Heterocyclic compounds for activating mucosal-associated invariant t cells

Abstract

The invention provides compounds of formula (I) for activating mucosal-associated invariant T (MAIT) cells. Pharmaceutical compositions comprising the compounds for activating MAIT cells and methods for treating cancer with the compounds for activating MAIT cells are also described. (Formula (I))

Description

HETEROCYCLIC COMPOUNDS FOR ACTIVATING MUCOSAL-ASSOCIATED INVARIANT T CELLSCROSS-REFERENCE TO RELATED APPLICATION

[0001] This patent application claims the benefit of U.S. Provisional Patent Application No. 63 / 696,421, filed September 19, 2024, which is incorporated by reference in its entirety herein.STATEMENT REGARDINGFEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] This invention was made with Government support under project number ZIA BC 011345 by the National Institutes of Health, National Cancer Institute. The Government has certain rights in this invention.BACKGROUND OF THE INVENTION

[0003] According to the American Cancer Society, liver cancer with almost 30,000 new cases every year is the 6thmost common cause of cancer related death in the United States [Rahib et al., JAMA Netw Open, 4(4): e214708 (2021)]. Immunotherapeutic protocols using checkpoint inhibitors targeting conventional, peptide-reactive T cells, have been the main focus of cancer immunotherapy and have revolutionized treatment of many types of cancer including liver cancer [Ruf et al., Cell. Mol. Immunol, 18(1): 112-127 (2021)]. However, emerging studies show that current immunotherapeutic approaches induce durable responses in only a subset of liver cancer patients [Ruf et al., Cell. Mol. Immunol. , 18(1): 112-127 (2021) and Greten et al., Nat. Rev. Clin. Oncol, 20(11): 780-798 (2023)].

[0004] Amongst the immune cells in the liver, unconventional, innate-like T cells, mucosal-associated invariant T (MAIT) cells are some of the most abundant cells and have been shown to be pivotal in anti -turn or immunity [Ruf et al., Nat. Rev. Cancer, 23(6): 351- 371 (2023)]. The location of these cells in the liver tissue puts them at the forefront to respond immediately to a growing tumor and to attract other immune cells. However, targeting MAIT cells remains challenging, and no specific MAIT-targeted treatment approach has been successfully applied for cancer immunotherapy in the clinic thus far.

[0005] MAIT cells express a limited repertoire of T-cell receptors and are restricted by MR1, a monomorphic class I-related MHC molecule, which has a highly conserved ligand-binding groove. Unlike conventional T cells which are reactive to peptide antigens, MAIT cells recognize microbial non-peptide antigens such as riboflavin derivates, suggesting their role in controlling microbial infection. A growing body of primary research literature and review articles have covered this challenge, and nicely summarized the problem [Verrapen et al., Mol. Immunol., 129: 114-120 (2021) and Mak et al., Acc. Chem. Res., 54(17): 3462-3475 (2021)].

[0006] To date, 5-OP-RU (5-(2-oxopropylideneamino)-6-D-ribitylaminouracil) remains the most potent MAIT cell activator because of its ability to both up-regulate MR1 and interact with the MAIT T-cell receptor (TCR) [Patel et al., Nat. Commun., 4: 2142 (2013); Corbett et al., Nature, 509(7500): 361-365 (2014); Gherardin et al., Immunity, 44(1): 32-45 (2016); Keller et al., Nat. Immunol., 18(4): 402-411 (2017); and Mak et al., Nat. Commun., 8: 14599 (2017)]. However, 5-OP-RU is an unstable compound in solution with a half-life of less than 3 hours. Pharmacological agents require storage and the chemical stability necessary to act on a systemic basis, so overcoming the chemical instability of natural compounds has emerged as a major problem in the field.

[0007] Thus, there remains a need to develop alternatives to 5-OP-RU, which have (i) increased stability relative to 5-OP-RU and (ii) stimulatory activity, including enhanced MR1 binding and upregulation and recognition by the MAIT TCR, which is equal to or better than 5-OP-RU.

[0008] The invention provides such small molecules that have (i) increased stability relative to 5-OP-RU and (ii) stimulatory activity, including enhanced MR1 binding and upregulation and recognition by the MAIT TCR, which is equal to or better than 5-OP-RU. These, and other advantages of the invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.BRIEF SUMMARY OF THE INVENTION

[0009] In some aspects, the invention provides a compound of Formula (I):a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, whereinR0is hydrogen or a C1-C6alkyl group,R1is a C2-C5alkyl group substituted with 1 to 4 hydroxyl groups, R2and R3combine to form a C3-C8cycloalkyl group, a 3-6 membered heterocylic group, an aryl group, or a heteroaryl group, each of which is optionally substituted with one or more substituents selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, difluoromethyl, trifluoromethyl, C1-C6alkoxy, arylated C1-C6alkoxy, difluoromethyl, trifluoromethylated C1-C6alkoxy, -C(O)OH, -C(O)O-( C1-C6alkyl), -C(O)-(C1-C6alkyl), -(C1-C3alkyl)-C(O)OH, - (C1-C3alkyl)-C(O)O-(C1-C6alkyl), -(C1-C3alkyl)-C(O)-(C1-C6alkyl), -NH-C(O)OH, -NH- C(O)O-(C1-C6alkyl), -NH-C(O)-(C1-C6alkyl), -(C1-C3alkyl)-NH-C(O)OH, -(C1-C3alkyl)- NH-C(O)O-(C1-C6alkyl), -(C1-C3alkyl)-NH-C(O)-(C1-C6alkyl), -(C1-C6alkyl)-O-(C1-C6alkyl), -O-(C1-C6alkyl)-O-(C1-C6alkyl), -(C1-C6alkyl)-OH, -(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-COOH, -(C1-C6alkyl)-C(O)O-(C1-C6alkyl), -(C1-C6alkyl)-(C1-C6cycloalkyl)-OH, - (C1-C6alkyl)-NH2, -(C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)-(C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)-heterocycloalkyl, -(C1-C6alkyl)-heterocycloalkyl-(C1-C6alkyl), -(C1-C6alkyl)-C(O)- heterocycloalkyl, -(C1-C6alkyl)-C(O)-heterocycloalkyl-(C1-C6alkyl), halo (e.g., fluoro), nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; -NH-aryl, -NH- heterocycloalkyl, -NH-heterocycloalkyl-(C1-C6alkyl), -C1-C6haloalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, aryl, heteroaryl, -CN, -(C1-C3alkyl)-CN, carbonyl, amino acid, amino acid methyl ester, and a combination thereof, and R4is absent, hydrogen, or a C1-C6alkyl group.

[0010] In some aspects, the invention provides Compounds A, C, F, H, I, K, L-N, V-Y, AH, AJ-AL, and CA-CL, a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

[0011] In some aspects, the invention provides Compounds B, D, E, G, J, O-U, Z, AA- AG, Al, and CM-CP, a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

[0012] In some aspects, the invention provides Compounds AM-BZ and CQ-DF, a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

[0013] The invention also provides pharmaceutical compositions comprising a compound of Formula (I), Formula (II), or Formula (III) (e.g., Compounds A-DF), a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

[0014] The invention further provides methods of activating mucosal-associated invariant T (MAIT) cells in a subject comprising administering to the subject compounds or pharmaceutical compositions of aspects of the present invention.

[0015] The invention also provides methods of treating cancer in a subject comprising administering to the subject compounds or pharmaceutical compositions of aspects of the present invention.

[0016] The invention also provides methods of treating an infectious disease in a subject comprising administering to the subject compounds or pharmaceutical compositions of aspects of the present invention.BRIEF DESCRIPTION OF THE DRAWINGS

[0017] FIG. 1A is a graph showing the frequency of hepatic MAIT cells (defined astetramer+) expanded in the liver of mice treated with 5-OP-RU, Compound U, Compound B, Compound K, or Compound Q.

[0018] FIG. IB is a graph showing the number of MAIT cells expanded per gram of liver of mice treated with 5-OP-RU, Compound U, Compound B, Compound K, or Compound Q.DETAILED DESCRIPTION OF THE INVENTION

[0019] In some aspects, the invention provides a compound of Formula (I):(I) a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, whereinR0is hydrogen or a C1-C6alkyl group,R1is a C2-C5(e.g., C2, C3, C4, or C5) alkyl group substituted with 1 to 4 hydroxyl groups,R2and R3combine to form a C3-C8(e.g., C3, C4, C5, C6, C7, or C8) cycloalkyl group, a 3-6 membered heterocylic group, an aryl group, or a heteroaryl group, each of which is optionally substituted with one or more substituents selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, difluoromethyl, trifluoromethyl, C1-C6alkoxy, arylated C1-C6alkoxy, trifluoromethylated C1-C6alkoxy, -C(O)OH, -C(O)O-(C1-C6alkyl), -C(O)-(C1-C6alkyl), - (C1-C3alkyl)-C(O)OH, -(C1-C3alkyl)-C(O)O-(C1-C6alkyl), -(C1-C3alkyl)-C(O)-(C1-C6alkyl), -NH-C(O)OH, -NH-C(O)O-(C1-C6alkyl), -NH-C(O)-(C1-C6alkyl), -(C1-C3alkyl)- NH-C(O)OH, -(C1-C3alkyl)-NH-C(O)O-(C1-C6alkyl), -(C1-C3alkyl)-NH-C(O)-(C1-C6alkyl), -(C1-C6alkyl)-O-(C1-C6alkyl), -O-(C1-C6alkyl)-O-(C1-C6alkyl), -(C1-C6alkyl)-OH, - (C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-COOH, -(C1-C6alkyl)-C(O)O-(C1-C6alkyl), -(C1-C6alkyl)-(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-NH2, -(C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)- (C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)-heterocycloalkyl, -(C1-C6alkyl)-heterocycloalkyl- (C1-C6alkyl), -(C1-C6alkyl)-C(O)-heterocycloalkyl, -(C1-C6alkyl)-C(O)-heterocycloalkyl- (C1-C6alkyl), halo (e.g., fluoro), nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl- amino; -NH-aryl, -NH-heterocycloalkyl, -NH-heterocycloalkyl-(C1-C6alkyl), -C1-C6haloalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, aryl, heteroaryl, -CN, -(C1-C3alkyl)-CN, carbonyl, amino acid, amino acid methyl ester, and a combination thereof, andR4is absent, hydrogen, or a C1-C6alkyl group.

[0020] Variable R0is hydrogen or a C1-C6alkyl group (e.g., methyl, ethyl, propyl, butyl, pentyl, or hexyl). In some aspects, R0is hydrogen or methyl. In some aspects, R0is hydrogen. In some aspects, R0is methyl.

[0021] Variable R1is a C2-C5alkyl group substituted with 1 to 4 hydroxyl groups. The C2-C5alkyl group can be branched or liner and can be ethyl, propyl, butyl, or pentyl. In some aspects, the C2-C5alkyl group is linear and has less hydroxyl groups than carbon atoms. Exemplary R1groups include:In some aspects, variable R1is

[0022] Variables R2and R3combine to form a C3-C8cycloalkyl group, a 3-6 membered heterocylic group, an aryl group, or a heteroaryl group, each of which is optionally substituted with one or more substituents selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, difluoromethyl, trifluoromethyl, C1-C6alkoxy, arylated C1-C6alkoxy, trifluoromethylated C1-C6alkoxy, -C(O)OH, -C(O)O-(C1-C6alkyl), -C(O)-(C1-C6alkyl), - (C1-C3alkyl)-C(O)OH, -(C1-C3alkyl)-C(O)O-(C1-C6alkyl), -(C1-C3alkyl)-C(O)-(C1-C6alkyl), -NH-C(O)OH, -NH-C(O)O-(C1-C6alkyl), -NH-C(O)-(C1-C6alkyl), -(C1-C3alkyl)- NH-C(O)OH, -(C1-C3alkyl)-NH-C(O)O-(C1-C6alkyl), -(C1-C3alkyl)-NH-C(O)-(C1-C6alkyl), -(C1-C6alkyl)-O-(C1-C6alkyl), -O-(C1-C6alkyl)-O-(C1-C6alkyl), -(C1-C6alkyl)-OH, - (C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-COOH, -(C1-C6alkyl)-C(O)O-(C1-C6alkyl), -(C1-C6alkyl)-(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-NH2, -(C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)- (C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)-heterocycloalkyl, -(C1-C6alkyl)-heterocycloalkyl- (C1-C6alkyl), -(C1-C6alkyl)-C(O)-heterocycloalkyl, -(C1-C6alkyl)-C(O)-heterocycloalkyl- (C1-C6alkyl), halo (e.g., fluoro), nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl- amino; -NH-aryl, -NH-heterocycloalkyl, -NH-heterocycloalkyl-(C1-C6alkyl), -C1-C6haloalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, aryl, heteroaryl, -CN, -(C1-C3alkyl)-CN, carbonyl, amino acid, amino acid methyl ester, and a combination thereof. In some aspects, variables R2and R3combine to form a C3-C8cycloalkyl group, a 3-6 membered heterocylic group, an aryl group, or a heteroaryl group, each of which is optionally substituted with one or more substituents selected from C1-C6alkyl, trifluoromethyl, C1-C6alkoxy, -C(O)-(C1-C6alkyl), halo (e.g., fluoro), hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino, and a combination thereof. In some aspects, variables R2and R3combine to form a C3-C6cycloalkyl group, which is optionally substituted with one or more substituents selected from C1-C6alkyl, trifluoromethyl, C1-C6alkoxy, -C(O)-(C1-C6alkyl), halo (e.g., fluoro), hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino, and a combination thereof. In some aspects, variables R2and R3combine to form a C3-C6cycloalkyl group, which is optionally substituted with one or more substituents selected from C1-C6alkyl, trifluoromethyl, halo (e.g., fluoro), and a combination thereof. In some aspects, variables R2and R3combine to form a C3-C6cycloalkyl group. In some aspects, variables R2and R3combine to form a a 3-6 membered heterocylic group, which is optionally substituted with one or more substituents selected from C1-C6alkyl, trifluoromethyl, C1-C6alkoxy, -C(O)-(C1-C6alkyl), halo (e.g., fluoro), hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; and a combination thereof. In some aspects, variables R2and R3combine to form a an aryl group, which is optionally substituted with one or more substituents selected from C1-C6alkyl, trifluoromethyl, C1-C6alkoxy, -C(O)-(C1-C6alkyl), halo (e.g., fluoro), hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino, and a combination thereof. In some aspects, variables R2and R3combine to form a heteroaryl group, which is optionally substituted with one or more substituents selected from C1-C6alkyl, trifluoromethyl, C1-C6alkoxy, -C(O)-(C1-C6alkyl), halo (e.g., fluoro), hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino, and a combination thereof. In certain aspects, variables R2and R3combine to form a C3-C8cycloalkyl group, which is optionally substituted with one or more substituents selected from C1-C6alkyl, trifluoromethyl, C1-C6alkoxy, -C(O)-(C1-C6alkyl), halo (e.g., fluoro), hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino, and a combination thereof. In preferred aspects, variables R2and R3combine to form a C3-C8cycloalkyl group.

[0023] Variable R4is absent, hydrogen, or a C1-C6alkyl group (e.g., methyl, ethyl, propyl, butyl, pentyl, or hexyl). In some aspects R4is absent, hydrogen, or a methyl group. In some aspects, particularly those where R2and R3combine to form an aryl group or a heteroaryl group, R4is absent. In some aspects, particularly those where R2and R3combine to form a C3-C8cycloalkyl group or a 3-6 membered heterocylic group, R4is hydrogen or a C1-C6alkyl group (e.g., methyl, ethyl, propyl, butyl, pentyl, or hexyl).

[0024] In some aspects, R2and R3combine to form a C3-C6cycloalkyl group, which is optionally substituted with one or more substituents selected from C1-C6alkyl, trifluoromethyl, C1-C6alkoxy, -C(O)-(C1-C6alkyl), halo (e.g., fluoro), hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino, and a combination thereof, and R4is hydrogen or a C1-C6alkyl group (e.g., a methyl group).

[0025] In some aspects, R2and R3combine to form a C3-C6cycloalkyl group, which is optionally substituted with one or more substituents selected from C1-C6alkyl, trifluoromethyl, halo (e.g., fluoro), and a combination thereof, and R4is hydrogen or a C1-C6alkyl group (e.g., a methyl group).

[0026] In some aspects, R2and R3combine to form a C3-C6cycloalkyl group, and R4is hydrogen or a C1-C6alkyl group (e.g., a methyl group).

[0027] In some aspects, R2and R3combine to form a a 3-6 membered heterocylic group, which is optionally substituted with one or more substituents selected from C1-C6alkyl, trifluoromethyl, C1-C6alkoxy, -C(O)-(C1-C6alkyl), halo (e.g., fluoro), hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; and a combination thereof, and R4is hydrogen or a C1-C6alkyl group (e.g., a methyl group).

[0028] In some aspects, R2and R3combine to form a an aryl group, which is optionally substituted with one or more substituents selected from C1-C6alkyl, trifluoromethyl, C1-C6alkoxy, -C(O)-(C1-C6alkyl), halo (e.g., fluoro), hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino, and a combination thereof, and R4is absent.

[0029] In some aspects, R2and R3combine to form a heteroaryl group, which is optionally substituted with one or more substituents selected from C1-C6alkyl, trifluoromethyl, C1-C6alkoxy, -C(O)-(C1-C6alkyl), halo (e.g., fluoro), hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino, and a combination thereof, and R4is absent.

[0030] In some aspects, R2and R3combine to form a C3-C6cycloalkyl group, which is optionally substituted with one or more substituents selected from C1-C6alkyl, trifluoromethyl, C1-C6alkoxy, -C(O)-(C1-C6alkyl), halo (e.g., fluoro), hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino, and a combination thereof, R4is hydrogen or a C1-C6alkyl group (e.g., a methyl group), and R1is

[0031] In some aspects, R2and R3combine to form a C3-C6cycloalkyl group, which is optionally substituted with one or more substituents selected from C1-C6alkyl,trifluoromethyl, halo (e.g., fluoro), and a combination thereof, R4is hydrogen or a C1-C6alkyl group (e.g., a methyl group), and R1is

[0032] In some aspects, R2and R3combine to form a C3-C6cycloalkyl group, R4is hydrogen or a C1-C6alkyl group (e.g., a methyl group), and R1is

[0033] In some aspects, R2and R3combine to form a a 3-6 membered heterocylic group, which is optionally substituted with one or more substituents selected from C1-C6alkyl, trifluoromethyl, C1-C6alkoxy, -C(O)-(C1-C6alkyl), halo (e.g., fluoro), hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; and a combination thereof, and R4is hydrogen or a C1-C6alkyl group (e.g., a methyl group), R1is

[0034] In some aspects, R2and R3combine to form a an aryl group, which is optionally substituted with one or more substituents selected from C1-C6alkyl, trifluoromethyl, C1-C6alkoxy, -C(O)-(C1-C6alkyl), halo (e.g., fluoro), hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino, and a combination thereof, R4is absent, and R1is

[0035] In some aspects, R2and R3combine to form a heteroaryl group, which is optionally substituted with one or more substituents selected from C1-C6alkyl,trifluoromethyl, C1-C6alkoxy, -C(O)-(C1-C6alkyl), halo (e.g., fluoro), hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino, and a combination thereof, R4is absent, and R1is

[0036] In some aspects, the invention provides a compound selected from:a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

[0037] In some aspects, the invention provides a compound of Formula (II):a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R0is hydrogen or a C1-C6alkyl group,R5is a C2-C5(e.g., C2, C3, C4, or Cs) alkyl group substituted with 1 to 4 hydroxyl groups, andR6, R7, and R8are each independently selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, difluoromethyl, trifluoromethyl, C1-C6alkoxy, arylated C1-C6alkoxy, trifluoromethylated C1-C6alkoxy, -C(O)OH, -C(O)O-(C1-C6alkyl), -C(O)-(C1-C6alkyl), - (C1-C3alkyl)-C(O)OH, -(C1-C3alkyl)-C(O)O-(C1-C6alkyl), -(C1-C3alkyl)-C(O)-(C1-C6alkyl), -NH-C(O)OH, -NH-C(O)O-(C1-C6alkyl), -NH-C(O)-(C1-C6alkyl), -(C1-C3alkyl)- NH-C(O)OH, -(C1-C3alkyl)-NH-C(O)O-(C1-C6alkyl), -(C1-C3alkyl)-NH-C(O)-(C1-C6alkyl), -(C1-C6alkyl)-O-(C1-C6alkyl), -O-(C1-C6alkyl)-O-(C1-C6alkyl), -(C1-C6alkyl)-OH, - (C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-COOH, -(C1-C6alkyl)-C(O)O-(C1-C6alkyl), -(C1-C6alkyl)-(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-NH2, -(C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)- (C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)-heterocycloalkyl, -(C1-C6alkyl)-heterocycloalkyl- (C1-C6alkyl), -(C1-C6alkyl)-C(O)-heterocycloalkyl, -(C1-C6alkyl)-C(O)-heterocycloalkyl- (C1-C6alkyl), halo, nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; -NH- aryl, -NH-heterocycloalkyl, -NH-heterocycloalkyl-(C1-C6alkyl), -C1-C6haloalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, aryl, heteroaryl, -CN, -(C1-C3alkyl)-CN, carbonyl, amino acid, amino acid methyl ester, and a combination thereof, and wherein the compound of Formula (II) is not 5-(2-oxopropylideneamino)-6-D- ribitylaminouracil (i.e., 5-OP-RU).

[0038] Variable R0is hydrogen or a C1-C6alkyl group (e.g., methyl, ethyl, propyl, butyl, pentyl, or hexyl). In some aspects, R0is hydrogen or methyl. In some aspects, R0is hydrogen. In some aspects, R0is methyl.

[0039] Variable R5is a C2-C5alkyl group substituted with 1 to 4 hydroxyl groups. The C2-C5alkyl group can be branched or liner and can be ethyl, propyl, butyl, or pentyl. In some aspects, the C2-C5alkyl group is linear and has less hydroxyl groups than carbon atoms.Exemplary R5groups include:In some aspects, variable R5is

[0040] Variables R6, R7, and R8are each independently selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, difluoromethyl, trifluoromethyl, C1-C6alkoxy, arylated C1-C6alkoxy, trifluoromethylated C1-C6alkoxy, -C(O)OH, -C(O)O-(C1-C6alkyl), -C(O)-(C1- C6alkyl), -(C1-C3alkyl)-C(O)OH, -(C1-C3alkyl)-C(O)O-(C1-C6alkyl), -(C1-C3alkyl)-C(O)- (C1-C6alkyl), -NH-C(O)OH, -NH-C(O)O-(C1-C6alkyl), -NH-C(O)-(C1-C6alkyl), -(C1-C3alkyl)-NH-C(O)OH, -(C1-C3alkyl)-NH-C(O)O-(C1-C6alkyl), -(C1-C3alkyl)-NH-C(O)-(C1- C6alkyl), -(C1-C6alkyl)-O-(C1-C6alkyl), -O-(C1-C6alkyl)-O-(C1-C6alkyl), -(C1-C6alkyl)- OH, -(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-COOH, -(C1-C6alkyl)-C(O)O-(C1-C6alkyl), - (C1-C6alkyl)-(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-NH2, -(C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)-(C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)-heterocycloalkyl, -(C1-C6alkyl)- heterocycloalkyl-(C1-C6alkyl), -(C1-C6alkyl)-C(O)-heterocycloalkyl, -(C1-C6alkyl)-C(O)- heterocycloalkyl-(C1-C6alkyl), halo, nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; -NH-aryl, -NH-heterocycloalkyl, -NH-heterocycloalkyl-(C1-C6alkyl), -C1-C6haloalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, aryl, heteroaryl, -CN, -(C1-C3alkyl)-CN, carbonyl, amino acid, amino acid methyl ester, and a combination thereof. In some aspects, variables R6, R7, and R8are each independently selected from hydrogen, C1-C6alkyl,difluoromethyl, trifluoromethyl, C1-C6alkoxy, halo, nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino, aryl, heteroaryl, and -CN. In some aspects, variables R6, R7, and R8are each independently selected from hydrogen, C1-C6alkyl, difluoromethyl, trifluoromethyl, C1-C6alkoxy, halo, hydroxy, and aryl. In some aspects, variables R6, R7, and R8are each independently selected from hydrogen, C1-C6alkyl, difluoromethyl, trifluoromethyl, and halo. In some aspects at least one of R6, R7, and R8comprises a fluorine atom. In some aspects, R6, R7, and R8are defined as follows: R6is halo, R7is halo, and R8is halo; R6is hydrogen, R7is halo, and R8is halo; R6is hydrogen, R7is hydrogen, and R8is halo; R6is hydrogen, R7is hydrogen, and R8is aryl; R6is hydrogen, R7is hydrogen, and R8is alkoxy; R6is hydrogen, R7is hydrogen, and R8is trifluoromethyl; R6is hydrogen, R7is hydrogen, and R8is difluoromethyl; R6is halo, R7is halo, and R8is trifluoromethyl; R6is halo, R7is halo, and R8is difluoromethyl; R6is C1-C6alkyl, R7is halo, and R8is halo; R6is C1-C6alkyl, R7is C1-C6alkyl, and R8is halo; R6is C1-C6alkyl, R7is halo, and R8is halo; R6is C1-C6alkyl, R7is C1-C6alkyl, and R8is halo; or Re is C1-C6alkyl, R7is hydrogen, and R8is halo.

[0041] In some aspects, the invention provides a compound selected from:a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

[0042] In some aspects, the invention provides a compound of Formula (III):a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R0is hydrogen or a C1-C6alkyl group,X is absent, -CH2-, or -C(O)-,R9is a C3-C8(e.g., C3, C4, C5, C6, C7, or C8) cycloalkyl group, a 3-6 membered heterocylic group, or a heteroaryl group, each of which is optionally substituted with one or more substituents selected from hydroxy, oxo, and a combination thereof, and(i) R10, R11, and R12are each independently selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, difluoromethyl, trifluoromethyl, C1-C6alkoxy, arylated C1-C6alkoxy, trifluoromethylated C1-C6alkoxy, -C(O)OH, -C(O)O- (C1-C6alkyl), -C(O)-(C1-C6alkyl), -(C1-C3alkyl)-C(O)OH, -(C1-C3alkyl)- C(O)O-(C1-C6alkyl), -(C1-C3alkyl)-C(O)-(C1-C6alkyl), -NH-C(O)OH, -NH- C(O)O-(C1-C6alkyl), -NH-C(O)-(C1-C6alkyl), -(C1-C3alkyl)-NH-C(O)OH, - (C1-C3alkyl)-NH-C(O)O-(C1-C6alkyl), -(C1-C3alkyl)-NH-C(O)-(C1-C6alkyl), -(C1-C6alkyl)-O-(C1-C6alkyl), -O-(C1-C6alkyl)-O-(C1-C6alkyl), -(C1- C6alkyl)-OH, -(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-COOH, -(C1-C6alkyl)-C(O)O-(C1-C6alkyl), -(C1-C6alkyl)-(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)- NH2, -(C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)-(C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)-heterocycloalkyl, -(C1-C6alkyl)-heterocycloalkyl-(C1-C6alkyl), -(C1-C6alkyl)-C(O)-heterocycloalkyl, -(C1-C6alkyl)-C(O)-heterocycloalkyl-(C1-C6alkyl), halo, nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; - NH-aryl, -NH-heterocycloalkyl, -NH-heterocycloalkyl-(C1-C6alkyl), -C1-C6haloalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, aryl, heteroaryl, -CN, - (C1-C3alkyl)-CN, carbonyl, amino acid, amino acid methyl ester, and a combination thereof or(ii) R10and R11combine to form a C3-C8(e.g., C3, C4, C5, C6, C7, or C8) cycloalkyl group, a 3-6 membered heterocylic group, an aryl group, or a heteroaryl group, each of which is optionally substituted with one or more substituents selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, difluoromethyl, trifluoromethyl, C1-C6alkoxy, arylated C1-C6alkoxy, trifluoromethylated C1-C6alkoxy, -C(O)OH, -C(O)O-(C1-C6alkyl), -C(O)- (C1-C6alkyl), -(C1-C3alkyl)-C(O)OH, -(C1-C3alkyl)-C(O)O-(C1-C6alkyl), - (C1-C3alkyl)-C(O)-(C1-C6alkyl), -NH-C(O)OH, -NH-C(O)O-(C1-C6alkyl), - NH-C(O)-(C1-C6alkyl), -(C1-C3alkyl)-NH-C(O)OH, -(C1-C3alkyl)-NH- C(O)O-(C1-C6alkyl), -(C1-C3alkyl)-NH-C(O)-(C1-C6alkyl), -(C1-C6alkyl)- O-(C1-C6alkyl), -O-(C1-C6alkyl)-O-(C1-C6alkyl), -(C1-C6alkyl)-OH, -(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-COOH, -(C1-C6alkyl)-C(O)O-(C1-C6alkyl), - (C1-C6alkyl)-(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-NH2, -(C1-C6cycloalkyl)- NH2, -(C1-C6alkyl)-(C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)-heterocycloalkyl, -(C1-C6alkyl)-heterocycloalkyl-(C1-C6alkyl), -(C1-C6alkyl)-C(O)- heterocycloalkyl, -(C1-C6alkyl)-C(O)-heterocycloalkyl-(C1-C6alkyl), halo (e.g., fluoro), nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; -NH-aryl, -NH-heterocycloalkyl, -NH-heterocycloalkyl-(C1-C6alkyl), -C1-C6haloalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, aryl, heteroaryl, -CN, - (C1-C3alkyl)-CN, carbonyl, amino acid, amino acid methyl ester, and a combination thereof, and R12is absent, hydrogen, or a C1-C6alkyl group.

[0043] Variable X is absent, -CH2-, or -C(O)-. In some aspects, X is absent. In some aspects, X is -CH2-. In some aspects, X is -C(O)-.

[0044] Variable R0is hydrogen or a C1-C6alkyl group (e.g., methyl, ethyl, propyl, butyl, pentyl, or hexyl). In some aspects, R0is hydrogen or methyl. In some aspects, R0is hydrogen. In some aspects, R0is methyl.

[0045] Variable R9is a C3-C8cycloalkyl group, a 3-6 membered heterocylic group or a heteroaryl group, each of which is optionally substituted with one or more substituents selected from hydroxy, oxo, and a combination thereof. In some aspects, R9is a C3-C8cycloalkyl group, which is optionally substituted with one or more substituents selected from hydroxy, oxo, and a combination thereof. In some aspects, R9is a 3-6 membered heterocylic group, which is optionally substituted with one or more substituents selected from hydroxy, oxo, and a combination thereof. In some aspects, R9is a heteroaryl group, which is optionally substituted with one hydroxyl groups. In some aspects, R9is a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, a tetrahydropyranyl group, a pyrrolyl group, or an imidazoyl group, each of which is optionally substituted with one or more substituents selected from hydroxy, oxo, and a combination thereof. In some aspects, R9is a cyclopentyl group, a cyclohexyl group, pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, or an imidazoyl group, each of which is optionally substituted with one or more substituents selected from hydroxy, oxo, and a combination thereof. Variable R9can be bound to via a carbon atom or a nitrogen atom. In some aspects, R9is a carbon bound group. In some aspects, R9is a nitrogen bound group.

[0046] In some aspects, R10, R11, and R12are each independently selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, difluoromethyl, trifluoromethyl, C1-C6alkoxy, arylated C1-C6alkoxy, trifluoromethylated C1-C6alkoxy, -C(O)OH, -C(O)O-(C1-C6alkyl), - C(O)-(C1-C6alkyl), -(C1-C3alkyl)-C(O)OH, -(C1-C3alkyl)-C(O)O-(C1-C6alkyl), -(C1-C3alkyl)-C(O)-(C1-C6alkyl), -NH-C(O)OH, -NH-C(O)O-(C1-C6alkyl), -NH-C(O)-(C1-C6alkyl), -(C1-C3alkyl)-NH-C(O)OH, -(C1-C3alkyl)-NH-C(O)O-(C1-C6alkyl), -(C1-C3alkyl)- NH-C(O)-(C1-C6alkyl), -(C1-C6alkyl)-O-(C1-C6alkyl), -O-(C1-C6alkyl)-O-(C1-C6alkyl), - (C1-C6alkyl)-OH, -(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-COOH, -(C1-C6alkyl)-C(O)O-(C1- C6alkyl), -(C1-C6alkyl)-(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-NH2, -(C1-C6cycloalkyl)- NH2, -(C1-C6alkyl)-(C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)-heterocycloalkyl, -(C1-C6alkyl)- heterocycloalkyl-(C1-C6alkyl), -(C1-C6alkyl)-C(O)-heterocycloalkyl, -(C1-C6alkyl)-C(O)- heterocycloalkyl-(C1-C6alkyl), halo, nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; -NH-aryl, -NH-heterocycloalkyl, -NH-heterocycloalkyl-(C1-C6alkyl), -C1-C6haloalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, aryl, heteroaryl, -CN, -(C1-C3alkyl)-CN, carbonyl, amino acid, amino acid methyl ester, and a combination thereof.

[0047] In some aspects, R10and R11combine to form a C3-C8(e.g., C3, C4, C5, C6, C7, or C8) cycloalkyl group, a 3-6 membered heterocylic group, an aryl group, or a heteroaryl group, each of which is optionally substituted with one or more substituents selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, difluoromethyl, trifluoromethyl, C1-C6alkoxy, arylated C1-C6alkoxy, trifluoromethylated C1-C6alkoxy, -C(O)OH, -C(O)O-(C1-C6alkyl), -C(O)-(C1- C6alkyl), -(C1-C3alkyl)-C(O)OH, -(C1-C3alkyl)-C(O)O-(C1-C6alkyl), -(C1-C3alkyl)-C(O)- (C1-C6alkyl), -NH-C(O)OH, -NH-C(O)O-(C1-C6alkyl), -NH-C(O)-(C1-C6alkyl), -(C1-C3alkyl)-NH-C(O)OH, -(C1-C3alkyl)-NH-C(O)O-(C1-C6alkyl), -(C1-C3alkyl)-NH-C(O)-(C1- C6alkyl), -(C1-C6alkyl)-O-(C1-C6alkyl), -O-(C1-C6alkyl)-O-(C1-C6alkyl), -(C1-C6alkyl)- OH, -(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-COOH, -(C1-C6alkyl)-C(O)O-(C1-C6alkyl), - (C1-C6alkyl)-(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-NH2, -(C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)-(C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)-heterocycloalkyl, -(C1-C6alkyl)- heterocycloalkyl-(C1-C6alkyl), -(C1-C6alkyl)-C(O)-heterocycloalkyl, -(C1-C6alkyl)-C(O)- heterocycloalkyl-(C1-C6alkyl), halo (e.g., fluoro), nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; -NH-aryl, -NH-heterocycloalkyl, -NH-heterocycloalkyl-(C1-C6alkyl), -C1-C6haloalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, aryl, heteroaryl, -CN, -(C1-C3alkyl)-CN, carbonyl, amino acid, amino acid methyl ester, and a combination thereof, and R12 is absent, hydrogen, or a C1-C6alkyl group.

[0048] In certain aspects, (a) R10, R11, and R12 are each independently selected from hydrogen, C1-C6alkyl or (b) R10and R11combine to form a C3-C8(e.g., C3, C4, C5, C6, C7, or C8) cycloalkyl group and R12is hydrogen or a C1-C6alkyl group.

[0049] In some aspects, the invention provides a compound selected from:a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

[0050] In some aspects, the compound described herein is not 5-(2- oxopropylideneamino)-6-D-ribitylaminouracil (i.e., 5-OP-RU). In some aspects, the compound described herein is not a compound of Formula (IV):a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R5is, and R13is C1-C6alkyl. In some aspects, the compound described herein is not a compound of Formula (IV), a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R5is a C2-C5(e.g., C2, C3, C4, or C5) alkyl group substituted with 1 to 4 hydroxyl groups, and R13 is methyl. In some aspects, the compound described herein is not a compound of Formula (IV), a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R5is a C2-C5(e.g., C2, C3, C4, or C5) alkyl group substituted with 1 to 4 hydroxyl groups, and R13is C1-C6alkyl. In some aspects, the compound described herein is not a compound of Formula (IV), a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R5is a C2-C5(e.g., C2, C3, C4, or C5) alkyl group substituted with 1 to 4 hydroxyl groups, and R13 is an optionally substituted C1-C6alkyl.

[0051] As used herein, the term “alkyl” implies a straight-chain or branched alkyl substituent containing the designated number of carbon atoms, for example, from about 1 to about 6 carbon atoms, e.g., from about 1 to about 4 carbon atoms. Examples of alkyl groups include methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert -butyl, n- pentyl, isopentyl, n- hexyl, and the like. The alkyl can be substituted or unsubstituted, as described herein. Even in instances in which the alkyl is an alkylene chain (e.g., -(CH2)n-), the alkyl group can be substituted or unsubstituted.

[0052] As used herein, the term “alkenyl” means a linear alkenyl substituent containing the designated number of carbon atoms, for example, about 2 to about 6 carbon atoms (branched alkenyls are about 3 to about 6 carbon atoms), e.g., from about 3 to about 5 carbon atoms (branched alkenyls are about 3 to about 6 carbon atoms). In accordance with an aspect of the invention, the alkenyl group is a C2-C4alkenyl. Examples of alkenyl group include ethenyl, allyl, 2-propenyl, 1-butenyl, 2-butenyl, 1 -pentenyl, 2-pentenyl, 3-pentenyl, 1- hexenyl, and the like. The alkenyl can be substituted or unsubstituted, as described herein.

[0053] As used herein, the term “cycloalkyl” means a cyclic alkyl moiety containing the designated number of carbon atoms, for example, 3 to 6 carbon atoms or from 5 to 6 carbon atoms. Examples of such moieties include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The cycloalkyl may contain a carbonyl such that there is an exocylclic (=O) group (i.e., an oxo group). The cycloalkyl can be substituted or unsubstituted, as described herein. The cycloalkyl may also be fused to a neighboring substituent (e.g., a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl), i.e., sharing two atoms and a bond with a neighboring substituent.

[0054] As used herein, the term “aryl” refers to a mono, bi, or tricyclic carbocyclic ring system having one, two, or three aromatic rings, for example, phenyl, naphthyl, anthracenyl, or biphenyl. The term “aryl” refers to an unsubstituted or substituted aromatic carbocyclic moiety, as commonly understood in the art, and includes monocyclic and polycyclic aromatics such as, for example, phenyl, biphenyl, naphthyl, anthracenyl, pyrenyl, and the like. An aryl moiety generally contains from, for example, 6 to 30 carbon atoms, from 6 to 18 carbon atoms, from 6 to 14 carbon atoms, or from 6 to 10 carbon atoms. It is understood that the term aryl includes carbocyclic moieties that are planar and comprise 4n+2 π electrons, according to Huckel’s Rule, wherein n = 1, 2, or 3. This definition also applies wherever “aryl” occurs as part of a group, such as, e.g., in haloaryl (e.g., monohaloaryl, dihaloaryl, and trihaloaryl), arylalkyl, etc. The aryl can be substituted or unsubstituted, asdescribed herein. The aryl may also be fused to a neighboring substituent (e.g., a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl), i.e., sharing two atoms and a bond with a neighboring substituent.

[0055] As used herein, the term “heteroaryl” refers to aromatic 5 or 6 membered monocyclic groups, 9 or 10 membered bicyclic groups, and 11 to 14 membered tricyclic groups which have at least one heteroatom (O, S, or N) in at least one of the rings. Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and / or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atoms may optionally be quaternized. Heteroaryl groups which are bicyclic or tricyclic must include at least one fully aromatic ring but the other fused ring or rings may be aromatic or non-aromatic. The heteroaryl group may be attached at any available nitrogen or carbon atom of any ring. Illustrative examples of heteroaryl groups are pyridinyl, pyridazinyl, pyrimidyl, pyrazinyl, benzimidazolyl, triazinyl, imidazolyl, (1,2,3)- and (1,2,4)-triazolyl, pyrazinyl, tetrazolyl, furyl, pyrrolyl, thienyl, isothiazolyl, thiazolyl, isoxazolyl, and oxadiazolyl. The heteroaryl can be substituted or unsubstituted, as described herein. The heteroaryl may also be fused to a neighboring substituent (e.g., a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl), i.e., sharing two atoms and a bond with a neighboring substituent.

[0056] As used herein, the term “heterocycloalkyl” means a stable, saturated, or partially unsaturated monocyclic, fused bicyclic, and spiro bicyclic ring system containing 3 to 6 ring members of carbon atoms and other atoms selected from nitrogen, sulfur, and / or oxygen. In an aspect, a heterocycloalkyl is a 5 or 6-membered monocyclic ring and contains one, two, or three heteroatoms selected from nitrogen, oxygen, and sulfur. The heterocycloalkyl may be attached to the parent structure through a carbon atom or through any heteroatom of the heterocycloalkyl that results in a stable structure. Alternatively, or additionally, the heterocycloalkyl may contain a carbonyl such that there is an exocylclic (=O) group (i.e., an oxo group). In other words, as used herein when referring to a substituent, the term “carbonyl” refers to a (=O) group. Examples of such heterocycloalkyl rings are isoxazolyl, thiazolinyl, imidazolidinyl, piperazinyl, homopiperazinyl, pyrrolyl, pyrrolinyl, pyrazolyl,pyranyl, piperidyl, oxazolyl, and morpholinyl. The heterocycloalkyl can be substituted or unsubstituted, as described herein.

[0057] As used herein, the term “hydroxy” refers to the group -OH.

[0058] As used herein, the term “cyano” refers to the group -CN.

[0059] As used herein, the terms “alkoxy” and “cycloalkyloxy” embrace linear or branched alkyl and cycloalkyl groups, respectively, that are attached to a divalent oxygen or form a divalent oxygen atom by way of their attachment. The alkyl and cycloalkyl groups are the same as described herein.

[0060] As used herein, the term “halo” refers to a halogen selected from fluorine, chlorine, bromine, and iodine.

[0061] As used herein, the term “amino” refers to the group -NH2. The term “alkylamino” refers to -NHR, whereas the term “dialkylamino” refers to -NRR’ . R and R' are the same or different and each is a substituted or unsubstituted alkyl group, as described herein.

[0062] As used herein, the term “amido” refers to the group -C(O)NRR’, which R and R’ are the same or different and each is hydrogen or a substituted or unsubstituted alkyl group, as described herein.

[0063] As used herein, the term “amino acid” refers to any amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In some aspects, when used as a substituent, the amino acid is alanine or glycine. In certain aspects, when used as a substituent, the amino acid is nitrogen bound. In any of the aspects described herein, the term “amino acid methyl ester” refers to any amino acid described herein that has been converted to the methyl ester.

[0064] In any of the aspects of the compounds of Formula (I), Formula (II), or Formula (III), any substituent that is not hydrogen (e.g., C1-C6alkyl, C2-C6alkenyl, C3-C6cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, or heterocycloalkylalkyl) can be an optionally substituted moiety. The substituted moiety typically comprises at least one substituent (e.g., 1, 2, 3, 4, 5, 6, etc.) in any suitable position (e.g., 1-, 2-, 3-, 4-, 5-, or 6- position, etc.). When an aryl group is substituted with a substituent, e.g., halo, amino, alkyl, OH, alkoxy, and others, the aromatic ring hydrogen is replaced with the substituent and this can take place in any of the available hydrogens, e.g., 2, 3, 4, 5, and / or 6-position wherein the 1 -position is the point of attachment of the aryl group in the compound of the presentinvention. Suitable substituents include, e.g., halo, alkyl, alkenyl, hydroxy, oxo (i.e., where two hydrogens are replaced to form a carbonyl), nitro, cyano, amino, alkylamino, alkoxy, aryloxy, arylalkoxy, carboxyl, carboxyalkyl, carboxyalkyloxy, amido, alkylamido, haloalkylamido, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl, each of which is described herein. In some aspects, the one or more substituents is selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, difluoromethyl, trifluoromethyl, C1-C6alkoxy, arylated C1-C6alkoxy, trifluoromethylated C1-C6alkoxy, -(C1-C6alkyl)-OH, -(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-COOH, -(C1-C6alkyl)-NH2, -(C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)-(C1-C6cycloalkyl)-NH2, -(C1-C6alkyl) heterocycloalkyl, halo, nitro, hydroxy, oxo (i.e., where two hydrogens are replaced to form a carbonyl), amino, C1-C6alkylamino, di-C1-C6alkyl-amino; -NH-aryl, C1-C6haloalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, aryl, heteroaryl, fused aryl, -CN, -(C1-C3alkyl)-CN, carbonyl, and a combination thereof. In some instances, the substituent is at least one alkyl, halo, and / or haloalkyl (e.g., 1 or 2).

[0065] In any of the aspects of the compounds of Formula (I), Formula (II), or Formula (III), whenever a range of the number of atoms in a structure is indicated (e.g., a C3-8, C1-6, C3-6, C1-4, etc.), it is specifically contemplated that any sub-range or individual number of carbon atoms falling within the indicated range also can be used. Thus, for instance, the recitation of a range of 1-8 carbon atoms (e.g., C1-C8), 1-6 carbon atoms (e.g., C1-C6), 1-4 carbon atoms (e.g., C1-C4), 1-3 carbon atoms (e.g., C1-C3), or 2-8 carbon atoms (e.g., C2-C8) as used with respect to any chemical group (e.g., alkyl, cycloalkyl, etc.) referenced herein encompasses and specifically describes 1, 2, 3, 4, 5, 6, 7, and / or 8 carbon atoms, as appropriate, as well as any sub-range thereof (e.g., 1-2 carbon atoms, 1-3 carbon atoms, 1-4 carbon atoms, 1-5 carbon atoms, 1-6 carbon atoms, 1-7 carbon atoms, 1-8 carbon atoms, 2-3 carbon atoms, 2-4 carbon atoms, 2-5 carbon atoms, 2-6 carbon atoms, 2-7 carbon atoms, 2-8 carbon atoms, 3-4 carbon atoms, 3-5 carbon atoms, 3-6 carbon atoms, 3-7 carbon atoms, 3-8 carbon atoms, 4-5 carbon atoms, 4-6 carbon atoms, 4-7 carbon atoms, 4-8 carbon atoms, etc., as appropriate).

[0066] Any of the compounds of Formula (I), Formula (II), or Formula (III) (e.g., Compounds A-DF) can exist as any suitable stereoisomer thereof. For example, the invention provides enantiomers and diastereomers of any of the compounds disclosed herein. Alternatively, any of the compounds of Formula (I), Formula (II), or Formula (III) (e.g., Compounds A-DF) can exist as a racemic mixture, an enantioenriched mixture, anenantiomerically pure mixture, a mixture of diastereomers, and / or a diastereomerically pure mixture.

[0067] For example, Compound AM can exist as the following two enantiomers:or any mixture thereof. Similarly, Compound AS can exist as the following two enantiomers:or any mixture thereof.

[0068] In any of the aspects of the compounds disclosed herein, the phrase “salt” or “pharmaceutically acceptable salt” is intended to include nontoxic salts synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. For example, an inorganic acid (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, or hydrobromic acid), an organic acid (e.g., oxalic acid, malonic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid, ascorbic acid, methylsulfonicacid, or benzylsulfonic acid), an inorganic base (e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, or ammonium hydroxide), an organic base(e.g., methylamine, diethylamine, triethylamine, triethanolamine, ethylenediamine, tris(hydroxymethyl)methylamine, guanidine, choline, or cinchonine), or an amino acid (e.g., lysine, arginine, or alanine) can be used. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical. Lists of suitable salts are found in Remington 's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, 1990, p. 1445, and Journal of Pharmaceutical Science, 66, 2-19 (1977). For example, they can be a salt of an alkali metal (e.g., sodium or potassium), alkaline earth metal (e.g., calcium), or ammonium of salt. In an aspect, the salt is a trifluoroacetate salt.

[0069] In some aspects, the compound of Formula (I), Formula (II), or Formula (III) (e.g., Compounds A-DF), a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof exhibits improved stability in aqueous solution (e.g., phosphate buffered saline). For example, the compound of Formula (I), Formula (II), or Formula (III) (e.g., Compounds A-DF), a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof can have a half-life (ti / 2) in phosphate buffered saline at pH 7.4 and 37 °C, using the method described in Example 82, of 80 minutes or greater, 90 minutes or greater, 100 minutes or greater, 110 minutes or greater, 120 minutes or greater, 150 minutes or greater, or 180 minutes or greater. In some aspects, the compound of Formula (I), Formula (II), or Formula (III) (e.g., Compounds A-DF), a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof can have a half-life (ti / 2) in phosphate buffered saline at pH 7.4 and 37 °C, using the method described in Example 82, of 90 minutes or greater. In certain aspects, the compound of Formula (I), Formula (II), or Formula (III) (e.g., Compounds A-DF), a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof can have a half-life (ti / 2) in phosphate buffered saline at pH 7.4 and 37 °C, using the method described in Example 82, of 120 minutes or greater.

[0070] In some aspects, the compound of Formula (I), Formula (II), or Formula (III) (e.g., Compounds A-DF), a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof exhibits improved stability in human plasma. For example, the compound of Formula (I), Formula (II), or Formula (III) (e.g., Compounds A- DF), a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof can have a half-life (ti / 2) in human plasma at 37 °C, using the method described in Example 82, of 80 minutes or greater, 90 minutes or greater, 100 minutes or greater, 110minutes or greater, 120 minutes or greater, 150 minutes or greater, or 180 minutes or greater. In some aspects, the compound of Formula (I), Formula (II), or Formula (III) (e.g., Compounds A-DF), a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof can have a half-life (ti / 2) in human plasma at 37 °C, using the method described in Example 82, of 90 minutes or greater. In certain aspects, the compound of Formula (I), Formula (II), or Formula (III) (e.g., Compounds A-DF), a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof can have a half-life (ti / 2) in human plasma at 37 °C, using the method described in Example 82, of 120 minutes or greater.Pharmaceutical Compositions

[0071] An aspect of the invention provides pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutical carrier. The pharmaceutical compositions contain a pharmaceutically acceptable carrier. For example, the pharmaceutical composition of the present invention can comprise a compound of Formula (I), Formula (II), or Formula (III) (e.g., Compounds A- DF), a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof. The compound of Formula (I), Formula (II), or Formula (III) (e.g., Compounds A- DF) can be present in the pharmaceutical composition in any suitable amount. For example, the compound of Formula (I), Formula (II), or Formula (III) (e.g., Compounds A-DF) can present in the pharmaceutical composition in an amount of about 0.01 mg per milliliter (mL) or more (e.g., about 0.05 mg / mL or more, about 0.1 mg / mL or more, about 0.5 mg / mL or more, about 1 mg / mL or more, about 2 mg / mL or more, about 5 mg / mL or more, about 10 mg / mL or more, about 20 mg / mL or more, or about 50 mg / mL or more. Typically, the pharmaceutical composition will comprise the compound of Formula (I), Formula (II), or Formula (III) (e.g., Compounds A-DF) in an amount of about 100 mg / mL or less (e.g., about 75 mg / mL or less, about 50 mg / mL or less, about 40 mg / mL or less, about 30 mg / mL or less, about 20 mg / mL or less, about 15 mg / mL or less, about 10 mg / mL or less, or about 5 mg / mL or less). Any two of the foregoing endpoints can be used to define a close-ended range, or a single endpoint can be used to define an open-ended range. For example, the compound of Formula (I), Formula (II), or Formula (III) (e.g., Compounds A-DF) can be present in the pharmaceutical composition in a concentration of from about 0.1 mg / mL to about 50 mg / mL, about 0.1 mg / mL to about 20 mg / mL, or about 1 mg / mL to about 20 mg / mL. It will be understood that any of the compounds disclosed herein can also be formulated in solid (e.g.,pill) form. As a result, each of the foregoing mass per volume (mg / mL) amounts can also be expressed as a mass per mass (mg / g) amount.

[0072] In an aspect, the compound has a purity of at least about 85% (e.g., at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, or at least about 99.9%).

[0073] The pharmaceutical composition can comprise a compound of the present invention (e.g., a compound of Formula (I), Formula (II), or Formula (III) (e.g., Compounds A-DF), a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof) in combination with one or more other pharmaceutically active agents or drugs, such as a chemotherapeutic agent, e.g., a topoisomerase I inhibitor, asparaginase, busulfan, carboplatin, cisplatin, daunorubicin, doxorubicin, fluorouracil, gemcitabine, hydroxyurea, methotrexate, paclitaxel, rituximab, vinblastine, vincristine, etc. Alternatively, or additionally, the pharmaceutical composition can comprise a compound of the present invention (e.g., a compound of Formula (I), Formula (II), or Formula (III) (e.g., Compounds A-DF), a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof) in combination with one or more immunotherapeutic agents, such as, for example, toll-like receptor (TLR) agonists, immune checkpoint inhibitors, adoptive cell transfer agents (e.g., chimeric antigen receptor (CAR) T cells, chimeric antigen receptor (CAR) NK cells, or other immune cells), mRNA (e.g., mRNA coding for immune activating agents), antibodies (e.g., monoclonal antibodies, antibodies targeting myeloid cells, antibodies targeting macrophages, antibodies targeting monocytes, antibodies targeting regulatory T cells, antibodies targeting B cells, antibodies targeting NK cells, antibodies targeting NKT cells, antibodies targeting innate lymphoid cells, or the like), T cell engagers, chemokines, cytokines, oncolytic virus therapies, and combinations thereof.[0074J In some aspects, the composition comprises a compound of the present invention (e.g., a compound of Formula (I), Formula (II), or Formula (III) (e.g., Compounds A-DF), a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof) in combination with an immune checkpoint inhibitor. As used herein, the term “immune checkpoint inhibitors” refers to any modulator that inhibits the activity of the immune checkpoint molecule. Immune checkpoint inhibitors can include, but are not limited to,immune checkpoint molecule binding proteins, small molecule inhibitors, antibodies, antibody-derivatives (including Fc fusions, Fab fragments and scFvs), antibody-drug conjugates, antisense oligonucleotides, siRNA, aptamers, peptides and peptide mimetics. Exemplary immune checkpoint inhibitors include, but are not limited to, anti-PD-1 (programmed cell death protein 1) inhibitors (e.g., pembrolizumab, nivolumab, or cemiplimab), anti-PD-Ll (programmed death-ligand 1) inhibitors (e.g., atezolizumab, durvalumab, or avelumab), or anti-CTLA-4 (cytotoxic T-lymphocyte antigen 4) inhibitors (e.g., ipilimumab or tremelimumab).

[0075] In some aspects, the composition comprises a compound of the present invention (e.g., a compound of Formula (I), Formula (II), or Formula (III) (e.g., Compounds A-DF), a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof) in combination with a TLR agonist. In certain aspects, the TLR agonist is a TLR9 agonist. Examples of TLR9 agonists include single strand cytosine-phosphate-guanine (CpG) oligodeoxynucleotides (CpG ODN). Three major classes of stimulatory CpG ODNs have been identified based on structural characteristics and activity on human peripheral blood mononuclear cells (PBMCs), in particular B cells and plasmacytoid dendritic cells (pDCs). These three classes are Class A (Type D), Class B (Type K), and Class C. In some aspects, the TLR agonist is a cytosine-phosphate-guanine (CpG) dinucleotide.

[0076] In some aspects, the pharmaceutical composition further comprises a pharmaceutical carrier. The pharmaceutical carrier can be any of those conventionally used and is limited only by chemi co-phy si cal considerations, such as solubility and lack of reactivity with the active compound(s), and by the route of administration. The pharmaceutical carriers described herein, for example, vehicles, adjuvants, excipients, and diluents, are well-known to those skilled in the art and are readily available to the public. It is preferred that the pharmaceutical acceptable carrier be one which is chemically inert to the active agent(s) and one which has no detrimental side effects or toxicity under the conditions of use.

[0077] The choice of carrier will be determined in part by the particular compounds, as well as by the particular method used to administer the compounds. Accordingly, there are a variety of suitable formulations of the pharmaceutical composition of the invention. The compounds, a pharmaceutically acceptable salt thereof, can be administered in any suitable manner (e.g., orally, intravenously, intramuscularly, intrathecally, subcutaneously, sublingually, buccally, rectally, vaginally, by ocular route, by otic route, nasally, byinhalation, by nebulization, topically, systemically, transdermally, or a combination thereof). In an aspect, the pharmaceutical composition of the invention is administered orally.

[0078] The following formulations for administration are exemplary and are in no way limiting. More than one route can be used to administer the compounds, and in certain instances, a particular route can provide a more immediate and more effective response than another route.

[0079] Formulations suitable for administration include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. The compounds can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol or hexadecyl alcohol, a glycol, such as propylene glycol or polyethylene glycol, dimethylsulfoxide, glycerol, ketals such as 2,2-dimethyl-l,3-dioxolane- 4-methanol, ethers, poly(ethyleneglycol) 400, oils, fatty acids, fatty acid esters or glycerides, or acetylated fatty acid glycerides with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agents and other pharmaceutical adjuvants.

[0080] Oils, which can be used in formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral. Suitable fatty acids for use in formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.

[0081] Suitable soaps for use in formulations include fatty alkali metal, ammonium, and triethanolamine salts, and suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylenepolypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl-β-aminopropionates, and 2-alkyl- imidazoline quaternary ammonium salts, and (e) mixtures thereof.

[0082] The formulations will typically contain from about 0.5% to about 25% by weight of the compounds in solution. Preservatives and buffers may be used. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations will typically range from about 5% to about 15% by weight. Suitable surfactants include polyethylene glycol sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol. The formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described. The requirements for effective pharmaceutical carriers for compositions are well-known to those of ordinary skill in the art (see, e.g., Lloyd et al. (eds.), Remington: The Science and Practice of Pharmacy, 22nd Ed., Pharmaceutical Press (2012)).

[0083] It will be appreciated by one of skill in the art that, in addition to the abovedescribed pharmaceutical compositions, the compounds of the invention can be formulated as inclusion complexes, such as cyclodextrin inclusion complexes, in liposomes, or as a part of a nanoparticle (e.g., a lipid-based nanoparticle or a protein-based nanoparticle) delivery technology (e.g., by encapsulating the compound, along with any of the other components disclosed herein, in a nanoparticle).

[0084] For purposes of the invention, the amount or dose of the compounds administered should be sufficient to effect a desired response, e.g., a therapeutic or prophylactic response, in the mammal over a reasonable time frame. For example, the dose of the compounds should be sufficient to inhibit growth of a target cell or treat or prevent cancer in a period of from about 2 hours or longer, e.g., 12 to 24 or more hours, from the time of administration. In certain aspects, the time period could be even longer. The dose will be determined by the efficacy of the particular compounds and the condition of the mammal (e.g., human), as well as the body weight of the mammal (e.g., human) to be treated.

[0085] Many assays for determining an administered dose are known in the art. An administered dose may be determined in vitro (e.g., cell cultures) or in vivo (e.g., animal studies). For example, an administered dose may be determined by determining the IC50(thedose that achieves a half-maximal inhibition of symptoms), LD50 (the dose lethal to 50% of the population), the ED50 (the dose therapeutically effective in 50% of the population), and the therapeutic index in cell culture and / or animal studies. The therapeutic index is the ratio of LD50 to ED50 (i.e., LD50 / ED50).

[0086] The dose administered to the subject, particularly human and other mammals, in accordance with the present invention should be sufficient to affect the desired response. One skilled in the art will recognize that dosage will depend upon a variety of factors, including the age, condition or disease state, predisposition to disease, genetic defect or defects, and body weight of the mammal. The size of the dose will also be determined by the route, timing and frequency of administration as well as the existence, nature, and extent of any adverse side-effects that might accompany the administration of a particular inhibitor and the desired effect. It will be appreciated by one of skill in the art that various conditions or disease states may require prolonged treatment involving multiple administrations.

[0087] In some aspects, the inventive methods comprise administering an effective amount of a compound of Formula (I), Formula (II), or Formula (III) (e.g., Compounds A- DF), a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof. An “effective amount” means an amount sufficient to show a meaningful benefit in an individual, e.g., treatment, healing, prevention, delay of onset, halting, or amelioration of other relevant medical condition(s) associated with an infectious disease, promoting at least one aspect of tumor cell cytotoxicity (e.g., inducing apoptosis, inhibition of growth, inhibiting survival of a cancer cell, reducing proliferation, reducing size and / or mass of a tumor (e.g., solid tumor)), or treatment, healing, prevention, delay of onset, halting, or amelioration of other relevant medical condition(s) associated with a particular cancer. The meaningful benefit observed in the subject can be to any suitable degree (about 10% or more, about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more) relative to the state of the subject / tissue / cell prior to the inventive method. In some aspects, one or more symptoms of the infectious disease or cancer are prevented, reduced, halted, or eliminated subsequent to administration of a compound of Formula (I), Formula (II), or Formula (III) (e.g., Compounds A-DF), a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, thereby effectively treating the infectious disease or cancer to at least some degree.

[0088] Effective amounts may vary depending upon the biological effect desired in the individual, condition to be treated, the specific characteristics of the compound of Formula (I), Formula (II), or Formula (III) (e.g., Compounds A-DF), and / or the individual. In this respect, any suitable dose of the compound of Formula (I), Formula (II), or Formula (III) (e.g., Compounds A-DF) can be administered to the subject (e.g., human), according to the type of infectious disease or cancer to be treated. Various general considerations taken into account in determining the “effective amount” are known to those of skill in the art and are described, e.g., in Gilman et al., eds., Goodman and Gilman’s: The Pharmacological Bases of Therapeutics, 8th ed., Pergamon Press, 1990; and Remington’s Pharmaceutical Sciences, 17th Ed., Mack Publishing Co., Easton, Pa., 1990, each of which is herein incorporated by reference.

[0089] The dose of the compound of Formula (I), Formula (II), or Formula (III) (e.g.,Compounds A-DF) desirably comprises about 0.01 mg per kilogram (kg) of the body weight of the subject (mg / kg) or more (e.g., about 0.05 mg / kg or more, about 0.1 mg / kg or more, about 0.5 mg / kg or more, about 1 mg / kg or more, about 2 mg / kg or more, about 5 mg / kg or more, about 10 mg / kg or more, about 15 mg / kg or more, about 20 mg / kg or more, about 30 mg / kg or more, about 40 mg / kg or more, about 50 mg / kg or more, about 75 mg / kg or more, about 100 mg / kg or more, about 125 mg / kg or more, about 150 mg / kg or more, about 175 mg / kg or more, about 200 mg / kg or more, about 225 mg / kg or more, about 250 mg / kg or more, about 275 mg / kg or more, about 300 mg / kg or more, about 325 mg / kg or more, about 350 mg / kg or more, about 375 mg / kg or more, about 400 mg / kg or more, about 425 mg / kg or more, about 450 mg / kg or more, or about 475 mg / kg or more) per day. Typically, the dose will be about 500 mg / kg or less (e.g., about 475 mg / kg or less, about 450 mg / kg or less, about 425 mg / kg or less, about 400 mg / kg or less, about 375 mg / kg or less, about 350 mg / kg or less, about 325 mg / kg or less, about 300 mg / kg or less, about 275 mg / kg or less, about 250 mg / kg or less, about 225 mg / kg or less, about 200 mg / kg or less, about 175 mg / kg or less, about 150 mg / kg or less, about 125 mg / kg or less, about 100 mg / kg or less, about 75 mg / kg or less, about 50 mg / kg or less, about 40 mg / kg or less, about 30 mg / kg or less, about 20 mg / kg or less, about 15 mg / kg or less, about 10 mg / kg or less, about 5 mg / kg or less, about 2 mg / kg or less, about 1 mg / kg or less, about 0.5 mg / kg or less, or about 0.1 mg / kg or less). Any two of the foregoing endpoints can be used to define a close-ended range, or a single endpoint can be used to define an open-ended range. For example, the dose of the compound of Formula (I), Formula (II), or Formula (III) (e.g., Compounds A-DF) can be from about0.01 mg / kg to about 500 mg / kg, about 1 mg / kg to about 200 mg / kg, or about 10 mg / kg to about 100 mg / kg.Methods of Use

[0090] In an aspect, the invention provides methods of activating mucosal-associated invariant T (MAIT) cells in a subject, the method comprising administering to the subject a compound or pharmaceutical composition of the invention. As used herein, “activating” can mean about 5% or more, about 10% or more, about 15% or more, about 20% or more, about 25% or more, about 30% or more, about 35% or more, about 40% or more, about 45% or more, about 50% or more, about 55% or more, about 60% or more, about 65% or more, about 70% or more, about 75% or more, about 80% or more, about 85% or more, about 90% or more, about 95% or more, or about 100% or more increase in activity of mucosal-associated invariant T (MAIT) cells.

[0091] In some aspects, the methods of activating mucosal-associated invariant T (MAIT) cells in a subject comprise upregulating MHC class I-related protein 1 (MR1) in the subject. As used herein, “upregulating” can mean about 5% or more, about 10% or more, about 15% or more, about 20% or more, about 25% or more, about 30% or more, about 35% or more, about 40% or more, about 45% or more, about 50% or more, about 55% or more, about 60% or more, about 65% or more, about 70% or more, about 75% or more, about 80% or more, about 85% or more, about 90% or more, about 95% or more, or about 100% or more increase in MHC class I-related protein 1 (MR1) in the subject.

[0092] In another aspect, the invention provides methods of treating cancer in a subject, the method comprising administering to the subject a compound or pharmaceutical composition of the invention. Without being bound by a particular theory or mechanism, it is believed that the compounds activate mucosal-associated invariant T (MAIT) cells and / or upregulate MHC class I-related protein 1 (MR1) in the subject.

[0093] The term “treat” as well as words stemming therefrom, as used herein, do not necessarily imply 100% or complete treatment or prevention. Rather, there are varying degrees of treatment or prevention of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect. In this respect, the methods of an aspect of the invention can provide any amount of any level of treatment of cancer in a subject. Furthermore, the treatment provided by the method of an aspect of the invention can include treatment of one or more conditions or symptoms of the disease, e.g., cancer, being treated.Also, for purposes herein, “treatment” can encompass delaying the onset of the disease, or a symptom or condition thereof.

[0094] With respect to the methods of aspects of the invention, the cancer can be any cancer, including any of adrenal gland cancer, sarcomas (e.g., synovial sarcoma, osteogenic sarcoma, leiomyosarcoma uteri, angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma, and teratoma), lymphomas (e.g., small lymphocytic lymphoma, Hodgkin lymphoma, and non-Hodgkin lymphoma), hepatocellular carcinoma, glioma, head cancers (e.g., squamous cell carcinoma), neck cancers (e.g., squamous cell carcinoma), acute lymphocytic cancer, leukemias (e.g., hairy cell leukemia, myeloid leukemia (acute and chronic), lymphatic leukemia (acute and chronic), prolymphocytic leukemia (PEL), myelomonocytic leukemia (acute and chronic), and lymphocytic leukemia (acute and chronic)), bone cancer (osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing’s sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumors), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, and retinoblastoma), fallopian tube cancer, breast cancer, cancer of the anus, anal canal, or anorectum, cancer of the eye, cancer of the intrahepatic bile duct, cancer of the joints, cancer of the neck, gallbladder, or pleura, cancer of the nose, nasal cavity, or middle ear, cancer of the oral cavity, cancer of the vulva (e.g., squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, and fibrosarcoma), myeloproliferative disorders (e.g., chronic myeloid cancer), colon cancers (e.g., colon carcinoma), esophageal cancer (e.g., squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma), cervical cancer (cervical carcinoma and pre-invasive cervical dysplasia), gastric cancer, gastrointestinal carcinoid tumor, hypopharynx cancer, larynx cancer, liver cancers (e.g., hepatocellular carcinoma, fibrolamellar carcinoma (EEC), fibrolamellar hepatocellular carcinoma (FL-HCC), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma), lung cancers (e.g., bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, and adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, chondromatous hamartoma, small cell lung cancer, non-small cell lung cancer, and lung adenocarcinoma), malignant mesothelioma, skin cancer (e.g., melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi’s sarcoma,nevi, dysplastic nevi, lipoma, angioma, dermatofibroma, and keloids), multiple myeloma, nasopharynx cancer, ovarian cancer (e.g., ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, endometrioid carcinoma, and clear cell adenocarcinoma), granulosa-theca cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, and malignant teratoma), pancreatic cancer (e.g., ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, and VIPoma), peritoneum, omentum, mesentery cancer, pharynx cancer, prostate cancer (e.g., adenocarcinoma and sarcoma), rectal cancer, kidney cancer (e.g., adenocarcinoma, Wilms tumor (nephroblastoma), and renal cell carcinoma), small intestine cancer (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi’s sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma), soft tissue cancer, stomach cancer (e.g., carcinoma, lymphoma, and leiomyosarcoma), testicular cancer (e.g., seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, Leydig cell tumor, fibroma, fibroadenoma, adenomatoid tumors, and lipoma), cancer of the uterus (e.g., endometrial carcinoma), thyroid cancer, and urothelial cancers (e.g., squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, ureter cancer, and urinary bladder cancer). In an aspect of the invention, the cancer is liver cancer (e.g., hepatocellular carcinoma, fibrolamellar carcinoma (FLC), fibrolamellar hepatocellular carcinoma (FL- HCC), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma).

[0095] In certain aspects of the invention, the compounds of aspects of the invention, or pharmaceutically acceptable salts thereof, can be co-administered with an anti-cancer agent (e.g., a chemotherapeutic agent or an immunotherapeutic agent such as, for example, a TLR agonist, an immune checkpoint inhibitor, an adoptive cell transfer agent (e.g., chimeric antigen receptor (CAR) T cells, chimeric antigen receptor (CAR) NK cells, or other immune cells), mRNA (e.g., mRNA coding for immune activating agents), an antibody (e.g., monoclonal antibodies, antibodies targeting myeloid cells, antibodies targeting macrophages, antibodies targeting monocytes, antibodies targeting regulatory T cells, antibodies targeting B cells, antibodies targeting NK cells, antibodies targeting NKT cells, antibodies targeting innate lymphoid cells, or the like), a T cell engager, a chemokine, a cytokine, an oncolytic virus therapy, or a combinations thereof) and / or radiation therapy. In an aspect, the compounds of aspects of the invention, or pharmaceutically acceptable salts thereof, are administered in an amount that is effective to sensitize the cancer cells to one or more therapeutic regimens (e.g., chemotherapy or radiation therapy). The terms “co-administered”or “co-administration” refer to simultaneous or sequential administration. The compounds of aspects of the invention, or pharmaceutically acceptable salts thereof, can be administered before, concurrently with, or after administration of another anti-cancer agent (e.g., a chemotherapeutic agent or an immunotherapeutic agent such as, for example, a TLR agonist, an immune checkpoint inhibitor, an adoptive cell transfer agent (e.g., chimeric antigen receptor (CAR) T cells, chimeric antigen receptor (CAR) NK cells, or other immune cells), mRNA (e.g., mRNA coding for immune activating agents), an antibody (e.g., monoclonal antibodies, antibodies targeting myeloid cells, antibodies targeting macrophages, antibodies targeting monocytes, antibodies targeting regulatory T cells, antibodies targeting B cells, antibodies targeting NK cells, antibodies targeting NKT cells, antibodies targeting innate lymphoid cells, or the like), a T cell engager, a chemokine, a cytokine, an oncolytic virus therapy, or a combinations thereof). In some aspects, the compounds of the invention, or pharmaceutically acceptable salts thereof, are co-administered with a TLR agonist and / or an immune checkpoint inhibitor disclosed herein.

[0096] One or more than one, e.g., two, three, or more anti-cancer agents can be administered. In this regard, the present invention is directed to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a combination of the compounds of aspects of the invention, or pharmaceutically acceptable salts thereof, and at least one anti -cancer agent (e.g., chemotherapeutic agent or an immunotherapeutic agent such as a TLR agonist or an immune checkpoint inhibitor).

[0097] Examples of anti-cancer agents include platinum compounds (e.g., cisplatin, carboplatin, oxaliplatin), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, nitrogen mustard, thiotepa, melphalan, busulfan, procarbazine, streptozocin, temozolomide, dacarbazine, bendamustine), antitumor antibiotics (e.g., daunorubicin, doxorubicin, idarubicin, epirubicin, mitoxantrone, bleomycin, mitomycin C, plicamycin, dactinomycin), taxanes (e.g., paclitaxel and docetaxel), antimetabolites (e.g., 5-fluorouracil, cytarabine, pemetrexed, thioguanine, floxuridine, capecitabine, and methotrexate), nucleoside analogues (e.g., fludarabine, clofarabine, cladribine, pentostatin, nelarabine), topoisomerase inhibitors (e.g., topotecan and irinotecan), hypomethylating agents (e.g., azacitidine and decitabine), proteosome inhibitors (e.g., bortezomib), epipodophyllotoxins (e.g., etoposide and teniposide), DNA synthesis inhibitors (e.g., hydroxyurea), vinca alkaloids (e.g., vincristine, vindesine, vinorelbine, and vinblastine), tyrosine kinase inhibitors (e.g., imatinib, dasatinib, nilotinib, sorafenib, sunitinib), monoclonal antibodies (e.g., rituximab, cetuximab,panitumumab, tositumomab, trastuzumab, alemtuzumab, gemtuzumab ozogamicin, bevacizumab), nitrosoureas (e.g., carmustine, fotemustine, and lomustine), enzymes (e.g., L- Asparaginase), biological agents (e.g., interferons and interleukins), hexamethylmelamine, mitotane, angiogenesis inhibitors (e.g., thalidomide, lenalidomide), steroids (e.g., prednisone, dexamethasone, and prednisolone), hormonal agents (e.g., tamoxifen, raloxifene, leuprolide, bicalutamide, granisetron, flutamide), aromatase inhibitors (e.g., letrozole and anastrozole), arsenic trioxide, tretinoin, nonselective cyclooxygenase inhibitors (e.g., nonsteroidal antiinflammatory agents, salicylates, aspirin, piroxicam, ibuprofen, indomethacin, naprosyn, diclofenac, tolmetin, ketoprofen, nabumetone, oxaprozin), selective cyclooxygenase-2 (COX- 2) inhibitors, cellular immunotherapy (e.g., chimeric antigen receptor T cell therapy, chimeric antigen receptor NK cell therapy, tumor-infiltrating lymphocyte therapy, or the like), TLR agonists (e.g., CpG ODNs), immune checkpoint inhibitors (e.g., anti-PD-1 inhibitors (e.g., antibodies), anti-PD-Ll inhibitors (e.g., antibodies) or anti-CTLA-4 inhibitors (e.g., antibodies), mRNA (e.g., mRNA coding for immune activating agents), antibodies targeting myeloid cells, antibodies targeting macrophages, antibodies targeting monocytes, antibodies targeting regulatory T cells, antibodies targeting B cells, antibodies targeting NK cells, antibodies targeting NKT cells, antibodies targeting innate lymphoid cells, T cell engagers, chemokines, cytokines, oncolytic virus therapies, or any combination thereof. In some aspects, the anti-cancer agent is cisplatin, cytarabine, methotrexate, doxorubicin, or a combination thereof. In other aspects, the anti -cancer agent is an immunotherapeutic agent such as a TLR agonist or an immune checkpoint inhibitor.

[0098] In another aspect, the invention provides methods of treating an infectious disease (e.g., a multi-drug resistant infection) in a subject, the method comprising administering to the subject a compound or pharmaceutical composition of the invention. Without being bound by a particular theory or mechanism, it is believed that the compounds activate mucosal-associated invariant T (MAIT) cells thereby aiding in the treatment of infectious diseases such as tuberculosis and other bacterial, viral and fungal infections. Exemplary infectious diseases include, but are not limited to, salmonellas, shigellas, Clostridium difficile, mycobacteria (e.g., tuberculosis), protozoa (e.g., malaria), thread-shaped threadworms (e.g., filariasis), schistosomes (e.g., schistosomiasis), toxoplasmas (e.g., toxoplasmosis), leishmania (e.g., leishmaniasis), HCV and HBC (e.g., hepatitis C and hepatitis B), and herpes simplex viruses (e.g., herpes). In some aspects, the infectious disease is tuberculosis.

[0099] In some aspects, the compounds disclosed herein (e.g., the compounds of Formula (III)) exhibit MR1 upregulation; however, the compounds do not activate or expand MAIT cells. In such a situation, the compounds disclosed herein (e.g., the compounds of Formula (III)) may provide therapeutic benefits by acting as non-agonist ligands. Thus, the invention also provides a method for the prevention or treatment of a condition associated with a lack of MR1 -specific T cell responses, or with too much of an MR1 -specific T cell response, comprising administering a compound disclosed herein (e.g., a compound of Formula (III)) to a subject. For example, the compounds disclosed herein (e.g., the compounds of Formula (III)) can be used to prevent or treat diseases where MAIT cell activation is pathogenic, including for example autoimmune diseases and inflammatory disorders such as inflammatory bowel disease, multiple sclerosis, and rheumatoid arthritis. Without wishing to be bound by any particular theory, it is believed that the compounds disclosed herein (e.g., the compounds of Formula (III)) which exhibit MR1 upregulation, but do not activate or expand MAIT cells, can aid in reduction of tissue inflammation associated with such diseases and disorders.

[0100] In certain aspects of the invention, the compounds of aspects of the invention, or pharmaceutically acceptable salts thereof, can be attached to targeting molecules. Such targeting molecules include antibodies (for ADCs).

[0101] In some aspects, the subject is a mammal. As used herein, the term “mammal” refers to any mammal, including, but not limited to, mammals of the order Rodentia, including mice and hamsters, mammals of the order Logomorpha, including rabbits, mammals from the order Carnivora, including Felines (cats) and Canines (dogs), mammals from the order Artiodactyla, including Bovines (cows) and Swines (pigs), mammals from the order Perssodactyla, including Equines (horses), mammals of the order Primates, Ceboids, or Simoids (monkeys), and mammals of the order Anthropoids (humans and apes). An especially preferred mammal is the human.Examples of Non-Limiting Aspects of the Disclosure

[0102] Aspects of the present subject matter described herein may be beneficial alone or in combination, with one or more other aspects. Without limiting the foregoing description, certain non-limiting aspects of the disclosure numbered 1-29 are provided below. As will be apparent to those of skill in the art upon reading this disclosure, each of the individually numbered aspects may be used or combined with any of the preceding or followingindividually numbered aspects. This is intended to provide support for all such combinations of aspects and is not limited to combinations of aspects explicitly provided below:

[0103] (1) A compound of Formula (I):a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R0is hydrogen or a C1-C6alkyl group,R1is a C2-C5alkyl group substituted with 1 to 4 hydroxyl groups, R2and R3combine to form a C3-C8cycloalkyl group, a 3-6 membered heterocylic group, an aryl group, or a heteroaryl group, each of which is optionally substituted with one or more substituents selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, difluoromethyl, trifluoromethyl, C1-C6alkoxy, arylated C1-C6alkoxy, trifluoromethylated C1-C6alkoxy, - C(O)OH, -C(O)O-(C1-C6alkyl), -C(O)-(C1-C6alkyl), -(C1-C3alkyl)-C(O)OH, -(C1-C3alkyl)- C(O)O-(C1-C6alkyl), -(C1-C3alkyl)-C(O)-(C1-C6alkyl), -NH-C(O)OH, -NH-C(O)O-(C1-C6alkyl), -NH-C(O)-(C1-C6alkyl), -(C1-C3alkyl)-NH-C(O)OH, -(C1-C3alkyl)-NH-C(O)O-(C1- C6alkyl), -(C1-C3alkyl)-NH-C(O)-(C1-C6alkyl), -(C1-C6alkyl)-O-(C1-C6alkyl), -O-(C1-C6alkyl)-O-(C1-C6alkyl), -(C1-C6alkyl)-OH, -(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-COOH, - (C1-C6alkyl)-C(O)O-(C1-C6alkyl), -(C1-C6alkyl)-(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)- NH2, -(C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)-(C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)- heterocycloalkyl, -(C1-C6alkyl)-heterocycloalkyl-(C1-C6alkyl), -(C1-C6alkyl)-C(O)- heterocycloalkyl, -(C1-C6alkyl)-C(O)-heterocycloalkyl-(C1-C6alkyl), halo, nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; -NH-aryl, -NH-heterocycloalkyl, -NH- heterocycloalkyl-(C1-C6alkyl), -C1-C6haloalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, aryl, heteroaryl, -CN, -(C1-C3alkyl)-CN, carbonyl, amino acid, amino acid methyl ester, and a combination thereof, and R4is absent, hydrogen, or a C1-C6alkyl group.

[0104] (2) The compound of aspect 1, a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R1is selected from:

[0105] (3) The compound of aspect 1, a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R1is

[0106] (4) The compound of any one of aspects 1-3, a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R2and R3combine to form a C3-C8cycloalkyl group, a 3-6 membered heterocylic group, an aryl group, or a heteroaryl group, each of which is optionally substituted with one or more substituents selected from C1-C6alkyl, trifluoromethyl, C1-C6alkoxy, -C(O)-(C1-C6alkyl), halo, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino, and a combination thereof.

[0107] (5) The compound of any one of aspects 1-3, a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R2and R3combine to form a C3-C6cycloalkyl group, which is optionally substituted with one or more substituents selected from C1-C6alkyl, trifluoromethyl, C1-C6alkoxy, -C(O)-(C1-C6alkyl), halo, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino, and a combination thereof, and R4is hydrogen or a C1-C6alkyl group.

[0108] (6) The compound of any one of aspects 1-3, a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R2and R3combine to form a C3-C6cycloalkyl group, which is optionally substituted with one or more substituents selected from C1-C6alkyl, trifluoromethyl, halo, and a combination thereof, andR4is hydrogen or a C1-C6alkyl group.

[0109] (7) The compound of any one of aspects 1-3, a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R2and R3combine to form a C3-C6cycloalkyl group, and R4is hydrogen or a C1-C6alkyl group.

[0110] (8) The compound of any one of aspects 1-3, a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R2and R3combine to form a a 3-6 membered heterocylic group, which is optionally substituted with one or more substituents selected from C1-C6alkyl, trifluoromethyl, C1-C6alkoxy, -C(O)-(C1-C6alkyl), halo, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; and a combination thereof, and R4is hydrogen or a C1-C6alkyl group.

[0111] (9) The compound of any one of aspects 1-3, a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R2and R3combine to form a an aryl group, which is optionally substituted with one or more substituents selected from C1-C6alkyl, trifluoromethyl, C1-C6alkoxy, -C(O)-(C1-C6alkyl), halo, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino, and a combination thereof, and R4is absent.

[0112] (10) The compound of any one of aspects 1-3, a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R2and R3combine to form a heteroaryl group, which is optionally substituted with one or more substituents selected from C1-C6alkyl, trifluoromethyl, C1-C6alkoxy, -C(O)-(C1- Ce alkyl), halo, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino, and a combination thereof, and R4is absent.

[0113] (11) The compound of aspect 1, wherein the compound is selected fromCompounds A, C, F, H, I, K, L-N, V-Y, AH, AJ-AL, and CA-CL, a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

[0114] (12) A compound of Formula (II):a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R0is hydrogen or a C1-C6alkyl group, R5is a C2-C5alkyl group substituted with 1 to 4 hydroxyl groups, and R6, R7, and R8are each independently selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, difluoromethyl, trifluoromethyl, C1-C6alkoxy, arylated C1-C6alkoxy, trifluoromethylated C1-C6alkoxy, -C(O)OH, -C(O)O-(C1-C6alkyl), -C(O)-(C1-C6alkyl), - (C1-C3alkyl)-C(O)OH, -(C1-C3alkyl)-C(O)O-(C1-C6alkyl), -(C1-C3alkyl)-C(O)-(C1-C6alkyl), -NH-C(O)OH, -NH-C(O)O-(C1-C6alkyl), -NH-C(O)-(C1-C6alkyl), -(C1-C3alkyl)- NH-C(O)OH, -(C1-C3alkyl)-NH-C(O)O-(C1-C6alkyl), -(C1-C3alkyl)-NH-C(O)-(C1-C6alkyl), -(C1-C6alkyl)-O-(C1-C6alkyl), -O-(C1-C6alkyl)-O-(C1-C6alkyl), -(C1-C6alkyl)-OH, - (C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-COOH, -(C1-C6alkyl)-C(O)O-(C1-C6alkyl), -(C1-C6alkyl)-(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-NH2, -(C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)- (C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)-heterocycloalkyl, -(C1-C6alkyl)-heterocycloalkyl- (C1-C6alkyl), -(C1-C6alkyl)-C(O)-heterocycloalkyl, -(C1-C6alkyl)-C(O)-heterocycloalkyl- (C1-C6alkyl), halo, nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; -NH- aryl, -NH-heterocycloalkyl, -NH-heterocycloalkyl-(C1-C6alkyl), -C1-C6haloalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, aryl, heteroaryl, -CN, -(C1-C3alkyl)-CN, carbonyl, amino acid, amino acid methyl ester, and a combination thereof, and wherein the compound of Formula (II) is not 5-(2-oxopropylideneamino)-6-D- ribity laminouracil .

[0115] (13) The compound of aspect 12, wherein the compound is selected fromCompounds B, D, E, G, J, O-U, Z, AA-AG, Al, and CM-CP, a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

[0116] (14) A compound of Formula (III):a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, whereinX is absent, -CH2-, or -C(O)-, R0is hydrogen or a C1-C6alkyl group, R9is a C3-C8cycloalkyl group, a 3-6 membered heterocylic group, or a heteroaryl group, each of which is optionally substituted with one or more substituents selected from hydroxy, oxo, and a combination thereof, and(i) R10, R11, and R12 are each independently selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, difluoromethyl, trifluoromethyl, C1-C6alkoxy, arylated C1-C6alkoxy, trifluoromethylated C1-C6alkoxy, -C(O)OH, -C(O)O-(C1-C6alkyl), -C(O)-(C1-C6alkyl), -(C1-C3alkyl)-C(O)OH, -(C1-C3alkyl)-C(O)O-(C1-C6alkyl), -(C1-C3alkyl)-C(O)-(C1- C6alkyl), -NH-C(O)OH, -NH-C(O)O-(C1-C6alkyl), -NH-C(O)-(C1-C6alkyl), -(C1-C3alkyl)- NH-C(O)OH, -(C1-C3alkyl)-NH-C(O)O-(C1-C6alkyl), -(C1-C3alkyl)-NH-C(O)-(C1-C6alkyl), -(C1-C6alkyl)-O-(C1-C6alkyl), -O-(C1-C6alkyl)-O-(C1-C6alkyl), -(C1-C6alkyl)-OH, - (C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-COOH, -(C1-C6alkyl)-C(O)O-(C1-C6alkyl), -(C1-C6alkyl)-(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-NH2, -(C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)- (C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)-heterocycloalkyl, -(C1-C6alkyl)-heterocycloalkyl- (C1-C6alkyl), -(C1-C6alkyl)-C(O)-heterocycloalkyl, -(C1-C6alkyl)-C(O)-heterocycloalkyl- (C1-C6alkyl), halo, nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; -NH- aryl, -NH-heterocycloalkyl, -NH-heterocycloalkyl-(C1-C6alkyl), -C1-C6haloalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, aryl, heteroaryl, -CN, -(C1-C3alkyl)-CN, carbonyl, amino acid, amino acid methyl ester, and a combination thereof or(ii) R10and R11combine to form a C3-C8cycloalkyl group, a 3-6 membered heterocylic group, an aryl group, or a heteroaryl group, each of which is optionallysubstituted with one or more substituents selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, difluoromethyl, trifluoromethyl, C1-C6alkoxy, arylated C1-C6alkoxy, trifluoromethylated C1-C6alkoxy, -C(O)OH, -C(O)O-(C1-C6alkyl), -C(O)-(C1-C6alkyl), - (C1-C3alkyl)-C(O)OH, -(C1-C3alkyl)-C(O)O-(C1-C6alkyl), -(C1-C3alkyl)-C(O)-(C1-C6alkyl), -NH-C(O)OH, -NH-C(O)O-(C1-C6alkyl), -NH-C(O)-(C1-C6alkyl), -(C1-C3alkyl)- NH-C(O)OH, -(C1-C3alkyl)-NH-C(O)O-(C1-C6alkyl), -(C1-C3alkyl)-NH-C(O)-(C1-C6alkyl), -(C1-C6alkyl)-O-(C1-C6alkyl), -O-(C1-C6alkyl)-O-(C1-C6alkyl), -(C1-C6alkyl)-OH, - (C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-COOH, -(C1-C6alkyl)-C(O)O-(C1-C6alkyl), -(C1-C6alkyl)-(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-NH2, -(C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)- (C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)-heterocycloalkyl, -(C1-C6alkyl)-heterocycloalkyl- (C1-C6alkyl), -(C1-C6alkyl)-C(O)-heterocycloalkyl, -(C1-C6alkyl)-C(O)-heterocycloalkyl- (C1-C6alkyl), halo, nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; -NH- aryl, -NH-heterocycloalkyl, -NH-heterocycloalkyl-(C1-C6alkyl), -C1-C6haloalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, aryl, heteroaryl, -CN, -(C1-C3alkyl)-CN, carbonyl, amino acid, amino acid methyl ester, and a combination thereof, and R12is absent, hydrogen, or a C1-C6alkyl group.

[0117] (15) The compound of aspect 14, wherein the compound is selected fromCompounds AM-BZ and CQ-DF, a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

[0118] (16) A pharmaceutical composition comprising a compound of any one of aspects1-15, a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutical carrier.

[0119] (17) The pharmaceutical composition of aspect 16, wherein the pharmaceutical composition further comprises a TLR agonist.

[0120] (18) The pharmaceutical composition of aspect 17, wherein the TLR agonist is aTLR9 agonist.

[0121] (19) The pharmaceutical composition of aspect 17 or aspect 18, wherein the TLR agonist is a cytosine-phosphate-guanine (CpG) dinucleotide.

[0122] (20) A method of activating mucosal-associated invariant T (MAIL) cells in a subject, the method comprising administering to the subject a compound of any one of aspects 1-15, a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of aspects 16-19.

[0123] (21) The method of aspect 20, wherein the method comprises upregulating MHC class I-related protein 1 (MR1) in the subject.

[0124] (22) A method of treating cancer in a subject, the method comprising administering to the subject a compound of any one of aspects 1-15, a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of aspects 16-19.

[0125] (23) The method of aspect 22, wherein the method comprises activating MAIT cells in the subject.

[0126] (24) The method of aspect 22 or aspect 23, wherein the method comprises upregulating MR1 in the subject.

[0127] (25) The method of any one of aspects 22-24, wherein the cancer is liver cancer.

[0128] (26) A method of treating an infectious disease in a subject, the method comprising administering to the subject a compound of any one of aspects 1-15, a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of aspects 16-19.

[0129] (27) The method of aspect 26, wherein the method comprises activating MAIT cells in the subject.

[0130] (28) The method of aspect 26 or aspect 27, wherein the infectious disease is tuberculosis

[0131] (29) The method of any one of aspects 20-28, wherein the subject is human.EXAMPLES

[0132] The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.

[0133] General procedure for ultra-performance liquid chromatography (UPLC) ofExamples 1-76:Table 1. Method-AEXAMPLE 1

[0135] This example provides an exemplary synthesis of 5-amino-6-(((2S,3 S,4R)-2, 3,4,5- tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (5-A-RU), which is used as a starting material in other syntheses.Scheme 1: Preparation of 5-amino-6-(((2S, 3 S,4R)-2,3,4,5- tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (5-A-RU)

[0136] Preparation of (2R,3S,4S)-5-(benzylamino)pentane-l,2,3,4-tetraol (3): To a stirred solution of (3R,4S,5R)-5-(hydroxymethyl)tetrahydrofuran-2,3,4-triol (20.0 g, 133 mmol) and benzylamine (14.2 g, 133 mmol) in methanol (200 mL) was added platinum (IV) oxide (4.00 g) under an argon atmosphere. The reaction was placed under hydrogen atmosphere using balloon and stirred at room temperature for 24 hours. The mixture was filtered through celite. The obtained filtrate was concentrated to give a crude material which was triturated with methyl tert-butyl ether. The solid was collected by filtration and dried under reduced pressure to afford (2R,3S,4S)-5-(benzylamino)pentane-1,2,3,4-tetraol (24.0 g, Yield: 75%) as an off-white solid. MS (ESI) m / z 242 [C12H19NO4 + H]+.

[0137] Preparation of (2R,3S,4S)-5-aminopentane-l,2,3,4-tetraol (4): To a stirred solution of (2R,3S,4S)-5-(benzylamino)pentane-l,2,3,4-tetraol (14.0 g, 58.0 mmol) in methanol (200 mL) was added palladium hydroxide (20% on charcoal, 2.80 g) under an argon atmosphere. Aqueous ammonium hydroxide solution (1 mL) was added to the reaction and stirred under hydrogen atmosphere using a balloon at room temperature for 24 hours. The reaction mixture was filtered through celite. The obtained filtrate was concentrated to give (2R,3S,4S)-5-aminopentane-l,2,3,4-tetraol as a viscous oil. (8.00 g, crude). This crude material was used directly without further purification. MS (ESI) m / z 152 [C5H13NO4 + H]+.

[0138] Preparation of 5-nitro-6-(((2S,3S,4R)-2, 3,4,5- tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (6): Potassium hydroxide (2N in water, 2.60 mL, 5.20 mmol) was added dropwise to a stirred solution of (2R,3S,4S)-5- aminopentane-1,2,3,4-tetraol (0.80 g, 5.29 mmol) and 6-chloro-5-nitropyrimidine- 2,4(1H,3H)-dione (1.01 g, 5.29 mmol) in ethanol (8 mL) and water (3 mL). The reactionmixture was stirred at 80 °C for 8 hours. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The mixture was cooled to room temperature and the solid precipitate was collected by filtration. The solid was washed with ethanol and dried under reduced pressure to afford 5-nitro-6-(((2S,3 S,4R)-2, 3,4,5- tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (0.70 g, Yield: 44%) as an off-white solid. MS (ESI) m / z 307 [C9H14N4O8+ H]+.

[0139] Preparation of 5-amino-6-(((2S,3S,4R)-2, 3,4,5- tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (5-A-RU): To a solution of 5-nitro-6-(((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)- dione (0.70 g, 2.3 mmol) in IN aqueous hydrochloric acid (3 mL) under an argon atmosphere was added 10% palladium on charcoal (0.15 g) at room temperature. The mixture was placed under a hydrogen atmosphere using a balloon and stirred at room temperature for 16 hours. The reaction turned pink in color. The resulted solution was filtered through celite. The filtrate was concentrated under reduced pressure to afford 5-amino-6-(((2S,3 S,4R)-2, 3,4,5- tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (0.65 g, crude) as a pink solid. MS (ESI) m / z 277 [C9H17CIN4O6 + H]+.EXAMPLE 2

[0140] This example provides an exemplary synthesis for Compound A.Scheme 2:2,3,4,5-tetrahydroxypentvl) amino) pyrimidine-2,4(1H,3H)-dione (Compound A)

[0141] Preparation of 5-(((E)-2-cyclopropyl-2-oxoethylidene)amino)-6-(((2S,3S,4R)-2, 3, 4, 5-tetrahydroxypentyl)amino)pyrimidine-2, 4(1H, 3H) -dione ( Compound A) : 5 -Amino-6- (((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (0.10 g, 0.32 mmol) in dimethyl sulfoxide (0.50 mL) was treated with IN aqueous sodium hydroxide solution to adjust to pH ~8 at room temperature. 2-Cyclopropyl-2- oxoacetaldehyde (0.04 g, 0.38 mmol) was added dropwise, and the reaction was stirred atroom temperature for 2 hours. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 lOum 150*30mm, Mobile phase A: ACN, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The fractions containing pure product were dried by lyophilization to afford 5-(((E)-2-cyclopropyl-2-oxoethylidene) amino)-6-(((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl) amino) pyrimidine-2,4(1H,3H)-dione (27.0 mg, Yield: 23.0%) as a yellow solid.1H-NMR (400 MHz, D2O): δ 8.90 (s, 1H), 3.89 - 3.85 (m, 1H), 3.80 - 3.71 (m, 2H), 3.65-3.54 (m, 4H), 2.96 - 2.90 (m 1H), 1.03 (t, J = 8.4 Hz, 4H); MS (ESI) m / z 357.1 [C14H20N4O7 + H]+; Chiral Purity: >99% (Method-B).EXAMPLE 3

[0142] This example provides an exemplary synthesis for Compound B.Scheme 3 : Preparation of 5-(((E)-2-oxobutylidene)amino)-6-(((2S,3S,4R)-2,3,4,5- tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (Compound B)

[0143] Preparation of 5-( ( fE)-2-oxobutylidene)amino)-6-( ( (2S, 3S, 4R)-2, 3, 4, 5- tetrahydroxypentyl)amino)pyrimidine-2, 4(1H, 3H)-dione ( Compound B) : The solution of 5- amino-6-(((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (0.10 g, 0.32 mmol) in dimethyl sulfoxide (0.50 mL) was treated with IN aqueous sodium hydroxide solution to adjust to pH ~8 at room temperature. 2-Oxobutanal (0.03 g, 0.38 mmol) was added dropwise, and the reaction was stirred at room temperature for 2 hours. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 10um 150*30mm, Mobile phase A: ACN, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The fractions containing pure product were dried by lyophilization to afford 5-(((E)-2- oxobutylidene)amino)-6-(((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine- 2,4(1H,3H)-dione (12.0 mg, Yield: 11.0%) as a yellow solid.1H-NMR (400 MHz, D2O): δ8.75 (s, 1H), 3.96 - 3.87 (m, 1H), 3.83 - 3.73 (m, 2H), 3.67 - 3.51 (m, 4H), 2.84 (q, J 132Hz, 14.72 Hz, 2H),), 1.01 (t, J = 7.6 Hz, 3H); MS (ESI) m / z 345.1 [C13H20N4O7 + H]+; Chiral Purity: >99% (Method-B).EXAMPLE 4

[0144] This example provides an exemplary synthesis for Compound E.Scheme 4: Preparation of 5-(((E)-3,3-Dimethyl-2-oxobutylidene)amino)-6-(((2S,3 S,4R)-2,3,4,5-tetrahvdroxvpentvl)amino)pyrimidine-2,4(1H,3H)-dione (Compound E)

[0145] Preparation of 3, 3 -Dimethyl-2 -oxobutanal: To a solution of selenium dioxide(11.2 g, 100 mmol) in 1,4-di oxane (95 mL) and water (5 mL), was added 4,4- dimethylpentane-2,3-dione (10.0 g, 100 mmol) at room temperature. The reaction was heated to 100 °C for 16 hours and the progress of the reaction was monitored by TLC. The reaction was cooled to room temperature and passed through diatomaceous earth. The filtrate under fractional distillation provided 3,3-dimethyl-2-oxobutanal (6 mL with traces of dioxane) at 140 °C as a pale-yellow oil. The product with traces of dioxane was used directly for the next step.

[0146] Preparation of 5-( ( (E)-3, 3-Dimethyl-2-oxobutylidene)amino)-6-( ( (2S, 3S, 4R)- 2,3,4,5-tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (Compound E) : The stirred solution of 5-amino-6-(((2S,3S,4S)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)- dione hydrochloride (350 mg, 1.21 mmol) and 3,3-dimethyl-2-oxobutanal (0.80 mL with traces of dioxane) in dimethyl sulfoxide (2 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred at room temperature for 30 minutes. The reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini -NX C18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried bylyophilization to afford 5-(((E)-3,3-dimethyl-2-oxobutylidene)amino)-6-(((2S,3S,4R)-2,3,4,5- tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (90.0 mg, 21%) as a yellow solid:1H NMR (400 MHz, DMSO-d6) δ 10.58 (br s, 1H), 9.15 (s, 1H), 7.17 (m, 1H), 5.44 - 4.61 (m, 3H), 4.42 (br s, 1H), 3.81 - 3.77 (m, 1H), 3.63 - 3.58 (m, 2H), 3.53 - 3.39 (m, 4H), 1.23 (s, 9H) (one amidic NH was not detecting);13C NMR (100 MHz, DMSO-d6) δ 204.88, 158.99, 155.58, 150.24, 142.16, 98.32, 73.24, 73.03, 70.50, 63.66, 44.16, 42.94, 27.57; MS (ESI) m / z 373 [C15H24N4O7 + H]+; UPLC (Method-G) 96.6% (AUC) fe = 2.11 min.EXAMPLE 5

[0147] This example provides an exemplary synthesis for Compound F.Scheme 5: Preparation of 5-(((E)-2-Oxo-2-(thiophen-2-yl)ethylidene)amino)-6-(((2S,3S,4R)-2,3,4,5-tetrahvdroxvpentvl)amino)pyrimidine-2,4(1H,3H)-dione (Compound F)

[0148] Preparation of 2-Oxo-2-(thiophen-2-yl)acetaldehyde : The stirred solution of selenium dioxide (8.79 g, 79.2 mmol) in mixture of 1,4-dioxane (90 mL) and water (10 mL) was heated to 85 °C for 1 hour. Then, 1-(thiophen-2-yl)ethan-1-one (10.0 g, 79.2 mmol) was added to the reaction at same temperature. The reaction was heated to 85 °C for 16 hours. The reaction was cooled to room temperature and passed through diatomaceous earth. The filtrate under fractional distillation provided 2-oxo-2-(thiophen-2-yl) acetaldehyde (4 mL with traces of dioxane) at 140 °C as a pale-yellow oil. The product with traces of dioxane was used directly for the next step.

[0149] Preparation of 5-(((E)-2-Oxo-2-(thiophen-2-yl)ethylidene)amino)-6-(((2S,3S,4R)- 2,3,4,5-tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (Compound F) : The stirred solution of 5-amino-6-(((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine- 2,4(1H,3H)-dione hydrochloride (300 mg, 0.96 mmol) and 2-oxo-2-(thiophen-2- yl)acetaldehyde (2 mL with traces of 1,4-dioxane) in dimethyl sulfoxide (2 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature.The reaction was stirred for 15 minutes. The reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford 5-(((E)-2-oxo-2-(thiophen-2-yl)ethylidene)amino)-6-(((2S,3S,4R)- 2,3,4,5-tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (95.2 mg, 24%) as a pale yellow solid:1H NMR (400 MHz, DMSO-d6) δ 10.53 (br s, 1H), 9.24 (s, 1H), 7.97 (dd, J = 1.2, 3.8 Hz, 1H), 7.92 (dd, J = 0.8, 5.0 Hz, 1H), 7.22 (dd, J = 4.0, 4.8 Hz, 1H), 7.19 (s, 1H), 5.09 (br s, 2H), 4.44 (br s, 1H), 3.84 - 3.81 (m, 1H), 3.67 - 3.51 (m, 4H), 3.47 - 3.40 (m, 2H) (one amidic proton and one hydroxy proton were not detected);13C NMR (100 MHz, DMSO-d6) δ 182.26, 158.31, 156.13, 150.30, 141.22, 138.07, 134.31, 132.82, 126.88, 98.76, 72.27, 71.77, 69.95, 62.53, 43.26; MS (ESI) m / z 399 [C15H18N4O7S + H]+; UPLC (Method-A) 97.7% (AUC) tR= 3.07 min.EXAMPLE 6

[0150] This example provides an exemplary synthesis for Compound G.Scheme 6: Preparation of 5-(((E)-2-Oxo-3-phenylpropylidene)aminc2,3,4,5-tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (Compound G)

[0151] The stirred solution of 5-amino-6-(((2S,3 S,4R)-2, 3,4,5- tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (300 mg, 0.96 mmol) and 2-oxo-3-phenylpropanal (150 mg, 1.05 mmol) in dimethyl sulfoxide (2 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 15 minutes and the reaction progress was monitored by UPLC- MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford 5-(((E)-2-oxo-3-phenylpropylidene)amino)-6-(((2S,3S,4R)- 2,3,4,5-tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (84.5 mg, 21%) as a yellowsolid: 'HNMR (400 MHz, DMSO-d6) δ 10.63 (hr s, 1H), 8.87 (s, 1H), 7.77 (hr s, 1H), 7.30 - 7.17 (m, 5H), 5.61 - 4.43 (m, 3H), 4.16 (q, J = 14.8 Hz, 2H), 3.86 - 3.82 (m, 1H), 3.70 - 3.48 (m, 5H), 3.47 - 3.37 (m, 1H) (one NH and one OH were not detected);13C NMR (100 MHz, DMSO): 6 200.01, 159.10, 155.63, 150.27, 143.23, 136.66, 130.16, 128.65, 126.54, 98.59, 73.60, 73.17, 70.15, 63.58, 44.81, 42.14, MS (ESI) m / z 407 [C18H22N4O7 + H]+; UPLC (Method-A) 95.2% (AUC) tR= 3.21 min; Chiral HPLC (Method-C) 95.6% (AUC) tR= 12.21 min.EXAMPLE 7

[0152] This example provides an exemplary synthesis for Compound H.Scheme 7: Preparation of 5-(((E)-2-Oxo-2-(piperidin-4-yl)ethylidene)amino)-6- (((2S,3S,4R)-2,3,4,5-tetrahvdroxvpentvl)amino)pyrimidine-2,4(1H,3H)-dione (Compound H)

[0153] Preparation of tert-Butyl 4-(2-oxoacetyl)piperidine-l -carboxylate: To a stirred solution of tert-butyl 4-acetylpiperidine-l -carboxylate (2.00 g, 8.81 mmol) in 1,4-dioxane (20 mL), was added selenium dioxide (1.93 g, 17.62 mmol) at room temperature. The reaction was heated to 85 °C for 16 hours and the progress of the reaction was monitored by thin layer chromatography and UPLC-MS. The reaction was cooled to room temperature and filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to give tert-butyl 4-(2-oxoacetyl) piperidine- 1 -carboxylate (1.85 g, crude) as a yellow semi solid: MS (ESI) m / z 242 [C12H19NO4 + H]+. The crude material was used directly without purification.

[0154] Preparation of tert-Butyl 4-((E)-2-((2,4-dioxo-6-(((2S,3S,4R)-2,3,4,5- tetrahydroxypentyl)amino)-1,2,3,4-tetrahydropyrimidin-5-yl)imino)acetyl)piperidine-l- carboxylate: To a stirred solution of 5-amino-6-(((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (300 mg, 1.08 mmol) in dimethyl sulfoxide (0.60 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. tert-Butyl 4-(2-oxoacetyl)piperidine-1- carboxylate (390 mg, 1.82 mmol) was added dropwise to the reaction and stirred for 15 minutes. The reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford tertbutyl 4-((E)-2-((2,4-dioxo-6-(((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)amino)-l,2,3,4- tetrahydropyrimidin-5-yl)imino)acetyl)piperidine-1-carboxylate (94.0 mg, 17%) as a yellow solid.

[0155] Preparation of 5-(((E)-2-Oxo-2-(piperidin-4-yl)ethylidene )amino)-6-(((2S,3S,4R)- 2,3,4,5-tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (Compound H): The stirred solution of tert-butyl 4-((E)-2-((2,4-dioxo-6-(((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)amino)- 1,2,3,4-tetrahydropyrimidin-5-yl)imino)acetyl)piperidine-1-carboxylate (90.0 mg, 0.18 mmol) in 2,2,2-triflouroethanol (1 mL) was treated with trimethyl silyl chloride (0.13 mL) at 0 °C.The reaction was stirred for 10 minutes and the reaction progress was monitored by UPLC- MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX C18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The fractions containing pure product were dried by lyophilization to afford 5-(((E)-2-oxo-2-(piperidin-4- yl)ethylidene)amino)-6-(((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine- 2,4(1H,3H)-dione (24.0 mg, 26%) as yellow solid:1H NMR (400 MHz, D2O) δ 8.74 (s, 1H), 3.89 (q, J = 6.0 Hz, 1H), 3.80 - 3.50 (m, 7H), 3.46 - 3.43 (m, 2H), 3.14 - 3.07 (m, 2H), 2.06 - 2.03 (m, 2H), 1.82 - 1.72 (m, 2H); MS (ESI) m / z 400 [C16H25N5O7 + H]+; UPLC (Method-A) 95.2% (AUC) tR= 1.72 min.EXAMPLE 8

[0156] This example provides an exemplary synthesis for Compound J.Scheme 8: Preparation of 5-(((E)-3-Methyl-2-oxobutylidene)amino)-6-(((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (Compound J)

[0157] The stirred solution of 5-amino-6-(((2S,3 S,4R)-2, 3,4,5- tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (300 mg, 0.96 mmol) and 3-methyl-2-oxobutanal (1 mL with traces of 1,4-di oxane) in dimethyl sulfoxide (3 mL) was adjusted to pH ~9 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 30 minutes and the reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford 5-(((E)-3-methyl-2-oxobutylidene)amino)-6- (((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (95.0 mg, 12%) as a pale yellow solid:1H NMR (400 MHz, D2O) δ 8.80 (s, 1H), 3.90 - 3.86 (m, 1H), 3.81 - 3.72 (m, 2H), 3.66 - 3.51 (m, 5H), 1.57 (d, J = 6.8 Hz, 6H); MS (ESI) m / z 359 [C14H22N4O7 + H]+; UPLC (Method-A) 98.0% (AUC) tR= 2.74 min.EXAMPLE 9

[0158] This example provides an exemplary synthesis for Compound K.Scheme 9: Preparation of 5-(((E)-2-Cyclobutyl-2-oxoethylidene)amino)-6-(((2S,3 S,4R)-2,3,4,5-tetrahvdroxvpentvl)amino)pyrimidine-2,4(1H,3H)-dione (Compound K)

[0159] Preparation of 2 -Cyclobuty 1-2 -oxoacetaldehyde : The stirred solution of selenium dioxide (2.26 g, 20.4 mmol) in 1,4-dioxane (18 mL) and water (2 mL) was heated to 60 °C for 1 hour. 1-Cyclobutylethan-1-one (2.00 g, 20.4 mmol) was added to the reaction at same temperature. The reaction was heated to 90 °C for 16 hours, cooled to room temperature and filtered through diatomaceous earth. The filtrate under fractional distillation provided 2- cyclobutyl-2-oxoacetaldehyde (5 mL with traces of dioxane) at 140 °C as a pale-yellow oil. The product with traces of dioxane was used directly for the next step without further purification.

[0160] Preparation of 5-(((E)-2-Cyclobutyl-2-oxoethylidene)amino)-6-(((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (Compound K) : The stirred solution of 5-amino-6-(((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine- 2,4(1H,3H)-dione hydrochloride (400 mg, 1.28 mmol) and 2-cyclobutyl-2-oxoacetaldehyde (4 mL with traces of dioxane) in dimethyl sulfoxide (3 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 15 minutes and the reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 10μm 150*30mm, Mobile phase A: ACN, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried under lyophilization to afford 5-(((E)-2-cyclobutyl-2-oxoethylidene)amino)-6-(((2S,3S,4R)-2,3,4,5- tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (78.7 mg, 16%) as a pale yellow solid:1H NMR (400 MHz, DMSO-d6) δ 10.53 (br s, 1H), 8.78 (s, 1H), 7.51 (s, 1H), 5.35 - 5.05 (m, 2H), 4.23 - 4.15 (m, 1H), 3.83 - 3.79 (m, 1H), 3.66 - 3.60 (m, 2H), 3.54 - 3.40 (m, 4H), 2.16 - 2.09 (m, 4H), 2.06 - 1.94 (m, 1H), 1.80 - 1.76 (m, 1H) (one amidic NH and two OH’s were not detected);13C NMR (100 MHz, DMSO-d6) δ 202.94, 159.06, 155.69, 150.52, 142.51, 98.36, 73.47, 73.19, 70.34, 63.65, 44.51, 39.06, 25.28, 24.65, 18.30; MS (ESI) m / z 371 [C15H22N4O7 + H]+; UPLC (Method-A) 95.2% (AUC) tR= 2.68 min; Chiral HPLC (Method-C) 98.9% (AUC) tR= 7.69 min.EXAMPLE 10

[0161] This example provides an exemplary synthesis for Compound L.Scheme 10:2,3,4,5-tetrahvdroxvpentvl)amino)pyrimidine-2,4(1H,3H)-dione (Compound L)

[0162] Preparation of 2 -Cyclopenty 1-2 -oxoacetaldehyde : The stirred solution of selenium dioxide (4.94 g, 44.6 mmol) in 1,4-dioxane (45 mL) and water (5 mL) was heated to 60 °C for 1 hour. 1-Cyclohexylethan-1-one (5.00 g, 44.6 mmol) was added to the reaction at same temperature. The reaction was heated to 85 °C for 16 hours, cooled to room temperature and filtered through diatomaceous earth. The filtrate under fractional distillation provided 2-cyclopentyl-2-oxoacetaldehyde (3 mL with traces of 1,4-dioxane) at 140 °C as a pale-yellow oil. The product with traces of dioxane was used directly for the next step without purification.

[0163] Preparation of 5-(((E)-2-Cyclopentyl-2-oxoethylidene)amino)-6-(((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (Compound L): The stirred solution of 5-amino-6-(((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine- 2,4(1H,3H)-dione hydrochloride (500 mg, 1.59 mmol) and 2-cyclopentyl-2-oxoacetaldehyde (2.50 mL with traces of 1,4-dioxane) in dimethyl sulfoxide (3 mL) was adjusted to pH ~9 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 30 minutes and the reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford 5-(((E)-2-cyclopentyl-2-oxoethylidene)amino)-6-(((2S,3S,4R)- 2,3,4,5-tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (65.0 mg, 11%) as a pale yellow solid:1H NMR (400 MHz, DMSO-d6) δ 10.21 (br s, 1H), 8.76 (s, 1H), 7.39 (t, J = 5.2 Hz, 1H), 4.97 - 4.03 (m, 2H), 3.88 - 3.70 (m, 4H), 3.41 - 3.34 (m, 6H), 1.83 - 1.65 (m, 2H), 1.59 - 1.45 (m, 6H)(one amidic proton is not detected);13C NMR (100 MHz, DMSO-d6) δ 205.11, 159.30, 157.00, 151.70, 142.79, 98.72, 73.28, 73.23, 70.68, 63.57, 44.41, 43.07, 30.28, 29.78, 26.48; MS (ESI) m / z 385.1 [C16H24N4O7 + H]+; UPLC (Method-G) 96.9% (AUC) tR= 2.43 min.EXAMPLE 11

[0164] This example provides an exemplary synthesis for Compound M.Scheme 11 : Preparation of 5-(((E)-2-Cvclohexvl-2-oxoethylidene)amino)-6-(((2S,3 S,4R)-2,3,4.5-tetrahvdroxvpentvl)amino)pyrimidine-2,4(1H,3H)-dione (Compound M)

[0165] Preparation of 2 -Cyclohexyl-2 -oxoacetaldehyde : The stirred solution of selenium dioxide (4.40 g, 39.6 mmol) in 1,4-dioxane (45 mL) and water (5 mL) was heated to 85 °C for 1 hour. 1-Cyclohexylethan-1-one (5.00 g, 39.6 mmol) was added to the reaction and stirring was continued for 4 hours. The reaction was cooled to room temperature and passed through diatomaceous earth. The filtrate under fractional distillation provided 2-cyclohexyl- 2-oxoacetaldehyde (3 mL with traces of 1,4-dioxane) at 140 °C as a pale-yellow oil. The product with traces of dioxane was used directly for the next step.

[0166] Preparation of 5-(((E)-2-Cyclohexyl-2-oxoethylidene)amino)-6-(((2S,3S,4R)~2,3,4,5-tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (Compound M) : The stirred solution of 5-amino-6-(((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine- 2,4(1H,3H)-dione hydrochloride (350 mg, 1.12 mmol) and 2-cyclohexyl-2-oxoacetaldehyde (2 mL with traces of 1,4-dioxane) in dimethyl sulfoxide (3 mL) was adjusted to pH ~9 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 30 minutes and the reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford 5-(((E)-2-cyclohexyl-2-oxoethylidene)amino)-6-(((2S,3S,4R)-2,3,4,5- tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (55.0 mg, 12%) as a pale yellow solid:1H NMR (400 MHz, DMSO-d6) δ 10.45 (br s, 1H), 8.77 (s, 1H), 7.41 (t, J = 5.6 Hz, 1H), 5.11 - 4.30 (m, 1H), 3.84 - 3.80 (m, 1H), 3.67 - 3.60 (m, 5H), 3.57 - 3.53 (m, 5H), 1.70 - 1.11 (m, 10H) (one amidic NH proton was not detected);13C NMR (100 MHz, DMSO-d6) δ206.88, 159.07, 155.99, 150.96, 142.77, 98.61, 72.81, 72.79, 70.08, 63.06, 43.99, 43.07,29.34, 29.00, 25.92, 25.42, 25.34; MS (ESI) m / z 399 [C17H26N4O7 + H]+; UPLC (Method-G) 95.7% (AUC) tR= 2.56 min.EXAMPLE 12

[0167] This example provides an exemplary synthesis for Compound N.Scheme 12: Preparation of 5-(((E)-2-(2,4-Difluorophenyl)-2-oxoethylidene)amino)-6- (((2S,3S,4R)-2,3,4,5-tetrahvdroxvpentvl)amino)pyrimidine-2,4(1H,3H)-dione (Compound N)

[0168] The stirred solution of 5-amino-6-(((2S,3 S,4R)-2, 3,4,5- tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (300 mg, 0.98 mmol) and 2-(2,4-difluorophenyl)-2-oxoacetaldehyde (180 mg, 0.98 mmol) in dimethyl sulfoxide (3 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 15 minutes and the reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX C18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford 5-(((E)-2-(2,4-difluorophenyl)-2- oxoethylidene)amino)-6-(((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine- 2,4(1H,3H)-dione (65.0 mg, 15%) as a yellow solid:1H NMR (400 MHz, DMSO-d6) δ 10.57 (br s, 1H), 9.16 (d, J = 0.8 Hz, 1H), 7.59 (q, J = 8.0 Hz, 1H), 7.28 (dd, J = 2.0, 9.8 Hz, 1H), 7.13 (dd, J = 2.4, 8.4 Hz, 1H), 6.79 (br s, 1H), 5.52 - 4.42 (m, 4H), 3.68 - 3.64 (m, 1H), 3.58 - 3.56 (m, 1H), 3.49 - 3.44 (m, 2H), 3.42 - 3.37 (m, 2H), 2.95 - 2.91 (m, 1H) (one amidic proton was not detected);19F NMR (376 MHz, DMSO-d6) δ -106.31 (br s, IF); 6 -107.8 (d, JF-F = 7.52 Hz, IF);13C NMR (100 MHz, DMSO) δ 191.37, 165.20, 165.09, 162.73, 162.60, 161.66, 161.52, 159.16, 158.99, 156.22, 150.84, 132.58, 132.53, 132.48, 124.09, 123.97, 112.16, 111.95, 105.29, 105.03, 104.77, 99.59, 73.35, 72.51, 70.56, 63.52, 44.06; MS (ESI) m / z 429 [C17H18F2N4O7+ H]+; UPLC (Method-G) 95.9% (AUC) tR= 2.33 min.EXAMPLE 13

[0169] This example provides an exemplary synthesis for Compound O.Scheme 13: Preparation of 5-(((E)-4-Methyl-2-oxopentvlidene)amino)-6-(((2S,3S,4R)-2,3,4,5-tetrahvdroxvpentvl)amino)pyrimidine-2,4(1H,3H)-dione (Compound O)

[0170] Preparation of 4-Methyl-2-oxopentanal: The stirred solution of selenium dioxide (16.6 g, 149 mmol) in 1,4-dioxane (95 mL) and water (5 mL) was heated to 60 °C for 1 hour. 4-Methylpentan-2-one (10.0 g, 100 mmol) was added to the reaction at same temperature. The reaction was heated to 95 °C for 6 hours, cooled to room temperature and filtered through diatomaceous earth. The filtrate under fractional distillation provided 2-oxo-2- (thi ophen-2 -yl) acetaldehyde (10 mL with traces of dioxane) at 140 °C as a pale-yellow oil. The product with traces of dioxane was used directly for the next step without further purification.

[0171] Preparation of 5-(((E)-4-Methyl-2-oxopentylidene)amino)-6-(((2S,3S,4R)-2,3,4,5- tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (Compound O): The stirred solution of 5-amino-6-(((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (500 mg, 1.59 mmol) and 4-methyl-2-oxopentanal (2 mL with traces of dioxane) in dimethyl sulfoxide (3 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 15 minutes and the reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford 5-(((E)-4- methyl-2-oxopentylidene)amino)-6-(((2S,3S,4R)-2,3,4,5- tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (75.5 mg, 12%) as a pale-yellow solid:1H NMR (400 MHz, DMSO-d6) δ 10.47 (br s, 1H), 8.80 (d, J = 16.8 Hz, 1H), 7.49 (br s, 1H), 4.74 (br s, 3H), 3.83 - 3.79 (m, 1H), 3.61 - 3.39 (m, 6H), 2.74 - 2.61 (m, 2H), 2.08 -2.01 (m, 1H), 0.89 - 0.87 (m, 6H) (one ami die proton and one OH were not detected);13c NMR (100 MHz, DMSO-d6) δ 202.67, 159.16, 156.04, 150.82, 143.88, 98.38, 73.39, 73.25, 70.48, 63.65, 44.50, 44.11, 25.52, 23.10; MS (ESI) m / z 373 [C15H24N4O7 + H]+; UPLC (Method- A) 96.9% (AUC) tR= 3.22 min.EXAMPLE 14

[0172] This example provides an exemplary synthesis for Compound Q.Scheme 14: Preparation of 6-(((2S,3S,4R)-2,3,4,5-Tetrahydroxypentyl)amino)-5-(((E)-4,4,4-trifluoro-2-oxobutvlidene)amino)pyrimidine-2,4(1H,3H)-dione (Compound O)

[0173] Preparation of 4,4,4-Trifluoro-2-oxobutanal: The stirred solution of selenium dioxide (2.64 g, 23.8 mmol) in 1,4-dioxane (27 mL) and water (3 mL) was heated to 60 °C for 1 hour. The 4,4,4-trifluorobutan-2-one (3.00 g, 23.8 mmol) was added to the reaction at same temperature. The reaction was heated to 100 °C for 16 hours. The reaction was cooled to room temperature and passed through diatomaceous earth. The filtrate was purified by fractional distillation and collected 4,4,4-trifluoro-2-oxobutanal (5 mL with traces of dioxane) at 140 °C as a pale-yellow oil. The product with traces of dioxane was used directly for the next step.

[0174] Preparation of 6-(((2S,3S,4R)-2,3,4,5-Tetrahydroxypentyl)amino)-5-(((E)-4,4,4- trifluoro-2-oxobutylidene)amino)pyrimidine-2,4(1H,3H)-dione (Compound Q): The stirred solution of 5-amino-6-(((2S,3S,4S)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (350 mg, 1.12 mmol) and 4,4,4-trifluoro-2-oxobutanal (0.47 mL with traces of 1,4-dioxane) in dimethyl sulfoxide (2 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 15 minutes and the reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini -NX C18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate inwater, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford 6-(((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)amino)-5-(((E)-4,4,4- trifluoro-2-oxobutylidene)amino)pyrimidine-2,4(1H,3H)-dione (38.0 mg, 9%) as a yellow solid: 'HNMR (400 MHz, DMSO-d6) δ 10.68 (br s, 1H), 8.89 (s, 1H), 7.93 (br s, 1H), 5.15 - 4.75 (m, 2H), 4.44 (br s, 1H), 4.12 - 4.00 (m, 2H), 3.83 - 3.79 (m, 1H), 3.67 - 3.40 (m, 6H) (one amidic NH and one hydroxy OH were not detected);13C NMR (100 MHz, DMSO-d6) δ 192.97, 159.14, 155.73, 150.14, 142.23, 127.25, 98.99, 73.66, 73.08, 70.63, 63.49, 45.05, 39.06;19F NMR (376 MHz, DMSO-d6) δ 60.32 (s, IF); MS (ESI) m / z 399 [C13H17F3N4O7 + H]+; UPLC (Method-A) 98.4% (AUC) tR = 3.26 min.EXAMPLE 15

[0175] This example provides an exemplary synthesis for Compound S. Scheme 15: Preparation of (S,E)-6-((2J-Dihydroxypropyl)amino)-5-((2- oxobutylidene)amino)pyrimidine-2,4(1HJH)-dione (Compound S)

[0176] Preparation of 2, 4-Bis(benzyloxy)-6-chloro-5-nitropyrimidine (9): Sodium hydride (60% in mineral oil, 1.05 g, 44.0 mmol) was added portion wise to a stirred solution of benzyl alcohol (4.75 g, 44.0 mmol) in tetrahydrofuran (75 mL) at room temperature. The reaction was stirred for 30 minutes. This solution was added dropwise to a separate flaskcontaining solution of 2,4,6-trichloro-5-nitropyrimidine (5.00 g, 22.0 mmol) in tetrahydrofuran (75 mL) at -20 °C. The reaction was stirred at same temperature for 4 hours. The reaction progress was monitored by thin layer chromatography and quenched with acetic acid and concentrated under reduced pressure. The crude material was purified by flash chromatography using 100-200 mesh silica gel and eluting with 8% ethyl acetate in hexanes. The pure fractions were collected and concentrated under reduced pressure to afford 2,4- bis(benzyloxy)-6-chloro-5-nitropyrimidine (3.00 g, Yield: 36%) as a pale-yellow solid.1H NMR (400 MHz, CDCl3) δ 7.46 - 7.36 (m, 10H), 5.51 (s, 2H), 5.45 (s, 2H); MS (ESI) m / z 372 [C18H14CIN3O4 + H]+.

[0177] Preparation of (S)-N-Benzyl-l-(2,2-dimethyl-l,3-dioxolan-4-yl)methanamine (2):To a stirred solution of (R)-2,2-dimethyl-l,3-dioxolane-4-carbaldehyde (5.00 g, 38.5 mmol) and benzylamine (4.93 mL, 46.2 mmol) in methanol (50 mL), was added platinum oxide (0.50 g) at room temperature under argon atmosphere. The reaction was stirred under hydrogen atmosphere using a balloon for 16 hours. The progress was monitored by thin layer chromatography and UPLC-MS. The reaction was passed through diatomaceous earth and washed with methanol (100 mL). The filtrate was evaporated under reduced pressure to give a crude oil. The crude material was purified by flash chromatography using silica gel (100- 200 mesh) by eluting with 20% ethyl acetate in hexanes. The pure fractions were collected and concentrated under reduced pressure to afford (S)-N-benzyl-1-(2,2-dimethyl-l,3- dioxolan-4-yl) methanamine (4.50 g, 52%) as a colorless oil:1H NMR (400 MHz, DMSO- d6) 5 7.31 - 7.30 (m, 4H), 7.24 - 7.20 (m, 1H), 4.14 - 4.08 (m, 1H), 3.96 (dd, J = 6.0, 8.0 Hz, 1H), 3.70 (s, 2H), 3.60 (dd, J = 6.4, 8.0 Hz, 1H), 2.63 - 2.59 (m, 1H), 2.53 - 2.52 (m, 1H), 2.11 (br s, 1H), 1.29 (s, 3H), 1.25 (s, 3H); MS (ESI) m / z 222 [C13H19NO2 + H]+.

[0178] Preparation of (S)-N-Benzyl-2, 6-bis(benzyloxy)-N-( (2, 2-dimethyl-l, 3-dioxolan-4- yl)methyl)-5-nitropyrimidin-4-amine (3): To a stirred solution of (S)-N-benzyl-1-(2,2- dimethyl-l,3-dioxolan-4-yl) methanamine (0.50 g, 2.3 mmol), 2,4-bis(benzyloxy)-6-chloro-5- nitropyrimidine (0.92 g, 2.5 mmol) in N,N-dimethylformamide (10 mL), was added triethylamine (0.95 mL, 6.8 mmol) under an argon atmosphere. The reaction was stirred at room temperature for 2 hours and the reaction progress was monitored by thin layer chromatography and UPLC-MS. The reaction was diluted with ethyl acetate (100 mL), washed with water (50 mL), brine (30 mL), dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure.The crude material was purified by flash chromatography using silica gel (100-200 mesh) andeluting with 10% ethyl acetate in hexanes. The pure fractions were collected and concentrated under reduced pressure to afford (S)-N-benzyl-2,6-bis(benzyloxy)-N-((2,2- dimethyl-l,3-dioxolan-4-yl)methyl)-5-nitropyrimidin-4-amine (1.00 g, 80%) as a yellow oil:1H NMR (400 MHz, CDCl3) δ 7.36 - 7.26 (m, 13H), 7.20 - 7.18 (m, 2H), 5.46 (s, 2H), 5.30 (d, J = 6.4 Hz, 2H), 4.93 (d, J = 16.0 Hz, 1H), 4.67 (d, J = 16.0 Hz, 1H), 4.35 - 4.29 (m, 1H), 3.95 (dd, J = 6.0, 8.6 Hz, 1H), 3.57 - 3.53 (m, 1H), 3.47 (dd, J = 6.8, 8.4 Hz, 1H), 3.42 - 3.36 (m, 1H), 1.38 (s, 3H), 1.31 (s, 3H); MS (ESI) m / z 578 [C31H32N4O6 + Na]+.

[0179] Preparation of (S)-5-Amino-6-((2,3-dihydroxypropyl)amino)pyrimidine- 2,4(1H,3H)-dione hydrochloride (4): To a solution of (S)-N-benzyl-2,6-bis(benzyloxy)-N- ((2,2-dimethyl-l,3-dioxolan-4-yl)methyl)-5-nitropyrimidin-4-amine (400 mg, 0.71 mmol) in IN aqueous hydrochloric acid solution (2 mL) and tetrahydrofuran (2 mL), was added 10% palladium on charcoal (200 mg) under argon atmosphere at room temperature. The reaction was stirred under hydrogen atmosphere using a balloon for 16 hours. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to afford (S)-5-amino-6-((2,3-dihydroxypropyl)amino)pyrimidine- 2,4(1H,3H)-dione hydrochloride (0.16 g, crude) as a pink solid (hygroscopic):1H NMR (400 MHz, D2O) δ 3.90 - 3.84 (m, 1H), 3.61 - 3.52 (m, 2H), 3.51 - 3.46 (m, 1H), 3.39 (dd, J = 10.8, 13.0 Hz, 1H); (MS (ESI) m / z 217 [C7H13CIN4O4 + H]+.

[0180] Preparation of (S,E)-6-((2,3-Dihydroxypropyl)amino)-5-((2- oxobutylidene)amino)pyrimidine-2,4(1H,3H)-dione (Compounds): The stirred solution of (S)-5-amino-6-((2,3-dihydroxypropyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (100 mg, 0.39 mmol) and 2-oxobutanal (0.10 mL with traces of 1,4-dioxane) in dimethyl sulfoxide (1 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 30 minutes. The reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX C18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford (S,E)-6-((2,3- dihydroxypropyl)amino)-5-((2-oxobutylidene)amino)pyrimidine-2,4(1H,3H)-dione (15.0 mg, 13%) as a yellow solid:1H NMR (400 MHz, D2O) δ 8.76 (s, 1H), 3.87 - 3.83 (m, 1H), 3.60 - 3.51 (m, 3H), 3.43 (dd, J = 6.4, 14.4 Hz, 1H), 2.85 (q, J = 7.6 Hz, 2H), 1.03 (t, J = 7.2 Hz,3H); MS (ESI) m / z 285 [C11H16N4O5 + H]+; Chiral HPLC (Method-C) >99% (AUC) tR3.99 min.EXAMPLE 16

[0181] This example provides an exemplary synthesis for Compound U.Scheme 16: trihydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (Compound U)

[0182] Preparation of (2R,3R,4R)-l,l-Bis(propylthio)pentane-2,3,4-triol (4): To a stirred solution of (2S,3R,4R,5R)-5-methyltetrahydrofuran-2,3,4-triyl triacetate (15.0 g, 57.7 mmol) in dry methanol (100 mL), was added 5.0M NaOMe in methanol (0.76 mL, 0.58 mmol) dropwise at 0 °C under argon atmosphere. The mixture was stirred at 0 °C for 3 hours. The reaction progress was monitored by thin layer chromatography. The reaction was adjusted to pH ~6 by slow addition of amberlite IR120 resin and passed the reaction through the cotton plug. The filtrate was concentrated under reduced pressure at 30 °C to afford (2R,3R,4R)-2,3,4-trihydroxypentanal (7.50 g crude) as light pink oil. To the crude (2R,3R,4R)-2,3,4- trihydroxypentanal (6.00 g, 44.8 mmol) in concentrated hydrochloric acid (6 mL), was added propane-1 -thiol (6.80 g, 89.6 mmol) dropwise at 0 °C under argon atmosphere. The reaction was stirred at 0 °C for 2 hours and the reaction progress was monitored by thin layer chromatography. The reaction was poured into ice water (20 mL) and extracted with di chloromethane (3 x 50 mL). The combined organic extracts were washed with brine (30mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography using silica gel (100-200 mesh) and eluting with 20% ethyl acetate in hexanes. The pure fractions were collected and concentrated under reduced pressure to afford (2R,3R,4R)-l,l-bis(propylthio)pentane-2,3,4- triol (7.00 g, 54% for two steps) as a colorless oil:1H NMR (400 MHz, DMSO-d6) δ 5.12 (d, J = 4.8 Hz, 1H), 4.49 (dd, J = 5.2, 12.4 Hz, 2H), 4.15 (d, J = 1.6 Hz, 1H), 3.82 - 3.78 (m, 1H), 3.61 - 3.50 (m, 2H), 2.64 - 2.61 (m, 4H), 1.60 - 1.51 (m, 4H), 1.03 (d, J = 6.4 Hz, 3H), 0.96 - 0.92 (m, 6H); MS (ESI) m / z 291 [C11H24O3S2 + Na]+.

[0183] Preparation of ( (2R, 3R, 4R)-2, 3, 4-Tris(benzyloxy)pentane-l , 1- diyl)bis(propylsulfane) (5): To a stirred solution of (2R,3R,4R)-l,l-bis(propylthio)pentane- 2,3,4-triol (7.00 g, 26.1 mmol) in tetrahydrofuran (100 mL), was added sodium hydride (60% in paraffin oil, 4.17 g, 104 mmol) portion wise at 0 °C. After stirring for 30 min, benzyl bromide (17.7 g, 104 mmol) was added dropwise. The reaction was heated to 60 °C and stirred for 16 hours. The progress was monitored by thin layer chromatography and UPLC- MS. The reaction was diluted with water (200 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography using silica gel (100-200 mesh) and eluting with 5% ethyl acetate in hexanes. Pure fractions were collected and concentrated under reduced pressure to afford ((2R,3R,4R)-2,3,4-tris(benzyloxy)pentane-l,l-diyl)bis(propylsulfane) (12.0 g, 85%) as a colorless oil:1H NMR (400 MHz, CDCl3) δ 7.35 - 7.26 (m, 15H), 4.92 (d, J = 3.6 Hz, 1H), 4.95 (d, J = 3.2 Hz, 1H), 4.64 - 4.58 (m, 4H), 4.22 (d, J = 2.4 Hz, 1H), 4.10 (dd, J = 2.0, 8.0 Hz, 1H), 3.96 - 3.91 (m, 1H), 3.75 (dd, J = 2.8, 8.0 Hz, 1H), 2.64 - 2.52 (m, 4H), 1.58 - 1.53 (m, 4H), 1.17 (d, J = 6.4 Hz, 3H), 0.97 - 0.93 (m, 6H); MS (ESI) m / z 561 [C32H42O3S2 + Na]+.

[0184] Preparation of (2R,3R,4R)-2,3,4-Tris(benzyloxy)pentanal (6): To a solution of ((2R,3R,4R)-2,3,4-tris(benzyloxy)pentane-l,l-diyl)bis(propylsulfane) (9.00 g, 16.7 mmol) and sodium bicarbonate (3.08 g, 36.7 mmol) in mixture of acetone (180 mL) and water (45 mL), was added iodine (9.32 g, 36.7 mmol) portion wise at 0 °C. The reaction was warmed to room temperature and stirred for 6 hours. The progress was monitored by thin layer chromatography and UPLC-MS. The reaction was quenched with aqueous sodium thiosulfate solution (50 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography using 100-200 mesh silica gel and eluting with 5% ethyl acetate in hexanes. The pure fractions were collected and concentrated under reduced pressure to afford (2R,3R,4R)-2,3,4-tris(benzyloxy)pentanal (5.20 g, 77%) as a colorless oil:1H NMR (400 MHz, CDCl3) δ 9.51 (d, J = 0.8 Hz, 1H), 7.34 - 7.26 (m, 15H), 4.76 - 4.46 (m, 6H), 4.06 (dd, J = 0.8, 2.6 Hz, 1H), 3.86 - 3.81 (m, 1H), 3.68 (dd, J = 2.4, 8.0 Hz, 1H), 1.23 (d, J = 6.0 Hz, 3H).

[0185] Preparation of (2S,3R,4R)-N-Benzyl-2,3,4-tris(benzyloxy)pentan-l-amine (7): To a stirred solution of (2R,3R,4R)-2,3,4-tris(benzyloxy)pentanal (5.20 g, 12.9 mmol) and benzyl amine (1.65 g, 15.4 mmol) in methanol (52 mL), was added platinum oxide (0.50 g, catalytic) at room temperature under argon atmosphere. The reaction was stirred under hydrogen atmosphere using a balloon for 16 hours. The progress was monitored by thin layer chromatography and UPLC-MS. The reaction was passed through diatomaceous earth and washed with methanol (100 mL). The filtrate was concentrated under reduced pressure, and the crude material was purified by flash chromatography using 100-200 mesh silica gel. The pure product was eluted with 10% ethyl acetate in hexanes and pure fractions were concentrated under reduced pressure to afford (2S,3R,4R)-N-benzyl-2,3,4- tris(benzyloxy)pentan-1-amine (5.00 g, 78%) as a colorless oil:1H NMR (400 MHz, CDCI3) δ 7.34 - 7.27 (m, 17H), 7.26 - 7.20 (m, 3H), 4.78 - 4.69 (m, 2H), 4.60 - 4.46 (m, 4H), 3.83 - 3.70 (m, 5H), 2.94 - 2.80 (m, 2H), 1.22 (d, J = 6.0 Hz, 3H) (NH is not detected); MS (ESI) m / z 496 [C33H37NO3+ H]+.

[0186] Preparation of N-Benzyl-2, 6-bis(benzyloxy)-5-nitro-N-( (28, 3R, 4R)-2, 3, 4- tris(benzyloxy)pentyl)pyrimidin-4-amine (8): To a stirred solution of (2S,3R,4R)-N-benzyl- 2,3,4-tris(benzyloxy)pentan-1-amine (1.10 g, 2.21 mmol), 2,4-bis(benzyloxy)-6-chloro-5- nitropyrimidine (0.90 g, 2.44 mmol) in N,N-dimethylformamide (22 mL), was added triethylamine (0.93 mL, 6.63 mmol) dropwise under argon atmosphere. The reaction was stirred at room temperature for 2 hours and the reaction progress was monitored by thin layer chromatography. The reaction was diluted with ethyl acetate (100 mL), washed with water (50 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography using silica gel (100-200 mesh) and product was eluted with 5% ethyl acetate in hexanes. The pure fractions were collected and concentrated under reduced pressure to afford N-benzyl-2,6- bis(benzyloxy)-5-nitro-N-((2S,3R,4R)-2,3,4-tris(benzyloxy)pentyl)pyrimidin-4-amine (1.70g, 92%) as a yellow oil:1H NMR (400 MHz, CDCl3) δ 7.39 - 7.29 (m, 10H), 7.24 - 7.18 (m, 18H), 7.05 - 7.02 (m, 2H), 5.41 (s, 2H), 5.22 - 5.13 (m, 2H), 4.71 - 4.57 (m, 5H), 4.53 - 4.44 (m, 2H), 4.37 (d, J = 11.6 Hz, 1H), 4.08 - 4.04 (m, 1H), 3.78 (d, J = 15.2 Hz, 1H), 3.66 - 3.60 (m, 2H), 3.57 - 3.55 (m, 1H), 1.22 (d, J = 6.0 Hz, 3H); MS (ESI) m / z 831 [C51H50N4O7 + H]+.

[0187] Preparation of (28, 3R, 4R)-l-( (5-Amino-2, 6-dihydroxypyrimidin-4- yl)amino)pentane-2,3,4-triol hydrochloride: To a solution ofN-benzyl-2,6-bis(benzyloxy)-5- nitro-N-((2S,3R,4R)-2,3,4-tris(benzyloxy)pentyl)pyrimidin-4-amine (1.00 g, 1.20 mmol) in IN aqueous hydrochloric acid (8 mL) and tetrahydrofuran (30 mL), was added 10% palladium on charcoal (10% wet, 500 mg) under argon atmosphere at room temperature. The reaction was stirred under hydrogen atmosphere using a balloon at room temperature for 16 hours. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction was passed through diatomaceous earth, and the filtrate was concentrated under reduced pressure to afford (2S,3R,4R)-1-((5-amino-2,6- dihydroxypyrimidin-4-yl)amino)pentane-2,3,4-triol hydrochloride (390 mg, crude) as a pink solid: MS (ESI) m / z 831 [C51H50N4O7 + H]+; The crude product was used directly for the next step without purification.

[0188] Preparation of 5-(((E)-2-Oxobutylidene)amino)-6-(((2S,3R,4R)-2,3,4- trihydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (Compound U): The stirred solution of (2S,3R,4R)-1-((5-amino-2,6-dihydroxypyrimidin-4-yl)amino)pentane-2,3,4-triol hydrochloride (300 mg, 1.15 mmol) in dimethyl sulfoxide (3 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. 2-Oxobutanal (200 mg, 2.30 mmol) was added dropwise to the reaction and stirred for 10 minutes. The reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX C18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford (E)-5-((2- oxobutylidene)amino)-6-(((5-oxopyrrolidin-2-yl)methyl)amino)pyrimidine-2,4(1H,3H)-dione (81.5 mg, 28%) as a yellow solid:1H NMR (400 MHz, D2O) δ 8.73 (s, 1H), 3.95 - 3.91 (m, 1H), 3.78 - 3.75 (m, 1H), 3.66 - 3.63 (m, 1H), 3.55 - 3.51 (m, 2H), 2.83 (q, J = 7.2 Hz, 2H), 1.15 (d, J = 6.4 Hz, 3H), 1.01 (t, J = 7.6 Hz, 3H);13C NMR (100 MHz, DMSO-d6) δ 203.10, 159.89, 159.64, 141.22, 99.27, 75.80, 72.22, 68.02, 44.85, 28.43, 19.00, 9.01, 0.58; MS (ESI) m / z 329 [C13H20N4O6 + H]+; UPLC (Method-A) 93.8% (AUC) tR= 2.91 min.EXAMPLE 17

[0189] This example provides an exemplary synthesis for Compound W.Scheme 17: Preparation of (S,E)-5-((2-Cvclopropyl-2-oxoethvlidene)amino)-6-((2,3- dihvdroxvpropvl)amino)pyrimidine-2,4(1H,3H)-dione (Compound W)

[0190] The stirred solution of (S)-5-amino-6-((2,3-dihydroxypropyl)amino)pyrimidine- 2,4(1H,3H)-dione hydrochloride (300 mg, 1.19 mmol) in dimethyl sulfoxide (3 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. 2-Cyclopropyl-2-oxoacetaldehyde (1.50 mL with traces of 1,4-dioxane) was added dropwise to the reaction and stirred for 0.5 hours. The reaction progress was monitored by UPLC-MS. The precipitate was collected by filtration, washed with water followed by acetonitrile and dried under vacuum to afford (S,E)-5-((2-cyclopropyl-2- oxoethylidene)amino)-6-((2,3-dihydroxypropyl)amino)pyrimidine-2,4(1H,3H)-dione (235 mg, 66%) as a yellow solid:1H NMR (400 MHz, DMSO-d6) δ 11.03 (br s, 1H), 10.73 (s, 1H), 8.96 (s, 1H), 7.80 (t, J = 6.0 Hz, 1H), 5.70 - 5.35 (m, 1H), 5.12 - 4.81 (m, 1H), 3.68 - 3.63 (m, 1H), 3.59 - 3.53 (m, 1H), 3.47 - 3.40 (m, 2H), 3.38 - 3.26 (m, 2H), 0.91 - 0.83 (m, 4H);13C-NMR (100 MHZ, DMSO-d6) δ 201.60, 159.06, 155.04, 149.63, 144.95, 98.56, 70.50, 63.99, 45.83, 14.01, 11.07, 11.05; MS (ESI) m / z 297 [C12H16N4O5 + H]+; UPLC (Method-A) 96.5% (AUC) tR= 2.60 min.EXAMPLE 18

[0191] This example provides an exemplary synthesis for Compound Y.Scheme 18: Preparation of 5-(((E)-2-Cvclopropyl-2-oxoethvlidene)amino)-6-(((2S,3R,4R)-2,3,4-trihydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (Compound Y)

[0192] The stirred solution of (2S,3R,4R)-1-((5-amino-2,6-dihydroxypyrimidin-4- yl)amino)pentane-2,3,4-triol hydrochloride (260 mg, 0.87 mmol) in dimethyl sulfoxide (2 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. 2-Cyclopropyl-2-oxoacetaldehyde (0.70 mL with traces of dioxane) was added dropwise to the reaction and stirred for 15 minutes. The reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX C18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford 5-(((E)-2-cyclopropyl-2- oxoethylidene)amino)-6-(((2S,3R,4R)-2,3,4-trihydroxypentyl)amino)pyrimidine-2,4(1H,3H)- dione (70.0 mg, 26%) as a yellow solid:1H NMR (400 MHz, DMSO-d6) δ 10.35 (br s, 1H), 8.94 (s, 1H), 7.66 (br s, 1H), 4.65 (br s, 1H), 3.71 - 3.60 (m, 3H), 3.59 - 3.48 (m, 1H), 3.29 - 3.22 (m, 2H), 1.07 (d, J = 4.0 Hz, 3H), 0.87 - 0.69 (m, 4H) (one amidic NH and two OH’s were not detected);13C-NMR (100 MHz, DMSO-d6) δ 201.43, 159.36, 156.95, 151.36, 143.56, 99.02, 76.46, 71.20, 67.78, 45.22, 19.18, 13.97, 10.90, 10.82; MS (ESI) m / z 341 [C14H20N4O6 + H]+; UPLC (Method- A) 94.1% (AUC) tR= 3.09 min.EXAMPLE 19

[0193] This example provides an exemplary synthesis for Compound AA.Scheme 19: Preparation of (S,E)-6-((2,3-Dihvdroxvpropyl)amino)-5-((3-methvl-2- oxobutylidene)amino)pyrimidine-2,4(1H,3H)-dione (Compound AA)

[0194] Preparation of 3 -Me thy 1-2 -oxobutanal: To a stirred solution of selenium dioxide(12.8 g, 116 mmol) in 1,4-dioxane (95 mL) and water (5 mL), was added 3-methylbutan-2- one (10.0 g, 116 mmol) at room temperature. The reaction was heated to 85 °C for 4 hours. The reaction was cooled to room temperature and passed through diatomaceous earth. The fractional distillation of the filtrate provided 3-methyl-2-oxobutanal (5 mL with traces of 1,4-dioxane) at 140 °C as a pale-yellow oil. The product with traces of dioxane was used directly without further purification.

[0195] Preparation of (S,E)-6-((2,3-Dihydroxypropyl)amino)-5-((3-methyl-2- oxobutylidene)amino)pyrimidine-2,4(1H,3H)-dione (Compound AA) : The stirred solution of (S)-5-Amino-6-((2,3-dihydroxypropyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (Compound 4 from Example 15, 150 mg, 0.59 mmol) and 3-methyl-2-oxobutanal (0.15 mL with traces of 1,4-dioxane) in dimethyl sulfoxide (1 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 15 minutes and the reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini -NX C18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried under lyophilization to afford (S,E)-6-((2,3-dihydroxypropyl)amino)-5-((3-methyl-2- oxobutylidene)amino)pyrimidine-2,4(1H,3H)-dione (62.0 mg, 35%) as a yellow solid:1H NMR (400 MHz, D2O) δ 8.79 (s, 1H), 3.87 - 3.82 (m, 1H), 3.59 - 3.50 (m, 4H), 3.41 (dd, J = 6.8, 14.2 Hz, 1H), 1.04 (d, J = 6.8 Hz, 6H); MS (ESI) m / z 299 [C12H18N4O5 + H]+; UPLC (Method-G) 97.5% (AUC) tR= 2.05 min.EXAMPLE 20

[0196] This example provides an exemplary synthesis for Compound AC.Scheme 20:2,3,4-trihydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (Compound AC)

[0197] The stirred solution of (2S,3R,4R)-1-((5-amino-2,6-dihydroxypyrimidin-4- yl)amino)pentane-2,3,4-triol hydrochloride (300 mg, 1.15 mmol) in dimethyl sulfoxide (3 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. 3-Methyl-2-oxobutanal (1 mL with traces of 1,4-dioxane) was added dropwise to the reaction and stirred for 15 minutes. The reaction progress was monitored by UPLC-MS. The reaction mixture was purified by mass triggered preparative HPLC(Column: Gemini-NX C18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were by under lyophilization to afford 5-(((E)-3-methyl-2-oxobutylidene)amino)-6- (((2S,3R,4R)-2,3,4-trihydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (80.0 mg, 31%) as a yellow solid:1H NMR (400 MHz, D2O) δ 8.79 (s, 1H), 3.97 - 3.91 (m, 1H), 3.78 - 3.73 (m, 1H), 3.67 - 3.63 (m, 1H), 3.58 - 3.48 (m, 3H), 1.14 (d, J = 6.4 Hz, 3H), 1.05 (d, J = 6.8 Hz, 6H);13C NMR (100 MHz, DMSO-d6) δ 203.46, 177.37, 159.16, 154.79, 150.18, 144.39, 98.38, 53.82, 46.28, 29.96, 28.72, 23.93, 8.62; MS (ESI) m / z 343 [C14H22N4O6 + H]+; UPLC (Method-A) 95.7% (AUC) tR= 2.84 min.EXAMPLE 21

[0198] This example provides an exemplary synthesis for Compound AD.Scheme 21 : Preparation of 5-(((E)-2-Oxopropylidene)amino)-6-(((2S,3R,4R)-2,3,4- trihydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (Compound AD)

[0199] The stirred solution of (2S,3R,4R)-1-((5-amino-2,6-dihydroxypyrimidin-4- yl)amino)pentane-2,3,4-triol hydrochloride (260 mg, 0.87 mmol) in dimethyl sulfoxide (3 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. 2-oxopropanal (0.47 mL, 2.63 mmol, 40% in water) was added dropwise to the reaction and stirred at room temperature for 15 minutes. The reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX C18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The fractions containing pure product were dried by lyophilization to afford 5-(((E)-3-methyl-2- oxobutylidene)amino)-6-(((2S,3R,4R)-2,3,4-trihydroxypentyl)amino)pyrimidine-2,4(1H,3H)- dione (58.0 mg, 24%) as a yellow solid:1H NMR (400 MHz, D2O) δ 8.70 (s, 1H), 3.96 - 3.90 (m, 1H), 3.80 - 3.79 (m, 1H), 3.67 - 3.64 (m, 1H), 3.55 - 3.50 (m, 2H), 2.34 (s, 3H), 1.15 (d, J = 6.4 Hz, 3H);13C NMR (100 MHz, DMSO-d6) δ 200.83, 159.49, 157.70, 152.21, 142.87, 98.88, 76.23, 71.37, 67.86, 44.98, 23.99, 19.07; MS (ESI) m / z 315 [C12H18N4O6 + H]+;UPLC (Method-A) 95.6% (AUC) tR= 2.44 min.EXAMPLE 22

[0200] This example provides an exemplary synthesis for Compound AH.Scheme 22:(((2S,3S,4R)-2,3,4,5-tetrahvdroxvpentvl)amino)pyrimidine-2,4(1H,3H)-dione (CompoundAH)

[0201] Preparation of 2-(l-Methylcyclopropyl)-2-oxoacetaldehyde: To a stirred solution of l-(l-methylcyclopropyl)ethan-1-one (1.00 g, 10.2 mmol) in 1,4-dioxane (15 mL) and water (1.50 mL), was added selenium dioxide (1.12 g, 10.20 mmol) at room temperature. The reaction was heated to 85 °C for 16 hours and the progress of the reaction was monitored by thin layer chromatography and UPLC-MS. The reaction was cooled to room temperature and filtered through diatomaceous earth. The filtrate under fractional distillation provided 2- (l-methylcyclopropyl)-2-oxoacetaldehyde (0.80 mL with traces of 1,4-dioxane) at 140 °C as pale-yellow oil. The product with traces of dioxane was used directly for the next step without purification.

[0202] Preparation of 5-( ( (E)-2-( 1 -Methylcyclopropyl)-2-oxoethylidene)amino)-6-(((2S, 38, 4R)-2, 3, 4, 5-tetrahydroxypentyl)amino)pyrimidine-2, 4(1H, 3H)-dione ( Compound AH): The stirred solution of 5-amino-6-(((2S,3 S,4R)-2, 3,4,5- tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (300 mg, 1.33 mmol) in dimethyl sulfoxide (0.60 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. 2-(l-Acetylpiperidin-4-yl)-2- oxoacetaldehyde (0.30 mL with traces of 1,4-dioxane) was added dropwise to the reaction and stirred for 15 minutes. The reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini -NX C18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The fractions containing pure product weredried by lyophilization to afford 5-(((E)-2-(l-methylcyclopropyl)-2-oxoethylidene)amino)-6- (((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (31.5 mg, 8%) as a yellow solid:1H NMR (400 MHz, DMSO-d6) δ 10.21 (hr s, 1H), 9.00 (s, 1H), 7.21 (hr s, 1H), 4.55 - 4.29 (m, 2H), 3.68 (t, J = 2.8 Hz, 1H), 3.54 - 3.51 (m, 3H), 3.36 - 3.31 (m, 3H), 1.29 (s, 3H), 1.26 (q, J = 3.2 Hz, 2H), 0.75 (q, J = 3.6 Hz, 2H) (one amidic and two OH’s were not detected);13C NMR (100 MHz, DMSO-d6) δ 200.59, 159.19, 157.07, 151.42, 140.44, 99.03, 73.26, 72.91, 71.07, 63.55, 44.23, 26.66, 21.16, 17.62; MS (ESI) m / z 371 [C15H22N4O7 + H]+; UPLC (Method-G) 96.2% (AUC) tR= 1.71 min.EXAMPLE 23

[0203] This example provides an exemplary synthesis for Compound Al, including diastereomers Compound AL(S) and Compound AI-(R).Scheme 23: Preparation of 5-(((E)-3-Methyl-2-oxopentylidene)amino)-6-(((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (Compound Al)

[0204] Preparation of 3-Methyl-2-oxopentanal: The stirred solution of selenium dioxide(3.32 g, 29.9 mmol) in 1,4-dioxane (25 mL) and water (1 mL) was heated to 60 °C for 1 hour. 3-Methylpentan-2-one (2.50 g, 24.9 mmol) was added to the reaction at same temperature. The reaction was heated to 100 °C for 16 hours, cooled to room temperature and passed through diatomaceous earth. The filtrate under fractional distillation provided 3-methyl-2- oxopentanal (4 mL with traces of dioxane) at 140 °C as a pale-yellow oil. The product with traces of dioxane was used directly for the next step without purification.

[0205] Preparation of 5-(((E)-3-Methyl-2-oxopentylidene)amino)-6-(((2S, 3S, 4R)-2, 3,4,5- tetrahydroxypentyl)amino)pyrimidine-2, 4(1H, 3H)-dione ( Compound Al) : The stirred solution of 5-amino-6-(((2S,3S,4S)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine- 2,4(1H,3H)-dione hydrochloride (350 mg, 1.12 mmol) and 2-cyclobutyl-2-oxoacetaldehyde (0.50 mL with traces of dioxane) in dimethyl sulfoxide (2 mL) was adjusted to pH ~8 by slowaddition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 15 minutes and the reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini -NX CIS 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford 5-(((E)-3-methyl-2-oxopentylidene)amino)-6-(((2S,3S,4R)-2,3,4,5- tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (38.0 mg, 9%) as a yellow solid:1H NMR (400 MHz, DMSO-d6) δ 10.61 (br s, 1H), 8.83 (d, J = 2.4 Hz, 1H), 7.56 - 7.55 (m, 1H), 5.10 - 4.61 (m, 3H), 4.44 (br s, 1H), 3.81 - 3.71 (m, 1H), 3.69 - 3.41 (m, 7H), 1.61 - 1.51 (m, 1H), 1.39 - 1.28 (m, 1H), 0.97 (d, J = 6.8 Hz, 3H), 0.81 - 0.79 (m, 3H) (one amidic NH was not detected);13C NMR (100 MHz, DMSO-d6) δ 206.30, 206.28, 159.04, 155.40, 150.18, 143.48, 98.25, 73.46, 73.43, 73.15, 70.32, 63.63, 44.61, 38.42, 38.30, 26.97, 26.80, 17.39, 17.17, 12.18, 12.13 (Mixture of diastereomers); MS (ESI) m / z 373 [C15H24N4O7 + H]+;UPLC (Method-A) >99% (AUC) tR= 3.14 min; Chiral HPLC (Method-C) 98.6% (AUC) tR= 4.56 min.Scheme 24:2,3,4,5-tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (Compound AI-(S))

[0206] Preparation of (S)-N-Methoxy-N,2-dimethylbutanamide: To a stirred solution of (S)-2-methylbutanoic acid (5.00 g, 48.9 mmol) and N,O-dimethyl hydroxylamine (7.15 g, 73.37 mmol) in dichloromethane (50 mL), was added triethylamine (20.3 mL, 146 mmol) at 0 °C. After stirring for 5 min, propyl phosphonic anhydride (50% in ethyl acetate, 46.7 mL,73.3 mmol) was added to the reaction. The reaction was warmed to room temperature for 16 hours. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction was quenched with saturated sodiumbicarbonate solution (250 mL) and extracted with di chloromethane (2 × 250 mL). The combined organic extracts were washed with brine (100 mL), dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography using silica-gel (200-400 mesh) and eluting with 50% ethyl acetate in hexanes. The pure fractions were concentrated under reduced pressure to afford (S)-N-methoxy-N,2-dimethylbutanamide (5.12 g, 72%) as a colorless oil;1H NMR (400 MHz, DMSO-d6) δ 3.66 (s, 3H), 3.09 (s, 3H), 2.77 - 2.72 (m, 1H), 1.58 - 1.51 (m, 1H), 1.35 - 1.30 (m, 1H), 1.00 (d, J = 6.8 Hz, 3H), 0.81 (t, J = 7.6 Hz, 3H); MS (ESI) m / z 146 [C7H15NO2 + H]+.

[0207] Preparation of (S)-3-Methylpentan-2-one : To a stirred solution of (S)-N- methoxy-N,2-dimethylbutanamide (5.00 g, 34.4 mmol) in tetrahydrofuran (25 mL), was added methyl magnesium bromide (IM in tetrahydrofuran, 41.3 mL, 41.3 mmol) at 0 °C. The reaction was stirred for 1 hour and the reaction progress was monitored by UPLC-MS. The reaction was quenched with saturated ammonium chloride solution (50 mL) and extracted with methyl tert-butyl ether (2 × 50 mL). The combined organic extracts were washed with brine (100 mL), dried over sodium sulfate, filtered. The filtrate was concentrated by conventional distillation to afford (S)-3-methylpentan-2-one (3.05 g, crude) as a pale-yellow oil. The crude product was used directly for the next step without purification.

[0208] Preparation of (S)-3-Methyl-2-oxopentanal: The stirred solution of selenium dioxide (3.32 g, 29.9 mmol) in 1,4-dioxane (25 mL) and water (1 mL) was heated to 60 °C for 1 hour. (S)-3-Methylpentan-2-one (2.50 g, 24.9 mmol) was added to the reaction at same temperature. The reaction was heated to 100 °C for 16 hours. The reaction was cooled to room temperature and passed through diatomaceous earth. The filtrate under fractional distillation provided (S)-3-methyl-2-oxopentanal (3 mL with traces of dioxane) at 140 °C as a pale-yellow oil. The product with traces of dioxane was used directly for the next step without further purification.

[0209] Preparation of 5-(((S,E)-3-Methyl-2-oxopentylidene)amino)-6-(((2S,3S,4R)~2, 3, 4, 5-tetrahydroxypentyl)amino)pyrimidine-2,4(1H, 3H)-dione ( Compound AI-(S)): The stirred solution of 5-amino-6-(((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine- 2,4(1H,3H)-dione hydrochloride (300 mg, 0.96 mmol) and (S)-3-methyl-2-oxopentanal (3 mL with traces of dioxane) in dimethyl sulfoxide (3 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction wasstirred for 15 minutes and the reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford 5-(((S,E)-3-methyl-2-oxopentylidene)amino)-6-(((2S,3S,4R)-2,3,4,5- tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (165 mg, 46%) as a pale yellow solid:1H NMR (400 MHz, DMSO-d6) δ 10.43 (br s, 1H), 10.82 (s, 1H), 7.47 (br s, 1H), 4.83 (br s, 3H), 3.80 - 3.78 (m, 1H), 3.76 - 3.57 (m, 3H), 3.54 - 3.38 (m, 4H), 1.60 - 1.51 (m, 1H), 1.36 - 1.29 (m, 1H), 0.97 (d, J = 6.8 Hz, 3H), 0.79 (t, J = 7.6 Hz, 3H) (one amidic NH and one OH were not detected);13C NMR (100 MHz, DMSO) 6 206.17, 159.20, 156.21, 150.90, 142.92, 98.47, 73.35, 73.23, 70.61, 63.64, 44.51, 38.36, 26.85, 17.44, 12.21; MS (ESI) m / z 373 [C15H24N4O7 + H]+; UPLC (Method- A) 98.0% (AUC) tR= 3.43 min; Chiral HPLC (Method-C) >99% (AUC) tR= 4.16 min.Scheme 25 : Preparation of 5-(((R,E)-3-Methyl-2-oxopentylidene)amino)-6-(((2S,3 S,4R)- 2,3,4,5-tetrahvdroxvpentvl)amino)pyrimidine-2,4(1H,3H)-dione (Compound AI-(R))

[0210] Preparation of (R)-N-Methoxy-N,2-dimethylbutanamide: To a stirred solution of (R)-2-methylbutanoic acid (5.00 g, 48.9 mmol) and N,O-dimethylhydroxylamine (7.15, 73.37 mmol) in dichloromethane (50 mL), was added triethylamine (20.3 mL, 146 mmol) at 0 °C. After stirring for 5 min, propyl phosphonic anhydride (50% in ethyl acetate, 46.7 mL, 73.3 mmol) was added to the reaction. The reaction was warmed to room temperature and stirred for 16 hours. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction was quenched with saturated sodium bicarbonate solution (50 mL) and extracted with dichloromethane (2 × 50 mL). The combined organic extracts were washed with brine (100 mL), dried over sodium sulfate,filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography using silica-gel (200-400 mesh) and eluting with 50% ethyl acetate in hexanes. The pure fractions were concentrated under reduced pressure to afford (R)-N-methoxy-N,2-dimethylbutanamide (5.05 g, 70%) as a pale-yellow oil:1H NMR (400 MHz, DMSO-d6) δ 3.66 (s, 3H), 3.09 (s, 3H), 2.77 - 2.72 (m, 1H), 1.57 - 1.48 (m, 1H), 1.35 - 1.28 (m, 1H), 0.99 (d, J = 6.8 Hz, 3H), 0.81 (t, J = 7.2 Hz, 3H); MS (ESI) m / z 146 [C7H15NO2 + H]+.

[0211] Preparation of (R)-3-Methylpentan-2-one: To a stirred solution of (R)-N- methoxy-N,2-dimethylbutanamide (5.00 g, 34.4 mmol) in tetrahydrofuran (25 mL), was added methyl magnesium bromide (IM in tetrahydrofuran, 41.3 mL, 41.3 mmol) at 0 °C. The reaction was stirred for 1 hour and the reaction progress was monitored by UPLC-MS. The reaction was quenched with saturated ammonium chloride solution (150 mL) and extracted with methyl tert-butyl ether (2 × 150 mL). The combined organic extracts were washed with brine (100 mL), dried over sodium sulfate, filtered. The filtrate was concentrated by conventional distillation to afford (R)-3-methylpentan -2-one (2.65 g, crude) as a pale-yellow oil. The crude product was used directly for the next step without purification.

[0212] Preparation of (R)-3-Methyl-2-oxopentanal: The stirred solution of selenium dioxide (3.32 g, 29.9 mmol) in 1,4-dioxane (25 mL) and water (1 mL) was heated to 60 °C for 1 hour. (R)-3-Methylpentan-2-one (2.50 g, 24.9 mmol) was added to the reaction at same temperature. The reaction was heated to 100 °C for 16 hours. The reaction was cooled to room temperature and passed through diatomaceous earth. The filtrate under fractional distillation provided (R)-3-methyl-2-oxopentanal (4 mL with traces of dioxane) at 140 °C as a pale-yellow oil. The product with traces of dioxane was used directly for the next step without purification.

[0213] Preparation of 5-(((R,E)-3-Methyl-2-oxopentylidene)amino)-6-(((2S,3S,4R)- 2, 3, 4, 5-tetrahydroxypentyl)amino)pyrimidine-2,4(1H, 3H)-dione ( Compound AI-(R) ) : The stirred solution of 5-amino-6-(((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine- 2,4(1H,3H)-dione hydrochloride (300 mg, 0.96 mmol) and (R)-3-methyl-2-oxopentanal (3 mL with traces of dioxane) in dimethyl sulfoxide (3 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 15 minutes and the reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 10μm150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford 5-(((R,E)-3-methyl-2-oxopentylidene)amino)-6-(((2S,3S,4R)-2,3,4,5- tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (125 mg, 35%) as a pale yellow solid:1H NMR (400 MHz, DMSO-d6) δ 10.48 (br s, 1H), 8.82 (s, 1H), 7.51 (br s, 1H), 5.11 - 4.43 (m, 3H), 3.81 - 3.78 (m, 1H), 3.71 - 3.58 (m, 3H), 3.54 - 3.39 (m, 4H), 1.61 - 1.51 (m, 1H), 1.37 - 1.30 (m, 1H), 0.97 (d, J = 6.8 Hz, 3H), 0.79 (t, J = 7.6 Hz, 3H) (one amidic NH and one OH were not detected);13C NMR (100 MHz, DMSO) 6 205.13, 158.09, 154.97, 149.66, 141.99, 97.35, 72.33, 72.14, 69.37, 62.56, 43.50, 37.18, 25.92, 16.14; MS (ESI) m / z 373 [C15H24N4O7 + H]+; UPLC (Method-A) 98.1% (AUC) tR= 3.35 min; Chiral HPLC (Method-C) >99% (AUC) tR= 4.18 min.EXAMPLE 24

[0214] This example provides an exemplary synthesis for Compound AJ.Scheme 26: Preparation of (E)-5-((2-Oxopropylidene)amino)-6-(((2-oxopyrrolidin-3- yl)methvl)amino)pyrimidine-2,4(1H,3H)-dione (Compound AJ)

[0215] Preparation of N-Methoxy-N,3-dimethyloxetane-3-carboxamide : To a stirred solution of 3 -methyloxetane-3 -carboxylic acid (15.0 g, 129 mmol) in dichloromethane (200 mL), were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (36.7 g, 193 mmol), 1 -hydroxybenzotriazole monohydrate (26.1 g, 193 mmol) and triethylamine (54.4 mL, 387 mmol) and N,O-dimethylhydroxylamine hydrochloride (15.0 g, 155 mmol) under nitrogen atmosphere at 0 °C. The reaction was warmed to room temperature and stirred for 16 hours. The reaction progress was monitored by UPLC-MS until complete consumption ofstarting material was observed. The reaction was quenched with ice water (250 mL) and extracted with di chloromethane (2 × 250 mL). The combined organic extracts were washed with brine (250 mL), dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography using silica gel (200-400 mesh) and eluting with 15-20% ethyl acetate in hexanes. The pure fractions were concentrated under reduced pressure to afford N-methoxy-N,3- dimethyloxetane-3 -carboxamide (9.00 g, 45%) as a color less oil: MS (ESI) m / z 160 [C7H13NO3+ H]+.

[0216] Preparation of l-(3-Methyloxetan-3-yl)ethan-l-one: To a stirred solution ofN- m ethoxy -N, 3 -dimethyloxetane-3 -carboxamide (15.0 g, 94.3 mmol) in tetrahydrofuran (150 mL), was added methyl magnesium bromide (113 mL, 113 mmol, 1.0 M in tetrahydrofuran) under nitrogen atmosphere at -10 °C. The reaction was warmed to room temperature and stirred for 4 hours. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction was quenched with saturated aqueous ammonium chloride solution (250 mL) and extracted with ethyl acetate (2 × 250 mL). The combined organic extracts were washed with brine (250 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to get crude l-(3-methyloxetan-3- yl)ethan-1-one (8.50 g, crude) as a color less oil: MS (ESI) m / z 115 [C6H10O2 + H]+. The crude product was used directly for the next step without purification.

[0217] Preparation of 2 -( 3 -Methyloxetan- 3 -y I) -2 -oxoacetaldehyde: The sealed tube was charged with l-(3-methyloxetan-3-yl)ethan-1-one (2.00 g, 17.5 mmol), selenium dioxide (1.94 g, 17.5 mmol), 1,4-dioxane (14.5 mL), acetic acid (0.50 mL) and water (0.50 mL) at room temperature. Sealed the tube and heated to 100 °C for 16 hours. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction was passed through diatomaceous earth, washed with 1,4-dioxane (10 mL). The filtrate [2-(3-methyloxetan-3-yl)-2-oxoacetaldehyde (25 mL with 14-di oxane), a pale yellow solution] was used directly for the next step without purification: MS (ESI) m / z 129 [C6H8O3 + H]+.

[0218] Preparation of 5-(((E)-2-(3-Methyloxetan-3-yl)-2-oxoethylidene)amino)-6- (((2S, 3S, 4R)-2, 3, 4, 5-tetrahydroxypentyl)amino)pyrimidine-2, 4(1H, 3H)-dione ( Compound AJ): The stirred solution of 5-amino-6-(((2S,3 S,4R)-2, 3,4,5- tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (450 mg, 1.73 mmol) and 2-(3-methyloxetan-3-yl)-2-oxoacetaldehyde (3 mL) in dimethyl sulfoxide (4 mL, crude)was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 15 minutes and progress of reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford 5-(((E)-2-(3-methyloxetan-3-yl)-2- oxoethylidene)amino)-6-(((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine- 2,4(1H,3H)-dione (92.0 mg, 14%) as a pale yellow solid:1H NM (4R00 MHz, DMSO-d6) δ 8.64 (s, 1H), 7.30 - 6.60 (br s, 1H), 6.50 - 6.40 (m, 1H), 6.20 - 6.10 (br s, 1H), 4.85 (d, J = 5.2 Hz, 2H), 4.42 - 4.40 (m, 2H), 3.64 - 3.48 (m, 4H), 3.42 - 3.38 (m, 2H), 3.29 - 3.27 (m, 1H), 1.64 (s, 3H) (Four OH’s were not detected);13C NMR (100 MHz, DMSO-d6) δ 201.98, 162.18, 159.53, 156.45, 133.44, 123.59, 99.81, 78.89, 72.65, 71.75, 71.08, 62.48, 47.27, 42.35, 24.27; MS (ESI) m / z 387 [C15H22N4O8 + H]+; UPLC (Method-A) 98.6% (AUC) tR= 2.86 min.EXAMPLE 25

[0219] This example provides an exemplary synthesis for Compound AK.Scheme 27: Preparation of 5-(((E)-2-(l-Methylcyclobutyl)-2-oxoethylidene)amino)-6- (((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (Compound AK)

[0220] Preparation of N-Methoxy-N,1 -dimethylcyclobutane- 1 -carboxamide: To a stirred solution of 1 -methylcyclobutane- 1 -carboxylic acid (5.00 g, 52.57 mmol) and N,O- dimethylhydroxylamine (7.66 g, 78.9 mmol) in dichloromethane (50 mL), was addedtriethylamine (22 mL, 157 mmol) at 0 °C. After stirring for 5 min, propyl phosphonic anhydride (50% in ethyl acetate, 51.4 mL, 78.9 mmol) was added to the reaction. The reaction was warmed to room temperature and stirred for 16 hours. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction was quenched with saturated sodium bicarbonate solution (150 mL) and extracted with di chloromethane (2 × 150 mL). The combined organic extracts were washed with brine (100 mL), dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by flash column chromatography using silica-gel (200-400 mesh) and eluting with 40% ethyl acetate in hexanes. The pure fractions were concentrated under reduced pressure to afford N-methoxy-N,1- dimethylcyclobutane-1 -carboxamide (6.20 g, 75%) as a colorless oil:1H NMR (400 MHz, CDCl3) δ 3.66 (s, 3H), 3.16 (s, 3H), 2.51 - 2.43 (m, 2H), 2.06 - 1.92 (m, 1H), 1.85 - 1.79 (m, 2H), 1.74 - 1.66 (m, 1H).

[0221] Preparation of 1-(1 -Methyldifluorocyclobutyl) ethan-1 -one: To a stirred solution of N-methoxy-N, 1 -dimethylcyclobutane- 1 -carboxamide (6.20 g, 39.44 mmol) in tetrahydrofuran (60 mL), was added methyl magnesium bromide (IM in tetrahydrofuran, 52 mL, 51.27 mmol) at 0 °C. The reaction was stirred for 2 hours and the reaction progress was monitored by UPLC-MS. The reaction was quenched with saturated ammonium chloride solution (100 mL) and extracted with methyl tert-butyl ether (2 × 100 mL). The combined organic extracts were washed with brine (50 mL), dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography using silica-gel (200-400 mesh) and eluting with 25%-35% ethyl acetate in hexanes. The pure fractions were concentrated under reduced pressure to afford 1-(1- methyldifluorocyclobutyl)ethan-1-one (3.30 g, 75%) as a pale-brown oil:1H NMR (400 MHz, CDCl3) δ 2.43 - 2.35 (m, 2H), 2.09 (s, 3H) 2.03 - 1.91 (m, 1H), 1.82 - 1.66 (m, 3H), 1.38 (s, 3H).

[0222] Preparation of 2-(l-Methydifluorocyclobutyl)-2-oxoacetaldehyde: The stirred solution of selenium dioxide (4.89 g, 44.1 mmol) in 1,4-dioxane (35 mL) and water (3.50 mL) was heated to 60 °C for 1 hour. l-(l-Methyldifluorocyclobutyl)ethan-1-one (3.30 g, 29.41 mmol) was added to the reaction. The reaction was heated to 95 °C for 16 hours. The reaction mixture was cooled to room temperature and passed through diatomaceous earth. The filtrate under fractional distillation provided 2-(1-methydifluorocyclobutyl)-2-oxoacetaldehyde (20 mL with traces of dioxane) at 140 °C as a pale-yellow oil. The product with traces of dioxane was used directly for the next step without purification.

[0223] Preparation of 5-(((E)-2-(l-Methylcyclobutyl)-2-oxoethylidene)amino)-6- (((2S, 38, 4R)-2, 3, 4, 5-tetrahydroxypentyl)amino)pyrimidine-2, 4(1H, 3H)-dione ( Compound AK): The stirred solution of 5-amino-6-(((2S,3 S,4R)-2, 3,4,5- tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (300 mg, 0.96 mmol) and 2-(l-methydifluorocyclobutyl)-2-oxoacetaldehyde (5 mL with traces of 1,4-di oxane) in dimethyl sulfoxide (3 mL) was adjusted to pH ~9 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 30 minutes and the reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford 5-(((E)-2-(l- methylcyclobutyl)-2-oxoethylidene)amino)-6-(((2S,3S,4R)-2,3,4,5- tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (28.0 mg, 8%) as a pale yellow solid:1H NMR (400 MHz, DMSO-d6) δ 11.21 (br s, 1H), 10.69 (br s, 1H), 8.79 (s, 1H), 7.02 (t, J = 5.6 Hz, 1H), 5.23 (br s, 1H), 4.90 (br s, 1H), 4.76 (d, J = 4.8 Hz, 1H), 4.46 (t, J = 5.6 Hz, 1H), 3.91 - 3.71 (m, 1H), 3.66 - 3.57 (m, 2H), 3.51 - 3.47 (m, 1H), 3.45 - 3.32 (m, 3H), 2.46 - 2.39 (m, 2H), 2.04 - 1.90 (m, 3H), 1.74 - 1.62 (m, 1H), 1.50 (s, 3H);13C NMR (100 MHz, DMSO-d6) δ 205.92, 158.85, 154.83, 149.85, 141.99, 97.83, 73.20, 72.95, 70.21, 63.68, 48.09, 43.98, 32.03, 31.91, 25.89, 15.69; MS (ESI) m / z 385 [C16H24N4O7 + H]+;UPLC (Method-G) 98.5% (AUC) tR= 2.50 min; Chiral HPLC (Method-C) >99% (AUC) tR= 5.18 min.EXAMPLE 26

[0224] This example provides an exemplary synthesis for Compound AL.Scheme 28: Preparation of 5-(((E)-2-(2,2-Difluoro-1-methylcyclopropyl)-2 oxoethvlidene)amino)-6-(((2S,3S,4R)-2,3,4,5-tetrahvdroxvpentvl)amino)pyrimidine-2,4(1H,3H)-dione (Compound AL)

[0225] Preparation of 2-(2,2-Difluoro-l-methylcyclopropyl)-2-oxoacetaldehyde: The stirred solution of selenium dioxide (198 mg, 1.79 mmol) in 1,4-dioxane (1 mL) in acetic acid and water (0.20 mL, 1 : 1) was heated to 60 °C for 1 hour. l-(2,2-Difluoro-1- methylcyclopropyl)ethan-1-one (200 mg, 1.49 mmol) was added to the reaction at same temperature. The reaction was heated to 100 °C for 20 hours, cooled to room temperature and filtered through diatomaceous earth. The filtrate under fractional distillation provided 2- (2,2-difluoro-1-methylcyclopropyl)-2-oxoacetaldehyde (1 mL with traces of dioxane) at 130 °C as a pale-yellow oil. The product with traces of dioxane was used directly for the next step without purification.

[0226] Preparation of 5-( ( (E)-2-(2, 2-Difluoro-l-methylcyclopropyl)-2- oxoethylidene)amino)-6-( ( (28, 38, 4R)-2, 3, 4, 5-tetrahydroxypentyl)amino)pyrimidine- 2,4(1H,3H)-dione (Compound AL) : The stirred solution of 5-amino-6-(((2S,3 S,4R)-2, 3,4,5- tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (100 mg, 0.32 mmol) and 2-(2,2-difluoro-1-methylcyclopropyl)-2-oxoacetaldehyde (0.80 mL with traces of 1,4- dioxane) in dimethyl sulfoxide (1 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 15 minutes and the reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford 5-(((E)-2-(2,2- difluoro-1-methylcyclopropyl)-2-oxoethylidene)amino)-6-(((2S,3S,4R)-2,3,4,5- tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (33.2 mg, 25%, Mixture of diastereomers) as a pale yellow solid:1H NMR (400 MHz, DMSO-d6) δ 10.69 (br s, 1H), 8.92 (2s, 1H), 7.13 - 7.09 (m, 1H), 5.15 - 4.77 (m, 2H), 4.44 (br s, 1H), 3.82 - 3.76 (m, 1H), 3.70 - 3.38 (m, 6H), 1.92 - 1.85 (m, 1H), 1.53 (s, 3H), 1.51 - 1.46 (m, 1H) (one amidic NH and one OH were not detected) (mixture of diastereomers);13C NMR (100 MHz, DMSO-d6)δ 194.81, 159.01, 155.83, 155.66, 150.23, 140.87, 140.70, 98.95, 98.90, 73.35, 73.24, 73.03, 72.70, 70.52, 70.48, 63.63, 63.59, 44.43, 44.35, 34.41, 34.31, 19.98, 17.07 (mixture of diastereomers);19F NMR (376 MHz, DMSO-d6) δ -130.70, -131.09 (2d, JF-F = 52.64, IF), 6 -135.88, -136.28 (2d, JF-F = 94.02 Hz, IF) (mixture of diastereomers); MS (ESI) m / z 407 [C15H20F2N4O7 + H]+; UPLC (Method-A) 95.7% (AUC) tR= 2.95 min.EXAMPLE 27

[0227] This example provides an exemplary synthesis for Compound AM, including enantiomers Compound AM-(S) and Compound AM-(R).Scheme 29: Preparation of (E)-5-((2-oxopropylidene)amino)-6-((pyrrolidin-2- ylmethyl)amino)pyrimidine-2,4(1H,3H)-dione (Compound AM)

[0228] Preparation of tert-butyl 2-(((5-nitro-2,6-dioxo-l,2,3,6-tetrahydropyrimidin-4- yl)amino)methyl)pyrrolidine-l -carboxylate (3): Potassium hydroxide solution (2N in H2O, 5 mL, 5.00 mmol) was added dropwise to a stirred solution of tert-butyl 2- (aminomethyl)pyrrolidine-1-carboxylate (1.00 g, 5.00 mmol) and 6-chloro-5-nitropyrimidine- 2,4(1H,3H)-dione (0.96 g, 5.0 mmol) in ethanol (5 mL) and water (2.50 mL). The reaction mixture was stirred at 80 °C for 8 hours. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The mixture was cooled to room temperature, and a solid precipitate formed upon cooling. The solid was collected by filtration, washed with ethanol, and dried under reduced pressure to afford tert-butyl 2-(((5- nitro-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)amino)methyl)pyrrolidine-1-carboxylate (1.10 g, Yield: 62%) as an off-white solid. MS (ESI) m / z 356 [C14H21N5O6 + H]+.

[0229] Preparation of 5-amino-6-( (pyrrolidin-2-ylmethyl)amino)pyrimidine-2, 4(1H, 3H)- dione hydrochloride (4): To a solution of tert-butyl 2-(((5-nitro-2,6-dioxo-l, 2,3,6- tetrahydropyrimidin-4-yl)amino)methyl)pyrrolidine-1-carboxylate (0.50 g, 1.4 mmol) in IN aqueous hydrochloric acid (2 mL) and tetrahydrofuran (2 mL) under an argon atmosphere was added 10% palladium on charcoal (0.20 g) at room temperature. The mixture was stirred under hydrogen atmosphere using a balloon at room temperature for 16 hours. The reaction was filtered through celite. The filtrate was concentrated under reduced pressure to afford 5- amino-6-((pyrrolidin-2-ylmethyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (0.30 g, crude). MS (ESI) m / z 226.1 [C9H16CIN5O2 + H]+. This crude material was used directly without further purification.

[0230] Preparation of (E)-5-((2-oxopropylidene)amino)-6-((pyrrolidin-2- ylmethyl)amino)pyrimidine-2,4(1H,3H)-dione (Compound AM) : A solution of 5-Amino-6- ((pyrrolidin-2-ylmethyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (0.20 g, 0.67 mmol) in dimethyl sulfoxide (0.50 mL) was treated with IN aqueous sodium hydroxide solution to adjust to pH ~8 at room temperature. 2-Oxopropanal (0.073 g, 1.00 mmol, 40% in H2O) was added dropwise to the reaction mixture and stirred at room temperature for 15 minutes. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 10um 150*30mm, Mobile phase A: ACN, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The fractions containing pure product were dried by lyophilization to afford (E)-5-((2- oxopropylidene)amino)-6-((pyrrolidin-2-ylmethyl)amino)pyrimidine-2,4(1H,3H)-dione (13.5 mg, Yield: 7.0%, Curia lot # IN-PHK-K- 187-1) as yellow solid.1H-NMR (400 MHz, D2O ): δ 8.72 (s, 1H), 3.83 - 3.79 (m, 1H), 3.78 - 3.69 (m, 1H), 3.63 - 3.57 (m, 1H), 3.28 - 3.21 (m, 2H), 2.30 (s, 3H), 2.13 - 2.05 (m, 1H), 2.00 - 1.89 (m, 2H), 1.82 - 1.77 (m, 1H); MS (ESI) m / z 280.1 [C12H17N5O3 + H]+; UPLC Purity: 96.5%. (Method- A).Scheme 30: Preparation of (S,E)-5-((2-Oxopropvlidene)amino)-6-((pyrrolidin-2- ylmethyl)amino)pyrimidine-2,4(1H,3H)-dione (Compound AM-(S))

[0231] Preparation of tert-Butyl (S)-2-(((5-nitro-2,6-dioxo-l,2,3,6-tetrahydropyrimidin- 4-yl)amino)methyl)pyrrolidine-l -carboxylate: Potassium hydroxide solution (2N in water, 3.75 mL, 7.50 mmol) was added dropwise to a stirred solution of tert-butyl (S)-2- (aminomethyl)pyrrolidine-1-carboxylate (1.50 g, 7.50 mmol) and 6-chloro-5-nitropyrimidine- 2,4(1H,3H)-dione (1.57 g, 8.25 mmol) in ethanol (15 mL) and water (5 mL). The reaction heated to 80 °C for 8 hours and the reaction progress was monitored by UPLC-MS. The reaction was cooled to room temperature. The precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to afford tert-butyl (S)-2-(((5-nitro-2,6-dioxo- 1,2,3,6-tetrahydropyrimidin-4-yl)amino)methyl)pyrrolidine-1-carboxylate (2.05 g, crude) as an off-white solid: MS (ESI) m / z 356 [C14H21N5O6 + H]+. The crude was used directly for the next step.

[0232] Preparation of (S)-5-Amino-6-((pyrrolidin-2-ylmethyl)amino)pyrimidine- 2,4(1H,3H)-dione hydrochloride: To a solution of tert-butyl (S)-2-(((5-nitro-2,6-dioxo- 1,2,3,6-tetrahydropyrimidin-4-yl)amino)methyl)pyrrolidine-1-carboxylate (2.00 g, 5.63 mmol) in IN aqueous hydrochloric acid (8 mL) and tetrahydrofuran (8 mL), was added 10% palladium on charcoal (200 mg) under an argon atmosphere at room temperature. The reaction was stirred under hydrogen atmosphere using a balloon for 16 hours. The reaction was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to afford (S)-5-amino-6-((pyrrolidin-2-ylmethyl)amino)pyrimidine-2,4(1H,3H)- dione hydrochloride (1.60 g, crude): MS (ESI) m / z 226 [C9H16CIN5O2 + H]+. This crude material was used directly for the next step.

[0233] Preparation of (S,E)-5-((2-Oxopropylidene)amino)-6-((pyrrolidin-2- ylmethyl)amino)pyrimidine-2,4(1H,3H)-dione (Compound AM-(S)) : The stirred solution of (S)-5-amino-6-((pyrrolidin-2-ylmethyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (300 mg, 1.33 mmol) in dimethyl sulfoxide (0.60 mL) was adjusted to pH ~8 by slowaddition of IN aqueous sodium hydroxide solution at room temperature. 2-Oxopropanal (0.48 mL, 2.66 mmol, 40% in water) was added dropwise to the reaction and stirred for 15 minutes. The reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX C18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The fractions containing pure product were dried by lyophilization to afford (S,E)-5-((2-oxopropylidene)amino)-6-((pyrrolidin-2-ylmethyl)amino)pyrimidine- 2,4(1H,3H)-dione (61.5 mg, 17%) as a yellow solid:1H NM (R400 MHz, DMSO-d6) δ 9.50 (br s, 1H), 8.81 (s, 1H), 7.15 (t, J = 5.6 Hz, 1H), 3.69 - 3.64 (m, 1H), 3.61 - 3.50 (m, 3H), 3.18 - 3.11 (m, 1H), 3.03 - 2.96 (m, 1H), 2.30 (s, 3H), 1.98 - 1.65 (m, 4H) (Amidic NH was not detected);13C NMR (100 MHz, DMSO-d6: δ 200.86, 163.36, 160.67, 156.81, 140.98, 100.43, 60.33, 44.45, 43.58, 26.99, 25.09, 24.01; MS (ESI) m / z 280 [C12H17N5O3 + H]+; UPLC (Method-A) 96.2% (AUC) tR= 2.72 min.Scheme 31 : Preparation of (R,E)-5-((2-Oxopropylidene)amino)-6-((pyrrolidin-2- ylmethvl)amino)pyrimidine-2,4(1H,3H)-dione (Compound AM-(R))The stirred solution of (R)-5-amino-6-((pyrrolidin-2-ylmethyl)amino)pyrimidine-2,4(1H,3H)- dione hydrochloride (300 mg, 1.33 mmol) in dimethyl sulfoxide (0.60 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. 2- Oxopropanal (0.48 mL, 2.66 mmol, 40% in water) was added dropwise to the reaction and stirred for 15 minutes. The reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX C18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The fractions containing pure product were dried by lyophilization to afford (R,E)-5-((2-oxopropylidene)amino)-6-((pyrrolidin-2- ylmethyl)amino)pyrimidine-2,4(1H,3H)-dione (84.0 mg, 23%) as a yellow solid:1H NMR (400 MHz, DMSO-d6) δ 9.50 (br s, 1H), 8.81 (s, 1H), 7.15 (t, J = 5.6 Hz, 1H), 3.69 - 3.65 (m, 1H), 3.61 - 3.49 (m, 3H), 3.16 - 3.11 (m, 1H), 3.03 - 2.96 (m, 1H), 2.30 (s, 3H), 1.97 - 1.67 (m, 4H) (Amidic NH was not detected);13C NMR (100 MHz, DMSO-d6) δ 200.98, 163.49,160.66, 157.12, 141.00, 100.49, 60.39, 44.53, 43.48, 27.01, 25.02, 24.02; MS (ESI) m / z 280 [C12H17N5O3 + H]+; UPLC (Method- A) 98.2% (AUC) tR= 2.81 min.EXAMPLE 28

[0234] This example provides an exemplary synthesis for Compound AP, including enantiomers Compound AP-(S) and Compound AP-(R).Scheme 32: Preparation of (E)-5-((2-Oxopropylidene)amino)-6-(((5-oxopyrrolidin-2- yl)methvl)amino)pyrimidine-2,4(1H,3H)-dione (Compound AP)

[0235] The stirred solution of 5-amino-6-(((5-oxopyrrolidin-2- yl)methyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (170 mg, 0.61 mmol) in dimethyl sulfoxide (1 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. 2-Oxopropanal (0.44 mL, 2.47 mmol, 40% in water) was added dropwise to the reaction and stirred for 15 minutes. The reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX C18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried under lyophilization to afford (E)-5-((2-oxobutylidene)amino)- 6-(((5-oxopyrrolidin-2-yl)methyl)amino)pyrimidine-2,4(1H,3H)-dione (26.1 mg, 14%) as a yellow solid:1H NMR (400 MHz, DMSO-d6) δ 11.23 (br s, 1H), 10.59 (br s, 1H), 8.84 (s, 1H), 7.75 (s, 1H), 7.47 (t, J = 6.0 Hz, 1H), 3.80 - 3.71 (m, 1H), 3.59 - 3.52 (m, 1H), 3.48 - 3.42 (m, 1H), 2.34 (s, 3H), 2.22 - 2.06 (m, 3H), 1.75-1.69 (m, 1H);13C NMR (100 MHz, DMSO-d6) δ 201.03, 177.34, 159.22, 155.24, 150.53, 144.46, 98.60, 53.84, 46.26, 29.95, 24.27, 23.96; MS (ESI) m / z 294 [C12H15N5O4 + H]+; UPLC (Method-G) 95.0% (AUC) tR= 0.73 min.Scheme 33: Preparation of (S,E)-5-((2-Oxopropylidene)amino)-6-(((5-oxopyrrolidin-2- yl)methyl)amino)pyrimidine-2,4(1H,3H)-dione (Compound AP-(S))

[0236] Preparation of (S)-5-Nitro-6-(((5-oxopyrrolidin-2-yl)methyl)amino)pyrimidine- 2,4(1H,3H)-dione: To a stirred solution of (S)-5-(aminomethyl)pyrrolidin-2-one hydrochloride (1.50 g, 10.0 mmol) and 6-chloro-5-nitropyrimidine-2,4(1H,3H)-dione (2.10 g, 11.0 mmol) in ethanol (30 mL) and water (10 mL), was added potassium hydroxide solution (2N in water, 5 mL, 10.0 mmol) dropwise at room temperature. The reaction was heated to 80 °C for 8 hours. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction was cooled to room temperature. The precipitate was collected by filtration, washed with ethanol and dried under vacuum to afford (S)-5-nitro-6-(((5-oxopyrrolidin-2-yl)methyl)amino)pyrimidine- 2,4(1H,3H)-dione (2.70 g, crude) as a yellow solid: MS (ESI) m / z 270 [C9H11N5O5 + H]+. The crude product was used directly for the next step without purification.

[0237] Preparation of (S)-5-Amino-6-(((5-oxopyrrolidin-2-yl)methyl)amino)pyrimidine- 2,4(1H,3H)-dione hydrochloride: To a stirred solution of (S)-5-nitro-6-(((5-oxopyrrolidin-2- yl)methyl)amino)pyrimidine-2,4(1H,3H)-dione (1.00 g, 3.71 mmol) in IN aqueous hydrochloric acid (10 mL), ethanol (20 mL) and tetrahydrofuran (20 mL), was added 10% palladium on charcoal (500 mg, 50% wet) under argon atmosphere at room temperature. The reaction was stirred under hydrogen atmosphere using a balloon for 48 hours. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction mixture was filtered through diatomaceous earth bed, and the filtrate was concentrated under reduced pressure to afford of (S)-5-amino-6-(((5-oxopyrrolidin-2- yl)methyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (500 mg, crude) as a pink color solid: MS (ESI) m / z 240 [C9H14CIN5O3 + H]+.

[0238] Preparation of (S,E)-5-((2-Oxopropylidene)amino)-6-( ( (5-oxopyrrolidin-2- yl)methyl)amino)pyrimidine-2,4(1H,3H)-dione (Compound AP-(S)) : The stirred solution of (S)-5-amino-6-(((5-oxopyrrolidin-2-yl)methyl)amino)pyrimidine-2,4(1H,3H)-dionehydrochloride (300 mg, 1.09 mmol) and 2-oxopropanal (0.39 mL, 2.18 mmol, 40% in water) in dimethyl sulfoxide (2 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 15 minutes and progress of reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford (S,E)- 5-((2-oxopropylidene)amino)-6-(((5-oxopyrrolidin-2-yl)methyl)amino)pyrimidine- 2,4(1H,3H)-dione (22.0 mg, 7%) as a yellow solid:1H NM (R400 MHz, DMSO-d6) δ 10.53 (br s, 1H), 8.84 (s, 1H), 7.76 (s, 1H), 7.45 (t, J = 6.4 Hz, 1H), 3.78 - 3.75 (m, 1H), 3.58 - 3.51 (m, 1H), 3.48 - 3.41 (m, 1H), 2.34 (s, 3H), 2.23 - 2.06 (m, 4H), 1.76 - 1.69 (m, 1H);13C NMR (100 MHz, DMSO-d6) δ 199.93, 176.26, 158.18, 154.39, 149.66, 143.21, 97.58, 52.76, 45.14, 28.87, 23.18, 22.89; MS (ESI) m / z 294 [C12H15N5O4 + H]+; UPLC (Method-A) 97.6% (AUC) tR 2.87 min; Chiral HPLC (Method-K) >99% (AUC) tR= 4.13 min.Scheme 34: Preparation of (R,E)-5-((2-Oxopropylidene)amino)-6-(((5-oxopyrrolidin-2- yl)methvl)amino)pyrimidine-2,4(1H,3H)-dione (Compound AP-(R))

[0239] Preparation of (R)-5-Nitro-6-(((5-oxopyrrolidin-2-yl)methyl)amino)pyrimidine-2,4(1H,3H)-dione: To a stirred solution of (R)-5-(aminomethyl)pyrrolidin-2-one hydrochloride (1.50 g, 10.0 mmol) and 6-chloro-5-nitropyrimidine-2,4(1H,3H)-dione (2.10g, 11.0 mmol) in ethanol (30 mL) and water (10 mL), was added potassium hydroxide solution (2N in water, 5 mL, 10.0 mmol) dropwise at room temperature. The reaction was heated to 80 °C for 8 hours and the reaction progress was monitored by UPLC-MS. The reaction was cooled to room temperature. The precipitate was collected by filtration, washed with ethanol and dried under vacuum to afford (S)-5-nitro-6-(((5-oxopyrrolidin-2- yl)methyl)amino)pyrimidine-2,4(1H,3H)-dione (2.80 g, crude) as an off white solid: MS(ESI) m / z 270 [C9H11N5O5 + H]+. The crude product was used directly for the next step without purification.

[0240] Preparation of (R)-5-Amino-6-(((5-oxopyrrolidin-2-yl)methyl)amino)pyrimidine- 2,4(1H,3H)-dione hydrochloride: To a stirred solution of (R)-5-nitro-6-(((5-oxopyrrolidin-2- yl)methyl)amino)pyrimidine-2,4(1H,3H)-dione (1.00 g, 3.71 mmol) in IN aqueous hydrochloric acid (10 mL), ethanol (20 mL) and acetic acid (20 mL), was added 10% palladium on charcoal (500 mg, 50% wet) under argon atmosphere at room temperature. The reaction was stirred under hydrogen atmosphere using a balloon for 16 hours. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction was passed through diatomaceous earth, and the filtrate was concentrated under reduced pressure to afford (R)-5-amino-6-(((5-oxopyrrolidin-2- yl)methyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (480 mg, crude) as a pink solid: MS (ESI) m / z 240 [C9H14CIN5O3 + H]+. The crude product was used directly for the next step without purification.

[0241] Preparation of (R,E)-5-((2-Oxopropylidene)amino)-6-( ( (5-oxopyrrolidin-2- yl)methyl)amino)pyrimidine-2,4(1H,3H)-dione (Compound AP-(R)): The stirred solution of (R)-5-amino-6-(((5-oxopyrrolidin-2-yl)methyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (400 mg, 1.45 mmol) and 2-oxopropanal (0.52 mL, 0.29 mmol, 40% in water) in dimethyl sulfoxide (3 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 15 minutes and progress of reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford (R,E)- 5-((2-oxopropylidene)amino)-6-(((5-oxopyrrolidin-2-yl)methyl)amino)pyrimidine- 2,4(1H,3H)-dione (62.0 mg, 14%) as a yellow solid:1H NM (R400 MHz, DMSO-d6) δ 11.15 (br s, 1H), 10.63 (s, 1H), 8.85 (s, 1H), 7.75 (s, 1H), 7.50 (t, J = 6.8 Hz, 1H), 3.78 - 3.74 (m, 1H), 3.59 - 3.52 (m, 1H), 3.49 - 3.42 (m, 1H), 2.34 (s, 3H), 2.23 - 2.16 (m, 1H), 2.14 - 2.61 (m, 2H), 1.75 - 1.73 (m, 1H);13C NMR (100 MHz, DMSO-d6) δ 199.98, 176.28, 158.09, 153.91, 149.25, 143.56, 97.45, 52.76, 45.22, 28.88, 23.21, 22.87; MS (ESI) m / z 294 [C12H15N5O4+ H]+; UPLC (Method- A) 97.5% (AUC) tR= 2.85 min; Chiral HPLC (Methodic) >99% (AUC) tR= 3.32 min.EXAMPLE 29

[0242] This example provides an exemplary synthesis for Compound AR, including enantiomers Compound AR-(S) and Compound AR-(R).Scheme 35: Preparation of (E)-9-((2-Oxopropylidene)amino)-L2,3,4-tetrahydro-6H- pyrimido[1,6-a]pyrimidine-6,8(7H)-dione (Compound AR)

[0243] The stirred solution of 5-amino-6-((pyrrolidin-2-ylmethyl)amino)pyrimidine- 2,4(1H,3H)-dione hydrochloride (300 mg, 1.33 mmol) in dimethyl sulfoxide (0.60 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. 2-oxobutanal (220 mg, 2.66 mmol) was added dropwise to the reaction and stirred for 15 minutes. The reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini -NX C18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The fractions containing pure product were dried by lyophilization to afford (E)-5-((2-oxobutylidene)amino)-6-((pyrrolidin-2- ylmethyl)amino)pyrimidine-2,4(1H,3H)-dione (26.5 mg, 7%) as a yellow solid:1H NMR (400 MHz, D2O) δ 8.77 (s, 1H), 4.10 - 3.81 (m, 3H), 3.23 (t, J = 6.8 Hz, 2H), 2.81 (q, J = 7.2 Hz, 2H), 2.17 - 1.64 (m, 4H), 1.04 (t, J = 7.2 Hz, 3H);13C NMR (100 MHz, DMSO-d6) δ 203.26, 163.16, 160.69, 156.48, 140.56, 100.21, 60.21, 44.35, 43.67, 28.30, 26.99, 25.17, 9.01; MS (ESI) m / z 294 [C13H19N5O3 + H]+; UPLC (Method-A) >99% (AUC) tR= 3.25 min. Scheme 36: Preparation of (S,E)-5-((2-Oxobutylidene)amino)-6-((pyrrolidin-2- ylmethyl)amino)pyrimidine-2,4(1H,3H)-dione (Compound AR-(S))

[0244] The stirred solution of (S)-5-amino-6-((pyrrolidin-2-ylmethyl)amino)pyrimidine- 2,4(1H,3H)-dione hydrochloride (300 mg, 1.33 mmol) in dimethyl sulfoxide (0.60 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. 2-Oxobutanal (0.30 mL with traces of 1,4-dioxane) was added dropwise to thereaction and stirred for 15 minutes. The reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini -NX Cl 8 10μm 150*30mm, Mobile phase A: ACN, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The fractions containing pure product were dried by lyophilization to afford (S,E)-5-((2-oxobutylidene)amino)-6-((pyrrolidin-2- ylmethyl)amino)pyrimidine-2,4(1H,3H)-dione (48.5 mg, 13%) as a yellow solid:1H NMR (400 MHz, DMSO-d6) δ 10.57 (br s, 1H), 9.49 (s, 1H), 8.83 (s, 1H), 7.12 (t, J = 5.6 Hz, 1H), 3.70 - 3.48 (m, 4H), 3.16 - 3.10 (m, 1H), 3.02 - 2.96 (m, 1H), 2.86 (q, J = 7.2 Hz, 2H), 1.97 - 1.67 (m, 4H), 1.04 (t, J = 7.2 Hz, 3H);13C NMR (100 MHz, DMSO-d6) δ 203.52, 163.43, 160.64, 157.12, 140.66, 100.34, 60.46, 44.57, 43.46, 28.44, 27.01, 24.98, 9.00; MS (ESI) m / z 294 [C13H19N5O3 + H]+; UPLC (Method-G) 95.1% (AUC) tR= 1.28 min.Scheme 37: Preparation of (R,E)-5-((2-Oxobutvlidene)amino)-6-((pyrrolidin-2- ylmethyl)amino)pyrimidine-2,4(1H,3H)-dione (Compound AR-(R))

[0245] Preparation of tert-Butyl (R)-2-(((5-nitro-2, 6-dioxo-l,2,3, 6-tetrahydropyrimidin- 4-yl)amino)methyl)pyrrolidine-l -carboxylate: Potassium hydroxide solution (2N in water, 2.60 mL, 5.23 mmol) was added dropwise to a stirred solution of tert-butyl (R)-2- (aminomethyl)pyrrolidine-l -carboxylate (1.00 g, 5.23 mmol) and 6-chloro-5-nitropyrimidine- 2,4(1H,3H)-dione (1.04 g, 5.23 mmol) in ethanol (10 mL) and water (5 mL) at room temperature. The reaction was heated to 80 °C for 8 hours and the reaction progress was monitored by UPLC-MS. The mixture was cooled to room temperature, and the precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to afford tert-butyl (R)-2-(((5-nitro-2,6-dioxo-l,2,3,6-tetrahydropyrimidin-4- yl)amino)methyl)pyrrolidine-l -carboxylate (1.40 g, crude) as an off-white solid. MS (ESI) m / z 356 [C14H21N5O6 + H]+.

[0246] Preparation of (R)-5-Amino-6-((pyrrolidin-2-ylmethyl)amino)pyrimidine- 2,4(1H,3H)-dione hydrochloride: To a solution of tert-butyl (S)-2-(((5-nitro-2,6-dioxo- 1,2,3,6-tetrahydropyrimidin-4-yl)amino)methyl)pyrrolidine-1-carboxylate (2.00 g, 5.63 mmol) in IN aqueous hydrochloric acid (8 mL) and tetrahydrofuran (8 mL), was added 10% palladium on charcoal (0.20 g) under an argon atmosphere at room temperature. The reaction was stirred under hydrogen atmosphere using a balloon for 16 hours. The reaction was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to afford (R)-5-amino-6-((pyrrolidin-2-ylmethyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (1.60 g, crude): MS (ESI) m / z 226.1 [C9H16CIN5O2 + H]+. This crude material was used directly for the next step.

[0247] Preparation of (R,E)-5-((2-Oxobutylidene)amino)-6-((pyrrolidin-2- ylmethyl)amino)pyrimidine-2,4(1H,3H)-dione (Compound AR-(R)) : The stirred solution of (R)-5-amino-6-((pyrrolidin-2-ylmethyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (300 mg, 1.33 mmol) in dimethyl sulfoxide (0.60 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. 2-Oxobutanal (0.30 mL with traces of 1,4-di oxane) was added dropwise to the reaction and stirred at same temperature for 15 minutes. The reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini -NX Cl 8 10μm 150*30mm, Mobile phase A: ACN, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The fractions containing pure product were dried by lyophilization to afford (R,E)-5-((2-oxobutylidene)amino)-6-((pyrrolidin-2- ylmethyl)amino)pyrimidine-2,4(1H,3H)-dione (48.5 mg, 13%) as a yellow solid:1H NMR (400 MHz, DMSO-d6) δ 10.57 (br s, 1H), 9.49 (s, 1H), 8.83 (s, 1H), 7.12 (t, J = 5.6 Hz, 1H), 3.68 - 3.65 (m, 1H), 3.58 - 3.50 (m, 3H), 3.16 - 3.10 (m, 1H), 3.02 - 2.96 (m, 1H), 2.86 (q, J = 7.2 Hz, 2H), 1.97 - 1.67 (m, 4H), 0.98 (t, J = 7.2 Hz, 3H);13C NMR (100 MHz, DMSO-d6) δ 203.55, 163.49, 160.64, 157.24, 140.67, 100.37, 60.48, 44.60, 43.42, 28.45, 27.01, 24.95, 8.99; MS (ESI) m / z 294 [C13H19N5O3 + H]+; UPLC (Method-A) 97.0% (AUC) tR= 3.08 min.EXAMPLE 30

[0248] This example provides an exemplary synthesis for Compound AU, including enantiomers Compound AU-(S) and Compound AU-(R).Scheme 38: Preparation of (E)-5-((2-Oxobutvlidene)amino)-6-(((5-oxopyrrolidin-2- yl)methyl)amino)pyrimidine-2,4(1H,3H)-dione (Compound AU)

[0249] Preparation of 5-Nitro-6-(((5-oxopyrrolidin-2-yl)methyl)amino)pyrimidine- 2,4(1H,3H)-dione: To a stirred solution of 5-(aminomethyl)pyrrolidin-2-one (1.00 g, 8.77 mmol) and 6-chloro-5-nitropyrimidine-2,4(1H,3H)-dione (1.84 g, 9.64 mmol) in ethanol (20 mL) and water (6 mL), was added potassium hydroxide solution (2N in water, 4.38 mL, 8.77 mmol) dropwise at room temperature. The reaction was heated to 80 °C for 8 hours. The reaction progress was monitored by UPLC-MS and the reaction mixture was cooled to room temperature. The precipitate was collected by filtration, washed with ethanol and dried under vacuum to afford 5-nitro-6-(((5-oxopyrrolidin-2-yl)methyl)amino)pyrimidine-2,4(1H,3H)- dione (2.50 g, Crude) as a light yellow solid: MS (ESI) m / z 270 [C9H11N5O5 + H]+.

[0250] Preparation of 5-Amino-6-(((5-oxopyrrolidin-2-yl)methyl)amino)pyrimidine- 2,4(1H,3H)-dione hydrochloride: To a solution of 5-nitro-6-(((5-oxopyrrolidin-2- yl)methyl)amino)pyrimidine-2,4(1H,3H)-dione (2.50 g, 9.29 mmol) in IN aqueous hydrochloric acid (15 mL), ethanol (20 mL) and tetrahydrofuran (20 mL), was added 10% palladium on charcoal (50% wet, 1.25 g) under argon atmosphere at room temperature. The reaction was stirred under hydrogen atmosphere using a balloon for 48 hours. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction was passed through diatomaceous earth, and the filtrate was concentrated under reduced pressure to afford 5-amino-6-(((5-oxopyrrolidin-2- yl)methyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (2.00 g, crude) as a pink solid: MS (ESI) m / z 240 [C9H14CIN5O3+ H]+. The crude product was used directly for the next step without purification.

[0251] Preparation of (E)-5-((2-Oxobutylidene)amino)-6-(((5-oxopyrrolidin-2- yl)methyl)amino)pyrimidine-2,4(1H,3H)-dione (Compound AU) : The stirred solution of 5-amino-6-(((5-oxopyrrolidin-2-yl)methyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (250 mg, 0.90 mmol) in dimethyl sulfoxide (4 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. 2-Oxobutanal (150 mg, 1.81 mmol) was added dropwise to the reaction and stirred for 15 minutes. The reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX C18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford (E)-5-((2-oxobutylidene)amino)-6- (((5-oxopyrrolidin-2-yl)methyl)amino)pyrimidine-2,4(1H,3H)-dione (59.1 mg, 21%) as a yellow solid:1H NMR (400 MHz, D2O) δ 11.13 (br s, 1H), 10.66 (br s, 1H), 8.87 (s, 1H), 7.75 (s, 1H), 7.47 (t, J = 6.8 Hz, 1H), 3.83 - 3.71 (m, 1H), 3.58 - 3.42 (m, 2H), 2.90 (q, J = 7.2 Hz, 2H), 2.23 - 2.06 (m, 3H), 1.75 - 1.68 (m, 1H), 0.99 (t, J = 7.2 Hz, 3H);13C NMR (100 MHz, DMSO-d6) δ 203.46, 177.37, 159.16, 154.79, 150.18, 144.39, 98.38, 53.82, 46.28, 29.96, 28.72, 23.93, 8.62; MS (ESI) m / z 308 [C13H17N5O4 + H]+; UPLC (Method-A) 95.3% (AUC) tR= 2.87 min.Scheme 39: Preparation of (S,E)-5-((2-Oxobutvlidene)amino)-6-(((5-oxopyrrolidin-2- yl)methyl)amino)pyrimidine-2,4(1H,3H)-dione (Compound AU-(S))

[0252] The stirred solution of (S)-5-amino-6-(((5-oxopyrrolidin-2- yl)methyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (300 mg, 1.09 mmol) and 2- oxobutanal (1.50 mL with traces of l,4-dioxaen)in dimethyl sulfoxide (3 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 15 minutes and progress of reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford (S,E)-5-((2-oxopropylidene)amino)-6-(((5- oxopyrrolidin-2-yl)methyl)amino)pyrimidine-2,4(1H,3H)-dione (40.0 mg, 12%) as a yellow solid:1H NMR (400 MHz, DMSO-d6) δ 11.56 (br s, 1H), 10.51 (s, 1H), 8.86 (s, 1H), 7.75 (s, 1H), 7.40 (t, J = 6.4 Hz, 1H), 3.78 - 3.75 (m, 1H), 3.58 - 3.51 (m, 1H), 3.47 - 3.41 (m, 1H),2.89 (q, J = 7.2 Hz, 2H), 2.22 - 2.17 (m, 1H), 2.15 - 2.06 (m, 2H), 1.75 - 1.68 (m, 1H), 0.99 (t, J = 7.6 Hz, 3H);13C NMR (100 MHz, DMSO-d6) δ 202.29, 176.26, 158.28, 154.80, 150.06, 142.53, 97.59, 52.77, 45.03, 28.91, 27.59, 22.90, 7.62; MS (ESI) m / z 308 [C13H17N5O4 + H]+; UPLC (Method-A) 98.1% (AUC) tR= 2.91 min; Chiral HPLC (Method-K) >99% (AUC) tR= 3.63 min.Scheme 40: yl)methvl)amino)pyrimidine-2,4(1H,3H)-dione (Compound AU-(R))

[0253] The stirred solution of (R)-5-amino-6-(((5-oxopyrrolidin-2- yl)methyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (300 mg, 1.09 mmol) and 2- oxobutanal (1.20 mL with traces of 1,4-dioxane) in dimethyl sulfoxide (2 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 15 minutes and progress of reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford (R,E)-5-((2-oxobutylidene)amino)-6-(((5- oxopyrrolidin-2-yl)methyl)amino)pyrimidine-2,4(1H,3H)-dione (28.0 mg, 8%) as a yellow solid:1H NMR (400 MHz, DMSO-d6) δ 11.54 (br s, 1H), 10.65 (s, 1H), 8.87 (s, 1H), 7.75 (s, 1H), 7.47 (t, J = 6.8 Hz, 1H), 3.83 - 3.72 (m, 1H), 3.57- 3.51 (m, 1H), 3.49 - 3.44 (m, 1H), 2.89 (q, J =7.2 Hz, 2H), 2.25 - 2.18 (m, 1H), 2.16 - 2.06 (m, 2H), 1.74 - 1.70 (m, 1H), 0.99 (t, J = 7.6 Hz, 3H);13C NMR (100 MHz, DMSO-d6) δ 202.36, 176.27, 158.08, 153.73, 149.11, 143.28, 97.29, 52.73, 45.19, 28.87, 27.63, 22.84, 7.54; MS (ESI) m / z 308 [C13H17N5O4 + H]+; UPLC (Method-A) >99% (AUC) tR= 3.36 min; Chiral HPLC (Method-K) >99% (AUC) tR= 3.29 min.EXAMPLE 31

[0254] This example provides an exemplary synthesis for Compound AW.Scheme 41 : ylmethyl)amino)pyrimidine-2,4(1H,3H)-dione (Compound AW)

[0255] The stirred solution of 5-amino-6-((pyrrolidin-2-ylmethyl)amino)pyrimidine- 2,4(1H,3H)-dione hydrochloride (300 mg, 1.33 mmol) in dimethyl sulfoxide (0.60 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. 3 -Methyl -2-oxobutanal (0.30 mL with traces of 1,4-dioxane) was added dropwise to the reaction and stirred for 15 minutes. The reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX C18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The fractions containing pure product were dried by lyophilization to afford (E)-5-((3-methyl-2- oxobutylidene)amino)-6-((pyrrolidin-2-ylmethyl)amino)pyrimidine-2,4(1H,3H)-dione (54.4 mg, 13%) as a yellow solid:1H NMR (400 MHz, D2O) δ 8.88 (s, 1H), 3.83 - 3.71 (m, 2H), 3.63 - 3.57 (m, 1H), 3.49 - 3.41 (m, 1H), 3.22 (t, J = 6.8 Hz, 2H), 2.13 - 2.05 (m, 1H), 2.01 - 1.87 (m, 2H), 1.84 - 1.74 (m, 1H), 1.06 (s, 3H), 1.04 (s, 3H);13C NMR (100 MHz, DMSO- d6) 5 206.45, 163.45, 160.66, 156.94, 139.55, 100.45, 60.43, 44.51, 43.53, 31.40, 27.01, 25.03, 19.87, 19.66; MS (ESI) m / z 308 [C14H21N5O3 + H]+; UPLC (Method-A) 98.2% (AUC) tR 3.53 min.EXAMPLE 32

[0256] This example provides an exemplary synthesis for Compound AY.Scheme 42: Preparation of (E)-6-(((1H-Imidazol-2-yl)methyl)amino)-5-((3-methyl-2- oxobutylidene)amino)pyrimidine-2,4(1H,3H)-dione (Compound AY)

[0257] The stirred solution of 6-(((1H-imidazol-2-yl)methyl)amino)-5-aminopyrimidine-2,4-diol hydrochloride (250 mg, 0.96 mmol) and 3-methyl-2-oxobutanal (1 mL with traces of1,4-di oxane) in dimethyl sulfoxide (2 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 15 minutes and the reaction progress was monitored by UPLC-MS which showed a majority of an undesired mass along with a minority of Compound AY mass. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford (E)-6- (((1H-imidazol-2-yl)methyl)amino)-5-((3-methyl-2-oxobutylidene)amino)pyrimidine- 2,4(1H,3H)-dione (Compound AY, 6.00 mg, 2%) as a yellow solid:1H NMR (400 MHz, DMSO-d6) 6 10.71 (s, 1H), 8.85 (s, 1H), 7.94 (t, J = 6.0 Hz, 1H), 7.03 (s, 2H), 4.69 (d, J = 6.0 Hz, 2H), 3.98 - 3.91 (m, 1H), 1.00 (s, 3H), 0.98 (s, 3H) (one amidic NH and one imidazole NH were not detected): MS (ESI) m / z 305 [C13H16N6O3 + H]+; UPLC (Method-A) 98.4% (AUC) tR = 3.16 min.EXAMPLE 33

[0258] This example provides an exemplary synthesis for Compound AZ.Scheme 43 : oxopyrrolidin-2-yl)methyl)amino)pyrimidine-2,4(1H,3H)-dione (Compound AZ)

[0259] The stirred solution of 5-amino-6-(((5-oxopyrrolidin-2- yl)methyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (400 mg, 1.45 mmol) in dimethyl sulfoxide (4 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. 3 -Methyl -2-oxobutanal (2 mL with traces of 1,4- di oxane) was added dropwise to the reaction and stirred for 15 minutes. The reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX C18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford (E)-5-((3- methyl-2-oxobutylidene)amino)-6-(((5-oxopyrrolidin-2-yl)methyl)amino)pyrimidine- 2,4(1H,3H)-dione (97.2 mg, 21%) as a yellow solid:1H NM (R400 MHz, D2O): δ 11.15 (br s,1H), 10.66 (br s, 1H), 8.84 (s, 1H), 7.72 (s, 1H), 7.43 (t, J = 6.4 Hz, 1H), 3.93 - 3.91 (m, 1H), 3.71 - 3.63 (m, 1H), 3.61 - 3.54 (m, 1H), 3.48 - 3.42 (m, 1H), 2.19 - 2.08 (m, 3H), 1.78 - 1.68 (m, 1H), 1.00 (d, J = 7.2 Hz, 6H);13C NMR (100 MHz, DMSO-d6) δ 206.51, 177.45, 159.14, 154.89, 150.14, 143.36, 98.48, 53.74, 46.02, 31.97, 29.98, 23.82, 19.49, 19.42; MS (ESI) m / z 322 [C14H19N5O4 + H]+; UPLC (Method-A) 97.6% (AUC) tR= 3.28 min.EXAMPLE 34

[0260] This example provides an exemplary synthesis for Compound BB.Scheme 44: Preparation of (E)-5-((2-Cvclopropvl-2-oxoethvlidene)amino)-6-((pyrrolidin-2-ylmethyl)amino)pyrimidine-2,4(1H,3H)-dione (Compound BB)

[0261] The stirred solution of 5-amino-6-((pyrrolidin-2-ylmethyl)amino)pyrimidine- 2,4(1H,3H)-dione hydrochloride (300 mg, 1.33 mmol) in dimethyl sulfoxide (0.60 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. 2-Cyclopropyl-2-oxoacetaldehyde (0.30 mL with traces of 1,4-dioxane) was added dropwise to the reaction and stirred at room temperature for 15 minutes. The reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX C18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The fractions containing pure product were dried by lyophilization to afford (E)-5-((2-cyclopropyl-2-oxoethylidene)amino)-6-((pyrrolidin-2- ylmethyl)amino)pyrimidine-2,4(1H,3H)-dione (130 mg, 38%) as a yellow solid:1H-NMR (400 MHz, DMSO-d6) δ 10.57 (br s, 1H), 9.52 (s, 1H), 8.94 (s, 1H), 7.25 (t, J = 5.6 Hz, 1H), 3.71 - 3.58 (m, 1H), 3.58 - 3.49 (m, 2H), 3.38 - 3.33 (m, 2H), 3.17 - 3.11 (m, 1H), 3.03 - 2.96 (m, 1H), 1.97 - 1.85 (m, 2H), 1.80 - 1.66 (m, 2H), 0.82 - 0.81 (m, 4H);13C NMR (100 MHz, DMSO-d6) δ 201.52, 163.53, 160.67, 157.05, 141.25, 100.86, 60.41, 44.53, 43.48, 27.00, 25.02, 13.87, 10.70, 10.57; MS (ESI) m / z 306 [C14H19N5O3 + H]+; UPLC (Method-A) 96.3% (AUC) tR= 3.03 min.EXAMPLE 35

[0262] This example provides an exemplary synthesis for Compound BD.Scheme 45: Preparation of (E)-6-(((1H-Imidazol-2-yl)methyl)amino)-5-((2-cyclopropyl-2- oxoethvlidene)amino)pyrimidine-2,4(1H,3H)-dione (Compound BD)

[0263] Preparation of N-( 1H-Imidazol-2-yl)methyl)-2, 6-bis(benzyloxy)-5- nitropyrimidin-4-amine: To a stirred solution of (1H-imidazol-2-yl)methanamine dihydrochloride (500 mg, 2.94 mmol) and 2,4-bis(benzyloxy)-6-chloro-5-nitropyrimidine (1.20 g, 3.23 mmol) in N,N-dimethyl formamide (10 mL), was added triethylamine (1.23 mL, 8.82 mmol) dropwise at room temperature. The reaction was stirred for 8 hours and the reaction progress was monitored by UPLC-MS. The reaction was poured in ice cold water (50 mL) and stirred for 30 minutes. The precipitate was collected by filtration, washed with water (50 mL) and methyl tert-butyl ether (10 mL). The crude material was purified by flash chromatography by using silica gel (100-200 Mesh) and eluting with 5-6% of methanol in di chloromethane. The pure fractions were collected and concentrated under reduced pressure to afford N-((1H-imidazol-2-yl)methyl)-2,6-bis(benzyloxy)-5-nitropyrimidin-4-amine (1.00 g, 78%) as an off white solid:1H NMR (400 MHz, DMSO-d6) δ 11.91 (br s, 1H), 9.35 (t, J = 5.6 Hz, 1H), 7.48 - 7.26 (m, 10H), 6.95 (s, 2H), 5.51 (s, 2H), 5.33 (s, 2H), 4.76 (d, J = 5.2 Hz, 2H); MS (ESI) m / z 433 [C22H20N6O4 + H]+; MS (ESI) m / z 433 [C22H20N6O4 + H]+.

[0264] Preparation of 6-( ( < 1H-Imidazol-2-yl)methyl)amino)-5-aminopyrimidine-2, 4-diol hydrochloride: To a solution of N-((1H-imidazol-2-yl)methyl)-2,6-bis(benzyloxy)-5- nitropyrimidin-4-amine (1.00 g, 9.29 mmol) in IN aqueous hydrochloric acid (10 mL) and tetrahydrofuran (20 mL), was added 10% palladium on charcoal (500 mg, 50% wet) under argon atmosphere at room temperature. The reaction was stirred under hydrogen atmosphereusing a balloon for 16 hours. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction was passed through diatomaceous earth, and the filtrate was concentrated under reduced pressure to afford 6- (((1H-imidazol-2-yl)methyl)amino)-5-aminopyrimidine-2,4-diol hydrochloride (700 mg, crude): MS (ESI) m / z 259 [CsHnQNeCh + H]+. The crude was used directly for the next step without purification.

[0265] Preparation of (E)-6-(((1H-Imidazol-2-yl)methyl)amino)-5-((2-cyclopropyl-2- oxoethylidene)amino)pyrimidine-2,4(1H,3H)-dione (Compound BD) : The stirred solution of 6-(((1H-imidazol-2-yl)methyl)amino)-5-aminopyrimidine-2,4-diol hydrochloride (280 mg,I.08 mmol) in dimethyl sulfoxide (2 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. 2-Cyclopropyl-2-oxoacetaldehyde (1 mL with traces of dioxane) was added dropwise to the reaction and stirred for 15 minutes. The reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX C18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried under lyophilization to afford (E)-5-((2- oxobutylidene)amino)-6-(((5-oxopyrrolidin-2-yl)methyl)amino)pyrimidine-2,4(1H,3H)-dione (65.0 mg, 20%) as a yellow solid:1H NMR (400 MHz, DMSO-d6) δ 10.60 (br s, 1H), 8.98 (s, 1H), 8.06 (t, J = 6.0 Hz, 1H), 7.01 (s, 2H), 4.69 (d, J = 6.4 Hz, 2H), 3.57 - 3.23 (m, 1H), 0.86 (d, J = 6.4 Hz, 4H) (one amidic NH and one imidazole NH were not detected);13C NMR (100 MHz, DMSO-d6) δ 201.62, 159.40, 156.12, 150.66, 144.71, 144.50, 122.34, 99.37, 14.01,I I.03; MS (ESI) m / z 303 [C13H14N6O3 + H]+; UPLC (Method-A) 93.0% (AUC) tR= 3.12 min.EXAMPLE 36

[0266] This example provides an exemplary synthesis for Compound BE.Scheme 46: Preparation (E)-5-((2-Cyclopropyl-2-oxoethylidene)amino)-6-(((5- oxopvrrolidin-2-vl)methvl)amino)pyrimidine-2,4(1H,3H)-dione (Compound BE)

[0267] The stirred solution of 5-amino-6-(((5-oxopyrrolidin-2- yl)methyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (250 mg, 0.90 mmol) in dimethyl sulfoxide (2 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. 2-cyclopropyl-2-oxoacetaldehyde (0.70 mL with traces of dioxane) was added dropwise to the reaction and stirred for 15 minutes. The reaction progress was monitored by UPLC-MS. The reaction mixture was purified by mass triggered preparative HPLC (Column: Gemini-NX C18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were by under lyophilization to afford (E)-5-((3- methyl-2-oxobutylidene)amino)-6-(((5-oxopyrrolidin-2-yl)methyl)amino)pyrimidine- 2,4(1H,3H)-dione (145 mg, 50%) as a yellow solid:1H NMR (400 MHz, DMSO-d6) δ 11.15 (br s, 1H), 10.75 (br s, 1H), 8.98 (s, 1H), 7.77 (s, 1H), 7.66 (t, J = 6.4 Hz, 1H), 3.81 - 3.73 (m, 1H), 3.60 - 3.53 (m, 1H), 3.48 - 3.44 (m, 1H), 3.40 - 3.38 (m, 1H), 2.28 - 2.06 (m, 3H), 1.73 - 1.68 (m, 1H), 0.89 - 0.87 (m, 4H);13C NMR (100 MHz, DMSO-d6) δ 201.69, 177.39, 159.10, 154.56, 149.84, 145.10, 98.76, 53.80, 46.40, 29.95, 23.90, 14.10, 11.18, 11.11; MS (ESI) m / z 320 [C14H17N5O4 + H]+; UPLC (Method-A) 95.3% (AUC) tR= 2.97 min.EXAMPLE 37

[0268] This example provides an exemplary synthesis for Compound BG.Scheme 47: Preparation of 6-(((lR,2S)-2-Hvdroxycvclopentvl)amino)-5-(((E)-2- oxopropylidene)amino)pyrimidine-2,4(1H,3H)-dione (Compound BG)

[0269] The stirred solution of 5-amino-6-(((1R,2S)-2- hydroxycyclopentyl)amino)pyrimidine-2,4-diol hydrochloride (300 mg, 1.14 mmol) and 2- oxopropanal (0.40 mL, 2.22 mmol, 40% in water) in dimethyl sulfoxide (3 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 15 minutes and the reaction progress was monitored by UPLC- MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions weredried by lyophilization to afford 6-(((lR,2S)-2-hydroxycyclopentyl)amino)-5-(((E)-2- oxopropylidene)amino)pyrimidine-2,4(1H,3H)-dione (18.5 mg, 6%) as a pale yellow solid:1H NMR (400 MHz, DMSO-d6) δ 10.59 (br s, 1H), 8.70 (s, 1H), 7.51 (d, J = 8.0 Hz, 1H), 4.03 - 4.00 (m, 1H), 3.95 - 3.94 (m, 1H), 2.19 (s, 3H), 2.03 - 1.95 (m, 1H), 1.81 - 1.65 (m, 2H), 1.58 -1.51 (m, 1H), 1.44 - 1.33 (m, 2H) (One ami die NH and one OH were not detected);13C NMR (100 MHz, DMSO) 6 200.45, 158.91, 154.15, 150.34, 143.86, 98.03, 71.11, 55.22, 33.22, 30.15, 23.66, 20.91; MS (ESI) m / z 281 [C12H16N4O4 + H]+; ]+; UPLC (Method-G) 95.0% (AUC) tR= 2.35 min; Chiral HPLC Purity: >99% (Method-I), tR= 2.06 min.EXAMPLE 38

[0270] This example provides an exemplary synthesis for Compound BH.Scheme 48: Preparation 6-(((lR,2S)-2-Hvdroxycvclopentvl)amino)-5-(((E)-2- oxobutylidene)amino)pyrimidine-2,4(1H,3H)-dione (Compound BH)

[0271] Preparation of (IS, 2R)-2-( (2, 6-Bis(benzyloxy)-5-nitropyrimidin-4- yl) amino) cyclopentan- l-ol: Potassium hydroxide (2N in water, 7.30 mL, 14.59 mmol) was added dropwise to a stirred solution of 6-chloro-5-nitropyrimidine-2,4-diol (2.50 g, 14.6 mmol) and (lS,2R)-2-aminocy cl opentan- l-ol (2.00 g, 14.59 mmol) in ethanol (20 mL) and water (8 mL). The reaction was heated to 80 °C for 8 hours and the reaction progress was monitored by UPLC-MS. The mixture was cooled to room temperature and the precipitate was collected by filtration, washed with ethanol and dried under vacuum to afford (1S,2R)-2- ((2,6-bis(benzyloxy)-5-nitropyrimidin-4-yl)amino)cyclopentan-1-ol (1.50 g, crude) as an off- white solid: MS (ESI) m / z 257 [C9H12N4O5 + H]+. The crude was used directly for the next step without purification.

[0272] Preparation of 5-Amino-6-( C1R, 2S)-2-hydroxycyclopentyl)amino)pyrimidine-2,4- diol hydrochloride: To a stirred solution of (lS,2R)-2-((2,6-bis(benzyloxy)-5-nitropyrimidin-4-yl)amino)cyclopentan-1-ol (1.50 g, 5.86 mmol) in IN aqueous hydrochloric acid (3 mL), tetrahydrofuran (15 mL) and ethanol (15 mL), was added 10% palladium on charcoal (500 mg, 50% wet) under argon atmosphere at room temperature. The reaction was stirred under hydrogen atmosphere using balloon for 16 hours. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to afford of 5-amino-6-(((lR,2S)-2-hydroxycyclopentyl)amino)pyrimidine-2,4-diol hydrochloride (450 mg, crude) as a pink solid: MS (ESI) m / z 227 [C9H14N4O + H]+.

[0273] Preparation 6-( C1R, 2S)-2-Hydroxycyclopentyl)amino)-5-( ( (E)-2- oxobutylidene)amino)pyrimidine-2,4(1H,3H)-dione (Compound BH) : The stirred solution of5-amino-6-(((lR,2S)-2-hydroxycyclopentyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (300 mg, 1.14 mmol) and 2-oxobutanal (1 mL with traces of 1,4-dioxane) in dimethyl sulfoxide (3 mL) was adjusted to pH ~9 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 15 minutes and the reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford 6-(((lR,2S)-2- hydroxycyclopentyl)amino)-5-(((E)-2-oxobutylidene)amino)pyrimidine-2,4(1H,3H)-dione (13.0 mg, 4%) as a pale yellow solid:1H NMR (400 MHz, DMSO-d6) δ 10.81 (br s, 2H), 8.79 (s, 1H), 7.53 (d, J = 8.8 Hz, 1H), 5.75 - 5.06 (m, 1H), 4.21 - 4.01 (m, 2H), 2.83 - 2.74 (m, 2H), 2.06 - 2.01 (m, 1H), 1.87 - 1.70 (m, 2H), 1.65 - 1.58 (m, 1H), 1.51 - 1.45 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H);13C NMR (100 MHz, DMSO-d6) δ 202.95, 158.91, 154.00, 150.24, 143.49, 97.89, 71.09, 55.23, 33.19, 30.13, 28.57, 20.89, 8.84; MS (ESI) m / z 295 [C13H18N4O4 + H]+; UPLC (Method- A) 95.1% (AUC) tR= 3.82 min; Chiral HPLC (Method-C) >99% (AUC) tR= 3.86 min.EXAMPLE 39

[0274] This example provides an exemplary synthesis for Compound BI.Scheme 49: oxopropvlidene)amino)pyrimidine-2,4(1H,3H)-dione (Compound BI)

[0275] Preparation of ( 1R, 2S)-2-( (2, 6-Bis(benzyloxy)-5-nitropyrimidin-4- yl) amino) cyclopentan- l-ol: Potassium hydroxide (2N in water, 2.70 mL, 5.39 mmol) was added dropwise to a stirred solution of 2,4-bis(benzyloxy)-6-chloro-5-nitropyrimidine (2.00 g, 5.39 mmol) and (1R,2S)-2-aminocyclopentan-1-ol (880 mg, 6.46 mmol) in ethanol (20 mL) and water (8 mL). The reaction was heated to 80 °C for 8 hours and the reaction progress was monitored by UPLC-MS. The reaction was cooled to room temperature and the precipitate was collected by filtration, washed with ethanol and dried under vacuum to afford (lR,2S)-2-((2,6-bis(benzyloxy)-5-nitropyrimidin-4-yl)amino)cyclopentan-1-ol (1.60 g, crude) as an off-white solid:1H NMR (400 MHz, DMSO-d6) δ 9.11 (d, J = 7.2 Hz, 1H), 7.48 - 7.34 (m, 10H), 5.53 (s, 2H), 5.38 (s, 2H), 4.39 - 4.32 (m, 1H), 4.28 - 4.22 (m, 1H), 2.11 - 2.02 (m, 1H), 1.99 - 1.88 (m, 2H), 1.78 - 1.69 (m, 2H), 1.68 - 1.64 (m, 2H); MS (ESI) m / z 437 [C23H24N4O + H]+.

[0276] Preparation of 5-Amino-6-( (1S, 2R)-2-hydroxycyclopentyl)amino)pyrimidine-2, 4- diol hydrochloride: To a solution of (lR,2S)-2-((2,6-bis(benzyloxy)-5-nitropyrimidin-4- yl)amino)cyclopentan-1-ol (1.20 g, 2.75 mmol) in IN aqueous hydrochloric acid (12 mL), tetrahydrofuran (6 mL) and ethanol (6 mL), was added 10% palladium on charcoal (360 mg) under argon atmosphere at room temperature. The reaction was stirred under hydrogen atmosphere using a balloon at room temperature for 16 hours. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction was passed through diatomaceous earth, and the filtrate was concentrated under reduced pressure to afford of 5-amino-6-(((lS,2R)-2-hydroxycyclopentyl)amino)pyrimidine- 2,4-diol hydrochloride (720 mg, crude) as a pink solid; MS (ESI) m / z 227 [C9H14N4O + H]+.

[0277] Preparation of 6-(((1S,,2R)-2-Hydroxycyclopentyl)amino)-5-(((E)-2- oxopropylidene)amino)pyrimidine-2,4(1H,3H)-dione (Compound BI) : The stirred solution of 5-amino-6-(((l S,2R)-2-hydroxycyclopentyl)amino)pyrimidine-2,4-diol hydrochloride (300 mg, 1.14 mmol) and 2-oxopropanal (0.40 mL, 2.22 mmol, 40% in water) in dimethyl sulfoxide (3 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 15 minutes and the reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford 6-(((lS,2R)-2- hydroxycyclopentyl)amino)-5-(((E)-2-oxopropylidene)amino)pyrimidine-2,4(1H,3H)-dione (30.5 mg, 9%) as a pale yellow solid:1H NMR (400 MHz, DMSO-d6) δ 10.56 (br s, 1H), 8.74 (s, 1H), 7.36 - 7.40 (m, 1H), 5.78 - 5.12 (m, 1H), 4.09 - 4.02 (m, 2H), 2.23 (s, 3H), 2.02 - 1.99 (m, 1H), 1.85 - 1.73 (m, 2H), 1.63 - 1.57 (m, 1H), 1.50 - 1.41 (m, 2H) (one amidic proton was not detected);13C NMR (100 MHz, DMSO) 6 200.54, 158.90, 154.12, 150.31, 143.89, 98.02, 71.13, 55.22, 33.20, 30.13, 23.66, 20.89; MS (ESI) m / z 281 [C12H16N4O4 + H]+; UPLC (Method-G) 97.9% (AUC) tR= 2.31 min; Chiral HPLC (Method-C) >99% (AUC) tR= 4.60 min.EXAMPLE 40

[0278] This example provides an exemplary synthesis for Compound BJ.Scheme 50: Preparation of 6-(((lS,2R)-2-Hydroxycyclopentyl)amino)-5-(((E)-2- oxobutylidene)amino)pyrimidine-2A(1H3H)-dione (Compound BJ)

[0279] The stirred solution of 5-amino-6-(((lS,2R)-2- hydroxycyclopentyl)amino)pyrimidine-2,4-diol hydro chloride (500 mg, 1.73 mmol) and 2- oxobutanal (0.90 mL with traces of 1,4-dioxane) in dimethyl sulfoxide (3 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 15 minutes and the reaction progress was monitored by UPLC- MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NXc18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: lOmM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford 6-(((lS,2R)-2-hydroxycyclopentyl)amino)-5-(((E)-2- oxobutylidene)amino)pyrimidine-2,4(lH,3H)-dione (50.3 mg, 15%) as a pale yellow solid:1H NMR (400 MHz, CDCl3) δ 10.61 (br s, 1H), 8.78 (s, 1H), 7.53 - 7.51 (m, 1H), 5.67 - 5.12 (m, 1H), 4.07 - 4.01 (m, 2H), 2.80 - 2.73 (m, 2H), 2.07 - 2.00 (m, 1H), 1.87 - 1.70 (m, 2H), 1.65 - 1.59 (m, 1H), 1.50 - 1.43 (m, 2H), 0.97 - 0.99 (m, 3H) (one amidic proton was not detected);13C NMR (100 MHz, DMSO) 6 202.92, 158.94, 154.17, 150.37, 143.42, 97.95, 71.11, 55.24, 33.20, 30.13, 28.57, 20.88, 8.86; MS (ESI) m / z 295 [C13H18N4O4 + H]+; UPLC (Method- A) 98.1% (AUC) tR= 3.63 min; Chiral HPLC (Method-C) >99% (AUC) tR= 5.13 min.EXAMPLE 41

[0280] This example provides an exemplary synthesis for Compound BK.Scheme 51 : Preparation of 6-(((lR,2R)-2 -Hydroxy cyclopentyl)amino)-5-(((E)-2- oxopropvlidene)amino)pyrimidine-2,4(lH,3H)-dione (Compound BK)

[0281] Preparation of 6-(((lR,2R)-2-Hydroxycyclopentyl)amino)-5-nitropyrimidine- 2,4(lH,3H)-dione: Potassium hydroxide (2N in water, 2.50 mL, 4.95 mmol) was added dropwise to a stirred solution of (lR,2R)-2-aminocyclopentan-l-ol (500 mg, 4.95 mmol) and 6-chloro-5-nitropyrimidine-2,4(lH,3H)-dione (940 mg, 4.95 mmol) in ethanol (5 mL) and water (2.50 mL) at room temperature. The reaction was heated to 80 °C for 8 hours and the progress of the reaction was monitored by UPLC-MS. The reaction was cooled to room temperature, the precipitate was collected by filtration, washed with ethanol and dried under vacuum to afford 6-(((lR,2R)-2-hydroxycyclopentyl)amino)-5-nitropyrimidine-2,4(lH,3H)- dione (850 mg, crude) as an off-white solid:1H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.99 (d, J = 8.0 Hz, 1H), 5.90 (br s, 1H) 4.03 - 3.97 (m, 2H), 2.15 - 2.09 (m, 1H), 1.95 - 1.89 (m, 1H), 1.73 - 1.60 (m, 3H), 1.55 - 1.47 (m, 1H) (one amidic NH is not detected); MS (ESI) m / z 257 [C9H12N4O5+ H]+.

[0282] Preparation of 5-Amino-6-( flR, 2R)-2-hydroxycyclopentyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride: To a solution of 6-(((lR,2R)-2- hydroxycyclopentyl)amino)-5-nitropyrimidine-2,4(1H,3H)-dione (900 mg, 3.51 mmol) in IN aqueous hydrochloric acid (10 mL), was added 10% palladium on charcoal (300 mg) under argon atmosphere at room temperature. The reaction was stirred under hydrogen atmosphere using a balloon for 16 hours. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction was passed through diatomaceous earth, and the filtrate was concentrated under reduced pressure to afford 5- amino-6-(((lR,2R)-2-hydroxycyclopentyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (0.65 g, crude) as a pink solid:1H NM (R400 MHz, DMSO-d6) δ 10.94 (s, 1H), 10.60 (s, 1H), 9.45 (br s, 3H), 8.14 (d, J = 6.0 Hz, 1H), 3.91 (q, J = 6.4 Hz, 1H), 3.80 - 3.74 (m, 1H), 2.06 - 1.96 (m, 1H), 1.95 - 1.90 (m, 1H), 1.74 - 1.62 (m, 3H), 1.64 - 1.45 (m, 1H) (one OH was not detected); MS (ESI) m / z 227 [C9H15CIN4O3 + H]+.

[0283] Preparation of 6-(((lR,2R)-2-Hydroxycyclopentyl)amino)-5-(((E)-2- oxopropylidene)amino)pyrimidine-2,4(1H,3H)-dione (Compound BK) : The stirred solution of 5-amino-6-(((lR,2R)-2-hydroxycyclopentyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (400 mg, 1.52 mmol) and methylglyoxal (0.82 mL, 40% in water) in dimethyl sulfoxide (5 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 30 minutes and the reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford 6-(((lR,2R)-2- hydroxycyclopentyl)amino)-5-(((E)-2-oxopropylidene)amino)pyrimidine-2,4(1H,3H)-dione (75.0 mg, 17%) as a yellow solid:1H NMR (400 MHz, DMSO-d6) δ 10.69 (br s, 1H), 8.82 (s, 1H), 7.05 (d, J = 7.2 Hz, 1H), 3.98 (q, J = 6.8 Hz, 1H), 3.94 - 3.93 (m, 1H), 2.33 (s, 3H), 2.11 - 2.05 (m, 1H), 1.97 - 1.89 (m, 1H), 1.72 - 1.62 (m, 3H), 1.55 - 1.46 (m, 1H) (one amidic NH and one OH were not detected);13C NMR (100 MHz, DMSO-d6) δ 200.80, 159.14, 154.94, 150.14, 144.67, 98.29, 77.28, 60.60, 32.43, 29.78, 24.22, 20.30; MS (ESI) m / z 281 [C12H16N4O4 + H]+; UPLC (Method- A) 98.1% (AUC) tR= 3.58 min; Chiral HPLC (Method- I) 97.2% (AUC) tR= 1.24 min.EXAMPLE 42

[0284] This example provides an exemplary synthesis for Compound BL.Scheme 52: Preparation of 6-(((lR,2R)-2-Hydroxvcvclopentyl)amino)-5-(((E)-2- oxobutvlidene)amino)pyrimidine-2,4(1H,3H)-dione (Compound BL)

[0285] The stirred solution of 5-amino-6-(((lR,2R)-2- hydroxycyclopentyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (300 mg, 1.14 mmol) and 2-oxobutana (1 mL with traces of 1,4-dioxane) in dimethyl sulfoxide (2 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 15 minutes and the reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford 6-(((lR,2R)-2-hydroxycyclopentyl)amino)-5- (((E)-2-oxobutylidene)amino)pyrimidine-2,4(1H,3H)-dione (40.0 mg, 10%) as a yellow solid:1H NMR (400 MHz, DMSO-d6) δ 10.65 (br s, 1H), 8.84 (s, 1H), 6.99 (d, J = 7.6 Hz, 1H), 3.97 (q, J = 6.8 Hz, 1H), 3.94 - 3.88 (m, 1H), 2.90 - 2.84 (m, 2H), 2.11 - 2.06 (m, 1H), 2.04 -1.89 (m, 1H), 1.73 - 1.60 (m, 3H), 1.58 - 1.46 (m, 1H), 0.99 (t, J = 7.2 Hz, 3H) (one amidic NH and hydroxy OH were not detected);13C NMR (100 MHz, DMSO-d6) δ 203.17, 159.15, 154.89, 150.06, 144.32, 98.18, 77.28, 60.56, 32.41, 29.79, 28.79, 20.27, 8.59; MS (ESI) m / z 295 [C13H18N4O4 + H]+; UPLC (Method-A) >99% (AUC) tR= 3.88 min.EXAMPLE 43

[0286] This example provides an exemplary synthesis for Compound BM.Scheme 53: Preparation of 6-(((l S,2S)-2 -Hydroxycyclopentyl)amino)-5-(((E)-2- oxopropvlidene)amino)pyrimidine-2,4(1H,3H)-dione (Compound BM)

[0287] Preparation of 6-( ((IS, 2S)-2-Hydroxycyclopentyl)amino)-5-nitropyrimidine- 2,4(1H,3H)-dione: Potassium hydroxide (2N in water, 2.60 mL, 5.23 mmol) was added dropwise to a stirred solution of (lR,2R)-2-aminocyclopentan-1-ol (1.00 g, 5.23 mmol) and 6-chloro-5-nitropyrimidine-2,4(1H,3H)-dione (0.86 g, 6.27 mmol) in ethanol (10 mL) and water (4 mL) at room temperature. The reaction was heated to 80 °C for 8 hours and the progress of the reaction was monitored by UPLC-MS. The reaction was cooled to room temperature, the precipitate was collected by filtration, washed with ethanol and dried under vacuum to afford 6-(((lR,2R)-2-hydroxycyclopentyl)amino)-5-nitropyrimidine-2,4(1H,3H)- dione (1.20 g, crude) as an off-white solid: MS (ESI) m / z 257 [C9H12N4O5+ H]+. The crude product was used directly for the next step without purification.

[0288] Preparation of 5-Amino-6-( ((1S, 2S)-2-hydroxycyclopentyl)amino)pyrimidine- 2,4(1H,3H)-dione hydrochloride: To a solution of 6-(((lR,2R)-2- hydroxycyclopentyl)amino)-5-nitropyrimidine-2,4(1H,3H)-dione (1.20 g, 4.68 mmol) in IN aqueous hydrochloric acid (10 mL), was added 10% palladium on charcoal (600 mg) under argon atmosphere at room temperature. The reaction was stirred under hydrogen atmosphere using a balloon for 16 hours. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction was passed through diatomaceous earth, and the filtrate was concentrated under reduced pressure to afford 5- amino-6-(((lR,2R)-2-hydroxycyclopentyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (800 mg, crude) as a pink solid: MS (ESI) m / z 227 [C9H14N4O3 + H]+. The crude product was used directly for the next step without purification.

[0289] Preparation of 6-(((1S,,SR)-2-Hydroxycyclopentyl)amino)-5-(((E)-2- oxopropylidene)amino)pyrimidine-2,4(1H,3H)-dione (Compound BM) : The stirred solution of 5-amino-6-(((lS,2S)-2 -hydroxy cyclopentyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (350 mg, 1.33 mmol) and methylglyoxal (0.70 mL, 40% in water, 3.99 mmol) in dimethyl sulfoxide (3 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 15 minutes and the reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggeredpreparative HPLC (Column: Gemini-NX c18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford 6-(((lS,2S)-2- hydroxycyclopentyl)amino)-5-(((E)-2-oxopropylidene)amino)pyrimidine-2,4(1H,3H)-dione (55.0 mg, 15%) as a yellow solid:1H NMR (400 MHz, DMSO-d6) δ 10.68 (br s, 1H), 8.22 (s, 1H), 7.05 (d, J = 7.2 Hz, 1H) 3.98 (q, J = 6.8 Hz, 1H), 3.94 - 3.89 (m, 1H), 2.33 (s, 3H), 2.11 - 2.05 (m, 1H), 1.97 - 1.89 (m, 1H), 1.72 - 1.61 (m, 3H), 1.55 - 1.46 (m, 1H) (one amidic NH and one OH were not detected);13C NMR (100 MHz, DMSO-d6) δ 200.84, 159.13, 154.93, 150.08, 144.66, 98.28, 77.28, 60.60, 32.42, 29.76, 24.24, 20.29; MS (ESI) m / z 281 [C12H16N4O4 + H]+; UPLC (Method- A) 98.0% (AUC) tR= 3.54 min.EXAMPLE 44

[0290] This example provides an exemplary synthesis for Compound BN.Scheme 54: Preparation of 6-(((lS,2S)-2 -Hydroxy cyclopentyl)amino)-5-(((E)-2- oxobutylidene)amino)pyrimidine-2,4(1H,3H)-dione (Compound BN)

[0291] The stirred solution of 5-amino-6-(((lS,2S)-2- hydroxycyclopentyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride salt (350 mg, 1.33 mmol) and 2-oxobutanal (1 mL with traces of 1,4-di oxane) in dimethyl sulfoxide (3 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 15 minutes and the reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford 6-(((lS,2S)-2-hydroxycyclopentyl)amino)-5- (((E)-2-oxobutylidene)amino)pyrimidine-2,4(1H,3H)-dione (52.0 mg, 13%) as a yellow solid:1H NMR (400 MHz, DMSO-d6) δ 10.57 (br s, 1H), 8.83 (s, 1H), 6.96 (d, J = 7.2 Hz, 1H), 3.98 - 3.87 (m, 2H), 2.89 - 2.83 (m, 2H), 2.11 - 2.04 (m, 1H), 1.95 - 1.89 (m, 1H), 1.72 - 1.60 (m, 3H), 1.53 - 1.46 (m, 1H), 0.99 (t, J = 7.2 Hz, 3H) (one amidic NH and one OH were not detected);13C NMR (100 MHz, DMSO-d6) δ 203.22, 159.23, 155.24, 150.56, 143.90,98.33, 77.36, 60.57, 32.43, 29.83, 28.90, 20.31, 8.63; MS (ESI) m / z 295 [C13H18N4O4 + H]+;UPLC (Method-A) >99% (AUC) tR= 3.38 min.EXAMPLE 45

[0292] This example provides an exemplary synthesis for Compound CA.Scheme 55: Preparation of 5-(((E)-2-((S)-2,2-Difluorocyclopropyl)-2- oxoethylidene)amino)-6-(((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine- 2,4(1H,3H)-dione (Compound CA)

[0293] Preparation of (S)-2,2-Difluoro-N-methoxy-N-methylcyclopropane-l- carboxamide: To a stirred solution of (S)-2,2-difluorocyclopropane-1-carboxylic acid (5.00 g, 40.9 mmol) and N,O-dimethylhydroxylamine (5.99 g, 61.4 mmol) in dichloromethane (100 mL), was added triethylamine (11.3 mL, 81.9 mmol) at 0 °C. After stirring for 5 min, propyl phosphonic anhydride (50% in ethyl acetate, 39 mL, 61.4 mmol) was added to the reaction. The reaction was warmed to room temperature and stirred for 16 hours. The reaction progress was monitored by thin layer chromatography. The reaction was quenched with saturated sodium bicarbonate solution (50 mL) and extracted with dichloromethane (2 × 50 mL). The combined organic extracts were washed with brine (100 mL), dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography using silica-gel (200-400 mesh) and eluting with 40% ethyl acetate in hexanes. The pure fractions were concentrated under reduced pressure to afford (S)-2,2-difluoro-N-methoxy-N-methylcyclopropane-l -carboxamide (5.10 g, 76%) as a pale-yellow oil:1H NMR (400 MHz, CDCl3) δ 3.76 (s, 3H), 3.25 (s, 3H), 2.97 - 2.89 (m, 1H), 2.19 - 2.11 (m, 1H), 1.75 - 1.64 (m, 1H); MS (ESI) m / z 166 [C6H9F2NO2 + H]+.

[0294] Preparation of (S)-1-(2,2-Difluorocyclopropyl)ethan-1-one: To a stirred solution of (S)-2,2-difluoro-N-methoxy-N-methylcyclopropane-1-carboxamide (5.00 g, 30.2 mmol) in tetrahydrofuran (25 mL), was added methyl magnesium bromide (2M in tetrahydrofuran, 22.7 mL, 45.4 mmol) at 0 °C. The reaction was warmed to room temperature and stirred for 2 hours. The reaction progress was monitored by thin layer chromatography. The reaction was quenched with saturated ammonium chloride solution (150 mL) and extracted with methyl tert-butyl ether (2 × 150 mL). The combined organic extracts were washed with brine (100 mL), dried over sodium sulfate and filtered. The filtrate was concentrated by conventional distillation at 100 °C to afford (S)-1-(2,2-difluorocyclopropyl) ethan-1-one (2.20 g) as a brown oil:1H NMR (400 MHz, CDCl3) δ 2.79 - 2.71 (m, 1H), 2.32 (s, 3H), 2.20 - 2.12 (m, 1H), 1.72 - 1.63 (m, 1H).

[0295] Preparation of (S)-2-(2,2-Difluorocyclopropyl)-2-oxoacetaldehyde: To a stirred solution of (S)-1-(2,2-difluorocyclopropyl) ethan-1-one (4.00 g, 33.0 mmol) in 1,4-dioxane (36 mL) and water (4 mL), was added selenium dioxide (5.49 g, 49.5 mmol) at room temperature. The reaction was heated to 100 °C for 16 hours, cooled to room temperature and then passed through diatomaceous earth. After fractional distillation of the filtrate (S)-2- (2,2-difluorocyclopropyl)-2-oxoacetaldehyde (4 mL with traces of dioxane) at 140 °C was collected as a pale-yellow oil. The product contained traces of dioxane and was used directly for the next step without further purification.

[0296] Preparation of 5-( ( (E)-2-((S)-2, 2 -Difluor ocyclopr opyl)-2-oxoethylidene)amino)-6-(((2S, 38, 4R)-2, 3, 4, 5-tetrahydroxypentyl)amino)pyrimidine-2, 4(1H, 3H)-dione ( Compound CA): The stirred solution of 5-amino-6-(((2S,3 S,4R)-2, 3,4,5- tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (300 mg, 0.96 mmol) in dimethyl sulfoxide (3 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. (S)-2-(2,2-difluorocyclopropyl)-2-oxoacetaldehyde (1.50 mL with traces of 1,4-dioxane) was added to the reaction dropwise and stirred for 15 minutes. The reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX C18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford 5- (((E)-2-((S)-2,2-difluorocyclopropyl)-2-oxoethylidene)amino)-6-(((2S,3S,4R)-2,3,4,5- tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione_(30.5 mg, 8%) as a yellow solid:1H NMR (400 MHz, DMSO-d6) δ 10.45 (br s, 1H), 9.02 (s, 1H), 7.86 (br s, 1H), 5.31 - 4.77 (m,2H), 4.40 - 4.18 (m, 1H), 3.78 - 3.75 (m, 1H), 3.67 - 3.38 (m, 6H), 2.08 - 2.02 (m, 1H), 1.91 - 1.81 (m, 1H) (one amidic NH and two hydroxy OH were not detected);19F NMR (376 MHz, DMSO-d6) δ -123.48 (d, JF-F = 146.64 Hz, IF), -139.65 (d, JF-F = 142.88 Hz, IF);13C NMR(100 MHz, DMSO-d6) δ 192.38, 159.32, 156.87, 151.16, 142.43, 116.65, 113.82, 110.98, 99.54, 73.64, 73.15, 70.46, 63.50, 45.04, 26.40, 26.30, 15.98, 15.89; MS (ESI) m / z 393 [C14H18F2N4O7 + H]+; UPLC (Method-G) 98.7% (AUC) tR= 2.47 min.EXAMPLE 46

[0297] This example provides an exemplary synthesis for Compound CB.Scheme 56: Preparation of 5-(((E)-2-((R)-2,2-Difluorocvclopropyl)-2- oxoethylidene)amino)-6-(((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione Compound CB)

[0298] Preparation of (R)-2,2-Difluoro-N-methoxy-N-methylcyclopropane-l- carboxamide: To a stirred solution of (R)-2,2-difluorocyclopropane-l -carboxylic acid (5.00 g, 40.9 mmol) and N,O-dimethylhydroxylamine (5.99 g, 61.4 mmol) in dichloromethane (100 mL), was added triethylamine (11.3 mL, 81.9 mmol) at 0 °C. After stirring for 5 min, propyl phosphonic anhydride (50% in ethyl acetate, 39 mL, 61.4 mmol) was added to the reaction. The reaction was warmed to room temperature and stirred for 16 hours. The reaction progress was monitored by thin layer chromatography. The reaction was quenched with saturated sodium bicarbonate solution (50 mL) and extracted with dichloromethane (2 × 50 mL). The combined organic extracts were washed with brine (100 mL), dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography using silica-gel (200-400 mesh) and eluting with 50% ethyl acetate in hexanes. The pure fractions were concentrated under reduced pressure toafford (R)-2,2-difluoro-N-methoxy-N-methylcyclopropane-l -carboxamide (5.02 g, 70%) as a pale-yellow oil:1H NMR (400 MHz, CDC13) 5 3.76 (s, 3H), 3.25 (s, 3H), 2.97 - 2.89 (m, 1H), 2.19 - 2.10 (m, 1H), 1.73 - 1.64 (m, 1H); MS (ESI) m / z 166 [C6H9F2NO2 + H]+.

[0299] Preparation of (R)-l-(2,2-Difluorocyclopropyl)ethan-l-one: To a stirred solution of (R)-2,2-difluoro-N-methoxy-N-methylcyclopropane-l -carboxamide (5.00 g, 30.2 mmol) in tetrahydrofuran (50 mL), was added methyl magnesium bromide (2M in tetrahydrofuran, 22.7 mL, 45.4 mmol) at 0 °C. The reaction was warmed to room temperature and stirred for 2 hours. The reaction progress was monitored by thin layer chromatography. The reaction was quenched with saturated ammonium chloride solution (150 mL) and extracted with methyl tert-butyl ether (2 × 150 mL). The combined organic extracts were washed with brine (100 mL), dried over sodium sulfate and filtered. The filtrate was concentrated by conventional distillation at 100 °C to afford (R)-1-(2,2-difluorocyclopropyl) ethan-1-one (5.05 g, 70%) as a brown oil:1H NMR (400 MHz, CDCl3) δ 2.79 - 2.71 (m, 1H), 2.32 (s, 3H), 2.20 - 2.12 (m, 1H), 1.72 - 1.63 (m, 1H).

[0300] Preparation of (R)-2-(2,2-Difluorocyclopropyl)-2-oxoacetaldehyde: To a stirred solution of (R)-1-(2,2-difluorocyclopropyl) ethan-1-one (5.00 g, 41.3 mmol) in 1,4-di oxane (36 mL) and water (4 mL), selenium dioxide (6.80 g, 61.9 ml) was added at room temperature. The reaction was heated to 100 °C for 16 hours. The reaction was cooled to room temperature and passed through diatomaceous earth. Fractional distillation provided (R)-2-(2,2-difluorocyclopropyl)-2-oxoacetaldehyde (5 mL with traces of dioxane) at 140 °C as a pale-yellow oil. The product contained traces of dioxane and was used directly for the next step without further purification.

[0301] Preparation of 5-(((E)-2-((R)-2,2-Difluorocyclopropyl)-2-oxoethylidene)amino)~6-( <( (2S, 3S, 4R)-2, 3, 4, 5-tetrahydroxypentyl)amino)pyrimidine-2, 4(1H, 3H)-dione ( Compound CB): The stirred solution of 5-amino-6-(((2S,3 S,4R)-2, 3,4,5- tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (300 mg, 0.96 mmol) in dimethyl sulfoxide (3 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. (R)-2-(2,2-difluorocyclopropyl)-2-oxoacetaldehyde (1.50 mL with traces of 1,4-dioxane) was added dropwise to the reaction and stirred for 15 minutes. The reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX C18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford 5-(((E)-2-((R)-2,2-difluorocyclopropyl)-2-oxoethylidene)amino)-6-(((2S,3S,4R)-2,3,4,5- tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione_(27.5 mg, 7%) as a yellow solid:1H NMR (400 MHz, DMSO-d6) δ 10.45 (hr s, 1H), 8.99 (s, 1H), 7.37 (hr s, 1H), 5.35 - 4.67 (m, 1H), 4.37 - 4.13 (m, 1H), 3.68 - 3.62 (m, 1H), 3.64 - 3.43 (m, 6H), 2.06 - 1.97(m, 1H), 1.87 - 1.79 (m, 1H) (one amidic NH and three hydroxy OH were not detected);19F NMR (376 MHz, DMSO-d6) δ -123.22 (d, JF-F = 142.88 Hz, IF), -139.87 (d, JF-F = 146.64 Hz, IF);13C NMR (100 MHz, DMSO-d6) δ 192.08, 159.76, 158.97, 153.06, 141.21, 116.68, 113.86, 105.71, 100.27, 73.37, 73.24, 71.75, 63.50, 44.77, 26.50, 26.40, 26.30, 15.86, 15.77; MS (ESI) m / z 393 [C14H18F2N4O7 + H]+; UPLC (Method-G) >99% (AUC) tR= 2.47 min.EXAMPLE 47

[0302] This example provides an exemplary synthesis for Compound CC.Scheme 57: Preparation of 5-(((E)-2-((S)-2,2-Difluorocvclopropyl)-2- oxoethylidene)amino)-6-(((2S,3R,4R)-2,3,4-trihydroxypentyl)amino)pyrimidine-2,4(1H,3H)- dione (Compound CC)

[0303] The stirred solution of 5-amino-6-(((2S,3R,4R)-2,3,4- trihydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dionehydrochloride (300 mg, 1.22 mmol) in dimethyl sulfoxide (3 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. (S)-2-(2,2-Difluorocyclopropyl)-2-oxoacetaldehyde (1.50 mL with traces of 1,4-dioxane) was added to the reaction dropwise and stirred for 15 minutes. The reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX C18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford 5-(((E)-2-((S)-2,2-difluorocyclopropyl)-2-oxoethylidene)amino)-6-(((2S,3R,4R)-2,3,4- trihydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (60.5 mg, 13%) as a yellow solid:1H NMR (400 MHz, DMSO-d6) δ 10.54 (br s, 1H), 9.02 (s, 1H), 7.91 (br s, 1H), 5.31 - 4.63 (m, 1H), 4.29 - 4.21 (m, 1H), 3.70 - 3.49 (m, 5H), 2.09 - 2.01 (m, 1H), 1.92 - 1.83 (m, 1H), 1.61 (d, J = 6.4 Hz, 3H) (one amidic NH and two hydroxy OH were not detected);19F NMR (376 MHz, DMSO-d6) δ -123.37 (d, JF-F = 142.88 Hz, 1F), -139.76 (d, JF-F = 142.88 Hz, IF);13C NMR (100 MHz, DMSO-d6) δ 192.42, 159.21, 156.32, 150.62, 142.81, 116.65, 113.81, 110.98, 99.35, 76.81, 70.71, 67.75, 45.48, 26.40, 19.22, 16.01; MS (ESI) m / z 377 [C14H18F2N4O6 + H]+; UPLC (Method-G) >99% (AUC) tR= 2.60 min.EXAMPLE 48

[0304] This example provides an exemplary synthesis for Compound CD.Scheme 58: oxoethylidene)amino)-6-(((2S,3R,4R)-2,3,4-trihydroxypentyl)amino)pyrimidine-2,4(1H,3H)- dione (Compound CD)

[0305] The stirred solution of 5-amino-6-(((2S,3R,4R)-2,3,4- trihydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dionehydrochloride (300 mg, 1.22 mmol) in dimethyl sulfoxide (3 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. (R)-2-(2,2-Difluorocyclopropyl)-2-oxoacetaldehyde (1.50 mL with traces of 1,4-dioxane) was added dropwise to the reaction and stirred for 15 minutes. The reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX C18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford 5- (((E)-2-((R)-2,2-difluorocyclopropyl)-2-oxoethylidene)amino)-6-(((2S,3R,4R)-2,3,4-trihydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (50.5 mg, 11%) as a yellow solid:1H NMR (400 MHz, DMSO-d6) δ 10.53 (br s, 1H), 9.03 (s, 1H), 7.80 (br s, 1H), 5.21 - 4.61 (m, 1H), 4.31 - 4.21 (m, 1H), 3.72 - 3.63 (m, 1H), 3.62 -3.50 (m, 3H), 3.29 - 3.26 (m, 1H), 2.09 - 2.01 (m, 1H), 1.91 - 1.83 (m, 1H), 1.60 (d, J = 6.4 Hz, 3H)(one amidic NH and two hydroxy OH were not detected);19F NMR (376 MHz, DMSO-d6) δ -123.29 (d, JF-F = 142.88 Hz, IF), -139.80 (d, JF-F = 146.64 Hz, IF);13C NMR (100 MHz, DMSO-d6) δ 192.43, 159.28, 156.58, 150.76, 142.81, 116.62, 113.78, 110.96, 99.48, 76.26, 71.54, 67.79, 45.34, 26.41, 19.02, 16.00; MS (ESI) m / z 377 [C14H18F2N4O6 + H]+; UPLC (Method-G) 98.4% (AUC) tR= 2.39 min.EXAMPLE 49

[0306] This example provides an exemplary synthesis for Compound CE.Scheme 59: Preparation of 5-(((E)-2-Cyclobutyl-2-oxoethylidene)amino)-6-(((2S,3R,4R)-2,3,4-trihydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (Compound CE)

[0307] The stirred solution of 5-amino-6-(((2S,3R,4R)-2,3,4- trihydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (300 mg, 1.01 mmol) in 2-cyclobutyl-2-oxoacetaldehyde (1.50 mL with traces of dioxane) dimethyl sulfoxide (3 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 15 minutes and the reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford 5-(((E)-2-cyclobutyl-2-oxoethylidene)amino)- 6-(((2S,3R,4R)-2,3,4-trihydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (28.5 mg, 8%) as a yellow solid:1H NMR (400 MHz, DMSO-d6) δ 10.56 (br s, 1H), 8.78 (s, 1H), 7.50 (br s, 1H), 5.24 - 4.65 (m, 2H), 4.25 - 4.15 (m, 1H), 3.71 - 3.58 (m, 3H), 3.52 - 3.46 (m, 1H), 2.19 - 1.94 (m, 6H), 1.78 - 1.69 (m, 1H), 1.10 (d, J = 6.4 Hz, 3H) (one amidic NH and one OH were not detected);13C NMR (100 MHz, DMSO) δ 203.03, 159.03, 155.46, 150.30, 142.66, 98.29, 76.39, 70.59, 67.76, 44.91, 39.06, 25.31, 24.61, 19.26, 18.29; MS (ESI) m / z 383 [C15H22N4O6+ H]+; UPLC (Method- A) 95.8% (AUC) tR= 3.53 min; Chiral HPLC (Method-C) >99% (AUC) tR= 4.17 min.EXAMPLE 50

[0308] This example provides an exemplary synthesis for Compound CF.Scheme 60: Preparation of 5-(((E)-2-Cyclobutyl-2-oxoethylidene)amino)-6-(((2S,3S,4S)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (Compound CF)

[0309] The stirred solution of 5-amino-6-(((2S,3 S,4S)-2, 3,4,5- tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (400 mg, 1.28 mmol) and 2-cyclobutyl-2-oxoacetaldehyde (1.50 mL with traces of 1,4-dioxane) in dimethyl sulfoxide (2 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 15 minutes and the reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford 5-(((E)-2- cyclobutyl-2-oxoethylidene)amino)-6-(((2S,3S,4S)-2,3,4,5- tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (40.0 mg, 9%) as a yellow solid:1H NMR (400 MHz, DMSO-d6) δ 10.59 (br s, 1H), 8.79 (s, 1H), 7.40 (t, J = 5.6 Hz, 1H), 4.52 (br s, 1H), 4.32 (br s, 1H), 4.24 - 4.15 (m, 1H), 3.75 - 3.36 (m, 3H), 3.56 - 3.49 (m, 1H), 3.46 - 3.42 (m, 2H), 3.36 (dd, J = 1.2, 8.6 Hz, 1H), 2.15 - 2.07 (m, 4H), 2.03 - 1.94 (m, 1H), 1.79 - 1.72 (m, 1H) (one amidic NH and two OH’s are not detected);13C NMR (100 MHz, DMSO- d6) δ 201.84, 157.95, 154.46, 149.20, 141.63, 97.23, 70.45, 69.18, 68.36, 62.11, 44.64, 38.01, 24.05, 23.67, 17.24; MS (ESI) m / z 371 [C15H22N4O7 + H]+; UPLC (Method-A) 95.6% (AUC) tR 3.19 min; Chiral HPLC (Method-C) >99% (AUC) tR= 7.59 min.EXAMPLE 51

[0310] This example provides an exemplary synthesis for Compound CG.Scheme 61 :(((2S.3S.4R)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine-2,4(1H3H)-dione (CompoundCG)

[0311] Preparation of 3, 3-Difluoro-N-methoxy-N-methylcyclobutane-1 -carboxamide : T o a stirred solution of 3,3-difluorocyclobutane-1-carboxylic acid (25.0 g, 183 mmol) and N,O- dimethylhydroxylamine (10.7 g, 110 mmol) in tetrahydrofuran (125 mL), were added diisopropylamine (74.3 g, 734 mmol) and l-[bis(dimethylamino)methylene]-1H-l,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (41.9 g, 110 mmol) under argon atmosphere at 0 °C. The reaction was warmed to room temperature and stirred for 16 hours. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction was diluted with water (250 mL) and extracted with ethyl acetate (2 × 250 mL). The combined organic extracts were washed with brine (100 mL), dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography using silica-gel (200-400 mesh) and eluting with 40% ethyl acetate in hexanes. The pure fractions were concentrated under reduced pressure to afford 3,3-difluoro-N-methoxy-N-methylcyclobutane-1- carboxamide (10.2 g, 31%) as a colorless oil:1H NM (R400 MHz, CDCl3) δ 3.69 (s, 3H), 3.32 - 3.23 (m, 1H), 3.21 (s, 3H), 2.96 - 2.80 (m, 2H), 2.78 - 2.66 (m, 2H).

[0312] Preparation of 1-(3,3-Difluorocyclobutyl)ethan-l-one: To a stirred solution of 3,3-difluoro-N-methoxy-N-methylcyclobutane-1-carboxamide (10.2 g, 56.9 mmol) in tetrahydrofuran (100 mL), was added methyl magnesium bromide (IM in tetrahydrofuran, 74 mL, 74.0 mmol) at 0 °C. The reaction was stirred for 2 hours and the reaction progress was monitored by UPLC-MS. The reaction was quenched with saturated ammonium chloride solution (50 mL) and extracted with methyl tert-butyl ether (2 × 50 mL). The combinedorganic extracts were washed with brine (100 mL) dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography using silica-gel (200-400 mesh) and eluting with 20 - 30% ethyl acetate in hexanes. The pure fractions were concentrated under reduced pressure to afford 1 -(3,3- difluorocyclobutyl)ethan-1-one (3.50 g, 46%) as a pale-yellow oil:1H NMR (400 MHz, CDCl3) δ 3.09 - 3.02 (m, 1H), 2.84 - 2.66 (m, 4H), 2.18 (s, 3H).

[0313] Preparation of 2-(3,3-Difluorocyclobutyl)-2-oxoacetaldehyde: The stirred solution of selenium dioxide (4.34 g, 39.1 mmol) in 1,4-dioxane (35 mL) and water (3.5 mL) was heated to 60 °C for 1 hour. l-(3,3-Difluorocyclobutyl)ethan-1-one (3.50 g, 26.1 mmol) was added to the reaction. The reaction was heated to 95 °C for 16 hours, cooled to room temperature and passed through diatomaceous earth. The filtrate under fractional distillation provided 2-(3,3-difluorocyclobutyl)-2-oxoacetaldehyde (1.50 g with traces of dioxane) at 140 °C as a pale-yellow oil. The product with traces of dioxane was used directly for the next step without purification.

[0314] Preparation of (5-(((E)-2-(3,3-Difluorocyclobutyl)-2-oxoethylidene)amino)-6- (((2S, 3S, 4R)-2, 3, 4, 5-tetrahydroxypentyl)amino)pyrimidine-2, 4(1H, 3H)-dione ( Compound CG): The stirred solution of (S)-5-amino-6-((2,3-dihydroxypropyl)amino)pyrimidine- 2,4(1H,3H)-dione hydrochloride (350 mg, 1.19 mmol) and 2-(3,3-difluorocyclobutyl)-2- oxoacetaldehyde (4 mL with traces of 1,4-dioxane) in dimethyl sulfoxide (3 mL) was adjusted to pH ~9 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 15 minutes and the reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford (5-(((E)-2-(3,3-difluorocyclobutyl)-2- oxoethylidene)amino)-6-(((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine- 2,4(1H,3H)-dione (36.0 mg, 8%) as a yellow solid:1H NM (R400 MHz, DMSO-d6) δ 10.49 (br s, 1H), 8.88 (s, 1H), 7.61 - 7.44 (m, 1H), 5.75 - 4.43 (m, 4H), 4.08 - 3.99 (m, 1H), 3.82 - 3.78 (m, 1H), 3.67 - 3.59 (m, 2H), 3.55 - 3.40 (m, 4H), 2.87 - 2.60 (m, 4H)(one amidic NH was not detected);19F NMR (376 MHz, DMSO-d6) δ -80.94 (d, JF-F = 188.1 Hz, IF), -92.18 (d, JF-F = 188.1 Hz, IF);13C NMR (100 MHz, DMSO-d6) δ 200.52, 159.16, 156.02, 150.68, 141.51, 98.85, 73.46, 73.19, 70.41, 63.55, 44.58, 26.56, 26.49, 26.44, 26.37; MS (ESI) m / z 407 [C15H20F2N4O7 + H]+; UPLC (Method-G) 98.2% (AUC) tR= 2.47 min.EXAMPLE 52

[0315] This example provides an exemplary synthesis for Compound CH.Scheme 62: Preparation of 5-(((E)-2-(3,3-Difluorocvclobutvl)-2-oxoethylidene)amino)-6-(((2S,3R,4R)-2,3,4-trihvdroxvpentvl)amino)pyrimidine-2,4(1H,3H)-dione (Compound CH):

[0316] The stirred solution of (2S,3R,4R)-1-((5-amino-2,6-dihydroxypyrimidin-4- yl)amino)pentane-2,3,4-triol hydrochloride (450 mg, 1.52 mmol) and 2-(3,3- difluorocyclobutyl)-2-oxoacetaldehyde (5 mL with traces of 1,4-di oxane) in dimethyl sulfoxide (5 mL) was adjusted to pH ~9 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 10 minutes and the reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford 5-(((E)-2-(3,3- difluorocyclobutyl)-2-oxoethylidene)amino)-6-(((2S,3R,4R)-2,3,4- trihydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (39.0 mg, 6%) as a yellow solid:1H NMR (400 MHz, DMSO-d6) δ 10.61 (br s, 1H), 8.89 (s, 1H), 7.69 - 7.56 (m, 1H), 5.54 - 4.64 (m, 3H), 4.10 - 4.00 (m, 1H), 3.73 - 3.60 (m, 3H), 3.54 - 3.48 (m, 1H), 3.29 - 3.20 (m, 1H), 2.88 - 2.63 (m, 4H), 1.10 (d, J = 6.0 Hz, 3H) (one amidic NH was not detected);19F NMR (376 MHz, DMSO-d6) δ -80.90 (d, JF-F = 188.5 Hz, IF), -92.25 (d, JF-F = 188.5 Hz, IF);13C NMR (100 MHz, DMSO-d6) δ 200.52, 159.11, 155.75, 150.39, 141.72, 98.77, 76.49, 70.71, 67.79, 45.04, 26.57, 26.50, 26.44, 26.37, 19.25; MS (ESI) m / z 391 [C15H20F2N4O6 + H]+; UPLC (Method-G) 96.7% (AUC) tR= 2.63 min.EXAMPLE 53

[0317] This example provides an exemplary synthesis for Compound CI.Scheme 63 :(((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (CompoundCI)

[0318] Preparation ofN-Methoxy-N-methyltetrahydrofuran-2-carboxamide: To a stirred solution of tetrahydrofuran-2-carboxylic acid (10.0 g, 86.0 mmol) and N,O-dimethyl hydroxylamine (12.5 g, 129 mmol) in dichloromethane (200 mL), was added triethylamine (23.8 mL, 172 mmol) at 0 °C. After stirring for 5 min, propyl phosphonic anhydride (50% in ethyl acetate, 82.1 mL, 129 mmol) was added to the reaction. The reaction was warmed to room temperature and stirred for 16 hours. The reaction progress was monitored by UPLC- MS until complete consumption f starting material was observed. The reaction was quenched with saturated sodium bicarbonate solution (100 mL) and extracted with dichloromethane (2 x 100 mL). The combined organic extracts were washed with brine (100 mL) dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography using silica-gel (200-400 mesh) and eluting with 50% ethyl acetate in hexanes. The pure fractions were concentrated under reduced pressure to afford N-methoxy-N-methyltetrahydrofuran-2-carboxamide (9.12 g, 67%) as a colorless oil:1H NMR (400 MHz, CDCl3) δ 4.77 (br s, 1H), 4.06 - 4.01 (m, 1H), 3.93 - 3.88 (m, 1H), 3.72 (s, 3H), 3.20 (s, 3H), 3.23 - 3.21 (m, 1H), 2.02 - 1.98 (m, 2H), 1.94 - 1.88 (m, 1H); MS (ESI) m / z 160 [C7H13NO3 + H]+.

[0319] Preparation of l-(Tetrahydrofuran-2-yl)ethan-l-one: To a stirred solution of N- methoxy-N-methyltetrahydrofuran-2-carboxamide (4.00 g, 25.1 mmol) in tetrahydrofuran (40 mL), was added methyl magnesium bromide (IM in tetrahydrofuran, 37.6 mL, 37.6 mmol) at 0 °C and stirred for 1 hour. The reaction progress was monitored by thin layer chromatography which showed consumption of starting material. The reaction was quenched with saturated ammonium chloride solution (40 mL) and extracted with methyl tert-butyl ether (2 × 40 mL). The combined organic extracts were washed with brine (50 mL), driedover sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to afford l-(tetrahydrofuran-2-yl)ethan-1-one (1.92 g, crude) as a pale-yellow liquid. The crude product was used directly for the next step without purification.

[0320] Preparation of 2-Oxo-2-(tetrahydrofuran-2-yl) acetaldehyde: The stirred solution of selenium dioxide (2.33 g, 21.0 mmol) in 1,4-dioxane (7.2 mL) and water (0.80 mL) was heated to 60 °C for 1 hour. l-(Tetrahydrofuran-2-yl) ethan-1-one (1.60 g, 14.0 mmol) was added to the reaction at same temperature. The reaction was heated to 100 °C for 16 hours. The reaction was cooled to room temperature and passed through diatomaceous earth. The filtrate [2-oxo-2-(tetrahydrofuran-2-yl) acetaldehyde, 6 mL, crude, a pale-yellow oil] was directly used for the next step without further distillation.

[0321] Preparation of 5-(((E)-2-Oxo-2-(tetrahydrofuran-2-yl)ethylidene)amino)-6-(((2S, 38, 4R)-2, 3, 4, 5-tetrahydroxypentyl)amino)pyrimidine-2, 4(1H, 3H)-dione ( Compound CI): The stirred solution of 5-amino-6-(((2S,3 S,4R)-2, 3,4,5- tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (300 mg, 0.96 mmol) and 2-oxo-2-(tetrahydrofuran-3-yl)acetaldehyde (3 mL, crude) in dimethyl sulfoxide (3 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 15 minutes and the reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford 5-(((E)-2-oxo-2-(tetrahydrofuran-2- yl)ethylidene)amino)-6-(((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine- 2,4(1H,3H)-dione (93.5 mg, 25%) as a pale yellow solid:1H NM (4R00 MHz, DMSO-d6) δ 10.24 (br s, 1H), 8.81 (s, 1H), 7.38 (m, 1H), 5.45 - 5.41 (m, 1H), 4.55 (br s, 1H), 3.82 - 3.73 (m, 3H), 3.60 - 3.50 (m, 4H), 3.42 - 3.38 (m, 2H), 2.30 - 2.22 (m, 1H), 1.84 - 1.77 (m, 2H), 1.74 - 1.65 (m, 1H); (one amidic NH and three OH’s were not detected);13C NMR (100 MHz, DMSO) δ 201.11, 159.23, 156.15, 150.86, 141.83, 98.88, 77.60, 77.52, 73.56, 73.49, 73.21, 70.73, 70.29, 68.87, 63.64, 44.73, 44.55, 30.79, 30.63, 25.80 (mixture of diastereomers); MS (ESI) m / z 387 [C15H22N4O8 + H]+; UPLC (Method-A) 95.0% (AUC) tR= 2.83 min; Chiral HPLC (Method-C) 51.09% (AUC) tR= 9.37 min and 48.91% (AUC) tR= 12.03 min.EXAMPLE 54

[0322] This example provides an exemplary synthesis for Compound CJ.Scheme 64: Preparation of 5-(((E)-2-Oxo-2-(tetrahvdrofuran-3-vl)ethylidene)amino)-6-(((2S,3S,4R)-2,3,4,5-tetrahvdroxvpentvl)amino)pyrimidine-2,4(1H,3H)-dione (Compound CJ)

[0323] Preparation of N-Methoxy-N-methyltetrahydrofuran-3-carboxamide : To a stirred solution of tetrahydrofuran-3 -carboxylic acid (10.0 g, 86.0 mmol) and N,O-dimethyl hydroxylamine (12.5 g, 129 mmol) in dichloromethane (200 mL), was added triethylamine (23.8 mL, 172 mmol) at 0 °C. After stirring for 5 min, propyl phosphonic anhydride (50% in ethyl acetate, 82.1 mL, 129 mmol) was added to the reaction. The reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction was quenched with saturated sodium bicarbonate solution (100 mL) and extracted with di chloromethane (2 × 100 mL). The combined organic extracts were washed with brine (100 mL), dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to afford N-methoxy-N-methyltetrahydrofuran-3-carboxamide (10.2 g, crude) as a colorless oil: MS (ESI) m / z 160 [C7H13NO3 + H]+. The crude product was used directly for the next step without purification.

[0324] Preparation of l-(Tetrahydrofuran-3-yl)ethan-l-one: To a stirred solution of N- methoxy-N-methyltetrahydrofuran-3-carboxamide (10.0 g, 62.8 mmol) in tetrahydrofuran (50 mL), was added methyl magnesium bromide (IM in tetrahydrofuran, 94.3 mL, 94.3 mmol) at 0 °C. The reaction was stirred for 1 hour and the reaction progress was monitored by thin layer chromatography. The reaction was quenched with saturated ammonium chloridesolution (100 mL) and extracted with methyl tert-butyl ether (2 × 100 mL). The combined organic extracts were washed with brine (100 mL) dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to afford l-(tetrahydrofuran-3-yl)ethan-1- one (5.20 g, crude) as a pale-yellow oil. The crude product was used directly for the next step without purification.

[0325] Preparation of 2-Oxo-2-(tetrahydrofuran-3-yl)acetaldehyde: The stirred solution of selenium dioxide (2.18 g, 19.7 mmol) in 1,4-dioxane (6.75 mL) and water (0.75 mL) was heated to 60 °C for 1 hour. l-(Tetrahydrofuran-3-yl)ethan-1-one (1.50 g, 13.1 mmol) was added to the reaction at same temperature and the reaction was heated to 100 °C for 16 hours. The reaction was cooled to room temperature and passed through diatomaceous earth. The filtrate [2-oxo-2-(tetrahydrofuran-3-yl)acetaldehyde, 8 mL, crude, a pale-yellow oil] was directly used for the next step without further distillation.

[0326] Preparation of 5-(((E)-2-Oxo-2-( tetrahydrofuran-3-yl)ethylidene)amino)-6-(((2S, 3S, 4R)-2, 3, 4, 5-tetrahydroxypentyl)amino)pyrimidine-2, 4(1H, 3H)-dione ( Compound CJ): The stirred solution of 5-amino-6-(((2S,3 S,4R)-2, 3,4,5- tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (300 mg, 0.96 mmol) and 2-oxo-2-(tetrahydrofuran-3-yl)acetaldehyde (3 mL, crude) in dimethyl sulfoxide (3 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 15 minutes and the reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford 5-(((E)-2-oxo-2-(tetrahydrofuran-3- yl)ethylidene)amino)-6-(((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine- 2,4(1H,3H)-dione (80.5 mg, 21%) as a pale yellow solid:1H NM (4R00 MHz, DMSO-d6) δ 8.81 (s, 1H), 6.90 (br s, 1H), 6.33 - 5.41 (m, 4H), 4.25 - 4.15 (m, 1H), 3.96 - 3.91 (m, 1H),3.70 (t, J = 6.8 Hz, 2H), 3.59 - 3.55 (m, 4H), 3.52 - 3.51 (m, 2H), 3.43 - 3.41 (m, 1H), 3.29 - 3.27 (m, 1H), 2.00 - 1.94 (m, 2H), (Two ami die NH’s were not detected);13C NMR (100 MHz, DMSO) 6 201.67, 162.67, 160.39, 156.73, 138.70, 100.69, 73.60, 72.98, 72.93, 72.43, 72.38, 70.79, 70.65, 68.33, 68.31, 63.51, 44.11, 43.26, 43.18, 29.84, 29.58 (mixture of diastereomers); MS (ESI) m / z 387.1 [C15H22N4O8 + H]+; UPLC (Method-A) 96.5% (AUC) tR= 2.88 min; Chiral HPLC (Method-C) 44.3% (AUC) tR= 6.38 min and 51.0% (AUC) tR=8.71 min.EXAMPLE 55

[0327] This example provides an exemplary synthesis for Compound CK.Scheme 65: Preparation of 5-(((E)-2-Oxo-2-(tetrahvdro-2H-pyran-4-vl)ethvlidene)amino)-6-(((2S,3S,4R)-2,3,4,5-tetrahvdroxvpentvl)amino)pyrimidine-2,4(1H,3H)-dione (Compound CK)

[0328] Preparation of 2-Oxo-2-(tetrahydro-2H-pyran-4-yl)acetaldehyde : The sealed vial was charged with selenous acid (3.01 g, 79.2 mmol), l-(tetrahydro-2H-pyran-4-yl)ethan-1- one (2.00 g, 15.6 mmol) and 1,4-di oxane (10 mL) at room temperature. Sealed the vial with cap and heated the reaction to 100 °C for 8 hours. The reaction was cooled to room temperature and passed through diatomaceous earth. The filtrate [2-oxo-2-(tetrahydro-2H- pyran-4-yl)acetaldehyde, 5 mL, crude, as a pale-yellow oil] was used directly for the next step without further distillation.

[0329] Preparation of 5-(((E)-2-Oxo-2-( tetrahydro-2H-pyran-4-yl)ethylidene)amino)-6-(((2S, 38, 4R)-2, 3, 4, 5-tetrahydroxypentyl)amino)pyrimidine-2, 4(1H, 3H)-dione ( Compound CK): The stirred solution of 5-amino-6-(((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl) amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (300 mg, 0.96 mmol) and 2-oxo-2- (tetrahydro-2H-pyran-4-yl)acetaldehyde (3 mL, crude) in dimethyl sulfoxide (3 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 15 minutes and the reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford 5-(((E)-2-oxo-2-(tetrahydro-2H-pyran-4-yl) ethylidene) amino)-6-(((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl) amino) pyrimidine- 2,4(1H,3H)-dione (98.5 mg, 26%) as a pale yellow solid:1H NMR(400 MHz, DMSO-d6) δ10.45 (br s, 1H), 8.76 (s, 1H), 7.41 (br s, 1H), 5.45 - 4.44 (m, 2H), 3.85 - 3.70 (m, 4H), 3.61 - 3.58 (m, 2H), 3.53 - 3.39 (m, 6H), 1.59 - 1.42 (m, 4H); (one amidic NH and two OH’s were not detected);13C NMR (100 MHz, DMSO) δ 203.87, 159.44, 157.21, 151.97, 141.23, 98.87, 73.35, 73.32, 70.54, 66.89, 63.65, 44.28, 29.49, 29.08; MS (ESI) m / z 401.1 [CI6H24N4O8 + H]+; UPLC (Method-A) 95.7% (AUC) tR= 2.93 min; Chiral HPLC (Method-C) 98.8% (AUC) tR= 8.10 min.EXAMPLE 56

[0330] This example provides an exemplary synthesis for Compound CL.Scheme 66:(((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (CompoundCL)

[0331] Preparation of l-(Piperidin-4-yl)ethan-l-one hydrochloride: To a stirred solution of tert-butyl 4-acetylpiperidine-1-carboxylate (15.0 g, 66.1 mmol) in 1,4-dioxane (150 mL), was added 4M HC1 in 1,4-dioxane (15 mL) at 0 °C. The reaction was warmed to room temperature and stirred for 16 hours. The progress of the reaction was monitored by thin layer chromatography and UPLC-MS. The precipitate was collected by filtration and dried under vacuum to afford l-(piperidin-4-yl)ethan-1-one hydrochloride (9.00 g, crude) as a white solid: MS (ESI) m / z 113 [C7H12O + H]+. The crude product was used directly without purification.

[0332] Preparation of 1,1 -(Piperidine- l,4-diyl)bis(ethan-l -one: To a stirred solution of l-(piperidin-4-yl)ethan-1-one hydrochloride (3.00 g, 18.4 mmol) in di chloromethane (30 mL), were added triethylamine (7.70 mL, 55.2 mmol), followed by acetic anhydride (2.80 mL, 27.6 mmol) at 0 °C. The reaction was warmed to room temperature and stirred for 3 hours. The progress of the reaction was monitored by thin layer chromatography and UPLC- MS. The reaction was diluted with water (30 mL) and extracted with dichloromethane (2 ×100 mL). The combined organic extracts were washed with brine (50 mL) and dried over sodium sulphate, filtered and the filtrate was concentrated under reduced pressure to afford 1, 1'-(piperi dine- l,4-diyl)bis(ethan-l -one (3.10 g, crude) as a colorless oil: MS (ESI) m / z 170.1 [C9Hi5NO2+ H]+.

[0333] Preparation of 2-(l-Acetylpiperidin-4-yl)-2-oxoacetaldehyde: To a stirred solution 1,1'-(piperidine-l,4-diyl)bis(ethan-1-one (1.00 g, 5.91 mmol) in 1,4-dioxane (15 mL), was added selenium dioxide (1.30 g, 5.91 mmol) at room temperature. The reaction was heated to 85 °C for 16 hours and the progress of the reaction was monitored by thin layer chromatography and UPLC-MS. The reaction was cooled to room temperature, filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure to afford 2-(l-acetylpiperidin-4-yl)-2-oxoacetaldehyde (800 mg, crude) as a yellow thick oil: MS (ESI) m / z 184.1 [C9H15NO2 + H]+.

[0334] Preparation of 5-( ( (E)-2-( 1 -Acetylpiperidin-4-yl)-2-oxoethylidene)amino)-6-(((2S, 38, 4R)-2, 3, 4, 5-tetrahydroxypentyl)amino)pyrimidine-2, 4(1H, 3H)-dione ( Compound CL): The stirred solution of (R)-5-amino-6-((pyrrolidin-2-ylmethyl)amino)pyrimidine- 2,4(1H,3H)-dione hydrochloride (300 mg, 1.33 mmol) in dimethyl sulfoxide (0.60 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. 2-(l-Acetylpiperidin-4-yl)-2-oxoacetaldehyde (390 mg, 2.18 mmol) was added dropwise to the reaction and stirred for 15 minutes. The reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford 5-(((E)-2-(l-acetylpiperidin-4-yl)-2- oxoethylidene)amino)-6-(((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine- 2,4(1H,3H)-dione (18.9 mg, 4%) as a yellow solid:1H NM (R400 MHz, DMSO-d6) δ 10.24 (br s, 1H), 8.76 (s, 1H), 7.40 (br s, 1H), 4.78 - 4.29 (m, 4H), 3.82 - 3.39 (m, 10H), 3.20 - 3.14 (m, 1H), 2.73 - 2.66 (m, 1H), 1.99 (s, 3H), 1.68 - 1.66 (m, 2H), 1.49 - 1.39 (m, 1H), 1.33 - 1.20 (m, 1H) (One amidic NH was not detected); MS (ESI) m / z 442 [C18H27N5O8 + H]+;UPLC (Method-A) 96.6% (AUC) tR= 2.89 min.EXAMPLE 57

[0335] This example provides an exemplary synthesis for Compound CM.Scheme 67: Preparation of 5-(((E)-2-Oxobutylidene)amino)-6-(((2S,3S,4R)-2,3,4,5- tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H (Compound CM)

[0336] Preparation of (2S,3S,4S)-5-(Benzylamino)pentane-l,2,3,4-tetraol: To a stirred solution of (2R,3R,4S)-2,3,4,5-tetrahydroxypentanal (5.00 g, 33.3 mmol) and benzylamine (3.56 g, 33.3 mmol) in methanol (50 mL), was added platinum (IV) oxide (500 mg) under argon atmosphere at room temperature. The reaction was stirred under hydrogen atmosphere using a balloon for 24 hours. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction was passed through diatomaceous earth and the filtrate was concentrated under reduced pressure. The crude material was triturated with methyl tert-butyl ether, the precipitate was collected by filtration and dried under vacuum to afford (2S,3S,4S)-5-(benzylamino)pentane-l,2,3,4-tetraol (6.80 g, 84%) as an off-white solid:1H NMR (400 MHz, DMSO-d6) δ 7.32 - 7.31 (m, 4H), 7.24 - 7.20 (m, 1H), 4.57 (br s, 1H), 4.44 (br s, 1H), 4.41 - 4.10 (m, 2H), 3.70 (s, 2H), 3.65 - 3.61 (m, 1H), 3.59 - 3.54 (m, 1H), 3.41 - 3.31 (m, 4H), 2.75 (dd, J = 5.2, 11.8 Hz, 1H), 2.54 (dd, J = 6.4, 11.8 Hz, 1H): MS (ESI) m / z 242 [C12H19NO4 + H]+.

[0337] Preparation of (2S,3S,4S)-5-Aminopentane-l,2,3,4-tetraol: To a stirred solution of (2S,3S,4S)-5-(benzylamino)pentane-l,2,3,4-tetraol (4.00 g, 16.6 mmol) in methanol (40 mL), was added palladium hydroxide (20% on charcoal, 800 mg) under argon atmosphere at room temperature. Aqueous ammonium hydroxide solution (0.50 mL) to the reaction and stirred under hydrogen atmosphere using a balloon at room temperature for 24 hours. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction was passed through diatomaceous earth and the filtrate was concentrated under reduced pressure to afford (2S,3S,4S)-5-aminopentane-l,2,3,4-tetraol(2.20 g, crude) as a colorless viscous oil:1H NMR (400 MHz, DMSO-d6) δ 4.56 (br s, 1H), 4.42 (br s, 1H), 4.37 (br s, 1H), 4.31 (br s, 1H), 3.65 - 3.61 (m, 1H), 3.42 - 3.24 (m, 6H), 2.74 (dd, J = 4.4, 12.6 Hz, 1H), 2.58 (dd, J = 5.6, 12.6 Hz, 1H): MS (ESI) m / z 152 [C5H13NO4 + H]+. The crude product was used directly without purification.

[0338] Preparation of 5-Nitro-6-(((2S,3S,4S)-2, 3,4,5- tetrahydroxypentyl)amino)pyrimidine-2,4(1H, 3H)-dione : Potassium hydroxide (2N in water, 4.96 mL, 5.29 mmol) was added dropwise to a stirred solution of (2S,3S,4S)-5- aminopentane-l,2,3,4-tetraol (1.50 g, 9.93 mmol) and 5-nitro-6- tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (1.89 g, 9.93 mmol) in ethanol (10 mL) and water (2.50 mL) at room temperature. The reaction was heated to 80 °C for 8 hours and the progress of the reaction was monitored by UPLC-MS. The reaction was cooled to room temperature, the precipitate was collected by filtration, washed with ethanol and dried under vacuum to afford 5-nitro-6-(((2S,3S,4S)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine- 2,4(1H,3H)-dione (2.60 g, crude) as an off-white solid:1H NMR (400 MHz, DMSO-d6) δ 11.40 (br s, 1H), 10.79 (s, 1H), 10.22 (t, J = 4.8 Hz, 1H), 5.51 (br s, 1H), 4.63 - 4.32 (m, 3H), 3.77 - 3.75 (m, 1H), 3.71 - 3.62 (m, 3H), 3.41 - 3.37 (m, 3H); MS (ESI) m / z 307 [C9H14N4O8+ H]+. The crude was used directly for the next step without purification.

[0339] Preparation of 5-Amino-6-( < (28, 38, 4S)-2, 3, 4, 5- tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride: To a solution of 5- nitro-6-(((2S,3S,4S)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (1.50 g, 4.90 mmol) in IN aqueous hydrochloric acid (15 mL), was added 10% palladium on charcoal (300 mg) under argon atmosphere at room temperature. The reaction was stirred under hydrogen atmosphere using a balloon for 16 hours. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction was passed through diatomaceous earth, and the filtrate was concentrated under reduced pressure to afford 5-amino-6-(((2S,3S,4S)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)- dione hydrochloride (1.20 g, crude) as a pink solid (hygroscopic):1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 10.60 (s, 1H), 9.32 (br s, 3H), 7.89 (br s, 1H), 3.79 - 3.61 (m, 4H), 3.57 - 3.53 (m, 2H), 3.48 - 3.29 (m, 3H), 3.06 (br s, 1H), 2.72 (br s, 1H); MS (ESI) m / z 277 [C9H17CIN4O6 + H]+. The crude was used directly for the next step without purification.

[0340] Preparation of 5-( ( <E)-2-Oxobutylidene)amino)-6-( < (28, 38, 4R)-2, 3, 4, 5- tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H (Compound CM): The stirred solution of 5- amino-6-(((2S,3S,4S)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dionehydrochloride (400 mg, 1.28 mmol) and 2-oxobutanal (1.50 mL with traces of 1,4-dioxane) in dimethyl sulfoxide (2 mL) was adjusted to pH ~9 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 15 minutes and the reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford 5-(((E)-2- oxobutylidene)amino)-6-(((2S,3S,4S)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine- 2,4(1H,3H)-dione (48.0 mg, 11%) as a yellow solid:1H NMR (400 MHz, DMSO-d6) δ 10.50 (br s, 1H), 8.84 (s, 1H), 7.46 (t, J = 5.2 Hz, 1H), 4.50 (br s, 1H), 4.28 (br s, 1H), 3.72 - 3.63 (m, 3H), 3.55 - 3.50 (m, 1H), 3.41 (t, J = 6.4 Hz, 2H), 3.35 - 3.33 (m, 1H), 2.85 (q, J = 7.2 Hz, 2H), 0.99 (t, J = 7.6 Hz, 3H) (one amidic NH and two OH’s were not detected);13C NMR (100 MHz, DMSO-d6) δ 202.21, 158.11, 154.81, 149.46, 142.57, 97.22, 70.47, 69.17, 68.66, 62.07, 44.82, 27.55, 7.70; MS (ESI) m / z 345 [C13H20N4O7 + H]+; UPLC (Method-A) 97.6% (AUC) tR= 2.77 min; Chiral HPLC (Method-C) >99% (AUC) tR= 6.14 min.EXAMPLE 58

[0341] This example provides an exemplary synthesis for Compound CN.Scheme 68: Preparation of 5-(((E)-4,4,4-Trifluoro-2-oxobutylidene)amino)-6-(((2S,3R,4R)-2,3,4-trihvdroxvpentvl)amino)pyrimidine-2,4(1H,3H)-dione (Compound CN)

[0342] The stirred solution of 5-amino-6-(((2S,3R,4R)-2,3,4- trihydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (500 mg, 1.68 mmol) and 4,4,4-trifluoro-2-oxobutanal (2.50 mL with traces of 1,4-dioxane) in dimethyl sulfoxide (3 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 15 minutes and the reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B:10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford 5-(((E)-4,4,4-trifluoro-2- oxobutylidene)amino)-6-(((2S,3R,4R)-2,3,4-trihydroxypentyl)amino)pyrimidine-2,4(1H,3H)- dione (60.0 mg, 9%) as a yellow solid:1H NMR (400MHz, DMSO-d6) δ 10.64 (br s, 1H), 8.90 (s, 1H), 7.90 (br s, 1H), 4.95 - 4.77 (m, 2H), 4.14 - 4.01 (m, 2H), 3.73 - 3.68 (m, 1H), 3.66 - 3.61 (m, 2H), 3.56 - 3.49 (m, 1H), 3.29 - 3.27 (m, 1H), 1.09 (d, J = 6.4 Hz, 3H) (one amidic NH and one OH were not detected);13C NMR (100 MHz, DMSO-d6) δ 192.97, 159.23, 156.22, 150.54, 141.97, 127.24, 124.50, 99.16, 76.53, 71.14, 67.73, 45.40, 19.06;19F NMR (376 MHz, DMSO-d6) δ -60.31 (s, 3F); MS (ESI) m / z 383 [C13H17F3N4O6 + H]+; UPLC (Method-A) >99% (AUC) tR= 3.58 min.EXAMPLE 59

[0343] This example provides an exemplary synthesis for Compound CO.Scheme 69: Preparation of 6-(((2S,3S,4S)-2,3,4,5-Tetrahydroxypentyl)amino)-5-(((E)-4,4,4-trifluoro-2-oxobutylidene)amino)pyrimidine-2,4(1H,3H)-dione (Compound CO)OH

[0344] The stirred solution of 5-amino-6-(((2S,3 S,4S)-2, 3,4,5- tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (400 mg, 1.28 mmol) and 4,4,4-trifluoro-2-oxobutanal (1.50 mL with traces of 1,4-dioxane) in dimethyl sulfoxide (2 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 15 minutes and the reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford 6-(((2S,3 S,4S)-2, 3,4,5- tetrahydroxypentyl)amino)-5-(((E)-4,4,4-trifluoro-2-oxobutylidene)amino)pyrimidine- 2,4(1H,3H)-dione (35.0 mg, 7%) as a yellow solid:1H NMR (400MHz, DMSO-d6) δ 10.46 (br s, 1H), 8.90 (s, 1H), 7.74 (s, 1H), 4.50 (br s, 1H), 4.26 (br s, 1H), 4.08 (q, J = 11.6 Hz, 2H), 3.71 - 3.63 (m, 3H), 3.58 - 3.53 (m, 1H), 3.41 - 3.35 (m, 3H, (one ami di c NH and twoOH’s were not detected);13C NMR (100 MHz, DMSO-d6) δ (192.82, 159.37, 150.94, 141.64, 127.36, 124.61, 99.37, 71.70, 70.22, 63.16, 46.10, 38.97, 38.71);19F NMR (376 MHz, DMSO-d6) δ 60.26 (s, 3F); MS (ESI) m / z 399 [C13H17F3N4O7 + H]+; UPLC (Method-A) 93.4% (AUC) tR= 3.17 min; Chiral HPLC (Method-C) >99% (AUC) tR= 3.89 min.EXAMPLE 60

[0345] This example provides an exemplary synthesis for Compound CP.Scheme 70: Preparation of 5-(((E)-2-Oxohexylidene)amino)-6-(((2S,3S,4R)-2,3,4,5- tetrahvdroxvpentvl)amino)pyrimidine-2,4(1H,3H)-dione (Compound CP)

[0346] Preparation of 2-Oxohexanal: The stirred solution of selenium dioxide (6.10 g, 55.0 mmol) in 1,4-di oxane (45 mL) and water (5 mL) was heated to 60 °C for 1 hour. Hexan-2-one (5.00 g, 50.0 mmol) was added to the reaction at same temperature. The reaction was heated to 85 °C for 16 hours. The reaction was cooled to room temperature and passed through diatomaceous earth. The filtrate under fractional distillation provided 2- oxohexanal (20 mL with traces of dioxane) at 140 °C as a pale-yellow oil. The product with traces of dioxane was used directly for the next step without purification.

[0347] Preparation of 5-(((E)-2-Oxohexylidene)amino)-6-(((2S,3S,4R)-2, 3,4,5- tetrahydroxypentyl)amino)pyrimidine-2,4(1H,3H)-dione (Compound CP): The stirred solution of 5-amino-6-(((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine- 2,4(1H,3H)-dione hydrochloride (300 mg, 0.96 mmol) and 2-oxohexanal (2 mL with traces of 1,4-di oxane) in dimethyl sulfoxide (3 mL) was adjusted to pH ~9 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 30 minutes and the reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford 5-(((E)-2-oxohexylidene)amino)-6-(((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)amino)pyrimidine- 2,4(1H,3H)-dione (56.0 mg, 16%) as a pale yellow solid:1H NM (4R00 MHz, DMSO-d6) δ 11.04 (br s, 1H), 10.75 (br s, 1H), 8.83 (s, 1H), 7.64 - 7.62 (m, 1H), 5.39 (br s, 1H), 5.19 (br s, 1H), 4.78 (br s, 1H), 4.45 (t, J = 5.2 Hz, 1H), 3.82 - 3.82 (m, 1H), 3.68 - 3.58 (m, 2H), 3.51 - 3.42 (m, 3H), 3.41 - 3.38 (m, 1H), 2.88 - 2.76 (m, 2H), 1.53 - 1.46 (m, 2H), 1.33 - 1.24 (m, 2H), 0.87 (t, J = 7.6 Hz, 3H);13C NMR (100 MHz, DMSO-d6) δ 203.05, 158.96, 154.87, 149.78, 144.39, 98.04, 73.59, 73.13, 70.15, 63.64, 44.67, 34.98, 26.82, 22.41, 14.43; MS (ESI) m / z 373 [C15H24N4O7 + H]+; UPLC (Method-G) 98.1% (AUC) tR= 2.51 min; Chiral HPLC (Method-C) >99% (AUC) tR= 5.67 min.EXAMPLE 61

[0348] This example provides an exemplary synthesis for Compound CQ.Scheme 71 : Preparation of 6-((((2R,4R)-4-Hvdroxv-5-oxopyrrolidin-2-vl)methvl)amino)-5-(((E)-2-oxopropylidene)amino)pyrimidine-2,4(1H,3H)-dione (Compound CO)

[0349] The stirred solution of (R)-5-amino-6-(((6-oxopiperidin-2- yl)methyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (250 mg, 0.85 mmol) and 2- oxopropanal (0.57 mL, 1.71 mmol, 40% in water) in dimethyl sulfoxide (2.50 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 15 minutes and the reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford 6-((((2R,4R)-4-hydroxy-5-oxopyrrolidin-2- yl)methyl)amino)-5-(((E)-2-oxopropylidene)amino)pyrimidine-2,4(1H,3H)-dione (30.5 mg, 11%) as a pale yellow solid:1H NMR (400 MHz, DMSO-d6) δ 11.07 (br s, 1H), 10.64 (br s, 1H), 8.84 (s, 1H), 7.92 (s, 1H), 7.59 (t, J = 6.4 Hz, 1H), 5.51 - 5.42 (m, 1H), 4.07 (t, J = 8.8 Hz, 1H), 3.63 - 3.47 (m, 3H), 2.42 - 2.37 (m, 1H), 2.34 (s, 3H), 1.51 - 1.43 (m, 1H);13C NMR (100 MHz, DMSO-d6) δ 201.20, 176.98, 159.18, 155.11, 150.38, 144.60, 98.58, 68.98, 50.00,46.03, 34.29, 24.34; MS (ESI) m / z 310 [C12H15N5O5 + H]+; UPLC (Method-A) 96.8% (AUC) tR= 2.60 min; Chiral HPLC (Method- J) >99% (AUC) tR= 2.85 min.EXAMPLE 62

[0350] This example provides an exemplary synthesis for Compound CR.Scheme 72: Preparation of 6-((((2R,4S)-4-Hydroxy-5-oxopyrrolidin-2-yl)methyl)amino)-5-(((E)-2-oxopropylidene)amino)pyrimidine-2,4(1H,3H)-dione (Compound CR)

[0351] The stirred solution of 5-amino-6-((((2R,4S)-4-hydroxy-5-oxopyrrolidin-2- yl)methyl)amino)pyrimidine-2,4(1H,3H)-dione (250 mg, 0.85 mmol) and 2-oxopropanal (0.77 mL, 4.28 mmol, 40% in water) in dimethyl sulfoxide (2.50 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 15 minutes and the reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX cl 8 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford 6-((((2R,4S)-4-hydroxy-5-oxopyrrolidin-2- yl)methyl)amino)-5-(((E)-2-oxopropylidene)amino)pyrimidine-2,4(1H,3H)-dione (43.0 mg, 16%) as a pale yellow solid:1H NMR (400 MHz, DMSO-d6) δ 11.11 (br s, 1H), 10.96 (br s, 1H), 8.85 (s, 1H), 7.87 (s, 1H), 7.55 (t, J = 6.8 Hz, 1H), 5.43 (d, J = 5.6 Hz, 1H), 4.18 - 4.12 (m, 1H), 3.70 - 3.69 (m, 1H), 3.57 - 3.42 (m, 2H), 2.35 (s, 3H), 2.15 - 2.07 (m, 1H), 1.93 - 1.85 (m, 1H);13C NMR (100 MHz, DMSO) 6 201.13, 177.15, 159.12, 154.63, 150.07, 144.89, 98.45, 67.83, 50.75, 46.42, 33.83, 24.33; MS (ESI) m / z 359 [C12H15N5O5 + H]+;UPLC (Method-A) 96.3% (AUC) tR= 2.52 min; Chiral HPLC (Method- J) >99% (AUC) tR= 2.92 min.EXAMPLE 63

[0352] This example provides an exemplary synthesis for Compound CS.Scheme 73: oxopropvlidene)amino)pyrimidine-2,4(1H,3H)-dione (Compound CS)

[0353] Preparation of (R)-2-((6-Oxopiperidin-2-yl)methyl)isoindoline-l, 3-dione: To a stirred solution of (R)-6-(hydroxymethyl)piperidin-2-one (2.00 g, 15.4 mmol) and isoindoline-1, 3-dione (2.27 g, 15.4 mmol) in tetrahydrofuran (40 mL), were added triphenylphosphine (4.05 g, 15.4 mmol ) and diisopropyl azodi carb oxy late (3.13 g, 15.4 mmol) under argon atmosphere at 0 °C. The reaction was warmed to room temperature and stirred for 16 hours. The progress of the reaction was monitored by thin layer chromatography and UPLC-MS. The reaction was diluted with water (20 mL) and extracted with methyl tert-butyl ether (2 × 20 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulphate, filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography using silica-gel (200-400 mesh) and eluting with 8% methanol in dichloromethane. The pure fractions were concentrated under reduced pressure to afford (R)-2-((6-Oxopiperidin-2- yl)methyl)isoindoline-l, 3-dione (2.05 g, 51%) as a white solid:1H NMR (400 MHz, DMSO d6) δ 7.88 - 7.82 (m, 4H), 7.66 (br s, 1H), 3.71 - 3.62 (m, 2H), 3.53 - 3.48 (m, 1H), 2.14 - 2.11 (m, 2H), 1.81- 1.78 (m, 2H), 1.63 - 1.55 (m, 1H), 1.46 - 1.39 (m, 1H); MS (ESI) m / z 259 [C14H14N2O3 + H]+.

[0354] Preparation of (R)-6-(Amino methyl) piper idin-2 -one: To a stirred solution of(R)-2-((6-oxopiperidin-2-yl) methyl) isoindoline-1, 3-dione (2.50 g, 9.68 mmol) in ethanol (50 mL), was added hydrazine hydrate (80% solution in water, 1.02 mL, 19.3 mmol) at room temperature. The reaction was heated to 80 °C for 2 hours and the reaction progress was monitored by UPLC-MS. The reaction was cooled to room temperature and passed through diatomaceous earth, washed with ethanol. The filtrate was concentrated under reduced pressure to afford (R)-6-(amino methyl) piperidin-2-one (1.50 g, Crude) as colorless thick oil:MS (ESI) m / z 129 [C6H12N2O+ H]+. The crude product was used directly for the next step without purification.

[0355] Preparation of (R)-5-Nitro-6-(((6-oxopiperidin-2-yl)methyl)amino)pyrimidine-2,4(1H,3H)-dione: Potassium hydroxide (2N in water, 3.39 mL, 6.78 mmol) was added dropwise to a stirred solution of (R)-6-(amino methyl) piperidin-2-one (1.30 g, 6.78 mmol) and 6-chloro-5-nitropyrimidine-2,4(1H,3H)-dione (1.30 g, 10.1 mmol) in ethanol (13 mL) and water (5 mL) at room temperature. The reaction was heated to 80 °C for 8 hours and the reaction progress was monitored by UPLC-MS. The reaction was cooled to room temperature, the precipitate was collected by filtration, washed with ethanol and dried under vacuum to afford (R)-5-nitro-6-(((6-oxopiperidin-2-yl)methyl)amino)pyrimidine-2,4(1H,3H)- dione (1.60 g, crude) as an off-white solid: MS (ESI) m / z 284 [C10H13N5O5 + H]+. The crude product was used directly for the next step without purification.

[0356] Preparation of (R)-5-Amino-6-(((6-oxopiperidin-2-yl)methyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride: To a solution of (R)-5-nitro-6-(((6-oxopiperidin-2- yl)methyl)amino)pyrimidine-2,4(1H,3H)-dione (1.50 g, 5.29 mmol) in IN aqueous hydrochloric acid (15 mL), tetrahydrofuran and ethanol (15 mL, 1 : 1), was added 10% palladium on charcoal (300 mg) under argon atmosphere at room temperature. The reaction was stirred under hydrogen atmosphere using a balloon for 16 hours and the reaction progress was monitored by UPLC-MS. The reaction was passed through diatomaceous earth and the filtrate was concentrated under reduced pressure to afford (R)-5-amino-6-(((6-oxopiperidin-2- yl)methyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (1.05 g, crude) as a pink solid: MS (ESI) m / z 254 [C10H15N5O3 + H]+. The crude product was used directly for the next step without purification.

[0357] Preparation of (R,E)-5-((2-Oxobutylidene)amino)-6-(((6-oxopiperidin-2- yl)methyl)amino)pyrimidine-2,4(1H,3H)-dione (Compound CS): The stirred solution of (R)- 5-amino-6-(((6-oxopiperidin-2-yl)methyl)amino)pyrimidine-2,4(1H,3H)-dione hydrochloride (500 mg, 1.73 mmol) and 2-oxopropanal (0.62 mL, 3.46 mmol, 40% in water) in dimethyl sulfoxide (3 mL) was adjusted to pH ~8 by slow addition of IN aqueous sodium hydroxide solution at room temperature. The reaction was stirred for 15 minutes and the reaction progress was monitored by UPLC-MS. The reaction was purified by mass triggered preparative HPLC (Column: Gemini-NX c18 10μm 150*30mm, Mobile phase A: acetonitrile, Mobile phase B: 10mM ammonium bicarbonate in water, Flow rate: 30 mL / min, Run time: 20 min). The pure fractions were dried by lyophilization to afford (R,E)-5-((2-×xobutylidene)amino)-6-(((6-oxopiperi din-2 -yl)methyl)amino)pyrimidine-2,4(1H,3H)-di one (65.3 mg, 12%) as a pale yellow solid:1H NMR (400 MHz, DMSO-d6) δ 10.26 (br s, 1H), 8.82 (s, 1H), 7.43 (s, 1H), 7.34 (br s, 1H), 3.63 - 3.39 (m, 3H), 2.31 (s, 3H), 2.17 - 2.08 (m, 2H), 1.81 - 1.78 (m, 2H), 1.64 - 1.55 (m, 1H), 1.43 - 1.36 (m, 1H) (one amidic NH was not detected);13C NMR (100 MHz, DMSO-d6) δ 200.90, 171.27, 159.51, 157.03, 152.14, 143.41, 99.12, 52.33, 45.71, 31.69, 25.53, 24.17, 19.20; MS (ESI) m / z 359 [C13H17N5O4 + H]+; UPLC (Method-A) 98.9% (AUC) tR= 3.38 min; Chiral HPLC (Method-I) >99% (AUC) tR= 1.22 min.EXAMPLE 64

[0358] This example provides an exemplary synthesis for Compound CT.Scheme 74: Preparation of (S,E)-6-(((6-Oxopiperidin-2-yl)methyl)amino)-5-((2- oxopropvlidene)amino)pyrimidine-2,4(1H,3H)-dione (Compound CT)

[0359] Preparation of (S)-2-((6-Oxopiperidin-2-yl)methyl)isoindoline-l,3-dione: To a stirred solution of (S)-6-(hydroxymethyl)piperidin-2-one (2.00 g, 15.4 mmol) and isoindoline-1, 3-dione (2.27 g, 15.4 mmol) in tetrahydrofuran (40 mL), were added triphenylphosphine (4.05 g, 15.4 mmol ) and diisopropyl azodi carb oxy late (3.13 g, 15.4 mmol) under argon atmosphere at 0 °C. The reaction was warmed to room temperature and stirred for 16 hours. The progress of the reaction was monitored by thin layer chromatography and UPLC-MS. The reaction was diluted with water (20 mL) and extracted with methyl tert-butyl ether (2 × 20 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulphate, filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography using silica-gel (200-400 mesh) and eluting with 8% methanol in dichloromethane. The pure fractions wereconcentrated under reduced pressure to afford (S)-2-((6-Oxopiperidin-2- yl)methyl)isoindoline-l, 3-dione (1.70 g, 43%) as a white solid; MS (ESI) m / z 259 [C14H14N2O3 + H]+;1H-NMR (400 MHz, DMSO-d6): 5 7.88 - 7.82 (m, 4H), 7.67 (s, 1H), 3.71 - 3.62 (m, 2H), 3.51 (dd, J = 4.8, 12.2 Hz, 1H), 2.14 - 2.07 (m, 2H), 1.83 - 1.76 (m, 2H), 1.64 - 1.61 (m, 1H), 1.46 - 1.40 (m, 1H).

[0360] Preparation of (S)-6-(Amino methyl) piperidin-2-one: To a stirred solution of (S)- 2-((6-oxopiperidin-2-yl) methyl) isoindoline-1, 3-dione (1.70 g, 6.58 mmol) in ethanol (20 mL), was added hydrazine hydrate (80% solution in water, 0.80 mL, 13.7 mmol) at room temperature. The reaction was heated to 80 °C for 2 hours and the reaction progress was monitored by UPLC-MS. The reaction was cooled to room temperature and passed through diatomaceous earth, washed with ethanol. The filtrate was concentrated under reduced pressure to afford (S)-6-(amino methyl) piperidin-2-one (0.94 g, crude) as a colorless thick oil: MS (ESI) m / z 129 [C6H12N2O+ H]+. The crude product was used directly for the next step without purification.

[0361] Preparation of (S)-5-Nitro-6-(((6-oxopiperidin-2-yl)methyl)amino)pyrimidine- 2,4(1H,3H)-dione: Potassium hydroxide (2N in water, 2.60 ...

Claims

CLAIM(S):

1. A compound of Formula (I):a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R0is hydrogen or a C1-C6alkyl group,R1is a C2-C5alkyl group substituted with 1 to 4 hydroxyl groups, R2and R3combine to form a C3-C8cycloalkyl group, a 3-6 membered heterocylic group, an aryl group, or a heteroaryl group, each of which is optionally substituted with one or more substituents selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, difluoromethyl, trifluoromethyl, C1-C6alkoxy, arylated C1-C6alkoxy, trifluoromethylated C1-C6alkoxy, - C(O)OH, -C(O)O-(C1-C6alkyl), -C(O)-(C1-C6alkyl), -(C1-C3alkyl)-C(O)OH, -(C1-C3alkyl)- C(O)O-(C1-C6alkyl), -(C1-C3alkyl)-C(O)-(C1-C6alkyl), -NH-C(O)OH, -NH-C(O)O-(C1-C6alkyl), -NH-C(O)-(C1-C6alkyl), -(C1-C3alkyl)-NH-C(O)OH, -(C1-C3alkyl)-NH-C(O)O-(C1- C6alkyl), -(C1-C3alkyl)-NH-C(O)-(C1-C6alkyl), -(C1-C6alkyl)-O-(C1-C6alkyl), -O-(C1-C6alkyl)-O-(C1-C6alkyl), -(C1-C6alkyl)-OH, -(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-COOH, - (C1-C6alkyl)-C(O)O-(C1-C6alkyl), -(C1-C6alkyl)-(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)- NH2, -(C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)-(C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)- heterocycloalkyl, -(C1-C6alkyl)-heterocycloalkyl-(C1-C6alkyl), -(C1-C6alkyl)-C(O)- heterocycloalkyl, -(C1-C6alkyl)-C(O)-heterocycloalkyl-(C1-C6alkyl), halo, nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; -NH-aryl, -NH-heterocycloalkyl, -NH- heterocycloalkyl-(C1-C6alkyl), -C1-C6haloalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, aryl, heteroaryl, -CN, -(C1-C3alkyl)-CN, carbonyl, amino acid, amino acid methyl ester, and a combination thereof, and R4is absent, hydrogen, or a C1-C6alkyl group.

2. The compound of claim 1, a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R1is selected from:

3. The compound of claim 1, a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R1is4. The compound of any one of claims 1-3, a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R2and R3combine to form a C3-C8cycloalkyl group, a 3-6 membered heterocylic group, an aryl group, or a heteroaryl group, each of which is optionally substituted with one or more substituents selected from C1-C6alkyl, trifluoromethyl, C1-C6alkoxy, -C(O)-(C1-C6alkyl), halo, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino, and a combination thereof.

5. The compound of any one of claims 1-3, a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R2and R3combine to form a C3-C6cycloalkyl group, which is optionally substituted with one or more substituents selected from C1-C6alkyl, trifluoromethyl, C1-C6alkoxy, -C(O)-(C1-C6alkyl), halo, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino, and a combination thereof, and R4is hydrogen or a C1-C6alkyl group.

6. The compound of any one of claims 1-3, a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R2and R3combine to form a C3-C6cycloalkyl group, which is optionally substituted with one or more substituents selected from C1-C6alkyl, trifluoromethyl, halo, and a combination thereof, and R4is hydrogen or a C1-C6alkyl group.

7. The compound of any one of claims 1-3, a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R2and R3combine to form a C3-C6 cycloalkyl group, and R4is hydrogen or a C1-C6alkyl group.

8. The compound of any one of claims 1-3, a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R2and R3combine to form a a 3-6 membered heterocylic group, which is optionally substituted with one or more substituents selected from C1-C6alkyl, trifluoromethyl, C1-C6alkoxy, -C(O)-(C1-C6alkyl), halo, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; and a combination thereof, and R4is hydrogen or a C1-C6alkyl group.

9. The compound of any one of claims 1-3, a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R2and R3combine to form a an aryl group, which is optionally substituted with one or more substituents selected from C1-C6alkyl, trifluoromethyl, C1-C6alkoxy, -C(O)-(C1-C6alkyl), halo, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino, and a combination thereof, and R4is absent.

10. The compound of any one of claims 1-3, a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R2and R3combine to form a heteroaryl group, which is optionally substituted with one or more substituents selected from C1-C6alkyl, trifluoromethyl, C1-C6alkoxy, -C(O)-(C1- C6alkyl), halo, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino, and a combination thereof, and R4is absent.

11. The compound of claim 1, wherein the compound is selected from:a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

12. A compound of Formula (II):a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R0is hydrogen or a C1-C6alkyl group, R5is a C2-C5alkyl group substituted with 1 to 4 hydroxyl groups, and R6, R7, and R8are each independently selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, difluoromethyl, trifluoromethyl, C1-C6alkoxy, arylated C1-C6alkoxy, trifluoromethylated C1-C6alkoxy, -C(O)OH, -C(O)O-(C1-C6alkyl), -C(O)-(C1-C6alkyl), - (C1-C3alkyl)-C(O)OH, -(C1-C3alkyl)-C(O)O-(C1-C6alkyl), -(C1-C3alkyl)-C(O)-(C1-C6alkyl), -NH-C(O)OH, -NH-C(O)O-(C1-C6alkyl), -NH-C(O)-(C1-C6alkyl), -(C1-C3alkyl)- NH-C(O)OH, -(C1-C3alkyl)-NH-C(O)O-(C1-C6alkyl), -(C1-C3alkyl)-NH-C(O)-(C1-C6alkyl), -(C1-C6alkyl)-O-(C1-C6alkyl), -O-(C1-C6alkyl)-O-(C1-C6alkyl), -(C1-C6alkyl)-OH, - (C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-COOH, -(C1-C6alkyl)-C(O)O-(C1-C6alkyl), -(C1-C6alkyl)-(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-NH2, -(C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)- (C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)-heterocycloalkyl, -(C1-C6alkyl)-heterocycloalkyl- (C1-C6alkyl), -(C1-C6alkyl)-C(O)-heterocycloalkyl, -(C1-C6alkyl)-C(O)-heterocycloalkyl-(C1-C6alkyl), halo, nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; -NH- aryl, -NH-heterocycloalkyl, -NH-heterocycloalkyl-(C1-C6alkyl), -C1-C6haloalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, aryl, heteroaryl, -CN, -(C1-C3alkyl)-CN, carbonyl, amino acid, amino acid methyl ester, and a combination thereof, and wherein the compound of Formula (II) is not 5-(2-oxopropylideneamino)-6-D- ribity laminouracil .

13. The compound of claim 12, wherein the compound is selected from:a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

14. A compound of Formula (III):a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, whereinX is absent, -CH2-, or -C(O)-, R0is hydrogen or a C1-C6alkyl group, R9is a C3-C8cycloalkyl group, a 3-6 membered heterocylic group, or a heteroaryl group, each of which is optionally substituted with one or more substituents selected from hydroxy, oxo, and a combination thereof, and(iii) R10, R11, and R12are each independently selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, difluoromethyl, trifluoromethyl, C1-C6alkoxy, arylated C1-C6alkoxy, trifluoromethylated C1-C6alkoxy, -C(O)OH, -C(O)O-(C1-C6alkyl), -C(O)-(C1-C6alkyl), -(C1-C3alkyl)-C(O)OH, -(C1-C3alkyl)-C(O)O-(C1-C6alkyl), -(C1-C3alkyl)-C(O)-(C1- C6alkyl), -NH-C(O)OH, -NH-C(O)O-(C1-C6alkyl), -NH-C(O)-(C1-C6alkyl), -(C1-C3alkyl)- NH-C(O)OH, -(C1-C3alkyl)-NH-C(O)O-(C1-C6alkyl), -(C1-C3alkyl)-NH-C(O)-(C1-C6alkyl), -(C1-C6alkyl)-O-(C1-C6alkyl), -O-(C1-C6alkyl)-O-(C1-C6alkyl), -(C1-C6alkyl)-OH, - (C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-COOH, -(C1-C6alkyl)-C(O)O-(C1-C6alkyl), -(C1-C6alkyl)-(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-NH2, -(C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)- (C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)-heterocycloalkyl, -(C1-C6alkyl)-heterocycloalkyl- (C1-C6alkyl), -(C1-C6alkyl)-C(O)-heterocycloalkyl, -(C1-C6alkyl)-C(O)-heterocycloalkyl- (C1-C6alkyl), halo, nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; -NH- aryl, -NH-heterocycloalkyl, -NH-heterocycloalkyl-(C1-C6alkyl), -C1-C6haloalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, aryl, heteroaryl, -CN, -(C1-C3alkyl)-CN, carbonyl, amino acid, amino acid methyl ester, and a combination thereof or(iv) R10and R11combine to form a C3-C8cycloalkyl group, a 3-6 membered heterocylic group, an aryl group, or a heteroaryl group, each of which is optionally substituted with one or more substituents selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, difluoromethyl, trifluoromethyl, C1-C6alkoxy, arylated C1-C6alkoxy, trifluoromethylated C1-C6alkoxy, -C(O)OH, -C(O)O-(C1-C6alkyl), -C(O)-(C1-C6alkyl), - (C1-C3alkyl)-C(O)OH, -(C1-C3alkyl)-C(O)O-(C1-C6alkyl), -(C1-C3alkyl)-C(O)-(C1-C6alkyl), -NH-C(O)OH, -NH-C(O)O-(C1-C6alkyl), -NH-C(O)-(C1-C6alkyl), -(C1-C3alkyl)- NH-C(O)OH, -(C1-C3alkyl)-NH-C(O)O-(C1-C6alkyl), -(C1-C3alkyl)-NH-C(O)-(C1-C6alkyl), -(C1-C6alkyl)-O-(C1-C6alkyl), -O-(C1-C6alkyl)-O-(C1-C6alkyl), -(C1-C6alkyl)-OH, - (C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-COOH, -(C1-C6alkyl)-C(O)O-(C1-C6alkyl), -(C1-C6alkyl)-(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-NH2, -(C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)- (C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)-heterocycloalkyl, -(C1-C6alkyl)-heterocycloalkyl- (C1-C6alkyl), -(C1-C6alkyl)-C(O)-heterocycloalkyl, -(C1-C6alkyl)-C(O)-heterocycloalkyl- (C1-C6alkyl), halo, nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; -NH- aryl, -NH-heterocycloalkyl, -NH-heterocycloalkyl-(C1-C6alkyl), -C1-C6haloalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, aryl, heteroaryl, -CN, -(C1-C3alkyl)-CN, carbonyl, amino acid, amino acid methyl ester, and a combination thereof, and R12 is absent, hydrogen, or a C1-C6alkyl group.

15. The compound of claim 14, wherein the compound is selected from:a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising a compound of any one of claims 1-15, a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutical carrier.

17. The pharmaceutical composition of claim 16, wherein the pharmaceutical composition further comprises a TLR agonist.

18. The pharmaceutical composition of claim 17, wherein the TLR agonist is a TLR9 agonist.

19. The pharmaceutical composition of claim 17 or claim 18, wherein the TLR agonist is a cytosine-phosphate-guanine (CpG) dinucleotide.

20. A method of activating mucosal -associated invariant T (MAIT) cells in a subject, the method comprising administering to the subject a compound of any one of claims 1-15, a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 16-19.

21. The method of claim 20, wherein the method comprises upregulating MHC class I-related protein 1 (MR1) in the subject.

22. A method of treating cancer in a subject, the method comprising administering to the subject a compound of any one of claims 1-15, a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 16-19.

23. The method of claim 22, wherein the method comprises activating MAIT cells in the subject.

24. The method of claim 22 or claim 23, wherein the method comprises upregulating MR1 in the subject.

25. The method of any one of claims 22-24, wherein the cancer is liver cancer.

26. A method of treating an infectious disease in a subject, the method comprising administering to the subject a compound of any one of claims 1-15, a diastereomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 16-19.

27. The method of claim 26, wherein the method comprises activating MAIT cells in the subject.

28. The method of claim 26 or claim 27, wherein the infectious disease is tuberculosis.

29. The method of any one of claims 20-28, wherein the subject is human.

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