Aminoquinazoline compounds as A2A antagonist

Patent metadata

Field	Value
Publication number	US-10138212-B2
Application number	US-201615549242-A
Country	US
Kind code	B2
Filing date	Feb 1, 2016
Priority date	Feb 6, 2015
Publication date	Nov 27, 2018
Grant date	Nov 27, 2018

Abstract

The present invention is directed to compounds of generic formula I: or pharmaceutically acceptable salts thereof that are believed to be useful as an A2A-receptor antagonist.

First claim

The invention claimed is:

1. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof, wherein:
R represents hydrogen or —C 1-6 alkyl;
R 1 is selected from the group consisting of —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —C 1-4 haloalkyl, —OC 1-4 haloalkyl, CN, —SC 1-6 alkyl, —SO 2 C 1-6 alkyl, and —(CH 2 ) n C 4-10 heteroaryl;
R 2 and R 3 when present are independently selected from the group consisting of hydrogen, deuterium, C 3-10 cycloalkyl, and C 1-6 alkyl, said alkyl optionally substituted with 1 to 3 groups of R b ; or
R 2 and R 3 can combine to form a 3 to 6 membered cycloalkyl ring;
R 4 when present represents —(CH 2 ) n C 6-10 aryl, or —(CH 2 ) n C 4-10 heterocycle, said aryl and heterocycle optionally substituted with 1 to 3 groups of R a ; or
R 2 , R 3 and R 4 can combine to form a C 4-10 heterocyclic group, said heterocyclic group optionally substituted with 1 to 3 groups of R a ; or
R5 represents hydrogen or halogen;
R a is selected from the group consisting of —CN, halogen, —C 1-4 haloalkyl, —OC 1-4 haloalkyl, —C 1-6 alkyl, —(CH 2 ) n OR, —(CH 2 ) n C 6-10 aryl, —(CH 2 ) n C 4-10 heterocycle,
—(CH 2 ) n O(CH 2 ) n C 3-6 cycloalkyl, C 3-6 cycloalkyl, C(C 3-6 cycloalkyl)OR, —(CH 2 ) n O(CH 2 ) n C 6-10 aryl, —(CH 2 ) n O(CH 2 ) n C 4-10 heterocycle, —(CH 2 ) n SC 6-10 aryl, —(CH 2 ) n SC 4-10 heterocycle, ═O, C(O)OR, said alkyl, cycloalkyl, aryl and heterocycle, wherein one or more hydrogen atoms therein are optionally replaced by an equal number of deuterium atoms, and optionally substituted with 1 to 3 groups of R b ;
R b is selected from the group consisting of —C 1-6 alkyl, —C 1-6 alkylOR, OR, O(CH 2 ) 1-2 OR, —C 1-4 haloalkyl, halogen, CN, —C 6-10 aryl, —C 4-10 heterocycle, C(CH 3 ) 2 O(CH 2 ) 1-2 OR, said alkyl, aryl and heterocycle optionally substituted with 1 to 3 groups of R c ;
R c is selected from the group consisting of: (i) —C 1-6 alkyl; (ii) halogen; (iii) —C 1-6 alkylOR; (iv) O(CH 2 ) 1-2 OR; and (v) OR; and
n represents 0-4.

2. The compound according to claim 1 wherein R 1 is selected from the group consisting of —OC 1-6 alkyl, —C 1-4 haloalkyl, —OC 1-4 haloalkyl, and halogen, or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 wherein R 1 is —OCH 3 , or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein both of R 2 and R 3 are hydrogen or deuterium.

5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof wherein R 4 is —(CH 2 ) n C 6-10 aryl optionally substituted with 1 to 3 groups of R a .

6. The compound according to claim 5 wherein the R 4 is aryl which is optionally substituted phenyl.

7. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is —(CH 2 ) n C 4-10 heterocycle and is optionally substituted with 1 to 3 groups of R a , wherein, optionally, one or more hydrogen atoms in R a is substituted by deuterium.

8. The compound according to claim 7 wherein the heterocycle is selected from the group consisting unsubstituted or substituted pyridyl, quinolyl, pyridinone, oxazolyl, pyrimidinyl, benzodioxolyl, imidazopyridyl, thiazolyl, isoxazolyl, dihydrobenzoxazinyl and piperidyl, or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 8 wherein the heterocycle is selected from the group consisting substituted pyridyl, quinolyl, and pyridinone, or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 and R 4 combine to form a C 4-10 heterocyclic group selected from the group consisting of indanyl, tetralinyl, dihydrocyclopentapyridinyl, and tetrahydroquinolinyl, said groups optionally substituted with 1 to 3 groups of R a .

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R a is selected from the group consisting of halogen, —C 1-4 haloalkyl, —C 1-6 alkyl, —(CH 2 ) n OR, —(CH 2 ) n C 6-10 aryl, —(CH 2 ) n C 4-10 heterocycle, —(CH 2 )O(CH 2 ) n C 6-10 aryl, —(CH 2 )O(CH 2 ) n C 4-10 heterocycle, C 3-6 cycloalkyl, —O—CH 3 , —C(O)OR, C(D 2 )C 6-10 aryl, —C(D 2 )C 4-10 heterocycle, said alkyl, aryl and heterocycle optionally substituted with 1 to 3 groups of R b .

12. The compound according to claim 1 , represented by structural formula II:

or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 12 wherein R 4 is selected from the group consisting of phenyl, pyridyl, pyridinone, quinolyl, oxazolyl, pyrimidinyl, benzodioxolyl, imidazopyridinyl, thiazolyl, isoxazolyl, dihydrobenzoxazinyl, and piperidyl, said groups optionally substituted with 1 to 3 groups of R a , and R 1 is selected from the group consisting of —OC 1-6 alkyl, —C 1-4 haloalkyl, —OC 1-4 haloalkyl, and halogen, or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 13 wherein R a is selected from the group consisting of —C(CH 3 ) 2 OH, OCH 3 , CF 3 , —OCH(CH 3 ) 2 , methyl, ethyl, propyl, butyl, —CH(CH 3 ) 2 , —C(CH 3 )(CF 3 )—OH, CH 2 OCH 2 CH(CH 3 ) 2 , a moiety of the formula:

—CH 2 OH, fluorine, chlorine, bromine, iodine, cyclobutyl, cyclopropyl, (CH 2 ) n phenyl, (CH 2 ) n pyridyl, (CH 2 ) n piperidyl, (CH 2 ) n piperizinyl, oxo, (CH 2 ) n pyrazolyl, (CH 2 ) n pyrimidinyl, (CH 2 ) n thiazolyl, (CH 2 ) n oxazolyl, C(O)OCH 3 , (CH 2 ) n morpholinyl, (CH 2 ) n —O-phenyl, (CH 2 ) n —S-phenyl, (CH 2 ) n —O-pyridyl, (CH 2 ) n —S-pyridyl, (CH 2 ) n —S-benzimidazolyl, CH 2 —O—CH 2 -cyclopentyl, (CH 2 ) n —O-tetrahydrofuranyl, (CD 2 ) n phenyl, and (CD 2 ) n pyridyl, said methyl, ethyl, propyl, butyl, phenyl, pyridyl, piperidyl, piperizinyl, pyrazolyl, pyrimidinyl, thiazolyl, oxazolyl, morpholinyl, and benzimidazolyl optionally substituted with 1 to 3 groups of R b , or a pharmaceutically acceptable salt thereof.

15. The compound according to any of claims 12 - 14 wherein R 4 is unsubstituted or substituted pyridyl or pyridinone, or a pharmaceutically acceptable salt thereof.

16. The compound according any of claims 12 - 14 wherein R 4 is unsubstituted or substituted quinolyl, or a pharmaceutically acceptable salt thereof.

17. A compound which is:
2-amino-N-[[6-(1-hydroxy-1-methyl-ethyl)-3-methoxy-2-pyridyl]methyl]-8-methoxy-quinazoline-4-carboxamide,
2-amino-N-[[6-(1-hydroxy-1-methyl-ethyl)-3-methyl-2-pyridyl]methyl]-8-methoxy-quinazoline-4-carboxamide,
2-amino-8-methoxy-N-[[6-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-2-pyridyl]methyl]quinazoline-4-carboxamide,
2-amino-N-[[6-(1-hydroxycyclobutyl)-2-pyridyl]methyl]-8-methoxy-quinazoline-4-carboxamide,
2-amino-N-[(6-isopropyl-2-pyridyl)methyl]-8-methoxy-quinazoline-4-carboxamide,
2-amino-N-[(6-cyclobutyl-2-pyridyl)methyl]-8-methoxy-quinazoline-4-carboxamide,
2-amino-N-[(6-cyclopropyl-2-pyridyl)methyl]-8-methoxy-quinazoline-4-carboxamide,
2-amino-N-[[6-(3-hydroxyphenyl)-2-pyridyl]methyl]-8-methoxy-quinazoline-4-carboxamide,
2-amino-N-[[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]methyl]-8-methoxy-quinazoline-4-carboxamide,
2-amino-8-methoxy-N-[[6-(2-pyridyl)-2-pyridyl]methyl]quinazoline-4-carboxamide,
2-amino-N-[(

Assignees

• Merck Sharp & Dohme

Inventors

• Ali Amjad
• Kuang Rongze
• Lim Yeon-Hee
• Lo Michael Man-Chu
• Ting Pauline C
• Biju Purakkattle
• De Lera Ruiz Manuel
• Degrado Sylvia J
• Tung Alexander L
• Henderson Timothy J
• Hong Liwu
• Kim Jae-Hun
• Kim Dong Won-Shik
• Lee Joe
• Wu Jie
• Wu Heping
• Xiao Yushi
• Yu Tao
• Zhou Gang
• Zhu Xiaohong
• Mccormick Kevin D
• Tagat Jayaram R
• Xiao Dong
• Khan Tanweer
• Cao Jianhua
• Berlin Michael
• Zhang Yonglian

Classifications

• C07D417/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D239/84 Primary

  Nitrogen atoms · CPC title