Agents for preventing and treating disorders involving modulation of the ryanodine receptors

A compound which is selected from the group consisting of formula I-g, I-h, I-k-1, I-l-1, or I-m-1:

• wherein
• (a) the compound of formula I-g or I-h is:
• wherein W is S or O;
• n is 0, 1, or 2;
• q is 0, 1, 2, 3, or 4;
• each R is located at position 6, 7, 8 or 9 on the benzothiazepine ring;
• each R is independently selected from the group consisting of halogen, —OH, —NH2, —NO2, —CN, —CF3, —OCF3, —N3, —SO3H, —S(═O)2alkyl, —S(═O)alkyl, —OS(═O)2CF3, acyl, alkyl, alkoxyl, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-)aryl, (hetero-)arylthio, and (hetero-)arylamino;
• wherein each acyl, alkyl, alkoxyl, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-)aryl, (hetero-)arylthio, and (hetero-)arylamino may be substituted or unsubstituted;
• R15 and R16 independently are selected from the group consisting of H, acyl, alkenyl, alkoxyl, OH, NH2, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;
• wherein each acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted or unsubstituted;
• and optionally R15 and R16 together with the N to which they are bonded may form a heterocycle which may be substituted or unsubstituted;
• and
• R′ and R″ are independently selected from the group consisting of H, halogen, —OH, —NH2, —NO2, —CN, —CF3, —OCF3, —N3, —SO3H, —S(═O)2alkyl, —S(═O)alkyl, —OS(═O)2CF3, acyl, alkyl, alkoxyl, alkylamino, alkylthio, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-)arylthio, and (hetero-)arylamino;
• wherein each acyl, alkyl, alkoxyl, alkylamino, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, and (hetero-)arylthio may be substituted or unsubstituted;
• provided that
• when q is 0 and n is 0, then —C(═W)NR15R16 is not —C(═O)NH2, —C(═O)NHPh, —C(═S)NH-nButyl, or —C(═O)NHC(═O)CH2Cl;
• when q is 0, n is 0 or 2, then —C(═W)NR15R16 is not —C═ONHPh, —C═ONHCOCH2Cl, —C═ONH2, —C═ONH(n-Bu), —C═S(NHPh), —C═S(NHCOCH2Cl), —C═S(NH2), or —C═SNH(n-Bu);
• (b) the compound of formula I-k-1 is:
• wherein
• n is 0, 1, or 2;
• R18 is selected from the group consisting of —NR15R16, —C(═O)—NR15R16, —OR15, —C(═O)—OR15, alkyl, aryl, cycloalkyl and heterocyclyl, wherein each alkyl, aryl, cycloalkyl and heterocyclyl may be unsubstituted or substituted;
• R15 and R16 independently are selected from the group consisting of H, acyl, alkenyl, alkoxyl, OH, NH2, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;
• wherein each acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted or unsubstituted;
• and optionally R15 and R16 together with the N to which they are bonded may form a heterocycle which may be substituted or unsubstituted;
• p is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
• R′ is selected from the group consisting of halogen, —OH, —NH2, —NO2, —CN, —CF3, —OCF3, —N3, —SO3H, —S(═O)2alkyl, —S(═O)alkyl, —OS(═O)2CF3, acyl, alkyl, alkoxyl, alkylamino, alkylthio, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-)arylthio, and (hetero-)arylamino;
• wherein each acyl, alkyl, alkoxyl, alkylamino, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, and (hetero-)arylthio may be substituted or unsubstituted;
• and
• R″ is H;
• provided that when n is 0, and R′ is OH or C1-C3 alkoxyl, then —(CH2)p—R18 is not —(CH2)3-4-benzylpiperidine;
• (c) the compound of formula I-l-1 is:
• wherein
• n is 0, 1, or 2;
• R6 is selected from the group consisting of —OR15, —NHNR15R16, —NHOH, —CH2X, acyl, alkenyl, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;
• wherein each acyl, alkenyl, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted or unsubstituted;
• R15 and R16 independently are selected from the group consisting of H, acyl, alkenyl, alkoxyl, OH, NH2, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;
• wherein each acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted or unsubstituted;
• and optionally R15 and R16 together with the N to which they are bonded may form a heterocycle which may be substituted or unsubstituted;
• X is selected from the group consisting of halogen, —CN, —CO2R15, —C(═O)NR15R16, —NR15R16, —OR15, —SO2R7, and —P(═O)R8R9;
• R7 is selected from the group consisting of —OR15, —NR15R16, —NHNR15R16, —NHOH, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;
• wherein each alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted or unsubstituted;
• R8 and R9 independently are selected from the group consisting of OH, acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;
• wherein each acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted or unsubstituted;
• and
• R′ and R″ are independently selected from the group consisting of H, halogen, —OH, —NH2, —NO2, —CN, —CF3, —OCF3, —N3, —SO3H, —S(═O)2alkyl, —S(═O)alkyl, —OS(═O)2CF3, acyl, alkyl, alkoxyl, alkylamino, alkylthio, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-)arylthio, and (hetero-)arylamino;
• wherein each acyl, alkyl, alkoxyl, alkylamino, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, and (hetero-) arylthio may be substituted or unsubstituted;
• or
• (d) the compound of formula I-m-1 is:
• wherein
• n is 0, 1, or 2;
• R8 and R9 independently are selected from the group consisting of OH, acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;
• wherein each acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted or unsubstituted;
• R′ and R″ are independently selected from the group consisting of H, halogen, —OH, —NH2, —NO2, —CN, —CF3, —OCF3, —N3, —SO3H, —S(═O)2alkyl, —S(═O)alkyl, —OS(═O)2CF3, acyl, alkyl, alkoxyl, alkylamino, alkylthio, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-)arylthio, and (hetero-) arylamino;
• wherein each acyl, alkyl, alkoxyl, alkylamino, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, and (hetero-) arylthio may be substituted or unsubstituted.