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WO2021037198A1 - Composés deutérés et leur utilisation dans le traitement du cancer - Google Patents

Composés deutérés et leur utilisation dans le traitement du cancer Download PDF

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WO2021037198A1
WO2021037198A1 PCT/CN2020/112062 CN2020112062W WO2021037198A1 WO 2021037198 A1 WO2021037198 A1 WO 2021037198A1 CN 2020112062 W CN2020112062 W CN 2020112062W WO 2021037198 A1 WO2021037198 A1 WO 2021037198A1
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compound
acid
deuterated
substituted
unsubstituted
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PCT/CN2020/112062
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English (en)
Chinese (zh)
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吕佳声
顾家敏
陈刚
张启国
孙成勇
孔宪起
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润佳（苏州）医药科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/6574—Esters of oxyacids of phosphorus
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/6574—Esters of oxyacids of phosphorus
    • C07F9/65744—Esters of oxyacids of phosphorus condensed with carbocyclic or heterocyclic rings or ring systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to N-(tri-deuterated methyl)-2-((3-((1E)-2-(2-pyridyl)vinyl)-1H-indazole-6 which is a tyrosine kinase inhibitor -Yl)thio)benzamide and its derivatives, and their use in inhibiting or regulating the activity of tyrosine kinases or treating disease symptoms or disorders mediated by tyrosine kinases, such as cancer.
  • Axitinib (chemical name: N-methyl-2-((3-((1E)-2-(2-pyridyl)vinyl)-1H-indazol-6-yl)sulfanyl)benzyl Amide; trade name: ) Is a small molecule tyrosine kinase inhibitor (TKI) used to treat cancer (for example, see WO2001002369, the structure of the compound is shown below). It has been shown that Axitinib can significantly inhibit the growth of breast cancer in animal xenograft models (Wilmes, LJet al., Magn. Reson. Imaging, 2007, 25(3): 319-327).
  • the drug has shown a partial response in clinical trials of renal cell carcinoma (RCC) (Rini, B. et al., J. of Clin. Oncol. 2005, ASCO Annual Meeting Proceedings, 23(16S): 4509), and It also showed partial response to several other tumor types (Rugo, HSet al., J. Clin. Oncol., 2005, 23:5474-5483).
  • RCC renal cell carcinoma
  • axitinib has been approved by the US Food and Drug Administration for the treatment of RCC.
  • Axitinib is as follows:
  • axitinib is used for targeted anti-cancer therapy is that it targets and binds to the vascular endothelial growth factor receptor (VEGFR) inside cancer cells.
  • VEGFR vascular endothelial growth factor receptor
  • Axitinib blocks an important way to promote angiogenesis (new blood vessels forming tumors) (Escudier, B. and Gore, M., "Axitinib for the Management of Metastatic Renal Cell Carcinoma", Drugs in R&D, 2011, 11(2): 113–126).
  • Axitinib to treat cancer is its side effects. Many different side effects have been reported, including diarrhea, high blood pressure, fatigue, loss of appetite, nausea, dysphonia, hand-foot syndrome, weight loss, vomiting, fatigue, and constipation, and the most common side effects occur in more than 20% of patients (FDA Prescribing Information, January 30, 2012).
  • PK pharmacokinetics
  • CYP3A4/5 expression has 10 to 40-fold variability
  • Axitinib is a low extraction rate drug, the metabolic clearance rate of Axitinib is particularly sensitive to different levels of liver and intestinal metabolic enzymes. Another possible explanation is the variability of axitinib plasma binding between subjects. For high residual (intra-subject) variability, the dissolution of Axitinib and subsequent gastrointestinal absorption differences may be a contributing factor. Since the solubility of Axitinib depends on the pH, as the pH increases, the solubility decreases. Therefore, changes in the pH of the stomach and duodenum may cause changes in the dissolution of Axitinib.
  • Axitinib Since the plasma exposure of Axitinib not only affects its toxicity, but also its clinical effects, it is important to determine the clinical factors that lead to the variability of Axitinib PK. In order to reduce toxicity and maintain a stable therapeutic effect, it is necessary to eliminate or reduce the PK variability of Axitinib.
  • Prodrugs are drugs or compounds that are metabolized (i.e. converted in the body) into pharmacologically active drugs after administration (for example, see Rautio, J. et al., "The expanding role of prodrugs in contemporary drug design and development", Nat. Rev. .Drug Discov.,2018,17,559-587; and Miles H.,et al.,Pharmacology:Principles and Practice.Academic Press,Jun 19,2009,pp.216-217).
  • Inactive prodrugs are pharmacologically inactive drugs that are metabolized in the body into an active form.
  • the corresponding prodrug is used to improve the absorption, distribution, metabolism and/or excretion mode (ADME) of the drug (for example, see Malhotra, B., et al., "The design and development of fesoterodine as a prodrug of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of tolterodine",Curr.Med.Chem.,2009,16(33):4481-9; and Stella,VJ,etal," Prodrugs.Do they have advantages in clinical practice?",Drugs,1985,29(5):455-73). Prodrugs can be used to improve the selectivity of drug interactions with unintended target cells or processes.
  • ADME absorption, distribution, metabolism and/or excretion mode
  • tenofovir alafenamide (TAF)
  • TAF tenofovir alafenamide
  • deuterium is the stable, non-radioactive, and most common isotope of hydrogen. Its mass is about twice that of hydrogen. Szarnik reported on deuterated axitinib in the US patent application US2009062347 filed in 2009. However, US2009062347 only describes various deuterated axitinib in general, and does not further explain or explain the chemical properties and biological activities of any deuterium-enriched axitinib.
  • the purpose of the present invention is to at least improve some of the defects in the prior art. Based at least in part on the inventors’ comments on the development of N-(trideuteromethyl)-2-((3-((1E)-2-(2-pyridyl)vinyl)-1H-indazol-6-yl )Thio)benzamide and its derivatives are used to adjust or improve the pharmacokinetic properties of axitinib to make it suitable for understanding the needs of therapeutic applications, thereby developing the present invention.
  • isotope-enriched drugs can potentially affect the metabolism, release, absorption, and/or clearance of therapeutic drugs, and appropriate prodrug strategies can also change the process and/or rate of the drug’s metabolic pathway To adjust the pharmacokinetic properties of the drug. For example, deuterium enrichment at a specific site; or changing the electron density of the system; protecting the ring nitrogen atoms in the molecular structure; to adjust the oxidation rate, thereby regulating the metabolism of the compound. For example, when a protecting group is introduced to a nitrogen atom in pyrazole, the occurrence of glucuronidation reaction on the nitrogen can be avoided or reduced at least to a certain extent.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, ester, solvate or various polymorphs thereof:
  • R 1 and R 2 are independently hydrogen (H) or a protecting group (P); R 3 may be present or absent; when R 3 exists and is a protecting group, the nitrogen atom is positively charged and there is a counter ion; Provided that the compound of formula I is not deuterated axitinib.
  • the protecting groups may be the same or different.
  • the compound of formula I is a compound of formula II or a pharmaceutically acceptable salt, ester, solvate or polymorph thereof:
  • R 1 and R 2 are independently hydrogen (H) or a protecting group, and when R 1 and R 2 are both protecting groups, the protecting groups may be the same or different.
  • the compound of formula I is a compound of formula III or a pharmaceutically acceptable salt, ester, solvate or polymorph thereof:
  • R 3 is a protecting group, and It is a counter ion.
  • the protecting group is selected from acyl, alkylcarbonyl, arylcarbonyl, alkylthiocarbonyl, formylthioacyl, alkylcarbamoyl, arylcarbamoyl, substituted or unsubstituted acetyl Group, substituted or unsubstituted aminoalkanoyl, substituted or unsubstituted ⁇ -aminoalkanoyl, natural or unnatural amino acid-derived acyl with or without substituents, acyl of peptide residues, cycloalkylcarbonyl, hetero Cycloalkylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, heteroalkoxycarbonyl, heteroaryloxycarbonyl, and oligoglycolated carbonyl with or without substituents.
  • the protecting group may also be R 4 (R 5 R 6 C) m -or -CHRaOR.
  • Ra is H or lower alkyl;
  • R is selected from hydrogen, alkyl, alkylcarbonyl, heteroarylcarbonyl, adamantylcarbonyl, arylcarbonyl, alkylthiocarbonyl, arylthiocarbonyl , Alkylcarbamoyl, arylcarbamoyl, substituted or unsubstituted acetyl, substituted or unsubstituted aminoalkanoyl, substituted or unsubstituted ⁇ -aminoalkanoyl, natural or unnatural amino acid derived with or Unsubstituted acyl, peptide residue acyl, cycloalkylcarbonyl, heterocycloalkylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, heteroalkoxycarbonyl, heteroaryloxycarbonyl, with or without The oligoglycolated carbonyl group of the substituent and R 4 W(R 5 R)
  • the prerequisite is that the compound of formula I, formula II or formula III is not deuterated axitinib.
  • the counterion is selected, but not limited to, halogen ions (F -, Cl -, Br - and I -), sulfate ion, methanesulfonate ion, toluenesulfonate ion, oxalate ion, tartrate Ions and other pharmaceutically acceptable anionic moieties.
  • the compound provided herein is a prodrug of deuterated axitinib, which is metabolized or converted to deuterated axitinib in a subject.
  • the compound of formula I to III is the compound shown in Table 1 or a pharmaceutically acceptable salt, ester, chelate, hydrate, solvent compound, stereoisomer or polymorph thereof .
  • the present invention provides a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier.
  • the present invention provides a pharmaceutical composition comprising a compound represented by Formula I, Formula II, or Formula III, or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier.
  • the invention provides methods of inhibiting or modulating tyrosine kinase activity in a subject.
  • the present invention provides a method for treating disease symptoms or disorders mediated by tyrosine kinases in a subject in need thereof, comprising adding an effective amount of the above-mentioned formula I, formula II or The compound of formula III and/or the pharmaceutical composition is administered to the subject.
  • tyrosine-mediated disease conditions or conditions in which a subject can be treated by the methods provided herein include various tumors and cancers. Examples of tumors and cancers that can be treated include, but are not limited to: renal cell tumors (RCC), breast cancer, and thyroid cancer.
  • the compound of Formula I, Formula II, or Formula III and/or a pharmaceutical composition thereof is administered to modulate the pharmacokinetic properties of Axitinib/Deuterated Axitinib, for example, as compared with the administration of Axitinib.
  • a pharmaceutical composition thereof improves bioavailability, changes the duration of effective plasma concentration, reduces the variability of plasma levels, reduces side effects and/or improves axitinib/deuterated in subjects The therapeutic effect of Axitinib.
  • the administration of the compound of Formula I, Formula II, or Formula III and/or the pharmaceutical composition thereof improves biodistribution, reduces metabolism and/or Expand the therapeutic application of Axitinib/Deuterated Axitinib in subjects.
  • the administration of the compound of Formula I, Formula II, or Formula III and/or the pharmaceutical composition thereof to increase or adjust the PK characteristics The half-life of Axitinib/Deuterated Axitinib, thereby reducing or changing the frequency of administration of the compound to the subject.
  • the present invention provides a method for treating a disease condition or symptom mediated by a tyrosine kinase in a subject in need thereof, the method comprising adding an effective amount of Formula I, Formula II, or Formula III The compound or the pharmaceutical composition thereof is administered to the subject, thereby treating the disease condition or symptom.
  • the present invention provides a method of treating tumor or cancer in a subject in need thereof, the method comprising administering an effective amount of a compound of formula I, formula II or formula III or a pharmaceutical composition thereof To the subject, thereby treating the tumor or cancer.
  • the compounds of Formula I, Formula II, or Formula III of the present invention and the above methods are used alone in a subject to treat disease conditions or symptoms mediated by tyrosine kinases.
  • the compounds and methods of Formula I, Formula II, or Formula III of the present invention are used in combination with other therapeutic agents or methods, including but Not limited to programmed cell death protein-1 (also known as programmed cell death-1, PD-1) and programmed cell death ligand 1 (also known as programmed cell death protein-1 ligand, PD-L1) Inhibitor.
  • kits comprising one or more compounds of Formula I, Formula II, or Formula III or pharmaceutical compositions described herein.
  • the kit may further include one or more additional therapeutic agents and/or instructions, such as instructions for using the kit to treat symptoms or conditions of diseases mediated by tyrosine kinases.
  • the present invention also relates to a tri-deuterated axitinib or a pharmaceutically acceptable salt, ester, chelate, hydrate, solvent compound, stereoisomer or polymorph thereof ;
  • the three deuterated axitinib (compound A) has the following structure:
  • the comparative PK experiment of compound A and axitinib proves that the pharmacokinetics of the compound A shown in the present invention is superior to that of axitinib.
  • the present invention also relates to a pharmaceutical composition comprising Compound A, and a method for preparing Compound A.
  • the present invention provides a method for preparing a compound of Formula I, Formula II, or Formula III from Compound A.
  • the present invention further relates to a method for compound A to treat a disease condition or symptom mediated by a tyrosine kinase in a subject in need thereof, the method comprising combining an effective amount of N-(trideuterated Methyl)-2-((3-((1E)-2-(2-pyridyl)vinyl)-1H-indazol-6-yl)thio)benzamide or its pharmaceutical composition is administered to recipients Try to treat disease symptoms or symptoms.
  • the present invention provides a method of treating tumor or cancer in a subject in need thereof, the method comprising adding an effective amount of N-(trideuterated methyl)-2-((3- ((1E)-2-(2-pyridyl)vinyl)-1H-indazol-6-yl)thio)benzamide or a pharmaceutical composition thereof is administered to a subject, thereby treating the tumor or cancer.
  • the compound A of the present invention and its pharmaceutical composition compound and the above-mentioned method alone are used in a subject to treat disease conditions or symptoms mediated by tyrosine kinase.
  • the method of compound A and its composition of the present invention is used in combination with other therapeutic agents or methods, including but not limited to procedures Inhibitors of apoptosis protein-1 (also known as programmed cell death-1, PD-1) and programmed cell death ligand 1 (also known as programmed cell death protein-1 ligand, PD-L1).
  • Figure 1 shows the concentration-time curve of compound A in plasma after compound A and compound 5 were orally administered respectively.
  • “- ⁇ -” and “- ⁇ -” represent the changes in the concentration of compound A in plasma over time after oral administration of equimolar doses of Compound A and Compound 5, respectively.
  • Figure 2 shows the concentration-time curves of Compound A and Axitinib in plasma after oral administration of Compound A and Axitinib, respectively.
  • "- ⁇ -" and “- ⁇ -” respectively represent the changes in the concentration of compound A and axitinib in plasma over time.
  • the word “a” may mean “one/kind”, but it also means “one or more”, “at least one” and “an Or more than one”. Similarly, the word “another” can mean at least a second or more.
  • derivative used in the present invention should be understood as another compound that is similar in structure and different in some subtle structures.
  • substituted or “has a substituent” means that the parent compound or moiety has at least one substituted group.
  • unsubstituted or “unsubstituted” means that the parent compound or part does not have other substituents except for the chemical saturation of the undetermined valence by a hydrogen atom.
  • substituteduent or “substituent group” means selected from halogen (F, Cl, Br or I), hydroxyl, mercapto, amino, nitro, carbonyl, carboxy, alkyl, alkoxy, Alkylamino, aryl, aryloxy, arylamino, acyl, sulfinyl, sulfonyl, phosphono or other organic moieties conventionally used and accepted in organic chemistry.
  • halogen F, Cl, Br or I
  • hydroxyl hydroxyl
  • mercapto amino, nitro, carbonyl, carboxy, alkyl, alkoxy, Alkylamino, aryl, aryloxy, arylamino, acyl, sulfinyl, sulfonyl, phosphono or other organic moieties conventionally used and accepted in organic chemistry.
  • alkyl used in the present invention refers to a saturated hydrocarbon having 1 to 12 carbon atoms, including straight chain, branched chain and cyclic alkyl groups.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, isopropyl, tert-butyl, sec-butyl, isopropyl Butyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.
  • alkyl includes unsubstituted alkyl and substituted alkyl.
  • C 1 -C n alkyl (wherein n is an integer from 2 to 12) represents an alkyl group having 1 to the indicated "n" carbon atoms.
  • Alkyl residues can be substituted or unsubstituted.
  • the alkyl group may be substituted with a group such as a hydroxyl group, an amino group, a carboxyl group, a carboxylate, an amide, a carbamate, or an aminoalkyl group.
  • the "lower” in “lower aliphatic”, “lower alkyl”, “lower alkenyl” and “lower alkynyl” as used herein means that the moiety has at least one (for alkene The group and the alkynyl group are at least two) and equal to or less than 6 carbon atoms.
  • cycloalkyl refers to a monocyclic, spirocyclic (shared one atom) or fused (shared at least one bond) carbocyclic ring system containing saturation or part An unsaturated carbocyclic group in which the carbocyclic ring system has 3 to 15 carbon atoms.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopenten-1-yl, cyclopenten-2-yl, cyclopenten-3-yl, cyclohexyl, cyclohexyl En-1-yl, cyclohexen-2-yl, cyclohexene-3 cycloheptyl, bicyclo[4,3,0]nonyl, norbornyl, etc.
  • the term cycloalkyl includes unsubstituted cycloalkyl and substituted cycloalkyl.
  • C 3 -C n cycloalkyl wherein n is an integer from 4 to 15, represents a cycloalkyl group having 3 to the indicated "n" carbon atoms in the ring structure.
  • the "lower cycloalkyl” group used in the present invention refers to having at least 3 and equal to or less than 8 carbon atoms in its ring structure.
  • cycloalkyl residue used in the present invention may be saturated or a group containing one or more double bonds in the ring system. In particular, they may be saturated or contain a double bond in the ring system. In the unsaturated cycloalkyl residue, the double bond may be present in any suitable position.
  • Monocycloalkyl residues include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclononyl, Cyclodecyl, cycloundecyl, cyclododecyl or cyclotetradecyl, which may also be substituted with C 1-4 alkyl.
  • substituted cycloalkyl residues are 4-methylcyclohexyl and 2,3-dimethylcyclopentyl.
  • Examples of the parent structure of the bicyclic system are norbornane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.1]octane.
  • heterocycloalkyl and equivalent expressions used in the present invention refer to a group containing saturated or partially unsaturated carbocyclic rings in a monocyclic, spirocyclic (shared one atom) or fused (shared at least one bond) carbocyclic ring system , Which has a group of 3 to 15 carbon atoms, including 1 to 6 heteroatoms (such as N, O, S, P) or containing heteroatoms (such as NH, NRx (Rx is alkyl, acyl, aryl) , Heteroaryl or cycloalkyl), PO 2 , SO, SO 2 etc.).
  • heterocycloalkyl group can be attached to C or attached to a heteroatom (e.g., through a nitrogen atom).
  • heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, tetrahydrodithienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl Oxalanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxalanyl, thiolanyl, oxazide Azazinyl, diazepinyl, thiazepine, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyran Group,
  • heterocycloalkyl includes unsubstituted heterocycloalkyl and substituted heterocycloalkyl.
  • C 3 -C n heterocycloalkyl represents a heterocycloalkyl group having 3 to "n" atoms in the ring structure, including at least one as defined above Heterogroup or atom.
  • the "lower heterocycloalkyl group” used in the present invention refers to having at least 3 and equal to or less than 8 carbon atoms in its cyclic structure.
  • oxygen heterocyclic ring as used herein specifically refers to a 4 to 8 membered ring having 1 oxygen atom in the ring structure, for example, a 4 to 7 membered ring, a 5 to 6 membered ring and the like.
  • aryl and aryl ring used in the present invention refer to having "4n+2" ( ⁇ ) electrons in a conjugated monocyclic or polycyclic ring system (fused or non-fused), and has 6 An aromatic group of up to 14 ring atoms, where n is an integer from 1 to 3.
  • the polycyclic ring system includes at least one aromatic ring.
  • the aryl group can be attached directly or through a C 1 -C 3 alkyl group (also known as arylalkyl or aralkyl).
  • aryl groups include, but are not limited to, phenyl, benzyl, phenethyl, 1-phenylethyl, tolyl, naphthyl, biphenyl, terphenyl, indenyl, benzocyclooctenyl, benzene And cycloheptenyl, azulenyl, acenaphthyl, fluorenyl, phenanthryl, anthracenyl, etc.
  • aryl includes unsubstituted aryl and substituted aryl.
  • C 6 -C n aryl (wherein n is an integer from 6 to 15) means an aryl group having 6 to "n" carbon atoms in the ring structure, including at least one heterocyclic group as defined above Group or atom.
  • heteroaryl and “heteroaryl ring” used in the present invention refer to an aromatic having "4n+2" ( ⁇ ) electrons in a conjugated monocyclic or polycyclic ring system (fused or non-fused).
  • Group group where n is an integer from 1 to 3, and includes one to six heteroatoms (such as N, O, S) or heteroatoms (such as NH, NRx (Rx is alkyl, acyl, aryl, hetero Aryl or cycloalkyl), SO, SO 2 etc.) groups.
  • the polycyclic ring system includes at least one heteroaromatic ring.
  • the heteroaryl group can be connected directly or through a C 1 -C 3 alkyl group (also known as heteroarylalkyl or heteroaralkyl). Heteroaryl groups can be attached to carbon or attached to a heteroatom (e.g., through a nitrogen atom).
  • heteroaryl groups include, but are not limited to, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl; isoxazolyl, thiazolyl, oxazolyl, isothiazole Group, pyrrolidinyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, chromenyl, isochromenyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl , Indazinyl, phthalazinyl, pyridazinyl, pyrazinyl, triazinyl, isoindolyl, pteridyl, furanyl, benzofuranyl, benzothiazolyl, benzothienyl, benzo Thiazolyl, benzoxazolyl,
  • heteroaryl includes unsubstituted heteroaryl and substituted heteroaryl.
  • C 5 -C n heteroaryl represents a heteroaryl group having from 5 to "n" atoms in the ring structure, including at least one heteroaryl group as defined above Ring group or atom.
  • heterocyclic or “heterocyclic” as used in the present invention includes heterocycloalkyl and heteroaryl.
  • heterocycles include, but are not limited to, acridinyl, azeinyl, benzimidazolyl, benzofuranyl, benzothienyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzo Triazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, 4 ⁇ H-carbazolyl, carboline, chromanyl, chromenyl, cinnoline, ten Hydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl , 1H-indazoly
  • amine or “amino” used in the present invention refers to an unsubstituted or substituted, wherein R a and R b are each independently hydrogen, an alkyl group, an aryl group or a heterocyclic group, or R a and R b, together form a heterocyclic ring with the nitrogen atom to which they are attached.
  • amino means that at least one carbon or heteroatom in a compound or fragment is covalently bonded to a nitrogen atom. Therefore, the terms “alkylamino” and “dialkylamino” used in the present invention refer to an amino group having one and at least two C 1 -C 6 alkyl groups connected to a nitrogen atom, respectively.
  • arylamino and diarylamino include groups to which at least one or two aryl groups are bonded to a nitrogen atom.
  • amide or “aminocarbonyl” refers to a structure in which the carbon of the carbonyl or thiocarbonyl group of a compound or fragment is connected to a nitrogen atom.
  • acylamino refers to a structure in which an amino group is directly linked to an acyl group.
  • alkylmercapto refers to an alkyl group having a mercapto group attached to it.
  • Suitable alkylsulfhydryl groups include groups having 1 to about 12 carbon atoms, preferably 1 to about 6 carbon atoms.
  • alkylcarboxy refers to an alkyl group having a carboxy group attached to it.
  • alkoxy refers to a structure in which an alkyl group is connected to an oxygen atom.
  • Representative alkoxy groups include groups having 1 to about 6 carbon atoms, such as methoxy, ethoxy, propoxy, tert-butoxy and the like.
  • Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, butoxy, pentoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy , Chloromethoxy, dichloromethoxy, trichloromethoxy, etc.
  • alkoxy includes unsubstituted or substituted alkoxy, as well as perhaloalkoxy and the like.
  • carbonyl or “carboxy” as used in the present invention refers to compounds and fragments containing a carbon connected to an oxygen atom through a double bond.
  • examples of the carbonyl group-containing moiety include aldehydes, ketones, carboxylic acids, amides, esters, acid anhydrides, and the like.
  • acyl used in the present invention refers to the carbon atom of the carbonyl group connected to hydrogen (ie formyl), aliphatic group (C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Such as acetyl), cycloalkyl (C 3 -C 8 cycloalkyl), heterocyclic group (C 3 -C 8 heterocycloalkyl and C 5 -C 6 heteroaryl), aryl (C 6 aryl) , Such as benzoyl) connected to the carbonyl structure.
  • the acyl group may be an unsubstituted or substituted acyl group (e.g., salicyl group).
  • solvate refers to the physical association of a compound with one or more solvent molecules (whether organic or inorganic). This physical association includes hydrogen bonding. In some cases, solvates can be separated, for example when one or more solvent molecules are incorporated into the crystal lattice of the crystal. "Solvate” includes solvent compounds in solution phase and solvates that can be separated. Examples of “solvates” include, but are not limited to, hydrates, ethanolates, methanolates, hemiethanolates, and the like.
  • a “pharmaceutically acceptable salt” of a compound refers to a salt of a pharmaceutically acceptable compound.
  • the salt (basic, acidic or charged functional group) of the desired compound can retain or improve the biological activity and properties of the parent compound as defined in the present invention, and is not biologically undesirable.
  • Examples of pharmaceutically acceptable salts are mentioned by Berge et al. in "Pharmaceutical Salts", J. Pharm. Sci. 66, 1-19 (1977), including but not limited to:
  • a base addition salt obtained by adding a base; wherein the metal ion includes alkaline metal ions (such as lithium, sodium, potassium), alkaline earth metal ions (Magnesium, calcium, barium) or other metal ions such as aluminum, zinc, iron, etc.; or coordinate with organic bases, where organic bases such as ammonia, ethylamine, diethylamine, N,N'-dibenzylethylenediamine , Ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, piperazine, chloroprocaine, procaine, choline, lysine, etc.
  • alkaline metal ions such as lithium, sodium, potassium
  • alkaline earth metal ions Magnnesium, calcium, barium
  • other metal ions such as aluminum, zinc, iron, etc.
  • organic bases such as ammonia, ethylamine, diethylamine, N,N'-dibenzylethylenediamine , Ethano
  • salts can be synthesized from parent compounds containing basic or acidic fragments by conventional chemical methods. Generally, such salts are prepared by reacting a compound (free acid or base) with an equivalent stoichiometric amount of base or acid in water or organic solvent or in a mixture of both. The salt can be prepared in situ during the final isolation or purification of the agent, or prepared by reacting the purified compound of the present invention in free acid or base form with the desired corresponding base or acid separately and isolating the salt formed thereby.
  • pharmaceutically acceptable salt also includes zwitterionic compounds containing a cationic group covalently bonded to an anionic group, and they are referred to as "internal salts.” It should be understood that all acids, salts, bases and other ionic and non-ionic forms of the compounds of the present invention are encompassed within the scope of the present invention. For example, if the compound in the present invention is an acid, the salt form of the compound is also encompassed within the scope of the present invention. Likewise, if the compound in the present invention is a salt, the acid and/or base form of the compound is also encompassed within the scope of the present invention.
  • the term "effective amount” refers to the amount of a therapeutic agent (such as a compound) that provides a desired therapeutic, diagnostic, or prognostic effect in the subject after being administered to a subject in a single dose or multiple doses Or dose.
  • a therapeutic agent such as a compound
  • the attending doctor or diagnosing doctor can easily determine the effective amount by using known techniques and by observing the results obtained in similar situations.
  • the effective amount or dosage of the compound to be administered many factors are considered, including but not limited to: the weight, age and general health of the subject; the specific disease involved; the degree or severity of the disease or condition to be treated The individual subject’s response; the specific compound administered; the mode of administration; the bioavailability characteristics of the administered formulation; the selected dosage regimen; the use of concomitant drugs; and other relevant considerations.
  • “Pharmaceutically acceptable” refers to drugs, drugs, inert ingredients, etc. described by the term, suitable for contact with human and animal cells or tissues without abnormal toxicity, incompatibility, instability, or irritation Sex, allergic reactions, etc., are commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable carrier” refers to a diluent, adjuvant, excipient, carrier, or carrier with which the compound is administered.
  • pharmaceutically acceptable carrier and “pharmaceutically acceptable carrier” are used interchangeably herein.
  • “Pharmaceutical composition” refers to the compound as described herein, and at least one component depending on the requirements of the administration mode and dosage form, and the at least one component includes a pharmaceutically acceptable carrier, diluent, adjuvant Agents, excipients or carriers, such as preservatives, fillers, disintegrating agents, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants and Dispersant, etc.
  • a pharmaceutically acceptable carrier such as preservatives, fillers, disintegrating agents, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants and Dispersant, etc.
  • Prevention or “prevention” is used to mean at least reducing the possibility of acquiring a disease or condition (or susceptibility) to acquire a disease or disorder (ie, preventing the clinical symptoms of at least one disease from developing into possible exposure to or susceptibility to disease but Patients who have not experienced or displayed symptoms of disease).
  • treating” or “treating” any disease or condition refers to alleviating at least one disease or condition.
  • treatment or “treatment” refers to alleviating at least one physical parameter, which can be distinguishable or indistinguishable by the patient.
  • treatment or “treatment” refers to Physically (e.g., stabilization of discernible symptoms) or physiologically (e.g., stabilization of physical parameters) or both.
  • treatment or “treatment” refers to A subject in need thereof improves the quality of life or the side effects of the disease.
  • “Therapeutically effective amount” refers to the amount of the compound administered to the subject for the treatment or prevention of the disease that is sufficient to achieve the effect of treating or preventing the disease. "Therapeutic effect is effective.” “Amount” will vary depending on the compound; the disease and its severity; the age, weight, etc. of the subject to be treated or prevented from suffering from the disease. As used herein, “therapeutically effective amount” means that the compound or composition is sufficient Prevent, treat, inhibit, reduce, alleviate or eliminate diseases, such as one or more causes, symptoms or complications of cancer.
  • subject refers to animals including mammals and humans, especially humans.
  • prodrug or its equivalent expression refers to a drug that is directly or indirectly converted into an active form in vitro or in vivo (see, for example, RBSilverman, 1992, “The Organic Chemistry of Drug Design and Drug Action,” Academic Press, Chapter 8 ;Bundgaard,Hans;Editor.Neth.(1985),”Design of Prodrugs".360pp.Elsevier,Amsterdam; Stella,V.; Borchardt,R.;Hageman,M.;Oliyai,R.;Maag,H.; Tilley, J. (Eds.) (2007), “Prodrugs: Challenges and Rewards, XVIII, 1470p. Springer).
  • Prodrugs can be used to change the biodistribution of a specific drug (for example, so that the drug usually does not enter the protease reaction site) Or pharmacokinetics.
  • Various groups such as esters, ethers, phosphate esters/salts, etc. have been used to modify compounds to form prodrugs.
  • the prodrug When the prodrug is administered to a subject, the group is enzymatically or non-enzymatically Promote, reduce, oxidize or hydrolyze, or otherwise release the active compound.
  • prodrugs include pharmaceutically acceptable salts, or pharmaceutically acceptable solvates, and the above Any crystalline form of the present. Prodrugs are usually (though not necessarily) pharmaceutically inactive until they are converted to active formation.
  • esters refers to a compound represented by the formula RCOOR' (carboxylic acid ester) or formula RSO 3 R'(sulfonic acid ester), usually by the reaction between carboxylic acid or sulfonic acid and alcohol (elimination of one molecule of water) To form.
  • R and R' are called ester-forming groups
  • R is, for example, a lower alkyl group or an aryl group, such as methylene, ethylene, isopropylene, phenylene, etc., but not limited thereto;
  • R' Such as lower alkyl, cycloalkyl or aryl, such as methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl Etc., but not limited to this.
  • R is, for example, a lower alkyl group or an aryl group, such as methylene, ethylene, isopropylene, phenylene, etc., but not limited thereto;
  • R′ is, for example, a lower alkyl group, a cycloalkyl group, or an aryl group , Such as methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, etc., but not limited thereto.
  • carbonate-containing hydrocarbon group is used to indicate the structure of "-ROCOOR'" (R' is generally an alkyl group and other non-H groups).
  • R is, for example, a lower alkyl group or an aryl group, such as methylene, ethylene, isopropylene, phenylene, etc., but not limited thereto;
  • R′ is, for example, a lower alkyl group, a cycloalkyl group, or an aryl group , Such as methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, etc., but not limited thereto.
  • salt-forming moiety used in the present invention refers to a moiety capable of forming a salt with an acidic group, such as a carboxyl group, such as but not limited to sodium, potassium, tetraethylamine, tetrabutylamine and the like.
  • ether can be represented by the general formula ROR' (R' is generally an alkyl group and other non-H groups), wherein R and R'are referred to as "ether-forming group” or "ether-forming part".
  • R is, for example, a lower alkyl or aryl group, such as methylene, ethylene, isopropylene, phenylene, etc., but not limited thereto;
  • R′ is, for example, a lower alkyl or aryl group, for example, methyl , Ethyl, propyl, isopropyl, butyl, phenyl, naphthyl, etc., but not limited thereto.
  • amino acid generally refers to an organic compound containing both a carboxylic acid group and an amino group.
  • amino acid includes “natural” and “non-natural” amino acids.
  • amino acid includes O-alkylated amino acids or N-alkylated amino acids, as well as amino acids with side chains containing nitrogen, sulfur, or oxygen (for example, Lys, Cys, or Ser), in which nitrogen, sulfur or oxygen atoms Can be acylated or alkylated with or without.
  • Amino acids may be pure L-isomers or D-isomers, or mixtures of L-isomers and D-isomers, including but not limited to racemic mixtures.
  • natural amino acid and equivalent expressions refer to L-amino acids commonly found in naturally occurring proteins.
  • natural amino acids include, but are not limited to, alanine (Ala), cysteine (Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly) , Histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro ), glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), ⁇ -Alanine ( ⁇ -Ala) and ⁇ -aminobutyric acid (GABA).
  • non-natural amino acid refers to any derivative of a natural amino acid, including D-type amino acids, as well as ⁇ - and ⁇ -amino acid derivatives.
  • unnatural amino acid and “not natural amino acid” are used interchangeably herein. It should be noted that certain amino acids that can be classified as unnatural amino acids in the present invention (for example, hydroxyproline) may also be present in certain biological tissues or specific proteins in nature. Amino acids with many different protecting groups suitable for direct application in solid-phase peptide synthesis are commercially available.
  • 2-aminoadipate (Aad), 3-aminoadipate ( ⁇ -Aad), 2-aminobutyric acid (2-Abu), ⁇ , ⁇ -dehydro-2-aminobutyric acid (8-AU), 1-aminocyclopropane-1-carboxylic acid (ACPC), amino Isobutyric acid (Aib), 3-aminoisobutyric acid ( ⁇ -Aib), 2-amino-thiazoline-4-carboxylic acid, 5-aminovaleric acid (5-Ava), 6-aminocaproic acid (6- Ahx), 2-aminoheptanoic acid (Ahe), 8-aminooctanoic acid (8-Aoc), 11-aminoundecanoic acid (11-Aun), 12-aminododecanoic acid (12-A
  • the compounds provided herein also include their salts and pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt refers to a salt prepared from pharmaceutically acceptable non-toxic acids or bases (including inorganic acids and bases and organic acids and bases).
  • pharmaceutically acceptable non-toxic acids including inorganic acids and organic acids.
  • acids suitable for use in the present invention include, but are not limited to, acetic acid, benzenesulfonic acid (benzenesulfonate), benzoic acid, camphorsulfonic acid, citric acid, vinylsulfonic acid, fumaric acid, gluconic acid, glutamic acid Amino acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid Toluenesulfonic acid and so on.
  • pharmaceutically acceptable bases suitable for use in the present invention include, but are not limited to, metal salts made of aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, or metal salts made of lysine, N, Organic salt made of N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
  • the present invention provides a method for improving the therapeutic effect of Axitinib/Deuterated Axitinib in a subject in need, the method comprising: adding an effective amount of Formula I, Formula II Or a compound of formula III or a pharmaceutical composition thereof, or an effective amount of Compound A or a pharmaceutical composition thereof is administered to the subject, so as to increase the asitinib as compared with the use of axitinib/deuterated axitinib itself.
  • the compound is a prodrug of deuterated axitinib.
  • a compound of Formula I, Formula II, or Formula III provided herein prodrug of Deuterated Axitinib
  • the pharmaceutical composition improves one or more of the following: the bioavailability of axitinib/deuterated axitinib; AUC of axitinib/deuterated axitinib in blood or plasma; axitin C max of Ni/Deuterated Axitinib ; T max of Axitinib/Deuterated Axitinib ; T 1/2 of Axitinib/Deuterated Axitinib; Axitinib/Deuterium Therapeutic biodistribution of Axitinib; Therapeutic level of Axitinib/Deuterated Axitinib in selected tissues; and/or Axitinib/Deuterated Axitinib in subjects Bioa
  • a compound of Formula I, Formula II, or Formula III provided herein prodrug of Deuterated Axitinib
  • a pharmaceutical composition to reduce one or more of the following: the metabolism of axitinib/deuterated axitinib in a subject; and the side effects of axitinib/deuterated axitinib in a subject .
  • the present invention provides a method for obtaining target pharmacokinetic parameters of deuterated axitinib in a subject, comprising adding an effective amount of a compound of formula I, formula II or formula III described herein (deuterium Axitinib prodrug) or a pharmaceutical composition thereof is administered to a subject, thereby obtaining the target pharmacokinetic parameters of Axitinib/Deuterated Axitinib in the subject.
  • target pharmacokinetic parameters include target bioavailability, AUC in blood or plasma, C max , T max , biodistribution, levels in selected tissues, half-life (t 1/2 ), biosorption And the amount or rate of metabolism.
  • the pharmacokinetic parameters can be calculated using methods known in the art.
  • a pharmaceutical composition which includes a compound of the present invention, such as a compound of Formula I, Formula II, and Formula III, or a pharmaceutically acceptable salt, ester, solvate or polymorph thereof , And a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a compound of formula I, formula II, formula III, or compound A or their pharmaceutically acceptable salts, esters, solvates or polymorphs, and their pharmaceutically acceptable Acceptable carrier.
  • a pharmaceutical composition comprising the compound of Table 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a compound of Table 1 or a pharmaceutically acceptable salt thereof, an additional therapeutic agent, and a pharmaceutically acceptable carrier.
  • reaction temperature was raised to room temperature, and the reaction mixture was stirred at room temperature for 1 hour, and then methyl 2-mercaptobenzoate (2.62 g, 15.59 mmol, 1.0 eq.) was added dropwise thereto.
  • the reaction temperature was raised to 40°C and stirred at this temperature overnight.
  • 5M hydrochloric acid solution (30 mL) was added dropwise to the reaction mixture under this cooling condition to quench the reaction.
  • the aqueous layer was extracted and washed with dichloromethane three times (30 mL each time). The organic layer and the dichloromethane extraction wash were combined and concentrated.
  • reaction mixture was stirred at 80°C for 16 hours. After cooling to room temperature, water (200 mL) and ethyl acetate (400 mL) were added to the above mixture. The resulting mixture was filtered through Celite, and the filtrate was collected. The organic layer was separated and washed three times with saturated brine (200 mL each time).
  • the residue was cooled with an ice-water bath, and under cooling conditions, the pH was adjusted to about 9-10 with a saturated sodium bicarbonate aqueous solution, and a large amount of solids were precipitated.
  • the solid was collected by filtration, and 1.7 g of brown solid was obtained after drying.
  • the solid was mixed with glacial acetic acid (9 mL), heated to 80° C., stirred until clear, and activated carbon (100 mg) was added, and stirring was continued at this temperature for 1 hour.
  • the brown liquid was filtered while hot, and the filter cake was washed with hot acetic acid.
  • Triethylene glycol monomethyl ether 500mg, 3.045mmol, 1.0eq.
  • tetrahydrofuran 10mL
  • triethylamine 616mg, 6.09mmol, 2.0eq.
  • a tetrahydrofuran solution of phenyl p-nitrochloroformate 675 mg dissolved in 10 mL of tetrahydrofuran, 3.350 mmol, 1.1 eq.
  • Example 3 N-(Tri-deuterated methyl)-2-((3-((1E)-2-(2-pyridyl)vinyl)-1-((1-naphthyloxy)((1S )-(1-Methoxycarbonylethyl)amino)phosphinyl)-1H-indazol-6-yl)thio)benzamide (Compound 10)
  • the experimental animals were CD1 mice, males, weighing 18-22 g.
  • the experimental animals (72) were randomly divided into 4 groups, each with 18 animals. Blood samples were collected at 0.5, 1, 2, 4, 6, and 8 hours after administration.
  • the test compound is formulated into an experimental solution or suspension in a solvent and administered by intragastric administration.
  • the composition of the solvent is: DMSO: 0.5wt%-CMC-Na aqueous solution (5/95, v/v).
  • the concentration of the test compound was 3 mg/mL equivalent of deuterated axitinib. After the animals were fasted for 12 hours, 30 mg/kg deuterated axitinib equivalent was given by gavage.

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Abstract

La présente invention concerne un composé de formule (I), un sel ou un ester pharmaceutiquement acceptable de celui-ci, une composition pharmaceutique de celui-ci, et les utilisations du composé et de la composition pharmaceutique de la présente invention pour inhiber ou réguler l'activité de tyrosine kinases et traiter des symptômes ou des états pathologiques, y compris le cancer, médiés par les tyrosine kinases.
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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090062347A1 (en) * 2007-08-29 2009-03-05 Protia, Llc Deuterium-enriched axitinib
CN102040588A (zh) * 2009-10-16 2011-05-04 苏州康益明华生物医药科技有限公司 一种酪氨酸激酶抑制剂及其在治疗恶性肿瘤中的药物应用
CN103159680A (zh) * 2011-12-14 2013-06-19 爱美尼迪药物有限公司 咪唑二酮类化合物及其用途
CN104211683A (zh) * 2013-05-29 2014-12-17 成都海创药业有限公司 咪唑二酮类化合物及其用途
CN104788372A (zh) * 2014-07-25 2015-07-22 上海圣考医药科技有限公司 一种氘代卡博替尼衍生物、其制备方法、应用及其中间体
CN108467385A (zh) * 2017-06-27 2018-08-31 浙江同源康医药股份有限公司 一种氘代奥斯替尼衍生物及其应用
CN110372598A (zh) * 2018-04-13 2019-10-25 成都海创药业有限公司 一种合成氘代酰胺及氘代磺酰胺的新方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011113369A1 (fr) * 2010-03-18 2011-09-22 苏州泽璟生物制药有限公司 Procédés de préparation d'une méthyl-d3-amine et de sels de celle-ci
CN106478596A (zh) * 2015-08-25 2017-03-08 李建成 一种作为治疗眼科疾病的新化合物

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090062347A1 (en) * 2007-08-29 2009-03-05 Protia, Llc Deuterium-enriched axitinib
CN102040588A (zh) * 2009-10-16 2011-05-04 苏州康益明华生物医药科技有限公司 一种酪氨酸激酶抑制剂及其在治疗恶性肿瘤中的药物应用
CN103159680A (zh) * 2011-12-14 2013-06-19 爱美尼迪药物有限公司 咪唑二酮类化合物及其用途
CN104211683A (zh) * 2013-05-29 2014-12-17 成都海创药业有限公司 咪唑二酮类化合物及其用途
CN104788372A (zh) * 2014-07-25 2015-07-22 上海圣考医药科技有限公司 一种氘代卡博替尼衍生物、其制备方法、应用及其中间体
CN108467385A (zh) * 2017-06-27 2018-08-31 浙江同源康医药股份有限公司 一种氘代奥斯替尼衍生物及其应用
CN110372598A (zh) * 2018-04-13 2019-10-25 成都海创药业有限公司 一种合成氘代酰胺及氘代磺酰胺的新方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ZHANG HUI, LI MINGHUA, QIAO YUFENG: "Graphical Synthetic Routes of Axitinib", CHINESE JOURNAL OF PHARMACEUTICALS, vol. 45, no. 9, 30 September 2014 (2014-09-30), pages 896 - 898, XP055787156, ISSN: 1001-8255 *

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