IP Library › Granted Patent US 12,264,161

Granted Patent B2

US 12,264,161 · App. 18/323,510 · Granted Apr 1, 2025

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 12,264,161
App. No.: 18/323,510
Granted: Apr 1, 2025
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 (267)

1. A method of treating a disease or disorder in a patient,

the method comprising administering to the patient a therapeutically effective amount of a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is heteroaryl or aryl, provided that Ring A is furanyl when R 4 is H, aryl, or heteroaryl;

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;

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;

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;

wherein the disease or disorder is associated with abnormal expression of A2A or A2B receptors, and wherein the disease or disorder is:

a cancer selected from the group consisting of lung cancer, non-small cell lung cancer, melanoma, malignant melanoma, renal cell cancer, triple negative breast cancer, colorectal cancer, bladder cancer, metastatic castration resistant prostate, cervical cancer, ovarian cancer, colorectal cancer, pancreatic cancer, esophageal cancer, prostate cancer, kidney cancer, skin cancer, thyroid cancer, liver cancer, and uterine cancer;

an inflammatory disease selected from the group consisting of a respiratory disorder, sepsis, reperfusion injury, and thrombosis;

a cardiovascular disease selected from the group consisting of coronary artery-disease, cerebrovascular disease, peripheral artery disease, aortic atherosclerosis, and aneurysm; or

Parkinson's disease.

2. The method of claim 1 , wherein R 1 is H or C 1-4 alkyl.

3. The method of claim 1 , 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 method of claim 3 , wherein R 2 is H or methyl, acetyl, or —C(O)-cyclopropyl.

5. The method of claim 1 , wherein R 3 is H, C 1-4 alkyl, halo, —CN, or —CONH 2 .

6. The method of claim 1 , wherein R 4 is H, C 1-4 alkyl, C 1-4 hydroxyalkyl, halo, C 1-4 haloalkyl, —NH 2 , —COOH, or —COO—C 1-4 alkyl.

7. The method of claim 1 , 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.

8. The method of claim 1 , 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 .

9. The method of claim 1 , wherein Q 1 is N, and Z is N or CR 6 ; or Q 2 is N, and Z is N.

10. The method of claim 1 , wherein the compound of formula I is a compound of formula IA, IB, or IC:

or a pharmaceutically acceptable salt thereof.

11. The method of claim 10 , wherein the compound of formula I is a compound of formula IA or a pharmaceutically acceptable salt thereof, wherein

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

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

12. The method of claim 10 , wherein the compound of formula I is a compound of formula IB or a pharmaceutically acceptable salt thereof, wherein

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

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

13. The method of claim 10 , wherein the compound of formula I is a compound of formula IC or a pharmaceutically acceptable salt thereof, 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.

14. The method of claim 1 , wherein the compound of formula I is a compound of formula IVA, IVB, or IVC:

or a pharmaceutically acceptable salt thereof.

15. The method of claim 1 , wherein the compound of formula I is 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,

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,

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,

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,

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,

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,

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,

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,

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,

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,

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

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,

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,

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,

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,

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,

and pharmaceutically acceptable salts thereof.

16. The method of claim 1 , wherein the disease or disorder is a cancer selected from the group consisting of lung cancer, non-small cell lung cancer, melanoma, malignant melanoma, renal cell cancer, triple negative breast cancer, colorectal cancer, bladder cancer, metastatic castration resistant prostate, cervical cancer, ovarian cancer, colorectal cancer, pancreatic cancer, esophageal cancer, prostate cancer, kidney cancer, skin cancer, thyroid cancer, liver cancer, and uterine cancer.

17. The method of claim 1 , wherein the disease or disorder is an inflammatory disease selected from the group consisting of a respiratory disorder, sepsis, reperfusion injury, and thrombosis.

18. The method of claim 1 , wherein the disease or disorder is a cardiovascular disease selected from the group consisting of coronary artery-disease, cerebrovascular disease, peripheral artery disease, aortic atherosclerosis, and aneurysm.

19. The method of claim 1 , wherein the disease or disorder is Parkinson's disease.

20. A pharmaceutical composition comprising a compound of formula I:

or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient, wherein:

Ring A is heteroaryl or aryl, provided that Ring A is furanyl when R 4 is H, aryl, or

heteroaryl;

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;

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 15, 2023

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

To: EXELIXIS, INC.

Reel/Frame 065570/0487 →

Continuity (3)

Continuation 17201380 · Mar 15, 2021

Provisional Application 62990105 · Mar 16, 2020

Related Publication 20230382917A1 · Nov 30, 2023

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