Ectonucleotidase inhibitors and methods of use thereof

1. A compound of Formula (I):

or a pharmaceutically acceptable salt 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 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; 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, 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 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 );

each R 7 and R 8 is independently selected from H, alkyl, acyloxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;

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, alkenyl, alkynyl, —S(O) 2 R 10 , 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, preferably H; and

m is 1 or 2;

provided that if R 3 is H and R 1a and R 2a are each hydroxy, then at least one of R 1b and R 2b is C 1-6 alkyl.

2. The compound of claim 1 , wherein R 1a is fluoro and R 1b is H.

3. The compound of claim 1 , wherein R 2a is fluoro and R 2b is H.

4. The compound of claim 1 , wherein R 1a and R 1b are each fluoro.

5. The compound of claim 1 , wherein R 2a and R 2b are each fluoro.

6. The compound of claim 1 , wherein R 1a is fluoro and R 2a is C 1-6 alkoxy.

7. The compound of claim 1 , wherein R 1a is fluoro and R 2a is meth-6alkyl.

8. The compound of claim 1 , wherein R 1a is fluoro and R 2a is methyl or ethyl.

9. The compound of claim 1 , wherein R 2a is hydroxy and R 2b is methyl.

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

11. The compound of claim 10 , wherein R 1a is in the α-configuration.

12. The compound of claim 11 , wherein the compound of Formula (I) has the structure (IA):

13. The compound of claim 10 , wherein R 1a is in the β-configuration.

14. The compound of claim 13 , wherein the compound of Formula (I) has the structure (IB):

15. The compound of claim 4 , wherein R 2a is in the α-configuration.

16. The compound of claim 15 , wherein the compound of Formula (I) has the structure (IC):

17. The compound of claim 10 , wherein R 2a is in the β-configuration.

18. The compound of claim 17 , wherein the compound of Formula (I) has the structure (ID):

19. The compound of claim 10 , wherein the compound of Formula (I) has the structure (IE):

20. The compound of claim 1 , wherein R 3 is H.

21. The compound of claim 1 , wherein R 3 is unsubstituted C 1-6 alkyl.

22. The compound 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.

23. The compound of claim 22 , wherein the substituents are selected from halo, CN, azido, alkoxy, carbonyl, amino, amido, and alkoxycarbonyl.

24. The compound 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 ).

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

26. The compound of claim 1 , wherein R 4 is alkyl.

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

28. The compound 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.

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

30. The compound of claim 28 , wherein R 5 is aralkyl or heteroaralkyl.

31. The compound of claim 30 , wherein R 5 is aralkyl, and the aryl ring is substituted or unsubstituted phenyl or naphthyl.

32. The compound of claim 30 , 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 compound of claim 28 , wherein the substituents are selected from tetrazolyl, substituted or unsubstituted phenyl, or substituted or unsubstituted benzyl.

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

35. The compound of claim 1 , wherein R 6 is —P(O)(OR 11 )(OR 12 ), and R 11 and R 12 are each H.

36. The compound of claim 1 , wherein R 7 is H or C 1-6 alkyl.

37. The compound of claim 1 , wherein R 8 is H.

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

39. The compound of claim 1 , wherein R 11 and R 12 are each H.

40. The compound of claim 1 , wherein R 11 and R 12 are each alkyl.

41. The compound of claim 1 , wherein the substituents on each R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are selected from halo, CN, azido, alkoxy, carbonyl, amino, amido, and alkoxycarbonyl.

42. The compound of claim 1 , wherein Y is O.

43. The compound of claim 1 , wherein Z is O.

44. The compound of claim 1 , wherein Het is a purinyl ring or a 5-methyl-pyrimidin-2,4-dione ring 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.

45. The compound of claim 44 , wherein the substituents are selected from halo, CN, azido, alkoxy, carbonyl, amino, amido, and alkoxycarbonyl.

46. The compound of claim 1 , wherein Het is purinyl.

47. The compound of claim 1 , wherein Het is

48. The compound of claim 1 , wherein Het is

49. The compound of claim 44 , wherein Het is selected from

50. The compound of claim 1 , wherein

represents

51. The compound of claim 1 , wherein

represents

wherein:

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

k is 1, 2, or 3.

52. A compound having the structure:

wherein:

R 5 is:

(i) phenylC 1-6 alkyl or naphthylC 1-6 alkyl wherein phenyl and naphthyl are optionally substituted with one, two, or three substituents independently selected from —C 1-6 alkyl, —OC 1-6 alkyl, —C 1-6 alkyl substituted with one to five fluoro, —OC 1-6 alkyl (substituted with one to five fluoro), —C 1-6 alkylene-CO 2 H, —C 1-6 alkylene-CO 2 C 1-6 alkyl, —C 2-6 alkenylene-CO 2 H, —OC 1-6 alkylene-CO 2 H, —OC 1-6 alkylene-CO 2 C 1-6 alkyl, —C 1-6 alkyl substituted with one or two hydroxy, —OC 1-6 alkyl substituted with one or two hydroxy, —C 1-6 alkyl substituted with one or two —OC 1-6 alkyl, —OC 1-6 alkyl (substituted with one or two —OC 1-6 alkyl), —CO 2 H, —COOC 1-6 alkyl, hydroxy, halo, nitro, —PO 3 H 2 , cyano, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —CONR e R f (where R e and R f are independently hydrogen, —C 1-6 alkyl, —C 1-6 alkylene-CO 2 H, —C 1-6 alkylene-CO 2 C 1-6 alkyl, or —C 1-6 alkylene-substituted with one or two substituents independently selected from hydroxy, NH 2 , —NHC 1-6 alkyl or —N(C 1-6 alkyl) 2 ), —SO 2 (C 1-6 alkyl), —SO 2 NR g R h (where R g and R h are independently hydrogen, —C 1-6 alkyl, —C 1-6 alkylene-CO 2 H, or —C 1-6 alkylene-CO 2 C 1-6 alkyl), —SC 1-6 alkyl, —SOC 1-6 alkyl, —SO 2 NHCOR j (where R j is —C 1-6 alkyl, —NHC 1-6 alkyl, or —N(C 1-6 alkyl) 2 ), phenyl, —C 1-6 alkylenephenyl, phenoxy, —OC 1-6 alkylenephenyl, 5- or 6-membered monocyclic heteroaryl containing one to four heteroatoms independently selected from O, N, and S [wherein the heteroaryl ring is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, CN, —CO 2 H, —COOC 1-6 alkyl, —C 1-6 alkyl, —OC 1-6 alkyl, —C 1-6 alkyl (substituted with one to five fluoro), —OC 1-6 alkyl (substituted with one to five fluoro), —C 1-6 alkylene-CO 2 H, —C 1-6 alkylene-CO 2 C 1-6 alkyl, tetrazolyl, —SO 2 C 1-6 alkyl, —SO 2 NH 2 , —SO 2 NHC 1-6 alkyl, —SO 2 N(C 1-6 alkyl) 2 , —CONH 2 , —CONHC 1-6 alkyl, or —CON(C 1-6 alkyl) 2 ], —OR i , —C 1-6 alkylene-R i , —OC 1-6 alkylene-R i , —SR i , —SC 1-6 alkylene-R i , heterocyclyl, —C 1-6 alkyleneheterocyclyl, —OC 1-6 alkylene-heterocyclyl, —SC 1-6 alkyleneheterocyclyl, —CONR m C 1-6 alkyleneheterocyclyl, —NR m COC 1-6 alkyleneNR o R p , —NR m COheterocyclyl, —NR m COC 1-6 alkyleneheterocyclyl, —COheterocyclyl, —CONR m R i , —CONR m C 1-6 alkylene-R i , —OCONR m R m , —NR m —COR y , —NR m —CO—NR m R y , —NR m —SO 2 —R y , —NR m —SO 2 —NR m R y , and —CONHSO 2 R z ; or

(ii) 5-10 membered heteroarylC 1-6 alkyl having one to three heteroatoms independently selected from N, O, or S and 5-10 membered heteroaryl in 5-10 membered heteroarylC 1-6 alkyl is optionally substituted with one or two substituents independently selected from —C 1-6 alkyl, —OC 1-6 alkyl, —C 1-6 alkyl substituted with one to five fluoro, —OC 1-6 alkyl substituted with one to five fluoro, —C 1-6 alkylene-CO 2 H, —C 1-6 alkylene-CO 2 C 1-6 alkyl, —C 2-6 alkenylene-CO 2 H, —C 1-6 alkyl substituted with one or two hydroxy, —OC 1-6 alkyl substituted with one or two hydroxy, —C 1-6 alkyl substituted with one or two —OC 1-6 alkyl, —OC 1-6 alkyl (substituted with one or two —OC 1-6 alkyl), —CO 2 H, —COOC 1-6 alkyl, hydroxy, halo, nitro, —PO 3 H 2 , cyano, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —CONR e R f (where R e and R f are independently hydrogen, —C 1-6 alkyl, —C 1-6 alkylene-CO 2 H, —C 1-6 alkylene-CO 2 C 1-6 alkyl, or —C 1-6 alkyl substituted with one or two hydroxyl, —NHC 1-6 alkyl or —N(C 1-6 alkyl) 2 ), —SO 2 (C 1-6 alkyl), —SO 2 NR g R h (where R g and R h are independently hydrogen, —C 1-6 alkyl, —C 1-6 alkylene-CO 2 H, or —C 1-6 alkylene-CO 2 C 1-6 alkyl), —SC 1-6 alkyl, —SOC 1-6 alkyl, —SO 2 NHCOR j (where R J is —C 1-6 alkyl, —NH 2 , —NHC 1-6 alkyl, or —N(C 1-6 alkyl) 2 ), phenyl, —C 1-6 alkylenephenyl, phenoxy, —OC 1-6 alkylenephenyl, 5- or 6-membered monocyclic heteroaryl containing one to four heteroatoms independently selected from O, N, and S [wherein the heteroaryl ring is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, CN, —CO 2 H, —COOC 1-6 alkyl, —C 1-6 alkyl, —OC 1-6 alkyl, —C 1-6 alkyl (substituted with one to five fluoro), —OC 1-6 alkyl (substituted with one to five fluoro), —C 1-6 alkylene-CO 2 H, —C 1-6 alkylene-CO 2 C 1-6 alkyl, tetrazolyl, —SO 2 C 1-6 alkyl, —SO 2 NH 2 , —SO 2 NHC 1-6 alkyl, —SO 2 N(C 1-6 alkyl) 2 , —CONH 2 , —CONHC 1-6 alkyl, and —CON(C 1-6 alkyl) 2 ], —OR i , —C 1-6 alkylene-R i , —OC 1-6 alkylene-R i , —SR i , —SC 1-6 alkylene-R i , heterocyclyl, —C 1-6 alkyleneheterocyclyl, —OC 1-6 alkyleneheterocyclyl, —SC 1-6 alkyleneheterocyclyl, —CONR m C 1-6 alkyleneheterocyclyl, —NR m COC 1-6 alkyleneNR o R p , —NR m COheterocyclyl, —NR m COC 1-6 alkyleneheterocyclyl, —COheterocyclyl, —CONR m R i , —CONR m alkylene-R i , —OCONR m R m , —NR m —COR Y , —NR m —CO—NR m R y , —NR m —SO 2 —R y , —NR m —SO 2 —NR m R y , and —CONHSO 2 R z ; and

the R 5 5-10 membered heteroaryl ring is additionally optionally substituted with an additional substituent selected from —C 1-6 alkyl, —C 1-6 alkyl (wherein alkyl is substituted with one to five fluoro), —O—C 1-6 alkyl, —OC 1-6 alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, —NH 2 , and hydroxy; wherein:

each R m is hydrogen or —C 1-6 alkyl;

R o , R p , and R y are each independently hydrogen or —C 1-6 alkyl;

R z is —C 1-6 alkyl, —NHC 1-6 alkyl, or —N(C 1-6 alkyl) 2 ;

phenyl by itself or as part of —C 1-6 alkylenephenyl, phenoxy, or —OC 1-6 alkylenephenyl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, CN, —CO 2 H, —COOC 1-6 alkyl, —C 1-6 alkyl, —OC 1-6 alkyl, —C 1-6 alkyl substituted with one to five fluoro, —OC 1-6 alkyl (substituted with one to five fluoro), —C 1-6 alkylene-CO 2 H, —C 1-6 alkylene-CO 2 C 1-6 alkyl, tetrazolyl, —SO 2 C 1-6 alkyl, —SO 2 NH 2 , —SO 2 NHC 1-6 alkyl, —SO 2 N(C 1-6 alkyl) 2 , —CONH 2 , —CONHC 1-6 alkyl, or —CON(C 1-6 alkyl) 2 ;

each R i is independently 5- or 6-membered monocyclic heteroaryl containing one to four heteroatoms independently selected from O, N, and S and wherein the heteroaryl ring is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, CN, —CO 2 H, —COOC 1-6 alkyl, —C 1-6 alkyl, —OC 1-6 alkyl, —C 1-6 alkyl substituted with one to five fluoro, —OC 1-6 alkyl (substituted with one to five fluoro), —C 1-6 alkylene-CO 2 H, and —C 1-6 alkylene-CO 2 C 1-6 alky, tetrazolyl, —SO 2 C 1-6 alkyl, —SO 2 NH 2 , —SO 2 NHC 1-6 alkyl, —SO 2 N(C 1-6 alkyl) 2 , —CONH 2 , —CONHC 1-6 alkyl, or —CON(C 1-6 alkyl) 2 1;

heterocyclyl by itself or as part of —C 1-6 alkyleneheterocyclyl, —OC 1-6 alkyleneheterocyclyl, —SC 1-6 alkyleneheterocyclyl, —CONR m C 1-6 alkyleneheterocyclyl, —NR m COC 1-6 alkylene-heterocyclyl, —COheterocyclyl, or —NR m COheterocyclyl is optionally substituted with one, two, or three substituents independently selected from hydroxy, halo, —COOC 1-6 alkyl, —C 1-6 alkyl, —OC 1-6 alkyl, or —C 1-6 alkyl (substituted with hydroxy or —OC 1-6 alkyl); and

Het is a group of formula (iii) or (xiv) below:

 wherein:

R u is —NH 2 , —NHR 20 , —NHCOR 20 , and —NR 20 R 21 ;

R w is hydrogen, halo, —NHR 22 , —NR 22 R 23 , —R 22 , —OH, or —OR 22 ;

R o and R x is hydrogen, halo, haloC 1-6 alkyl, —NH 2 , —NHR 24 , —NR 24 R 25 , —R 24 , —SR 24 , cyano, —OH, —OR 24 , —SO 2 R 24 , —C 1-6 alkyleneNH 2 , —C 1-6 alkyleneNHR 24 , —C 1-6 alkyleneNR 24 R 25 , R 24 , —C 1-6 alkyleneSR 24 , —C 1-6 alkyleneOH, —C 1-6 alkyleneOR 24 , or —C 1-6 alkyleneSO 2 R 24 ,

R s is hydrogen, halo, or C 1-6 alkyl; and

 wherein:

R 20 , R 21 , R 22 , R 23 , R 24 and R 25 are independently optionally substituted C 1-6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclyl C 1-6 alkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylC 1-6 alkyl, optionally substituted aryl, optionally substituted arylC 1-6 alkyl, optionally substituted heteroaryl, or optionally substituted heteroarylC 1-6 alkyl; or

R 20 and R 21 , R 22 and R 23 , and/or R 24 and R 25 , together with the nitrogen to which they are attached form an optionally substituted nitrogen-containing heterocyclyl;

and further wherein, unless otherwise specified:

C 1-6 alkyl is unsubstituted;

C 1-6 alkyl of C 1-6 alkyloxy is unsubstituted;

haloC 1-6 alkyl is C 1-6 alkyl substituted with one to five halo atoms;

haloC 1-6 alkyloxy is C 1-6 alkyloxy substituted with one to five halo atoms;

C 2-6 alkenyl is unsubstituted;

C 2-6 alkynyl is unsubstituted;

C 1-6 alkylene is unsubstituted;

C 2-6 alkenylene is unsubstituted;

optionally substituted C 1-6 alkyl is optionally substituted with one or two substituents independently selected from hydroxy, C 1-6 alkyloxy, halo, haloC 1-6 alkyl, haloC 1-6 alkyloxy, cyano, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl;

carbocyclyl is an unsubstituted saturated or partially unsaturated mono or bicyclic ring containing 3 to 10 carbon atoms;

optionally substituted carbocyclyl is optionally substituted with one, two, or three substituents independently selected from C 1-6 alkyl, halo, hydroxy, or C 1-6 alkoxy; optionally substituted aryl is optionally substituted with one, two, or three substituents independently selected from hydroxy, C 1-6 alkyloxy, halo, haloC 1-6 alkyl, haloC 1-6 alkyloxy, cyano, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 ;

aryl is phenyl or naphthyl;

optionally substituted carbocyclyl, aryl [optionally substituted with one, two, or three substituents independently selected from hydroxy, C 1-6 alkyloxy, halo, haloC 1-6 alkyl, haloC 1-6 alkyloxy, cyano, —NH 2 , —NH(C 1-6 alkyl), and —N(C 1-6 alkyl) 2 ], heteroaryl [optionally substituted with one, two, or three substituents independently selected from hydroxy, C 1-6 alkyloxy, halo, haloC 1-6 alkyl, haloC 1-6 alkyloxy, cyano, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 ], and heterocyclyl [optionally substituted with one, two, or three substituents independently selected from hydroxy, C 1-6 alkyloxy, halo, haloC 1-6 alkyl, haloC 1-6 alkyloxy, cyano, —NH 2 , —NH(C 1-6 alkyl), —N(unsubstituted C 1-6 alkyl) 2 ];

heteroaryl is an unsubstituted five to ten membered or five to six membered aromatic ring containing one to four or one to three heteroatoms independently selected from N, O, and S; the remaining ring atoms being carbon;

optionally substituted heteroaryl is a five to ten membered aromatic ring containing one to four heteroatoms independently selected from N, O, and S; the remaining ring atoms being carbon, that is optionally substituted with one, two, or three substituents independently selected from hydroxy, C 1-6 alkyloxy, halo, haloC 1-6 alkyl, haloC 1-6 alkyloxy, cyano, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , optionally substituted carbocyclyl, aryl [optionally substituted with one, two, or three substituents independently selected from hydroxy, C 1-6 alkyloxy, halo, haloC 1-6 alkyl, haloC 1-6 alkyloxy, cyano, —NH 2 , —NH(C 1-6 alkyl), and —N(C 1-6 alkyl) 2 ], heteroaryl [optionally substituted with one, two, or three substituents independently selected from hydroxy, unsubstituted C 1-6 alkyloxy, halo, haloC 1-6 alkyl, haloC 1-6 alkyloxy, cyano, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 ], and heterocyclyl [optionally substituted with one, two, or three substituents independently selected from hydroxy, C 1-6 alkyloxy, halo, haloC 1-6 alkyl, haloC 1-6 alkyloxy, cyano, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 ];

heterocyclyl is an unsubstituted monocyclic, saturated or partially unsaturated 4 to 8 membered ring containing one to three heteroatoms independently selected from N, O, S, SO, and SO 2 and optionally contains one or two CO, the remaining atoms in the ring being carbon that is optionally fused to phenyl or 5 to 6 membered carbocyclyl or 5 or 6 heteroaryl ring;

nitrogen-containing heterocyclyl is a heterocyclyl ring that has at least a nitrogen atom;

optionally substituted heterocyclyl is heterocyclyl that is optionally substituted with one, two, or three substituents independently selected from hydroxy, C 1-6 alkyloxy, halo, haloC 1-6 alkyl, haloC 1-6 alkyloxy, cyano, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , optionally substituted carbocyclyl, aryl [optionally substituted with one, two, or three substituents independently selected from hydroxy, C 1-6 alkyloxy, halo, haloC 1-6 alkyl, haloC 1-6 alkyloxy, cyano, —NH 2 , —NH(C 1-6 alkyl), and —N(C 1-6 alkyl) 2 ], heteroaryl [optionally substituted with one, two, or three substituents independently selected from hydroxy, C 1-6 alkyloxy, halo, haloC 1-6 alkyl, haloC 1-6 alkyloxy, cyano, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 ], and heterocyclyl optionally substituted with one, two, or three substituents independently selected from hydroxy, C 1-6 alkyloxy, halo, haloC 1-6 alkyl, haloC 1-6 alkyloxy, cyano, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 ];

optionally substituted carbocyclyl C 1-6 alkyl is optionally substituted carbocyclyl attached via C 1-6 alkyl;

optionally substituted heterocyclylC 1-6 alkyl is optionally substituted heterocyclyl attached via C 1-6 alkyl;

optionally substituted arylC 1-6 alkyl is optionally substituted aryl attached via C 1-6 alkyl;

optionally substituted heteroarylC 1-6 alkyl is optionally substituted heteroaryl attached via C 1-6 alkyl;

provided that the compound of Formula (I) is not:

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;

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

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;

diethyl 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)malonate;

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;

diethyl 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)malonate;

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

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

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;

diethyl 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)malonate;

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;

diethyl 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)malonate;

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;

diethyl 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)malonate;

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;

diethyl 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)malonate;

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;

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

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

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

1-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)ethane-1,1,2-tricarboxylic acid;

3-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-4-ethoxy-3-(ethoxycarbonyl)-4-oxobutanoic acid;

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

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

((R)-1-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-methoxy-2-oxoethyl)phosphonic acid;

((S)-1-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-methoxy-2-oxoethyl)phosphonic acid;

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;

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

((R)-1-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(methylamino)-2-oxoethyl)phosphonic acid;

((S)-1-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)-2-(methylamino)-2-oxoethyl)phosphonic acid;

or a pharmaceutically acceptable salt thereof.

53. The compound of claim 52 having the structure:

54. A compound of claim 1 selected from:

Cpd. #

Compound

Name

1

(1-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- ethoxy-2-oxoethyl)phosphonic acid

2

(1-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- ethoxy-2-oxoethyl)phosphonic acid

3

(1-(((2R,3R,4S,5R)-5-(6-((tert-butoxy- carbonyl)amino)-2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-ethoxy-2- oxoethyl)phosphonic acid

4

(1-(((2R,3R,4S,5R)-5-(6-((tert-butoxy- carbonyl)amino)-2-chloro-9H-purin-9-yl)-4- fluoro-3-hydroxytetrahydrofuran-2- yl)methoxy)-2-ethoxy-2- oxoethyl)phosphonic acid

5

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

6

2-(((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H- purin-9-yl)-4-fluoro-3-hydroxytetrahydro- 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

9

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

18

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

19

1-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2- yl)methoxy)ethane-1,1,2-tricarboxylic 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

24

(1-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- methoxy-2-oxoethyl)phosphonic 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

26

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

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

29

(1-(((2R,3R,4S,5R)-5-(6-amino-2-chloro- 9H-purin-9-yl)-4-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)-2- (methylamino)-2-oxoethyl)phosphonic acid

30

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

31

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

33

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

(S)-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

(R)-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-(2H-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

52

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

53

2-(3-(2H-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-(2H-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- hydroxytetrahydrofuran-2-yl)methoxy)-2- (4-(trifluoromethyl)benzyl)malonate

63

2-(((2R,3R4S,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)methyl)malonic 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- hydroxytetrahydrofuran-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

(R)-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)methoxy)-3- methoxy-3-oxopropanoic acid

82

(S)-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)methoxy)-3- methoxy-3-oxopropanoic acid

83

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

84

(S)-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- hydroxytetrahydrofuran-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- hydroxytetrahydro-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

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

or a pharmaceutically acceptable salt thereof.

55. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

56. A method of inhibiting CD73 in a cell, comprising contacting the cell with a compound, or a pharmaceutically acceptable salt thereof, according to claim 1 .