METHODS OF TREATING OR PREVENTING VIRAL INFECTION WITH FLUORINATED AlphaV INTEGRIN ANTAGONISTS

1 . A method of treating or preventing a viral infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an integrin inhibitor represented by Formula (I):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

Z is

Q is

X is CR 4 or N;

Y is CR 4 or N;

R and R′ are each independently H or F, or R and R′, together with the carbon atom to which they are attached, form a 3—or 4-membered carbocyclic or heterocyclic ring;

R 1 is H, F, Cl, C 1 -C 4 alkyl substituted with 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, or C 1 -C 6 alkoxy substituted with 0, 1, 2, 3, 4, 5, 6, or 7 fluorine atoms;

R 2 and R 3 are each independently H, F, CH 2 F, CHF 2 , or CF 3 , provided that one of R 2 and R 3 is not H;

each R 4 is independently H, CH 2 F, CHF 2 , or CF 3 ; and

R 51 and R 52 are each independently H, F, or Cl;

provided that the compound of Formula (I) contains at least one fluorine atom; and

wherein the viral infection is an infection by human adenovirus, human cytomegalovirus, Kaposi's sarcoma-associated herpesvirus, Epstein-Barr virus, human immunodeficiency virus, HPS-associated hantaviruses, Sin Nombre virus, rotavirus, echovirus, foot-and-mouth disease virus, coxsackievirus, West Nile virus, Ebola virus, Ross River virus, human papillomavirus, or coronavirus.

2 . A method of treating or preventing a condition or symptom associated with a viral infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an integrin inhibitor represented by Formula (I):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

Z is

Q is

X is CR 4 or N;

Y is CR 4 or N:

R and R′ are each independently H or F, or R and R′, together with the carbon atom to which they are attached, form a 3—or 4-membered carbocyclic or heterocyclic ring;

R 1 is H, F, Cl, C 1 -C 4 alkyl substituted with 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, or C 1 -C 6 alkoxy substituted with 0, 1, 2, 3, 4, 5, 6, or 7 fluorine atoms;

R 2 and R 3 are each independently H, F, CH 2 F, CHF 2 , or CF 3 , provided that one of R 2 and R 3 is not H;

each R 4 is independently H, CH 2 F, CHF 2 , or CF 3 ; and

R 51 and R 52 are each independently H, F, or Cl;

provided that the compound of Formula (I) contains at least one fluorine atom; and

wherein the viral infection is an infection by human adenovirus, human cytomegalovirus, Kaposi's sarcoma-associated herpesvirus, Epstein-Barr virus, human immunodeficiency virus, HPS-associated hantaviruses, Sin Nombre virus, rotavirus, echovirus, foot-and-mouth disease virus, coxsackievirus, West Nile virus, Ebola virus, Ross River virus, human papillomavirus, or coronavirus.

3 . (canceled)

4 . (canceled)

5 . The method of claim 1 , wherein the virus is selected from the group consisting of: human adenovirus, human cytomegalovirus, Kaposi's sarcoma-associated herpesvirus, Epstein-Barr virus, West Nile virus, Ebola virus, Ross River virus, human papillomavirus, and coronavirus.

6 . The method of claim 5 , wherein the virus is a coronavirus.

7 . The method of claim 6 , wherein the coronavirus is selected from SARS-CoV, MERS-CoV, and SARS-CoV-2.

8 . The method of claim 7 , wherein the coronavirus is SARS-CoV-2.

9 . The method of claim 2 , wherein the condition or symptom is an inflammatory or immunological response to the viral infection.

10 . The method of claim 9 , wherein the inflammatory or immunological response comprises increased cytokine and/or chemokine production.

11 . The method of claim 9 , wherein the inflammatory or immunological response is selected from increased secretion or expression and/or elevated plasma level of one or more of IL-1β, IFN-γ, IP-10, MCP-1, IL-2, IL-4, IL-5, IL-6, IL-7, IL-1β, GCSF, MCP-1, MIP-1A, TNF-α, TNF-β, CXCL9, CXCL10, CCL2, CCL3, CCL5, CXCR3, CCR2, and/or CCR5.

12 . The method of claim 2 , wherein the condition or symptom is selected from fever, chill, cough, sore throat, shortness of breath, anosmia, diarrhea, nausea/vomiting, skin rashes, muscle pain, stomach pain, headache, pneumonia, kidney failure, thrombosis, organ failure, COVID-19, acute respiratory distress syndrome (ARDS), and severe acute respiratory syndrome (SARS).

13 . The method of claim 1 , further comprising administering a second therapeutic agent.

14 . The method of claim 13 , wherein the second therapeutic agent is selected from an anti-viral agent, an immune-suppressive agent, an anti-thrombotic agent, an anti-coagulant, an antibiotics, and other therapeutic agents that are capable of treating or preventing a viral infection or a condition or symptom associated with the viral infection.

15 . The method of claim 1 , wherein the integrin inhibitor is a compound of Formula (I-1):

or a pharmaceutically acceptable salt thereof, wherein:

Z is

Q is

X is CR 4 or N;

Y is CR 4 or N;

R and R′ are each independently H or F, or R and R′, together with the carbon atom to which they are attached, form a 3—or 4-membered carbocyclic or heterocyclic ring;

R 1 is H, F, Cl, C 1 -C 4 alkyl substituted with 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, or C 1 -C 6 alkoxy substituted with 0, 1, 2, 3, 4, 5, 6, or 7 fluorine atoms;

each R 4 is independently H, CH 2 F, CHF 2 , or CF 3 ; and

R 51 and R 52 are each independently H, F, or Cl;

provided that the compound of Formula (I-1) contains at least one fluorine atom.

16 . The method of claim 1 , wherein the integrin inhibitor is a compound of Formula (Ia):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

Z is

R and R′ are each independently H or F, or R and R′, together with the carbon atom to which they are attached, form a 3—or 4-membered carbocyclic or heterocyclic ring;

Q is

X is CH or N;

Y is CH or N;

R 1 is C 1 -C 4 alkyl substituted with 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, or C 1 -C 6 alkoxy substituted with 0, 1, 2, 3, 4, 5, 6, or 7 fluorine atoms; and

R 2 and R 3 are each independently H, F, CH 2 F, CHF 2 , or CF 3 , provided that one of R 2 and R 3 is not H,

provided that the compound of Formula (Ia) contains at least one fluorine atom.

17 . The method of claim 1 , wherein the integrin inhibitor is a compound of Formula (Ib):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

Z is

Q is

X is CR 4 or N;

Y is CR 4 or N;

R 1 is H, F, Cl, C 1 -C 4 alkyl substituted with 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, or C 1 -C 6 alkoxy substituted with 0, 1, 2, 3, 4, 5, 6, or 7 fluorine atoms;

R 2 and R 3 are each independently H, F, CH 2 F, CHF 2 , or CF 3 , provided that one of R 2 and R 3 is not H;

each R 4 is independently H, CH 2 F, CHF 2 , or CF 3 ; and

R 51 and R 52 are each independently H, F, or Cl;

provided that the compound of Formula (T) contains at least one fluorine atom, and provided that when Z is

 R 1 is not H, F, or Cl, and R 51 and R 52 are each H, then at least one of X and Y is CR 4 , and R 4 is C 1 H 2 F, CHF 2 , or CF 3 .

18 . The method of claim 1 , wherein the integrin inhibitor is a compound selected from Table 1a or Table 1b or a pharmaceutically acceptable salt thereof:

TABLE 1a

Cmpd No.

Chemical Structure

Cmpd No.

Chemical Structure

A1

A8

A2

A9

A3

A10

A4

A11

A5

A12

A6

A13

A7

A14

TABLE lb

Cmpd No.

Chemical Structure

Cmpd No.

Chemical Structure

A15

A15s

A16

A16s

A17

A17s

A18

A18s

A19

A19s

A20

A20s

A21

A21s

A21-1 enantiomer 1

A21-2 enantiomer 2

A22

A22s

A23

A23s

A24

A24s

A25

A25s

A26

A26s

A27

A27s

A28

A28s

A29

A29s

A30

A30s

19 . The method of claim 1 , wherein the integrin inhibitor is Compound A1:

or a pharmaceutically acceptable salt thereof.

20 - 27 . (canceled)

28 . A method of treating or preventing a viral infection by SARS-CoV-2 or a condition or symptom associated with SARS-CoV-2 infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound A1:

or a pharmaceutically acceptable salt or solvate thereof.

29 - 32 . (canceled)

33 . The method of claim 28 , wherein the method comprises administering to the subject a therapeutically effective amount of Compound A1:

or a pharmaceutically acceptable salt thereof.