US 12,172,990 B2
Modulators of TREX1
Anna Gardberg, Boston, MA (US); Victor S. Gehling, Somerville, MA (US); Avinash Khanna, Cambridge, MA (US); Julian R. Levell, Arlington, MA (US); Jonathan E. Wilson, Arlington, MA (US); and Kennedy Taveras, Lynn, MA (US)
Assigned to Constellation Pharmaceuticals, Inc., Boston, MA (US)
Appl. No. 17/311,526
Filed by Constellation Pharmaceuticals, Inc., Boston, MA (US)
PCT Filed Dec. 6, 2019, PCT No. PCT/US2019/064825
§ 371(c)(1), (2) Date Jun. 7, 2021,
PCT Pub. No. WO2020/118133, PCT Pub. Date Jun. 11, 2020.
Claims priority of provisional application 62/776,031, filed on Dec. 6, 2018.
Prior Publication US 2022/0017502 A1, Jan. 20, 2022
Int. Cl. C07D 413/12 (2006.01); A61P 35/00 (2006.01); C07D 413/14 (2006.01)
CPC C07D 413/12 (2013.01) [A61P 35/00 (2018.01); C07D 413/14 (2013.01)] 19 Claims
 
1. A compound of having the Formula I:

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof, wherein:
R1 is hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, 3- to 4-membered cycloalkyl, —ORf, —SRf, or —NReRf;
R2 is hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, or 3- to 4-membered cycloalkyl;
X is a bond, NR3, O, S, or (C1-C4)alkylene, wherein said (C1-C4)alkylene is optionally substituted with 1 to 2 groups selected from R4;
R3 is hydrogen, (C1-C4)alkyl, —C(O)Rd, or —C(S)Rd;
R4 is halo, (C1-C4)alkyl, phenyl, —NHC(O)ORa, —NHC(S)ORa, —C(O)Rb, —NHC(O)NHRg, —NHC(S)NHRg, —NHS(O) 2NHRg, —C(S)Rb, S(O)2Rc, S(O)Re, —C(O)OR4, —C(S)OR4, —C(O)NHRe, —C(S)NHRe, —NHC(O)Rd, —NHC(S)Rd, —ORe, —SRe, —O(C1-C4)alkylORe, or —NReRf, wherein said phenyl for R4 is optionally substituted with 1 or 2 groups selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4) alkoxy, and halo(C1-C4) alkoxy;
Ring A is phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocyclyl, or 3- to 7-membered cycloalkyl, each of which are optionally and independently substituted with 1 or 2 groups selected from R5;
R5 is (C1-C4)alkyl, halo(C1-C4)alkyl, halo(C1-C4) alkoxy, halo, phenyl, —NHC(O)ORa, —NHC(S)ORa, —C(O)Rb, —NHC(O)NHRg, —NHC(S)NHRg, —NHS(O)2NHRg, —C(S)Rb, S(O)2Rc, S(O)Rc, —C(O)OR4, —C(S)OR4, —C(O)NReRf, —C(S)NHRe, —NHC(O)R4, —NHC(S)Rd, —ORe, —SRe, —O(C1-C4)alkylORe, —NReRf, 4- to 6-membered heteroaryl, or 4- to 7-membered heterocyclyl, wherein said phenyl for R5 is optionally substituted with 1 or 2 groups selected from Rg, said (C1-C4)alkyl for R5 is optionally substituted with 1 or 2 groups selected from ORh, —NRjRk, phenyl, and 5- to 6-membered heteroaryl, said 4- to 7-membered heterocyclyl and 4- to 6-membered heteroaryl are each optionally and independently substituted with 1 or 2 groups selected from Rm, and wherein said phenyl and 5- to 6-membered heteroaryl of the optional substituents listed for (C1-C4)alkyl in R5 are each optionally and independently substituted with 1 or 2 groups selected from Rg;
Rg, Rh, Rj, Rk, and Rm are each independently hydrogen, halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4) alkoxy, halo(C1-C4) alkoxy, phenyl, —(C1-C4)alkylphenyl, 3- to 4-membered cycloalkyl, 4- to 6-membered heteroaryl, or 4- to 7-membered heterocyclyl, and wherein said 4- to 7-membered heterocyclyl for Rg, Rh, Rj and Rk is further optionally substituted with ═O,
Ra, Rb, Rc, Rd, Re and Rf are each independently hydrogen, halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4) alkoxy, halo(C1-C4) alkoxy, phenyl, 3- to 4-membered cycloalkyl, 4- to 6-membered heteroaryl, or 4- to 7-membered heterocyclyl, wherein i) said (C1-C4)alkyl for Ra, Rb, Rc, Rd, Re and Rg is optionally substituted with 1 or 2 groups selected from phenyl, —ORh, —NRjRk; ii) said phenyl, 4- to 6-membered heteroaryl, and 4- to 7-membered heterocyclyl for Ra, Rb, Rc, Rd, Re, and Rf are each optionally and independently substituted with 1 or 2 groups selected from Rg, and iii) said 4- to 7-membered heterocyclyl for Ra, Rb, Rc, Rd, Re, and Rf is further optionally substituted with ═O.