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 .- 5 . (canceled)
6 . A method of treating a dermatological disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of Formula (I),
or a salt, solvate or hydrate thereof;
wherein:
R 1 is selected from the group consisting of OH and OR 7 , wherein R 7 is selected from the group consisting of substituted C 1-6 alkyl and C 1-6 alkyl;
R 2 is selected from the group consisting of OH and OR 7 , wherein R 7 is selected from the group consisting of substituted C 1-6 alkyl and C 1-6 alkyl;
R 3 is selected from the group consisting of substituted C 1-6 alkyl and C 1-6 alkyl;
R 4 is selected from the group consisting of H, —(CR 18 R 19 ) t COOR 8 , and —(CR 18 R 19 ) t C(O)NR 9 R 10 ; wherein t is 0, R 8 is selected from the group consisting of H substituted C 1-6 alkyl and C 1-6 alkyl, R 9 is H and R 10 is selected from the group consisting of substituted C 1-6 alkyl and C 1-6 alkyl;
R 5 is H; and
R 6 is selected from the group consisting of H and halo;
wherein the term substituted C 1-6 alkyl, refers to a C 1-6 alkyl substituted one or more times with a substituent independently selected from the group consisting of halo; hydroxy; hydroxy substituted C 1-3 alkyl; C 1-3 alkoxy; halo substituted C 1-3 alkoxy; S(O) m C 1-3 alkyl; NR 22 R 23 , wherein R 22 and R 23 are independently selected from H or C 1-3 alkyl or wherein R 22 and R 23 together with the nitrogen to which they are attached form a 5 to 7 membered ring which optionally contains an additional heteroatom selected from O, N, or S; C 1-3 alkyl; C 3-7 cycloalkyl, or C 3-7 cycloalkyl C 1-3 alkyl group; halo substituted C 1-3 alkyl; substituted aryl or substituted aryl C 1-3 alkyl and wherein these aryl containing moieties may also be substituted one to two times by halo; hydroxy; hydroxy substituted C 1-3 alkyl; C 1-3 alkoxy; S(O) m C 1-3 alkyl; amino, mono and di-substituted C 1-3 alkylamino; C 1-3 alkyl, or CF 3 ;
to thereby treat the dermatological disorder.
7 . The method according to claim 6 , wherein:
R 1 is selected from the group consisting of OH and OR 7 , wherein R 7 is C 1-6 alkyl;
R 2 is selected from the group consisting of OH and OR 7 , wherein R 7 is substituted C 1-6 alkyl and the substituent is NR 22 R 23 , wherein R 22 and R 23 are independently selected from H and C 1-3 alkyl;
R 4 is selected from the group consisting of H, —COOH, —COOCH 3 , and —C(O)NR 9 R 10 ;
wherein R 9 is H and R 10 is selected from the group consisting of amino substituted C 1-6 alkyl and —(CH 2 ) 2 NHC(O)O-t-butyl;
R 5 is H; and
R 6 is selected from the group consisting of H and halo.
8 . The method according to claim 6 , wherein:
R 1 is selected from the group consisting of OH and —OCH 3 ;
R 2 is selected from the group consisting of OH, —OCH 3 and —O—(CH 2 ) 3 NH 2 ;
R 3 is C 1-6 alkyl;
R 4 is selected from the group consisting of H, —COOH, —COOCH 3 , —C(O)NH(CH 2 ) 2 NH 2 ; and —C(O)NH(CH 2 ) 2 NHC(O)O-t-butyl;
R 5 is H; and
R 6 is selected from the group consisting of H and bromo.
9 . The method according to claim 6 , wherein:
R 1 is selected from the group consisting of OH and —OCH 3 ;
R 2 is selected from the group consisting of OH, —OCH 3 and —O—(CH 2 ) 3 NH 2 ;
R 3 is isopropyl;
R 4 is selected from the group consisting of H, —COOH, —COOCH 3 , —C(O)(CH 2 ) 2 NH 2 ; and —C(O)NH(CH 2 ) 2 NHC(O)O-t-butyl;
R 5 is H; and
R 6 is selected from the group consisting of H and bromo.
10 . The method according to claim 6 , wherein the compound is selected from the group consisting of:
or a salt, solvate or hydrate thereof.
11 . The method according to claim 6 , wherein the compound is:
12 . The method according to claim 6 wherein the dermatological condition is selected from the group consisting of psoriasis, atopic dermatitis, vitiligo, acne, uveitis radiation dermatitis.
13 . The method according to claim 6 wherein the dermatological condition is selected from the group consisting of psoriasis, atopic dermatitis, and acne.
14 . The method according to claim 6 wherein the dermatological condition is selected from the group consisting of psoriasis, atopic dermatitis, and acne.
15 . The method according to claim 6 wherein the dermatological condition is selected from the group consisting of psoriasis, atopic dermatitis, and acne.
16 . The method according to claim 6 wherein the compound, or a pharmaceutically acceptable salt, solvate or hydrate thereof, is administered topically.
17 . The method according to claim 6 , wherein the compound is at least 90% pure by weight.
18 . The method according to claim 6 , wherein the compound is at least 95% pure by weight.
19 . The method according to claim 6 , wherein the compound is at least 98% pure by weight.
20 . The method according to claim 6 , wherein the compound is at least 99% pure by weight.
21 . A method of treating a dermatological disorder selected from the group consisting of psoriasis, acne, and atopic dermatitis, in a subject in need thereof, comprising administering to said subject a pharmaceutical composition comprising therapeutically effective amount of a compound of Formula (I):
or a salt, solvate or hydrate thereof;
wherein:
R 1 is selected from the group consisting of OH and OR 7 , wherein R 7 is selected from the group consisting of substituted C 1-6 alkyl and C 1-6 alkyl;
R 2 is selected from the group consisting of OH and OR 7 , wherein R 7 is selected from the group consisting of substituted C 1-6 alkyl and C 1-6 alkyl;
R 3 is selected from the group consisting of substituted C 1-6 alkyl and C 1-6 alkyl;
R 4 is selected from the group consisting of H, —(CR 18 R 19 ) t COOR 8 , and —(CR 18 R 19 ) t C(O)NR 9 R 10 ; wherein t is 0, R 8 is selected from the group consisting of H substituted C 1-6 alkyl and C 1-6 alkyl, R 9 is H and R 10 is selected from the group consisting of substituted C 1-6 alkyl and C 1-6 alkyl;
R 5 is H; and
R 6 is selected from the group consisting of H and halo;
wherein the term substituted C 1-6 alkyl, refers to a C 1-6 alkyl substituted one or more times with a substituent independently selected from the group consisting of halo; hydroxy; hydroxy substituted C 1-3 alkyl; C 1-3 alkoxy; halo substituted C 1-3 alkoxy; S(O) m C 1-3 alkyl; NR 22 R 23 , wherein R 22 and R 23 are independently selected from H or C 1-3 alkyl or wherein R 22 and R 23 together with the nitrogen to which they are attached form a 5 to 7 membered ring which optionally contains an additional heteroatom selected from O, N, or S; C 1-3 alkyl; C 3-7 cycloalkyl, or C 3-7 cycloalkyl C 1-3 alkyl group; halo substituted C 1-3 alkyl; substituted aryl or substituted aryl C 1-3 alkyl and wherein these aryl containing moieties may also be substituted one to two times by halo; hydroxy; hydroxy substituted C 1-3 alkyl; C 1-3 alkoxy; S(O) m C 1-3 alkyl; amino, mono and di-substituted C 1-3 alkylamino; C 1-3 alkyl, or CF 3 ; and a pharmaceutically acceptable carrier or diluent;
to thereby treat the dermatological disorder.
22 . The method according to claim 21 , wherein the compound is selected from the group consisting of:
or a salt, solvate or hydrate thereof.
23 . The method according to claim 21 , wherein the pharmaceutically acceptable carrier or diluent is suitable for topical administration.
24 . The method according to claim 21 , wherein the pharmaceutically acceptable carrier or diluent is suitable for a gel topical administration or a cream topical administration.
25 . The method according to claim 21 , wherein the pharmaceutical composition is administered topically.