cGAS antagonist compounds

Patent metadata

Field	Value
Publication number	US-12065416-B2
Application number	US-202318158046-A
Country	US
Kind code	B2
Filing date	Jan 23, 2023
Priority date	Apr 5, 2016
Publication date	Aug 20, 2024
Grant date	Aug 20, 2024

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 Ib:

wherein:
X is S;
Y is O or S;
Z is O, or NR 1a ;
G is Nor C;
if G is N, and Z is O, then R 1 is methyl;
if G is N, and Z is NR 1a , then 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 is NR 1a and R 1 -R 1a are connected as a ═CH—CH═CH—, ═N—CH═CH—, or ═CH—N═CH— group;

R 2 is hydrogen, halogen, C 1-6 alkyl, or C 1-6 alkyl substituted 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 or R 2 -R 3 are connected as a —CH 2 CH 2 — or —CH 2 CH 2 CH 2 —group;
R 5 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, 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;
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 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
wherein 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 optionally substituted 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, 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)-groups;
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 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
wherein 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 optionally substituted 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 alky)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 , —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, 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;
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 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 alkeny, and C 2-6 alkynyl groups; and
wherein 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 optionally substituted 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 1-6 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 1-6 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, thiazolyl, or tetrazolyl groups are optionally substituted with 1-3 substituents independently selected from 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
wherein 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 optionally substituted 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; or

R 6 is —OR 3a , —OCH 2 R 3b , or —OCH(CH 3 )R 3b ;
wherein R 3a and R 3b are independently phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl, quinolinyl, isoquinolinyl, thiazolyl, tetrazolyl, C 1-6 alkyl, cyclic —(C 1-6 alkyl)-, cyclic —(C 1-6 oxaalkyl)-, cyclic —(C 1-6 azaalkyl)-, C 2-6 alkenyl, or C 2-6 alkynyl groups;
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 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 alkeny, and C 2-6 alkynyl groups; and
wherein the C 1-6 alkyl, cyclic —(C 1-6 alkyl)-, cyclic —(C 1-6 oxaalkyl)-, cyclic —(C 1-6 azaalkyl)-, C 2-6 alkenyl, or C 2-6 alkynyl groups are substituted 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

Assignees

• Immunesensor Therapeutics Inc
• Univ Texas

Inventors

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

Classifications

• C07D513/04

  Ortho-condensed systems · CPC title

• C07D495/04

  Ortho-condensed systems · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D417/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D417/10

  linked by a carbon chain containing aromatic rings · CPC title