Antiviral pyridopyrazinedione compounds

Patent metadata

Field	Value
Publication number	US-11072610-B2
Application number	US-201916569107-A
Country	US
Kind code	B2
Filing date	Sep 12, 2019
Priority date	Sep 12, 2018
Publication date	Jul 27, 2021
Grant date	Jul 27, 2021

Abstract

The invention provides compounds of Formula (I)

as described herein, along with pharmaceutically acceptable salts, pharmaceutical compositions containing such compounds, and methods to use these compounds, salts and compositions for treating viral infections, particularly infections caused by herpesviruses.

First claim

The invention claimed is:

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
Cy is phenyl, pyridinyl, pyrimidinyl, or a 5-8 membered cycloalkyl, and Cy is optionally substituted with up to three groups selected from halo, CN, hydroxy, —N(R′) 2 , C 3-6 cycloalkyl, C 1-3 alkoxy, C 1-3 haloalkyl, and C 1-3 alkyl substituted up to three (0-3) times with Z, wherein two of said C 1-3 alkyl substituted up to three times with Z, when directly attached to the same carbon atom, can be taken together with the carbon to which both are attached to form a 3-5 membered cycloalkyl ring substituted up to three times with Z;
R 1 is selected from H and C 1-3 alkyl;
R 2 is selected from H and C 1-3 alkyl;
or R 1 and R 2 taken together with the carbon to which they are attached can form a 3-6 membered cycloalkyl ring;

R 3 represents up to two (0-2) optional substituents on the ring to which -L-W is directly attached, each of which is independently selected from halo, CN, C 1-3 alkoxy, C 1-3 alkyl, COOR′, and C(O)NR′R′;
R 4 is H, halo, or C 1-3 alkyl;
R 6 is selected from H, halo, CN, C 1-3 alkoxy, —NR′R′, C 1-3 alkyl substituted up to three times with Z 5 , C 2-4 alkenyl substituted up to three times with Z 5 , C 2-4 alkynyl substituted up to three times with Z 5 , and a ring selected from a 3-6 membered cycloalkyl ring, a 4-6 membered heterocyclic ring containing one or two heteroatoms selected from N, O and S as ring members, and a 5-6 membered heteroaryl ring containing up to four heteroatoms selected from N, O and S as ring members, where the 3-6 membered cycloalkyl ring, 4-6 membered heterocyclic ring, or 5-6 membered heteroaryl ring is optionally substituted with 1-2 Z 5 ;
L is a C 1 -C 4 straight chain or branched alkylene linker, or L can be a C 1 -C 4 straight chain or branched alkylene linker or a bond when W is an optionally substituted ring;
W is H, —OH, —OR, —C(O)NR′R′, —COOR′, —NR′R′, —NR′COOR, —NR′C(O)R, —S 2 R, —SO 2 NR′R′, —NR′SO 2 R, —P(O)(OR′) 2 , or an optionally substituted ring selected from 3-6 membered cycloalkyl, phenyl, 5-6-membered heterocyclyl containing one or two N, O or S heteroatoms as ring members, and 5-membered heteroaryl containing up to 4 heteroatoms selected from N, O and S as ring members that is optionally fused to phenyl,
wherein the optional substituents for said optionally substituted ring are 1-3 groups selected from C 1-3 alkyl, oxo, halo, C 1-3 haloalkyl, -L 2 -OH, -L 2 -OR, -L 2 -OC(O)—NR′R′, -L 2 -SO 2 R, -L 2 -SO 2 NR′R′, -L 2 -SO 2 NR′—C(O)R, -L 2 -C(O)—NR′—SO 2 R, -L 2 -SOR, -L 2 -S(═O)(═NR′)R, -L 2 -NR′SO 2 NR′R′, -L 2 -NR′SO 2 R, -L 2 -NR′R′, -L 2 -NR′C(O)R′, -L 2 -NR′COOR, -L 2 -C(O)NR′R′, and -L 2 -COOR′;
R at each occurrence is selected from C 1-4 alkyl, 3-6 membered cycloalkyl, phenyl, 5-6 membered heteroaryl containing up to 4 heteroatoms selected from N, O and S as ring members, and 4-6 membered heterocyclyl containing one or two heteroatoms selected from N, O and S as ring members,
wherein each R is optionally substituted with one or two groups selected from C 1-4 alkyl, C 1-2 haloalkyl, oxo, -L 3 -CN, -L 3 -halo, -L 3 -C 1-3 alkoxy, -L 3 -OH, -L 3 -OC(O)—NR′R′, -L 3 -SO 2 R′, -L 3 -SO 2 NR′R′, -L 3 -SO 2 NR′—C(O)R′, -L 3 -C(O)—NR′—SO 2 R′, -L 3 -SOR′, -L 3 -S(═O)(═NR′)R′, -L 3 -NR′SO 2 NR′R′, -L 3 -NR′SO 2 R′, -L 3 -NR′R′, -L 3 -NR′C(O)R′, -L 3 -NR‘COOR’, -L 3 -C(O)NR′R′, and -L 3 -COOR′, -L 3 -(5-6-membered heterocyclyl containing one or two N, O or S heteroatoms as ring members), -L 3 -C 3-5 cycloalkyl, and -L 3 -(5-6 membered heteroaryl ring having up to four heteroatoms comprising 1-4 nitrogen atoms, 0-1 oxygen atoms, and 0-1 sulfur atoms as ring members), where the C 1-4 alkyl, 5-6-membered heterocyclyl, C 3-5 cycloalkyl and 5-6 membered heteroaryl ring are each optionally further substituted with up to three groups independently selected from halo, C 1-3 alkyl, C 1-3 haloalkyl, -L 4 -OR′, -L 4 -CN, and -L 4 -N(R′) 2 ;

R′ at each occurrence is independently selected from H, C 1-4 alkyl optionally substituted with halo, —OH, amino, or C 1-2 alkoxy, and C 3-6 cycloalkyl optionally substituted with halo, —OH, amino, or C 1-2 alkoxy;
or two R′ taken together with a nitrogen atom to which both are directly attached can form a 4-6 membered ring optionally containing an additional N, O or S as a ring member and optionally substituted with one to three groups selected from C 1-2 alkyl, C 1-2 alkoxy, oxo, and hydroxy;
each L 2 and L 3 and L 4 is independently a bond or a straight chain or branched C 1-3 alkylene;

Z and Z 5 are independently selected at each occurrence from halo, hydroxy, CN, C 1-3 alkoxy, C 1-3 alkyl, and C 3-5 cycloalkyl,
and two Z groups, or two Z 5 groups, taken together with a carbon atom to which both are directly attached can form a 3-5 membered cycloalkyl ring or a 4-6 membered heterocyclic ring containing O, N or S as a ring member and optionally substituted by up to two groups selected from oxo and C 1-3 alkyl.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is H.

3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is H.

4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy is selected from phenyl, pyridin-3-yl, and cyclohexyl, each of which is optionally substituted with 1 to 3 groups selected from halo, CF 3 , and CN.

5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is H.

6. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is H, halo, methyl, or halomethyl.

7. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is absent, or R 3 represents one or two methyl groups.

8. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is —CH 2 — or —(CH 2 ) 2 —.

9. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is cyclopropyl substituted with a group selected from C 1-3 alkyl, oxo, halo, OH, —SO 2 R, —SO 2 NR′R′, —SOR, —S(═O)(═NR′)R, —NR′SO 2 NR′R′, —NR′SO 2 R, —NR′R′, —OR, —NR′COOR, —C(O)NR′R′, and COOR′.

10. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the moiety W-L- is selected from the group consisting of

11. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy is phenyl, and is optionally substituted with 1 or 2 groups selected from halo, CN, OH, C 1-3 alkyl, and C 1-3 alkoxy.

12. The compound according to claim 11 , or a pharmaceutically acceptable salt thereof, wherein Cy is selected from

13. A compound of Formula (II):

or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is H or methyl;
Z 3 and Z 4 are independently selected from H, halo, CN, Me, and OMe;
L is a C 1 -C 4 straight chain or branched alkylene linker;
W is —SO 2 R, —SO 2 NR′R′, —NR′SO 2 R, or an optionally substituted C 1 -C 3 alkyl, or an optionally substituted 3-6 membered cycloalkyl;
wherein the optional substituents fo

Assignees

• Novartis Ag

Inventors

• Becker Christopher
• Li Xiaolin
• Lu Peichao
• Rajapaksa Naomi Samadara
• Tully David Charles
• Wang Xiaojing Michael
• Zhao Qian

Classifications

• A61P31/22

  for herpes viruses · CPC title

• A61P31/12 Primary

  Antivirals · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/4985

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