cGAS antagonist compounds

Patent metadata

Field	Value
Publication number	US-10947206-B2
Application number	US-201815953494-A
Country	US
Kind code	B2
Filing date	Apr 15, 2018
Priority date	Apr 5, 2016
Publication date	Mar 16, 2021
Grant date	Mar 16, 2021

Abstract

Disclosed are novel compounds of Formula I that are cGAS antagonists, methods of preparation of the compounds, pharmaceutical compositions comprising the compounds, and their use in medical therapy.

First claim

The invention claimed is:

1. A compound, wherein the compound is one of Formula Ic:

wherein:
X is NH or S;
Y is O or S;
Z is O, S, CHR 1a or NR 1a ;
wherein R 1a is hydrogen, C 1-6 alkyl, or C 1-6 alkyl selectively functionalized with one or more halogen, thiol, hydroxyl, carbonyl, carboxyl, carbonyloxyl, C 1-6 alkoxy, C 1-6 hydroxyalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, or azido groups;

G is N or C;
if G is N, then R 1 is C 1-6 alkyl or C 1-6 alkyl selectively functionalized with one or more halogen, thiol, hydroxyl, carbonyl, carbonyloxyl, C 1-6 alkoxy, C 1-6 hydroxyalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, or azido groups, or R 1 -R 1a are connected as a —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH═CH—, —C(CH 3 )═CH— or —CH═C(CH 3 )— group; and
if G is C, then Z includes R 1a and R 1 -R 1a are connected as a ═CH—CH═CH—, ═N—CH═CH—, or ═CH—N═CH— group;

W is OR 10a or NHR 10a ;
wherein R 10a is hydrogen, C 1-6 alkyl, or C 1-6 alkyl selectively functionalized with one or more halogen, thiol, hydroxyl, carbonyl, carboxyl, carbonyloxyl, C 1-6 alkoxy, C 1-6 hydroxyalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, or azido groups, or R 10a -R 6 are connected as a —CH 2 —CH 2 —, —CH═CH—, —N═CH—, or —CH═N— group;

R 2 is hydrogen, halogen, C 1-6 alkyl, or C 1-6 alkyl selectively functionalized with one or more halogen, thiol, hydroxyl, carbonyl, carboxyl, carbonyloxyl, C 1-6 alkoxy, C 1-6 hydroxyalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, or azido groups;
R 3 is halogen, —SR 3a , —S(O)R 3a , —OR 3a , —OCH 2 R 3b , —OCH(CH 3 )R 3b , —OC(O)NHR 3a , —NR 3a R 4a , —NHSO 2 R 3a , azido, —CHO, —CO 2 R 3a , cyano, C 1-6 alkyl, —CR 5a R 6a R 7a , C 2-6 alkenyl, —C(R 5a )═C(R 8a )(R 9a ), C 2-6 alkynyl, —C≡CR 8a , or R 2 —R 3 are connected as a —CH 2 CH 2 —or —CH 2 CH 2 CH 2 — group;
wherein R 3a , R 3b , and R 4a are independently hydrogen, phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl, quinolinyl, isoquinolinyl, thiazolyl, tetrazolyl groups, C 1-6 alkyl, cyclic-(C 1-8 alkyl)-, cyclic-(C 1-6 oxaalkyl)-, cyclic-(C 1-6 azaalkyl)-, C 2-6 alkenyl, or C 2-6 alkynyl;
wherein the phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl, quinolinyl, isoquinolinyl, thiazolyl, or tetrazolyl groups are optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, thiol, C 1-6 alkyl thioether, C 1-6 alkyl sulfoxide, C 1-6 alkyl, C 1-6 alkoxyl, amino, C 1-6 alkylamino, C 1-6 dialkylamino, C 1-6 alkyl sulfonamide, azido, —CHO, —CO 2 H, C 1-6 alkyl carboxylate, cyano, C2-6alkenyl, and C 2-6 alkynyl group; and the C 1-6 alkyl, cyclic-(C 1-8 alkyl)-, cyclic-(C 1-6 oxaalkyl)-, cyclic-(C 1-6 azaalkyl)-, C 2-6 alkenyl, or C 2-6 alkynyl groups are selectively functionalized with one or more halogen, thiol, hydroxyl, carbonyl, carboxyl, carbonyloxyl, C 1-6 alkoxy, C 1-6 hydroxyalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, azido, piperidinyl, phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl, quinolinyl, isoquinolinyl, thiazolyl, or tetrazolyl groups;

wherein R 5a , R 6a , R 7a , R 8a , and R 9a are independently hydrogen, phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl, quinolinyl, isoquinolinyl, thiazolyl, tetrazolyl groups, C 1-6 alkyl, cyclic-(C 1-8 alkyl)-, cyclic-(C 1-6 oxaalkyl)-, cyclic-(C 1-6 azaalkyl)-, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxyl, cyclic-(C 1-8 alkoxyl)-, cyclic-(C 1-6 oxaalkoxyl)-, or cyclic-(C 1-6 azaalkoxyl)-;
wherein the phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl, quinolinyl, isoquinolinyl, or thiazolyl, tetrazolyl groups are optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, thiol, C 1-6 alkyl thioether, C 1-6 alkyl sulfoxide, C 1-6 alkyl, C 1-6 alkoxyl, amino, C 1-6 alkylamino, C 1-6 dialkylamino, C 1-6 alkyl sulfonamide, azido, —CHO, —CO 2 H, C 1-6 alkyl carboxylate, cyano, C 2-6 alkenyl, and C 2-6 alkynyl groups; and the C 1-6 alkyl, cyclic-(C 1-8 alkyl)-, cyclic-(C 1-6 oxaalkyl)-, cyclic-(C 1-6 azaalkyl)-, C 2-6 alkenyl, or C 2-6 alkynyl groups are selectively functionalized with one or more halogen, thiol, hydroxyl, carbonyl, carboxyl, carbonyloxyl, C 1-6 alkoxy, C 1-6 hydroxyalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, azido, piperidinyl, phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl, quinolinyl, isoquinolinyl, thiazolyl, or tetrazolyl groups;

R 6 is hydrogen, halogen, —SR 3a , —S(O)R 3a , —OR 3a , —OCH 2 R 3b , —OCH(CH 3 )R 3b , —OC(O)NHR 3a , —NR 3a R 4a , —NHSO 2 R 3a , azido, —CHO, CO 2 R 3a , cyano, C 1-6 alkyl, —CR 5a R 6a R 7a , C 2-6 alkenyl, —C(R 5a )═C(R 8a )(R 9a ), C 2-6 alkynyl, or —C≡CR 8a ;
wherein R 3a , R 3b , and R 4a are independently hydrogen, phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl, quinolinyl, isoquinolinyl, thiazolyl, tetrazolyl groups, C 1-6 alkyl, cyclic—(C 1-8 alkyl)—, cyclic—(C 1-6 oxaalkyl)—, cyclic—(C 1-6 azaalkyl)—, C 2-6 alkenyl, or C 2-6 alkynyl;
wherein the phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3—triazolyl, quinolinyl, isoquinolinyl, thiazolyl, or tetrazolyl groups are optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, thiol, C 1-6 alkyl thioether, C 1-6 alkyl sulfoxide, C 1-6 alkyl, C 1-6 alkoxyl, amino, C 1-6 alkylamino, C 1-6 dialkylamino, C 1-6 alkyl sulfonamide, azido, —CHO, —CO 2 H, C 1-6 alkyl carboxylate, cyano, C 2-6 alkenyl, and C 2-6 alkynyl group; and the C 1-6 alkyl, cyclic—(C 1-8 alkyl)—, cyclic—(C 1-6 oxaalkyl)—, cyclic—(C 1-6 azaalkyl)—, C 2-6 alkenyl, or C 2-6 alkynyl groups are selectively functionalized with one or more halogen, thiol, hydroxyl, carbonyl, carboxyl, carbonyloxyl, C 1-6 alkoxy, C 1-6 hydroxyalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, azido, piperidinyl, phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3—triazolyl, quinolinyl, quinolinyl, isoquinolinyl, thiazolyl, or tetrazolyl groups;

wherein R 5a , R 6a , R 7a , R 8a , and R 9a are independently hydrogen, phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3—triazolyl, quinolinyl, isoquinolinyl, thiazolyl, tetrazolyl groups, C 1-6 alkyl, cyclic—(C 1-8 alkyl)—, cyclic—(C 1-6 oxaalkyl)—, cyclic—(C 1-6 azaalkyl)—, C 2-6 alkenyl, C 2-6 alkynyl, C 2-6 alkynyl, C 1-6 alkoxyl, cyclic—(C 1-8 alkoxyl)—, cyclic—(C 1-6 oxaalkoxyl)—, or cyclic—(C 1-6 azaalkoxyl)—;
wherein the phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3—triazolyl, quinolinyl, isoquinolinyl, or thiazolyl, tetrazolyl groups are optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, thiol, C 1-6 alkyl thioether, C 1-6 alkyl sulfoxide, C 1-6 alkyl, C 1-6 alkoxyl, amino, C 1-6 alkylamino, C 1-6 diakylamino, C 1-6 alkyl sulfonamide, azido, —CHO, —CO 2 H, C 1-6 alkyl carboxylate, cyano, C 2-6 alkenyl, and C 2-6 alkynyl groups; and the C 1-6 alkyl, cyclic—(C 1-8 alkyl)—, cyclic—(C 1-6 oxaalkyl)—, cyclic—(C 1-6 azaalkyl)—, C 2-6 alkenyl, or C 2-6 alkynyl groups are selectively functionalized with one or more halogen, thiol, hydroxyl, carbonyl, carboxyl, carbonyloxyl, C 1-6 alkoxy, C 1-6 hydroxyalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, azido, piperidinyl, phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3—triazolyl, quinolinyl, isoquinolinyl, thiazolyl, or tetrazolyl groups;

R 4 is hydrogen or halogen;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein X is S; Z is O or S; and
G is N; and R 1 is C 1-6 alkyl or C 1-6 alkyl selectively functionalized with one or more halogen, thiol, hydroxy

Assignees

• Immunesensor Therapeutics Inc
• Univ Texas

Inventors

• Zhong Boyu
• Sun Lijun
• Shi Heping
• Li Jing
• Chen Chuo
• Chen Zhijian

Classifications

• A61K31/381

  having five-membered rings · CPC title

• A61K31/4709

  Non-condensed quinolines and containing further heterocyclic rings · CPC title

• A61K31/433

  Thidiazoles · CPC title

• A61K31/426

  1,3-Thiazoles · CPC title

• A61K31/427

  not condensed and containing further heterocyclic rings · CPC title