Inhibitors of gas for treating autoinflammatory diseases and cancer metastasis

Patent metadata

Field	Value
Publication number	US-12522603-B2
Application number	US-202017437974-A
Country	US
Kind code	B2
Filing date	Mar 12, 2020
Priority date	Mar 13, 2019
Publication date	Jan 13, 2026
Grant date	Jan 13, 2026

Abstract

Tri-cyclyl nitrogen-containing heterocyclic compounds

are disclosed. The compounds are inhibitors of human cGAS in interferon-producing cell types. They are thus useful as therapeutic agents for treating cGAS-related autoimmune diseases in humans.

First claim

The invention claimed is:

1 . A compound of formula (I):

wherein:
the structure

 represents a fused 6,5 ring system wherein both rings are aromatic and all backbone atoms are sp 2 -hybridized;
X 1 is N or N—R 1 ;
X 2 is C or N;
X 3 is N;
X 4 is C—R 4 or N;
X 5 is C—R 5 or N;
or
X 1 is N or N—R 1 ;
X 2 is C or N;
X 3 is N or C;
X 4 is N;
X 5 is C—R 5 or N;
or
X 1 is N or N—R 1 ;
X 2 is C or N;
X 3 is N or C;
X 4 is C—R 4 or N;
X 5 is N;
R 1 is hydrogen, (C 1 -C 3 )alkyl, CH 2 CH 2 —OR 3a , or fluoro(C 1 -C 3 )alkyl;
R 2 is hydrogen, (C 1 -C 3 )alkyl, or CH 2 CH 2 —OR 3b , or, taken together along with the atoms to which they are attached, R 2 and R 30 may form a 4- to 6-membered oxygen-containing non-aromatic heterocyclic ring;
R 3a is hydrogen or (C 1 -C 3 )alkyl;
R 3b is hydrogen or (C 1 -C 3 )alkyl;
R 4 is chosen from optionally substituted monocyclic heterocyclyl, hydrogen, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, fluoro(C 1 -C 6 )alkyl, fluoro(C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, fluoro(C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyloxy, fluoro(C 3 -C 6 )cycloalkyloxy, cyano, optionally substituted phenyl, optionally substituted bicyclic heterocyclyl, amino(C 1 -C 3 )alkyl, (C 1 -C 3 )alkylamino(C 1 -C 3 )alkyl, (C 1 -C 3 )dialkylamino(C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy (C 1 -C 3 )alkyl, (C 1 -C 6 )hydrocarbyl, heterocyclyl(C 1 -C 3 )alkyl, benzyl, heterocyclyl-substituted benzyl, (C 1 -C 3 )alkylaminocarbonyl, and (C 1 -C 3 )acylamino;
R 5 is chosen from hydrogen, (C 1 -C 6 )alkoxy, optionally substituted monocyclic heterocyclyl, halogen, (C 1 -C 6 )alkyl, fluoro(C 1 -C 6 )alkyl, fluoro(C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, fluoro(C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyloxy, fluoro(C 3 -C 6 )cycloalkyloxy, cyano, optionally substituted phenyl, optionally substituted bicyclic heterocyclyl, amino(C 1 -C 3 )alkyl, (C 1 -C 3 )alkylamino(C 1 -C 3 )alkyl, (C 1 -C 3 )dialkylamino(C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy (C 1 -C 3 )alkyl, (C 1 -C 6 )hydrocarbyl, heterocyclyl(C 1 -C 3 )alkyl, benzyl, heterocyclyl-substituted benzyl, (C 1 -C 3 )alkylaminocarbonyl, and (C 1 -C 3 )acylamino;
wherein:
said optionally substituted monocyclic heterocyclyl may be substituted with one or more substituents chosen from: (C 1 -C 3 )alkyl, amino, cyano, (C 1 -C 3 )alkylamino, (C 1 -C 3 )alkoxy, oxo, fluoro(C 1 -C 3 )alkyl, halogen, hydroxy, and hydroxy(C 1 -C 3 )alkyl;
said optionally substituted phenyl may be substituted with one or more substituents chosen from: amino, (C 1 -C 3 )alkylamino, (C 1 -C 3 )dialkylamino, (C 1 -C 3 )alkoxy, hydroxy, halogen, cyano, aminocarbonyl, methylenedioxy, ethylenedioxy, (C 1 -C 3 )acylamino, fluoro(C 1 -C 3 )acylamino, and hydroxy(C 1 -C 3 )alkylaminosulfonyl; and
said optionally substituted bicyclic heterocyclyl may be substituted with one or more substituents chosen from: (C 1 -C 3 )alkyl, hydroxy, and oxo;

R 6 and R 7 are independently chosen from halogen, hydrogen, cyano, —C≡CH, —CH═CH 2 , (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, fluoro(C 1 -C 3 )alkyl, fluoro(C 1 -C 3 )alkoxy, (C 3 -C 4 )cycloalkyl, and fluoro(C 3 -C 4 )cycloalkyl;
R 20 is hydrogen or (C 1 -C 3 )alkyl, or, taken together with the carbon to which they are attached, R 20 and R 21 may form a 3- to 5-membered aliphatic carbocyclic ring;
R 21 is hydrogen or (C 1 -C 3 )alkyl, or, taken together with the carbon to which they are attached, R 21 and R 20 may form a 3- to 5-membered aliphatic carbocyclic ring;
R 30 is hydrogen, or, taken together along with the atoms to which they are attached, R 30 and R 2 may form a 4- to 6-membered oxygen-containing non-aromatic heterocyclic; and
n is 1 or 2.

2 . The compound according to claim 1 wherein:
i) R 30 is hydrogen; and
ii) n is 1.

3 . The compound according to claim 2 wherein X 1 is N, X 2 is C, X 3 is N, and R 2 is hydrogen or methyl.

4 . The compound according to claim 3 wherein:
i) R 6 and R 7 are independently chosen from halogen, hydrogen, methoxy, cyano, and trifluoromethyl;
ii) X 5 is C—R 5 , wherein R 5 is chosen from hydrogen, (C 1 -C 3 )alkoxy, halogen, cyano, and trifluoromethyl.

5 . The compound according to claim 4 wherein X 4 is C—R 4 and R 4 is chosen from optionally substituted monocyclic heteroaryl, hydrogen, optionally substituted phenyl, and optionally substituted bicyclic heterocyclyl.

6 . The compound according to claim 2 wherein X 1 is N—R 1 , X 2 is C, X 3 is C, and X 4 is N.

7 . The compound according to claim 6 wherein X 5 is C—R 5 and R 5 is chosen from hydrogen, halogen, (C 1 -C 3 )alkyl, and (C 1 -C 3 )alkoxy.

8 . The compound according to claim 6 wherein R 6 and R 7 are independently chosen from hydrogen and halogen.

9 . The compound according to claim 8 wherein:
i) R 1 and R 2 are independently chosen from hydrogen and methyl;
ii) R 20 and R 21 are independently chosen from hydrogen and (C 1 -C 3 )alkyl.

10 . The compound according to claim 2 wherein X 1 is N—R 1 , X 2 is C; X 3 is C, X 4 is C—R 4 , and X 5 is N.

11 . The compound according to claim 10 wherein R 4 is chosen from optionally substituted monocyclic heteroaryl or heterocyclyl, hydrogen, (C 1 -C 6 )alkoxy, optionally substituted phenyl, and optionally substituted bicyclic heterocyclyl.

12 . The compound according to claim 11 wherein R 4 is phenyl, optionally substituted with a substituent chosen from amino, halogen, cyano, methoxy, hydroxy, and aminocarbonyl.

13 . The compound according to claim 11 wherein R 4 is a monocyclic heteroaryl or heterocyclyl, optionally substituted with a substituent chosen from methyl, amino, halogen, difluoromethyl, methoxy, and cyano.

14 . The compound according to claim 13 wherein said optionally substituted monocyclic heteroaryl or heterocyclyl is chosen from pyrazolyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, oxadiazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiophen, phenyl, dihydropyran, tetrahydropyran, tetrahydrofuranyl, oxetane, and azetidinyl.

15 . The compound according to claim 14 wherein said optionally substituted monocyclic heteroaryl is pyrazolyl or triazolyl.

16 . The compound according to claim 2 wherein:
i) X 1 and X 2 are N;
ii) X 3 is C;
iii) X 5 is C—R 5 and R 5 is chosen from hydrogen, (C 1 -C 3 )alkoxy, halogen, cyano, and trifluoromethyl;
iv) R 2 is hydrogen or methyl; and
v) R 6 and R 7 are independently chosen from halogen, hydrogen, methoxy, cyano, and trifluoromethyl.

17 . A method of inhibiting inflammation, dsDNA-triggered interferon expression, or cGAS in a patient comprising administering a compound according to claim 1 .

18 . A method of treating Aicardi Goutières Syndrome, Parkinson's disease, Alzheimer's disease, Systemic lupus erythematosus, or cancer metastasis in a patient comprising administering a compound according to claim 1 .

19 . A medicament comprising the compound according to claim 1 and optionally a therapeutic agent for Ai

Assignees

• Univ Rockefeller
• Memorial Sloan Kettering Cancer Center

Inventors

• Tomita Daisuke
• Lama Lodoe
• Tuschl Thomas
• Patel Dinshaw
• Glickman J Fraser
• Kamei Taku
• Miller Michael
• Asano Yasutomi
• Okamoto Rei
• Hashizume Shogo
• Aida Jumpei
• Imaeda Toshihiro
• Michino Mayako
• Kuroita Takanobu

Classifications

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P35/04

  specific for metastasis · CPC title