Cyclic deoxyribonucleotide compounds

Abstract

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

Description

[Technical field]

[0001] Field The present disclosure relates to the fields of chemistry and medicine. More specifically, the present disclosure relates to cyclic deoxyribonucleotide compounds, their preparation and their use. In some aspects, such compounds are useful for selectively delivering certain pharmaceuticals to the liver. [Background technology]

[0002] background 5-Fluorouracil is a synthetic analogue of uracil, one of the four nucleobases in RNA, and has been used as a therapeutic agent to treat various forms of cancer. It is on the WHO's list of essential medicines due to its efficacy and safety, and is available in intravenous and topical forms. The mechanism of action of 5-fluorouracil is primarily as a thymidylate synthase inhibitor, blocking the synthesis of the pyrimidine thymidine, causing thymidine depletion in cells, leading to cell death. As a thymidylate synthase inhibitor, the active form of 5-fluorouracil is fluorodeoxyuridine monophosphate (FdUMP), which is produced primarily in the liver.

[0003] 5-Fluorouracil has a very short biological half-life (approximately 16 minutes), a very narrow therapeutic index and various side effects that can be very severe. The development of new 5-fluorouracil analogue compounds towards better efficacy and safety has been ongoing for many years, and several compounds are on the market. Floxuridine, also known as 5-fluorodeoxyuridine, has been used to treat colorectal cancer via continuous hepatic artery injection. Doxifluridine has been used in certain countries as a cytostatic drug in chemotherapy. Capecitabine has been used orally to treat breast, gastric and colorectal cancer. Despite the progress in the field, there is a need for new compounds to further improve drug delivery efficiency or to address 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, thus reducing the pharmacological or toxicological effects of the drug outside the target tissue. Thus, new compounds with liver-targeting properties could significantly improve the therapeutic index of 5-fluorouracil mechanism-based therapies. Summary of the Invention

[0004] overview Novel 5-fluorouracil-derived cyclic deoxyribonucleotide compounds, their preparation and their use are described. Some embodiments relate to novel 5-fluorouracil-derived cyclic deoxyribonucleotide compounds that are delivered orally to the liver, where therapeutic benefits are provided. Another aspect includes the use of 5-fluorouracil-derived cyclic deoxyribonucleotide compounds to treat diseases that benefit from improved 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, 5-fluorouracil-derived cyclic deoxyribonucleotide compounds are used to enhance the pharmacological or clinical activity of certain classes of pharmaceutical compounds, such as 5-fluorouracil-derived analog compounds. In another aspect, the 5-fluorouracil-derived cyclic deoxyribonucleotide compounds are used to reduce the potential side effects of certain classes of pharmaceutical compounds, such as 5-fluorouracil-derived analog compounds, particularly side effects that occur outside the liver. In some embodiments, the 5-fluorouracil-derived cyclic deoxyribonucleotide compounds are useful in more efficient oral delivery of 5-fluorouracil-derived analog compounds to the liver.

[0005] Some embodiments provided herein include a compound of formula I, Ia, or II: TIFF0007625542000001.tif145128 or a stereoisomer or a pharma- ceutically acceptable salt thereof, In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 has any of the values ​​described herein.

[0006] Some embodiments relate to pharmaceutical compositions comprising any of the above compounds and a pharma- ceutically acceptable excipient.

[0007] Some embodiments relate to pharmaceutical compositions further comprising one or more anti-cancer agents.

[0008] Some embodiments relate to methods of treating a disease, disorder, or condition comprising administering an effective amount of any of the above compounds.

[0009] In some embodiments, the disease, disorder or condition is a liver disease, disorder or condition.

[0010] In some embodiments, the disease, disorder or condition is a metabolic, cardiovascular or hormonal disease in which the liver is involved in the production and / or homeostatic control of the biochemical end products of the disease, disorder or condition.

[0011] In some embodiments, the disease, disorder or condition is one in which the liver is involved in the production and / or homeostatic control of the biochemical end products of the disease, disorder or condition.

[0012] In some embodiments, the disease, disorder or condition is selected from the group consisting of hepatocellular carcinoma, renal cancer, colorectal cancer, breast cancer, stomach cancer, gastric cancer, esophageal cancer, pancreatic cancer, and cervical cancer.

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

[0014] In some embodiments, the non-liver disease, disorder or condition is various types of cancer or other diseases in which the 5-fluorouracil derived cyclic deoxyribonucleotide compounds enhance the distribution of active drugs to target tissues or cells.

[0015] Some embodiments relate to a method of treating liver disease comprising administering to a subject in need thereof an effective amount of any of the compounds described above.

[0016] Some embodiments further comprise administering to a subject in need thereof an effective amount of at least one additional therapeutic agent.

[0017] In some embodiments, the subject is a mammal.

[0018] In some embodiments, the subject is a human.

[0019] Some embodiments relate to methods of inhibiting viral replication in a cell comprising contacting the cell with any of the above compounds.

[0020] Some embodiments relate to methods of intervening in a molecular pathway or modulating a target within a cell comprising contacting a cell with any of the above compounds.

[0021] In some embodiments, the cell is in vivo.

[0022] In some embodiments, the cells are ex vivo.

[0023] In some embodiments, the cell is a hepatocyte.

[0024] In some embodiments, the cell is a cancer cell.

[0025] In some embodiments, the cell is mammalian.

[0026] In some embodiments, the cells are human.

[0027] Some embodiments of the compounds, compositions, and methods provided herein include pharmaceutical compositions comprising any of the compounds provided herein and a pharma- ceutically acceptable excipient.

[0028] Some embodiments of the compounds, compositions, and methods provided herein include a method of treating a liver disease or condition in a subject comprising administering to a subject in need thereof an effective amount of any of the compounds provided herein.

[0029] Some embodiments also include administering to a subject in need thereof an effective amount of one or more additional therapeutic agents.

[0030] In some embodiments, the subject is a mammal.

[0031] In some embodiments, the subject is a human.

[0032] Some embodiments of the compounds, compositions, and methods provided herein include the use of any one of the compounds provided herein to treat a disease of the liver, or a disease or condition whose physiological or pathogenic pathway involves the liver, in a subject.

[0033] Some embodiments also include the use of any one of the compounds provided herein in combination with an additional therapeutic agent.

[0034] Some embodiments of the compounds, compositions, and methods provided herein include any one of the compositions provided herein for use in the preparation of a medicament for treating a disease or condition of the liver, or a disease or condition in which a physiological or pathogenic pathway involves the liver. [The present invention 1001] A compound of formula I, Ia, or II, or a stereoisomer or pharma- ceutically acceptable salt thereof: TIFF0007625542000002.tif140128 During the ceremony R 1 H, halo, C 1 ~C 10 Alkyl, -OC 1~6 Alkyl, -O-carboxy, -OCH 2 OR 9 , -CH(OR9 ) 2 , -C-carboxy, -C-amido, -CH 2 OCH 2 OR 9 、 TIFF0007625542000003.tif12128 , and -CH 2 O-carboxy; Each R 2 are independently H, halo, or C 1 ~C 10 is alkyl; R 3 is -O-carboxy, -OCH 2 OR 9 , -CH(OR 9 ) 2 , -C-carboxy, -C-amido, -CH 2 OCH 2 OR 9 、 TIFF0007625542000004.tif12128 , -CH 2 O-Carboxy, C 1 ~C 10 Alkyl, and C 3 ~C 10 cycloalkyl; R 4 is optionally substituted C 1 ~C 10 is alkyl; Each R 5 and R 6 are independently H or C 1 ~C 10 or alternatively, R 5 and R 6 together with the atom to which they are attached, 3 ~C 10 may form a cycloalkyl; Each R 7 and R 8 are independently H or C 1 ~C 10 or alternatively, R 7 and R 8 together with the atom to which they are attached, 3 ~C 10 may form a cycloalkyl; and R 9 is optionally substituted C 1 ~C 10 is alkyl; However, the compound TIFF0007625542000005.tif113128TIFF0007625542000006.tif203124TIFF0007625542000007.tif102135 is not selected. [The present invention 1002] The compound of the present invention is a compound of formula (I) or (II), or a stereoisomer or a pharma- ceutically acceptable salt thereof: TIFF0007625542000008.tif93128 During the ceremony R 1 is H, F, C 1 ~C 10 Alkyl, -OMe, -OEt, -O-carboxy, -OCH 2 OR 9 , -CH(OR 9 ) 2 , -C-carboxy, -C-amido, -CH 2 OCH 2 OR 9 、 TIFF0007625542000009.tif12128 , and -CH 2 O-carboxy; and R 2 is H, F, or C 1 ~C 10 It is an alkyl. [The present invention 1003] R 1 is H; and R 2 The compound of the present invention 1001 or 1002, wherein is H or F. [The present invention 1004] R 1 -OMe, -OEt, -O-carboxy, -OCH 2 OR 9 , -CH(OR 9 ) 2 , -C-carboxy, -C-amido, -CH 2 OCH 2 OR 9 、 TIFF0007625542000010.tif12128 , and -CH 2 The compound of claim 1001 or 1002, selected from the group consisting of O-carboxy. [The present invention 1005] R 1 The compound of the present invention 1001 or 1002, wherein [The present invention 1006] R 1 The compound of claim 1001 or 1002, wherein is -C-carboxy. [The present invention 1007] R 2 The compound according to any one of claims 1001 to 1006, wherein [The present invention 1008] R 2 The compound according to any one of claims 1001 to 1006, wherein [The present invention 1009] R 3 -O-carboxy, -OCH 2 OR 9 , -CH(OR 9 ) 2 , -C-carboxy, -C-amido, -CH 2 OCH 2 OR 9 、 TIFF0007625542000011.tif12128 , and -CH 2 The compound of claim 1001 or 1002, selected from the group consisting of O-carboxy. [The present invention 1010] R 3 C 1 ~C 10 Alkyl or C 3 ~C 10 The compound of the present invention 1001 or 1002, which is cycloalkyl. [The present invention 1011] Formula Ia TIFF0007625542000012.tif44128 The compound of the present invention having the structure: or a stereoisomer or a pharma- ceutically acceptable salt thereof. [The present invention 1012] R 4 C 1 ~C 10 The compound of the present invention 1011, which is alkyl. [The present invention 1013] Each R 2 The compound of claim 1011 or 1012, wherein [The present invention 1014] TIFF0007625542000013.tif200152TIFF0007625542000014.tif222152 1. A compound selected from the group consisting of: [The present invention 1015] A pharmaceutical composition comprising any one of the compounds of the present invention 1001 to 1014 and a pharma- ceutically acceptable excipient. [The present invention 1016] The pharmaceutical composition of the present invention 1015 further comprising one or more anti-cancer agents. [The present invention 1017] A method for treating a disease, disorder, or condition, comprising the step of administering an effective amount of any of the compounds of the present inventions 1001 to 1014 to a subject in need thereof. [The present invention 1018] The method of claim 1017, wherein said disease, disorder, or condition is a liver disease, disorder, or condition. [The present invention 1019] The method of claim 1017, wherein said disease, disorder, or condition is selected from the group consisting of hepatocellular carcinoma, renal cancer, colorectal cancer, breast cancer, stomach cancer, gastric cancer, esophageal cancer, pancreatic cancer, and cervical cancer. [The present invention 1020] A method for treating a liver disease, comprising the step of administering an effective amount of any of the compounds of the present inventions 1001 to 1014 to a subject in need thereof. [The present invention 1021] The method of any of claims 1017 to 1020, further comprising the step of administering an effective amount of at least one additional therapeutic agent to a subject in need thereof. [The present invention 1022] The method according to any one of claims 1017 to 1020, wherein the subject is a mammal. [The present invention 1023] The method of any one of claims 1017 to 1020, wherein the subject is a human. [The present invention 1024] The method of the present invention 1021, wherein the additional therapeutic agent is selected from the group of sorafenib, regorafenib, immuno-oncology agents, such as PD-1 or PD-L1 checkpoint inhibitors, for the treatment of HCC. [The present invention 1025] A compound of any of claims 1001 to 1014 for use in treating a disease of the liver, or a disease or condition whose physiological or pathogenic pathway involves the liver, in a subject. [The present invention 1026] Any of the compounds of claims 1001 to 1014 for use in medical treatment. [The present invention 1027] The use of the present invention 1026, wherein the medical procedure is TACE. [The present invention 1028] Use of any of the compounds of claims 1001-1014 in the preparation of a medicament for treating a disease or condition of the liver, or a disease or condition whose physiological or pathogenic pathway involves the liver. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0035] Detailed Description The present embodiments are directed to novel 5-fluorouracil-derived cyclic deoxyribonucleotide compounds, compositions and methods relating to their preparation and their use. In some embodiments, the novel 5-fluorouracil-derived cyclic deoxyribonucleotide compounds facilitate the delivery of 5-fluorouracil-derived therapeutic agents, such as 5-fluorouracil, doxifluridine, 5-fluorouridine monophosphonate and / or 5-fluorodeoxyuridine monophosphonate, to cells.

[0036] These 5-fluorouracil-derived cyclic deoxyribonucleotide compounds and their stereoisomers and pharma- ceutically acceptable salts have the formula I, Ia, or II: TIFF0007625542000015.tif142128 or a stereoisomer or a pharma- ceutically acceptable salt thereof; In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 has any of the values ​​described herein.

[0037] In some embodiments, the compound has Formula I or II: TIFF0007625542000016.tif93128, or stereoisomers and pharma- ceutically acceptable salts thereof, wherein R 1 H, F, C1~C 10Alkyl, -OMe, -OEt, -O-carboxy, -OCH2OR 9 , -CH(OR 9 )2, -C-Carboxy, -C-Amido, -CH2OCH2OR 9 , -TIFF0007625542000017.tif12128, and -CH2O-carboxy; and R 2 is H, F, or C1-C 10 It is an alkyl.

[0038] In some embodiments, R 1 H, Halo, C1~C 10 Alkyl, -OC 1~6 Alkyl, -O-carboxy, -OCH2OR 9 , -CH(OR 9 )2, -C-Carboxy, -C-Amido, -CH2OCH2OR 9 , TIFF0007625542000018.tif12128, and -CH2O-carboxy.

[0039] In some embodiments, each R 2 are independently H, halo, or C1-C 10 It is an alkyl.

[0040] In some embodiments, R 3 is -O-carboxy, -OCH2OR 9 , -CH(OR 9 )2, -C-Carboxy, -C-Amido, -CH2OCH2OR 9 , TIFF0007625542000019.tif12128, -CH2O-Carboxy, C1~C 10 Alkyl, and C3-C 10 cycloalkyl.

[0041] In some embodiments, R 4 is optionally substituted C1-C 10 It is an alkyl.

[0042] In some embodiments, each R 5 and R 6 are independently H or C1-C 10 or alternatively, R 5 and R 6 Together with the atoms to which they are attached, 10 It may also form a cycloalkyl.

[0043] In some embodiments, each R 7 and R 8 are independently H or C1-C 10 or alternatively, R 7 and R 8 Together with the atoms to which they are attached, 10 It may also form a cycloalkyl.

[0044] In some embodiments, R 9 is optionally substituted C1-C 10 It is an alkyl.

[0045] In some embodiments, the compound is Not selected from TIFF0007625542000020.tif205154 and TIFF0007625542000021.tif182154.

[0046] In some embodiments, R 1 is H; and R 2 is H or F.

[0047] In some embodiments, R 1 -OMe, -OEt, -O-carboxy, -OCH2OR 9 , -CH(OR 9 )2, -C-Carboxy, -C-Amido, -CH2OCH2OR 9 , TIFF0007625542000022.tif12128, and -CH2O-carboxy.

[0048] In some embodiments, R 1 is F. In some embodiments, R 1 is -C-carboxy.

[0049] In some embodiments, R 2 is H. In some embodiments, R 2 is F.

[0050] In some embodiments, R 3 is -O-carboxy, -OCH2OR 9 , -CH(OR 9 )2, -C-Carboxy, -C-Amido, -CH2OCH2OR 9 , In some embodiments, R is selected from the group consisting of -TIFF0007625542000023.tif12128, and -CHO-carboxy. 3 is C1~C 10 Alkyl or C3-C 10 It is cycloalkyl.

[0051] Some embodiments are of formula Ia: The present invention relates to a compound having the structure of TIFF0007625542000024.tif38128, or a stereoisomer or pharma- ceutically acceptable salt thereof.

[0052] In some embodiments, R 4 is C1~C 10 It is an alkyl.

[0053] In some embodiments, each R 2 is H.

[0054] Some embodiments include TIFF0007625542000025.tif82152TIFF0007625542000026.tif214152TIFF0007625542000027.tif122152, or a stereoisomer or pharma- ceutically acceptable salt thereof.

[0055] In some embodiments, the 5-fluorouracil-derived cyclic deoxyribonucleotide compounds of Formulas I and II are substrates for hepatic enzymes such as the cytochrome p450 isoenzyme CYP3A (a family of monooxygenases), dehydrogenases, esterases, and amidases.

[0056] CYP3A4 is expressed in the liver at a much higher level than 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 primarily activated in the liver through CYP3A4. In some embodiments, compounds of formula I and II have high efficiency in liver targeting through selective delivery of biologically active agents to the liver. In some embodiments, compounds of formula I and II are used to increase the therapeutic index of drugs, since they are likely to have no or low activity outside the liver.

[0057] In some embodiments, the liver targeting of the 5-fluorouracil-derived cyclic deoxyribonucleotide compounds of Formulas I and II allows the compounds to be used to treat diseases that benefit from improved drug distribution to the liver and similar tissues and cells, including, but not limited to, diseases of the liver such as hepatocellular carcinoma.

[0058] In some embodiments, the disclosed compounds are used to improve pharmacokinetic properties, such as increasing half-life or improving drug absorption.In addition, the disclosed methodology can be used to achieve sustained delivery of active therapeutic agents.The improved pharmacokinetic properties of the 5-fluorouracil-derived cyclic deoxyribonucleotide compounds of formula I and II allow the compounds to be used to treat diseases that benefit from improved drug properties, including but not limited to diseases such as various types of cancer.In some embodiments, methods for making these compounds are described.

[0059] When referring to compounds of formula I and II in general, certain compounds of formula I and II have asymmetric centers where the stereochemistry is not necessarily specified, and includes diastereomeric mixtures of these compounds as well as individual stereoisomers.

[0060] Some embodiments of the compounds, compositions and methods provided herein include a pharmaceutical composition comprising a compound provided herein and a pharma- ceutically acceptable carrier.

[0061] Some embodiments relate to pharmaceutical compositions further comprising one or more anti-cancer agents.

[0062] Some embodiments relate to methods of treating a disease, disorder, or condition comprising administering to a subject in need thereof an effective amount of a compound described herein.

[0063] Some embodiments also include administering to a subject in need thereof an effective amount of a second or more therapeutic agents in combination with the compounds provided herein.

[0064] In some embodiments, the subject is a mammal.

[0065] In some embodiments, the subject is a human.

[0066] Some embodiments of the compounds, compositions and methods provided herein include methods of testing a compound in a cell, comprising contacting a cell with a disclosed compound.

[0067] Some embodiments of the compounds, compositions and methods provided herein include the use of the compounds provided herein in the treatment of a disease, disorder, or condition of the liver.

[0068] Some embodiments include the use of the compounds provided herein in combination with an additional therapeutic agent for the treatment of diseases of the liver.

[0069] In some embodiments, the disease, disorder, or condition is selected from the group consisting of hepatocellular carcinoma, renal cancer, colorectal cancer, breast cancer, stomach cancer, gastric cancer, esophageal cancer, pancreatic cancer, and cervical cancer.

[0070] Some embodiments relate to a method of treating liver disease comprising administering to a subject in need thereof an effective amount of a compound described herein.

[0071] Some embodiments further comprise administering to a subject in need thereof an effective amount of at least one additional therapeutic agent.

[0072] In some embodiments, the additional therapeutic agent is selected from the group of sorafenib, regorafenib, immuno-oncology agents, such as PD-1 or PD-L1 checkpoint inhibitors, for the treatment of HCC.

[0073] Some embodiments relate to the compounds described herein for use in medical treatment.

[0074] In some embodiments, the medical procedure is transarterial chemoembolization (TACE).

[0075] Some embodiments of the compounds, compositions and methods provided herein include the use of the compounds provided herein in the treatment of a disease or condition by intervening in a molecular pathway in the liver.

[0076] Some embodiments include the use of the compounds provided herein in combination with an additional therapeutic agent for the treatment of a disease or condition by intervening in a molecular pathway in the liver.

[0077] Some embodiments of the compounds, compositions and methods provided herein include the use of the compounds provided herein in the treatment of non-liver diseases, such as various types of cancer.

[0078] Some embodiments include the use of the compounds provided herein in combination with additional therapeutic agents for the treatment of non-liver diseases, such as various types of cancer.

[0079] 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. Separation of individual isomers or selective synthesis of individual isomers can be achieved by applying various methods well known to those skilled in the art. Unless otherwise indicated, all such isomers and mixtures thereof are included in the scope of the compounds disclosed herein. Furthermore, the compounds disclosed herein can exist in one or more crystalline or amorphous forms. Unless otherwise indicated, all such forms are included in the scope of the compounds disclosed herein, including any polymorphic forms. In addition, some of the compounds disclosed herein can form solvates with water (i.e., hydrates) or common organic solvents. Unless otherwise indicated, such solvates are included in the scope of the compounds disclosed herein.

[0080] Those skilled in the art will recognize that some of the structures depicted herein may be resonance forms or tautomers of compounds that may be properly represented by other chemical structures, even if kinetic ones; those skilled in the art will recognize that such structures may represent only a small portion of the instances of such compounds. Although such compounds are considered to be within the scope of the depicted structures, such resonance forms or tautomers are not depicted herein.

[0081] Isotopes may exist in the compounds described. Each chemical element represented in the compound structure may include any isotope of the element. For example, in the compound structure, hydrogen atoms may be expressly disclosed or interpreted as existing in the compound. In any position of the compound where a hydrogen atom may exist, the hydrogen atom may be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all possible isotopic forms, unless the context clearly indicates otherwise.

[0082] definition In accordance with this disclosure and as used herein, the following terms are defined with the following meanings unless otherwise indicated: It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not limitations of the claimed subject matter. In this application, the use of the singular includes the plural unless specifically stated otherwise. In this application, the use of "or" means "and / or" unless specifically stated otherwise. Furthermore, the use of the term "including" and other forms such as "includes" and "included" are not exclusive.

[0083] As used herein, ranges and amounts may be expressed as "about" a particular value or range. "About" includes the exact amount. Thus, "about 10%" means "about 10%" and also "10%."

[0084] As used herein, "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes cases where the event or circumstance occurs and cases where it does not occur. For example, an optionally substituted group means that the group is unsubstituted or substituted.

[0085] 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 containing "a therapeutic agent" includes a composition containing one or more therapeutic agents.

[0086] As used herein, "C" refers to a set of integers where "a" and "b" are integers. a ~C b " or "C a~b " refers to the number of carbon atoms in the specified group. That is, a group may contain from "a" to "b" (inclusive) carbon atoms. Thus, for example, "C1-C4 alkyl" or "C 1~4 An "alkyl" group refers to all alkyl groups having 1 to 4 carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-.

[0087] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain that is fully saturated (i.e., contains no double or triple bonds). An alkyl group may have 1-20 carbon atoms (wherever it appears herein, a numerical range such as "1-20" refers to each integer within the given range; for example, "1-20 carbon atoms" means that an alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, but this definition also extends to occurrences of the term "alkyl" where no numerical range is specified). An alkyl group may also be a medium-sized alkyl having 1-9 carbon atoms. An alkyl group may also be a lower alkyl having 1-4 carbon atoms. An alkyl group may be referred to as "C1-C4 alkyl" or similar designations. By way of example only, "C1-C4 alkyl" indicates that there are 1-4 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 t-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.

[0088] As used herein, a substituted group is derived from an unsubstituted parent group in which one or more hydrogen atoms have been replaced with another atom or group. Unless otherwise indicated, when a group is considered to be "substituted", the group can be any of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 carbocyclyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7-carbocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 3-C7-aryl ... 10-membered heterocyclyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 3-10-membered heterocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy). aryl(C1-C6)alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy); 5-10 membered heteroaryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy); 5-10 membered heteroaryl(C1-C6)alkyl (halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy); haloalkoxy), halo, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy(C1-C6)alkyl (i.e., ether), aryloxy (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7 carbocyclyloxy (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy),3-10 membered heterocyclyl-oxy (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heteroaryl-oxy (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7-carbocyclyl-C1-C6-alkoxy (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy, 3-10 membered heterocyclyl-C1-C6-alkoxy (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl(C1-C6)alkoxy (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heteroaryl(C1-C6)alkoxy (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), alkoxy), sulfhydryl (mercapto), halo(C1-C6)alkyl (e.g., -CF3), halo(C1-C6)alkoxy (e.g., -OCF3), C1-C6 alkylthio, arylthio (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7 carbocyclylthio (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 3-1 0-membered heterocyclyl-thio (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10-membered heteroaryl-thio (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7-carbocyclyl-C1-C6-alkylthio (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy),3-10 membered heterocyclyl-C1-C6-alkylthio (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl(C1-C6)alkylthio (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heteroaryl(C1-C6)alkylthio (halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloaryl, and C1-C6 haloalkoxy), It is meant that the group is substituted with one or more substituents independently selected from: amino, amino(C1-C6)alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, and oxo (=O). Whenever a group is described as "optionally substituted," the group can be substituted with the above-mentioned substituents.

[0089] As used herein, "acyl" refers to -C(=O)R, where R is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl. Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acryl.

[0090] "Heteroacyl" refers to -C(=O)R, where R is C 1~6 It is heteroalkyl.

[0091] "Alkyloxymethylene" refers to -CHOR, where R is C 1~6 It is alkyl or heteroalkyl, either of which may be substituted.

[0092] An "O-carboxy" group refers to a "-OC(=O)R" group, where R is hydrogen, C, 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl.

[0093] A "C-carboxy" group refers to a "-C(=O)OR" group, where R is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 Selected from aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl. Non-limiting examples include carboxyl (i.e., -C(=O)OH).

[0094] A "cyano" group refers to a "-CN" group.

[0095] A "cyanato" group refers to a "-OCN" group.

[0096] An "isocyanato" group refers to a "-NCO" group.

[0097] A "thiocyanato" group refers to a "-SCN" group.

[0098] An "isothiocyanato" group refers to a "-NCS" group.

[0099] A "sulfinyl" group refers to a "-S(=O)R" group, where R is hydrogen, C, 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl.

[0100] A "sulfonyl" group refers to a "-SO2R" group, where R is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl.

[0101] The "S-sulfonamide" group is "-SONR A R B " group, where R A and R B are each independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl.

[0102] The "N-sulfonamide" group is "-N(R A )SO2R B " group, where R A and R b are each independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl.

[0103] The "O-carbamyl" group is "-OC(=O)NR A R B " group, where R A and R B are each independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl.

[0104] The "N-carbamyl" group is "-N(R A )C(=O)OR B " group, where R A and R B are each independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl.

[0105] The "O-thiocarbamyl" group is "-OC(=S)NR A R B " group, where R A and R B are each independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl.

[0106] The "N-thiocarbamyl" group is "-N(R A )C(=S)OR B " group, where R A and R B are each independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl.

[0107] The "C-amide" group is "-C(=O)NR A R B " group, where R A and R B are each independently hydrogen, —OH, C 1~6 Alkyl, C 3~7 Carbocyclyl, C 6~10 Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, C 1~6 C optionally substituted with alkoxy or -OH 1~6 Alkyl, and C 1~6 C optionally substituted with alkoxy or -OH 1~6 C, optionally substituted with one or more substituents selected from the group consisting of alkoxy 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl.

[0108] The "N-amide" group is "-N(R A )C(=O)R B " group, where R A and R B are each independently hydrogen, —OH, C 1~6 Alkyl, C 3~7 Carbocyclyl, C 6~10 Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, C 1~6 C optionally substituted with alkoxy or -OH 1~6 Alkyl, and C 1~6 C optionally substituted with alkoxy or -OH 1~6 C, optionally substituted with one or more substituents selected from the group consisting of alkoxy 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10It is selected from aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl.

[0109] The "amino" group is "-NR A R B " group, where R A and R B are each independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 Selected from aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl. Non-limiting examples include free amino (i.e., -NH2).

[0110] An "aminoalkyl" group refers to an amino group linked via an alkylene group.

[0111] The "alkoxyalkyl" group is 2~8 "Alkoxyalkyl" refers to an alkoxy group linked via an alkylene group.

[0112] The term "acyloxy" refers to -OC(O)R, where R is alkyl.

[0113] The term "alkoxy" or "alkyloxy" refers to OR, where R is alkyl or heteroalkyl, either of which may be optionally substituted.

[0114] The term "carboxyl" refers to C(O)OH.

[0115] The term "oxo" refers to the group ═O.

[0116] The term "halogen" or "halo" refers to F (fluoro), Cl (chloro), Br (bromo) and I (iodo).

[0117] The term "haloalkyl" refers to an alkyl group that contains at least one halogen, and in a further aspect 1 to 3 halo atoms. Suitable halo atoms include F, Cl, and Br.

[0118] The term "haloacyl" refers to a -C(O)-haloalkyl group.

[0119] The term "alkenyl" refers to unsaturated groups having 2 to 12 atoms and containing at least one carbon-carbon double bond, including straight-chain, branched-chain and cyclic groups. Alkenyl groups may be substituted. Suitable alkenyl groups include allyl.

[0120] The term "alkynyl" refers to unsaturated groups 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.

[0121] As used herein, "aryl" refers to an aromatic ring or ring system (i.e., two or more fused rings sharing two adjacent carbon atoms) that contains only carbon in the ring backbone. When an aryl is a ring system, all rings in the system are aromatic. An aryl group may have from 6 to 18 carbon atoms, although this definition extends to occurrences of the term "aryl" where no numerical range is specified. In some embodiments, an aryl group has from 6 to 10 carbon atoms. An aryl group is defined as "C 6~10 Aryl, C6 or C 10 Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.

[0122] As used herein, "heteroaryl" refers to an aromatic ring or ring system (i.e., two or more fused rings sharing two adjacent atoms) that contains one or more heteroatoms, i.e., elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur, in the ring backbone. When a heteroaryl is a ring system, all rings in the system are aromatic. Heteroaryl groups may have 5-18 ring members (i.e., the number of atoms that make up the ring backbone, including carbon atoms and heteroatoms), although this definition also encompasses occurrences of the term "heteroaryl" where no numerical range is specified. In some embodiments, heteroaryl groups have 5-10 ring members or 5-7 ring members. Heteroaryl groups may be referred to as "5-7 membered heteroaryl," "5-10 membered heteroaryl," or similar names. Heteroaryl groups may be substituted. Examples of heteroaryl groups include, but are not limited to, aromatic C3-8 heterocyclic groups containing one oxygen or sulfur atom or up to four nitrogen atoms, or a combination of one oxygen or sulfur atom and up to two nitrogen atoms, and substituted and benzo- and pyrido-fused derivatives thereof, e.g., linked through one of the ring-forming carbon atoms. In some embodiments, heteroaryl groups are halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, C 1~6 -Alkoxy, C 1~6 -Alkyl, C 1~6-optionally substituted with one or more substituents independently selected from hydroxyalkyl, C1-6-aminoalkyl, C1-6-alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl. Examples of heteroaryl groups include, but are not limited to, unsubstituted and mono- or di-substituted derivatives of 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, quinolizine, cinnoline, phthalazine, quinazoline, and quinoxaline. In some embodiments, the substituents are halo, hydroxy, cyano, OC 1~6 -Alkyl, C 1~6 -Alkyl, Hydroxy-C 1~6 -Alkyl, and amino-C 1~6 -alkyl.

[0123] As used herein, "cycloalkyl" means a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. A cycloalkyl group may have from 3 to 10 carbon atoms (wherever it appears herein, numerical ranges such as "3-10" refer to each integer within the given range). A cycloalkyl group may be referred to as "C3-C8 cycloalkyl" or similar designations. By way of example only, "C3-C8 cycloalkyl" denotes that there are from 3 to 8 carbon atoms in the carbocyclyl ring or ring system.

[0124] As used herein, "heterocyclyl" refers to a non-aromatic cyclic ring or ring structure that is fully or partially saturated and contains at least one heteroatom selected from nitrogen, oxygen, and sulfur in the ring backbone. Heterocyclyl may have any degree of saturation, provided that at least one ring in the ring system is not aromatic. The heteroatom may be present in either a non-aromatic or aromatic ring in the ring system. Heterocyclyl groups may have 3 to 20 ring members (i.e., the number of atoms that make up the ring backbone, including carbon atoms and heteroatoms), although this definition extends to occurrences of the term "heterocyclyl" where no numerical range is specified. Heterocyclyl groups may also be medium-sized heterocyclyls having 3 to 10 ring members. Heterocyclyl groups may also be heterocyclyls having 3 to 6 ring members. Heterocycloalkyl groups are also referred to as "3- to 15-membered heterocycloalkyls," "4- to 10-membered heterocycloalkyls," "3- to 15-membered heterocycloalkyls," "4- to 15-membered heterocycloalkyls," "5- to 15-membered heterocycloalkyls," "6- to 15-membered heterocycloalkyls," "8- to 15-membered heterocycloalkyls," "9- to 15-membered heterocycloalkyls," "10- to 15-membered heterocycloalkyls," "15- to 15-membered heterocycloalkyls," "20- to 20-membered heterocycloalkyls," "30- to 20-membered heterocycloalkyls," "40- to 15-membered heterocycloalkyls," "50- to 15-membered heterocycloalkyls," "15- to 20-membered heterocycloalkyls," "10- to 20-membered heterocycloalkyls," "20- to 20-membered heterocycloalkyls," "30- to 20-membered heterocycloalkyl 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 3~5Heterocyclyl groups may be referred to as "C2-C9 heterocyclyl" or similar names. Heterocyclyl groups may be C2-C9 heterocyclyl having 3-10 ring members with from 1 to up to 3 O (oxygen), N (nitrogen) or S (sulfur). Heterocyclyl groups may be referred to as "3-10 membered C2-C9 heterocyclyl" or similar names. In preferred 6-membered monocyclic heterocyclyls, the heteroatoms are selected from 1 to up to 3 O (oxygen), N (nitrogen) or S (sulfur), and in preferred 5-membered monocyclic heterocyclyls, the heteroatoms are selected from 1 or 2 heteroatoms selected from O (oxygen), N (nitrogen) or S (sulfur). Examples of heterocyclyl rings are azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidionyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyi, 1,4-oxathiynyl, 1,4-oxathianyi, 2H-1,2-oxazinyl, trioxanyl, hexahydro, 1,2-dioxazinyl ... -1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, and tetrahydroquinoline.

[0125] Whenever a substituent is shown as a diradical (i.e., having two points of attachment to the remainder of the molecule), it is understood that the substituent can be attached in any orientation unless otherwise indicated. Thus, for example, -AE- or A substituent depicted as TIFF0007625542000028.tif8128 includes the substituent oriented such that A is attached to the leftmost attachment point of the molecule as well as the substituent oriented such that A is attached to the rightmost attachment point of the molecule.

[0126] The term "therapeutically effective amount" refers to an amount of a compound or combination of compounds that partially or completely reverses, reduces, or eliminates one or more symptoms of a particular disease or condition, or prevents, alters, 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 according to a regimen in which it is effective. Repeated administration may be required to achieve the desired result (e.g., treatment of a disease and / or condition).

[0127] The term "pharmaceutically acceptable salts" includes salts of the compounds of formulas I, II, and III derived from the combination of the compounds of the present embodiment with an organic or inorganic acid or base. 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, methylbromide acid, methylsulfuric ... acid), 2-naphthalenesulfonic acid, oleic acid, 4,4'-methylenebis-[3-hydroxy-2-naphthalenecarboxylic acid], polygalacturonic acid, stearic acid, sulfosalicylic acid, tannic acid, terphthalic acid, and the like. Inorganic bases from which salts can be derived include bases containing, for example, 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 the compounds disclosed herein with an inorganic base results in the loss of a labile hydrogen from the compound, resulting in the loss of 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, specifically, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, and the like.

[0128] Where the number of any given substituent is not specified (e.g., "haloalkyl"), one or more substituents may be present. For example, "haloalkyl" can include one or more of the same or different halogens. For example, "haloalkyl" includes each of the substituents CF3, CHF2, and CH2F.

[0129] The term "patient" refers to the animal being treated, including mammals such as dogs, cats, cows, horses, sheep, and humans. In some embodiments, the patient is a mammal, either male or female. In some embodiments, the patient is a male or female human.

[0130] The term "prodrug" as used herein refers to any compound that, when administered to a biological system, results in a biologically active compound as a result of spontaneous, enzyme-catalyzed, and / or metabolic chemical reactions, or a combination of each. Standard prodrugs are formed with groups attached to the functional groups associated with the drug, such as HO-, HS-, HOOC-, HOOPR2-, etc., that are cleaved in vivo. Standard prodrugs include, but are not limited to, carboxylic acid esters, where the group is alkyl, aryl, aralkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and hydroxyl, thiol, and amine esters, where the attached group is acyl, alkoxycarbonyl, aminocarbonyl, phosphate, or sulfate. The groups listed are examples and are not exhaustive, and a variety of other known prodrugs can be prepared by one of ordinary skill in the art. Prodrugs must undergo some form of chemical transformation to produce a compound that is biologically active or a precursor to the biologically active compound. In some cases, prodrugs are biologically active, although usually less so than the drug itself, and serve to improve the efficacy or safety of a drug through improved oral bioavailability, pharmacodynamic half-life, etc. Prodrug forms of a compound may be utilized, for example, to improve bioavailability, improve subject acceptability, such as by masking or reducing unpleasant characteristics such as bitter taste or gastrointestinal irritation, modify 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.

[0131] The term "stereoisomer" refers to the relative or absolute spatial relationships of the R groups attached to a stereocenter, either a carbon or phosphorus atom, and refers to an individual isomer or any combination of individual isomers, such as racemic and diastereomeric mixtures. When a compound has two stereocenters, four stereoisomers are possible.

[0132] The term "hepatic" refers to the organ called the liver.

[0133] The term "liver specificity" refers to the ratio measured in animals treated with a drug or prodrug: [Drug or drug metabolites in liver tissue] / [Drug or drug metabolites in blood or other tissues] The ratio can be determined by measuring tissue levels at specific times, or may represent the AUC (area under the curve) based on values ​​measured at three or more time points.

[0134] The term "increased or improved 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.

[0135] The term "enhanced oral bioavailability" refers to an increase in absorption of a dose of a reference drug by at least about 50%. In an additional aspect, the increase in oral bioavailability of a compound (relative to a reference drug) is at least about 100%, i.e., a doubling of absorption. Measurement of oral bioavailability typically refers to the measurement of prodrug, drug, or drug metabolites in blood, plasma, tissues, or urine following oral administration compared to measurements following parenteral administration.

[0136] 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 undesirable response such as death, elevation of a marker indicative of toxicity, and / or side pharmacological effects.

[0137] The term "sustained delivery" refers to the increased period of time during which therapeutically effective drug levels are extended due to the presence of a prodrug.

[0138] The term "treating" or "treatment" of a disease includes inhibiting the disease (slowing, halting or partially halting its progression), preventing the disease, providing relief from the symptoms or side effects of the disease (including palliative treatment), and / or relieving the disease (causing regression of the disease).

[0139] The term "biological agent" refers to a compound that has biological activity or has molecular properties that can be used for therapeutic or diagnostic purposes, such as compounds with radioisotopes or heavy atoms.

[0140] 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 a physiological or pathophysiological function in a living animal.

[0141] Administration and Pharmaceutical Compositions The disclosed compounds may be used alone or in combination with other treatments. When used in combination with other drugs, these compounds may be administered in a daily dose or an appropriate fraction of a daily dose (e.g., twice a day). The compounds may be administered after a course of treatment with another drug, during a course of therapy with another drug, as part of a treatment regimen, or before therapy with another drug in a treatment program.

[0142] Examples of pharma- ceutically acceptable salts include acetate, adipate, besylate, bromide, camsylate, chloride, citrate, edisylate, estolate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hyclate, hydrobromide, hydrochloride, iodide, isethionate, lactate, lactobionate, maleate, mesylate, methyl bromide, methyl sulfate, napsylate, nitrate, oleate, palmoate, phosphate, polygalacturonate, stearate, succinate, sulfate, sulfosalicylate, tannate, tartrate, terphthalate, tosylate, and ethyl triiodide.

[0143] The composition containing the active ingredient may be in any form suitable for the intended method of administration. In some embodiments, the compounds of the methods and / or compositions described herein may be provided via oral, rectal, transmucosal, intestinal, enteral, topical, transdermal, intrathecal, intraventricular, intraperitoneal, intranasal, intraocular and / or parenteral administration.

[0144] When the compound is administered via oral administration, it may be prepared, for example, in the form of tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents, including sweeteners, flavorings, colorants and preservatives, to provide a palatable preparation. Tablets containing the active ingredient in combination with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents such as calcium or sodium carbonate, lactose, calcium 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 may be uncoated or may be coated by known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract, thereby providing a sustained action 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.

[0145] Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient may be mixed with an inert solid diluent, for example, 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.

[0146] Preparations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions, which may contain, for example, antioxidants, buffers, bacteriol, and solutes that 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 provided in unit-dose or multi-dose sealed containers, such as ampoules and vials, or may be stored in a freeze-dried (lyophilized) state, requiring only the addition of a sterile liquid carrier, such as water for injection, immediately prior to use. Injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the type previously described.

[0147] In some embodiments, unit dose formulation contains a daily dose or unit of drug, a daily dose portion, or a suitable fraction thereof.However, it will be understood that the specific dose level for any particular patient will vary according to various 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; excretion rate; other drugs previously administered; the severity of the specific disease being treated, as well understood by those skilled in the art.

[0148] The actual dose of the compounds described herein will vary depending on the specific compound and the condition being treated; selection of the appropriate dose 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 of body weight. Thus, for administration to a 70 kg person, the dosage range would be from about 7 mg per day to about 7000 mg per day, from about 35 mg per day to about 2000 mg per day or more, from about 70 mg per day to about 1000 mg per day.

[0149] Treatment methods Some embodiments include a method for treating a disease, disorder or condition selected from the group consisting of 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 a subject in need thereof.In some embodiments, the subject can be an animal, for example a mammal, a human.In some embodiments, the subject is a human.

[0150] Further embodiments include administering a combination of compounds to a subject in need thereof. The combination may include a compound, composition, or pharmaceutical composition described herein with an additional drug.

[0151] Some embodiments include co-administering the compounds, compositions, and / or pharmaceutical compositions described herein with additional drugs or additional therapeutic agents. By "co-administered" it is meant that two or more agents can be found in the patient's bloodstream at the same time, regardless of when or how they are actually administered. In one embodiment, the agents are administered simultaneously. In one such embodiment, administration in combination is achieved by combining the agents in a single dosage form. In another embodiment, the agents are administered sequentially. In one embodiment, the agents are administered via the same route, such as orally. In another embodiment, the agents are administered via different routes, such as one being administered orally and the other being administered intravenously.

[0152] Examples of additional drugs include therapeutic agents selected from the group consisting of other types of chemotherapy agents such as cyclophosphamide, methotrexate, doxorubicin, docetaxel, cisplatin, epirubicin, oxaliplatin, and folinic acid; and other targeted antitumor agents such as HDAC inhibitors. In some embodiments, the additional therapeutic agent for treating HCC may be one or more of sorafenib, regorafenib, immuno-tumor agents, such as PD-1 or PD-L1 checkpoint inhibitors.

[0153] Examples of additional agents also include medical procedures selected from the group consisting of tumor resection, selective internal radiation therapy (SIRT), and transarterial chemoembolization (TACE).

[0154] The following examples are included to further illustrate the compounds described herein.The examples should not be interpreted as specifically limiting the scope of the compounds, of course.Variations of these examples that are within the scope of claims are within the knowledge of those skilled in the art and are considered to be within the scope of the compounds described and claimed herein.Readers will recognize that those skilled in the art with this disclosure and the skills in the field can prepare and use compounds without exhaustive examples.

[0155] Synthesis of compounds The following procedures for the preparation of novel compounds outline the general procedure used to prepare 5-fluorouracil-derived cyclic deoxyribonucleotide compounds.

[0156] Scheme I describes the general synthesis of compounds of formula I and II. Floxuridine (1) is reacted with phosphanediamine (2) in the presence of 4,5-dicyanoimidazole to give the cyclic products of structure 3, and the crude reaction mixture is then treated with an oxidizing agent such as tert-butyl hydroperoxide to give the final products of structure 4. TIFF0007625542000029.tif70153R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , and R 8 has any of the values ​​described herein. EXAMPLES

[0157] Some compounds of formula I and II are prepared as outlined below.

[0158] Example 1 5-Fluoro-1-((4aR,6R,7aS)-2-(heptyloxy)-2-oxidetetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinine-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 101) TIFF0007625542000030.tif24128

[0159] Compound 101 was prepared from N,N,N',N'-tetraisopropyl-1-heptyloxyphosphanediamine and floxuridine according to the method described in Scheme I and was isolated as a mixture of two isomers. 16 H 24 FN2O7P's [M-1] + Calculated: 405.12; Measured: 405.0.

[0160] Example 2 5-Fluoro-1-((4aR,6R,7aS)-2-(octyloxy)-2-oxidetetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinine-6-yl)pyrimidine-2,4(1H,3H)-dione (compound 102) TIFF0007625542000031.tif24128

[0161] Compound 102 was prepared from N,N,N',N'-tetraisopropyl-1-octyloxyphosphanediamine and floxuridine according to the method described in Scheme I and was isolated as a mixture of two isomers. 17 H 26 FN2O7P's [M-1] + Calculated: 419.14; Measured: 419.0.

[0162] Example 3 5-Fluoro-1-((4aR,6R,7aS)-2-(6-methylheptyloxy)-2-oxidetetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinine-6-yl)pyrimidine-2,4(1H,3H)-dione (compound 103) TIFF0007625542000032.tif24128

[0163] Compound 103 was prepared from N,N,N',N'-tetraisopropyl-1-(6-methylheptyloxy)phosphanediamine and floxuridine according to the method described in Scheme I and was isolated as a mixture of two isomers. 17 H 26 FN2O7P's [M-1] + Calculated: 419.14; Measured: 419.0.

[0164] Example 4 5-Fluoro-1-((4aR,6R,7aS)-2-(cyclopropylmethyloxy)-2-oxidetetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinine-6-yl)pyrimidine-2,4(1H,3H)-dione (compound 104) TIFF0007625542000033.tif24128

[0165] Compound 104 was prepared from N,N,N',N'-tetraisopropyl-1-(cyclopropylmethyloxy)phosphanediamine and floxuridine according to the method described in Scheme I and was isolated as a mixture of two isomers. 13 H 16 FN2O7P's [M-1] + Calculated: 361.06; Measured: 361.0.

[0166] Example 5 5-Fluoro-1-((4aR,6R,7aS)-2-(cyclopentylmethyloxy)-2-oxidetetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinine-6-yl)pyrimidine-2,4(1H,3H)-dione (compound 105) TIFF0007625542000034.tif24128

[0167] Compound 105 was prepared from N,N,N',N'-tetraisopropyl-1-(cyclopentylmethyloxy)phosphanediamine and floxuridine according to the method described in Scheme I and was isolated as a mixture of two isomers. 15 H 20 FN2O7P's [M-1] + Calculated: 389.09; Measured: 389.0.

[0168] Example 6 5-Fluoro-1-((4aR,6R,7aS)-2-(2-cyclopentylethyloxy)-2-oxidetetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinine-6-yl)pyrimidine-2,4(1H,3H)-dione (compound 106) TIFF0007625542000035.tif24128

[0169] Compound 106 was prepared from N,N,N',N'-tetraisopropyl-1-(2-cyclopentylethyloxy)phosphanediamine and floxuridine according to the method described in Scheme I and was isolated as a mixture of two isomers. 16 H 22 FN2O7P's [M-1] + Calculated: 403.10; Measured: 403.0.

[0170] Example 7 5-Fluoro-1-((4aR,6R,7aS)-2-(3-cyclopentylpropyloxy)-2-oxidetetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinine-6-yl)pyrimidine-2,4(1H,3H)-dione (compound 107) TIFF0007625542000036.tif24128

[0171] Compound 107 was prepared from N,N,N',N'-tetraisopropyl-1-(3-cyclopentylpropyloxy)phosphanediamine and floxuridine according to the method described in Scheme I and was isolated as a mixture of two isomers. 17 H 24 FN2O7P's [M+1] + Calculated: 419.14; Measured: 419.1.

[0172] Example 8 5-Fluoro-1-((4aR,6R,7aS)-2-(2-methoxybenzyloxy)-2-oxidetetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinine-6-yl)pyrimidine-2,4(1H,3H)-dione (compound 108) TIFF0007625542000037.tif24128

[0173] Compound 108 was prepared from N,N,N',N'-tetraisopropyl-1-(2-methoxybenzyloxy)phosphanediamine and floxuridine according to the method described in Scheme I and was isolated as a mixture of two isomers. 17 H 18FN2O8P's [M-1] + Calculated: 427.07; Measured: 427.0.

[0174] Example 9 5-Fluoro-1-((4aR,6R,7aS)-2-(4-fluorophenethoxy)-2-oxidetetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinine-6-yl)pyrimidine-2,4(1H,3H)-dione (compound 109) TIFF0007625542000038.tif24128

[0175] Compound 109 was prepared from N,N,N',N'-tetraisopropyl-1-(4-fluorophenethoxy)phosphanediamine and floxuridine according to the method described in Scheme I and was isolated as a mixture of two isomers. 17 H 17 F2N2O8P [M-1] + Calculated: 429.06; Measured: 429.0.

[0176] Example 10 5-Fluoro-1-((4aR,6R,7aS)-2-(3-fluorophenethoxy)-2-oxidetetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinine-6-yl)pyrimidine-2,4(1H,3H)-dione (compound 110) TIFF0007625542000039.tif24128

[0177] Compound 110 was prepared from N,N,N',N'-tetraisopropyl-1-(3-fluorophenethoxy)phosphanediamine and floxuridine according to the method described in Scheme I and was isolated as a mixture of two isomers. 17 H 17 F2N2O8P [M-1] + Calculated: 429.06; Measured: 429.0.

[0178] Example 11 5-Fluoro-1-((4aR,6R,7aS)-2-(2,4-difluorophenethoxy)-2-oxidetetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinine-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 111) TIFF0007625542000040.tif24128

[0179] Compound 111 was prepared from N,N,N',N'-tetraisopropyl-1-(2,4-difluorophenethoxy)phosphanediamine and floxuridine according to the method described in Scheme I and was isolated as a mixture of two isomers. 17 H 16 F3N2O8P [M-1] + Calculated: 447.05; Measured: 447.0.

[0180] Example 12 5-Fluoro-1-((4aR,6R,7aS)-2-(4-methylphenethoxy)-2-oxidetetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinine-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 112) TIFF0007625542000041.tif24128

[0181] Compound 112 was prepared from N,N,N',N'-tetraisopropyl-1-(4-methylphenethoxy)phosphanediamine and floxuridine according to the method described in Scheme I and was isolated as a mixture of two isomers. 18 H 20 FN2O8P's [M-1] + Calculated: 425.09; Measured: 425.1.

[0182] Example 13 5-Fluoro-1-((4aR,6R,7aS)-2-(2-fluorophenethoxy)-2-oxidetetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinine-6-yl)pyrimidine-2,4(1H,3H)-dione (compound 113) TIFF0007625542000042.tif24128

[0183] Compound 113 was prepared from N,N,N',N'-tetraisopropyl-1-(2-fluorophenethoxy)phosphanediamine and floxuridine according to the method described in Scheme I and was isolated as a mixture of two isomers. 17 H 17 F2N2O8P [M-1] + Calculated: 429.06; Measured: 429.1.

[0184] Example 14 5-Fluoro-1-((4aR,6R,7aS)-2-(2,6-difluorophenethoxy)-2-oxidetetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinine-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 114) TIFF0007625542000043.tif27128

[0185] Compound 114 was prepared from N,N,N',N'-tetraisopropyl-1-(2,6-difluorophenethoxy)phosphanediamine and floxuridine according to the method described in Scheme I and was isolated as a mixture of two isomers. 17 H 16 F3N2O8P [M-1] + Calculated: 447.05; Measured: 447.1.

[0186] Example 15 5-Fluoro-1-((4aR,6R,7aS)-2-(2,4,6-trifluorophenethoxy)-2-oxidetetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinine-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 115) TIFF0007625542000044.tif27128

[0187] Compound 115 was prepared from N,N,N',N'-tetraisopropyl-1-(2,4,6-trifluorophenethoxy)phosphanediamine and floxuridine according to the method described in Scheme I and was isolated as a mixture of two isomers. 17 H 15 F4N2O8P's [M-1] + Calculated: 465.05; Measured: 465.0.

[0188] Example 16 5-Fluoro-1-((4aR,6R,7aS)-2-(4-fluoro-2-methylbenzyloxy)-2-oxidetetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinine-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 116) TIFF0007625542000045.tif24128

[0189] Compound 116 was prepared from N,N,N',N'-tetraisopropyl-1-(2-methoxybenzyloxy)phosphanediamine and floxuridine according to the method described in Scheme I and was isolated as a mixture of two isomers. 17 H 17 F2N2O8P [M-1] + Calculated: 429.06; Measured: 429.1.

[0190] Example 17 5-Fluoro-1-((4aR,6R,7aS)-2-oxido-2-((1-phenylcyclopropyl)methoxy)tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinine-6-yl)pyrimidine-2,4(1H,3H)-dione (compound 117) TIFF0007625542000046.tif24128

[0191] Compound 117 was prepared from N,N,N',N'-tetraisopropyl-1-((1-phenylcyclopropyl)methoxy)phosphanediamine and floxuridine according to the method described in Scheme I and was isolated as a mixture of two isomers.19 H 20 FN2O7P's [M-1] + Calculated: 437.09; Measured: 437.1.

[0192] Example 18 1-((4aR,6R,7aS)-2-((2-(diethoxymethyl)benzyl)oxy)-2-oxidetetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinine-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (compound 118) TIFF0007625542000047.tif30128

[0193] Compound 118 was prepared from N,N,N',N'-tetraisopropyl-1-((2-diethoxymethyl)benzyloxy)phosphanediamine and floxuridine according to the method described in Scheme I and was isolated as a mixture of two isomers. 21 H 26 FN2O9P's ​​[M-1] + Calculated: 499.13; Measured: 499.0.

[0194] Example 19 1-((4aR,6R,7aS)-2-((2-(1,3-dioxolan-2-yl)-4-fluorobenzyl)oxy)-2-oxidetetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinine-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (compound 119) TIFF0007625542000048.tif29128

[0195] Compound 119 was prepared from N,N,N',N'-tetraisopropyl-1-((2-(1,3-dioxolan-2-yl)-4-fluorobenzyloxy)phosphanediamine and floxuridine according to the method described in Scheme I and was isolated as a mixture of two isomers. 19 H 19 F2N2O9P [M-1] + Calculated: 487.07; Measured: 487.0.

[0196] Example 20 5-Fluoro-1-((4aR,6R,7aS)-2-(3-phenylpropyloxy)-2-oxidetetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinine-6-yl)pyrimidine-2,4(1H,3H)-dione (compound 120) TIFF0007625542000049.tif24128

[0197] Compound 120 was prepared from N,N,N',N'-tetraisopropyl-1-(3-phenylpropyloxy)phosphanediamine and floxuridine according to the method described in Scheme I and was isolated as a mixture of two isomers. 18 H 20 FN2O7P's [M+1] + Calculated: 425.09; Measured: 425.1.

[0198] Example 21 5-Fluoro-1-((4aR,6R,7aS)-2-(3-(2-fluorophenyl)propyloxy)-2-oxidetetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinine-6-yl)pyrimidine-2,4(1H,3H)-dione (compound 121) TIFF0007625542000050.tif24128

[0199] Compound 121 was prepared from N,N,N',N'-tetraisopropyl-1-(3-(2-fluorophenyl)propyloxy)phosphanediamine and floxuridine according to the method described in Scheme I and was isolated as a mixture of two isomers. 18 H 19 F2N2O7P's [M+1] + Calculated: 443.08; Measured: 443.0.

[0200] Example 22 5-Fluoro-1-((4aR,6R,7aS)-2-(3-(4-fluorophenyl)propyloxy)-2-oxidetetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinine-6-yl)pyrimidine-2,4(1H,3H)-dione (compound 122) TIFF0007625542000051.tif25128

[0201] Compound 122 was prepared from N,N,N',N'-tetraisopropyl-1-(3-(4-fluorophenyl)propyloxy)phosphanediamine and floxuridine according to the method described in Scheme I and was isolated as a mixture of two isomers. 18 H 19 F2N2O7P's [M+1] + Calculated: 443.08; Measured: 443.0.

[0202] Example 23 1-((4aR,6R,7aS)-2-(4,4-dipropoxybutoxy)-2-oxidetetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinine-6-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione (compound 123) TIFF0007625542000052.tif24128

[0203] Compound 123 was prepared from N,N,N',N'-tetraisopropyl-1-(4,4-bis-(propyloxy)butyloxy)phosphanediamine and floxuridine according to the method described in Scheme I and was isolated as a mixture of two isomers. 19 H 30 FN2O9P's ​​[M+1] + Calculated: 479.16; Measured: 479.0.

[0204] Example 24 2-((((4aR,6R,7aS)-6-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-oxidetetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl)oxy)methyl)isopropyl benzoate (compound 124) TIFF0007625542000053.tif27128

[0205] Compound 124 was prepared from N,N,N',N'-tetraisopropyl-1-(2-isopropyloxycarbonylbenzyloxy)phosphanediamine and floxuridine according to the method described in Scheme I and was isolated as a mixture of two isomers. 20 H 22 FN2O9P's ​​[M-1] + Calculated: 483.09; Measured: 483.0.

[0206] Example 25 2-((((4aR,6R,7aS)-6-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-oxidetetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl)oxy)methyl)ethyl benzoate (compound 125) TIFF0007625542000054.tif27128

[0207] Compound 125 was prepared from N,N,N',N'-tetraisopropyl-1-(2-ethoxycarbonylbenzyloxy)phosphanediamine and floxuridine according to the method described in Scheme I and was isolated as a mixture of two isomers. 19 H 20 FN2O9P's ​​[M-1] + Calculated: 469.08; Measured: 469.1.

[0208] Example 26 2-((((4aR,6R,7aS)-6-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-oxidetetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinine-2-yl)oxy)methyl)propylbenzoate (Compound 126) TIFF0007625542000055.tif27128

[0209] Compound 126 was prepared from N,N,N',N'-tetraisopropyl-1-(2-propyloxycarbonylbenzyloxy)phosphanediamine and floxuridine according to the method described in Scheme I and was isolated as a mixture of two isomers. 20 H 22 FN2O9P's ​​[M-1] + Calculated: 483.09; Measured: 483.0.

[0210] Example 27 2-((((4aR,6R,7aS)-6-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-oxidetetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinine-2-yl)oxy)methyl)benzoate methyl (compound 127) TIFF0007625542000056.tif27128

[0211] Compound 127 was prepared from N,N,N',N'-tetraisopropyl-1-(2-methoxycarbonylbenzyloxy)phosphanediamine and floxuridine according to the method described in Scheme I and was isolated as a mixture of two isomers. 18 H 18 FN2O9P's ​​[M-1] + Calculated: 455.06; Measured: 455.1.

[0212] Example 28 2-((((4aR,6R,7aS)-6-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-oxidetetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinine-2-yl)oxy)methyl)butyl benzoate (compound 128) TIFF0007625542000057.tif27128

[0213] Compound 128 was prepared from N,N,N',N'-tetraisopropyl-1-(2-butyloxycarbonylbenzyloxy)phosphanediamine and floxuridine according to the method described in Scheme I and was isolated as a mixture of two isomers. 21 H 24 FN2O9P's ​​[M-1] + Calculated: 497.11; Measured: 497.1.

[0214] Biological Examples Examples of uses of the method include the following: It will be understood that the following are examples and that the method is not limited to only these examples.

[0215] Example 29: Tissue distribution following oral administration of reference and disclosed compounds The liver specificity of the disclosed compounds is compared to corresponding active compounds in the liver and other organs that may be targets of toxicity.

[0216] method: Reference compounds and cyclic deoxyribonucleotide compounds are administered orally at 5-50 mg / kg to fasted rats. Plasma concentrations of metabolites and parent compounds in the circulating blood and in the hepatic portal vein are determined by HPLC-UV, and concentrations in the liver, small intestine, and other organs are measured by LC-MS using standard chromatographic methods.

[0217] result: Table 1 shows the results of selected novel compounds, which demonstrate the liver targeting properties of cyclic deoxyribonucleotide compounds and provide evidence of the improved efficiency of these compounds in achieving high levels of activity in the liver compared to other types of prodrug compounds.This can only occur due to the highly efficient liver targeting provided by cyclic deoxyribonucleotide compounds.

[0218] (Table 1) Prodrug and metabolite levels in liver and blood 1 hour after oral administration of 5 mg / kg dose of control and selected compounds in rats TIFF0007625542000058.tif88152FdUMP = floxuridine monophosphate; FUDR = floxuridine; capecitabine = active ingredient in Xeloda, a prodrug; NUC-3373 = ProTide prodrug developed by NuCana PLC.

[0219] All numerical values ​​expressing quantities of ingredients, reaction conditions, and so forth used in the specification are to be understood as being modified in all instances by the term "about." Accordingly, unless otherwise indicated, the numerical parameters set forth herein are approximations that may vary depending upon the desired properties sought to be obtained. 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 ordinary rounding approaches.

[0220] As used herein, words of degree such as "approximately," "about," "generally," and "substantially" refer to a value, amount, or characteristic that is close to the stated value, amount, or characteristic, yet still performs a desired function or achieves a desired result. For example, the terms "approximately," "about," "generally," and "substantially" can refer to an amount that is 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 "generally parallel" and "substantially parallel" refer to a value, amount, or characteristic that deviates from perfect parallelism by 15%, 10%, 5%, 3%, 1%, 0.1% or less. Similarly, in certain correspondences, the terms "generally perpendicular" and "substantially perpendicular" refer to a value, amount, or characteristic that deviates from perfect perpendicularity by 15%, 10%, 5%, 3%, 1%, 0.1% or less.

[0221] The above description discloses some methods and materials. The compounds described herein are susceptible to modification of the methods and materials, and alterations of the preparation methods and devices. Such modifications will be apparent to those skilled in the art from consideration of this disclosure or practice of the compounds disclosed herein. Therefore, it is intended that the compounds described herein are not limited to the specific embodiments disclosed herein, and include all modifications and alternatives that fall within the true scope and spirit of the compounds described.

[0222] All documents cited herein, including, but not limited to, published and unpublished applications, patents, and references, are incorporated herein by reference in their entirety and made a part of this specification. In the event that the publications and patents or patent applications incorporated by reference conflict with the disclosure contained herein, it is intended that the present specification take precedence and / or supersede any such conflicting material.

[0223] Although various compounds have been described with reference to embodiments and examples, it is to be understood that numerous and various modifications can be made without departing from the spirit of the compounds described. Accordingly, the compounds are limited only by the claims that follow.

Claims

1. A compound of formula I, Ia, or II, or a pharma- ceutically acceptable salt thereof: During the ceremony R 1 H, halo, C 1 ~C 10 Alkyl, -OC 1～6 Alkyl, -O-carboxy, -OCH 2 OR 9 , -CH(OR 9 ) 2 , -C-carboxy, -C-amido, -CH 2 OCH 2 OR 9 , , and -CH 2 O-carboxy; Each R 2 are independently H, halo, or C 1 ~C 10 is alkyl; R 3 is -O-carboxy, -OCH 2 OR 9 , -CH(OR 9 ) 2 , -C-carboxy, -C-amido, -CH 2 OCH 2 OR 9 , , -CH 2 O-Carboxy, C 1 ~C 10 Alkyl, and C 3 ~C 10 cycloalkyl; R 4 is optionally substituted C 1 ~C 10 is alkyl; Each R 5 and R 6 are independently H or C 1 ~C 10 or alternatively, R 5 and R 6 together with the atom to which they are attached, 3 ~C 10 may form a cycloalkyl; Each R 7 and R 8 are independently H or C 1 ~C 10 or alternatively, R 7 and R 8 together with the atom to which they are attached, 3 ~C 10 may form a cycloalkyl; and R 9 is optionally substituted C 1 ~C 10 is alkyl; However, the compound is not selected.

2. 2. The compound of claim 1, which is a compound of formula (I) or (II), or a pharma- ceutically acceptable salt thereof: During the ceremony R 1 is H, F, C 1 ~C 10 Alkyl, -OMe, -OEt, -O-carboxy, -OCH 2 OR 9 , -CH(OR 9 ) 2 , -C-carboxy, -C-amido, -CH 2 OCH 2 OR 9 , , and -CH 2 O-carboxy; and R 2 is H, F, or C 1 ~C 10 It is an alkyl.

3. R 1 is H; and R 2 The compound of claim 1 or 2, wherein is H or F.

4. R 1 -OMe, -OEt, -O-carboxy, -OCH 2 OR 9 , -CH(OR 9 ) 2 , -C-carboxy, -C-amido, -CH 2 OCH 2 OR 9 , , and -CH 2 3. The compound of claim 1 or 2, selected from the group consisting of: O-carboxy.

5. R 1 The compound of claim 1 or 2, wherein is F.

6. R 1 3. The compound of claim 1 or 2, wherein is -C-carboxy.

7. R 2 The compound of any one of claims 1 to 6, wherein is H.

8. R 2 The compound of any one of claims 1 to 6, wherein is F.

9. R 3 -O-carboxy, -OCH 2 OR 9 , -CH(OR 9 ) 2 , -C-carboxy, -C-amido, -CH 2 OCH 2 OR 9 , , and -CH 2 3. The compound of claim 1 or 2, selected from the group consisting of: O-carboxy.

10. R 3 C 1 ~C 10 Alkyl or C 3 ~C 10 3. The compound of claim 1 or 2, which is cycloalkyl.

11. Formula Ia 2. The compound of claim 1 having the structure: or a pharma- ceutically acceptable salt thereof.

12. R 4 C 1 ~C 10 12. The compound of claim 11, which is alkyl.

13. Each R 2 The compound of claim 11 or 12, wherein is H.

14. A compound selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 and a pharma- ceutically acceptable excipient.

16. 16. The pharmaceutical composition of claim 15, further comprising one or more anti-cancer agents.

17. 15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 for use in treating a disease of the liver, or a disease or condition whose physiological or pathogenic pathway involves the liver, in a subject.

18. 18. The pharmaceutical composition of claim 17, wherein the subject is a mammal.

19. 18. The pharmaceutical composition of claim 17, wherein the subject is a human.

20. 20. The pharmaceutical composition of any one of claims 15 to 19, for use in combination with a medical treatment.

21. 21. The pharmaceutical composition of claim 20, wherein the medical treatment is transarterial chemoembolization.

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