Compositions and methods for inhibiting influenza RNA polymerase PA endonuclease

Patent metadata

Field	Value
Publication number	US-10889556-B2
Application number	US-201816125468-A
Country	US
Kind code	B2
Filing date	Sep 7, 2018
Priority date	Mar 8, 2016
Publication date	Jan 12, 2021
Grant date	Jan 12, 2021

Abstract

There are provided inter alia metalloenzyme inhibitors, such as inhibitors of influenza A RNA dependent RNA polymerase PA subunit endonuclease, and methods of synthesis and use of the same.

First claim

What is claimed is:

1. A compound having the formula:

wherein,
Y is O, S, or NH;
W 1 is —CH(R 1 )—, or —N(R 1 )—;
R 1 is hydrogen;
W 2 is —C(R 2 )═;
R 2 is hydrogen, halogen, —CX 2 3 , —CHX 2 2 , —CH 2 X 2 , —OCX 2 3 , —OCH 2 X 2 , —OCHX 2 2 , —CN, —SO n2 R 2D , —SO v2 NR 2A R 2B , —NHC(O)NR 2A R 2B , —N(O) m2 , —NR 2A R 2B , —C(O)R 2C , —C(O)—OR 2C , —C(O)NR 2A R 2B , —OR 2D , —NR 2A SO 2 R 2D , —NR 2A C(O)R 2C , —NR 2A C(O)OR 2C , —NR 2A OR 2C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 3 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 4 is halogen, —CX 4 3 , —CHX 4 2 , —CH 2 X 4 , —OCX 4 3 , —OCH 2 X 4 , —OCHX 4 2 , —CN, —SO n4 R 4D , —SO v4 NR 4A R 4B , —NHC(O)NR 4A R 4B , —N(O) m4 , —NR 4A R 4B , —C(O)R 4C , —C(O)—OR 4C , —C(O)NR 4A R 4B , —OR 4D , —NR 4A SO 2 R 4D , —NR 4A C(O)R 4C , —NR 4A C(O)OR 4C , —NR 4A OR 4C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
each R 2A , R 2B , R 2C , R 2D , R 4A , R 4B , and R 4D are independently hydrogen, —CX 3 , —CN, —COOH, —CONH 2 , —CHX 2 , —CH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2A and R 2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 4A and R 4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
R 1D is hydrogen;
R 4C is hydrogen;
each X, X 2 , and X 4 is independently —F, —Cl, —Br, or —I;
n2 and n4 are independently an integer from 0 to 4; and
m2, m4, v2 and v4 are independently an integer from 1 to 2.

2. The compound of claim 1 , wherein Y is S or O.

3. The compound of claim 1 , wherein W 1 is —N(R 1 )—.

4. The compound of claim 1 , wherein W 2 is —C(R 2 )═.

5. The compound of claim 4 , wherein R 2 is hydrogen, —OR 2D , —C(O)R 2C , —C(O)—OR 2C , —C(O)NR 2A R 2B , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

6. The compound of claim 1 , wherein R 3 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

7. The compound of claim 1 , wherein R 4 is halogen, —C(O)R 4c , —C(O)—OR 4c , —C(O)NR 4A R 4B , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

8. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.

9. A method of inhibiting RNA-dependent RNA polymerase PA subunit endonuclease protein activity, said method comprising contacting the RNA-dependent RNA polymerase PA subunit endonuclease protein with an effective amount of a compound of claim 1 , wherein the RNA-dependent RNA polymerase PA subunit endonuclease protein is an influenza virus protein.

10. A method of treating a viral infection, said method comprising administering to a subject in need thereof an effective amount of a compound of claim 1 , wherein the viral infection is an influenza virus infection.

11. The method of claim 10 , wherein the viral infection is an influenza virus A infection.

12. The compound of claim 1 having the formula:

13. The compound of claim 1 , wherein R 3 is R 30 -substituted or unsubstituted aryl;
wherein,
R 30 is independently oxo, halogen, —CX 30 3 , —CHX 30 2 , —CH 2 X 30 , —OCX 30 3 , —OCH 2 X 30 , —OCHX 30 2 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OR 31 , —NHR 31 , —N(CH 3 )R 31 , —COOR 31 , —CONHR 31 , —SR 31 , —SO 2 NHR 31 , —SO 2 R 31 , R 31 -substituted or unsubstituted alkyl, R 31 -substituted or unsubstituted heteroalkyl, R 31 -substituted or unsubstituted cycloalkyl, R 31 -substituted or unsubstituted heterocycloalkyl, R 31 -substituted or unsubstituted aryl, or R 31 -substituted or unsubstituted heteroaryl;
X 30 is independently —F, —Cl, —Br, or —I;
R 31 is independently oxo, halogen, —CX 31 3 , —CHX 31 2 , —CH 2 X 31 , —OCX 31 3 , —OCH 2 X 31 , —OCHX 31 2 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O) NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OR 32 , —NHR 32 , —N(CH 3 )R 32 , —COOR 32 , —CONHR 32 , —SR 32 , R 32 -substituted or unsubstituted alkyl, R 32 -substituted or unsubstituted heteroalkyl, R 32 -substituted or unsubstituted cycloalkyl, R 32 -substituted or unsubstituted heterocycloalkyl, R 32 -substituted or unsubstituted aryl, or R 32 -substituted or unsubstituted heteroaryl;
X 31 is independently —F, —Cl, —Br, or —I;
R 32 is independently oxo, halogen, —CX 32 3 , —CHX 32 2 , —CH 2 X 32 , —OCX 32 3 , —OCH 2 X 32 , —OCHX 32 2 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl; and
X 32 is independently —F, —Cl, —Br, or —I.

14. The compound of claim 13 , wherein R 3 is R 30 -substituted or unsubstituted —CH 2 N(CH 3 )Ph, or R 30 -substituted or unsubstituted phenyl.

15. The compound of claim 1 , wherein R 4 is —C(O)R 4C , —C(O)—OR 4C , —C(O)NR 4A R 4B , or substituted or unsubstituted heteroaryl.

16. The compound of claim 15 , wherein R 4 is —C(O)OH, —C(O)NHCH 3 , or unsubstituted tetrazolyl.

Assignees

• Univ California

Inventors

• Cohen Seth M
• Credille Cy V
• Puerta David T

Classifications

• C07C2601/18

  with a ring being at least seven-membered · CPC title

• C07C62/38

  containing keto groups · CPC title

• C07D213/90

  having more than three double bonds between ring members or between ring members and non-ring members · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D401/10

  linked by a carbon chain containing aromatic rings · CPC title