WO2021202669A2

WO2021202669A2 - Nucleoside and nucleotide conjugate compounds and uses thereof

Info

Publication number: WO2021202669A2
Application number: PCT/US2021/025095
Authority: WO
Inventors: Frank Shujie HOU; Jian XUE; Yushan ZHAO; Dezu MIAO
Original assignee: Reyoung Corporation; Reyoung Drug Discovery Co., Ltd.
Priority date: 2020-04-01
Filing date: 2021-03-31
Publication date: 2021-10-07
Also published as: WO2021202669A3

Abstract

This disclosure provides nucleoside and nucleotide conjugate compounds, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders, such as viral infections and cancers.

Description

NUCLEOSIDE AND NUCLEOTIDE CONJUGATE COMPOUNDS AND

USES THEREOF

RELATED APPLICATIONS

[0001] This application claims the priority benefit of U.S. provisional application 63/003,645 filed April 1, 2020, the entire contents of which are incorporated herein by reference.

BACKGROUND

[0002] Nucleoside and nucleotide analogs are structurally modified nucleosides mimicking endogenous nucleosides and block cellular division /viral replication by impairment DNA/RNA synthesis or inhibition of cellular/viral enzymes involved in nucleoside and nucleotide metabolism [Jordheim L.P.; Durantel D.; Zoulim F. etal ., Advances in the development of nucleoside and nucleotide analogues for cancer and viral diseases. Nat Rev Drug Discov 2013,

12: 447-464] More than 20 different nucleoside analogues have been approved to treat the viral infections / cancer via a measure of the stepwise formation of the mono-, di-, and the active triphosphate nucleoside analogue metabolites by cellular or viral kinases. The active triphosphate nucleoside analogue metabolite can act as competitive inhibitor of viral and cellular DNA or RNA polymerases or alternatively can be incorporated into growing DNA or RNA strands, leading to chain termination [De Clercq, E., Li, G., Approved antiviral drugs over the past 50 years, Clin. Microbiol. Rev. 2016, 29, 695-747; and De Clercq E., Neyts T, Antiviral agents acting as DNA or RNA chain terminators, Handb Exp Pharmacol 2009, 189, 53-84] To overcome the inefficiently monophosphorylation of nucleoside analogues /poor oral bioavailability /poor stability, many prodrugs with have been created and moved to different clinical stages [Jordheim L.P., Durantel D., Zoulim F. et al., Advances in the development of nucleoside and nucleotide analogues for cancer and viral diseases, Nat Rev Drug Discov 2013, 12: 447-464] Among those approaches, monophosphate and monophosphonate prodrug approaches have been widely used and successfully led to a few of FDA-approved drugs such as sofosbuvir, tenofovir alafenamide and clinical candidates, such as GS-5734 [Serpi M., Pertusati F., Phosphoramidates and phosphonamidates (ProTides) with antiviral activity , Antivir Chem Chemother. 2018, 26, 1-31] Structurally, sofosbuvir (W02006/012440, WO2008/121634), tenofovir alafenamide (W02002/08241) as well GS-5734 (WO2009/132135) are nucleotide alkylalaninyl phenyl phosphonoamidate prodrugs and their intercellular hydrolysis mainly initiated by the lysosomal cathepsin A [Birkus, G., Wang, R., Liu, X. et al., Cathepsin A is the major hydrolase catalyzing the intracellular hydrolysis of the antiretroviral nucleotide phosphonoamidate prodrugs GS-7340 and GS-9131 , Antimicrob. Agents Chemother. 2007, 51, 543-550; and Cha A., Budovich A., Sofosbuvir: A New Oral Once-Daily Agent for The Treatment of Hepatitis C Virus Infection, P T. 2014, 39(5): 345-352; and Warren T. K., Jordan R., Lo M. K. et ah, Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys, Nature 2016, 531(7594): 381-385] to form the nucleotide-amino acid conjugate metabolites, which has limited stability in the acid condition of lysosome resulting in hydrolysis of the P-N bond due to the acidic environment of lysosomes and/or phosphoramidase-type enzyme [Birkus, G., Kutty, N., Frey, C. R. et al, Role of cathepsin A and lysosomes in the intracellular activation of novel antipapillomavirus agent GS-9191 , Antimicrob. Agents Chemother. 2011, 55, 2166-2173; and Birkus, G. et al, Activation of 9-[(R)-2-[[(S)-[[(S)-l- (Isopropoxy carbonyl) ethyl] amino] phenoxyphosphinylj-methoxy] propyl] adenine (GS-7340) and other tenofovir phosphonoamidate prodrugs by human proteases, Mol. Pharmacol. 2008, 74,92- 100] and further be activated to form the triphosphate metabolites. Such studies indicate that those phosphonoamidate prodrugs first primarily hydrolyzed in lysosomes and then translocate to the cytosol.

[0003] Chloroquine and its structural analogues have been used for decades for malaria treatment by targeting of lysosome. Studies indicate the entry, replication and infection processes of several viruses are highly dependent on endosomal-lysosomal acidification and the activities of several host endosomal proteases which are also active in acidic pH environments, and increasing evidences showing chloroquine and its analogues have broad of antiviral activities [Keyaerts E., Li S., Vijgen L. et al. , Antiviral Activity of Chloroquine against Human Coronavirus OC43 Infection in Newborn Mice, Antimicrob. Agents Chemother. 2009, 53, 3416- 3421; Peter B., Madrid P.B.;, Chopra S., Manger I. D. et al., A Systematic Screen of FDA- Approved Drugs for Inhibitors of Biological Threat Agents, Plos One 2013, 8(4), e60579; Savarino A., Boelaert J.R., Cassone A., Majori G., Cauda R, Effects of chloroquine on f GS- 9191: an old drug against today's diseases ?, Lancet Infect Dis. 2003, 3(11), 722-727; and Liu J., Cao R., Xu M. et al, Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro, Cell Discovery 2020, 6,16] Furthermore, studies have also indicated that when cotreated chloroquine, the intracellular metabolites (cPrMEDAP-Phe and cPrMEDAP) of the phosphonoamidate prodrugs GS-9191(WO 2005/066189) was significantly increased [Birkus, G., Kutty, N., Frey, C. R. et al. , Role of cathepsin A and lysosomes in the intracellular activation of novel antipapillomavirus agent GS-9191, Antimicrob. Agents Chemother. 2011, 55, 2166-2173]

[0004] This disclosure provides novel conjugate of nucleoside and nucleotide with analogues of chloroquine, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases.

SUMMARY

[0005] Provided in one aspect is a compound of Formula (I), or an enantiomer, a enantiomeric mixture, a diastereomer, a diasteromeric mixture, or a pharmaceutically acceptable salt thereof:

wherein

A is unsubstituted or substituted nucleoside or unsubstituted or substituted nucleoside analogue, unsubstituted or substituted nucleotide, or unsubstituted or substituted nucleotide analogue;

where * is point of attachment for A; R is hydrogen, halo, CN, unsubstituted or substituted Ci-Cio alkyl, unsubstituted or substituted Ci-Cio haloalkyl, or unsubstituted or substituted Ci-Cio alkyl ether; Xi is O, S, NH, CH 2;

X2 is O, S, NH, CH₂;

YI and Y2 are each independently OH, H, halo, CN, CF3, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C3-C1₀ cycloalkyl, unsubstituted or substituted C1-C10 acyl, unsubstituted or substituted C1-C10 carboxyl ester, unsubstituted or substituted C1-C10 alkyl ketone, or unsubstituted or substituted C1-C10 alkyl ether;

Ri is NH-X_3-X4, 0-X_3-X4, or G2;

X₃ is unsubstituted or substituted C1-C2₀ alkylene, unsubstituted or substituted Ci- C2₀ alkenylene, unsubstituted or substituted C₃-C2₀ cycloalkylene, unsubstituted or substituted C1-C2₀ heterocyclylene, unsubstituted or substituted C1-C2₀ acyl, unsubstituted or substituted C1-C2₀ carboxy ester, unsubstituted or substituted C2- C2₀ alkyl ketone, unsubstituted or substituted C2-C2₀ alkyl ether, or unsubstituted or substituted C1-C2₀ alkyl amine;

X4 is hydrogen, unsubstituted or substituted C1-C2₀ heterocyclyl, unsubstituted or substituted heteroaryl, NRA-XS-X6-GI, NRA-XS-NRA-XT-GI, or Gi;

R2 is Ri, OH, O-Xs, G2, O-X9-G1, or G₃; or

Ri and R2 are taken together with the P atom to which they are attached to form an unsubstituted or substituted C2-C1₀ heterocyclyl;

X5 is unsubstituted or substituted C1-C2₀ alkylene;

Xe is absent or unsubstituted or substituted arylene;

X7 is unsubstituted or substituted C1-C2₀ alkylene; each RA is independently H or unsubstituted or substituted C1-C2₀ alkyl;

Giis

Ni, N2, and N3 are each independently OH, H, halo, CN, CF3, NO2, unsubstituted or substituted C1-C1₀ alkyl, unsubstituted or substituted C₃-C1₀ cycloalkyl, unsubstituted or substituted C1-C1₀ acyl, unsubstituted or substituted C1-C1₀ carboxyl ester, unsubstituted or substituted C1-C1₀ alkyl ketone, or unsubstituted or substituted Ci-Cioalkyl ether; or

N2 and N₃ are taken together with the carbon atoms to which they are attached to form a unsubstituted or substituted C5-C1₀ cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, or unsubstituted or substituted C1-C1₀ heterocyclyl;

X8 is unsubstituted or substituted C1-C2₀ alkyl, -C(RB)2-C02-RB, or unsubstituted or substituted aryl; each RB is independently H or unsubstituted or substituted C1-C2₀ alkyl;

X9 is unsubstituted or substituted arylene or unsubstituted or substituted C1-C₆ alkylene;

R₃, R4, and R5 are each independently OH, H, halo, CN, CF₃, NO2, unsubstituted or substituted C1-C1₀ alkyl, unsubstituted or substituted C₃-C1₀ cycloalkyl, unsubstituted or substituted C1-C1₀ acyl, unsubstituted or substituted C1-C1₀ carboxyl ester, unsubstituted or substituted C1-C1₀ alkyl ketone, or unsubstituted or substituted C1-C1₀ alkyl ether; or

R₃ and R4 are taken together with the carbon atoms to which they are attached to form a unsubstituted or substituted C5-C1₀ cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, or unsubstituted or substituted C1-C1₀ heterocyclyl; Mi is unsubstituted or substituted C1-C20 alkylene, unsubstituted or substituted C1-C20 alkenylene, unsubstituted or substituted C3-C20 cycloalkylene, unsubstituted or substituted Ci-C2o_heterocyclylene, unsubstituted or substituted C1-C20 acyl, unsubstituted or substituted C1-C20 carboxy ester, unsubstituted or substituted C2-C20 alkyl ketone, or unsubstituted or substituted C2-C20 alkyl ether; and

M2 and M3 are each independently unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted C1-C10 acyl, unsubstituted or substituted C1-C10 carboxyl ester, unsubstituted or substituted C1-C10 alkyl ketone, unsubstituted or substituted C1-C10 alkyl ether; or M2 and M3 are taken together with the N atom to which they are attached to form a unsubstituted or substituted C5-C10 cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, or unsubstituted or substituted C1-C10 heterocyclyl;

2 ;

B is unsubstituted or substituted G, cycloalkyl; and

Re and R7 are each independently OH, H, halo, CN, CF3, NO2, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted C1-C10 acyl, unsubstituted or substituted C1-C10 carboxyl ester, unsubstituted or substituted C1-C10 alkyl ketone, or unsubstituted or substituted C1-C10 alkyl ether. R

[0006] In some embodiments, X is

. In some embodiments, R is any one of the following: (a) hydrogen; (b) halo; (c) unsubstituted or substituted Ci-Cio alkyl; (d) unsubstituted or substituted Ci-Cio haloalkyl; and (e) unsubstituted or substituted Ci-Cio alkyl ether. In some embodiments, R is any one of the following: (a) hydrogen; (b) unsubstituted or substituted Ci- Cio alkyl; (c) unsubstituted or substituted Ci-Cio haloalkyl; and (d) unsubstituted or substituted Ci-Cio alkyl ether. In some embodiments, R is any one of the following: (a) hydrogen; (b) F, Cl, Br, or I; (c) CH₃ or CH2OH; and (d) CH2F or CF3.

[0007] In some embodiments, X is

; and R is H or CN. In some embodiment, R is H. In some embodiments, R is CN. In some embodiments, Xi is any one of the following: (a) O; (b) S; (c) NH; and (d) CFb. In some embodiments, Xi is any one of the following: (a) O; (b) S; and (c) NH. In some embodiments, X2 is any one of the following: (a)

O; (b) S; (c) NH; and (d) CFh. In some embodiments, X2 is any one of the following: (a) O; (b) S; and (c) NH. In some embodiments, Yi is any one of the following: (a) OH; (b) H; (c) halo;

(d) CN; (e) CF3; (f) unsubstituted or substituted C1-C10 alkyl; (g) unsubstituted or substituted C3- C10 cycloalkyl; (h) unsubstituted or substituted C1-C10 acyl; (i) unsubstituted or substituted Ci- C10 carboxyl ester; (j) unsubstituted or substituted C1-C10 alkyl ketone; and (k) or unsubstituted or substituted Ci-Cioalkyl ether. In some embodiments, Yi is any one of the following: (a) OH; (b) H; (c) CN; (d) CF3; and (e) unsubstituted or substituted C1-C10. In some embodiments, Y2 is any one of the following: (a) OH; (b) H; (c) halo; (d) CN; (e) CF3; (f) unsubstituted or substituted C1-C10 alkyl; (g) unsubstituted or substituted C3-C1₀ cycloalkyl; (h) unsubstituted or substituted C1-C10 acyl; (i) unsubstituted or substituted C1-C10 carboxyl ester; (j) unsubstituted or substituted C1-C10 alkyl ketone; and (k) or unsubstituted or substituted Ci-Cioalkyl ether. In some embodiments, Y2 is any one of the following: (a) OH; (b) H; (c) CN; (d) CF3; and (e) unsubstituted or substituted C1-C10. [0008] In some embodiments, X is

. In some embodiments, Xi is any one of the following: (a) O; (b) S; (c) NH; and (d) CH2. In some embodiments, X2 is any one of the following: (a) O; (b) S; (c) NH; and (d) CH2. In some embodiments, Yi is any one of the following: (a) OH; (b) H; (c) halo; (d) CN; (e) CF3; (f) unsubstituted or substituted C1-C10 alkyl; (g) unsubstituted or substituted C3-C10 cycloalkyl; (h) unsubstituted or substituted C1-C10 acyl; (i) unsubstituted or substituted C1-C10 carboxyl ester; (j) unsubstituted or substituted C1-C10 alkyl ketone; and (k) or unsubstituted or substituted Ci-Cioalkyl ether. In some embodiments, Y2 is any one of the following: (a) OH; (b) H; (c) halo; (d) CN; (e) CF3; (f) unsubstituted or substituted C1-C10 alkyl; (g) unsubstituted or substituted C3-C10 cycloalkyl; (h) unsubstituted or substituted C1-C10 acyl; (i) unsubstituted or substituted C1-C10 carboxyl ester; (j) unsubstituted or substituted C1-C10 alkyl ketone, and (k) or unsubstituted or substituted Ci-Cioalkyl ether.

[0009] In some embodiments, Ri is NH-X3-X4. In some embodiments, Ri is O-X3-X4. In some embodiments, X3 is any one of the following: (a) unsubstituted or substituted C1-C20 alkylene; (b) unsubstituted or substituted C1-C20 alkenylene; (c) unsubstituted or substituted C3- C20 cycloalkylene; (d) unsubstituted or substituted C1-C20 heterocyclylene; (e) unsubstituted or substituted C1-C20 acyl; (f) unsubstituted or substituted C1-C20 carboxy ester; (g) unsubstituted or substituted C2-C20 alkyl ketone; (h) unsubstituted or substituted C2-C20 alkyl ether; and (i) or unsubstituted or substituted C1-C20 alkyl amine. In some embodiments, X3 is any one of the following: (a) unsubstituted or substituted C1-C20 alkylene; (b) unsubstituted or substituted Ci- C20 alkenylene; (c) unsubstituted or substituted C1-C20 acyl; (d) unsubstituted or substituted Ci- C20 carboxy ester; (e) unsubstituted or substituted C2-C20 alkyl ketone; (f) unsubstituted or substituted C2-C20 alkyl ether; and (g) or unsubstituted or substituted C1-C20 alkyl amine. In some embodiments, X4 is any one of the following: (a) hydrogen; (b) unsubstituted or substituted Ci-C2oheterocyclyl; (c) unsubstituted or substituted heteroaryl; (d) NR4-X5-X6-G1; (e) NRA-XS- NRA-X7-G1; and (f) Gi. In some embodiments, X4 is any one of the following: (a) hydrogen; (b) unsubstituted or substituted Ci-C2oheterocyclyl; (c) unsubstituted or substituted heteroaryl; (d) NRA-X5-X6-G1; and (e) Gi. In some embodiments, RA is H. In some embodiments, RA is unsubstituted or substituted C1-C20 alkyl.

[0010] In some embodiments, X4 is NRA-XS-X6-GI, and Ni is any one of the following: (a)

OH; (b) H; (c) halo; (d) CN; (e) CF3; (f) NO2; (g) unsubstituted or substituted C1-C10 alkyl; (h) unsubstituted or substituted C3-C10 cycloalkyl; (i) unsubstituted or substituted C1-C10 acyl; (j) unsubstituted or substituted C1-C10 carboxyl ester; (k) unsubstituted or substituted C1-C10 alkyl ketone; and (1) or unsubstituted or substituted C1-C10 alkyl ether. In some embodiments, X4 is NRA-X5-X6-G1, and Ni is any one of the following: (a) OH; (b) H; (c) halo; (d) CN; (e) CF3; (f) NO2; (g) unsubstituted or substituted C1-C10 alkyl; (h) unsubstituted or substituted C1-C10 alkyl ketone; and (i) unsubstituted or substituted C1-C10 alkyl ether. In some embodiments, X4 is NH- X5-X6-G1, and N2 and N3 are each independently any one of the following: (a) OH; (b) H; (c) halo; (d) CN; (e) CF3; (f) NO2; (g) unsubstituted or substituted C1-C10 alkyl; (h) unsubstituted or substituted C3-C10 cycloalkyl; (i) unsubstituted or substituted C1-C10 acyl; (j) unsubstituted or substituted C1-C10 carboxyl ester; (k) unsubstituted or substituted C1-C10 alkyl ketone; and (1) or unsubstituted or substituted C1-C10 alkyl ether. In some embodiments, X4 is NH-X5-X6-G1, and N2 and N3 are each independently any one of the following: (a) OH; (b) H; (c) halo; (d) CN; (e) CF3; (f) NO2; (g) unsubstituted or substituted C1-C10 alkyl; (h) unsubstituted or substituted Ci- C10 alkyl ketone; and (i) unsubstituted or substituted C1-C10 alkyl ether.

[0011] In some embodiments, X4 is NRA-X5-X6-G1, and N2 and N3 are taken together with the carbon atoms to which they are attached to form any one of the following: (a) unsubstituted or substituted C5-C10 cycloalkyl; (b) unsubstituted or substituted aryl; (c) unsubstituted or substituted heteroaryl; and (d) unsubstituted or substituted C1-C10 heterocyclyl.

[0012] In some embodiments, X4 is NRA-XS-NRA-XT-GI, and Ni is any one of the following: (a) OH; (b) H; (c) halo; (d) CN; (e) CF3; (f) NO2; (g) unsubstituted or substituted C1-C10 alkyl; (h) unsubstituted or substituted C3-C10 cycloalkyl; (i) unsubstituted or substituted C1-C10 acyl; (j) unsubstituted or substituted C1-C10 carboxyl ester; (k) unsubstituted or substituted C1-C10 alkyl ketone; and (1) or unsubstituted or substituted C1-C10 alkyl ether. [0013] In some embodiments, X4 is NRA-XS-NRA-XT-GI, and N2 and N3 are each independently any one of the following: (a) OH; (b) H; (c) halo; (d) CN; (e) CF3; (f) NO2; (g) unsubstituted or substituted C1-C1₀ alkyl; (h) unsubstituted or substituted C₃-C1₀ cycloalkyl; (i) unsubstituted or substituted C1-C1₀ acyl; (j) unsubstituted or substituted C1-C1₀ carboxyl ester;

(k) unsubstituted or substituted C1-C10 alkyl ketone; and (1) or unsubstituted or substituted C1-C10 alkyl ether.

[0014] In some embodiments, X4 is NRA-XS-NRA-XT-GI, then N2 and N3 are taken together with the carbon atoms to which they are attached to form any one of the following: (a) unsubstituted or substituted C5-C1₀ cycloalkyl; (b) unsubstituted or substituted aryl; (c) unsubstituted or substituted heteroaryl; and (d) unsubstituted or substituted C1-C1₀ heterocyclyl.

[0015] In some embodiments, X4 is Gi, and Ni is any one of the following: (a) OH; (b) H; (c) halo; (d) CN; (e) CF₃; (f) NO2; (g) unsubstituted or substituted C1-C1₀ alkyl; (h) unsubstituted or substituted C₃-C1₀ cycloalkyl; (i) unsubstituted or substituted C1-C1₀ acyl; (j) unsubstituted or substituted C1-C1₀ carboxyl ester; (k) unsubstituted or substituted C1-C1₀ alkyl ketone; and (1) or unsubstituted or substituted C1-C1₀ alkyl ether. In some embodiments, X4 is Gi, and Ni is any one of the following: (a) OH; (b) H; (c) halo; (d) CN; (e) CF₃; (f) NO2; (g) unsubstituted or substituted C1-C1₀ alkyl; (h) unsubstituted or substituted C1-C1₀ alkyl ketone; and (i) unsubstituted or substituted C1-C1₀ alkyl ether.

[0016] In some embodiments, X4 is Gi, and N2 and N₃ are each independently any one of the following: (a) OH; (b) H; (c) halo; (d) CN; (e) CF₃; (f) NO2; (g) unsubstituted or substituted Ci- C10 alkyl; (h) unsubstituted or substituted C₃-C1₀ cycloalkyl; (i) unsubstituted or substituted Ci- C10 acyl; (j) unsubstituted or substituted C1-C1₀ carboxyl ester; (k) unsubstituted or substituted C1-C1₀ alkyl ketone; and (1) or unsubstituted or substituted C1-C1₀ alkyl ether. In some embodiments, X4 is Gi, and N2 and N₃ are each independently any one of the following: (a) OH; (b) H; (c) halo; (d) CN; (e) CF₃; (f) NO2; (g) unsubstituted or substituted C1-C1₀ alkyl; (h) unsubstituted or substituted C1-C1₀ alkyl ketone; and (i) unsubstituted or substituted C1-C1₀ alkyl ether. [0017] In some embodiments, X4 is Gi, and N2 and N3 are taken together with the carbon atoms to which they are attached to form any one of the following: (a) unsubstituted or substituted Cs- C10 cycloalkyl; (b) unsubstituted or substituted aryl; (c) unsubstituted or substituted heteroaryl; and (d) unsubstituted or substituted C1-C10 heterocyclyl.

[0018] In some embodiments, Ri is NH-X3-X4 and is any one of the following: (a) X3 is unsubstituted or substituted C1-C20 carboxy ester, and X4 is hydrogen; (b)

X3 is unsubstituted or substituted C1-C20 alkylene, and X4 is NRA-X5-X6-G1; (d) X3 is unsubstituted or substituted C4 alkylene, X4 is NRA-X5-X6-G1, X5 is unsubstituted or substituted

Ci alkylene, Xe is unsubstituted or substituted phenylene,

(e) X3 is unsubstituted or substituted C1-C20 alkylene, and X4 is NRA-XS-NRA-XT-GI; (f) X3 is unsubstituted or substituted C3-C4 alkylene, X4 is NRA-XS-NRA-XT-GI, X5 and X7 are each unsubstituted or substituted C3-C4 alkylene,

unsubstituted or substituted C1-C20 alkylene, and X4 is Gi;

and (h) X3 is unsubstituted or substituted C4-C14 alkylene,

[0019] In some embodiments, Ri is O-X3-X4 and is any one of the following: (a) X3 is unsubstituted or substituted C1-C20 alkylene, and X4 is NR4-X5-X6-G1; (b) X3 is unsubstituted or substituted C2 alkylene, X4 is NR.4-X5-X6-G1, X5 is unsubstituted or substituted Ci alkylene, Xr_> is absent,

unsubstituted or substituted C1-C20 alkylene, and

X4 is Gi; and (d) X3 is unsubstituted or substituted C4-C14 alkylene, X4 is Gi, and Gi is

[0020] In some embodiments, Ri is G2. In some embodiments, Ri is G2, and R3 and R4 are independently any one of the following: (a) OH; (b) H; (c) halo; (d) CN; (e) CF3; (f) NO2; (g) unsubstituted or substituted C1-C10 alkyl; (h) unsubstituted or substituted C3-C10 cycloalkyl; (i) unsubstituted or substituted C1-C10 acyl; (j) unsubstituted or substituted C1-C10 carboxyl ester;

(k) unsubstituted or substituted C1-C10 alkyl ketone; and (1) unsubstituted or substituted C1-C10 alkyl ether.

[0021] In some embodiments, Ri is G2, and R3 and R4 are taken together with the carbon atoms to which they are attached to form any one of the following: (a) unsubstituted or substituted Cs- Cio cycloalkyl; (b) unsubstituted or substituted aryl; (c) unsubstituted or substituted heteroaryl; and (d) unsubstituted or substituted Ci-Cio heterocyclyl.

[0022] In some embodiments, Ri is G2, and R5 is any one of the following: (a) OH; (b) H; (c) halo; (d) CN; (e) CF3; (f) NO2; (g) unsubstituted or substituted C1-C10 alkyl; (h) unsubstituted or substituted C3-C10 cycloalkyl; (i) unsubstituted or substituted C1-C10 acyl; (j) unsubstituted or substituted C1-C10 carboxyl ester; (k) unsubstituted or substituted C1-C10 alkyl ketone; and (1) unsubstituted or substituted Ci-Cioalkyl ether.

[0023] In some embodiments, Ri is G2, and Mi is any one of the following: (a) unsubstituted or substituted C1-C20 alkylene; (b) unsubstituted or substituted C1-C20 alkenylene; (c) unsubstituted or substituted C3-C20 cycloalkylene; (d) unsubstituted or substituted Ci-C2oheterocyclylene; (e) unsubstituted or substituted C1-C20 acyl; (f) unsubstituted or substituted C1-C20 carboxy ester; (g) unsubstituted or substituted C2-C20 alkyl ketone; and (h) unsubstituted or substituted C2-C20 alkyl ether.

[0024] In some embodiments, Ri is G2, and M2 and M3 are each independently any one of the following: (a) unsubstituted or substituted C1-C10 alkyl; (b) unsubstituted or substituted C3-C10 cycloalkyl; (c) unsubstituted or substituted C1-C10 acyl; (d) unsubstituted or substituted C1-C10 carboxyl ester; (e) unsubstituted or substituted C1-C10 alkyl ketone; and (f) unsubstituted or substituted C1-C10 alkyl ether.

[0025] In some embodiments, Ri is G2, and M2 and M3 are taken together with the N atom to which they are attached to form any one of the following: (a) unsubstituted or substituted C5-C10 cycloalkyl; (b) unsubstituted or substituted aryl; (c) unsubstituted or substituted heteroaryl; and

(d) unsubstituted or substituted C1-C10 heterocyclyl.

[0026] In some embodiments, R2 is any one of the following: (a) Ri; (b) OH; (c) O-Xs; (d) G2;

(e) O-X9-G1; and (f) G3. In some embodiments, R2 is any one of the following: (a) OH; (b) O- X8; and (c) O-X9-G1. In some embodiments, if R2 is O-Xs, then Xs is any one of the following: (a) unsubstituted or substituted C1-C20 alkyl; (b) -C(RB)2-C02-RB; and (c) unsubstituted or sub stituted aryl. In some embodiments, RB is H. In some embodiments, RB is unsubstituted or substituted C1-C20 alkyl. In some embodiments, RB is -CH2-C02-(CH)(CH3)2.

[0027] In some embodiments, R2 is G2, and R3 and R4 are independently any one of the following: (a) OH; (b) H; (c) halo; (d) CN; (e) CF3; (f) NO2; (g) unsubstituted or substituted Ci- C10 alkyl; (h) unsubstituted or substituted C3-C10 cycloalkyl; (i) unsubstituted or substituted Ci- C10 acyl; (j) unsubstituted or substituted C1-C10 carboxyl ester; (k) unsubstituted or substituted C1-C10 alkyl ketone; and (1) unsubstituted or substituted C1-C10 alkyl ether.

[0028] In some embodiments, R2 is G2, and R3 and R4 are taken together with the carbon atoms to which they are attached to form any one of the following: (a) unsubstituted or substituted Cs- C10 cycloalkyl; (b) unsubstituted or substituted aryl; (c) unsubstituted or substituted heteroaryl; and (d) unsubstituted or substituted C1-C10 heterocyclyl.

[0029] In some embodiments, R2 is G2, and Rs is any one of the following: (a) OH; (b) H; (c) halo; (d) CN; (e) CF3; (f) NO2; (g) unsubstituted or substituted C1-C10 alkyl; (h) unsubstituted or substituted C3-C10 cycloalkyl; (i) unsubstituted or substituted C1-C10 acyl; (j) unsubstituted or substituted C1-C10 carboxyl ester; (k) unsubstituted or substituted C1-C10 alkyl ketone; and (1) unsubstituted or substituted Ci-Cioalkyl ether.

[0030] In some embodiments, R2 is G2, and Mi is any one of the following: (a) unsubstituted or substituted C1-C20 alkylene; (b) unsubstituted or substituted C1-C20 alkenylene; (c) unsubstituted or substituted C3-C20 cycloalkylene; (d) unsubstituted or substituted Ci-C2oheterocyclylene; (e) unsubstituted or substituted C1-C20 acyl; (f) unsubstituted or substituted C1-C20 carboxy ester; (g) unsubstituted or substituted C2-C20 alkyl ketone; and (h) unsubstituted or substituted C2-C20 alkyl ether.

[0031] In some embodiments, R2 is G2, and M2 and M3 are each independently any one of the following: (a) unsubstituted or substituted C1-C10 alkyl; (b) unsubstituted or substituted C3-C10 cycloalkyl; (c) unsubstituted or substituted C1-C10 acyl; (d) unsubstituted or substituted C1-C10 carboxyl ester; (e) unsubstituted or substituted Ci-Cio alkyl ketone; and (f) unsubstituted or substituted Ci-Cio alkyl ether.

[0032] In some embodiments, R2 is G2, and M2 and M3 are taken together with the N atom to which they are attached to form any one of the following: (a) unsubstituted or substituted C5-C10 cycloalkyl; (b) unsubstituted or substituted aryl; (c) unsubstituted or substituted heteroaryl; and (d) unsubstituted or substituted C1-C10 heterocyclyl.

[0033] In some embodiments, R2 is O-X9-G1, and Ni is any one of the following: (a) OH; (b)

H; (c) halo; (d) CN; (e) CF3; (f) NO2; (g) unsubstituted or substituted C1-C10 alkyl; (h) unsubstituted or substituted C3-C10 cycloalkyl; (i) unsubstituted or substituted C1-C10 acyl; (j) unsubstituted or substituted C1-C10 carboxyl ester; (k) unsubstituted or substituted C1-C10 alkyl ketone; and (1) or unsubstituted or substituted C1-C10 alkyl ether.

[0034] In some embodiments, R2 is O-X9-G1, and N2 and N3 are each independently any one of the following: (a) OH; (b) H; (c) halo; (d) CN; (e) CF3; (f) NO2; (g) unsubstituted or substituted C1-C10 alkyl; (h) unsubstituted or substituted C3-C10 cycloalkyl; (i) unsubstituted or substituted C1-C10 acyl; (j) unsubstituted or substituted C1-C10 carboxyl ester; (k) unsubstituted or substituted C1-C10 alkyl ketone; and (1) or unsubstituted or substituted C1-C10 alkyl ether.

[0035] In some embodiments, R2 is O-X9-G1, and N2 and N3 are taken together with the carbon atoms to which they are attached to form any one of the following: (a) unsubstituted or substituted C5-C10 cycloalkyl; (b) unsubstituted or substituted aryl; (c) unsubstituted or substituted heteroaryl; and (d) unsubstituted or substituted C1-C10 heterocyclyl.

[0036] In some embodiments, R2 is G3, and Mi is any one of the following: (a) unsubstituted or substituted C1-C20 alkylene; (b) unsubstituted or substituted C1-C20 alkenylene; (c) unsubstituted or substituted C3-C20 cycloalkylene; (d) unsubstituted or substituted Ci-C2oheterocyclylene; (e) unsubstituted or substituted C1-C20 acyl; (f) unsubstituted or substituted C1-C20 carboxy ester; (g) unsubstituted or substituted C2-C20 alkyl ketone; and (h) unsubstituted or substituted C2-C20 alkyl ether. [0037] In some embodiments, R2 is G3, and M2 and M3 are each independently any one of the following: (a) unsubstituted or substituted C1-C10 alkyl; (b) unsubstituted or substituted C3-C10 cycloalkyl; (c) unsubstituted or substituted C1-C10 acyl; (d) unsubstituted or substituted C1-C10 carboxyl ester; (e) unsubstituted or substituted C1-C10 alkyl ketone; and (f) unsubstituted or substituted C1-C10 alkyl ether.

[0038] In some embodiments, R2 is G3, and M2 and M3 are taken together with the N atom to which they are attached to form any one of the following: (a) unsubstituted or substituted C5-C10 cycloalkyl; (b) unsubstituted or substituted aryl; (c) unsubstituted or substituted heteroaryl; and (d) unsubstituted or substituted C1-C10 heterocyclyl.

[0039] In some embodiments, R2 is any one of the following:

unsubstituted or substituted C1-C20 alkylene, and M2 and M3 are each independently unsubstituted or substituted C1-C10 alkyl; (b) O-X9-G1, X9 is unsubstituted or substituted phenylene, and Gi is

unsubstituted or substituted

C1-C20 alkylene, and M2 and M3 are each independently unsubstituted or substituted C1-C10 alkyl.

[0040] In some embodiments, Ri and R2 are taken together with the P atom to which they are attached to form an unsubstituted or substituted C2-C10 heterocyclyl.

[0041] In some embodiments, the compound has the structure of Formula (II):

wherein,

Si is X10-G1; and

Xiois unsubstituted or substituted C1-C20 alkylene.

[0042] In some embodiments, the compound has the structure of Formula (III):

wherein,

S2 is hydrogen, unsubstituted or substituted C1-C20 alkyl, unsubstituted or substituted Ci- C20 alkenyl, unsubstituted or substituted C3-C20 cycloalkyl, unsubstituted or substituted C1-C20 heterocyclyl, unsubstituted or substituted C1-C20 acyl, unsubstituted or substituted C1-C2₀ carboxy ester, unsubstituted or substituted C2-C2₀ alkyl ketone, or unsubstituted or substituted C2-C2₀ alkyl ether;

S3 is X11-G1; and

X11 is unsubstituted or substituted C1-C2₀ alkylene.

[0043] In some embodiments, the compound has the structure of Formula IV:

[0044] In some embodiments, any one of the following: (a) R3, R4, and Rs are each hydrogen;

(b) R₃ and R4 are taken together with the carbon atoms to which they are attached to form a unsubstituted or substituted aryl and Rs is hydrogen; (c) R₃ and R4 are taken together with the carbon atoms to which they are attached to form a unsubstituted or substituted aryl, and Rs is halo; (d) R₃ and R4 are taken together with the carbon atoms to which they are attached to form a unsubstituted or substituted C5-C1₀ cycloalkyl, and Rs is hydrogen; (e) Mi is unsubstituted or substituted C1-C2₀ alkylene; and (f) M2 and M₃ are each independently unsubstituted or substituted C1-C1₀ alkyl.

[0045] In some embodiments, A comprises any one of the following: (a) adenine; (b) cytosine;

(c) guanine; (d) thymine; (e) uridine; and (f) pyrrolo[2,l-f][l,2,4]triazin-4-amine. In some embodiments, A is unsubstituted or substituted nucleoside. In some embodiments, A is unsubstituted or substituted nucleoside analogue. In some embodiments, the unsubstituted or substituted nucleoside or unsubstituted or substituted nucleoside analogue comprises any one of the following: (a) adenine; (b) cytosine; (c) guanine; (d) thymine; (e) uridine; and (f) pyrrolo[2,l- f] [ 1 ,2,4]triazin-4-amine. [0046] In some embodiments, A is unsubstituted or substituted nucleotide. In some embodiments, A is unsubstituted or substituted nucleotide analogue. In some embodiments, the unsubstituted or substituted nucleotide or unsubstituted or substituted nucleotide analogue comprises any one of the following: (a) adenine; (b) cytosine; (c) guanine; (d) thymine; (e) uridine; and (f) pyrrolo[2,l-f][l,2,4]triazin-4-amine.

[0047] In some embodiments, the compound of Formula I has the following structure:

[0048] In some embodiments, the compound of Formula I has the following structure:

[0049] Provided in another aspect is a compound having a structure selected from any one of the following structures:

or an enantiomer, an enantiomeric mixture, a diastereomer, a diasteromeric mixture, or a pharmaceutically acceptable salt thereof.

[0050] Also provided herein in one aspect is pharmaceutical composition comprising any one of the compounds disclosed herein or an enantiomer, an enantiomeric mixture, a diastereomer, a diasteromeric mixture, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0051] Also provided herein is a method for treating a viral infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any one of the compounds, or an enantiomer, an enantiomeric mixture, a diastereomer, a diasteromeric mixture, or a pharmaceutically acceptable salt thereof. In some embodiments, the viral infection is caused by hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), Ebola virus, or human coronavirus.

[0052] Also provided herein is a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any one of the compounds, or an enantiomer, an enantiomeric mixture, a diastereomer, a diasteromeric mixture, or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is heptacellular carcinoma (HCC), lung cancer, breast cancer, pancreatic cancer, biliary tract cancer, or colorectal cancer. DETAILED DESCRIPTION

[0053] This disclosure provides nucleoside and nucelotide compounds that are conjugated with chloroquine analogues. Also disclosed herein are methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions and diseases, which include viral infections and cancer.

Compounds

[0054] Provided in one aspect is a compound of Formula (I), or an enantiomer, a enantiomeric mixture, a diastereomer, a diasteromeric mixture, or a pharmaceutically acceptable salt thereof:

wherein

where * is point of attachment for A;

R is hydrogen, CN, halo, unsubstituted or substituted Ci-Cio alkyl, unsubstituted or substituted Ci-Cio haloalkyl, or unsubstituted or substituted Ci-Cio alkyl ether; Xi is O, S, NH, CH ₂;

X₂ is O, S, NH, CH₂;

YI and Y₂ are each independently OH, H, halo, CN, CF3, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C3-C1₀ cycloalkyl, unsubstituted or substituted C1-C10 acyl, unsubstituted or substituted C1-C10 carboxyl ester, unsubstituted or substituted C1-C10 alkyl ketone, or unsubstituted or substituted C1-C10 alkyl ether; Ri is NH-X3-X4, O-X3-X4, or G2;

X3 is unsubstituted or substituted C1-C20 alkylene, unsubstituted or substituted Ci- C20 alkenylene, unsubstituted or substituted C3-C20 cycloalkylene, unsubstituted or substituted C1-C20 heterocyclylene, unsubstituted or substituted C1-C20 acyl, unsubstituted or substituted C1-C20 carboxy ester, unsubstituted or substituted C2- C20 alkyl ketone, unsubstituted or substituted C2-C20 alkyl ether, or unsubstituted or substituted C1-C20 alkyl amine;

X4 is hydrogen, unsubstituted or substituted C1-C2₀ heterocyclyl, unsubstituted or substituted heteroaryl, NR.4-X5-X6-G1, NRA-XS-NRA-XT-GI, or Gi;

R2 is Ri, OH, O-Xs, G2, O-X9-G1, or G3; or

Ri and R2 are taken together with the P atom to which they are attached to form an unsubstituted or substituted C2-C10 heterocyclyl;

X5 is unsubstituted or substituted C1-C2₀ alkylene;

Xe is absent or unsubstituted or substituted arylene;

X7 is unsubstituted or substituted C1-C20 alkylene; each RA is independently H or unsubstituted or substituted C1-C20 alkyl;

Ni, N2, and N3 are each independently OH, H, halo, CN, CF3, NO2, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted C1-C10 acyl, unsubstituted or substituted C1-C10 carboxyl ester, unsubstituted or substituted C1-C10 alkyl ketone, or unsubstituted or substituted Ci-Cioalkyl ether; or

N2 and N3 are taken together with the carbon atoms to which they are attached to form a unsubstituted or substituted C5-C10 cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, or unsubstituted or substituted C1-C10 heterocyclyl; X8 is unsubstituted or substituted C1-C2₀ alkyl, -C(RB)2-C02-RB, or unsubstituted or substituted aryl; each RB is independently H or unsubstituted or substituted C1-C2₀ alkyl;

R3, R4, and R5 are each independently OH, H, halo, CN, CF3, NO2, unsubstituted or substituted C1-C1₀ alkyl, unsubstituted or substituted C₃-C1₀ cycloalkyl, unsubstituted or substituted C1-C1₀ acyl, unsubstituted or substituted C1-C1₀ carboxyl ester, unsubstituted or substituted C1-C1₀ alkyl ketone, or unsubstituted or substituted C1-C1₀ alkyl ether; or

R₃ and R4 are taken together with the carbon atoms to which they are attached to form a unsubstituted or substituted C5-C1₀ cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, or unsubstituted or substituted C1-C1₀ heterocyclyl;

Mi is unsubstituted or substituted C1-C2₀ alkylene, unsubstituted or substituted C1-C2₀ alkenylene, unsubstituted or substituted C₃-C2₀ cycloalkylene, unsubstituted or substituted Ci-C2o_heterocyclylene, unsubstituted or substituted C1-C2₀ acyl, unsubstituted or substituted C1-C2₀ carboxy ester, unsubstituted or substituted C2-C2₀ alkyl ketone, or unsubstituted or substituted C2-C2₀ alkyl ether; and

M2 and M₃ are each independently unsubstituted or substituted C1-C1₀ alkyl, unsubstituted or substituted C₃-C1₀ cycloalkyl, unsubstituted or substituted C1-C1₀ acyl, unsubstituted or substituted C1-C1₀ carboxyl ester, unsubstituted or substituted C1-C1₀ alkyl ketone, unsubstituted or substituted C1-C1₀ alkyl ether; or M2 and M3 are taken together with the N atom to which they are attached to form a unsubstituted or substituted C5-C10 cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, or unsubstituted or substituted C1-C10 heterocyclyl;

B is unsubstituted or substituted Cr_> cycloalkyl; and

Re and R7 are each independently OH, H, halo, CN, CF3, NO2, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted C1-C10 acyl, unsubstituted or substituted C1-C10 carboxyl ester, unsubstituted or substituted C1-C10 alkyl ketone, or unsubstituted or substituted C1-C10 alkyl ether.

[0055] In some embodiments, A is unsubstituted or substituted nucleoside or unsubstituted or substituted nucleoside analogue; X is:

, ;

R is hydrogen, halo, unsubstituted or substituted Ci-Cio alkyl, unsubstituted or substituted Ci-Cio haloalkyl, or unsubstituted or substituted Ci-Cio alkyl ether; Ri is NH-X3-X4 or O-X3-X4; X4 is hydrogen, unsubstituted or substituted C1-C2₀ heterocyclyl, unsubstituted or substituted heteroaryl, NH-X5-X6-G1, NH-X5-NRA-X7-G1, or Gi; and Xx is unsubstituted or substituted Ci- C2₀ alkyl.

R

[0056] In some embodiments, X is

. In some embodiments, R is hydrogen. In some embodiments, R is halo. In some embodiments, R is unsubstituted or substituted C1-C10 alkyl. In some embodiments, R is unsubstituted or substituted Ci-Cio haloalkyl. In some embodiments, R is unsubstituted or substituted Ci-Cio alkyl ether. In some embodiments, R is F, Cl, Br, or I. In some embodiments, R is CFb or CH2OH. In some embodiments, R is CH2F or CF3.

[0057] In some embodiments, X is

; and R is H or CN . In some

embodiments, X is

. In some embodiments, X is

^² . In some embodiments, Xi is O. In some embodiments, Xi is S. In some embodiments, Xi is NFL In some embodiments, Xi is CFh. In some embodiments, X2 is O. In some embodiments, X2 is S. In some embodiments, X2 is NFL In some embodiments, X2 is CFb. In some embodiments, Yi is OH. In some embodiments, Yi is H. In some embodiments, Yi is halo. In some embodiments, Yi is CN. In some embodiments, Yi is CF3. In some embodiments, Yi is unsubstituted or substituted C1-C10 alkyl. In some embodiments, Yi is unsubstituted or substituted C3-C1₀ cycloalkyl. In some embodiments, Yi is unsubstituted or substituted C1-C10 acyl. In some embodiments, Yi is unsubstituted or substituted C1-C10 carboxyl ester. In some embodiments, Yi is unsubstituted or substituted C1-C10 alkyl ketone. In some embodiments, Yi is unsubstituted or substituted Ci-Cioalkyl ether. In some embodiments, Y2 is OH. In some embodiments, Y2 is H. In some embodiments, Y2 is halo. In some embodiments, Y2 is CN. In some embodiments, Y2 is CF3. In some embodiments, Y2 is unsubstituted or substituted C1-C10 alkyl. In some embodiments, Y2 is unsubstituted or substituted C3-C1₀ cycloalkyl. In some embodiments, Y2 is unsubstituted or substituted C1-C10 acyl. In some embodiments, Y2 is unsubstituted or substituted C1-C10 carboxyl ester. In some embodiments, Y2 is unsubstituted or substituted C1-C10 alkyl ketone. In some embodiments, Y2 is unsubstituted or substituted Ci- Cioalkyl ether. [0058] In some embodiments, X is

. In some embodiments, Xi is O. In some embodiments, Xi is S. In some embodiments, Xi is NH. In some embodiments, Xi is CH2. In some embodiments, X2 is O. In some embodiments, X2 is S. In some embodiments, X2 is NH.

In some embodiments, X2 is CH2. In some embodiments, Yi is OH. In some embodiments, Yi is H. In some embodiments, Yi is halo. In some embodiments, Yi is CN. In some embodiments, Yi is CF3. In some embodiments, Yi is unsubstituted or substituted C1-C1₀ alkyl. In some embodiments, Yi is unsubstituted or substituted C3-C1₀ cycloalkyl. In some embodiments, Yi is unsubstituted or substituted C1-C1₀ acyl. In some embodiments, Yi is unsubstituted or substituted C1-C1₀ carboxyl ester. In some embodiments, Yi is unsubstituted or substituted C1-C1₀ alkyl ketone. In some embodiments, Yi is unsubstituted or substituted Ci- Cioalkyl ether. In some embodiments, Y2 is OH. In some embodiments, Y2 is H. In some embodiments, Y2 is halo. In some embodiments, Y2 is CN. In some embodiments, Y2 is CF_3. In some embodiments, Y2 is unsubstituted or substituted C1-C1₀ alkyl. In some embodiments, Y2 is unsubstituted or substituted C₃-C1₀ cycloalkyl. In some embodiments, Y2 is unsubstituted or substituted C1-C1₀ acyl. In some embodiments, Y2 is unsubstituted or substituted C1-C1₀ carboxyl ester. In some embodiments, Y2 is unsubstituted or substituted C1-C1₀ alkyl ketone. In some embodiments, Y2 is unsubstituted or substituted C1-C1₀ alkyl ether.

[0059] In some embodiments, Ri is NH-X_3-X4. In some embodiments, Ri is O-X_3-X4. In some embodiments, X₃ is unsubstituted or substituted C1-C2₀ alkylene. In some embodiments,

X₃ is unsubstituted or substituted C1-C2₀ alkenylene. In some embodiments, X₃ is unsubstituted or substituted C₃-C2₀ cycloalkylene. In some embodiments, X₃ is unsubstituted or substituted C1-C2₀ heterocyclylene. In some embodiments, X₃ is unsubstituted or substituted C1-C2₀ acyl. In some embodiments, X₃ is unsubstituted or substituted C1-C2₀ carboxy ester. In some embodiments, X₃ is unsubstituted or substituted C2-C2₀ alkyl ketone. In some embodiments, X₃ is unsubstituted or substituted C2-C2₀ alkyl ether. In some embodiments, X₃ is unsubstituted or substituted C1-C2₀ alkyl amine. In some embodiments, X4 is hydrogen. In some embodiments, X4 is unsubstituted or substituted C1-C2₀ heterocyclyl. In some embodiments, X4 is unsubstituted or substituted heteroaryl. In some embodiments, X4 is NR.4-X5-X6-G1. In some embodiments, X4 is NH-X5-X6-G1. In some embodiments, X4 is NRA-X5-NRA-X7-G1. In some embodiments, X4 is NH-X5-NRA-X7-G1. In some embodiments, RA is H. In some embodiments, RA is unsubstituted or substituted C1-C20 alkyl. In some embodiments, X4 is Gi.

[0060] In some embodiments, X4 is NRA-X5-X6-G1, and Ni is OH. In some embodiments, X4 is NRA-X5-X6-G1, and Ni is H. In some embodiments, X4 is NRA-X5-X6-G1, and NI is halo. In some embodiments, X4 is NRA-X5-X6-G1, and Ni is CN. In some embodiments, X4 is NRA-XS- Cd-Gi, and Ni is CF3. In some embodiments, X4 is NRA-X5-X6-G1, and Ni is NO2. In some embodiments, X4 is NRA-X5-X6-G1, and Ni is unsubstituted or substituted C1-C10 alkyl. In some embodiments, X4 is NRA-X5-X6-G1, and Ni is unsubstituted or substituted C3-C10 cycloalkyl. In some embodiments, X4 is NRA-X5-X6-G1, and Ni is unsubstituted or substituted C1-C10 acyl. In some embodiments, X4 is NRA-X5-X6-G1, and Ni is unsubstituted or substituted C1-C10 carboxyl ester. In some embodiments, X4 is NRA-X5-X6-G1, and Ni is unsubstituted or substituted C1-C10 alkyl ketone. In some embodiments, X4 is NRA-X5-X6-G1, and Ni is unsubstituted or substituted C1-C10 alkyl ether.

[0061] In some embodiments, X4 is NH-X5-X6-G1, and Ni is OH. In some embodiments, X4 is NH-X5-X6-G1, and Ni is H. In some embodiments, X4 is NH-X5-X6-G1, and Ni is halo. In some embodiments, X4 is NH-X5-X6-G1, and Ni is CN. In some embodiments, X4 is NH-X5-X6-G1, and Ni is CF3. In some embodiments, X4 is NH-X5-X6-G1, and Ni is NO2. In some embodiments, X4 is NH-X5-X6-G1, and Ni is unsubstituted or substituted C1-C10 alkyl. In some embodiments, X4 is NH-X5-X6-G1, and Ni is unsubstituted or substituted C3-C10 cycloalkyl. In some embodiments, X4 is NH-X5-X6-G1, and Ni is unsubstituted or substituted C1-C10 acyl. In some embodiments, X4 is NH-X5-X6-G1, and Ni is unsubstituted or substituted C1-C10 carboxyl ester. In some embodiments, X4 is NH-X5-X6-G1, and Ni is unsubstituted or substituted C1-C10 alkyl ketone. In some embodiments, X4 is NH-X5-X6-G1, and Ni is unsubstituted or substituted C1-C10 alkyl ether. [0062] In some embodiments, X4 is NRA-X5-X6-G1, and N2 and N3 are each independently OH. In some embodiments, X4 is NR.4-X5-X6-G1, and N2 and N3 are each independently H. In some embodiments, X4 is NR.4-X5-X6-G1, and N2 and N3 are each independently halo. In some embodiments, X4 is NR.4-X5-X6-G1, and N2 and N3 are each independently CN. In some embodiments, X4 is NR.4-X5-X6-G1, and N2 and N3 are each independently CF3. In some embodiments, X4 is NR.4-X5-X6-G1, and N2 and N3 are each independently NO2. In some embodiments, X4 is NR.4-X5-X6-G1, and N2 and N3 are each independently unsubstituted or substituted C1-C10 alkyl. In some embodiments, X4 is NR.4-X5-X6-G1, and N2 and N3 are each independently unsubstituted or substituted C3-C10 cycloalkyl. In some embodiments, X4 is NRA- X5-X6-G1, and N2 and N3 are each independently unsubstituted or substituted C1-C10 acyl. In some embodiments, X4 is NR.4-X5-X6-G1, and N2 and N3 are each independently unsubstituted or substituted C1-C10 carboxyl ester. In some embodiments, X4 is NR.4-X5-X6-G1, and N2 and N3 are each independently unsubstituted or substituted C1-C10 alkyl ketone. In some embodiments, X4 is NRA-X5-X6-G1, and N2 and N3 are each independently unsubstituted or substituted C1-C10 alkyl ether.

[0063] In some embodiments, X4 is NH-X5-X6-G1, and N2 and N3 are each independently OH. In some embodiments, X4 is NH-X5-X6-G1, and N2 and N3 are each independently H. In some embodiments, X4 is NH-X5-X6-G1, and N2 and N3 are each independently halo. In some embodiments, X4 is NH-X5-X6-G1, and N2 and N3 are each independently CN. In some embodiments, X4 is NH-X5-X6-G1, and N2 and N3 are each independently CF3. In some embodiments, X4 is NH-X5-X6-G1, and N2 and N3 are each independently NO2. In some embodiments, X4 is NH-X5-X6-G1, and N2 and N3 are each independently unsubstituted or substituted C1-C10 alkyl. In some embodiments, X4 is NH-X5-X6-G1, and N2 and N3 are each independently unsubstituted or substituted C3-C10 cycloalkyl. In some embodiments, X4 is NH- X5-X6-G1, and N2 and N3 are each independently unsubstituted or substituted C1-C10 acyl. In some embodiments, X4 is NH-X5-X6-G1, and N2 and N3 are each independently unsubstituted or substituted C1-C10 carboxyl ester. In some embodiments, X4 is NH-X5-X6-G1, and N2 and N3 are each independently unsubstituted or substituted C1-C10 alkyl ketone. In some embodiments, X4 is NH-X5-X6-G1, and N2 and N3 are each independently unsubstituted or substituted C1-C10 alkyl ether.

[0064] In some embodiments, X4 is NR.4-X5-X6-G1, and N2 and N3 are taken together with the carbon atoms to which they are attached to form unsubstituted or substituted C5-C10 cycloalkyl. In some embodiments, X4 is NR.4-X5-X6-G1, and N2 and N3 are taken together with the carbon atoms to which they are attached to form unsubstituted or substituted aryl. In some embodiments, X4 is NR.4-X5-X6-G1, and N2 and N3 are taken together with the carbon atoms to which they are attached to form unsubstituted or substituted heteroaryl. In some embodiments, X4 is NRA-X5-X6-G1, and N2 and N3 are taken together with the carbon atoms to which they are attached to form unsubstituted or substituted C1-C10 heterocyclyl.

[0065] In some embodiments, X4 is NH-X5-X6-G1, and N2 and N3 are taken together with the carbon atoms to which they are attached to form unsubstituted or substituted C5-C10 cycloalkyl. In some embodiments, X4 is NH-X5-X6-G1, and N2 and N3 are taken together with the carbon atoms to which they are attached to form unsubstituted or substituted aryl. In some embodiments, X4 is NH-X5-X6-G1, and N2 and N3 are taken together with the carbon atoms to which they are attached to form unsubstituted or substituted heteroaryl. In some embodiments, X4 is NH-X5-X6-G1, and N2 and N3 are taken together with the carbon atoms to which they are attached to form unsubstituted or substituted C1-C10 heterocyclyl.

[0066] In some embodiments, X4 is NRA-XS-NRA-XV-GI, and Ni is OH. In some embodiments, X4 is NRA-XS-NRA-XT-GI, and Ni is H. In some embodiments, X4 is NR.A-XS- NRA-X7-G1, and Ni is halo. In some embodiments, X4 is NRA-XS-NRA-XV-GI, and Ni is CN. In some embodiments, X4 is NRA-XS-NRA-XV-GI, and Ni is CF3. In some embodiments, X4 is NRA-X5-NRA-X7-G1, and Ni is NO2. In some embodiments, X4 is NRA-X5-NRA-X7-G1, and Ni is unsubstituted or substituted C1-C10 alkyl. In some embodiments, X4 is NRA-X5-NRA-X7-G1, and Ni is unsubstituted or substituted C3-C10 cycloalkyl. In some embodiments, X4 is NR.A-XS- NRA-X7-G1, and Ni is unsubstituted or substituted C1-C10 acyl. In some embodiments, X4 is NRA-X5-NRA-X7-G1, and Ni is unsubstituted or substituted C1-C10 carboxyl ester. In some embodiments, X4 is NRA-X5-NRA-X7-G1, and Ni is unsubstituted or substituted C1-C1₀ alkyl ketone. In some embodiments, X4 is NRA-XS-NRA-XT-GI, and Ni is unsubstituted or substituted C1-C1₀ alkyl ether.

[0067] In some embodiments, X4 is NH-X5-NRA-X7-G1, and Ni is OH. In some embodiments, X4 is NH-X5-NRA-X7-G1, and Ni is H. In some embodiments, X4 is NH-X5-NRA-X7-G1, and Ni is halo. In some embodiments, X4 is NH-X5-NRA-X7-G1, and Ni is CN. In some embodiments, X4 is NH-X5-NRA-X7-G1, and Ni is CF3. In some embodiments, X4 is NH-X5-NRA-X7-G1, and Ni is NO2. In some embodiments, X4 is NH-X5-NRA-X7-G1, and Ni is unsubstituted or substituted C1-C1₀ alkyl. In some embodiments, X4 is NH-X5-NRA-X7-G1, and Ni is unsubstituted or substituted C3-C1₀ cycloalkyl. In some embodiments, X4 is NH-X5-NRA-X7-G1, and Ni is unsubstituted or substituted C1-C1₀ acyl. In some embodiments, X4 is NH-X5-NRA-X7- Gi, and Ni is unsubstituted or substituted C1-C1₀ carboxyl ester. In some embodiments, X4 is NH-X5-NRA-X7-G1, and Ni is unsubstituted or substituted C1-C1₀ alkyl ketone. In some embodiments, X4 is NH-X5-NRA-X7-G1, and Ni is unsubstituted or substituted C1-C1₀ alkyl ether.

[0068] In some embodiments, X4 is NRA-X5-NRA-X7-G1, and N2 and N₃ are each independently OH. In some embodiments, X4 is NRA-X5-NRA-X7-G1, and N2 and N₃ are each independently H. In some embodiments, X4 is NRA-X5-NRA-X7-G1, and N2 and N₃ are each independently halo. In some embodiments, X4 is NRA-X5-NRA-X7-G1, and N2 and N₃ are each independently CN. In some embodiments, X4 is NRA-X5-NRA-X7-G1, and N2 and N₃ are each independently CF_3. In some embodiments, X4 is NRA-X5-NRA-X7-G1, and N2 and N₃ are each independently NO2. In some embodiments, X4 is NRA-X5-NRA-X7-G1, and N2 and N₃ are each independently unsubstituted or substituted C1-C1₀ alkyl. In some embodiments, X4 is NRA-XS- NRA-X7-G1, and N2 and N₃ are each independently unsubstituted or substituted C₃-C1₀ cycloalkyl. In some embodiments, X4 is NRA-X5-NRA-X7-G1, and N2 and N₃ are each independently unsubstituted or substituted C1-C1₀ acyl. In some embodiments, X4 is NRA-XS- NRA-X7-G1, and N2 and N₃ are each independently unsubstituted or substituted C1-C1₀ carboxyl ester. In some embodiments, X4 is NRA-X5-NRA-X7-G1, and N2 and N₃ are each independently unsubstituted or substituted Ci-Cio alkyl ketone. In some embodiments, X4 is NRA-XS-NRA-X?- GI, and N2 and N3 are each independently unsubstituted or substituted C1-C10 alkyl ether.

[0069] In some embodiments, X4 is NH-X5-NRA-X7-G1, and N2 and N3 are each independently OH. In some embodiments, X4 is NH-X5-NRA-X7-G1, and N2 and N3 are each independently H. In some embodiments, X4 is NH-X5-NRA-X7-G1, and N2 and N3 are each independently halo. In some embodiments, X4 is NH-X5-NRA-X7-G1, and N2 and N3 are each independently CN. In some embodiments, X4 is NH-X5-NRA-X7-G1, and N2 and N3 are each independently CF3. In some embodiments, X4 is NH-X5-NRA-X7-G1, and N2 and N3 are each independently NO2. In some embodiments, X4 is NH-X5-NRA-X7-G1, and N2 and N3 are each independently unsubstituted or substituted C1-C10 alkyl. In some embodiments, X4 is NH-X5-NRA-X7-G1, and N2 and N3 are each independently unsubstituted or substituted C3-C10 cycloalkyl. In some embodiments, X4 is NH-X5-NRA-X7-G1, and N2 and N3 are each independently unsubstituted or substituted C1-C10 acyl. In some embodiments, X4 is NH-X5-NRA-X7-G1, and N2 and N3 are each independently unsubstituted or substituted C1-C10 carboxyl ester. In some embodiments, X4 is NH-X5-NRA-X7-G1, and N2 and N3 are each independently unsubstituted or substituted C1-C10 alkyl ketone. In some embodiments, X4 is NH-X5-NRA-X7-G1, and N2 and N3 are each independently unsubstituted or substituted C1-C10 alkyl ether.

[0070] In some embodiments, X4 is NRA-X5-NRA-X7-G1, then N2 and N3 are taken together with the carbon atoms to which they are attached to form unsubstituted or substituted C5-C10 cycloalkyl. In some embodiments, X4 is NRA-X5-NRA-X7-G1, then N2 and N3 are taken together with the carbon atoms to which they are attached to form unsubstituted or substituted aryl. In some embodiments, X4 is NRA-X5-NRA-X7-G1, then N2 and N3 are taken together with the carbon atoms to which they are attached to form unsubstituted or substituted heteroaryl. In some embodiments, X4 is NRA-X5-NRA-X7-G1, then N2 and N3 are taken together with the carbon atoms to which they are attached to form unsubstituted or substituted C1-C10 heterocyclyl.

[0071] In some embodiments, X4 is NH-X5-NRA-X7-G1, then N2 and N3 are taken together with the carbon atoms to which they are attached to form unsubstituted or substituted C5-C10 cycloalkyl. In some embodiments, X4 is NH-X5-NRA-X7-G1, then N2 and N3 are taken together with the carbon atoms to which they are attached to form unsubstituted or substituted aryl. In some embodiments, X4 is NH-X5-NRA-X7-G1, then N2 and N3 are taken together with the carbon atoms to which they are attached to form unsubstituted or substituted heteroaryl. In some embodiments, X4 is NH-X5-NRA-X7-G1, then N2 and N₃ are taken together with the carbon atoms to which they are attached to form unsubstituted or substituted C1-C1₀ heterocyclyl.

[0072] In some embodiments, X4 is Gi, and Ni is OH. In some embodiments, X4 is Gi, and Ni is H. In some embodiments, X4 is Gi, and Ni is halo. In some embodiments, X4 is Gi, and Ni is CN. In some embodiments, X4 is Gi, and Ni is CF_3. In some embodiments, X4 is Gi, and Ni is NO2. In some embodiments, X4 is Gi, and Ni is unsubstituted or substituted C1-C1₀ alkyl. In some embodiments, X4 is Gi, and Ni is unsubstituted or substituted C₃-C1₀ cycloalkyl. In some embodiments, X4 is Gi, and Ni is unsubstituted or substituted C1-C1₀ acyl. In some embodiments, X4 is Gi, and Ni is unsubstituted or substituted C1-C1₀ carboxyl ester. In some embodiments, X4 is Gi, and Ni is unsubstituted or substituted C1-C1₀ alkyl ketone. In some embodiments, X4 is Gi, and Ni is unsubstituted or substituted C1-C1₀ alkyl ether.

[0073] In some embodiments, X4 is Gi, and N2 and N₃ are each independently OH. In some embodiments, X4 is Gi, and N2 and N₃ are each independently H. In some embodiments, X4 is Gi, and N2 and N₃ are each independently halo. In some embodiments, X4 is Gi, and N2 and N₃ are each independently CN. In some embodiments, X4 is Gi, and N2 and N₃ are each independently CF_3. In some embodiments, X4 is Gi, and N2 and N₃ are each independently NO2. In some embodiments, X4 is Gi, and N2 and N₃ are each independently unsubstituted or substituted C1-C1₀ alkyl. In some embodiments, X4 is Gi, and N2 and N₃ are each independently unsubstituted or substituted C₃-C1₀ cycloalkyl. In some embodiments, X4 is Gi, and N2 and N₃ are each independently unsubstituted or substituted C1-C1₀ acyl. In some embodiments, X4 is Gi, and N2 and N₃ are each independently unsubstituted or substituted C1-C1₀ carboxyl ester. In some embodiments, X4 is Gi, and N2 and N₃ are each independently unsubstituted or substituted C1-C1₀ alkyl ketone. In some embodiments, X4 is Gi, and N2 and N₃ are each independently unsubstituted or substituted C1-C1₀ alkyl ether. [0074] In some embodiments, X4 is Gi, and N2 and N3 are taken together with the carbon atoms to which they are attached to form unsubstituted or substituted C5-C10 cycloalkyl. In some embodiments, X4 is Gi, and N2 and N3 are taken together with the carbon atoms to which they are attached to form unsubstituted or substituted aryl. In some embodiments, X4 is Gi, and N2 and N3 are taken together with the carbon atoms to which they are attached to form unsubstituted or substituted heteroaryl. In some embodiments, X4 is Gi, and N2 and N3 are taken together with the carbon atoms to which they are attached to form unsubstituted or substituted C1-C10 heterocyclyl.

[0075] In some embodiments, Ri is NH-X3-X4 , X3 is unsubstituted or substituted C1-C20 carboxy ester, and X4 is hydrogen. In some embodiments, Ri is NH-X3-X4 and is

. In some embodiments, Ri is NH-X3-X4 , X3 is unsubstituted or substituted Ci-

C20 alkylene, and X4 is NH-X5-X6-G1. In some embodiments, Ri is NH-X3-X4 , X3 is unsubstituted or substituted C4 alkylene, X4 is NR.4-X5-X6-G1, X5 is unsubstituted or substituted

Ci alkylene, Xr_> is unsubstituted or substituted phenylene,

In some embodiments, Ri is NH-X3-X4 , X3 is unsubstituted or substituted C1-C20 alkylene, and

X4 is NRA-X5-NRA-X7-G1. In some embodiments, Ri is NH-X3-X4 , X3 is unsubstituted or substituted C3-C4 alkylene, X4 is NRA-XS-NR.A-XT-GI, X5 and X7 are each unsubstituted or substituted C3-C4 alkylene,

In some embodiments, Ri is NH-X3-X4 , X3 is unsubstituted or substituted C1-C20 alkylene, and X4 is Gi. In some embodiments, Ri is NH-X3-X4 , X3 is unsubstituted or substituted C4-C14 alkylene,

[0076] In some embodiments, Ri is NH-X3-X4 , X3 is unsubstituted or substituted C1-C20 carboxy ester, and X4 is hydrogen. In some embodiments, Ri is NH-X3-X4 and is

In some embodiments, Ri is NH-X3-X4 , X3 is unsubstituted or substituted Ci-

C20 alkylene, and X4 is NH-X5-X6-G1. In some embodiments, Ri is NH-X3-X4 , X3 is unsubstituted or substituted C4 alkylene, X4 is NH-X5-X6-G1, X5 is unsubstituted or substituted

Ci alkylene, Xr, is unsubstituted or substituted phenylene,

In some embodiments, Ri is NH-X3-X4 , X3 is unsubstituted or substituted C1-C20 alkylene, and X4 is NH-X5-NRA-X7-G1. In some embodiments, Ri is NH-X3-X4 , X3 is unsubstituted or substituted C3-C4 alkylene, X4 is NH-X5-NRA-X7-G1, X5 and X7 are each unsubstituted or substituted C3-C4 alkylene,

[0077] In some embodiments, Ri is O-X3-X4 , X3 is unsubstituted or substituted C1-C20 alkylene, and X4 is NR4-X5-X6-G1. In some embodiments, Ri is O-X3-X4, X3 is unsubstituted or substituted C2 alkylene, X4 is NRA-XS-X6-GI, X5 is unsubstituted or substituted Ci alkylene, Xr_> is absent,

some embodiments, Ri is O-X3-X4 , X3 is unsubstituted or substituted C1-C20 alkylene, and X4 is Gi. In some embodiments, Ri is O-X3-

X4 , X3 is unsubstituted or substituted C4-C14 alkylene,

[0078] In some embodiments, Ri is O-X3-X4 , X3 is unsubstituted or substituted C1-C20 alkylene, and X4 is NH-X5-X6-G1. In some embodiments, Ri is O-X3-X4, X3 is unsubstituted or substituted C2 alkylene, X4 is NH-X5-X6-G1, X5 is unsubstituted or substituted Ci alkylene, Xr_> is absent,

some embodiments, Ri is O-X3-X4 , X3 is unsubstituted or substituted C1-C20 alkylene, and X4 is Gi. In some embodiments, Ri is O-X3-X4 , X3 is unsubstituted or substituted C4-C14 alkylene,

[0079] In some embodiments, Ri is G2. In some embodiments, Ri is G2, and R3 and R4 are independently OH. In some embodiments, Ri is G2, and R3 and R4 are independently H. In some embodiments, Ri is G2, and R3 and R4 are independently halo. In some embodiments, Ri is G2, and R3 and R4 are independently CN. In some embodiments, Ri is G2, and R3 and R4 are independently CF3. In some embodiments, Ri is G2, and R3 and R4 are independently NO2. In some embodiments, Ri is G2, and R3 and R4 are independently unsubstituted or substituted Ci- C10 alkyl. In some embodiments, Ri is G2, and R3 and R4 are independently unsubstituted or substituted C3-C10 cycloalkyl. In some embodiments, Ri is G2, and R3 and R4 are independently unsubstituted or substituted C1-C10 acyl. In some embodiments, Ri is G2, and R3 and R4 are independently unsubstituted or substituted C1-C10 carboxyl ester. In some embodiments, Ri is G2, and R3 and R4 are independently unsubstituted or substituted C1-C10 alkyl ketone. In some embodiments, Ri is G2, and R3 and R4 are independently unsubstituted or substituted C1-C10 alkyl ether. [0080] In some embodiments, Ri is G2, and R3 and R4 are taken together with the carbon atoms to which they are attached to form an unsubstituted or substituted C5-C1₀ cycloalkyl. In some embodiments, Ri is G2, and R3 and R4 are taken together with the carbon atoms to which they are attached to form an unsubstituted or substituted aryl. In some embodiments, Ri is G2, and R₃ and R4 are taken together with the carbon atoms to which they are attached to form an unsubstituted or substituted heteroaryl. In some embodiments, Ri is G2, and R₃ and R4 are taken together with the carbon atoms to which they are attached to form an unsubstituted or substituted C1-C1₀ heterocyclyl.

[0081] In some embodiments, Ri is G2, and Rs is OH. In some embodiments, Ri is G2, and Rs is H. In some embodiments, Ri is G2, and Rs is halo. In some embodiments, Ri is G2, and Rs is CN. In some embodiments, Ri is G2, and Rs is CF_3. In some embodiments, Ri is G2, and Rs is NO2. In some embodiments, Ri is G2, and Rs is unsubstituted or substituted C1-C1₀ alkyl. In some embodiments, Ri is G2, and Rs is unsubstituted or substituted C₃-C1₀ cycloalkyl. In some embodiments, Ri is G2, and Rs is unsubstituted or substituted C1-C1₀ acyl. In some embodiments, Ri is G2, and Rs is unsubstituted or substituted C1-C1₀ carboxyl ester. In some embodiments, Ri is G2, and Rs is unsubstituted or substituted C1-C1₀ alkyl ketone. In some embodiments, Ri is G2, and Rs is unsubstituted or substituted Ci-Cioalkyl ether.

[0082] In some embodiments, Ri is G2, and Mi is unsubstituted or substituted C1-C2₀ alkylene. In some embodiments, Ri is G2, and Mi is unsubstituted or substituted C1-C2₀ alkenylene. In some embodiments, Ri is G2, and Mi is unsubstituted or substituted C₃-C2₀ cycloalkylene. In some embodiments, Ri is G2, and Mi is unsubstituted or substituted C1-C2₀ heterocyclylene. In some embodiments, Ri is G2, and Mi is unsubstituted or substituted C1-C2₀ acyl. In some embodiments, Ri is G2, and Mi is unsubstituted or substituted C1-C2₀ carboxy ester. In some embodiments, Ri is G2, and Mi is unsubstituted or substituted C2-C2₀ alkyl ketone. In some embodiments, Ri is G2, and Mi is unsubstituted or substituted C2-C2₀ alkyl ether.

[0083] In some embodiments, Ri is G2, and M2 and M₃ are each independently unsubstituted or substituted C1-C1₀ alkyl. In some embodiments, Ri is G2, and M2 and M₃ are each independently unsubstituted or substituted C3-C10 cycloalkyl. In some embodiments, Ri is G2, and M2 and M3 are each independently unsubstituted or substituted C1-C10 acyl. In some embodiments, Ri is G2, and M2 and M3 are each independently unsubstituted or substituted C1-C10 carboxyl ester. In some embodiments, Ri is G2, and M2 and M3 are each independently unsubstituted or substituted C1-C10 alkyl ketone. In some embodiments, Ri is G2, and M2 and M3 are each independently unsubstituted or substituted C1-C10 alkyl ether.

[0084] In some embodiments, Ri is G2, and M2 and M3 are taken together with the N atom to which they are attached to form an unsubstituted or substituted C5-C10 cycloalkyl. In some embodiments, Ri is G2, and M2 and M3 are taken together with the N atom to which they are attached to form an unsubstituted or substituted aryl. In some embodiments, Ri is G2, and M2 and M3 are taken together with the N atom to which they are attached to form an unsubstituted or substituted heteroaryl. In some embodiments, Ri is G2, and M2 and M3 are taken together with the N atom to which they are attached to form an unsubstituted or substituted C1-C10 heterocyclyl.

[0085] In some embodiments, R2 is Ri. In some embodiments, R2 is OH. In some embodiments, R2 is O-Xs. In some embodiments, R2 is G2. In some embodiments, R2 is O-X9- Gi. In some embodiments, R2 is G3. In some embodiments, if R2 is O-Xs, then Xs is unsubstituted or substituted C1-C20 alkyl. In some embodiments, if R2 is O-Xx, then Xx is - C(RB)2-C0₂-RB. In some embodiments, if R2 is O-Xx, then Xx is unsubstituted or substituted aryl. In some embodiments, RB is H. In some embodiments, RB is unsubstituted or substituted C1-C20 alkyl. In some embodiments, RB is -CH2-C02-(CH)(CH3)2.

[0086] In some embodiments, R2 is G2, and R3 and R4 are independently OH. In some embodiments, R2 is G2, and R3 and R4 are independently H. In some embodiments, R2 is G2, and R3 and R4 are independently halo. In some embodiments, R2 is G2, and R3 and R4 are independently CN. In some embodiments, R2 is G2, and R3 and R4 are independently CF3. In some embodiments, R2 is G2, and R3 and R4 are independently NO2. In some embodiments, R2 is G2, and R3 and R4 are independently unsubstituted or substituted C1-C10 alkyl. In some embodiments, III is G2, and R3 and R4 are independently unsubstituted or substituted C3-C1₀ cycloalkyl. In some embodiments, R2 is G2, and R₃ and R4 are independently unsubstituted or substituted C1-C1₀ acyl. In some embodiments, R2 is G2, and R₃ and R4 are independently unsubstituted or substituted C1-C1₀ carboxyl ester. In some embodiments, R2 is G2, and R₃ and R4 are independently unsubstituted or substituted C1-C1₀ alkyl ketone. In some embodiments, R2 is G2, and R₃ and R4 are independently unsubstituted or substituted C1-C1₀ alkyl ether.

[0087] In some embodiments, R2 is G2, and R₃ and R4 are taken together with the carbon atoms to which they are attached to form unsubstituted or substituted C5-C1₀ cycloalkyl. In some embodiments, R2 is G2, and R₃ and R4 are taken together with the carbon atoms to which they are attached to form unsubstituted or substituted aryl. In some embodiments, R2 is G2, and R₃ and R4 are taken together with the carbon atoms to which they are attached to form unsubstituted or substituted heteroaryl. In some embodiments, R2 is G2, and R₃ and R4 are taken together with the carbon atoms to which they are attached to form unsubstituted or substituted C1-C1₀ heterocyclyl.

[0088] In some embodiments, R2 is G2, and Rs is OH. In some embodiments, R2 is G2, and Rs is H. In some embodiments, R2 is G2, and Rs is halo. In some embodiments, R2 is G2, and Rs is CN. In some embodiments, R2 is G2, and Rs is CF_3. In some embodiments, R2 is G2, and Rs is NO2. In some embodiments, R2 is G2, and Rs is unsubstituted or substituted C1-C1₀ alkyl. In some embodiments, R2 is G2, and Rs is unsubstituted or substituted C₃-C1₀ cycloalkyl. In some embodiments, R2 is G2, and Rs is unsubstituted or substituted C1-C1₀ acyl. In some embodiments, R2 is G2, and Rs is unsubstituted or substituted C1-C1₀ carboxyl ester. In some embodiments, R2 is G2, and Rs is unsubstituted or substituted C1-C1₀ alkyl ketone. In some embodiments, R2 is G2, and Rs is unsubstituted or substituted Ci-Cioalkyl ether.

[0089] In some embodiments, R2 is G2, and Mi is unsubstituted or substituted C1-C2₀ alkylene. In some embodiments, R2 is G2, and Mi is unsubstituted or substituted C1-C2₀ alkenylene. In some embodiments, R2 is G2, and Mi is unsubstituted or substituted C₃-C2₀ cycloalkylene. In some embodiments, R2 is G2, and Mi is unsubstituted or substituted C1-C2₀ heterocyclylene. In some embodiments, R2 is G2, and Mi is unsubstituted or substituted C1-C2₀ acyl. In some embodiments, III is G2, and Mi is unsubstituted or substituted C1-C2₀ carboxy ester. In some embodiments, R2 is G2, and Mi is unsubstituted or substituted C2-C2₀ alkyl ketone. In some embodiments, R2 is G2, and Mi is unsubstituted or substituted C2-C2₀ alkyl ether.

[0090] In some embodiments, R2 is G2, and M2 and M3 are each independently unsubstituted or substituted C1-C1₀ alkyl. In some embodiments, R2 is G2, and M2 and M3 are each independently unsubstituted or substituted C₃-C1₀ cycloalkyl. In some embodiments, R2 is G2, and M2 and M₃ are each independently unsubstituted or substituted C1-C1₀ acyl. In some embodiments, R2 is G2, and M2 and M₃ are each independently unsubstituted or substituted C1-C1₀ carboxyl ester. In some embodiments, R2 is G2, and M2 and M₃ are each independently unsubstituted or substituted C1-C1₀ alkyl ketone. In some embodiments, R2 is G2, and M2 and M₃ are each independently unsubstituted or substituted C1-C1₀ alkyl ether.

[0091] In some embodiments, R2 is G2, and M2 and M₃ are taken together with the N atom to which they are attached to form unsubstituted or substituted C5-C1₀ cycloalkyl. In some embodiments, R2 is G2, and M2 and M₃ are taken together with the N atom to which they are attached to form unsubstituted or substituted aryl. In some embodiments, R2 is G2, and M2 and M₃ are taken together with the N atom to which they are attached to form unsubstituted or substituted heteroaryl. In some embodiments, R2 is G2, and M2 and M₃ are taken together with the N atom to which they are attached to form unsubstituted or substituted C1-C1₀ heterocyclyl.

[0092] In some embodiments, R2 is O-X9-G1, and Ni is OH. In some embodiments, R2 is O- X9-G1, and Ni is H. In some embodiments, R2 is O-X9-G1, and Ni is halo. In some embodiments, R2 is O-X9-G1, and Ni is CN. In some embodiments, R2 is O-X9-G1, and Ni is CF_3. In some embodiments, R2 is O-X9-G1, and Ni is NO2. In some embodiments, R2 is O-X9- Gi, and Ni is unsubstituted or substituted C1-C1₀ alkyl. In some embodiments, R2 is O-X9-G1, and Ni is unsubstituted or substituted C₃-C1₀ cycloalkyl. In some embodiments, R2 is O-X9-G1, and Ni is unsubstituted or substituted C1-C1₀ acyl. In some embodiments, R2 is O-X9-G1, and Ni is unsubstituted or substituted C1-C1₀ carboxyl ester. In some embodiments, R2 is O-X9-G1, and Ni is unsubstituted or substituted C1-C1₀ alkyl ketone. In some embodiments, R2 is O-X9-G1, and Ni is unsubstituted or substituted Ci-Cio alkyl ether. In some embodiments, X9 is unsubstituted or substituted arylene. In some embodiments, X9 is unsubstituted or substituted C1-C6 alkylene.

[0093] In some embodiments, R2 is O-X9-G1, and N2 and N3 are each independently OH. In some embodiments, R2 is O-X9-G1, and N2 and N3 are each independently H. In some embodiments, R2 is O-X9-G1, and N2 and N3 are each independently halo. In some embodiments, R2 is O-X9-G1, and N2 and N3 are each independently CN. In some embodiments, R2 is O-X9-G1, and N2 and N3 are each independently CF3. In some embodiments, R2 is O-X9- Gi, and N2 and N3 are each independently NO2. In some embodiments, R2 is O-X9-G1, and N2 and N3 are each independently unsubstituted or substituted C1-C10 alkyl. In some embodiments, R2 is O-X9-G1, and N2 and N3 are each independently unsubstituted or substituted C3-C10 cycloalkyl. In some embodiments, R2 is O-X9-G1, and N2 and N3 are each independently unsubstituted or substituted C1-C10 acyl. In some embodiments, R2 is O-X9-G1, and N2 and N3 are each independently unsubstituted or substituted C1-C10 carboxyl ester. In some embodiments, R2 is O-X9-G1, and N2 and N3 are each independently unsubstituted or substituted C1-C10 alkyl ketone. In some embodiments, R2 is O-X9-G1, and N2 and N3 are each independently unsubstituted or substituted C1-C10 alkyl ether. In some embodiments, X9 is unsubstituted or substituted C1-C6 alkylene.

[0094] In some embodiments, R2 is O-X9-G1, and N2 and N3 are taken together with the carbon atoms to which they are attached to form unsubstituted or substituted C5-C10 cycloalkyl. In some embodiments, R2 is O-X9-G1, and N2 and N3 are taken together with the carbon atoms to which they are attached to form unsubstituted or substituted aryl. In some embodiments, R2 is O-X9- Gi, and N2 and N3 are taken together with the carbon atoms to which they are attached to form unsubstituted or substituted heteroaryl. In some embodiments, R2 is O-X9-G1, and N2 and N3 are taken together with the carbon atoms to which they are attached to form unsubstituted or substituted C1-C10 heterocyclyl. In some embodiments, X9 is unsubstituted or substituted C1-C6 alkylene. [0095] In some embodiments, R2 is G3, and Mi is unsubstituted or substituted C1-C20 alkylene. In some embodiments, R2 is G3, and Mi is unsubstituted or substituted C1-C20 alkenylene. In some embodiments, R2 is G3, and Mi is unsubstituted or substituted C3-C20 cycloalkylene. In some embodiments, R2 is G3, and Mi is unsubstituted or substituted C1-C20 heterocyclylene. In some embodiments, R2 is G3, and Mi is unsubstituted or substituted C1-C20 acyl. In some embodiments, R2 is G3, and Mi is unsubstituted or substituted C1-C20 carboxy ester. In some embodiments, R2 is G3, and Mi is unsubstituted or substituted C2-C20 alkyl ketone. In some embodiments, R2 is G3, and Mi is unsubstituted or substituted C2-C20 alkyl ether.

[0096] In some embodiments, R2 is G3, and M2 and M3 are each independently unsubstituted or substituted C1-C10 alkyl. In some embodiments, R2 is G3, and M2 and M3 are each independently unsubstituted or substituted C3-C10 cycloalkyl. In some embodiments, R2 is G3, and M2 and M3 are each independently unsubstituted or substituted C1-C10 acyl. In some embodiments, R2 is G3, and M2 and M3 are each independently unsubstituted or substituted C1-C10 carboxyl ester. In some embodiments, R2 is G3, and M2 and M3 are each independently unsubstituted or substituted C1-C10 alkyl ketone. In some embodiments, R2 is G3, and M2 and M3 are each independently unsubstituted or substituted C1-C10 alkyl ether.

[0097] In some embodiments, R2 is G3, and M2 and M3 are taken together with the N atom to which they are attached to form unsubstituted or substituted C5-C10 cycloalkyl. In some embodiments, R2 is G3, and M2 and M3 are taken together with the N atom to which they are attached to form unsubstituted or substituted aryl. In some embodiments, R2 is G3, and M2 and M3 are taken together with the N atom to which they are attached to form unsubstituted or substituted heteroaryl. In some embodiments, R2 is G3, and M2 and M3 are taken together with the N atom to which they are attached to form unsubstituted or substituted C1-C10 heterocyclyl. [0098] In some embodiments,

unsubstituted or substituted C1-C20 alkylene, and M2 and M3 are each independently unsubstituted or substituted C1-C10 alkyl. In some embodiments, R2 is O-X9-G1, X9 is unsubstituted or substituted phenylene, and Gi is

unsubstituted or substituted C1-C20 alkylene, and M2 and M3 are each independently unsubstituted or substituted C1-C10 alkyl.

[0099] In some embodiments, Ri and R2 are taken together with the P atom to which they are attached to form an unsubstituted or substituted C2-C10 heterocyclyl.

[0100] In some embodiments, the compound has the structure of Formula (II):

wherein,

Si is Xio-Gi; and

Xiois unsubstituted or substituted C1-C20 alkylene.

[0101] In some embodiments, Si is X10-G1, and Ni is OH. In some embodiments, Si is X10-G1, and Ni is H. In some embodiments, Si is X10-G1, and Ni is halo. In some embodiments, Si is X10-G1, and Ni is CN. In some embodiments, Si is X10-G1, and Ni is CF3. In some embodiments, Si is X10-G1, and Ni is NO2. In some embodiments, Si is X10-G1, and Ni is unsubstituted or substituted C1-C1₀ alkyl. In some embodiments, Si is X10-G1, and Ni is unsubstituted or substituted C3-C1₀ cycloalkyl. In some embodiments, Si is X10-G1, and Ni is unsubstituted or substituted C1-C1₀ acyl. In some embodiments, Si is X10-G1, and Ni is unsubstituted or substituted C1-C1₀ carboxyl ester. In some embodiments, Si is X10-G1, and Ni is unsubstituted or substituted C1-C1₀ alkyl ketone. In some embodiments, Si is X10-G1, and Ni is unsubstituted or substituted C1-C1₀ alkyl ether.

[0102] In some embodiments, Si is X10-G1, and N2 and N₃ are each independently OH. In some embodiments, Si is X10-G1, and N2 and N₃ are each independently H. In some embodiments, Si is X10-G1, and N2 and N₃ are each independently halo. In some embodiments, Si is X10-G1, and N2 and N₃ are each independently CN. In some embodiments, Si is X10-G1, and N2 and N₃ are each independently CF_3. In some embodiments, Si is X10-G1, and N2 and N₃ are each independently NO2. In some embodiments, Si is X10-G1, and N2 and N₃ are each independently unsubstituted or substituted C1-C1₀ alkyl. In some embodiments, Si is X10-G1, and N2 and N₃ are each independently unsubstituted or substituted C₃-C1₀ cycloalkyl. In some embodiments, Si is X10-G1, and N2 and N₃ are each independently unsubstituted or substituted C1-C1₀ acyl. In some embodiments, Si is X10-G1, and N2 and N₃ are each independently unsubstituted or substituted C1-C1₀ carboxyl ester. In some embodiments, Si is X10-G1, and N2 and N3 are each independently unsubstituted or substituted C1-C10 alkyl ketone. In some embodiments, Si is X10-G1, and N2 and N3 are each independently unsubstituted or substituted C1-C10 alkyl ether.

[0103] In some embodiments, Si is X10-G11, and N2 and N3 are taken together with the carbon atoms to which they are attached to form unsubstituted or substituted C5-C10 cycloalkyl. In some embodiments, Si is X10-G1, and N2 and N3 are taken together with the carbon atoms to which they are attached to form unsubstituted or substituted aryl. In some embodiments, Si is X10-G1, and N2 and N3 are taken together with the carbon atoms to which they are attached to form unsubstituted or substituted heteroaryl. In some embodiments, Si is X10-G1, and N2 and N3 are taken together with the carbon atoms to which they are attached to form unsubstituted or substituted C1-C10 heterocyclyl.

[0104] In some embodiments, the compound has the structure of Formula (III):

wherein,

52 is hydrogen, unsubstituted or substituted C1-C20 alkyl, unsubstituted or substituted Ci- C20 alkenyl, unsubstituted or substituted C3-C20 cycloalkyl, unsubstituted or substituted C1-C20 heterocyclyl, unsubstituted or substituted C1-C20 acyl, unsubstituted or substituted C1-C20 carboxy ester, unsubstituted or substituted C2-C20 alkyl ketone, or unsubstituted or substituted C2-C20 alkyl ether;

53 is X11-G1; and

X11 is unsubstituted or substituted C1-C20 alkylene.

[0105] In some embodiments, S2 is hydrogen. In some embodiments, S2 is unsubstituted or substituted C1-C20 alkyl. In some embodiments, S2 is unsubstituted or substituted C1-C20 alkenyl. In some embodiments, S2 is unsubstituted or substituted C3-C20 cycloalkyl. In some embodiments, S2 is unsubstituted or substituted C1-C2₀ heterocyclyl. In some embodiments, S2 is unsubstituted or substituted C1-C2₀ acyl. In some embodiments, S2 is unsubstituted or substituted C1-C2₀ carboxy ester. In some embodiments, S2 is unsubstituted or substituted C2-C2₀ alkyl ketone. In some embodiments, S2 is unsubstituted or substituted C2-C2₀ alkyl ether.

[0106] In some embodiments, S3 is X11-G1, and Ni is OH. In some embodiments, S3 is X11-G1, and Ni is H. In some embodiments, S₃ is X11-G1, and Ni is halo. In some embodiments, S₃ is X11-G1, and Ni is CN. In some embodiments, S₃ is X11-G1, and Ni is CF_3. In some embodiments, S₃ is X11-G1, and Ni is NO2. In some embodiments, S₃ is X11-G1, and Ni is unsubstituted or substituted C1-C1₀ alkyl. In some embodiments, S₃ is X11-G1, and Ni is unsubstituted or substituted C₃-C1₀ cycloalkyl. In some embodiments, S₃ is X11-G1, and Ni is unsubstituted or substituted C1-C1₀ acyl. In some embodiments, S₃ is X11-G1, and Ni is unsubstituted or substituted C1-C1₀ carboxyl ester. In some embodiments, S₃ is X11-G1, and Ni is unsubstituted or substituted C1-C1₀ alkyl ketone. In some embodiments, S₃ is X11-G1, and Ni is unsubstituted or substituted C1-C1₀ alkyl ether.

[0107] In some embodiments, S₃ is X11-G1, and N2 and N₃ are each independently OH. In some embodiments, S₃ is X11-G1, and N2 and N₃ are each independently H. In some embodiments, S₃ is X11-G1, and N2 and N₃ are each independently halo. In some embodiments, S₃ is X11-G1, and N2 and N₃ are each independently CN. In some embodiments, S₃ is X11-G1, and N2 and N₃ are each independently CF_3. In some embodiments, S₃ is X11-G1, and N2 and N₃ are each independently NO2. In some embodiments, S₃ is X11-G1, and N2 and N₃ are each independently unsubstituted or substituted C1-C1₀ alkyl. In some embodiments, S₃ is X11-G1, and N2 and N₃ are each independently unsubstituted or substituted C₃-C1₀ cycloalkyl. In some embodiments, S₃ is X11-G1, and N2 and N₃ are each independently unsubstituted or substituted C1-C1₀ acyl. In some embodiments, S₃ is X11-G1, and N2 and N₃ are each independently unsubstituted or substituted C1-C1₀ carboxyl ester. In some embodiments, S₃ is X11-G1, and N2 and N₃ are each independently unsubstituted or substituted C1-C1₀ alkyl ketone. In some embodiments, S₃ is X11-G1, and N2 and N₃ are each independently unsubstituted or substituted C1-C1₀ alkyl ether. [0108] In some embodiments, S3 is X11-G1, and N2 and N3 are taken together with the carbon atoms to which they are attached to form unsubstituted or substituted C5-C10 cycloalkyl. In some embodiments, S3 is X11-G1, and N2 and N3 are taken together with the carbon atoms to which they are attached to form unsubstituted or substituted aryl. In some embodiments, S3 is X11-G1, and N2 and N3 are taken together with the carbon atoms to which they are attached to form unsubstituted or substituted heteroaryl. In some embodiments, S3 is X11-G1, and N2 and N3 are taken together with the carbon atoms to which they are attached to form unsubstituted or substituted C1-C10 heterocyclyl.

[0109] In some embodiments, the compound has the structure of Formula (IV):

[0110] In some embodiments, R3, R4, and Rs are each hydrogen. In some embodiments, R3 and R4 are taken together with the carbon atoms to which they are attached to form a unsubstituted or substituted aryl and Rs is hydrogen. In some embodiments, R3 and R4 are taken together with the carbon atoms to which they are attached to form a unsubstituted or substituted aryl, and Rs is halo. In some embodiments, R3 and R4 are taken together with the carbon atoms to which they are attached to form a unsubstituted or substituted C5-C10 cycloalkyl, and Rs is hydrogen. In some embodiments, Mi is unsubstituted or substituted C1-C20 alkylene. In some embodiments, M2 and M3 are each independently unsubstituted or substituted C1-C10 alkyl.

[0111] In some embodiments, A is unsubstituted or substituted nucleoside. In some embodiments, A is unsubstituted or substituted nucleoside analogue. In some embodiments, the unsubstituted or substituted nucleoside or unsubstituted or substituted nucleoside analogue comprises adenine. In some embodiments, the unsubstituted or substituted nucleoside or unsubstituted or substituted nucleoside analogue comprises cytosine. In some embodiments, the unsubstituted or substituted nucleoside or unsubstituted or substituted nucleoside analogue comprises guanine. In some embodiments, the unsubstituted or substituted nucleoside or unsubstituted or substituted nucleoside analogue comprises thymine. In some embodiments, the unsubstituted or substituted nucleoside or unsubstituted or substituted nucleoside analogue comprises uridine. In some embodiments, the unsubstituted or substituted nucleoside or unsubstituted or substituted nucleoside analogue comprises pyrrolo[2,l-f [l,2,4]triazin-4-amine.

[0112] In some embodiments, A is unsubstituted or substituted nucleotide. In some embodiments, A is unsubstituted or substituted nucleotide analogue. In some embodiments, the unsubstituted or substituted nucleotide or unsubstituted or substituted nucleotide analogue comprises adenine. In some embodiments, the unsubstituted or substituted nucleotide or unsubstituted or substituted nucleotide analogue comprises cytosine. In some embodiments, the unsubstituted or substituted nucleotide or unsubstituted or substituted nucleotide analogue comprises guanine. In some embodiments, the unsubstituted or substituted nucleotide or unsubstituted or substituted nucleotide analogue comprises thymine. In some embodiments, the unsubstituted or substituted nucleotide or unsubstituted or substituted nucleotide analogue comprises uridine. In some embodiments, the unsubstituted or substituted nucleotide or unsubstituted or substituted nucleotide analogue comprises pyrrolo[2,l-f][l,2,4]triazin-4-amine.

[0113] In some embodiments, the compound of Formula I has the following structure:

In some embodiments, R is unsubstituted or substituted Ci-Cio alkyl. In some embodiments, R is unsubstituted or substituted C1-C₆ alkyl. In some embodiments, R is unsubstituted or substituted C1-C4 alkyl. In some embodiments, R is methyl. [0114] In some embodiments, the compound of Formula I has the following structure:

[0115] In some embodiments, the compound of Formula I has the following structure:

In some embodiments, R is CN.

[0116] In some embodiments, the compound of Formula I has the following structure:

[0117] In any of the embodiments disclosed herein, the compound is any one of the compounds disclosed in the following tables.

TABLE 1.

TABLE 2.

[0118] In some embodiments, provided herein is an enantiomer, an enantiomeric mixture, a diastereomer, a diasteromeric mixture, or a pharmaceutically acceptable salt of a compound that is described in Table 1.

[0119] In one aspect, compounds described herein are in the form of pharmaceutically acceptable salts. As well, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure.

[0120] In some embodiments, the compounds described herein possess one or more stereocenters and each stereocenter exists independently in either the R or S configuration. The compounds presented herein include all diastereomeric, enantiomeric, atropisomers, and epimeric forms as well as the appropriate mixtures thereof.

Synthesis of Compounds

[0121] Compounds described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with methods described herein.

[0122] Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed.

[0123] Compounds are prepared using standard organic chemistry techniques known to one of skilled in the art. Alternative reaction conditions for the synthetic transformations described herein may be employed such as variation of solvent, reaction temperature, reaction time, as well as different chemical reagents and other reaction conditions. The starting materials are available from commercial sources or are readily prepared

[0124] The compounds described herein can prepared by the general synthetic routes described in the below schemes. Schemes 1 and 2 each show a non-limiting general synthetic route for the preparation of compounds of Formula I and IV.

Scheme 1

O o

P-, = OH or NH₂ P₂ = O or NH

Scheme 2

Pharmaceutical Compositions

[0125] In one aspect, described herein is a pharmaceutical composition comprising a compound described herein, or an enantiomer, an enantiomeric mixture, a diastereomer, a diasteromeric mixture, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient and/or carrier. Examples of a pharmaceutically acceptable excipient, include but are not limited to, a binding agent a flavor agent, a lubricating agent, a disintegration agent, a delay agent, an organic solvent, a suspending agent an isotonicity agent, a buffer, an emulsifier, stabilizer and a preservative.

[0126] In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ophthalmic administration. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, or oral administration.

[0127] In some embodiments, the pharmaceutical composition is in the form of a tablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion, a solution, an emulsion, an ointment, or a lotion. In some embodiments, the pharmaceutical composition is in the form of a tablet, a pill, or a capsule.

Methods of Treatment

[0128] Also provided herein is a method for treating a viral infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any one of the compounds, an enantiomer, an enantiomeric mixture, a diastereomer, a diasteromeric mixture, or a pharmaceutically acceptable salt.

[0129] The compounds disclosed herein may be used to treat infections associated with the following viruses, such orthomyxoviridae, paramyxoviridae, arenaviridae, bunyaviridae, fiaviviridae, filoviridae, togaviridae, picornaviridae, and corona. Examples of such viruses include, but are not limited, adenovirus, rhinovirus, hepatitis A virus, hepatitis C virus (HCV), polio virus, measles virus, Ebola virus, Coxsackie virus, West Nile virus, smallpox virus, yellow fever virus, Dengue Fever virus, influenza A virus, influenza B virus, lassa virus, lymphocytic choriomeningitis virus, Junin virus, machuppo virus, guanarito virus, hantavirus, Rift Valley Fever virus, La Crosse virus, California encephalitis virus, Crimean-Congo virus, Marburg virus, Japanese encephalitis virus, Kyasanur Forest virus, Venezuelan equine encephalitis virus,

Eastern equine encephalitis virus, Western equine encephalitis virus, severe acute respiratory syndrome (SARS) virus, parainfluenza virus, respiratory syncytial virus (RSV), Punta Toro virus, Tacaribe virus, Pichinde virus, human immunodeficiency viruses 1 and 2 (HIV-1 and HIV- 2) including drug resistant strains, human T-cell leukemia viruses 1 and 2 (HTLV-1 and HTLV- 2), human papilloma virus (HPV), hepatitis B virus (HBV), Epstein-Barr virus (EBV), varicella zoster virus (VZV), cytomegalovirus (CMV), herpes simplex viruses 1 and 2 (HSV-1 and HSV- 2), human herpes virus 8 (HHV-8, also known as Kaposi's sarcoma-associated virus) and flaviviruses, and West Nile viruses.

[0130] In some embodiments, the viral infection is caused by hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), Ebola virus, or human coronavirus. In some embodiments, the viral infection is caused by hepatitis B virus (HBV). In some embodiments, the viral infection is caused by hepatitis C virus (HCV). In some embodiments, the viral infection is caused by human immunodeficiency virus (HIV). In some embodiments, the viral infection is caused by Ebola virus. In some embodiments, the viral infection is caused by human coronavirus.

[0131] Also provided herein is a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any one of the compounds, an enantiomer, an enantiomeric mixture, a diastereomer, a diasteromeric mixture, or a pharmaceutically acceptable salt.

[0132] In some embodiments, the cancer is heptacellular carcinoma (HCC), lung cancer, breast cancer, pancreatic cancer, biliary tract cancer, or colorectal cancer. In some embodiments, the cancer is heptacellular carcinoma (HCC). In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is biliary tract cancer. In some embodiments, the cancer is colorectal cancer.

[0133] The term "cancer" shall refer to a proliferation of tumor cells having the unique trait of loss of normal controls, resulting in unregulated growth, lack of differentiation, local tissue invasion, and/or metastasis. As used herein, neoplasms include, without limitation, morphological irregularities in cells in tissue of a subject or host, as well as pathologic proliferation of cells in tissue of a subject, as compared with normal proliferation in the same type of tissue. Additionally, neoplasms include benign tumors and malignant tumors (e.g., colon tumors) that are either invasive or noninvasive. Malignant neoplasms are distinguished from benign neoplasms in that the former show a greater degree of dysplasia, or loss of differentiation and orientation of cells, and have the properties of invasion and metastasis. The term cancer also within context, includes drug resistant cancers, including multiple drug resistant cancers. Examples of neoplasms or neoplasias from which the target cell of the present invention may be derived include, without limitation, carcinomas (e.g., squamous-cell carcinomas, adenocarcinomas, hepatocellular carcinomas, and renal cell carcinomas), particularly those of the bladder, bone, bowel, breast, cervix, colon (colorectal), esophagus, head, kidney, liver, lung, nasopharyngeal, neck, ovary, pancreas, prostate, and stomach; leukemias, such as acute myelogenous leukemia, acute lymphocytic leukemia, acute promyelocytic leukemia (APL), acute T-cell lymphoblastic leukemia, adult T-cell leukemia, basophilic leukemia, eosinophilic leukemia, granulocytic leukemia, hairy cell leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, megakaryocyte leukemia, micromyeloblastic leukemia, monocytic leukemia, neutrophilic leukemia and stem cell leukemia; benign and malignant lymphomas, particularly Burkitf s lymphoma, Non-Hodgkin's lymphoma and B-cell lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, particularly Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, and synovial sarcoma; tumors of the central nervous system (e.g., gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas); germ-line tumors (e.g., bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer (e.g., small cell lung cancer, mixed small cell and non-small cell cancer, pleural mesothelioma, including metastatic pleural mesothelioma small cell lung cancer and non-small cell lung cancer), ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, and melanoma; mixed types of neoplasias, particularly carcinosarcoma and Hodgkin's disease; and tumors of mixed origin, such as Wilms' tumor and teratocarcinomas, among others. Contemplated cancers also include but not limited to ovarian cancer, breast cancer, colon cancer, head and neck cancer, medulloblastoma, and B-cell lymphoma.

Definitions

[0134] Various embodiments are described hereinafter. It should be noted that the specific embodiments are not intended as an exhaustive description or as a limitation to the broader aspects discussed herein. One aspect described in conjunction with a particular embodiment is not necessarily limited to that embodiment and can be practiced with any other embodiment(s).

[0135] As used herein, “about” will be understood by persons of ordinary skill in the art and will vary to some extent depending upon the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art, given the context in which it is used, “about” will mean up to plus or minus 10% of the particular term.

[0136] The use of the terms “a” and “an” and “the” and similar referents in the context of describing the elements (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the embodiments and does not pose a limitation on the scope of the claims unless otherwise stated. No language in the specification should be construed as indicating any non-claimed element as essential.

[0137] As used herein, Ci-Cx includes C1-C2, C1-C3 . . . Ci-Cx. By way of example only, a group designated as “C1-C4” indicates that there are one to four carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, “C1-C4 alkyl” indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso butyl, sec-butyl, and t-butyl.

[0138] An “alkyl” group by itself or as part of another molecule refers to an aliphatic hydrocarbon group. The alkyl group is branched or straight chain. In some embodiments, the “alkyl” group has 1 to 20 carbon atoms, i.e. a Ci- C2oalkyl. Whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., “1 to 20 carbon atoms” means that the alkyl group consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, an alkyl is a C1-C6 alkyl. In one aspect the alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.

[0139] An "alkylene" group refers to a divalent alkyl radical. Any of the above mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. In some embodiments, an alkylene is a C1-C2₀ alkylene. In other embodiments, an alkylene is a C1-C1₀ alkylene. In other embodiments, an alkylene is a C1-C₆ alkylene. In certain embodiments, an alkylene comprises one to four carbon atoms (e.g., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C₃ alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., Ci alkylene). In other embodiments, an alkylene comprises two carbon atoms (e.g., C2 alkylene). In other embodiments, an alkylene comprises two to four carbon atoms (e.g., C2-C4 alkylene). Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH₃)-, -C(CH₃)₂-, -CH2CH2-, -CH₂CH(CH₃)-, -CH₂C(CH₃)₂-, - CH2CH2CH2-, -CH2CH2CH2CH2-, and the like.

[0140] The term “alkenyl” refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an alkenyl group has the formula -C(R)=CR.2, wherein R refers to the remaining portions of the alkenyl group, which may be the same or different. In some embodiments, R is H or an alkyl. In some embodiments, an alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Non-limiting examples of an alkenyl group include -CH=CH2, -C(CH₃)=CH2, - CH=CHCH₃, -C(CH₃)=CHCH₃, and -CH₂CH=CH_2.

[0141] The term “alkynyl” refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, an alkynyl group has the formula -CºC-R, wherein R refers to the remaining portions of the alkynyl group. In some embodiments, R is H or an alkyl. In some embodiments, an alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of an alkynyl group include -CºCH, -CºCCH₃, - CºCCH₂CH₃, and -CH₂CºCH.

[0142] An “alkoxy” group refers to a -O(alkyl) group, where alkyl is as defined herein.

[0143] The term “alkylamine” refers to the -N(alkyl)_xH_y group, where x is 0 and y is 2, or where x is 1 and y is 1, or where x is 2 and y is 0.

[0144] The term “aromatic” refers to a planar ring having a delocalized p-electron system containing 4n+2 p electrons, where n is an integer. The term “aromatic” includes both carbocyclic aryl (“aryl”, e.g. , phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.

[0145] The term “carbocyclic” or “carbocycle” refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from “heterocyclic” rings or “heterocycles” in which the ring backbone contains at least one atom which is different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. Carbocycle includes cycloalkyl and aryl.

[0146] As used herein, the term "aryl" refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. In one aspect, aryl is phenyl or a naphthyl. In some embodiments, an aryl is a phenyl. In some embodiments, an aryl is a C6-C10 aryl. Depending on the structure, an aryl group is a monoradical or a diradical (i.e., an arylene group).

[0147] The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls are spirocyclic or bridged compounds. In some embodiments, cycloalkyls are optionally fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom. Cycloalkyl groups include groups having from 3 to 10 ring atoms. In some embodiments, cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbomyl and bicyclo[l.l.l]pentyl. In some embodiments, a cycloalkyl is a C3-C6 cycloalkyl. In some embodiments, a cycloalkyl is a monocyclic cycloalkyl. Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbomyl {i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.

[0148] The term “halo” or, alternatively, “halogen” or “halide” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0149] The term “haloalkyl” refers to an alkyl in which one or more hydrogen atoms are replaced by a halogen atom. In one aspect, a fluoroalkyl is a C1-C6 fluoroalkyl.

[0150] The term “fluoroalkyl” refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom. In one aspect, a fluoroalkyl is a C1-C6 fluoroalkyl. In some embodiments, a fluoroalkyl is selected from trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1 -fluoromethyl -2 -fluoroethyl, and the like. [0151] The term "heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, - N(alkyl)-, sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6 heteroalkyl.

[0152] The term “heterocycle” or “heterocyclic” refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroalicyclic groups) containing one to four heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S and N, wherein each heterocyclic group has from 3 to 20 or 3 to 10 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms. In some embodiments, heterocycles are monocyclic, bicyclic, polycyclic, spirocyclic or bridged compounds. Non aromatic heterocyclic groups (also known as heterocycloalkyls) include rings having 3 to 10 atoms or 3 to 20 in its ring system and aromatic heterocyclic groups include rings having 5 to 10 atoms in its ring system. The heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2, 3, 6- tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3- azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-l-onyl, isoindoline-l,3-dionyl, 3,4-dihydroisoquinolin-l(2H)-onyl, 3,4-dihydroquinolin-2(lH)-onyl, isoindoline-l,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, lH-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups are either C-attached (or C-linked) or N-attached where such is possible. For instance, a group derived from pyrrole includes both pyrrol-l-yl (N-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole includes imidazol-l-yl or imidazol-3-yl (both N- attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=0) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic.

[0153] The term “heterocyclyl” refers to any univalent radical formed by removing a hydrogen atom from any ring atom of a heterocyclic compound as defined herein. Depending on the structure, an heterocyclyl group is a monoradical or a diradical (i.e., an heterocyclylene group).

[0154] The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls. Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, a heteroaryl contains 0-4 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 0 atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 0 atoms, and 0-1 S atoms in the ring. In some embodiments, heteroaryl is a Ci-Cio heteroaryl. In some embodiments, monocyclic heteroaryl is a C1-C5 heteroaryl. In some embodiments, monocyclic heteroaryl is a 5-membered or 6- membered heteroaryl. In some embodiments, bicyclic heteroaryl is a C₆-C9 heteroaryl. Depending on the structure, an heteroaryl group is a monoradical or a diradical (i.e., an heteroaryl ene group). [0155] A “heterocycloalkyl” or “heteroalicyclic” group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, a heterocycloalkyl is fused with an aryl or heteroaryl. In some embodiments, the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2, 5-dithionyl, pyrrolidine-2, 5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl. The term heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. In one aspect, a heterocycloalkyl is a C1-C2₀ heterocycloalkyl. In one aspect, a heterocycloalkyl is a C1-C14 heterocycloalkyl. In one aspect, a heterocycloalkyl is a C1-C1₀ heterocycloalkyl. In one aspect, a heterocycloalkyl is a C2-C14 heterocycloalkyl. In one aspect, a heterocycloalkyl is a C2-C 1₀ heterocycloalkyl. In another aspect, a heterocycloalkyl is a C4-C1₀ heterocycloalkyl. In another aspect, a heterocycloalkyl is a C5-C1₀ heterocycloalkyl. In some embodiments, a heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring. Depending on the structure, an heteroaryl group is a monoradical or a diradical (i.e., an heteroarylene group).

[0156] The term “bond” or “single bond” refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. In one aspect, when a group described herein is a bond, the referenced group is absent thereby allowing a bond to be formed between the remaining identified groups.

[0157] The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[0158] The term “optionally substituted” or “substituted” means that the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from D, halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -C02alkyl, - C(=0)NH₂, -C(=0)NH(alkyl), -C(=0)N(alkyl)₂, -S(=0)₂NH₂, -S(=0)₂NH(alkyl), - S(=0)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, optional substituents are independently selected from D, halogen, -CN, -NH2, -NH(CH3), -N(CH₃)2, -OH, -CO2H, - C0₂(Ci-C4alkyl), -C(=0)NH₂, -C(=0)NH(Ci-C₄alkyl), -C(=0)N(Ci-C₄alkyl)2, -S(=0)₂NH₂, - S(=0)₂NH(Ci-C₄alkyl), -S(=0)₂N(Ci-C₄alkyl)2, Ci-C₄alkyl, Cs-Cecycloalkyl, Ci-C₄fluoroalkyl, Ci-C₄heteroalkyl, Ci-C₄alkoxy, Ci-C₄fluoroalkoxy, -SCi-C₄alkyl, -S(=0)Ci-C₄alkyl, and - S(=0)2Ci-C₄alkyl. In some embodiments, optional substituents are independently selected from D, halogen, -CN, -NH2, -OH, -NH(CH₃), -N(CH₃)₂, -CH₃, -CH₂CH₃, -CF₃, -OCH₃, and -OCF₃. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic) includes oxo (=0).

[0159] The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0160] The terms “administer,” “administering,” “administration,” and the like, as used herein, refer to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0161] The terms “co-administration” or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time. [0162] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.

[0163] The terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.

[0164] The terms “kit” and “article of manufacture” are used as synonyms.

[0165] The term "inhibit" as used herein refers to the partial or complete elimination of a potential effect, while inhibitors are compounds that have the ability to inhibit.

[0166] The term “pharmaceutically acceptable salt” refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation.

[0167] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound described herein with an acid to provide a "pharmaceutically acceptable acid addition salt." In some embodiments, the compound described herein (i.e. free base form) is basic and is reacted with an organic acid or an inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include, but are not limited to, 1 -hydroxy-2- naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4- acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor- 10- sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane-1, 2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (- L); malonic acid; mandelic acid (DL); methanesulfonic acid; monomethyl fumarate, naphthalene- 1, 5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; proprionic acid; pyroglutamic acid (- L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+ L); thiocyanic acid; toluenesulfonic acid (p); and undecylenic acid.

[0168] In some embodiments, the compound described herein is acidic and is reacted with a base. In such situations, an acidic proton of the compound described herein is replaced by a metal ion, e.g., lithium, sodium, potassium, magnesium, calcium, or an aluminum ion. In some cases, compounds described herein coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N- methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases used to form salts with compounds that include an acidic proton, include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like. In some embodiments, the compounds provided herein are prepared as a sodium salt, calcium salt, potassium salt, magnesium salt, meglumine salt, N- methylglucamine salt or ammonium salt.

[0169] It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms. In some embodiments, solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of isolating or purifying the compound with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms.

[0170] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.

[0171] The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.

[0172] The present invention, thus generally described, will be understood more readily by reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present invention.

EXAMPLES

Example 1. Preparation of 2-((4-((7-chloroquinolin-4-yl)amino)pentyl)(ethyl)amino)ethyl hydrogen ((((/?)-l-(6-amino-9 -purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (Compound 1)

1-1 8% yield Compound 1

[0173] To a mixture of 1-2 (343 mg, 1.193 mmol, 1.0 eq) in DMF (10 mL) and pyridine (2.5 mL) was added 1-1 (400 mg, 1.193 mmol, 1.0 eq), followed by addition of DCC (370 mg, 1.786 mmol, 1.5 eq). The mixture was stirred at 60 °C overnight. The mixture was purified by flash column chromatography (60 g, 0-100% MeOH (0.5% NH4OH) in DCM, 254 nm, 280 nm) to afford the desired product as a yellow solid. The product was further purified by pre-HPLC (20- 95% ACN in H2O, 0.5% NH4HCO3 in H2O). The product was then freeze dried to obtain Compound 1 as yellow solid (70 mg, 8% yield, NITri, 9 % yield).

[0174] Compound 1: ¾ NMR (DMSO- e, 400 MHz) 51.00 (t, 3H, J= 6.4 Hz), 1.15 (t, 3H, J = 6.4 Hz), 1.20 (d, 3H, J= 6.4 Hz), 1.53-1.68 (m, 2H), 1.77-1.94 (m, 2H), 2.96-3.04 (m, 6H), 3.53-3.55 (m, 2H), 3.72-3.76 (m, 1H), 3.87-3.94 (m, 3H), 4.11-4.15 (m, 1H), 4.25-4.28 (m,. 1H), 6.49 (t, 1H, J= 6.4 Hz), 7.20 (s, 2H), 7.25 (bs, 1H), 7.39 (dd, 1H, J= 9.2, 2.4 Hz,), 7.75 (d, 1H, J = 2.0 Hz,), 8.14 (s, 1H), 8.22 (d, 1H, 7= 4.0 Hz,), 8.35 (t, 1H, 7= 4.0 Hz), 8.48-8.51 (m, 1H).

MS (ESI) calcd for [M+H]⁺ (m/z): 605.2, found: 605.3.

Example 2. Preparation of 10-((6-chloro-2-methoxyacridin-9-yl)amino)decyl hydrogen ((((/?)-l-(6-amino-9T/-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (Compound 2)

Step 1. Preparation of 10-hydroxydecyl 4-methylbenzenesulfonate (2-2)

[0175] To a mixture of 2-1 (1050 mg, 6.0 mmol, 1.0 eq), DMAP (366 mg, 3.0 mmol, 0.5 eq) and TEA (2430 mg, 24.0 mmol, 4.0 eq) in DCM (30 mL) was added TsCl (1370 mg, 7.2 mmol, 1.2 eq) at 0 °C under N2 atmosphere. Then the mixture was stirred at room temperature overnight. The mixture was then purified by flash column chromatography (60 g, 0-20% EA in PE, 254 nm, 280 nm) to obtain 2-2 as a yellow solid (740 mg, 38% yield).

Step 2. Preparation of 10-azidodecan-l-ol (2-3)

[0176] A mixture of 2-2 (658 mg, 2.0 mmol, 1.0 eq) and NaN3 (520 mg, 8.0 mmol, 4.0 eq) in DMF (15 mL) was stirred at 60 °C under N2 atmosphere overnight. Then the mixture was cooled to room temperature, poured to water, and extracted with EtOAc. The organic layer was washed by brine, dried over Na2SC>4 and concentrated to afford 2-3 as a white solid (395 mg, 98% yield).

Step 3. Preparation of 10-aminodecan-l-ol (2-4)

[0177] Pd/C (395 mg) was added to the solution of 2-3 (395 mg, 1.98 mmol, 1.0 eq) in MeOH (10 mL) at 0 °C under Eh atmosphere. Then the mixture was stirred at room temperature for 2 hours. The mixture was then filtered to remove the solids. Removal of the solvent afforded 2-4 as a white solid (316 mg, 91% yield).

Step 4. Preparation of 10-((6-chloro-2-methoxyacridin-9-yl)amino)decan-l-ol (2-6)

[0178] A mixture of 2-5 (420 mg, 1.51 mmol, 1.2 eq) in phenol (5 mL) was stirred at 105 °C under N2 atmosphere 0.5 h. Then 2-4 (218 mg, 1.26 mmol, 1.0 eq) was added to the mixture and stirred at 105 °C for 1 h. The mixture was purified by flash column chromatography (60 g, 0- 100% MeOH (0.1% Et3N) in DCM (0.1% Et₃N), 254 nm, 280 nm) to afford 2-6 as a yellow solid (300 mg, 57% yield).

Step 5. Preparation of 10-((6-chloro-2-methoxyacridin-9-yl)amino)decyl hydrogen ((((/?)-l- (6-amino-9/ -purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (Compound 2)

[0179] To a mixture of 2-7 (69 mg, 0.24 mmol, 1.0 eq) in DMF (2 mL) and pyridine (0.5 mL) was added 2-6 (100 mg, 0.24 mmol, 1.0 eq), followed by addition of DCC (75 mg, 0.361 mmol, 1.5 eq). The mixture was stirred at 60 °C overnight. Then, DCC (100 mg, 0.480 mmol, 2.0 eq) and 2-7 (138 mg, 0.48 mmol, 2.0 eq) were added to the mixture at room temperature, and the reaction heated to 80 °C overnight. The mixture was purified by flash column chromatography (40 g, 0-100% MeOH (0.5% NH4OH) in DCM, 254 nm, 280 nm) to obtain Compound 2 as a yellow solid. Then the product was purified by pre-HPLC (20-95% ACN in H2O, 0.5% NH4HCO3 in H2O). Then the fractions were combined and freeze dried to afford Compound 2 as a yellow solid (15 mg, 9% yield, MTf salt).

[0180] Compound 2: ¾ NMR (CD3OD, 400 MHz) d 1.00-1.12 (m, 8H), 1.15 (d, 3H,

6.4

Hz), 1.20-1.25 (m, 2H), 1.33-1.40 (m, 4H), 1.89-1.93 (m, 2H), 3.49-3.54 (m, 1H), 3.71-3.78 (m, 3H), 3.88-3.93 (m, 1H), 3.98 (s, 3H), 4.10-4.21 (m, 3H), 4.31-4.36 (m, 1H), 7.45 (dd, 1H, J =

9.2, 2.0 Hz), 7.59 (dd, 1H, J= 9.2, 2.4 Hz), 7.77 (d, 1H, J= 2.4 Hz,), 7.83 (d, 1H, J= 9.2 Hz), 7.88 (d, 1H, J= 2.0 Hz,), 8.13 (s, 1H), 8.26 (s, 1H), 8.41 (d, 1H, J= 9.6 Hz). MS (ESI) calcd for [M+H]⁺ (m/z): 684.3 found: 684.4.

Example 3. Preparation of 10-((7-chloroquinolin-4-yl)amino)decyl hydrogen ((((R)-l-(6- amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (Compound 3)

Step 1. Preparation of 10-((7-chloroquinolin-4-yl)amino)decan-l-ol (3-3)

[0181] To a mixture of 3-1 (377 mg, 2.175 mmol, 2.0 eq) and 3-2 (215 mg, 1.088 mmol, 1.0 eq) in dioxane (10 mL) was added CS2CO3 (708 mg, mol, 2.0 eq), followed by addition of BINAP (68 mg, 0.109 mmol, 0.1 eq) and Pd2(dba)3 (50 mg, 0.054 mmol, 0.05 eq). The mixture was stirred at 105 °C under N2 atmosphere overnight. Then the mixture was cooled to room temperature, poured to water, and Tilted. The filtrate was extracted with EtOAc, and the organic layer was washed with brine, dried over Na2SC>4, and concentrated. The mixture was purified by flash column chromatography (60 g, 0-10% MeOH in DCM, 254 nm, 280 nm) to provide 3-3 as a yellow solid (210 mg, 58% yield).

Step 2. Preparation of 10-((7-chloroquinolin-4-yl)amino)decyl hydrogen ((((R)-l-(6-amino- 9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (Compound 3)

[0182] To a mixture of 3-4 (275 mg, 0.956 mmol, 2.0 eq) in DMF (12 mL) and pyridine (3 mL) was added 3-3 (160 mg, 0.478 mmol, 1.0 eq), followed by addition of DCC (295 mg, 1.433 mmol, 3.0 eq). The mixture was stirred at 100 °C overnight. The product was purified by pre- HPLC (20-95% ACN in H2O, 0.5% NH4HCO3 in H2O). Then fractions were combined and freeze dried to obtain Compound 3 as a white solid (118 mg, 40% yield, NLfC).

[0183] Compound 3: ¹HNMR (CD3OD, 600 MHz) 51.16 (d,3H, J= 6.0 Hz), 1.19 (bs, 6H), 1.24-1.26 (m, 2H), 1.34-1.36 (m, 2H), 1.41-1.45 (m, 4H), 1.76-1.78 (m, 2H), 3.48-3.52 (m, 1H), 3.57 (t,2H, J= 7.2 Hz), 3.71-3.76 (m, 3H), 3.91-3.92 (m, 1H), 4.19-4.22 (m, 1H), 4.33-4.36 (m, 1H), 6.82 (d,lH, J= 7.2 Hz), 7.63 (dd, 1H, J= 1.8, 9.0 Hz), 7.88 (d,lH, J= 1.8 Hz), 8.16 (s, 1H), 8.27 (s, 1H), 8.33 (s, 1H), 8.35 (d, 1H, J= 3.0 Hz). MS (ESI) calcd for [M+H]⁺ (m/z): 604.2, found: 604.3.

Example 4. Preparation of 13-((7-chloroquinolin-4-yl)amino)tridecyl hydrogen ((((R)-l-(6- amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (Compound 4)

Step 1. Preparation of 13-((7-chloroquinolin-4-yl)amino)-13-oxotridecanoic acid (4-3)

[0184] DIPEA (2.31 g, 17.9 mmol, 5.0 eq) was added to a stirring solution of 4-1 (1.75 g, 7.17 mmol, 2.0 eq) in DMF(15 ml). HATU (2.99 g, 7.87 mmol, 2.2 eq) was then added under N2. After 0.5 hours, 4-2 (640 mg, 3.58 mmol, 1.0 eq) was added, then the solution was stirred at 65 °C overnight. Removal of the solvent and purification by flash column chromatography (60 g, 0- 10% MeOH in DCM, 254 nm, 280 nm) provided 4-3 as a white solid (3.8 g, used as crude).

Step 2. Preparation of methyl 13-((7-chloroquinolin-4-yl)amino)-13-oxotridecanoate (4-4)

[0185] SOCh (2 ml) was added to a stirring solution of 4-3 (3.48 g, 2.7 mmol, 1.0 eq) in MeOH (40 ml) under ice-water bath, N2. Then, the reaction was stirred at 60 °C for 1 h and the solution was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2S04 and concentrated. Purification by flash column chromatography (60 g, 0-5% MeOH in DCM, 254 nm, 214 nm) afforded 4-4 as a white solid (902 mg, 66% yield).

Step 3. Preparation of 13-((7-chloroquinolin-4-yl)amino)tridecan-l-ol (4-5)

[0186] LiAlEE (1.9 g, 50 mmol, 22.0 eq) was added to the solution of 4-4 (902 mg, 2.27 mmol, 1.0 eq) in THF (100 ml) under ice-water bath and N2. The solution was then allowed to stir at room temperature overnight. A solution of H2O/THF (1.8 g H2O in THF 120 ml) was added to the mixture. The solution was then dried over Na2SC>4, concentrated, and then purified by flash column chromatography (60 g, 0-100% MeOH in DCM, 254 nm, 214 nm) to obtain 4-5 as a white solid (446 mg, 53% yield).

Step 4. Preparation of 13-((7-chloroquinolin-4-yl)amino)tridecyl hydrogen ((((R)-l-(6- amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (Compound 4)

[0187] To a mixture of 4-6 (362 mg, 1.26 mmol, 2.0 eq) in a solution of DMF/ pyridine (pyridine 4 ml in DMF 10 ml) was added 4-5 (237 mg, 0.63 mmol, 1.0 eq). DCC (389 mg, 1.89 mmol, 3.0 eq) was then added, and the mixture was stirred at 100 °C overnight. The mixture was purified by flash column chromatography (60 g, 0-100% MeOH (0.5% NH4OH) in DCM, 254 nm, 280 nm) to get 220 mg of crude product as a white solid. The crude product was purified by pre-HPLC (20-95% ACN in H2O, 0.1% NH4HCO3 in H2O). Then combined fractions were freeze dried to obtain Compound 4 as a yellow solid (23 mg, 6% yield, MTf salt).

[0188] Compound 4: ¾ NMR (DMSO-4, 400 MHz) d 0.93 (s, 4H), 0.99-1.15(m, 14H), 1.25- 1.28 (m, 2H), 1.33-1.38 (m, 4H), 1.65 (t, 2H, J= 9.2 Hz), 3.60-3.67 (m, 2H), 4.14- 4.15 (m, 1H), 4.23- 4.24 (m, 1H), 6.75 (d, 1H, J= 8.0 Hz,), 7.17 (s, 2H), 7.64 (d, 1H, J= 8.0 Hz,), 8.10 (s, 2H), 8.21 (s, 1H), 8.36 (d, 1H, J= 6.8 Hz), 8.50 (d, 1H, J= 9.2 Hz), 9.07 (s, 1H). MS (ESI) calcd for [M+H]⁺ (m/z): 646.30, found: 646.30.

Example 5. Preparation of 7-((6-chloro-2-methoxyacridin-9-yl)amino)heptyl hydrogen ((((/?)-l-(6-amino-9E/-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (Compound 5)

Step 1. Preparation of methyl 7-((6-chloro-2-methoxyacridin-9-yl)amino)heptanoate (5-3)

[0189] A mixture of 5-1 (556 mg, 2.0 mmol, 1.0 eq), 5-2 (1175 mg, 6.0 mmol, 3.0 eq) and DIPEA (1035 mg, 8.0 mmol, 4.0 eq) in EtOH (12 mL) was prepared. The mixture was stirred at 120 °C in a sealed tube overnight. The mixture was purified by flash column chromatography (60 g, 0-10% MeOH in DCM, 254 nm, 280 nm) to obtain 5-3 as a yellow solid (700 mg, 87% yield).

Step 2. Preparation of 7-((6-chloro-2-methoxyacridin-9-yl)amino)heptan-l-ol (5-4)

[0190] LiAlHi (225 mg, 5.874 mmol, 3.0 eq) was added to the solution of 5-3 (785 mg, 1.958 mmol, 1.0 eq) in THF (10 mL) at 0 °C under N2 atmosphere. Then the temperature was allowed to warm to room temperature. After stirrring at room temperature 1 hour, the a mixture of water (3 mL) and THF (10 mL) was added. After stirring for another 0.5 hour, the mixture was filtered. Removal of the solvent obtained 5-4 as a yellow solid. (707 mg, 97% yield).

Step 3. Preparation of 7-((6-chloro-2-methoxyacridin-9-yl)amino)heptyl hydrogen ((((/?)-l- (6-amino-9//-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (Compound 5)

[0191] To a mixture of 5-5 (358 mg, 1.247 mmol, 1.0 eq) in DMF (10 mL) and pyridine (2.5 mL) was added 5-4 (465 mg, 1.247 mmol, 1.0 eq). DCC (386 mg, 1.87 mmol, 1.5 eq) was then added, and the mixture was stirred at 60 °C overnight. The mixture was purified by flash column chromatography (60 g, 0-100% MeOH (0.5% NH4OH) in DCM, 254 nm, 280 nm) to provide Compound 5 as a yellow solid. Then the product was purified by pre-HPLC (20-95% ACN in H2O, 0.1% TFA in ACN, 0.1% TFA in H2O). The fractions were combined and freeze dried to afford the product as a yellow solid. Then 1M HC1 (10 mL) was added to the mixture of product in MeOH (2 mL) and stirred at room temperature 1 hour. Removal of the organic solvent and freeze drying obtained Compound 5 as a yellow solid (60 mg, 8% yield, 2 HC1).

[0192] Compound 5: ¾NMR (DMSO- e, 400 MHz) 51.27 (d, 3H, J= 2.8 Hz), 1.29-1.38 (m, 6H), 1.45-1.48 (m, 2H), 1.87- 1.91 (m, 2H), 3.62-3.68 (m, 5H), 3.70- 3.78 (m, 4H), 3.94 (s, 4H), 3.95-3.97 (m, 2H), 4.07-4.09 (m, 1H), 4.23-4.35 (m,. 1H), 7.53 (d,lH, J= 9.2 Hz), 7.68 (d,lH, J = 2.4 Hz), 7.71 (d, 1H, J= 2.4 Hz), 7.92 (s, 1H), 8.39 (s, 1H), 8.53 (s, 1H), 9.90 (s, 1H), 14.22 (s, 1H). MS (ESI) calcd for [M+H]⁺ (m/z): 642.09, found: 642.3.

Example 6. Preparation of 2-((((R)-l-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)-6- (4-((6-chloro-2-methoxyacridin-9-yl)amino)pentyl)-l,3,6,2-dioxazaphosphocane 2-oxide (Compound 6)

Compound 6

Step 1. Preparation of 2,2'-((4-((6-chloro-2-methoxyacridin-9-yl)amino)pentyl)azanediyl) bis(ethan-l-ol) (6-3)

[0193] To a mixture of 6,9-dichloro-2-methoxyacridine (6-1, 3.0 g, 10.8 mmol) and phenol (6.1 g, 65 mmol) was added 2,2'-((4-aminopentyl)azanediyl)bis(ethan-l-ol) (6-2, 3.1 g, 16.2 mmol). The reaction was then stirred at 120°C for 6 hours. NaOH (aq. 1 M, 180 mL) was added and the reaction mixture was extracted with EA (100 ml x 3). The organic layer was combined, washed with saturated brine (200 mL), dried over anhydrous Na2SC>4, filtered, concentrated in vacuum, and purified by silica gel column chromatography (10% MeOH in DCM) to afford 2,2'- ((4-((6-chloro-2-methoxyacridin-9-yl)amino)pentyl)azanediyl)bis(ethan-l-ol) (6-3, 630 mg, 21% yield) as an orange oil.

Step 2. Preparation of 2-((((R)-l-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)-6-(4- ((6-chloro-2-methoxyacridin-9-yl)amino)pentyl)-l,3,6,2-dioxazaphosphocane 2-oxide (Compound 6)

[0194] To 2,2'-((4-((6-chloro-2-methoxyacridin-9-yl)amino)pentyl)azanediyl)bis(ethan-l-ol) (6-3, 300 mg, 0.70 mmol) in pyridine (15 mL) was added (R)-(((l-(6-amino-9H-purin-9- yl)propan-2-yl)oxy)methyl)phosphonic acid (6-4, 300 mg, 1.04 mmol) and EDCI (685 mg, 3.48 mmol). The mixture was stirred at 70 °C for 3 hours and then concentrated in vacuum to dryness. The residue was added water (50 mL) and extracted with i-BuOH (50 mL). The combined organic layer was washed with saturated brine (40 mL), dried over anhydrous Na2S04, filtered, concentrated in vacuum, and purified by silica gel column chromatography (10% MeOH in DCM) to afford 2-((((R)-l-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)-6-(4-((6-chloro-2- methoxyacridin-9-yl)amino)pentyl)-l,3,6,2-dioxazaphosphocane 2-oxide (Compound 6, 48 mg, 10% yield) as a light-green oil.

[0195] Compound 6: ¹HNMR: (400 MHz, DMSO- d) d 8.41 (brs, 1H), 8.14 (s, 1H), 8.05 (d, J = 1.2 Hz, 1H), 7.98 (s, 1H), 7.93 (d, J = 4.2 Hz, 1H), 7.86 (s, 1H), 7.66-7.62 (m, 1H), 7.53-7.51 (m, 1H), 7.30 (s, 1H), 7.18 (s, 2H), 4.38-4.20 (m, 1H), 4.12-4.11 (m, 2H), 3.97 (s, 3H), 3.97-3.90 (m, 1H), 3.90-3.70 (m, 3H), 3.70-3.50 (m, 3H), 2.95 (s, 2H), 2.68 (s, 3H), 2.05-1.95 (m, 2H), 1.89-1.86 (m, 2H), 1.53 (s, 3H), 1.20 (d, J = 6.6 Hz, 3H), 1.08 (d, J = 6.0 Hz, 3H). LCMS (ESI): m/z 342 [M/2+1 ]⁺; 229 [M/3+l]⁺; 683 [M+l]⁺.

Example 7. Preparation of 2-((((R)-l-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)-6- (4-((6-chloro-l,2,3,4-tetrahydroacridin-9-yl)amino)pentyl)-l,3,6,2-dioxazaphosphocane 2- oxide (Compound 7)

Step 1. Preparation of 6,9-dichloro-l,2,3,4-tetrahydroacridine (7-1)

[0196] To a mixture of 2-amino-4-chlorobenzoic acid (18.0 g, 105 mmol) and cyclohexanone (11 mL, 105 mmol) was added POCb (88 mL). The mixture was stirred at 110 °C for 3 hours. The mixture was concentrated in vacuum, poured into 500 mL ice-water, stirred overnight, and then filtered. The filter cake was dried in vacuum to afford 6,9-dichloro-l,2,3,4- tetrahydroacridine as a yellow solid (7-1, 22.9 g, 87% yield). LCMS (ESI): m/z 252 [M+l]⁺.

Step 2. Preparation of 2,2'-((4-((6-chloro-l,2,3,4-tetrahydroacridin-9- yl)amino)pentyl)azanediyl)bis(ethan-l-ol) (7-3)

[0197] To a mixture of 6,9-dichloro-l,2,3,4-tetrahydroacridine (7-1, 3.0 g, 12.0 mmol) and phenol (6.8 g, 72 mmol) was added 2,2'-((4-aminopentyl)azanediyl)bis(ethan-l-ol) (7-2, 3.4 g, 18.0 mmol) and then stirred at 120 °C for 6 hours. The residue was added NaOH (aq. IN, 180 mL) and then extracted with EA (100 mL x 3). The organic layer was combined, washed with saturated brine (200 mL), dried over anhydrous Na2SC>4, filtered, concentrated in vacuum, and purified by silica gel column chromatography (10% MeOH in DCM) to afford 2,2'-((4-((6- chloro-l,2,3,4-tetrahydroacridin-9-yl)amino)pentyl)azanediyl)bis(ethan-l-ol) as a yellow oil (7- 3, 960 mg, 27% yield). LCMS (ESI): m/z 203 [M/2+l]⁺, 406 [M+l]⁺. Step 3. Preparation of 2-((((R)-l-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)-6-(4- ((6-chloro-l,2,3,4-tetrahydroacridin-9-yl)amino)pentyl)-l,3,6,2-dioxazaphosphocane 2- oxide (Compound 7)

[0198] To 2,2'-((4-((6-chloro-l,2,3,4-tetrahydroacridin-9-yl)amino)pentyl)azanediyl)bis(ethan- l-ol) (7-3, 400 mg, 0.99 mmol) in pyridine (20 mL) was added (R)-(((l-(6-amino-9H-purin-9- yl)propan-2-yl)oxy)methyl)phosphonic acid (7-4, 425 mg, 1.48 mmol) and EDCI (972 mg, 4.94 mmol). The mixture was stirred at 70 °C for 3 hours and then concentrated in vacuum. The residue was extracted with i-BuOH (50 mL) and water (50 ml). The organic layer was washed with saturated brine (40 mL), dried with anhydrous Na2SC>4, filtered, concentrated in vacuum, and purified by silica gel column chromatography (10% MeOH in DCM) to afford 2-((((R)-l-(6- amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)-6-(4-((6-chloro- 1,2,3, 4-tetrahy droacridin-9- yl)amino)pentyl)-l,3,6,2-dioxazaphosphocane 2-oxide as an orange oil (Compound 7, 62 mg, 10.1% yield) as an orange oil.

Example 8. Preparation of 2-((((R)-l-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)-6- (4-((7-chloroquinolin-4-yl)amino)pentyl)-l,3,6,2-dioxazaphosphocane 2-oxide (Compound 8)

Step 1. Preparation of 5-chloropentan-2-one O-benzyl oxime (8-1)

[0199] To a solution of 5-chloropentan-2-one (9.6 g, 80 mmol) in MeOH (100 mL) was added O-Benzylhydroxylamine hydrochloride (12.8 g, 80 mmol). The mixture was stirred at room temperature for 4 hours and then concentrated in vacuum. EA (500 mL) was added to the mixture and the reaction mixture was stirred for 20 minutes and filtered. The filtrate was concentrated in vacuum and purified by silica gel column chromatography (5% EA in PE) to afford 5-chloropentan-2-one O-benzyl oxime as a colorless oil (8-1, 16.8 g, 93% yield). LCMS (ESI): m/z 226 [M+l]⁺.

Step 2. Preparation of 5-(bis(2-hydroxyethyl)amino)pentan-2-one O-benzyl oxime (8-2)

[0200] To a solution of 5-chloropentan-2-one O-benzyl oxime (8-1, 16.8 g, 74.6 mmol) in DMF (120 mL) was added diethanolamine (15.7 g, 149 mmol), K2CO3 (30.9 g, 224 mmol) and KI (6.2 g, 37.3 mmol). The mixture was stirred at 70 °C for 4 hours. The residue was extracted with DCM (250 mL x3 ) and H2O (300 mL). The organic layer was combined, washed with saturated brine (300 mL), dried over anhydrous Na2S04, filtered, concentrated in vacuum, and purified by silica gel column chromatography (5%~10% MeOH in DCM) to afford 5-(bis(2- hydroxyethyl)amino)pentan-2-one O-benzyl oxime as a light-orange oil (8-2, 15.1 g, 69% yield). LCMS (ESI): m/z 295 [M+l]⁺.

Step 3. Preparation of 2,2'-((4-aminopentyl)azanediyl)bis(ethan-l-ol) (8-3)

[0201] To a solution of 5-(bis(2-hydroxyethyl)amino)pentan-2-one O-benzyl oxime (8-2, 6.2 g, 21.1 mmol) in MeOH (60 mL) was added Raney -Ni (65 mg, cat.). The mixture was stirred at room temperature overnight. The reaction mixture was filtered through Celite to remove the catalyst. The filtrate was concentrated in vacuum and purified by silica gel column chromatography (20% MeOH in DCM) to afford 2,2'-((4-aminopentyl)azanediyl)bis(ethan-l-ol) as a colorless oil (8-4, 3.4 g, 84.8% yield). LCMS (ESI): m/z 191 [M+l]⁺.

Step 4. Preparation of 2,2'-((4-((7-chloroquinolin-4-yl)amino)pentyl)azanediyl)bis(ethan-l- ol) (8-4) [0202] To a mixture of 4,7-dichloroquinoline (2.0 g, 10.0 mmol) and phenol (8.5 g, 90 mmol) was added 2,2'-((4-aminopentyl)azanediyl)bis(ethan-l-ol) (8-4, 3.0 g, 15.8 mmol) and then stirred at 120°C for 6 hours. The NaOH (aq. IN, 60 mL) was then added, and reaction mixture was then extracted with EA (60 mL x3). The organic layers were combined, washed with saturated brine (100 mL), dried over anhydrous Na2SC>4, filtered, concentrated in vacuum, and purified by silica gel column chromatography (10% MeOH in DCM) to afford 2,2'-((4-((7- chloroquinolin-4-yl)amino)pentyl)azanediyl)bis(ethan-l-ol) as a colorless oil (8-4, 960 mg, 27% yield). LCMS (ESI): m/z 177 [M/2+l]⁺, 352 [M+l]⁺.

Step 5. Preparation of 2-((((R)-l-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)-6-(4- ((7-chloroquinolin-4-yl)amino)pentyl)-l,3,6,2-dioxazaphosphocane 2-oxide (Compound 8)

[0203] To a solution of 2,2'-((4-((7-chloroquinolin-4-yl)amino)pentyl)azanediyl)bis(ethan-l-ol) (8-4, 300 mg, 0.85 mmol) in pyridine (20 mL) was added (R)-(((l-(6-amino-9H-purin-9- yl)propan-2-yl)oxy)methyl)phosphonic acid (8-5, 368 mg, 1.28 mmol) and EDCI (841 mg, 4.27 mmol). The mixture was stirred at 70°C for 3 hours and then concentrated in vacuum. The residue was extracted with i-BuOH (50 mL) and water (50 mL). The organic layer was washed with saturated brine (40 mL), dried over anhydrous Na2SC>4, filtered, concentrated in vacuum, and purified by silica gel column chromatography (10% MeOH in DCM) to afford 2-((((R)-l-(6- amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)-6-(4-((7-chloroquinolin-4-yl)amino)pentyl)- 1,3,6,2-dioxazaphosphocane 2-oxide as an off-white solid (Compound 8, 52 mg, 10.1% yield).

[0204] Compound 8: ¾ NMR: (400 MHz, DMSO-d6) d 8.38-8.36 (m, 2H), 8.13 (s, 1H), 8.06 (s, 1H), 7.76 (d, J = 1.6 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.18 (s, 2H), 6.94 (d, J = 8.0 Hz, 1H), 6.49 (d, J = 5.6 Hz, 1H), 4.22-4.17 (m, 1H), 4.15-4.11 (m, 1H), 3.96-3.90 (m, 3H), 3.78-3.66 (m, 5H), 2.76-2.72 (m, 2H), 2.67-2.60 (m, 2H), 2.33-2.16 (m, 2H), 1.77-1.73 (m, 1H), 1.54-1.46 (m, 3H), 1.22 (d, J = 6.0 Hz, 3H), 1.08 (d, J = 5.6 Hz, 3H). LCMS (ESI): m/z 302 [M/2+l]⁺ 202 [M/3+l]⁺603 [M+l]⁺.

Example 9. Preparation of 2-((((R)-l-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)-5- (4-((7-chloroquinolin-4-yl)amino)butyl)-l,3,2-oxazaphosphinane 2-oxide (Compound 9)

Step 1. Preparation of 4-(tert-butoxycarbonyl)butyl methanesulfonate (9-1)

[0205] To a solution of tert-butyl 4-hydroxybutylcarbamate (25 g, 132.1 mmol) in DCM (250 ml) was added TEA (47.7 mL, 330.25 mmol) and then a solution of MS2O (27.6 g, 158.5 mmol) in DCM (50 mL) was added drop wise to the mixture at 5 °C. The mixture was stirred at room temperature overnight, washed with water (100 mL), 0.5M HC1 (100 mL), and saturated brine, dried over anhydrous Na2SC>4, filtered, and concentrated in vacuum to afford crude 4-(tert- butoxycarbonyl)butyl methanesulfonate (9-1, 38 g) as a light-brown oil for next step without further purification. LCMS: (ESI) m/z 290 [M+23]⁺.

Step 2. Preparation of ethyl 6-(tert-butoxycarbonyl)-2-cyanohexanoate (9-2)

[0206] To a solution of 4-(tert-butoxycarbonyl)butyl methanesulfonate (9-1, 38 g, crude) in MeCN (450 ml) was added ethyl 2-cyanoacetate (30 g, 264.2 mmol), K2C03(18 g, 132.1 mmol) and 18-crown-6 (0.5 g, cat.). The mixture was stirred at 60 °C overnight. Then the mixture was filtered, and the filtrate was concentrated in vacuum. The resulting residue was purified by silica gel column chromatography (PE:EA=20: 1-8:1) to afford ethyl 6-(tert-butoxycarbonyl)-2- cyanohexanoate (9-2, 40g, crude) as a light-orange oil. LCMS: (ESI) m/z 307 [M+23]⁺.

Step 3. Preparation of ethyl 6-amino-2-cyanohexanoate hydrochloride (9-3)

[0207] To a solution of ethyl 6-(tert-butoxycarbonyl)-2-cyanohexanoate (9-2, 8 g, crude, 28.17 mmol) in dioxane (10 mL) was added 4M HCl-dioxane (30 mL). The mixture was stirred at room temperature overnight. The precipitate was collected by filtration, washed with the solution of PE and MTBE(v:v=l : 1,10 mL x 2), dried in vacuum to afford ethyl 6-amino-2- cyanohexanoate hydrochloride (9-3, 45% yield) as a white solid. LCMS: (ESI) m/z 185 [M+l]⁺.

Step 4. Preparation of ethyl 6-(7-chloroquinolin-4-ylamino)-2-cyanohexanoate (9-4)

[0208] To a mixture of 4,7-dichloroquinoline (3.16 g, 16 mmol) and phenol (9 g, 96 mmol) was added ethyl 6-amino-2-cyanohexanoate hydrochloride (9-3, 4.4 g, 20 mmol) and TEA (800 mg, 8 mmol). The mixture was stirred at 120 °C for 4 hours, then cooled to r.t. MTBE (100 mL) and 1M HC1 (100 mL) was added to the mixture, and the water layer was washed with MTBE twice. The aqueous phase was adjusted pH to 10 with sodium hydroxide, extracted with EA twice, the combined organic layers were washed with saturated brine, dried over anhydrous Na2S04. The organic layers were filtered, and the filtrate was concentrated in vacuum. The resulting residue was purified by silica gel column chromatography (DCM/MeOH=20:l) to afford ethyl 6-(7-chloroquinolin-4-ylamino)-2-cyanohexanoate (9-4, 3.2g, 58.2% yield) as a colorless oil.

[0209] 9-4: ¾ NMR: (400 MHz, DMSO-d6): d 8.40 (d, J = 7.2 Hz, 1H), 8.28 (d, J = 9.2 Hz,

1H), 7.79 (d, J = 2.4 Hz, 1H), 7.46 (dd, J = 8.8 Hz, J = 2.0 Hz,IH), 7.42 (t, J = 5.2Hz, 1H), 6.50 (d, J = 5.6 Hz, 1H), 4.14~4.28(m, 3H), 3.27-3.32(m, 2H), 1.89~1.92(m,2H), 1.69~1.73(m,2H), 1.51~1.54(m,2H), 1.19(t, J = 7.2Hz, 3H). LCMS: (ESI) m/z 346[M+1]⁺.

Step 5. Preparation of 6-(7-chloroquinolin-4-ylamino)-2-(hydroxymethyl)hexanenitrile (9-

5)

[0210] To a solution of ethyl 6-(7-chloroquinolin-4-ylamino)-2-cyanohexanoate (9-4, 2.6 g, 7.54 mmol) in MeOH was added NaBHi (855 mg, 22.62 mmol) at r.t. in portion wise. The mixture was stirred at r.t. for 2h and concentrated in vacuum. A solution of NaHCCb in water and EA was added to the residue, and the water layer was extracted with EA. The combined organic layer was washed with saturated brine, dried over anhydrous Na2SC>4. The organic layers were filtered, and the filtrate was concentrated in vacuum to afford 6-(7-chloroquinolin-4- ylamino)-2-(hydroxymethyl)hexanenitrile (9-5, 1.9 g, 82.6% yield) as a pink solid. LCMS:

(ESI) m/z 304[M+1]⁺.

Step 6. Preparation of 2-(aminomethyl)-6-(7-chloroquinolin-4-ylamino)hexan-l-ol (9-6)

[0211] To a suspension of LAH (l.Og, 26.3mmol) in dry THF was added a solution of 6-(7- chloroquinolin-4-ylamino)-2-(hydroxymethyl)hexanenitrile (9-5, 2.0 g, 6.58 mmol) in dry THF drop wise at 0 °C under N2. The mixture was stirred for 5h at 0 °C. Sodium sulfate decahydrate was added to the mixture and stirred for lh at r.t. EA and MeOH were added to the mixture and the precipitate was filtered off. The filtrate was concentrated in vacuum, and the residue was purified by silica gel column chromatography (DCM/MeOH=20: 1-5:1, containing 0.1% NH3.H2O) to afford 2-(aminomethyl)-6-(7-chloroquinolin-4-ylamino)hexan-l-ol (9-6, 1.3 g, 55.9% yield) as a colorless oil.

[0212] 9-6: ¹HNMR: (400 MHz, DMSO-d6): d 8.38 (d, J = 5.6 Hz, 1H), 8.27 (d, J = 8.8 Hz,

1H), 7.77 (d, J = 2.4 Hz, 1H), 7.43 (dd, J = 8.8 Hz, J = 2.0 Hz,IH), 7.31 (brs, 1H), 6.46 (d, J =

5.2 Hz, 1H), 3.25~3.28(m, 4H), 2.51~2.61(m, 2H), 1.60~1.66(m,2H), 1.34~1.40(m,3H), 1.23~1.28(m,2H) . LCMS: (ESI) m/z 154.8[M/2+l]⁺, 308[M+1]⁺.

Step 6. Preparation of 2-((((R)-l-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)-5-(4- ((7-chloroquinolin-4-yl)amino)butyl)-l,3,2-oxazaphosphinane 2-oxide (Compound 9)

[0213] To a solution of 2-(aminomethyl)-6-(7-chloroquinolin-4-ylamino)hexan-l-ol (9-6, 307 mg, 1.0 mmol) in pyridine (25 ml) was added (R)-(((l-(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)phosphonic acid (1.4 g, 5.0 mmoL), EDCI (2.8 g, 15.0 mmol) and TEA (1.5 g, 15.0 mmol) at r.t. under N2. The mixture was stirred at 60 °C for 2 hours and then concentrated in vacuum. The residue was diluted with i-BuOH (50 mL) and water (50 mL). The organic layer was separated, washed with water(20 mL*2) and saturated brine (40 mL), dried over anhydrous Na2SC>4, concentrated in vacuum and purified by silica gel column chromatography (DCM/MeOH=20: 1-10:1) to afford Compound 9 (60 mg, 10.7% yield) as a colorless solid.

[0214] Compound 9: ¾ NMR: (400 MHz, DMSO-d6): d 8.40 (d, J = 5.6 Hz, 1H), 8.28 (d, J = 9.2Hz, 1H), 8.10-8.14 (m, 2H) , 7.78 (d, J = 1.6 Hz, 1H), 7.44 (dd, J = 10.8 Hz, J = 2.8 Hz,IH), 7.27-7.29 (m, 1H), 7.21(s, 2H), 6.47 (d, J = 5.6 Hz, 1H), 4.85-5.08(m, 1H), 4.17~4.27(m, 2H), 3.96~4.00(m,2H), 3.69~3.88(m, 3H), 3.25-3.36(m, 4H), 1.83(brs,lH), 1.59~1.65(m, 3H), 1.30~1.38(m,3H), 1.08~1.12(m,3H). LCMS: (ESI) m/z 280 [M/2+l]⁺, 559 [M+l]⁺.

Example 10. Preparation of ethyl 2-(2-((((R)-l-(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)-5-(4-((7-chloroquinolin-4-yl)amino)butyl)-2-oxido-l,3,2-oxazaphosphinan-3- yl)acetate (Compound 10)

Step 1. Preparation of ethyl 2-(6-(7-chloroquinolin-4-ylamino)-2-(hydroxymethyl)hexyl amino)acetate (10-2)

[0215] To a solution of 2-(aminomethyl)-6-(7-chloroquinolin-4-ylamino)hexan-l-ol (10-1, 500 mg, 1.62 mmol) in EtOH (20 ml) was added ethyl 2-oxoacetate (400 mg, 1.95mmol), HO Ac (2 drops, cat.) and 4Ά molecular sieves (200 mg) at r.t. The mixture was stirred overnight at r.t. until starting material was converted into intermediate. NaBH^CN (408 mg, 6.5 mmol) was added to the reaction mixture portion wise at r.t. The reaction mixture was filtered though Celite, and the filtrate was concentrated in vacuum and purified by silica gel column chromatography (DCM/MeOH=20: 1-10:1) to afford ethyl 2-(6-(7-chloroquinolin-4-ylamino)-2- (hydroxymethyl)hexylamino)acetate (10-2, 400mg, 62.5% yield) as a colorless solid.

[0216] 10-2: ¾ NMR: (400 MHz, DMSO-d6): d 8.38 (d, J = 5.6 Hz, 1H), 8.28 (d, J = 5.6 Hz,

1H), 7.78 (d, J = 2.0 Hz, 1H), 7.44 (dd, J = 8.4 Hz, J = 2.0 Hz,IH), 7.32 (t, J = 5.2Hz, 1H), 6.46 (d, J = 4.8Hz, 1H), 4.05-4. ll(m, 2H), 3.45-3.52(m, 2H), 3.24~3.32(m,5H), 2.47~2.50(m,2H),

I.61~1.67(m,2H), 1.49~1.52(m,2H), 1.36~1.44(m,2H), 1.21~1.34(m,2H), 1.18(t, J = 7.2Hz, 3H). LCMS: (ESI) m/z 394 [M+l]⁺, 197.8 [M/2+l]⁺.

Step 2. Preparation of ethyl 2-(2-((((R)-l-(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)-5-(4-((7-chloroquinolin-4-yl)amino)butyl)-2-oxido-l,3,2-oxazaphosphinan-3- yl)acetate (Compound 10)

[0217] To a solution of ethyl 2-(6-(7-chloroquinolin-4-ylamino)-2-(hydroxymethyl)hexyl amino)acetate (10-2, 300 mg, 0.7616 mmol) in pyridine (20 ml) was added (R)-(((l-(6-amino- 9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonic acid (1.09 g, 3.8 mmol) , EDCI (2.19 g,

I I .42 mmol) and TEA (1.15 g, 11.42 mmol) at r.t. under N2. The mixture was stirred at 60 °C for 2 hours, and additional EDCI (0.5 g, 2.6 mmol) was added to the mixture and stirred at 60 °C until the reaction was completed. Then the mixture was concentrated in vacuum. The residue was diluted with i-BuOH (50 m:) and water (50 mL). The organic layer was separated, washed with water (20mL*2) and saturated brine (40 mL), dried over anhydrous Na2SC>4, concentrated in vacuum, and purified by silica gel column chromatography (DCM/MeOH=20: 1-10:1) to afford Compound 10 (lOmg, 2% yield) as a colorless solid.

[0218] Compound 10: ¾ NMR: (400 MHz, DMSO-d6): d 8.49 (d, J = 5.2 Hz, 1H), 8.42 (d, J = 8.8Hz, 1H), 8.20-8.25 (m, 2H), 7.90 (s, 1H), 7.53-7.58 (m, 2H), 7.31 (s, 2H), 6.58-6.60 (m, 1H), 4.31-4.34 (m, 2H), 4.08-4.20 (m, 4H), 3.75-3.99 (m, 5H), 3.32-3.42 (m, 4H), 2.00-2.20 (m, 1H), 1.85~1.89(m, 2H), 1.72~1.75(m, 2H), 1.25-1.37 (m, 3H), 1.17~1.24(m,5H). LCMS: (ESI) m/z 323 [M/2+l]⁺, 645 [M+l]⁺. Example 11: Preparation of N-(13-{[({[(2R)-l-(6-amino-9H-purin-9-yl)propan-2- yl]oxy}methyl)({[(propan-2-yloxy)carbonyl]oxy}methoxy)phosphoryl]amino}tridecyl)-7- chloroquinolin-4-amine (Compound 11)

Step 1. Preparation of N'-(7-chloroquinolin-4-yl)tridecanediamide (11-3)

[0219] SOCh (11 ml) was add to a stirring solution of 11-1 (1.41 g, 5.77 mmol, 1.0 eq) in DCM (40 mL) under ice-water bath, N2, and stirred at 50 °C for 4 h. Then the solvent was removed, and the resulting product was co-evaporated with DCM for three times to give a colorless oil, which was dissolved in DCM (40 mL). 11-2 (1.03 g, 5.77 mmol, 1.0 eq) and DIPEA (1.48 g, 11.54 mmol, 2.0 eq) were added under ice-salt bath and N2. After stirring at room temperature for 30 min, NELOH (3 ml) was added after 30 min. Removal of the the solvent and purification by column chromatography (0-100% EA in PE, then 0-10% MeOH in DCM) afforded 11-3 as a yellow oil (2.3 g, used as crude).

Step 2. Preparation of methyl N¹-(7-chloroquinolin-4-yl)tridecane-l, 13-diamine (11-4) [0220] BH3 (84 ml, 84 mmol, 20 eq) was added to a stirring solution of 11-3 (1.71 g, 4.2 mmol, 1.0 eq) in THF (100 ml) under ice-water bath and N2. Then the reaction was stirred at 70 °C for 2 h. Hydrochloric acid (20 ml, 1 mol/L) was added slowly to the solution under ice-water and then extracted with EtOAc. Then sodium hydroxide (20 ml, 1 mol/L) was added, and the pH was adjusted to 9. Following extraction with EtOAc, the extract was washed with brine, dried over Na2S04, concentrated, and purified by flash column chromatography (60 g, 0-40% MeOH in DCM, 0.1% TFAin DCM, 254 nm, 214 nm) to obtain 11-4 as a yellow oil (370 mg, 24% yield).

Step 3. Preparation of ({[(2R)-l-(6-amino-9H-purin-9-yl)propan-2- yl]oxy}methyl)({[(propan-2-yloxy)carbonyl]oxy}methoxy)phosphinic acid (11-7)

[0221] 11-6 (2.27 g, 14.9 mmol, 1.3 eq) was added to a stirring solution of 11-5 (3.29 g, 11.46 mmol, 1.0 eq) and DIPEA (7.39 g, 57.3 mmol, 5.0 eq) in DMF (30 ml) under N2. The reaction was stirred at 70 °C overnight. Removal of the solvent and purification by flash column chromatography (60 g, 0-100% MeOH in DCM, 254 nm, 214 nm) provided 11-7 as a yellow oil (3.84 g, 83% yield).

Step 4. Preparation of N-(13-{[({[(2R)-l-(6-amino-9H-purin-9-yl)propan-2- yl]oxy}methyl)({[(propan-2-yloxy)carbonyl]oxy}methoxy)phosphoryl]amino}tridecyl)-7- chloroquinolin-4-amine (Compound 11)

[0222] SOCI2 (320 mg, 2.7 mmol, 6.7 eq) was add to a stirring solution of 11-7 (204 mg, 0.51 mmol, 1.3 eq) in ACN (8 ml), and stirred at 80 °C for 1 h. Removal of the solvent provided a colorless oil, which was added to a solution of 11-4 (146 mg, 0.39 mmol, 1.0 eq) and DIPEA (250 mg, 1.95 mmol, 5.0 eq) in ACN/DCM (25 ml) under ice-salt bath, N2, then the mixture was stirred at room temperature overnight. Removal of the solvent and purification by flash column chromatography (25 g, 0-40% MeOH in DCM, 254 nm, 280 nm) provided 145 mg of crude product as a yellow oil. Then the product was purified by flash column chromatography (10 g, 0- 15% MeOH in DCM, 254 nm, 280 nm) to obtain Compound 11 as a yellow oil (27 mg, 9% yield).

[0223] Compound 11: ¾ NMR (CDsOD-de, 400 MHz) d 1.19- 1.21 (m, 26H), 1.25-1.27 (m, 4H), 1.36-1.47 (m, 2H), 1.73-1.80 (m, 2H), 2.76-2.82 (m, 2H), 3.49-3.52 (t, 2H, J = 14.4 Hz), 3.61-3.68 (m, 1H), 3.83-3.88 (m, 1H), 3.93-3.97 (m, 1H), 4.18- 4.24 (m, 1H), 4.34- 4.38 (m, 1H), 4.81- 4.86 (m, 1H), 5.45- 5.56 (m, 2H), 6.74- 6.75 (d, 1H, J = 6.8 Hz), 7.57- 7.59 (m, 1H), 7.82 (s, 1H), 8.14-8.15 (d, 1H, J = 3.2 Hz), 8.19 (s, 1H), 8.28-8.30 (d, 1H, J = 9.2 Hz), 8.34-8.36 (d, 1H, J = 6.8 Hz). MS (ESI) calcd for [M+H]⁺ (m/z): 760.36, found: 760.36.

Example 12. Preparation of N-(10-{[({[(2R)-l-(6-amino-9H-purin-9-yl)propan-2- yl]oxy}methyl)({[(propan-2-yloxy)carbonyl]oxy}methoxy)phosphoryl]amino}decyl)-7- chloroquinolin-4-amine (Compound 12)

step 2: 12-4, ACN, DIPEA,

0 °C-RT, overnight 6% yield

Step 1. Preparation of N¹-(7-chloroquinolin-4-yl)decane-l, 10-diamine (12-3)

[0224] DIPEA (2.3 g, 18.0 mmol, 3.0 eq) was added to a stirring solution of 12-1 (1.2 g, 6.0 mmol, 1.0 eq) and 12-2 (3.1 g, 18.0 mmol, 3.0 eq) in EtOH (20 ml) in a sealed tube. The reaction was stirred at 125 °C overnight. Removal of the solvent under vacuum and purification by flash column chromatography (25 g, 0-100% MeOH in DCM, 1% Et3N) provided 12-3 as a yellow solid (2.1 g, used as crude).

Step 2. Preparation of N-(10-{[({[(2R)-l-(6-amino-9H-purin-9-yl)propan-2- yl]oxy}methyl)({[(propan-2-yloxy)carbonyl]oxy}methoxy)phosphoryl]amino}decyl)-7- chloroquinolin-4-amine (Compound 12) [0225] SOCI2 (370 mg, 3.11 mmol, 6.2 eq) was added to a stirring solution of 12-4 (340 mg, 0.84 mmol, 1.6 eq) in ACN (8 ml), and stirred at 80 °C for 1 h. Removal of the solvent provided a colorless oil, which was added to a solution of 12-3 (167 mg, 0.5 mmol, 1.0 eq) and TEA (300 mg, 2.5 mmol, 5.0 eq) in ACN/DCM (20 mL) under ice-salt bath and N2. The mixture was stirred at room temperature overnight. Removal of the solvent and purification by flash column chromatography (10 g, 0-15% MeOH in DCM, 254 nm, 280 nm) to obtain Compound 12 as a colorless oil (21 mg, 6% yield).

[0226] Compound 12: ¾ NMR (CDsOD-de, 400 MHz) 51.19-1.21 (m, 4H), 1.24-1.38 (m, 21H), 1.44-1.46 (m, 2H), 1.73-1.80 (m, 2H), 2.75-2.82 (m, 2H), 3.48-3.50 (t, 2H, J = 7.6 Hz), 3.61-3.68 (m, 1H), 3.83-3.88 (m, 1H), 3.93-3.97 (m, 1H), 4.18- 4.24 (m, 1H), 4.33- 4.38 (m, 1H), 5.44- 5.56 (m, 2H), 6.73- 6.75 (d, 1H, J = 6.8 Hz), 7.57- 7.59 (d, 1H, J = 9.2 Hz), 7.81-7.82 (s, 1H), 8.14-8.15 (d, 1H, J = 3.2 Hz), 8.19 (s, 1H), 8.28-8.30 (d, 1H, J = 9.2 Hz), 8.34-8.36 (d, 1H,

J = 6.8 Hz). MS (ESI) calcd for [M+H]⁺ (m/z): 718.31, found: 718.31.

Example 13. Preparation of N-(7-{[({[(2R)-l-(6-amino-9H-purin-9-yl)propan-2- yl]oxy}methyl)({[(propan-2-yloxy)carbonyl]oxy}methoxy)phosphoryl]amino}heptyl)-7- chloroquinolin-4-amine (Compound 13)

Step 1. Preparation of N¹-(7-chloroquinolin-4-yl)heptane-l, 7-diamine (13-3)

[0227] DIPEA (400 mg, 3.1 mmol, 3.0 eq) was added to a stirring solution of 13-1 (205 mg, 1.03 mmol, 1.0 eq) and 13-2 (403 mg, 3.1 mmol, 3.0 eq) in EtOH (8 ml) in a sealed tube. The reaction was stirred at 125 °C overnight. Removal of the solvent under vacuum and purification by flash column chromatography (25 g, 0-25% MeOH in DCM, 1% Et3N) provided 13-3 as a yellow solid (365 mg, used as crude).

Step 2. Preparation of N-(7-{[({[(2R)-l-(6-amino-9H-purin-9-yl)propan-2- yl]oxy}methyl)({[(propan-2-yloxy)carbonyl]oxy}methoxy)phosphoryl]amino}heptyl)-7- chloroquinolin-4-amine (Compound 13)

[0228] Bop (884 mg, 2.0 mmol, 2.0 eq) was added to a stirring solution of 13-3 (290 mg, 1.0 mmol, 1.0 eq) and 13-4 (524 mg, 1.3 mmol, 1.3 eq) in DCM (15 ml), followed by DIPEA (387 mg, 3.0 mmol, 3.0 eq). The reaction was stirred at 50 °C for 5 h. Then the solution was poured into water and extracted with EtOAc. The extract was washed by brine, dried over NaiSCri, concentrated, and purified by flash column chromatography (25 g, 0-15% MeOH in DCM, 254 nm, 214 nm) to provide Compound 13 as a yellow oil (27 mg, 4% yield).

[0229] Compound 13: ¾NMR (CDsOD-de, 600 MHz) 51.19-1.45 (m, 27H), 1.74 (s, 2H), 2.77-2.82 (m, 2H), 3.39-3.42 (t, 2H, J = 16.8 Hz), 3.61-3.66 (m, 1H), 3.84-3.87 (m, 1H), 3.88- 3.97 (m, 1H), 4.18-4.22 (m, 1H), 4.33-4.36 (m, 1H), 5.48-5.52 (m, 2H), 6.58-6.59 (m, 1H), 7.44- 7.45 (m, 1H), 7.82 (s, 1H), 8.14-8.16 (m, 2H), 8.20 (s, 1H), 8.36-8.37 (d,lH, J = 6 Hz). MS (ESI) calcd for [M+H]⁺ (m/z): 676.27, found: 676.27.

Example 14. Preparation of N-(7-{[({[(2/?)-l-(6-amino-9//-purin-9-yl)propan-2- yl]oxy}methyl)({[(propan-2-yloxy)carbonyl]oxy}methoxy)phosphoryl]amino}heptyl)-6- chloro-2-methoxyacridin-9-amine (Compound 14)

Step 1. Preparation of A^l-(6-chloro-2-methoxyacridin-9-yl)heptane-l, 7-diamine (14-3)

[0230] A mixture of 14-1 (278 mg, 1.0 mmol, 1.0 eq), 14-2 (390 mg, 3.0 mmol, 3.0 eq) and DIPEA (388 mg, 3 mmol, 3.0 eq) in EtOH (5 mL) was stirred in a sealed tube at 120 °C overnight. Concentration and purification by flash column chromatography (40 g, 0-100%

MeOH in DCM, 254 nm, 280 nm) provided 14-3 as a yellow solid (160 mg, 43% yield).

Step 2. Preparation of N-(7-{[({[(2/?)-l-(6-amino-9 -purin-9-yl)propan-2- yl]oxy}methyl)({[(propan-2-yloxy)carbonyl]oxy}methoxy)phosphoryl]amino}heptyl)-6- chloro-2-methoxyacridin-9-amine (Compound 14)

[0231] SOCh (180 mg, 1.505 mmol, 7.0 eq) was added to a stirring solution of 14-4 (130 mg, 0.323 mmol, 1.5 eq) in ACN (2 mL), and stirred at 80 °C for 1 h. Removal of the solvent under N2 atmosphere provided a colorless oil, which was added to a solution of 14-3 (80 mg, 0.215 mmol, 1.0 eq) and DIPEA (170 mg, 1.29 mmol, 6.0 eq) in ACN (4 ml) under ice-salt bath under N2 atmosphere. Then the mixture was stirred at room temperature 1 h. Removal of the solvent and purification by flash column chromatography (10 g, 0-15% MeOH in DCM, 254 nm, 280 nm) to afford Compound 14 as a yellow solid (17 mg, 10% yield).

[0232] Compound 14: ¾ NMR (CD3OD, 400 MHz) d 0.78-0.88 (m, 1H), 1.18-1.45 (m, 17H), 1.96-1.99 (m, 2H), 2.77-2.79 (m, 2H), 3.19- 3.21 (m, 1H), 3.61-3.75 (m, 2H), 3.84- 4.00 (m, 2H), 4.00 (s, 3H), 4.31-4.32 (m, 1H), 4.82-4.87 (m, 1H), 5.47-5.53 (m, 2H), 7.49 (d, 1H, J= 2.0 Hz), 7.67 (d, 1H, J= 2.8 Hz), 7.73-7.83 (m, 3H), 8.14 (d, 2H, J= 14.4 Hz), 8.46 (d, 1H, J= 9.2 Hz). MS (ESI) calcd for [M+H]⁺ (m/z): 757.22, found: 757.2.

Example 15. Preparation of A-(10-{[({[(2/?)-l-(6-amino-9//-purin-9-yl)propan-2- yl]oxy}methyl)({[(propan-2-yloxy)carbonyl]oxy}methoxy)phosphoryl]amino}decyl)-6- chloro-2-methoxyacridin-9-amine (Compound 15)

Step 1. Preparation of A⁴-(6-chloro-2-methoxyacridin-9-yl)decane-l, 10-diamine (15-3)

[0233] A mixture of 15-1 (556 mg, 2.0 mmol, 1.0 eq), 15-2 (1035 mg, 6.0 mmol, 3.0 eq) and DIPEA (775 mg, 6 mmol, 3.0 eq) in EtOH (10 mL) was stirred in a sealed tube at 120 °C overnight. Concentration and purification by flash column chromatography (40 g, 0-100% MeOH in DCM, 254 nm, 280 nm) provided 15-3 as a yellow solid (620 mg, 75% yield).

Step 2. Preparation of A-(10-{[({[(2/?)-l-(6-amino-9//-purin-9-yl)propan-2- yl]oxy}methyl)({[(propan-2-yloxy)carbonyl]oxy}methoxy)phosphoryl]amino}decyl)-6- chloro-2-methoxyacridin-9-amine (Compound 15)

[0234] SOCh (240 mg, 2.023 mmol, 7.0 eq) was added to a stirring solution of 15-4 (175 mg, 0.435 mmol, 1.5 eq) in ACN (4 ml), and stirred at 80 °C for 1 h. Removal of the solvent under N2 atmosphere provided a colorless oil, which was added to a solution of 15-3 (120 mg, 0.289 mmol, 1.0 eq) and DIPEA (225 mg, 1.73 mmol, 6.0 eq) in ACN (4 ml) under ice-salt bath and N2 atmosphere. The mixture was stirred at room temperature 1 h. Removal of the solvent and purification by flash column chromatography (10 g, 0-15% MeOH in DCM, 254 nm, 280 nm) to provide Compound 15 as a yellow solid (35 mg, 15% yield).

[0235] Compound 15: ¹HNMR (CD₃OD, 600 MHz) d 1.20-1.46 (m, 32H), 1.95-1.99 (m, 2H), 2.78-2.81 (m, 2H), 3.20-3.25 (m, 1H), 3.62-3.68 (m, 1H), 3.84-3.97 (m, 2H), 4.00 (s, 3H), 4.12- 4.20 (m, 2H), 4.21- 4.24 (m, 1H), 4.34-4.38 (m, 1H), 4.85-4.87 (m, 1H), 5.51-5.56 (m, 2H), 7.49 (d, 1H, J= 2.4 Hz), 7.67 (d, 1H, J= 4.2 Hz), 7.76 (d, 2H, J= 9.0 Hz), 7.78 (d, 2H, J= 19.2 Hz), 8.14 (d, 2H, J= 21.6 Hz), 8.46 (d, 1H, J= 13.8 Hz). MS (ESI) calcd for [M+H]⁺ (m/z): 799.31, found: 799.3.

Example 16. Preparation of 9-((5-(diethylamino)pentan-2-yl)amino)acridin-4-yl hydrogen ((((R)-l-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (Compound 16)

Step 1. Preparation of 9-chloro-4-methoxyacridine (16-2)

[0236] To a mixture of 2-chlorobenzoic acid (3 g, 14.9 mmol) and 2-methoxyaniline (2.29 mL, 15.6 mmol) was added potassium carbonate (2.06g, 14.9mmol), copper(I) oxide (85mg, 0.596 mmol) and copper power (83mg, 1.31 mmol) in 2-ethoxy ethanol under N2 atmosphere. The mixture was stirred for reflux overnight. Then the reaction was cooled to room temperature, and 1M HC1 was added drop wise to the mixture. The resulting precipitate was collected, washed with 1M HC1 and water, and dried in vacuum to obtain 16-1 (2.8 g, 62% yield) as a yellow solid. 16-1 as solid was added to POCb (20 mL), then stirred at 110°C for 3 hours. The mixture was concentrated in vacuum, poured into 200 mL of ice-water, and then filtered. The filter cake was washed with water (200ml x 2) and DCM (30ml x 2), dried in vacuum to afford 9-chloro-4- methoxyacridine (16-2, 2.5g, 83% yield) as a yellow solid. LCMS: (ESI) m/z 244 [M+l]⁺.

Step 2. Preparation of N^NEdiethyl-Nb^-methoxyacridin^-y^pentane-l, 4-diamine (16-3)

[0237] To a mixture of 9-chloro-4-methoxyacridine (16-2, 2.5 g, 10.2 mmol) and phenol (1.93 g, 20.4mmol) was added N^;,N^;-diethylpentane- 1,4-diamine (1.6g, 10.2 mmol) and then stirred at 120 °C for 6 hours. To the reaction mixture was added NaOH (aq. IN, 180 mL) and then extracted with EA (100 ml x 3). The organic layer was combined, washed with saturated brine (200 mL), dried over anhyrous Na2SC>4, concentrated in vacuum, and purified by silica gel column chromatography (10% MeOH in DCM) to afford N^;,N^;-diethyl-N -(4-methoxyacridin-9- yl)pentane- 1,4-diamine (16-3, 2.4 g, 64% yield) as an orange solid. LCMS: (ESI) m/z 183 [M/2+1 ]⁺, 366 [M+l]⁺.

Step 3. Preparation of 9-((5-(diethylamino)pentan-2-yl)amino)acridin-4-ol (16-4)

[0238] To a solution of 16-3 (830 mg.2.2mmol) in CH2CI2 (50 ml) was added BBn (1 4g, 8mmol) at 0 °C and stirred for lh. Removal of BBn was by reduced pressure to afford 9-((5- (diethylamino)pentan-2-yl)amino)acridin-4-ol (16-4, 640mg, 59% yield) as an orange solid. LCMS: (ESI) m/z 176 [M/2+1 ]⁺, 352 [M+l]⁺.

Step 4. Preparation of 9-((5-(diethylamino)pentan-2-yl)amino)acridin-4-yl hydrogen ((((R)- l-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (Compound 16)

[0239] To a solution of 9-((5-(diethylamino)pentan-2-yl)amino)acridin-4-ol (16-4, 400 mg, 1.1 mmol) in NMP (20 mL) was added (R)-(((l-(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)phosphonic acid (475 mg, 1.65 mmol) and EDCI (1.2g, 6.6mmol). The mixture was stirred at room temperature for 3 hours and then concentrated in vacuum and purified by silica gel column chromatography (10% MeOH in DCM) to afford 9-((5-(diethylamino)pentan- 2-yl)amino)acridin-4-yl hydrogen ((((R)- 1 -(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)phosphonate (Compound 16, 22 mg, 12% yield) as a yellow oil. LCMS: (ESI) m/z 311 [M/2+1 ]⁺; 621[M+1]⁺.

Example 17. Preparation of ((2/?,3A,4/?,5/?)-5-(4-aminopyrrolo[2,l-/|[l₅2,4]triazin-7-yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl phenyl (10-((7-chloroquinolin-4- yl)amino)decyl)phosphoramidate (Compound 17)

overnight, Sealed tube, rt yield:79% N₂, 1.0 h

17-1

Step 1. Preparation of A4-(7-chloroquinolin-4-yl)decane-l, 10-diamine (17-2)

[0240] A mixture of 4,7-dichloroquinoline (1.57 g, 7.93 mmol, 1.0 eq), decane- 1,10-diamine (4.1 g, 23.8 mmol, 3.0 eq) and DIPEA (3.07 g, 23.8 mmol, 3.0 eq) in EtOH (20 mL) was stirred at 125°C (oil bath) for 20 h in a sealed tube (a clear yellow solution). After cooling to rt, a yellow solid was formed, which was filtrated off (mostly the un-reacted decane- 1,10-diamine and DIEA-HC1 salt). The filtrate was concentrated and the resulting residue was purified by flash column chromatography (A: DCM; B: 5% NH40H in MeOH, 0-80% B in A) to provide 17-2 as yellow solid (2.1 g, 79% yield).

Step 2. Preparation of 4-nitrophenyl phenyl (10-((7-chloroquinolin-4-yl)amino)decyl) phosphoramidate (17-3)

[0241] A white suspension of 17-2 (884 mg, 2.65 mmol, 1.0 eq) in DCM (15 mL) was cooled under ice-water bath and charged with N2 3 times. Phenyl phosphorodichloridate (560 mg, 2.65 mmol, 1.0 eq) in DCM (0.5 mL) was added, followed by addition of DIEA (342 mg, 2.65 mmol, 1.0 eq) in DCM (1.0 mL) dropwise over 5 min. After stirring with cooling bath for 0.5 h and warming to rt for an additional 0.5 h, the mixture was re-cooled under an ice-water bath, and 4- nitrophenol (368 mg, 2.65 mmol, 1.0 eq) added portion wise, followed by DIEA (342 mg, 2.65 mmol, 1.0 eq). The mixture was stirred and gently warmed to rt overnight. Removal of the solvent under vacuum and purification of the resulting residue by flash column chromatography (MeOH in DCM, 0.1% to 100%) provided crude 17-3 (about 70% of the 17-3 and 25% of a byproduct) as a yellow solid (1.6 g), which was used to next step without further purification.

Step 3. Preparation of ((2/?,3A,4/?,5/?)-5-(4-aminopyrrolo[2,l-/Hl₉2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxytetrahydrofuran-2-yl)methyl phenyl (10-((7-chloroquinolin-4- yl)amino)decyl)phosphoramidate (Compound 17)

[0242] To a yellow solution of 17-3 (100 mg, 0.16 mmol, 1.0 eq) and 17-4 (46 mg, 0.16 mmol, 1.0 eq) in DMF/ACN(1/1, 4 mL) was added MgCh (54 mg, 0.58 mmol, 3.6 eq) and DIPEA (82 mg, 0.64 mmol, 4.0 eq). The reaction mixture was heated to 50 °C (oil bath) for 5 h. The mixture was filtered and concentrated. The resulting residue was purified by flash column chromatography and eluted with MeOH(4% MEOH) in DCM (0-80%) to provide Compound 17 as a yellow solid (48 mg, yield 16%, two batches, two steps).

[0243] Compound 17: ¾NMR (CD3OD, 600MHz) d 1.17-1.41 (m, 14H), 1.73 (bs, 2H), 2.81- 2.87 (m, 2H), 3.46 (bs, 2H), 4.2 (bs, 1H), 4.6-4.28 (m, 1H), 4.39 (bs, 2H), 4.80 (dd, 1H, J= 4.8, 15.6 Hz), 6.69 (d,

6.0 Hz), 6.85-6.90 (m, 2H), 7.12-7.31 (m, 3H), 7.26-7.31 (m, 2H),

7.54 (d, 1H, J= 8.4 Hz), 7.80-7.84 (m, 2H), 8.25 (d, 1H, J= 9.0 Hz), 8.33 (d, 1H, J= 6.0 Hz). MS (ESI) calcd for [M+H]⁺ (m/z): 763.2, found: 763.3. Example 18. Preparation of ((((((R)-l-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((4- ((7-chloroquinolin-4-yl)amino)butyl)amino)phosphoryl)oxy)methyl isopropyl carbonate (Compound 18)

Step 1. Preparation of tert-butyl (4-((7-chloroquinolin-4-yl)amino)butyl)carbamate (18-3)

[0244] A stirring solution of 18-1 (1.18 g, 6.0 mmol, 1.0 eq) in phenol (5.64 g, 60 mmol, 10.0 eq) was heated to 105 °C for 3 h. 18-2 (403 mg, 3.1 mmol, 3.0 eq) was added, and the reaction was stirred at 105 °C overnight. Then the mixture was purified by flash column chromatography (50 g, 0-40% MeOH in DCM, 1% Et3N, 254 nm) to provide 18-3 as a yellow solid (2.10 g, used as crude).

Step 2. Preparation of A¹-(7-chloroquinolin-4-yl)butane-l, 4-diamine (18-4)

[0245] HCl/MeOH (3 mL, 12 mmol/mL) was added to a stirring solution of 18-3 (332 mg, 0.95 mmol, 1.0 eq) in MeOH (3 ml) under ice-water bath and then stirred at 20 °C overnight.

Removal of the solvent provided 18-4 as a red solid (280 mg, used as crude). Step 3. Preparation of ((((((R)-l-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((4-((7- chloroquinolin-4-yl)amino)butyl)amino)phosphoryl)oxy)methyl isopropyl carbonate (Compound 18)

[0246] SOCh (900 mg, 7.5 mmol, 5.0 eq) was added to a stirring solution of 18-5 (604 mg, 1.5 mmol, 1.5 eq) in ACN (15 ml) and stirred at room temperature for 2 h. 18-4 (280 mg, 0.95 mmol, 1.0 eq) was added, followed by DIPEA (1935 mg, 15.0 mmol, 15.0 eq) under ice-salt bath. The reaction was stirred at room temperature for 1 h. Removal of the solvent and purification by flash column chromatography (25 g, 0-10% MeOH in DCM, 254 nm, 214 nm) provided Compound 18 as a yellow solid (256 mg, 42% yield).

[0247] Compound 18: ¾NMR (CDsOD- e, 400 MHz) 51.17-1.18 (d,3H, J= 6 Hz), 1.22-1.25 (m, 9H), 1.53-1.58 (m, 2H), 1.73-1.78 (m, 2H), 2.87-2.91 (m, 2H), 3.43-3.47 (m, 2H), 3.62-3.68 (m, 1H), 3.83-3.95 (m, 2H), 4.15-4.2 (m, 1H), 4.30-4.35 (m, 1H), 4.80-4.85 (m, 1H), 5.45-5.55 (m, 2H), 6.66-6.68 (m, 1H), 7.48-7.50 (m, 1H), 7.78 (s, 1H), 8.12-8.13 (d, 1H, J= 4.8 Hz), 8.18- 8.22 (m, 2H), 8.34-8.35 (d, 1H, J= 4.8 Hz). MS (ESI) calcd for [M+H]⁺ (m/z): 635.3, found: 635.3.

Example 19. Preparation of ((((((R)-l-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((4- ((6-chloro-2-methoxyacridin-9-yl)amino)butyl)amino)phosphoryl)oxy)methyl isopropyl carbonate (Compound 19)

Step 1. Preparation of tert-butyl (4-((6-chloro-2-methoxyacridin-9-yl)amino)butyl) carbamate (19-3)

[0248] A mixture of 19-1 (447 mg, 1.71 mmol, 1.0 eq) and phenol (2 g, 21.3 mmol, 12.0 eq) was heated to 105 °C for 0.5 h. Then 19-2 (355 mg, 1.89 mmol, 1.2 eq) was added and stirred at 105 °C overnight. The reaction mixture was then purified by flash column chromatography (50 g, 0-10% MeOH in DCM, 254 nm) to provide 19-3 as a yellow solid (630 mg, 86% yield).

Step 2. Preparation of A¹-(6-chloro-2-methoxyacridin-9-yl)butane-l, 4-diamine (19-4)

[0249] HCl/MeOH (2 mL, 12 mmol/mL) was added to a stirring solution of 19-3 (250 mg, 0.57 mmol, 1.0 eq) in MeOH (2 ml) under ice-water bath. The reaction was then stirred at 20 °C overnight. Removal of solvent provided 19-4 as a red solid (229 mg, used as crude).

Step 3. Preparation of ((((((R)-l-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((4-((6- chloro-2-methoxyacridin-9-yl)amino)butyl)amino)phosphoryl)oxy)methyl isopropyl carbonate (Compound 19)

[0250] SOCh (400 mg, 3.36 mmol, 6.7 eq) was added to a stirring solution of 19-5 (210 mg, 0.5 mmol, 1.1 eq) in ACN (8 ml) and stirred at room temperature for 2 h. 19-4 (200 mg, 0.47 mmol, 1.0 eq) was added, followed by DIPEA (967 mg, 7.5 mmol, 15.0 eq) under ice-salt bath. Then the reaction was stirred at room temperature for 1 h. Removal of the solvent and purification by flash column (25 g, 0-10% MeOH in DCM, 254 nm, 214 nm) to obtain Compound 19 as a yellow solid (86 mg, 24% yield).

[0251] Compound 19: ¾ NMR (CDsOD- e, 400 MHz) 51.15-1.17 (d,3H, J= 6.4 Hz), 1.20- 1.25 (m, 9H), 1.57-1.59 (m, 2H), 1.97-1.98 (m, 2H), 2.88-2.93 (m, 2H), 3.61-3.65 (m, 1H), 3.83- 3.96 (m, 2H), 3.99 (s, 3H) 4.06-4.18 (m, 5H), 4.28-4.33 (m, 1H), 4.79-4.82 (m, 1H), 5.45-5.51 (m, 2H), 7.48 (s, 1H), 7.64 (s, 1H), 7.72-7.78 (m, 3H), 8.10-8.13 (m, 2H), 8.43-8.46 (d, 1H, J = 9.2 Hz). MS (ESI) calcd for [M+H]⁺ (m/z): 715.3, found: 715.3.

Example 20. Preparation of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,l-i][l₉2,4]triazin-7-yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl hydrogen (10-((6-chloro-2- methoxyacridin-9-yl)amino)decyl)phosphoramidate (Compound 20)

Step 1. Preparation of A^l-(6-chloro-2-methoxyacridin-9-yl)decane-l, 10-diamine (20-3)

[0252] To solution of 20-1 (500 mg, 1.8 mmol, 1.0 eq) and 20-2 (930 mg, 5.4 mmol, 3.0 eq) in EtOH (10 mL) was added DIPEA (698 mg, 5.4 mmol, 3.0 eq) in a sealed tube. The mixture was stirred at 125 °C for 12 hours. After the completion of the reaction as identified by LCMS, the reaction mixture was quenched by water and extracted with EA (10 mL><3). The EA layer was washed with brine (10 mL><3), dried over NaiSCE and concentrated to give a crude product as yellow oil. The crude product was purified by Pre-HPLC (Cl 8, A = 0.1% TFA in water, B = 0.1% TFA in CFECN, 10%- 90% B in A) to give the TFA salt product as a white solid. Then the TFA salt was diluted by MeOH (5 mL) and HC1 (6N aq, 7 mL), the mixture was stirred at rt for 0.5h. The mixture was then concentrated under vacuum to remove the MeOH, then freeze dried to give the HC1 salt of 20-3 as a yellow solid (450 mg, 2 HC1 salt, 60 % yield).

Step 2. Preparation of 4-nitrophenyl phenyl (10-((6-chloro-2-methoxyacridin-9- yl)amino)decyl)phosphoramidate (20-6)

[0253] To a solution of 20-3 (220 mg, 0.53 mmol, 1.0 eq), 20-4 (112 mg, 0.53 mmol, 1.0 eq ) in DCM (4 mL) was added DIPEA (205 mg, 1.6 mmol, 3.0 eq) under ice-salt bath. Then the reaction was stirred at 0 °C under N2 for 1 hours. 20-5 (66 mg, 0.48 mmol, 0.9 eq ) and DIPEA (68 mg, 0.53 mmol, 1.0 eq ) were added then stirred at room temperature under N2 for 2 hours. After the completion of the reaction as identified by LCMS, the mixture was concentrated and purified by flash column (DCM: MeOH = 10 : 1) to provide 20-6 as a yellow oil (320 mg, 87% yield).

Step 3. Preparation of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,l-f][l,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxytetrahydrofuran-2-yl)methyl phenyl (10-((6-chloro-2-methoxyacridin-9- yl)amino)decyl)phosphoramidate (20-8)

[0254] To solution of 20-6 (320 mg, 0.48 mmol, 1.0 eq ) and 20-7(136 mg, 0.48 mmol, 1.0 eq ) in DMF (5 mL) were added DIPEA (248 mg, 1.92 mmol, 4.0 eq) and MgCh (164 mg, 1.73 mmol, 3.6 eq) at room temperature. The reaction was then stirred at 55 °C under N2 for 3 hours. After the completion of the reaction as identified by LCMS, the mixture was concentrated and purified by flash column chromatography (DCM: MeOH = 10 : 1) to provide 20-8 as a yellow solid (120 mg, 30 % yield).

Step 4. Preparation of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,l-f][l,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxytetrahydrofuran-2-yl)methyl hydrogen (10-((6-chloro-2-methoxyacridin-9- yl)amino)decyl)phosphoramidate (Compound 20)

[0255] To solution of 20-8 (120 mg, 0.14 mmol, 1.0 eq) in THF (1 mL) was added NaOH (12 mg, 0.28 mmol, 2.0 eq) in water (1 mL) at room temperature. The mixture was stirred at room temperature for 12 hours. After the completion of the reaction as identified by LCMS, the reaction mixture was purified by pre-HPLC (Cl 8, A = water, B = CTLCN, 10% - 90% B in A) and freeze dried to provide Compound 20 as a yellow solid (Na salt; 32 mg, 30 % yield).

[0256] Compound 20: ¾NMR (DMSO, 400 MHz) d 1.14 - 1.28 (m, 14H), 1.70 - 1.74 (m, 2H), 2.57 - 2.62 (m, 2H), 3.77 - 3.78 (m, 4H). 3.96 (s, 3H), 4.07 (s, 1H), 4.14-4.16(m,lH), 4.62 - 4.64 (m, 1H), 6.47 (s, 1H), 6.84 -6.86 (m, 3H), 7.04 (s, 1H), 7.34 (d, 1H, J = 8.4 Hz), 7.44 (d,

1H, J = 8.4 Hz), 7.67 (s, 1H), 7.85 -7.94 (m, 5H), 8.37 (d, 1H, J = 8.4 Hz). MS (ESI) calcd for [M+H]⁺ (m/z): 767.21, found: 767.3

Example 21. Preparation of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,l-f][C2,4]triazin-7-yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl hydrogen (10-((7-chloroquinolin-4- yl)amino)decyl)phosphoramidate (Compound 21)

Step 1. Preparation of A¹-(7-chloroquinolin-4-yl)decane-l, 10-diamine (21-3)

[0257] To solution of 21-1 (800 mg, 4.04 mmol, 1.0 eq) and 21-2 (2.09 g, 12.12 mmol, 3.0 eq) in EtOH (15 mL) was added DIPEA (1.57 g, 12.12 mmol, 3.0 eq) in a sealed tube. The mixture was stirred at 125 °C for 12 hours. After cooling to rt, the solid was collected by filtration. The solid was dissolved in MeOH and 6N HC1 aq. After stirring at rt for 0.5h the solution was then concentrated and freeze dried to give 21-3 as 2HC1 salt (460 mg, 35 % yield, yellow solid).

Step 2. Preparation of 4-nitrophenyl phenyl (10-((7-chloroquinolin-4-yl)amino)decyl) phosphoramidate (21-6)

[0258] To solution of 21-3 (460 mg, 1.38 mmol, 1.0 eq ), 21-4 (290 mg, 1.38 mmol, 1.0 eq ) in DCM (10 mL) was added DIPEA (534 mg, 4.14 mmol, 3.0 eq) at ice-salt bath. The reaction was then stirred at 0 °C under N2 for 1 hour. After then 21-5 (172 mg, 1.24 mmol, 0.9 eq ) and DIPEA (178 mg, 1.38 mmol, 1.0 eq ) were added and the reaction was stirred at room temperature under N2 for 2 hours. After the completion of the reaction as identified by LCMS, the mixture was concentrated and purified by flash column chromatography (DCM: MeOH = 10 : 1) to provide 21-6 as a yellow oil (300 mg, 36 % yield).

Step 3. Preparation of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,l-f][l,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxytetrahydrofuran-2-yl)methyl phenyl (10-((7-chloroquinolin-4- yl)amino)decyl)phosphoramidate (21-8)

[0259] To solution of 21-6 (300 mg, 0.49 mmol, 1.0 eq) and 21-7 (143 mg, 0.49 mmol, 1.0 eq) in DMF (5 mL) were added DIPEA (253 mg, 1.96 mmol, 4.0 eq) and MgCh (168 mg, 1.76 mmol, 3.6 eq) at room temperature. The reaction was then stirred at 55 °C under N2 for 3 hours. After the completion of the reaction as identified by LCMS, the mixture was concentrated and purified by flash column chromatography (DCM: MeOH = 10 : 1) to provide 21-8 as a yellow solid (180 mg, 48 % yield).

Step 4. Preparation of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,l-f][l,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxytetrahydrofuran-2-yl)methyl hydrogen (10-((7-chloroquinolin-4- yl)amino)decyl)phosphoramidate (Compound 21)

[0260] To solution of 21-8 (180 mg, 0.24 mmol, 1.0 eq) in THF (1.5 mL) was added NaOH (19 mg, 0.48 mmol, 2.0 eq) in water (1.5 mL) at room temperature. The mixture was stirred at room temperature for 12 hours. After the completion of the reaction as identified by LCMS, the reaction mixture was purified by pre-HPLC (Cl 8, A = water, B = CH3CN, 10% - 90% B in A) to provide Compound 21 as a yellow solid (Na salt, 55 mg, 34 % yield).

[0261] Compound 21: ¹HNMR (DMSO, 400 MHz) d 1.18 - 1.38 (m, 14H), 1.65 - 1.69 (m, 3H), 2.53 - 2.63 (m, 2H), 3.24 - 3.29 (m, 2H). 3.79 (t, 2H, J = 7.2 Hz), 4.07 - 4.10 (m,lH), 4.15 - 4.17 (m,lH), 4.65 (s, 1H), 6.46 - 6.48 (m,lH), 6.57 (s, 1H), 6.78 - 6.94 (m, 2H), 7.43 - 7.46 (m,2H), 7.79 -8.02 (m, 4H), 8.34 - 8.41 (m,2H). MS (ESI) calcd for [M+H]⁺ (m/z): 687.25, found: 687.3. Example 22. Preparation of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,l-f][l₉2,4]triazin-7-yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylhydrogen(10-((7-chloro-2- methoxybenzo[b][l,5]naphthyridin-10-yl)amino)decyl)phosphoramidate (Compound 22)

Step 1. Preparation of A^-(7-chloro-2-methoxybenzo[b][l,5]naphthyridin-10-yl)decane- 1, 10-diamine (22-3)

[0262] To solution of 22-1 (580 mg, 2.08 mmol, 1.0 eq) and 22-2 (1076 mg, 6.25 mmol, 3.0 eq) in EtOH (30 mL) was added DIPEA (806 mg, 5.25 mmol, 3.0 eq) in a sealed tube. The mixture was stirred at 125 °C for 12 hours. After the completion of the reaction as identified by LCMS, the mixture was concentrated and purified by flash column chromatography (0-100% MeOH in DCM, 254 nm) to afford 22-3 as a yellow oil (663 mg, 77 % yield). Step 2. Preparation of 4-nitrophenyl phenyl (10-((7-chloro-2- methoxybenzo[b][l,5]naphthyridin-10-yl)amino)decyl)phosphoramidate (22-7)

[0263] To solution of 22-3 (579 mg, 1.4 mmol, 1.0 eq) and 22-4 (294 mg, 1.4 mmol, 1.0 eq) in DCM (15 mL) was added DIPEA (180 mg, 1.4 mmol, 1.0 eq) at ice-salt bath. The reaction was then stirred at 0 °C under N2 for 1 hours. After then, 22-6 (195 mg, 1.4 mmol, 1.0 eq) and DIPEA (180 mg, 1.4 mmol, 1.0 eq) were added and the reaction was then stirred at room temperature under N2 for 4 hours. After the completion of the reaction as identified by LCMS, the mixture was concentrated and purified by flash column chromatography (0-10% MeOH in DCM, 254 nm) to give 22-7 as a yellow oil (538 mg, 56 % yield).

Step 3. Preparation of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,l-f][l,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxytetrahydrofuran-2-yl)methyl phenyl (10-((7-chloro-2- methoxybenzo[b][l,5]naphthyridin-10-yl)amino)decyl)phosphoramidate (22-9)

[0264] To a solution of 22-7 (380 mg, 0.55 mmol, 1.0 eq) and 22-8 (160 mg, 0.55 mmol, 1.0 eq) in DMF (10 mL) were added DIPEA (284 mg, 2.2 mmol, 4.0 eq) and MgCh (188 mg, 1.98 mmol, 3.6 eq) at room temperature. Then the reaction was stirred at 55 °C under N2 for 13 hours. After the completion of the reaction identified by LCMS, the mixture was concentrated and purified by flash column chromatography (0-50% MeOH in DCM, 254 nm) to provide 854 mg of crude product. The crude produce was dissolved in ACN/ MeOH and then crystallized to provide 22-9 as a yellow solid (433 mg, 80% yield).

Step 4. Preparation ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,l-f][l,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxytetrahydrofuran-2-yl)methyl hydrogen (10-((7-chloro-2- methoxybenzo[b][l,5]naphthyridin-10-yl)amino)decyl)phosphoramidate (Compound 22)

[0265] To solution of 22-9 (284 mg, 0.25 mmol, 1.0 eq) in THF/ACN (5 mL) was added NaOH (1.2 mmol, 4.0 eq) in water (1.0 mL) at room temperature. The reaction was then stirred at room temperature for 12 hours. After the completion of the reaction as identified by LCMS, the reaction mixture was purified by Pre-HPLC (Cl 8, A: water, B: CH3CN, 10% - 90% B in A, 214 nm) and freeze-dried to obtain Compound 22 as a yellow solid (Na salt; 59 mg, 29 % yield). [0266] Compound 22: ¾NMR (DMSO, 400 MHz) d 1.16 - 1.40 (m, 14H), 1.74 - 1.79 (m, 2H), 2.57 - 2.63 (m, 2H), 3.80 - 3.81 (m, 2H), 4.02 (s, 4H), 4.13-4.19 (m, 3H), 4.62 (s, 1H), 6.38 (s, 1H), 6.84 -6.85 (m, 1H), 6.92-6.93 (d, 1H, J= 4.4 Hz), 7.26-7.29 (d, 1H, J= 9.2 Hz), 7.36- 7.38 (m, 1H), 7.64-7.66 (m, 1H), 7.87-7.94 (m, 4H), 8.12-8.14 (d, 1H, J= 9.2 Hz), 8.48-8.50 (d, 1H, J= 9.2 Hz). MS (ESI) calcd for [M+H]⁺ (m/z): 768.4, found: 768.4.

Example 23 - In Vitro Anti-Virus Assay

[0267] The following procedure is based on the procedure as described in Microbiol Immunol. 2014 Mar; 58(3): 180-187.

[0268] The test compounds, such as any one of the compounds disclosed herein, are dissolved in DMSO to obtain stock solutions at 10 or 30 mg/mL. The stock solutions are stored at -20 °C until used. Huh7 cells are seeded in 24-well plates (1.6 ^c 105 cells/well). Viruses, which include HCV, HBV, Coronavirus, and Ebola, are mixed with serial dilutions of the test samples (100, 30, 10, 3 and 1 pg/mL) and are inoculated into the cells. After 2 hr, the cells are washed with the medium to remove residual virus and are further incubated in medium containing the same concentrations of the samples as those during virus inoculation. In time-of-addition experiments, treatment with the samples are performed only during or after virus inoculation in order to assess the mode of action of the samples examined. Culture supernatants are collected 1 and 2 days post-infection and titrated for virus infectivity, as described below. Virus and cells are treated with medium containing 0.1% DMSO served as controls. Percent inhibition of the virus infectivity for each dilution of the samples are calculated by comparison with mock-treated controls and ICso determined.

Virus Titration

[0269] Virus samples are diluted serially 10-fold in complete medium and are inoculated onto Huh7 cells seeded on glass coverslips in a 24-well plate. After virus adsorption for 2 hr, the cells are washed with medium to remove residual virus and are cultured for 24 hr. The virus-infected cells are stained with an indirect immunofluorescence method. In brief, the virus-infected cells are washed with PBS, are fixed with 4% paraformaldehyde for 15 min and are permeabilized with 0.1% Triton X-100 in PBS for 15 min at room temperature. After being washed three times with PBS, the cells are incubated with virus-infected patient's serum for 1 hr, followed by incubation with FITC-conjugated goat anti-human IgG (MBL, Nagoya, Japan). The cells are counterstained with Hoechst 33342 (Molecular Probes, Eugene, OR, USA) for 5 min and virus- infected cells are counted under a BZ-9000 fluorescence microscope (Keyence, Osaka, Japan)

Example 24 - Quantification of drug-induced cytotoxicity

[0270] Cell viability is estimated by the MTT assay, which detects the conversion of MTT to formazan by the mitochondria of living cells. Contemplated cell lines include HepG2 (HCCs), A549 (lung), CFPAC-1 (pancreas), COLO-205 (colon), MCF-7 (breast), PC-3 (prostate), and A- 375 (melanoma). Cells are seeded into 96-well microcultureplates at 10,000 cells per well and are allowed to attach for 24 hours. Cells are then treated with any one of the compounds disclosed herein for 72 hours. Following drug treatment, MTT is added and formazan absorbance was quantified using a Molecular Devices microplate reader. The estimated cell viability under each experimental condition is calculated by normalizing the respective formazan optical density to the density of control cells. Proapoptotic effects following in vitro drug exposure are quantified by propidium iodide (PI) staining and fluorescence-activated cell sorting (FACS) analysis of sub-Go/Gi DNA content and by measurement of active caspase-3 by flow cytometry using a commercial kit (BD Biosciences).

[0271] The above experiments will show that the compounds disclosed herein have potent antiviral infection activity and/or potent anticancer activity.

[0272] While certain embodiments have been illustrated and described, it should be understood that changes and modifications can be made therein in accordance with ordinary skill in the art without departing from the technology in its broader aspects as defined in the following claims.

[0273] The embodiments, illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising,” “including,” “containing,” etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed technology. Additionally, the phrase “consisting essentially of’ will be understood to include those elements specifically recited and those additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase “consisting of’ excludes any element not specified.

[0274] The present disclosure is not to be limited in terms of the particular embodiments described in this application. Many modifications and variations can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and compositions within the scope of the disclosure, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. The present disclosure is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled. It is to be understood that this disclosure is not limited to particular methods, reagents, compounds, or compositions, which can of course vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0275] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0276] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like, include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member.

[0277] All publications, patent applications, issued patents, and other documents referred to in this specification are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure.

[0278] Other embodiments are set forth in the following claims.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (I), or an enantiomer, a enantiomeric mixture, a diastereomer, a diasteromeric mixture, or a pharmaceutically acceptable salt thereof:

O

A-C— P— R-i

¾ (I), wherein

A is unsubstituted or substituted nucleoside or unsubstituted or substituted nucleoside analogue, unsubstituted or substituted nucleotide or unsubstituted or substituted nucleotide analogue;

where * is point of attachment for A;

R is hydrogen, halo, CN, unsubstituted or substituted Ci-Cio alkyl, unsubstituted or substituted Ci-Cio haloalkyl, or unsubstituted or substituted Ci-Cio alkyl ether; Xi is O, S, NH, CH₂;

X₂ is O, S, NH, CH₂;

YI and Y₂ are each independently OH, H, halo, CN, CF3, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C3-C1₀ cycloalkyl, unsubstituted or substituted C1-C10 acyl, unsubstituted or substituted C1-C10 carboxyl ester, unsubstituted or substituted C1-C10 alkyl ketone, or unsubstituted or substituted C1-C10 alkyl ether;

Ri is NH-X_3-X4, O-X_3-X4, or G₂;

X₃ is unsubstituted or substituted Ci-C₂o alkylene, unsubstituted or substituted Ci- C₂o alkenylene, unsubstituted or substituted C₃-C₂o cycloalkylene, unsubstituted or substituted Ci-C₂o heterocyclylene, unsubstituted or substituted Ci-C₂o acyl, unsubstituted or substituted Ci-C₂o carboxy ester, unsubstituted or substituted C₂- C2₀ alkyl ketone, unsubstituted or substituted C2-C2₀ alkyl ether, or unsubstituted or substituted C1-C2₀ alkyl amine;

R2 is Ri, OH, O-Xs, G2, O-X9-G1, or G₃; or

X5 is unsubstituted or substituted C1-C2₀ alkylene;

Xe is absent or unsubstituted or substituted arylene;

Giis

2 ;

Its, R4, and R5 are each independently OH, H, halo, CN, CF3, NO2, unsubstituted or substituted C1-C1₀ alkyl, unsubstituted or substituted C₃-C1₀ cycloalkyl, unsubstituted or substituted C1-C1₀ acyl, unsubstituted or substituted C1-C1₀ carboxyl ester, unsubstituted or substituted C1-C1₀ alkyl ketone, or unsubstituted or substituted C1-C1₀ alkyl ether; or

M2 and M₃ are each independently unsubstituted or substituted C1-C1₀ alkyl, unsubstituted or substituted C₃-C1₀ cycloalkyl, unsubstituted or substituted C1-C1₀ acyl, unsubstituted or substituted C1-C1₀ carboxyl ester, unsubstituted or substituted C1-C1₀ alkyl ketone, unsubstituted or substituted C1-C1₀ alkyl ether; or M2 and M₃ are taken together with the N atom to which they are attached to form a unsubstituted or substituted C5-C1₀ cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, or unsubstituted or substituted C1-C1₀ heterocyclyl;

B is unsubstituted or substituted Cr_> cycloalkyl; and

Re and R7 are each independently OH, H, halo, CN, CF3, NO2, unsubstituted or substituted C1-C1₀ alkyl, unsubstituted or substituted C₃-C1₀ cycloalkyl, unsubstituted or substituted C1-C1₀ acyl, unsubstituted or substituted C1-C1₀ carboxyl ester, unsubstituted or substituted C1-C1₀ alkyl ketone, or unsubstituted or substituted C1-C1₀ alkyl ether.

2. The compound of claim 1, or an enantiomer, an enantiomeric mixture, a diastereomer, a diasteromeric mixture, or a pharmaceutically acceptable salt thereof, wherein X is

3. The compound of claim 2, or an enantiomer, an enantiomeric mixture, a diastereomer, a diasteromeric mixture, or a pharmaceutically acceptable salt thereof, wherein R is any one of the following:

(a) hydrogen;

(b) unsubstituted or substituted C1-C1₀ alkyl;

(c) unsubstituted or substituted C1-C1₀ haloalkyl; and

(d) unsubstituted or substituted C1-C1₀ alkyl ether.

4. The compound of claim 1, or an enantiomer, an enantiomeric mixture, a diastereomer, a diasteromeric mixture, or a pharmaceutically acceptable salt thereof, wherein X is

5. The compound of claim 4, or an enantiomer, an enantiomeric mixture, a diastereomer, a diasteromeric mixture, or a pharmaceutically acceptable salt thereof, wherein Xi or X2 is any one of the following:

(a) 0;

(b) S; and

(c) NH.

6. The compound of claim 4, or an enantiomer, an enantiomeric mixture, a diastereomer, a diasteromeric mixture, or a pharmaceutically acceptable salt thereof, wherein Yi or Y2 is any one of the following:

(a) OH;

(b) H;

(c) CN;

(d) CF3; and

(e) unsubstituted or substituted C1-C10 alkyl.

7. The compound of any one of claims 1-6, or an enantiomer, an enantiomeric mixture, a diastereomer, a diasteromeric mixture, or a pharmaceutically acceptable salt thereof, wherein Ri is NH-X3-X4.

8. The compound of any one of claims 1-6, or an enantiomer, an enantiomeric mixture, a diastereomer, a diasteromeric mixture, or a pharmaceutically acceptable salt thereof, wherein Ri is O-X3-X4.

9. The compound of any one of claims 1-8, or an enantiomer, an enantiomeric mixture, a diastereomer, a diasteromeric mixture, or a pharmaceutically acceptable salt thereof, wherein X3 is any one of the following:

(a) unsubstituted or substituted C1-C2₀ alkylene;

(b) unsubstituted or substituted C1-C2₀ alkenylene;

(c) unsubstituted or substituted C1-C2₀ acyl;

(d) unsubstituted or substituted C1-C2₀ carboxy ester;

(e) unsubstituted or substituted C2-C2₀ alkyl ketone;

(f) unsubstituted or substituted C2-C2₀ alkyl ether; and

(g) or unsubstituted or substituted C1-C2₀ alkyl amine.

10. The compound of any one of claims 1-9, or an enantiomer, an enantiomeric mixture, a diastereomer, a diasteromeric mixture, or a pharmaceutically acceptable salt thereof, wherein X4 is any one of the following:

(a) hydrogen;

(b) unsubstituted or substituted C1-C2₀ heterocyclyl;

(c) unsubstituted or substituted heteroaryl;

(d) M -Xs-Xe-Gi; and

(e) Gi.

11. The compound of claim 10, or an enantiomer, an enantiomeric mixture, a diastereomer, a diasteromeric mixture, or a pharmaceutically acceptable salt thereof, wherein X4 is NRA-XS- Cd-Gi, and Ni is any one of the following:

(a) OH;

(b) H;

(c) halo;

(d) CN;

(e) CF3;

(f) NO2;

(g) unsubstituted or substituted C1-C1₀ alkyl; (h) unsubstituted or substituted Ci-Cio alkyl ketone; and

(i) unsubstituted or substituted Ci-Cio alkyl ether.

12. The compound of claim 10, or an enantiomer, an enantiomeric mixture, a diastereomer, a diasteromeric mixture, or a pharmaceutically acceptable salt thereof, wherein X4 is NRA-XS- Cd-Gi, and N2 and N3 are each independently any one of the following:

(a) OH;

(b) H;

(c) halo;

(d) CN;

(e) CF3;

(f) NO2;

(g) unsubstituted or substituted C1-C10 alkyl;

(h) unsubstituted or substituted C1-C10 alkyl ketone; and

(i) or unsubstituted or substituted C1-C10 alkyl ether.

13. The compound of claim 10, or an enantiomer, an enantiomeric mixture, a diastereomer, a diasteromeric mixture, or a pharmaceutically acceptable salt thereof, wherein X4 is NRA-XS- Cd-Gi, and N2 and N₃ are taken together with the carbon atoms to which they are attached to form any one of the following:

(a) unsubstituted or substituted C5-C1₀ cycloalkyl;

(b) unsubstituted or substituted aryl;

(c) unsubstituted or substituted heteroaryl; and

(d) unsubstituted or substituted C1-C10 heterocyclyl.

14. The compound of claim 10, or an enantiomer, an enantiomeric mixture, a diastereomer, a diasteromeric mixture, or a pharmaceutically acceptable salt thereof, wherein X4 is Gi, and Ni is any one of the following:

(a) OH;

(b) H; (c) halo;

(d) CN;

(e) CF₃;

(f) NO2;

(g) unsubstituted or substituted C1-C1₀ alkyl;

(h) unsubstituted or substituted C1-C1₀ alkyl ketone; and

(i) unsubstituted or substituted C1-C1₀ alkyl ether.

15. The compound of claim 10, or an enantiomer, an enantiomeric mixture, a diastereomer, a diasteromeric mixture, or a pharmaceutically acceptable salt thereof, wherein X4 is Gi, and N2 and N3 are each independently any one of the following:

(a) OH;

(b) H;

(c) halo;

(d) CN;

(e) CF3;

(f) NO2;

(g) unsubstituted or substituted C1-C1₀ alkyl;

(h) unsubstituted or substituted C1-C1₀ alkyl ketone; and

(i) unsubstituted or substituted C1-C1₀ alkyl ether.

16. The compound of claim 10, or an enantiomer, an enantiomeric mixture, a diastereomer, a diasteromeric mixture, or a pharmaceutically acceptable salt thereof, wherein X4 is Gi, and N2 and N3 are taken together with the carbon atoms to which they are attached to form any one of the following:

(a) unsubstituted or substituted C5-C1₀ cycloalkyl;

(b) unsubstituted or substituted aryl;

(c) unsubstituted or substituted heteroaryl; and

(d) unsubstituted or substituted C1-C1₀ heterocyclyl.

17. The compound of any one of claims 1-6, or an enantiomer, an enantiomeric mixture, a diastereomer, a diasteromeric mixture, or a pharmaceutically acceptable salt thereof, wherein Ri is G2.

18. The compound of any one of claims 1-17, or an enantiomer, an enantiomeric mixture, a diastereomer, a diasteromeric mixture, or a pharmaceutically acceptable salt thereof, wherein R2 is any one of the following:

(a) OH;

(b) 0-X8; and

(c) O-X9-G1.

19. The compound of claim 18, or an enantiomer, an enantiomeric mixture, a diastereomer, a diasteromeric mixture, or a pharmaceutically acceptable salt thereof, wherein if R2 is O-Xx, then X8 is any one of the following:

(a) unsubstituted or substituted C1-C20 alkyl;

(b) -C(RB)2-C02-RB; and

(c) unsubstituted or substituted aryl.

20. The compound of any one of claims 1-6, or an enantiomer, an enantiomeric mixture, a diastereomer, a diasteromeric mixture, or a pharmaceutically acceptable salt thereof, wherein Ri and R2 are taken together with the P atom to which they are attached to form an unsubstituted or substituted C2-C10 heterocyclyl.

21. The compound of claim 20, or an enantiomer, an enantiomeric mixture, a diastereomer, a diasteromeric mixture, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (II):

wherein, Si is Xio-Gi; and

Xiois unsubstituted or substituted C1-C20 alkylene.

22. The compound of claim 20, or an enantiomer, an enantiomeric mixture, a diastereomer, a diasteromeric mixture, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (III):

wherein,

53 is X11-G1; and

X11 is unsubstituted or substituted C1-C20 alkylene.

23. The compound of any one of claims 1-22, or an enantiomer, an enantiomeric mixture, a diastereomer, a diasteromeric mixture, or a pharmaceutically acceptable salt thereof, wherein A comprises any one of the following:

(a) adenine;

(b) cytosine;

(c) guanine;

(d) thymine;

(e) uridine; and

(f) pyrrolo[2, 1 -f] [ 1 ,2,4]triazin-4-amine.

24. The compound of any one of claims 1 and 7-23, or an enantiomer, an enantiomeric mixture, a diastereomer, a diasteromeric mixture, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I has the following structure:

25. The compound of any one of claims 1 and 7-23, or an enantiomer, an enantiomeric mixture, a diastereomer, a diasteromeric mixture, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I has the following structure:

26. A compound having a structure selected from any one of the following structures:

27. A pharmaceutical composition comprising a compound of any one of claims 1-26, or an enantiomer, an enantiomeric mixture, a diastereomer, a diasteromeric mixture, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

28. A method for treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-26, or an enantiomer, an enantiomeric mixture, a diastereomer, a diasteromeric mixture, or a pharmaceutically acceptable salt thereof.

29. The method of claim 28, wherein the disease or disorder is a viral infection or cancer.

30. The method of claim 29, wherein the viral infection is caused by hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), Ebola virus, or human coronavirus.

31. The method of claim 29, wherein the cancer is heptacellular carcinoma (HCC), lung cancer, breast cancer, pancreatic cancer, biliary tract cancer, or colorectal cancer.

32. A compound of any one of claims 1-26, or an enantiomer, an enantiomeric mixture, a diastereomer, a diasteromeric mixture, or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder in a subject in need thereof.

33. Use of a compound of any one of claims 1-26, or an enantiomer, an enantiomeric mixture, a diastereomer, a diasteromeric mixture, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or disorder in a subject in need thereof.