Cyclic phosphate ester compounds

Abstract

Provided herein are cyclic phosphate compounds, their preparation, and their uses, for example, to treat diseases or conditions of the liver or diseases or conditions that involve the liver in the physiological or pathological pathway.

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 aspects, these compounds are useful for selectively delivering certain drugs to the liver. [Background technology]

[0002] background The following description of the background is provided to facilitate an 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, are the building blocks of DNA and RNA. Nucleosides in humans are obtained primarily from digestion of dietary nucleic acids and can be biosynthesized when needed, particularly in the liver. Nucleosides can be phosphorylated to nucleotides in cells by specific nucleoside kinases to maintain normal cell function and proliferation. These kinases can be impaired in one or more tissues by genetic defects or non-genetic factors, 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).

[0004] Theoretically, nucleotide supplementation may address deficiencies in the body, but nucleotides have molecular properties, such as hydrophilicity, that prevent them from easily passing through cell membranes, and therefore nucleotide supplementation may be inefficient or require large amounts of supplementation. Synthetic nucleosides (nucleotides) are widely used as antiviral or anticancer agents. Prodrug technology has been used to improve the molecular properties of nucleotides to allow for improved bioavailability, including improved oral bioavailability of nucleotides. Thus, novel compounds that exhibit a liver targeting profile in addition to improved oral bioavailability may significantly improve the therapeutic efficacy of nucleoside (nucleotide)-based therapies. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] 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) Summary of the Invention

[0006] overview Novel cyclic phosphate compounds, their preparation, and their uses are described. Some embodiments are novel cyclic phosphate compounds that are orally delivered to the liver to achieve therapeutic effects there. Further embodiments include novel cyclic phosphate compounds that treat 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 compounds to treat diseases that benefit from improved drug distribution to the liver and similar tissues and cells. In another aspect, the cyclic phosphate 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, the cyclic phosphate 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 compounds.

[0007] Some embodiments provided herein include compounds of formula I, Ia, Ib, Ic, and Id, or a stereoisomer or pharma- ceutically acceptable salt thereof: TIFF0007661235000001.tif179128In formula, 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 value described herein.

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

[0009] Some embodiments relate to a pharmaceutical composition comprising one to four of the above compounds and a pharma- ceutically acceptable excipient.

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

[0011] Some embodiments relate to a method of treating a disease, disorder, or condition, 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 one in which the liver is involved in the production and / or homeostatic control of the biochemical end products of the disease, disorder, or condition.

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

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

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

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

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

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

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

[0021] Some embodiments relate to a method of intervening in a molecular pathway or modulating a target in a cell, 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 cells are 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 cells are human cells.

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

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

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

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

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

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

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

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

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

[0036] Some embodiments of the compounds, compositions, and methods provided herein include one or more compositions provided herein for use in the preparation of a medicament for treating a disease or condition in the liver or a disease or condition that involves the liver in a physiological or pathological pathway.

[0037] Some embodiments of the compounds, compositions, and methods provided herein include one or more compositions provided herein for use in the preparation of a medicament for treating a non-hepatic disease or condition. [The present invention 1001] A compound of formula I, or a stereoisomer or a pharma- ceutically acceptable salt thereof: TIFF0007661235000002.tif33128 During the ceremony, R 2a and R2b 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 are each independently H, OH, halo, CN, or N 3 and optionally substituted C 1 ~C 10 selected from the group consisting of alkyl; 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 TIFF0007661235000003.tif12128 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 OR8 , -CH 2 N(R 8 ) 2 , -CH 2 OCH 2 OR 8 , and TIFF0007661235000004.tif12128 selected from the group consisting of; Each R 6 are independently halo and optionally substituted C 1 ~C 10 selected from the group consisting of alkyl; Each R 7 are independently H and optionally substituted C 1 ~C 10 selected from the group consisting of alkyl; Each R 8 are independently H, C(O)R 7 , C(O)OR 7 , and C(O)NHR 7 selected from the group consisting of: 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 may be a natural nucleoside base or a derivative or analogue thereof; However, the base is TIFF0007661235000005.tif21128 If , then q is 1 and R 5a Even though it's H TIFF0007661235000006.tif12128 But no. [The present invention 1002] The compound of the present invention, wherein the base is selected from the group consisting of: TIFF0007661235000007.tif40162 During the ceremony, R 9 H, Halo, -CD 3 or optionally substituted C 1 ~C 10 is alkyl; R 10 is 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 OH, NH 2 , N.H.O.R. 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 Selected from the group consisting of O-; R 12 H, NH 2 , optionally substituted C 1 ~C10 Alkylamino, 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)NH-, optionally substituted (C 6~10 aryl)-OC(O)NH-, and optionally substituted C 1 ~C 10 Alkyl-OCH 2 NH-. [The present invention 1003] R 9 The compound of the present invention 1002, wherein is H. [The present invention 1004] R 9 is unsubstituted C 1 ~C 10 The compound of the present invention 1002, which is alkyl. [The present invention 1005] R 9 The compound of the present invention 1004, wherein is methyl. [The present invention 1006] R 9 Ga-CD 3 The compound of the present invention 1002, [The present invention 1007] R 10 The compound according to any one of 1002 to 1006 of the present invention, wherein [The present invention 1008] R 11 NH 2 The compound of any one of the present invention Nos. 1002 to 1007, [The present invention 1009] R 12 The compound according to any one of 1002 to 1008 of the present invention, wherein [The present invention 1010] R 12 NH 2 The compound of any one of the present inventions 1002 to 1008, [The present invention 1011] R 2a and R2b The compound of any one of 1001 to 1010 of the present invention, wherein at least one of the following is H. [The present invention 1012] R 2a and R 2b The compound of any one of 1001 to 1010 according to the present invention, wherein each of [The present invention 1013] R 2a is unsubstituted C 1 ~C 10 The compound of any one of 1001 to 1010, which is alkyl. [The present invention 1014] R 2a is methyl and R 2b The compound of the present invention 1013, wherein is fluoro. [The present invention 1015] R 2a Any of the compounds of 1001 to 1010 according to the present invention, wherein is OH. [The present invention 1016] R 2a and R 2b and each is halo. [The present invention 1017] R 2a and R 2b The compound of the present invention 1016, wherein each of [The present invention 1018] R 3 The compound of any one of 1001 to 1017, wherein is halo. [The present invention 1019] R 3 The compound according to any one of claims 1001 to 1017, wherein [The present invention 1020] R 4 The compound of any one of 1001 to 1019 of the present invention, wherein is halo. [The present invention 1021] R 4 The compound of any one of 1001 to 1019 of the present invention, wherein [The present invention 1022] The base TIFF0007661235000008.tif21128 then m is 1, q is 1, n is 0, r is 0, and R 5a Even if it's H TIFF0007661235000009.tif12128 But, R 5b Any of the compounds of the present invention 1001 to 1021, wherein is not methyl. [The present invention 1023] The compound of formula I has the formula (Ia): TIFF0007661235000010.tif21128 The compound according to any one of the present invention Nos. 1001 to 1022, or a stereoisomer or a pharma- ceutically acceptable salt thereof, which is represented by the following formula: [The present invention 1024] R 5b C is substituted 1 ~C 10 The compound of the present invention 1023, which is alkyl. [The present invention 1025] R 5b is unsubstituted C 1 ~C 10 The compound of the present invention 1023, which is alkyl. [The present invention 1026] R 5b The compound of the present invention 1025, wherein is octyl. [The present invention 1027] R 5b The compound of the present invention 1025, wherein is heptyl. [The present invention 1028] R 5b C is substituted 6~10 The compound of the present invention 1023, which is aryl. [The present invention 1029] R 5b But, -COOR 13 phenyl substituted with 13 is unsubstituted C 1 ~C 6 The compound of the present invention 1028, which is alkyl. [The present invention 1030] R 13 The compound of the present invention 1029, wherein is i-propyl. [The present invention 1031] R 13 The compound of the present invention 1029, wherein is n-propyl. [The present invention 1032] The compound of formula I has the formula (Ib): TIFF0007661235000011.tif25128 The compound according to any one of the present invention Nos. 1001 to 1022, or a stereoisomer or a pharma- ceutically acceptable salt thereof, which is represented by the following formula: [The present invention 1033] R 5a But -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 TIFF0007661235000012.tif12128 The compound of the present invention 1032 selected from the group consisting of: [The present invention 1034] R 5a But -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 The compound of the present invention 1032 selected from the group consisting of: [The present invention 1035] R 5a -COOR 13 where R 13 is unsubstituted C 1 ~C 10 The compound of the present invention 1032, which is alkyl. [The present invention 1036] R 13 The compound of the present invention 1035, wherein is i-propyl. [The present invention 1037] R 13 The compound of the present invention 1035, wherein is n-propyl. [The present invention 1038] The compound of any one of 1032 to 1037 according to the present invention, wherein n is 0. [The present invention 1039] The compound of formula I has the formula (Ic): TIFF0007661235000013.tif35128 The compound according to any one of the present invention Nos. 1001 to 1022, or a stereoisomer or a pharma- ceutically acceptable salt thereof, which is represented by the following formula: [The present invention 1040] The compound of the present invention 1039, wherein n is 0. [The present invention 1041] The compound of claim 1039 or 1040, wherein m is 1. [The present invention 1042] The compound of formula I has the formula (Id): TIFF0007661235000014.tif26128 The compound according to any one of the present invention Nos. 1001 to 1022, or a stereoisomer or a pharma- ceutically acceptable salt thereof, which is represented by the following formula: [The present invention 1043] The base TIFF0007661235000015.tif23128 The compound of the present invention 1042 selected from the group consisting of: [The present invention 1044] The compound of the present invention 1043, wherein m is 0. [The present invention 1045] R 5b C is substituted 1 ~C 10 The compound of the present invention 1042 or 1043, which is alkyl. [The present invention 1046] R 5b is unsubstituted C 1 ~C 10 The compound of the present invention 1042 or 1043, which is alkyl. [The present invention 1047] R 5b The compound of the present invention 1046, wherein is heptyl. [The present invention 1048] R 5b The compound of the present invention 1046, wherein is hexyl. [The present invention 1049] The compound according to any one of claims 1001 to 1022, wherein at least one of m, q, and r is not 0. [The present invention 1050] R 5b may be 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 TIFF0007661235000016.tif12128 The compound of any one of 1001 to 1022 of the present invention, selected from the group consisting of: [The present invention 1051] A compound of the present invention, selected from the group consisting of: TIFF0007661235000017.tif153157 。 [The present invention 1052] A pharmaceutical composition comprising any one of the compounds of the present invention 1001 to 1051 and a pharma- ceutically acceptable excipient. [The present invention 1053] Any of the compounds of claims 1001 to 1051 for use in treating in a subject a disease in the liver, or a disease or condition which involves the liver in a physiological or pathological pathway. [The present invention 1054] A 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 claims 1001 to 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 pathological pathway. [The present invention 1056] A method for treating a disease, disorder, or condition, comprising administering to a subject in need thereof an effective amount of any of the compounds of the present invention 1001-1051. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0038] Detailed Description The present aspects relate to compositions and methods relating to, their preparation, and their uses of novel cyclic phosphate compounds. In some aspects, the novel cyclic phosphate 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 compounds, and their stereoisomers and pharma- ceutically acceptable salts, are represented by Formulas I, Ia, Ib, Ic, and Id, or a stereoisomer or pharma- ceutically acceptable salt thereof: TIFF0007661235000018.tif175128In formula, R 2a , R 2b , R 3 , R 4 , R 5a , R 5b , R 6 , n, m, q, r, and the base have any value described herein.

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

[0041] In some embodiments, R 3 and R 4 are independently H, OH, CN, N3, and optionally substituted C1 to C 10 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 The file is TIFF0007661235000019.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(R 8 )2, -CH2OCH2OR 8 , and TIFF0007661235000020.tif12128.

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

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

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

[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 is In some embodiments, the base is If TIFF0007661235000022.tif21128, then q is 1 and R 5a Even though it's H In some embodiments, the base is If TIFF0007661235000024.tif21128, then m is 1, q is 1, n is 0, r is 0, and R 5a Even though it's H Not TIFF0007661235000025.tif12128, nor R 5b is not methyl.

[0050] In some embodiments, the base is TIFF0007661235000026.tif40145.

[0051] In some embodiments, the base is TIFF0007661235000027.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)-.

[0054] In some embodiments, R 11 OH, NH2, NHOR 8 , optionally substituted C1 to 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 10Alkyl-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-OCHO-.

[0055] In some embodiments, 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-, optionally substituted C1-C 10 alkyl-OCH2NH-.

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

[0057] In some embodiments, R 11 is NH2, optionally substituted C1-C 10 Acylamino and optionally substituted C1-C 10 In some embodiments, R is selected from the group consisting of alkylamino. 11 is NH2.

[0058] In some embodiments, R 12 is H or optionally substituted C1-C 10 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 It is an alkyl.

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

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

[0062] In some embodiments, the base is TIFF0007661235000028.tif21128. In some embodiments, the bases are TIFF0007661235000029.tif22128. In some embodiments, the bases are TIFF0007661235000030.tif19128. In some embodiments, the bases are TIFF0007661235000031.tif21128. In some embodiments, the bases are TIFF0007661235000032.tif21128. In some embodiments, the bases are The file is TIFF0007661235000033.tif14128.

[0063] In some embodiments, R 5b is an optionally substituted C1 to 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 TIFF0007661235000034.tif12128. 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 H, respectively.

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

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

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

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

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

[0070] In some embodiments, R 2a 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 F.

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

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

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

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

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

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

[0079] In some embodiments, R 5b is unsubstituted C1~C 10 It is an 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 5b is a substitution C 6~10 It is aryl.

[0084] In some embodiments, R 5b -COOR 13 phenyl substituted with 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 -CH(OR 7 )2, -C(O)OR 7 , -C(O)N(R 7 )2, -CH2OR 8 , -CH2N(R 8 )2, -CH2OCH2OR 8 , and TIFF0007661235000035.tif12128. In some embodiments, 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 In some embodiments, R 5a -COOR 13 where R 13 is unsubstituted C1~C 10 It is an 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: TIFF0007661235000036.tif109158TIFF0007661235000037.tif36128, or a pharma- ceutically acceptable salt thereof.

[0093] In some embodiments, the compound comprises: TIFF0007661235000038.tif128164 or a pharma- ceutically acceptable salt thereof.

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

[0095] In some embodiments, the cyclic phosphate compounds of formula I, Ia, Ib, Ic, and Id include a lipophilic R 5b or other groups.

[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 a much higher level in the liver than in other tissues (DeWaziers et al. J Pharm Exp Ther 253:387 (1990)). Certain cyclic phosphate compounds of formula I, Ia, Ib, Ic, and Id are activated by CYP3A4 mainly in the liver. In some embodiments, compounds of formula I, Ia, Ib, Ic, and Id show high efficiency in liver targeting by selectively delivering biologically relevant nucleotides to the liver. In some embodiments, cyclic phosphate compounds are used to increase the therapeutic index of drugs. Because compounds of formula I, Ia, Ib, Ic, and Id may have no activity or relatively low activity outside the liver.

[0098] In some embodiments, the cyclic phosphate compounds of formulas I, Ia, Ib, Ic, and Id, due to their liver targeting properties, are used to treat diseases that benefit from improved drug distribution to the liver and similar tissues and cells, including, but not limited to, liver diseases.

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

[0100] In some embodiments, the disclosed compounds are used to improve pharmacokinetic properties, such as extending the half-life or increasing the absorption rate of nucleotides.Furthermore, the disclosed methodology can be used to achieve sustained delivery of biorelevant nucleotides.The cyclic phosphate compounds of formula I, Ia, Ib, Ic, and Id have improved pharmacokinetic properties and are therefore used to treat diseases that benefit from improved drug properties.In some embodiments, methods of making these compounds are described.

[0101] Certain compounds of formula I, Ia, Ib, Ic, and Id have asymmetric centers that may be of unspecified stereochemical configuration, and general references to compounds of formula II, Ia, Ib, Ic, and Id include diastereomeric mixtures of these compounds as well as 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 pharma- ceutically acceptable carrier.

[0104] Some embodiments also include administering to a subject in need thereof an effective amount of a combination 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 a method of testing a compound in a cell comprising contacting the cell with a disclosed compound.

[0108] Some embodiments of the compounds, compositions, and methods provided herein include the use of the compounds provided herein in treating liver disease in a subject, or a disease or condition that involves the liver in a physiological or pathological pathway.

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

[0110] Some embodiments of the compounds, compositions, and methods provided herein include the use of the compounds provided herein in the treatment of a disease or condition by intervening in a molecular pathway in the liver.

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

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

[0113] Some embodiments include the use of a combination of a compound provided herein with an additional therapeutic agent for the treatment of a non-hepatic disease.

[0114] Some embodiments relate to the use of a compound provided herein in the preparation of a medicament for treating a disease or condition in the liver or a disease or condition that involves the liver in a physiological or pathological pathway.

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

[0116] When the compounds disclosed herein have at least one chiral center, they may exist as individual enantiomers and diastereomers, or as mixtures of said isomers, including racemates. Separation of individual isomers or selective synthesis of individual isomers can be achieved by application of various methods well known to those skilled in the art. Unless otherwise indicated, all these isomers and mixtures thereof are included within the scope of the compounds disclosed herein. Furthermore, the compounds disclosed herein may exist in one or more crystalline or amorphous forms. Unless otherwise indicated, all these forms, including any polymorphs, are included within the scope of the compounds disclosed herein. Furthermore, some of the compounds disclosed herein may form solvates with water (i.e., hydrates) or 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 depicted herein, even when dynamically represented, may be resonance forms or tautomers of compounds that may legitimately be represented by other chemical structures, and that the structures may represent only a small portion of a sample of the compounds. Although these resonance forms or tautomers are not depicted herein, these compounds are considered to be within the scope of the depicted structures.

[0118] Isotopes may be present in the compounds described. Each chemical element depicted in a compound structure may include any isotope of that element. For example, in a compound structure, a hydrogen atom may be expressly disclosed or understood as being present in the compound. At any position of 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). Thus, unless the context clearly indicates otherwise, reference to a compound herein encompasses all possible isotopic forms.

[0119] definition The following terms, in accordance with this disclosure and as used herein, are defined by the following meanings unless expressly stated otherwise. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the claimed subject matter. In this application, the use of the singular includes the plural unless specifically stated otherwise. In this application, the use of "or" means "and / or" unless specifically stated otherwise. Furthermore, the use of the term "including" as well as other forms such as "includes" and "included" are non-limiting.

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

[0121] As used herein, "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes cases where the event or circumstance occurs and cases where it does not occur. For example, an optionally substituted group means that the group is 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, reference to a composition containing a "therapeutic agent" includes a composition having one or more therapeutic agents.

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

[0124] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain that is fully saturated (i.e., contains no double or triple bonds). The alkyl group may have 1-20 carbon atoms (wherever alkyl groups appear herein, numerical ranges such as "1-20" refer to each integer within the given range. For example, "1-20 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 20 carbon atoms or less, but this definition also covers the occurrence of the term "alkyl" without a numerical range specified). The alkyl group may be a medium alkyl having 1-9 carbon atoms. The alkyl group may be a lower alkyl having 1-4 carbon atoms. The alkyl group may be designated as "C1-C4 alkyl" or a similar designation. Merely by way of example, "C1-C4 alkyl" indicates that there are 1-4 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.

[0125] As used herein, a "substituted group" is one that is derived from an unsubstituted parent group in which one or more hydrogen atoms have been replaced with another atom or group. Unless otherwise indicated, when a group is said to be "substituted", it is meant that the group in question is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 carbocyclyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7-carbocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy). 3-10 membered heterocycle (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 3-10 membered heterocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy). aryl(C1-C6)alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy); 5-10 membered heteroaryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy); 5-10 membered heteroaryl(C1-C6)alkyl (halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy); 6 haloalkoxy), halo, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy(C1-C6)alkyl (i.e., ether), aryloxy (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7 carbocyclyloxy (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy),3-10 membered heterocyclyl-oxy (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heteroaryl-oxy (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7-carbocyclyl-C1-C6-alkoxy (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy). 3-10 membered heterocyclyl-C1-C6-alkoxy (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl(C1-C6)alkoxy (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heteroaryl(C1-C6)alkoxy (halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy). alkoxy), sulfhydryl (mercapto), halo(C1-C6)alkyl (e.g., -CF3), halo(C1-C6)alkoxy (e.g., -OCF3), C1-C6 alkylthio, arylthio (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7 carbocyclylthio (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 3-10 5-membered heterocyclyl-thio (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10-membered heteroaryl-thio (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7-carbocyclyl-C1-C6-alkylthio (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy),3-10 membered heterocyclyl-C1-C6-alkylthio (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl(C1-C6)alkylthio (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heteroaryl(C1-C6)alkylthio (halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloaryl, and C1-C6 haloalkoxy), substituted with one or more substituents independently selected from: amino, amino(C1-C6)alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, and oxo (=O). Whenever a group is described as "optionally substituted," the group in question may be optionally substituted with the above-mentioned substituents.

[0126] As used herein, "acyl" refers to an acyl group in which R is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl. Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acryl.

[0127] "Heteroacyl" means that R is C 1~6 It refers to heteroalkyl, -C(=O)R.

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

[0129] An "O-carboxy" group is a group where R is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 "--OC(.dbd.O)R" group selected from aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl.

[0130] A "C-carboxy" group refers to a group in which R is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 means the group "-C(=O)OR" selected from aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl. Non-limiting examples include carboxyl (i.e., -C(=O)OH).

[0131] A "cyano" group refers to a "-CN" group.

[0132] A "cyanato" group refers to a "-OCN" group.

[0133] An "isocyanato" group refers to a "-NCO" group.

[0134] A "thiocyanato" group refers to a "-SCN" group.

[0135] An "isothiocyanato" group refers to a "-NCS" group.

[0136] A "sulfinyl" group refers to a group in which R is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 "--S(.dbd.O)R" group selected from aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl.

[0137] A "sulfonyl" group refers to a group where R is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 "-SO2R" group selected from aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl.

[0138] An "S-sulfonamide" group is R A and R B each independently represents hydrogen as defined herein; 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; A R B " group.

[0139] An "N-sulfonamide" group is R A and R b each independently represents hydrogen as defined herein; C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 "-N(R A )SO2R B " group.

[0140] An "O-carbamyl" group is R A and R B each independently represents hydrogen as defined herein; C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10"-OC(=O)NR 1 selected from aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl" A R B " group.

[0141] An "N-carbamyl" group is R A and R B each independently represents hydrogen as defined herein; C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 "-N(R A )C(=O)OR B " group.

[0142] An "O-thiocarbamyl" group is R A and R B each independently represents hydrogen as defined herein; C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 "-OC(=S)NR 1" is selected from aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl; A R B " group.

[0143] An "N-thiocarbamyl" group is R A and R B each independently represents hydrogen as defined herein; C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 "-N(R A )C(=S)OR B " group.

[0144] A "C-amide" group is a group consisting of RA and R B each independently represents hydrogen as defined herein; 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, each of which is selected from -OH, C 1~6 Alkyl, C 3~7 Carbocyclyl, C 6~10 Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, C 1~6 C optionally substituted with alkoxy or -OH 1~6 Alkyl, and C 1~6 C optionally substituted with alkoxy or -OH 1~6 "-C(=O)NR A R B " group.

[0145] An "N-amide" group is R A and R B each independently represents hydrogen as defined herein; 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, each of which is selected from -OH, C 1~6 Alkyl, C 3~7 Carbocyclyl, C 6~10 Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, C 1~6 C optionally substituted with alkoxy or -OH 1~6 Alkyl, and C 1~6 C optionally substituted with alkoxy or -OH 1~6 "-N(R A )C(=O)R B " group.

[0146] An "amino" group is R A and R B each independently represents hydrogen as defined herein; 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; A R B " group. A non-limiting example includes a free amino (i.e., -NH2).

[0147] An "aminoalkyl" group refers to an amino group connected through an alkylene group.

[0148] An "alkoxyalkyl" group is an alkoxy group connected by an alkylene group, e.g., "C 2~8 "Alkoxyalkyl" and the like.

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

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

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

[0152] The term "oxo" means the group ═O.

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

[0154] The term "haloalkyl" refers to an alkyl group that includes at least one halogen, and in a further aspect, one to three halo atoms. Suitable halo atoms include F, Cl, and Br.

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

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

[0157] The term "alkynyl" refers to unsaturated groups having 2 to 12 atoms and containing at least one carbon-carbon triple bond, including straight-chain, branched-chain, and cyclic groups. Alkynyl groups may be optionally substituted. Suitable alkynyl groups include ethynyl.

[0158] As used herein, "aryl" refers to an aromatic ring or ring system (i.e., two or more fused rings sharing two adjacent carbon atoms) that contains only carbon in the ring backbone. When aryl is a ring system, all rings in the system are aromatic. An aryl group can have from 6 to 18 carbon atoms, although this definition also covers occurrences of the term "aryl" where no numerical range is specified. In some embodiments, an aryl group has from 6 to 10 carbon atoms. An aryl group is defined as "C 6~10 Aryl, C6 or C 10 Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.

[0159] As used herein, "heteroaryl" refers to an aromatic ring or ring system (i.e., two or more fused rings sharing two adjacent atoms) that contains one or more heteroatoms, i.e., elements other than carbon, in the ring backbone, including but not limited to nitrogen, oxygen, and sulfur. When heteroaryl is a ring system, all rings in the system are aromatic. Heteroaryl groups can have 5 to 18 ring members (i.e., the number of atoms that make up the ring backbone, including carbon atoms and heteroatoms), although this definition also covers occurrences of the term "heteroaryl" where no numerical range is specified. In some embodiments, heteroaryl groups have 5 to 10 ring members or 5 to 7 ring members. Heteroaryl groups may be designated as "5-7 membered heteroaryl", "5-10 membered heteroaryl", or similar designations. Heteroaryl groups may be substituted. Examples of heteroaryl groups include, but are not limited to, aromatic C3-8 heterocyclic groups containing one oxygen or sulfur atom or up to four nitrogen atoms, or a combination of one oxygen or sulfur atom and up to two nitrogen atoms, and substituted and pyrido-fused derivatives thereof, e.g., linked by one ring-forming carbon atom. In some embodiments, heteroaryl groups are halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, C 1~6 -Alkoxy, C 1~6 -Alkyl, C 1~6-Optionally substituted by one or more substituents independently selected from hydroxyalkyl, C1-6-aminoalkyl, C1-6-alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl. Examples of heteroaryl groups include, but are not limited to, unsubstituted and mono- or di-substituted derivatives of furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole, quinoline, isoquinoline, pyridazine, pyrimidine, purine, pyrazine, furazan, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, triazole, benzotriazole, pteridine, phenoxazole, oxadiazole, benzopyrazole, quinolizine, cinnoline, phthalazine, quinazoline, and quinoxaline. In some embodiments, the substituents are halo, hydroxy, cyano, OC 1~6 -Alkyl, C 1~6 -Alkyl, Hydroxy-C 1~6 -Alkyl, and amino-C 1~6 -alkyl.

[0160] As used herein, "cycloalkyl" refers to a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. A cycloalkyl group can have 3 to 10 carbon atoms (wherever a cycloalkyl group appears herein, a numerical range such as "3 to 10" refers to each integer within the given range). A cycloalkyl group may be designated as "C3-C8 cycloalkyl" or a similar designation. Merely by way of example, "C3-C8 cycloalkyl" indicates that there are 3 to 8 carbon atoms in the carbocyclyl ring or ring system.

[0161] As used herein, "heterocyclyl" refers to a non-aromatic ring or ring structure that is fully or partially saturated and contains at least one heteroatom selected from nitrogen, oxygen, and sulfur in the ring backbone. Heterocyclyl can have any degree of saturation, provided that at least one ring in the ring system is not aromatic. The heteroatom can be present in a non-aromatic or aromatic ring in the ring system. Heterocyclyl groups can have 3 to 20 ring members (i.e., the number of atoms that make up the ring backbone, including carbon atoms and heteroatoms), although this definition also covers the occurrence of the term "heterocyclyl" without a specified numerical range. Heterocyclyl groups can be medium heterocyclyls having 3 to 10 ring members. Heterocyclyl groups can be heterocyclyls having 3 to 6 ring members. Heterocycloalkyl groups are also referred to as "3-15 membered heterocycloalkyl", "4-10 membered heterocycloalkyl", "3-15 membered C heterocycloalkyl", "4-15 membered C heterocycloalkyl", "5-15 membered C heterocycloalkyl", "6-15 membered C heterocycloalkyl", "7-15 membered C heterocycloalkyl", "8-15 membered C heterocycloalkyl", "9-15 membered C heterocycloalkyl", "10-15 membered C heterocycloalkyl", "15-15 membered C heterocycloalkyl", "15-15 membered C heterocycloalkyl", "15-15 membered C heterocycloalkyl", "20-25 membered C heterocycloalkyl", "30-25 membered C heterocycloalkyl", "40-25 membered C heterocycloalkyl", "50-25 membered C heterocycloalkyl", "15-15 membered C heterocycloalkyl", "20-25 membered C heterocycloalkyl", "30-25 membered C heterocycloalkyl", "15-15 membered C heterocycloalkyl", "20-25 membered C heterocycloalkyl", "30-25 membered C heterocyclo 2~14 Heterocycloalkyl, 5-9 membered C 4~8 Heterocycloalkyl, 5-10 membered C 4~9 Heterocycloalkyl, 5-membered C 3~4 Heterocycloalkyl, 6-membered C 4~5 Heterocycloalkyl, 7-membered C 5~6 Heterocycloalkyl, bicyclic or tricyclic 9-15 membered C 8~14 Heterocycloalkyl, monocyclic or bicyclic 3-10 membered C 2~9 Heterocycloalkyl, Bicyclic 8-10 membered C 4~9 Heterocycloalkyl, Bicyclic 8-10 membered C 5~9 Heterocycloalkyl, Monocyclic 4-7 Membered C 3~6 Heterocycloalkyl, Monocyclic 5-6 Membered C 3~5Heterocyclyl groups may be named as "C2-C9 heterocyclyl" or similar names. Heterocyclyl groups may be C2-C9 heterocyclyl having 3-10 ring members containing 1 to up to 3 O (oxygen), N (nitrogen), or S (sulfur). Heterocyclyl groups may be named as "3-10 membered C2-C9 heterocyclyl" or similar names. In preferred 6-membered monocyclic heterocyclyls, the heteroatoms are selected from 1 to up to 3 O (oxygen), N (nitrogen), or S (sulfur), and in preferred 5-membered monocyclic heterocyclyls, the heteroatoms are selected from 1 or 2 heteroatoms selected from O (oxygen), N (nitrogen), or S (sulfur). Examples of heterocyclyl rings include azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidinonyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathiinyl, 1,4-oxathiinyl, 2H-1,2-oxazinyl, trioxazinyl, 1,4 ... Examples of aryl groups include, but are not limited to, xanyl, 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, thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, and tetrahydroquinoline.

[0162] Similarly, when two "adjacent" R groups are said to form a ring "together with the atoms to which they are attached," it is meant that the atoms, intervening bonds, and the two R groups collectively make up the ring. For example, given the following structure: TIFF0007661235000039.tif27128R 1 and R 2 is defined as being selected from the group consisting of hydrogen and alkyl, or R 1 and R 2 When they are taken together with the atom to which they are attached to form an aryl or carbocyclyl, R 1 and R 2 may be selected from hydrogen or alkyl, or it is meant that the moiety has the structure: TIFF0007661235000040.tif27128 where A is an aryl ring or carbocyclyl containing the double bond shown.

[0163] Whenever a substituent is depicted as a diradical (i.e., having two points of attachment to the remainder of the molecule), it is to be understood that the substituent may be attached in any orientation unless otherwise indicated. Thus, for example, -AE- or The substituent depicted as TIFF0007661235000041.tif9128 includes the substituent oriented such that A is attached at the leftmost attachment point of the molecule, as well as the case where A is attached at the rightmost attachment point of the molecule.

[0164] The phrase "therapeutically effective amount" refers to an amount of a compound or combination of compounds that partially or completely ameliorate, attenuate, or eliminate one or more symptoms of a particular disease or condition, or prevent, regulate, or delay the onset of one or more symptoms of a particular disease or condition. This amount may be administered in a single dosage form or according to a regimen that makes this amount 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 salt" includes salts of compounds of formula I derived from the combination of a compound of this embodiment with an organic or inorganic acid or base. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, adipic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, (+)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-methanesulfonic acid, 1,2-ethanedisulfonic acid. , dodecylsulfonic acid, salicylic acid, glucoheptonic acid, gluconic acid, glucuronic acid, hippuric acid, hydrochloric acid, hemiethanolic acid, 2-hydroxyethanesulfonic acid, lactic acid, lactobionic acid, methyl bromide acid, methyl sulfate, 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. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum-containing bases, with ammonium, potassium, sodium, calcium, and magnesium salts being particularly preferred. In some embodiments, treatment of the compounds disclosed herein with an inorganic base results in the loss of a labile hydrogen from the compound to Li + , Na + , K + , Mg 2+ , and Ca 2+Salt forms can be obtained with inorganic cations such as, for example, 1,2,3,4,5,6,7,8,9,9,10,11,12,13,14,15,16,17,18,19,19,10,11,12,13,14,15,16,17,18,19,19,10,11,14,19 ...

[0166] When the number of any given substituent is not specified (e.g., "haloalkyl"), one or more of the substituents can be present. For example, "haloalkyl" can include one or more of the same or different halogens. For example, "haloalkyl" includes the respective substituents CF3, CHF2, and CH2F.

[0167] The term "patient" refers to the animal being treated, including mammals such as dogs, cats, cows, horses, sheep, and humans. In some embodiments, the patient is a male or female mammal. In some embodiments, the patient is a male or female human.

[0168] The term "prodrug" as used herein means any compound that produces a biologically active compound as a result of spontaneous, enzyme-catalyzed, and / or metabolic chemical reactions, or a combination of reactions, when administered to a biological system. Standard prodrugs are formed using groups that are attached to functional groups, such as HO-, HS-, HOOC-, HOOPR2-, and associated with the drug, that are cleaved in vivo. Standard prodrugs include, but are not limited to, carboxylate esters, where the group is alkyl, aryl, aralkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and esters of hydroxyl, thiol, and amines, where the attached group is acyl, alkoxycarbonyl, aminocarbonyl, phosphate, or sulfate. The groups shown are examples and are not exhaustive, and one skilled in the art may prepare a variety of other known prodrugs. To produce a compound that is biologically active or a precursor of a biologically active compound, the prodrug must undergo some form of chemical transformation. In some cases, the prodrug has a biological activity that is usually less than that of the drug itself and serves to improve the efficacy or safety of the drug through improved oral bioavailability, pharmacodynamic half-life, etc. Prodrug forms of a compound can be used, for example, to improve bioavailability, to improve subject acceptance by masking or reducing unpleasant properties such as bitter taste or gastrointestinal irritability, to modify solubility, for example for intravenous use, to provide long-term or sustained release or delivery, to improve ease of formulation, or to provide site-specific delivery of the compound.

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

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

[0171] The term "liver specificity" refers to the ratio: [Drugs or drug metabolites in liver tissue] / [Drugs or drug metabolites in blood or other tissues] Measured in animals treated with a drug or prodrug. The ratio may be determined by measuring tissue levels at a particular time point, or may represent the AUC (area under the curve) based on values ​​measured at three or more time points.

[0172] The term "increased or improved liver specificity" refers to an increase in the liver specificity ratio in animals treated with the prodrug relative to animals treated with the parent drug.

[0173] The term "improved oral bioavailability" refers to an increase in the absorption rate of a dose of a reference drug of at least about 50%. In a further aspect, the increase in oral bioavailability of a compound (relative to a reference drug) is at least about 100%, or a doubling of the absorption rate. Typically, measuring oral bioavailability refers to a comparison of measurements of prodrug, drug, or drug metabolites in blood, plasma, tissues, or urine following oral administration with measurements following parenteral administration.

[0174] The term "therapeutic index" refers to the ratio of the dose of a drug or prodrug that produces a therapeutically beneficial response to the dose that produces an undesirable response, such as death, elevation of markers indicating toxicity, and / or side pharmacological effects.

[0175] The term "sustained delivery" refers to the increased period during which therapeutically effective drug levels are extended by the presence of a prodrug.

[0176] The term "treating" a disease or "treatment" of a disease includes inhibiting the disease (slowing or arresting or partially halting the onset of the disease), preventing the disease, alleviating the symptoms or side effects of the disease (including symptomatic treatment), and / or relieving the disease (causing regression of the disease).

[0177] The term "biological agent" refers to a compound that has biological activity or has molecular properties that can be used for therapeutic or diagnostic purposes, such as compounds that possess radioisotopes or heavy atoms.

[0178] The term "molecular pathway" refers to a sequence of molecular events in a tissue, such as a receptor regulatory sequence, an enzyme regulatory sequence, or a biosynthetic sequence, that is involved in the physiology or pathophysiology of a living animal.

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

[0180] Examples of pharma- ceutically acceptable salts include acetate, adipate, besylate, bromide, camsylate, chloride, citrate, edisylate, estolate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hyclate, hydrobromide, hydrochloride, iodide, isethionate, lactate, lactobionate, maleate, mesylate, methyl bromide, methyl sulfate, napsylate, nitrate, oleate, pamoate, phosphate, polygalacturonate, stearate, succinate, sulfate, sulfosalicylate, tannate, tartrate, terephthalate, tosylate, and triethiodide.

[0181] The composition containing the active ingredient may be in any form suitable for the intended method of administration. In some embodiments, the compounds of the methods and / or compositions described herein may be administered orally, rectally, transmucosally, intestinal, enteral, topically, transdermally, intrathecally, intraventricularly, intraperitoneally, intranasally, intraocularly, and / or parenterally.

[0182] For example, when the compound is administered by oral administration, it can be prepared as a tablet, a troche, a lozenge, an aqueous or oily suspension, a dispersible powder or granule, an emulsion, a hard or soft capsule, a syrup, or an elixir. Compositions intended for oral administration 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 auxiliary agents, including sweeteners, flavorings, colorings, and preservatives, so as to obtain a palatable preparation. Tablets containing a mixture of active ingredient and non-toxic pharmaceutically acceptable excipients suitable for tablet manufacture are acceptable. These excipients can be, for example, inert diluents such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binding agents such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

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

[0184] The preparation suitable for parenteral administration includes aqueous and non-aqueous isotonic sterile injection solutions, which may contain, for example, antioxidants, buffers, bacteriostatic agents, and solutes that make the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents.The preparations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried condition, requiring only the addition of sterile liquid carriers, such as water for injection, immediately before use.Injection solutions and injection suspensions can be prepared from the above-mentioned types of sterile powders, granules, and tablets.

[0185] In some embodiments, the unit dosage formulation comprises a daily dose or daily unit, daily sub-dose, or an appropriate fraction thereof, of drug.However, as those skilled in the art will appreciate, the specific dose level for any particular patient will depend on a variety of factors, including the activity of the particular compound used; the age, weight, general health, sex, and diet of the individual being treated; the time and route of administration; excretion rate; other drugs previously administered; 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 being treated, and the selection of an appropriate dosage is well within the knowledge of one of ordinary skill in the art. In some embodiments, the daily dosage may be from about 0.1 mg / kg to about 100 mg or more per kg of body weight, from about 0.25 mg / kg to about 50 mg / kg, from about 0.5 mg / kg to about 25 mg / kg, or from about 1.0 mg / kg to about 10 mg / kg of 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 to about 2000 mg per day or more, or from about 70 mg per day to about 1000 mg per day.

[0187] Treatment Some aspects of the present invention include a method of treating a disease, disorder, or condition selected from the group consisting of hepatitis, liver cancer, liver fibrosis, fatty liver, malaria, viral infection, parasitic infection, 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 the compounds, compositions, and pharmaceutical compositions described herein. In some embodiments, the subject can be an animal, such as a mammal, a human. In some embodiments, the subject is a human.

[0188] Further aspects include administering to a subject in need thereof a combination of compounds. The combination may include a compound, composition, pharmaceutical composition described herein together with an additional pharmaceutical agent.

[0189] Some embodiments include co-administration of the compounds, compositions, and / or pharmaceutical compositions described herein with additional medicaments or additional therapeutic agents. "Co-administration" means that two or more agents can be found in the patient's bloodstream at the same time, regardless of when or how they are actually administered. In one embodiment, the agents are co-administered. In one such embodiment, the agents are combined in one dosage form to achieve co-administration. In another embodiment, the agents are administered sequentially. In one embodiment, the agents are administered through the same route, e.g., orally. In another embodiment, the agents are administered through different routes, e.g., one agent is administered orally and another agent is administered intravenously.

[0190] Examples of additional medicaments include therapeutic agents selected from the group consisting of other types of chemotherapy agents such as cyclophosphamide, methotrexate, doxorubicin, docetaxel, cisplatin, epirubicin, oxaliplatin and folinic acid; and other targeted antitumor agents such as histone deacetylase (HDAC) inhibitors.In some embodiments, the additional therapeutic agent for treating hepatocellular carcinoma (HCC) can be one or more of sorafenib, regorafenib, tumor immunotherapy agents, such as PD-1 or PD-L1 checkpoint inhibitors.

[0191] The following examples are included to further illustrate the invention. Of course, the examples should not be construed as specifically limiting the invention. Variations of these examples within the scope of the claims are within the skill of one of ordinary skill in the art and are considered to be within the scope of the invention as described and claimed herein. The reader will recognize that one of ordinary skill in the art, armed with this disclosure and the skill in the art, can make and use the invention without the exhaustive examples.

[0192] Compound synthesis The following procedures for the preparation of novel compounds are illustrative of the general procedures used to prepare cyclic phosphate compounds.

[0193] Scheme I describes the general synthesis of compounds of formula I. Nucleosides (1) are reacted with phosphanediamines (2) in the presence of 4,5-dicyanoimidazole to give cyclic products of structure 3, which are then treated with an oxidizing agent such as tert-butyl hydroperoxide to give the final products of formula I.

[0194] Scheme I TIFF0007661235000042.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-oxidetetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinine-2-yl)oxy)methyl)benzoate (Compound 101) Compound 101 was prepared from 1-chloro-N,N,N',N'-tetraisopropylphosphanediamine and deoxyuridine according to the method described in TIFF0007661235000043.tif35128 Scheme I as follows.

[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 nearly quantitative yield. A solution of the benzoic acid derivative (10 g, 48 mmol) in THF was treated with excess borane dimethylsulfide at 0-20° C. for 2 h. Standard work-up and silica gel chromatography afforded the title compound (4.1 g, 44%).

[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., triethylamine (1.3 g, 1.5 eq.) was added, and the resulting mixture was stirred overnight and warmed to 30° C. The reaction mixture was dried and used as the crude product in the next reaction.

[0199] Compound 101 A reaction mixture of the crude phosphanediamine, deoxyuridine (1.0 equiv.), and DCI (2.5 equiv.) 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 give the crude product. The crude product was then dissolved in THF and treated with 2.5 equiv. of TBHP at 0° C. for 0.5 h. Standard workup followed by silica gel chromatography afforded compound 101 as a mixture of two isomers in about 15% overall yield from deoxyuridine. [M-1] + C 20 H 23 Calculated N2O9P: 465.10. Found: 465.1.

[0200] Example 2 4-Amino-1-((4aR,6R,7aS)-2-(nonyloxy)-2-oxidetetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinine-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-nonyloxyphosphanediamine and deoxyuridine according to the method described in Scheme I. [M-1] + C 18 H 30 Calculated N3O6P: 414.18. Found: 414.1.

[0201] Example 3 5-Methyl-1-((4aR,6R,7aS)-2-(octyloxy)-2-oxidetetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinine-6-yl)pyrimidine-2,4(1H,3H)-dione (compound 103) Compound 103 was prepared as a mixture of two isomers from N,N,N',N'-tetraisopropyl-1-octyloxyphosphanediamine and thymidine according to the method described in Scheme I. [M-1] + C 18 H 29Calculated N2O7P: 415.16. Found: 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) 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 TIFF0007661235000046.tif34128 Scheme I. [M-1] + C 18 H 20 Calculated N5O5P: 416.11. Found: 416.1.

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

[0204] Example 6 Propyl 2-((((4aR,6R,7aS)-6-(5-(methyl-d3)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-oxidetetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinine-2-yl)oxy)methyl)benzoate (Compound 106) Compound 106 was prepared as a mixture of two isomers from N,N,N',N'-tetraisopropyl-1-(2-(1-propyloxycarbonyl)benzyloxy)phosphanediamine and thymidine-d3 according to the method described in TIFF0007661235000048.tif35128 Scheme I. [M-1] + C 21 H 22 Calculated value for D3N5O7P: 482.14. Found value: 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-oxidetetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl)oxy)methyl)benzoate (Compound 107) Compound 107 was prepared as a mixture of two isomers from N,N,N',N'-tetraisopropyl-1-(2-(2-isopropyloxy)carbonylbenzyloxy)phosphanediamine and a uridine derivative according to the method described in TIFF0007661235000049.tif34128 Scheme I. [M-1] + C 21 H 24 Calculated value for FN2O9P: 497.11. Found value: 497.1.

[0206] Example 8 Isopropyl 2-((((4aR,6R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7,7-difluoro-2-oxidetetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinine-2-yl)oxy)methyl)benzoate (Compound 108) Compound 108 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 TIFF0007661235000050.tif35128 Scheme I. [M-1]+ C 20 H 22 Calculated value for F2N3O8P: 500.10. Found value: 500.1.

[0207] Example 9 Isopropyl 2-((((4aR,6R,7S,7aS)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-2-oxidetetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinine-2-yl)oxy)methyl)benzoate (Compound 109) 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 TIFF0007661235000051.tif35128 Scheme I. [M-1] + C 20 H 24 Calculated for N3O9P: 480.39. Found: 480.3.

[0208] Biological Examples Examples of uses of the method include the following, although it will be understood that the following are examples and the method is not limited to only these examples:

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

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

[0211] Table 1 shows the results of selected compounds compared to the corresponding reference compounds, and the results demonstrated improved efficiency of oral delivery of known nucleosides.

[0212] Table 1. Comparison of novel compounds with corresponding reference compounds in terms of nucleoside phosphate levels in liver and nucleoside levels in hepatic portal vein (HPV) and systemic blood 1 hour after oral administration of selected compounds at a dose of 5 mg / kg nucleoside equivalent in rats. TIFF0007661235000052.tif38163"-" = undetermined; NTP = nucleoside triphosphate; NMP = nucleoside monophosphate; NUC = nucleoside

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

[0214] All numbers expressing quantities of ingredients, reaction conditions, and so forth 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 claims in any application claiming priority to this application, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches.

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

[0216] The above description discloses some methods and materials. The present invention is open to modifications of the methods and materials, and alterations of the fabrication methods and equipment. These modifications will be apparent to those skilled in the art upon consideration of this disclosure or by practicing the invention disclosed herein. Thus, the present invention is not intended to be limited to the specific embodiments disclosed herein, but is intended to cover all modifications and alternatives falling within the true scope and spirit of the invention.

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

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

Claims

1. A compound of formula Ib, or a stereoisomer or a pharma- ceutically acceptable salt thereof: During the ceremony, R 2a H, OH, OR 8 , halo, CN, and optionally substituted C 1 ~C 10 selected from the group consisting of alkyl; R 2b H, OR 8 , halo, CN, and optionally substituted C 1 ~C 10 selected from the group consisting of alkyl; R 3 and R 4 are each independently H, OH, halo, CN, or N 3 and optionally substituted C 1 ~C 10 selected from the group consisting of alkyl; R 5a は、-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 、および selected from the group consisting of; Each R 6 are independently halo and optionally substituted C 2 ~C 10 selected from the group consisting of alkyl; Each R 7 are independently H and optionally substituted C 1 ~C 10 selected from the group consisting of alkyl; Each R 8 are independent, C(O)R 7 , C(O)OR 7 , and C(O)NHR 7 selected from the group consisting of: n is 0, 1, 2, or 3; The bases are: 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 selected from the group consisting of 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-; R 12 is selected from the group of H, NH 2 , optionally substituted C 1 -C 10 alkylamino, 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)NH-, optionally substituted (C 6-10 aryl)-OC(O)NH-, and optionally substituted C 1 -C 10 alkyl-OCH 2 NH-; However, the base is If R 5a teeth isn't it.

2. R 9 The compound of claim 1, wherein

3. R 9 is unsubstituted C 1 ~C 10 2. The compound of claim 1, which is alkyl.

4. R 9 Ga-CD 3 2. The compound of claim 1, wherein

5. R 2a and R 2b The compound of any one of claims 1 to 4, wherein at least one of is H.

6. R 2a is unsubstituted C 1 ~C 10 The compound of any one of claims 1 to 4, which is alkyl.

7. R 2a is methyl and R 2b 7. The compound of claim 6, wherein is fluoro.

8. R 2a The compound of any one of claims 1 to 4, wherein is OH.

9. R 2a and R 2b The compound of any one of claims 1 to 4, wherein each is halo.

10. R 2a and R 2b 10. The compound of claim 9, wherein each is fluoro.

11. R 5a が、-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 、および The compound according to any one of claims 1 to 10, selected from the group consisting of:

12. R 5a -COOR 13 where R 13 is unsubstituted C 1 ~C 10 The compound of any one of claims 1 to 10, which is alkyl.

13. R 13 13. The compound of claim 12, wherein is i-propyl.

14. R 13 13. The compound of claim 12, wherein is n-propyl.

15. The compound of any one of claims 11 to 14, wherein n is 0.

16. 10. The compound of claim 1, selected from the group consisting of: 。

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16 and a pharma- ceutically acceptable excipient.

18. 17. A pharmaceutical composition for treating a disease in the liver, or a disease or condition involving the liver in a physiological or pathological pathway in a subject, comprising a compound according to any one of claims 1 to 16.

19. 20. The pharmaceutical composition of claim 18, wherein the composition is administered in combination with one or more additional therapeutic agents.

Images