IP Library › Granted Patent US 10,793,561

Granted Patent B2

US 10,793,561 · App. 16/039,301 · Granted Oct 6, 2020

1,8-naphthyridinone compounds and uses thereof

Inventors: Son Minh Pham (San Francisco, CA); Jiyun Chen (Moraga, CA); Amantullah Ansari (Noida, IN); Pradeep S. Jadhavar (Greater Noida, IN); Varshavekumar S. Patil (Greater Noida, IN); Farha Khan (New Delhi, IN); Sreekanth A. Ramachandran (Greater Noida, IN); Anil Kumar Agarwal (Noida, IN); Sarvajit Chakravarty (Edmond, OK)

Assignee: NUVATION BIO INC.

C07D471/04 C07D519/00

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Quick Facts

Patent No.: US 10,793,561
App. No.: 16/039,301
Granted: Oct 6, 2020
Kind: B2

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Abstract

1,8-naphthyridinone compounds as modulators of an adenosine receptor are provided. The compounds may find use as therapeutic agents for the treatment of diseases mediated through a G-protein-coupled receptor signaling pathway and may find particular use in oncology.

Claims (142)

1. A compound of Formula (I):

or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

R 1 is H or C 1 -C 6 alkyl wherein the C 1 -C 6 alkyl of R 1 is optionally substituted with oxo or R a ;

R 2 is H, R b or oxo;

R 4 is H, oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, —CN, —OR 8 , —SR 8 , —NO 2 , —C═NH(OR 8 ), —C(O)R 8 , —OC(O)R 8 , —C(O)OR 8 , —C(O)NR 9 R 10 , —OC(O)NR 9 R 10 , —NR 8 C(O)OR 9 , —NR 8 C(O)NR 9 R 10 , —S(O)R 8 , —S(O) 2 R 8 , —NR 8 S(O)R 9 , —C(O)NR 8 S(O)R 9 , —NR 8 S(O) 2 R 9 , —C(O)NR 8 S(O) 2 R 9 , —S(O)NR 9 R 10 , —S(O) 2 NR 9 R 10 , —P(O)(OR 9 )(OR 10 ), C 3 -C 6 cycloalkyl, 3-12-membered heterocyclyl, 5- to 10-membered heteroaryl, C 6 -C 14 aryl, —(C 1 -C 3 alkylene)CN, —(C 1 -C 3 alkylene)OR 8 , —(C 1 -C 3 alkylene)SR 8 , —(C 1 -C 3 alkylene)NR 9 R 10 , —(C 1 -C 3 alkylene)CF 3 , —(C 1 -C 3 alkylene)NO 2 , —C═NH(OR 8 ), —(C 1 -C 3 alkylene)C(O)R 8 , —(C 1 -C 3 alkylene)OC(O)R 8 , —(C 1 -C 3 alkylene)C(O)OR 8 , —(C 1 -C 3 alkylene)C(O)NR 9 R 10 , —(C 1 -C 3 alkylene)OC(O)NR 9 R 10 , —(C 1 -C 3 alkylene)NR 8 C(O)R 9 , —(C 1 -C 3 alkylene)NR 8 C(O)OR 9 , —(C 1 -C 3 alkylene)NR 8 C(O)NR 9 R 10 , —(C 1 -C 3 alkylene)S(O)R 8 , —(C 1 -C 3 alkylene)S(O) 2 R 8 , —(C 1 -C 3 alkylene)NR 8 S(O)R 9 , —C(O)(C 1 -C 3 alkylene)NR 8 S(O)R 9 , —(C 1 -C 3 alkylene)NR 8 S(O) 2 R 9 , —(C 1 -C 3 alkylene)C(O)NR 8 S(O) 2 R 9 , —(C 1 -C 3 alkylene)S(O)NR 9 R 10 , —(C 1 -C 3 alkylene)S(O) 2 NR 9 R 10 , —(C 1 -C 3 alkylene)P(O)(OR 9 )(OR 10 ), —(C 1 -C 3 alkylene)(C 3 -C 6 cycloalkyl), —(C 1 -C 3 alkylene)(3-12-membered heterocyclyl), —(C 1 -C 3 alkylene)(5-10-membered heteroaryl) or -(C 1 -C 3 alkylene)(C 6 -C 14 aryl), each of which is independently optionally substituted by halogen, oxo, —OR 11 , —NR 11 R 12 , —C(O)R 11 , —CN, —S(O)R 11 , —S(O) 2 R 11 , —P(O)(OR 11 )(OR 12 ), —(C 1 -C 3 alkylene)OR 11 , —(C 1 -C 3 alkylene)NR 11 R 12 , —(C 1 -C 3 alkylene)C(O)R 11 , —(C 1 -C 3 alkylene)S(O)R 11 , —(C 1 -C 3 alkylene)S(O) 2 R 11 , —(C 1 -C 3 alkylene)P(O)(OR 11 )(OR 12 ), C 3 -C 8 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by oxo, —OH or halogen;

R 3 and R 5 are each independently H or R c ;

each R a , R b , and R c is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, —CN, —OR 8 , —SR 8 , —NR 9 R 10 , —NO 2 , —C═NH(OR 8 ), —C(O)R 8 , —OC(O)R 8 , —C(O)OR 8 , —C(O)NR 9 R 10 , —OC(O)NR 9 R 10 , —NR 8 C(O)R 9 , —NR 8 C(O)OR 9 , —NR 8 C(O)NR 9 R 10 , —S(O)R 8 , —S(O) 2 R 8 , —NR 8 S(O)R 9 , —C(O)NR 8 S(O)R 9 , —NR 8 S(O) 2 R 9 , —C(O)NR 8 S(O) 2 R 9 , —S(O)NR 9 R 10 , —S(O) 2 NR 9 R 10 , —P(O)(OR 9 )(OR 10 ), C 3 -C 6 cycloalkyl, 3-12-membered heterocyclyl, 5- to 10-membered heteroaryl, C 6 -C 14 aryl, —(C 1 -C 3 alkylene)CN, —(C 1 -C 3 alkylene)OR 8 , —(C 1 -C 3 alkylene)SR 8 , —(C 1 -C 3 alkylene)NR 9 R 10 , —(C 1 -C 3 alkylene)CF 3 , —(C 1 -C 3 alkylene)NO 2 , —C═NH(OR 8 ), —(C 1 -C 3 alkylene)C(O)R 8 , —(C 1 -C 3 alkylene)OC(O)R 8 , —(C 1 -C 3 alkylene)C(O)OR 8 , —(C 1 -C 3 alkylene)C(O)NR 9 R 10 , —(C 1 -C 3 alkylene)OC(O)NR 9 R 10 , —(C 1 -C 3 alkylene)NR 8 C(O)R 9 , —(C 1 -C 3 alkylene)NR 8 C(O)OR 9 , —(C 1 -C 3 alkylene)NR 8 C(O)NR 9 R 10 , —(C 1 -C 3 alkylene)S(O)R 8 , —(C 1 -C 3 alkylene)S(O) 2 R 8 , —(C 1 -C 3 alkylene)NR 8 S(O)R 9 , —C(O)(C 1 -C 3 alkylene)NR 8 S(O)R 9 , —(C 1 -C 3 alkylene)NR 8 S(O) 2 R 9 , —(C 1 -C 3 alkylene)C(O)NR 8 S(O) 2 R 9 , —(C 1 -C 3 alkylene)S(O)NR 9 R 10 , —(C 1 -C 3 alkylene)S(O) 2 NR 9 R 10 , —(C 1 -C 3 alkylene)P(O)(OR 9 )(OR 10 ), —(C 1 -C 3 alkylene)(C 3 -C 6 cycloalkyl), —(C 1 -C 3 alkylene)(3-12-membered heterocyclyl), —(C 1 -C 3 alkylene)(5-10-membered heteroaryl) or -(C 1 -C 3 alkylene)(C 6 -C 14 aryl), wherein each R a , R b , and R c is independently optionally substituted by halogen, oxo, —OR 11 , —NR 11 R 12 , —C(O)R 11 , —CN, —S(O)R 11 , —S(O) 2 R 11 , —P(O)(OR 11 )(OR 12 ), —(C 1 -C 3 alkylene)OR 11 , —(C 1 -C 3 alkylene)NR 11 R 12 , —(C 1 -C 3 alkylene)C(O)R 11 , —(C 1 -C 3 alkylene)S(O)R 11 , —(C 1 -C 3 alkylene)S(O) 2 R 11 , —(C 1 -C 3 alkylene)P(O)(OR 11 )(OR 12 ), C 3 -C 8 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by oxo, —OH or halogen;

wherein when R 1 is C 1 -C 6 alkyl, R 4 is other than —NR 9 R 10 and R 3 is other than —C(O)R 8 ;

------ is a single bond or a double bond, wherein when ------ is a double bond, R 2 is oxo;

is a single bond or a double bond, wherein when is a double bond, R 4 is oxo;

one of ------ and is a double bond and the other is a single bond;

A is C 6 -C 12 aryl, 5- to 10-membered heteroaryl, 9- to 10-membered carbocycle, or 9- to 10-membered heterocycle, wherein the C 6 -C 12 aryl, 5- to 10-membered heteroaryl or 9- to 10-membered carbocycle, or 9- to 10-membered heterocycle of A is optionally further substituted with R 6 ;

B is phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered carbocycle, 5- to 6-membered heterocycle, or 9- to 10-membered heteroaryl, wherein the phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered carbocycle, 5- to 6-membered heterocycle, or 9- to 10-membered heteroaryl of B is optionally further substituted with R 7 ;

wherein when B is 5- to 6-membered heterocycle, A is other than phenyl optionally further substituted with R 6 or pyridyl optionally further substituted with R 6 ;

each R 6 and R 7 is independently oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, —CN, —OR 8 , —SR 8 , —NR 9 R 10 , —NO 2 , —C═NH(OR 8 ), —C(O)R 8 , —OC(O)R 8 , —C(O)OR 8 , —C(O)NR 9 R 10 , —OC(O)NR 9 R 10 , —NR 8 C(O)R 9 , —NR 8 C(O)OR 9 , —NR 8 C(O)NR 9 R 10 , —S(O)R 8 , —S(O) 2 R 8 , —NR 8 S(O)R 9 , —C(O)NR 8 S(O)R 9 , —NR 8 S(O) 2 R 9 , —C(O)NR 8 S(O) 2 R 9 , —S(O)NR 9 R 10 , —S(O) 2 NR 9 R 10 , —P(O)(OR 9 )(OR 10 ), C 3 -C 6 cycloalkyl, 3-12-membered heterocyclyl, 5- to 10-membered heteroaryl, C 6 -C 14 aryl, —(C 1 -C 3 alkylene)CN, —(C 1 -C 3 alkylene)OR 8 , —(C 1 -C 3 alkylene)SR 8 , —(C 1 -C 3 alkylene)NR 9 R 10 , —(C 1 -C 3 alkylene)CF 3 , —(C 1 -C 3 alkylene)NO 2 , —C═NH(OR 8 ), —(C 1 -C 3 alkylene)C(O)R 8 , —(C 1 -C 3 alkylene)OC(O)R 8 , —(C 1 -C 3 alkylene)C(O)OR 8 , —(C 1 -C 3 alkylene)C(O)NR 9 R 10 , —(C 1 -C 3 alkylene)OC(O)NR 9 R 10 , —(C 1 -C 3 alkylene)NR 8 C(O)R 9 , —(C 1 -C 3 alkylene)NR 8 C(O)OR 9 , —(C 1 -C 3 alkylene)NR 8 C(O)NR 9 R 10 , —(C 1 -C 3 alkylene)S(O)R 8 , —(C 1 -C 3 alkylene)S(O) 2 R 8 , —(C 1 -C 3 alkylene)NR 8 S(O)R 9 , —C(O)(C 1 -C 3 alkylene)NR 8 S(O)R 9 , —(C 1 -C 3 alkylene)NR 8 S(O) 2 R 9 , —(C 1 -C 3 alkylene)C(O)NR 8 S(O) 2 R 9 , —(C 1 -C 3 alkylene)S(O)NR 9 R 10 , —(C 1 -C 3 alkylene)S(O) 2 NR 9 R 10 , —(C 1 -C 3 alkylene)P(O)(OR 9 )(OR 10 ), —(C 1 -C 3 alkylene)(C 3 -C 6 cycloalkyl), —(C 1 -C 3 alkylene)(3-12-membered heterocyclyl), —(C 1 -C 3 alkylene)(5-10-membered heteroaryl) or -(C 1 -C 3 alkylene)(C 6 -C 14 aryl), wherein each R 6 and R 7 is independently optionally substituted by halogen, oxo, —OR 11 , —NR 11 R 12 , —C(O)R 11 , —CN, —S(O)R 11 , —S(O) 2 R 11 , —P(O)(OR 11 )(OR 12 ), —(C 1 -C 3 alkylene)OR 11 , —(C 1 -C 3 alkylene)NR 11 R 12 , —(C 1 -C 3 alkylene)C(O)R 11 , —(C 1 -C 3 alkylene)S(O)R 11 , —(C 1 -C 3 alkylene)S(O) 2 R 11 , —(C 1 -C 3 alkylene)P(O)(OR 11 )(OR 12 ), C 3 -C 8 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by oxo, —OH or halogen;

R 8 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -C 14 aryl, 5-6-membered heteroaryl, 3-6-membered heterocyclyl, —(C 1 -C 3 alkylene)(C 3 -C 6 cycloalkyl), —(C 1 -C 3 alkylene)(C 6 -C 14 aryl), —(C 1 -C 3 alkylene)(5-6-membered heteroaryl), or -(C 1 -C 3 alkylene)(3-6-membered heterocyclyl), wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -C 14 aryl, 5-6-membered heteroaryl, 3-6-membered heterocyclyl, —(C 1 -C 3 alkylene)(C 3 -C 6 cycloalkyl), —(C 1 -C 3 alkylene)(C 6 -C 14 aryl), —(C 1 -C 3 alkylene)(5-6-membered heteroaryl), and -(C 1 -C 3 alkylene)(3-6-membered heterocyclyl) are independently optionally substituted by halogen, oxo, —CN, —OR 13 , —NR 13 R 14 , —P(O)(OR 13 )(OR 14 ), phenyl optionally substituted by halogen, or C 1 -C 6 alkyl optionally substituted by halogen, —OH or oxo;

R 9 and R 10 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -C 14 aryl, 5-6-membered heteroaryl, 3-6 membered heterocyclyl, —(C 1 -C 3 alkylene)NR 11 R 12 , C 3 alkylene)(C 3 -C 6 cycloalkyl), —(C 1 -C 3 alkylene)(3-6-membered heterocyclyl), —(C 1 -C 3 alkylene)(5-6-membered heteroaryl) or -(C 1 -C 3 alkylene)(C 6 aryl), wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -C 14 aryl, 5-6-membered heteroaryl, 3-6 membered heterocyclyl, —(C 1 -C 3 alkylene)(C 3 -C 6 cycloalkyl), —(C 1 -C 3 alkylene)(3-6-membered heterocyclyl), —(C 1 -C 3 alkylene)(5-6-membered heteroaryl) and —(C 1 -C 3 alkylene)(C 6 aryl) are independently optionally substituted by halogen, oxo, —CN, —OR 13 , —NR 13 R 14 or C 1 -C 6 alkyl optionally substituted by halogen, —OH or oxo;

or R 9 and R 10 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo, —OR 13 , —NR 3 R 14 or C 1 -C 6 alkyl optionally substituted by halogen, oxo or —OH;

R 11 and R 12 are each independently hydrogen, C 1 -C 6 alkyl optionally substituted by halogen or oxo, C 2 -C 6 alkenyl optionally substituted by halogen or oxo, or C 2 -C 6 alkynyl optionally substituted by halogen or oxo;

or R 11 and R 12 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or C 1 -C 6 alkyl optionally substituted by halogen or oxo; and

R 13 and R 14 are each independently hydrogen, C 1 -C 6 alkyl optionally substituted by halogen or oxo, C 2 -C 6 alkenyl optionally substituted by halogen or oxo, or C 2 -C 6 alkynyl optionally substituted by halogen or oxo;

or R 13 and R 14 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or C 1 -C 6 alkyl optionally substituted by oxo or halogen.

2. The compound of claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

R 1 is H or C 1 -C 6 alkyl wherein the C 1 -C 6 alkyl of R 1 is optionally substituted with oxo or R a ;

R 2 is H, R b or oxo;

R 3 and R 5 are each independently H or R c ;

wherein when R 1 is C 1 -C 6 alkyl, R 4 is other than —NR 9 R 10 and R 3 is other than —OC(O)R 8 ;

------ is a single bond or a double bond, wherein when ------- is a double bond, R 2 is oxo;

is a single bond or a double bond, wherein when is a double bond, R 4 is oxo;

one of ------ and is a double bond and the other is a single bond;

wherein when B is 5- to 6-membered heterocycle, A is other than phenyl optionally further substituted with R 6 or pyridyl optionally further substituted with R 6 ;

R 8 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -C 14 aryl, 5-6-membered heteroaryl or 3-6-membered heterocyclyl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -C 14 aryl, 5-6-membered heteroaryl and 3-6-membered heterocyclyl are independently optionally substituted by halogen, oxo, —CN, —OR 13 , —NR 13 R 14 , —P(O)(OR 13 )(OR 14 ), phenyl optionally substituted by halogen, or C 1 -C 6 alkyl optionally substituted by halogen, —OH or oxo;

R 9 and R 10 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -C 14 aryl, 5-6-membered heteroaryl or 3-6 membered heterocyclyl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -C 14 aryl, 5-6-membered heteroaryl and 3-6 membered heterocyclyl are independently optionally substituted by halogen, oxo, —CN, —OR 13 , —NR 13 R 14 or C 1 -C 6 alkyl optionally substituted by halogen, —OH or oxo;

3. The compound of claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is H or methyl.

4. The compound of claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 5 is H, C 1 -C 6 alkyl, halogen, —CN, or —OR 8 .

5. The compound of claim 1 , wherein the compound is of the Formula (II):

or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein A, B, R 1 , R 3 , R 4 , and R 5 are as defined for Formula (I).

6. The compound of claim 5 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein at least one of R 3 , R 4 , and R 5 is not H.

7. The compound of claim 5 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein at least one of R 3 , R 4 , and R 5 is C 1 -C 6 alkyl, halogen, C 6 -C 14 aryl, —CN, or —OR 8 .

8. The compound of claim 5 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 , R 3 , R 4 , and R 5 are each H.

9. The compound of claim 1 , wherein the compound is of the Formula (III):

or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein A, B, R 1 , R 2 , R 3 , and R 5 are as defined for Formula (I).

10. The compound of claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein at least one of R 2 , R 3 , and R 5 is not H.

11. The compound of claim 9 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein at least one of R 2 , R 3 , and R 5 is C 1 -C 6 alkyl, halogen, C 6 -C 14 aryl, —CN, or —OR 8 .

12. The compound of claim 9 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 , R 2 , R 3 , and R 5 are each H.

13. The compound of claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is H.

14. The compound of claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein A is C 6 -C 12 aryl optionally further substituted with R 6 .

15. The compound of claim 14 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein A is phenyl or naphthyl, optionally substituted with R 6 .

16. The compound of claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein A is 5- to 10-membered heteroaryl optionally further substituted with R 6 .

17. The compound of claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein A is

wherein R 6a , R 6b , R 6c , R 6d , R 6e , and R 6f are each independently H, C 1 -C 6 alkyl, halogen, —CN, or —OC 1 -C 6 alkyl.

18. The compound of claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein A is

wherein R 6b , R 6c , R 6d , R 6e , R 6f , and R 6g are each independently H, C 1 -C 6 alkyl, halogen, —CN, or —OC 1 -C 6 alkyl.

19. The compound of claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein A is

wherein X 1 is selected from the group consisting of N, C, and CH; X 2 is selected from the group consisting of NH, O, and S; and R 6a , R 6b , and R 6c are each independently H, C 1 -C 6 alkyl, halogen, —CN, or —OC 1 -C 6 alkyl.

20. The compound of claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein A is

wherein X 1 is selected from the group consisting of N, C, and CH; X 2 is selected from the group consisting of NH, O, and S; and R 6g , R 6b , and R 6c are each independently H, C 1 -C 6 alkyl, halogen, —CN, or —OC 1 -C 6 alkyl.

21. The compound of claim 16 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein A is selected from the group consisting of pyridyl, quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, quinazolinyl, naphthyridinyl, benzoxazolyl, benzothiazolyl, benzoimidazoyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, oxadiazolyl, thiophenyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzofuranyl, benzoisoxazolyl, benzoxadiazolyl, benzothiophenyl, benzoisothiazolyl, benzothiadiazolyl, pyrrolopyridinyl, pyrazolopyridinyl, imidazopyridinyl, triazolopyridinyl, furopyridinyl, oxazolopyridinyl, isoxazolopyridinyl, oxadiazolopyridinyl, thienopyridinyl, thiazolopyridinyl, isothiazolopyridinyl, thiadiazolopyridinyl, thienopyridinyl, phthalazinyl, pyrazolothiazolyl, pyrazolothiazolyl and imidazothiazolyl, each optionally substituted with R 6 .

22. The compound of claim 16 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein A is selected from the group consisting of:

each optionally substituted with R 6 .

23. The compound of claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein A is a 9- to 10-membered carbocycle optionally further substituted with R 6 .

24. The compound of claim 23 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein A is selected from the group consisting of decahydronaphthalenyl, octahydroindenyl, 1,2,3,4-tetrahydronaphthalenyl, and 2,3-dihydroindenyl, each optionally substituted with R 6 .

25. The compound of claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein A is a 9- to 10-membered heterocycle optionally further substituted with R 6 .

26. The compound of claim 24 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein A is selected from the group consisting of tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, indolinyl, isoindolinyl, tetrahydronaphthyridinyl and hexahydrobenzoimidazolyl, each optionally further substituted with R 6 .

27. The compound of claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein A is selected from the group consisting of

each optionally substituted with R 6 .

28. The compound of claim 14 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein each R 6 is independently selected from the group consisting of halogen, —CN, —OR 8 , —SR 8 , —NR 9 R 10 , —NO 2 , —C(O)R 8 , —C(O)OR 8 , —C(O)NR 9 R 10 , —C(O)NR 8 S(O) 2 R 9 , —OC(O)R 8 , —OC(O)NR 9 R 10 , —NR 8 C(O)R 9 , —NR 8 C(O)NR 9 R 10 , —S(O)R 8 , —S(O) 2 R 8 , C 3 -C 6 cycloalkyl and C 1 -C 6 alkyl optionally substituted by halogen.

29. The compound of claim 28 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein each R 6 is independently selected from the group consisting of C 1 -C 6 alkyl, halogen, —CN, and —OR 8 .

30. The compound of claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein A is selected from the group consisting of:

31. The compound of claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein B is phenyl, optionally further substituted with R 7 .

32. The compound of claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein B is 5- to 6-membered heteroaryl optionally further substituted with R 7 .

33. The compound of claim 32 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein B is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, oxadiazolyl, thiophenyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, or tetrazinyl, each optionally substituted with R 7 .

34. The compound of claim 32 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein B is furanyl, pyridinyl, oxazoyl, or oxadiazoyl, each optionally substituted with R 7 .

35. The compound of claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein B is a 5- to 6-membered fully saturated carbocycle optionally further substituted with R 7 .

36. The compound of claim 35 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein B is cyclopentyl or cyclohexyl, optionally further substituted with R 7 .

37. The compound of claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein B is a 5- to 6-membered fully saturated heterocycle optionally further substituted with R 7 .

38. The compound of claim 37 , or a tautomer thereof or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein B is pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydrothiophenyl, oxathiolanyl, sulfolanyl, piperidinyl, piperazinyl, tetrahydropyranyl, dioxanyl, thianyl, dithianyl, trithianyl, morpholinyl, thiomorpholinyl optionally further substituted with R 7 .

39. The compound of claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein B is a 9- to 10-membered heteroaryl optionally further substituted with R 7 .

40. The compound of claim 39 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein B is selected from the group consisting of pyridyl, quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, quinazolinyl, naphthyridinyl, benzoxazolyl, benzothiazolyl, benzoimidazoyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, oxadiazolyl, thiophenyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzofuranyl, benzoisoxazolyl, benzoxadiazolyl, benzothiophenyl, benzoisothiazolyl, benzothiadiazolyl, pyrrolopyridinyl, pyrazolopyridinyl, imidazopyridinyl, triazolopyridinyl, furopyridinyl, oxazolopyridinyl, isoxazolopyridinyl, oxadiazolopyridinyl, thienopyridinyl, thiazolopyridinyl, isothiazolopyridinyl, thiadiazolopyridinyl, thienopyridinyl, phthalazinyl, pyrazolothiazolyl, pyrazolothiazolyl and imidazothiazolyl, each optionally substituted with R 7 .

41. The compound of claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein each R 7 is independently selected from the group consisting of halogen, —CN, —OR 8 , —SR 8 , —NR 9 R 10 , —NO 2 , —C(O)R 8 , —C(O)OR 8 , —C(O)NR 9 R 10 , —C(O)NR 8 S(O) 2 R 9 , —OC(O)R 8 , —OC(O)NR 9 R 10 , —NR 8 C(O)R 9 , —NR 8 C(O)NR 9 R 10 , —S(O)R 8 , —S(O) 2 R 8 , C 3 -C 6 cycloalkyl and C 1 -C 6 alkyl optionally substituted by halogen.

42. The compound of claim 41 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 7 is halogen.

43. The compound of claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein B is selected from the group consisting of:

44. A compound selected from the group consisting of

or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

45. The compound of claim 44 , wherein the compound is selected from in the group consisting of

or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

46. The compound of claim 44 , or a pharmaceutically acceptable salt thereof.

47. A pharmaceutical composition comprising a compound of claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable carrier.

48. A method of treating cancer in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

49. A method of inhibiting adenosine receptors of subtypes A 2a , A 2b or A 3 in a cell, comprising administering a compound of claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, to the cells.

50. The method of claim 49 , wherein the adenosine receptors are of subtype A 2a .

51. A kit comprising a compound of claim 1 , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

52. The compound of claim 44 , wherein the compound is selected from the group consisting of: