g), hydroxypropylmethylcellulose E (150g), starch (200g), povidone K30 and magnesium stearate (1g) prepared in Example 60 were mixed, granulated, and compressed. .
  • the compounds prepared in Examples 1-94 can be given different pharmaceutical excipients into capsules, powders, granules, pills, injections, syrups, oral liquids, inhalants, ointments, according to the conventional preparation method of the pharmacopoeia 2015 edition. Agent, suppository or patch, etc.

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Abstract

L'invention concerne un composé benzothiazole représenté par la formule I et son utilisation médicale, et concerne en particulier un composé d'agent de régulation du domaine à extrémité C-terminale de benzothiazole USP7 ou un sel, ester ou solvate pharmaceutiquement acceptable de celui-ci, son procédé de préparation et son utilisation. Le composé ou un sel pharmaceutiquement acceptable, ester ou solvate de celui-ci selon la présente invention a une forte force de liaison avec une protéine à extrémité C-terminale USP7, un effet régulateur sur un domaine à extrémité C-terminale USP7, un effet significatif de prolifération des cellules tumorales et une activité anti-inflammatoire, et peut être utilisé pour préparer un médicament destiné à la prévention ou au traitement du syndrome myélodysplasique, de tumeurs malignes, de l'inflammation ou de maladies auto-immunes.
PCT/CN2021/078798 2020-03-03 2021-03-03 Composé benzothiazole et son utilisation médicale Ceased WO2021175234A1 (fr)

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