Aqueous solutions containing purines and pyrimidines and uses thereof

Abstract

Compositions are provided that include a first heteroaryl compound and a second heteroaryl compound dissolved in an aqueous liquid. Methods for treating a patient are also provided, including orally administering such aqueous liquid to a patient, for example, a patient diagnosed with mitochondrial depletion syndrome. Kits are provided that include a first heteroaryl compound, a second heteroaryl compound, and optionally instructions for dissolving the first heteroaryl compound and the second heteroaryl compound in an aqueous liquid and administering the solution to a patient.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 166,860, filed March 26, 2021, which is incorporated by reference in its entirety. [Background technology]

[0002] Mitochondrial DNA depletion syndrome (MDS or MDDS) is a type of mitochondrial disease that can cause severe childhood encephalomyopathy, including encephalopathy (brain damage) and myopathy (muscle disease). Mitochondrial DNA depletion syndrome is molecularly characterized by a reduction in mitochondrial DNA (mtDNA) copy number in tissues and insufficient synthesis of mitochondrial respiratory chain (RC) complexes (Non-Patent Document 1). Mutations in several nuclear genes, including TK2, DGUOK, POLG, POLG2, SCLA25A4, MPV17, RRM2B, SUCLA2, SUCLG1, TYMP, OPA1, and ClOorfl (PEOl), have been identified as causes of infantile MDS (Non-Patent Documents 2-10). Furthermore, mutations in these nuclear genes can also cause multiple deletions of mtDNA with or without mtDNA depletion (Non-Patent Documents 11-20).

[0003] One of the genes involved in MDS is TK2, which encodes thymidine kinase (TK2), a mitochondrial enzyme required for phosphorylation of pyrimidine nucleosides (thymidine and deoxycytidine) to generate deoxythymidine monophosphate (dTMP) and deoxycytidine monophosphate (dCMP) (Non-Patent Document 21). Mutations in TK2 impair the mitochondrial nucleoside / nucleotide salvage pathway required for synthesis of deoxynucleotide triphosphates (dNTPs), the building blocks for mDNA replication and repair.

[0004] Symptom improvement has been observed after administration of thymidine and deoxycytidine to patients diagnosed with TK2 deficiency (Patent Document 1). However, relatively high doses of thymidine and deoxycytidine were administered (e.g., each nucleoside was initially administered at 130 mg / kg / day, divided into three equal daily doses of approximately 43 mg / kg / dose). If the tolerability profile is acceptable after two weeks, the dose can be increased to 260 mg / kg / day of each nucleoside, then 400 mg / kg / day. Thus, a 100 kg patient who reaches the upper limit of the daily dose can be administered up to 80 g of active substance per day (40 g deoxycytidine and 40 g thymidine).

[0005] Given the relatively low solubility of some nucleosides, such as thymidine, in water, large volumes of solution containing the nucleoside are required to administer the nucleoside as an oral solution. However, swallowing may be difficult for some MDS patients due to myopathy (muscle problems) associated with the disease. Thus, swallowing the large amounts of liquid required to dissolve the nucleoside may present difficulties for some MDS patients. Consuming nucleosides in solid form, such as in pill form, may also be problematic for MDS patients due to swallowing difficulties. Indeed, in some cases, patients are given most or all food and liquids through a tube, for example via a gastrostomy tube or a nasogastric tube, due to swallowing difficulties.

[0006] Taking these considerations into account, the International Conference on Harmonisation (ICH) has developed guidelines for the formulation of drugs. The pediatric ICH guidelines promote considerations such as ease of accurate dose measurement and the ability to deliver small volumes of liquid to minimise the risk of dosing errors, particularly in neonates, infants and young children. Such approaches can include clearly marked dosing devices and / or devices with scaling capabilities designed for precise measurement of minimum dose volumes and dose increments. [See, e.g., Non-Patent Documents 22 and 23.] [Prior art documents] [Chartered documents]

[0007]

Patent Document 1

Non-licensed literature

[0008] [Non-licensed document 1] Hirano et al,2001 [Non-licensed document 2] Bourdon, et al., Nat Genet 39,776-780(2007) [Non-licensed document 3] Copeland, Ann. Rev. Med. 59: 131-146 (2008)

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[0009] [Means for solving the problem]

[0010] In some embodiments, a composition is provided that includes one or more heteroaryl compounds dissolved in an aqueous liquid. In some embodiments, the heteroaryl compounds are selected from purines, pyrimidines, and combinations thereof.

[0011] In some embodiments, compositions are provided that include purines, pyrimidines, and combinations thereof dissolved in an aqueous liquid. In some embodiments, compositions are provided that include purine and pyrimidine combinations that exhibit 1) increased water solubility compared to the particular purine or pyrimidine alone, and 2) decreased dissolution times compared to the particular purine or pyrimidine alone. Improved solubility allows for quicker reconstitution and allows for less liquid to be used when making therapeutic formulations to minimize the risk of dosing errors. In some embodiments, increased water solubility and decreased dissolution times are exhibited by purine and purine combinations, pyrimidine and pyrimidine combinations, and purine and pyrimidine combinations.

[0012] In some embodiments, the composition comprises two purines in a molar ratio of about 10:1 to about 1:10. In some embodiments, the composition comprises two pyrimidines in a molar ratio of about 10:1 to about 1:10. In some embodiments, the composition comprises a purine and a pyrimidine in a molar ratio of about 10:1 to about 1:10, respectively. In some embodiments, the composition comprises a pyrimidine and a purine in a molar ratio of about 10:1 to about 1:10, respectively.

[0013] In some embodiments, compositions are provided that include purines, pyrimidines, and combinations thereof dissolved in an aqueous liquid. In some embodiments, the purines and pyrimidines may be selected from one or more of the purines and pyrimidines disclosed in U.S. Application No. 17 / 046,865, the entirety of which is incorporated herein by reference.

[0014] In some embodiments, the purines and pyrimidines can be selected from one or more purine or pyrimidine bases. In some embodiments, the purine or pyrimidine bases can be selected from cytosine, thymine, guanine, adenine, uracil, xanthine, and combinations thereof. In some embodiments, the purine or pyrimidine bases can be selected from derivatives of cytosine, derivatives of thymine, derivatives of guanine, derivatives of adenine, derivatives of uracil, derivatives of xanthine, and combinations thereof.

[0015] In some embodiments, compositions are provided that include two or more purines, two or more pyrimidines, or a mixture of two or more purines and pyrimidines. In some embodiments, the compositions include two purines. In some embodiments, the compositions include two pyrimidines. In some embodiments, the compositions include one purine and one pyrimidine. In some embodiments, the purine is a purine base selected from adenine and guanine. In some embodiments, the pyrimidine is a pyrimidine base selected from cytosine and thymine.

[0016] In some embodiments, the purine is a nucleoside or nucleoside derivative. In some embodiments, the purine is a nucleoside selected from guanosine and adenosine. In some embodiments, the purine is a deoxynucleoside selected from deoxyguanosine and deoxyadenosine.

[0017] In some embodiments, the pyrimidine is a nucleoside or nucleoside derivative. In some embodiments, the pyrimidine is a nucleoside selected from cytidine, thymidine, and uridine. In some embodiments, the pyrimidine is a deoxynucleoside selected from deoxycytidine, deoxyuridine, and thymidine.

[0018] In some embodiments, a composition is provided that includes thymidine and deoxycytidine dissolved in an aqueous liquid. In some embodiments, a composition is provided that includes a derivative of deoxyguanosine and a derivative of deoxyadenosine dissolved in an aqueous liquid.

[0019] In some embodiments, the composition comprises deoxyguanosine. In some embodiments, the composition comprises deoxyadenosine. In some embodiments, the composition comprises deoxyguanosine and deoxyadenosine.

[0020] In some embodiments, the composition comprises a derivative of deoxyguanosine. In some embodiments, the composition comprises a derivative of deoxyadenosine. In some embodiments, the composition comprises a derivative of deoxyguanosine and a derivative of deoxyadenosine.

[0021] In some embodiments, the composition comprises Compound C: [ka]

[0022] In some embodiments, the composition comprises a compound T: [ka]

[0023] In some embodiments, the composition comprises compound G: [ka]

[0024] In some embodiments, the composition comprises Compound A: [ka]

[0025] In some embodiments, the composition comprises compound G and compound A. In some embodiments, the composition comprises compound G and compound A in a molar ratio of about 1:0.1 to about 1:1. In some embodiments, the composition comprises compound G and compound A in a molar ratio of about 1:0.5 to about 1:1.

[0026] In some embodiments, the composition comprises thymidine and deoxycytidine in a weight ratio of about 1:0.1 to about 1:1. In some embodiments, the composition comprises thymidine and deoxycytidine in a weight ratio of about 1:0.4 to about 1:1.

[0027] In some embodiments, the composition comprises Compound C and Compound T. In some embodiments, the composition comprises Compound C and Compound T in a molar ratio of about 1:0.1 to about 1:1. In some embodiments, the composition comprises Compound C and Compound T in a molar ratio of about 1:0.5 to about 1:1.

[0028] In some embodiments, the composition comprises Compound G, Compound A, Compound C, and Compound T. In some embodiments, the composition comprises Compound G, Compound A, Compound C, and Compound T in an equimolar ratio.

[0029] In some embodiments, the composition comprises Compound G, Compound A, deoxycytidine (dC) and thymidine (dT). In some embodiments, the composition comprises Compound G, Compound A, deoxycytidine (dC) and thymidine (dT) in an equimolar ratio.

[0030] In some embodiments, a composition is provided that comprises a first heteroaryl compound and a second heteroaryl compound dissolved in an aqueous liquid, wherein the concentration of the first heteroaryl compound is greater compared to a composition that comprises the first heteroaryl compound dissolved in an aqueous liquid that does not include the second heteroaryl compound, and wherein the first heteroaryl compound and the second heteroaryl compound are selected from optionally substituted pyrimidines and optionally substituted purines.

[0031] In some embodiments, a composition is provided that includes a first heteroaryl compound and a second heteroaryl compound dissolved in an aqueous liquid, the concentration of the first heteroaryl compound is higher than a composition that includes the first heteroaryl compound dissolved in an aqueous liquid without the second heteroaryl compound, together with a third heteroaryl compound and a fourth heteroaryl compound, and the concentration of the third heteroaryl compound is higher than a composition that includes the third heteroaryl compound dissolved in an aqueous liquid without the fourth heteroaryl compound. In some embodiments, the composition includes a mixture of thymidine or a thymidine prodrug, deoxycytidine or a deoxycytidine prodrug, deoxyguanosine or a deoxyguanosine prodrug, and deoxyadenosine or a deoxyadenosine prodrug. In some embodiments, a composition that includes a mixture of thymidine or a thymidine prodrug, deoxycytidine or a deoxycytidine prodrug, deoxyguanosine or a deoxyguanosine prodrug, and deoxyadenosine or a deoxyadenosine prodrug enhances the solubility of both substituted pyrimidine pairs and substituted purine pairs.

[0032] In some embodiments, the optionally substituted pyrimidine and the optionally substituted purine are selected from a deoxynucleoside, a deoxynucleotide having 1 to 3 phosphate groups, a nucleoside, a nucleotide having 1 to 3 phosphate groups, and a prodrug of any of the foregoing.

[0033] In some embodiments, the optionally substituted pyrimidine has formula Ia: [ka] During the ceremony, R 2 is hydrogen or C 1 -C 4 alkyl; R 3 is hydrogen, amino, hydroxy, -OR 5 , -NHR 6 or carbonyl; R 5 is selected from hydrogen, halogen, optionally substituted alkyl, or optionally substituted aralkyl; R 6 is hydrogen, optionally substituted alkyl, optionally substituted aralkyl, -C(O)N(R 7 )(R 7´ ), -C(O)OR 8 , or -R 9 Selected from; R 7 , R 7´ , R 8 , and R 10 each independently represents hydrogen, optionally substituted C-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C3-C 10 selected from cycloalkyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R 9 teeth, [ka] and; R 11 is hydrogen, optionally substituted C1-C 10 Alkyl and optionally substituted C-C 10 alkenyl; R 13 is hydrogen or hydroxy; and [ka] represents a single bond or a double bond.

[0034] In some embodiments, the optionally substituted purine has the formula IIa: [ka] During the ceremony, R 3 is hydrogen, amino, hydroxy, -OR 5 , -NHR 6 or carbonyl; R 4 is hydrogen, amino, or -NHR 6 is selected from R 5 is selected from hydrogen, halogen, optionally substituted alkyl, or optionally substituted aralkyl; R 6 is hydrogen, optionally substituted alkyl, optionally substituted aralkyl, -C(O)N(R 7 )(R 7´ ), -C(O)OR 8 , or -R 9 Selected from; R 7 , R 7´ , R 8 , and R 10 each independently represents hydrogen, optionally substituted C-C 10Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C3-C 10 selected from cycloalkyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R 9 teeth, [ka] and; R 11 is hydrogen, optionally substituted C1-C 10 Alkyl and optionally substituted C-C 10 alkenyl; R 13 is hydrogen or hydroxy; and [ka] represents a single bond or a double bond.

[0035] In some embodiments, the first heteroaryl compound is thymidine and the second heteroaryl compound is deoxycytidine. In some embodiments, the thymidine is at a concentration of about 20 mg / mL or greater. In some embodiments, the thymidine is at a concentration ranging from about 40 mg / mL to about 60 mg / mL. In some embodiments, the thymidine is at a concentration ranging from about 50 mg / mL to about 90 mg / mL. In some embodiments, the mass of thymidine ranges from 0.5 g to 6.0 g per dose unit.

[0036] In some embodiments, deoxycytidine is at a concentration of about 20 mg / mL or greater. In some embodiments, deoxycytidine is at a concentration ranging from about 40 mg / mL to about 60 mg / mL. In some embodiments, deoxycytidine is at a concentration ranging from about 50 mg / mL to about 90 mg / mL. In some embodiments, the mass of deoxycytidine ranges from 0.5 g to 6.0 g per dosage unit. In some embodiments, the mass of deoxycytidine ranges from about 40% to about 100% of the mass of thymidine. In some embodiments, the mass of deoxycytidine ranges from about 90% to about 110% of the mass of thymidine.

[0037] In some embodiments, the combined mass of thymidine and deoxycytidine ranges from 1.0 g to 12.0 g per dosage unit.

[0038] In some embodiments, the first heteroaryl compound is compound G and the second heteroaryl compound is compound A. [ka]

[0039] In some embodiments, compound G is at a concentration of about 20 mg / mL or more. In some embodiments, compound G is at a concentration ranging from about 40 mg / mL to about 100 mg / mL. In some embodiments, compound G is at a concentration ranging from about 60 mg / mL to about 100 mg / mL. In some embodiments, compound A is at a concentration ranging from about 5 mg / mL to about 100 mg / mL. In some embodiments, the molar ratio of compound G to compound A is about 1:0.1 to about 1:1. In some embodiments, the molar ratio of compound G to compound A is about 1:0.5 to about 1:1. In some embodiments, the mass of compound G is in the range of 0.5 g to 6.0 g per dose unit. In some embodiments, the mass of compound A is in the range of 0.5 g to 6.0 g per dose unit. In some embodiments, the total mass of compound G and compound A is in the range of 1.0 g to 12.0 g per dose unit. In some embodiments, the mass of compound A is in the range of about 40% to about 100% of the mass of compound G. In some embodiments, the mass of compound A is in the range of about 90% to about 110% of the mass of compound G.

[0040] In some embodiments, the first heteroaryl compound and the second heteroaryl compound are selected from a derivative of a nucleoside and a derivative of a deoxynucleoside. In some embodiments, the first heteroaryl compound and the second heteroaryl compound are selected from a prodrug of a nucleoside and a prodrug of a deoxynucleoside.

[0041] In some embodiments, the first heteroaryl compound is a derivative of deoxyguanosine and the second heteroaryl compound is a derivative of deoxyadenosine, in some embodiments, the first heteroaryl compound is a prodrug of deoxyguanosine and the second heteroaryl compound is a prodrug of deoxyadenosine.

[0042] In some embodiments, the first heteroaryl compound and the second heteroaryl compound are selected from Group I: [ka]

[0043] In some embodiments, the first heteroaryl compound and the second heteroaryl compound are selected from Group II: [ka]

[0044] In some embodiments, a composition is provided that includes a first heteroaryl compound, a second heteroaryl compound, a third heteroaryl compound, and a fourth heteroaryl compound, in some embodiments, the first heteroaryl compound and the second heteroaryl compound are selected from Group I, and the third heteroaryl compound and the fourth heteroaryl compound are selected from Group II.

[0045] In some embodiments, the first heteroaryl compound is compound G and the second heteroaryl compound is compound A. [ka]

[0046] In some embodiments, compound G is present at a concentration ranging from about 40 mg / mL to about 100 mg / mL. In some embodiments, compound G is present at a concentration ranging from about 60 mg / mL to about 100 mg / mL. In some embodiments, compound A is present at a concentration ranging from about 5 mg / mL to about 100 mg / mL. In some embodiments, the mass of compound G ranges from about 0.5 g to about 6.0 g per dose unit. In some embodiments, the mass of compound A ranges from 0.5 g to 6.0 g per dose unit. In some embodiments, the total mass of compound G and compound A ranges from 1.0 g to 12.0 g per dose unit. In some embodiments, the molar ratio of compound G to compound A is about 1:0.1 to about 1:1. In some embodiments, the molar ratio of compound G to compound A is about 1:0.5 to about 1:1.

[0047] In some embodiments, the compositions disclosed herein are provided for use in treating patients with a mutation in the TK2 gene that results in mitochondrial depletion. In some embodiments, the compositions comprise a first heteroaryl compound and a second heteroaryl compound dissolved in an aqueous liquid, the concentration of the first heteroaryl compound is higher than that of a composition comprising the first heteroaryl compound dissolved in an aqueous liquid that does not contain the second heteroaryl compound, and the first heteroaryl compound and the second heteroaryl compound are selected from optionally substituted pyrimidines and optionally substituted purines.

[0048] In some embodiments, a method for treating a patient with a mutation in the TK2 gene that results in mitochondrial depletion is provided, comprising administering a composition disclosed herein. In some embodiments, a method for treating a patient with a mutation in the TK2 gene that results in mitochondrial depletion is provided, comprising administering a composition comprising a first heteroaryl compound and a second heteroaryl compound dissolved in an aqueous liquid, wherein the concentration of the first heteroaryl compound is higher than that of a composition comprising a first heteroaryl compound dissolved in an aqueous liquid that does not contain the second heteroaryl compound, and the first heteroaryl compound and the second heteroaryl compound are selected from an optionally substituted pyrimidine and an optionally substituted purine.

[0049] In some embodiments, a method is provided that includes dissolving a first heteroaryl compound and a second heteroaryl compound in an aqueous liquid to form a solution, wherein a concentration of the first heteroaryl compound is greater as compared to a composition comprising the first heteroaryl compound dissolved in an aqueous liquid without the second heteroaryl compound, and wherein the first heteroaryl compound and the second heteroaryl compound are selected from optionally substituted pyrimidines and optionally substituted purines.

[0050] In some embodiments, the dissolution is carried out for about 5 minutes or less and at least about 95% of the first heteroaryl compound and at least about 95% of the second heteroaryl compound are dissolved. In some embodiments, the dissolution is carried out for about 2 minutes or less and at least about 95% of the first heteroaryl compound and at least about 95% of the second heteroaryl compound are dissolved.

[0051] In some embodiments, the first heteroaryl compound is thymidine and the second heteroaryl compound is deoxycytidine. In some embodiments, thymidine is present at a concentration ranging from about 40 mg / mL to about 60 mg / mL. In some embodiments, thymidine is present at a concentration ranging from about 50 mg / mL to about 90 mg / mL. In some embodiments, the mass of thymidine ranges from about 0.5 g to about 6.0 g per dose unit. In some embodiments, deoxycytidine is present at a concentration ranging from about 40 mg / mL to about 60 mg / mL. In some embodiments, deoxycytidine is at a concentration ranging from about 50 mg / mL to about 90 mg / mL. In some embodiments, the mass of deoxycytidine ranges from 0.5 g to 6.0 g per dose unit. In some embodiments, the combined mass of thymidine and deoxycytidine ranges from 1.0 g to 12.0 g per dose unit.

[0052] In some embodiments, the aqueous liquid is placed inside a container that includes markings corresponding to a particular volume, in some embodiments, the markings indicate the number of packages of the first heteroaryl compound and the second heteroaryl compound to be used in the dissolving step.

[0053] In some embodiments, the method further comprises orally administering the solution to the subject. In some embodiments, the solution is orally administered using a syringe. In some embodiments, the syringe is configured to contain between 1 mL and 150 mL of liquid. In some embodiments, the solution is orally administered through a nasogastric or gastrostomy tube.

[0054] In some embodiments, the subject has been diagnosed with mitochondrial DNA depletion syndrome and has a mutation in a gene involved in maintaining a balanced mitochondrial nucleotide pool, such as the TK2 gene, or in a mitochondrial DNA replication protein, such as POLG1. Other genetic mutations in genes involved in maintaining nucleotide pools or mitochondrial DNA replication include dGUOK, POLG2, SCLA25A4, MPV17, RRM2B, SUCLA2, SUCLGl, TYMP, OPA1, and C10orf2 (PEOl), as disclosed in U.S. Patent No. 10,471,087 and U.S. Patent Application Publication No. 20180161332. Those skilled in the art will recognize the necessary combination of nucleosides or prodrugs effective to treat the symptoms caused by the gene mutation based on the function of the protein expressed from the gene.

[0055] In some embodiments, the subject has been diagnosed with a thymidine deficiency, a deoxycytidine deficiency, a deoxyguanosine deficiency, a deoxyadenosine deficiency, or a combination thereof.

[0056] In some embodiments, the subject has been diagnosed with a pervasive developmental disorder associated with elevated purine levels, such as autism, or an autism spectrum disorder treatable, for example, with uridine. In some embodiments, the subject has been diagnosed with depression or suicide attempt in bipolar depression treatable, for example, with uridine. (Kondo, et al., J Child Adolesc Psychopharmacol. 21(2):171-5 (2011)).

[0057] Uridine and cytidine acyl derivatives, such as uridine triacetate, can be used to treat or prevent a variety of physiological and pathological conditions, including the treatment of liver disease or injury, cerebrovascular accidents, respiratory distress syndrome, and cardiac injury, as disclosed in U.S. Pat. No. 6,258,795.

[0058] In some embodiments, a kit is provided that includes a first heteroaryl compound and a second heteroaryl compound, wherein the first heteroaryl compound and the second heteroaryl compound are selected from an optionally substituted pyrimidine and an optionally substituted purine.

[0059] In some embodiments, the kit further comprises printed instructions instructing a user to dissolve the first heteroaryl compound and said second heteroaryl compound in a specific volume of aqueous liquid, in some embodiments, the printed instructions further instruct the user to dissolve the first heteroaryl compound and the second heteroaryl compound in a specific volume of aqueous liquid by inverting the closed container one or more times and then standing it upright.

[0060] In some embodiments, the kit further comprises a container having a lid and including markings corresponding to a specific volume of aqueous liquid. In some embodiments, the markings indicate the number of packages of the first heteroaryl compound and the second heteroaryl compound to be used in the dissolving step. In some embodiments, at least one package contains both the first heteroaryl compound and the second heteroaryl compound. In some embodiments, at least one package contains the second heteroaryl compound but does not contain the first heteroaryl compound. In some embodiments, each package contains 0.5 g to 4.0 g of the first heteroaryl compound or the second heteroaryl compound. In some embodiments, the container further comprises a second marking corresponding to a second specific volume of aqueous liquid.

[0061] In some embodiments, the kit further comprises instructions directing a user to orally administer the solution to a subject. In some embodiments, the subject has been diagnosed with mitochondrial DNA depletion syndrome, thymidine deficiency, deoxycytidine deficiency, deoxyguanosine deficiency, deoxyadenosine deficiency, a mutation in the TK2 gene, or a combination thereof. In some embodiments, the instructions state that the first heteroaryl compound and the second heteroaryl compound are each independently to be administered at a dose ranging from 100 mg / kg / day to 500 mg / kg / day. In some embodiments, the instructions state that the first heteroaryl compound and the second heteroaryl compound are each independently to be administered at a dose ranging from about 1 g / day to about 50 g / day, or from about 1 g / day to about 40 g / day, or from about 1 g / day to about 30 g / day, or from about 1 g / day to about 20 g / day, or from about 1 g / day to about 10 g / day, or from about 1 g / day to about 5 g / day.

[0062] In some embodiments, the kit includes instructions instructing a user to use the syringe to orally administer the solution. In some embodiments, the kit further includes a syringe. In some embodiments, the syringe is configured to contain between 1 mL and 150 mL of liquid.

[0063] In some embodiments, the kit includes instructions instructing a user to administer the solution through a nasogastric or gastrostomy tube, hi some embodiments, the kit further includes a nasogastric or gastrostomy tube.

[0064] In some embodiments, the first heteroaryl compound is thymidine and the second heteroaryl compound is deoxycytidine.

[0065] In some embodiments, the first heteroaryl compound is compound G and the second heteroaryl compound is compound A. [ka]

[0066] Also provided is a method of treating a patient, for example a patient diagnosed with mitochondrial depletion syndrome, comprising orally administering such an aqueous liquid to the patient. A kit is provided comprising instructions for dissolving deoxycytidine, thymidine, and optionally a nucleoside in the aqueous liquid and administering the solution to the patient. [Brief description of the drawings]

[0067] [Figure 1] 1 shows an exemplary container having markings indicating the number of packages of nucleoside to use for a given volume of water. [Diagram 2] 1 shows an exemplary container having markings indicating vertical heights corresponding to a volume of water. [Diagram 3] 1 shows the results of a reconstitution study of thymidine in aqueous liquids containing different amounts of deoxycytidine as a percentage of dT mass content. Detailed Description of the Invention

[0068] Before describing the present invention in more detail, it is to be understood that this invention is not limited to particular embodiments described, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0069] Where a range of values ​​is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit, between the upper and lower limits of that range is also specifically disclosed, unless the context clearly dictates otherwise. Each smaller range between any stated or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may be independently included or excluded in the range, and each range in which either or both limits are included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where a stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0070] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, some potential and exemplary methods and materials may be described here. Any publications mentioned herein are incorporated by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. It is understood that the present disclosure supersedes any disclosure of the incorporated publication to the extent that there is a conflict.

[0071] It should be noted that, as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to "a droplet" includes a plurality of such droplets, a reference to "the discrete entity" includes a reference to one or more discrete entities, and so forth. It should further be noted that the claims may be drafted to exclude any element, e.g., any optional element. Thus, this statement is intended to serve as a predicate for use of exclusive terminology, such as "solely," "only," and the like, in connection with the recitation of claim elements or the use of a "negative" limitation.

[0072] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Further, the publication dates provided may be different from the actual publication dates, which may need to be independently confirmed. To the extent that a definition or use of any term in this specification conflicts with a definition or use of the term in an application or reference incorporated herein by reference, this application shall control.

[0073] As will be apparent to those skilled in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has individual components and features which may be readily separated or combined with the features of any of the other several embodiments without departing from the scope or spirit of the invention. Any recited method can be carried out in the order of events recited or in any other order which is logically possible.

[0074] definition Deoxycytidine may be abbreviated herein as "dC". As used herein, deoxycytidine and dC refer to the free base form of the compound as well as its salts. The free base of deoxycytidine has Chemical Abstract Services (CAS) number 951-77-9 and the chemical structure shown below. [ka]

[0075] Deoxythymidine is used only in the assembly of DNA, not RNA, and assumes the presence of a deoxyribose ring, and is therefore sometimes abbreviated herein as "dT" and is also referred to herein as "thymidine." Thus, "thymidine" and "deoxythymidine" are used interchangeably throughout this application. As used herein, thymidine, deoxythymidine, and dT refer to the free base forms of the compounds as well as their salts. The free base of deoxythymidine has the CAS number 50-89-5 and the chemical structure shown below. [ka]

[0076] Uridine may be abbreviated herein as "U" and is incorporated into an RNA strand where it pairs with adenine. As used herein, uridine and U refer to the free base form of the compound as well as its salts. The free base of uridine has the Chemical Abstract Services (CAS) number 58-96-8 and the chemical structure shown below. [ka]

[0077] Deoxyguanosine may be abbreviated herein as "dG." As used herein, deoxyguanosine and dG refer to the free base form of the compound as well as its salts. The free base of deoxyguanosine has Chemical Abstract Services (CAS) number 961-07-9 and the chemical structure shown below. [ka]

[0078] Compound G, as used herein, is a derivative of deoxyguanosine and refers to the free base form of Compound G as well as salts thereof. The free base of Compound G has the chemical structure shown below. [ka]

[0079] In some embodiments, compound G can be prepared from deoxyguanosine and L-valine using methods known in the art. In some embodiments, compound G can be prepared using protection / deprotection strategies known in the art for nucleosides, deoxynucleosides, and their derivatives. In some embodiments, compound G can be prepared by selectively protecting the 5' hydroxy group of deoxyguanosine, esterifying the 3' hydroxy group with amine-protected L-valine, and then removing the protecting groups from the 5' hydroxy group and the amine.

[0080] Deoxyadenosine may be abbreviated herein as "dA." As used herein, deoxyadenosine and dA refer to the free base form of the compound as well as its salts. The free base of deoxyadenosine has Chemical Abstract Services (CAS) number 958-09-8 and the chemical structure shown below. [ka]

[0081] Compound A, as used herein, is a derivative of deoxyadenosine and refers to the free base form of Compound A as well as salts thereof. Compound A free base has the chemical structure shown below. [ka]

[0082] In some embodiments, compound A can be prepared from deoxyadenosine and L-valine using methods known in the art. In some embodiments, compound A can be prepared using protection / deprotection strategies known in the art for nucleosides, deoxynucleosides, and their derivatives. In some embodiments, compound A can be prepared by selectively protecting the 5' hydroxy group of deoxyadenosine, esterifying the 3' hydroxy group with amine-protected L-valine, and then removing the protecting groups from the 5' hydroxy group and the amine.

[0083] As used herein in its ordinary sense as understood by one of ordinary skill in the art, the term "aqueous composition" refers to a composition disclosed herein that contains one or more pyrimidines and / or purines, wherein the one or more pyrimidines and / or purines are dissolved in an aqueous liquid, such as water.

[0084] As used herein in the ordinary sense understood by one of ordinary skill in the art, the term "pyrimidine" refers to an optionally substituted heterocyclic aromatic ("heteroaryl") compound consisting of one ring having the following general structure: [ka]

[0085] As used herein in its ordinary sense as understood by those of skill in the art, the term "purine" refers to an optionally substituted heteroaromatic compound consisting of two rings (pyrimidine and imidazole) fused together. Purines have the following general structure: [ka]

[0086] As used herein in its ordinary sense as understood by those of skill in the art, the term "nucleoside" refers to an optionally substituted compound consisting of a purine or pyrimidine base (e.g., adenosine or cytidine) linked to a sugar (e.g., naturally occurring or synthetically modified ribose).

[0087] The term "nucleoside derivative," as used herein in its ordinary sense as understood by one of skill in the art, refers to an optionally substituted nucleoside or deoxynucleoside that has been modified, for example, by modifying (e.g., acylation or alkylation) one or more hydroxy groups on the sugar or by modifying the purine or pyrimidine base. Examples of modifications include the addition of one or more optional substituents to the nucleoside. Nucleoside derivatives include, but are not limited to, prodrugs of nucleosides and deoxynucleosides.

[0088] As used herein in its ordinary sense as understood by one of ordinary skill in the art, the term "deoxynucleoside" refers to any nucleoside that contains a deoxy sugar, i.e., any compound that is formally derived from a sugar by replacing a hydroxy group with a hydrogen atom, e.g., deoxyribose.

[0089] As used herein in its ordinary sense as understood by those of skill in the art, the term "nucleotide" refers to an optionally substituted compound consisting of a nucleoside linked to one or more phosphate groups.

[0090] As used herein in its ordinary sense as understood by one of skill in the art, the term "deoxynucleotide" refers to any nucleotide that contains a deoxy sugar, i.e., any compound that is formally derived from a sugar by replacing a hydroxy group with a hydrogen atom, e.g., deoxyribose.

[0091] The term "prodrug" is used herein in the ordinary sense understood by those skilled in the art and includes derivatives of the compounds disclosed herein, including but not limited to nucleosides, deoxynucleosides, nucleotides, and deoxynucleotides, that undergo conversion under conditions of use, such as in the body, to release nucleosides, deoxynucleosides, nucleotides, and deoxynucleotides. Prodrugs are often, but not necessarily, pharmacologically inactive until converted to their active form. Prodrugs can be obtained by attaching a promoiety to a drug, typically via a functional group.

[0092] The term "purine base" is used herein in its ordinary sense as understood by one of ordinary skill in the art and includes its tautomers. A non-limiting list of optionally substituted purine bases includes purine, adenine, guanine, hypoxanthine, xanthine, alloxanthine, 7-alkylguanines (e.g., 7-methylguanine), theobromine, caffeine, uric acid, and isoguanine.

[0093] The term "pyrimidine base" is used herein in its ordinary sense as understood by one of ordinary skill in the art and includes its tautomers. A non-limiting list of optionally substituted pyrimidine bases includes, but is not limited to, cytosine, thymine, uracil, 5,6-dihydrouracil, and 5-alkylcytosine (e.g., 5-methylcytosine).

[0094] Whenever a group is described as "optionally substituted," the group may be unsubstituted or substituted with one or more substituents. If substituted, the substituent(s) may be selected from one or more of the indicated substituents. When no substituents are indicated, the indicated "optionally substituted" or "substituted" group may include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), heterocyclyl(alkyl), hydroxy, =O, alkoxy, aryloxy, acyl, mercapto, alkylthio, arylthio, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N -amide, S-sulfonamide, N-sulfonamide, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, azido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamide, amino acid, amino, monosubstituted amino group, disubstituted amino group, phosphate group (including but not limited to monophosphate, diphosphate and triphosphate groups) and protected derivatives thereof.

[0095] The term "alkyl" as used herein refers to a straight or branched hydrocarbon chain containing a fully saturated (no double or triple bonds) hydrocarbon group. The alkyl group may have 1-20 carbon atoms (wherever it appears herein, a numerical range such as "1-20" refers to each integer within the given range. For example, "1-20 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 20 carbon atoms, but this definition also encompasses the occurrence of the term "alkyl" without a numerical range specified). The alkyl group may be a medium sized alkyl having 1-10 carbon atoms. The alkyl group may be a lower alkyl having 1-6 carbon atoms. The alkyl group of the compound may be designated as "C1-C4 alkyl" or similar designation. By way of example only, "C1-C4 alkyl" indicates that there are 1-4 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl. Alkyl groups can be substituted or unsubstituted.

[0096] The term "alkenyl" as used herein refers to an alkyl group containing one or more double bonds in a straight or branched hydrocarbon chain. Examples of alkenyl groups include allenyl, vinylmethyl and ethenyl. Alkenyl groups can be unsubstituted or substituted.

[0097] The term "alkynyl" as used herein refers to an alkyl group containing one or more triple bonds in a straight or branched hydrocarbon chain. Examples of alkynyl include ethynyl and propynyl. Alkynyl groups can be unsubstituted or substituted.

[0098] The term "cycloalkyl" as used herein refers to a monocyclic or polycyclic hydrocarbon ring system that is fully saturated (no double or triple bonds). When composed of more than one ring, the rings may be joined together in a fused fashion. Cycloalkyl groups can contain 3 to 10 atoms in the ring(s), or 3 to 8 atoms in the ring(s). Cycloalkyl groups can be unsubstituted or substituted. Exemplary cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0099] The term "cycloalkenyl" as used herein refers to a monocyclic or polycyclic hydrocarbon ring system containing one or more double bonds in at least one ring, provided that if more than one is present, the double bonds cannot form a completely delocalized pi-electron system through all rings (otherwise the group would be "aryl" as defined herein). When composed of more than one ring, the rings may be connected together in a fused fashion. A cycloalkenyl can contain 3 to 10 atoms in the ring(s), or 3 to 8 atoms in the ring(s). Cycloalkenyl groups can be unsubstituted or substituted.

[0100] The term "aryl" as used herein refers to a carbocyclic (all carbon) monocyclic or polycyclic aromatic ring system (including fused ring systems in which two carbocyclic rings share a chemical bond) that has a fully delocalized pi-electron system throughout all rings. The number of carbon atoms in an aryl group can vary. For example, an aryl group can be a C6-C14 aryl group, a C6-C10 aryl group, or a C6 aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. An aryl group can be substituted or unsubstituted.

[0101] The term "heteroaryl" as used herein refers to monocyclic, bicyclic, and tricyclic aromatic ring systems (ring systems having a fully delocalized pi-electron system) containing one or more heteroatoms (e.g., 1-5 heteroatoms), i.e., elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur. The number of atoms in the ring(s) of a heteroaryl group can vary. For example, a heteroaryl group can contain 4-14 atoms in the ring(s), 5-10 atoms in the ring(s), or 5-6 atoms in the ring(s). Additionally, the term "heteroaryl" includes fused ring systems in which two rings share at least one chemical bond, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, and triazine. Heteroaryl groups can be substituted or unsubstituted.

[0102] The term "heterocyclyl" or "heteroalicyclyl" as used herein refers to monocyclic, bicyclic, and tricyclic ring systems of up to 3, 4, 5, 6, 7, 8, 9, 10, 18 members, in which carbon atoms together with 1 to 5 heteroatoms make up said ring system. However, heterocycles may optionally contain one or more unsaturated bonds positioned such that a fully delocalized pi-electron system does not occur throughout all rings. The heteroatom(s) are elements other than carbon, including but not limited to oxygen, sulfur, and nitrogen. Heterocycles may further contain one or more carbonyl or thiocarbonyl functional groups, such that the definition includes oxo and thio systems, such as lactams, lactones, cyclic imides, cyclic thioimides, and cyclic carbamates. When composed of more than one ring, the rings may be joined together in a fused fashion. Additionally, any nitrogen in a heteroalicyclic may be quaternized. Heterocyclyl or heteroalicyclic groups may be unsubstituted or substituted.Examples of such "heterocyclyl" or "heteroalicyclyl" groups include 1,3-dioxine, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiine, 1,3-oxathiolane, 1,3-dithiole, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline, imidazoline, tetrahydro-1,4-thiazine ... These include, but are not limited to, lysine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N-oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone, and their benzo-fused analogs (e.g., benzimidazolidinone, tetrahydroquinoline, and 3,4-methylenedioxyphenyl).

[0103] The terms "aralkyl" and "aryl(alkyl)" as used herein refer to an aryl group connected as a substituent through a lower alkylene group. The lower alkylene and aryl groups of the aryl(alkyl) can be substituted or unsubstituted. Examples include, but are not limited to, benzyl, 2-phenyl(alkyl), 3-phenyl(alkyl) and naphthyl(alkyl).

[0104] The terms "heteroaralkyl" and "heteroaryl(alkyl)" as used herein refer to a heteroaryl group connected as a substituent via a lower alkylene group. The lower alkylene group and the heteroaryl group of the heteroaryl(alkyl) can be substituted or unsubstituted. Examples include, but are not limited to, 2-thienyl(alkyl), 3-thienyl(alkyl), furyl(alkyl), thienyl(alkyl), pyrrolyl(alkyl), pyridyl(alkyl), isoxazolyl(alkyl), imidazolyl(alkyl) and their benzo-fused analogs.

[0105] The term "alkoxy" as used herein refers to the formula -OR, where R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaryl(alkyl) or heterocyclyl(alkyl) as defined herein. A non-limiting list of alkoxy is methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy and benzoxy. Alkoxy can be substituted or unsubstituted.

[0106] The term "acyl" as used herein refers to an amino acid connected as a substituent through a hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaryl(alkyl), heterocyclyl(alkyl), or carbonyl group (e.g., through an ester bond). Examples include formyl, acetyl, propanoyl, benzoyl, and acryl. Acyl can be substituted or unsubstituted.

[0107] The term "amino acid" as used herein refers to any amino acid (both standard and non-standard), including but not limited to α-amino acids, β-amino acids, γ-amino acids and δ-amino acids. Examples of suitable amino acids include, but are not limited to, alanine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine. Further examples of suitable amino acids include, but are not limited to, ornithine, hypusine, 2-aminoisobutyric acid, dehydroalanine, γ-aminobutyric acid, citrulline, β-alanine, α-ethyl-glycine, α-propyl-glycine and norleucine.

[0108] As used herein, the term "amino acid" includes natural and synthetic β, γ or δ amino acids, and the amino acids may be in the D or L configuration. The amino acid may be a derivative of alanyl, valinyl, leucinyl, isoleucinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl, argininyl, histidinyl, β-alanyl, β-valinyl, β-leucinyl, β-isoleucinyl, β-prolinyl, β-phenylalaninyl, β-tryptophanyl, β-methioninyl, β-glycinyl, β-serinyl, β-threoninyl, β-cysteinyl, β-tyrosinyl, β-asparaginyl, β-glutaminyl, β-aspartoyl, β-glutaroyl, β-lysinyl, β-arginyl, or β-histidinyl.

[0109] The term "about" as used herein in its ordinary sense as understood by one of ordinary skill in the art includes the recited number ±10%. Thus, "about 10" means 9 to 11. As will be understood by one of ordinary skill in the art, reference herein to "about" a value or parameter includes (and describes) the value or parameter itself. For example, a statement of "about X" includes the statement "X".

[0110] As used herein in its ordinary sense as understood by one of ordinary skill in the art, the term "ribose sugar" includes groups having the following structure: [ka]

[0111] As used herein in its ordinary sense as understood by one of ordinary skill in the art, the term "deoxyribose sugar" includes groups having the following structure: [ka]

[0112] As used herein in its ordinary sense as understood by one of ordinary skill in the art, the term "dosage unit" refers to an individual unit (e.g., a packet, pack, package, sachet, stick, stick pack, etc.) containing a particular amount of a first heteroaryl compound and / or a particular amount of a second heteroaryl compound. In some embodiments, the compositions disclosed herein are prepared by adding a particular volume of liquid (e.g., an aqueous liquid or water) to the dosage unit.

[0113] When referring to the administration of a compound to a subject, the terms "dose," "amount," and "administration" are used interchangeably. The unit mg / kg / day refers to how many milligrams of compound are administered to a subject per kilogram of the patient's body weight within a 24-hour period. For example, a patient weighing 100 kg and receiving 200 mg / kg / day of deoxycytidine will receive 20,000 mg of deoxycytidine within a 24-hour period. The unit mg / kg / day can be expressed in mg / (kg·day) or mg·kg -1 ·day -1 This can also be written as:

[0114] "Administering a target dose" may also be referred to as "administration of a target dose" or "target administration." Similarly, administering a first dose may also be referred to as a first administration, and administering a second dose may also be referred to as a second administration. Administering an adjusted dose may alternatively be referred to as an adjusted administration.

[0115] The terms active agent, active pharmaceutical ingredient, pharmacologically active agent, and drug are used interchangeably herein and refer to chemical compounds or compounds that, when administered to an organism (human or animal), induce a desired pharmacological and / or physiological effect by local and / or systemic action. In some embodiments, the purines and pyrimidines disclosed herein (e.g., deoxycytidine, thymidine, Compound G, and Compound A) are active agents, active pharmaceutical ingredients, pharmacologically active agents, and drugs.

[0116] The terms "individual," "host," "subject," and "patient" are used interchangeably herein and refer to humans of any age, including "infants" (birth to 2 years of age), "children" (3 to 10 years of age), "adolescents" (10 to 19 years of age), and "adults" (20 years of age or older). Non-human animal models, such as mammals, e.g., non-human primates, mice, rabbits, and the like, can be used for experimental and non-clinical investigations.

[0117] As used herein, the terms "treatment", "treating" and the like refer to obtaining a desired pharmacological and / or physiological effect, such as a reduction in viral titer. The effect may be preventative, in that it completely or partially prevents the disease or its symptoms, and / or may be therapeutic, in that it partially or completely cures the disease and / or the adverse symptoms caused by the disease. As used herein, "treatment" encompasses any treatment of disease in a mammal, particularly a human, and includes (a) preventing the disease or symptoms of the disease from occurring in a subject who may have a predisposition to the disease, but has not yet been diagnosed as having it (including, for example, diseases that may be associated with or caused by a primary disease, such as liver fibrosis that may occur in the context of chronic HCV infection); (b) inhibiting the disease, i.e., halting its development; and (c) relieving the disease, i.e., causing regression of the disease (e.g., a reduction in viral titer or improvement in disease biomarkers). Age at onset of symptoms, rate of progression of debilitation, and survival rate after onset are the defining variables of the three clinical subtypes of TK2 deficiency. Subtypes are classified as infantile-onset myopathy (birth to 2 years of age), childhood-onset myopathy (between 3 and 12 years of age) and late-onset disease. Nervous system involvement often complicates the clinical course of the infantile-onset form, which typically progresses to disability and death more quickly, whereas extraocular muscle and facial involvement is characteristic of the late-onset form along with a longer post-onset survival time.

[0118] A "therapeutically effective dose", "therapeutically effective dose" or "therapeutic dose" is a dose sufficient to result in a desired clinical outcome (i.e., achieving therapeutic efficacy, achieving a desired therapeutic response, etc.). A therapeutically effective dose may be administered in one or more administrations. For purposes of this disclosure, a therapeutically effective dose of a composition is a dose that, when administered to an individual, is sufficient to palliate, ameliorate, stabilize, reverse, prevent, slow or delay the progression of a disease condition (e.g., cancer, etc.) present in the subject.

[0119] As used herein, the terms "monitoring," "determining," "measuring," "evaluating," and "assaying" are used interchangeably and include both quantitative and qualitative determinations.

[0120] composition In some embodiments, a composition is provided that comprises a first heteroaryl compound and a second heteroaryl compound dissolved in an aqueous liquid, wherein the concentration of the first heteroaryl compound is greater compared to a composition that comprises the first heteroaryl compound dissolved in an aqueous liquid that does not include the second heteroaryl compound.

[0121] In some embodiments, the first heteroaryl compound and the second heteroaryl compound are selected from optionally substituted pyrimidines and optionally substituted purines.

[0122] In some embodiments, the optionally substituted pyrimidines and optionally substituted purines are selected from deoxynucleosides, deoxynucleotides having 1-3 phosphate groups, nucleosides, nucleotides having 1-3 phosphate groups, and prodrugs of any of the above. In some embodiments, the optionally substituted pyrimidines and optionally substituted purines are selected from deoxynucleosides. In some embodiments, the optionally substituted pyrimidines and optionally substituted purines are selected from deoxynucleotides having 1-3 phosphate groups. In some embodiments, the optionally substituted pyrimidines and optionally substituted purines are selected from nucleosides. In some embodiments, the optionally substituted pyrimidines and optionally substituted purines are selected from nucleotides having 1-3 phosphate groups.

[0123] In some embodiments, the optionally substituted pyrimidines and optionally substituted purines are selected from prodrugs of deoxynucleosides. In some embodiments, the optionally substituted pyrimidines and optionally substituted purines are selected from prodrugs of deoxynucleotides having 1 to 3 phosphate groups. In some embodiments, the optionally substituted pyrimidines and optionally substituted purines are selected from prodrugs of nucleosides. In some embodiments, the optionally substituted pyrimidines and optionally substituted purines are selected from prodrugs of nucleotides having 1 to 3 phosphate groups.

[0124] In some embodiments, the optionally substituted pyrimidine is an optionally substituted uridine. In some embodiments, the pyrimidine is a uridine.

[0125] In some embodiments, the optionally substituted pyrimidine is an optionally substituted deoxyuridine. In some embodiments, the pyrimidine is a deoxyuridine.

[0126] In some embodiments, the optionally substituted pyrimidine has the structure of Formula I: [ka] During the ceremony, R 1 is selected from hydrogen or optionally substituted heterocyclyl; R 2 is selected from hydrogen or optionally substituted alkyl; R 3 is hydrogen, amino, hydroxy, -OR 5 , -NHR 6 or carbonyl; R 5 is selected from hydrogen, halogen, optionally substituted alkyl, or optionally substituted aralkyl; and R 6 is hydrogen, optionally substituted alkyl, optionally substituted aralkyl, -C(O)N(R 7 )(R 7´ ), -C(O)OR 8 , or -R 9 Selected from; R 7 , R 7´ , R 8 , and R 10 each independently represents hydrogen, optionally substituted C-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C3-C 10 selected from cycloalkyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R 9 teeth, [ka] and; R 11 is hydrogen, optionally substituted C1-C 10 Alkyl and optionally substituted C-C 10 alkenyl; and [ka] represents a single bond or a double bond.

[0127] In some embodiments, the optionally substituted pyrimidine has the structure of Formula II below, or a tautomer thereof: [ka] During the ceremony, R 1 , R 2 , R 3 , R 5, R 6 , R 7 , R 7´ , R 8 , R 9 and R 10 is defined above; R 4 is hydrogen, halogen, amino, hydroxy, alkyl, and -NHR 6 Selected from: [ka] represents a single bond or a double bond.

[0128] In some embodiments, R 1 is an optionally substituted 5-membered heterocyclyl. In some embodiments, R 1 is an optionally substituted 6-membered heterocyclyl. In some embodiments, R 1 is an optionally substituted 5- or 6-membered heterocyclyl, the heterocyclyl containing, as heteroatoms, one or more oxygen atoms, one or more nitrogen atoms, one or more sulfur atoms, or a mixture thereof. In some embodiments, R 1 is an optionally substituted tetrahydrofuran. In some embodiments, R 1 may be substituted with an acyl group. In some embodiments, the acyl group is -C(O)R 12 where R 12 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, In some embodiments, the acyl group is an amino acid.

[0129] In some embodiments, R 1 may be substituted with a phosphate group. In some embodiments, R 1 may be substituted with a monophosphate. In some embodiments, R 1 may be substituted with a diphosphate. In some embodiments, R 1may be substituted with a triphosphate.

[0130] In some embodiments, R 1 is an optionally substituted sugar moiety. In some embodiments, R 1 is an optionally substituted ribose sugar. In some embodiments, R 1 is an optionally substituted 2-deoxyribose radical (IUPAC nomenclature: (2R,3S)-2-(hydroxymethyl)oxolan-3-ol). In some embodiments, R 1 is an optionally substituted ribose radical (IUPAC nomenclature: (2R,3S,4S)-2-(hydroxymethyl)oxolane-3,4-diol). In some embodiments, the ribose sugar is substituted at one or more positions with an acyl group. In some embodiments, the acyl group is -C(O)R 12 where R 12 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl. In some embodiments, the acyl group is an amino acid. In some embodiments, the ribose sugar is substituted at one or more positions by a phosphate group. In some embodiments, the ribose sugar is substituted at one or more positions by a monophosphate. In some embodiments, the ribose sugar is substituted at one or more positions by a diphosphate. In some embodiments, the ribose sugar is substituted at one or more positions by a triphosphate. In some embodiments, the ribose sugar is substituted at one or more positions by a cyclic phosphate.

[0131] In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is optionally substituted alkyl. In some embodiments, R 2 is an optionally substituted C1-C5 alkyl. In some embodiments, R 2is selected from methyl, ethyl, isopropyl, and n-propyl. 2 is methyl.

[0132] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is amino. In some embodiments, R 3 is hydroxy. In some embodiments, R 3 -OR 5 In some embodiments, R 3 -NHR 6 It is.

[0133] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is a halogen. In some embodiments, the halogen is selected from chlorine, bromine, fluorine, and iodine. In some embodiments, the halogen is chlorine. In some embodiments, the halogen is bromine.

[0134] In some embodiments, R 4 is amino. In some embodiments, R 4 is hydroxy. In some embodiments, R 4 is optionally substituted alkyl. In some embodiments, R 4 is an optionally substituted C1-C5 alkyl. In some embodiments, R 4 is selected from methyl, ethyl, isopropyl, and n-propyl. 4 is methyl.

[0135] In some embodiments, R 5 is hydrogen. In some embodiments, R 5is a halogen. In some embodiments, the halogen is selected from chlorine, bromine, fluorine, and iodine. In some embodiments, the halogen is chlorine. In some embodiments, the halogen is bromine.

[0136] In some embodiments, R 5 is optionally substituted alkyl. In some embodiments, R 5 is an optionally substituted C1-C5 alkyl. In some embodiments, R 5 is selected from methyl, ethyl, isopropyl, and n-propyl. 5 is methyl. In some embodiments, R 5 is an optionally substituted aralkyl. In some embodiments, R 5 is optionally substituted benzyl.

[0137] In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is optionally substituted alkyl. In some embodiments, R 6 is an optionally substituted C1-C5 alkyl. In some embodiments, R 6 is selected from methyl, ethyl, isopropyl, and n-propyl. 6 is methyl. In some embodiments, R 6 is an optionally substituted aralkyl. In some embodiments, R 6 is optionally substituted benzyl. In some embodiments, R 6 is -C(O)N(R 7 )(R 7´ In some embodiments, R 6 is -C(O)OR 8 In some embodiments, R 6 -R 9 It is.

[0138] In some embodiments, R7 is hydrogen. In some embodiments, R 7 is optionally substituted C1-C 10 In some embodiments, R 7 is an optionally substituted C1-C5 alkyl. In some embodiments, R 7 is selected from methyl, ethyl, isopropyl, and n-propyl. 7 is optionally substituted C2-C 10 In some embodiments, R is alkenyl. 7 is an optionally substituted C-C alkenyl. In some embodiments, R 7 is an optionally substituted C3-C 10 In some embodiments, R 7 is an optionally substituted C5 or C6 cycloalkyl. In some embodiments, R 7 is an optionally substituted C cycloalkyl. In some embodiments, R 7 is an optionally substituted C cycloalkyl. In some embodiments, R 7 is an optionally substituted 3-10 membered heterocyclyl. In some embodiments, R 7 is an optionally substituted 5-membered heterocyclyl. In some embodiments, R 7 is an optionally substituted 6-membered heterocyclyl. In some embodiments, R 7 is optionally substituted aryl. In some embodiments, R 7 is optionally substituted phenyl. In some embodiments, R 7 is optionally substituted heteroaryl. In some embodiments, R 7 is an optionally substituted 5- or 6-membered heteroaryl. In some embodiments, R 7 is an optionally substituted 5-membered heteroaryl. In some embodiments, R 7 is an optionally substituted 6-membered heteroaryl.

[0139] In some embodiments, R 7´ is hydrogen. In some embodiments, R 7´ is optionally substituted C1-C 10 In some embodiments, R 7´ is an optionally substituted C1-C5 alkyl. In some embodiments, R 7´ is selected from methyl, ethyl, isopropyl, and n-propyl. 7´ is optionally substituted C2-C 10 In some embodiments, R is alkenyl. 7´ is an optionally substituted C-C alkenyl. In some embodiments, R 7´ is an optionally substituted C3-C 10 In some embodiments, R 7´ is an optionally substituted C5 or C6 cycloalkyl. In some embodiments, R 7´ is an optionally substituted C cycloalkyl. In some embodiments, R 7´ is an optionally substituted C cycloalkyl. In some embodiments, R 7´ is an optionally substituted 3-10 membered heterocyclyl. In some embodiments, R 7´ is an optionally substituted 5-membered heterocyclyl. In some embodiments, R 7´ is an optionally substituted 6-membered heterocyclyl. In some embodiments, R 7´ is optionally substituted aryl. In some embodiments, R 7´ is optionally substituted phenyl. In some embodiments, R 7´ is optionally substituted heteroaryl. In some embodiments, R 7´ is an optionally substituted 5- or 6-membered heteroaryl. In some embodiments, R 7´ is an optionally substituted 5-membered heteroaryl. In some embodiments, R 7´is an optionally substituted 6-membered heteroaryl.

[0140] In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is optionally substituted C 1 -C 10 In some embodiments, R 8 is optionally substituted C 1 -C 5 In some embodiments, R 8 is selected from methyl, ethyl, isopropyl, and n-propyl. 8 is optionally substituted C2-C 10 In some embodiments, R is alkenyl. 8 is an optionally substituted C-C alkenyl. In some embodiments, R 8 is an optionally substituted C3-C 10 In some embodiments, R 8 is an optionally substituted C5 or C6 cycloalkyl. In some embodiments, R 8 is an optionally substituted C cycloalkyl. In some embodiments, R 8 is an optionally substituted C cycloalkyl. In some embodiments, R 8 is an optionally substituted 3-10 membered heterocyclyl. In some embodiments, R 8 is an optionally substituted 5-membered heterocyclyl. In some embodiments, R 8 is an optionally substituted 6-membered heterocyclyl. In some embodiments, R 8 is optionally substituted aryl. In some embodiments, R 8 is optionally substituted phenyl. In some embodiments, R 8 is optionally substituted heteroaryl. In some embodiments, R 8is an optionally substituted 5- or 6-membered heteroaryl. In some embodiments, R 8 is an optionally substituted 5-membered heteroaryl. In some embodiments, R 8 is an optionally substituted 6-membered heteroaryl.

[0141] In some embodiments, R 10 is hydrogen. In some embodiments, R 10 is optionally substituted C1-C 10 In some embodiments, R 10 is an optionally substituted C1-C5 alkyl. In some embodiments, R 10 is selected from methyl, ethyl, isopropyl, and n-propyl. 10 is methyl. In some embodiments, R 10 is optionally substituted C2-C 10 In some embodiments, R is alkenyl. 10 is an optionally substituted C-C alkenyl. In some embodiments, R 10 is an optionally substituted C3-C 10 In some embodiments, R 10 is an optionally substituted C5 or C6 cycloalkyl. In some embodiments, R 10 is an optionally substituted C cycloalkyl. In some embodiments, R 10 is an optionally substituted C cycloalkyl. In some embodiments, R 10 is an optionally substituted 3-10 membered heterocyclyl. In some embodiments, R 10 is an optionally substituted 5-membered heterocyclyl. In some embodiments, R 10 is an optionally substituted 6-membered heterocyclyl. In some embodiments, R 10 is optionally substituted aryl. In some embodiments, R 10is optionally substituted phenyl. In some embodiments, R 10 is optionally substituted heteroaryl. In some embodiments, R 10 is an optionally substituted 5- or 6-membered heteroaryl. In some embodiments, R 10 is an optionally substituted 5-membered heteroaryl. In some embodiments, R 10 is an optionally substituted 6-membered heteroaryl.

[0142] In some embodiments, R 11 is hydrogen. In some embodiments, R 11 is optionally substituted C1-C 10 In some embodiments, R 11 is an optionally substituted C1-C5 alkyl. In some embodiments, R 11 is selected from methyl, ethyl, isopropyl, and n-propyl. 11 is optionally substituted C2-C 10 In some embodiments, R is alkenyl. 11 is an optionally substituted C2-C5 alkenyl.

[0143] In some embodiments, R 9 teeth [ka] where R 10 is optionally substituted alkyl, R 11 is hydrogen.

[0144] In some embodiments, R 9 teeth [ka] where R 10 is methyl, R11 is hydrogen.

[0145] In some embodiments, the optionally substituted pyrimidine has formula Ia: [ka] During the ceremony, R 2 is selected from hydrogen or C1-C4 alkyl; R 3 is hydrogen, amino, hydroxy, -OR 5 , -NHR 6 or carbonyl; R 5 is selected from hydrogen, halogen, optionally substituted alkyl, or optionally substituted aralkyl; R 6 is hydrogen, optionally substituted alkyl, optionally substituted aralkyl, -C(O)N(R 7 )(R 7´ ), -C(O)OR 8 , or -R 9 Selected from; R 7 , R 7´ , R 8 , and R 10 each independently represents hydrogen, optionally substituted C-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C3-C 10 selected from cycloalkyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R 9 teeth, [ka] and; R 11 is hydrogen, optionally substituted C1-C 10Alkyl and optionally substituted C-C 10 alkenyl; R 13 is hydrogen or hydroxy; and [ka] represents a single bond or a double bond.

[0146] In some embodiments, the optionally substituted purine has the formula IIa: [ka] During the ceremony, R 3 is hydrogen, amino, hydroxy, -OR 5 , -NHR 6 or carbonyl; R 4 is hydrogen, amino, or -NHR 6 is selected from R 5 is selected from hydrogen, halogen, optionally substituted alkyl, or optionally substituted aralkyl; R 6 is hydrogen, optionally substituted alkyl, optionally substituted aralkyl, -C(O)N(R 7 )(R 7´ ), -C(O)OR 8 , or -R 9 Selected from; R 7 , R 7´ , R 8 , and R 10 each independently represents hydrogen, optionally substituted C-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C3-C 10 selected from cycloalkyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R 9 teeth, [ka] and; R 11 is hydrogen, optionally substituted C1-C 10 Alkyl and optionally substituted C-C 10 alkenyl; R 13 is hydrogen or hydroxy; and [ka] represents a single bond or a double bond.

[0147] In some embodiments, the composition comprises two purines in a molar ratio of about 20:1 to about 1:20. In some embodiments, the composition comprises two purines in a molar ratio of about 15:1 to about 1:15. In some embodiments, the composition comprises two purines in a molar ratio of about 10:1 to about 1:10. In some embodiments, the composition comprises two purines in a molar ratio of about 1:1 to about 1:10. In some embodiments, the composition comprises two purines in a molar ratio of about 10:1 to about 1:1. In some embodiments, the composition comprises two purines in a molar ratio of about 1:0.1 to about 1:1. In some embodiments, the composition comprises two purines in a molar ratio of about 1:0.2 to about 1:1. In some embodiments, the composition comprises two purines in a molar ratio of about 1:0.3 to about 1:1. In some embodiments, the composition comprises two purines in a molar ratio of about 1:0.4 to about 1:1. In some embodiments, the composition comprises two purines in a molar ratio of about 1:0.5 to about 1:1. In some embodiments, the composition comprises two purines in a molar ratio of about 1:0.1. In some embodiments, the composition comprises two purines in a molar ratio of about 1:0.2. In some embodiments, the composition comprises two purines in a molar ratio of about 1:0.3. In some embodiments, the composition comprises two purines in a molar ratio of about 1:0.4. In some embodiments, the composition comprises two purines in a molar ratio of about 1:0.5. In some embodiments, the composition comprises two purines in a molar ratio of about 1:0.6. In some embodiments, the composition comprises two purines in a molar ratio of about 1:0.7. In some embodiments, the composition comprises two purines in a molar ratio of about 1:0.8. In some embodiments, the composition comprises two purines in a molar ratio of about 1:0.9. In some embodiments, the composition comprises two purines in a molar ratio of about 1:1.

[0148] In some embodiments, the composition comprises two pyrimidines in a molar ratio of about 20:1 to about 1:20. In some embodiments, the composition comprises two pyrimidines in a molar ratio of about 15:1 to about 1:15. In some embodiments, the composition comprises two pyrimidines in a molar ratio of about 10:1 to about 1:10. In some embodiments, the composition comprises two pyrimidines in a molar ratio of about 1:1 to about 1:10. In some embodiments, the composition comprises two pyrimidines in a molar ratio of about 10:1 to about 1:1. In some embodiments, the composition comprises two pyrimidines in a molar ratio of about 1:0.1 to about 1:1. In some embodiments, the composition comprises two pyrimidines in a molar ratio of about 1:0.2 to about 1:1. In some embodiments, the composition comprises two pyrimidines in a molar ratio of about 1:0.3 to about 1:1. In some embodiments, the composition comprises two pyrimidines in a molar ratio of about 1:0.4 to about 1:1. In some embodiments, the composition comprises two pyrimidines in a molar ratio of about 1:0.5 to about 1:1. In some embodiments, the composition comprises two pyrimidines in a molar ratio of about 1:0.1. In some embodiments, the composition comprises two pyrimidines in a molar ratio of about 1:0.2. In some embodiments, the composition comprises two pyrimidines in a molar ratio of about 1:0.3. In some embodiments, the composition comprises two pyrimidines in a molar ratio of about 1:0.4. In some embodiments, the composition comprises two pyrimidines in a molar ratio of about 1:0.5. In some embodiments, the composition comprises two pyrimidines in a molar ratio of about 1:0.6. In some embodiments, the composition comprises two pyrimidines in a molar ratio of about 1:0.7. In some embodiments, the composition comprises two pyrimidines in a molar ratio of about 1:0.8. In some embodiments, the composition comprises two pyrimidines in a molar ratio of about 1:0.9. In some embodiments, the composition comprises two pyrimidines in a molar ratio of about 1:1.

[0149] In some embodiments, the composition comprises purines and pyrimidines in a molar ratio of about 20:1 to about 1:20, respectively. In some embodiments, the composition comprises purines and pyrimidines in a molar ratio of about 15:1 to about 1:15, respectively. In some embodiments, the composition comprises purines and pyrimidines in a molar ratio of about 10:1 to about 1:10, respectively. In some embodiments, the composition comprises purines and pyrimidines in a molar ratio of about 1:1 to about 1:10, respectively. In some embodiments, the composition comprises purines and pyrimidines in a molar ratio of about 10:1 to about 1:1, respectively. In some embodiments, the composition comprises purines and pyrimidines in a molar ratio of about 1:0.1 to about 1:1, respectively. In some embodiments, the composition comprises purines and pyrimidines in a molar ratio of about 1:0.2 to about 1:1, respectively. In some embodiments, the composition comprises purines and pyrimidines in a molar ratio of about 1:0.3 to about 1:1, respectively. In some embodiments, the composition comprises purines and pyrimidines in a molar ratio of about 1:0.4 to about 1:1, respectively. In some embodiments, the composition comprises purines and pyrimidines in a molar ratio of about 1:0.5 to about 1:1, respectively. In some embodiments, the composition comprises purines and pyrimidines in a molar ratio of about 1:0.1, respectively. In some embodiments, the composition comprises purines and pyrimidines in a molar ratio of about 1:0.2, respectively. In some embodiments, the composition comprises purines and pyrimidines in a molar ratio of about 1:0.3, respectively. In some embodiments, the composition comprises purines and pyrimidines in a molar ratio of about 1:0.4, respectively. In some embodiments, the composition comprises purines and pyrimidines in a molar ratio of about 1:0.5, respectively. In some embodiments, the composition comprises purines and pyrimidines in a molar ratio of about 1:0.6, respectively. In some embodiments, the composition comprises purines and pyrimidines in a molar ratio of about 1:0.7, respectively. In some embodiments, the composition comprises purines and pyrimidines in a molar ratio of about 1:0.8, respectively. In some embodiments, the composition comprises purines and pyrimidines in a molar ratio of about 1:0.9, respectively. In some embodiments, the composition comprises purines and pyrimidines in a molar ratio of about 1:1, respectively.

[0150] In some embodiments, the composition comprises pyrimidines and purines in a molar ratio of about 20:1 to about 1:20, respectively. In some embodiments, the composition comprises pyrimidines and purines in a molar ratio of about 15:1 to about 1:15, respectively. In some embodiments, the composition comprises pyrimidines and purines in a molar ratio of about 10:1 to about 1:10, respectively. In some embodiments, the composition comprises pyrimidines and purines in a molar ratio of about 1:1 to about 1:10, respectively. In some embodiments, the composition comprises pyrimidines and purines in a molar ratio of about 10:1 to about 1:1, respectively. In some embodiments, the composition comprises pyrimidines and purines in a molar ratio of about 1:0.1 to about 1:1, respectively. In some embodiments, the composition comprises pyrimidines and purines in a molar ratio of about 1:0.2 to about 1:1, respectively. In some embodiments, the composition comprises pyrimidines and purines in a molar ratio of about 1:0.3 to about 1:1, respectively. In some embodiments, the composition comprises pyrimidines and purines in a molar ratio of about 1:0.4 to about 1:1, respectively. In some embodiments, the composition comprises pyrimidines and purines in a molar ratio of about 1:0.5 to about 1:1, respectively. In some embodiments, the composition comprises pyrimidines and purines in a molar ratio of about 1:0.1, respectively. In some embodiments, the composition comprises pyrimidines and purines in a molar ratio of about 1:0.2, respectively. In some embodiments, the composition comprises pyrimidines and purines in a molar ratio of about 1:0.3, respectively. In some embodiments, the composition comprises pyrimidines and purines in a molar ratio of about 1:0.4, respectively. In some embodiments, the composition comprises pyrimidines and purines in a molar ratio of about 1:0.5, respectively. In some embodiments, the composition comprises pyrimidines and purines in a molar ratio of about 1:0.6, respectively. In some embodiments, the composition comprises pyrimidines and purines in a molar ratio of about 1:0.7, respectively. In some embodiments, the composition comprises pyrimidines and purines in a molar ratio of about 1:0.8, respectively. In some embodiments, the composition comprises pyrimidines and purines in a molar ratio of about 1:0.9, respectively. In some embodiments, the composition comprises pyrimidines and purines in a molar ratio of about 1:1, respectively.

[0151] As noted above, in some embodiments, the present disclosure provides compositions comprising thymidine and deoxycytidine dissolved in an aqueous liquid. For example, in some embodiments, the aqueous liquid can be water, such as tap water or bottled water, or fruit juice.

[0152] In some embodiments, the mass of the first heteroaryl compound is in the range of about 0.5 g to 10.0 g per dose unit. In some embodiments, the mass of the first heteroaryl compound is in the range of about 0.5 g to 8.0 g per dose unit. In some embodiments, the mass of the first heteroaryl compound is in the range of about 0.5 g to 6.0 g per dose unit. In some embodiments, the mass of the first heteroaryl compound is in the range of about 0.5 g to 5.0 g per dose unit. In some embodiments, the mass of the first heteroaryl compound is in the range of about 0.5 g to 4.0 g per dose unit. In some embodiments, the mass of the first heteroaryl compound is about 0.5 g per dose unit. In some embodiments, the mass of the first heteroaryl compound is about 1.0 g per dose unit. In some embodiments, the mass of the first heteroaryl compound is about 1.5 g per dose unit. In some embodiments, the mass of the first heteroaryl compound is about 2.0 g per dose unit. In some embodiments, the mass of the first heteroaryl compound is about 2.5 g per dose unit. In some embodiments, the mass of the first heteroaryl compound is about 3.0 g per dose unit. In some embodiments, the mass of the first heteroaryl compound is about 3.5 g per dose unit. In some embodiments, the mass of the first heteroaryl compound is about 4.0 g per dose unit. In some embodiments, the mass of the first heteroaryl compound is about 4.5 g per dose unit. In some embodiments, the mass of the first heteroaryl compound is about 5.0 g per dose unit. In some embodiments, the mass of the first heteroaryl compound is about 5.5 g per dose unit. In some embodiments, the mass of the first heteroaryl compound is about 6.0 g per dose unit. In some embodiments, the mass of the first heteroaryl compound is about 7.0 g per dose unit. In some embodiments, the mass of the first heteroaryl compound is about 8.0 g per dose unit. In some embodiments, the mass of the first heteroaryl compound is about 9.0 g per dose unit.In some embodiments, the mass of the first heteroaryl compound is about 10.0 g per dosage unit.

[0153] In some embodiments, the mass of the second heteroaryl compound is in the range of about 0.5 g to 10.0 g per dose unit. In some embodiments, the mass of the second heteroaryl compound is in the range of about 0.5 g to 8.0 g per dose unit. In some embodiments, the mass of the second heteroaryl compound is in the range of about 0.5 g to 6.0 g per dose unit. In some embodiments, the mass of the second heteroaryl compound is in the range of about 0.5 g to 5.0 g per dose unit. In some embodiments, the mass of the second heteroaryl compound is in the range of about 0.5 g to 4.0 g per dose unit. In some embodiments, the mass of the second heteroaryl compound is about 0.5 g per dose unit. In some embodiments, the mass of the second heteroaryl compound is about 1.0 g per dose unit. In some embodiments, the mass of the second heteroaryl compound is about 1.5 g per dose unit. In some embodiments, the mass of the second heteroaryl compound is about 2.0 g per dose unit. In some embodiments, the mass of the second heteroaryl compound is about 2.5 g per dose unit. In some embodiments, the mass of the second heteroaryl compound is about 3.0 g per dose unit. In some embodiments, the mass of the second heteroaryl compound is about 3.5 g per dose unit. In some embodiments, the mass of the second heteroaryl compound is about 4.0 g per dose unit. In some embodiments, the mass of the second heteroaryl compound is about 4.5 g per dose unit. In some embodiments, the mass of the second heteroaryl compound is about 5.0 g per dose unit. In some embodiments, the mass of the second heteroaryl compound is about 5.5 g per dose unit. In some embodiments, the mass of the second heteroaryl compound is about 6.0 g per dose unit. In some embodiments, the mass of the second heteroaryl compound is about 7.0 g per dose unit. In some embodiments, the mass of the second heteroaryl compound is about 8.0 g per dose unit. In some embodiments, the mass of the second heteroaryl compound is about 9.0 g per dose unit.In some embodiments, the mass of the second heteroaryl compound is about 10.0 g per dosage unit.

[0154] In some embodiments, the total mass of the first heteroaryl compound and the second heteroaryl compound is in the range of about 1.0 g to about 20.0 g per dose unit. In some embodiments, the total mass of the first heteroaryl compound and the second heteroaryl compound is in the range of about 1.0 g to about 15.0 g per dose unit. In some embodiments, the total mass of the first heteroaryl compound and the second heteroaryl compound is in the range of about 1.0 g to about 12.0 g per dose unit. In some embodiments, the total mass of the first heteroaryl compound and the second heteroaryl compound is in the range of about 1.0 g to about 10.0 g per dose unit. In some embodiments, the total mass of the first heteroaryl compound and the second heteroaryl compound is in the range of about 1.0 g to about 8.0 g per dose unit. In some embodiments, the total mass of the first heteroaryl compound and the second heteroaryl compound is about 1.0 g per dose unit. In some embodiments, the combined mass of the first heteroaryl compound and the second heteroaryl compound is about 2.0 g per dose unit. In some embodiments, the combined mass of the first heteroaryl compound and the second heteroaryl compound is about 4.0g per dose unit. In some embodiments, the combined mass of the first heteroaryl compound and the second heteroaryl compound is about 6.0g per dose unit. In some embodiments, the combined mass of the first heteroaryl compound and the second heteroaryl compound is about 8.0g per dose unit. In some embodiments, the combined mass of the first heteroaryl compound and the second heteroaryl compound is about 10.0g per dose unit. In some embodiments, the combined mass of the first heteroaryl compound and the second heteroaryl compound is about 12.0g per dose unit.

[0155] In some embodiments, the first heteroaryl compound is thymidine and the second heteroaryl compound is deoxycytidine.

[0156] In some embodiments, thymidine is at a concentration of about 20 mg / mL or more. In some embodiments, thymidine is at a concentration in the range of about 20 mg / mL to about 100 mg / mL. In some embodiments, thymidine is at a concentration in the range of about 20 mg / mL to about 90 mg / mL. In some embodiments, thymidine is at a concentration in the range of about 30 mg / mL to about 90 mg / mL. In some embodiments, thymidine is at a concentration in the range of about 50 mg / mL to about 90 mg / mL. In some embodiments, thymidine is at a concentration in the range of about 60 mg / mL to about 90 mg / mL. In some embodiments, thymidine is at a concentration in the range of about 40 mg / mL to about 60 mg / mL. In some embodiments, thymidine is at a concentration of about 20 mg / mL. In some embodiments, thymidine is at a concentration of about 30 mg / mL. In some embodiments, thymidine is at a concentration .... In some embodiments, the thymidine is at a concentration of about 50 mg / mL. In some embodiments, the thymidine is at a concentration of about 60 mg / mL. In some embodiments, the thymidine is at a concentration of about 70 mg / mL. In some embodiments, the thymidine is at a concentration of about 80 mg / mL. In some embodiments, the thymidine is at a concentration of about 90 mg / mL. In some embodiments, the thymidine is at a concentration of about 100 mg / mL. In some embodiments, the composition can include dissolved thymidine at a concentration of 10 mg / mL or more, e.g., 20 mg / mL or more, 30 mg / mL or more, 40 mg / mL or more, 50 mg / mL or more, 60 mg / mL or more, 70 mg / mL or more, 80 mg / mL or more, or 90 mg / mL or more. For example, in some embodiments, the concentration of dissolved thymidine can range from 30 mg / mL to 90 mg / mL, e.g., 30 mg / mL to 75 mg / mL, or 40 mg / mL to 60 mg / mL.

[0157] In some embodiments, deoxycytidine is at a concentration of about 20 mg / mL or more. In some embodiments, deoxycytidine is at a concentration ranging from about 20 mg / mL to about 100 mg / mL. In some embodiments, deoxycytidine is at a concentration ranging from about 30 mg / mL to about 90 mg / mL. In some embodiments, deoxycytidine is at a concentration ranging from about 40 mg / mL to about 90 mg / mL. In some embodiments, deoxycytidine is at a concentration ranging from about 50 mg / mL to about 90 mg / mL. In some embodiments, deoxycytidine is at a concentration ranging from about 40 mg / mL to about 60 mg / mL. In some embodiments, deoxycytidine is at a concentration of about 20 mg / mL. In some embodiments, deoxycytidine is at a concentration of about 30 mg / mL. In some embodiments, deoxycytidine is at a concentration of about 40 mg / mL. In some embodiments, deoxycytidine is at a concentration of about 50 mg / mL. In some embodiments, deoxycytidine is at a concentration of about 60 mg / mL. In some embodiments, deoxycytidine is at a concentration of about 70 mg / mL. In some embodiments, deoxycytidine is at a concentration of about 80 mg / mL. In some embodiments, deoxycytidine is at a concentration of about 90 mg / mL. In some embodiments, deoxycytidine is at a concentration of about 100 mg / mL.

[0158] In some embodiments, the composition can include dissolved deoxycytidine at a concentration of 10 mg / mL or more, e.g., 20 mg / mL or more, 30 mg / mL or more, 40 mg / mL or more, 50 mg / mL or more, or 60 mg / mL or more. For example, in some embodiments, the dissolved deoxycytidine concentration can range from 30 mg / mL to 75 mg / mL, e.g., 40 mg / mL to 60 mg / mL.

[0159] In some embodiments, the composition can include a relatively high concentration of deoxycytidine and thymidine, for example, a specific mass of each nucleoside can be orally administered to a patient in a relatively small volume of solution. In other words, in some cases, the patient's medical condition can increase the difficulty of orally administering a solution to a patient. For example, the patient may have difficulty swallowing. In some cases, the patient is administered liquid, food, or a combination thereof through a tube due to swallowing difficulties. Exemplary tubes include gastrostomy tubes and nasogastric tubes. Therefore, it can be advantageous to reduce the volume of liquid administered to a patient while still providing a desired amount of thymidine and deoxycytidine. In some embodiments, the composition of the present invention can have a relatively high concentration of these nucleosides, thereby allowing a specific amount of each nucleoside to be administered with a lower volume of liquid.

[0160] The presence of deoxycytidine can increase the solubility of thymidine in the aqueous liquid. Stated another way, in some embodiments, the solubility of thymidine in the aqueous liquid can be increased by 10% or more, such as 25% or more, 50% or more, or 75% or more, compared to an otherwise identical aqueous liquid lacking deoxycytidine. In some embodiments, the solubility of thymidine can be increased by 10 mg / mL or more, such as 20 mg / mL or more, compared to an otherwise identical aqueous liquid lacking deoxycytidine.

[0161] In some embodiments, the volume of the aqueous liquid is in the range of 1 mL to 1,000 mL, e.g., 10 mL to 750 mL, 15 mL to 500 mL, 20 mL to 400 mL, or 30 mL to 300 mL. In some embodiments, the mass of thymidine in the solution can be in the range of 0.1 g to 10 g per dose unit, e.g., 0.2 g to 8 g per dose unit, or 0.5 g to 4 g per dose unit. The mass of deoxycytidine in the solution can be in the range of 0.1 g to 10 g per dose unit, e.g., 0.2 g to 8 g per dose unit, or 0.5 g to 4 g per dose unit. In some embodiments, the mass of deoxycytidine is in the range of 50% to 200%, e.g., 60% to 175%, 70% to 150%, 80% to 125%, 90% to 110%, and 95% to 105% of the mass of thymidine.

[0162] In some embodiments, the mass of thymidine is in the range of about 0.5 g to 10.0 g per dose unit. In some embodiments, the mass of thymidine is in the range of about 0.5 g to 8.0 g per dose unit. In some embodiments, the mass of thymidine is in the range of about 0.5 g to 6.0 g per dose unit. In some embodiments, the mass of thymidine is in the range of about 0.5 g to 5.0 g per dose unit. In some embodiments, the mass of thymidine is in the range of about 0.5 g to 4.0 g per dose unit. In some embodiments, the mass of thymidine is about 0.5 g per dose unit. In some embodiments, the mass of thymidine is about 1.0 g per dose unit. In some embodiments, the mass of thymidine is about 1.5 g per dose unit. In some embodiments, the mass of thymidine is about 2.0 g per dose unit. In some embodiments, the mass of thymidine is about 2.5 g per dose unit. In some embodiments, the mass of thymidine is about 3.0 g per dose unit. In some embodiments, the mass of thymidine is about 3.5 g per dose unit. In some embodiments, the mass of thymidine is about 4.0 g per dose unit. In some embodiments, the mass of thymidine is about 4.5 g per dose unit. In some embodiments, the mass of thymidine is about 5.0 g per dose unit. In some embodiments, the mass of thymidine is about 5.5 g per dose unit. In some embodiments, the mass of thymidine is about 6.0 g per dose unit. In some embodiments, the mass of thymidine is about 7.0 g per dose unit. In some embodiments, the mass of thymidine is about 8.0 g per dose unit. In some embodiments, the mass of thymidine is about 9.0 g per dose unit. In some embodiments, the mass of thymidine is about 10.0 g per dose unit.

[0163] In some embodiments, the mass of deoxycytidine is in the range of about 0.5 g to 10.0 g per dose unit. In some embodiments, the mass of deoxycytidine is in the range of about 0.5 g to 8.0 g per dose unit. In some embodiments, the mass of deoxycytidine is in the range of about 0.5 g to 6.0 g per dose unit. In some embodiments, the mass of deoxycytidine is in the range of about 0.5 g to 5.0 g per dose unit. In some embodiments, the mass of deoxycytidine is in the range of about 0.5 g to 4.0 g per dose unit. In some embodiments, the mass of deoxycytidine is about 0.5 g per dose unit. In some embodiments, the mass of deoxycytidine is about 1.0 g per dose unit. In some embodiments, the mass of deoxycytidine is about 1.5 g per dose unit. In some embodiments, the mass of deoxycytidine is about 2.0 g per dose unit. In some embodiments, the mass of deoxycytidine is about 2.5 g per dose unit. In some embodiments, the mass of deoxycytidine is about 3.0 g per dose unit. In some embodiments, the mass of deoxycytidine is about 3.5 g per dose unit. In some embodiments, the mass of deoxycytidine is about 4.0 g per dose unit. In some embodiments, the mass of deoxycytidine is about 4.5 g per dose unit. In some embodiments, the mass of deoxycytidine is about 5.0 g per dose unit. In some embodiments, the mass of deoxycytidine is about 5.5 g per dose unit. In some embodiments, the mass of deoxycytidine is about 6.0 g per dose unit. In some embodiments, the mass of deoxycytidine is about 7.0 g per dose unit. In some embodiments, the mass of deoxycytidine is about 8.0 g per dose unit. In some embodiments, the mass of deoxycytidine is about 9.0 g per dose unit. In some embodiments, the mass of deoxycytidine is about 10.0 g per dosage unit.

[0164] In some embodiments, the total mass of thymidine and deoxycytidine is in the range of about 1.0 g to about 20.0 g per dose unit. In some embodiments, the total mass of thymidine and deoxycytidine is in the range of about 1.0 g to about 15.0 g per dose unit. In some embodiments, the total mass of thymidine and deoxycytidine is in the range of about 1.0 g to about 12.0 g per dose unit. In some embodiments, the total mass of thymidine and deoxycytidine is in the range of about 1.0 g to about 10.0 g per dose unit. In some embodiments, the total mass of thymidine and deoxycytidine is in the range of about 1.0 g to about 8.0 g per dose unit. In some embodiments, the total mass of thymidine and deoxycytidine is about 1.0 g per dose unit. In some embodiments, the total mass of thymidine and deoxycytidine is about 2.0 g per dose unit. In some embodiments, the total mass of thymidine and deoxycytidine is about 4.0 g per dose unit. In some embodiments, the total mass of thymidine and deoxycytidine is about 6.0 g per dose unit. In some embodiments, the total mass of thymidine and deoxycytidine is about 8.0 g per dose unit. In some embodiments, the total mass of thymidine and deoxycytidine is about 10.0 g per dose unit. In some embodiments, the total mass of thymidine and deoxycytidine is about 12.0 g per dose unit.

[0165] In some embodiments, the mass of deoxycytidine is in the range of about 20% to about 120% of the mass of thymidine. In some embodiments, the mass of deoxycytidine is in the range of about 30% to about 110% of the mass of thymidine. In some embodiments, the mass of deoxycytidine is in the range of about 40% to about 110% of the mass of thymidine. In some embodiments, the mass of deoxycytidine is in the range of about 40% to about 100% of the mass of thymidine. In some embodiments, the mass of deoxycytidine is in the range of about 70% to about 120% of the mass of thymidine. In some embodiments, the mass of deoxycytidine is in the range of about 80% to about 120% of the mass of thymidine. In some embodiments, the mass of deoxycytidine is in the range of about 90% to about 110% of the mass of thymidine. In some embodiments, the mass of deoxycytidine is about 20% of the mass of thymidine. In some embodiments, the mass of deoxycytidine is about 30% of the mass of thymidine. In some embodiments, the mass of deoxycytidine is about 40% of the mass of thymidine. In some embodiments, the mass of deoxycytidine is about 50% of the mass of thymidine. In some embodiments, the mass of deoxycytidine is about 60% of the mass of thymidine. In some embodiments, the mass of deoxycytidine is about 70% of the mass of thymidine. In some embodiments, the mass of deoxycytidine is about 80% of the mass of thymidine. In some embodiments, the mass of deoxycytidine is about 90% of the mass of thymidine. In some embodiments, the mass of deoxycytidine is about 100% of the mass of thymidine. In some embodiments, the mass of deoxycytidine is about 110% of the mass of thymidine. In some embodiments, the mass of deoxycytidine is about 120% of the mass of thymidine.

[0166] In some embodiments, the first heteroaryl compound and the second heteroaryl compound are selected from derivatives of nucleosides and derivatives of deoxynucleosides. In some embodiments, the first heteroaryl compound and the second heteroaryl compound are selected from prodrugs of nucleosides and deoxynucleosides.

[0167] In some embodiments, the first heteroaryl compound is a derivative of deoxyguanosine and the second heteroaryl compound is a derivative of deoxyadenosine, in some embodiments, the first heteroaryl compound is a prodrug of deoxyguanosine and the second heteroaryl compound is a prodrug of deoxyadenosine.

[0168] In some embodiments, the nucleoside derivatives and deoxynucleoside derivatives include nucleosides and deoxynucleosides substituted at one or more positions on the sugar moiety of the nucleoside and deoxynucleoside. In some embodiments, the substitution on the sugar moiety includes substitution on the hydroxy group of the sugar moiety. In some embodiments, the substitution includes, but is not limited to, acyl groups and alkyl groups on the hydroxy group of the sugar moiety. In some embodiments, the nucleoside derivatives and deoxynucleoside derivatives are substituted with one or more acyl groups. In some embodiments, the nucleoside derivatives and deoxynucleoside derivatives are substituted with one or more amino acids. In some embodiments, the nucleoside derivatives and deoxynucleoside derivatives are substituted with one or more amino acids and one or more acyl groups.

[0169] In some embodiments, derivatives or prodrugs can be prepared using protection / deprotection strategies known in the art for nucleosides, deoxynucleosides, and their derivatives.

[0170] In some embodiments, the first heteroaryl compound and the second heteroaryl compound are selected from: [ka]

[0171] In some embodiments, the first heteroaryl compound is compound G and the second heteroaryl compound is compound A. [ka]

[0172] In some embodiments, compound G is at a concentration of about 20 mg / mL or more. In some embodiments, compound G is at a concentration in the range of about 20 mg / mL to about 100 mg / mL. In some embodiments, compound G is at a concentration in the range of about 40 mg / mL to about 100 mg / mL. In some embodiments, compound G is at a concentration in the range of about 50 mg / mL to about 100 mg / mL. In some embodiments, compound G is at a concentration in the range of about 60 mg / mL to about 100 mg / mL. In some embodiments, compound G is at a concentration in the range of about 60 mg / mL to about 90 mg / mL. In some embodiments, compound G is at a concentration of about 20 mg / mL. In some embodiments, compound G is at a concentration of about 30 mg / mL. In some embodiments, compound G is at a concentration of about 40 mg / mL. In some embodiments, compound G is at a concentration of about 50 mg / mL. In some embodiments, compound G is at a concentration of about 60 mg / mL. In some embodiments, compound G is at a concentration of about 70 mg / mL. In some embodiments, compound G is at a concentration of about 80 mg / mL. In some embodiments, compound G is at a concentration of about 90 mg / mL. In some embodiments, compound G is at a concentration of about 100 mg / mL.

[0173] In some embodiments, compound A is at a concentration ranging from about 1 mg / mL to about 100 mg / mL. In some embodiments, compound A is at a concentration ranging from about 5 mg / mL to about 100 mg / mL. In some embodiments, compound A is at a concentration ranging from about 5 mg / mL to about 90 mg / mL. In some embodiments, compound A is at a concentration ranging from about 5 mg / mL to about 80 mg / mL. In some embodiments, compound A is at a concentration ranging from about 5 mg / mL to about 70 mg / mL. In some embodiments, compound A is at a concentration ranging from about 5 mg / mL to about 60 mg / mL. In some embodiments, compound A is at a concentration of about 5 mg / mL. In some embodiments, compound A is at a concentration of about 10 mg / mL. In some embodiments, compound A is at a concentration of about 20 mg / mL. In some embodiments, compound A is at a concentration of about 30 mg / mL. In some embodiments, compound A is at a concentration of about 40 mg / mL. In some embodiments, Compound A is at a concentration of about 50 mg / mL. In some embodiments, Compound A is at a concentration of about 60 mg / mL. In some embodiments, Compound A is at a concentration of about 70 mg / mL. In some embodiments, Compound A is at a concentration of about 80 mg / mL. In some embodiments, Compound A is at a concentration of about 90 mg / mL. In some embodiments, Compound A is at a concentration of about 100 mg / mL.

[0174] In some embodiments, the molar ratio of compound G to compound A is about 1:0.1 to about 1:1.2. In some embodiments, the molar ratio of compound G to compound A is about 1:0.1 to about 1:1. In some embodiments, the molar ratio of compound G to compound A is about 1:0.25 to about 1:1. In some embodiments, the molar ratio of compound G to compound A is about 1:0.5 to about 1:1. In some embodiments, the molar ratio of compound G to compound A is about 1:0.75 to about 1:1. In some embodiments, the molar ratio of compound G to compound A is about 1:0.1. In some embodiments, the molar ratio of compound G to compound A is about 1:0.2. In some embodiments, the molar ratio of compound G to compound A is about 1:0.25. In some embodiments, the molar ratio of compound G to compound A is about 1:0.3. In some embodiments, the molar ratio of compound G to compound A is about 1:0.4. In some embodiments, the molar ratio of compound G to compound A is about 1:0.5. In some embodiments, the molar ratio of compound G to compound A is about 1:0.6. In some embodiments, the molar ratio of compound G to compound A is about 1:0.7. In some embodiments, the molar ratio of compound G to compound A is about 1:0.75. In some embodiments, the molar ratio of compound G to compound A is about 1:0.8. In some embodiments, the molar ratio of compound G to compound A is about 1:0.9. In some embodiments, the molar ratio of compound G to compound A is about 1:1. In some embodiments, the molar ratio of compound G to compound A is about 1:1.1. In some embodiments, the molar ratio of compound G to compound A is about 1:1.2.

[0175] In some embodiments, the mass of compound G is in the range of about 0.5 g to 10.0 g per dose unit. In some embodiments, the mass of compound G is in the range of about 0.5 g to 8.0 g per dose unit. In some embodiments, the mass of compound G is in the range of about 0.5 g to 6.0 g per dose unit. In some embodiments, the mass of compound G is in the range of about 0.5 g to 5.0 g per dose unit. In some embodiments, the mass of compound G is in the range of about 0.5 g to 4.0 g per dose unit. In some embodiments, the mass of compound G is about 0.5 g per dose unit. In some embodiments, the mass of compound G is about 1.0 g per dose unit. In some embodiments, the mass of compound G is about 1.5 g per dose unit. In some embodiments, the mass of compound G is about 2.0 g per dose unit. In some embodiments, the mass of compound G is about 2.5 g per dose unit. In some embodiments, the mass of compound G is about 3.0 g per dose unit. In some embodiments, the mass of compound G is about 3.5 g per dose unit. In some embodiments, the mass of compound G is about 4.0 g per dose unit. In some embodiments, the mass of compound G is about 4.5 g per dose unit. In some embodiments, the mass of compound G is about 5.0 g per dose unit. In some embodiments, the mass of compound G is about 5.5 g per dose unit. In some embodiments, the mass of compound G is about 6.0 g per dose unit. In some embodiments, the mass of compound G is about 7.0 g per dose unit. In some embodiments, the mass of compound G is about 8.0 g per dose unit. In some embodiments, the mass of compound G is about 9.0 g per dose unit. In some embodiments, the mass of compound G is about 10.0 g per dose unit.

[0176] In some embodiments, the mass of compound A is in the range of about 0.5 g to 10.0 g per dose unit. In some embodiments, the mass of compound A is in the range of about 0.5 g to 8.0 g per dose unit. In some embodiments, the mass of compound A is in the range of about 0.5 g to 6.0 g per dose unit. In some embodiments, the mass of compound A is in the range of about 0.5 g to 5.0 g per dose unit. In some embodiments, the mass of compound A is in the range of about 0.5 g to 4.0 g per dose unit. In some embodiments, the mass of compound A is about 0.5 g per dose unit. In some embodiments, the mass of compound A is about 1.0 g per dose unit. In some embodiments, the mass of compound A is about 1.5 g per dose unit. In some embodiments, the mass of compound A is about 2.0 g per dose unit. In some embodiments, the mass of compound A is about 2.5 g per dose unit. In some embodiments, the mass of compound A is about 3.0 g per dose unit. In some embodiments, the mass of compound A is about 3.5 g per dose unit. In some embodiments, the mass of compound A is about 4.0 g per dose unit. In some embodiments, the mass of compound A is about 4.5 g per dose unit. In some embodiments, the mass of compound A is about 5.0 g per dose unit. In some embodiments, the mass of compound A is about 5.5 g per dose unit. In some embodiments, the mass of compound A is about 6.0 g per dose unit. In some embodiments, the mass of compound A is about 7.0 g per dose unit. In some embodiments, the mass of compound A is about 8.0 g per dose unit. In some embodiments, the mass of compound A is about 9.0 g per dose unit. In some embodiments, the mass of compound v is about 10.0 g per dose unit.

[0177] In some embodiments, the total mass of compound G and compound A is in the range of about 1.0 g to about 20.0 g per dose unit. In some embodiments, the total mass of compound G and compound A is in the range of about 1.0 g to about 15.0 g per dose unit. In some embodiments, the total mass of compound G and compound A is in the range of about 1.0 g to about 12.0 g per dose unit. In some embodiments, the total mass of compound G and compound A is in the range of about 1.0 g to about 10.0 g per dose unit. In some embodiments, the total mass of compound G and compound A is in the range of about 1.0 g to about 8.0 g per dose unit. In some embodiments, the total mass of compound G and compound A is about 1.0 g per dose unit. In some embodiments, the total mass of compound G and compound A is about 2.0 g per dose unit. In some embodiments, the total mass of compound G and compound A is about 4.0 g per dose unit. In some embodiments, the total mass of compound G and compound A is about 6.0 g per dose unit. In some embodiments, the combined mass of Compound G and Compound A is about 8.0 g per dose unit. In some embodiments, the combined mass of Compound G and Compound A is about 10.0 g per dose unit. In some embodiments, the combined mass of Compound G and Compound A is about 12.0 g per dose unit.

[0178] In some embodiments, the mass of compound A is in the range of about 20% to about 120% of the mass of compound G. In some embodiments, the mass of compound A is in the range of about 30% to about 110% of the mass of compound G. In some embodiments, the mass of compound A is in the range of about 40% to about 110% of the mass of compound G. In some embodiments, the mass of compound A is in the range of about 40% to about 100% of the mass of compound G. In some embodiments, the mass of compound A is in the range of about 70% to about 120% of the mass of compound G. In some embodiments, the mass of compound A is in the range of about 80% to about 120% of the mass of compound G. In some embodiments, the mass of compound A is in the range of about 90% to about 110% of the mass of compound G. In some embodiments, the mass of compound A is about 20% of the mass of compound G. In some embodiments, the mass of compound A is about 30% of the mass of compound G. In some embodiments, the mass of compound A is about 40% of the mass of compound G. In some embodiments, the mass of compound A is about 50% of the mass of compound G. In some embodiments, the mass of compound A is about 60% of the mass of compound G. In some embodiments, the mass of compound A is about 70% of the mass of compound G. In some embodiments, the mass of compound A is about 80% of the mass of compound G. In some embodiments, the mass of compound A is about 90% of the mass of compound G. In some embodiments, the mass of compound A is about 100% of the mass of compound G. In some embodiments, the mass of compound A is about 110% of the mass of compound G. In some embodiments, the mass of compound A is about 120% of the mass of compound G.

[0179] In some embodiments, the compositions disclosed herein are provided for use in treating patients with a mutation in the TK2 gene that results in mitochondrial depletion. In some embodiments, the compositions comprise a first heteroaryl compound and a second heteroaryl compound dissolved in an aqueous liquid, the concentration of the first heteroaryl compound is higher than that of a composition comprising the first heteroaryl compound dissolved in an aqueous liquid that does not contain the second heteroaryl compound, and the first heteroaryl compound and the second heteroaryl compound are selected from optionally substituted pyrimidines and optionally substituted purines.

[0180] In some embodiments, a method for treating a patient with a mutation in the TK2 gene that results in mitochondrial depletion is provided, comprising administering a composition disclosed herein. In some embodiments, a method for treating a patient with a mutation in the TK2 gene that results in mitochondrial depletion is provided, comprising administering a composition comprising a first heteroaryl compound and a second heteroaryl compound dissolved in an aqueous liquid, wherein the concentration of the first heteroaryl compound is higher than that of a composition comprising a first heteroaryl compound dissolved in an aqueous liquid that does not contain the second heteroaryl compound, and the first heteroaryl compound and the second heteroaryl compound are selected from an optionally substituted pyrimidine and an optionally substituted purine.

[0181] method In some embodiments, the present disclosure provides a method of preparing a composition disclosed herein.

[0182] In some embodiments, the present disclosure provides a method comprising dissolving a first heteroaryl compound and a second heteroaryl compound in an aqueous liquid to form a solution, wherein the concentration of the first heteroaryl compound is higher compared to a composition comprising the first heteroaryl compound dissolved in an aqueous liquid without the second heteroaryl compound. In some embodiments, the first heteroaryl compound and the second heteroaryl compound are selected from optionally substituted pyrimidines and optionally substituted purines.

[0183] In some embodiments, the dissolution occurs over a period of about 10 minutes or less. In some embodiments, the dissolution occurs over a period of about 9 minutes or less. In some embodiments, the dissolution occurs over a period of about 8 minutes or less. In some embodiments, the dissolution occurs over a period of about 7 minutes or less. In some embodiments, the dissolution occurs over a period of about 6 minutes or less. In some embodiments, the dissolution occurs over a period of about 5 minutes or less. In some embodiments, the dissolution occurs over a period of about 4 minutes or less. In some embodiments, the dissolution occurs over a period of about 3 minutes or less. In some embodiments, the dissolution occurs over a period of about 2 minutes or less. In some embodiments, the dissolution occurs over a period of about 1 minute or less.

[0184] In some embodiments, dissolving is performed by mixing the first heteroaryl compound and the second heteroaryl compound in a mixer. In some embodiments, the mixer includes, but is not limited to, a stir bar in a mixing vessel. In some embodiments, dissolving is performed by mixing the first heteroaryl compound and the second heteroaryl compound at about 50 rpm to about 1000 rpm. In some embodiments, dissolving is performed by mixing the first heteroaryl compound and the second heteroaryl compound at about 100 rpm to about 800 rpm. In some embodiments, dissolving is performed by mixing the first heteroaryl compound and the second heteroaryl compound at about 150 rpm to about 650 rpm. In some embodiments, dissolving is performed by mixing the first heteroaryl compound and the second heteroaryl compound at about 50 rpm. In some embodiments, dissolving is performed by mixing the first heteroaryl compound and the second heteroaryl compound at about 100 rpm. In some embodiments, dissolving is performed by mixing the first heteroaryl compound and the second heteroaryl compound at about 150 rpm. In some embodiments, the dissolution is performed by mixing the first heteroaryl compound and the second heteroaryl compound at about 200 rpm. In some embodiments, the dissolution is performed by mixing the first heteroaryl compound and the second heteroaryl compound at about 300 rpm. In some embodiments, the dissolution is performed by mixing the first heteroaryl compound and the second heteroaryl compound at about 400 rpm. In some embodiments, the dissolution is performed by mixing the first heteroaryl compound and the second heteroaryl compound at about 500 rpm. In some embodiments, the dissolution is performed by mixing the first heteroaryl compound and the second heteroaryl compound at about 600 rpm. In some embodiments, the dissolution is performed by mixing the first heteroaryl compound and the second heteroaryl compound at about 650 rpm.In some embodiments, the dissolving is performed by mixing the first heteroaryl compound and the second heteroaryl compound at about 700 rpm. In some embodiments, the dissolving is performed by mixing the first heteroaryl compound and the second heteroaryl compound at about 800 rpm. In some embodiments, the dissolving is performed by mixing the first heteroaryl compound and the second heteroaryl compound at about 900 rpm. In some embodiments, the dissolving is performed by mixing the first heteroaryl compound and the second heteroaryl compound at about 1000 rpm.

[0185] In some embodiments, the dissolution is performed by mixing the first heteroaryl compound and the second heteroaryl compound at about 50 rpm to about 1000 rpm for 10 minutes or less. In some embodiments, the dissolution is performed by mixing the first heteroaryl compound and the second heteroaryl compound at about 50 rpm to about 1000 rpm for 7 minutes or less. In some embodiments, the dissolution is performed by mixing the first heteroaryl compound and the second heteroaryl compound at about 50 rpm to about 1000 rpm for 5 minutes or less. In some embodiments, the dissolution is performed by mixing the first heteroaryl compound and the second heteroaryl compound at about 50 rpm to about 1000 rpm for 3 minutes or less. In some embodiments, the dissolution is performed by mixing the first heteroaryl compound and the second heteroaryl compound at about 50 rpm to about 1000 rpm for 2 minutes or less.

[0186] In some embodiments, the dissolution is performed by mixing the first heteroaryl compound and the second heteroaryl compound at about 150 rpm to about 650 rpm for 10 minutes or less. In some embodiments, the dissolution is performed by mixing the first heteroaryl compound and the second heteroaryl compound at about 150 rpm to about 650 rpm for 5 minutes or less. In some embodiments, the dissolution is performed by mixing the first heteroaryl compound and the second heteroaryl compound at about 150 rpm to about 650 rpm for 3 minutes or less. In some embodiments, the dissolution is performed by mixing the first heteroaryl compound and the second heteroaryl compound at about 150 rpm to about 650 rpm for 2 minutes or less.

[0187] In some embodiments, the dissolution is performed by mixing the first heteroaryl compound and the second heteroaryl compound at about 650 rpm for about 1 minute, and then mixing the first heteroaryl compound and the second heteroaryl compound at about 150 rpm for about 1 minute.

[0188] In some embodiments, dissolution is performed by mixing a first heteroaryl compound and a second heteroaryl compound in a volume of an aqueous liquid to form a mixture, and then shaking the mixture and / or inverting the mixture to dissolve the second heteroaryl compound and / or the first heteroaryl compound.

[0189] In some embodiments, at least 80% of the first heteroaryl compound and at least 80% of the second heteroaryl compound are dissolved. In some embodiments, at least 85% of the first heteroaryl compound and at least 85% of the second heteroaryl compound are dissolved. In some embodiments, at least 90% of the first heteroaryl compound and at least 90% of the second heteroaryl compound are dissolved. In some embodiments, at least 95% of the first heteroaryl compound and at least 95% of the second heteroaryl compound are dissolved. In some embodiments, 100% of the first heteroaryl compound and 100% of the second heteroaryl compound are dissolved. In some embodiments, at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99% of the first heteroaryl compound are dissolved. In some embodiments, at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99% of the second heteroaryl compound is dissolved.

[0190] In some embodiments, the dissolution is carried out for about 5 minutes or less and at least about 95% of the first heteroaryl compound and at least about 95% of the second heteroaryl compound are dissolved. In some embodiments, the dissolution is carried out for about 2 minutes or less and at least about 95% of the first heteroaryl compound and at least about 95% of the second heteroaryl compound are dissolved.

[0191] In some embodiments, the first heteroaryl compound is thymidine and the second heteroaryl compound is deoxycytidine.

[0192] In some embodiments, the first heteroaryl compound is compound G and the second heteroaryl compound is compound A. [ka]

[0193] In some embodiments, the present disclosure provides a method that includes dissolving a first heteroaryl compound and a second heteroaryl compound (e.g., thymidine and deoxycytidine) in an aqueous liquid to form a solution. For example, in some embodiments, the first heteroaryl compound and the second heteroaryl compound (e.g., powdered thymidine and powdered deoxycytidine) can be poured into the aqueous liquid and agitated, e.g., stirred, until the compounds (e.g., nucleosides) are dissolved. In some embodiments, the dissolution is carried out for 10 minutes or less, e.g., 5 minutes or less, or 1 minute or less. In some embodiments, all of the nucleosides are dissolved. In some embodiments, most of the compounds (e.g., nucleosides) are dissolved, e.g., at least 90%, at least 95%, or at least 99% of each compound (e.g., nucleoside) is dissolved. In some embodiments, the dissolution step can form any of the compositions described above. For example, in some embodiments, the dissolving step can be carried out for 5 minutes or less to produce a solution containing 20 mg / mL or more, e.g., 40 mg / mL to 60 mL, of each of the dissolved first and second heteroaryl compounds (e.g., thymidine and deoxycytidine).

[0194] In some embodiments, the aqueous liquid is placed in a container that includes markings that correspond to a particular volume during dissolution. For example, in some embodiments, the markings can include volume units, such as milliliters, cups, fluid ounces, tablespoons, teaspoons, or dram. Stated differently, in some embodiments, the markings can correspond to a particular volume. For example, FIG. 2 shows an exemplary container with three markings labeled with particular volumes, namely, 50 mL, 100 mL, and 150 mL. In some embodiments, the container can have three markings labeled with different particular volumes, including but not limited to, 40 mL, 80 mL, and 120 mL. The markings on the container can include any increments that correspond to volumes relevant to the preparation of the composition or product. In some embodiments, the markings can indicate the number of packages of the first heteroaryl compound and the second heteroaryl compound (e.g., deoxycytidine and thymidine) to be used in the dissolution step. For example, FIG. 1 shows an exemplary container with three markings, each marking having a line indicating the height of the liquid, a symbol corresponding to the package, and a number associated with the number of packages. 1 represents a paper or foil package torn near its top, e.g., along a perforation. For example, a user can empty a package of a desired number of compounds (e.g., nucleosides) into a container and then add an amount of liquid up to the indicated height mark.

[0195] In some embodiments, each package can contain one of the compounds (e.g., nucleosides) or both of the compounds (e.g., nucleosides). For example, in some embodiments, a package can contain both a first heteroaryl compound and a second heteroaryl compound (e.g., deoxycytidine and thymidine). In some cases, at least one package contains a second heteroaryl compound (e.g., deoxycytidine) but not a first heteroaryl compound (e.g., thymidine), or a first heteroaryl compound (e.g., thymidine) but not a second heteroaryl compound (e.g., deoxycytidine). The method can include adding the contents of one or more packages, such as two or more, three or more, four or more, or five or more packages, to the container. In some cases, the mass of the compound (e.g., nucleoside) per package ranges from 0.1 g to 10 g, such as 0.5 g to 4.0 g.

[0196] The method can also include orally administering a solution containing the compound (e.g., a nucleoside) to the patient. For example, the solution can be administered using a syringe, e.g., a syringe configured to contain 1 mL to 150 mL, e.g., 25 mL to 100 mL of liquid. The solution can be administered orally, e.g., through a nasogastric or gastrostomy tube, e.g., using a syringe. In some cases, oral administration is once a day, twice a day, three times a day, or four or more times a day. Administration can be repeated for 10 days or more, e.g., 30 days or more, or 90 days or more.

[0197] In some embodiments, the subject is diagnosed with mitochondrial DNA depletion syndrome, thymidine production deficiency, deoxycytidine production deficiency, mutation of TK2 gene, or combinations thereof.In such cases, administration of deoxycytidine and thymidine can sometimes improve the health of the subject.For example, in some cases, the subject gains weight, e.g., gains weight at a faster rate than before administration of the solution.These increases in health, e.g., evidenced by increased weight gain, may first be observed after long-term administration of the solution, e.g., for 10 days or more.

[0198] kit In some embodiments, kits are also provided that can be used to make the compositions and practice the methods described above.

[0199] In some embodiments, the kit can include a second heteroaryl compound (e.g., deoxycytidine) and a first heteroaryl compound (e.g., thymidine). For example, in some embodiments, the kit can include one or more packages, each containing one of the compounds (e.g., a nucleoside) or both of the compounds (e.g., a nucleoside). For example, in some embodiments, the package can contain both the second heteroaryl compound (e.g., deoxycytidine) and the first heteroaryl compound (e.g., thymidine). In some embodiments, at least one package contains the second heteroaryl compound (e.g., deoxycytidine) but not the first heteroaryl compound (e.g., thymidine), or contains the first heteroaryl compound (e.g., thymidine) but not the second heteroaryl compound (e.g., deoxycytidine). Exemplary packages include foil packages, paper packages, and plastic bottles. In some embodiments, the package can be configured to be torn to expose the compound (e.g., nucleoside) contained therein, e.g., a foil or paper package can have perforations. In some cases, the mass of compound (e.g., nucleoside) per package ranges from 0.1 g to 10 g, e.g., 0.5 g to 4.0 g.

[0200] In some embodiments, the kit can include a container for dissolving a compound (e.g., a nucleoside) in an aqueous liquid. For example, in some embodiments, the container can include a lid and markings corresponding to a specific volume during dissolution. For example, in some embodiments, the markings can include volume units, such as milliliters, cups, fluid ounces, tablespoons, teaspoons, or dram. Stated differently, in some embodiments, the markings can correspond to a specific volume. For example, FIG. 2 shows an exemplary container with three markings labeled with specific volumes, namely, 50 mL, 100 mL, and 150 mL. In some embodiments, the container can have three markings labeled with different specific volumes, including but not limited to, 40 mL, 80 mL, and 120 mL. The markings on the container can correspond to any specific volume relevant to the preparation of the composition or product. In some embodiments, the markings can indicate the number of packages of the second heteroaryl compound (e.g., deoxycytidine) and the first heteroaryl compound (e.g., thymidine) to be used in the dissolution step. For example, Figure 1 shows an exemplary container with three markings, each marking having a line indicating the height of the liquid, a symbol corresponding to the package, and a number associated with the number of packages. The symbol in Figure 1 represents a paper or foil package torn near its top, e.g., along a perforation. For example, in some embodiments, a user can empty a desired number of packages of a compound (e.g., a nucleoside) into the container and then add an amount of liquid up to the indicated height mark. In some embodiments, the container comprises plastic, e.g., clear plastic.

[0201] In some embodiments, the kit can include a syringe for use in orally administering a compound (e.g., a nucleoside)-containing solution to a subject. In some embodiments, the syringe can be configured to contain 1 mL to 150 mL of liquid. In some embodiments, the kit includes a nasogastric or gastrostomy tube. For example, in some embodiments, the kit can include both a syringe and a tube, where the syringe is configured to mate with the tube for delivery of the solution to the subject.

[0202] In some embodiments, the kit can include printed instructions for using any of the items in the kit, e.g., for practicing any of the methods described herein. In some embodiments, the instructions can include words, symbols, or combinations thereof printed on paper, printed on a package, or printed on any other suitable surface. In some embodiments, the instructions can be provided in electronic format, e.g., on a non-transitory computer readable medium. In some embodiments, the instructions can be provided as a reference to an internet address that describes the use of the items, e.g., the kit can include a Quick Response Code (QR Code), which can be interpreted by a computer system to provide the internet address.

[0203] In some embodiments, the instructions instruct the user to dissolve the second heteroaryl compound (e.g., deoxycytidine) and the first heteroaryl compound (e.g., thymidine) in a specific volume of aqueous liquid. For example, in some embodiments, the instructions can instruct the user to dissolve two packages, each containing a second heteroaryl compound (e.g., deoxycytidine) and a first heteroaryl compound (e.g., thymidine), into a container and fill the container with water to the mark corresponding to the two packages. In some embodiments, the user can be a patient, a medical professional, or a non-professional caregiver, such as a family member of the patient. In some embodiments, the instructions instruct the user to mix the second heteroaryl compound (e.g., deoxycytidine) and / or the first heteroaryl compound (e.g., thymidine) in a specific volume of aqueous liquid to form a mixture, and then shake the mixture and / or invert the mixture to dissolve the second heteroaryl compound and / or the first heteroaryl compound. In some embodiments, the printed instructions further instruct the user to dissolve the first heteroaryl compound and the second heteroaryl compound in a particular volume of aqueous liquid by inverting the closed container one or more times and then standing it upright.

[0204] In some embodiments, the instructions instruct the user to dissolve a single dose of a second heteroaryl compound (e.g., deoxycytidine) and a single dose of a first heteroaryl compound (e.g., thymidine) in a particular volume of an aqueous liquid to form a solution and then administer the solution to the patient. In some embodiments, the instructions instruct the user to dissolve a daily dose of a second heteroaryl compound (e.g., deoxycytidine) and a daily dose of a first heteroaryl compound (e.g., thymidine) in a particular volume of an aqueous liquid to form a solution, divide the solution into multiple individual doses, and then administer each of the individual doses separately to the patient throughout the day.

[0205] In some embodiments, the instructions instruct the user to orally administer the solution to the subject. In some embodiments, the solution can be orally administered to the subject directly into the mouth of the subject, with or without a syringe. In some embodiments, the solution can be orally administered to the subject through a nasogastric or gastrostomy tube, with or without a syringe. In some embodiments, the instructions can instruct the user to administer the solution any suitable number of times per day, such as once per day, twice per day, three times per day, or four or more times per day. For example, in some embodiments, each administration throughout the day can be the same amount of nucleoside. In some embodiments, the instructions state that the second heteroaryl compound (e.g., deoxycytidine) and the first heteroaryl compound (e.g., thymidine) should each be administered independently at a dose ranging from 100 mg / kg / day to 500 mg / kg / day. In some embodiments, the instructions state that the second heteroaryl compound (e.g., deoxycytidine) and the first heteroaryl compound (e.g., thymidine) are each independently to be administered at a dose ranging from 1 g / day to 5 g / day. In some embodiments, the instructions state that the solution is for administration to a subject diagnosed with mitochondrial DNA depletion syndrome, thymidine deficiency, deoxycytidine deficiency, a mutation in the TK2 gene, or a combination thereof.

[0206] In some embodiments, the kit comprises a first heteroaryl compound and a second heteroaryl compound. In some embodiments, the first heteroaryl compound is thymidine and the second heteroaryl compound is deoxycytidine. In some embodiments, the first heteroaryl compound is compound G and the second heteroaryl compound is compound A. [ka] EXAMPLES

[0207] The following examples are provided to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the invention, and are not intended to limit the scope of what the inventors regard as the invention, nor are they intended to represent that the following experiments are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.), but some experimental error and deviation should be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric. Standard abbreviations may be used, such as bp (base pairs); kb (kilobases); pl (picoliters); s or sec (seconds); min (minutes); h or hr (hours); aa (amino acids); nt (nucleotides), etc.

[0208] Example 1: Solubility of Thymidine in Aqueous Liquids The solubility of thymidine was investigated in which the dissolution medium was water, pH 3 buffered water, and water containing deoxycytidine. The deoxycytidine used in the solubility study is referred to as Form A deoxycytidine, as described, for example, in U.S. Patent Application Publication No. 2021 / 0054014, which is incorporated herein by reference. Form A deoxycytidine is characterized by an X-ray diffraction pattern including peaks at 8.4, 12.9, 14.2, 16.8, 18.4, 19.4, 28.4, 30.0, and 30.6 degrees two-theta (2θ) (+ / -0.2). The X-ray diffraction pattern can be recorded using CuKα1 radiation.

[0209] The procedure involved adding 300 mg of thymidine to 3.0 mL of liquid and stirring. The three liquids were water, water with 50 mg / mL of deoxycytidine already dissolved in it, and water buffered at approximately pH 3. pH 3 buffered water was made by adding 821 mg of anhydrous citric acid and 213 mg of sodium citrate dihydrate to a 100 mL volumetric flask and adding water to the 100 mL mark while dissolving the solids. Deoxycytidine solution was made by adding 500 mg of deoxycytidine to a 10 mL volumetric flask and topping off the flask with water while dissolving the solids to give a pH of 8.23 ​​and a deoxycytidine concentration of approximately 50 mg / mL.

[0210] The liquid was stirred and samples were removed at 5 min, 10 min and 24 h. At each time point, 0.7 mL of the suspension was removed and filtered through a 0.45 μm PTFE filter, and 0.3 mL of the suspension was removed and centrifuged at 10,000 rpm for 2 min. The filtered filtrate and centrifugation supernatant were subjected to high performance liquid chromatography (HPLC) to determine the amount of dissolved thymidine.

[0211] The results of the solubility studies are shown below in Table 1. Solubility is reported in mg / mL. [Table 1]

[0212] The pH of the suspension was also recorded, see Table 2 below. [Table 2]

[0213] After 5 minutes, about 52 mg / mL of thymidine was dissolved in water and about 58 mg / mL was dissolved in buffered water at pH 3. In particular, the 50 mg / mL deoxycytidine solution provided a thymidine solubility of about 72 mg / mL, which is about 38% higher than the solubility of thymidine in water (i.e., 52 mg / mL).

[0214] Moreover, at 10 minutes of stirring, the solubility of thymidine further increased to about 87 mg / mL for the deoxycytidine solution. At 10 minutes, the solubility of thymidine in water and pH 3 buffer increased to about 55 and 60 mg / mL, respectively. Thus, at 10 minutes, the solubility of thymidine in the deoxycytidine solution was about 58% higher than in water (i.e., 87 mg / mL compared to 55 mg / mL).

[0215] These experiments demonstrate that deoxycytidine can significantly increase the solubility of thymidine in aqueous liquids. In other words, the presence of deoxycytidine increased the solubility of thymidine in the liquid.

[0216] Example 2: Reconstitution of thymidine in aqueous liquids The solubility of thymidine in combination with different amounts of deoxycytidine was determined using HPLC and reconstitution methods as described below.

[0217] Standard solutions Deoxycytidine (dC) and thymidine (dT) 0.1 mg / mL standard solutions were prepared by adding 5 mg each of deoxycytidine and thymidine to a 50 mL volumetric flask and diluting with approximately 40 mL of diluent (e.g., water) to form a mixture. The mixture was shaken at 125 rpm for 10 minutes on a laboratory shaker. 10 mL of diluent (e.g., water) was then added and the mixture was mixed. Standard solutions were prepared in duplicate.

[0218] Sample preparation Stock solutions Each 50 mg / mL stock solution was prepared by adding 120 mL of purified water to a 400 mL beaker, stirring the water at 650 rpm, and then adding the amounts of thymidine and / or deoxycytidine listed in Table 3 below for each sample to form a mixture. [Table 3]

[0219] Each mixture was stirred at 650 rpm for approximately 1 minute, after which the stirring was reduced to 150 rpm and maintained at 150 rpm for approximately 1 minute. After a total of approximately 2 minutes, the mixture was filtered through a 0.45 μm syringe filter to obtain a filtered stock solution of each sample.

[0220] Intermediate solution An intermediate solution of 0.9 mg / mL of each of the above samples was prepared by adding 1.0 mL of the respective filtered stock solution to a 50 mL volumetric flask, diluting to volume with diluent (eg, water) and mixing.

[0221] Working solution A 0.09 mg / mL working solution of each of the above samples was prepared by adding 1.0 mL of each intermediate solution to a 10 mL volumetric flask, diluting to volume with diluent (e.g., water), and mixing. The resulting mixture was transferred to an HPLC vial.

[0222] HPLC method HPLC system parameters The working solutions of each sample above were subjected to HPLC analysis using the conditions and parameters below and in Table 4. The data collected from the HPLC analysis was then used to calculate the percentage of dissolved thymidine for each sample after 2 minutes of mixing.

[0223] Mobile phase A: Purified water (degassed by sonication)

[0224] Mobile phase A: Acetonitrile (degassed by sonication) [Table 4]

[0225] calculation Content

number

[0226] A 試料= Peak area of ​​dC or dT in the sample solution

[0227] W Std = weight of dC or dT reference material [mg]

[0228] Purity Std = Purity of dC or dT reference material (% / 100)

[0229] V 試料 = dC or dT corrected dilution of sample solution [mL]

[0230] LCFW = Label claim and fill weight correction factor / 0.4825 (2000mg / 4145mg)

[0231] A Std = Average peak area of ​​dC or dT in the six injections of Std1 at the start

[0232] W 試料 = weight of sample (mg)

[0233] V Std = dilution of standard solution [mL] / 50mL

[0234] 100=Conversion (%)

[0235] result The results obtained from the above procedure are shown below in Table 5 and in Figure 3. The dC level is the percentage of dC by mass relative to dT. The dT content is the percentage of dT in solution within 2 minutes of stirring in the presence of the indicated dC level. [Table 5]

[0236] Table 5 and FIG. 3 show that as the concentration of deoxycytidine increases, the amount of thymidine dissolved after 2 minutes of mixing increases, with the amount of dissolved thymidine reaching its maximum value at at least 40% deoxycytidine. Example 3: Preparation of Compound G

[0237] Step 1: Starting from deoxyguanosine, the 5´-hydroxy group of deoxyguanosine was selectively protected by adding a TBDPS (t-butyldiphenylsilyl) group under the reaction conditions of t-butyldiphenylsilyl chloride (TBDPSCl) / dimethylaminopyridine (DMAP) in dimethylformamide (DMF) at room temperature (rt).

[0238] Step 2: Esterification of the 3'-hydroxy group was achieved using (carbobenzoxy)Boc-L-valine and dicyclohexylcarbodiimide (DCC) in CH2Cl2 (DCM) to give the protected intermediate, which was purified by silica column chromatography in an overall yield of 49%.

[0239] Step 3: The TBDPS group was then removed using n-Bu4NF (TBAF) in tetrahydrofuran (THF) at room temperature to give the free hydroxy compound in 75% yield after column purification.

[0240] Step 4: Hydrogenation with hydrogen gas in solution with palladium on carbon catalyst in the presence of L-tartaric acid gave compound G as the L-tartrate salt. Example 4: Preparation of Compound A

[0241] Step 1: Starting from deoxyadenosine, the 5′-hydroxy group was selectively protected by 4,4′-dimethoxytrityl (DMTr) group in pyridine at 0-10 °C to give the protected compound in 60% yield after column purification.

[0242] Step 2: Esterification of the 3'-hydroxy group was achieved with Boc-L-valine and DCC in DCM at room temperature as in Example 3 to give the protected intermediate, which was purified by silica column chromatography in an overall yield of 84%.

[0243] Step 3: Removal of the DMTr group was achieved with 80% aqueous AcOH at room temperature. The product was purified by silica column chromatography in 74% yield.

[0244] Step 4: H3PO4 / DCM was used for de-Boc protection, followed by L-tartaric acid charging to give compound A as the L-tartrate salt in 76% yield upon crystallization.

[0245] Example 5: Solubility Test The solubility of Compound G in combination with multiple concentrations of Compound A was determined. [ka]

[0246] Compound G and Compound A were added to phosphate buffered saline (PBS) at pH 7.4 at room temperature in the ratios and concentrations listed in Table 6 below to form 15 different samples. The solubility of each sample was observed for each sample. [Table 6]

[0247] As shown in Table 6, at molar ratios of 1:0, 1:0.1, and 1:0.25, the samples were cloudy. However, the samples became clear at molar ratios of 1:0.5 and 1:1. The term "mostly dissolved" indicates a small amount of precipitate.

[0248] Although the foregoing invention has been described in some detail by way of illustration and example for clarity of understanding, it will be readily apparent to those skilled in the art in light of the teachings of this invention that certain changes and modifications can be made without departing from the spirit or scope of the appended claims.

[0249] Thus, the above merely illustrates the principles of the invention. It will be appreciated that those skilled in the art can devise various configurations that embody the principles of the invention and fall within its spirit and scope, although not expressly described or shown herein. Furthermore, all examples and conditional language recited herein are intended primarily to aid the reader in understanding the principles of the invention and the concepts that the inventors have contributed to advancing the art, and should not be construed as being limited to such specifically recited examples and conditions. Furthermore, all statements herein reciting principles, aspects, and embodiments of the invention, as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Moreover, such equivalents are intended to include both currently known equivalents and equivalents developed in the future, i.e., any elements developed that perform the same function, regardless of structure. Furthermore, nothing disclosed herein is intended to be publicly available, regardless of whether such disclosure is expressly recited in the claims.

[0250] Therefore, the scope of the present invention is not intended to be limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of the present invention is embodied in the appended claims. In the claims, 35 USC §112(f) or 35 USC §112(6) is expressly defined as being invoked for a limitation in a claim only if the precise phrase "means for" or the precise phrase "step for" is recited at the beginning of such limitation in the claim. If such precise phrases are not used in a limitation of a claim, then 35 USC §112(f) or 35 USC §112(6) is not invoked.

Claims

1. A composition comprising a first heteroaryl compound and a second heteroaryl compound dissolved in an aqueous liquid, a concentration of the first heteroaryl compound is greater than a concentration of the first heteroaryl compound in a composition comprising the first heteroaryl compound dissolved in an aqueous liquid that does not contain the second heteroaryl compound; the first heteroaryl compound and the second heteroaryl compound are selected from optionally substituted pyrimidines and optionally substituted purines; The composition, wherein the optionally substituted pyrimidine and the optionally substituted purine are selected from a deoxynucleoside, a deoxynucleotide having 1 to 3 phosphate groups, a nucleoside, a nucleotide having 1 to 3 phosphate groups, and a prodrug of any of the foregoing.

2. 2. The composition of claim 1, wherein the optionally substituted pyrimidine has the formula Ia: 【Chemistry 1】 During the ceremony, R ２ is hydrogen or C １ -C ４ alkyl; R ３ is hydrogen, amino, hydroxy, -OR ５ , -NHR ６ or carbonyl; R ５ is selected from hydrogen, halogen, optionally substituted alkyl, or optionally substituted aralkyl; R ６ is hydrogen, optionally substituted alkyl, optionally substituted aralkyl, -C(O)N(R ７ ) (R ７’ ), -C(O)OR ８ , or -R ９ Selected from: R ７ , R ７’ , R ８ , and R １０ Each independently represents hydrogen or optionally substituted C １ -C １０ Alkyl, optionally substituted C ２ -C １０ Alkenyl, optionally substituted C ３ -C １０ selected from cycloalkyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R ９ teeth, 【Chemistry 2】 and R １１ is hydrogen, optionally substituted C １ -C １０ Alkyl and optionally substituted C ２ -C １０ alkenyl; R １３ is hydrogen or hydroxy; and 【Chemistry 3】 represents a single or double bond; and The optionally substituted purine has the formula IIa: 【Chemistry 4】 During the ceremony, R 3 is selected from hydrogen, amino, hydroxy, —OR 5 , —NHR 6 , or carbonyl; R 4 is selected from hydrogen, amino or —NHR 6 ; R 5 is selected from hydrogen, halogen, optionally substituted alkyl, or optionally substituted aralkyl; R 6 is selected from hydrogen, optionally substituted alkyl, optionally substituted aralkyl, -C(O)N(R 7 )(R 7 ), -C(O)OR 8 , or -R 9 ; R 7 , R 7′ , R 8 , and R 10 are each independently selected from hydrogen, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R 9 is 【Chemistry 5】 and R 11 is selected from hydrogen, optionally substituted C 1 -C 10 alkyl, and optionally substituted C 2 -C 10 alkenyl; R 13 is hydrogen or hydroxy; and 【Chemistry 6】 represents a single bond or a double bond.

3. 2. The composition of claim 1, wherein the first heteroaryl compound is thymidine and the second heteroaryl compound is deoxycytidine.

4. the thymidine is at a concentration of about 20 mg / mL or greater; and 4. The composition of claim 3, wherein the deoxycytidine is at a concentration of about 20 mg / mL or greater.

5. 5. The composition of claim 4, wherein the mass of thymidine is in the range of 0.5 g to 6.0 g per dosage unit and the mass of deoxycytidine is in the range of 0.5 g to 6.0 g per dosage unit.

6. the mass of deoxycytidine is in the range of about 40% to about 100% or in the range of about 90% to about 110% of the mass of thymidine; and / or The composition of claim 3, wherein the combined mass of thymidine and deoxycytidine ranges from 1.0 g to 12.0 g per dosage unit.

7. 2. The composition of claim 1 , wherein the first heteroaryl compound is compound G and the second heteroaryl compound is compound A: 【Chemistry 7】

8. 8. The composition of claim 7, wherein Compound G is at a concentration of about 20 mg / mL or greater, or at a concentration ranging from about 40 mg / mL to about 100 mg / mL.

9. 8. The composition of claim 7, wherein compound A is at a concentration ranging from about 5 mg / mL to about 100 mg / mL, or the molar ratio of compound G to compound A is from about 1:0.1 to about 1:

1.

10. the mass of compound G is in the range of 0.5 g to 6.0 g per dosage unit, or the mass of compound A is in the range of 0.5 g to 6.0 g per dosage unit; and / or The combined mass of compound G and compound A is in the range of 1.0 g to 12.0 g per dosage unit; and / or The composition of claim 7, wherein the mass of compound A ranges from about 40% to about 100% of the mass of compound G.

11. The composition of claim 1 for use in treating mitochondrial DNA depletion syndrome, thymidine deficiency, deoxycytidine deficiency, deoxyguanosine deficiency, deoxyadenosine deficiency, mutations in the TK2 gene, or combinations thereof.

12. a first heteroaryl compound; and a second heteroaryl compound; and Including, The kit, wherein the first heteroaryl compound and the second heteroaryl compound are selected from an optionally substituted pyrimidine and an optionally substituted purine.

13. 13. The kit of claim 12, further comprising printed instructions instructing a user to dissolve the first heteroaryl compound and the second heteroaryl compound in a specific volume of aqueous liquid, and / or a container having a lid and including markings corresponding to the specific volume of aqueous liquid.

14. 13. The kit of claim 12, wherein the first heteroaryl compound is thymidine and the second heteroaryl compound is deoxycytidine.

15. 13. The kit of claim 12, wherein the first heteroaryl compound is compound G and the second heteroaryl compound is compound A: 【Chemistry 9】

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