Cyclic deoxyribonucleotide compounds

Abstract

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

Description

Technical Field

[0001] The present disclosure relates to the fields of chemistry and medicine. More specifically, the present disclosure relates to cyclic deoxyribonucleotide compounds, their preparation and uses. In some embodiments, such compounds can be used to selectively deliver certain agents to the liver. Background Art

[0002] 5-fluorouracil is a synthetic analog of uracil, one of the four nucleobases in RNA, and has been used as a therapeutic agent to treat various forms of cancer. 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 primarily as a thymidylate synthase inhibitor, which blocks the synthesis of the pyrimidine thymidine, causing cells to lack thymidine, leading to cell death. The active form of 5-fluorouracil as a thymidylate synthase inhibitor is fluorodeoxyuridine monophosphate (FdUMP), which is primarily produced in the liver.

[0003] 5-fluorouracil has a very short biological half-life (~16 minutes), a very narrow therapeutic index, and various side effects that may be very serious. The development of new 5-fluorouracil analog compounds with better efficacy and safety has been carried out for many years, and several compounds have been put on the market. Floxuridine, also known as 5-fluorodeoxyuridine, has been used to treat colorectal cancer by continuous hepatic artery infusion. In some countries, deoxyfluridine has been used as a cytostatic in chemotherapy. Capecitabine has been used orally for the treatment of breast cancer, gastric cancer and colorectal cancer. Despite progress in this field, new compounds are still needed to further improve drug delivery efficiency or solve new applications based on new technologies. For example, liver-targeted compounds that can reach the liver more efficiently and are not active outside the liver reduce the pharmacological or toxicological effects of agents outside the target tissue. Therefore, new compounds with liver-targeted properties can significantly improve the therapeutic index of therapies based on the 5-fluorouracil mechanism. SUMMARY OF THE INVENTION

[0005] The present invention describes novel 5-fluorouracil derived cyclic deoxyribonucleotide compounds, their preparation and use. Some embodiments relate to novel 5-fluorouracil derived cyclic deoxyribonucleotide compounds, which are delivered orally to the liver, where the compounds provide therapeutic benefits. On the other hand, it includes the use of 5-fluorouracil derived cyclic deoxyribonucleotide compounds to treat 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. On the other hand, the 5-fluorouracil derived cyclic deoxyribonucleotide compounds are used to enhance the pharmacological or clinical activity of certain classes of drug compounds (such as 5-fluorouracil derived analog compounds). On the other hand, 5-fluorouracil derived cyclic deoxyribonucleotide compounds are used to reduce the potential side effects of certain classes of drug compounds (such as 5-fluorouracil derived analog compounds), especially side effects that occur outside the liver. In some embodiments, the 5-fluorouracil derived cyclic deoxyribonucleotide compounds can be used to more efficiently orally deliver 5-fluorouracil derived analog compounds to the liver.

[0006] Some embodiments provided herein include compounds of Formula I, Ia or II:

[0007]

[0008] or a stereoisomer or a pharmaceutically acceptable salt thereof,

[0009] Where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 has any value described herein.

[0010] Some embodiments relate to pharmaceutical compositions comprising any of the above-described compounds and a pharmaceutically acceptable excipient.

[0011] Some embodiments relate to pharmaceutical compositions further comprising one or more anti-cancer agents.

[0012] Some embodiments are directed to methods of treating a disease, condition, or disorder comprising administering an effective amount of any of the compounds described above.

[0013] In some embodiments, the disease, condition or disorder is a liver disease, condition or disorder.

[0014] In some embodiments, the disease, condition or disorder is a metabolic disease, cardiovascular disease, or hormonal disease, wherein the liver is involved in the production of biochemical end products and / or homeostasis control of the disease, condition or disorder.

[0015] In some embodiments, the disease, condition or disorder is one in which the liver is involved in the production of the biochemical end-products of the disease, condition or disorder and / or in the control of homeostasis.

[0016] In some embodiments, the disease, condition, or disorder is selected from hepatocellular carcinoma, renal cancer, colorectal cancer, breast cancer, gastric cancer, stomach cancer, esophageal cancer, pancreatic cancer, and cervical cancer.

[0017] In some embodiments, the disease, condition or disorder is a non-hepatic disease, condition or disorder.

[0018] In some embodiments, the non-hepatic disease, condition or disorder is various types of cancer, or other diseases in which the 5-fluorouracil-derived cyclic deoxyribonucleotide compound enhances the distribution of the active drug to target tissues or cells.

[0019] Some embodiments are directed to methods of treating liver disease comprising administering to a subject in need thereof an effective amount of any of the compounds described above.

[0020] Some embodiments further comprise administering to an individual in need thereof an effective amount of at least one additional therapeutic agent.

[0021] In some embodiments, the individual is a mammal.

[0022] In some embodiments, the individual is a human.

[0023] Some embodiments relate to a method of inhibiting viral replication in a cell, comprising contacting the cell with any of the above-described compounds.

[0024] Some embodiments relate to methods of intervening in a molecular pathway or modulating a target in a cell, comprising contacting the cell with any of the above-described compounds.

[0025] In some embodiments, the cell is in vivo.

[0026] In some embodiments, the cells are ex vivo.

[0027] In some embodiments, the cell is a hepatocyte.

[0028] In some embodiments, the cell is a cancer cell.

[0029] In some embodiments, the cell is mammalian.

[0030] In some embodiments, the cell is human.

[0031] 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.

[0032] Some embodiments of the compounds, compositions, and methods provided herein include methods of treating a disease or disorder in the liver of an individual comprising administering to the individual in need thereof an effective amount of any of the compounds provided herein.

[0033] Some embodiments further comprise administering to an individual in need thereof an effective amount of one or more additional therapeutic agents.

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

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

[0036] Some embodiments of the compounds, compositions, and methods provided herein include use of any of the compounds provided herein for treating a liver disease, or a disease or disorder in which a physiological or pathogenic pathway involves the liver, in a subject.

[0037] Some embodiments also include the use of any of the compounds provided herein in combination with other therapeutic agents.

[0038] 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

[0040] The present embodiment relates to compositions and methods related to novel 5-fluorouracil derived cyclic deoxyribonucleotide compounds, their preparation and use. In some embodiments, the novel 5-fluorouracil derived cyclic deoxyribonucleotide compounds promote the delivery of 5-fluorouracil derived therapeutic agents (such as 5-fluorouracil, deoxyfluridine, 5-fluorouridine monophosphonate and / or 5-fluorodeoxyuridine monophosphonate) into cells.

[0041] These 5-fluorouracil derived cyclic deoxyribonucleotide compounds and stereoisomers and pharmaceutically acceptable salts thereof are represented by Formula I, Ia or II:

[0042]

[0043] or a stereoisomer or a pharmaceutically acceptable salt thereof,

[0044] Where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 has any value described herein.

[0045] In some embodiments, the compound is represented by Formula I or II:

[0046]

[0047]

[0048] or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R 1 Selected from H, F, C 1 -C 10 Alkyl, -OMe, -OEt, -O-carboxyl, -OCH 2 OR 9 、-CH(OR 9 ) 2 , -C-carboxyl, -C-amido, -CH 2 OCH 2 OR 9 , and -CH 2 O-carboxyl; and R 2 H, F or C 1 -C 10 alkyl.

[0049] In some embodiments, R 1 Selected from H, halogen, C 1 -C 10 Alkyl, -OC 1-6 Alkyl, -O-carboxyl, -OCH 2 OR 9 、-CH(OR 9 ) 2 , -C-carboxyl, -C-amido, -CH 2 OCH 2 OR 9 , and -CH 2 O-Carboxyl.

[0050] In some embodiments, each R2 are independently H, halogen or C 1 -C 10 alkyl.

[0051] In some embodiments, R 3 Selected from -O-carboxyl, -OCH 2 OR 9 、-CH(OR 9 ) 2 , -C-carboxyl, -C-amide, -CH 2 OCH 2 OR 9 , -CH 2 O-carboxyl, C 1 -C 10 Alkyl and C 3 -C 10 Cycloalkyl.

[0052] In some embodiments, R 4 is an optionally substituted C 1 -C 10 alkyl.

[0053] In some embodiments, R 5 and R 6 Each independently is H or C 1 -C 10 Alkyl; or, R attached to the same carbon atom 5 and R 6 Together with the atoms to which they are attached, they form C 3 -C 10 Cycloalkyl.

[0054] In some embodiments, R 7 and R 8 Each independently is H or C 1 -C 10 Alkyl; or, R attached to the same carbon atom 7 and R 8 Together with the atoms to which they are attached, they form C 3 -C 10 Cycloalkyl.

[0055] In some embodiments, R 9 is an optionally substituted C 1 -C 10 alkyl.

[0056] In some embodiments, the compound is not selected from:

[0057]

[0058]

[0059]

[0060] In some embodiments, R 1 is H; and R 2 It is H or F.

[0061] In some embodiments, R 1 Selected from -OMe, -OEt, -O-carboxyl, -OCH 2 OR 9 、-CH(OR 9 ) 2 , -C-carboxyl, -C-amide, -CH 2 OCH 2 OR 9 , and -CH 2 O-Carboxyl.

[0062] In some embodiments, R 1 is F. In some embodiments, R 1 It is -C-carboxyl.

[0063] In some embodiments, R 2 is H. In some embodiments, R 2 For F.

[0064] In some embodiments, R 3 Selected from -O-carboxyl, -OCH 2 OR 9 、-CH(OR 9 ) 2 , -C-carboxyl, -C-amide, -CH 2 OCH 2 OR 9 , and -CH 2 In some embodiments, R 3 C 1 -C 10 Alkyl or C 3 -C 10 Cycloalkyl.

[0065] Some embodiments are directed to compounds having the structure of Formula Ia:

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

[0067] In some embodiments, R 4 C 1 -C10 In some embodiments, each R 2 is H. Some embodiments include compounds selected from the group consisting of:

[0068]

[0069] or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0070] In some embodiments, the 5-fluorouracil derived cyclic deoxyribonucleotide compounds of Formula I and II are substrates for liver enzymes such as cytochrome p450 isozymes CYP3As (monooxygenase family), dehydrogenases, esterases, and amidases.

[0071] 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)). Certain 5-fluorouracil-derived cyclic deoxyribonucleotide compounds of Formula I and II are activated primarily by CYP3A4 in the liver. In some embodiments, the compounds of Formula I and II have high efficiency in liver targeting by selectively delivering the bioactive agent to the liver. In some embodiments, the cyclic deoxyribonucleotide compounds are used to increase the therapeutic index of the drug because the compounds of Formula I and II may have no activity or low activity outside the liver.

[0072] In some embodiments, due to the liver-targeted properties of the 5-fluorouracil-derived cyclic deoxyribonucleotide compounds of Formulas I and II, 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).

[0073] In some embodiments, the disclosed compounds are used to improve pharmacokinetic properties (such as extending the half-life of a drug or enhancing the absorption of a drug). In addition, the disclosed methods can be used to achieve sustained delivery of active therapeutic agents. Due to the enhanced pharmacokinetic properties of the 5-fluorouracil-derived cyclic deoxyribonucleotide compounds of Formulas I and II, 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.

[0074] Certain compounds of Formula I and II possess asymmetric centers which may have unspecified stereochemistry, and the present invention includes diastereomeric mixtures of these compounds, as well as individual stereoisomers when referring generally to compounds of Formula I and II.

[0075] Some embodiments of the compounds, compositions, and methods provided herein include pharmaceutical compositions comprising a compound provided herein and a pharmaceutically acceptable carrier.

[0076] Some embodiments relate to pharmaceutical compositions further comprising one or more anti-cancer agents.

[0077] Some embodiments relate to methods of treating a disease, condition, or disorder comprising administering to a subject in need thereof an effective amount of a compound described herein.

[0078] Some embodiments further include administering to a subject in need thereof an effective amount of a second therapeutic agent or agents in combination with a compound provided herein.

[0079] In some embodiments, the individual is a mammal.

[0080] In some embodiments, the individual is a human.

[0081] Some embodiments of the compounds, compositions, and methods provided herein include methods of testing a compound in a cell, comprising contacting the cell with a disclosed compound.

[0082] Some embodiments of the compounds, compositions, and methods provided herein include use of a compound provided herein in treating a liver disease, condition, or disorder.

[0083] Some embodiments include the use of a compound provided herein in combination with one or more other therapeutic agents for the treatment of liver disease.

[0084] In some embodiments, the disease, condition or disorder is selected from hepatocellular carcinoma, renal cancer, colorectal cancer, breast cancer, stomach cancer, gastric cancer, esophageal cancer, pancreatic cancer, and cervical cancer.

[0085] Some embodiments relate to methods of treating liver disease comprising administering to a subject in need thereof an effective amount of a compound described herein.

[0086] Some embodiments further comprise administering to an individual in need thereof an effective amount of at least one additional therapeutic agent.

[0087] In some embodiments, the one or more additional therapeutic agents are for HCC treatment and are selected from sorafenib, regorafenib, immuno-oncology agents such as PD-1 or PD-L1 checkpoint inhibitors.

[0088] Some embodiments relate to compounds described herein for use in a medical procedure.

[0089] In some embodiments, the medical procedure is transarterial chemoembolization (TACE).

[0090] Some embodiments of the compounds, compositions, and methods provided herein include the use of the compounds provided herein to treat a disease or condition by intervening in a molecular pathway in the liver.

[0091] Some embodiments include the use of the compounds provided herein in combination with one or more other therapeutic agents to treat a disease or condition by intervening in molecular pathways in the liver.

[0092] Some embodiments of the compounds, compositions, and methods provided herein include the use of the compounds provided herein in treating non-liver diseases, such as various types of cancer.

[0093] Some embodiments include the use of the compounds provided herein with one or more other therapeutic agents for the combined treatment of non-liver diseases, such as various types of cancer.

[0094] When the compounds disclosed herein have at least one chiral center, they can exist as individual enantiomers and diastereomers or as mixtures of such isomers (including racemates). The separation of each isomer and the selective synthesis of each isomer 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 in 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 in the scope of the compounds disclosed herein, including any polymorphic forms. In addition, some compounds disclosed herein may form solvates (i.e., hydrates) with water or form solvates with common organic solvents. Unless otherwise stated, such solvates are included in the scope of the compounds disclosed herein.

[0095] Those skilled in the art will recognize that some structures described herein may be resonance forms or tautomers of compounds that 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 depicted structures, even though such resonance forms or tautomers are not represented herein.

[0096] Isotopes may be present in the compound. Each chemical element as represented in the compound structure may include any isotope of the 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 of 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). Therefore, unless the context clearly indicates otherwise, the compounds mentioned herein all encompass all possible isotopic forms.

[0097] definition

[0098] According to the present disclosure and as used herein, unless otherwise expressly stated, the following terms are defined with the following meanings. It should be understood that the above overview and the following detailed description are merely exemplary and illustrative 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 stated, the use of "or" refers to "and / or". In addition, the use of the term "including" and other forms (such as "includes" and "included") is not restrictive.

[0099] 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%".

[0100] As used herein, "optional" or "optionally / optionally present" means that the subsequently described event or circumstance occurs or does not occur, and that the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not occur. For example, an optionally substituted group means that the group is unsubstituted or substituted.

[0101] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a composition comprising "a therapeutic agent" includes compositions having one or more therapeutic agents.

[0102] 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 a given group. That is, the group may contain from “a” to “b” (inclusive) carbon atoms. Thus, for example, “C 1 -C 4 Alkyl" or "C 1-4 "Alkyl" refers to all alkyl groups having 1 to 4 carbons, i.e., CH 3 -、CH 3 CH2 -、CH 3 CH 2 CH 2 -、(CH 3 ) 2 CH-、CH 3 CH 2 CH 2 CH 2 -、CH 3 CH 2 CH(CH 3 )- and (CH 3 ) 3 C-.

[0103] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain that is fully saturated (i.e., does not contain double or triple bonds). An alkyl group may have 1 to 20 carbon atoms (wherever it appears in the present text, a numerical range such as "1 to 20" refers to each integer in the given range; for example, "1 to 20 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, but the definition also covers the occurrence of the term "alkyl" without specifying a numerical range). An alkyl group may also be a medium-sized alkyl group having 1 to 9 carbon atoms. An alkyl group may also be a low-sized alkyl group having 1 to 4 carbon atoms. An alkyl group may be designated as "C 1 -C 4 Alkyl" or similar designation. By way of example only, "C 1 -C 4 "Alkyl" means that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of: 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.

[0104] As used herein, a substituted group is derived from an unsubstituted parent group wherein there is an exchange of one or more hydrogen atoms with another atom or group. Unless otherwise specified, when a group is considered to be "substituted", it means that the group is substituted with one or more groups independently selected from the following: C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Carbocyclic group (optionally substituted with halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C6 Haloalkyl and C 1 -C 6 substituted with haloalkoxy), C 3 -C 7 -Carbocyclyl-C 1 -C 6 -alkyl (optionally substituted with halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl and C 1 -C 6 substituted with halogenated alkoxy), 3-10 membered heterocyclic group (optionally substituted with halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl and C 1 -C 6 substituted with haloalkoxy), 3-10 membered heterocyclyl-C 1 -C 6 -alkyl (optionally substituted with halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl and C 1 -C 6 substituted with haloalkoxy), aryl (optionally substituted with halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl and C 1 -C 6 substituted with haloalkoxy), aryl (C 1 -C 6 ) alkyl (optionally substituted with halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl and C 1 -C 6 substituted with halogenated alkoxy), 5-10 membered heteroaryl (optionally substituted with halogen, C 1 -C 6 Alkyl, C 1 -C6 Alkoxy, C 1 -C 6 Haloalkyl and C 1 -C 6 substituted with haloalkoxy), 5-10 membered heteroaryl (C 1 -C 6 ) alkyl (optionally substituted with halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl and C 1 -C 6 substituted with haloalkoxy), halogen, cyano, hydroxyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkoxy (C 1 -C 6 ) alkyl (ie ether), aryloxy (optionally substituted with halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl and C 1 -C 6 substituted with haloalkoxy), C 3 -C 7 Carbocyclyloxy (optionally substituted with halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl and C 1 -C 6 substituted with halogenated alkoxy), 3-10 membered heterocyclyl-oxy (optionally substituted with halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl and C 1 -C 6 substituted with haloalkoxy), 5-10 membered heteroaryl-oxy (optionally substituted with halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl and C1 -C 6 substituted with haloalkoxy), C 3 -C 7 -Carbocyclyl-C 1 -C 6 -alkoxy (optionally substituted with halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl and C 1 -C 6 substituted with haloalkoxy), 3-10 membered heterocyclyl-C 1 -C 6 -alkoxy (optionally substituted with halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl and C 1 -C 6 substituted with haloalkoxy), aryl (C 1 -C 6 ) alkoxy (optionally substituted with halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl and C 1 -C 6 substituted with haloalkoxy), 5-10 membered heteroaryl (C 1 -C 6 ) alkoxy (optionally substituted with halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl and C 1 -C 6 substituted with halogenated alkoxy), sulfhydryl (thiol), halogenated (C 1 -C 6 )alkyl (e.g., -CF 3 ), halogenated (C 1 -C 6 ) alkoxy (e.g., -OCF 3 ), C 1 -C 6 Alkylthio, arylthio (optionally substituted with halogen, C 1 -C6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl and C 1 -C 6 substituted with haloalkoxy), C 3 -C 7 Carbocyclylthio (optionally substituted with halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl and C 1 -C 6 substituted with halogenated alkoxy), 3-10 membered heterocyclyl-thio (optionally substituted with halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl and C 1 -C 6 substituted with halogenated alkoxy), 5-10 membered heteroaryl-thio (optionally substituted with halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl and C 1 -C 6 substituted with haloalkoxy), C 3 -C 7 -Carbocyclyl-C 1 -C 6 -alkylthio (optionally substituted with halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl and C 1 -C 6 substituted with haloalkoxy), 3-10 membered heterocyclyl-C 1 -C 6 -alkylthio (optionally substituted with halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl and C 1 -C6 substituted with haloalkoxy), aryl (C 1 -C 6 ) alkylthio (optionally substituted with halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl and C 1 -C 6 substituted with haloalkoxy), 5-10 membered heteroaryl (C 1 -C 6 ) alkylthio (optionally substituted with halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl and C 1 -C 6 substituted with haloalkoxy), amino, amino(C 1 -C 6 )alkyl, nitro, O-carbamoyl, N-amidoformyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxyl, O-carboxyl, 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 substituents described above.

[0105] As used herein, "acyl" refers to -C(=O)R, wherein R is 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 heterocyclyl are as defined herein. Non-limiting examples include formyl, acetyl, propionyl, benzoyl and acryl.

[0106] "Heteroacyl" refers to -C(=O)R, where R is C 1-6 Heteroalkyl.

[0107] "Alkoxymethylene" refers to -CH 2 OR, where R is C 1-6 Alkyl or heteroalkyl, each of which is optionally substituted.

[0108] An "O-carboxyl" group refers to a "-OC(=O)R" group, wherein 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 heterocyclyl are as defined herein.

[0109] A "C-carboxyl" group refers to a "C(=O)OR" group, wherein 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 heterocyclyl are as defined herein. Non-limiting examples include carboxyl (ie, -C(=O)OH).

[0110] A "cyano" group refers to a "-CN" group.

[0111] A "cyanato" group refers to a "-OCN" group.

[0112] An "isocyanato" group refers to a "-NCO" group.

[0113] A "thiocyanato" group refers to a "-SCN" group.

[0114] An "isothiocyanato" group refers to a "-NCS" group.

[0115] A "sulfinyl" group refers to a "-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 6-10 Aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl are as defined herein.

[0116] A "sulfonyl" group refers to a "-SO 2 R" group, wherein 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 heterocyclyl are as defined herein.

[0117] The "S-sulfonylamino" group refers to the "-SO 2 NR A R B " group, where RA 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 heterocyclyl are as defined herein.

[0118] An "N-sulfonylamino" group refers to an "-N(R A )SO 2 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 heterocyclyl are as defined herein.

[0119] An "O-carbamyl" group refers to a "-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, 5-10 membered heteroaryl and 3-10 membered heterocyclyl are as defined herein.

[0120] An "N-carbamyl" group refers to an "-N(R A )C(=O)OR 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 heterocyclyl are as defined herein.

[0121] An "O-thiocarbamoyl" group refers to an "-OC(=S)NR A R B " group, where R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl are as defined herein.

[0122] An "N-thiocarbamoyl" group refers to an "-N(R A )C(=S)OR 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 heterocyclyl are as defined herein.

[0123] A "C-amido" group refers to a "-C(=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, 5-10 membered heteroaryl and 3-10 membered heterocyclyl, as defined herein, each of which is optionally substituted by 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, optionally substituted by C 1-6 Alkoxy or -OH substituted C 1-6 alkyl, and optionally C 1-6 Alkoxy or -OH substituted C 1-6 Alkoxy.

[0124] An "N-amido" group refers to an "-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 heterocyclyl, as defined herein, each of which is optionally substituted by one or more groups selected from: -OH, C 1-6Alkyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclic group, optionally substituted by C 1-6 Alkoxy or -OH substituted C 1-6 alkyl, and optionally C 1-6 Alkoxy or -OH substituted C 1-6 Alkoxy.

[0125] An "amino" group refers to an "-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 heterocyclyl, as defined herein. Non-limiting examples include free amino (i.e., -NH 2 ).

[0126] An "aminoalkyl" group refers to an amino group attached through an alkylene group.

[0127] An "alkoxyalkyl" group refers to an alkoxy group (e.g., "C 2-8 "alkoxyalkyl" etc.).

[0128] The term "acyloxy" refers to a -OC(O)R group, where R is an alkyl group.

[0129] The term "alkoxy" or "alkyloxy" refers to OR, where R is alkyl or heteroalkyl, each of which is optionally substituted.

[0130] The term "carboxyl" refers to C(O)OH.

[0131] The term "oxo" refers to a =0 group.

[0132] The term "halogen" or "halo" refers to F (fluorine), Cl (chlorine), Br (bromine) and I (iodine).

[0133] The term "haloalkyl" refers to an alkyl group containing at least one halogen (in another aspect 1 to 3 halogen atoms). Suitable halogen atoms include F, Cl and Br.

[0134] The term "haloacyl" refers to a -C(O)-haloalkyl group.

[0135] The term "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.

[0136] 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. Alkynyl groups may be optionally substituted. Suitable alkynyl groups include ethynyl.

[0137] 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 that share two adjacent carbon atoms). When aryl is a ring system, each ring in the system is aromatic. An aryl group 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, an aryl group has 6 to 10 carbon atoms. The aryl group may be designated as "C 6-10 Aryl", "C 6 or C 10 Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.

[0138] As used herein, "heteroaryl" refers to an aromatic ring or ring system (i.e., two or more fused rings sharing two adjacent atoms) containing one or more heteroatoms (i.e., elements other than carbon, including but not limited to nitrogen, oxygen and sulfur) in the main chain of the ring. When the heteroaryl is a ring system, each ring in the system is aromatic. The heteroaryl group may have 5 to 18 ring members (i.e., the number of atoms constituting the main chain of the ring, including carbon atoms and heteroatoms), but the present definition also encompasses the occurrence of the term "heteroaryl" in which no numerical range is specified. In some embodiments, the heteroaryl group has 5 to 10 ring members or 5 to 7 ring members. The heteroaryl group may be designated as "5-7 yuan heteroaryl" or "5-10 yuan heteroaryl" or similar designations. The heteroaryl group may be optionally substituted. Examples of heteroaryl groups include, but are not limited to, aromatic C containing one oxygen atom or sulfur atom or up to four nitrogen atoms, or a combination of one oxygen atom or sulfur atom and up to two nitrogen atoms. 3-8 Heterocyclic groups, and their substituted derivatives and benzo- and pyrido-fused derivatives, for example, are attached via one of the ring carbon atoms. In some embodiments, the heteroaryl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, cyano, nitro, alkylamido, 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, 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, benzoxazole, oxadiazole, benzopyrazole, quinolizine, cinnoline, phthalazine, quinazoline and quinoxaline. In some embodiments, the substituents are halogen, hydroxy, cyano, OC 1-6 -alkyl, C 1-6 -alkyl, hydroxy-C 1-6 -Alkyl and amino C 16 -alkyl.

[0139] As used herein, "cycloalkyl" refers to a fully saturated carbocyclic ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. A cycloalkyl group may have 3 to 10 carbon atoms (wherever it appears herein, a numerical range such as "3 to 10" refers to each integer within the given range). A cycloalkyl group may be designated as "C 3 -C 8 Cycloalkyl" or similar designation. By way of example only, "C 3 -C 8 "Cycloalkyl" means there are 3 to 8 carbon atoms in the carbocyclic ring or ring system.

[0140] As used herein, "heterocyclyl" 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 main chain of the ring. The heterocyclyl can have any degree of saturation, provided that at least one ring in the ring system is not aromatic. The heteroatom may be present in a non-aromatic or aromatic ring in the ring system. The heterocyclyl may have 3 to 20 ring members (i.e., the number of atoms that make up the main chain of the ring, including carbon atoms and heteroatoms), but this definition also covers the occurrence of the term "heterocyclyl" in which no numerical range is specified. The heterocyclyl can also be a medium-sized heterocyclyl having 3 to 10 ring members. The heterocyclyl can also be a heterocyclyl having 3 to 6 ring members. 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 3-4Heterocycloalkyl", "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 Heterocyclyl can also be a C having 3 to 10 ring members (having 1 to 3 O (oxygen), N (nitrogen) or S (sulfur)) 2 -C 9 Heterocyclic groups. Heterocyclic groups can be designated as "3-10 membered C 2 -C 9 "heterocyclyl" or similar designations. In preferred six-membered monocyclic heterocyclyls, the heteroatoms are selected from 1 to 3 O (oxygen), N (nitrogen) or S (sulfur), and in preferred five-membered monocyclic heterocyclyls, the heteroatoms are selected from 1 to 2 heteroatoms selected from O (oxygen), N (nitrogen) or S (sulfur). Examples of heterocyclyl rings include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxirane, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxinyl, 1,4-dioxinyl, 1,4-dioxinyl, 1,4-dioxinyl, 1, 3-oxathianyl, 1,4-oxathiinyl, 1,4-oxathiinyl, 2H-1,2-oxazinyl, trioxanyl, hexahydro-1,3,5-triazinyl, 1,3-dioxinyl, 1,3-dioxolyl, 1,3-dithiolyl, 1, 3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinone, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiomorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl and tetrahydroquinoline.

[0141] Whenever a substituent is described as a diradical (i.e., having two points of attachment to the rest of the molecule), it is understood that the substituent may be attached in any orientation unless otherwise specified. Thus, for example, a substituent described as -AE- or or including substituents oriented such that A is attached at the leftmost attachment point of the molecule, as well as cases where A is attached at the rightmost attachment point of the molecule.

[0142] The phrase "therapeutically effective amount" refers to an amount of a compound or combination of compounds that partially or completely improves, alleviates or eliminates one or more symptoms of a particular disease or condition, or prevents, improves or delays the onset of one or more symptoms of a particular disease or condition. Such an amount can be administered as a single dose or can be administered according to an effective regimen. Repeated administration may be required to achieve the desired result (e.g., treatment of a disease and / or condition).

[0143] The term "pharmaceutically acceptable salt" includes salts of compounds of Formulas I, II and III derived from combinations of compounds of the present embodiments with organic or inorganic acids or bases. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, adipic acid, propionic acid, glycolic acid, 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; ammonium, potassium, sodium, calcium, and magnesium salts are particularly preferred. In some embodiments, treatment of a compound disclosed herein with an inorganic base results in the loss of labile hydrogen from the compound to provide an inorganic cation (e.g., Li + 、Na + , K + Mg 2+ and Ca 2+Organic bases from which salts can be derived include, for example, primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins and the like, particularly such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine.

[0144] Where the number of any given substituent is not specified (e.g., "haloalkyl"), one or more substituents may be present. For example, "haloalkyl" may contain one or more halogens which may be the same or different. For example, "haloalkyl" includes the substituent CF 3 , CHF 2 and CH 2 Each of F.

[0145] 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.

[0146] As used herein, the term "prodrug" refers to any compound that produces a biologically active compound due to a spontaneous chemical reaction, an enzyme-catalyzed chemical reaction, and / or a metabolic chemical reaction, or a combination of various reactions when administered to a biological system. Standard prodrugs are formed using groups connected to functional groups, such as HO-, HS-, HOOC-, HOOPR2- associated with the drug, which are cleaved in vivo. Standard prodrugs include, but are not limited to, carboxylates (wherein the group is an alkyl, aryl, aralkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl) and esters of hydroxyl, thiol and amine (wherein the connected group is an acyl, alkoxycarbonyl, aminocarbonyl, phosphate or sulfate). The groups described are examples, not exhaustive, and those skilled in the art can prepare other known types of prodrugs. Prodrugs must undergo some form of chemical transformation to produce a compound that is biologically active or a precursor of a biologically active compound. In some cases, prodrugs are biologically active, and their biological activity is generally less than that of the drug itself, and improve drug efficacy or safety by improved oral bioavailability, drug efficacy half-life, etc. Prodrug forms of the compounds can be used, for example, to improve bioavailability, improve acceptability in individuals (e.g., by masking or reducing unpleasant properties such as bitter taste or gastrointestinal irritation), alter solubility (e.g., for intravenous use), provide extended or sustained release or delivery, improve ease of formulation, or provide site-specific delivery of the compound.

[0147] The term "stereoisomer" refers to the relative or absolute spatial relationship of the R groups attached to the stereogenic center of the carbon or phosphorus atom, and refers to an individual isomer or any combination of individual isomers (such as a racemic mixture and a diastereomeric mixture). When a compound has two stereogenic centers, there are 4 possible stereoisomers.

[0148] The term "liver" refers to the liver organ.

[0149] The term "liver specific" refers to the following ratios as measured in animals treated with the drug or prodrug:

[0150] [Drug or drug metabolite in liver tissue] / [Drug or drug metabolite in blood or other tissues]

[0151] The ratio can be determined by measuring tissue levels at a specific time, or the AUC (area under the curve) can be expressed based on values ​​measured at three or more time points.

[0152] The term "increased or enhanced liver specificity" refers to an increase in the ratio of liver specificity in animals treated with the prodrug relative to animals treated with the parent drug.

[0153] The term "enhanced oral bioavailability" refers to an increase in absorption of a reference drug dose by at least about 50%. On the other hand, the increase in oral bioavailability of the compound (compared to the reference drug) is at least about 100%, or a doubling of absorption. Measurements of oral bioavailability generally refer to measurements of prodrugs, drugs, or drug metabolites in blood, plasma, tissues, or urine after oral administration compared to measurements after parenteral administration.

[0154] The term "therapeutic index" refers to the ratio of doses of a drug or prodrug that produce a therapeutically beneficial response relative to those that produce an undesirable response (eg, death, elevation of markers indicative of toxicity, and / or pharmacological side effects).

[0155] The term "sustained delivery" refers to the increase in therapeutically effective drug levels over a prolonged period of time due to the presence of the prodrug.

[0156] 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 palliating the disease (causing regression of the disease).

[0157] The term "biologic" refers to a compound that has biological activity or has molecular properties that can be used for therapeutic or diagnostic purposes (such as compounds carrying radioactive isotopes or heavy atoms).

[0158] The term "molecular pathway" refers to a series of molecular events in a tissue (eg, a receptor regulatory sequence, an enzyme regulatory sequence, or a biosynthetic sequence, which is involved in a physiological or pathophysiological function in a living animal).

[0159] Administration and pharmaceutical compositions

[0160] The disclosed compounds can be used alone or in combination with other treatments. When used in combination with other agents, these compounds can be administered as a daily dose or an appropriate fraction of a daily dose (e.g., twice a day). The compound can be administered after a course of treatment with another agent, during a course of treatment with another agent, as part of a treatment regimen, or can be administered before treatment with another agent during the course of treatment.

[0161] Examples of pharmaceutically acceptable salts include acetate, adipate, benzenesulfonate, bromide, camphorsulfonate, chloride, citrate, edisylate, etopoate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hyclate, hydrobromide, hydrochloride, iodide, isethionate, lactate, lactobionate, maleate, methanesulfonate, methylbromide, methylsulfate, naphthylsulfonate, nitrate, oleate, palmitate, phosphate, polygalacturonate, stearate, succinate, sulfate, sulfosalicylate, tannate, tartrate, terephthalate, toluenesulfonate, and triethiodide.

[0162] The composition containing the active ingredient can be in any form suitable for the intended method of administration. In some embodiments, the compound 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.

[0163] When the compound is administered orally, tablets, lozenges, troches, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs, for example, can be prepared. 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 sweeteners, flavoring agents, colorants and preservatives, in order to provide a palatable preparation. Tablets containing active ingredients mixed with non-toxic pharmaceutically acceptable excipients are acceptable, and the excipients are suitable for preparing tablets. These excipients can be, for example, inert diluents (such as calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium phosphate); granulating agents and disintegrants (such as corn starch or alginic acid); binders (such as starch, gelatin or gum arabic); 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 adsorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

[0164] Formulations for oral use may also be provided as hard gelatin capsules, in which the active ingredient may be mixed with an inert solid diluent such as calcium phosphate or kaolin, or as soft gelatin capsules, in which the active ingredient may be mixed with water or an oil medium such as peanut oil, liquid paraffin or olive oil.

[0165] Preparations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions, which may contain, for example, antioxidants, buffers, bacteriostats, and solutes that make the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. The preparations may be present in unit dose or multi-dose sealed containers, such as ampoules and vials, and may be stored under freeze-dried (lyophilized) conditions, requiring only the addition of a sterile liquid carrier, such as water for injection, immediately before use. Injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the aforementioned types.

[0166] In some embodiments, the unit dosage formulation contains a daily dose or unit of drug, a daily subdose, or an appropriate fraction thereof. However, it should be understood that the specific dosage level for any particular patient will depend on a variety of factors, including the activity of the specific compound used; the age, weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs that have been previously administered; and the severity of the specific disease being treated, as is well understood by those skilled in the art.

[0167] The actual dosage of the compounds described herein depends on the specific compound and the condition to be treated; the selection of an appropriate dosage is well within the knowledge of those skilled in the art. In some embodiments, the daily dosage may be from about 0.1 mg / kg to about 100 mg / kg or more, 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 of body weight. Thus, for a 70 kg person, the dosage range would 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.

[0168] Treatment

[0169] Some embodiments include methods of treating a disease, condition or disorder selected from liver cancer and various types of cancer with the compounds and compositions comprising the compounds described herein. Some methods include administering the compounds, compositions, pharmaceutical compositions described herein to an individual in need thereof. In some embodiments, the individual can be an animal, such as a mammal, a human. In some embodiments, the individual is a human.

[0170] Additional embodiments include administering a combination of compounds to an individual in need thereof. The combination may include a compound, composition, pharmaceutical composition described herein and other agents.

[0171] Some embodiments include co-administration of compounds, compositions and / or pharmaceutical compositions described herein with other medicaments or other therapeutic agents. "Co-administration" means that two or more medicaments can be found in the patient's bloodstream at the same time, regardless of the time or mode of actual administration. In one embodiment, multiple medicaments are administered simultaneously. In one such embodiment, co-administration is achieved by combining multiple medicaments in a single dosage form. In another embodiment, multiple medicaments are administered sequentially. In one embodiment, multiple medicaments are administered by the same route (such as oral). In another embodiment, multiple medicaments are administered by different routes (such as oral administration and intravenous administration).

[0172] Examples of other drugs include therapeutic agents selected from other types of chemotherapeutic drugs (such as cyclophosphamide, methotrexate, doxorubicin, docetaxel, cisplatin, epirubicin, oxaliplatin and folinic acid); and other targeted anti-tumor agents (such as HDAC inhibitors). In some embodiments, the 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).

[0173] Examples of other drugs also include medical procedures selected from tumor ablation, selective internal radiation therapy (SIRT), and transarterial chemoembolization (TACE).

[0174] To further illustrate the compounds described herein, the following examples are included. Of course, these examples should not be construed as specifically limiting the scope of the compounds. 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 invention as described and claimed herein. The reader will recognize that the skilled person and those skilled in the art who grasp the present invention are able to prepare and use the compounds without exhaustive examples.

[0175] Synthesis of compounds

[0176] The following procedures for preparing novel compounds illustrate the general procedures used to prepare the described 5-fluorouracil-derivatized cyclic deoxyribonucleotide compounds.

[0177] Scheme I describes the general synthesis of compounds of formula I and II. Fluridine (1) is reacted with phosphanediamine (2) in the presence of 4,5-dicyanoimidazole to give a cyclic product of structure 3, and the crude reaction mixture is then treated with an oxidizing agent such as tert-butyl hydroperoxide to give a final product of structure 4.

[0178] Route I

[0179]

[0180] R1, R2, R3, R5, R6, R7 and R8 have any value described herein Example

[0181] Some compounds of formula I and II were prepared as described below.

[0182] Example 1

[0183] 5-Fluoro-1-((4aR,6R,7aS)-2-(heptyloxy)-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 101)

[0184]

[0185] Compound 101 was prepared from N,N,N',N'-tetraisopropyl-1-heptyloxyphosphine diamine and floxuridine according to the method described in Scheme I and isolated as a mixture of two isomers. 16 H 24 FN 2 O 7 P's [M-1] + Calculated value: 405.12; measured value: 405.0.

[0186] Example 2

[0187] 5-Fluoro-1-((4aR,6R,7aS)-2-(octyloxy)-2-oxytetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinane-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 102)

[0188]

[0189] Compound 102 was prepared from N,N,N',N'-tetraisopropyl-1-octyloxyphosphine diamine and floxuridine according to the method described in Scheme I and isolated as a mixture of two isomers. 17 H 26 FN 2 O 7 P's [M-1] + Calculated value: 419.14; measured value: 419.0.

[0190] Example 3

[0191] 5-Fluoro-1-((4aR,6R,7aS)-2-(6-methylheptyloxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinane-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 103)

[0192]

[0193] Compound 103 was prepared from N,N,N',N'-tetraisopropyl-1-(6-methylheptyloxy)phosphine diamine and floxuridine according to the method described in Scheme I and isolated as a mixture of two isomers. 17 H 26 FN 2 O 7 P's [M-1] + Calculated value: 419.14; measured value: 419.0.

[0194] Example 4

[0195] 5-Fluoro-1-((4aR,6R,7aS)-2-(cyclopropylmethoxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinane-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 104)

[0196]

[0197] Compound 104 was prepared from N,N,N',N'-tetraisopropyl-1-(cyclopropylmethoxy)phosphine diamine and floxuridine according to the method described in Scheme I and isolated as a mixture of two isomers. 13 H 16 FN 2 O 7 P's [M-1] + Calculated value: 361.06; measured value: 361.0.

[0198] Example 5

[0199] 5-Fluoro-1-((4aR,6R,7aS)-2-(cyclopentylmethoxy)-2-oxytetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinane-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 105)

[0200]

[0201] Compound 105 was prepared from N,N,N',N'-tetraisopropyl-1-(cyclopentylmethoxy)phosphine diamine and floxuridine according to the method described in Scheme I and isolated as a mixture of two isomers. 15 H 20 FN 2 O 7 P's [M-1] + Calculated value: 389.09; measured value: 389.0.

[0202] Example 6

[0203] 5-Fluoro-1-((4aR,6R,7aS)-2-(2-cyclopentylethoxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinane-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 106)

[0204]

[0205] Compound 106 was prepared from N,N,N',N'-tetraisopropyl-1-(2-cyclopentylethoxy)phosphine diamine and floxuridine according to the method described in Scheme I and isolated as a mixture of two isomers.16 H 22 FN 2 O 7 P's [M-1] + Calculated value: 403.10; measured value: 403.0.

[0206] Example 7

[0207] 5-Fluoro-1-((4aR,6R,7aS)-2-(3-cyclopentylpropoxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinane-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 107)

[0208]

[0209] Compound 107 was prepared from N,N,N',N'-tetraisopropyl-1-(3-cyclopentylpropoxy)phosphine diamine and floxuridine according to the method described in Scheme I and isolated as a mixture of two isomers. 17 H 24 FN 2 O 7 P's [M+1] + Calculated value: 419.14; measured value: 419.1.

[0210] Example 8

[0211] 5-Fluoro-1-((4aR,6R,7aS)-2-(2-methoxybenzyloxy)-2-oxytetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinane-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 108)

[0212]

[0213] Compound 108 was prepared from N,N,N',N'-tetraisopropyl-1-(2-methoxybenzyloxy)phosphine diamine and floxuridine according to the method described in Scheme I and isolated as a mixture of two isomers. 17 H 18 FN 2 O 8 P's [M-1] + Calculated value: 427.07; measured value: 427.0.

[0214] Example 9

[0215] 5-Fluoro-1-((4aR,6R,7aS)-2-(4-fluorophenethoxy)-2-oxytetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinane-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 109)

[0216]

[0217] Compound 109 was prepared from N,N,N',N'-tetraisopropyl-1-(4-fluorophenethoxy)phosphine diamine and floxuridine according to the method described in Scheme I and isolated as a mixture of two isomers. 17 H 17 F 2 N 2 O 8 P's [M-1] + Calculated value: 429.06; measured value: 429.0.

[0218] Example 10

[0219] 5-Fluoro-1-((4aR,6R,7aS)-2-(3-fluorophenethoxy)-2-oxytetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinane-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 110)

[0220]

[0221] Compound 110 was prepared from N,N,N',N'-tetraisopropyl-1-(3-fluorophenethoxy)phosphine diamine and floxuridine according to the method described in Scheme I and isolated as a mixture of two isomers. 17 H 17 F 2 N 2 O 8 P's [M-1] + Calculated value: 429.06; measured value: 429.0.

[0222] Embodiment 11

[0223] 5-Fluoro-1-((4aR,6R,7aS)-2-(2,4-difluorophenethoxy)-2-oxytetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinane-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 111)

[0224]

[0225] Compound 111 was prepared from N,N,N',N'-tetraisopropyl-1-(2,4-difluorophenethoxy)phosphine diamine and floxuridine according to the method described in Scheme I and isolated as a mixture of two isomers. 17 H 16 F 3 N 2 O 8 P's [M-1] + Calculated value: 447.05; measured value: 447.0.

[0226] Example 12

[0227] 5-Fluoro-1-((4aR,6R,7aS)-2-(4-methylphenethoxy)-2-oxytetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinane-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 112)

[0228]

[0229] Compound 112 was prepared from N,N,N',N'-tetraisopropyl-1-(4-methylphenethoxy)phosphine diamine and floxuridine according to the method described in Scheme I and isolated as a mixture of two isomers. 18 H 20 FN 2 O 8 P's [M-1] + Calculated value: 425.09; measured value: 425.1.

[0230] Embodiment 13

[0231] 5-Fluoro-1-((4aR,6R,7aS)-2-(2-fluorophenethoxy)-2-oxytetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinane-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 113)

[0232]

[0233] Compound 113 was prepared from N,N,N',N'-tetraisopropyl-1-(2-fluorophenethoxy)phosphine diamine and floxuridine according to the method described in Scheme I and isolated as a mixture of two isomers. 17 H 17 F 2 N 2 O 8 P's [M-1] + Calculated value: 429.06; measured value: 429.1.

[0234] Embodiment 14

[0235] 5-Fluoro-1-((4aR,6R,7aS)-2-(2,6-difluorophenethoxy)-2-oxytetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinane-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 114)

[0236]

[0237] Compound 114 was prepared from N,N,N',N'-tetraisopropyl-1-(2,6-difluorophenethoxy)phosphine diamine and floxuridine according to the method described in Scheme I and isolated as a mixture of two isomers. 17 H 16 F 3 N 2 O 8 P's [M-1] + Calculated value: 447.05; measured value: 447.1.

[0238] Embodiment 15

[0239] 5-Fluoro-1-((4aR,6R,7aS)-2-(2,4,6-trifluorophenethoxy)-2-oxytetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinane-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 115)

[0240]

[0241] Compound 115 was prepared from N,N,N',N'-tetraisopropyl-1-(2,4,6-trifluorophenethoxy)phosphine diamine and floxuridine according to the method described in Scheme I and isolated as a mixture of two isomers. 17 H 15 F 4 N 2 O 8 P's [M-1] + Calculated value: 465.05; measured value: 465.0.

[0242] Example 16

[0243] 5-Fluoro-1-((4aR,6R,7aS)-2-(4-fluoro-2-methylbenzyloxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinane-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 116)

[0244]

[0245] Compound 116 was prepared from N,N,N',N'-tetraisopropyl-1-(2-methoxybenzyloxy)phosphine diamine and floxuridine according to the method described in Scheme I and isolated as a mixture of two isomers. 17 H 17 F 2 N 2 O 8 P's [M-1] + Calculated value: 429.06; measured value: 429.1.

[0246] Embodiment 17

[0247] 5-Fluoro-1-((4aR,6R,7aS)-2-oxido-2-((1-phenylcyclopropyl)methoxy)tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinane-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 117)

[0248]

[0249] Compound 117 was prepared from N,N,N',N'-tetraisopropyl-1-((1-phenylcyclopropyl)methoxy)phosphine diamine and floxuridine according to the method described in Scheme I and isolated as a mixture of two isomers. 19 H 20 FN 2 O 7 P's [M-1] + Calculated value: 437.09; measured value: 437.1.

[0250] Embodiment 18

[0251] 1-((4aR,6R,7aS)-2-((2-(diethoxymethyl)benzyl)oxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinane-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 118)

[0252]

[0253] Compound 118 was prepared from N,N,N',N'-tetraisopropyl-1-((2-diethoxymethyl)benzyloxy)phosphine diamine and floxuridine according to the method described in Scheme I and isolated as a mixture of two isomers. 21 H 26 FN 2 O 9 P's [M-1] + Calculated value: 499.13; measured value: 499.0.

[0254] Embodiment 19

[0255] 1-((4aR,6R,7aS)-2-((2-(1,3-dioxolan-2-yl)-4-fluorobenzyl)oxy)-2-oxytetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinane-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 119)

[0256]

[0257] Compound 119 was prepared from N,N,N',N'-tetraisopropyl-1-((2-(1,3-dioxolan-2-yl)-4-fluorobenzyloxy)phosphine diamine and floxuridine according to the method described in Scheme I and isolated as a mixture of two isomers. 19 H 19 F 2 N 2 O 9 P's [M-1] + Calculated value: 487.07; measured value: 487.0.

[0258] Embodiment 20

[0259] 5-Fluoro-1-((4aR,6R,7aS)-2-(3-phenylpropoxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinane-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 120)

[0260]

[0261] Compound 120 was prepared from N,N,N',N'-tetraisopropyl-1-(3-phenylpropoxy)phosphine diamine and floxuridine according to the method described in Scheme I and isolated as a mixture of two isomers. 18 H 20 FN 2 O 7 P's [M+1] + Calculated value: 425.09; measured value: 425.1.

[0262] Embodiment 21

[0263] 5-Fluoro-1-((4aR,6R,7aS)-2-(3-(2-fluorophenyl)propoxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinane-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 121)

[0264]

[0265] Compound 121 was prepared from N,N,N',N'-tetraisopropyl-1-(3-(2-fluorophenyl)propoxy)phosphine diamine and floxuridine according to the method described in Scheme I and isolated as a mixture of two isomers. 18 H 19 F 2 N 2 O 7 P's [M+1] + Calculated value: 443.08; measured value: 443.0.

[0266] Embodiment 22

[0267] 5-Fluoro-1-((4aR,6R,7aS)-2-(3-(4-fluorophenyl)propoxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinane-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 122)

[0268]

[0269] Compound 122 was prepared from N,N,N',N'-tetraisopropyl-1-(3-(4-fluorophenyl)propoxy)phosphine diamine and floxuridine according to the method described in Scheme I and isolated as a mixture of two isomers. 18 H 19 F 2 N 2 O 7 P's [M+1] + Calculated value: 443.08; measured value: 443.0.

[0270] Embodiment 23

[0271] 1-((4aR,6R,7aS)-2-(4,4-dipropoxybutoxy)-2-oxytetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinane-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (Compound 123)

[0272]

[0273] Compound 123 was prepared from N,N,N',N'-tetraisopropyl-1-(4,4-bis-(propoxy)butoxy)phosphine diamine and floxuridine according to the method described in Scheme I and isolated as a mixture of two isomers. 19 H 30 FN 2 O 9 P's [M+1] +Calculated value: 479.16; measured value: 479.0.

[0274] Embodiment 24

[0275] Isopropyl 2-((((4aR,6R,7aS)-6-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinane-2-yl)oxy)methyl)benzoate (Compound 124)

[0276]

[0277] Compound 124 was prepared from N,N,N',N'-tetraisopropyl-1-(2-isopropoxycarbonylbenzyloxy)phosphine diamine and floxuridine according to the method described in Scheme I and isolated as a mixture of two isomers. 20 H 22 FN 2 O 9 P's [M-1] + Calculated value: 483.09; measured value: 483.0.

[0278] Embodiment 25

[0279] Ethyl 2-((((4aR,6R,7aS)-6-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinane-2-yl)oxy)methyl)benzoate (Compound 125)

[0280]

[0281] Compound 125 was prepared from N,N,N',N'-tetraisopropyl-1-(2-ethoxycarbonylbenzyloxy)phosphine diamine and floxuridine according to the method described in Scheme I and isolated as a mixture of two isomers. 19 H 20 FN 2 O 9 P's [M-1] + Calculated value: 469.08; measured value: 469.1.

[0282] Embodiment 26

[0283] 2-((((4aR,6R,7aS)-6-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinane-2-yl)oxy)methyl)benzoic acid propyl ester (Compound 126)

[0284]

[0285] Compound 126 was prepared from N,N,N',N'-tetraisopropyl-1-(2-propoxycarbonylbenzyloxy)phosphine diamine and floxuridine according to the method described in Scheme I and isolated as a mixture of two isomers. 20 H 22 FN 2 O 9 P's [M-1] + Calculated value: 483.09; measured value: 483.0.

[0286] Embodiment 27

[0287] Methyl 2-((((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]dioxaphosphinane-2-yl)oxy)methyl)benzoate (Compound 127)

[0288]

[0289] Compound 127 was prepared from N,N,N',N'-tetraisopropyl-1-(2-methoxycarbonylbenzyloxy)phosphine diamine and floxuridine according to the method described in Scheme I and isolated as a mixture of two isomers. 18 H 18 FN 2 O 9 P's [M-1] + Calculated value: 455.06; measured value: 455.1.

[0290] Embodiment 28

[0291] Butyl 2-((((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]dioxaphosphinane-2-yl)oxy)methyl)benzoate (Compound 128)

[0292]

[0293] Compound 128 was prepared from N,N,N',N'-tetraisopropyl-1-(2-butoxycarbonylbenzyloxy)phosphine diamine and floxuridine according to the method described in Scheme I and isolated as a mixture of two isomers. 21 H 24 FN 2 O 9 P's [M-1]+ Calculated value: 497.11; measured value: 497.1.

[0294] Biological Examples

[0295] Examples of using this method include the following. It should be understood that the following are examples, and the method is not limited to these examples.

[0296] Example 29: Tissue distribution after oral administration of reference compounds and disclosed compounds

[0297] The liver specificity of the disclosed compounds was compared relative to corresponding active compounds in the liver and other organs that may be targets of toxicity.

[0298] method:

[0299] Reference compounds and the cyclic deoxyribonucleotide compounds were administered to fasted rats at 5-50 mg / kg by oral gavage. Plasma concentrations of metabolites and parent compounds were determined in the circulation and in the hepatic portal vein by HPLC-UV, and concentrations in the liver, small intestine, and other organs were determined by LC-MS using standard chromatographic methods.

[0300] result:

[0301] Table 1 provides the results for selected novel compounds, which demonstrate the liver targeting properties of the cyclic deoxyribonucleotide compounds and provide evidence that the compounds have improved efficiency in achieving high levels of active agent in the liver compared to other types of prodrug compounds. This can only be achieved through the efficient liver targeting provided by the cyclic deoxyribonucleotide compounds.

[0302] Table 1. Prodrug and metabolite levels in liver and blood 1 hour after oral administration of reference compounds and selected compounds at 5 mg / kg in rats

[0303]

[0304] FdUMP = floxuridine monophosphate; FUDR = floxuridine; Capecitabine = the active ingredient of Xeloda, a prodrug; NUC-3373 = ProTide prodrug developed by NuCana PLC.

[0305] All numerals used in the specification that represent the amount of components, reaction conditions, etc. should be understood to be modified by the term "about" in all cases. Therefore, unless otherwise indicated, the numerical parameters given herein are approximate values, which can vary according to the desired properties that the present invention intends to obtain. At least, and without attempting to limit the application of the doctrine of equivalents to the scope of any claim in any application claiming priority to this application, each numerical parameter should be interpreted according to the numerical value of the significant digits and the usual rounding method.

[0306] The language of degree used herein (such as the terms "approximately", "about", "usually" and "substantially") refers to a value, quantity or characteristic that is close to the value, quantity or characteristic, and it still performs the desired function or achieves the desired result. For example, the terms "approximately", "about", "usually" and "substantially" can refer to an amount within less than 10%, less than 5%, less than 1%, less than 0.1% and less than 0.01% of the amount. As another example, in certain embodiments, the terms "roughly parallel" and "substantially parallel" refer to a value, quantity or characteristic that deviates from exact parallelism by less than or equal to 15%, 10%, 5%, 3%, 1%, 0.1% or other. Similarly, in certain embodiments, the terms "roughly perpendicular" and "substantially perpendicular" refer to a value, quantity or characteristic that deviates from exact perpendicularity by less than or equal to 15%, 10%, 5%, 3%, 1%, 0.1% or other.

[0307] The above description discloses several methods and materials. The compounds described herein may be subject to modifications in these methods and materials and changes in manufacturing methods and devices. Such modifications will become apparent to one of ordinary skill in the art from considerations of the present disclosure or practice of the compounds disclosed herein. Therefore, it is not intended that the compounds described herein be limited to the specific embodiments disclosed herein, but rather that they encompass all modifications and alternatives that fall within the true scope and spirit of the compounds.

[0308] 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 thus constitute a part of this specification. In the event that the publications and patents or patent applications incorporated by reference conflict with the disclosure contained in this specification, this specification is intended to replace and / or take precedence over any such conflicting materials.

[0309] Although various compounds have 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 compounds described. Therefore, the compounds are limited only by the appended claims.

Claims

1. Compounds of formula I or II: or a pharmaceutically acceptable salt thereof, in: R 1 selected from H, -C(=O)OR and Each R 2 are independently H or F; R 3 Selected from C1-C 10 Alkyl and C3-C 10 Cycloalkyl; R 5 and R 6 are each independently H; or, R attached to the same carbon atom 5 and R 6 Together with the atom to which they are attached, they can form a C3-C 10 Cycloalkyl; R 7 and R 8 are each independently H; and R is a C1-C6 alkyl group; Provided that the compound is not selected from:

2. The compound according to claim 1, wherein R 1 For H.

3. The compound according to claim 1, wherein R 1 Selected from -C(=O)OR and 4. The compound according to claim 1, wherein R 1 for 5. The compound according to claim 1, wherein R 1 It is -C(=O)OR.

6. The compound according to claim 1, wherein R 2 For H.

7. The compound according to claim 1, wherein R 2 For F.

8. The compound according to claim 1, wherein R 3 It is a C1-C4 alkyl group or a C3-C8 cycloalkyl group.

9. A compound selected from: or a pharmaceutically acceptable salt thereof.

10. A compound selected from: or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising the compound according to any one of claims 1 to 10, and a pharmaceutically acceptable excipient.

12. The pharmaceutical composition of claim 11, further comprising one or more anticancer agents.

13. Use of a compound according to any one of claims 1 to 10 in the preparation of a medicament for treating a liver disease or disorder, or a disease or disorder in which the liver is involved in a physiological or pathogenic pathway.

Images