Modulators of trex1

Patent metadata

Field	Value
Publication number	US-2024262814-A1
Application number	US-202218289467-A
Country	US
Kind code	A1
Filing date	May 4, 2022
Priority date	May 5, 2021
Publication date	Aug 8, 2024
Grant date	—

Abstract

Provided are compounds of Formula (I): and pharmaceutically acceptable salts and compositions thereof, which are useful for treating a variety of conditions associated with TREX1.

First claim

1 . A compound having the Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is halo, hydrogen, (C 1 -C 4 )alkyl, or halo(C 1 -C 4 )alkyl;
R 2 is hydrogen, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkylOR a , —(C 1 -C 4 )alkylSR a , —(C 1 -C 4 )alkylNR a R b ,
R a and R b are each independently selected from hydrogen, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, COOR c , and —C(O)NR c R d ;
R 3 and R 4 are each independently hydrogen, halo, (C 1 -C 4 )alkyl, or halo(C 1 -C 4 )alkyl, wherein when R 3 is halo then R 4 is halo and wherein when R 3 is hydrogen then R 4 is (C 1 -C 4 )alkyl or halo(C 1 -C 4 )alkyl;
R 5 and R 6 are each independently (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, halo, cyano, or —C(O)NR c R d ;
R c and R d are each independently hydrogen or (C 1 -C 4 )alkyl; and
t and q are independently 0, 1, 2, or 3.

2 . The compound of claim 1 , wherein the compound is of the Formula II:

or a pharmaceutically acceptable salt thereof.

3 . The compound of claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein R 1 is H.

4 . The compound of any one of claims 1 to 3 , or a pharmaceutically acceptable salt thereof, wherein R 2 is (C 1 -C 4 )alkyl.

5 . The compound of any one of claims 1 to 4 , or a pharmaceutically acceptable salt thereof, wherein R 3 is halo.

6 . The compound of any one of claims 1 to 4 , or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen.

7 . The compound of any one of claims 1 to 6 , or a pharmaceutically acceptable salt thereof, wherein R 4 is halo.

8 . The compound of any one of claims 1 to 6 , or a pharmaceutically acceptable salt thereof, wherein R 4 is (C 1 -C 4 )alkyl or halo(C 1 -C 4 )alkyl.

9 . The compound of any one of claims 1 to 6 , or a pharmaceutically acceptable salt thereof, wherein R 4 is (C 1 -C 4 )alkyl.

10 . The compound of any one of claims 1 to 9 , or a pharmaceutically acceptable salt thereof, wherein R 5 is halo, cyano, or —C(O)NR a R b .

11 . The compound of any one of claims 1 to 10 , or a pharmaceutically acceptable salt thereof, wherein R 6 is halo, cyano, or —C(O)NR a R b .

12 . The compound of any one of claims 1 to 11 , or a pharmaceutically acceptable salt thereof, wherein R 6 is halo or cyano.

13 . The compound of claim 1 , wherein the compound is selected from:

or a pharmaceutically acceptable salt of any one of the foregoing.

14 . A pharmaceutical composition comprising the compound of any one of claims 1 to 13 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

15 . A method of treating a disease responsive to the inhibition of TREX1 in a subject, comprising administering to the subject, a therapeutically effective amount of a compound of any one of claims 1 to 13 , or a pharmaceutically acceptable salt thereof, or the composition of claim 14 .

16 . The method of claim 15 , wherein the disease is cancer.

Assignees

• Constellation Pharmaceuticals Inc

Inventors

• Levell Julian R
• Coffin Aaron
• Khanna Avinash
• Wilson Jonathan E

Classifications

• A61K31/513

  having oxo groups directly attached to the heterocyclic ring, e.g. cytosine · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D413/12 Primary

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