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 CR 3 ; wherein R 3 is hydrogen or C 1-12 alkyl;
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 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 CH;
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 having the following formula Ib, or a pharmaceutically acceptable salt thereof:
5. The compound of claim 4 , 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.
6. The compound of claim 1 having one of the following formulae Ic and Id, or a pharmaceutically acceptable salt thereof:
7. The compound of claim 6 having the following formula Ie, or a pharmaceutically acceptable salt thereof:
8. The compound of claim 6 having the following formula If, or a pharmaceutically acceptable salt thereof:
9. The compound of claim 7 , 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.
10. The compound of claim 1 , wherein W is O, or a pharmaceutically acceptable salt thereof.
11. The compound of claim 1 , wherein W is CH 2 , or a pharmaceutically acceptable salt thereof.
12. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
13. A composition which comprises an inert carrier and a compound of claim 1 or a pharmaceutically acceptable salt thereof.
14. A method for slowing or interrupting the progression of a P2X3 and/or P2X2/3 associated disease or disorder, wherein the disorder is pain, comprising administering to a subject in need thereof an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
15. The compound of claim 3 , 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.
16. The compound of claim 15 , wherein W is CH 2 , or a pharmaceutically acceptable salt thereof.
17. The compound of claim 8 , 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.
18. The compound of claim 17 , wherein W is O, or a pharmaceutically acceptable salt thereof.