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

1. A method for the treatment of a PI3K-mediated cancer, comprising administration to a mammal in need thereof, a therapeutically effective dose of a composition in an amount effective to inhibit PI3K enzyme activity, comprising a compound of Formula IA:

or a pharmaceutically acceptable salt 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 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 3-7 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 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 method of claim 1 , wherein the pharmaceutically acceptable salt is the salt of an acid selected from the group consisting of acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (−)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid.

3. The method of claim 1 , wherein the pharmaceutically acceptable salt is the salt of an acid selected from the group consisting of methanesulfonic acid, succinic acid, citric acid, and hydrochloric acid.

4. The method of claim 2 , wherein R 1 is independently hydrogen, methoxy, or dimethylaminopropoxy;

R 2 is independently hydrogen or amino;

R 3 and R 4 are each independently 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 groups;

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

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

wherein each R 8 is independently hydrogen or methyl; and

X, Y, and Z are each a nitrogen atom.

5. The method of claim 4 , wherein the pharmaceutically acceptable salt is the salt of an acid selected from the group consisting of methanesulfonic acid, succinic acid, citric acid, and hydrochloric acid.

6. The method of claim 2 , wherein the compound of Formula IA is Formula V:

or a pharmaceutically acceptable salt thereof;

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;

U is N or CH;

G is —CH 2 —, or —CH 2 CH 2 —; and

X, Y, and Z are each a nitrogen atom.

7. The method of claim 6 , wherein the pharmaceutically acceptable salt is the salt of an acid selected from the group consisting of methanesulfonic acid, succinic acid, citric acid, and hydrochloric acid.

8. The method of claim 2 , 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 mesylate.

9. The method of claim 2 , 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 mesylate.

10. The method of claim 2 , wherein the compound is 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 hydrochloride.

11. The method of claim 2 , wherein the PI3K-mediated cancer is hemangiosarcoma, mastocytosis, breast cancer, osteosarcoma, melanoma, lymphoma, renal cell carcinoma, astrocytoma, bladder cancer, non-small cell lung cancer, colon or rectal cancer, ovarian cancer, multiple myeloma, non-Hodgkin lymphoma, leukemia, or promyelocytic leukemia.

12. The method of claim 11 , wherein the composition is an oral dosage form and is administered in an amount of between about 0.1 to about 50 mg/kg/day.

13. The method of claim 12 , wherein the composition is an oral dosage form and is administered in an amount of between about 0.5 to about 25 mg/kg/day.

14. The method of claim 12 , wherein the mammal is a dog or a cat.

15. The method of claim 7 , wherein the PI3K-mediated cancer is hemangiosarcoma, mastocytosis, breast cancer, osteosarcoma, melanoma, lymphoma, renal cell carcinoma, astrocytoma, bladder cancer, non-small cell lung cancer, colon or rectal cancer, ovarian cancer, multiple myeloma, non-Hodgkin lymphoma, leukemia, or promyelocytic leukemia.

16. The method of claim 15 , wherein the composition is an oral dosage form and is administered in an amount of between about 0.1 to about 50 mg/kg/day.

17. The method of claim 16 , wherein the composition is an oral dosage form and is administered in an amount of between about 0.5 to about 25 mg/kg/day.

18. The method of claim 16 , wherein the mammal is a dog or a cat.

19. The method of claim 9 , wherein the PI3K-mediated cancer is hemangiosarcoma, mastocytosis, breast cancer, osteosarcoma, melanoma, lymphoma, renal cell carcinoma, astrocytoma, bladder cancer, non-small cell lung cancer, colon or rectal cancer, ovarian cancer, multiple myeloma, non-Hodgkin lymphoma, leukemia, or promyelocytic leukemia.

20. The method of claim 19 , wherein the composition is an oral dosage form and is administered in an amount of between about 0.1 to about 50 mg/kg/day.

21. The method of claim 20 , wherein the composition is an oral dosage form and is administered in an amount of between about 0.5 to about 25 mg/kg/day.

22. The method of claim 20 , wherein the mammal is a dog or a cat.