RU2796403C2 - Phosphorus(n)amidateacetal and phosph(oh)atacetal compounds - Google Patents

Abstract

FIELD: organic chemistry; pharmacology.

SUBSTANCE: group of inventions relates to the preparation of nucleos(t)ide analogs targeted at the liver. A compound of formula IVa or a pharmaceutically acceptable salt of the said compound, where R¹ and R² are independently selected from the group consisting of C₁-C₆ alkyl; or alternatively R¹ and R² together with the atoms to which they are attached form a four to ten-membered heterocycle with two oxygen atoms as heteroatoms, optionally substituted with C₁-C₆ alkyl; each R³ is independently selected from the group consisting of hydrogen and C₁-C₆ alkyl, optionally substituted with phenyl; each R⁶ is independently C₁-C₆ alkyl; m is 0, 1, 2 or 3; n is 1 or 2; and X is O (oxygen) or NH are revealed. In addition, pharmaceutical compositions for the treatment of HIV and viral liver infection, methods for treating HIV and viral liver infection, as well as a method for inhibiting viral replication in the hepatocyte are disclosed. In addition, the use of the disclosed compound for the preparation of a medicament for the treatment of a viral infection of the liver, as well as the use of the compound for the treatment of a viral infection of the liver, is described.

EFFECT: group of inventions provides effective treatment of viral infection of the liver and HIV by interfering with molecular pathways in the liver.

49 cl, 3 tbl, 62 ex

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority from U.S. Provisional Application No. 62/615851, filed January 10, 2018, titled "PHOSPHOR(N)AMIDATACETAL AND PHOSPH(ON)ATALCETAL COMPOUNDS" ("Phosphorus(n)amidate acetal and phosph( he)atacetal compounds"), the entire content of which is incorporated into this description by reference.

Technical field

[0002] The present invention relates to the field of chemistry and medicine. More specifically, the present invention relates to phosphorus(n)amidate acetal and phosph(one)acetal compounds, their preparation and use. In some embodiments of the present invention, these compounds are useful for the selective delivery of certain nucleotides to the liver.

State of the art

[0003] The following description of the prior art is provided to assist in understanding the invention, but is not intended to represent or describe the prior art of the present invention.

[0004] Nucleo(t)ide compounds of natural origin are essential molecular building blocks in living organisms, and many nucleo(t)ide analogues are widely used as antiviral and anticancer agents. However, due to their low lipophilicity, nucleo(t)ide analogs are rarely used as oral agents. Nucleo(t)ide analogs can be administered in an oral enhanced form (eg see: P. J. Thornton, et al. Journal of Medicinal Chemistry 59:10400-10410 (2016) and J. Rautio, et al. Nature Reviews Drug Discovery 7:255-270 (2008)).

[0005] In addition to known nucleo(t)ide analogs, there is a need for new compounds that have favorable physicochemical, biopharmaceutical or pharmacokinetic properties, for example, liver-targeted compounds that are not active outside the liver, which reduces pharmacological or toxicological effects biologically. active agent outside the target tissue. Thus, there is a need for improved liver-targeting compounds that remain relatively non-cytotoxic outside the liver.

SHORT DESCRIPTION

[0006] Novel phosphor(n)amidate acetal and phosph(one)ate acetal nucleos(t)ide compounds, their preparation and use are described. Some embodiments of the present invention relate to novel phosphorus(n)amidate acetal and phosph(one)acetal compounds that are absorbed in the intestine and pass through the hepatic portal vein to the liver, where said compounds provide a therapeutic effect. Another aspect of the present invention includes the use of phosphorus(n)amidate acetal and phosph(one)acetal compounds for the treatment of diseases in which it is useful to improve the distribution of the drug in the liver and similar tissues and cells, including, but not limited to, hepatitis, cancer, liver fibrosis. , fatty liver, and metabolic and cardiovascular diseases in which the liver is involved in the production and/or control of homeostasis of biochemical end products, such as glucose, cholesterol, fatty acids, triglycerides, lipoproteins and apolipoproteins. In another aspect of the present invention, phosphorus(n)amidate acetal and phosph(one)acetal compounds are used to increase the pharmacological or clinical activity of certain nucleo(t)ide analogues. In another aspect, phosphorus(n)amidate acetal and phosph(one)acetal compounds are used to reduce the potential side effects of certain nucleo(t) analogs, especially non-hepatic side effects. In some embodiments of the present invention, phosphorus(n)amidate acetal and phosph(one)acetal compounds are useful for delivering diagnostic imaging agents to the liver. Some additional embodiments of the present invention relate to a process for the preparation of phosphorus(n)amidate acetal and phosph(one)acetal compounds.

[0007] Some embodiments of the present invention provided herein relate to a compound of Formula I:

or a stereoisomer or pharmaceutically acceptable salt of said compound,

where R ¹ , R ³ , R ⁴ , R ⁵ , X, Y and n have any of the meanings described herein.

[0008] In some embodiments of the present invention, R ⁴ is the R ⁴ portion of a monophosphate or monophosphonate therapeutic agent having the structure:

.

.

[0009] In some embodiments of the present invention, R ⁴ contains a nucleoside or its amide or ester. In some embodiments of the present invention, R ⁴ contains a nucleoside or nucleoside analogue. In some embodiments of the present invention, R ⁴ contains a ribonucleoside, a deoxyribonucleoside, or an amide or ester of these compounds. In some embodiments of the present invention, R ⁴ contains a ribonucleoside, a ribonucleoside analog, a deoxyribonucleoside, a deoxyribonucleoside analog, or an amide or ester of these compounds. In some embodiments of the present invention, R ⁴ contains a naturally occurring ribonucleoside, a naturally occurring deoxyribonucleoside, a non-naturally occurring ribonucleoside, a non-naturally occurring deoxyribonucleoside, or an amide or ester of these compounds. In some embodiments of the present invention, R ⁴ contains a nucleic base or its amide. In some embodiments of the present invention, R ⁴ contains a nucleic base analog or amide. In some embodiments of the present invention, R ⁴ contains a purine nucleobase, a pyrimidine nucleobase, or an amide of these compounds. In some embodiments of the present invention, R ⁴ contains a purine nucleobase analog, a pyrimidine nucleobase analog, or an amide or ester of these compounds. In some embodiments of the present invention, R ⁴ contains a nucleic base of natural or non-natural origin or its amide. In some embodiments of the present invention, R ⁴ contains a substituted tetrahydrofuran. In some embodiments of the present invention, R ⁴ contains tetrahydrofuran substituted with one to four R ^1A , where one R ^1A is a nucleic base or its amide. In some embodiments of the present invention, R ⁴ contains tetrahydrofuran substituted with one to four R ^1A , where one R ^1A is a nucleobase analog or amide. In some embodiments of the present invention, R ⁴ contains tetrahydrofuran substituted with one to four R ^1A , where one R ^1A is a purine nucleobase, a pyrimidine nucleobase, or an amide of these compounds. In some embodiments of the present invention, R ⁴ contains tetrahydrofuran substituted with one to four R ^1A , where one R ^1A is a purine nucleobase analog, a pyrimidine nucleobase analog, or an amide or ester of these compounds. In some embodiments of the present invention, R ⁴ contains tetrahydrofuran substituted with one to four R ^1A , where one R ^1A is a naturally occurring or non-naturally occurring nucleobase or an amide thereof.

[0010] Some embodiments of the present invention relate to a compound of formulas II, III, IV, V, and VI:

or a stereoisomer or pharmaceutically acceptable salt of said compound,

or a stereoisomer or pharmaceutically acceptable salt of said compound,

or a stereoisomer or pharmaceutically acceptable salt of said compound,

or a stereoisomer or pharmaceutically acceptable salt of said compound,

or a stereoisomer or pharmaceutically acceptable salt of said compound,

where R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , X, Y, m and n are any of the meanings described herein.

[0011] Some embodiments of the present invention relate to a compound of formula Ia IIa, IIIa, IVa, Va and VIa:

or a stereoisomer or pharmaceutically acceptable salt of said compound,

or a stereoisomer or pharmaceutically acceptable salt of said compound,

or a stereoisomer or pharmaceutically acceptable salt of said compound,

or a stereoisomer or pharmaceutically acceptable salt of said compound,

or a stereoisomer or pharmaceutically acceptable salt of said compound,

or a stereoisomer or pharmaceutically acceptable salt of said compound,

where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , X, m and n are any of the meanings described herein.

[0012] Some embodiments of the present invention relate to a pharmaceutical composition containing any of the above compounds and a pharmaceutically acceptable excipient.

[0013] Some embodiments of the present invention relate to a method of treating a disease, disorder, or condition, comprising administering an effective amount of any of the above compounds.

[0014] In some embodiments of the present invention, the specified disease, disorder or condition is a disease, disorder or condition of the liver.

[0015] In some embodiments of the present invention, said disease, disorder, or condition is a metabolic, cardiovascular, or hormonal disease in which the liver is involved in the production and/or homeostasis control of the biochemical end products of said disease, disorder, or condition.

[0016] In some embodiments of the present invention, the specified disease, disorder or condition is selected from the group consisting of hepatitis, cancer, liver fibrosis, fatty liver, malaria, viral infection, parasitic infection, diabetes, hyperlipidemia, atherosclerosis, obesity, dyslipidemia, hyperglycemia and hormonal status.

[0017] In some embodiments of the present invention, said non-liver disease, disorder, or condition is a viral infection, cancer, or other disease in which said phosphorus(n)amidate acetal and phosph(one)acetal compounds enhance the distribution of the active drug to target tissue or cells.

[0018] Some embodiments of the present invention relate to a method of treating liver disease, comprising administering an effective amount of a compound of any of the above compounds to a subject in need thereof, where R ⁴ is an antiviral or anticancer agent, which is a nucleoside or nucleoside equivalent.

[0019] Some embodiments of the present invention further include administering an effective amount of at least one additional therapeutic agent to a subject in need thereof.

[0020] Some embodiments of the present invention relate to a method for delivering a diagnostic imaging agent to the liver of a subject in need thereof, comprising administering to said subject an effective amount of any of the above compounds.

[0021] In some embodiments of the present invention, the subject is a mammal.

[0022] In some embodiments of the present invention, the subject is a human.

[0023] Some embodiments of the present invention relate to a method for inhibiting viral replication in a cell, comprising contacting the cell with any of the above compounds.

[0024] Some embodiments of the present invention relate to a method of interfering with a molecular pathway or modulating a target in a cell, comprising bringing the cell into contact with any of the above compounds.

[0025] In some embodiments of the present invention, said cell is in vivo.

[0026] In some embodiments of the present invention, said cell is ex vivo.

[0027] In some embodiments of the present invention, said cell is a hepatocyte.

[0028] In some embodiments of the present invention, said cell is a mammalian cell.

[0029] In some embodiments of the present invention, said cell is a human cell.

[0030] Some embodiments of the compounds, compositions, and methods provided herein include a pharmaceutical composition containing any of the compounds provided herein and a pharmaceutically acceptable excipient.

[0031] 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 an effective amount of any of the compounds provided herein to a subject in need thereof.

[0032] Some embodiments provided herein include a method of treating a disease or condition by interfering with a molecular pathway/target (e.g., receptor or enzyme or the like) in the liver of a subject, comprising administering to a subject in need thereof an effective amount any fatty acid prodrug that is absorbed through the hepatic portal vein into the liver.

[0033] Some embodiments of the present invention also include administering an effective amount of one or more additional therapeutic agents to a subject in need thereof.

[0034] In some embodiments of the present invention, the subject is a mammal.

[0035] According to some embodiments of the present invention, the subject is a human.

[0036] Some embodiments of the present invention also include the use of any of the compounds provided herein in combination with an additional therapeutic agent.

[0037] Some embodiments of the compounds, compositions, and methods provided herein include any one of the compositions provided herein for use in the preparation of a medicament for the treatment of a liver disease or condition, or a disease or condition in which physiological or pathogenic pathways include the liver.

DETAILED DESCRIPTION OF THE INVENTION

[0038] Nucleoside monophosphates and nucleoside monophosphonates are of interest as drug targets because conversion to the active triphosphate/phosphonodiphosphate is rapid and initial rate-limiting phosphorylation is not required. However, nucleoside monophosphates and nucleoside monophosphonates are not efficiently transported to the therapeutic target in cells, so they are limited as potential drugs. Thus, strategies have been developed to facilitate the delivery of nucleoside monophosphates and nucleoside monophosphonates into cells. The nucleoside drugs sofosbuvir, gemcitabine and oral tenofovir are approved for the treatment of hepatitis C, cancer, hepatitis B and HIV, respectively. Table 1 presents unmasked sofosbuvir monophosphate and gemcitabine monophosphate and tenofovir in unmasked monophosphonate form. These compounds are known to undergo rapid phosphorylation to the active triphosphate/phosphonodiphosphate forms (e.g., see P. J. Thornton, et al. J. Med. Chem., (2016), 59(23):10400-10410).

[0039] The present embodiments of the present invention are directed to compositions and methods related to novel phosphorus(n)amidate acetal and phosph(one)acetal compounds, their preparation and use. In some embodiments of the present invention, the novel phosphorus(n)amidate acetal and phosph(one)acetal compounds facilitate the delivery of monophosphate and monophosphonate therapeutic agents, such as nucleoside monophosphates and nucleoside monophosphonates, to cells. In some embodiments of the present invention, the novel phosphorus(n)amidate acetal and phosph(one)acetal compounds facilitate the delivery of unmasked sofosbuvir monophosphate, gemcitabine monophosphate or tenofovir into cells.

[0040] Said phosphorus(n)amidate acetal and phosph(one)acetal compounds and their stereoisomers and their pharmaceutically acceptable salts are represented by formulas I, II, III, IV, V and VI:

where R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , X, Y, m and n are any of the meanings described herein.

[0041] In some embodiments of the present invention, Y is OR ² or H (hydrogen). In some embodiments of the present invention, R ¹ and R ² are independently selected from the group consisting of optionally substituted C ₁ -C ₆ alkyl, optionally substituted C _6-10 aryl, and optionally substituted 5-10 membered heteroaryl, or alternatively R ¹ and R ² together with the atoms to which they are attached, form a four to ten-membered heterocycle, optionally substituted with C ₁ -C ₆ alkyl. In some embodiments of the present invention, Y is OR ² and R ¹ and R ² are independently selected from the group consisting of optionally substituted C ₁ -C ₆ alkyl, optionally substituted aryl, and optionally substituted heteroaryl. In some embodiments of the present invention, Y is OR ² and R ¹ and R ² together with the atoms to which they are attached, form a four to ten-membered heterocycle, optionally substituted with C ₁ -C ₆ alkyl. In some embodiments of the present invention, Y is H (hydrogen) and R ¹ is selected from the group consisting of hydrogen, optionally substituted with C ₁ -C ₆ alkyl-C(O)-, optionally substituted with C ₁ -C ₆ alkyl-OCH ₂ - and optionally substituted phenyl-OCH ₂ -.

[0042] In some embodiments of the present invention, R ³ is selected from the group consisting of H, optionally substituted C ₁ -C ₆ alkyl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl.

. Например, в цидофовире R⁴ представляет собой

. В PMEA R⁴ представляет собой

.[0043] In some embodiments of the present invention, R ⁴ is a biological agent or part of a biological agent linked through a carbon or oxygen atom, for example, a nucleoside or nucleoside analogue. In some embodiments of the present invention, R ⁴ is part of R ⁴ monophosphate or monophosphonate therapeutic agent having the structure:

. For example, in cidofovir, R ⁴ is

. In PMEA R ⁴ is

.

[0044] In some embodiments of the present disclosure, R ⁵ is an optionally substituted aryl.

[0045] In some embodiments of the present invention, R ⁶ is independently selected from the group consisting of halogen, optionally substituted C ₁ -C ₆ alkyl, and optionally substituted C ₁ -C ₆ alkyloxy.

[0046] In some embodiments of the present invention, R ⁷ and R ⁸ are independently selected from the group consisting of H, optionally substituted C ₁ -C ₆ acyl, optionally substituted C ₁ -C ₆ alkyloxycarbonyl, and optionally substituted C ₁ -C ₆ carbamoyl.

[0047] In some embodiments of the present invention, X is O or NR ⁹ .

[0048] In some embodiments of the present invention, R ⁹ is selected from the group consisting of H (hydrogen), optionally substituted C ₁ -C ₆ alkyl-OCH ₂ - and optionally substituted phenyl-OCH ₂ -, or alternatively R ⁹ and R ¹ Together with the atoms to which they are attached, they form a five-membered heterocycle.

[0049] In some embodiments of the present invention, X is O or NH.

[0050] In some embodiments of the present invention, n is 1 or 2.

[0051] In some embodiments of the present invention, m is 0, 1, 2, or 3.

[0052] In some embodiments of the present invention, the phosphorus(n)amidate acetal and phosph(on)acetal compounds of formula I, II, III, IV, V, and VI are substrates of liver enzymes such as cytochrome p450 isoenzymes CYP3As (monooxygenase family), dehydrogenases, esterases and amidases.

[0053] CYP3A4 is expressed in the liver at a much higher level than in other tissues (DeWaziers et al. J Pharm Exp Ther 253:387 (1990)). The phosphorus(n)amidate acetal and phosph(one)acetal compounds of formulas I, II, III, IV, V and VI are predominantly activated by CYP3A4 in the liver. In some embodiments of the present invention, the compounds of formula I, II, III, IV, V and VI are highly effective in targeting the liver due to the selective delivery of biologically active agents to the liver. In some embodiments of the present invention, phosphorus(n)amidate acetal and phosph(one)acetal compounds are used to increase the therapeutic index of the drug, since the compounds of formulas I, II, III, IV, V and VI may be inactive or less active outside the liver.

[0054] In some embodiments of the present invention, due to the property of phosphorus(n)amidate acetal and phosph(on)acetal compounds of formulas I, II, III, IV, V and VI to target the liver, these compounds are used to treat diseases in which improved distribution drug in the liver and similar tissues and cells will be beneficial, including, but not limited to, liver diseases such as hepatitis, liver cancer, liver fibrosis, fatty liver, malaria, other viral and parasitic infections, and metabolic, cardiovascular vascular and/or hormonal diseases in which the liver is involved in the production and/or control of homeostasis of biochemical end products, such as glucose (eg, diabetes); cholesterol, fatty acids, bile acids, triglycerides (eg, hyperlipidemia, atherosclerosis, and obesity), lipoproteins, apolipoproteins, and sex hormone-binding globulin (SHBG).

[0055] In some embodiments of the present invention, the described compounds are used to improve pharmacokinetic properties, such as prolonging the half-life or enhancing drug absorption. In addition, the methodology described herein can be used to achieve sustained delivery of an active therapeutic agent. By enhancing the pharmacokinetic properties of the phosphorus(n)amidate acetal and phosph(on)acetal compounds of formulas I, II, III, IV, V and VI, these compounds are useful in the treatment of diseases that would benefit from improved drug properties, including but not limited to them, diseases such as HIV and cancer. In some embodiments, implementation of the present invention describes a method for obtaining these compounds. In some embodiments of the present invention, these compounds are also useful for delivering diagnostic imaging agents to the liver or other tissues.

[0056] Some compounds of formulas I, II, III, IV, V and VI have asymmetric centers where the stereochemistry may be uncertain, and diastereomeric mixtures of these compounds are included within the scope of the present invention, as well as individual stereoisomers when referring to the general compound formulas I, II, III, IV, V and VI.

[0057] Some embodiments of the compounds, compositions, and methods provided herein include a pharmaceutical composition containing a compound provided herein and a pharmaceutically acceptable carrier.

[0058] Some embodiments of the present invention also include administering an effective amount of a second or more therapeutic agents in combination with a compound provided herein to a subject in need thereof.

[0059] In some embodiments of the present invention, the subject is a mammal.

[0060] In some embodiments of the present invention, the subject is a human.

[0061] Some embodiments of the compounds, compositions, and methods described herein include a method for testing a compound in a cell, comprising contacting said cell with the compounds described herein.

[0062] Some embodiments of the compounds, compositions, and methods described herein include the use of a compound provided herein for the treatment of liver disease.

[0063] Some embodiments of the present invention include the use of a compound described herein in combination with additional therapeutic agent(s) for the treatment of liver disease.

[0064] Some embodiments of the compounds, compositions, and methods described herein include the use of a compound described herein for the treatment of a disease or condition by interfering with a molecular pathway in the liver.

[0065] Some embodiments of the present invention include the use of a compound described herein in combination with additional therapeutic agent(s) to treat a disease or condition by interfering with a molecular pathway in the liver.

[0066] Some embodiments of the compounds, compositions and methods described herein include the use of a compound described herein for the treatment of a non-liver related disease such as HIV infection or cancer.

[0067] Some embodiments of the present invention include the use of a compound described herein in combination with additional therapeutic agent(s) for the treatment of a non-liver related disease such as HIV infection or cancer.

[0068] In cases where the compounds described herein contain at least one chiral center, they may exist as single enantiomers and diastereomers, or as mixtures of such isomers, including racemates. Separation of individual isomers or selective synthesis of individual isomers is carried out using various methods well known in the art. Accordingly, unless otherwise indicated, all such isomers and mixtures thereof are included within the scope of the compounds described herein. In addition, the compounds of the present invention may exist in one or more crystalline or amorphous forms. Unless otherwise indicated, all such forms are included within the scope of the compounds described herein, including all polymorphic forms. In addition, according to the present invention, it is envisaged that some of the compounds described herein may be in the form of solvates in which the solvent is water (ie hydrates) or common organic solvents. Unless otherwise indicated, such solvates are included within the scope of the compounds described herein.

[0069] One of skill in the art will appreciate that some of the structures described herein may be resonance forms or tautomers of compounds that can be adequately described by other chemical structures, even in a kinetic sense; one skilled in the art will appreciate that such structures may represent a very small fraction of a sample of such compound(s). It is assumed that such compounds are included in the scope of the depicted structures, although such resonance forms or tautomers are not presented in the present text.

[0070] The described compounds may contain isotopes. Each chemical element present in the structure of a compound can include any isotope of that element. For example, in the structure of a compound, a hydrogen atom may be explicitly described or implied to be present in the compound. At any position on the compound where a hydrogen atom may be present, said hydrogen atom may be any isotope of hydrogen, including, but not limited to, hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference to a compound herein includes all possible isotopic forms unless the context clearly dictates otherwise.

Definitions

[0071] As used herein and as used herein, the following terms are defined by the following meanings, unless expressly stated otherwise. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and do not limit the spirit of the claimed invention. In this document, the use of the singular includes the plural unless specifically stated otherwise. In this document, the use of "or" means "and/or" unless otherwise indicated. In addition, the use of the term "including" as well as other forms such as "includes" and "included" is not limiting.

[0072] As used herein, ranges and amounts may be expressed as "about" a certain value or range. "About" also includes the exact amount. Therefore, "about 10%" means "about 10%" as well as "10%".

[0073] As used herein, the term "optionally" means that the subsequently described event or circumstance occurs or does not occur, and that the description of the present invention includes cases where the specified event or circumstance occurs, and cases in which the specified event or circumstance has no place. For example, "optionally substituted group" means that the specified group is unsubstituted or substituted.

[0074] As used herein, terms in the singular include the plural unless the context clearly indicates otherwise. Thus, for example, reference to a composition containing a "therapeutic agent" includes compositions with one or more therapeutic agents.

[0075] As used herein, "C _a - C _b " or "C _ab ", where "a" and "b" are integers, refer to the number of carbon atoms in the specified group. That is, such a group may contain from "a" to "b", inclusive, carbon atoms. Accordingly, for example, "C ₁ -C ₄ alkyl" or "C _1-4 alkyl" refers to all alkyl groups containing from 1 to 4 carbon atoms, i.e. CH ₃ -, CH ₃ CH ₂ -, CH ₃ CH ₂ CH ₂ -, (CH ₃ ) ₂ CH-, CH ₃ CH ₂ CH ₂ CH ₂ -, CH ₃ CH ₂ CH (CH ₃ ) - and (CH ₃ ) ₃ C-.

[0076] As used herein, the term "alkyl" refers to a straight or branched hydrocarbon chain that is fully saturated (i.e., free of double and triple bonds). The alkyl group may contain from 1 to 20 carbon atoms (whenever referred to herein, a numerical range such as "1 to 20" refers to each integer in the given range; for example, "1 to 20 carbon atoms "means that an alkyl group may consist of 1 carbon, 2 carbons, 3 carbons, etc., up to 20 carbons, although this definition also covers those cases where no numerical value is designated for the term" alkyl ". range). The alkyl group may also be a medium sized alkyl having 1 to 9 carbon atoms. The alkyl group may also be a lower alkyl having 1 to 4 carbon atoms. The alkyl group may be referred to as "C ₁ -C ₄ alkyl" or other similar designation. By way of example only, "C ₁ -C ₄ alkyl" indicates that the alkyl chain contains from one to four carbon atoms, i. the alkyl chain is selected from the group consisting of the following: methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl. Representative alkyl groups include, but are by no means limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.

[0077] As used herein, a substituted group is derived from an unsubstituted parent group in which one or more hydrogen atoms have been replaced with another atom or group. Unless otherwise stated, when a group is considered "substituted", this means that the specified group contains one or more substituents independently selected from C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₇ carbocyclyl (optionally substituted with halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and C ₁ -C ₆ haloalkoxy), C ₃ -C ₇ carbocyclyl-C ₁ -C ₆ -alkyl (optionally substituted with halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and C ₁ -C ₆ haloalkoxy), 3-10 membered heterocyclyl (optionally substituted with halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and C ₁ -C ₆ haloalkoxy), 3-10 membered heterocyclyl-C ₁ -C ₆ -alkyl (optionally substituted with halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and C ₁ -C ₆ haloalkoxy), aryl (optionally substituted with halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and C ₁ -C ₆ haloalkoxy), aryl(C ₁ -C ₆ )alkyl (optionally substituted with halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and C ₁ -C ₆ haloalkoxy), 5-10 membered heteroaryl (optionally substituted with halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and C ₁ -C ₆ haloalkoxy), 5-10 membered heteroaryl( C ₁ -C ₆ )alkyl (optionally substituted with halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and C ₁ -C ₆ haloalkoxy), halogen, cyano, hydroxy, C ₁ - C ₆ alkoxy, C ₁ -C ₆ alkoxy (C ₁ -C ₆ )alkyl (e.g. ether), aryloxy (optionally substituted with halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and C ₁ -C ₆ haloalkoxy), C ₃ -C ₇ carbocyclyloxy (optionally substituted with halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and C ₁ -C ₆ haloalkoxy), 3 -10 membered heterocyclyloxy (optionally substituted with halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and C ₁ -C ₆ haloalkoxy), 5-10 membered heteroaryl oxy ( optionally substituted with halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and C ₁ -C ₆ haloalkoxy), C ₃ -C ₇ carbocyclyl-C ₁ -C ₆ alkoxy (optional substituted with halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and C ₁ -C ₆ haloalkoxy), 3-10 membered heterocyclyl-C ₁ -C ₆ alkoxy (optionally substituted with halogen , C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and C ₁ -C ₆ haloalkoxy), aryl (C ₁ -C ₆ )alkoxy (optionally substituted with halogen, C ₁ -C ₆ alkyl , C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and C ₁ -C ₆ haloalkoxy), 5-10 membered heteroaryl (C ₁ -C ₆ ) alkoxy (optionally substituted with halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and C ₁ -C ₆ haloalkoxy), sulfhydryl (mercapto), halogen(C ₁ -C ₆ )alkyl (for example, -CF ₃ ), halo(C ₁ -C ₆ )alkoxy (for example, -OCF ₃ ), C ₁ -C ₆ alkylthio, arylthio (optionally substituted with halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and C ₁ -C ₆ haloalkoxy ), C ₃ -C ₇ carbocyclylthio (optionally substituted with halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and C ₁ -C ₆ haloalkoxy), 3-10 membered heterocyclylthio (optionally substituted with halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and C ₁ -C ₆ haloalkoxy), 5-10 membered heteroaryl-thio (optionally substituted with halogen, C ₁ - C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and C ₁ -C ₆ haloalkoxy), C ₃ -C ₇ -carbocyclyl-C ₁ -C ₆ -alkylthio (optionally substituted with halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and C ₁ -C ₆ haloalkoxy), 3-10 membered heterocyclyl-C ₁ -C ₆ alkylthio (optionally substituted with halogen, C ₁ -C ₆ alkyl , C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and C ₁ -C ₆ haloalkoxy), aryl (C ₁ -C ₆ )alkylthio (optionally substituted with halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy , C ₁ -C ₆ haloalkyl and C ₁ -C ₆ haloalkoxy), 5-10 membered heteroaryl (C ₁ -C ₆ )alkylthio (optionally substituted with halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and C ₁ -C ₆ haloalkoxy), amino, amino (C ₁ -C ₆ ) 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). Where a group is described as "optionally substituted", the group may contain the above substituents.

[0078] As used herein, the term "acyl" refers to -C(=O)R, where R is hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 carbocyclyl, C aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl as defined herein. Non-limiting examples include formyl, acetyl, propanoyl, benzyl, and acrylic.

[0079] The group "O-carboxy" refers to the group "-OC(=O)R", where R is selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 carbocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl as defined herein.

[0080] The group "C-carboxy" refers to the group "-C(=O)R", where R is selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 carbocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl as defined herein. A non-limiting example includes carboxyl (ie -C(=O)OH).

[0081] The "cyano" group refers to the "-CN" group.

[0082] The "cyanato" group refers to the "-OCN" group.

[0083] The "isocyanato" group refers to the "-NCO" group.

[0084] The "thiocyanato" group refers to the "-SCN" group.

[0085] The "isothiocyanato" group refers to the "-NCS" group.

[0086] The group "sulfinyl" refers to the group "-S(=O)R", in which R is selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 carbocyclyl , C _6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl as defined herein.

[0087] The group "sulfonyl" refers to the group "-SO ₂ R", where R is selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 carbocyclyl, C _{6- 10} aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl as defined herein.

[0088] The "S-sulfonamido" group refers to the "-SO ₂ NR _A R _B " group, wherein R _A and R _B are each independently selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _{2- 6} alkynyl, C _3-7 carbocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl as defined herein.

[0089] The group "N-sulfonamido" refers to the group "-N(R _A )SO ₂ R _B ", where each of R _A and R _b is independently selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 carbocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

[0090] The "O-carbamyl" group refers to the "-OC(=O)NR _A R _B " group, where R _A and R _B are each independently selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 carbocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl as defined herein.

[0091] The group "N-carbamyl" refers to the group "-N(R _A )C(=O)OR _B ", where each of R _A and R _B is independently selected from hydrogen, C _1-6 alkyl, C _{2- 6} alkenyl, C _2-6 alkynyl, C _3-7 carbocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl as defined herein.

[0092] The group "O-thiocarbamyl" refers to the group "-OC(=S)NR _A R _B ", where each of R _A and R _B is independently selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 carbocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl as defined herein.

[0093] The group "N-thiocarbamyl" refers to the group "-N(R _A )C(=S)OR _B ", where each of R _A and R _B is independently selected from hydrogen, C _1-6 alkyl, C _{2- 6} alkenyl, C _2-6 alkynyl, C _3-7 carbocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl as defined herein.

[0094] The group "C-amido" refers to the group "-C(=O)NR _A R _B ", where each of R _A and R _B is independently selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 carbocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl as defined herein, each of which is optionally substituted with one or more substituents selected from a group consisting of -OH, C _1-6 alkyl, C _3-7 carbocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, C _1-6 alkyl, optionally substituted with C _{1- 6} alkoxy or -OH; and C _1-6 alkoxy optionally substituted with C _1-6 alkoxy or -OH.

[0095] The group "N-amido" refers to the group "-N(R _A )C(=O)R _B ", where each of R _A and R _B is independently selected from hydrogen, C _1-6 alkyl, C _{2- 6} alkenyl, C _2-6 alkynyl, C _3-7 carbocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl as defined herein, each of which is optionally substituted with one or more substituents selected from the group consisting of -OH, C _1-6 alkyl, C _3-7 carbocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, C _1-6 alkyl, optionally substituted C _1-6 alkoxy or -OH and C _1-6 alkoxy optionally substituted with C _1-6 alkoxy or -OH.

[0096] The group "amino" refers to the group "-NR _A R _B ", where each of R _A and R _B is independently selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 carbocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl as defined herein. A non-limiting example includes a free amino group (ie -NH ₂ ).

[0097] An "aminoalkyl" group refers to an amino group attached through an alkylene group.

[0098] The "alkoxyalkyl" group refers to an alkoxy group attached through an alkylene group, such as "C _2-8 alkoxyalkyl" and the like.

[0099] The term "acyloxy" refers to the group -OC(O)R, where R is alkyl.

[0100] The term "alkoxy" or "alkyloxy" refers to the group OR, where R is an optionally substituted alkyl or heteroalkyl.

[0101] The term "carboxyl" refers to a C(O)OH group.

[0102] the Term "oxo" refers to the group =O.

[0103] The term "halogen" or "halo" refers to F (fluorine), Cl (chlorine), Br (bromine), and I (iodine).

[0104] The term "haloalkyl" refers to alkyl groups containing at least one halogen atom, in an additional aspect they contain from 1 to 3 halogen atoms. Suitable halogen atoms include F, Cl and Br.

[0105] The term "haloacyl" refers to -C(O)-haloalkyl groups.

[0106] The term "alkenyl" refers to unsaturated groups containing from 2 to 12 atoms and at least one carbon-carbon double bond, and includes straight chain, branched chain and cyclic groups. Alkenyl groups may optionally be substituted. Suitable alkenyl groups include allyl.

[0107] The term "alkynyl" refers to unsaturated groups containing from 2 to 12 atoms and at least one carbon-carbon triple bond, and includes straight chain, branched chain and cyclic groups. Alkynyl groups may optionally be substituted. Suitable alkynyl groups include ethynyl.

[0108] As used herein, the term "aryl" refers to an aromatic ring or ring system (i.e., two or more fused rings with a common pair of adjacent carbon atoms) containing only carbon in the backbone of the rings. If aryl is a ring system, each ring in the system is aromatic. An aryl group may contain from 6 to 18 carbon atoms, although the present definition also covers those cases where the term "aryl" is given without specifying a numerical range. According to some variants of implementation of the present invention, the aryl group contains from 6 to 10 carbon atoms. An aryl group may be referred to as "C _6-10 aryl", "C ₆ or C ₁₀ aryl" or similar designations. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.

[0109] As used herein, the term "heteroaryl" refers to an aromatic ring or ring system (i.e., two or more fused rings with a common pair of adjacent atoms) which(s) contains or contains in the ring backbone one or more heteroatoms representing are elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur. When heteroaryl is a ring system, each ring in the system is aromatic. A heteroaryl group may contain 5-18 ring members (i.e., the number of ring backbone atoms, including carbon atoms and heteroatoms), although the present definition also covers those cases where the term "heteroaryl" is given without specifying a numerical range. In some embodiments of the present invention, the heteroaryl group has 5 to 10 ring members or 5 to 7 ring members. The heteroaryl group may be referred to as "5-7 membered heteroaryl", "5-10 membered heteroaryl", or using similar designations. Heteroaryl groups may optionally be substituted. Examples of heteroaryl groups include, but are not limited to, aromatic C _3-8 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 their substituted derivatives, as well as benzo- and pyrido-fused derivatives, for example, linked through one of the carbon atoms forming the ring. In some embodiments of the present invention, the heteroaryl groups are optionally substituted with one or more substituents independently selected from halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, C _1-6 alkoxy, C _1-6 alkyl, C _1-6 -hydroxyalkyl, C _1-6 -aminoalkyl, C _1-6 -alkylamino, alkylsulphenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl or trifluoromethyl. Examples of heteroaryl groups include, but are not limited to, unsubstituted and mono- or disubstituted derivatives of furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole , indazole, tetrazole, quinoline, isoquinoline, pyridazine, pyrimidine, purine and pyrazine, furazan, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, triazole, benzotriazole, pteridine, phenoxazole , oxadiazole, benzopyrazole, quinolysine, cinnoline, phthalazine, quinazoline and quinoxaline. In some embodiments of the present invention, these substituents are halogen, hydroxy, cyano, O-C _1-6 -alkyl, C _1-6 -alkyl, hydroxy-C _1-6 -alkyl and amino-C _1-6 -alkyl.

[0110] As used herein, the term "cycloalkyl" refers to a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. A cycloalkyl group may contain from 3 to 10 carbon atoms (whenever referred to herein, a numerical range such as "3-10" denotes each integer in that range). A cycloalkyl group may be referred to as "C ₃ -C ₈ cycloalkyl" or other similar designation. By way of example only, "C ₃ -C ₈ cycloalkyl" means that the carbocyclyl ring or ring system contains from three to eight carbon atoms.

[0111] As used herein, the term "heterocyclyl" refers to a non-aromatic cyclic ring or ring system containing at least one heteroatom in the ring. Heterocyclyls can be linked to form a fused, bridged, or spiro system. Heterocyclyls may have any degree of saturation, provided that at least one ring in the ring system is non-aromatic. The heteroatom or heteroatoms may be present in both the non-aromatic and the aromatic ring of the ring system. The heterocyclyl group may contain from 3 to 20 ring members (i.e., the number of atoms that make up the backbone of the ring, including carbon atoms and heteroatoms), although the present definition also covers those cases where the term "heterocyclyl" is given without specifying a numerical range. The heterocyclyl group may also be a medium sized heterocyclyl containing 3 to 10 ring members. The heterocyclyl group may also be a heterocyclyl having 3 to 6 ring members. The heteroaryl group may be referred to as "3-6 membered heterocyclyl" or using similar designations. In preferred six-membered monocyclic heterocyclyls, the heteroatom(s) is(are) selected from one to three O (oxygen), N (nitrogen), or S (sulphur), and in preferred five-membered monocyclic heterocyclyls, the heteroatom(s) are(s) selected from one or two heteroatoms selected from O (oxygen), N (nitrogen) or S (sulfur). Examples of heterocyclic rings include, but are not limited to: azepenyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanil, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-pi peridonil, pyrazolinil, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl, 1,4-oxathiinyl, 1,4-oxathianyl, 2H-1,2- oxazinyl, trioxanyl, hexahydro-1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl and tetrahydroquinoline.

[0112] It should be understood that some radical names may include monovalent radicals or divalent radicals, depending on the context. For example, in the case where a substituent requires two points of attachment to the rest of the molecule, it is understood that this substituent is divalent. For example, a substituent defined as alkyl that requires two points of attachment includes divalent radicals such as -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH(CH ₃ )CH ₂ - and the like. Other radical naming systems explicitly indicate that the radical is divalent, such as "alkylene" or "alkenylene".

[0113] When it is said that two R groups form a ring (e.g., a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring) "together with the atoms to which they are attached", this means that the common unit consisting of the indicated atoms and two groups R is the specified ring. Said ring is not otherwise limited by any definition of each R group taken alone. For example, when the following substructure is present:

and R ¹ and R ² are defined as being selected from the group consisting of alkyl and aryl, or R ¹ and R ² together with the oxygen atom to which they are each attached, form heterocyclyl, which means that R ¹ and R ² can be are selected from alkyl or aryl, or alternatively the substructure has the structure:

where Ring A is a heterocyclic ring containing the depicted oxygen atoms.

[0114] Similarly, when it is said that two "adjacent" R groups form a ring "together with the atom to which they are attached", this means that the common unit, consisting of said atoms, intermediate bonds, and these two R groups, represents the indicated ring. For example, when the following substructure is present:

and R ¹ and R ² are defined as being selected from the group consisting of hydrogen and alkyl, or R ¹ and R ² together with the atoms to which they are attached form aryl or carbocyclyl, which means that R ¹ and R ² can be selected from hydrogen or alkyl, or alternatively the substructure has the structure:

where A is an aryl ring or a carbocyclyl containing the depicted double bond.

, включает заместитель, ориентированный так, что A присоединен в крайней левой точке присоединения молекулы, а также случай, когда A присоединен в крайней правой точке присоединения молекулы.[0115] In cases where the substituent is in the form of a diradical (i.e., has two points of attachment to the rest of the molecule), it should be understood that the specified substituent can be attached in any directional configuration, unless otherwise indicated. So, for example, a substituent designated as -AE- or

, includes a substituent oriented so that A is attached at the leftmost point of attachment of the molecule, as well as the case where A is attached at the rightmost point of attachment of the molecule.

[0116] The expression "therapeutically effective amount" means an amount of a compound or combination of compounds that partially or completely improves, reduces or eliminates one or more of the symptoms of a particular disease or condition, or prevents, modifies or delays the onset of one or more symptoms of a particular disease or condition . Such an amount may be administered as a single dose, or may be administered according to a regimen in which it will be effective. Repeated administration may be required to achieve the desired result (eg, treatment of the disease and/or condition).

[0117] The term "pharmaceutically acceptable salt" includes salts of compounds of formulas I, II, III and IV, obtained by combining the compounds according to the presented embodiments of the present invention and an organic or inorganic acid or base. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be formed include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be formed include, for example, acetic acid, adipic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid , p-toluenesulfonic acid, (+)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-methanesulfonic acid, 1,2-ethanedisulfonic acid, dodecylsulfonic acid, salicylic acid, glucoheptonic acid, gluconic acid, glucuronic acid, hippuric acid, hydrochloride hemiethanolic acid, 2-hydroxyethanesulfonic acid, lactic acid, lactobionic acid, methyl bromide acid, methyl sulfuric acid, 2-naphthalenesulfonic acid, oleic acid, 4,4'-methylenebis-[3 -hydroxy-2-naphthalenecarboxylic acid], polygalacturonic acid, stearic acid, sulfosalicylic acid, tannic acid, terphthalic acid, and the like. Inorganic bases from which salts can be formed include, for example, bases containing sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. In some embodiments of the present invention, treatment of the compounds described herein with an inorganic base results in the loss of labile hydrogen from said compound to form a salt containing an inorganic cation such as Li ⁺ , Na ⁺ , K ⁺ , Mg ²⁺ and Ca ²⁺ and so on. Organic bases from which salts may be formed include, for example, primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, such as, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine.

[0118] In the event that the number of any specific substituents is not specified (eg, "haloalkyl"), one or more substituents may be present. For example, "haloalkyl" may contain one or more of the same or different halogens. For example, "haloalkyl" contains each of the substituents CF ₃ , CHF ₂ and CH ₂ F.

[0119] The term "patient" refers to an animal that is being treated, including mammals such as dog, cat, cow, horse, sheep, and human. In some embodiments of the present invention, the patient is a mammal: male or female. In some embodiments of the present invention, the patient is a human male or female.

[0120] The term "prodrug" as used herein refers to any compound that, when introduced into a biological system, forms a biologically active compound as a result of a spontaneous chemical reaction(s), an enzyme-catalyzed chemical reaction(s) and/or a metabolic chemical reaction. (reactions) or combinations thereof. Standard prodrugs are prepared using groups associated with functional groups, eg HO-, HS-, HOOC-, HOOPR2-, associated with the drug, which are cleaved in vivo. Standard prodrugs include, but are not limited to, carboxylate esters, where said group is alkyl, aryl, aralkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and hydroxyl, thiol, and amine esters, where the attached group is an acyl group, alkoxycarbonyl, aminocarbonyl, or sulfate. The groups given are not exhaustive examples, and other known types of prodrugs can be prepared by one skilled in the art. Prodrugs must undergo some chemical transformation to obtain a compound that is a biologically active compound or is a precursor of a biologically active compound. In some cases, the prodrug is biologically active, usually less active than the drug itself, and serves to increase the efficacy or safety of the drug through improved oral bioavailability, pharmacodynamic half-life, and so on. Prodrug forms of compounds may be used, e.g. to improve bioavailability, improve subject tolerance, e.g. by masking or reducing unpleasant characteristics such as bitter taste or gastrointestinal irritation, change in solubility, e.g. or delivering, facilitating formulation of the dosage form, or providing delivery of the compound to a specific site.

[0121] The term "stereoisomer" refers to the relative or absolute spatial ratio of the R group(s) attached to the stereogenic centers of carbon atoms or phosphorus atoms, and refers to a single isomer or any combination of individual isomers, such as a racemic mixture and a mixture of diastereomers. When a compound has two stereogenic centers, there are 4 potential stereoisomers.

[0122] The term "liver" refers to the liver organ.

[0123] The term "liver specificity" refers to the ratio of:

[drug or its metabolite in liver tissue] /

[drug or its metabolite in blood or other tissue]

when measured in animals treated with the drug or prodrug. The ratio may be determined by measuring tissue levels at a specific time, or it may be an AUC (area under the curve) based on values measured at three or more time points.

[0124] The term "enhanced or increased liver specificity" refers to an increase in the ratio of liver specificity in prodrug-treated animals to liver specificity in parent drug-treated animals.

[0125] The term "increased oral bioavailability" refers to an increase in absorption of a dose of a comparative drug by at least about 50%. In a further aspect, an increase in oral bioavailability of a compound (compared to a comparative drug) means an increase in absorption of at least about 100%, or a doubling of absorption. Measurement of oral bioavailability generally refers to measurements of the level of a prodrug, drug, or drug metabolite in blood, plasma, tissues, or urine after oral administration compared to measurements after parenteral administration.

[0126] The term "therapeutic index" refers to the ratio of the dose of a drug or prodrug that elicits a therapeutically favorable response compared to the dose that elicits an undesirable response such as death, elevation of markers that indicate toxicity, and/or pharmacological side effects. effects.

[0127] The term "sustained delivery" refers to an increase in the period during which there is a prolongation of therapeutically effective drug levels due to the presence of a prodrug.

[0128] The terms "treat" or "treatment" of a disease include inhibiting the disease (slowing, stopping, or partially stopping its progression), preventing the disease, alleviating the symptoms or side effects of the disease (including palliative care), and/or alleviating the disease (causing regression of the disease) .

[0129] The term "biological agent" refers to a compound that has biological activity or properties that can be used for therapeutic or diagnostic purposes, for example, a compound that carries a radioactive isotope or heavy atom. In some embodiments of the present invention, the specified biological agent may be part of a monophosphate, diphosphate or triphosphate therapeutic agent, while the specified part is a nucleoside or nucleoside analogue. In some embodiments of the present invention, said biological agent may be a portion of a monophosphate therapeutic agent and the corresponding diphosphate or triphosphate, wherein said portion is a nucleoside or nucleoside equivalent. In some embodiments of the present invention, the specified biological agent may be part of a monophosphonate therapeutic agent and the corresponding monophosphate or diphosphate, while the specified part is the equivalent of a nucleoside. Table 2 lists the biological agents that can be enhanced with phosphor(n)amidate acetal and phosph(one)acetal compounds of formula I.

Table 2 Known nucleosides and nucleoside analogs with antiviral and antitumor activity

[0130] The term "molecular pathway" refers to a set of molecular events in tissues, such as a receptor modulation sequence, an enzyme modulation sequence, or a biosynthetic sequence that is involved in the physiological or pathophysiological functions of a living animal.

Introduction and pharmaceutical compositions

[0131] The compounds described herein can be used alone or in combination with other treatments. When these compounds are used in combination with other agents, they can be administered as a daily dose or an appropriate fraction of the daily dose (eg twice a day). The compounds may be administered after a course of treatment with another agent, during a course of therapy with another agent, may be administered as part of a treatment regimen, or may be administered prior to therapy with another agent in a treatment program.

[0132] 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, napsilate, nitrate, oleate, palmoate, phosphate, polygalacturonate, stearate, succinate, sulfate, sulfosalicylate, tannate, tartrate, terphthalate, tosylate, and triethiodide.

[0133] Compositions containing active ingredients may be in any form suitable for the intended route of administration. In some embodiments of the present invention, the compounds, methods and/or compositions described herein can be provided via oral administration, rectal administration, transmucosal administration, intestinal administration, enteral administration, topical administration, transdermal administration, intrathecal administration, intraventricular administration, intraperitoneal administration. administration, intranasal administration, intraocular administration and/or parenteral administration.

[0134] When the compounds are administered orally, for example, tablets, shaped lozenges, lozenges for sucking, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs can be obtained. Compositions intended for oral administration may be prepared according to any method known in the art for the manufacture of a pharmaceutical composition and such compositions may contain one or more agents, including sweeteners, flavoring agents, coloring agents, and preservatives, in order to provide a composition that is pleasant to the touch. taste. Suitable tablets are those containing the active ingredient in admixture with a non-toxic pharmaceutically acceptable excipient which is suitable for the manufacture of tablets. These fillers may be, for example, inert diluents such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents such as cornstarch or alginic acid; binding agents such as starch, gelatin or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known methods, including microencapsulation, to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained release over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate, alone or with wax, may be used.

[0135] Compositions for oral administration may also be presented as hard gelatin capsules in which the active ingredient(s) can be mixed with an inert solid diluent such as calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oily medium such as peanut butter, liquid paraffin or olive oil.

[0136] Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injectable solutions, which may contain, for example, antioxidants, buffers, bacteriostatics, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickeners. Formulations may be presented in single-dose or multi-dose sealed containers, such as sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) state when only the addition of a sterile liquid carrier, such as water for injection, is required immediately prior to use. Injectable solutions and suspensions can be prepared from sterile powders, granules and tablets of the type previously described.

[0137] In some embodiments of the present invention, unit dosage forms contain a daily dose or drug unit, a daily subdose, or an appropriate proportion. However, it will be understood that the specific dosage level for any particular patient will depend on a variety of factors, including the potency of the particular compound being used; age, body weight, general health, sex and diet of the patient; time and route of administration; withdrawal speed; other drugs that were previously administered; and the severity of the particular disease being treated, as is well known to those skilled in the art.

[0138] The actual dose of the compounds described herein depends on the particular compound and the condition being treated; the selection of the appropriate dose is within the skill of the skilled artisan. In some embodiments of the present invention, the daily dose may be from about 0.1 mg/kg of body weight to about 100 mg/kg or more, from about 0.25 mg/kg or less to about 50 mg/kg, from about 0. 5 mg/kg or less to about 25 mg/kg, from about 1.0 mg/kg to about 10 mg/kg of body weight. Thus, for administration to a 70 kg human, the dosage range may be from about 7 mg per day to about 7000 mg per day, from about 35 mg per day or less to about 2000 mg per day or more, from about 70 mg per day to 1000 mg per day.

Methods of treatment

[0139] 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 status, HIV and various types of cancer using the compounds described herein, and compositions containing these compounds. Some methods include administering a compound, composition, pharmaceutical composition described herein to a subject in need thereof. According to some variants of implementation of the present invention, the subject may be an animal, for example, a mammal, a human. In some embodiments of the present invention, the subject is a human.

[0140] Additional embodiments of the present invention include administering a combination of compounds to a subject in need thereof. The combination may include a compound, composition, pharmaceutical composition described herein with an additional drug.

[0141] Some embodiments of the present invention include the co-administration of a compound, composition and/or pharmaceutical composition described herein with an additional drug or additional therapeutic agents. By "co-administration" is meant that two or more agents can be detected in the blood of a subject at the same time, regardless of how they were actually administered. According to one embodiment of the present invention, the agents are administered simultaneously. In one such embodiment, the implementation of the present invention, the introduction in combination is carried out by combining agents in a single dosage form. In another embodiment of the present invention, the agents are administered sequentially. According to one embodiment of the present invention, these agents are administered by the same route, such as the oral route. In another embodiment of the present invention, the agents are administered by various routes, for example, one is administered orally and the other is administered intravenously.

[0142] Examples of additional drugs include therapeutic agent(s) selected from the group consisting of thymosin alfa-1, interferon-λ, HCV protease inhibitor, NS5A HCV replication complex inhibitor, NS5B HCV polymerase inhibitor, HCV helicase inhibitor , cyclophilin inhibitor, inosine monophosphate dehydrogenase inhibitor, ribavirin, interferon-α and pegylated interferon-α. In some embodiments of the present invention, additional drugs include one or more of cobicistat, emtricitabine, and elvitegravir. In some embodiments of the present invention, additional drugs include two or more of cobicistat, emtricitabine and elvitegravir. In some embodiments of the present invention, additional drugs include cobicistat, emtricitabine, and elvitegravir. In some embodiments of the present invention, the additional drugs include one or more of ribavirin, peginterferon-alpha, simeprevir, ledipasvir, and daclatasvir. In some embodiments of the present invention, the specified additional therapeutic agent may be one or more of cobicistat, emtricitabine and elvitegravir. In some embodiments of the present invention, the specified additional therapeutic agent may be two or more of cobicistat, emtricitabine and elvitegravir. In some embodiments of the present invention, the specified additional therapeutic agent may be cobicistat, emtricitabine and elvitegravir. In some embodiments of the present invention, said additional therapeutic agent is one or more of ribavirin, peginterferon-alpha, simeprevir, ledipasvir, and daclatasvir. In some embodiments of the present invention, said additional therapeutic agent for the treatment of HBV can be one or more of an HBV entry inhibitor, an HBV covalently continuous cDNA inhibitor, an HBV capsid inhibitor, an interferon, an inhibitor of HBV assembly. In some embodiments of the present invention, said additional therapeutic agent for the treatment of HCC may be one or more of sorafenib, regorafenib, an immuno-oncological agent such as a PD-1 or PD-L1 checkpoint inhibitor.

[0143] To further illustrate the present invention, the following examples are given. These examples are not to be construed as limiting the present invention in any way. Variants of these examples within the scope of the claims are within the purview of a person skilled in the art and are considered to be within the scope of the invention as described and claimed herein. The reader will appreciate that a person skilled in the art, armed with this document and knowledge of the art, can prepare and apply the present invention without overarching examples.

Synthesis of compounds

[0144] The following procedures for the preparation of novel compounds illustrate the general procedures used for the preparation of phosphorus(n)amidate acetal and phosph(one)acetal drugs. The protecting group can be introduced at various stages of drug synthesis. In some embodiments of the present invention, they are introduced at a later stage due to the general sensitivity of these groups to different reaction conditions. Optically pure compounds containing a single isomer at the phosphorus center can be obtained, for example, by separation of diastereomers using a combination of column chromatography and/or crystallization, or by enantioselective synthesis of chirally activated phosph(on)ate intermediates.

[0145] Scheme I shows general strategies for the synthesis of compounds of formula I. A compound of structure 1 is condensed with an optionally substituted phenol or naphthol of structure 2 in the presence of a base to give a product of structure 3. The acetal compound of structure 4 is prepared from the corresponding aldehyde by standard procedures described in the literature. . Reaction of compounds of structures 3 and 4 in the presence of a base gives the final product of structure 5. Alternatively, the aryloxyphosphate chloride of structure 6 combines with an acetal compound of structure 4 to form an intermediate of structure 7, which is reacted with a compound of structure 8 containing an active agent to obtain the final product of structure 5.

Scheme I

EXAMPLES

[0146] Certain compounds of formulas I, II, III, IV, V, and VI are prepared as follows.

Example 1

[0147] (2R,3R,4R,5R)-2-(((((S)-1-(1,3-dioxolan-2-yl)ethyl)amino)(phenoxy)phosphoryl)oxy)methyl) -5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-4-methyltetrahydrofuran-3-yl propionate (compound 101)

[0148] Compound 101 was prepared according to scheme I from phenyl phosphorodichloridate, (S)-N-Cbz-2-aminopropanol and 2'-deoxy-2'-fluoro-2'-C-methyl-3'-propionyloxyuridine as follows .

(S)-N-Cbz-2-aminopropanol:

[0149] (S)-N-Cbz-2-aminopropanol (10 g, 48 mmol) and 2-iodoxybenzoic acid (IBX) (34 g, 120 mmol) in EtOAc (300 ml) were refluxed for 2- 4 hours. After completion of the reaction (monitoring by TLC), IBX was filtered through celite. The filtrate was concentrated to dryness in vacuo to give the product (9.5 g, 94%).

[0150] (S)-1-(1,3-dioxolan-2-yl)-ethane-1-amine:

[0151] A mixture in the form of a suspension of the above aldehyde (5.0 g, 24 mmol), ethylene glycol (7.6 g, 122 mmol), PPTS (0.6 g, 2.4 mmol) and triethyl orthoformate (3.6 g, 24 mmol) in toluene (50 ml) was stirred at 80°C for 12 hours. Then the specified reaction mixture was successively washed with aq. HCl (1 M), NaHCO ₃ (sat.) and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was chromatographed on silica gel (PE:EA=4:1) to give the protected N-Cbz product, 50% yield (3.0 g). A suspension mixture of N-Cbz-amine (2 g) and activated Pd/C (20 wt%) in ethyl acetate (30 ml) was stirred overnight at room temperature in the presence of hydrogen gas (H2 balloon). The Pd/C was filtered through Celite and the filtrate was concentrated to dryness in vacuo to give the product.

[0152] Phenyl ((S)-1-(1,3-dioxolan-2-yl)-3-methylbutyl)phosphoramidochloridate:

[0153] To a solution of phenylphosphoric dichloridate (0.4 g, 1.9 mmol) in dichloromethane at -78°C was added the above compound (0.2 g, 1.7 mmol) in the presence of excess triethylamine, and the resulting mixture was stirred for 2 hours. The standard work-up procedure allowed the crude product to be obtained in ~60% yield (0.3 g).

[0154] Connection 101:

[0155] To a solution of the crude phenylphosphoramidochloridate in dichloromethane (0.5 ml) was added a solution of 2'-deoxy-2'-fluoro-2'-C-methyl-3'-propionyloxyuridine (0.2 g, 1.2 mmol) and N-methylimidazole (0.4 g, 5 mmol) in dichloromethane (0.5 ml) at -78° C. under nitrogen. This mixture was then allowed to slowly warm to room temperature and stirred for 1 hour. Standard workup followed by HPLC afforded compound 101 as a 3:2 mixture of two diastereomers (120 mg, 44%).

[0156] [M+H] ⁺ calculated for C ₂₄ H ₃₁ FN ₃ O ₁₀ P: 572.18; found: 572.05. ¹ H NMR (300 MHz, CD ₃ OD) 7.68 (d, J = 8.1, 1H) (large), 7.62 (d, J = 8.1, 1H) (small), 7.40 - 7.10 (m, 5H), 5.68 (d, J = 8.1, 1H) (large), 5.49 (d, J = 8.1, 1H) (small), 1.34 ( d, J = 22.5, 3H) (large), 1.33 (d, J = 22.5, 3H) (small).

Example 2

[0157] ((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2 -yl)methylphenyl (S)-((S)-1-(1,3-dioxolan-2-yl)-3-methylbutyl)phosphoramidate (compound 102)

[0158] Compound 102 was obtained in accordance with scheme I, similarly as described in example 1, from phenylphosphoric dichloridate, (S)-N-Cbz-2-amino-4-methylpentanol and 2'-deoxy-2'-fluoro- 2'-C-methyluridine. [M+H] ⁺ calculated for C ₂₄ H ₃₃ FN ₃ O ₉ P: 558.20; found: 558.35.

Example 3

[0159] ((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2 -yl)methylphenyl (R)-((S)-1-(1,3-dioxolan-2-yl)-3-methylbutyl)phosphoramidate (compound 103)

[0160] Compound 103 was isolated as a minor diastereomer from Example 2. [M+H] ⁺ calculated for C ₂₄ H ₃₃ FN ₃ O ₉ P: 558.20; found: 558.30.

Example 4

[0161] 2,3-dimethylphenyl ((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy- 4-methyltetrahydrofuran-2-yl)methyl ((S)-1-(1,3-dioxepan-2-yl)ethyl)phosphoramidate (compound 104)

[0162] Compound 104 was obtained as a mixture of two diastereomers in accordance with scheme I in the same way as described in example 1, from 2,3-dimethylphenyl phosphorodichloridate, (S)-N-Cbz-2-aminopropanol and 2'-deoxy- 2'-fluoro-2'-C-methyluridine. [M+H] ⁺ calculated for C ₂₅ H ₃₅ FN ₃ O ₉ P: 572.22; found: 572.2.

Example 5

[0163] (2R,3R,4R,5R)-2-(((((S)-1-(1,3-dioxolan-2-yl)ethyl)amino)(phenoxy)phosphoryl)oxy)methyl) -5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-4-methyltetrahydrofuran-3-yl butyrate (compound 105)

[0164] Compound 105 was obtained as a mixture of two diastereomers in accordance with scheme I, similarly as described in example 1, from phenylphosphorodichlorate, (S)-N-Cbz-2-aminopropanol and 2'-deoxy-2'-fluoro- 2'-C-methyl-3'-butyryloxyuridine. [M+H] ⁺ calculated for C ₂₅ H ₃₃ FN ₃ O ₁₀ P: 586.20; found: 586.20.

Example 6

[0165] (2R,3R,4R,5R)-2-((((((S)-1-(1,3-dioxolan-2-yl)ethyl)amino)(phenoxy)phosphoryl)oxy)methyl) -5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-4-methyltetrahydrofuran-3-yl pentanoate (compound 106)

[0166] Compound 106 was obtained as a mixture of two diastereomers in accordance with scheme I, similarly as described in example 1, from phenylphosphorodichlorate, (S)-N-Cbz-2-aminopropanol and 2'-deoxy-2'-fluoro- 2'-C-methyl-3'-pentanoinyloxyuridine. [M+H] ⁺ calculated for C ₂₆ H ₃₅ FN ₃ O ₁₀ P: 600.21; found: 600.25.

Example 7

[0167] (2R,3R,4R,5R)-2-((((((S)-1-(1,3-dioxolan-2-yl)ethyl)amino)(naphthalen-1-yloxy)phosphoryl) hydroxy)methyl)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-4-methyltetrahydrofuran-3-yl propionate (compound 107)

[0168] Compound 107 was obtained as a mixture of two diastereomers in accordance with scheme I, similarly as described in example 1, from 1-naphthyl phosphorodichloridate, (S)-N-Cbz-2-aminopropanol and 2'-deoxy-2'-fluoro-2'-C-methyl-3'-propionyloxyuridine. [M+H] ⁺ calculated for C ₂₈ H ₃₃ FN ₃ O ₁₀ P: 622.20; found: 622.25.

Example 8

[0169] (2R,3R,4R,5R)-2-((((((S)-1-(1,3-dioxan-2-yl)ethyl)amino)(phenoxy)phosphoryl)oxy)methyl) -5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-4-methyltetrahydrofuran-3-yl propionate (compound 108)

[0170] Compound 108 was obtained as a mixture of two diastereomers in accordance with scheme I, similarly as described in example 1, from phenyl phosphorodichloridate, (S)-N-Cbz-2-aminopropanol and 2'-deoxy-2'-fluoro- 2'-C-methyl-3'-propionyloxyuridine. [M+H] ⁺ calculated for C ₂₅ H ₃₃ FN ₃ O ₁₀ P: 586.20; found: 586.20.

Example 9

[0171] (2R,3R,4R,5R)-2-((((((S)-1-(1,3-dioxolan-2-yl)ethyl)amino)(phenoxy)phosphoryl)oxy)methyl) -5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-4-methyltetrahydrofuran-3-yl hexanoate (compound 109)

[0172] Compound 109 was obtained as a mixture of two diastereomers in accordance with scheme I, similarly as described in example 1, from phenyl phosphorodichloridate, (S)-N-Cbz-2-aminopropanol and 2'-deoxy-2'-fluoro- 2'-C-methyl-3'-hexanoyloxyuridine. [M+H] ⁺ calculated for C ₂₇ H ₃₇ FN ₃ O ₁₀ P: 614.23; found: 614.25.

Example 10

[0173] (2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-((((((1S)-1-( 4-ethyl-1,3-dioxolan-2-yl)ethyl)amino)(phenoxy)phosphoryl)oxy)methyl)-4-fluoro-4-methyltetrahydrofuran-3-yl propionate (compound 110)

[0174] Compound 110 was obtained as a mixture of four diastereomers in accordance with scheme I, similarly as described in example 1, from phenylphosphorodichlorate, (S)-N-Cbz-2-aminopropanol and 2'-deoxy-2'-fluoro- 2'-C-methyl-3'-propionyloxyuridine. [M+H] ⁺ calculated for C ₂₆ H ₃₅ FN ₃ O ₁₀ P: 600.20; found: 600.30.

Example 11

[0175] (2R,3R,4R,5R)-2-(((((S)-1-(1,3-dioxepan-2-yl)ethyl)amino)(phenoxy)phosphoryl)oxy)methyl) -5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-4-methyltetrahydrofuran-3-yl propionate (compound 111)

[0176] Compound 111 was obtained as a mixture of four diastereomers in accordance with scheme I, similarly as described in example 1, from phenyl phosphorodichlorate, (S)-N-Cbz-2-aminopropanol and 2'-deoxy-2'-fluoro- 2'-C-methyl-3'-propionyloxyuridine. [M+H] ⁺ calculated for C ₂₆ H ₃₅ FN ₃ O ₁₀ P: 600.20; found: 600.25.

Example 12

[0177] (2R,3R,4R,5R)-2-(((((S)-1-(1,3-dioxolan-2-yl)propyl)amino)(phenoxy)phosphoryl)oxy)methyl) -5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-4-methyltetrahydrofuran-3-yl propionate (compound 112)

[0178] Compound 112 was obtained as a mixture of two diastereomers in accordance with scheme I, similarly as described in example 1, from phenyl phosphorodichloridate, (S)-N-Cbz-2-aminobutanol and 2'-deoxy-2'-fluoro- 2'-C-methyl-3'-propionyloxyuridine. [M+H] ⁺ calculated for C ₂₅ H ₃₃ FN ₃ O ₁₀ P: 586.20; found: 586.25.

Example 13

[0179] (2R,3R,4R,5R)-2-((((((1S)-1-(4,5-dimethyl-1,3-dioxolan-2-yl)ethyl)amino)(phenoxy) phosphoryl)oxy)methyl)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-4-methyltetrahydrofuran-3-yl propionate (compound 113)

[0180] Compound 113 was obtained as a mixture of four diastereomers in accordance with scheme I, similarly as described in example 1, from phenylphosphorodichloridate, (S)-N-Cbz-2-aminopropanol and 2'-deoxy-2'-fluoro- 2'-C-methyl-3'-propionyloxyuridine. [M+H] ⁺ calculated for C ₂₆ H ₃₅ FN ₃ O ₁₀ P: 600.20; found: 600.25.

Example 14

[0181] (2R,3R,4R,5R)-2-(((((S)-1-(1,3-dioxolan-2-yl)propoxy)(phenoxy)phosphoryl)oxy)methyl)-5 -(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-4-methyltetrahydrofuran-3-yl propionate (compound 114A) and (2R,3R,4R,5R)-2 -((((((R)-1-(1,3-dioxolan-2-yl)propoxy)(phenoxy)phosphoryl)oxy)methyl)-5-(2,4-dioxo-3,4-dihydropyrimidine- 1(2H)-yl)-4-fluoro-4-methyltetrahydrofuran-3-yl propionate (compound 114B)

[0182] Compounds 114A and 114B were prepared and separated by HPLC as two separate mixtures of two diastereomers according to Scheme I, similarly as described in Example 1, from phenyl phosphorodichloridate, 2-hydroxybutanal and 2'-deoxy-2'- fluoro-2'-C-methyl-3'-propionyloxyuridine. [M+H] ⁺ calculated for C ₂₅ H ₃₂ FN ₂ O ₁₁ P: 587.18; found: 587.2.

Example 15

[0183] 2,3-dimethylphenyl ((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy- 4-methyltetrahydrofuran-2-yl)methyl ((S)-1-(1,3-dioxepan-2-yl)ethyl)phosphoramidate (compound 115)

[0184] Compound 115 was obtained as a mixture of two diastereomers in accordance with scheme I, similarly as described in example 1, from 2,3-dimethylphenyl phosphorodichlorate, (S)-N-Cbz-2-aminopropanol and 2'-deoxy- 2'-fluoro-2'-C-methyl-3'-propionyloxyuridine. [M+H] ⁺ calculated for C ₂₅ H ₃₅ FN ₃ O ₉ P: 572.22; found: 572.2.

Example 16

[0185] Phenyl N-((S)-1-(1,3-dioxolan-2-yl)ethyl)-P-((((R)-1-(6-amino-9H-purin-9-yl )propan-2-yl)oxy)methyl)phosphonamidate (compound 116)

[0186] Compound 116 was obtained as a mixture of two diastereomers in accordance with scheme I from phenol, (S)-N-Cbz-2-aminopropanol and (R)-(((1-(6-amino-9H-purine-9 -yl)propan-2-yl)oxy)methyl)phosphonic dichloride. [M+H] ⁺ calculated for C ₂₀ H ₂₇ N ₆ O ₅ P: 463.19; found: 463.1.

Example 17

[0187] Phenyl N-((S)-1-(1,3-dioxolan-2-yl)-3-methylbutyl)-P-((((R)-1-(6-amino-9H-purine- 9-yl)propan-2-yl)oxy)methyl)phosphonamidate (compound 117)

[0188] Compound 117 was obtained as a mixture of two diastereomers in accordance with scheme I from phenol, (S)-N-Cbz-2-amino-4-methylpentanol and (R)-(((1-(6-amino-9H -purin-9-yl)propan-2-yl)oxy)methyl)phosphonic dichloride. [M+H] ⁺ calculated for C ₂₃ H ₃₃ N ₆ O ₅ P: 505.24; found: 505.2.

Example 18

[0189] Phenyl P-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)-N-(1-(4-ethyl-1 ,3-dioxolan-2-yl)propan-2-yl)phosphonamidate (compound 118)

[0190] Compound 118 was obtained as a mixture of four or more diastereomers in accordance with scheme I from phenol, (S)-N-Cbz-3-aminobutanol and (R)-(((1-(6-amino-9H-purine -9-yl)propan-2-yl)oxy)methyl)phosphonic dichloride. [M+H] ⁺ calculated for C ₂₃ H ₃₃ N ₆ O ₅ P: 505.24; found: 505.2.

Example 19

[0191] Phenyl N-((S)-1-(1,3-dioxolan-2-yl)propyl)-P-((((R)-1-(6-amino-9H-purin-9-yl )propan-2-yl)oxy)methyl)phosphonamidate (compound 119)

[0192] Compound 119 was obtained as a mixture of two diastereomers in accordance with scheme I from phenol, (S)-N-Cbz-2-aminobutanol and (R)-(((1-(6-amino-9H-purine-9 -yl)propan-2-yl)oxy)methyl)phosphonic dichloride. [M+H] ⁺ calculated for C ₂₁ H ₂₉ N ₆ O ₅ P: 477.20; found: 477.2.

Example 20

[0193] Phenyl N-((S)-1-(1,3-dioxan-2-yl)ethyl)-P-((((R)-1-(6-amino-9H-purin-9-yl )propan-2-yl)oxy)methyl)phosphonamidate (compound 120)

[0194] Compound 120 was obtained as a mixture of two diastereomers in accordance with scheme I from phenol, (S)-N-Cbz-2-aminopropanol and (R)-(((1-(6-amino-9H-purine-9 -yl)propan-2-yl)oxy)methyl)phosphonic dichloride. [M+H] ⁺ calculated for C ₂₁ H ₂₉ N ₆ O ₅ P: 477.20; found: 477.2.

Example 21

[0195] 3,5-dimethylphenyl N-((S)-1-(1,3-dioxolan-2-yl)ethyl)-P-((((R)-1-(6-amino-9H-purine -9-yl)propan-2-yl)oxy)methyl)phosphonamidate (compound 121)

[0196] Compound 121 was obtained as a mixture of two diastereomers in accordance with scheme I from 3,5-dimethylphenol, (S)-N-Cbz-2-aminopropanol and (R)-(((1-(6-amino-9H -purin-9-yl)propan-2-yl)oxy)methyl)phosphonic dichloride. [M+H] ⁺ calculated for C ₂₂ H ₃₁ N ₆ O ₅ P: 491.22; found: 491.2.

Example 22

[0197] Phenyl N-((S)-1-(1,3-dioxepan-2-yl)ethyl)-P-((((R)-1-(6-amino-9H-purin-9-yl )propan-2-yl)oxy)methyl)phosphonamidate (compound 122)

[0198] Compound 122 was obtained as a mixture of two diastereomers in accordance with scheme I from phenol, (S)-N-Cbz-2-aminopropanol and (R)-(((1-(6-amino-9H-purine-9 -yl)propan-2-yl)oxy)methyl)phosphonic dichloride. [M+H] ⁺ calculated for C ₂₂ H ₃₁ N ₆ O ₅ P: 491.22; found: 491.2.

Example 23

[0199] Phenyl N-((S)-1-(1,3-dioxolan-2-yl)-2-methylpropyl)-P-((((R)-1-(6-amino-9H-purine- 9-yl)propan-2-yl)oxy)methyl)phosphonamidate (compound 123)

[0200] Compound 123 was obtained as a mixture of two diastereomers in accordance with scheme I from phenol, (S)-N-Cbz-2-amino-3-methylbutanol and (R)-(((1-(6-amino-9H -purin-9-yl)propan-2-yl)oxy)methyl)phosphonic dichloride. [M+H] ⁺ calculated for C ₂₂ H ₃₁ N ₆ O ₅ P: 491.22; found: 491.2.

Example 24

[0201] Phenyl N-((S)-1-(1,3-dioxolan-2-yl)-2-phenylethyl)-P-((((R)-1-(6-amino-9H-purine- 9-yl)propan-2-yl)oxy)methyl)phosphonamidate (compound 124)

[0202] Compound 124 was obtained as a mixture of two diastereomers in accordance with scheme I from phenol, (S)-N-Cbz-2-amino-3-phenylpropanol and (R)-(((1-(6-amino-9H -purin-9-yl)propan-2-yl)oxy)methyl)phosphonic dichloride. [M+H] ⁺ calculated for C ₂₆ H ₃₁ N ₆ O ₅ P: 539.22; found: 539.2.

Example 25

[0203] Phenyl N-((S)-1-(1,3-dioxocan-2-yl)ethyl)-P-((((R)-1-(6-amino-9H-purin-9-yl )propan-2-yl)oxy)methyl)phosphonamidate (compound 125)

[0204] Compound 125 can be prepared as a mixture of two diastereomers according to Scheme I from phenol, (S)-N-Cbz-2-aminopropanol and (R)-(((1-(6-amino-9H-purine -9-yl)propan-2-yl)oxy)methyl)phosphonic dichloride.

Example 26

[0205] 2,3-dimethylphenyl N-((S)-1-(1,3-dioxepan-2-yl)ethyl)-P-((((R)-1-(6-amino-9H-purine -9-yl)propan-2-yl)oxy)methyl)phosphonamidate (compound 126)

[0206] Compound 126 was obtained as a mixture of two diastereomers in accordance with scheme I from 3-ethylphenol, (S)-N-Cbz-2-aminopropanol and (R)-(((1-(6-amino-9H-purine -9-yl)propan-2-yl)oxy)methyl)phosphonic dichloride. [M+H] ⁺ calculated for C ₂₄ H ₃₅ N ₆ O ₅ P: 519.25; found: 519.2.

Example 27

[0207] Phenyl N-((S)-1-(1,3-dioxepan-2-yl)propyl)-P-((((R)-1-(6-amino-9H-purin-9-yl )propan-2-yl)oxy)methyl)phosphonamidate (compound 127)

[0208] Compound 127 was obtained as a mixture of two diastereomers in accordance with scheme I from phenol, (S)-N-Cbz-2-aminopropanol and (R)-(((1-(6-amino-9H-purine-9 -yl)propan-2-yl)oxy)methyl)phosphonic dichloride. [M+H] ⁺ calculated for C ₂₃ H ₃₃ N ₆ O ₅ P: 505.24; found: 505.2

Example 28

[0209] Phenyl P-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)-N-((S)-1,1- diethoxypropan-2-yl)phosphonamidate (compound 128)

[0210] Compound 128 was obtained as a mixture of two diastereomers in accordance with scheme I from phenol, (S)-N-Cbz-2-aminopropanol and (R)-(((1-(6-amino-9H-purine-9 -yl)propan-2-yl)oxy)methyl)phosphonic dichloride. [M+H] ⁺ calculated for C ₂₂ H ₃₃ N ₆ O ₅ P: 493.24; found: 493.2.

Example 29

[0211] 2,3-dimethylphenyl N-((S)-1-(1,3-dioxan-2-yl)ethyl)-P-((((R)-1-(6-amino-9H-purine -9-yl)propan-2-yl)oxy)methyl)phosphonamidate (compound 129)

[0212] Compound 129 was obtained as a mixture of two diastereomers in accordance with scheme I from 2,3-dimethylphenol, (S)-N-Cbz-2-aminopropanol and (R)-(((1-(6-amino-9H -purin-9-yl)propan-2-yl)oxy)methyl)phosphonic dichloride. [M+H] ⁺ calculated for C ₂₃ H ₃₃ N ₆ O ₅ P: 505.24; found: 505.2.

Example 30

[0213] Phenyl P-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)-N-(1S)-1-((4S )-4-ethyl-1,3-dioxolan-2-yl)ethyl)(phosphonamidate (compound 130)

[0214] Compound 130 was obtained as a mixture of two diastereomers in accordance with scheme I from phenol, (S)-N-Cbz-2-aminopropanol and (R)-(((1-(6-amino-9H-purine-9 -yl)propan-2-yl)oxy)methyl)phosphonic dichloride. [M+H] ⁺ calculated for C ₂₂ H ₃₁ N ₆ O ₅ P: 491.22; found: 491.2.

Example 31

[0215] Phenyl P-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)-N-(1S)-1-((4R )-4-ethyl-1,3-dioxolan-2-yl)ethyl)(phosphonamidate (compound 131)

[0216] Compound 131 was isolated as a mixture of two diastereomers in the preparation of compound 114 in Example 14. [M+H] ⁺ calculated for C ₂₂ H ₃₁ N ₆ O ₅ P: 491.22; found: 491.2.

Example 32

[0217] 1-(1,3-dioxolan-2-yl)propyl phenyl ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl) phosphonate (compound 132)

[0218] Compound 132 can be prepared as a mixture of four diastereomers according to Scheme I from phenol, 2-hydroxybutanal and (R)-(((1-(6-amino-9H-purin-9-yl)propan-2 -yl)oxy)methyl)phosphonic dichloride.

Example 33

[0219] Phenyl (S)-N-((R)-1-(1,3-dioxepan-2-yl)ethyl)-P-((((R)-1-(6-amino-9H-purine -9-yl)propan-2-yl)oxy)methyl)phosphonamidate (compound 133A) and phenyl (R)-N-((R)-1-(1,3-dioxepan-2-yl)ethyl)-P -((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonamidate (compound 133B)

[0220] Compounds 133A and 133B were prepared and separated by HPLC according to Scheme I from phenol, (R)-N-Cbz-2-aminopropanol and (R)-(((1-(6-amino-9H-purine -9-yl)propan-2-yl)oxy)methyl)phosphonic dichloride. [M+H] ⁺ calculated for C ₂₂ H ₃₁ N ₆ O ₅ P: 492.22; found: 492.2.

Example 34

[0221] Phenyl (S)-N-((R)-1-(1,3-dioxepan-2-yl)ethyl)-P-((((S)-1-(6-amino-9H-purine -9-yl)propan-2-yl)oxy)methyl)phosphonamidate (compound 134A) and phenyl (R)-N-((R)-1-(1,3-dioxepan-2-yl)ethyl)-P -((((S)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonamidate (compound 134B)

[0222] Compounds 134A and 134B were prepared and separated by HPLC according to Scheme I from phenol, (S)-N-Cbz-2-aminopropanol and (R)-(((1-(6-amino-9H-purine -9-yl)propan-2-yl)oxy)methyl)phosphonic dichloride. [M+H] ⁺ calculated for C ₂₂ H ₃₁ N ₆ O ₅ P: 492.22; found: 492.2.

Example 35

[0223] 3-ethylphenyl N-((S)-1-(1,3-dioxan-2-yl)ethyl)-P-((((R)-1-(6-amino-9H-purine-9 -yl)propan-2-yl)oxy)methyl)phosphonamidate (compound 135)

[0224] Compound 135 was obtained as a mixture of two diastereomers in accordance with scheme I from 3-ethylphenol, (S)-N-Cbz-2-aminopropanol and (R)-(((1-(6-amino-9H-purine -9-yl)propan-2-yl)oxy)methyl)phosphonic dichloride. [M+H] ⁺ calculated for C ₂₃ H ₃₃ N ₆ O ₅ P: 505.24; found: 505.3.

Example 36

[0225] 3-ethylphenyl P-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)-N-((S)-1, 1-diethoxypropan-2-yl)phosphonamidate (compound 136)

[0226] Compound 136 was obtained as a mixture of two diastereomers in accordance with scheme I from 3-ethylphenol, (S)-N-Cbz-2-aminopropanol and (R)-(((1-(6-amino-9H-purine -9-yl)propan-2-yl)oxy)methyl)phosphonic dichloride. [M+H] ⁺ calculated for C ₂₃ H ₃₃ N ₆ O ₅ P: 521.27; found: 521.2.

Example 37

[0227] 3-ethylphenyl P-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)-N-((S)-1, 1-dimethoxypropan-2-yl)phosphonamidate (compound 137)

[0228] Compound 137 was obtained as a mixture of two diastereomers in accordance with scheme I from 3-ethylphenol, (S)-N-Cbz-2-aminopropanol and (R)-(((1-(6-amino-9H-purine -9-yl)propan-2-yl)oxy)methyl)phosphonic dichloride. [M+H] ⁺ calculated for C ₂₃ H ₃₃ N ₆ O ₅ P: 493.23; found: 493.2

Example 38

[0229] (2R,3R,5R)-2-((((((S)-1-(1,3-dioxolan-2-yl)ethyl)amino)(phenoxy)phosphoryl)oxy)methyl)-5 -(4-amino-2-oxopyrimidin-1(2H)-yl)-4,4-difluorotetrahydrofuran-3-yl propionate (compound 138)

[0230] Compound 138 was obtained as a mixture of two diastereomers according to scheme I from phenol, (S)-N-Cbz-2-aminopropanol and (2R,3R,5R)-5-(4-amino-2-oxopyrimidine- 1(2H)-yl)-4,4-difluoro-2-(hydroxymethyl)tetrahydrofuran-3-yl propionate. [M+H] ⁺ calculated for C ₂₃ H ₂₉ F ₂ N ₄ O ₉ P: 575.17; found: 575.30.

Example 39

[0231] ((2R,3R,5R)-5-(4-butyramido-2-oxypyrimidin-1(2H)-yl)-4,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methyl phenyl (R) -((S)-1-(1,3-dioxolan-2-yl)ethyl)phosphoramidate (compound 139)

[0232] Compound 124 was prepared according to scheme I from phenol, (S)-N-Cbz-2-amino-3-aminopropanol and N-(1-((2R,4R,5R)-3,3-difluoro- 4-hydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)butyramide. [M+H] ⁺ calculated for C ₂₄ H ₃₁ F ₂ N ₄ O ₉ P: 589.19; found: 589.35.

Example 40

[0233] ((2R,3R,5R)-5-(4-butyramido-2-oxopyrimidin-1(2H)-yl)-4,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methyl phenyl (S) -((S)-1-(1,3-dioxolan-2-yl)ethyl)phosphoramidate (compound 140)

[0234] Compound 140 was isolated as a minor diastereomer in the preparation of compound 131 in Example 31. [M+H] ⁺ calculated for C ₂₄ H ₃₁ F ₂ N ₄ O ₉ P: 589.19; found: 589.30.

Example 41

[0235] (2S)-2-((((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl)amino) propyl propionate (compound 141)

[0236] Compound 141 was obtained as a mixture of two diastereomers according to scheme I from phenol, (S)-2-aminopropanol and (R)-(((1-(6-amino-9H-purin-9-yl)propane -2-yl)oxy)methyl)phosphonic dichloride. [M+H] ⁺ calculated for C ₂₁ H ₂₉ N ₆ O ₅ P: 477.20; found: 477.2.

Example 42

[0237] 3-(((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl)amino)butyl acetate (Compound 142)

[0238] Compound 142 was obtained as a mixture of four diastereomers in accordance with scheme I from phenol, 3-aminobutanol and (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl )oxy)methyl)phosphonic dichloride. [M+H] ⁺ calculated for C ₂₁ H ₂₉ N ₆ O ₅ P: 477.20; found: 477.1.

Example 43

[0239] 3-ethylphenyl P-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)-N-((2,2-diethoxyethyl ) phosphonamidate (compound 143)

[0240] Compound 143 was obtained as a mixture of two diastereomers in accordance with scheme I from 3-ethylphenol, 2-aminoethanol and (R)-(((1-(6-amino-9H-purin-9-yl)propan-2 -yl)oxy)methyl)phosphonic dichloride. [M+H] ⁺ calculated for C ₂₃ H ₃₅ N ₆ O ₅ P: 507.25; found: 507.2.

Example 44

[0241] Phenyl P-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)-N-((S)-1,1- dipropoxypropan-2-yl)phosphonamidate (compound 144)

[0242] Compound 144 was obtained as a mixture of two diastereomers in accordance with scheme I from phenol, (S)-N-Cbz-2-aminopropanol and (R)-(((1-(6-amino-9H-purine-9 -yl)propan-2-yl)oxy)methyl)phosphonic dichloride. [M+H] ⁺ calculated for C ₂₄ H ₃₇ N ₆ O ₅ P: 521.27; found: 521.2.

Example 45

[0243] Phenyl P-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)-N-((S)-1,1- dibutoxypropan-2-yl)phosphonamidate (compound 145)

[0244] Compound 145 was obtained as a mixture of two diastereomers in accordance with scheme I from phenol, (S)-N-Cbz-2-aminopropanol and (R)-(((1-(6-amino-9H-purine-9 -yl)propan-2-yl)oxy)methyl)phosphonic dichloride. [M+H] ⁺ calculated for C ₂₆ H ₄₁ N ₆ O ₅ P: 549.30; found: 549.3.

Example 46

[0245] Phenyl P-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)-N-((2,2-dibutoxyethyl)phosphonamidate (compound 146)

[0246] Compound 146 was obtained as a mixture of two diastereomers in accordance with scheme I from phenol, (S)-N-Cbz-2-aminopropanol and (R)-(((1-(6-amino-9H-purine-9 -yl)propan-2-yl)oxy)methyl)phosphonic dichloride. [M+H] ⁺ calculated for C ₂₅ H ₃₉ N ₆ O ₅ P: 535.28; found: 535.3.

Example 47

[0247] Phenyl P-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)-N-((2,2-dipropoxyethyl)phosphonamidate (compound 147)

[0248] Compound 147 was obtained as a mixture of two diastereomers in accordance with scheme I from phenol, 2-aminoethanol and (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl )oxy)methyl)phosphonic dichloride. [M+H] ⁺ calculated for C ₂₃ H ₃₅ N ₆ O ₅ P: 507.25; found: 507.2.

Example 48

[0249] (2R,3R,4R,5R)-2-((((((2,2-diethoxyethyl)amino)(phenoxy)phosphoryl)oxy)methyl)-5-(2,4-dioxo-3, 4-dihydropyrimidin-1(2H)-yl)-4-fluoro-4-methyltetrahydrofuran-3-yl propionate (compound 148)

[0250] Compound 148 was obtained as a mixture of two diastereomers in accordance with scheme I from phenol, 2-aminoethanol and (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl )oxy)methyl)phosphonic dichloride. [MH] ⁺ calculated for C ₂₅ H ₃₅ FN ₃ O ₁₀ P: 586.2; found: 586.4.

Example 49

[0251] (2S)-2-((((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl)amino) propyl 2,2-dimethylpropionate (compound 149)

[0252] Compound 149 was obtained as a mixture of two diastereomers in accordance with scheme I from phenol, (S)-2-aminopropanol and (R)-(((1-(6-amino-9H-purin-9-yl)propane -2-yl)oxy)methyl)phosphonic dichloride. [M+H] ⁺ calculated for C ₂₃ H ₃₃ N ₆ O ₅ P: 505.24; found: 505.2.

Example 50

[0253] (2R,3S,5R)-2-((((((S)-1,1-diethoxypropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)-5-(5-fluoro -2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3-yl propionate (compound 150)

[0254] Compound 150 was prepared as a mixture of two diastereomers according to Scheme I from phenol, (S)-N-Cbz-2-aminopropanol and 5-fluoro-1-((2R,4S,5R)-4-hydroxy- 5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2,4(1H,3H)-dione. [MH] ⁺ calculated for C ₂₅ H ₃₅ FN ₃ O ₁₀ P: 586.2; found: 586.1.

Example 51

[0255] ((2R,3S,5R)-5-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methyl phenyl ( (S)-1,1-dipropoxypropan-2-yl)phosphoramidate (compound 151)

[0256] Compound 151 was obtained as a mixture of two diastereomers according to scheme I from phenol, (S)-N-Cbz-2-aminopropanol and 5-fluoro-1-((2R,4S,5R)-4-hydroxy- 5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2,4(1H,3H)-dione. [M+H] ⁺ calculated for C ₂₄ H ₃₅ FN ₃ O ₉ P: 558.2; found: 558.0.

Example 52

[0257] (2R,3S,5R)-2-((((((S)-1,1-dipropoxypropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)-5-(5-fluoro -2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3-yl propionate (compound 152)

[0258] Compound 152 was obtained as a mixture of two diastereomers according to scheme I from phenol, (S)-N-Cbz-2-aminopropanol and 5-fluoro-1-((2R,4S,5R)-4-hydroxy- 5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2,4(1H,3H)-dione. [MH] ⁺ calculated for C ₂₇ H ₃₉ FN ₃ O ₁₀ P: 614.23; found: 614.2.

Example 53

[0259] (2R,3S,5R)-2-((((((S)-1,1-diethoxypropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)-5-(5-fluoro -2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3-yl 2,2-dimethylpropionate (compound 153)

[0260] Compound 153 was obtained as a mixture of two diastereomers according to scheme I from phenol, (S)-N-Cbz-2-aminopropanol and 5-fluoro-1-((2R,4S,5R)-4-hydroxy- 5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2,4(1H,3H)-dione. [MH] ⁺ calculated for C ₂₇ H ₃₉ FN ₃ O ₁₀ P: 614.23; found: 614.2.

Example 54

[0261] Phenyl P-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)-N-((S)-1,1- diisopropoxypropan-2-yl)phosphonamidate (compound 154)

[0262] Compound 154 was obtained as a mixture of two diastereomers according to scheme I from phenol, (S)-N-Cbz-2-aminopropanol and 5-fluoro-1-((2R,4S,5R)-4-hydroxy- 5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2,4(1H,3H)-dione. [MH] ⁺ calculated for C ₂₄ H ₃₇ N ₆ O ₅ P: 520.26; found: 521.2.

Example 55

[0263] Phenyl (S)-P-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)-N-((S)- 1,1-dipropoxypropan-2-yl)phosphonamidate (compound 155)

[0264] Compound 155 was isolated by chiral HPLC from a mixture of two diastereomers (compound 144).

Example 56

[0265] Phenyl (R)-P-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)-N-((S)- 1,1-dipropoxypropan-2-yl)phosphonamidate (compound 156)

[0266] Compound 156 was isolated by chiral HPLC from a mixture of two diastereomers (compound 144).

Example 57

[0267] (2R,3S,5R)-2-((((((S)-1,1-dimethoxypropan-2-yl)amino)(3-ethylphenoxy)phosphoryl)oxy)methyl)-5-(5 -fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3-yl propionate (compound 157)

[0268] Compound 157 was obtained as a mixture of two diastereomers according to scheme I from 3-ethylphenol, (S)-N-Cbz-2-aminopropanol and 5-fluoro-1-((2R,4S,5R)-4- hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2,4(1H,3H)-dione. [MH] ^- calculated for C ₂₅ H ₃₅ FN ₃ O ₁₀ P: 586.19; found: 586.2.

Example 58

[0269] (2R,3S,5R)-2-((((((S)-1,1-dimethoxypropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)-5-(5-fluoro -2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3-yl propionate (compound 158)

[0270] Compound 158 was obtained as a mixture of two diastereomers according to scheme I from phenol, (S)-N-Cbz-2-aminopropanol and 5-fluoro-1-((2R,4S,5R)-4-hydroxy- 5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2,4(1H,3H)-dione. [MH] ^- calculated for C ₂₃ H ₃₁ FN ₃ O ₁₀ P: 558.16; found: 558.2.

Example 59

[0271] (2R,3S,5R)-2-(((((2,2-dimethoxyethyl)amino)(phenoxy)phosphoryl)oxy)methyl)-5-(5-fluoro-2,4-dioxo-3 ,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3-yl propionate (compound 159)

[0272] Compound 159 was obtained as a mixture of two diastereomers according to scheme I from phenol, N-Cbz-2-aminoethanol and 5-fluoro-1-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl )tetrahydrofuran-2-yl)pyrimidin-2,4(1H,3H)-dione. ¹ H-NMR (400 MHz, CDCl ₃ ) 7.88 (d, J = 6.0, 1H), 7.81 (d, J = 6.0, 1H), 7.46 - 7.15 (m , 12H), 6.33 - 6.20 (m, 2H), 5.30 (m, 2H).

Example 60

[0273] (2R,3S,5R)-2-((((((S)-1-(1,3-dioxolan-2-yl)ethyl)amino)(phenoxy)phosphoryl)oxy)methyl)-5 -(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3-yl propionate (compound 160)

[0274] Compound 160 was obtained as a mixture of two diastereomers according to scheme I from phenol, (S)-N-Cbz-2-aminopropanol and 5-fluoro-1-((2R,4S,5R)-4-hydroxy- 5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2,4(1H,3H)-dione. [M+H] ⁺ calculated for C ₂₃ H ₂₉ FN ₃ O ₁₀ P: 558.17; found: 558.2.

Example 61

[0275] (2R,3S,5R)-2-((((((S)-1,1-dimethoxypropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)-5-(4-ethoxy -5-fluoro-2-oxopyrimidin-1(2H)-yl)tetrahydrofuran-3-yl propionate (compound 161)

[0276] Compound 161 was obtained as a mixture of two diastereomers according to scheme I from phenol, (S)-N-Cbz-2-aminopropanol and (2R,3S,5R)-5-(4-ethoxy-5-fluoro- 2-oxopyrimidin-1(2H)-yl)-2-(hydroxymethyl)tetrahydrofuran-3-yl propionate. ¹ H-NMR (400 MHz, CDCl ₃ ) 8.00 (d, J = 6.0, 1H), 7.95 (d, J = 5.6, 1H), 7.40 - 7.10 (m , 12H), 6.33 - 6.18 (m, 2H), 5.27 (m, 2H).

Biological examples

[0277] Examples of application of the method include the following. It should be understood that the following are examples and that the method is not limited to these examples.

Example A Tissue Distribution of Control Compounds and Described Compounds after Oral Administration

[0278] The liver specificity of the described compounds was compared with the corresponding active compound in the liver and other organs that may be targets of toxicity.

Ways

[0279] The control phosphorus(n)amidate acetal and phosph(one)acetal compounds were administered to fasted rats at a dose of 5-20 mg/kg orally by gavage. Plasma concentrations of active agents, metabolites, and phosphorus(n)amidate acetal and phosph(one)acetal compounds in the circulation and in the hepatic portal vein were determined by HPLC-UV, and concentrations in the liver, small intestine, and other organs were determined by LC-MS using a standard chromatography method.

Results:

[0280] Table 3 shows the results of some of the new compounds; the results demonstrate the targeting of phosphor(n)amidate acetal and phosph(one) acetal compounds to the liver and indicate an increased efficiency of these compounds compared to other types of compounds in targeting the liver and achieving high levels of active agents in the liver. This may be due solely to the highly efficient liver targeting provided by the phosphorus(n)amidate acetal and phosph(one)acetal compounds.

Table 3. Hepatic nucleoside triphosphate (NTP) levels and blood nucleotide (Nuc) levels in rats following oral administration of some compounds at 5 mg/kg

[0281] All numbers expressing quantities of ingredients, reaction conditions, and so on, used herein, in all cases should be understood as accompanied by the term "about". Accordingly, unless otherwise indicated, the numerical parameters given in this document are approximate values that may vary depending on the desired properties that need to be provided. Not as an attempt to limit the application of the doctrine of equivalents to the scope of any claims in any application claiming priority by date of filing of this application, each numerical parameter is to be construed in light of the number of significant digits and normal rounding.

[0282] As used herein, expressions such as "approximately", "about", "generally", and "substantially" denote a value, amount, or characteristic that is close to the specified value, amount, or characteristic that still performs the desired function or allow you to achieve the desired result. For example, the terms "about", "about", "generally", and "substantially" may refer to an amount that is less than 10%, less than 5%, less than 1%, less than 0, 1% and within less than 0.01% of the indicated amount. As another example, in certain embodiments of the present invention, the expressions "generally parallel" and "substantially parallel" refer to a value, amount or characteristic that deviates from strictly parallel by an amount less than or equal to 15%, 10%, 5% , 3% 1%, 0.1% or otherwise. Similarly, in certain embodiments of the present invention, the expressions "generally perpendicular" and "substantially perpendicular" refer to a value, amount or characteristic that deviates from strictly perpendicular by an amount less than or equal to 15%, 10%, 5%, 3% 1%, 0.1% or otherwise.

[0283] Several methods and materials are described herein. You can make changes in the methods and materials of the present invention, as well as in the methods of manufacture and equipment. Such modifications will become apparent to those skilled in the art from this document or the practice of the invention described herein. Therefore, the present invention is not intended to be limited to the specific embodiments described herein, but the present invention is intended to cover all modifications and alternatives falling within the true scope and spirit of the invention.

[0284] All references cited herein, including but not limited to published and unpublished applications, patents, and literature references, are incorporated herein by reference in their entirety and hereby form part of the present disclosure. If publications and patents or patent applications incorporated herein by reference conflict with the present invention described herein, this document supersedes and/or supersedes any such conflicting material.

[0285] Although the present invention has been described with reference to embodiments and examples, it should be understood that numerous and various modifications can be made without deviating from the spirit of the invention. Accordingly, the present invention is only limited by the following claims.

Claims (59)

1. Compound of formula IVa:

or a pharmaceutically acceptable salt of said compound, Where: R ¹ and R ² are independently selected from the group consisting of C ₁ -C ₆ alkyl; or alternatively R ¹ and R ² together with the atoms to which they are attached, form a four to ten-membered heterocycle with two oxygen atoms as heteroatoms, optionally substituted with C ₁ -C ₆ alkyl; each R ³ is independently selected from the group consisting of hydrogen and C ₁ -C ₆ alkyl optionally substituted with phenyl; each R ⁶ is independently C ₁ -C ₆ alkyl; m is 0, 1, 2, or 3; n is 1 or 2; And X is O (oxygen) or NH. 2. A compound according to claim 1, wherein each R ³ is independently C ₁ -C ₆ alkyl optionally substituted with phenyl. 3. The compound according to claim 1, characterized in that m is 0, 1 or 2. 4. The compound according to claim 1, characterized in that n is equal to 1. 5. A compound according to claim 1, wherein X is NH. 6. A compound according to claim 1, wherein R ³ is hydrogen or C _1- C ₆ alkyl. 7. The compound according to claim 1, characterized in that m is 1, 2 or 3. 8. The compound according to claim 1, characterized in that said compound is selected from the group consisting of:

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

And

. 9. Pharmaceutical composition for the treatment of HIV, where the composition contains a therapeutically effective amount of a compound according to any one of paragraphs. 1-8 and a pharmaceutically acceptable excipient. 10. Pharmaceutical composition for the treatment of a viral infection of the liver, where the composition contains a therapeutically effective amount of a compound according to any one of paragraphs. 1-8 and a pharmaceutically acceptable excipient. 11. Pharmaceutical composition according to any one of paragraphs. 9, 10, additionally containing one or more of cobicistat, emtricitabine and elvitegravir. 12. Pharmaceutical composition according to any one of paragraphs. 9, 10, additionally containing two or more of cobicistat, emtricitabine and elvitegravir. 13. Pharmaceutical composition according to any one of paragraphs. 9, 10, additionally containing cobicistat, emtricitabine and elvitegravir. 14. Pharmaceutical composition according to any one of paragraphs. 9, 10, additionally containing one or more of ribavirin, peginterferon-alpha, simeprevir, ledipasvir, or daclatasvir. 15. A method of treating HIV, comprising administering an effective amount of a compound according to any one of paragraphs. 1-8 to the subject in need. 16. A method of treating a viral infection of the liver, comprising administering an effective amount of a compound according to any one of paragraphs. 1-8 to the subject in need. 17. The method according to claim 16, wherein the viral infection of the liver is hepatitis. 18. The method according to any one of paragraphs. 15, 16, further comprising administering an effective amount of at least one additional therapeutic agent to a subject in need thereof. 19. The method according to any one of paragraphs. 15-18, characterized in that said subject is a mammal. 20. The method according to any one of paragraphs. 15-19, characterized in that said subject is a human. 21. A method of inhibiting viral replication in a hepatocyte, comprising bringing said hepatocyte into contact with any of the compounds according to paragraphs. 1-8. 22. The method according to p. 21, characterized in that the specified hepatocyte is in vivo . 23. The method according to claim 21, characterized in that said hepatocyte is located ex vivo . 24. The method of claim 21, wherein said hepatocyte is a mammalian hepatocyte. 25. The method according to claim 21, wherein said hepatocyte is a human hepatocyte. 26. The use of a compound according to any one of paragraphs. 1-8 for treating a viral liver infection in a subject. 27. Use according to claim 26 in combination with one or more additional therapeutic agents. 28. Use according to claim 27, characterized in that said additional therapeutic agent is selected from the group consisting of thymosin alfa-1, interferon-λ, HCV protease inhibitor, HCV replication complex inhibitor NS5A, HCV polymerase NS5B inhibitor, HCV helicase inhibitor, cyclophilin inhibitor, inosine monophosphate dehydrogenase inhibitor, ribavirin, interferon-α and pegylated interferon-α. 29. Use according to claim 27, characterized in that said additional therapeutic agent contains interferon-α or pegylated interferon-α. 30. Use according to claim 27, characterized in that said additional therapeutic agent contains a direct antiviral agent. 31. Use according to claim 30, characterized in that said direct antiviral agent is selected from the group consisting of an HCV protease inhibitor, an inhibitor of the HCV replication complex NS5A, a nucleoside inhibitor of HCV polymerase NS5B, a non-nucleoside inhibitor of HCV polymerase NS5B, and an inhibitor of HCV helicase. 32. Application according to any one of paragraphs. 26-31, characterized in that said viral infection of the liver includes hepatitis C (HCV). 33. Application according to any one of paragraphs. 26-32, characterized in that said subject is a mammal. 34. Application according to any one of paragraphs. 26-33, characterized in that said subject is a human. 35. The use of a compound according to any one of paragraphs. 1-8 to obtain a drug for the treatment of viral infection of the liver. 36. Use according to claim 35, characterized in that said medicinal product contains one or more additional therapeutic agents. 37. Use according to claim 36, characterized in that said additional therapeutic agent is selected from the group consisting of thymosin alfa-1, interferon-λ, HCV protease inhibitor, NS5A HCV replication complex inhibitor, NS5B HCV polymerase inhibitor, HCV helicase inhibitor, cyclophilin inhibitor, inosine monophosphate dehydrogenase inhibitor, ribavirin, interferon-α and pegylated interferon-α. 38. Use according to claim 36, characterized in that said additional therapeutic agent contains interferon-α or pegylated interferon-α. 39. Use according to claim 36, characterized in that said additional therapeutic agent contains a direct-acting antiviral agent. 40. Use according to claim 39, characterized in that said direct antiviral agent is selected from the group consisting of an HCV protease inhibitor, an HCV replication complex inhibitor NS5A, a nucleoside inhibitor of HCV polymerase NS5B, a non-nucleoside inhibitor of HCV polymerase NS5B, and an inhibitor of HCV helicase. 41. The use of a composition according to any one of paragraphs. 10-14 for treating a viral liver infection in a subject. 42. Use of a composition according to claim 41, wherein said composition further comprises an additional therapeutic agent. 43. Use according to claim 42, characterized in that said additional therapeutic agent is selected from the group consisting of thymosin alpha-1, interferon-λ, HCV protease inhibitor, HCV replication complex inhibitor NS5A, HCV polymerase NS5B inhibitor, HCV helicase inhibitor, cyclophilin inhibitor, inosine monophosphate dehydrogenase inhibitor, ribavirin, interferon-α and pegylated interferon-α. 44. Use according to claim 43, characterized in that said additional therapeutic agent contains interferon-α or pegylated interferon-α. 45. Use according to claim 42, characterized in that said additional therapeutic agent contains a direct-acting antiviral agent. 46. Use according to claim 45, characterized in that said direct antiviral agent is selected from the group consisting of an HCV protease inhibitor, an inhibitor of the HCV replication complex NS5A, a nucleoside inhibitor of HCV polymerase NS5B, a non-nucleoside inhibitor of HCV polymerase NS5B, and an inhibitor of HCV helicase. 47. Use according to claim 42, characterized in that said additional therapeutic agent is selected for the treatment of HBV from the group consisting of HBV entry inhibitors, HBV covalently continuous circular DNA inhibitor, HBV capsid inhibitor, interferon, HBV assembly inhibitor. 48. Use according to claim 42, wherein said additional therapeutic agent is selected for the treatment of HCC from the group consisting of sorafenib, regorafenib, and an immuno-oncological agent such as a PD-1 or PD-L1 checkpoint inhibitor. 49. Use according to claim 42, wherein said additional therapeutic agent is selected for the treatment of HIV from the group consisting of non-nucleoside inhibitors of HIV reverse transcriptase, other nucleoside analogues of HIV reverse transcriptase inhibitors, and protease inhibitors.