Cyclic phosphate compounds

Abstract

To provide a cyclic phosphate compound useful for selective delivery of a specific drug to the liver.SOLUTION: The present invention provides a compound of formula I, or its stereoisomer or pharmaceutically acceptable salt, (where R2a and R2b are each independently H, OR8, halo, or the like; R3 and R4 are each independently H, OH, halo, CN, or the like; R5a is H, -CH(OR7)2, -C(O)OR7, -C(O)N(R7)2, or the like; R5b is H, substituted / unsubstituted C1-C10 alkyl, substituted / unsubstituted C3-C10 cycloalkyl, or the like; each R6 is independently halo or substituted / unsubstituted C1-C10 alkyl; each R7 is independently H or substituted / unsubstituted C1-C10 alkyl; each R8 is independently H, C(O)R7, C(O)OR7, or C(O)NHR7; m is 0, 1, or 2; n is 0, 1, 2, or 3; q is 0 or 1; r is 0 or 1; the base is a natural nucleoside base or a derivative or analog thereof).SELECTED DRAWING: None

Description

Technical Field

[0001] Field The present disclosure relates to the fields of chemistry and pharmacy. More specifically, the present disclosure relates to cyclic nucleotide compounds, their preparation, and their use. In some embodiments, these compounds are useful for selectively delivering certain agents to the liver.

Background Art

[0002] Background The following description of the background is provided to facilitate understanding of the present invention and is not admitted to be prior art or to describe prior art.

[0003] Natural nucleosides, when phosphorylated to nucleotides, become building blocks of DNA and RNA. Nucleosides in humans are mainly obtained by digestion of dietary nucleic acids and can be biosynthesized particularly in the liver when needed. Phosphorylation of nucleosides by specific nucleoside kinases in cells to form nucleotides allows maintenance of normal cell function and cell proliferation. These kinases can be impaired by genetic defects or non-genetic factors in one or more tissues, which can result in certain diseases or conditions including, but not limited to, certain mitochondrial DNA deficiency syndromes. See, for example, El-Hattab, A. and F. Scaglia (2013) Neurotherapeutics. 2013 Apr; 10(2): 186-198 (published online 2013 Feb 6. doi: 10.1007 / s13311-013-0177-6) (Non-Patent Document 1).

[0004] Theoretically, nucleotide supplementation can address deficiencies in the body. However, nucleotides have molecular properties, such as hydrophilicity, that prevent them from easily passing through cell membranes. Therefore, treatment by nucleotide supplementation can be inefficient or may require large amounts of supplements. Synthetic nucleosides (nucleotides) are widely used as antiviral or anticancer agents. Prodrug technology has been used to improve the molecular properties of nucleotides to enable improved bioavailability, including improved oral bioavailability of nucleotides. Therefore, in addition to improved oral bioavailability, novel compounds showing a liver targeting profile may significantly improve the therapeutic effect of nucleoside (nucleotide)-based therapies.

Prior Art Documents

Non-Patent Documents

[0005]

Non-Patent Document 1

Summary of the Invention

[0006] Summary Novel cyclic phosphate ester compounds, their preparation, and their use are described. Some embodiments are novel cyclic phosphate ester compounds that are orally delivered to the liver to achieve a therapeutic effect in the liver. Further embodiments include novel cyclic phosphate ester compounds for treating diseases, disorders, or conditions including certain mitochondrial DNA deficiency syndromes, hepatitis, liver cancer, liver fibrosis, fatty liver, malaria, viral infections, parasitic infections, diabetes, hyperlipidemia, atherosclerosis, obesity, dyslipidemia, hyperglycemia, hormonal conditions, HIV, and various types of cancer. Another aspect includes the use of cyclic phosphate ester compounds for treating diseases in which improved drug distribution to the liver and similar tissues and cells is beneficial. In another aspect, cyclic phosphate ester compounds are used to increase the pharmacological or clinical activity of certain classes of pharmaceutical compounds, such as nucleotide-derived analog compounds. In some embodiments, cyclic phosphate ester compounds are useful in improving the efficiency of oral delivery of nucleotide compounds to the liver and other tissues. Some further embodiments relate to methods of making cyclic phosphate ester compounds.

[0007] Some embodiments provided herein include compounds of Formula I, Ia, Ib, Ic, and Id, or stereoisomers or pharmaceutically acceptable salts thereof: TIFF2025106352000001.tif179128 wherein R 2 、R 2a 、R 2b 、R 3 、R 4 、R 5a 、R 5b 、R 6 、n, m, q, r, and the base have any of the values described herein.

[0008] Some embodiments relate to pharmaceutical compositions comprising one or more of the above compounds and a pharmaceutically acceptable excipient.

[0009] Some embodiments relate to pharmaceutical compositions comprising from one to four of the above compounds and a pharmaceutically acceptable excipient.

[0010] Some embodiments relate to methods of treating a disease, disorder, or condition, the method comprising administering an effective amount of one or more of the above compounds.

[0011] Some embodiments relate to methods of treating a disease, disorder, or condition, the method comprising administering an effective amount of one to four of the above compounds.

[0012] In some embodiments, the disease, disorder, or condition is a liver disease, liver disorder, or liver condition.

[0013] In some embodiments, the disease, disorder, or condition is a disease in which the liver is involved in the production and / or homeostasis control of the biochemical end products of the disease, disorder, or condition.

[0014] In some embodiments, the disease, disorder, or condition is a non-liver disease, non-liver disorder, or non-liver condition.

[0015] Some embodiments relate to methods of treating a liver disease, the method comprising administering an effective amount of one or more of the above compounds to a subject in need thereof.

[0016] Some embodiments relate to methods of treating a non-liver disease, the method comprising administering an effective amount of a combination of one or more of the above compounds to a subject in need thereof.

[0017] Some embodiments further comprise administering an effective amount of at least one additional therapeutic agent to a subject in need thereof.

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

[0019] In some embodiments, the subject is a human.

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

[0021] Some embodiments relate to methods of intervening in a molecular pathway or modulating a target in a cell, the method comprising contacting the cell with one to four of the above compounds.

[0022] In some embodiments, the cell is in vivo.

[0023] In some embodiments, the cell is ex vivo.

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

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

[0026] In some embodiments, the cell is a human cell.

[0027] Some embodiments of the compounds, compositions, and methods provided herein include pharmaceutical compositions comprising one or more of the compounds provided herein and a pharmaceutically acceptable excipient.

[0028] Some embodiments of the compounds, compositions, and methods provided herein include pharmaceutical compositions comprising one to four of the compounds provided herein and a pharmaceutically acceptable excipient.

[0029] Some embodiments of the compounds, compositions, and methods provided herein include methods of treating a liver disease or condition in a subject, the method comprising administering to a subject in need thereof an effective amount of one or more of the compounds provided herein.

[0030] Some aspects of the compounds, compositions, and methods provided herein are methods of treating a disease or condition in a subject, the method comprising administering to the subject in need thereof an effective amount of one or more of the compounds provided herein.

[0031] Some aspects also include administering to the subject in need thereof an effective amount of one or more additional therapeutic agents.

[0032] In some aspects, the subject is a mammal.

[0033] In some aspects, the subject is a human.

[0034] Some aspects also include the use of a combination of one or more of the compounds provided herein and an additional therapeutic agent.

[0035] Some aspects also include the use of a combination of one or more of the compounds provided herein and one or more additional therapeutic agents.

[0036] Some aspects of the compounds, compositions, and methods provided herein are for use in the preparation of a medicament for treating a disease or condition in the liver, or a disease or condition in which the liver is involved in a physiological or pathogenic pathway, and include one or more of the compositions provided herein.

[0037] Some aspects of the compounds, compositions, and methods provided herein are for use in the preparation of a medicament for treating a non-liver disease or non-liver condition and include one or more of the compositions provided herein. [The present invention 1001] A compound of formula I, or a stereoisomer or pharmaceutically acceptable salt thereof: TIFF2025106352000002.tif33128 wherein, R 2a and R 2bare each independently H, OR 8 , halo, CN, and optionally substituted C1-C 10 alkyl, selected from the group consisting of; R 3 and R 4 are each independently H, OH, halo, CN, N3, and optionally substituted C1-C 10 alkyl, selected from the group consisting of; R 5a is H, -CH(OR 7 )2, -C(O)OR 7 , -C(O)N(R 7 )2, -CH2OR 8 , -CH2N(R 8 )2, -CH2OCH2OR 8 , and TIFF2025106352000003.tif12128, selected from the group consisting of; R 5b is H, optionally substituted C1-C 10 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted C1-C 10 alkyloxy, optionally substituted (C 6~10 aryl), optionally substituted (C 6~10 aryl)-CH2-, optionally substituted (C 6~10 aryl)-CH2CH2-, -CH(OR 7 )2, -C(O)OR 7 , -C(O)N(R 7 )2, -CH2OR 8 , -CH2N(R 8 )2, -CH2OCH2OR 8 , and TIFF2025106352000004.tif12128, selected from the group consisting of; each R 6 is independently selected from the group consisting of halo and optionally substituted C1-C 10 alkyl; each R 7 is independently H and optionally substituted C1-C 10selected from the group consisting of alkyl; each R 8 is independently H, C(O)R 7 C(O)OR 7 and C(O)NHR 7 selected from the group; m is 0, 1, or 2; n is 0, 1, 2, or 3; q is 0 or 1; r is 0 or 1; the base is a natural nucleoside base or a derivative or analog thereof, provided that when the base is TIFF2025106352000005.tif21128, q is 1 and R 5a is neither H nor TIFF2025106352000006.tif12128. [Invention 1002] A compound of Invention 1001, wherein the base is selected from the group consisting of: TIFF2025106352000007.tif40162 wherein R 9 is H, halo, -CD3, or optionally substituted C1-C 10 alkyl; R 10 is H, optionally substituted C1-C 10 alkyl, optionally substituted C1-C 10 alkyl-OCH2-, optionally substituted C1-C 10 alkyl-NHCH2-, optionally substituted C1-C 10 acyl, optionally substituted C1-C 10 alkyl-OC(O)-, optionally substituted (C 6~10 aryl)-CH2OCH2-, optionally substituted (C 6~10 aryl)-OCH2-, optionally substituted (C 6~10 aryl)-C(O)-, and optionally substituted (C 6~10 aryl)-OC(O)- selected from the group; R 11is OH, NH2, NHOR 8 , optionally substituted C1-C 10 alkyloxy, optionally substituted C1-C 10 alkylamino, optionally substituted C1-C 10 acyloxy, optionally substituted C1-C 10 acylamino, optionally substituted C1-C 10 alkyl-OC(O)NH-, optionally substituted (C 6~10 aryl)-C(O)O-, optionally substituted (C 6~10 aryl)-C(O)NH-, optionally substituted (C 6~10 aryl)-OC(O)NH-, optionally substituted C1-C 10 alkyl-OCH2NH-, and optionally substituted C1-C 10 alkyl-OCH2O- and is selected from the group consisting of; R 12 is H, NH2, optionally substituted C1-C 10 alkylamino, optionally substituted C1-C 10 acylamino, optionally substituted C1-C 10 alkyl-OC(O)NH-, optionally substituted (C 6~10 aryl)-C(O)NH-, optionally substituted (C 6~10 aryl)-OC(O)NH-, and optionally substituted C1-C 10 alkyl-OCH2NH- and is selected from the group. [Invention 1003] R 9 is H, the compound of Invention 1002. [Invention 1004] R 9 is unsubstituted C1-C 10 alkyl, the compound of Invention 1002. [Invention 1005] R 9 is methyl, the compound of Invention 1004. [Invention 1006] R 9 is -CD3, the compound of Invention 1002. [Invention 1007] R 10 A compound according to any one of Inventions 1002 to 1006, wherein R is H. [Invention 1008] R 11 A compound according to any one of Inventions 1002 to 1007, wherein R is NH2. [Invention 1009] R 12 A compound according to any one of Inventions 1002 to 1008, wherein R is H. [Invention 1010] R 12 A compound according to any one of Inventions 1002 to 1008, wherein R is NH2. [Invention 1011] R 2a and R 2b A compound according to any one of Inventions 1001 to 1010, wherein at least one of them is H. [Invention 1012] R 2a and R 2b A compound according to any one of Inventions 1001 to 1010, wherein each of them is H. [Invention 1013] R 2a is unsubstituted C1 - C 10 alkyl, a compound according to any one of Inventions 1001 to 1010. [Invention 1014] R 2a is methyl and R 2b is fluoro, a compound according to Invention 1013. [Invention 1015] R 2a is OH, a compound according to any one of Inventions 1001 to 1010. [Invention 1016] R 2a and R 2b are each halo, a compound according to any one of Inventions 1001 to 1010. [Invention 1017] R 2a and R 2b are each fluoro, a compound according to Invention 1016. [Invention 1018] R3 A compound according to any one of the present inventions 1001 to 1017, wherein it is halo. [Present Invention 1019] R 3 A compound according to any one of the present inventions 1001 to 1017, wherein it is H. [Present Invention 1020] R 4 A compound according to any one of the present inventions 1001 to 1019, wherein it is halo. [Present Invention 1021] R 4 A compound according to any one of the present inventions 1001 to 1019, wherein it is H. [Present Invention 1022] When the base is TIFF2025106352000008.tif21128, m is 1, q is 1, n is 0, r is 0, and R 5a is neither H nor TIFF2025106352000009.tif12128, and R 5b is not methyl, a compound according to any one of the present inventions 1001 to 1021. [Present Invention 1023] The compound of formula I is of formula (Ia): A compound according to any one of the present inventions 1001 to 1022, represented by TIFF2025106352000010.tif21128, or a stereoisomer or pharmaceutically acceptable salt thereof. [Present Invention 1024] R 5b is substituted C1 - C 10 alkyl, the compound of Present Invention 1023. [Present Invention 1025] R 5b is unsubstituted C1 - C 10 alkyl, the compound of Present Invention 1023. [Present Invention 1026] R 5b is octyl, the compound of Present Invention 1025. [Present Invention 1027] R 5b is heptyl, the compound of Present Invention 1025. [Present Invention 1028] R5b is substituted with C 6~10 The compound of the present invention 1023, which is aryl. [The present invention 1029] R 5b is -COOR 13 and is phenyl substituted with, wherein R 13 is unsubstituted C1-C6 alkyl, the compound of the present invention 1028. [The present invention 1030] R 13 is i-propyl, the compound of the present invention 1029. [The present invention 1031] R 13 is n-propyl, the compound of the present invention 1029. [The present invention 1032] The compound of formula I is of formula (Ib): Any compound of the present invention 1001-1022, or a stereoisomer or pharmaceutically acceptable salt thereof, represented by TIFF2025106352000011.tif25128. [The present invention 1033] R 5a is -CH(OR 7 )2, -C(O)OR 7 , -C(O)N(R 7 )2, -CH2OR 8 , -CH2N(R 8 )2, -CH2OCH2OR 8 , and The compound of the present invention 1032, selected from the group consisting of TIFF2025106352000012.tif12128. [The present invention 1034] R 5a is -CH(OR 7 )2, -C(O)OR 7 , -C(O)N(R 7 )2, -CH2OR 8 , -CH2N(R 8 )2, and -CH2OCH2OR 8 selected from the group consisting of, the compound of the present invention 1032. [The present invention 1035] R 5a is -COOR 13and in the formula, R 13 is unsubstituted C1-C 10 alkyl, the compound of the present invention 1032. [The present invention 1036] R 13 is i-propyl, the compound of the present invention 1035. [The present invention 1037] R 13 is n-propyl, the compound of the present invention 1035. [The present invention 1038] n is 0, any compound of the present invention 1032-1037. [The present invention 1039] The compound of formula I is of formula (Ic): TIFF2025106352000013.tif35128, any compound of the present invention 1001-1022, or a stereoisomer or pharmaceutically acceptable salt thereof. [The present invention 1040] n is 0, the compound of the present invention 1039. [The present invention 1041] m is 1, the compound of the present invention 1039 or 1040. [The present invention 1042] The compound of formula I is of formula (Id): TIFF2025106352000014.tif26128, any compound of the present invention 1001-1022, or a stereoisomer or pharmaceutically acceptable salt thereof. [The present invention 1043] The base is TIFF2025106352000015.tif23128, the compound of the present invention 1042 selected from the group consisting of. [The present invention 1044] m is 0, the compound of the present invention 1043. [The present invention 1045] R 5b is substituted C1-C 10 alkyl, the compound of the present invention 1042 or 1043. [The present invention 1046] R 5b is unsubstituted C1-C 10The compound of the present invention 1042 or 1043 which is alkyl. [The present invention 1047] R 5b The compound of the present invention 1046 where R is heptyl. [The present invention 1048] R 5b The compound of the present invention 1046 where R is hexyl. [The present invention 1049] The compound of any one of the present inventions 1001 to 1022 where at least one of m, q, and r is not 0. [The present invention 1050] R 5b R is optionally substituted C1 - C 10 alkyl, optionally substituted C3 - C 10 cycloalkyl, optionally substituted C1 - C 10 alkyloxy, optionally substituted (C 6~10 aryl), optionally substituted (C 6~10 aryl)-CH2-, optionally substituted (C 6~10 aryl)-CH2CH2-, -CH(OR 7 )2, -C(O)OR 7 , -C(O)N(R 7 )2, -CH2OR 8 , -CH2N(R 8 )2, -CH2OCH2OR 8 , and The compound of any one of the present inventions 1001 to 1022 selected from the group consisting of TIFF2025106352000016.tif12128. [The present invention 1051] The compound of the present invention 1001, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: TIFF2025106352000017.tif153157. [The present invention 1052] A pharmaceutical composition comprising the compound of any one of the present inventions 1001 to 1051 and a pharmaceutically acceptable excipient. [The present invention 1053] Any of the compounds of the present invention 1001 - 1051 for use in treating diseases in the liver, or diseases or conditions in which the liver is involved in a physiological or pathogenesis pathway. [The present invention 1054] The compound of the present invention 1053 in combination with one or more additional therapeutic agents. [The present invention 1055] Use of any of the compounds of the present invention 1001 - 1051 in the preparation of a medicament for treating a disease or condition in the liver, or a disease or condition in which the liver is involved in a physiological or pathogenesis pathway. [The present invention 1056] A method of treating a disease, disorder, or condition, the method comprising administering to a subject in need thereof an effective amount of any of the compounds of the present invention 1001 - 1051.

Mode for Carrying Out the Invention

[0038] Detailed Description This aspect relates to compositions and methods related to novel cyclic phosphate ester compounds, their preparation, and their use. In some aspects, the novel cyclic phosphate ester compounds facilitate the delivery of nucleotide-derived substances, such as ribonucleotides and deoxyribonucleotides containing adenine, cytosine, guanine, inosine, thymine, uracil, and their derivatives and prodrugs, into cells.

[0039] These cyclic phosphate ester compounds, and their stereoisomers and pharmaceutically acceptable salts, are represented by formula I, Ia, Ib, Ic, and Id, or their stereoisomers or pharmaceutically acceptable salts: TIFF2025106352000018.tif175128 wherein R 2a , R 2b , R 3 , R 4 , R 5a , R 5b , R 6 , n, m, q, r, and the base have any of the values described herein.

[0040] In some embodiments, R 2a and R 2b are independently selected from the group consisting of H, OR 8 , halo, CN, and optionally substituted C1-C 10 alkyl. In some embodiments, the alkyl is methyl. In some embodiments, the halo is F or Cl.

[0041] In some embodiments, R 3 and R 4 are independently selected from the group consisting of H, OH, CN, N3, and optionally substituted C1-C 10 alkyl. In some embodiments, the alkyl is methyl. In some embodiments, the halo is F.

[0042] In some embodiments, R 5a is H, -CH(OR 7 )2, -C(O)OR 7 , -C(O)N(R 7 )2, -CH2OR 8 , -CH2N(R 8 )2, -CH2OCH2OR 8 , and TIFF2025106352000019.tif12128.

[0043] In some embodiments, R 5b is H, optionally substituted C1-C 10 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted C1-C 10 alkyloxy, optionally substituted (C 6~10 aryl), optionally substituted (C 6~10 aryl)-CH2-, optionally substituted (C 6~10 aryl)-CH2CH2-, -CH(OR 7 )2, -C(O)OR 7 , -C(O)N(R 7 )2, -CH2OR 8 , -CH2N(R8 ) 2, -CH2OCH2OR 8 and selected from the group of TIFF2025106352000020.tif12128.

[0044] In some embodiments, each R 6 is independently selected from the group of halo and optionally substituted C1-C 10 alkyl. In some embodiments, the halo is F or Cl. In some embodiments, the optionally substituted alkyl is methyl.

[0045] In some embodiments, each R 7 is independently selected from the group of H and optionally substituted C1-C 10 alkyl.

[0046] In some embodiments, each R 8 is independently selected from the group of H, C(O)R 7 C(O)OR 7 and C(O)NHR 7 .

[0047] In some embodiments, n is 0, 1, 2, or 3.

[0048] In some embodiments, m, q, and r are independently 0, 1, or 2.

[0049] In some embodiments, the base is a derivative or analog of a natural nucleoside base optimized for pharmaceutical use, where the base does not include TIFF2025106352000021.tif21128. In some embodiments, when the base is TIFF2025106352000022.tif21128, q is 1 and R 5a is neither H nor TIFF2025106352000023.tif12128. In some embodiments, when the base When TIFF2025106352000024.tif is 21128, m is 1, q is 1, n is 0, r is 0, and R 5a is also H is neither TIFF2025106352000025.tif nor 12128, and R 5b is not methyl.

[0050] In some embodiments, the base is selected from the group of TIFF2025106352000026.tif40145.

[0051] In some embodiments, the base is selected from the group of TIFF2025106352000027.tif23128.

[0052] In some embodiments, R 9 is H, halo, CD3, or optionally substituted alkyl. In some embodiments, halo is F. In some embodiments, alkyl is methyl.

[0053] In some embodiments, R 10 is H, optionally substituted C1-C 10 alkyl, optionally substituted C1-C 10 alkyl - OCH2 -, optionally substituted C1-C 10 alkyl - NHCH2 -, optionally substituted C1-C 10 acyl, optionally substituted C1-C 10 alkyl - OC(O)-, optionally substituted (C 6~10 aryl)-CH2OCH2 -, optionally substituted (C 6~10 aryl)-OCH2 -, optionally substituted (C 6~10 aryl)-C(O)-, and optionally substituted (C 6~10 aryl)-OC(O)- selected from the group.

[0054] In some embodiments, R 11 is OH, NH2, NHOR 8, C1 - C which may be substituted 10 Alkyloxy, C1 - C which may be substituted 10 Alkylamino, C1 - C which may be substituted 10 Acetyloxy, C1 - C which may be substituted 10 Acylamino, C1 - C which may be substituted 10 Alkyl - OC(O)NH -, (C which may be substituted 6~10 Aryl)-C(O)O -, (C which may be substituted 6~10 Aryl)-C(O)NH -, (C which may be substituted 6~10 Aryl)-OC(O)NH -, C1 - C which may be substituted 10 Alkyl - OCH2NH -, and C1 - C which may be substituted 10 Alkyl - OCH2O - selected from the group.

[0055] In some embodiments, R 12 is H, NH2, C1 - C which may be substituted 10 Alkylamino, C1 - C which may be substituted 10 Acylamino, C1 - C which may be substituted 10 Alkyl - OC(O)NH -, (C which may be substituted 6~10 Aryl)-C(O)NH -, (C which may be substituted 6~10 Aryl)-OC(O)NH -, C1 - C which may be substituted 10 Alkyl - OCH2NH - selected from the group.

[0056] In some embodiments, R 9 is H. In some embodiments, R 10 is H.

[0057] In some embodiments, R 11 is NH2, C1 - C which may be substituted 10 Acylamino, and C1 - C which may be substituted 10 Alkylamino selected from the group. In some embodiments, R 11 is NH2.

[0058] In some embodiments, R 12 is H or optionally substituted C1-C 10 acylamino. In some embodiments, R 12 is H. In some embodiments, R 12 is NH2.

[0059] In some embodiments, R 9 is unsubstituted C1-C 10 alkyl.

[0060] In some embodiments, R 9 is methyl.

[0061] In some embodiments, R 9 is -CD3.

[0062] In some embodiments, the base is TIFF2025106352000028.tif21128. In some embodiments, the base is TIFF2025106352000029.tif22128. In some embodiments, the base is TIFF2025106352000030.tif19128. In some embodiments, the base is TIFF2025106352000031.tif21128. In some embodiments, the base is TIFF2025106352000032.tif21128. In some embodiments, the base is TIFF2025106352000033.tif14128.

[0063] In some embodiments, R 5b is optionally substituted C1-C 10 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted C1-C 10 alkyloxy, optionally substituted (C 6~10(Aryl), optionally substituted (C 6~10 (Aryl)-CH2-, optionally substituted (C 6~10 (Aryl)-CH2CH2-, -CH(OR 7 )2, -C(O)OR 7 , -C(O)N(R 7 )2, -CH2OR 8 , -CH2N(R 8 )2, -CH2OCH2OR 8 , and TIFF2025106352000034.tif12128 selected from the group consisting of. In some embodiments, R 2a and R 2b at least one of them is H.

[0064] In some embodiments, R 2a and R 2b are each H.

[0065] In some embodiments, R 2a is unsubstituted C1-C 10 alkyl.

[0066] In some embodiments, R 2a is methyl and R 2b is fluoro.

[0067] In some embodiments, R 2a is OH.

[0068] In some embodiments, R 2a and R 2b are each halo.

[0069] In some embodiments, R 2a is H and R 2b is OR 8 .

[0070] In some embodiments, R 2a is OR 8 and R 2b is H.

[0071] In some embodiments, R 2a is Me, and R 2b is F or Cl.

[0072] In some embodiments, R 2a and R 2b are both H, or both are F.

[0073] In some embodiments, R 2a and R 2b are each fluoro.

[0074] In some embodiments, R 3 is halo.

[0075] In some embodiments, R 3 is H.

[0076] In some embodiments, R 4 is H.

[0077] In some embodiments, R 4 is halo.

[0078] In some embodiments, R 5b is substituted C1 - C 10 alkyl.

[0079] In some embodiments, R 5b is unsubstituted C1 - C 10 alkyl.

[0080] In some embodiments, R 5b is octyl.

[0081] In some embodiments, R 5b is hexyl.

[0082] In some embodiments, R 5b is heptyl.

[0083] In some embodiments, R 5bis substituted C 6~10 is aryl.

[0084] In some embodiments, R 5b is phenyl substituted with -COOR 13 , wherein R 13 is unsubstituted C1-C6 alkyl.

[0085] In some embodiments, R 13 is i-propyl.

[0086] In some embodiments, R 13 is n-propyl.

[0087] In some embodiments, R 5a is selected from the group consisting of -CH(OR 7 )2, -C(O)OR 7 , -C(O)N(R 7 )2, -CH2OR 8 , -CH2N(R 8 )2, -CH2OCH2OR 8 , and TIFF2025106352000035.tif12128. In some embodiments, R 5a is selected from the group consisting of -CH(OR 7 )2, -C(O)OR 7 , -C(O)N(R 7 )2, -CH2OR 8 , -CH2N(R 8 )2, and -CH2OCH2OR 8 . In some embodiments, R 5a is -COOR 13 , wherein R 13 is unsubstituted C1-C 10 alkyl.

[0088] In some embodiments, n is 0.

[0089] In some embodiments, m is 0.

[0090] In some embodiments, m is 1.

[0091] In some embodiments, at least one of m, q, and r is not zero.

[0092] In some embodiments, the compound is the following compound: selected from the group consisting of TIFF2025106352000036.tif109158TIFF2025106352000037.tif36128, or a pharmaceutically acceptable salt thereof.

[0093] In some embodiments, the compound is the following: neither a compound selected from the group consisting of TIFF2025106352000038.tif128164 nor a pharmaceutically acceptable salt thereof.

[0094] In some embodiments, the cyclic phosphate ester compounds of Formula I, Ia, Ib, Ic, and Id are substrates of hepatic enzymes such as cytochrome p450 isozyme CYP3A (a family of monooxygenases), dehydrogenases, esterases, and amidases.

[0095] In some embodiments, the cyclic phosphate ester compounds of Formula I, Ia, Ib, Ic, and Id have a lipophilic R 5b or other group that promotes cellular uptake of the compound.

[0096] In some embodiments, the compound is activated intracellularly upon cleavage of the prodrug moiety to release the active form of the compound.

[0097] CYP3A4 is expressed at much higher levels in the liver than in other tissues (DeWaziers et al. J Pharm Exp Ther 253:387 (1990)). Certain cyclic phosphate ester compounds of Formula I, Ia, Ib, Ic, and Id are primarily activated by CYP3A4 in the liver. In some embodiments, the compounds of Formula I, Ia, Ib, Ic, and Id exhibit high efficiency in liver targeting by the selective delivery of bio-related nucleotides to the liver. In some embodiments, the cyclic phosphate ester compounds are used to increase the therapeutic index of a drug, since the compounds of Formula I, Ia, Ib, Ic, and Id may be inactive or have relatively low activity outside the liver.

[0098] In some embodiments, the cyclic phosphate ester compounds of Formula I, Ia, Ib, Ic, and Id have properties of targeting the liver, and thus are used to treat diseases, including but not limited to liver diseases, where improved drug distribution to the liver as well as similar tissues and cells is beneficial.

[0099] In some embodiments, the cyclic phosphate ester compounds of Formula I, Ia, Ib, Ic, and Id can be effectively activated by enzymes other than CYP3A4, and the compounds are used to treat non-liver diseases.

[0100] In some embodiments, the disclosed compounds are used for improving pharmacokinetic properties such as prolonging the half-life of nucleotides or improving the absorption rate. Further, the disclosed methodology can be used to achieve sustained delivery of bio-related nucleotides. The cyclic phosphate ester compounds of Formula I, Ia, Ib, Ic, and Id are used to treat diseases where improved drug properties are beneficial since their pharmacokinetic properties are improved. In some embodiments, methods for making these compounds are described.

[0101] Certain compounds of Formulas I, Ia, Ib, Ic, and Id have asymmetric centers where the stereochemical configuration may be unspecified, and when referring generally to the compounds of Formulas I, Ia, Ib, Ic, and Id, diastereomeric mixtures of these compounds are included as well as the individual stereoisomers.

[0102] In some embodiments, an effective amount of the disclosed compounds is used to treat a disease, disorder, or condition in a subject in need thereof.

[0103] Some embodiments of the compounds, compositions, and methods provided herein include pharmaceutical compositions comprising a compound provided herein and a pharmaceutically acceptable carrier.

[0104] Some embodiments also include administering to a subject in need thereof a combination of an effective amount of a second or multiple therapeutic agents and a compound provided herein.

[0105] In some embodiments, the subject is a mammal.

[0106] In some embodiments, the subject is a human.

[0107] Some embodiments of the compounds, compositions, and methods provided herein include methods of testing a compound in a cell, the method comprising contacting the cell with the disclosed compound.

[0108] Some embodiments of the compounds, compositions, and methods provided herein include use of a compound provided herein in the treatment of liver disease, or a disease or condition in which the liver is involved in a physiological or pathogenic pathway.

[0109] Some embodiments include use of a combination of a compound provided herein and one or more additional therapeutic agents for the treatment of liver disease.

[0110] Some aspects 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.

[0111] Some aspects include the use of a combination of a compound provided herein and an additional therapeutic agent for the treatment of a disease or condition by intervening in a molecular pathway in the liver.

[0112] Some aspects of the compounds, compositions, and methods provided herein include the use of the compounds provided herein in the treatment of non-liver diseases.

[0113] Some aspects include the use of a combination of a compound provided herein and an additional therapeutic agent for the treatment of non-liver diseases.

[0114] Some aspects relate to the use of the compounds provided herein in the preparation of a medicament for treating a disease or condition in the liver, or a disease or condition in which the liver is involved in a physiological or pathogenic pathway.

[0115] Some aspects relate to a method of treating a disease, disorder, or condition, the method comprising administering to a subject in need thereof an effective amount of a compound provided herein.

[0116] Compounds disclosed herein, when having at least one chiral center, may exist as individual enantiomers and diastereomers, or as mixtures of such isomers including racemates. Separation of individual isomers or selective synthesis of individual isomers is achieved by application of various methods well known to those skilled in the art. Unless otherwise indicated, all of these isomers and mixtures thereof are included within the scope of the compounds disclosed herein. Further, the compounds disclosed herein may exist as one or more crystalline or amorphous forms. Unless otherwise indicated, all of these forms including any polymorphs are included within the scope of the compounds disclosed herein. Additionally, some of the compounds disclosed herein may form solvates (i.e., hydrates) with water or solvates with common organic solvents. Unless otherwise indicated, these solvates are included within the scope of the compounds disclosed herein.

[0117] Those skilled in the art will recognize that some of the structures described herein may be resonance forms or tautomers of compounds that can be legitimately represented by other chemical structures even when dynamically represented, and that those skilled in the art will recognize that the structure may represent only a very small portion of a sample of the compound. These resonance forms or tautomers are not represented herein, but these compounds are considered to be within the scope of the illustrated structures.

[0118] Isotopes may be present in the compounds described. Each chemical element represented in a compound structure may include any isotope of that element. For example, in a compound structure, a hydrogen atom may be clearly disclosed or understood to be present in the compound. At any position in the compound where a hydrogen atom may be present, the hydrogen atom may be any hydrogen isotope including, but not limited to, hydrogen-1 (protium) and hydrogen-2 (deuterium). Accordingly, unless the context clearly indicates otherwise, all references to compounds herein encompass all potential isotopic forms.

[0119] Definitions The following terms conforming to the present disclosure and used herein are defined by the following meanings unless otherwise clearly described. It should be understood that both the foregoing general description and the following detailed description are merely exemplary and explanatory and do not limit the claimed subject matter. In this application, unless otherwise specifically described, the use of the singular form includes the plural form. In this application, unless otherwise described, the use of "or" means "and / or". Further, the use of the term "including", as well as other forms such as "includes" and "included", is non-limiting.

[0120] Ranges and amounts used herein may be expressed as "about" a particular value or particular range. "About" includes the exact amount. Thus, "about 10%" means "about 10%" and "10%".

[0121] As used herein, "optional" or "optionally" means that the subsequently described event or situation may or may not occur, and that the description includes both the case where the event or situation occurs and the case where it does not occur. For example, a group that may be substituted means that the group is either unsubstituted or substituted.

[0122] As used herein, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to a composition containing "a therapeutic agent" includes a composition having one or more therapeutic agents.

[0123] As used herein, "C a ~C b " or "C a~b " where "a" and "b" are integers means the number of carbon atoms in the specified group. That is, this group may contain "a" or more and "b" or fewer carbon atoms. Thus, for example, a "C1-C4 alkyl" group or "C 1~4The term "alkyl" means all alkyl groups having 1 to 4 carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-.

[0124] As used herein, "alkyl" means a straight-chain or branched hydrocarbon chain that is fully saturated (i.e., contains no double or triple bonds). An alkyl group can have 1 to 20 carbon atoms (when the alkyl group appears in this specification, the numerical range such as "1 to 20" always refers to each integer within the given range. For example, "1 to 20 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to 20 carbon atoms or less, but this definition also covers cases where the term "alkyl" appears without a specified numerical range). The alkyl group may be a medium-chain alkyl having 1 to 9 carbon atoms. The alkyl group may be a lower alkyl having 1 to 4 carbon atoms. The alkyl group may be named as "C1-C4 alkyl" or a similar name. By way of example only, "C1-C4 alkyl" means that there are 1 to 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, etc.

[0125] As used herein, a "substituted group" is derived from an unsubstituted parent group, where one or more hydrogen atoms have been replaced by another atom or group. Unless otherwise indicated, when a group is said to be "substituted", the group may be C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 carbocyclic (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7-carbocyclic-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 3- to 10-membered heterocyclic (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 3- to 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- to 10-membered heteroaryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5- to 10-membered heteroaryl(C1-C6)alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), halo, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy(C1-C6)alkyl (i.e., an ether), aryloxy (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7 carbocyclic oxy (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy),3- to 10-membered heterocyclyloxy (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5- to 10-membered heteroaryloxy (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- to 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- to 10-membered heteroaryl(C1-C6)alkoxy (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 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- to 10-membered heterocyclyl-thio (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5- to 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- to 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- to 10-membered heteroaryl(C1-C6)alkylthio (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), amino, amino(C1-C6)alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, and one or more substituents independently selected from oxo(=O), provided that when a group is described as "optionally substituted", the group may always be optionally substituted with the above substituents.,

[0126] As used herein, "acyl" means -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- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl. Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acrylyl.

[0127] "Heteroacyl" means -C(=O)R where R is C 1~6 heteroalkyl.

[0128] "Alkyloxymethylene" means -CH2OR where R is C 1~6 alkyl or heteroalkyl, both of which may be optionally substituted.

[0129] The "O-carboxy" group means a "-OC(=O)R" group, where R is hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic, as selected from.

[0130] The "C-carboxy" group means a "-C(=O)OR" group, where R is hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic, as selected from. Non-limiting examples include carboxyl (i.e., -C(=O)OH).

[0131] The "cyano" group means a "-CN" group.

[0132] The "cyanato" group means a "-OCN" group.

[0133] The "isocyanato" group means a "-NCO" group.

[0134] The "thiocyanato" group means a "-SCN" group.

[0135] The "isothiocyanato" group means a "-NCS" group.

[0136] The "sulfinyl" group means a "-S(=O)R" group, where R is hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic, as selected from.

[0137] The "sulfonyl" group means a "-SO2R" group where R is hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic, each independently selected from those defined herein.

[0138] The "S-sulfonamide" group means a "-SO2NR A and R B where each is independently hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic, each independently selected from those defined herein, of the "-SO2NR A R B " group.

[0139] The "N-sulfonamide" group means a "-N(R A and R b where each is independently hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic, each independently selected from those defined herein, of the "-N(R A )SO2R B " group.

[0140] The "O-carbamyl" group means a 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 carbocyclic, C 6~10" -OC(=O)NR", which is selected from aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl A R B " group.

[0141] The "N-carbamoyl" group means that R A and R B are each independently hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl as defined herein, and means the "-N(R A )C(=O)OR B " group.

[0142] The "O-thiocarbamoyl" group means that R A and R B are each independently hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl as defined herein, and means the "-OC(=S)NR A R B " group.

[0143] The "N-thiocarbamoyl" group means that R A and R B are each independently hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl as defined herein, and means the "-N(R A )C(=S)OR B " group.

[0144] The "C-amide" group means that RA and R B are each independently hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic, each optionally substituted with -OH, C 1~6 alkyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclic, C 1~6 alkyl optionally substituted with alkoxy or -OH, and C 1~6 alkyl, and C 1~6 alkyl optionally substituted with alkoxy or -OH, and C 1~6 alkoxy, and is optionally substituted with one or more substituents selected from the group consisting of, a "-C(=O)NR A R B " group.

[0145] The "N-amide" group means that R A and R B are each independently hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic, each optionally substituted with -OH, C 1~6 alkyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclic, C 1~6 alkyl optionally substituted with alkoxy or -OH, and C 1~6 alkyl, and C 1~6 alkyl optionally substituted with alkoxy or -OH, and C 1~6 alkoxy, and is optionally substituted with one or more substituents selected from the group consisting of, a "-N(R A )C(=O)R B " group.

[0146] The term "amino" group means -NR A and R B each independently being hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic selected, "-NR A R B ". Non-limiting examples include free amino (i.e., -NH2).

[0147] The term "aminoalkyl" group means an amino group connected by an alkylene group.

[0148] The term "alkoxyalkyl" group means an alkoxy group connected by an alkylene group, for example, "C 2~8 alkoxyalkyl", etc.

[0149] The term "acyloxy" means -OC(O)R where R is alkyl.

[0150] The term "alkoxy" or "alkyloxy" means OR where R is alkyl or heteroalkyl, both of which may be optionally substituted.

[0151] The term "carboxyl" means C(O)OH.

[0152] The term "oxo" means =O group.

[0153] The term "halogen" or "halo" means F (fluoro), Cl (chloro), Br (bromo), and I (iodo).

[0154] The term "haloalkyl" means an alkyl group containing at least one halogen and, in a further aspect, 1 to 3 halo atoms. Suitable halo atoms include F, Cl, and Br.

[0155] The term "haloacyl" means a -C(O)-haloalkyl group.

[0156] The term "alkenyl" means an unsaturated group having 2 to 12 atoms and containing at least one carbon-carbon double bond, including straight-chain groups, branched-chain groups, and cyclic groups. The alkenyl group may be substituted. A suitable alkenyl group is allyl.

[0157] The term "alkynyl" means an unsaturated group having 2 to 12 atoms and containing at least one carbon-carbon triple bond, including straight-chain groups, branched-chain groups, and cyclic groups. The alkynyl group may be substituted. A suitable alkynyl group is ethynyl.

[0158] As used herein, "aryl" means an aromatic ring or aromatic ring system (i.e., two or more fused rings sharing two adjacent carbon atoms) containing only carbon in the ring backbone. When the aryl is a ring system, all rings in the system are aromatic rings. The aryl group may have 6 to 18 carbon atoms, but this definition also encompasses cases where the term "aryl" appears without a specified numerical range. In some embodiments, the aryl group has 6 to 10 carbon atoms. The aryl group may be named as "C 6~10 aryl", "C6 or C 10 aryl", or a similar name. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.

[0159] As used herein, "heteroaryl" means an aromatic ring or aromatic 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 ring backbone. When heteroaryl is a ring system, all rings in the system are aromatic rings. A heteroaryl group can have 5 to 18 ring members (i.e., the number of atoms constituting the ring backbone, including carbon atoms and heteroatoms), but this definition also encompasses cases where the term "heteroaryl" appears without a specified numerical range. In some embodiments, the heteroaryl group has 5 to 10 ring members or 5 to 7 ring members. The heteroaryl group may be named as "5- to 7-membered heteroaryl", "5- to 10-membered heteroaryl", or a similar name. The heteroaryl group may be substituted. Examples of heteroaryl groups include aromatic C3-8 heterocyclic groups containing one oxygen or sulfur atom or up to 4 nitrogen atoms, or a combination of one oxygen or sulfur atom and up to 2 nitrogen atoms, as well as their substituted derivatives, and benzo-fused derivatives and pyrido-fused derivatives connected, for example, by one ring-forming carbon atom, but are not limited thereto. In some embodiments, the heteroaryl group is halo, hydroxy, amino, cyano, nitro, alkylamide, acyl, C 1~6 -alkoxy, C 1~6 -alkyl, C 1~6-Hydroxyalkyl, C1-6-aminoalkyl, C1-6-alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl, and may be substituted with one or more substituents independently selected therefrom. Examples of heteroaryl groups include furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzoisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole, quinoline, isoquinoline, pyridazine, pyrimidine, purine, pyrazine, furazan, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, triazole, benzotriazole, pteridine, phenoxazole, oxadiazole, benzopyrazole, quinolidine, cinnoline, phthalazine, quinazoline, and quinoxaline, including but not limited to unsubstituted derivatives and mono- or di-substituted derivatives thereof. In some embodiments, the substituents are halo, hydroxy, cyano, O-C 1~6 -alkyl, C 1~6 -alkyl, hydroxy-C 1~6 -alkyl, and amino-C 1~6 -alkyl.

[0160] As used herein, "cycloalkyl" means a fully saturated carbocyclic ring or carbocyclic ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. A cycloalkyl group may have 3 to 10 carbon atoms (when a cycloalkyl group appears herein, the numerical range such as "3 to 10" always refers to each integer within the given range). A cycloalkyl group may be named as "C3-C8 cycloalkyl" or a similar name. By way of example only, "C3-C8 cycloalkyl" indicates that there are 3 to 8 carbon atoms in the carbocyclic ring or carbocyclic ring system.

[0161] As used herein, "heterocyclyl" means a non-aromatic ring or non-aromatic ring structure that is fully saturated or partially saturated and contains at least one heteroatom selected from nitrogen, oxygen, and sulfur in the ring skeleton. Heterocyclyl may have any degree of saturation, provided that at least one ring in the ring system is not an aromatic ring. The heteroatom may be present in a non-aromatic ring or an aromatic ring in the ring system. A heterocyclyl group may have 3 to 20 ring members (i.e., the number of atoms constituting the ring skeleton, including carbon atoms and heteroatoms), but this definition also encompasses cases where the term "heterocyclyl" appears without a specified numerical range. The heterocyclyl group may be a medium-sized heterocyclyl having 3 to 10 ring members. The heterocyclyl group may be a heterocyclyl having 3 to 6 ring members. A heterocycloalkyl group is "3- to 15-membered heterocycloalkyl", "4- to 10-membered heterocycloalkyl", "3- to 15-membered C 2~14 heterocycloalkyl", "5- to 9-membered C 4~8 heterocycloalkyl", "5- to 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- to 15-membered C 8~14 heterocycloalkyl", "monocyclic or bicyclic 3- to 10-membered C 2~9 heterocycloalkyl", "bicyclic 8- to 10-membered C 4~9 heterocycloalkyl", "bicyclic 8- to 10-membered C 5~9 heterocycloalkyl", "monocyclic 4- to 7-membered C 3~6 heterocycloalkyl", "monocyclic 5- to 6-membered C 3~5"heterocycloalkyl", or may be named as a similar name. The heterocyclyl group may be a C2-C9 heterocyclyl having 3 to 10 ring members containing 1 to a maximum of 3 O (oxygen), N (nitrogen), or S (sulfur). The heterocyclyl group may be named as "3- to 10-membered C2-C9 heterocyclyl" or a similar name. In a preferred 6-membered monocyclic heterocyclyl, the heteroatom is selected from 1 to a maximum of 3 O (oxygen), N (nitrogen), or S (sulfur), and in a preferred 5-membered monocyclic heterocyclyl, the heteroatom is selected from heteroatoms selected from 1 or 2 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, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl, 1,4-oxathiinyl, 1,4-oxathianyl, 2H-1,2-oxazinyl, trioxanyl, hexahydro-1,3,5-triazinyl, 1,3-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, thiomorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, and tetrahydroquinoline.

[0162] Similarly, when two "adjacent" R groups are said to "together with the atoms to which they are attached" form a ring, it means that the atoms, intervening bonds, and the collective unit of the two R groups become the said ring. For example, the following structures exist: TIFF2025106352000039.tif27128R 1 and R 2 is defined to be selected from the group consisting of hydrogen and alkyl, or R 1 and R 2 when together with the atoms to which they are attached form an aryl or carbocyclic ring, R 1 and R 2 can be selected from hydrogen or alkyl, or it means that the partial structure has the following structure: TIFF2025106352000040.tif27128 wherein A is an aryl ring or carbocyclic ring containing the depicted double bond.

[0163] When a substituent is depicted as a diradical (i.e., having two attachment points to the rest of the molecule), it should always be understood that the substituent can be attached in any orientation unless otherwise indicated. Thus, for example, a substituent depicted as -AE- or TIFF2025106352000041.tif9128 includes cases where A is attached at the leftmost attachment point of the molecule and cases where A is attached at the rightmost attachment point of the molecule.

[0164] The term "therapeutically effective amount" means an amount of a compound or combination of compounds that partially or completely alleviates, attenuates, or eliminates one or more symptoms of a particular disease or condition, or prevents, modulates, or delays the onset of one or more symptoms of a particular disease or condition. This amount may be administered as a single dosage form or according to a regimen in which this amount is effective. Repeated administration may be required to achieve the desired result (e.g., treatment of a disease and / or condition).

[0165] The term "pharmaceutically acceptable salts" includes salts of the compounds of Formula I derived from combinations of the compounds of the present aspect with organic or inorganic acids or bases. Pharmaceutically acceptable acid addition salts can be formed by inorganic acids and organic acids. Examples of inorganic acids from which the salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Examples of organic acids from which the 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, hydrochloric acid, 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, terephthalic acid, and the like. Examples of inorganic bases from which the salts can be derived include, for example, bases containing sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like, and ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts are particularly preferred. In some embodiments, treating the compounds disclosed herein with an inorganic base causes the loss of labile hydrogen from the compound, resulting in Li + 、Na + 、K + 、Mg 2+ 、and Ca 2+A salt form containing inorganic cations such as etc. is obtained. Examples of organic bases that can be derived from the salt include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc. Specifically, examples include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.

[0166] When 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 of the same or different halogens. For example, "haloalkyl" includes each substituent CF3, CHF2, and CH2F.

[0167] The term "patient" means an animal to be 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.

[0168] As used herein, the term "prodrug" means any compound that, when administered to a living system, gives rise to a bioactive compound as a result of spontaneous chemical reactions, enzyme-catalyzed chemical reactions, and / or metabolic chemical reactions, or combinations of each reaction. Standard prodrugs are formed using groups that are cleaved in vivo, which are attached to functional groups such as HO-, HS-, HOOC-, HOOPR2- and associated with the drug. Standard prodrugs include carboxylic acid esters in which the group is alkyl, aryl, aralkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and esters of hydroxyl, thiol, and amine in which the attached group is an acyl group, alkoxycarbonyl, aminocarbonyl, phosphate ester, or sulfate ester, but are not limited thereto. The groups shown are examples and are not exhaustive, and those skilled in the art may prepare various other known prodrugs. In order to give rise to a compound that is bioactive or a precursor of a bioactive compound, the prodrug must undergo some form of chemical conversion. In some cases, the prodrug has bioactivity that is usually lower than that of the drug itself and plays a role in improving the effectiveness or safety of the drug through improvements such as oral bioavailability and pharmacodynamic half-life. The prodrug form of a compound can be utilized, for example, to improve bioavailability, to improve subject acceptability by masking or reducing unpleasant properties such as bitterness or gastrointestinal hypersensitivity, to modify solubility for intravenous use, to achieve long-term or sustained release or delivery, to improve ease of formulation, or to achieve site-specific delivery of the compound.

[0169] The term "stereoisomer" refers to the relative or absolute spatial relationship of R groups attached to an asymmetric center that is a carbon atom or a phosphorus atom, and refers to individual isomers, or any combination of individual isomers, such as racemic mixtures and diastereoisomeric mixtures. If a compound has two asymmetric centers, four potential stereoisomers exist.

[0170] The term "liver" means the liver organ.

[0171] The term "liver specificity" means the following ratio: [Drug or drug metabolite in liver tissue] / [Drug or drug metabolite in blood or another tissue] Measured in an animal treated with a drug or prodrug. This ratio may be determined by measuring tissue levels at a specific point in time or may represent the AUC (area under the curve) based on values measured at three or more time points.

[0172] The term "increase or improvement in liver specificity" means an increase in the liver specificity ratio in an animal treated with a prodrug relative to an animal treated with the parent drug.

[0173] The term "improvement in oral bioavailability" means an increase of at least about 50% in the absorption rate of the dose of a reference drug. In a further aspect, the increase in the oral bioavailability of a compound (compared to a reference drug) is at least about 100% or a doubling of the absorption rate. Usually, measurement of oral bioavailability means comparison of the measured values of a prodrug, drug, or drug metabolite in blood, plasma, tissue, or urine after oral administration with the measured values after parenteral administration.

[0174] The term "therapeutic index" means 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, an increase in a marker indicating toxicity, and / or a pharmacological side effect.

[0175] The term "sustained delivery" means an increase in the period during which a therapeutically effective drug level is prolonged by the presence of a prodrug.

[0176] The term "treating" a disease or "treatment" of a disease includes inhibiting the disease (slowing, stopping, or partially stopping the development of the disease), preventing the disease, reducing the symptoms or side effects of the disease (including palliative treatment), and / or reducing the disease (causing regression of the disease).

[0177] The term "biological agent" means a compound having biological activity, or a compound having molecular properties that can be used for therapeutic or diagnostic purposes, for example, a compound carrying a radioisotope or a heavy atom.

[0178] The term "molecular pathway" means a series of molecular events in a tissue that are involved in the physiological or pathophysiological functions of a living animal, such as receptor regulatory sequences, enzyme regulatory sequences, or biosynthetic sequences.

[0179] Administration and Pharmaceutical Compositions The disclosed compounds may be used alone or in combination with other therapeutic agents. When these compounds are used in combination with other agents, they may be administered as a daily dose or as an appropriate fraction of the daily dose (for example, twice a day). The present compounds may be administered after treatment with another agent that is part of the treatment regimen, during treatment with another agent, or before treatment with another agent in the treatment program.

[0180] Examples of pharmaceutically 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, terephthalate, tosylate, and triethiodide.

[0181] The composition containing the active ingredient can be in any form suitable for the intended method of administration. In some embodiments, the compounds of the methods and / or compositions described herein can be administered orally, rectally, transmucosally, enterally, enterically, topically, transdermally, subarachnoidally, intracerebroventricularly, intraperitoneally, intranasally, intravitreally, and / or parenterally.

[0182] For example, when the present compound is administered by oral administration, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs can be prepared. Compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and these compositions may contain one or more auxiliaries including sweetening agents, flavoring agents, coloring agents, and preservatives so as to obtain a good-tasting preparation. Tablets containing a mixture of an active ingredient and a non-toxic pharmaceutically acceptable excipient suitable for the manufacture of tablets are acceptable. These excipients can be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrating agents such as corn starch or alginic acid; binding agents such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. The tablets may or may not be coated and may be coated by known techniques including microencapsulation so as to delay disintegration and adsorption in the gastrointestinal tract and thereby achieve a sustained action over a longer period. For example, a time-delay substance such as glyceryl monostearate or glyceryl distearate can be used alone or in combination with a wax.

[0183] Oral formulations may be presented as hard gelatin capsules in which the active ingredient can be mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient can be mixed with a water or oil medium, for example peanut oil, liquid paraffin, or olive oil.

[0184] Formulations suitable for parenteral administration include, for example, aqueous and non-aqueous isotonic sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may contain suspending and thickening agents. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried condition requiring only the addition of a sterile liquid carrier, for example, water for injection, immediately prior to use. Injection solutions and injection suspensions may be prepared from sterile powders, granules, and tablets of the kind previously described.

[0185] In some embodiments, unit dosage form formulations contain the daily amount or unit of the drug, a divided daily dose, or an appropriate fraction thereof. However, as will be well understood by those skilled in the art, the specific dosage level for any particular patient will depend upon a variety of factors including the activity of the specific compound being used; the age, body weight, general health, sex, and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs previously administered; and the severity of the particular disease being treated.

[0186] The actual dosage of the compounds described herein will depend on the particular compound and the condition to be treated, and the selection of the appropriate dosage is well within the knowledge of those skilled in the art. In some embodiments, the daily amount may be from about 0.1 mg / kg to about 100 mg or more / kg 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 body weight. Thus, for administration to a 70 kg individual, the dosage range would be from about 7 mg per day to about 7000 mg per day, from about 35 mg per day or less to about 2000 mg per day or more, from about 70 mg per day to about 1000 mg per day.

[0187] Methods of Treatment Some aspects of the present invention include methods of treating a disease, disorder, or condition selected from the group consisting of hepatitis, liver cancer, liver fibrosis, fatty liver, malaria, viral infections, parasitic infections, diabetes, hyperlipidemia, atherosclerosis, obesity, dyslipidemia, hyperglycemia, hormonal conditions, HIV, and various types of cancer with the compounds described herein and compositions comprising the compounds. Some methods include administering to a subject in need thereof a compound, composition, or pharmaceutical composition described herein. In some aspects, the subject can be an animal, such as a mammal, a human. In some aspects, the subject is a human.

[0188] A further aspect includes administering to a subject in need thereof a combination of compounds. The combination can include a compound, composition, or pharmaceutical composition described herein together with a further medicament.

[0189] Some aspects include co-administering a compound, composition, and / or pharmaceutical composition described herein with a further medicament or a further therapeutic agent. "Co-administering" means that two or more agents can be found in the patient's bloodstream simultaneously, regardless of when or how the agents are actually administered. In one aspect, the agents are co-administered. In such an aspect, co-administration is achieved by combining the agents in one dosage form. In another aspect, the agents are administered sequentially. In one aspect, the agents are administered via the same route, such as orally. In another aspect, the agents are administered via different routes, such as one agent is administered orally and another agent is administered intravenously.

[0190] As further examples of medicaments, there may be mentioned other types of chemotherapeutic agents such as cyclophosphamide, methotrexate, doxorubicin, docetaxel, cisplatin, epirubicin, oxaliplatin, and folic acid; and therapeutic agents selected from the group consisting of other targeted anti-tumor agents such as histone deacetylase (HDAC) inhibitors. In some embodiments, further therapeutic agents for treating hepatocellular carcinoma (HCC) may be sorafenib, regorafenib, tumor immunotherapeutic agents, such as one or more of PD-1 or PD-L1 checkpoint inhibitors.

[0191] For further illustration of the present invention, the following examples are included. Of course, the examples should not be construed as specifically limiting the present invention. Modifications of these examples within the scope of the claims are within the skill of those in the art and are considered to be within the scope of the invention as described and claimed herein. The reader will recognize that those having skill in the art with the present disclosure will be able to prepare and use the present invention without undue experimentation.

[0192] Synthesis of Compounds The following procedures for the preparation of novel compounds illustrate the general procedures used for preparing cyclic phosphate ester compounds.

[0193] Scheme I describes the general synthesis of the compounds of formula I. After reacting a nucleoside (1) with a phosphane diamine (2) in the presence of 4,5-dicyanoimidazole to obtain a cyclic product of structure 3, the crude reaction mixture is treated with an oxidizing agent such as tert-butyl hydroperoxide to obtain the final product of formula I.

[0194] Scheme I TIFF2025106352000042.tif63158

Examples

[0195] Some compounds of formula I are prepared as outlined below.

[0196] Example 1 Isopropyl 2-((((4aR,6R,7aS)-6-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-oxide tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl)oxy)methyl)benzoate (Compound 101) TIFF2025106352000043.tif35128 Compound 101 was prepared from 1-chloro-N,N,N',N'-tetraisopropylphosphanediamine and deoxyuridine as follows according to the method described in Scheme I.

[0197] Isopropyl 2-(Hydroxymethyl)benzoate A mixture of phthalic anhydride (20 g, 0.15 mol) in isopropanol was heated at 90 °C for 6 h, and the resulting mixture was dried to give 2-(isopropoxycarbonyl)benzoic acid in almost quantitative yield. A THF solution of the benzoic acid derivative (10 g, 48 mmol) was treated with an excess of borane dimethyl sulfide at 0 - 20 °C for 2 h. The title compound (4.1 g, 44%) was obtained by standard workup and silica gel chromatography.

[0198] N,N,N',N'-Tetraisopropyl-1-(2-(2-Isopropyloxy)carbonylbenzyloxy)phosphanediamine To a solution of 1-chloro-N,N,N',N'-tetraisopropylphosphanediamine (2.3 g, 8.6 mml) and the above benzyl alcohol (1.8 g, 8.6 mmol) in a 1:3 mixture of n-hexane and methyl tert-butyl ether at 0 °C was added triethylamine (1.3 g, 1.5 equiv), and the resulting mixture was stirred overnight and warmed to 30 °C. The reaction mixture was dried and used in the next reaction as the crude product.

[0199] Compound 101 The reaction mixture of the above-mentioned crude phosphandiamine, deoxyuridine (1.0 equivalent), and DCI (2.5 equivalents) in a 3:1 mixture of THF and DMF was heated at 55 °C for 0.5 h, and the resulting mixture was dried to obtain a crude product. Next, the crude product was dissolved in THF and treated with 2.5 equivalents of TBHP at 0 °C for 0.5 h. After standard work-up and subsequent silica gel chromatography, compound 101 was obtained as a mixture of two isomers from deoxyuridine in an overall yield of about 15%. [M-1] + C 20 H 23 Calculated for C H N2O9P: 465.10. Found: 465.1.

[0200] Example 2 4-Amino-1-((4aR,6R,7aS)-2-(nonyloxy)-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-6-yl)pyrimidin-2(1H)-one (Compound 102) Compound 102 was prepared as a mixture of two isomers from N,N,N',N'-tetraisopropyl-1-nonyloxyphosphandiamine and deoxyuridine according to the method described in Scheme I. [M-1] + C 18 H 30 Calculated for C H N3O6P: 414.18. Found: 414.1.

[0201] Example 3 5-Methyl-1-((4aR,6R,7aS)-2-(octyloxy)-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 103) Compound 103 was prepared as a mixture of two isomers from N,N,N',N'-tetraisopropyl-1-octyloxyphosphandiamine and thymidine according to the method described in Scheme I. [M-1] + C 18 H 29Calculated value of N2O7P: 415.16. Measured value: 415.1.

[0202] Example 4 (4aR,6R,7aS)-6-(6-Amino-9H-purin-9-yl)-2-phenethoxytetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinine 2-oxide (Compound 104) TIFF2025106352000046.tif34128 Compound 104 was prepared as a mixture of two isomers from N,N,N',N'-tetraisopropyl-1-(2-phenylethoxy)phosphanediamine and deoxyadenosine according to the method described in Scheme I. [M-1] + C 18 H 20 Calculated value of N5O5P: 416.11. Measured value: 416.1.

[0203] Example 5 2-Amino-9-((4aR,6R,7aS)-2-(octyloxy)-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-6-yl)-1,9-dihydro-6H-purin-6-one (Compound 105) TIFF2025106352000047.tif34128 Compound 105 was prepared as a mixture of two isomers from N,N,N',N'-tetraisopropyl-1-octyloxyphosphanediamine and deoxyguanosine according to the method described in Scheme I. [M-1] + C 18 H 28 Calculated value of N5O6P: 440.17. Measured value: 440.2.

[0204] Example 6 Propyl 2-((((4aR,6R,7aS)-6-(5-(methyl-d3)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl)oxy)methyl)benzoate (Compound 106) TIFF2025106352000048.tif35128 Compound 106 was prepared as a mixture of two isomers from N,N,N',N'-tetraisopropyl-1-(2-(1-propyloxycarbonyl)benzyloxy)phosphane diamine and thymidine-d3 according to the method described in Scheme I. [M-1] + C 21 H 22 Calculated value of C18H33N5O7P: 482.14. Found: 482.1.

[0205] Example 7 Isopropyl 2-((((4aR,6R,7R,7aR)-6-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-7-fluoro-7-methyl-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl)oxy)methyl)benzoate (Compound 107) TIFF2025106352000049.tif34128 Compound 107 was prepared as a mixture of two isomers from N,N,N',N'-tetraisopropyl-1-(2-(2-isopropyloxy)carbonylbenzyloxy)phosphane diamine and a uridine derivative according to the method described in Scheme I. [M-1] + C 21 H 24 Calculated value of C17H27FN2O9P: 497.11. Found: 497.1.

[0206] Example 8 Isopropyl 2-((((4aR,6R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7,7-difluoro-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl)oxy)methyl)benzoate (Compound 108) TIFF2025106352000050.tif35128 Compound 108 was prepared as a mixture of two isomers from N,N,N',N'-tetraisopropyl-1-(2-(2-isopropyloxy)carbonylbenzyloxy)phosphane diamine and a cytidine derivative according to the method described in Scheme I. [M-1]+ C 20 H 22 Calculated value of F2N3O8P: 500.10. Measured value: 500.1.

[0207] Example 9 Isopropyl 2 - ((((4aR,6R,7S,7aS)-6-(4 - amino - 2 - oxopyrimidin - 1(2H)-yl)-7 - hydroxy - 2 - oxide tetrahydro - 4H - furo[3,2 - d][1,3,2]dioxaphosphinin - 2 - yl)oxy)methyl)benzoate (Compound 109) TIFF2025106352000051.tif35128 Compound 109 was prepared as a mixture of two isomers from N,N,N',N'-tetraisopropyl - 1-(2-(2 - isopropyloxy)carbonylbenzyloxy)phosphanediamine and a cytidine derivative according to the method described in Scheme I. [M - 1] + C 20 H 24 Calculated value of N3O9P: 480.39. Measured value: 480.3.

[0208] Biological Examples Examples of the use of this method are as follows. It should be understood that the following are examples and the method is not limited to only these examples.

[0209] Example 10 Tissue distribution after oral administration of reference compounds and the disclosed compounds The liver specificity of the disclosed compounds is compared with the corresponding active compounds in the liver and other organs that can be targets of toxicity.

[0210] Method Reference compounds and cyclic phosphate ester compounds were administered to fasted rats at 5 - 50 mg / kg by oral gavage. Plasma concentrations of metabolites and parent compounds in the circulation and the portal vein were determined by HPLC - UV, and concentrations in the liver, small intestine, and other organs were measured by LC - MS using standard chromatography methods.

[0211] Table 1 shows a comparison of the results of the selected compounds with the corresponding reference compounds, and the results demonstrated that the oral delivery efficiency of known nucleosides was improved.

[0212] (Table 1) Ratio of the novel compound to the corresponding reference compound with respect to the nucleoside phosphate levels in the liver, and the nucleoside levels in the hepatic portal vein (HPV) and systemic blood, 1 hour after oral administration at a nucleoside equivalent dose of 5 mg / kg of the selected compounds in rats TIFF2025106352000052.tif38163 "-" = undetermined; NTP = nucleoside triphosphate; NMP = nucleoside monophosphate; NUC = nucleoside

[0213] These results demonstrate that Compounds 106 and 107 exhibit substantially higher nucleoside phosphate levels in the liver compared to the reference compounds.

[0214] All numbers representing amounts of ingredients, reaction conditions, etc. used herein should be understood to be modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth herein are approximations that 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 claim in any application claiming the priority of this application, each numerical parameter should be construed in light of the number of significant figures and the ordinary rounding approach.

[0215] As used herein, terms of degree such as "approximately", "about", "generally", and "substantially" still mean a value, amount, or property that is close to the recited value, amount, or property and that performs the desired function or achieves the desired result. For example, the terms "approximately", "about", "generally", and "substantially" can mean an amount within less than 10%, less than 5%, less than 1%, less than 0.1%, and less than 0.01% of the recited amount. As another example, in certain embodiments, the terms "generally parallel" and "substantially parallel" mean a value, amount, or property that deviates from exact parallelism by 15% or less, 10% or less, 5% or less, 3% or less, 1% or less, 0.1% or less, etc. Similarly, in certain embodiments, the terms "generally perpendicular" and "substantially perpendicular" mean a value, amount, or property that deviates from exact perpendicularity by 15% or less, 10% or less, 5% or less, 3% or less, 1% or less, 0.1% or less, etc.

[0216] The foregoing description discloses several methods and materials. The present invention permits modifications of the methods and materials, as well as alterations of the manufacturing methods and equipment. These modifications will be apparent to those skilled in the art in view of the present disclosure or in practicing the invention disclosed herein. Accordingly, the present invention is not intended to be limited to the specific embodiments disclosed herein, but is intended to cover all modifications and alternatives within the true scope and spirit of the present invention.

[0217] All references cited herein, including but not limited to published applications and unpublished applications, patents, and reference documents, are hereby incorporated by reference in their entirety and made a part hereof. If the publications and patents or patent applications incorporated by reference conflict with the disclosure contained herein, the present specification is intended to supersede and / or take precedence over any such conflicting materials.

[0218] Although some aspects and examples have been described, it should be understood that numerous various modifications can be made without departing from the true spirit of the present invention.

Claims

1. A compound of formula I, or a stereoisomer or pharmaceutically acceptable salt thereof: wherein, R 2a and R 2b are each independently H, OR 8 , halo, CN, and optionally substituted C 1 ~C 10 selected from the group consisting of alkyl; R 3 and R 4 each independently represents H, OH, halo, CN, N 3 , and optionally substituted C 1 -C 10 alkyl selected from the group consisting of; R 5a is H, -CH(OR 7 ) 2 , -C(O)OR 7 , -C(O)N(R 7 ) 2 , -CH 2 OR 8 , -CH 2 N(R 8 ) 2 , -CH 2 OCH 2 OR 8 , and is selected from the group consisting of; R 5b is H, optionally substituted C 1 ~C 10 alkyl, optionally substituted C 3 ~C 10 cycloalkyl, optionally substituted C 1 ~C 10 alkyloxy, optionally substituted (C 6～10 aryl), optionally substituted (C 6～10 aryl)-CH 2 -, optionally substituted (C 6～10 aryl)-CH 2 CH 2 -, -CH(OR 7 ) 2 、-C(O)OR 7 、-C(O)N(R 7 ) 2 、-CH 2 OR 8 、-CH 2 N(R 8 ) 2 、-CH 2 OCH 2 OR 8 、and is selected from the group consisting of; Each R 6 is independently selected from the group consisting of halo and optionally substituted C 1 -C 10 -alkyl; Each R 7 is independently selected from the group consisting of H and optionally substituted C 1 -C 10 -alkyl; Each R 8 is independently selected from the group consisting of H, C(O)R 7 , C(O)OR 7 , and C(O)NHR 7 ; m is 0, 1, or 2; n is 0, 1, 2, or 3; q is 0 or 1; r is 0 or 1; the base is a natural nucleoside base or a derivative or analog thereof; provided that, the base is not When it is the case, q is 1, and R 5a is also H either.

2. The compound according to claim 1, wherein the base is selected from the group consisting of: wherein, R 9 is H, halo, -CD 3 , or optionally substituted C 1 ~C 10 alkyl; R 10 is selected from the group consisting of H, optionally substituted C 1 ~C 10 alkyl, optionally substituted C 1 ~C 10 alkyl - OCH 2 -, optionally substituted C 1 ~C 10 alkyl - NHCH 2 -, optionally substituted C 1 ~C 10 acyl, optionally substituted C 1 ~C 10 alkyl - OC(O)-, optionally substituted (C 6～10 aryl)-CH 2 OCH 2 -, optionally substituted (C 6～10 aryl)-OCH 2 -, optionally substituted (C 6～10 aryl)-C(O)-, and optionally substituted (C 6～10 aryl)-OC(O)-; R 11 is OH, NH 2 , NHOR 8 , optionally substituted C 1 ~C 10 alkyloxy, optionally substituted C 1 ~C 10 alkylamino, optionally substituted C 1 ~C 10 acyloxy, optionally substituted C 1 ~C 10 acylamino, optionally substituted C 1 ~C 10 alkyl-OC(O)NH-, optionally substituted (C 6～10 aryl)-C(O)O-, optionally substituted (C 6～10 aryl)-C(O)NH-, optionally substituted (C 6～10 aryl)-OC(O)NH-, optionally substituted C 1 ~C 10 alkyl-OCH 2 NH-, and optionally substituted C 1 ~C 10 alkyl-OCH 2 O- and is selected from the group consisting of; R 12 is selected from the group consisting of H, NH 2 , optionally substituted C 1 to C 10 alkylamino, optionally substituted C 1 to C 10 acylamino, optionally substituted C 1 to C 10 alkyl-OC(O)NH-, optionally substituted (C 6～10 aryl)-C(O)NH-, optionally substituted (C 6～10 aryl)-OC(O)NH-, and optionally substituted C 1 to C 10 alkyl-OCH 2 NH-.

3. R 9 The compound according to claim 2, wherein R is H.

4. R 9 is unsubstituted C 1 -C 10 alkyl, the compound according to claim 2.

5. R 9 The compound according to claim 4, wherein R is methyl.

6. R 9 is -CD 3 The compound according to claim 2, wherein it is

7. R 10 The compound according to any one of claims 2 to 6, wherein R is H.

8. R 11 is NH 2 The compound according to any one of claims 2 to 7, wherein

9. R 12 The compound according to any one of claims 2 to 8, wherein R is H.

10. R 12 is NH 2 and is a compound according to any one of claims 2 to 8.

11. R 2a and R 2b The compound according to any one of claims 1 to 10, wherein at least one of them is H.

12. R 2a and R 2b The compound according to any one of claims 1 to 10, wherein each of them is H.

13. R 2a is unsubstituted C 1 -C 10 alkyl, and the compound according to any one of claims 1 to 10.

14. R 2a is methyl and R 2b is fluoro, the compound according to claim 13.

15. R 2a The compound according to any one of claims 1 to 10, wherein R is OH.

16. R 2a and R 2b wherein each of R and R is halo, a compound according to any one of claims 1 to 10.

17. R 2a and R 2b each being fluoro, the compound according to claim 16

18. R 3 The compound according to any one of claims 1 to 17, wherein R is a halo.

19. R 3 The compound according to any one of claims 1 to 17, wherein R is H.

20. R 4 The compound according to any one of claims 1 to 19, wherein R is a halo.

21. R 4 The compound according to any one of claims 1 to 19, wherein R is H.

22. the base is In the case where m is 1, q is 1, n is 0, r is 0, and R 5a is H as well nor R 5b is not methyl, a compound according to any one of claims 1 to 21.

23. The compound according to any one of claims 1 to 22, wherein the compound of formula I is of formula (Ia): or a stereoisomer or pharmaceutically acceptable salt thereof.

24. R 5b is replaced by C 1 ~C 10 The compound according to claim 23, wherein it is alkyl.

25. R 5b is unsubstituted C 1 -C 10 alkyl, the compound according to claim 23.

26. R 5b The compound according to claim 25, wherein R is octyl.

27. R 5b The compound according to claim 25, wherein R is heptyl.

28. R 5b is substituted with C 6～10 The compound according to claim 23, wherein it is aryl.

29. R 5b is phenyl substituted by -COOR 13 wherein R 13 is unsubstituted C 1 to C 6 alkyl, the compound according to claim 28.

30. R 13 The compound according to claim 29, wherein R is i-propyl.

31. R 13 The compound according to claim 29, wherein R is n-propyl.

32. The compound according to any one of claims 1 to 22, wherein the compound of formula I is of formula (Ib): or a stereoisomer or pharmaceutically acceptable salt thereof.

33. R 5a is -CH(OR 7 ) 2 , -C(O)OR 7 , -C(O)N(R 7 ) 2 , -CH 2 OR 8 , -CH 2 N(R 8 ) 2 , -CH 2 OCH 2 OR 8 , and The compound according to claim 32, selected from the group consisting of:

34. R 5a is -CH(OR 7 ) 2 , -C(O)OR 7 , -C(O)N(R 7 ) 2 , -CH 2 OR 8 , -CH 2 N(R 8 ) 2 , and -CH 2 OCH 2 OR 8 and is selected from the group consisting of, a compound according to claim 32.

35. R 5a is -COOR 13 wherein R 13 is unsubstituted C 1 to C 10 alkyl, the compound according to claim 32.

36. R 13 The compound according to claim 35, wherein R is i-propyl.

37. R 13 The compound according to claim 35, wherein R is n-propyl.

38. The compound according to any one of claims 32 to 37, wherein n is 0.

39. The compound according to any one of claims 1 to 22, wherein the compound of formula I is of formula (Ic): or a stereoisomer or pharmaceutically acceptable salt thereof.

40. The compound according to claim 39, wherein n is 0.

41. The compound according to claim 39 or 40, wherein m is 1.

42. The compound according to any one of claims 1 to 22, wherein the compound of formula I is of formula (Id): or a stereoisomer or pharmaceutically acceptable salt thereof.

43. the base is The compound according to claim 42, selected from the group consisting of:

44. The compound according to claim 43, wherein m is 0.

45. R 5b is replaced by C 1 ~C 10 The compound according to claim 42 or 43, wherein it is alkyl.

46. R 5b is unsubstituted C 1 -C 10 alkyl, a compound according to claim 42 or 43.

47. R 5b The compound according to claim 46, wherein R is heptyl.

48. R 5b The compound according to claim 46, wherein R is hexyl.

49. The compound according to any one of claims 1 to 22, wherein at least one of m, q, and r is not 0.

50. R 5b is optionally substituted C 1 - C 10 alkyl, optionally substituted C 3 - C 10 cycloalkyl, optionally substituted C 1 - C 10 alkyloxy, optionally substituted (C 6～10 aryl), optionally substituted (C 6～10 aryl)-CH 2 -, optionally substituted (C 6～10 aryl)-CH 2 CH 2 -, -CH(OR 7 ) 2 -, -C(O)OR 7 -, -C(O)N(R 7 ) 2 -, -CH 2 OR 8 -, -CH 2 N(R 8 ) 2 -, -CH 2 OCH 2 OR 8 and A compound according to any one of claims 1 to 22, selected from the group consisting of.

51. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: 。

52. A pharmaceutical composition comprising a compound according to any one of claims 1 to 51 and a pharmaceutically acceptable excipient.

53. A compound according to any one of claims 1 to 51 for use in the treatment of a disease in the liver, or a disease or condition in which the liver is involved in a physiological or pathogenic pathway.

54. A compound according to claim 53 in combination with one or more additional therapeutic agents.

55. Use of a compound according to any one of claims 1 to 51 in the preparation of a medicament for treating a disease or condition in the liver, or a disease or condition in which the liver is involved in a physiological or pathogenic pathway.

56. A method of treating a disease, disorder, or condition, the method comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 51.

Images