AGENTS FOR TREATING DISORDERS INVOLVING RYANODINE RECEPTORS

1 . A compound of Formula (I):

wherein

each R 1a , R 1b , R 1c , and R 1d is independently alkyl, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, aryl, benzyl, heteroaryl, heterocyclyl, —CN, —NO 2 , —N 3 , —NR 3 R 4 , —OR 5 , —SO 3 H, —SO 2 R 6 , —OSO 2 R 6 , —S(O)R 6 , or —SR 7 , each of which is independently substituted or unsubstituted, or hydrogen or halogen;

R 2 is alkyl, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, aryl, benzyl, heteroaryl, heterocyclyl, —C(O)NR 3 R 4 , —C(O)C(O)NR 3 R 4 , —C(O)R 8 , —C(O)OR 8 , or —C(O)C(O)OR 8 , each of which is independently substituted or unsubstituted;

each R 3 and R 4 is independently alkyl, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, aryl, benzyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen or halogen; or R 3 and R 4 together with the nitrogen atom to which R 3 and R 4 are attached form a heterocyclic or heteroaromatic ring, which is unsubstituted or substituted; and

each R 5 , R 6 , R 7 , and R 8 is independently alkyl, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, aryl, benzyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen or halogen;

or a pharmaceutically-acceptable salt thereof,

provided that

(a) compounds wherein (i) R 1a , R 1b , R 1c , and R 1d are each hydrogen; (ii) R 1b is OH or methoxy; or (iii) R 2 is —C(O)OtBu or —C(O)OCH 2 Ph, are excluded;

(b) when R 1d is methyl, then R 2 is not 4-methoxybenzyl; and

(c) when R 1a is methyl, Cl, CN, or F, or when R 1b is Br, then R 2 is not methyl, —C(═O)H, —C(═O)Me, —C(═O)Et, or —C(═O)Ph.

2 . The compound of claim 1 , wherein at least one of R 1a , R 1b , R 1c , and R 1d is haloalkyl.

3 . The compound of claim 1 , wherein at least one of R 1a , R 1b , R 1c , and R 1d is trifluoromethyl.

4 . The compound of claim 1 , wherein at least one of R 1a , R 1b , R 1c , and R 1d is halogen.

5 - 8 . (canceled)

9 . The compound of claim 1 , wherein at least one of R 1a , R 1b , R 1c , and R 1d is haloalkoxy.

10 . The compound of claim 1 , wherein at least one of R 1a , R 1b , R 1c , and R 1d is trifluoromethoxy.

11 . The compound of claim 1 , wherein R 1a is trifluoromethyl.

12 . The compound of claim 1 , wherein R 1b is trifluoromethyl.

13 . The compound of claim 1 , wherein R 1c is trifluoromethyl.

14 . The compound of claim 1 , wherein R 1d is trifluoromethyl.

15 - 18 . (canceled)

19 . The compound of claim 1 , wherein R 2 is —C(O)NR 3 R 4 .

20 . The compound of claim 0 , wherein R 3 and R 4 together with the nitrogen atom to which R 3 and R 4 are attached form a heterocyclic ring, which is unsubstituted or substituted.

21 . (canceled)

22 . The compound of claim 1 , wherein the compound is of formula II

wherein

R 9 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, benzyl, heterocyclyl, heteroaryl, —C(O)NR 3 R 4 , —C(O)R 8 , or —C(O)OR 8 , each of which is independently substituted or unsubstituted, or hydrogen;

each R 10 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, benzyl, heterocyclyl, heteroaryl, —NR 3 R 4 , —OR 5 , or —SR 7 , each of which is unsubstituted or substituted; and

m is 0, 1, 2, 3, 4, 5, 6, 7, or 8;

or a pharmaceutically-acceptable salt thereof.

23 . The compound of claim 1 , wherein the compound is of formula III

or a pharmaceutically-acceptable salt thereof.

24 . (canceled)

25 . The compound of claim 1 , wherein the compound is piperazin-1-yl(8-(trifluoromethyl)-2,3-dihydrobenzo[f][1,4]thiazepin-4(5H)-yl)methanone, or a pharmaceutically-acceptable salt thereof.

26 . The compound of claim 1 , wherein the compound is piperazin-1-yl(6-(trifluoromethoxy)-2,3-dihydrobenzo[f][1,4]thiazepin-4(5H)-yl)methanone, or a pharmaceutically-acceptable salt thereof.

27 . The compound of claim 1 , wherein the compound is (7,8-difluoro-2,3-dihydrobenzo[f][1,4]thiazepin-4(5H)-yl)(piperazin-1-yl)methanone, or a pharmaceutically-acceptable salt thereof.

28 . The compound of claim 1 , wherein the compound is piperazin-1-yl(7-(trifluoromethyl)-2,3-dihydrobenzo[f][1,4]thiazepin-4(5H)-yl)methanone, or a pharmaceutically-acceptable salt thereof.

29 . (canceled)

30 . The compound of claim 1 , wherein the compound is piperazin-1-yl(7-(trifluoromethoxy)-2,3-dihydrobenzo[f][1,4]thiazepin-4(5H)-yl)methanone, or a pharmaceutically-acceptable salt thereof.

31 - 36 . (canceled)

37 . A method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound of Formula (I):

wherein

each R 1a , R 1b , R 1c , and R 1d is independently alkyl, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, aryl, benzyl, heteroaryl, heterocyclyl, —CN, —NO 2 , —N 3 , —NR 3 R 4 , —OR 5 , —SO 3 H, —SO 2 R 6 , —OSO 2 R 6 , —S(O)R 6 , or —SR 7 , each of which is independently substituted or unsubstituted, or hydrogen or halogen;

R 2 is alkyl, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, aryl, benzyl, heteroaryl, heterocyclyl, —C(O)NR 3 R 4 , —C(O)C(O)NR 3 R 4 , —C(O)R 8 , —C(O)OR 8 , or —C(O)C(O)OR 8 , each of which is independently substituted or unsubstituted;

each R 3 and R 4 is independently alkyl, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, aryl, benzyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen or halogen; or R 3 and R 4 together with the nitrogen atom to which R 3 and R 4 are attached form a heterocyclic or heteroaromatic ring, which is unsubstituted or substituted; and

each R 5 , R 6 , R 7 , and R 8 is independently alkyl, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, aryl, benzyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen or halogen;

or a pharmaceutically-acceptable salt thereof,

provided that

(a) compounds wherein (i) R 1a , R 1b , R 1c , and R 1d are each hydrogen; (ii) R 1b is OH or methoxy; or (iii) R 2 is —C(O)OtBu or —C(O)OCH 2 Ph, are excluded;

(b) when R 1d is methyl, then R 2 is not 4-methoxybenzyl, and

(c) when R 1a is methyl, Cl, CN, or F, or when R b is Br, then R 2 is not methyl, —C(═O)H, —C(═O)Me, —C(═O)Et, or —C(═O)Ph.

38 . The method of claim 37 , wherein the condition is a central nervous system condition.

39 - 60 . (canceled)

61 . The method of claim 37 , wherein the condition is a cardiac condition.

62 . (canceled)

63 . The method of claim 37 , wherein the condition is catecholaminergic polymorphic ventricular tachycardia.

64 . The method of claim 37 , wherein the condition is heart failure.

65 - 75 . (canceled)

76 . The method of claim 37 , wherein the condition is RYR1-related myopathy.

77 - 85 . (canceled)