Substituted pyrrolo[1,2-a]pyrazines and pyrrolo[1,2-a][1,4]diazepines as TREX1 inhibitors
The present invention provides compounds of Formula I wherein X, R 1 , R 2 , R 3 and R 4 are as defined herein, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug ester or solvate form thereof, wherein all of the variables are as defined herein. These compounds are effective at modulating the TREX1 protein and thus can be used as medicaments for treating or preventing disorders affected by the inhibition of TREX1.
1. A compound of Formula I:
or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein:
X is —C 1 -C 6 alkylene-NR 5 C(O)—, —C 1 -C 6 alkylene-NR 5 S(O) 2 —, —C(O)NR 5 —, —C(O)NR 5 S(O) 2 —, or a 5-membered heteroarylene, wherein the 5-membered heteroarylene contains at least 1 nitrogen heteroatom;
R 1 is C 1 -C 6 alkylene-NR 5 R 6 or NR 5 R 6 ;
R 2 is C 1 -C 6 alkyl, C 1 -C 6 alkylene-O—C 6 -C 10 aryl, C 1 -C 6 alkylene-O-5- to 10-membered heteroaryl, C 1 -C 6 alkylene-S—C 6 -C 10 aryl, C 1 -C 6 alkylene-S—5- to 10-membered heteroaryl, C 1 -C 6 alkylene-S(O)—C 6 -C 10 aryl, C 1 -C 6 alkylene-S(O)-5- to 10-membered heteroaryl, C 1 -C 6 alkylene-S(O) 2 —C 6 -C 10 aryl, C 1 -C 6 alkylene-S(O) 2 -5 to 10-membered heteroaryl, C 1 -C 6 alkylene-C 6 -C 10 aryl, or C 1 -C 6 alkylene-5- to 10-membered heteroaryl, wherein any C 6 -C 10 aryl or 5- to 10-membered heteroaryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, OH, OC 1 -C 4 alkyl, and OC 1 -C 4 haloalkyl;
R 3 is C 1 -C 6 alkyl, C 1 -C 6 alkylene-C 3 -C 6 cycloalkyl, C 1 -C 6 alkylene-C 6 -C 10 aryl, C 1 -C 6 alkylene-5- to 10-membered heteroaryl, or C 6 -C 10 aryl, wherein any C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, OH, OC 1 -C 4 alkyl, and OC 1 -C 6 haloalkyl;
R 4 is C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with 1 or more substituents independently selected from the group consisting of CN, C(O)NR 8 R 9 , C(O)NR 8 S(O) 2 R 9 , C(O)NR 8 S(O) 2 NR 28 R 29 , C(O)OH, NR 8 R 9 , NR 28 C(O)NR 8 R 9 , NR 28 C(O)NR 8 S(O) 2 R 9 , NR 8 S(O) 2 R 9 , OH, ONR 8 R 9 , SR 9 , S(O)R 9 , S(O) 2 R 9 , S(O) 2 NR 8 R 9 , S(O) 2 OH, C 6 -C 10 aryl, and a 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl contains at least 1 nitrogen heteroatom, and further wherein any C 6 -C 10 aryl or 5- to 10-membered heteroaryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, OH, ═O, OC 1 -C 4 alkyl, and OC 1 -C 4 haloalkyl;
each R 5 is independently H, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
each R 6 is independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C(O)R 7 ;
each R 7 is independently C 1 -C 6 alkyl or OC 1 -C 6 alkyl;
each R 8 is independently H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C(O)C 1 -C 4 alkyl, OC 1 -C 4 alkyl, or OC 1 -C 4 haloalkyl;
each R 9 is independently H, C 1 -C 4 alkyl, OH, OC 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, or C 6 -C 10 aryl, wherein each C 1 -C 4 alkyl, OC 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, and C 6 -C 10 aryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, OH, ═O, OC 1 -C 4 alkyl, and OC 1 -C 4 haloalkyl;
each R 28 is independently H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, OC 1 -C 4 alkyl, or OC 1 -C 4 haloalkyl; and
each R 29 is independently H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, OC 1 -C 4 alkyl, or OC 1 -C 4 haloalkyl.
2. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein:
X is —C 1 -C 6 alkylene-NR 5 C(O)—, —C(O)NR 5 —, —C(O)NR 5 S(O) 2 —, or a 5-membered heteroarylene, wherein the 5-membered heteroarylene contains at least 1 nitrogen heteroatom;
R 2 is C 1 -C 6 alkyl, C 1 -C 6 alkylene-O—C 6 -C 10 aryl, C 1 -C 6 alkylene-S—C 6 -C 10 aryl, C 1 -C 6 alkylene-S(O)—C 6 -C 10 aryl, C 1 -C 6 alkylene-S(O) 2 -C 6 -C 10 aryl, or C 1 -C 6 alkylene-C 6 -C 10 aryl, wherein any C 6 -C 10 aryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, OH, OC 1 -C 4 alkyl, and OC 1 -C 4 haloalkyl;
R 3 is C 1 -C 6 alkyl, C 1 -C 6 alkylene-C 6 -C 10 aryl, C 1 -C 6 alkylene-5- to 10-membered heteroaryl, or C 6 -C 10 aryl, wherein any C 6 -C 10 aryl or the 5- to 10-membered heteroaryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, OH, OC 1 -C 4 alkyl, and OC 1 -C 6 haloalkyl;
R 4 is C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with 1 or more substituents independently selected from the group consisting of CN, C(O)NR 8 R 9 , C(O)OH, OH, C 6 -C 10 aryl, and 5-membered heteroaryl, wherein the 5-membered heteroaryl contains at least 1 nitrogen heteroatom, and further wherein any C 6 -C 10 aryl or 5-membered heteroaryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, OH, ═O, OC 1 -C 4 alkyl, and OC 1 -C 4 haloalkyl;
each R 8 is independently H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or OC 1 -C 4 alkyl; and
each R 9 is independently H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or OC 1 -C 4 alkyl.
3. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein:
X is —C 1 -C 6 alkylene-NR 5 C(O)—, —C(O)NR 5 —, or a 5-membered heteroarylene, wherein the 5-membered heteroarylene contains at least 1 nitrogen heteroatom;
R 2 is C 1 -C 6 alkyl, C 1 -C 6 alkylene-O—C 6 -C 10 aryl, C 1 -C 6 alkylene-S—C 6 -C 10 aryl, or C 1 -C 6 alkylene-C 6 -C 10 aryl, wherein any C 6 -C 10 aryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C alkyl, C 1 -C 4 haloalkyl, OH, OC 1 -C 4 alkyl, and OC 1 -C 4 haloalkyl;
R 3 is C 1 -C 6 alkyl, C 1 -C 6 alkylene-C 6 -C 10 aryl, C 1 -C 6 alkylene-5-membered heteroaryl, or C 6 -C 10 aryl, wherein any C 6 -C 10 aryl or 5-membered heteroaryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, OH, OC 1 -C 4 alkyl, and OC 1 -C 6 haloalkyl;
R 4 is C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with 1 or more substituents independently selected from the group consisting of CN, C(O)NR 8 R 9 , C(O)OH, OH, C 6 -C 10 aryl, and 5-membered heteroaryl, wherein the 5-membered heteroaryl contains at least 1 nitrogen heteroatom, and further wherein any C 6 -C 10 aryl or 5-membered heteroaryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, OH, ═O, OC 1 -C 4 alkyl, and OC 1 -C 4 haloalkyl;
each R 8 is independently H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or OC 1 -C 4 alkyl; and
each R 9 is independently H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or OC 1 -C 4 alkyl.
4. The compound of claim 3 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein:
X is —C(O)NR 5 —;
R 1 is NR 5 R 6 ;
R 2 is C 1 -C 6 alkylene-C 6 -C 10 aryl, wherein the C 6 -C 10 aryl is optionally substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4 alkyl, OH, and OC 1 -C 4 haloalkyl;
R 3 is C 1 -C 6 alkylene-C 6 -C 10 aryl, wherein the C 6 -C 10 aryl is optionally substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and OH;
R 4 is C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with 1 or more substituents independently selected from the group consisting of C(O)OH, OH, C 6 -C 10 aryl, and 5-membered heteroaryl, wherein the 5-membered heteroaryl contains at least 1 nitrogen heteroatom, and further wherein any C 6 -C 10 aryl or 5-membered heteroaryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, OH, ═O, OC 1 -C 4 alkyl, and OC 1 -C 4 haloalkyl;
each R 5 is independently H or CH 3 ; and
R 6 is H or C 1 -C 6 alkyl.
5. The compound of claim 4 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein:
6. The compound of claim 5 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein R 4 is C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is substituted with 1 substituent selected from the group consisting of C(O)OH and 5-membered heteroaryl, wherein the 5-membered heteroaryl contains at least 1 nitrogen heteroatom, and further wherein the 5-membered heteroaryl is optionally substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, OH, ═O, OC 1 -C 4 alkyl, and OC 1 -C 4 haloalkyl.
7. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein:
X is —C 1 -C 6 alkylene-NR 5 C(O)— or —C(O)NR 5 —;
R 2 is C 1 -C 6 alkyl, C 1 -C 6 alkylene-O—C 6 -C 10 aryl, or C 1 -C 6 alkylene-C 6 -C 10 aryl, wherein any C 6 -C 10 aryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, OH, OC 1 -C 4 alkyl, and OC 1 -C 4 haloalkyl;
R 3 is C 1 -C 6 alkyl, C 1 -C 6 alkylene-C 6 -C 10 aryl, or C 6 -C 10 aryl, wherein any C 6 -C 10 aryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, OH, OC 1 -C 4 alkyl, and OC 1 -C 6 haloalkyl;
R 4 is C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with 1 or more substituents independently selected from the group consisting of CN, C(O)NR 8 R 9 , C(O)OH, OH, and C 6 -C 10 aryl, wherein any C 6 -C 10 aryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, OH, OC 1 -C 4 alkyl, and OC 1 -C 4 haloalkyl;
each R 8 is independently H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or OC 1 -C 4 alkyl; and
each R 9 is independently H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or OC 1 -C 4 alkyl.
8. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein:
X is —C 1 -C 6 alkylene-NR 5 C(O)— or —C(O)NR 5 —;
R 2 is C 1 -C 6 alkyl or C 1 -C 6 alkylene-C 6 -C 10 aryl, wherein the C 6 -C 10 aryl is optionally substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, OH, OC 1 -C 4 alkyl, and OC 1 -C 4 haloalkyl;
R 3 is C 1 -C 6 alkyl, C 1 -C 6 alkylene-C 6 -C 10 aryl, or C 6 -C 10 aryl, wherein any C 6 -C 10 aryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, OH, OC 1 -C 4 alkyl, and OC 1 -C 6 haloalkyl;
R 4 is C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with 1 or more substituents independently selected from the group consisting of CN, C(O)NR 8 R 9 , C(O)OH, OH, and C 6 -C 10 aryl, wherein any C 6 -C 10 aryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, OH, OC 1 -C 4 alkyl, and OC 1 -C 4 haloalkyl;
each R 8 is independently H, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl; and
each R 9 is independently H, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl.
9. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein:
X is —C(O)NR 5 —;
R 1 is NR 5 R 6 ;
R 2 is C 1 -C 6 alkyl or C 1 -C 6 alkylene-C 6 -C 10 aryl, wherein the C 6 -C 10 aryl is optionally substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and OH;
R 3 is C 1 -C 6 alkyl, C 1 -C 6 alkylene-C 6 -C 10 aryl, or C 6 -C 10 aryl, wherein the C 6 -C 10 aryl is optionally substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and OH;
R 4 is C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with 1 or more substituents independently selected from the group consisting of C(O)OH, OH, and C 6 -C 10 aryl, wherein any C 6 -C 10 aryl is optionally substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and OH;
each R 5 is independently H or C 1 -C 6 alkyl;
R 6 is H, C 1 -C 6 alkyl, or C(O)R 7 ; and
R 7 is C 1 -C 6 alkyl or OC 1 -C 6 alkyl.
10. The compound of claim 6 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.
11. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound, or pharmaceutically acceptable salt or stereoisomer thereof, is selected from the group consisting of:
or a solvate or tautomer thereof.
12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, alone or in combination with another therapeutic agent.
13. The pharmaceutical composition of claim 12 , wherein the other therapeutic agent is selected from the group consisting of an anti-cancer agent, an anti-viral compound, an adjuvant, an antigen, a biotherapeutic agent, a cell transfected with a gene that encodes an immune stimulating cytokine, a checkpoint inhibitor, a chemotherapeutic agent, a cytotoxic agent, an immunogenic agent, an immunomodulatory cell line, a lipid, a liposome, and a peptide.