Novel equilibrative nucleoside transporter inhibitors and methods of making and using same

A compound of formula (II), or a pharmaceutically acceptable salt thereof:

• wherein:
• G1 is a 6- to 12-membered aryl or a 5- to 12-membered heteroaryl, wherein G1 is optionally substituted with 1-4 R1x, wherein, at each occurrence, R1x is independently —NO2, halogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, —OR1a, —NR1aR1b, —SR1a, —NR1aC(O)R1c, cyano, —C(O)OR1a, —C(O)NR1aR1b, —C(O)R1c, —SO2R1d, —SO2NR1aR1b, G1a, —C1-3alkylene-G1a, or —C1-3alkylene-Q1a;
• R1a, R1b, and R1c, at each occurrence, are each independently hydrogen, C1-6alkyl, C1-6haloalkyl, G1a, or —C1-3alkylene-G1a;
• R1d, at each occurrence, is independently C1-6alkyl, C1-6haloalkyl, G1a, or —C1-3alkylene-G1a;
• G1a, at each occurrence, is independently a C3-8cycloalkyl, a 4- to 12-membered heterocyclyl, a 6- to 12-membered aryl, or a 5- to 12-membered heteroaryl, wherein G1a is optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, oxo, C1-4alkyl, —OC1-4alkyl, —OC1-4haloalkyl, —OH, NH2, —NHC1-4alkyl, —N(C1-4alkyl)2, cyano, —C(O)OC1-4alkyl, —C(O)NH2, —C(O)NHC1-4alkyl, and —C(O)N(C1-4alkyl)2;
• Q1a at each occurrence, is independently —OC1-4alkyl, —OC1-4haloalkyl, —OH, —NH2, —NHC1-4alkyl, —N(C1-4alkyl)2, cyano, —C(O)OC1-4alkyl, —C(O)NH2, —C(O)NHC1-4alkyl, or —C(O)N(C1-4alkyl)2;
• L1 is C1-4alkylene or absent;
• X1 is O, S, or NH;
• when G1-L1-X1 is present G2 is phenylene;
• when G1-L1-X1 is absent G2 is phenyl;
• G2 is optionally substituted with 1-4 R2x, wherein, at each occurrence, R2x is independently halogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, —OR2a, —NO2, —NR2aR2b, —SR2a, —NR2aC(O)R2c, cyano, —C(O)OR2a, —C(O)R2c, —C(O)NR2aR2b, —SO2NR2aR2b, —SO2R2d, G2a, —C1-3alkylene-G2a, or —C1-3alkylene-Q2a;
• R2a, R2b, and R2c, at each occurrence, are each independently hydrogen, C1-6alkyl, C1-6haloalkyl, G2a, or —C1-3alkylene-G2a;
• R2d, at each occurrence, is independently C1-6alkyl, C1-6haloalkyl, G2a, or —C1-3alkylene-G2a;
• G2a, at each occurrence, is independently a C3-6cycloalkyl, a phenyl, a 4- to 6-membered heterocyclyl, or a 5- to 6-membered heteroaryl;
• wherein G2a is optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, oxo, C1-4alkyl, —OC1-4alkyl, —OC1-4haloalkyl, —OH, —NH2, —NHC1-4alkyl, —N(C1-4alkyl)2, cyano, —C(O)OC1-4alkyl, —C(O)NH2, —C(O)NHC1-4alkyl, and —C(O)N(C1-4alkyl)2;
• Q2a, at each occurrence, is independently —OC1-4alkyl, —OC1-4haloalkyl, —OH, —NH2, —N(C1-4alkyl)2, cyano, —C(O)OC1-4alkyl, —C(O)NH2, —C(O)NHC1-4alkyl, or —C(O)N(C1-4alkyl)2;
• L2a is
• L2b is C1-3alkylene, C2-3alkenylene, C2-3alkynylene, or absent;
• L3a is C1-3alkylene, C2-3alkenylene, C2-3alkynylene, or absent;
• and
• L3b is
• G3 is a 6- to 12-membered arylene or a 5- to 12-membered heteroarylene, wherein G3 is optionally substituted with 1-4 R3x, wherein, at each occurrence, R3x is independently halogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, —OR3a, —NO2, —NR3aR3b, —SR3a, —NR3aC(O)R3c, cyano, —C(O)OR3a, —C(O)NR3aR3b, —C(O)R3c, —SO2R3d, —SO2NR3aR3b, G3a, —C1-3alkylene-G3a, or —C1-3alkylene-Q3a;
• R3a, R3b, and R3c, at each occurrence, are each independently hydrogen, C1-6alkyl, C1-6haloalkyl, G3a, or —C1-3alkylene-G3a;
• R3d, at each occurrence, is independently C1-6alkyl, C1-6haloalkyl, G3a, or —C1-3alkylene-G3a;
• G3a, at each occurrence, is independently a C3-8cycloalkyl, a 4- to 12-membered heterocyclyl, a 6- to 12-membered aryl, or a 5- to 12-membered heteroaryl, wherein G3a is optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, oxo, C1-4alkyl, —OC1-4alkyl, —OC1-4haloalkyl, —OH, NH2, —NHC1-4alkyl, —N(C1-4alkyl)2, cyano, —C(O)OC1-4alkyl, —C(O)NH2, —C(O)NHC1-4alkyl, and —C(O)N(C1-4alkyl)2;
• and
• Q3a, at each occurrence, is independently —OC1-4alkyl, —OC1-4haloalkyl, —OH, —NH2, —NHC1-4alkyl, —N(C1-4alkyl)2, cyano, —C(O)OC1-4alkyl, —C(O)NH2, —C(O)NHC1-4alkyl, or —C(O)N(C1-4alkyl)2.

A compound of formula (III), or a pharmaceutically acceptable salt thereof:

• wherein:
• G1 is a 6- to 12-membered aryl or a 5- to 12-membered heteroaryl, wherein G1 is optionally substituted with 1-4 R1x, wherein, at each occurrence, R1x is independently —NO2, halogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, —OR1a, —NR1aR1b, —SR1a, —NR1aC(O)R1c, cyano, —C(O)OR1a, —C(O)NR1aR1b, —C(O)R1c, —SO2R1d, —SO2NR1aR1b, G1a, —C1-3alkylene-G1a, or —C1-3alkylene-Q1a;
• R1a, R1b, and R1c, at each occurrence, are each independently hydrogen, C1-6alkyl, C1-6haloalkyl, G1a, or —C1-3alkylene-G1a;
• R1d, at each occurrence, is independently C1-6alkyl, C1-6haloalkyl, G1a, or —C1-3alkylene-G1a;
• G1a, at each occurrence, is independently a C3-8cycloalkyl, a 4- to 12-membered heterocyclyl, a 6- to 12-membered aryl, or a 5- to 12-membered heteroaryl, wherein G1a is optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, oxo, C1-4alkyl, —OC1-4alkyl, —OC1-4haloalkyl, —OH, NH2, —NHC1-4alkyl, —N(C1-4alkyl)2, cyano, —C(O)OC1-4alkyl, —C(O)NH2, —C(O)NHC1-4alkyl, and —C(O)N(C1-4alkyl)2;
• Q1a at each occurrence, is independently —OC1-4alkyl, —OC1-4haloalkyl, —OH, —NH2, —NHC1-4alkyl, —N(C1-4alkyl)2, cyano, —C(O)OC1-4alkyl, —C(O)NH2, —C(O)NHC1-4alkyl, or —C(O)N(C1-4alkyl)2;
• L1 is C1-4alkylene or absent;
• X1 is O, S, or NH;
• G2 is phenylene, wherein G2 is optionally substituted with 1-4 R2x, wherein, at each occurrence, R2x is independently halogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, —OR2a, —NO2, —NR2aR2b, —SR2a, —NR2aC(O)R2c, cyano, —C(O)OR2a, —C(O)NR2aR2b, —C(O)R2c, —SO2R2d, —SO2NR2aR2b, G2a, —C1-3alkylene-G2a, or —C1-3alkylene-Q2a;
• R2a, R2b, and R2c, at each occurrence, are each independently hydrogen, C1-6alkyl, C1-6haloalkyl, G2a, or —C1-3alkylene-G2a;
• R2d, at each occurrence, is independently C1-6alkyl, C1-6haloalkyl, G2a, or —C1-3alkylene-G2a;
• G2a, at each occurrence, is independently a C3-6cycloalkyl, a phenyl, a 4- to 6-membered heterocyclyl, or a 5- to 6-membered heteroaryl;
• wherein G2a is optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, oxo, C1-4alkyl, —OC1-4alkyl, —OC1-4haloalkyl, —OH, —NH2, —NHC1-4alkyl, —N(C1-4alkyl)2, cyano, —C(O)OC1-4alkyl, —C(O)NH2, —C(O)NHC1-4alkyl, and —C(O)N(C1-4alkyl)2;
• Q2a, at each occurrence, is independently —OC1-4alkyl, —OC1-4haloalkyl, —OH, —NH2, —N(C1-4alkyl)2, cyano, —C(O)OC1-4alkyl, —C(O)NH2, —C(O)NHC1-4alkyl, or —C(O)N(C1-4alkyl)2;
• L2a is
• and
• Z1 is C1-6alkyl, or C3-6cycloalkyl.