Patent Application

App. No. 17/684,626

Abstract

Claims (48)

1 . A compound of the formula (I):

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

A is selected from the group consisting of:

B is a phenyl optionally substituted by R 3 , C 3 -C 6 cycloalkyl optionally substituted by R 4 , 3- to 6-membered heterocyclyl optionally substituted by R 4 or a 5- to 10-membered heteroaryl optionally substituted by R 4 ;

R 1 is a hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, —(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), —(C 1 -C 3 alkylene)(C 6 aryl), —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —NR 1b R 1c , —S(O) 2 R 1a , —(C 1 -C 3 alkylene)C(O)NR 1b R 1c , —(C 1 -C 3 alkylene)C(O)R 1a or —(C 1 -C 3 alkylene)NR 1b R 1c , wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, —(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) of R 1 are independently optionally substituted by R 4 ;

each R 1a is independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 3-6-membered heterocyclyl, C 6 aryl, 5-6-membered heteroaryl, —(C 1 -C 3 alkylene)(C 3 -C 6 cycloalkyl), —(C 1 -C 3 alkylene)(3-6-membered heterocyclyl), —(C 1 -C 3 alkylene)(C 6 aryl) or —(C 1 -C 3 alkylene)(5-6-membered heteroaryl), wherein each of which is optionally substituted by methyl, ethyl, halogen, oxo, —CF 3 , —OH, —OCH 3 , —CN, —C(O)OCH 3 , —C(O)OC 2 H 5 , —NH 2 or —NHCH 3 ;

each R 1b and R 1c is independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 3-6-membered heterocyclyl, C 6 aryl, 5-6-membered heteroaryl, —(C 1 -C 3 alkylene)(C 3 -C 6 cycloalkyl), —(C 1 -C 3 alkylene)(3-6-membered heterocyclyl), —(C 1 -C 3 alkylene)(C 6 aryl) or —(C 1 -C 3 alkylene)(5-6-membered heteroaryl), wherein each of which is optionally substituted by methyl, ethyl, halogen, oxo, —CF 3 , —OH, —OCH 3 , —CN, —C(O)OCH 3 , —C(O)OC 2 H 5 , —NH 2 or —NHCH 3 ;

or R 1b and R 1c are taken together with the nitrogen atom to which they are attached to form a 3- to 6-membered heterocyclyl;

R 2 is —OR 2a , —NHR 2b , —C(O)NHR 2b , or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl of R 2 is substituted by —OR 2c , —NHR 2c , or —C(O)NHR 2c ;

each R 2a and R 2b is independently cyclohexane, 6-membered heterocyclyl, —(C 1 -C 3 alkylene)N(C 2 H 5 ) 2 , —(C 1 -C 3 alkylene)(C 3 -C 6 cycloalkyl), —(C 1 -C 3 alkylene)(3-6-membered heterocyclyl), or —(C 1 -C 3 alkylene)(5-6-membered heteroaryl), wherein each of which is optionally substituted by methyl, ethyl, halogen, oxo, —CF 3 , —OH, —OCH 3 , —CN, —C(O)OCH 3 , —C(O)OC 2 H 5 , —NH 2 or —NHCH 3 ;

R 2c is 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is further substituted by C 1 -C 6 alkyl optionally substituted by halogen, —OH or oxo;

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

each R 4 is independently oxo or R 3 ;

R 5 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl or 3- to 6-membered heterocyclyl, wherein each of which is optionally substituted by halogen, oxo, —CN, —OR 8 , —NR 8 R 9 , —C(O)R 8 , —C(O)OR 8 , —C(O)NR 8 R 9 , —NR 8 C(O)R 9 , —S(O)R 8 , —S(O) 2 R 8 , —S(O) 2 NR 8 R 9 , —NR 8 S(O) 2 R 9 , or C 1 -C 6 alkyl optionally substituted by oxo, —OH or halogen;

R 6 and R 7 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl or 3- to 6-membered heterocyclyl, wherein each of which is optionally substituted by halogen, oxo, —CN, —OR 8 , —NR 8 R 9 , —C(O)R 8 , —C(O)OR 8 , —C(O)NR 8 R 9 , —NR 8 C(O)R 9 , —S(O)R 8 , —S(O) 2 R 8 , —S(O) 2 NR 8 R 9 , —NR 8 S(O) 2 R 9 , or C 1 -C 6 alkyl optionally substituted by oxo, —OH or halogen;

or R 6 and R 7 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo, —CN, —OR 8 , —NR 8 R 9 , —C(O)R 8 , —C(O)OR 8 , —C(O)NR 8 R 9 , —NR 8 C(O)R 9 , —S(O)R 8 , —S(O) 2 R 8 , —S(O) 2 NR 8 R 9 , —NR 8 S(O) 2 R 9 or C 1 -C 6 alkyl optionally substituted by oxo, —OH or halogen;

R 8 and R 9 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl or 3- to 6-membered heterocyclyl, wherein each of which is optionally substituted by halogen, OH, oxo or NH 2 ;

or R 8 and R 9 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, OH, oxo or NH 2 .

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

B is a phenyl optionally substituted by R 3 , or a 5- or 6-membered heteroaryl optionally substituted by R 4 ;

R 1 is a hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , or —NR 1b R 1c , wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl and 3- to 6-membered heterocyclyl of R 1 are independently optionally substituted by R 4 ;

each R 1a is independently hydrogen, C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl;

each R 1b and R 1c is independently hydrogen, C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl;

or R 1b and R 1c are taken together with the nitrogen atom to which they are attached to form a 3- to 6-membered heterocyclyl.

3 . (canceled)

4 . The compound of claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is hydrogen.

5 . (canceled)

6 . The compound of claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is —OR 2a .

7 . The compound of claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is —NHR 2b .

8 . The compound of claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is —C(O)NHR 2b .

9 . The compound of claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is C 1 -C 6 alkyl substituted by —OR 2c , —NHR 2c , or —C(O)NHR 2c .

10 - 12 . (canceled)

13 . The compound of claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 4 is R 3 and each R 3 is independently selected from the group consisting of halogen, —CN, —OR 5 , —SR 5 , —NR 6 R 7 , —NO 2 , —C(O)R 5 , —C(O)OR 5 , —C(O)NR 6 R 7 , —C(O)NR 5 S(O) 2 R 6 , —OC(O)R 5 , —OC(O)NR 6 R 7 , —NR 5 C(O)R 6 , —NR 5 C(O)NR 6 R 7 , —S(O)R 5 , —S(O) 2 R 5 , C 3 -C 6 cycloalkyl and C 1 -C 6 alkyl optionally substituted by halogen.

14 . The compound of claim 13 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein each R 3 is independently selected from the group consisting of halogen, —OR 5 and C 1 -C 6 alkyl optionally substituted by halogen.

15 . (canceled)

16 . The compound of claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein B is a phenyl optionally substituted by R 3 .

17 . The compound of claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein B is a 5- to 6-membered heteroaryl optionally substituted by R 4 .

18 . The compound of claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein B is a 6-membered heteroaryl selected from the group consisting of pyridyl and pyrimidinyl, which is optionally substituted by R 4 .

19 - 20 . (canceled)

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

22 - 29 . (canceled)

30 . A compound of Table 1, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

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

32 . A method of treating a disease mediated by an adenosine signaling pathway 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 stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

33 . 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 stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

34 . A method of inhibiting an adenosine receptor of subtype A 2A , A 2B or A 3 in a cell, comprising administering a compound of claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, to the cell.

35 . The method of claim 34 , wherein the adenosine receptor is of subtype A 2A .

36 - 37 . (canceled)

Assignments (9)