(Alpha-substituted aralkylamino and heteroarylalkylamino) pyrimidinyl and 1,3,5-triazinyl benzimidazoles, pharmaceutical compositions thereof, and their use in treating proliferative diseases

1. A compound of Formula I:

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:

X, Y, and Z are each independently N or CR X , with the proviso that at least two of X, Y, and Z are nitrogen atoms; where R X is hydrogen or C 1-6 alkyl;

R 1 and R 2 are each independently (a) hydrogen, cyano, halo, or nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(NR 1a )NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(═NR 1a )NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ; wherein each R 1a , R 1b , R 1c , and R 1d is independently (i) hydrogen; (ii) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R 1b and R 1c together with the N atom to which they are attached form heterocyclyl;

R 3 and R 4 are each independently hydrogen or C 1-6 alkyl; or R 3 and R 4 are linked together to form a bond, C 1-6 alkylene, C 1-6 heteroalkylene, C 2-6 alkenylene, or C 2-6 heteroalkenylene;

R 5a is (a) hydrogen or halo; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(NR 1a )NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(═NR 1a )NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ;

R 5b is (a) halo; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(NR 1a )NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(═NR 1a )NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ;

R 5c is —(CR 5f R 5g ) n —(C 6-14 aryl)

R 5d and R 5e are each independently (a) hydrogen or halo; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(NR 1a )NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(═NR 1a )NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ;

R 5f and R 5g are each independently (a) hydrogen or halo; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(NR 1a )NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(═NR 1a )NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c ; or —S(O) 2 NR 1b R 1c ; or (d) when one occurrence of R 5f and one occurrence of R 5g are attached to the same carbon atom, the R 5f and R 5g together with the carbon atom to which they are attached form a C 3-10 cycloalkyl or heterocyclyl;

R 6 is hydrogen, C 1-6 alkyl, —S—C 1-6 alkyl, —S(O)—C 1-6 alkyl, or —SO 2 —C 1-6 alkyl;

m is 0 or 1; and

n is 0, 1, 2, 3, or 4;

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl in R 1 , R 2 , R 3 , R 4 , R 6 , R X , R 1a , R 1b , R 1c , R 1d , R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , and R 5g is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; and (c) —C(O)R a , —C(O)OR a , —C(O)NR b R c , —C(NR a )NR b R c , —OR a , —OC(O)R a , —OC(O)OR a , —OC(O)NR b R c , —OC(═NR a )NR b R c , —OS(O)R a , —OS(O) 2 R a , —OS(O)NR b R c , —OS(O) 2 NR b R c , —NR b R c , —NR a C(O)R d , —NR a C(O)OR d , —NR a C(O)NR b R c , —NR a C(═NR d )NR b R c , —NR a S(O)R d , —NR a S(O) 2 R d , —NR a S(O)NR b R c , —NR a S(O) 2 NR b R c , —SR a , —S(O)R a , —S(O) 2 R a , —S(O)NR b R c , and —S(O) 2 NR b R c , wherein each R a , R 1 ', R c , and R d is independently (i) hydrogen; (ii) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; or (iii) R b and R c together with the N atom to which they are attached form heterocyclyl, which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ;

wherein each Q a is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl,C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R e , —C(O)OR e , —C(O)NR f R g , —C(NR e )NR f R g , —OR e , —OC(O)R e , —OC(O)OR e , —OC(O)NR f R g , —OC(═NR e )NR f R g , —OS(O)R e , —OS(O) 2 R e , —OS(O)NR f R g , —OS(O) 2 NR f R g , —NR f R g , —NR e C(O)R h , —NR e C(O)OR h , —NR e C(O)NR f R g , —NR e C(═NR h )NR f R g , —NR e S(O)R h , —NR e S(O) 2 R h , —NR e S(O)NR f R g , —NR e S(O) 2 NR f R g , —SR e , —S(O)R e , —S(O) 2 R e , —S(O)NR f R g , and —S(O) 2 NR f R g ; wherein each R e , R f , R g , and R h is independently (i) hydrogen; (ii) C 1-6 alkyl,C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl;or (iii) R f and R g together with the N atom to which they are attached form heterocyclyl.

2. The compound of claim 1 , wherein the compound is not 4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-N-(2-phenyl-2-(pyrrolidin-1-yl)ethyl)-1,3,5-triazin-2-amine or 6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(1-(4-((R)-3-(methoxymethyl)morpholino)phenyl)ethyl)-2-morpholinopyrimidin-4-amine.

3. The compound of claim 1 , wherein R 5b is (a) halo; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, or heteroaryl; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(NR 1a )NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(═NR 1a )NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —S(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c .

4. The compound of claim 1 , wherein R 5a and R 5b are each independently (a) halo; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(NR 1a )NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(═NR 1a )NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c .

5. The compound of claim 4 , wherein R 5a and R 5b are each methyl, optionally substituted with one or more halo.

6. The compound of claim 1 , wherein n is 1.

7. The compound of claim 1 , wherein R 5f and R 5g are each hydrogen.

8. The compound of claim 1 , wherein n is 0.

9. The compound of claim 1 , wherein m is 0.

10. The compound of claim 1 , having the structure of Formula Ia:

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

11. The compound of claim 1 , having the structure of Formula Ib:

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

12. The compound of claim 1 , having the structure of Formula II:

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

13. The compound of claim 12 , having the structure of Formula IIa:

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

14. The compound of claim 12 , having the structure of Formula IIb:

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

15. The compound of claim 1 , wherein R 5c is C 6-14 aryl, optionally substituted with one or more substituents Q.

16. The compound of claim 15 , wherein R 5c is phenyl, optionally substituted with one or more substituents Q.

17. The compound of claim 15 , wherein R 5c is naphthyl, optionally substituted with one or more substituents Q.

18. The compound of claim 1 , wherein R 5c is —(CH 2 )-phenyl, wherein the phenyl is optionally substituted with one or more substituents Q.

19. The compound of claim 1 , wherein R 5c is —(CH 2 )-naphthyl, wherein the naphthyl is optionally substituted with one or more substituents Q.

20. The compound of claim 1 , having the structure of Formula VII:

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R 7a , R 7b , R 7c , R 7d , and R 7e are each independently (a) hydrogen, cyano, halo, or nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(NR 1a )NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(═NR 1a )NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ; or

two of R 7a , R 7b , R 7c , R 7d , and R 7e that are adjacent to each other form C 3-10 cycloalkenyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q.

21. The compound of claim 20 , having the structure of Formula VIIa:

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

22. The compound of claim 20 , having the structure of Formula VIIb:

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

23. The compound of claim 1 , having the structure of Formula XI:

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R 7a , R 7b , R 7c , R 7d , and R 7e are each independently (a) hydrogen, cyano, halo, or nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(NR 1a )NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(═NR 1a )NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ; or

two of R 7a , R 7b , R 7c , R 7d , and R 7e that are adjacent to each other form C 3-10 cycloalkenyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q.

24. The compound of claim 23 , having the structure of Formula XIa:

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

25. The compound of claim 23 , having the structure of Formula XIb:

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or produg thereof.

26. The compound of claim 23 , wherein R 7a is hydrogen, halo, C 1-6 alkyl optionally substituted with one or more substituents Q, or —OR 1a .

27. The compound of claim 26 , wherein R 7a is hydrogen.

28. The compound of claim 25 , wherein R 7a is (a) cyano, halo, or nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(NR 1a )NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , OC(NR 1a )NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(═NR 1 )NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c .

29. The compound of claim 25 , wherein R 7a is (i) halo; (ii) C 1-6 alkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (iii) —OR 1a or —NR 1b R 1c .

30. The compound of claim 23 , wherein R 7b is hydrogen, halo, C 1-6 alkyl optionally substituted with one or more substituents Q, or —OR 1a .

31. The compound of claim 30 , wherein R 7b is hydrogen.

32. The compound of claim 23 , wherein R 7c is hydrogen, halo, C 1-6 alkyl optionally substituted with one or more substituents Q, or —OR 1a .

33. The compound of claim 32 , wherein R 7c is hydrogen, halo, or —OR 1a .

34. The compound of claim 32 , wherein R 7c is chloro.

35. The compound of claim 32 , wherein R 7c is —O—C 1-6 alkyl, optionally substituted with one or more substituents Q.

36. The compound of claim 23 , wherein R 7d is hydrogen, halo, C 1-6 alkyl optionally substituted with one or more substituents Q, or —OR 1a .

37. The compound of claim 36 , wherein R 7d is hydrogen.

38. The compound of claim 23 , wherein R 7e is hydrogen, halo, C 1-6 alkyl optionally substituted with one or more substituents Q, or —OR 1a .

39. The compound of claim 38 , wherein R 7e is hydrogen.

40. The compound of claim 23 , wherein two of R 7a , R 7b , R 7c , R 7d , and R 7e that are adjacent to each other form C 3-10 cycloalkenyl, C 6-14 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q.

41. The compound of claim 40 , wherein R 7a and R 7b together with the carbon atoms to which they are attached from C 6-14 aryl, optionally substituted with one or more substituents Q.

42. The compound of claim 40 , wherein R 7b and R 7c together with the carbon atoms to which they are attached from C 6-14 aryl, optionally substituted with one or more substituents Q.

43. The compound of claim 1 , wherein R 5a is hydrogen.

44. The compound of claim 1 , wherein R 5a is C 1-6 alkyl, optionally substituted with one or more substituents Q.

45. The compound of claim 1 , wherein R 5a is hydrogen, methyl, or ethyl.

46. The compound of claim 1 , wherein R 5b is C 1-6 alkyl, optionally substituted with one or more substituents Q.

47. The compound of claim 46 , wherein R 5b is methyl, ethyl, or propyl.

48. The compound of claim 1 , wherein R 5b is —C(O)OR 1a .

49. The compound of claim 48 , wherein R 5b is —C(O)O—C 1-6 alkyl.

50. The compound of claim 48 , wherein R 5b is —C(O)OCH 3 .

51. The compound of claim 23 , having the structure of Formula XV:

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

52. The compound of claim 51 , having the structure of Formula XVa:

or an isotopic variant thereof or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

53. The compound of claim 51 , having the structure of Formula XVb:

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

54. The compound of claim 51 , wherein R 5a is C 1-6 alkyl, optionally substituted with one or more substituents Q.

55. The compound of claim 54 , wherein R 5a is methyl.

56. The compound of claim 51 , wherein R 5b is C 1-6 alkyl, optionally substituted with one or more substituents Q.

57. The compound of claim 56 , wherein R 5b is methyl.

58. The compound of claim 51 , wherein R 5a and R 5b are methyl.

59. The compound of claim 51 , wherein R 7a is hydrogen, halo, C 1-6 alkyl, C 6-14 aryl, heteroaryl, or heterocyclyl, where the alkyl, aryl, heteroaryl, and heterocyclyl are each optionally substituted with one or more substituents Q.

60. The compound of claim 59 , wherein R 7a is C 6-14 aryl, optionally substituted with one or more substituents Q.

61. The compound of claim 60 , wherein R 7a is phenyl, optionally substituted with one or more substituents Q.

62. The compound of claim 60 , wherein R 7a is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, or 3-morpholin-4-ylmethylphenyl.

63. The compound of claim 59 , wherein R 7a is heteroaryl, optionally substituted with one or more substituents Q.

64. The compound of claim 63 , wherein R 7a is monocyclic heteroaryl, optionally substituted with one or more substituents Q.

65. The compound of claim 63 , wherein R 7a is 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents Q.

66. The compound of claim 65 , wherein R 7a is imidazolyl, pyrozolyl, pyridinyl, or pyrimidinyl, each optionally substituted with one or more substituents Q.

67. The compound of claim 65 , wherein R 7a is imidazol-1-yl, pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl.

68. The compound of claim 59 , wherein R 7a is heterocyclyl, optionally substituted with one or more substituents Q.

69. The compound of claim 68 , wherein R 7a is monocyclic heterocyclyl, optionally substituted with one or more substituents Q.

70. The compound of claim 68 , wherein R 7a is 5- or 6-membered heterocyclyl, each optionally substituted with one or more substituents Q.

71. The compound of claim 70 , wherein R 7a is pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q.

72. The compound of claim 70 , wherein R 7a is pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl, piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl, 1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl, 1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

73. The compound of claim 51 , wherein R 7b is hydrogen, halo, or C 1-6 alkyl optionally substituted with one or more substituents Q.

74. The compound of claim 73 , wherein R 7b is hydrogen.

75. The compound of claim 51 , wherein R 7c is hydrogen, halo, or C 1-6 alkyl optionally substituted with one or more substituents Q.

76. The compound of claim 75 , wherein R 7c is hydrogen.

77. The compound of claim 51 , wherein R 7d is hydrogen, halo, or C 1-6 alkyl optionally substituted with one or more substituents Q.

78. The compound of claim 77 , wherein R 7d is hydrogen.

79. The compound of claim 51 , wherein R 7e is hydrogen, halo, or C 1-6 alkyl optionally substituted with one or more substituents Q.

80. The compound of claim 79 , wherein R 7e is hydrogen.

81. The compound of claim 51 , wherein R 7a is C 6-14 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; and R 7b , R 7c , R 7d , and R 7e are hydrogen.

82. The compound of claim 1 , wherein R 1 is hydrogen.

83. The compound of claim 1 , wherein R 2 is hydrogen.

84. The compound of claim 1 , wherein R 3 is hydrogen.

85. The compound of claim 1 , wherein R 4 is hydrogen.

86. The compound of claim 1 , wherein R 6 is C 1-6 alkyl, optionally substituted with one or more substituents Q.

87. The compound of claim 86 , wherein R 6 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl.

88. The compound of claim 86 , wherein R 6 is difluoromethyl.

89. The compound of claim 1 , wherein X is N.

90. The compound of claim 1 , wherein Y is N.

91. The compound of claim 1 , wherein Y is CR X .

92. The compound of claim 91 , wherein Y is CH.

93. The compound of claim 1 , wherein Z is N.

94. The compound of claim 1 , wherein X, Y, and Z are N.

95. The compound of claim 1 selected from the group consisting of:

and enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, and isotopic variants thereof; and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof.

96. A pharmaceutical composition comprising the compound of claim 1 , or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof and one or more pharmaceutically acceptable excipients.

97. The pharmaceutical composition of claim 96 , wherein the composition is formulated for single dose administration.

98. The pharmaceutical composition of claim 96 , wherein the composition is formulated as an oral, parenteral, or intravenous dosage form.

99. The pharmaceutical composition of claim 98 , wherein the composition is formulated as an oral dosage form.

100. The pharmaceutical composition of claim 99 , wherein the oral dosage form is a tablet or capsule.

101. The pharmaceutical composition of claim 96 , further comprising a therapeutic agent.

102. A method for the treatment, or amelioration of one or more symptoms of a PI3K-mediated disorder, disease, or condition in a subject, which comprises administering to the subject the compound of claim 1 .

103. The method of claim 102 , wherein the PI3K-mediated disorder, disease, or condition is an inflammatory disease.

104. The method of claim 102 , wherein the compound is administered in combination with a therapeutic agent.

105. A method for inhibiting PI3K enzymatic activity, comprising contacting a PI3K enzyme with the compound of claim 1 .

106. The method of claim 102 , wherein the PI3K is a wild type.

107. The method of claim 102 , wherein the PI3K is a PI3K variant.

108. The method of claim 102 , wherein the PI3K is a Class I PI3K.

109. The method of claim 108 , wherein the PI3K is p110γ.