Compounds for treatment of cardiac arrhythmias and heart failure

1. A compound, or a stereoisomer, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, according to the formula

wherein:

R B is H, aliphatic, —O-aliphatic, —S-aliphatic, —O—C(O)-aliphatic, or halogen;

R C is H or aliphatic;

R D is —(CR 7 2 ) n- X-(CR 7 2 ) m- N(R 4 )R 5 , —(CH 2 ) q SO 3 M, —(CH 2 ) q NH 2 , or —(CH 2 ) q OH;

R E is H, —O-aliphatic, aliphatic, —S-aliphatic, —O—C(O)-aliphatic, or halogen;

Q is C-R 3 ;

X is N(R 6 );

R 1 and R 2 independently are H or aliphatic;

R 3 is H, aliphatic, —O-aliphatic, or —S-aliphatic;

R 4 and R 5 independently are H, aliphatic, aryl or heteroaryl, or R 4 and R 5 together with N form a heterocycloaliphatic or heteroaryl ring;

R 6 is H or aliphatic;

each R 7 independently is H, halogen, or aliphatic;

M is a monatomic cation; and

m, n, and q independently are integers from 1 to 10,

wherein if R D is —(CR 7 2 ) n X—(CR 7 2 ) m —N(R 4 )R 5 , then at least one of the following conditions applies

(i) at least one of R 1 and R 2 is other than H, or

(ii) at least one of R C and R E is other than H, or

(iii) X is other than N(H), or

(iv) m is not 2, or

(v) n is not 1, or

(vi) if Q is CH then R B is not —O-aliphatic, or

(vii) if R B is H then Q is not C-R 3 where R 3 is —O-aliphatic, and

wherein the compound is not.

2. The compound according to claim 1 , wherein

R B is H, aliphatic, —O-aliphatic, —S-aliphatic, or halogen.

3. The compound according to claim 2 , wherein:

R D is —(CR 7 2 ) n- X-(CR 7 2 ) m- N(R 4 )R 5 ; and

X is N(R 6 ) where R 6 is aliphatic.

4. The compound according to claim 1 , wherein:

(i) R 4 and R 5 are alkyl; or

(ii) m is 2, or n is 1, or m is 2 and n is 1; or

(iii) R 6 is H, or each R 7 is H, or R 6 is H and each R 7 is H; or

(iv) any combination thereof.

5. The compound according to claim 1 , wherein

R D is —(CH 2 ) q NH 2 , —(CH 2 ) q OH, or —(CH 2 ) q SO 3 M where q is an integer from 1 to 10 and M is a monatomic cation.

6. The compound according to claim 1 , wherein the compound is:

N 1 -(4-amino-2-methoxybenzyl)-N 2 ,N 2 -diethylethane-1,2-diamine;

3-methoxy-4-(((2-(pyrrolidin-1-yl)ethyl)amino)methyl)aniline;

sodium (4-amino-2-methoxyphenyl)methanesulfonate;

sodium (4-(dibutylamino)-3-methoxyphenyl)methanesulfonate;

sodium (4-amino-3-methoxyphenyl)methanesulfonate;

4-((2-(diethylamino)ethoxy)methyl)-2,3-dimethoxyaniline; or

N 1 -(4-amino-3-methylbenzyl)-N 2 ,N 2 -diethylethane-1,2-diamine.

7. A pharmaceutical composition, comprising:

a therapeutically effective amount of at least one compound according to claim 2 , or a stereoisomer, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof; and

at least one pharmaceutically acceptable additive.

8. A method, comprising:

inhibiting activity of a ryanodine receptor by contacting the ryanodine receptor with an effective amount of a compound according to claim 2 , or a stereoisomer, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof.

9. The method of claim 8 , wherein contacting the ryanodine receptor comprises administering the effective amount of the compound, or stereoisomer, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, to a subject.

10. The method of claim 9 , wherein the subject is a subject identified as having, or being at risk of having, a cardiac arrhythmia or heart failure.

11. The method of claim 8 , wherein the compound is:

N 1 -(4-amino-2-methoxybenzyl)-N 2 ,N 2 -diethylethane-1,2-diamine;

3-methoxy-4-(((2-(pyrrolidin-1-yl)ethyl)amino)methyl)aniline;

sodium (4-amino-2-methoxyphenyl)methanesulfonate; or

any combination thereof.

12. A method for ameliorating at least one sign or symptom of a cardiac arrhythmia or heart failure, the method comprising:

administering one or more therapeutically effective doses of a compound according to claim 1 , or a stereoisomer, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, over an effective period of time to a subject identified as having, or being at risk of having, a cardiac arrhythmia or heart failure, thereby ameliorating at least one sign or symptom of the cardiac arrhythmia or heart failure.

13. The method of claim 12 , wherein the compound is:

N 1 -(4-amino-2-methoxybenzyl)-N 2 ,N 2 -diethylethane-1,2-diamine;

3-methoxy-4-(((2-(pyrrolidin-1-yl)ethyl)amino)methyl)aniline;

sodium (4-amino-2-methoxyphenyl)methanesulfonate; or

any combination thereof.

14. The method of claim 8 , wherein the compound has a calcium spark response IC 50 value within a range of from 20 nM to 500 nM as determined in cells from a catecholaminergic polymorphic ventricular tachycardic (CPVT) mouse model.