Ectonucleotidase inhibitors and methods of use thereof

1. A method of treating cancer, comprising administering to a subject in need thereof a compound of Formula (I):

or a pharmaceutically acceptable salt and/or prodrug thereof, wherein

X is O;

Y is O or S;

Z is NR 19 , O or S;

Het is an optionally substituted purinyl ring or an optionally substituted 5-methyl-pyrimidin-2,4-dione ring;

R 1a is selected from H, halo, hydroxy, cyano, azido, amino, C 1-6 alkyl, hydroxyC 1-6 alkyl, amino-C 1-6 alkyl, —O—C(O)—O—C 1-6 alkyl, C 1-6 acyloxy, C 1-6 alkoxy, C 2-6 alkenyl, and C 2-6 alkynyl; and

R 1b is selected from H, halo, C 1-6 alkyl, hydroxy-C 1-6 alkyl, amino-C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl; or

R 1a and R 1b , together with the carbon atom to which they are attached, form a C═CH 2 or C═C(H)C 1-6 alkyl;

R 2a is selected from H, halo, hydroxy, cyano, azido, amino, C 1-6 alkyl, hydroxy-C 1-6 alkyl, amino-C 1-6 alkyl, C 1-6 acyloxy, —O—C(O)—O—C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, and C 2-6 alkynyl;

R 2b is selected from H, halo, C 1-6 alkyl, hydroxy-C 1-6 alkyl, amino-C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl; or

R 2a and R 2b , together with the carbon atom to which they are attached, form a C═CH 2 or C═C(H)C 1-6 alkyl;

R 3 is selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, and —(CH 2 )—C(O)OR 9 ;

R 4 is selected from heteroaryl, alkyl, —C(O)OR 9 , —C(O)NR 11 R 12 , —S(O) 2 R 10 , —P(O)(OR 11 )(OR 12 ), and —P(O)(OR 11 )(NR 13 R 15 );

R 5 is selected from H, cyano, alkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroaralkyl, and —C(O)OR 9 ;

R 6 is selected from —C(O)OR 9 and —P(O)(OR 11 )(OR 12 );

R 9 is independently selected from H, alkyl, acyloxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl, and —(CHR 13 ) m —Z—C(O)—R 14 ;

each R 10 is independently selected from alkyl, alkenyl, alkynyl, amino, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; and

each R 11 and R 12 is independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl and —(CHR 13 ) m —Z—C(O)—R 14 ; or

R 11 and R 12 , together with the atoms to which they are attached, form a 5- to 7-membered heterocyclyl; and

each R 13 is independently H or alkyl;

each R 14 is independently selected from alkyl, aminoalkyl, heterocyclyl, and heterocyclylalkyl;

R 15 is selected from alkyl, aralkyl, —C(R 16 )(R 17 )—C(O)O—R 18 ;

each R 16 and R 17 are selected from H, alkyl, amino-alkyl, hydroxy-alkyl, mercapto-alkyl, sulfonyl-alkyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, heteroaralkyl, and —(CH 2 )C(O)OR 9 ;

R 18 is selected from H, alkyl, alkoxyalkyl, aminoalkyl, haloalkyl, amido, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl;

R 19 is H or alkyl; and

m is 1 or 2;

provided that:

a) R 4 is tetrazolyl, or R 5 is aralkyl or heteroaralkyl, or both, or

b) if R 1a and R 2a are each hydroxy, then R 2b is C 1-6 alkyl or C 2-6 alkynyl.

2. The method of claim 1 , wherein R 1a is selected from H, halo, hydroxy, cyano, azido, amino, C 1-6 alkyl, hydroxyC 1-6 alkyl, amino-C 1-6 alkyl, C 1-6 acyloxy, C 1-6 alkoxy, C 2-6 alkenyl, and C 2-6 alkynyl.

3. The method of claim 1 , wherein R 1a is fluoro.

4. The method of claim 1 , wherein R 1a is chloro.

5. The method of claim 1 , wherein R 1a is hydroxy.

6. The method of claim 1 , wherein R 2a is selected from H, halo, hydroxy, cyano, azido, amino, C 1-6 alkyl, hydroxyC 1-6 alkyl, amino-C 1-6 alkyl, C 1-6 acyloxy, C 1-6 alkoxy, C 2-6 alkenyl, and C 2-6 alkynyl.

7. The method of claim 1 , wherein R 2a is C 1-6 alkyl.

8. The method of claim 1 , wherein R 2a is hydroxy.

9. The method of claim 1 , wherein R 2a is ethynyl.

10. The method of claim 1 , wherein R 2b is C 1-6 alkyl.

11. The method of claim 1 , wherein R 1a is fluoro and R 1b is H.

12. The method of claim 1 , wherein R 1a is fluoro and R 2a is hydroxy.

13. The method of claim 1 , wherein R 1a is chloro and R 2a is hydroxy.

14. The method of claim 1 , wherein R 1a is hydroxy and R 2a is C 1-6 alkyl.

15. The method of claim 1 , wherein R 1a is hydroxy and R 2a is hydroxyl and R 2b is C 1-6 alkynyl.

16. The method of claim 1 , wherein R 1a is hydroxy and R 2a is C 1-6 alkynyl.

17. The method of claim 1 , wherein R 3 is H.

18. The method of claim 1 , wherein R 3 is unsubstituted C 1-6 alkyl.

19. The method of claim 1 , wherein R 3 is alkyl, and the alkyl is unsubstituted or substituted with one or more substituents selected from halo, CN, NO 2 , azido, hydroxy, alkoxy, alkylthio, thioalkoxy, carbonyl, thiocarbonyl, amidino, imino, amino, amido, alkoxycarbonyl, carbamate, urea, sulfinamido, sulfonamido, sulfinyl, sulfinamido, sulfonyl, phosphoryl, phosphate, phosphonate, and phosphinate.

20. The method of claim 19 , wherein the substituents are selected from halo, CN, azido, alkoxy, carbonyl, amino, amido, and alkoxycarbonyl.

21. The method of claim 1 , wherein R 4 is heteroaryl.

22. The method of claim 1 , wherein R 4 is tetrazolyl.

23. The method of claim 1 , wherein R 4 is selected from —C(O)OR 9 , —C(O)NR 11 R 12 , —S(O) 2 R 10 , and —P(O)(OR 11 )(OR 12 ).

24. The method of claim 1 , wherein R 4 is —C(O)OR 9 .

25. The method of claim 1 , wherein R 4 is alkyl.

26. The method of claim 1 , wherein R 4 is —C(O)NR 11 R 12 .

27. The method of claim 1 , wherein R 5 is selected from alkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl and heteroaralkyl, and each is unsubstituted or substituted with one or more substituents, selected from halo, CN, NO 2 , azido, hydroxy, alkoxy, alkylthio, thioalkoxy, carbonyl, thiocarbonyl, amidino, imino, amino, amido, alkoxycarbonyl, carbamate, urea, sulfinamido, sulfonamido, sulfinyl, sulfinamido, sulfonyl, phosphoryl, phosphate, phosphonate, phosphinate, cycloalkyl, heterocyclyl, arylalkyl and heteroarylalkyl.

28. The method of claim 27 , wherein the substituents are selected from halo, CN, azido, alkoxy, carbonyl, amino, amido, and alkoxycarbonyl.

29. The method of claim 1 , wherein R 5 is selected from H, alkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, and heteroaralkyl.

30. The method of claim 1 , wherein R 5 is H or aralkyl.

31. The method of claim 1 , wherein R 5 is aralkyl or heteroaralkyl.

32. The method of claim 31 , wherein R 5 is heteroaralkyl, wherein the heteroaryl ring is selected from benzofuranyl, benzothienyl, benzothiazolyl, pyridyl, thienyl, furanyl, pyrazolyl, thiazolyl, and oxazolyl, and oxadiazolyl, each of which may be substituted or unsubstituted.

33. The method of claim 31 , wherein R 5 is unsubstituted or substituted with one or more substituents selected from halo, CN, OH, alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkyl sulfonyl, sulfonamido, amido, amino, hydroxycarbonyl, alkoxycarbonyl, heteroaryl, aryl, aralkyl, and heteroaralkyl.

34. The method of claim 33 , wherein the substituents are selected from halo, CN, haloalkyl, haloalkoxy, carboxy, alkoxycarbonyl, and aryl.

35. The method of claim 33 , wherein the substituents are selected from tetrazolyl, substituted or unsubstituted phenyl, or substituted or unsubstituted benzyl.

36. The method of claim 33 , wherein R 1 is unsubstituted or substituted with one or more substituents, selected from chloro, trifluoromethyl, trifluoromethoxy, phenyloxy, dimethylamido, methylsulfonyl, CN, and carboxylic acid.

37. The method of claim 1 , wherein R 6 is —C(O)OR 9 .

38. The method of claim 1 , wherein R 9 is H, C 1-6 alkyl or amido.

39. The method of claim 1 , wherein R 9 is H, methyl or ethyl.

40. The method of claim 1 , wherein R 11 and R 12 are each H.

41. The method of claim 1 , wherein R 11 and R 12 are each alkyl.

42. The method of claim 1 , wherein each R 8 , R 9 , R 10 , R 11 and R 12 is independently selected from alkyl, alkenyl, alkynyl, amido, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl, and each is unsubstituted or substituted, with one or more selected from halo, CN, NO 2 , azido, hydroxy, alkoxy, alkylthio, thioalkoxy, carbonyl, thiocarbonyl, amidino, imino, amino, amido, alkoxycarbonyl, carbamate, urea, sulfinamido, sulfonamido, sulfinyl, sulfinamido, sulfonyl, phosphoryl, phosphate, phosphonate, and phosphinate.

43. The method of claim 42 , wherein the substituents on each R 8 , R 9 , R 10 , R 11 and R 12 are selected from halo, CN, azido, alkoxy, carbonyl, amino, amido, and alkoxycarbonyl.

44. The method of claim 1 , wherein Y is O.

45. The method of claim 1 , wherein Z is O.

46. The method of claim 1 , wherein Het is unsubstituted or substituted, with one or more substituents selected from halo, CN, NO 2 , azido, hydroxy, alkoxy, alkylthio, thioalkoxy, carbonyl, thiocarbonyl, amidino, imino, amino, amido, alkoxycarbonyl, carbamate, urea, sulfinamido, sulfonamido, sulfinyl, sulfinamido, sulfonyl, phosphoryl, phosphate, phosphonate, and phosphinate.

47. The method of claim 46 , wherein the substituents are selected from halo, CN, azido, alkoxy, carbonyl, amino, amido, and alkoxycarbonyl.

48. The method of claim 1 , wherein Het is

49. The method of claim 1 , wherein Het is

50. The method of claim 1 , wherein Het is substituted with one or two substituents selected from halo, aralkyl, amino, azido and hydroxy.

51. The method of claim 50 , wherein Het is selected from

52. The method of claim 1 , wherein

represents

53. The method of claim 1 , wherein

represents

54. The method of claim 1 , wherein

represents

where each R A is independently selected from H, halo, CN, OH, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkyl sulfonyl, sulfonamido, amido, amino, hydroxycarbonyl, alkoxycarbonyl, heteroaryl, aryl, aralkyl, and heteroaralkyl; and

k is 1, 2, or 3.

55. The method of claim 54 , wherein R A is selected from pyridyl, pyrazolyl, pyrrolidinonyl, azapanonyl, morpholinonyl, piperazonyl, tetrahydropyrimidinonyl, phenyl, and benzyloxy.

56. The method of claim 1 , wherein the compound of formula (I) is selected from:

Cpd. #

Compound

Name

6

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H- purin-9-yl)-4-fluoro-3-hydroxytetrahdyro- furan-2-yl)methoxy)-2-benzylmalonic acid

7

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H- purin-9-yl)-4-fluoro-3-hydroxytetrahydro- furan-2-yl)methoxy)-2-(4-carboxybenzyl)- malonic acid

8

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H- purin-9-yl)-4-fluoro-3-hydroxytetrahydro- furan-2-yl)methoxy)-2-((6-chloropyridin-3- yl)methyl)malonic acid

10

2-(((2R,3R,4R,5R)-5-(6-amino-9H-purin-9- yl)-4-fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-benzylmalonic acid

12

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- (4-(2-carboxyethyl)benzyl)malonic acid

13

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- (3-phenoxybenzyl)malonic acid

15

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- (3-(trifluoromethoxy)benzyl)malonic acid

16

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- (3-(trifluoromethyl)benzyl)malonic acid

17

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-puriin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- (naphthalen-2-ylmethyl)malonic acid

20

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- (4-(trifluoromethyl)benzyl)malonic acid

21

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- (4-(methylsulfonyl)benzyl)malonic acid

22

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- (3-(dimethylcarbamoyl)benzyl)malonic acid

23

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- (thiophen-3-ylmethyl)malonic acid

25

diethyl 2-(((2R,3R,4S,5R)-5-(6-amino-2- chloro-9H-purin-9-yl)-4-fluoro-3- (isobutyryloxy)tetrahydrofuran-2- yl)methoxy)-2-(4- (trifluoromethoxy)benzyl)malonate

27

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- (3-aminobenzyl)malonic acid

28

2-benzyl-2-(((2R,3R,4S,5R)-5-(6- (benzylamino)-2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)malonic acid

32

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- ((6-(trifluoromethyl)pyridin-3- yl)methyl)malonic acid

34

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- (4-cyanobenzyl)malonic acid

35

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahyrofuran-2-yl)methoxy)-2- (3-cyanobenzyl)malonic acid

36

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- (4-(trifluoromethoxy)benzyl)malonic acid

37

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-3- ethoxy-3-oxo-2-(4- (trifluoromethoxy)benzyl)propanoic acid

38

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-3- ethoxy-3-oxo-2-(4- (trifluoromethoxy)benzyl)propanoic acid

39

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- (4-(hydroxymethyl)benzyl)malonic acid

40

2-(((2R,3R,4S,5R)-5-(6-amino-2-azido-9H- purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- (3-cyanobenzyl)malonic acid

41

2-(((2R,3R,4S,5R)-5-(2-azido-6-((tert- butoxycarbonyl)amino)-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-(3-cyanobenzyl)malonic acid

42

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydro-furan-2-yl)methoxy)-2- (3-carboxybenzyl)-malonic acid

43

2-(3-(1H-tetrazol-5-yl)benzyl)-2- (((2R,3R,4S,5R)-5-(6-amino-2-azido-9H- purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2- yl)methoxy)malonic acid

44

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- (3-fluorobenzyl)malonic acid

45

diethyl 2-(((2R,3R,4S,5R)-5-(6-amino-2- chloro-9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- (3-fluorobenzyl)malonate

46

diethyl 2-(((2R,3R,4S,5R)-5-(6-amino-2- chloro-9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- (4-fluorobenzyl)malonate

47

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- (4-fluorobenzyl)malonic acid

48

diethyl 2-(((2R,3R,4S,5R)-5-(6-amino-2- chloro-9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- (4-(trifluoromethoxy)benzyl)malonate

49

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- (3-methoxybenzyl)malonic acid

50

2-((1H-tetrazol-5-yl)methyl)-2- (((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H- purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2- yl)methoxy)malonic acid

51

2-(((2S,3S,4R,5R)-3-amino-5-(6-amino-2- chloro-9H-purin-9-yl)-4- hydroxytetrahydrofuran-2-yl)methoxy)-2- benzylmalonic acid

53

2-(3-(1H-tetrazol-5-yl)benzyl)-2- (((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H- purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2- yl)methoxy)malonic acid

54

2-(4-(1H-tetrazol-5-yl)benzyl)-2- (((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H- purin-9-yl)-4-fluoro-3-hydroxytetrahydro- furan-2-yl)methoxy)malonic acid

55

2-(((2R,3S,4R,5R)-4-amino-5-(6-amino-2- chloro-9H-purin-9-yl)-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- benzylmalonic acid

56

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- (3-hydroxybenzyl)malonic acid

57

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- (4-carboxy-2-fluorobenzyl)malonic acid

58

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydro-furan-2-yl)methoxy)-2- (4-carboxy-3-fluorobenzyl)malonic acid

59

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydro-furan-2-yl)methoxy)-2- ((5-(trifluoromethyl)-furan-2- yl)methyl)malonic acid

60

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydro-furan-2-yl)methoxy)-2- (3-fluoro-4-(trifluoromethyl)benzyl)malonic acid

61

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- ((3-phenylisoxazol-5-yl)methyl)malonic acid

62

dimethyl 2-(((2R,3R,4S,5R)-5-(6-amino-2- chloro-9H-purin-9-yl)-4-fluoro-3- hydroxytetrahdyrofuran-2-yl)methoxy)-2- (4-(trifluoromethyl)benzyl)malonate

63

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydro-furan-2-yl)methoxy)-2- ((1-benzyl-1H-pyrazol-4-yl)methyl)malonic acid

64

2-((1H-pyrazol-4-yl)methyl)-2- (((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H- purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2- yl)methoxy)malonic acid

65

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- (4-(benzyloxy)benzyl)malonic acid

66

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- (4-hydroxybenzyl)malonic acid

67

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydro-furan-2-yl)methoxy)-2- ((2-carboxythiazol-5-yl)methyl)malonic acid

68

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydro-furan-2-yl)methoxy)-2- ((2-carboxythiazol-4-yl)ethyl)malonic acid

69

2-([1,1′-biphenyl]-4-ylmethyl)-2- (((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H- purin-9-yl)-4-fluooro-3-hydroxytetrahydro- furan-2-yl)methoxy)-3-ethoxy-3- oxopropanoic acid

70

diethyl 2-(((2R,3R,4S,5R)-5-(6-amino-2- chloro-9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- (4-(2-methoxy-2-oxoethyl)benzyl)malonate

71

diethyl 2-(((2R,3R,4S,5R)-5-(6-amino-2- chloro-9H-purin-9-yl)-4-fluoro-3- (isobutyryloxy)tetrahydrofuran-2- yl)methoxy)-2-((5- (methoxycarbonyl)thiophen-3- yl)methyl)malonate

72

diethyl 2-(((2R,3R,4S,5R)-5-(6-amino-2- chloro-9H-purin-9-yl)-4-fluoro-3- hydroxytetrahdyrofuran-2-yl)methoxy)-2- ((5-(methoxycarbonyl)-1-methyl-1H- pyrazol-3-yl)methyl)malonate

73

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- ((5-carboxy-1-methyl-1H-pyrazol-3- yl)methyl)malonic acid

74

2-benzyl-2-(((2R,3R,4S,5R)-5-(2-chloro-6- hydroxy-9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2- yl)methoxy)malonic acid

75

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- (4-cyano-3-fluorobenzyl)malonic acid

76

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydro-furan-2-yl)methoxy)-2- ((5-carboxythiophen-3-yl)methyl)malonic acid

77

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydro-furan-2-yl)methoxy)-2- ((5-carboxythiophen-2-yl)methyl)malonic acid

78

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- (4-(carboxymethyl)benzyl)malonic acid

79

2-([1,1′-biphenyl]-4-ylmethyl)-2- (((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H- purin-9-yl)-4-fluoro-3-hydroxytetrahydro- furan-2-yl)methoxy)malonic acid

80

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- (4-chloro-2-fluorobenzyl)malonic acid

81

2-([1,1′-biphenyl]-4-ylmethyl)-2- (((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H- purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)mthoxy)-3- methoxy-3-oxopropanoic acid

82

2-([1,1′-biphenyl]-4-ylmethyl)-2- (((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H- purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)mthoxy)-3- methoxy-3-oxopropanoic acid

83

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahdyrofuran-2-yl)methoxy)-2- ((3-carboxyisoxazol-5-yl)methyl)malonic acid

84

2-([1,1′-biphenyl]-4-ylmethyl)-2- (((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H- purin-9-yl)-4-fluoro-3-hydroxytetrahydro- furan-2-yl)methoxy)-3-ethoxy-3- oxopropanoic acid

85

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahdyrofuran-2-yl)methoxy)-2- (3-chloro-4-methoxybenzyl)malonic acid

86

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- (4-sulfamoylbenzyl)malonic acid

87

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahdyro-furan-2-yl)methoxy)-2- (4-((2-carboxy- ethyl)carbamoyl)benzyl)malonic acid

88

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydro-furan-2-yl)methoxy)-2- ((2-carboxybenzofuran-5-yl)methyl)malonic acid

89

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- (4-(2,2,2-trifluoroethoxy)benzyl)malonic acid

90

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H- purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- (4-((E)-2-carboxyvinyl)benzyl)malonic acid

91

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H- purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- (4-(methoxycarbonyl)benzyl)malonic acid

92

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H- purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- (4-(carboxymethoxy)benzyl)malonic acid

93

2-benzyl-2-(((2R,3R,4S,5R)-5-(2-chloro-6- oxo-1H-purin-9(6H)-yl)-4-fluoro-3- hydroxytetrahydrofuran-2- yl)methoxy)malonic acid

94

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H- purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- (4-(5-methyl-1,3,4-oxadiazol-2- yl)benzyl)malonic acid

95

of 2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- ((2′-cyano-[1,1′-biphenyl]-4-yl)- methyl)malonic acid

96

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H- purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- ((5-chlorobenzo[b]thiophen-3-yl)methyl)- malonic acid

97

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H- purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- (benzo[d]thiazol-2-ylmethyl)malonic acid

98

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H- purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- (4-(methylcarbamoyl)benzyl)malonic acid

99

Diethyl 2-(((2R,3S,4R,5R)-5-(6-amino-2- chloro-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)-2- benzyl malonate

100

2-(((2R,3S,4R,5R)-5-(6-amino-2-chloro-9H- purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methoxy)-2-(4-carboxybenzyl)malonic acid

101

S)-2-(((2R,3S,4R,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)-2- (1H-tetrazol-5-yl)acetic acid

102

(R)-2-(((2R,3S,4R,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)-2- (1H-tetrazol-5-yl)acetic acid

103

(S)-2-(((2R,3S,4R,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)-3- phenyl-2-(1H-tetrazol-5-yl)propanoic acid

104

(R)-2-(((2R,3S,4R,5R)-5-(6-amino-2- chloro-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)-3- phenyl-2-(1H-tetrazol-5-yl)propanoic acid

105

(S)-2-(((2R,3S,4R,5R)-5-(6-amino-2- methoxy-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)-3- phenyl-2-(1H-tetrazol-5-yl)propanoic acid

106

(R)-2-(((2R,3S,4R,5R)-5-(6-amino-2- methoxy-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)-3- phenyl-2-(1H-tetrazol-5-yl)propanoic acid

Cpd. #

Compound

108

109

110

111

113

114

115

116

117

118

119

120

122

123

124

125

126

127

128

129

130

131

133

134

135

136

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

or a pharmaceutically acceptable salt thereof.

57. The method of claim 1 , wherein the compound of formula (I) is selected from:

or a pharmaceutically acceptable salt thereof.

58. The method of claim 1 , wherein the cancer is selected from bladder cancer, bone cancer, brain cancer, breast cancer, cardiac cancer, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, fibrosarcoma, gastric cancer, gastrointestinal cancer, head & neck cancer, Kaposi's sarcoma, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, myeloma, ovarian cancer, pancreatic cancer, penile cancer, prostate cancer, testicular germcell cancer, thymoma and thymic carcinoma.

59. The method of claim 58 , wherein the cancer is selected from breast cancer, brain cancer, colon cancer, fibrosarcoma, kidney cancer, lung cancer, melanoma, ovarian cancer, and prostate cancer.

60. The method of claim 59 , wherein the cancer is breast cancer.

61. The method of claim 58 , further comprising conjointly administering one or more additional chemotherapeutic agents.

62. The method of claim 61 , wherein the one or more additional chemotherapeutic agents are selected from 1-amino-4-phenylamino-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-hydroxyphenyl-amino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-aminophenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[1-naphthylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-fluoro-2-carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[2-anthracenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, navitoclax, afatinib dimaleate, axitinib, aminoglutethimide, amsacrine, anastrozole, adenosine-5′-O-[(phosphonomethyl)phosphonic acid], asparaginase, capivasertib, Bacillus Calmette-Guérin vaccine, bicalutamide, bleomycin, bortezomib, buserelin, busulfan, cabazitaxel, cabozantinib, campothecin, capecitabine, carboplatin, carfilzomib, carmustine, ceritinib, chlorambucil, chloroquine, cisplatin, cladribine, clodronate, cobimetinib, colchicine, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, demethoxyviridin, dexamethasone, dichloroacetate, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gefitinib, gemcitabine, genistein, goserelin, trametinib, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, ixabepilone, lenalidomide, letrozole, leucovorin, leuprolide, levamisole, lomustine, lonidamine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, metformin, methotrexate, miltefosine, mitomycin, mitotane, mitoxantrone, 8-[4-(1-Aminocyclobutyl)phenyl]-9-phenyl-2H-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3-one, mutamycin, N-(4-sulfamoylphenylcarbamothioyl) pivalamide, 8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-2H-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3-one, 8-[[4-[[4-[[4-[[4-[(4,6,8 trisulfonatonaphthalen-1-yl)carbamoyl]phenyl]carbamoyl]phenyl]carbamoylamino]benzoyl]amino]benzoyl]amino]naphth alene-1,3,5-trisulfonate, nilutamide, nocodazole, octreotide, olaparib, oxaliplatin, paclitaxel, pamidronate, pazopanib, pemexetred, pentostatin, perifosine, 2-amino-8-((1r,4r)-4-(2-hydroxyethoxy)cyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one, plicamycin, pomalidomide, porfimer, 4-[[4-formyl-5-hydroxy-6-methyl-3-(phosphonooxymethyl)pyridin-2-yl]diazenyl]benzene-1,3-disulfonic acid, procarbazine, quercetin, raltitrexed, ramucirumab, reactive blue 2, rituximab, rolofylline, romidepsin, rucaparib, selumetinib, sirolimus, sodium 2,4-dinitrobenzenesulfonate, sorafenib, streptozocin, sunitinib, suramin, talazoparib, tamoxifen, temozolomide, temsirolimus, teniposide, testosterone, thalidomide, thioguanine, thiotepa, titanocene dichloride, tonapofylline, topotecan, trametinib, trastuzumab, tretinoin, veliparib, vinblastine, vincristine, vindesine, vinorelbine, and vorinostat.

63. The method of claim 61 , wherein the one or more additional chemotherapeutic agents are selected from 1-amino-4-phenylamino-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-hydroxyphenyl-amino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-aminophenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[1-naphthylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-fluoro-2-carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[2-anthracenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, adenosine-5′-O-[(phosphonomethyl)phosphonic acid], β-methylene-ADP, capecitabine, cladribine, cytarabine, fludarabine, doxorubicin, gemcitabine, N-(4-sulfamoylphenylcarbamothioyl) pivalamide, 8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-2H-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3-one, 8-[[4-[[4-[[4-[[4-[(4,6,8-trisulfonatonaphthalen-1-yl)carbamoyl]phenyl]carbamoyl]phenyl]carbamoylamino]benzoyl]amino]benzoyl]amino]naphth alene-1,3,5-trisulfonate, 4-[[4-formyl-5-hydroxy-6-methyl-3-(phosphonooxymethyl)pyridin-2-yl]diazenyl]benzene-1,3-disulfonic acid, quercetin, reactive blue 2, rolofylline sodium 2,4-dinitrobenzenesulfonate, sumarin, and tonapofylline.

64. The method of claim 61 , wherein the additional chemotherapeutic agent is an immuno-oncology agent.