TW201936585A - 5-fluorouracil compounds - Google Patents

Abstract

Provided herein are 5-fluorouracil derived acetal and hemiaminal ether compounds, their preparation and their uses, such as treating liver diseases or various types of cancer.

Description

5-fluorouracil compound

[Cross-reference to related applications] This application claims the right of priority of the invention entitled "5-Fluorouracil Compound" with the provisional name of the US Provisional Application No. 62 / 619,557 filed on January 19, 2018 in accordance with the Patent Law, The content of this application is incorporated herein by reference in its entirety.

This disclosure is related to the fields of chemistry and medicine. More specifically, the present disclosure relates to a compound derived from 5-fluorouracil, including acetal and hemiamine acetal ether compounds, the preparation of these, and the use of these. In some embodiments, such compounds are useful for selectively delivering some agents to the liver.

The following description of the prior art is provided to assist in understanding the present invention, but is not admitted as prior art of the present invention or for describing the prior art of the present invention.

5-Fluorouracil is a synthetic analog of uracil, one of the four nucleobases in RNA, and has been used as a therapeutic agent to treat various forms of cancer. 5-Fluorouracil is one of the essential medicines in the World Health Organization (WHO) list because of its efficacy and safety, and can be used intravenously and locally. The mechanism of action of 5-fluorouracil is mainly as a thymidylate synthase inhibitor, which blocks the synthesis of pyrimidine thymidine to cause thymidine cell starvation and cause cell death. The active form of 5-fluorouracil as a thymidine synthase inhibitor is fluorodeoxyuridine monophosphate (FdUMP), which is mainly produced in the liver.

5-Fluorouracil has a very short biological half-life (~ 16 minutes), a very narrow therapeutic index, and produces different side effects and can be very serious. For better efficacy and safety, new 5-fluorouracil analog compounds have been continuously developed for several years and several compounds have been made on the market. 5-Fluoro-2 ' -floxuridine, also known as 5-fluorodeoxyuridine, has been used to treat colorectal cancer via continuous hepatic arterial infusion. 5'-deoxy-5-fluorouridine (doxifluridine) has been used as a cytostatic agent in chemotherapy in some countries. Capecitabine has been used orally to treat breast cancer, gastric cancer, and colorectal cancer. Despite advances in this field, new compounds are still needed to further improve the efficiency of drug delivery or to propose new applications based on new technologies. For example, a target compound of the liver can reach the liver more efficiently and is inactive outside the liver, while reducing the pharmacological or toxicological effects of the agent outside the target tissue. Therefore, new compounds with a targeted profile of the liver can significantly improve the therapeutic index of 5-fluorouracil-based therapies.

A novel 5-fluorouracil-derived acetal and hemiamine acetal ether compound, the preparation of these and their uses have been described. Some embodiments are related to a novel 5-fluorouracil-derived acetal and hemiamine acetal ether compound, which is orally delivered to the liver, and the compound provides therapeutic benefits in the liver. Another aspect includes the use of the 5-fluorouracil-derived acetal and hemiamine acetal ether compounds for the treatment of a disease that would benefit from enhanced drug distribution in the liver and similar tissues and cells, including But not limited to: Hepatocellular carcinoma (HCC), kidney cancer, colorectal cancer, breast cancer, gastric cancer, gastric cancer, esophageal cancer, pancreatic cancer and cervical cancer. In another aspect, 5-fluorouracil-derived acetals and hemiamine acetal ether compounds are used to increase the pharmacological or clinical activity of some grades of pharmaceutical compounds, such as 5-fluorouracil-derived analog compounds. In another aspect, 5-fluorouracil-derived acetals and hemiamine acetal ether compounds are used to reduce potential side effects of some grades of pharmaceutical compounds, such as 5-fluorouracil-derived analog compounds, especially produced outside the liver Side effects. In some embodiments, the 5-fluorouracil-derived acetal and hemiamine acetal ether compound are useful for more efficient oral delivery of the 5-fluorouracil-derived analog compound to the liver. Some additional embodiments relate to a method for manufacturing an acetal and a hemiamine acetal ether compound derived from 5-fluorouracil.

Some embodiments provided herein include a compound of Formula I:

(I)
Or its stereoisomers or pharmaceutically acceptable salts,
In the formula, R ¹ and R ² have any of the values described herein.

Some embodiments are related to a compound of formula II, III, IV, V and VI:

(II)
Or its stereoisomers or pharmaceutically acceptable salts,

(III)
Or its stereoisomers or pharmaceutically acceptable salts,

(IV)
Or its stereoisomers or pharmaceutically acceptable salts,

(V)
Or its stereoisomers or pharmaceutically acceptable salts,

(VI)
Or its stereoisomers or pharmaceutically acceptable salts,
In the formula, R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , X, Y, and Z have any of the values described herein.

Some embodiments relate to a pharmaceutical composition comprising any of the aforementioned compounds and a pharmaceutically acceptable excipient.

Some embodiments relate to a method of treating a disease, disorder, or condition, which comprises administering an effective amount of any of the compounds described above.

In some embodiments, the disease, disorder or condition is a liver disease, disorder or condition.

In some embodiments, the disease, disorder, or condition is a disease, wherein the liver is involved in the production and / or constant control of the biochemical end product of the disease, disorder, or condition.

In some embodiments, the disease, disorder or condition is selected from the group consisting of hepatocellular carcinoma, kidney cancer, colorectal cancer, breast cancer, gastric cancer, gastric cancer, esophageal cancer, pancreatic cancer, and cervical cancer.

In some embodiments, the disease, disorder, or condition is a non-liver disease, disorder, or condition.

In some embodiments, the non-hepatic disease, disorder or condition is various types of cancer, or other diseases, wherein the acetal and hemiamine acetal ether compound derived from 5-fluorouracil will enhance the distribution of active drugs in target tissues and cells .

Some embodiments relate to a method of treating a liver disease comprising administering an effective amount of any of the above compounds to a subject in need thereof.

Some embodiments include administering an effective amount of at least one additional therapeutic agent to a subject in need thereof.

In some embodiments, the subject is a mammal.

In some embodiments, the object is a human.

Some embodiments are directed to a method of inhibiting viral replication in a cell, comprising contacting the cell with any of the compounds described above.

Some embodiments are methods of interfering with molecular pathways or modulating targets in a cell, comprising contacting the cell with any of the compounds described above.

In some embodiments, the cell is in vivo.

In some embodiments, the cell is in vitro.

In some embodiments, the cell is a hepatocyte.

In some embodiments, the cell is a cancer cell.

In some embodiments, the cell is a mammal.

In some embodiments, the cell is human.

Some embodiments of the compounds, compositions and methods provided herein include a pharmaceutical composition comprising any of the compounds provided herein and a pharmaceutically acceptable excipient.

Some embodiments of the compounds, compositions and methods provided herein include a method of treating a disease or condition in the liver of a subject, comprising administering an effective amount of any of the compounds provided herein to a subject in need thereof.

Some embodiments also include administering an effective amount of one or more additional therapeutic agents to a subject in need thereof.

In some embodiments, the subject is a mammal.

In some embodiments, the object is a human.

Some embodiments of the compounds, compositions and methods provided herein include the use of any of the compounds provided herein for the treatment of liver diseases, or diseases involving a physiological or pathogenic pathway in the liver of a subject Or condition.

Some embodiments also include the use of any of the compounds provided herein for use with additional therapeutic agents.

Some embodiments of the compounds, compositions, and methods provided herein include any of the compounds provided herein for use in the preparation of a medicament for the treatment of a disease or condition in the liver, or a physiological or physiological condition involving the liver. A disease or condition of a pathogenic pathway.

This embodiment is related to a composition and method. The composition and method are related to the novel 5-fluorouracil-derived acetal and hemiamine acetal ether compound, the preparation of these, and the use of these. In some embodiments, the novel 5-fluorouracil-derived acetal and hemiamine acetal ether compound promote the delivery of 5-fluorouracil-derived therapeutic agents to cells. The 5-fluorouracil-derived therapeutic agents are, for example: 5- Fluorouracil, 5'-deoxy-5-fluorouridine, 5-fluorouridine monophosphate, and / or 5-fluorodeoxyuridine monophosphate.

These 5-fluorouracil-derived acetals and hemiamine acetal ether compounds and the stereoisomers and pharmaceutically acceptable salts of these are shown by the formulae I, II, III, IV, V, and VI:

(I)
Or its stereoisomers or pharmaceutically acceptable salts,

(II)
Or its stereoisomers or pharmaceutically acceptable salts,

(III)
Or its stereoisomers or pharmaceutically acceptable salts,

(IV)
Or its stereoisomers or pharmaceutically acceptable salts,

(V)
Or its stereoisomers or pharmaceutically acceptable salts,

(VI)
Or its stereoisomers or pharmaceutically acceptable salts,
In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , X, Y, and Z have any of the values described herein.

In some embodiments, R ¹ and R ² are independently from H, optionally substituted C ₁ to C ₁₀ alkyl-OCH _2- , and optionally substituted (C _{6 to 10} aryl) -CH ₂ -OCH ₂ -, Optionally substituted (5- to 10-membered heteroaryl) -CH ₂ -OCH _2- , optionally substituted (C _{6 to 10-} aryl) -OCH ₂ -and optionally substituted (5 to 10-membered heteroaryl) Aryl) -OCH ₂ -is selected from the group, and at least one of R ¹ and R ² is not H.

In some embodiments, R ³ is from H, optionally substituted C ₁ to C ₁₀ alkyl-OCH _2- , optionally substituted C ₁ to C ₁₀ alkyl-NHCH _2- , optionally substituted C ₁ to C ₁₀ acyl, upon any substituent of C ₁ ~ C ₁₀ alkyl group -OC (O) -, once any substituent of (C _{6 ~ 10} aryl) -CH ₂ OCH ₂ -, once any substituent of (C _{6 ~ (10} aryl) -OCH _2- , once optionally substituted (C _{6 to 10} aryl) -C (O)-, once optionally substituted (5 to 10 member heteroaryl) -CH ₂ OCH _2- , once optionally Substituted (5- to 10-membered heteroaryl) -OCH _2- , once optionally substituted (C _{6 to 10-} aryl) -OC (O)-, once optionally substituted (5--10 membered heteroaryl) -C (O)-and a group of (5- to 10-membered heteroaryl)-OC (O)-optionally substituted.

In some embodiments, R ⁴ and R ⁵ are independently selected from H, optionally substituted C ₁ to C ₁₀ alkyl-OCH _2- , optionally substituted C ₁ to C ₁₀ fluorenyl, and optionally substituted (C _{6 to 10} aryl) -CH ₂ OCH _2- , (C _{6 to 10} aryl) -OCH _2- , optionally (C _{6 to 10} aryl) -C (O)-, Arbitrarily substituted (5 to 10-membered heteroaryl) -CH ₂ OCH _2- , once optionally substituted (5 to 10-membered heteroaryl) -OCH _2- , optionally substituted (5 to 10-membered heteroaryl) -C (O) -, optionally substituted by one of C ₁ ~ C ₁₀ alkyl group -NR ^7A CH ₂ -, optionally substituted by one of (C _{6 ~ 10} aryl) -NR ^7A CH ₂ -, optionally substituted by one of (5 ~ 10 member heteroaryl)-NR ^7A CH _2- , NR ^7A CH ₂ -and -L-CH ₂ -selected from the group; R ^7A is independently selected from H, and optionally substituted C ₁ -C ₁₀ alkane Selected from the group consisting of an optionally substituted C ₁ to C ₁₀ fluorenyl group, an optionally substituted C _{6 to 10} aryl group, and an optionally substituted 5 to 10 member heteroaryl group; X is O or NR ^1A ; Y is O or NR ^1B; R ^1A from H, optionally substituted by one of C ₁ ~ C ₁₀ Group -OCH ₂ -, optionally substituted by one of (C _{6 ~ 10} aryl) -OCH ₂ - and optionally substituted by one of (5-10 membered heteroaryl) -OCH ₂ - group of selected; R ^1B from Once optionally substituted C ₁ to C ₁₀ alkyl-OCH _2- , once optionally substituted C ₁ to C ₁₀ fluorenyl, once optionally substituted C ₁ to C ₁₀ alkyl-OC (O)-, once optionally substituted (C _{6 to 10} aryl) -OCH _2- , (C _{6 to 10} aryl) -C (O)-, optionally substituted (5 to 10 member heteroaryl) -OCH _2- , Once optionally substituted (C _{6 to 10} aryl) -OC (O)-, once optionally substituted (5 to 10-membered heteroaryl) -C (O)-and once optionally substituted (5 to 10-membered heteroaryl) Group) -OC (O)-is selected from the group; and L is a 4- to 10-membered nitrogen-containing heterocyclic ring optionally substituted; and when R ³ is H or -X-R ³ is -NHC (O) O- In the case of an alkyl group, at least one of R ⁴ and R ⁵ is not H.

In some embodiments, R ⁶ is H or R ^6A ; R ^6A is C ₁ to C ₁₀ alkyl, C _{6 to 10} aryl, 5 to 10-membered heteroaryl, or 4 to 10-membered heterocyclic group, and Groups are optionally substituted with 1 to 4 R ^6AA ; R ^6AA is independently independently selected from halogen, OH, C ₁ to C ₁₀ alkyl-OCH ₂ O-, and C ₁ to C ₁₀ alkyl C (O) O-, optionally substituted C ₁ to C ₁₀ alkyl-OC (O) O-, optionally substituted C ₁ to C ₁₀ alkyl, optionally substituted C ₁ to C ₁₀ alkoxy Group, optionally substituted C ₃ to C ₁₀ cycloalkyl, optionally substituted C _{6 to 10} aryl, optionally substituted 5 to 10 member heteroaryl, optionally substituted 4 to 10 member heterocyclic group, It is selected from the group of (C _{6 to 10} aryl) -OCH ₂ -which is arbitrarily substituted and (5 to 10-membered heteroaryl) -OCH ₂ -of arbitrarily substituted.

In some embodiments, R ⁷ is from an optionally substituted C ₁ to C ₂₀ alkyl group, an optionally substituted C ₃ to C ₂₀ cycloalkyl group, an optionally substituted C ₂ to C ₂₀ alkenyl group, C _{6 to 10} aryl, 5 to 10 membered heteroaryl, optionally substituted C ₁ to C ₁₀ alkyl-OCH _2- , optionally substituted C ₁ to C ₁₀ alkyl-CO-OCH _2- , optionally substituted (C _{6 to 10} aryl) -OCH _2- , optionally substituted (5 to 10 member heteroaryl) -OCH _2- , once optionally substituted (C _{6 to 10} aryl) -CH ₂ -and an optionally substituted (5 to 10-membered heteroaryl) -CH ₂ -group is selected;

In some embodiments, X is O or NR ^1A ; and R ^1A is from H, optionally substituted C ₁ to C ₁₀ alkyl-OCH _2- , optionally substituted (C _{6 to 10} aryl) -OCH ₂ -And selected from the group of (5 to 10-membered heteroaryl) -OCH ₂ -arbitrarily substituted;

In some embodiments, Y is O or NR ^1B ; and R ^1B is from an optionally substituted C ₁ to C ₁₀ alkyl-OCH _2- , an optionally substituted C ₁ to C ₁₀ fluorenyl, and an optionally substituted C ₁ to C ₁₀ alkyl-OC (O)-, once optionally substituted (C _{6 to 10} aryl) -OCH _2- , once optionally substituted (C _{6 to 10} aryl) -C (O)-, once Arbitrarily substituted (5 to 10-membered heteroaryl) -OCH _2- , once optionally substituted (C _{6 to 10} aryl) -OC (O)-, once optionally substituted (5 to 10 member heteroaryl)- C (O) —and an optionally substituted (5- to 10-membered heteroaryl) —OC (O) — group is selected.

In some embodiments, Z is O or NR ^1C ; and R ^1C is selected from the group consisting of H, optionally substituted C ₁ to C ₁₀ alkyl, and optionally substituted aryl.

In some embodiments, the acetal and hemiamine acetal ether compounds derived from 5-fluorouracil of formulas I, II, III, IV, V, and VI are substrates of liver enzymes, such as cytochrome p450 isoforms. Enzymes CYP3As (monooxygenase family), dehydrogenases, esterases and amidases, etc.

CYP3As appears to be much higher in the liver than other tissues (DeWaziers et al., J Pharm Exp Ther 253: 387 (1990)). The acetal and hemiacetal ether compounds derived from 5-fluorouracil of formulae I, II, III, IV, V and VI are mainly activated in the liver via CYP3A4. In some embodiments, the compounds of the formulae I, II, III, IV, V, and VI have highly efficient liver targeting by selectively transporting bioactive agents to the liver. In some embodiments, because compounds of formulae I, II, III, IV, V, and VI may not be active or may be less active outside the liver, acetals and hemiamine acetal ether compounds are used to increase the therapeutic index of drugs .

In some embodiments, due to the liver target properties of acetal and hemiacetal ether compounds derived from 5-fluorouracil of formulas I, II, III, IV, V, and VI, the compound is used to treat a disease. It would benefit from enhanced drug distribution in the liver and similar tissues and cells. The disease includes, but is not limited to, liver diseases such as hepatocellular carcinoma.

In some embodiments, the compounds of the present disclosure are used to improve pharmacokinetic properties, such as extending half-life or enhancing drug absorption. In addition, the methodology disclosed herein can be used to achieve continuous delivery of active therapeutic agents. Due to the enhanced pharmacokinetic properties of acetal and hemiamine acetal ether compounds derived from 5-fluorouracil of formulas I, II, III, IV, V and VI, the use of this compound to treat a disease will benefit from the enhancement The medicinal properties of the disease include, but are not limited to, diseases such as various types of cancer. In some embodiments, methods for making these compounds have been described.

Some compounds of formulae I, II, III, IV, V and VI have asymmetric centers, in which stereochemistry may not be specific, and when compounds of formulae I, II, III, IV, V and VI are generally represented, this is included And other non-mirromeric mixtures of compounds, as well as individual stereoisomers.

Some embodiments of the compounds, compositions and methods provided herein include a pharmaceutical composition comprising any of the compounds provided herein and a pharmaceutically acceptable carrier.

Some embodiments also include administering an effective amount of the second or more therapeutic agents to a subject in need thereof together with a compound provided herein.

In some embodiments, the subject is a mammal.

In some embodiments, the object is a human.

Some embodiments of the compounds, compositions, and methods provided herein include a method of testing a compound in a cell, comprising contacting the cell with a compound of the present disclosure.

Some embodiments of the compounds, compositions and methods provided herein include uses of the compounds provided herein for the treatment of liver diseases.

Some embodiments include the use of a compound provided herein for use with additional therapeutic agents to treat liver diseases.

Some embodiments of the compounds, compositions and methods provided herein include the use of the compounds provided herein for the treatment of diseases or conditions involving the molecular pathways of the liver.

Some embodiments include the use of a compound provided herein for use with an additional therapeutic agent to treat a disease or condition involving a molecular pathway of the liver.

Some embodiments of the compounds, compositions and methods provided herein include the use of the compounds provided herein for the treatment of non-liver diseases such as various types of cancer.

Some embodiments include the use of a compound provided herein for use with additional therapeutic agents to treat non-liver diseases such as various types of cancer.

Where the compounds disclosed herein have at least one palm center, they can exist as individual and non-image isomers, or as a mixture of such isomers, including racemates. Isolation of individual isomers or selective synthesis of individual isomers is accomplished by applying various methods well known to those skilled in the art. Unless otherwise indicated, all such isomers and mixtures thereof are included within the scope of the compounds disclosed herein. In addition, the compounds disclosed herein may exist in one or more crystalline or amorphous forms. Unless otherwise indicated, all such forms are included within the scope of the compounds disclosed herein, including any polymorphic form. In addition, part of the compounds disclosed herein can form solvates with water (ie, hydrates) or general organic solvents. Unless indicated, such solvates are included within the scope of the compounds disclosed herein.

Those skilled in the art can confirm that some of the structures described herein can be resonant forms or tautomers of the compounds, which can be fully represented by other chemical structures, even in kinetics; those skilled in the art can It was confirmed that such a structure might represent only a very small part of a sample of such a compound. Although such resonant forms or tautomers are not represented herein, such compounds should be considered within the scope of the structures described.

Isotopes may be present in the compounds described. Chemical elements as represented in the compound structure may each include any isotope of the recited element. For example, in the structure of a compound, a hydrogen atom can be explicitly revealed or understood in the compound. The hydrogen atom may be present at any position in the compound, and the hydrogen atom may be any isotope of hydrogen, including but not limited to hydrogen-1 (tritium) and hydrogen-2 (deuterium). Therefore, unless the context clearly dictates, the compounds referred to herein include all potential isotopic forms.
[definition]

In accordance with the present disclosure and as used herein, the following terms are defined in the following meanings unless explicitly stated otherwise. It should be understood that the foregoing general description and the following embodiments are merely exemplary and illustrative, and are not intended to limit the subject matter for which protection is sought. In this case, the use of the singular includes the plural unless specifically stated otherwise. In this case, the use of "or" means "and / or" unless stated otherwise. In addition, the use of the terms "including" and other forms (such as "including" and "included") is not restrictive.

As used herein, ranges and amounts may be expressed as "about" a particular value or range. "About" also includes the precise amount. Thus "about 10%" means "about 10%" and also means "10%".

As used herein, "arbitrarily" or "arbitrarily" means that the event or situation described later occurs or does not occur, and means that the narrative includes examples of the event or situation occurring and the event or situation does not Happening example. For example: an optionally substituted group means that the group is unsubstituted or substituted.

As used herein, unless the context clearly indicates otherwise, the singular forms "a" and "the" include plural referents. Thus, for example, reference to a composition comprising a "therapeutic agent" includes a composition having one or more therapeutic agents.

In the like as used herein, "C _a ~ C _b" or _{"C a ~ b""a} " and "b" is an integer number of carbon atoms of the group designated specifically. That is, the group may contain carbon atoms including "a" to "b". Therefore, for example: "C ₁ to C ₄ alkyl" or "C ₁ to ₄ alkyl" means all alkyl groups having 1 to 4 carbons, that is, CH _3- , CH ₃ CH _2- , CH ₃ CH ₂ CH _2- , (CH ₃ ) ₂ CH-, CH ₃ CH ₂ CH ₂ CH _2- , CH ₃ CH ₂ CH (CH ₃ )-, and (CH ₃ ) ₃ C-.

As used herein, "alkyl" refers to a straight or branched chain hydrocarbon that is fully saturated (i.e., does not contain double or reference bonds). An alkyl group may have 1 to 20 carbon atoms (each occurrence in this text, for example, a numerical range such as "1 to 20" means each integer in a given range; for example: "1 to 20 carbon atoms" means An alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the definition also includes the term "alkyl" which does not indicate a numerical range). The alkyl group may be an alkyl group having an equal size among 1 to 9 carbon atoms. The alkyl group may also be a smaller alkyl group having 1 to 4 carbon atoms. Alkyl groups may be labeled as "C ₁ -C ₄ alkyl" or similar. For example only, "C ₁ -C ₄ alkyl" indicates that there are one to four carbon atoms in the alkyl chain, that is, the alkyl chain is from methyl, ethyl, propyl, isopropyl, n-butyl, Selected from the group consisting of isobutyl, secondary butyl and tertiary butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.

As used herein, a substituted radical is derived from an unsubstituted primitive radical in which one or more hydrogen atoms are exchanged for another atom or radical. Unless otherwise indicated, when a group is regarded as "substituted", it means that the group is independently substituted with one or more substituents selected from the group consisting of: C ₁ to C ₆ alkyl, C ₂ to C ₆ alkenyl, C ₂ to C ₆ alkynyl, C ₃ to C ₇ carbocyclyl (via halogen, C ₁ to C ₆ alkyl, C ₁ to C ₆ alkoxy, C ₁ to C ₆ Haloalkyl and C ₁ to C ₆ haloalkoxy are optionally substituted), C ₃ to C ₇ -Carbocyclyl -C ₁ to C ₆ -alkyl (via halogen, C ₁ to C ₆ alkyl, C ₁ to C ₆ alkoxy, C ₁ to C ₆ haloalkyl, and C ₁ to C ₆ haloalkoxy optionally substituted), 3 to 10 membered heterocyclic groups (via halogen, C ₁ to C ₆ alkyl, C ₁ to C ₆ alkoxy, C ₁ to C ₆ haloalkyl, and C ₁ to C ₆ haloalkoxy optionally substituted), 3 to 10-membered heterocyclyl-C ₁ to C ₆ -alkyl (via halogen, C ₁ ～ C ₆ alkyl, C ₁ ～ C ₆ alkoxy, C ₁ ～ C ₆ haloalkyl, and C ₁ ～ C ₆ halalkoxy optionally substituted), aryl (via halogen, C ₁ ～ C ₆ alkyl , C ₁ to C ₆ alkoxy, C ₁ to C ₆ haloalkyl, and C ₁ to C ₆ haloalkoxy optionally substituted), aryl (C ₁ to C ₆ ) alkyl (via halogen, C ₁ to C ₆ alkyl, C ₁ ~ C ₆ alkoxy group, C ₁ ~ C ₆ haloalkyl C ₁ ~ C ₆ alkoxy group is optionally substituted with halo), 5 to 10 membered heteroaryl group (halogen, C ₁ ~ C ₆ alkyl group, C ₁ ~ C ₆ alkoxy group, C ₁ ~ C ₆ alkyl and halo C ₁ to C ₆ haloalkoxy optionally substituted), 5 to 10-membered heteroaryl (C ₁ to C ₆ ) alkyl (via halogen, C ₁ to C ₆ alkyl, C ₁ to C ₆ alkoxy, C ₁ to C ₆ haloalkyl and C ₁ to C ₆ haloalkoxy are optionally substituted), halogen, cyano, hydroxyl, C ₁ to C ₆ alkoxy, C ₁ to C ₆ alkoxy (C ₁ to C ₆ ) alkyl (ie, ether), aryloxy (via halogen, C ₁ to C ₆ alkyl, C ₁ to C ₆ alkoxy, C ₁ to C ₆ haloalkyl, and C ₁ to C ₆ halogen Alkoxy optionally substituted), C ₃ to C ₇ carbon epoxy (via halogen, C ₁ to C ₆ alkyl, C ₁ to C ₆ alkoxy, C ₁ to C ₆ haloalkyl, and C ₁ to C ₆ -haloalkoxy optionally substituted), 3 to 10-membered heterocyclyl-oxy (via halogen, C ₁ to C ₆ alkyl, C ₁ to C ₆ alkoxy, C ₁ to C ₆ haloalkyl, and C ₁ to C ₆ haloalkoxy optionally substituted), 5 to 10-membered heteroaryl-oxy (via halogen, C ₁ to C ₆ alkyl, C ₁ to C ₆ alkoxy, C ₁ to C ₆ haloalkane And C ₁ to C ₆ haloalkoxy are optionally substituted), C ₃ to C ₇ -carbocyclyl-C ₁ to C ₆ -alkane Oxygen (optionally substituted by halogen, C ₁ to C ₆ alkyl, C ₁ to C ₆ alkoxy, C ₁ to C ₆ haloalkyl, and C ₁ to C ₆ haloalkoxy), 3 to 10 members Cyclo-C ₁ to C ₆ -alkoxy (via halogen, C ₁ to C ₆ alkyl, C ₁ to C ₆ alkoxy, C ₁ to C ₆ haloalkyl, and C ₁ to C ₆ haloalkoxy Group optionally substituted), aryl (C ₁ to C ₆ ) alkoxy (via halogen, C ₁ to C ₆ alkyl, C ₁ to C ₆ alkoxy, C ₁ to C ₆ haloalkyl, and C ₁ to C ₆ haloalkoxy optionally substituted), 5 to 10-membered heteroaryl (C ₁ to C ₆ ) alkoxy (via halogen, C ₁ to C ₆ alkyl, C ₁ to C ₆ alkoxy, C ₁ ~ C ₆ haloalkyl and C ₁ ~ C ₆ haloalkoxy optionally substituted), hydrogenthio (mercapto), halo (C ₁ -C ₆ ) alkyl (eg -CF ₃ ), halo (C ₁ -C ₆ ) Alkoxy (for example, -OCF ₃ ), C ₁ to C ₆ alkylthio, arylthio (via halogen, C ₁ to C ₆ alkyl, C ₁ to C ₆ alkoxy, C ₁ to C ₆ Haloalkyl and C ₁ to C ₆ haloalkoxy optionally substituted), C ₃ to C ₇ carbocyclylthio (via halogen, C ₁ to C ₆ alkyl, C ₁ to C ₆ alkoxy, C ₁ ~ C ₆ haloalkyl and C ₁ ~ C ₆ haloalkoxy optionally substituted), 3 to 10-membered heterocyclyl-thio (via halogen, C ₁ to C ₆ alkyl, C ₁ to C ₆ alkoxy, C ₁ to C ₆ haloalkyl, and C ₁ to C ₆ haloalkoxy optionally substituted), 5 to 10-membered heteroaryl-thio ( Optionally substituted with halogen, C ₁ to C ₆ alkyl, C ₁ to C ₆ alkoxy, C ₁ to C ₆ haloalkyl, and C ₁ to C ₆ haloalkoxy), C ₃ to C ₇ -carbocycle -C ₁ to C ₆ -alkylthio (via halogen, C ₁ to C ₆ alkyl, C ₁ to C ₆ alkoxy, C ₁ to C ₆ haloalkyl, and C ₁ to C ₆ haloalkoxy Optionally substituted), 3 to 10-membered heterocyclyl-C ₁ to C ₆ -alkylthio (via halogen, C ₁ to C ₆ alkyl, C ₁ to C ₆ alkoxy, C ₁ to C ₆ haloalkyl And C ₁ to C ₆ haloalkoxy optionally substituted), aryl (C ₁ to C ₆ ) alkylthio (via halogen, C ₁ to C ₆ alkyl, C ₁ to C ₆ alkoxy, C ₁ to C ₆ haloalkyl and C ₁ to C ₆ haloalkoxy optionally substituted), 5 to 10-membered heteroaryl (C ₁ to C ₆ ) alkylthio (via halogen, C ₁ to C ₆ alkyl, C ₁ ~ C ₆ alkoxy, C ₁ ~ C ₆ haloalkyl and C ₁ ~ C ₆ haloalkoxy optionally substituted), amine, amine (C ₁ -C ₆ ) alkyl, nitro, O-amine Formamidine, N-aminoformamyl, O-thioaminoformamyl, N-thioaminoformamyl, C-fluorenylamine, N-fluorenylamine , S-sulfoamido, N-sulfoamido, C-carboxyl, O-carboxyl, fluorenyl, cyano, isocyano, thiocyano, isothiocyano, sulfinamido , Sulfofluorenyl, and keto (= O). Whenever a group is described as "optionally substituted", the group may be arbitrarily substituted with the above-mentioned substituents.

As used herein, "fluorenyl" represents -C (= O) R, where R is hydrogen, C _{1 to 6} alkyl, C _{2 to 6} alkenyl, C _{2 to 6} alkynyl, C _{3 to 7} carbocyclyl, C _{6 to 10} aryl, 5 to 10 membered heteroaryl, and 3 to 10 membered heterocyclyl, as defined herein. Non-limiting examples include: methylamyl, ethylamyl, propylamyl, benzamyl, and acrylamyl.

"Heterofluorenyl" means -C (= O) R, wherein R is a C _{1 to 6} heteroalkyl group.

"Alkoxymethylene" means -CH ₂ OR, wherein R is a C _{1 to 6} alkyl group or a heteroalkyl group, and these may be optionally substituted.

"O-carboxy" means a "-OC (= O) R" group, wherein R is from hydrogen, C _{1 to 6} alkyl, C _{2 to 6} alkenyl, C _{2 to 6} alkynyl, C _{3 to 7} carbons A cyclic group, a C _{6 to 10} aryl group, a 5 to 10 member heteroaryl group, and a 3 to 10 member heterocyclic group are selected as defined herein.

"C-carboxy" means a "-C (= O) OR" group, wherein R is from hydrogen, C _{1 to 6} alkyl, C _{2 to 6} alkenyl, C _{2 to 6} alkynyl, C _{3 to 7} carbons A cyclic group, a C _{6 to 10} aryl group, a 5 to 10 member heteroaryl group, and a 3 to 10 member heterocyclic group are selected as defined herein. Non-limiting examples include carboxyl (ie, -C (= O) OH).

"Cyano" means "-CN".

The "cyano group" means a "-OCN" group.

"Isocyanate" means a "-NCO" group.

The "thiocyanate group" means a "-SCN" group.

"Isothiocyanate" means "-NCS" group.

"Sulfinylene" refers to a "-S (= O) R" group, wherein R is hydrogen, C _{1 to 6} alkyl, C _{2 to 6} alkenyl, C _{2 to 6} alkynyl, C _{3 to 7} A carbocyclic group, a C _{6 to 10} aryl group, a 5 to 10 member heteroaryl group, and a 3 to 10 member heterocyclic group are selected as defined herein.

"Sulfonyl" represents a "-SO ₂ R" group, wherein R is hydrogen, C _{1 to 6} alkyl, C _{2 to 6} alkenyl, C _{2 to 6} alkynyl, C _{3 to 7} carbocyclyl, A C _{6 to 10} aryl group, a 5 to 10 member heteroaryl group, and a 3 to 10 member heterocyclic group are selected as defined herein.

"S-sulfonamido" means a "-SO ₂ NR _A R _B " group, in which R _A and R _B are independently selected from hydrogen, C _{1 to 6} alkyl, C _{2 to 6} alkenyl, and C _{2 ~ 6} alkynyl group, C _{3 ~ 7} carbocyclic group, C _{6 - 10} aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclic group selected among, like as defined herein.

"N-sulfonamido" means a "-N (R _A ) SO ₂ R _B " group, in which R _A and R _B are each independently selected from hydrogen, C _{1 to 6} alkyl, and C _{2 to 6} alkenyl , C _{2 to 6} alkynyl, C _{3 to 7} carbocyclyl, C _{6 to 10} aryl, 5 to 10-membered heteroaryl, and 3 to 10-membered heterocyclyl, as defined herein.

"O-Aminomethyl" refers to a "-OC (= O) NR _A R _B " group, in which R _A and R _B are independently selected from hydrogen, C _{1 to 6} alkyl, and C _{2 to 6} alkenyl , C _{2 to 6} alkynyl, C _{3 to 7} carbocyclyl, C _{6 to 10} aryl, 5 to 10-membered heteroaryl, and 3 to 10-membered heterocyclyl, as defined herein.

"N-aminomethylamidino" means a "-N (R _A ) C (= O) OR _B " group, wherein R _A and R _B are independently selected from hydrogen, C _{1 to 6} alkyl, and C _{2 to 6} alkenyl, C _{2 to 6} alkynyl, C _{3 to 7} carbocyclyl, C _{6 to 10} aryl, 5 to 10-membered heteroaryl, and 3 to 10-membered heterocyclyl, as selected herein By definition.

"O-thioaminomethane" means a "-OC (= S) NR _A R _B " group, wherein R _A and R _B are independently selected from hydrogen, C _{1 to 6} alkyl, and C _{2 to 6} Alkenyl, C _{2 to 6} alkynyl, C _{3 to 7} carbocyclyl, C _{6 to 10} aryl, 5 to 10-membered heteroaryl, and 3 to 10-membered heterocyclyl, as defined herein Like.

"N-thioaminomethane" means a "-NR _A C (= S) OR _B " group, wherein R _A and R _B are each independently selected from hydrogen, C _{1 to 6} alkyl, and C _{2 to 6} Alkenyl, C _{2 to 6} alkynyl, C _{3 to 7} carbocyclyl, C _{6 to 10} aryl, 5 to 10-membered heteroaryl, and 3 to 10-membered heterocyclyl, as defined herein Like.

"C-fluorenylamino" means a "-C (= O) NR _A R _B " group, in which R _A and R _B are independently selected from hydrogen, C _{1 to 6} alkyl, C _{2 to 6} alkenyl, C _{2 to 6} alkynyl, C _{3 to 7} carbocyclyl, C _{6 to 10} aryl, 5 to 10-membered heteroaryl, and 3 to 10-membered heterocyclyl are selected as defined herein. One or more substituents selected from the group consisting of: -OH, C _{1 to 6} alkyl, C _{3 to 7} carbocyclyl, C _{6 to 10} aryl, 5 to 10 heteroaryl group, 3-10-membered heterocyclyl, C _{1 ~ 6} alkoxy group optionally substituted with -OH or the C _{1 ~ 6} alkyl group, C _{1 ~ 6} and by alkoxy or optionally substituted -OH of C _{1 to 6} alkoxy.

"N-fluorenylamino" means a "-N (R _A ) C (= O) R _B " group, in which R _A and R _B are independently selected from hydrogen, C _{1 to 6} alkyl, and C _{2 to 6} Alkenyl, C _{2 to 6} alkynyl, C _{3 to 7} carbocyclyl, C _{6 to 10} aryl, 5 to 10-membered heteroaryl, and 3 to 10-membered heterocyclyl, as defined herein Generally, they are arbitrarily substituted by one or more substituents selected from the group consisting of: -OH, C _{1 to 6} alkyl, C _{3 to 7} carbocyclyl, C _{6 to 10} aryl , 5-10 membered heteroaryl, 3-10-membered heterocyclyl, C _{1 ~ 6} alkoxy group optionally substituted with -OH or the C _{1 ~ 6} alkyl group, C _{1 ~ 6} and by alkoxy or -OH Optionally substituted C _{1 to 6} alkoxy.

"Amine group" means a "-NR _A R _B " group, wherein R _A and R _B are each independently selected from hydrogen, C _{1 to 6} alkyl, C _{2 to 6} alkenyl, C _{2 to 6} alkynyl, C _{It is selected from a 3 to 7} carbocyclic group, a C _{6 to 10} aryl group, a 5 to 10 member heteroaryl group, and a 3 to 10 member heterocyclic group, as defined herein. Non-limiting examples include a free amine group (i.e., -NH _2).

"Aminoalkyl" means an amine group connected via an alkylene group.

"Alkoxyalkyl" means an alkoxy group connected via an alkylene group, and examples thereof include "C _{2 to 8} alkoxyalkyl" and the like.

The term "fluorenyloxy" means -OC (O) R, wherein R is an alkyl group.

The term "alkoxy" or "alkyloxy" means OR, wherein R is an alkyl group or a heteroalkyl group, and these are optionally substituted.

The term "carboxy" means C (O) OH.

The term "keto group" means a = 0 group.

The term "halogen" or "halogen" means F (fluorine), Cl (chlorine), Br (bromine), and I (iodine).

The term "haloalkyl" means an alkyl group containing at least one halogen, and in a further embodiment, 1 to 3 halogen atoms. Suitable halogen atoms include F, Cl, and Br.

The term "halofluorenyl" refers to -C (O) -haloalkyl.

The term "alkenyl" refers to an unsaturated group having 2 to 12 atoms, containing at least one carbon-carbon double bond, and including straight chain, branched chain, and cyclic groups. The alkenyl group may be optionally substituted. Suitable alkenyls include allyl.

The term "alkynyl" refers to an unsaturated group, which has 2 to 12 atoms, contains at least one carbon-carbon reference bond, and includes linear, branched, and cyclic groups. The alkynyl may be optionally substituted. Suitable alkynyl groups include ethynyl.

As used herein, "aryl" refers to an aromatic ring or ring system (ie, two or more fused rings sharing two adjacent carbon atoms) whose ring skeleton contains only carbon. When aryl is a ring system, each ring in the system is aromatic. An aryl group may have 6 to 18 carbon atoms, although the term "aryl" as used in this definition also encompasses unspecified numerical ranges. In some embodiments, the aryl group has 6 to 10 carbon atoms. The aryl group may be labeled as "C _{6 to 10} aryl group", "C ₆ or C ₁₀ aryl group", or the like. Examples of aryl include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.

As used herein, "heteroaryl" refers to an aromatic ring or ring system (that is, two or more fused rings sharing two adjacent carbon atoms) whose ring backbone contains one or more A heteroatom, which is an element different from carbon, including but not limited to: nitrogen, oxygen, and sulfur. When heteroaryl is a ring system, each ring in the system is aromatic. Heteroaryl groups can have 5 to 18 ring members (ie, the number of atoms that make up the ring skeleton, including carbon atoms and heteroatoms), although this definition also covers the use of the term "heteroaryl" which does not indicate a numerical range. In some embodiments, the heteroaryl group has 5 to 10 ring members or 5 to 7 ring members. Heteroaryl groups can be labeled as "5- to 7-membered heteroaryl", "5- to 10-membered heteroaryl", or similar. Heteroaryl groups can be optionally substituted. Examples of heteroaryl include, but are not limited to, aromatic C3-8 heterocyclic groups containing one oxygen or sulfur atom or up to four nitrogen atoms, or a combination of one oxygen or sulfur atom and up to two nitrogen atoms, and the like Substituents and benzo- and pyrido-fused derivatives are connected, for example, via a ring-forming carbon atom. In some embodiments, the heteroaryl group is arbitrarily substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, amino, cyano, nitro, alkylamino, fluorenyl, C _{1 to 6} -alkoxy, C _{1 to 6} -alkyl, C _{1 to 6} -hydroxyalkyl, C _{1 to 6} -aminoalkyl, C _{1 to 6} -alkylamino, alkylsulfenyl Alkylsulfenyl, alkylsulfenyl, alkylsulfenyl, sulfamoyl, or trifluoromethyl. Examples of heteroaryl include, but are not limited to, unsubstituted or mono- or di-substituted derivatives of the following compounds: furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzo Oxazole, isoxazole, benzoisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole, quinoline, isoquinoline, pyridazine, Pyrimidine, purine, and pyrazine, furazan, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, triazole, benzotriazole Azole, pteridine, phenoxazole, oxadiazole, benzopyrazole, quinazine, cinnoline, phthalazine, quinazoline, and quinoxaline. In some embodiments, the substituents are halogen, hydroxy, cyano, OC _{1 to 6} -alkyl, C _{1 to 6} -alkyl, hydroxy-C _{1 to 6} -alkyl, and amine -C _{1 to 6-} alkyl.

As used herein, "cycloalkyl" means a fully saturated carbocyclyl ring or ring system. Examples include: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. A cycloalkyl group may have 3 to 10 carbon atoms (whenever it appears herein, a numerical range such as "3 to 10" means each integer in a given range). Cycloalkyl can be labeled as "C ₃ -C ₈ cycloalkyl" or similar. By way of example only, "C ₃ ~ C ₈ cycloalkyl group" indicated carbocyclic ring or ring system has 3- to eight carbon atoms.

As used herein, "heterocyclyl" means a non-aromatic cyclic ring or ring structure that is fully saturated or partially saturated, and that the ring skeleton includes at least one heteroatom selected from nitrogen, oxygen, and sulfur . A heterocyclyl can have any degree of saturation, provided that at least one of the rings in the ring system is not aromatic. Heteroatoms may exist in non-aromatic or aromatic rings in the ring system. Heterocyclyl may have 3 to 20 ring members (ie, the number of atoms constituting the ring skeleton, including carbon atoms and heteroatoms), although the definition also encompasses the term "heterocyclyl" which does not indicate a numerical range. The heterocyclic group may be a heterocyclic group having an equal size among 3 to 10 ring members. The heterocyclic group may be a heterocyclic group having 3 to 6 ring members. Heterocycloalkyl can be labeled as "3 to 15-membered heterocycloalkyl", "4 to 10-membered heterocycloalkyl", "3 to 15-membered C _{2 to 14} heterocycloalkyl", "5 to 9-membered C _{4 to 8} heterocycloalkyl "," 5 to 10-membered C _{4 to 9} heterocycloalkyl "," 5-membered C _{3 to 4} heterocycloalkyl "," 6-membered C _{4 to "5} heterocycloalkyl", "7-membered C _{5 to 6} heterocycloalkyl", "bicyclic or reference ring 9 to 15-membered C _{8 to 14} heterocycloalkyl", "monocyclic or bicyclic 3 to 10- Member C _{2 to 9} heterocycloalkyl "," bicyclic 8 to 10-membered C _{4 to 9} heterocycloalkyl "," bicyclic 8 to 10-membered C _{5 to 9} heterocycloalkyl "," monocyclic 4 to 7-membered C _{3 to 6} heterocycloalkyl "," monocyclic 5 to 6-membered C _{3 to 5} heterocycloalkyl ", or similar designations. The heterocyclic group may also be a C ₂ to C ₉ heterocyclic group having 3 to 10 ring members having one to three O (oxy), N (nitrogen), or S (sulfur). The heterocyclic group may be labeled as "3 to 10-membered C ₂ to C ₉ heterocyclic group" or the like. In the preferred six-membered monocyclic heterocyclic group, the heteroatom is selected from one to a maximum of three O (oxygen), N (nitrogen) or S (sulfur), and the preferred five-membered monocyclic heterocyclic group Here, the hetero atom is selected from one or two hetero atoms selected from O (oxygen), N (nitrogen), or S (sulfur). Examples of heterocyclyl rings include, but are not limited to: azepinyl, acridinyl, carbazolyl, fluorenyl, dioxolanyl, imidazoline, imidazolyl, Phenyl, oxepanyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, diketopiperazinyl, pyrrolidinyl, pyrrolidine Keto, pyrrolidinone, 4-piperidinone, pyrazolinyl, pyrazolinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1 1,4-Dioxinyl, 1,4-Dioxanyl, 1,3-oxathianyl, 1,4-oxathiinyl, 1,4-oxathianyl, 2H- 1,2-oxazinyl, trioxanyl, hexahydro-1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolyl Alkyl, 1,3-dithiolyl, 1,3-dithiolyl, isoxazoline, isoxazolyl, oxazoline, oxazolyl Group, oxazolidinyl, thiazolinyl, thiazolinyl, 1,3-oxathialanyl, indololinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropiperanyl, tetrahydrofuranyl Hydrothio Phenyl, tetrahydrothianyl, tetrahydro-1,4-thiazinyl, thiomorpholinyl, dihydrobenzofuranyl, benzimidazolyl, and tetrahydroquinolinyl.

As used herein, "cyclic acetal" means a cyclic group containing a moiety in which two oxygens form part of a cyclic skeleton:
.

It should be understood that some base naming rules may include one-base or two-base depending on the context. For example: when a substituent needs to be connected to the rest of the molecule at two points, it should be understood that the substituent is a di- group. For example, the substituents of the alkyl group identified as requiring two points of attachment include, for example, -CH _2- , -CH ₂ CH _2- , -CH ₂ CH (CH ₃ ) CH _2- , and other di- groups and the like. Other radical nomenclature explicitly indicates that the radical is a di-radical such as "alkylene" or "alkenyl".

When referring to two R groups "together with the atoms to which they are attached" to form a ring (such as a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring), it means that the atom and the two The R-based aggregate unit is the ring described. When used individually, the ring is not limited by the definition of each R group. Example: When the following infrastructure exists:

And R ¹ and R ^{2 are} defined as selected from the group consisting of alkyl and aryl groups, or when R ¹ and R ² form a heterocyclic group together with the oxygen to which these groups are respectively connected, it means R ¹ and R ² may be selected from an alkyl group or an aryl group, or the basic structure has the following structure:

Among them, ring A is a heterocyclic ring containing the described oxygen.

Similarly, when referring to two "adjacent" R radicals "together with the atoms to which they are attached" to form a ring, it means that the atom and the bond in between and the two R radicals are a collection The unit is the ring described. Example: When the following infrastructure exists:

And R ¹ and R ^{2 are} defined as selected from the group consisting of hydrogen and alkyl, or when R ¹ and R ² together with these connected atoms form an aryl or carbocyclic group, it means R ¹ and R ² may be selected from hydrogen or alkyl, or the basic structure has the following structure:

Wherein, A is an aryl ring or a carbocyclic group containing the described double bond.

Whenever a substituent is described as a di-group (ie, having two points attached to the rest of the molecule), it should be understood that the substituent may be attached to any directional structure unless specifically noted. So, for example: described as -AE-or The substituent includes a substituent oriented in such a manner that A is connected to the leftmost connection point of the molecule, and the case where A is connected to the rightmost connection point of the molecule.

The phrase "therapeutically effective amount" means an amount of a compound or combination of compounds that partially or completely ameliorates, reduces or eliminates one or more symptoms of a particular disease or condition, or prevents, alleviates or delays a particular disease Or one or more symptoms of the condition. Such an amount can be administered as a single dose, or it can be administered depending on the therapy, thereby making it effective. Repeated administrations may be required to achieve desired results (e.g., treatment of disease and / or condition).

The term "pharmaceutically acceptable salt" includes salts of the compounds of the formulae I, II, and III derived from the combination of the compound of this embodiment and an organic or inorganic acid or base. Pharmaceutically acceptable acid addition salts can be formed from inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example: acetic acid, adipic acid, propionic acid, glycolic acid, pyruvate, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, Cinnamic acid, mandelic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, (+)-7,7-dimethyl-2-ketobicyclo [2.2.1] heptane-1- Methanesulfonic acid, 1,2-ethanedisulfonic acid, dodecylsulfonic acid, salicylic acid, grape heptanoic acid, gluconic acid, glucuronic acid, hippuric acid, hemiglycolic acid hydrochloride, 2-hydroxyethanesulfonic acid, lactic acid , Lactobionic acid, methyl bromic acid, methylsulfuric acid, 2-naphthalenesulfonic acid, oleic acid, 4,4'-methylenebis [3-hydroxy-2-naphthoic acid], polygalacturonic acid, stearic acid Acids, sulfosalic acid, tannic acid, terephthalic acid, and the like. Inorganic bases from which salts can be derived include, for example: bases containing sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, magnesium, aluminum, and the like; particularly preferred are ammonium, potassium, sodium, calcium And magnesium salts. Some embodiment, the inorganic base to the compounds disclosed herein, resulting in the loss of the processing result from the unstable hydrogen compounds, to provide a salt form, including, for example ^{Li +, Na +, K +} , Mg 2 + and Ca ^{2 +} and inorganic cations and the like. Organic bases from which salts can be derived include, for example: primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, alkali ion exchange resins, and the like, specifically Isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.

When no given number of substituents is specified (eg "haloalkyl"), then one or more substituents may be present. For example: "haloalkyl" may include one or more of the same or different halogens. For example: "haloalkyl" includes any of the substituents CF ₃ , CHF ₂ and CH ₂ F.

The term "patient" refers to the animal being treated, including mammals such as dogs, cats, cattle, horses, sheep, and humans. In some embodiments, the patient is a mammal, male or female. In some embodiments, the patient is a male or female human.

The term "prodrug" as used herein means any compound that, when administered to a biological system, produces a biologically active compound that is a spontaneous chemical reaction, an enzyme-catalyzed chemical reaction, and / or a metabolic chemical reaction, Or the result of any combination. Standard prodrugs are formed using the following functions: HO-, HS-, HOOC-, HOOPR2, etc., which are cleaved in vivo, with functional bases related to drugs. Standard prodrugs include, but are not limited to, carboxylic acid esters, in which the radicals are alkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyloxyalkyl; and esters of hydroxyl, thiol, and amine Wherein, the linked group is fluorenyl, alkoxycarbonyl, aminocarbonyl, phosphate or sulfate. The illustrated bases are merely examples and are not exhaustive. Those skilled in the art to which the present invention pertains can prepare other known types of prodrugs. Prodrugs must undergo some form of chemical conversion to produce a compound that is biologically active or a precursor to a biologically active compound. In some cases, the prodrug has biological activity, which is generally lower than the drug itself, and provides improved drug efficacy or safety by improving oral bioavailability, pharmacodynamic half-life, and the like. Prodrug-preventing forms of compounds can be used, for example: improving bioavailability; improving subject acceptability, such as masking or reducing unpleasant features such as bitterness or gastrointestinal irritation; etc .; altering solubility for, for example, intravenous Use, etc .; provide extended or sustained release or delivery; improve ease of formulation; or provide targeted delivery of compounds.

The term "stereoisomer" refers to the relative or absolute spatial relationship of the R group attached to a carbon or phosphorus atom at the center of a stereo source, and refers to the isolation of separate isomers such as racemic mixtures and non-mirromeric isomers. Or any combination. When a compound has two stereogenic centers, there are four possible stereoisomers.

The term "liver" means a liver organ.

The term "liver specific" means the following ratios as measured in animals treated with drugs or prodrugs:
[Drug or drug metabolite in liver tissue] / [Drug or drug metabolite in blood or other tissue].
The ratio can be determined by measuring tissue levels at specific times, or can represent AUC (area under the curve) based on values measured at three or more time points.

The term "increased or enhanced liver specificity" means an increase in the liver-specific proportion of animals treated with a previous drive relative to animals treated with a prototype drug.

The term "enhanced oral bioavailability" means that the absorbed dose of the reference drug is increased by at least about 50%. In additional aspects, the oral bioavailability of the compound (compared to the reference drug) is increased by at least about 100%, or doubled by absorption. The measurement of oral bioavailability usually means that the measured value of the previous drug, drug or drug metabolite in blood, plasma, tissue or urine after oral administration is compared to the measured value after parenteral administration.

The term "therapeutic index" refers to the ratio of the dose of a drug or prodrug that produces a therapeutically beneficial response to the dose that produces an undesired response such as death, an increase in a marker showing toxicity, and / Or pharmacological side effects.

The term "continuous delivery" means an increase in the period during which the prodrug is present so that the level of therapeutically effective drug is prolonged.

The term "treatment" of a disease includes inhibiting the disease (slowing down or preventing or partially preventing its onset), preventing the disease, providing relief from the symptoms or side effects of the disease (including tranquillity therapy), and / or alleviating the disease (causing the disease to resolve).

The term "biological agent" means a compound that is biologically active or has molecular properties useful for therapeutic or diagnostic purposes, such as a compound that carries a radioisotope or heavy atom.

The term "molecular pathway" refers to a series of molecular events in tissues, such as receptor regulatory sequences, enzyme regulatory sequences, or biosynthetic sequences involved in the physiological or pathological physiological functions of living animals.
[Administration and pharmaceutical composition]

The compounds of the present disclosure may be used alone or in combination with other treatments. These compounds may be administered as a daily dose or an appropriate portion of a daily dose (e.g. bid (twice daily), etc.) when used in combination with other agents. The compound may be administered after the course of treatment with another agent, during the course of treatment with another agent, as part of a therapy, or in a treatment regimen before treatment with another agent .

Examples of pharmaceutically acceptable salts include acetate, adipate, besylate, bromide, camphor sulfonate, chloride, citrate, ethanedisulfonate, lauryl sulfate, Fumar Hydrochloride, glucoheptanoate, gluconate, glucuronide, hippurate, hydrochloride, hydrobromide, hydrochloride, iodide, isethionate, lactate, lactose Acid salt, maleate salt, methanesulfonate salt, methyl bromide, methyl sulfate salt, naphthalenesulfonate salt, nitrate salt, oleate salt, palmitate salt, phosphate salt, polygalacturonate salt, stearin Acid salts, succinates, sulfates, sulfosalates, tannins, tartrates, terephthalates, tosylate, and triethyl iodide.

The composition containing the active ingredient may be in any form suitable for the intended administration method. In some embodiments, the compounds of the methods and / or compositions described herein can be provided via: oral administration, rectal administration, transmucosal administration, enteral administration, enteral administration, local administration , Percutaneous administration, intrathecal administration, intraventricular administration, intraperitoneal administration, intranasal administration, intraocular administration, and / or parenteral administration.

When the compound is administered orally, for example: tablets, laryngeals, dragees, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs. Compositions intended for oral use may be prepared according to any method of making pharmaceutical compositions known in the art, and to provide a palatable preparation, such compositions may contain one or more agents, including sweeteners, flavorings Agents, colorants and preservatives. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets are acceptable. Such excipients may be, for example: inert diluents such as calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium phosphate, etc .; granulating and disintegrating agents such as corn starch or alginic acid, etc .; binders such as starch, Gelatin or gum arabic, etc .; and lubricants such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be used alone or with wax.

Formulations for oral use can also be presented as: hard gelatin capsules in which the active ingredient can be mixed with an inert solid diluent such as calcium phosphate or kaolin; or soft gelatin capsules in which the active ingredient can be mixed with water or for example peanut oil, liquid Mix with oily medium such as paraffin or olive oil.

Formulations suitable for parenteral administration include aqueous and non-aqueous osmotic aseptic injection solutions, which may contain, for example, antioxidants, buffers, bacteriostatic agents and solutes, which allow the formulation to be osmolar with the blood of the intended recipient; And aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. The formulations can be presented in unit or multi-dose sealed containers, such as ampoules and vials, and can be stored under freeze-dried (lyophilized) conditions, requiring only the addition of a sterile liquid carrier for injection just before use, such as water. Injectable solutions and suspensions can be prepared from sterile powders, granules and tablets of the kind previously described.

In some embodiments, the unit dose formulation contains a daily dose or unit of the drug, a daily sub-dose, or an appropriate portion thereof. However, as is known to those of ordinary skill in the art to which this invention belongs, it should be understood that the specific dosage level of any particular patient will depend on a number of factors, including: the activity of the specific compound used; the age and weight of the individual being treated , General health, gender, and diet; time and route of administration; excretion rate; other drugs previously taken; and the severity of the specific disease being treated.

The actual dosage of the compounds described herein depends on the specific compound and the condition to be treated; the selection of the appropriate dosage is fully within the knowledge of those with ordinary knowledge in the technical field to which this invention belongs. In some embodiments, the daily dose may be about 0.1 mg / kg body weight to about 100 mg / kg body weight or higher, about 0.25 mg / kg body weight or lower to about 50 mg / kg body weight, and about 0.5 mg / kg body weight. Or lower to about 25 mg / kg body weight, about 1.0 mg / kg body weight to about 10 mg / kg body weight. Therefore, for administration to humans up to 70 kg, the dosage range is about 7 mg / day to about 7000 mg / day, about 35 mg / day or lower to about 2000 mg / day or higher, about 70 mg / day to About 1000 mg / day.
[treatment method]

Some embodiments of the invention include methods of treating a disease, disorder, or condition with a compound described herein and a composition comprising the compound, the disease, disorder, or condition being from hepatitis, hepatocellular carcinoma, liver fibrosis, fatty liver , Malaria, viral infection, parasite infection, diabetes, hyperlipidemia, atherosclerosis, obesity, dyslipidemia, hyperglycemia, hormone conditions, HIV (human immunodeficiency virus), and various types of cancer institutions Select from the group. Some methods include administering the compounds, compositions, and pharmaceutical compositions described herein to a subject in need thereof. In some embodiments, the subject may be an animal such as a mammal or a human. In some embodiments, the subject is a human.

Further embodiments include administering a combination of compounds to a subject in need thereof. Combinations can include compounds, compositions, pharmaceutical compositions, and additional agents described herein.

Some embodiments include co-administering a compound, composition, and / or pharmaceutical composition described herein with an additional agent or additional therapeutic agent. "Co-administration" means that two or more agents can be found in the patient's bloodstream at the same time, no matter when or how they are actually administered. In one embodiment, the reagents are administered simultaneously. In one such embodiment, combined administration is accomplished by combining the agents into a single dosage form. In another embodiment, the reagents are administered sequentially. In one embodiment, the agent is administered through the same route, such as orally. In another embodiment, the agent is administered through different routes, for example, one is administered orally and the other is i.v. (intravenous).

Examples of additional agents include a therapeutic agent, which is selected from the group consisting of: other types of chemotherapy, such as cyclophosphamide, methotrexate, doxorubicin , Docetaxel, cisplatin, epirubicin, oxaliplatin, and folinic acid; and other targeted antineoplastic agents, such as HDAC (Histone Removal) Acetylase) inhibitors and the like. In some embodiments, the additional therapeutic agent used for the treatment of HCC may be sorafenib, regorafenib, for example, immunological oncology agents such as PD-1 or PD-L1 checkpoint inhibitors. One or more.

The following examples are included to further illustrate the present invention. Of course, these embodiments should not be construed as specifically limiting the invention. Variations of these embodiments within the scope of the claims are within the scope of those having ordinary knowledge in the technical field to which the present invention pertains and should be considered to fall within the scope of the present invention described and claimed herein. The reader can confirm that those skilled in the art after referring to the present disclosure and those having ordinary knowledge in the technical field to which the present invention pertains can make and use the present invention without detailed examples.

[Synthesis of compounds]
The following steps for the preparation of new compounds illustrate the general procedures used to prepare 5-fluorouracil-derived acetals and hemiamine acetal ether compounds.

Scheme I describes a general strategy for the synthesis of compounds of Formula I. 5-Fluorouracil (1) is reacted with an alkylating agent of structure 2 in the presence of a base to obtain a product of structure 3, and the product of structure 3 can be further reacted with a second alkylating agent of structure 4 in the presence of a base Reaction to obtain the final product of structure 5. Alternatively, if the two alkylating agents are the same, the fluorouracil can be dialkylated in one step, resulting in the final product of structure 5.
[Reaction formula I]

Compounds of formulae II and IV are synthesized in a similar manner to reaction formula I using 5'-deoxy-5-fluorouridine as a starting material. Scheme II describes a general strategy for synthesizing compounds of Formulas III and V. 5'-deoxy-5-fluorouridine (6) is condensed with an aldehyde of structure 7 in the presence of an acid catalyst under standard conditions to produce a ketal product of structure 8, which can be further combined with the structure The alkylating or sulfonating agent of 9 reacts to provide the final product of structure 10.
[Reaction formula II]

Scheme III describes the general synthesis of compounds of formula VI. 5-Fluoro-2'-deoxyuridine (11) is reacted with phosphanediamine (12) in the presence of 4,5-dicyanoimidazole to obtain a cyclic product of structure 13, and then, for example, tertiary This crude reaction mixture is treated with an oxidant such as butyl hydroperoxide to provide the final product of structure 14.
[Reaction formula III]
[Example]

Some compounds of formulae I, II, III, IV, V and VI were prepared as described below.
[Example 1]

1-((benzyloxy) methyl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 101)

Compound 101 was prepared from chloromethylbenzyl ether and 5-fluorouracil according to Reaction Formula I. To a solution of 5-fluorouracil (1.0 g, 7.7 mmol) in dichloromethane in the presence of excess DIPEA (N, N-diisopropylethylamine) was added chloromethylbenzyl ether (1.2 g, 7.7 mmol), and the obtained solution was stirred at room temperature overnight. After standard work-up, pre-HPLC (high performance liquid chromatography) was performed to obtain compound 101 (190 mg, 10%).

[Example 2]

3-((benzyloxy) methyl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 102)

Compound 102 was isolated from the reaction described in Example 1 in 18% yield.

[Example 3]

1,3-bis ((benzyloxy) methyl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 103)

Compound 103 was isolated from the reaction described in Example 1 in a 25% yield.

[Example 4]

1,3-bis ((ethoxy) methyl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 104)

Compound 104 was prepared from chloromethylethyl ether and 5-fluorouracil according to Reaction Formula I.

[Example 5]

3-((benzyloxy) methyl) -1-((2R, 3R, 4S, 5R) -3,4-dihydroxy-5-methyltetrahydrofuran-2-yl) -5-fluoropyrimidine-2 , 4 (1H, 3H) -dione (Compound 105)

Compound 105 was prepared according to a method similar to that of Reaction Formula I from chloromethylbenzyl ether and 5'-deoxy-5-fluorouridine.

[Example 6]

1-((2R, 3R, 4R, 5R) -3-((benzyloxy) methoxy) -4-hydroxy-5-methyltetrahydrofuran-2-yl) -3-((benzyloxy ) Methyl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (compound 106)

Compound 106 was prepared from chloromethylbenzyl ether and 5'-deoxy-5-fluorouridine according to a method similar to that of Reaction Formula I.

[Example 7]

1-((2R, 3R, 4R, 5R) -4-((benzyloxy) methoxy) -4-hydroxy-5-methyltetrahydrofuran-2-yl) -3-((benzyloxy ) Methyl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 107)

Compound 107 was prepared according to a method similar to that of Reaction Formula I from chloromethylbenzyl ether and 5'-deoxy-5-fluorouridine.

[Example 8]

1-((2R, 3R, 4R, 5R) -3- (ethoxymethoxy) -4-hydroxy-5-methyltetrahydrofuran-2-yl) -3- (ethoxymethyl) -5 -Fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 108)

Compound 108 was prepared from chloromethylethyl ether and 5'-deoxy-5-fluorouridine according to a method similar to that of Reaction Formula I.

[Example 9]

1-((2R, 3R, 4R, 5R) -4- (ethoxymethoxy) -4-hydroxy-5-methyltetrahydrofuran-2-yl) -3- (ethoxymethyl) -5 -Fluoropyrimidine-2,4 (1H, 3H) -dione (compound 109)

Compound 109 was prepared from chloromethylethyl ether and 5'-deoxy-5-fluorouridine according to a method similar to that of Reaction Formula I.

[Example 10]

(1-((2R, 3R, 4S, 5R) -3,4-dihydroxy-5-methyltetrahydrofuran-2-yl) -5-fluoro-2-one-1,2-dihydropyrimidine-4 -Yl) (ethoxymethyl) pentyl carbamate (compound 110)

Compound 110 was prepared from chloromethylethyl ether and capecitabine according to a method similar to that of Reaction Formula I.

[Example 11]

(1-((2R, 3R, 4S, 5R) -3,4-dihydroxy-5-methyltetrahydrofuran-2-yl) -3- (ethoxymethyl) -5-fluoro-2-one -2,3-Dihydropyrimidine-4 (1H) -diyl) pentyl carbamate (Compound 111)

Compound 111 was prepared from chloromethyl ethyl ether and capecitabine according to a method similar to that of Reaction Formula I.

[Example 12]

(1-((3aR, 4R, 6R, 6aR) -2,6-dimethyltetrahydrofuro [3,4-d] [1,3] dioxol-4-yl) -5-fluoro -2-keto-1,2-dihydropyrimidin-4-yl) amyl carbamate (Compound 112)

Compound 112 was prepared from acetaldehyde and capecitabine according to the method described in Reaction Scheme II.

[Example 13]

(1-((3aR, 4R, 6R, 6aR) -2- (3,5-dimethylphenyl) -6-methyltetrahydrofuro [3,4-d] [1,3] dioxane (Penten-4-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (compound 113)

Compound 113 was prepared from 3,5-dimethylbenzaldehyde and capecitabine according to the method described in Reaction Formula II, and separated into a 3: 1 mixture of two stereoisomers.

[Example 14]

1-((3aR, 4R, 6R, 6aR) -2- (benzo [d] [1,3] dioxol-5-yl) -6-methyltetrahydrofuro [3,4-d ] [1,3] Dioxol-4-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 114)

Compound 114 was prepared from benzo [d] [1,3] dioxolane-5-carbaldehyde and capecitabine according to the method described in Reaction Formula II, and separated into three of the two stereoisomers: 1 Mixture.

[Example 15]

1-((3aR, 4R, 6R, 6aR) -2- (2- (4-ethyl-1,3-dioxolane-2-yl) phenyl) -6-methyltetrahydrofuro [ 3,4-d] [1,3] dioxol-4-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 115)

Compound 115 was prepared from 2- (4-ethyl-1,3-dioxolane-2-yl) benzaldehyde and capecitabine according to the method described in Reaction Formula II and separated into stereoisomers. Of a mixture.

[Example 16]

5-fluoro-1-((3aR, 4R, 6R, 6aR) -2- (4-hydroxyphenyl) -6-methyltetrahydrofuro [3,4-d] [1,3] dioxolane Alkenyl-4-yl) pyrimidine-2,4 (1H, 3H) -dione (Compound 116)

Compound 116 was prepared from 4-hydroxybenzaldehyde and capecitabine according to the method described in Reaction Formula II and separated into a 6: 1 mixture of two stereoisomers.

[Example 17]

3- (ethoxymethyl) -5-fluoro-1-((3aR, 4R, 6R, 6aR) -2- (4-hydroxyphenyl) -6-methyltetrahydrofuro [3,4-d] [1,3] Dioxol-4-yl) pyrimidine-2,4 (1H, 3H) -dione (Compound 117)

Compound 117 was prepared from chloromethyl ethyl ether, 4-hydroxybenzaldehyde, and capecitabine according to the method described in Reaction Formula II, and separated into a mixture of two stereoisomers.

[Example 18]

5-fluoro-1-((3aR, 4R, 6R, 6aR) -2- (4-methoxyphenyl) -6-methyltetrahydrofuro [3,4-d] [1,3] dioxane Cyclopenten-4-yl) pyrimidine-2,4 (1H, 3H) -dione (Compound 118)

Compound 118 was prepared from 4-methoxybenzaldehyde and capecitabine according to the method described in Reaction Formula II, and separated into a mixture of two stereoisomers.

[Example 19]

Isobutyric acid 4-((3aR, 4R, 6R, 6aR) -4- (5-fluoro-2,4-diketo-3,4-dihydropyrimidin-1 (2H) -yl) -6-form Tetrahydrofuro [3,4-d] [1,3] dioxol-2-yl) phenyl ester (Compound 119)

Compound 119 was prepared from 4-hydroxybenzaldehyde, capecitabine, and isobutyric acid according to the method described in Reaction Formula II, and separated into a mixture of two stereoisomers.

[Example 20]

1-((3aR, 4R, 6R, 6aR) -2- (4- (ethoxymethoxy) phenyl) -6-methyltetrahydrofuro [3,4-d] [1,3] dioxy Heteropenten-4-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 120)

Compound 120 was prepared from 4-methoxybenzaldehyde, capecitabine, and chloromethylethyl ether according to the method described in Reaction Formula II, and separated into a mixture of two stereoisomers.

[Example 21]

1-((4aR, 6R, 7aS) -2- (3,5-dimethylphenyl) tetrahydro-4H-furo [3,2-d] [1,3] dioxin-6-yl ) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 121)

Compound 121 can be prepared from 4-methoxybenzaldehyde and 5-fluoro-2'-deoxyuridine according to the method described in Reaction Formula II.
[Example 22]

5-Fluoro-1-((4aR, 6R, 7aS) -2-oxo-2-phenoxytetrahydro-4H-furo [3,2-d] [1,3,2] dioxaphos Heterophenyl-6-yl) pyrimidine-2,4 (1H, 3H) -dione (5-fluoro-1-((4aR, 6R, 7aS) -2-oxido-2-phenoxytetrahydro-4H-furo [3, 2-d] [1,3,2] dioxaphosphinin-6-yl) pyrimidine-2,4 (1H, 3H) -dione) (Compound 122)

Prepare compound 122 from N, N, N ', N'-tetraisopropyl-1-phenoxyphosphorane diamine and 5-fluoro-2'-deoxyuridine according to the method described in Reaction Formula III, and Separated into a mixture of 2 stereoisomers.

[Example 23]

5-fluoro-1-((2S, 4aR, 6R, 7aS) -2-oxo-2-phenoxytetrahydro-4H-furo [3,2-d] [1,3,2] dioxy Heterophosphate heterophenyl-6-yl) pyrimidine-2,4 (1H, 3H) -dione (Compound 123)

Compound 123 was isolated from compound 122 by HPLC.
[Example 24]

5-Fluoro-1-((2R, 4aR, 6R, 7aS) -2-oxo-2-phenoxytetrahydro-4H-furo [3,2-d] [1,3,2] dioxy Heterophosphate heterophenyl-6-yl) pyrimidine-2,4 (1H, 3H) -dione (Compound 124)

Compound 124 was isolated from compound 122 by HPLC.
[Example 25]

5-fluoro-1-((4aR, 6R, 7aS) -2-oxo-2- (4-chlorophenoxy) tetrahydro-4H-furo [3,2-d] [1,3,2 ] Dioxaphosphaphenyl-6-yl) pyrimidine-2,4 (1H, 3H) -dione (Compound 125)

From N, N, N ', N'-tetraisopropyl-1- (4-chlorophenoxy) phosphorane diamine and 5-fluoro-2'-deoxyuridine according to the method described in Reaction Formula III Compound 125 was prepared and isolated as a single isomer.

[Example 26]

1-((4aR, 6R, 7aS) -2- (benzyloxy) -2-oxotetrahydro-4H-furo [3,2-d] [1,3,2] dioxaphospha Phenyl-6-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 126)

Compound 126 was prepared from N, N, N ', N'-tetraisopropyl-1-benzyloxyphosphone diamine and 5-fluoro-2'-deoxyuridine according to the method described in Reaction Formula III, And separated into a mixture of two isomers.

[Example 27]

1-((4aR, 6R, 7aS) -2- (4-chlorobenzyloxy) -2-oxotetrahydro-4H-furo [3,2-d] [1,3,2] dioxy Heterophosphaphenyl-6-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 127)

From N, N, N ', N'-tetraisopropyl-1- (4-chlorobenzyloxy) phosphorane diamine and 5-fluoro-2'-deoxyuria according to the method described in Reaction Formula III Glycosides prepare compound 127 and separate into single isomers (absolute stereochemistry not shown).

[Example 28]

5-fluoro-1-((4aR, 6R, 7aS) -2- (naphthalene-1-ylmethoxy) -2-oxotetrahydro-4H-furo [3,2-d] [1,3 , 2] Dioxaphospha-6-yl) pyrimidine-2,4 (1H, 3H) -dione (Compound 128)

From N, N, N ', N'-tetraisopropyl-1- (1-naphthylmethoxy) phosphorane diamine and 5-fluoro-2'-deoxyuria according to the method described in Reaction Formula III Glycosides prepared compound 128 and separated into single isomers (absolute stereochemistry not shown).

[Example 29]

1-((4aR, 6R, 7aS) -2- (3-chlorobenzyloxy) -2-oxotetrahydro-4H-furo [3,2-d] [1,3,2] dioxy Heterophosphate heterophenyl-6-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 129)

From N, N, N ', N'-tetraisopropyl-1- (3-chlorobenzyloxy) phosphorane diamine and 5-fluoro-2'-deoxyuria according to the method described in Reaction Formula III Compound 129 was prepared by glycosides and separated into a mixture of two isomers.

[Example 30]

1-((4aR, 6R, 7aS) -2- (2-chlorobenzyloxy) -2-oxotetrahydro-4H-furo [3,2-d] [1,3,2] dioxy Heterophosphate heterophenyl-6-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 130)

From N, N, N ', N'-tetraisopropyl-1- (2-chlorobenzyloxy) phosphorane diamine and 5-fluoro-2'-deoxyuria according to the method described in Reaction Formula III Compound 130 is prepared by glycosides and separated into a mixture of two isomers.

[Example 31]

5-fluoro-1-((4aR, 6R, 7aS) -2- (hexyloxy) -2-oxotetrahydro-4H-furo [3,2-d] [1,3,2] dioxy Heterophosphaphenyl-6-yl) pyrimidine-2,4 (1H, 3H) -dione (Compound 131)

Prepare compound 131 from N, N, N ', N'-tetraisopropyl-1-hexyloxyphosphorane diamine and 5-fluoro-2'-deoxyuridine according to the method described in Reaction Formula III, Separated into a mixture of two isomers.

[Example 32]

5-fluoro-1-((4aR, 6R, 7aS) -2- (nonyloxy) -2-oxotetrahydro-4H-furo [3,2-d] [1,3,2] dioxy Heterophospha-6-yl) pyrimidine-2,4 (1H, 3H) -dione (Compound 132)

Compound 132 is prepared from N, N, N ', N'-tetraisopropyl-1-nonoxyphosphorane diamine and 5-fluoro-2'-deoxyuridine according to the method described in Reaction Formula III, and Separated into a mixture of two isomers.

[Example 33]

5-fluoro-1-((4aR, 6R, 7aS) -2- (non-5-oxy) -2-oxotetrahydro-4H-furo [3,2-d] [1,3,2 ] Dioxaphosphaphenyl-6-yl) pyrimidine-2,4 (1H, 3H) -dione (Compound 133)

From N, N, N ', N'-tetraisopropyl-1- (non-5-oxy) phosphorane diamine and 5-fluoro-2'-deoxyuridine according to the method described in Reaction Formula III Compound 133 was prepared and isolated as a mixture of two isomers.

[Example 34]

3-(((4aR, 6R, 7aS) -6- (5-fluoro-2,4-diketo-3,4-dihydropyrimidin-1 (2H) -yl) -2-oxotetrahydro- 4H-furo [3,2-d] [1,3,2] dioxaphospha-2-yl) oxy) propionitrile (Compound 134)

From N, N, N ', N'-tetraisopropyl-1- (2-cyanoethoxy) phosphorane diamine and 5-fluoro-2'-deoxyuridine according to the method described in Reaction Formula III Compound 134 was prepared and isolated as a single isomer (absolute stereochemistry not shown).

[Example 35]

5-fluoro-1-((4aR, 6R, 7aS) -2-oxo-2-(((S) -4- (prop-1-en-2-yl) cyclohex-1-ene-1- Yl) methoxy) tetrahydro-4H-furo [3,2-d] [1,3,2] dioxaphospha-6-yl) pyrimidine-2,4 (1H, 3H) -di Ketone (Compound 135)

From (S) -N, N, N ', N'-tetraisopropyl-1-((4- (prop-1-en-2-yl) cyclohex-1- Alkenyl-1-yl) methoxy) phosphorane diamine and 5-fluoro-2'-deoxyuridine were used to prepare compound 135 and separated into a mixture of two isomers.

[Example 36]

1-((4aR, 6R, 7aS) -2- (4-fluorobenzyloxy) -2-oxotetrahydro-4H-furo [3,2-d] [1,3,2] dioxy Heterophosphate heterophenyl-6-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 136)

From N, N, N ', N'-tetraisopropyl-1- (4-fluorobenzyloxy) phosphorane diamine and 5-fluoro-2'-deoxyuria according to the method described in Reaction Formula III The compound 136 was prepared by glycosides and separated into a mixture of two isomers.

[Example 37]

1-((4aR, 6R, 7aS) -2- (3,4-difluorobenzyloxy) -2-oxotetrahydro-4H-furo [3,2-d] [1,3,2 ] Dioxaphosphaphenyl-6-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 137)

From N, N, N ', N'-tetraisopropyl-1- (3,4-difluorobenzyloxy) phosphorane diamine and 5-fluoro-2'- Deoxyuridine prepares compound 137 and separates it into a mixture of two isomers.

[Example 38]

1-((4aR, 6R, 7aS) -2- (2,4-difluorobenzyloxy) -2-oxotetrahydro-4H-furo [3,2-d] [1,3,2 ] Dioxaphosphaphenyl-6-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 138)

From N, N, N ', N'-tetraisopropyl-1- (2,4-difluorobenzyloxy) phosphorane diamine and 5-fluoro-2'- Deoxyuridine prepares compound 138 and separates it into a mixture of two isomers.

[Example 39]

1-((4aR, 6R, 7aS) -2- (2-fluorobenzyloxy) -2-oxotetrahydro-4H-furo [3,2-d] [1,3,2] dioxy Heterophosphaphenyl-6-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 139)

From N, N, N ', N'-tetraisopropyl-1- (2-fluorobenzyloxy) phosphorane diamine and 5-fluoro-2'-deoxyuria according to the method described in Reaction Formula III Compound 139 was prepared by glycosides and separated into a mixture of two isomers.

[Example 40]

5-fluoro-1-((2S, 4aR, 6R, 7aS) -2-((2-fluorobenzyl) oxy) -2-oxotetrahydro-4H-furo [3,2-d] [1,3,2] Dioxaphospha-6-yl) pyrimidine-2,4 (1H, 3H) -dione (Compound 140)

Compound 140 was isolated from compound 139 by HPLC.
[Example 41]

5-fluoro-1-((2R, 4aR, 6R, 7aS) -2-((2-fluorobenzyl) oxy) -2-oxotetrahydro-4H-furo [3,2-d] [1,3,2] Dioxaphosphaphenyl-6-yl) pyrimidine-2,4 (1H, 3H) -dione (Compound 141)

Compound 141 was isolated from compound 139 by HPLC.
[Example 42]

1-((4aR, 6R, 7aS) -2- (4-chloro-2-fluorobenzyloxy) -2-oxotetrahydro-4H-furo [3,2-d] [1,3, 2) Dioxaphosphino-6-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 142)

From N, N, N ', N'-tetraisopropyl-1- (4-chloro-2-fluorobenzyloxy) phosphorane diamine and 5-fluoro-2' according to the method described in Reaction Formula III -Deoxyuridine prepares compound 142 and separates into a mixture of two isomers.

[Example 43]

1-((4aR, 6R, 7aS) -2- (2-chloro-4-fluorobenzyloxy) -2-oxotetrahydro-4H-furo [3,2-d] [1,3, 2) Dioxaphosphino-6-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 143)

From N, N, N ', N'-tetraisopropyl-1- (2-chloro-4-fluorobenzyloxy) phosphorane diamine and 5-fluoro-2' according to the method described in Reaction Scheme III -Deoxyuridine prepares compound 143 and separates into a mixture of two isomers.

[Example 44]

1-((4aR, 6R, 7aS) -2- (2,4,6-trifluorobenzyloxy) -2-oxotetrahydro-4H-furo [3,2-d] [1,3 , 2) Dioxaphosphaphenyl-6-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 144)

From N, N, N ', N'-tetraisopropyl-1- (2,4,6-trifluorobenzyloxy) phosphorane diamine and 5-fluoro-2 according to the method described in Reaction Formula III '-Deoxyuridine prepares compound 144 and separates it into a mixture of two isomers.

[Example 45]

5-fluoro-1-((2S, 4aR, 6R, 7aS) -2-oxo-2-((2,4,6-trifluorobenzyl) oxy) tetrahydro-4H-furo [3 , 2-d] [1,3,2] dioxaphospha-6-yl) pyrimidine-2,4 (1H, 3H) -dione (Compound 145)

Compound 145 was isolated from compound 144 by HPLC.
[Example 46]

5-fluoro-1-((2R, 4aR, 6R, 7aS) -2-oxo-2-((2,4,6-trifluorobenzyl) oxy) tetrahydro-4H-furo [3 , 2-d] [1,3,2] Dioxaphospha-6-yl) pyrimidine-2,4 (1H, 3H) -dione (Compound 146)

Compound 146 was isolated from compound 144 by HPLC.
[Example 47]

1-((4aR, 6R, 7aS) -2- (4-ethylbenzyloxy) -2-oxotetrahydro-4H-furo [3,2-d] [1,3,2] Oxaphospha-6-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (compound 147)

From N, N, N ', N'-Tetraisopropyl-1- (4-ethylbenzyloxy) phosphorane diamine and 5-fluoro-2'-deoxy according to the method described in Reaction Formula III Compound 147 is prepared from uridine and separated into a mixture of two isomers.

[Example 48]

1-((4aR, 6R, 7aS) -2- (4-isopropylbenzyloxy) -2-oxotetrahydro-4H-furo [3,2-d] [1,3,2] Dioxaphosphino-6-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 148)

From N, N, N ', N'-tetraisopropyl-1- (4-isopropylbenzyloxy) phosphorane diamine and 5-fluoro-2'- Oxyuridine prepares compound 148 and separates it into a mixture of two isomers.

[Example 49]

1-((4aR, 6R, 7aS) -2- (4-tert-butylbenzyloxy) -2-oxotetrahydro-4H-furo [3,2-d] [1,3,2 ] Dioxaphosphaphenyl-6-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 149)

From N, N, N ', N'-tetraisopropyl-1- (4-tert-butylbenzyloxy) phosphorane diamine and 5-fluoro-2'- Deoxyuridine prepares compound 149 and separates it into a mixture of two isomers.

[Example 50]

1-((4aR, 6R, 7aS) -2- (3,5-dimethylbenzyloxy) -2-oxotetrahydro-4H-furo [3,2-d] [1,3, 2) Dioxaphosphino-6-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 150)

From N, N, N ', N'-tetraisopropyl-1- (3,5-dimethylbenzyloxy) phosphorane diamine and 5-fluoro-2' according to the method described in Reaction Scheme III -Deoxyuridine prepares compound 150 and separates into a mixture of two isomers.

[Example 51]

1-((4aR, 6R, 7aS) -2- (2,4-dichlorobenzyloxy) -2-oxotetrahydro-4H-furo [3,2-d] [1,3,2 ] Dioxaphosphaphenyl-6-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 151)

From N, N, N ', N'-tetraisopropyl-1- (2,4-dichlorobenzyloxy) phosphorane diamine and 5-fluoro-2'- Deoxyuridine prepares compound 151 and separates it into a mixture of two isomers.

[Example 52]

1-((4aR, 6R, 7aS) -2- (2,6-dichlorobenzyloxy) -2-oxotetrahydro-4H-furo [3,2-d] [1,3,2 ] Dioxaphosphaphenyl-6-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 152)

From N, N, N ', N'-tetraisopropyl-1- (2,6-dichlorobenzyloxy) phosphorane diamine and 5-fluoro-2'- Deoxyuridine prepares compound 152 and separates it into a mixture of two isomers.

[Example 53]

1-((4aR, 6R, 7aS) -2- (2,6-difluorobenzyloxy) -2-oxotetrahydro-4H-furo [3,2-d] [1,3,2 ] Dioxaphosphaphenyl-6-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 153)

From N, N, N ', N'-tetraisopropyl-1- (2,6-difluorobenzyloxy) phosphorane diamine and 5-fluoro-2'- Deoxyuridine prepares compound 153 and separates it into a mixture of two isomers.

[Example 54]

1-((4aR, 6R, 7aS) -2- (3-fluorobenzyloxy) -2-oxotetrahydro-4H-furo [3,2-d] [1,3,2] dioxy Heterophosphate heterophenyl-6-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 154)

From N, N, N ', N'-tetraisopropyl-1- (3-fluorobenzyloxy) phosphorane diamine and 5-fluoro-2'-deoxyuria according to the method described in Reaction Formula III The compound 154 is prepared by glycosides and separated into a mixture of two isomers.

[Example 55]

1-((4aR, 6R, 7aS) -2- (2-fluoro-5-methoxybenzyloxy) -2-oxotetrahydro-4H-furo [3,2-d] [1, 3,2) dioxaphospha-6-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 155)

From N, N, N ', N'-tetraisopropyl-1- (2-fluoro-5-methoxybenzyloxy) phosphorane diamine and 5-fluoro- 2'-Deoxyuridine was prepared as compound 155 and separated into a mixture of two isomers.

[Example 56]

5-fluoro-1-((4aR, 6R, 7aS) -2-oxo-2-((4- (trifluoromethyl) benzyl) oxy) tetrahydro-4H-furo [3,2 -d] [1,3,2] dioxaphospha-6-yl) pyrimidine-2,4 (1H, 3H) -dione (Compound 156)

From N, N, N ', N'-tetraisopropyl-1-((4- (trifluoromethyl) benzyl) oxy) phosphorane diamine and 5- Compound 156 was prepared from fluoro-2'-deoxyuridine and separated into a mixture of two isomers.

[Example 57]

1-((2R, 4aR, 6R, 7aS) -2-((4-ethylbenzyl) amino) -2-oxotetrahydro-4H-furo [3,2-d] [1, 3,2) Dioxaphosphaphenyl-6-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 157)

From N, N, N ', N'-tetraisopropyl-1-((4-ethylbenzyl) amino) phosphorane diamine and 5-fluoro-2' according to the method described in Reaction Scheme III -Deoxyuridine to prepare compound 157.

[Example 58]

1-((2S, 4aR, 6R, 7aS) -2-((4-ethylbenzyl) amino) -2-oxotetrahydro-4H-furo [3,2-d] [1, 3,2) Dioxaphospha-6-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 158)

Compound 158 was isolated from the reaction of compound 157.

[Example 59]

1-((2R, 4aR, 6R, 7aS) -2-((2,4-difluorobenzyl) amino) -2-oxotetrahydro-4H-furo [3,2-d] [ 1,3,2) dioxaphosphaphenyl-6-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 159)

From N, N, N ', N'-tetraisopropyl-1-((2,4-difluorobenzyl) amino) phosphorane diamine and 5-fluoro- 2'-Deoxyuridine to prepare compound 159.

[Example 60]

1-((2S, 4aR, 6R, 7aS) -2-((2,4-difluorobenzyl) amino) -2-oxotetrahydro-4H-furo [3,2-d] [ 1,3,2) Dioxaphospha-6-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 160)

Compound 160 was isolated as a minor isomer.

[Example 61]

1-((4aR, 6R, 7aS) -2- (3,5-difluorobenzyloxy) -2-oxotetrahydro-4H-furo [3,2-d] [1,3,2 ] Dioxaphosphaphenyl-6-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 161)

From N, N, N ', N'-tetraisopropyl-1- (3,5-difluorobenzyloxy) phosphorane diamine and 5-fluoro-2'- Deoxyuridine prepares compound 161 and separates it into a mixture of two isomers.

[Example 62]

1-((4aR, 6R, 7aS) -2- (2,3,4,5,6-pentafluorobenzyloxy) -2-oxotetrahydro-4H-furo [3,2-d] [1,3,2] Dioxaphosphaphenyl-6-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 162)

From N, N, N ', N'-tetraisopropyl-1- (2,3,4,5,6-pentafluorobenzyloxy) phosphorane diamine and 5 according to the method described in Reaction Formula III -Fluoro-2'-deoxyuridine to prepare compound 162 and separate it into a mixture of two isomers.

[Example 63]

1-((4aR, 6R, 7aS) -2- (2,3,4-trifluorobenzyloxy) -2-oxotetrahydro-4H-furo [3,2-d] [1,3 , 2] Dioxaphospha-6-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 163)

From N, N, N ', N'-tetraisopropyl-1- (2,3,4-trifluorobenzyloxy) phosphorane diamine and 5-fluoro-2 according to the method described in Reaction Formula III '-Deoxyuridine prepares compound 163 and separates it into a mixture of two isomers.

[Example 64]

1-((4aR, 6R, 7aS) -2- (2,4,5-trifluorobenzyloxy) -2-oxotetrahydro-4H-furo [3,2-d] [1,3 , 2) Dioxaphospha-6-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 164)

From N, N, N ', N'-tetraisopropyl-1- (2,4,5-trifluorobenzyloxy) phosphorane diamine and 5-fluoro-2 according to the method described in Reaction Formula III '-Deoxyuridine prepares compound 164 and separates it into a mixture of two isomers.

[Example 65]

5-fluoro-1-((4aR, 6R, 7aS) -2- (propoxy) -2-oxotetrahydro-4H-furo [3,2-d] [1,3,2] dioxy Heterophosphaphenyl-6-yl) pyrimidine-2,4 (1H, 3H) -dione (Compound 165)

Prepare compound 165 from N, N, N ', N'-tetraisopropyl-1-propoxyphosphorane diamine and 5-fluoro-2'-deoxyuridine according to the method described in Reaction Formula III, and Separated into a mixture of two isomers.

[Example 66]

5-fluoro-1-((4aR, 6R, 7aS) -2- (2,2,3,3,3-pentafluoropropoxy) -2-oxotetrahydro-4H-furo [3,2 -d] [1,3,2] dioxaphospha-6-yl) pyrimidine-2,4 (1H, 3H) -dione (Compound 166)

From N, N, N ', N'-tetraisopropyl-1- (2,2,3,3,3-pentafluoropropoxy) phosphorane diamine and 5- Compound 166 was prepared from fluoro-2'-deoxyuridine and separated into a mixture of two isomers.

[Example 67]

1-((4aR, 6R, 7aS) -2- (2- (diethoxymethyl) phenoxy) -2-oxotetrahydro-4H-furo [3,2-d] [1, 3,2] Dioxaphospha-6-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 167)

From N, N, N ', N'-tetraisopropyl-1- (2-diethoxymethylphenoxy) phosphorane diamine and 5-fluoro-2' according to the method described in Reaction Formula III -Deoxyuridine prepares compound 167 and separates it into a mixture of 2 stereoisomers.

[Example 68]

5-fluoro-1-((4aR, 6R, 7aS) -2- (2-fluorophenoxy) -2-oxotetrahydro-4H-furo [3,2-d] [1,3,2 ] Dioxaphosphaphenyl-6-yl) pyrimidine-2,4 (1H, 3H) -dione (Compound 168)

From N, N, N ', N'-tetraisopropyl-1- (2-fluorophenoxy) phosphorane diamine and 5-fluoro-2'-deoxyuridine according to the method described in Reaction Formula III Compound 168 was prepared and isolated as a mixture of two stereoisomers.

[Example 69]

Trimethylacetic acid (((4aR, 6R, 7aS) -6- (5-fluoro-2,4-diketo-3,4-dihydropyrimidin-1 (2H) -yl) -2-oxotetra Hydrogen-4H-furo [3,2-d] [1,3,2] dioxaphospha-2-yl) oxy) methyl ester (Compound 169)

Compound 169 was prepared from iodomethyl trimethyl acetate and 5-fluoro-2'-deoxyuridine according to known methods, and separated into a mixture of two stereoisomers.

[Example 70]

1-((4aR, 6R, 7aS) -2-((4- (ethoxymethoxy) benzyl) oxy) -2-oxotetrahydro-4H-furo [3,2-d ] [1,3,2] Dioxaphosphaphenyl-6-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 170)

From N, N, N ', N'-tetraisopropyl-1- (4-ethoxymethoxybenzyloxy) phosphorane diamine and 5-fluoro- 2'-Deoxyuridine was used to prepare compound 170 and separated into a mixture of two stereoisomers.

[Example 71]

1-((4aR, 6R, 7aS) -2- (benzo [d] [1,3] dioxol-5-ylmethoxy) -2-oxotetrahydro-4H-furo [3,2-d] [1,3,2] Dioxaphosphaphenyl-6-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 171)

From N, N, N ', N'-tetraisopropyl-1- (benzo [d] [1,3] dioxol-5-ylmethoxy group according to the method described in Reaction Formula III The compound 171 was prepared from phosphine diamine and 5-fluoro-2'-deoxyuridine, and separated into a mixture of two stereoisomers.

[Example 72]

1-((4aR, 6R, 7aS) -2-((2- (1,3-dioxolane-2-yl) benzyl) oxy) -2-oxotetrahydro-4H- Furo [3,2-d] [1,3,2] dioxaphospha-6-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 172)

From N, N, N ', N'-tetraisopropyl-1- (2- (1,3-dioxolane-2-yl) benzyloxy according to the method described in Reaction Scheme III The compound 172 was prepared from phosphine diamine and 5-fluoro-2'-deoxyuridine and separated into a mixture of two stereoisomers.

[Example 73]

1-((4aR, 6R, 7aS) -2- (cyclohexyloxy) -2-oxotetrahydro-4H-furo [3,2-d] [1,3,2] dioxaphospha Phenyl-6-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 173)

Compound 173 was prepared from N, N, N ', N'-tetraisopropyl-1-cyclohexyloxyphosphorane diamine and 5-fluoro-2'-deoxyuridine according to the method described in Reaction Formula III, And separated into a mixture of two stereoisomers.

[Example 74]

5-fluoro-1-((4aR, 6R, 7aS) -2-isopropoxy-2-oxotetrahydro-4H-furo [3,2-d] [1,3,2] dioxane Phosphaphenyl-6-yl) pyrimidine-2,4 (1H, 3H) -dione (Compound 174)

Compound 174 was prepared from N, N, N ', N'-tetraisopropyl-1-isopropoxyphosphorane diamine and 5-fluoro-2'-deoxyuridine according to the method described in Reaction Formula III, And separated into a mixture of two stereoisomers.

[Example 75]

1-((4aR, 6R, 7aS) -2- (cyclohexylmethoxy) -2-oxotetrahydro-4H-furo [3,2-d] [1,3,2] dioxaphos Heterophenyl-6-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 175)

Compound 175 was prepared from N, N, N ', N'-tetraisopropyl-1-cyclohexylmethoxyphosphadiamine and 5-fluoro-2'-deoxyuridine according to the method described in Reaction Formula III. And separated into a mixture of 2 stereoisomers.

[Example 76]

1-((4aR, 6R, 7aS) -2- (pentyloxy) -2-oxotetrahydro-4H-furo [3,2-d] [1,3,2] dioxaphosphane -6-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 176)

Prepare compound 176 from N, N, N ', N'-tetraisopropyl-1-pentoxyphosphorane diamine and 5-fluoro-2'-deoxyuridine according to the method described in Reaction Formula III, and Separated into a mixture of 2 stereoisomers.

[Example 77]

1-((4aR, 6R, 7aS) -2- (2-phenylethoxy) -2-oxotetrahydro-4H-furo [3,2-d] [1,3,2] dioxy Heterophosphate heterophenyl-6-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 177)

From N, N, N ', N'-tetraisopropyl-1- (2-phenylethoxy) phosphorane diamine and 5-fluoro-2'-deoxyuria according to the method described in Reaction Formula III Compound 177 was prepared by glycosides and separated into a mixture of two stereoisomers.

[Example 78]

1-((3aR, 4R, 6R, 6aR) -2- (6-chlorobenzo [d] [1,3] dioxol-5-yl) -6-methyltetrahydrofuro [3, 4-d) [1,3] dioxolen-4-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 178)

Compound 178 was prepared from benzo [d] [1,3] dioxolane-4-chloro-5-carbaldehyde and capecitabine according to the method described in Reaction Formula II, and separated into two stereoisomers. 1: 1 mixture of things.

[Example 79]

1-((3aR, 4R, 6R, 6aR) -2- (6-fluorobenzo [d] [1,3] dioxol-5-yl) -6-methyltetrahydrofuro [3, 4-d] [1,3] dioxolene-4-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 179)

Compound 179 was prepared from benzo [d] [1,3] dioxolane-4-fluoro-5-carbaldehyde and capecitabine according to the method described in Reaction Formula II and separated into two stereoisomers. 1: 1 mixture of things.

[Example 80]

1-((3aR, 4R, 6R, 6aR) -2- (6-methylbenzo [d] [1,3] dioxol-5-yl) -6-methyltetrahydrofuro [3 , 4-d] [1,3] dioxol-4-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione (Compound 180)

Compound 180 was prepared from benzo [d] [1,3] dioxolane-4-methyl-5-carbaldehyde and capecitabine according to the method described in Reaction Formula II, and separated into two stereoisomeric forms. Structure 3: 2 mixture.

[Example 81]

1-((2R, 3R, 4S, 5R) -4- (ethoxymethoxy) -3-hydroxy-5-methyltetrahydrofuran-2-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -diketone (Compound 181)

Compound 181 was prepared according to a method similar to that of Reaction Formula I from chloromethylethyl ether and 5'-deoxy-5-fluorouridine.

[Example 82]

1-((2R, 3R, 4S, 5R) -3- (ethoxymethoxy) -4-hydroxy-5-methyltetrahydrofuran-2-yl) -5-fluoropyrimidine-2,4 (1H, 3H) -diketone (compound 182)

Compound 182 was isolated from the reaction described in Example 49.

[Biological Example]

Examples of the method of use include the following. It should be understood that the following are examples only and the methods are not limited to these examples.
[Example A]: Tissue distribution after oral administration of a reference compound and a compound of the present disclosure

The liver specificity of the compounds of the present disclosure is compared with corresponding active compounds in the liver and other organs that may be targets of toxicity.
[method]

The reference compound and the acetal and hemacetal ether compound were administered to fasted rats by oral gavage at 5-50 mg / kg. Plasma concentrations of metabolites and original compounds in the circulation and hepatic portal vein were determined by HPLC-UV (ultraviolet light) method, and by LC-MS (liquid chromatography-mass spectrometry) using standard chromatography Measure liver, small intestine and other organ concentrations.
[result]

Table 1 provides the results of the selected new compounds, which confirm the liver target properties of the acetal and hemiamine acetal ether compounds, and provide that the efficiency of the compound in liver target properties has been improved and improved over other types of compounds. Evidence of high levels of activity in the liver. This can occur only through the high-efficiency liver targeting provided by acetal and hemacetal ether compounds.
[Table 1] Drug and metabolite levels in liver and blood 1 hour after oral administration of selected compounds to rats at a dose of 5 mg / kg

All amounts expressing the amounts of ingredients, reaction conditions, and others used in this specification are to be understood as modified in all cases by the term "about". Thus, unless stated to the contrary, the numerical parameters set forth herein are approximations and may vary depending on the desired properties sought to be obtained. At the very least, it is not an attempt to limit the application of equality to any claim in any application claiming priority in this case, and each numerical parameter should be interpreted in terms of the number of significant figures and ordinary rounding methods.

The expressions of degree used in this text, such as "about," "about," "substantially," and "substantially," as used herein, indicate a value, quantity, or characteristic, and its proximity still shows An established value, quantity, or characteristic of a desired function or achievement of a desired result. For example: the terms "about", "about", "approximately" and "substantially" may mean a quantity that is less than 10%, less than 5%, less than 1%, or less than 0.1% of the established quantity. Less than 0.01%. As another example, in some embodiments, the terms "substantially parallel" and "substantially parallel" indicate a value, quantity, or characteristic whose deviation from perfect parallelism is less than or equal to 15%, 10%, 5%, 3%, 1%, 0.1%, or whatever. Similarly, in some embodiments, the terms "substantially vertical" and "substantially vertical" indicate a value, amount, or characteristic whose deviation from the vertical is less than or equal to 15%, 10%, 5%, 3%, or 1% , 0.1%, or other.

The above description reveals several methods and materials. The present invention is easy to modify methods and materials, and to change manufacturing methods and equipment. Such modifications will become apparent to those having ordinary knowledge in the technical field to which this invention pertains from considering this disclosure or implementing the invention disclosed herein. Therefore, it is not intended to limit the invention to the specific embodiments disclosed herein, but to cover all modifications and alternatives falling within the true scope and spirit of the invention.

All references cited herein, including but not limited to published and unpublished applications, patents and references, are incorporated herein by reference in their entirety and are hereby incorporated as part of this specification. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in this specification, this specification is intended to supersede and / or take precedence over any such contradictory information.

Although the present invention has been described with reference to the embodiments and examples, it should be understood that many and various modifications can be made without departing from the spirit of the present invention. Therefore, the present invention is limited only by the following claims.

Domestic storage information (please note in order of storage organization, date, and number)
no

Information on foreign deposits (please note according to the order of the country, institution, date, and number)
no

Claims (56)

A compound of formula I: (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ² are independently from H, once optionally substituted C ₁ to C ₁₀ alkyl-OCH _2- , once optionally substituted (C _{6 to 10} aryl) -CH ₂ -OCH _2- , (5 to 10-membered heteroaryl) optionally substituted -CH ₂ -OCH _2- , (C _{6 to 10} aryl) optionally substituted -OCH ₂ -and an optionally substituted (5- to 10-membered heteroaryl) -OCH ₂ -group are selected, and at least one of R ¹ and R ² is not H. The compound according to claim 1, wherein R ¹ is H; and R ² is from an optionally substituted C ₁ to C ₁₀ alkyl-OCH _2- , or an optionally substituted (C _{6 to 10} aryl)- CH ₂ -OCH ₂ -, optionally substituted by one of (5-10 membered heteroaryl) -CH ₂ -OCH ₂ -, optionally substituted by one of (C _{6 ~ 10} aryl) -OCH ₂ - and optionally substituted by one of ( 5 to 10-membered heteroaryl) -OCH ₂ -is selected from the group. The compound according to claim 2, wherein R ² is from an optionally substituted C ₁ to C ₁₀ alkyl-OCH _2- , an optionally substituted (C _{6 to 10} aryl) -CH ₂ -OCH _2- And selected from the group of (5- to 10-membered heteroaryl) -CH ₂ -OCH ₂ -arbitrarily substituted. The compound according to claim 3, wherein R ² is C ₁ to C ₆ alkyl-OCH _2- , or phenyl-CH ₂ -OCH _2- . The compound according to claim 1, wherein R ² is H; and R ¹ is from an optionally substituted C ₁ to C ₁₀ alkyl-OCH _2- , or an optionally substituted (C _{6 to 10} aryl)- CH ₂ -OCH ₂ -, optionally substituted by one of (5-10 membered heteroaryl) -CH ₂ -OCH ₂ -, optionally substituted by one of (C _{6 ~ 10} aryl) -OCH ₂ - and optionally substituted by one of ( 5 to 10-membered heteroaryl) -OCH ₂ -is selected from the group. The compound according to claim 5, wherein R ¹ is C ₁ to C ₁₀ alkyl-OCH _2- , optionally substituted (C _{6 to 10} aryl) -CH ₂ -OCH _2- And selected from the group of (5- to 10-membered heteroaryl) -CH ₂ -OCH ₂ -arbitrarily substituted. The compound according to claim 6, wherein R ¹ is C ₁ to C ₆ alkyl-OCH _2- , or phenyl-CH ₂ -OCH _2- . The compound according to claim 1, wherein R ¹ is C ₁ to C ₆ alkyl-OCH _2- , or phenyl-CH ₂ -OCH _2- ; and R ² is C ₁ to C ₆ alkyl-OCH _2- , or phenyl-CH ₂ -OCH _2- . The compound according to claim 8, wherein R ¹ is phenyl-CH ₂ -OCH _2- ; and R ² is phenyl-CH ₂ -OCH _2- . A compound of formula II: (II) or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R ³ is from H, optionally substituted C ₁ to C ₁₀ alkyl-OCH _2- , optionally substituted C ₁ to C ₁₀ alkyl-NHCH _2- , optionally substituted C ₁ to C ₁₀ fluorenyl, optionally substituted C ₁ to C ₁₀ alkyl-OC (O)-, optionally substituted (C _{6 to 10} aryl) -CH ₂ OCH _2- , (C _{6 to 10} aryl) optionally substituted -OCH _2- , (C _{6 to 10} aryl) -C (O)-optionally substituted (5 to 10-membered heteroaryl) -CH ₂ OCH _2- , optionally substituted (5 to 10-membered heteroaryl) -OCH _2- , optionally substituted (C _{6 to 10} aryl) -OC (O)-, Selected from the group of (5-10 membered heteroaryl) -C (O)-and (5-10 membered heteroaryl) -OC (O)-optionally substituted; R ⁴ and R ⁵ Independently from H, an optionally substituted C ₁ to C ₁₀ alkyl-OCH _2- , an optionally substituted C ₁ to C ₁₀ fluorenyl, and an optionally substituted (C _{6 to 10} aryl) -CH ₂ OCH _2- , (C _{6 to 10} aryl) optionally substituted -OCH _2- , (C _{6 to 10} aryl) -C (O)-, optionally substituted (5- to 10-membered heteroaryl) -CH ₂ OCH _2- , optionally substituted (5- to 10-membered heteroaryl) -OCH _2- (5 to 10-membered heteroaryl) optionally substituted-C (O)-, C ₁ to C ₁₀ alkyl substituted-NR ^7A CH ₂ -optionally substituted (C _{6 to 10} aryl) )-NR ^7A CH _2- , and optionally substituted (5- to 10-membered heteroaryl)-NR ^7A CH _2- , NR ^7A CH ₂ -and-L-CH ₂ -or R ⁴ and R ⁵ forms a 5-6 membered cyclic acetal together with the atom to which these groups are connected and the atom in between, and the 5-6 membered cyclic acetal is optionally passed through one or more R ^6A substituents; ^{R. 6A} are each independently C ₁ ~ C ₁₀ alkyl group, C _{6 ~ 10} aryl, 5-10 membered heteroaryl or 4 to 10 membered heterocyclic group, and these groups are substituted with 1 to 4 R ^{6AA is} arbitrarily substituted; R ^6AA is independently selected from halogen, OH, optionally substituted C ₁ to C ₁₀ alkyl-OCH ₂ O-, optionally substituted C ₁ to C ₁₀ alkyl C (O) O-, optionally substituted by one of C ₁ ~ C ₁₀ alkyl group -OC (O) O-, substituted by any of C ₁ ~ C ₁₀ alkyl, Meaning substituted with C ₁ ~ C ₁₀ alkoxy, substituted with any of C ₃ ~ C ₁₀ cycloalkyl, the optionally substituted C _{6 ~ 10} aryl, optionally substituted 5-10-membered heteroaryl of aryl, any Selected from the group of substituted 4 to 10-membered heterocyclic groups, (C _{6 to 10} aryl) -OCH ₂ -and (5 to 10-membered heteroaryl) -OCH ₂ -that are optionally substituted; R ^7A is independently selected from H, an optionally substituted C ₁ to ₁₀ alkyl group, an optionally substituted C ₁ to C ₁₀ fluorenyl group, an optionally substituted C _{6 to 10} aryl group, and an optionally substituted 5 to 10 member Selected from the group of heteroaryl groups; X is O or NR ^1A ; Y is O or NR ^1B ; R ^1A is from H, optionally substituted C ₁ to C ₁₀ alkyl-OCH _2- , optionally substituted ( C _{6 ～ 10} aryl) —OCH ₂ —and one optionally substituted (5- to 10-membered heteroaryl) —OCH ₂ —selected from the group; R ^1B is selected from an optionally substituted C ₁ ～ C ₁₀ alkyl -OCH _2- , optionally substituted C ₁ to C ₁₀ fluorenyl, optionally substituted C ₁ to C ₁₀ alkyl-OC (O)-, optionally substituted (C _{6 to 10} aryl) -OCH ₂ －, Once replaced arbitrarily (C _{6 ～ 10} Aryl) -C (O)-, optionally substituted (5- to 10-membered heteroaryl) -OCH _2- , optionally substituted (C _{6 to 10} aryl) -OC (O)-, once optionally substituted And (5 to 10-membered heteroaryl) -C (O)-and (5- to 10-membered heteroaryl) -OC (O)-optionally substituted; and L is an optionally substituted 4- to 10-membered heterocyclic ring of nitrogen, and when R ³ is H or -X-R ³ is -NHC (O) O-C ₁ -C ₁₀ alkyl, at least one of R ⁴ and R ⁵ is not H or R ⁴ and R ⁵ form a 5- to 6-membered cyclic acetal together with the atom to which these groups are connected and the atom in between, and the 5- to 6-membered cyclic acetal undergoes one or more Multiple R ^{6A's are} optionally substituted. The compound according to claim 10, wherein R ⁵ is H, and optionally substituted C ₁ to C ₁₀ alkyl-OCH ₂ -or optionally substituted (C _{6 to 10} aryl) -CH ₂ OCH _2- . The compound according to claim 11, wherein R ⁵ is H. The compound according to claim 11, wherein R ⁵ is C ₁ to C ₁₀ alkyl-OCH ₂ -or phenyl-CH ₂ OCH _2- . The compound according to claim 10, wherein R ⁴ is H, and optionally substituted C ₁ to C ₁₀ alkyl-OCH ₂ -or optionally substituted (C _{6 to 10} aryl) -CH ₂ OCH _2- . The compound according to claim 14, wherein R ⁴ is H. The compound according to claim 14, wherein R ⁴ is C ₁ to C ₁₀ alkyl-OCH ₂ -or phenyl-CH ₂ OCH _2- . A compound according to claim 10, having the formula III: (III) or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R ⁶ is H or R ^6A . The compound according to claim 17, wherein R ⁶ is R ^6A . The compound according to claim 18, wherein R ^6A is a C ₁ to C ₆ alkyl group, a C _{6 to 10} aryl group, a 5 to 10 member heteroaryl group, or a 4 to 10 member heterocyclic group, and these groups are respectively Arbitrarily substituted by 1 to 4 R ^6AA . The compound according to claim 19, wherein R ^6A is a C ₁ -C ₆ alkyl group optionally substituted with 1 to 4 R ^6AA . The compound according to claim 18, wherein R ^6A is a phenyl group or a 4- to 10-membered heterocyclic group, and these groups are optionally substituted with 1 to 3 R ^6AA, respectively. The compound according to claim 21, wherein R ^6A is a phenyl group optionally substituted with 1 to 3 R ^6AA . The compound according to claim 21, wherein R ^6A is a 4- to 10-membered heterocyclic group optionally substituted with 1 to 3 R ^6AA . The compound according to claim 21, wherein R ^6A is benzo [d] [1,3] dioxol-5-yl optionally substituted with 1 to 3 R ^6AA . The compound according to claim 17, wherein R ^6AA is independently selected from OH, C ₁ to C ₆ alkyl-OCH ₂ O-, C ₁ to C ₆ alkyl C (O) O-, and C ₁ to C ₆ alkyl, C ₁ to C ₆ alkoxy, and optionally substituted 4 to 10 member heterocyclic groups are selected. The compound according to claim 25, wherein R ^6AA is OH, methoxy, or methyl. The compound according to claim 25, wherein R ^6AA is CH ₃ CH ₂ OCH ₂ O— or (CH ₃ ) ₂ CHC (O) O—. The compound according to claim 25, wherein R ^6AA is a 4- to 10-membered heterocyclic group substituted with a C ₁ to C ₆ alkyl group. The compound according to claim 28, wherein R ^6AA is 1,3-dioxolane-2-yl substituted with a methyl group or an ethyl group. A compound of formula IV or V: (IV) or a stereoisomer or pharmaceutically acceptable salt thereof, (V) or a stereoisomer or a pharmaceutically acceptable salt thereof, and R ³ is from H, optionally substituted C ₁ to C ₁₀ alkyl-OCH _2- , optionally substituted C ₁ to C ₁₀ alkyl —NHCH ₂ —, optionally substituted C ₁ to C ₁₀ fluorenyl, optionally substituted C ₁ to C ₁₀ alkyl —OC (O) —, optionally substituted (C _{6 to 10} aryl) —CH ₂ OCH _2- , (C _{6 to 10} aryl) optionally substituted-OCH _2- , (C _{6 to 10} aryl) -C (O)-optionally substituted (5 to 10 member) Aryl) -CH ₂ OCH _2- , (5 to 10 member heteroaryl) optionally substituted -OCH _2- , (C _{6 to 10} aryl) -OC (O)-optionally substituted (5 to 10-membered heteroaryl) -C (O)-and an optionally substituted (5--10-membered heteroaryl) -OC (O)-group; R ⁴ and R ⁵ are independently selected From H, optionally substituted C ₁ to C ₁₀ alkyl-OCH _2- , optionally substituted C ₁ to C ₁₀ fluorenyl, optionally substituted (C _{6 to 10} aryl) -CH ₂ OCH _2- , once the optionally substituted (C _{6 ~ 10} aryl) -OCH ₂ -, optionally substituted by one of (C _{6 ~ 10} Yl) -C (O) - optionally substituted with the (5-10 membered heteroaryl) -OCH _2, once - -, substituted upon any, upon any substituent of (5-10 membered heteroaryl) -CH ₂ OCH ₂ (5- to 10-membered heteroaryl) -C (O)-, optionally substituted C ₁ to C ₁₀ alkyl-NR ^7A CH _2- , optionally substituted (C _{6 to 10} aryl) -NR ^7A CH ₂ －, arbitrarily substituted (5- to 10-membered heteroaryl) -NR ^7A CH ₂ －, NR ^7A CH ₂ －, and —L-CH ₂ －, or R ⁴ and R ⁵ and this The atom to which the iso groups are connected and the atom in between form a 5-6 membered cyclic acetal, and the 5-6 membered cyclic acetal is optionally substituted with one or more R ^6A ; R ⁶ Is H or R ^6A ; R ^{6A is} independently C ₁ to C ₁₀ alkyl, C _{6 to 10} aryl, 5 to 10-membered heteroaryl, or 4 to 10-membered heterocyclic group, and each of these groups is 1 ～ 4 R ^{6AA are} arbitrarily substituted; R ^6AA is independently independently selected from halogen, OH, C ₁ ～ C ₁₀ alkyl-OCH ₂ O-, and C ₁ ～ C ₁₀ alkyl C (O ) O-, the optionally substituted by a C ₁ ~ C ₁₀ alkyl group -OC (O) O-, substituted by any of C ₁ ~ C ₁₀ alkyl , Substituted by any of C ₁ ~ C ₁₀ alkoxy, substituted with any of C ₃ ~ C ₁₀ cycloalkyl, the optionally substituted C _{6 ~ 10} aryl, the optionally substituted 5-10 membered heteroaryl, In the group of optionally substituted 4 to 10-membered heterocyclic group, (C _{6 to 10} aryl) -OCH ₂ -and optionally (5 to 10 membered heteroaryl) -OCH _2- elected; R ^7A is independently selected from H, a by optionally substituted the C ₁ ~ ₁₀ alkyl, upon any substituent of C ₁ ~ C ₁₀ acyl, upon any substituent of C _{6 ~ 10} aryl group, and upon any substituent of 5 ~ 10 members of the heteroaryl group; R ^1A is selected from H, optionally substituted C ₁ to C ₁₀ alkyl-OCH _2- , optionally substituted (C _{6 to 10} aryl) -OCH _2- , and Once arbitrarily substituted (5 to 10-membered heteroaryl) -OCH ₂ -is selected from the group; R ^1B is selected from C ₁ ～ C ₁₀ alkyl-OCH ₂ －, C ₁ ～ C ₁₀ acyl, upon any substituent of C ₁ ~ C ₁₀ alkyl group -OC (O) -, once any substituent of (C _{6 ~ 10} aryl) -OCH ₂ -, once any substituent of (C _{6 ~ 10} aryl Base)-C (O)-, once It is intended to replace it (5-10 membered heteroaryl) -OCH ₂ -, substituents of (C _{6 ~ 10} aryl group) -OC (O) upon any -, substituted with the (5-10 membered heteroaryl) on a arbitrary - C (O)-and an optionally substituted (5- to 10-membered heteroaryl) -OC (O)-are selected from the group; and L is an optionally substituted nitrogen-containing 4 to 10-membered heterocyclic ring, and when R ^{When 3} is H, at least one of R ⁴ and R ⁵ is not H or R ⁴ and R ⁵ form a 5- to 6-membered ring together with the atom to which these groups are connected and the atom in between. Acetal, and the 5- to 6-membered cyclic acetal is optionally substituted with one or more R ^6A . A compound of formula VI: (VI) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein R ³ is from H, optionally substituted C ₁ to C ₁₀ alkyl-OCH _2- , optionally substituted C ₁ to C ₁₀ alkyl-NHCH _2- , optionally substituted C ₁ to C ₁₀ fluorenyl, optionally substituted C ₁ to C ₁₀ alkyl-OC (O)-, optionally substituted (C _{6 to 10} aryl) -CH ₂ OCH _2- , (C _{6 to 10} aryl) optionally substituted -OCH _2- , (C _{6 to 10} aryl) -C (O)-optionally substituted (5 to 10-membered heteroaryl) -CH ₂ OCH _2- , optionally substituted (5 to 10-membered heteroaryl) -OCH _2- , optionally substituted (C _{6 to 10} aryl) -OC (O)-, A group of (5 to 10-membered heteroaryl) -C (O)-and a group of (5--10-membered heteroaryl) -OC (O)-that are arbitrarily substituted; R ⁷ is selected from the group of Optionally substituted C ₁ to C ₂₀ alkyl, once optionally substituted C ₂ to C ₂₀ alkenyl, once optionally substituted C ₃ to C ₂₀ cycloalkyl, once optionally substituted C _{6 to 10} aryl, once optionally substituted 5 to 10-membered heteroaryl, optionally substituted C ₁ to C ₁₀ alkyl-OCH _2- , optionally substituted C ₁ to C ₁₀ alkyl-CO-OCH _2- , optionally substituted (C _{6 to 10} aryl) -OCH _2- , optionally substituted (5 to 10 member heteroaryl ) -OCH _2- , once optionally substituted (C _{6 to 10} aryl) -CH ₂ -and once optionally substituted (5 to 10 member heteroaryl) -CH ₂ -selected from the group; Z is O or NR ^1C ; R ^1C is selected from the group consisting of H, an optionally substituted C ₁ to C ₁₀ alkyl group, and an optionally substituted aryl group. A pharmaceutical composition comprising the compound according to any one of claims 1 to 31 and a pharmaceutically acceptable excipient. The pharmaceutical composition according to claim 32, which further comprises one or more anticancer agents. The pharmaceutical composition according to claim 32, which contains two or more anticancer agents. The pharmaceutical composition according to claim 32, which further comprises an anticancer agent. A method of treating a disorder or condition, comprising administering an effective amount of a compound described in any one of claims 1 to 31 to a subject in need thereof. The method according to claim 36, wherein the disease, disorder or condition is a liver disease, disorder or condition. The method of claim 36, wherein the disease, disorder or condition is a metabolic, cardiovascular or hormonal disease, wherein the liver is involved in the production of a biochemical end product of the disease, disorder or condition and / or Constant control. The method according to claim 36, wherein the disease, disorder or condition is composed of hepatocellular carcinoma, kidney cancer, colorectal cancer, breast cancer, gastric cancer, gastric cancer, esophageal cancer, pancreatic cancer and cervical cancer Selected in the group. A method for treating liver disease, comprising administering an effective amount of the compound according to any one of claims 1 to 31 to a subject in need thereof. The method of claim 36, which comprises administering an effective amount of at least one additional therapeutic agent to a subject in need thereof. The method of claim 36, wherein the object is a mammal. The method according to claim 36, wherein the object is a human. A method for inhibiting viral replication in a cell, comprising contacting the cell with a compound according to any one of claims 1 to 31. A method of intervening a molecular pathway or modulating a target in a cell comprising contacting the cell with a compound of any one of claims 1 to 31. The method according to claim 44, wherein the cell is in vivo. The method of claim 44 wherein the cell is in vitro. The method according to claim 44, wherein the cell is a hepatocyte. The method according to claim 44, wherein the cell is a mammal. The method according to claim 44, wherein the cell is a human. A use of a compound according to any one of claims 1 to 31, for treating a viral liver infection in a subject. Use according to claim 51, for use with an additional therapeutic agent. The use according to claim 52, wherein the additional therapeutic agent is a group of immuno-oncology agents such as sorafenib, cancer reg, such as PD-1 or PD-L1 checkpoint inhibitors for the treatment of HCC Selected in the group. A compound according to any one of claims 1 to 31, which is for treating a disease of the liver, or a disease or condition involving a physiological or pathogenic pathway of the liver of a subject. A compound as claimed in claim 54 for use with an additional therapeutic agent. A use of a compound according to any one of claims 1 to 31, for preparing a medicament for treating a disease or condition of the liver, or involving a physiological or pathogenic nature of the liver Disease or condition.