Substituted pyrazole-pyrimidines, variants thereof, and uses therefore
Disclosed herein are substituted pyrazole-pyrimidine compounds of Formula I and variants thereof for the treatment, for example, of diseases associated with P2X purinergic receptors: In one embodiment, the P2X3 and/or P2X2/3 antagonists disclosed herein are potentially useful, for example, for the treatment of visceral organ, cardiovascular and pain-related diseases, conditions and disorders.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
ring
is selected from the group consisting of:
W is CH 2 , NH, N—C 1-6 alkylene, O or S;
X 6 is N;
Y is hydrogen or —NHR d ; wherein R d is selected from the group consisting of hydrogen, C 1-12 alkyl, C 3-12 cycloalkyl, aryl, and heteroaryl; wherein each of the C 1-12 alkyl, C 3-12 cycloalkyl, aryl, and heteroaryl is optionally substituted with one to three substituents independently selected from halogen, hydroxyl and C 1-6 alkyl;
D is an optional oxygen;
each occurrence of R 1 is independently selected from the group consisting of hydrogen, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl; wherein each of the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl is optionally substituted with one to three substituents independently selected from halogen and hydroxyl;
each occurrence of R 2 is independently selected from the group consisting of hydrogen, halogen, —NH—R f , —C(O)—NHR f , —C(O)—C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, and —O—C 1-12 alkyl;
each occurrence of R f is independently selected from the group consisting of hydrogen, C 1-12 alkyl, hydroxyl, —SO 2 —NH 2 , and —SO 2 —C 1-6 alkyl; and
R 7 is selected from the group consisting of hydrogen, C 1-12 alkyl, and C 3-12 cycloalkyl.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
W is CH 2 or O;
X 6 is N;
Y is hydrogen or —NHR d ; wherein R d is selected from the group consisting of hydrogen or C 1-6 alkyl; wherein the C 1-6 alkyl is optionally substituted with one to three substituents independently selected from halogen and hydroxyl;
D is absent;
each occurrence of R 1 is independently selected from the group consisting of hydrogen and C 1-6 alkyl;
each occurrence of R 2 is independently selected from the group consisting of hydrogen, halogen, —NH—R f , —C(O)—NHR f , —C(O)—C 1-6 alkyl, C 2-6 alkenyl, and —O—C 1-6 alkyl;
each occurrence of R f is independently selected from the group consisting of hydrogen, C 1-6 alkyl, hydroxyl, —SO 2 —NH 2 , and —SO 2 —C 1-6 alkyl; and
R 7 is selected from the group consisting of hydrogen and C 1-6 alkyl.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having formulae Ia:
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
W is CH 2 or O;
R 1 is selected from the group consisting of hydrogen and C 1-6 alkyl;
R 2 is selected from the group consisting of hydrogen, halogen, —NH 2 ; —C(O)—NH 2 , —C(O)—C 1-6 alkyl, and —O—C 1-6 alkyl; and
R d is selected from the group consisting of hydrogen and C 1-6 alkyl,
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the following formula Ic or the following formula Id:
6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein:
W is CH 2 or O;
R 1 is selected from the group consisting of hydrogen and C 1-6 alkyl;
R 2 is selected from the group consisting of hydrogen, halogen, —NH 2 , —C(O)—NH 2 , —C(O)—C 1-6 alkyl, and —O—C 1-6 alkyl; and
R d is selected from the group consisting of hydrogen and C 1-6 alkyl,
or a pharmaceutically acceptable salt thereof.
7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein W is O.
8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein W is CH 2 .
9. A composition which comprises an inert carrier and a compound of claim 1 or a pharmaceutically acceptable salt thereof.
10. A compound of claim 1 or a pharmaceutically acceptable salt thereof for use in therapy.
11. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherin
W is CH 2 or O;
R 1 is selected from the group consisting of hydrogen and C 1-6 alkyl;
R 2 is selected from the group consisting of hydrogen, halogen, —NH 2 ; —C(O)—NH 2 , —C(O)—C 1-6 alkyl, and —O—C 1-6 alkyl; and
R d is selected from the group consisting of hydrogen and C 1-6 alkyl.
12. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein W is CH 2 .