Benzyloxyphosphoric acid esters (phosphonic acid esters) compound

Abstract

To provide 2-substituted benzyloxyphosphate (phosphonate) compounds and their use.SOLUTION: Provided is a compound of general formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof: Also provided is a method of treating liver disease comprising administering the compound.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 2-substituted benzyloxyphosphate (phosphonate) compounds, their preparation, and their use. In some embodiments, these compounds are useful for effectively delivering specific drugs to target cells or target organs. [Background technology]

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

[0003] Phosphate (phosphonate) esters are an important class of compounds that can be used as medicinal agents to improve human health. Many types of phosphate (phosphonate) derivative compounds have been designed as prodrugs to enhance oral absorption and delivery of active ingredients to target cells or organs. Synthetic nucleotides and their derivatives are widely used as antiviral or anticancer drugs. Prodrug technology has been used to improve the molecular properties of nucleotides to enable increased bioavailability, including improved oral bioavailability. Therefore, novel compounds that exhibit improved bioavailability may significantly improve the therapeutic efficacy of nucleoside (nucleotide)-based therapies. Summary of the Invention

[0004] overview Novel 2-substituted benzyloxyphosphate (phosphonate) compounds, their preparation, and their uses are described. Some embodiments are novel 2-substituted benzyloxyphosphate (phosphonate) compounds that are orally delivered to the liver and other organs to achieve therapeutic effects there. Further embodiments include novel 2-substituted benzyloxyphosphate (phosphonate) compounds that treat diseases, disorders, or conditions, including certain mitochondrial DNA deficiency syndromes, hepatitis, 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 2-substituted benzyloxyphosphate (phosphonate) compounds to treat diseases that benefit from improved drug distribution to target cells or organs. In another aspect, 2-substituted benzyloxyphosphate (phosphonate) 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 2-substituted benzyloxyphosphate(ester) compounds are useful in improving the efficiency of oral delivery of nucleotide or derivative compounds thereof to the liver and / or other target organs. Some further embodiments relate to methods of making the 2-substituted benzyloxyphosphate(ester) compounds.

[0005] Some embodiments provided herein include compounds of Formula I or Formula Ia, or a stereoisomer or pharmaceutically acceptable salt thereof: TIFF2026032020000001.tif67128 formula, R 1 , R 2 , R 3 , R 4 , R 5 , and n has any of the values ​​described herein.

[0006] Some embodiments relate to pharmaceutical compositions comprising one of the above compounds and a pharmaceutically acceptable excipient.

[0007] Some embodiments relate to methods of treating a disease, disorder, or condition comprising administering an effective amount of the compound described above.

[0008] In some embodiments, the disease, disorder, or condition is a liver disease, disorder, or condition.

[0009] In some embodiments, the disease, disorder, or condition is a non-hepatic disease, disorder, or condition.

[0010] Some embodiments relate to a method of treating liver disease comprising administering to a subject in need thereof an effective amount of one of the above compounds.

[0011] 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 of the above-described compound combinations.

[0012] Some embodiments further comprise administering to a subject in need thereof an effective amount of at least one additional therapeutic agent.

[0013] In some embodiments, the subject is a mammal.

[0014] In some embodiments, the subject is a human.

[0015] 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 of the above compounds.

[0016] In some embodiments, the cell is in vivo.

[0017] In some embodiments, the cells are ex vivo.

[0018] In some embodiments, the cells are hepatocytes.

[0019] In some embodiments, the cell is a mammalian cell.

[0020] In some embodiments, the cells are human cells.

[0021] Some embodiments of the compounds, compositions, and methods provided herein include pharmaceutical compositions comprising one of the compounds provided herein and a pharmaceutically acceptable excipient.

[0022] 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 of the compounds provided herein.

[0023] 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 of the compounds provided herein.

[0024] Some embodiments also include administering to a subject in need thereof an effective amount of one or more additional therapeutic agents.

[0025] In some embodiments, the subject is a mammal.

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

[0027] Some embodiments also include the use of a combination of one compound provided herein with an additional therapeutic agent.

[0028] Some embodiments also include the use of one or more compounds provided herein in combination with an additional therapeutic agent.

[0029] 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 of the liver, or a disease or condition that involves the liver in a physiological or pathological pathway.

[0030] 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 pharmaceutically acceptable salt thereof: TIFF2026032020000002.tif25128 formula, R 1 is -CH(OR 6 )2, -C(O)N(R 6 )2, -CH2OR 7 , CH2SR 7 , -CHN(R 7 )2, -CH2OCH2OR 6 , -COOR 5 , and Selected from the group consisting of TIFF2026032020000003.tif12128; Each R 2 is independently selected from the group consisting of halogen, optionally substituted alkyl, and optionally substituted alkyloxy; R 3 is selected from the group consisting of H, optionally substituted aryl, and a therapeutic or diagnostic moiety; R 4 is selected from a nucleoside or analog thereof, or a nucleoside base or analog thereof, or R 4 and R 3 together with the atoms to which they are attached form a monocyclic heterocyclyl substituted with a nucleoside base or analog thereof, or R 4 and R 5together with the atoms to which they are attached form a heterocyclyl substituted with a nucleoside base or analog thereof; R 5 is H or optionally substituted alkyl; Each R 6 is independently optionally substituted alkyl; R 7 is H, optionally substituted C1 to C 10 Acyl, optionally substituted C1-C 10 alkyl-OC(O)-, optionally substituted (C 6~10 aryl)-C(O)-, and optionally substituted (C 6~10 aryl)-OC(O)-; n is 0, 1, 2, or 3. [The present invention 1002] 1001. A compound of the present invention, wherein the nucleoside base or analog thereof is a therapeutically active fragment of a drug selected from the group consisting of abacavir, acicovir, acyclovir, cytarabine, didanosine, edoxudine, emtricitabine, entecavir, galidesivir, ganciclovir, gemcitabine, ibacitabine, idoxuridine, inosine, lamivudine, maribavir, molnupiravir, penciclovir, remdesivir, ribavirin, stavudine, telbivudine, trifluridine, vidarabine, zalcitabine, and zidovudine. [The present invention 1003] 1001. A compound of the present invention, wherein the nucleoside base or analog thereof is a therapeutically active fragment of a drug selected from the group consisting of adefovir, brincidofovir, cidofovir, and tenofovir. [The present invention 1004] The compound of the present invention, wherein the nucleoside base or analog thereof is selected from the group consisting of: TIFF2026032020000004.tif48128In formula, R 9 is H, halo, or optionally substituted C1-C 10 is alkyl; R 10 is H, optionally substituted C1 to 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)-; R 11 are OH, NH2, and NHOR 7 , 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 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-OCHO-; R 12 is H, NH2, optionally substituted C1 to C 10 Alkylamino, optionally substituted C1-C 10 Acylamino, optionally substituted C1-C 10 alkyl-OC(O)NH-, optionally substituted (C 6~10aryl)-C(O)NH-, optionally substituted (C 6~10 aryl)-OC(O)NH-, and optionally substituted C1-C 10 alkyl-OCH2NH-. [The present invention 1005] Nucleoside bases or their analogs The compound of the present invention 1004 is TIFF2026032020000005.tif20128. [The present invention 1006] R 11 The compound of the present invention 1005, wherein is NH2. [The present invention 1007] R 12 The compound of claim 1005 or 1006, wherein is H. [The present invention 1008] Nucleoside bases or their analogs The compound of the present invention 1004 is TIFF2026032020000006.tif21128. [The present invention 1009] R 9 The compound of the present invention 1008, wherein is H. [The present invention 1010] R 11 The compound of the present invention 1008 or 1009, wherein is NH2. [The present invention 1011] The compound of any one of claims 1001 to 1010, wherein n is 1. [The present invention 1012] R 3 is selected from the group consisting of H and optionally substituted aryl. [The present invention 1013] R 1 But -CH(OR 6 )2, -C(O)N(R 6 )2, and Any of compounds 1001 to 1012 of the present invention selected from the group consisting of TIFF2026032020000007.tif12128. [The present invention 1014] Any of compounds 1001 to 1012 of the present invention, wherein the compound of formula I is represented by formula (Ia): TIFF2026032020000008.tif27128 or a stereoisomer or pharmaceutically acceptable salt thereof. [The present invention 1015] R 5 is unsubstituted C1-C6 alkyl. [The present invention 1016] R 5 The compound of the present invention 1015, wherein is ethyl. [The present invention 1017] R 5 1015. The compound of the present invention, wherein is i-propyl. [The present invention 1018] R 5 The compound of the present invention 1014, wherein is H. [The present invention 1019] R 3 1014. The compound of the present invention, wherein is unsubstituted aryl. [The present invention 1020] R 3 The compound of the present invention 1014, wherein is phenyl. [The present invention 1021] below The compound of the present invention 1001 selected from the group consisting of TIFF2026032020000009.tif90128. [The present invention 1022] 22. Any of the compounds of claims 1001 to 1021 for use in treating liver disease. [The present invention 1023] A compound of the present invention in combination with one or more additional therapeutic agents. [The present invention 1024] Use of any of the compounds of claims 1001 to 1021 in the preparation of a medicament for treating liver disease. [The present invention 1025] A method for treating liver disease, comprising administering to a subject in need thereof an effective amount of any of the compounds of the present inventions 1001 to 1021. [The present invention 1026] The method of claim 1025, wherein the subject is a mammal. [The present invention 1027] The method of claim 1026, wherein the mammal is a human. DETAILED DESCRIPTION OF THE INVENTION

[0031] Detailed Description The present embodiments relate to compositions and methods relating to, their preparation, and uses of novel 2-substituted benzyloxyphosphate (phosphonate) compounds. In some embodiments, the novel 2-substituted benzyloxyphosphate (phosphonate) compounds facilitate the delivery of nucleotide or nucleotide derivative or nucleotide analog substances into cells.

[0032] These 2-substituted benzyloxyphosphate (phosphonate) compounds, and their stereoisomers and pharmaceutically acceptable salts, are represented by Formula I or Formula Ia, or a stereoisomer or pharmaceutically acceptable salt thereof: TIFF2026032020000010.tif67128 formula, R 1 , R 2 , R 3 , R 4 , R 5 , and n has any of the values ​​described herein.

[0033] In some embodiments, R 1 -CH(OR 6 )2, -C(O)N(R 6 )2, -CH2OR 7 , CH2SR 7 , -CHN(R 7 )2, -CH2OCH2OR 6 , -COOR 5 , and TIFF2026032020000011.tif12128 group.

[0034] In some embodiments, R 1 -CH(OR 6 )2, -C(O)N(R6 )2, and TIFF2026032020000012.tif12128 group.

[0035] In some embodiments, each R 2 is independently selected from the group of halogen, optionally substituted alkyl, and optionally substituted alkyloxy.

[0036] In some embodiments, R 3 is selected from the group of H, optionally substituted aryl, and a therapeutic or diagnostic moiety.

[0037] In some embodiments, R 3 is selected from the group consisting of H and optionally substituted aryl.

[0038] In some embodiments, R 3 is unsubstituted aryl.

[0039] In some embodiments, R 3 is phenyl.

[0040] In some embodiments, R 4 is selected from a nucleoside or analog thereof, or a nucleoside base or analog thereof, or R 4 and R 3 together with the atoms to which they are attached form a monocyclic heterocyclyl substituted with a nucleoside base or analog thereof, or R 4 and R 5 together with the atoms to which they are attached form a heterocyclyl substituted with a nucleoside base or analog thereof.

[0041] In some embodiments, the nucleoside or analog thereof is a therapeutically active fragment of a drug such as abacavir, acicovir, acyclovir, cytarabine, didanosine, edoxudine, emtricitabine, entecavir, galidesivir, ganciclovir, gemcitabine, ibacitabine, idoxuridine, inosine, lamivudine, maribavir, molnupiravir, penciclovir, remdesivir, ribavirin, stavudine, telbivudine, trifluridine, vidarabine, zalcitabine, and zidovudine; or, in some embodiments, the nucleoside or analog thereof is a therapeutically active fragment of a drug such as adefovir, brincidofovir, cidofovir, and tenofovir.

[0042] In some embodiments, R 5 is selected from the group of H and optionally substituted alkyl.

[0043] In some embodiments, R 5 is unsubstituted C1-C6 alkyl.

[0044] In some embodiments, R 5 is ethyl.

[0045] In some embodiments, R 5 is i-propyl.

[0046] In some embodiments, R 5 is H.

[0047] In some embodiments, each R 6 is independently an optionally substituted alkyl.

[0048] In some embodiments, R 7 is H, optionally substituted C1-C 10 Acyl, optionally substituted C1-C 10 alkyl-OC(O)-, optionally substituted (C 6~10 aryl)-C(O)-, and optionally substituted (C 6~10aryl)-OC(O)-.

[0049] In some embodiments, n is 0, 1, 2, or 3.

[0050] In some embodiments, n is 1.

[0051] In some embodiments, the nucleoside base or analog thereof is TIFF2026032020000013.tif47128.

[0052] In some embodiments, R 9 is H, halo, or optionally substituted C1-C 10 It is alkyl.

[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 7 , optionally substituted C1 to C 10 Alkyloxy, optionally substituted C1-C 10 Alkylamino, optionally substituted C1-C 10 Acyloxy, optionally substituted C1-C 10Acylamino, 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-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-, and optionally substituted C1-C 10 alkyl-OCH2NH-.

[0056] In some embodiments, the nucleoside base or analog thereof is TIFF2026032020000014.tif20128.

[0057] In some embodiments, R 11 is NH2.

[0058] In some embodiments, R 12 is H.

[0059] In some embodiments, the nucleoside base or analog thereof is The file is TIFF2026032020000015.tif21128.

[0060] In some embodiments, the nucleoside base or analog thereof is The file is TIFF2026032020000016.tif21128.

[0061] In some embodiments, R 9 is H.

[0062] In some embodiments, R 11 is NH2.

[0063] In some embodiments, R 1 -CH(OR 6 )2, -C(O)N(R 6 )2, and TIFF2026032020000017.tif12128 group.

[0064] In some embodiments, R 2 is H.

[0065] In some embodiments, the nucleoside base or analog thereof is TIFF2026032020000018.tif50128, wherein L is a sugar or sugar analog.

[0066] In some embodiments, the nucleoside base or analog thereof is TIFF2026032020000019.tif107154TIFF2026032020000020.tif113154.

[0067] In some embodiments, the nucleoside base or analog thereof is TIFF2026032020000021.tif29128.

[0068] In some embodiments, the nucleoside base or analog thereof is The file is TIFF2026032020000022.tif25128.

[0069] In some embodiments, the compound is TIFF2026032020000023.tif52149.

[0070] In some embodiments, the 2-substituted benzyloxyphosphate (phosphonate) compounds of Formula I and Ia are substrates for hepatic enzymes such as the cytochrome p450 isozyme CYP3A (a family of monooxygenases), dehydrogenases, esterases, and amidases.

[0071] In some embodiments, the compound is activated intracellularly upon cleavage of the prodrug moiety to release the active form of the compound.

[0072] In some embodiments, the 2-substituted benzyloxyphosphate(ester) compounds of Formula I and Ia, 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.

[0073] In some embodiments, the disclosed compounds are used to improve the pharmacokinetic properties of nucleotides or their analogs, such as extending their half-life or increasing their absorption. Furthermore, the disclosed methodology can be used to achieve sustained delivery of biologically relevant nucleotides or their analogs. The 2-substituted benzyloxyphosphate (phosphonate) compounds of Formulas I and Ia have improved pharmacokinetic properties and are therefore used to treat diseases that benefit from improved drug properties. In some embodiments, methods for making these compounds are described.

[0074] Certain compounds of Formula I and Ia have asymmetric centers that may be of unspecified stereochemical configuration, and general references to compounds of Formula I and Ia include diastereomeric mixtures of these compounds as well as individual stereoisomers.

[0075] 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.

[0076] Some embodiments of the compounds, compositions, and methods provided herein include pharmaceutical compositions comprising a compound provided herein and a pharmaceutically acceptable carrier.

[0077] 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.

[0078] In some embodiments, the subject is a mammal.

[0079] In some embodiments, the subject is a human.

[0080] 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.

[0081] Some embodiments of the compounds, compositions, and methods provided herein include the use of the compounds provided herein in the treatment of liver disease.

[0082] Some embodiments include the use of a compound provided herein in combination with an additional therapeutic agent for the treatment of liver disease.

[0083] In some aspects, the compounds provided herein are used in the preparation of a medicament for treating liver disease.

[0084] In some aspects, the compounds provided herein are used in a method of treating liver disease, the method comprising administering to a subject in need thereof an effective amount of the compound.

[0085] 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.

[0086] 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.

[0087] When the compounds disclosed herein contain at least one chiral center, they 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 can be achieved by applying various methods known to those skilled in the art. Unless otherwise indicated, all such 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 such 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.

[0088] Those skilled in the art will recognize that some 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 represented herein, these compounds are considered to be within the scope of the depicted structures.

[0089] 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, a compound structure may explicitly disclose or be understood to include a hydrogen atom 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). Therefore, unless the context clearly indicates otherwise, reference to a compound herein encompasses all possible isotopic forms.

[0090] definition In accordance with this disclosure and as used herein, the following terms are defined with 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" is non-limiting.

[0091] 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%."

[0092] 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.

[0093] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a composition comprising a "therapeutic agent" includes a composition having one or more therapeutic agents.

[0094] As used herein, "C" refers to a group 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-.

[0095] 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 can have 1 to 20 carbon atoms. (Whenever alkyl appears herein, a numerical range, such as "1 to 20," 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; however, this definition also encompasses appearances of the term "alkyl" without a specified numerical range.) The alkyl group may be a medium 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 designated as "C1-C4 alkyl" or similar designation. By way of example only, "C1-C4 alkyl" indicates 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 in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.

[0096] As used herein, a "substituted group" is one 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 referred to as "substituted," it means 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- to 10-membered heterocyclyl (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 (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), C6 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 (substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy). 3-10-membered heterocyclyl-C1-C6-alkoxy (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl(C1-C6)alkoxy (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10-membered heteroaryl(C1-C6)alkoxy (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), alkoxy), sulfhydryl (mercapto), halo(C1-C6)alkyl (e.g., -CF3), halo(C1-C6)alkoxy (e.g., -OCF3), C1-C6 alkylthio, arylthio (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7 carbocyclylthio (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 3-10 5-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),3-10-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 haloalkoxy, "C1-C6 haloalkoxy," which means substituted by 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," that group may be substituted with the above substituents.

[0097] As used herein, "acyl" refers to a group in which R is hydrogen, C is a hydroxyl group, 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It refers to -C(=O)R, which is aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl. Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acryl.

[0098] "Heteroacyl" means that R is C 1~6 It refers to heteroalkyl, -C(=O)R.

[0099] "Alkyloxymethylene" means that R is C 1~6 It refers to -CH2OR, which is alkyl or heteroalkyl, either of which may be substituted.

[0100] An "O-carboxy" group is a group where R is hydrogen, C is 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 means a "-OC(=O)R" group selected from aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl.

[0101] A "C-carboxy" 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 "-C(=O)OR" means a group selected from aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl. Non-limiting examples include carboxyl (i.e., -C(=O)OH).

[0102] A "cyano" group refers to a "-CN" group.

[0103] A "cyanato" group refers to an "-OCN" group.

[0104] An "isocyanato" group refers to an "-NCO" group.

[0105] A "thiocyanato" group refers to a "-SCN" group.

[0106] An "isothiocyanato" group refers to a "-NCS" group.

[0107] A "sulfinyl" 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 means a "-S(=O)R" group selected from aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl.

[0108] A "sulfonyl" 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 means a "-SO2R" group selected from aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl.

[0109] An "S-sulfonamide" group is a group consisting of R A and R B are each independently hydrogen as defined herein, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 "-SO2NR2" is selected from aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl. A R B " group.

[0110] An "N-sulfonamide" group is R A and R b are each independently 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)" is selected from aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl. A )SO2R B " group.

[0111] An "O-carbamyl" group is R A and R B are each independently 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" selected from aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl A R B " group.

[0112] An "N-carbamyl" group is R A and R B are each independently 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)" is selected from aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl. A )C(=O)OR B " group.

[0113] An "O-thiocarbamyl" group is R A and R B are each independently 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" selected from aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl A R B " group.

[0114] An "N-thiocarbamyl" group is R A and R B are each independently 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)" is selected from aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl. A )C(=S)OR B " group.

[0115] A "C-amide" group is a group consisting of RA and R B are each independently 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- to 10-membered heteroaryl, 3- to 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" optionally substituted with one or more substituents selected from the group consisting of alkoxy A R B " group.

[0116] An "N-amido" group is a group consisting of R A and R B are each independently 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- to 10-membered heteroaryl, 3- to 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.

[0117] An "amino" group is R A and R B are each independently hydrogen as defined herein, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 "-NR" is selected from 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).

[0118] An "aminoalkyl" group refers to an amino group connected by an alkylene group.

[0119] An "alkoxyalkyl" group is an alkoxy group connected by an alkylene group, e.g., "C 2~8 "Alkoxyalkyl" means "alkoxyalkyl" or the like.

[0120] The term "acyloxy" refers to -OC(O)R, where R is alkyl.

[0121] The term "alkoxy" or "alkyloxy" refers to OR, where R is alkyl or heteroalkyl, either of which may be optionally substituted.

[0122] The term "carboxyl" means C(O)OH.

[0123] The term "oxo" means the group =O.

[0124] The term "halogen" or "halo" means F (fluoro), Cl (chloro), Br (bromo), and I (iodo).

[0125] The term "haloalkyl" refers to an alkyl group that includes at least one halogen, and in a further aspect, 1 to 3 halo atoms. Suitable halo atoms include F, Cl, and Br.

[0126] The term "haloacyl" refers to a -C(O)-haloalkyl group.

[0127] 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 optionally substituted. Suitable alkenyl groups include allyl.

[0128] The term "alkynyl" refers to an unsaturated group having 2 to 12 atoms and containing at least one carbon-carbon triple bond, including straight-chain, branched-chain, and cyclic groups. Alkynyl groups may be optionally substituted. Suitable alkynyl groups include ethynyl.

[0129] As used herein, "aryl" refers to an aromatic ring or ring system (i.e., two or more fused rings that share 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. Aryl groups can have from 6 to 18 carbon atoms, although this definition also covers instances where the term "aryl" appears without a specified numerical range. In some embodiments, aryl groups have 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.

[0130] As used herein, "heteroaryl" refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent atoms) containing 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 comprising the ring backbone, including carbon atoms and heteroatoms), although this definition also encompasses appearances of the term "heteroaryl" without a specified numerical range. In some embodiments, heteroaryl groups have 5 to 10 ring members or 5 to 7 ring members. Heteroaryl groups may also be designated as "5- to 7-membered heteroaryl," "5- to 10-membered heteroaryl," or similar names. Heteroaryl groups may be substituted. Examples of heteroaryl groups include, but are not limited to, aromatic C3-8 heterocyclic groups containing one oxygen or sulfur atom or up to four nitrogen atoms, or a combination of one oxygen or sulfur atom and up to two nitrogen atoms, and substituted derivatives thereof, as well as benzo- and pyrido-fused derivatives, for example, connected by one ring-forming carbon atom. In some embodiments, heteroaryl groups are selected from halo, hydroxy, amino, cyano, nitro, alkylamido, 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. 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.

[0131] As used herein, "cycloalkyl" means a fully saturated carbocyclyl ring or carbocyclyl ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. A cycloalkyl group can have 3 to 10 carbon atoms (wherever cycloalkyl groups appear herein, numerical ranges such as "3 to 10" refer to each integer within the given range). A cycloalkyl group may also be designated as "C3-C8 cycloalkyl" or similar designations. By way of example only, "C3-C8 cycloalkyl" indicates that there are 3 to 8 carbon atoms in the carbocyclyl ring or carbocyclyl ring system.

[0132] 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. Heterocyclyls 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 comprising the ring backbone, including carbon atoms and heteroatoms), although this definition also encompasses appearances of the term "heterocyclyl" without specifying a numerical range. Heterocyclyl groups can be medium heterocyclyls having 3 to 10 ring members. Heterocyclyl groups can also be heterocyclyls having 3 to 6 ring members. Heterocycloalkyl groups include "3- to 15-membered heterocycloalkyl," "4- to 10-membered heterocycloalkyl," "3- to 15-membered C heterocycloalkyl," and "4- to 15-membered C heterocycloalkyl." 2~14 Heterocycloalkyl, 5-9 membered C 4~8 Heterocycloalkyl, 5-10 membered C 4~9 Heterocycloalkyl, 5-membered C 3~4 Heterocycloalkyl, 6-membered C 4~5 heterocycloalkyl," "7-membered C 5~6 Heterocycloalkyl, bicyclic or tricyclic 9-15 membered C 8~14 Heterocycloalkyl, monocyclic or bicyclic 3-10 membered C 2~9 Heterocycloalkyl, bicyclic 8-10 membered C 4~9 Heterocycloalkyl, bicyclic 8-10 membered C 5~9 Heterocycloalkyl, monocyclic 4- to 7-membered C 3~6 Heterocycloalkyl, monocyclic 5-6 membered C 3~5The heterocyclyl group may be designated as "heterocycloalkyl" or similar designations. The heterocyclyl group may be a C2-C9 heterocyclyl having 3 to 10 ring members containing 1 to up to 3 O (oxygen), N (nitrogen), or S (sulfur). The heterocyclyl group may be designated as "3-10-membered C2-C9 heterocyclyl" or similar designations. 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-oxathianyl, 1,4-oxathiinyl, 2H-1,2-oxazinyl, trioxazinyl, 1H-1,2- ... These 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.

[0133] 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: TIFF2026032020000024.tif26128R 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 the moiety has the following structure: TIFF2026032020000025.tif26128In the formula, A is an aryl ring or carbocyclyl containing the double bond shown.

[0134] Whenever a substituent is depicted as a diradical (i.e., having two points of attachment to the rest of the molecule), it should be understood that the substituent may be attached in any orientation unless otherwise indicated. Thus, for example, -AE- or The substituent depicted as TIFF2026032020000026.tif8128 includes the substituent oriented such that A is attached at the leftmost attachment point of the molecule, as well as when A is attached at the rightmost attachment point of the molecule.

[0135] 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 that prevents, modulates, or delays 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).

[0136] 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, and 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, bases containing sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum, with ammonium, potassium, sodium, calcium, and magnesium salts being particularly preferred. In some embodiments, treating a compound disclosed herein with an inorganic base results in the loss of a labile hydrogen from the compound, resulting in the formation of Li. + , Na + , K. + , Mg 2+ , and Ca 2+Salt forms are obtained with inorganic cations such as, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.

[0137] Where the number of any given substituent is not specified (e.g., "haloalkyl"), one or more substituents can be present. For example, "haloalkyl" can include one or more of the same or different halogens. For example, "haloalkyl" includes the substituents CF, CHF, and CHF, respectively.

[0138] 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.

[0139] As used herein, the term "prodrug" refers to any compound that, upon administration to a biological system, generates a biologically active compound as a result of spontaneous, enzyme-catalyzed, and / or metabolic chemical reactions, or a combination of these reactions. Standard prodrugs are formed using a group that is cleaved in vivo and attached to a functional group, such as HO-, HS-, HOOC-, or HOOPR2-, associated with the drug. Standard prodrugs include, but are not limited to, carboxylic acid esters in which the group is alkyl, aryl, aralkyl, acyloxyalkyl, or alkoxycarbonyloxyalkyl, as well as hydroxyl, thiol, and amine esters in which the attached group is acyl, alkoxycarbonyl, aminocarbonyl, phosphate, or sulfate. The groups shown are examples and are not exhaustive; one skilled in the art may prepare a variety of other known prodrugs. To yield a compound that is biologically active or a precursor to a biologically active compound, a prodrug must undergo some form of chemical transformation. In some cases, prodrugs typically have less biological activity than the drug itself and serve 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 achieve long-term or sustained release or delivery, to improve ease of formulation, or to achieve site-specific delivery of the compound.

[0140] The term "stereoisomer" refers to the relative or absolute spatial relationships of the R groups attached to a carbon or phosphorus asymmetric center, and refers to an individual isomer or any combination of individual isomers, such as racemic and diastereomeric mixtures. If a compound has two asymmetric centers, four potential stereoisomers exist.

[0141] The term "liver" means the liver organ.

[0142] The term "liver specificity" refers to the ratio: [Drugs or drug metabolites in liver tissue] / [drug 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 specific time points, or may represent the AUC (area under the curve) based on values ​​measured at three or more time points.

[0143] 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.

[0144] The term "improved oral bioavailability" refers to an increase in the absorption rate of a reference drug dose of at least about 50%. In a further aspect, the increase in oral bioavailability of a compound (compared to the 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 after oral administration with measurements after parenteral administration.

[0145] 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, an increase in markers of toxicity, and / or a pharmacological side effect.

[0146] The term "sustained delivery" refers to the increased period during which therapeutically effective drug levels are extended by the presence of a prodrug.

[0147] The term "treating" a disease or "treatment" of a disease includes inhibiting the disease (slowing or arresting or partially arresting 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).

[0148] The term "therapeutic or diagnostic moiety" means a moiety that itself exhibits a therapeutic or diagnostic property when the compound to which it is attached is administered to a subject, or that, when cleaved from the rest of the molecule to which it is attached, forms a compound that exhibits a therapeutic or diagnostic property. In some embodiments, the therapeutic or diagnostic moiety comprises a radioisotope or a heavy atom.

[0149] 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.

[0150] "Nucleoside or analog thereof" refers to a naturally occurring nucleoside or an analog or derivative of a naturally occurring nucleoside, including compounds or moieties comprising a nucleobase and a sugar or sugar analog. The nucleoside or analog thereof can include therapeutically active fragments of known therapeutic nucleoside analogs or nucleotide analogs. Known therapeutic nucleoside analogs can include agents selected from the group consisting of abacavir, acisiovir, acyclovir, cytarabine, didanosine, edoxudine, emtricitabine, entecavir, galidesivir, ganciclovir, gemcitabine, ibacitabine, idoxuridine, inosine, lamivudine, penciclovir, remdesivir, ribavirin, stavudine, telbivudine, trifluridine, vidarabine, zalcitabine, and zidovudine. Known therapeutic nucleotide analogs can include drugs selected from the group consisting of adefovir, brincidofovir, cidofovir, and tenofovir. When a nucleoside or analog thereof is a therapeutically active fragment of a therapeutic nucleotide analog, the fragment can include a portion of the nucleotide analog remaining after cleavage of any phosphate ester groups from the nucleotide.

[0151] By "therapeutically active fragment" is meant a portion of a molecule that retains therapeutic activity when it is cleaved from the remainder of the molecule to which it is attached, including when cleavage occurs in vivo.

[0152] Administration and Pharmaceutical Compositions The disclosed compounds may be used alone or in combination with other therapeutic agents. When used in combination with other drugs, 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 drug administered as part of a therapeutic regimen, during a course of treatment with another drug, or before treatment with another drug in a treatment program.

[0153] 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, pamoate, phosphate, polygalacturonate, stearate, succinate, sulfate, sulfosalicylate, tannate, tartrate, terephthalate, tosylate, and triethiodide.

[0154] Compositions 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 given by oral, rectal, transmucosal, enteral, intestinal, topical, transdermal, intrathecal, intraventricular, intraperitoneal, intranasal, intraocular, and / or parenteral administration.

[0155] For example, when the compound is administered orally, it can be prepared as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs. 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 additives, including sweeteners, flavorings, colorings, and preservatives, to obtain a palatable formulation. Tablets containing a mixture of active ingredients and non-toxic pharmaceutically acceptable excipients suitable for tablet manufacture are acceptable. These excipients can be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders 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.

[0156] 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.

[0157] Preparations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions, which may contain 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 lyophilized 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.

[0158] In some embodiments, the unit dosage form contains a daily dose or daily unit, daily sub-dose, or an appropriate fraction thereof of a 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 specific compound used; the age, weight, general health, sex, and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs previously administered; and the severity of the particular disease being treated.

[0159] The actual dosage of the compounds described herein will depend on the particular compound and the condition being treated, and 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 7,000 mg per day, from about 35 mg per day to about 2,000 mg per day or more, or from about 70 mg per day to about 1,000 mg per day.

[0160] Treatment method Some embodiments of the present invention include methods for 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, or pharmaceutical compositions described herein. In some embodiments, the subject can be an animal, e.g., a mammal, or a human. In some embodiments, the subject is a human.

[0161] Further aspects include administering to a subject in need thereof a combination of compounds. The combination may include a compound, composition, or pharmaceutical composition described herein together with an additional pharmaceutical agent.

[0162] Some embodiments include co-administering a compound, composition, and / or pharmaceutical composition described herein with an additional medicament or additional therapeutic agent. "Co-administration" means that two or more agents can be found in a 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 co-administration is achieved by combining the agents in a single dosage form. In another embodiment, the agents are administered sequentially. In one embodiment, the agents are administered via the same route, e.g., orally. In another embodiment, the agents are administered via different routes, e.g., one agent is administered orally and another agent is administered intravenously.

[0163] The following examples are included to further illustrate the present 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 skill in the art, can make and use the invention without the need for exhaustive examples.

[0164] Compound synthesis The following procedures for the preparation of novel compounds are illustrative of the general procedure used to prepare 2-substituted benzyloxyphosphate (phosphonate) compounds.

[0165] Scheme I describes the general synthesis of phosphate (phosphonate) compounds of Formula I. Reaction of 2-substituted benzyl alcohol (1) with phosphate (phosphonate) chloride (2) provides the final product of Formula I, structure 3. Scheme I TIFF2026032020000027.tif29128 [Example]

[0166] Some compounds of formula I and Ia are prepared as outlined below.

[0167] Example 1 Ethyl 2-(((((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)-phosphoryl)oxy)methyl)benzoate (Compound 101) Compound 101 was prepared as a mixture of two isomers from ethyl 2-(hydroxymethyl)benzoate and phenyl ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonochloridate according to the method described in Scheme I. [M+1] + C 25 H 28 Calculated value for N5O6P: 526.19. Found value: 526.1.

[0168] Example 2 Isopropyl 2-((((5S)-5-((4-amino-2-oxopyrimidin-1(2H)-yl)methyl)-2-oxide-1,4,2-dioxaphosphinan-2-yl)oxy)methyl)benzoate (Compound 102) Compound 102 was prepared as a mixture of two isomers from (S)-(((1-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-hydroxypropan-2-yl)oxy)methyl)phosphonic acid according to the method described in Scheme I. [M+1] + C 19 H 24 Calculated value for N3O7P: 436.13. Found value: 436.1.

[0169] Example 3 4-Amino-1-(((6S)-3-oxido-9-oxo-3-phenoxy-1,4,6,7,9-pentahydrobenzo[i][1,4,7]trioxa[2]phosphacycloundecin-6-yl)methyl)pyrimidin-2(1H)-one (Compound 103) Compound 103 can be prepared as a mixture of two isomers [M+1] from 2-(chloromethyl)benzoic acid chloride and phenylhydrogen (S)-(((1-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-hydroxypropan-2-yl)oxy)methyl)phosphonic acid according to the method described in Scheme I. + C 22 H 22 Calculated value for N3O7P: 472.13.

[0170] Biological Examples Examples of uses of the method include the following: It will be understood that the following are examples and the method is not limited to only these examples.

[0171] Example 4 Tissue distribution after oral administration of reference compounds and disclosed compounds The prodrug efficacy of the disclosed compounds is compared to the corresponding active compounds in target organs.

[0172] method Reference compounds and compounds disclosed herein are administered by oral gavage to fasted rats at 5-50 mg / kg. Plasma concentrations of metabolites and parent compound in the circulation and hepatic portal vein are determined by HPLC-UV, and concentrations in the liver, small intestine, and other organs are measured by LC-MS using standard chromatographic methods.

[0173] 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.

[0174] As used herein, terms relating to degree, such as the terms "approximately," "about," "generally," and "substantially," 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 less than 10%, less than 5%, less than 1%, less than 0.1%, and less than 0.01% of the stated amount. As another example, in certain embodiments, the terms "generally parallel" and "substantially parallel" refer to a value, amount, or characteristic that deviates from exact parallelism by no more than 15%, 10%, 5%, 3%, 1%, 0.1%, or the like. Similarly, in certain embodiments, the terms "generally perpendicular" and "substantially perpendicular" refer to a value, amount, or characteristic that deviates from exact perpendicular by no more than 15%, 10%, 5%, 3%, 1%, 0.1%, or the like.

[0175] The above description discloses several methods and materials. The present invention is susceptible to modifications of the methods and materials, and to alterations in the fabrication methods and equipment. These modifications will become apparent to those skilled in the art from consideration of this disclosure or from practice of the invention disclosed herein. Accordingly, the present invention is not intended to be limited to the particular embodiments disclosed herein, but rather is intended to cover all modifications and alternatives falling within the true scope and spirit of the invention.

[0176] 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.

[0177] 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 I, or a stereoisomer or pharmaceutically acceptable salt thereof: During the ceremony, R 1 is -CH(OR 6 ) 2 , -C(O)N(R 6 ) 2 , -CH 2 OR 7 , C.H. 2 SR 7 , -CH 2 N(R 7 ) 2 , -CH 2 OCH 2 OR 6 , -COOR 5 , and selected from the group consisting of: Each R 2 is independently selected from the group consisting of halogen, optionally substituted alkyl, and optionally substituted alkyloxy; R 3 is selected from the group consisting of H, optionally substituted aryl, and a therapeutic or diagnostic moiety; R 4 is selected from a nucleoside or analog thereof, or a nucleoside base or analog thereof, or R 4 and R 3 together with the atoms to which they are attached form a monocyclic heterocyclyl substituted with a nucleoside base or analog thereof, or R 4 and R 5 together with the atoms to which they are attached form a heterocyclyl substituted with a nucleoside base or analog thereof; R 5 is H or optionally substituted alkyl; Each R 6 is independently optionally substituted alkyl; R 7 is H, optionally substituted C 1 ~C 10 Acyl, optionally substituted C 1 ~C 10 alkyl-OC(O)-, optionally substituted (C 6～10 aryl)-C(O)-, and optionally substituted (C 6～10 aryl)-OC(O)-; n is 0, 1, 2, or 3.

2. 2. The compound of claim 1, wherein the nucleoside base or analog thereof is a therapeutically active fragment of a drug selected from the group consisting of abacavir, acicovir, acyclovir, cytarabine, didanosine, edoxudine, emtricitabine, entecavir, galidesivir, ganciclovir, gemcitabine, ibacitabine, idoxuridine, inosine, lamivudine, maribavir, molnupiravir, penciclovir, remdesivir, ribavirin, stavudine, telbivudine, trifluridine, vidarabine, zalcitabine, and zidovudine.

3. 10. The compound of claim 1, wherein the nucleoside base or analog thereof is a therapeutically active fragment of a drug selected from the group consisting of adefovir, brincidofovir, cidofovir, and tenofovir.

4. 10. The compound of claim 1, wherein the nucleoside base or analog thereof is selected from the group consisting of: During the ceremony, R 9 is H, halo, 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 , NHOR 7 , 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 is 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- is selected from the group

5. Nucleoside bases or their analogs 5. The compound of claim 4, wherein:

6. R 11 NH 2 6. The compound of claim 5, wherein:

7. R 12 7. The compound of claim 5 or 6, wherein is H.

8. Nucleoside bases or their analogs 5. The compound of claim 4, wherein:

9. R 9 9. The compound of claim 8, wherein is H.

10. R 11 NH 2 10. The compound of claim 8 or 9, wherein:

11. 11. The compound of any one of claims 1 to 10, wherein n is 1.

12. R 3 12. The compound of any one of claims 1-11, wherein is selected from the group consisting of H and optionally substituted aryl.

13. R 1 But -CH(OR 6 ) 2 , -C(O)N(R 6 ) 2 , and 13. The compound according to any one of claims 1 to 12, selected from the group consisting of:

14. The compound of any one of claims 1 to 12, wherein the compound of formula I is represented by formula (Ia): or a stereoisomer or a pharmaceutically acceptable salt thereof.

15. R 5 is unsubstituted C 1 ~C 6 15. The compound of claim 14, wherein said compound is alkyl.

16. R 5 16. The compound of claim 15, wherein is ethyl.

17. R 5 16. The compound of claim 15, wherein is i-propyl.

18. R 5 15. The compound of claim 14, wherein is H.

19. R 3 15. The compound of claim 14, wherein is unsubstituted aryl.

20. R 3 15. The compound of claim 14, wherein is phenyl.

21. below 2. The compound of claim 1, selected from the group consisting of:

22. 22. A compound according to any one of claims 1 to 21 for use in treating liver disease.

23. 23. The compound of claim 22 in combination with one or more additional therapeutic agents.

24. 22. Use of a compound according to any one of claims 1 to 21 in the preparation of a medicament for treating liver disease.

25. 22. A method of treating liver disease, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-21.

26. 26. The method of claim 25, wherein the subject is a mammal.

27. 27. The method of claim 26, wherein the mammal is a human.

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