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CN112442010B - Prodrug compounds and application thereof in treating cancers - Google Patents

Prodrug compounds and application thereof in treating cancers Download PDF

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CN112442010B
CN112442010B CN201910818675.XA CN201910818675A CN112442010B CN 112442010 B CN112442010 B CN 112442010B CN 201910818675 A CN201910818675 A CN 201910818675A CN 112442010 B CN112442010 B CN 112442010B
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compound
acid
axitinib
pharmaceutically acceptable
methyl
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CN112442010A (en
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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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Risen Suzhou Pharma Tech Co Ltd
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Risen Suzhou Pharma Tech Co Ltd
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Priority to US17/005,852 priority patent/US20210078970A1/en
Priority to CA3147801A priority patent/CA3147801A1/en
Priority to AU2020338490A priority patent/AU2020338490A1/en
Priority to PCT/CA2020/051177 priority patent/WO2021035360A1/en
Priority to PCT/CN2020/111981 priority patent/WO2021037183A1/en
Priority to EP20857153.9A priority patent/EP4021912A4/en
Publication of CN112442010A publication Critical patent/CN112442010A/en
Priority to IL290798A priority patent/IL290798A/en
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • 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
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    • A61K31/4965—Non-condensed pyrazines
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Abstract

The present invention provides compounds of formula (I) and pharmaceutically acceptable salts or esters thereof, and pharmaceutical compositions thereof; and the use of the compounds, pharmaceutical compositions of the invention for inhibiting or modulating tyrosine kinase activity, treating disease symptoms or conditions mediated by tyrosine kinase, including cancer.

Description

Prodrug compounds and application thereof in treating cancers
Technical Field
The present invention relates to prodrugs of N-methyl-2- ((3- ((1E) -2- (2-pyridinyl) vinyl) -1H-indazol-6-yl) thio) benzamide, which are tyrosine kinase inhibitors, and compositions thereof, and their use in inhibiting or modulating tyrosine kinase-mediated activity, treating disease symptoms or conditions mediated by tyrosine kinase, such as cancer.
Background
Axitinib (chemical name: N-methyl-2- ((3- ((1E) -2- (2-pyridyl) vinyl) -1H-indazol-6-yl) thio) benzamide:) Is a small molecule Tyrosine Kinase Inhibitor (TKI) useful in the treatment of cancer (see, for example, WO2001002369, below showing the structure of the compound). It has been shown that axitinib is capable of significantly inhibiting the growth of breast cancer in animal xenograft models (Wilmes, l.j. Et al., magn. Resin. Imaging,2007,25 (3): 319-327). The drug has shown 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 also shows partial response for several other tumor types (Rugo, H.S.et al, J.Clin.Oncol.,2005, 23:5474-5483). After showing a modest increase in progression free survival, axitinib has been approved by the U.S. food and drug administration for the treatment of RCC.
The structure of axitinib is shown below:
axitinib is used for targeted anti-cancer therapy because it targets and binds to Vascular Endothelial Growth Factor Receptor (VEGFR) inside cancer cells. VEGFR is present on the surface of many normal and cancer cells. By binding to these receptors, axitinib blocks an important pathway that promotes angiogenesis (new blood vessels for tumor formation) (Escudier, b.and Gore, m., "Axitinib for the Management of Metastatic Renal Cell Carcinoma", drugs in R & D,2011,11 (2): 113-126).
Furthermore, data from multicenter phase II studies in patients with intermediate and late stage differentiated (papillary, follicular or invasive) thyroid cancer support phase I 131 Refractory diseases or unacceptable I 131 Axitinib (Cohen, ezra E.W. et al, J.Clin.Oncol.,2008,26 (29): 4708-4713) was used. Another needleMulticenter phase II studies on advanced thyroid cancer are also supported in treatment I 131 Axitinib (location, L.D. et al, cancer,2014,120 (17): 2694-2703) was used in refractory diseases. Thus, axitinib is also used in the treatment of (differentiated, advanced) thyroid cancer outside of drug approval markers.
One problem with the treatment of cancer with axitinib is its side effects. Many different side effects have been reported, including diarrhea, hypertension, fatigue, loss of appetite, nausea, dysphonia, hand-foot syndrome, weight loss, vomiting, debilitation and constipation, and the most common side effects occur in more than 20% of patients (FDA Prescribing Information, january 30,2012).
Like other oral drugs, including other tyrosine kinase inhibitors, the Pharmacokinetics (PK) of axitinib vary in healthy volunteers and cancer patients (Garrett, m.et al, br.j. Clin. Pharmacol.,2013,77 (3): 480-492). Notably, the large variability of the axitinib PK was evident from the estimated residual standard deviation of orally administered axitinib (50.9%) and of intravenously injected axitinib (34.2%), and could not be reduced by introducing individual differences over time (inter-occasion variability, IOV) in the model.
The exact reasons for variability in axitinib PK remain to be elucidated. It is known that the metabolism of axitinib is severe (Smith, B.J.et al., drug Metab. Dispos.,2014,42:918-931; and Zientek, M.A, et al., drug Meta. Dispos.,2016,44 (1): 102-114). Of the three major metabolites, one is the glucuronidation product at the nitrogen atom of the central pyrazole ring (M7), while the other two are metabolites from a single oxidation step. Since axitinib is metabolized mainly by CYP3A4/5, one of the main reasons for variability is presumably the difference in CYP3A4/5 expression and/or the difference in liver and intestinal activity (it is reported that CYP3A4/5 expression has a 10 to 40-fold variability in healthy subjects).
As axitinib is a low extraction drug, the metabolic clearance of axitinib is particularly sensitive to different levels of liver and intestinal metabolic enzymes. Another possible explanation is the variability in the binding of axitinib plasma between subjects. For high residual (in-subject) variability, the difference in dissolution and subsequent gastrointestinal absorption of axitinib may be a contributor. The solubility of axitinib is pH dependent, and the solubility decreases with increasing pH, so that a change in pH in the stomach and duodenum may result in a change in the solubility of axitinib.
Since plasma exposure of axitinib affects not only its toxicity but also its clinical efficacy, it is critical to identify clinical factors that lead to variability in axitinib PK. In order to reduce toxicity and maintain a stable therapeutic effect, it is desirable to eliminate or reduce PK variability of axitinib.
Prodrugs are drugs or compounds that are metabolized (i.e., converted in vivo) to pharmacologically active drugs after administration (see, e.g., rautio, J.et al., "The expanding role of prodrugs in contemporary drug design and development", nat. Rev. Drug discovery., 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 vivo to active forms. Thus, rather than direct administration, the corresponding prodrugs can be used to improve absorption, distribution, metabolism and/or excretion patterns (ADME) of the drug (see, e.g., malhotra, B., et al, "The design and development of fesoterodine as a prodrug of-hydroxymethyl tolterodine (5-HMT), the active metabolite of tolterodine," Curr. Med. Chem.,2009,16 (33): 4481-9; and stilla, V.J., et al, "Prodrug. Do they have advantages in clinical practice", drugs,1985,29 (5): 455-73). Prodrugs can be used to improve the selectivity of the cellular or process interactions of a drug with unintended targets. This can reduce the side effects or unexpected effects of the drug, especially for treatments such as chemotherapy that often have serious unexpected and unexpected side effects. For example, tenofovir Alafenamide (TAF), a new tenofovir prodrug, was developed to provide enhanced antiviral efficacy and reduced systemic toxicity (Byrne, r., et al, therapeutic.
Derivatives of axitinib have been reported to be useful in the treatment of ophthalmic diseases, such as CN106317017, CN106336397, and CN106478596, among others. In these reports, the resulting axitinib derivatives were only used to improve the water solubility of axitinib to meet the requirements of injection into the vitreous cavity. However, there is no reference to any derivative of axitinib which addresses the above-mentioned drawbacks and which is useful for inhibiting tyrosine kinase activity or for treating symptoms or conditions of a disease mediated by tyrosine kinase. Moreover, there is no understanding or involvement of the pharmacokinetics of the relevant derivatives in the animal body, the actual metabolic processes of the derivatives, how the treatment is affected thereby, etc.
Disclosure of Invention
It is an object of the present invention to at least ameliorate some of the disadvantages of the prior art. The present invention has been developed based, at least in part, on the inventors' understanding that the pharmacokinetic properties of this particular compound are modulated or improved by developing prodrugs of the methyl 2- ((3- ((1E) -2- (2-pyridinyl) vinyl) -1H-indazol-6-yl) thio) benzamide to render it suitable for therapeutic application needs. The use and need for, and other needs in inhibiting or modulating the activity of tyrosine kinases, as well as in treating diseases or conditions mediated by tyrosine kinases, such as cancer, and the like, may be met by the axitinib derivatives and/or prodrugs, pharmaceutical compositions, and uses thereof, as defined herein.
Without wishing to be bound by theory, it is believed that protecting the nitrogen atom in axitinib by molecular modification may alter the physical, chemical and biological properties of the compound, such as compound solubility, lipophilic hydrophilic capacity, biofilm penetration, stability in the digestive system and liver, and the metabolic rate and pathway of the prodrug compound-based prodrug compound. These changes in properties can lead to changes in the PK parameters of the drug substance, and thus modulate the therapeutic efficacy and range of application of the drug substance molecule.
In a first aspect, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt, ester, solvate or various polymorphs thereof, in the manufacture of a medicament for inhibiting the activity of a tyrosine kinase or in the manufacture of a medicament for treating a disease condition or symptom mediated by a tyrosine kinase:
wherein R is 1 And R is 2 Independently hydrogen H or a protecting group-CHRaOR; r is R 3 May or may not be present; when R is 3 When present and a protecting group, the nitrogen atom is positively charged and a counterion is present; provided that the compound of formula I is not axitinib. At R 1 And R is 2 In embodiments in which both are protecting groups, the protecting groups may be the same or different.
In some embodiments, a compound provided herein is a prodrug of axitinib, i.e., metabolized or converted to axitinib in a subject.
In one embodiment, the compound of formula I is a compound of formula II, or a pharmaceutically acceptable salt, ester, solvate, or polymorph thereof:
wherein R is 1 And R is 2 Independently hydrogen (H) or a protecting group-CHRaOR, and when R 1 And R is 2 When both are protecting groups, the protecting groups may be the same or different.
In another embodiment, the compound of formula I is a compound of formula III, or a pharmaceutically acceptable salt, ester, solvate, or polymorph thereof:
wherein R is 3 Is a protecting group (P), andis a counter ion.
In one embodiment, in the protecting group-CHRaOR, ra is H or lower alkyl; r is selected from the group consisting of hydrogen, alkyl, acyl, alkylcarbonyl, adamantylcarbonyl, heteroarylcarbonyl, arylcarbonyl, alkylthio carbonyl, formyl-thio acyl, alkylcarbamoyl, arylcarbamoyl, substituted or unsubstituted acetyl, substituted or unsubstituted aminoalkyl, substituted or unsubstituted α -aminoalkyl, acyl with or without substituents derived from natural or unnatural amino acids, acyl of peptide residues, cycloalkylcarbonyl, heterocyclylalkylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, heteroalkoxycarbonyl, heteroaryloxycarbonyl, oligopegylated carbonyl with or without substituents.
In another embodiment, 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, W is oxygen (O), sulfur (S), nitrogen (N) or is absent, R 5 And R is 6 Independently is hydrogen or lower alkyl, and R 4 Is thatOr->Wherein X is oxygen (O), sulfur (S), nitrogen (N) or carbon (C); r is R 7 And R is 8 Independently hydrogen, substituted or unsubstituted alkyl or cycloalkyl, substituted or unsubstituted aryl or heteroaryl, having the structure R 10 -(OCH 2 CH 2 ) n -PEG residues, such as lower alkyl or aryl ester-forming groups, wherein n = 1 to 10, r 10 Is hydrogen or lower alkyl; alternatively, when X is oxygen or sulfur, R 7 And R is 8 Independently a salifying moiety such as sodium, potassium, tetraethylammonium or tetrabutylammonium; alternatively, R 7 And X taken together form a substituted or unsubstituted alkyl or aryl group; r is R 9 Selected from lower alkyl, hydroxy, halogen (-F, -Cl, -Br or-I), nitro, amino, lower alkylamino and lower alkoxy, or R 9 Together with the benzene ring to which they are attached form a non-aromatic or aromatic condensed ring group, e.g. substitutedOr unsubstituted naphthyl; provided that the compound of formula I, formula II or formula III is not axitinib.
In other embodiments, ra, R in the protecting group-CHRaOR, and the carbon and oxygen atom to which they are attached, together form a substituted or unsubstituted oxaheterocyclyl group, such as tetrahydrofuran-2-yl, tetrahydropyran-2-yl, 1-oxocyclohepta-2-yl, and the like.
In some embodiments, the counterion is selected from, but not limited to, a halide (F - 、Cl - 、Br - And I - ) Sulfate ion, methanesulfonate ion, toluenesulfonate ion, oxalate ion, tartrate ion, and other pharmaceutically acceptable anionic moieties.
In some embodiments, the compounds of formulas I-III are compounds shown in table 1 or a pharmaceutically acceptable salt, ester, chelate, hydrate, solvate, stereoisomer, or polymorph thereof.
TABLE 1 examples of Axitinib-derived compounds
In a second broad aspect, the present invention provides a compound of formula I as defined above, wherein the compound of formula I is not axitinib, N-methyl-N- (phosphonooxy) methyl-2- ((3- ((E) -2- (2-pyridinyl) vinyl) -1H-indazol-6-yl) thio) benzamide, N-methyl-2- ((3- ((E) -2- (2-pyridinyl) vinyl) -1- (lauroyloxy) methyl-1H-indazol-6-yl) thio) benzamide, N-methyl-N- (phosphonooxy) methyl-2- ((3- ((E) -2- (2-pyridinyl) vinyl) -1- (lauroyloxy) methyl-1H-indazol-6-yl) thio) benzamide, N-methyl-N- (lauroyloxy) methyl-2- ((E) -2- (2-pyridinyl) vinyl) -1-hydroxymethyl-1H-indazol-6-yl) thio) benzamide, N-methyl-2- ((3- ((E) -2- (N- (acetoxy) methylpyridin-2-yl) vinyl) -1- (lauroyloxy) methyl-1H-indazol-6-yl) thio) benzamide chloride, and N-methyl-2- ((3- ((E) -2- (N- (1- (isopropoxycarbonyloxy) -1-ethyl) pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) benzamide chloride.
In a third broad aspect, the invention provides a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier. In some embodiments, the invention provides pharmaceutical compositions comprising a compound of formula I, formula II, or formula III, or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier.
In a fourth broad aspect, the invention provides a method of inhibiting or modulating tyrosine kinase activity in a subject. In some embodiments, the invention provides methods of treating a disease symptom or condition mediated by tyrosine kinase in a subject in need thereof, comprising administering to the subject an effective amount of a compound and/or pharmaceutical composition described above. Non-limiting examples of tyrosine mediated disease conditions or disorders that can be treated in a subject by the methods provided herein include various tumors and cancers. Examples of treatable tumors and cancers include, but are not limited to: renal Cell Carcinoma (RCC), breast cancer, and thyroid cancer. Furthermore, the present invention is useful in the treatment of diseases mediated by tyrosine kinases, excluding ophthalmic diseases.
In some embodiments, 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, e.g., to increase bioavailability, alter the duration of effective plasma concentration, reduce variability in plasma levels, reduce side effects, and/or improve the therapeutic effect of axitinib in a subject as compared to administration of axitinib.
In other embodiments, the compound of formula I, formula II, or formula III and/or a pharmaceutical composition thereof is administered to improve biodistribution, reduce metabolism, and/or extend the therapeutic use of axitinib in a subject as compared to administration of axitinib.
In another embodiment, a compound of formula I, formula II, or formula III and/or a pharmaceutical composition thereof is administered to increase or modulate the half-life of the axitinib by modulating PK properties, thereby reducing or altering the frequency of administration of the compound to a subject, as compared to administration of axitinib.
In some embodiments, the invention provides a method of treating a disease condition or symptom mediated by tyrosine kinase in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula I, formula II, or formula III, or a pharmaceutical composition thereof, thereby treating the disease condition or symptom. In another embodiment, the invention provides a method of treating a tumor or cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula I, formula II or formula III, or a pharmaceutical composition thereof, thereby treating the tumor or cancer.
In another general aspect, the compounds and methods of the invention are used alone in a subject for treating a disease condition or symptom mediated by tyrosine kinase. In some embodiments, for the treatment of a disease condition or symptom mediated by tyrosine kinase in a subject, the compounds and methods of the invention are used in combination with other therapeutic agents or methods, including, but not limited to, apoptosis protein-1 (also known as apoptosis-1, PD-1) and apoptosis ligand 1 (also known as apoptosis protein-1 ligand, PD-L1) inhibitors.
In another broad aspect, the invention provides a kit comprising one or more compounds or pharmaceutical compositions described herein. The kit may further comprise one or more additional therapeutic agents and/or instructions, for example instructions for using the kit to treat a patient suffering from a disease symptom or condition mediated by a tyrosine kinase. Furthermore, the present invention is useful in the treatment of diseases mediated by tyrosine kinases, excluding ophthalmic diseases.
Drawings
For a better understanding of the invention, and to show more clearly how it may be carried into effect, the same will now be further elucidated, by way of example, with reference to the accompanying drawings, which show aspects and features according to embodiments of the invention, wherein:
Fig. 1 shows the concentration of axitinib in plasma as a function of time following oral administration of equimolar doses of axitinib, compound 2, compound 4, compound 12 and compound 13; wherein,, - -x-corresponds to axitinib, respectively compound 2, compound 4, compound 12, and compound 13.
Detailed Description
Definition of the definition
In order to provide a clear and consistent understanding of the terms used in the description of the present invention, some definitions are provided below. Furthermore, unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
When used in conjunction with the term "comprising" in the claims and/or the specification, the use of the word "a" or "an" may mean "one or more", "at least one" and "one or more" as well. Similarly, the word "another" may mean at least a second or a plurality.
The word "comprising" (and any form of comprising, such as "comprising" and "comprises"), "having" (and any form of having, "having", "including" and "containing") as used in this specification and claims is inclusive and open-ended and does not exclude additional unrecited elements or process steps.
The term "about" is used to indicate that the value includes errors in the instruments and methods used in determining the value.
The term "derivative" as used herein is understood to be another compound that is structurally similar and differs in some minor structures.
The present specification relates to a number of chemical terms and abbreviations used by those skilled in the art. However, for the sake of clarity and consistency, definitions of selected terms are provided.
As used herein, the term "substituted" or "having a substituent" means that the parent compound or moiety has at least one substituent group. The term "unsubstituted" or "without substituents" means that the parent compound or moiety has no substituents other than chemical saturation of the undefined valence with a hydrogen atom.
As used herein, "substituent" or "substituent group" refers to a moiety selected from halogen (F, cl, br or I), hydroxy, mercapto, amino, nitro, carbonyl, carboxyl, alkyl, alkoxy, alkylamino, aryl, aryloxy, arylamino, acyl, sulfinyl, sulfonyl, phosphonyl, or other organic moieties conventionally used and accepted in organic chemistry.
The term "alkyl" as used herein refers to saturated hydrocarbons having 1 to 12 carbon atoms, including straight, branched and cyclic alkyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, isopropyl, t-butyl, sec-butyl, isobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. The term alkyl includes unsubstituted alkyl groups and substituted alkyl groups. The term "C 1 -C n Alkyl "(which is)N is an integer from 2 to 12) represents an alkyl group having 1 to the "n" carbon atoms shown. The alkyl residue may be substituted or unsubstituted. In some embodiments, for example, an alkyl group may be substituted with a hydroxyl, amino, carboxyl, carboxylate, amide, carbamate, or aminoalkyl group, or the like.
As used herein, "lower" in "lower aliphatic", "lower alkyl", "lower alkenyl" and "lower alkynyl" means that the moiety has at least one (at least two for alkenyl and alkynyl) and equal to or less than 6 carbon atoms unless the carbon number is limited.
The terms "cycloalkyl", "alicyclic", "carbocycle" and equivalents refer to a group comprising a saturated or partially unsaturated carbocycle in a monocyclic, spiro (sharing one atom) or fused (sharing at least one bond) carbocycle system, wherein the carbocycle system has 3 to 15 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopenten-1-yl, cyclopenten-2-yl, cyclopenten-3-yl, cyclohexyl, cyclohexen-1-yl, cyclohexen-2-yl, cyclohexen-3-cycloheptyl, bicyclo [4,3,0]Nonyl, norbornyl, and the like. The term cycloalkyl includes unsubstituted cycloalkyl and substituted cycloalkyl. The term "C 3 -C n Cycloalkyl "wherein n is an integer from 4 to 15, means cycloalkyl having 3 to the" n "carbon atoms shown in the ring structure. As used herein, unless otherwise indicated, a "lower cycloalkyl" group refers to a group having at least 3 and equal to or less than 8 carbon atoms in its ring structure.
The term cycloalkyl residue as used herein may be a 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 unsaturated cycloalkyl residues, the double bond may be present at any suitable position. The 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 An alkyl group. Examples of substituted cycloalkyl residues are 4-methylcyclohexyl and 2, 3-dimethylcyclopentyl. Examples of parent structures of the bicyclic ring system are norbornane, bicyclo [2.2.1 ]]Heptane, bicyclo [2.2.2]Octane and bicyclo [3.2.1]Octane.
The term "heterocycloalkyl" and equivalents as used herein refers to a radical containing a saturated or partially unsaturated carbocycle having 3 to 15 carbon atoms, including 1 to 6 heteroatoms (e.g., N, O, S, P) or containing heteroatoms (e.g., NH, NRx (Rx is alkyl, acyl, aryl, heteroaryl or cycloalkyl), PO, in a monocyclic, spiro (sharing one atom) or fused (sharing at least one bond) carbocycle system 2 、SO、SO 2 Etc.). The heterocycloalkyl group may be attached to the C or to a heteroatom (e.g., through a nitrogen atom). Examples of heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, tetrahydrodithioanyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazalkyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxapentanyl, thiapentanyl, oxazepinyl, diazanyl, thiazanyl, 1,2,3, 6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxane, 1, 3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothiophenyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo [3,1,0 ]]Hexyl, 3-azabicyclo [ 4.1.0 ]]Heptyl, 3H-indolyl, quinolizinyl, sugar, and the like. The term heterocycloalkyl includes unsubstituted heterocycloalkyl and substituted heterocycloalkyl. The term "C 3 -C n Heterocycloalkyl ", wherein n is an integer from 4 to 15, represents a heterocycloalkyl group having 3 to the" n "atoms shown in the ring structure, including at least one hetero group or atom as defined above. As used herein, unless otherwise indicated, "lower heterocycloalkyl" means having at least 3 and equal to or less than 8 carbon atoms in its cyclic structure. Wherein "oxa ring" as used herein specifically means 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, etc.
The terms "aryl" and "aryl ring" as used herein refer to aromatic groups having "4n+2" electrons (pi) in conjugated single or multiple ring systems (fused or non-fused), and having 6 to 14 ring atoms, wherein n is an integer from 1 to 3. The polycyclic ring system includes at least one aromatic ring. The aryl groups may be directly attached or through C 1 -C 3 Alkyl (also known as arylalkyl or aralkyl) linkages. Examples of aryl groups include, but are not limited to, phenyl, benzyl, phenethyl, 1-phenylethyl, tolyl, naphthyl, biphenyl, terphenyl, indenyl, benzocyclooctenyl, benzocycloheptenyl, azulenyl, acenaphthylenyl, fluorenyl, phenanthryl, anthracenyl, and the like. The term aryl includes unsubstituted aryl and substituted aryl. The term "C 6 -C n Aryl "(where n is an integer from 6 to 15) represents an aryl group having from 6 to the" n "carbon atoms shown in the ring structure, including at least one heterocyclic group or atom as defined above.
The terms "heteroaryl" and "heteroaryl ring" as used herein refer to aromatic groups having "4n+2" electrons (pi) in conjugated monocyclic or polycyclic ring systems (fused or unfused), where n is an integer from 1 to 3, and include one to six heteroatoms (e.g., N, O, S) or heteroatoms (e.g., NH, NRx (Rx is alkyl, acyl, aryl, heteroaryl or cycloalkyl), SO 2 Etc.). The polycyclic ring system includes at least one heteroaromatic ring. Heteroaryl groups may be directly attached or through C 1 -C 3 Alkyl (also known as heteroarylalkyl or heteroaralkyl) linkages. Heteroaryl groups may be attached to a carbon or to a heteroatom (e.g., through a nitrogen atom). Examples of heteroaryl groups include, but are not limited to, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl; isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolidinyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, chromene, isochromene, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, pyrazinyl, triazinyl, isoindolyl, pteridinyl, furanyl, benzofuranyl, benzothiazolyl, benzothienyl, benzothiazolyl, benzeneAnd oxazolyl, quinazolinyl, quinolinyl, quinolinonyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, carbazolyl, phenanthridinyl, acridinyl, perylenyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl, dibenzofuranyl, dibenzothienyl, and the like. The term heteroaryl includes unsubstituted heteroaryl and substituted heteroaryl. The term "C 5 -C n Heteroaryl ", wherein n is an integer from 6 to 15, represents heteroaryl groups having from 5 to the" n "atoms shown in the ring structure, including at least one heterocyclic group or atom as defined above.
The term "heterocycle" or "heterocyclic" as used herein includes heterocycloalkyl and heteroaryl. Examples of heterocycles include, but are not limited to, acridinyl, azecinyl, benzimidazolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzotriazole, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, 4αh-carbazolyl, carbolinyl, chromanyl, chromene, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro [2,3-b ] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, 3H-indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolyl, oxadiazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl; 1,3, 4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazole, pyridinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quininyl, tetrahydrofuranyl, tetrahydroisoquinolyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2, 5-thiadiazinyl, 1,2, 3-thiadiazolyl, 1,2, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, 1,3, 4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 5-triazolyl, 1,3, 4-triazolyl, xanthenyl and the like. The term "heterocycle" includes unsubstituted heterocyclyl and substituted heterocyclyl.
As used herein, the term "amine" or "amino" refers to an unsubstituted or substituted group of the general formula-NR a R b Wherein R is a fragment of a And R is b Each independently is hydrogen, alkyl, aryl or heterocyclyl, or R a And R is b Together with the nitrogen atom to which they are attached form a heterocyclic ring. The term amino refers to a compound or fragment in which at least one carbon or heteroatom is covalently bonded to a nitrogen atom. Thus, the terms "alkylamino" and "dialkylamino" as used herein refer to a compound having one and at least two C's, respectively 1 -C 6 An amine group in which an alkyl group is bonded to a nitrogen atom. The terms "arylamino" and "diarylamino" include at least one or two aryl-bonded groups attached to a nitrogen atom. The term "amide" or "aminocarbonyl" refers to a compound or fragment in which the carbon of the carbonyl or thiocarbonyl group is attached to a nitrogen atom. The term "acylamino" refers to a structure in which an amino group is attached directly to an acyl group.
The term "alkylthio" refers to an alkyl group having a mercapto group attached thereto. Suitable alkylthio groups include groups having from 1 to about 12 carbon atoms, preferably from 1 to about 6 carbon atoms. The term "alkylcarboxy" as used herein refers to an alkyl group having a carboxy group attached thereto.
The term "alkoxy" or "lower alkoxy" as used herein refers to a structure in which an alkyl group is attached to an oxygen atom. Representative alkoxy groups include groups having from 1 to about 6 carbon atoms, such as methoxy, ethoxy, propoxy, t-butoxy, and the like. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, butoxy, pentyloxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, and the like. The term "alkoxy" includes unsubstituted or substituted alkoxy, and perhaloalkoxy and the like.
The term "carbonyl" or "carboxyl" as used herein means compounds and fragments containing a carbon attached to an oxygen atom through a double bond. Examples of carbonyl containing moieties include aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, and the like.
As used herein, the term "acyl" is a carbonyl group having a carbon atom attached to hydrogen (i.e., formyl), an aliphatic radical (C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl groups, e.g. acetyl), cycloalkyl groups (C 3 -C 8 Cycloalkyl group, heterocyclic group (C) 3 -C 8 Heterocycloalkyl and C 5 -C 6 Heteroaryl), aryl (C) 6 Aryl, such as benzoyl). The acyl group may be an unsubstituted or substituted acyl group (e.g., salicyloyl group).
The term "solvate" refers to a physical association of a compound with one or more solvent molecules (whether organic or inorganic). The physical association includes hydrogen bonding. In some cases, the solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice. "solvate" includes solvent compounds in the solution phase and solvates that can be separated. Examples of "solvates" include, but are not limited to, hydrates, ethanolates, methanolates, hemiethanolates, and the like.
"pharmaceutically acceptable salt" of a compound refers to a salt of a pharmaceutically acceptable compound. Salts of desirable compounds (basic, acidic or charged functional groups) may retain or improve the biological activity and properties of the parent compound as defined herein and are not biologically undesirable. Examples of pharmaceutically acceptable salts are mentioned, for example, in Berge et al, "Pharmaceutical Salts", J.Pharm.Sci.66,1-19 (1977), and include, but are not limited to:
(1) Acid addition salts formed by addition of acids to basic or positively charged functional groups, to which inorganic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, carbonates, may be added; or adding an organic acid such as acetic acid, propionic acid, lactic acid, oxalic acid, glycolic acid, pivalic acid, t-butyl acetic acid, beta-hydroxybutyric acid, valeric acid, caproic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, succinic acid, malic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, cyclohexylsulfamic acid, benzenesulfonic acid, sulfanilic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 3-phenylpropionic acid, laurylsulfuric acid, oleic acid, palmitic acid, stearic acid, lauric acid, pamoic acid, pantothenic acid, lactobionic acid, alginic acid, galacturonic acid, gluconic acid, glucoheptonic acid, glutamic acid, naphthoic acid, hydroxynaphthoic acid, salicylic acid, ascorbic acid, stearic acid, muconic acid, and the like.
(2) A base addition salt obtained by adding a base when an acidic proton is present in the parent compound or is substituted with a metal ion; wherein the metal ions include alkaline metal ions (e.g., lithium, sodium, potassium), alkaline earth metal ions (magnesium, calcium, barium) or other metal ions such as aluminum, zinc, iron, etc.; or with an organic base such as ammonia, ethylamine, diethylamine, N' -dibenzylethylenediamine, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, piperazine, chloroprocaine, procaine, choline, lysine, and the like.
Pharmaceutically acceptable salts can be synthesized from the parent compound containing a basic or acidic fragment by conventional chemical methods. Typically, such salts are prepared by reacting a compound (free acid or base) with an isostoichiometric amount of base or acid in water or an organic solvent or in a mixture of both. Salts may be prepared in situ during the final isolation or purification of the pharmaceutical agent or by separately reacting the purified compound of the invention in free acid or base form with the corresponding base or acid desired and isolating the salt formed thereby. The term "pharmaceutically acceptable salts" also includes zwitterionic compounds comprising cationic groups covalently bonded to anionic groups, which are referred to as "inner salts". It is to be understood that all acid, salt, base and other ionic and non-ionic forms of the compounds of the present invention are contemplated as falling within the scope of the present invention. For example, if the compound of the present invention is an acid, the salt form of the compound is also within the scope of the present invention. Also, if the compounds of the present invention are salts, the acid and/or base forms of the compounds are also encompassed within the scope of the present invention.
As used herein, the term "effective amount" refers to the amount or dose of a therapeutic agent (e.g., a compound) that provides a desired therapeutic, diagnostic, or prognostic effect in a subject after administration to the subject in a single dose or multiple doses. The effective amount can be readily determined by the attending physician or diagnostician by known techniques and by observing results obtained under similar circumstances. In determining an effective amount or dose of a compound to be administered, a number of factors are considered, including, but not limited to: the weight, age, and general health of the subject; specific diseases involved; the degree of involvement or severity of the disease or condition to be treated; responses of the subject individual; the particular compound being administered; mode of administration; bioavailability characteristics of the administered formulation; a selected dosage regimen; use of concomitant medications; and other related considerations.
By "pharmaceutically acceptable" is meant that the term describes a drug, pharmaceutical product, inert ingredient, etc., suitable for use in contact with cells or tissues of humans and animals without undue toxicity, incompatibility, instability, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio. Generally refers to compounds or compositions approved or approvable by a regulatory agency of the federal or a state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
By "pharmaceutically acceptable carrier" is meant a diluent, adjuvant, excipient, carrier, or vehicle with which the compound is administered. The terms "pharmaceutically acceptable carrier" and "pharmaceutically acceptable carrier" are used interchangeably herein.
"pharmaceutical composition" is meant to include a compound as described herein, and at least one component, including pharmaceutically acceptable carriers, diluents, adjuvants, excipients or vehicles, such as preserving, bulking, disintegrating, wetting, emulsifying, suspending, sweetening, flavoring, perfuming, antibacterial, antifungal, lubricating, dispersing agents and the like, depending on the mode of administration and the requirements of the dosage form. "preventing" or "prevention" is used to mean at least reducing the likelihood of acquiring a disease or disorder (or susceptibility) to acquire a disease or disorder (i.e., not allowing the clinical symptoms of at least one disease to develop into a patient that may be exposed to or susceptible to the disease but has not experienced or displayed symptoms of the disease).
In some embodiments, "treating" or "treating" any disease or disorder refers to alleviating at least one disease or disorder. In certain embodiments, treatment "or" treatment "refers to alleviation of at least one physical parameter, which may be distinguishable or indistinguishable by the patient. In certain embodiments, "treatment" or "treatment" refers to inhibiting a disease or disorder physically (e.g., stabilization of a discernible symptom) or physiologically (e.g., stabilization of a physical parameter) or both. In certain embodiments, "treatment" or "treatment" refers to an adverse effect of improving quality of life or disease in a subject in need thereof. By "therapeutically effective amount" is meant an amount of a compound administered to a subject for treating or preventing a disease that is sufficient to achieve an effect of treating or preventing the disease. "therapeutically effective amount" will depend on the compound; disease and severity thereof; the age, weight, etc. of the subject to be treated or prevented from suffering from the disease. As used herein, a "therapeutically effective amount" refers to a compound or composition that is sufficient to prevent, treat, inhibit, reduce, alleviate or eliminate one or more etiologies, symptoms, or complications of a disease, such as cancer.
The term "subject" refers to animals, including mammals and humans, and particularly humans.
The term "prodrug" or its equivalent refers to an agent that is converted directly or indirectly to an active form in vitro or in vivo (see, e.g., 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; stilla, 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 alter the biodistribution (e.g., such that the agent does not normally enter the protease reaction site) or pharmacokinetics of a particular drug. Various groups such as esters, ethers, phosphates, and the like have been used to modify compounds to form prodrugs. When the prodrug is administered to a subject, the group is cleaved off enzymatically or non-enzymatically, reduced, oxidized, or hydrolyzed, or otherwise releasing the active compound. As used herein, "prodrug" includes pharmaceutically acceptable salts, or pharmaceutically acceptable solvates, as well as any crystalline form of the above. Prodrugs are typically (although not necessarily) pharmaceutically inactive until they are converted to active forms.
The term "ester" refers to a compound that may be represented by the formula RCOOR (carboxylate) or RSO3R' (sulfonate), and that may generally be formed by the reaction between a carboxylic acid or sulfonic acid, respectively, and an alcohol (elimination of a molecule of water).
The term "ester" means a compound which can be represented by the formula RCOOR' (carboxylate) or by the formula RSO 3 The compounds represented by R' (sulfonate) can generally be formed by the reaction (elimination of one molecule of water) between a carboxylic acid or a sulfonic acid, respectively, and an alcohol. Wherein R and R' are referred to as ester forming groups, R is such as lower alkyl or aryl, e.g., methylene, ethylene, isopropylidene, phenylene, etc., but is not limited thereto; r' is, for example, lower alkyl, cycloalkyl or aryl, such as methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, etc., but is not limited thereto.
The expression "carboxylate-containing hydrocarbyl" is used to denote a structure containing an ester functional group-RCOOR '(R' is typically other than an H group such as an alkyl group) in the fragment. Wherein R is, for example, lower alkyl or aryl, such as methylene, ethylene, isopropylidene, phenylene, etc., but is not limited thereto; r' is, for example, lower alkyl, cycloalkyl or aryl, such as methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, etc., but is not limited thereto.
The expression "carbonate-containing hydrocarbon group" is used to denote the structure of "-ROCOOR '" (R' is typically other than an H group such as an alkyl group). Wherein R is, for example, lower alkyl or aryl, such as methylene, ethylene, isopropylidene, phenylene, etc., but is not limited thereto; r' is, for example, lower alkyl, cycloalkyl or aryl, such as methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, etc., but is not limited thereto.
The term "salt forming moiety" as used herein refers to a moiety capable of forming a salt with an acidic group, such as a carboxyl group, for example, but not limited to, sodium, potassium, tetraethylamine, tetrabutylamine, and the like.
The term "ether" may be represented by the general formula ROR ' (R ' is typically an alkyl group or other non-H group) where R and R ' are referred to as "ether-forming groups" or "ether-forming moieties". Wherein R is, for example, lower alkyl or aryl, such as methylene, ethylene, isopropylidene, phenylene, etc., but is not limited thereto; r' is, for example, lower alkyl or aryl, such as methyl, ethyl, propyl, isopropyl, butyl, phenyl, naphthyl, etc., but is not limited thereto.
The term "amino acid" generally refers to an organic compound that contains both carboxylic acid groups and amino groups. The term "amino acid" includes "natural" and "unnatural" amino acids. In addition, the term amino acid includes O-alkylated amino acids or N-alkylated amino acids, as well as amino acids having a side chain containing nitrogen, sulfur or oxygen (e.g., lys, cys or Ser), where the nitrogen, sulfur or oxygen atom may or may not be acylated or alkylated. The amino acid may be a pure L-isomer or D-isomer, or a mixture of L-and D-isomers, including but not limited to a racemic mixture.
The term "natural amino acid" and equivalent expression refers to an L-amino acid that is typically found in naturally occurring proteins. Examples of 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 (gin), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), beta-alanine (beta-Ala), and gamma-aminobutyric acid (GABA).
The term "unnatural amino acid" refers to any derivative of a natural amino acid, including D-form amino acids, as well as alpha-and beta-amino acid derivatives. The terms "unnatural amino acid" and "not a natural amino acid" are used interchangeably herein. It should be noted that certain amino acids (e.g., hydroxyproline) that may be categorized as unnatural amino acids in the present invention may also be found in certain biological tissues or in certain proteins in nature. Amino acids having many different protecting groups suitable for direct use in solid phase peptide synthesis are commercially available. In addition to the twenty most common natural amino acids, the following exemplary unnatural amino acids and amino acid derivatives (common abbreviations in brackets) can be used in accordance with the invention: 2-aminoadipic acid (Aad), 3-aminoadipic acid (β -Aad), 2-aminobutyric acid (2-Abu), α, β -dehydro-2-aminobutyric acid (8-AU), 1-aminocyclopropane-1-carboxylic Acid (ACPC), aminoisobutyric acid (Aib), 3-aminoisobutyric acid (β -Aib), 2-aminothiazolin-4-carboxylic acid, 5-aminopentanoic acid (5-Ava), 6-aminocaproic acid (6-Ahx), 2-aminoheptanoic acid (Ahe), 8-aminocaprylic acid (8-Aoc), 11-aminoundecanoic acid (11-Aun), 12-aminododecanoic acid (12-Ado), 2-aminobenzoic acid (2-Abz), 3-aminobenzoic acid (3-Abz), 4-aminobenzoic acid (4-Abz), 4-amino-3-hydroxy-6-methylheptanoic acid (aprotinin, sta), aminooxyacetic acid (Aoa), 2-aminotetrahydronaphthalene-2-carboxylic Acid (ATC), 4-amino-5-cyclohexyl-3-hydroxypentanoic acid (acnh) and (acnh-3-p-amino) 2 Phe), 2-aminopimelic acid (Apm), biphenylalanine (Bip), p-bromophenylalanine (4-Br-Phe), o-chlorophenylalanine (2-Cl-Phe), m-chlorophenylalanine (3-Cl-Phe), p-chlorophenylalanine (4-Cl-Phe), m-chlorotyrosine (3-Cl-Tyr), p-benzoylphenylalanine (Bpa), t-butylglycine (TLG), cyclohexylalanine (Cha), cyclohexylglycine (Chg), desmin (Des), 2-diaminopimelic acid (Dpm), 2, 3-diaminopropionic acid (Dpr), 2, 4-diaminobutyric acid (Dbu), 3, 4-dichlorophenylalanine (3, 4-Cl-2-Phe), 3, 4-difluorophenylalanine (3, 4-F2-Phe), 3, 5-diiodotyrosine (3, 5-I2-Tyr), N-ethylglycine (EtGly), N-ethylamide (E)tAsn), o-fluorophenylalanine (2-F-Phe), m-fluorophenylalanine (3-F-Phe), p-fluorophenylalanine (4-F-Phe), m-fluorophenylalanine (3-F-Tyr), homoserine (Hse), homophenylalanine (Hfe), homotyrosine (Htyr), hydroxylysine (Hyl), isohydroxylysine (aHyl), 5-hydroxytryptophan (5-OH-Trp), 3-or 4-hydroxyproline (3-or 4-Hyp), p-iodophenylalanine-iso-tyrosine (3-I-Tyr), indoline-2-carboxylic acid (Idc), iso Ai Dumei hormone (Ide), isoleucine (alpha-Ile), isopiperidine acid (Inp), N-methylisoleucine (Melle), N-methyllysine (MeLys), m-methyltyrosine (3-Me-Tyr), N-methylvaline (Val), 1-naphthylalanine (1-Nal), 2-naphthylalanine (2-Nal), p-nitrophenylalanine (4-NO) 2 Phe), 3-nitrotyrosine (3-NO 2 -Tyr), norleucine (Nle), norvaline (Nva), ornithine (Orn), ortho-phosphotyrosine (H) 2 PO 3 -Tyr), octahydroindole-2-carboxylic acid (Oic), penicillamine (Pen), pentafluorophenylalanine (F5-Phe), phenylglycine (Phg), piperidinic acid (Pip), propargylglycine (Pra), pyroglutamic acid (PGLU), sarcosine (Sar), tetrahydroisoquinoline-3-carboxylic acid (Tic), thiophenylalanine and thiazolidine-4-carboxylic acid (thioproline, th).
For the compounds provided herein, in some embodiments, salts, pharmaceutically acceptable salts thereof are also included. Those skilled in the art will be aware of the many possible salt forms (e.g., TFA salt, tetrazole salt, sodium salt, potassium salt, etc.), and may also select suitable salts based on considerations known in the art. The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases (including inorganic acids and bases and organic acids and bases). For example, for compounds containing basic nitrogen, salts thereof may be prepared with pharmaceutically acceptable non-toxic acids (including inorganic and organic acids). Pharmaceutically acceptable 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, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and the like. When the compound contains an acidic side chain, pharmaceutically acceptable bases suitable for use in the present invention include, but are not limited to, metal salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
In some embodiments, the present invention provides a method of increasing the therapeutic effect of axitinib in a subject in need thereof, the method comprising: an effective amount of a compound of formula I, formula II or formula III, or a pharmaceutical composition thereof, is administered to a subject to increase the therapeutic effect of axitinib as compared to the use of axitinib itself. In some embodiments, the compound is a prodrug of axitinib.
In some embodiments, one or more of the following is improved by administration of a compound provided herein (a prodrug of axitinib) or a pharmaceutical composition thereof, as compared to administration of axitinib itself: the bioavailability of axitinib; AUC of axitinib in blood or plasma; axitinib C max The method comprises the steps of carrying out a first treatment on the surface of the T of Axitinib max The method comprises the steps of carrying out a first treatment on the surface of the T of axitinib 1/2 The method comprises the steps of carrying out a first treatment on the surface of the Therapeutic biodistribution of axitinib; therapeutic levels of axitinib in selected tissues; and/or biological absorption of axitinib in a subject. In some embodiments, one or more of the following is reduced by administering a compound provided herein (a prodrug of axitinib) or a pharmaceutical composition thereof, as compared to administering axitinib itself: metabolism of axitinib in a subject; and side effects of axitinib in a subject.
In some embodiments, the present invention provides methods of obtaining an axitinib target pharmacokinetic parameter in a subject comprising administering to the subject an effective amount of a compound described herein (an axitinib prodrug) or a pharmaceutical composition thereof, thereby obtaining the axitinib target pharmacokinetic parameter in the subject. Non-limiting examples of target pharmacokinetic parameters include target bioavailability, AUC in blood or plasma, C max 、T max Biodistribution, level in selected tissue, half-life (t 1/2 ) Bioadsorption, and metabolic amount or rate. Pharmacokinetic parameters can be calculated using methods known in the art.
Composition and method for producing the same
In one embodiment, a pharmaceutical composition is provided that includes a compound of the invention, e.g., a compound of formula I, formula II, formula III, or a pharmaceutically acceptable salt, ester, solvate, or polymorph thereof, and a pharmaceutically acceptable carrier. In another embodiment, a pharmaceutical composition is provided comprising a compound of table 1, or a pharmaceutically acceptable salt, ester, solvate or polymorph thereof, and a pharmaceutically acceptable carrier therefor. In yet another embodiment, 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 is provided.
Examples
The invention will be more readily understood by reference to the following examples, which are provided to illustrate the invention and should not be construed to limit the scope of the invention in any way.
Unless defined otherwise or the context clearly indicates otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It should be understood that any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention.
Example 1: preparation of N-methyl-2- ((3- ((E) -2- (2-pyridinyl) vinyl) -1- (pivaloyloxy) methyl-1H-indazol-6-yl) thio) benzamide (Compound 1)
To the reaction flask were added axitinib (200 mg,0.518mmol,1.0 eq.) DMF (4 mL), chloromethyl pivalate (94 mg, 0.6271 mmol,1.2 eq.) and triethylamine (104.7 mg,1.03mmol,2.0 eq.). The reaction mixture was stirred at room temperature overnight. TLC showed almost complete consumption of starting axitinib. To the reaction mixture was added water (20 mL) and ethyl acetate (30 mL), and the layers were washed. After the organic layer was separated, it was washed three times with saturated brine (30 mL each time), and then concentrated. The residue was purified by column chromatography on silica gel (dichloromethane: A) Alcohol=100:0 to 100:5) to give compound 1 (80 mg, 30%). 1 H 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)； 13 C 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)。
Example 2: preparation of N-methyl-2- ((3- ((E) -2- (2-pyridinyl) vinyl) -1-hydroxymethyl-1H-indazol-6-yl) thio) benzamide (Compound 2)
To the reaction flask were added axitinib (1 g,2.578mmol,1.0 eq.), DMF (10 mL), triethylamine (789 mg,7.74mmol,3.0 eq.) and 30% aqueous formaldehyde (774 mg,7.74mmol,3.0 eq.). The reaction mixture was stirred at 0 ℃ for 3 hours. TLC showed almost complete consumption of starting axitinib. To the reaction mixture were added water (50 mL) and ethyl acetate (50 mL), and the layers were washed. After separating the organic layer, it was washed three times with saturated brine (50 mL each time) and then concentrated to give compound 2 (1 g, 93%). 1 H NMR(500MHz,DMSO-d 6 ):δppm 2.78(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)； 13 C 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)。
Example 3: preparation of N-methyl-2- ((3- ((E) -2- (2-pyridinyl) vinyl) -1- (benzoyloxy) methyl-1H-indazol-6-yl) thio) benzamide (Compound 3)
To a reaction flask was added compound 2 (200 mg,0.48 mmo)l,1.0 eq.), dichloromethane (4 mL), triethylamine (98 mg,0.97mmol,2.0 eq.) and benzoyl chloride (80.6 mg,0.58mmol,1.2 eq.). The reaction mixture was stirred at room temperature for 5 hours. TLC showed almost complete consumption of starting compound 2. The reaction mixture was concentrated directly, and the obtained residue was separated and purified by a silica gel column (dichloromethane: methanol=100:0 to 100:5) to obtain compound 3 (120.8 mg, 48%). 1 H 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)； 13 C 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)。
Example 4: preparation of N-methyl-2- ((3- ((E) -2- (2-pyridinyl) vinyl) -1- (lauroyloxy) methyl-1H-indazol-6-yl) thio) benzamide (Compound 4)
Lauric acid (500 mg,2.49mmol,1.0 eq.) and thionyl chloride (1.5 ml,2.9g,10 eq.) and DMF (1 drop) were added to the reaction flask, and the reaction mixture was stirred at 78 ℃ for 3 hours and then concentrated to give lauroyl chloride (550 mg, 100%).
To a reaction flask were added compound 2 (200 mg,0.48mmol,1.0 eq.), dichloromethane (4 mL), triethylamine (98 mg,0.97mmol,2.0 eq.) and lauroyl chloride (126 mg,0.58mmol,1.2 eq.) in this order. The reaction was stirred at room temperature overnight. TLC showed almost complete consumption of starting compound 2. The reaction mixture was concentrated directly and the residue was purified with silica gel column (dichloromethane: methanol=100:0 to 100:3) to give compound 4. 1 H 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)； 13 CNMR(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)。
Example 5: preparation of N-methyl-2- ((3- ((E) -2- (2-pyridinyl) vinyl) -1- (tetrahydropyran-2-yl) -1H-indazol-6-yl) thio) benzamide (Compound 5)
To the reaction flask were added axitinib (350 mg,0.91mmol,1.0 eq.), DMF (10 mL), 3, 4-dihydro-2H-pyran (91 mg,1.1mmol,1.2 eq.) and p-toluenesulfonic acid (190 mg,1.0mmol,1.1 eq.). The reaction mixture was stirred at 80℃for 16 hours. TLC plates showed complete consumption of starting axitinib. Water (50 mL) and ethyl acetate (50 mL) were then added to the reaction mixture, and the layers were washed. The organic layer was separated and washed three times with saturated brine (50 mL each) and then concentrated, and the residue was purified with silica gel column (dichloromethane: methanol=100:0 to 100:2) to give compound 5 (300 mg, 70%). 1 H 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)； 13 C 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)。
Example 6: preparation of N-methyl-2- ((3- ((E) -2- (2-pyridinyl) vinyl) -1- (tetrahydrofurane-2-yl) -1H-indazol-6-yl) thio) benzamide (Compound 6)
To the reaction flask were added, in order, axitinib (350 mg,0.91mmol,1.0 eq.) DMF (10 mL), 2, 3-dihydro-2H-furan (96 mg,1.36mmol,1.5 eq.) and p-toluenesulfonic acid (190 mg,1.0mmol,1.1 eq.). Mixing the reactionThe material was stirred at 80 ℃ for 2 hours, TLC showed almost complete consumption of the starting material, axitinib. Water (50 mL) and ethyl acetate (50 mL) were then added to the reaction mixture, and the layers were washed. The organic layer was washed three times with saturated brine (50 mL each) and then concentrated. The residue was purified by silica gel column (dichloromethane: methanol=100:0 to 100:2) to give compound 6 (400 mg, 96%). 1 H 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)； 13 C 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)。
Example 7: preparation of N-methyl-N-hydroxymethyl-2- ((3- ((E) -2- (2-pyridinyl) vinyl) -1H-indazol-6-yl) thio) benzamide (Compound 7)
In a reaction flask were added axitinib (1 g,2.6mmol,1.0 eq.), DMF (15 mL), N- (2- (trimethylsilyl) ethoxycarbonyloxy) succinimide (811 mg,3.1mmol,1.2 eq.) and DBU (593 mg,3.9mmol,1.5 eq.). The mixture was stirred at room temperature for 4h, tlc showed complete consumption of the starting axitinib. Most of the solvent was removed by rotary evaporation, then water (20 mL) and ethyl acetate (30 mL) were added and the layers were washed. The organic layer was washed three times with saturated brine (30 mL each) and then concentrated. The resulting residue was purified by column on silica gel (dichloromethane: methanol=100:0 to 100:3) to give N-methyl-2- ((3- ((E) -2- (2-pyridinyl) vinyl) -1- (3- (trimethylsilyl) propionyloxy) -1H-indazol-6-yl) thio) benzamide (1.1 g, 75%).
N-methyl-2- ((3- ((E) -2- (2-pyridinyl) vinyl) -1- (3- (trimethylsilyl) propionyloxy) -1H-indazol-6-yl) thio) benzamide (1 g,1.9mmol,1.0 eq.) DMF (15 mL), formaldehyde, N- [2- (trimethylsilyl) ethoxycarbonyloxy ] succinimide (560 mg,19mmol,10 eq.) and triethylamine (1.92 g,19mmol,10 eq.) were added to the reaction flask and the mixture stirred at 50℃overnight. Water (20 mL) and ethyl acetate (30 mL) were then added and the layers were washed. The organic layer was separated and washed three times with saturated brine (30 mL each) and then concentrated. The resulting residue was purified on a silica gel column (dichloromethane: methanol=100:0 to 100:3) to give N-methyl-N-hydroxymethyl-2- ((3- ((E) -2- (2-pyridyl) vinyl) -1- (3- (trimethylsilyl) propionyloxy) -1H-indazol-6-yl) thio) benzamide (500 mg, 47%).
The foregoing product (500 mg,0.89mmol,1.0 eq.) was placed in a reaction flask, tetrahydrofuran (10 mL) was then added, and the temperature was reduced to-15 ℃. Then, a tetrahydrofuran solution of TBAF (1 mol/L,0.89mL,1.0 eq.) was added dropwise thereto, and stirring was continued at-15℃for 4 hours. TLC showed complete consumption of starting material. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column (dichloromethane: methanol=100:0 to 100:3) to give mixture 7 (200 mg, 54%). H NMR (500 MHz, 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)； 13 C 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)。
Example 8: preparation of N-methyl-N-benzoyloxymethyl-2- ((3- ((E) -2- (2-pyridinyl) vinyl) -1-tert-butoxycarbonyl-1H-indazol-6-yl) thio) benzamide (Compound 8)
To the reaction flask were added axitinib (1 g,2.6mmol,1.0 eq.), DMF (15 mL), BOC anhydride (678 mg,3.1mmol,1.2 eq.) and triethylamine (390 mg,3.9mmol,1.5 eq.) and the resulting reaction mixture was stirred at room temperature overnight. After most of the solvent was spun off, water (20 mL) and ethyl acetate (30 mL) were added and the layers were washed. The organic layer was washed three times with saturated brine (30 mL each time) and then concentrated. The residue was purified by silica gel column (dichloromethane: methanol=100:0 to 100:3) to give the product N-methyl-2- ((3- ((E) -2- (2-pyridinyl) vinyl) -1-tert-butoxycarbonyl-1H-indazol-6-yl) thio) benzamide (1 g, 77%). The aforementioned product (1 g,2.6mmol,1.0 eq.) was placed in a reaction flask, followed by the sequential addition of DMF (15 mL), formaldehyde (1.5 g,52mmol,20 eq.) and triethylamine (5.2 g,52mmol,20 eq.). After the resulting mixture was stirred at room temperature overnight, water (20 mL) and ethyl acetate (30 mL) were added thereto, and the layers were separated by extraction. The organic layer was separated and washed with saturated brine five times (30 mL each). The washed organic layer was concentrated, and the resulting residue was purified with silica gel column (dichloromethane: methanol=100:0-100:2) to give N-methyl-N-hydroxymethyl-2- ((3- ((E) -2- (2-pyridyl) vinyl) -1-t-butoxycarbonyl-1H-indazol-6-yl) thio) benzamide (800 mg, 61%).
In a reaction flask was added (N-methyl-N-hydroxymethyl-2- ((3- ((E) -2- (2-pyridinyl) vinyl) -1-tert-butoxycarbonyl-1H-indazol-6-yl) thio) benzamide (500 mg,0.97mmol,1.0 eq.), DCM (15 mL), benzoyl chloride (200 mg,3.1mmol,1.2 eq.) and triethylamine (200 mg,1.94mmol,2 eq.) the reaction mixture was stirred at room temperature overnight and then concentrated the resulting residue was purified with a silica gel column (dichloromethane: methanol=100:0 to 100:2) to give mixture 8 (300 mg, 48%). 1 H NMR(500MHz,CD 3 OD):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)； 13 C 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)。
Example 9: preparation of N-methyl-N-benzoyloxymethyl-2- ((3- ((E) -2- (2-pyridinyl) vinyl) -1-tert-butoxycarbonyl-1H-indazol-6-yl) thio) benzamide (Compound 9)
N-methyl-N-hydroxymethyl-2- ((3- ((E) -2- (2-pyridinyl) vinyl) -1- (3- (trimethylsilyl) propionyloxy) -1H-indazol-6-yl) thio) benzamide (see example 7,1g,1.7mmol,1.0 eq.) DCM (15 mL), benzoyl chloride (288 mg,2.04mmol,1.2 eq.) and TEA (258 mg,2.6mmol,1.5 eq.) were added sequentially to the reaction flask. The reaction mixture was stirred at room temperature for 4h and then concentrated. The residue was purified by column on silica gel (dichloromethane: methanol=100:0 to 100:3) to give the product N-methyl-N-benzoyloxymethyl-2- ((3- ((E) -2- (2-pyridinyl) vinyl) -1- (3- (trimethylsilyl) propionyloxy) -1H-indazol-6-yl) thio) benzamide (800 mg, 73%).
The reaction product (500 mg,0.78mmol,1.0 eq.) was placed in a reaction flask, tetrahydrofuran (10 mL) was then added and the temperature was reduced to-15 ℃. A tetrahydrofuran solution of TBAF (1 mol/L,0.78mL,1.0 eq.) was added dropwise with cooling. The reaction mixture was stirred at-15 ℃ for 4h and then concentrated. The resulting residue was purified by silica gel column (dichloromethane: methanol=100:0 to 100:3) to give compound 9 (190 mg, 47%). 1 H NMR(500MHz,CD 3 OD):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)； 13 C 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)。
Example 10: preparation of N-methyl-N-methoxymethyl-2- ((3- ((E) -2- (2-pyridinyl) vinyl) -1H-indazol-6-yl) thio) benzamide (Compound 10)
N-methyl-N-hydroxymethyl-2- ((3- ((E) -2- (2-pyridinyl) vinyl) -1- (3- (trimethylsilyl) propionyloxy) -1H-indazol-6-yl) thio) benzamide (see example 7,1g,1.7mmol,1.0 eq.) MeOH (15 mL) and concentrated hydrochloric acid 0.5mL were added to the reaction flask and the reaction mixture stirred at room temperature for 16H. The reaction mixture was then concentrated and the resulting residue was purified with a silica gel column (dichloromethane: methanol=100:0 to 100:3) to give the intermediate N-methyl-N-methoxymethyl-2- ((3- ((E) -2- (2-pyridinyl) vinyl) -1- (3- (trimethylsilyl) propionyloxy) -1H-indazol-6-yl) thio) benzamide (600 mg, 60%).
The above intermediate (500 mg,0.94mmol,1.0 eq.) was placed in a reaction flask, then added (tetrahydrofuran (10 mL) and cooled to-15 ℃ C. Tetrahydrofuran solution of TBAF (1 mol/L,0.94mL,1.0 eq.) was added dropwise with this cooling, the reaction mixture was stirred for a further 4h at-15 ℃ C. TLC showed complete consumption of starting material, the reaction mixture was concentrated and the residue was purified with a silica gel column (dichloromethane: methanol=100:0-100:3) to give compound 10 (230 mg, 57%). 1 H 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)； 13 C 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)。
Example 11: preparation of N-methyl-2- ((3- ((E) -2- (2-pyridinyl) vinyl) -1- (adamantan-1-acetoxy) methyl-1H-indazol-6-yl) thio) benzamide (Compound 11)
1-adamantaneacetic acid (1 g,5.2mmol,1 eq.) and oxalyl chloride (6.5 g,10.0 eq.) were added to the reaction flask, the mixture was stirred at room temperature for 5 hours, and after spinning dry, 1-adamantaneacetyl chloride (1 g, 91%) was obtained as a white solid, which was used directly in the subsequent reaction.
To the reaction flask were added compound 2 (500 mg,1.2mmol,1.0 eq.), dichloromethane (10 mL), TEA (242 mg,2.4mmol,2.0 eq.) and 1-adamantane acetyl chloride (319 mg,1.44mmol,1.2 eq.). The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was then concentrated directly and the residue was purified with a silica gel column (dichloromethane: methanol=100:0 to 100:5) to give compound 11 (230 mg, 32%). 1 H 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)； 13 C 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)。
Example 12: preparation of N-methyl-2- ((3- ((E) -2- (2-pyridinyl) vinyl) -1- (nicotinoyloxy) methyl-1H-indazol-6-yl) thio) benzamide (Compound 12)
Nicotinic acid (132.9 mg,1.08mmol,1.0 eq.) methylene chloride (10 mL), and DMF (0.05 mL) were added to the reaction flask, and the mixture was cooled with an ice-water bath, followed by dropwise addition of oxalyl chloride (822.5 mg,6.48mmol,6.0 eq.). After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 3 hours, and then the mixture was directly concentrated to give nicotinoyl chloride (152.9 mg, 100%), which was directly used for the subsequent reaction.
In a reaction flask were added compound 2 (300 mg,0.72mmol,1.0 eq.), dichloromethane (10 mL), and triethylamine (219 mg,2.16mmol,3.0 eq.) and cooled in an ice-water bath. To the above mixture was added, while cooling, nicotinoyl chloride (152.9 mg,1.08mmol,1.5 eq.). The resulting reaction mixture was stirred at room temperature overnight. TLC showed complete consumption of starting material. After the reaction mixture was directly concentrated, the residue was purified with a silica gel column (dichloromethane: methanol=100:0 to 100:3) to give compound 12 (250 mg, 66%). 1 H 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)； 13 C 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)。
Example 13: preparation of N-methyl-2- ((3- ((E) -2- (2-pyridinyl) vinyl) -1- (1-methyl-1H-indole-3-formyloxy) methyl-1H-indazol-6-yl) thio) benzamide (Compound 13)
To the reaction flask were added 1-methyl-1H-indole-3-carboxylic acid (378.3 mg,2.16mmol,1.0 eq.) thionyl chloride (1.55 g,12.96mmol,6.0 eq.) and DMF (0.05 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was then concentrated directly to give 1-methyl-1H-indole-3-carbonyl chloride (418.24 mg, 100%).
To the reaction flask were added compound 2 (400 mg,0.96mmol,1.0 eq.), dichloromethane (10 mL), and triethylamine (387.8 mg,3.86mmol,4.0 eq.) and the mixture was cooled under an ice-water bath. 1-methyl-1H-indole-3-carbonyl chloride (278.88 mg,1.44mmol,1.5 eq.) was added to the mixture under cooling, and the reaction mixture was stirred overnight at room temperature. After the reaction mixture was directly concentrated, the residue was purified by a silica gel column (dichloromethane: methanol=100:0 to 100:3) to give compound 13 (235 mg, 42%). 1 H 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)； 13 C 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)。
Example 14: pharmacokinetic experimental method
The experimental animals adopt CD1 mice, male, and the weight is 18 g-22 g. Experimental animals were randomly grouped, 18 per group. Blood samples were collected at 0.5, 1, 2, 4, 6, 8h after dosing, respectively. Preparing a tested compound into an experimental solution or suspension in a solvent, and carrying out gastric administration, wherein the solvent comprises 0.5wt% CMC-Na solution; DMSO:0.5wt% CMC-Na aqueous solution (5/95, v/v); DMSO: etOH:0.5wt% CMC-Na (5/5/90, v/v/v); or EtOH:0.5wt% -CMC-Na (10/90, v/v). The test compound concentrations were all 3mg/mL equivalent of axitinib. Animals were fasted for 12 hours and dosed with 30mg/kg axitinib equivalent for intragastric administration. After administration, whole blood samples were collected from orbital blood collection to heparinized EP tubes at a pre-set time point, centrifuged at 5000rpm for 10min at 4 ℃ and plasma samples were collected and stored at low temperature. 10. Mu.L of plasma sample was taken, 110. Mu.L of acetonitrile was added to precipitate, and after mixing well, the mixture was centrifuged at 12000rpm at 4℃for 10min, and the supernatant was taken for LC-MS/MS analysis. The analytical targets were 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 profile of axitinib in plasma after oral administration of a portion of the compounds is shown in fig. 1: wherein,, -, and-X-each represents an equimolar amount of axitinib administered orally after compound 2, compound 4, compound 12, and compound 13, concentration of axitinib in plasma over time.
TABLE 2 pharmacokinetic parameters of axitinib after administration of the respective prodrugs
* 0.5% CMC-Na; b, 5% DMSO and 95% CMC-Na; 10% EtOH and 90% CMC-Na.
Although the present invention has been described in detail with reference to the embodiments thereof, these embodiments are provided for the purpose of illustration and not limitation of the invention. Other embodiments that can be obtained according to the principles of the present invention fall within the scope of the invention as defined in the claims.
The contents of all documents and documents listed herein are incorporated by reference in their entirety.

Claims (13)

1. Use of a compound of formula I or a pharmaceutically acceptable salt thereof, as shown below, for the manufacture of a medicament for inhibiting tyrosine kinase activity:
wherein:
R 1 is a protecting group;
R 2 is H;
R 3 Absence of;
the protecting group is-CHRaOR;
wherein Ra is H;
r is selected from hydrogen, C1-12 alkylcarbonyl, heteroaryl, and the heteroaryl is selected from pyridyl.
2. Use of a compound of formula I or a pharmaceutically acceptable salt thereof, as shown below, in the manufacture of a medicament for the treatment of a disease condition or symptom mediated by tyrosine kinase:
wherein:
R 1 is a protecting group;
r2 is H;
R 3 absence of;
the protecting group is-CHRaOR;
wherein Ra is H;
r is selected from hydrogen, C1-12 alkylcarbonyl, heteroaryl carbonyl, said heteroaryl being pyridinyl.
3. Use according to claim 1 or 2, wherein the compound is selected from the compounds shown below:
。
4. use according to claim 1 or 2, wherein the use is suitable for mammals.
5. Use according to claim 1 or 2, wherein the use is suitable for use in humans.
6. The use according to claim 2, wherein the disease condition or symptom mediated by tyrosine kinase is a tumour.
7. The use according to claim 2, wherein the disease condition or symptom mediated by tyrosine kinase is breast cancer, renal cell carcinoma and/or thyroid cancer.
8. The use according to claim 1 or 2, wherein the medicament is used in combination with other therapeutic agents.
9. The use of claim 8, wherein the additional therapeutic agent comprises apoptosis protein-1 and an inhibitor of apoptosis ligand 1.
10. A compound of formula I, or a pharmaceutically acceptable salt thereof:
wherein:
R 1 is a protecting group;
R 2 is H;
R 3 absence of;
the protecting group is-CHRaOR;
wherein Ra is H;
r is selected from hydrogen, C1-12 alkylcarbonyl, heteroaryl, and the heteroaryl is selected from pyridyl.
11. The compound of claim 10, wherein the compound is
12. A pharmaceutical composition, the pharmaceutical composition comprising: a compound according to any one of claims 10 to 11 and pharmaceutically acceptable salts thereof; and, a pharmaceutically acceptable carrier.
13. A kit, the kit comprising: at least one compound according to any one of claims 10 to 11, or a pharmaceutical composition according to claim 12; and instructions for use thereof.
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CN103570696B (en) * 2013-11-06 2016-02-24 湖南欧亚生物有限公司 A kind of preparation method of Axitinib intermediate and preparing the application in Axitinib
CN106336397A (en) * 2015-07-07 2017-01-18 郭明山 Novel compound for treating ophthalmic diseases
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WO2006048746A2 (en) * 2004-11-02 2006-05-11 Pfizer Inc. Methods for the removal of heavy metals
CN101044138A (en) * 2004-11-02 2007-09-26 辉瑞有限公司 The preparation method of indazole compound
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