Thiadiazolyl derivatives as DNA polymerase theta inhibitors and uses thereof
Disclosed herein are compounds of Formula (I): that inhibit DNA Polymerase Theta (Polθ) activity, in particular inhibit Polθ activity by inhibiting ATP dependent helicase domain activity of Polθ. Also, disclosed are pharmaceutical compositions comprising such compounds and methods of treating and/or preventing diseases treatable by inhibition of Polθ such as cancer, including homologous recombination (HR) deficient cancers.
1. A compound of Formula (I):
wherein:
R 1 is H, halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, or C 1-4 haloalkoxy;
each R 2 is independently halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy;
X is a prodrug moiety;
R 3 is C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, or heterocycloalkyl, wherein said C 3-6 cycloalkyl and said heterocycloalkyl are optionally substituted with 1 to 4 R 3a substituents, each of which is independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, -L 3 -O—C 1-4 alkyl, -L 3 -OH, and oxo;
each L 3 is independently selected from a bond and C 1-4 alkylene;
each heterocycloalkyl has from 4 to 6 ring members and from 1 to 3 heteroatoms as ring vertices independently selected from N, O, and S; and
n is 0, 1, 2, or 3;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is —CH(R c )—O—P(O)(OR a )(OR b ), —CH(R c )—O—C(O)—C 1-6 alkylene-CO 2 H, —CH(R c )—O—C(O)—C 1-6 alkylene-O—P(O)(OR a )(OR b ), —CH(R c )—O—C(O)—C 1-6 alkylene-P(O)(OR a )(OR b ), —CH(R c )—O—C(O)—C 1-6 alkylene-NR a R b , or —CH(R c )—O—C(O)—C 1-6 alkylene-heterocycloalkyl, and wherein R a and R b are each independently H or C 1-4 alkyl, and R c is independently selected from hydrogen and methyl.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1-4 alkyl.
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 2 is independently halo, C 1-4 alkoxy, or C 1-4 haloalkoxy.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, or 3.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is C 1-4 alkyl or C 1-4 haloalkyl.
9. A pharmaceutical composition comprising a compound of claim 1 , and at least one pharmaceutically acceptable excipient.
10. The compound of claim 1 , having the structure:
or a pharmaceutically acceptable salt thereof.
11. A compound having the structure:
or a pharmaceutically acceptable salt thereof.
12. A compound having the structure:
13. A pharmaceutical composition comprising a compound of claim 11 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.