Prodrugs for sustained-release therapeutic agents and their uses

Abstract

This disclosure relates to prodrugs for sustained release of therapeutic agents, and methods of treating diseases using such prodrugs.

Description

Invention Field

[0001] This disclosure relates to prodrugs for sustained release of therapeutic agents, and methods of treating diseases using such prodrugs. Background Technology

[0002] Most therapeutic agents are delivered systemically to the body via oral / GI absorption or systemic injection. The agent then travels through the bloodstream to its site of action, thus exposing the agent to the entire body. In some cases, unintended exposure to the agent in other parts of the body can lead to side effects, sometimes serious ones. To reduce side effects from systemic exposure, many locally delivered formulations have been developed. A good example is inhaled formulations for treating respiratory diseases such as COPD and asthma. These agents target receptors in the airways and open the airways for more efficient oxygen exchange. Many other examples of locally delivered drugs exist, such as topical corticosteroids for skin rashes, intravitreal injections of anti-VEGF for wet age-related macular degeneration (AMD), and intra-articular injections of corticosteroids for osteoarthritis. The aim of these locally delivered formulations is to achieve high local drug concentrations for therapeutic efficacy while minimizing systemic drug exposure to have minimal side effects. However, locally delivered formulations are difficult to use in most cases, especially locally injected formulations. Therefore, a delivery system that can slowly release a drug to have a prolonged duration of action, thereby reducing the frequency of dosing, is desired, such as a sustained-release or controlled-release formulation. The prodrug approach is one of the sustained-release mechanisms commonly used by those known in the art.

[0003] Drugs circulating systemically are metabolized and eliminated from the system via enzymes or excretion. To maintain concentrations above the effective concentration at all times, a peak concentration much higher than the effective concentration is required, so that the trough between doses will be higher than the effective concentration. However, in some cases, peak concentrations can lead to undesirable side effects. Many methods exist to reduce peak concentrations without proportionally reducing trough concentrations. The most popular method is to use polymers to slow the release of the drug from the delivery system. Many orally administered sustained-release / controlled-release systems use this method. This method has advantages and disadvantages in some cases, especially for locally injected delivery systems aimed at release over a period of weeks or months. Using polymer systems to control drug release can also present challenges in terms of product manufacturing processes and quality control. Another method for more precise control of drug release is to provide a prodrug that releases the drug through the cleavage of chemical bonds. In this case, the release mechanism is essentially a chemical reaction, more specifically, a first-order chemical reaction. Due to the consistency of the environment within the biological system, the rate of drug release is more predictable. Furthermore, by controlling the solubility of the prodrug, it is possible to establish a system that can use solubility as a rate-limiting step to release the drug in a zero-order or pseudo-zero manner. Summary of the Invention

[0004] This disclosure relates to a prodrug system that controls the drug release rate through the chemical structure of the prodrug portion for a specific location and indication.

[0005] In one aspect, this disclosure provides a prodrug compound comprising a parent drug portion and a tail portion, wherein

[0006] The parent drug portion is derived from a parent drug containing a reactive group selected from the group consisting of amines, amino groups, hydroxyl groups, carboxylic acid esters, ketones, and amides.

[0007] The tail portion is covalently connected to the parent drug portion and has formula (I):

[0008]

[0009] in:

[0010] L 1 The reactive group of the parent drug is partially linked to the parent drug to form a cleavable bond;

[0011] L represents a direct bond or an alkyl group;

[0012] U is selected from the following group: direct bond, cycloalkyl, heterocyclic, aryl, and heteroaryl;

[0013] V is a direct bond or an alkyl group;

[0014] W is selected from the group consisting of: direct bond, cycloalkyl, heterocyclic, aryl, and heteroaryl;

[0015] Z is selected from the following group: direct bond, alkyl, aryl, NR 1 R 2 and OR 3 The alkyl and aryl groups are optionally separated by one or more R groups. 4 replace;

[0016] R 1 R 2 and R 3 Independently hydrogen, alkyl, or cycloalkyl; and

[0017] R 4 Selected from the following group: alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0018] The condition is that when U is not a direct bond, V, W, and Z are not all direct bonds simultaneously.

[0019] Or its pharmaceutically acceptable salt.

[0020] In some embodiments, this disclosure provides a prodrug compound having a formula selected from the group consisting of:

[0021]

[0022]

[0023] Or its pharmaceutically acceptable salt.

[0024] In some embodiments, this disclosure provides a prodrug compound having a formula selected from the group consisting of:

[0025]

[0026]

[0027] Or its pharmaceutically acceptable salt.

[0028] In some embodiments, this disclosure provides a prodrug compound having the following formula:

[0029]

[0030] Or its pharmaceutically acceptable salt.

[0031] In some embodiments, this disclosure provides a prodrug compound having the following formula:

[0032]

[0033] Or its pharmaceutically acceptable salt.

[0034] In another aspect, this disclosure provides a pharmaceutical composition comprising a prodrug compound provided herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0035] In another aspect, this disclosure provides a method of treating a disease in a subject in need, comprising administering to the subject a therapeutically effective amount of the prodrug compound provided herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein. Attached Figure Description

[0036] Figure 1 and 2 The plasma and gastric concentrations of fluorouracil following continuous intragastric administration of exemplary compounds of the present disclosure to male Sprague Dawley rats and continuous intravenous infusion or single oral administration of free fluorouracil are described, respectively. Detailed Implementation

[0037] Certain embodiments of this disclosure will now be described in detail with reference to the accompanying structures and formulas. While this disclosure is described in conjunction with the enumerated embodiments, it should be understood that it is not intended to limit this disclosure to those embodiments. Rather, this disclosure is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of this disclosure as defined in the claims. Those skilled in the art will recognize many methods and materials similar to or equivalent to those described herein, which can be used to practice this disclosure. This disclosure is by no means limited to the methods and materials described. In the event that one or more of the incorporated references and similar materials (including, but not limited to, defined terminology, usage of terminology, described techniques, etc.) differ from or contradict this application, this disclosure shall prevail. All references, patents, and patent applications cited in this disclosure are incorporated herein by reference in their entirety.

[0038] It should be understood that certain features of this disclosure described in the context of different embodiments for clarity may also be provided in combination in a single embodiment. Conversely, various features of this disclosure described in the context of a single embodiment for brevity may also be provided separately or in any suitable sub-combination. It must be noted that, unless the context explicitly specifies otherwise, the singular forms “a / an” and “the” as used in the specification and appended claims include their plural forms.

[0039] definition

[0040] The definitions of specific functional groups and chemical terms are described in more detail below. For the purposes of this disclosure, chemical elements are identified according to the periodic table, CAS version, Handbook of Chemistry and Physics, 75th edition, inner cover, and specific functional groups are generally defined as described therein. In addition, the general principles of organic chemistry, as well as specific functional parts and reactivity, are described in *Organic Chemistry*, Thomas Sorrell, 2nd ed., University Science Books, Sausalito, 2006; *March's Advanced Organic Chemistry*, Smith and March, 6th ed., John Wiley & Sons, Inc., New York, 2007; *Comprehensive Organic Transformations*, 3rd ed., VCH Publishers, Inc., New York, 2018; and *Some Modern Methods of Organic Synthesis*, Carruthers, 4th ed., Cambridge University Press, Cambridge, 2004, the entire contents of each of which are incorporated herein by reference.

[0041] Linking substituents are described in several places in this disclosure. It is particularly desirable that each linking substituent include both its forward and reverse forms. For example, -NR(CR'R")- includes both -NR(CR'R")- and -(CR'R")NR-. Where the structure explicitly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For instance, if the structure requires a linking group and the Markush group definition of the variable lists "alkyl", then it should be understood that said "alkyl" refers to a linked alkylene group.

[0042] When the bond to a substituent shows a cross bond with two atoms in the connecting ring, then the substituent may bond to any atom in the ring. When the listed substituent does not indicate that the substituent is bonded to any atom in the remaining part of the given compound, then the substituent may bond via any atom in the formula. Combinations of substituents and / or variables are permissible, but only if the combination produces a stable compound.

[0043] When any variable (e.g., R) i When a group appears more than once in any component or formula of a compound, its definition for each occurrence is independent of its definition for each subsequent occurrence. Therefore, for example, if a group is shown as being surrounded by 0-2 R... i If partially substituted, then the group can optionally be replaced by up to two R groups. i Partial replacement, and R i Each time it appears, it is independently selected from R. i The definition of [the compound]. Furthermore, combinations of substituents and / or variables are permissible, but only if the combination produces a stable compound.

[0044] As used in this article, the term "C" i-j "Indicates the range of carbon atoms, where i and j are integers, and the range includes the endpoints (i.e., i and j) and every integer point in between, where j is greater than i. For example, C..." 1-6 The term "C" indicates a range of one to six carbon atoms, including one, two, three, four, five, and six carbon atoms. In some embodiments, the term "C" is used... 1-12 "Indicates 1 to 12, especially 1 to 10, especially 1 to 8, especially 1 to 6, especially 1 to 5, especially 1 to 4, especially 1 to 3 or especially 1 to 2 carbon atoms."

[0045] Whether used as part of another term or independently, as used herein, the term "alkyl" refers to a saturated straight-chain or branched hydrocarbon group, which may optionally be independently substituted by one or more substituents as described below. The term "C i-j "Alkyl" refers to an alkyl group having i to j carbon atoms. In some embodiments, the alkyl group contains 1 to 10 carbon atoms. In some embodiments, the alkyl group contains 1 to 9 carbon atoms. In some embodiments, the alkyl group contains 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. "C 1-10 Examples of "alkyl" include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. "C" 1-6 Examples of "alkyl" include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, etc.

[0046] Whether used as part of another term or independently, as used herein, the term "alkenyl" refers to a straight-chain or branched hydrocarbon group having at least one carbon-carbon double bond, which may optionally be substituted independently by one or more substituents described herein, and includes groups having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. In some embodiments, the alkenyl group contains 2 to 12 carbon atoms. In some embodiments, the alkenyl group contains 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, the alkenyl group contains 2 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethylenyl, allyl, butenyl, pentenyl, 1-methyl-2-but-1-yl, 5-hexenyl, etc.

[0047] Whether used as part of another term or independently, as used herein, the term "alkynyl" refers to a straight-chain or branched hydrocarbon group having at least one carbon-carbon triple bond, which may optionally be substituted independently by one or more substituents as described herein. In some embodiments, the alkenyl group contains 2 to 12 carbon atoms. In some embodiments, the alkynyl group contains 2 to 11 carbon atoms. In some embodiments, the alkynyl group contains 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, the alkynyl group contains 2 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, etc.

[0048] As used herein, the term "amide" refers to -C(=O)NR'-, where R' represents hydrogen, N-protecting group, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl and other suitable organic groups.

[0049] As used herein, the term "amine" refers to a derivative of ammonia in which one or more hydrogen atoms are replaced by substituents and can be derived from N(H). n (R') 3-n The expression indicates that n is 0, 1, or 2, and each R' is independently a hydroxyl, nitro, N-protecting group, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, and other suitable organic group, or two R' together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic or heteroaryl group.

[0050] As used in this article, the term "amino" refers to -NH2.

[0051] As used herein, the term "acetal" refers to -O-CH(R')-O-, where R' represents alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, and other suitable organic groups.

[0052] Whether used as part of another term or independently, as used herein, the term "aryl" refers to monocyclic and polycyclic ring systems having a total of 5 to 20 ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains 3 to 12 ring members. Examples of "aryl" include, but are not limited to, phenyl, biphenyl, naphthyl, anthracene, etc., which may have one or more substituents. As used herein, groups in which the aromatic ring is fused with one or more additional rings are also included within the scope of the term "aryl". In the case of polycyclic ring systems, only one ring is required to be aromatic (e.g., 2,3-dihydroindole), although all rings may also be aromatic (e.g., quinoline). The second ring may also be fused or bridged. Examples of polycyclic aryl groups include, but are not limited to, benzofuranyl, indanyl, phthalimide, naphthimide, phenidyl, or tetrahydronaphthyl. The aryl group may be substituted at one or more ring positions with substituents as described above.

[0053] Whether used as part of another term or independently, as used herein, the term "cycloalkyl" refers to a monovalent, non-aromatic, saturated or partially unsaturated monocyclic and polycyclic ring system in which all ring atoms are carbon and contain at least three cyclic carbon atoms. In some embodiments, the cycloalkyl group may contain 3 to 12 cyclic carbon atoms, 3 to 10 cyclic carbon atoms, 3 to 9 cyclic carbon atoms, 3 to 8 cyclic carbon atoms, 3 to 7 cyclic carbon atoms, 3 to 6 cyclic carbon atoms, 3 to 5 cyclic carbon atoms, 4 to 12 cyclic carbon atoms, 4 to 10 cyclic carbon atoms, 4 to 9 cyclic carbon atoms, 4 to 8 cyclic carbon atoms, 4 to 7 cyclic carbon atoms, 4 to 6 cyclic carbon atoms, or 4 to 5 cyclic carbon atoms. The cycloalkyl group may be saturated or partially unsaturated. The cycloalkyl group may be substituted. In some embodiments, the cycloalkyl group may be a saturated cyclic alkyl group. In some embodiments, the cycloalkyl group may be a partially unsaturated cycloalkyl group containing at least one double or triple bond in its ring system. In some embodiments, the cycloalkyl group may be monocyclic or polycyclic. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Examples of polycyclic cycloalkyl groups include, but are not limited to, adamantyl, norbornel, fluorenyl, spiropeptadienyl, spiro[3,6]decyl, bicyclo[1,1,1]pentenyl, bicyclo[2,2,1]heptenyl, etc.

[0054] As used in this article, the term "carboxylate" refers to -C(=O)O-.

[0055] As used herein, the term "phosphate ester" refers to -OP(=O)(OR')O-, where R' represents hydrogen, N-protecting group, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl and other suitable organic groups.

[0056] As used herein, the term "carbamate" refers to -NR'(C=O)O-, where R' represents hydrogen, N-protecting group, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl and other suitable organic groups.

[0057] As used herein, the term "thiocarbamate" refers to -NR'(C=S)O-, where R' represents hydrogen, N-protecting group, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl and other suitable organic groups.

[0058] As used in this article, the term "carbonate" refers to -OC(=O)O-.

[0059] As used in this article, the term "thiocarbonate" refers to -OC(=S)O-.

[0060] As used herein, the term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, as well as any quaternized form of basic nitrogen (including N-oxides).

[0061] Whether used as part of another term or independently, as used herein, the term "heteroaryl" refers to an aryl group having one or more heteroatoms in addition to a carbon atom. Heteroaryl groups can be monocyclic. Examples of monocyclic heteroaryl groups include, but are not limited to, thiophene, furanyl, pyrrole, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, indoleazinyl, purine, naphridinyl, benzofuranyl, and pteridinyl. Heteroaryl groups also include polycyclic groups fused with one or more aryl, cycloaliphatic, or heterocyclic rings, wherein the linking group or linking point is located on the heteroaryl ring. Examples of polycyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, benzothiophene, benzofuranyl, benzo[1,3]-dioxacyclopentenyl, dibenzofuranyl, indazoleyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, terolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinazinyl, carbazolyl, acridineyl, phenazinyl, phenothiazinyl, phenotoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0062] As used herein, the term "heterocyclic group" refers to a saturated or partially unsaturated carbocyclic group, wherein one or more ring atoms are heteroatoms independently selected from oxygen, sulfur, nitrogen, phosphorus, etc., and the remaining ring atoms are carbon, wherein one or more ring atoms may optionally be independently substituted by one or more substituents. In some embodiments, the heterocyclic group is a saturated heterocyclic group. In some embodiments, the heterocyclic group is a partially unsaturated heterocyclic group having one or more double bonds in its ring system. In some embodiments, the heterocyclic group may contain any oxidized form of carbon, nitrogen, or sulfur and any quaternized form of basic nitrogen. "Heterocyclic group" also includes a group in which the heterocyclic group is fused with a saturated, partially unsaturated, or fully unsaturated (i.e., aromatic) carbocyclic or heterocyclic ring. Where possible, the heterocyclic group may be carbon-linked or nitrogen-linked. In some embodiments, the heterocycle is carbon-linked. In some embodiments, the heterocycle is nitrogen-linked. For example, a pyrrole-derived group may be pyrrole-1-yl (nitrogen-linked) or pyrrole-3-yl (carbon-linked). In addition, the groups derived from imidazole can be imidazole-1-yl (nitrogen-linked) or imidazole-3-yl (carbon-linked).

[0063] In some embodiments, the term "3- to 12-membered heterocyclic group" refers to a 3- to 12-membered saturated or partially unsaturated monocyclic or polycyclic heterocyclic ring system having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Fused, spirocyclic, and bridging ring systems are also included within the scope of this definition. Examples of monocyclic heterocyclic groups include (but are not limited to) oxoheterocyclic butyl, 1,1-dioxothiocyclic butylpyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, piperidyl, piperazinyl, piperidinyl, morpholinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyridinoneyl, pyridinoneyl, pyridinoneyl, pyridinoneyl, pyrrolidinyl, triazinoneyl, etc. Examples of fused heterocyclic groups include, but are not limited to, phenyl fused rings or pyridyl fused rings, such as quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, quinazinyl, quinazolinyl, azaindolazinyl, pteridinyl, chromenyl, isochromenyl, indolyl, isoindolyl, indolazinyl, indazole, purine, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothiopheneyl, benzothiazolyl, carbazole, phenazinyl, phenthiazolyl, phenidinyl, imidazole[1,2-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,3]triazolo[4,3-a]pyridinyl, etc. Examples of spirocyclic heterocyclic groups include, but are not limited to, spirocyclic pyranyl, spirocyclic oxazinyl, etc. Examples of bridging heterocyclic groups include, but are not limited to, morphanyl, hexamethylenetetramine, 3-azabicyclo[3.1.0]hexane, 8-azabicyclo[3.2.1]octane, 1-azabicyclo[2.2.2]octane, and 1,4-diazabicyclo[2.2.2]octane (DABCO).

[0064] As used herein, the term "hydrazone" refers to -C(R')=N-NH-, where R' represents hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl and other suitable organic groups.

[0065] As used in this article, the term "hydroxyl group" refers to -OH.

[0066] As used in this article, the term "ketone" refers to -C(=O)-.

[0067] As used herein, the term "phosphonamide ester" refers to -OP(=O)(R')(NR”)-, where R' and R” are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl and other suitable organic groups.

[0068] As used herein, the term "imine" refers to -C(R')=N-, where R' represents hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl and other suitable organic groups.

[0069] As used herein, the term "bond" or "joint" refers to a bond or chemical part formed by a chemical reaction between functional groups of at least two entities to be joined, thereby forming a molecule or maintaining a sufficiently close proximity of the entities. The bond may be integrated into the resulting linked molecule or structure, having or not having its reacted functional group. Such bonds can be covalent or non-covalent. Hydrolyzable or degradable bonds mean that the bond can be degraded in water or aqueous solutions (including, for example, bodily fluids, such as blood). Enzymatically unstable or degradable bonds mean that the bond can be degraded by one or more enzymes. Such degradable bonds include, but are not limited to, ester bonds formed by a carboxylic acid in one entity and an alcohol group on a bioactive agent, wherein such ester groups are generally hydrolyzed under physiological conditions to release the bioactive agent. Other hydrolyzable bonds include, but are not limited to, carbonate bonds, imine bonds formed by the reaction of amines with aldehydes, phosphate ester bonds formed by the reaction of phosphate groups with alcohols, hydrazone bonds formed by the reaction of hydrazides with aldehydes, acetal bonds formed by the reaction of aldehydes with alcohols, and amide bonds formed by the reaction of amines with carboxyl groups.

[0070] As used herein, the term "partially unsaturated" refers to a group comprising at least one double or triple bond. The term "partially unsaturated" is intended to cover rings having multiple unsaturated sites, but is not intended to include aromatic (i.e., completely unsaturated) moieties.

[0071] As used herein, the term “pharmaceutically acceptable” means that a substance or composition is chemically and / or toxicologically compatible with other components constituting the formulation and / or with subjects treated thereunder.

[0072] As used herein, the term “substituted,” whether or not preceded by the term “optionally,” means that one or more hydrogen atoms of the specified moiety are replaced by suitable substituents. It should be understood that “substituted” or “substituted” includes the implied limitation that such substitution is consistent with the permissible valence state of the substituted atom, and that the substitution produces a stable or chemically viable compound, such as a compound that does not spontaneously transform as by rearrangement, cyclization, elimination, etc. Unless otherwise indicated, a “optionally substituted” group may have suitable substituents at each substituted position of the group, and the substituents at each position may be the same or different when more than one position in any given structure can be substituted by more than one substituent selected from the specified group. Those skilled in the art will understand that, where appropriate, the substituent itself may be substituted. Unless specifically stated as “unsubstituted,” references to the chemical portion herein should be understood to include substituted variants. For example, references to an “aryl” group or part implicitly include both substituted and unsubstituted variants.

[0073] As used herein, the terms “therapeutic agent,” “drug,” “bioactive molecule,” “bioactive agent,” “active agent,” etc., refer to any substance that can affect any physical or biochemical properties of a living organism, including but not limited to viruses, bacteria, fungi, plants, animals, and humans. Specifically, as used herein, a therapeutic agent includes any substance intended for the diagnosis, cure, relief, treatment, or prevention of disease in humans or other animals, or for otherwise enhancing the physical or mental health of humans or animals.

[0074] Delivering therapeutic drugs to specific tissues or sites within the body presents several challenges, especially when it is necessary to deliver therapeutic drugs locally to specific tissues and to sustain the release of therapeutic drugs, as well as when it is necessary to avoid high systemic concentrations of therapeutic drugs that could lead to toxic side effects.

[0075] compound

[0076] Therefore, this disclosure provides a prodrug compound capable of locally delivering a therapeutic agent and releasing the therapeutic agent in a controlled and sustained manner, with reduced systemic side effects. This is achieved by intentionally designing the prodrug compound to achieve a balance between the solubility of the prodrug compound and the rate at which the prodrug compound releases the parent drug.

[0077] In one aspect, this disclosure provides a prodrug compound comprising a parent drug portion and a tail portion, wherein

[0078] The parent drug portion is derived from a parent drug containing a reactive group selected from the group consisting of amines, amino groups, hydroxyl groups, and amides.

[0079] The tail portion is covalently connected to the parent drug portion and has formula (I):

[0080]

[0081] in:

[0082] L 1 The reactive group of the parent drug is partially linked to the parent drug to form a cleavable bond;

[0083] L represents a direct bond or an alkyl group;

[0084] U is selected from the following group: direct bond, cycloalkyl, heterocyclic, aryl, and heteroaryl;

[0085] V is a direct bond or an alkyl group;

[0086] W is selected from the group consisting of: direct bond, cycloalkyl, heterocyclic, aryl, and heteroaryl;

[0087] Z is selected from the following group: direct bond, alkyl, aryl, NR 1 R 2 and OR 3 The alkyl and aryl groups are optionally separated by one or more R groups. 4 replace;

[0088] R 1 R 2 and R 3 Independently hydrogen, alkyl, or cycloalkyl; and

[0089] R 4 Selected from the following group: alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0090] The condition is that when U is not a direct bond, V, W, and Z are not all direct bonds simultaneously.

[0091] Or its pharmaceutically acceptable salt.

[0092] In some embodiments, the parent drug contains at least one reactive group capable of reacting with reactive functional groups of a second entity (e.g., the tail portion provided herein) and optional co-reactants to form a cleavable bond, thereby attaching a portion of the parent drug to the second entity (e.g., the tail portion).

[0093] A “cleavable bond” is a relatively unstable bond that breaks down under physiological conditions. An exemplary releasable bond is a hydrolyzable bond that breaks down (i.e., hydrolyzes) upon reaction with water. The tendency of a bond to hydrolyze in water may depend not only on the general type of bond connecting the two atoms but also on the substituents attached to those atoms. Suitable hydrolyzable unstable or weak bonds include, but are not limited to, carboxylic esters, phosphate esters, acid anhydrides, acetals, ketals, amides, acyloxyalkyl ethers, imines, hydrazones, orthoesters, peptides, oligonucleotides, thioesters, ureas, thioureas, carbamates, thiocarbamates, aminophosphates, phosphonamide esters, carbonates, and thiocarbonates. Some functional groups have atoms that can be chemically degraded by processes other than hydrolysis. Exemplary releasable bonds in this category include certain carbamates and Fmoc derivatives. Some molecules containing functional groups of these categories with suitable bonds may undergo chemical degradation (release) upon alkaline action. In such cases, “cleavage” may occur at higher pH values ​​or through the action of biomolecules containing a basic moiety (e.g., histidine). Another example of a cleavable bond is an enzymatically cleavable bond. An "enzymatically cleavable bond" means a bond that is easily cleaved by one or more enzymes.

[0094] In some implementations, the parent drug is selected from the group consisting of: anticancer agents, anti-inflammatory drugs, antibiotics, antifungal agents, JAK inhibitors, and VEGF inhibitors.

[0095] In some implementations, the parent drug is an anticancer agent.

[0096] In some implementations, the parent drug is an anti-inflammatory drug.

[0097] In some implementations, the parent drug is an antibiotic.

[0098] In some implementations, the parent drug is an antifungal agent.

[0099] In some embodiments, the parent drug is selected from the group consisting of fluorouracil, temozolomide, daunorubicin, 10-hydroxycamptothecin, and 7-ethyl-10-hydroxycamptothecin.

[0100] In some embodiments, the reactive group of the parent drug reacts with the reactive functional group of the tail portion and optionally with a co-reactant to form a cleavable bond selected from the group consisting of carbonates, thiocarbonates, carbamates, thiocarbamates, carboxylic acids, phosphates, amides, imines, hydrazones, phosphonamides, and acetals.

[0101] In some implementations, L 1 Selected from direct bonds, *-CH2OC(=O)O-, *-CH2OC(=S)O-, *-C(=O)O-, *-OC(=S)-, *-C(=O)-, *-C(=O)N(R) a )-、*-C(=S)N(R a )-、*-CH2OP(=O)(R a O- and

[0102] *-P(=O)(R a )N(R a )-, where R a It is hydrogen, alkyl, alkenyl, or alkynyl, and L 1 The * end is connected to the parent drug portion.

[0103] In some implementations, L 1 Selected from the following groups: direct bond, *-CH2OC(=O)O-, *-C(=O)O-, *-C(=O)-, *-C(=O)N(R) a )-、*-CH2OP(=O)(R a )O- and *-P(=O)(R a )N(R a )-.

[0104] In some embodiments, the parent drug comprises an amino group that reacts with the reactive functional group of the tail portion and optionally with a co-reactant, such that a group selected from *-CH2OC(=O)O-, *-C(=O)O-, *-C(=O)-, and *-CH2OP(=O)(R a)O-ofL 1 .

[0105] In some embodiments, the parent drug comprises an amino group that reacts with the reactive functional group of the tail portion and optionally with a co-reactant, such that an L-type bond selected from direct bonds and *-C(=O)O- is formed. 1 .

[0106] In some embodiments, the parent drug comprises a hydroxyl group that reacts with a reactive functional group of the tail portion and optionally with a co-reactant, such that a group selected from *-C(=O)-, *-C(=O)O-, *-C(=O)N(R) is formed. a )- and *-P(=O)(R a )N(R a )- of L 1 .

[0107] In some implementations, L is a direct key.

[0108] In some embodiments, L is an alkyl group. In some embodiments, L is a C group. 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 alkyl.

[0109] In some embodiments, L is methyl, ethyl, or hexyl.

[0110] In some implementations, U is a direct key.

[0111] In some embodiments, U is a heterocyclic group. In some embodiments, U is a saturated heterocyclic group. In some embodiments, U is a partially unsaturated heterocyclic group.

[0112] In some embodiments, U is a 5- to 12-membered heterocyclic group, a 5- to 11-membered heterocyclic group, a 5- to 10-membered heterocyclic group, a 5- to 9-membered heterocyclic group, a 5- to 8-membered heterocyclic group, a 5- to 7-membered heterocyclic group, or a 5- to 6-membered heterocyclic group.

[0113] In some embodiments, U is a 5- to 12-membered saturated heterocyclic group, a 5- to 11-membered saturated heterocyclic group, a 5- to 10-membered saturated heterocyclic group, a 5- to 9-membered saturated heterocyclic group, a 5- to 8-membered saturated heterocyclic group, a 5- to 7-membered heterocyclic group, or a 5- to 6-membered saturated heterocyclic group.

[0114] In some embodiments, U is piperidinyl.

[0115] In some embodiments, U is a 5- to 12-membered partially unsaturated heterocyclic group, a 5- to 11-membered partially unsaturated heterocyclic group, a 5- to 10-membered partially unsaturated heterocyclic group, a 5- to 9-membered partially unsaturated heterocyclic group, a 5- to 8-membered partially unsaturated heterocyclic group, a 5- to 7-membered heterocyclic group, or a 5- to 6-membered partially unsaturated heterocyclic group.

[0116] In some embodiments, U is 1,2,3,4-tetrahydro-isoquinolinyl.

[0117] In some embodiments, U is an aryl group. In some embodiments, U is a 5- to 12-membered aryl group, a 5- to 10-membered aryl group, a 5- to 8-membered aryl group, or a 5- to 6-membered aryl group.

[0118] In some embodiments, U is phenyl.

[0119] In some implementations, L is a direct bond, and U is a direct bond, a heterocyclic group, or an aryl group.

[0120] In some embodiments, L is a direct bond, and U is a direct bond, a 5- to 12-membered saturated or partially unsaturated heterocyclic group, or a 5- to 12-membered aryl group.

[0121] In some embodiments, L is a direct bond, and U is selected from the group consisting of: direct bond, 1,2,3,4-tetrahydro-isoquinolinyl, and phenyl.

[0122] In some embodiments, L is an alkyl group and U is a direct bond, a heterocyclic group, or an aryl group.

[0123] In some implementations, L is C 1-6 Alkyl group, and U is a direct bond, a 5- to 12-membered saturated or partially unsaturated heterocyclic group, or a 5- to 12-membered aryl group.

[0124] In some implementations, L is C 1-6 Alkyl group, and U is selected from the group consisting of direct bond, piperidinyl and phenyl.

[0125] In some implementations, V is a direct key.

[0126] In some embodiments, V is an alkyl group. In some embodiments, V is a C group. 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 alkyl.

[0127] In some embodiments, V is a methyl group.

[0128] In some implementations, W is a direct key.

[0129] In some embodiments, W is an aryl group. In some embodiments, W is a 5- to 12-membered aryl group, a 5- to 10-membered aryl group, a 5- to 8-membered aryl group, or a 5- to 6-membered aryl group.

[0130] In some embodiments, W is phenyl.

[0131] In some embodiments, W is a heterocyclic group. In some embodiments, W is a saturated heterocyclic group. In some embodiments, W is a partially unsaturated heterocyclic group.

[0132] In some embodiments, W is a 5- to 12-membered heterocyclic group, a 5- to 11-membered heterocyclic group, a 5- to 10-membered heterocyclic group, a 5- to 9-membered heterocyclic group, a 5- to 8-membered heterocyclic group, a 5- to 7-membered heterocyclic group, or a 5- to 6-membered heterocyclic group.

[0133] In some embodiments, W is a 5- to 12-membered saturated heterocyclic group, a 5- to 11-membered saturated heterocyclic group, a 5- to 10-membered saturated heterocyclic group, a 5- to 9-membered saturated heterocyclic group, a 5- to 8-membered saturated heterocyclic group, a 5- to 7-membered heterocyclic group, or a 5- to 6-membered saturated heterocyclic group.

[0134] In some embodiments, W is pyrrolidinyl, piperidinyl, or piperazineyl.

[0135] In some implementations, Z is a direct key.

[0136] In some implementations, Z is optionally represented by one or more R 4 Substituted alkyl groups. In some embodiments, Z is optionally replaced by one or more R groups. 4 Replacement C 1-8 alkyl.

[0137] In some implementations, R 4 It is cycloalkyl or aryl.

[0138] In some implementations, Z is C 1-8 alkyl.

[0139] In some implementations, Z is C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 Alkyl groups, each of which is composed of one or two R groups 4 Replace, and R 4 It can be cycloalkyl or aryl independently.

[0140] In some embodiments, Z is methyl or ethyl, which is reacted with one or two R 4 Replace, and R 4 It can be either adamantyl or phenyl.

[0141] In some implementations, Z is optionally represented by one or more R 4 Substituted aryl group. In some embodiments, Z is optionally replaced by one or more R groups. 4 Replaced 5 to 12 aryl groups.

[0142] In some implementations, R 4 It is an alkyl group.

[0143] In some implementations, Z is optionally represented by one or more R 4 Substituted phenyl, wherein R 4 C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 alkyl.

[0144] In some implementations, Z is the result of one or more R 4 Substituted phenyl, wherein R 4 It can be methyl or ethyl.

[0145] In some implementations, Z is NR 1 R 2 .

[0146] In some implementations, R 1 and R 2 It can be alkyl or cycloalkyl on its own.

[0147] In some implementations, R 1 and R 2 Independently for C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 alkyl.

[0148] In some implementations, R 1 and R 2 Independently for C 3-6 Cycloalkyl.

[0149] In some implementations, Z is OR 3 .

[0150] In some implementations, R 3 It is an alkyl group. In some embodiments, R 3 C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 Alkyl group. In some embodiments, R3 It is a methyl group.

[0151] In some embodiments, this disclosure provides a prodrug compound having a formula selected from the group consisting of:

[0152]

[0153] Or its pharmaceutically acceptable salts, wherein L, U, V, W, Z and R a As defined above.

[0154] In some embodiments, in prodrug compounds having formula (II), (III), (IV) or (V),

[0155] L stands for direct bond.

[0156] U can be a heterocyclic group, aryl group, or heteroaryl group.

[0157] V is a direct bond or an alkyl group.

[0158] W can be a direct bond, a heterocyclic group, or an aryl group;

[0159] Z represents alkyl, aryl, or NR. 1 R 2 OR 3 The alkyl and aryl groups are optionally separated by one or more R groups. 4 Replace, where R 1 R 2 R 3 and R 4 As defined above.

[0160] In some embodiments, this disclosure provides a prodrug compound having a formula selected from the group consisting of:

[0161]

[0162] Or a pharmaceutically acceptable salt thereof, wherein Q is hydrogen or ethyl, and L, U, V, W, Z and R a As defined above.

[0163] In some embodiments, in prodrug compounds having formulas (VI), (VII), (VIII) or (IX),

[0164] L represents a direct bond or an alkyl group.

[0165] U is a direct bond or an aryl group.

[0166] V stands for direct bond.

[0167] W can be a direct bond or a heterocyclic group;

[0168] Z is NR 1R 2 Or optionally by one or more R 4 Substituted alkyl groups.

[0169] Where R 1 R 2 and R 4 As defined above.

[0170] In some embodiments, this disclosure provides a prodrug compound having the following formula:

[0171]

[0172] Or a pharmaceutically acceptable salt thereof, wherein L, U, V, W and Z are as defined above.

[0173] In some embodiments, this disclosure provides a prodrug compound having the following formula:

[0174]

[0175] Or a pharmaceutically acceptable salt thereof, wherein L, U, V, W and Z are as defined above.

[0176] In some embodiments, the solubility of the prodrug compound provided herein is lower than that of the parent drug at biological pH. In some embodiments, this disclosure provides a prodrug compound selected from the group consisting of:

[0177]

[0178]

[0179]

[0180] The prodrug compounds described herein are described with reference to both general formulas and specific compounds. Furthermore, the prodrug compounds of this disclosure can exist in many different forms or derivatives, all of which are within the scope of this disclosure. These include, for example, tautomers, stereoisomers, racemic mixtures, regioisomers, salts, solvated forms, amorphous forms, different crystalline forms, or polymorphs.

[0181] Depending on the choice of substituents, the prodrug compounds of this disclosure may contain one or more asymmetric centers and therefore may be in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the prodrug compounds provided herein may have an asymmetric carbon center, and therefore the compounds provided herein may have (R) or (S) stereoconfigurations at the carbon asymmetric center. Thus, the prodrug compounds of this disclosure may be in individual enantiomers, diastereomers, or geometric isomers, or may be in mixtures of stereoisomers.

[0182] As used herein, the term "enantiomer" refers to two stereoisomers of a compound that are non-overlapping mirror images of each other. The term "diastereomer" refers to a pair of optical isomers that are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral characteristics, and reactivity.

[0183] When specific enantiomers are preferred, in some embodiments they may be provided substantially free of the opposing enantiomers and may also be referred to as “optical enrichment.” As used herein, “optical enrichment” means that the compound consists of a significantly larger proportion of one enantiomer. In some embodiments, the compound consists of at least about 90 wt% of the preferred enantiomer. In other embodiments, the compound consists of at least about 95 wt%, 98 wt%, or 99 wt% of the preferred enantiomer. The preferred enantiomers can be separated from the racemic mixture by any method known to those skilled in the art, such as by chromatography or crystallization, synthesis using stereochemically homogeneous starting materials, or stereoselective synthesis. Optionally, derivatization may be performed prior to the separation of the stereoisomers. The separation of the mixture of stereoisomers may be performed as an intermediate step during the synthesis of the compound provided herein or may be performed on the final racemic product. Absolute stereochemistry can be determined by X-ray crystallography of the crystalline product or crystalline intermediate, which, if necessary, has been derivatized with a reagent containing a stereocenter of known configuration. Alternatively, absolute stereochemistry can be determined by vibrational circular dichroism (VCD) spectroscopy. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, SH et al., Tetrahedron 33:2725 (1977); Eliel, EL., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH., Tables of Resolving Agents and Optical Resolutions, p. 268 (E.L. Eliel, ed., University of Notre Dame Press, Notre Dame, IN 1972).

[0184] In some embodiments, a mixture of diastereomers is provided, such as a mixture enriched with 51% or more of one of the diastereomers, including, for example, 60% or more, 70% or more, 80% or more, or 90% or more of one of the diastereomers.

[0185] This disclosure also covers compounds in the form of individual isomers that are substantially free of other isomers, and alternatively, in the form of mixtures of multiple isomers (e.g., racemic mixtures of enantiomers).

[0186] The prodrug compounds disclosed herein may also exist in different tautomer forms, and all such forms are covered within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to structural isomers of different energies that can interconvert via low energy barriers. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton migration, such as keto-enol, amide-imino, lactam-lactamimide, imine-enamine isomerization, and cyclic forms, wherein a proton can occupy two or more positions in a heterocyclic system (e.g., 1H-imidazole and 3H-imidazole, 1H-1,2,4-triazole, 2H-1,2,4-triazole and 4H-1,2,4-triazole, 1H-isoindole and 2H-isoindole, and 1H-pyrazole and 2H-pyrazole). Valence tautomers include interconversions through the recombination of some bonding electrons. Tautomers may be in equilibrium or spatially locked into one form by appropriate substitution. Unless otherwise stated, the compounds of this disclosure identified by name or structure as a particular tautomer form are intended to include other tautomer forms.

[0187] This disclosure also intends to include all isotopes of atoms in the compounds. Isotopes of atoms include atoms having the same number of atoms but different mass numbers. For example, unless otherwise stated, the isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, or iodine in the compounds of this disclosure are also intended to include, but are not limited to: 1 H, 2 H, 3 H, 11 C 12 C 13 C 14 C 14 N、 15 N、 16 O、 17 O、 18 O、 31 P, 32 P, 32 S, 33 S, 34 S, 36 S, 17F, 18 F, 19 F, 35 Cl、 37 Cl、 79 Br、 81 Br、 124 I, 127 I and 131 I. In some embodiments, hydrogen includes protium, deuterium, and tritium. In some embodiments, carbon includes... 12 C and 13 C. Isotope-enriched compounds of formula (I) can be prepared without excessive experimentation using conventional techniques well known to those skilled in the art or using processes similar to those described in the schemes and examples herein, using appropriate isotope-enriching reagents and / or intermediates.

[0188] The prodrug compounds disclosed herein can be formulated as pharmaceutically acceptable salts or in the form of pharmaceutically acceptable salts. Unless otherwise stated, the prodrug compounds provided herein include pharmaceutically acceptable salts of such compounds.

[0189] As used herein, the term "pharmaceutically acceptable" indicates that a substance or composition is chemically and / or toxicologically compatible with other components constituting the formulation and / or with the subject being treated therein.

[0190] As used herein, unless otherwise indicated, the term "pharmaceutically acceptable salt" includes salts that retain the bioavailability of the specified compound as a free acid and base and are not biologically or otherwise undesirable. Considered pharmaceutically acceptable salt forms include, but are not limited to, monosalts, disalts, trisalts, tetrasalts, etc. Pharmaceutically acceptable salts are non-toxic at the amount and concentration at which they are administered. The preparation of such salts can facilitate pharmacological use by altering the physical characteristics of the compound without impairing its physiological effects. Useful alterations to physical properties include lowering the melting point to facilitate transmucosal administration and increasing solubility to facilitate administration of higher drug concentrations.

[0191] Pharmaceutically acceptable salts include acid addition salts, such as those containing the following acids: sulfates, chlorides, hydrochlorides, fumarates, maleates, phosphates, aminosulfonates, acetates, citrates, lactates, tartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylaminosulfonates, and quinates. Pharmaceutically acceptable salts can be obtained from acids such as: hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, aminosulfonic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylaminosulfonic acid, fumaric acid, and quinates.

[0192] Pharmaceutically acceptable salts, when acidic functional groups (such as carboxylic acids or phenols) are present, also include base addition salts, such as those containing the following base addition salts: benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, tert-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamines, and zinc. See, for example, *Remington's Pharmaceutical Sciences*, 19th edition, Mack Publishing Co., Easton, PA, Vol. 2, p. 1457, 1995; Stahl and Wermuth, *Handbook of Pharmaceutical Salts: Properties, Selection, and Use*, Wiley-VCH, Weinheim, Germany, 2002. These salts can be prepared using appropriate corresponding bases.

[0193] Pharmaceutically acceptable salts can be prepared using standard techniques. For example, the free base form of a compound can be dissolved in a suitable solvent (such as an aqueous solution or a water-alcohol solution containing a suitable acid) and then separated by evaporation of the solution. Therefore, if a particular compound is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art, for example, by treating the free base with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or with organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranoic acids (such as glucuronic acid or galacturonic acid), α-hydroxy acids (such as citric acid or tartaric acid), amino acids (such as aspartic acid or glutamic acid), aromatic acids (such as benzoic acid or cinnamic acid), sulfonic acids (such as p-toluenesulfonic acid or ethanesulfonic acid), etc.

[0194] Similarly, if a particular compound is an acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method, for example, by treating the free acid with an inorganic or organic base such as an amine (primary, secondary, or tertiary), an alkali metal hydroxide, or an alkaline earth metal hydroxide. Illustrative examples of suitable salts include organic salts derived from amino acids such as L-glycine, L-lysine, and L-arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines such as hydroxyethylpyrrolidine, piperidine, morpholine, or piperazine; and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0195] It should also be understood that the compounds disclosed herein may exist in non-solventized, solvated (e.g., hydrated) and solid (e.g., crystalline or polycrystalline) forms, and this disclosure is intended to cover all such forms.

[0196] As used herein, the term "solvent" or "solventized form" refers to a solvation form containing stoichiometric or non-stoichiometric amounts of solvent. Some compounds tend to retain a fixed molar proportion of solvent molecules in a crystalline solid state, thereby forming a solvate. If the solvent is water, the resulting solvate is a hydrate; and if the solvent is an alcohol, the resulting solvate is an alcohol. Hydrates are formed by the combination of one or more water molecules with a molecule of another substance, wherein the water retains its molecular state as H₂O. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

[0197] As used herein, the terms "crystalline form," "polycrystalline form," "polymorph," and "polymorph" are used interchangeably and refer to the crystal structures in which a compound (or its salts or solvates) can crystallize in different crystalline arrangements, all of which have the same elemental composition. Different crystalline forms typically exhibit different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can cause one crystalline form to dominate. Polymorphs of a compound can be prepared by crystallization under different conditions.

[0198] Compound Synthesis

[0199] The synthesis of the prodrug compounds provided herein is illustrated in the synthetic protocols of the examples. The prodrug compounds provided herein can be prepared using any known organic synthetic technique and can be synthesized according to any of a variety of possible synthetic routes; therefore, these protocols are merely illustrative and not intended to limit other possible methods that can be used to prepare the compounds provided herein. Furthermore, the steps in the protocols are for better illustration and may be modified where appropriate. The embodiments for synthesizing the prodrug compounds in the examples are for research purposes and possibly for submission to regulatory authorities.

[0200] The reactions used to prepare the prodrug compounds of this disclosure can be carried out in suitable solvents that can be readily selected by those skilled in the art of organic synthesis. Suitable solvents are those that do not substantially react with the starting materials (reactants), intermediates, or products at the temperature at which the reaction takes place, for example, at a temperature in the range of the solvent's freezing temperature to its boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the specific reaction step, a suitable solvent for that particular reaction step can be selected by those skilled in the art.

[0201] The preparation of the prodrug compounds disclosed herein may involve the protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of appropriate protecting groups can be readily determined by those skilled in the art. The chemical properties of protecting groups can be found, for example, in T.W. Greene and P.G. M.Muts, *Protective Groups in Organic Synthesis*, 3rd ed., Wiley & Sons, Inc., New York (1999); P. Kocienski, *Protecting Groups*, Georg Thieme Verlag, 2003; and Peter G.M. Muts, *Greene's Protective Groups in Organic Synthesis*, 5th ed., Wiley, 2014. All of these references are incorporated herein by reference in their entirety.

[0202] The reaction can be monitored using any suitable method known in the field. For example, it can be monitored using spectroscopic techniques, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13C) Infrared spectroscopy (IR), spectrophotometry (e.g., UV-Vis), mass spectrometry, or chromatography, such as high-performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), or thin-layer chromatography (TLC), can be used to monitor product formation. Those skilled in the art can purify compounds using a variety of methods, including high-performance liquid chromatography (HPLC) (“Preparative LC-MS Purification: Improved Compound Specific Method Optimization”, Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs, *J. Combi. Chem.*, 2004, 6(6), 874-883, which is incorporated herein by reference in its entirety) and normal-phase silica chromatography.

[0203] The known starting materials disclosed herein can be synthesized using or according to methods known in the art, or can be purchased from commercial suppliers. Unless otherwise indicated, analytical grade solvents and commercially available reagents are used without further purification.

[0204] Unless otherwise specified, all reactions in this disclosure are carried out under positive pressure of nitrogen or argon or in anhydrous solvent using a drying tube, and the reaction flasks are typically fitted with rubber septa for introducing substrates and reagents via syringe. Glassware is dried and / or heat-dried.

[0205] Uses of compounds

[0206] In one aspect, this disclosure provides a prodrug compound capable of locally delivering a therapeutic agent and releasing the therapeutic agent in a controlled and sustained manner, wherein systemic exposure and potential side effects attributable to systemic exposure are reduced. Therefore, depending on the parent drug selected for release, the prodrug compound of this disclosure, or a pharmaceutically acceptable salt thereof, is suitable as a treatment or preventative agent for a variety of diseases.

[0207] As used herein, the term "therapy" is intended to have its general meaning as the treatment of a disease to completely or partially alleviate one, some, or all of its symptoms, or to correct or compensate for the underlying pathology, thereby achieving a beneficial or desired clinical outcome. For the purposes of this disclosure, beneficial or desired clinical outcomes include, but are not limited to, symptom relief, reduction of disease severity, stabilization of disease status (i.e., no worsening), delay or slowing of disease progression, improvement or mitigation of disease condition, and remission (partial or complete), whether detectable or undetectable. "Therapy" may also mean prolonged survival compared to expected survival without therapy. Situations requiring therapy include pre-existing conditions or symptoms, as well as conditions predisposing to or requiring prevention of conditions or symptoms. Unless specifically indicated to the contrary, the term "therapy" also encompasses prevention. The terms "therapeutic" and "therapeutically" should be interpreted accordingly.

[0208] The term “treatment” is used synonymously with “therapeutic treatment.” Similarly, the term “treatment” can be considered as “the application of a therapeutic treatment,” where “therapeutic treatment” is as defined herein.

[0209] As used herein, the term “prevention” is intended to have its usual meaning and includes primary prevention for preventing the development of disease, as well as secondary prevention, where the disease has already developed and the patient is temporarily or permanently protected from disease exacerbation or worsening or the development of new disease-related symptoms.

[0210] The prodrug compounds or pharmaceutically acceptable salts of the present disclosure exhibit the desired overall release rate of the parent drug by controlling the solubility of the parent drug at biological pH and the release of the parent drug at different pH values.

[0211] In some embodiments, at biological pH, the solubility of the prodrug compound of this disclosure or its pharmaceutically acceptable salt is lower than that of the parent drug.

[0212] In some embodiments, the prodrug compound of this disclosure or a pharmaceutically acceptable salt thereof exhibits higher solubility at acidic pH than at biological pH. In some embodiments, the ratio of the solubility of the prodrug compound of this disclosure or a pharmaceutically acceptable salt thereof at acidic pH to its solubility at biological pH is greater than 5, greater than 10, greater than 20, greater than 30, greater than 40, greater than 50, greater than 60, greater than 70, greater than 80, greater than 90, greater than 100, greater than 200, greater than 300, greater than 400, greater than 500, greater than 600, greater than 700, greater than 800, greater than 900, greater than 1000, greater than 1100, greater than 1200, greater than 1300, greater than 1400, greater than 1500, or even higher.

[0213] The reduced solubility of the prodrug compounds presented in this article can avoid high local concentrations after administration, thereby providing a solubility-controlled zero-order sustained release mechanism.

[0214] The parent drug can be released from the prodrug compound provided herein via the cleavage of the bond between the parent drug portion and the tail portion. The release of the parent drug can involve enzymatic or non-enzymatic processes. In some embodiments, the parent drug is released from the prodrug compound provided herein via a hydrolysis process.

[0215] The release of a parent drug can be influenced by a variety of factors, such as the choice of a specific parent drug, the bond between the parent drug moiety and the tail moiety, and the administration of the tail moiety and the prodrug compound (e.g., site of administration, route of administration). This disclosure considers parent drugs with different reactive groups and bonds to the tail moiety.

[0216] This disclosure also envisions different administration methods of the prodrug compound provided herein. In some embodiments, the prodrug compound provided herein is administered topically to a subject in need. In some embodiments, the prodrug compound provided herein is administered topically to a subject in need via injection. In some embodiments, the prodrug compound provided herein is administered topically to a subject in need via oral dosage form. In some embodiments, the prodrug compound provided herein is administered topically to a subject in need via inhalation. In some embodiments, the prodrug compound provided herein is administered topically to a subject in need via implantation. In some embodiments, the prodrug compound provided herein is administered topically to a subject in need via local application. Depending on the specific combination of parent drug, cleavable bond, and tail portion, the release of the parent drug after administration to the subject can occur at multiple sites.

[0217] In some embodiments, the prodrug compound or its pharmaceutically acceptable salt provided herein may release the parent drug at different ratios via hydrolysis.

[0218] In some embodiments, the release rate of the parent drug from the prodrug compound or its pharmaceutically acceptable salt provided herein can be characterized by the percentage of the parent drug released from the prodrug compound at pH 7.4 within 6 hours after administration. In some embodiments, the release rate of the parent drug from the prodrug compound at pH 7.4 can vary from about 50% to about 100% within 6 hours after administration, for example, about 55% to about 100%, about 60% to about 100%, about 65% to about 100%, about 70% to about 100%, about 75% to about 100%, about 80% to about 100%, about 85% to about 100%, about 90% to about 100%, about 95% to about 100%, about 96% to about 100%, about 97% to about 100%, about 98% to about 100%, about 99% to about 100%, or even about 100%.

[0219] In some embodiments, the release rate of the parent drug from the prodrug compound or its pharmaceutically acceptable salt provided herein can be characterized by the percentage of the parent drug released from the prodrug compound at pH 7.4 within 0.5 hours after administration. In some embodiments, the release rate of the parent drug from the prodrug compound at pH 7.4 can vary from about 5% to about 100% within 0.5 hours after administration, for example, about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 90% to about 100%, about 95% to about 100%, about 96% to about 100%, about 97% to about 100%, about 98% to about 100%, about 99% to about 100%, or even about 100%.

[0220] In some embodiments, at pH 2.0, the release rate of the parent drug from the prodrug compound within 6 hours after administration is no greater than 70%, for example, no greater than 65%, no greater than 60%, no greater than 55%, no greater than 50%, no greater than 45%, no greater than 40%, no greater than 35%, no greater than 30%, no greater than 25%, no greater than 20%, no greater than 15%, no greater than 10%, no greater than 5%, no greater than 4%, no greater than 3%, no greater than 2%, or no greater than 1%. In some embodiments, at pH 2.0, the prodrug compound provided herein remains stable without releasing the parent drug through hydrolysis.

[0221] In some embodiments, the release rate of the parent drug from the prodrug compound or its pharmaceutically acceptable salt provided herein can be determined by the hydrolysis constant (K) of the prodrug compound within 6 hours after administration. h Characterization. In some embodiments, the Ki of the prodrug compound provided herein is characterized at pH 7.4.h The value can be in the range of about 0.1 to about 15, for example about 0.1 to about 14, about 0.1 to about 13, about 0.1 to about 12, about 0.1 to about 11, about 0.1 to about 10, about 0.1 to about 9, about 0.1 to about 8, about 0.1 to about 7, about 0.1 to about 6, about 0.1 to about 5, about 0.1 to about 4, about 0.1 to about 3, about 0.1 to about 2, about 0.1 to about 1, about 0.1 to about 0.5, about 0.1 to about 0.4, about 0.1 to about 0.3, or about 0.1 to about 0.2.

[0222] In some embodiments, at pH 2.0, the K of the prodrug compound provided herein is... h The value may not exceed 0.2, for example, not exceeding 0.15, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, or 0.01. In some embodiments, the K of the prodrug compound provided herein... h The value can be 0.

[0223] In some implementations, the prodrug compound provided herein releases more parent drug within 6 hours after administration at pH 7.4 compared to pH 2.0.

[0224] In some embodiments, the ratio of the percentage of parent drug released from the prodrug compound provided herein within 6 hours after administration at pH 7.4 to the percentage at pH 2.0 is greater than 1, for example, greater than 1.1, greater than 1.2, greater than 1.3, greater than 1.4, greater than 1.5, greater than 2, greater than 2.5, greater than 3, greater than 3.5, greater than 4, greater than 4.5, greater than 5, greater than 5.5, greater than 6, greater than 7, greater than 8, greater than 9, greater than 10, etc.

[0225] In some embodiments, the prodrug compound provided herein is K at pH 7.4. h Value and K at pH 2.0 h The ratio of the value is greater than 1, such as greater than 1.5, greater than 2, greater than 3, greater than 4, greater than 5, greater than 10, greater than 20, greater than 30, greater than 40, greater than 50, greater than 60, greater than 70, greater than 80, greater than 90, greater than 100, greater than 150, greater than 200, greater than 250, greater than 300, greater than 350, greater than 400, etc.

[0226] By intentionally selecting appropriate parent drug and tail fractions to achieve the desired combination of solubility and release profiles, the prodrug compounds presented herein can provide sustained release of the parent drug over a period of 1–12 hours.

[0227] Pharmaceutical Composition

[0228] In another aspect, a pharmaceutical composition comprising the prodrug compound disclosed herein is provided.

[0229] In another aspect, a pharmaceutical composition comprising a prodrug compound of the present disclosure and at least one pharmaceutically acceptable excipient is provided.

[0230] As used herein, the term "pharmaceutical composition" refers to a formulation containing a drug delivery system of the present disclosure in a form suitable for administration to a subject.

[0231] As used herein, the term "pharmaceuticalally acceptable excipient" means an excipient suitable for the preparation of pharmaceutical compositions that are generally safe and non-toxic and biologically and otherwise desirable, and includes excipients acceptable for veterinary and human pharmaceutical use. As used herein, "pharmaceuticalally acceptable excipient" includes one or more such excipients. The term "pharmaceuticalally acceptable excipient" also covers "pharmaceuticalally acceptable carriers" and "pharmaceuticalally acceptable diluents."

[0232] The pharmaceutical compositions described herein may be in any form that allows the composition to be administered to subjects (including, but not limited to, humans) and formulated to be compatible with the intended route of administration.

[0233] Multiple routes of administration are considered for the pharmaceutical compositions provided herein, and therefore the pharmaceutical compositions provided herein may be supplied in bulk or unit dosage forms depending on the intended route of administration. For example, for oral, buccal, and sublingual administration, powders, granules, tablets, pills, capsules, capsule tablets, and capsule sachets may be acceptable as solid dosage forms, and emulsions, syrups, elixirs, suspensions, and solutions may be acceptable as liquid dosage forms. For injectable administration, gels, solutions, emulsions, and suspensions may be acceptable as liquid dosage forms, and powders suitable for reconstitution with appropriate solutions may be acceptable as solid dosage forms. For inhalation administration, solutions, sprays, dry powders, and aerosols may be acceptable dosage forms. For topical (including buccal and sublingual) or transdermal administration, powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches may be acceptable dosage forms. For vaginal administration, vaginal suppositories, tampons, creams, gels, pastes, foams, and sprays may be acceptable dosage forms. For implantable administration, solid, semi-solid, and gel dosage forms may be acceptable dosage forms.

[0234] In some embodiments, the pharmaceutical compositions of this disclosure may be in the form of an oral administration formulation.

[0235] In some embodiments, the pharmaceutical compositions of this disclosure may be in the form of an injectable formulation.

[0236] In some embodiments, the pharmaceutical compositions disclosed herein may be in the form of an inhalation formulation.

[0237] In some embodiments, the pharmaceutical compositions of this disclosure may be in the form of a topical application formulation.

[0238] In some embodiments, the pharmaceutical compositions provided herein may be formulated in the form of skin patches, as is well known to those skilled in the art.

[0239] In addition to the representative dosage forms mentioned above, pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are therefore included in this disclosure. Such excipients and carriers are described, for example, in Remington's Pharmaceutical Sciences, Mark Publishing, NJ (1991), Remington: The Science and Practice of Pharmacy, University of the Sciences in Philadelphia, ed., 21st ed., LWW (2005), which are incorporated herein by reference.

[0240] In some embodiments, the pharmaceutical compositions of this disclosure may be formulated as a single dose. The amount of the prodrug compound provided herein in a single dose will vary depending on the subject being treated and the specific administration method.

[0241] In some embodiments, the pharmaceutical compositions disclosed herein may be formulated for administration to a subject at intervals of days, weeks, months or even longer.

[0242] On the other hand, pharmaceutical compositions incorporating the drug delivery system of this disclosure are also provided as two or more combination therapies.

[0243] application

[0244] On the other hand, the use of the prodrug compound provided herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof in the preparation of a medicament for treating a disease in a subject in need is provided.

[0245] Methods of treating diseases

[0246] On the other hand, a method for treating a disease in a subject in need is provided, comprising administering to the subject a therapeutically effective amount of the prodrug compound or pharmaceutical composition provided herein.

[0247] The disease to be treated depends on the parent drug selected in the prodrug compound or pharmaceutical composition provided herein. In some embodiments, the disease may be selected from the group consisting of: anal cancer, breast cancer, colorectal cancer, esophageal cancer, pancreatic cancer, head and neck cancer, brain cancer, liver cancer, gastric cancer, bladder cancer, oral mucosal cancer, esophageal cancer, anaplastic astrocytoma, glioblastoma multiforme, acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, Kaposi's sarcoma, and neuroblastoma.

[0248] In some implementations, the parent drug is selected from anticancer agents, anti-inflammatory drugs, antibiotics, antifungal agents, JAK inhibitors, and VEGF inhibitors.

[0249] In some embodiments, the selected parent drug is fluorouracil, and therefore the prodrug compounds provided herein are suitable for treating cancers, including colon cancer, esophageal cancer, gastric cancer, rectal cancer, breast cancer, biliary tract cancer, stomach cancer, head and neck cancer, cervical cancer, pancreatic cancer, renal cell carcinoma, and carcinoid.

[0250] In some embodiments, the selected parent drug is temozolomide, and therefore the prodrug compounds provided herein are suitable for the treatment of anaplastic astrocytoma and glioblastoma multiforme.

[0251] In some embodiments, the parent drug is daunorubicin, and therefore the prodrug compounds provided herein are suitable for the treatment of acute non-lymphocytic leukemia (myeloid, monocytic, erythroid) and acute lymphoblastic leukemia.

[0252] In some embodiments, the selected parent drugs are 10-hydroxycamptothecin and 7-ethyl-10-hydroxycamptothecin, and therefore the prodrug compounds provided herein are suitable for treating cancers, including gastric cancer, esophageal cancer, cardia cancer, colon cancer, liver cancer, lung cancer, bladder cancer, acute leukemia, chronic myeloid leukemia, and choriocarcinoma.

[0253] In this context, the term "therapeutic effective amount" refers to the amount of a selected therapeutic agent or its pharmaceutically acceptable salt in the drug delivery system provided herein, which is effective in providing "therapy" or "treatment" to a subject's ailment, disease, or condition.

[0254] Example

[0255] For illustrative purposes, the following examples are included. However, it should be understood that these examples do not limit the present disclosure and are intended only to illustrate the methods of practicing the present disclosure. Those skilled in the art will recognize that the described chemical reactions are readily applicable to the preparation of many other compounds of the present disclosure or pharmaceutically acceptable salts thereof, and alternative methods for the preparation of the compounds of the present disclosure or pharmaceutically acceptable salts thereof are considered within the scope of the present disclosure. For example, non-exemplary compounds according to the present disclosure can be successfully synthesized by modifications obvious to those skilled in the art, such as by appropriately protecting interfering groups, by utilizing other suitable reagents and building blocks known in the art besides the described reagents and building blocks, and / or by conventionally changing the reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be considered suitable for the preparation of other compounds of the present disclosure.

[0256] As used herein, the notation and conventions employed in these processes, protocols, and embodiments are consistent with those used in contemporary scientific literature, such as the *Journal of the American Chemical Society* or the *Journal of Biological Chemistry*. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. For example, the following abbreviations may be used in the examples and throughout the specification: g (gram); mg (milligram); L (liter); mL (milliliters); μL (microliter); psi (pounds per square inch); M (molar); mM (millimole); iv (intravenous); Hz (hertz); MHz (megahertz); aq. (aqueous solution); mol (molar); mmol (millimole); rt (room temperature); min (minute); h (hour); mp (melting point); TLC (thin-layer chromatography); Rt (retention time); RP (reversed phase); AcOH (acetic acid); MeOH (methanol); i-PrOH (isopropanol); TEA (triethylamine); TFA (trifluoroacetic acid); THF (tetrahydrofuran); DMSO (dimethyl sulfoxide); EtOAc (ethyl acetate); DCM (dichloromethane); HCHO (formaldehyde); MeCN (acetonitrile); DIPEA (N,N-diisopropylethylamine); PE (petroleum ether); DMF (N,N-dimethylformamide); Pd2dba3 (tris(diphenylmethyleneacetone)dipalladium); NMP (1-methyl-2-pyrrolidone); HATU (2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylureon hexafluorophosphate); BOP ((benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate).

[0257] Unless otherwise indicated, all temperatures are expressed in °C (degrees Celsius). Unless otherwise specified, all reactions are carried out under an inert atmosphere at rt.

[0258] 1 ¹H NMR spectra were recorded on an Agilent 400MR NMR spectrometer. Chemical shifts are expressed in parts per million (ppm). Coupling constants are expressed in Hertz (Hz). Splitting modes describe obvious multiplicity and are represented as s (singleton), d (doublet), t (triplet), q (quartet), m (multiplet), and br (broad peak).

[0259] Low-resolution mass spectrometry (MS) and compound purity data were acquired on an Agilent LC / MS single quadrupole system equipped with an electrospray ionization (ESI) source and UV detectors (215 and 254 nm).

[0260] Example 1

[0261] ((5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)carbonate 2-(1-(4-(dibutylamino)phenyl)piperidin-4-yl)ethyl ester(1)

[0262]

[0263] Synthetic pathway of 1

[0264]

[0265] 5-Fluoro-1-(hydroxymethyl)pyrimidine-2,4(1H,3H)-dione (1a)

[0266]

[0267] The reaction mixture of 5-fluorouracil (10 g, 76.9 mmol) and 37% HCHO (aq.) (100 mL) in a sealed tube was stirred at 60 °C for 5 hours, and the mixture was concentrated to give the crude product 5-fluoro-1-(hydroxymethyl)pyrimidine-2,4(1H,3H)-dione (1a), which was used directly in the next step. MS-ESI (m / z): 161 [M+1] + .

[0268] 2-(1-(4-nitrophenyl)piperidin-4-yl)ethyl acetate (1b)

[0269]

[0270] The reaction mixture of 1-fluoro-4-nitrobenzene (248 mg, 1.76 mmol), 2-(piperidin-4-yl)ethyl acetate hydrochloride (443 mg, 2.13 mmol), and K₂CO₃ (738 mg, 5.34 mmol) in MeCN (10 mL) was stirred at 110 °C for 5 hours in a sealed tube. The mixture was then filtered and concentrated to give the crude product 2-(1-(4-nitrophenyl)piperidin-4-yl)ethyl acetate (1b), which was used directly in the next step. MS-ESI (m / z): 293 [M+1] + .

[0271] 2-(1-(4-aminophenyl)piperidin-4-yl)ethyl acetate (1c)

[0272]

[0273] A mixture of ethyl 2-(1-(4-nitrophenyl)piperidin-4-yl)ethyl acetate (1b) (415 mg, 1.42 mmol), Fe powder (1.5 g, 26.8 mmol), (NH4)2SO4 (108 mg, 0.81 mmol), and 1 M HCl (2.5 mL) in EtOH (20 mL) was refluxed and heated for 3 hours. The mixture was filtered and concentrated to give crude ethyl 2-(1-(4-aminophenyl)piperidin-4-yl)ethyl acetate (1c), which was used directly in the next step. MS-ESI (m / z): 263 [M+1] + .

[0274] 2-(1-(4-(dibutylamino)phenyl)piperidin-4-yl)ethyl acetate (1d)

[0275]

[0276] AcOH (1 mL), n-butyraldehyde (415 μL, 4.7 mmol), and NaBH3CN (820 mg, 13.0 mmol) were added to a solution of ethyl 2-(1-(4-aminophenyl)piperidin-4-yl)ethyl acetate (1c) (370 mg, 1.41 mmol) in MeOH (20 mL). The mixture was stirred for 1.5 h, then concentrated to remove MeOH, dissolved in EtOAc and washed with NaHCO3 (aq), dried, and concentrated to give the crude product ethyl 2-(1-(4-(dibutylamino)phenyl)piperidin-4-yl)ethyl acetate (1d), which was used directly in the next step. MS-ESI (m / z): 375 [M+1] + .

[0277] 2-(1-(4-(dibutylamino)phenyl)piperidin-4-yl)ethanol-1-ol (1e)

[0278]

[0279] 1 M LiAlH4-THF (35 mL, 35 mmol) was added to a solution of ethyl 2-(1-(4-(dibutylamino)phenyl)piperidin-4-yl)acetate (1d) (2.1 g, 5.6 mmol) in THF (24 mL). The mixture was stirred overnight, quenched with water, extracted with EtOAc, dried, and concentrated. The residue was purified by silica gel column chromatography, eluting with petroleum ether and EtOAc, to give 304 mg of 2-(1-(4-(dibutylamino)phenyl)piperidin-4-yl)ethanol-1-ol (1e). MS-ESI (m / z): 333 [M+1] + .

[0280] ((5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)carbonate 2-(1-(4-(dibutylamino)phenyl)piperidin-4-yl)ethyl ester(1)

[0281]

[0282] A solution of 2-(1-(4-(dibutylamino)phenyl)piperidin-4-yl)ethanol-1-ol (1e) (160 mg, 0.48 mmol) in DCM (5 mL) cooled to below -50 °C was supplemented with a solution of DIPEA (850 μL, 4.8 mmol) and triphosgene (142 mg, 0.48 mmol) in DCM (1.4 mL). The mixture was stirred at ambient temperature for 2 h and then added to a solution of 5-fluoro-1-(hydroxymethyl)pyrimidine-2,4(1H,3H)-dione (1a) (310 mg, 1.9 mmol) in MeCN (5 mL). The reactants were stirred overnight and purified by preparative chromatography, eluting with MeCN and 0.1% TFA-H2O to give 2-(1-(4-(dibutylamino)phenyl)piperidin-4-yl)ethyl carbonate (1) (39 mg). MS-ESI (m / z): 519 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.03(d,J=5.0Hz,1H),8.14(d,J=6.5Hz,1H),7.38(brs,2H),6. 67(brs,2H),5.58(s,2H),4.18(t,J=6.2Hz,2H),3.61-2.93(m,8H),2.03-0.58(m,21H).

[0283] Example 2

[0284] ((5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)carbonate 4'-(dipropylamino)-[1,1'-biphenyl]-4-yl ester (2)

[0285]

[0286] Synthetic pathway of 2

[0287]

[0288] 4'-Amino-[1,1'-biphenyl]-4-ol (2a)

[0289]

[0290] The reaction mixture of 4'-nitro-[1,1'-biphenyl]-4-ol (500 mg, 2.32 mmol), Fe powder (2.63 g, 47.0 mmol), NH4Cl (125 mg, 2.32 mmol), AcOH (500 μL), and 1 M HCl (250 μL) in EtOH (40 mL) was refluxed and heated for 3.5 h. The mixture was filtered and concentrated to give the crude product 4'-amino-[1,1'-biphenyl]-4-ol (2a), which was used directly in the next step. MS-ESI (m / z): 186 [M+1] + .

[0291] 4'-(dipropylamino)-[1,1'-biphenyl]-4-ol (2b)

[0292]

[0293] 4'-Amino-[1,1'-biphenyl]-4-ol (2a) (400 mg, 2.16 mmol) was dissolved in MeOH (40 mL) and treated with propionaldehyde (760 μL, 10.4 mmol), AcOH (500 μL), and NaBH3CN (1.75 g, 27.9 mmol). The mixture was stirred overnight. The reaction mixture was filtered and concentrated, and the residue was diluted with EtOAc and washed with NaHCO3 (aq.). The aqueous layer was extracted twice with EtOAc. The combined layers were dried over Na2SO4 and concentrated to dryness. The residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to give the product 4'-(dipropylamino)-[1,1'-biphenyl]-4-ol (2b) (510 mg). MS-ESI (m / z): 270 [M+1] + .

[0294] ((5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)carbonate 4'-(dipropylamino)-[1,1'-biphenyl]-4-yl ester (2)

[0295]

[0296] A solution of 4'-(dipropylamino)-[1,1'-biphenyl]-4-ol (2b) (270 mg, 1 mmol) in DCM (5 mL) cooled to below 50 °C was added to a solution of DCM (3 mL) containing DIPEA (1.8 mL, 10 mmol) and triphosgene (300 mg, 1 mmol), and the mixture was stirred at -50 °C for 2 h. A suspension of 5-fluoro-1-(hydroxymethyl)pyrimidin-2,4(1H,3H)-dione (1a) (640 mg) in MeCN (5 mL) was added to the mixture and stirred for 1 h. The reaction mixture was filtered and purified by preparative chromatography, eluting with MeCN and 0.1% TFA-H2O to give ((5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)carbonate 4'-(dipropylamino)-[1,1'-biphenyl]-4-yl ester (2) (39 mg). MS-ESI(m / z): 456[M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.06(d,J=5.0Hz,1H),8.16(d,J=6.5Hz,1H),7.67-7.39(m,4H),7.27(d ,J=8.3Hz,2H),6.72(brs,2H),5.70(s,2H),3.28(brs,4H),1.50(brs,4H),0.87(t,J=7.4Hz,6H).

[0297] Example 3

[0298] ((5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)carbonate 4-(dipentanamino)phenyl ester(3)

[0299]

[0300] Synthetic pathway of 3

[0301]

[0302] 4-(Dipentanamino)phenol (3a)

[0303]

[0304] K₂CO₃ (5.2 g, 37.4 mmol) was added to a mixture of 4-aminophenol (4.0 g, 36.6 mmol), 1-iodopentane (17.1 g, 86.5 mmol), and DMF (72 mL). The reaction mixture was stirred at 75 °C for 1.5 h. The reaction mixture was poured into water (300 mL) and extracted three times with EtOAc. The combined organic layers were washed with Na₂S₂O₃ (aq.), dried over Na₂SO₄, and evaporated to dryness. The residue was purified by silica gel chromatography, eluting with PE and EA, to give 4-(dipentanamino)phenol (3a). MS-ESI (m / z): 250 [M+1] + .

[0305] ((5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)carbonate 4-(dipentylamino)phenyl ester(3)

[0306]

[0307] DIPEA (1.8 mL, 10 mmol) and triphosgene (300 mg, 1 mmol) were added to a solution of 4-(dipentylamino)phenol (3a) (250 mg, 1 mmol) cooled to below -50 °C in DCM (5 mL), and the mixture was stirred for 1 h. The mixture was then added to a suspension of 5-fluoro-1-(hydroxymethyl)pyrimidine-2,4(1H,3H)-dione (1a) (800 mg) in MeCN (5 mL), and the mixture was stirred for 1 h. The molecular sieve was dried and stirred for 1 h. The reaction mixture was filtered and purified by preparative chromatography to give ((5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)carbonate 4-(dipentylamino)phenyl ester (3) (95 mg). MS-ESI (m / z): 436 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ12.05(d,J=5.0Hz,1H),8.14(d,J=6.5Hz,1H),7.28-6.40(m,4H) ,5.67(s,2H),3.47-3.11(m,4H),1.42(s,4H),1.31-1.13(m,8H),0.83(t,J=6.8Hz,6H).

[0308] Example 4

[0309] ((5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)carbonate 4-(1-(3,5-dimethylphenyl)piperidin-4-yl)phenyl ester(4)

[0310]

[0311] Synthetic pathway of 4

[0312]

[0313] 4-(1-(3,5-dimethylphenyl)piperidin-4-yl)phenol (4a)

[0314]

[0315] A mixture of 1-bromo-3,5-xylene (0.74 g, 4 mmol), 4-(piperidin-4-yl)phenol hydrobromide (1.04 g, 4 mmol), 2-(di-tert-butylphosphino)-1,1'-biphenyl (300 mg, 1 mmol), Pd2dba3 (370 mg, 0.40 mmol), and t-BuONa (0.76 g, 7.9 mmol) in diethyloxazine dione (40 mL) was stirred at 55 °C for 3 h under nitrogen. Separately, 2-(di-tert-butylphosphino)-1,1'-biphenyl (300 mg, 1 mmol), Pd2dba3 (370 mg, 0.40 mmol), and t-BuONa (0.76 g, 7.9 mmol) were added to the reaction mixture. The reaction mixture was stirred at 55 °C for 5 h. The mixture was filtered, washed with EtOAc, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give 4-(1-(3,5-dimethylphenyl)piperidin-4-yl)phenol (4a) (638 mg). MS-ESI (m / z): 282 [M+1] + .

[0316] ((5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)carbonate 4-(1-(3,5-dimethylphenyl)piperidin-4-yl)phenyl ester(4)

[0317]

[0318] DIPEA (1.0 mL, 5.6 mmol) and triphosgene (167 mg, 0.56 mmol) were added to a solution of 4-(1-(3,5-dimethylphenyl)piperidin-4-yl)phenol (4a) (158 mg, 0.56 mmol) in DCM (4 mL) cooled to below -50 °C, and the mixture was stirred for 1 h. The reaction mixture was added to a suspension of 5-fluoro-1-(hydroxymethyl)pyrimidin-2,4(1H,3H)-dione (1a) (450 mg) in MeCN (5 mL) and stirred for 1 h. The reaction mixture was filtered and purified by preparative chromatography to give 4-(1-(3,5-dimethylphenyl)piperidin-4-yl)phenyl ester (4) (40 mg) of ((5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)carbonate. MS-ESI (m / z): 468 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.05(d,J=5.0Hz,1H),8.14(d,J=6.6Hz,1H),7.33(d,J=8.4Hz,2H),7.21(d,J=8.3 Hz,2H),7.07-6.60(m,3H),5.69(s,2H),4.57-3.59(m,4H),2.83(brs,1H),2.25(s,6H),2.04-1.76(m,4H).

[0319] Example 5

[0320] (2-(4-propylphenyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)carbonate (5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl ester (5)

[0321]

[0322] Synthetic pathway of 5

[0323]

[0324] 2-(4-propylphenyl)-1,2,3,4-tetrahydroisoquinoline-6-ol (5a)

[0325]

[0326] A suspension of 1,2,3,4-tetrahydroisoquinoline-6-ol (0.50 g, 3.36 mmol), 1-bromo-4-propylbenzene (0.75 g, 3.75 mmol), Pd2dba3 (200 mg, 0.22 mmol), dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (300 mg, 0.63 mmol), and Cs2CO3 (3.0 g, 9.2 mmol) in PhMe (15 mL) was stirred at 110 °C for 7 h in a sealed tube. The mixture was diluted with EtOAc and filtered. The filtrate was concentrated and purified by silica gel column chromatography to give 2-(4-propylphenyl)-1,2,3,4-tetrahydroisoquinoline-6-ol (5a) (109 mg). MS-ESI (m / z): 268 [M+1] + .

[0327] (2-(4-propylphenyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)carbonate (5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl ester (5)

[0328]

[0329] DIPEA (200 μL, 1.1 mmol) and triphosgene (30 mg, 0.1 mmol) were added to a solution of 2-(4-propylphenyl)-1,2,3,4-tetrahydroisoquinoline-6-ol (5a) (26.7 mg, 0.1 mmol) in DCM (1 mL) cooled to below -50 °C, and the mixture was stirred for 1 h. The reaction mixture was then added to a suspension of 5-fluoro-1-(hydroxymethyl)pyrimidine-2,4(1H,3H)-dione (1a) (80 mg) in MeCN (1 mL), and the mixture was stirred. The molecular sieve was dried and stirred for 1 h. The reaction mixture was filtered and purified by preparative chromatography to give methyl (2-(4-propylphenyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)carbonate (5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) (5) (2.0 mg). MS-ESI (m / z): 454 [M+1] + .

[0330] Example 6

[0331] (4-((1-(4-propylphenyl)piperidin-4-yl)methyl)phenyl)carbonate(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl ester(6)

[0332]

[0333] Synthetic pathway of 6

[0334]

[0335] (4-Methoxyphenyl)(1-(4-propylphenyl)piperidin-4-yl)methyl ketone (6a)

[0336]

[0337] A suspension of (4-methoxyphenyl)(piperidin-4-yl) methyl ketone hydrochloride (1.0 g, 3.9 mmol), 1-bromo-4-propylbenzene (0.8 g, 4.0 mmol), Pd2dba3 (732 mg, 0.8 mmol), dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (1.15 g, 2.4 mmol), and t-BuONa (1.1 g, 11.4 mmol) in PhMe (20 mL) was stirred in a sealed tube at 110 °C under nitrogen for 4 h. The mixture was filtered. The filtrate was concentrated and purified by silica gel column chromatography to give (4-methoxyphenyl)(1-(4-propylphenyl)piperidin-4-yl) methyl ketone (6a) (1.09 g). MS-ESI (m / z): 338 [M+1] + .

[0338] 4-(4-Methoxybenzyl)-1-(4-propylphenyl)piperidine (6b)

[0339]

[0340] NaBH4 (200 mg, 5.33 mmol) was added to a solution of (4-methoxyphenyl)(1-(4-propylphenyl)piperidin-4-yl)methyl ketone (6a) (600 mg, 1.78 mmol) in MeOH (20 mL). After stirring for 40 min, another 200 mg, 5.33 mmol of NaBH4 was added to the mixture. The reaction mixture was stirred for 1.5 h and quenched with an aqueous solution of NaHCO3. The mixture was extracted with EtOAc, dried over Na2SO4, and evaporated to dryness to give a black oily residue.

[0341] The residue was dissolved in TFA (20 mL), followed by the addition of triethylsilane (3 mL). The reaction mixture was stirred at 80 °C for 1 h and quenched with an aqueous solution of NaHCO3. The mixture was extracted with EtOAc to give the crude product 4-(4-methoxybenzyl)-1-(4-propylphenyl)piperidine (6b) (1.87 g), which was used directly in the next step. MS-ESI (m / z): 324 [M+1] + .

[0342] 4-((1-(4-propylphenyl)piperidin-4-yl)methyl)phenol(6c)

[0343]

[0344] A solution of 1 M BBr3-DCM (6 mL) was added to a solution of 1.87 g of 4-(4-methoxybenzyl)-1-(4-propylphenyl)piperidine (6b) in 10 mL of DCM. The reaction mixture was stirred for 1 h. After quenching with NaHCO3 aqueous solution, the mixture was extracted with DCM. The crude product was purified by silica gel chromatography to give 4-((1-(4-propylphenyl)piperidin-4-yl)methyl)phenol (6c) (400 mg). MS-ESI (m / z): 310 [M+1] + .

[0345] (4-((1-(4-propylphenyl)piperidin-4-yl)methyl)phenyl)carbonate(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl ester(6)

[0346]

[0347] DIPEA (1.7 mL, 10.3 mmol) and triphosgene (307 mg, 1.0 mmol) were added to a solution of 4-((1-(4-propylphenyl)piperidin-4-yl)methyl)phenol (6c) (320 mg, 1.0 mmol) in DCM (5 mL) cooled to below -50 °C, and the mixture was stirred for 1 h. The reaction mixture was added to a suspension of 5-fluoro-1-(hydroxymethyl)pyrimidin-2,4(1H,3H)-dione (1a) (830 mg) in MeCN (5 mL) and stirred for 1 h. The reaction mixture was filtered and purified by preparative chromatography to give (4-((1-(4-propylphenyl)piperidin-4-yl)methyl)phenyl)carbonate (5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl ester (6) (49 mg). MS-ESI (m / z): 496 [M+1] + . 1 H NMR(400MHz, DMSO-d6)δ12.05(d,J=5.0Hz,1H),8.14(d,J=6.5Hz,1H),7.43-7.09(m,8H),5.69(s,2H),3.85-2.96(m,4H), 2.60(d,J=6.7Hz,2H), 2.52(d,J=7.6Hz,2H), 1.78(d,J=14.3Hz,3H), 1.53(dt,J=16.6,8.4Hz,4H), 0.85(t,J=7.3Hz,3H).

[0348] Example 7

[0349] ((5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)carbonate 4-(1-(2,2-diphenylethyl)piperidin-4-yl)phenyl ester(7)

[0350]

[0351] Synthetic pathway of 7

[0352]

[0353] 4-(1-(2,2-diphenylethyl)piperidin-4-yl)phenol (7a)

[0354]

[0355] NaBH3CN (1.0 g, 15.9 mmol) was added to a solution of 4-(piperidin-4-yl)phenol hydrobromide (500 mg, 1.9 mmol), 2,2-diphenylacetaldehyde (400 mg, 2.0 mmol), and AcOH (0.5 mL) in MeOH (20 mL). The reaction mixture was stirred overnight at ambient temperature. After removing the solvent by evaporation, the residue was partitioned between EtOAc and NaHCO3 (aq.). The separated organic layers were dried over Na2SO4 and evaporated to dryness. The crude product was purified by silica gel chromatography to give 4-(1-(2,2-diphenylethyl)piperidin-4-yl)phenol (7a) (400 mg). MS-ESI (m / z): 358 [M+1] + .

[0356] ((5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)carbonate 4-(1-(2,2-diphenylethyl)piperidin-4-yl)phenyl ester(7)

[0357]

[0358] DIPEA (1.8 mL, 10.3 mmol) and triphosgene (315 mg, 1.06 mmol) were added to a solution of 4-(1-(2,2-diphenylethyl)piperidin-4-yl)phenol (7a) (380 mg, 1.06 mmol) in DCM (5 mL) cooled to below -50 °C, and the mixture was stirred for 0.5 h. The reaction mixture was added to a suspension of 5-fluoro-1-(hydroxymethyl)pyrimidin-2,4(1H,3H)-dione (1a) (855 mg) in MeCN (5 mL) and stirred for 2 h. The reaction mixture was filtered and purified by preparative chromatography to give 4-(1-(2,2-diphenylethyl)piperidin-4-yl)phenyl ester (7) (39 mg) of ((5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)carbonate. MS-ESI (m / z): 544 [M+1] + .

[0359] Example 8

[0360] ((5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)carbonate 4-(1-(adamantane-1-ylmethyl)piperidin-4-yl)phenyl ester(8)

[0361]

[0362] Synthetic pathway of 8

[0363]

[0364] Adamantane-1-yl(4-(4-hydroxyphenyl)piperidin-1-yl)methyl ketone (8a)

[0365]

[0366] DIPEA (1 mL, 5.7 mmol) was added to a mixture of 4-(piperidin-4-yl)phenol hydrobromide (520 mg, 2 mmol) and adamantane-1-formyl chloride (400 mg, 2 mmol) in DCM (20 mL). The reaction mixture was stirred at ambient temperature for 4 h, followed by evaporation to give the crude product adamantane-1-yl(4-(4-hydroxyphenyl)piperidin-1-yl)methyl ketone (8a), which was used directly in the next step. MS-ESI (m / z): 340 [M+1] + .

[0367] 4-(1-(adamantane-1-ylmethyl)piperidin-4-yl)phenol (8b)

[0368]

[0369] Adamantane-1-yl(4-(4-hydroxyphenyl)piperidin-1-yl) methyl ketone (8a) (650 mg, 1.9 mmol) was dissolved in THF (20 mL), followed by the addition of 1 M LiAlH4-THF (6 mL, 6 mmol) at ambient temperature. The reaction mixture was stirred for 0.5 h and quenched by the addition of NaOH solution. The mixture was filtered and the filtrate was concentrated. The crude product was purified by column chromatography to give 4-(1-(adamantane-1-ylmethyl)piperidin-4-yl)phenol (8b) (595 mg). MS-ESI (m / z): 326 [M+1] + .

[0370] ((5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)carbonate 4-(1-(adamantane-1-ylmethyl)piperidin-4-yl)phenyl ester(8)

[0371]

[0372] DIPEA (2.9 mL, 16.6 mmol) and triphosgene (524 mg, 1.77 mmol) were added to a solution of 4-(1-(adamantane-1-ylmethyl)piperidin-4-yl)phenol (8b) cooled to below -50 °C in DCM (5 mL), and the mixture was stirred for 0.5 h. The reaction mixture was added to a suspension of 5-fluoro-1-(hydroxymethyl)pyrimidin-2,4(1H,3H)-dione (1a) (1.13 g) in MeCN (6 mL) and stirred for 1 h. The reaction mixture was filtered and purified by preparative chromatography to give 4-(1-(adamantane-1-ylmethyl)piperidin-4-yl)phenyl ester (8) (167 mg) of ((5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)carbonate. MS-ESI (m / z): 512 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.05 (d, J = 5.0 Hz, 1H), 8.13 (d, J = 6.6 Hz, 1H), 7.41-7.19 (m, 4H), 5.69 (s, 2H), 3.76-2.77 (m, 7H), 2.18-1.55 (m, 19H).

[0373] Example 9

[0374] ((5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)carbonate 4-((1-diphenylmethylpiperidin-4-yl)methyl)phenyl ester(9)

[0375]

[0376] Synthetic pathway of 9

[0377]

[0378] (1-Diphenylmethylpiperidin-4-yl)(4-methoxyphenyl)methyl ketone (9a)

[0379]

[0380] A suspension of (4-methoxyphenyl)(piperidin-4-yl) methyl ketone hydrochloride (520 mg, 2.0 mmol), (bromomethylene)diphenyl (520 mg, 2.1 mmol), KI (340 mg, 2.0 mmol), and K₂CO₃ (820 mg, 5.9 mmol) in MeCN (20 mL) was stirred overnight at 90 °C. The mixture was filtered and the filtrate was evaporated to dryness to give the crude product (1-diphenylmethylpiperidin-4-yl)(4-methoxyphenyl) methyl ketone (9a). MS-ESI (m / z): 386 [M+1] + .

[0381] (1-Diphenylmethylpiperidin-4-yl)(4-methoxyphenyl)methanol (9b)

[0382]

[0383] (1-Diphenylmethylpiperidin-4-yl)(4-methoxyphenyl)methyl ketone (9a) (750 mg, 1.94 mmol) was dissolved in THF (20 mL), followed by the addition of 1 M LiAlH4-THF solution (4 mL, 4 mmol). The reaction mixture was stirred for 0.5 h and quenched with NaOH (aq.) solution. The mixture was filtered and the filtrate was evaporated to dryness to give the crude product (1-diphenylmethylpiperidin-4-yl)(4-methoxyphenyl)methanol (9b). MS-ESI (m / z): 388 [M+1] + .

[0384] 1-Diphenylmethyl-4-(4-methoxyphenylmethyl)piperidine (9c)

[0385]

[0386] (1-Diphenylmethylpiperidin-4-yl)(4-methoxyphenyl)methanol (9b) (939 mg, 2.43 mmol) was dissolved in TFA (5 mL), followed by the addition of HSiEt3 (2.5 mL). The reaction mixture was stirred for 1 h and concentrated. The residue was dissolved in DCM and washed with NaHCO3 solution. The organic layer was dried over Na2SO4 and concentrated to give the crude product 1-diphenylmethyl-4-(4-methoxyphenylmethyl)piperidine (9c). MS-ESI (m / z): 372 [M+1] + .

[0387] 4-((1-Diphenylmethylpiperidin-4-yl)methyl)phenol (9d)

[0388]

[0389] 1-Diphenylmethyl-4-(4-methoxyphenylmethyl)piperidine (9c) (1.07 g, 2.88 mmol) was dissolved in DCM (8 mL), followed by the addition of 1 M BBr3-DCM solution (6 mL, 6 mmol). The mixture was stirred at room temperature for 5 h. The reaction mixture was diluted with DCM and quenched with NaHCO3 (aq.) solution. The aqueous layer was extracted with DCM. The combined DCM layers were dried over Na2SO4 and concentrated to dryness. The residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to give the product 4-((1-diphenylmethylpiperidin-4-yl)methyl)phenol (9d) (504 mg). MS-ESI (m / z): 358 [M+1] + .

[0390] ((5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)carbonate 4-((1-diphenylmethylpiperidin-4-yl)methyl)phenyl ester(9)

[0391]

[0392] DIPEA (700 μL, 4.2 mmol) and triphosgene (100 mg, 0.34 mmol) were added to a solution of 4-((1-diphenylmethylpiperidin-4-yl)methyl)phenol (9d) (100 mg, 0.28 mmol) in DCM (3 mL) cooled to below -50 °C, and the mixture was stirred for 0.5 h. The reaction mixture was added to a suspension of 5-fluoro-1-(hydroxymethyl)pyrimidin-2,4(1H,3H)-dione (1a) (180 mg) in MeCN (3 mL) and stirred for 1 h. The reaction mixture was filtered and purified by preparative chromatography to give 4-((1-diphenylmethylpiperidin-4-yl)methyl)phenyl carbonate (9) (27 mg). MS-ESI (m / z): 544 [M+1] + . 1 H NMR (400MHz, chloroform-d) δ7.61(d,J=5.2Hz,1H),7.37(d,J=7.5Hz,4H),7.29-7.10(m,8H),7.05(d,J=8.5Hz,2H),5.74(s,2H),4.21(s ,1H),2.84(d,J=11.4Hz,2H),2.53(d,J=6.6Hz,2H),2.35(s,1H),1.76(t,J=11.5Hz,2H),1.61-1.42(m,3H),1.38-1.24(m,2H).

[0393] Example 10

[0394] 5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-carboxylic acid 4-(4-butylpiperidin-1-yl)phenylethyl ester (10)

[0395]

[0396] Synthetic pathway of 10

[0397]

[0398] 2-(4-(4-butylpiperidin-1-yl)phenyl)methyl acetate (10a)

[0399]

[0400] A suspension of methyl 2-(4-bromophenyl)acetate (241.2 mg, 1.05 mmol), 4-butylpiperidine hydrochloride (207.6 g, 1.17 mmol), Pd2dba3 (33 mg, 0.035 mmol), dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (67 mg, 0.14 mmol), and Cs2CO3 (1.14 g, 3.51 mmol) in PhMe (10 mL) was stirred in a sealed tube at 110 °C for 18 h. The mixture was diluted with MeCN and filtered. The filtrate was concentrated to give crude methyl 2-(4-(4-butylpiperidine-1-yl)phenyl)acetate (10a), which was used directly in the next step. MS-ESI (m / z): 290 [M+1] + .

[0401] 2-(4-(4-butylpiperidin-1-yl)phenyl)ethyl-1-ol (10b)

[0402]

[0403] Methyl 2-(4-(4-butylpiperidin-1-yl)phenyl)acetate (10a) (300 mg, 1.03 mmol) was dissolved in THF (11 mL), followed by the addition of 1 M LiAlH4-THF (3 mL). The mixture was stirred overnight at room temperature. The reaction mixture was quenched with water. The aqueous layer was extracted three times with EtOAc. The combined EtOAc layers were dried over Na2SO4 and evaporated to dryness. The residue was purified by preparative chromatography to give 2-(4-(4-butylpiperidin-1-yl)phenyl)ethanol-1-ol (10b) (281 mg). MS-ESI (m / z): 262 [M+1] + .

[0404] 5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-carboxylic acid 4-(4-butylpiperidin-1-yl)phenylethyl ester (10)

[0405]

[0406] A mixture of 2-(4-(4-butylpiperidin-1-yl)phenyl)ethyl-1-ol (10b) (94 mg, 0.36 mmol), triphosgene (108 mg, 0.36 mmol), and DIPEA (650 μL) cooled to below -50 °C in DCM (3.5 mL) was stirred for 2 h, followed by the addition of a suspension of fluorouracil (50 mg, 0.38 mmol) in MeCN (3.6 mL). The reaction mixture was stirred at room temperature for 2 h, followed by concentration to dryness. The crude product was purified by preparative chromatography to give 4-(4-butylpiperidin-1-yl)phenylethyl ester (10) (35 mg) of 5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-carboxylic acid. MS-ESI (m / z): 418 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.00(d,J=4.9Hz,1H),8.12(d,J=7.2Hz,1H),7.44-7.16(m,4H),4.45(t ,J=6.6Hz,2H),3.62-2.94(m,4H),1.83(d,J=13.2Hz,2H),1.58-0.96(m,11H),0.90-0.77(m,3H).

[0407] Example 11

[0408] 5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-carboxylic acid 2-(1-(4-(dibutylamino)phenyl)piperidin-4-yl)ethyl ester (11)

[0409]

[0410] Synthetic pathway of 11

[0411]

[0412] 5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-carboxylic acid 2-(1-(4-(dibutylamino)phenyl)piperidin-4-yl)ethyl ester (11)

[0413]

[0414] A solution of 2-(1-(4-(dibutylamino)phenyl)piperidin-4-yl)ethanol-1-ol (1e) (278 mg, 0.84 mmol) in DCM (7 mL) cooled to below -50 °C was added to a solution of DIPEA (1.4 mL, 8.4 mmol) in DCM (2.5 mL). The mixture was stirred at ambient temperature for 1.5 h and then added to a suspension of fluorouracil (109 mg, 0.84 mmol) in MeCN (10 mL). The reaction mixture was stirred overnight and purified by preparative chromatography, eluting with MeCN and 0.1% TFA-H2O, to give 2-(1-(4-(dibutylamino)phenyl)piperidin-4-yl)ethyl ester of 5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-carboxylic acid (11) (99 mg). MS-ESI(m / z): 489[M+1] + . 1 H NMR(400MHz,DMSO-d6)δ12.02(s,1H),8.21(d,J=7.2Hz,1H),7.39(brs,2H),6.67(brs ,2H),4.37(t,J=6.1Hz,2H),3.90-3.15(m,8H),2.12-1.05(m,15H),0.92-0.68(m,6H).

[0415] Example 12

[0416] ((5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)methylphosphonic acid 4-((1-diphenylmethylpiperidin-4-yl)methyl)phenyl ester(12)

[0417]

[0418] Synthetic pathway of 12

[0419]

[0420] ((5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)methylphosphonic acid 4-((1-diphenylmethylpiperidin-4-yl)methyl)phenyl ester(12)

[0421]

[0422] At ambient temperature, NEt3 (310 μL, 2.24 mmol) and dichloromethylphosphine (90 mg, 0.67 mmol) were added to a solution of 4-((1-diphenylmethylpiperidin-4-yl)methyl)phenol (9d) (200 mg, 0.56 mmol) in DCM (2 mL), and the mixture was stirred for 0.5 h. The reaction mixture was then added to a suspension of 5-fluoro-1-(hydroxymethyl)pyrimidin-2,4(1H,3H)-dione (1a) (360 mg) in NMP (2 mL) and stirred for 3 h. The reaction mixture was filtered and purified by preparative chromatography to give 4-((1-diphenylmethylpiperidin-4-yl)methyl)phenyl ester (12) (90 mg) of methylphosphonic acid. MS-ESI (m / z): 578 [M+1] + . 1 ¹H NMR (400MHz, chloroform-d) δ 7.41–7.29 (m, 5H), 7.24–7.18 (m, 4H), 7.18–7.09 (m, 2H), 7.07–6.89 (m, 4H), 5.72–5.31 (m, 2H), 4.22 (s, 1H), 2.95–2.78 (m, 2H), 2.55–2.42 (m, 2H), 1.83–1.65 (m, 4H), 1.55–1.20 (m, 6H).

[0423] Example 13

[0424] 2-(1-(2,2-diphenylethyl)piperidin-4-yl)acetic acid (S)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7] indo[1,2-b]quinoline-9-yl ester (13)

[0425]

[0426] Synthetic pathway of 13

[0427]

[0428] 2-(1-(2,2-diphenylethyl)piperidin-4-yl)acetic acid (13a)

[0429]

[0430] NaBH3CN (2.0 g, 31.8 mmol) was added to a suspension of 2-(piperidin-4-yl)acetic acid hydrochloride (2.3 g, 12.8 mmol), 2,2-diphenylacetaldehyde (2.5 g, 12.7 mmol), and AcONa (3.1 g, 37.8 mmol) in MeOH (25 mL). The reaction mixture was stirred at ambient temperature for 4.5 h. After removing the solvent by evaporation, the residue was partitioned between EtOAc and H2O. The separated organic layer was dried over Na2SO4 and evaporated to dryness. The crude product was purified by silica gel chromatography to give 2-(1-(2,2-diphenylethyl)piperidin-4-yl)acetic acid (13a) (517 mg). MS-ESI (m / z): 324 [M+1] + .

[0431] 2-(1-(2,2-diphenylethyl)piperidin-4-yl)acetic acid (S)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7] indo[1,2-b]quinoline-9-yl ester (13)

[0432]

[0433] A mixture of 10-hydroxycamptothecin (36 mg, 0.1 mmol), 2-(1-(2,2-diphenylethyl)piperidin-4-yl)acetic acid (13a) (32 mg, 0.1 mmol), HATU (114 mg, 0.3 mmol), and DIPEA (105 μL, 0.6 mmol) in NMP (2 mL) was stirred at room temperature for 23 h. The reaction mixture was purified by preparative chromatography to give 2-(1-(2,2-diphenylethyl)piperidin-4-yl)acetic acid (S)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7] indo[1,2-b]quinoline-9-yl ester (13) as a trifluoroacetate. MS-ESI (m / z): 670 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.65(s,1H),8.20(d,J=9.2Hz,1H),7.89(d,J=2.8Hz,1 H),7.65(dd,J=9.3,2.6Hz,1H),7.47-7.18(m,11H),6.52(brs,1H),5.41(s,2H),5.28(s,2H) ,4.60-4.53(m,1H),3.95-3.85(m,2H),3.51(d,J=12.0Hz,2H),3.31-2.85(m,2H),2.63(d,J =7.0Hz,2H),2.15-1.72(m,5H),1.60-1.45(m,1H),1.12-0.96(m,1H),0.86(t,J=7.3Hz,3H).

[0434] Example 14

[0435] Diphenylmethylproline (S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7] indo[1,2-b]quinoline-9-yl ester (14)

[0436]

[0437] Synthetic pathway of 14

[0438]

[0439] Diphenylmethylproline (14a)

[0440]

[0441] The reaction mixture of proline methyl ester hydrochloride (6.0 g, 36.2 mmol), diphenylchloromethane (8.1 g, 40.0 mmol), K₂CO₃ (15.0 g, 108.5 mmol), and KI (6.0 g, 36.1 mmol) in MeCN (120 mL) was stirred at 60 °C for 24 hours. The reaction mixture was filtered and concentrated, and the residue was dissolved in EtOAc and washed with water. The aqueous layer was extracted with EtOAc. The combined layers were washed with aqueous Na₂S₂O₃ solution, dried over Na₂SO₄, and concentrated to give crude diphenylmethylproline methyl ester (12.0 g), which was used directly in the next step. MS-ESI (m / z): 296 [M+1] + .

[0442] A solution of NaOH (4.9 g, 122.5 mmol) in water (50 mL) was added to a solution of the crude product (12.0 g) in MeOH (50 mL). The reaction mixture was stirred at 50 °C for 17 hours. The mixture was concentrated under reduced pressure at 45 °C to remove MeOH, and the remaining aqueous solution was washed with methyl tert-butyl ether. The aqueous phase was acidified with 1 M HCl until pH 5–6 and extracted six times with DCM. The combined organic layers were dried over Na₂SO₄ and concentrated to give diphenylmethylproline (14a) (7.8 g). MS-ESI (m / z): 282 [M+1] + .

[0443] Diphenylmethylproline (S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7] indo[1,2-b]quinoline-9-yl ester (14)

[0444]

[0445] The mixture of (S)-4,11-diethyl-4,9-dihydroxy-1,12-dihydro-14H-pyrano[3',4':6,7] nitro[1,2-b]quinoline-3,14(4H)-dione (50 mg, 0.13 mmol), diphenylmethylproline (14a) (72 mg, 0.26 mmol), HATU (145 mg, 0.38 mmol) and DIPEA (135 μL, 0.76 mmol) in NMP (2 mL) was stirred at room temperature for 3.5 h. The reaction mixture was purified by preparative chromatography to give diphenylmethylproline (S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7] indo[1,2-b]quinoline-9-yl ester (14) (31 mg). MS-ESI (m / z): 656 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ8.16(d,J=9.1Hz,1H),7.56(dd,J=5.3,2.8Hz,5H),7. 44-7.21(m,8H),5.42(s,2H),5.33(s,2H),5.04(brs,1H),3.92(brs,1H),3.16 (q,J=7.6Hz,2H),3.00(brs.,1H),2.80-2.60(m,1H),2.44-2.30(m,1H),2.25 -2.12(m,1H),2.05-1.78(m,4H),1.31(t,J=7.5Hz,3H),0.86(t,J=7.3Hz,3H).

[0446] Example 15

[0447] N-Diphenylmethyl-P-methylphosphonamide (S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7] indo[1,2-b]quinoline-9-yl ester (15)

[0448]

[0449] Synthetic pathway of 15

[0450]

[0451] N-Diphenylmethyl-P-methylphosphonamide (S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7] indo[1,2-b]quinoline-9-yl ester (15)

[0452]

[0453] Dichloromethylphosphine (60 mg, 0.45 mmol) was added to a suspension of (S)-4,11-diethyl-4,9-dihydroxy-1,12-dihydro-14H-pyrano[3',4':6,7] indo[1,2-b]quinoline-3,14(4H)-dione (120 mg, 0.3 mmol) and DIPEA (280 μL, 1.6 mmol) in DCM (4 mL). The reaction mixture was stirred at room temperature for 45 min, followed by treatment with a solution of aminodiphenylmethane (80 μL, 0.46 mmol) and DIPEA (80 μL, 0.46 mmol) in DCM (1 mL). The mixture was stirred for 35 min and concentrated to dryness. The residue was purified by preparative chromatography to give N-diphenylmethyl-P-methylphosphonamide (S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7] indo[1,2-b]quinoline-9-yl ester (15) (34 mg). MS-ESI (m / z): 636 [M+1] + . 1 H NMR (400MHz, chloroform-d) δ8.10 (d, J = 9.2Hz, 1H), 7.81 (s, 1H), 7.66 (s, 1H), 7.50-7. 43(m,1H),7.35-6.98(m,10H),5.80(brs,1H),5.73(d,J=16.3Hz,1H),5.50(t ,J=9.75Hz,1H),5.35-5.25(m,2H),5.21(s,2H),3.04-2.90(m,2H),1.95-1.8 2(m,2H),1.66(d,J=16.7Hz,3H),1.18(t,J=7.0Hz,3H),1.03(t,J=7.3Hz,3H).

[0454] Example 16

[0455] ((1-Diphenylmethylpyrrolidone-2-yl)methyl)carbamate (S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7] indo[1,2-b]quinoline-9-yl ester (16)

[0456]

[0457] Synthetic pathway of 16

[0458]

[0459] 1-Diphenylmethylpyrrolidine-2-carboxamide (16a)

[0460]

[0461] Benzyl chloroformate (0.8 mL, 5.6 mmol) was added to a mixture of diphenylmethylproline (14a) (1.0 g, 3.6 mmol) and DIPEA (2 mL, 11.5 mmol) cooled in ice water in MeCN (20 mL). The reaction mixture was stirred for 3 h, then treated with ammonium hydroxide (4 mL) and subsequently kept at room temperature overnight. After solvent removal, a crude product, 1-diphenylmethylpyrrolidine-2-carboxamide (16a), was obtained as a brown oil and used directly in the next step. MS-ESI (m / z): 281 [M+1] + .

[0462] (1-Diphenylmethylpyrrolidone-2-yl)methylamine (16b)

[0463]

[0464] 1-Diphenylmethylpyrrolidone-2-carboxamide (16a) (3.6 mmol) was dissolved in THF (25 mL), followed by the addition of 1 M LiAlH4-THF solution (22 mL, 22 mmol). The reaction mixture was stirred overnight and quenched with NaOH (aq.) solution. The mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 5:1) to give the product (1-diphenylmethylpyrrolidone-2-yl)methylamine (16b) (600 mg). MS-ESI (m / z): 267 [M+1] + .

[0465] ((1-Diphenylmethylpyrrolidone-2-yl)methyl)carbamate (S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7] indo[1,2-b]quinoline-9-yl ester (16)

[0466]

[0467] A solution of 4-nitrobenzene chloroformate (58 mg, 0.29 mmol) in NMP (0.25 mL) was added at -10 °C to a solution of (S)-4,11-diethyl-4,9-dihydroxy-1,12-dihydro-14H-pyrano[3',4':6,7] indo[1,2-b]quinoline-3,14(4H)-dione (50 mg, 0.13 mmol) and DIPEA (0.2 mL, 1.15 mmol) in NMP (1 mL). The mixture was stirred for 1.5 h, followed by the addition of a solution of (1-diphenylmethylpyrrolidone-2-yl)methylamine (16b) (77 mg, 0.29 mmol) in NMP (0.25 mL). The reaction mixture was stirred for 2.5 h and purified by preparative chromatography to obtain ((1-diphenylmethylpyrrolidone-2-yl)methyl)carbamate (S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7] indo[1,2-b]quinoline-9-yl ester (16) (36 mg). MS-ESI (m / z): 685 [M+1] + . 1 ¹H NMR (400MHz, chloroform-d) δ 8.17 (d, J = 9.2Hz, 1H), 8.08 (s, 1H), 7.79–7.63 (m, 5H), 7.50–7.34 (m, 5H), 7.33–7.22 (m, 2H), 5.74 (d, J = 16.3Hz, 1H), 5.29 (d, J = 26.2Hz, 3H), 4.88 (s, 1H), 4.02 (s, 1H), 3 .88-3.76(m,1H),3.54(dt,J=15.1,7.2Hz,1H),3.43-3.32(m,1H),3.26-3.08(m,3H),2.43-2. 31(m,1H),2.27-2.04(m,3H),1.97-1.82(m,2H),1.39(t,J=7.6Hz,3H),1.02(t,J=7.3Hz,3H).

[0468] Example 17

[0469] (S)-(4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indo[1,2-b]quinoline-9-yl)carbonate 4-(1-butylpiperidin-4-yl)phenyl ester (17)

[0470]

[0471] Synthetic pathway of 17

[0472]

[0473] 4-(1-Butylpiperidin-4-yl)phenol (17a)

[0474]

[0475] Sodium cyanoborohydride (250 mg, 3.98 mmol) was added to a mixture of 4-(piperidin-4-yl)phenol hydrobromide (500 mg, 1.94 mmol), n-butyraldehyde (200 μL, 2.17 mmol), and AcOH (2 mL) in MeOH (20 mL), and the reaction mixture was stirred overnight at room temperature. The mixture was concentrated to remove MeOH, diluted with EtOAc (30 mL), and washed with NaHCO3 (aq.) (30 mL). The aqueous layer was extracted with EtOAc (30 mL), and the combined organic layers were dried over Na2SO4 and evaporated to dryness to give crude 4-(1-butylpiperidin-4-yl)phenol (17a), which was used directly in the next step (380 mg). MS-ESI (m / z): 234 [M+1] + .

[0476] (S)-(4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indo[1,2-b]quinoline-9-yl)carbonate 4-(1-butylpiperidin-4-yl)phenyl ester (17)

[0477]

[0478] A solution of triphosgene (360 mg, 1.2 mmol) in DCM (3.6 mL) was added to a solution of 4-(1-butylpiperidin-4-yl)phenol (17a) (240 mg, 1.0 mmol) and DIPEA (1.9 mL, 10.9 mmol) in DCM (10 mL) cooled to below -50 °C. The mixture was stirred for 1 h, followed by the addition of (S)-4,11-diethyl-4,9-dihydroxy-1,12-dihydro-14H-pyrano[3',4':6,7] indo[1,2-b]quinoline-3,14(4H)-dione (300 mg, 0.76 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with MeCN and purified by preparative chromatography to give (S)-(4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indo[1,2-b]quinoline-9-yl)carbonate 4-(1-butylpiperidin-4-yl)phenyl ester (17) (5 mg). MS-ESI (m / z): 652 [M+1] + .1 H NMR (400MHz, chloroform-d) δ8.27(d,J=9.2Hz,1H),8.04(d,J=2.6Hz,1H),7.72(dd,J =9.4,2.5Hz,1H),7.65(s,1H),7.36-7.09(m,4H),5.75(d,J=16.4Hz,1H),5. 35-5.24(m,3H),3.80-3.69(m,2H),3.17(q,J=7.8Hz,2H),3.05-2.65(m,4H) ,2.43-2.22(m,1H),2.08-1.65(m,8H),1.48-1.16(m,5H),1.08-0.86(m,6H).

[0479] Example 18

[0480] ((1-Heptylpiperidin-4-yl)methyl)carbonate(S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7] indo[1,2-b]quinoline-9-yl ester (18)

[0481]

[0482] Synthetic pathway of 18

[0483]

[0484] (1-Heptylpiperidin-4-yl)methanol(18a)

[0485]

[0486] Sodium cyanoborohydride (2.2 g, 34.8 mmol) was added to a mixture of piperidin-4-ylmethanol (2.0 g, 17.4 mmol), n-heptanal (2.0 g, 17.4 mmol), and AcOH (6 mL) in MeOH (60 mL), and the reaction mixture was stirred overnight at room temperature. The mixture was distilled to remove MeOH and dissolved in EtOAc (100 mL), and washed with NaHCO3 (aq.) (100 mL). The aqueous layer was extracted with EtOAc (100 mL), and the combined organic layers were dried over Na2SO4 and evaporated to dryness to give crude product (1-heptylpiperidin-4-yl)methanol (18a), which was used directly in the next step (3.8 g). MS-ESI (m / z): 214 [M+1] + .

[0487] ((1-Heptylpiperidin-4-yl)methyl)carbonate(S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7] indo[1,2-b]quinoline-9-yl ester (18)

[0488]

[0489] A solution of 4-nitrobenzene chloroformate (82 mg, 0.41 mmol) in NMP (0.3 mL) was added at -10 °C to a solution of (S)-4,11-diethyl-4,9-dihydroxy-1,12-dihydro-14H-pyrano[3',4':6,7] indo[1,2-b]quinoline-3,14(4H)-dione (55 mg, 0.14 mmol) and DIPEA (0.2 mL, 1.2 mmol) in NMP (1 mL). The mixture was stirred for 1 h, followed by the addition of a solution of (1-heptaylpiperidin-4-yl)methanol (18a) (94 mg, 0.43 mmol) in NMP (0.2 mL). The reaction mixture was stirred for 4.5 h and purified by preparative chromatography to obtain ((1-heptaylpiperidin-4-yl)methyl)carbonate (S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7] indo[1,2-b]quinoline-9-yl ester (18) (4 mg). MS-ESI (m / z): 632 [M+1] + . 1 H NMR (400MHz, chloroform-d) δ8.23(d,J=9.2Hz,1H),7.91(s,1H),7.65(s,1H),7.62(d,J= 9.2Hz,1H),5.74(d,J=16.3Hz,1H),5.29(d,J=24.0Hz,3H),4.22(d,J=5.6Hz,2H) ,3.77(d,J=11.9Hz,2H),3.15(q,J=7.7Hz,2H),2.99(s,2H),2.74-2.59(m,2H), 2.14-1.62(m,3H),1.44-1.14(m,14H),1.03(t,J=7.4Hz,3H),0.95-0.70(m,6H).

[0490] Example 19

[0491] Dicyclohexylglycine (S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7] indo[1,2-b]quinoline-9-yl ester (19)

[0492]

[0493] Synthetic pathway of 19

[0494]

[0495] Dicyclohexylglycine ethyl ester (19a)

[0496] A solution of dicyclohexylamine (3.66 g, 20.2 mmol) and ethyl 2-bromoacetate (1.67 g, 10 mmol) in EtOAc (20 mL) was heated overnight at 70 °C. The mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to give the product dicyclohexylglycine ethyl ester (19a) (2.42 g). MS-ESI (m / z): 268 [M+1] + .

[0497] Dicyclohexylglycine (19b)

[0498] A solution of LiOH (650 mg, 27.1 mmol) in water (5 mL) was added to a solution of dicyclohexylglycine ethyl ester (19a) (2.42 g, 9.1 mmol) in MeOH (5 mL). The reaction mixture was stirred overnight at 50 °C and concentrated under reduced pressure. The residue was diluted with water (30 mL) and EtOAc (60 mL) and acidified with formic acid (2 mL). The aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na₂SO₄ and concentrated to give dicyclohexylglycine (19b) (870 mg). MS-ESI (m / z): 240 [M+1] + .

[0499] Dicyclohexylglycine (S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7] indo[1,2-b]quinoline-9-yl ester (19)

[0500]

[0501] A mixture of dicyclohexylglycine (19b) (37 mg, 0.15 mmol), (S)-4,11-diethyl-4,9-dihydroxy-1,12-dihydro-14H-pyrano[3',4':6,7] nitro[1,2-b]quinoline-3,14(4H)-dione (42 mg, 0.11 mmol), HATU (113 mg, 0.30 mmol), and DIPEA (105 μL, 0.60 mmol) in NMP (1 mL) was stirred overnight at room temperature. The reaction mixture was purified by preparative chromatography to give dicyclohexylglycine (S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7] indo[1,2-b]quinoline-9-yl ester (19) (6.4 mg). MS-ESI (m / z): 614 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.95(s,1H),8.28(d,J=9.1Hz,1H),8.07(d,J=2.5Hz,1H),7.74(dd,J=9.2,2.5Hz,1H),7.32(s,1H),5.42(s,2 H), 5.35 (s, 2H), 4.69 (s, 2H), 3.18 (q, J = 7.7Hz, 2H), 2.09-1.94 (m, 4H), 1.94-1.75 (m, 6H), 1.75-1.04 (m, 17H), 0.86 (t, J = 7.3Hz, 3H).

[0502] Example 20

[0503] ((S)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7] indo[1,2-b]quinoline-9-yl)carbonate (1-diphenylmethylpyrrolidine-2-yl)methyl ester (20)

[0504]

[0505] Synthetic pathway of 20

[0506]

[0507] (1-Diphenylmethylpyrrolidone-2-yl)methanol (20a)

[0508] 1 M LiAlH4-THF (10 mL, 10 mmol) was added dropwise to a solution of diphenylmethylproline (14a) (1.0 g, 3.6 mmol) in THF (20 mL). The reaction mixture was quenched with NaHCO3 (aq.) and extracted twice with EtOAc. The organic layers were combined, dried over Na2SO4, and concentrated under reduced pressure to give (1-diphenylmethylpyrrolidone-2-yl)methanol (20a) (900 mg). MS-ESI (m / z): 268 [M+1] + .

[0509] ((S)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7] indo[1,2-b]quinoline-9-yl)carbonate (1-diphenylmethylpyrrolidine-2-yl)methyl ester (20)

[0510]

[0511] A solution of 4-nitrobenzene chloroformate (150 mg, 0.74 mmol) in NMP (0.5 mL) was added at -10 °C to a solution of (S)-4-ethyl-4,9-dihydroxy-1,12-dihydro-14H-pyrano[3',4':6,7] indo[1,2-b]quinoline-3,14(4H)-dione (100 mg, 0.27 mmol) and DIPEA (0.4 mL, 2.3 mmol) in NMP (1 mL). The mixture was stirred for 2 h, followed by the addition of a solution of (1-diphenylmethylpyrrolidone-2-yl)methanol (20a) (98 mg, 0.37 mmol) and DMAP (54 mg, 0.46 mmol) in NMP (0.5 mL). The reaction mixture was stirred for 1 h and purified by preparative chromatography to obtain ((S)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7] indo[1,2-b]quinoline-9-yl)carbonate (20) (30 mg). MS-ESI (m / z): 658 [M+1] + . 1¹H NMR (400MHz, chloroform-d) δ 8.36 (s, 1H), 8.22 (d, J = 9.2Hz, 1H), 7.78 (d, J = 2.6Hz, 1H), 7.76–7.66 (m, 5H), 7.59 (dd, J = 9.2, 2.5Hz, 1H), 7.50–7.33 (m, 6H), 5.74 (d, J = 16.4Hz, 1H), 5.35–5.26 (m, 3H),5.05(s,1H),4.46-4.36(m,2H),4.10(brs,1H),4.12-3.80(m,2H),3.24(s,1H),2.48-2 .36(m,1H),2.36-2.26(m,1H),2.23-2.08(m,2H),1.98-1.82(m,2H),1.03(t,J=7.4Hz,3H).

[0512] Example 21

[0513] (3-Methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetraazine-8-carbonyl)carbamate 4-((1-diphenylmethylpiperidin-4-yl)methyl)phenyl ester (21)

[0514]

[0515] Synthetic pathway of 21

[0516]

[0517] 3-Methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetraazine-8-carbonyl isocyanate (21a)

[0518] A mixture of temozolomide (200 mg, 1.0 mmol) and oxaloyl chloride (175 μL, 2.1 mmol) in 1,2-dichloroethane (25 mL) was stirred at 85 °C for 4 h. The reaction mixture was concentrated under reduced pressure to give 3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetraazine-8-carbonyl isocyanate (21a), which was used directly in the next step. MS-ESI (m / z): 275 [M + MeOH + Na] + (The sample was quenched with MeOH.)

[0519] (3-Methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetraazine-8-carbonyl)carbamate 4-((1-diphenylmethylpiperidin-4-yl)methyl)phenyl ester (21)

[0520] A mixture of 3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetraazine-8-carbonyl isocyanate (21a) (1 mmol) in DCM was added to a solution of 4-((1-diphenylmethylpiperidin-4-yl)methyl)phenol (9d) (1 mmol) and DIPEA (900 μL, 5.2 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 1.5 h, followed by evaporation. The residue was purified by preparative chromatography to give 4-((1-diphenylmethylpiperidin-4-yl)methyl)phenyl ester (21) (109 mg) of (3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetraazine-8-carbonyl)carbamate. MS-ESI (m / z): 578 [M+1] + . 1 H NMR (400MHz, chloroform-d) δ9.63(s,1H),8.46(s,1H),7.69-7.56(m,4H),7.43-7.31(m,6H),7.19-7.04 (m,4H),4.89(s,1H),4.08(s,3H),3.47(d,J=12.0Hz,2H),2.63-2.46(m,4H),1.92-1.64(m,5H).

[0521] Example 22

[0522] (3-Methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetraazine-8-carbonyl)carbamate 4-((1-diphenylmethylpiperidin-4-yl)methyl)phenyl ester (22)

[0523]

[0524] Synthetic pathway of 22

[0525]

[0526] 1-Diphenylmethylpiperidin-4-one (22a)

[0527]

[0528] A suspension of 4-piperidinone hydrochloride (1.0 g, 7.4 mmol), (chloromethylene)diphenyl (1.57 g, 7.7 mmol), K₂CO₃ (22.1 mmol), and KI (7.4 mmol) in MeCN (30 mL) was stirred overnight at 60 °C. The mixture was filtered and the filtrate was concentrated to dryness. The residue was dissolved in EtOAc (50 mL) and washed with water (50 mL), and the organic layer was dried over Na₂SO₄ and evaporated to dryness to give the crude product 1-diphenylmethylpiperidin-4-one (22a) (2.2 g), which was used directly in the next step. MS-ESI (m / z): 266 [M+1] + .

[0529] 4-((1-Diphenylmethylpiperidin-4-ylidene)methyl)benzonitrile (22b)

[0530]

[0531] A solution of dimethyl (4-cyanophenylmethyl)phosphonate (2.2 g, 9.8 mmol) cooled at -50 °C in 20 mL of THF was added fractionally with 2.3 g of 60% NaH, followed by a solution of 7.7 mmol of 1-diphenylmethylpiperidin-4-one (22a) in 20 mL of THF. The reaction mixture was stirred for 4 h and quenched with 100 mL of water. The mixture was extracted twice with EtOAc, and the combined organic layers were dried over Na2SO4 and evaporated to dryness to give 4-((1-diphenylmethylpiperidin-4-yl)methyl)benzonitrile (22b). MS-ESI (m / z): 365 [M+1] + .

[0532] (4-((1-Diphenylmethylpiperidin-4-yl)methyl)phenyl)methylamine(22c)

[0533]

[0534] A suspension of 4-((1-diphenylmethylpiperidin-4-yl)methyl)benzonitrile (22b) (1.4 g, 3.8 mmol) and 10% Pd / C (200 mg) in THF (20 mL) was degassed under vacuum and purged several times with H2. The mixture was stirred overnight at room temperature using an H2 balloon. The suspension was filtered, and a solution of LiAlH4 (50 mmol) in THF (35 mL) was added to the filtrate. The reaction mixture was stirred for 3.5 h, followed by the addition of 2 mL of NaOH (aq.), and the suspension was filtered, with the filter cake washed with EtOAc. The combined filtrates were concentrated to dryness to give (4-((1-diphenylmethylpiperidin-4-yl)methyl)phenyl)methylamine (22c) (1.26 g), which was used directly in the next step. MS-ESI (m / z): 371 [M+1]+ .

[0535] N-(4-((1-diphenylmethylpiperidin-4-yl)methyl)benzyl)-3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetraazine-8-carboxamide (22)

[0536]

[0537] To a solution of 3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetraazine-8-carboxylic acid (200 mg, 1.0 mmol) and DIPEA (1 mL, 5.7 mmol) in DCM (20 mL), HATU (1.15 g, 3.0 mmol) and (4-((1-diphenylmethylpiperidin-4-yl)methyl)phenyl)methylamine (22c) (400 mg, 1.1 mmol) were added. The reaction mixture was stirred at room temperature for 3 h, followed by the addition of water and DCM. The organic layer was dried over Na2SO4 and evaporated to dryness. The crude product was purified by silica gel chromatography and preparative chromatography to give N-(4-((1-diphenylmethylpiperidin-4-yl)methyl)benzyl)-3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetraazine-8-carboxamide (22) (43 mg). MS-ESI (m / z): 548 [M+1] + . 1 ¹H NMR (400 MHz, chloroform-d) δ 8.37 (s, 1H), 7.68–7.57 (m, 4H), 7.43–7.31 (m, 6H), 7.22 (d, J = 7.7 Hz, 2H), 7.02 (d, J = 7.6 Hz, 2H), 4.69–4.60 (m, 2H), 4.02 (s, 3H), 3.55–3.42 (m, 4H), 2.56–2.46 (m, 3H), 1.96–1.55 (m, 5H).

[0538] Example 23

[0539] Acetic acid (2S,3S,4S,6R)-6-(((1S,3S)-3-acetyl-3,5,12-trihydroxy-10-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetraphenyl-1-yl)oxy)-2-methyl-4-(((4-((4-methylpiperazin-1-yl)methyl)phenoxy)carbonyl)amino)tetrahydro-2H-pyran-3-yl ester (23)

[0540]

[0541] Synthetic pathway of 23

[0542]

[0543] 4-((4-methylpiperazin-1-yl)methyl)phenol (23a)

[0544]

[0545] A mixture of 4-hydroxybenzaldehyde (2.0 g, 20 mmol), 1-methylpiperazine (2.44 g, 20 mmol), AcOH (8 mL), and NaBH3CN (2.51 g, 40 mmol) in MeOH (80 mL) was stirred overnight at room temperature. The reaction mixture was evaporated to dryness and dissolved in EtOAc (50 mL) and NaHCO3 (aq.) (50 mL). The organic layer was dried over Na2SO4 and evaporated to dryness to give 4-((4-methylpiperazin-1-yl)methyl)phenol (23a) (2.37 g), which was used directly in the next step. MS-ESI (m / z): 207 [M+1] + .

[0546] Acetic acid (2S,3R,4S,6R)-6-(((1S,3S)-3-acetyl-3,5,12-trihydroxy-10-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetraphenyl-1-yl)oxy)-4-(λ2-hydrochloric acid)-2-methyltetrahydro-2H-pyran-3-yl ester hydrochloride (23b)

[0547]

[0548] A suspension of daunorubicin hydrochloride (656 mg, 1.24 mmol) in trimethyl orthoformate (10 mL) was heated at 110 °C for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with acetone (40 mL), followed by the addition of 1 N HCl (4 mL) and HCl (0.1 mL). The mixture was evaporated to dryness and recrystallized from MeOH (4 mL), EtOAc (40 mL), and PE (40 mL) to give acetic acid (2S,3R,4S,6R)-6-(((1S,3S)-3-acetyl-3,5,12-trihydroxy-10-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetraphenyl-1-yl)oxy)-4-(λ2-hydrochloric acid)-2-methyltetrahydro-2H-pyran-3-yl ester hydrochloride (23b) (622 mg). MS-ESI(m / z): 570 [M+1] + .

[0549] Acetic acid (2S,3S,4S,6R)-6-(((1S,3S)-3-acetyl-3,5,12-trihydroxy-10-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetraphenyl-1-yl)oxy)-2-methyl-4-(((4-((4-methylpiperazin-1-yl)methyl)phenoxy)carbonyl)amino)tetrahydro-2H-pyran-3-yl ester (23)

[0550]

[0551] A solution of 4-nitrobenzene chloroformate (80 mg, 0.2 mmol) in NMP (0.5 mL) was added at -10 °C to a solution of 4-((4-methylpiperazin-1-yl)methyl)phenol (23a) (40 mg, 0.1 mmol) and DIPEA (90 μL, 0.5 mmol) in NMP (1 mL). The mixture was stirred for 4 h, and then a solution of (2S,3R,4S,6R)-6-(((1S,3S)-3-acetyl-3,5,12-trihydroxy-10-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetraphenyl-1-yl)oxy)-4-(λ2-hydrochloric acid)-2-methyltetrahydro-2H-pyran-3-yl ester hydrochloride (23b) (50 mg, 0.083 mmol) in NMP (0.5 mL) was added. The reaction mixture was stirred for 1 h and purified by preparative chromatography to give (2S,3S,4S,6R)-6-(((1S,3S)-3-acetyl-3,5,12-trihydroxy-10-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetraphenyl-1-yl)oxy)-2-methyl-4-(((4-((4-methylpiperazin-1-yl)methyl)phenoxy)carbonyl)amino)tetrahydro-2H-pyran-3-yl ester (23) (25 mg). MS-ESI (m / z): 802 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ13.26 (s, 1H), 7.95-7.84 (m, 3H), 7.69-7.62 (m, 1H), 7.29 (d, J = 8.2 Hz,2H),7.02(d,J=8.2Hz,2H),5.54(brs,1H),5.33(s,1H),5.02-4.92(m,2H),4.39(q,J=5 .6Hz,1H),3.97(s,3H),4.15-3.55(m,10H),3.35(brs,1H),2.98(brs,1H),2.93(s,2H),2. 73(s,2H),2.33-2.05(m,8H),1.95-1.83(m,1H),1.68-1.56(m,1H),1.03(d,J=6.4Hz,3H).

[0552] Example 24

[0553] Hexyl carbonate (5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) methyl ester (24)

[0554]

[0555] Synthetic pathway of 24

[0556]

[0557] Hexyl carbonate (5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) methyl ester (24)

[0558]

[0559] DIPEA (1 mL, 5.6 mmol) was added to a solution of 5-fluoro-1-(hydroxymethyl)pyrimidin-2,4(1H,3H)-dione (1a) (640 mg) and hexyl chloroformate (165 μL, 1.0 mmol) in MeCN (5 mL). The reaction mixture was stirred at room temperature for 2 h, followed by preparative HPLC purification to give hexyl carbonate (5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl ester (24). MS-ESI (m / z): 289 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.01 (s, 1H), 8.12 (d, J = 6.6Hz, 1H), 5.56 (s, 2H), 4. 09(t,J=6.6Hz,2H),1.61-1.52(m,2H),1.31-1.18(m,6H),0.87-0.79(m,3H).

[0560] Example 25

[0561] (4-Methoxyphenyl)carbonate (5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl ester (25)

[0562]

[0563] Synthetic pathway of 25

[0564]

[0565] (4-Methoxyphenyl)carbonate (5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl ester (25)

[0566]

[0567] The title compound (25) was prepared according to the method of Example 24 by using 4-methoxyphenyl chloroformate instead of hexyl chloroformate. MS-ESI (m / z): 311 [M+1] + .

[0568] Example 26

[0569] 4-(1-(2,2-diphenylethyl)piperidin-4-yl)benzoic acid (5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl ester (26)

[0570]

[0571] Synthetic pathway of 26

[0572]

[0573] 4-(1-(2,2-diphenylethyl)piperidin-4-yl)benzoic acid (26a)

[0574]

[0575] NaBH3CN (250 mg, 3.9 mmol) was added to a solution of 4-(piperidin-4-yl)benzoate (317 mg, 1.3 mmol), 2,2-diphenylacetaldehyde (510 mg, 2.6 mmol), and AcOH (1.0 mL) in MeOH (13 mL). The mixture was stirred at ambient temperature for 2 h. After removing the solvent by evaporation, the residue was dissolved in EtOAc and washed with NaHCO3 (aq.) solution. The organic layer was dried over Na2SO4 and evaporated to dryness. The crude product was purified by silica gel chromatography to give 4-(1-(2,2-diphenylethyl)piperidin-4-yl)benzoic acid (26a) (340 mg). MS-ESI (m / z): 386 [M+1] + .

[0576] 4-(1-(2,2-diphenylethyl)piperidin-4-yl)benzoic acid (5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl ester (26)

[0577]

[0578] DIPEA (690 μl, 3.9 mmol) was added to a solution of 4-(1-(2,2-diphenylethyl)piperidin-4-yl)benzoic acid (26a) (300 mg, 0.78 mmol) and 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (520 mg, 1.2 mmol) in MeCN (8 mL). The mixture was stirred at room temperature for 1 h, and then added to a suspension of 5-fluoro-1-(hydroxymethyl)pyrimidin-2,4(1H,3H)-dione (1a) (435 mg) in MeCN (7 mL) and stirred for 1 h. The suspension was filtered and the filtrate was distilled to obtain the residue. The residue was purified by silica gel column chromatography followed by preparative HPLC to give methyl 4-(1-(2,2-diphenylethyl)piperidin-4-yl)benzoic acid (5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) ester (26) (192 mg). MS-ESI (m / z): 528 [M+1] + . 1H NMR (400MHz, chloroform-d) δ7.61(d,J=5.2Hz,1H),7.37(d,J=7.4Hz,4H),7.29-7.20(m,4H),7.20-7.10(m,4H),7.06(d,J=8.6Hz,2H),5.7 4(s,2H),4.22(s,1H),2.85(d,J=11.5Hz,2H),2.53(d,J=6.7Hz,2H),1.77(t,J=11.3Hz,2H),1.63-1.43(m,3H),1.39-1.25(m,2H).

[0579] Example 27

[0580] Drug release analysis

[0581] method

[0582] Preparation of pH 2.0 buffer solution

[0583] A pH 2.0 buffer solution was prepared by adding 50 mL of 0.1 M phosphate solution to a 200 mL volumetric flask, adjusting the pH to 2.0 with 0.1 M sodium dihydrogen phosphate solution, and then diluting with water to 200 mL.

[0584] Preparation of pH 7.4 buffer solution

[0585] A pH 7.4 buffer solution was prepared by adding 50 mL of 0.1 M disodium hydrogen phosphate solution to a 200 mL volumetric flask, adjusting the pH to 7.4 with 0.1 M phosphoric acid solution, and then diluting with water to 200 mL.

[0586] HPLC conditions

[0587]

[0588] Hydrolysis rate test method

[0589] The compound was dissolved in a pH 7.4 / pH 2.0 buffer solution and placed in a thermostatic shaker at 37°C and 200 rpm. Samples were taken at 0 h, 0.5 h, and 6 h. The residual content of the compound relative to 0 h was measured at each time point.

[0590] The release rate (%) was calculated using the following equation: Release rate (%) = [A(0h) - A(xh)] / A(0h) × 100%, (x = 0, 0.5, 6), where A(xh) is the peak area of ​​the compound as measured by HPLC at the specified time point.

[0591] Calculate the hydrolysis constant (K) using the following equation. h ): Hydrolysis constant Kh = -ln[100% - release rate (%)] / t

[0592] result

[0593] The results of parent drug release from exemplary prodrug compounds of this disclosure are shown in Table 1.

[0594] Table 1

[0595]

[0596]

[0597] As shown in Table 1, the hydrolysis constant (K) of the compounds disclosed in this invention at pH 7.4 is... h It is greater than the hydrolysis constant at pH 2.

[0598] Example 28

[0599] Rat pharmacokinetic analysis

[0600] The objective of this study was to evaluate the pharmacokinetics of free fluorouracil and the exemplary compounds of this disclosure in the stomach and plasma following continuous intragastric administration of the exemplary compounds of this disclosure and continuous intravenous infusion or single oral administration of free fluorouracil to male Sporgodory rats.

[0601] After administering the exemplary compound and free fluorouracil in equal molar amounts, the plasma and gastric concentrations of fluorouracil were tested and shown, respectively. Figure 1 and Figure 2 middle.

[0602] according to Figure 1 As can be seen, the concentration of fluorouracil released from the exemplary compound in plasma is lower compared to the concentrations achieved by continuous intravenous infusion or a single oral administration of free fluorouracil. This indicates that the prodrug of this disclosure has lower systemic exposure and reduced systemic side effects of fluorouracil compared to the parent drug. Figure 2 As can be seen, the concentration of fluorouracil released from the exemplary compound in gastric tissue is higher than the concentration achieved by continuous intravenous infusion or a single oral administration of free fluorouracil. This indicates that the prodrug of this disclosure achieves sustained release of fluorouracil in gastric tissue. The above description is to be considered merely as an illustration of the principles of this disclosure. Furthermore, since many modifications and variations will be apparent to those skilled in the art, it is not intended to limit the invention to the exact construction and process shown above. Therefore, all suitable modifications and equivalents can be considered to fall within the scope of the invention as defined by the appended claims.

Claims

1. A prodrug compound having the formula selected from the group consisting of: Or its pharmaceutically acceptable salt; in L represents a direct bond or an alkyl group. U can be a heterocyclic group, aryl group, or heteroaryl group. V is a direct bond or an alkyl group. W can be a direct bond, a heterocyclic group, or an aryl group; Z represents alkyl, aryl, or NR. 1 R 2 OR 3 The alkyl and aryl groups are optionally separated by one or more R groups. 4 replace; R 1 R 2 and R 3 Independently hydrogen, alkyl, or cycloalkyl; and R 4 Selected from the following group: alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; R a It can be hydrogen, alkyl, alkenyl, or alkynyl; The condition is that V and W are not both direct keys; Alternatively, in equation (II), L is a hexyl group, and U, V, W, and Z are direct bonds.

2. A prodrug compound having the formula selected from the group consisting of: Or its pharmaceutically acceptable salt, wherein Q is hydrogen or ethyl; L represents a direct bond or an alkyl group. U is a direct bond or an aryl group. V stands for direct bond. W can be a direct bond or a heterocyclic group; Z is NR 1 R 2 Or optionally by one or more R 4 Substituted alkyl groups; R 1 R 2 Independently hydrogen, alkyl, or cycloalkyl; and R 4 Selected from the following group: alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; R a It can be hydrogen, alkyl, alkenyl, or alkynyl; The condition is that when U is not a direct bond, V, W, and Z are not all direct bonds at the same time.

3. A prodrug compound having the following formula: Or its pharmaceutically acceptable salt; L represents a direct bond or an alkyl group; U is selected from the following group: direct bond, cycloalkyl, heterocyclic, aryl, and heteroaryl; V is a direct bond or an alkyl group; W is selected from the group consisting of: direct bond, cycloalkyl, heterocyclic, aryl, and heteroaryl; Z is selected from the following group: direct bond, alkyl, aryl, NR 1 R 2 and OR 3 The alkyl and aryl groups are optionally separated by one or more R groups. 4 replace; R 1 R 2 and R 3 Independently hydrogen, alkyl, or cycloalkyl; and R 4 Selected from the following group: alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl. The condition is that when U is not a direct bond, V, W, and Z are not all direct bonds at the same time.

4. A prodrug compound having the following formula: Or its pharmaceutically acceptable salt; L represents a direct bond or an alkyl group; U is selected from the following group: direct bond, cycloalkyl, heterocyclic, aryl, and heteroaryl; V is a direct bond or an alkyl group; W is selected from the group consisting of: direct bond, cycloalkyl, heterocyclic, aryl, and heteroaryl; Z is selected from the following group: direct bond, alkyl, aryl, NR 1 R 2 and OR 3 The alkyl and aryl groups are optionally separated by one or more R groups. 4 replace; R 1 R 2 and R 3 Independently hydrogen, alkyl, or cycloalkyl; and R 4 Selected from the following group: alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl. The condition is that when U is not a direct bond, V, W, and Z are not all direct bonds at the same time.

5. A prodrug compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

6. A pharmaceutical composition comprising a prodrug compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and a pharmaceutically acceptable excipient.

7. The use of the prodrug compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 6, in the preparation of a medicament for treating a disease in a subject in need.

8. The application according to claim 7, wherein the disease is selected from one or more of the following: anal cancer, breast cancer, colorectal cancer, esophageal cancer, pancreatic cancer, head and neck cancer, brain cancer, liver cancer, gastric cancer, bladder cancer, oral mucosal cancer, anaplastic astrocytoma, glioblastoma multiforme, acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, Kaposi's sarcoma, and neuroblastoma.

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