Pyridopyrazine and pyridotriazine inhibitors of influenza virus replication

Patent metadata

Field	Value
Publication number	US-12037333-B2
Application number	US-201917275158-A
Country	US
Kind code	B2
Filing date	Sep 10, 2019
Priority date	Sep 10, 2018
Publication date	Jul 16, 2024
Grant date	Jul 16, 2024

Abstract

Provided herein are compounds that can inhibit the replication of influenza viruses, reduce the amount of influenza viruses, and/or treat influenza. (I)

First claim

What is claimed is:

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

Assignees

• Cocrystal Pharma Inc
• Merck Sharp & Dohme Llc

Inventors

• Jacobson Irina C
• Lin Biing Yuan
• Sanchez Emiliano J
• Lee Sam S K
• Xiao Hong

Classifications

• A61K31/53

  having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495}) · CPC title

• A61K31/4985

  Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems · CPC title

• A61P31/16

  for influenza or rhinoviruses · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title