Bridged bicyclic RHO kinase inhibitor compounds, composition and use
View Patent ↗The present invention is directed to synthetic bridged bicyclic compounds that are inhibitors of rho-associated protein kinase. The present invention is also directed to pharmaceutical compositions comprising such compounds and a pharmaceutically acceptable carrier. The invention is additionally directed to a method of preventing or treating diseases or conditions associated with cytoskeletal reorganization. The method comprises administering to a subject a therapeutically effective amount of a Rho kinase inhibitory compound of Formula I, wherein said amount is effective to influence the actomyosin interactions, for example, by leading to cellular relaxation and alterations in cell-substratum adhesions. In one embodiment, the method treats increased intraocular pressure, such as primary open-angle glaucoma. In another embodiment, the method treats diseases or conditions of the lung associated with excessive cell proliferation, remodeling, inflammation, vasoconstriction, bronchoconstriction, airway hyperreactivity and edema.
1. A compound of Formula I:
wherein:
R 1 is substituted aryl;
Q is (CR 4 R 5 ) v C(═O), (CR 4 R 5 ) v SO 2 , or (CR 4 R 5 ) v , in which C(═O) and SO 2 are connected to ring;
v is 0, 1, 2, or 3;
R 2 is selected from the following heteroaryl systems, optionally substituted:
ring is selected from the following bridged bicyclic systems:
in which N of ring is connected to Q, and the other line is connected to NR 2 R 3 ;
i is 1, 2, or 3;
j, k, l, and m are independently 0, 1, or 2;
the ring is optionally substituted by alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, halo, oxo, OR 6 , NR 6 R 7 , or SR 6 ;
R 3 —R 7 are independently H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocycle, (heterocycle)alkyl, (heterocycle)alkenyl, (heterocycle)alkynyl, optionally substituted;
when ring is ring-1, then 1≦j+k+1+m≦6.
2. The Compound according to claim 1 , wherein the ring is selected from one of the following rings:
3. The Compound according to claim 2 , wherein the ring is
4. The Compound according to claim 1 , wherein the ring is ring-1, j=k=1=m=0 or 1, and i=1 or 2.
5. The Compound according to claim 1 , wherein Q=(CR 4 R 5 ) v , and v=1-3.
6. The compound according to claim 1 , wherein R 1 has 1-3 substituents each independently in the form of Y—Z, in which Z is attached to Q and Y is a substituent on Z;
Y is independently selected from the group consisting of: H, alkyl, halogen, OR 8 , NR 8 R 9 , NO 2 , SR 8 , SOR 8 , SO 2 R 8 , SO 2 NR 8 R 9 , NR 8 SO 2 R 9 , OCF 3 , CONR 8 R 9 , NR 8 C(═O)R 9 , NR 8 C(═O)OR 9 , OC(═O)NR 8 R 9 , and NR 8 C(═O)NR 9 R 10 ;
Z is independently selected from the group consisting of: alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocycle, (heterocycle)alkyl, (heterocycle)alkenyl, (heterocycle)alkynyl, and absent, with the proviso that if Z is absent, then Y is not H;
R 8 —R 13 are independently H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, (heterocycle)alkyl, (heterocycle)alkenyl, (heterocycle)alkynyl, or heterocycle; and
R 8 —R 10 are optionally substituted by halogen, OR 11 , NR 11 R 12 , NO 2 , SR 11 , SOR 11 , SO 2 R 11 , SO 2 NR 11 R 12 , NR 11 SO 2 R 12 , OCF 3 , CONR 11 R 12 , NR 11 C(═O)R 12 , NR 11 C(═O)OR 12 , OC(═O)NR 11 R 12 , or NR 11 C(═O)NR 12 R 13 .
7. The compound according to claim 6 , wherein Y is H, alkyl, halogen, OR 8 , SR 8 , SOR 8 , SO 2 R 8 , SO 2 NR 8 R 9 , NR 8 SO 2 R 9 , CONR 8 R 9 , or NR 8 C(═O)NR 9 R 10 .
8. The compound according to claim 7 , wherein Y is alkyl, halogen, OR 8 , or NR 8 SO 2 R 9 .
9. The compound according to claim 6 , wherein Z is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, or is absent.
10. The compound according to claim 6 , wherein R 8 is H, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl, or heterocycle, optionally substituted with halogen, OR 11 , NR 11 R 12 , SR 11 , SOR 11 , SO 2 R 11 , SO 2 NR 11 R 12 , NR 11 SO 2 R 12 , CONR 11 R 12 , NR 11 C(═O)R 12 , and R 9 —R 13 are H or alkyl.
11. The compound according to claim 1 , which is N—((RS,3rs,5SR)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indazol-5-amine; N-((1RS,3rs,5SR)-8-(4-methylbenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indazol-5-amine; 2-(3-(((1RS,3rs,5SR)-3-((1H-indazol-5-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)methyl)phenoxy)ethanol; 2-(5-(((1RS,3rs,5SR)-3-((1H-indazol-5-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-2-methylphenoxy)ethanol; N-((1RS,3rs,5SR)-8-(4-methylbenzyl)-8-azabicyclo[3.2.1]octan-3-yl)isoquinolin-5-amine; 2-(5-(((1RS,3rs,5SR)-3-(isoquinolin-5-ylamino)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-2-methylphenoxy)ethanol; 4-(3-(((1RS,3rs,5SR)-8-(4-methylbenzyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)phenyl)-1,2,5-oxadiazol-3-amine; N-((1RS,3sr,5SR)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indazol-5-amine; N-((1RS,3sr,5SR)-8-(4-methylbenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indazol-5-amine; 2-(5-(((1RS,3sr,5SR)-3-((1H-indazol-5-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-2-methylphenoxy)ethanol; N-((1RS,3sr,5SR)-8-(3-fluorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indazol-5-amine; N-((1RS,3sr,5SR)-8-(4-methylbenzyl)-8-azabicyclo[3.2.1]octan-3-yl)isoquinolin-5-amine; 2-(5-(((1RS,3sr,5SR)-3-(isoquinolin-5-ylamino)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-2-methylphenoxy)ethanol; N-((1SR,4SR,7RS)-2-benzyl-2-azabicyclo[2.2.1]heptan-7-yl)-1H-indazol-5-amine; N-((1SR,4SR,7RS)-2-(4-methylbenzyl)-2-azabicyclo[2.2.1]heptan-7-yl)-1H-indazol-5-amine; N-((1SR,4SR,7RS)-2-(4-chlorobenzyl)-2-azabicyclo[2.2.1]heptan-7-yl)-1H-indazol-5-amine; N-(5-(((1SR,4SR,7RS)-7-((1H-indazol-5-yl)amino)-2-azabicyclo[2.2.1]heptan-2-yl)methyl)-2-methylphenyl)methanesulfonamide; N-((1SR,4SR,7RS)-2-(4-methylbenzyl)-2-azabicyclo[2.2.1]heptan-7-yl)isoquinolin-5-amine; 2-(5-(((1SR,4SR,7RS)-7-(isoquinolin-5-ylamino)-2-azabicyclo[2.2.1]heptan-2-yl)methyl)-2-methylphenoxy)ethanol; 4-(4-(((1SR,4SR,7RS)-2-(4-methylbenzyl)-2-azabicyclo[2.2.1]heptan-7-yl)amino)phenyl)-1,2,5-oxadiazol-3-amine; N-((1SR,4SR,7SR)-2-(4-methylbenzyl)-2-azabicyclo[2.2.1]heptan-7-yl)-1H-indazol-5-amine; 2-(5-(((1SR,4SR,7SR)-7-((1H-indazol-5-yl)amino)-2-azabicyclo[2.2.1]heptan-2-yl)methyl)-2-methylphenoxy)ethanol; N-((1SR,4SR,7SR)-2-(4-methylbenzyl)-2-azabicyclo[2.2.1]heptan-7-yl)isoquinolin-5-amine; N-(5-(((1SR,4SR,7SR)-7-(isoquinolin-5-ylamino)-2-azabicyclo[2.2.1]heptan-2-yl)methyl)-2-methylphenyl)methanesulfonamide; N-((1SR,4SR,7SR)-2-(3-fluorobenzyl)-2-azabicyclo[2.2.1]heptan-7-yl)isoquinolin-5-amine; N-((1SR,4SR,6SR)-2-(4-methylbenzyl)-2-azabicyclo[2.2.1]heptan-6-yl)-1H-indazol-5-amine; N-((1SR,4SR,6SR)-2-(3-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-6-yl)-1H-indazol-5-amine; 2-(3-(((1SR,4SR,6SR)-6-((1H-indazol-5-yl)amino)-2-azabicyclo[2.2.1]heptan-2-yl) methyl)phenoxy)ethanol; N-((1SR,4SR,6SR)-2-(4-methylbenzyl)-2-azabicyclo[2.2.1]heptan-6-yl)isoquinolin-5-amine; N-(3-(((1SR,4SR,6SR)-6-(isoquinolin-5-ylamino)-2-azabicyclo[2.2.1]heptan-2-yl)methyl)phenyl)methanesulfonamide; 4-(4-(((1SR,4SR,6SR)-2-(4-methylbenzyl)-2-azabicyclo[2.2.1]heptan-6-yl)amino)phenyl)-1,2,5-oxadiazol-3-amine; N-((1SR,4SR,6RS)-2-(4-methylbenzyl)-2-azabicyclo[2.2.1]heptan-6-yl)-1H-indazol-5-amine; N-(3-(((1SR,4SR,6RS)-6-((1H-indazol-5-yl)amino)-2-azabicyclo[2.2.1]heptan-2-yl)methyl)phenyl)methanesulfonamide; N-((1SR,4SR,6RS)-2-(4-methylbenzyl)-2-azabicyclo[2.2.1]heptan-6-yl)isoquinolin-5-amine; 2-(3-(((1SR,4SR,6RS)-6-(isoquinolin-5-ylamino)-2-azabicyclo[2.2.1]heptan-2-yl) methyl)phenoxy)ethanol; N-((1SR,4SR,6RS)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-6-yl)isoquinolin-5-amine; 4-(4-(((1SR,4SR,6RS)-2-(4-methylbenzyl)-2-azabicyclo[2.2.1]heptan-6-yl)amino)phenyl)-1,2,5-oxadiazol-3-amine; N-((1RS,4RS,5SR)-2-(4-methylbenzyl)-2-azabicyclo[2.2.1]heptan-5-yl)-1H-indazol-5-amine; 2-(5-(((1RS,4RS,5SR)-5-((1H-indazol-5-yl)amino)-2-azabicyclo[2.2.1]heptan-2-yl)methyl)-2-methylphenoxy)ethanol; N-((1RS,4RS,5SR)-2-(3-chlorobenzyl)-2-azabicyclo[2.2.1]heptan-5-yl)-1H-indazol-5-amine; N-((1RS,4RS,5SR)-2-(4-methylbenzyl)-2-azabicyclo[2.2.1]heptan-5-yl)isoquinolin-5-amine; N-(5-((1RS,4RS,5SR)-5-(isoquinolin-5-ylamino)-2-azabicyclo[2.2.1]heptan-2-yl)methyl)-2-methylphenyl)methanesulfonamide; N-((1RS,4RS,5RS)-2-(4-methylbenzyl)-2-azabicyclo[2.2.1]heptan-5-yl)-1H-indazol-5-amine; N-(5-(((1RS,4RS,5RS)-5-(1H-indazol-5-yl)amino)-2-azabicyclo[2.2.1]heptan-2-yl)methyl)-2-methylphenyl)methanesulfonamide; N-((1RS,4RS,5RS)-2-(4-methylbenzyl)-2-azabicyclo[2.2.1]heptan-5-yl)isoquinolin-5-amine; 2-(5-(((1RS,4RS,5RS)-5-(isoquinolin-5-ylamino)-2-azabicyclo[2.2.1]heptan-2-yl)methyl)-2-methylphenoxy)ethanol; N-((1RS,4RS,5RS)-2-(4-fluorobenzyl)-2-azabicyclo[2.2.1]heptan-5-yl)isoquinolin-5-amine; N-((1SR,2RS,4RS)-7-(4-methylbenzyl)-7-azabicyclo[2.2.1]heptan-2-yl)-1H-indazol-5-amine; N-(5-(((1SR,2RS,4RS)-2-((1H-indazol-5-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methyl)-2-methylphenyl)methanesulfonamide; N-((1SR,2RS,4RS)-7-(4-methoxybenzyl)-7-azabicyclo[2.2.1]heptan-2-yl)-1H-indazol-5-amine; N-((1SR,2RS,4RS)-7-(4-methylbenzyl)-7-azabicyclo[2.2.1]heptan-2-yl)isoquinolin-5-amine; 2-(5-(((1SR,2RS,4RS)-2-(isoquinolin-5-ylamino)-7-azabicyclo[2.2.1]heptan-7-yl)methyl)-2-methylphenoxy)ethanol; (1RS,4SR,6RS)—N-(1H-indazol-5-yl)-2-(4-methylbenzyl)-2-azabicyclo[2.2.2]octan-6-amine; 2-(5-(((1RS,4SR,6RS)-6-((1H-indazol-5-yl)amino)-2-azabicyclo[2.2.2]octan-2-yl)methyl)-2-methylphenoxy)ethanol; (1RS,4SR,6RS)—N-(isoquinolin-5-yl)-2-(4-methylbenzyl)-2-azabicyclo[2.2.2]octan-6-amine; N-(5-(((1RS,4SR,6RS)-6-(isoquinolin-5-ylamino)-2-azabicyclo[2.2.2]octan-2-yl)methyl)-2-methylphenyl)methanesulfonamide; (1RS,4SR,6RS)-2-(4-chlorobenzyl)-N-(isoquinolin-5-yl)-2-azabicyclo[2.2.2]octan-6-amine; (1RS,4SR,6SR)—N-(1H-indazol-5-yl)-2-(4-methylbenzyl)-2-azabicyclo[2.2.2]octan-6-amine; 2-(5-(((1RS,4SR,6SR)-6-((1H-indazol-5-yl)amino)-2-azabicyclo[2.2.2]octan-2-yl)methyl)-2-methylphenoxy)ethanol; (1RS,4SR,6SR)—N-(1H-indazol-5-yl)-2-(3-methylbenzyl)-2-azabicyclo[2.2.2]octan-6-amine; (1RS,4SR,6SR)—N-(isoquinolin-5-yl)-2-(4-methylbenzyl)-2-azabicyclo[2.2.2]octan-6-amine; or N-(5-(((1RS,4SR,6SR)-6-(isoquinolin-5-ylamino)-2-azabicyclo[2.2.2]octan-2-yl)methyl)-2-methylphenyl)methanesulfonamide.
12. The compound according to claim 11 , which is N-((1RS,3rs,5SR)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indazol-5-amine; N-((1RS,3rs,5SR)-8-(4-methylbenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indazol-5-amine; 2-(3-(((1RS,3rs,5SR)-3-((1H-indazol-5-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)methyl)phenoxy)ethanol; 2-(5-(((1RS,3rs,5SR)-3-((1H-indazol-5-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-2-methylphenoxy)ethanol; N-((1RS,3sr,5SR)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indazol-5-amine; or N-((1SR,4SR,7RS)-2-benzyl-2-azabicyclo[2.2.1]heptan-7-yl)-1H-indazol-5-amine.
13. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
14. The compound according to claim 12 , which is N-((1RS,3rs,5SR)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indazol-5-amine.