PYRROLOPYRIMIDINE NUCLEOSIDES FOR TREATING OR PREVENTING A SARS-COV-2 INFECTION

1 . A method of treating or preventing a SARS-CoV-2 infection or a SARS-CoV-2-infection associated disease or disorder (e.g., COVID-19) comprising administering, or causing to be administered, to a subject in need thereof an effective amount of a compound of Formula II,

a prodrug thereof, a metabolite thereof, or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, racemate or mixture thereof, wherein:

Y is —C(O)—, or

 wherein X 1 is independently O, NH, or S, X 2 is independently a bond, —O—, —S—, or —NH—, and X 3 is independently —OR, —NHR, or —SR;

R is independently —H, —C 1 -C 20 alkyl, —C 2 -C 20 alkenyl, —C 2 -C 20 alkynyl, —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, aryl, heteroaryl, or heterocyclyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halogen, oxo, R 1 , —OR 1 , —NR 1 R 2 , —SR 1 , —OC(O)R 1 , —C(O)OR 1 , —NHC(O)OR 1 , or —NHC(O)R 1 ;

R a and R b are each independently, at each occurrence, —H, —C 1 -C 20 alkyl, —C 2 -C 20 alkenyl, —C 2 -C 20 alkynyl, —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, aryl, heteroaryl, or heterocyclyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halogen, oxo —OR 1 , —NR 1 R 2 , —SR 1 , —OC(O)R 1 , —C(O)OR 1 —NHC(O)OR 1 , or —NHC(O)R 1 ;

R 1 and R 2 are each independently, at each occurrence, —H, —C 1 -C 20 alkyl, —C 2 -C 20 alkenyl, —C 2 -C 20 alkynyl, —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, aryl, heteroaryl, or heterocyclyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halogen, oxo, R 3 , R 4 , —OR 3 , —NR 3 R 4 , —SR 3 , —OC(O)R 3 , —C(O)OR 3 , —NHC(O)OR 3 , or —NHC(O)R 3 ;

R 3 and R 4 are each independently, at each occurrence, —H, —C 1 -C 20 alkyl, —C 2 -C 20 alkenyl, —C 2 -C 20 alkynyl, —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, aryl, heteroaryl, or heterocyclyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halogen, oxo, aryl, heteroaryl, —OH, —NH 2 , —SH, —OC(O)H, —C(O)OH, —NHC(O)OH, or —NHC(O)H;

R c is independently —H or -D; and

n is independently 0, 1, 2 or 3.

2 . The method of claim 1 , wherein the compound is:

a prodrug thereof, or a metabolite thereof.

3 . The method of claim 1 , wherein the compound is:

4 . The method of claim 1 , wherein the compound is:

5 . The method of claim 1 , wherein the compound is:

6 . The method of claim 1 , wherein the compound is:

7 . The method of claim 1 , wherein the compound is:

8 . The method of claim 1 , wherein the compound is:

9 . The method of claim 1 , wherein the compound is:

10 . The method of claim 1 , wherein the compound is:

11 . The method of claim 1 , wherein the compound is:

12 . The method of claim 1 , wherein the compound is:

13 . The method of claim 1 , wherein the compound is:

14 . The method of claim 1 , wherein the compound is:

15 . The method of claim 1 , wherein the compound is:

16 . The method of claim 1 , wherein the compound is:

17 . The method of claim 1 , wherein the compound is:

18 . The method of claim 1 , wherein the compound is:

19 . The method of claim 1 , wherein the compound is:

20 . The method of any one of claims 1-19 , wherein the compound of Formula II is administered to the lungs of the subject.

21 . The method of any one of claims 1-20 , wherein the compound of Formula II is administered to the subject via inhalation.

22 . The method of any one of claims 1-20 , wherein the compound of Formula II is administered to the subject intratracheally, nasally, or intranasally.

23 . The method of any one of claims 1-22 , wherein the compound of Formula II is administered to the subject via a nebulizer, metered dose inhaler (MDI), a propellant-driven metered dose inhaler (pMDI) breath actuated devices (BAIs) such as a dry powder inhaler (DPI), heat vaporizer, soft mist inhaler, thermal aerosol inhaler, or electrohydrodynamic-based solution misting inhaler.

24 . The method of any one of claims 1-22 , wherein the compound of Formula II is administered to the subject via a dry powder inhaler.

25 . The method of any one of claims 1-22 , wherein the compound of Formula II is administered to the subject via a nebulizer.

26 . The method of any one of claims 1-22 , wherein the compound of Formula II is administered to the subject via a metered dose inhaler.

27 . The method of any one of claims 1-26 , wherein the method comprises administering a pharmaceutical composition comprising a compound of Formula II and a pharmaceutically acceptable carrier.

28 . The method of claim 27 , wherein the pharmaceutical composition is formulated for delivery by inhalation.

29 . The method of claim 27 , wherein the pharmaceutical composition is formulated for delivery intratracheally, nasally, or intranasally.

30 . The method of claim 27 , wherein the pharmaceutical composition is formulated for delivery by a nebulizer, metered dose inhaler (MDI), a propellant-driven metered dose inhaler (pMDI) breath actuated devices (BAIs) such as a dry powder inhaler (DPI), heat vaporizer, soft mist inhaler, thermal aerosol inhaler, or electrohydrodynamic-based solution misting inhaler.

31 . The method of claim 27 , wherein the pharmaceutical composition is formulated for delivery by a dry powder inhaler.

32 . The method of claim 27 , wherein the pharmaceutical composition is formulated for delivery by a nebulizer.

33 . The method of claim 27 , wherein the pharmaceutical composition is formulated for delivery by metered dose inhaler.

34 . The method of claims 1-33 , wherein the method further comprises administering a second therapeutic agent.

35 . The method of claim 34 , wherein the second therapeutic agent is selected from the group consisting of: an mRNA vaccine, a viral vector vaccine, sarilumab, tocilizumab, remdesivir, nirmatrelvir, molnupiravir, paxlovid, favipiravir, oseltamivir, camostat, a CYP3A4 inhibitor (e.g. ritonavir), a corticosteroid, an anticoagulation drug, a janus kinase inhibitor (e.g. baricitinib), and immunoglobulin therapy, intravenous immunoglobulin (IVIG), COVID-19 sera, anti-COVID-19 monoclonal antibodies, or blood transfusions from recovered COVID-19 patients.

36 . A method of any one of the preceding claims , wherein the method prevents a patient from developing acute respiratory distress syndrome.

37 . A method of any one of the preceding claims , wherein the method prevents the progression of acute respiratory distress syndrome in a patient.

38 . Use of a compound of Formula II for preparing a medicament for preventing a SARS-CoV-2 infection or a SARS-CoV-2-infection associated disease or disorder (e.g., COVID-19) in a patient in need thereof.

39 . A compound of Formula II for use in preventing a SARS-CoV-2 infection or a SARS-CoV-2-infection associated disease or disorder (e.g., COVID-19) in a patient in need thereof.

40 . A method for treating or preventing a SARS-CoV-2 infection or a SARS-CoV-2-infection associated disease or disorder (e.g., COVID-19) in a patient in need thereof, comprising administering, or causing to be administered, to the patient a compound of Formula II, a prodrug thereof, a metabolite thereof, or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, racemate or mixture thereof.

41 . The method of claim 40 , comprising causing to be administered to the patient one or more active metabolites by in vivo formation.

42 . The method of claim 41 , wherein the active metabolite is one or more of a monophosphate, a diphosphate, or a triphosphate analog of a compound of Formula II.

43 . The method of claim 42 , wherein the active metabolite is Compound 1

or a monophosphate, a diphosphate, or a triphosphate analog thereof.