WO2021037183A1 - 一类前药化合物及其在治疗癌症方面的应用 - Google Patents

一类前药化合物及其在治疗癌症方面的应用 Download PDF

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WO2021037183A1
WO2021037183A1 PCT/CN2020/111981 CN2020111981W WO2021037183A1 WO 2021037183 A1 WO2021037183 A1 WO 2021037183A1 CN 2020111981 W CN2020111981 W CN 2020111981W WO 2021037183 A1 WO2021037183 A1 WO 2021037183A1
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substituted
unsubstituted
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acid
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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
    • A61K31/33—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
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • 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-methyl-2-((3-((1E)-2-(2-pyridyl)vinyl)-1H-indazol-6-yl)sulfan which is a tyrosine kinase inhibitor )
  • 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 exists on the surface of many normal cells and cancer cells. By binding to these receptors, 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
  • Axitinib is mainly metabolized by CYP3A4/5, it is speculated that one of the main reasons for the variability may be the difference in the expression of CYP3A4/5 and/or the difference in activity in the liver and intestine (according to reports, in healthy subjects Among them, the expression of CYP3A4/5 has a 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.
  • the solubility of Axitinib is pH-dependent, and the solubility decreases with the increase of pH. Therefore, changes in the pH value in the stomach and duodenum may lead to changes in the solubility 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,et al," 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
  • axitinib derivatives of Axitinib can be used in the treatment of ophthalmic diseases, such as CN106317017, CN106336397, and CN106478596.
  • the obtained axitinib derivatives are only used to improve the water solubility of axitinib to meet the requirements of injection into the vitreous cavity.
  • it does not involve any axitinib derivatives that are used to inhibit the activity of tyrosine kinases or treat disease symptoms or disorders mediated by tyrosine kinases against the above defects.
  • 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’ understanding of the development of the methyl 2-((3-((1E)-2-(2-pyridyl)vinyl)-1H-indazol-6-yl)thio)benzamide To adjust or improve the pharmacokinetic properties of the specific compound to make it suitable for understanding the needs of therapeutic applications, the present invention was developed. Through the axitinib derivatives and/or prodrugs, pharmaceutical compositions, and their applications as defined herein, it is possible to inhibit or regulate the activity of tyrosine kinases and treat diseases mediated by tyrosine kinases. Or diseases, such as cancer, and other uses and needs, as well as other needs.
  • the protection of the nitrogen atom in Axitinib through molecular modification can change the physical, chemical and biological properties of the compound, such as compound solubility, lipophilicity and hydrophilicity, and biomembrane penetration. , Stability in the digestive system and liver, and the metabolic rate and pathway of the prodrug compound-based original drug compound. Changes in these properties will cause changes in the PK parameters of the original drug compound, thereby adjusting the therapeutic effect and scope of application of the original drug molecule.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, ester, solvate or various polymorphs thereof, in the preparation of a medicament for inhibiting the activity of tyrosine kinase
  • a compound of formula (I) or a pharmaceutically acceptable salt, ester, solvate or various polymorphs thereof, in the preparation of a medicament for inhibiting the activity of tyrosine kinase
  • R 1 and R 2 are independently hydrogen H or a protecting group -CHRaOR; 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; the condition is The compound of I is not axitinib.
  • the protecting groups may be the same or different.
  • the compound provided herein is a prodrug of axitinib, that is, it is metabolized or converted to axitinib in a subject.
  • 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 -CHRaOR, 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 (P), and It is a counter ion.
  • Ra is H or lower alkyl
  • R is selected from hydrogen, alkyl, acyl, alkylcarbonyl, adamantylcarbonyl, heteroarylcarbonyl, arylcarbonyl, alkyl Thiocarbonyl, formylthioacyl, alkylcarbamoyl, arylcarbamoyl, substituted or unsubstituted acetyl, substituted or unsubstituted aminoalkanoyl, substituted or unsubstituted ⁇ -aminoalkane
  • Acyl groups natural or unnatural amino acids derived from acyl groups with or without substituents, acyl groups of peptide residues, cycloalkylcarbonyl, heterocycloalkylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, heteroalkoxycarbonyl, Heteroaryloxycarbonyl, oligoglycolated carbonyl with
  • Ra in the protecting group -CHRaOR is H or lower alkyl
  • R is R 4 W(R 5 R 6 C) m -, wherein m is an integer selected from 0 to 6, and W is Oxygen (O), sulfur (S), nitrogen (N) or not present
  • R 5 and R 6 are independently hydrogen or lower alkyl
  • R 4 is Wherein, X is oxygen (O), sulfur (S), nitrogen (N) or carbon (C);
  • the Ra and R in the protecting group -CHRaOR, and the carbon and oxygen atoms to which they are attached together form a substituted or unsubstituted oxygen heterocyclic group, such as tetrahydrofuran-2-yl, tetrahydropyridine Pyr-2-yl, 1-oxocycloheptan-2-yl, etc.
  • 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 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 compound of formula I as defined above, with the proviso that the compound of formula I is not axitinib, N-methyl-N-(phosphonooxy)methyl-2- ((3-((E)-2-(2-pyridyl)vinyl)-1H-indazol-6-yl)thio)benzamide, N-methyl-2-((3-(( E)-2-(2-pyridyl)vinyl)-1-(lauroyloxy)methyl-1H-indazol-6-yl)thio)benzamide, N-methyl-N-( Phosphonoyloxy)methyl-2-((3-((E)-2-(2-pyridyl)vinyl)-1-(lauroyloxy)methyl-1H-indazol-6-yl )Thio)benzamide, N-methyl-N-(lauroyloxy)methyl-2-((3-((E)-2-(2-pyridyl)
  • 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 a disease symptom or disorder mediated by tyrosine kinase in a subject in need thereof, comprising combining an effective amount of the above-mentioned compound and/or drug The substance 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 present invention is used to treat diseases mediated by tyrosine kinases, excluding ophthalmic diseases.
  • a compound of Formula I, Formula II, or Formula III and/or a pharmaceutical composition thereof is administered to modulate the pharmacokinetic properties of Axitinib, for example, when compared with the administration of Axitinib, Among the subjects, increase bioavailability, change the duration of effective plasma concentration, reduce the variability of plasma levels, reduce side effects and/or improve the therapeutic effect of axitinib.
  • the administration of a compound of Formula I, Formula II, or Formula III and/or a pharmaceutical composition thereof improves biodistribution, reduces metabolism and/or expands the exposure of Axitinib. Therapeutic application among the subjects.
  • the compound of formula I, formula II or formula III and/or a pharmaceutical composition thereof is administered to increase or adjust the half-life of axitinib by adjusting the PK characteristics, 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 and methods of the invention are used alone in a subject to treat disease conditions or symptoms mediated by tyrosine kinases.
  • the compounds and methods 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) inhibitors.
  • kits comprising one or more compounds 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 is used to treat diseases mediated by tyrosine kinases, excluding ophthalmic diseases.
  • Figure 1 shows the curve of the concentration of axitinib in plasma over time after oral administration of equimolar doses of axitinib, compound 2, compound 4, compound 12 and compound 13; wherein, - ⁇ -,- ⁇ -, - ⁇ -, - ⁇ -, and -x- correspond to axitinib, compound 2, compound 4, compound 12, and compound 13, respectively.
  • 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 RSO3R' (sulfonic acid ester), and can usually be formed by the reaction between carboxylic acid or sulfonic acid and alcohol (elimination of one molecule of water), respectively.
  • 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.
  • hydrocarbon group containing carboxylic acid ester is used to indicate a structure in which the fragment contains an ester functional group -RCOOR' (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.
  • 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 in a subject in need thereof, the method comprising: adding an effective amount of a compound of formula I, formula II or formula III or The pharmaceutical composition is administered to the subject, thereby improving the therapeutic effect of axitinib compared with the use of axitinib itself.
  • the compound is a prodrug of axitinib.
  • the administration of a compound provided herein (a prodrug of Axitinib) or a pharmaceutical composition thereof improves one or more of the following compared with the administration of Axitinib itself: Bioavailability; AUC of Axitinib in blood or plasma; C max of Axitinib; T max of Axitinib; t 1/2 of Axitinib; Therapeutic biodistribution of axitinib ; The therapeutic level of axitinib in selected tissues; and/or the bioabsorption of axitinib in the subject.
  • axitinib prodrug compared with administering axitinib itself, one or more of the following is reduced by administering a compound provided herein (axitinib prodrug) or a pharmaceutical composition thereof: Metabolism in subjects; and Side effects of Axitinib in subjects.
  • the present invention provides a method for obtaining target pharmacokinetic parameters of Axitinib in a subject, comprising combining an effective amount of a compound described herein (axitinib prodrug) or a drug combination thereof The drug is administered to the subject, thereby obtaining the target pharmacokinetic parameters of 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 the compound of Table 1 or a pharmaceutically acceptable salt, ester, solvate or polymorph thereof, and a pharmaceutically acceptable carrier thereof.
  • a pharmaceutical composition comprising a compound of Formula I, Formula II, Formula III, or a compound of Table 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • axitinib 200mg, 0.518mmol, 1.0eq.
  • DMF 4mL
  • chloromethyl pivalate 94mg, 0.621mmol, 1.2eq.
  • triethylamine 104.7mg, 1.03 mmol, 2.0 eq.
  • axitinib (1g, 2.578mmol, 1.0eq.), DMF (10mL), triethylamine (789mg, 7.74mmol, 3.0eq.) and 30% aqueous formaldehyde solution (774mg, 7.74mmol, 3.0 eq.).
  • the reaction mixture was stirred at 0°C for 3 hours. TLC showed that the raw material axitinib was almost consumed.
  • Water (50 mL) and ethyl acetate (50 mL) were added to the reaction mixture, and the layers were extracted and washed.
  • Axitinib (350mg, 0.91mmol, 1.0eq.), DMF (10mL), 2,3-dihydro-2H-furan (96mg, 1.36mmol, 1.5eq.) and p-toluenesulfon were added to the reaction flask in sequence Acid (190 mg, 1.0 mmol, 1.1 eq.).
  • the reaction mixture was stirred at 80°C for 2 hours, and TLC showed that the raw material axitinib was almost consumed.
  • water 50 mL
  • ethyl acetate 50 mL
  • Axitinib (1g, 2.6mmol, 1.0eq.), DMF (15mL), BOC anhydride (678mg, 3.1mmol, 1.2eq.) and triethylamine (394mg, 3.9mmol, 1.5eq.) were added to the reaction flask. ), the resulting reaction mixture was stirred at room temperature overnight. After spinning off most of the solvent, add water (20 mL) and ethyl acetate (30 mL), extract and wash the layers. The organic layer was washed three times with saturated brine (30 mL each time), and then the organic layer was concentrated.
  • Niacin 132.9mg, 1.08mmol, 1.0eq.
  • dichloromethane 10mL
  • DMF 0.05mL
  • oxalyl chloride 82.5mg, 6.48mmol, 6.0eq.
  • the reaction mixture was stirred at room temperature for 3 hours, and then the mixture was directly concentrated to obtain nicotinyl chloride (152.9 mg, 100%), which was directly used in the subsequent reaction.
  • the experimental animals were CD1 mice, males, weighing 18g-22g. The experimental animals were randomly divided into groups, 18 in each group. Blood samples were collected at 0.5, 1, 2, 4, 6, and 8 hours after administration.
  • the compound to be tested is formulated into an experimental solution or suspension in a solvent, and administered by intragastric administration.
  • the composition of the solvent is 0.5wt% CMC-Na solution; DMSO: 0.5wt%-CMC-Na aqueous solution (5/95, v/ v); DMSO: EtOH: 0.5 wt%-CMC-Na (5/5/90, v/v/v); or EtOH: 0.5 wt%-CMC-Na (10/90, v/v).
  • the concentration of the test compound was 3 mg/mL equivalent of axitinib. After the animals were fasted for 12 hours, 30 mg/kg axitinib equivalent was given by gavage. After the administration, blood was collected from the orbit at a preset time point into the heparinized EP tube, the whole blood sample was centrifuged at 5000 rpm at 4°C for 10 min, and the plasma sample was collected and stored at low temperature. Take 10 ⁇ L of plasma sample, add 110 ⁇ L of acetonitrile to precipitate, mix well, centrifuge at 12000rpm at 4°C for 10min, take the supernatant for LC-MS/MS analysis.
  • the analysis targets are Axitinib and the corresponding prodrug molecules.
  • the pharmacokinetic data obtained in plasma after oral administration of the relevant compounds are summarized in Table 2.
  • the concentration-time curve of axitinib in plasma after oral administration of some compounds is shown in Figure 1: Among them, - ⁇ -, - ⁇ -, - ⁇ -, - ⁇ -, and -x- represent oral administration, etc.
  • Figure 1 The concentration-time curve of axitinib in plasma after oral administration of some compounds.

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Abstract

本发明提供了式（I）的化合物及其药物上可接受的盐或酯，及其药物组合物；以及本发明的化合物、药物组合物在抑制或调节酪氨酸激酶的活性、治疗由酪氨酸激酶介导的包括癌症在内的疾病症状或病症中的用途。

Description

一类前药化合物及其在治疗癌症方面的应用
相关申请的交叉引用
本申请基于申请号为201910818675.X、申请日为2019年08月30日的中国专利申请提出，并要求该中国专利申请的优先权，该中国专利申请的全部内容在此引入本申请作为参考。
技术领域
本发明涉及为酪氨酸激酶抑制剂的N-甲基-2-((3-((1E)-2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)硫基)苯甲酰胺的前药以及其组合物，以及其在抑制或调节酪氨酸激酶介导的活性、治疗由酪氨酸激酶介导的疾病症状或病症，诸如癌症中的应用。
背景技术
阿西替尼(化学名称：N-甲基-2-((3-((1E)-2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)硫基)苯甲酰胺；商品名：
Figure PCTCN2020111981-appb-000001
)是一种用于治疗癌症的小分子酪氨酸激酶抑制剂(TKI)(例如，参见WO2001002369，下文示出了该化合物的结构)。已经表明，阿西替尼在动物异种移植模型中能够显著地抑制乳腺癌的生长(Wilmes,L.J.et al.,Magn.Reson.Imaging,2007,25(3):319–327)。该药物已经在肾细胞癌(RCC)的临床实验中显示出部分响应(Rini,B.et al.,J.of Clin.Oncol.2005,ASCO Annual Meeting Proceedings,23(16S):4509)，并且对于若干种其它肿瘤类型同样显示出部分响应(Rugo,H.S.et al.,J.Clin.Oncol.,2005,23:5474-5483)。在无进展生存期显示出适度增加后，阿西替尼已被美国食品和药品管理局批准用于治疗RCC。
阿西替尼的结构如下所示：
Figure PCTCN2020111981-appb-000002
阿西替尼之所以被用于靶向抗癌治疗，是由于它以癌细胞内部的血管内皮生长因子受体(VEGFR)为靶点并与之相结合。VEGFR存在于许多正常细胞和癌细胞的表面上。通过与这些受体结合，阿西替尼阻断了促进血管生成(肿瘤形成的新血管)的重要途径(Escudier,B.and Gore,M.,"Axitinib for the Management of Metastatic Renal Cell Carcinoma",Drugs in R&D,2011,11(2):113-126)。
此外，来自于中晚期分化(乳头状、滤泡状或损伤性)的甲状腺癌患者的多中心II 期研究的数据支持了在I 131-难治性疾病或不能接受I 131的患者中使用阿西替尼(Cohen,Ezra E.W.et al.,J.Clin.Oncol.,2008,26(29):4708-4713)。另一项针对晚期甲状腺癌的多中心II期研究也支持在治疗I 131-难治性疾病时使用阿西替尼(Locati,L.D.et al.,Cancer,2014,120(17):2694-2703)。因此，阿西替尼还在药品核准标示外用于治疗(分化型的、晚期的)甲状腺癌。
使用阿西替尼治疗癌症的一个问题是它的副作用。已经报道了许多不同的副作用，包括腹泻、高血压、疲劳、食欲下降、恶心、发声困难、手足综合征、体重下降、呕吐、乏力和便秘，并且在20％以上的患者中出现最常见的副作用(FDA Prescribing Information,January 30,2012)。
正如其他口服药物(包括其他酪氨酸激酶抑制剂)一样，阿西替尼的药代动力学(PK)在健康志愿者和癌症患者中是变化的(Garrett,M.et al.,Br.J.Clin.Pharmacol.,2013,77(3):480-492)。值得注意的是，从口服施用阿西替尼的估算残留标准差(50.9％)和静脉注射阿西替尼的估算残留标准差(34.2％)可以明显看出阿西替尼PK的巨大变化性，从而不能通过在模型中引入个体随时间的差异(inter-occasion variability，IOV)来降低。
阿西替尼PK的变化性的确切原因尚待阐明。已知的是阿西替尼代谢严重(Smith,B.J.et al.,Drug Metab.Dispos.,2014,42:918-931；和Zientek,M.A,et al.,Drug Meta.Dispos.,2016,44(1):102–114)。在三种主要的代谢物中，一种是中心吡唑环(M7)的氮原子处的葡糖醛酸化产物，而另外两种是由单氧化步骤的代谢产物。由于阿西替尼主要由CYP3A4/5代谢，因此推测导致变化性的一个主要原因可能是CYP3A4/5表达中的差异和/或在肝脏和肠道中活性的差异(据报道，在健康受试者中，CYP3A4/5表达具有10至40倍的变化性)。
由于阿西替尼是一种低提取率药物，因此阿西替尼的代谢清除率对于不同水平的肝脏和肠道代谢酶特别敏感。另一种可能的解释是阿西替尼血浆结合在受试者之间的变化性。对于高残留(受试者内)变化性，阿西替尼的溶解和随后胃肠道吸收的差异可能是一个促成因素。阿西替尼的溶解度是pH依赖性，溶解度随着pH的增加而降低，因此胃和十二指肠中pH值的变化可能导致阿西替尼的溶解度的变化。
由于阿西替尼的血浆暴露不仅会影响其毒性，也会影响其临床效果，因此确定导致阿西替尼PK变化性的临床因素是至关重要的。为了降低毒性并保持稳定的治疗效果，需要消除或减少阿西替尼的PK变化性。
前药是施用后被代谢(即在体内转化)为药理活性药物的药物或化合物(例如，参见Rautio,J.et al.,"The expanding role of prodrugs in contemporary drug design and development",Nat.Rev.Drug Discov.,2018,17,559-587；和Miles H.,et al.,Pharmacology:Principles and Practice.Academic Press,Jun 19,2009,pp.216-217)。非活性前药是在体内代谢成活性形式的药理学无活性的药物。因此，可不是直接给药，而是使用相应的前药来改善药物的吸收、分布、代谢和/或排泄方式(ADME)(例如，参见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,V.J.,et al,"Prodrugs.Do they have advantages in clinical practice？",Drugs,1985,29(5):455-73)。前药可用于改善药物与非预期靶标的细胞或过程相互作用的选择性。这可以减少药物的副作用或非预期效果，对于化疗等经常有严重非预期和非预期副作用的治疗尤其重要。例如，替诺福韦艾拉酚胺(TAF)，一种新的替诺福韦前药，被开发用来提供增强的抗病毒效力和降低的系统毒性(Byrne,R.,et al.,Therap.Adv.Gastroenterol.,2018,11:1-12)。
已有报道了公开了阿西替尼的衍生物可用于眼科疾病的治疗，例如CN106317017、CN106336397、以及CN106478596等。在这些报道中，所得阿西替尼衍生物仅用于改善阿西替尼的水溶性以达到注射进入玻璃体腔的要求。但是并未涉及任何针对上述缺陷且用于抑制酪氨酸激酶活性或者治疗由酪氨酸激酶介导的疾病症状或病症的阿西替尼衍生物。并且，对于相关衍生物在动物体内的药代动力学、衍生物的实际代谢过程、以及如何由此对治疗产生影响等，并无任何理解和涉及。
发明内容
本发明的目的是至少改善现有技术中存在的一些缺陷。至少部分地基于发明者对通过开发该甲基2-((3-((1E)-2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)硫基)苯甲酰胺的前药来调节或改善该具体化合物的药代动力学特性以使其适用于治疗应用需求的理解，从而研发了本发明。通过本文所限定的阿西替尼衍生物和/或前药，药物组合物，以及它们的应用，可以满足抑制或调节酪氨酸激酶的活性，以及治疗由酪氨酸激酶介导的疾病症或病症，例如癌症，等方面的用途和需求以及其他方面的需求。
不希望受理论的限制，据认为经过分子修饰对阿西替尼中氮原子进行保护，可改变化合物的物理、化学和生物学性质，诸如化合物溶解度、亲脂亲水能力、生物膜穿透性能、在消化系统及肝脏中的稳定性、以及前药化合物基原药化合物的代谢速率和途径等。这些性质的改变会引起原药化合物PK参数改变，进而调节原药分子的治疗效果和适用范围。
在第一方面，本发明提供了式(I)的化合物，或其药学上可接受的盐、酯、溶剂化物或各种多晶型体在制备用于抑制酪氨酸激酶的活性的药物中的用途或者在制备用于治疗由酪氨酸激酶介导的疾病病症或症状的药物中的用途：
Figure PCTCN2020111981-appb-000003
其中，R 1和R 2独立地为氢H或保护基-CHRaOR；R 3可存在或不存在；当R 3存在并为保护基时，氮原子带正电，并且存在平衡离子；条件是式I的化合物不是阿西替尼。在R 1和R 2均为保护基的实施方式中，保护基可相同或不同。
在一些实施方式中，本文所提供的化合物是阿西替尼的前药，即，在受试者中代谢或转化为阿西替尼。
在一个实施方式中，式I的化合物为式II的化合物或其药学上可接受的盐、酯、溶剂化物或多晶型：
Figure PCTCN2020111981-appb-000004
其中，R 1和R 2独立地为氢(H)或保护基-CHRaOR，并且当R 1和R 2均为保护基时，保护基可相同或不同。
在另一实施方式中，式I的化合物为式III的化合物或其药学上可接受的盐、酯、溶剂化物或多晶型：
Figure PCTCN2020111981-appb-000005
其中，R 3为保护基(P)，并且
Figure PCTCN2020111981-appb-000006
为平衡离子。
在一个实施方式中，保护基-CHRaOR中，Ra为H或低级烷基；R选自氢、烷基、酰基、烷基羰基、金刚烷基羰基、杂芳基羰基、芳基羰基、烷基硫代羰基、甲酰基硫代酰基、烷基氨基甲酰基、芳基氨基甲酰基、取代的或未取代的乙酰基、取代的或未取代的氨基烷酰基、取代或未取代的α-氨基烷酰基、天然或非天然氨基酸衍生具有或不具有取代基的酰基、肽残基的酰基、环烷基羰基、杂环烷基羰基、烷氧基羰基、芳氧基羰基、杂烷氧基羰基、杂芳氧基羰基、具有或不具有取代基的低聚乙二醇化羰基。
在另一实施方式中，保护基-CHRaOR中的Ra为H或低级烷基，R为R 4W(R 5R 6C) m-，其中，m为选自0至6的整数，W为氧(O)、硫(S)、氮(N)或不存在，R 5和R 6独立地为氢或低级烷基，并且R 4为
Figure PCTCN2020111981-appb-000007
Figure PCTCN2020111981-appb-000008
其中，X为氧(O)、硫(S)、氮(N)或碳(C)；R 7和R 8独立地为氢，取代或未取代的烷基或环烷基，具有取代基或不具有取代基的芳基或杂芳基，结构为R 10-(OCH 2CH 2) n-的PEG残基，诸如低级烷基或芳基的成酯基团，其中，n＝1至10，R 10为氢或低级烷基；或者，当X为氧或硫时，R 7和R 8独立为成盐部分，诸如 钠、钾、四乙铵或四丁铵；或者，R 7和X的组合一起形成取代或未取代的烷基或芳基；R 9选自低级烷基、羟基、卤素(-F、-Cl、-Br或-I)、硝基、氨基、低级烷基氨基和低级烷氧基，或者R 9和其所连接的苯环一起形成非芳香族或芳香族稠环基团，例如取代或未取代的萘基；前提条件是式I、式II或式III的化合物不是阿西替尼。
在另一些实施方式中，保护基-CHRaOR中的Ra、R、以及它们所连接的碳、氧原子一起形成一个取代或未取代的氧杂环基团，例如四氢呋喃-2-基，四氢吡喃-2-基、以及1-氧代环庚-2-基等。
在一些实施方式中，平衡离子选自，但不限于卤素离子(F -、Cl -、Br -和I -)、硫酸根离子、甲磺酸根离子、甲苯磺酸根离子、草酸根离子、酒石酸根离子和其它药学上可接受的阴离子部分。
在一些实施方式中，式I至III的化合物为表1中示出的化合物或其药学上可接受的盐、酯、螯合物、水合物、溶剂化合物、立体异构体或多晶型体。
表1.阿西替尼衍生化合物的实例
Figure PCTCN2020111981-appb-000009
Figure PCTCN2020111981-appb-000010
Figure PCTCN2020111981-appb-000011
在第二概括性方面，本发明提供如上所限定的式I的化合物，其中条件是式I的化合物不是阿西替尼、N-甲基-N-(膦酰氧基)甲基-2-((3-((E)-2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)硫基)苯甲酰胺、N-甲基-2-((3-((E)-2-(2-吡啶基)乙烯基)-1-(月桂酰氧基)甲基-1H-吲唑-6-基)硫基)苯甲酰胺、N-甲基-N-(膦酰氧基)甲基-2-((3-((E)-2-(2-吡啶基)乙烯基)-1-(月桂酰氧基)甲基-1H-吲唑-6-基)硫基)苯甲酰胺、N-甲基-N-(月桂酰氧基)甲基 -2-((3-((E)-2-(2-吡啶基)乙烯基)-1-羟甲基-1H-吲唑-6-基)硫基)苯甲酰胺、N-甲基-2-((3-((E)-2-(N-(乙酰氧基)甲基吡啶-2-基)乙烯基)-1-(月桂酰氧基)甲基-1H-吲唑-6-基)硫基)苯甲酰胺氯化物、和N-甲基-2-((3-((E)-2-(N-(1-(异丙氧基羰基氧基)-1-乙基)吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫基)苯甲酰胺氯化物。
在第三概括性方面中，本发明提供了一种包括本文所述化合物或其药学上可接受的盐或酯，以及药学上可接受的载体的药物组合物。在一些实施方式中，本发明提供了包括式I、式II或式III所示化合物或其药物学上可接受的盐或酯，以及药学上可接受的载体的药物组合物。
在第四概括性方面，本发明提供了抑制或调节受试者中酪氨酸激酶活性的方法。在一些实施方式中，本发明提供了在有需要的受试者中治疗由酪氨酸激酶介导的疾病症状或病症的方法，包括将有效量的上文所述的化合物和/或药物组合物施用至受试者。通过本文所提供的方法可治疗受试者的由酪氨酸介导的疾病病症或病症的非限制性实例包括各种肿瘤和癌症。可治疗的肿瘤和癌症的实例包括但不限于：肾细胞肿瘤(RCC)、乳腺癌和甲状腺癌。并且，本发明用于治疗由酪氨酸激酶介导的疾病中，不包括眼科疾病。
在一些实施方式中，施用式I、式II或式III的化合物和/或其药物组合物以调节阿西替尼的药代动力学特性，例如，与施用阿西替尼相比，在受试者中提高生物利用度、改变有效血浆浓度的持续时间、降低血浆水平的变化性、降低副作用和/或改善阿西替尼的治疗效果。
在其他实施方式中，与施用阿西替尼相比，施用式I、式II或式III的化合物和/或其药物组合物以改善生物分布、降低代谢和/或扩展阿西替尼在受试者中的治疗应用。
在另一实施方式中，与施用阿西替尼相比，施用式I、式II或式III的化合物和/或其药物组合物以通过调整PK特性来增加或调节阿西替尼的半衰期，从而降低或改变该化合物对受试者的给药频率。
在一些实施方式中，本发明提供了在有需要的受试者中治疗由酪氨酸激酶介导的疾病病症或症状的方法，所述方法包括将有效量的式I、式II或式III的化合物或其药物组合物施用至受试者，从而治疗疾病病症或症状。在另一实施方式中，本发明提供了在有需要的受试者中治疗肿瘤或癌症的方法，所述方法包括将有效量的式I、式II或式III的化合物或其药物组合物施用至受试者，从而治疗该肿瘤或癌症。
在另一概括性的方面中，本发明的化合物和方法单独在受试者中用于治疗由酪氨酸激酶介导的疾病病症或症状。在一些实施方式中，为了治疗受试者中由酪氨酸激酶介导的疾病病症或症状，本发明的化合物和方法与其它治疗剂或方法联合使用，包括但不限于程序性细胞死亡蛋白-1(亦称为程序性细胞死亡-1，PD-1)和程序性细胞死亡配体1(亦称为程序性细胞死亡蛋白-1配体，PD-L1)抑制剂。
在另一概括性的方面中，本发明提供了包括本文所述的一种或多种化合物或药物组合物的试剂盒。该试剂盒可进一步包括一种或多种额外的治疗剂和/或说明，例如使用该试剂盒以治疗患有由酪氨酸激酶介导的疾病症状或病症的说明。并且，本发明用于治疗 由酪氨酸激酶介导的疾病中，不包括眼科疾病。
附图说明
为了更好地理解本发明以及更清楚了示出如何实施本发明，现将通过实例的方式并参考附图来进一步阐述本发明，其中附图示出了根据本发明的实施例的方面和特征，其中：
图1示出了口服施用等摩尔剂量的阿西替尼、化合物2、化合物4、化合物12和化合物13后，血浆中阿西替尼的浓度随时间的变化曲线；其中，-○-、-◇-、-◆-、-Δ-、以及-x-分别对应阿西替尼、化合物2、化合物4、化合物12、和化合物13。
具体实施方式
定义
为了对本发明的说明书中所使用的术语提供清楚且一致的理解，在下文中提供一些定义。此外，除了特殊说明，本发明所用的全部技术和科学术语具有同本发明所属领域中普通技术人员通常所理解的相同的含义。
当在权利要求和/或说明书中与术语“包括”结合使用时，词语“一”的使用可以表示“一个/种”，但它也表示“一个或多个”，“至少一个”和“一个或多于一个”的含义。类似地，词语“另一个”可以表示至少第二个或者很多个。
如在本说明书和权利要求中所使用的词语“包括”(以及包括的任何形式，诸如“包括”和“包含”)，“具有”(以及任何形式的具有，“具有”、“包含”和“含有”)是包括性的和开放式的，并且不排除另外的未列出的要素或处理步骤。
术语“约”用于表示该值包括在确定该值中所用的仪器和方法带来的误差。
本发明所用的术语“衍生物”应理解为是结构上类似，在一些细微结构上不同的另一种化合物。
本说明书涉及了本领域技术人员所使用的许多化学术语和缩写。然而，为了清楚和一致性，提供了所选术语的定义。
如本文所使用的，术语“取代”或“具有取代基”是指母体化合物或部分具有至少一个取代基团。术语“未取代的”或“不具有取代基”是指母体化合物或部分除了未确定的化合价被氢原子化学饱和外，不具有其他取代基。
如本文所述，“取代基”或“取代基团”是指选自卤素(F、Cl、Br或I)、羟基、巯基、氨基、硝基、羰基、羧基、烷基、烷氧基、烷基氨基、芳基、芳基氧基、芳基氨基、酰基、亚硫酰基、磺酰基、膦酰基或在有机化学中常规使用和接受的其它有机部分。
本发明所用术语“烷基”是指具有1至12个碳原子的饱和烃，包括直链，支链和环状烷基。烷基的实例包括但不限于甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、壬基、癸基、异丙基、叔丁基、仲丁基、异丁基、环丙基、环戊基、环己基、环庚基、环辛基等。术语烷基包括未取代的烷基和取代的烷基。术语“C 1-C n烷基”(其中n是2 至12的整数)表示具有1至所示“n”个碳原子的烷基。烷基残基可以是取代的或未取代的。在一些实施方式中，例如，烷基可以被羟基、氨基、羧基、羧酸酯、酰胺、氨基甲酸酯或氨基烷基等基团取代。
除非对碳数有限定，否则本文中所使用的“低级脂肪族”、“低级烷基”、“低级烯基”和“低级炔基”中的“低级”表示该部分具有至少一个(对于烯基和炔基为至少两个)且等于或小于6个碳原子。
术语“环烷基”，“脂环族”，“碳环”和等同表述是指在单环、螺环(共享一个原子)或稠合(共享至少一个键)碳环体系中包含饱和或部分不饱和碳环的基团，其中碳环体系具有3至15个碳原子。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环戊烯-1-基、环戊烯-2-基、环戊烯-3-基、环己基、环己烯-1-基、环己烯-2-基、环己烯-3环庚基、双环[4,3,0]壬基、降冰片基等。术语环烷基包括未取代的环烷基和取代的环烷基。术语“C 3-C n环烷基”其中n是4至15的整数，表示在环结构中具有3至所示“n”个碳原子的环烷基。除非另有说明，否则本发明使用的“低环烷基”基团指在其环结构中具有至少3个且等于或小于8个碳原子。
本发明所用术语环烷基残基可以是饱和的或在环体系中含有一个或多个双键的基团。特别地，它们可以是饱和的或在环体系内含有一个双键。在不饱和环烷基残基中，双键可存在于任何合适的位置。单环烷基残基包括例如环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环庚基、环庚烯基、环辛基、环壬基、环癸基、环十一烷基、环十二烷基或环十四烷基，其也可取代有C 1-4烷基。取代的环烷基残基的实例是4-甲基环己基和2,3-二甲基环戊基。双环体系的母体结构的实例是降冰片烷、双环[2.2.1]庚烷、双环[2.2.2]辛烷和双环[3.2.1]辛烷。
本发明所用术语“杂环烷基”和等同表述是指在单环、螺环(共享一个原子)或稠合(共享至少一个键)碳环体系中包含饱和或部分不饱和碳环的基团，其具有3个至15个碳原子的基团，包括1至6个杂原子(例如N、O、S、P)或者含杂原子(例如NH、NRx(Rx是烷基、酰基、芳基、杂芳基或环烷基)，PO 2、SO、SO 2等)的基团。杂环烷基可以与C连接或与杂原子连接的(例如通过氮原子)。杂环烷基的实例包括但不限于吡咯烷基、四氢呋喃基、四氢二噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、噻噁烷基、哌嗪基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、高哌啶基、氧杂环戊烷基、硫杂环戊烷基、氧氮杂卓基、二氮杂卓基、硫氮杂基、1,2,3,6-四氢吡啶基、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、2H-吡喃基、4H-吡喃基、二氧六环基、1,3-二氧戊环基、吡唑啉基、二噻烷基、二硫杂环戊烷基、二氢吡喃基、二氢噻吩基、二氢呋喃基、吡唑烷基、咪唑啉基、咪唑烷基、3-氮杂双环[3,1,0]己基、3-氮杂双环[4,1,0]庚基、3H-吲哚基、喹嗪基和糖等。术语杂环烷基包括未取代的杂环烷基和取代的杂环烷基。术语“C 3-C n杂环烷基”，其中n是4至15的整数，表示在环结构中具有3至所示“n”个原子的杂环烷基，包括至少一个如上所定义的杂基团或原子。除非另有说明，否则本发明使用的“低杂环烷基”指在其环状结构中具有至少3个且等于或小于8个碳原子。其中，如本文中所使用的“氧杂环”特定地表示环结构中具有1个氧原子的4至 8元环，例如4至7元环，5至6元环等。
本发明所用术语“芳基”和“芳基环”是指在共轭单环或多环体系(稠和或非稠和的)中具有“4n+2”个(π)电子，并具有6至14个环原子的芳族基团，其中n是1至3的整数。多环系统包括至少一个芳环。芳基可以直接连接或通过C 1-C 3烷基(也称为芳基烷基或芳烷基)连接。芳基的实例包括但不限于苯基、苄基、苯乙基、1-苯基乙基、甲苯基、萘基、联苯基、三联苯基、茚基、苯并环辛烯基、苯并环庚烯基、薁基、苊基、芴基、菲基、蒽基等。术语芳基包括未取代的芳基和取代的芳基。术语“C 6-C n芳基”(其中n是6至15的整数)表示在环结构中具有6至所示“n”个碳原子的芳基，包括至少一个如上所定义的杂环基团或原子。
本发明所用术语“杂芳基”和“杂芳基环”是指在共轭单环或多环体系(稠和或非稠和的)中具有“4n+2”个(π)电子的芳族基团，其中n是1至3的整数，并包括一个至六个杂原子(例如N、O、S)或者包括杂原子(例如NH、NRx(Rx是烷基、酰基、芳基、杂芳基或环烷基)，SO、SO 2等)的基团。多环系统包括至少一个杂芳环。杂芳基可以直接连接或通过C 1-C 3烷基(也称为杂芳基烷基或杂芳烷基)连接。杂芳基可以与碳连接的或者与杂原子连接的(例如，通过氮原子)。杂芳基的实例包括但不限于吡啶基、咪唑基、嘧啶基、吡唑基、三唑基、四唑基、呋喃基、噻吩基；异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯烷基、喹啉基、异喹啉基、吲哚基、异吲哚基、色烯基、异色烯基、苯并咪唑基、苯并呋喃基、噌啉基、吲唑基、吲嗪基、酞嗪基、哒嗪基、吡嗪基、三嗪基、异吲哚基、喋啶基、呋喃基、苯并呋喃基、苯并噻唑基、苯并噻吩基、苯并噻唑基、苯并噁唑基、喹唑啉基、喹啉基、喹啉酮基、异喹啉酮基、喹喔啉基、萘啶基、呋喃并吡啶基、咔唑基、菲啶基、吖啶基、苝基、菲咯啉基、吩嗪基、吩噻嗪基、吩噁嗪基、二苯并呋喃基、二苯并噻吩基等。术语杂芳基包括未取代的杂芳基和取代的杂芳基。术语“C 5-C n杂芳基”，其中n是6至15的整数，表示在环结构中具有从5至所示“n”个原子的杂芳基，包括至少一个如上所定义的杂环基团或原子。
本发明所用术语“杂环”或“杂环的”包括杂环烷基和杂芳基。杂环的实例包括但不限于吖啶基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并噻吩基、苯并噁唑基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异噁唑基、苯并异噻唑基、4αH-咔唑基、咔啉基、苯并二氢吡喃基、色烯基、噌啉基、十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、二氢吲哚基、3H-吲哚基、异喹啉基、异噻唑基、异噁唑基、亚甲二氧基苯基、吗啉基、萘啶基、八氢异喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑烷基、噁唑基、噁唑烷基、嘧啶基、菲啶基、菲咯啉基、吩嗪基、吩噻嗪基、吩噁嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并噁唑、吡啶并咪唑、吡啶并噻唑、吡啶基、吡啶基、吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、四唑基、6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、 1,3,4-噻二唑基、噻蒽基、噻唑基、噻吩基、噻吩并噻唑基、噻吩并噁唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基、呫吨基等。术语“杂环”包括未取代的杂环基和取代的杂环基。
本发明所用术语“胺”或“氨基”是指未取代或取代的通式-NR aR b的片段，其中R a和R b各自独立地为氢、烷基、芳基或杂环基，或R a和R b一起与它们所连接的氮原子形成杂环。术语氨基指化合物或片段中至少一个碳或杂原子与氮原子共价键合。因此，本发明所用术语“烷基氨基”和“二烷基氨基”是指分别具有一个和至少两个C 1-C 6烷基与氮原子连接的胺基。术语“芳基氨基”和“二芳基氨基”包括至少一个或两个芳基结合的基团与氮原子连接。术语“酰胺”或“氨基羰基”指化合物或片段的羰基或硫代羰基的碳与氮原子相连的结构。术语“酰基氨基”是指氨基直接于酰基连接的结构。
术语“烷巯基”是指具有巯基连接其上的烷基。合适的烷巯基包括具有1至约12个碳原子，优选1至约6个碳原子的基团。本文所用的术语“烷基羧基”是指具有羧基连接其上的烷基。
本发明所用术语“烷氧基”或“低级烷氧基”是指烷基与氧原子相连的结构。代表性的烷氧基包括具有1至约6个碳原子的基团，例如甲氧基、乙氧基、丙氧基、叔丁氧基等。烷氧基的实例包括但不限于甲氧基、乙氧基、异丙氧基、丙氧基、丁氧基、戊氧基、氟甲氧基、二氟甲氧基、三氟甲氧基、氯甲氧基、二氯甲氧基、三氯甲氧基等。术语“烷氧基”包括未取代或取代的烷氧基，以及全卤代烷氧基等。
本发明所用术语“羰基”或“羧基”是指化合物和片段含有通过双键与氧原子连接的碳。含有羰基的部分的实例包括醛、酮、羧酸、酰胺、酯、酸酐等。
本发明所用术语“酰基”是羰基的碳原子连接到氢(即甲酰基)、脂族基团(C 1-C 6烷基，C 2-C 6烯基，C 2-C 6炔基，例如乙酰基)、环烷基(C 3-C 8环烷基)、杂环基(C 3-C 8杂环烷基和C 5-C 6杂芳基)、芳基(C 6芳基，例如苯甲酰基)相连的羰基结构。酰基可以是未取代的或取代的酰基(例如水杨酰基)。
术语“溶剂化物”是指化合物与一种或多种溶剂分子(无论是有机的还是无机的)的物理缔合。该物理缔合包括氢键。在某些情况下，溶剂化物能够被分离，例如当一个或多个溶剂分子并入晶体的晶格中时。“溶剂合物”包括溶液相的溶剂化合物和可被分离的溶剂化物。“溶剂化物”的实例包括但不限于水合物、乙醇化物、甲醇化物、半乙醇化物等。
化合物的“药学上可接受的盐”是指药学上可接受的化合物的盐。理想的化合物的盐(碱性、酸性或带电官能团)可以保留或改善如本发明所定义的母体化合物的生物活性和性质，并且不是生物学上不需要的。药学上可接受的盐的实例如Berge等人在"Pharmaceutical Salts",J.Pharm.Sci.66,1-19(1977)所提到的，包括但不限于：
(1)通过加入酸在碱性或带正电荷的官能团上形成的酸加成盐，其中可加入无机酸，诸如盐酸、氢溴酸、氢碘酸、硫酸、氨基磺酸、硝酸、磷酸、碳酸盐；或者加入有机酸，诸如乙酸、丙酸、乳酸、草酸、乙醇酸、新戊酸、叔丁基乙酸、β-羟基丁酸、戊酸、己酸、环戊烷丙酸、丙酮酸、丙二酸、琥珀酸、苹果酸、富马酸、酒石酸、柠檬酸、 苯甲酸、3-(4-羟基苯甲酰基)苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙二磺酸、2-羟基乙磺酸、环己基氨基磺酸、苯磺酸、磺胺酸、4-氯苯磺酸、2-萘磺酸、4-甲苯磺酸、樟脑磺酸、3-苯基丙酸、月桂基磺酸、月桂基硫酸、油酸、棕榈酸、硬脂酸、月桂酸、扑酸(扑酸)、扑酸、泛酸、乳糖酸、藻酸、半乳糖二酸、半乳糖醛酸、葡萄糖酸、葡庚糖酸、谷氨酸、萘甲酸、羟基萘甲酸、水杨酸、抗坏血酸、硬脂酸、粘康酸等。
(2)当母体化合物中存在酸性质子或者其被金属离子取代时，通过加入碱得到的碱加成盐；其中所述金属离子包括碱性金属离子(例如锂、钠、钾)，碱土金属离子(镁、钙、钡)或其它金属离子如铝、锌、铁等；或者与有机碱配位，其中有机碱诸如氨、乙胺、二乙胺、N,N'-二苄基乙二胺、乙醇胺、二乙醇胺、三乙醇胺、氨基丁三醇、N-甲基葡萄糖胺、哌嗪、氯普鲁卡因、普鲁卡因、胆碱、赖氨酸等。
药学上可接受的盐可以由含有碱性或酸性片段的母体化合物通过常规化学方法合成。通常，这种盐通过化合物(游离酸或碱)与等化学计量的碱或酸在水中或有机溶剂中或在两者的混合物中反应来制备。盐可以在药剂的最终分离或纯化过程中原位制备，或者将游离酸或碱形式的已纯化的本发明化合物单独的与所期望的相应碱或酸反应并分离由此形成的盐而制备。术语“药学上可接受的盐”还包括含有共价键合至阴离子基团的阳离子基团的两性离子化合物，它们被称作“内盐”。应当理解的是，本发明的化合物的所有酸，盐，碱和其它离子和非离子形式均涵盖在本发明的范围内。例如，如果本发明中化合物为酸，该化合物盐的形式也涵盖在本发明的范围内。同样，如果本发明中化合物为盐，该化合物的酸和/或碱的形式也涵盖在本发明的范围内。
如本文所使用的，术语“有效量”是指以单剂量或多剂量施用至受试者后，在受试者中提供所需的治疗、诊断或预后效应的治疗剂(例如化合物)的量或剂量。主治医生或诊断医生通过已知技术并通过观察在类似情况下获得的结果可容易地确定有效量。在确定施用的化合物的有效量或剂量时，考虑许多因素，包括但不限于：受试者的体重、年龄和一般健康状况；涉及的具体疾病；待治疗的疾病或病症的涉及程度或严重程度；受试者个体的回应；施用的特定化合物；施用模式；所施用制剂的生物利用度特征；所选的剂量方案；使用伴随药物；和其他相关考虑。
“药学上可接受的”是指该术语描述的药物、药品、惰性成分等，适合用于与人和动物的细胞或组织相接触，而没有异常毒性、不相容性、不稳定性、刺激性、过敏反应等，与合理的利益/风险比率相称。通常是指由联邦或州政府的管理机构批准或可批准，或者在美国药典或其它公认的药典中列出的用于动物，更尤其是用于人的化合物或组合物。
“药学上可接受上的载体”是指与化合物一起施用的稀释剂、佐剂、赋形剂、载体或载剂。术语“药学上可接受的载剂”和“药学上可接受的载体”在本文中可互换使用。
“药物组合物”是指包括如本文所述的化合物，以及取决于给药方式和剂型的要求的至少一种组分，该至少一种组分包括药学上可接受的载体、稀释剂、佐剂、赋形剂或载剂，诸如防腐剂、填充剂、崩解剂、润湿剂、乳化剂、悬浮剂、甜味剂、调味剂、芳香剂、抗菌剂、抗真菌剂、润滑剂和分散剂等。“预防”或“预防”用于表示至少降低获得疾病或病症(或易感性)获得疾病或障碍的可能性(即，使至少一种疾病的临床症状不发 展为可能暴露于或易患疾病但尚未经历或显示疾病症状的患者)。
在一些实施方式中，“治疗”或“治疗”任何疾病或病症是指缓解了至少一种疾病或病症。在某些实施方式中，治疗”或“治疗”是指缓解至少一种身体参数，其可以是患者可以分辨的或不可分辨的。在某些实施方式中，“治疗”或“治疗”是指身体上(例如，可辨别的症状的稳定)或生理学上(例如，身体参数的稳定)或这两者上来抑制疾病或病症。在某些实施方式中，“治疗”或“治疗”是指在有需要的受试者中改善生活品质或疾病的副作用。“治疗有效量”是指施用至受试者用于治疗或预防疾病的化合物的量足以达到治疗或预防该疾病的效果。“治疗有效量”将依据化合物；疾病及其严重程度；待治疗或预防患有疾病的受试者的年龄、体重等而变化。如本文中所使用的，“治疗有效量”是指化合物或组合物足以预防、治疗、抑制、降低、缓解或消除疾病，诸如癌症的一种或多种病因、症状或并发症。
术语“受试者”是指包括哺乳动物和人的动物，尤其是指人。
术语“前药”或其等同表述是指在体外或体内直接或间接转化成活性形式的药剂(例如参见R.B.Silverman,1992,"The Organic Chemistry of Drug Design and Drug Action,"Academic Press,Chap.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)。前药可用于改变具体药物的生物分布(例如，使药剂通常不会进入蛋白酶反应位点)或药代动力学。已经使用多种基团例如酯、醚、磷酸酯/盐等来修饰化合物以形成前药。当将前药施用至受试者时，该基团通过酶促或非酶促、还原、氧化或水解地裂解掉，或者以其它方式释放出活性化合物。如本文中所使用的，“前药”包括药学上可接受的盐，或药学上可接受的溶剂化物，以及上文的任何结晶形式。前药通常(尽管不一定)是药学上无活性的，直至其转化为活性形成。
术语“酯”是指可由式RCOOR(羧酸酯)或式RSO3R'(磺酸酯)表示的化合物，通常可分别由羧酸或磺酸与醇之间反应(消除一分子水)来形成。
术语“酯”是指可由式RCOOR'(羧酸酯)或式RSO 3R'(磺酸酯)表示的化合物，通常可分别由羧酸或磺酸与醇之间反应(消除一分子水)来形成。其中，R和R'称之为成酯基团，R诸如为低级烷基或芳基，例如亚甲基、亚乙基、异亚丙基、亚苯基等，但不限于此；R'诸如为低级烷基、环烷基或芳基，例如甲基、乙基、丙基、异丙基、丁基、环丙基、环丁基、环戊基、环己基、苯基、萘基等，但不限于此。
表述“含有羧酸酯的烃基”用于表示片段中含有酯官能团-RCOOR'(R'一般为烷基等其他非H基团)的结构。其中，R诸如为低级烷基或芳基，例如亚甲基、亚乙基、异亚丙基、亚苯基等，但不限于此；R′诸如为低级烷基、环烷基或芳基，例如甲基、乙基、丙基、异丙基、丁基、环丙基、环丁基、环戊基、环己基、苯基、萘基等，但不限于此。
表述“含有碳酸酯的烃基”用于表示“-ROCOOR'”(R'一般为烷基等其他非H基团)的结构。其中，R诸如为低级烷基或芳基，例如亚甲基、亚乙基、异亚丙基、亚苯基等，但不限于此；R′诸如为低级烷基、环烷基或芳基，例如甲基、乙基、丙基、异丙基、丁 基、环丙基、环丁基、环戊基、环己基、苯基、萘基等，但不限于此。
本发明所用术语“成盐部分”是指能够与酸性基团，如羧基形成盐的部分，例如但不限于钠、钾、四乙胺、四丁胺等。
术语“醚”可由通式ROR'(R'一般为烷基等其他非H基团)来表示，其中R和R'称之为“成醚基团”或“成醚部分”。其中，R诸如为低级烷基或芳基，例如亚甲基、亚乙基、异亚丙基、亚苯基等，但不限于此；R′诸如为低级烷基或芳基，例如甲基、乙基、丙基、异丙基、丁基、苯基、萘基等，但不限于此。
术语“氨基酸”通常是指同时包含羧酸基团和氨基基团的有机化合物。术语“氨基酸”包括“天然”和“非天然”的氨基酸。另外，术语氨基酸包括O-烷基化的氨基酸或N-烷基化的氨基酸，以及具有含氮、硫或氧的侧链(例如Lys，Cys或Ser)的氨基酸，其中氮、硫或氧原子可以被或不被酰基化或烷基化。氨基酸可以是纯的L-异构体或D-异构体，或者是L-异构体和D-异构体的混合物，包括(但不限于)外消旋混合物。
术语“天然氨基酸”和等同表达是指通常在天然存在的蛋白质中发现的L-氨基酸。天然氨基酸的实例包括但不限于丙氨酸(Ala)、半胱氨酸(Cys)、天冬氨酸(Asp)、谷氨酸(Glu)、苯丙氨酸(Phe)、甘氨酸(Gly)、组氨酸(His)、异亮氨酸(Ile)、赖氨酸(Lys)、亮氨酸(Leu)、甲硫氨酸(Met)、天冬酰胺(Asn)、脯氨酸(Pro)、谷氨酰胺(Gln)、精氨酸(Arg)、丝氨酸(Ser)、苏氨酸(Thr)、缬氨酸(Val)、色氨酸(Trp)、酪氨酸(Tyr)、β-丙氨酸(β-Ala)和γ-氨基丁酸(GABA)。
术语“非天然氨基酸”是指天然氨基酸的任何衍生物，包括D-型氨基酸，以及α-和β-氨基酸衍生物。术语“非天然氨基酸”和“不是天然氨基酸”在本文中可互换使用。应注意的是，在本发明中可归类为非天然氨基酸的某些氨基酸(例如羟脯氨酸)也可存在于自然界中的某些生物组织或特定蛋白质中。具有许多不同保护基团、适于固相肽合成中直接应用的氨基酸是可以通过购买得到的。除了二十种最常见的天然氨基酸，根据本发明可使用如下示例性非天然氨基酸和氨基酸衍生物(括号中为常见的缩写)：2-氨基己二酸(Aad)、3-氨基己二酸(β-Aad)、2-氨基丁酸(2-Abu)、α,β-脱氢-2-氨基丁酸(8-AU)、1-氨基环丙烷-1-羧酸(ACPC)、氨基异丁酸(Aib)、3-氨基异丁酸(β-Aib)、2-氨基-噻唑啉-4-羧酸、5-氨基戊酸(5-Ava)、6-氨基己酸(6-Ahx)、2-氨基庚酸(Ahe)、8-氨基辛酸(8-Aoc)、11-氨基十一烷酸(11-Aun)、12-氨基十二烷酸(12-Ado)、2-氨基苯甲酸(2-Abz)、3-氨基苯甲酸(3-Abz)、4-氨基苯甲酸(4-Abz)、4-氨基-3-羟基-6-甲基庚酸(抑胃酶氨酸，Sta)、氨基氧基乙酸(Aoa)、2-氨基四氢化萘-2-羧酸(ATC)、4-氨基-5-环己基-3-羟基戊酸(ACHPA)、对氨基苯丙氨酸(4-NH 2-Phe)、2-氨基庚二酸(Apm)、联苯基丙氨酸(Bip)、对溴苯丙氨酸(4-Br-Phe)、邻氯苯丙氨酸(2-Cl-Phe)、间氯苯丙氨酸(3-Cl-Phe)、对氯苯丙氨酸(4-Cl-Phe)、间-氯酪氨酸(3-Cl-Tyr)、对苯甲酰基苯丙氨酸(Bpa)、叔丁基甘氨酸(TLG)、环己基丙氨酸(Cha)、环己基甘氨酸(Chg)、锁链素(Des)、2,2-二氨基庚二酸(Dpm)、2,3-二氨基丙酸(Dpr)、2,4-二氨基丁酸(Dbu)、3,4-二氯苯丙氨酸(3,4-Cl-2-Phe)、3,4-二氟苯丙氨酸(3,4-F2-Phe)、3,5-二碘酪氨酸(3,5-I2-Tyr)、N-乙基甘氨酸(EtGly)、N-乙基天冬酰胺(EtAsn)、邻氟苯丙氨酸 (2-F-Phe)、间氟苯丙氨酸(3-F-Phe)、对氟苯丙氨酸(4-F-Phe)、间-氟酪氨酸(3-F-Tyr)、高丝氨酸(Hse)、高苯丙氨酸(Hfe)、高酪氨酸(Htyr)、羟基赖氨酸(Hyl)、异羟基赖氨酸(aHyl)、5-羟色氨酸(5-OH-Trp)、3-或4-羟基脯氨酸(3-或4-Hyp)、对碘苯丙氨酸-异酪氨酸(3-I-Tyr)、二氢吲哚-2-羧酸(Idc)、异艾杜霉素(Ide)、异亮氨酸(α-Ile)、异哌啶酸(Inp)、N-甲基异亮氨酸(Melle)、N-甲基赖氨酸(MeLys)、间甲基酪氨酸(3-Me-Tyr)、N-甲基缬氨酸(MeVal)、1-萘基丙氨酸(1-Nal)、2-萘基丙氨酸(2-Nal)、对硝基苯丙氨酸(4-NO 2-Phe)、3-硝基酪氨酸(3-NO 2-Tyr)、正亮氨酸(Nle)、正缬氨酸(Nva)、鸟氨酸(Orn)、邻磷酸酪氨酸(H 2PO 3-Tyr)、八氢吲哚-2-羧酸(Oic)、青霉胺(Pen)、五氟苯丙氨酸(F5-Phe)、苯基甘氨酸(Phg)、哌啶酸(Pip)、炔丙基甘氨酸(Pra)、焦谷氨酸(PGLU)、肌氨酸(Sar)、四氢异喹啉-3-羧酸(Tic)、噻吩丙氨酸和噻唑烷-4-羧酸(硫代脯氨酸，Th)。
对于本文所提供的化合物，在一些实施方式中，还包括其盐，药学上可接受的盐。本领域技术人员将知晓多种可能的盐形式(例如，TFA盐、四唑盐、钠盐、钾盐等)，也可基于本领域已知的考虑选择合适的盐。术语“药学上可接受的盐”是指由药学上可接受的没有毒性的酸或碱(包括无机酸和碱以及有机酸和碱)制备的盐。例如，对于含有碱性氮的化合物，其盐可以通过药学上可接受的没有毒性的酸(包括无机酸和有机酸)来制备。适用于本发明的药学上可接受的酸包括但不限于乙酸、苯磺酸(苯磺酸盐)、苯甲酸、樟脑磺酸、柠檬酸、乙烯磺酸、富马酸、葡糖酸、谷氨酸、氢溴酸、盐酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、粘酸、硝酸、扑酸、泛酸、磷酸、琥珀酸、硫酸、酒石酸、对甲苯磺酸等。当化合物含有酸性侧链时，适用于本发明的药学上可接受的碱包括但不限于由铝、钙、锂、镁、钾、钠和锌制成的金属盐或由赖氨酸、N,N'-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、葡甲胺(N-甲基葡萄糖胺)和普鲁卡因制成的有机盐。
在一些实施方式中，本发明提供了在有需要的受试者中提高阿西替尼的治疗效果的方法，所述方法包括：将有效量的式I、式II或式III的化合物或其药物组合物施用至受试者，从而与使用阿西替尼本身相比，提高阿西替尼的治疗效果。在一些实施例中，该化合物是阿西替尼的前药。
在一些实施方式中，与施用阿西替尼本身相比，通过施用本文提供的化合物(阿西替尼的前药)或其药物组合物改善了以下一种或多种：阿西替尼的生物利用度；阿西替尼在血液或血浆中的AUC；阿西替尼的C max；阿西替尼的T max；阿西替尼的t 1/2；阿西替尼的治疗生物分布；阿西替尼在选定组织中的治疗水平；和/或阿西替尼在受试者中的生物吸收。在一些实施方式中，与施用阿西替尼本身相比，通过施用本文提供的化合物(阿西替尼的前药)或其药物组合物来降低以下一种或多种：阿西替尼在受试者中的代谢；和阿西替尼在受试者中的副作用。
在一些实施方式中，本发明提供了在受试者中获得阿西替尼目标药动学参数的方法，包括将有效量的本文所述的化合物(阿西替尼前药)或其药物组合物施用至受试者，从而在受试者中获得阿西替尼的目标药动学参数。目标药代动力学参数的非限制性示例 包括目标生物利用度、血液或血浆中的AUC、C max、T max、生物分布、所选组织中的水平、半衰期(t 1/2)、生物吸附以及代谢量或速率。药代动力学参数可使用本领域已知的方法计算。
组合物
在一实施方式中，提供了药物组合物，该药物组合物包括本发明的化合物，例如式I、式II、式III的化合物或其药学上可接受的盐、酯、溶剂化物或多晶型，以及药学上可接受的载体。在另一实施方式中，提供了一种药物组合物，包括表1的化合物或其药物上可接受的盐、酯、溶剂化物或多晶型，以及其药学上可接受的载体。在又一实施方式中，提供了包括式I、式II、式III化合物或表1的化合物或其药学上可接受的盐，以及药学上可接受的载体的药物组合物。
实施例
通过参考以下实施例将更容易理解本发明，所述实施例用于说明本发明，而不应被解释为以任何方式限制本发明的范围。
除非另有定义或上下文另有明确规定，本文使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的相同的含义。应当理解，与本文所述类似或等同的任何方法和材料可用于本发明的实践或测试。
实施例1：N-甲基-2-((3-((E)-2-(2-吡啶基)乙烯基)-1-(特戊酰氧基)甲基-1H-吲唑-6-基)硫基)苯甲酰胺(化合物1)的制备
向反应瓶中加入阿西替尼(200mg，0.518mmol，1.0eq.)、DMF(4mL)、特戊酸氯甲酯(94mg，0.621mmol，1.2eq.)和三乙胺(104.7mg，1.03mmol，2.0eq.)。将反应混合物于室温下搅拌过夜。TLC显示原料阿西替尼几乎消耗完毕。向反应混合物中加入水(20mL)和乙酸乙酯(30mL)，萃洗分层。分出有机层后，用饱和食盐水洗三次(每次30mL)，然后浓缩。残留物用硅胶柱(二氯甲烷：甲醇＝100:0至100:5)分离纯化，得到化合物1(80mg，30％)。 1H NMR(500MHz,CDCl 3):δppm 1.13(s,9H),2.92(d,J＝4.8Hz,3H),6.23(s,2H),6.42(s,1H),7.18-7.23(m,1H),7.25(d,J＝6.7Hz,1H),7.32(dd,J＝10.4,8.2Hz,3H),7.48(d,J＝7.7Hz,1H),7.53(s,1H),7.60(d,J＝16.0Hz,2H),7.72(t,J＝7.4Hz,1H),7.88(d,J＝16.2Hz,1H),7.97(d,J＝8.3Hz,1H),8.64(d,J＝4.0Hz,1H)； 13C NMR(125MHz,CDCl 3):δppm 26.81,27.03,39.00,70.38,112.31,121.74,122.35,122.44,122.69,123.30,125.45,127.78,128.85,130.87,131.23,133.08,133.49,135.93,137.08,138.24,141.93,144.36,149.50,155.14,168.72,178.06；m/z(ESI +):501.0(M+H)。
实施例2：N-甲基-2-((3-((E)-2-(2-吡啶基)乙烯基)-1-羟甲基-1H-吲唑-6-基)硫基)苯甲酰胺(化合物2)的制备
于反应瓶中加入阿西替尼(1g，2.578mmol，1.0eq.)、DMF(10mL)、三乙胺(789mg，7.74mmol，3.0eq.)和30％甲醛水溶液(774mg，7.74mmol，3.0eq.)。将反应混合物于0℃下搅拌3小时。TLC显示原料阿西替尼几乎消耗完毕。向反应混合物中加入水(50mL)和乙酸乙酯(50mL)，萃洗分层。分出有机层后，用饱和食盐水洗三次(每次50mL)，然后浓缩，得到化合物2(1g，93％)。 1H NMR(500MHz,DMSO-d 6):δppm2.78(s,3H),5.74(d,J＝7.0Hz,2H),6.85(s,1H),6.98(d,J＝7.3Hz,1H),7.25(dd,J＝26.4, 15.7Hz,4H),7.49(s,1H),7.61(d,J＝15.9Hz,1H),7.68(s,1H),7.82(s,1H),7.93(d,J＝21.3Hz,2H),8.23(d,J＝7.3Hz,1H),8.41(s,1H),8.61(s,1H)； 13C NMR(125MHz,DMSO-d 6):δppm 26.07,71.18,115.37,121.76,121.91,122.63,122.77,125.89,126.53,127.72,129.48,130.01,130.25,132.56,136.09,136.40,136.87,140.74,141.56,149.57,154.66,167.80；m/z(ESI +):417.0(M+H)。
实施例3：N-甲基-2-((3-((E)-2-(2-吡啶基)乙烯基)-1-(苯甲酰氧基)甲基-1H-吲唑-6-基)硫基)苯甲酰胺(化合物3)的制备
向反应瓶中依次加入化合物2(200mg，0.48mmol，1.0eq.)、二氯甲烷(4mL)、三乙胺(98mg，0.97mmol，2.0eq.)和苯甲酰氯(80.6mg，0.58mmol，1.2eq.)。将反应混合物于室温下搅拌5小时。TLC显示原料化合物2几乎消耗完毕。直接浓缩反应混合物，所得残留物用硅胶柱(二氯甲烷：甲醇＝100:0至100:5)分离纯化，得到化合物3(120.8mg，48％)。 1H NMR(500MHz,DMSO-d 6):δppm 2.77(d,J＝3.7Hz,3H),6.68(s,2H),7.05(s,1H),7.24-7.34(m,4H),7.52(d,J＝7.4Hz,3H),7.68(dd,J＝18.5,10.4Hz,3H),7.82(d,J＝6.9Hz,1H),7.93(d,J＝8.5Hz,3H),8.11(s,1H),8.25(d,J＝8.1Hz,1H),8.41(s,1H),8.63(s,1H)； 13C NMR(125MHz,DMSO-d 6):δppm 26.05,70.94,114.84,121.76,122.02,122.06,122.89,123.01,126.21,126.77,127.79,128.66,128.87,129.39,129.93,130.27,131.39,133.87,134.12,135.34,136.91,141.67,143.66,149.61,154.37,164.98,167.76；m/z(ESI +):521.1(M+H)。
实施例4：N-甲基-2-((3-((E)-2-(2-吡啶基)乙烯基)-1-(月桂酰氧基)甲基-1H-吲唑-6-基)硫基)苯甲酰胺(化合物4)的制备
向反应瓶中加入月桂酸(500mg，2.49mmol，1.0eq.)、氯化亚砜(1.5mL，2.9g，10eq.)和DMF(1滴)，在78℃下搅拌反应混合物3小时，然后浓缩，得到月桂酰氯(550mg，100％)。
在反应瓶中依次加入化合物2(200mg，0.48mmol，1.0eq.)、二氯甲烷(4mL)、三乙胺(98mg，0.97mmol，2.0eq.)和月桂酰氯(126mg，0.58mmol，1.2eq.)。反应化合物于室温下搅拌过夜。TLC显示原料化合物2几乎消耗完毕。直接浓缩反应混合物，残留物用硅胶柱(二氯甲烷：甲醇＝100:0至100:3)纯化，得到化合物4。 1H NMR(500MHz,CDCl 3):δppm 0.83(d,J＝6.9Hz,3H),1.18(s,16H),1.53(s,2H),2.27(t,J＝7.2Hz,2H),2.89(d,J＝4.1Hz,3H),6.21(s,2H),6.60(s,1H),7.24(dd,J＝30.0,8.2Hz,5H),7.48(d,J＝7.5Hz,1H),7.52-7.65(m,3H),7.73(t,J＝7.2Hz,1H),7.88(d,J＝16.4Hz,1H),7.94(d,J＝8.3Hz,1H),8.58(s,1H)； 13C NMR(125MHz,CDCl 3):δppm 14.14,22.71,24.71,26.74,29.03,29.23,29.36,29.46,29.62,31.94,34.02,69.84,112.31,121.69,122.39,122.42,122.74,123.77,125.54,127.69,128.78,130.47,130.79,132.99,133.48,136.02,137.56,138.21,141.90,144.34,148.84,154.78,168.70,173.27；m/z(ESI +):599.2(M+H)。
实施例5：N-甲基-2-((3-((E)-2-(2-吡啶基)乙烯基)-1-(四氢吡喃-2-基)-1H-吲唑-6-基)硫基)苯甲酰胺(化合物5)的制备
在反应瓶中加入阿西替尼(350mg，0.91mmol，1.0eq.)、DMF(10mL)、3,4-二氢-2H-吡喃(91mg，1.1mmol，1.2eq.)和对甲苯磺酸(190mg，1.0mmol，1.1eq.)。将反应混合物于80℃下搅拌16小时。TLC板显示原料阿西替尼消耗完毕。然后向反应 混合物中加入水(50mL)和乙酸乙酯(50mL)，萃洗分层。分出有机层并用饱和食盐水洗三次(每次50mL)，然后将有机层浓缩，残留物用硅胶柱(二氯甲烷：甲醇＝100:0至100:2)纯化，得到化合物5(300mg，70％)。 1H NMR(500MHz,DMSO-d 6):δppm 1.59(s,2H),1.76(s,1H),2.00(d,J＝13.9Hz,2H),2.42(d,J＝12.3Hz,1H),2.78(d,J＝4.1Hz,3H),3.76(s,1H),3.89(d,J＝10.6Hz,1H),5.92(d,J＝8.9Hz,1H),6.98(d,J＝7.6Hz,1H),7.19-7.35(m,4H),7.50(d,J＝7.3Hz,1H),7.60(d,J＝16.4Hz,1H),7.69(d,J＝7.7Hz,1H),7.82(t,J＝7.6Hz,1H),8.00-7.87(m,2H),8.22(d,J＝8.2Hz,1H),8.39(s,1H),8.61(s,1H)； 13C NMR(125MHz,DMSO-d 6):δppm 21.97,24.66,26.02,28.82,66.52,84.10,115.27,121.61,121.89,122.61,122.67,122.78,125.90,126.67,127.71,129.49,130.21,132.82,135.91,136.44,136.83,141.02,141.56,149.49,154.60,167.72；m/z(ESI +):471(M+H)。
实施例6：N-甲基-2-((3-((E)-2-(2-吡啶基)乙烯基)-1-(四氢呋喃-2-基)-1H-吲唑-6-基)硫基)苯甲酰胺(化合物6)的制备
向反应瓶中依次加入阿西替尼(350mg，0.91mmol，1.0eq.)、DMF(10mL)、2,3-二氢-2H-呋喃(96mg，1.36mmol，1.5eq.)和对甲苯磺酸(190mg，1.0mmol，1.1eq.)。将反应混合物于80℃下搅拌2小时，TLC显示原料阿西替尼几乎消耗完毕。然后向反应混合物中加入水(50mL)和乙酸乙酯(50mL)，萃洗分层。有机层用饱和食盐水洗三次(每次50mL)，然后浓缩。残留物用硅胶柱(二氯甲烷：甲醇＝100:0至100:2)纯化，得到化合物6(400mg，96％)。 1H NMR(500MHz,DMSO-d 6):δppm 2.03(dd,J＝17.7,5.1Hz,1H),2.23-2.45(m,2H),2.70(dd,J＝6.2,4.4Hz,1H),2.78(d,J＝4.0Hz,3H),3.92(dd,J＝15.3,7.4Hz,2H),6.57(s,1H),7.01(d,J＝7.8Hz,1H),7.17-7.37(m,4H),7.50(d,J＝7.2Hz,1H),7.60(d,J＝16.4Hz,1H),7.69(d,J＝7.8Hz,1H),7.82(t,J＝7.3Hz,1H),7.92(d,J＝15.6Hz,2H),8.21(d,J＝8.5Hz,1H),8.39(s,1H),8.60(s,1H)； 13C NMR(125MHz,DMSO-d 6):δppm 24.56,25.97,29.87,68.20,86.46,114.61,121.49,121.80,122.55,122.89,126.06,126.24,127.67,129.91,130.15,130.19,133.16,135.49,136.73,136.89,141.22,141.75,149.46,154.60,167.73；m/z(ESI +):457.0(M+H)。
实施例7：N-甲基-N-羟甲基-2-((3-((E)-2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)硫基)苯甲酰胺(化合物7)的制备
于反应瓶中加入阿西替尼(1g，2.6mmol，1.0eq.)、DMF(15mL)、N-(2-(三甲基硅基)乙氧羰氧基)琥珀酰亚胺(811mg，3.1mmol，1.2eq.)和DBU(593mg，3.9mmol，1.5eq.)。将混合物于室温搅拌4h，TLC显示原料阿西替尼消耗完毕。旋转蒸发除去大部分溶剂，然后加入水(20mL)和乙酸乙酯(30mL)，萃洗分层。将有机层用饱和食盐水洗三次(每次30mL)，然后浓缩。所得残留物用硅胶柱(二氯甲烷：甲醇＝100:0至100:3)纯化，得到N-甲基-2-((3-((E)-2-(2-吡啶基)乙烯基)-1-(3-(三甲基硅基)丙酰氧基)-1H-吲唑-6-基)硫基)苯甲酰胺(1.1g，75％)。
在反应瓶中加入N-甲基-2-((3-((E)-2-(2-吡啶基)乙烯基)-1-(3-(三甲基硅基)丙酰氧基)-1H-吲唑-6-基)硫基)苯甲酰胺(1g，1.9mmol，1.0eq.)、DMF(15mL)、甲醛、N-[2-(三甲基硅基)乙氧羰氧基]琥珀酰亚胺(570mg，19mmol，10eq.)和三乙胺(1.92g，19mmol，10eq.)，将混合物于50℃下搅拌过夜。然后加入水(20mL)和乙酸乙酯(30mL)，萃 洗分层。分出有机层并用饱和食盐水洗三次(每次30mL)，然后浓缩。所得残留物以硅胶柱(二氯甲烷：甲醇＝100:0至100:3)纯化，得到N-甲基-N-羟甲基-2-((3-((E)-2-(2-吡啶基)乙烯基)-1-(3-(三甲基硅基)丙酰氧基)-1H-吲唑-6-基)硫基)苯甲酰胺(500mg，47％)。
将前述产物(500mg，0.89mmol，1.0eq.)置于反应瓶中，然后加入四氢呋喃(10mL)，并将温度降到-15℃。然后向其中滴加TBAF的四氢呋喃溶液(1mol/L，0.89mL，1.0eq.)，继续在-15℃下搅拌4h。TLC显示原料消耗完毕。将反应混合物浓缩，所得残留物用硅胶柱(二氯甲烷：甲醇＝100:0至100:3)纯化，得到混合物7(200mg，54％)。H NMR(500MHz,DMSO-d 6):δppm 2.87(d,J＝99.0Hz,3H),4.64(dd,J＝229.8,6.8Hz,2H),6.04(t,J＝6.7Hz,1H),7.15(d,J＝8.4Hz,1H),7.25–7.43(m,5H),7.49(d,J＝8.6Hz,1H),7.56(d,J＝16.3Hz,1H),7.66(d,J＝7.9Hz,1H),7.81(td,J＝7.7,1.5Hz,1H),7.93(d,J＝16.3Hz,1H),8.17(d,J＝8.4Hz,1H),8.60(d,J＝4.4Hz,1H),13.29(s,1H)； 13C NMR(126MHz,DMSO-d 6):δppm 31.34,73.51,113.28,120.39,121.98,123.02,124.04,124.65,127.72,128.05,129.67,130.28,132.84,133.63,137.32,139.22,142.18,142.41,149.99,155.29,169.05；m/z(ESI +):417.0(M+H)。
实施例8：N-甲基-N-苯甲酰氧基甲基-2-((3-((E)-2-(2-吡啶基)乙烯基)-1-叔丁氧羰基-1H-吲唑-6-基)硫基)苯甲酰胺(化合物8)的制备
向反应瓶中加入阿西替尼(1g，2.6mmol，1.0eq.)、DMF(15mL)、BOC酸酐(678mg，3.1mmol，1.2eq.)和三乙胺(394mg，3.9mmol，1.5eq.)，将所得反应混合物在室温下搅拌过夜。旋去大部分溶剂后，加入水(20mL)和乙酸乙酯(30mL)，萃洗分层。将有机层用饱和食盐水洗三次(每次30mL)，然后将有机层浓缩。残留物用硅胶柱纯化(二氯甲烷：甲醇＝100:0至100:3)，得到产物N-甲基-2-((3-((E)-2-(2-吡啶基)乙烯基)-1-叔丁氧羰基-1H-吲唑-6-基)硫基)苯甲酰胺(1g，77％)。将前述产物(1g，2.6mmol，1.0eq.)置于反应瓶中，然后依次加入DMF(15mL)、甲醛(1.5g，52mmol，20eq.)、和三乙胺(5.2g，52mmol，20eq.)。所得混合物于室温下搅拌过夜后，向其中加入水(20mL)和乙酸乙酯(30mL)，萃洗分层。将有机层分出并用饱和食盐水洗五次(每次30mL)。将洗后的有机层浓缩，所得残留物用硅胶柱(二氯甲烷：甲醇＝100:0-100:2)纯化，得到N-甲基-N-羟甲基-2-((3-((E)-2-(2-吡啶基)乙烯基)-1-叔丁氧羰基-1H-吲唑-6-基)硫基)苯甲酰胺(800mg，61％)。
在反应瓶中加入(N-甲基-N-羟甲基-2-((3-((E)-2-(2-吡啶基)乙烯基)-1-叔丁氧羰基-1H-吲唑-6-基)硫基)苯甲酰胺(500mg，0.97mmol，1.0eq.)、DCM(15mL)、苯甲酰氯(200mg，3.1mmol，1.2eq.)和三乙胺(200mg，1.94mmol，2eq.)。将反应混合物于室温下搅拌过夜，然后浓缩。所得残留物用硅胶柱(二氯甲烷：甲醇＝100:0至100:2)纯化，得到混合物8(300mg，48％)。 1H NMR(500MHz,CD 3OD):δppm 1.57(d,J＝12.9Hz,9H),3.12(d,J＝105.7Hz,3H),5.43(s,2H),7.17–7.30(m,2H),7.36(s,2H),7.45–7.60(m,4H),7.67(dd,J＝23.4,15.1Hz,6H),7.81–8.80(m,3H),8.59(s,1H)； 13C NMR(126MHz,CDCl 3):δppm 26.95,28.02,32.91,36.63,71.21,85.36,115.55,121.21,121.66,122.62,123.18,125.50,127.29,128.35,128.80,129.02,129.65,129.94,130.63,131.55,133.60, 134.14,136.70,137.51,137.89,138.75,139.34,140.95,146.96,148.73,149.80,154.65,165.63,170.64；m/z(ESI +):621.3(M+H)。
实施例9：N-甲基-N-苯甲酰氧基甲基-2-((3-((E)-2-(2-吡啶基)乙烯基)-1-叔丁氧羰基-1H-吲唑-6-基)硫基)苯甲酰胺(化合物9)的制备
在反应瓶中依次加入N-甲基-N-羟甲基-2-((3-((E)-2-(2-吡啶基)乙烯基)-1-(3-(三甲基硅基)丙酰氧基)-1H-吲唑-6-基)硫基)苯甲酰胺(见实施例7，1g，1.7mmol，1.0eq.)、DCM(15mL)、苯甲酰氯(288mg，2.04mmol，1.2eq.)和TEA(258mg，2.6mmol，1.5eq.)。将反应混合物于室温下搅拌4h，然后浓缩。残留物用硅胶柱(二氯甲烷：甲醇＝100:0至100:3)纯化，得到产物N-甲基-N-苯甲酰氧基甲基-2-((3-((E)-2-(2-吡啶基)乙烯基)-1-(3-(三甲基硅基)丙酰氧基)-1H-吲唑-6-基)硫基)苯甲酰胺(800mg，73％)。
将前述反应产物(500mg，0.78mmol，1.0eq.)置于反应瓶中，然后加入四氢呋喃(10mL)，并将温度降到-15℃。于冷却条件下滴入TBAF的四氢呋喃溶液(1mol/L，0.78mL，1.0eq.)。将该反应混合物在-15℃下搅拌4h，然后浓缩。所得残留物用硅胶柱(二氯甲烷：甲醇＝100:0至100:3)纯化，得到化合物9(190mg，47％)。 1H NMR(500MHz,CD 3OD):δ3.12(d,J＝97.8Hz,3H),5.45(d,J＝34.6Hz,2H),7.13(d,J＝8.3Hz,1H),7.25–7.33(m,1H),7.33-7.63(m,9H),7.68(d,J＝7.9Hz,1H),7.77-8.06(m,5H),8.54(d,J＝4.6Hz,1H)； 13C NMR(125MHz,DMSO-d 6):δ33.04,76.00,112.91,120.43,122.00,123.18,124.30,127.40,127.78,128.32,128.71,129.31,129.74,130.91,132.49,133.14,133.31,134.09,138.20,138.96,142.27,149.24,154.87,165.47,165.96,170.29；m/z(ESI -):518.9(M-H)。
实施例10：N-甲基-N-甲氧甲基-2-((3-((E)-2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)硫基)苯甲酰胺(化合物10)的制备
于反应瓶中加入N-甲基-N-羟甲基-2-((3-((E)-2-(2-吡啶基)乙烯基)-1-(3-(三甲基硅基)丙酰氧基)-1H-吲唑-6-基)硫基)苯甲酰胺(见实施例7，1g，1.7mmol，1.0eq.)、MeOH(15mL)和浓盐酸0.5mL，将反应混合物在室温下搅拌16h。然后将反应混合物浓缩，所得残留物用硅胶柱(二氯甲烷：甲醇＝100:0至100:3)纯化，得到中间产物N-甲基-N-甲氧甲基-2-((3-((E)-2-(2-吡啶基)乙烯基)-1-(3-(三甲基硅基)丙酰氧基)-1H-吲唑-6-基)硫基)苯甲酰胺(600mg，60％)。
将上述中间产物(500mg，0.94mmol，1.0eq.)置于反应瓶中，然后加入(四氢呋喃(10mL)，并降温到-15℃。在此冷却条件下滴加入TBAF的四氢呋喃溶液(1mol/L，0.94mL，1.0eq.)，于-15℃下将反应混合物继续搅拌4h。TLC显示原料消耗完毕。将反应混合物浓缩，残留物用硅胶柱纯化(二氯甲烷：甲醇＝100:0-100:3)，得到化合物10(230mg，57％)。 1H NMR(500MHz,CDCl 3):δ3.03(d,J＝123.2Hz,3H),3.33(d,J＝132.0Hz,3H),4.77(d,J＝247.0Hz,2H),7.12–7.36(m,6H),7.54(d,J＝7.8Hz,1H),7.62(d,J＝16.6Hz,2H),7.76(s,1H),7.98(dd,J＝15.6,12.5Hz,2H),8.62(d,J＝4.9Hz,1H)； 13C NMR(125MHz,CDCl 3):δ33.38,56.01,82.09,114.90,121.01,121.46,122.02,122.35,124.17,125.17,125.27,126.73,127.44,129.62,130.04,131.06,131.76,132.92,134.47,136.95,142.48,149.35,155.45,170.67；m/z(ESI -):428.9(M-H)。
实施例11：N-甲基-2-((3-((E)-2-(2-吡啶基)乙烯基)-1-(金刚烷-1-乙酰氧基)甲基-1H-吲唑-6-基)硫基)苯甲酰胺(化合物11)的制备
于反应瓶中加入1-金刚烷乙酸(1g，5.2mmol，1eq.)和草酰氯(6.5g，10.0eq)，将混合物于室温下搅拌5小时，旋干后得到白色固体1-金刚烷乙酰氯(1g，91％)，直接用于后续反应。
在反应瓶中加入化合物2(500mg，1.2mmol，1.0eq.)、二氯甲烷(10mL)、TEA(242mg，2.4mmol，2.0eq.)和1-金刚烷乙酰氯(319mg，1.44mmol，1.2eq.)。将反应混合物于室温下搅拌5小时。然后将反应混合物直接浓缩，残留物用硅胶柱(二氯甲烷：甲醇＝100:0至100:5)纯化，得化合物11(230mg，32％)。 1H NMR(500MHz,CDCl 3):δppm 1.42–1.53(m,9H),1.62(s,3H),1.86(s,3H),2.05(s,2H),2.94(d,J＝4.9Hz,3H),6.24(s,2H),6.41(s,1H),7.21(dd,J＝16.4,10.0Hz,2H),7.28(d,J＝4.8Hz,1H),7.33(dd,J＝5.8,3.5Hz,2H),7.46(d,J＝7.7Hz,1H),7.54–7.65(m,3H),7.70(t,J＝7.7Hz,1H),7.86(d,J＝16.4Hz,1H),7.95(d,J＝8.3Hz,1H),8.64(d,J＝4.1Hz,1H)； 13C NMR(125MHz,CDCl 3):δppm 26.87,28.59,33.02,36.67,42.33,48.59,69.44,112.77,121.69,122.53,122.71,125.57,127.69,128.79,130.91,131.68,132.87,133.68,135.69,136.85,137.98,141.97,144.58,149.87,155.23,168.79,171.31；m/z(ESI +):593.2(M+H)。
实施例12：N-甲基-2-((3-((E)-2-(2-吡啶基)乙烯基)-1-(烟酰氧基)甲基-1H-吲唑-6-基)硫基)苯甲酰胺(化合物12)的制备
于反应瓶中加入烟酸(132.9mg，1.08mmol，1.0eq.)、二氯甲烷(10mL)、和DMF(0.05mL)，并将混合物用冰水浴冷却，然后滴入草酰氯(822.5mg，6.48mmol，6.0eq.)。滴加完成后，将反应混合物于室温下搅拌3小时，然后直接将混合物浓缩，得到烟酰氯(152.9mg，100％)，该产物直接用于后续反应。
在反应瓶中加入化合物2(300mg，0.72mmol，1.0eq.)、二氯甲烷(10mL)、和三乙胺(219mg，2.16mmol，3.0eq.)，并置于冰水浴中冷却。在冷却条件下，向上述混合物中加入烟酰氯(152.9mg，1.08mmol，1.5eq.)。将所得反应混合物于室温下搅拌过夜。TLC显示原料消耗完毕。将反应混合物直接浓缩后，残留物用硅胶柱(二氯甲烷：甲醇＝100:0至100:3)纯化，得到化合物12(250mg，66％)。 1H NMR(500MHz,CDCl 3)δppm:2.91(d,J＝4.9Hz,3H),6.45(s,1H),6.52(s,2H),7.20(dd,J＝6.7,4.9Hz,1H),7.24(d,J＝1.2Hz,1H),7.29-7.39(m,4H),7.46(d,J＝7.9Hz,1H),7.60(d,J＝16.3Hz,1H),7.62-7.68(m,2H),7.70(td,J＝7.7,1.6Hz,1H),7.86(d,J＝16.3Hz,1H),7.96(d,J＝8.5Hz,1H),8.26(dd,J＝8.0,1.8Hz,1H),8.63(d,J＝4.1Hz,1H),8.76(dd,J＝4.8,1.6Hz,1H),9.18(d,J＝1.3Hz,1H)； 13C NMR(125MHz,CDCl 3)δppm:26.81,70.68,112.34,121.71,122.42,122.52,122.73,123.44,125.01,125.61,127.66,128.73,130.85,131.84,132.80,133.55,136.06,136.83,137.48,137.89,141.94,144.83,149.75,151.22,154.06,155.00,164.74,168.70；m/z(ESI +):522.1(M+H)。
实施例13：N-甲基-2-((3-((E)-2-(2-吡啶基)乙烯基)-1-(1-甲基-1H-吲哚-3-甲酰氧基)甲基-1H-吲唑-6-基)硫基)苯甲酰胺(化合物13)的制备
向反应瓶中加入1-甲基-1H-吲哚-3-甲酸(378.3mg，2.16mmol，1.0eq.)、氯化亚砜 (1.55g，12.96mmol，6.0eq.)和DMF(0.05mL)。于室温下搅拌反应混合物3小时。然后直接浓缩反应混合物，得到1-甲基-1H-吲哚-3-甲酰氯(418.24mg，100％)。
向反应瓶中加入化合物2(400mg，0.96mmol，1.0eq.)、二氯甲烷(10mL)、和三乙胺(387.8mg，3.86mmol，4.0eq.)，并将混合物于冰水浴下冷却。在冷却条件下，向混合物中加入1-甲基-1H-吲哚-3-碳酰氯(278.88mg，1.44mmol，1.5eq.)，然后在室温条件下，搅拌反应混合物过夜。直接将反应混合物浓缩后，将残留物用硅胶柱纯化(二氯甲烷：甲醇＝100:0至100:3)，得到化合物13(235mg，42％)。 1H NMR(500MHz,CDCl 3)δppm:2.74(d,J＝4.8Hz,3H),3.78(s,3H),6.45(s,2H),6.59(s,1H),7.15-7.20(m,1H),7.23(d,J＝8.5Hz,1H),7.26-7.40(m,6H),7.46(d,J＝7.9Hz,1H),7.59(d,J＝18.6Hz,2H),7.63(d,J＝6.9Hz,1H),7.69(t,J＝7.2Hz,1H),7.78(s,1H),7.87(d,J＝16.3Hz,1H),7.93(d,J＝8.4Hz,1H),8.09(d,J＝8.2Hz,1H),8.62(d,J＝3.8Hz,1H)； 13C NMR(125MHz,CDCl 3)δppm:26.70,33.63,69.19,105.24,111.06,111.67,121.42,121.48,122.09,122.29,122.42,122.63,122.98,123.24,124.70,126.71,128.16,128.72,130.87,131.51,132.53,133.85,136.32,136.53,136.79,137.32,139.18,141.97,144.35,149.84,155.30,163.94,168.99；m/z(ESI +):596.2(M+Na)。
实施例14：药代动力学实验方法
实验动物采用CD1小鼠，雄性，体重18g～22g。将实验动物随机分组，每组18只。分别于给药后0.5、1、2、4、6、8h收集血样。将被测试化合物于溶媒中配制成实验用溶液或混悬液，灌胃给药，溶媒组成为0.5wt％CMC-Na溶液；DMSO：0.5wt％-CMC-Na水溶液(5/95,v/v)；DMSO：EtOH：0.5wt％-CMC-Na(5/5/90,v/v/v)；或者EtOH：0.5wt％-CMC-Na(10/90,v/v)。测试化合物浓度均为3mg/mL当量的阿西替尼。将动物禁食12小时后，以30mg/kg阿西替尼当量灌胃给药。于给药后，在预设时间点从眼眶采血至肝素化的EP管中，全血样品于5000rpm在4℃下离心10min后收集血浆样品，低温保存。取10μL血浆样品，加入110μL乙腈沉淀，混合均匀后，于12000rpm在4℃下离心10min，取上清液进行LC-MS/MS分析。分析目标为阿西替尼和相应的前药分子。
有关化合物口服给药后，在血浆中所得到的药代动力学数据概括于表2。部分化合物口服给药后在血浆中的阿西替尼浓度—时间曲线见图1：其中，-○-、-◇-、-◆-、-Δ-、以及-x-分别代表口服给与等摩尔剂量的为阿西替尼、化合物2、化合物4、化合物12、和化合物13后，血浆中阿西替尼的浓度随时间的变化。
表2.各前药给药后阿西替尼的药代动力学参数
Figure PCTCN2020111981-appb-000012
*A:0.5％CMC-Na；B:5％DMSO和95％的0.5％-CMC-Na；C:10％EtOH和90％的0.5％-CMC-Na。
尽管参照本发明的实施例详细描述了本发明，但提供这些实施例是为了说明而不是限制本发明。根据本发明原理能够得到的其它实施例均属于本发明权利要求所界定的范畴。
本文所列出的所有文件和文献的内容通过引用而整体并入本文中。

Claims (14)

  1. 下式I所示的化合物或其药学上可接受的盐、酯、螯合物、水合物、溶剂化物、立体异构体或多晶型在制备用于抑制酪氨酸激酶活性的药物中的用途：
    Figure PCTCN2020111981-appb-100001
    其中：
    R 1和R 2独立选自氢或保护基；
    R 3不存在，或者为保护基，其中当R 3为保护基时，氮原子带正电，并且存在平衡离子；
    所述保护基为-CHRaOR；
    其中，Ra为H或低级烷基；
    R选自氢、烷基、烷基羰基、金刚烷基羰基、芳基羰基、烷基硫代羰基、芳基硫代羰基、烷基氨基甲酰基、芳基氨基甲酰基、取代或未取代的乙酰基、取代或未取代的氨基烷酰基、取代或未取代的α-氨基烷酰基、天然或非天然氨基酸衍生的具有或不具有取代基的酰基、肽残基的酰基、环烷基羰基、杂环烷基羰基、烷氧基羰基、芳氧基羰基、杂烷氧基羰基、杂芳氧基羰基、具有或不具有取代基的低聚乙二醇化羰基和R 4W(R 5R 6C) m-；
    其中，m为选自0至6的整数；
    W为氧(O)、硫(S)、氮(N)或不存在；
    R 5和R 6独立地为氢或低级烷基；并且，
    R 4为
    Figure PCTCN2020111981-appb-100002
    其中，X为氧(O)、硫(S)、氮(N)或碳(C)；
    R 7和R 8独立地为氢、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的氧杂烃基、取代或未取代的羟甲基、含有碳酸酯或羧酸酯的烃基、具有取代基或不具有取代基的芳基或杂芳基、结构为R 10-(OCH 2CH 2) n-的PEG残基、诸如低级烷基或芳基的成酯基团或诸如低级烷基或芳基的成醚部分，其中，n＝1至10，R 10为氢或低级烷基；或者当X为氧或硫时，R 7和R 8独立为成盐部分，诸如钠、钾、四乙铵或四丁铵；或者，R 7和X的组合一起形成取代或未取代的烷基或芳基；或者，当X为氮 时，R 7和X的组合一起形成取代或未取代的氨基酸衍生物，并且X是该氨基酸中氨基的氮原子；
    R 9选自低级烷基、羟基、卤素、硝基、氨基、低级烷基氨基和低级烷氧基，或者R 9和其所连接的苯环一起形成非芳香族或芳香族稠环基团；
    或者，Ra和R以及它们所连接的碳、氧原子一起形成氧杂环；
    条件是式I的化合物不是阿西替尼。
  2. 下式I所示的化合物或其药学上可接受的盐、酯、螯合物、水合物、溶剂化物、立体异构体或多晶型在制备用于治疗由酪氨酸激酶介导的疾病病症或症状的药物中的用途：
    Figure PCTCN2020111981-appb-100003
    其中：
    R 1和R 2独立选自氢或保护基；
    R 3不存在，或者为保护基，其中当R 3为保护基时，氮原子带正电，并且存在平衡离子；
    所述保护基为-CHRaOR；
    其中，Ra为H或低级烷基；
    R选自氢、烷基、烷基羰基、金刚烷基羰基、芳基羰基、杂芳基羰基、烷基硫代羰基、芳基硫代羰基、烷基氨基甲酰基、芳基氨基甲酰基、取代或未取代的乙酰基、取代或未取代的氨基烷酰基、取代或未取代的α-氨基烷酰基、天然或非天然氨基酸衍生的具有或不具有取代基的酰基、肽残基的酰基、环烷基羰基、杂环烷基羰基、烷氧基羰基、芳氧基羰基、杂烷氧基羰基、杂芳氧基羰基、具有或不具有取代基的低聚乙二醇化羰基和R 4W(R 5R 6C) m-；
    其中，m为选自0至6的整数；
    W为氧(O)、硫(S)、氮(N)或不存在；
    R 5和R 6独立地为氢或低级烷基；并且，
    R 4为
    Figure PCTCN2020111981-appb-100004
    其中，X为氧(O)、硫(S)、氮(N)或碳(C)；
    R 7和R 8独立地为氢、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的氧杂烃基、取代或未取代的羟甲基、含有碳酸酯或羧酸酯的烃基、具有取 代基或不具有取代基的芳基或杂芳基、结构为R 10-(OCH 2CH 2) n-的PEG残基、诸如低级烷基或芳基的成酯基团或诸如低级烷基或芳基的成醚部分，其中，n＝1至10，R 10为氢或低级烷基；或者当X为氧或硫时，R 7和R 8独立为成盐部分，诸如钠、钾、四乙铵或四丁铵；或者，R 7和X的组合一起形成取代或未取代的烷基或芳基；或者，当X为氮时，R 7和X的组合一起形成取代或未取代的氨基酸衍生物，并且X是该氨基酸中氨基的氮原子；
    R 9选自低级烷基、羟基、卤素、硝基、氨基、低级烷基氨基和低级烷氧基；或者R 9和其所连接的苯环一起形成非芳香族或芳香族稠环基团；
    或者，Ra和R以及它们所连接的碳、氧原子一起形成氧杂环；
    条件是式I的化合物不是阿西替尼。
  3. 根据权利要求1或2所述的用途，其中，所述化合物为式II所示的化合物或其药学上可接受的盐或酯：
    Figure PCTCN2020111981-appb-100005
    其中，
    R 1和R 2独立地为H或保护基-CHRaOR；
    其中，Ra为H；R如权利要求1中所限定；
    或者，Ra和R以及它们所连接的碳、氧原子一起形成氧杂环；
    条件是R 1和R 2不同时为H。
  4. 根据权利要求1或2所述的用途，其中，所述化合物为式III的化合物或其药学上可接受的盐或酯：
    Figure PCTCN2020111981-appb-100006
    其中，
    Figure PCTCN2020111981-appb-100007
    为平衡离子并且选自药学上可接受的阴离子；
    R 3为保护基-CHRaOR；
    其中，Ra为H，R如权利要求1中所限定。
  5. 根据权利要求1或2所述的用途，其中，所述化合物选自以下示出的化合物：
    Figure PCTCN2020111981-appb-100008
    Figure PCTCN2020111981-appb-100009
    Figure PCTCN2020111981-appb-100010
  6. 根据权利要求1或2所述的用途，其中，所述用途适用于哺乳动物，尤其是人。
  7. 根据权利要求2所述的用途，其中，所述由酪氨酸激酶介导的疾病病症或症状为肿瘤或癌症，特别是乳腺癌、肾细胞癌和/或甲状腺癌。
  8. 根据权利要求1或2所述的用途，其中，所述药物与其它治疗剂联合使用，所述其它治疗剂包括程序性细胞死亡蛋白-1和程序性细胞死亡配体1抑制剂。
  9. 一种式I所示的化合物，或其药学上可接受的盐或酯或其药学上可接受的盐、酯、螯合物、水合物、溶剂化物、立体异构体或多晶型：
    Figure PCTCN2020111981-appb-100011
    其中：
    R 1和R 2独立选自氢或保护基；
    R 3不存在，或者为保护基，其中当R 3为保护基时，氮原子带正电，并且存在平衡离子；
    所述保护基为-CHRaOR；
    其中，Ra为H或低级烷基；
    R选自氢、烷基、烷基羰基、金刚烷基羰基、芳基羰基、杂芳基羰基、烷基硫代羰基、芳基硫代羰基、烷基氨基甲酰基、芳基氨基甲酰基、取代或未取代的乙酰基、取代或未取代的氨基烷酰基、取代或未取代的α-氨基烷酰基、天然或非天然氨基酸衍生的具有或不具有取代基的酰基、肽残基的酰基、环烷基羰基、杂环烷基羰基、烷氧基羰基、芳氧基羰基、杂烷氧基羰基、杂芳氧基羰基、具有或不具有取代基的低聚乙二醇化羰基和R 4W(R 5R 6C) m-；
    其中，m为选自0至6的整数；
    W为氧(O)、硫(S)、氮(N)或不存在；
    R 5和R 6独立地为氢或低级烷基；并且，
    R 4为
    Figure PCTCN2020111981-appb-100012
    其中，X为氧(O)、硫(S)、氮(N)或碳(C)；
    R 7和R 8独立地为氢、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的氧杂烃基、取代或未取代的羟甲基、含有碳酸酯或羧酸酯的烃基、具有取代基或不具有取代基的芳基或杂芳基、结构为R 10-(OCH 2CH 2) n-的PEG残基、诸如低级烷基或芳基的成酯基团或诸如低级烷基或芳基的成醚部分，其中，n＝1至10，R 10为氢或低级烷基；或者当X为氧或硫时，R 7和R 8独立为成盐部分，诸如钠、钾、四乙铵或四丁铵；或者，R 7和X的组合一起形成取代或未取代的烷基或芳基；或者，当X为氮时，R 7和X的组合一起形成取代或未取代的氨基酸衍生物，并且X是该氨基酸中氨基的氮原子；
    R 9选自低级烷基、羟基、卤素、硝基、氨基、低级烷基氨基和低级烷氧基；或者R 9和其所连接的苯环一起形成非芳香族或芳香族稠环基团；
    或者，Ra和R以及它们所连接的碳、氧原子一起形成氧杂环；
    条件是式I的化合物不是阿西替尼、N-甲基-N-(膦酰氧基)甲基-2-((3-((E)-2-(2-吡啶基)乙烯基)-1H-吲唑-6-基)硫基)苯甲酰胺、N-甲基-2-((3-((E)-2-(2-吡啶基)乙烯基)-1-(月桂酰氧基)甲基-1H-吲唑-6-基)硫基)苯甲酰胺、N-甲基-N-(膦酰氧基)甲基-2-((3-((E)-2-(2-吡啶基)乙烯基)-1-(月桂酰氧基)甲基-1H-吲唑-6-基)硫基)苯甲酰胺、N-甲基-N-(月桂酰氧基)甲基-2-((3-((E)-2-(2-吡啶基)乙烯基)-1-羟甲基-1H-吲唑-6-基)硫基)苯甲酰胺、N-甲基-2-((3-((E)-2-(N-(乙酰氧基)甲基吡啶-2-基)乙烯基)-1-(月桂酰氧基)甲基-1H-吲唑-6-基)硫基)苯甲酰胺氯化物和N-甲基-2-((3-((E)-2-(N-(1-(异丙氧基羰基氧基)-1-乙基)吡啶-2-基)乙烯基)-1H-吲唑-6-基)硫基)苯甲酰胺氯化物。
  10. 根据权利要求9所述的化合物，其中，所述化合物为式II所示的化合物或其药学上可接受的盐或酯：
    Figure PCTCN2020111981-appb-100013
    其中，
    R 1和R 2独立地为H或保护基-CHRaOR；
    其中，Ra为H；R如权利要求8中所限定；
    或者，Ra和R以及它们所连接的碳、氧原子一起形成氧杂环；
    条件和权利要求9一致。
  11. 根据权利要求9所述的化合物，其中，所述化合物为式III的化合物或其药学上可接受的盐或酯：
    Figure PCTCN2020111981-appb-100014
    其中，
    Figure PCTCN2020111981-appb-100015
    为平衡离子并且选自药学上可接受的阴离子；
    R 3为保护基-CHRaOR；
    其中，Ra为H，R如权利要求9中所限定；
    条件和权利要求9一致。
  12. 一种药物组合物，所述药物组合物包括：根据权利要求9至11中任一项所述的化合物及其药学上可接受的盐或酯；以及，药学上可接受的载体。
  13. 一种试剂盒，所述试剂盒包括：至少一种权利要求9至11中任一项所述的化合物，或者权利要求12所述的药物组合物；以及其使用说明。
  14. 根据权利要求9至11所述的化合物和根据权利要求12所述的药物组合物与其它治疗剂或方法的联合使用，所述其它治疗剂包括程序性细胞死亡蛋白-1和程序性细胞死亡配体1抑制剂。
PCT/CN2020/111981 2019-08-30 2020-08-28 一类前药化合物及其在治疗癌症方面的应用 WO2021037183A1 (zh)

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