Saturated spirocyclics as antiviral agents

1. A compound represented by Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

A is selected from:

1) —R 11 ;

2) —OR 12 ;

3) —NR 17 R 18 ; and

4) —C(R 13 R 14 )N(R 17 R 18 );

n is 1, 2, or 3;

Q 1 is selected from:

1) —CN;

2) —C(O)R 15 ;

3) —CH(OH)SO 3 R 16 ;

4) —C(O)NR 13 R 14 ;

5) —C(O)C(O)NR 13 R 14 ; and

6) Optionally substituted —C 2 -C 8 alkynyl;

R 1 , R 2 , R 3 , Q 2 , and Q 3 are each independently selected from:

1) Hydrogen;

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

3) Optionally substituted —C 2 -C 8 alkenyl;

4) Optionally substituted —C 2 -C 8 alkynyl;

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

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

7) Optionally substituted aryl;

8) Optionally substituted arylalkyl;

9) Optionally substituted heteroaryl; and

10) Optionally substituted heteroarylalkyl;

alternatively, R 1 and R 2 are taken together with the carbon atom to which they are attached to form an optionally substituted 3- to 8-membered carbocyclic ring or an optionally substituted 3- to 8-membered heterocyclic ring;

alternatively, Q 2 and Q 3 are taken together with the carbon atom to which they are attached to form an optionally substituted 3- to 8-membered carbocyclic ring or an optionally substituted 3- to 8-membered heterocyclic ring;

R 4 is hydrogen, optionally substituted —C 1 -C 4 alkyl, optionally substituted C 2 -C 4 -alkenyl, or optionally substituted —C 3 -C 6 cycloalkyl;

R 11 and R 12 are each independently selected from:

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

2) Optionally substituted —C 2 -C 8 alkenyl;

3) Optionally substituted —C 2 -C 8 alkynyl;

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;

R 13 , R 14 , and R 17 each independently selected from:

1) Hydrogen;

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

3) Optionally substituted —C 2 -C 8 alkenyl;

4) Optionally substituted —C 2 -C 8 alkynyl;

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

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

7) Optionally substituted aryl;

8) Optionally substituted arylalkyl;

9) Optionally substituted heteroaryl; and

10) Optionally substituted heteroarylalkyl;

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

R 15 is hydrogen, hydroxy, or optionally substituted —C 1 -C 8 alkyl;

R 16 is hydrogen or Na 30 ; and

R 18 is selected from:

—C(O)R 11 ;

—C(O)OR 11 ;

—C(O)NR 13 R 14 ;

—S(O) 2 R 11 ;

Hydrogen;

Optionally substituted —C 1 -C 8 alkyl;

Optionally substituted —C 2 -C 8 alkenyl;

Optionally substituted —C 2 -C 8 alkynyl;

Optionally substituted —C 3 -C 8 cycloalkyl;

Optionally substituted 3- to 8-membered heterocycloalkyl;

Optionally substituted aryl;

Optionally substituted arylalkyl;

Optionally substituted heteroaryl; and

Optionally substituted heteroarylalkyl.

2. The compound of claim 1 , wherein Q 1 is —CN, and R 4 is hydrogen.

3. The compound of claim 1 , wherein A is derived from one of the following by removal of a hydrogen atom and is optionally substituted:

4. The compound of claim 1 represented by Formulae (IV-1) or Formula (IV-2), or a pharmaceutically acceptable salt thereof:

wherein A, Q 1 , Q 2 , Q 3 , R 1 , and R 3 are as defined in claim 1 .

5. The compound of claim 1 , represented by one of Formulae (VII-1) to (VII-9), or a pharmaceutically acceptable salt thereof:

wherein each R 21 and R 22 are independently selected from:

1) Halogen;

2) —CN;

3) —OR 13 ;

4) —SR 13 ;

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;

m is 0, 1, 2, 3, or 4; v is 0, 1, or 2, and R 1 , R 13 , and R 14 are as defined in claim 1 .

6. The compound of claim 1 , represented by one of Formulae (VIII-1) to (VIII-9), or a pharmaceutically acceptable salt thereof:

wherein each R 21 and R 22 is independently selected from:

1) Halogen;

2) —CN;

3) —OR 13 ;

4) —SR 13 ;

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;

m is 0, 1, 2, 3, or 4; v is 0, 1, or 2, and R 1 , R 13 , and R 14 are as defined in claim 1 .

7. The compound of claim 1 , represented by Formula (X), or a pharmaceutically acceptable salt thereof:

wherein E is —C(R 13 R 14 )—, —N(R 13 )—, or —O—, t is 0, 1, 2, 3, or 4, and n, A, Q 1 , R 13 , R 14 , R 1 , and R 3 as defined in claim 1 .

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

Compound

Structure

1

2

3

4

9. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or excipient.

10. A method of treating or preventing a virus infection in a subject susceptible to or suffering from the virus infection, the method comprising administering to the subject an effective amount of a compound according to claim 1 .

11. 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 .

12. The method according to claim 11 , wherein the coronavirus is a 229E, NL63, OC43, HKU1, SARS-CoV-1, SARS-CoV-2 or a MERS coronavirus.

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

14. The method according to claim 13 , wherein the subject is a human.

15. A method of treating a respiratory disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of claim 1 .

16. The method according to claim 15 , wherein the compound or pharmaceutical composition is administered orally, subcutaneously, intravenously or by inhalation.