Pyrimidinyl and 1,3,5-triazinyl benzimidazole sulfonamides and their use in cancer therapy

1. A compound of Formula IA:

or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, or prodrug thereof;

wherein:

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 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a , —C(O)OR 1b , —C(O)NR 1b R 1c , —C(NR a )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 3-7 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 5 is independently C 1-6 alkyl or C 2-6 alkenyl, each optionally substituted with one or more substituents, each of which is independently selected from the group consisting of heterocyclyl and —NR f R g ; or R 5 is —NR 5m R 5n , where R 5m and R 5n are each independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl;

R 6 is independently hydrogen or C 1-6 alkyl;

Q is C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 3-7 cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene;

T 1 is independently a bond, C 1-6 alkylene, —O—, or —NR 8 —;

T 2 is independently a bond, C 1-6 alkylene, or —NR 8 —; wherein each R 8 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl; and

with the proviso that at least one of the two atoms that are directly attached to the —SO 2 — group is nitrogen;

X, Y, and Z are each independently a nitrogen atom or CR 9 , with the proviso that at least two of X, Y, and Z are nitrogen atoms; where R 9 is hydrogen or C 1-6 alkyl;

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene in R 1 , R 2 , R 3 , R 4 , R 6 , R 8 , R 9 , R 1a , R 1b , R 1c , R 1d , R 5m , R 5n , Q, T 1 , and T 2 , is optionally substituted with one or more groups, each independently selected from (a) cyano, halo, and nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q 1 ;

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)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 b , R c , and R d is independently (i) hydrogen; (ii) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q 1 ; or (iii) R b and R c together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q 1 ;

wherein each Q 1 is independently selected from the group consisting of (a) cyano, halo, and nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 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 3-7 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 , having the structure of Formula Ia:

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

4. The compound of claim 1 , wherein R 1 is independently hydrogen or —OR 1a , where R 1a is C 1-6 alkyl, optionally substituted with —NR f R g ; and R f and R g are each independently hydrogen or C 1-6 alkyl.

5. The compound of claim 4 , wherein R 1 is hydrogen, methoxy, or dimethylaminopropoxy.

6. The compound of claim 1 , wherein R 2 is independently hydrogen, C 1-6 alkyl, or —NR 1b R 1c ; where R 1b and R 1c are each independently (a) hydrogen; or (b) C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, each optionally substituted with one or more substituents, where each substituent is independently —OR e or —NR f R g .

7. The compound of claim 6 , wherein R 2 is independently hydrogen or amino.

8. The compound of claim 1 , wherein R 3 and R 4 are each independently hydrogen or C 1-6 alkyl, optionally substituted with one or more groups.

9. The compound of claim 8 , wherein R 3 and R 4 are hydrogen.

10. The compound of claim 1 , wherein R 5 is independently —(CR 5a R 5b ) m —R 5c , where R 5a and R 5b are each independently (a) hydrogen, cyano, or nitro; or (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; each optionally substituted with one or more substituents; R 5c is hydrogen, —NR 5d R 5e , or heterocyclyl; R 5d and R 5e are each independently hydrogen or C 1-6 alkyl; and m is an integer of 0, 1, 2, or 3; and where each alkyl and heterocyclyl is independently, optionally substituted with one or more groups.

11. The compound of claim 10 , wherein R 5c is hydrogen.

12. The compound of claim 10 , wherein R 5b is hydrogen.

13. The compound of claim 10 , wherein R 5c is hydrogen.

14. The compound of claim 10 , wherein R 5c is —NR 5d R 5e , and R 5d and R 5e are each independently hydrogen or C 1-6 alkyl, optionally substituted with one or more groups.

15. The compound of claim 14 , wherein R 5d is hydrogen or methyl.

16. The compound of claim 14 , wherein R 5e is hydrogen or methyl.

17. The compound of claim 10 , wherein R 5c is amino, methylamino, or dimethylamino.

18. The compound of claim 10 , wherein m is 1, 2, or 3.

19. The compound of claim 1 , wherein R 5 is independently methyl, ethenyl, dimethylaminomethyl, dimethylaminoethyl, or dimethylaminopropyl.

20. The compound of claim 1 , wherein R 6 is independently C 1-6 alkyl, optionally substituted with one to three halo.

21. The compound of claim 20 , wherein R 6 is independently methyl, fluoromethyl, difluoromethyl, or trifluoromethyl.

22. The compound of claim 1 , wherein Q is independently C 3-7 cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclene.

23. The compound of claim 22 , wherein Q is independently cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, phenylene, azetidinylene, pyrrolidinylene, piperidinylene, piperazinylene, pyrrolylene, thiazolylylene, pyrazolylene, or pyridylene.

24. The compound of claim 22 , wherein Q is independently 1,3-azetidinylene, 1,3-pyrrolidinylene, 1,3-piperidinylene, 1,4-piperidinylene, or 1,4-piperazinylene.

25. The compound of claim 1 , wherein T 1 is independently a bond or methylene.

26. The compound of claim 1 , wherein T 2 is independently —NR 8 —.

27. The compound of claim 26 , wherein R 8 is independently hydrogen or C 1-6 alkyl.

28. The compound of claim 27 , wherein R 8 is independently hydrogen or methyl.

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

2-(difluoromethyl)-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;

2-(difluoromethyl)-4-methoxy-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;

2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole;

({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)-N,N-dimethylmethylamine;

N-[2-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-N,N-dimethylamine;

N-[3-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)propyl]-N,N-dimethylamine;

2-(difluoromethyl)-4-methoxy-1-(4-(4-morpholinyl)-6-{4-[(4-morpholinylmethyl)sulfonyl]-1-piperazinyl}-1,3,5-triazin-2-yl)-1H-benzimidazole;

2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(4-morpholinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;

2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[3-(4-morpholinyl)propyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;

N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}methanesulfonamide;

N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-N-methylmethanesulfonamide;

N-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-[1-(methylsulfonyl)-4-piperidinyl]amine;

N-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-methyl-N-[1-(methylsulfonyl)-4-piperidinyl]amine;

2-(difluoromethyl)-4-methoxy-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-6-ylamine;

2-(difluoromethyl)-4-methoxy-1-[4-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;

N-[2-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperidinyl}sulfonyl)ethyl]-N,N-dimethylamine;

2-(difluoromethyl)-4-methoxy-1-[4-[1-(methylsulfonyl)-3-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;

2-(difluoromethyl)-4-methoxy-[4-{[1-(methylsulfonyl)-4-piperidinyl]oxy}-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;

N 1 -[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N 3 ,N 3 -dimethyl-N 1 -[1-(methylsulfonyl)-3-piperidinyl]-1,3-propanediamine;

4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[1-(methylsulfonyl)-3-piperidinyl]-6-(4-morpholinyl)-N-[3-(4-morpholinyl)propyl]-1,3,5-triazin-2-amine;

N 1 -[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N 3 ,N 3 -dimethyl-N 1 -[1-(methylsulfonyl)-4-piperidinyl]-1,3-propanediamine;

4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-N-[3-(4-morpholinyl)propyl]-1,3,5-triazin-2-amine;

4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-{3-[4-(methylsulfonyl)-1-piperazinyl]propyl}-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;

N-{(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperidinyl}-N-[3-(dimethylamino)propyl]methane-sulfonamide;

N-[2-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-N,N-diethylamine;

2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(1-piperidinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;

N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-2-(dimethylamino)ethanesulfonamide;

N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-2-(dimethylamino)-N-methylethanesulfonamide;

N-{4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]phenyl}-2-(dimethylamino)ethanesulfonamide;

N-{4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]phenyl}-2-(dimethylamino)-N-methylethanesulfonamide;

N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinyl}-2-(dimethylamino)ethanesulfonamide;

N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinyl}-2-(dimethylamino)-N-methylethanesulfonamide;

trans-N-(4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}cyclohexyl)methanesulfonamide;

cis-N-(4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}cyclohexyl)methanesulfonamide;

N-[2-({4-[4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-N,N-dimethylamine;

N-[2-({4-[4-[6-amino-2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-N,N-dimethylamine;

2-(difluoromethyl)-4-methoxy-1-{4-[4-(methylsulfonyl)-1-piperazinyl]-6-tetrahydro-2H-pyran-4-yl-1,3,5-triazin-2-yl}-1H-benzimidazole;

4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N,N-dimethyl-1-piperazinesulfonamide;

1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N,N-dimethyl-4-piperidinesulfonamide;

1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-methyl-4-piperidinesulfonamide;

1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-[2-(dimethylamino)ethyl]-4-piperidinesulfonamide;

1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-methyl-3-pyrrolidinesulfonamide;

1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-[2-(dimethylamino)ethyl]-3-pyrrolidinesulfonamide;

N-(5-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-2-pyridinyl)methanesulfonamide;

N-(5-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-2-pyridinyl)-N-methylmethanesulfonamide;

4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;

3-{4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-[4-(methylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-8-oxa-3-azabicyclo[3.2.1]octane;

2-(difluoromethyl)-4-methoxy-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-2-pyrimidinyl]-1H-benzimidazole;

4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[1-(methylsulfonyl)-3-azetidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;

4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[1-(methylsulfonyl)-3-azetidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;

N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinyl}methanesulfonamide;

N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinyl}-N-methylmethanesulfonamide;

4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[(3R)-1-(methylsulfonyl)pyrrolidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;

4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[(3R)-1-(methylsulfonyl)pyrrolidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;

4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[(3S)-1-(methylsulfonyl)pyrrolidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;

4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[(3S)-1-(methylsulfonyl)pyrrolidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;

N-{(3R)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]pyrrolidinyl}methanesulfonamide;

N-{(3R)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]pyrrolidinyl}-N-methylmethanesulfonamide;

N-{(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]pyrrolidinyl}methanesulfonamide;

N-{(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]pyrrolidinyl}-N-methylmethanesulfonamide;

4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[(3R)-1-(methylsulfonyl)piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;

4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[(3R)-1-(methylsulfonyl)piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;

4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[(3S)-1-(methylsulfonyl)piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;

4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[(3S)-1-(methylsulfonyl)piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;

N-{(3R)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperidinyl}methanesulfonamide;

N-{(3R)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperidinyl}-N-methylmethanesulfonamide;

N-{(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperidinyl}methanesulfonamide;

N-{(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperidinyl}-N-methylmethanesulfonamide;

N-{2-[(4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]oxy}-1-piperidinyl)sulfonyl]ethyl}-N,N-dimethylamine;

2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[(1-{[2-(4-morpholinyl)ethyl]sulfonyl}-4-piperidinyl)oxy]-1,3,5-triazin-2-yl}-1H-benzimidazole;

N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-N-[3-(dimethylamino)propyl]-methanesulfonamide;

N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-N-[3-(4-morpholinyl)propyl]-methanesulfonamide;

2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(1-pyrrolidinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;

3-[2-({4-[4-[2-(Difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-8-oxa-3-azabicyclo[3.2.1]octane;

2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole;

N-[3-({2-(difluoromethyl)-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-4-yl}oxy)propyl]-N,N-dimethylamine;

4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;

2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-4-pyrimidinamine; and

N-[3-({2-(difluoromethyl)-1-[4-{[1-(methylsulfonyl)-4-piperidinyl]oxy}-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-4-yl}oxy)propyl]-N,N-dimethylamine;

and enantiomers, mixtures of enantiomers, or mixtures of two or more diastereomers thereof;

and pharmaceutically acceptable salts, and prodrugs thereof.

30. A pharmaceutical composition comprising a 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, or prodrug thereof; and one or more pharmaceutically acceptable carriers.

31. The pharmaceutical composition of claim 30 , further comprising a second therapeutic agent.

32. The pharmaceutical composition of claim 30 , wherein the composition is formulated for single dose administration.

33. The pharmaceutical composition of claim 30 , wherein the composition is formulated as oral, parenteral, or intravenous dosage form.

34. The pharmaceutical composition of claim 33 , wherein the oral dosage form is a tablet or capsule.

35. 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 effective to inhibit PI3K enzymatic activity.

36. The method of claim 35 wherein the PI3K-mediated disorder, disease, or condition is cancer.

37. The method of claim 35 , wherein the compound or the composition is administered in combination with a therapeutic agent.

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

39. The method of claim 35 , wherein the PI3K is a wild type.

40. The method of claim 35 , wherein the PI3K is a PI3K mutant.

41. The method of claim 39 , wherein the PI3K is a Class I PI3K.

42. The method of claim 41 , wherein the PI3K is p110α.

43. The method of claim 42 , wherein the PI3K is a p110α mutant.

44. The method of claim 43 , wherein the p110α mutant is R38H, K111N, N345K, C420R, P539R, E542K, E545A, E545G, E545K, Q546K, Q546P, I800L, T1025S, M1043I, H1047L, H1047R, or H1047Y.

45. The compound of claim 2 , having the structure of Formula Ia, wherein:

R 1 is independently hydrogen, methoxy, or dimethylaminopropoxy;

R 2 is independently hydrogen or amino;

R 3 and R 4 are hydrogen; or R 3 and R 4 are linked together to form ethylene;

R 5 is independently methyl, ethenyl, dimethylaminomethyl, dimethylaminoethyl, or dimethylaminopropyl;

R 6 is difluoromethyl;

Q is phenylene, optionally substituted with one or more substituents;

T 1 is independently a bond, —O—, or —NR 8 —;

T 2 is independently a bond or —NR 8 —, with the proviso that the atom that is attached to —SO 2 R 5 is nitrogen;

each R 8 is independently hydrogen or methyl; and

X, Y, and Z are each independently a nitrogen atom or CH, with the proviso that at least two of X, Y, and Z are nitrogen atoms.

46. The compound of claim 45 , wherein Q is 1,4-phenylene.

47. The compound of claim 45 , wherein T 1 is a bond.

48. The compound of claim 45 , wherein T 2 is —NH—.

49. The compound of claim 1 , wherein the compound is N-{4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]phenyl}-2-(dimethylamino)ethanesulfonamide.

50. The compound of claim 1 , wherein the compound is N-{-4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]phenyl}-2-(dimethylamino)-N-methylethanesulfonamide.

51. The compound of claim 1 , wherein the compound is 2-(difluoromethyl)-4-methoxy-1-[4-{4-[(4-methyl-1-piperazinyl)sulfonyl]phenyl}-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole.