Pyridopyrazine and pyridotriazine inhibitors of influenza virus replication

1. A compound having a structure of Formula (I), or a pharmaceutically acceptable salt thereof:

wherein

ring A is

M is N or CH;

each of X and X′ is independently CH 2 , CH 2 CH 2 , OCH 2 , or CH 2 O;

each of R 1 and R 2 is independently H, halo, OH, CO 2 H, CN, CHO, C 1-6 alkyl optionally substituted by 1-3 of substituent group A, C 2-6 alkenyl optionally substituted by 1-3 of substituent group A, C 2-6 alkynyl optionally substituted by 1-3 of substituent group A, C 1-6 alkoxy optionally substituted by 1-3 of substituent group A, C 1-6 alkyl-C(O)— optionally substituted by 1-3 of substituent group A, C 1-6 alkyl-OC(O)— optionally substituted by 1-3 of substituent group A, C 3-10 carbocyclyl-C 0-6 alkylene optionally substituted by 1-3 of substituent group A, C 3-10 carbocyclyl-C(O)— optionally substituted by 1-3 of substituent group A, C 3-10 carbocyclyl-O-optionally substituted by 1-3 of substituent group A, C 3-10 carbocyclyl-OC(O)— optionally substituted by 1-3 of substituent group A, 3-7 membered heterocyclyl-C 0-6 alkylene optionally substituted by 1-3 of substituent group A, 3-7 membered heterocyclyl-C(O)— optionally substituted by 1-3 of substituent group A, 3-7 membered heterocyclyl-O— optionally substituted by 1-3 of substituent group A, or 3-7 membered heterocyclyl-OC(O)— optionally substituted by 1-3 of substituent group A, wherein the heterocyclyl comprises 1-4 ring heteroatoms independently selected from N, O, and S;

R 3 is H, OH, CO 2 H, CN, CHO, C 1-6 alkyl optionally substituted by 1-3 of substituent group A, C 2-6 alkenyl optionally substituted by 1-3 of substituent group A, C 2-6 alkynyl optionally substituted by 1-3 of substituent group A, C 1-6 alkoxy optionally substituted by 1-3 of substituent group A, C 1-6 alkyl-C(O)— optionally substituted by 1-3 of substituent group A, C 1-6 alkyl-OC(O)— optionally substituted by 1-3 of substituent group A, C 3-10 carbocyclyl-C 0-6 alkylene optionally substituted by 1-3 of substituent group A, C 3-10 carbocyclyl-O—C 1-6 alkylene optionally substituted by 1-3 of substituent group A, C 3-10 carbocyclyl-C(O)— optionally substituted by 1-3 of substituent group A, C 3-10 carbocyclyl-OC(O)— optionally substituted by 1-3 of substituent group A, 3-7 membered heterocyclyl-C 0-6 alkylene optionally substituted by 1-3 of substituent group A, 3-7 membered heterocyclyl-C(O)— optionally substituted by 1-3 of substituent group A, 3-7 membered heterocyclyl-OC(O)— optionally substituted by 1-3 of substituent group A, wherein the heterocyclyl comprises 1-4 ring heteroatoms independently selected from N, O, and S, or

R 3 and R 5 together with the atoms to which they are attached form a 5-7 heterocyclyl having 1-4 total ring heteroatoms selected from N, O, and S, and can be optionally substituted with 1-3 of substituent group A;

R 4 , when present, is H, OH, C 1-3 alkyl, C 1-3 haloalkyl, or C 1-3 alkoxy;

R 5 and R 6 are each independently H, OH, CO 2 H, CN, CHO, C 1-6 alkyl optionally substituted by 1-3 of substituent group A, C 2-6 alkenyl optionally substituted by 1-3 of substituent group A, C 2-6 alkynyl optionally substituted by 1-3 of substituent group A, C 1-6 alkyl carbonyl optionally substituted by 1-3 of substituent group A, C 1-6 alkyl-O—C(O)— optionally substituted by 1-3 of substituent group A, C 3-8 carbocyclylC 1-6 alkylene optionally substituted by 1-3 of substituent group A, C 3-8 carbocyclyl-O—C 1-6 alkylene optionally substituted by 1-3 of substituent group A, C 3-8 carbocyclyl-C(O)— optionally substituted by 1-3 of substituent group A, C 3-8 carbocyclyl-OC(O)— optionally substituted by 1-3 of substituent group A, 3-7 membered heterocyclyl-C 0-6 alkylene optionally substituted by substituent group A, 3-7 membered heterocyclyl-O—C 1-6 alkylene optionally substituted by 1-3 of substituent group A, 3-7 membered heterocyclyl-C(O)— optionally substituted by 1-3 of substituent group A, or 3-7 membered heterocyclyl-OC(O)— optionally substituted by 1-3 of substituent group A, wherein the heterocyclyl comprises 1-4 ring heteroatoms independently selected from N, O, and S, or

R 5 and R 6 together with the atom to which they are attached form a C 3-7 carbocyclyl or 3-7 membered heterocyclyl having 1-3 ring heteroatoms selected N, O, and S, and is optionally substituted with 1-3 of substituent group A;

optionally one of R 1 , R 2 , R 3 , R 5 , and R 6 can be

—Z—N(R N )(R N ),

—Z—N(R N )—SO 2 —R x2 ,

—Z—C(O)—N(R N )—SO 2 —R x2 ,

—Z—N(R N )—C(O)—R x1 ,

—Z—C(O)—N(R N )(R N ),

—Z—S(O) 0-2 —R x2 ,

—Z—N(R N )—C(O)O—R x1 ,

—Z—N(R N )—C(O)—N(R N )(R N ),

—Z—C(O)—N(R N )—C(O)—N(R N )(R N ), or

—Z—N(R N )—C(O)—C(O)—R x1 ,

in which:

each R N and R x1 independently is hydrogen, C 1-6 alkyl optionally substituted by 1-3 of substituent group A, C 2-6 alkenyl optionally substituted by 1-3 of substituent group A, C 2-6 alkynyl optionally substituted by 1-3 of substituent group A, C 3-10 carbocylyl-C 0-6 alkylene optionally substituted by 1-3 of substituent group A, or 3-7 membered heterocyclyl-C 0-6 alkylene optionally substituted by 1-3 of substituent group A, and the heterocyclyl group comprises 1-4 ring heteroatoms independently selected from N, O, and S, or

two R N attached to the same nitrogen atom can together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclyl having 0-2 additional ring heteroatoms selected from N, O, and S;

each R x2 is independently C 1-6 alkyl optionally substituted by 1-3 of substituent group A, C 2-6 alkenyl optionally substituted by 1-3 of substituent group A, C 2-6 alkynyl optionally substituted by 1-3 of substituent group A, C 3-10 carbocylyl-C 0-6 alkylene optionally substituted by 1-3 of substituent group A, or 3-7 membered heterocyclyl-C 0-6 alkylene optionally substituted by 1-3 of substituent group A, and the heterocyclyl group comprises 1-4 ring heteroatoms independently selected from N, O, and S, and

Z is a bond or C 1-6 alkylene;

substituent group A is halo, CN, OH, CO 2 H, CHO, NH 2 , oxo, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkyl-OH, C 3-10 carbocyclyl, 3-7 membered heterocyclyl, C 6-10 aryl, C 3-10 carbocyclyl-C 1-6 alkoxy, C 3-10 carbocyclyl-O—C 1-6 alkylene, C 3-10 carbocyclyl-C 1-6 alkoxy-C 1-6 alkylene, 3-7 membered heterocyclyl-C 1-6 alkoxy, 3-7 membered heterocyclyl-O—C 1-6 alkylene, 3-7 membered heterocyclyl-C 1-6 alkoxy-C 1-6 alkylene, C 1-6 haloalkoxy, C 1-6 alkoxy-C 1-6 alkylene, C 1-6 alkoxy-C 1-6 alkoxy, C 1-6 alkyl-C(O)—, C 1-6 alkyl-C(O)O—, NHC 1-6 alkyl, C 1-6 alkyl-C(O)NH—, C 1-6 haloalkyl-C(O)NH, C 1-6 alkyl-NHC(O)—, C 1-6 alkyl-SO 2 —, C 1-6 alkyl-SO—, and C 1-6 alkylSO 2 NH—; and

each of Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 is independently H, halo, CN, OH, CO 2 H, CHO, NH 2 , NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, or C 1-6 alkyl-OH.

2. The compound or salt of claim 1 , wherein M is N.

3. The compound or salt of claim 1 , having a structure of Formula (IIA) or (IIB).

4. The compound or salt of claim 1 , wherein at least one of R 1 and R 2 is H.

5. The compound or salt of claim 1 , wherein R 4 is H, OH or OMe.

6. The compound or salt of claim 1 , wherein at least one of R 5 and R 6 is H.

7. The compound or salt of claim 1 , wherein R 5 and R 6 together with the atom to which they are attached form a C 3-7 carbocyclyl or 3-7 membered heterocyclyl having 1-3 ring heteroatoms selected N, O, and S, and is optionally substituted with 1-3 of substituent group A.

8. The compound or salt of claim 1 , wherein R 3 and R 5 together with the atoms to which they are attached form a 5-7 membered heterocyclyl having 1-4 total ring heteroatoms selected N, O, and S, and can be optionally substituted with 1-3 of substituent group A.

9. The compound or salt of claim 1 , wherein R 3 is C 1-6 alkyl, C 3-6 carbocyclyl-C 1-6 alkylene, C 3-6 carbocyclyl-O—C 1-6 alkylene, or 3-7 membered heterocyclyl-C 1-6 alkylene.

10. The compound or salt of claim 1 , wherein R 3 is

—Z—N(R N )(R N ),

—Z—N(R N )—SO 2 —R x2 ,

—Z—C(O)—N(R N )—SO 2 —R x2 ,

—Z—N(R N )—C(O)—R x1 ,

—Z—C(O)—N(R N )(R N ),

—Z—S(O) 0-2 —R x2 ,

—Z—N(R N )—C(O)O—R x1 ,

—Z—N(R N )—C(O)—N(R N )(R N ),

—Z—C(O)—N(R N )—C(O)—N(R N )(R N ), or

—Z—N(R N )—C(O)—C(O)—R x1 .

11. The compound or salt of claim 1 , wherein at least two of Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 are H.

12. The compound or salt of claim 1 , wherein at least two of Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 are halo.

13. The compound or salt of claim 12 , wherein the halo is F.

14. The compound or salt of claim 1 , wherein

ring A is

each of R 1 , R 2 , R 4 , R 5 , and R 6 is H;

M is N;

each of X and X′ are CH 2 ;

R 3 is H, OH, CO 2 H, CN, CHO, C 1-6 alkyl optionally substituted by 1-3 of substituent group A, C 3-10 carbocyclyl-C 0-6 alkylene optionally substituted by 1-3 of substituent group A, C 3-10 carbocyclyl-O—C 1-6 alkylene optionally substituted by 1-3 of substituent group A, 3-7 membered heterocyclyl-C 0-6 alkylene optionally substituted by 1-3 of substituent group A, 3-7 membered heterocyclyl-C(O)— optionally substituted by 1-3 of substituent group A wherein the heterocyclyl comprises 1-4 ring heteroatoms independently selected from N, O, and S;

substituent group A is halo; and

each of Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 is iH or halo, provided that at least two of Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 are H.

15. The compound or salt of claim 1 having a structure of

16. A pharmaceutical formulation comprising the compound or salt of claim 1 and a pharmaceutically acceptable excipient.

17. A method of inhibiting endonuclease activity of influenza polymerase PA in an influenza A or B virus, comprising contacting the virus with the compound or salt of claim 1 .

18. A method for treating or preventing an Influenza A or Influenza B infection in a host, comprising administering to the host a therapeutic amount of the compound or salt of claim 1 .

19. A method for reducing endonuclease activity of influenza polymerase PA in an influenza A or B virus in a host, comprising administering to the host a therapeutic amount of the compound or salt of claim 1 .

20. A method for reducing influenza virus replication in a host, comprising administering to the host a therapeutic amount of the compound or salt of claim 1 .

21. The method of claim 17 , further comprising contacting the influenza A or B virus with or administering to the host a therapeutically effective amount of a second antiviral agent.

22. The method of claim 21 , wherein the second antiviral agent is a pyrazinecarboxamide antiviral compound, an influenza neuraminidase inhibitor, an influenza PB1 polymerase domain inhibitor, or an influenza CAP-binding PB2 domain inhibitor.