MX2008002687A - Agents for preventing and treating disorders involving modulation of the ryr receptors - Google Patents

Abstract

The present invention provides compounds of Formula I, (I) and salts, hydrates, solvates, complexes, and prodrugs thereof. The present invention further provides methods for synthesizing compounds of Formula I. The invention additionally provides pharmaceutical compositions comprising the compounds of Formula I and methods of using the pharmaceutical compositions of Formula I to treat and prevent disorders and diseases associated with the RyR receptors that regulate calcium channel functioning in cells.

Description

AGENTS TO AVOID AND TREAT DISORDERS INVOLVING THE MODULATION OF RYR RECEIVERS This invention is made with government support under NIH government grant number P01 HL 67849-01. As such, the Government of the United States of America may have certain rights in this invention. This application claims the priority of the patent application of the United States of America series number 11 / 212,413, filed on August 25, 2005.

FIELD OF THE INVENTION This invention relates to compounds and their use to prevent and treat disorders and diseases associated with RyR receptors that regulate the calcium channel that functions in cells. More particularly, the invention is described in relation to compounds that are related to 1,4-benzothiazepines and are useful for treating skeletal muscle and cardiac disorders. The invention also discloses pharmaceutical compositions comprising the compounds of articles of manufacture comprising the pharmaceutical compositions.

BACKGROUND OF THE INVENTION The sarcoplasmic reticulum (SR) is a structure in cells that functions, among other things, as a store of specialized intracellular calcium (Ca2 +). The channels in the sarcoplasmic reticulum called ryanodine receptors (RyRs) open and close to regulate the release of calcium from the sarcoplasmic reticulum into the intracellular cytoplasm of the cell. The release of calcium into the cytoplasm from the sarcoplasmic reticulum increases the cytoplasmic calcium concentration. The open probability (Po) of the RyR receptors refers to the possibility that the RyR channel is opened at any time, and therefore is able to release calcium within the cytoplasm from the sarcoplasmic reticulum.

These three types of ryanodine receptors, all of which are highly related calcium channels: RyRl, RyR2, RyR3. RyR1 is predominant in the skeletal muscle as well as in other tissues, RyR2 is found predominantly in the heart as well as in other tissues, and RyR3 is found in the brain as well as in other tissues. The RyR channels are formed by four RyR polypeptides in association with four binding proteins FK506 (FKBPs), specifically FKBP12 (calstabinl) and RKBP12.6 (calstabin2). Calstabin 1 agglutinates RyRl, calstabin2 agglutinates RyR2, and Calstabin 1 agglutinates RyR3. The FKBP proteins (calstabil and calstabin2) agglutinate the RyR channel (one molecule per subunit RyR), stabilize the RyR channel operation, and facilitate the gate coupled between the neighboring RyR channels, thus avoiding the abnormal activation of the channel during the closed state of the channel.

In addition to the calstabin binder proteins, protein kinase A (PKA) also agglutinates to the cytoplasmic surface of RyR receptors. PKA phosphorylation of RyR receptors causes partial dissociation of the RyRs calstabins. The dissociation of calstabin from RyR increases the open probability of RyR, and thus increases the release of calcium from the sarcoplasmic reticulum into the intracellular cytoplasm.

The release of calcium from the sarcoplasmic reticulum in skeletal muscle cells and heart cells is a key physiological mechanism that controls muscle performance, due to the increased concentration of calcium in the intracellular cytoplasm that causes muscle contraction.

The excitation-contraction (EC) coupling in the skeletal muscles involves the electrical depolarization of the plasma membrane in the transverse tubule (T-tubule), which activates gate-voltage type L calcium channels (LTCCs). Calcium triggers the LTCCs released from the sarcoplasmic reticulum through physical interaction with RyRl. The resulting increase in cytoplasmic calcium concentration induces an actin-myocin interaction and muscle contraction. To allow for relaxation, intracellular calcium is pumped back into the sarcoplasmic reticulum via SR Ca2 + -ATPase pumps (SERCAs), which is regulated by phospholamban (PLB) depending on the type of muscle fiber.

It has been shown that the disease forms this result in the sustained activation of the sympathetic nervous system and increases the levels of plasma catecholamine that cause a poorly adapted activation of the intracellular voltage projectors resulting in destabilization of the closed state of the RyR1 channel and the filtering of intracellular calcium. The sarcoplasmic reticulum calcium filtrate through the RyR1 channels was found to deplete intracellular sarcoplasmic reticulum calcium stores, to increase the compensatory energy consumption, and to result in a significant acceleration of muscle fatigue. The stress-induced muscle defect permanently reduces the muscle isolated in the performance in vivo particularly in situations of increased demand.

It has also been shown that the destabilization of the closed state RyRl occurs under pathological conditions of increased sympathetic activation and involves the depletion of the stabilizing channel sub-unit of calstabinl (FKBP12). The proof-of-principle experiments have shown that PKA activation as an end effect of the sympathetic nervous system increases phosphorylation RyRl PKA to Ser-2843 which decreases the binding affinity of calstabinl to RyRl and increases the open probability of channel.

In cardiac striated muscle, RyR2 is the main calcium release channel required for the excitation-contraction and muscle contraction coupling. During the excitation-contraction coupling, the depolarization of the cardiac muscle cell membrane during the zero phase of the potential action activates the gate-voltage calcium channels. The influx of calcium through the open gate-voltage channels in turn initiates the release of calcium from the sarcoplasmic reticulum through RyR2. This process is known as calcium-induced calcium release. The calcium-induced calcium release measured with RyR2 then releases the activities of the contraction proteins in the cardiac cell resulting in a contraction of the cardiac muscle.

Cardiac RyR2 phosphorylation by PKA is an important part of the "fight or fly" response that increases the gain of cardiac excitation-contraction coupling by increasing the amount of calcium released by a given trigger. This signaling path provides a mechanism by which the activation of the sympathetic nervous system, in response to stress, results in an increased cardiac output. PKA phosphorylation of RyR2 increases the open probability of the channel by disassociating calstabin2 (FKBP12.6) from the channel complex. This in turn increases the sensitivity of RyR2 to calcium-dependent activation.

Despite advances in treatment, heart failure remains a major cause of mortality in Western countries. An important finding of heart failure is reduced myocardial contraction. In heart failure, contraction abnormalities result, in part, from alterations in the signaling path that allows cardiac action potential to trigger calcium release through the RyR2 channels and muscle contraction. In particular, in hearts that fail, the transient complete cell calcium amplitude is decreased and the duration prolonged.

Cardiac arrhythmia, a common failure of heart failure results in many of the deaths associated with the disease. Atrial fibrillation (AF) is the most common cardiac arrhythmia in humans, and represents a leading cause of mortality and morbidity. Structural and electrical remodeling, including shortening of atrial refraction, loss of adaptation related to the refractive cup, and shortening of the wavelength of re-entrant waves-accompany sustained tachycardia. This remodeling is feasibly important in the development, maintenance and progression of atrial fibrillation. Studies suggest that calcium management plays a role in electrical remodeling in atrial fibrillation.

Approximately 50% of all patients with heart disease die from fatal cardiac arrhythmias. In some cases, a ventricular arrhythmia in the heart is rapidly fatal-a phenomenon referred to as "sudden cardiac death" (SCD). Fatal ventricular arrhythmias and sudden cardiac death can occur in young or otherwise healthy individuals who do not know they have a structural heart disease. In fact, ventricular arrhythmia is the most common cause of sudden death in otherwise healthy individuals.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited disorder in individuals with structurally normal hearts. This is characterized by a stress-induced ventricular tachycardia-a fatal arrhythmia that causes sudden cardiac death. In subjects with catecholaminergic polymorphic ventricular tachycardia, physical exercise and / or stress induce bidirectional and / or polyformic ventricular tachycardia leading to sudden cardiac death even in the absence of detectable structural heart disease. The inherited catecholaminergic polymorphic ventricular tachycardia in a dominant autosomal form. Individuals with catecholaminergic polymorphic ventricular tachycardia have ventricular arrhythmias when undergoing exercise, but do not develop arrhythmias at rest. Studies have identified mutations in the human RyR2 gene on chromosomes Iq42-q43 in individuals with catecholaminergic polymorphic ventricular tachycardia.

Failing hearts (for example, in patients with heart failure in animal models of heart failure) are characterized by a maladaptive response that includes chronic hyperadrenergic stimulation. In heart failure, chronic beta-adrenergic stimulation is associated with the activation of beta-adrenergic receptors in the heart, which, through coupling with G-proteins, activate adenylyl cyclase and therefore increase the intracellular cAMP concentration . CAMP activates the PKA-dependent cAMP, which has been shown to induce hypersphorylation of RyR2. Therefore, chronic heart failure is a chronic hyperadrenergic state that results in several pathological consequences, including PKA hyperphosphorylation of RyR2.

PKA hyperphosphorylation of RyR2 has been proposed as a factor that contributes to the function of depressed contraction and to arrhythmogenesis in heart failure. Consistent with this hypothesis, PKA hyperphosphorylation of RyR2 in failing hearts has been demonstrated, in vivo, in both animal models and in patients with heart failure who undergo cardiac transplantation.

In failing hearts, hyperphosphorylation of RyR2 by PKA induces the dissociation of FKBP12.6 (calstabin2) of channel RyR2. This causes marked changes in the biophysical properties of the RyR2 channel, including the increased open probability (Po) due to an increased sensitivity of calcium-dependent activation; the destabilization of the channel, resulting in states of sub-conductance; and the damped coupled gate of the channels, resulting in defective extension-contraction coupling and cardiac dysfunction. Therefore, the hyperphosphorylated RyR2 PKA is very sensitive to low level calcium stimulation, and this also manifests itself as a calcium effusion of sarcoplasmic diastolic reticulum through the channel RyR2 hyperphosphorylated PKA.

The maladaptive response to stress in heart failure results in depletion of the FKBP12.6 from the macromolecular channel complex. This leads to a shift to the left in the sensitivity of RyR2 to calcium-induced calcium release, resulting in channels that are more active at low-to-moderate calcium concentrations. Over time, the increased "filtering" through RyR2 results in the relocation of sarcoplasmic reticulum calcium content to a lower level, which in turn reduces the gain of excitation-contraction coupling and contributes to impaired systolic contraction .

Additionally, a sub-population of RyR2 that are particularly "drained" can release sarcoplasmic reticulum calcium during the resting phase of the cardiac cycle, diastole. This results in depolarizations of the cardiomyocyte membrane known as delayed posterior depolarization (DADs), which are known to trigger fatal ventricular cardiac arrhythmias.

In patients with catecholaminergic polymorphic ventricular tachycardia mutations in their RyR2 and in otherwise structurally normal hearts, a similar phenomenon is working. Specifically, it is known that exercise and stress induce the release of catecholamines that activate beta-adrenergic receptors in the heart. Activation of beta-adrenergic receptors leads to PKA hyperphosphorylation of RyR2 channels. The evidence also suggests that PKA hyperphosphorylation of RyR2 results from the activation of the beta-adrenergic receptor that makes the RyR2 channels more feasible to open in the relaxation phase of the cardiac cycle, increasing the possibility of arrhythmias.

Cardiac arrhythmias are known to be associated with diastolic sarcoplasmic reticulum calcium filtrates in patients with catecholaminergic polymorphic ventricular tachycardia mutations and their RyR2 and in otherwise structurally normal hearts. In these cases, the most common mechanism for the induction and maintenance of ventricular tachycardia is abnormal automaticity. In a form of abnormal automaticity, known as triggered arrhythmia is associated with the aberrant release of sarcoplasmic reticulum calcium, which initiates delayed posterior depolarizations. Later delayed depolarizations are abnormal depolarizations in cardiomyocytes that occur after repolarization of a cardiac action potential. The molecular phase of abnormal sarcoplasmic reticulum calcium release resulting in delayed posterior depolarizations has not been fully elucidated. However, delayed posterior depolarizations are known to be blocked by ryanodine, providing evidence that RyR2 plays a key panel in the pathogenesis of this aberrant calcium release.

U.S. Patent No. 6,489,125 discusses JTV-519 (4- [3- (4-benzylpiperidine-1-yl) propionyl] -7-methoxy-2, 3, 4, 5-tetrahydro-l, 4- benzothiazepine monohydrochloride, also known as k201 or ICP-Calstan 100), to 1,4-benzothiazepine, as a new modulator of the calcium ion channels RyR.

The also pending US application number 10 / 763,498 discusses RyR2 as an object to treat and prevent heart failure and cardiac arrhythmias, including atrial fibrillation and cardiac arrhythmias that cause sudden cardiac death induced by exercise (SCD). ). The RyR2 channels with 7 mutations of different catecholaminergic polymorphic ventricular tachycardia (eg, S2246L, R2474S, N4104K, R4497C, P2328S, Q4201R, V4653F) were found to have functional defects that resulted in channels being drained (eg, calcium filtrate) when they are stimulated during exercise. The mechanism for ventricular tachycardia in catecholaminergic polymorphic ventricular tachycardia has been shown to be the same as the mechanism for ventricular tachycardia in heart failure.

It has been found that exercise-induced arrhythmias and sudden death (in patients with catecholaminergic polymorphic ventricular tachycardia) result from a reduced affinity of FKBP12.6 (calstabin2) for RyR2. Additionally, it has been shown that exercise activates RyR2 as a result of phosphorylation by adenosine 3 ', 5' -monophosphate (cAMP) protein dependent kinase (PKA). The RyR2 mutant channels which have a normal function in the flat lipid bilayers under basal conditions, sensitive to activation by PKA-phosphorylation exhibiting increased activity (open probability) and prolonged open states, compared to wild-type channels. In addition, PKR-phosphorylated mutant RyR2 channels were resistant to inhibition by Mg2 +, a physiological inhibitor of the channel, and showed reduced binding to FKBP12.6 (aka calstabin2, which stabilizes the channel in the closed state). These findings indicate that during exercise, when RyR2 is PKA-phosphorylated, mutant catecholaminergic polymorphic ventricular tachycardia channels are more likely to open in the relaxation phase of the cardiac cycle (diastole), increasing the possibility of arrhythmias triggered by the filtrate. of sarcoplasmic reticulum calcium.

Additionally, the pending United States of America patent application 09 / 288,606 discusses a method for regulating the contraction of a subject's heart by administering a compound that regulates PKA phosphorylation of a RyR2 receptor and specifically decreases PKA phosphorylation. U.S. Patent Application also pending 10 / 608,723 also discusses a method for treating and prophylaxis for atrial tachyarrhythmia and stress-induced arrhythmias and exercise by administering an agent which inhibits PKA phosphorylation. RyR2.

SYNTHESIS OF THE INVENTION In view of the foregoing, there is a need to identify new effective agents to treat or avoid the disorders and diseases associated with RyR receptors that regulate the functioning of calcium channel in cells, including skeletal muscle disorders and diseases and especially diseases. and cardiac disorders. More particularly, there is a need to identify new components that can be used to treat the disorders associated with RyR by, for example, repairing the filtrate in the RyR channels, and improving the binding of the proteins.

FKBP (calstabinl and calstabin2) to the PKA-phosphorylated RyR and to the mutant RyR which otherwise has a reduced affinity for, or which does not agglutinate to FKBP12 and FKBP12.6. Embodiments of the invention solve some or all of these needs.

Thus, the present invention generally provides compounds that can be classified as 1,4-benzothiazepines and are sometimes referred to herein as "RyCals".

The present invention also provides compounds of the formula I: Where, n is 0, 1 or 2; q is O, 1, 2, 3 or 4; each R is independently selected from the group consisting of H, halogen, -OH, -NH2, -N02, -CN, -CF3, -OCF3, -N3, -S03H, -S (= 0) 2alkyl, -S (= 0) alkyl, -OS (= 0) 2, CF3, acyl, -O-acyl, alkyl, alkoxy, alkylamino, alkylarylamino, alkylthio, cycloalkyl, alkylaryl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, ) aryl, (hetero-) arylthio, and (hetero-) arylamino; wherein each acyl, -O-acyl, alkyl, alkoxy, alkylamino, alkylarylamino, alkylthio, cycloalkyl, alkylaryl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-) aryl, (hetero-) arylthio, and ( hetero-) arylamino can be optionally substituted; Ri is selected from the group consisting of H, oxo, alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl and heterocyclyl; wherein each alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl, and heterocyclyl can optionally be substituted; R2 is selected from the group consisting of H, -C (= 0) Rs, C (= S) R6, -SO2R7, -P (= O) R8R9, - (CH2) m-R10, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl, cycloalkylalkyl, and heterocyclyl; wherein each alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl, cycloalkylalkyl and heterocyclyl can be optionally substituted; R3 is selected from the group consisting of H, -C02Y, -C (= 0) NHY, acyl, -O-acyl, alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl, and heterocyclyl; wherein each alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl and heterocyclyl can be optionally substituted; and wherein Y is selected from the group consisting of H, alkyl, aryl, alkylaryl, cycloalkyl, heteroaryl and heterocyclyl and wherein each alkyl, aryl, alkylaryl, cycloalkyl, heteroaryl and heterocyclyl can be optionally substituted; R is selected from the group consisting of H, alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl, and heterocyclyl; wherein each alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl and heterocyclyl can be optionally substituted; R5 is selected from the group consisting of -R15R16, - (CH2) qNR15Ri6, -NHOH, -OR15, -C (= 0) NHNR15R? 6, -C02R15, -C (= 0) NR15R? 6, -CH2X, acyl , alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, and heterocyclylalkyl; wherein each acyl, alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, and heterocyclylalkyl can optionally be substituted, and wherein q is 1, 2, 3, 4, 5 or 6; * Rd is selected from the group consisting of -OR15, -NHNR15R16, -NHOH, -NR15R16, -CH2X, acyl, alkenyl, alkyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, and heterocyclylalkyl; wherein each acyl, alkenyl, alkyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, and heterocyclylalkyl may optionally be substituted; R is selected from the group consisting of -OR15, -R? 5R? 6, -NH R15R16, -NHOH, -CH2X, alkyl, alkenyl, alkynyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, and heterocyclylalkyl, wherein each alkyl, alkenyl, alkynyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, and heterocyclylalkyl can optionally be substituted; R8 and R9 independently are selected from the group consisting of OH, acyl, alkenyl, alkoxy, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkyalkyl, heteroaryl, heterocyclyl, and heterocyclylalkyl; in each acyl, alkenyl, alkoxy, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkalkyl, heteroaryl, heterocyclyl, and heterocyclylalkyl may optionally be substituted; Rio is selected from the group consisting of -NR15R16, OH, M-SO2Ru, -NHSO2R ?, C (= 0) R? 2), NHC = 0 (Ri2), -0C = 0 (R12), and -P (= 0) R? 3R? 4; Rii Ri2 / R13 and Ri4 independently are selected from the group consisting of H, OH, NH2, -NHNH2, -NHOH, acyl, alkenyl, alkoxy, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, and heterocyclylalkyl; wherein each acyl, alkenyl, alkoxy, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, and heterocyclylalkyl may be optionally substituted; X is selected from the group consisting of halogen-CN, -C02R15, -C (= 0) NR15Ri6, -ORi5, -S02R7, and -P (= 0) R8R9; Y R15 and RI independently are selected from the group consisting of H, acyl, alkenyl, alkoxy, OH, NH2, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkyalkyl, heteroaryl, heterocyclyl, and heterocyclylalkyl; wherein each acyl, alkenyl, alkoxy, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkyalkyl, heteroaryl, heterocyclyl, and heterocyclylalkyl may be optionally substituted, and optionally R15 and Ri6 together with the N which are attached to form a heterocycle which can be substituted; the nitrogen in the benzothiazepine ring can optionally be a quaternary nitrogen; and the enantiomeric, diastereomeric, tautomeric, pharmaceutically acceptable salts, hydrates, solvates, complexes and prodrugs thereof; whenever q is 0 and n is 0, then R2 is not H, Et, C (= 0) NH2, (= 0) NHPh, -C (= S) NH-nButyl, -C (= 0) NHC (= 0) ) CH2C1, -C (= 0) H, -C (= 0) Me, -C (= 0) Et, -C (= 0) CH = CH2, -S (= 0) 2Me, or -S (= 0) 2Et; as long as q is 0 and n is 1 or 2, then R2 is not -C (= 0) Me, -C (= 0) Et, -S (= 0) 2Me, or -S (= 0) 2Et; also provided that when q is 1, and R is Me, Cl, or F in the 6-position of the benzothiazepine ring, then R2 is not H, Me, -C (= 0) H, -C (= 0) Me, -C (= 0) Et, -C (= 0) Ph, -S (= 0) 2, Me, or -S (= 0) 2Et; Y also provided that when q is 1, n is 0, and R is OCT3, OH, C 1 -C 3 alkoxy at position 7 of the benzothiazepine ring, then R 2 is not H, -C (= 0) CH = CH 2 or In one embodiment, the present invention provides compounds of the formula I, as described above, with the proviso that the compound is not S24 or S68.

In an embodiment of the present invention, compounds of the formula I-a are provided: Where: n is 0, 1 or 2; q is 0, 1, 2, 3, or 4; each R is independently selected from the group consisting of H, halogen, -OH, -NH2, -N02, -CN, -CF3, -OCF3, -N3, -S03H, -S (= 0) 2alkyl, -S (= 0) alkyl, -OS (= 0) 2, CF3, acyl, alkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-) aryl, (hetero-) arylthio, and ( hetero-) arylamino; wherein each acyl, alkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-) aryl, (hetero-) arylthio, and (hetero-) arylamino can be substituted or unsubstituted; R2 is selected from the group consisting of H, -C (= 0) R5, C (= S) R6, -S02R7, -P (= 0) R8R9, - (CH2) mR? O, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl, cycloalkylalkyl, and heterocyclyl; wherein each alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl, cycloalkylalkyl and heterocyclyl can be optionally substituted or unsubstituted; R5 is selected from the group consisting of -NR? 5R? 6 _NR? 5R? 6, -NHOH, -OR15, -C (= 0) NHNR? 5R? 6, -C02R? 5, -C (= 0) NR ? 5R? 6, -CH2X, acyl, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; where each; acyl, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl can be substituted or unsubstituted; Rd is selected from the group consisting of -0Ri5, -NHNR? 5R? 6, -NHOH, -NR15R16, -CH2X, acyl, alkenyl, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each acyl, alkenyl, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl can be substituted or unsubstituted; R7 is selected from the group consisting of H, -OR15, -NR? 5R? 6, -NHNR15R16, -NHOH, -CH2X, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each alkyl , alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl can optionally be substituted unsubstituted; R8 and Rg independently are selected from the group consisting of OH, acyl, alkenyl, alkoxy, alkyl, alkylamino, aryl, cycloalkyl, cycloalkyalkyl, heterocyclyl, and heterocyclylalkyl; in each acyl, alkenyl, alkoxy, alkyl, alkylamino, aryl, cycloalkyl, cycloalkyalkyl, heterocyclyl, and heterocyclylalkyl can optionally be substituted unsubstituted; Rio is selected from the group consisting of -NR? 5R? 6, OH, -SO2R?, - NHSO2R?, - C (= 0) R? 2, -NH (C = O) R? 2, -O (C = O) R12, and -P (= 0) Ri3R? 4; m is 0, 1, 2, 3, or 4; Rii / R12 R13 and R1 independently are selected from the group consisting of H, OH, NH2, -NHNH2, -NHOH, acyl, alkenyl, alkoxy, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each acyl, alkenyl, alkoxy, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be optionally substituted or unsubstituted; X is selected from the group consisting of halogen, -CN, -C02Ri5, -C (= 0) NR? 5Ri6, -NRi5Ri6, -ORi5, -S02R7 and -P (= 0) R8R9; Y R15 and Ri6 independently are selected from the group consisting of H, acyl, alkenyl, alkoxy, OH, NH2, alkyl, alkylamino, aryl, cycloalkyl, cycloalkyalkyl, heterocyclyl, and heterocyclylalkyl; wherein each acyl, alkenyl, alkoxy, alkyl, alkylamino, aryl, cycloalkyl, cycloalkyalkyl, heterocyclyl, and heterocyclylalkyl can be substituted, and optionally R 5 and Ri 6 together with N which are linked to form a heterocycle which it can be replaced; the nitrogen in the benzothiazepine ring can optionally be a quaternary nitrogen; and enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, complexes and prodrugs thereof; provided that when q is 0 and n is 0, then R2 is not H, Et, -C (= 0) NH2, (= 0) NHPh, -C (= S) NH-nButyl, -C (= 0) NHC ( = 0) CH2C1, -C (= 0) H, -C (= 0) Me, -C (= 0) Et, -C (= 0) CH = CH2, -S (= 0) 2Me, or -S (= 0) 2Et; furthermore, provided that when q is 0 and n is 1 or 2, then R2 is not -C (= 0) Me, -C (= 0) Et, -S (= 0) 2Me, or -S (= 0) 2Et; also provided that when q is 1, and R is Me, Cl, or F in position 6 of the benzothiazepine ring, then R2 is not H, Me, -C (= 0) H, -C (= 0) Me, -C (= 0) Et, -C (= 0) Ph, -S (= 0) 2, Me, or -S (= 0) 2Et; Y further provided that when q is 1, n is 0, and R is 0CT3, OH, C? -C3 alkoxy at position 7 of the benzothiazepene ring, then R2 is not H, -C (= 0H) CH = CH2, or In certain embodiments of the present invention there are provided compounds of formula Ia, wherein each R is independently selected from the group consisting of H, halogen, -OH-OMe, -NH2, -N02, -CN, -CF3, -OCF3 -N3, -S (= 0) 2 C? -C4 alkyl, -S (= 0) C? -C4 alkyl, -S-C? -C4 alkyl, -OS (= 0) 2CF3, Ph, -NHCH2Ph, -C (= 0) Me, -OC (= 0) Me, morpholinyl and propenyl and n is 0, 1 or 2.

In other embodiments, the present invention provides compounds of the formula Ia, wherein R2 is selected from the group consisting of -C = 0 = 0 (R5), -C = S (Re), -S02R7, -P (P = 0) R8, R9, and - (CH2) mR? O.

In yet another embodiment, the present invention provides compounds of I-b: wherein R 'and R "are independently selected from the group consisting of H, halogen, -OH, -NH2-N02, -CN-CF3, -OCF3, -N3, -S03H, -S (= 0) 2alkyl, -S (= 0) alkyl, -OS (= 0) 2 CF 3, acyl, alkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-) aryl, (hetero-) arylthio, and (hetero-) arylamino; and wherein each acyl, alkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-) aryl, (hetero-) arylthio, and (hetero-) arylamino can be substituted or unsubstituted; R2 and n are as defined in the compounds of the formula I-a above; And the enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, complexes and pro-drugs thereof.

In certain embodiments, the present invention provides compounds of formula Ib wherein R 'and R "are independently selected from the group consisting of H, halogen, -OH, OMe, -NH2, -N02-CH, -CF3, - 0CF3, -N3, -S (= 0) 2 C? -C4 alkyl, -S (= 0) C? -C alkyl, -S- C? -C4 alkyl, -OS (= 0) 2CF3, Ph, - NHCH2Ph, -C (= 0) Me, -OC (= 0) Me, morpholinyl and propenyl; and n is 0, 1 or 3. In some cases, R 'is H or OMe, and R "is H.

In other embodiments, the present invention provides compounds of the formula Ib, wherein R2 is selected from the group consisting of -C = 0 (R5), -C = S (Rβ), -S02R7, -P (= 0) R8R9 , and - (CH2) mR? o- In yet another embodiment, the present invention provides compounds of the formula I-c: wherein each R, R, q and n are as defined in the compounds of formula I-a given above; and the enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, complexes and pro-drugs thereof.

In certain embodiments, the present invention provides compounds of formula IC, wherein R is independently selected from the group consisting of H, halogen, -OH, OMe, -NH2, -N02-CH, -CF3, -0CF3, -N3 , -S (= 0) 2 C? -C4 alkyl, -S (= 0) C? -C4 alkyl, -S- C? -C4 alkyl, -OS (= 0) 2CF3, Ph, -NHCH2Ph, -C (= 0) Me, -OC (= 0) Me, morpholinyl and propenyl; and n is 0, 1 or 2.

In other embodiments, the present invention provides compounds of the formula I-c, wherein R7 is selected from the group consisting of -OH, -NR? 5R? 6, alkyl, alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each alkyl, alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl can be substituted or unsubstituted.

In a further embodiment, the present invention provides compounds of the formula I-d: wherein R 'and R "are independently selected from the group consisting of H, halogen, -OH, -NH2-N02, -CN-CF3, -OCF3, -N3, -S03H, -S (= 0) 2alkyl, -S (= 0) alkyl, -OS (= 0) 2 CF 3, acyl, alkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-) aryl, (hetero-) arylthio, and (hetero-) arylamino; and wherein each acyl, alkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-) aryl, (hetero-) arylthio, and (hetero-) arylamino can be substituted or unsubstituted; R7 and n are as defined in the compounds of the formula I-a; and the enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, complexes and pro-drugs thereof.

In certain embodiments, the present invention provides compounds of the formula Id, wherein R 'and R "are independently selected from the group consisting of H, halogen, -OH, OMe, -NH2, -N02-CH, -CF3, -0CF3, -N3, -S (= 0) 2 alkyl C? -C4, -S (= 0) C? -C4 alkyl, -S- C? -C alkyl, -OS (= 0) 2CF3, Ph, -NHCH2Ph, -C (= 0) Me, -OC ( = 0) Me, morpholinyl and propenyl; and n is 0, 1 or 3. In some cases, R 'is H or OMe, and R "is H.

In other embodiments, the present invention provides compounds of the formula I-d, wherein R7 is selected from the group consisting of -OH, -NR? 5R? 6, alkyl, alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each alkyl, alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl can be substituted or unsubstituted.

In one embodiment, the present invention provides compounds of formula I-e: wherein each R, R5, q and n is like the defined compounds of the formula I-a given above; and the enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, complexes and pro-drugs thereof.

In certain embodiments of the present invention there are provided compounds of the formula Ie, wherein each R is independently selected from the group consisting of H, halogen, -OH, OMe, -NH2, -N02-CH, -CF3, -0CF3, -N3, -S (= 0) 2 C? -C4 alkyl, -S (= 0) C? -C4 alkyl, -S- C? -C4 alkyl, -OS (= 0) 2CF3, Ph, -NHCH2Ph, -C (= 0) Me, -OC (= 0) Me, morpholinyl and propenyl; and n is 0, 1 or 2.

In other embodiments, the present invention provides compounds of the formula Ie, wherein R5 is selected from the group consisting of -NR? 5R? 6, -NHOH, -OR15, -CH2X, alkyl, alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl; wherein each alkyl, alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl can be substituted or unsubstituted.

In some embodiments, the present invention provides compounds of the formula I-e, wherein R 5 is an alkyl substituted with at least one labeling group, such as a fluorescer, a bioluminescent, a chemiluminescent, a colorimetric and a radioactive labeling group. A fluorescent labeling group can be selected from bodipy, dansil, fluorescein, rhodamine, Texas red, cyanine dyes, pyrene, coumarin, Cascade® blue, Pacific blue, marine blue, Oregon green, 4 ', 6-diamidino-2-phenylindole. (DAPI), indopira dyes, lucifer yellow, propidium iodine, porphyrins, arginine and variants and derivatives thereof.

In another embodiment, the present invention provides compounds of the formula I-f: wherein R 'and R "are independently selected from the group consisting of H, halogen, -OH, -NH2-N02, -CN-CF3, -0CF3, -N3, -S03H, -S (= 0) 2alkyl, -S (= 0) alkyl, -OS (= 0) 2 CF 3, acyl, alkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-) aryl, (hetero-) arylthio, and (hetero-) arylamino; and wherein each acyl, alkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-) aryl, (hetero-) arylthio, can be substituted or unsubstituted; R5 and n are as defined in the compounds of the formula I-a above; and enantiomers and diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, complexes and pro-drugs thereof.

In certain embodiments, the present invention provides compounds of the formula If, wherein R 'and R "are independently selected from the group consisting of H, halogen, -OH, OMe, -NH2, -N02-CH, -CF3, -0CF3, -N3, -S (= 0) 2 C? -C4 alkyl, -S (= 0) C? -C alkyl, -S- Cx-C alkyl, -OS (= 0) 2CF3, Ph, - NHCH2Ph, -C (= 0) Me, -0C (= 0) Me, morpholinyl and propenyl; and n is 0, 1 or 3. In some cases, R 'is H or OMe, and R "is H.

In other embodiments, the present invention provides compounds of the formula If, wherein R5 is selected from the group consisting of -NR? 5R? 6, -NHOH, -OR15, -CH2X, alkyl, alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl; wherein each alkyl, alkenyl, aryl, cycloalkyl, cycloalkyl, heterocyclyl and heterocyclylalkyl can be substituted or unsubstituted.

In some other embodiment, the present invention provides compounds of the formula I-g: (i-gl where S is 0, each R, R? 5, R? 6, qyn is as defined in the compounds of formula Ia, given above, and the enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, complexes and pro-drugs thereof.

In certain embodiments, the present invention provides compounds of the formula Ig, wherein each R is independently selected from the group consisting of H, halogen, -OH, OMe, -NH2, -N02-CH, -CF3, -0CF3, - N3, -S (= 0) 2 C? -C4 alkyl, -S (= 0) C? -C4 alkyl, -S- C? -C4 alkyl, -OS (= 0) 2CF3, Ph, -NHCH2Ph, - C (= 0) Me, -0C (= 0) Me, morpholinyl and propenyl; and n is 0, 1 or 2.

In other embodiments, the present invention provides compounds of formula I-g, wherein R15 and R independently are selected from the group consisting of H, OH, NH2, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl can be substituted; and optionally R15 and Ri6 together with the N to which they are attached can form a heterocycle which can be substituted.

In some embodiments, the present invention provides compounds of formula I-g, wherein W is 0 or S.

In yet another embodiment, the present invention provides compounds of the formula I-h: where is S ú 0; wherein R 'and R "are independently selected from the group consisting of H, halogen, -OH, -NH2-N02, -CN-CF3, -0CF3, -N3, -S03H, -S (= 0) 2alkyl, -S (= 0) alkyl, -OS (= 0) 2 CF 3, acyl, alkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-) aryl, (hetero-) arylthio, and (hetero-) arylamino; and wherein each acyl, alkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-) aryl, (hetero-) arylthio, can be substituted or unsubstituted; R15 and íe and n are as defined in the compounds of the formula-a given above; and the enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, complexes and pro-drugs thereof.

In certain embodiments, the present invention provides compounds of formula Ih, wherein R 'and R "are independently selected from the group consisting of H, halogen, -OH, OMe, -NH2, -N02-CH, -CF3, -OCF3, -N3, -S (= 0) 2 C? -C4 alkyl, -S (= 0) C? -C4 alkyl, -S- C? -C4 alkyl, -OS (= 0) 2CF3, Ph, -NHCH2Ph, -C (= 0) Me, -0C (= 0) Me, morpholinyl and propenyl; and n is 0, 1 or 3. In some cases, R 'is H or OMe, and R "is H.

In other embodiments, the present invention provides compounds of formula I-h, wherein R15 and R6 are independently selected from the group consisting of H, OH, NH2, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl can be substituted, and optionally Ri5 and Ri6 together with the N to which these are attached can form a heterocycle which can be substituted.

In some embodiments, the present invention provides compounds of formula I-g, wherein W is 0 or S.

In other embodiments, the present invention provides compounds of the formula I-i: wherein R17 is selected from the group consisting of -NR? 5R? 6, -NHNR15R16, -NHOH, -ORi5, -CH2X, alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl can be substituted or unsubstituted;each R, q and n is defined as in the compounds of the formula I-a given above; the enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, complexes and pro-drugs thereof.

In certain embodiments, the present invention provides compounds of the formula Ii, wherein each R is independently selected from the group consisting of H, halogen, -OH, OMe, -NH2, -N02-CH, -CF3, -0CF3, - N3, -S (= 0) 2 C? -C4 alkyl, -S (= 0) C? -C alkyl, -S- C? -C4 alkyl, -OS (= 0) 2CF3, Ph, -NHCH2Ph, - C (= 0) Me, -OC (= 0) Me, morpholinyl and propenyl; and n is 0, 1 or 2.

In other embodiments, the present invention provides compounds of the formula 1-i, wherein Ri7 is -NR15R16, and -OR15. In certain other embodiments, Ri7 is -OH, OMe, -NEt, -NHEt, -NHPh, -NH2, or -NHCH2pyridyl.

In one embodiment, the present invention provides compounds of the formula I-j: wherein R 'and R "are independently selected from the group consisting of H, halogen, -OH, -NH2-N02, -CN-CF3, -OCF3, -N3, -S03H, -S (= 0) 2alkyl, -S (= 0) alkyl, -OS (= 0) 2 CF 3, acyl, alkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-) aryl, (hetero-) arylthio, and (hetero-) arylamino; and wherein each acyl, alkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-) aryl, (hetero-) arylthio, can be substituted or unsubstituted; R17 is selected from the group consisting of -NR? 5R? 6, NHNR15R16, -NHOH, -OR15, -CH2X, alkenyl, aryl, cycloalkyl, cycloalkyalkyl, heterocyclyl, and heterocyclylalkyl; wherein each alkenyl, aryl, cycloalkyl, cycloalkyalkyl, heterocyclyl, and heterocyclylalkyl can be substituted or unsubstituted; n is as defined in the compounds of the formula I-a; Y enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, complexes and pro-drugs thereof.

In certain embodiments, the present invention provides compounds of the formula Ij, wherein R 'and R "are independently selected from the group consisting of H, halogen, -OH, OMe, -NH2, -N02-CH, - CF 3, -OCF 3, -N 3, -S (= 0) 2 C 1 -C 4 alkyl, -S (= 0) C 1 -C 4 alkyl, -S- C 1 -C 4 alkyl, -OS (= 0) 2 CF 3, Ph, -NHCH2Ph, -C (= 0) Me, -OC (= 0) Me, morpholinyl and propenyl; and n is 0, 1 or 3. In some cases, R 'is H or OMe, and R "is H.

In other embodiments, the present invention provides compounds of the formula I-i, wherein R 7 is -NR 15 R 16, and -OR 15. In certain other embodiments, R7 is -OH, OMe, -NEt, -NHEt, -NHPh, -NH2, or -NHCH2pyridyl.

In another embodiment of the present invention, compounds of the formula I-k are provided: wherein R 'and R "are independently selected from the group consisting of H, halogen, -OH, -NH2-N02, -CN-CF3, -OCF3, -N3, -S03H, -S (= 0) 2alkyl, -S (= 0) alkyl, -OS (= 0) 2 CF 3, acyl, alkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-) aryl, (hetero-) arylthio, and (hetero-) arylamino; and wherein each acyl, alkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-) aryl, (hetero-) arylthio, can be substituted or unsubstituted; RIA is selected from the group consisting of -NR? 5R? 6, -C (= 0) NR? 5R? 6, - (C = 0) OR? 5, -ORi5, alkyl, aryl, cycloalkyl, heterocyclyl and a group tagger; wherein each alkyl, aryl, cycloalkyl, heterocyclyl can be substituted or unsubstituted; wherein p is 1, 2 3, 4, 5, 6, 7, 8, 9, or 10; and n is 0, 1 or 2; and the enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, complexes and pro-drugs thereof.

In certain embodiments, the present invention provides compounds of formula Ik, wherein R 'and R "are independently selected from the group consisting of H, halogen, -OH, OMe, -NH2, -N02-CH, -CF3, -OCF3, -N3, -S (= 0) 2 C? -C4 alkyl, -S (= 0) C? -C alkyl, -S- C? -C4 alkyl, -OS (= 0) 2CF3, Ph, -NHCH2Ph, -C (= 0) Me, -OC (= 0) Me, morpholinyl and propenyl; and n is 0, 1 or 3. In some cases, R 'is H or OMe, and R "is H.

In other embodiments, the present invention provides compounds of the formula I-k, wherein R8 is selected from the group consisting of -R15R16, - (C = 0) OR15, -OR15, alkyl, aryl and at least one labeling group; and wherein each alkyl and aryl can be substituted or unsubstituted. In some cases, m is 1, and R 8 is Ph, C (= 0) OMe, C (= 0) OH, aminoalkyl, NH 2, NHOH, or NHCbz. In some cases, m is 0, and Ris is C? -C alkyl, such as Me, Et, propyl, and butyl. In still other cases, m is 2, and R8 is pyrrolidine, piperidine, piperazine or morpholine. In some embodiments, m is 3, 4, 5, 5, 7, or 8 and Ris is a fluorescent labeling group selected from the group consisting of bodipile, dansyl, fluorescein, rhodamine, Texas red, cyanine dyes, pyrene, coumarins, blue Cascade®, Pacific Blue, Navy Blue, Oregon Green, 4 ', 6-Diamidino-2-phenylindole (DAPI), indopira dyes, lucifer yellow, propidium iodine, porphyrins, arginine and variants and derivatives thereof.

In yet another embodiment, the present invention provides compounds of the formula 1-1: wherein R 'and R "are independently selected from the group consisting of H, halogen, -OH, -NH2-N02, -CN-CF3, -0CF3, -N3, -S03H, -S (= 0) 2alkyl, -S (= 0) alkyl, -OS (= 0) 2 CF 3, acyl, alkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-) aryl, (hetero-) arylthio, and (hetero-) arylamino; and wherein each acyl, alkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-) aryl, (hetero-) arylthio, can be substituted or unsubstituted; Re and n are defined in compounds of formula I-a; and enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, complexes and pro-drugs thereof.

In certain embodiments, the present invention provides compounds of formula 1-1, wherein R 'and R "are independently selected from the group consisting of H, halogen, -OH, OMe, -NH2, -N02-CH, - CF3, -OCF3, -N3, -S (= 0) 2 C? -C4 alkyl, -S (= 0) C? -C4 alkyl, -S- C? -C4 alkyl, -OS (= 0) 2 CF3, Ph, -NHCH2Ph, -C (= 0) Me, -0C (= 0) Me, morpholinyl and propenyl; and n is 0, 1 or 3. In some cases, R 'is H or OMe, and R "is H.

In other embodiments, the present invention provides compounds of the formula 1-1, wherein Re is selected from the group consisting of -NR? 5R? 6, -NHNR? 5R? 6, -OR15, -NHOH, -CH2X- acyl , alkenyl, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each acyl, alkenyl, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl can be substituted or unsubstituted. In some cases, R6 is -NR? 5R? 6 such as -NHPh, pyrrolidine, piperidine, piperazine, morpholine and the like. In other cases, R6 is alkoxy, such as -0-tBu.

In a further embodiment, the present invention provides compounds of the formula I-m: wherein R 'and R "are independently selected from the group consisting of H, halogen, -OH, -NH2-N02, -CN-CF3, -OCF3, -N3, -S03H, -S (= 0) 2alkyl, -S (= 0) alkyl, -OS (= 0) 2 CF 3, acyl, alkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-) aryl, (hetero-) arylthio, and (hetero-) arylamino; and wherein each acyl, alkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-) aryl, (hetero-) arylthio, can be substituted or unsubstituted; R8, R9 and n are as defined in compounds of formula I-a given above, and enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, dodolvates, compeljos and pro-drugs thereof.

In certain embodiments, the present invention provides compounds of the formula Im, wherein R 'and R "are independently selected from the group consisting of H, halogen, -OH, OMe, -NH2, -N02-CH, -CF3, -0CF3, -N3, -S (= 0) 2 alkyl C? -C4, -S (= 0) C? -C alkyl, -S- C? -C4 alkyl, -OS (= 0) 2CF3, Ph, -NHCH2Ph, -C (= 0) Me, -OC ( = 0) Me, morpholinyl and propenyl; and n is 0, 1 or 3. In some cases, R 'is H or OMe, and R "is H.

In other embodiments, the present invention provides compounds of formula I-m, wherein R 8 and R g are independently alkyl, aryl, -OH, alkoxy, or alkylamino.

In some cases, R 8 is C 1 -C 4 alkyl such as Me, Et, propyl and butyl; and Rg is aryl such as phenyl.

In some embodiment, the compound is selected from the group consisting of SI, S2, S3, S4, S5, S6, S7, S9, Sil, S12, S13, S14, S19, S20, S22, S23, S25, S26, S36. , S37, S38, S40, S43, S44, S45, S46, S47, S48, S49, S50, S52, S53, S54, S55, S56, S57, S58, S59, S60, S61, S62, S63, S64, S66 , S67, S68, S69, S70, S71, S72, S73, S74, S75, S76, S77, S78, S79, S80, S81, S82, S83, S84, S85, S87, S88, S89, S90, S91, S92 , S93, S94, S95, S96, S97, S98, S99, SlOO, S101, S102, S104, S105, S107, S108, S109, S110, S110, S112, S113, S114, S115, S116, S117, S118, S119 , S120, S121, S122 and S123.

The compounds of the invention may optionally comprise a labeling group, such as a fluorescent, bioluminescent, chemiluminescent, colorimetric group or a radioactive labeling group. Suitable fluorescent labeling groups include, but are not limited to, bodipi, densil, fluorescein, rhodamine, Texas red, cyanine, pyrene, coumarin, Cascade® blue, Pacific blue, marine blue, Oregon green, 6-diamidino-2 dyes. phenylindole (DAPI), indopira dyes, lucifer yellow, propidium iodine, porphyrins and variants and derivatives thereof. One skilled in the art can easily select an appropriate marker or labeling group, and conjugate such a labeling group to any of the compounds of the invention without undue experimentation.

The present invention also provides methods for the synthesis of the compounds of formula I, I-a, I-b, I-c, I-d. I-e, I-f, I-g, I-h, I-i, I-j, I-k, 1-1 and I-m, and salts, hydrates, solvents and complexes and pro-drugs thereof.

The present invention further provides a method for treating or preventing various disorders and diseases in a subject that are associated with the R and R receptors such as cardiac and muscular disorders, which comprises administering to the subject a quantity of the effective compound to prevent or treat a disorder, or disease associated with RyR receptors, wherein the compound is of Formula I, Ia, Ib, Ic, Id. I-e, I-f, I-g, I-h, I-i, I-j, I-k, 1-1 or I-m, or salts, hydrates, solvents, complexes and pro-drugs thereof.

A method is also provided for avoiding or treating a filtrate at a RyR2 receptor in a subject, including administering to the subject an amount of the effective compound to prevent or treat a filtrate at the RyR2 receptor wherein the compound of Formula I, Ia, Ib, Ic, Id. I-e, I-f, I-g, I-h, I-i, I-j, I-k, 1-1 or I-m, or salts, hydrates, solvents, complexes and pro-drugs thereof. The subject is, for example, a system in Vitro (for example tissues or cultured cells) or a live system (for example animal or human).

In addition, the present invention provides a method of modulating the binding of RyR and FKBP in a subject including administering to the subject an amount of an effective compound for modulating the level of RyK-bound FKBP, wherein the compound is of Formula I, Ia, Ib, Ic, Id. I-e, I-f, I-g, I-h, I-i, I-j, I-k, 1-1 or I-m, or salts, hydrates, solvents, complexes and pro-drugs thereof. The subject is like for example, a In Vitro system (for example, tissues or cultured cells) or a live system (for example animal or human).

The present invention also provides articles of manufacture for treating and preventing disorders and diseases associated with RyR receptors, such as muscular and cardiac disorders in a subject. The articles of manufacture comprise a pharmaceutical composition of one or more of the compounds of Formula I, I-a, I-b, I-c, I-d. I-e, I-f, I-g, I-h, I-i, I-j I-k, 1-1 or I-m, or salts, hydrates, solvents, complexes and pro-drugs thereof. The articles of manufacture are packaged with indications for various disorders that are capable of treating and / or avoiding pharmaceutical compositions.

Other features and advantages of the present invention will be apparent from the detailed description that follows. It should be understood, however, that the detailed description and specific examples even when indicating several embodiments in the invention are given by way of illustration only, since various changes and modifications may be made within the spirit and scope of the invention as being apparent to those experts in the art of the description that follows.

BRIEF DESCRIPTION OF THE FIGURES Figure 1, incorporations A, B, C, and D are, respectively, (A) immunoblots of phosphorylated RyR2 PKA in the presence of FKBP12.6 and increasing concentrations of JTV-519; (B9) RyR2 PKA phosphorylated immunostains in the presence of 0.5nM S36; (C) a plot of a current through a plasma membrane, the voltage dependent of the dependent L-type calcium channels which are completely blocked by nifedipine but not by S36 in isolated mouse cardiomyocytes; And (D) a graph of voltage dependence of the L-type calcium current in channels in the presence of JTV-519 and S36.

Figure 2, incorporations A, B, C, and D demonstrate the prevention of exercise-induced ventricular arrhythmias by JTV-519 in calstabin (FKBP12.6) + ~ haploinsufficient mice. Incorporation A are representative telemetric electrocardiograms (ECGs) of a mouse (left) not treated with calstabin 2 (FKBP12.6) + ", a mouse (middle) calstabin2 (FKBP12.6) + ~ treated with JTV-519, a mouse (right) (FKBP12.6) + ~ calstabin 2. Incorporation B are telemetric recordings of a sustained polymorphic ventricular tachycardia (SVT) in a calstabin 2 mouse (FKBP12.6) + ~ untreated haploinsufficient and a mouse calstabin 2 (FKBP12.6) + ~ JTV-519-treated, each subject to an exercise test immediately after injection with 0.5 milligrams of epinephrine per kilogram of body weight. Incorporation C are graphs showing the numbers of mice with cardiac death (left) sustained ventricular tachycardia (medium) and nonsustained ventricular tachycardia (right) in experimental groups of mice undergoing exercise and injection testing with 0.5 mg. / kilogram of epinephrine. Incorporation D provides graphs comparing the dose dependence of the pharmacological effects of JTV-519 and S36 in relation to sudden cardiac death (left) sustained ventricular tachycardia (middle) and nonsustained ventricular tachycardia (right).

Figure 3 is a graph showing the fractional shortening (FS) of the left ventricle evaluated by M-mode echocardiography two weeks after myocardial infarction in placebo against mice treated with S36. S36 treated mice show a significant improvement in the lOOnM and 200 nM groups compared to placebo.

Figure 4 is a graph showing the weight proportions of the heart to body weight (HW / BW) quantifications of pressure-volume circuits (Dp / dt) one week after myocardial infarction of placebo and mice treated with S-36. The S36 treatment results in a beneficial reduction in the ratio of heart weight to body weight and an increased rate of pressure development in S36 compared to mice treated with placebo.

Figure 5 is a graph that summarizes the values EC50 of JTV-519 and the Rycal series of compounds indicating several compounds with superior biological activity as evidenced by the EC50 values significantly lower compared to JTV-519.

Figure 6, A, B, C incorporations, are, respectively, (A) single-channel current indications of non-phosphorylated RyR2-P2328S and non-phosphorylated RyR2-WT treated with S36; (B) indices of single channel current of phosphorylated RyR2-P2328S and non-phosphorylated RyR2-P2328S treated with S36; (C) immunostaining analysis of agglutination of calstabin-2 RyR2-P2328S the presence or absence of PKA and S36.

Figure 7, incorporations A and B, are, respectively (A) an immunoblot of RyR2 immunoprecipitated with the antibody against RyR2, and the immunoblots of RyR2 PKA phosphorylation to Ser-2809 and calstabin2; And (B) a bar graph that quantifies the relative amount of RyR2 PKA phosphorylated to Ser-2808 (corresponding to human Ser-2809) bound to RyR2 in the wild type (control) and mice (FKBP12.6_ ") calstabin- 2 deficient.

Figure 8, incorporations A, B and C, are, respectively, bar graphs of (A) quantitative mo M live echocardiograms comparing ejection function (EF) Before and after the sham operation or the descending coronary artery ligand (LAD) left anterior permanent in the wild type and knockin mice RyR2-S2808A; (B) quantification of pressure-volume circuit in vivo of maximum pressure loading over time (dp / dt) in wild-type and knocking RyR2-S2808A mice after sham operation or coronary artery ligand (LAD) descendant left anterior permanent, and (C) M-mode echocardiographic assessment of extreme-systolic diameter (ESD) in the wild-type knockin R and R2-S2808A mice after a sham operation or a left anterior descending coronary artery (LAD) ligand permanent.

Figure 9, incorporations A, B, C and D demonstrate the effect of JTV-519 on the affinity of calstabin2 to RyR2 in mice (FKBP12.6) + ~ haploions- calstabin2 after exercise. Incorporation A is immunoblots in equivalent amounts of RyR2 immunoprecipitated with an antibody against RyR2 (upper). Incorporation B are bar graphs showing the amount of PKA phosphorylation from RyR2 to Ser-2809 and the amount of calstabin2 bound to RyR2 from control animals and animals after exercise immediately after injection with 0.5 mg / kg. of epinephrine. Incorporation C are indications of single channel RyR2 channels isolated from hearts of mice deficient in calstabin2_ ~ and calstabin2 + ~ haploionsucifientes immediately after the exercise test and the injection of 0.5mg of epinephrine per kg. of body weight, both untreated (upper) and after treatment (middle and bottom) with JTV-519. The open average probability (Po) in open time (To) the average closed time (To) are indicated and in closed state it is indicated by "c". The highlighted lines indicate sub-conductance levels for partial RyR2 openings. Incorporation D is a bar graph that summarizes the open probabilities by means of singular RyR2 channels of mice deficient in calstabin2_ ~ Y calstabin2 + ~ haploinsufficient after exercise with and without JTV-519 treatment. "*" indicates the level of meaning P < 0.05. The numbers on the bars indicate the number of singular channels measured.

Figure 10, incorporations A, B, C, D, E and F demonstrate the periodic activation of normalized RyR2 channel and the agglutination of calstabin2 increased to the RyR2 channels after treatment with JTV-519. Incorporation A are immunoblots of RyR2 (RyR2-WT) channels of wild type immounoprecipitates phosphorylated by PKA in the absence or presence of the PKI5_24 inhibitor peptide incubated with calstabin 2 (250Nm) at the indicated JTV-519 concentrations; the immunomachas show the amount of RyR2 (upper) and the amount of calstabin2 (background) associated with RyR2 immunoprecipitated after incubation with or without the stated concentrations of JTV-519. Incorporation B is immunoblots of RyR2-S2809D which mimics the constitutive PKA phosphorylation of RyR2, analyzed as in incorporation A. The C incorporation are 35S binding curves / radiolabeling calstabin2 to non-phosphorylated RyR2 or phosphorylated PKA or to RyR2-S2809D in the presence or in the absence of JTV-519, documenting the differences in the binding affinity of calstabin2 for RyR2. Incorporations D, E and F are indications of singular channel (left) and amplitude programs (right) RyR2s PKA-phosphorylated (incorporations E and F) or non-phosphorylated (incorporation D in the presence of the inhibitor PKA PKI4) incubated with calstabin2 (250nM) with (incorporation F) or without (incorporations D and E) JTV-519 (lμM). The indications of single channel are shown at 150 Nm [Ca2] which mimics the diastolic phase of rest in the heart; the channel openings are upwards, the dotted line indicates the complete channel opening level (4pA), and "c" indicates the closed state of the channels. Amplitude histograms have amplitude represented on the x-axis, and events on the y-axis indicate the number of channel openings.

Figure 11, incorporations A, B, C, D, E, and F demonstrate that the RyR1 channel fraction is increased and normalized in mdx mice treated with JTV-519. Incorporations A and B are respectively a single channel current signal and an amplitude histogram of RyRl of soleus muscle of a control (wild type) mouse under resting conditions. Incorporations C and D are, respectively, a sign of singular channel current and an amplitude histogram of RyRl of soleus muscle of an mdx mouse. The incorporation E and F are, respectively, a sign of singular channel current and an amplitude histogram of RyR1 of soleus muscle of a mdx mouse treated with JTV-519.

Figure 12, incorporations A and B, are, respectively, immunoblots of RyRl, Rl-pSer 2843 associated with calstabin 1 in mdx mice and wild-type mice; and the bar graphs of relative amounts of RyRl, Rl-pSer 2843 and calstabin 1 mdx and wild-type mice.

Figure 13, incorporations A, B, and C demonstrate that sarcoplasmic reticulum calcium filtering is detectable in the skeletal muscles of animals with heart failure. Incorporations A and B are fluorescence line scan images of calcium sparks in myofibers respectively, from rats with simulated infarction and post-myocardial infarction (PMI). Incorporation C provides bar graphs summarizing the amplitude of the elevation time, FDHM, and FWHM of the calcium sparks for the simulated rats (open symbols) and PPMI (closed symbols).

Figure 14, incoporations A and B demonstrate that the treatment of wild-type mice, JTV-519 improves the fatigue times of soleus muscle. Incorporation A provides maximum tetanus strength fatigue time indices for the wild type and calstabin2_ / ~ mice treated with JTV-519 or placebo as indicated. Incorporation B are bar graphs summarizing the mean time to fatigue for the wild type and the calstaben2_ ~ mice, treated with JTV-519 or placebo as indicated.

Figure 15, incorporations A and B, show that the beneficial effects of JTV-519 treatment on skeletal muscle function depend on calstabinl and not on calstabin2 binding to RyRl. Incorporation A provides a bar graph of PKA phosphorylation from RyRl to Ser-2844 in protons, which correspond to Ser-2843 in humans. Incorporation B are graphs of the amount of calstabinl bound to RyR1 of the wild-type calstabin2_ "mice treated with JTV-519 or placebo.

Figure 16, incorporations A, B, C, and D demonstrate that JTV-519 normalizes the function of normal RyRl channel or that it is filtered in vivo. Incorporations A and C are indications of wild-type mouse single channel current with heart failure treated with placebo (A) and JTV-519 (C). Incorporations B and D are amplitude histograms for wild type mice with placebo-treated heart failure (B) JTV-519 (D).

Figure 17, incorporations A and B, demonstrate that JTV-519 enhances the agglutination calstabin RyR forforylated PKA. Incorporation A are immunostains of calstabinl incubated and associated with RyR1 and calstabin2 incubated and associated with RyR2 at increasing concentrations of JTV-519. Incorporation B provides graphs summarizing the ratio of calstabinl and calstabin2 bound to RyRl and RyR2 as indicated.

Figure 18, incorporations A, B, C and D demonstrate that the PKA phosphorylation of Ser-2843 increases the open probability and the syn the periodic activation of RyR1 channels. Incorporation A provides indices of single channel current and a corresponding histogram of wild-type RyRl. Incorporation B provides unique channel current signals and a corresponding histogram of wild-type RyRl which is phosphorylated PKA. Incorporation C provides indices of singular channel current and corresponding histogram of RYR1-Ser-2843A. Incorporation D provides the singular channel current and corresponding histogram indices of RyRl-Ser-2843D.

Figure 19, incorporations A and B, demonstrate PKA hyperphosphorylation and calstabinl deficiency of RyR1 channels after sustained exercise. Incorporation A are immunoblots of RyRl, RyRl-pSer2844, RyRl-pSer2849 and calstabinl for control and swimming mice after an exercise regimen. Incorporation B is a bar graph that summarizes the relative amounts of the indicated compounds after the exercise regimen.

Figure 20, incorporations A and B, demonstrate that PKA RyRl phosphorylation increases after exposure to increased durations of sustained exercise. Incorporation A provides RyRl and RyRl-pSer 2844 immunoblots after increased durations of exercise. Incorporation B is a graph that shows the relative PKA phosphorylation of RyRl for variable durations of exercise.

Figure 21, incorporations A, B, and C, show that RyRl PKA phosphorylation increases with muscle fatigue. Incorporations A and B are, respectively, indications of fatigue time and the bar graph showing the main fatigue times for heart failure rat soleus muscle and control subjects. Incorporation C is the PKA phosphorylation plot against fatigue time.

Figure 22 are trichrome and exhematoxylin-eosin stains from cross sections of mouse M. extensor digitorum longus as demonstrated by myofiber degeneration consistent with dystrophic remodeling after sustained exercise.

Figure 23 shows a sample of hERG current sign before (control) and after the application of ARM036 at 100 μM. The voltage pulsation protocol used to evoke the hERG currents is also shown.

Figure 24 shows a typical time course of the effect of ARM036 on the current amplitude hERG the application of lOμM of ARM036 is indicated by the horizontal bar.

Figure 25 is a response-concentration plot showing the percent inhibition of the hERG current after the application of ARM036 at various concentrations.

Figure 26 is a response-concentration plot showing the percent inhibition of the hERG current after the application of ARM036-Na to several concentrations.

Figure 27 is a response-concentration plot showing the percent inhibition of the hERG current after the application of ARM047 to various concentrations.

Figure 28 is a response-concentration graph that shows the percent inhibition of the hERG current after the application of ARM048 at various concentrations.

Figure 29 is a response-concentration graph showing the percent inhibition of the hERG current after the application of ARM050 to several concentrations.

Figure 30 is a response-concentration plot showing the percent inhibition of the hERG current after the application of ARM057 to several concentrations.

Figure 31 is a response-concentration graph showing the percent inhibition of the hERG current after the application of ARM064 to several concentrations.

Figure 32 is a response-concentration graph showing the percent inhibition of the hERG current after the application of ARM074 to several concentrations.

Figure 33 is a response-concentration plot showing the percentage of inhibition of the hERG current after the application of ARM075 to several concentrations.

Figure 34 is a response-concentration plot showing the percent inhibition of the hERG current after the application of ARM076 at various concentrations.

Figure 35 is a response-concentration plot showing the percentage of inhibition of the hERG current after the application of ARM077 at various concentrations.

Figure 36 is a response-concentration plot showing the percent inhibition of the hERG current after the application of ARM101 to various concentrations.

Figure 37 is a response-concentration graph showing the percent inhibition of the hERG current after the application of ARM102 to several concentrations.

Figure 38 is a response-concentration graph showing the percent inhibition of the hERG current after the application of ARM103 to various concentrations.

Figure 39 is a response-concentration plot showing the percent inhibition of the hERG current after the application of ARM104 to various concentrations.

Figure 40 is a response-concentration plot showing the percent inhibition of the hERG current after the application of ARM106 at various concentrations.

Figure 41 is a response-concentration plot showing the percentage of inhibition of the hERG current after the application of ARM107 to several concentrations.

Figure 42 is a response-concentration plot showing the percent inhibition of the hERG current after the application of S26 to several concentrations.

Figure 43 is a concentration-response plot showing the percentage of hERG current inhibition after the application of JTV-519 ("ARMOXX") at various concentrations.

DETAILED DESCRIPTION OF THE INVENTION As used here and in the accompanying clauses, the singular forms of "a," "an," and "the" include plural references unless the content clearly dictates otherwise. Thus, for example, reference to "an agent" includes the probability of such equivalent agents thereof known to those skilled in the art, and the reference to "FKB12.6 polypeptide" is a reference to one or more FKB12 polypeptides. .6 (also known as calstabin2) and the equivalents thereof known to those skilled in the art and others. All publications, patent applications, patents and other references mentioned herein are incorporated by this mention in their entirety.

The following are definitions of terms used in the present description. The initial definition provides a group or term here applied to that group or term throughout the present description individually as part of another group, unless otherwise indicated.

As used herein, the term "RyCal compounds" refers to compounds of the general formula I, Ia, Ib, Ic, Id.Ie, If, Ig, Ih, Ii, Ij, Ik, 1-1 or Im, or as provided by the invention, and mentioned herein, "compounds of the invention".

The compounds of the invention are mentioned herein using a naming system, with compounds number 1 to 123 provided there. These numbered compounds are referred to by the prefix "S" or the prefix "ARM". Therefore, the first numbered compound is mentioned as either "SI" or "ARM001", the second numbered compound is referred to, as either "S2" or "ARM002, the third numbered compound is mentioned as either" S3" Or "ARM003", and others the naming system "S" and "ARM" are used interchangeably through the description, the drawings and the claims.

The term "alkyl" will be used in quotes and as used herein and refers to a straight or branched saturated hydrocarbon having from 1 to 6 carbon atoms. Representative alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, noepentyl, hexyl, isohexyl, neohexyl. The term "C 1 -C 4 alkyl" refers to a straight or branched chain alkane radical (hydrocarbons) containing from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl and isobutyl.

The term "alkynyl" as used herein refers to a linear branched hydrocarbon having from 2 to 6 carbon atoms and having at least one carbon-carbon double bond. In one embodiment the alkynyl has one or two double bonds. The alkynyl moiety may exist in the E or Z conformation and the compounds of the present invention include both conformations.

The term "alkynyl" as used herein refers to a linear branched hydrocarbon having from 2 to 6 carbon atoms and having at least one carbon-carbon triple bond.

The term "aryl" as used herein refers to an aromatic group containing from 1 to 3 aromatic rings, either fused or linked.

The term "cyclic group" as used herein includes the cycloalkyl group and the cyclic hetero group.

The term "cycloalkyl group" as used herein refers to a saturated, or partially saturated, carbon ring of three to seven members, any suitable ring position of the alkyl group may be covalently linked to the defined chemical structure. Examples of the cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

The term "halogen" will be used in quotation marks, as used herein and refers to fluorine, chlorine, bromine and iodine.

The term "heterocyclic group" or "heterocyclic" or "heterocyclyl" or "heterocycle" as used herein refers to aromatic cyclic groups (for example "heteroaryl") completely saturated or partially or completely unsaturated (for example monocyclic ring systems) from 4 to 7 members, bicyclic of 7 to 11 members or tricyclic of 10 to 16 members) which have at least one heteroatom in at least one ring containing a carbon atom. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3, or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and / or sulfur atoms, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized and the Nitrogen heteroatoms can optionally be quaternized. The heterocyclic group can be attached to the rest of the molecule at any heteroatom or carbon atom of the ring or ring system. Exemplary heterocyclic groups include, but are not limited to, accephenyl, acididinyl, dioxalanyl furanyl, furazanyl, homo pipuranyl, imidazolidinyl, imidazolinyl, isiotozolyl, isosiazolyl, morpholinyl, oxiodizolyl, oxyozolidinyl, oxozolyl, oxozolidinyl, pyrinidinyl, tridinyl, phenanpronilino, phenanthridinyl, phenanthrolinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyrazinyl, pirodooxazolilo, pyridoimidazolyl, piridotiozolilo, pyridinyl, pyrimidinyl, pyrrolidinyl, pirronilino, quinoclidinilo, tetrahydrofuranyl, teodiacinilo, teodiazolilo, tianilo, tianotioziolilo, tianooxiazolilo, tianoimidazolilo, thiomofolidino, thiophenyl, triacyl, triasolyl. Exemplary bicyclic heterocyclic groups include indolyl, isoindolyl, benzotiosolilo, benzoxasolilo, benzooxadiasolilo, benzothianyl, quinoclidinilo, quininolinilo, tetrahidroizoquinolinilo, izoquinolinilo, benzimidazolyl, benzopyranyl, indonizinilo, benzofuryl, benzofuranzanilo, chromonyl, comarinilo, benzopyranyl, cinnolinyl, quinozalinyl, indozalolilo I pyrrolopyridyl , furopyrindinyl, (such as furo [2, 3-c] pyridinyl, furo [3, 2-b] pyrindinyl] or furo [2,3-b] pyrindinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro- 4-oxo-quinoxonilino), triazinilazepinyl, tetrahydroquinolinyl and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrylino, acrdidinyl, phenanthrinyl, xanthenyl, and the like.

The term "phenyl" as used herein refers to the group of substituted or unsubstituted phenyls.

The aforementioned terms "alkyl" "alkenyl" "alkynyl" "aryl", "phenyl", "cyclic group," "cycloalkyl," "heterocyclyl," "heterocycle" and "heterocycly" may be optionally substituted with one or more substituents. Exemplary substituents include but are not limited to one or more of the following groups: hydrogen, halogen, CF3, 0CF3, cyano, nitro, N3 oxo, cycloalkyl, alkynyl, alkynyl, heterocyclic, aryl, alkylaryl, heteroaryl, 0Ra, SRa , S (= 0) Re, S (= 0) Re, P (= 0) 2Re, S (= 0) 20Ra, NRbRc, NRbS (= 0) 2Re, NRbP (= 0) 2Re, S (= 0) 2NRbRc, P (= 0) 2NRbRc, C (= 0) 0 Ra, C (= 0) 0Ra, C (= 0) NRbRc, OC (= 0) Ra, 0C (= 0) NRbRcNRbC (= 0) 0RaNRbRc, NRdS (= 0) 2 NRbRc, NRdP (= 0) 2NRbRc, NRbC (= 0) ORa or NRbP (= 0) 2Re, wherein Ra is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl alkylaryl, heteroaryl, heterocycle, or aryl; Rb, Rc, and Rd / are independently hydrogen, alkyl, cycloalkyl, alkylaryl, heteroaryl, heterocycle, aryl or said R, RC / together with N to which these are optionally attached form a heterocycle; And Re is alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, alkylaryl, heteroaryl, heterocycle, or aryl. In the above-mentioned example substituents, groups such as such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, alkylaryl, heteroaryl, heterocycle, and aryl may themselves be optionally substituted.

The example substituents may optionally also include at least one labeling group, such as a fluorescent group, a bioluminescent group, a chemiluminescent group, a colorimetric group and a radioactive labeling group. The fluorescent labeling group may be selected from bodipy, dansyl, fluorescein, rhodamine, Texas red, cyanine, pyrene, coumarin, Cascade Blue, Pacific Blue, Navy Blue, Oregon 4 'Green, 6-Diamidino-2-feninendole ( DAPI) dyes indopira, yellow lucifer iodopropyl, porphyrins, alginin and variants and derivatives thereof. For example ARM118 of the present invention contains a BODIPY labeling group, which is a family of florophores based on half of, 4-difluoro-4-bora-3a, 4a-diaza-s-indecene. For additional information on the fluorescent label halves and fluorescence techniques see for example, "The Fluorescent and Chemical Research Probes Manual," by Richard P. Haughland, Sixth Edition, Molecular Probes, (1996), which is incorporated here by reference in its entirety. A person skilled in the art can easily select a suitable labeling group, and conjugate such a labeling group with any of the compounds of the invention without undue experimentation.

The term "quaternary nitrogen" refers to the positively charged tetravalent nitrogen atom including, for example, the positively charged nitrogen in a tetralkylammonium group (eg tetralkylammonium, N-methylpyridimium), the positively charged nitrogen in the protolated ammonium species (for example, trimethylhydroammonium, N-hydropyridine), the positively charged nitrogen in N-oxide salt (for example N-methyl-morpholine-N-oxide, pyridine-N-oxide), the nitrogen positively charged in a group of N-amino-ammonium (for example N-aminopyridimium).

Through the specification, unless otherwise noted the nitrogen in the benzothiazepine ring of compounds of the present invention can optionally be quaternary nitrogen. Non-limiting examples include ARM-113 and ARM-119.

The compounds of the present invention can exist in tautomeric form (for example as an amido or imino ether). All tautomeric forms are contemplated herein as part of the present invention.

The term "prodrug" as used herein denotes a compound that upon administration to the subject undergoes chemical conversion by metabolic or chemical processes to give compounds of the present invention.

All stereoisomers of the compounds of the present invention (for example, those which exist due to asymmetric carbons on various substituents), including enantiomeric forms and diastereomeric forms, are contemplated within the scope of this invention. The individual stereoisomers of the compounds of the invention may, for example, be essentially free of other isomers (for example, as an essentially pure optical isomer having a specified activity) or they may be mixed, for example, as race partners or with all other or other selected stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 recommendations. The racemic forms can be resolved by physical methods, such as, for example, factional crystallization, separation or crystallization of derivatives diasteromeric or separation by chiral column chromatography. The individual optical isomers can be obtained from the racemic mixtures by any suitable method, including without limitation, conventional methods such as, for example, salt formation with any optically active acid, followed by crystallization.

The compounds of the present invention are, subsequent to their preparation preferably isolated and purified to obtain a composition containing an amount of weight equal to or greater than 99% of the compound ("essentially pure compound"), which is then used and formulated as wrote here Such "essentially pure" compounds of the present invention are also contemplated herein as part of the present invention.

All configuration isomers of the compounds of the present invention are contemplated, either in admixture or in a pure or essentially pure form. The definition of the compounds of the present invention encompasses both cis (Z) and trans (E) alkene isomers, as well as the cis and trans isomers of cyclic hydrocarbon or heterocyclic rings.

Through the description, the groups and substituents thereof can be chosen to provide the stable moieties and the compounds.

The present invention provides compounds that are capable of treating and preventing disorders and diseases associated with RyR receptors that regulate the calcium channel functioning in cells. More particularly, the present invention provides compounds that are capable of treating or preventing filtering in the RyR channels. "Disorders and diseases associated with RyR receptors" means disorders and diseases that can be treated and / or avoided by the modulation of the RyR receptors that regulate the calcium channel functioning in the cells. "Disorders and diseases associated with RyR receptors" include without limitation, cardiac disorders and diseases, disorders and skeletal muscle diseases, disorders and diseases of knowledge, malignant hyperthermia, diabetes, and sudden infant death syndrome. Heart diseases and disorders include, but are not limited to disorders and irregular heartbeat diseases; irregular heartbeat disorders induced by exercise and diseases; sudden cardiac death; sudden cardiac death induced by exercise; congestive heart failure; lung disease of chronic obstruction; and high blood pressure. Heart disorders and disorders of irregular heartbeat include but are not limited to atrial and ventricular arrhythmia, atrial and ventricular fibrillation; atrial and ventricular tachyarrhythmia; atrial and ventricular tachycardia; catecholaminergic polymorphic ventricular tachycardia (CPVT); and the variants induced by exercise thereof. Diseases and skeletal muscle disorders include, but are not limited to skeletal muscle fatigue, skeletal muscle fatigue induced by exercise, muscular dystrophy, bladder disorders and incontinence. Disorders of knowledge and diseases include, but are not limited to, Alzheimer's disease, forms of memory loss, and memory loss depending on age.

Compounds In one embodiment, the present invention provides compounds of the formula I: wherein, n is 0, 1, or 2; q is 0, 1,2,3 or 4; each R is independently selected from the group consisting of H, halogen, -OH, -NH2, -N02, -CN, -CF3, -OCF3, -N3, -S03H, S (= 0) 2alkyl, S (= 0) alkyl, -OS (= 0) 2CF3, acyl, -O-acyl, alkyl, alkoxy, alkylamino, alkylarylamino, alkylthio, cycloalkyl, alkylaryl, aryl, heteroaryl, heterocyclyl, hererocyclylalkyl, alkenyl, alkynyl, (hetero-) aryl, ( hetero-) arylthio, (hetero-) arylamino; wherein each acyl, -0-acyl, alkyl, alkoxy, alkylamino, alkylarylamino, alkylthio, cycloalkyl, alkylaryl, aryl, hereroaryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-) aryl, (hetero-) arylthio, (hetero -) arylamino; they can be optionally substituted; Ri is selected from the group consisting of H, oxo, alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl, heterocyclyl; wherein each alkyl, aryl alkenyl, alkylaryl, cycloalkyl, heteroaryl, and heterocyclyl can be optionally substituted; R2 is selected from the group consisting of H, -C (= 0) R5, C (= S) R6, SO2R7, -P (= 0) R8R9, (CH2) mR? Or, - alkyl, aryl, alkylaryl, heteroaryl , cycloalkyl, cycloalkylalkyl and heterocyclyl; wherein each alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl, cycloalkylalkyl and heterocyclyl; they can be optionally substituted; R3 is selected from the group consisting of H, -C02Y2, C (= 0) NHYR, acyl, -O-acyl, alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl, and heterocyclyl; wherein each acyl, alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl and heterocyclyl can be optionally substituted; and wherein Y is selected from the group consisting of H, alkyl, aryl, alkylaryl, cycloalkyl, heteroaryl, and heterocyclyl; wherein each alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl and heterocyclyl can be optionally substituted; R 4 is selected from the group consisting of H, alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl and heterocyclyl wherein each alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl and heterocyclyl can be optionally substituted; R5 is selected from the group consisting of -NR? 5Ri6, - (CH2) q, NRisRie, "NR? 5Ri6, -NHOH, -ORi5, -C (= 0) NHNR? 5R? 6-C02Ri5, C (= 0 ) NR? 5Ri6, -CH2X acyl, alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heterocyclyl heterocyclyl, heterocyclylalkyl, wherein each acyl, alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heterocyclyl heterocyclyl, heterocyclylalkyl may optionally be substituted and as q is 1,2,3,4,5 or 6; Re is selected from the group consisting of -OR , -NR15R16, -NHOH, -NR? 5Ri6, CH2X, acyl, alkenyl, alkyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heterocyclyl heterocyclyl, and heterocyclylalkyl; wherein each acyl, alkenyl, alkyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, heterocyclylalkyl may be optionally substituted; R7 is selected from the group consisting of -OR , -NR? 5Ri6, -NHNR? 5Ri6 -NHOH, -CH2X, alkyl, alkenyl, alkynyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, and heterocyclylalkyl; wherein each alkyl, alkenyl, alkynyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, and heterocyclylalkyl may be optionally substituted; R8 and Rg independently are selected from the group consisting of OH, acyl, alkenyl, alkoxy, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, and heterocyclylalkyl wherein each acyl, alkenyl, alkoxy, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, and heterocyclylalkyl may be optionally substituted; Rio is selected from the group consisting of NR? 5R? 6, OH, S02R?, - NHS02 -R ?, C (= 0) (Ri2), NHC = 0 (Ri2), -0C = 0 (Ri2) yP (= 0) Ri3R? 4; Ru, R 2, Ri 3 and Ri 4 independently are selected from the group consisting of H, OH, NH 2, NHNH 2, -NH0H acyl, alkenyl, alkoxy, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, and heterocyclylalkyl wherein each acyl, alkenyl, alkoxy, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, and heterocyclylalkyl may be optionally substituted; X is selected from the group consisting of halogen, -CN, -CO15-C (= 0) NR? 5R? 6, -NR? 5R? 6, 0R? 5, -S02R7, and P (= 0) R8R9, and R15 and Rie independently are selected from the group consisting of H, acyl, alkenyl, alkoxy, OH, NH2 alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, and heterocyclylalkyl wherein each acyl, alkenyl, alkoxy, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, and heterocyclylalkyl may be optionally substituted; and optionally R15 and Ri6 together with the N to which they are attached can form a heterocycle can be substituted; the nitrogen in the benxothiazepine ring, can optionally be a quaternary nitrogen; and enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvents, complexes and prodrugs thereof; provided that when q is 0 and n is 0, then R2 is not H, Et-C (= 0) NH2, (= 0) NHPh, -C (= S) NH-nButil, -C (= 0) NHC (= 0) CH2C ?, -C (= 0) H, C (= 0) Me, -C (= 0) Et, -C (= 0) CH = CH2-S (= 0) 2Me, or -S (= 0) 2Et; Also provided that when q is 0, and n is l or 2, then R2 is not -C (= 0) Me, -C (= 0) Et, -S (= 0) 2Me, or -S (= 0) 2Et; Also provided that when q is 1 and R is Me, Cl, or F at position 6 of the benzothiazepine ring, then R2 is not H, Me, -C (= 0) H, C (= 0) Me, - C (= 0) Et, -C (= 0) Ph, - S (= 0) 2Me, or -S (= 0) 2Et; Y further provided that when q is 1, n is 0 and R is 0CT3, OH, C? -C3 alkoxy at position 7 of the benzothiazepine ring, then R2 is not H, C (= 0) CH = CH2, or In one embodiment, the present invention comprises compounds of the formula I as described above, with the proviso that said compound is not S24 or S 68.

In one embodiment, the present invention provides compounds of the formula I-a: where n is 0, 1, or 2; q is 0,1,2,3 or 4; each R is independently selected from the group consisting of H, halogen, -0HmNH2, -N2, -CN, -CF3-OCF3, -N3, -S03H S (= 0) 2alkyl S (= 0) alkyl, -OS (= 0) 2CF3, alkoxy, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, achenyl, alkynyl, (hetero-) aryl, (hetero-) arylthio, and (hetero-) arylamino; wherein each alkyl, alkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, achanyl, alkynyl, (hetero-) aryl, (hetero-) arylthio, and (hetero-) arylamino can be substituted or unsubstituted; R2 is selected from the group consisting of H, -C (= 0) R5, C (= S) R6, SO2R7, -P (= 0) R8R9, (CH2) mR? 0, - alkyl, aryl, heteroaryl, cycloalkyl , cycloalkylalkyl and heterocyclyl; wherein each alkyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl and heterocyclyl; they can be replaced or not replaced; Rs is selected from the group consisting of -NR15R16, -NR15R16, "NHOH, -OR15, -C (= 0) NHNR? 5R? 6-C02Ri5, C (= 0) NR? 5R? 6, -CH2X acyl, alkyl alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, wherein each acyl, alkyl, alkenyl, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl can be substituted or unsubstituted; R6 is selected from the group consisting of -OR15, -NHNR? 5R? 6, -NHOH, -NR? 5R? 6, CH2X, acyl, alkenyl, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each acyl, alkenyl, alkyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl can be substituted or unsubstituted; R7 is selected from the group consisting of H -OR15, -NR? 5R? 6, -NHNR? 5R? 6, -NHOH, -CH2X, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl can be substituted or unsubstituted; R8 and Rg independently are selected from the group consisting of OH, acyl, alkenyl, alkoxy, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl wherein each acyl, alkenyl, alkoxy, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl can be substituted or unsubstituted; Rio is selected from the group consisting of R15R16, OH, SOzRu, -NHS02-Rn, C (= 0) (Ri2), NH (C = 0 (R12), -0 (C = 0) (R? 2) and P (= 0) R? 3R? 4; m is 0, 1, 2, 3 or 4; Rii / R12 R13 and R14 independently are selected from the group consisting of H, 0H, NH2 / NHNH2, -NH0H acyl, alkenyl, alkoxy, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl wherein each acyl, alkenyl , alkoxy, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted or unsubstituted; X is selected from the group consisting of halogen, -CN, -C02R? 5-C (= 0) NR? 5R? 6, -NR? 5R? 6, ORi5, -S02R7, and-P (= 0) R8R9, and R15 and Ri6 independently are selected from the group consisting of H, acyl, alkenyl, alkoxy, OH, NH2 alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each acyl, alkenyl, alkoxy, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl can be substituted or unsubstituted; and optionally R15 and R16 together with the N to which they are attached can form a heterocycle which can be substituted or unsubstituted; the nitrogen in the benxothiazepine ring, can optionally be a quaternary nitrogen; and enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvents, complexes and prodrugs thereof; provided that when q is 0 and n is 0, then R2 is not H, Et-C (= 0) NH2, (= 0) NHPh, -C (= S) NH-nButil, -C (= 0) NHC (= 0) CH2C ?, -C (= 0) H, -C (= 0) Me, -C (= 0) Et, -C (= 0) CH = CH2-S (= 0) 2Me, or -S ( = 0) 2Et; Also whenever q is 0, and n is l or 2, then R2 is not -C (= 0) Me, -C (= 0) Et, -S (= 0) 2Me, or -S (= 0) 2Et; Also provided that when q is 1 and R is Me, Cl, or F at position 6 of the benzothiazepine ring, then R2 is not H, Me, -C (= 0) H, C (= 0) Me, - C (= 0) Et, -C (= 0) Ph, - S (= 0) 2Me, or -S (= 0) 2Et; Y further provided that when q is 1, n is 0 and R is 0CT3, OH, C? -C3 alkoxy at position 7 of the benzothiazepine ring, then R2 is not H, C (= 0) CH = CH2, or In certain embodiments, the present invention provides compounds of formula Ia, wherein each R is independently selected from the group consisting of H halogen, -OH, OMe, -NH2-N02, -CN, -CF3, -OCF3-Ne, -S (= 0) 2C? -C4alkyl, -S (= 0) C? -C4alkyl, -S-C1-Calkyl, -OS (= 0) 2CF3, Ph, -NHCH2Ph, -C (= 0) Me, -OC (= 0) I morpholinyl and propenyl and n is 0,1, or 2 In other embodiments, the present invention provides compounds of the formula Ia, wherein R2 is independently selected from the group of C = 0Rs, C = S (R6), - S02R7-P (= 0) R8R9 and- (CH2) m- R10.

In yet another embodiment the present invention provides compounds of the formula I-b: (I-b) Wherein R 'and R "are independently selected from the group consisting of H, halogen, -OH, -NH2, -N02, -CN, CF3-OCF3-N3-S03H, S (= 0) 2alkyl, -S ( = 0) alkyl, -OS (= 0) 2 CF 3, acyl, alkyl, alkoxy, alkylamino, allylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl (hetero-) aryl, (hetero-) arylthio, and (hetero-) ) arylamino,; wherein each acyl, alkyl, alkoxy, alkylamino, alkenylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl (hetero-) aryl, (hetero-) arylthio, and can be substituted or unsubstituted; R2 and n are as defined in the compounds of formula I-a given above; and enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvents, complexes and pro-drugs thereof.

In certain embodiments, the present invention provides compounds of the formula Ib, wherein R 'and R "are independently selected from the group consisting of H, halogen, OH, -NH2-N02, -CN, -CF3-OCF3-N3 -S02H, C? -C4Salkyl, -S-Ci-C4alkyl, OS (= 0) 2CF3, Ph, NHCH2Ph, -C (= 0) Me, -OC (= 0) Me, -OC (= 0) Me, morpholinyl and propenyl; And n is 0.1 or 3. In some cases, R 'is H or OMe, and R "is H.

In other embodiments, the present invention provides compounds of the formula Ib, wherein R2 is selected from the group consisting of-C = 0 (R5), -C = S (R6), -S02R7, -P (= 0) R8R9, and - (CH2) MR? 0.

In yet another embodiment, the present invention provides compounds of the formula I-c: (I-c) Wherein each R, R7 q, and n is as defined in the compounds of the formula I-a and enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvents, complexes and pro-drugs thereof.

In certain embodiments, the present invention provides compounds of formula Ic wherein each R is independently selected from the group consisting of H, halogen, -OH, -OMe, N02, -CN, CF3-OCF3-N3-S (= 0) 2 C? -Calkyl, -SC? ~ Calkyl, OS (= 0) 2CF3, Ph, NHCH2Ph, -C (= 0) Me, -OC (= 0) Me, -OC (= 0) Me, morpholinyl , and propenyl and n is 0, 1 or 2.

In other embodiments, the present invention provides compounds of formula I-c wherein R7 is independently selected from the group consisting of OH, -NR15 R16, alkyl, alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl; wherein each alkyl, alkenyl, aryl, cycloalkyl, cycloalkylalkyl heterocyclyl, heterocyclylalkyl can be substituted or unsubstituted.

In a further embodiment the present invention provides compounds of the formula I-d: wherein R 'and R "are independently selected from the group consisting of H, halogen, -OH, -NH2, -N02, -CN, CF3-OCF3-N3-S03H, S (= 0) 2alkyl, -S (= 0) alkyl, -OS (= 0) 2 CF 3, acyl, alkyl, alkoxy, alkylamino, allylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl (hetero-) aryl, (hetero-) arylthio, and (hetero-) arylamino,; wherein each acyl, alkyl, alkoxy, alkylamino, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl (hetero-) aryl, (hetero-) arylthio, can be substituted or unsubstituted; R7 and in n are as defined in the compounds of the formula I-a above; and enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvents, complexes and pro-drugs thereof.

Certain embodiments, the present invention provides compounds of the formula Id, wherein R 'and R "are independently selected from the group consisting of H, halogen, OH, OMe, -NH2, -N02, -CN, CF3-OCF3- N3- S02H, C? -C4alkyl, -S-Ci-C4alkyl, OS (= 0) 2CF3, Ph, NHCH2Ph, -C (= 0) e, -OC (= 0) Me, -OC (= 0) Me , morpholinyl and propenyl and n is 0.1 or 3. In some cases, R 'is H or OMe, or R "is H.

In other embodiments, the present invention provides compounds of formula I-d, wherein R7 is selected from the group consisting of -OH, -NR? 5NR? 6 alkyl, alkenyl, aryl, cycloalkyl, cycloalkylalkyl heterocyclyl, heterocyclylalkyl; wherein each alkyl, alkenyl, aryl, cycloalkyl, cycloalkylalkyl heterocyclyl, heterocyclylalkyl can be substituted or unsubstituted.

In one embodiment, the present invention provides compounds of formula I-e: Wherein each R, R5, q and n is as defined in the compounds of formula I-a given above; and the enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, complexes and pro-drugs thereof.

In certain embodiments, the present invention provides compounds of the formula Ie, wherein each R is independently selected from the group consisting of H, halogen, -OH, OMe, -NH2, -N02-CH, -CF3, -0CF3, - N3, -S (= 0) 2 C? -C4 alkyl, -S (= 0) C? -C4 alkyl, -S- C? -C alkyl, -OS (= 0) 2CF3, Ph, -NHCH2Ph, - C (= 0) Me, -OC (= 0) Me, morpholinyl and propenyl; and n is 0, 1 or 2.

In other embodiments, the present invention provides compounds of the formula Ie, wherein R5 is selected from the group consisting of -NR? 5R? 6, -NHOH, -OR15, CH2X, alkyl, alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl , and heterocyclylalkyl; wherein each alkyl, alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl can be substituted or unsubstituted; In some embodiments, the present invention provides compounds of the formula I-e, wherein R 5 is an alkyl, substituted by at least one labeling group, such as a fluorescent, bioluminescent, chemiluminescent, colorimetric group and a radioactive labeling group. A fluorescent labeling group can be selected from bodipi, densil, fluoresceia, rhodamine, red Texas, cyanine, pyrene, coumarin, Cascade® blue, pacific blue, navy blue, Oregon green, '6-diamidino-2-phenylindole (DAPI), indopira dyes, lucifer yellow, propidium iodine, porphyrins and variants and derivatives of the same.

In another embodiment, the present invention provides compounds of the formula I-f: wherein R 'and R "are independently selected from the group consisting of H, halogen, -OH, -NH2-N02, -CN-CF3, -OCF3, -N3, -S03H, -S (= 0) 2alkyl, -S (= 0) alkyl, -OS (= 0) 2 CF 3, acyl, alkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-) aryl, (hetero-) arylthio, and (hetero-) arylamino; and wherein each acyl, alkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-) aryl, (hetero-) arylthio, can be substituted or unsubstituted; R5 and n are as defined in the compounds of formula I-a given above; And enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, complexes and pro-drugs thereof.

In certain embodiments, the present invention provides compounds of the formula If, wherein R 'and R "are independently selected from the group consisting of H, halogen, -OH, OMe, -NH2, -N02-CH, -CF3, -0CF3, -N3, -S (= 0) 2 C? -C4 alkyl, -S (= 0) C? -C alkyl, -S- C? -C4 alkyl, -OS (= 0) 2CF3, Ph, -NHCH2Ph, -C (= 0) Me, -OC (= 0) Me, morpholinyl and propenyl; and n is 0, 1 or 3. In some cases, R 'is H or OMe, and R "is H.

In other embodiments, the present invention provides compounds of the formula If, wherein R5 is selected from the group consisting of -NR? 5R? 6, -NHNR15R16, -OR15, -NHOH, -CH2X- alkyl, alkenyl, cycloalkyl, cycloalkylalkyl , heterocyclyl, and heterocyclylalkyl; wherein each alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl can be substituted or unsubstituted.

In yet another embodiment, the present invention provides compounds of the formula I-g: where W is S ú O; each R, R15, R16, q, and n is as defined in the compounds of the formula I-a given above; and enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, complexes and pro-drugs thereof.

In certain embodiments, the present invention provides compounds of the formula Ig, wherein each R is independently selected from the group consisting of H, halogen, -OH, OMe, -NH2, -N02-CH, -CF3, -OCF3, - N3, -S (= 0) 2 C? -C alkyl, -S (= 0) C? -C4 alkyl, -S- C? -C alkyl, -OS (= 0) 2CF3, Ph, -NHCH2Ph, - C (= 0) Me, -OC (= 0) Me, morpholinyl and propenyl; and n is 0, 1 or 2.

In other embodiments, the present invention provides compounds of the formula Ig, wherein R 5 and R 6 are independently selected from the group consisting of H, OH, NH 2, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl.; wherein each alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl can be substituted; and optionally R15 and R16 together with the N to which these are attached can form a heterocycle which can be substituted.

In some embodiments, the present invention provides compounds of formula I-g, wherein W is 0 or S.

In yet another embodiment, the present invention provides compounds of the formula I-h: Where W is S ú 0; wherein R 'and R "are independently selected from the group consisting of H, halogen, -OH, -NH2-N02, -CN-CF3, -OCF3, -N3, -S03H, -S (= 0) 2alkyl, -S (= 0) alkyl, -OS (= 0) 2CF3, acyl, alkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-) aryl, (hetero-) arylthio, and (hetero-) arylamino; and wherein each acyl, alkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-) aryl, (hetero-) arylthio, can be substituted or unsubstituted; Ri5 / Rie and n are as defined in the compounds of formula I-a given above; And enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, complexes and pro-drugs thereof.

In certain embodiments, the present invention provides compounds of the formula Ih, wherein R 'and R "are independently selected from the group consisting of H, halogen, -OH, OMe, -NH2, -N02-CH, -CF3, -0CF3, -N3, -S (= 0) 2 C? -C4 alkyl, -S (= 0) C? -C4 alkyl, -S- C? -C alkyl, -OS (= 0) 2CF3, Ph, -NHCH2Ph, -C (= 0) Me, -0C (= 0) Me, morpholinyl and propenyl; and n is 0, 1 or 3. In some cases, R 'is H or OMe, and R "is H.

In other embodiments, the present invention provides compounds of formula I-h, wherein R15, and R16, are independently selected from the group consisting of H, OH, NH2, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl can be substituted; and optionally R 5 and R 6 together with the N to which these are attached can form a heterocycle which can be substituted.

In some embodiments, the present invention provides compounds of formula I-g, wherein W is O or S.

In still another embodiment, the present invention provides compounds of the formula I-i: wherein R17 is selected from the group consisting of -NR? 5R? 6, -NHNR? 5R? 6, -NH0H, -0Ri5, -CH2X, alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl can be substituted or unsubstituted; each R, q, and n is as defined in the compounds of formula I-a given above; and the enantiomers, diastereomers, tatuomers, pharmaceutically acceptable salts, hydrates, solvates, complexes and pro-drugs thereof.

In certain embodiments, the present invention provides compounds of the formula Ii, wherein each R is independently selected from the group consisting of H, halogen, -OH, OMe, -NH2, -N02-CH, -CF3, -0CF3, - N3, -S (= 0) 2 C? -C alkyl, -S (= 0) C? -C alkyl, -S- C? -C4 alkyl -OS (= 0) 2CF3, Ph, -NHCH2Ph, -C (= 0) Me, -0C (= 0) Me, morpholinyl and propenyl; and n is 0, 1 or 2.

In other embodiments, the present invention provides compounds of the formula I-i, wherein R? is -NR15R? 6, and -OR15. In certain other embodiments, R7 is -OH, -OMe, -NEt, -NHEt, -NHPh, -NH2, or -NHCH2pyridyl? .

In one embodiment, the present invention provides compounds of the formula I-j: wherein R 'and R "are independently selected from the group consisting of H, halogen, -OH, -NH2-N02, -CN-CF3, -0CF3, -N3, -S03H, -S (= 0) 2alkyl, -S (= 0) alkyl, -OS (= 0) 2 CF 3, acyl, alkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-) aryl, (hetero-) arylthio, and (hetero-) arylamino; and wherein each acyl, alkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-) aryl, (hetero-) arylthio, can be substituted or unsubstituted; R1 is selected from the group consisting of -NR? 5R16, -NHNR? 5R16, -NHOH, -OR15, CH2X, alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl can be substituted or unsubstituted; n is as defined in the compounds of the formula I-a; Y enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, complexes and pro-drugs thereof.

In certain embodiments, the present invention provides compounds of formula Ij, wherein R 'and R "are independently selected from the group consisting of H, halogen, -OH, OMe, -NH2, -N02-CH, -CF3, -OCF3, -N3, -S (= 0) 2 C? -C4 alkyl, -S (= 0) C? -C4 alkyl, -S- C-C4 alkyl, -OS (= 0) 2CF3, Ph, - NHCH2Ph, -C (= 0) Me, -0C (= 0) Me, morpholinyl and propenyl; and n is 0, 1 or 3. In some cases, R 'is H or OMe, and R "is H.

In other embodiments, the present invention provides compounds of the formula I-j, wherein R? 7, is-NR15R? 6, or -OR15. In certain other embodiments, R7 is -OH, -OMe, -NEt, -NHEt, -NHPh, -NH2, or -NHCH2pyridyl.

In other embodiments, the present invention provides compounds of the formula I-k: CH ^ Rtg / au wherein R 'and R "are independently selected from the group consisting of H, halogen, -OH, -NH2-N02, -CN-CF3, -OCF3, -N3, -S03H, -S (= 0) 2alkyl , -S (= 0) alkyl, -OS (= 0) 2CF3, acyl, alkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-) aryl, (hetero-) arylthio, and (hetero-) arylamino; and wherein each acyl, alkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-) aryl, (hetero-) arylthio, can be substituted or unsubstituted; Rie is selected from the group consisting of -NR15R16, -C (= 0) NR15R16, - (C = 0) 0R? 5, -OR15, alkyl, aryl, cycloalkyl, heterocyclyl, and in a labeled group; wherein each alkyl, aryl, cycloalkyl heterocyclyl can be substituted or unsubstituted; wherein p is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and n is 0, 1 or 2; and enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, complexes and pro-drugs thereof.

In certain embodiments, the present invention provides compounds of formula Ik, wherein R 'and R "are independently selected from the group consisting of H, halogen, -OH, OMe, -NH2, -N02-CH, -CF3, -OCF3, -N3, -S (= 0) 2 C? -C alkyl, -S (= 0) C? -C4 alkyl, -S- C? -C4 alkyl, -OS (= 0) 2CF3, Ph, -NHCH2Ph, -C (= 0) Me, -OC (= 0) Me, morpholinyl and propenyl; and n is 0, 1 or 3. In some cases, R 'is H or OMe, and R "is H.

In other embodiments, the present invention provides compounds of the formula Ik, wherein R? 8 is selected from the group consisting of -NR15R? 6, - (C = 0) 0R15, 0R15, alkyl, aryl and in a labeling group; and wherein each alkyl and aryl can be substituted or unsubstituted. In some cases, m is 1 and R18 is Ph, C (= 0) 0Me, C (= 0) 0H, aminoalkyl, NH2, NHOH, or NHCbz. In other cases, m is 0 and R? 8 is C? -C4 alkyl, such as Me, Et, propyl and butyl. In still other cases, m is 2 and R 8 is pyrrolidine, piperidine, piperazine or morpholine. In some embodiments, m is 3, 4, 5, 5, 7 or 8 and R? 8 is a fluorescent labeling group selected from bodipi, densil, fluoresceia, rhodamine, Texas red, cyanine, pyrene, coumarin, Cascade® blue. , pacific blue, marine blue, Oregon green, 4 '6-diamidino-2-phenylindole (DAPI), indopira dyes, lucifer yellow, propidium iodine, porphyrins and variants and derivatives thereof.

In yet another embodiment, the present invention provides compounds of the formula 1-1: wherein R 'and R "are independently selected from the group consisting of H, halogen, -OH, -NH2-N02, -CN-CF3, -OCF3, -N3, -S03H, -S (= 0) 2alkyl, -S (= 0) alkyl, -OS (= 0) 2 CF 3, acyl, alkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-) aryl, (hetero-) arylthio, and (hetero-) arylamino; and wherein each acyl, alkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-) aryl, (hetero-) arylthio, can be substituted or unsubstituted; RI and n are as defined in compounds of the formula I-a; and enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, complexes and pro-drugs thereof.

In certain embodiments, the present invention provides compounds of formula 1-1, wherein R 'and R "are independently selected from the group consisting of H, halogen, -OH, OMe, -NH2, -N02-CH, - CF3, -OCF3, -N3, -S (= 0) 2 C 1 -C 4 alkyl, -S (= 0) dC 4 alkyl, -S- C 1 -C 4 alkyl, -OS (= 0) 2CF 3, Ph , -NHCH2Ph, -C (= 0) Me, -0C (= 0) Me, morpholinyl and propenyl; and n is 0, 1 or 3. In some cases, R 'is H or OMe, and R "is H.

In other embodiments, the present invention provides compounds of formula 1-1, wherein Re is selected from the group consisting of -NR15R16, -NHNR15R16, -ORis, -NHOH, -CH2X-acyl, alkenyl, alkyl, aryl, cycloalkyl. , cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each acyl, alkenyl, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl can be substituted or unsubstituted. In some cases, R6 is -NR? 5R? 6 such as -NHPh, pyrrolidine, piperidine, piperazine, morpholine and the like. In other cases, R is alkoxy, such as -O-tBu.

In another embodiment, the present invention provides compounds of the formula I-M: s-) wherein R 'and R "are independently selected from the group consisting of H, halogen, -OH, -NH2-N02, -CN-CF3, -OCF3, -N3, -S03H, -S (= 0 ) 2alkyl, -S (= 0) alkyl, -OS (= 0) 2CF3, acyl, alkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-) aryl, (hetero- ) arylthio, and (hetero-) arylamino; and wherein each acyl, alkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-) aryl, (hetero-) arylthio, can be substituted or unsubstituted; R8, Rg and n are as defined in compounds of formula I-a given above; and enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, complexes and pro-drugs thereof.

In certain embodiments, the present invention provides compounds of the formula Im, wherein R 'and R "are independently selected from the group consisting of H, halogen, -OH, OMe, -NH2, -N02-CH, -CF3, -0CF3, -N3, -S (= 0) 2 C? -C alkyl, -S (= 0) Cx-C4 alkyl, -S- C? -C4 alkyl, -OS (= 0) 2CF3, Ph, - NHCH2Ph, -C (= 0) Me, -0C (= 0) Me, morpholinyl and propenyl; and n is 0, 1 or 3. In some cases, R 'is H or OMe, and R "is H.

In other embodiments, the present invention provides compounds of formula I-m, wherein R 8 and R g are independently alkyl, aryl, -OH, alkoxy, or alkylamino. In some cases, R 8 is C 1 -C 4 alkyl such as Me, Et, propyl and butyl; and R9 is aryl such as phenyl.

The compounds of formula I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, I-j, I-k, 1-1 and I-m treat and prevent the disorders and diseases associated with RyR receptors.

Examples of such compounds include without limitation, SI, S2, S3, S4, S5, S6, S7, S9, Sil, S12, S13, S14, S19, S20, S22, S23, S25, S26, S36, S37, S38. , S40, S43, S44, S45, S46, S47, S48, S49, S50, S52, S53, S53, S54, S55, S56, S57, S58, S59, S60, S61, S62, S63, S64, S66, S67, S68 , S69, S70, S71, S72, S73, S74, S75, S76, S77, S78, S79, S80, S81, S82, S83, S84, S85, S87, S88, S89, S90, S91, S92, S93, S94 , S95, S96, S97, S98, S99, SlOO, S101, S102, S104, S105, S107, S108, S109, S110, S1, S112, S113, S114, S115, S116, S117, S118, S119, S120, S121 , S122 and S123. These compounds have the following structures: twenty S22 S 5 S2 S43 S68 S69 S70 S71 S72 74 S76 S78 S79 1 S81 S82 S83 S84 S91 S92 - € QloCM- S95 O S97 S99 S101 S102 S103 SI04 twenty twenty fifteen S120 Afí?) 121 S121 S122 Yes 23 A? Ro120 In an embodiment of the present invention, for compounds of Formula I, if R2 is C = 0 (R5) or S02R7, then R is in positions 2, 3 or 5 of the benzene ring.

In yet another embodiment of the invention, for the compounds of Formula I, if R2 is C = 0 (Rs) or S02R7, then each R is independently selected from the group consisting of H, halogen -OH, -NH2, -N02 , -CN, -N3, -S03H, acyl, alkyl, alkylamino, cycloalkyl, heterocyclyl, heterocyclylalkyl, alkenyl, (hetero-) aryl, (hetero-) arylthio, and (hetero-) arylamino; wherein each acyl, alkyl, alkylamino, cycloalkyl, heterocyclyl, heterocyclylalkyl, alkenyl, (hetero-) aryl, (hetero-) arylthio, and (hetero-) arylamino can be substituted with one or more radicals independently selected from the group consisting of halogen, N, 0, -S-, -CN, -N3-SH, nitro, oxo, acyl, alkyl, alkoxy, alkylamino, alkenyl, aryl, (heter-) cycloalkyl, and (hetero-) cyclyl.

In another embodiment of the invention, for the compounds of the formula I, if R2 C = 0 (R5) or S02R7, then there are at least two Rs attached to the benzene ring. In addition, there are at least two R groups attached to the benzene ring, and both R groups are attached at positions 2, 3 or 5 on the benzene ring. Still further, each R is independently selected from the group consisting of H, halogen -OH, -NH2, -N02, -CN, -N3, -S03H, acyl, alkyl, alkylamino, cycloalkyl, heterocyclyl, heterocyclylalkyl, alkenyl, -) aryl, (hetero-) arylthio, and (hetero-) arylamino; wherein each acyl, alkyl, alkylamino, cycloalkyl, heterocyclyl, heterocyclylalkyl, alkenyl, (hetero-) aryl, (hetero-) arylthio, and (hetero-) arylamino can be substituted with one or more radicals independently selected from the group consisting of halogen, N, 0, -S-, -CN, -N3-SH, nitro, oxo, acyl, alkyl, alkoxy, alkylamino, alkenyl, aryl, (heter-) cycloalkyl, and (hetero-) cyclyl.

In another embodiment of the invention, for the compounds of the formula I, If R2 is C = 0 (R5), then R5 is selected from the group consisting of -NR16, NHNHR16, NHOH, -OR15, CONH2NHR? E, CONRie, CH2X, acyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclic, and heterocyclylalkyl; wherein each acyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclic, and heterocyclylalkyl can be substituted with one or more radicals independently selected from the group consisting of halogen, N, 0, -S-, -CN, -N3, nitro, oxo, acyl, alkyl, alkoxy, alkylamino, alkenyl, aryl, (hetero-) cycloalkyl, and (hetero-) cyclyl.

In another embodiment, the present invention provides compounds of formula II: wherein R = OR '' ', SR' '', NR '' ', alkyl or halide and R' '' = alkyl, aryl, or H, and wherein R can be in the 6, 7, 8 position, or 9. Formula II is also discussed in pending application 10 / 680,988, the description of which is hereby incorporated by reference in its entirety.

Activity Routes The compounds of the invention such as the compounds of the formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij, Ik, 1-1 and Im, reduce the open probability of RyR by increasing the affinity of FKBP12 (calstabinl) and FKBP12.6 (calstabin2), for respectively the PKA-phosphorylated RyRl and the PKA-phosphorylated RyR2. In addition, the compounds of the invention normalize the periodic activation of mutant RyR channels, including mutant RyR2 channels associated with catecholaminergic polymorphic ventricular tachycardia, by increasing the binding affinity of FKBP12 (calstabin2) and FKBP12.6 (calstabin2). Therefore, the compounds of the invention refer to disorders and conditions that involve the modulation of RyR receptors, particularly the RyR1 and RyR2 receptors. Examples of such disorders and conditions include, without limitation, cardiac disorders and diseases, skeletal muscle disorders and disorders, disorders and diseases of knowledge, malignant hyperthermia, diabetes and sudden infant death syndrome. Disorder and heart disease include, but are not limited to disorders and irregular heartbeat diseases; disorders and diseases of irregular heartbeat induced by exercise, sudden cardiac death; sudden cardiac death induced by exercise; congestive heart failure; pulmonary disease chronic obstruction; and high blood pressure. Disorders and diseases of irregular heartbeats include and diseases and disorders of irregular heartbeat induced by exercise include, but are not limited to atrial and ventricular arrhythmia; atrial and ventricular fibrillation; atrial and ventricular tachyarrhythmia; atrial and ventricular tachycardia; catecholaminergic polymorphic ventricular tachycardia (CPVT); and the variants induced by exercising them. Skeletal-muscular diseases and disorders include, but are not limited to, muscular skeletal fatigue, exercise-induced skeletal muscle fatigue, muscular dystrophy, bladder disorders and incontinence. Disorders and diseases of knowledge include but are not limited to Alzheimer's disease, forms of memory loss and a loss of age-dependent memory. The compounds of the invention treat these disorders and conditions by increasing the binding affinity of FKBP12 (calstabinl) -R and Rl and increasing the binding affinity of FKBP12.6 (calstabin2) -R and R2.

In accordance with the foregoing, the present invention provides a method for limiting or preventing a decrease in the level of RK-bound FKBP (calstabin) in the cells of a subject. As used here, RyR includes RyRl, RyR2 and RyR3. Additionally, the FKBP includes both FKBP12 (calstabinl) and FKBP12.6 (calstabin2). The joined FKBP RyR therefore refers to the bound FKBP12 (calstabinl) RyRl, FKBP12.6 (calstabin2) bound RyR2 and the bound FKBP12 (calstabinl) RyR3.

As used herein, "RyR" also includes a "RyR protein" and an "RyR analog". An "RyR analog" is a functional variant of the RyR protein, the biological activity RyR having 60% or more greater amino acid sequence homology with the RyR protein. The RyR of the present invention are non-phosphorylated, phosphorylated (for example by PKA) or hyperphosphorylated (for example by PKA). As further used herein, the term "biological activity RyR" refers to the activity of a protein or peptide that demonstrates an ability to physically associate with, or bind, FKBP12 (calstabinl) in the case of RyR1 and RyR3, and FKBP12.6 (calstabin2) in the case of RyR2 (for example the union of approximately twice or approximately five times, above the background junction of a negative control) under the test conditions described herein.

As used herein, "FKBP" includes both "one FKBP protein" and one "FKBP analog", whether it is FKBP12 (calstabinl) or FKBP12.6 (casltabin2). Unless stated otherwise herein, "protein" will include a protein, protein domain, polypeptide or peptide or any fragment thereof. An "FKBP analogue" is a functional variant of the FKBP protein, having the biological activity FKBP, which has 60% or more sequence-amino acid homology with the FKBP protein, whether it is FKBP12 (calstabinl) or FKBP12 .6 (calstabin2). As further used herein, the term "FKBP biological activity" refers to the activity of a protein or peptide that demonstrates an ability to physically associate with or agglutinate with non-phosphorylated or non-hyperphosphorylated RyR2 (e.g., the binding of approximately two times or about five times above the background binding of a negative control) under the conditions of the assays described herein.

The FKBP joins the RyR channel, one molecule per sub-unit RyR. Thus, as used herein, the term "FKBP-linked RyR" includes a molecule of a FKBP12 protein (calstabin) that is linked to a RyR1 protein sub-unit or a FKBP12 tetramer that is in association with a tetramer of RyRl, a jprotein molecule FKBP12.6 (calstabin2) that is linked to a RyR2 protein subunit or a tetramer of FKBP12.6, which is in association with a RyR2 tetramer, and a molecule of a FKBP12 protein (calstabinl) ) which is linked to a RyR3 protein subunit unit or a FKBP12 tetramer that is in association with a RyR3 tetramer. Thus, FKBP bound RyR refers to FKBP12 bound RyRl, "FKBP12.6 bound RyR2" and "FKBP12 bound RyR3".

According to the method of the present invention, a "decrease" or "disorder" at the level of FKBP bound RyR in the cells of a subject refers to a detected decrease, decrease or reduction detected at the level of FKBP bound RyR in the subject's cells. Such a decrease is limited or prevented in the cells of a subject when the decrease is in any way arrested, impaired, prevented, obstructed or reduced by the administration of the compounds of the invention, so that the level of FKBP bound RyR in the cells of the subject is superior to what would otherwise be in the absence of the compound administered.

The level of FKBP bound RyR in a subject is detected by standard assays and techniques, including those readily determined from known art (e.g. immunological phenonics, hybridization analysis, immunoprecipitation, Western blot analysis, fluorescence imaging techniques and / or radiation detection, etc.), as well as any assay and detection methods described herein. For example, the protein is isolated and purified from cells of a subject using standard methods known in the art, including, without limitation, extraction of cells (for example with a detergent that solubilizes the protein) where necessary, followed by purification of affinity on a column, chromatography (for example FTLC and HPLC), immunoprecipitation (with an anti-body) and precipitation (for example with isopropanol and a reagent such as Trizol). Isolation and prurification of the protein followed by electrophoresis (for example, on an SDS-polyacrylamide gel). A decrease in the level of FKBP bound RyR in a suejto, or as the limitation or prevention thereof is determined by comparing the amount of FKBP bound RyR detected prior to administration of JTV-519 or a compound of formula I , Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, 1-1 or Im, (according to the methods described below) with the amount detected an adequate time after the administration of the compound A decrease in the level of FKBP bound RyR in the cells of a subject was limited or prevented, for example by inhibiting the dissociation of FKBP and RyR in the cells of the subject; and by increasing the binding between FKBP and RyR in the cells of the subject; or by stabilizing the RyR-FKBP complex in the cells of a subject. As used herein, the term "inhibit dissociation" includes blocking, decreasing, inhibiting, limiting or preventing the physical disassociation or separation of a FKBP subunit from a RyR molecule in the subject's cells, and blocking, decreasing, inhibiting , limiting or avoiding the disassociation or physical separation of a RyR molecule from a FKBP subunit in the cells of a subject. As further used herein, the term "binding with increment" includes improving, increasing or enhancing the ability of the phosphorylated RyR to physically associate with the FKBP (e.g., the binding of approximately two times or approximately five times, above the binding). background of a negative control) in cells of the subject and improving, increasing or increasing the ability of the FKBP to physically associate with the phosphorylated RyR (for example the binding of approximately twice or approximately five times, above the background binding of a negative control) in cells of the subject. Additionally, a decrease in the level of RyR-bound KFBP in the cells of a subject is limited or prevented by directly decreasing the level of phosphorylated RyR in the subject's cells by indirectly decreasing the level of phosphorylated RyR in the cells (e.g. specify an enzyme (such as PKA) or another endogenous molecule that regulates or modulates the functions or levels of phosphorylated RyR in cells). In one embodiment, the level of phosphorylated RyR in the cells is decreased by at least 10% in the method of the present invention. In another embodiment, the level of forformed RyR is decreased by at least 20%.

The subjects of the present invention are the in vitro and in vivo systems, including without limitation the isolated or cultured tissues or cells and the in vitro test systems without cell and an animal (for example an amphibian, a bird, a fish, a a mammal, a marsupial, a human, a pet (such as a cat, dog, monkey, mouse or rat) or a commercial animal (such as a cow or a pig)).

The cells of a subject include striated muscle cells. A striated muscle is a muscle in which the repetitive units (sarcomeres) of the contractile myofibers are arranged in coincidence through the cell, resulting in transverse or oblique striations that are observed at the level of a light microscope. Examples of striated muscle cells include, without limitation, voluntary (skeletal) muscle cells and cardiac muscle cells. In one embodiment, the cell used in the method of the present invention is a human cardiac muscle cell. As used herein, the term "cardiac muscle cell" includes cardiac muscle fibers, such as those found in the myocardium of the heart. Cardiac muscle fibers are composed of contiguous muscle-heart cell chains or cardiomyocytes, joined end-to-end in interspersed discs. The discs possess two kinds of cell joints: expanded desmosomes that extend along their transverse parts and separation joints, the largest which lies along their longitudinal parts.

A decrease in the level of RyR-bound FKBP is limited or edited in the cells of the suejto by administering the compounds of the invention to the subject; this also allows contact between cells of the subject and the compounds of the invention. The compounds of the invention are modulators of calcium-ion channels. In addition to regulating calcium levels in the myocardial cells, the compounds of the invention modulate the Na + current and rectifier K + current inwards in the cells, such as guinea pig ventricular cells, and inhibit the K + current of the cells. delayed rectifier in the cells, such as the ear cells of the guinea pig.

Pharmaceutical composition The compounds of the invention are formulated in pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo. According to another aspect, the present invention provides a pharmaceutical composition comprising compounds of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, I_k, 1-1 or Im, in combination with the pharmaceutically acceptable diluent and / or carrier. The pharmaceutically acceptable carrier must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the container thereof. The pharmaceutically acceptable carrier used herein is selected from various organic or inorganic materials that are used as materials for pharmaceutical formulations and which are incorporated analgesic agents, buffers, binders, disintegrants, diluents, emulsifiers, excipients, engenders, glidants, solubilizers, stabilizers, suspension agents, tonicity agents, vehicles and viscosity increase agents. If necessary, pharmaceutical additives such as anti-oxidants, aromatics, colorants, flavoring agents, preservatives and sweeteners are also added. Examples of acceptable pharmaceutical carriers include carboxymethylcellulose, crystalline cellulose, glycerin, gum arabic, lactose, magnesium stearate, methyl cellulose, powders, salt water, sodium alginate, sucrose, starch, talc and water, among others.

The pharmaceutical formulations of the present invention are prepared by methods well known in the pharmaceutical arts. For example, the compounds of the formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, 1-1 or Im, are put in association with a carrier and / or a diluent as a suspension or solution. Optionally, one or more accessory ingredients (e.g., buffers, flavor agents, active surface agents and the like) are also added. The choice of carrier is determined by the solubility and chemical nature of the compounds, the chosen route of administration and standard pharmaceutical practice.

The compounds of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, I_h, Ii, I_j, Ik, 1-1 or Im, are administered to a subject by contacting the specific cells (e.g. cardiac muscle cells) in vivo in the subject with the compounds. The compounds are contacted with (for example, introduced into) the cells of the subject using the known techniques used for the introduction and administration of proteins, nucleic acids and other drugs. Examples of methods for contacting the cells with (for example treating the cells with) the compounds of the invention include, without limitation, absorption, electroporation, immersion, injection, introduction, delivery of lipose, transfection, transfusion, vectors and other methods and vehicles for drug delivery. When the target cells are located in a particular portion of a subject, it is desirable to introduce the compounds of the invention directly into the cells, by injection or by some other means (e.g., by introducing the compounds into the blood or other body fluid). The target cells are contained in the tissue of a subject and are detected by the readily determined standard detection methods of the known art, examples of which include, without limitation, immunological techniques (e.g. immunoistochemical staining), training techniques of fluorescence image and microscopic techniques.

Additionally, the compounds of the present invention are administered to a human or an animal subject through known methods, including without limitation, oral administration, sub-lingual or buccal administration., parenteral administration, transdermal administration, through inhalation or intranasally, vaginally, rectally and intramuscularly. The compounds of the invention are administered parenterally, by epifacial, intracapsular, intracranial, intracutaneous, intrathecal, intramuscular, intraorbital, intraperitoneal, intraspinal, intrasternal, intramuscular, intravenous, parequimal, subcutaneous or sub-lingual injection or by any manner of catheter. In one embodiment, the agent is administered to the subject via delivery to the subject's muscles including, but not limited to, the subject's cardiac muscles. In one embodiment, the agent is administered to the subject via a target delivery to the cardiac muscle cells through a catheter inserted into the subject's heart.

For oral administration, the formulation of the compounds of the invention can be present as capsules, tablets, powders, granules or as a suspension or solution. The formulation has conventional additives, such as lactose, mannitol, corn starch or potato starch. The formulation is also presented as binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatin. Additionally, the formulation is presented with disintegrators, such as corn starch, potato starch or sodium carboxymethylcellulose. The formulation is also presented as a sodium starch or anhydrous dibasic calcium phosphate glycolate. Finally, the formulation is presented with lubricants such as magnesium stearate or talc.

For parenteral administration (eg, administration by injection through a route other than the alimentary canal), the compounds of the invention are combined with a sterile aqueous solution which is isotonic with the bleed of the subject. Such a formulation is prepared by dissolving a solid active ingredient in water containing physiologically compatible substances, such as sodium chloride, glycine and the like, and having a buffered pH compatible with physiological conditions, such as to produce an aqueous solution and then making said solution sterile. The formulation is presented in multiple dose or dose unit containers, such as sealed containers or ampoules. The formulation is delivered by any injection mode, including, without epifacial, intracapsular, intracranial, intracutaneous, intrathecal, intramuscular, intraorbital, intraperitoneal, intraspinal, intrasternal, intramuscular, intravenous, parequimatose, subcutaneous, or sublingual by any form of the catheter. of the subject's heart.

For transdermal administration, the compounds of the invention are combined with skin penetration enhancers, such as propylene glycol, polyethylene glycol, isopropanol, ethanol, oleic acid, N-methyl pyrrolidone and the like, which increase the permeability of the skin. to the compounds of the invention and allow the compounds to penetrate through the skin and into the bloodstream. The enhancer / compound compositions can also be further combined with a polymeric substance, such as ethyl cellulose, hydropropyl cellulose, ethylene / vinyl acetate, polyvinyl pyrrolidone and the like, to provide the composition in the form of a gel, which are dissolved in a solvent , such as methylene chloride, and not stopped at the desired viscosity and then applied to the backing material to provide a patch.

In some embodiments, the composition is in a unit dosage form such as a tablet, capsule or single-dose vial. Suitable unit doses, for example, therapeutically effective amounts, can be determined during properly designed chemical tests for each of the conditions for which the administration of the chosen compound is indicated and will, of course, vary depending on the endpoint. desired clinical The present invention also provides articles of manufacture for treating and preventing disorders, such as cardiac disorders, in a subject. The articles of manufacture comprise a pharmaceutical composition of one or more of the compounds of formula I, Ia, Ib, Ic, Id, Ie, If,? -q, Ih, Ii, Ij, I ~ k, 1-1, or Im, as described here. The articles of manufacture are packaged with indications for various disorders that are capable of treating and / or preventing pharmaceutical compositions. For example, articles of manufacture comprise a unit dose of a compound described herein that is capable of treating or preventing a muscle disorder, and an indication that the unit dose is capable of treating or preventing a certain disorder, for example a arrhythmia.

According to a method of the present invention, the compounds of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, 1-1, or Im, are administered to the subject (or are contacted with the cells of the subject) in an amount effective to limit or prevent a decrease in the level of FKBP RyR in the subject, particularly in the cells of the subject. The amount is easily determined by a skilled artisan, based on known methods, including the analysis of the splitting curves established in vivo and the test methods described herein. In one embodiment, an adequate amount of the compounds of the invention effective to limit or prevent the decrease in the level of FKBP bound RyR in the subject ranges from about 0.01 mg / kg / day to about 20 mg / kg / day. , and / or is an amount sufficient to achieve plasma levels ranging from about 300 ng / ml to about 1,000 ng / ml. In one embodiment, the amount of compound of the invention ranges from about 10 mg / kg / day to about 20 mg / kg / day. In another embodiment, from about 0.01 mg / kg / day to about 10 mg / kg / day is administered. In another embodiment it is administered, from about 0.01 mg / kg / day to about 5 mg / kg / day. In another embodiment, it is administered from about 0.05 mg / kg / day to about 5 mg / kg / day. In another preferred embodiment, it is administered from about 0.05 mg / kg / day to about 1 mg / kg / day.

Applications The present invention provides a new range of therapeutic treatments for patients with various disorders involving the modulation of RyR receptors, particularly muscle skeletal disorders (RyRl), cardiac disorders (RyR2), and knowledge disorders.

(RyR3).

In one embodiment, of the present invention, the subject has not yet developed a disorder, such as cardiac disorders (eg, cardiac arrhythmia induced by exercise). In another embodiment of the present invention, the subject requires treatment for a disorder including a cardiac disorder.

Various disorders that can prevent or treat the compounds of the invention include, but are not limited to, cardiac disorders and heart diseases, skeletal muscle disorders and disorders, disorders and diseases of consciousness, malignant hyperthermia, diabetes and sudden infant death syndrome. Cardiac disorders and diseases include, but are not limited to disorders and diseases of irregular heartbeat; irregular heartbeat disorders and diseases induced by exercise; sudden cardiac death; sudden cardiac death induced by exercise; congestive heart failure; chronic obstructive pulmonary disease; and blood pressure higher. Irregular heartbeat disorders and diseases include and irregular exercise-induced heartbeat disorders and diseases include, but are not limited to, atrial and ventricular arrhythmia; atrial and ventricular fibrillation; articular and ventricular tachyarrhythmia; atrial and ventricular tachycardia; catecholaminergic polymorphic ventricular tachycardia (CPVT); and the variants induced by exercising them. Muscle skeleton disorders and diseases include, but are not limited to, skeletal muscle fatigue, exercise-induced skeletal muscle fatigue, muscular dystrophy, bladder disorders and incontinence. Disorders of knowledge and diseases include, but are not limited to, Alzheimer's disease, or forms of memory loss and age-dependent memory loss. One skilled in the art will recognize that still other uses, including but not limited to the muscular and cardiac disorders that are useful in treating the compounds of the invention, according to the invention are provided herein.

The amount of compounds of the invention effective to limit or prevent a decrease in the level of FKBP 12.6 bound RyR2 in the subject is an effective amount to avoid exercise-induced cardiac arrhythmia in the subject. Cardiac arrhythmia is a disturbance of the electrical activity of the heart that manifests as an abnormality in the heart rate or heart rhythm. As used here, an amount of compounds of the invention "effective to avoid exercise-induced cardiac arrhythmia" includes an amount of the compounds of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, 1-1, or Im, effective to prevent the development of injury or clinical symptoms of exercise-induced cardiac arrhythmia (eg, palpitations, fainting, ventricular fibrillation, ventricular tachycardia and sudden cardiac death.) The amount of the compounds effective for avoiding cardiac arrhythmia induced by exercise in the subject will vary depending on the particular factors of each case, including the type of cardiac arrhythmia induced by exercise, the weight of the subject, the severity of the condition of the subject, and the mode of administration of the subjects. This amount is easily determined by an expert artisan, based on known procedures, including clinical trials, and methods described herein. the amount of the compounds of the invention effective to prevent exercise-induced cardiac arrhythmia is an effective amount to prevent sudden cardiac death induced by exercise in the subject. In another embodiment, the compounds of the invention prevent cardiac arrhythmia induced by exercise and sudden cardiac death induced by exercise in the subject.

Because of their ability to stabilize the bound RyK FKBP and maintain and restore balance in the context of dynamic PKA phosphorylation and RyR dephosphorylation, the compounds of the invention are useful for treating a subject who has already experienced clinical symptoms of RyR. These various disorders. For example, if the symptoms of the disorder are observed in the subject sufficiently early, the compounds of the formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, I_k, 1-1 , or Im, are effective to limit or prevent an additional decrease in the level of FKBP bound RyR in the subject.

Additionally, the subject of the present invention is a candidate part. cardiac disorders induced by exercise, such as cardiac arrhythmia induced by exercise. Exercise-induced cardiac arrhythmia is a condition of the heart (eg, ventricular fibrillation or ventricular tachycardia, including any that leads to sudden cardiac death) that develops during / after a subject has uploaded a physical exercise. A "candidate" for an exercise-induced cardiac disorder is a subject that is known, or is believed to be, suspected of being at risk of developing a cardiac disorder during / after exercise. Examples of candidates for cardiac arrhythmia induced by exercise include, without limitation, an animal / person known to have a catecholaminergic polymorphic ventricular tachycardia (CPVT); an animal / person suspected of having a catecholaminergic polymorphic ventricular tachycardia; and a person / animal that is known or believed to be suspected of being at risk of developing cardiac arrhythmia during / after physical exercise, and who is about to exercise, is currently exercising or has just completed the exercise. As discussed above, catecholaminergic polymorphic ventricular tachycardia is an inherited disorder in individuals with structurally normal hearts. This is characterized by stress-induced ventricular tachycardia-a lethal arrhythmia that causes sudden cardiac death. In subjects with catecholaminergic polymorphic ventricular tachycardia, physical exercise and / or stress induce bidirectional and / or polymorphic ventricular tachycardia leading to sudden cardiac death (SCD) in the absence of a detected structural heart disease. Individuals with catecholaminergic polymorphic ventricular tachycardia have ventricular arrhythmias when undergoing exercise, but do not develop arrhythmias at rest.

Therefore, in yet another embodiment of the presumed invention, the subject has exercised, or is exercising and has developed a disorder induced by exercise. In this case, the amount of the compounds of the invention effective to limit or prevent a decrease in the level of RyK-bound FKBP in the subject is an amount of compound effective to treat the disorder induced by exercise in the subject. As used herein, an amount of compounds of the invention "effective to treat an exercise-induced disorder" includes an amount of a compound of the formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii , Ij, Ik, 1-1, or Im, effective to alleviate or lessen the injury or clinical symptoms of exercise-induced disorder (e.g. in the case of cardiac arrhythmia, palpitations, fainting, ventricular fibrillation, ventricular tachycardia and sudden cardiac death) ). The amount of the compounds of the invention effective to treat an exercise-induced disorder in the subject will vary depending on the particular factors of each case, including the type of disorder induced by exercise, the subject's weight, the severity of the subject's condition , and the mode of administration of the compounds. This amount is easily determined by the skilled artisan, based on known procedures, including clinical trials, and method described herein. In one embodiment, the compounds of the formula I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, I-j, I-k, 1-1, or I-m, treat the disorders induced by exercise in the subject.

The present invention further provides a method for treating exercise-induced disorders in a subject. The method comprises administering the compounds of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, 1-1, or Im, to the subject in an effective amount to treat the disorder induced by exercise in the subject. A suitable amount of the compounds effective to treat, for example, exercise-induced cardiac arrhythmia in the subject varies from about 5 milligrams / kilogram / day to about 20 milligrams / kilogram / day and / or is an amount sufficient for achieve plasma levels ranging from about 300 ng / ml to about 1,000 ng / ml. The present invention also provides a method for preventing an exercise-induced disorder in a subject. The method comprises administering the compounds of the invention to the subject in an amount effective to prevent exercise-induced disorder in the subject. An adequate amount of the compounds of the invention effective to prevent exercise-induced disorder in the subject ranges from about 5 mg / kg / day to about 20 mg / kg / day and / or is an amount sufficient to achieve levels plasma ranging from about 300 ng / ml to about 1,000 ng / ml. Additionally, the present invention provides a method for avoiding disorders induced by exercise in a subject. The method comprises administering the compounds of the invention to the subject in an amount effective to prevent an exercise-induced disorder in the subject. An adequate amount of the compounds of the invention effective to prevent an exercise-induced disorder in the subject ranges from about 5 mg / kg / day to about 20 mg / kg / day, and / or is a sufficient amount to achieve plasma levels ranging from about 300 ng / ml to about 1,000 ng / ml.

Additionally, the compounds avoid irregular heartbeat disorders in subjects with heterozygosity defects in the FKBP 12.6 gene.

The compounds of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, 1-1, or Im, can be used alone, in combination with each other, or in combination with other agents having cardiovascular activity including, but not limited to, diuretics, anticoagulants, antiplatelet agents, antiarrhythmics, inotropic agents, chronotropic agents, a and b blockers, angiotensin inhibitors and vasodilators. In addition, such combinations of the compounds of the present invention and other cardiovascular agents are administered separately or in conjunction. In addition, the administration of an element of the combination is prior to, concurrent or subsequent to the administration of other agents.

In several embodiments of the methods described above, cardiac arrhythmia induced by exercise in the subject is associated with ventricular tachycardia. In some embodiments, ventricular tachycardia is catecholaminergic polymorphic ventricular tachycardia. In other embodiments of these methods, the subject is a candidate for exercise-induced cardiac arrhythmia, including candidates for sudden cardiac death induced by exercise.

In view of the above methods, the present invention also provides the use of the compounds of the invention in a method for limiting or preventing a disorder at the level of RyK-bound FKBP in a subject who is a candidate for a disorder. The present invention also provides the use of the compounds of the invention in a method for treating or preventing a muscle disorder in a subject. In addition, the present invention provides the use of the compounds of the invention in a method for preventing the treatment or preventing muscle disorders induced by exercise in a subject.

Accordingly, therefore, the present invention further provides a method for testing the effects of the compounds of the invention to prevent disorders and diseases associated with RyR receptors. The method comprises the steps of: (a) obtaining or generating a cell culture containing RyR; (b) contacting the cells with one or more of the compounds of the invention; (c) exposing the cells to one or more known conditions because it increases the phosphorylation of RyR in the cells; and (d) determining whether one or more compounds of the invention limit or prevent a decrease in the level of FKBP bound RyR in the cells. As used herein, a "RyR containing" cell is a cell in which the RyR, including RyR1, RyR2, and RyR3, or a derivative or homologue thereof, is naturally expressed or occurs naturally. The conditions known to increase the phosphorylation of RyR in cells include, without limitation, PKA.

In the method of the present invention, the cells are contacted with one or more of the compounds of the invention by any of the standard methods for effecting contact between the drugs / agents and cells, including any modes of introduction and administration described. here. The level of FKBP bound RyR in the cell is measured is detected by known methods, including any of the methods, molecular procedures and assays known to one skilled in the art or described herein. In one embodiment of the present invention, the one or more compounds of the invention limits or prevents a decrease in the level of FKB bound RyR in the cells.

The RyR, including RyRl, RyR2 and RyR3, have been implicated in the number of biological events in the cells. For example, it has been shown that RyR2 channels play an important role in EC coupling and contraction in cardiac muscle cells. Therefore, it is clear that preventive drugs designed to limit or prevent a decrease in the level of FKBP bound RyR in cells, particularly the FKBP 12.6 bound RyR2 in cardiac muscle cells are useful in regulating a number of biological events associated RyR, including contraction and EC coupling. Therefore, the one or more compounds of the invention are evaluated for effects on EC coupling and contraction in cells, particularly heart muscle cells, and therefore, useful in preventing sudden cardiac death induced by exercise.

Thus, the method of the present invention further comprises the steps of contacting one or more compounds with a cell culture containing RyR; and determining if one or more compounds has an effect on a biological event associated with RyR in the cells. As used herein, a "biological event associated with RyR" includes a biochemical or physiological process in which RyR levels or activity have been implicated. As discussed herein, examples of biological events associated with RyR include, without limitation, EC coupling and contraction in cardiac muscle cells. According to this method of the present invention, the one or more compounds are contacted with one or more cells (such as heart muscle cells) in vitro. For example, a culture of the cells is incubated with a preparation containing one or more compounds of the formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, 1-1, or Im. The effect of the compounds on the biological event associated with RyR is then evaluated by any assays or biological methods known in the art, including the single-channel, immunoblotting and any others described herein.

The present invention is further directed to one or more compounds of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij Ik, 1-1, or Im, identified by the identification method described above, as well as the pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier and / or diluent. The compounds are useful for preventing sudden cardiac death induced by exercise in a subject, and for treating or avoiding other conditions associated with RyR. As used herein, an "associated RyR condition" is a condition, disease or disorder in which the RyR level or activity is involved and includes a biological event associated with RyR. The associated condition RyR is treated or prevented in the subject by administering to the subject a quantity of the effective compound to treat or avoid the associated RyR condition in the subject. This amount is easily determined by an expert in the art. In one embodiment, the present invention provides a method for preventing sudden cardiac death induced by exercise in a subject, by administering the one or more compounds of the invention to the subject in an effective amount to prevent sudden cardiac death induced by exercise in the subject.

The present invention also provides a method in vivo for testing the effectiveness of the compounds of the invention to prevent disorders and diseases associated with RyR receptors. The method comprises the steps of: (a) obtaining or generating an animal containing RyR; (b) administering one or more of the compounds of the invention to the animal; (c) exposing the animal to one or more known conditions because they increase the phosphorylation of RyR in the cells; and (d) determining the extent of the limits of the compound or preventing a decrease in the level of FKBP bound RyR in the animal. The method further comprises the steps of: (e) administering one or more of the compounds of the invention to an animal containing RyR; and (f) determining the extent of the effect of the compound on an associated biological event RyR in the animal. A pharmaceutical composition comprising that compound is also provided; and a method for preventing sudden cardiac death induced by exercise in a subject, by administering that compound to the subject in an effective amount to avoid sudden cardiac death induced by exercise in the subject.

It has been shown that compounds which block PKA activation can be expected to reduce activation of the RyR channel, resulting in less calcium release within the cell. The compounds that agglutinate the RyR channel at the FKBP binding site, but do not exit outside the channel when the channel is phosphorylated by PK. It would also be expected that the activity of the channel would decrease in response to PK activation or other triggers that activate the RyR channel. Such compounds will also result in less calcium release inside the cell.

By way of example, diagnostic assays explore the release of calcium into cells through the RyR channel, using calcium-sensitive fluorescent dyes (e.g., fluo-3, fura-2, and the like). The cells are loaded with the fluorescent dye of choice, then simulated with RyR activators to determine the reduction of the calcium-dependent fluorescent signal (Brilliant and others, stabilization of the function of calcium channel release (ryanodine receptor) by protein FK506 binding cell 77: 513-23, 1994; Gillo et al., calcium entry during induced differentiation in murine erythroleukemia cells, Sangre, 81: 783-92, 1993; Jayaraman et al., inositol regulation 1, 4, 5 tri-phosphate receptor by tyrosine phosphorylation Science (272: 1492-94, 1996) Fluorescent signals depending on calcium are monitored with a photomultiplier tube, and analyzed with appropriate software This assay can be easily automated to explore compounds of the invention using multiple well plates.

To demonstrate that the compounds for inhibiting PK-dependent activation of RyR-mediated intracellular calcium release, any assay involves the expression of recombinant RyR channels in a heterologous expression system, such as Sf9, HEK293, or CHO cells. RyR can also be expressed in conjunction with beta-adrenergic receptors. This will allow the evaluation of the effect of the compounds of the invention on RyR activation, in response to the addition of beta-adrenergic receptor agonists.

PK phosphorylation level of RyR2 which correlates with the degree of heart failure is also tested and then used to determine the efficacy of one or more compounds of the invention to block PKA phosphorylation of the RyR2 channel. Such an assay is based on the use of antibodies that are specific for the RyR2 protein. For example, the RyR2 channel protein is immunoprecipitated and then phosphorylated back with PK and [gamma32P] -ATP. The amount of radioactive [32 P] tag is transferred to the RyR2 protein then measured using a phosphimagner (Marx et al., PKA diasocia phosphorylation FKBP12.6 calcium channel release (ryanodine receptor): defective regulation in failing hearts, Cell, 101: 365-76, 2000).

Another assay of the compounds of the invention involves the use of a specific antibody-phosphoepitope that detects RyR1 which is PKA phosphorylated on Ser 2843 or RyR2 which is PKA phosphorylated on Ser 2809. Immunoblotting with such antibody can be used to evaluate the efficacy of these compounds for therapy for heart failure and cardiac arrhythmias. Additionally, RyR2 S2809A and RyR2 S2809D mice are used to evaluate the efficacy of therapy for heart failure and cardiac arrhythmias. Such mice also provide evidence that PKA hyperphosphorylation of RyR2 is a contributing factor in heart failure and cardiac arrhythmias by showing that the RyR2 S2809 mutation inhibits heart failure and arrhythmias, and that the RyR2 S2809D mutation becomes worse heart failure and arrhythmias.

Thus, in a specific embodiment, the present invention provides a method for the treatment of heart failure, atrial fibrillation or exercise-induced cardiac arrhythmia, comprising administering to an animal in need thereof, a therapeutically effective amount of a compound selected from the compounds of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, 1-1, or Im.

Intracellular calcium filtering is proposed as a major mediator of depressed muscle performance and dystrophic muscle remodeling. Muscular dystrophies are heterogeneous hereditary diseases characterized by weakness and wasting of progressive muscle. Of all the forms of muscle atrophies, involving the protein complex used with dystrophy (here referred to as dystrophinopathy), Duchenne muscular dystrophy (DMD) is one of the most frequent genetic diseases (X-linked, 1 in 3,500 children) with death usually occurring before 30 years of age due to respiratory and / or cardiac failure in high numbers of patients. Becker muscular dystrophy (BMD) represents a milder form of the disease associated with a reduction in the amount or expression of a truncated form of the dystrophin protein whereas the Duchenne patients have been characterized by a complete absence or very low levels of dystrophin . Becker and Duchenne muscular dystrophy (DMD / BMD) are caused by mutations in the gene coding for the dystrophin proteins 427-kDa cytoskeleton. However, with increasing age in cardiac symptoms BMD are more common than in DMD patients and do not correlate with skeletal muscle symptoms. Since genetic analysis does not eliminate DMD due to the high incidence of sporadic cases, an effective therapy is highly desirable. DMD / BMD has been consistently associated with calcium metabolism in the disturbed cell. Due to alterations of intracellular calcium concentrations in DMD myofibers is thought to represent a central pathogenic mechanism, the development of a therapeutic intervention that avoids intracellular calcium abnormalities as a cause of skeletal muscle degeneration is highly desirable.

It is well established that the lack of dystrophin expression is the primary genetic defect in DMD and BMD. However, the key mechanism that leads to progressive muscle damage is largely unknown. It has been suggested that elevations in intracellular calcium concentrations ([Ca2 +] i) under resting conditions directly contribute to cell damage (myofibra) of toxic muscle and the concurrent activation of Ca2 + calcium-dependent proteases. Given that calpain activity is increased in the necrotic muscle fibers of mdx mice and calpain dysfunction contributes to limb-girdle muscular dystrophy, the preventive activation of calcium-dependent proteases by inhibiting intracellular calcium elevations represents a strategy to avoid wasting the muscle in DMD. Significant increases in [Ca2 +] i between normal and dystrophic muscles have been reported in myotubes and animal models including the dystrophin-deficient mdx mouse. The intracellular calcium elevations are avoided by administration of a pharmaceutical composition comprising a compound of formula I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, I-j, I-k, 1-1, or I-m.

The present invention also provides a method of diagnosing a disease or disorder in a subject, said method comprising: obtaining a cell or tissue sample from a subject; get the DNA from the cell or tissue; compare the DNA of the cell or tissue with the control DNA encoding RyR to determine if a mutation is present in the cell or tissue DNA, the presence of a mutation indicating a disease or disorder. In one embodiment, the mutation is a RyR2 mutation on chromosome Iq42-q43. In another embodiment, the mutation is one or more catecholaminergic polymorphic ventricular tachycardia mutations. In another embodiment, the mutation may be a mutation that is present in the DNA encoding RyR2 of the subject SIDS. The diagnostic method is used to detect the presence of a disease or disorder in an adult, a child or a fetus. Disease and disorder includes, but is not limited to, heart disease and disorders, skeletal muscle disorders and disorders, knowledge disorders and knowledge diseases, malignant hyperthermia, diabetes, and sudden infant death syndrome. Cardiac disorder and disease include, but are not limited to disorders and diseases of irregular heart fiber; disorders of irregular heartbeat induced by exercise and diseases; sudden cardiac death; sudden cardiac death induced by exercise; congestive heart failure; chronic obstructive pulmonary disease; and high blood pressure. Irregular heartbeat disorders and diseases include and irregular heartbeat disorders and diseases indications for exercise include, but are not limited to atrial and ventricular arrhythmia, atrial and ventricular fibrillation; atrial and ventricular tachyarrhythmia; and atrial and ventricular tachycardia; catecholaminergic polymorphic ventricular tachycardia (CPVT); and the variants induced by exercising them. The skeletal muscle disorder and diseases include, but are not limited to, skeletal muscle fatigue, exercise-induced skeletal muscle fatigue, muscular dystrophy, bladder disorders and incontinence. The disorders and diseases of knowledge include, but are not limited to, Alzheimer's disease, forms of memory loss and loss of age-dependent memory.

The present invention further provides a method of diagnosing disorders and diseases in a subject, said method comprising: obtaining a sample of cells or tissue from the subject; incubating the cells or tissue sample with the compound of the invention under conditions which increase the phosphorylation of RyR to the cells; determine (a) whether RyR is bound to casltabin (for example, RyR1 bound to calstabin 1, RyR2 bound to calstabin 2 or RyR3 bound to calstabin 1) is increased in cells or tissue compared to RyR bound to calstabin in cells or control tissues said control cells or tissues lacking mutant RyR calcium channels, or (b) if a decrease in calcium release occurs in the RyR channels compared to a lack of decrease in calcium release to the cells of control; an increase in bound-RyR in (a) indicating a disorder or disease in the subject or a decrease in the release of calcium in the RyR channels in (b) compared to the control cells indicating a disease or cardiac disorder in the subject . The diagnostic method is used to detect the presence of a disease or disorder in an adult such as a child or a fetus. Disorder and disease includes, but is not limited to disorders and heart diseases, skeletal muscle disorders and disorders, disorders of knowledge and diseases, malignant hyperthermia, diabetes, and sudden infant death syndrome. Heart disorders and disorders include, but are not limited to, irregular heartbeat disorders and diseases; irregular heartbeat disorders and diseases induced by exercise; sudden cardiac death; sudden cardiac death induced by exercise; congestive heart failure; chronic obstructive pulmonary disease; and high blood pressure. Irregular heartbeat disorders and diseases include irregular heartbeat disorders and diseases induced by exercise include, but are not limited to, atrial and ventricular arrhythmia; atrial and ventricular fibrillation; atrial and ventricular tachyarrhythmia; atrial and ventricular tachycardia; catecholaminergic polymorphic ventricular tachycardia (CPVT); and the variants induced by exercising them. Muscle skeleton disorders and diseases include, but are not limited to, skeletal muscle fatigue, exercise-induced skeletal muscle fatigue, muscular dystrophy, bladder disorders and incontinence. Disorders of knowledge and diseases include, but are not limited to, Alzheimer's disease, or forms of memory loss and age-dependent memory loss.

The present invention further provides a method of diagnosing a cardiac disorder or disease in a subject, said method comprising: obtaining cells or cardiac tissue samples from a subject; incubating the cells or cardiac tissue sample with the compound of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, I_h, Ii, Ij, Ik, 1-1, or Im, under conditions which increase the phosphorylation of RyR2 in cells; determine (a) whether RyR2 bound to casltabin 2 is increased in cells or tissue compared to RyR2 bound to calstabin 2 in control cells or in tissues said control cells or tissues lacking calcium channels RyR2 mutants, or ( b) whether a decrease in the release of calcium occurs in the RyR2 channels compared to a lack of decrease in the release of calcium in the control cells; an increase in calstabin 2 bound-RyR2 in (a) indicating a disorder or disease in the subject or a decrease in the release of calcium in the RyR2 channels in (b) compared to the control cells indicating a disease or cardiac disorder in the subject. The provided method is used to diagnose catecholaminergic polymorphic ventricular tachycardia. The method provided is also used to diagnose sudden infant death syndrome (SIDS). The method further provided is used to diagnose cardiac irregular heartbeat disorders and disorders; disorders and irregular heartbeat disorders induced by exercise; sudden cardiac death; sudden cardiac death induced by exercise; congestive heart failure; chronic obstructive pulmonary disease; and high blood pressure. Irregular heartbeat disorders and diseases include and irregular exercise-induced heartbeat disorders and diseases include, but are not limited to, atrial and ventricular arrhythmia; atrial and ventricular fibrillation; atrial and ventricular tachyarrhythmia; atrial and ventricular tachycardia; catecholaminergic polymorphic ventricular tachycardia (CPVT); and the variants induced by exercising them.

In addition, to the aforementioned therapeutic uses, the compounds of the invention are also useful in diagnostic assays, screening assays or research tools.

Synthesis Methods The present invention provides in one aspect, processes for the preparation of a compound of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, 1-1, or Im, and the salts, sorbates, hydrates, complexes and pro-drugs thereof and pharmaceutically acceptable salts of such prodrugs. More particularly, the present invention provides processes for the preparation of compounds selected from the group consisting of SI, S2, S3, S4, S5, S6, S7, S9, Sil, S12, S13, S14, S19, S20, S22, S23. , S26, S36, S37, S38, S40, S43, S44, S45, S46, S47, S48, S48, S49, S50, S51, S52, S53, S54, S55, S56, S57, S58, S59, S60, S61, S62 , S63, S64, S66, S67, S69, S70, S72, S73, S74, S75, S76, S77, S78, S79, S80, S81, S82, S83, S84, S85, S86, S87, S88, S89, S90 , S91, S92, S93, S94, S95, S96, S97, S98, S99, SlOO, S101, S102, S103, S104, S105, S107, A108, A109, A110, SIII, S112, S113, S114, S115, S116 , S117, S118, S119, S120, S121, S122, and S123, and salts, sorbates, hydrates, complexes and pro-drugs thereof and the pharmaceutically acceptable salts of such pro-drugs. The various synthetic routes to the compounds are described here.

Some of the following syntheses use solvents. In one embodiment, the solvent is an organic solvent. In another embodiment, the organic solvent is methylene chloride (CH2C12), chloroform (CC14), formaldehyde (CH20) or methanol (CH3P0H). Some of the following syntheses also use a base catalyst. In one embodiment, the base catalyst is an amine compound. In another incorporation, the base catalyst is an alkyl amine such as triethylamine (TEA). In yet another embodiment, the base catalyst is pyridine. Some of the following syntheses also use basic solutions. In one embodiment, the basic solution is sodium bicarbonate or calcium carbonate. In another embodiment, the basic solution is saturated sodium bicarbonate or saturated calcium carbonate. Some of the syntheses use acidic solutions. In one embodiment, the acidic solution is a solution of sulfuric acid, a solution of hydrochloric acid, or a solution of nitric acid. In one embodiment, the solution is N HCl. An expert in the art will appreciate still other solvents, organic solvents, base catalysts, basic solutions, and acidic solutions that are used in the incorporations according to the description given herein. Solvents, organic solvents, reagents, catalysts, washing solutions and others are added at appropriate temperatures (for example, room temperature or around 20 ° C-25 ° C, at 0 ° C, etc.).

Some of the following syntheses use compound S68 as a starting material. S68 is commercially available from MicroChemistry Limited (from Moscow, Russia). Also see WO 01/55118 for the preparation of S68.

Several of the following syntheses use S26 as a starting material. S26 is synthesized as an intermediate in the synthesis of S3, S4, S5 and S54, as illustrated in scheme 1 in example 4. Methods for synthesizing S26 are also described in the patent application of the United States of America No. 10 / 680,988.

Some of the following syntheses require purification of the reaction mixture to give an end point. The purification of the reaction mixture involves one or more processes such as the removal of any solvent, the crystallization of the product, the chromatography separation of the product (including HPLC, silica gel chromatography, column chromatography and others), washing with basic solution, the washing with acidic solution, the redissolution of the product in another solvent and others. An expert in the art will appreciate still other processes that are used in the incorporations, according to the description given here.

The reactions are carried out as required (for example, one hour, several hours, overnight, 24 hours, etc.) to obtain the yields. desired or optimal of the desired compounds. Frequently, the reaction mixtures are stirred. The reactions are carried out at appropriate temperatures (for example, at room temperature or around 20 ° C-25 ° C, 0 ° C, 100 ° C, te).

The Synthon S26 is prepared according to the methods described in the patent application of the United States of America No. 10 / 680,988.

S3, S4, S5, and S54 are prepared from S26. He S26 is reacted with RS02C1, where R is CH2 = CH- (S3), Me- (S4), p-Me-C6H4- (S5), or NH-2-Py (S54), to form a product. The product is purified, for example by column chromatography, to give S3, S4, S5, or S54. In one embodiment, the reaction occurs in a solvent, such as an organic solvent CH2C12, so that a reaction mixture is formed, and the solvent is removed from the reaction mixture before or during the purification of the product. If necessary, a base catalyst, such as triethylamine, is used in the synthesis. Also, basic washes (for example, saturated sodium bicarbonate) and acidic washes (for example IN HCl) are used if necessary to purify the reaction mixture and / or product, and unaccompanied by drying, for example over Sodium sulfate if required. Column chromatography, for example, is used to purify the residue to isolate the desired product.

SI and S2 are prepared from S3 by the reaction with HNR? R2, where R is (SI) or NBu2 (S2). The product is purified, for example, by column chromatography, to give SI or S2. In one embodiment, the reaction occurs in a solvent such as an organic solvent such as CH2C12, so that the reaction mixture is formed, and the solvent is removed from the reaction mixture before or during the purification of the product. Column chromatography, for example, is used to purify the residue to isolate the desired product.

S7, S9, S27 and S40 are prepared from S26 by the reaction with an alcohol of the formula RCOX, wherein X is Cl or NHS and R is ICH2- (S7) m Ph- (S9), CH2 = CH- (S27) ) mo 4-N3-2-OH-C6H5 (S40). In one embodiment, the reaction mixture occurs in a solvent, such as an organic solvent such as CH2C12, so that the reaction mixture is formed, and the solvent is removed from the reaction mixture before or during the purification of the product. If necessary, a base catalyst, such as triethylamine is used in the synthesis. Also, basic washes (for example, saturated sodium bicarbonate) and acidic (eg, IN HCl) are used if required to purify the reaction mixture and / or the product, and are accompanied by drying if required. In another embodiment, S40 is formed by the reaction with an alcohol of the formula RCOX, wherein R is 4-N3-2-OH-C6H5 and X is NHS. Column chromatography, for example, is used to purify the residue to isolate the desired product.Sil and S12 are prepared from S26 by reaction with a compound of the formula C5H4 NCX, wherein X is O (Sil) or S (S12). In one embodiment, the reaction occurs in a solvent such as an organic solvent such as CH2C12, so that the reaction mixture is formed, and the solvent is removed from the reaction mixture before or during the purification of the product. If necessary, a base catalyst, such as triethylamine or pyridine as used in the synthesis. In another embodiment, a base catalyst such as pyridine is used as the solvent in which the reaction takes place, and the additional solvent, such as ethylene acetate or other appropriate organic solvent is added after the reaction occurs. Also, basic (eg, saturated sodium bicarbonate) and acidic (eg, IN HCl) washes are used if required to purify the reaction mixture and / or the product, and are accompanied by drying if required. Column chromatography, for example, is used to purify the residue to isolate the desired product.

The S13 and S14 isomers are prepared from S26 by reaction with phenyl methoxyphosphonyl chloride (Ph (MeO) P (0) Cl). In one embodiment, the reaction occurs in a solvent, such as an organic solvent, such as methylene chloride. If necessary, a base catalyst such as triethanolamine can be used, for example, by adding to it a reaction mixture formed by mixing reagents in a solvent. Also, the reaction mixture is washed with basic solution, for example saturated sodium bicarbonate if necessary. The isomers are prepared and purified, for example, using silica gel chromatography. 519 and 22 are prepared from S26 by reaction with a compound of the formula ClOC-X-CoCl, wherein X is CH2C12 (S19) or ^ x ^ (S22). In one embodiment, the reaction occurs in the presence of a solvent, such as an organic solvent, such as methylene chloride. If necessary, a base catalyst such as triethylanine is added to the reaction mixture formed by mixing the reactants in a solvent. Also, the base acid (eg, saturated sodium bicarbonate) (eg, IN NH1), and water washings are used to remove unwanted compounds from the reaction mixture, if necessary. 520 and S23 are prepared from a compound intermediate of the formula, where R is CH2 = CH- (S20) or (S23). The intermediate compound is treated with H202. If necessary, sodium thiosulfate is also used to treat the intermediate. In one embodiment the reaction occurs in the presence of a solvent, such as an organic solvent, such as methanol (CH30H), forming a reaction mixture. The solvent is removed from the reaction mixture after the reaction takes place, if desired, the residue is dissolved in another solvent, such as an organic solvent, such as ethyl acetate. The reaction mixture is washed with the basic solution (for example, saturated sodium carbonate) if desired to remove the unwanted compounds from the reaction mixture. The reaction mixture is dried (for example using sodium sulfate) if it is washed with a basic solution. The final residue is purified, for example, by column chromatography, to obtain the final product.

S57 is prepared from S26 and methyl chlorooxoacetate.

In one embodiment, the reaction occurs in the presence of a solvent, such as an organic solvent such as methylene chloride. A base catalyst such as pyridine is used as necessary to facilitate or rush the reaction. The reaction mixture formed by the mixing of the reactants and a solvent is washed with the basic solution (for example, sodium bicarbonate), the acidic solution (for example HCl) and water. Purification such as silica gel chromatography gives S57.

S36 is prepared from S57 by the reaction with sodium hydroxide. In one embodiment, the reaction takes place in a solvent, such as an organic solvent, such as methanol. The solvent is removed from the reaction mixture formed by mixing the reactants and the solvent, thereby forming the residue. The residue is dissolved in water and washed with another organic solvent such as ether, to remove the unwanted hydrophobic compounds. The aqueous phase of the basic washes is acidified and the product is extracted therefrom using an organic solvent, such as methylene chloride. The additional purification is used if necessary.

S38 is prepared in a similar way to S36, except for a compound of the formula it is used as the starting material in the synthesis.

S44 is prepared by treating S36 with thionyl chloride to form crude S36-C1. Excess thionyl chloride, if any, is removed from the reaction mixture. The crude S36-C1 is then dissolved in a solvent, such as an organic solvent such as methylene chloride, and reacted with the mono-protected cystamine (for example, protected mono-Boc). A base catalyst such as pyridine is used if desired, and the reaction mixture is cooled as a basic solution (for example, saturated sodium bicarbonate). The reaction mixture formed by the mixing of cystamine and active S36-C1 is purified. Protecting groups (for example Boc) are removed using an appropriate acid or base wash (for example, trifluoroacetic acid in organic solvent in the case of the Boc protecting group). The final product is then purified, for example, using chromatography techniques.

S57 and S59 are prepared from S36-C1, which is reacted with methanol (S57) or ethylamine (S59).

S43 and S45 are prepared from S36-cystamine, which is prepared as described herein. S36 cystamine is reacted with the NHS activated ester of an appropriate azido compound to give S43 and S45. The reaction takes place in a solvent, such as an organic solvent.

S37 is prepared from S26 by the reaction with 4-nitrophenyl chloroformate (N02C6H5OCOCl). The reaction takes place in a solvent, and if desired, a base catalyst such as triethylamine can be used. The reaction mixture formed by mixing the reactants and a solvent is washed with water to remove undesired hydrophilic compounds. The solvent is removed from the reaction mixture to form a residue, which is purified (for example using chromatography techniques) to give S37.

S6, S46-53, S64, S66 and S67 are prepared from S37 by reaction an amine of the formula RNH2, wherein NR is NH2 (S46), NEt2 (S48), NHCH2Ph (S49), NHOH (S51), (S53), (S64), (S66), or (S67) The reaction takes place in the presence of a solvent, such as an organic solvent, such as DMF. In one embodiment, only one equivalent of amine is used in the reaction. The purification is achieved, for example by Si02 column chromatography.

S6, S46-53, S-64, S66 and S67 are also prepared from S25, with the intermediate S26-phosgene. The S26-phosgene intermediate is formed by reacting S-26 with triphosgene.

Then, S26-phosgene is reacted with the amine of the formula RNH2, wherein NR is NH2 (S46), NEt2 (S48), NHCH2Ph (S64) (S67). The reaction takes place in the presence of a solvent, such as an organic solvent. In one embodiment, only one equivalent of amine is used in the reaction. The purification is achieved, for example by Si02 column chromatography.

S55, S56, S58, and S60-63 are prepared from S27 by the reaction with HNR? R2, where N lR2 (S60).

The reaction occurs in a solvent, such as an organic solvent such as chloroform, thus forming a reaction mixture.

The solvent is removed from the reaction mixture to form a residue which is purified, for example by column chromatography on silica gel to give the final product.

S69-75 are prepared from S68, through the intermediate S58-phosgene. S68 is treated with triphosgene to form the intermediate, which in turn is treated with an amine RNH2, wherein NR is NH2 (S70), NEt2 (S75), NHOH (S74), (S72) (vS73). The reaction occurs in a solvent, such as an organic solvent, such as chloroform, thus forming a reaction mixture. The solvent is removed from the reaction mixture to form a residue, which is purified, for example by silica column chromatography to give the final product.

S76 is prepared from S68 by the reaction with methyl chlorooxoacetate. In one embodiment, the reaction occurs in the presence of a solvent, such as an organic solvent, such as methylene chloride. A base catalyst such as pyridine is used as necessary to facilitate or rush the reaction. The reaction mixture is formed by mixing the reactants and a solvent is washed with the basic solution (for example saturated sodium bicarbonate), acidic solution (for example HCl), and water. Purification such as silica gel chromatography gives S76.

S77 is prepared from S76 by reaction with sodium hydrogen. In one embodiment, the reaction takes place in a solvent, such as an organic solvent, such as methanol. The solvent is removed from the reaction mixture formed by mixing the reactants and the solvent, thereby forming a residue. The residue is dissolved in water and washed with another organic solvent, such as ether, to remove unwanted hydrophobic compounds. The aqueous phase of the basic washes is acidified and the product is extracted therefrom using an organic solvent, such as methylene chloride. The additional purification is used if necessary.

S78-S81 are prepared by treating S77 with thionyl chloride to form S77-C1. Excess thionyl chloride, if any, is removed from the reaction mixture. The crude S77-C1 is then dissolved in a solvent, such as an organic solvent such as methylene chloride, and reacted with HX, wherein X is NHEt (S78), NHPh (S79), NH2 (S80), and NHCH2- pyridine (S81). The solvent is removed, and the residue is purified.

S82 is prepared from S68. S68 is reacted with CH2CHS02C1 in a manner analogous to the production of S3. The product is then treated with HNR? R2 in a manner analogous to the production of SI and S2, except that NR? NR2 is S83 is prepared from S68. S68 is reacted with RC0C1, where R is, in a manner analogous to the production of S7, S9 and S40.

S84 is prepared from S68 by the reaction with benzyl bromide. In one embodiment, the reaction takes place in a solvent, such as an organic solvent such as methylene chloride. A base catalyst such as triethylamine is added as necessary to catalyze the reaction. The reaction mixture formed by mixing the reactants and the solvent is purified to give S84. 585 is prepared from S26. S26 is reacted with di-tert-butyl dicarbonate in a solvent, for example an organic solvent such as methylene chloride. A base catalyst such as triethylamine is also used, if necessary. The reaction mixture formed by mixing the reactants and the solvent is washed with a saturated sodium bicarbonate solution and the aqueous layer is extracted with organic solvent. The combined organic layers are dried and the concentrate provides S85. 586 is prepared from S85 in a solvent, for example an organic solvent. S85 is treated with BBr3 to form a reaction mixture. If necessary, a base catalyst, such as triethylamine, is used in the reaction. The reaction is cooled (for example, in the case of triethylamine with methanol) and concentrated. Purification, for example by column chromatography, gives S86. 587 is prepared by reacting S86 with trifluoromethylsulfonyl anhydride. The reaction is carried out in a solvent, such as an organic solvent. A base catalyst such as triethylamine is added if necessary. In the case of triethylamine, the reaction mixture formed by the mixing of the reactants and the solvent is quenched with water, after which the aqueous layer is extracted with an appropriate organic solvent. If desired, the organic layers with dried (for example using magnesium sulfate) and the organic layers are concentrated. Purification of the concentrated organic layers gives S87. 588 is prepared from S87 by the reaction of morpholine, tris (dibenzylideneacetone) dipalladium (0), 2- (di-tert-butylphosphino) -biphenyl, and potassium phosphate. The reaction mixture is diluted with solvent, such as methylene chloride or other appropriate organic solvent, and washed with water. The aqueous layer, formed by washing with water, is extracted with the organic solvent, such as methylene chloride. The organic layers are then dried (for example over magnesium sulfate) and concentrated. The residue is purified, for example by flash chromatography of silica gel to give S88. 589 is prepared from S87 by reaction with benzenethiol and i-Pr2Net in a solvent, such as CH3CN or other suitable organic solvent. After the reaction, an organic solvent such as ethyl acetate is added to the reaction mixture. If necessary, the reaction mixture is washed with one or more of the acidic (for example HCl), basic (e.g. NaOH), and water solutions. After drying (for example, with Na 2 SO 4), the solution is concentrated. Purification, for example by chromatography, gives S89. In an alternative, reflux S87 with benzethiol in an appropriate solvent such as dioxane with a catalyst such as i-Pr2Net / Pd2 (dba) 3 / xantphos gives S89. 590 is prepared from S87 reacted with a base, phenylboronic acid and a catalyst. In one embodiment, the base is K2C03 and the catalyst is (Pd (Ph3P) 4). In one embodiment, the reaction occurs in a solvent, such as an organic solvent, such as dioxane. The reaction mixture formed by the mixing of the reactants and the solvent is diluted with a solvent (for example methylene chloride) and washed with water to remove undesirable hydrophilic compounds. The concentration and purification of the residue gives S90.

S92 is prepared from S87 reacted with zinc cyanide. In one embodiment, the reaction occurs in a solvent, such as an organic solvent such as DMF. A catalyst such as Pd (Ph3P) 4 is also used to facilitate and rush the reaction. The reaction mixture formed by mixing the reactants and the solvent, if necessary, is diluted with water of an acidic solution and extracted with an organic solvent. The organic extracts are then washed using a salt solution, dried, filtered and concentrated. The purification of the residue proceeds, for example, by means of silica gel column chromatography. 594 is prepared for S86 by the reaction with acetic anhydride. In one embodiment, the reaction takes place in a solvent, such as an organic solvent, such as methylene chloride. The triethylamine or other base catalyst is added if necessary. Washing with water, followed by drying (for example using sodium sulfate) is used as desired. The purification of the waste gives S94. 595 is prepared from S94 by reaction with anhydrous A1C13, in a solvent if desired. The solvent is an organic solvent such as benzene. The reaction mixture is refluxed and cooled on ice. Extraction with organic solvent, concentration and purification of the residue gives S95. 596 is prepared from S86 by iodination. For example, S86 is added to a solvent, such as an organic solvent such as methanol, with excess Nal and Chloramine-T. The reaction mixture is quenched with Na2S203 solution. The concentration and purification of residue gives S96 as a mixture of mono-iodinated and di-iodinated products. 597 is prepared from S86 by the reaction with nitric acid. S86 is protected (for example using the Boc protection groups) and added to the concentrated sulfuric acid. Nitric acid is added to the reaction mixture. The reaction mixture is cooled and neutralized (for example using Na 2 CO 3) to cool the reaction. Organic extraction and subsequent concentration is used to isolate the product. Purification gives S97. 598 is prepared by hydrogenation of S97. For example, S97 is added to a solution, such as an organic solution such as methanol. The H2 gas is bubbled through the solution and the Pd / C catalyst or other applicable catalyst is added. Filtration to remove the catalyst and purification gives S97.

SlOO is prepared from S98. S98 is dissolved in acid solution such as aqueous HCl. This solution of sodium nitrite and then NaN3 in water are added. The reaction mixture is extracted using an organic solvent. If required, the extract is washed with the basic solution (for example, saturated sodium bicarbonate) and water. The organic layers of the washings are dried using, for example, anhydrous sodium sulfate and concentrated to form a residue. The residue is purified to give SlOO. To prepare S99, NaN3 is substituted with NaBF4 in a similar manner.

S101, S102 and S103 can each be prepared from S68.

S101 can be prepared from S68 as follows. The triphosgene is reacted with S68 in the presence of a solvent (such as organic solvent dichloromethane, CH2C12) to generate phosgene S68. Optionally, a base is also present or added to the purification acid generated during the reaction. Any suitable base can be used. For example, organic bases such as organic amines such as triethylamine, di-isopropylethylamine or pyridine can be used. Inorganic bases such as sodium bicarbonate can also be used. Then, without the need for purification, the reaction mixture containing phosgene S68 is treated with 1-piperonylpiperazine. If necessary, the reaction mixture is washed as one or more of acidic (for example HCl), basic (for example NaOH), and water solutions. The solvents are removed, for example under reduced pressure. The product S101 can then be purified, for example using Si02 column chromatography. 5102 can be prepared from S68 using the same scheme for SlOl, with the exception that pyridine is used in place of piperonylpiperazine. 5103 can be prepared from S68 using the same scheme for SlOl, with the exception that N-Boc 1-piperazine is used in place of piperonylpiperazine. Also, trifluoroacetic acid (TFA) is added to deprotect the Boc group. 5104 can be prepared by reacting S36 with hydrogen peroxide (H202) in the presence of a solvent (such as MeOH). The solvents are removed (for example under reduced pressure) and the product S104 can then be purified, for example by recrystallization. 5105 can be prepared from S68 as follows. S68 is then reacted with CH30-C (0) C (O) Cl in the presence of a solvent (such as organic solvent dichloromethane (CH2C12)) and optionally a catalyst (such as pyridine). Preferably, the CH30-C (0) C (0) Cl should be added in the form of drops. If necessary, the reaction mixture is washed with one or more of acidic (for example HCl), basic (e.g. NaOH), and water solutions. The solvents are removed and the product can also be purified, for example by Si02 column chromatography.

S107 can be prepared from S26 as follows. To a solution of S26 in a solvent (such as MeOH), formaldehyde (CH20) and sodium cyanoborohydride (NaBCNH3) are added and allowed to react. Preferably, the reaction mixture is maintained at about a pH of 4-5, for example by the addition of a few drops of IN HCl. The solvents are then removed, for example under reduced pressure. If necessary, the residue can be dissolved in ethyl acetate and washed with one or more of a basic solution (for example NaOH), and water. The solvents can be removed and the product can be further purified, for example using Si02 column chromatography.

S108 can be prepared as follows. A mixture of N-benzyloxycarbonyl-glycine (Cbz-Gly,), diisopropyl-carbodiimide (DIC), and N-hydroxysuccinimide (NHS) are reacted together in a solvent (such as organic solvent dichloromethane (CH2C12)) for a quantity of time adequate The S26 is then added to the mixture and the reaction is allowed to proceed further. If necessary, the reaction mixture is washed with one or more of the acidic (for example HCl) basic solutions (for example NaOH), and water. The solvents can then be removed, for example, by evaporation.

The product can also be purified, for example using Si02 column chromatography.

S109 can be prepared from S108, as follows. S108 in a solvent (such as dichloromethane in organic solvent (CH2C12)) is reacted with HBr / CH3C02H. After a suitable amount of time, the reaction mixture is evaporated, for example under reduced pressure. The residue is dissolved in a suitable solvent, such as MeOH, and treated with propylene oxide. The solvent can then be removed, under reduced pressure, to provide crude S109. The SlOO can also be purified, for example by dissolving in an acidic solution (such as HCl), washing with ethyl acetate and evaporation.

The SOL can be prepared as follows. A mixture of S26, methyl 1-bromoacetate and pyridine are reacted in DMF for an appropriate amount of time. To this mixture, ethyl acetate is added, if necessary, the reduction mixture is washed with a basic solution (for example NaHCO3) or water. The product SllO, as an oil, can be purified, for example by Si02 column chromatography.

SII can be prepared as follows. A base (such as ÍN NaOH) is added to SllO in a solvent (such as MeOH), and the mixture is allowed to react for an adequate amount of time. The solvents are then recovered, under reduced pressure, and the residue can then be dissolved in an aqueous solution such as water. The aqueous phase can be washed with ethyl acetate and acidified, for example with IN HCl, at a pH of about 4. The solvents can then be removed, for example under reduced pressure to produce crude Slll. The NaCl can be removed using an alcohol, such as ethanol to give pure Slll as a solid.

S112 can be prepared as follows. To a mixture of S26 and pyridine in a solvent (such as organic solvent dichloromethane (CH2C12)) S02C12 is added with drops at about 0 ° C and reacted for an adequate amount of time. The solvents can be removed, for example under reduced pressure. The residue can be dissolved in a suitable basic solution such as NaOH. The aqueous solution can then be washed with ethyl acetate, and acidified (for example with INN NC1) to around a pH of 4. The aqueous phase can be extracted again with ethyl acetate and the ethyl acetate phase can be evaporated, by example under reduced pressure, such as to provide S112, as a powder.

S113, can be pre-weighted as follows. S107 in ethyl acetate is treated with CH3I. The mixture is stirred for a suitable amount of time, and the product S113, as a white solid, is collected by filtration. 5114 can be prepared as follows. Compound S26, in a solvent such as the organic solvent CH2C12 is ideally cooled to about 0 ° C. To this solution, triphosphene is added. Optionally, a base is also present or is added to the purification acid generated during the reaction. Any suitable base can be used. For example, organic bases such as organic amines such as triethylamine di-isopropylethylamine or pyridine can also be used. Inorganic bases such as sodium bicarbonate can also be used. The reaction is allowed to proceed (ideally at about 0 ° C) for an adequate amount of time (for example about 1 hour). Without the need for purification, the resulting S26-phosgene in the reaction mixture can then be treated with N-Boc 1-piperazine, again ideally at about 0 ° C, and the reaction is allowed to proceed (ideally around 0 ° C) for an adequate amount of time (for example about 1 hour). If necessary, the reaction mixture is washed with one or more of the acidic (for example HCl), basic (e.g. NaOH), and water solutions. The solvents are removed and the product can also be purified, for example by Si02 column chromatography. 5115 can be prepared as follows. A mixture of S114 and Lawesson Reagent in toluene is stirred at about 90 ° C for several hours. The mixture is cooled to room temperature and washed with a suitable base such as saturated NaHCO 3. The product S115 can be purified, for example by Si02 chromatography.

S116 can be prepared as follows. A mixture of S115 and trifluoroacetic acid (TFA) in a suitable solvent (such as organic solvent dichloromethane (CH2C12)) is stirred at a room temperature for a suitable amount of time (for example about 2 hours). Evaporation of the solvents, for example under reduced pressure produces S116. 5117 (S117) can be prepared as follows. A solution of S057 in a suitable solvent (such as organic solvent dichloromethane (CH2C12)) is cooled to about -78 ° C. To this, IM BBr3 is added a suitable solvent (such as organic solvent dichloromethane (CH2C12)) is added and the mixture is stirred at about 78 ° C for an adequate amount of time (for example about 3 hours) and then wSed at room temperature. If necessary, the mixture is washed with an acid (such as IN HCl) and / or H20. After removal of the solvents, the product S117 can be purified, for example by Si02 column chromatography. 5118 can be synthesized as follows. S26 in a suitable solvent (such as organic solvent dichloromethane (CH2C12)) is treated with BODIPY TMR-X, SE (from Molecular Probes Inc.) for an appropriate amount of time (for example about 3 hours). If necessary, the mixture can be washed with an acid (such as 0.01 N HCl) and / or a base (such as NaHCO 3). The removal of the solvents (for example under reduced reduction will give S118.

S119 can be synthesized as follows. A mixture of S107, H202 (for example about 50%) and an alcohol (such as MeOH) is stirred at room temperature for an adequate amount of time (typically about 2 days). If desired, mass spectrometry can be used to monitor the disappearance of S107 and the formation of product S119). The solvents can be removed, for example under reduced pressure to give S119.

S120 can be synthesized as follows. A mix S26, benzyl bromide and Na2CO3 in a solvent (such as DMF), is reacted for an adequate amount of time, preferably overnight. The ethyl acetate is added to the reaction and then, if necessary, the reaction is washed with a suitable solvent, for example with H20 (4x10 ml). The organic phase can be concentrated, for example, under reduced pressure, and the residue can be purified, for example by chromatography to give S121.

S121 can be synthesized as for S120, but using instead of the 4-OH-benzyl bromide bromide bromide. 5122 can be synthesized as follows. To a cold solution of an S26 compound in a solvent, such as the organic solvent in CH2C12, DIEA is added and subsequently the acetoxyacetyl chloride is added. The reaction is allowed to proceed for a suitable amount of time and then dissolved (for example with 1.0 M aqueous HCl solution) and extracted (for example using CH2C12). The organic layers combined if necessary, washed (for example with H20, brine), dried (for example with Na2SO4) are filtered and dried (for example by evaporation). The product can also be purified, for example, by chromatography on a silica gel column, and can be eluted with a gradient increasing polarity from 0 to 50% of petroleum and ethyl acetate. The relevant fractions can then be combined to give the desired product. 5123 can be synthesized as follows. To a solution of a compound S122 in a solvent (such as MeOH) and THF, preferably at room temperature, LiOH is secreted. The reaction is allowed to proceed for a suitable amount of time at a suitable temperature (ideally at room temperature and can then be diluted (for example with an aqueous solution of 1.0 M HCl) and extracted (for example with CH2C12). combined organic can be washed (for example with H20, brine), dried (for example with Na2SO4), filtered and dried (for example by evaporation) The crude product can be purified, for example by chromatography on a column of silica gel , eluted, for example with an increasing polarity gradient from 0 to 70% oil in ethyl acetate.The relevant fractions can then be combined to give S123.

It should be noted that the compounds used as starting materials for, or generated as intermediates in, the synthesis of the compounds of the invention may themselves have structures encompassed by the formulas of the invention, and / or may themselves be active agents. useful in the methods and compositions of the present invention. Such starting materials and intermediates may be useful for, among others, treating or avoiding various disorders and diseases associated with RyR receptors such as cardiac and muscular disorders, attempting to avoid filtering at the RyR2 receptor in a subject, or modulating the binding of RyR and FKBP in a subject. The present invention encompasses any of the starting or intermediate materials described herein that have structures encompassed by the formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, 1-1 or Im , and / or which are useful as active agents in the methods and combinations of the present invention. For example, in one embodiment compound S68, which is useful as a starting material for the synthesis of compounds S69 and S75, can be used among others to try to avoid various disorders and diseases associated with RyR receptors, to try to avoid filtering in a RyR2 receptor or modulate the binding of RyR and FKBP in a subject.

In another embodiment, compound S26, which is useful in the synthesis of many compounds described herein (including S3, S4, S5, S7, S9, Sil, S12, S13, S14 and other compounds) can be used, inter alia, to try to avoid various disorders and diseases associated with the RyR receptors, try to avoid filtering in the RyR2 receptor or modulate the binding of RyR and FKBP in a subject.

Similarly, in another embodiment, compound S25 (see United States of America patent application number 10 / 809,089) may also be used, among others to try to avoid various disorders and diseases associated with RyR receptors, to treat of avoiding filtering in a RyR2 receptor, or modulating the binding of RyR and FKBP in a subject.

The compounds of the present invention are prepared in different forms, such as salts, hydrates, solvates, complexes, pro-drugs or salts of pro-drugs and the invention includes all variant forms of the compounds.

The term "compound or compounds of the invention" as used herein encompasses a compound of the formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, 1-1 or Im, and salts, hydrates, pro-drugs and solvates thereof.

A "pharmaceutical composition" refers to a mixture of one or more of the compounds described herein, or pharmaceutically acceptable salts, hydrates or pro-drugs thereof, with other chemical components such as physiologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of a compound for an organism.

A "pro-drug" refers to an agent which is converted into the parent drug in vivo. Pro-drugs are often useful because in some situations, they are easier to administer than the parent drug. These are bioavailable, for example, by oral administration while the parent drug is not. The pro-drug also has an improved solubility in the pharmaceutical compositions on the parent drug. For example, the compound carries protective groups which are divided by hydrolysis in the body fluids, for example in the blood stream, thereby releasing the active compound or oxidized or reduced in body fluids to release the compound.

A compound of the present invention can also be formulated as a pharmaceutically acceptable salt, for example, the acid addition salt and the complexes thereof. The preparation of such salts can facilitate pharmacological use by altering the physical characteristics of the agent without avoiding the physiological effect. Examples of useful alterations in physical properties include, but are not limited to, lowering the melting point to facilitate transmucosal administration and increase solubility to facilitate administration of the higher concentrations of the drug.

The term "pharmaceutically acceptable salt" means an acid addition salt which is suitable for or is compatible with the treatment of a patient or a subject such as a human patient or an animal such as a dog.

The term "pharmaceutically acceptable acid addition salt" as used herein means any non-toxic organic or inorganic salt of any base compounds represented by the formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, 1-1 or Im, or any of its intermediates. Illustrative inorganic acids which form the suitable acid addition salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids, as well as metal salts such as monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids which form the suitable acid addition salts include mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, masonic, succinic, glutamic, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic , phenylacetic, cinnamic and salicylic, as well as sulfonic acids such as p-toluene sulfonic acid and methanesulfonic acids. Any of the mono or di-acidic ales can be formed, such salts exist in either the hydrated, solvated or substantially anhydrous form. In general, the acid addition salts of the compounds of the formulas I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, I-j, I_k, 1-1 and I-m, are more soluble in water and various hydrophilic organic solvents, and generally show higher melting points compared to their free base forms. The selection of an appropriate salt will be known to one skilled in the art. Other non-pharmaceutically acceptable salts, for example oxalates are used, for example in the isolation of the compounds of the invention for laboratory use or for a subsequent conversion to a pharmaceutically acceptable acid addition salt.

The compounds of the present invention form hydrates or solvates, which are included in the scope of the claims. When the compounds of the present invention exist as regioisomers, the configurational isomers, the conformers or the diastereoisomeric forms of such forms and various mixtures thereof are included in the scope of the formulas I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, I-j, I-k, 1-1 and I-m. It is possible to isolate the individual isomers using known purification and separation methods as desired. For example, when a compound of the present invention is a racemic mixture, the racemic mixture can be separated in the (S) -composed and in (R) -composed by optical resolution.

The individual optical isomers and mixtures thereof are included in the scope of formulas I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, I-j, I-k, 1-1 and I-m.

The term "solvate" as used herein is a compound of the formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, 1-1 or Im, or a pharmaceutically acceptable salt of them, where the molecules of a suitable solvent are incorporated in a crystal network. A suitable solvent is physiologically tolerated at the dose administered. Examples of suitable solvents are ethanol, water and the like. When water is the solvent, the molecule is referred to as a "hydrate".

The term "effective amount", "sufficient amount" or "therapeutically effective amount" of an agent is used herein as the amount sufficient to effect beneficial or desired results, including clinical results, and as such an "effective amount" depends on the context which is being applied. The answer is preventive and / or therapeutic. The term "effective amount" also includes the amount of the compound of formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, 1-1 or Im, which "is therapeutically effective "and which essentially prevents or attenuates unwanted side effects.

As used here and well understood in the art "treatment" is an approach to obtain desired results, including clinical results. Beneficial or desired clinical outcomes may include but are not limited to the alleviation or amelioration of one or more symptoms or conditions, the decrease in the extent of the disease, the stabilized (for example, not worsening) state of the disease, avoidance of spreading of the disease, delaying or discouraging the progression of the disease, reducing or weakening the disease state and remission (either total or partial), whether detectable or not detectable. "Treatment" can also mean prolonging survival compared to expected survival if treatment is not received.

The terms "animal," "subject," and "patient" as used herein include all members of the animal kingdom, including but not limited to mammals, animals (eg, cats, dogs, horses, etc.) and humans. .

The present invention further provides a composition comprising radio label compounds of formula I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, I-j, I-k, 1-1 and I-m. The labeling of the compounds is accomplished using a variety of different radioactive labels known in the art. The radioactive labeling of the present invention is for example, a radioisotope. The radioisotope is any isotope that emits a radiation that can be detected including without limitation 35S, 125I, 3H, or 14C. The radioactivity emitted by the radioisotope can be detected by techniques well known in the art. For example, the gamma emission of the radioisotope is detected by using the techniques of gamma image formation, particularly, the scintigraphic image formation.

By way of example, the radiolabelled compounds of the invention are prepared as follows. A compound of the invention can be demethylated in the phenyl ring using BBr3. The resulting phenol compound is then re-methylated with a radiolabeled methylating agent (such as 3H-dimethyl sulfate) in the presence of a base (such as NaH) to provide the 3H-labeled compounds.

The present invention also provides compounds which can be classified as 1,4-benzothiazepines, including by way of example and without limitation SI, S2, S3, S4, S5, S6, S7, S9, Sil, S12, S13, S14, S19 , S20, S22, S23, S25, S26, S36, S37, S38, S40, S43, S44, S45, S45, S47, S48, S49, S50, S52, S53, S54, S55, S56, S57, S58, S59 , S60, S61, S62, S63, S64, S64, S66, S67, S68, S69, S70, S71, S72, S73, S74, S75, S76, S77, S78, S79, S80, S81, S82, S83, S84, S85 , S87, S88, S89, S90, S91, S92, S93, S94, S95, S96, S97, S98, S99, SlOO, SlOl, S102, S104, S105, S107, S108, S109, SllO, Slll, S112, S113 , S114, S115, S116, S117, S118, S119, S120, S121, S122 and S123.

These and other compounds of the present invention are associated with a pharmaceutically acceptable carrier as described above, such as for forming a pharmaceutical composition.

According to the method of the present invention, the decrease in the level of RyK-bound FKBP is limited or prevented in the subject by decreasing the level of phosphorylated RyR in the subject. In one embodiment, the amount of the agent effective to prevent a decrease in the level of FKBP12.6 bound RyR2 in the subject is an amount of the effective agent to try to prevent heart failure, atrial fibrillation and / or induced cardiac arrhythmia. by exercise on the subject. In another embodiment, the amount of agent effective to limit or prevent the decrease in the level of FKBP12.6 bound RyR2 in the subject is an amount of the agent effective to prevent sudden cardiac death induced in the subject.

In view of the foregoing, the present invention further provides a method for treating or preventing exercise-induced cardiac arrhythmia in a subject, comprising administering to the subject a 1-benzothiazepine compound, as discussed herein, in an effective amount to treat of avoiding cardiac arrhythmia induced by exercise in the subject. Similarly, the present invention provides a method for preventing sudden cardiac death induced by exercise in a subject, comprising administering to the subject a 1,4-benzothiazepine compound, as described herein, in an amount effective to prevent cardiac death. sudden induced by exercise in the subject. Additionally, the present invention provides a method for treating or preventing atrial fibrillation or heart failure in a subject, comprising administering to a subject a compound, as described herein, in an amount effective to treat or prevent atrial fibrillation or heart failure in the subject. In each of these methods, the compound is selected from the group of compounds consisting of compounds of the formula: where, n is 0, 1 or 2; R is located in one or more positions of the benzene ring; each R is independently selected from the group consisting of H, halogen -OH, NH2, -N02, -CN, -N3-S03H, acyl, alkyl, alkoxy, alkylamino, cycloalkyl, heterocyclyl, heterocycloalkyl, alkenyl, (hetero-) aryl , (hetero-) arylthio, and (hetero-) arylamino; wherein each acyl, alkyl, alkoxy, alkylamino, cycloalkyl, heterocyclyl, heterocycloalkyl, alkenyl, (hetero-) aryl, (hetero-) arylthio, and (hetero-) arylamino can be substituted with one or more radicals independently selected from the group consists of halogen, N, O, -S-, -CN, -N3, -SH, nitro, oxo, acyl, alkyl, alkoxy, alkylamino, alkenyl, aryl, (hetero-) cycloalkyl, and (hetero-) cyclyl; Ri is selected from the group consisting of H, oxo, alkyl, alkenyl, aryl, cycloalkyl and heterocyclyl; wherein each alkyl, alkenyl, aryl, cycloalkyl and heterocyclyl can be substituted with one or more radicals independently selected from the group consisting of halogen, N, O, -S -, - CN, -N3, -SH, nitro, oxo, acyl, alkyl, alkoxy, alkylamino, alkenyl, aryl, (hetero-) cycloalkyl, and (hetero-) cyclyl; R2 is selected from the group consisting of H, -C = 0 (Rs), -C = S (R6), -S02R7, -P0R8Rg, - (CH2) mR? 0, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl and heterocyclic; wherein each alkyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl and heterocyclic can be substituted with one or more radicals independently selected from the group consisting of halogen, N, 0, -S-, -CN, -N3, nitro, oxo, acyl , alkyl, alkoxy, alkylamino, alkenyl, aryl, (hetero-) cycloalkyl, and (hetero-) cyclyl; R3 is selected from the group consisting of H, C02Y, CONY, acyl, alkyl, alkenyl, aryl, cycloalkyl, and heterocyclyl; wherein each acyl, alkyl, alkenyl, aryl, cycloalkyl, and heterocyclyl can be substituted with one or more radicals independently selected from the group consisting of halogen, N, 0, -S-, -CN, -N3, -SH, nitro , oxo, acyl, alkyl, alkoxy, alakylamino, alkenyl, aryl, (hetero-) cycloalkyl, and (hetero-) cyclyl; and in each Y is selected from the group consisting of H, alkyl, aryl, cycloalkyl and heterocyclyl; R 4 is selected from the group consisting of H, alkyl, alkenyl, aryl, cycloalkyl, and heterocyclyl; wherein each alkyl, alkenyl, aryl, cycloalkyl, and heterocyclyl can be substituted with one or more radicals independently selected from the group consisting of halogen, N, 0, -S-, -CN, -N3, -SH, nitro, oxo , acyl, alkyl, alkoxy, alakylamino, alkenyl, aryl, (hetero-) cycloalkyl, and (hetero-) cyclyl; R5 is selected from the group consisting of -OR15, NHNR16, NHOH ,, -0Ri5, CONH2NHR? 6, C02R? 5, C0NR? 6, CH2X, acyl, alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each acyl, alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl can be substituted with one or more radicals independently selected from the group consisting of halogen, N, 0, -S-, -CN, -N3, -SH, nitro, oxo, acyl, alkyl, alkoxy, alakylamino, alkenyl, aryl, (hetero- (cycloalkyl, and (hetero-) cyclyl; R6 is selected from the group consisting of -OR15, NHNR? 6, NHOH, -NR16, CH2X, acyl, alkenyl, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each acyl, alkenyl, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl can be substituted with one or more radicals independently selected from the group consisting of halogen, N, 0, -S-, -CN, -N3, -SH, nitro, oxo, acyl, alkyl, alkoxy, alakylamino, alkenyl, aryl, (hetero-) cycloalkyl, and (hetero-) cyclyl; R7 is selected from the group consisting of -OR15, -NR? 6, NHNHRie, NHOH, CH2X, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl can be substituted with one or more radicals independently selected from the group consisting of halogen, N, O, -S-, -CN, -N3, -SH, nitro, oxo, acyl, alkyl, alkoxy, alakylamino, alkenyl, aryl, (hetero-) cycloalkyl, and (hetero-) cyclyl; Ra and Rg independently are selected from the group consisting of OH, acyl, alkenyl, alkoxy, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl; wherein each acyl, alkenyl, alkoxy, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl can be substituted with one or more radicals independently selected from the group consisting of halogen, N, O, -S-, -CN, -N3, nitro, oxo, acyl, alkyl, alkoxy, alakylamino, alkenyl, aryl, (hetero-) cycloalkyl, and (hetero-) cyclyl; Rio is selected from the group consisting of NH2, OH, -S02Rn, -NHS02Rn, C = 0 (Ri2), NHC = 0 (Ri2), -0C = 0 (R? 2) and -P0R13R? 4; Riif Ri2f R13 and R14 are independently selected from the group consisting of H, OH, NH2, NHNH2, HHOH, acyl, alkenyl, alkoxy, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocycloalkyl; wherein each acyl, alkenyl, alkoxy, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocycloalkyl can be substituted with one or more radicals independently selected from the group consisting of halogen, N, 0, -S-, -CN, -N3, nitro, oxo, acyl, alkyl, alkoxy, alakylamino, amino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl and hydroxy; X is selected from the group consisting of halogen, CN, C02Ri5, CONRig, -NR16, -0R15, -S02R7, and -POR8R9; Y R15 and Ri6 independently are selected from the group consisting of H, acyl, alkenyl, alkoxy, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each acyl, alkenyl, alkoxy, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl can be substituted with one or more radicals independently selected from the group consisting of halogen, N, 0, -S-, -CN, -N3, nitro, oxo, acyl, alkenyl, alkoxy, alkyl, alakylamino, amino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl; and hydroxyl; wherein each acyl, alkenyl, alkoxy, alkyl, alkylamino, aryl, and cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl radical may itself be sub-substituted with one or more radicals independently selected from the group consisting of halogen, -N- , -0-, -S-, -CN, -N3, nitro, oxo, acyl, alkenyl, alkoxy, alkyl, alkylamino, amino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl and hydroxy; and the salts, hydrates, solvates, complexes and pro-drugs thereof.

Examples of such compounds include, without limitation, SI, S2, S3, S4, S5, S6, S7, S9, Sil, S12, S13, S14, S19, S20, S22, S23, S25, S26, S36, S37, S38. , S40, S43, S44, S45, S46, S47, S48, S49, S50, S52, S53, S53, S54, S55, S56, S57, S58, S59, S60, S61, S62, S63, S64, S66, S67, S68 , S69, S70, S71, S72, S73, S74, S75, S76, S77, S78, S79, S80, S81, S82, S83, S84, S85, S87, S88, S89, S90, S91, S92, S93, S94 , S95, S96, S97, S98, S99, SlOO, SlOl, S102, S104, S105, S107, S108, S109, SllO, Slll, S112, S113, S114, S115, S116, S117, S118, S119, S120, S121 , S122 and S123.

In an embodiment of the present invention, if R2 is C = 0 (R5) or S02R7, then R is in positions 2, 3 or 5 of the benzene ring.

In another embodiment of the invention if R2 is C = 0 (R5) or S02R7, then each R is independently selected from the group consisting of H, halogen, -OH, -NH2-N02, -CN, -N3, -S03H, acyl, alkyl, alkylamino, cycloalkyl, heterocyclyl, heterocyclylalkyl, alkenyl, (hetero-) aryl, (hetero-) arylthio, and (hetero-) arylamino; wherein each acyl, alkyl, alkylamino, cycloalkyl, heterocyclyl, heterocyclylalkyl, alkenyl, (hetero-) aryl, (hetero-) arylthio, and (hetero-) arylamino can be substituted with one or more radicals independently selected from the group consisting of halogen, N, 0, -S-, -CN, -N3, -SH, nitro, oxo, acyl, alkyl, alkoxy, alkylamino, alkenyl, aryl, (hetero-) cycloalkyl, and (hetero-) cyclyl.

In another embodiment of the invention, if R2 is C = 0 (Rs) or S02R7, then there are at least two R groups attached to the benzene ring. Further, wherein there are at least two R groups attached to the benzene ring, and both R groups are joined at positions 2, 3 or 5 on the benzene ring. Still further, each R is independently selected from the group consisting of H, halogen, -OH, -NH2, -N02, -CN, -N3, S03H, acyl, alkyl, alkylamino, cycloalkyl, heterocyclyl, heterocyclylalkyl, alkenyl, (hetero) -) aryl, (hetero-) arylthio, and (hetero-) arylamino; wherein each acyl, alkyl, alkylamino, cycloalkyl, heterocyclyl, heterocyclylalkyl, alkenyl, (hetero-) aryl, (hetero-) arylthio, and (hetero-) arylamino can be substituted with one or more radicals independently selected from the group consisting of halogeni, N, 0, -S-, -CN, -N3, -SH, nitro, oxo, acyl, alkyl, alkoxy, alkylamino, alkenyl, aryl, (hetero-) cycloalkyl, and (hetero-) cyclyl.

In another embodiment of the invention, if R2 is C = 0 (Rs), wherein R5 is selected from the group consisting of -NR? 6, NHNHRig, NHOH, -0R? 5, CONH2NHR? 6, C0NR16, CH2X, acyl , aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl; wherein each acyl, aryl, cycloalkyl, cyanoalkylalkyl, heterocyclyl and heterocyclylalkyl can be substituted with one or more radicals independently selected from the group consisting of halogen, N, 0, -S-, -CN, -N3, nitro, oxo, acyl , alkyl, alkoxy, alkylamino, alkenyl, aryl, (hetero-) cycloalkyl, and (hetero-) cyclyl.

Efficiency Demonstrations As shown by Figure 1, incorporations A, B, C, and D, S36 is more potent to increase the binding of KBP12.6 and RyR2 than JTV-519 and does not block the L-type calcium channel (Ica, L ) or the channel HERG K + (Ikr) - In the A incorporation the phosphorylated RyR2 PKA is generated as follows: cardiac sarcoplasmic reticulum membrane preparations (5 μl, 50 μg) are added to a total of 100 μl of kinase buffer (8 mM MgC12, 10 mM EGTA, 40 mM Tris-PIPES, pH 6.8) containing 100 μM MgATP and 40 units of PKA, and incubated at room temperature. The samples are centrifuged at 95,000 g for 10 minutes and the pellets are washed three times in 0.2 milliliters of imidazole buffer. The final pellets are stagnated and suspended again in imiodazole buffer (final concentration "10 μg / μl). To test the meeting efficiency of FKBP12.6 of JTV-519, PKA Phosphorylated Cardiac Sarcoplasmic Reticulum (50mg) IS INCUBATED FOR 30 minutes at room temperature with the test compounds and 250 nM FKBP12.6 in lOnM of imidizole buffer, pH7.0. The samples are then centrifuged at 100,000g for 10 minutes and the pellets are washed 3 times with imidazole buffer.

After washing the proteins are fractionated in size on 15% PAGE. Immunoblots are developed using an anti-FKBP antibody (1: 3,000 dilution). The amount of reagents quantified using the Western blot densitrometry is compared to the amount of FKBP associated with RyR in the non-phosphorylated sarcoplasmic reticulum. The EC50 < s for the compounds are determined by generating the FKBP binding data using compound concentrations ranging from 0.5-1000 Nm. In incorporation B, the currents through the L-type calcium channels in the isolated mouse cardiomyocytes are recorded using the full-cell patch clamp recording the Ba2 + conditions as the charge carrier. The extracellular solution contains (in mM): (n-methyl-D-glucamine, 125, BaCl220, Cs Cl, 5, MgCL2l, HEPES, 10, glucose, 5, pH 7.4 (HCl) .The intracellular solution contains (in mM): CsCl, 60, CaCl2 1, EGTA, ll, MgCl2, l; K2ATP, 5; HEPES, 10; aspartic acid, 50: Ph7.4 (CsOH). Under these conditions, it is expected that the measured current would be carried by Ba2 + primarily through the L-type calcium channels which is referred to as ICa, L. The drugs are applied by a local solution exchanger and reach the cell membrane within 1 s The effects of nifedipine and S36 are tested with clamp-voltage steps of 20 ms long to + 10 or + 20MV (peak of the current-voltage ratio for each individual cell) from the retention potentials of -80 mV or 40mV. Voltage dependence of the L-type calcium current blocked by JTV-519 (lμM9 and S36 (lμM) are measured and presented.

As demonstrated by Figure 2, incorporations A, B, C, and D, S36 avoid sudden cardiac death induced by exercise at lower plasma levels and compared to JTV-519. In an embodiment A ECGs representative of a mouse and mice FKPB12.6 + ~ are shown. Mice are treated with 0.5 milligrams of JTV-519 / M per kilogram of body weight per hour for 7 days with an implanted mini osmotic pump. JTV-519 has no effect on resting heart rate or other ECG parameters such as heart rate (HR). In B incorporation, the sustained polymorphic ventricular tachycardia recorded by telemetry in an untreated FKPB12.6 + mouse (upper index) subjected to the exercise test immediately followed by the injection with 0.5 milligrams of epinephrine per kilogram of body weight are shown. The telemetry ECG record representative of a FKPB12.6 + mouse "treated with JTV-519 following the same protocol is shown in the background. In an incorporation C are shown the numbers of mice with cardiac death (left), sustained ventricular tachycardia (>10 beats, means) and non-sustained ventricular tachycardia (3 to 10 arrhythmogenic beats, right) in groups of mice undergoing exercise testing and the injection of 0.5 milligrams / epinephrine. In embodiment D, the dose dependence of the pharmacological effects of JTV-519 and S35 is shown. Plasma levels of IμM JTV-519 prevent cardiac arrhythmias and sudden cardiac death of FKPB12.6 + ~ mice. Plasma levels of lμM and 0.02μM S36 also prevent cardiac arrhythmias and sudden cardiac death in mice FKPB12.6 + As demonstrated by Figure 3, S36 prevents the development of post-myocardial infarction of acute heart failure. Mice treated with placebo or treated with S36 (100 nM or 200 nM plasma concentrations) undergo permanent ligation of the left anterior descending coronary artery resulting in myocardial infarction. S36 significantly improves the fractional shortening evaluated by echocardiography mode -M 2 weeks after myocardial infarction, compared to placebo.

As demonstrated by Figure 4, S36 improves cardiac function in later myocardial infarction of chronic heart failure. The wild-type mice are subjected to a permanent ligation of the left anterior descending coronary artery resulting in a myocardial infarction. Seven days after myocardial infarction, mice are tested with S36 (200 nM plasma concentration) or placebo. The proportions to weight of heart to body weight (HW / BW) the quantifications of pressure-volume circuits (Dp / dt, inclination of the maximum derivative of change in systolic pressure over time) showed a reversal remodeling and improved cardiac contraction in mice treated with S36 compared with placebo.

Figure 5 is a summary graph of EC50 values of JTV-519 and compounds S1-S67 described herein. The FKPB12.6 binding assay described above is used to determine the amount of FKPB12.6 by binding phosphorylated RyR2 at various concentrations (0.5 lOOONm) of the compounds shown. The EC50 values are calculated using the Michaellis-Menten adjustment curve.

As demonstrated by Figure 6, incorporations A, B, and C, S-36 normalizes the structure and function of the RyR2-P2328S channel associated with catecholaminergic polymorphic ventricular tachycardia. At incorporation A the single channel current indications representative of non-phosphorylated RyR2-P2328S and RyR2-WT phosphorylated with PKA treated with S36 are shown to show no influence of JTV-519 on the baseline channel function. However, in RyR2-P2328S PKA phosphorylated as shown in incorporation B, S36 normalizes the closed state of single channel to levels approaching those seen in incorporation A by reducing the open probability from 14.4% to 0-3% after administration 0. lμmol / LS36. The inserts in additions A and B show the channel openings > 1 pA at a higher resolution. Incorporation C shows the immunoblot analysis of the calstabin-2 binding of RyR2-P2328S, in the presence or in the absence of PKA and 0. lμmol / LS36, as indicated. RyR2-P2328S is immunoprecipitated and the PKA in Vitro was forsphorylated as described above.

As demonstrated in Figure 7, incorporations A and B, treatment with JTV-519 reduces PKA phosphorylation of RyR2 in mice with heart failure. The amounts of RyR2 are immunoprecipitated with an antibody against RyR2 (upper spot). The representative immunoblots (incorporation A) and the bar graphs (incorporation B) shows the amount of RyR2 phosphorylated with PKA at Ser-2808 to RyR2 binding in wild-type mice and calstabin 2 (FKPB12.6_ / "). Treatment with JTV-519 (0.5mg / kg / h) for 28 days after myocardial infarction subsequently reduces the PKA phosphorylation of RyR2 presumably due to inverse cardiac remodeling, in wild type mice but not in those of calstabin-2 FKPB12.6 ~ _).

As demonstrated in Figure 8, A and B incorporations, mice in which cardiac RyR2 can not be phosphorylated PKA (mice hitting RyR2-S2898A) have improved cardiac function after myocardial infarction. Shown in embodiment A is the quantification of M-mode RyR2-S2898A echocardiograms compared to wild-type echocardiograms 28 days after the permanent coronary artery ligand. In additions B and C are shown the volume-pressure circuit quantifications showing (B incorporation) an improved cardiac contraction and a decreased cardiac output (C incorporation) in wild-type S2808A knockin mice after myocardial infarction.

Figure 9 incorporations A, B, C, and D demonstrate the effect of JTV-519 on the affinity of calstabin2 to RyR2 in calstabin2 (FKBP12.6 + ~) mice haploinsufficient after exercise the average probability that the RyR2 channels are open in calstabin2 + ~) mice subjected to exercise was significantly increased compared to those channels of wild-type (control, calstabin2 + +) mice exercised, which are predominantly closed under conditions that simulate diastole in the heart per say. As shown in C and D incorporations, the treatment of calstabin2 + / "mice exercised with JTV-519 significantly reduced the open channel (pQ) likelihood compared to that of untrained mice channels, consistent with the increased amounts of calstabin2 in the RyR2 channel complex.Therefore, JTV-519 increases the affinity of calstabin2 to RyR2.In contrast the treatment of JTV-519 from mice deficient in calstabin2_ / ~ did not result in channels with a PC, low indicating that the presence of calstabin2 is necessary for effects JTV-519 which are documented as binding of calstabin2 to RyR2.

Figure 10, incorporations A, B, C.D, E and F demonstrate, respectively, the periodic channel activation RyR2 normalized and the binding of calstabin2 increased to the RyR2 channels after JTV-519 treatment. The immunoblots in the A and B incorporations show the amounts of calstabin2 and RyR2 associated with RyR2 immunoprecipitated after incubation with the indicated concentrations of JTV-519 for, respectively, the RyR2 and (RyR2-WT) channels of wild type and RyR-S2809D. The binding curves at C incorporation demonstrate that JTV-519 significantly increases the affinity of calstabin2 for phosphorylated RyA2 PKR channels. The results also demonstrate that the depletion of calstabin2 from the macromolecular complex RyR2 which is associated with the open probability of RyR2 increases, ventricular tachycardia and sudden cardiac death in calstabin2 + mice "haploinsufficient" which is reversed by treatment with JTV-519 Therefore, JTV-519 and related compounds avoid the disorders and conditions associated with RyR2 receptors.

As shown in Figure 11, the A, B, C, D and E incorporations of the RyR1 channel function is increased and normalized in mdx (dystrophin deficient) mice treated with JTC-519. In figure 11 the channel openings are shown as upward deflections; "c" indicates the closed state; and an open amplitude of 4pA current is indicated by a dash. The upper indications represent 5 seconds and the lower indications represent 500 ms; the dotted lines indicate the states of subconduction.

Incorporation A of Figure 11 shows a single channel current signal from RyR1 of the control mouse soleus muscle (wild type) under resting conditions (150 nM cytoplasmic calcium). As seen, RyRl is predominantly closed. Embodulation C of Figure 11 shows that the RyR1 channel works in the mdx mouse showing a significantly increased open probability an increased average aperture and closed dwell times by diminished means, To and Te, respectively. Po in mdx mice is consistent with intracellular calcium filtering. The amplitude histograms in the incorporations B, D and F show multiple sub-inductance states consisting of the depletion of calstabinl (FKBP12) in RyR of the soleo mdx muscle. The incorporation E of Figure 11 shows a mdx mouse treated with 1.0 μMJTV-519. As seen, the RyR1 channels of the mouse treated with JTV-519 demonstrate a normal activity that is not significantly different from the untreated wild-type indices thus indicating that the JTV-519 can normalize the function of the RyR1 channel and the mdx mice .

The data of Figure 11 are consistent with normalized sarcoplasmic reticulum calcium filtration in mdx mice.

The data in Figure 11 are consistent with sarcoplasmic reticulum calcium filtering through channels RyRl as the cause of increased cytosolic calcium filtering in the skeletal muscle of mdx mice (dystrophin deficient).

Figure 12 incorporations A and B demonstrate that the skeletal muscle mdx has normal levels of PKA RyRl phosphorylation, but neither depleted levels of calstabinl. Immunoblots in incorporation A show that mdx-type mice have depleted levels of calstabinl compared to a control (wild-type) mouse. The bar graphs summarizing the B incorporation that the mdx mouse, however, have an equivalent level of PKA-phosphorylation. Therefore, it is concluded that the depletion of calstabin is a defect that is consistent with the intracellular calcium filtration observed in skeletal muscle cells of mdx mice and myofibers of human mutation carriers. Ca2 + filtering of intracellular sarcoplasmic reticulum is feasible that contributes to the death of myofibra and the wasting of muscle mass by the overload of toxic intracellular calcium and the activation of proteases.

Figure 13, incorporations A, B and C, demonstrate that sarcoplasmic reticulum calcium filtering at the subcellular level in the skeletal muscles of animals with heart failure is detectable. The quality of life and the prognosis in patients with heart failure (HF) is severely diminished due to skeletal muscle dysfunction (eg shortness of breath due to diaphragmatic weakness and intolerance of exercise due to fatigue of the skeleton muscle of the limb ) in addition to a depressed cardiac function. Deregulation of intracellular sarcoplasmic reticulum calcium release is a pathogenic mechanism underlying skeletal muscle dysfunction in heart failure. Heart failure in animals causes significant accelerations of intrinsic skeletal muscle fatigue.

Embodiments A and B of Figure 13 are? F / F fluorescence line scan images of representative examples of calcium initiation in myofibers from rats with posterior myocardial infarction (PMI) and simulated and the spark time course of corresponding calcium. Incorporation C shows the relative distribution of the temporary properties of calcium sparks. The graphs indicate percentages of 25, 50, 75, the horizontal lines indicate the range of from 1-99% of the distribution. Simulated, open symbols (n = 137, three animals); postmyocardial infarction (PMI), gray symbols (n = 82, two animals). *, P < 0.05. FDHM, full duration at an amplitude of 50% peak; full width FWHM at an amplitude of 50% peak.

Figure 14, incorporations A and B, demonstrates that treatment of wild-type mice with JTV-519 improved fatigue times of soleus muscle compared to placebo. The soleo muscles of wild-type mice treated with JTV-519 or calstabin mice with heart failure from myocardial infarction are more resistant to fatigue (P <0.05) compared to mice treated with placebo. After completing the treatment, the soleus muscle was dissected and mounted in a tissue bath to evaluate the function of isolated skeletal muscle. The representative 50% of the indications of maximal strength titanic fatigue time are shown for the wild type and calstabin2_ / "mice, treated with JTV519 or place, in the incorporation A. In the incorporation B is shown the bar graph that summarize the average time to fatigue.

In summary, JTV-519 treatment improved skeletal muscle fatigue in animals with heart failure in vivo. Interestingly, the calstabin2_ ~ mice, the fatigue times were also significantly improved in the mice treated with JTV519, suggesting that the beneficial effects on the function of isolated skeletal muscle depend on calstabinl and not on calstabin2 binding to RyRl. Indeed, calstabinl appears to be the only isoform of functional meaning expressed in skeletal muscle.

Figure 15, incorporations A and B, demonstrate that in the mouse model of heart failure of posterior myocardial infarction, RyRl in the soleus muscle is also PKA-hyperphosphorylated. Both in the wild type and the calstabin2_ "mice, JTV-519 increased the binding of calstabinl to RyRl in the soleus muscle, suggesting that JTV-519 improves skeletal muscle fatigue by normalizing the calstabinl pool to the channel complex. Equivalent amounts of RyRl were immunoprecipitated with an antibody against RyRl Incorporation A provides bar graphs showing the amount of PKA phosphorylation of RyRl to Ser-2844 in mice (corresponding to Ser-2843 in humans). of PKA RyRl phosphorylation in wild-type animals treated with JTV 519 is feasibly resulting from the beneficial cardiac effects and secondary reduction of sympathetic nerve activity.The B incorporation are bar graphs showing the amount of calstabinl bound to RyRl of the wild type mice or casltabin2 ~ / ~ treated with JTV519 a placebo.Mice were treated with JTV-519 by mini Osmotic pumps that can be implanted using a dose of 0.05 mg / kilogram / day. In summary, the treatment of JTV-519 resulted in a highly significant increase in calstabinl in the RyRl complex in the soleus muscles in vivo.

Figure 16, incorporations A, B, C and D show that the calstabinl to RyRl meeting through JTV519 normalizes the function of RyRl channel filtering or abnormal in vivo. In additions A and C, the single-channel RyR1 indications at 150 nM cytoplasmic calcium representing rest conditions in skeletal muscle are shown for wild-type mice treated with placebo and JTV-519. Treatment of JTV-519 from mice with heart failure and increased muscle fatigue normalized the periodic activation of the RyR1 channel in the skeletal muscle in vivo. The channel openings are facing up, the dash indicates the complete level of channel opening (4 pA), the dotted lines indicate sub-driving levels, and "c" indicates the closed state of the channels. For amplitude histograms in additions B and D, the amplitude is represented on the x axis and the events indicate the number of channel openings. The Po, To and Te values correspond to the representative indications. Treatment as indicated on the top part of signs. The insert shows a higher resolution of the open states.

In summary, the data show that JTV519 treatment in vivo normalizes skeletal muscle function and RyR1 channel dysfunction consistent with avoiding intracellular sarcoplasmic reticulum calcium filtering as a cause of increased skeletal muscle fatigue.

Figure 17 demonstrates that JTV-519 also increases the binding affinity of calstabin for RyR1 in the skeletal muscle in vivo. This probably explains why mice treated with JTV519 with heart failure have increased levels of calstabinl bound to RyRl in the soleus muscle. In incorporation A, the equivalent amounts of RyR1 skeleton or cardiac RyR2 were immunoprecipitated, phosphorylated with PKA and incubated with calstabinl or calstabin2 at increasing concentrations of JTV519, respectively. The sediment represents only the binding of calstabin to RyR. The unmanned showed that > 50 nM of JTV519 increased the binding affinity of calstabin for RyR. The B incorporation graphs further demonstrate that PKA phosphorylation of RyRl reduces the affinity of calstabinl for RyRl (open circles) while treatment with JTV519 (full circles) restored the binding affinity of calstabinl for RyRl to that of non-phosphorylated RyRl with PKA (open squares).

Figure 18, incorporations A, B, C and D demonstrate that Ser-2843 is the only PKA phosphorylation site in the skeletal RyR channels. (A) Single channel indications representative of wild-type RyRl mice, (B) exogenous PKA phosphorylation effect of RyRl (wt RyRl-P), (C) PKA does not affect RyRl-S2843A that contains a non-functional PKA phosphorylation site. Since PKA does not increase the RyR1-S2843A activity, Ser-2843d seems to constitute the single PKA phosphorylation site in the RyR1 channels in the skeletal muscle. Therefore, (D) constitutively phosphorylated RyRl-S2843D mimics the exogenous PKA phosphorylation shown in (B) confirming that Ser-2843 is the only phosphorylation site PKA in the RyRl skeleton channels. The single-channel RyR1 records in flat lipid bilayers show channel activity at 150 nM [Ca2 +] cis (cytosolid sides) with 1 mM ATP. The registers were at 0 mV, closed state of the channels as indicated by "c", and the channel openings are deflections upwards. All point amplitude histograms are shown on the right. The open probability (PQ) and closed average (Te) and the open dwell times (To) are indicated above each channel cue.

Figure 19, incorporations A and B demonstrate the depletion of the stabilizing casltabinl and PKA hyperphosphorylation of the RyR1 channels of sustained exercise. Aerobic exercise can be defined as a form of physical exercise that increases the heart rate and improves oxygen intake for improved performance. Examples of aerobic exercise are running, cycling and swimming. ng the study of figure 19, the mice were challenged by aerobic exercise (forced swimming) for 90 minutes twice a day. The animals were used to swimming in pre-liminary training sections: day-3 twice 30 minutes, day -2 twice 45 minutes, day-1 twice 60 minutes, day 0 and following two times 90 minutes. The mice were then exercised for 1, 7 or 21 additional consecutive days for 90 minutes twice a day. Between the swim sessions separated by a four-hour rest period the mice were kept warm and fed and drunk. An adjustable running water pond was used to exercise the mice with the swim. The acrylic pond (90 centimeters long by 45 centimeters wide by 45 centimeters deep) is filled with water to a depth of 25 centimeters was used. A current in the pond was generated by a pump. The speed of the current ng the swim session was at a constant speed of 11 / minute flow rate. The water temperature was maintained at 34 ° C with an electric heater. Equal weight and age mice were used to exclude differences in body fat flotation.

Using the forced side as an efficient protocol to increase the aerobic capacity of skeletal muscle in mice, the composition and state of phosphorylation of the skeletal RyR channel complex has been investigated. Unexpectedly, after three weeks of 90 minutes of swimming, twice daily, the wild-type C57B16 mice showed a significant increase in the forsphorylation of RyRl by PKA while the phosphorylation of calmodulin kinase II (CaMKII) -Ca2 + was not changed indicating the that RyRl protein expression was stable for effort trajectory, however, RyR1 channels were depleted of the calstabinl (FKBP12) sub-unit stabilizer. It has been shown that RyR1 hyperphosphorylation and calstabinl depletion are consistent with the RyR1 filtering channels that cause intracellular sarcoplasmic reticulum calcium filtering.

The RyR1 channels are hyperphosphorylated PKA depleted of the stabilizing calstabinl subunit after three weeks of 90 minutes of swimming twice a day. As seen in incorporation A, the immunoprecipitated macromolecular RYR1 channel complex showed increased PKA phosphorylation to Ser-2844 (corresponding to human RyRl-Ser-2843) while phosphorylation CaMKII to Ser-2849 (corresponded to RyRl-Ser- 2848 human) is not changed. Concomitantly hyperphosphorylation of increased PKA RyRl-Ser-2844, calstabin is depleted of the channel complex.

As seen in incorporation B, the normalization of phosphorylation and the calstabinl content for four subunits of the tetrameric channel complex showed a significant increase in PKA phosphorylation and depletion of the stabilizing calstabinl subunit. Control non-exercised mice; mice exercised 90 minutes twice daily by swimming for 3 weeks (preliminary data). P < 0.05.

Figure 20, incorporations A and B, demonstrate that phosphorylation of PKA increases for durations of sustained exercise increase. To investigate the influence of sustained exercise duration on the effect of calcium channel release RyRl, mice were exposed to the swim for 1, 7 or 21 days followed by an immediate sacrifice. Longer exposure to sustained exercise resulted in a significant increase in PKA hyperphosphorylation of RyRl, starting at 7 days and saturating at 21 days.

Figure 20, embodiment A, the immunoprecipitated RyR1 channel complex showed significant and physiological higher levels of PKA phosphorylation increased to Ser-2844 (corresponding to human RyRl-Ser-2843) after 7 days of swimming exercise. In Figure 20, incorporation B, normalization of RyR2-Ser-2844 phosphorylation within the tetrameric channel complex documents a significant increase in PKA phosphorylation. *, P < 0.05; **, P < 0.005.

In summary, the data in Figure 20 show that sustained exercise results in a RyR1 phosphorylation significantly increased by protein kinase A (PKA) which contributes to the depletion of the stabilizing calstabinl subunit of the channel complex as the cause of a function gain defect.

Figure 21 provides data showing that the chronically increased sympathetic stimulus of the skeletal muscles results in an intracellular calcium filtration dependent on RyRl and significantly increases muscle fatigue. What is the functional consequence of PKA hyperphosphorylation of RyRl chronically increased ?. As shown in Figure 21 for mice and rats with heart failure from myocardial infarction, PKA hyperphosphorylation of RyRl results in increased muscle fatigue.

In embodiment A, it can be seen that the skeletal muscle of heart failure fatigates earlier than the control. The rat soleus muscle (n = 5 control, n = 8 HF) was mounted on a tissue bath to evaluate the contraction function. The sign of representative fatigue time is shown for the HF control skeletal muscles. The bar graph shows a mean time (± SD) at 40% fatigue. *, P < 0.05. In embodiment B, it can be seen that the skeletal muscle of heart failure achieved maximum tetanus strength more slowly than the control skeletal muscles. The tetanic force was induced by a high frequency field stimulation. The bar graph shows the contraction time of 50% tetanic. **, P < 0.01. Incorporation C demonstrates the correlation between time to fatigue and PKA RyRl phosphorylation (r = 0.88) in the rat skeletal muscle of animals with heart failure and simulated. The muscle function and PKA phosphorylation of RyRl were evaluated using the contralateral soleus muscles of each animal.

In summary, Figure 21 provides data showing that sustained exercise causes PKA hyperphosphorylation of RyRl and depletion of calstabinl, and Figure 21 shows that an identical defect occurs in disease forms with increased sympathetic activity causing a leak of intracellular sarcoplasmic reticulum calcium and a significantly accelerated skeletal muscle fatigue.

An additional problem during exercise and sustained stress is skeletal muscle degeneration that also contributes to decreased skeletal muscle performance. To evaluate the structural changes during sustained exercise, the histological changes in the muscles of fast contraction of mice exposed to 3 weeks of exercise by swimming has been characterized. The results are shown in Figure 22. The cross sections of the mouse M. extensor digi torum longus (EDL) showed histological changes consistent with myofiber degeneration of intracellular calcium overload of defective RyRl channels. Therefore, sustained exercise for 90 minutes twice daily triggers a dystrophic phenotype in the EDL muscles of normal C57B16 mice.

The trichrome spot shows the packed myofiber of similar cross-sectional dimension in control (left) mice without exercise (WT). The three weeks of swimming result in myofiber degeneration in interstitial collagen deposits with irregular fiber sizes. Hematoxylin-eosin stain (H & E) indicates nuclear changes and death of myofibra. These changes are consistent with dystrophic remodeling.

The fast retracted potassium rectifier channel (I (Kr)) is important for the repolarization of the cardiac action potential. The HERG is the pore formation sub-unit of channel I (Kr). The suppression of the function I (Kr), for example as a collateral example of a drug or a result of a mutation in hERG, can lead to a long QT syndrome (LQT), which is associated with an increased risk of arrhythmias. they threaten life The compounds of the present invention exhibit a lower level of hERG blocking activity than JTV-519 as demonstrated in Figures 23-43. Therefore, the compounds of the present invention are expected to be less toxic and / or to exhibit fewer side effects than JTV-519.

Figures 23 to 26 illustrate the effect of the compound ARM035 (also referred to as S36) and ARM036-Na (a sodium salt of ARM036) on hERG currents.

Figure 23 shows a record of typical clamp-voltage hERG voltage before (control) and after the application of ARM036 at 100μM. The voltage pulse protocol used to activate the hERG currents is illustrated below the current Index. It can be seen that, after activation by the pre-pulse conditioning (at + 20mV), the partial repolarization (-50mV test pulse) of the membrane evoked a slowly decaying outward tail stream. The application of ARM036 minimally reduced the tail current out in a time and concentration dependent manner.

Figure 24 shows a typical time course of the effect of ARM036 at 100mM on the amplitude of the channel current hERG.

Figure 25 is a graph showing the concentration-dependence of the effect of ARM036 on the current hERG. Table 1 provides the numerical data that are graphically illustrated in Figure 25. Due to the higher concentration of ARM036 tested that resulted in less than 50% of the current inhibition, it was not possible to determine an IC50 value for ARM036.

Table 1 Figure 26 is a graph showing the concentration-dependence of the effect of ARM036-Na on the hERG current. Table 2 provides the numerical data that are illustrated graphically in Figure 26. Because the highest ARM036-Na concentration tested resulted in less than 50% of the current inhibition, it was not possible to determine an IC50 value for ARM036-NA .

Table 2 Figure 27 is a graph showing the concentration-dependence of the effect of ARM047 on the current hERG. Table 3 provides the numerical data that are illustrated graphically in Figure 27. The IC50 value for the ARM047 block for the current hERG was 2,496 μM.

Table 3 Figure 28 is a graph showing the concentration-dependence of the effect of ARM048 on the current hERG. Table 4 provides the numerical data that are illustrated graphically in Figure 28. Because the highest concentration of ARM048 tested resulted in less than 50% current inhibition, it was not possible to determine an IC50 value for ARM048.

Table 4 Figure 29 is a graph showing the dependence-concentration of the effect of ARM050 on the current hERG. Table 5 provides the numerical data that are illustrated graphically in Figure 29. Due to the higher concentration of the tested ARM050 resulted in less than 50% of the current inhibition, it was not possible to determine the IC50 value for ARM050.

Table 5 Figure 30 is a graph showing the concentration-dependence of the effect of ARM057 on the current hERG. Table 6 provides the numerical data that are illustrated graphically in Figure 30. Because the highest concentration of ARM057 tested resulted in less than 50% current inhibition it was not possible to determine the IC50 value for ARM057.

Table 6 Figure 31 is a graph showing the concentration-dependence of the effect of ARM064 on the current hERG. Table 7 provides the numerical data that are illustrated graphically in Figure 31 because the highest concentration of ARM064 tested resulted in less than 50% current inhibition, it was not possible to determine an IC50 value for ARM064.

Table 7 Figure 32 is a graph showing the concentration-dependence of the effect of ARM064 on the current hERG. Table 8 provides the numerical data that are illustrated graphically in Figure 32. Because the highest concentration of ARM050 tested resulted in less than 50% current inhibition, it was not possible to determine an IC50 value for ARM074.

Table 8 Figure 33 is a graph showing the concentration-dependence of the effect of ARM075 on the current hERG. Table 9 provides the numerical data that are illustrated graphically in Figure 33. Because the highest concentration of ARM075 tested resulted in less than 50% current inhibition, it was not possible to determine an IC50 value for ARM075.

Table 9 Figure 34 is a graph showing the concentration-dependence of the effect of ARM076 on the current hERG. Table 10 provides the numerical data that are illustrated graphically in Figure 34. Because the highest concentration of ARM076 tested resulted in less than 50% current inhibition, it was not possible to determine an IC50 value for ARM076.

Table 10 Figure 35 is a graph showing the concentration-dependence of the effect of ARM077 on the current hERG. Table 11 provides the numerical data that are illustrated graphically in Figure 35. Because the highest concentration of ARM077 tested resulted in less than 50% current inhibition, it was not possible to determine an IC50 value for ARM077.

Table 11 Figure 36 is a graph showing the concentration-dependence of the effect of ARM101 on the current hERG. Table 12 provides the numerical data that are illustrated graphically in Figure 36. Because the highest concentration of ARM101 tested resulted in less than 50% current inhibition, it was not possible to determine an IC50 value for ARM101.

Table 12 Figure 37 is a graph showing the concentration-dependence of the effect of ARM102 on the current hERG. Table 13 provides the numerical data that are illustrated graphically in Figure 37. Because the highest concentration of ARM102 tested resulted in less than 50% current inhibition, it was not possible to determine an IC50 value for ARM102.

Table 13 Figure 38 is a graph showing the concentration-dependence of the effect of ARM103 on the current hERG. Table 14 provides the numerical data that are illustrated graphically in Figure 38. Because the highest concentration of ARM103 tested resulted in less than 50% current inhibition, it was not possible to determine an IC50 value for ARM103.

Table 14 Figure 39 is a graph showing the concentration-dependence of the effect of ARM104 on the current hERG. Table 15 provides the numerical data that are illustrated graphically in Figure 39. Because the highest concentration of ARM104 tested resulted in less than 50% current inhibition, it was not possible to determine an IC50 value for ARM104.

Table 15 Figure 40 is a graph showing the concentration-dependence of the effect of ARM106 on the current hERG. Table 16 provides the numerical data that are illustrated graphically in Figure 40. Because the highest concentration of ARM106 tested resulted in less than 50% current inhibition, it was not possible to determine an IC50 value for ARM106.

Table 16 Figure 41 is a graph showing the concentration-dependence of the effect of ARM107 on the current hERG. Table 17 provides the numerical data that are illustrated graphically in Figure 41. Because the highest concentration of ARM107 tested resulted in less than 50% current inhibition, it was not possible to determine an IC50 value for ARM107.

Table 17 Figure 42 is a graph showing the concentration-dependence of the effect of S26 ARM076 on the current hERG. Table 18 provides the numerical data that are illustrated graphically in Figure 42. The C50 value for S26 was 7.029 μM.

Table 18 Figure 43 is a graph showing the concentration-dependence of the effect of JTV-519 (mentioned in the figure as "ARMOXX") on the current hERG. Table 19 provides the numerical data that are illustrated graphically in Figure 43. The IC50 value for JTV-519 was 0. 463 μM.

Table 19 The antiarrhythmic drug E-4031, a known blocker of hERG currents, was used as a positive control. The E-4031 blocked the hERG current with an IC5o of 0.5 μM (n-6).

In summary, the compounds of the present invention exhibited a reduced hERG blocking activity compared to JTV-V519. Therefore, the compounds of the invention are expected to be less toxic and / or exhibit fewer side effects than JTV-519.

Table 20 below provides EC50 values for compounds S1-S107. These EC50 data were obtained using three FKBP12.6 pooling assays described above to determine the amount of FKBP12.6 that binds RYR2 PKA-phosphorylated at various concentrations (0.5-1000 nM) of the compounds shown in Table 20. The EC50 values are calculated by the Michaelis-Mind cure setting.

Table 20 High production exploration methods In addition to the compounds described herein, other compounds can be discovered which are capable of modulating calcium ion channel activity, in particular those channels related to the RyR series of calcium ion channels. Here a highly efficient assay is provided for the exploration of high production of other compounds that are capable of modulating calcium ion channel activity.

By way of example, and as shown in example 5 given below, a highly efficient assay for high throughput screening for small molecules was developed by immobilizing the FKPB, either FKBP12 or FKBP12.6 (eg, FKBP12.6 wild type or a fusion protein, such as GST-FKBP12.6) on a 96-well plate coated with glutionate, using standard procedures. The phosphorylated ryanodine receptor -PKA (RyR) specifically RyR1 or RyR3 in the case of KKBP12 and RyR2 in the case of FKBP12.6, is loaded onto a FKBP coated plate and incubated with compounds at various concentrations (10-100 nM) for 30 minutes. Then, the plate is washed to remove unbound RyR and then incubated with an anti-RyR antibody (for example 30 minutes). The plate is washed again to remove unbound anti-RyR antibody and then treated with a fluorescent labeled secondary antibody. The plate is read by an automated fluorescent plate reader for binding activity.

Alternatively, RyR is PKA-phosphorylated in the presence of 32P-ATP. The radiolabeled phosphorylated Ryr PKA is loaded onto a 96-well plate coated with FKBP, in the presence of analogs JTV-519 and other compounds at various concentrations (10-100 nM) for 30 minutes. The plate is washed to remove the unlinked radio-labeled RyR, and then read by an automatic plate reader. The PKA-phosphorylated RyR is also coated to the plate, and incubated with 32K labeled FKBP in the presence of the compounds.

The present invention is described in the following examples, which are set forth to aid in the understanding of the invention and are not to be construed as limiting in any way the scope of the invention as defined in the clauses that follow thereafter.

EXAMPLES EXAMPLE 1- PKA RYR2 FOSFORILATION AND UNION KKBP12.6 The sarcoplasmic cardiac reticulum members are prepared, as previously described (Marx et al., PKA disassociation phosphorylation FKBP12.6 of the calcium release channel (ryanodine receptor): defective regulation in failing hearts Cell, 101: 365-76 , 2000; Kaflan et al., Effects of rapacimine on ryanodine receptor / calcium channel release channels of cardiac muscle. Circ. Res., 78: 990-97, 1996). Labeling FKBP12,635-S was generated using the TNT® fast coupled transcription / transcription system from Promega (Madison, Wisconsin). The reading of [3H] ryanodine is used to quantify the RyR2 levels. 100 μg of microsomes are diluted in 100 μl of 10-mM imidazole buffer (pH 6.8) incubated with 250-nM (final concentration) [35S] -FKBP12.6 at 37 ° C for 60 minutes, then quenched with 500 μl of imidazole ice-cold buffer. The samples are centrifuged at 100,000 g for 10 minutes and washed three times in imidazole buffer. The amount of binding [35S] -FKBP12.6 was determined by the liquid flash count of the pellet.

EXAMPLE 2- IMMUNOMANCHES The microsomal immunostaining (50 μg) was carried out as described with the anti-FKBP12 / 12.6 (1: 1,000), anti-ryR-5029 (1: 3,000) (Jayaraman, et al., Associated FK506 binding protein with the calcium release channel (ryanodine receptor) J. Biol. Chem., 267: 9474-77, 1992), or anti-phospho Ryr "-P2809 (1: 5,000) for 1 hour at room temperature (Reiken and others, Beta-Blockers restore the calcium channel release fusion and improve cardiac muscle performance in human heart failure Circulation, 107: 2459-66,2003.) The specific anti-RyR2 antibody-phosphoepitope P2809 is an affinity-purified polyclonal rabbit antibody made by Zymed Laboriatories (San Francisco, California) using the peptide CRTRRI- (pS) -QTSQ, which corresponds to the PKA-phosphorylated RyR2 to Ser2809. After incubation with labeled anti-rabbit HRP IgG (1: 5,000 dilution; Transduction Laboratories, Lexington, Kentucky) spots are developed using ECL (from Amersham Pharmacia, Piscataway, New Jersey).

EXAMPLE 3- SINGLE CHANNEL RECORDS Single channel records of RyR2 native to mouse hearts, or recombinant RyR2 are acquired under clamp-voltage conditions at 0 mV, as previously described (Marx et al., PKA phosphorylation disassociates FKBP12.6 from the release channel of calcium (ryanodine receptor): defective regulation in failing hearts. Cell, 101: 365-76,2000). The symmetric solutions used for the channel recordings are: trans-compartment-HEPES, 250 mmol (L; Ba (OH) 2, 53 mmol / L (in some experiments, Ba (OH) 2 is replaced by Ca (OH) 2 ), pH 7.35, and cis compartment-HEPES, 250 mmol (L; tris-Base, 125 mmol / L; EGTA, 1.0 mmol / L; and Cacl2, 0.5 mmol / L; pH 7.35. Unless indicated otherwise Thus, the single channel recordings are made in the presence of 150-nM [Ca2 +] and 1.0-mM [Mg2 +] in the cis compartment.Ryanodine (5mM) is applied to the cis compartment to confirm the identity of all channels. The data is analyzed from digitized current registers using the Fetchan software (from Axon Instruments, of Union City, California). All data are expressed as ± SE medium. The unpaired student t test used for statistical comparison of main values between experiments. A value of p < 0.05 is considered statistically significant.

EXAMPLE 4 - COMPOUNDS AND METHODS FOR THEIR SYNTHESIS Scheme 1 Synthesis of S3, S4, S5 and S54 Sinthon S26 was prepared according to the methods described in United States of America patent application number 10 / 680,988.

The synthesis of S3 (Scheme 1): For a stirred solution of vinyl sulfonic acid (22 mg, 0.2 mmol) in CH2C12 (5 mL) anhydrous is added to the ethionyl chloride (2M in CH2C12, 0.1 mL, 0.2 mmol). The reaction mixture is stirred at room temperature overnight and evaporated under vacuum. The residue is dissolved in CH2C12 (5 ml). To this solution, a solution of S26 (20 mg, 0.1 mmol) in CH2C12 (3ml) was added with drops at 0 ° C. The reaction mixture is stirred at 0 ° C for one hour and at room temperature for another hour and washed with saturated sodium bicarbonate in IN HCl. After removal of the solvent, the product S3 is purified by Si02 column chromatography as a colorless oil (18 mg, 65).

Synthesis of S4 (Scheme 1): To a stirred solution of S26 (20 mg, 0.1 mmol) in CH2C12 (5 mL) was added methylsulfonyl chloride (26 mg, 0.2 mmol) and triethylamine (30 mg, 0.3 mmol) at 0 ° C. The resulting mixture was stirred at 0 ° C for one hour at room temperature overnight. The organic phase is washed with saturated aqueous sodium bicarbonate and dried over sodium sulfate. After filtration and evaporation of the organic solvents, the product S4 is purified by Si02 column chromatography (25 mg of oil, gave: 90%). Similarly, S5 and S54 are synthesized in 95% and 91% yield respectively.

Scheme 2: Synthesis of SI and S2 S3 Synthesis of SI and S2 (Scheme 2): To a solution of S3 (28 mg, 0.1 mmol) in chloroform (5 mL) was added 4-benzylpiperidine (18 mg, 0.1 mmol). The resul mixture is mixed at room temperature for one day. After removal of the organic solvent, the residue is purified on a column of silica gel. The product SI is obtained as a colorless oil (34 mg, yield 75%). S2 is similarly synthesized from S3 and dibutylamine in 78% yield.

Scheme 3: Synthesis of S7, S9 and S40.

Synthesis of S7, S9, S27 and S40 (Scheme 3): To a stirred solution of iodacetic acid (37 mg, 0.2 mmol) in CH2C12 (10 mL) was added thionyl chloride (2 M solution in CH2C12, 0.1 mL, 0.2 mmol). The resul mixture is stirred at 0 ° C for one hour and at room temperature overnight. After removal of the solvent, the crude acid chloride is added to a stirred solution of S26 (20 mg, 0.1 mmol) and triethylamine (30 mg, 0.3 mmol) in CH2C12 (10 mL) at 0 ° C. The mixture is stirred at 0 ° C for one hour and at room temperature overnight. The organic phase is washed with saturated sodium bicarbonate in IN HCl. The crude product is purified by column chromatography to give S7 as a colorless oil (34 mg, yield, 95%). Similarly, S9 is synthesized in 95% yield; S27 synton is synthesized in 96% yield; and S40 is synthesized in 91% yield using N-hydroxysuccinimidyl 4-azidosalicylic acid (NHS-ASA).

Scheme 4: Synthesis of Sil and S12 S26 S11: X = 0 S12: X = S Synthesis of Sil and S12 (Scheme 4): To a solution of S26 (20 mg, 0.1 mmol) in pyridine (1 ml) was added phenyl isocyanate (18 mg, 0.15 mmol). The resul mixture is stirred at room temperature for 24 hours. Then ethyl acetate (10 ml) is added and the organic phase is washed with IN HCl and saturated with sodium bicarbonate. The product Sil is purified by Si02 column chromatography as a white solid (27 mg, yield: 86%). Similarly, S12 is synthesized from S26 and phenyl isothiocyanate in 85% yield.

Scheme 5: Synthesis of S13 and S14 S2T S13 / S14 Synthesis of S13 and S14 (Scheme 5): A S26 (20 mg, 0.1 mmol) in CH2C12 (5 mL) was added triethylamine (30 mg, 0.3 mmol) and methoxyphosphonyl phenyl chloride (38 mg, 0.2 mmol) at 0 ° C. After stirring for two hours at room temperature, the reaction mixture is washed with saturated sodium bicarbonate. The isomers are separated and purified by column of silica gel to give S13 (14 mg, yield: 40%) and S14 (16 mg, yield: 45%).

Scheme 6: Synthesis of S19, S22 S19: X = CH2-CH2 S22: X ^? Y' Synthesis of S19 (Scheme 6): To a stirred solution of S26 (20 mg, 0.1 mmol) and triethylamine (30 mg, 0.3 mmol) in CH2C12 (5 mL) was added 1,4-butyldic acid chloride (8 mg, 0.05). mmol) at 0 ° C. The resul mixture was stirred at 0 ° C for one hour and at room temperature overnight. The organic phase is washed with saturated sodium bicarbonate and IN HCl and water. After removal of the solvent, the S19 product is purified by column chromatography (oil, 19 mg, 80% yield). In a similar manner S22 was prepared from 2,6-pyridyl dicarboxylic acid dichloride.

Scheme 7: Synthesis of S20 and S23 Synthesis of S20 and S23 (Scheme 7): S27 (25 mg, 0.1 mmol) in MeOH (5 mL) was treated with CH2C12 (30%, 0.5 mL) at room temperature for 1 day. After treatment with sodium thiosulfate solution, the methanol is removed by evaporation. The resul residue is dissolved in ethyl acetate (10 mL) and washed with saturated sodium carbonate. After drying over sodium sulfate, the solvent is evaporated to give a crude product which is purified by silica gel column chromatography to give S20 as a colorless oil (16 mg, 60% yield). In a similar way S23 is synthesized from S10.

Scheme 8: Synthesis of S36, S43, S44, S45, S57, S59 Synthesis of S36 and S57 (Scheme 8): To a stirred solution of S26 (0.85g, 4.4mmol) and pyridine (0.70g, 8.8mmol) in CH2C12 (50 ml) at 0 ° C was added methyl chlorooxoacetate with trickle ( 0.81 g, 6.6mmol). The reaction mixture is stirred at 0 ° C for two hours and then washed with saturated sodium bicarbonate, IN HCl, and water. Column chromatography on silica gel provides S57 as a white solid (1.lg, 90% yield). S57 (l.lg, 3.9 mmol) is dissolved in methanol (lOml) and then a solution of sodium hydroxide (0.3g, 7.5 mmol) in water (10 ml) is added. The reaction mixture is stirred at room temperature for one hour. After the solvent is removed, the residue is dissolved in water (10 ml) and washed with ether (2 x 10 ml). The aqueous phase is acidified in IN HCl to pH = 2. The product is extracted with CH2C12 (2 x 20 mL). Removal of the solvent gives the product S36 as a white solid (l.Og, 100% yield). The product can also be purified by recrystallization. S38 is similarly synthesized (see structure list).

Synthesis of S43, S44, S45 and S59 (Scheme 8): S36 (150 mg, 0.56 mmol) is treated with thionyl chloride (5 ml) at room temperature overnight. After removal of the excess thionyl chloride, the crude product S36-C1 is dissolved in CH2C12 (10 ml) and, to this solution, the protected mono-Boc cystamine and pyridine (0.2 ml, 196 mg, 2.48 mmol) are added. ) are added at 0 ° C. The reaction mixture is stirred at 0 ° C for one hour and at room temperature overnight and is cooled with saturated sodium bicarbonate. The organic phase is separated and the solvent is removed to give intermediate S36-cystamine, which is purified by Si02 column chromatography in 80% yield. Deprotection of the Boc-group is achieved with trifluoroacetic acid in CH2C12, and the deprotected S36-cystamine is used for the synthesis of S43 and S45 by the reaction of NHS-activated ester of azido compounds. The performance is 75% for S43 and 80% for S45.

S44 is synthesized as a product derived from the following reaction: S36 (50 mg, 0.19 mmol) is treated with thionyl chloride (2 ml) at room temperature overnight. After removal of the excess thionyl chloride, the crude product is dissolved in CH2C12 (5ml). To this solution, cystamine (134 mg, 0.88 mmol) and pyridine (98 mg, 1.23 mmol) in CH2C12 (10 L) are added and the reaction mixture is stirred at room temperature overnight. S44 is purified by column as a white solid (20 mg, 16%). Similarly, S57 and S59 are synthesized by reaction of S36-C1 with methanol or ethylamine (Scheme 8).

Scheme 9: Synthesis of analogs based on urea S6, S46-S53, S64, S66, S67 CHjíP Synthesis of analogs based on urea S6, S46-S53, S64, S66, S67 (Scheme 9). S26 (195 mg, 1.0 mmol) in CH2C12 (20ml) is added to 4-nitrophenyl chloroformate (220 mg, 1.1 mmol) and triethylamine (120 mg, 1.2 mmol) at 0 ° C. The reaction mixture is stirred for two hours at room temperature and washed with water. Removal of the solvents, followed by purification using column chromatography provides compound S37 (330 mg, 91%). Reaction of S37 (36 mg, 0.1 mmol) with one equivalent of amine in DMF (3ml) overnight provides urea-based compounds in a yield of > 60% after purification by Si02 column chromatography. Alternatively, the urea-based compounds can be synthesized through S26-versatile and more reactive intermediate phosgene shown in Scheme 9.

Scheme 10: Synthesis of S55, S56, S58, S60-S63 Synthesis of S55, S56, S58, S60-S63 (Scheme 10): The reaction mixture of S27 (25 mg, 0.1 mmol) and 4- (4-aminobenzyl) piperidine (19 mg, 0.1 mmol) in chloroform (5 ml) is stirred at room temperature for two days.

After removal of the solvent, the S60 product is purified by silica gel column chromatography as a white solid (36 mg, 90% yield). The S55, S56, S58 and S61-S63 are similarly synthesized according to the method described above.

Experiment for new compounds Scheme 11: Synthesis of analogs based on urea S69-S75 Analogs S69-S75, not having methoxyl groups on the benzene ring (R = H in formula I), are synthesized as shown in scheme 11 in a manner similar to that used in the synthesis of S46-S53 ( see Scheme 9). The synthesis begins with commercially available S68 and involves the versatile intermediate S68-phosgene to provide S69-S75 in a yield of 60-95%.

Scheme 12: Synthesis of S76-S81 S76 S77 S77-CI S78: X * NHEtS79: X = NHPh S80: NH2 S8t: X = NHCH2-p? Wlp? Scheme 13: Synthesis of S82-S84 By analogy the synthesis of S36, S43-S45, S57 and S59 (Scheme 8), S76-S81 are synthesized from commercially available S68 as shown in scheme 12 in a yield of 70-95%. Using S68 as starting material, compounds S82, S83 and S84, as shown in Scheme 13, are also synthesized similarly to compounds which have a methoxy group on the benzene ring (R = 4-OCH3 in the Formula I) Scheme 14: Synthesis of S88-S93 S92: R = CN S93: R = PhCH2NH Synthesis of S85-S93 is achieved as shown in scheme 14. The following are examples of the synthesis.

Synthesis of S85: A solution of S26 (10 mmol), di-tert-butyl dicarbonate (11 mmol), and triethylamine (12 mmol) in dichloromethane (100 ml) is mixed at room temperature for 5 hours. The reaction mixture is washed with saturated sodium bicarbonate solution (lOml) and the aqueous layer is extracted with dichloromethane (2 x 15 mL). The combined organic layers are dried over magnesium sulfate and concentrated under vacuum to give S85 as a colorless oil (2.90 g, 98% yield).

Synthesis of S86: To a solution of S85 (2.36 g, 8 mmol) in dichloromethane (100 ml) at -78 ° C was added BBr3 (1.0 M solution in dichloromethane) (18 ml, 18 mmol) with dropper. The solution is warmed to room temperature and the reaction mixture is quenched with methanol (100 ml) and concentrated in vacuo. The S86 product is purified by column chromatography.

Synthesis of S87: To a solution of S86 (6 mmol) in dichloromethane (40 ml) at 0 ° C was added triethylamine (7 mmol) followed by trifluoromethylsulfonyl anhydride (7 mmol). The solution is stirred at room temperature for 30 minutes, and the reaction mixture is quenched with water (10 ml). The aqueous layer is extracted with dichloromethane (2 x 15 mL), and the combined organic layers are dried over magnesium sulfate and concentrated under vacuum. The crude product is purified by silica gel scintillation chromatography to give S87 in a 75% yield.

Synthesis of S88: A mixture of S87 (1 mmol), morpholino (8 ml), tris (dibenzylideneacetone) dipalladium (0) (5 mol%), 2- (di-tert-butylphosphino) -biphenyl (20 mol%), and potassium phosphate (1.2 mmol) is heated at 80 ° C in a sealed tube for 12 hours. The reaction mixture is cooled to room temperature, diluted with dichloromethane (50 ml), and washed with water (10 ml). The aqueous layer is extracted with dichloromethane (2 x 15 ml), and the combined organic layers are dried over dried magnesium sulfate and concentrated under vacuum. The crude product is purified by silica gel scintillation chromatography to give S88 in an 81% yield.

Synthesis of S89: A solution of S87 (1 mmol), benzenetiol (2 mmol) and i-Pr2NEt (2 mmol) in CH3CN (20 mL) is heated at 80 ° C for 18 hours. After cooling, ethyl acetate (30 ml) is added and then washed with IN HCl, water and then IN NaOH. After drying with Na 2 SO 4, the solution was concentrated. The product S89 was purified by chromatography in 59% yield. Alternatively, S89 is synthesized by refluxing S87 with benzethiol in dioxane for 10 hours using i-Pr2NEt / Pd2 (dba) 3 / xanthoε as a catalyst.

Synthesis of S90: To a solution of S87 (1.0 mmol) in dioxane (10 mL) are added K2C03 (2 mmol), phenylboronic acid (1 mmol), and (Pd (Ph3P) 4 (0.11 mmol), and the mixture is stirred at 90 ° C for 16 hours.The reaction mixture is cooled to 25 ° C, diluted with CH2C12 (30 mL), washed with water (10 mL), and the organic phase is evaporated under vacuum drying. Column chromatography gives S90 in 40% yield.

Synthesis of S92: To a solution of S87 (1.0 mmol) in DMF (5 mL) are added zinc cyanide (1 mmol) and Pd (Ph3P) 4 (0.11 mmol). The reaction mixture is stirred at 100 ° C for one hour, followed by cooling, dilution with water (50 mL) and 2 M sulfuric acid (5 mL), and extraction with EtOAc (3x). The combined organic extracts are washed with brine (2x), dried over magnesium sulfate, filtered and evaporated under vacuum. The product S92 is purified with silica gel column chromatography in an 80% yield.

Scheme 15: Synthesis of S94-S100 Synthesis of S94: To a solution of S86 (1 mmol) in CH2C12 (10 mL) were added at 0 ° C acetic anhydride (1.2 mmol) and triethylamine (1.3 mmol). The reaction mixture is stirred at room temperature overnight, then washed with H20. After drying with Na2SO4, the solvent is evaporated and the product S94 (98% yield by NMR) is used for the next reaction without further purification.

Synthesis of S95: To a stirred solution of S84 (0.5 mmol) in benzene (20 mL) is added anhydrous A1C13 (0.6 mmol) with drip. The reaction mixture is refluxed for 5 hours and poured onto crushed ice (10 g). After extraction and concentration, the S95 product is purified by silica gel column chromatography in 83% yield.

Synthesis of S96: To a solution of S86 (0.1 mmol) in methanol (5 ml) is added Nal (10 mg excess) and chloramine-T (0.3 mmol). The reaction mixture is stirred for 30 minutes and cooled with a Na2S203 solution. The solvent is evaporated. The product is purified by silica gel column chromatography with a mixture of mono-iodinated or di-iodinated products in a combiand yield of 60%.

Synthesis of S97: S86 (3 mmol) is added to concentrated H2SO4 (2 mL). To the stirred mixture is added, slowly, the concentrated HN03 (2 ml) with dripping. After 10 minutes, the reaction mixture is poured onto the crushed ice (5 g) and neutralized with Na 2 CO 3 at pH = 7. The Boc-deprotected nitro intermediate is collected by extraction with EtOAc and converted back to S97 by reaction with Boc20. Purification by silica gel column chromatography affords S97 in a 78% yield.

Synthesis of S98: A mixture of S97 (2 mmol) and 10% Pd / C (0.1 g) in methanol (20 ml) is bubbled through with H2 gas for 2 hours. After filtration and concentration, the amine product is used for the following reactions without further purification.

Synthesis of S99 and SlOO: S98 (1 mmol) is dissolved in aqueous HCl (2 mmol HCl, lOml H20). To this solution is added at 0 ° C slowly a solution of sodium nitrate (1 mmol) in water (5 ml). The reaction mixture is stirred at 0 ° C for one hour, then the NaN3 (2 mmol) in water (2 ml) is added dropwise at 0 ° C. The resulting mixture is stirred at 0 ° C for one hour and at room temperature overnight. The product is extracted with ethyl acetate and washed with saturated sodium bicarbonate and water. The organic layer is dried over anhydrous sodium sulfate and concentrated to give a crude product S98. The column purification on silica gel provides the product in 71% yield. In a similar way, S99 is synthesized in 60% yield.

Synthesis of SlOl, S102, and S103 (also referred to herein as ARM101, ARM102, and ARM103, respectively) can be achieved as shown in scheme 16. The following are examples of the syntheses.

Scheme 16: Synthesis of ARM101, ARM102, and ARM103 a) N-Boc1. piperazine b) TFA Synthesis of SlOl: A solution of S68 (165 mg, 1 mmol) in CH2C12 (50 mL) was cooled to 0 ° C. To this solution, triphosgene (150 mg, 0.5 mmol) and pyridine were added. (0.5 ml of excess) and stirred at 0 ° C for 1 hour. Without purification, the resulting S68-phosgene in the reaction mixture was treated with 1-piperonylpiperazine (233 mg, 1.1 mmol) at 0 ° C. After stirring at 0 ° C for 1 hour, the reaction mixture was washed with H20 (2 x 10 mL), IN HCl (2 x 10 mL) and saturated with NaHCO3 (2 x 10 mL), and the solvents they were removed under reduced pressure. Purification by Si02 column chromatography afforded ARM101 having a yield of 80%. The structure of the product was confirmed by nuclear magnetic resonance (NMR), mass spectroscopy (MS) and / or by elemental analysis.

Synthesis of S102: S102 was synthesized from S68 using the same method used to synthesize SlOl, with the exception that piperidine was used in place of 1-piperonylpiperazine. The structure of the product was confirmed by nuclear magnetic resonance (NMR), mass spectroscopy (MS) and / or by elemental analysis.

Synthesis of S103: S103 was synthesized from S68 using the same method used to synthesize SlOl, with the exception that N-Boc 1-piperazine was used in place of 1-piperonylpiperazine, and in a subsequent step the Boc group was deprotected using the trifluoroacetic acid (TFA). The structure of the product was confirmed by nuclear magnetic resonance (NMR), mass spectroscopy (MS) and / or by elemental analysis.

Scheme 17: Synthesis of ARM104 Synthesis of S104 (ARM104) can be achieved as shown in scheme 17. The following is an example of the synthesis. A mixture ARM036 (S36) (27 mg, 0.1 mmol), 50% H202 (1 mL), and MeOH (3 mL) was stirred at room temperature for two days to generate product ARM104. Mass spectroscopy (MS) was used to monitor the disappearance of ARM036 and the appearance of the ARM104 product. The solvents were removed under reduced pressure, and the product was purified by re-crystallization. The final yield was 26 mg of ARM104 at a purity of 85%. The structure of the final product was determined by nuclear magnetic resonance (NMR) and / or MS.

Scheme 18: Synthesis of ARM105 Synthesis of S105 (ARM105) can be achieved as shown in scheme 18. The following is an example of the synthesis: To a stirred solution of S68 (80 mg, 0.48 mmol) and pyridine (0.1 ml, excess) in CH2C12 ( 50 ml) at 0 ° C, CH30-C (0) C (0) C1 (70 mg, 0.58 mmol) was added dropwise. The reaction mixture was stirred at 0 ° C for 2 hours and washed with IN HCl, saturated with sodium bicarbonate and water. Removal of the solvents and purification by Si02 column chromatography was carried out to produce the ARM105 product as a white solid (yield: 95 mg, 94%) Scheme 19: Synthesis of ARM107 NaBCNH3 S "'5326 Arm107 Synthesis of S107 (ARM107) can be achieved as shown in scheme 19. The following is an example of the synthesis: A S26 (180 mg, 0.92 mmol) in MeOH (20 ml) were added 30% CH20 solution ( 1.5 ml in excess) and sodium cyanoborohydride (NaBCNH3) (0.4 g in excess). The reaction mixture was stirred at room temperature, and the pH of the solution was maintained at about 1 pH of 4-5 by the addition of a few drops of IN HCl. After 3 hours, the solvents were removed under reduced pressure. The residue was dissolved in 20 ml of ethyl acetate and washed with H20 and saturated with NaHCO3 (2 x 10 ml). The solvents were removed and the ARM107 was purified by Si02 column chromatography to give a yield: 170 mg, 93%.

Scheme 20: Synthesis of ARM108 Synthesis of S108 (ARM108) can be achieved as shown in scheme 20. The following is an example of the synthesis: A mixture of N-benzyloxycarbonyl-glycine (Cbz-Gly, 129 mg, 0.61 mmol), Diisopropyl-carbodiimide ( DIC, 90 mg, 0.71 mmol), N-hydroxysuccinimide (NHS, 70.4 mg, 0.71 mmol) in CH2C12 (50 mL) was stirred at 0.5 hours at room temperature. S26 (100 mg, 0.51 mmol) was added to this mixture and the mixture was stirred at room temperature overnight. After washing with 1NC1 (2 x 10 ml) and saturated with the NaHCO3 solution (2 x 10 ml), the solvents were removed by evaporation. The product ARM108 was purified by Si02 column chromatography to give a yield of 120 mg, 61%.

Scheme 21: Synthesis of ARM109 Arm108 Arm109 Synthesis of S109 (ARM109) can be achieved as shown in scheme 21. The following is an example of the synthesis: ARM108 (40 mg, 0.1 mmol) in CH2C12 (5 ml) was treated with 1 ml of 30% of HBr / CH3C02H. After stirring at room temperature overnight, the reaction mixture was evaporated under reduced pressure. The residue was dissolved in MeOH (3 mL) and treated with propylene oxide (1 mL). The solvents were removed under reduced pressure to provide crude ARM109 which was further purified by dissolving in a solution of 0.15 N HCl H20 (3.5 ml), followed by washing with ethyl acetate (3 ml) and evaporation. The yield of ARM109 was 28.3 mg, 95% (white powder, HCl salt).

Scheme 22: Synthesis of ARM110 S2G Arm110 Synthesis of SllO (ARM110) can be achieved as shown in scheme 22. The following is an example of the synthesis: A mixture of S26 (100 mg, 0.51 mmol) and methyl 1-bromoacetate (100 mg, 1.2 eq .) and pyridine (50 mg) in DMF (5ml) was stirred at room temperature overnight. To this mixture, ethyl acetate (50 ml) was added and washed with a solution of NaHCO3 (2 x 10 ml) and H20 (2 x 10 ml). The product ARM110 as an oil was purified by Si02 column chromatography, to give a yield of 32 mg, 23%.

Scheme 23: Synthesis of ARM111 Synthesis of SIII (ARM111) can be achieved as shown in scheme 23. The following is an example of the synthesis: A mixture of ARM110 (16 mg, 0.06 mmol) in MeOH (2 ml) was added to INN of NaOH (0.1 ml) and the mixture was stirred at room temperature overnight. Solvents were removed under reduced pressure and dissolved in H20 (10 mi) The aqueous phase was washed with ethyl acetate (2 x 5 mL) and acidified with IN HCl at pH = 4. The removal of the solvents under reduced pressure gave crude ARM111, the NaCl was removed using ethanol to give pure ARM111 as a solid, having a yield of 13mg, 87%.

Scheme 24: Synthesis of ARM112 Synthesis of S112 (ARM112) can be achieved as shown in scheme 24. The following is an example of the synthesis: To a mixture of S26 (100 mg, 0.51 mmol) and pyridine (100 mg) in CH2C12 (20 ml) , S02C12 (89 mg, 1.2 eqquivalent) was added dropwise at 0 ° C and stirred at room temperature overnight. The solvents were removed under reduced pressure and the residue was dissolved in 5.5 ml of NaOH solution (5 ml of H20 + 0.5 ml of NaOH). The water solution was washed with ethyl acetate (2 x 5 ml), and acidified with IN of HCl to pH4. The aqueous phase was extracted with ethyl acetate (3 x 5 mL) and the ethyl acetate phase was evaporated under reduced pressure to provide ARM112, as a powder, in a yield of 9 mg.

Scheme 25: Synthesis of ARM113 Synthesis of S113 (ARM113) can be achieved as shown in scheme 25. The following is an example of the synthesis: ARM107 (45 mg, 0.21 mmol) in ethyl acetate (2 ml) was treated with CH3I (200 mg, excess ). The mixture was stirred at room temperature overnight and the product ARM113, as a white solid, was collected by filtration to give a yield of 69 mg, 97%.

Scheme 25A: Synthesis of ARM114 Synthesis of S114 (ARM114) can be achieved as shown in scheme 25A. The following is an example of the synthesis S26 (195 mg, 1 mmol) in CH2C12 (50 mL) was cooled to 0 ° C. To this solution, triphosgene (150 mg, 0.5 mmol) and pyridine (0.5 ml excess) were added and stirred at 0 ° C for one hour. Without purification, the phosgene S26 resulting in the reaction mixture was treated with N-Boc 1-piperazine (200 mg, 1.1 mmol) at 0 ° C. After stirring at 0 ° C for 1 hour, the reaction mixture was washed with H20 (2 x 10 mL), IN HCl (2 x 10 mL), and saturated with NaHCO3 (2 x 10 mL) and the solvents they were removed under reduced pressure. The purification of Si02 column chromatography afforded ARM114 with a yield of 80%.

Scheme 26: Synthesis of ARM115 Synthesis of S115 (ARM115) can be achieved as shown in scheme 26. The following is an example of the synthesis: A mixture of ARM114 (200 mg, 0.49 mmol) and Lawesson reagent (400 mg) in toluene (50 ml) they were stirred at 90 ° C for 5 hours. The mixture was cooled to room temperature and washed with saturated NaHCO3 (2 x 20 mL). The product ARM115 was purified by Si02 column chromatography to give a yield of 160 mg, 75%.

Scheme 27: Synthesis of ARM116 Synthesis of S116 (ARM116) can be achieved as shown in scheme 27. The following is an example of the synthesis: A mixture of ARM115 (10 mg, 0.02 mmol) and trifluoroacetic acid (TFA, 0.5 ml) in CH2C12 (10 ml ) was stirred at room temperature for 2 hours. Evaporation of the solvents under reduced pressure produced ARM116 with a yield of 6 mg, 92%.

Scheme 28: Synthesis of ARM117 Synthesis of S117 (ARM117) can be achieved as shown in scheme 28. The following is an example of the synthesis: A solution of ARM057 (200 mg, 0.71 mmol) in CH2C12 (20 mL) was cooled to -78 ° C. For this, 1M BBr3 in CH2C12 (1 ml) was added and the mixture was stirred at -78 ° C for 3 hours and then warmed to room temperature overnight. The mixture was washed with IN HCl (2 x 10 mL) and H20 (1 x 10 mL). After removal of the solvents, the ARM117 product was purified by Si02 column chromatography to give a yield of 60 mg, 33%.

Scheme 29: Synthesis of ARM118 Synthesis of S118 (ARM118) can be achieved as shown in scheme 29. The following is an example of the synthesis: S26 (3.6 mg, 0.018 mmol) in CH2C12 (3 ml) was treated with BODIPY TMR-X, SE ( Molecular Probes Inc.) (4 mg, 0.006 mmol) for 3 hours. The mixture was washed with 0.01 N HCl (2 x 1 mL) and saturated with NaHCO 3 (2 x 1 mL). Removal of the solvents under reduced pressure produced pure ARM118 (98%).

Scheme 30: Synthesis of ARM119 Arm107 Arm119 Synthesis of S119 (ARM119) can be achieved as shown in scheme 30. The following is an example of the synthesis: A mixture of RNA 107 (50 mg, 0.24 mmol), 50% H202 (1 ml), MeOH (3 ml) was stirred at room temperature for two days (mass spectrometry was used to monitor the disappearance of ARM 107 and the formation of the product). The solvents were removed under reduced pressure to give ARM 110, having a yield of 26 mg, 45%.

Scheme 31: Synthesis of ARM 120 and ARM 121.

The synthesis of S120 (ARM 120) and S121 (ARM 121) can be achieved as shown in scheme 31. The following is an example of the synthesis: a mixture S26 (195 mg, 1 mmol), benzyl bromide (1.1 mmol) and Na 2 CO 3 (10 mmol) in DMF (10 mL) was stirred overnight. Ethyl acetate (30 ml) was added to the reaction and then the reaction was washed with H20 (4x10 ml). The organic phase was concentrated under reduced pressure and the residue was purified by column chromatography to give S121 as a white powder, in a yield of 280 mg to 98%. S120 was similarly synthesized by the use of 4-OH-benzyl bromide instead of benzyl bromide.

The Synthesis of S122 (ARM 122) (LB 21300-30). The following is an example of the synthesis: to a cold solution of the compound S26 (250 mg, 1.28 mmol, 1 equivalent) in CH2C12 (50 ml) at 0 ° C was added the DIEA (0.67 mL, 3.8 mmol, 3.0 equivalent). Followed by acetoxyacetyl chloride (0.17 mL, 1.58 mmol, 1.24 equivalent), then the reaction sample was stirred at 0 ° C for 20 minutes, diluted with 1.0 μg HCl aqueous solution (100 mL) and extracted by CH2C12 ( 3 x 50 mL). The combined organic layers were washed (H20, brine), dried (Na2SO4), filtered and evaporated for drying. The crude product was purified by chromatography with silica gel column, eluted with an ingredient increasing in polarity from 0 to 50% of oil in methyl acetate. The relevant fractions were combined to give the desired compound (350 mg, 93%).

The Synthesis of S123 (ARM 123) (LB 21300-34). The following is an example of the synthesis: to a solution of compound S122 (287 mg, 0.97 mmol, 1 equivalent) in MeOH (5 mL) and THF (8 mL) at 23 ° C was added to LiOH (140 mg, 3.33 mmol, 3.44 equivalent in H20 5 mL). The reaction mixture was applied at 23 ° C for 20 minutes, diluted with 1.0 M aqueous HCl solution (100 mL) and extracted by CH2C12 (3 x 50 mL). The combined organic layers were washed (H20, brine), dried (Na2SO4), filtered and evaporated on drying. The crude product was purified by chromatography on a silica gel column, eluted with an ingredient increasing in polarity from 0 to 70% oil in methyl acetate. The relevant fractions were combined to give S123 (244 mg, 100%).

EXAMPLE 5 - HIGH PRODUCTION FILTERING METHOD Tests to filter biologically active small molecules have been developed. These assays are based on the assembly of the protein FKBP 12 to RyR.

A highly efficient assay for filtering high production for small molecules was developed by immobilizing FKBP 12.6 (GST-fusion protein) on a 96-well plate coated with glutathione. The phosphorylated ryanodine receptor with PKA type 2 (RyR2) is loaded onto the plate coated with FKBP 12.6, and incubated with analogous JTV-519 at various concentrations (10-100 nM) for 30 minutes. Then, the plate is washed to remove unbound RyR2, and then incubated with the anti-RyR2 antibody for 20 minutes. The plate is again washed to remove unbound anti-RyR2 antibody and then treated with a fluorescent-labeled secondary antibody. The plate is read by an automatic fluorescent plate reader regarding the binding activity.

In an alternate assay, RyR2 is PKA-phosphorylated in the presence of 32P-ATP. The radioactive phosphorylated RyR2 PKA is loaded onto the 96 well plate coated with FKBP 12.6 in the presence of JTV-519 analogues at various concentrations (10-100 nM) for 30 minutes. The plate is washed to remove the unlinked radiolabel RyR2 and then read by the automatic plate reader.

EXAMPLE 6 - EFFECT OF COMPOUNDS ARM 036 ON CORRIENTES hERG The effects of the compounds of the invention on hERG currents were studied using cultured human embryonic kidney cells 293 (KEK 293) which had been stably transferred with hERG cDNA. HEK 293 cells do not express endogenous hERG. HEK 293 cells were transfected with a plasmid containing the hERG cDNA and a neomycin resistance gene. Stable transfectants were selected by cell culture in the presence of G418. The pressure selection was maintained by continuous culture in the presence of G418. Cells were cultured in modified Eagle's medium / Mizture F-12 nutrient (D-MEM / F-12) from Dulbecco supplemented with 10% fetal bovine serum, 199U / ml sodium penicillin G, 10 μg / ml sulfate streptomycin and 500 μg / mL G418. The cells for use in electrophysiology were cultured in 35-millimeter dishes.

The electrophysiological recordings (using the full-cell patch clamp method) were carried out at room temperature (18 ° C-24 ° C). Each cell acted as its own control. The effect of ARM0036 was evaluated at two concentrations: 10 and 100 μM. Each concentration was tested in at least three cells (n> 3). 90 nM of Cisapride (commercially available from TOCRIS Bioscience) was used as a positive control for hERG blockade. For the record, the cells were transferred to the recording chamber and super merged with the vehicle control solution. The patch pipette solution for the entire cell record contained 130 mM of potassium aspartate, 5 mM of MgCl2, 5 mM of EGTA, 4 mM of ATP and 10 mM of HEPES. The pH was adjusted to 7.2 with KOH. The pipette solution was prepared in loads, in aliquots and stored frozen. A fresh aliquot was thawed and used every day. The patch pipettes were made of a glass capillary tube using a P-97 micropipette squeegee (from Sutter Instruments, Novato, California). A commercial patch clamp amplifier was used for complete cell records. Prior to fingering, the current records were filtered from low pass to one fifth of the sampling frequency.

The start and steady state block of hERG current was measured using a pulse pattern with fixed amplitudes (conditioning prepulsing: +20 mV for 2 seconds; test pulse: _50 mV for 2 seconds) repeated at 10 second intervals from Retention potential of -80 mV. Peak tail current was measured during the 2 second step at _50 mV. A steady state was maintained for at least 30 seconds before applying the test compound or the positive control. The peak tail current was monitored until a new steady state was achieved. The concentrations of the test compound were applied cumulatively in ascending order without washing between applications.

The acquisition of data analysis was carried out using the pCLAMP program set (Vre.2.2) (from Axon Instruments, of Union City, California). The steady state was defined by the constant limiting rate of change over time (linear time dependence). The steady state before and after the application of the control test compounds was used to calculate the percentage of current inhibited at each concentration. The response-concentration data were adjusted to an equation of the form: % Block =. { 1-1 / [Test] / IC50) N]} x100 where [Test] is the concentration of the test compound, ICS0 (inhibitory concentration 50) is the concentration of the test compound yielding the mean-maximum inhibition, N is the Hill coefficient, and the percent block is the percentage of current hERG inhibited in each concentration of the test compound. The non-linear square adjustments were solved with the Solver aggregate for Excel 2000 (Microsoft, Redmond, Washington). For some compounds it was not possible to determine the IC50 due to the highest concentration of the test compound that was used that did not block the hERG channel by 50% or more.

EXAMPLE 7 - EFFECT OF VARIOUS COMPOUNDS ON HERG CURRENTS The multiple compounds of the invention were tested for their effects on the hERG currents. The compounds tested were ARM036-Na ARM047, ARM048, ARM050, ARM057, ARM064, ARM074, ARM075, ARM076, ARM077, ARM101, ARM102, ARM103, ARM104, ARM106, ARM107 and ARM26. By way of comparison, the effect JTV-519 (mentioned in the figures as ARMOXX) on the hERG currents was also tested. The electrophysiological recordings were made using PatchXpress 7000A automatic parallel patch clamp system (molecular devices). Each compound was tested at 0.01, 0.1, 1 and 10 mM, with each concentration tested on 2 cells (n> 2). The duration of exposure to each test concentration was 5 minutes. Other aspects of the experimental protocols were essentially similar to those described in Example 6. For some of the compounds or it was possible to determine the IC50 due to the highest concentration of the test compound used that did not block the hERG channel by 50% or plus.

All publications, references, patents and patent applications cited herein are incorporated by reference in their entirety to the same extent as if each individual application, patent or patent application was specified and individually indicated to be incorporated by reference in its entirety.

Even though the above invention has been described in some detail for purposes of clarity and understanding, it will be appreciated by one skilled in the art, from a reading of the description, that various changes may be made in the form and details without departing from the true scope of the invention. the invention in the appended claims.

Claims (33)

R E I V I N D I C A C I O N S
1. A compound of formula I: (Formula I) or a pharmaceutically acceptable salt therefore, where : n is 0, 1, or 2; q is 0, 1, 2, 3, or 4; each R is independently halogen, -OH, -NH2, -N02, -CN, -CF3, -OCF3, -N3, -S03H, -S (= 0) 2alkyl, -S (= 0) alkyl, -0S (= 0) 2CF3, acyl, -O-acyl, alkyl , alkoxy, alkylamino, alkylarylamino, alkylthio, cycloalkyl, alkylaryl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-) aryl, (hetero-) arylthio, or (hetero-) arylamino; wherein each acyl, -O-acyl, alkyl, alkoxy, alkylamino, alkylarylamino, alkylthio, cycloalkyl, alkylaryl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-) aryl, (hetero-) arylthio, and ( hetero-) arylamino can be substituted; R x is H, oxo, alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl, or heterocyclyl; wherein each alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl, and heterocyclyl can be substituted; R2 is H, -C (= 0) R5, -C (= S) R6, -S02R7, -P (= 0) R8R9, - (CH2) m -R10, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl, cycloalkylalkyl , or heterocyclyl; wherein each alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl, cycloalkylalkyl, and heterocyclyl can be substituted; m is O, 1, 2, 3, 4, 5, 5, 7, or 8; R3 is H, -C02Y, -C (= 0) NHY, acyl, -O-acyl, alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl, or heterocyclyl; wherein each acyl, alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl, or heterocyclyl can be substituted; Y is H, alkyl, aryl, alkylaryl, cycloalkyl, heteroaryl, or heterocyclyl; and wherein each alkyl, aryl, alkylaryl, cycloalkyl, heteroaryl, and heterocyclyl can be substituted; R 4 is H, alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl or heterocyclyl; wherein each alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl, and heterocyclyl can be substituted; or one or more of R, R1 # R2, R3, or R4 comprises a fluorescent, biolucent, chemiluminescent, colorimetric or radioactive labeling group; Rs is -NR1SR16, is alkyl substituted with -NR15R16, -NHNR1SR16, -NHOH, -OR15, -C (= 0) NHR15R16, -C02R15, -C (= 0) NR15R16, -CH2X, acyl, alkyl, alkenyl, aryl , alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl; wherein each acyl, alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, and heterocyclylalkyl can be substituted; R6 is -0R1S, -NHNR15R16, -NHOH, -NR15R16, -CH2X, acyl, alkenyl, alkyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl; wherein each acyl, alkenyl, alkyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, and heterocyclylalkyl can be substituted; R7 is -0R15, -NR15R16, -NHNR15R16, -NHOH, -CH2X, alkyl, alkenyl, alkynyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl or heterocyclylalkyl; wherein each alkyl, alkenyl, alkynyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, and heterocyclylalkyl can be substituted; R8 and R9 independently are OH, acyl, alkenyl, alkoxy, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl or heterocyclylalkyl; wherein each acyl, alkenyl, alkoxy, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, and heterocyclylalkyl can be substituted; R10 is -NR15R16, -OH, -SOaR11 # -NHSOaRll f C (= 0) R12, NHC = OR12, -OC = OR12, O-P (= 0) R13R14; R11 # R12, R13, and R14 independently are are H, -OH, -NH2, -NHNH2, -NHOH, acyl, alkenyl, alkoxy, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl or heterocyclylalkyl; wherein each acyl, alkenyl, alkoxy, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, and heterocyclylalkyl can be substituted; X is halogen, -CN, -C02R15, -C (= 0) NR15R16, -NR15R16, -0R15, -S02R7, or -P (= 0) R8R9; R1S and R16 independently are H, acyl, alkenyl, alkoxy, -OH, -NH2, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl; wherein each acyl, alkenyl, alkoxy, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, and heterocyclylalkyl can be substituted; or optionally R15 and R16 together with the N to which they are attached can form a heterocycle which can be substituted; Y the nitrogen in the benzothiazepine ring can optionally be quaternary nitrogen; or an enantiomer, diastereomer, tautomer, pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof; provided that when q is 0 and n is 0, then R2 is not H, Et, -C (= 0) NH2, -C (= 0) NHPh, -C (= S) NH-n-butyl, C (= 0) NHC (= 0) CH2C1, -C (= 0) H, -C (= 0) Me, -C (= 0) Et, -C (= 0) CH = CH2, -S (= 0) 2Me, or - S (= 0) 2Et; further provided that when q is 0 and n is l or 2, then R2 is not -C (= 0) Me, -C (= 0) Et, -S (= 0) 2Me, or -S (= 0) 2Et; also provided that when q is 1, and R is Me, Cl, or F at position 6 of the benzothiazepine ring, then R2 is not H, Me, -C (= 0) H, -C (= 0) Me, -C (= 0) Et, -C (= 0) Ph, -S (= 0) 2Me, or -S (= 0) 2Et; also provided that when q is 1, n is 0, and R is OH or C1-C3 alkoxy at the 7-position of the benzothiazepine ring, then R2 is not H, -C (= 0) CH = CH2, or further provided that the compound is not SI, S3, S4, S6, S7, S20, S24, S25, S26, S27, or S36; further provided that when q is 1, n is 0, R is -OCH3 at the 7-position of the benzothiazepine ring, and R1 # R3, and R4 are each H, then R2 is not -C (= 0) CH2I, - C (= 0) C (= 0) OH, (4-benzylpiperidine-1-yl) propyl, -S (= 0) 2R19, -S (= O) 2NR20, C (= O) NHR20 or -C (= O) OR20, wherein R19 is R20 or alkenyl; R20 is aryl, alkyl, - (CH2) DN (R21) 2, or - (CH2) DSR21; j is 0, 1, 2, or 3; and R21 is alkyl or cycloalkyl; further provided that when q is l, n is 1 or 2 R is -0CH3 at the 7-position of the benzothiazepine ring and R ?, R3, and R4 are each H, then R2 is not CO (CH2) tA (R2? ) 2, S02 (CH2) t (R2?) 2, or SO-NH (CH2) tA (R2?) 2, A is N or S, and t is 1.2 or 3; Y also provided that the following structures are excluded from the formula I wherein is 0 or 1, R22 is OR29, SR29, NR29 alkyl, or halide at positions 6,7,8 or 9 on the benzothiazepine ring; R29 is alkyl, aryl or H; R23 and R24 are independently H, alkyl, or aryl R25 is H, OR30, SR30, NR30 alkyl, or halide at positions 6,7,8 or 9 on the benzothiazepine ring; R 30 is alkyl, aryl or acyl; R26 and R27 are independently H, alkyl, alkenyl, or aryl; and R2g is H, halide, alkenyl, carbonyl or alkyl containing 0, S or N.
2. 2. A compound of the selected group consisting of S Sil S S1 S2 S S47 S S51 S54 S61 S6 S69 S70 S71 S72 O S73 S74 S76 S77 S78 S79 S81 S82 S83 S85 S89 S91 S92 PhCH NH S93 S94 S96 S97 S99 SlOO SlOl S102 S103 S104 S108 Slll 10 S113 S1 10 S120 S121 Anm122 S122 Arm123 S123 or a pharmaceutically acceptable salt or hydrate thereof
3. 3. The compound as claimed in clause 2 characterized in that it has the formula or a pharmaceutically acceptable salt or hydrate thereof.
4. . The compound as claimed in clause 3 characterized in that the pharmaceutically acceptable salt is a hydrochloride salt.
5. 5. The compound as claimed in clause 2 characterized in that it has the formula (S107) or a pharmaceutically acceptable salt or hydrate thereof.
6. 6. The compound as claimed in clause 5, characterized in that the faraceutically acceptable salt is a hydrochloride salt.
7. 7. The compound as claimed in clause 1, characterized in that it has the formula I-a: (Formula I-a) or an enantiomer, or diesteromer, tautomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, wherein R, R2, q, and n are as defined in cell 1.
8. 8. The compound as claimed in clause 7, characterized in that it has the formula I-e: (formula I-e) Where R5 is -NR15R? 6; formula I-i: ~ c (0 r) nr (formula I-i) wherein Ri7 is -NR? 5R? 6, -NHNR? 5R? 6, -NHOH, -OR15, -CH2X, alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocycloalkyl, each alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl , or heterocycloalkyl, can be substituted; formula I: (formula I) wherein Ri, R3, and R4 are H, and R2 is - (CH2) m -R? 0; or formula I-k: (formula Ik) wherein R 'and R "are independently H, halogen, -OH, -NH2, -N02, -CN, -CF3, -OCF3, -N3, -S03H, -S (= 0) 2alkyl, - S (= 0) alkyl, -OS (= 0) 2CF3, acyl, alkenyl, alkoxy, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-) aryl, (hetero-arylthio), or (hetero-) arylamino; , and wherein each acyl, alkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-) aryl, (hetero-arylthio), or (hetero-) arylamino can be substituted; Ris is H, -NR15R16, -C (= 0) NR? 5R16, - (C = 0) 0R? , -OR15, alkyl, aryl, cycloalkyl, and heterocyclyl, can be substituted; and p is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; where n, q, R, R15, R16, X, m, and Rio are as defined in clause 1; or an enantiomer, or diesteromer, tautomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrugs thereof.
9. 9. A pharmaceutically acceptable salt of a compound of the formula: with a pharmaceutically acceptable base.
10. 10. The compound as claimed in clause 9 characterized in that the pharmaceutically acceptable salt is a sodium salt.
11. 11. A pharmaceutical composition comprising a compound as claimed in any of 1 to 10 and at least one additive selected from the group consisting of antioxidants, aromatics, buffers, binders, colorants, disintegrants, diluents, emulsifiers, excipients, extenders , flavor improving agents, gelatins, glidants, preservatives, skin penetration enhancers, solubilizers, stabilizers, suspending agents, sweeteners, tonicity agents, vehicles and viscosity increase agents.
12. 12. A pharmaceutical composition as claimed in clause 11, characterized in that it is in the form of capsule, granule, powder, solution, suspension, or tablet is designed for administration by an oral, sublingual, buccal, parenteral, intravenous, transdermal, inhalation, intranasal, vaginal, intramuscular or rectal.
13. 13. A method for making a pharmaceutical composition for the treatment or prevention of disorders of diseases associated with the RyR receptors that regulate the calcium channel functioning in the cells which comprises associating a compound according to any one of clauses 1 to 10 with so less an additive selected from the group consisting of antioxidants, aromatics, buffers, binders, colorants, disintegrants, diluents, emulsifiers, excipients, spreaders, flavor enhancers, gelatins, glidants, preservatives, skin penetration enhancers, solubilizers, stabilizers , suspending agents, sweeteners, tonicity agents, vehicles and viscosity increase agents.
14. 14. The method as claimed in clause 13 characterized in that the disorders are selected from the group consisting of disorders and heart diseases, skeletal muscle disorders and disorders, disorders and diseases of knowledge, malignant hypertrophy, diabetes and sudden infant death syndrome.
15. 15. The method as claimed in clause 14 characterized in that the cardiac disorders and diseases are selected from the group consisting of disorders of irregular heartbeat diseases; disorders and heart diseases irregular heart induced by exercise; sudden cardiac death; sudden cardiac death induced by exercise; congestive heart failure; chronic obstructive pulmonary disease and high blood pressure.
16. 16. The method as claimed in clause 15 characterized in that disorders and irregular heartbeat disorders and irregular heartbeat disorders and diseases induced by exercise are selected from the group consisting of atrial and ventricular arrhythmia; atrial and ventricular fibrillation; atrial and ventricular tachyarrhythmia; atrial and ventricular tachycardia; catecholaminergic polymorphic ventricular tachycardia (CPTV); and variants induced by exercise thereof;
17. 17. The method as claimed in clause 14 characterized in that skeletal muscle disorders and disorders are selected from the group consisting of skeletal muscle fatigue, exercise induced skeletal muscle fatigue, muscular dystrophy, bladder disorders and incontinence.
18. 18. The method as claimed in clause 14 characterized in that the disorders of knowledge and diseases are selected from the group consisting of Alzheimer's disease, forms of memory loss, age-dependent memory loss.
19. 19. The use of a compound as claimed in any of clauses 1 to 10 for the treatment of disorders and diseases associated with RyR receptors that regulate the functioning of calcium channel in cells.
20. 20. The use as claimed in clause 19 characterized in that the disorders and diseases are selected from the group consisting of disorders and heart diseases, muscular skeletal disorders and disorders, disorders and diseases of knowledge, malignant hyperthermia, diabetes, and death syndrome of sudden infant.
21. 21. The use as claimed in clause 20 characterized in that the cardiac disorders and diseases are selected from the group consisting of disorders and diseases of irregular heart beat; disorders and irregular heartbeat diseases induced by exercise; sudden cardiac death induced by exercise; sudden cardiac death; congestive heart failure; chronic obstructive pulmonary disease; and high blood pressure
22. 22. The use as claimed in clause 21 characterized in that irregular heartbeat disorders and diseases and irregular heartbeat disorders and chills induced by exercise are selected from the group consisting of atrial and ventricular arrhythmia; atrial and ventricular fibrillation, atrial and ventricular tachyarrhythmia; atrial and ventricular tachycardia; catecholaminergic polymorphic ventricular tachycardia (CPTV); and variants induced by exercising them.
23. 23. The use as claimed in clause 20 characterized in that skeletal muscle disorders and disorders are selected from the group consisting of muscular skeletal fatigue; Skeletal muscle fatigue induced by exercise, muscular dystrophy, bladder disorders and incontinence.
24. 24. The use as claimed in clause 20 characterized in that the disorders and diseases are selected from the group consisting of Alzheimer's disease, forms of memory loss and age-dependent memory loss.
25. 25. A method for the synthesis of a compound of the formula Al: (To the), where R 'is OMe or H, and n, R? 5 and R? 6 are as defined in clause 1; (i) reacting a compound of the formula formula A2 With triphosgene to form a compound of the formula A3 (ii) reacting the compound of the formula A3 with an amine of the formula HNR15R16 under conditions sufficient to form the compound of the formula Al; or (i) reacting an amino of the formula H R? 5R? 6 with triphosgene to form a compound of the formula A4: Cl 3 CO (C = 0) NR 15 R 16 (A4); and (ii) reacting a compound of formula A4 with a compound of formula A2: (A2) under sufficient conditions to form the compound of the formula Al.
26. 26. A method for the synthesis of a compound of the formula A5: in R 'is OMe or H, n is 0, 1, or 2, and Raa is alkyl or aryl, C? -C4 comprising: (i) reacting to a compound of the formula A2: with an acid chloride of the formula ClC (= 0) C (= 0) ORaa in the presence of a base under conditions sufficient to form the compound of the formula A5.
27. 27. A method for the synthesis of a compound of the formula A6, Where R 'is OMe or H; and n is 0, 1, or 2, which comprises reacting a compound of the formula A5 where Raa is as defined in clause 26, with an acid or a base under conditions sufficient to form the compound of the formula A6.
28. 28. The method as claimed in clause 27, in n is 0 and R 'is -OCH3.
29. 29. A method for the synthesis of a compound of the formula A7: wherein R is OR '' ', SR' '', NR '' ', alkyl, H, or halide and R' '' is alkyl, aryl, or H, which comprises reacting a compound of the formula A8: with formaldehyde (CH20) and sodium cyanoborohydride (NaB (CN) H3) under sufficient conditions to form the compound of the formula A7.
30. 30. A method for the synthesis of a compound of the formula A9: wherein R is selected from the group consisting of OR '' ', SR' '', NR '' ', alkyl, H, and halide and R' '' is alkyl, aryl, or H, which comprises (i) reacting a compound of the formula A8: with methyl-1-bromoacetate and pyridine, under conditions sufficient to form a compound of the formula AlO: (Hello); And (ii) treating the compound of the formula AlO with sodium hydroxide, under conditions sufficient to form the compound of the formula A9.
31. 31. A compound of the formula I: (Formula I] where n, q, m, X, Y, R, Ri, R2, R3, R4, R6, R8, R9, R? 0, Rn, R? 2, R? 3, R? 4, and Ri6 are as identified in clause 1; or one or more of R, R, R2, R3, or R4 comprises a group labeled fluorescent, bioluminescent, chemiluminescent, colorimetric or radioactive; R5 is -NHNR? 5R? 6, -NHOH, -C (= 0) NHR? 5R? 6, -C (= 0) NR? 5Ri6, ~ C02Ri5, -CH2X, acyl, aryl, allaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, wherein each acyl, aryl, allaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, and heterocyclylalkyl, may be substituted with one or more of halogen, CF3, OCF3, cyano, nitro, N3, oxo, cycloalkyl , alkenyl, alkynyl, heterocycle, aryl, alkylaryl, heteroaryl, 0Ra, SRa, S (= 0) Re, S (= 0) 2Re, P (= 0) 2Re, S (= 0) 2ORa, P (= 0) 2ORa, NRbRc, NRbS (= 0) 2Re, NRbP (= 0) 2Re, S (= 0) 2NRbRc, P (= 0) 2NRbRc, C (= 0) 0Ra, C (= 0) Ra, C (= 0) ) NRbRc, 0C (= 0) Ra, 0C (= 0) NRbRc, NRbC (= 0) 0Ra, NRdC (= 0) NRbRc, NRdS (= 0) 2NRbRc, NRdP (= 0) 2NRbRc, NRbC (= 0) Ra, or NRbP (= 0) 2 Re, wherein Ra is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, alkylaryl, heteroaryl, heterocycle, or aryl; Rb, Rc and Rd are independently hydrogen, alkyl, cycloalkyl, alkylaryl, heteroaryl, heterocycle, aryl, or said Rb and Rc together with the N to which these are optionally attached form a heterocycle; and Re is alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, alkylaryl, heteroaryl, heterocyclyl, or aryl; and wherein the alkyl can be substituted into one or more of CF3; R7 is -0R? 5, -NHNR? 5R? 6, -NHOH, -CH2X, alkynyl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl; wherein each alkynyl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, and heterocyclylalkyl can be substituted; X is -CN, -C02Ri5, -C (= 0) NR? 5R? 6, -OR15, -S02R, or -P (= 0) R8R9; R15 is acyl; alkenyl, alkoxy, -OH, -NH2 alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl; wherein each acyl, alkenyl, alkoxy, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, and heterocyclylalkyl can be substituted; and optionally R15 and Ri6 together with N to which these are attached can form a heterocycle which can be substituted; Y the nitrogen in the benzothiazepine ring can optionally be quaternary nitrogen; or an antiomer, diastereomer, tautomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof. provided that when q is 0 and n is 0, then R2 is not H, Et, -C (= 0) NH2, -C (= 0) NHPh, -C (= S) NH-nButyl, -C (= 0) NHC (= 0) CH2C1, -C (= 0) H, -C (= 0) Me, -C (= 0) Et, -C (= 0) CH = CH2, -S (= 0) 2Me, or -S (= 0) 2Et; also provided that when q is 0 and n is 1 or 2, then R2 is not -C (= 0) Me, -C (= 0) Et, -S (= 0) 2Me, or -S (= 0) 2Et; also provided that when q is 1, and R is Me, Cl, or F at position 6 of the benzothiazepine ring, then R2 is not H, Me, -C (= 0) H, -C (= 0) Me, -C (= 0) Et, -C (= 0) Ph, -S (= 0) 2Me, or -S (= 0) 2Et; further provided that when q is 1, n is 0, and R is OH or or C? -C3 alkoxy at position 7 of the benzothiazepine ring, then R2 is not H, -C (= 0) CH = CH2, or provided that the compound is not SI, S3, S4, S6, S7, S20, S24, S25, S26, S27, or S36.
32. 32. A compound of the formula I: (Formula I) wherein n, q, m, X, Y, R, Ri, R2, R3, R4, R5, R6, R7, R8, R9, Rio iir Ri2f RI3? RI < W i5 / and i6 are as defined in clause 1 and; the nitrogen in the benzothiazepine ring may optionally be a quaternary nitrogen; an enantiomer, diastereomer, tauteromer, pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof; provided that when q is 0 and n is 0, then R2 is not H, Et, -C (= 0) NH2, -C (= 0) NHPh, -C (= S) NH-nButyl, C (= 0) NHC (= 0) CH2C1, -C (= 0) H, -C (= 0) Me, -C (= 0) Et, -C (= 0) CH = CH2, -S (= 0) 2Me, oS ( = 0) 2Et; further provided that when q is 0 and n is l or 2, then R2 is not -C (= 0) Me, -C (= 0) Et, -S (= 0) 2Me, or -S (= 0) 2Et; also provided that when q is 1, and R is Me, Cl, or F at the 6-position of the benzothiazepine ring, then R2 is not H, Me, -C (= 0) H, -C (= 0) Me, -C (= 0) Et, -C (= 0) Ph, -S (= 0) 2Me, or -S (= 0) 2Et; further provided that when q is 1, n is 0, and R is OH or C? -C3 alkoxy in the 7-position of the benzotizepin ring, then R2 is not H, -C (= 0) CH = CH2, or further provided that R2 -C = 0 (R5) or -S02R7, then there are at least two R groups attached to the benzene ring; Y also provided that the compound is not SI, S3, S4, S6, S7, S20, S24, S25, S26, S27, or S36.
33. 33. A compound having the formula I-a: (Formula I-a) Where: n, q, m, X, Y, Rl R2, R3, R4, R5, R6, R7, R8, R9, Rio / Rii / R12 / Ri3 / Ri4 Ri5 / and Ri6 are as mentioned in clause 1; Y each R is independently halogen, -OH, -NH2, -N02, -CN, -CF3, -OCF3, -N3, -S03H, -S (= 0) 2alkyl, -S (= 0) alkyl, -0S (= 0) 2CF3, acyl, alkyl, cycloalkyl, alkylaryl, aryl, heteroaryl, heterocyclyl, heterocycloalkyl, alkenyl, alkynyl, (hetero-) aryl, (hetero-) arylthio, or (hetero-) arylamino; wherein each, acyl, alkyl, cycloalkyl, alkylaryl, aryl, heteroaryl, heterocyclyl, heterocycloalkyl, alkenyl, alkynyl, (hetero-) aryl, (hetero-) arylthio, or (hetero-) arylamino can be substituted or unsubstituted; and the nitrogen in the benzothiazepine ring may optionally be a quaternary nitrogen or an enantiomer, diesteromer, tautomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof; provided that when q is 0 and n is 0, then R2 is not H, Et, -C (= 0) NH2, -C (= 0) NHPh, -C (= S) NH-nButyl, C (= 0) NHC (= 0) CH2C1, -C (= 0) H, -C (= 0) Me, -C (= 0) Et, -C (= 0) CH = CH2, -S (= 0) 2Me, or - S (= 0) 2Et; also provided that when q is O and n is l or 2, then R2 is not -C (= 0) Me, -C (= 0) Et, -S (= 0) 2Me, or -S (= 0) 2Et; also provided that when q is 1, and R is Me, Cl, or F in position 6 of the benzothiazepine ring then R2 is not H, Me, -C (= 0) H, -C (= 0) Me, - C (= 0) Et, -C (= 0) Ph, -S (= 0) 2Me, or -S (= 0) 2Et; further provided that when q is 1, n is 0, and R is OH or C?-C3 alkoxy at position 7 of the benzothiazepine ring then R2 is not H, -C (= 0) CH = CH2, or provided that the compound is not SI, S3, S4, S6, S7, S20, S24, S25, S26, S27, or S36. SUMMARY The present invention provides compounds of Formula I, (I) and salts, hydrates, solvates, complexes and prodrugs thereof. The present invention further provides methods for synthesizing the compounds of formula I. The invention further provides pharmaceutical compositions comprising the compounds of Formula I and methods for using the pharmaceutical compositions of Formula I to treat and prevent disorders and diseases associated with the RyR receptors that regulate the calcium channel that works in cells.