3,4-Dihydroisoquinolin-1(2H)-Ones Derivatives as STING Antagonists and the Use Thereof
The disclosure herein provides compounds as well as their compositions and methods of use. The compounds disclosed herein modulate, e.g., antagonize, stimulator of interferon genes (STING) activity and are useful in the treatment of various inflammatory diseases including systemic lupus erythematosus.
1 . A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a deuterated analog thereof,
wherein:
is a single bond or a double bond;
is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl or triazolyl;
X 1 is CH 2 ;
X 2 is CR x2 ;
X 3 is CR x3 ;
X 4 is CR x4 ;
X 5 is CR x5 ;
X 6 is CR x6 ;
X 7 is CR x7 ;
at each of its occurrences, R 1 is hydrogen, halogen, —C 1-8 alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each of said —C 1-8 alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with at least one substituent R 1d ;
R 1a is selected from hydrogen and —C 1-8 alkyl, said —C 1-8 alkyl is optionally substituted with at least one substituent R 1f ;
R 1d and R 1f are each independently selected from hydrogen, halogen, —CN, and —OR 1g ,
R 2 is hydrogen;
R 3 is —C 1-8 alkyl or cycloalkyl;
R x2 , R x3 and R x4 are each independently hydrogen;
R 5x , R 6x and R 7x are each independently hydrogen;
n1 and n2 are each independently 0, 1, 2, or 3, provided that the valency theory is met;
n3 is 0, 1, or 2.
2 - 9 . (canceled)
10 . The compound of claim 1 , wherein R 1 is hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, methoxy, ethoxy, propoxy butoxy pentoxy, hexoxy, heptoxy, octoxy, —CF 3 , —O—CF 3 , —CHF 2 or —CH 2 F.
11 - 17 . (canceled)
18 . The compound of claim 1 , wherein the
moiety is selected from
19 - 24 . (canceled)
25 . The compound of claim 1 , wherein the
moiety is
26 - 32 . (canceled)
33 . The compound of claim 1 , wherein R 3 is methyl, ethyl, propyl, butyl.
34 . The compound of claim 1 , wherein R 3 is methyl, ethyl, n-propyl, iso-propy, n-butyl, sec-butyl, iso-butyl, tert-butyl, cyclopropyl, cyclobutyl, or cyclopentyl.
35 . A compound selected from
36 . A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient.
37 . A method of treating a disease that can be modulated by STING pathway, comprises administrating a subject in need thereof an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
38 . Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease that can be modulated by STING pathway.
39 . A pharmaceutical composition comprising a compound of claim 35 or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient.
40 . A method of treating a disease that can be modulated by STING pathway, comprises administrating a subject in need thereof an effective amount of a compound of claim 35 or a pharmaceutically acceptable salt thereof.
41 . Use of a compound of claim 35 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease that can be modulated by STING pathway.