COMPOSITIONS COMPRISING ASPACYTARABINE AND ADDITIONAL COMPOUNDS, AND USE THEREOF

FIELD OF THE INVENTION

[001] The present invention relates to novel compositions comprising (l-((2R,3S,4S,5R)-3,4- dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-l,2-d ihydropyrimidin-4-yl)-L-asparagine (also known as BST-236, Astarabine® or Aspacytarabine) or pharmaceutically acceptable salt thereof and additional compounds, and uses thereof for the treatment of neoplastic diseases.

BACKGROUND OF THE INVENTION

[002] International Patent Application Publication No. WO/2017/093993 teaches prodrugs comprising cytarabine conjugated to a single amino acid selected from the group consisting of aspartic acid, glutamic acid, asparagine, and glutamine, for use in treating neoplastic diseases in medically compromised subjects. Aspacytarabine is a conjugate of cytarabine and aspartic acid wherein cytarabine is covalently attached to the carboxyl group of the side chain of aspartic acid. It is useful for treatment neoplastic diseases including hematological cancers such as leukemias thereby prolonging the survival of the patients in need of the treatment.

[003] Aspacytarabine is manufactured according to strict Good Manufacturing Practices (GMP) processes, and the product composition is carefully monitored. Composition of the final Active Pharmaceutical Ingredient (API) is crucial and affects the efficacy and safety of the final product. According to regulatory requirement, it is mandatory to identify qualitatively and quantitatively the final API composition including all related compounds (ICH Q7). Related compounds are defined as any components present in the intermediate or API that are not the desired entity and the final profile is a description of the identified and unidentified related compounds present in an API. The profile is normally dependent upon the production process and origin of the API.

[004] The present disclosure provides a composition comprising the final product identified as aspacytarabine and identified compounds within the final product. SUMMARY OF THE INVENTION

[005] In one aspect, the present disclosure relates to a composition comprising aspacytarabine or pharmaceutically acceptable salt thereof and at least one compound, selected from: a. at least one cytarabine-di-aspartic acid-compound, ,

Compound (6a), Compound (6b), or a mixture thereof, Compound (7), and

Compound (12) or pharmaceutically acceptable salt thereof, wherein the weight ratio of aspacytarabine relating to the weight of the compound in the composition is from 99.99:0.01 to 60:40.

[006] In another aspect, the present disclosure relates to a method of treating a neoplastic disease comprising administering to a subject in need thereof a pharmaceutical composition comprising aspacytarabine and at least one compound, selected from at least one cytarabine-di-aspartic acidcompound, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of Compound (6a) and Compound (6b). Compound (7), and Compound (12), or a salt thereof, wherein the weight ratio of aspacytarabine relating to the weight of the compound in the composition is from 99.99:0.01 to 60:40.

[007] In some aspects, the neoplastic disease is selected from the group consisting of hematological cancers and non-hematological cancers. In some further aspects, the hematological cancer is selected from the group consisting of leukemias, lymphomas, myelomas and Myelodysplastic Syndromes (MDS).

[008] In some aspects, the pharmaceutical composition is administered parenterally, orally or by inhalation. In some further aspects, pharmaceutical composition is administered by intravenous, intraarterial, intramuscular, subcutaneous, intraperitoneal, intracerebral, intracerebroventricular, intrathecal or intradermal administration route.

[009] In some aspects, the pharmaceutical composition is administered by intravenous infusion for a period ranging from 15 minutes to 24 hours.

[0010] In another aspect, the present disclosure relates to a compound defined by the following structure: Compound (1) or pharmaceutically acceptable salt thereof. spect, the present disclosure relates to a compound defined by the following Compound (4) or pharmaceutically acceptable salt thereof. [0012] In another aspect, the present disclosure relates to a compound defined by the following structure:

Compound (6a) or pharmaceutically acceptable salt thereof.

[0013] In another aspect, the present disclosure relates to a compound defined by the following structure: Compound (6b) or pharmaceutically acceptable salt thereof.

[0014] In another aspect, the present disclosure relates to a compound defined by the following structure: Compound (12) or pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0015] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, it will be understood by those skilled in the art that the present invention may be practiced without these specific details. In other instances, well-known methods, procedures, and components have not been described in detail so as not to obscure the present invention.

[0016] Unless otherwise defined herein, scientific and technical terms used in connection with the present application shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. [0017] A skilled artisan would appreciate that the term “comprising” encompasses inclusion of the recited elements, but not excluding others which may be optional.

[0018] A skilled artisan would understand that when a range of values is expressed, another embodiment includes one limit value and/or the other limit value of the range. Additionally, all ranges are inclusive and combinable.

[0019] The term “about” in reference to a numerical value stated herein is to be understood as the stated value +/- 10%.

[0020] In some embodiments, the present disclosure relates to a composition comprising aspacytarabine and at least one compound, selected from: a. at least one cytarabine-di-aspartic acid-compound, ,

5 Compound (6 a), Compound (6b), or a mixture thereof, Compound (7), and

or a salt thereof, wherein the weight ratio of aspacytarabine relating to the weight of the compound in the composition is from 99.99:0.01 to 60:40.

[0021] In another embodiment, the at least one cytarabine-di-aspartic acid-compound is selected from Compounds 8-11 and any combination thereof; represented by the following structures: , p , p .

Aspacytarabine and additional analogous Compounds

[0022] Aspacytarabine, also known as BST-236 and Astarabine®, is a conjugate of cytarabine and aspartic acid wherein cytarabine is covalently attached to the carboxyl group of the side chain of aspartic acid, with the following IUPAC nomenclature: N ⁴ -(l-((2R,3S,4S,5R)-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-l,2-dihydropyrimi din-4-yl)-L-asparagine.

[0023] The molecular formula of the free base is C ₁₃ H ₁₈ N ₄ O ₈ and the molecular weight is 358.31 g/Mol.

[0024] Aspacytarabine is represented by the structure below:

[0025] In one embodiment, the aspacytarabine acceptable salt is of an organic or inorganic acid selected from the group consisting of acetic acid, hydrochloric acid, methanesulfonic acid, phosphoric acid, cirtic acid, lactic acid, succinic acid, tartaric acid, boric acid, benzoic acid, toluenesulfonic acid, benzenesulfonic acid, ascorbic acid, sulfuric acid, maleic acid, formic acid, malonic acid, nicotinic acid and oxalic acid.

[0026] In one embodiment, the aspacytarabine acceptable salt is acetic acid. In another embodiment, the aspacytarabine acceptable salt is hydrochloric acid. In another embodiment, the aspacytarabine acceptable salt is methanesulfonic acid. In another embodiment, the aspacytarabine acceptable salt is phosphoric acid. In another embodiment, the aspacytarabine acceptable salt is cirtic acid. In another embodiment, the aspacytarabine acceptable salt is lactic acid. In another embodiment, the aspacytarabine acceptable salt is succinic acid. In another embodiment, the aspacytarabine acceptable salt is tartaric acid. In another embodiment, the aspacytarabine acceptable salt is boric acid. In another embodiment, the aspacytarabine acceptable salt is benzoic acid. In another embodiment, the aspacytarabine acceptable salt is toluenesulfonic acid. In another embodiment, the aspacytarabine acceptable salt is benzenesulfonic acid. In another embodiment, the aspacytarabine acceptable salt is ascorbic acid. In another embodiment, the aspacytarabine acceptable salt is sulfuric acid. In another embodiment, the aspacytarabine acceptable salt is maleic acid. In another embodiment, the aspacytarabine acceptable salt is formic acid. In another embodiment, the aspacytarabine acceptable salt is malonic acid. In another embodiment, the aspacytarabine acceptable salt is nicotinic acid. In another embodiment, the aspacytarabine acceptable salt is oxalic acid.

[0027] The present invention relates to a composition comprising (l-((2R,3S,4S,5R)-3,4-dihydroxy- 5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo- 1 ,2-dihydropyrimidin-4-yl)-L-asparagine (also known as BST-236, Astarabine® or Aspacytarabine) or pharmaceutically acceptable salt thereof and at least one additional compound.

[0028] In one embodiment, the additional compound is cytarabine-di-aspartic acid-compound. In one embodiment, the cytarabine-di-aspartic acid-compounds are to be understood as active prodrugs of conjugates comprising cytarabine and two aspartic acids, substituted on both the sugar and the cytosine moieties of the drug or two aspartic acids on the cytosine moiety.

[0029] In one embodiment, the cytarabine-di-aspartic acid-compound is presented by the structure below of Formula (1)-

Formula (1) wherein R ¹ , R ² , R ³ and R ⁵ are each independently H or an aspartic acid, wherein when one of R ¹ , R ² , R ³ and R ⁵ is aspartic acid, the others are H.

[0030] In some embodiments, provided herein a composition comprising (l-((2R,3S,4S,5R)-3,4- dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-l,2-d ihydropyrimidin-4-yl)-L-asparagine (also known as BST-236, Astarabine® or Aspacytarabine) or pharmaceutically acceptable salt thereof and at least one additional compound.

[0031] In other embodiments, the additional compound is selected from at least one of the compounds listed in Table 1 below: Table 1

[0032] In one embodiment, the additional compound is a cytarabine-di-aspartic acid-compound comprising compound (8), compound (9), compound (10), compound (11) or any combination thereof. In another embodiment, the cytarabine-di-aspartic acid-compound comprises compound (8). In another embodiment, the cytarabine-di-aspartic acid-compound comprises compound (9). In another embodiment, the cytarabine-di-aspartic acid-compound comprises compound (10). In another embodiment, the cytarabine-di-aspartic acid-compound comprises compound (11).

[0033] In one embodiment, the additional compound is a mixture of compound (6a) and compound

Compound (6a) Compound (6b)

[0034] In one embodiment, the mixture of compound (6a) and Compound (6b) is a mixture comprising 50% of compound (6a) and 50% of compound (6b). In another embodiment, the mixture comprises 55% of compound (6a) and 45% of compound (6b). In another embodiment, the mixture comprises 60% of compound (6a) and 40% of compound (6b). In another embodiment, the mixture comprises 65% of compound (6a) and 35% of compound (6b). In another embodiment, the mixture comprises 70% of compound (6a) and 30% of compound (6b). In another embodiment, the mixture comprises 75% of compound (6a) and 25% of compound (6b). In another embodiment, the mixture comprises 80% of compound (6a) and 20% of compound (6b). In another embodiment, the mixture comprises 85% of compound (6a) and 15% of compound (6b). In another embodiment, the mixture comprises 90% of compound (6a) and 10% of compound (6b). In another embodiment, the mixture comprises 95% of compound (6a) and 5% of compound (6b). In another embodiment, the mixture comprises 98% of compound (6a) and 2% of compound (6b). In another embodiment, the mixture comprises 99% of compound (6a) and 1% of compound (6b). In another embodiment, the mixture comprises 99.5% of compound (6a) and 0.5% of compound (6b). In another embodiment, the mixture comprises 99.9% of compound (6a) and 0.1% of compound (6b).

[0035] In one embodiment, the present disclosure relates to a compound defined by the following structure: ound (1) or pharmaceutically acceptable salt thereof.

[0036] In one embodiment, the present disclosure relates to a compound defined by the following structure: Compound (4) or pharmaceutically acceptable salt thereof. [0037] In one embodiment, the present disclosure relates to a compound defined by the following structure:

Compound (6a) or pharmaceutically acceptable salt thereof.

[0038] In another aspect, the present disclosure relates to a compound defined by the following structure:

Compound (6b).

[0039] In one embodiment, the present disclosure relates to a compound defined by the following structure - Compound (12). Compositions

[0040] In some embodiments, the present disclosure relates to a composition comprising aspacytarabine or pharmaceutically acceptable salt thereof and at least one additiona compound, selected from at least one cytarabine-di-aspartic acid-compound, compound (1), compound (2), compound (3), compound (4), compound (5), compound (6a), compound (6b), a mixture of Compound (6a) and Compound (6b), compound (7), and compound (12) or pharmaceutically acceptable salt thereof, wherein the weight ratio of aspacytarabine relating to the weight of the compound in the composition is from 99.99:0.01 to 60:40.

[0041] In one embodiment, the ratio of aspacytarabine relating to the weight of the additional compound in the composition is 99.99:0.01. In another embodiment, the ratio of aspacytarabine relating to the weight of the additional compound in the composition is 99: 1. In another embodiment, the ratio of aspacytarabine relating to the weight of the additional compound in the composition is 90:10. In another embodiment, the ratio of aspacytarabine relating to the weight of the additional compound in the composition is 85:15. In another embodiment, the ratio of aspacytarabine relating to the weight of the additional compound in the composition is 80:20. In another embodiment, the ratio of aspacytarabine relating to the weight of the additional compound in the composition is 75:25. In another embodiment, the ratio of aspacytarabine relating to the weight of the additional compound in the composition is 70:30. In another embodiment, the ratio of aspacytarabine relating to the weight of the additional compound in the composition is 65:35. In another embodiment, the ratio of aspacytarabine relating to the weight of the additional compound in the composition is 60:40.

[0042] In one embodiment, the composition comprises aspacytarabine or pharmaceutically acceptable salt thereof and at least one cytarabine-di-aspartic acid-compound or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises aspacytarabine or pharmaceutically acceptable salt thereof and compound (2) or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises aspacytarabine or pharmaceutically acceptable salt thereof and compound (3) or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises aspacytarabine or pharmaceutically acceptable salt thereof and compound (4) or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises aspacytarabine or pharmaceutically acceptable salt thereof and compound (5) or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises aspacytarabine or pharmaceutically acceptable salt thereof and compound (6a) or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises aspacytarabine or pharmaceutically acceptable salt thereof and compound (6b) or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises aspacytarabine or pharmaceutically acceptable salt thereof and a mixture of compound (6a) and compound (6b) or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises aspacytarabine or pharmaceutically acceptable salt thereof and compound (7) or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises aspacytarabine or pharmaceutically acceptable salt thereof and compound (8) or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises aspacytarabine or pharmaceutically acceptable salt thereof and compound (9) or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises aspacytarabine or pharmaceutically acceptable salt thereof and compound (10) or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises aspacytarabine or pharmaceutically acceptable salt thereof and compound (11) or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises aspacytarabine or pharmaceutically acceptable salt thereof and compound (12) or pharmaceutically acceptable salt thereof.

[0043] In one embodiment, the present disclosure relates to a composition comprising aspacytarabine or pharmaceutically acceptable salt thereof and at least one additional compound, selected from at least one cytarabine-di-aspartic acid-compound, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of Compound (6a) and Compound (6b), Compound (7), and Compound (12) or pharmaceutically acceptable salt thereof, wherein a. at least one cytarabine-di-aspartic acid-compound or pharmaceutically acceptable salt thereof is present in the composition in an amount of 0.01- 40% w/w, or b. Compound (1) or pharmaceutically acceptable salt thereof is present in the composition in an amount of 0.01- 40% w/w, 0.01-0.1 % w/w, 0.1-1% w/w, 1-5% w/w, 5-10% w/w, 10-15% w/w, 15-20% w/w, 20-25% w/w, 25-30% w/w, 30-35% w/w, 35-40% w/w, 0.01-20%w/w, or 0.01-30%, or c. Compound (2) or pharmaceutically acceptable salt thereof is present in the composition in an amount of 0.01- 40% w/w, 0.01-0.1 % w/w, 0.1-1% w/w, 1-5% w/w, 5-10% w/w, 10-15% w/w, 15-20% w/w, 20-25% w/w, 25-30% w/w, 30-35% w/w, 35-40% w/w, 0.01-20%w/w, or 0.01-30%, or d. Compound (3) or pharmaceutically acceptable salt thereof is present in the composition in an amount of 0.01- 40% w/w, 0.01-0.1 % w/w, 0.1-1% w/w, 1-5% w/w, 5-10% w/w, 10-15% w/w, 15-20% w/w, 20-25% w/w, 25-30% w/w, 30-35% w/w, 35-40% w/w, 0.01-20%w/w, or 0.01-30%, or e. Compound (4) or pharmaceutically acceptable salt thereof is present in the composition in an amount of 0.01- 40% w/w, 0.01-0.1 % w/w, 0.1-1% w/w, 1-5% w/w, 5-10% w/w, 10-15% w/w, 15-20% w/w, 20-25% w/w, 25-30% w/w, 30-35% w/w, 35-40% w/w, 0.01-20%w/w, or 0.01-30%, or f. Compound (5) or pharmaceutically acceptable salt thereof is present in the composition in an amount of 0.01- 40% w/w, 0.01-0.1 % w/w, 0.1-1% w/w, 1-5% w/w, 5-10% w/w, 10-15% w/w, 15-20% w/w, 20-25% w/w, 25-30% w/w, 30-35% w/w, 35-40% w/w, 0.01-20%w/w, or 0.01-30% or g. Compound (6a) or pharmaceutically acceptable salt thereof is present in the composition in an amount of 0.01- 40% w/w, 0.01-0.1 % w/w, 0.1-1% w/w, 1-5% w/w, 5-10% w/w, 10-15% w/w, 15-20% w/w, 20-25% w/w, 25-30% w/w, 30-35% w/w, 35-40% w/w, 0.01-20%w/w, or 0.01-30% or h. Compound (6b) or pharmaceutically acceptable salt thereof is present in the composition in an amount of 0.01- 40% w/w, 0.01-0.1 % w/w, 0.1-1% w/w, 1-5% w/w, 5-10% w/w, 10-15% w/w, 15-20% w/w, 20-25% w/w, 25-30% w/w, 30-35% w/w, 35-40% w/w, 0.01-20%w/w, or 0.01-30%, or i. a mixture of Compound (6a) and Compound (6b) or pharmaceutically acceptable salt thereof are present in the composition in an amount of 0.01- 40% w/w, 0.01-0.1 % w/w, 0.1-1% w/w, 1-5% w/w, 5-10% w/w, 10-15% w/w, 15-20% w/w, 20-25% w/w, 25-30% w/w, 30-35% w/w, 35-40% w/w, 0.01-20%w/w, or 0.01-30%. or j. Compound (7) or pharmaceutically acceptable salt thereof is present in the composition in an amount of 0.01- 40% w/w, 0.01-0.1 % w/w, 0.1-1% w/w, 1-5% w/w, 5-10% w/w, 10-15% w/w, 15-20% w/w, 20-25% w/w, 25-30% w/w, 30-35% w/w, 35-40% w/w, 0.01-20%w/w, or 0.01-30%, or k. Compound (12) or pharmaceutically acceptable salt thereof is present in the composition in an amount of 0.01- 40% w/w, 0.01-0.1 % w/w, 0.1-1% w/w, 1-5% w/w, 5-10% w/w, 10-15% w/w, 15-20% w/w, 20-25% w/w, 25-30% w/w, 30-35% w/w, 35-40% w/w, 0.01-20%w/w, or 0.01- 30%, or any combination thereof.

[0044] In one embodiment, at least one cytarabine-di-aspartic acid-compound is present in the composition in an amount of about 0.01% w/w. In one embodiment, at least one cytarabine-di-aspartic acid-compound is present in the composition in an amount of about 0.05% w/w. In another embodiment, at least one cytarabine-di-aspartic acid-compound is present in the composition in an amount of about 0.1% w/w. In one embodiment, at least one cytarabine-di-aspartic acid-compound is present in the composition in an amount of about 0.5% w/w. In another embodiment, at least one cytarabine-di-aspartic acid-compound is present in the composition in an amount of about 1% w/w. In one embodiment, at least one cytarabine-di-aspartic acid-compound is present in the composition in an amount of about 5% w/w. In another embodiment, at least one cytarabine-di-aspartic acidcompound is present in the composition in an amount of about 10% w/w. In one embodiment, at least one cytarabine-di-aspartic acid-compound is present in the composition in an amount of about 15% w/w. In another embodiment, at least one cytarabine-di-aspartic acid-compound is present in the composition in an amount of about 20% w/w. In one embodiment, at least one cytarabine-di-aspartic acid-compound is present in the composition in an amount of about 25% w/w. In another embodiment, at least one cytarabine-di-aspartic acid-compound is present in the composition in an amount of about 30% w/w. In one embodiment, at least one cytarabine-di-aspartic acid-compound is present in the composition in an amount of about 35% w/w. In another embodiment, at least one cytarabine-di-aspartic acid-compound is present in the composition in an amount of about 40% w/w. [0045] In one embodiment, compound (1) is present in the composition in an amount of about 0.01% w/w. In another embodiment, compound (1) is present in the composition in an amount of about 0.05% w/w. In another embodiment, compound (1) is present in the composition in an amount of about 0.1% w/w. In another embodiment, compound (1) is present in the composition in an amount of about 0.5% w/w. In another embodiment, compound (1) is present in the composition in an amount of about 1% w/w. In another embodiment, compound (1) is present in the composition in an amount of about 5% w/w. In another embodiment, compound (1) is present in the composition in an amount of about 10% w/w. In another embodiment, compound (1) is present in the composition in an amount of about 15% w/w. In another embodiment, compound (1) is present in the composition in an amount of about 20% w/w. In another embodiment, compound (1) is present in the composition in an amount of about 25% w/w. In another embodiment, compound (1) is present in the composition in an amount of about 30% w/w. In another embodiment, compound (1) is present in the composition in an amount of about 35% w/w. In another embodiment, compound (1) is present in the composition in an amount of about 40% w/w.

[0046] In one embodiment, compound (2) is present in the composition in an amount of about 0.01% w/w. In another embodiment, compound (2) is present in the composition in an amount of about 0.05% w/w. In another embodiment, compound (2) is present in the composition in an amount of about 0.1% w/w. In another embodiment, compound (2) is present in the composition in an amount of about 0.5% w/w. In another embodiment, compound (2) is present in the composition in an amount of about 1% w/w. In another embodiment, compound (2) is present in the composition in an amount of about 5% w/w. In another embodiment, compound (2) is present in the composition in an amount of about 10% w/w. In another embodiment, compound (2) is present in the composition in an amount of about 15% w/w. In another embodiment, compound (2) is present in the composition in an amount of about 20% w/w. In another embodiment, compound (2) is present in the composition in an amount of about 25% w/w. In another embodiment, compound (2) is present in the composition in an amount of about 30% w/w. In another embodiment, compound (2) is present in the composition in an amount of about 35% w/w. In another embodiment, compound (2) is present in the composition in an amount of about 40% w/w.

[0047] In one embodiment, compound (3) is present in the composition in an amount of about 0.01% w/w. In another embodiment, compound (3) is present in the composition in an amount of about 0.05% w/w. In another embodiment, compound (3) is present in the composition in an amount of about 0.1% w/w. In one embodiment, compound (3) is present in the composition in an amount of about 0.5% w/w. In another embodiment, compound (3) is present in the composition in an amount of about 1% w/w. In another embodiment, compound (3) is present in the composition in an amount of about 5% w/w. In another embodiment, compound (3) is present in the composition in an amount of about 10% w/w. In another embodiment, compound (3) is present in the composition in an amount of about 15% w/w. In another embodiment, compound (3) is present in the composition in an amount of about 20% w/w. In another embodiment, compound (3) is present in the composition in an amount of about 25% w/w. In another embodiment, compound (3) is present in the composition in an amount of about 30% w/w. In another embodiment, compound (3) is present in the composition in an amount of about 35% w/w. In another embodiment, compound (3) is present in the composition in an amount of about 40% w/w.

[0048] In one embodiment, compound (4) is present in the composition in an amount of about 0.01% w/w. In another embodiment, compound (4) is present in the composition in an amount of about 0.5% w/w. In another embodiment, compound (4) is present in the composition in an amount of about 0.1% w/w. In another embodiment, compound (4) is present in the composition in an amount of about 0.5% w/w. In another embodiment, compound (4) is present in the composition in an amount of about 1% w/w. In another embodiment, compound (4) is present in the composition in an amount of about 5% w/w. In another embodiment, compound (4) is present in the composition in an amount of about 10% w/w. In another embodiment, compound (4) is present in the composition in an amount of about 15% w/w. In another embodiment, compound (4) is present in the composition in an amount of about 20% w/w. In another embodiment, compound (4) is present in the composition in an amount of about 25% w/w. In another embodiment, compound (4) is present in the composition in an amount of about 30% w/w. In another embodiment, compound (4) is present in the composition in an amount of about 35% w/w. In another embodiment, compound (4) is present in the composition in an amount of about 40% w/w. [0049] In one embodiment, compound (5) is present in the composition in an amount of about 0.01% w/w. In another embodiment, compound (5) is present in the composition in an amount of about 0.5% w/w. In another embodiment, compound (5) is present in the composition in an amount of about 0.1% w/w. In another embodiment, compound (5) is present in the composition in an amount of about 0.5% w/w. In another embodiment, compound (5) is present in the composition in an amount of about 1% w/w. In another embodiment, compound (5) is present in the composition in an amount of about 5% w/w. In another embodiment, compound (5) is present in the composition in an amount of about 10% w/w. In another embodiment, compound (5) is present in the composition in an amount of about 15% w/w. In another embodiment, compound (5) is present in the composition in an amount of about 20% w/w. In another embodiment, compound (5) is present in the composition in an amount of about 25% w/w. In another embodiment, compound (5) is present in the composition in an amount of about 30% w/w. In another embodiment, compound (5) is present in the composition in an amount of about 35% w/w. In another embodiment, compound (5) is present in the composition in an amount of about 40% w/w.

[0050] In one embodiment, compound (6a) is present in the composition in an amount of about 0.01% w/w. In another embodiment, compound (6a) is present in the composition in an amount of about 0.5% w/w. In another embodiment, compound (6a) is present in the composition in an amount of about 0.1% w/w. In another embodiment, compound (6a) is present in the composition in an amount of about 0.5% w/w. In another embodiment, compound (6a) is present in the composition in an amount of about 1% w/w. In another embodiment, compound (6a) is present in the composition in an amount of about 5% w/w. In another embodiment, compound (6a) is present in the composition in an amount of about 10% w/w. In another embodiment, compound (6a) is present in the composition in an amount of about 15% w/w. In another embodiment, compound (6a) is present in the composition in an amount of about 20% w/w. In another embodiment, compound (6a) is present in the composition in an amount of about 25% w/w. In another embodiment, compound (6a) is present in the composition in an amount of about 30% w/w. In another embodiment, compound (6a) is present in the composition in an amount of about 35% w/w. In another embodiment, compound (6a) is present in the composition in an amount of about 40% w/w.

[0051] In one embodiment, compound (6b) is present in the composition in an amount of about 0.01% w/w. In another embodiment, compound (6b) is present in the composition in an amount of about 0.5% w/w. In another embodiment, compound (6b) is present in the composition in an amount of about 0.1% w/w. In another embodiment, compound (6b) is present in the composition in an amount of about 0.5% w/w. In another embodiment, compound (6b) is present in the composition in an amount of about 1% w/w. In another embodiment, compound (6b) is present in the composition in an amount of about 5% w/w. In another embodiment, compound (6b) is present in the composition in an amount of about 10% w/w. In another embodiment, compound (6b) is present in the composition in an amount of about 15% w/w. In another embodiment, compound (6b) is present in the composition in an amount of about 20% w/w. In another embodiment, compound (6b) is present in the composition in an amount of about 25% w/w. In another embodiment, compound (6b) is present in the composition in an amount of about 30% w/w. In another embodiment, compound (6b) is present in the composition in an amount of about 35% w/w. In another embodiment, compound (6b) is present in the composition in an amount of about 40% w/w.

[0052] In one embodiment, a mixture of compound (6a) and compound (6b) is present in the composition in an amount of about 0.01% w/w. In another embodiment, a mixture of compound (6a) and compound (6b) is present in the composition in an amount of about 0.05% w/w. In another embodiment, a mixture of compound (6a) and compound (6b) is present in the composition in an amount of about 0.1% w/w. In another embodiment, a mixture of compound (6a) and compound (6b) is present in the composition in an amount of about 0.5% w/w. In another embodiment, a mixture of compound (6a) and compound (6b) is present in the composition in an amount of about 1% w/w. In another embodiment, a mixture of compound (6a) and compound (6b) is present in the composition in an amount of about 5% w/w. In another embodiment, a mixture of compound (6a) and compound (6b) is present in the composition in an amount of about 10% w/w. In another embodiment, a mixture of compound (6a) and compound (6b) is present in the composition in an amount of about 15% w/w. In another embodiment, a mixture of compound (6a) and compound (6b) is present in the composition in an amount of about 20% w/w. In another embodiment, a mixture of compound (6a) and compound (6b) is present in the composition in an amount of about 25% w/w. In another embodiment, a mixture of compound (6a) and compound (6b) is present in the composition in an amount of about 30% w/w. In another embodiment, a mixture of compound (6a) and compound (6b) is present in the composition in an amount of about 35% w/w. In another embodiment, a mixture of compound (6a) and compound (6b) is present in the composition in an amount of about 40% w/w.

[0053] In one embodiment, compound (7) is present in the composition in an amount of about 0.01% w/w. In another embodiment, compound (7) is present in the composition in an amount of about 0.05% w/w. In another embodiment, compound (7) is present in the composition in an amount of about 0.1% w/w. In another embodiment, compound (7) is present in the composition in an amount of about 0.5% w/w. In another embodiment, compound (7) is present in the composition in an amount of about 1% w/w. In another embodiment, compound (7) is present in the composition in an amount of about 5% w/w. In another embodiment, compound (7) is present in the composition in an amount of about 10% w/w. In another embodiment, compound (7) is present in the composition in an amount of about 15% w/w. In another embodiment, compound (7) is present in the composition in an amount of about 20% w/w. In another embodiment, compound (7) is present in the composition in an amount of about 25% w/w. In another embodiment, compound (7) is present in the composition in an amount of about 30% w/w. In another embodiment, compound (7) is present in the composition in an amount of about 35% w/w. In another embodiment, compound (7) is present in the composition in an amount of about 40% w/w.

[0054] In one embodiment, compound (8) is present in the composition in an amount of about 0.01% w/w. In another embodiment, compound (8) is present in the composition in an amount of about 0.05% w/w. In another embodiment, compound (8) is present in the composition in an amount of about 0.1% w/w. In another embodiment, compound (8) is present in the composition in an amount of about 0.5% w/w. In another embodiment, compound (8) is present in the composition in an amount of about 1% w/w. In another embodiment, compound (8) is present in the composition in an amount of about 5% w/w. In another embodiment, compound (8) is present in the composition in an amount of about 10% w/w. In another embodiment, compound (8) is present in the composition in an amount of about 15% w/w. In another embodiment, compound (8) is present in the composition in an amount of about 20% w/w. In another embodiment, compound (8) is present in the composition in an amount of about 25% w/w. In another embodiment, compound (8) is present in the composition in an amount of about 30% w/w. In another embodiment, compound (8) is present in the composition in an amount of about 35% w/w. In another embodiment, compound (8) is present in the composition in an amount of about 40% w/w.

[0055] In one embodiment, compound (9) is present in the composition in an amount of about 0.01% w/w. In another embodiment, compound (9) is present in the composition in an amount of about 0.05% w/w. In another embodiment, compound (9) is present in the composition in an amount of about 0.1% w/w. In another embodiment, compound (9) is present in the composition in an amount of about 0.5% w/w. In another embodiment, compound (9) is present in the composition in an amount of about 1% w/w. In another embodiment, compound (9) is present in the composition in an amount of about 5% w/w. In another embodiment, compound (9) is present in the composition in an amount of about 10% w/w. In another embodiment, compound (9) is present in the composition in an amount of about 15% w/w. In another embodiment, compound (9) is present in the composition in an amount of about 20% w/w. In another embodiment, compound (9) is present in the composition in an amount of about 25% w/w. In another embodiment, compound (9) is present in the composition in an amount of about 30% w/w. In another embodiment, compound (9) is present in the composition in an amount of about 35% w/w. In another embodiment, compound (9) is present in the composition in an amount of about 40% w/w. [0056] In one embodiment, compound (10) is present in the composition in an amount of about 0.01% w/w. In another embodiment, compound (10) is present in the composition in an amount of about 0.05% w/w. In another embodiment, compound (10) is present in the composition in an amount of about 0.1% w/w. In another embodiment, compound (10) is present in the composition in an amount of about 0.5% w/w. In another embodiment, compound (10) is present in the composition in an amount of about 1% w/w. In another embodiment, compound (10) is present in the composition in an amount of about 5% w/w. In another embodiment, compound (10) is present in the composition in an amount of about 10% w/w. In another embodiment, compound ( 10) is present in the composition in an amount of about 15% w/w. In another embodiment, compound (10) is present in the composition in an amount of about 20% w/w. In another embodiment, compound ( 10) is present in the composition in an amount of about 25% w/w. In another embodiment, compound (10) is present in the composition in an amount of about 30% w/w. In another embodiment, compound ( 10) is present in the composition in an amount of about 35% w/w. In another embodiment, compound (10) is present in the composition in an amount of about 40% w/w.

[0057] In one embodiment, compound (11) is present in the composition in an amount of about 0.01% w/w. In another embodiment, compound (11) is present in the composition in an amount of about 0.05% w/w. In another embodiment, compound (11) is present in the composition in an amount of about 0.1% w/w. In another embodiment, compound (11) is present in the composition in an amount of about 0.5% w/w. In another embodiment, compound (11) is present in the composition in an amount of about 1% w/w. In another embodiment, compound (11) is present in the composition in an amount of about 5% w/w. In another embodiment, compound (11) is present in the composition in an amount of about 10% w/w. In another embodiment, compound (11) is present in the composition in an amount of about 15% w/w. In another embodiment, compound (11) is present in the composition in an amount of about 20% w/w. In another embodiment, compound (11) is present in the composition in an amount of about 25% w/w. In another embodiment, compound (11) is present in the composition in an amount of about 30% w/w. In another embodiment, compound (11) is present in the composition in an amount of about 35% w/w. In another embodiment, compound (11) is present in the composition in an amount of about 40% w/w.

[0058] In one embodiment, compound (12) is present in the composition in an amount of about 0.01% w/w. In another embodiment, compound (12) is present in the composition in an amount of about 0.05% w/w. In another embodiment, compound (12) is present in the composition in an amount of about 0.1% w/w. In another embodiment, compound (12) is present in the composition in an amount of about 0.5% w/w. In another embodiment, compound (12) is present in the composition in an amount of about 1% w/w. In another embodiment, compound (12) is present in the composition in an amount of about 5% w/w. In another embodiment, compound (12) is present in the composition in an amount of about 10% w/w. In another embodiment, compound ( 12) is present in the composition in an amount of about 15% w/w. In another embodiment, compound (12) is present in the composition in an amount of about 20% w/w. In another embodiment, compound ( 12) is present in the composition in an amount of about 25% w/w. In another embodiment, compound (12) is present in the composition in an amount of about 30% w/w. In another embodiment, compound ( 12) is present in the composition in an amount of about 35% w/w. In another embodiment, compound (12) is present in the composition in an amount of about 40% w/w.

[0059] In one embodiment, provided herein a composition comprising aspacytarabine or pharmaceutically acceptable salt thereof and a. at least one compound, selected from at least one cytarabine-di-aspartic acid-compound, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), and Compound (12); or pharmaceutically acceptable salt thereof, or b. at least two compounds, selected from at least one cytarabine-di-aspartic acid-compound, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), and Compound (12);or pharmaceutically acceptable salt thereof, or c. at least three compounds, selected from at least one cytarabine-di-aspartic acid-compound, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), and Compound (12); or pharmaceutically acceptable salt thereof, or d. at least four compounds, selected from at least one cytarabine-di-aspartic acid-compound, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), and Compound (12); or pharmaceutically acceptable salt thereof, or e. at least five compounds, selected from at least one cytarabine-di-aspartic acid-compound, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), and Compound (12); or pharmaceutically acceptable salt thereof, or f. at least six compounds, selected from at least one cytarabine-di-aspartic acid-compound, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), and Compound (12); or pharmaceutically acceptable salt thereof, or g. at least seven compounds, selected from at least one cytarabine-di-aspartic acid-compound, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), and Compound (12); or pharmaceutically acceptable salt thereof, or h. at least eight compounds, selected from at least one cytarabine-di-aspartic acid-compound, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), and Compound (12); or pharmaceutically acceptable salt thereof, or i. at least nine compounds, selected from at least one cytarabine-di-aspartic acid-compounds, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), and Compound (12); or pharmaceutically acceptable salt thereof, or j. at least ten compounds, selected from at least onecytarabine-di-aspartic acid-compounds, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), and Compound (12); or pharmaceutically acceptable salt thereof, or k. at least eleven compounds, selected from two cytarabine-di-aspartic acid-compounds, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), and Compound (12); or pharmaceutically acceptable salt thereof, or l. at least twelve compounds, selected from three cytarabine-di-aspartic acid-compounds, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), and Compound (12); or pharmaceutically acceptable salt thereof, or m. at least thirteen compounds, selected from four cytarabine-di-aspartic acid-compounds, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), and Compound (12); or pharmaceutically acceptable salt thereof.

[0060] In one embodiment, provided herein a composition comprising aspacytarabine or pharmaceutically acceptable salt thereof and a. at least one compound, selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or b. at least two compounds, selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or c. at least three compounds, selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or d. at least four compounds, selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or e. at least five compounds, selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or f. at least six compounds, selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or g. at least seven compounds, selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or h. at least eight compounds, selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or i. at least nine compounds, selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or j. at least ten compounds, selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or k. at least eleven compounds, selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or l. at least twelve compounds, selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or m. at least thirteen compounds, selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof.

[0061] In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises an excipient. A skilled artisan would appreciate that, in some embodiments, excipients are selected according to the delivery mode of the pharmaceutical composition.

[0062] In one embodiment, the pharmaceutical composition further comprises at least one stabilizer and/or solubilizer. In one embodiment, the at least one stabilizer and/or solubilizer is a water-soluble linear polymer. In another embodiment, the linear polymer is ionic or non-ionic. In some embodiments, non-ionic water soluble linear polymer comprise poly(vinyl alcohol), polyacrylamide, polyethylene glycol (polyethylene oxide) (PEG), polyethylene oxide (PEG) or polyoxyethylene (POE), triblock copolymers comprising polyoxypropylene (polypropylene oxide)) two polyoxyethylene (poly(ethylene oxide)) (Poloxamer), polyvinyl pyrrolidone (PVP), derivative thereof or any combination thereof. In some embodiments, ionic water soluble linear polymer comprise ionic derivatives of poly(vinyl alcohol), polyacrylamide, polyethylene glycol (polyethylene oxide) (PEG), polyethylene oxide (PEO) or polyoxyethylene (POE), triblock copolymers comprising polyoxypropylene (polypropylene oxide)) and two polyoxyethylene (polypthylene oxide)) (Poloxamer), polyvinyl pyrrolidone (PVP), polystyrene sulfonic acid, polystyrene sulfonates derivatives thereof or any combination thereof.

[0063] In another embodiment, the at least one linear polymer is poloxamer. In another embodiment, the at least one water soluble linear polymer is combination of poloxamer and polyvinyl pyrrolidone (PVP). In another embodiment, the at least one water soluble linear polymer is cyclodextrin. In another embodiment, non-limiting examples of cyclodextrin (CD) include a-CD, P- CD, y-CD, HP-P-CD (hydroxypropylated), SBE-P-CD (sulfobutyl-ether - modified), RM-P-CD (randomly methylated) and any combination thereof. Each possibility represents a separate embodiment of the present invention.

[0064] In another embodiment, the compositions as described herein further comprises a poloxamer. In another embodiment, the compositions further comprise a combination of poloxamer and polyvinyl pyrrolidone (PVP). In another embodiment, the compositions further comprise cyclodextrin. Each possibility represents a separate embodiment of the present invention.

[0065] The term “water-soluble stabilizer” refers to a chemical ingredient that stabilizes the aspacytarabine or pharmaceutically acceptable salt thereof and prevents its decomposition. In some embodiments, the water-soluble stabilizer is also a solubilizer. In some embodiments, the water- soluble stabilizer is selected from a water-soluble linear polymer, a cyclodextrin or combination thereof.

[0066] In one embodiment, the composition as described herein is formulated as a parenteral, oral, intranasal or inhalation composition. In one embodiment, the parenteral composition is selected from a solution, a suspension, an emulsion for injection or infusion, particles for injection or infusion, liposomes as injectable delivery system, a powder for injection or infusion, and a gel for injection. In another embodiment, the parenteral composition is administered by intravenous, intraarterial, intramuscular, subcutaneous, intraperitoneal, intracerebral, intracerebroventricular, intrathecal or intradermal administration route. In another embodiment, the oral composition is selected from a tablet, a pill, a capsule, a drage, a gel, a syrup, a slurry, a suspension, a powder, or a liquid form. Each possibility represents a separate embodiment of the present invention.

[0067] In one embodiment, the composition as described herein further comprises a pharmaceutically acceptable carrier. In one embodiment, the carrier is water, saline solution, isotonic solution, aqueous dextrose, multiple electrolyte injection or aqueous glycerol solution. Each possibility represents a separate embodiment of the present invention.

[0068] In one embodiment, the composition as described herein is formulated for infusion or injection in a pharmaceutically acceptable carrier, wherein the carrier is selected from water, saline solution, isotonic solution, solutions accepted for infusion, aqueous dextrose or aqueous glycerol solution, wherein the composition having a pH range of between 2.2 and 8. In one embodiment, the pH range is between 4 and 8. In another embodiment, the pH range is between 7 and 8. In another embodiment, the pH range is between 4-5. In another embodiment, the pH is physiological. In another embodiment, a buffer is used in order to maintain and/or adjust the required pH range. In another embodiment, the buffer can be a pharmaceutically acceptable mono-ionic buffer system or a poly- ionic buffer system having an ionization pK in the range of 2.2 - 8. In another embodiment, various buffers can be used, for example, ACES (N-(acetamido)-2-aminoethansulfonic acid); Acetate; N-(2- acetamido)-2 -iminodiacetic acid; BES (N,N-bis[2-hydroxyethyl]-2-aminoethansulfonic acid); Bicine (2-(Bis(2-hydroxyethyl)amino)acetic acid); Bis-Tris methane (2-[Bis(2 -hydroxy ethyl)amino] -2- (hydroxymethyl)propane- 1,3 -diol); Bis-Tris propane (1,3- bis(tris(hydroxymethyl)methylamino)propane); Carbonate; Citrate; 3,3-dimethyl glutarate; DIPSO (3-[N,N-bis(2-hydroxyethyl)amino]-2-hydroxypropansulfonic acid); N-ethylmorpholine; Glycerol- 2-phosphate; Glycine; Glycine-amid; HEPBS (N-(2-hydroxyethyl)piperazin-N’-4-buthanesulfonic acid); HEPES (N-(2-hydroxyethyl)piperazin-N’-2-ethanesulfonic acid); HEPPS (N-(2- hydroxyethyl)piperazin-N’ -(3 -propanesulfonic acid)); HEPPS O (N-(2-hydroxyethyl)piperazin-N’- (2-hydroxypropanesulfonic acid); Histidine; Hydrazine; Imidazole; Maleate; 2-methylimidazole; MES (2-(N-morpholino)ethanesulfonic acid); MOBS (4-(N-morpholino)-butansulfonic acid); MOPS (3-(N-morpholino)-propanesulfonic acid; MOPSO (3-(N-morpholino)-2-hydroypropanesulfonic acid); Oxalate; Phosphate; Piperazine; PIPES (1,4-Piperazine-diethanesulfonic acid); POPSO (Piperazine-N,N’-bis(2-hydroxypropanesulfonic acid)); Succinate; Sulfite; TAPS (3-[[l,3- dihydroxy-2-(hydroxymethyl)propan-2-yl]amino]propane-l-sulfo nic acid); TAPSO (3-[[l,3- dihydroxy-2-(hydroxymethyl)propan-2-yl]amino]-2-hydroxypropa ne-l -sulfonic acid); Tartaric acid; TES (2-[[l,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]amino]ethane sulfonic acid); THAM (Tris) (2-Amino-2-hydroxymethyl-propane-l,3-diol); and Tricine (N-(2 -Hydroxy- 1,1- bis(hydroxymethyl)ethyl)glycine); a sulfonic acid derivative buffer ; a carboxylic acid derivative buffer including, but not limited to, Acetatate, N-(2-acetamido)-2-iminodiacetic acid, 2-(Bis(2- hydroxyethyl) amino) acetic acid, Carbonate, Citrate, 3,3-dimethyl glutarate, Lactate, Maleate, Oxalate, Succinate, and Tartaric acid buffer; an amino acid derivative buffer including, but not limited to, Bicine, Glycine, Glycine-amid, Histidine, and Tricine buffer; a phosphoric acid derivative buffer including, but not limited to, Glycerol-2 -phosphate and phosphate buffer; and other buffer systems such as: Hank’s balanced salt solution, Earle’s balanced salt solution, Gey’s balanced salt solution, HEPES buffered saline, phosphate buffered saline, Plasma-lyte, Ringer’s solution, Ringer Acetate, Ringer lactate, Saline citrate, Tris buffered saline, acid-citrate-dextrose solution and Elliott’s B solution; and any combination thereof. Each possibility represents a separate embodiment of the present invention.

[0069] In other embodiments, pharmaceutical compositions for parenteral administration include aqueous solutions of the active ingredients in water-soluble form. Additionally, suspensions of the active compound may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acids esters such as ethyl oleate, triglycerides or liposomes.

[0070] In other embodiment, the compositions as described herein may be formulated as a liquid formulation.

[0071] The compositions can be formulated as solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides, microcrystalline cellulose, gum tragacanth or gelatin. Each possibility represents a separate embodiment of the present invention. [0072] The compositions can further comprise excipients including, but not limited to, sodium chloride, potassium chloride, magnesium chloride, sodium gluconate, sodium acetate, calcium chloride, sodium lactate, and the like. The compositions, if desired, can also contain minor amounts of sugar alcohols, wetting or emulsifying agents, and pH adjusting agents. Antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; and agents for the adjustment of tonicity such as sodium chloride or dextrose are also envisioned. Each possibility represents a separate embodiment of the present invention.

[0073] For oral administration, the compositions as described herein can be formulated readily by combining aspacytarabine and at least one stabilizer and/or solubilizer selected from a linear polymer, cyclodextrin or combination thereof with additional components as known in the art. Such components enable the composition as described herein to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a subject. Pharmacological preparations for oral use can be made using a solid component, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or dragee cores. Suitable components are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carbomethylcellulose. If desired, disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate.

[0074] In addition, enteric coating can be useful if it is desirable to prevent exposure of the compounds of the invention to the gastric environment.

[0075] Pharmaceutical compositions which can be used orally include push-fit capsules made of gelatin as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules may contain the active ingredients in admixture with filler such as lactose, binders such as starches, lubricants such as talc or magnesium stearate and, optionally, stabilizers.

[0076] In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. [0077] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0078] For administration by inhalation, the active compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or a nebulizer with the use of a suitable propellant, e. g., dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e. g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the peptide and a suitable powder base such as lactose or starch.

[0079] An intranasal composition may be formulated as a powder, an aqueous solution or a nonaqueous solution. A preferred method of administering the solutions of the invention is using a spray device. Spray devices can be single (“unit”) dose or multiple dose systems. The powder formulation is preferably administered to the patient in aerosolized form whereby energy from patient inhalation (sniffing) is used to aerosolize the powder into the nasal cavity or where the device itself provides the aerosolization energy, such as via compressed air.

[0080] As used herein a "pharmaceutical composition" refers to a preparation of one or more of the compounds described herein, or physiologically acceptable salts or solvents thereof, with other chemical components such as physiologically suitable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to a subject.

[0081] The term “pharmaceutically acceptable salt” of a drug refers to a salt according to IUPAC conventions. Pharmaceutically acceptable salt is an inactive ingredient in a salt form combined with a drug. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral, base, acid or salt. Acid salts are also known as acid addition salts (see herein below). Pharmaceutically acceptable salts are known in the art (Stahl and Wermuth, 2011, Handbook of pharmaceutical salts, Second edition). The acid is a strong acid and is selected from the group consisting of acetic acid, hydrochloric acid, hydrobromide acid, methanesulfonic acid, phosphoric acid, toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, sulfuric acid, bisulfuric acid, and trifluoroacetic acid. In one embodiment, the salt is a hydrochloride salt. Each possibility represents a separate embodiment of the invention. [0082] The term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U. S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0083] The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents.

Method of treatment

[0084] In some embodiments, the present disclosure relates to a method of treating a neoplastic disease comprising administering to a subject in need thereof a pharmaceutical composition comprising aspacytarabine or pharmaceutically acceptable salt thereof and at least one additional compound, selected from at least one cytarabine-di-aspartic acid-compound, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of Compound 6a and Compound 6b, Compound (7), and Compound (12); or pharmaceutically acceptable salt thereof, wherein the weight ratio of aspacytarabine relating to the weight of the additional compound in the composition is from 99.99:0.01 to 60:40.

[0085] In another aspect, the present disclosure relates to a method of treating a neoplastic disease comprising administering to a subject in need thereof a pharmaceutical composition comprising aspacytarabine or pharmaceutically acceptable salt thereof and at least one compound, selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of Compound (6a) and Compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12), or pharmaceutically acceptable salt thereof, wherein the weight ratio of aspacytarabine relating to the weight of the compound in the composition is from 99.99:0.01 to 60:40.

[0086] In one embodiment, the present disclosure relates to a method of treating a neoplastic disease comprising administering to a subject in need thereof a pharmaceutical composition comprising aspacytarabine or pharmaceutically acceptable salt thereof, and a. at least one compound, selected from at least one cytarabine-di-aspartic acid-compound, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), and Compound (12); or pharmaceutically acceptable salt thereof, or b. at least two of at least one cytarabine-di-aspartic acid-compound, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), and Compound (12); or pharmaceutically acceptable salt thereof, or c. at least three of at least one cytarabine-di-aspartic acid-compound, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), and Compound (12); or pharmaceutically acceptable salt thereof, or d. at least four of at least one cytarabine-di-aspartic acid-compound, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), and Compound (12); or pharmaceutically acceptable salt thereof, or e. at least five of at least one cytarabine-di-aspartic acid-compound, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), and Compound (12); or pharmaceutically acceptable salt thereof, or f. at least six of at least one cytarabine-di-aspartic acid-compound, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), and Compound (12); or pharmaceutically acceptable salt thereof, or g. at least seven of at least one cytarabine-di-aspartic acid-compound, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), and Compound (12); or pharmaceutically acceptable salt thereof, or h. at least eight of at least one cytarabine-di-aspartic acid-compound, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), and Compound (12); or pharmaceutically acceptable salt thereof, or i. at least nine of at least one cytarabine-di-aspartic acid-compounds, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), and Compound (12); or pharmaceutically acceptable salt thereof, or j. at least ten of at least one cytarabine-di-aspartic acid-compounds, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), and Compound (12); or pharmaceutically acceptable salt thereof, or k. at least eleven of two cytarabine-di-aspartic acid-compounds, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), and Compound (12); or pharmaceutically acceptable salt thereof, or l. at least twelve of three cytarabine-di-aspartic acid-compounds, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), and Compound (12); or pharmaceutically acceptable salt thereof, or m. at least thirteen of four cytarabine-di-aspartic acid-compounds, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), and Compound (12); or pharmaceutically acceptable salt thereof.

[0087] In one embodiment, the present disclosure relates to a method of treating a neoplastic disease comprising administering to a subject in need thereof a pharmaceutical composition comprising aspacytarabine or pharmaceutically acceptable salt thereof and a. at least one compound, selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12) or pharmaceutically acceptable salt thereof; or b. at least two compounds, selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or c. at least three compounds, selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or d. at least four compounds, selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or e. at least five compounds, selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or f. at least six compounds, selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or g. at least seven compounds, selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or h. at least eight compounds, selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or i. at least nine compounds, selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or j. at least ten compounds, selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or k. at least eleven compounds, selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or l. at least twelve compounds, selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or m. at least thirteen compounds, selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof. [0088] In one embodiment, the term “treatment” refers to any process, action, application, therapy, or the like, wherein a subject, including a human being, is subjected to medical aid with the object of improving the subject's condition, directly or indirectly. In another embodiment, the term “treating” refers to reducing incidence, alleviating symptoms, eliminating recurrence, preventing recurrence, preventing incidence, improving symptoms, improving prognosis or combinations thereof in other embodiments.

[0089] “Treating” embraces in another embodiment, the amelioration of an existing condition. The skilled artisan would understand that treatment does not necessarily result in the complete absence or removal of symptoms. Treatment also embraces palliative effects: that is, those that reduce the likelihood of a subsequent medical condition. The alleviation of a condition that results in a more serious condition is encompassed by this term.

[0090] In one embodiment, the neoplastic disease is selected from the group consisting of hematological cancers and non-hematological cancers. In another embodiment, the neoplastic disease is hematological cancer. In another embodiment, the neoplastic disease is non-hematological cancer. [0091] In one embodiment, the hematological cancer is selected from the group consisting of leukemias, lymphomas, myelomas and Myelodysplastic Syndromes (MDS). In another embodiment, the hematological cancer is leukemia. In another embodiment, the hematological cancer is lymphoma. In another embodiment, the hematological cancer is myeloma. In another embodiment, the hematological cancer is Myelodysplastic Syndrome (MDS).

[0092] The term "Myelodysplastic Syndromes" (MDS) refers to a heterogeneous group of hematopoietic malignancies characterized by blood cytopenias, ineffective hematopoiesis and a hypercellular bone marrow. The MDSs are preleukemic conditions in which transformation into acute myeloid leukemia (AML) occurs in approximately 30-40% of cases. Unless allogenic stem cell transplantation can be offered, MDS is generally considered to be an uncurable condition.

[0093] Non-hematological cancers also known as solid tumors include, but are not limited to, sarcoma, carcinoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endothelio sarcoma, mesothelioma, Ewing's tumor leiomyd sarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, astrocytoma, Kaposi's sarcoma, and melanoma. Each possibility represents a separate embodiment of the invention.

[0094] Non-hematological cancers include cancers of organs, wherein the cancer of an organ includes, but is not limited to, breast cancer, bladder cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, lung cancer, cervical cancer, pancreatic cancer, prostate cancer, testicular cancer, thyroid cancer, ovarian cancer, brain cancer including ependymoma, glioma, glioblastoma, medulloblastoma, craneopharyngioma, pinealoma, acustic neuroma, hemangioblastoma, oligodendroglioma, menangioma, neuroblastoma, retinoblastoma, and their metastasis. Each possibility represents a separate embodiment of the invention.

[0095] In one embodiment, the leukemia is selected from the group consisting of Acute Myeloid Leukemia (AML), Acute Lymphoblastic Leukemia (ALL), Chronic Myeloid Leukemia (CML), and Chronic Lymphoblastic Leukemia (CLL). In another embodiment, the leukemia is Acute Myeloid Leukemia (AML). In another embodiment, the leukemia is Acute Lymphoblastic Leukemia (ALL). In another embodiment, the leukemia is Chronic Myeloid Leukemia (CML). In another embodiment, the leukemia is Chronic Lymphoblastic Leukemia (CLL).

[0096] In one embodiment, the AML is selected from the group consisting of newly diagnosed AML, secondary AML, and relap sed/refractory AML. In another embodiment, the AML is newly diagnosed AML. In another embodiment, the AML is secondary AML. In another embodiment, the AML is relap sed/refractory AML.

[0097] In one embodiment the lymphoma is selected from the group consisting of Hodgkin’s lymphoma and non-Hodgkin’ s lymphoma. In another embodiment, the lymphoma is Hodgkin’s lymphoma. In another embodiment, the lymphoma is non-Hodgkin’ s lymphoma.

[0098] In one embodiment, the pharmaceutical composition is administered parenterally, orally or by inhalation. In another embodiment, the pharmaceutical composition is administered parenterally. In another embodiment, the pharmaceutical composition is administered orally. In another embodiment, the pharmaceutical composition is administered by inhalation.

[0099] In one embodiment, the pharmaceutical composition is administered by intravenous, intraarterial, intramuscular, subcutaneous, intraperitoneal, intracerebral, intracerebroventricular, intrathecal or intradermal administration route. In another embodiment, the pharmaceutical composition is administered by intravenous administration route. In another embodiment, the pharmaceutical composition is administered by intraarterial administration route. In another embodiment, the pharmaceutical composition is administered by intramuscular administration route. In another embodiment, the pharmaceutical composition is administered by subcutaneous administration route. In another embodiment, the pharmaceutical composition is administered by intraperitoneal administration route. In another embodiment, the pharmaceutical composition is administered by intracerebral administration route. In another embodiment, the pharmaceutical composition is administered by intracerebroventricular administration route. In another embodiment, the pharmaceutical composition is administered by intrathecal administration route. In another embodiment, the pharmaceutical composition is administered by intradermal administration route. [00100] In one embodiment, the pharmaceutical composition is administered by intravenous infusion for a period ranging from 15 minutes to 24 hours. In another embodiment, the pharmaceutical composition is administered by intravenous infusion for a period of 15 minutes. In another embodiment, the pharmaceutical composition is administered by intravenous infusion for a period of 30 minutes. In another embodiment, the pharmaceutical composition is administered by intravenous infusion for a period of 45 minutes. In another embodiment, the pharmaceutical composition is administered by intravenous infusion for a period of 60 minutes. In another embodiment, the pharmaceutical composition is administered by intravenous infusion for a period of 4 hours. In another embodiment, the pharmaceutical composition is administered by intravenous infusion for a period of 8 hours. In another embodiment, the pharmaceutical composition is administered by intravenous infusion for a period of 12 hours. In another embodiment, the pharmaceutical composition is administered by intravenous infusion for a period of 16 hours. In another embodiment, the pharmaceutical composition is administered by intravenous infusion for a period of 20 hours. In another embodiment, the pharmaceutical composition is administered by intravenous infusion for a period of 24 hours.

EXAMPLES

General Methods:

[00101] NMR spectra were recorded on Bruker Avance 400 MHz for ¹ H NMR and ¹³ C-NMR.

[00102] LCMS and HPLC were taken on a quadrupole Mass Spectrometer on Agilent 1290 system equipped with DAD detector or equivalent (Column: Sielc Prime 100 (3.2 x 150 mm, 3.0 pm).

Example 1: Preparation and analysis of Compound 1

[00103] The structure of Compound 1 is presented below: Compound (1) N ⁴ -( l-(( 2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran- 2-yl)-2-oxo-l,2- dihydropyrimidin-4-yl)-D-asparagine

[00104] Compound 1 was synthetized in 4 steps. In step 1, a mixture of tert-butyldimethylsilyl chloride (TBDMS-C1, 13.3 g) and toluene (15.4 mL) was added to a mixture of 4-amino-l- ((2S,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofura n-2-yl)pyrimidin-2(lH)-one (cytarabine, 10.0 g), imidazole (7.00 g.) and anhydrous dimethylformamide (DMF, lOOmL) . After stirring the obtained reaction mixture was quenched with 15% NaCl, ethyl acetate was added and the organic layer was dried and used in the next step. In step 2, the silylated cytarabine from step 1 in ethyl acetate was added to a solution prepared from (S)-4-(benzyloxy)-3- (((benzyloxy)carbonyl)amino)-4-oxobutanoic acid (Boc-Asp-OBzl), 1 -hydroxybenzotriazole

(HOBt) and 3-{[(Ethylimino)methylidene]amino}-N,N-dimethylpropan-l-amin e-HCl (EDC-HC1). After stirring, the obtained reaction mixture was quenched with 15% NaCl solution and washed with 5% NaHCO ₃ solution and 15% NaCl solution. The water in the organic reaction mixture was removed by vacuum distillation of ethyl acetate. In step 3, triethylamine trihydrofluoride (TREAT-HF, 4.31 g). was added to the reaction mixture of step 2 in ethyl acetate. After stirring the reaction mixture was quenched with 10% Na2COa solution and the solid (NaF with step 3 product) was filtered, washed few times with water to remove NaF and step 3 product was dried under vacuum. In step 4, the solid product of step 3 was added to a hydrogenator and dissolved with a mixture of N-Methyl-2- pyrrolidone (NMP, 30 mL) and water (30 mL). Palladium on carbon (10% Pd/C, 50% wet, 1.5%,) was charged, and hydrogenolysis was accomplished after 4 hours stirring at 25°C with 20 psi of hydrogen. Pd/C was removed by filtration and washed with water from the reactor rinsing. The NMP was extracted from the reaction mixture by dichloromethane (DCM)and Compound 1 precipitated by slow addition of acetone (60 mL) The solid was filtered, washed with acetone (20 mL) and dried in vacuum to obtain 1.10 g with 98.1% LCMS purity (254 nm). Compound 1 was characterized by MS, ^J H and ¹³ C-NMR. [00105] ¹ H-NMR (400 MHz, D ₂ O): 5=3.13-3.22 (dq, 2H), 3.83-3.88 (dq, 2H), 4.07-4.11 (m, 3H), 4.44 (m 1H), 6.19 (d, 1H, J=4.8Hz), 7.29 (d, 1H, J=7.6Hz), 8.23 (d, 1H, J=7.6Hz),

[00106] ¹³ C-NMR (400MHZ, D ₂ O): δ3=6.88, 50.59, 60.73, 75.23, 75.32, 84.02, 87.09, 97.46, 146.73, 156.65, 162.37, 171.73, 173.02.

[00107] MS (ES ⁺ ): [M+H] ⁺ =359.13

Example 2: Preparation and analysis of Compound 4

[00108] Compound 4 was synthetized, and the structure was confirmed by ¹ H-NMR, ¹³ C-NMR and MS. The structure of Compound 4 is shown below: Compound (4)

(N ⁴ -(3-( l-(( 2R,3S,4S,5R )-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)ureido )propanoyl)- L-asparagine)

[00109] Compound 4 was synthetized by the following method: 10g of benzyl N ² - ((benzyloxy)carbonyl)-N ⁴ -(l-((2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetr ahydrofuran-2- yl)-2-oxo-l,2-dihydropyrimidin-4-yl)-L-asparaginate (BC-BST-236) was added to 250 ml Fisher- Porter bottle with magnetic stirrer bar, followed by 1g Pd/C (type 91, Sigma-Aldrich), 116ml ethyl acetate and 70ml water. The biphasic mixture was degassed with N ₂ . The bottle was charged and purged with H ₂ four times and filled with H ₂ to 20 psi for 4 days. The reaction mixture was filtered through a prepacked celite funnel to remove the catalyst and the filter cake was rinsed with 2ml water, the phases were separated, and the water phase was lyophilized to give 5.7g of white solid (88% yield) with chemical purity of 100%.

[00110] ¹ H-NMR (400 MHz, D ₂ O): 2 δ.6=8-2.74 (dt, 2H), 2.81-2.99 (dABq, 2H), 3.47-3.56 (m, 1H), 3.64-3.3.72 (m 1H), 3.87-3.93 (m, 1H), 3.98-4.03 (m, 1H), 4.04-4.09 (m, 1H), 4.39 (t, 1H, J=6.8Hz), 6.07 (d, 1H, 7=6.8Hz),

[00111] ¹³ C-NMR (400MHz, D ₂ O): 33 δ=.05, 37.35, 40.77, 54.18, 63.40, 77.36, 78.86, 83.29, 86.40, 157.12, 176.02, 177.05, 177.32. [00112] MS (ES ⁺ ): [M+H] ⁺ =379.15

Example 3: Preparation and analysis of Compound 5 Compound (5)

N ⁴ -(2-oxo-l ,2-dihydropyrimidin-4-yl)-L-asparagine

[00113] Step 1: A solution of benzyl chloroformate (3.52 g,) in dioxane (21.0 mL) was added to a solution of N-(tert-butoxycarbonyl)-L-aspartic acid (Boc-Asp-OH, 3.00 g), dioxane (17.0 mL), water (34.0 mL) and NaHCO ₃ (4.00 g). After stirring for 16 hours the reaction mixture was quenched with water and the aqueous phase was washed with ethyl acetate. After acidifying to pH 2 the reaction mixture was extracted by ethyl acetate and the organic phase was concentrated and purified by column chromatography (SiCL) to give N-carbobenzyloxy-L- aspartic acid alpha tert-butyl ester (Z-Asp- OtBu, 3.10 g, 60.4% yield).

[00114] To Z-Asp-OtBu (2.60 g) in DMF (18.2 mL) was added cytosine (893 mg), ((1H- Benzo[d] [ 1 ,2,3]triazol- 1 -yl)oxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP, castro’s reagent.29, 3.56 g,), N,N-Diisopropylethylamine (DIEA, 2.08 g). The mixture was stirred at 25 °C for 6 hrs. The crude product was triturated with a mixture of MeOH (20.0 mL) and THF (20.0 mL) and dried to give tert-butyl A ² -((benzyloxy)carbony l)-N ⁴ -(2 -oxo- 1,2-dihy dropyrimidin-4-yl)-L- asparaginate (1.90 g, 56.1% yield) as light-yellow solid.

[00115] To a solution of tert-butyl A ² -((benzyloxy)carbonyl)-N ⁴ -(2-oxo-l,2-dihydropyrimidin-4- yl)-L-asparaginate (0.70 g) in EtOAc (14.0 mL) was added HCl/EtOAc (4 M, 3.00 mL) and stirred at 25 °C for 16 hrs. The crude product was triturated with EtOAc (5.00 mL) and filtered. The filter cake was collected and dried to give A ² -((benzyloxy)carbony l)-N ⁴ -(2 -oxo- 1,2-dihy dropyrimidin-4-yl)-L- asparagine as a white solid (0.50 g, 27.5% yield).

[00116] To N ² -((bcnzyloxy)carbonyl)-A ⁷ -(2-oxo- 1 ,2-dihydropyrimidin-4-yl)-L-asparaginc (0.50 g) was added 33% HBr in AcOH (7.45 g, 5.00 mL) at 25 °C. The mixture was stirred, filtered and the crude product was triturated with EtOAc (5.00 mL) at 25 °C for 1 h to give Compound 5 HBr salt (300 mg, 70% yield) as a white solid. Compound 5 HBr salt was treated with NaHCOa to neutralize HBr. The reaction mixture was filtered and dried to give Compound 5 (180 mg, 57%) as white solid. Compound 5 was characterized by MS, ¹ H NMR and ¹³ C-NMR.

[00117] ¹ H-NMR (400 MHz, DMSO-d ₆ +TFA): 6=3.07-3.21 (dq, 2H), 4.15 (brs, 1H), 6.97 (d, 1H, J=7.2Hz), 8.00 (d, 1H, J=7.2Hz), 8.17 (brs, 3H, N-H) ¹³ C-NMR (400MHz, DMSO-d ₆ +TFA): 6=37.08, 48.44, 95.63, 151.01, 153.40, 161.60, 170.33, 170.85.

[00118] MS (ES ⁺ ), [M+H] ⁺ =227.10

Example 4: Preparation and analysis of Compound 6a

Compound 6a

(l-(( 2R,3S,4S,5R )-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo -l,2- dihydropyrimidin-4-yl)-L-asparagine

[00119] Compound 6a was synthetized by 4 steps. In step 1, to a solution of uracil arabinoside (10.0 g) in dichloromethane (70.0 mL) was added tert-Butyldimethylsilyl chloride (TBSC1,, 30.8g ), 4- dimethylaminopyridine (DMAP, 500 mg) and imidazole (11.1 g). After stirring (16 hours) the mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried, filtered and concentrated under pressure. The residue was purified by prep- HPLC (Column: DAC-150 luna). The fraction with the product was concentrated and lyophilized to give l-((2R,3S,4R,5R)-3,4-bis((tert-butyldimethylsilyl)oxy)-5-((( tert- butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)pyrimidin e-2,4(lH,3H)-dione, (6.40 g, 21.3% yield) as a white solid. In step 2, to the solution of step 1 (6.40 g) in DCM (112 mL) was added DMAP (133 mg). The reaction mixture was cooled to 0 °C, and N,N-diisopropylethylamine (DIPEA, 7.05 g) and 2,4,6-triisopropylbenzenesulfonyl chloride (6.60 g) were added. The reaction mixture was stirred (4 hours) and washed by NaHCO ₃ (80 mL x 3) at 0 °C. The organic layers was washed with brine (50 mL x 3), dried, filtered and concentrated to give a residue that was purified by column chromatography (SiO2) to give l-((2R,3S,4R,5R)-3,4-bis((tert-butyldimethylsilyl)oxy)-5-((( tert- butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl) -2-oxo- l,2-dihydropyrimidin-4-yl 2,4,6- triisopropylbenzenesulfonate (3.70 g, 35.7% yield) as a white solid. In step 3, to a solution of step 2 (2.50 g,) in 1-propanol (25.0 mL) were added tert-butyl L-asparaginate, (827 mg,) and N,N- diisopropylethylamine (DIPEA, 1.14 g). The mixture was stirred (14 hours), quenched by addition NaHCO ₃ 25 mL and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue that was purified by prep-HPLC. The fractions with the product were concentrated and lyophilized to give tert-butyl (l-((2R,3S,4R,5R)-3,4-bis((tert-butyldimethylsilyl)oxy)-5-(( (tert- butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-2-oxo-l, 2-dihydropyrimidin-4-yl)-L- asparaginate (1.20 g, 45.6% yield, 84.4% purity by LCMS) as a white solid. In step 4, to a solution of step 3 (500 mg) in EtOAc (10.0 mL) was added HCl/EtOAc (4 M, 10.0 mL). The mixture was stirred at 40 °C (4 hours) and concentrated. The residue was purified by prep-HPLC. The fractions with the product were concentrated and lyophilized to give Compound 6a (100 mg, 99.5% purity) as a white solid. The structure was confirmed by MS, ¹ H-NMR and ¹³ C-NMR.

[00120] ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ2=.39-2.52 (dq, 2H), 3.56-3.58 (m, 2H), 3.71-3.73 (m, 1H), 3.88-3.90 (m, 1H), 3.91-3.92 (m, 1H), 3.94-3.9 (m, 1H), 5.89 (d, 1H, J=7.2Hz), 6.01-6.02 (m,

1H), 6.77 (brs, 1H, N-H), 7.49 (d, 1H, J=7.2Hz), 7.91 (brs, 1H, N-H).

[00121] ¹³ C-NMR (400MHZ, DMSO-d ₆ , Na ⁺ salt): δ3=9.65, 53.87, 62.85, 76.75, 78.15, 86.50, 88.37, 96.06, 142.80, 158.67, 164.69, 176.27, 177.62.

[00122] MS (ES ⁺ ), [M+H] ⁺ =359.2

Example 5: Preparation and analysis of Compound 6b Compound 6b

(S)-4-amino-3-((l-((2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxy methyl)tetrahydrofuran-2-yl)-2-oxo- l,2-dihydropyrimidin-4-yl)amino)-4-oxobutanoic acid

[00123] Compound 6b was synthetized by a 4 steps process. In step 1, to a solution of uracil arabinoside (10.0 g) in dichloromethane (70.0 mL) was added tert-Butyldimethylsilyl chloride (TBSC1,, 30.8g ), 4-dimethylaminopyridine (DMAP, 500 mg) and imidazole (11.1 g). After stirring (16 hours) the mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried, filtered and concentrated under pressure. The residue was purified by prep-HPLC (Column: DAC-150 luna). The fraction with the product was concentrated and lyophilized to give l-((2R,3S,4R,5R)-3,4-bis((tert-butyldimethylsilyl)oxy)-5-((( tert- butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)pyrimidin e-2,4(lH,3H)-dione, (6.40 g, 21.3% yield) as a white solid. In step 2, to the solution of step 1 (6.40 g) in DCM (112 mL) was added DMAP (133 mg). The reaction mixture was cooled to 0 °C, and N,N-diisopropylethylamine (DIPEA, 7.05 g) and 2,4,6-triisopropylbenzenesulfonyl chloride (6.60 g) were added. The reaction mixture was stirred (4 hours) and washed by NaHCO3 (80 mL x 3) at 0 °C. The organic layers was washed with brine (50 mL x 3), dried, filtered and concentrated to give a residue that was purified by column chromatography (SiO2) to give l-((2R,3S,4R,5R)-3,4-bis((tert-butyldimethylsilyl)oxy)-5-((( tert- butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-2-oxo- 1 ,2-dihydropyrimidin-4-yl 2,4,6- triisopropylbenzenesulfonate (3.70 g, 35.7% yield) as a white solid. In step 3, to a solution of step 2 (1.0 g,) in 1-propanol (10 mL) were added tert-butyl (S)-3,4-diamino-4-oxobutanoate (331mg) and N,N-diisopropylethylamine (DIPEA, 303 mg). The mixture was stirred at 100 °C for 14 hours, quenched by addition NaHCO ₃ (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. To the residue (0.5g) in dioxane (10.0 mL) was added HCl/Dioxane (4 M, 10 mL). The mixture was stirred at 40°C for 4 hrs. White solid appeared. The reaction mixture was filtered and the solid concentrated under reduced pressure to give the residue as HC1 salt. The HC1 salt was dissolved in water and basic base resin (0.5 g) was added, and stir for 10 h (the pH = 9) and concentrated to give the residue as free base. The residue was triturated with MeOH (5 mL) for 30 min, and then the mixture was filtered.

[00124] MS (ES ⁺ ), [M+H] ⁺ =359.2

Example 6: Characterization of structures of Compounds 8-12

[00125] Characterization of Compounds 8-12 was performed by means of High-Resolution Mass Spectrometric (HRMS), H-NMR and C-NMR analyses and described below. HRMS analysis was performed on the Waters Xevo G2-XS QTOF using high performance liquid chromatography with electrospray ionization time of flight mass spectrometry (HPLC-ESLTOF LC/MS). Electrospray ionization was performed in negative ion mode. The instrument parameters were listed as below:

NMR spectrum was collected in dimethylsulfoxide-d6 ( DMSO-d ₆ ) by a Bruker AscendTM 400 MHz

NMR spectrometer.

Compound 8:

[00126] ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=2.76 (m, 2H), 2.93 (m, 2H), 3.60 (m, 2H), 3.83 (brs, 1H), 3.93 (brs, 1H), 4.06 (brs, 1H), 4.64 (brs, 2H), 6.05 (brs, 1H), 7.16, (brd, 1H, 7=6.4Hz), 8.07 (brd,

1H, 7=6.4Hz). ¹³ C-NMR (400MHZ, DMSO-d ₆ ): δ=39.39 (2C), 49.02 (2C), 61.05, 74.59, 76.16, 85.84, 87.04, 94.44, 146.81, 154.53, 162.09, 171.06 (2C), 171.08 (2C).

[00127] HRMS (TOF MS ES'): [M-H] ⁺ =472.1309, calculated (C ₁₇ H ₂ 2N ₅ O ₁₁ )=472.1316

Compound 9: [00128] ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=2.62 (brs, 2H), 2.89 (brs, 1H), 3.05 (brs, 1H), 3.62 (m,

1H), 3.63 (m, 1H), 3.65 (m, 1H), 3.88 (m, 1H), 3.90 (m, 1H), 4.09 (brs, 1H), 5.27 (t, 1H, 7=3.88), 6.16 (brd, 1H, 7=4.38), 7.21 (d, 1H, 7=7.4Hz), 8.24 (d, 1H, 7=7.5Hz).

[00129] ¹³ C-NMR (400MHZ, DMSO-d ₆ ): δ=35.15 (2C), 37.78 (2C), 49.99, 50.19, 60.79, 73.22, 77.65, 85.15, 85.35, 96.78, 146.79, 155.73, 163.09, 169.83, 170.28, 170.89, 171.73. HRMS (TOF MS ES-): [M-H] ⁺ =472.1300, calculated (C ₁₇ H ₂ 2N ₅ O ₁₁ )=472.1316 Compound 10:

[00130] ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ2=.86-2.96 (m, 2H), 2.91-3.06 (m, 2H) 3.98 (ms, 1H), 4.02-4.10 (m, 2H), 4.05 (m, 1H), 4.10 (m, 1H), 4.27 (m, 1H), 4.38 (m, 1H), 6.11 (d, 1H, 7=3.50), 7.18 (d, 1H, 7=7.3), 7.99 (d, 1H, 7=7.4Hz).

[00131] ¹³ C-NMR (400MHZ, DMSO-d ₆ ): 3 δ4=.81 (2C), 36.99 (2C), 48.61, 49.26, 64.56, 74.04, 76.68, 82.68, 87.56, 94.74, 147.16, 154.42, 162.04, 169.52, 169.78, 170.02, 170.41.

[00132] HRMS (TOF MS ES'): [M-H] ⁺ =472.1492, calculated (C ₁₇ H ₂ 2N ₅ O ₁₁ )=472.1316

Compound 11:

[00133] ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ3=.07-3.17 (m, 4H), 3.86 (m, 2H), 4.10 (m, 2H), 4.26 (brs, 1H), 4.57 (brs, 1H), 5.10 (brs, 1H), 6.13 (brs, 1H), 7.27 (d, 1H, 7=7.3Hz), 8.23 (d, 1H, 7=7.4Hz). [00134] ¹³ C-NMR (400MHZ, DMSO-d ₆ ): 34 δ=.46, 36.73, 50.38 (2C), 60.84, 72.68, 78.92, 82.54, 87.62, 97.45, 146.84, 156.46, 162.49, 170.78 (2C), 171.61 (2C).

[00135] HRMS (TOF MS ES'): [M-H] ⁺ =472.1442, calculated (C ₁₇ H ₂₂ N ₅ O ₁₁ )=472.1316

Compound 12:

[00136] ¹ H-NMR (400 MHz, DMSO-d ₆ ): 2 δ.=93 (brs, 1H), 3.05 (brs, 1H), 3.12 (brs, 2H), 3.62 (m, 2H), 3.84 (m, 1H), 3.93 (m, 1H), 3.97 (m, 2H), 4.06 (m, 1H), 4.08 (m, 1H), 4.09 (m, 1H), 4.35 (m, 1H), 4.48 (m, 1H), 6.04 (brd, 1H, J=3.4Hz), 6.07 (brd, 1H, 7=3.1Hz), 7.92 (brd, 1H, 7=7.4Hz), 8.07 (brd, 1H, 7=7.4Hz)

[00137] ¹³ C-NMR (400MHZ, DMSO-d ₆ ): 37 δ.=09, 37.66, 48.67, 49.43, 61.43, 65.91, 74.31, 74.61, 75.04, 76.58, 83.18, 86.24, 87.54, 88.22, 94.89, 95.14, 147.34, 147.42, 154.85 (2C), 162.26, 162.49, 169.36, 170.32, 170.51, 171.14.

[00138] HRMS (TOF MS ES'): [M-H] ⁺ =697.2034, calculated (C ₂₆ H ₃₃ N ₈ O ₁₅ )=697.2065

While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those of ordinary skill in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention.