Isoquinoline compounds and their use in treating AhR imbalance
The present invention is directed to novel compounds of Formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof. Pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, are also described. The invention is also directed to use of the compounds of Formula (I) for treating a condition in a mammal associated with AhR imbalance, such as an inflammatory disease or disorder.
1. A process for preparing a compound of Formula 8
or a pharmaceutically acceptable salt, solvate or hydrate thereof, comprising:
a) coupling a compound of Formula 6
wherein OTf is —O—SO 2 CF 3 ,
or a pharmaceutically acceptable salt thereof with a compound of Formula 5
or a pharmaceutically acceptable salt thereof to form a compound of Formula 7
or a pharmaceutically acceptable salt thereof; and
b) demethylating the compound of Formula 7 to form the compound of Formula 8, and optionally converting the compound of Formula 8 to a pharmaceutically acceptable salt, solvate or hydrate thereof.
2. The process of claim 1 wherein the compound of Formula 6 or a pharmaceutically acceptable salt thereof, is prepared by treating isoquinoline-3-ol with a triflating agent.
3. The process of claim 1 wherein the compound of Formula 5 or a pharmaceutically acceptable salt thereof, is prepared by a process comprising:
a) alkylating 2,6-dihydroxyacetophenone or a pharmaceutically acceptable salt, thereof, to form a compound of Formula 2
or a pharmaceutically acceptable salt thereof;
b) treating the compound of Formula 2 or a pharmaceutically acceptable salt thereof with a Grignard reagent, followed by elimination of water under acidic conditions to form a compound of Formula 3
or a pharmaceutically acceptable salt thereof;
c) hydrogenating the compound of Formula 3 or a pharmaceutically acceptable salt thereof to form a compound of Formula 4
or a pharmaceutically acceptable salt thereof; and
d) borylating the compound of Formula 4 or a pharmaceutically acceptable salt thereof to form the compound of Formula 5 or a pharmaceutically acceptable salt thereof.
4. The process of claim 1 wherein the demethylation comprises
a) treating the compound of Formula 7 with boron tribromide to form the compound of Formula 7-1
and
b) hydrogenating the compound of Formula 7-1 to form the compound of Formula 8.
5. The process of claim 1 , further comprising purifying the compound of Formula 8.
6. The process of claim 5 wherein the purifying comprises crystallization.
7. A process for preparing a compound of Formula 8
or a pharmaceutically acceptable salt, solvate or hydrate thereof, comprising:
a) preparing a compound of Formula 5
or a pharmaceutically acceptable salt thereof, comprising
1) alkylating 2,6-dihydroxyacetophenone or a pharmaceutically acceptable salt thereof, to form a compound of Formula 2
or a pharmaceutically acceptable salt thereof;
2) treating the compound of Formula 2 or a pharmaceutically acceptable salt thereof with a Grignard reagent, followed by elimination of water under acidic conditions to form a compound of Formula 3
or a pharmaceutically acceptable salt thereof;
3) hydrogenating the compound of Formula 3 or a pharmaceutically acceptable salt thereof to form a compound of Formula 4
or a pharmaceutically acceptable salt thereof; and
4) borylating the compound of Formula 4 or a pharmaceutically acceptable salt thereof to form the compound of Formula 5
or a pharmaceutically acceptable salt thereof;
b) preparing a compound of Formula 6
wherein OTf is —O—SO 2 CF 3 ,
or a pharmaceutically acceptable salt thereof comprising treating isoquinoline-3-ol with a triflating agent; and
c) coupling the compound of Formula 6 or a pharmaceutically acceptable salt thereof with the compound of Formula 5 or a pharmaceutically acceptable salt thereof to form a compound of Formula 7
or a pharmaceutically acceptable salt thereof; and
d) demethylating the compound of Formula 7 to form the compound of Formula 8 and optionally converting the compound of Formula 8 to a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein steps a) and b) can be done in either order or simultaneously in different reaction vessels.
8. The process of claim 7 , further comprising purifying the compound of Formula 8.
9. The process of claim 8 wherein the purifying comprises crystallization.
10. A process for preparing compound of Formula 8
or a pharmaceutically acceptable salt, solvate or hydrate thereof, comprising demethylating a compound of Formula 7
or a pharmaceutically acceptable salt thereof, to form the compound of Formula 8, and optionally converting the compound of Formula 8 to a pharmaceutically acceptable salt, solvate or hydrate thereof.
11. The process of claim 10 further comprising coupling a compound of Formula 6
wherein OTf is —O—SO 2 CF 3 ,
or a pharmaceutically acceptable salt thereof with a compound of Formula 5
or a pharmaceutically acceptable salt thereof to form the compound of Formula 7.
12. The process of claim 11 further comprising borylating a compound of Formula 4
or a pharmaceutically acceptable salt thereof to form the compound of Formula 5.
13. The process of claim 12 further comprising hydrogenating a compound of Formula 3
or a pharmaceutically acceptable salt thereof to form the compound of Formula 4.
14. The process of claim 13 further comprising treating a compound of Formula 2
or a pharmaceutically acceptable salt thereof with a Grignard reagent, followed by elimination of water under acidic conditions to form the compound of Formula 3.
15. The process of claim 14 further comprising alkylating 2,6-dihydroxyacetophenone or a pharmaceutically acceptable salt thereof, to form the compound of Formula 2.
16. The process of claim 10 wherein the demethylation comprises treating the compound of Formula 7 with boron tribromide.
17. The process of claim 10 , further comprising purifying the compound of Formula 8.
18. The process of claim 17 wherein the purifying comprises crystallization.