WO2014183520A1 - Dérivé de miazines de tiophène, son procédé de préparation et ses applications médicales - Google Patents

Dérivé de miazines de tiophène, son procédé de préparation et ses applications médicales Download PDF

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WO2014183520A1
WO2014183520A1 PCT/CN2014/075387 CN2014075387W WO2014183520A1 WO 2014183520 A1 WO2014183520 A1 WO 2014183520A1 CN 2014075387 W CN2014075387 W CN 2014075387W WO 2014183520 A1 WO2014183520 A1 WO 2014183520A1
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group
cancer
alkyl
tautomer
aryl
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PCT/CN2014/075387
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English (en)
Chinese (zh)
Inventor
李心
孙飘扬
兰炯
彭建彪
陈阳
王斌
董庆
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上海恒瑞医药有限公司
江苏恒瑞医药股份有限公司
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Priority to CN201480001855.4A priority Critical patent/CN104470921B/zh
Publication of WO2014183520A1 publication Critical patent/WO2014183520A1/fr
Priority to HK15106672.5A priority patent/HK1206025A1/xx

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a novel pyridopyrimidine derivative, a process for the preparation thereof, and a pharmaceutical composition containing the same, and its use as a cancer therapeutic agent, particularly as a CDK4 and/or CDK6 inhibitor.
  • CDKs cyclin-dependent kinases
  • Cyclin B/CDK1, Cyclin A/CDK2 Cyclin E/CDK2, Cyclin D/CDK4, Cyclin D/CDK6 and other heterodimers are important regulators of cell cycle progression. Additional functions of the Cyclin/CDK heterodimer include regulation of transcription, DNA repair, differentiation, and programmed cell death.
  • CDK4 and CDK6 are highly homologous, CDK4 single knockout mice have diabetes signs and cell defects, and CDK6 single knockout mice have mild anemia symptoms due to defects in hematopoietic cell proliferation, while CDK4 and CDK6 (CDK4/6) pairs Gene knockout impairs the proliferative capacity of hematopoietic precursor cells, leading to double knockout of mouse embryonic death.
  • CDK4 and CDK6 (CDK4/6) pairs Gene knockout impairs the proliferative capacity of hematopoietic precursor cells, leading to double knockout of mouse embryonic death.
  • Superactivation of the CDK4/6- C ydin D/Rb signaling pathway is commonly found in tumor cells. Under the stimulation of various mitotic signals inside and outside the cell, cyclin D is highly expressed, regulating the interaction of CDK4/6 protein with cyclin D, promoting CDK4/6 localization and kinase activity.
  • Activated CDK4/6 inhibits the activity of Rb tumor suppressor protein by phosphorylation, dissociates the Rb-E2F complex, releases free E2F into the nucleus, regulates protein transcription, and initiates cell cycle progression.
  • Superactivation of CDK4 is often found in epithelial malignancies, whereas superactivation of CDK6 is often found in stromal cell tumors such as sarcomas and hematological cancers. Construction of a breast cancer-bearing mouse model revealed that wild-type nude mice all formed tumors, while CDK4 knockout nude mice could not form tumors completely; while anti-CDK4 siRNA interfered with CDK4 expression, tumor growth in nude mice was found to be significantly inhibited.
  • CDK inhibitors can also be used to treat cardiovascular disorders such as restenosis and atherosclerosis and other vascular disorders caused by abnormal cell proliferation; for the treatment of diseases caused by various infectious agents , including fungi, protozoan parasites (such as Plasmodium falciparum) and DNA and RNA viruses; can also be used to improve various autoimmune disorders, studies have found that in the rat model of arthritis, joint swelling is basically expressed by pl6 Inhibited by viral treatment, CDK inhibitors can effectively fight other cells Proliferative disorders, including psoriasis (characterized by hyperproliferation of keratinocytes), glomerulonephritis, and lupus.
  • G1/S transition phase and G2/M phase cells are extremely sensitive to DNA damaging agents such as ionizing radiation (IR), and the process of cell transition from G1 to S phase requires at least 3 cell cycles.
  • IR ionizing radiation
  • Protein-dependent kinases (CDK2, CDK4, and CDK6) and their regulatory subunit cyclins co-phosphorylate Rb family proteins for regulation.
  • Selective CDK4/6 inhibitors can induce G1 arrest in cells, thereby increasing the tolerance of hematopoietic stem/progenitor cells to DNA damaging agents such as IR, and effectively reducing various hematopoietic toxicities caused by radiation, including myelosuppression, hooliganism.
  • CDK inhibitors are difficult to identify compounds that specifically inhibit CDK proteins but not other enzymes. Thus, despite the potential to treat a variety of diseases, CDK inhibitors have not yet been approved for commercial use.
  • PD-0332991 inhibits the phosphorylation of Rb by inhibiting the activity of CDK4 and CDK6, leaving the E2F-Rb complex in the cytosol and blocking the initiation of the cell cycle.
  • Clinical trials showed that patients with letrozole monotherapy had a progression-free survival (PFS) of 7.5 months, whereas patients with letrozole and PD-0332991 were treated with progression-free survival. Extended to 26.1 months.
  • PFS progression-free survival
  • CDK4 and CDK6 include WO2003062236, WO2006008874, WO2009126584, WO2010075074, WO2011101409, and WO2012129344.
  • the present invention will provide a novel structure of selective CDK4 and CDK6 inhibitors, and find that compounds having such structures exhibit excellent effects and effects, particularly excellent pharmacogen absorption activities. Summary of the invention
  • the object of the present invention is to provide a compound represented by the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer or a mixture thereof.
  • ⁇ is a single key or double key
  • a 1 or A 2 are each independently selected from -CR' or N;
  • R' is selected from a hydrogen atom, a halogen, a cyano group, a nitro group, a fluorenyl group, a halogenated fluorenyl group, a hydroxy group or a decyloxy group;
  • Y is selected from S or 0;
  • R 1 is selected from a hydrogen atom, a halogen, a fluorenyl group, a halogenated fluorenyl group, a hydroxy fluorenyl group or a cyclodecyl group;
  • R 2 is selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a nitro group, a decyl group, an alkenyl group, an alkynyl group, a cyclodecyl group, a heterocyclic fluorenyl group, an aryl group, a heteroaryl group, -0R 7 , -C(0)R 7 , -C(0)OR 7 , or -OC(0)R 7 , wherein said fluorenyl, alkenyl, alkynyl, cyclodecyl, heterocycloalkyl, aryl or heteroaryl are each independently Optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, amino, hydroxy, oxo, decyl, 3, 4, decyl, hydroxy, decyl, cyclodecyl, heterocycloalkyl Substituted with a substituent of an
  • R 3 is selected from a hydrogen atom, a fluorenyl group, a cyclodecyl group, a heterocyclic fluorenyl group, an aryl group or a heteroaryl group, wherein the fluorenyl group, the cycloalkyl group, the heterocyclic fluorenyl group, the aryl group or the heteroaryl group are each independently Optionally optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, amino, hydroxy, oxo, decyl, 3 ⁇ 4 hydrazino, hydroxy fluorenyl, decyloxy, cyclodecyl, heterocyclic hydrazine Substituted by a substituent of a aryl group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group;
  • R 4 is selected from a hydrogen atom, a decyl group, an alkenyl group, an alkynyl group, a cyclodecyl group, a heterocyclic fluorenyl group, an aryl group, a heteroaryl group, -OR 7 , -C(0)R 7 or -C(0)OR.
  • fluorenyl, alkenyl, alkynyl, cyclodecyl, heterocycloalkyl, aryl or heteroaryl group is each independently optionally further selected from one or more selected from the group consisting of halogen, cyano, and nitro a substituent of an amino group, a hydroxyl group, an oxo group, a decyl group, a 3 ⁇ 4 fluorenyl group, a hydroxy group, a decyloxy group, a cyclodecyl group, a heterocyclic fluorenyl group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group Replaced
  • R 5 or R 6 are each independently selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a nitro group, an oxo group, a decyl group, an alkenyl group, an alkynyl group, a cyclodecyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -OR 7 , -C(0)R 7 -CCC OR 7 or -OCCC R 7 , wherein each of the indenyl, alkenyl, alkynyl, cyclodecyl, heterocycloalkyl, aryl or heteroaryl groups Optionally optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, amino, hydroxy, oxo, decyl, halohydrazino, hydroxydecyl, decyloxy, cyclodecyl, heterocycle Substituted
  • R 7 is selected from a hydrogen atom, a fluorenyl group, a hydroxyl group, a halogen, a decyloxy group, a cyclodecyl group, a heterocyclic fluorenyl group, an aryl group or a hetero An aryl group, wherein said fluorenyl, decyloxy, cyclodecyl, heterocycloalkyl, aryl or heteroaryl are each independently optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, a substituent of an amino group, a hydroxyl group, an oxo group, a decyl group, a halogenated fluorenyl group, a hydroxymethyl group, a decyloxy group, a cyclodecyl group, a heterocyclic fluorenyl group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate
  • a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein each of A 1 or A 2 is independently -CH.
  • a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein R 5 or R 6 are each independently selected from a hydrogen atom, a halogen, a thiol group or a hydroxy group.
  • a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein R 4 is selected from a hydrogen atom or a fluorenyl group, wherein the thiol group is further optionally further substituted by one or more substituents selected from halogen, hydroxy or cyclodecyl Replaced.
  • a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula ( ⁇ ) or a tautomer, a mesogen, a racemate, an enantiomer, a non-pair Isomer or its mixed salt:
  • RR 6 is as defined in the general formula (I).
  • a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (III) or a tautomer, a mesogen, a racemate, an enantiomer, a non-pair Isomer or its mixed salt:
  • RR 6 is as defined in the general formula (I).
  • Typical compounds of the invention include, but are not limited to:
  • the present invention also provides a compound of the formula (IC) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer or a mixture thereof, It can be used for the synthesis or further synthesis of the compound of the formula (I) or its tautomer, mesogen, racemate, enantiomer, diastereomer Intermediates for isomers:
  • ⁇ is a single key or double key
  • Boc is a tert-butoxycarbonyl group
  • R is a sulfhydryl group
  • a 1 or A 2 are each independently selected from -CR' or N;
  • R' is selected from a hydrogen atom, a halogen, a cyano group, a nitro group, a fluorenyl group, a halogenated fluorenyl group, a hydroxy group or a decyloxy group;
  • Y is selected from S or 0;
  • R 1 is selected from a hydrogen atom, a halogen, a fluorenyl group, a halogenated fluorenyl group, a hydroxy fluorenyl group or a cyclodecyl group;
  • R 3 is selected from a hydrogen atom, a fluorenyl group, a cyclodecyl group, a heterocyclic fluorenyl group, an aryl group or a heteroaryl group, wherein the fluorenyl group, the cycloalkyl group, the heterocyclic fluorenyl group, the aryl group or the heteroaryl group are each independently Optionally optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, amino, hydroxy, oxo, decyl, 3 ⁇ 4 hydrazino, hydroxy fluorenyl, decyloxy, cyclodecyl, heterocyclic hydrazine Substituted by a substituent of a aryl group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group;
  • R 5 or R 6 are each independently selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a nitro group, an oxo group, a decyl group, an alkenyl group, an alkynyl group, a cyclodecyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -OR 7 , -C(0)R 7 -CCC OR 7 or -OCCC R 7 , wherein each of the indenyl, alkenyl, alkynyl, cyclodecyl, heterocycloalkyl, aryl or heteroaryl groups Optionally optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, amino, hydroxy, oxo, decyl, halohydrazino, hydroxydecyl, decyloxy, cyclodecyl, heterocycle Substituted
  • R 7 is selected from a hydrogen atom, a fluorenyl group, a hydroxyl group, a halogen, a decyloxy group, a cyclodecyl group, a heterocyclic fluorenyl group, an aryl group or a heteroaryl group, wherein the fluorenyl group, the decyloxy group, the cyclodecyl group, and the hetero aryl group
  • the cycloalkyl, aryl or heteroaryl are each independently optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, amino, hydroxy, oxo, decyl, halodecyl, hydroxy fluorenyl Substituted by a substituent of a decyloxy group, a cyclodecyl group, a heterocyclic fluorenyl group, an aryl group, a heteroaryl group, a carboxyl group or a
  • a compound of the formula (IC) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer Body or a mixture thereof, or A pharmaceutically acceptable salt, wherein R is a butyl group the present invention also provides a compound of the formula (I) or a tautomer thereof, a mesogen, an oxime, an enantiomer, a non- a method of enantiomers or mixtures thereof, or a pharmaceutically acceptable salt thereof,
  • the compound of the formula (IA) and the compound of the formula (IB) are subjected to a substitution reaction under basic conditions, optionally under the action of a catalyst to obtain a compound of the formula (IC); a compound of the formula (IC) in a solvent, under acidic conditions, Performing a deprotection reaction, optionally further performing a substitution reaction to obtain a compound of the formula (I);
  • X is a halogen
  • Boc is a tert-butoxycarbonyl group
  • R 4 is preferably a hydrogen atom or a fluorenyl group, wherein the fluorenyl group is optionally further substituted with one or more substituents selected from a halogen, a hydroxyl group or a cyclodecyl group.
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer thereof A form, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for inhibiting CDK4 and/or CDK6.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for the treatment of abnormal cell proliferative diseases, infections (eg, viral infections such as herpes, HIV, fungal infections, etc.), inflammatory conditions (eg, rheumatoid arthritis, bone and joint) Inflammation, etc., autoimmune diseases (eg psoriasis, lupus, type I diabetes, diabetic nephropathy, multiple sclerosis, glomerulonephritis, etc.), cardiovascular disease (eg myocardial infarction, stroke, atherosclerosis, surgery) Use in a medicament for a posterior vessel stenosis, restenosis, or the like, or a neurodegenerative disease (e.g., Alzheimer's disease, Parkinson's disease, etc.), where
  • the invention further relates to a compound of the formula (I) or a tautomer thereof, a mesogen, a racemic form Use of a body, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of a medicament for treating cancer, wherein the cancer is selected from the group consisting of breast Cancer, ovarian cancer, prostate cancer, melanoma, brain tumors (such as gliomas with malignant astroglia and oligodendroglioma), esophageal cancer, stomach cancer, liver cancer, pancreatic cancer, Colorectal cancer (eg colon cancer, rectal cancer, etc.), lung cancer (eg non-small cell lung cancer, small cell lung cancer, primary or metastatic squamous cell carcinoma, etc.), kidney cancer, skin cancer, glioblastoma, neuromuscular Cell tumor, sarcoma, liposarcoma, osteochond
  • the present invention relates to a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer or a mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for preventing or treating a hematopoietic toxic disease caused by radiation, wherein said radiation-induced hematopoietic toxic diseases include, but are not limited to, myelosuppression, neutrophils Reduced, leukopenia, anemia.
  • the invention also relates to a method of inhibiting the activity of CDK4 and/or CDK6 comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer, mesogen, exosome thereof A form of a rot, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the present invention relates to the treatment of abnormal cell proliferative diseases, infections (eg, viral infections such as herpes, HIV, fungal infections, etc.), inflammatory conditions (eg, rheumatoid arthritis, osteoarthritis, etc.), autoimmune Diseases (eg psoriasis, lupus, type I diabetes, diabetic nephropathy, multiple sclerosis, glomerulonephritis, etc.), cardiovascular disease (eg myocardial infarction, stroke, atherosclerosis, postoperative vascular stenosis, restenosis, etc.) Or a method of a neurodegenerative disease (eg, Alzheimer's disease, Parkinson's disease, etc.) comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt
  • infections
  • the invention further relates to a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer, mesogen, racemate, enantiomer thereof Is a form of an isomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor (eg, glioblastoma with malignant astroglia and oligodendroglioma, etc.), esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer (eg colon cancer, rectal cancer, etc.), Lung cancer (eg non-small cell lung cancer, small cell lung cancer, primary or metastatic squamous cell carcinoma, etc.), kidney cancer, skin cancer, glioblastoma, neuroblasto
  • the invention also relates to a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer, mesogen, racemate, enantiomer thereof An isomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in combination with one or more other anticancer agents, the anticancer agent being selected from the group consisting of Deuterated agents (eg cyclophosphamide, ifosfamide, melphalan, busulfan, nimodin, ramustine, dacarbazine, temozolomide, nitrogen mustard, dibromomannitol, etc.), platinum Complexing agents (eg cisplatin, carboplatin, oxaliplatin, etc.), metabolic antagonists (eg methotrexate, 5-fluorouracil, tegafur, gemcitabine, capecitabine,
  • the present invention also relates to a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a non-pair thereof, which is a drug which inhibits the activity of CDK4 and/or CDK6. Or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the invention also relates to the treatment of abnormal cell proliferative diseases, infections (eg viral infections such as herpes, HIV, fungal infections, etc.), inflammatory conditions (eg rheumatoid arthritis, osteoarthritis, etc.), autoimmune diseases (such as psoriasis, lupus, type I diabetes, diabetic nephropathy, multiple sclerosis, glomerulonephritis, etc.), cardiovascular disease (eg myocardial infarction, stroke, atherosclerosis, postoperative vascular stenosis, restenosis, etc.) or a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer of a drug for a neurodegenerative disease (for example, Alzheimer's disease, Parkinson's disease, etc.)
  • infections eg viral infections such as herpes, HIV, fungal infections, etc.
  • inflammatory conditions eg rheumatoid arthritis, osteoarthritis
  • the present invention further relates to a compound represented by the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer thereof or a drug for treating cancer. a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor (eg, malignant astrocyte and Glioma of oligodendroglioma, etc.), esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer (eg colon cancer, rectal cancer, etc.), lung cancer (eg non-small cell lung cancer, small cell lung cancer) , primary or metastatic squamous cell carcinoma, etc., kidney cancer, skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma
  • the present invention also relates to a compound represented by the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer thereof or a drug for treating cancer. a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, and one or more anticancer agents selected from the group consisting of oximation agents (eg, cyclophosphamide, ifosfamide) , melphalan, busulfan, nimodin, ramustine, dacarbazine, temozolomide, hydrochloric acid mustard, dibromomannitol, etc.), platinum complexing agents (eg cisplatin, carboplatin, oxa Lipoplatin, etc., metabolic antagonists (eg methotrexate, 5-fluorouracil, tegafur, gemcitabine, capecitabine, fluoride Vesicle, pemetrexed, etc
  • the pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture.
  • Oral compositions can be prepared according to any method known in the art for preparing a pharmaceutical composition, such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives, To provide a pleasing and tasty pharmaceutical preparation. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets for mixing.
  • excipients may be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn Starch or alginic acid; a binder such as starch, gelatin, polyvinylpyrrolidone or gum arabic; and a lubricant such as magnesium stearate, stearic acid or talc.
  • These tablets may be uncoated or may be coated by a known technique which provides a sustained release effect over a long period of time by masking the taste of the drug or delaying disintegration and absorption in the gastrointestinal tract.
  • water-soluble taste masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or extended-time materials such as ethylcellulose, cellulose acetate butyrate may be used.
  • hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin or olive oil.
  • Soft gelatin capsules provide oral preparations.
  • the aqueous suspension contains the active substance and excipients suitable for the preparation of the aqueous suspension for mixing.
  • excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and gum arabic; dispersing or wetting agents can be a naturally occurring phospholipid such as lecithin, or a condensation product of an alkylene oxide with a fatty acid such as polyoxyethylene stearate, or a condensation product of an epoxy oxime with a long chain fatty alcohol, such as a heptadecylethyleneoxy whale Heptadecaethyleneoxy cetanol, or a condensation product of epoxy oxime with a partial ester derived from a fatty acid and a hexitol, such as polyepoxide sorbitan monooleate, or oxirane with a fatty acid and hexitol
  • the aqueous suspensions may also contain one or more preservatives such as ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents. Flavoring agents such as sucrose, saccharin or aspartame.
  • the oil suspension can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin.
  • the oil suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
  • the above sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of an anti-oxidant such as butylated hydroxyanisole or (X-tocopherol).
  • Dispersible powders and granules suitable for use in the preparation of aqueous suspensions may be employed in the preparation of aqueous dispersions in the presence of a dispersible or wetting agent, a suspending agent or one or more preservatives. Suitable dispersing or wetting agents and suspending agents can be used to illustrate the above examples. Other excipients such as sweetening, flavoring, and coloring agents can also be added. These compositions are preserved by the addition of an anti-oxidant such as ascorbic acid.
  • the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion.
  • the oil phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids, such as soy lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of the partial esters and oxirane, For example, poly(ethylene oxide sorbitol monooleate).
  • the emulsions may also contain sweeteners, flavoring agents, preservatives, and antioxidants.
  • Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
  • sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
  • the pharmaceutical composition may be in the form of a sterile injectable aqueous solution.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase.
  • the active ingredient is dissolved in a mixture of soybean oil and lecithin.
  • the oil solution is then added to a mixture of water and glycerin to form a microemulsion.
  • the injection or microemulsion can be injected into the patient's bloodstream by local injection.
  • the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compound of the invention.
  • a continuous intravenous delivery device can be used.
  • An example of such a device is the Deltec CADD-PLUS. TM. 5400 intravenous pump.
  • the pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration.
  • the suspension may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, a solution prepared in 1,3-butanediol.
  • sterile fixed oils can be conveniently employed as a solvent or suspension medium. For this purpose, any blended fixed oil including synthetic mono- or diglycerides can be used.
  • fatty acids such as oleic acid can also be prepared as an injection.
  • the compounds of the invention may be administered in the form of a suppository for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and thus dissolves in the rectum to release the drug.
  • suitable non-irritating excipient include a mixture of cocoa butter, glycerin gelatin, hydrogenated vegetable oil, polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.
  • the dosage of the drug depends on a variety of factors including, but not limited to, the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the performance of the patient, the patient Diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; alternatively, the preferred mode of treatment, such as the mode of treatment, the daily amount of the compound of formula (I) or a pharmaceutically acceptable salt
  • the preferred mode of treatment such as the mode of treatment, the daily amount of the compound of formula (I) or a pharmaceutically acceptable salt
  • mercapto refers to a saturated aliphatic hydrocarbon group, including straight chain and branched chain groups of 1 to 20 carbon atoms.
  • fluorenyl groups having 1 to 10 carbon atoms more preferably fluorenyl groups having 1 to 6 carbon atoms, most preferably fluorenyl groups having 1 to 4 carbon atoms, most preferably methyl groups.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1, 1-dimethylpropyl,
  • n-heptyl 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4- Dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethyl Hexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2- Ethylhexyl, 3-ethylhexyl, 4-ethylhexyl,
  • lower fluorenyl groups having 1 to 6 carbon atoms non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl , n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3 -methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl , 2,3-dimethylbutyl and the like.
  • the thiol group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from the group consisting of fluorenyl groups. , alkenyl, alkynyl, decyloxy, sulfonylthio, decylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cyclodecyl, heterocycloalkyl, aryl, heteroaryl, cyclooxy A heterocyclic methoxy group, a cyclodecylthio group, a heterocyclic thiol group, an oxo group, an amino group, a 3 ⁇ 4 alkyl group, a hydroxy group, a carboxyl group or a carboxylate group.
  • fluorenyl groups alkenyl, alkynyl, decyloxy, sulfonylthio,
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably the cyclodecyl ring comprises from 3 to The 10 carbon atoms, most preferably the cyclodecyl ring contains 3 to 6 carbon atoms, most preferably a cyclopropyl or cyclopentyl group.
  • Non-limiting examples of monocyclic cyclodecyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • the group, the cyclooctyl group and the like are preferably a cyclopropyl group or a cyclopentyl group.
  • Polycyclic fluorenyl groups include spiro, fused, and cyclic fluorenyl groups.
  • the cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of an anthracenyl group, an alkenyl group, an alkynyl group, a decyloxy group, a hydrazine sulfonium group.
  • Base mercaptoamino, 3 ⁇ 4, fluorenyl, hydroxy, nitro, cyano, cyclodecyl, heterocycloalkyl, aryl, heteroaryl, cyclodecyloxy, heterocyclomethoxy, cyclodecylthio , heterocyclic thiol, oxo, amino, halogen Mercapto, hydroxymethyl, carboxyl or carboxylate groups.
  • alkenyl refers to a fluorenyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or -butenyl and the like.
  • Preferred is a C 2 .1Q alkenyl group, more preferably a C 2 . 6 alkenyl group, most preferably a C 2 . 4 alkenyl group, most preferably a vinyl group.
  • the alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of a fluorenyl group, an alkenyl group, an alkynyl group, a decyloxy group, a thiol group, Mercaptoamino, 3 ⁇ 4, fluorenyl, hydroxy, nitro, cyano, cyclodecyl, heterocycloalkyl, aryl, heteroaryl, cyclodecyloxy, heterocyclomethoxy, cyclodecylthio, hetero Cyclodecylthio, oxo, amino, halodecyl, hydroxydecyl, carboxy or carboxylate.
  • the substituent is preferably one or more of the following groups independently selected from the group consisting of a fluorenyl group, an alkenyl group, an alkynyl group, a decyloxy group,
  • alkynyl refers to a fluorenyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, for example ethynyl, 1-propynyl, 2-propynyl, 1-, 2- Or 3-butynyl and the like.
  • C 2. 1Q alkynyl group more preferably C 2. 6 alkynyl group, most preferably C 2. 4 alkynyl group.
  • the alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of an anthracenyl group, an alkenyl group, an alkynyl group, a decyloxy group, a thiol group, Mercaptoamino, 3 ⁇ 4, fluorenyl, hydroxy, nitro, cyano, cyclodecyl, heterocycloalkyl, aryl, heteroaryl, cyclodecyloxy, heterocyclomethoxy, cyclodecylthio, hetero Cyclodecylthio, oxo, amino, halodecyl, hydroxydecyl, carboxy or carboxylate.
  • the substituent is preferably one or more of the following groups independently selected from the group consisting of an anthracenyl group, an alkenyl group, an alkynyl group, a decyloxy group
  • heterocyclic fluorenyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen or S(0) A hetero atom of m (wherein m is an integer of 0 to 2), but does not include a ring moiety of -0-0-, -0-S- or -SS-, and the remaining ring atoms are carbon.
  • It preferably comprises from 3 to 12 ring atoms, wherein 1 to 4 are hetero atoms, more preferably the heterocyclic indenyl ring contains 3 to 10 ring atoms, and more preferably the heterocyclic indenyl ring contains 5 to 6 ring atoms.
  • monocyclic heterocyclic fluorenyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, tetrahydrofuranyl and the like.
  • the polycyclic heterocyclic fluorenyl group includes a spiro ring, a fused ring, and a heterocyclic fluorenyl group of a bridged ring.
  • the heterocyclic fluorenyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of a fluorenyl group, an alkenyl group, an alkynyl group, a decyloxy group, and an anthracene group.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring sharing a pair of adjacent carbon atoms) having a conjugated ⁇ -electron system, preferably 6 to 10 members, more preferably Phenyl and naphthyl are most preferred.
  • the aryl ring may be fused to a heteroaryl, heterocycloalkyl or cyclodecyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples comprising:
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups. Independently selected from the group consisting of fluorenyl, alkenyl, alkynyl, decyloxy, sulfonylthio, decylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cyclodecyl, heterocycloalkyl, aryl, hetero Aryl, cyclodecyloxy, heterocyclomethoxy, cyclodecylthio, heterocyclic thiol, amino, 3 ⁇ 4 fluorenyl, hydroxydecyl, carboxy or carboxylate.
  • heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen.
  • the heteroaryl group is preferably 5 to 10 members, more preferably 5 or 6 members, such as thiadiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl, thiazolyl, furyl , thienyl, pyridyl, pyrrolyl, fluorenyl-fluorenyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like.
  • the heteroaryl ring may be fused to an aryl, heterocycloalkyl or cyclodecyl ring, wherein the parent structure is attached to one:
  • the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of fluorenyl, alkenyl, alkynyl, decyloxy, sulfonium sulfide Base, mercaptoamino, halogen, fluorenyl, hydroxy, nitro, cyano, cyclodecyl, heterocycloalkyl, aryl, heteroaryl, cyclodecyloxy, heterocyclomethoxy, cyclodecylthio, A heterocyclic thiol group, an amino group, a 3 ⁇ 4 fluorenyl group, a hydroxy group, a carboxyl group or a carboxylate group.
  • decyloxy refers to -0-(fluorenyl) and -0-(unsubstituted cycloalkyl), wherein the fluorenyl and cyclodecyl are as defined above.
  • Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • the decyloxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of an anthracenyl group, an alkenyl group, an alkynyl group, a decyloxy group, and an anthracene group.
  • Haloalkyl means that the fluorenyl group is substituted by one or more halogens, wherein the fluorenyl group is as defined above.
  • Hydrolysis means a hydrazine group.
  • Haldroxycarbonyl refers to a fluorenyl group substituted with a hydroxy group, wherein the fluorenyl group is as defined above.
  • Halogen means fluoro, chloro, bromo or iodo, preferably fluoro or iodo.
  • Amino means - ⁇ 2 .
  • Neitro means -N0 2 .
  • Carboxy means -C(0)OH.
  • Carboxylic acid ester group means -C(0)0(fluorenyl) or (cycloalkyl), wherein the indenyl or cyclodecyl group is as defined above.
  • “Optional” or “optionally” means that the event or environment described subsequently may, but need not, occur, including where the event or environment occurs or does not occur.
  • “heterocyclic fluorenyl group optionally substituted by thiol” means that fluorenyl may be, but not necessarily, present, including the case where the heterocyclic fluorene group is substituted by a thiol group and the heterocyclic fluorenyl group is not decyl The situation of substitution.
  • Substituted means that one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms are independently substituted with each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory;) possible or impossible substitutions without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., a registered) bond.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
  • the purpose of the pharmaceutical composition is to promote administration to an organism, to facilitate absorption of the active ingredient and to exert biological activity. Synthetic method of the present invention
  • the compound of the formula (IA) and the compound of the formula (IB) are subjected to a substitution reaction under basic conditions, optionally under the action of a catalyst to obtain a compound of the formula (IC); a compound of the formula (IC) in a solvent, under acidic conditions, Performing a deprotection reaction, optionally further performing a substitution reaction to obtain a compound of the formula (I);
  • X is a halogen
  • Boc is a tert-butoxycarbonyl group
  • R 4 is preferably a hydrogen atom or a fluorenyl group, wherein the fluorenyl group is optionally further substituted by one or more substituents selected from halogen, hydroxy or cycloalkyl;
  • R 2 is preferably -C(0)R 7 And R 7 is a fluorenyl group.
  • a method of medicinal salt comprising:
  • the compound of the formula (II-C) is obtained by a substitution reaction of a compound of the formula ( ⁇ - ⁇ ) with a compound of the formula ( ⁇ - ⁇ ) under basic conditions, optionally under the action of a catalyst; a compound of the formula (II-C); Deprotection reaction in a solvent under acidic conditions, optionally further performing a substitution reaction to obtain a compound of the formula ( ⁇ );
  • X is a halogen
  • Boc is a tert-butoxycarbonyl group
  • R 4 is preferably a hydrogen atom or a fluorenyl group, wherein the fluorenyl group is optionally further substituted by one or more substituents selected from halogen, hydroxy or cycloalkyl;
  • R 2 is preferably -C(0)R 7 And R 7 is a fluorenyl group.
  • the compound of the formula (III-C) is obtained by substituting a compound of the formula (III-C) with a compound of the formula (IB) under basic conditions, optionally under a catalyst; a compound of the formula (III-C) in a solvent a deprotection reaction under acidic conditions, optionally further performing a substitution reaction to obtain a compound of the formula (III);
  • X is a halogen
  • Boc is a tert-butoxycarbonyl group
  • R 4 is preferably a hydrogen atom or a fluorenyl group, wherein the fluorenyl group is optionally further substituted by one or more substituents selected from halogen, hydroxy or cycloalkyl;
  • R 2 is preferably -C(0)R 7 And R 7 is a fluorenyl group.
  • the reagents providing basic conditions include organic bases including, but not limited to, lithium hexamethyldisilazide, sodium hexamethyldisilazide, and diisopropylamino groups.
  • organic bases including, but not limited to, lithium hexamethyldisilazide, sodium hexamethyldisilazide, and diisopropylamino groups.
  • Inorganic bases include, but are not limited to, cesium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide or sodium hydride.
  • Conditions which provide acidity include, but are not limited to, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, trifluoroacetic acid, and hydroxyethanesulfonic acid, preferably trifluoroacetic acid or hydroxyethanesulfonic acid.
  • Catalysts include, but are not limited to, 4,5-bisdiphenylphosphino-9,9-dimethyloxaxime, tris(dibenzylideneacetone)dipalladium, anthracene, fluorene-binaphthyl-2,2'-di Phenylphosphine, [ ⁇ , ⁇ -bis(diphenylphosphino)ferrocene] palladium dichloride, bis(triphenylphosphine)palladium dichloride, triphenylphosphine, palladium dichloride, palladium acetate, iodine Cuprous, palladium/carbon or Raney nickel.
  • Solvents used include, but are not limited to, 1,4-dioxane, toluene, water, acetonitrile, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, methanol, ethanol, n-butanol, dimethyl Sulfone or N,N-dimethylformamide. detailed description
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • the MR displacement ( ⁇ ) is given in units of 10 ⁇ 6 (ppm).
  • the MR was measured using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-i3 ⁇ 4, deuterated chloroform (CDC1 3 ), and the internal standard was tetramethylsilyl (TMS)).
  • the MS was assayed using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
  • ESI FINNIGAN LCQAd
  • the HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column;) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column;).
  • the thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the silica gel plate used for thin layer chromatography (TLC) has a specification of 0.15 mm ⁇ 0.2 mm, and the thin layer chromatography separation and purification product adopts the specification of 0.4 mm. ⁇ 0.5 mm.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc. Companies such as chemicals.
  • reaction can be carried out under an argon atmosphere or a nitrogen atmosphere.
  • An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the pressurized hydrogenation reaction was carried out using a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 type hydrogen generator or a HC2-SS type hydrogenation apparatus.
  • the hydrogenation reaction is usually carried out, charged with hydrogen, and operated three times.
  • the solution means an aqueous solution.
  • reaction temperature is room temperature and is 20 ° C to 30 ° C.
  • the progress of the reaction in the examples was monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the system used for the reaction was: A: chloroform and methanol system, B: n-hexane and ethyl acetate system, C: petroleum In the ether and ethyl acetate systems, the volume ratio of the solvent is adjusted depending on the polarity of the compound.
  • the system of the eluent for column chromatography and the developer system for thin layer chromatography using the purified compound include:
  • A dichloromethane and methanol system
  • B n-hexane and ethyl acetate system
  • C dichloromethane, methanol and ethyl acetate system
  • the volume ratio of the solvent is adjusted according to the polarity of the compound, or Adjust with a small amount of alkaline or acidic reagent such as triethylamine and acetic acid.
  • EtOAc (EtOAc m.) Cyclopentyl-5-methyl-2-((1',2',3',6'-tetrahydro-[3,4'-bipyridyl]-6-yl;)amino;)pyridino[2 , 3- ⁇ /]pyrimidin-7 (8H; >-keto 1 (750 mg, yellow solid;). 150 mg of the title product was purified using EtOAc (EtOAc)
  • 6-Acetyl-8-cyclopentyl-2-((5-(4-hydroxypiperidin-4-yl)pyridin-2-yl)amino)-5-methylpyrido[2,3-0 Pyrimidine-7(8H)-one 3 (20 mg, 0.043 mmol) 36% aqueous formaldehyde (6.5 mg, 0.065 mmol) and 10 mL of dichloromethane were added to a 25 mL eggplant-shaped flask and stirred at room temperature 2 After an hour, sodium borohydride (27 mg, 0.129 mmol) was added, and stirring was continued at room temperature for 16 hours, the reaction was stopped, 1 mL of aqueous ammonia was added, and concentrated under reduced pressure to dryness.
  • 6-Acetyl-8-cyclopentyl-2-((5-(4-hydroxy-1-methylpiperidin-4-yl)pyridin-2-yl)amino)-5-methylpyridino[ 2,3- ⁇ /]pyrimidine-7(8H)-one 4 (10 mg, 0.021 mmol) was dissolved in 5 mL of dichloromethane, then dimethylamino trifluoride was added under cooling in dry ice-acetone bath. Sulfur (2 drops), after stirring for 30 minutes, the reaction was monitored by TLC. Most of the starting materials were unreacted, and 2 drops of dimethylaminosulfur trifluoride were added. After stirring for 1 hour, the reaction was terminated.
  • 6-Acetyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyridino[2,3-0-pyrimidine- 7(8H)-one 6 (20 mg, 0.047 mmol), acetic acid (20 mg, 0.45 mmol), 4 mL of 1,2-dichloroacetone and sodium borohydride (25 mg, 0.11 mmol). , react at room temperature for 12 hours. The reaction was stopped, 3 mL of methanol was added, and the mixture was stirred for 5 min.
  • 6-Acetyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyridino[2,3-0-pyrimidine- 7(8H)-one 6 (15 mg, 0.033 mmol) cyclopropyl bromide (8.37 mg, 0.062 mmol), potassium carbonate (20.7 mg, 0.15 mmol) and 3 mL acetonitrile were added to the reaction flask and heated to 80 ° C, the reaction was stopped for 2 hours.
  • 6-Acetyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrido[2,3-pyrimidine-7 ( 8H)-keto 6 (15 mg, 0.033 mmol) was dissolved in 4 mL of acetonitrile and heated with 1-bromo-2,2-difluoroethane (24.36 mg, 0.168 mmol) and potassium carbonate (30 mg, 0.22 mmol) The reaction was stopped at 80 ° C for 6 hours. After cooling to room temperature, the mixture was filtered, and the filtered cake was washed with methylene chloride (3 mL?), and the filtrate was concentrated under reduced pressure.
  • Test Example 1 Determination of CDK kinase activity by the compounds of the present invention
  • CDK4 In vitro CDK (CDK4, CDK6, CDK1, CDK2, CDK9) kinase activities were tested by the following methods.
  • CDK kinase used in this experiment CDK4/human cyclin Dl (Invitrogen, Cat. No. PV4400) or CDK4/CycD3 (Carna biosciences, Cat. No. 04-105); CDK6 human cyclin D1 (Invitrogen, Cat. No. PV4401) or CDK6/CycD3 (Carna biosciences, Cat. No. 04-107); CDKl/human cyclin B (Invitrogen, Cat. No. PV3292); CDK2 human cyclin A (Invitrogen, Cat. No. PV3267) or CDK2/CycA2 (Carna biosciences, Cat. No. 04-103); CDK9/human cyclin Tl (Invitrogen, Cat. No. PR7541B) or CDK9/CycTl (Cama biosciences, Cat. No. 04-110).
  • CDK4/human cyclin Dl Invitrogen, Cat. No. PV4400
  • the in vitro kinase assay described below can determine the inhibitory activity of a test compound against CDK (CDK4, CDK6, CDK1, CDK2, CDK9) kinase.
  • kit '-LYTETM Ser/Thr 12 Phosphorylated Peptide Substrate (Invitrogen, Cat. No. PV3675) and lx Buffer A are formulated as a phosphorylated peptide mixture to be used; 2.5 ⁇ L of the configured test compound solution is added to the well, 2.5 ⁇ 400 ⁇ ⁇ solution and 5 ⁇ L of enzyme and substrate mixture; control well 1 plus 5 ⁇ L ⁇ enzyme and substrate mixture, 2.5 ⁇ 4% dimethyl sulfoxide solution and 2.5 ⁇ ⁇ buffer ⁇ ; control well 2 Add 5 ⁇ L of enzyme and substrate mixture, 2.5 ⁇ 4% dimethyl sulfoxide solution and 2.5 ⁇ 400 ⁇ solution; add 5 ⁇ phosphorylated peptide mixture to control well 3, 2.5 ⁇ 4% dimethyl Sulfone solution and 2.5 ⁇ lx Flush A.
  • Reagent A Invitrogen, Cat. No. PV3295
  • Buffer BC Invitrogen Cat. No. P3127
  • CDK4 and CDK6 The CDK (CDK4, CDK6, CDK1, CDK2, CDK9) kinase biochemical inhibitory activity of the compounds of the present invention was determined by the above test, and the IC 5Q values measured are shown in Table 1 for CCDK4 and CDK6), and Table 2 (CDK1, CDK2, and CDK9).
  • the compounds of the present invention have a significant inhibitory effect on the activity of CDK kinase (CDK4, CDK6), and the inhibition of CDK kinase (CDK4, CDK6) by the compounds of the present invention compared to the inhibition of the activity of CDK kinase (CDK1, CDK2, CDK9).
  • Selective. Test Example 2 Inhibition of proliferation of the human colon cancer cell line Colo205 by the compound of the present invention The following in vitro test was conducted to determine the proliferation inhibitory activity of the compound of the present invention against the human colon cancer cell line Colo205.
  • the in vitro cell assay described below can determine the proliferation inhibitory activity of a test compound against a human colon cancer cell line, and its activity can be expressed by an IC 5Q value.
  • the general protocol for this type of trial is as follows: First, Colo205 cells (Chinese Academy of Sciences cell bank, article number TCHul02) were seeded on a 384-well culture plate at a suitable cell concentration of 500 cells/well, and then the cells were cultured in a carbon dioxide incubator at 37 °C.
  • test compound solution a medium with a range of concentration (1000 nM, 250 nM, 62.5 nM, 15.62 nM, 3.91 nM, 0.98 nM, 0.24 nM, 0.06 nM, 0.02 nM) test compound solution , return the plate to the incubator and continue to culture for 72 hours. After 72 hours, the test compound was tested for inhibition of cell proliferation activity by CCK8 (Cell Counting Kit-8, Cat. No.: CK04, purchased from Tongren Chemical). The IC 5Q value can be calculated from the inhibition values of the test compound for the cells at a range of different concentrations.
  • the preferred compounds of the present invention have significant proliferation inhibitory activity against Colo205 cells.
  • Test Example 3 The inhibition of proliferation of human breast cancer cell line MCF-7 by the compound of the present invention
  • the following in vitro assay was used to determine the proliferation inhibitory activity of the compounds of the invention against human breast cancer cell line MCF-7.
  • the in vitro cell assay described below can determine the proliferation inhibitory activity of a test compound on a human breast cancer cell line, and its activity can be expressed by an IC 5Q value.
  • the general protocol for such an experiment is as follows: First, MCF-7 cells (purchased in Institute of biochemistry and cell biology) are seeded on a 96-well culture plate at a suitable cell concentration of 4000 cells/mL, and then the cells are placed in a carbon dioxide incubator. Incubate at 37 ° C, grow to overnight, and change the medium to a medium supplemented with a series of concentration (10000 nM, 1000 nM, 100 nM, 10 nM, 1 nM, 0.1 nM) test compound solution. Return to the incubator and continue to culture for 72 hours.
  • test compound was assayed for inhibition of cell proliferation activity using CCK8 (Cell Counting Kit-8, Cat. No.: CK04, purchased from Tongren Chemical;).
  • CCK8 Cell Counting Kit-8, Cat. No.: CK04, purchased from Tongren Chemical;
  • the IC 5 o value can be calculated from the inhibition values of the test compound for the cells at a range of different concentrations.
  • SD rats were used as test animals, and the concentration of the drug in plasma at different times after the administration of the compound of Example 7 by intragastric administration was determined by LC/MS/MS.
  • the pharmacokinetic behavior of the compounds of the present invention in rats was investigated and their pharmacokinetic characteristics were evaluated.
  • Test plan 2.1 Test drug: PD-0332991, Example 6 and Example 7 compounds.
  • Blood was collected before administration and 0.5, 1, 2, 4, 6, 8, 11, 24 hours after administration, placed in heparinized anticoagulation tubes, centrifuged at 3500 rpm for 10 minutes, plasma was separated, and stored at -20 °C. . Eat 2 hours after administration.
  • the content of the test compound in the plasma of rats after intragastric administration was determined by LC/MS/MS method.
  • the analytical method has a linear range of 1.00-500 ng/mL and a lower limit of quantification of 1.00 ng/mL.
  • Plasma samples are pretreated with precipitated proteins for analysis.
  • the pharmacokinetic parameters of the compounds of the invention are as follows:
  • the Beagle dog was used as the test animal, and the concentration of the drug in plasma was measured by LC/MS/MS method in dogs after administration of PD-0332991 and the compounds of Examples 6 and 7.
  • the pharmacokinetic behavior of the compounds of the invention in rats was investigated and their pharmacokinetic characteristics were evaluated.
  • Test drug PD-0332991, Example 6 and Example 7 compound.
  • the intravenous administration group received 1.0 mL of blood from the forelimb vein before and 5 minutes after administration, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 12.0, 24.0 hours, placed in heparinized tubes, centrifuged at 3500 rpm. Plasma was separated in minutes and stored at -20 °C.
  • the rats in the gavage administration group were subjected to blood collection before administration and 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, 24.0 hours after administration, and the treatment method was the same as that of the intravenous administration group. Eat 3 hours after administration.
  • the content of the test compound in the plasma of rats after intravenous and intragastric administration was determined by LC/MS/MS.
  • the pharmacokinetic parameters of the compounds of the invention are as follows:
  • Test Example 6 Test of the ability of the compound of Example 6 of the present invention to produce a reactive metabolite in comparison with PD-0332991
  • liver microsomes protein concentration 20 mg/mL, purchased from BD GentestTM in the United States; male rat liver microsomes, protein concentration 20 mg/mL, purchased from BD GentestTM, USA; ⁇ -NADPH, chemical purity 93 -100%, purchased from Sigma, USA. L-reduced glutathione, purity >98%, was purchased from Sigma, USA.
  • the total hatching system was 100 ⁇ and the medium was 100 mM phosphate buffer (PBS, pH 7.4).
  • PBS phosphate buffer
  • the precursor GX scan was used to detect the possible GSH adducts, and the peak area of the total GSH adduct formed by the test compound and the total GSH adduct peak formed by clozapine.
  • the area ratio (Ratio) evaluates the ability of a compound to generate a reactive metabolite.
  • Inventive Example 6 showed no significant GSH adduct production in both human and rat liver microsome incubation systems, and had a low ability to generate reactive metabolites.
  • PD-0332991 has a human liver microsome ratio of 0.76 and is capable of generating reactive metabolites in a moderately strong manner.
  • Example 6 of the present invention has low ability to generate reactive metabolites in human and rat liver microsomes, and PD-0332991 has a moderately strong ability to generate reactive metabolites in human liver microsomes.

Abstract

L'invention concerne un dérivé de miazines de tiophène de formule générale (I), un sel pharmaceutique de celui-ci, son procédé de préparation, et une application pour son utilisation en tant qu'agent thérapeutique pour traiter un cancer et utilisé en particulier comme inhibiteur de CDK4 et/ou CDK6, les groupes substituants de la formule générale (I) étant tels que définis dans la description.
PCT/CN2014/075387 2013-05-17 2014-04-15 Dérivé de miazines de tiophène, son procédé de préparation et ses applications médicales WO2014183520A1 (fr)

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