Granted Patent B2

US 11,254,670 · App. 16/746,769 · Granted Feb 22, 2022

Inventors: Son Minh Pham (San Francisco, CA); Jayakanth Kankanala (St. Paul, MN); Pradeep S. Jadhavar (Uttar Pradesh, IN); Baban Mohan Mulik (Uttar Pradesh, IN); Farha Khan (Uttar Pradesh, IN); Sreekanth A. Ramachandran (Uttar Pradesh, IN)

Assignee: NUVATION BIO INC.

C07D471/04A61P35/04C07D519/00

Abstract

Claims (63)

1. A compound of the Formula (I):

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

R 2 and R 4 are each independently H, R b or oxo;

R 3 is independently H or R c ;

each 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 b and R c is independently optionally substituted by halogen, oxo, —CN, —OR 11 , —NR 11 R 12 , —C(O)R 11 , —OC(O)R 11 , —C(O)OR 11 , —C(O)NR 11 R 12 , —OC(O)NR 11 R 12 , —NR 11 C(O)R 12 , —NR 11 C(O)OR 12 , —S(O)R 11 , —S(O) 2 R 11 , —NR 11 S(O)R 12 , —C(O)NR 11 S(O)R 12 , —NR 11 S(O) 2 R 12 , —C(O)NR 11 S(O) 2 R 12 , —S(O)NR 11 R 12 , —S(O) 2 NR 11 R 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)C(O)NR 11 R 12 , —(C 1 -C 3 alkylene)NR 11 C(O)R 12 , —(C 1 -C 3 alkylene)NR 11 S(O) 2 R 12 , —(C 1 -C 3 alkylene)S(O) 2 NR 11 R 12 , 3-6-membered heterocyclyl optionally substituted by oxo, —OH, NH 2 or halogen, C 3 -C 8 cycloalkyl optionally substituted by oxo, —OH, NH 2 or halogen, —(C 1 -C 3 alkylene)3-6-membered heterocyclyl optionally substituted by oxo, —OH, NH 2 or halogen, —(C 1 -C 3 alkylene)C 3 -C 8 cycloalkyl optionally substituted by oxo, —OH, NH 2 or halogen, or C 1 -C 6 alkyl optionally substituted by oxo, —OH, NH 2 or halogen;

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

wherein

is a single bond or a double bond;

X 1 is N or CR′, wherein R′ is —NR 8 S(O) 2 R 9 or oxo;

X 2 is N, NR′ or CR′, wherein R″ is R 7 ,

or R′ and R″ are taken together with the atoms to which they attach to form a 5- or 6-membered heteroaryl ring containing one, two, three, or four N atoms;

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

provided that when A is optionally substituted quinolinyl, optionally substituted isoquinolinyl, optionally substituted quinoxalinyl, optionally substituted cinnolinyl, optionally substituted quinazolinyl, or optionally substituted benzimidazolyl, then B is substituted with 1, 2, 3, or 4 R 7 and at least one R 7 is —CN, and

when X 1 is N and X 2 is CR″, then B is substituted with 1, 2, 3, or 4 R 7 and at least one R 7 is —CN;

R 6 is H or R 7 ;

each 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 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;

each 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) of R 8 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 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) 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) of R 9 and R 10 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 stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is H, 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 , —C(O)NR 9 R 10 , —NR 8 C(O)R 9 , —C(O)OR 8 , —(C 1 -C 3 alkylene)NR 9 R 10 , —NR 8 C(O)NR 9 R 10 , —S(O)R 8 , —S(O) 2 R 8 , —NR 8 S(O)R 9 , —NR 8 S(O) 2 R 9 , —S(O)NR 9 R 10 , —S(O) 2 NR 9 R 10 , C 3 -C 6 cycloalkyl, 3-12-membered heterocyclyl, 5- to 10-membered heteroaryl or C 6 -C 14 aryl.

3. 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 H, oxo, halogen, —OR 8 , —C(O)NR 9 R 10 , —C(O)OR 8 , or —(C 1 -C 3 alkylene)NR 9 R 10 .

4. 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 selected from the group consisting of: H, oxo, bromo, methoxy,

5. 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 H.

6. The compound of claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound of formula (II):

7. 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 H, 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 , —C(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 , —NR 8 S(O)R 9 , —NR 8 S(O) 2 R 9 , —S(O)NR 9 R 10 , —S(O) 2 NR 9 R 10 , C 3 -C 6 cycloalkyl, 3-12-membered heterocyclyl, 5- to 10-membered heteroaryl or C 6 -C 14 aryl .

8. 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 H.

9. The compound of claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of formula (III):

10. The compound of claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 is H, 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 , —C(O)NR 9 R 10 , —(C 1 -C 3 alkylene)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 , —NR 8 S(O)R 9 , —NR 8 S(O) 2 R 9 , —S(O)NR 9 R 10 , —S(O) 2 NR 9 R 10 , C 3 -C 6 cycloalkyl, 3-12-membered heterocyclyl, 5- to 10-membered heteroaryl or C 6 -C 14 aryl.

11. The compound of claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 is H, —CN, —C(O)NR 9 R 10 , or —(C 1 -C 3 alkylene)NR 9 R 10 .

12. The compound of claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 is selected from the group consisting of: H, —CN,

13. The compound of claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 is CR′.

14. The compound of claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 is N.

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

16. The compound of claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 2 is NR″.

17. The compound of claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 2 is CR″.

18. The compound of claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 is CR′ and X 2 is CR″, and R′ and R″ are taken together with the atoms to which they attach to form a 5- or 6-membered heteroaryl ring containing one, two, three, or four N atoms.

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

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

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 5- to 6-membered heteroaryl optionally further substituted with R 7 .

22. The compound of claim 1 , or a tautomer or stereoisomer 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 .

23. The compound of claim 1 , or a tautomer or stereoisomer 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 .

24. 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 9- to 10-membered heteroaryl optionally further substituted with R 7 .

25. 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 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 .

26. 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

each of which is optionally substituted with R 7 .

27. The compound of claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 7 is independently halogen, —CN, or C 1 -C 6 alkyl optionally substituted by halogen.

28. 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:

29. 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.

30. 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 stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, to the cells.

31. The method of claim 30 , wherein the adenosine receptors are of subtype A 2a .

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

33. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

34. The compound of claim 33 , or a pharmaceutically acceptable salt thereof, wherein the compound is

35. The compound of claim 33 , or a pharmaceutically acceptable salt thereof, wherein the compound is

36. The compound of claim 33 , or a pharmaceutically acceptable salt thereof, wherein the compound is

37. The compound of claim 33 , or a pharmaceutically acceptable salt thereof, wherein the compound is

Assignments (9)

Continuity (2)