WO2020156189A1 - Camptothecin derivative and water-soluble prodrug thereof, pharmaceutical composition containing same, preparation method, and use - Google Patents

Abstract

The present invention relates to a camptothecin derivative of formula (I), a pharmaceutical composition containing same, a preparation method, an intermediate, and use (in particular, use for treating cancers and/or tumors and related diseases).

Description

Camptothecin derivatives, water-soluble prodrugs thereof, pharmaceutical compositions containing them, and preparation methods and uses thereof Invention field

The present invention relates to camptothecin derivatives and their water-soluble prodrugs, pharmaceutical compositions containing them, preparation methods, intermediates and uses thereof (especially use for the treatment of cancer and/or tumors and related diseases).

Background of the invention

Camptothecin (CPT) is an alkaloid isolated from the bark of the Davidia family plant Camptothecin (CPT) by Wall and Wani in 1958. Subsequently, its structure was confirmed as a five-ring quinoline core compound of the following formula, which is composed of quinoline ring AB, pyrrole ring C, pyridone ring D and α-hydroxylactone ring E, where the 20-position is S structure.

Studies have shown that camptothecin can form a ternary complex with cellular DNA topoisomerase I, thereby inhibiting the unwinding of DNA, causing DNA replication to be blocked, and cell death (Cancer Res.1989.49.6365). Camptothecin and its derivatives have strong anti-tumor activity in animal models such as lung cancer, breast cancer, colorectal cancer, and ovarian cancer (Nature Review Cancer.2006.6.789).

The main disadvantage of camptothecin is its low solubility in water and it is difficult to make medicine. By introducing water-soluble groups or preparing as prodrugs, the solubility is increased to increase the drug potential. In recent years, three camptothecin derivatives have increased their solubility through the above-mentioned methods, and they have finally been approved to be marketed for tumor treatment (Med Res Rev. 2015.35.753). Irinotecan was first approved by the FDA in 1994 and is the first-line treatment for colorectal cancer. Topotecan was first approved by the FDA in 1996 for the treatment of ovarian cancer. Belotecan was approved for the treatment of small cell lung cancer in South Korea in 2005. Structure-activity relationship studies have shown that the lactone ring structure of camptothecin derivatives is an important group for inhibiting topoisomerase I (Nature Review Cancer.2006.6.789), which is closely related to its anti-tumor activity and toxicity. Clinical experiments have found that these compounds have a balance between the closed-loop lactone form and the open-loop carboxylate form in the body. The products of the lactone ring opening will preferentially bind to human plasma albumin (HAS) to form a stable The complex shifts the balance to an open-loop form, which reduces the content of the lactone form with anti-tumor activity in the body and increases the toxic and side effects (Anal Biochem. 1993.212.285).

Summary of the invention

Through a lot of research, the inventor of the present application surprisingly found that the camptothecin derivative represented by formula (I-1) has good activity, its lactone ring is more stable, but its solubility is poor; by formula (I- 1) The introduction of a phosphate fragment into the compound forms a water-soluble prodrug as shown in formula (I), which significantly increases the solubility of the compound and can be quickly converted into the compound shown in formula (I-1) in vivo; Surprisingly, it was found that the water-soluble prodrug has better safety and has obvious drug-making potential.

One aspect of the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein The compound has the structure of formula (I-1):

among them:

R is selected from -C(=O)R ³ , -S(=O)R ³ and -S(=O) ₂ R ³ ; and

R ^{3 is} selected from C _1-6 alkyl, halogenated C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3 to 10-membered heterocyclic group, C _6-10 aryl, and 5-14 membered heteroaryl.

Another aspect of the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein The compound has the structure of formula (I):

among them:

p and q are the number of positive charges carried by R ¹ and R ² respectively, and are each independently selected from 1, 2 and 3;

R ¹ and R ² are each independently selected from hydrogen ion, deuterium ion, metal ion, protonated amine and protonated amino acid;

R is selected from -C(=O)R ³ , -S(=O)R ³ and -S(=O) ₂ R ³ ; and

R ^{3 is} selected from C _1-6 alkyl, halogenated C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3 to 10-membered heterocyclic group, C _6-10 aryl, and 5-14 membered heteroaryl.

Another aspect of the present invention provides a pharmaceutical composition, which comprises a preventive or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N- Oxide, isotope-labeled compound, metabolite or prodrug and one or more pharmaceutically acceptable carriers.

Another aspect of the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or pro The use of the medicine or the pharmaceutical composition of the present invention in the preparation of a medicine for preventing or treating cancer and/or tumors and related disorders.

Another aspect of the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or pro The medicine or the pharmaceutical composition of the present invention is used to prevent or treat cancer and/or tumors and related disorders.

Another aspect of the present invention provides a method for preventing or treating cancer and/or tumors and related disorders, the method comprising administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt or ester thereof to an individual in need thereof , Stereoisomers, polymorphs, solvates, N-oxides, isotope-labeled compounds, metabolites or prodrugs, or the pharmaceutical composition of the present invention.

Another aspect of the present invention provides methods for preparing the compounds of the present invention and related intermediates.

Brief description of the drawings

Figure 1 shows the average drug-time curve of T01-1 and T01 in female rat plasma after intravenous administration of T01-1 and T01.

Figure 2 shows the average drug-time curve of T01-1 and T01 in male rat plasma after intravenous administration of T01-1 and T01.

Detailed description of the invention

definition

Unless otherwise defined below, the meanings of all technical and scientific terms used herein are intended to be the same as those commonly understood by those skilled in the art. The reference to the technology used herein is intended to refer to the technology generally understood in the art, including those technical changes or equivalent technology substitutions obvious to those skilled in the art. Although it is believed that the following terms are well understood by those skilled in the art, the following definitions are still set forth to better explain the present invention.

The terms "including", "including", "having", "containing" or "involving" and other variants herein are inclusive or open-ended, and do not exclude other unlisted elements Or method steps.

As used herein, the term "alkyl" is defined as a linear or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, for example 1 to 6 carbon atoms. For example, as used herein, the term "C _1-6 alkyl" refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl Group, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents Such as halogen substitution (in this case the group is called "haloalkyl") (for example, CH ₂ F, CHF ₂ , CF ₃ , CCl ₃ , C ₂ F ₅ , C ₂ Cl ₅ , CH ₂ CF ₃ , CH ₂ Cl Or -CH ₂ CH ₂ CF _3, etc.). The term "C _1-4 alkyl" refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Sec-butyl or tert-butyl).

As used herein, the term "alkenyl" means a linear or branched monovalent hydrocarbon group that contains one double bond; for example, "C _2-6 alkenyl" is an alkenyl group having 2-6 carbon atoms. The alkenyl group is, for example, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2 -Hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl. When the compound of the present invention contains an alkenylene group, the compound may exist in the form of pure E (entgegen), pure Z (zusammen) or any mixture thereof.

As used herein, the term "alkynyl" refers to a monovalent hydrocarbon group containing one or more triple bonds; for example, "C _2-6 alkynyl" is an alkynyl group having 2 to 6 carbon atoms. The alkynyl group is, for example, ethynyl or propynyl.

As used herein, the term "cycloalkyl" refers to saturated (ie, "cycloalkyl") having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring carbon atoms Or unsaturated (that is, having one or more double bonds and/or triple bonds in the ring) monocyclic or polycyclic hydrocarbon ring, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cycloheptyl, cyclooctyl, cyclononyl, cyclohexenyl, etc.

As used herein, the term "heterocyclyl" means having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring atoms, wherein at least one ring atom is selected from N , O, S, and P heteroatoms and the remaining ring atoms are saturated (ie, heterocycloalkyl) or partially unsaturated (ie, have one or more double bonds and/or triple bonds in the ring) cyclic Group. For example, a "3- to 10-membered heterocyclic group" has 2-9 (such as 2, 3, 4, 5, 6, 7, 8 or 9) ring carbon atoms and is independently selected from N, O and S One or more (for example, 1, 2, 3, or 4) heteroatom saturated or partially unsaturated heterocyclic groups. Examples of heterocyclic groups include, but are not limited to: oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolyl ( dioxolinyl), pyrrolidinyl, pyrrolidinone, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, Piperazinyl or trithianyl. The group also encompasses bicyclic ring systems, including spiro rings, fused or bridged systems (such as 8-azaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 2-nitrogen Heterobicyclo[2.2.2]octane etc.). The heterocyclyl group may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) suitable substituents.

As used herein, the term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π-electron system. For example, as used herein, the term "C _6-10 aryl" means an aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl. The aryl group is optionally substituted with 1 or more (such as 1 to 3) suitable substituents (e.g. halogen, -OH, -CN, -NO ₂ , C _1-6 alkyl, etc.).

As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic aromatic ring system, for example, "5-14 membered heteroaryl" means that it has 5, 6, 8, 9, 10, 11 , 12, 13 or 14 ring atoms, especially 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and it contains at least one heteroatom which may be the same or different (the heteroatom is for example Oxygen, nitrogen, or sulfur), and, in addition, may be benzo-fused in each case. Examples of "heteroaryl" include, but are not limited to: thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, three Azolyl, thiadiazolyl, etc., and their benzo derivatives; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives.

As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

The term "substitution" means that one or more (eg, one, two, three or four) hydrogens on the specified atom are replaced by a selection from the indicated group, provided that no more than the specified atom is present In the case of normal valence and the substitution forms a stable compound. Combinations of substituents and/or variables are only permissible when such combinations form stable compounds.

If a substituent is described as "optionally substituted," the substituent can be (1) unsubstituted or (2) substituted. If the carbon of a substituent is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the carbon (to the extent of any hydrogen present) may be independently and/or together independently Optional substitution of optional substituents. If the nitrogen of a substituent is described as being optionally substituted with one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogens present) can each be independently selected optionally Substituent substitution.

If substituents are described as being "independently selected from" a group, then each substituent is selected independently of the other. Therefore, each substituent may be the same or different from another (other) substituent.

As used herein, the term "one or more" means one or more than one under reasonable conditions, such as two, three, four, five, or ten.

Unless otherwise specified, as used herein, the point of attachment of a substituent can be from any suitable position of the substituent.

The present invention also includes all pharmaceutically acceptable isotope-labeled compounds, which are the same as the compounds of the present invention, except that one or more atoms have the same atomic number but the atomic mass or mass number is different from the predominant atomic mass in nature. Or atomic substitution of mass number. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (such as deuterium ( ² H), tritium ( ³ H)); isotopes of carbon (such as ¹¹ C, ¹³ C, and ¹⁴ C) ; Isotopes of chlorine (such as ³⁶ Cl); isotopes of fluorine (such as ¹⁸ F); isotopes of iodine (such as ¹²³ I and ¹²⁵ I); isotopes of nitrogen (such as ¹³ N and ¹⁵ N); isotopes of oxygen (such as ¹⁵ O , ¹⁷ O and ¹⁸ O); phosphorus isotopes (such as ³² P); and sulfur isotopes (such as ³⁵ S). Certain isotope-labeled compounds of the invention (such as those incorporating radioisotopes) can be used in drug and/or substrate tissue distribution studies (such as analysis). The radioisotopes tritium (ie ³ H) and carbon-14 (ie ¹⁴ C) are particularly useful for this purpose because they are easy to incorporate and easy to detect. Substitution with positron emission isotopes (such as ¹¹ C, ¹⁸ F, ¹⁵ O, and ¹³ N) can be used to test substrate receptor occupancy in positron emission tomography (PET) studies. The isotopically-labeled compounds of the present invention can be prepared by methods similar to those described in the attached routes and/or examples and preparations by using appropriate isotopically-labeled reagents instead of previously used non-labeled reagents. The pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be replaced by isotope, for example, D ₂ O, acetone-d ₆ or DMSO-d ₆ .

The term "stereoisomer" means an isomer due to at least one asymmetric center. In compounds with one or more (for example, one, two, three, or four) asymmetric centers, it can produce racemic mixtures, single enantiomers, diastereomeric mixtures and individual The diastereomers. Certain individual molecules can also exist as geometric isomers (cis/trans). Similarly, the compounds of the present invention may exist in a mixture of two or more structurally different forms (commonly referred to as tautomers) in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait. It should be understood that the scope of the present application covers all such items in any ratio (for example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%). %) isomers or mixtures thereof.

Solid lines can be used in this article

Solid wedge

Virtual wedge

Depicts the chemical bonds of the compounds of the invention. The use of a solid line to depict the bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers at that carbon atom (e.g., specific enantiomers, racemic mixtures, etc.) are included. The use of real or imaginary wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the stereoisomers shown exist. When present in a racemic mixture, use real and imaginary wedges to define relative stereochemistry, rather than absolute stereochemistry. Unless otherwise specified, the compounds of the present invention are intended to be stereoisomers (which include cis and trans isomers, optical isomers (such as R and S enantiomers), diastereomers, Geometric isomers, rotamers, conformational isomers, atropisomers and mixtures thereof) exist. The compounds of the present invention can exhibit more than one type of isomerism, and are composed of mixtures thereof (for example, racemic mixtures and diastereomeric pairs).

The present invention covers all possible crystalline forms or polymorphs of the compounds of the present invention, which can be a single polymorph or a mixture of more than one polymorph in any ratio.

It should also be understood that certain compounds of the present invention may exist in free form for treatment, or, when appropriate, in the form of their pharmaceutically acceptable derivatives. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites or prodrugs, which are given to patients in need thereof. After medication, the compound of the present invention or its metabolite or residue can be directly or indirectly provided. Therefore, when the "compound of the present invention" is referred to herein, it is also intended to encompass the above-mentioned various derivative forms of the compound.

The pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.

Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts.

Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts.

For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.

As used herein, the term "ester" means an ester derived from each compound of the general formula in this application, which includes physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the free acid or alcohol form of the present invention Compound). The compound of the present invention may itself be an ester.

The compound of the present invention may exist in the form of a solvate (preferably a hydrate), wherein the compound of the present invention contains a polar solvent as a structural element of the compound crystal lattice, in particular, for example, water, methanol or ethanol. The amount of polar solvent, especially water, can be present in a stoichiometric or non-stoichiometric ratio.

Those skilled in the art will understand that since nitrogen requires available lone pairs of electrons to oxidize to oxides, not all nitrogen-containing heterocycles can form N-oxides; those skilled in the art will recognize that N-oxides can be formed. Nitrogen-containing heterocycle. Those skilled in the art will also recognize that tertiary amines can form N-oxides. The synthetic methods for the preparation of heterocyclic and tertiary amine N-oxides are well known to those skilled in the art, including the use of peroxyacids such as peroxyacetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl Hydrogen peroxide such as tert-butyl hydroperoxide, sodium perborate, and dioxirane such as dimethyldioxirane oxidize heterocycles and tertiary amines. These methods for the preparation of N-oxides have been extensively described and reviewed in the literature, see for example: TLGilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750; AR Katritzky and AJ Boulton, Eds., Academic Press ; And GWHCheeseman and ESGWerstiuk, Advances in Heterocyclic Chemistry, vol.22, pp 390-392, ARKatritzky and AJBoulton, Eds., Academic Press.

Also included within the scope of the present invention are metabolites of the compounds of the present invention, that is, substances formed in the body when the compounds of the present invention are administered. Such products can be produced by, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound. Therefore, the present invention includes metabolites of the compounds of the present invention, including compounds produced by a method in which the compounds of the present invention are contacted with a mammal for a time sufficient to produce their metabolites.

The present invention further includes within its scope the prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity when administered to or on the body. It can be converted into the compound of the present invention having the desired activity by, for example, hydrolytic cleavage. Generally such prodrugs will be functional group derivatives of the compound, which are easily converted into the desired therapeutically active compound in vivo. For other information about the use of prodrugs, please refer to "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella). The prodrugs of the present invention can be used, for example, by using certain parts known to those skilled in the art as "pro-moiety (for example, "Design of Prodrugs", described in H. Bundgaard (Elsevier, 1985))" It is prepared by substituting appropriate functional groups existing in the compounds of the present invention.

The present invention also encompasses compounds of the present invention containing protecting groups. In any process of preparing the compounds of the present invention, protection of sensitive groups or reactive groups on any relevant molecule may be necessary and/or desirable, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, such as those described in T.W. Greene & P.G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, these references are incorporated herein by reference. Using methods known in the art, the protecting group can be removed at an appropriate subsequent stage.

The term "about" means within ±10% of the stated value, preferably within ±5%, more preferably within ±2%.

Compound

In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, or prodrug thereof , Wherein the compound has the structure of formula (I-1):

among them:

R is selected from -C(=O)R ³ , -S(=O)R ³ and -S(=O) ₂ R ³ ; and

R ^{3 is} selected from C _1-6 alkyl, halogenated C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3 to 10-membered heterocyclic group, C _6-10 aryl, and 5-14 membered heteroaryl group, preferably, R ³ is methyl or phenyl.

In a preferred embodiment, the compound of formula (I-1) is selected from:

In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound metabolite or prodrug thereof, The compound has the structure of formula (I):

among them:

p and q are the number of positive charges carried by R ¹ and R ² respectively, and are each independently selected from 1, 2 and 3;

R ¹ and R ² are each independently selected from hydrogen ion, deuterium ion, metal ion, protonated amine and protonated amino acid;

R is selected from -C(=O)R ³ , -S(=O)R ³ and -S(=O) ₂ R ³ ; and

R ^{3 is} selected from C _1-6 alkyl, halogenated C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3 to 10-membered heterocyclic group, C _6-10 aryl, and 5-14 membered heteroaryl.

In some embodiments, when the compound of formula (I) is administered (for example, intravenous or oral administration), it can be converted into the compound of formula (I-1) by the action of phosphatase.

In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, or prodrug thereof , Wherein the metal ion is selected from alkali metal ions (such as lithium ion, sodium ion or potassium ion), alkaline earth metal ion (such as magnesium ion or calcium ion) and aluminum ion; the amine is selected from N-methylglucamine , Tromethamine, ethanolamine, triethanolamine and triethylamine; and the amino acid is selected from arginine and lysine.

In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, or prodrug thereof , Where R ³ is methyl or phenyl.

In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, or prodrug thereof , Where R is -C(=O)CH ₃ , -S(=O) ₂ CH ₃ , -S(=O) ₂ Ph or -C(=O)Ph.

In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, or prodrug thereof , Where R ¹ and R ² are both hydrogen ions.

The present invention covers any combination of the above embodiments.

In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, or prodrug thereof , Wherein the compound is selected from:

Synthetic methods and intermediates

In some embodiments, the present invention provides a method of preparing the compound of formula (I-1),

Where R is as defined above;

The method includes combining belotecan hydrochloride with a reagent capable of introducing R groups (such as RX, where X is a halogen, such as chlorine, bromine, or iodine) under appropriate conditions (such as in a base (such as triethylamine) In the presence), the compound of formula (I-1) is obtained.

In other embodiments, the present invention provides methods for preparing compounds of formula (I),

among them:

Y is a phosphono protecting group, preferably selected from benzyl, tert-butyl and allyl;

The remaining groups are as defined above;

The reaction conditions of each step are as follows:

Step 1: Combine belotecan hydrochloride with a reagent that can introduce R groups (such as RX, where X is a halogen, such as chlorine, bromine or iodine) under appropriate conditions (such as in a base (such as triethylamine) In the presence of) react to obtain a compound of formula (I-1);

The second step: reacting the compound of formula (I-1) with dimethyl sulfoxide in the presence of acetic anhydride and acetic acid to obtain the compound of formula (I-2);

The third step: the compound of formula (I-2) with N-halosuccinimide (for example, N-iodosuccinimide) and a reagent of formula HOP(=O)(OY) ₂ (for example, phosphoric acid two Benzyl ester) to obtain the compound of formula (I-3);

Step 4: Remove the Y group in the compound of formula (I-3) (for example, when Y is a benzyl group, remove the benzyl group by catalytic hydrogenolysis (for example, by Pd/C catalysis)) to obtain Compound of formula (I).

In some embodiments, the present invention provides a compound of formula (I-2) or a pharmaceutically acceptable salt thereof:

among them:

R is selected from -C(=O)R ³ , -S(=O)R ³ and -S(=O) ₂ R ³ ; and

R ^{3 is} selected from C _1-6 alkyl, halogenated C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3 to 10-membered heterocyclic group, C _6-10 aryl, and 5-14 membered heteroaryl;

Preferably, the compound is selected from:

In some embodiments, the present invention provides a compound of formula (I-3) or a pharmaceutically acceptable salt thereof:

among them:

R is selected from -C(=O)R ³ , -S(=O)R ³ and -S(=O) ₂ R ³ ;

R ^{3 is} selected from C _1-6 alkyl, halogenated C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3 to 10-membered heterocyclic group, C _6-10 aryl, and 5-14 membered heteroaryl group; and

Y is a phosphono protecting group, preferably selected from benzyl, tert-butyl and allyl;

Preferably, the compound is selected from:

Pharmaceutical composition and treatment method

In some embodiments, the present invention provides a pharmaceutical composition comprising a preventive or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxides, isotope-labeled compounds, metabolites or prodrugs, and one or more pharmaceutically acceptable carriers. The pharmaceutical composition is preferably a solid preparation, a semi-solid preparation, a liquid preparation or a gaseous preparation. In some embodiments, the pharmaceutical composition may also include one or more other therapeutic agents. In a preferred embodiment, the pharmaceutical composition is preferably administered by oral, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal route.

In some embodiments, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite thereof Or the use of the prodrug or the pharmaceutical composition of the present invention in the preparation of a medicament for the prevention or treatment of cancer and/or tumors and related disorders.

In some embodiments, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite thereof Or a prodrug or a pharmaceutical composition of the present invention, which is used to prevent or treat cancer and/or tumors and related disorders.

In some embodiments, the present invention provides a method of preventing or treating cancer and/or tumors and related disorders, the method comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to an individual in need thereof , Esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically-labeled compounds, metabolites or prodrugs, or the pharmaceutical composition of the present invention.

In some embodiments, the cancer and/or tumor and related disorders are preferably native to the esophagus, stomach, intestine, rectum, oral cavity, pharynx, larynx, lung, colon, breast, uterus, endometrium, ovary, prostate, testis , Bladder, kidney, liver, pancreas, bone, connective tissue, skin, eye, brain and central nervous system cancer, as well as thyroid cancer, leukemia, Hodgkin’s disease, lymphoma and myeloma.

In the present invention, "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle administered with the therapeutic agent, and it is suitable for contact with humans and/or within the scope of reasonable medical judgment Tissues of other animals without excessive toxicity, irritation, allergic reactions, or other problems or complications corresponding to a reasonable benefit/risk ratio.

The pharmaceutically acceptable carriers that can be used in the pharmaceutical composition of the present invention include, but are not limited to, sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, and minerals. Oil, sesame oil, etc. When the pharmaceutical composition is administered intravenously, water is an exemplary carrier. It is also possible to use physiological saline and aqueous glucose and glycerol solutions as liquid carriers, especially for injections. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene glycol, water, Ethanol, etc. The composition may also contain small amounts of wetting agents, emulsifiers or pH buffering agents as needed. Oral preparations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

The pharmaceutical composition of the present invention can act systemically and/or locally. For this purpose, they can be administered by a suitable route, such as by injection (such as intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including drip) or transdermal administration; or by oral, buccal, or transdermal Administration is nasal, transmucosal, topical, in the form of ophthalmic preparations or by inhalation.

For these administration routes, the pharmaceutical composition of the present invention can be administered in a suitable dosage form.

The dosage form includes but not limited to tablet, capsule, lozenge, hard candy, powder, spray, cream, ointment, suppository, gel, paste, lotion, ointment, aqueous suspension , Injectable solutions, elixirs, syrups.

The term "effective amount" as used herein refers to the amount of a compound that will relieve one or more symptoms of the condition being treated to a certain extent after being administered.

The dosage regimen can be adjusted to provide the best desired response. For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgent need of the treatment situation. It should be noted that the dose value may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It should be further understood that for any particular individual, the specific dosing regimen should be adjusted over time according to the needs of the individual and the professional judgment of the person administering the composition or supervising the administration of the composition.

The amount of the compound of the present invention administered will depend on the individual being treated, the severity of the disorder or condition, the rate of administration, the treatment of the compound, and the judgment of the prescribing physician. Generally, the effective dose is about 0.0001 to about 50 mg per kg body weight per day, for example, about 0.01 to about 10 mg/kg/day (single or divided administration). For a 70 kg person, the total is about 0.007 mg/day to about 3500 mg/day, for example, about 0.7 mg/day to about 700 mg/day. In some cases, a dose level not higher than the lower limit of the aforementioned range may be sufficient, while in other cases, a larger dose may still be used without causing any harmful side effects, provided that the larger The dose is divided into several smaller doses to be administered throughout the day.

The content or amount of the compound of the present invention in the pharmaceutical composition can be about 0.01 mg to about 1000 mg.

Unless otherwise specified, as used herein, the term "treating" means reversing, alleviating, or inhibiting the progression of one or more symptoms of the disorder or condition to which such term is applied, Or prevent such a disorder or condition or one or more symptoms of such a disorder or condition.

"Individual" as used herein includes human or non-human animals. Exemplary human individuals include human individuals (referred to as patients) or normal individuals suffering from diseases such as those described herein. In the present invention, "non-human animals" include all vertebrates, such as non-mammals (such as birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals and/or domesticated animals (such as sheep, dogs). , Cats, cows, pigs, etc.).

In some embodiments, the pharmaceutical composition of the present invention may also include one or more additional therapeutic or preventive agents.

detailed description

Example

The present invention is further described below in conjunction with examples and experimental examples, but the provision of these examples is not intended to limit the scope of the present invention.

The structure of the compound was confirmed by nuclear magnetic resonance spectroscopy ( ¹ H NMR) or mass spectrometry (MS).

The measuring instrument for nuclear magnetic resonance spectroscopy ( ¹ H NMR) is a Bruker 400MHz nuclear magnetic resonance instrument; the measuring solvent is hexa-deuterated dimethyl sulfoxide (DMSO-d ₆ ); the internal standard substance is tetramethylsilane (TMS).

The meanings of abbreviations in NMR spectrum are as follows: s: singlet; d: doublet; t: triplet; q: quartet; dd: double doublet; qd: quadruple doublet; ddd: double doublet Peak; ddt: double double triplet; dddd: double double double doublet; m: multiplet; br: broad peak; J: coupling constant; Hz: Hertz.

The chemical shift (δ) is given in units of parts per million (ppm).

The measuring instrument for mass spectrometry (MS) is Agilent (ESI) mass spectrometer, the model is Agilent 6120B.

The preparative chromatographic conditions used in the following examples are as follows:

Method A:

Model of preparative chromatography instrument: GeLai;

Preparation column: C18 ODS (10μm*150mm*450mm);

Mobile phase A: acetonitrile; mobile phase B: ultrapure water (containing 0.05% NH ₄ HCO ₃ )

Time (min)	Mobile phase A[%]	Mobile phase B [%]	Flow rate [ml/min]
0.00	40.0	60.0	300
50.00	90.0	10.0	300

Method B:

Preparative chromatography instrument model: Agilent Prep;

Preparation column: Waters XBridge Prep C18 OBD (5μm*19mm*150mm);

Mobile phase A: acetonitrile; mobile phase B: ultrapure water (containing 0.05% TFA)

Time (min)	Mobile phase A[%]	Mobile phase B [%]	Flow rate [ml/min]
0.00	30.0	70.0	twenty four
15.00	60.0	40.0	twenty four

The abbreviations in this article have the following meanings:

Example 1: (S)-((4-ethyl-11-(2-(N-isopropylmethylsulfonylamino)ethyl)-3,14-dioxo-3,4,12, 14-Tetrahydro-1H-pyrano[3',4': 6,7]indazino[1,2-b]quinolin-4-yl)oxy)methyl dihydrogen phosphate (T01) Synthesis

Step 1: (S)-N-(2-(4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3', 4': Synthesis of 6,7] indazino[1,2-b]quinolin-11-yl)ethyl)-N-isopropyl methanesulfonamide (T01-1)

Methanesulfonyl chloride (462mg, 12.77mmol, purity about 70%) was added dropwise to a solution of belotecan hydrochloride (3.00g, 6.38mmol) and triethylamine (2.60g, 25.54mmol) in dichloromethane (40mL), React for 2h at room temperature. The reaction solution was suction filtered, and the filter cake was washed three times with dichloromethane (3 mL) to obtain the title compound (2.20 g).

The structural characterization data are as follows:

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.32 (d, J = 8.4 Hz, 1H), 8.20 (dd, J = 8.4, 1.2 Hz, 1H), 7.93-7.84 (m, 1H), 7.79 ( t, J = 7.6 Hz, 1H), 7.35 (s, 1H), 6.56 (s, 1H), 5.44 (d, J = 9.2 Hz, 4H), 3.98 (p, J = 6.7 Hz, 1H), 3.50 ( t, J = 8.0 Hz, 2H), 3.42-3.35 (m, 2H), 3.00 (s, 3H), 1.93-1.82 (m, 2H), 1.15 (d, J = 6.7 Hz, 6H), 0.88 (t , J=7.3Hz, 3H).

ESI-MS (m/z): 512.2 [M+H] ⁺ .

Step 2: (S)-N-(2-(4-ethyl-4-((methylthio)methoxy)-3,14-dioxo-3,4,12,14-tetrahydro- 1H-pyrano[3',4': 6,7] indazino[1,2-b]quinolin-11-yl)ethyl)-N-isopropyl methanesulfonamide (T01-2) Synthesis

At 25°C, Ac ₂ O (94.00 mL) and AcOH (26.10 mL) were sequentially added to a DMSO (188 mL) solution of compound (T01-1) (5.00 g, 9.77 mmol), and replaced with nitrogen three times. The reaction solution was stirred at this temperature for 75h, the reaction was stopped, and the mixture was allowed to stand for 30 min. A yellow insoluble matter precipitated. The reaction solution was poured into ice water (2200ml) and stirred for 30min. The reaction solution was suction filtered through a Buchner funnel, and the filter cake was washed with ice water (800ml*3) and dried to obtain compound (T01-2) (5.43g).

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.32 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 8.4, 1H), 7.86 (t, J = 8 Hz 1H), 7.81-7.77 ( t, J = 8 Hz, 1H), 7.21 (s, 1H), 7.46-7.13 (m, 4H), 4.57-4.51 (q, J = 11.2 Hz, 2H), 4.02-3.95 (m, 1H), 3.53- 349(m, 2H), 3.39-3.36(m, 2H), 3.00(s, 3H), 2.19(s, 3H), 2.14-2.06(m, 2H), 1.15(d, J=6.7Hz, 6H) , 0.88 (t, J=7.3Hz, 3H).

ESI-MS (m/z): 572.1 [M+H] ⁺ .

Step 3: (S)-(((4-ethyl-11-(2-(N-isopropylmethylsulfonylamino)ethyl)-3,14-dioxo-3,4,12, 14-Tetrahydro-1H-pyrano[3',4': 6,7]indazino[1,2-b]quinolin-4-yl)oxy)methyl)dibenzyl phosphate (T01 -3) Synthesis

At 25° C., to a solution of compound (T01-2) (10.43 g, 18.26 mmol), N-iodosuccinimide (14.38 g, 63.91 mmol) in anhydrous DCM (200 mL) was added freshly dried

Molecular sieve (4g), nitrogen replacement 3 times, stirring for 30 min. Add a solution of dibenzyl phosphate (17.78g, 63.91mmol) in anhydrous THF (70mL)

Molecular sieve (5g), stirring for 30min. In a nitrogen atmosphere, the THF solution of dibenzyl phosphate was transferred to the mixed solution of compound (T01-2), replaced with nitrogen three times, and the reaction was continued while maintaining at 25°C. After reacting for 5 hours, the reaction solution was filtered, the filter cake and

The molecular sieve was washed with DCM (50ml*3), the filtrate was spin-dried, and the residue was passed through preparative chromatography (preparative chromatography method A) to obtain the title compound (10.83g).

Retention time: 39.4min.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.32 (d, J = 10 Hz, 1H), 8.05 (d, J = 8, 1H), 7.83-7.76 (m, 2H), 7.38-7.25 (m, 11H), 5.48-5.17 (d, J=4, 2H), 5.43-5.33 (m, 3H), 5.25-5.21 (q, J=6, 1H), 5.13-5.10 (m, 2H), 5.06-5.03 (m, 2H), 3.55-344(m, 2H), 3.38-3.34(m, 2H), 3.00(s, 3H), 2.14-2.04(m, 2H), 1.15(d, J=6.7Hz, 6H ), 0.88(t, J=7.3Hz, 3H).

ESI-MS (m/z): 802.1[M+H] ⁺ .

Step 4: (S)-((4-ethyl-11-(2-(N-isopropylmethylsulfonylamino)ethyl)-3,14-dioxo-3,4,12,14 -Tetrahydro-1H-pyrano[3',4': 6,7]indazino[1,2-b]quinolin-4-yl)oxy)methyl dihydrogen phosphate (T01) synthesis

At 25°C, compound (T01-3) (3.10g, 3.87mmol) was dissolved in a mixture of tetrahydrofuran (150ml) and water (15ml), 10% Pd/C (3.10g) was added, and replaced by a hydrogen balloon Gas three times and react for 2 hours. The reaction solution was filtered, and the filtrate was spin-dried. The target compound (0.79 g) was purified by preparative chromatography (preparative chromatography method B).

Retention time: 11.5min.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.33 (d, J = 8 Hz, 1H), 8.23 (d, J = 8, 1H), 7.91-7.87 (t, J = 7.9, 1H), 7.81 7.77(t, J=8, 1H), 7.33(s, 1H), 5.47-5.43(d, 16H), 5.28-5.24(m, 1H), 5.07-5.04(m, 1H), 4.02-3.96(m , 1H), 3.53-3.49 (m, 2H), 3.40-3.36 (m, 2H), 3.00 (s, 3H), 2.18-2.09 (m, 2H), 1.15 (d, J=6.7Hz, 6H), 0.88(t, J=7.3Hz, 3H).

ESI-MS (m/z): 622.1 [M+H] ⁺ .

Experimental example 1: Determination of solubility

Refer to the high performance liquid chromatography (Chinese Pharmacopoeia 2015 edition of the four general rules 0512) determination.

Instrument: high performance liquid chromatography

Chromatographic conditions: octadecylsilane bonded silica gel as filler (Agilent poroshell 120 SB-C18, 4.6mm×100mm, 2.7μm);

Mobile phase A: water (containing 0.05% trifluoroacetic acid)-acetonitrile (90:10);

Mobile phase B: Acetonitrile (containing 0.03% trifluoroacetic acid);

The elution gradient is as follows:

Injection volume: 20μl; column temperature: 40°C; flow rate: 1.0ml/min; detection wavelength: 240nm;

The preparation process of the test solution is as follows:

Buffer: Weigh 3.00g NaH ₂ PO _{4 and} dissolve it in 500mL ultrapure water, adjust the pH to 7.00 with NaOH solution, add 3.15g NaCl, shake well, and get it. The pH of the resulting buffer was measured to be 6.86.

T01-1 (0.9% NaCl): Weigh 10.18 mg of T01-1 into a 10 ml vial, add 5 mL of 0.9% NaCl solution with a 5 ml syringe, shake for a while, then sonicate it with an ultrasonic instrument for 1 min, take it out, and put it in a magnetic Put on a rubber stopper, place it on a magnetic stirrer and stir for 30 min, take it out, filter with a 0.22 μm filter membrane (polyethersulfone), and take the filtrate for sample analysis.

Use the same method to prepare T01-1 (pH 6.86 buffer).

T01 (0.9% NaCl): Weigh 10.18 mg of T01 and place it in a 10 ml vial, add 5 mL of 0.9% NaCl solution with a 5 ml syringe, shake for a while, then sonicate it with an ultrasonic instrument for 1 min, take it out, put in a magnet, and stopper The rubber stopper is placed on a magnetic stirrer and stirred for 30 minutes, then taken out, accurately measure 1 mL and place it in a 20 ml volumetric flask, dilute with 0.9% NaCl solution and dilute to the mark, shake well, and analyze the sample.

T01 (pH 6.86 buffer): Weigh 30 mg of T01 into a 20ml vial, add 10 mL of pH 6.86 buffer with a 20ml syringe, shake for a while, then sonicate it with an ultrasound for 1 min, take it out, put in the magnet, and stopper The rubber stopper is placed on a magnetic stirrer and stirred for 30 minutes. Take it out, accurately measure 1mL and place it in a 20ml volumetric flask, dilute with pH 6.86 buffer and dilute to the mark, shake well, and then analyze.

The preparation process of the reference solution is as follows:

T01-1 control stock solution (concentration about 0.15mg/ml): Weigh 1.506mg of T01-1 and place it in a 10ml volumetric flask, dissolve in acetonitrile-water (50:50) (v/v) ultrasonically and dilute to the mark. Shake well.

T01-1 control solution 1 (0.9% NaCl): Measure the T01-1 control stock solution and dilute with 0.9% NaCl solution to make T01-1 0.012mg per ml.

Prepare T01-1 control solution 2 (pH 6.86 buffer) in the same way.

T01 control solution 1 (0.9% NaCl): accurately weigh T01 and dilute with 0.9% NaCl solution to make 0.15 mg of T01 per ml.

Prepare T01 control solution 2 (pH 6.86 buffer) in the same way.

Accurately measure 20μl of the reference solution and the test solution into the liquid chromatograph, and record the chromatogram.

According to HPLC detection, the solubility of the test compound in 0.9% NaCl solution and NaH ₂ PO ₄ +NaOH+NaCl solution (pH=6.86) was calculated according to the external standard method, as shown in Table 1.

Table 1. Solubility results of test compounds in different solvents

The test results show that the solubility of compound T01 is significantly improved compared with compound T01-1.

Biological assay

Experimental example 2: In vitro inhibition of tumor cell proliferation activity

Dilute the test compound with RPMI1640 (containing 2% FBS) medium. The tumor cells HCC1806 (breast cancer, Nanjing Kebai Biotechnology) were digested by conventional methods using trypsin, the cells were collected, and resuspended in RPMI1640 (containing 2% FBS) medium. The diluted test compound was added to a 96-well plate, and then tumor cells were added for co-cultivation. Then add 20μL of CCK8 reagent (Dongren Chemical Technology Co., Ltd., Cat: CK04, Lot: JJ744) to each well, react for 4 hours, use a microplate reader (manufacturer: Molecular Devices, model: SpectraMax M2) to read (detection wavelength is 450nm) , To detect the activity of dehydrogenase in mitochondria. The test results are shown in Table 2.

Table 2.

The results show that the tested compound has a killing effect on tumor cells.

Experimental example 3: Pharmacokinetic determination

A single intravenous injection of compounds T01-1 and T01 to SD (Sprague Dawley) rats was carried out for pharmacokinetic studies.

Specifically, SD rats were taken, 6 rats/group, half male and half male, and randomly divided into groups, and a single intravenous injection of compound T01-1 (diluted with 20% HP-β-CD according to the dose when used to obtain a test solution) or Compound T01 (use NaH ₂ PO ₄ + NaOH + NaCl solution, dilute according to the dose to obtain the test solution), respectively before and after administration 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h Plasma was collected at and 24h, the concentration of compound T01-1 and compound T01 in the plasma was detected by LC-MS/MS method, pharmacokinetic parameters were calculated (see Table 3 for the results) and the conversion rate of compound T01 in rats was evaluated.

table 3

The test results show that after intravenous administration of T01 to rats, T01 can be basically eliminated within 0.5h (the blood concentration of T01 is less than 3% of C _max ), indicating that T01 can be rapidly transformed in vivo. After intravenous administration of T01 and T01-1 to rats, the drug-time curve of T01-1 detected in rat plasma can basically be fitted, indicating that T01 can basically be quantitatively converted into T01-1 (see Figure 1 and Figure 2).

Experimental Example 4: Single-dose toxicity test

The single-dose toxicity test was performed by intravenously injecting T01 into SD rats, and observation was made for 14 days after the administration. Forty SD rats were randomly divided into 4 groups (vehicle phosphate buffer group and T01 low, medium and high dose groups), 10 per group, half male and female. The low, medium and high doses of T01 administered were 30, 60 and 120 mg/kg, respectively. Since T01 (molecular weight 621) is rapidly hydrolyzed into T01-1 (molecular weight 512) under the action of phosphatase in the body, the molecular weight ratio of T01 to T01-1 is about 1:0.824. Therefore, the dose of 30, 60 or 120 mg/kg of T01 is equivalent to the dose of 24.7, 49.4 or 98.8 mg/kg of T01-1. After administration of T01, it was found that 1 rat in the 60mg/kg group died on the 8th day after administration, and 3 rats in the 120mg/kg group died on the 7th to 8th day after administration; at the same time in the T0130mg/kg group No adverse reactions related to the administration of T01 were observed.

In addition to those embodiments described herein, various modifications of the present invention will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference (including all patents, patent applications, journal articles, books and any other publications) cited in this application is incorporated herein by reference in its entirety.

Claims (12)

1. A compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein the compound has the formula (I -1) Structure:

   

   among them:

   R is selected from -C(=O)R ³ , -S(=O)R ³ and -S(=O) ₂ R ³ ; and

   R ^{3 is} selected from C _1-6 alkyl, halogenated C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3 to 10-membered heterocyclic group, C _6-10 aryl, and 5-14 membered heteroaryl group, preferably, R ³ is methyl or phenyl.
2. The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, or prodrug thereof, wherein the compound Selected from:

   
3. A compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein the compound has the formula (I )Structure:

   

   among them:

   p and q are the number of positive charges carried by R ¹ and R ² respectively, and are each independently selected from 1, 2 and 3;

   R ¹ and R ² are each independently selected from hydrogen ion, deuterium ion, metal ion, protonated amine and protonated amino acid;

   R is selected from -C(=O)R ³ , -S(=O)R ³ and -S(=O) ₂ R ³ ; and

   R ^{3 is} selected from C _1-6 alkyl, halogenated C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3 to 10-membered heterocyclic group, C _6-10 aryl, and 5-14 membered heteroaryl.
4. The compound of claim 3 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein the metal Ions are selected from alkali metal ions (such as lithium ion, sodium ion or potassium ion), alkaline earth metal ions (such as magnesium ion or calcium ion) and aluminum ion; the amine is selected from N-methylglucamine, tromethamine , Ethanolamine, triethanolamine and triethylamine; and the amino acid is selected from arginine and lysine.
5. The compound of claim 3 or 4 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein R ³ is methyl or phenyl.
6. The compound of any one of claims 3-5 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or pro Medicine, where R ¹ and R ² are both hydrogen ions.
7. The compound of any one of claims 3-6 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or pro Medicine, wherein the compound is selected from:

   
8. A pharmaceutical composition comprising a preventive or therapeutically effective amount of the compound according to any one of claims 1-7 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N- Oxide, isotope-labeled compound, metabolite or prodrug, and one or more pharmaceutically acceptable carriers, the pharmaceutical composition is preferably a solid preparation, semi-solid preparation, liquid preparation or gaseous preparation, and The pharmaceutical composition is preferably administered by oral, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal routes.
9. The compound of any one of claims 1-7 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or pro The use of the drug or the pharmaceutical composition of claim 8 in the preparation of a drug for the prevention or treatment of cancer and/or tumor and related disorders, wherein the cancer and/or tumor and related disorders are preferably free from the esophagus, stomach, and intestines , Rectum, oral cavity, pharynx, larynx, lung, colon, breast, uterus, endometrium, ovary, prostate, testis, bladder, kidney, liver, pancreas, bone, connective tissue, skin, eye, brain and central nervous system Cancers, as well as thyroid cancer, leukemia, Hodgkin’s disease, lymphoma and myeloma.
10. A method of preparing the compound of formula (I) of any one of claims 3-7,

    

    among them:

    Y is a phosphono protecting group, preferably selected from benzyl, tert-butyl and allyl;

    The remaining groups are as defined in any one of claims 3-7;

    The reaction conditions of each step are as follows:

    Step 1: Combine belotecan hydrochloride with a reagent that can introduce R groups (such as RX, where X is a halogen, such as chlorine, bromine or iodine) under appropriate conditions (such as in a base (such as triethylamine) In the presence of) react to obtain a compound of formula (I-1);

    The second step: reacting the compound of formula (I-1) with dimethyl sulfoxide in the presence of acetic anhydride and acetic acid to obtain the compound of formula (I-2);

    The third step: the compound of formula (I-2) with N-halosuccinimide (for example, N-iodosuccinimide) and a reagent of formula HOP(=O)(OY) ₂ (for example, phosphoric acid two Benzyl ester) to obtain the compound of formula (I-3);

    Step 4: Remove the Y group in the compound of formula (I-3) (for example, when Y is a benzyl group, remove the benzyl group by catalytic hydrogenolysis (for example, by Pd/C catalysis)) to obtain Compound of formula (I).
11. The compound of formula (I-2) or a pharmaceutically acceptable salt thereof:

    

    among them:

    R is selected from -C(=O)R ³ , -S(=O)R ³ and -S(=O) ₂ R ³ ; and

    R ^{3 is} selected from C _1-6 alkyl, halogenated C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3 to 10-membered heterocyclic group, C _6-10 aryl, and 5-14 membered heteroaryl;

    Preferably, the compound is selected from:

    
12. The compound of formula (I-3) or a pharmaceutically acceptable salt thereof:

    

    among them:

    R is selected from -C(=O)R ³ , -S(=O)R ³ and -S(=O) ₂ R ³ ;

    R ^{3 is} selected from C _1-6 alkyl, halogenated C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3 to 10-membered heterocyclic group, C _6-10 aryl, and 5-14 membered heteroaryl group; and

    Y is a phosphono protecting group, preferably selected from benzyl, tert-butyl and allyl;

    Preferably, the compound is selected from:

    

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