2,3,4,5-TETRAHYDRO-1H-PYRIDO[4, 3-b]INDOLE INHIBITORS OF cGAS FOR TREATING AUTOINFLAMMATORY DISEASES

Patent metadata

Field	Value
Publication number	US-2021155625-A1
Application number	US-201916967656-A
Country	US
Kind code	A1
Filing date	Feb 5, 2019
Priority date	Feb 5, 2018
Publication date	May 27, 2021
Grant date	—

Abstract

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

1 . A compound of formula (I):

wherein:
R 1 is hydrogen, (C 1 -C 3 )alkyl, CH 2 CH 2 —OR 3 , or fluoro(C 1 -C 3 )alkyl;
R 2 is hydrogen, (C 1 -C 3 )alkyl, or CH 2 CH 2 —OR 3 , or, taken together along with the atoms to which they are attached, R 2 and R 30 may form a 4- to 6-membered aliphatic ring;
R 3 is hydrogen or (C 1 -C 3 )alkyl;
R 4 is chosen from hydrogen, halogen, (C 1 -C 3 )alkoxy, optionally substituted monocyclic heterocyclyl ring, cyano, optionally substituted phenyl ring, optionally substituted bicyclic heterocyclyl ring, 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, (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, meta-(C 1 -C 3 )dialkylamino, (C 1 -C 3 )alkoxy, hydroxy, halogen, ortho-cyano, meta-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 5 is chosen from hydrogen, halogen, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, fluoro(C 1 -C 3 )alkyl, fluoro(C 1 -C 3 )alkoxy, cyano, and

R 6 is chosen from hydrogen, halogen, cyano, —C≡CH, —CH═CH 2 , methyl, and trifluoromethyl;
R 7 is chosen from hydrogen, halogen, (C 1 -C 3 )alkoxy, fluoro(C 1 -C 3 )alkoxy, cyano, (C 1 -C 3 )alkyl, and fluoro(C 1 -C 3 )alkyl;
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 aliphatic ring; and
n is 1 or 2;
with the provisos that:
(1) when R 2 is (C 1 -C 3 )alkyl, not all of R 4 , R 5 , R 6 , and R 7 can be hydrogen;
(2) when R 1 is hydrogen, R 2 is methyl and R 5 is halogen, R 7 cannot be H or chloro; and
(3) when R 2 is (C 1 -C 3 )alkyl, and R 5 is methoxy or carboxy, R 7 cannot be H.

2 . A compound according to claim 1 wherein:
i) R 20 is hydrogen or (C 1 -C 3 )alkyl;
ii) R 21 is hydrogen;
iii) R 30 is hydrogen; and
iv) n is 1.

3 . (canceled)

4 . A compound according to claim 2 wherein R 1 is hydrogen.

5 . (canceled)

6 . A compound according to claim 2 wherein R 2 is hydrogen.

7 - 8 . (canceled)

9 . A compound according to claim 2 wherein R 7 is chloro or fluoro.

10 . A compound according to claim 2 wherein R 7 is fluoro.

11 . A compound according to claim 2 wherein R 6 is halogen.

12 - 14 . (canceled)

15 . A compound according to claim 11 wherein R 7 is fluoro.

16 - 17 . (canceled)

18 . A compound according to claim 15 wherein R 5 is hydrogen.

19 . A compound according to claim 2 wherein R 20 is hydrogen or methyl.

20 - 22 . (canceled)

23 . A compound according to claim 2 wherein R 4 is a monocyclic heteroaryl, optionally substituted with a substituent chosen from amino, halogen, methyl, difluoromethyl, methoxy, and cyano.

24 . A compound according to claim 23 wherein said optionally substituted monocyclic heteroaryl is chosen from furan, thiophene, pyrrole, pyrazole, oxazole, oxadiazole, thiazole, isoxazole, isothiazole, imidazole, triazole, pyridine, pyrimidine, pyrazine, and pyridazine.

25 . A compound according to claim 24 wherein said optionally substituted monocyclic heteroaryl is chosen from pyrazole, oxazole, isoxazole, triazole, oxadiazole, and imidazole.

26 . A compound according to claim 25 wherein said optionally substituted monocyclic heteroaryl is pyrazole or triazole.

27 . A compound according to claim 26 wherein the optional substituent is methyl.

28 . A compound according to claim 18 wherein R 4 is:

R 20 is hydrogen or methyl, and R 2 is hydrogen.

29 - 30 . (canceled)

31 . A method of inhibiting an inflammatory response in a patient comprising administering a compound of formula (II):

wherein:
R 1 is hydrogen, (C 1 -C 3 )alkyl, CH 2 CH 2 —OR 3 , or fluoro(C 1 -C 3 )alkyl;
R 2 is hydrogen or (C 1 -C 3 )alkyl, CH 2 CH 2 —OR 3 , or, taken together along with the atoms to which they are attached, R 2 and R 30 may form a 4- to 6-membered aliphatic ring;
R 3 is hydrogen or (C 1 -C 3 )alkyl;
R 4 is chosen from hydrogen, halogen, (C 1 -C 3 )alkoxy, optionally substituted monocyclic heterocyclyl, 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, (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, meta-(C 1 -C 3 )dialkylamino, (C 1 -C 3 )alkoxy, hydroxy, halogen, ortho-cyano, meta-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 5 is chosen from hydrogen, halogen, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, fluoro(C 1 -C 3 )alkyl, fluoro(C 1 -C 3 )alkoxy, cyano, and

R 6 is chosen from hydrogen, halogen, cyano, —C≡CH, —CH═CH 2 , methyl, and trifluoromethyl;
R 7 is chosen from hydrogen, halogen, (C 1 -C 3 )alkoxy, fluoro(C 1 -C 3 )alkoxy, cyano, (C 1 -C 3 )alkyl, and fluoro(C 1 -C 3 )alkyl;
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 car

Assignees

• Univ Rockefeller
• Memorial Sloan Kettering Cancer Center

Inventors

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

Classifications

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title