Benzyl oxyphosphate (phosphonic acid ester) compounds

Abstract

Provided herein are 2-substituted benzyloxyphosphate (phosphonate) compounds, their preparation, and their uses, for example, to treat diseases or conditions of the liver.

Description

[Technical Field]

[0001] field This disclosure relates to the fields of chemistry and pharmaceuticals. More specifically, this disclosure relates to 2-substituted benzyloxyphosphate (phosphonic acid) compounds, their preparations, and their uses. In some embodiments, these compounds are useful for effectively delivering specific drugs to target cells or target organs. [Background technology]

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

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

[0004] overview Novel 2-substituted benzyl oxyphosphate (phosphonate) compounds, their preparations, and their uses are described. Some embodiments are novel 2-substituted benzyl oxyphosphate (phosphonate) compounds that are orally delivered to the liver and other organs to exert a therapeutic effect thereon. Further embodiments include novel 2-substituted benzyl oxyphosphate (phosphonate) compounds that treat diseases, disorders, or conditions including certain mitochondrial DNA deficiency syndromes, hepatitis, cancer, hepatic fibrosis, fatty liver, malaria, viral infections, parasitic infections, diabetes mellitus, hyperlipidemia, atherosclerosis, obesity, dyslipidemia, hyperglycemia, hormonal conditions, HIV, and various types of cancer. Another aspect involves the use of 2-substituted benzyl oxyphosphate (phosphonate) compounds to treat diseases in which improved drug distribution to target cells or target organs is beneficial. Another aspect involves 2-substituted benzyl oxyphosphate (phosphonate) compounds being used to increase the pharmacological or clinical activity of a particular class of pharmaceutical compounds, e.g., nucleotide-derived analog compounds. In some embodiments, 2-substituted benzyloxyphosphate (phosphonate) compounds are useful in improving the efficiency of oral delivery of nucleotides or their derivative compounds to the liver and / or other target organs. Some further embodiments relate to methods for producing 2-substituted benzyloxyphosphate (phosphonate) compounds.

[0005] Some embodiments provided herein include compounds of formula I or formula Ia, their stereoisomers, or pharmaceutically acceptable salts: TIFF0007836769000001.tif67128 formula, R 1 , R 2 , R 3 , R 4 , R 5 , and n have any of the values ​​specified herein.

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

[0007] Some embodiments relate to a method for treating a disease, disorder, or condition, comprising the step of administering an effective amount of the compound.

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

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

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

[0011] Some embodiments relate to a method for treating a non-hepatic disease, comprising the step of administering an effective amount of one of the above-mentioned compound combinations to a subject in need thereof.

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

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

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

[0015] Some embodiments relate to methods for intervening in molecular pathways or modulating targets within cells, comprising the step of bringing the cell into contact with one of the compounds.

[0016] In some embodiments, the cells are in vivo.

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

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

[0019] In some aspects, the cells are mammalian cells.

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

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

[0022] Some embodiments of the compounds, compositions, and methods provided herein include methods for treating a liver disease or condition in a subject, comprising the step of administering an effective amount of one of the compounds provided herein to a subject in need thereof.

[0023] Some embodiments of the compounds, compositions, and methods provided herein include methods for treating a disease or condition in a subject, comprising the step of administering an effective amount of one of the compounds provided herein to a subject in need thereof.

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

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

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

[0027] Some embodiments also include the use of a compound provided herein in combination with a further therapeutic agent.

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

[0029] Some aspects of the compounds, compositions, and methods provided herein include one or more of the compositions provided herein for use in the preparation of a medicament for treating a liver disease or condition, or a disease or condition in which the liver is involved in a physiological or pathogenic pathway.

[0030] Some aspects of the compounds, compositions, and methods provided herein include one or more of the compositions provided herein for use in the preparation of a medicament for treating a non-liver disease or condition. [Invention 1001] Compounds of formula I, their stereoisomers, or pharmaceutically acceptable salts: TIFF0007836769000002.tif25128 During the ceremony, R 1 is -CH(OR 6 ) 2 ,-C(O)N(R 6 ) 2 ,-CH 2 Ure 7 CH 2 SR 7 ,-CH 2 N(R 7 ) 2 ,-CH 2 OCH 2 Ure 6 ,-COOR 5 , and TIFF0007836769000003.tif12128 Selected from the group consisting of; Each R 2 These are independently selected from the group consisting of halogens, optionally substituted alkyls, and optionally substituted alkyloxys; R 3 This is selected from the group consisting of H, an optionally substituted aryl, and a therapeutic or diagnostic moiety; R 4 is selected from nucleosides or their analogues, or nucleoside bases or their analogues, or R 4 and R 3 They, together with the atoms to which they are bonded, form monocyclic heterocyclines substituted with nucleoside bases or their analogues, or R 4 and R 5 These, together with the atoms to which they are bonded, form heterocyclines substituted with nucleoside bases or their analogues; R 5 is H or an optionally substituted alkyl group; Each R 6 is independently an alkyl which may be substituted; R 7 H, and C may be substituted. 1 ~C 10 Acyl, C is fine even if substituted. 1 ~C 10 Alkyl-OC(O)-, may be substituted (C 6~10 aryl)-C(O)-, and may be substituted (C 6~10 Selected from the group consisting of aryl)-OC(O)-; n is 0, 1, 2, or 3. [Invention 1002] The compound of the present invention 1001, wherein the nucleoside base or its analogue is a therapeutic active fragment of a drug selected from the group consisting of abacavir, aciiovir, acyclovir, cytarabine, didanosine, edoxudine, emtricitabine, entecavir, galidesivir, ganciclovir, gemcitabine, ibacitabine, idoxuridine, inosine, lamivudine, maribavir, mornupyravir, penciclovir, remdesivir, ribavirine, stabudine, terbivudine, trifluridine, vidarabine, zalcitabine, and zidovudine. [Invention 1003] The compound of the present invention 1001, wherein the nucleoside base or its analogue is a therapeutically active fragment of a drug selected from the group consisting of adefovir, brincidofovir, cidofovir, and tenofovir. [Invention 1004] A compound of the present invention 1001, wherein the nucleoside base or its analogue is selected from the group consisting of the following: TIFF0007836769000004.tif48128 During the ceremony, R 9 is H, halo, or C which may be substituted. 1 ~C 10 It is alkyl; R 10 H, and C may be substituted. 1 ~C 10 Alkyl, possibly substituted C 1 ~C 10 Alkyl-OCH 2 - C may be substituted 1 ~C 10 Alkyl-NHCH 2 - C may be substituted 1 ~C 10 Acyl, C is fine even if substituted. 1 ~C 10 Alkyl-OC(O)-, may be substituted (C 6~10 Ariel)-CH 2 OCH 2 -, may be replaced (C 6~10 Aryl)-OCH 2 -, may be replaced (C 6~10 aryl)-C(O)-, and may be substituted (C 6~10 Selected from the group consisting of aryl)-OC(O)-; R 11 OH, NH 2 NHOR 7 , C which may be substituted 1 ~C 10 Alkyloxy, possibly substituted C 1 ~C 10 Alkylamino, C may be substituted. 1 ~C 10 Acyloxy, C may be substituted. 1 ~C 10 Acylamino, C may be substituted 1 ~C 10 Alkyl-OC(O)NH-, may be substituted (C 6~10 aryl)-C(O)O-, may be substituted (C 6~10 aryl)-C(O)NH-, may be substituted (C 6~10 aryl)-OC(O)NH-, C may be substituted. 1 ~C 10 Alkyl-OCH 2 NH-, and C which may be substituted. 1 ~C 10 Alkyl-OCH 2 Selected from the group consisting of O-; R 12 H, NH 2 , C may be substituted 1 ~C 10 Alkylamino, C may be substituted. 1 ~C 10 Acylamino, C may be substituted 1 ~C 10 Alkyl-OC(O)NH-, may be substituted (C 6~10 aryl)-C(O)NH-, may be substituted (C 6~10 Aryl)-OC(O)NH-, and possibly substituted C 1 ~C 10 Alkyl-OCH 2 Selected from the NH- group. [Invention 1005] Nucleoside bases or their analogues TIFF0007836769000005.tif20128 The compound of the present invention 1004. [Invention 1006] R 11 NH 2 The compound of the present invention 1005. [Invention 1007] R 12 A compound of the present invention 1005 or 1006, wherein is H. [Invention 1008] Nucleoside bases or their analogues TIFF0007836769000006.tif21128 The compound of the present invention 1004. [Invention 1009] R 9 A compound of the present invention 1008, wherein H is present. [Invention 1010] R 11 NH 2 The compound of the present invention 1008 or 1009. [Invention 1011] A compound from any of the inventions 1001 to 1010, wherein n is 1. [Invention 1012] R 3 However, any compound of the present invention 1001 to 1011, selected from the group consisting of H and optionally substituted aryl compounds. [Invention 1013] R 1 However, -CH(OR 6 ) 2 ,-C(O)N(R 6 ) 2 , and TIFF0007836769000007.tif12128 A compound selected from the group, one of the compounds 1001 to 1012 of the present invention. [Invention 1014] Compounds of any of the inventions 1001 to 1012, wherein the compound of formula I is represented by formula (Ia): TIFF0007836769000008.tif27128 or its stereoisomer or a pharmaceutically acceptable salt. [Invention 1015] R 5 is non-substituted C 1 ~C 6 A compound of the present invention 1014, which is alkyl. [Invention 1016] R 5 A compound of the present invention 1015, wherein the compound is ethyl. [Invention 1017] R 5 A compound of the present invention 1015, wherein i-propyl is present. [Invention 1018] R 5 A compound of the present invention 1014, wherein H is present. [Invention 1019] R 3 Compound 1014 of the present invention, wherein is an unsubstituted aryl compound. [Invention 1020] R 3 A compound of the present invention 1014, wherein the compound is phenyl. [Invention 1021] below TIFF0007836769000009.tif90128 A compound of the present invention 1001, selected from the group consisting of the following. [Invention 1022] Any compound 1001 to 1021 of the present invention for use in treating liver disease. [Invention 1023] Compound 1022 of the present invention, in combination with one or more further therapeutic agents. [Invention 1024] Use of any compound 1001 to 1021 of the present invention in the preparation of a pharmaceutical for treating liver disease. [Invention 1025] A method for treating liver disease, comprising the step of administering an effective amount of any of the compounds 1001 to 1021 of the present invention to a subject in need thereof. [Invention 1026] The method of the present invention 1025, wherein the subject is a mammal. [Invention 1027] The method of the present invention 1026, wherein the mammal is a human. [Modes for carrying out the invention]

[0031] Detailed explanation This embodiment relates to compositions and methods relating to novel 2-substituted benzyloxyphosphate (phosphonic acid ester) compounds, their preparation, and their use. In some embodiments, the novel 2-substituted benzyloxyphosphate (phosphonic acid ester) compounds facilitate the delivery of nucleotides or nucleotide derivatives or nucleotide analogs into cells.

[0032] These 2-substituted benzyloxyphosphate (phosphonic acid) compounds, as well as their stereoisomers and pharmaceutically acceptable salts, are represented by formula I or formula Ia, or their stereoisomers or pharmaceutically acceptable salts: TIFF0007836769000010.tif67128In formula, R 1 , R 2 , R 3 , R 4 , R 5 , and n have any of the values ​​specified herein.

[0033] In some embodiments, R 1 is -CH(OR 6 )2, -C(O)N(R 6 )2, -CH2OR 7 CH2SR 7 , -CH2N(R 7 )2, -CH2OCH2OR 6 ,-COOR 5 , and Selected from the group TIFF0007836769000011.tif12128.

[0034] In some embodiments, R 1 is -CH(OR 6 )2, -C(O)N(R 6 )2, and Selected from the group TIFF0007836769000012.tif12128.

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

[0036] In some embodiments, R 3 is selected from the group consisting 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 nucleoside or its analog, or nucleobase or its analog, or R 4 and R 3 together with the atoms to which they are attached form a monocyclic heterocyclyl substituted with a nucleobase or its analog, or R 4 and R 5 together with the atoms to which they are attached form a heterocyclyl substituted with a nucleobase or its analog.

[0041] In some embodiments, the nucleoside or its analogue is a therapeutically active fragment of drugs such as abacavir, aciiovir, acyclovir, cytarabine, didanosine, edoxudine, emtricitabine, entecavir, galidesivir, ganciclovir, gemcitabine, ibasitabine, idoxuridine, inosine, lamivudine, maribavir, mornupyravir, penciclovir, remdesivir, ribavirin, stabudine, terbivudine, trifluridine, vidarabine, zalcitabine, and zidovudine; or, in some embodiments, the nucleoside or its analogue is a therapeutically active fragment of drugs such as adefovir, brincidofovir, cidofovir, and tenofovir.

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

[0043] In some embodiments, R 5 These are unsubstituted C1-C6 alkyl groups.

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

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

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

[0047] In some embodiments, each R 6 These are independently alkyl groups that may be substituted.

[0048] In some embodiments, R 7 H is C1~C which may be substituted. 10 Acyl, C1-C may be substituted. 10 Alkyl-OC(O)-, may be substituted (C 6~10 aryl)-C(O)-, and may be substituted (C 6~10Selected from the group aryl)-OC(O)-.

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

[0050] In some embodiments, n is 1.

[0051] In some embodiments, nucleoside bases or their analogues Selected from the group consisting of TIFF0007836769000013.tif47128.

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

[0053] In some embodiments, R 10 H is C1~C which may be substituted. 10 Alkyl, possibly substituted C1-C 10 Alkyl-OCH2-, C1-C which may be substituted. 10 Alkyl-NHCH2-, C1-C which may be substituted. 10 Acyl, C1-C may be substituted. 10 Alkyl-OC(O)-, may be substituted (C 6~10 aryl)-CH2OCH2-, may be substituted (C 6~10 aryl)-OCH2-, may be substituted (C 6~10 aryl)-C(O)-, and may be substituted (C 6~10 Selected from the group consisting of aryl)-OC(O)-.

[0054] In some embodiments, R 11 These are OH, NH2, and NHOR. 7 C1~C may be substituted. 10 Alkyloxy, possibly substituted C1-C 10 Alkylamino, possibly substituted C1-C 10 Acyloxy, C1-C may be substituted. 10Acylamino, C1-C1 may be substituted. 10 Alkyl-OC(O)NH-, may be substituted (C 6~10 aryl)-C(O)O-, may be substituted (C 6~10 aryl)-C(O)NH-, may be substituted (C 6~10 Aryl)-OC(O)NH-, C1~C may be substituted. 10 Alkyl-OCH2NH- and optionally substituted C1-C 10 Selected from the group consisting of alkyl-OCH2O-.

[0055] In some embodiments, R 12 C1-C may be substituted with H, NH2, or C1-C 10 Alkylamino, possibly substituted C1-C 10 Acylamino, C1-C1 may be substituted. 10 Alkyl-OC(O)NH-, may be substituted (C 6~10 aryl)-C(O)NH-, may be substituted (C 6~10 Aryl)-OC(O)NH-, and possibly substituted C1~C 10 Selected from the alkyl-OCH2NH- group.

[0056] In some embodiments, nucleoside bases or their analogues The filename is TIFF0007836769000014.tif20128.

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

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

[0059] In some embodiments, nucleoside bases or their analogues The filename is TIFF0007836769000015.tif21128.

[0060] In some embodiments, nucleoside bases or their analogues The filename is TIFF0007836769000016.tif21128.

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

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

[0063] In some embodiments, R 1 is -CH(OR 6 )2, -C(O)N(R 6 )2, and Selected from the group TIFF0007836769000017.tif12128.

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

[0065] In some embodiments, a nucleoside base or its analogues is as follows: Selected from the group consisting of TIFF0007836769000018.tif50128, where L is a sugar or sugar analog.

[0066] In some embodiments, a nucleoside base or its analogues is as follows: Selected from the group consisting of TIFF0007836769000019.tif107154 and TIFF0007836769000020.tif113154.

[0067] In some embodiments, a nucleoside base or its analogues is as follows: Selected from the group consisting of TIFF0007836769000021.tif29128.

[0068] In some embodiments, nucleoside bases or their analogues The filename is TIFF0007836769000022.tif25128.

[0069] In some embodiments, the compound is as follows: Selected from the group consisting of TIFF0007836769000023.tif52149.

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

[0071] In some embodiments, the compound is activated within cells upon cleavage of the prodrug portion, releasing the active form of the compound.

[0072] In some embodiments, the 2-substituted benzyloxyphosphate (phosphonic acid) compounds of formulas I and Ia are used to treat diseases in which improved drug distribution to the liver and similar tissues and cells is beneficial, including but not limited to liver diseases, due to their liver-targeting properties.

[0073] 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 or their analogues. Furthermore, the disclosed methodologies can be used to achieve sustained delivery of bio-related nucleotides or their analogues. The 2-substituted benzyloxyphosphate (phosphonic acid) compounds of formulas I and Ia are used to treat diseases in which improved pharmacokinetic properties are beneficial, due to their enhanced pharmacokinetic properties. In some embodiments, methods for preparing these compounds are described.

[0074] Certain compounds of formulas I and Ia have chiral centers whose stereochemical configuration can be unspecified, and when referring to compounds of formulas I and Ia in general, diastereoisomers of these compounds are included as well as individual stereoisomers.

[0075] In some embodiments, an effective amount of the disclosed compound is used to treat a disease, disorder, or condition in an object that requires it.

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

[0077] Some embodiments also include the step of administering an effective amount of a combination of a second or more therapeutic agent and the compound provided herein to a subject requiring it.

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

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

[0080] Some embodiments of the compounds, compositions, and methods provided herein include methods for testing a compound in cells, comprising the step of bringing the cell into contact with the disclosed compound.

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

[0082] Some embodiments include the use of a combination of the compounds provided herein with further therapeutic agents for the treatment of liver disease.

[0083] In some embodiments, the compounds provided herein are used in the preparation of pharmaceuticals for treating liver diseases.

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

[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 combinations of the compounds provided herein with further therapeutic agents for the treatment of non-hepatic diseases.

[0087] The compounds disclosed herein may exist as individual enantiomers and diastereomers, or as mixtures of such isomers, including racemates, if they have at least one chiral center. Separation of individual isomers or selective synthesis of individual isomers can be achieved by applying various methods well known to those skilled in the art. Unless otherwise indicated, all these isomers and mixtures thereof are included in 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 in the scope of the compounds disclosed herein. Furthermore, some of the compounds disclosed herein may form solvates (i.e., hydrates) with water or with common organic solvents. Unless otherwise indicated, these solvates are included in the scope of the compounds disclosed herein.

[0088] Those skilled in the art will recognize that some of the structures described herein may be resonance forms or tautomers of compounds that could be properly represented by other chemical structures, even if they are dynamically represented, and that such structures may represent only a very small portion of a sample of the compound. These resonance forms or tautomers are not shown herein, but these compounds are considered to be within the range of the illustrated structures.

[0089] Isotopes may be present in the compounds described. Each chemical element represented in the compound structure may contain any isotope of that element. For example, in the compound structure, a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position in a 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 otherwise clearly indicated in the context, references to compounds herein encompass all potential isotopic forms.

[0090] definition The following terms, as used in accordance with this disclosure and herein, are defined as follows unless otherwise explicitly stated. It should be understood that the above general descriptions and the following detailed descriptions are illustrative and descriptive only and do not limit the subject matter claimed. In this application, unless otherwise specifically stated, the use of the singular includes the plural. In this application, unless otherwise specifically stated, the use of “or” means “and / or.” Furthermore, the use of the term “including,” as well as other forms such as “includes” and “included,” is not limiting.

[0091] As used herein, ranges and quantities may be expressed as "approximately" specific values ​​or ranges. "Approximately" includes exact quantities. Thus, "approximately 10%" means "approximately 10%" and "10%".

[0092] As used herein, “optional” or “optionally” means whether or not the event or situation described below occurs, and includes the cases in which such event or situation occurs and the cases in which it does not. For example, “a base that may be substituted” means that the base is either not substituted or is substituted.

[0093] As used herein, the singular forms "a," "an," and "the" include multiple references unless otherwise clearly indicated by the context. Therefore, for example, a reference to a composition containing a "therapeutic agent" includes compositions having one or more therapeutic agents.

[0094] In this specification, "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, this group may contain "a" or more carbon atoms and "b" or less carbon atoms. Therefore, for example, a "C1-C4 alkyl" group or "C 1~4 The "alkyl" group refers to all alkyl groups having 1 to 4 carbon atoms, namely CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-.

[0095] As used herein, “alkyl” means a fully saturated (i.e., non-double or triple bonded) straight or branched hydrocarbon chain. Alkyl chains may have 1 to 20 carbon atoms (wherever alkyl appears herein, the numerical range such as “1 to 20” refers to each integer within a given range. For example, “1 to 20 carbon atoms” means that an alkyl group may consist of 1, 2, 3 carbon atoms, and up to 20 carbon atoms; however, this definition also covers instances where the term “alkyl” does not specify a numerical range). Alkyl chains may be intermediate alkyl groups having 1 to 9 carbon atoms. Alkyl chains may be lower alkyl groups having 1 to 4 carbon atoms. Alkyl chains may be named “C1-C4 alkyl” or similar names. For illustrative purposes only, “C1-C4 alkyl” indicates that the alkyl chain contains 1 to 4 carbon atoms, 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 by no means limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl.

[0096] As used herein, “substituted groups” are derived from unsubstituted parent groups in which one or more hydrogen atoms are replaced by another atom or group. Unless otherwise indicated, when a group is considered “substituted,” it means that the group is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 carbocyryl (which may be substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), or C3-C7-carbocyryl-C1-C6-alkyl (which may be substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy). ), 3-10 member heterocyclyl (may be substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 3-10 member heterocyclyl-C1-C6-alkyl (may be substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl (may be substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy) (may be substituted with aryl(C1~C6)alkyl(halo, C1~C6alkyl, C1~C6alkoxy, C1~C6haloalkyl, and C1~C6haloalkoxy), 5~10-membered heteroaryl(C1~C6)alkyl(halo, C1~C6alkyl, C1~C6alkoxy, C1~C6haloalkyl, and C1~ (may be substituted with C6 haloalkoxy), halo, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy(C1-C6) alkyl (i.e., ether), aryloxy (may be substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7 carbocykyloxy (may be substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy),3-10 member heterocyclyl-oxy (may be substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 member heteroaryl-oxy (may be substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7-carbocykyl-C1-C6-alkoxy (may be substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy) (may be substituted with), 3-10 member heterocyclyl-C1-C6-alkoxy (halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl(C1-C6)alkoxy (halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 member heteroaryl(C1-C6)alkoxy (halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 halo (may be substituted with alkoxy), sulfhydryl (mercapto), halo(C1~C6)alkyl (e.g., -CF3), halo(C1~C6)alkoxy (e.g., -OCF3), C1~C6 alkylthio, arylthio (may be substituted with halo, C1~C6 alkyl, C1~C6 alkoxy, C1~C6 haloalkyl, and C1~C6 haloalkoxy), C3~C7 carbocyclylthio (may be substituted with halo, C1~C6 alkyl, C1~C6 alkoxy, C1~C6 haloalkyl, and C1~C6 haloalkoxy), 3~10 5-10 member heterocyclyl-thio (may be substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 member heteroaryl-thio (may be substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7-carbocykyl-C1-C6-alkylthio (may be substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy),3-10 member heterocyclyl-C1-C6-alkylthio (may be substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl(C1-C6)alkylthio (may be substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 member heteroaryl(C1-C6)alkylthio (may be substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy) This means that the group is substituted with one or more substituents independently selected from (which may be substituted with C1-C6 haloalkoxys), amino, amino(C1-C6)alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, and oxo (=O). Whenever a group is described as "may be substituted," that group may be substituted with any of the substituents listed above.

[0097] As used herein, "acyl" means that R is hydrogen as defined herein, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 -C(=O)R refers to aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl. Non-restrictive examples include formyl, acetyl, propanoyl, benzoyl, and acrylic.

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

[0099] "Alkyloxymethylene" means that R is C 1~6 This means an alkyl or heteroalkyl -CH2OR, which may be substituted.

[0100] The "O-carboxy" group means a "-OC(=O)R" group where R is hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic selected.

[0101] The "C-carboxy" group means a "-C(=O)OR" group where R is hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic selected. Non-limiting examples include carboxyl (i.e., -C(=O)OH).

[0102] The "cyano" group means a "-CN" group.

[0103] The "cyanato" group means a "-OCN" group.

[0104] The "isocyanato" group means a "-NCO" group.

[0105] The "thiocyanato" group means a "-SCN" group.

[0106] The "isothiocyanato" group means a "-NCS" group.

[0107] The "sulfinyl" group means a "-S(=O)R" group where R is hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic selected.

[0108] A "sulfonyl" group is defined as having R as hydrogen and C as defined herein. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 The "-SO2R" group is selected from aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl groups.

[0109] The "S-sulfonamide" group is R A and R B Each of these independently defines hydrogen and C as defined herein. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 Selected from aryls, 5-10 membered heteroaryls, and 3-10 membered heterocyclines, "-SO2NR A R B It means "base".

[0110] The "N-sulfonamide" group is R A and R b Each of these independently defines hydrogen and C as defined herein. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 Selected from aryls, 5-10 membered heteroaryls, and 3-10 membered heterocyclines, "-N(R A )SO2R B It means "base".

[0111] The "O-carbamyl" group is R A and R B Each of these independently defines hydrogen and C as defined herein. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10Selected from aryls, 5-10 membered heteroaryls, and 3-10 membered heterocyclines, "-OC(=O)NR" A R B It means "base".

[0112] The "N-carbamyl" group is R A and R B Each of these independently defines hydrogen and C as defined herein. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 Selected from aryls, 5-10 membered heteroaryls, and 3-10 membered heterocyclines, "-N(R A )C(=O)OR B It means "base".

[0113] The "O-thiocarbamyl" group is R A and R B Each of these independently defines hydrogen and C as defined herein. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 Selected from aryls, 5-10 membered heteroaryls, and 3-10 membered heterocyclines, "-OC(=S)NR A R B It means "base".

[0114] The "N-thiocarbamyl" group is R A and R B Each of these independently defines hydrogen and C as defined herein. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 Selected from aryls, 5-10 membered heteroaryls, and 3-10 membered heterocyclines, "-N(R A )C(=S)OR B It means "base".

[0115] The "C-amide" group is RA and R B Each of these independently defines hydrogen and C as defined herein. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 Selected from aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, respectively, with -OH and C 1~6 Alkyl, C 3~7 Carbocyclyl, C 6~10 Aryl, 5-10 member heteroaryl, 3-10 member heterocyclyl, C 1~6 C may be substituted with alkoxy or -OH groups. 1~6 Alkyl, and C 1~6 C may be substituted with alkoxy or -OH groups. 1~6 "-C(=O)NR" may be substituted with one or more substituents selected from the group consisting of alkoxys. A R B It means "base".

[0116] The "N-amide" group is R A and R B Each of these independently defines hydrogen and C as defined herein. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 Selected from aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, respectively, with -OH and C 1~6 Alkyl, C 3~7 Carbocyclyl, C 6~10 Aryl, 5-10 member heteroaryl, 3-10 member heterocyclyl, C 1~6 C may be substituted with alkoxy or -OH groups. 1~6 Alkyl, and C 1~6 C may be substituted with alkoxy or -OH groups. 1~6 "-N(R A )C(=O)R B It means "base".

[0117] The term "amino" group means -NR A and R B each independently being hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic selected, the "-NR A R B " group. Non-limiting examples include the free amino (i.e., -NH2).

[0118] The term "aminoalkyl" group means an amino group connected by an alkylene group.

[0119] The term "alkoxyalkyl" group means an alkoxy group connected by an alkylene group, such as "C 2~8 alkoxyalkyl", etc.

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

[0121] The term "alkoxy" or "alkyloxy" means 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 =O group.

[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 containing at least one halogen, and more specifically, one to three halo atoms. Preferred 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, and includes linear, branched, and cyclic groups. Alkenyl groups may be substituted. A preferred alkenyl group is an allyl.

[0128] The term "alkynyl" refers to an unsaturated group having 2 to 12 atoms and containing at least one carbon-carbon triple bond, and includes linear, branched, and cyclic groups. Alkynyl groups may be substituted. A preferred alkynyl group is ethynyl.

[0129] As used herein, "aryl" means an aromatic ring or aromatic ring system (i.e., two or more fused rings sharing two adjacent carbon atoms) containing only carbon atoms in its ring skeleton. When an aryl is a ring system, all rings in the system are aromatic rings. While an aryl group can have 6 to 18 carbon atoms, this definition also covers instances where the term "aryl" does not specify a numerical range. In some embodiments, an aryl group has 6 to 10 carbon atoms. 6~10 "Aryl," "C6 or C 10 They may be named "aryl" or similar names. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azlenyl, and anthracenyl.

[0130] As used herein, "heteroaryl" means an aromatic ring or aromatic ring system (i.e., two or more fused rings sharing two adjacent atoms) containing one or more heteroatoms, i.e., elements other than carbon, in its ring skeleton, including but not limited to nitrogen, oxygen, and sulfur. If the heteroaryl is a ring system, all rings in the system are aromatic rings. A heteroaryl group may have 5 to 18 ring members (i.e., the number of atoms constituting the ring skeleton, including carbon atoms and heteroatoms), but this definition also covers instances where the term "heteroaryl" does not specify a numerical range. In some embodiments, a heteroaryl group has 5 to 10 ring members or 5 to 7 ring members. A heteroaryl group may be named as a "5-7 membered heteroaryl," a "5-10 membered heteroaryl," or similar names. A heteroaryl group may be substituted. Examples of heteroaryl groups include, but are not limited to, aromatic C3-8 heterocyclic groups containing one oxygen or sulfur atom, up to four nitrogen atoms, or a combination of one oxygen or sulfur atom and up to two nitrogen atoms, as well as their substituted derivatives, and benzo-condensed and pyrido-condensed derivatives linked, for example, by one ring-forming carbon atom. In some embodiments, the heteroaryl group may be halo, hydroxy, amino, cyano, nitro, alkylamide, acyl, or C. 1~6 -alkoxy, C 1~6 -alkyl, C 1~6- May be substituted with one or more substituents independently selected from hydroxyalkyl, C1-6-aminoalkyl, C1-6-alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl. Examples of heteroaryl groups include, but are not limited to, unsubstituted and monosubstituted or disubstituted derivatives of furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzoisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole, quinoline, isoquinoline, pyridazine, pyrimidine, purine, pyrazine, furazan, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, triazole, benzotriazole, pteridine, phenoxazole, oxadiazole, benzopyrazole, quinolidine, cinnoline, phthalazine, quinazoline, and quinoxaline. 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 -It is alkyl.

[0131] As used herein, "cycloalkyl" means a fully saturated carbocyric ring or carbocyric ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups may have 3 to 10 carbon atoms (wherever cycloalkyl groups appear herein, the numerical range such as "3 to 10" refers to each integer within a given range). Cycloalkyl groups may be named "C3-C8 cycloalkyl" or similar names. For illustrative purposes only, "C3-C8 cycloalkyl" indicates the presence of 3 to 8 carbon atoms in the carbocyric ring or carbocyric ring system.

[0132] As used herein, "heterocyclyl" means a non-aromatic or non-aromatic ring structure that is fully saturated or partially saturated and contains at least one heteroatom selected from nitrogen, oxygen, and sulfur in its ring skeleton. A heterocyclyl can have any degree of saturation, provided that at least one ring in the ring system is not an aromatic ring. The heteroatom may be present in the non-aromatic or aromatic ring in the ring system. A heterocyclyl group may have 3 to 20 ring members (i.e., the number of atoms constituting the ring skeleton, including carbon atoms and heteroatoms), but this definition also covers cases where the term "heterocyclyl" does not specify a numerical range. A heterocyclyl group may be an intermediate heterocyclyl having 3 to 10 ring members. A heterocyclyl group may be a heterocyclyl having 3 to 6 ring members. Heterocycloalkyl groups are "3-15 member heterocycloalkyls," "4-10 member heterocycloalkyls," and "3-15 member C 2~14 "Heterocycloalkyl", "5-9 member C" 4~8 "Heterocycloalkyl", "5-10 member C" 4~9 "Heterocycloalkyl", "5-membered C" 3~4 "Hypercycloalkyl", "6-membered C 4~5 Heterocycloalkyl, 7-membered C 5~6 "Heterocycloalkyl," "bicyclic or tricyclic 9-15 member carbon 8~14 "Heterocycloalkyl," "monocyclic or bicyclic 3-10 member carbon atom" 2~9 "Heterocycloalkyl," "Bicyclic 8-10 member C" 4~9 "Heterocycloalkyl," "Bicyclic 8-10 member C" 5~9 "Heterocycloalkyl," "monocyclic 4-7 member carbon 3~6 "Heterocycloalkyl," "monocyclic 5-6 member carbon 3~5The heterocyclyl group may be named "heterocycloalkyl" or a similar name. The heterocyclyl group may be a C2-C9 heterocyclyl having 3 to 10 ring members, containing 1 to a maximum of 3 O (oxygen), N (nitrogen), or S (sulfur). The heterocyclyl group may be named "3-10 member C2-C9 heterocyclyl" or a similar name. In a preferred 6-membered monocyclic heterocyclyl, the heteroatoms are selected from 1 to a maximum of 3 O (oxygen), N (nitrogen), or S (sulfur), and in a preferred 5-membered monocyclic heterocyclyl, 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, dioxolanil, imidazolinyl, imidazolidinyl, morpholinyl, oxylanil, oxepanil, thiepanil, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxynyl, 1,3-dioxanyl, 1,4-dioxynyl, 1,4-dioxanyl, 1,3-oxathiinyl, 1,4-oxathiinyl, 2H-1,2-oxazinyl, trio Examples 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, oxazolidinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiadinyl, thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, and tetrahydroquinoline.

[0133] Similarly, when two "adjacent" R groups are said to "together with the atom to which they are bonded" to form a ring, it means that the atom, the intervening bond, and the collective unit of the two R groups constitute that ring. For example, the following structure exists: TIFF0007836769000024.tif26128R 1 and R 2 However, it is defined to be selected from the group consisting of hydrogen and alkyl, or R 1 and R 2 However, if they combine with the atoms to which they are bonded to form an aryl or carbocykryl, then R 1 and R 2 This means that the substructure can be selected from hydrogen or alkyl, or that the substructure has the following structure: In formula TIFF0007836769000025.tif26128, A is an aryl ring or carbocyrill containing the double bond shown in the figure.

[0134] Whenever a substituent is depicted as a diradical (i.e., having two bonding points to the rest of the molecule), it should be understood that the substituent can be bonded in any orientation unless otherwise indicated. Therefore, for example, -AE- or The substituents illustrated as TIFF0007836769000026.tif8128 include substituents oriented so that A is bonded at the leftmost bond point of the molecule, and substituents oriented so that A is bonded at the rightmost bond point of the molecule.

[0135] The term "therapeutic dose" refers to the amount of a compound or combination of compounds that partially or completely relieves, reduces or eliminates one or more symptoms of a particular disease or condition, or prevents, modulates or delays the onset of one or more symptoms of a particular disease or condition. This amount may be administered as a single dosage form or according to a regimen in which this amount is effective. Repeated administrations may be necessary to achieve the desired result (e.g., treatment of the disease and / or condition).

[0136] The term "pharmaceutically acceptable salt" includes salts of the compounds of formula I derived from combinations of the compounds of this embodiment with organic or inorganic acids or bases. pharmaceutically acceptable acid addition salts can be formed from inorganic and organic acids. Examples of inorganic acids from which salts can be derived include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of organic acids from which salts can be derived include 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. Examples include dodecyl sulfonic acid, salicylic acid, glucoheptonic acid, gluconic acid, glucuronic acid, hippuric acid, hydrochloric acid, hemiethanolic acid, 2-hydroxyethanesulfonic acid, lactic acid, lactobionic acid, methylbromidic acid, methylsulfate, 2-naphthalenesulfonic acid, oleic acid, 4,4'-methylenebis-[3-hydroxy-2-naphthalenecarboxylic acid], polygalacturonic acid, stearic acid, sulfosalicylic acid, tannic acid, terephthalic acid, etc. Examples of inorganic bases from which salts can be derived include bases containing sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum, with ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts being particularly preferred. In some embodiments, by treating the compounds disclosed herein with an inorganic base, unstable hydrogen is lost from the compounds, Li + kaNa + , K + Mg 2+ , and Ca 2+Salt forms containing inorganic cations such as these can be obtained. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally substituted amines, cyclic amines, and basic ion exchange resins, specifically, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.

[0137] If no given number of substituents is specified (e.g., "haloalkyl"), one or more substituents may be present. For example, "haloalkyl" may contain one or more identical or different halogens. For example, "haloalkyl" may contain each substituent CF3, CHF2, and CH2F.

[0138] The term "patient" refers to the animal being treated, including mammals such as dogs, cats, cattle, 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” means any compound that, when administered to a biological system, produces a bioactive compound as a result of a spontaneous chemical reaction, an enzyme-catalyzed chemical reaction, and / or a metabochemical reaction, or a combination thereof. Standard prodrugs are formed using a functional group, such as HO-, HS-, HOOC-, HOOPR2-, which is cleaved in vivo and associated with the drug. Standard prodrugs include, but are not limited to, carboxylic acid esters whose group is alkyl, aryl, aralkyl, acyloxyalkyl, or alkoxycarbonyloxyalkyl, as well as esters of hydroxyl, thiol, and amines whose bonded group is an acyl group, alkoxycarbonyl, aminocarbonyl, phosphate, or sulfate. The groups shown are examples and not exhaustive, and those skilled in the art may prepare a variety of other known prodrugs. Prodrugs must undergo some form of chemical transformation to produce a compound that is bioactive or a precursor to a bioactive compound. In some cases, prodrugs have bioactivity that is typically lower than that of the drug itself, and they play a role in improving the efficacy or safety of a drug through improvements such as oral bioavailability or pharmacodynamic half-life. Prodrug forms of compounds can be used, for example, to improve bioavailability, to improve tolerability by masking or reducing unpleasant properties such as bitterness or gastrointestinal irritation, to modify solubility for intravenous use, to achieve long-term or sustained release or delivery, to improve ease of formulation, or to achieve site-specific delivery of the compound.

[0140] The term "stereoisomer" refers to the relative or absolute spatial relationship of R groups bonded to a chiral center, which is a carbon or phosphorus atom, and can refer to individual isomers or any combination of individual isomers, such as racemic and diastereoisomeric mixtures. If a compound has two chiral centers, there are four potential stereoisomers.

[0141] The term "liver" refers to the liver organ.

[0142] The term "liver specificity" refers to the following ratio: [Drugs or drug metabolites in liver tissue] / [Drugs or drug metabolites in the blood or other tissues] Measured in animals treated with the drug or prodrug. This ratio may be determined by measuring tissue levels at a specific time point, or it may represent the area under the curve (AUC) based on values ​​measured at three or more time points.

[0143] The term "increased or improved liver specificity" means an increase in the liver specificity ratio in animals treated with the prodrug compared to animals treated with the parent drug.

[0144] The term "improved oral bioavailability" means an increase of at least approximately 50% in the absorption rate of a reference drug dose. In more detail, an increase in the oral bioavailability of a compound (compared to a reference drug) is at least approximately 100%, or a doubling of the absorption rate. Typically, the measurement of oral bioavailability means comparing the measured levels of a prodrug, drug, or drug metabolite in blood, plasma, tissue, or urine after oral administration with the measured levels 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, elevated markers of toxicity, and / or pharmacological side effects.

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

[0147] The terms “treating” a disease or “treatment” of a disease include inhibiting the disease (delaying, stopping, or partially stopping the onset of the disease), preventing the disease, reducing the symptoms or side effects of the disease (including symptomatic treatment), and / or reducing the disease (causing regression of the disease).

[0148] The term "therapeutic or diagnostic portion" means a portion of the compound to which it is bound that exhibits therapeutic or diagnostic properties when administered to a subject, or a portion that, when cleaved from the rest of the molecule to which it is bound, forms a compound exhibiting therapeutic or diagnostic properties. In some embodiments, the therapeutic or diagnostic portion contains a radioisotope or a heavy atom.

[0149] The term "molecular pathway" refers to a series of molecular events in tissues, such as receptor regulatory sequences, enzyme regulatory sequences, or biosynthetic sequences, that are involved in the physiological or pathophysiological functions of living animals.

[0150] "Nucleoside or analogue" means a natural nucleoside, or an analogue or derivative of a natural nucleoside, and includes compounds or parts containing a nucleic acid base and a sugar or sugar analogue. Nucleosides or analogues may include therapeutically active fragments of known therapeutic nucleoside analogues or nucleotide analogues. Known therapeutic nucleoside analogues include drugs selected from the group consisting of abacavir, asisiovir, acyclovir, cytarabine, didanosine, edoxudine, emtricitabine, entecavir, galidesivir, ganciclovir, gemcitabine, ivacitabine, idoxuridine, inosine, lamivudine, penciclovir, remdesivir, ribavirin, stabudine, terbivudine, trifluridine, vidarabine, zalcitabine, and zidovudine. Known therapeutic nucleotide analogs include drugs selected from the group consisting of adefovir, brincidofovir, cidofovir, and tenofovir. When a nucleoside or its analogue is the therapeutically active fragment of a therapeutic nucleotide analogue, the fragment may include a portion of the nucleotide analogue remaining after the cleavage of any phosphate ester group from the nucleotide.

[0151] A "therapeutic active fragment" refers to a portion of a molecule that retains therapeutic activity when it is cleaved from the rest of the molecule to which it is bound, including cases where the cleavage occurs in vivo.

[0152] Dosage and pharmaceutical composition The disclosed compounds may be used alone or in combination with other treatment agents. When used in combination with other agents, these compounds may be administered as a daily dose or as an appropriate portion of a daily dose (e.g., twice daily). The compounds may be administered after a treatment course with another agent as part of a treatment regimen, during a treatment course with another agent, or before treatment with another agent in a treatment program.

[0153] Examples of pharmaceutically acceptable salts include acetate, adipine, besilate, bromide, cansilate, chloride, citrate, edisylate, estolate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hyclate, hydrobromide, hydrochloride, iodide, isethionate, lactate, lactobionate, maleate, mesilate, methyl bromide, methyl sulfate, napsylate, nitrate, oleate, palmoate, phosphate, polygalacturonate, stearate, succinate, sulfate, sulfosalicylate, tannate, tartrate, terephthalate, tosylate, and triethiozide.

[0154] The composition containing the active ingredient may be in any form suitable for the desired method of administration. In some embodiments, compounds of the methods and / or compositions described herein may be administered orally, rectally, transmucosally, intestinally, intraintestinally, topically, transdermally, subarachnoidally, intraventricularly, intraperitoneally, intranasally, intraocularly, and / or parenterally.

[0155] For example, when the compound is administered orally, tablets, lozenges, licks, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs can be prepared. Compositions intended for oral use can be prepared according to any method known in the art with respect to the manufacture of pharmaceutical compositions, and these compositions may contain one or more excipients, including sweeteners, flavorings, colorants, and preservatives, to obtain a palatable formulation. Tablets containing a mixture of the active ingredient and non-toxic, pharmaceutically acceptable excipients are acceptable, suitable for the manufacture of tablets. These excipients may 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. The tablets do not need to be coated, but may be coated by known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract, thereby achieving a longer-lasting effect. For example, time-delaying substances such as glyceryl monostearate or glyceryl distearate can be used alone or in combination with wax.

[0156] Oral formulations may be presented as hard gelatin capsules in which the active ingredient can be mixed with an inert solid diluent, such as calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient can be mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0157] Suitable formulations for parenteral administration include aqueous and non-aqueous isotonic sterile injectable solutions that may contain, for example, antioxidants, buffers, bacteriostatic agents, and solutes that make the formulation isotonic with the blood of the target recipient; as well as aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickeners. The formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored under lyophilized conditions requiring only the addition of a sterile liquid carrier, such as sterile water for injection, immediately before use. Injectable solutions and injectable suspensions can be prepared from the sterile powders, granules, and tablets of the types described above.

[0158] In some embodiments, a unit dosage form formulation comprises a daily dose or daily unit, a divided daily dose, or an appropriate portion thereof. However, as those skilled in the art will understand, it will be understood that any particular dose level for any particular patient depends on a variety of factors, including the activity of the particular compound used; the age, weight, overall health, sex, and diet of the person 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 doses of the compounds described herein depend on the specific compound and the condition to be treated, and the selection of an appropriate dose is well within the knowledge of those skilled in the art. In some embodiments, the daily dose may be about 0.1 mg / kg to about 100 mg or more / kg body weight, about 0.25 mg or less / kg to about 50 mg / kg, about 0.5 mg or less / kg to about 25 mg / kg, and about 1.0 mg / kg to about 10 mg / kg body weight. Therefore, for administration to a 70 kg individual, the dose range would be about 7 mg to about 7000 mg per day, about 35 mg or less to about 2000 mg or more per day, and about 70 mg to about 1000 mg per day.

[0160] Treatment method Some aspects of the present invention include methods for treating diseases, disorders, or conditions selected from the group consisting of hepatitis, liver cancer, hepatic fibrosis, fatty liver, malaria, viral infections, parasitic infections, diabetes mellitus, hyperlipidemia, atherosclerosis, obesity, dyslipidemia, hyperglycemia, hormonal conditions, HIV, and various types of cancer with compounds described herein and compositions containing such compounds. Some methods include the step of administering the compounds, compositions, or pharmaceutical compositions described herein to a subject in need thereof. In some aspects, the subject may be an animal, such as a mammal or a human. In some aspects, the subject is a human.

[0161] Further embodiments include the step of administering a combination of compounds to a subject requiring such a combination. The combination may include the compounds, compositions, and pharmaceutical compositions described herein together with further pharmaceuticals.

[0162] Some embodiments include the step of co-administering the compounds, compositions, and / or pharmaceutical compositions described herein together with further pharmaceuticals or further therapeutic agents. "Co-administration" means that two or more drugs may be found in the patient's bloodstream at the same time, regardless of when or how they are actually administered. In one embodiment, the drugs are administered co-administered. In such an embodiment, co-administration is achieved by combining the drugs in a single dosage form. In another embodiment, the drugs are administered sequentially. In one embodiment, the drugs are administered through the same route, for example, orally. In another embodiment, the drugs are administered through different routes, for example, one drug is administered orally and the other intravenously.

[0163] To further illustrate the present invention, the following embodiments are included. Naturally, these embodiments should not be construed as specifically limiting the present invention. Variations of these embodiments within the claims are within the scope of the skill of those skilled in the art and are considered to be within the scope of the present invention as described and claimed herein. Readers will recognize that those skilled in the art, with the skills of this disclosure and in the art, can prepare and use the present invention without exhaustive examples.

[0164] Compound synthesis The following procedure for the preparation of novel compounds exemplifies a general procedure used to prepare 2-substituted benzyloxyphosphate (phosphonic acid ester) compounds.

[0165] Scheme I describes the general synthesis of the phosphate ester (phosphonic acid ester) compound of formula I. By reacting a 2-substituted benzyl alcohol (1) with a phosphate ester (phosphonic acid ester) chloride (2), the final product of formula I, structure 3, is obtained. Scheme I TIFF0007836769000027.tif29128 [Examples]

[0166] Several compounds of formulas I and Ia are prepared as outlined below.

[0167] Example 1 Ethyl 2-((((((((R)-1-(6-amino-9H-purine-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-purine-9-yl)propan-2-yl)oxy)methyl)phosphonochloride according to the method described in Scheme I. [M+1] + C 25 H 28 Calculated value of N5O6P: 526.19. Measured value: 526.1.

[0168] Example 2 Isopropyl 2-((((5S)-5-((4-amino-2-oxopyrimidine-1(2H)-yl)methyl)-2-oxide-1,4,2-dioxaphosfinan-2-yl)oxy)methyl)benzoate (compound 102) Compound 102 was prepared as a mixture of two isomers from TIFF0007836769000029.tif36128(S)-(((1-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxypropane-2-yl)oxy)methyl)phosphonic acid according to the method described in Scheme I. [M+1] + C 19 H 24 Calculated value of N3O7P: 436.13. Measured value: 436.1.

[0169] Example 3 4-Amino-1-(((6S)-3-oxide-9-oxo-3-phenoxy-1,4,6,7,9-pentahydrobenzo[i][1,4,7]trioxa[2]phosphacycloundecine-6-yl)methyl)pyrimidine-2(1H)-one (compound 103) Compound 103 can be prepared as a mixture of two isomers from TIFF0007836769000030.tif501282-(chloromethyl)benzoate and phenylhydrogen(S)-(((1-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxypropan-2-yl)oxy)methyl)phosphonic acid according to the method described in Scheme I. [M+1] + C 22 H 22 Calculated value of N3O7P: 472.13.

[0170] Biological examples Examples of how this method can be used are listed below. It should be understood that these are merely examples, and the method is not limited to these examples alone.

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

[0172] method The reference compound and the compounds disclosed herein were administered to fasted rats at a dose of 5–50 mg / kg via oral gastric tube feeding. Plasma concentrations of metabolites and parent compounds in circulation and in the 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 chromatography.

[0173] All figures used herein to express quantities of components, reaction conditions, etc., should be understood to be modified in all cases by the term “approximately.” Therefore, unless otherwise indicated, numerical parameters described herein are approximate values ​​that may vary depending on the desired properties to be obtained. At the very least, and without any intention to limit the application of the equivalence principle to the scope of any claim in any application claiming priority to this application, each numerical parameter should be interpreted in light of the number of significant figures and the usual rounding approach.

[0174] As used herein, terms relating to degree, such as “approximately,” “about,” “generally,” and “substantially,” mean values, quantities, or characteristics that are close to the stated value, quantity, or characteristic, and still perform the desired function or achieve the desired result. For example, “approximately,” “about,” “generally,” and “substantially” may mean quantities that are less than 10%, less than 5%, less than 1%, less than 0.1%, and less than 0.01% of the stated quantity. As another example, in certain embodiments, the terms “generally parallel” and “substantially parallel” mean values, quantities, or characteristics that deviate from the exact parallel by 15%, 10%, 5%, 3%, 1%, 0.1%, etc. Similarly, in certain embodiments, the terms “generally perpendicular” and “substantially perpendicular” mean values, quantities, or characteristics that deviate from the exact perpendicular by 15%, 10%, 5%, 3%, 1%, 0.1%, etc.

[0175] The above description discloses several methods and materials. The present invention allows for modifications of such methods and materials, as well as modifications of manufacturing methods and equipment. These modifications will be obvious to those skilled in the art by considering this disclosure or by practicing the invention disclosed herein. Accordingly, the present invention is not intended to be limited to any particular embodiment disclosed herein, but is intended to cover all modifications and substitutions that fall within the true scope and intent of the invention.

[0176] All reference materials cited herein, including but not limited to published and unpublished applications, patents, and references, are incorporated by reference and thus become part of this Spec. In the event of any conflict between a publication or patent or patent application incorporated by reference and any disclosure contained herein, this Spec. is intended to 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 present invention.

Claims

1. Compounds of formula I, their stereoisomers, or pharmaceutically acceptable salts: During the ceremony, R 1 is -CH(OR 6 ) 2 , -C(O)N(R 6 ) 2 , -CH 2 OR 7 , CH 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 These are independently selected from the group consisting of halogens, optionally substituted alkyls, and optionally substituted alkyloxys; R 3 is selected from the group consisting of H and optionally substituted aryls; R 4 R is selected from nucleoside bases or their analogues, or 4 and R 3 They, together with the atoms to which they are bonded, form monocyclic heterocyclines substituted with nucleoside bases or their analogues, or R 4 and R 5 These, together with the atoms to which they are bonded, form heterocyclines substituted with nucleoside bases or their analogues. The nucleoside base or its analogues are selected from the group consisting of the following: ; R 5 is H or an optionally substituted alkyl group; Each R 6 is independently an alkyl which may be substituted; R 7 H, and C may be substituted. 1 ~C 10 Acyl, C is fine even if substituted. 1 ~C 10 Alkyl-OC(O)-, may be substituted (C 6～10 aryl)-C(O)-, and may be substituted (C 6～10 Selected from the group consisting of aryl)-OC(O)-; R9 is H, a halo, or a C1-C10 alkyl group which may be substituted; R 10 is selected from the group consisting of H, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 alkyl-OCH2-, optionally substituted C1-C10 alkyl-NHCH2-, optionally substituted C1-C10 acyl, optionally substituted C1-C10 alkyl-OC(O)-, optionally substituted (C6-10 aryl)-CH2OCH2-, optionally substituted (C6-10 aryl)-OCH2-, optionally substituted (C6-10 aryl)-C(O)-, and optionally substituted (C6-10 aryl)-OC(O)-; R 11 is selected from the group consisting of OH, NH₂, NHOR₂, optionally substituted C1-C10 alkyloxy, optionally substituted C1-C10 alkylamino, optionally substituted C1-C10 acyloxy, optionally substituted C1-C10 acylamino, optionally substituted C1-C10 alkyl-OC(O)NH-, optionally substituted (C6-10 aryl)-C(O)O-, optionally substituted (C6-10 aryl)-C(O)NH-, optionally substituted (C6-10 aryl)-OC(O)NH-, optionally substituted C1-C10 alkyl-OCH₂NH-, and optionally substituted C1-C10 alkyl-OCH₂O-; R 12 is selected from the group consisting of H, NH2, optionally substituted C1-C10 alkylaminos, optionally substituted C1-C10 acylaminos, optionally substituted C1-C10 alkyl-OC(O)NH-, optionally substituted (C6-10 aryl)-C(O)NH-, optionally substituted (C6-10 aryl)-OC(O)NH-, and optionally substituted C1-C10 alkyl-OCH2NH-; n is 0, 1, 2, or 3.

2. The compound according to claim 1, wherein the nucleoside base or its analogue is selected from the group consisting of the following: 。

3. Nucleoside bases or their analogues The compound according to claim 2.

4. R 11 NH 2 The compound according to claim 3.

5. R 12 The compound according to claim 3 or 4, wherein is H.

6. Nucleoside bases or their analogues The compound according to claim 2.

7. R 9 The compound according to claim 6, wherein is H.

8. R 11 NH 2 The compound according to claim 6 or 7.

9. A compound according to any one of claims 1 to 8, wherein n is 1.

10. R 3 The compound according to any one of claims 1 to 9, wherein the compound is an aryl which may be substituted.

11. R 1 However, -CH(OR 6 ) 2 ,-C(O)N(R 6 ) 2 , and A compound according to any one of claims 1 to 10, selected from the group.

12. A compound according to any one of claims 1 to 10, wherein the compound of formula I is represented by formula (Ia): or its stereoisomer or a pharmaceutically acceptable salt.

13. R 5 is non-substituted C 1 ~C 6 The compound according to claim 12, wherein it is alkyl.

14. R 5 The compound according to claim 13, wherein is ethyl.

15. R 5 The compound according to claim 13, wherein i-propyl.

16. R 5 The compound according to claim 12, wherein is H.

17. R 3 The compound according to claim 12, wherein is an unsubstituted aryl.

18. R 3 The compound according to claim 12, wherein is phenyl.

19. below A compound according to claim 1, selected from the group consisting of the following.

20. A pharmaceutical composition for use in treating liver disease, comprising the compound according to any one of claims 1 to 19.

21. The pharmaceutical composition according to claim 20, to be used in combination with one or more further therapeutic agents.

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