FUNCTIONALIZED PEPTIDES AS ANTIVIRAL AGENTS

1 . A compound represented by Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

A is selected from:

1) Optionally substituted —C 1 -C 8 alkyl;

2) Optionally substituted —C 3 -C 12 cycloalkyl;

3) Optionally substituted 3- to 12-membered heterocycloalkyl;

4) Optionally substituted aryl; and

5) Optionally substituted heteroaryl;

L 1 is —C(R 11 R 12 )—;

L 2 is —C(R 11 R 12 )—;

n1 is 0, 1, 2, 3, or 4;

X is optionally substituted —C 1 -C 6 alkyl, —CN, —C(O)R 15 , —C(O)NR 13 R 14 , or —C(O)C(O)NR 13 R 14 ;

Q is —C(R 11 ′R 12 ′)—;

n2 is 0, 1, 2, 3, or 4;

Each R 11 , R 11 ′, R 12 , and R 12 ′ are each independently selected from:

1) Hydrogen;

2) Halogen;

3) —OR 16 ;

4) —SR 16 ;

5) —NR 13 R 14 ;

6) —OC(O)NR 13 R 14 ;

7) Optionally substituted —C 1 -C 6 alkyl;

8) Optionally substituted —C 3 -C 8 cycloalkyl;

9) Optionally substituted 3- to 8-membered heterocycloalkyl;

10) Optionally substituted aryl; and

11) Optionally substituted heteroaryl;

alternatively, R 11 and R 12 are taken together with the carbon atom to which they are attached to form an optionally substituted 3- to 8-membered carbocyclic or heterocyclic ring;

alternatively, when n1 is not 0, two adjacent Ru groups are taken together with the carbon atoms to which they are attached to form an optionally substituted 3- to 8-membered carbocyclic or heterocyclic ring;

alternatively, n1 is 2, 3 or 4, and the Ru groups on two non-adjacent carbon atoms are taken together with the carbon atoms to which they are attached to form an optionally substituted bridging moiety;

R 13 and R 14 are each independently selected from:

1) Hydrogen;

2) Optionally substituted —C 1 -C 6 alkyl;

3) Optionally substituted —C 3 -C 8 cycloalkyl;

4) Optionally substituted 3- to 8-membered heterocycloalkyl;

5) Optionally substituted aryl;

6) Optionally substituted arylalkyl;

7) Optionally substituted heteroaryl;

8) Optionally substituted heteroarylalkyl;

9) —C(O)R 15 ;

10) —S(O) 2 R 16 ; and

11) —NH 2 ;

alternatively, R 13 and R 14 are taken together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 8-membered heterocyclic ring;

R 15 is selected from:

1) Hydrogen;

2) Halogen;

3) —OH;

4) Optionally substituted —C 1 -C 6 alkyl;

5) Optionally substituted —C 1 -C 6 alkoxy;

6) Optionally substituted —C 3 -C 8 cycloalkyl;

7) Optionally substituted 3- to 8-membered heterocycloalkyl;

8) Optionally substituted aryl;

9) Optionally substituted arylalkyl;

10) Optionally substituted heteroaryl; and

11) Optionally substituted heteroarylalkyl;

R 16 is selected from:

1) Hydrogen;

2) —OH;

3) Optionally substituted —C 1 -C 6 alkyl;

4) Optionally substituted —C 3 -C 8 cycloalkyl;

5) Optionally substituted 3- to 8-membered heterocycloalkyl;

6) Optionally substituted aryl;

7) Optionally substituted arylalkyl;

8) Optionally substituted heteroaryl, and

9) Optionally substituted heteroarylalkyl.

2 . The compound of claim 1 , wherein A is derived from one of the following, and optionally substituted:

3 . The compound of claim 1 , wherein A is —C(NR 13 R 14 )R 24 R 25 , wherein R 24 is hydrogen, halogen, optionally substituted —C 1 -C 6 alkyl, optionally substituted —C 1 -C 6 alkoxy, optionally substituted —C 3 -C 12 cycloalkyl, optionally substituted 3- to 12-membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R 25 is hydrogen or halogen; and R 13 and R 14 are as defined in claim 1 .

4 . The compound of claim 1 , wherein X is —CN, —C(O)CH 2 OC(O)R 21 , —C(O)CH 2 C(O) 2 R 21 , —C(O)CH 2 OR 21 , —C(O)CH 2 R 22 , —C(O)C(O)NHR 21 , —C(O)R 21 , —CHR 21 OC(O)R 21 , —CHR 21 C(O) 2 R 21 , —CHR 21 (OR 21 ), or —CH(OR 21 ) 2 , R 21 is hydrogen, optionally substituted —C 1 -C 6 alkyl, optionally substituted —C 3 -C 8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and R 22 is halogen, or —NR 13 R 14 , and R 13 and R 14 are as defined in claim 1 .

5 . The compound of claim 1 , represented by one of Formulas (IV-1) to (IV-4), or a pharmaceutically acceptable salt thereof:

wherein R 17 is halogen, —OR 16 , —SR 16 ; —NR 13 R 14 ; —OC(O)NR 13 R 14 ; optionally substituted —C 1 -C 6 alkyl; optionally substituted —C 3 -C 8 cycloalkyl; optionally substituted 3- to 8-membered heterocycloalkyl; optionally substituted aryl; or optionally substituted heteroaryl; m1 is 0, 1, 2, or 3; m2 is 0, 1, 2, 3, or 4; A, R 11 , R 11 ′, and X are as defined in claim 1 .

6 . The compound of claim 1 , represented by one of Formula (V-1), Formula (V-2), Formula (V-3), or Formula (V-4), or a pharmaceutically acceptable salt thereof:

wherein each T is CR 11 ; each U is —C(R 11 R 12 )—; each V is —O—, —S—, —C(R 11 R 12 )—, or —N(R 13 R 14 )—; m is 0, 1 or 2; m′ is 0, 1, 2, or 3; and A, Q, n2, Ru, R 12 , R 13 , R 14 , and X are as defined in claim 1 .

7 . The compound of claim 1 , represented by one of Formulas (VI-1a) to (VI-8a), or a pharmaceutically acceptable salt thereof:

wherein X and A are as defined in claim 1 .

8 . The compound of claim 1 , represented by one of Formulas (IX-1) to (IX-8), or a pharmaceutically acceptable salt thereof:

wherein R 32 is hydrogen, —F, C 1 , —CH 3 , —CF 3 or —OR; R 33 is —Cl, —Br, —OR 21 , —NHR 21 , or —OC(O)R 21 ; R 34 is R 21 ; R 21 is hydrogen, optionally substituted —C 1 -C 6 alkyl, optionally substituted —C 3 -C 8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and A are as defined in claim 1 .

9 . The compound of claim 1 , represented by one of Formulas (IX-1) to (IX-8), or a pharmaceutically acceptable salt thereof:

wherein R 24 is hydrogen, halogen, optionally substituted —C 1 -C 6 alkyl, optionally substituted —C 1 -C 6 alkoxy, optionally substituted —C 3 -C 12 cycloalkyl, optionally substituted 3- to 12-membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R 25 is hydrogen or halogen; and X, R 13 and R 14 are as defined in claim 1 .

10 . The compound of claim 1 , represented by one of Formulas (XIII-1) to (XIII-4), or a pharmaceutically acceptable salt thereof:

wherein R 24 is hydrogen, halogen, optionally substituted —C 1 -C 6 alkyl, optionally substituted —C 1 -C 6 alkoxy, optionally substituted —C 3 -C 12 cycloalkyl, optionally substituted 3- to 12-membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; and R 15 and X are as defined in claim 1 .

11 . The compound of claim 1 , selected from the compounds set forth below or a pharmaceutically acceptable salt thereof:

Compound

Structure

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

12 . A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

13 . A method of treating or preventing a virus infection, including a virus infection from an RNA-based virus, a coronavirus, a rhinovirus and a norovirus, in a subject susceptible to or suffering from the virus infection, the method comprising administering to the subject an inhibitor of a 3C protease enzyme wherein the inhibitor is a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

14 . A method of treating or preventing a coronavirus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or a combination of compounds according to claim 1 , or a pharmaceutically acceptable salt thereof.

15 . A method according to claim 13 , wherein the virus is a coronavirus selected from a 229E, NL63, OC43, HKU1, SARS-CoV or a MERS coronavirus.

16 . A method of treating or preventing a virus infection in a subject in need thereof, comprising administering to the subject an inhibitor of a 3C protease enzyme wherein the inhibitor comprises a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

17 . A method of inhibiting viral 3C protease or viral 3CL protease in a mammal, comprising administering to said subject an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

18 . The method according to claim 17 , wherein the subject is a human.

19 . A method of treating a respiratory disorder, including acute asthma, lung disease secondary to environmental exposures, acute lung infection, chronic lung infection, in a subject in need thereof, comprising administering to the subject a compound of claim 1 .

20 . The method according to claim 19 wherein the compound or pharmaceutical composition is administered orally, subcutaneously, intravenously or by inhalation.