ECTONUCLEOTIDASE INHIBITORS AND METHODS OF USE THEREOF
The invention relates to novel heterocyclic compounds and pharmaceutical preparations thereof. The invention further relates to methods of treating or preventing cancer using the novel heterocyclic compounds of the invention.
1 . A compound of formula (I):
or a pharmaceutically acceptable salt and/or prodrug thereof, wherein
X is O, NR 7 or CR 7 R 8 ;
Y is O or S;
Z is NR 19 , O or S;
Het is heterocyclyl or heteroaryl;
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 );
each R 7 and R 8 is H
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, preferably H; and
m is 1 or 2;
provided that either R 4 is tetrazolyl, or R 5 is aralkyl or heteroaralkyl, or both.
2 .- 146 . (canceled)
147 . A compound selected from:
Cpd.
#
Compound
Name
6
2-(((2R,3R,4S,5R)-5-(6- amino-2-chloro-9H- purin-9-yl)-4-fluoro-3- hydroxytetrahydro-furan- 2-yl)methoxy)-2-benzyl- malonic 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-hydroxytetra- hydrofuran-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
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-chloro-9H- purin-9-yl)-4-fluoro-3- (isobutyryloxy)tetrahydro- furan-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-hydroxytetra- hydrofuran-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- 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
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-butoxy- carbonyl)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- hydroxytetrahydrofuran- 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) methyl)malonic acid
69
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
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-chloro-9H- purin-9-yl)-4-fluoro-3- (isobutyryloxy)tetrahydro- furan-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
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
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
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
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- dihydroxytetrahydro- furan-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- dihydroxytetrahydro- furan-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- dihydroxytetrahydro- furan-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- dihydroxytetrahydro- furan-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- dihydroxytetrahydro- furan-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- dihydroxytetrahydro- furan-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- dihydroxytetrahydro- furan-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.
148 . A compound selected from:
or a pharmaceutically acceptable salt thereof.
149 . A pharmaceutical composition comprising the compound claim 1 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
150 . A method of inhibiting CD73 in a cell, comprising contacting the cell with a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 .
151 . The method of claim 150 , wherein contacting the cell occurs in a subject in need thereof, thereby treating a disease or disorder selected from cancer, cerebral and cardiac ischemic diseases, fibrosis, immune and inflammatory disorders, inflammatory gut motility disorder, neurological, neurodegenerative and CNS disorders and diseases, depression, Parkinson's disease, and sleep disorders.
152 . The method of claim 151 , 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.
153 .- 158 . (canceled)