Substituted aminoquinazoline compounds as A2A antagonist

Patent metadata

Field	Value
Publication number	US-10822338-B2
Application number	US-201615738178-A
Country	US
Kind code	B2
Filing date	Jul 5, 2016
Priority date	Jul 10, 2015
Publication date	Nov 3, 2020
Grant date	Nov 3, 2020

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 A 2A -receptor antagonist. The invention is further directed to methods of treating a patient (preferably a human) for diseases or disorders in which the A 2A -receptor is involved. The invention further involves use of the compounds as an A 2A -receptor antagonist and/or inhibitor for the preparation of a medicament for the treatment and/or prevention of diseases associated with inhibiting the receptor, which includes central nervous system disorders such as Parkinson's disease. The invention is also directed to pharmaceutical compositions which include an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and the use of the compounds and pharmaceutical compositions of the invention in the treatment of such diseases.

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 hydrogen, —C 1-6 alkyl, —OC 1-6 alkyl, or halogen, said alkyl optionally substituted with 1 to 4 groups of R b ;
R 2 is selected from the group consisting of hydrogen, —C 1-6 alkyl, or halogen, said alkyl optionally substituted with 1 to 3 groups of R b ;
R 3 represents C 3-10 cycloalkyl, or C 3-10 heterocyclyl, said cycloalkyl and heterocyclyl optionally substituted with 1 to 3 groups of R a ;
wherein said C 3-10 heterocyclyl of R 3 is selected from piperidinyl, morpholinyl, tetradropyranyl, azabicyclooctyl, azabicycloheptyl, azepanyl, azetidinyl, pyrrolidinyl, and piperidinone, and wherein:
R a is selected from the group consisting of —CN, halogen, —C 1-4 haloalkyl, —OC 1-4 haloalkyl, —C 1-6 alkyl, —C 1-6 alkenyl, (CH 2 ) n N(R) 2 , —(CH 2 ) n OC 1-6 alkyl, OH, (CHR) n C 6-10 aryl, (CHR) n C 3-10 heterocyclyl, (CHR) n C 3-10 cycloalkyl, —C(O)C 1-6 alkyl, —C(O)C 3-10 cycloalkyl), SO 2 C 1-6 alkyl, C(O)C 3-10 heterocyclyl, C(O)C 6-10 aryl, SO 2 C 6-10 aryl, said alkyl, cycloalkyl, alkenyl, aryl and heterocyclyl optionally substituted with 1 to 4 groups of R b ;
R b is selected from the group consisting of —C 1-6 alkyl, C 2-4 alkynyl, —C 1-6 alkylOR, (CH 2 ) n OR, —(CH 2 ) n C 1-4 haloalkyl, —OC 1-4 haloalkyl, halogen, N(R) 2 , CN, C(O)R, C(O)CF 3 , —(CH 2 ) n C 6-10 aryl, —O(CH 2 ) n C 6-10 aryl, —(CH 2 ) n C 3-10 heterocyclyl, —(CH 2 ) n C 3-10 cycloalkyl;
and n represents 0-4.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is —OC 1-6 alkyl and R 2 is hydrogen.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is C 3-10 heterocyclyl, said heterocycle group optionally substituted with 1 to 3 groups of R a .

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is optionally substituted C 3-10 cycloalkyl.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group of optionally substituted cyclohexyl, cyclobutyl, cyclopropyl, and cyclopentyl.

6. The compound according to claim 1 wherein R a is selected from the group consisting of halogen, —C 1-4 haloalkyl, —OC 1-4 haloalkyl, —C 1-6 alkyl, (CH 2 ) n N(R) 2 , —(CH 2 ) n OC 1-6 alkyl, OH, (CHR) n C 6-10 aryl, (CHR) n C 3-10 heterocyclyl, (CHR)) n C 3-10 cycloalkyl, —C(O)C 1-6 alkyl, —C(O)C 3-10 cycloalkyl), —C(O)C 3-10 heterocyclyl, said alkyl, cycloalkyl, aryl and heterocyclyl optionally substituted with 1 to 4 groups of R b .

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein R a is selected from the group consisting of CH 3 , CH 2 CH 3 , —(CH 2 ) 3 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 2 CH 2 CH 3 , (CH 2 ) n OCH 3 , CH 2 CF 2 CF 3 , (CH 2 ) n CF 3 , halogen, (CH 2 ) CH(CF 3 ) 2 , CH 2 CHF 2 , C(CH 3 ) 2 C≡C, —(CH 2 ) n N(R) 2 , OH, C(O)cyclopropyl, (CHR) n cyclopropyl, (CHR) n pyridyl, (CHR) n tetrahydropyranyl, (CHR) n cyclobutyl, (CHR) n thiadiazolyl, (CHR) n oxetanyl, (CHR) n cyclopentyl, (CHR) n cyclohexyl, (CHR) n phenyl, (CHR) n thiazolyl, C(O)phenyl, C(O)pyridyl, C(O)C(CH 3 ) 2 F, C(O)oxazolyl, C(O)C(CH 3 ) 3 , C(O)thiophenyl, SO 2 phenyl, (CHR) n cyclopentyl, (CHRl) n morpholinyl, and (CHR) n tetrahydrofuranyl, said cyclopropyl, pyridyl, tetrahydropyranyl, cyclohexyl, cyclobutyl, thiadiazolyl, oxetanyl, cyclopentyl, phenyl, thiazolyl, oxazolyl, thiophenyl, morpholinyl, tetrahydrofuranyl, optionally substituted with 1 to 3 groups of R b .

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein R 3 is substituted with 1 to 3 groups of R a selected from the group consisting of CH 2 CF 3 , halogen, CF 3 , (CH 2 ) 2 CF 3 , CH 2 CHF 2 , N(R) 2 , OH, CH 3 , and CH 2 CH 3 .

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein R b is selected from halogen, CH 3 , CHF 2 , CF 3 , C(O)CF 3 , CH(CH 3 ) 2 , N(CH 3 ) 2 , C(CH 3 ) 3 , CH 2 CH 3 , C(CH 3 )F 2 , OCH 3 , OH, and CH 2 OH.

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

or a pharmaceutically acceptable salt thereof, wherein R c is hydrogen or R a , and R a1 is R a .

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

12. A compound according to claim 1 represented by structural formula III:

or a pharmaceutically acceptable salt thereof, wherein R c is hydrogen or R a , R a1 is R a .

13. The compound according to claim 12 or pharmaceutically acceptable salt thereof wherein R c is selected from the group consisting of hydrogen, halogen, —C 1-4 haloalkyl, —OC 1-4 haloalkyl, —C 1-6 alkyl, (CH 2 ) n N(R) 2 , —(CH 2 ) n OC 1-6 alkyl, OH, (CHR) n C 6-10 aryl, (CHR) n C 3-10 heterocyclyl, (CHR)) n C 3-10 cycloalkyl, —C(O)C 1-6 alkyl, —C(O)C 3-10 cycloalkyl), —C(O)C 3-10 heterocyclyl, said alkyl, cycloalkyl, aryl and heterocyclyl optionally substituted with 1 to 4 groups of R b .

14. The compound according to claim 1 represented by structural formula IV:

or a pharmaceutically acceptable salt thereof, wherein R c is hydrogen or R a .

15. The compound according to claim 14 or pharmaceutically acceptable salt thereof wherein R c is selected from the group consisting of hydrogen, halogen, —C 1-4 haloalkyl, —OC 1-4 haloalkyl, —C 1-6 alkyl, (CH 2 ) n N(R) 2 , —(CH 2 ) n OC 1-6 alkyl, OH, (CHR) n C 6-10 aryl, (CHR) n C 3-10 heterocyclyl, (CHR)) n C 3-10 cycloalkyl, —C(O)C 1-6 alkyl, —C(O)C 3-10 cycloalkyl), —C(O)C 3-10 heterocyclyl, said alkyl, cycloalkyl, aryl and heterocyclyl optionally substituted with 1 to 4 groups of R b .

16. A compound which is:
(R)-7-methoxy-2-(1-(3,3,3-trifluoropropyl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine,
(R)-7-methoxy-2-(1-(3,3,3-trifluoro-2-(trifluoromethyl)propyl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine,
(R)-2-(1-(2,2-difluoroethyl)piperidin-3-yl)-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine,
(R)-2-(1-(2-(dimethylamino)ethyl)piperidin-3-yl)-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine,
(R)-2-(1-ethylpiperidin-3-yl)-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine,
(R)-7-methoxy-2-(1-(2-methoxyethyl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine,
(R)-2-(1-butylpiperidin-3-yl)-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine,
(R)-2-(1-isobutylpiperidin-3-yl)-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine,
(R)-7-methoxy-2-(1-(2-methylbut-3-yn-2-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5

Assignees

• Merck Sharp & Dohme

Inventors

• Ali Amjad
• Huang Xianhai
• Lim Yeon-Hee
• Kuang Rongze
• Wu Heping
• Anand Rajan
• Yu Younong
• Metzger Edward
• Man-Chu Lo Michael
• Ting Pauline C
• Stamford Andrew W
• Tempest Paul

Classifications

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D491/153

  the condensed system containing two rings with oxygen as ring hetero atom and one ring with nitrogen as ring hetero atom · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title