WO2019080724A1 - Nucleoside phosphate compound and preparation method therefor and use thereof - Google Patents

Abstract

Disclosed are a nucleoside phosphate compound, a pharmaceutical composition comprising same, and a preparation method therefor and the use thereof. Such a compound can be successfully metabolized within liver cells, and can produce an active metabolite-nucleoside triphosphate, and hence can be used for treating or preventing related diseases, such as liver cancer.

Description

Nucleoside phosphate compound, preparation method and use thereof Field of invention

The present invention relates to a nucleoside phosphate compound, a pharmaceutical composition and kit comprising the same, a process for the preparation thereof, and use thereof for preventing or treating cancer and/or a tumor and a related disease thereof.

Background of the invention

Nucleoside analogues are an important class of anti-tumor drugs. The main mechanism of action is to inhibit tumors by specifically interfering with DNA synthesis in tumor cells, affecting the transcription process of RNA or protein synthesis, or directly acting on these macromolecules. The cells divide and proliferate, thereby causing apoptosis. With the deepening of research on nucleoside analogs in pharmacokinetics, metabolic mechanisms in vivo, metastasis mechanism and induction of apoptosis, it has been found that nucleoside antitumor drugs have very broad development prospects. In recent years, the structural modification of known nucleoside antitumor drugs, improving the bioavailability of drugs and reducing adverse reactions have become the research hotspots of this class of antitumor drugs.

Traditional nucleoside drugs (such as the anticancer drug gemcitabine) generate nucleoside triphosphates through phosphorylation and metabolism in the body. The latter is inserted into the DNA strand to inhibit DNA synthesis and prevent cell progression from G1 to S phase, resulting in tumor cells. The G1 phase arrests, thereby inhibiting the malignant proliferation of tumor cells (Oncology. 2002, 62(4), 354-362). In long-term use, these traditional nucleoside drugs often have resistance problems, mainly due to transporter variation and phosphorylation down-regulation. The former affects the absorption of the drug, resulting in poor bioavailability; while the latter affects the monophosphorylation of the nucleoside drug, which in turn causes the deficiency of the active component triphosphate.

The phosphorylation process requires the participation of three different kinases. Nucleoside analogs and their monophosphate and diphosphate metabolites may not be good substrates for the corresponding kinases. Studies have shown that the first kinase is most selective for the substrate during phosphorylation. Therefore the first step of phosphorylation is usually the most difficult step. To overcome this difficulty, delivery of monophosphate to cells is a necessary means. However, nucleoside monophosphates are negatively charged, hard to pass through the cell membrane, and are easily degraded by phosphatase. Therefore, the conversion of the nucleoside analog to the corresponding phosphate or phosphoramide prodrug can achieve the purpose of reducing the polarity of the drug, enhancing the biofilm penetration ability, and improving the bioavailability in the body. In addition, the efficiency of phosphorylation also determines the activity of nucleoside analogs as polymerase inhibitors or reverse transcriptase inhibitors. Specifically, the phosphorylation efficiency depends on the amount of nucleoside triphosphate produced, the rate of formation, and the time of existence. The more the amount of nucleoside triphosphate produced, the faster the rate of formation, and the longer the time of existence, the higher the inhibitory activity.

Summary of invention

One aspect of the invention provides a nucleoside phosphate compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or precursor thereof A drug, or a mixture thereof, which is metabolized in vivo to an active nucleoside triphosphate, has a good effect of preventing or treating a disease of cancer and/or a tumor and a related condition thereof. The compound is particularly easily metabolized into active nucleoside triphosphate in liver tissue, and has an excellent preventive or therapeutic effect on liver cancer. The compound has the structure of the following formula (I):

among them,

B is selected from:

L is selected from C _1-6 alkylene, C _2-6 alkenylene, C _2-6 alkynylene, optionally substituted by one or more R ^b , said alkylene, alkenylene or sub An alkynyl group is optionally interrupted by one or more -O-, -NR- or -S-;

Or L is selected from the following groups:

among them

Represents a single bond or a double bond, and is connected to B at the 1 position and to the phosphorus atom (P) at the 2 position;

X, Y and Z are each independently selected from CH ₂ , O, S and NR at each occurrence;

R ^a and R ^b are each independently selected from the group consisting of hydrogen, halogen, -OH, -CN, -NO ₂ , -N(R) ₂ , -N ₃ , C _1-6 alkyl, C _{3- 6} cycloalkyl, C _2-6 alkenyl, halo C _2-6 alkenyl and C _2-6 alkynyl;

q is 0, 1, 2, 3, 4, 5, 6, 7, or 8, with the following conditions:

q is not greater than the number of positions on the corresponding group that can be substituted;

When q is greater than 1, each R ^b may be the same or different;

n is 0, 1, 2 or 3, provided that:

n is not greater than the number of positions on the corresponding group that can be substituted;

When n is greater than 1, each R ^a may be the same or different;

Ar ¹ and Ar ² are each independently selected from C _6-14 aryl and 5-14 membered heteroaryl, the aryl and heteroaryl optionally being substituted by one or more R ^c ;

R ^c is each independently selected from the group consisting of hydrogen, halogen, -OH, -CN, -NO ₂ , -N(R) ₂ , C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy group, C _1-6 alkylthio group, C _3-6 cycloalkyl group, 3-10 membered heterocycloalkyl group and C _2-6 alkynyl group;

R is each independently selected from the group consisting of hydrogen, C _1-6 alkyl and C _3-6 cycloalkyl;

m is 1, 2 or 3;

p is 1, 2 or 3;

R ¹ and R ² are each independently selected from the group consisting of hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _6-14 aryl, and C _7-20 aralkyl. The alkyl, cycloalkyl, alkoxy, aryl, and aralkyl groups are each optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, -OH, -CN, and -NO ₂ ;

Or R ¹ and R ² together with the carbon atom to which they are attached form a C _3-6 cycloalkyl group or a 4-10 membered heterocycloalkyl group;

R ³ and R ⁴ are each independently selected from the group consisting of hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _6-14 aryl, and C _7-20 aralkyl. The alkyl, cycloalkyl, alkoxy, aryl, and aralkyl groups are each optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, -OH, -CN, and -NO ₂ ;

Or R ³ and R ⁴ together with the carbon atom to which they are attached form a C _3-6 cycloalkyl group or a 4-10 membered heterocycloalkyl group;

Or R ² and R ³ together with the carbon atom to which they are attached form a C _3-6 cycloalkyl group or a 4-10 membered heterocycloalkyl group;

R ^{5 is} selected from the group consisting of hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _6-14 aryl and C _7-20 aralkyl, said alkyl, ring The alkyl, alkoxy, aryl and aralkyl groups are each optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, -OH, -CN and -NO ₂ ;

Or R ⁵ and the substituent R ^c on Ar ² together with the carbon atom to which they are bonded form a C _4-6 cycloalkyl or 4-10 membered heterocycloalkyl fused to Ar ² ;

requirement is:

1) When B is

L is

Wherein the 1 position is linked to B, the 2 position is linked to the phosphorus atom (P); X is NH; m is 1; p is 1; R ³ , R ⁴ and R ⁵ are each hydrogen; Ar ² is 2-methyl Phenyl; and when Ar ¹ is phenyl,

R ¹ and R ^{2 are} not the case wherein R ¹ and R ² are each independently selected from hydrogen and methyl; or R ¹ and R ² together with the carbon atom to which they are attached form a cyclopropyl group;

2) When B is

L is

Wherein at position B 1 is connected, at the second position to the phosphorus atom (P) is connected; X is NH; m is 1; P is 1; R & lt ¹ and R ² are different and are each independently selected from hydrogen and methyl; R ³ , R ⁴ and R ⁵ are each hydrogen; and when Ar ² is 2-methylphenyl,

Ar ^{1 is} not α-naphthyl or β-naphthyl;

3) When B is

L is

Wherein at position B 1 is connected, at the second position to the phosphorus atom (P) is connected; X is NH; m is 1; P is 1; R & lt ¹ and R ² are different and are each independently selected from hydrogen and methyl; R ³ , R ⁴ and R ⁵ are each hydrogen; and when Ar ¹ is a phenyl group,

Ar ^{2 is} not 2-methylnaphthyl, 3-methylphenyl or 4-methylphenyl;

4) When B is

L is

Wherein 1 is attached to B, 2 is attached to a phosphorus atom (P); X is NH; m is 1; p is 1; R ³ , R ⁴ and R ⁵ are each hydrogen; Ar ¹ is phenyl; When Ar ² is 2-methylphenyl,

R ¹ and R ^{2 are} not the case wherein R ¹ and R ² are each independently selected from hydrogen and methyl; or R ¹ and R ² together with the carbon atom to which they are attached form a cyclopropyl group;

5) When B is

L is

Wherein at position B 1 is connected, at the second position to the phosphorus atom (P) is connected; X is NH; m is 1; P is 1; R & lt ¹ and R ² are different and are each independently selected from hydrogen and methyl; R ³ , R ⁴ and R ⁵ are each hydrogen; and when Ar ¹ is a phenyl group,

Ar ^{2 is} not 3-methylphenyl, 4-methylphenyl, 4-fluorophenyl, 2,6-dimethylphenyl or 2-methylnaphthyl;

6) When B is

L is

Wherein 1 is attached to B, 2 is attached to a phosphorus atom (P); X is NH; m is 1; p is 1; and R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each hydrogen; When Ar ¹ is a phenyl group,

Ar ^{2 is} not phenyl, 4-methylphenyl, 2-methoxyphenyl, 2-methoxy-4-methylphenyl, 2,4-dimethylphenyl, 2-methyl- 4-methoxyphenyl or 2-methyl-4-tert-butylphenyl;

7) When B is

L is

Wherein the 1 position is linked to B, the 2 position is linked to the phosphorus atom (P); X is NH; m is 1; p is 1; R ³ , R ⁴ and R ⁵ are each hydrogen; Ar ¹ is α-naphthyl And when Ar ² is 2-methylphenyl,

R ¹ and R ^{2 are} not the case where R ¹ and R ^{2 are} simultaneously hydrogen; or R ¹ is hydrogen and R ² is methyl; or R ¹ is methyl and R ² is hydrogen;

8) When B is

L is

Wherein the 1 position is linked to B, the 2 position is linked to the phosphorus atom (P); X is NH; m is 1; p is 1; R ³ , R ⁴ and R ⁵ are each hydrogen; R ¹ and R ^{2 are} different and Each of them is independently selected from hydrogen and methyl; and when Ar ¹ is β-naphthyl,

Ar ^{2 is} not a 2-methylnaphthyl group;

9) When B is

L is

Wherein 1 is attached to B, 2 is attached to a phosphorus atom (P); X is NH; m is 1; p is 1; and R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each hydrogen; When Ar ¹ is a 4-fluorophenyl group,

Ar ^{2 is} not 2-methylphenyl;

10) When B is

L is

Wherein 1 is attached to B, 2 is attached to a phosphorus atom (P); X is NCH ₃ ; m is 1; p is 1; and R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each hydrogen; And when Ar ¹ is a phenyl group,

Ar ^{2 is} not 2-methylphenyl;

11) When B is

L is

Wherein 1 is attached to B, 2 is attached to a phosphorus atom (P); X is NH; m is 1; p is 1; and R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each hydrogen; When Ar ¹ is a β-naphthyl group,

Ar ^{2 is} not a 2-methylphenyl group.

Another aspect of the invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph thereof , solvate, hydrate, metabolite or prodrug, or mixtures thereof, and one or more pharmaceutically acceptable carriers.

Another aspect of the present invention provides a method of preparing a pharmaceutical composition of the present invention, which comprises administering a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof, Polymorphs, solvates, hydrates, metabolites or prodrugs, or mixtures thereof, are combined with one or more pharmaceutically acceptable carriers.

Another aspect of the invention provides a kit comprising a compound of the invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate thereof, hydrated thereof , metabolite or prodrug, or a mixture thereof, or a pharmaceutical composition of the invention.

Another aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or prodrug thereof, Or the use of a mixture thereof or a pharmaceutical composition of the present invention for the preparation of a medicament for preventing or treating cancer and/or a tumor and a related disease thereof.

Another aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or prodrug thereof, Or a mixture thereof or a pharmaceutical composition of the invention for use in the prevention or treatment of cancer and/or tumors and related diseases.

Another aspect of the invention provides a method of preventing or treating cancer and/or a tumor and related diseases, the method comprising administering to an individual in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable salt or ester thereof , stereoisomers, tautomers, polymorphs, solvates, hydrates, metabolites or prodrugs, or mixtures thereof, or pharmaceutical compositions of the invention.

Another aspect of the invention provides a method of preparing a compound of the invention, the method comprising the steps of:

among them

B, L, X, Ar ¹ , Ar ² , R ^{1 -} R ⁵ , m and p are as defined above.

Detailed description of the invention

definition

Unless otherwise defined below, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques that are generally understood in the art, including those that are obvious to those skilled in the art. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the invention.

The terms "including", "comprising", "having", "containing", or "comprising", as used herein, and other variants thereof, are inclusive or open, and not Exclude other unlisted elements or method steps.

The term "alkylene" as used herein denotes a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, Propylene or butylene.

The term "alkenylene" as used herein denotes a divalent hydrocarbon radical containing one or more double bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, such as ethenylene, propenylene or Allylene. When the compounds of the invention contain alkenylene groups, the compounds may exist in pure E (entgegen) form, pure Z (zusammen) form, or any mixture thereof.

The term "alkynylene" as used herein denotes a divalent hydrocarbon radical containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, for example ethynylene or propynylene. .

As used herein, the term "alkyl" is defined as a straight or branched saturated aliphatic hydrocarbon group. In some embodiments, an alkyl group has from 1 to 12, such as from 1 to 6 carbon atoms. For example, as used herein, the term " _C1-6 alkyl" refers to a straight or branched chain group having from 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl), which is optionally substituted by one or more (such as 1 to 3) suitable substituents such as halogen (at this time) This group is referred to as "haloalkyl" such as CF ₃ , C ₂ F ₅ , CHF ₂ , CH ₂ F, CH ₂ CF ₃ , CH ₂ Cl or -CH ₂ CH ₂ CF _{3 ,} and the like.

As used herein, the term "alkenyl" is defined as an unsaturated straight or branched aliphatic hydrocarbon group containing at least one carbon to carbon double bond. In some embodiments, an alkenyl group has 2 to 10, such as 2 to 6 carbon atoms. For example, as used herein, the term "C _2-6 alkenyl" refers to a straight or branched alkenyl group containing from 2 to 6 carbon atoms, such as ethenyl, 1-propenyl, 2-propenyl, 1 a butenyl or 2-butenyl group which is optionally substituted by one or more (for example 1, 2, 3 or 4) suitable substituents.

As used herein, the term "alkynyl" is defined as an unsaturated straight or branched aliphatic hydrocarbon group containing at least one carbon-carbon triple bond. In some embodiments, an alkynyl group has 2 to 10, such as 2 to 6 carbon atoms. For example, as used herein, the term "C _2-6 alkynyl" refers to a straight or branched alkynyl group containing from 2 to 6 carbon atoms, such as ethynyl, 1-propynyl, 2-propynyl. , 1-butynyl or 2-butynyl, optionally substituted by one or more (eg, 1, 2, 3 or 4) suitable substituents.

As used herein, the term "cycloalkyl" refers to a saturated or unsaturated, non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (eg, a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, or bicyclic, including spiro, fused or bridged systems (such as bicyclo [1.1.1] pentyl, bicyclo [2.2.1] heptyl, bicyclo [ 3.2.1] octyl or bicyclo [5.2.0] decyl, decalinyl, etc.), which are optionally substituted by one or more (such as 1 to 3) suitable substituents. There are 3 to 15, for example 3 to 6 carbon atoms. For example, the term "C _3-6 cycloalkyl" refers to a saturated or unsaturated, non-aromatic monocyclic or polycyclic ring having 3 to 6 ring-forming carbon atoms. (such as a bicyclic) hydrocarbon ring (such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), which is optionally substituted by one or more (such as 1 to 3) suitable substituents, such as methyl substitution Cyclopropyl.

As used herein, the term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated pi-electron system. In some embodiments, the aryl has 6 to 14, such as 6 to 10 carbon atoms. For example, as used herein, the term " _C6-14 aryl" means an aromatic group containing from 6 to 14 carbon atoms, such as phenyl or naphthyl. Aryl is optionally substituted with one or more (such as 1 to 3) suitable substituent (e.g., _{halo, -OH, -CN, -NO 2,} C 1-6 alkyl, etc.) substituted.

The term "aralkyl" as used herein denotes an aryl-substituted alkyl group, wherein the aryl group and the alkyl group are as defined herein. Typically, the aryl group can have from 6 to 14 carbon atoms and the alkyl group can have from 1 to 6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl, and the like.

The term "heteroaryl" as used herein refers to a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 rings. An atom, particularly 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, and which comprises at least one hetero atom which may be the same or different (for example, oxygen, nitrogen or sulfur), In addition, in each case, it may be benzo-fused. In particular, the heteroaryl is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thia A oxazolyl group or the like, and a benzo derivative thereof; or a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a triazinyl group or the like, and a benzo derivative thereof.

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

As used herein, the term "alkoxy" refers to an alkyl group, as defined above, appended to the parent molecular moiety through an oxygen atom. Representative examples of _C1-6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, and the like. .

As used herein, the term "alkylthio" refers to an alkyl group, as defined above, appended to the parent molecular moiety through a sulfur atom. Representative examples of _C1-6 alkylthio include, but are not limited to, methylthio, ethylthio, tert-butylthio, hexylthio, and the like.

The term "heterocycloalkyl" as used herein refers to a saturated monovalent monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms and one in the ring. Or a plurality (for example, 1, 2, 3 or 4) selected from C(=O), O, S, S(=O), S(=O) ₂ and NR (wherein R represents a hydrogen atom, a hetero atom-containing group of a C _1-6 alkyl group or a C _3-6 cycloalkyl group such as, but not limited to, an oxiranyl group, an aziridine group, an azetidinyl group, an oxoheterocyclic group Oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholine Base, piperazinyl, trithianyl and the like.

The term "substituted" means that one or more (eg, 1, 2, 3 or 4) hydrogens on the designated atom are replaced by the selection of the indicated group, provided that the specified atom is not exceeded. The normal valence of the current case and the substitution form a stable compound. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.

If a substituent is described as "optionally substituted," the substituent may be unsubstituted or (2) substituted. If the carbon of the 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 The optional substituents selected are substituted. If the nitrogen of the substituent is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogen present) may each be independently selected. Substitute substitution.

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

As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10 under reasonable conditions.

Unless otherwise indicated, a point of attachment of a substituent, as used herein, may come from any suitable position of the substituent.

When a bond of a substituent is shown to pass through a bond connecting two atoms in the ring, such a substituent may be bonded to any of the ring-forming atoms in the substitutable ring.

The invention also includes all pharmaceutically acceptable isotopically-labeled compounds which are identical to the compounds of the invention, except that one or more atoms are of the same atomic number but the atomic mass or mass number differs from the atomic mass prevailing in nature. Or atomic substitution of mass. Examples of isotopes in the compounds of the invention include, but are not limited to, hydrogen isotopes (e.g., ² H, ³ H); carbon isotopes (e.g., ¹¹ C, ¹³ C, and ¹⁴ C); chlorine isotopes (e.g., ³⁶ Cl) Fluorine isotopes (eg ¹⁸ F); isotopes of iodine (eg ¹²³ I and ¹²⁵ I); isotopes of nitrogen (eg ¹³ N and ¹⁵ N); isotopes of oxygen (eg ¹⁵ O, ¹⁷ O and ¹⁸ O); phosphorus Isotope (eg ³² P); and sulfur isotope (eg ³⁵ S). Certain isotopically-labeled compounds of the invention (e.g., those incorporating radioisotopes) are useful in drug and/or substrate tissue distribution studies (e.g., assays). The radioisotope ruthenium (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) are particularly useful for this purpose because of their ease of incorporation and ease of detection. Substitution with positron emitting isotopes (eg, ¹¹ C, ¹⁸ F, ¹⁵ O, and ¹³ N) can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies. Isotopically labeled compounds of the invention can be prepared by replacing the previously employed non-labeled reagents with suitable isotopically labeled reagents by methods analogous to those described in the accompanying routes and/or examples and preparations. The pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be substituted with an isotope, for example, D ₂ O, acetone-d ₆ or DMSO-d ₆ .

The term "stereoisomer" as used herein denotes an isomer formed by at least one asymmetric center. In a compound having one or more (eg, 1, 2, 3, or 4) asymmetric centers, which can produce a racemic mixture, a single enantiomer, a mixture of diastereomers, and Separate diastereomers. Specific individual molecules can also exist as geometric isomers (cis/trans). Similarly, the compounds of the invention may exist as mixtures (often referred to as tautomers) of two or more different forms in a rapidly balanced structure. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait. It is to be understood that the scope of the present application covers all such ratios in any ratio (eg, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99). %) isomer or a mixture thereof.

Solid lines can be used in this article

Solid wedge

Virtual wedge

The linkages in the compounds of the invention are depicted. The use of solid lines to delineate linkages to an asymmetric atom in a compound of the invention is meant to include all possible stereoisomers at the atom (e.g., specific enantiomers, racemic mixtures, and the like). A solid wedge or a virtual wedge is used to characterize the linkages to the asymmetric atoms in the compounds of the invention, indicating the stereoisomers shown. When present in a racemic mixture, solid wedges and virtual wedges are used to define relative stereochemistry rather than absolute stereochemistry. Unless otherwise indicated, the compounds of the invention may be stereoisomers (including cis and trans isomers, optical isomers (eg, R and S enantiomers), diastereomers, Geometric isomers, rotamers, conformers, atropisomers, and mixtures thereof exist. The compounds of the invention may exhibit more than one type of isomerism and consist of a mixture thereof (e.g., a racemic mixture and a diastereomeric pair).

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

It will also be understood that certain compounds of the invention may exist in free form for treatment or, where 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, metabolites or prodrugs, which can be directly administered to a patient in need thereof The compound of the invention or a metabolite or residue thereof is provided indirectly or indirectly. Thus, when reference is made herein to a "compound of the invention," it is also intended to encompass the various derivative forms described above for the compound.

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

Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include aspartate, bicarbonate/carbonate, hydrogen sulfate/sulfate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrobromine Acid salts/bromides, hydroiodides/iodides, maleates, methyl sulfates, nicotinates, nitrates, orotates, palmitates and other similar salts.

Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, choline salts, diethylamine salts, lysine salts, magnesium salts, meglumine salts, potassium salts, sodium salts, tromethamine salts, and other similar salts.

As used herein, the term "ester" means an ester derived from a compound of the formulae herein, which includes a physiologically hydrolyzable ester (which can be hydrolyzed under physiological conditions to release the free acid or alcohol form of the invention). Compound). The compounds of the invention may also be esters per se.

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 crystal lattice of the compound, particularly such as water, methanol or ethanol. The amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric ratios.

Also included within the scope of the invention are metabolites of the compounds of the invention, i.e., substances formed in vivo upon administration of a compound of the invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidization, enzymatic hydrolysis, and the like of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including compounds prepared by contacting a compound of the invention with a mammal for a time sufficient to produce a metabolic product thereof.

The invention further includes within its scope prodrugs of the compounds of the invention which are certain derivatives of the compounds of the invention which may themselves have less or no pharmacological activity, when administered to or into the body It can be converted to a compound of the invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional group derivatives of the compounds which are readily converted in vivo to the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 ( Edited by EBRoche, American Pharmaceutical Association). Prodrugs of the invention may, for example, be known by those skilled in the art as "pro-moiety" (e.g., "Design of Prodrugs", H. Bundgaard (Elsevier, 1985))" It is prepared in place of the appropriate functional groups present in the compounds of the invention.

The invention also encompasses compounds of the invention containing a protecting group. In any process for preparing a compound of the invention, it may be necessary and/or desirable to protect a sensitive group or reactive group on any of the molecules of interest, thereby forming a chemically protected form of the compound of the invention. This can be achieved by conventional protecting groups such as those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & P. GM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. Protecting groups, which are incorporated herein by reference. The protecting group can be removed at a suitable subsequent stage using methods known in the art.

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

Compound

It is an object of the present invention to provide a compound of the formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate or metabolite thereof Or prodrugs, or mixtures thereof,

among them,

B is selected from:

L is selected from C _1-6 alkylene, C _2-6 alkenylene, C _2-6 alkynylene, optionally substituted by one or more R ^b , said alkylene, alkenylene or sub An alkynyl group is optionally interrupted by one or more -O-, -NR- or -S-;

Or L is selected from the following groups:

among them

Represents a single bond or a double bond, and is connected to B at the 1 position and to the phosphorus atom (P) at the 2 position;

X, Y and Z are each independently selected from CH ₂ , O, S and NR at each occurrence;

R ^a and R ^b are each independently selected from the group consisting of hydrogen, halogen, -OH, -CN, -NO ₂ , -N(R) ₂ , -N ₃ , C _1-6 alkyl, C _{3- 6} cycloalkyl, C _2-6 alkenyl, halogenated C _2-6 alkenyl and C _2-6 alkynyl;

q is 0, 1, 2, 3, 4, 5, 6, 7, or 8, with the following conditions:

q is not greater than the number of positions on the corresponding group that can be substituted;

When q is greater than 1, each R ^b may be the same or different;

n is 0, 1, 2 or 3, provided that:

n is not greater than the number of positions on the corresponding group that can be substituted;

When n is greater than 1, each R ^a may be the same or different;

Ar ¹ and Ar ² are each independently selected from C _6-14 aryl and 5-14 membered heteroaryl, the aryl and heteroaryl optionally being substituted by one or more R ^c ;

R ^c is each independently selected from the group consisting of hydrogen, halogen, -OH, -CN, -NO ₂ , -N(R) ₂ , C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy group, C _1-6 alkylthio group, C _3-6 cycloalkyl group, 3-10 membered heterocycloalkyl group and C _2-6 alkynyl group;

R is each independently selected from the group consisting of hydrogen, C _1-6 alkyl and C _3-6 cycloalkyl;

m is 1, 2 or 3;

p is 1, 2 or 3;

R ¹ and R ² are each independently selected from the group consisting of hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _6-14 aryl, and C _7-20 aralkyl. The alkyl, cycloalkyl, alkoxy, aryl, and aralkyl groups are each optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, -OH, -CN, and -NO ₂ ;

Or R ¹ and R ² together with the carbon atom to which they are attached form a C _3-6 cycloalkyl group or a 4-10 membered heterocycloalkyl group;

R ³ and R ⁴ are each independently selected from the group consisting of hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _6-14 aryl, and C _7-20 aralkyl. The alkyl, cycloalkyl, alkoxy, aryl, and aralkyl groups are each optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, -OH, -CN, and -NO ₂ ;

Or R ³ and R ⁴ together with the carbon atom to which they are attached form a C _3-6 cycloalkyl group or a 4-10 membered heterocycloalkyl group;

Or R ² and R ³ together with the carbon atom to which they are attached form a C _3-6 cycloalkyl group or a 4-10 membered heterocycloalkyl group;

R ^{5 is} selected from the group consisting of hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _6-14 aryl and C _7-20 aralkyl, said alkyl, ring The alkyl, alkoxy, aryl and aralkyl groups are each optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, -OH, -CN and -NO ₂ ;

Or R ⁵ and the substituent R ^c on Ar ² together with the carbon atom to which they are bonded form a C _4-6 cycloalkyl or 4-10 membered heterocycloalkyl fused to Ar ² ;

requirement is:

1) When B is

L is

Wherein the 1 position is linked to B, the 2 position is linked to the phosphorus atom (P); X is NH; m is 1; p is 1; R ³ , R ⁴ and R ⁵ are each hydrogen; Ar ² is 2-methyl Phenyl; and when Ar ¹ is phenyl,

R ¹ and R ^{2 are} not the case wherein R ¹ and R ² are each independently selected from hydrogen and methyl; or R ¹ and R ² together with the carbon atom to which they are attached form a cyclopropyl group;

2) When B is

L is

Wherein at position B 1 is connected, at the second position to the phosphorus atom (P) is connected; X is NH; m is 1; P is 1; R & lt ¹ and R ² are different and are each independently selected from hydrogen and methyl; R ³ , R ⁴ and R ⁵ are each hydrogen; and when Ar ² is 2-methylphenyl,

Ar ^{1 is} not α-naphthyl or β-naphthyl;

3) When B is

L is

Wherein at position B 1 is connected, at the second position to the phosphorus atom (P) is connected; X is NH; m is 1; P is 1; R & lt ¹ and R ² are different and are each independently selected from hydrogen and methyl; R ³ , R ⁴ and R ⁵ are each hydrogen; and when Ar ¹ is a phenyl group,

Ar ^{2 is} not 2-methylnaphthyl, 3-methylphenyl or 4-methylphenyl;

4) When B is

L is

Wherein 1 is attached to B, 2 is attached to a phosphorus atom (P); X is NH; m is 1; p is 1; R ³ , R ⁴ and R ⁵ are each hydrogen; Ar ¹ is phenyl; When Ar ² is 2-methylphenyl,

R ¹ and R ^{2 are} not the case wherein R ¹ and R ² are each independently selected from hydrogen and methyl; or R ¹ and R ² together with the carbon atom to which they are attached form a cyclopropyl group;

5) When B is

L is

Wherein at position B 1 is connected, at the second position to the phosphorus atom (P) is connected; X is NH; m is 1; P is 1; R & lt ¹ and R ² are different and are each independently selected from hydrogen and methyl; R ³ , R ⁴ and R ⁵ are each hydrogen; and when Ar ¹ is a phenyl group,

Ar ^{2 is} not 3-methylphenyl, 4-methylphenyl, 4-fluorophenyl, 2,6-dimethylphenyl or 2-methylnaphthyl;

6) When B is

L is

Wherein 1 is attached to B, 2 is attached to a phosphorus atom (P); X is NH; m is 1; p is 1; and R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each hydrogen; When Ar ¹ is a phenyl group,

Ar ^{2 is} not phenyl, 4-methylphenyl, 2-methoxyphenyl, 2-methoxy-4-methylphenyl, 2,4-dimethylphenyl, 2-methyl- 4-methoxyphenyl or 2-methyl-4-tert-butylphenyl;

7) When B is

L is

Wherein the 1 position is linked to B, the 2 position is linked to the phosphorus atom (P); X is NH; m is 1; p is 1; R ³ , R ⁴ and R ⁵ are each hydrogen; Ar ¹ is α-naphthyl And when Ar ² is 2-methylphenyl,

R ¹ and R ^{2 are} not the case where R ¹ and R ^{2 are} simultaneously hydrogen; or R ¹ is hydrogen and R ² is methyl; or R ¹ is methyl and R ² is hydrogen;

8) When B is

L is

Wherein the 1 position is linked to B, the 2 position is linked to the phosphorus atom (P); X is NH; m is 1; p is 1; R ³ , R ⁴ and R ⁵ are each hydrogen; R ¹ and R ^{2 are} different and Each of them is independently selected from hydrogen and methyl; and when Ar ¹ is β-naphthyl,

Ar ^{2 is} not a 2-methylnaphthyl group;

9) When B is

L is

Wherein 1 is attached to B, 2 is attached to a phosphorus atom (P); X is NH; m is 1; p is 1; and R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each hydrogen; When Ar ¹ is a 4-fluorophenyl group,

Ar ^{2 is} not 2-methylphenyl;

10) When B is

L is

Wherein 1 is attached to B, 2 is attached to a phosphorus atom (P); X is NCH ₃ ; m is 1; p is 1; and R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each hydrogen; And when Ar ¹ is a phenyl group,

Ar ^{2 is} not 2-methylphenyl;

11) When B is

L is

Wherein 1 is attached to B, 2 is attached to a phosphorus atom (P); X is NH; m is 1; p is 1; and R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each hydrogen; When Ar ¹ is a β-naphthyl group, Ar ^{2 is} not a 2-methylphenyl group.

According to some embodiments of the invention, X is O or NR and R is selected from the group consisting of hydrogen, _C1-6 alkyl and _C3-6 cycloalkyl. In some preferred embodiments, X is O or NR and R is selected from the group consisting of hydrogen and _C1-6 alkyl. In some more preferred embodiments, X is O, NH or NCH _3. In some further more preferred embodiments, X is NH.

According to some embodiments of the invention, Y is O or S. In some preferred embodiments, Y is O.

According to some embodiments of the invention, Z is O, S or CH ₂ . In some preferred embodiments, Z is O.

According to some embodiments of the invention, R ^a and R ^b are each independently selected from the group consisting of hydrogen, halogen, -OH, -N(R) ₂ , -N ₃ and C _1-6 alkyl. In some preferred embodiments, R ^a and R ^b are each independently selected from the group consisting of halogen, -OH, and -N(R) ₂ at each occurrence. In some more preferred embodiments, R ^a and R ^b are each independently selected from the group consisting of F, -OH, and NH ₂ at each occurrence.

According to some embodiments of the invention, each occurrence of R ^c is independently selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, and C _1-6 alkoxy. In some preferred embodiments, R ^c is each independently methyl, t-butyl, methoxy, fluoro or chloro at each occurrence.

According to some embodiments of the invention, B is selected from:

In some preferred embodiments, B is selected from the group consisting of:

In a particularly preferred embodiment, B is selected from the group consisting of

According to some embodiments of the invention, L is selected from:

One of the positions is connected to B, and the second position is connected to the phosphorus atom (P).

In some preferred embodiments, L is selected from the group consisting of:

One of the positions is connected to B, and the second position is connected to the phosphorus atom (P).

In a particularly preferred embodiment, L is selected from the group consisting of:

One of the positions is connected to B, and the second position is connected to the phosphorus atom (P).

According to some embodiments of the invention, Ar ¹ and Ar ² are each independently selected from the group consisting of phenyl, naphthyl and 5-6 membered heteroaryl (eg thienyl, pyridyl or pyrazolyl), said phenyl, naphthalene The base and the 5-6 membered heteroaryl are each independently optionally substituted with 1 or 2 substituents independently selected from the group consisting of hydrogen, _C1-6 alkyl, halogen and _C1-6 alkoxy. In some preferred embodiments, Ar ¹ and Ar ² are each independently selected from the group consisting of phenyl, naphthyl, thienyl, pyridyl and pyrazolyl, phenyl, naphthyl, thienyl, pyridyl and pyrazole The groups are each independently optionally substituted with 1 or 2 substituents independently selected from the group consisting of hydrogen, methyl, tert-butyl, methoxy, fluoro and chloro. In some more preferred embodiments, Ar ¹ and Ar ² are each independently selected from phenyl, which is optionally substituted with 1 methyl.

According to some embodiments of the invention, R ¹ and R ² are each independently selected from hydrogen and C _1-6 alkyl, optionally substituted by one or more selected from the group consisting of hydrogen, halogen, -OH, -CN Substituting with a substituent of -NO ₂ ; or R ¹ and R ² together with the carbon atom to which they are attached form a C _3-6 cycloalkyl group. In some preferred embodiments, R ¹ and R ² are each independently selected from hydrogen and methyl; or R ¹ and R ² together with the carbon atom to which they are attached form a cyclopropyl group. In some more preferred embodiments, R ¹ and R ² are each independently selected from the group consisting of hydrogen and methyl.

According to some embodiments of the invention, R ³ and R ⁴ are each independently selected from hydrogen and C _1-6 alkyl, the alkyl optionally being selected from one or more selected from the group consisting of hydrogen, halogen, -OH, -CN, and Substituting a substituent of -NO ₂ ; or R ³ and R ⁴ together with the carbon atom to which they are attached form a C _3-6 cycloalkyl group. In some preferred embodiments, R ³ and R ⁴ are each independently selected from hydrogen and methyl; or R ³ and R ⁴ together with the carbon atom to which they are attached form a cyclopropyl group. In some more preferred embodiments, both R ³ and R ⁴ are hydrogen.

According to some embodiments of the invention, R ^{5 is} selected from the group consisting of hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, each of which is optionally selected from one or more selected from the group consisting of hydrogen, Substituents for halogen, -OH, -CN, and -NO ₂ are substituted. In some preferred embodiments, R ⁵ is hydrogen.

According to some embodiments of the invention, m is 1 or 2.

According to some embodiments of the invention, p is 1 or 2.

According to some embodiments of the invention, the compound of the invention is a compound of formula (I-1), (I-2) or (I-3) or a pharmaceutically acceptable salt, ester, stereoisomer thereof, Tautomers, polymorphs, solvates, hydrates, metabolites or prodrugs, or mixtures thereof,

Wherein X, Y, Z, R ^a , R ^b , q, n, Ar ¹ , Ar ² , m, p, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above; preferably, X is NR, Y and Z are both O, and each occurrence of R ^a and R ^b is independently selected from the group consisting of halogen, -OH and -N(R) ₂ , q is 0, 1, 2 or 3, and n is 1 or 2, Ar ¹ and Ar ² are each independently selected from a C _6-10 aryl group optionally substituted by 1 or 2 C _1-6 alkyl groups, m is 1 or 2, p is 1 or 2, and R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R are each independently hydrogen or C _1-6 alkyl; and more preferably, X is NH, Y and Z are both O, and R ^a and R ^b are Each occurrence is independently selected from F, -OH and -NH ₂ , q is 1, 2 or 3, n is 1, and Ar ¹ and Ar ² are each independently selected from optionally 1 or 2 C. _{a 1-6} alkyl-substituted C _6-10 aryl group, m is 1, p is 1, and R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R are each independently hydrogen or methyl.

According to some embodiments of the invention, the compound of the invention is a compound of formula (II) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate thereof , hydrates, metabolites or prodrugs, or mixtures thereof,

Wherein m, p, R ¹ , R ² , R ³ , R ⁴ , Ar ¹ , Ar ² and X are as defined above; preferably, m is 1 or 2, and p is 1 or 2; more preferably, m is 1 and p is 1; and preferably Ar ¹ is a phenyl group, and Ar ² is a phenyl group optionally substituted by 1 methyl group.

According to some embodiments of the invention, the compound of the invention is a compound of formula (III) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate thereof , hydrates, metabolites or prodrugs, or mixtures thereof,

Wherein m, p, R ¹ , R ² , R ³ , R ⁴ , Ar ¹ , Ar ² and X are as defined above; preferably, m is 1 or 2, and p is 1 or 2; more preferably, m Is 1 and p is 1; and preferably Ar ¹ is a phenyl group, and Ar ² is a phenyl group optionally substituted with 1 methyl group.

According to some embodiments of the present invention, the compound of the present invention is a compound of the formula (IV) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph or solvate thereof. , hydrates, metabolites or prodrugs, or mixtures thereof,

Wherein m, p, R ¹ , R ² , R ³ , R ⁴ , Ar ¹ , Ar ² and X are as defined above; preferably, m is 1 or 2, and p is 1 or 2; more preferably, m is 1 and p is 1; and preferably Ar ¹ is a phenyl group, and Ar ² is a phenyl group optionally substituted by 1 methyl group.

The present invention encompasses compounds obtained by any combination of the various embodiments.

According to some embodiments of the invention, the compound of formula (I) of the invention is selected from the group consisting of

Preparation

Another object of the present invention is to provide a process for the preparation of a compound of the above formula (I) which comprises the steps of:

among them

B, L, X, Ar ¹ , Ar ² , R ^{1 -} R ⁵ , m and p are as defined above.

step 1:

According to some embodiments of the invention, step 1 is carried out in the presence of an organic or inorganic base. The organic base includes, but is not limited to, sodium t-butoxide, triethylamine, DIPEA, pyridine or DMAP. The inorganic base includes, but is not limited to, NaH, NaOH, Na ₂ CO ₃ or K ₂ CO ₃ .

According to some embodiments of the invention, step 1 is carried out at a temperature of from -80 °C to 0 °C, preferably from -70 °C to -20 °C.

According to some embodiments of the invention, the molar ratio of the compound of formula a, the compound of formula b and the compound of formula c is 1: (0.5-2): (0.5-2), preferably 1: (0.8-2): ( 0.8-2), more preferably 1: (1-1.5): (1-1.5).

According to some embodiments of the invention, the molar ratio of the compound of formula a, the compound of formula b, the compound of formula c to the organic or inorganic base is 1: (0.5-2): (0.5-2): (0.5-2 Preferably, 1: (0.8-2): (0.8-2): (0.8-2), more preferably 1: (1-1.5): (1-1.5): (1-1.5).

Step 2:

According to some embodiments of the invention, step 2 is carried out in the presence of an organic or inorganic base. The organic base or inorganic base includes, but is not limited to, t-butyl magnesium chloride, n-butyl lithium, lithium diisopropylamide, sodium t-butoxide, triethylamine, DIPEA, pyridine, DMAP, NaH, NaOH, Na ₂ CO ₃ or K ₂ CO ₃ .

According to some embodiments of the invention, step 2 is carried out at a temperature of from -80 °C to 25 °C, preferably from -30 °C to 10 °C.

According to some embodiments of the invention, the molar ratio of the compound of formula d to the compound of formula e is 1: (0.5-2), preferably 1: (0.75-1.5).

According to some embodiments of the invention, the molar ratio of the compound of formula d, the compound of formula e to the organic or inorganic base is 1: (0.5-2): (1-3), preferably 1: (0.75-1.5): (1-2).

The above steps 1 and 2 can be carried out in an organic solvent. The organic solvent may be a reaction solvent commonly used in the art, such as, but not limited to, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, saturated hydrocarbons (such as cyclohexane, hexane). Etc.), halogenated hydrocarbons (such as dichloromethane, chloroform, 1,2-dichloroethane, etc.), ethers (such as tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.) , nitriles (such as acetonitrile, etc.) and their mixed solvents.

Pharmaceutical compositions and kits

Another object of the present invention is to provide a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph thereof , solvate, hydrate, metabolite or prodrug, or mixtures thereof, and one or more pharmaceutically acceptable carriers.

"Pharmaceutically acceptable carrier" in the context of the present invention means a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered, and which is suitable for contacting humans and/or within the scope of sound medical judgment. Tissues of other animals without excessive toxicity, irritation, allergic reactions, or other problems or complications corresponding to a reasonable benefit/risk ratio.

Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions 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, minerals. Oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. It is also possible to use physiological saline and an aqueous solution of glucose and glycerin as a liquid carrier, particularly for injection. 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 and the like. The composition may also contain minor amounts of wetting agents, emulsifying agents or pH buffering agents as needed. Oral formulations 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 as described in Remington's Pharmaceutical Sciences (1990).

The pharmaceutical compositions of the invention may act systemically and/or locally. For this purpose, they may be administered in a suitable route, for example by injection (for example intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, including instillation) or transdermal administration; or by oral, buccal, or oral administration. Nasal, transmucosal, topical, in the form of ophthalmic preparations or by inhalation.

For these routes of administration, the pharmaceutical compositions of the invention may be administered in a suitable dosage form. The dosage forms include, but are not limited to, tablets, capsules, troches, hard candy, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions. Injectable solutions, elixirs, syrups, and the like.

The amount or amount of the compound of the present invention in the pharmaceutical composition may be from about 0.01 mg to about 1000 mg, suitably from 0.1 to 500 mg, preferably from 0.5 to 300 mg, more preferably from 1 to 150 mg, particularly preferably from 1 to 50 mg, for example, 1.5 mg, 2 mg, 4 mg, 10 mg, 25 mg, and the like.

According to some embodiments of the invention, the pharmaceutical composition may further comprise one or more additional therapeutic agents, such as other therapeutic agents for preventing or treating cancer and/or tumors and related diseases, including but not limited to Cytotoxic anti-tumor drugs, drugs that affect endocrine balance, biological response modifiers, molecularly targeted anti-tumor drugs, and other ancillary treatments.

Another object of the present invention is to provide a process for the preparation of a pharmaceutical composition of the present invention which comprises administering a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof, Polymorphs, solvates, hydrates, metabolites or prodrugs, or mixtures thereof, are combined with one or more pharmaceutically acceptable carriers.

Another object of the present invention is to provide a kit comprising a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate thereof, Hydrates, metabolites or prodrugs, or mixtures thereof, or pharmaceutical compositions of the invention.

Treatment and use

Another object of the present invention is to provide a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or prodrug thereof Or a mixture thereof or a pharmaceutical composition of the invention for use in the manufacture of a medicament for the prevention or treatment of cancer and/or a tumor and a related disease thereof.

Another object of the present invention is to provide a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or prodrug thereof Or a mixture thereof or a pharmaceutical composition of the invention for use in the prevention or treatment of cancer and/or tumors and related diseases.

Another object of the present invention is to provide a method for preventing or treating cancer and/or a tumor and a related disease thereof, which comprises administering to an individual in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt or ester thereof , stereoisomers, tautomers, polymorphs, solvates, hydrates, metabolites or prodrugs, or mixtures thereof, or pharmaceutical compositions of the invention.

According to some embodiments of the invention, a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite thereof or Prodrugs, or mixtures thereof, or pharmaceutical compositions of the invention prevent or treat cancer and/or tumors and related diseases.

The cancers and/or tumors described in the present invention include, but are not limited to, tumors and/or cancers occurring in the pancreas, lung (eg, non-small cell lung cancer), ovary, bladder, breast, stomach, colorectal, and liver, and related disease.

The term "effective amount" as used herein refers to an amount of a compound that, to a certain extent, relieves one or more symptoms of the prophylactic or therapeutic condition after administration.

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

The amount of the compound of the invention administered will depend on the severity of the individual, condition or condition being treated, the rate of administration, the handling of the compound, and the judgment of the prescribing physician. Generally, an effective dose will be from about 0.0001 to about 50 mg per kg body weight per day, for example from about 0.01 to about 10 mg/kg/day (single or divided doses). For a 70 kg person, this would add up to about 0.007 mg/day to about 3500 mg/day, such as from about 0.7 mg/day to about 700 mg/day. In some cases, a dose level that is not higher than the lower limit of the aforementioned range may be sufficient, while in other cases, a larger dose may still be employed 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 term "treating" as used herein refers to reversing, alleviating, inhibiting the progression of a condition or condition to which such a term applies or the progression of one or more symptoms of such a condition or condition, or preventing such condition or condition or such One or more symptoms of a condition or condition.

As used herein, the term "individual" includes human or non-human animals. Exemplary human individuals include a human individual (referred to as a patient) or a normal individual having a disease, such as the disease described herein. "Non-human animals" in the present invention include all vertebrates, such as non-mammals (eg, birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals, and/or domesticated animals (eg, sheep, dogs). , cats, cows, pigs, etc.).

Example

In order to make the objects and technical solutions of the present invention clearer, the present invention will be further described below in conjunction with specific embodiments. It is to be understood that the examples are not intended to limit the scope of the invention. Further, specific experimental methods not mentioned in the following examples were carried out in accordance with a conventional experimental method.

The abbreviations in this article have the following meanings:

The structures of the compounds described in the following examples were confirmed by ¹ H NMR or MS. ^{The 1} H NMR measuring instrument was measured using a Bruker 400 MHz nuclear magnetic resonance apparatus, and the solvent was CD ₃ OD, CDCl ₃ or DMSO-d ₆ , and the internal standard substance was TMS. The total δ value was expressed by ppm. The mass spectrometer (MS) assay instrument used an Agilent (ESI) mass spectrometer, model Agilent 6120B.

The mixture of diastereomers prepared in the examples can be separated by preparative high performance liquid chromatography to give the pure isomer. The preparative high performance liquid chromatography separation can be carried out according to methods known in the art. For example, under the following separation conditions: using octadecyl bonded silica as a filler, column temperature 30 ° C -50 ° C, flow rate 5.0-20.0 mL / min, detection wavelength 200-400 nm, using mobile phase A (for example, Water), mobile phase B (for example, methanol or acetonitrile), with a linear gradient elution.

Example 1. ((2R,3S,5R)-5-(5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2 -Methyl-phenyl-((S)-1-(2-methylbenzyloxy)propan-2-yl)phosphoramidate (Compound 21) Preparation

Step 1: Synthesis of ((S)-1-((2-methylbenzyloxy)propyl)-2-yl)phosphoric acid pentafluorophenyl ester phenyl ester (Compound 21-2)

(S)-1-((2-Methylbenzyloxy)propyl)-2-amine (Compound 21-1) (760 mg, 4.25 mmol) was added to a 100 mL 3-neck flask, and anhydrous dichloromethane was added. (10 mL). The temperature was lowered to -70 ° C, and a solution of triethylamine (450 mg, 4.46 mmol) in anhydrous dichloromethane (3 mL) and phenyl diphenyl phosphate (896 mg, 4.25 mmol) in anhydrous dichloromethane (3 mL) The solution was stirred at -70 ° C for 1 h, then warmed to 0 ° C and stirred for 2 h. The temperature was lowered to -70 ° C, and a solution of pentafluorophenol (820 mg, 4.46 mmol) and triethylamine (450 mg, 4.46 mmol) in anhydrous dichloromethane (5 mL) was slowly added dropwise. After completion of the dropwise addition, the mixture was warmed to room temperature and allowed to react overnight, and then worked up to give 1.4 g of Compound 21-2. ESI-MS (m/z): 502 [M+H] ⁺

Step 2: ((2R,3S,5R)-5-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2- Synthesis of methyl-phenyl-((S)-1-(2-methylbenzyloxy)propan-2-yl)phosphoramidate (Compound 21)

5-Fluoro-2'-deoxyurea nucleoside (162 mg, 0.72 mmol) was added to a 100 mL 3-neck flask and dissolved in anhydrous tetrahydrofuran (10 mL). The temperature was lowered to -20 ° C, and a solution of t-butylmagnesium chloride in tetrahydrofuran (1.0 mL, 1.05 mmol, 1 M) was added dropwise, and the mixture was warmed to 0 ° C and stirred for 2 h. Then, a solution of the compound 21-2 (300 mg, 0.60 mmol) in anhydrous tetrahydrofuran (3 mL) was added dropwise, and the mixture was warmed to room temperature overnight, and then worked up to give a crude product (yield: DCM:MeOH = 10:1) Purification afforded 23 mg of compound 21.

Its structural representation is as follows:

^{1 H NMR (400MHz, DMSO)} δ11.85 (s, 1H), 7.89 (dd, J = 9.1,6.9Hz, 1H), 7.33 (t, J = 7.9Hz, 2H), 7.27 (d, J = 7.0 Hz, 1H), 7.22-7.11 (m, 6H), 6.13 (m, 1H), 5.48-5.37 (m, 2H), 4.43 (s, 2H), 4.21 (m, 1H), 4.18-4.06 (m, 2H), 3.96 (m, 1H), 3.35 (m, 2H), 3.22-3.16 (m, 1H), 2.25 (s, 3H), 2.12-1.97 (m, 2H), 1.05 (dd, J = 6.2, 2.4Hz, 3H).

ESI-MS (m/z): 564.2 [M+H] ⁺ .

Example 2 Preparation of Compound 21 Isomer A and Compound 21 Isomer B

Compound 21 (340 mg) was separated by chiral chromatography, and the separation conditions were as follows: separation column CHIRALPAK OZ-H 0.46 cm ID × 15 cm, mobile phase: Hexane/EtOH = 50/50 (v/v), flow rate 1.0 ml/min The wavelength is UV 254 nm and the temperature is 35 °C.

There were obtained 168 mg of Compound 21 isomer A (Rt = 3.965 min, de% = 98.9%), and its structure was characterized as follows:

_{^{1 H NMR (400MHz, CDCl 3}} ): δ9.58 (s, 1H), 7.64 (d, J = 6.2Hz, 1H), 7.31-7.12 (m, 9H), 6.20 (t, J = 5.7Hz, 1H ), 4.44 (d, J = 2.3 Hz, 2H), 4.47 - 4.35 (m, 2H), 4.22-4.18 (m, 1H), 4.00 (s, 1H), 3.61-3.48 (m, 2H), 3.34 ( d, J = 4.1 Hz, 2H), 2.29 (s, 3H), 2.28-2.25 (m, 1H), 1.86-1.80 (m, 2H), 1.20 (d, J = 6.4 Hz, 3H).

ESI-MS (m/z): 564.2 [M+H] ⁺ .

There were obtained 214 mg of Compound 21 isomer B (Rt = 5.032 min, de% = 99.3%), and its structure was characterized as follows:

_{^{1 H NMR (400MHz, CDCl 3}} ): δ9.62 (s, 1H), 7.65 (d, J = 6.2Hz, 1H), 7.31-7.12 (m, 9H), 6.16 (t, J = 5.7Hz, 1H ), 4.45 (s, 2H), 4.36-4.28 (m, 3H), 3.97 (s, 1H), 3.62-3.48 (m, 2H), 3.41-3.31 (m, 2H), 2.29 (s, 3H), 2.34-2.25 (m, 1H), 2.06-1.87 (m, 2H), 1.15 (d, J = 6.4 Hz, 3H).

ESI-MS (m/z): 564.2 [M+H] ⁺ .

Example 3. ((2R,3R,5R)-5-(4-Amino-2-oxopyrimidin-1(2H)-yl)-4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) Preparation of methyl-phenyl-((S)-1-((2-methylbenzyloxy)propyl)-2-yl)phosphoramidate (Compound 49)

Step 1: Synthesis of ((S)-1-((2-methylbenzyloxy)propyl)-2-yl)phosphoric acid pentafluorophenyl ester phenyl ester (Compound 21-2)

Compound 21-2 was synthesized in the same manner as in the first step of the first embodiment.

Step 2: ((2R,3R,5R)-5-(4-Amino-2-oxopyrimidin-1(2H)-yl)-4,4-difluoro-3-hydroxytetrahydrofuran-2-yl) Synthesis of phenyl-phenyl-((S)-1-((2-methylbenzyloxy)propyl)-2-yl)phosphoramidate (Compound 49)

In the same manner as in Step 2 of Example 1, except that gemcitabine (1.57 g, 6.0 mmol) was used instead of 5-fluoro-2'-deoxyuridine, 600 mg of Compound 49 was synthesized.

Its structural representation is as follows:

_{^{1 H NMR (400MHz, CDCl 3}} ): δ8.99-8.75 (m, 1H), 7.41-7.28 (m, 1H), 7.23-7.08 (m, 10H), 6.11-5.98 (m, 2H), 4.41- 4.14 (m, 5H), 3.96 (s, 1H), 3.49-3.47 (m, 1H), 3.31-3.19 (m, 2H), 2.29-2.19 (m, 3H), 1.15-1.08 (m, 3H).

ESI-MS (m/z): 581.2 [M+H] ⁺ .

Example 4. Preparation of Compound 49 Isomer A and Compound 49 Isomer B

Compound 49 (217 mg) was isolated by chiral chromatography. The separation conditions were as follows: separation column CHIRALPAK OZ-H 0.46 cm ID × 15 cm, mobile phase: Hexane/EtOH = 65/35 (V/V), flow rate 1.0 ml/min The wavelength is UV 254 nm and the temperature is 35 °C.

There were obtained 80 mg of Compound 49 isomer A (Rt = 6.352 min, de% = 99.6%), and its structure was characterized as follows:

^{1 H NMR (400MHz, DMSO-} d 6): δ8.02 (s, 1H), 7.58 (s, 1H), 7.50 (d, J = 7.7Hz, 1H), 7.33-7.14 (m, 9H), 6.28 -6.24(m,1H), 5.89(d,J=7.6Hz,1H), 4.68(t,J=11.9Hz,1H),4.45(s,2H),4.46-4.39(m,1H), 4.32- 4.27(m,1H),4.24-4.16(m,1H),4.10-4.04(m,1H),3.58-3.48(m,1H),3.42-3.39(m,1H),3.35-3.32(m,1H) ), 2.30 (s, 3H), 1.18 (d, J = 6.6 Hz, 3H).

ESI-MS (m/z): 581.2 [M+H] ⁺ .

Thereto was obtained 160 mg of Compound 49 isomer B (Rt = 10.598 min, de% = 98.3%), and its structure was characterized as follows:

^{1 H NMR (400MHz, DMSO-} d 6): δ7.88 (s, 1H), 7.60 (s, 1H), 7.50 (d, J = 7.7Hz, 1H), 7.33-7.14 (m, 9H), 6.29 (t, J = 8.1 Hz, 1H), 5.89 (d, J = 7.6 Hz, 1H), 4.49 (s, 2H), 4.44 - 4.39 (m, 1H), 4.35 - 4.29 (m, 1H), 4.21 4.14 (m, 1H), 4.07-4.06 (m, 1H), 3.60-3.48 (m, 1H), 3.44-3.33 (m, 2H), 2.30 (s, 3H), 1.17 (d, J = 6.6 Hz, 3H).

ESI-MS (m/z): 581.2 [M+H] ⁺ .

Example 5. ((2R,4R)-4-(4-Amino-2-oxopyrimidin-1(2H)-yl)-1,3-dioxolan-2-yl)methyl-phenyl Synthesis of ((S)-1-((2-methylbenzyloxy)propyl)-2-yl)phosphoramidate (Compound 77)

Step 1: Synthesis of ((S)-1-((2-methylbenzyloxy)propyl)-2-yl)phosphoric acid pentafluorophenyl ester phenyl ester (Compound 21-2)

Compound 21-2 was synthesized in the same manner as in the first step of the first embodiment.

Step 2: ((2R,4R)-4-(4-Amino-2-oxopyrimidin-1(2H)-yl)-1,3-dioxolan-2-yl)methyl-phenyl- Synthesis of ((S)-1-((2-methylbenzyloxy)propyl)-2-yl)phosphoramidate (Compound 77)

2470 mg of Compound 77 was synthesized in a similar manner to Step 2 of Example 1 except that instead of 5-fluoro-2'-deoxyurea nucleoside with tresapabine (426 mg, 2.0 mmol).

Its structural representation is as follows:

ESI-MS (m/z): 531.2 [M+H] ⁺ .

The following compounds were synthesized by the methods of Example 1 to Example 5:

Biological test

1. In vitro screening and evaluation of the production of nucleoside triphosphate (3P), a metabolite of the compound of the present invention in human primary hepatocytes

1.1. Test System

Human primary hepatocytes were purchased from Bioreclamation IVT, an in vitro technology company.

1.2. Test methods

After thawing human primary hepatocytes, the culture medium is diluted to a concentration of 6×10 ⁵ cells/mL, and then the storage solution of the test compound of 25 mM concentration is diluted with the culture solution to a concentration of 50 μM working solution, wherein the organic solvent The final content is less than 1%. 250 μL of the hepatocyte solution and 250 μL of the test substance solution or the pure medium (NC group) containing the same solvent content were mixed and added to the 24-well plate so that the final concentration of the test compound was 25 μM. After incubating for 6 hours in a 37 ° C water bath, the sample was transferred to a test tube, and then the culture solution was removed by centrifugation. After washing the cells with PBS phosphate buffer, the supernatant was removed, 180 μL of 70% methanol was added, and the mixture was vortexed and placed at -20. °C overnight. After centrifugation at 12,000 rpm and 4 ° C for 10 min, 150 μL of the supernatant was transferred to a sample tube, and the amount of 3P product produced was measured by LC-MS/MS.

3P generation rate = (3P production amount * 150 μL) / (6 × 10 ⁵ cells / mL * 250 μL * 6h).

1.3. Experimental results

The amount of 3P produced and the rate of formation of the test compound are shown in Table 1.

Table 1

As can be seen from Table 1, the compound of the present invention can be smoothly metabolized in hepatocytes to produce an active metabolite nucleoside triphosphate, and the metabolite nucleoside triphosphate is produced in a large amount and has a high production rate. Therefore, the compound of the present invention has an antitumor or anticancer effect, and particularly has an excellent anti-liver cancer effect.

Claims (17)

1. a compound of the formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or prodrug thereof, or a compound thereof mixture,

   

   among them,

   B is selected from:

   

   L is selected from C _1-6 alkylene, C _2-6 alkenylene, C _2-6 alkynylene, optionally substituted by one or more R ^b , said alkylene, alkenylene or sub An alkynyl group is optionally interrupted by one or more -O-, -NR- or -S-;

   Or L is selected from the following groups:

   

   among them

   

   Represents a single bond or a double bond, and is connected to B at the 1 position and to the phosphorus atom (P) at the 2 position;

   X, Y and Z are each independently selected from CH ₂ , O, S and NR at each occurrence;

   R ^a and R ^b are each independently selected from the group consisting of hydrogen, halogen, -OH, -CN, -NO ₂ , -N(R) ₂ , -N ₃ , C _1-6 alkyl, C _{3- 6} cycloalkyl, C _2-6 alkenyl, halogenated C _2-6 alkenyl and C _2-6 alkynyl;

   q is 0, 1, 2, 3, 4, 5, 6, 7, or 8, with the following conditions:

   q is not greater than the number of positions on the corresponding group that can be substituted;

   When q is greater than 1, each R ^b may be the same or different;

   n is 0, 1, 2 or 3, provided that:

   n is not greater than the number of positions on the corresponding group that can be substituted;

   When n is greater than 1, each R ^a may be the same or different;

   Ar ¹ and Ar ² are each independently selected from a C _6-14 aryl group and a 5-14 membered heteroaryl group, which are optionally one or more (preferably 1, 2, 3, 4) Or 5, particularly preferably 1 or 2) R ^c substituted;

   R ^c is each independently selected from the group consisting of hydrogen, halogen, -OH, -CN, -NO ₂ , -N(R) ₂ , C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy group, C _1-6 alkylthio group, C _3-6 cycloalkyl group, 3-10 membered heterocycloalkyl group and C _2-6 alkynyl group;

   R is each independently selected from the group consisting of hydrogen, C _1-6 alkyl and C _3-6 cycloalkyl;

   m is 1, 2 or 3, preferably 1 or 2;

   p is 1, 2 or 3, preferably 1 or 2;

   R ¹ and R ² are each independently selected from the group consisting of hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _6-14 aryl, and C _7-20 aralkyl. The alkyl, cycloalkyl, alkoxy, aryl and aralkyl groups are each optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -CN and -NO ₂ ;

   Or R ¹ and R ² together with the carbon atom to which they are attached form a C _3-6 cycloalkyl group or a 4-10 membered heterocycloalkyl group;

   R ³ and R ⁴ are each independently selected from the group consisting of hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _6-14 aryl, and C _7-20 aralkyl. The alkyl, cycloalkyl, alkoxy, aryl and aralkyl groups are each optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -CN and -NO ₂ ;

   Or R ³ and R ⁴ together with the carbon atom to which they are attached form a C _3-6 cycloalkyl group or a 4-10 membered heterocycloalkyl group;

   Or R ² and R ³ together with the carbon atom to which they are attached form a C _3-6 cycloalkyl group or a 4-10 membered heterocycloalkyl group;

   R ^{5 is} selected from the group consisting of hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _6-14 aryl and C _7-20 aralkyl, said alkyl, ring The alkyl, alkoxy, aryl and aralkyl groups are each optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, -OH, -CN and -NO ₂ ;

   Or R ⁵ and the substituent R ^c on Ar ² together with the carbon atom to which they are bonded form a C _4-6 cycloalkyl or 4-10 membered heterocycloalkyl fused to Ar ² ;

   requirement is:

   1) When B is

   

   L is

   

   Wherein the 1 position is linked to B, the 2 position is linked to the phosphorus atom (P); X is NH; m is 1; p is 1; R ³ , R ⁴ and R ⁵ are each hydrogen; Ar ² is 2-methyl Phenyl; and when Ar ¹ is phenyl,

   R ¹ and R ^{2 are} not the case wherein R ¹ and R ² are each independently selected from hydrogen and methyl; or R ¹ and R ² together with the carbon atom to which they are attached form a cyclopropyl group;

   2) When B is

   

   L is

   

   Wherein at position B 1 is connected, at the second position to the phosphorus atom (P) is connected; X is NH; m is 1; P is 1; R & lt ¹ and R ² are different and are each independently selected from hydrogen and methyl; R ³ , R ⁴ and R ⁵ are each hydrogen; and when Ar ² is 2-methylphenyl,

   Ar ^{1 is} not α-naphthyl or β-naphthyl;

   3) When B is

   

   L is

   

   Wherein at position B 1 is connected, at the second position to the phosphorus atom (P) is connected; X is NH; m is 1; P is 1; R & lt ¹ and R ² are different and are each independently selected from hydrogen and methyl; R ³ , R ⁴ and R ⁵ are each hydrogen; and when Ar ¹ is a phenyl group,

   Ar ^{2 is} not 2-methylnaphthyl, 3-methylphenyl or 4-methylphenyl;

   4) When B is

   

   L is

   

   Wherein 1 is attached to B, 2 is attached to a phosphorus atom (P); X is NH; m is 1; p is 1; R ³ , R ⁴ and R ⁵ are each hydrogen; Ar ¹ is phenyl; When Ar ² is 2-methylphenyl,

   R ¹ and R ^{2 are} not the case wherein R ¹ and R ² are each independently selected from hydrogen and methyl; or R ¹ and R ² together with the carbon atom to which they are attached form a cyclopropyl group;

   5) When B is

   

   L is

   

   Wherein at position B 1 is connected, at the second position to the phosphorus atom (P) is connected; X is NH; m is 1; P is 1; R & lt ¹ and R ² are different and are each independently selected from hydrogen and methyl; R ³ , R ⁴ and R ⁵ are each hydrogen; and when Ar ¹ is a phenyl group,

   Ar ^{2 is} not 3-methylphenyl, 4-methylphenyl, 4-fluorophenyl, 2,6-dimethylphenyl or 2-methylnaphthyl;

   6) When B is

   

   L is

   

   Wherein 1 is attached to B, 2 is attached to a phosphorus atom (P); X is NH; m is 1; p is 1; and R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each hydrogen; When Ar ¹ is a phenyl group,

   Ar ^{2 is} not phenyl, 4-methylphenyl, 2-methoxyphenyl, 2-methoxy-4-methylphenyl, 2,4-dimethylphenyl, 2-methyl- 4-methoxyphenyl or 2-methyl-4-tert-butylphenyl;

   7) When B is

   

   L is

   

   Wherein the 1 position is linked to B, the 2 position is linked to the phosphorus atom (P); X is NH; m is 1; p is 1; R ³ , R ⁴ and R ⁵ are each hydrogen; Ar ¹ is α-naphthyl And when Ar ² is 2-methylphenyl,

   R ¹ and R ^{2 are} not the case where R ¹ and R ^{2 are} simultaneously hydrogen; or R ¹ is hydrogen and R ² is methyl; or R ¹ is methyl and R ² is hydrogen;

   8) When B is

   

   L is

   

   Wherein the 1 position is linked to B, the 2 position is linked to the phosphorus atom (P); X is NH; m is 1; p is 1; R ³ , R ⁴ and R ⁵ are each hydrogen; R ¹ and R ^{2 are} different and Each of them is independently selected from hydrogen and methyl; and when Ar ¹ is β-naphthyl,

   Ar ^{2 is} not a 2-methylnaphthyl group;

   9) When B is

   

   L is

   

   Wherein 1 is attached to B, 2 is attached to a phosphorus atom (P); X is NH; m is 1; p is 1; and R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each hydrogen; When Ar ¹ is a 4-fluorophenyl group,

   Ar ^{2 is} not 2-methylphenyl;

   10) When B is

   

   L is

   

   Wherein 1 is attached to B, 2 is attached to a phosphorus atom (P); X is NCH ₃ ; m is 1; p is 1; and R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each hydrogen; And when Ar ¹ is a phenyl group,

   Ar ^{2 is} not 2-methylphenyl;

   11) When B is

   

   L is

   

   Wherein 1 is attached to B, 2 is attached to a phosphorus atom (P); X is NH; m is 1; p is 1; and R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each hydrogen; When Ar ¹ is a β-naphthyl group,

   Ar ^{2 is} not a 2-methylphenyl group.
2. The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or prodrug thereof, or mixtures thereof Wherein Y is O or S, preferably O.
3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or prodrug thereof, or a mixture wherein Z is O, S or CH ₂ , preferably O.
4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or prodrug thereof, Or a mixture thereof, wherein B is selected from:

   

   Preferably selected from:

   

   More preferably selected from:

   
5. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or pre-form thereof Medicine, or a mixture thereof, wherein L is selected from:

   

   Preferably selected from:

   

   More preferably selected from:

   

   One of the positions is connected to B, and the second position is connected to the phosphorus atom (P).
6. A compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or pre-form thereof Or a mixture thereof, wherein X is O or NR, and R is selected from the group consisting of hydrogen, C _1-6 alkyl and C _3-6 cycloalkyl; preferably, X is O or NR, and R is selected from hydrogen and C _1-6 alkyl; more preferably, X is O, NH or NCH ₃ ; further more preferably, X is NH.
7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or pre-form thereof Or a mixture thereof, wherein R ¹ and R ² are each independently selected from hydrogen and C _1-6 alkyl, the alkyl optionally being selected from one or more selected from the group consisting of hydrogen, halogen, -OH, -CN Substituting with a substituent of -NO ₂ or R ¹ and R ² together with the carbon atom to which they are attached form a C _3-6 cycloalkyl group; preferably, R ¹ and R ² are each independently selected from hydrogen and methyl, Or R ¹ and R ² together with the carbon atom to which they are attached form a cyclopropyl group; more preferably, R ¹ and R ² are each independently selected from the group consisting of hydrogen and methyl.
8. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or pre-form thereof Or a mixture thereof, wherein R ³ and R ⁴ are each independently selected from hydrogen and C _1-6 alkyl, the alkyl optionally being selected from one or more selected from the group consisting of hydrogen, halogen, -OH, -CN Substituting with a substituent of -NO ₂ or R ³ and R ⁴ together with the carbon atom to which they are attached form a C _3-6 cycloalkyl group; preferably, R ³ and R ⁴ are each independently selected from hydrogen and methyl, Or R ³ and R ⁴ together with the carbon atom to which they are attached form a cyclopropyl group; more preferably, both R ³ and R ⁴ are hydrogen.
9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or pre-form thereof Or a mixture thereof, wherein R ^{5 is} selected from the group consisting of hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, each of which is optionally selected from one or more selected from the group consisting of hydrogen, Substituted by a substituent of halogen, -OH, -CN and -NO ₂ ; preferably, R ⁵ is hydrogen.
10. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or pre-form thereof Or a mixture thereof, wherein Ar ¹ and Ar ² are each independently selected from the group consisting of phenyl, naphthyl and 5-6 membered heteroaryl, each independently of phenyl, naphthyl and 5-6 membered heteroaryl Optionally substituted with 1 or 2 substituents independently selected from the group consisting of hydrogen, C _1-6 alkyl, halogen and C _1-6 alkoxy; preferably, Ar ¹ and Ar ² are each independently selected from phenyl , naphthyl, thienyl, pyrazolyl and pyridyl, said phenyl, naphthyl, thienyl, pyrazolyl and pyridyl are each independently optionally 1 or 2 independently selected from hydrogen, methyl Substituted with a substituent of a substituent of a t-butyl group, a methoxy group, a fluorine group, and a chlorine group; more preferably, each of Ar ¹ and Ar ^{2 is} independently selected from a phenyl group, and the phenyl group is optionally 1 A Substituted.
11. a compound represented by the formula (I-1), (I-2) or (I-3) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph thereof, solvent combination thereof a substance, hydrate, metabolite or prodrug, or a mixture thereof,

    

    Wherein X, Y, Z, R ^a , R ^b , q, n, Ar ¹ , Ar ² , m, p, R ¹ , R ² , R ³ , R ⁴ and R ^{5 are} as defined in claims 1-3 and 6- Defined in any one of 10;

    Preferably, X is NR, Y and Z are both O, and R ^a and R ^b are each independently selected from halogen, -OH and -N(R) ₂ at each occurrence, and q is 0, 1, 2 or 3 , n is 1 or 2, and Ar ¹ and Ar ² are each independently selected from a C _6-10 aryl group optionally substituted by 1 or 2 C _1-6 alkyl groups, m is 1 or 2, and p is 1 Or 2, and R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R are each independently hydrogen or C _1-6 alkyl;

    More preferably, X is NH, Y and Z are both O, and R ^a and R ^b are each independently selected from F, -OH and -NH ₂ at each occurrence, q is 1, 2 or 3, and n is 1 , Ar ¹ and Ar ² are each independently selected from C _6-10 aryl optionally substituted by 1 or 2 C _1-6 alkyl groups, m is 1, p is 1, and R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R are each independently hydrogen or methyl.
12. The compound of claim 11 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or prodrug thereof, or mixtures thereof, wherein The compound is as shown in formula (II), formula (III) or formula (IV):

    

    

    Wherein Ar ¹ is a phenyl group, and Ar ² is a phenyl group optionally substituted by one methyl group.
13. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or prodrug thereof, Or a mixture thereof, wherein the compound is selected from the group consisting of:

    

    

    
14. A pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvent thereof a compound, hydrate, metabolite or prodrug, or a mixture thereof, and one or more pharmaceutically acceptable carriers.
15. A kit comprising a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolism thereof Or prodrug, or a mixture thereof, or the pharmaceutical composition of claim 14.
16. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or prodrug thereof, Or a mixture thereof or the use of the pharmaceutical composition according to claim 14 for the preparation of a medicament for preventing or treating cancer and/or a tumor and a related disease thereof, wherein the medicament is preferably administered orally, intravenously, intraarterially, subcutaneously Or a drug for administration by intraperitoneal, intramuscular or transdermal route, wherein the cancer and/or tumor and related diseases are preferably selected from the group consisting of pancreatic cancer, lung cancer (such as non-small cell lung cancer), ovarian cancer, bladder cancer, breast Cancer, stomach cancer, colorectal cancer and liver cancer.
17. A process for the preparation of a compound according to any one of claims 1 to 13 comprising the steps of:

    

    among them

    B, L, X, Ar ¹ , Ar ² , R ^{1 -} R ⁵ , m and p are as defined in any one of claims 1-13.