IP Library › Granted Patent US 11,718,622

Granted Patent B2

US 11,718,622 · App. 17/201,380 · Granted Aug 8, 2023

Heterocyclic adenosine receptor antagonists

Inventors: Sunghoon Ma (Foster City, CA); Yong Wang (South San Francisco, CA); Wei Xu (Danville, CA)

Assignee: Exelixis Inc.

C07D487/04 C07D487/14 C07D513/14

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Quick Facts

Patent No.: US 11,718,622
App. No.: 17/201,380
Granted: Aug 8, 2023
Kind: B2

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Abstract

Heterocyclic compounds useful as antagonists of adenosine receptors, and methods of treatment of diseases using antagonists of adenosine receptors are disclosed herein. Also disclosed herein are pharmaceutical compositions and methods of administration of heterocyclic antagonists of adenosine receptors and processes for producing heterocyclic antagonists of adenosine receptors.

Claims (412)

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is furanyl;

R 1 is H or alkyl optionally substituted with 1, 2, 3, or 4 independently selected R a substituents;

R 2 is H, alkyl, —COR′″, —CONR′R″, —COOR′, —SO 2 R′, —SO 2 NR′R″, or —SO 2 OR′, wherein the alkyl of R 2 is optionally substituted with 1, 2, 3, or 4 independently selected R a substituents;

R 3 is H, alkyl, halo, —CN, or —CONR′R″, wherein the alkyl of R 3 is optionally substituted with 1, 2, 3, or 4 independently selected R a substituents;

or R 2 and R 3 together form 5-6 membered heterocycloalkyl or 5-6 membered heteroaryl, each of which is optionally substituted with 1, 2, 3, 4, or 5 independently selected R 7 substituents, and wherein when R 2 and R 3 together form 6-membered heteroaryl, then R 1 is absent;

R 4 is H, alkyl, halo, haloalkyl, —NR′R″, —COR′, —CONR′R″, —COOR′, SO 2 R′, —SO 2 NR′R″, —SO 2 OR′, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or —C 1-4 alkylene-R b , wherein R b is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or —C 1-4 alkylene-R b of R 4 is optionally substituted with 1, 2, 3, or 4 independently selected R a substituents;

each R 5 is independently H, alkyl, halo, haloalkyl, alkoxy, —CN, —COR′, —CONR′R″, —COOR′, —SO 2 R′, —SO 2 NR′R″, —SO 2 OR′, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl wherein the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl of R 5 is optionally substituted with 1, 2, 3, or 4 independently selected R a substituents;

n is 0, 1, 2, 3, 4, or 5;

one of Q 1 and Q 2 is N and the other is C;

Z is N or CR 6 ;

R 6 is H or alkyl, wherein the alkyl of R 6 is optionally substituted with 1, 2, 3, or 4 independently selected R a substituents;

each R 7 is independently oxo, alkyl, halo, haloalkyl, hydroxy, alkoxy, hydroxyalkyl, cycloalkyl, or heterocycloalkyl, wherein each cycloalkyl and heterocycloalkyl of R 7 is optionally and independently further substituted with 1, 2, or 3 of C 1-4 alkyl, halo, C 1-4 haloalkyl, hydroxy, or C 1-4 alkoxy;

R′ and R″ are each independently H or alkyl, wherein each alkyl of R′ and R″ is optionally substituted with 1, 2, 3, or 4 independently selected R a substituents;

R′″ is alkyl, haloalkyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, cycloalkyl or heterocycloalkyl of R′″ is optionally substituted with 1, 2, 3, or 4 independently selected R a substituents; and

each R a is independently alkyl, halo, haloalkyl, hydroxy, alkoxy, hydroxyalkyl, cycloalkyl, or heterocycloalkyl, wherein each cycloalkyl and heterocycloalkyl of R a is optionally and independently further substituted with 1, 2, or 3 of C 1-4 alkyl, halo, C 1-4 haloalkyl, hydroxy, or C 1-4 alkoxy.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is H or C 1-4 alkyl.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is H, C 1-4 alkyl, —C(O)—C 1-4 alkyl, —C(O)—C 1-4 haloalkyl —C(O)-cycloalkyl, —C(O)-heterocycloalkyl, —CONH 2 , —CONH—C 1-4 alkyl, —COO—C 1-4 alkyl, —SO 2 —C 1-6 alkyl or —CONH—C 1-4 alkylene-heterocycloalkyl, and wherein R 2 is optionally substituted with 1 or 2 independently selected R a substituents.

4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein R 2 is H or methyl.

5. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein R 2 is acetyl or —C(O)-cyclopropyl.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is H, C 1-4 alkyl, halo, —CN, or —CONH 2 .

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 together form 5-6 membered heterocycloalkyl or 5-6 membered heteroaryl, wherein the heterocycloalkyl or heteroaryl of R 2 and R 3 is optionally substituted with 1, 2, 3, or 4 independently selected R 7 substituents, wherein each R 7 is independently oxo, C 1-4 alkyl, C 1-4 hydroxyalkyl, or C 1-4 haloalkyl.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is H, C 1-4 alkyl, C 1-4 hydroxymethyl, halo, C 1-4 haloalkyl, —NH 2 , —COOH, or —COO—C 1-4 alkyl.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is benzyl, heterocycloalkyl, heteroaryl, or cycloalkyl, wherein the benzyl, heterocycloalkyl, heteroaryl, or cycloalkyl are optionally substituted with 1, 2 or 3 substituents independently selected from C 1-4 alkyl, halo, C 1-4 haloalkyl, hydroxy, and C 1-4 alkoxy.

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2 and wherein each R 5 is independently H, C 1-4 alkyl, halo, C 1-4 haloalkyl, C 1-4 alkoxy, —CN, acetyl, SO 2 NH 2 , SO 2 N(CH 3 ) 2 , SO 2 OH, or SO 2 CH 3 .

11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Q 1 is N, and Z is N or CR 6 ; or Q 2 is N, and Z is N.

12. The compound of claim 1 , having formula II:

or a pharmaceutically acceptable salt thereof, wherein:

Ring B is 5-6 membered heteroaryl or 5-6 membered heterocycloalkyl;

each R 7 is oxo, C 1-4 alkyl, halo, C 1-4 haloalkyl, hydroxy, C 1-4 alkoxy, or C 1-4 hydroxyalkyl and

m is 0, 1, or 2.

13. The compound of claim 1 , having formula III:

or a pharmaceutically acceptable salt thereof, wherein

R 7a and R 7b are each independently H, oxo, C 1-4 alkyl, halo, C 1-4 haloalkyl, hydroxy, C 1-4 alkoxy, or C 1-4 hydroxyalkyl;

R 4 is C 1-4 alkyl or C 1-4 haloalkyl; and

represents a single or double bond.

14. The compound of claim 1 , having formula IV:

or a pharmaceutically acceptable salt thereof, wherein R 5 is H, C 1-4 alkyl, halo, C 1-4 haloalkyl, or cycloalkyl.

15. The compound of claim 1 , having formula IA, IB, or IC:

or a pharmaceutically acceptable salt thereof.

16. The compound of claim 15 or a pharmaceutically acceptable salt thereof, having formula IA, wherein

R 2 is H, methyl, acetyl or —C(O)-cyclopropyl; and

R 4 is C 1-4 alkyl, haloalkyl, cycloalkyl or heterocycloalkyl.

17. The compound of claim 15 or a pharmaceutically acceptable salt thereof, having formula IB, wherein

R 2 is H, acetyl or —C(O)-cyclopropyl; and

R 4 is C 1-4 alkyl, haloalkyl, halo or amino.

18. The compound of claim 15 or a pharmaceutically acceptable salt thereof, having formula IC, wherein

R 2 is H or —C(O)-cyclopropyl; and

one of R 4 and R 6 is H and the other is C 1-4 alkyl.

19. The compound of claim 1 , having formula IIA, IIB, or IIC:

or a pharmaceutically acceptable salt thereof.

20. The compound of claim 1 , having formula IIIA, IIIB, or IIIC:

or a pharmaceutically acceptable salt thereof.

21. The compound of claim 14 , having formula IVA, IVB, or IVC:

or a pharmaceutically acceptable salt thereof.

22. A compound selected from the group consisting of:

2-Methyl-5-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-amine,

N-[2-methyl-5-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclopropanecarboxamide,

2-[(4-methoxyphenyl)methyl]-5-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-

amine,

N-[2-[(4-methoxyphenyl)methyl]-5-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclopropanecarboxamide,

N-[2-methyl-5-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]propanamide,

2,2-dimethyl-N-[2-methyl-5-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]propanamide,

2-ethyl-5-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-amine,

N-[2-ethyl-5-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclopropanecarboxamide,

(2S)-N-[2-methyl-5-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]pyrrolidine-2-

carboxamide,

N-[2-methyl-5-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclobutanecarboxamide,

8-chloro-2-methyl-5-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-amine,

N-[5-(5-methylfuran-2-yl)-2-propan-2-yl-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclopropanecarboxamide,

5-(5-methylfuran-2-yl)-2-propan-2-yl-[1,2,4]triazolo[1,5-c]pyrimidin-7-amine,

N-[2-methyl-5-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]azetidine-3-

carboxamide,

N-[8-chloro-2-methyl-5-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclopropanecarboxamide,

8-bromo-2-methyl-5-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-amine,

(2R)-N-[2-methyl-5-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]pyrrolidine-2-

carboxamide,

1-methyl-N-[2-methyl-5-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]azetidine-

3-carboxamide,

N-[2,8-dimethyl-5-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclopropanecarboxamide,

N-[5-(5-methylfuran-2-yl)-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclopropanecarboxamide,

5-(5-methylfuran-2-yl)-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-amine,

2,8-dimethyl-5-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-amine,

8-chloro-N,2-dimethyl-5-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-amine,

8-chloro-N,N,2-trimethyl-5-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-amine,

N-[2-methyl-5-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]acetamide,

7-amino-2-methyl-5-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidine-8-carbonitrile,

4-methyl-7-(5-methylfuran-2-yl)-12-thia-3,5,6,8,10-pentazatricyclo[7.3.0.0 2,6 ]dodeca-

1(9),2,4,7-tetraen-11-one,

4,12,12-trimethyl-7-(5-methylfuran-2-yl)-3,5,6,8,10-pentazatricyclo[7.3.0.0 2,6 ]dodeca-

1(9),2,4,7-tetraene,

N-[5-(furan-2-yl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]cyclopropanecarboxamide,

8-fluoro-2-methyl-5-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-amine,

N-[8-bromo-5-(furan-2-yl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclopropanecarboxamide,

7-amino-2-methyl-5-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidine-8-carboxamide,

8-chloro-2-methyl-5-phenyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-amine,

N-[5-(5-methylfuran-2-yl)-2-propan-2-yl-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]acetamide,

4-methyl-7-(5-methylfuran-2-yl)-3,5,6,8,10-pentazatricyclo[7.3.0.0 2,6 ]dodeca-1(9),2,4,7,11-

pentaene,

12,12-dimethyl-7-(5-methylfuran-2-yl)-4-propan-2-yl-3,5,6,8,10-

pentazatricyclo[7.3.0.0 2,6 ]dodeca-1(9),2,4,7-tetraene,

N-[5-(furan-2-yl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]acetamide,

N-[5-(5-cyclopropylfuran-2-yl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclopropanecarboxamide,

N-[8-fluoro-2-methyl-5-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclopropanecarboxamide,

8-chloro-2-methyl-5-(5-methylthiophen-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-amine,

N-[5-(5-methylfuran-2-yl)-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]acetamide,

8-chloro-5-(5-methylfuran-2-yl)-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-amine,

N-[5-(5-tert-butylfuran-2-yl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclopropanecarboxamide,

N-[2-methyl-5-(2-methyl-1,3-oxazol-5-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]acetamide,

4,11-dimethyl-7-(5-methylfuran-2-yl)-3,5,6,8,10-pentazatricyclo[7.3.0.0 2,6 ]dodeca-

1(9),2,4,7,11-pentaene,

7-amino-5-(5-methylfuran-2-yl)-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-c]pyrimidine-8-

carbonitrile,

N-[5-(2-methyl-1,3-oxazol-5-yl)-2-propan-2-yl-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]acetamide,

N-[5-(furan-2-yl)-2-propan-2-yl-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]acetamide,

N-[5-(1,3-oxazol-5-yl)-2-propan-2-yl-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]acetamide,

N-[5-(5-methylfuran-2-yl)-2-(oxolan-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclopropanecarboxamide,

N-[2-methyl-5-(1,3-oxazol-5-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]acetamide,

N-[5-(5-bromofuran-2-yl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclopropanecarboxamide,

N-[5-(3-cyanophenyl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclopropanecarboxamide,

N-[5-(5-methylfuran-2-yl)-2-(oxan-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclopropanecarboxamide,

N-[2-methyl-5-(5-propan-2-ylfuran-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclopropanecarboxamide,

N-[5-(4-cyanophenyl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclopropanecarboxamide,

8-chloro-2-methyl-5-(5-methylpyridin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-amine,

N-[5-(furan-2-yl)-2-propan-2-yl-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclopropanecarboxamide,

N-[5-(furan-2-yl)-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]acetamide,

N-[2-methyl-5-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]oxetane-3-

carboxamide,

N-[2-cyclopropyl-5-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]acetamide,

N-[2-cyclopropyl-5-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclopropanecarboxamide,

N-[2-cyclobutyl-5-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]acetamide,

N-[2-cyclobutyl-5-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclopropanecarboxamide,

N-[2-cyclopentyl-5-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]acetamide,

N-[2-cyclopentyl-5-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclopropanecarboxamide,

N-[2-(furan-2-yl)-5-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclopropanecarboxamide,

N-[5-(furan-2-yl)-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclopropanecarboxamide,

N-[2-methyl-5-[5-(trifluoromethyl)furan-2-yl]-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclopropanecarboxamide,

N-[2-methyl-5-(1-methylpyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclopropanecarboxamide,

N-[2-methyl-5-(1-methylpyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]acetamide,

N-[5-(furan-3-yl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]acetamide,

N-[5-(furan-3-yl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]cyclopropanecarboxamide,

8-chloro-2-methyl-5-pyridin-2-yl-[1,2,4]triazolo[1,5-c]pyrimidin-7-amine,

11-methyl-7-(5-methylfuran-2-yl)-4-propan-2-yl-3,5,6,8,10-pentazatricyclo[7.3.0.0 2,6 ]dodeca-

1(9),2,4,7,11-pentaene,

8-chloro-2-methyl-5-(6-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-amine,

8-chloro-5-(4-chlorophenyl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-amine,

8-chloro-5-(3-chlorophenyl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-amine,

8-chloro-2-methyl-5-pyridin-4-yl-[1,2,4]triazolo[1,5-c]pyrimidin-7-amine,

8-chloro-5-(4-fluorophenyl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-amine,

7-(furan-2-yl)-11-methyl-4-propan-2-yl-3,5,6,8,10-pentazatricyclo[7.3.0.0 2,6 ]dodeca-

1(9),2,4,7,11-pentaene,

7-(furan-2-yl)-11-methyl-4-(trifluoromethyl)-3,5,6,8,10-pentazatricyclo[7.3.0.0 2,6 ]dodeca-

1(9),2,4,7,11-pentaene,

8-bromo-5-(4-fluorophenyl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-amine,

8-chloro-5-(2-chlorophenyl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-amine,

N-[5-(5-fluorofuran-2-yl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclopropanecarboxamide,

8-chloro-5-phenyl-2-propan-2-yl-[1,2,4]triazolo[1,5-c]pyrimidin-7-amine,

8-chloro-5-phenyl-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-amine,

11-methyl-7-(5-methylfuran-2-yl)-4-(trifluoromethyl)-3,5,6,8,10-

pentazatricyclo[7.3.0.0 2,6 ]dodeca-1(9),2,4,7,11-pentaene,

8-bromo-2-methyl-5-phenyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-amine,

N-[5-(5-bromofuran-2-yl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]acetamide,

N-[5-(furan-2-yl)-2-(oxetan-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]acetamide,

N-[5-(furan-2-yl)-2-(oxetan-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclopropanecarboxamide,

N-[5-(3-acetylphenyl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]acetamide,

tert-butyl N-[5-(3-acetylphenyl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]carbamate,

1-[3-(7-amino-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)phenyl]ethanone,

N-[5-(3-acetylphenyl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclopropanecarboxamide,

4-methyl-7-(5-methylfuran-2-yl)-3,5,6,8,10-pentazatricyclo[7.3.0.0 2,6 ]dodeca-1(9),2,4,7-

tetraen-11-one,

7-(5-methylfuran-2-yl)-4-propan-2-yl-3,5,6,8,10-pentazatricyclo[7.3.0.0 2,6 ]dodeca-1(9),2,4,7-

tetraen-11-one,

N-[2-methyl-5-(4-methylsulfonylphenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclopropanecarboxamide,

tert-butyl N-[2-methyl-5-(4-methylsulfonylphenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]carbamate,

N-[2-methyl-5-(4-methylsulfonylphenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]acetamide,

4-methyl-7-(5-methylfuran-2-yl)-3,5,6,8,10,11-hexazatricyclo[7.3.0.0 2,6 ]dodeca-1(9),2,4,7,11-

pentaene,

N-[5-(furan-2-yl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]pyrrolidine-1-carboxamide,

(3R)-N-[5-(furan-2-yl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]-3-hydroxypyrrolidine-

1-carboxamide,

1-[3-(7-amino-8-chloro-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)phenyl]ethanone,

2-methyl-5-(4-methylsulfonylphenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-amine,

(3S)-N-[5-(furan-2-yl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]-3-hydroxypyrrolidine-1-

carboxamide,

1-[5-(furan-2-yl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]-3-methylurea,

N-[5-(5-methylfuran-2-yl)-2-(oxetan-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]acetamide,

N-[5-(5-methylfuran-2-yl)-2-(oxetan-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclopropanecarboxamide,

N-[5-(4-methoxyphenyl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclopropanecarboxamide,

tert-butyl N-[5-(4-methoxyphenyl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]carbamate,

N-[5-(4-methoxyphenyl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]acetamide,

N-[2-methyl-5-(4-sulfamoylphenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclopropanecarboxamide,

5-(4-methoxyphenyl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-amine,

N-[5-[4-(dimethylsulfamoyl)phenyl]-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclopropanecarboxamide,

N-[5-[4-(dimethylsulfamoyl)phenyl]-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]acetamide,

tert-butyl N-[5-[4-(dimethylsulfamoyl)phenyl]-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]carbamate,

4-(7-amino-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)-N,N-dimethylbenzenesulfonamide,

2-methyl-5-(5-methylfuran-2-yl)-8-propan-2-yl-3H-[1,2,4]triazolo[5,1-f]purine,

7-(5-methylfuran-2-yl)-4-propan-2-yl-3,5,6,8,10,11-hexazatricyclo[7.3.0.0 2,6 ]dodeca-

1(9),2,4,7,11-pentaene,

N-[2-(azetidin-3-yl)-5-(furan-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]acetamide,

N-[2-(azetidin-3-yl)-5-(furan-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclopropanecarboxamide,

4-[2-methyl-7-[(2-methylpropan-2-yl)oxycarbonylamino]-[1,2,4]triazolo[1,5-c]pyrimidin-5-

yl]benzenesulfonic acid,

4-[7-(cyclopropanecarbonylamino)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-5-

yl]benzenesulfonic acid,

N-[2-(difluoromethyl)-5-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]acetamide,

N-[2-(fluoromethyl)-5-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]acetamide,

N-[5-(3,4-difluorophenyl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclopropanecarboxamide,

N-[5-(3,4-difluorophenyl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]acetamide,

5-(3,4-difluorophenyl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-amine,

N-[5-(3-fluorophenyl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclopropanecarboxamide,

N-[5-(3-fluorophenyl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]acetamide,

N-[2-(difluoromethyl)-5-(furan-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]acetamide,

2-[4-methyl-7-(5-methylfuran-2-yl)-3,5,6,8,10-pentazatricyclo[7.3.0.0 2,6 ]dodeca-1(9),2,4,7,11-

pentaen-11-yl]propan-2-ol,

N-[5-(furan-2-yl)-2-(1-methylazetidin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclopropanecarboxamide,

4-methyl-7-(5-methylfuran-2-yl)-3,5,6,8,10-pentazatricyclo[7.4.0.0 2,6 ]trideca-1(9),2,4,7,10,12-

hexaene,

7-(furan-2-yl)-4-methyl-3,5,6,8,10-pentazatricyclo[7.4.0.0 2,6 ]trideca-1(9),2,4,7,10,12-hexaene,

8-chloro-2-(fluoromethyl)-5-phenyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-amine,

N-[2-(fluoromethyl)-5-(furan-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]acetamide,

1-[5-(3,4-difluorophenyl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]-3-methylurea,

8-chloro-5-(3,4-difluorophenyl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-amine,

5-(3-fluorophenyl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-amine,

2,2,2-trifluoro-N-[5-(furan-2-yl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]acetamide,

2,2-difluoro-N-[5-(furan-2-yl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]acetamide,

2-fluoro-N-[5-(furan-2-yl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]acetamide,

8-chloro-5-(3-fluorophenyl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-amine,

2-[7-(5-methylfuran-2-yl)-4-(trifluoromethyl)-3,5,6,8,10-pentazatricyclo[7.3.0.0 2,6 ]dodeca-

1(9),2,4,7,11-pentaen-11-yl]propan-2-ol,

N-[2-(difluoromethyl)-5-(furan-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclopropanecarboxamide,

N-[2-(fluoromethyl)-5-(furan-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclopropanecarboxamide,

N-[2-(azetidin-3-yl)-5-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]acetamide,

N-[5-(furan-2-yl)-2-(1-methylazetidin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]acetamide,

[5-(furan-2-yl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]urea,

7-(5-methylfuran-2-yl)-4-(trifluoromethyl)-3,5,6,8,10,11-hexazatricyclo[7.3.0.0 2,6 ]dodeca-

1(9),2,4,7,11-pentaene,

1-[5-(furan-2-yl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]-3-propylurea,

1-ethyl-3-[5-(furan-2-yl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]urea,

1-[5-(furan-2-yl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]-3-(2-methylpropyl)urea,

1-[5-(furan-2-yl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]-3-(2-pyrrolidin-1-

ylethyl)urea,

1-[5-(furan-2-yl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]-3-(2-piperidin-1-ylethyl)urea,

1-[5-(furan-2-yl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]-3-(2-morpholin-4-

ylethyl)urea,

8-chloro-2-(difluoromethyl)-5-phenyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-amine,

8-methyl-5-(5-methylfuran-2-yl)-2-(trifluoromethyl)-3H-[1,2,4]triazolo[5,1-f]purine,

2-[7-(5-methylfuran-2-yl)-4-propan-2-yl-3,5,6,8,10-pentazatricyclo[7.3.0.0 2,6 ]dodeca-

1(9),2,4,7,11-pentaen-11-yl]propan-2-ol,

1-[5-(furan-2-yl)-2-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]-3-propan-2-ylurea,

N-[2-(azetidin-3-yl)-5-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-

yl]cyclopropanecarboxamide,

5-(furan-2-yl)-8-methyl-2-(trifluoromethyl)-3H-[1,2,4]triazolo[5,1-f]purine,

8-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-amine,

N-[8-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl]cyclopropanecarboxamide,

2-methyl-8-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-amine,

N-[2-methyl-8-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-

yl]cyclopropanecarboxamide,

5-chloro-8-(4-fluorophenyl)-2-methyl-[1,2,4]triazolo[1,5-a]pyrazin-6-amine,

5-bromo-8-(4-fluorophenyl)-2-methyl-[1,2,4]triazolo[1,5-a]pyrazin-6-amine,

5-bromo-2-methyl-8-phenyl-[1,2,4]triazolo[1,5-a]pyrazin-6-amine,

N-[8-(5-methylfuran-2-yl)-2-propan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-6-

yl]cyclopropanecarboxamide,

N-[2-methyl-8-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl]acetamide,

5-chloro-2-methyl-8-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-amine,

5-chloro-2-methyl-8-phenyl-[1,2,4]triazolo[1,5-a]pyrazin-6-amine,

5-chloro-8-phenyl-2-propan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-6-amine,

5-chloro-8-phenyl-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-amine,

N-[8-(furan-2-yl)-2-methyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl]acetamide,

N-[8-(furan-2-yl)-2-methyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl]cyclopropanecarboxamide,

N-[8-(furan-2-yl)-2-propan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl]cyclopropanecarboxamide,

5-chloro-2-methyl-8-(2-methylphenyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-amine,

5-chloro-2-methyl-8-(3-methylphenyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-amine,

5-chloro-2-methyl-8-(4-methylphenyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-amine,

N-[2-(difluoromethyl)-8-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-

yl]cyclopropanecarboxamide,

N-[2-amino-8-(furan-2-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl]cyclopropanecarboxamide,

N-[2-amino-8-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-

yl]cyclopropanecarboxamide,

N-[2-bromo-8-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-

yl]cyclopropanecarboxamide,

N-[8-(5-methylfuran-2-yl)-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-

yl]cyclopropanecarboxamide,

N-[2-(fluoromethyl)-8-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-

yl]cyclopropanecarboxamide,

8-(5-methylfuran-2-yl)imidazo[1,2-a]pyrazin-6-amine,

N-[8-(5-methylfuran-2-yl)imidazo[1,2-a]pyrazin-6-yl]cyclopropanecarboxamide,

ethyl 6-(cyclopropanecarbonylamino)-8-(5-methylfuran-2-yl)imidazo[1,2-a]pyrazine-2-

carboxylate,

6-(cyclopropanecarbonylamino)-8-(5-methylfuran-2-yl)imidazo[1,2-a]pyrazine-2-carboxylic

acid,

8-(5-methylfuran-2-yl)-2-(trifluoromethyl)imidazo[1,2-a]pyrazin-6-amine,

N-[3-methyl-8-(5-methylfuran-2-yl)imidazo[1,2-a]pyrazin-6-yl]cyclopropanecarboxamide,

N-[8-(5-methylfuran-2-yl)-2-(trifluoromethyl)imidazo[1,2-a]pyrazin-6-

yl]cyclopropanecarboxamide,

3-methyl-8-(5-methylfuran-2-yl)imidazo[1,2-a]pyrazin-6-amine,

N-[2-methyl-8-(5-methylfuran-2-yl)imidazo[1,2-a]pyrazin-6-yl]cyclopropanecarboxamide,

2-methyl-8-(5-methylfuran-2-yl)imidazo[1,2-a]pyrazin-6-amine,

5-chloro-2-methyl-8-phenylimidazo[1,2-a]pyrazin-6-amine,

5-chloro-8-(4-fluorophenyl)-2-methylimidazo[1,2-a]pyrazin-6-amine,

5-bromo-2-methyl-8-phenylimidazo[1,2-a]pyrazin-6-amine,

5-chloro-8-phenyl-2-(trifluoromethyl)imidazo[1,2-a]pyrazin-6-amine,

N-[2-methyl-8-(5-methylfuran-2-yl)imidazo[1,2-a]pyrazin-6-yl]acetamide,

5-bromo-8-(4-fluorophenyl)-2-methylimidazo[1,2-a]pyrazin-6-amine,

5-chloro-2-methyl-8-(3-methylphenyl)imidazo[1,2-a]pyrazin-6-amine,

N-[8-(furan-2-yl)-2-methylimidazo[1,2-a]pyrazin-6-yl]cyclopropanecarboxamide,

N-[2-(hydroxymethyl)-8-(5-methylfuran-2-yl)imidazo[1,2-a]pyrazin-6-

yl]cyclopropanecarboxamide,

N-[2-(fluoromethyl)-8-(5-methylfuran-2-yl)imidazo[1,2-a]pyrazin-6-

yl]cyclopropanecarboxamide,

N-[8-(furan-2-yl)-2-methylimidazo[1,2-a]pyrazin-6-yl]acetamide,

N-[8-(furan-2-yl)-2-propan-2-ylimidazo[1,2-a]pyrazin-6-yl]cyclopropanecarboxamide,

5-chloro-8-phenyl-2-propan-2-ylimidazo[1,2-a]pyrazin-6-amine,

5-chloro-2-methyl-8-(4-methylphenyl)imidazo[1,2-a]pyrazin-6-amine,

N-[8-(5-methylfuran-2-yl)-2-propan-2-ylimidazo[1,2-a]pyrazin-6-

yl]cyclopropanecarboxamide,

5-chloro-2-methyl-8-(2-methylphenyl)imidazo[1,2-a]pyrazin-6-amine,

1-[8-(furan-2-yl)-2-methylimidazo[1,2-a]pyrazin-6-yl]-3-methylurea,

methyl N-[8-(furan-2-yl)-2-methylimidazo[1,2-a]pyrazin-6-yl]carbamate,

ethyl N-[8-(furan-2-yl)-2-methylimidazo[1,2-a]pyrazin-6-yl]carbamate,

N-[8-(furan-2-yl)-2-methylimidazo[1,2-a]pyrazin-6-yl]propanamide,

2,2-difluoro-N-[8-(furan-2-yl)-2-methylimidazo[1,2-a]pyrazin-6-yl]acetamide,

N-[8-(furan-2-yl)-2-methylimidazo[1,2-a]pyrazin-6-yl]butanamide,

1-ethyl-3-[8-(furan-2-yl)-2-methylimidazo[1,2-a]pyrazin-6-yl]urea,

N-[8-(furan-2-yl)-2-methylimidazo[1,2-a]pyrazin-6-yl]methanesulfonamide, and

N-[8-(furan-2-yl)-2-methylimidazo[1,2-a]pyrazin-6-yl]ethanesulfonamide,

or a pharmaceutically acceptable salt thereof.

23. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

24. A process for producing a compound of formula I

or a pharmaceutically acceptable salt thereof, comprising contacting a compound of formula G-1

with a compound of formula G-2

in the presence of a palladium catalyst, a solvent, and a base, wherein X′ is a halogen, and

wherein:

Ring A is furanyl;

R 1 is H or alkyl optionally substituted with 1, 2, 3, or 4 independently selected R a substituents;

R 3 is H, alkyl, halo, —CN, or —CONR′R″, wherein the alkyl of R 3 is optionally substituted with 1, 2, 3, or 4 independently selected R a substituents;

n is 0, 1, 2, 3, 4, or 5;

one of Q 1 and Q 2 is N and the other is C;

Z is N or CR 6 ;

R 6 is H or alkyl, wherein the alkyl of R 6 is optionally substituted with 1, 2, 3, or 4 independently selected R a substituents;

R′ and R″ are each independently H or alkyl, wherein each alkyl of R′ and R″ is optionally substituted with 1, 2, 3, or 4 independently selected R a substituents;

25. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is heteroaryl or aryl;

R 1 is H or alkyl optionally substituted with 1, 2, 3, or 4 independently selected R a substituents;

R 3 is H, alkyl, halo, —CN, or —CONR′R″, wherein the alkyl of R 3 is optionally substituted with 1, 2, 3, or 4 independently selected R a substituents;

n is 0, 1, 2, 3, 4, or 5;

one of Q 1 and Q 2 is N and the other is C;

Z is N or CR 6 ;

R 6 is H or alkyl, wherein the alkyl of R 6 is optionally substituted with 1, 2, 3, or 4 independently selected R a substituents;

R′ and R″ are each independently H or alkyl, wherein each alkyl of R′ and R″ is optionally substituted with 1, 2, 3, or 4 independently selected R a substituents;

wherein when R 4 is H, aryl, or heteroaryl, then Ring A is furanyl.

26. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl and R 4 is alkyl, halo, haloalkyl, —COR′, —CONR′R″, —COOR′, SO 2 R′, —SO 2 NR′R″, —SO 2 OR′, cycloalkyl, heterocycloalkyl, or —C 1-4 alkylene-R b , wherein R b is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or —C 1-4 alkylene-R b of R 4 is optionally substituted with 1, 2, 3, or 4 independently selected R a substituents.

27. The compound of claim 26 , wherein R 4 is C 1-4 alkyl.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 10, 2022

From: MA, SUNGHOON; WANG, YONG; XU, WEI

To: EXELIXIS, INC.

Reel/Frame 058976/0297 →

Continuity (2)

Provisional Application 62990105 · Mar 16, 2020

Related Publication 20210292332A1 · Sep 23, 2021