Substituted carboxamides as inhibitors of WDR5 protein-protein binding

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof,

wherein:

A is F;

X 1 is CR 10 ;

X 2 is CR 10 ;

X 3 is CR 10 ;

X 4 is CR 10 ;

X 5 is CH;

X 6 is CH;

X 7 is CH;

R 1 is heterocycloalkyl, optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-NR 5 R 6 , C 1-6 alkylene-OR 4 , C 1-6 alkylene-SR 4 , NR 5 R 6 , OR 4 , SR 4 , and C 3-10 cycloalkyl;

R 2 is selected from the group consisting of:

or a tautomer thereof;

R 4 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C(O)CH—, alkyl, or C(O)C 1-6 fluoroalkyl;

R 5 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-NH—C 1-6 alkyl, C 1-6 alkylene-N(C 1-6 alkyl)(C 1-6 alkyl), C 1-6 alkylene-O—C 1-6 alkyl, C 1-6 alkylene-C 3-6 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C(O)NHC 1-6 alkyl, C(O)OC 1-6 alkyl, S(O) 2 C 1-6 alkyl, S(O) 2 NHC 1-6 alkyl, or heterocycloalkyl;

R 6 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-NH—C 1-6 alkyl, C 1-6 alkylene-N(C 1-6 alkyl)(C 1-6 alkyl), C 1-6 alkylene-O—C 1-6 alkyl, C 1-6 alkylene-C 3-6 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C(O)NHC 1-6 alkyl, C(O)OC 1-6 alkyl, S(O) 2 C 1-6 alkyl, S(O) 2 NHC 1-6 alkyl, or heterocycloalkyl; or

R 5 and R 6 , together with the nitrogen atom to which they are attached, form a 3-10 membered heterocyclyl, optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-O—C 1-6 alkyl, C 1-6 alkylene-NH—C 1-6 alkyl, C 1-6 alkylene-N(C 1-6 alkyl)(C 1-6 alkyl),C 1-6 alkylene-C 3-6 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C(O)NHC 1-6 alkyl, C(O)OC 1-6 alkyl, OH, OC 1-6 alkyl, OC 1-6 fluoroalkyl, S(O) 2 C 1-6 alkyl, and S(O) 2 NHC 1-6 alkyl;

R 7 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C(O)C 1-6 alkyl, or C(O)C 1-6 fluoroalkyl;

R 8 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C(O)C 1-6 alkyl, or C(O)C 1-6 fluoroalkyl;

R 9 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C(O)C 1-6 alkyl, or C(O)C 1-6 fluoroalkyl; or

R 8 and R 9 , together with the nitrogen atom to which they are attached, form a 3-10 membered heterocyclyl, optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, C 1-6 alkyl, C 1-6 fluoroalkyl, OH, OC 1-6 alkyl, or OC 1-6 fluoroalkyl;

R 10 is H, halo, CN, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-R 14 , C 1-6 alkylene-NR 12 R 13 , C 1-6 alkylene-OR 11 , C 1-6 alkylene-SR 11 , C(O)NR 12 R 13 , C(O)OR 11 , C(S)NR 12 R 13 , C(S)OR 11 , NR 12 R 13 , OR 11 , OC 1-6 alkylene-R 14 , OC 1-6 alkylene-NR 12 R 13 , OC 1-6 alkylene-OR 11 , OC 1-6 alkylene-SR 11 , SR 11 , SC 1-6 alkylene-R 14 , SC 1-6 alkylene-NR 12 R 13 , SC 1-6 alkylene-OR 11 , SC 1-6 alkylene-SR 11 , or R 14 ;

R 11 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, or heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, C 1-6 alkyl, C 1-6 alkylene-NR 16 R 17 , C 1-6 alkylene-OR 15 , C 1-6 alkylene-SR 15 , C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-heteroaryl, C 1-6 alkylene-R 15 , C(O)NR 16 R 17 , C(O)OR 15 , C(O)R 15 , NR 16 R 17 , OR 15 , SR 15 , S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl;

R 12 is H, C 1-10 alkyl, C 1-10 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, or heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, C 1-6 alkyl, C 1-6 alkylene-NR 16 R 17 , C 1-6 alkylene-OR 15 , C 1-6 alkylene-SR 15 , C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-heteroaryl, C 1-6 alkylene-R 15 , C(O)NR 16 R 17 , C(O)OR 15 , C(O)R 15 , NR 16 R 17 , OR 15 , SR 15 , S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl;

R 13 is H, C 1-10 alkyl, C 1-10 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, or heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, C 1-6 alkyl, C 1-6 alkylene-NR 16 R 17 , C 1-6 alkylene-OR 15 , C 1-6 alkylene-SR 15 , C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-heteroaryl, C 1-6 alkylene-R 15 , C(O)NR 16 R 17 , C(O)OR 15 , C(O)R 15 , NR 16 R 17 , OR 15 , SR 15 , S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl; or

R 12 and R 13 , together with the nitrogen atom to which they are attached, form a 3-10 membered heterocyclyl, optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, C 1-6 alkyl, C 1-6 alkylene-NR 16 R 17 , C 1-6 alkylene-OR 15 , C 1-6 alkylene-SR 15 , C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-heteroaryl, C 1-6 alkylene-R 15 , C(O)NR 16 R 17 , C(O)OR 15 , C(O)R 15 , NR 16 R 17 , OR 15 , SR 15 , S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl;

R 14 is C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, or heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, C 1-6 alkyl, C 1-6 alkylene-NR 16 R 17 , C 1-6 alkylene-OR 15 , C 1-6 alkylene-SR 15 , C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C 1-6 alkylene-R 5 , C(O)R 15 , C(O)OR 5 , C(O)NR 16 R 17 , NR 16 R 17 , OR 15 , SR 15 , S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl;

R 15 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C 3-10 cycloalkyl, heterocycloalkyl, or C 6-10 aryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-NH 2 , C 1-6 alkylene-NHC 1-6 alkyl, C 1-6 alkylene-N(C 1-6 alkyl)(C 1-6 alkyl), C 1-6 alkylene-OH, C 1-6 alkylene-O—C 1-6 alkyl, C 1-6 alkylene-SH, C 1-6 alkylene-S—C 1-6 alkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C(O)NH 2 , C(O)NHC 1-6 alkyl, C(O)N(C 1-6 alkyl)(C 1-6 alkyl), C(O)OH, C(O)OC 1-6 alkyl, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl)(C 1-6 alkyl), OH, OC 1-6 alkyl, OC 1-6 fluoroalkyl, SH, SC 1-6 alkyl, SC 1-6 fluoroalkyl, S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl;

R 16 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C(O)C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, or C 6-10 aryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-NH 2 , C 1-6 alkylene-NHC 1-6 alkyl, C 1-6 alkylene-N(C 1-6 alkyl)(C 1-6 alkyl), C 1-6 alkylene-OH, C 1-6 alkylene-O—C 1-6 alkyl, C 1-6 alkylene-SH, C 1-6 alkylene-S—C 1-6 alkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C(O)NH 2 , C(O)NHC 1-6 alkyl, C(O)N(C 1-6 alkyl)(C 1-6 alkyl), C(O)OH, C(O)OC 1-6 alkyl, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl)(C 1-6 alkyl), OH, OC 1-6 alkyl, OC 1-6 fluoroalkyl, SH, SC 1-6 alkyl, SC 1-6 fluoroalkyl, S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl; and

R 17 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C(O)C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, or C 6-10 aryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-NH 2 , C 1-6 alkylene-NHC 1-6 alkyl, C 1-6 alkylene-N(C 1-6 alkyl)(C 1-6 alkyl), C 1-6 alkylene-OH, C 1-6 alkylene-O—C 1-6 alkyl, C 1-6 alkylene-SH, C 1-6 alkylene-S—C 1-6 alkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C(O)NH 2 , C(O)NHC 1-6 alkyl, C(O)N(C 1-6 alkyl)(C 1-6 alkyl), C(O)OH, C(O)OC 1-6 alkyl, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl)(C 1-6 alkyl), OH, OC 1-6 alkyl, OC 1-6 fluoroalkyl, SH, SC 1-6 alkyl, SC 1-6 fluoroalkyl, S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl; or

R 16 and R 17 , together with the nitrogen atom to which they are attached, form a 3-10 membered heterocyclyl, optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-NH 2 , C 1-6 alkylene-NHC 1-6 alkyl, C 1-6 alkylene-N(C 1-6 alkyl)(C 1-6 alkyl), C 1-6 alkylene-OH, C 1-6 alkylene-O—C 1-6 alkyl, C 1-6 alkylene-SH, C 1-6 alkylene-S—C 1-6 alkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C(O)NH 2 , C(O)NHC 1-6 alkyl, C(O)N(C 1-6 alkyl)(C 1-6 alkyl), C(O)OH, C(O)OC 1-6 alkyl, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl)(C 1-6 alkyl), OH, OC 1-6 alkyl, OC 1-6 fluoroalkyl, SH, SC 1-6 alkyl, SC 1-6 fluoroalkyl, S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl;

with the proviso that:

(1) R 1 comprises at least one basic nitrogen atom; and

(2) all alkyl and alkylene groups not otherwise specified are optionally substituted with fluoro.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

X 1 is CH;

X 2 is CH;

X 3 is CH; and

X 4 is CH.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

X 5 is CH;

X 6 is CH; and

X 7 is CH.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is heterocycloalkyl, optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-NR 5 R 6 , C 1-6 alkylene-OR 4 , and NR 5 R 6 .

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of:

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of:

or a tautomer thereof.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is H, C 1-6 alkyl, or C(O)C 1-6 alkyl.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is H, C 1-6 alkyl, or heterocycloalkyl; and

R 6 is H, C 1-6 alkyl, or heterocycloalkyl.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 , together with the nitrogen atom to which they are attached, form a 3-10 membered heterocyclyl, optionally substituted with one, two, or three substituents independently selected from the group consisting of halo and C 1-6 alkyl.

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

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 10 is H, halo, CN, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-R 14 , C 1-6 alkylene-NR 12 R 13 , C 1-6 alkylene-OR 11 , C(O)NR 12 R 13 , C(O)OR 11 , NR 12 R 13 , OR 11 , OC 1-6 alkylene-R 14 , OC 1-6 alkylene-NR 12 R 13 , OC 1-6 alkylene-OR 11 , or R 14 .

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 11 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, or heteroaryl.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

R 12 is H, C 1-10 alkyl, C 1-10 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, or heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo and C 1-6 alkyl; and

R 13 is H, C 1-10 alkyl, C 1-10 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, or heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo and C 1-6 alkyl.

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 12 and R 13 , together with the nitrogen atom to which they are attached, form a 3-10 membered heterocyclyl, optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-R 15 , NR 16 R 17 , OR 15 , S(O) 2 C 1-6 alkyl, and heterocycloalkyl.

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 14 is C 3-10 cycloalkyl or heterocycloalkyl.

16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 15 is H, C 1-6 alkylene-C 6-10 aryl, or C 6-10 aryl, wherein C 1-6 alkylene-C 6-10 aryl and C 6-10 aryl are each optionally substituted with one or more substituents independently selected from the group consisting of halo and C 1-6 alkyl.

17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

R 16 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 3-10 cycloalkyl, heterocycloalkyl, or C 6-10 aryl; and

R 17 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 3-10 cycloalkyl, heterocycloalkyl, or C 6-10 aryl.

18. The compound of claim 1 , wherein the compound is selected from the group consisting of:

N-[5-[5-[[(2S,6R)-2,6-dimethylmorpholin-4-yl]methyl]-2-fluorophenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-[5-[2-fluoro-4-(methoxymethoxy)-5-(2,4,4-trimethylpentan-2-ylcarbamoyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-[5-(5-carbamoyl-2-fluoro-4-hydroxyphenyl)-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-[5-[2-fluoro-5-(trifluoromethoxy)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-[5-[2-fluoro-5-(2-methylpropoxy)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-[5-[5-[(cyclohexylamino)methyl]-2-fluorophenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-1H-pyridazine-3-carboxamide;

N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-3-methoxybenzamide;

4-fluoro-N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-3,5-dimethylbenzamide;

N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide;

methyl 4-fluoro-3-[4-(4-methylpiperazin-1-yl)-3-[[6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonyl]-amino]phenyl]benzoate;

N-[5-[5-[(cyclopropylamino)methyl]-2-fluorophenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-[5-[5-[(cyclohexylamino)methyl]-2-fluorophenyl]-2-(4-methylpiperazin-1-yl)phenyl]-4-fluoro-3,5-dimethylbenzamide;

N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridazine-3-carboxamide;

N-[5-[5-(cyclopropylmethoxy)-2,4-difluorophenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-[5-[2-fluoro-3-(morpholin-4-ylmethyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-3-methylbenzamide;

N-[5-(2-fluorophenyl)-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-[2-(3,4-dimethylpiperazin-1-yl)-5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]phenyl]-6-hydroxy-4-(trifluoromethyl)pyridine-3-carboxamide;

N-(2′-fluoro-5′-(morpholinomethyl)-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide;

N-[2-[(2S)-2,4-dimethylpiperazin-1-yl]-5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-4-methyl-6-oxo-1H-pyridine-3-carboxamide;

N-(2′,6-difluoro-4-(4-methylpiperazin-1-yl)-5′-(morpholinomethyl)-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide;

N-[5-[5-(cyclohexylcarbamoyl)-2-fluorophenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-[5-[4-[(cyclopentylamino)methyl]-2-fluorophenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-[5-[4-[(cyclohexylamino)methyl]-2-fluorophenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-[5-[5-[(tert-butylamino)methyl]-2-fluorophenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

4-fluoro-N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-3-methylbenzamide;

N-[5-[2-fluoro-5-[(oxan-4-ylamino)methyl]phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-[5-[2-fluoro-4-(morpholin-4-ylmethyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-[5-[5-[(dimethylamino)methyl]-2-fluorophenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

4-fluoro-N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-3-methyl-5-(trifluoromethyl)benzamide;

N-[5-[5-[[(4,4-difluorocyclohexyl)amino]methyl]-2-fluorophenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-[5-[2-fluoro-5-[[methyl(oxetan-3-yl)amino]methyl]phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-4-hydroxy-2-(trifluoromethyl)benzamide;

N-[5-[5-[(cyclohexylamino)methyl]-2-fluorophenyl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-[5-[5-(cyclohexylcarbamoyl)-2-fluorophenyl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-[5-[2-fluoro-5-(morpholine-4-carbonyl)phenyl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

2,3-difluoro-N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-5-hydroxybenzamide;

4-(difluoromethyl)-N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-1H-pyridine-3-carboxamide;

(R)—N-(2′-fluoro-5′-((3-hydroxypyrrolidin-1-yl)methyl)-4-(4-methylpiperazin-1-yl)-[1,1′-biphenyl]-3-yl)-6-methoxy-4-(trifluoromethyl)nicotinamide;

N-[5-[2-fluoro-5-[(4-morpholin-4-ylpiperidin-1-yl)methyl]phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-methoxy-4-(trifluoromethyl)pyridine-3-carboxamide;

N-[5-[2-fluoro-5-[[(3S)-3-propan-2-ylpyrrolidin-1-yl]methyl]phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-methoxy-4-(trifluoromethyl)pyridine-3-carboxamide;

N-[5-[5-[(4-acetylpiperazin-1-yl)methyl]-2-fluorophenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-methoxy-4-(trifluoromethyl)pyridine-3-carboxamide;

N-[5-[2-fluoro-5-[(4-fluoropiperidin-1-yl)methyl]phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-methoxy-4-(trifluoromethyl)pyridine-3-carboxamide;

N-[5-[2-fluoro-5-(3-oxa-6-azabicyclo[3.1.1]heptan-6-ylmethyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-methoxy-4-(trifluoromethyl)pyridine-3-carboxamide;

(R)—N-(2′-fluoro-4-(4-methylpiperazin-1-yl)-5′-((3-(methylsulfonyl)pyrrolidin-1-yl)methyl)-[1,1′-biphenyl]-3-yl)-6-methoxy-4-(trifluoromethyl)nicotinamide;

(S)—N-(2′-fluoro-5′-((methyl(tetrahydrofuran-3-yl)amino)methyl)-4-(4-methylpiperazin-1-yl)-[1,1′-biphenyl]-3-yl)-6-methoxy-4-(trifluoromethyl)nicotinamide;

N-[5-[5-[(2,2-dimethylmorpholin-4-yl)methyl]-2-fluorophenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-methoxy-4-(trifluoromethyl)pyridine-3-carboxamide;

N-[2-(4-ethylpiperazin-1-yl)-5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-[5-[5-[(cyclohexylamino)methyl]-2-fluorophenyl]-2-(4-ethylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

[4-[4-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-[[6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonyl]amino]phenyl]-1-methylpiperazin-2-yl]methyl 2,2-dimethylpropanoate;

N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-[3-(hydroxymethyl)-4-methylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-[5-[5-[[4-(cyclopropylmethyl)piperazin-1-yl]methyl]-2-fluorophenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-[5-[5-[[cyclohexyl(methyl)amino]methyl]-2-fluorophenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-[5-[2-fluoro-5-[[4-[(4-fluorophenyl)methyl]piperazin-1-yl]methyl]phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

(R)—N-(2′-fluoro-5′-((3-hydroxypyrrolidin-1-yl)methyl)-4-(4-methylpiperazin-1-yl)-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide;

N-[5-[2-fluoro-5-[(4-morpholin-4-ylpiperidin-1-yl)methyl]phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

(R)—N-(5′-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-2′-fluoro-4-(4-methylpiperazin-1-yl)-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide;

N-[5-[2-fluoro-5-(piperazin-1-ylmethyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-[5-[2-fluoro-5-[(4-fluoropiperidin-1-yl)methyl]phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-[5-[2-fluoro-5-(3-oxa-6-azabicyclo[3.1.1]heptan-6-ylmethyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-[5-[2-fluoro-5-[[(3R)-3-methylsulfonylpyrrolidin-1-yl]methyl]phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

(S)—N-(2′-fluoro-5′-((methyl(tetrahydrofuran-3-yl)amino)methyl)-4-(4-methylpiperazin-1-yl)-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide;

N-[5-[5-[(2,2-dimethylmorpholin-4-yl)methyl]-2-fluorophenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-[5-(3-cyano-2,6-difluorophenyl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-[5-[5-[(cyclohexylamino)methyl]-2,4-difluorophenyl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-[5-[2-fluoro-5-(phenylcarbamoyl)phenyl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-(5′-(cyclohexylcarbamoyl)-4-(3,4-dimethylpiperazin-1-yl)-2′-fluoro-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide;

N-[5-[3-[(cyclohexylamino)methyl]-2,4-difluorophenyl]-2-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-(4-(3-(dimethylamino)pyrrolidin-1-yl)-2′-fluoro-5′-(morpholinomethyl)-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide;

N-(2′-fluoro-4-(4-methyl-1,4-diazepan-1-yl)-5′-(morpholinomethyl)-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide;

N-(2′-fluoro-4-(4-methyl-1,4-diazepan-1-yl)-5′-(morpholinomethyl)-[1,1′-biphenyl]-3-yl)-1-methyl-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide;

N-[5-[2-fluoro-5-(methylcarbamoyl)phenyl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-[2-[3-(dimethylamino)pyrrolidin-1-yl]-5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]phenyl]-4-fluoro-3,5-dimethylbenzamide;

4-fluoro-N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-(4-methyl-1,4-diazepan-1-yl)phenyl]-3,5-dimethylbenzamide;

N-[5-[5-(cyclopropylcarbamoyl)-2-fluorophenyl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

4-fluoro-N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-(2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl)phenyl]-3,5-dimethylbenzamide;

4-fluoro-N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]phenyl]-3,5-dimethylbenzamide;

N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-(2′,5-difluoro-4-(4-methylpiperazin-1-yl)-5′-(morpholinomethyl)-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide;

N-(2,2′-difluoro-4-(4-methylpiperazin-1-yl)-5′-(morpholinomethyl)-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide;

N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-(2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-[2-[3-(dimethylamino)pyrrolidin-1-yl]-5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]phenyl]-1-methyl-6-oxo-4-(trifluoromethyl)pyridine-3-carboxamide;

N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-[(2R)-2,4-dimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-1H-pyridine-3-carboxamide;

6-acetamido-N-[5-[2-fluoro-5-(morpholin-4-ylmethyl)phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-4-methylpyridine-3-carboxamide;

N-[5-[5-[[4-(cyclopropylmethyl)piperazin-1-yl]methyl]-2-fluorophenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-methoxy-4-(trifluoromethyl)pyridine-3-carboxamide;

N-[5-[5-[cyclohexyl(methyl)carbamoyl]-2-fluorophenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-[5-[5-[cyclohexyl(methyl)carbamoyl]-2-fluorophenyl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-[5-[2,4-difluoro-3-[[methyl(oxetan-3-yl)amino]methyl]phenyl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-[5-[2,4-difluoro-5-[[methyl(oxetan-3-yl)amino]methyl]phenyl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-[5-[3-[(cyclohexylamino)methyl]-2,6-difluorophenyl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-[5-[4-[(cyclohexylamino)methyl]-2,6-difluorophenyl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide;

N-(4′-carbamoyl-2′-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide;

N-(2′-fluoro-4′-morpholino-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide;

N-(5′-carbamoyl-2′-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide;

N-(2′,4′-difluoro-5′-((2,4,4-trimethylpentan-2-yl)carbamoyl)-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide;

N-(5′-carbamoyl-2′,4′-difluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide;

N-(2′,3′-difluoro-4′-((2,4,4-trimethylpentan-2-yl)carbamoyl)-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide;

N-(4′-carbamoyl-2′,3′-difluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide; and

N-(5′-(cyclohexylcarbamoyl)-2′-fluoro-4-(3,4,5-trimethylpiperazin-1-yl)-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide,

or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and/or diluent and a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

20. A method for inhibiting WD repeat domain 5-mixed lineage leukemia 1 protein-protein binding in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one compound of claim 1 , or a pharmaceutically acceptable salt thereof.

21. The method of claim 20 , wherein the subject has a disease selected from the group consisting of bladder cancer, breast cancer, Burkitt's lymphoma, colorectal cancer, gastric cancer, glioma, leukemia, medulloblastoma, MYCN-amplified neuroblastoma, pancreatic cancer, prostate cancer, testicular cancer, and thyroid cancer.

22. A compound of Formula (Ia):

or a pharmaceutically acceptable salt thereof,

wherein:

A 2 is F;

X 8 is CR 26 ;

X 9 is CR 26 ;

R 18 is heterocycloalkyl, optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-NR 21 R 22 , C 1-6 alkylene-OR 20 , C 1-6 alkylene-SR 20 , NR 21 R 22 , OR 20 , and SR 20 ;

R 19 is selected from the group consisting of:

or a tautomer thereof;

R 20 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C(O)C 1-6 alkyl, or C(O)C 1-6 fluoroalkyl;

R 21 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, or heterocycloalkyl;

R 21 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, or heterocycloalkyl;

R 22 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, or heterocycloalkyl; or

R 21 and R 22 , together with the nitrogen atom to which they are attached, form a 3-10 membered heterocyclyl, optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 fluoroalkyl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, OH, OC 1-6 alkyl, and OC 1-6 fluoroalkyl;

R 24 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C(O)C 1-6 alkyl, or C(O)C 1-6 fluoroalkyl;

R 25 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C(O)C 1-6 alkyl, or C(O)C 1-6 fluoroalkyl; or

R 24 and R 25 , together with the nitrogen atom to which they are attached, form a 3-10 membered heterocyclyl, optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 fluoroalkyl, OH, OC 1-6 alkyl, and OC 1-6 fluoroalkyl;

each R 26 is independently H, halo, CN, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-R 30 , C 1-6 alkylene-NR 28 R 29 , C 1-6 alkylene-OR 27 , C 1-6 alkylene-SR 27 , C(O)NR 28 R 29 , C(O)OR 27 , C(S)NR 28 R 29 , C(S)OR 27 , NR 28 R 29 , OR 27 , OC 1-6 alkylene-R 30 , OC 1-6 alkylene-NR 28 R 29 , OC 1-6 alkylene-OR 27 , OC 1-6 alkylene-SR 27 , SR 27 , SC 1-6 alkylene-R 30 , SC 1-6 alkylene-NR 28 R 29 , SC 1-6 alkylene-OR 27 , SC 1-6 alkylene-SR 27 , or R 30 ;

R 27 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, or heteroaryl, optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkylene-NR 32 R 33 , C 1-6 alkylene-OR 31 , C 1-6 alkylene-SR 31 , C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-heteroaryl, C 1-6 alkylene-R 31 , C(O)NR 32 R 33 , C(O)OR 31 , C(O)R 31 , NR 32 R 33 , OR 31 , SR 31 , S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl;

R 28 is H, C 1-10 alkyl, C 1-10 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, or heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkylene-NR 32 R 33 , C 1-6 alkylene-OR 31 , C 1-6 alkylene-SR 31 , C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-heteroaryl, C 1-6 alkylene-R 31 , C(O)NR 32 R 33 , C(O)OR 31 , C(O)R 31 , NR 32 R 33 , OR 31 , SR 31 , S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl;

R 29 is H, C 1-10 alkyl, C 1-10 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, or heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkylene-NR 32 R 33 , C 1-6 alkylene-OR 31 , C 1-6 alkylene-SR 31 , C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-heteroaryl, C 1-6 alkylene-R 31 , C(O)NR 32 R 33 , C(O)OR 31 , C(O)R 31 , NR 32 R 33 , OR 31 , SR 31 , S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl; or

R 28 and R 29 , together with the nitrogen atom to which they are attached, form a 3-10 membered heterocyclyl, optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkylene-NR 32 R 33 , C 1-6 alkylene-OR 31 , C 1-6 alkylene-SR 31 , C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C 1-6 alkylene-R 31 , C(O)NR 32 R 33 , C(O)OR 31 , C(O)R 31 , NR 32 R 33 , OR 31 , SR 31 , S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl;

R 30 is C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, or heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkylene-NR 32 R 33 , C 1-6 alkylene-OR 31 , C 1-6 alkylene-SR 31 , C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C 1-6 alkylene-R 31 , C(O)R 31 , C(O)OR 31 , C(O)NR 32 R 33 , NR 32 R 33 , OR 31 , SR 31 , S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl;

R 31 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C 3-10 cycloalkyl, heterocycloalkyl, or C 6-10 aryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-NH 2 , C 1-6 alkylene-NHC 1-6 alkyl, C 1-6 alkylene-N(C 1-6 alkyl)(C 1-6 alkyl), C 1-6 alkylene-OH, C 1-6 alkylene-O—C 1-6 alkyl, C 1-6 alkylene-SH, C 1-6 alkylene-S—C 1-6 alkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C(O)NH 2 , C(O)NHC 1-6 alkyl, C(O)N(C 1-6 alkyl)(C 1-6 alkyl), C(O)OH, C(O)OC 1-6 alkyl, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl)(C 1-6 alkyl), OH, OC 1-6 alkyl, OC 1-6 fluoroalkyl, SH, SC 1-6 alkyl, SC 1-6 fluoroalkyl, S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl;

R 32 is H, C 1-10 alkyl, C 1-10 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C(O)C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, or C 6-10 aryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-NH 2 , C 1-6 alkylene-NHC 1-6 alkyl, C 1-6 alkylene-N(C 1-6 alkyl)(C 1-6 alkyl), C 1-6 alkylene-OH, C 1-6 alkylene-O—C 1-6 alkyl, C 1-6 alkylene-SH, C 1-6 alkylene-S—C 1-6 alkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C(O)NH 2 , C(O)NHC 1-6 alkyl, C(O)N(C 1-6 alkyl)(C 1-6 alkyl), C(O)OH, C(O)OC 1-6 alkyl, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl)(C 1-6 alkyl), OH, OC 1-6 alkyl, OC 1-6 fluoroalkyl, SH, SC 1-6 alkyl, SC 1-6 fluoroalkyl, S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl; and

R 33 is H, C 1-10 alkyl, C 1-10 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C(O)C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, or C 6-10 aryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-NH 2 , C 1-6 alkylene-NHC 1-6 alkyl, C 1-6 alkylene-N(C 1-6 alkyl)(C 1-6 alkyl), C 1-6 alkylene-OH, C 1-6 alkylene-O—C 1-6 alkyl, C 1-6 alkylene-SH, C 1-6 alkylene-S—C 1-6 alkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C(O)NH 2 , C(O)NHC 1-6 alkyl, C(O)N(C 1-6 alkyl)(C 1-6 alkyl), C(O)OH, C(O)OC 1-6 alkyl, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl)(C 1-6 alkyl), OH, OC 1-6 alkyl, OC 1-6 fluoroalkyl, SH, SC 1-6 alkyl, SC 1-6 fluoroalkyl, S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl; or

R 32 and R 33 , together with the nitrogen atom to which they are attached, form a 3-10 membered heterocyclyl, optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-NH 2 , C 1-6 alkylene-NHC 1-6 alkyl, C 1-6 alkylene-N(C 1-6 alkyl)(C 1-6 alkyl), C 1-6 alkylene-OH, C 1-6 alkylene-O—C 1-6 alkyl, C 1-6 alkylene-SH, C 1-6 alkylene-S—C 1-6 alkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C(O)NH 2 , C(O)NHC 1-6 alkyl, C(O)N(C 1-6 alkyl)(C 1-6 alkyl), C(O)OH, C(O)OC 1-6 alkyl, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl)(C 1-6 alkyl), OH, OC 1-6 alkyl, OC 1-6 fluoroalkyl, SH, SC 1-6 alkyl, SC 1-6 fluoroalkyl, S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl;

with the proviso that:

(1) R 18 comprises at least one basic nitrogen atom; and

(2) all alkyl and alkylene groups not otherwise specified are optionally substituted with fluoro.

23. A compound of Formula (Ib):

or a pharmaceutically acceptable salt thereof,

wherein:

X 10 is CH;

X 11 is CH;

X 12 is CR 38 ;

X 13 is CH;

R 35 is

R 36 is CHF 2 or CF 3 ;

R 37 is H or CH 3 ;

R 38 is H, halo, CN, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-NR 40 R 41 , C 1-6 alkylene-OR 39 , C 1-6 alkylene-SR 39 , C 1-6 alkylene-R 42 , C(O)NR 40 R 41 , C(O)OR 39 , C(S)NR 40 R 41 , C(S)OR 39 , NR 40 R 41 , OC 1-6 alkylene-NR 40 R 41 , OC 1-6 alkylene-OR 39 , OC 1-6 alkylene-SR 39 , OC 1-6 alkylene-R 42 , OR 39 , SC 1-6 alkylene-NR 40 R 41 , SC 1-6 alkylene-OR 39 , SC 1-6 alkylene-SR 39 , SC 1-6 alkylene-R 42 , or SR 39 ;

R 39 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, or heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkylene-NR 44 R 45 , C 1-6 alkylene-OR 43 , C 1-6 alkylene-SR 43 , C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-heteroaryl, C 1-6 alkylene-R 43 , C(O)NR 44 R 45 , C(O)OR 43 , C(O)R 43 , NR 44 R 45 , OR 43 , SR 43 , S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl;

R 40 is H, C 1-10 alkyl, C 1-10 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, or heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkylene-NR 44 R 45 , C 1-6 alkylene-OR 43 , C 1-6 alkylene-SR 43 , C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-heteroaryl, C 1-6 alkylene-R 43 , C(O)NR 44 R 45 , C(O)OR 43 , C(O)R 43 , NR 44 R 45 , OR 43 , SR 43 , S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl;

R 41 is H, C 1-10 alkyl, C 1-10 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, or heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkylene-NR 44 R 45 , C 1-6 alkylene-OR 43 , C 1-6 alkylene-SR 43 , C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-heteroaryl, C 1-6 alkylene-R 43 , C(O)NR 44 R 45 , C(O)OR 43 , C(O)R 43 , NR 44 R 45 , OR 43 , SR 43 , S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl; or

R 40 and R 41 , together with the nitrogen atom to which they are attached, form a 3-10 membered heterocyclyl, optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkylene-NR 44 R 45 , C 1-6 alkylene-OR 43 , C 1-6 alkylene-SR 43 , C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-heteroaryl, C 1-6 alkylene-R 43 , C(O)NR 44 R 45 , C(O)OR 43 , C(O)R 43 , NR 44 R 45 , OR 43 , SR 43 , S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl;

R 42 is C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, or heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkylene-NR 44 R 45 , C 1-6 alkylene-OR 43 , C 1-6 alkylene-SR 43 , C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-heteroaryl, C 1-6 alkylene-R 43 , C(O)NR 44 R 45 , C(O)OR 43 , C(O)R 43 , NR 44 R 45 , OR 43 , SR 43 , S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl;

R 43 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C 3-10 cycloalkyl, heterocycloalkyl, or C 6-10 aryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-NH 2 , C 1-6 alkylene-NHC 1-6 alkyl, C 1-6 alkylene-N(C 1-6 alkyl)(C 1-6 alkyl), C 1-6 alkylene-OH, C 1-6 alkylene-O—C 1-6 alkyl, C 1-6 alkylene-SH, C 1-6 alkylene-S—C 1-6 alkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C(O)NH 2 , C(O)NHC 1-6 alkyl, C(O)N(C 1-6 alkyl)(C 1-6 alkyl), C(O)OH, C(O)OC 1-6 alkyl, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl)(C 1-6 alkyl), OH, OC 1-6 alkyl, OC 1-6 fluoroalkyl, SH, SC 1-6 alkyl, SC 1-6 fluoroalkyl, S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl;

R 44 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C(O)C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, or C 6-10 aryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-NH 2 , C 1-6 alkylene-NHC 1-6 alkyl, C 1-6 alkylene-N(C 1-6 alkyl)(C 1-6 alkyl), C 1-6 alkylene-OH, C 1-6 alkylene-O—C 1-6 alkyl, C 1-6 alkylene-SH, C 1-6 alkylene-S—C 1-6 alkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C(O)NH 2 , C(O)NHC 1-6 alkyl, C(O)N(C 1-6 alkyl)(C 1-6 alkyl), C(O)OH, C(O)OC 1-6 alkyl, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl)(C 1-6 alkyl), OH, OC 1-6 alkyl, OC 1-6 fluoroalkyl, SH, SC 1-6 alkyl, SC 1-6 fluoroalkyl, S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl; and

R 45 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C(O)C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, or C 6-10 aryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-NH 2 , C 1-6 alkylene-NHC 1-6 alkyl, C 1-6 alkylene-N(C 1-6 alkyl)(C 1-6 alkyl), C 1-6 alkylene-OH, C 1-6 alkylene-O—C 1-6 alkyl, C 1-6 alkylene-SH, C 1-6 alkylene-S—C 1-6 alkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C(O)NH 2 , C(O)NHC 1-6 alkyl, C(O)N(C 1-6 alkyl)(C 1-6 alkyl), C(O)OH, C(O)OC 1-6 alkyl, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl)(C 1-6 alkyl), OH, OC 1-6 alkyl, OC 1-6 fluoroalkyl, SH, SC 1-6 alkyl, SC 1-6 fluoroalkyl, S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl; or

R 44 and R 45 , together with the nitrogen atom to which they are attached, form a 3-10 membered heterocyclyl, optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene-NH 2 , C 1-6 alkylene-NHC 1-6 alkyl, C 1-6 alkylene-N(C 1-6 alkyl)(C 1-6 alkyl), C 1-6 alkylene-OH, C 1-6 alkylene-O—C 1-6 alkyl, C 1-6 alkylene-SH, C 1-6 alkylene-S—C 1-6 alkyl, C 1-6 alkylene-C 3-10 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C(O)NH 2 , C(O)NHC 1-6 alkyl, C(O)N(C 1-6 alkyl)(C 1-6 alkyl), C(O)OH, C(O)OC 1-6 alkyl, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl)(C 1-6 alkyl), OH, OC 1-6 alkyl, OC 1-6 fluoroalkyl, SH, SC 1-6 alkyl, SC 1-6 fluoroalkyl, S(O)C 1-6 alkyl, S(O) 2 C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, and heteroaryl;

with the proviso that:

(1) all alkyl and alkylene groups not otherwise specified are optionally substituted with fluoro.