Compounds and methods for the treatment of isocitrate dehydrogenase related diseases

1. A compound of Formula (TB) or Formula (IC), or a pharmaceutically acceptable salt thereof:

wherein:

n is 0;

q is 1;

X 2 is —O—

Cy1 is:

R 1 is C 1 -C 6 alkyl;

R 2 is:

R 12 is hydrogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, CONR 20 R 21 , C(O)R 20 , or C(O)OR 21 ;

R 13 , R 14 , and R 15 are each independently hydrogen;

R 16 is hydrogen, halogen, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl or substituted heteroaryl;

alternatively, when two of the R 13 , R 14 , R 15 , and R 16 groups are attached to a carbon atom, together said two groups and said carbon atom may form a carbonyl or an optionally substituted vinyl group;

u is 1;

w is 0, 1, 2, 3, 4, 5 or 6;

Cy3 is optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;

R 3 is selected from:

each R 13 ′, R 14 ′ and R 15 ′ is independently hydrogen, C 1 -C 6 alkyl, or substituted C 1 -C 6 alkyl;

each of R 16 ′ and R 17 ′ is independently hydrogen, C 1 -C 6 alkyl, or substituted C 1 -C 6 alkyl;

R 11 is:

R 13 ″ is hydrogen, halogen, —OR 20 , —SR 20 , —NR 20 R 21 , —CF 3 , —CN, —NO 2 , —N 3 , —C(O)R 20 , —C(O)OR 20 , —C(O)NR 20 R 21 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, aliphatic, substituted aliphatic, aryl or substituted aryl;

R 40 is selected from the group consisting of:

and

R 41 is hydrogen, halogen, aliphatic, substituted aliphatic, aryl, substituted aryl, —OR 20 , —SR 20 , —NR 20 R 21 , —CF 3 , —CN, —NO 2 , —N 3 , —C(O)R 20 , —C(O)OR 20 , —C(O)NR 20 R 21 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl;

q′ is 1;

and

R 20 and R 21 are each independently hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl.

2. The compound of claim 1 , wherein R 1 is methyl, ethyl or propyl.

3. The compound of claim 2 , wherein R 1 is methyl.

4. The compound of claim 1 , wherein R 12 is C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl.

5. The compound of claim 1 , wherein R 2 is:

6. The compound of claim 1 , wherein R 3 is:

7. The compound of claim 6 , wherein R 3 is

8. The compound of claim 1 , wherein R 11 is a moiety selected from those shown in Table B:

TABLE B

9. The compound of claim 1 , wherein w is 0, 1 or 2.

10. The compound of claim 1 selected from those shown in Table 1, or a pharmaceutically acceptable salt thereof:

TABLE 1

1

(4R,5R)-8-(cyclopent-1-en-1-yl)-2-((S)-1- hydroxypropan-2-yl)-4-methyl-5- ((methyl(pyridin-3-ylmethyl)amino)methyl)-2,3,4,5- tetrahydrobenzo[b][1,4,5]oxathiazocine 1,1-dioxide

4

N-(((4R,5R)-8-(cyclohexylethynyl)-2-((S)-1- hydroxypropan-2-yl)-4-methyl-1,1- dioxido-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocin- 5-yl)methyl)-N-methyl-2- (pyridin-4-yl)acetamide

6

N-(((4R,5R)-2-((R)-1-hydroxypropan-2- yl)-4-methyl-8-(4-methylpent-1-yn-1-yl)-1,1- dioxido-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocin- 5-yl)methyl)-N-methyl-2-(pyridin-3-yl)acetamide

8

(4R,5R)-8-(cyclopropylethynyl)-2-((R)-1-hydroxypropan- 2-yl)-4-methyl-5-((methyl(pyridin-3-ylmethyl)amino)methyl)- 2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocine 1,1-dioxide

10

(4S,5R)-2-((S)-1-hydroxypropan-2-yl)-4-methyl-5- ((methyl(pyridin-3-ylmethyl)amino)methyl)-8- (pent-1-yn-1-yl)-2,3,4,5- tetrahydrobenzo[b][1,4,5]oxathiazocine 1,1-dioxide

11

N-(((4R,5S)-2-((R)-1-hydroxypropan-2-yl)-4- methyl-8-(4-methylpent-1-yn-1-yl)-1,1- dioxido-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocin- 5-yl)methyl)-N-methyl-2-(pyridin-3-yl)acetamide

13

(4S,5S)-8-(cyclopent-1-en-1-yl)-2-((R)-1-hydroxypropan- 2-yl)-4-methyl-5-((methyl(pyridin-4-ylmethyl)amino)methyl)- 2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocine 1,1-dioxide

18

4-(((((4R,5R)-8-(3-cyclopentylprop-1-yn-1-yl)- 2-((R)-1-hydroxypropan-2-yl)-4- methyl-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4,5] oxathiazocin-5-yl)methyl)(methyl)amino)methyl) benzoic acid

N-(((4R,5R)-2-((S)-1-hydroxypropan-2-yl)-4-methyl-8- (3-methylbut-1-yn-1-yl)-1,1- dioxido-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocin- 5-yl)methyl)-N-methylnicotinamide

21

N-(((4S,5S)-2-((S)-1-hydroxypropan-2-yl)-4-methyl- 8-(4-methylpent-1-yn-1-yl)-1,1- dioxido-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocin-5- yl)methyl)-N-methyl-2-(pyridin-3-yl)acetamide.

11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1 .

12. The compound of claim 1 , wherein the compound has the Formula (IC).

13. The compound of claim 1 , wherein the compound has the Formula (TB).

14. The compound of claim 12 , wherein R 3 is

15. The compound of claim 14 , wherein R 1 is methyl.

16. The compound of claim 13 , wherein R 3 is

17. The compound of claim 16 , wherein R 1 is methyl.

18. The compound of claim 15 , wherein R 2 is:

19. The compound of claim 18 , wherein R 12 is CONR 20 R 21 , C(O)R 20 , or C(O)OR 21 .

20. The compound of claim 19 , wherein R 16 is C 1 -C 6 alkyl.

21. The compound of claim 1 , wherein R 12 is CONR 20 R 21 , C(O)R 20 , or C(O)OR 21 .

22. The compound of claim 21 , wherein R 16 is C 1 -C 6 alkyl.

23. The compound of claim 1 , wherein R 13 ″ is aryl or substituted aryl.

24. The compound of claim 23 , wherein R 13 ″ is phenyl or substituted phenyl.

25. The compound of claim 17 , wherein R 2 is:

26. The compound of claim 25 , wherein w is 1.

27. The compound of claim 26 , wherein R 12 is C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl.

28. The compound of claim 27 , wherein Cy3 is an optionally substituted aryl or an optionally substituted heteroaryl.

29. A method of ameliorating a cell proliferative disease in a patient in need thereof comprising the step of administering a compound according to claim 1 to said patient, wherein the cell proliferative disease is selected from glioma, acute myeloid leukemia (AML), Burkitt's leukemia/lymphoma (B-ALL), melanoma, and prostate cancer.

30. The method according to claim 29 , wherein said glioma is selected from astrocytomas, oligodendrogliomas, ependymomas and glioblastoma multiforme.