5-Fluorouracil compound

Abstract

The present invention provides 5-fluorouracil-derived acetal and hemiaminal ether compounds, their preparation and uses (such as for treating liver diseases or various types of cancers).

Description

[0001] Cross - reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 619,557, filed on January 19, 2018, entitled "5 - Fluorouracil Compounds", which is hereby incorporated by reference in its entirety. Technical field

[0003] The present disclosure relates to the fields of chemistry and medicine. More specifically, the present disclosure relates to 5 - fluorouracil - derived compounds, including acetal and hemiaminal ether compounds, their preparation, and uses. In some embodiments, such compounds can be used to selectively deliver certain agents to the liver. Background art

[0004] The following description of the background art is provided to assist in understanding the present invention, but does not admit that it is prior art to the present invention or a description of the prior art of the present invention.

[0005] 5 - Fluorouracil is a synthetic analog of uracil, one of the four nucleobases in RNA, and has been used as a therapeutic agent for treating various forms of cancer. Due to its efficacy and safety, it is one of the essential medicines on the WHO list and is available in both intravenous and topical forms. The mechanism of action of 5 - fluorouracil is mainly as a thymidylate synthase inhibitor, which blocks the synthesis of pyrimidine thymidine, causing cells to lack thymidine and leading to cell death. The active form of 5 - fluorouracil as a thymidylate synthase inhibitor is fluorodeoxyuridine monophosphate (FdUMP), which is mainly produced in the liver.

[0006] 5 - Fluorouracil has a very short biological half - life (~16 minutes), a very narrow therapeutic index, and various side effects that can be very severe. The development of new 5 - fluorouracil - analog compounds with better efficacy and safety has been ongoing for many years, and several compounds have been put on the market. Floxuridine, also known as 5 - fluorodeoxyuridine, has been used for the treatment of colorectal cancer by continuous hepatic artery perfusion. In certain countries, doxifluridine has been used as a cytostatic agent in chemotherapy. Capecitabine has been taken orally for the treatment of breast cancer, gastric cancer, and colorectal cancer. Despite the progress in this field, there is still a need for new compounds to further improve drug delivery efficiency or to address new applications based on new technologies. For example, liver - targeting compounds that can reach the liver more efficiently and are inactive outside the liver reduce the pharmacological or toxicological effects of the agent outside the target tissue. Therefore, new compounds with liver - targeting properties can significantly improve the therapeutic index of therapies based on the 5 - fluorouracil mechanism. Summary of the invention

[0008] The present invention describes novel 5-fluorouracil-derived acetals and hemiacetal amine ethers, their preparation and uses. Some embodiments relate to novel 5-fluorouracil-derived acetals and hemiacetal amine ethers that are orally delivered to the liver and provide therapeutic benefits in the liver. Another aspect includes the use of 5-fluorouracil-derived acetals and hemiacetal amine ethers in treating diseases that benefit from enhanced drug distribution to the liver and similar tissues and cells, including but not limited to hepatocellular carcinoma (HCC), renal cancer, colorectal cancer, breast cancer, stomach cancer, gastric cancer, esophageal cancer, pancreatic cancer, and cervical cancer. In another aspect, the 5-fluorouracil-derived acetals and hemiacetal amine ethers are used to enhance the pharmacological or clinical activity of certain classes of drug compounds, such as 5-fluorouracil-derived analog compounds. In another aspect, 5-fluorouracil-derived acetals and hemiacetal amine ethers are used to reduce the potential side effects of certain classes of drug compounds, such as 5-fluorouracil-derived analog compounds, especially those occurring outside the liver. In some embodiments, the 5-fluorouracil-derived acetals and hemiacetal amine ethers can be used to more efficiently orally deliver 5-fluorouracil-derived analog compounds to the liver. Some other embodiments relate to methods for preparing 5-fluorouracil-derived acetals and hemiacetal amine ethers.

[0009] Some embodiments provided herein include compounds of Formula I:

[0010]

[0011] or a stereoisomer or pharmaceutically acceptable salt thereof,

[0012] wherein R 1 and R 2 have any of the values described herein.

[0013] Some embodiments relate to compounds of Formula II, III, IV, V, and VI:

[0014]

[0015] or a stereoisomer or pharmaceutically acceptable salt thereof,

[0016]

[0017] or a stereoisomer or pharmaceutically acceptable salt thereof,

[0018]

[0019] or a stereoisomer or pharmaceutically acceptable salt thereof,

[0020]

[0021] or a stereoisomer or pharmaceutically acceptable salt thereof,

[0022]

[0023] or a stereoisomer or pharmaceutically acceptable salt thereof,

[0024] wherein R 3 、R 4 、R 5 、R 6 、R 7 、X, Y and Z have any of the values described herein.

[0025] Some embodiments relate to pharmaceutical compositions comprising any of the above compounds and a pharmaceutically acceptable excipient.

[0026] Some embodiments relate to methods of treating a disease, disorder or condition, comprising administering an effective amount of any of the above compounds.

[0027] In some embodiments, the disease, disorder or condition is a liver disease, disorder or condition.

[0028] In some embodiments, the disease, disorder or condition is a disease in which the liver is involved in the production of the biochemical end products of the disease, disorder or condition and / or homeostasis control.

[0029] In some embodiments, the disease, disorder or condition is selected from hepatocellular carcinoma, renal cancer, colorectal cancer, breast cancer, gastric cancer, gastric cancer, esophageal cancer, pancreatic cancer and cervical cancer.

[0030] In some embodiments, the disease, disorder or condition is a non-liver disease, disorder or condition.

[0031] In some embodiments, the non-liver disease, disorder or condition is various types of cancer, or other diseases in which 5-fluorouracil-derived acetal and hemiacetal amine ether compounds enhance the distribution of active drugs to target tissues or cells.

[0032] Some embodiments relate to methods of treating liver diseases, comprising administering an effective amount of any of the above compounds to an individual in need thereof.

[0033] Some embodiments further comprise administering an effective amount of at least one other therapeutic agent to an individual in need thereof.

[0034] In some embodiments, the individual is a mammal.

[0035] In some embodiments, the individual is a human.

[0036] Some embodiments relate to methods of inhibiting viral replication in a cell, which comprise contacting the cell with any of the above-described compounds.

[0037] Some embodiments relate to methods of intervening in a molecular pathway or modulating a target in a cell, which comprise contacting the cell with any of the above-described compounds.

[0038] In some embodiments, the cell is in vivo.

[0039] In some embodiments, the cell is ex vivo.

[0040] In some embodiments, the cell is a hepatocyte.

[0041] In some embodiments, the cell is a cancer cell.

[0042] In some embodiments, the cell is mammalian.

[0043] In some embodiments, the cell is human.

[0044] Some embodiments of the compounds, compositions, and methods provided herein include pharmaceutical compositions comprising any of the compounds provided herein and a pharmaceutically acceptable excipient.

[0045] Some embodiments of the compounds, compositions, and methods provided herein include methods of treating a disease or disorder in the liver of an individual, which comprise administering to the individual in need thereof an effective amount of any of the compounds provided herein.

[0046] Some embodiments further include administering to the individual in need thereof an effective amount of one or more other therapeutic agents.

[0047] In some embodiments, the individual is a mammal.

[0048] In some embodiments, the individual is a human.

[0049] Some embodiments of the compounds, compositions, and methods provided herein include the use of any one of the compounds provided herein for treating a liver disease in an individual or a disease or disorder in which a physiological or pathogenic pathway involves the liver.

[0050] Some embodiments further include the combined use of any one of the compounds provided herein with other therapeutic agents.

[0051] Some embodiments of the compounds, compositions, and methods provided herein include any of the compositions provided herein for use in the preparation of a medicament for treating a liver disease or disorder or a disease or disorder in which a physiological or pathogenic pathway involves the liver. Detailed Description of the Invention

[0053] This embodiment relates to compositions and methods related to novel 5-fluorouracil-derived acetals and hemiacetal amidoethers, their preparation, and uses. In some embodiments, the novel 5-fluorouracil-derived acetals and hemiacetal amidoethers facilitate the delivery of 5-fluorouracil-derived therapeutic agents (such as 5-fluorouracil, doxifluridine, 5-fluorouridine monophosphonate, and / or 5-fluorodeoxyuridine monophosphonate) into cells.

[0054] These 5-fluorouracil-derived acetals and hemiacetal amidoethers, their stereoisomers, and pharmaceutically acceptable salts are represented by Formulas I, II, III, IV, V, and VI:

[0055]

[0056] or a stereoisomer or pharmaceutically acceptable salt thereof,

[0057]

[0058] or a stereoisomer or pharmaceutically acceptable salt thereof,

[0059]

[0060] or a stereoisomer or pharmaceutically acceptable salt thereof,

[0061]

[0062] or a stereoisomer or pharmaceutically acceptable salt thereof,

[0063]

[0064] or a stereoisomer or pharmaceutically acceptable salt thereof,

[0065]

[0066] or a stereoisomer or pharmaceutically acceptable salt thereof,

[0067] wherein R 1 、R 2 、R 3 、R 4, R 5 , R 6 , R 7 , X, Y, and Z have any value as described herein.

[0068] In some embodiments, R 1 and R 2 are independently selected from: H, optionally substituted C1-C 10 alkyl-OCH2-, optionally substituted (C 6-10 aryl)-CH2-OCH2-, optionally substituted (5-10 membered heteroaryl)-CH2-OCH2-, optionally substituted (C 6-10 aryl)-OCH2-, and optionally substituted (5-10 membered heteroaryl)-OCH2-; provided that at least one of R 1 and R 2 is not H.

[0069] In some embodiments, R 3 is selected from: H, optionally substituted C1-C 10 alkyl-OCH2-, optionally substituted C1-C 10 alkyl-NHCH2-, optionally substituted C1-C 10 acyl, optionally substituted C1-C 10 alkyl-OC(O)-, optionally substituted (C 6-10 aryl)-CH2OCH2-, optionally substituted (C 6-10 aryl)-OCH2-, optionally substituted (C 6-10 aryl)-C(O)-, optionally substituted (5-10 membered heteroaryl)-CH2OCH2-, optionally substituted (5-10 membered heteroaryl)-OCH2-, optionally substituted (C 6-10 aryl)-OC(O)-, optionally substituted (5-10 membered heteroaryl)-C(O)-, and optionally substituted (5-10 membered heteroaryl)-OC(O)-.

[0070] In some embodiments, R 4 and R 5 are independently selected from: H, optionally substituted C1-C 10 alkyl-OCH2-, optionally substituted C1-C 10 acyl, optionally substituted (C 6-10 aryl)-CH2OCH2-, optionally substituted (C 6-10 aryl)-OCH2-, optionally substituted (C 6-10(aryl)-C(O)-, optionally substituted (5-10 heteroaryl)-CH2OCH2-, optionally substituted (5-10 membered heteroaryl)-OCH2-, optionally substituted (5-10 membered heteroaryl)-C(O)-, optionally substituted C1-C 10 alkyl-NR 7A CH2-, optionally substituted (C 6-10 aryl)-NR 7A CH2-, optionally substituted (5-10 membered heteroaryl)-NR 7A CH2-, N(R 7A )2CH2- and -L-CH2-; R 7A is independently selected from: H, optionally substituted C 1-10 alkyl, optionally substituted C 1-10 acyl, optionally substituted C 6-10 aryl and optionally substituted 5-10 membered heteroaryl; X is O or NR 1A ; Y is O or NR 1B ; R 1A is selected from: H, optionally substituted C1-C 10 alkyl-OCH2-, optionally substituted (C 6-10 aryl)-OCH2- and optionally substituted (5-10 membered heteroaryl)-OCH2-; R 1B is independently selected from: optionally substituted C1-C 10 alkyl-OCH2-, optionally substituted C1-C 10 acyl, optionally substituted C1-C 10 alkyl-OC(O)-, optionally substituted (C 6-10 aryl)-OCH2-, optionally substituted (C 6-10 aryl)-C(O)-, optionally substituted (5-10 membered heteroaryl)-OCH2-, optionally substituted (C 6-10 aryl)-OC(O)-, optionally substituted (5-10 membered heteroaryl)-C(O)- and optionally substituted (5-10 membered heteroaryl)-OC(O)-; and L is an optionally substituted 4-10 membered nitrogen-containing heterocycle, provided that: when R 3 is H or -X-R 3 is -NHC(O)O-alkyl, at least one of R 4 and R 5 is not H.

[0071] In some embodiments, R 6 is H or R 6A ; R 6A is C1-C 10 alkyl, C 6-10An aryl, 5- to 10-membered heteroaryl or 4- to 10-membered heterocyclic group, each of which is optionally substituted with 1 to 4 R 6AA ; each R 6AA is independently selected from: halogen, OH, optionally substituted C1-C 10 alkyl -OCH2O-, optionally substituted C1-C 10 alkyl C(O)O-, optionally substituted C1-C 10 alkyl -OC(O)O-, optionally substituted C1-C 10 alkyl, optionally substituted C1-C 10 alkoxy, optionally substituted C3-C 10 cycloalkyl, optionally substituted C 6-10 aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted 4- to 10-membered heterocyclic group, optionally substituted (C 6-10 aryl)-OCH2- and optionally substituted (5- to 10-membered heteroaryl)-OCH2-.

[0072] In some embodiments, R 7 is selected from: optionally substituted C1-C 20 alkyl, optionally substituted C3-C 20 cycloalkyl, optionally substituted C2-C 20 alkenyl, optionally substituted C 6-10 aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C1-C 10 alkyl -OCH2-, optionally substituted C1-C 10 alkyl -CO-OCH2-, optionally substituted (C 6-10 aryl)-OCH2-, optionally substituted (5- to 10-membered heteroaryl)-OCH2-, optionally substituted (C 6-10 aryl)-CH2- and optionally substituted (5- to 10-membered heteroaryl)-CH2-.

[0073] In some embodiments, X is O or NR 1A ; and R 1A is selected from: H, optionally substituted C1-C 10 alkyl -OCH2-, optionally substituted (C 6-10 aryl)-OCH2- and optionally substituted (5- to 10-membered heteroaryl)-OCH2-.

[0074] In some embodiments, Y is O or NR 1B ; and R 1B is selected from: optionally substituted C1-C 10 alkyl -OCH2-, optionally substituted C1-C 10 acyl, optionally substituted C1-C 10alkyl-OC(O)-, optionally substituted (C 6-10 aryl)-OCH2-, optionally substituted (C 6-10 aryl)-C(O)-, optionally substituted (5- to 10-membered heteroaryl)-OCH2-, optionally substituted (C 6-10 aryl)-OC(O)-, optionally substituted (5- to 10-membered heteroaryl)-C(O)-, and optionally substituted (5- to 10-membered heteroaryl)-OC(O)-.

[0075] In some embodiments, Z is O or NR 1C ; and R 1C is selected from: H, optionally substituted C1-C 10 alkyl, and optionally substituted aryl.

[0076] In some embodiments, the 5-fluorouracil-derived acetal and hemiaminal ether compounds of Formulas I, II, III, IV, V, and VI are substrates for liver enzymes such as cytochrome p450 isoenzymes CYP3As (monooxygenase family), dehydrogenases, esterases, and amidases.

[0077] The expression level of CYP3A4 in the liver is much higher than that in other tissues (DeWaziers et al., J Pharm Exp Ther 253:387 (1990)). The 5-fluorouracil-derived acetal and hemiaminal ether compounds of Formulas I, II, III, IV, V, and VI are mainly activated by CYP3A4 in the liver. In some embodiments, the compounds of Formulas I, II, III, IV, V, and VI have high efficiency in liver targeting by selectively delivering bioactive agents to the liver. In some embodiments, the acetal and hemiaminal amine compounds are used to increase the therapeutic index of drugs because the compounds of Formulas I, II, III, IV, V, and VI may be inactive or less active outside the liver.

[0078] In some embodiments, due to the liver-targeting properties of the 5-fluorouracil-derived acetal and hemiaminal ether compounds of Formulas I, II, III, IV, V, and VI, the compounds are used to treat diseases that benefit from enhanced drug distribution to the liver and similar tissues and cells, including but not limited to liver diseases such as hepatocellular carcinoma.

[0079] In some embodiments, the disclosed compounds are used to improve pharmacokinetic properties (such as prolonging the half-life of a drug or enhancing the absorption of a drug). Additionally, the disclosed methods can be used to achieve sustained delivery of an active therapeutic agent. Due to the enhanced pharmacokinetic properties of the 5-fluorouracil-derived acetal and hemiaminal ether compounds of Formulas I, II, III, IV, V, and VI, the compounds are used to treat diseases that benefit from enhanced drug properties, including but not limited to diseases such as various types of cancer. In some embodiments, methods for preparing these compounds are described.

[0080] Certain compounds of Formulas I, II, III, IV, V, and VI have asymmetric centers for which the stereochemistry may not be specified, and the present invention includes diastereomeric mixtures of these compounds, as well as the individual stereoisomers when generally referring to compounds of Formulas I, II, III, IV, V, and VI.

[0081] Some embodiments of the compounds, compositions, and methods provided herein include pharmaceutical compositions comprising a compound provided herein and a pharmaceutically acceptable carrier.

[0082] Some embodiments also include co-administering an effective amount of a second therapeutic agent or agents to an individual in need thereof with a compound provided herein.

[0083] In some embodiments, the individual is a mammal.

[0084] In some embodiments, the individual is a human.

[0085] Some embodiments of the compounds, compositions, and methods provided herein include methods of a compound in a test cell, the method comprising contacting the cell with the disclosed compound.

[0086] Some embodiments of the compounds, compositions, and methods provided herein include the use of a compound provided herein in the treatment of liver diseases.

[0087] Some embodiments include the use of a compound provided herein and one or more other therapeutic agents for the combined treatment of liver diseases.

[0088] Some embodiments of the compounds, compositions, and methods provided herein include the use of a compound provided herein to treat a disease or disorder by intervening in a molecular pathway in the liver.

[0089] Some embodiments include the use of a compound provided herein and one or more other therapeutic agents to jointly treat a disease or disorder by intervening in a molecular pathway in the liver.

[0090] Some embodiments of the compounds, compositions, and methods provided herein include the use of the compounds provided herein in the treatment of non-hepatic diseases such as various types of cancer.

[0091] Some embodiments include the use of the compounds provided herein in combination with one or more other therapeutic agents for the combined treatment of non-hepatic diseases such as various types of cancer.

[0092] When the compounds disclosed herein have at least one chiral center, they may exist as individual enantiomers and diastereomers or as mixtures of such isomers including racemates. The separation of the individual isomers and the selective synthesis of the individual isomers are carried out by applying various methods well known to those skilled in the art. Unless otherwise stated, 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 stated, all such forms are included within the scope of the compounds disclosed herein, including any polymorphic forms. In addition, some of the compounds disclosed herein may form solvates (i.e., hydrates) with water or solvates with common organic solvents. Unless otherwise stated, such solvates are included within the scope of the compounds disclosed herein.

[0093] Those skilled in the art will recognize that some of the structures described herein may be resonance forms or tautomers of the compounds, which may be clearly represented by other chemical structures, even kinetically; those skilled in the art recognize that such structures may represent only a very small portion of a sample of such compounds. Such compounds are considered to be within the scope of the structures depicted, although such resonance forms or tautomers are not represented herein.

[0094] Isotopes may be present in the compounds. Each chemical element as represented in the compound structure may include any isotope of that element. For example, in the compound structure, a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position in the compound where a hydrogen atom may be present, the hydrogen atom may be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, unless the context clearly indicates otherwise, the compounds referred to herein encompass all possible isotopic forms.

[0095] Definitions

[0096] As used in this disclosure and as used herein, unless otherwise expressly stated, the following terms are defined with the following meanings. It should be understood that both the foregoing summary and the following detailed description are merely exemplary and explanatory and do not limit the claimed subject matter. In this application, unless otherwise expressly stated, the use of the singular includes the plural. In this application, unless otherwise indicated, the use of "or" means "and / or". Further, the use of the term "including" and other forms (such as "includes" and "included") is not limiting.

[0097] As used herein, ranges and amounts may be expressed as "about" a particular value or range. "About" also includes the exact amount. Thus, "about 10%" means "about 10%" as well as "10%".

[0098] As used herein, "optional" or "optionally / optionally present" means that the subsequent described event or circumstance may or may not occur, and the description includes the case where the event or circumstance occurs and the case where the event or circumstance does not occur. For example, an optionally substituted group means that the group is unsubstituted or substituted.

[0099] As used herein, unless the context clearly indicates otherwise, the singular forms "a", "an", and "the" include plural referents. Thus, for example, reference to a composition containing a "therapeutic agent" includes compositions having one or more therapeutic agents.

[0100] As used herein, "C a to C b " or "C a-b " (where "a" and "b" are integers) refers to the number of carbon atoms in the specified group. That is, the group may contain from "a" to "b" (including the end values) carbon atoms. Thus, for example, "C1-C4 alkyl" or "C 1-4 alkyl" refers to all alkyls having 1-4 carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-.

[0101] As used herein, "alkyl" refers to a straight or branched chain hydrocarbon chain that is fully saturated (i.e., contains no double or triple bonds). An alkyl group can have from 1 to 20 carbon atoms (wherever it appears in the present text, a numerical range such as "1 to 20" refers to each integer within the given range; for example, "from 1 to 20 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, but this definition also encompasses the occurrence of the term "alkyl" without a specified numerical range). The alkyl group can also be a medium-sized alkyl group having 1 to 9 carbon atoms. The alkyl group can also be a lower alkyl group having 1 to 4 carbon atoms. The alkyl group can be designated as "C1-C4 alkyl" or a similar designation. By way of example only, "C1-C4 alkyl" means that there are one to four carbon atoms present in the alkyl chain, i.e., the alkyl chain is selected from: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like.

[0102] As used herein, a substituted group is derived from an unsubstituted parent group in which one or more hydrogen atoms are exchanged with another atom or group. Unless otherwise specified, when a group is considered to be "substituted", it means that the group is substituted by one or more groups independently selected from the following: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 carbocyclic group (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), C3-C7-carbocyclic-C1-C6-alkyl (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 3- to 10-membered heterocyclic group (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 3- to 10-membered heterocyclic-C1-C6-alkyl (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl(C1-C6)alkyl (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5- to 10-membered heteroaryl (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5- to 10-membered heteroaryl(C1-C6)alkyl (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), halogen, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy(C1-C6)alkyl (i.e., ether), aryloxy (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), C3-C7 carbocyclic oxy (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 3- to 10-membered heterocyclic-oxy (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5- to 10-membered heteroaryl-oxy (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), C3-C7-carbocyclic-C1-C6-alkoxy (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 3- to 10-membered heterocyclic-C1-C6-alkoxy (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy,substituted by C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl(C1-C6)alkoxy (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5-10 membered heteroaryl(C1-C6)alkoxy (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), mercapto, halo(C1-C6)alkyl (e.g., -CF3), halo(C1-C6)alkoxy (e.g., -OCF3), C1-C6 alkylthio, arylthio (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), C3-C7 carbocyclic thio (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 3-10 membered heterocyclic thio (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5-10 membered heteroaryl thio (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), C3-C7-carbocyclic-C1-C6-alkylthio (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 3-10 membered heterocyclic-C1-C6-alkylthio (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl(C1-C6)alkylthio (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5-10 membered heteroaryl(C1-C6)alkylthio (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), amino, amino(C1-C6)alkyl, nitro, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-carbamoyl, N-carbamoyl, S-sulfamoyl, N-sulfamoyl, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl and oxo(=O). When a group is described as "optionally substituted", the group may be substituted by the above substituents.,

[0103] As used herein, "acyl" means -C(=O)R, where R is hydrogen, C 1-6 alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclic group, as defined herein. Non-limiting examples include formyl, acetyl, propionyl, benzoyl and acrylyl.

[0104] "Heteroacyl" means -C(=O)R, where R is C 1-6 Heteroalkyl.

[0105] "Alkoxymethylene" means -CH2OR, where R is C 1-6 Alkyl or heteroalkyl, both of which are optionally substituted.

[0106] "O-carboxy" group means "-OC(=O)R" group, where R is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclic group, as defined herein.

[0107] "C-carboxy" group means "C(=O)OR" group, where R is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclic group, as defined herein. Non-limiting examples include carboxy (i.e., -C(=O)OH).

[0108] "Cyano" group means "-CN" group.

[0109] "Cyanooxy" group means "-OCN" group.

[0110] "Isocyanato" group means "-NCO" group.

[0111] "Thiocyanato" group means "-SCN" group.

[0112] "Isothiocyanato" group means "-NCS" group.

[0113] "Sulfinyl" group means "-S(=O)R" group, where R is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10An aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic group, as defined herein.

[0114] The "sulfonyl" group refers to the "-SO2R" group, where R is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic group, as defined herein.

[0115] The "S-sulfamoyl" group refers to the "-SO2NR A R B " group, where R A and R B are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic group, as defined herein.

[0116] The "N-sulfamoyl" group refers to the "-N(R A )SO2R B " group, where R A and R b are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic group, as defined herein.

[0117] The "O-carbamoyl" group refers to the "-OC(=O)NR A R B " group, where R A and R B are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic group, as defined herein.

[0118] The "N-carbamoyl" group refers to the "-N(R A )C(=O)OR B " group, where R A and R B are each independently selected from hydrogen, C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic group, as defined herein.

[0119] The “O-thiocarbamoyl” group means “-OC(=S)NR A R B ”, where R A and R B are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic group, as defined herein.

[0120] The “N-thiocarbamoyl” group means “-N(R A )C(=S)OR B ”, where R A and R B are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic group, as defined herein.

[0121] The “C-amide” group means “-C(=O)NR A R B ”, where R A and R B are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic group, as defined herein, each of which is optionally substituted with one or more groups selected from: -OH, C 1-6 alkyl, C 3-7 carbocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclic group, C 1-6 alkyl optionally substituted with alkoxy or -OH, and C 1-6 alkoxy optionally substituted with C 1-6 alkoxy or -OH, and C 1-6 alkoxy.

[0122] The "N - amido" group refers to the "-N(R A )C(=O)R B " group, where R A and R B are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclic group, C 6-10 aryl, 5 - 10 - membered heteroaryl, and 3 - 10 - membered heterocyclic group, as defined herein, each of which is optionally substituted with one or more groups selected from: -OH, C 1-6 alkyl, C 3-7 carbocyclic group, C 6-10 aryl, 5 - 10 - membered heteroaryl, 3 - 10 - membered heterocyclic group, C 1-6 alkyl optionally substituted with alkoxy or -OH, and C 1-6 alkoxy optionally substituted with C 1-6 alkoxy or -OH. 1-6

[0123] The "amino" group refers to the "-NR A R B " group, where R A and R B are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclic group, C 6-10 aryl, 5 - 10 - membered heteroaryl, and 3 - 10 - membered heterocyclic group, as defined herein. Non - limiting examples include the free amino group (i.e., -NH2).

[0124] The "aminoalkyl" group refers to an amino group linked through an alkylene group.

[0125] The "alkoxyalkyl" group refers to an alkoxy group linked through an alkylene group (such as "C 2-8 alkoxyalkyl", etc.).

[0126] The term "acyloxy" refers to -OC(O)R, where R is an alkyl group.

[0127] The term "alkoxy" or "alkyloxy" refers to OR, where R is an alkyl or heteroalkyl group, both of which are optionally substituted.

[0128] The term "carboxyl" refers to C(O)OH.

[0129] The term "oxo" refers to the =O group. ​

[0130] The term "halogen" or "halo" refers to F (fluorine), Cl (chlorine), Br (bromine), and I (iodine).

[0131] The term "haloalkyl" refers to an alkyl group containing at least one halogen (alternatively 1 to 3 halogen atoms). Suitable halogen atoms include F, Cl, and Br.

[0132] The term "haloacyl" refers to -C(O)-haloalkyl.

[0133] As used herein, "alkenyl" refers to an unsaturated group having 2 to 12 atoms and containing at least one carbon-carbon double bond, including straight-chain, branched-chain, and cyclic groups. The alkenyl group may be optionally substituted. Suitable alkenyl groups include allyl.

[0134] The term "alkynyl" refers to an unsaturated group having 2 to 12 atoms and containing at least one carbon-carbon triple bond, including straight-chain, branched-chain, and cyclic groups. The alkynyl group may be optionally substituted. Suitable alkynyl groups include ethynyl.

[0135] As used herein, "aryl" refers to an aromatic ring or ring system containing only carbon in the ring backbone (i.e., two or more fused rings sharing two adjacent carbon atoms). When the aryl is a ring system, each ring in the system is aromatic. The aryl may have 6 to 18 carbon atoms, but this definition also encompasses occurrences of the term "aryl" where no numerical range is specified. In some embodiments, the aryl has 6 to 10 carbon atoms. The aryl may be designated as "C 6-10 aryl", "C6 or C 10 aryl" or similar designations. Examples of aryl include, but are not limited to, phenyl, naphthyl, azulyl, and anthryl.

[0136] As used herein, "heteroaryl" refers to an aromatic ring or ring system containing one or more heteroatoms (i.e., elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur) in the ring backbone (i.e., two or more fused rings sharing two adjacent atoms). When the heteroaryl is a ring system, each ring in the system is aromatic. The heteroaryl may have 5 to 18 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), but this definition also encompasses occurrences of the term "heteroaryl" where no numerical range is specified. In some embodiments, the heteroaryl has 5 to 10 ring members or 5 to 7 ring members. The heteroaryl may be designated as "5-7 membered heteroaryl" or "5-10 membered heteroaryl" or similar designations. The heteroaryl may be optionally substituted. Examples of heteroaryl include, but are not limited to, aromatic C 3-8Heterocyclic groups, and their substituted derivatives and benzo- and pyrido-fused derivatives, are attached, for example, via one of the ring carbon atoms. In some embodiments, the heteroaryl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, cyano, nitro, alkylcarbonylamino, acyl, C 1-6 -alkoxy, C 1-6 -alkyl, C 1-6 -hydroxyalkyl, C 1-6 -aminoalkyl, C 1-6 -alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl or trifluoromethyl. Examples of heteroaryl include, but are not limited to, the unsubstituted following groups or their mono- or di-substituted derivatives: furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzisoxazole, 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, pteridine, phenoxazole, oxadiazole, benzopyrazole, quinazine, cinnoline, phthalazine, quinazoline and quinoxaline. In some embodiments, the substituents are halogen, hydroxy, cyano, O-C 1-6 -alkyl, C 1-6 -alkyl, hydroxy-C 1-6 -alkyl and amino C 16 -alkyl.

[0137] As used herein, "cycloalkyl" refers to a fully saturated carbocyclic ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl can have from 3 to 10 carbon atoms (wherever it appears herein, a numerical range such as "3 to 10" means each integer within the given range). The cycloalkyl can be designated as "C3-C8 cycloalkyl" or a similar designation. By way of example only, "C3-C8 cycloalkyl" means that there are 3 to 8 carbon atoms in the carbocyclic ring or ring system.

[0138] As used herein, "heterocyclic group" means a non-aromatic ring or ring structure that is fully saturated or partially saturated and contains at least one heteroatom selected from nitrogen, oxygen, and sulfur in the ring backbone. The heterocyclic group can have any degree of saturation, provided that at least one ring in the ring system is not aromatic. The heteroatom can be present in a non-aromatic or aromatic ring in the ring system. The heterocyclic group can have from 3 to 20 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), but this definition also encompasses occurrences of the term "heterocyclic group" where no numerical range is specified. The heterocyclic group can also be a medium-sized heterocyclic group having from 3 to 10 ring members. The heterocyclic group can also be a heterocyclic group having from 3 to 6 ring members. The heterocycloalkyl can be designated as "3-15 membered heterocycloalkyl", "4-10 membered heterocycloalkyl", "3-15 membered C 2-14 heterocycloalkyl", "5-9 membered C 4-8 heterocycloalkyl", "5-10 membered C 4-9 heterocycloalkyl", "5 membered C 3-4 heterocycloalkyl", "6 membered C 4-5 heterocycloalkyl", "7 membered C 5-6 heterocycloalkyl", "bicyclic or tricyclic 9-15 membered C 8-14 heterocycloalkyl", "monocyclic or bicyclic 3-10 membered C 2-9 heterocycloalkyl", "bicyclic 8-10-membered C 4-9 heterocycloalkyl", "bicyclic 8-10 membered C 5-9 heterocycloalkyl", "monocyclic 4-7 membered C 3-6- heterocycloalkyl", "monocyclic 5-6 membered C 3-5"Heterocycloalkyl" or similar designations. The heterocyclic group can also be a C2-C9 heterocyclic group having 3 to 10 ring members (with 1 to 3 O (oxygen), N (nitrogen), or S (sulfur)). The heterocyclic group can be designated as "3-10 membered C2-C9 heterocyclic group" or similar designations. In a preferred six-membered monocyclic heterocyclic group, the heteroatoms are selected from 1 to 3 O (oxygen), N (nitrogen), or S (sulfur), and in a preferred five-membered monocyclic heterocyclic group, the heteroatoms are selected from 1 to 2 heteroatoms selected from O (oxygen), N (nitrogen), or S (sulfur). Examples of heterocyclic group rings include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidoneyl, pyrrolidionyl, 4-piperidinonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 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-dioxinyl, 1,3-dioxolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinoneyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, dihydroindolyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiomorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, and tetrahydroquinoline.

[0139] As used herein, "cyclic acetal" refers to a cyclic group containing the following moiety, where two oxygens form part of the ring backbone:

[0140]

[0141] It should be understood that, depending on the context, certain radical naming conventions can include monoradicals or diradicals. For example, when a substituent requires two points of attachment to the rest of the molecule, the substituent should be understood as a diradical. For example, substituents of an alkyl group determined to require two points of attachment include diradicals (such as -CH2-, -CH2CH2-, -CH2CH(CH3)CH2-, etc.). Other radical naming conventions clearly indicate that the radical is a diradical (such as "alkylene" or "alkenylene").

[0142] When two R groups are said to "together with the atoms to which they are attached" form a ring (e.g., a carbocyclic, heterocyclic, aryl, or heteroaryl ring), it means that the atom and the collective unit of the two R groups are the said ring. When considered alone, the ring is not otherwise restricted by the definitions of each R group. For example, when there is the following substructure: and R 1 and R 2 are defined as selected from alkyl and aryl, or R 1 and R 2 together with the oxygen to which each is attached form a heterocyclic group, it means that R 1 and R 2 can be selected from alkyl or aryl, or the substructure has the following structure: where ring A is a heterocycle containing the indicated oxygen.

[0143] Similarly, when two "adjacent" R groups are said to "together with the atoms to which they are attached" form a ring, it means that the atom, the intervening bond, and the collective unit of the two R groups are the said ring. For example, when there is the following substructure: and R 1 and R 2 are defined as selected from hydrogen and alkyl, or R 1 and R 2 together with the atoms to which they are attached form an aryl or carbocyclic group, it means that R 1 and R 2 can be selected from hydrogen or alkyl, or the substructure has the following structure: where A is an aryl ring or carbocyclic group containing the indicated double bond.

[0144] Wherever a substituent is described as a diradical (i.e., having two points of attachment to the rest of the molecule), it should be understood that, unless otherwise specified, the substituent can be attached in any orientational configuration. Thus, for example, a substituent described as -AE- or or a substituent including such an orientation such that A is attached at the leftmost point of attachment of the molecule and A is attached at the rightmost point of attachment of the molecule.

[0145] The phrase "therapeutically effective amount" means the amount of a compound or combination of compounds that partially or completely ameliorates, alleviates, or eliminates one or more symptoms of a particular disease or disorder, or prevents, ameliorates, or delays the onset of one or more symptoms of a particular disease or disorder. Such an amount can be administered as a single dose or can be administered according to an effective regimen. Repeated dosing may be required to achieve the desired result (e.g., treatment of a disease and / or disorder).

[0146] The term "pharmaceutically acceptable salts" includes salts of the compounds of Formulas I, II, and III derived from combinations of the compounds of the present embodiments with organic or inorganic acids or bases. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids 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, pyruvic acid, 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-oxobicyclo[2.2.1]heptane-1-methanesulfonic acid, 1,2-ethanedisulfonic acid, dodecylsulfonic acid, salicylic acid, glucoheptonic acid, gluconic acid, glucuronic acid, hippuric acid, hydrochloride hemiethanolic acid, 2-hydroxyethanesulfonic acid, lactic acid, lactobionic acid, methylbromic acid, methylsulfuric acid, 2-naphthalenesulfonic acid, oleic acid, 4,4'-methylenebis-[3-hydroxy-2-naphthoic acid], polygalacturonic acid, stearic acid, sulfosalicylic 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, manganese, aluminum, and the like; particularly preferred are ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts. In some embodiments, treating the compounds disclosed herein with an inorganic base results in the loss of labile hydrogens from the compound to provide a salt form containing an inorganic cation (such as Li + 、Na + 、K + 、Mg 2+ and Ca 2+ etc.). Organic bases from which salts can be derived include, for example, primary amines, secondary amines, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and the like, particularly such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.

[0147] In the case where no number of any given substituent is specified (e.g., "haloalkyl"), one or more substituents may be present. For example, "haloalkyl" can contain one or more of the same or different halogens. For example, "haloalkyl" includes each of the substituents CF3, CHF2, and CH2F.

[0148] The term "patient" refers to an animal being treated, including mammals (such as dogs, cats, cows, horses, sheep, and humans). In some embodiments, the patient is a male or female mammal. In some embodiments, the patient is a male or female human.

[0149] As used herein, the term "prodrug" refers to any compound that, when administered to a biological system, gives rise to a biologically active compound as a result of spontaneous chemical reactions, enzyme-catalyzed chemical reactions, and / or metabolic chemical reactions, or combinations of various reactions. Standard prodrugs are formed using groups linked to functional groups, such as HO-, HS-, HOOC-, HOOPR2- associated with the drug, which cleave in vivo. Standard prodrugs include, but are not limited to, carboxylic acid esters (where the group is alkyl, aryl, aralkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl) and esters of hydroxy, thiol, and amine (where the linked group is acyl, alkoxycarbonyl, aminocarbonyl, phosphate, or sulfate). The groups illustrated are examples and are not exhaustive, and those skilled in the art can prepare other known types of prodrugs. A prodrug must undergo some form of chemical transformation to produce a compound that is biologically active or is a precursor to a biologically active compound. In some cases, the prodrug is biologically active, and its biological activity is generally less than that of the drug itself, and the therapeutic efficacy or safety of the drug is improved by improved oral bioavailability, pharmacodynamic half-life, etc. The prodrug form of a compound can be used, for example, to improve bioavailability, improve the acceptability of an individual (such as by masking or reducing undesirable properties such as bitterness or gastrointestinal irritation), alter solubility (such as for intravenous use), provide extended or sustained release or delivery, improve ease of formulation, or provide site-specific delivery of the compound.

[0150] The term "stereoisomer" refers to the relative or absolute spatial relationship of R groups attached to a stereocenter of a carbon or phosphorus atom and refers to individual isomers or any combination of individual isomers (such as racemic mixtures and mixtures of diastereomers). When a compound has two stereocenters, there are four possible stereoisomers.

[0151] The term "liver" refers to the liver organ.

[0152] The term "liver specificity" refers to the following ratio as measured in an animal treated with the drug or prodrug:

[0153] [Drug or drug metabolite in liver tissue] /

[0154] [Drug or drug metabolite in blood or other tissue]

[0155] This ratio can be determined by measuring tissue levels at a specific time or can be expressed as AUC (area under the curve) based on values measured at three or more time points.

[0156] The term "increased or enhanced liver specificity" refers to an increase in the liver specificity ratio in an animal treated with a prodrug relative to an animal treated with the parent drug.

[0157] The term "enhanced oral bioavailability" refers to an increase in the absorption of at least about 50% of the reference drug dose. In another aspect, the increase in the oral bioavailability of the compound (compared to the reference drug) is at least about 100%, or a doubling of absorption. The measurement of oral bioavailability generally refers to the measurement of a prodrug, drug, or drug metabolite in blood, plasma, tissue, or urine after oral administration compared to the measurement after parenteral administration.

[0158] 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, elevated markers indicative of toxicity, and / or pharmacological side effects).

[0159] The term "sustained delivery" refers to an increase in the period during which a therapeutically effective drug level is prolonged due to the presence of a prodrug.

[0160] The term "treating" or "treatment" of a disease includes inhibiting the disease (slowing or arresting or partially arresting its development), preventing the disease, alleviating the symptoms or side effects of the disease (including palliative treatment), and / or alleviating the disease (causing the disease to regress).

[0161] The term "biological agent" refers to a compound (such as a compound carrying a radioactive isotope or a heavy atom) that has biological activity or molecular properties that can be used for therapeutic or diagnostic purposes.

[0162] The term "molecular pathway" refers to a series of molecular events in a tissue (such as a receptor regulatory sequence, an enzyme regulatory sequence, or a biosynthetic sequence that is involved in the physiological or pathophysiological function of a living animal).

[0163] Administration and Pharmaceutical Compositions

[0164] The disclosed compounds can be used alone or in combination with other therapies. When used in combination with other agents, these compounds can be administered as a daily dose or an appropriate fraction of the daily dose (e.g., twice daily). The compounds can be administered after a course of another agent, during a course of another agent, as part of a treatment regimen, or can be administered prior to treatment with another agent during the course of treatment.

[0165] Examples of pharmaceutically acceptable salts include acetate, adipate, benzenesulfonate, bromide, camphorsulfonate, chloride, citrate, ethanedisulfonate, ethoate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hexaonate, hydrobromide, hydrochloride, iodide, hydroxyethylsulfonate, lactate, lactobionate, maleate, mesylate, methyl bromide, methyl sulfate, naphthalenesulfonate, nitrate, oleate, palmitate, phosphate, polygalacturonate, stearate, succinate, sulfate, sulfosalicylate, tannate, tartrate, terephthalate, tosylate, and triethiodide.

[0166] The composition containing the active ingredient can be in any form suitable for the intended method of administration. In some embodiments, the compounds of the methods and / or compositions described herein can be provided via oral administration, rectal administration, transmucosal administration, intestinal administration, enteral administration, topical administration, transdermal administration, intrathecal administration, intraventricular administration, intraperitoneal administration, intranasal administration, intraocular administration, and / or parenteral administration.

[0167] When the compound is administered orally, tablets, lozenges, troches, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft gelatin capsules, syrups, or elixirs can be prepared, for example. Compositions intended for oral use can be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions can contain one or more substances including sweetening agents, flavoring agents, coloring agents, and preservatives to provide palatable formulations. Tablets containing the active ingredient admixed with non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets are acceptable. These excipients can be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binding agents such as starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets can be uncoated or can be coated by known techniques including microencapsulation to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a delayed release material such as glyceryl monostearate or glyceryl distearate can be used alone or in combination with waxes.

[0168] Preparations for oral use can also be provided as hard gelatin capsules in which the active ingredient can be mixed with an inert solid diluent such as calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient can be mixed with a water or oil medium such as peanut oil, liquid paraffin, or olive oil.

[0169] Preparations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain, for example, antioxidants, buffers, bacteriostatic agents and solutes to render the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickening agents. The preparations may be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and may be stored under lyophilized (freeze-dried) conditions requiring only the immediate addition of a sterile liquid carrier, for example water for injection, prior to use. Injectable solutions and suspensions may be prepared from sterile powders, granules and tablets of the aforedescribed kinds.

[0170] In some embodiments, the unit dose preparation contains the daily dose or unit, daily sub-dose or appropriate fraction thereof of the drug. However, it should be understood that the specific dosage level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs previously administered; and the severity of the particular disease being treated, as is well understood by one of ordinary skill in the art.

[0171] 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 well within the knowledge of one of ordinary skill in the art. In some embodiments, the daily dose may be from about 0.1 mg / kg to about 100 mg / kg or more of body weight, from about 0.25 mg / kg or less to about 50 mg / kg, from about 0.5 mg / kg or less to about 25 mg / kg, from about 1.0 mg / kg to about 10 mg / kg. Thus, for a 70 kg person, the dosage range will be from about 7 mg / day to about 7000 mg / day, from about 35 mg / day or less to about 2000 mg / day or more, from about 70 mg / day to about 1000 mg / day.

[0172] Methods of treatment

[0173] Some embodiments of the invention include methods of treating diseases, conditions or disorders selected from the following: hepatitis, liver cancer, liver fibrosis, fatty liver, malaria, viral infections, parasitic infections, diabetes, hyperlipidemia, atherosclerosis, obesity, dyslipidemia, hyperglycemia, hormonal disorders, HIV and various types of cancer with the compounds and compositions comprising the compounds described herein. Some methods include administering to an individual in need thereof the compounds, compositions, pharmaceutical compositions described herein. In some embodiments, the individual may be an animal, such as a mammal, a human. In some embodiments, the individual is a human.

[0174] Additional embodiments include administering to an individual in need thereof a combination of compounds. The combination may comprise the compounds, compositions, pharmaceutical compositions described herein and other agents.

[0175] Some embodiments include co - administering the compounds, compositions, and / or pharmaceutical compositions described herein with other agents or other therapeutic agents. "Co - administering" means that two or more agents can be found simultaneously in the bloodstream of a patient, regardless of the actual time or manner of administration. In one embodiment, multiple agents are administered simultaneously. In one such embodiment, co - administration is achieved by combining multiple agents in a single dosage form. In another embodiment, multiple agents are administered sequentially. In one embodiment, multiple agents are administered via the same route (e.g., orally). In another embodiment, multiple agents are administered via different routes (e.g., oral administration and intravenous administration).

[0176] Examples of other drugs include therapeutic agents selected from other types of chemotherapeutic drugs (such as cyclophosphamide, methotrexate, doxorubicin, docetaxel, cisplatin, epirubicin, oxaliplatin, and leucovorin); and other targeted anti - tumor agents (such as HDAC inhibitors). In some embodiments, other therapeutic agents for HCC treatment can be one or more of sorafenib, regorafenib, immuno - oncology agents (such as PD - 1 or PD - L1 checkpoint inhibitors).

[0177] To further illustrate the present invention, the following examples are included. Of course, these examples should not be construed as specifically limiting the present invention. Variations of these examples within the scope of the claims are within the capabilities of those skilled in the art and are considered to fall within the scope of the present invention described and claimed herein. The reader will recognize that those skilled in the art of the present invention can prepare and use the present invention without an exhaustive set of examples.

[0178] Synthesis of Compounds

[0179] The following operating instructions for preparing new compounds are for the general procedure for preparing the 5 - fluorouracil - derived acetals and hemiacetal amine ethers compounds.

[0180] Route I describes the general strategy for synthesizing the compounds of formula I. 5 - Fluorouracil (1) reacts with an alkylating agent of structure 2 in the presence of a base to give a product of structure 3, which can further react with a second alkylating agent of structure 4 in the presence of a base to give the final product of structure 5. Alternatively, if the two alkylating agents are the same, fluorouracil can be doubly alkylated in one step to produce the final product of structure 5.

[0181] Route I

[0182]

[0183] In a manner similar to Route I, compounds of Formulas II and IV were synthesized using doxifluridine as the starting material. Route II describes the general strategy for synthesizing compounds of Formulas III and V. Under standard conditions and in the presence of an acid catalyst, doxifluridine (6) was condensed with the aldehyde of Structure 7 to produce the ketal product of Structure 8, which could be further reacted with an alkylating or acylating agent of Structure 9 to obtain the final product of Structure 10.

[0184] Route II

[0185]

[0186] Route III describes the general synthesis of compounds of Formula VI. Fluorouracil (11) was reacted with phosphanediamine (12) in the presence of 4,5-dicyanoimidazole to obtain a cyclic product of Structure 13, and then the crude reaction mixture was treated with an oxidizing agent such as tert-butyl hydroperoxide to obtain the final product of Structure 14.

[0187] Route III

[0188] Examples

[0189] Some compounds of Formulas I, II, III, IV, V, and VI were prepared as described below.

[0190] Example 1

[0191] 1-((Benzyloxy)methyl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 101)

[0192]

[0193] According to Route I, Compound 101 was prepared from chloromethyl benzyl ether and 5-fluorouracil. In the presence of an excess of DIPEA, chloromethyl benzyl ether (1.2 g, 7.7 mmol) was added to a dichloromethane solution of 5-fluorouracil (1.0 g, 7.7 mmol), and the resulting solution was stirred at room temperature overnight. Standard workup was carried out, followed by preparative HPLC to obtain Compound 101 (190 mg, 10%). C 12 H 11 [M-H] of FN2O3 - Calculated: 249.07; Found: 249.1. 1 1H-NMR (CDCl3, 400 MHz) δ 8.22 (bs, 1H), 7.40 - 7.30 (m, 6H), 5.21 (s, 2H), 4.63 (s, 2H).

[0194] Example 2

[0195] 3-((Benzyloxy)methyl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 102)

[0196]

[0197] Compound 102 was isolated from the reaction described in Example 1 in 18% yield. C 12 H 11 [M-H] of FN2O3 - Calculated: 249.07; Found: 249.1. 1 1H-NMR (CDCl3, 400 MHz) δ 9.33 (bs, 1H), 7.40 - 7.28 (m, 5H), 7.23 (d, J = 7.0, 1H), 5.49 (s, 2H), 4.71 (s, 2H).

[0198] Example 3

[0199] 1,3-Bis-((benzyloxy)methyl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 103)

[0200]

[0201] Compound 103 was isolated from the reaction described in Example 1 in 25% yield. C 20 H 19 [M-H] of FN2O4 - Calculated: 369.12; Found: 369.0. 1 1H-NMR (CDCl3, 400 MHz) δ 7.40 - 7.26 (m, 11H), 5.50 (s, 2H), 5.23 (s, 2H), 4.71 (s, 2H), 4.62 (s, 2H).

[0202] Example 4

[0203] 1,3-Bis-((ethoxy)methyl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 104)

[0204]

[0205] Compound 104 was prepared from chloroethyl methyl ether and 5-fluorouracil according to Route I. C 10 H 15 [M+H] of FN2O4 + Calculated: 247.11; Found: 247.1.

[0206] Example 5

[0207] 3-((Benzyloxy)methyl)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-methyltetrahydrofuran-2-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 105)

[0208]

[0209] Compound 105 was prepared from chloromethyl benzyl ether and deoxyfluorouridine according to a method similar to Route I.C 17 H 19 [M+H] of FN2O6 + Calculated value: 367.13; Found value: 367.1.

[0210] Example 6

[0211] 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)

[0212]

[0213] Compound 106 was prepared from chloromethyl benzyl ether and deoxyfluorouridine according to a method similar to Route I.C 25 H 27 [M+H2O] of FN2O7 + Calculated value: 504.19; Found value: 504.2.

[0214] Example 7

[0215] 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)

[0216]

[0217] Compound 107 was prepared from chloromethyl benzyl ether and deoxyfluorouridine according to a method similar to Route I.C 25 H 27 [M+H2O] of FN2O7 + Calculated value: 504.19; Found value: 504.2.

[0218] Example 8

[0219] 1-((2R,3R,4R,5R)-3-(Ethoxymethoxy)-4-hydroxy-5-methyltetrahydrofuran-2-yl)-3-(ethoxymethyl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 108)

[0220]

[0221] Compound 108 was prepared from chloromethyl ethyl ether and deoxyfluorouridine according to a method similar to Route I. 1 1H-NMR (CDCl3, 400 MHz) δ 7.41 (d, J = 6.0, 1H), 5.84 (s, 1H), 5.45 (d, J = 10.0, 1H), 5.41 (d, J = 10.0, 1H), 4.97 (d, J = 6.8, 1H), 4.88 (d, J = 6.8, 1H), 4.18 (dd, J = 5.6 and 2.0, 1H), 4.11 - 4.01 (m, 1H), 3.75 - 3.60 (m, 5H), 2.85 (d, J = 8.4, 1H), 1.47 (d, J = 6.0, 3H), 1.22 (t, J = 7.2, 6H).

[0222] Example 9

[0223] 1-((2R,3R,4R,5R)-4-(Ethoxymethoxy)-3-hydroxy-5-methyltetrahydrofuran-2-yl)-3-(ethoxymethyl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 109)

[0224]

[0225] Compound 109 was prepared from chloromethyl ethyl ether and deoxyfluorouridine according to a method similar to Route I. 1 1H-NMR (CDCl3, 400 MHz) δ 7.41 (d, J = 6.4, 1H), 5.74 (d, J = 3.6, 1H), 5.44 (d, J = 11.2, 1H), 5.41 (d, J = 11.2, 1H), 4.81 (d, J = 6.8, 1H), 4.77 (d, J = 6.8, 1H), 4.24 - 4.20 (m, 2H), 3.83 (t, J = 6.0, 1H), 3.72 - 3.65 (m, 4H), 1.44 (d, J = 6.4, 3H), 1.24 (t, J = 7.2, 3H), 1.22 (d, J = 7.2, 3H).

[0226] Example 10

[0227] (1-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methyltetrahydrofuran-2-yl)-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl)(ethoxymethyl)carbamic acid pentyl ester (Compound 110)

[0228]

[0229] Compound 110 was prepared from chloromethyl ethyl ether and capecitabine according to a method similar to Route I. 1 1H-NMR (CDCl3, 400 MHz) δ 7.97 (d, J = 6.4, 1H), 5.69 (d, J = 4.4, 1H), 5.37 (d, J = 10.4, 1H), 5.33 (d, J = 10.4, 1H), 4.45 - 4.35 (m, 1H), 4.30 - 4.20 (m, 3H), 3.91 (t, J = 4.4, 1H), 3.65 (q, J = 6.8, 2H), 1.70 - 1.64 (m, 2H), 1.40 (d, J = 6.4, 3H), 1.35 - 1.30 (m, 4H), 1.18 (t, J = 6.8, 3H), 0.90 (t, J = 6.8, 3H).

[0230] Example 11

[0231] (1-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methyltetrahydrofuran-2-yl)-3-(ethoxymethyl)-5-fluoro-2-oxo-2,3-dihydropyrimidin-4(1H)-ylidene)carbamic acid pentyl ester (Compound 111)

[0232]

[0233] Compound 111 was prepared from chloromethyl ethyl ether and capecitabine according to a method similar to Route I. 1 1H-NMR (CDCl3, 400 MHz) δ 7.37 (d, J = 7.2, 1H), 5.57 (d, J = 3.2, 1H), 5.51 (d, J = 9.6, 1H), 5.46 (d, J = 9.6, 1H), 4.35 - 4.25 (m, 1H), 4.25 - 4.15 (m, 4H), 3.92 - 3.88 (m, 1H), 3.73 (q, J = 6.8, 2H), 3.0 (d, J = 4.4, 1H), 1.75 - 1.66 (m, 2H), 1.40 (d, J = 6.4, 3H), 1.43 - 1.35 (m, 4H), 1.23 (t, J = 7.2, 3H), 0.93 (t, J = 7.2, 3H).

[0234] Example 12

[0235] Pentyl ((1-((3aR,4R,6R,6aR)-2,6-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl)carbamate (Compound 112)

[0236]

[0237] Compound 112 was prepared from acetaldehyde and capecitabine according to the method described in Route II.C 17 H 24 [M+1] of FN3O6 + Calculated value: 386.17; Found value: 386.1.

[0238] Example 13

[0239] 1-((3aR,4R,6R,6aR)-2-(3,5-Dimethylphenyl)-6-methyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 113)

[0240]

[0241] Compound 113 was prepared from 3,5-dimethylbenzaldehyde and capecitabine according to the method described in Route II and isolated as a 3:1 mixture of two stereoisomers.C 18 H 19 [M+1] of FN2O5 + Calculated value: 363.14; Found value: 363.1.

[0242] Example 14

[0243] 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)

[0244]

[0245] Compound 114 was prepared from benzo[d][1,3]dioxole-5-carbaldehyde and capecitabine according to the method described in Route II and isolated as a 3:1 mixture of two stereoisomers.C 17 H 15 [M+1] of FN2O7 + Calculated value: 379.1; Found value: 379.0.

[0246] Example 15

[0247] 1 - ((3aR,4R,6R,6aR)-2-(2-(4-Ethyl-1,3-dioxolan-2-yl)phenyl)-6-methyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 115)

[0248]

[0249] Compound 115 was prepared from 2-(4-Ethyl-1,3-dioxolan-2-yl)benzaldehyde and capecitabine according to the method described in Route II and isolated as a mixture of stereoisomers. C 21 H 23 [M+1] of FN2O7 + Calculated value: 435.16; Measured value: 435.1.

[0250] Example 16

[0251] 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 116)

[0252]

[0253] Compound 116 was prepared from 4-Hydroxybenzaldehyde and capecitabine according to the method described in Route II and isolated as a 6:1 mixture of 2 stereoisomers. C 16 H 15 [M+1] of FN2O6 + Calculated value: 351.1; Measured value: 351.0.

[0254] Example 17

[0255] 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)

[0256]

[0257] Compound 117 was prepared from chloromethyl ethyl ether, 4-Hydroxybenzaldehyde and capecitabine according to the method described in Route II and isolated as a mixture of 2 stereoisomers. C 19 H 21 [M+1] of FN2O7+ Calculated value: 409.14; Measured value: 409.1.

[0258] Example 18

[0259] 5-Fluoro-1-((3aR,4R,6R,6aR)-2-(4-methoxyphenyl)-6-methyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)pyrimidine-2,4(1H,3H)-dione (Compound 118)

[0260]

[0261] Compound 118 was prepared from 4-methoxybenzaldehyde and capecitabine according to the method described in Route II and isolated as a mixture of 2 stereoisomers. C 17 H 17 [M+1] of FN2O6 + Calculated value: 365.12; Measured value: 365.1.

[0262] Example 19

[0263] 4-((3aR,4R,6R,6aR)-4-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-6-methyltetrahydrofuro[3,4-d][1,3]dioxol-2-yl)phenyl isobutyrate (Compound 119)

[0264]

[0265] Compound 119 was prepared from 4-hydroxybenzaldehyde, capecitabine and isobutyric acid according to the method described in Route II and isolated as a mixture of 2 stereoisomers. C 20 H 21 [M+1] of FN2O7 + Calculated value: 421.24; Measured value: 421.1.

[0266] Example 20

[0267] 1-((3aR,4R,6R,6aR)-2-(4-(ethoxymethoxy)phenyl)-6-methyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 120)

[0268]

[0269] Compound 120 was prepared from 4-methoxybenzaldehyde, capecitabine and chloromethyl ethyl ether according to the method described in Route II and isolated as a mixture of 2 stereoisomers.1 1H-NMR (CDCl3, 400 MHz): δ 7.41 - 7.36 (m, 3H), 6.85 (d, J = 8.4, 2H), 5.93 (s, 1H), 5.75 (d, J = 2.4, 1H), 1.47 (d, J = 10, 3H).

[0270] Example 21

[0271] 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)

[0272]

[0273] Compound 121 can be prepared from 4-methoxybenzaldehyde and fluorouracil according to the method described in Route II.

[0274] Example 22

[0275] 5-Fluoro-1-((4aR,6R,7aS)-2-oxido-2-phenoxytetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 122)

[0276]

[0277] Compound 122 was prepared from N,N,N',N'-tetraisopropyl-1-phenoxyphosphorodiamide and fluorouracil according to the method described in Route III and isolated as a mixture of two stereoisomers. C 15 H 14 [M+1] of FN2O7P + Calculated: 385.06; Found: 385.0.

[0278] Example 23

[0279] 5-Fluoro-1-((2S,4aR,6R,7aS)-2-oxido-2-phenoxytetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 123)

[0280]

[0281] Compound 123 was separated from Compound 122 by HPLC.

[0282] Example 24

[0283] 5-Fluoro-1-((2R,4aR,6R,7aS)-2-oxido-2-phenoxytetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinine-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 124)

[0284]

[0285] Compound 124 was separated from Compound 122 by HPLC.

[0286] Example 25

[0287] 5-Fluoro-1-((4aR,6R,7aS)-2-oxido-2-(4-chlorophenoxy)tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinine-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 125)

[0288]

[0289] Compound 125 was prepared from N,N,N',N'-tetraisopropyl-1-(4-chlorophenoxy)phosphorodiamidite and fluorouracil according to the method described in Route III and isolated as a single isomer. 1 1H-NMR (MeOD, 400 MHz) 7.92 (d, J = 6.4, 1H), 7.43 (dd, J = 6.8 and 1.2, 2H), 7.32 (dd, J = 7.6 and 1.2, 2H), 6.26 (dd, J = 7.6 and 3.5, 1H).

[0290] Example 26

[0291] 1-((4aR,6R,7aS)-2-(Benzyloxy)-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinine-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 126)

[0292]

[0293] Compound 126 was prepared from N,N,N',N'-tetraisopropyl-1-benzyloxyphosphorodiamidite and fluorouracil according to the method described in Route III and isolated as a mixture of two isomers. C 16 H 16 [M+1] of FN2O7P + Calculated: 399.08; Found: 399.0.

[0294] Example 27

[0295] 1-((4aR,6R,7aS)-2-(4-chlorobenzyloxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 127)

[0296]

[0297] Compound 127 was prepared from N,N,N',N'-tetraisopropyl-1-(4-chlorobenzyloxy)phosphorodiamidite and fluorouracil according to the method described in Route III and isolated as a single isomer (absolute stereochemistry not assigned). C 16 H 15 [M+1] of ClFN2O7P + Calculated: 433.04; Found: 433.0.

[0298] Example 28

[0299] 5-Fluoro-1-((4aR,6R,7aS)-2-(naphthalen-1-ylmethoxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 128)

[0300]

[0301] Compound 128 was prepared from N,N,N',N'-tetraisopropyl-1-(naphthalen-1-ylmethoxy)phosphorodiamidite and fluorouracil according to the method described in Route III and isolated as a single isomer (absolute stereochemistry not assigned). C 20 H 18 [M-1] of FN2O7P + Calculated: 447.07; Found: 447.1.

[0302] Example 29

[0303] 1-((4aR,6R,7aS)-2-(3-chlorobenzyloxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 129)

[0304]

[0305] Compound 129 was prepared from N,N,N',N'-tetraisopropyl-1-(3-chlorobenzyloxy)phosphorodiamidite and fluorouracil according to the method described in Route III and isolated as a mixture of two isomers. C 16 H 15[M-1] of ClFN2O7P + Calculated value: 431.02; Measured value: 431.0.

[0306] Example 30

[0307] 1-((4aR,6R,7aS)-2-(2-Chlorobenzyloxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 130)

[0308]

[0309] Compound 130 was prepared from N,N,N',N'-tetraisopropyl-1-(2-chlorobenzyloxy)phosphorodiamide and fluorouracil according to the method described in Route III and isolated as a mixture of two isomers. C 16 H 15 [M-1] of ClFN2O7P + Calculated value: 431.02; Measured value: 431.0.

[0310] Example 31

[0311] 5-Fluoro-1-((4aR,6R,7aS)-2-(hexyloxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 131)

[0312]

[0313] Compound 131 was prepared from N,N,N',N'-tetraisopropyl-1-hexyloxyphosphorodiamide and fluorouracil according to the method described in Route III and isolated as a mixture of two isomers. C 15 H 20 [M-1] of FN2O7P + Calculated value: 391.10; Measured value: 391.0.

[0314] Example 32

[0315] 5-Fluoro-1-((4aR,6R,7aS)-2-(nonyloxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 132)

[0316]

[0317] Compound 132 was prepared from N,N,N',N'-tetraisopropyl-1-nonyloxyphosphorodiamide and fluorouracil according to the method described in Route III and isolated as a mixture of two isomers. C 18 H 28 [M-1] of FN2O7P + Calculated value: 433.15; Measured value: 433.1.

[0318] Example 33

[0319] 5-Fluoro-1-((4aR,6R,7aS)-2-(non-5-yloxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 133)

[0320]

[0321] Compound 133 was prepared from N,N,N',N'-tetraisopropyl-1-(non-5-yloxy)phosphorodiamide and fluorouracil according to the method described in Route III and isolated as a mixture of two isomers. C 18 H 28 [M-1] of FN2O7P + Calculated value: 433.15; Measured value: 433.1.

[0322] Example 34

[0323] 3-(((4aR,6R,7aS)-6-(5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-2-yl)oxy)propanenitrile (Compound 134)

[0324]

[0325] Compound 134 was prepared from N,N,N',N'-tetraisopropyl-1-(2-cyanoethoxy)phosphorodiamide and fluorouracil according to the method described in Route III and isolated as a single isomer (absolute stereochemistry not labeled). C 12 H 13 [M+1] of FN3O7P + Calculated value: 362.06; Measured value: 362.0.

[0326] Example 35

[0327] 5-Fluoro-1-((4aR,6R,7aS)-2-oxo-2-(((S)-4-(prop-1-en-2-yl)cyclohex-1-en-1-yl)methoxy)tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinane-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 135)

[0328]

[0329] Compound 135 was prepared from (S)-N,N,N',N'-tetraisopropyl-1-((4-(prop-1-en-2-yl)cyclohex-1-en-1-yl)methoxy)phosphorodiamidite and fluorouracil according to the method described in Route III and isolated as a mixture of two isomers. C 15 H 20 [M−1] of FN2O7P + Calculated: 441.12; Found: 441.1.

[0330] Example 36

[0331] 1-((4aR,6R,7aS)-2-(4-Fluorobenzyloxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinane-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 136)

[0332]

[0333] Compound 136 was prepared from N,N,N',N'-tetraisopropyl-1-(4-fluorobenzyloxy)phosphorodiamidite and fluorouracil according to the method described in Route III and isolated as a mixture of two isomers. C 16 H 15 [M−1] of F2N2O7P + Calculated: 415.05; Found: 415.0.

[0334] Example 37

[0335] 1-((4aR,6R,7aS)-2-(3,4-Difluorobenzyloxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinane-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 137)

[0336]

[0337] Compound 137 was prepared from N,N,N',N'-tetraisopropyl-1-(3,4-difluorobenzyloxy)phosphorodiamidite and fluorouracil according to the method described in Route III and isolated as a mixture of two isomers. C 16 H 14 [M+1] of F3N2O7P + Calculated value: 435.06; Found value: 435.0.

[0338] Example 38

[0339] 1-((4aR,6R,7aS)-2-(2,4-Difluorobenzyloxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 138)

[0340]

[0341] Compound 138 was prepared from N,N,N',N'-tetraisopropyl-1-(2,4-difluorobenzyloxy)phosphorodiamidite and fluorouracil according to the method described in Route III and isolated as a mixture of two isomers. C 16 H 14 [M-1] of F3N2O7P + Calculated value: 433.04; Found value: 433.0.

[0342] Example 39

[0343] 1-((4aR,6R,7aS)-2-(2-Fluorobenzyloxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 139)

[0344]

[0345] Compound 139 was prepared from N,N,N',N'-tetraisopropyl-1-(2-fluorobenzyloxy)phosphorodiamidite and fluorouracil according to the method described in Route III and isolated as a mixture of two isomers. [M-1] of C16H15F2N2O7P + Calculated value: 415.05; Found value: 415.0.

[0346] Example 40

[0347] 5-Fluoro-1-((2S,4aR,6R,7aS)-2-((2-fluorobenzyl)oxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 140)

[0348]

[0349] Compound 140 was isolated from Compound 139 by HPLC.

[0350] Example 41

[0351] 5-Fluoro-1-((2R,4aR,6R,7aS)-2-((2-fluorobenzyl)oxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 141)

[0352]

[0353] Compound 141 was isolated from Compound 139 by HPLC.

[0354] Example 42

[0355] 1-((4aR,6R,7aS)-2-(4-chloro-2-fluorobenzyloxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 142)

[0356]

[0357] Compound 142 was prepared from N,N,N',N'-tetraisopropyl-1-(4-chloro-2-fluorobenzyloxy)phosphorodiamidite and fluorouracil according to the method described in Route III and isolated as a mixture of two isomers. C 16 H 14 [M-1] of ClF2N2O7P + Calculated: 449.01; Found: 449.0.

[0358] Example 43

[0359] 1-((4aR,6R,7aS)-2-(2-chloro-4-fluorobenzyloxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 143)

[0360]

[0361] Compound 143 was prepared from N,N,N',N'-tetraisopropyl-1-(2-chloro-4-fluorobenzyloxy)phosphorodiamidite and fluorouracil according to the method described in Route III and isolated as a mixture of two isomers. C 16 H 14 [M-1] of ClF2N2O7P + Calculated: 449.01; Found: 449.0.

[0362] Example 44

[0363] 1-((4aR,6R,7aS)-2-(2,4,6-Trifluorobenzyloxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 144)

[0364]

[0365] Compound 144 was prepared from N,N,N',N'-tetraisopropyl-1-(2,4,6-trifluorobenzyloxy)phosphorodiamidite and fluorouracil according to the method described in Route III and isolated as a mixture of two isomers. C 16 H 13 [M-1] of F4N2O7P + Calculated: 451.03; Found: 451.0.

[0366] Example 45

[0367] 5-Fluoro-1-((2S,4aR,6R,7aS)-2-oxo-2-((2,4,6-trifluorobenzyl)oxy)tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 145)

[0368]

[0369] Compound 145 was separated from Compound 144 by HPLC.

[0370] Example 46

[0371] 5-Fluoro-1-((2R,4aR,6R,7aS)-2-oxo-2-((2,4,6-trifluorobenzyl)oxy)tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 146)

[0372]

[0373] Compound 146 was separated from Compound 144 by HPLC.

[0374] Example 47

[0375] 1 - ((4aR,6R,7aS)-2-(4-Ethylbenzyloxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 147)

[0376]

[0377] Compound 147 was prepared from N,N,N',N'-tetraisopropyl-1-(4-ethylbenzyloxy)phosphorodiamidite and fluorouracil according to the method described in Route III and isolated as a mixture of two isomers. C 18 H 20 [M - 1] of FN2O7P + Calculated: 425.09; Found: 424.75.

[0378] Example 48

[0379] 1 - ((4aR,6R,7aS)-2-(4-Isopropylbenzyloxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 148)

[0380]

[0381] Compound 148 was prepared from N,N,N',N'-tetraisopropyl-1-(4-isopropylbenzyloxy)phosphorodiamidite and fluorouracil according to the method described in Route III and isolated as a mixture of two isomers. C 19 H 22 [M + 1] of FN2O7P + Calculated: 439.10; Found: 439.1.

[0382] Example 49

[0383] 1 - ((4aR,6R,7aS)-2-(4-tert-Butylbenzyloxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 149)

[0384]

[0385] Compound 149 was prepared from N,N,N',N'-tetraisopropyl-1-(4-tert-butylbenzyloxy)phosphorodiamidite and fluorouracil according to the method described in Route III and isolated as a mixture of two isomers. C 20 H 24 [M-1] of FN2O7P + Calculated value: 453.12; Found value: 453.1.

[0386] Example 50

[0387] 1-((4aR,6R,7aS)-2-(3,5-Dimethylbenzyloxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 150)

[0388]

[0389] Compound 150 was prepared from N,N,N',N'-tetraisopropyl-1-(3,5-dimethylbenzyloxy)phosphorodiamidite and fluorouracil according to the method described in Route III and isolated as a mixture of two isomers. C 18 H 20 [M-1] of FN2O7P + Calculated value: 425.09; Found value: 425.0.

[0390] Example 51

[0391] 1-((4aR,6R,7aS)-2-(2,4-Dichlorobenzyloxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 151)

[0392]

[0393] Compound 151 was prepared from N,N,N',N'-tetraisopropyl-1-(2,4-dichlorobenzyloxy)phosphorodiamidite and fluorouracil according to the method described in Route III and isolated as a mixture of two isomers. C 16 H 14 [M-1] of Cl2FN2O7P + Calculated value: 464.97; Found value: 464.9.

[0394] Example 52

[0395] 1-((4aR,6R,7aS)-2-(2,6-dichlorobenzyloxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 152)

[0396]

[0397] Compound 152 was prepared from N,N,N',N'-tetraisopropyl-1-(2,6-dichlorobenzyloxy)phosphorodiamidite and fluorouracil according to the method described in Route III and isolated as a mixture of two isomers. C 16 H 14 [M+1] of Cl2FN2O7P + Calculated: 466.99; Found: 466.9.

[0398] Example 53

[0399] 1-((4aR,6R,7aS)-2-(2,6-difluorobenzyloxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 153)

[0400]

[0401] Compound 153 was prepared from N,N,N',N'-tetraisopropyl-1-(2,6-difluorobenzyloxy)phosphorodiamidite and fluorouracil according to the method described in Route III and isolated as a mixture of two isomers. C 16 H 14 [M-1] of F3N2O7P + Calculated: 433.04; Found: 433.0.

[0402] Example 54

[0403] 1-((4aR,6R,7aS)-2-(3-fluorobenzyloxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 154)

[0404]

[0405] Compound 154 was prepared from N,N,N',N'-tetraisopropyl-1-(3-fluorobenzyloxy)phosphorodiamidite and fluorouracil according to the method described in Route III and isolated as a mixture of two isomers. C 16 H 15[M-1] of F2N2O7P + Calculated value: 415.05; Measured value: 415.0.

[0406] Example 55

[0407] 1-((4aR,6R,7aS)-2-(2-Fluoro-5-methoxybenzyloxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 155)

[0408]

[0409] Compound 155 was prepared from N,N,N',N'-tetraisopropyl-1-(2-fluoro-5-methoxybenzyloxy)phosphorodiamide and fluorouracil according to the method described in Route III and isolated as a mixture of two isomers. C 17 H 17 [M-1] of F2N2O8P + Calculated value: 445.06; Measured value: 445.0.

[0410] Example 56

[0411] 5-Fluoro-1-((4aR,6R,7aS)-2-oxo-2-((4-(trifluoromethyl)benzyl)oxy)tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 156)

[0412]

[0413] Compound 156 was prepared from N,N,N',N'-tetraisopropyl-1-((4-(trifluoromethyl)benzyloxy)phosphorodiamide and fluorouracil according to the method described in Route III and isolated as a mixture of two isomers. C 17 H 15 [M-1] of F4N2O7P + Calculated value: 465.05; Measured value: 464.9.

[0414] Example 57

[0415] 1-((2R,4aR,6R,7aS)-2-((4-Ethylbenzyl)amino)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 157)

[0416]

[0417] Compound 157 was prepared from N,N,N',N'-tetraisopropyl-1-((4-ethylbenzylamino)phosphonic diamide and floxuridine according to the method described in Route III. C 18 H 21 [M+1] of FN3O6P + Calculated value: 426.13; Measured value: 426.2.

[0418] Example 58

[0419] 1-((2S,4aR,6R,7aS)-2-((4-ethylbenzyl)amino)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 158)

[0420]

[0421] Compound 158 was isolated from the reaction of Compound 157. C 18 H 21 [M+1] of FN3O6P + Calculated value: 426.13; Measured value: 426.2.

[0422] Example 59

[0423] 1-((2R,4aR,6R,7aS)-2-((2,4-difluorobenzyl)amino)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 159)

[0424]

[0425] Compound 159 was prepared from N,N,N',N'-tetraisopropyl-1-((2,4-difluorobenzylamino)phosphonic diamide and floxuridine according to the method described in Route III. C 16 H 15 [M+1] of F3N3O6P + Calculated value: 434.08; Measured value: 434.25.

[0426] Example 60

[0427] 1-((2S,4aR,6R,7aS)-2-((2,4-difluorobenzyl)amino)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 160)

[0428]

[0429] Compound 160 was isolated as the minor isomer. C 16 H 15 [M+1] of F3N3O6P + Calculated value: 434.08; Measured value: 434.25.

[0430] Example 61

[0431] 1-((4aR,6R,7aS)-2-(3,5-difluorobenzyloxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 161)

[0432]

[0433] Compound 161 was prepared from N,N,N',N'-tetraisopropyl-1-(3,5-difluorobenzyloxy)phosphorodiamidite and fluorouracil according to the method described in Route III and isolated as a mixture of two isomers. C 16 H 14 [M-1] of F3N2O7P + Calculated value: 433.04; Measured value: 433.0.

[0434] Example 62

[0435] 1-((4aR,6R,7aS)-2-(2,3,4,5,6-pentafluorobenzyloxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 162)

[0436]

[0437] Compound 162 was prepared from N,N,N',N'-tetraisopropyl-1-(2,3,4,5,6-pentafluorobenzyloxy)phosphorodiamidite and fluorouracil according to the method described in Route III and isolated as a mixture of two isomers. C 16 H 11 [M-1] of F6N2O7P + Calculated value: 487.01; Measured value: 487.0.

[0438] Example 63

[0439] 1-((4aR,6R,7aS)-2-(2,3,4-Trifluorobenzyloxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 163)

[0440]

[0441] Compound 163 was prepared from N,N,N',N'-tetraisopropyl-1-(2,3,4-trifluorobenzyloxy)phosphorodiamidite and fluorouracil according to the method described in Route III and isolated as a mixture of two isomers. C 16 H 13 [M-1] of F4N2O7P + Calculated: 451.03; Found: 451.0.

[0442] Example 64

[0443] 1-((4aR,6R,7aS)-2-(2,4,5-Trifluorobenzyloxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 164)

[0444]

[0445] Compound 164 was prepared from N,N,N',N'-tetraisopropyl-1-(2,4,5-trifluorobenzyloxy)phosphorodiamidite and fluorouracil according to the method described in Route III and isolated as a mixture of two isomers. C 16 H 13 [M+1] of F4N2O7P + Calculated: 453.05; Found: 453.0.

[0446] Example 65

[0447] 5-Fluoro-1-((4aR,6R,7aS)-2-(propoxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 165)

[0448]

[0449] Compound 165 was prepared from N,N,N',N'-tetraisopropyl-1-propoxyphosphorodiamidite and fluorouracil according to the method described in Route III and isolated as a mixture of two isomers. C 12 H 16[M-1] of FN2O7P + Calculated value: 349.06; Measured value: 349.0.

[0450] Example 66

[0451] 5-Fluoro-1-((4aR,6R,7aS)-2-(2,2,3,3,3-pentafluoropropoxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 166)

[0452]

[0453] Compound 166 was prepared from N,N,N',N'-tetraisopropyl-1-(2,2,3,3,3-pentafluoropropoxy)phosphorodiamide and fluorouracil according to the method described in Route III and isolated as a mixture of two isomers. C 12 H 11 [M-1] of F6N2O7P + Calculated value: 439.01; Measured value: 439.0.

[0454] Example 67

[0455] 1-((4aR,6R,7aS)-2-(2-(diethoxymethyl)phenoxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 167)

[0456]

[0457] Compound 167 was prepared from N,N,N',N'-tetraisopropyl-1-(2-diethoxymethylphenoxy)phosphorodiamide and fluorouracil according to the method described in Route III and isolated as a mixture of 2 stereoisomers. C 20 H 24 [M-1] of FN2O9P + Calculated value: 485.11; Measured value: 485.1.

[0458] Example 68

[0459] 5-Fluoro-1-((4aR,6R,7aS)-2-(2-fluorophenoxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 168)

[0460]

[0461] Compound 168 was prepared from N,N,N',N'-tetraisopropyl-1-(2-fluorophenoxy)phosphorodiamidite and fluorouracil according to the method described in Route III, and isolated as a mixture of two stereoisomers. C 15 H 13 [M-1] of F2N2O7P + Calculated value: 401.03; Measured value: 401.1.

[0462] Example 69

[0463] (((4aR,6R,7aS)-6-(5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-2-yl)oxy)methyl pivalate (Compound 169)

[0464]

[0465] Compound 169 was prepared from iodomethyl pivalate and fluorouracil according to a known method, and isolated as a mixture of two stereoisomers. C 15 H 20 [M-1] of FN2O9P + Calculated value: 421.08; Measured value: 421.1.

[0466] Example 70

[0467] 1-((4aR,6R,7aS)-2-((4-(Ethoxymethoxy)benzyl)oxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 170)

[0468]

[0469] Compound 170 was prepared from N,N,N',N'-tetraisopropyl-1-(4-ethoxymethoxybenzyloxy)phosphorodiamidite and fluorouracil according to the method described in Route III, and isolated as a mixture of two stereoisomers. C 19 H 22 [M-1] of FN2O9P + Calculated value: 471.09; Measured value: 471.2.

[0470] Example 71

[0471] 1-((4aR,6R,7aS)-2-(Benzo[d][1,3]dioxol-5-ylmethoxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 171)

[0472]

[0473] Compound 171 was prepared from N,N,N',N'-tetraisopropyl-1-(benzo[d][1,3]dioxol-5-ylmethoxy)phosphorodiamidite and fluorouracil according to the method described in Route III and isolated as a mixture of 2 stereoisomers. C 17 H 16 [M-1] of FN2O9P + Calculated value: 441.05; Measured value: 441.1.

[0474] Example 72

[0475] 1-((4aR,6R,7aS)-2-((2-(1,3-Dioxolan-2-yl)benzyl)oxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 172)

[0476]

[0477] Compound 172 was prepared from N,N,N',N'-tetraisopropyl-1-(2-(1,3-dioxolan-2-yl)benzyloxy)phosphorodiamidite and fluorouracil according to the method described in Route III and isolated as a mixture of 2 stereoisomers. C 19 H 20 [M-1] of FN2O9P + Calculated value: 469.08; Measured value: 469.1.

[0478] Example 73

[0479] 1-((4aR,6R,7aS)-2-(Cyclohexyloxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 173)

[0480]

[0481] According to the method described in Route III, compound 173 was prepared from N,N,N',N'-tetraisopropyl-1-cyclohexyloxyphosphorodiamide and fluorouracil and isolated as a mixture of two stereoisomers. C 15 H 20 [M-1] of FN2O7P + Calculated value: 389.09; Found value: 389.1.

[0482] Example 74

[0483] 5-Fluoro-1-((4aR,6R,7aS)-2-isopropoxy-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 174)

[0484]

[0485] According to the method described in Route III, compound 174 was prepared from N,N,N',N'-tetraisopropyl-1-isopropoxyphosphorodiamide and fluorouracil and isolated as a mixture of two stereoisomers. C 12 H 16 [M-1] of FN2O7P + Calculated value: 349.06; Found value: 349.0.

[0486] Example 75

[0487] 1-((4aR,6R,7aS)-2-(Cyclohexylmethoxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 175)

[0488]

[0489] According to the method described in Route III, compound 175 was prepared from N,N,N',N'-tetraisopropyl-1-cyclohexylmethoxyphosphorodiamide and fluorouracil and isolated as a mixture of two stereoisomers. C 16 H 22 [M-1] of FN2O7P + Calculated value: 403.10; Found value: 403.1.

[0490] Example 76

[0491] 1-((4aR,6R,7aS)-2-(Pentyloxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 176)

[0492]

[0493] Compound 176 was prepared from N,N,N',N'-tetraisopropyl-1-pentyloxyphosphorodiamidite and fluorouracil according to the method described in Route III and isolated as a mixture of two stereoisomers. C 14 H 20 [M-1] of FN2O7P + Calculated: 377.09; Found: 377.1.

[0494] Example 77

[0495] 1-((4aR,6R,7aS)-2-(2-Phenylethoxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphorin-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 177)

[0496]

[0497] Compound 177 was prepared from N,N,N',N'-tetraisopropyl-1-(2-phenylethoxy)phosphorodiamidite and fluorouracil according to the method described in Route III and isolated as a mixture of two stereoisomers. C 17 H 18 [M-1] of FN2O7P + Calculated: 411.07; Found: 411.1.

[0498] Example 78

[0499] 1-((3aR,4R,6R,6aR)-2-(6-Chlorobenzo[d][1,3]dioxol-5-yl)-6-methyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 178)

[0500]

[0501] Compound 178 was prepared from 4-chloro-5-formylbenzo[d][1,3]dioxole and capecitabine according to the method described in Route II and isolated as a 1:1 mixture of two stereoisomers. C 17 H 14[M+1] of ClFN2O7 + Calculated value: 413.06; Measured value: 413.0.

[0502] Example 79

[0503] 1 - ((3aR,4R,6R,6aR)-2-(6-Fluorobenzo[d][1,3]dioxol-5-yl)-6-methyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 179)

[0504]

[0505] Compound 179 was prepared from benzo[d][1,3]dioxole-4-fluoro-5-carbaldehyde and capecitabine according to the method described in Route II and isolated as a 1:1 mixture of two stereoisomers. C 17 H 14 [M-1] of F2N2O7 + Calculated value: 395.07; Measured value: 394.9.

[0506] Example 80

[0507] 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)

[0508]

[0509] Compound 180 was prepared from benzo[d][1,3]dioxole-4-methyl-5-carbaldehyde and capecitabine according to the method described in Route II and isolated as a 3:2 mixture of two stereoisomers. C 17 H 14 F2N2O7's [M-1] + Calculated value: 395.07; Measured value: 394.9.

[0510] Example 81

[0511] 1 - ((2R,3R,4S,5R)-4-(Ethoxymethoxy)-3-hydroxy-5-methyltetrahydrofuran-2-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 181)

[0512]

[0513] Compound 181 was prepared from chloromethyl ethyl ether and deoxyfluorouracil according to a method similar to Route I. C 12 H 17 [M-1] of FN2O6 + Calculated value: 303.10; Measured value: 303.0.

[0514] Example 82

[0515] 1-((2R,3R,4S,5R)-3-(Ethoxymethoxy)-4-hydroxy-5-methyltetrahydrofuran-2-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 182)

[0516]

[0517] Compound 182 was isolated from the reaction described in Example 49. C 12 H 17 [M-1] of FN2O6 + Calculated value: 303.10; Measured value: 303.0.

[0518] Biological Example

[0519] Examples using the method include the following. It should be understood that the following are examples and the method is not limited to these examples.

[0520] Example A: Tissue distribution after oral administration of a reference compound and the disclosed compound

[0521] The liver specificity of the disclosed compound was compared to the corresponding active compound in the liver and other organs that may be toxicity targets.

[0522] Method:

[0523] A reference compound and the acetal and hemiaminal compounds were administered to fasted rats via oral gavage at 5 - 50 mg / kg. Plasma concentrations of metabolites and parent compounds in the circulation and hepatic portal vein were determined by HPLC-UV, and concentrations in the liver, small intestine, and other organs were determined by LC-MS using standard chromatography.

[0524] Results:

[0525] Table 1 provides the results for selected new compounds, which demonstrate the liver targeting of the acetal and hemiaminal compounds and provide evidence that the compound has improved efficiency in liver targeting compared to other types of compounds and achieves a high level of activity in the liver. This can only be achieved through the efficient liver targeting provided by the acetal and hemiaminal compounds.

[0526] Table 1. Drug and metabolite levels in liver and blood 1 hour after oral administration of the selected compounds to rats at a dose of 5 mg / kg.

[0527] Compound <![CDATA[Drug 肝脏 (ng / g)]]> <![CDATA[Drug 血液 (ng / mL)]]> <![CDATA[Metabolite 肝脏 (ng / g)]]> <![CDATA[Metabolite 血液 (ng / mL)]]> 109 373 83.9 49.8 122 116 978 1,346 147 427 118 1,224 3,680 62.3 158 122 1,980 301 109 3.73 127 <6 7.81 1,141 47.9 132 1,366 59.9 327 <4 139 <6 11.3 1,534 34.0 147 <6 <1 135 1.96 156 <6 3.66 661 14.6

[0528] All numbers representing amounts of ingredients, reaction conditions, etc. used in the specification should be understood to be modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth herein are approximations that can vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of any claims in any application claiming priority to this application, each numerical parameter should be construed in light of the number of significant digits and by applying ordinary rounding techniques.

[0529] The language of degree used herein (such as the terms "approximate", "about", "generally", and "substantially" as used herein) means a value, quantity, or property that is close to the stated value, quantity, or property and that still performs the desired function or achieves the desired result. For example, the terms "approximate", "about", "generally", and "substantially" can refer to amounts within less than 10%, less than 5%, less than 1%, less than 0.1%, and less than 0.01% of the stated amount. As another example, in certain embodiments, the terms "substantially parallel" and "generally parallel" mean a deviation from exact parallelism of less than or equal to 15%, 10%, 5%, 3%, 1%, 0.1%, or other values, quantities, or properties. Similarly, in certain embodiments, the terms "substantially perpendicular" and "generally perpendicular" mean a deviation from exact perpendicularity of less than or equal to 15%, 10%, 5%, 3%, 1%, 0.1%, or other values, quantities, or properties.

[0530] The foregoing description discloses several methods and materials. The present invention is amenable to modifications in these methods and materials as well as variations in the methods of manufacture and apparatus. Such modifications will become apparent to those of ordinary skill in the art from a consideration of this disclosure or practice of the invention as disclosed herein. Accordingly, it is not intended that the invention be limited to the specific embodiments disclosed herein, but rather that it cover all modifications and alternative embodiments falling within the true scope and spirit of the invention.

[0531] 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 hereby constitute a part of this specification. In the event of any conflict between the incorporated publications and patents or patent applications and the disclosure contained herein, the specification is intended to supersede and / or take precedence over any such conflicting material.

[0532] Although the present invention has been described with reference to 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 appended claims.

Claims

1. A compound of formula VI: or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R 3 is H; R 7 selected from: C2-C 20 alkyl; phenyl; and (phenyl)-CH2- substituted by C1-C6 alkyl, halogen or halo(C1-C6)alkyl; and Z is O.

2. The compound according to claim 1, wherein R 7 is selected from: C3-C 15 alkyl, and phenyl-CH2- substituted with halogen.

3. The compound according to claim 1, wherein the compound is selected from: or a stereoisomer or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition comprising the compound according to any one of claims 1 to 3 and a pharmaceutically acceptable excipient.

5. The pharmaceutical composition according to claim 4, further comprising one or more anticancer agents.

6. The pharmaceutical composition according to claim 4, further comprising two or more anticancer agents.

7. The pharmaceutical composition according to claim 4, further comprising an anticancer agent.

8. Use of the compound according to any one of claims 1 to 3 in the manufacture of a medicament for the treatment of a disease, condition or disorder, wherein the disease, condition or disorder is hepatocellular carcinoma, renal cancer, colorectal cancer, breast cancer, gastric cancer, esophageal cancer, pancreatic cancer or cervical cancer.

9. The use according to claim 8, wherein the disease, condition or disorder is selected from colorectal cancer, breast cancer, gastric cancer and pancreatic cancer.

10. The use according to claim 8, wherein the medicament is formulated for use in combination with at least one other therapeutic agent in an individual in need thereof.

11. The use according to claim 10, wherein the one or more other therapeutic agents are selected from sorafenib, regorafenib, and immuno-oncology agents for the treatment of hepatocellular carcinoma.

12. The use according to claim 11, wherein the immuno-oncology agent is a PD-1 or PD-L1 checkpoint inhibitor.

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