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WO2025213998A1 - INHIBITEUR DOUBLE CIBLE PI3Kδ-MTOR, SON PROCÉDÉ DE PRÉPARATION ET SON UTILISATION - Google Patents

INHIBITEUR DOUBLE CIBLE PI3Kδ-MTOR, SON PROCÉDÉ DE PRÉPARATION ET SON UTILISATION

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Publication number
WO2025213998A1
WO2025213998A1 PCT/CN2025/080619 CN2025080619W WO2025213998A1 WO 2025213998 A1 WO2025213998 A1 WO 2025213998A1 CN 2025080619 W CN2025080619 W CN 2025080619W WO 2025213998 A1 WO2025213998 A1 WO 2025213998A1
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Prior art keywords
dmso
nmr
added
preparation
disease
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PCT/CN2025/080619
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English (en)
Chinese (zh)
Inventor
崔孙良
汤用美
李佳
周宇波
石玲珠
郭雨刚
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zhongshan Institute For Drug Discovery
Zhejiang University ZJU
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Zhongshan Institute For Drug Discovery
Zhejiang University ZJU
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Publication of WO2025213998A1 publication Critical patent/WO2025213998A1/fr
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Anticipated expiration legal-status Critical

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
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    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to the field of medicinal chemistry, and specifically to a class of PI3K ⁇ -mTOR dual-target inhibitors, and preparation methods and applications thereof.
  • the dual-target inhibitors exhibit inhibitory activity against type I PI3K, but have weaker inhibitory activity against PI3K ⁇ , PI3K ⁇ , and PI3K ⁇ than against PI3K ⁇ , thereby specifically and highly selectively inhibiting PI3K ⁇ .
  • the PI3K/AKT/mTOR signaling pathway is a highly conserved signaling network in eukaryotic cells that plays an important role in regulating cell proliferation, apoptosis, metabolism, angiogenesis, and various physiological processes. It is one of the most commonly overactivated signaling pathways in human cancer and is closely associated with the development of drug resistance and disease progression in cancer treatment.
  • the PI3K/AKT/mTOR signaling pathway is a complex network consisting of phosphatidylinositol 3-kinase (PI3K), protein kinase B (PKB, also known as Akt), and the mammalian target of rapamycin (mTOR), as well as multiple upstream regulators and downstream effectors.
  • PI3K and mTOR belong to the PIKK family, and there are certain similarities between their catalytic domains, which has also promoted the development of PI3K/mTOR dual inhibitors.
  • PI3K/mTOR dual inhibitors simultaneously target PI3K and mTOR. Compared with simple mTOR inhibitors, they can effectively overcome the problem of negative feedback activation of the PI3K signaling pathway observed when using mTORC1 inhibitors alone.
  • simultaneous inhibition of PI3K and mTOR activity can not only inhibit cell proliferation, but also induce cell apoptosis.
  • dual-target inhibitors show high efficacy even at low doses and are not prone to drug resistance, which indicates that PI3K/mTOR inhibitors are promising anti-cancer drugs.
  • PI3K/mTOR inhibitors have entered the clinical stage.
  • pan-type I PI3K/mTOR inhibitors they simultaneously target all type I PI3K isoforms, resulting in high toxicity and poor tolerability.
  • completely blocking the PI3K/AKT/mTOR signaling pathway may lead to compensatory activation of other signaling pathways, thereby causing drug resistance. Therefore, the development of isoform-specific dual inhibitors of PI3K and mTOR has the potential to improve efficacy while reducing the incidence of toxicity and drug resistance to a certain extent.
  • the present invention provides a compound of formula (1) that has the ability to inhibit the activity of PI3K ⁇ and mTOR kinases and can be used as a dual-target inhibitor.
  • X, Y, and Z are each independently selected from C or N;
  • M 1 is selected from N, O or S
  • M 2 is selected from N or S, and only one of M 1 and M 2 is N;
  • R 1 is selected from C 1-6 alkyl (e.g., methyl, ethyl, etc.);
  • R 2 is selected from one or more of hydrogen, halogen (such as F, etc.);
  • R3 is selected from pyridyl, C1-6 alkyl (including chain alkyl, cycloalkyl, chain alkyl and cycloalkyl combination, such as methyl, ethyl, isopropyl, cyclopropyl, cyclopropylmethyl etc.), phenyl, benzyl, thienyl, pyridylmethyl (e.g.
  • pyrazolyl which is optionally substituted by zero, one or more substituents selected from the following: -SO2 ( C1-6 alkyl), C1-6 alkyl (including chain alkyl, cycloalkyl, chain alkyl and cycloalkyl combinations, such as methyl, ethyl, isopropyl, cyclopropyl, cyclopropylmethyl etc.), C 1-6 haloalkyl (wherein the halo may be F, etc., the number of halo is not limited and may be one or more, and the alkyl includes chain alkyl, cycloalkyl, a combination of chain alkyl and cycloalkyl, etc., such as methyl, ethyl, isopropyl, cyclopropyl, cyclopropylmethyl etc.), halogen;
  • R 4 is selected from H or -NH 2 ;
  • R 5 is selected from H or -NH 2 .
  • the compound of formula (1) can be selected from any of the following compounds:
  • the present invention also relates to pharmaceutical compositions comprising the above compounds or pharmaceutically acceptable salts, solvates, esters, acids, metabolites or prodrugs thereof, as well as methods and uses of the compounds or pharmaceutical compositions for inhibiting PI3K ⁇ /mTOR kinase activity, and methods and uses of the compounds or pharmaceutical compositions for treating, preventing or ameliorating diseases, disorders or conditions regulated by or affected by PI3K ⁇ /mTOR kinase activity or in which PI3K ⁇ /mTOR kinase activity is involved.
  • the compounds provided herein may exhibit tautomerism, structural isomerism, and stereoisomerism.
  • the present invention encompasses any tautomeric, structural, or stereoisomer forms thereof, and mixtures thereof, which have the ability to modulate kinase activity, and this ability is not limited to any one isomer or mixture thereof.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula (1) or a pharmaceutically acceptable salt thereof, a racemic mixture, a hydrate, a solvate, a prodrug, an enantiomer, a diastereomer, a tautomer, and one or more pharmaceutically acceptable carriers, diluents, and excipients.
  • the compounds described herein can be made and/or used as pharmaceutically acceptable salts.
  • the types of pharmaceutically acceptable salts include, but are not limited to: (1) acid-forming salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, or the like; or by reacting the free base form of the compound with an organic acid, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, citric acid, succinic acid, maleic acid, tartaric acid, fumaric acid, trifluoroacetic acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,
  • 2-ene-1-carboxylic acid 2-naphthalenesulfonic acid, tert-butylacetic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, salicylic acid, hydroxynaphthoic acid, stearic acid, muconic acid, etc.; (2) forming salts with bases, which are formed when the acidic protons in the parent compound are replaced by metal ions, such as alkali metal ions (such as lithium, sodium, potassium), alkaline earth metal ions (such as magnesium or calcium) or aluminum ions; or coordinated with organic bases or inorganic bases, acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, trimethylamine, N-methylglucamine, etc.; acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydro
  • a pharmaceutically acceptable carrier is a carrier that is compatible with the active ingredient in the composition (in some embodiments, stabilizes the active ingredient) and is not harmful to the subject being treated.
  • Pharmaceutically acceptable carriers and/or excipients can be selected from diluents, fillers, salts, disintegrants, binders, lubricants, glidants, wetting agents, controlled release matrices, colorants, flavorings, buffers, stabilizers, solubilizers, and combinations thereof.
  • composition comprising the compound of formula (1) and/or its pharmaceutically acceptable salt described herein can be administered in various known ways, such as orally, topically, rectally, parenterally, by inhalation or by implantation.
  • the pharmaceutical composition can be prepared into various types of dosage unit forms, such as tablets, pills, powders, liquid preparations, suspensions, emulsions, granules, capsules, elixirs, tinctures, suppositories and injections (solutions and suspensions).
  • any excipient known and widely used in the art may be used.
  • carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and silicic acid; binders such as water, ethanol, propanol, ordinary syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinyl pyrrolidone, and the like; disintegrants such as dry starch, sodium alginate, agar powder, kelp powder, sodium bicarbonate, calcium carbonate, fatty acid esters of polyethylene sorbitan, sodium lauryl sulfate, monoglyceride of stearate, starch, and lactose; disintegration inhibitors such as white sugar, glyceryl tristearate, coconut oil, and hydrogenated oil; adsorption promoters such as quaternary ammonium hydrox
  • any excipient known and widely used in the art can be used, for example, carriers such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc; binders such as gum arabic powder, tragacanth powder, gelatin and ethanol; disintegrants such as agar and kelp powder;
  • any excipient known and widely used in the art may be used, for example, polyethylene glycol, coconut oil, higher alcohols, esters of higher alcohols, gelatin and semi-synthetic glycerides and the like.
  • the solution or suspension can be sterilized (preferably by adding an appropriate amount of sodium chloride, glucose, or glycerol) and prepared into an injection with an osmotic pressure equal to that of blood.
  • Any commonly used carrier in the art can be used in the preparation of the injection, such as water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and fatty acid esters of polyethylene sorbitan.
  • conventional solvents, buffers, and analgesics can also be added.
  • the method of administration of the pharmaceutical composition is not particularly limited.
  • Various dosage forms can be selected for administration based on the patient's age, gender, and other conditions and symptoms.
  • tablets, pills, solutions, suspensions, emulsions, granules, or capsules can be administered orally; injections can be administered alone or mixed with an injectable delivery fluid (such as a glucose solution or an amino acid solution) for intravenous injection; and suppositories are administered rectally.
  • an injectable delivery fluid such as a glucose solution or an amino acid solution
  • the present invention also provides a method for inhibiting PI3K and/or mTOR activity in vivo or in vitro, comprising contacting PI3K and/or mTOR with an effective amount of a compound of formula (1) and/or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a method for inhibiting PI3K and/or mTOR activity in vivo or in vitro, comprising contacting PI3K and/or mTOR with a pharmaceutical composition in an amount effective to inhibit PI3K and/or mTOR activity, wherein the pharmaceutical composition comprises a compound of formula (1) (e.g., any compound herein) and/or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • a compound of formula (1) e.g., any compound herein
  • a pharmaceutically acceptable salt thereof e.g., any compound herein
  • the present invention also provides a method for treating a disease responsive to inhibition of PI3K and/or mTOR in an individual, comprising administering to an individual in need thereof a compound of formula (1) and/or a pharmaceutically acceptable salt thereof in an amount effective to inhibit PI3K and/or mTOR in the individual.
  • the present invention also provides a method for treating a disease responsive to inhibition of PI3K and/or mTOR in an individual, comprising administering to an individual in need thereof a pharmaceutical composition in an amount effective to inhibit PI3K and/or mTOR in the individual, the pharmaceutical composition comprising a compound of formula (1) and/or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • the present invention also provides the use of the compound of formula (1) or its pharmaceutically acceptable salt, racemic mixture, hydrate, solvate, prodrug, enantiomer, diastereomer, tautomer, or pharmaceutical composition in the preparation of a PI3K inhibitor and/or an mTOR inhibitor.
  • the PI3K inhibitor may be a PI3K ⁇ inhibitor, an inhibitor of the p110 ⁇ isoform of PI3 kinase (PI3K).
  • the present invention also provides the use of the compound of formula (1) or its pharmaceutically acceptable salt, racemic mixture, hydrate, solvate, prodrug, enantiomer, diastereomer, tautomer, or pharmaceutical composition in the preparation of a medicament for treating a disease responsive to PI3K and/or mTOR inhibition.
  • the PI3K may be PI3K ⁇ , etc.
  • the diseases include inflammatory diseases, autoimmune diseases, cancer, infectious diseases, cardiovascular and cerebrovascular diseases, and nervous system diseases.
  • Inflammatory diseases refer to pathological conditions that result in an inflammatory response, particularly due to neutrophil chemotaxis.
  • diseases include inflammatory skin diseases (including psoriasis and atopic dermatitis); systemic scleroderma and sclerosis; reactions associated with inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis); ischemia-reperfusion injury, including tissue reperfusion injury caused by surgery, myocardial ischemia such as myocardial infarction, cardiac arrest, postoperative reperfusion after cardiac surgery, and abnormal coronary vasoconstriction after percutaneous transluminal coronary angioplasty; tissue reperfusion injury after stroke and abdominal aortic aneurysm surgery; cerebral edema secondary to stroke; cranial trauma; hemorrhagic shock; asphyxia; adult respiratory distress syndrome; acute lung injury; Behçet's disease; dermatomyositis; polymyositis; multiple sclerosis; dermatitis; men
  • Autoimmune diseases are diseases or conditions caused by an immune response to self-antigens, resulting in damage to the body's own tissues or organs.
  • autoimmune diseases include, but are not limited to, chronic obstructive pulmonary disease, allergic rhinitis, lupus erythematosus, myasthenia gravis, multiple sclerosis (MS), rheumatoid arthritis, psoriasis, inflammatory bowel disease, asthma, idiopathic thrombocytopenic purpura, and myeloproliferative disorders such as myelofibrosis and polycythemia vera/essential thrombocythemia myelofibrosis.
  • the inflammatory diseases and autoimmune diseases include rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), systemic vasculitis, allergic rhinitis, asthma, systemic lupus erythematosus, Sjögren's syndrome, pemphigus, multiple sclerosis, psoriasis, Hashimoto's thyroiditis, type I diabetes, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, Goodpasture's syndrome, pemphigus vulgaris, pemphigoid, primary biliary cirrhosis, multiple sclerosis, acute idiopathic polyneuritis, scleroderma, dermatomyositis, mixed connective tissue disease, autoimmune hemolytic anemia, autoimmune hepatitis, thyroid autoimmune disease, idiopathic thrombocytopenic purpura, etc.
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive
  • the cancer includes, but is not limited to, solid tumors or hematological malignancies, including cancers of the skin, tissues, organs, bones, cartilage, blood, and blood vessels, including both primary cancers and metastatic cancers.
  • solid tumors include pancreatic cancer; bladder cancer; colorectal cancer; breast cancer, including metastatic breast cancer; prostate cancer, including androgen-dependent and androgen-independent prostate cancer; kidney cancer, including, for example, metastatic renal cell carcinoma; hepatocellular carcinoma; lung cancer, including, for example, non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), and lung adenocarcinoma; ovarian cancer, including, for example, progressive epithelial carcinoma or primary peritoneal cancer; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer, including, for example, head and neck squamous cell carcinoma; skin cancer, including, for example, malignant melanoma; neuroendocrine cancer, including metastatic neuroen
  • Non-limiting examples of hematologic malignancies include acute myeloid leukemia (AML); chronic myeloid leukemia (CML), including accelerated phase CML and CML blast crisis (CML-BP); acute lymphocytic leukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin lymphoma; non-Hodgkin lymphoma (NHL), including follicular lymphoma and mantle cell lymphoma; B-cell lymphoma; T-cell lymphoma; multiple myeloma (MM); Waldenstrom's macroglobulinemia; myelodysplastic syndromes, including refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, and refractory anemia with excess blasts combined with acute transformation; and myeloproliferative syndromes.
  • AML acute myeloid leukemia
  • CML chronic myeloid leukemia
  • the cancer can be selected from leukemia, multiple myeloma (MM), lymphoma;
  • the leukemia is acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML);
  • the lymphoma is Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, B cell lymphoma, T cell lymphoma, diffuse large B cell lymphoma (DLBCL).
  • infectious diseases include but are not limited to bacterial infection, fungal infection, viral infection, and parasitic infection.
  • cardiovascular and cerebrovascular diseases include but are not limited to acute heart failure, hypotension, hypertension, angina pectoris, myocardial infarction, cardiomyopathy, congestive heart failure, atherosclerosis, coronary heart disease, restenosis and vascular stenosis, as well as traumatic brain injury, stroke, ischemia-reperfusion injury and arteriosclerosis.
  • the mental illnesses include but are not limited to neurodevelopmental diseases, such as autism; neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis; mood disorders, such as depression, mania, bipolar disorder and anxiety; thinking and will disorders, such as schizophrenia; consciousness disorders, such as epilepsy; in addition, they also include migraine, attention deficit hyperactivity disorder, prosopagnosia and amnesia, etc.
  • the compounds of formula (1) and/or pharmaceutically acceptable salts thereof described herein can be used in combination with other active ingredients for the treatment of inflammatory diseases, autoimmune diseases, cancer, infectious diseases, or cardiovascular and cerebrovascular diseases.
  • the compounds of formula (I) and/or pharmaceutically acceptable salts thereof can be used separately from other active ingredients or prepared into compound preparations.
  • Other active ingredients are those known to be effective in treating diseases mediated by PI3K and/or mTOR.
  • A3 A1 (2 g, 9.39 mmol), bipyralidoborane (3.58 g, 14.09 mmol), Pd(dppf) Cl2 (137 mg, 0.19 mmol), and potassium acetate (1.84 g, 18.78 mmol) were added to a two-necked flask. The mixture was evacuated and purged with argon three times. 30 mL of anhydrous dioxane was added, and the mixture was evacuated again and purged with argon. After purging, the mixture was reacted at 115°C for 18 h.
  • B3 B2 (6 g, 36.55 mmol) was added to a two-necked flask, and the argon atmosphere was replaced three times. Anhydrous THF was added, and the reaction solution was cooled to -10°C. Methylmagnesium chloride (36.55 mL, 3.0 M in THF) was slowly added dropwise. After the addition was completed, the reaction was moved to room temperature. After the reaction was completed, saturated ammonium chloride solution was added at low temperature to quench the reaction.
  • B5 B4 (4.1 g, 23.01 mmol), cuprous iodide (876 mg, 4.6 mmol), L-proline (1.06 g, 9.2 mmol), and potassium carbonate (6.36 g, 46.02 mmol) were weighed and added to a two-necked flask under argon protection. 30 mL of DMSO was added, and 3-bromopyridine (5.45 g, 34.52 mmol) was added at room temperature and the temperature was raised to 120°C for reaction. After the reaction was completed, the mixture was cooled to room temperature, 60 mL of ethyl acetate was added, and the mixture was stirred for 20 min.
  • the organic layer was collected, washed three times with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated.
  • the mixture was separated by column chromatography using DCM/MeOH (v/v, 30:1) as the eluent to afford a pale yellow solid (180 mg, 59.3%).
  • the product had a melting range of 274.2-276.3°C and a purity of 100.00%.
  • the preparation method is similar to that of Preparation Example 1, except that A3 is replaced with A5 to replace the reactants.
  • the synthetic route of A5 is as follows:
  • A4 (1.5 g, 6.55 mmol), diboronic acid pinacol ester (2.5 g, 9.83 mmol), Pd(dppf) Cl2 ⁇ CH2Cl2 (531 mg, 0.66 mmol), and potassium acetate (1.93 g, 19.65 mmol) were added to a two-necked flask. The mixture was evacuated and purged with argon three times. 30 mL of anhydrous dioxane was added, and the mixture was evacuated again and purged with argon. After complete purging, the mixture was reacted at 105°C for 12 h.
  • the preparation method is similar to that of Preparation Example 2, except that the reactants are replaced.
  • the preparation method is similar to that of Preparation Example 1, except that 3-bromopyridine is replaced with iodomethane and the reactants are replaced.
  • the preparation method is similar to that of Preparation Example 5, except that iodomethane is replaced by iodoethane.
  • the preparation method is similar to that of Preparation Example 5, except that iodomethane is replaced by 2-iodopropane, sodium hydroxide is replaced by cesium carbonate, and the solvent is anhydrous DMF.
  • the preparation method is similar to that of Preparation Example 7, except that 2-iodopropane is replaced by bromomethylcyclopropane, and cesium carbonate is replaced by potassium carbonate.
  • the preparation method is similar to that of Example 1, except that the reactants are replaced.
  • the preparation method is similar to that of Example 1, except that the reactants are replaced.
  • the preparation method is similar to that of Example 1, except that the reactants are replaced.
  • the preparation method is similar to that of Example 7, except that the reactants are replaced.
  • the preparation method is similar to that of Example 7, except that the reactants are replaced.
  • the preparation method is similar to that of Example 1, except that the reactants are replaced.
  • the preparation method is similar to that of Example 1, except that the reactants are replaced.
  • the preparation method is similar to that of Example 1, except that the reactants are replaced.
  • the preparation method is similar to that of Example 1, except that the reactants are replaced.
  • the preparation method is similar to that of Example 18, except that iodoethane is replaced with 2-iodopropane and anhydrous potassium carbonate is replaced with anhydrous cesium carbonate.
  • the preparation method is similar to that of Example 18, except that iodoethane is replaced with bromocyclopropane, and anhydrous potassium carbonate is replaced with anhydrous cesium carbonate.
  • the preparation method is similar to that of Preparation Example 1, except that 3-iodopyridine is replaced with 21-B.
  • the preparation method is similar to that of Preparation Example 1, except that 3-iodopyridine is replaced with 22-B.
  • the preparation method is similar to that of Example 18, except that iodoethane is replaced with bromomethylcyclopropane, and anhydrous potassium carbonate is replaced with anhydrous cesium carbonate.
  • the preparation method is similar to that of Preparation Example 1, except that methylmagnesium chloride is replaced with ethylmagnesium chloride.
  • the preparation method is similar to that of Example 1, except that 6-chloroindole is replaced with 6-methylindole.
  • the preparation method is similar to that of Preparation Example 1, except that B8 is replaced by B8-27.
  • the preparation method is similar to that of Preparation Example 1, except that B8 is replaced by B8-28.
  • the preparation method is similar to that of Example 1, except that the reactants are replaced.
  • the preparation method is similar to that of Preparation Example 27, except that the reactants are replaced.
  • the preparation method is similar to that of Preparation Example 27, except that the reactants are replaced.
  • the preparation method is similar to that of Example 1, except that the reactants are replaced.
  • the preparation method is similar to that of Preparation Example 27, except that the reactants are replaced.
  • the preparation method is similar to that of Preparation Example 27, except that the reactants are replaced.
  • the preparation method is similar to that of Example 1, except that the reactants are replaced.
  • the preparation method is similar to that of Example 1, except that the reactants are replaced.
  • the preparation method is similar to that of Preparation Example 27, except that the reactants are replaced.
  • the preparation method is similar to that of Preparation Example 27, except that the reactants are replaced.
  • the preparation method is similar to that of Example 1, except that the reactants are replaced.
  • the preparation method is similar to that of Example 1, except that the reactants are replaced.
  • the preparation method is similar to that of Preparation Example 27, except that the reactants are replaced.
  • the preparation method is similar to that of Preparation Example 27, except that the reactants are replaced.
  • 43-B (3 g, 8.73 mmol) was placed in a two-necked flask under argon protection. Anhydrous toluene was added to dissolve the mixture, cooled to -78°C, and DIBAL-H (17.5 mL, 1 M in hexane) was slowly added. The mixture was allowed to react at -78°C for 3 h. After completion of the reaction, methanol and water (v:v, 1:5) were slowly added dropwise at low temperature to quench the reaction. After stirring for 30 min, the mixture was filtered through celite and the residue was repeatedly washed with ethyl acetate. The organic layer was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. 43-C (2.5 g, 83.3%) was isolated by silica gel column chromatography using PE/EA (v/v, 2/1) as the developing solvent to obtain a light yellow solid.
  • 43-C (2 g, 5.79 mmol) was weighed and placed in a single-necked flask. 15 mL of methanol was added, followed by 5 mL of 6 M hydrochloric acid at room temperature, and the reaction was continued at room temperature for 2 h. After completion of the reaction, the methanol was removed by rotary evaporation, and the concentrate was separated by adding water/ethyl acetate. The aqueous layer was collected and made alkaline with sodium hydroxide solution. The aqueous phase was extracted three times with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 43-D (1.1 g, 78%) as a yellow oil.
  • the preparation method is the same as that of Preparation Example 43, except that S-(-)-tert-butylsulfenamide is replaced by R-(+)-tert-butylsulfenamide.
  • the preparation method is the same as that of Preparation Example 43, except that S-(-)-tert-butylsulfenamide is replaced by tert-butylsulfenamide and the reducing agent is sodium borohydride.
  • ADP-Glo TM Kinase assay was used for determination.
  • the test compound was diluted to the required concentration range, and 50 nL of each was transferred to a 384-well plate.
  • 50 nL of DMSO was added to the negative and positive control wells, respectively.
  • PI3K ⁇ , ⁇ , ⁇ , and ⁇ were diluted to 1.25 nM, 1.25 nM, 10 nM, and 1.25 nM, respectively, with kinase buffer. 2 ⁇ L was then added to each well of the 384-well plate.
  • 2.5 ⁇ L was added to the negative and positive control wells, centrifuged for 30 seconds, vortexed to mix, and incubated at room temperature for 10 minutes.
  • the log value of the concentration was used as the X-axis and the percentage inhibition rate was used as the Y-axis.
  • the log (inhibitor) vs. response-Variable slope analysis software GraphPad Prism 5 was used to fit the dose-effect curve to obtain the IC50 value of each compound on the enzyme activity.
  • mTOR kinase The inhibitory activity of the test compounds against mTOR kinase was determined using the Lance Ultra kinase assay.
  • mTOR kinase was purchased from Eurofins, ULight-4E-BP1 (Thr37/46) Peptide and Eu-anti-P-4E-BP1 (Thr37/46) were purchased from PerkinElmer, Triton X-100, MgCl2, DTT, and EGTA were purchased from Sigma, EDTA and HEPES (pH 7.5) were purchased from Gibco, and 384-well Echo plates were purchased from Labcyte.
  • test compound was diluted to a final concentration of 100-fold with 100% DMSO, followed by a 3-fold serial dilution in DMSO. 200 nL of the test solution was added to a 384-well plate via echo. Next, 10 ⁇ L of kinase solution (mTOR kinase added to 1x kinase buffer to a final concentration of 4 nM) was added to each well.
  • kinase solution mTOR kinase added to 1x kinase buffer to a final concentration of 4 nM
  • 1x kinase buffer (formula: 50 mM HEPES, pH 7.5, 10 mM MgCl2, 0.01% Triton X-100, 0.01% 10% BSA, 2 mM DTT) was added instead and incubated at room temperature for 10 min.
  • the substrate 4E-BP1 and ATP were added to the 1x kinase buffer to prepare a 2x substrate solution (final concentration of ATP: 8 ⁇ M, final concentration of 4E-BP1: 50 nM).
  • the reaction was initiated by adding 10 ⁇ L of the 2x substrate solution to each well of the assay plate and incubated at room temperature for 1 h.
  • a detection solution (containing 8 mM EDTA and 2 nM 4E-BP1 phosphoantibody) was then prepared at 2x the final concentration. Finally, 20 ⁇ L of the detection solution was added to each well of the assay plate to stop the reaction. The Lancet signal ratio (665 nm/615 nm) was read using Envision. The inhibition rate was calculated according to the formula, and the IC50 value was calculated based on the inhibition rate values at different concentrations.
  • the minimum value is the reading of the control well without adding kinase
  • the maximum value is the reading of the control well with adding DMSO.
  • Table 1 shows the IC 50 values of the compounds of the present invention against PI3K ⁇ , PI3K ⁇ and mTOR
  • Table 2 shows the IC 50 values of some compounds against type I PI3K and mTOR.
  • Table 1 Inhibitory activity of dual-target inhibitors (compounds 1-43 prepared above) against PI3K ⁇ , PI3K ⁇ and mTOR (wherein “E” indicates IC50 > 10 ⁇ M; “D” indicates 10 ⁇ M > IC50 > 1 ⁇ M; “C” indicates 1 ⁇ M > IC50 > 100 nM; “B” indicates 100 nM > IC50 > 10 nM; “A” indicates IC50 ⁇ 10 nM).
  • Table 2 Inhibitory activity of some dual-target inhibitors against type I PI3K and mTOR (wherein “E” indicates IC50 > 10 ⁇ M; “D” indicates 10 ⁇ M > IC50 > 1 ⁇ M; “C” indicates 1 ⁇ M > IC50 > 100 nM; “B” indicates 100 nM > IC50 > 10 nM; “A” indicates IC50 ⁇ 10 nM).
  • the dual-target inhibitors of the present invention exhibited strong inhibitory activity against both PI3K ⁇ and mTOR, and weaker inhibitory activity against PI3K ⁇ .
  • the anti-proliferative activity of Mino, MOLM13, NCI-H1975, and PANC-1 cells was tested using the CCK8 assay, and the anti-proliferative activity of MV-4-11 and B16-F10 cell lines was tested using the MTS assay.
  • Mino 5 ⁇ 10 3 cells/well
  • MV-4-11 (1 ⁇ 10 4 cells/well
  • MOLM13 5 ⁇ 10 3 cells/well
  • PANC-1 2 ⁇ 10 3 cells /well
  • B16-F10 5 ⁇ 10 2 cells/well
  • NCI-H1975 5 ⁇ 10 3 cells /well.
  • the compound stock solution was diluted with DMSO in a 96-well pointed bottom plate from 10 mM to 8 concentration gradients in 5-fold. 198 ⁇ L of cell culture medium was added to the 96-well plate, and 2 ⁇ L of compound was aspirated from the 500 ⁇ compound storage plate and added to the cell culture medium of the 96-well plate. 2 ⁇ L of DMSO was added to the vehicle control. After adding the compound or DMSO, the compound plate was placed on a shaker and gently shaken to mix.
  • the inhibition rate was calculated using the following formula: (OD Sample - OD Blank ) / (ODDMSO - OD Blank ) ⁇ 100%, where OD Sample represents the absorbance of the dosing well (OD 450 - OD 650 ), ODDMSO represents the absorbance of the DMSO control well (OD 450 - OD 650 ), and OD Blank represents the absorbance of the culture medium control well (OD 450 - OD 650 ).
  • IC 50 values were calculated using GraphPad Prism software. For MTS, the wavelengths were 490 nM and 690 nM, respectively.
  • Table 3 Antiproliferative activity of preferred compounds on lymphoma and leukemia cells.
  • PI3K ⁇ /mTOR inhibitors are more effective than simple PI3K ⁇ and mTOR inhibitors.
  • MCL mantle cell lymphoma
  • adelanib has been reported to exhibit intrinsic drug resistance in the treatment of MCL and has poor antiproliferative activity against most MCL cells.
  • Table 3 the selected compounds exhibited superior inhibitory activity compared to adelanib in the MCL cell line mino and the acute leukemia cell lines MV-4-11 and MOLM-13. In particular, adelanib had little effect on mino cells, with an IC 50 of approximately 10 ⁇ M.
  • the dual-target inhibitors effectively inhibited the proliferation of mino cells, demonstrating superior inhibitory efficacy compared to adelanib.
  • the pan-type I PI3K/mTOR inhibitor Gidalicept and the mTOR inhibitor Sapasertib were superior to our compounds in anti-proliferative inhibition at the cellular level. This is because Gidalicept targets all type I PI3Ks, more effectively blocking the PI3K/AKT/mTOR signaling pathway, resulting in a superior inhibitory effect.
  • Sapasertib targets not only mTOR and type I PI3Ks but also other kinases. Kinase profiling data showed that it has poor selectivity, which also makes it more effective in inhibiting cell proliferation.
  • Table 4 Antiproliferative activity of preferred compounds against solid tumor cells.

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Abstract

La présente invention concerne un composé de formule (1) ayant une activité inhibitrice de PI3Kδ et mTOR kinase, ou un sel pharmaceutiquement acceptable de celui-ci. X, Y et Z sont chacun indépendamment choisis parmi C ou N ; M1 est choisi parmi N, O ou S, M2 est choisi parmi N ou S, et un et seulement un parmi M1 et M2 est N ; R1 est choisi parmi alkyle en C1-6 ; R2 est choisi parmi un ou plusieurs parmi hydrogène et halogène ; R3 est choisi parmi pyridyle, alkyle en C1-6, phényle, benzyle, thiényle, pyridylméthyle ou pyrazolyle, et est éventuellement substitué par zéro, un ou plusieurs substituants choisis parmi les suivants : Alkyle en -SO2(C1-6), alkyle en C1-6, haloalkyle en C1-6 et halogène ; R4 est choisi parmi H ou -NH2 ; et R5 est choisi parmi H ou -NH2. Le composé peut être utilisé en tant qu'inhibiteur double cible pour le traitement de maladies sensibles à l'inhibition de PI3K et/ou l'inhibition de mTOR.
PCT/CN2025/080619 2024-04-08 2025-03-05 INHIBITEUR DOUBLE CIBLE PI3Kδ-MTOR, SON PROCÉDÉ DE PRÉPARATION ET SON UTILISATION Pending WO2025213998A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010059593A1 (fr) * 2008-11-18 2010-05-27 Intellikine, Inc. Procédés et compositions pour le traitement d'affections ophtalmiques
CN105102000A (zh) * 2012-11-01 2015-11-25 无限药品公司 使用pi3激酶亚型调节剂的癌症疗法
CN111918654A (zh) * 2017-12-21 2020-11-10 盖尔德马研究及发展公司 Mtor的抑制剂化合物
CN111918653A (zh) * 2017-12-21 2020-11-10 盖尔德马研究及发展公司 新型mtor抑制剂化合物
CN114591335A (zh) * 2021-03-29 2022-06-07 浙江大学 吲唑类化合物及其制备方法和应用

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010059593A1 (fr) * 2008-11-18 2010-05-27 Intellikine, Inc. Procédés et compositions pour le traitement d'affections ophtalmiques
CN105102000A (zh) * 2012-11-01 2015-11-25 无限药品公司 使用pi3激酶亚型调节剂的癌症疗法
CN111918654A (zh) * 2017-12-21 2020-11-10 盖尔德马研究及发展公司 Mtor的抑制剂化合物
CN111918653A (zh) * 2017-12-21 2020-11-10 盖尔德马研究及发展公司 新型mtor抑制剂化合物
CN114591335A (zh) * 2021-03-29 2022-06-07 浙江大学 吲唑类化合物及其制备方法和应用

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