IP Library › Patent Application 10552302

Patent Application

App. No. 10/552,302

Triazolo[1,5-c]pyrimidines and pyrazolo[1,5-c]pyrimidines useful as a2a adenosine receptor antagonists

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Patent No.: US None
App. No.: 10/552,302

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Abstract

The invention is based on the discovery that compounds of formula (I) possess unexpectedly high affinity for the A2a adenosine receptor, and can be useful as antagonists thereof for preventing and/or treating numerous diseases, including Parkinson's disease. In one embodiment, the invention features a compound of formula (I).

Claims (130)

1 . A compound of the following formula:

or a pharmaceutically acceptable salt or N-oxide thereof;

wherein

A is aryl or heteroaryl;

B is N or CR 2 ;

each of R 2 and R 3 is independently hydrogen, alkyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, or heteroaralkyl;

each of X 1 and X 2 is independently C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, or a bond;

L is a bond or a linker selected from the group consisting of:

wherein:

each of R′ and R″, independently, is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, sulfoxy, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, alkylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl; provided that two adjacent R′ groups can join together to form a 4- to 8-membered optionally substituted cyclic moiety;

X a is —C(R 2 )(R 3 )—, —S—, —SO—, or —SO 2 —;

X b is —C(R 2 )(R 3 )—, —NR 2 —, —O—, —S—, —SO—, or —SO 2 —;

each of p, q, m, and m1, is independently 0-3;

r is 1 or 2;

n1 is 0-6; and

n2 is 2-6;

Y is —C(R 2 )(R 3 )—, —O—, —S—, —SO—, —SO 2 —, —CO—, —CO 2 —, or a bond; and

R 1 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl;

provided that

(1) when L is

then X 1 is C 1-6 alkylene, C 2-6 alkenylene, or C 2-6 alkynylene;

(2) when L is

then R 1 is aryl or heteroaryl; and

(3) when L is a bond, X 1 is an alkynylene.

2 . The compound of claim 1 , wherein X 1 is C 2-6 alkynylene.

3 . The compound of claim 2 , wherein L is

or a bond.

4 . The compound of claim 2 , wherein X 2 is C 1-4 alkylene or a bond.

5 . The compound of claim 2 , wherein Y is a bond.

6 . The compound of claim 2 , wherein each of R 2 and R 3 is independently hydrogen or alkyl.

7 . The compound of claim 2 , wherein R 1 is alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl.

8 . The compound of claim 7 , wherein R 1 is optionally substituted with alkyl, halo, hydroxy, or phenyl.

9 . The compound of claim 2 , wherein L is

or a bond; X 2 is C 1-4 alkylene or a bond; each of R 2 and R 3 is independently hydrogen or alkyl; R 1 is alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, each of which being optionally substituted with alkyl, halo, hydroxy, or phenyl; A is heteroaryl; and B is N.

10 . The compound of claim 1 , wherein L is

11 . The compound of claim 10 , wherein X b is —C(R 2 )(R 3 )— or —NR 2 —.

12 . The compound of claim 11 , wherein X b is —C(R 2 )(R 3 )—.

13 . The compound of claim 12 , wherein p is 0-1 and q is 1.

14 . The compound of claim 13 , wherein nil is 14 and n2 is 2-4.

15 . The compound of claim 14 , wherein X 1 is C 1-6 alkylene or a bond.

16 . The compound of claim 14 , wherein X 2 is C 1-6 alkylene or a bond.

17 . The compound of claim 14 , wherein Y is —SO 2 —, —CO—, —CO 2 —, or a bond.

18 . The compound of claim 14 , wherein each of R 2 and R 3 is independently hydrogen or alkyl.

19 . The compound of claim 14 , wherein R 1 is aryl or heteroaryl, each of which being optionally substituted with alkyl, halo, hydroxy, or phenyl.

20 . The compound of claim 14 , wherein each of X 1 and X 2 is independently C 1-6 alkylene or a bond; Y is —SO 2 —, —CO—, —CO 2 —, or a bond; each of R 2 and R 3 is independently hydrogen or alkyl; and R 1 is aryl or heteroaryl, each of which being optionally substituted with alkyl, halo, hydroxy, or phenyl.

21 . The compound of claim 14 , wherein L is

X 1 is a bond; X 2 is C 1-4 alkylene; Y is a bond; each of R 2 and R 3 is independently hydrogen or alkyl; R 1 is aryl or heteroaryl, each of which being optionally substituted with alkyl, halo, hydroxy, or phenyl; A is heteroaryl; and B is N.

22 . The compound of claim 1 , wherein L is

23 . The compound of claim 22 , wherein X 1 is C 1-6 alkylene, C 2-6 alkynylene, or a bond.

24 . The compound of claim 22 , wherein X 2 is C 1-6 alkylene or a bond.

25 . The compound of claim 22 , wherein Y is SO 2 —, —CO—, —CO 2 —, or a bond.

26 . The compound of claim 22 , wherein each of R 2 and R 3 is independently hydrogen or alkyl.

27 . The compound of claim 22 , wherein R 1 is alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl.

28 . The compound of claim 27 , wherein R 1 is optionally substituted with alkyl, halo, hydroxy, or phenyl.

29 . The compound of claim 22 , wherein X 1 is C 1-6 alkylene, C 2-6 alkylene, or a bond; X 2 is C 1-6 alkylene or a bond; Y is —SO 2 —, —CO—, —CO 2 —, or a bond; each of R 2 and R 3 is independently hydrogen or alkyl; R 1 is alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, each of which being optionally substituted with alkyl, halo, hydroxy, or phenyl; A is heteroaryl; and B is N.

29 . The compound of claim 1 , said compound being

2-furan-2-yl-N 7 -[1-(5-methyl-isoxazol-3-ylmethyl)-pyrrolidin-2-ylmethyl]-[1,2,4]triazolo[1,5-c]pyrimidine-5,7-diamine;

2-furan-2-yl-N 7 -methyl-N 7 -[1-(5-methyl-isoxazol-3-ylmethyl]-pyrrolidin-2-ylmethyl]-[1,2,4]triazolo[1,5-c]pyrimidine-5,7-diamine;

N 7 -[1-(2-chloro-6-fluoro-benzyl)-pyrrolidin-2-ylmethyl]-2-furan-2-yl-[1,2,4]triazolo[1,5-c]pyrimidine-5,7-diamine;

2-furan-2-yl-N 7 -(1-pyridin-4-ylmethyl-pyrrolidin-2-ylmethyl)-[1,2,4]triazolo[1,5-c]pyrimidine-5,7-diamine;

N 7 -[1-(2,6-dichloro-pyridin-4-ylmethyl)-pyrrolidin-2-ylmethyl]-2-furan-2-yl-[1,2,4]triazolo[1,5-c]pyrimidine-5,7-diamine;

N 7 -[1-(2-chloro-pyridin-4-ylmethyl)-pyrrolidin-2-ylmethyl]-2-furan-2-yl-[1,2,4]triazolo[1,5-c]pyrimidine-5,7-diamine;

N 7 -[1-(2,3-difluoro-benzyl)-pyrrolidin-2-ylmethyl]-2-furan-2-yl-[1,2,4]triazolo[1,5-c]pyrimidine-5,7-diamine;

2-furan-2-yl-N 7 -methyl-N 7 -[1-(2,3,6-trifluoro-benzyl)-piperidin-2-ylmethyl]-[1,2,4]triazolo[1,5-c]pyrimidine-5,7-diamine;

N 7 -[1-(2,4-difluoro-benzyl)-piperidin-2-ylmethyl]-2-furan-N 7 -methyl-[1,2,4]triazolo[1,5-c]pyrimidine-5,7-diamine;

N 7 -[1-(2,6-difluoro-benzyl)-piperidin-2-ylmethyl]-2-furan-2-yl-N 7 -methyl-[1,2,4]triazolo[1,5-c]pyrimidine-5,7-diamine;

N 7 -[1-(2-fluoro-benzyl)-pyrrolidin-2-ylmethyl]-2-furan-2-yl-N 7 -methyl-[1,2,4]triazolo[1,5-c]pyrimidine-5,7-diamine;

N 7 -[1-(5-chloro-furan-2-ylmethyl)-pyrrolidin-2-ylmethyl]-2-furan-2-yl-N 7 -methyl-[1,2,4]triazolo[1,5-c]pyrimidine-5,7-diamine;

N 7 -(1-benzofuran-2-ylmethyl-pyrrolidin-2-ylmethyl)-2-furan-2-yl-N 7 -methyl-[1,2,4]triazolo[1,5-c]pyrimidine-5,7-diamine;

N 7 -[1-(5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethyl)-pyrrolidin-2-ylmethyl]-2-furan-2-yl-N 7 -methyl-[1,2,4]triazolo[1,5-c]pyrimidine-5,7-diamine;

N 7 -[1-(2,3-difluoro-benzyl)-pyrrolidin-2-ylmethyl]-2-furan-2-yl-N 7 -methyl-[1,2,4]triazolo[1,5-c]pyrimidine-5,7-diamine;

2-furan-2-yl-N 7 -methyl-N 7 -(1-pyridin-2-ylmethyl-pyrrolidin-2-ylmethyl)-[1,2,4]triazolo[1,5-c]pyrimidine-5,7-diamine;

2-furan-2-yl-N 7 -methyl-N 7 -(1-pyridin-3-ylmethyl-pyrrolidin-2-ylmethyl)-[1,2,4]triazolo[1,5-c]pyrimidine-5,7-diamine;

2-furan-2-yl-N 7 -methyl-N 7 -(1-pyridin-4-pyrrolidin-2-ylmethyl)-[1,2,4]triazolo[1,5-c]pyrimidine-5,7-diamine;

N 7 -[1-(6-chloro-pyridin-3-ylmethyl)-pyrrolidin-2-ylmethyl]-2-furan-2-yl-N 7 -methyl-[1,2,4]triazolo[1,5-c]pyrimidine-5,7-diamine;

2-furan-2-yl-N 7 -methyl-N 7 -[1-(2,3,5,6-tetrafluoro-benzyl)-pyrrolidin-2-ylmethyl]-[1,2,4]triazolo[1,5-c]pyrimidine-5,7-diamine;

1-(5-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-c]pyrimidin-7-ylethynyl)-cyclopentanol;

1-(5-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-c]pyrimidin-7-ylethynyl)-cyclohexanol;

4-(5-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-2-phenyl-but-3-yn-2-ol;

7-(3-cyclohexyl-prop-1-ynyl)-2-furan-2-yl-[1,2,4]triazolo[1,5-c]pyrimidin-5-ylamine;

7-{3-[4-(2,4-difluoro-phenyl)-piperazin-1-yl]-prop-1-ynyl}-2-furan-2-yl-[1,2,4]triazolo[1,5-c]pyrimidin-5-ylamine;

7-{3-[4-(2,4-difluoro-phenyl)-piperazin-1-yl]-propyl}-2-furan-2-yl-[1,2,4]triazolo[1,5-c]pyrimidin-5-ylamine;

N 7 -{2-[4-(2,4-difluoro-phenyl)-piperazin-1-yl]-ethyl}-2-furan-2-yl-[1,2,4]triazolo[1,5-c]pyrimidine-5,7-diamine;

2-furan-2-yl-N 7 -{2-[4-(2,4,6-trifluoro-phenyl)-piperazin-1-yl]-ethyl}-([1,2,4]triazolo[1,5-c]pyrimidine-5,7-diamine;

N 7 -{2-[4-(2-fluoro-phenyl)-piperazin-1-yl]-ethyl}-2-furan-2-yl-[1,2,4]triazolo[1,5-c]pyrimidine-5,7-diamine;

N 7 -{2-[4-(2,5-difluoro-phenyl)-piperazin-1-yl]-ethyl}-2-furan-2-yl-[1,2,4]triazolo[1,5-c]pyrimidine-5,7-diamine;

2-furan-2-yl-N 7 -methyl-N 7 -[2-(4-phenyl-piperazin-1-yl)-ethyl]-[1,2,4]triazolo[1,5-c]pyrimidine-5,7-diamine;

N 7 -{2-[4-(2,4-difluoro-phenyl)-piperazin-1-yl]-ethyl}-2-furan-2-yl-N-7-methyl-[1,2,4]triazolo[1,5-c]pyrimidine-5,7-diamine; and

2-furan-2-yl-N 7 -methyl-N 7 -{2-[4-(2,4,6-trifluoro-phenyl)-piperazin-1-yl]-ethyl}-[1,2,4]triazolo[1,5-c]pyrimidine-5,7-diamine.

30 . The compound of claim 1 , said compound being

2-furan-2-yl-N 7 -[1-(5-methyl-isoxazol-3-ylmethyl)-pyrrolidin-2-ylmethyl]-[1,2,4]triazolo[1,5-c]pyrimidine-5,7-diamine;

2-furan-2-yl-N 7 -methyl-N 7 -[1-(5-methyl-isoxazol-3-ylmethyl)-pyrrolidin-2-ylmethyl]-[1,2,4]triazolo[1,5-c]pyrimidine-5,7-diamine;