CYCLIC PHOSPHATE COMPOUNDS FIELD

[0001] The present disclosure relates to the field of chemistry and medicine. More specifically, the present disclosure relates to cyclic nucleotide compounds, their preparation and their uses. In some embodiments, such compounds are useful to selectively deliver certain pharmaceutical agents to the liver. BACKGROUND

[0002] The following description of the background is provided to aid in understanding the invention, but is not admitted to be, or to describe, prior art.

[0003] Natural nucleosides, once phosphorylated to nucleotides, are building blocks of DNA and RNA. The nucleosides in humans are obtained mainly from digestion of nucleic acids in the diet and can be biosynthesized, especially in the liver, when there is a need. Nucleosides can be phosphorylated to nucleotides in the cell by specific nucleoside kinases to maintain normal cell function and growth. These kinases can be impaired in one or more tissues due to genetic defects or non-genetic factors, which can lead to certain diseases or conditions, including but not limited to certain mitochondrial DNA depletion syndromes. For example, see El-Hattab, A. and F. Scaglia (2013) Neurotherapeutics. 2013 Apr; 10(2): 186–198 (published online 2013 Feb 6. doi: 10.1007/s13311-013-0177-6).

[0004] Nucleotide supplementation, in theory, can address the deficiency in the body; however, nucleotides have molecular properties, e.g., hydrophilicity, that prevent them from easily passing across cell membranes, so treatment with nucleotide supplements may be inefficient or may require large amounts of supplements. Synthetic nucleos(t)ides are widely used as antiviral or anticancer agents. Prodrug technologies have been used to improve the nucleotides molecular properties to enable the nucleotides to be more bioavailable, including improving oral bioavailability. Thus, new compounds with liver-targeting profile in addition to oral bioavailability enhancement may significantly improve the therapeutic benefits of nucleos(t)ide based therapies. SUMMARY

[0005] Novel cyclic phosphate compounds, their preparation and their uses are described. Some embodiments are novel cyclic phosphate compounds that are delivered orally to the liver where the compounds provide a therapeutic benefit. Additional embodiments include novel cyclic phosphate compounds that treat a disease, disorder or condition including: certain mitochondrial DNA depletion syndromes, hepatitis, liver cancer, liver fibrosis, fatty liver, malaria, viral infection, parasitic infection, diabetes, hyperlipidemia, atherosclerosis, obesity, dyslipidemia, hyperglycemia, a hormonal condition, HIV, and various types of cancer. Another aspect includes the use of the cyclic phosphate compounds to treat diseases that benefit from enhanced drug distribution to the liver and like tissues and cells. In another aspect, the cyclic phosphate compounds are used to increase the pharmacological or clinical activity of certain classes of pharmaceutical compounds such as nucleotide derived analog compounds. In some embodiments, the cyclic phosphate compounds are useful in the more efficient oral delivery of the nucleotide compounds to the liver and other tissues. Some additional embodiments relate to a method of making the cyclic phosphate compounds.

[0006] Some embodiments provided herein include a compound of Formulas I, Ia, Ib, Ic, and Id:

or a stereoisomer or a pharmaceutically acceptable salt thereof,

wherein R ² , R ^2a , R ^2b , R ³ , R ⁴ , R ^5a , R ^5b , R ⁶ , n, m, q, r, and Base have any of the values described herein.

[0007] Some embodiments relate to a pharmaceutical composition comprising one or more of the above compounds and a pharmaceutically acceptable excipient.

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

[0009] Some embodiments relate to a method of treating a disease, disorder or condition comprising administering an effective amount of one or more of the above compounds.

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

[0011] In some embodiments, the disease, disorder or condition is a disease, disorder or condition of the liver. [0012] In some embodiments, the disease, disorder or condition is a disease in which the liver is involved in the production and/or the homeostatic control of the biochemical end products of the disease, disorder or condition.

[0013] In some embodiments, the disease, disorder or condition is a non-liver disease, disorder or condition.

[0014] Some embodiments relate to a method of treating a liver disease comprising administering an effective amount of one or more of the above compounds to a subject in need thereof.

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

[0016] Some embodiments further comprise administering an effective amount of at least one additional therapeutic agent to the subject in need thereof.

[0017] In some embodiments, the subject is a mammal.

[0018] In some embodiments, the subject is human.

[0019] Some embodiments relate to a method of intervening in a molecular pathway or modulating a target in a cell comprising contacting the cell with one or more of the above compounds.

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

[0021] In some embodiments, the cell is in vivo.

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

[0023] In some embodiments, the cell is a hepatocyte.

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

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

[0026] Some embodiments of the compounds, compositions, and methods provided herein include a pharmaceutical composition comprising one or more of the compounds provided herein and a pharmaceutically acceptable excipient. [0027] Some embodiments of the compounds, compositions, and methods provided herein include a pharmaceutical composition comprising one to four of the compounds provided herein and a pharmaceutically acceptable excipient.

[0028] Some embodiments of the compounds, compositions, and methods provided herein include a method of treating a disease or condition of the liver in a subject comprising administering an effective amount of one or more of the compounds provided herein to a subject in need thereof.

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

[0030] Some embodiments also include administering an effective amount of one or more additional therapeutic agents to the subject in need thereof.

[0031] In some embodiments, the subject is a mammal.

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

[0033] Some embodiments also include the use of one or more of the compounds provided herein in combination with an additional therapeutic agent.

[0034] Some embodiments also include the use of one or more of the compounds provided herein in combination with one or more additional therapeutic agent(s).

[0035] Some embodiments of the compounds, compositions, and methods provided herein include one or more of the compositions provided herein for use in the preparation of a medicament for treating a disease or condition in the liver or a disease or condition in which the physiological or pathogenic pathways involve the liver.

[0036] Some embodiments of the compounds, compositions, and methods provided herein include one or more of the compositions provided herein for use in the preparation of a medicament for treating a non-liver disease or condition. DETAILED DESCRIPTION

[0037] The present embodiments are directed to compositions and methods related to novel cyclic phosphate compounds, their preparation and their uses. In some embodiments, the novel cyclic phosphate compounds facilitate delivery into cells of nucleotide derived agents, such as ribonucleotides and deoxyribonucleotides that contain adenine, cytosine, guanine, inosine, thymine, uracil, and their derivatives and prodrugs.

[0038] These cyclic phosphate compounds and their stereoisomers and pharmaceutically acceptable salts are represented by Formulas I, Ia, Ib, Ic, and Id:

or a stereoisom er or a pharmaceutically acceptable salt thereof,

wherein R ^2a , R ^2b , R ³ , R ⁴ , R ^5a , R ^5b , R ⁶ , n, m, q, r, and Base have any of the values described herein. [0039] In some embodiments, R ^2a and R ^2b are independently selected from a group of H, OR ⁸ , halo, CN, and an optionally substituted C ₁ -C ₁₀ alkyl. In some embodiments, the alkyl is methyl. In some embodiments, the halo is F or Cl.

[0040] In some embodiments, R ³ and R ⁴ are independently selected from a group of H, OH, CN, N3, and an optionally substituted C1-C10 alkyl. In some embodiments, the alkyl is methyl. In some embodiments, the halo is F.

[0041] In some embodiments, R ^5a is H, -CH(OR ⁷ )2, -C(O)OR ⁷ , -C(O)N(R ⁷ )2, -

[0042] In some embodiments, R ^5b is selected from a group of an H, optionally substituted C1-C10 alkyl, an optionally substituted C3-C10 cycloalkyl, an optionally substituted C ₁ -C ₁₀ alkyloxy, an optionally substituted (C _6-10 aryl), an optionally substituted (C _6-10 aryl)- CH2-, an optionally substituted (C6-10 aryl)-CH2CH2-, -CH(OR ⁷ )2, -C(O)OR ⁷ , -C(O)N(R ⁷ )2, -

[0043] In some embodiments, each R ⁶ is independently selected from a group of halo, and an optionally substituted C1-C10 alkyl. In some embodiments, the halo is F or Cl. In some embodiments, the optionally substituted alkyl is methyl.

[0044] In some embodiments, each R ⁷ is independently selected from a group of H and an optionally substituted C1-C10 alkyl.

[0045] In some embodiments, each R ⁸ is independently selected from a group of H, C(O)R ⁷ , C(O)OR ⁷ , and C(O)NHR ⁷ .

[0046] In some embodiments, n is 0, 1, 2, or 3.

[0047] In some embodiments, m, q, and r are independently 0, 1, or 2.

[0048] In some embodiments, Base is a derivative or analog of the natural nucleoside bases optimized for pharmaceutical use, wherein Base does not include

. In some embodiments, when Base is q is 1, and R ^5a is not H or

[0049] In some embodiments, Base is selected from a group of

.

[0050] In some embodiments, Base is selected from the group of

[0051] In some embodiments, R ⁹ is H, halo, CD3, or optionally substituted alkyl. In some embodiments, halo is F. In some embodiments, alkyl is methyl.

[0052] In some embodiments, R ¹⁰ is selected from a group of H, an optionally substituted C1-C10 alkyl, an optionally substituted C1-C10 alkyl-OCH2-, an optionally substituted C1-C10 alkyl-NHCH2-, an optionally substituted C1-C10 acyl, an optionally substituted C ₁ -C ₁₀ alkyl-OC(O)-, an optionally substituted (C _6-10 aryl)-CH ₂ OCH ₂ -, an optionally substituted (C6-10 aryl)-OCH2-, an optionally substituted (C6-10 aryl)-C(O)-, and an optionally substituted (C6-10 aryl)-OC(O)-.

[0053] In some embodiments, R ¹¹ is selected from a group of OH, NH ₂ , NHOR ⁸ , an optionally substituted C1-C10 alkyloxy, an optionally substituted C1-C10 alkylamino, an optionally substituted C1-C10 acyloxy, an optionally substituted C1-C10 acylamino, an optionally substituted C1-C10 alkyl-OC(O)NH-, an optionally substituted (C6-10 aryl)-C(O)O-, an optionally substituted (C _6-10 aryl)-C(O)NH-, an optionally substituted (C _6-10 aryl)- OC(O)NH-, an optionally substituted C ₁ -C ₁₀ alkyl-OCH ₂ NH-, and an optionally substituted C1-C10 alkyl-OCH2O-.

[0054] In some embodiments, R ¹² is selected from a group of H, NH2, an optionally substituted C ₁ -C ₁₀ alkylamino, an optionally substituted C ₁ -C ₁₀ acylamino, an optionally substituted C1-C10 alkyl-OC(O)NH-, an optionally substituted (C6-10 aryl)- C(O)NH-, an optionally substituted (C6-10 aryl)-OC(O)NH-, an optionally substituted C1-C10 alkyl-OCH ₂ NH-.

[0055] In some embodiments, R ⁹ is H. In some embodiments, R ¹⁰ is H.

[0056] In some embodiments, R ¹¹ is selected from the group consisting of NH2, an optionally substituted C ₁ -C ₁₀ acylamino, and an optionally substituted C ₁ -C ₁₀ alkylamino. In some embodiments, R ¹¹ is NH ₂ .

[0057] In some embodiments, R ¹² is H or an optionally substituted C1-C10 acylamino. In some embodiments, R ¹² is H. In some embodiments, R ¹² is NH2.

[0058] In some embodiments, R ⁹ is an unsubstituted C ₁ -C ₁₀ alkyl.

[0059] In some embodiments, R ⁹ is methyl.

[0060] In some embodiments, R ⁹ is -CD3.

[0061] In some embodiments, Base is In some embodiments, Base

is . In some embodiments, Base is . In some embodiments, Base

is . In some embodiments, Base is . In some embodiments, Base is

[0062] In some embodiments, R ^5b is selected from the group consisting of an optionally substituted C ₁ -C ₁₀ alkyl, an optionally substituted C ₃ -C ₁₀ cycloalkyl, an optionally substituted C ₁ -C ₁₀ alkyloxy, an optionally substituted (C _6-10 aryl), an optionally substituted (C6-10 aryl)-CH2-, an optionally substituted (C6-10 aryl)-CH2CH2-, -CH(OR ⁷ )2, -C(O)OR ⁷ , -

C(O)N(R ⁷ ) ₂ , -CH ₂ OR ⁸ , -CH ₂ N(R ⁸ ) ₂ , -CH ₂ OCH ₂ OR ⁸ , and In some embodiments,

at least one of R ^2a and R ^2b is H.

[0063] In some embodiments, R ^2a and R ^2b are each H.

[0064] In some embodiments, R ^2a is an unsubstituted C ₁ -C ₁₀ alkyl.

[0065] In some embodiments, R ^2a is methyl and R ^2b is fluoro.

[0066] In some embodiments, R ^2a is OH.

[0067] In some embodiments, R ^2a and R ^2b are each halo.

[0068] In some embodiments, R ^2a is H and R ^2b is OR ⁸ .

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

[0070] In some embodiments, R ^2a is Me and R ^2b is F or Cl.

[0071] In some embodiments, R ^2a and R ^2b are both H or both F.

[0072] In some embodiments, R ^2a and R ^2b are each fluoro.

[0073] In some embodiments, R ³ is halo.

[0074] In some embodiments, R ³ is H.

[0075] In some embodiments, R ⁴ is H.

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

[0077] In some embodiments, R ^5b is a substituted C ₁ -C ₁₀ alkyl.

[0078] In some embodiments, R ^5b is an unsubstituted C1-C10 alkyl.

[0079] In some embodiments, R ^5b is octyl.

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

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

[0082] In some embodiments, R ^5b is a substituted C6-10 aryl.

[0083] In some embodiments, R ^5b is phenyl substituted with–COOR ¹³ , wherein R ¹³ is an unsubstituted C ₁ -C ₆ alkyl.

[0084] In some embodiments, R ¹³ is i-propyl.

[0085] In some embodiments, R ¹³ is n-propyl. [0086] In some embodiments, R ^5a is selected from the group consisting of -

CH(OR ⁷ )2, -C(O)OR ⁷ , -C(O)N(R ⁷ )2, -CH2OR ⁸ , -CH2N(R ⁸ )2, -CH2OCH2OR ⁸ , and . In some embodiments, R ^5a is selected from the group consisting of -CH(OR ⁷ )2, -C(O)OR ⁷ , - C(O)N(R ⁷ ) ₂ , -CH ₂ OR ⁸ , -CH ₂ N(R ⁸ ) ₂ , and -CH ₂ OCH ₂ OR ⁸ . In some embodiments, R ^5a is– COOR ¹³ , wherein R ¹³ is an unsubstituted C ₁ -C ₁₀ alkyl.

[0087] In some embodiments, n is 0.

[0088] In some embodiments, m is 0.

[0089] In some embodiments, m is 1.

[0090] In some embodiments, at least one of m, q, and r is not 0.

[0091] In some embodiments, the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

[0092] In some embodiments, the compound is not a compound selected from the

or a pharmaceutically acceptable salt thereof.

[0093] In some embodiments, the cyclic phosphate compounds of Formula I, Ia, Ib, Ic, and Id are substrates of liver enzymes such as cytochrome p450 isozymes CYP3As (a family of monooxygenase), dehydrogenases, esterases, and amidases.

[0094] In some embodiments, the cyclic phosphate compounds of Formula I, Ia, Ib, Ic, and Id feature lipophilic R ^5b or other groups that facilitate cellular uptake of the compounds. [0095] In some embodiments, the compound is activated within a cell upon cleavage of the prodrug moieties, releasing an active form of the compound.

[0096] CYP3A4 is expressed in the liver in a level much higher than other tissues (DeWaziers et al. J Pharm Exp Ther 253:387 (1990)). Certain cyclic phosphate compounds of Formula I, Ia, Ib, Ic, and Id are predominantly activated via CYP3A4 in the liver. In some embodiments, the compounds of Formula I, Ia, Ib, Ic, and Id have high efficiency in liver- targeting via selective delivery of biologically relevant nucleotide to the liver. In some embodiments, the cyclic phosphate compounds are used to increase the therapeutic index of an agent, since the compounds of Formula I, Ia, Ib, Ic, and Id may not be active or may be less active outside the liver.

[0097] In some embodiments, due to the liver-targeting nature of the cyclic phosphate compounds of Formula I, Ia, Ib, Ic, and Id, the compounds are used to treat diseases that benefit from enhanced drug distribution to the liver and like tissues and cells, including but not limited to diseases of the liver.

[0098] In some embodiments, the cyclic phosphate compounds of Formula I, Ia, Ib, Ic, and Id may be effectively activated by enzymes other than CYP3A4 and the compounds are used to treat non-liver diseases.

[0099] In some embodiments, the disclosed compounds are used to improve pharmacokinetic properties such as prolonging half-life or enhancing absorption of a nucleotide. In addition, the disclosed methodology can be used to achieve sustained delivery of a biologically relevant nucleotide. Due to the pharmacokinetic property enhancement of the cyclic phosphate compounds of Formula I, Ia, Ib, Ic, and Id, the compounds are used to treat diseases that benefit from enhanced drug properties. In some embodiments, a method of making these compounds is described.

[0100] Certain compounds of Formula I, Ia, Ib, Ic, and Id have asymmetric centers where the stereochemistry may be unspecified, and the diastereomeric mixtures of these compounds are included, as well as the individual stereoisomers when referring to a compound of Formula I I, Ia, Ib, Ic, and Id generally.

[0101] In some embodiments, an effective amount of a disclosed compound is used to treat a disease, disorder, or condition in a subject in need thereof. [0102] Some embodiments of the compounds, compositions and methods provided herein include a pharmaceutical composition comprising a compound provided herein and a pharmaceutically acceptable carrier.

[0103] Some embodiments also include administering an effective amount of a second or multiple therapeutic agents in combination with a compound provided herein to the subject in need thereof.

[0104] In some embodiments, the subject is mammalian.

[0105] In some embodiments, the subject is human.

[0106] Some embodiments of the compounds, compositions and methods provided herein include a method of testing a compound in a cell comprising contacting the cell with the disclosed compounds.

[0107] Some embodiments of the compounds, compositions and methods provided herein include use of a compound provided herein in the treatment of a disease of the liver or a disease or condition in which the physiological or pathogenic pathways involve the liver in a subject.

[0108] Some embodiments include the use of a compound provided herein in combination with one or more additional therapeutic agent(s) for the treatment of a disease of the liver.

[0109] Some embodiments of the compounds, compositions and methods provided herein include use of a compound provided herein in the treatment of a disease or condition by intervening in a molecular pathway in the liver.

[0110] Some embodiments include the use of a compound provided herein in combination with additional therapeutic agent(s) for the treatment of a disease or condition by intervening in a molecular pathway in the liver.

[0111] Some embodiments of the compounds, compositions and methods provided herein include use of a compound provided herein in the treatment of a non-liver disease.

[0112] Some embodiments include the use of a compound provided herein in combination with additional therapeutic agent(s) for the treatment of a non-liver disease. [0113] Some embodiments related to use of the compounds provided herein in the preparation of a medicament for treating a disease or condition in the liver or a disease or condition in which the physiological or pathogenic pathways involve the liver.

[0114] Some embodiments relate to a method of treating a disease, disorder, or condition comprising administering an effective amount of the compounds provided herein to a subject in need thereof.

[0115] Where the compounds disclosed herein have at least one chiral center, they may exist as individual enantiomers and diastereomers or as mixtures of such isomers, including racemates. Separation of the individual isomers or selective synthesis of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art. Unless otherwise indicated, all such isomers and mixtures thereof are included in the scope of the compounds disclosed herein. Furthermore, compounds disclosed herein may exist in one or more crystalline or amorphous forms. Unless otherwise indicated, all such forms are included in the scope of the compounds disclosed herein including any polymorphic forms. In addition, some of the compounds disclosed herein may form solvates with water (i.e., hydrates) or common organic solvents. Unless otherwise indicated, such solvates are included in the scope of the compounds disclosed herein.

[0116] The skilled artisan will recognize that some structures described herein may be resonance forms or tautomers of compounds that may be fairly represented by other chemical structures, even when kinetically; the artisan recognizes that such structures may only represent a very small portion of a sample of such compound(s). Such compounds are considered within the scope of the structures depicted, though such resonance forms or tautomers are not represented herein.

[0117] Isotopes may be present in the compounds described. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound structure a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise. Definitions

[0118] In accordance with the present disclosure and as used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. In this application, the use of “or” means“and/or” unless stated otherwise. Furthermore, use of the term“including” as well as other forms, such as“includes,” and “included” is not limiting.

[0119] As used herein, ranges and amounts can be expressed as“about” a particular value or range. “About” also includes the exact amount. Hence“about 10%” means“about 10%” and also“10%.”

[0120] As used herein,“optional” or“optionally” means that the subsequently described event or circumstance does or does not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, an optionally substituted group means that the group is unsubstituted or is substituted.

[0121] As used herein, the singular forms“a,”“an” and“the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a composition comprising“a therapeutic agent” includes compositions with one or a plurality of therapeutic agents.

[0122] As used herein,“C _a to C _b ” or“C _a-b ” in which“a” and“b” are integers refer to the number of carbon atoms in the specified group. That is, the group can contain from “a” to“b”, inclusive, carbon atoms. Thus, for example, a“C1 to C4 alkyl” or“C1-4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, 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-.

[0123] As used herein,“alkyl” refers to a straight or branched hydrocarbon chain that is fully saturated (i.e., contains no double or triple bonds). The alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as“1 to 20” refers to each integer in the given range; e.g.,“1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term“alkyl” where no numerical range is designated). The alkyl group may also be a medium size alkyl having 1 to 9 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 4 carbon atoms. The alkyl group may be designated as“C1-C4 alkyl” or similar designations. By way of example only,“C1-C4 alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso- propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.

[0124] As used herein, a substituted group is derived from the unsubstituted parent group in which there has been an exchange of one or more hydrogen atoms for another atom or group. Unless otherwise indicated, when a group is deemed to be“substituted,” it is meant that the group is substituted with one or more substituents independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 carbocyclyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7-carbocyclyl- C ₁ -C ₆ -alkyl (optionally substituted with halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, and C1-C6 haloalkoxy), 3-10 membered heterocycle (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 3-10 membered heterocycyl- C ₁ -C ₆ -alkyl (optionally substituted with halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, and C1-C6 haloalkoxy), aryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1- C6 haloalkyl, and C1-C6 haloalkoxy), aryl(C1-C6)alkyl (optionally substituted with halo, C1- 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 halo, 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(C1-C6)alkyl (optionally substituted with halo, C1-C6 alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, and C ₁ -C ₆ haloalkoxy), halo, cyano, hydroxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy(C ₁ -C ₆ )alkyl (i.e., ether), aryloxy (optionally substituted with halo, C ₁ - C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7 carbocyclyloxy (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 3-10 membered heterocyclyl-oxy (optionally substituted with halo, C ₁ -C ₆ alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heteroaryl-oxy (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7-carbocyclyl-C1-C6-alkoxy (optionally substituted with halo, C1-C6 alkyl, 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 halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, and C ₁ - C6 haloalkoxy), aryl(C1-C6)alkoxy (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heteroaryl(C1-C6)alkoxy (optionally substituted with halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, and C ₁ -C ₆ haloalkoxy), sulfhydryl (mercapto), halo(C1-C6)alkyl (e.g.,–CF3), halo(C1-C6)alkoxy (e.g.,– OCF3), C1-C6 alkylthio, arylthio (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C ₁ -C ₆ haloalkyl, and C ₁ -C ₆ haloalkoxy), C ₃ -C ₇ carbocyclylthio (optionally substituted with halo, 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-thio (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C ₁ -C ₆ haloalkoxy), 5-10 membered heteroaryl-thio (optionally substituted with halo, 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-C1-C6-alkylthio (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1- C6 haloalkyl, and C1-C6 haloalkoxy), 3-10 membered heterocyclyl-C1-C6-alkylthio (optionally substituted with halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, and C ₁ -C ₆ haloalkoxy), aryl(C1-C6)alkylthio (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heteroaryl(C1-C6)alkylthio (optionally substituted with halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, and C ₁ -C ₆ haloalkoxy), amino, amino(C1-C6)alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, and oxo (=O). Wherever a group is described as“optionally substituted” that group can be substituted with the above substituents.

[0125] As used herein,“acyl” refers to–C(=O)R, wherein R is hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 carbocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocycyl, as defined herein. Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acryl.

[0126] An“heteroacyl” refers to–C(=O)R, wherein R is a C _1-6 heteroalkyl.

[0127] An“alkyloxymethylene” refers to–CH2OR, wherein R is a C1-6 alkyl, or heteroalkyl, all optionally substituted. [0128] An“O-carboxy” group refers to a“-OC(=O)R” group 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 heterocycyl, as defined herein.

[0129] A“C-carboxy” group refers to a“-C(=O)OR” group in which R is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5- 10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein. A non- limiting example includes carboxyl (i.e., -C(=O)OH).

[0130] A“cyano” group refers to a“-CN” group.

[0131] A“cyanato” group refers to an“-OCN” group.

[0132] An“isocyanato” group refers to a“-NCO” group.

[0133] A“thiocyanato” group refers to a“-SCN” group.

[0134] An“isothiocyanato” group refers to an“ -NCS” group.

[0135] A“sulfinyl” group refers to an“-S(=O)R” group in which R is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocycyl, as defined herein.

[0136] A“sulfonyl” group refers to an“-SO ₂ R” group in which R is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocycyl, as defined herein.

[0137] An“S-sulfonamido” group refers to a“-SO ₂ NR _A R _B ” group in which R _A and R _B are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocycyl, as defined herein.

[0138] An“N-sulfonamido” group refers to a“-N(R _A )SO ₂ R _B ” group in which R _A and R _b are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C _3-7 carbocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocycyl, as defined herein.

[0139] An“O-carbamyl” group refers to a“-OC(=O)NR _A R _B ” group in which R _A and R _B are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C _3-7 carbocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocycyl, as defined herein. [0140] An“N-carbamyl” group refers to an“-N(R _A )C(=O)OR _B ” group in which 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 heterocycyl, as defined herein.

[0141] An“O-thiocarbamyl” group refers to a“-OC(=S)NR _A R _B ” group in which R _A and R _B are each independently selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocycyl, as defined herein.

[0142] An“N-thiocarbamyl” group refers to an“-N(R _A )C(=S)OR _B ” group in which R _A and R _B are each independently selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2- 6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocycyl, as defined herein.

[0143] A“C-amido” group refers to a“-C(=O)NR _A R _B ” group in which R _A and R _B are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocycyl, as defined herein each optionally substituted with one or more substituents selected from the group consisting of–OH, C1-6 alkyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, 3-10 membered heterocycyl, C1-6 alkyl optionally substituted with C1-6 alkoxy or–OH and C _1-6 alkoxy optionally substituted with C _1-6 alkoxy or–OH.

[0144] An“N-amido” group refers to a“-N(R _A )C(=O)R _B ” group in which R _A and R _B are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C _3-7 carbocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocycyl, as defined herein each optionally substituted with one or more substituents selected from the group consisting of–OH, C1-6 alkyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, 3-10 membered heterocycyl, 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.

[0145] An“amino” group refers to a“-NR _A R _B ” group in which R _A and R _B are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocycyl, as defined herein. A non-limiting example includes free amino (i.e., -NH2). [0146] An“aminoalkyl” group refers to an amino group connected via an alkylene group.

[0147] An“alkoxyalkyl” group refers to an alkoxy group connected via an alkylene group, such as a“C2-8 alkoxyalkyl” and the like.

[0148] The term“acyloxy” refers to -OC(O)R where R is alkyl.

[0149] The term“alkoxy” or“alkyloxy” refers to OR where R is alkyl, or heteroalkyl, all optionally substituted.

[0150] The term“carboxyl” refers to a C(O)OH.

[0151] The term“oxo” refers to an =O group.

[0152] The term“halogen” or“halo” refers to F (fluoro), Cl (chloro), Br (bromo) and I (iodo).

[0153] The term“haloalkyl” refer to alkyl groups containing at least one halogen, in a further aspect are 1 to 3 haloatoms. Suitable haloatoms include F, Cl, and Br.

[0154] The term“haloacyl” refer to -C(O)-haloalkyl groups.

[0155] The term“alkenyl” refers to unsaturated groups which have 2 to 12 atoms and contain at least one carbon carbon double bond and includes straight chain, branched chain and cyclic groups. Alkenyl groups may be optionally substituted. Suitable alkenyl groups include allyl.

[0156] The term“alkynyl” refers to unsaturated groups which have 2 to 12 atoms and contain at least one carbon carbon triple bond and includes straight chain, branched chain and cyclic groups. Alkynyl groups may be optionally substituted. Suitable alkynyl groups include ethynyl.

[0157] As used herein,“aryl” refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent carbon atoms) containing only carbon in the ring backbone. When the aryl is a ring system, every ring in the system is aromatic. The aryl group may have 6 to 18 carbon atoms, although the present definition also covers the occurrence of the term“aryl” where no numerical range is designated. In some embodiments, the aryl group has 6 to 10 carbon atoms. The aryl group may be designated 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. [0158] As used herein,“heteroaryl” refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent atoms) that contain(s) one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the ring backbone. When the heteroaryl is a ring system, every ring in the system is aromatic. The heteroaryl group may have 5-18 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term“heteroaryl” where no numerical range is designated. In some embodiments, the heteroaryl group has 5 to 10 ring members or 5 to 7 ring members. The heteroaryl group may be designated as“5-7 membered heteroaryl,”“5-10 membered heteroaryl,” or similar designations. Heteroaryl groups may be optionally substituted. Examples of heteroaryl groups include, but are not limited to, aromatic C3-8 heterocyclic groups comprising 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 as well as benzo- and pyrido-fused derivatives, for example, connected via one of the ring-forming carbon atoms. In some embodiments, heteroaryl groups are optionally substituted with one or more substituents, independently selected from halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, C1-6-alkoxy, C1-6-alkyl, C1-6-hydroxyalkyl, C1-6-aminoalkyl, C1-6-alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl. Examples of heteroaryl groups include, but are not limited to, unsubstituted and mono- or di-substituted derivatives of furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole, quinoline, isoquinoline, pyridazine, pyrimidine, purine and pyrazine, furazan, 1,2,3-oxadiazole, 1,2,3- thiadiazole, 1,2,4-thiadiazole, triazole, benzotriazole, pteridine, phenoxazole, oxadiazole, benzopyrazole, quinolizine, cinnoline, phthalazine, quinazoline, and quinoxaline. In some embodiments, the substituents are halo, hydroxy, cyano, O-C _1-6 -alkyl, C _1-6 -alkyl, hydroxy-C _1- 6-alkyl, and amino-C1-6-alkyl.

[0159] As used herein,“cycloalkyl” means a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The cycloalkyl group may have 3 to 10 carbon atoms (whenever it appears herein, a numerical range such as“3 to 10” refers to each integer in the given range. The cycloalkyl group may be designated as“C3-C8 cycloalkyl” or similar designations. By way of example only,“C3-C8 cycloalkyl” indicates that there are three to eight carbon atoms in the carbocyclyl ring or ring system.

[0160] As used herein,“heterocyclyl” means a non-aromatic cyclic ring or ring structure that is fully saturated or partially saturated and includes at least one heteroatom selected from nitrogen, oxygen, and sulfur in the ring backbone. Heterocyclyls may have any degree of saturation provided that at least one ring in the ring system is not aromatic. The heteroatom(s) may be present in either a non-aromatic or aromatic ring in the ring system. The heterocyclyl group may have 3 to 20 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term“heterocyclyl” where no numerical range is designated. The heterocyclyl group may also be a medium size heterocyclyl having 3 to 10 ring members. The heterocyclyl group could also be a heterocyclyl having 3 to 6 ring members. The heterocycloalkyl group may be designated as “3-15-membered heterocycloalkyl,”“4-10-membered heterocycloalkyl,”“3-15-membered C ₂ - ₁₄ heterocycloalkyl,” “5-9-membered C ₄ - ₈ heterocycloalkyl,” “5-10-membered C4-9heterocycloalkyl,” “5-membered C3-4heterocycloalkyl,” “6-membered C4-5heterocycloalkyl,” “7-membered C5-6heterocycloalkyl,” “bicyclic or tricyclic 9-15-membered C _8-14 heterocycloalkyl,” “monocyclic or bicyclic 3-10-membered C2-9heterocycloalkyl,” “bicyclic 8-10-membered C4-9heterocycloalkyl,” “bicyclic 8-10-membered C5-9heterocycloalkyl,”“monocyclic 4-7-membered C3-6-heterocycloalkyl,” “monocyclic 5-6-membered C _3-5- heterocycloalkyl,” or similar designations. The heterocyclyl group could also be a C _2- C ₉ heterocyclyl having 3 to 10 ring members with from one up to three of O (oxygen), N (nitrogen) or S (sulfur). The heterocyclyl group may be designated as“3-10 membered C _2- C ₉ heterocyclyl” or similar designations. In preferred six membered monocyclic heterocyclyls, the heteroatom(s) are selected from one up to three of O (oxygen), N (nitrogen) or S (sulfur), and in preferred five membered monocyclic heterocyclyls, the heteroatom(s) are selected from one or two heteroatoms selected from O (oxygen), N (nitrogen) or S (sulfur). Examples of heterocyclyl rings include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl, 1,4- oxathiinyl, 1,4-oxathianyl, 2H-1,2-oxazinyl, trioxanyl, hexahydro-1,3,5-triazinyl, 1,3- dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, and tetrahydroquinoline.

[0161] Similarly, when two“adjacent” R groups are said to form a ring“together with the atom to which they are attached,” it is meant that the collective unit of the atoms, intervening bonds, and the two R groups are the recited ring. For example, when the following substructure is present:

and R ¹ and R ² are defined as 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 an aryl or carbocyclyl, it is meant that R ¹ and R ² can be selected from hydrogen or alkyl, or alternatively, the substructure has structure:

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

[0162] Wherever a substituent is depicted as a di-radical (i.e., has two points of attachment to the rest of the molecule), it is to be understood that the substituent can be attached in any directional configuration unless otherwise indicated. Thus, for example, a substituent depicted as–AE– or includes the substituent being oriented such that the A is attached at the leftmost attachment point of the molecule as well as the case in which A is attached at the rightmost attachment point of the molecule.

[0163] The phrase“therapeutically effective amount” means an amount of a compound or a combination of compounds that partially or fully ameliorates, attenuates 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 of the symptoms of a particular disease or condition. Such amount can be administered as a single dosage or can be administered according to a regimen, whereby it is effective. Repeated administration may be needed to achieve a desired result (e.g., treatment of the disease and/or condition).

[0164] The term“pharmaceutically acceptable salt” includes salts of compounds of Formula I derived from the combination of a compound of the present embodiments 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 derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, adipic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, (+)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-methanesulfoni c acid, 1,2-ethanedisulfonic acid, dodecyl sulfonic acid, salicylic acid, glucoheptonic acid, gluconic acid, glucuronic acid, hippuric acid, hydrochloride hemiethanolic acid, 2- hydroxyethanesulfonic acid, lactic acid, lactobionic acid, methylbromide acid, methyl sulfuric acid, 2-naphthalenesulfonic acid, oleic acid, 4,4ʹ-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 derived include, for example, bases that contain 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, treatment of the compounds disclosed herein with an inorganic base results in loss of a labile hydrogen from the compound to afford the salt form including an inorganic cation such as Li ⁺ , Na ⁺ , K ⁺ , Mg ²⁺ and Ca ²⁺ and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.

[0165] Where the number of any given substituent is not specified (e.g., "haloalkyl"), there may be one or more substituents present. For example, "haloalkyl" can include one or more of the same or different halogens. For example,“haloalkyl” includes each of the substituents CF3, CHF2 and CH2F.

[0166] The term“patient” refers to an animal being treated including a mammal, such as a dog, a cat, a cow, a horse, a sheep, and a human. In some embodiments, the patient is a mammal, either male or female. In some embodiments, the patient is a male or female human.

[0167] The term“prodrug” as used herein refers to any compound that when administered to a biological system generates a biologically active compound as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), and/or metabolic chemical reaction(s), or a combination of each. Standard prodrugs are formed using groups attached to functionality, e.g. HO-, HS-, HOOC-, HOOPR2-, associated with the drug, that cleave in vivo. Standard prodrugs include but are not limited to carboxylate esters where the group is alkyl, aryl, aralkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl as well as esters of hydroxyl, thiol and amines where the group attached is an acyl group, an alkoxycarbonyl, aminocarbonyl, phosphate or sulfate. The groups illustrated are examples, not exhaustive, and one skilled in the art could prepare other known varieties of prodrugs. Prodrugs must undergo some form of a chemical transformation to produce the compound that is biologically active or is a precursor of the biologically active compound. In some cases, the prodrug is biologically active, usually less than the drug itself, and serves to improve drug efficacy or safety through improved oral bioavailability, pharmacodynamic half-life, etc. Prodrug forms of compounds may be utilized, for example, to improve bioavailability, improve subject acceptability such as by masking or reducing unpleasant characteristics such as bitter taste or gastrointestinal irritability, alter solubility such as for intravenous use, provide for prolonged or sustained release or delivery, improve ease of formulation, or provide site specific delivery of the compound. [0168] The term “stereoisomer” refers to the relative or absolute spatial relationship of the R group(s) attached to the stereogenic centers either carbon or phosphorus atoms, and refers to individual or any combination of the individual isomers such as a racemic mixture and a diastereomeric mixture. When a compound has two stereogenic centers, there are 4 potential stereoisomers.

[0169] The term“liver” refers to the liver organ.

[0170] The term“liver specificity” refers to the ratio:

[drug or a drug metabolite in liver tissue]/

[drug or a drug metabolite in blood or another tissue]

[0171] as measured in animals treated with the drug or a prodrug. The ratio can be determined by measuring tissue levels at a specific time or may represent an AUC (area under a curve) based on values measured at three or more time points.

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

[0173] The term“enhanced oral bioavailability” refers to an increase of at least about 50% of the absorption of the dose of the reference drug. In an additional aspect, the increase in oral bioavailability of the compound (compared to the reference drug) is at least about 100%, or a doubling of the absorption. Measurement of oral bioavailability usually refers to measurements of the prodrug, drug, or drug metabolite in blood, plasma, tissues, or urine following oral administration compared to measurements following parenteral administration.

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

[0175] The term“sustained delivery” refers to an increase in the period in which there is a prolongation of therapeutically-effective drug levels due to the presence of the prodrug.

[0176] The terms“treating” or“treatment” of a disease includes inhibiting the disease (slowing or arresting or partially arresting its development), preventing the disease, providing relief from the symptoms or side effects of the disease (including palliative treatment), and/or relieving the disease (causing regression of the disease).

[0177] The terms“biological agent” refers to a compound that has biological activity or that has molecular properties that can be used for therapeutic or diagnosis purposes, such as a compound carrying a radioactive isotope or a heavy atom.

[0178] The terms“molecular pathway” refers to a series of molecular events in tissues such as a receptor modulating sequence, an enzyme modulating sequence, or a biosynthesis sequence that is involved in physiological or pathophysiological functions of a living animal.

Administration and Pharmaceutical Compositions

[0179] The disclosed compounds may be used alone or in combination with other treatments. These compounds, when used in combination with other agents, may be administered as a daily dose or an appropriate fraction of the daily dose (e.g., b.i.d.). The compounds may be administered after a course of treatment by another agent, during a course of therapy with another agent, administered as part of a therapeutic regimen, or may be administered prior to therapy with another agent in a treatment program.

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

[0181] Compositions containing the active ingredient may be in any form suitable for the intended method of administration. In some embodiments, the compounds of a method and/or composition 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, intranasal administration, intraocular administration and/or parenteral administration.

[0182] When the compounds are administered via oral administration, for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

[0183] Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient can be mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient can be mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

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

[0185] In some embodiments unit dosage formulations contain a daily dose or unit, daily sub-dose, or an appropriate fraction thereof, of a drug. It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs which have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those skilled in the art.

[0186] The actual dose of the compounds described herein depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan. In some embodiments, a daily dose may be from about 0.1 mg/kg to about 100 mg/kg or more of body weight, from about 0.25 mg/kg or less to about 50 mg/kg from about 0.5 mg/kg or less to about 25 mg/kg, from about 1.0 mg/kg to about 10 mg/kg of body weight. Thus, for administration to a 70 kg person, the dosage range would be from about 7 mg per day to about 7000 mg per day, from about 35 mg per day or less to about 2000 mg per day or more, from about 70 mg per day to about 1000 mg per day.

Methods of Treatment

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

[0188] Further embodiments include administering a combination of compounds to a subject in need thereof. A combination can include a compound, composition, pharmaceutical composition described herein with an additional medicament.

[0189] Some embodiments include co-administering a compound, composition, and/or pharmaceutical composition described herein, with an additional medicament or additional therapeutic agent(s). By“co-administration,” it is meant that the two or more agents may be found in the patient’s bloodstream at the same time, regardless of when or how they are actually administered. In one embodiment, the agents are administered simultaneously. In one such embodiment, administration in combination is accomplished by combining the agents in a single dosage form. In another embodiment, the agents are administered sequentially. In one embodiment, the agents are administered through the same route, such as orally. In another embodiment, the agents are administered through different routes, such as one being administered orally and another being administered i.v.

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

[0191] To further illustrate this invention, the following examples are included. The examples should not, of course, be construed as specifically limiting the invention. Variations of these examples within the scope of the claims are within the purview of one skilled in the art and are considered to fall within the scope of the invention as described, and claimed herein. The reader will recognize that the skilled artisan, armed with the present disclosure, and skill in the art is able to prepare and use the invention without exhaustive examples.

Synthesis of compounds

[0192] The following procedures for the preparation of the new compounds illustrate the general procedures used to prepare the cyclic phosphate compounds.

[0193] Scheme I describes general synthesis of the compounds of Formula I. Nucleoside (1) reacts with the phosphanediamine (2) in the presence of 4,5-dicyanoimidazole to give the cyclic product of structure 3 and the crude reaction mixture is then treated with an oxidation agent such as tert-butyl hydroperoxide to afford the final product of Formula I.

Scheme I

EXAMPLES

[0194] Some compounds of Formula I are prepared as outlined below.

Example 1

[0195] Isopropyl 2-((((4aR,6R,7aS)-6-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)- yl)-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2 -yl)oxy)methyl)benzoate (Compound 101)

[0196] Compound 101 was prepared according to the method described in Scheme I from 1-chloro-N,N,N',N'-tetraisopropylphosphanediamine and deoxyuridine as follows. Isopropyl 2-(hydroxymethyl)benzoate

[0197] A mixture of phthalic anhydride (20g, 0.15 mol) in isopropanol was heated at 90 ºC for 6 hours and the resulting mixture was dried to provide 2- (isopropoxycarbonyl)benzoic acid in almost quantitative yield. The benzoic acid derivative (10 g, 48 mmol) in THF was treated with excess borane dimethylsulfide for 2 hours at 0-20 ºC. Standard work-up and silica gel chromatography provided the title compound (4.1 g, 44%). N,N,N',N'-tetraisopropyl-1-(2-(2-isopropyloxy)carbonylbenzyl oxy)phosphanediamine

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

Compound 101

[0199] A reaction mixture of the above crude phosphanediamine, deoxyuridine (1.0 equiv.) and DCI (2.5 equiv.) in a 3:1 mixture of THF and DMF was heated at 55 ºC for 0.5 hour and the resulting mixture was dried to give the crude product. The crude was then dissolved in THF and treated with 2.5 equivalent of TBHP at 0 ºC for 0.5 hour. Standard work-up followed by silica gel chromatography gave Compound 101 as a mixture of two isomers in about 15% overall yield from deoxyuridine. [M-1] ⁺ calculated for C ₂₀ H ₂₃ N ₂ O ₉ P: 465.10. Found: 465.1.

Example 2

[0200] 4-Amino-1-((4aR,6R,7aS)-2-(nonyloxy)-2-oxidotetrahydro-4H-fu ro[3,2- d][1,3,2]dioxaphosphinin-6-yl)pyrimidin-2(1H)-one (Compound 102)

[0201] Compound 102 was prepared according to the method described in Scheme I from N,N,N',N'-tetraisopropyl-1-nonyloxyphosphanediamine and deoxycytidine as a mixture of two isomers. [M-1] ⁺ calculated for C18H30N3O6P: 414.18. Found: 414.1.

Example 3

[0202] 5-Methyl-1-((4aR,6R,7aS)-2-(octyloxy)-2-oxidotetrahydro-4H-f uro[3,2- d][1,3,2]dioxaphosphinin-6-yl)pyrimidine-2,4(1H,3H)-dione (Compound 103)

[0203] Compound 103 was prepared according to the method described in Scheme I from N,N,N',N'-tetraisopropyl-1-octyloxyphosphanediamine and thymidine as a mixture of two isomers. [M-1] ⁺ calculated for C ₁₈ H ₂₉ N ₂ O ₇ P: 415.16. Found: 415.1.

Example 4

[0204] (4aR,6R,7aS)-6-(6-Amino-9H-purin-9-yl)-2-phenethoxytetrahydr o-4H- furo[3,2-d][1,3,2]dioxaphosphinine 2-oxide (Compound 104)

[0205] Compound 104 was prepared according to the method described in Scheme I from N,N,N',N'-tetraisopropyl-1-(2-phenylethoxy)phosphanediamine and deoxyadenosine as a mixture of two isomers. [M-1] ⁺ calculated for C18H20N5O5P: 416.11. Found: 416.1.

Example 5

[0206] 2-Amino-9-((4aR,6R,7aS)-2-(octyloxy)-2-oxidotetrahydro-4H-fu ro[3,2- d][1,3,2]dioxaphosphinin-6-yl)-1,9-dihydro-6H-purin-6-one (Compound 105)

[0207] Compound 105 was prepared according to the method described in Scheme I from N,N,N',N'-tetraisopropyl-1-octoxyphosphanediamine and deoxyguanosine as a mixture of two isomers. [M-1] ⁺ calculated for C18H28N5O6P: 440.17. Found: 440.2. Example 6

[0208] Propyl 2-((((4aR,6R,7aS)-6-(5-(methyl-d3)-2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)-2-oxidotetrahydro-4H-furo[3,2-d][ 1,3,2]dioxaphosphinin-2- yl)oxy)methyl)benzoate (Compound 106)

[0209] Compound 106 was prepared according to the method described in Scheme I from N,N,N',N'-tetraisopropyl-1-(2-(1- propyloxycarbonyl)benzyloxy)phosphanediamine and thymidine-d ₃ as a mixture of two isomers. [M-1] ⁺ calculated for C21H22D3N5O7P: 482.14. Found: 482.1.

Example 7

[0210] Isopropyl 2-((((4aR,6R,7R,7aR)-6-(2,4-dioxo-3,4-dihydropyrimidin- 1(2H)-yl)-7-fluoro-7-methyl-2-oxidotetrahydro-4H-furo[3,2-d] [1,3,2]dioxaphosphinin-2- yl)oxy)methyl)benzoate (Compound 107)

[0211] Compound 107 was prepared according to the method described in Scheme I from N,N,N',N'-tetraisopropyl-1-(2-(2- isopropyloxy)carbonylbenzyloxy)phosphanediamine and the uridine derivative as a mixture of two isomers. [M-1] ⁺ calculated for C21H24FN2O9P: 497.11. Found: 497.1.

Example 8

[0212] Isopropyl 2-((((4aR,6R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7,7- difluoro-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphi nin-2-yl)oxy)methyl)benzoate (Compound 108)

[0213] Compound 108 was prepared according to the method described in Scheme I from N,N,N',N'-tetraisopropyl-1-(2-(2- isopropyloxy)carbonylbenzyloxy)phosphanediamine and the cytidine derivative as a mixture of two isomers. [M-1] ⁺ calculated for C ₂₀ H ₂₂ F ₂ N ₃ O ₈ P: 500.10. Found: 500.1.

Example 9

[0214] Isopropyl 2-((((4aR,6R,7S,7aS)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7- hydroxy-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphin in-2-yl)oxy)methyl)benzoate (Compound 109)

[0215] Compound 109 was prepared according to the method described in Scheme I from N,N,N',N'-tetraisopropyl-1-(2-(2- isopropyloxy)carbonylbenzyloxy)phosphanediamine and the cytidine derivative as a mixture of two isomers. [M-1] ⁺ calculated for C ₂₀ H ₂₄ N ₃ O ₉ P: 480.39. Found: 480.3.

Biological Examples

[0216] Examples of use of the method include the following. It will be understood that the following are examples and that the method is not limited solely to these examples. Example 10: Tissue Distribution Following Oral Administration of reference compounds and the disclosed compounds

[0217] The liver specificity of the disclosed compounds is compared relative to a corresponding active compound in liver and other organs that could be targets of toxicity. Methods:

[0218] Reference compounds and the cyclic phosphate compounds were administered at 5-50 mg/kg to fasted rats by oral gavage. Plasma concentrations of the metabolites, and parent compounds in circulation and in the hepatic portal vein were determined by HPLC-UV, and the liver, small intestine, and other organ concentrations were measured by LC-MS using standard chromatography methods.

[0219] Table 1 provides the results of selected compounds in comparison with their corresponding reference compounds, which demonstrated the improved efficiency of oral delivery of the known nucleosides. Table 1. Ratios of the new compounds vs corresponding reference compounds in nucleoside phosphates levels in the liver and nucleoside level in hepatic portal vein (HPV) and systemic blood one hour after oral administration of selected compounds at 5 mg/kg nucleoside equivalent doses in rats.

monophosphate; NUC = nucleoside

[0220] These results demonstrate that Compounds 106 and 107 provide substantially higher levels of nucleoside phosphates in the liver compared to the reference compounds.

[0221] All numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification are to be understood as being modified in all instances by the term“about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth herein are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of any claims in any application claiming priority to the present application, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches.

[0222] Language of degree used herein, such as the terms“approximately,” “about,”“generally,” and“substantially” as used herein represent a value, amount, or characteristic close to the stated value, amount, or characteristic that still performs a desired function or achieves a desired result. For example, the terms“approximately”,“about”, “generally,” and“substantially” may refer to an amount that is within less than 10% of, within less than 5% of, within less than 1% of, within less than 0.1% of, and within less than 0.01% of the stated amount. As another example, in certain embodiments, the terms “generally parallel” and“substantially parallel” refer to a value, amount, or characteristic that departs from exactly parallel by less than or equal to 15%, 10%, 5%, 3%, 1%, 0.1%, or otherwise. Similarly, in certain embodiments, the terms“generally perpendicular” and “substantially perpendicular” refer to a value, amount, or characteristic that departs from exactly perpendicular by less than or equal to 15%, 10%, 5%, 3%, 1%, 0.1%, or otherwise.

[0223] The above description discloses several methods and materials. This invention is susceptible to modifications in the methods and materials, as well as alterations in the fabrication methods and equipment. Such modifications will become apparent to those skilled in the art from a consideration of this disclosure or practice of the invention disclosed herein. Consequently, it is not intended that this invention be limited to the specific embodiments disclosed herein, but that it cover all modifications and alternatives coming within the true scope and spirit of the invention.

[0224] 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 are hereby made a part of this specification. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and/or take precedence over any such contradictory material.

[0225] Although some embodiments and examples have been described, it should be understood that numerous and various modifications can be made without departing from the spirit of the invention.