Substituted pyridines as PARP1 inhibitors

1. A compound of Formula (Ip):

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof,

wherein:

each R 1 ″ is independently H or R 1 ;

each R 1 is independently D, halogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein each C 1 -C 6 alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more independently selected R substituents;

Z is CR Z or N;

R Z is H, D, halogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein the C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more independently selected R substituents;

R 2 is H, D, halogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein the C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more independently selected R substituents;

R 3 is H, D, halogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein the C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more independently selected R substituents;

each R 4 is independently D, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; or

any two geminal R 4 , taken together with the carbon atom to which they are attached, form —C(O)—;

R 5 is H, D, halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, NR c R d , OH, OR a , cycloalkyl, or heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more independently selected R substituents;

R 6 is H, D, halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, NR c R d , OH, OR a , cycloalkyl, or heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more independently selected R substituents;

R 7 is H, D, halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, NR c R d , OH, OR a , cycloalkyl, or heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more independently selected R substituents;

R 8 is H, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more independently selected R substituents;

each R a is independently C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more independently selected R substituents;

each R c is independently H, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more independently selected R substituents;

each R d is independently H, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more independently selected R substituents; or

any R c and R d , taken together with the nitrogen atom to which they are attached, independently forms a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more independently selected R substituents;

each R is independently halogen, CN, C 1 -C 3 alkyl, C 1 -C 3 deuteroalkyl, C 1 -C 3 haloalkyl, C 1 -C 3 aminoalkyl, C 1 -C 3 hydroxyalkyl, C 1 -C 3 heteroalkyl, C(O)NH 2 , C(O)NHC 1 -C 3 alkyl, C(O)N(C 1 -C 3 alkyl) 2 , C(O)OH, C(O)C 1 -C 3 alkyl, C(O)OC 1 -C 3 alkyl, NH 2 , NHC 1 -C 3 alkyl, N(C 1 -C 3 alkyl) 2 , OH, OC 1 -C 3 alkyl, OC 1 -C 3 haloalkyl, SC 1 -C 3 alkyl, S(O)C 1 -C 3 alkyl, S(O) 2 C 1 -C 3 alkyl, S(O) 2 NH 2 , S(O) 2 NHC 1 -C 3 alkyl, S(O) 2 N(C 1 -C 3 alkyl) 2 , or C 3 -C 6 cycloalkyl; or

any two geminal R, taken together with the carbon atom to which they are attached, form —C(O)—; and

m is 0, 1, 2, 3, or 4.

2. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein each R 1 ′ is independently H.

3. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein Z is CR Z .

4. The compound of claim 3 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R Z is H, D, halogen, or C 1 -C 6 alkyl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein Z is N.

6. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 2 is H, D, or C 1 -C 6 alkyl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 3 is H, D, or C 1 -C 6 alkyl.

8. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:

R 2 is H; and

R 3 is H.

9. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 5 is H, halogen, or C 1 -C 6 alkyl.

10. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 5 is halogen.

11. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 6 is H, halogen, or C 1 -C 6 alkyl.

12. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 6 is H.

13. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 7 is H, halogen, or C 1 -C 6 alkyl.

14. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 7 is H.

15. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 8 is C 1 -C 6 alkyl or cycloalkyl, wherein the C 1 -C 6 alkyl or cycloalkyl is optionally substituted with one or more independently selected R substituents.

16. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 8 is C 1 -C 6 alkyl.

17. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein m is 0.

18. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.