Prodrugs of riluzole and their method of use

A compound having formula (I):

• including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein:
• R1 is selected from the group consisting of C1-C6 fluoroalkyl, OR2, (CR6aR6b)mNHR7, CR10aR10bNR11R12,
• R2 is selected from the group consisting of CH2(CH2)nNR3aR3b,
• R3a and R3b are independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, and CO2R4;
• R3a and R3b cannot both be C1-C6 alkyl;
• R3a and R3b are taken together with the atom to which they are bound to form an optionally substituted three to six membered saturated heterocyclic ring consisting of two to five carbon atoms and a member selected from the group consisting of O, NR, S, and SO2;
• n is 1 or 2;
• R4 is selected from the group consisting of C1-C6 alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, optionally substituted phenyl, and optionally substituted benzyl;
• R5 is selected from the group consisting of C1-C6 alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, and C2-C6 alkynyl;
• R6a and R6b are at each occurrence independently selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 branched alkyl, optionally substituted C3-C7 cycloalkyl, C2-C6 alkenyl, and C2-C6 alkynyl;
• R6a and R6b are taken together with the atom to which they are bound to form an optionally substituted 6 membered ring;
• m is 1, 2, or 3;
• R7 is selected from the group consisting of COCR8aR8b(NHR9),
• R8a and R8b are at each occurrence independently selected from the group consisting of hydrogen, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2OH, CH(OH)CH3, CH2Ph, CH2(4-OH-Ph), (CH2)4NH2, (CH2)3NHC(NH2)NH, CH2(3-indole), CH2(5-imidazole), CH2CO2H, CH2CH2CO2H, CH2CONH2, and CH2CH2CONH2;
• R9 is at each occurrence independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, and C2-C6 alkynyl;
• Y is at each occurrence independently selected from the group consisting of H2 or O;
• R10a and R10b are at each occurrence independently selected from the group consisting of hydrogen, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2OH, CH2OCH2Ph, CH(OH)CH3, CH2Ph, CH2(4-OH-Ph), (CH2)4NH2, (CH2)3NHC(NH2)NH, CH2(3-indole), CH2(5-imidazole), CH2(CCH), CH2(cyclohexyl), CH2CO2H, CH2CH2CO2H, CH2CONH2, and CH2CH2CONH2;
• R10a and R10b are taken together with the atom to which they are bound to form an optionally substituted three to six membered saturated carbocyclic ring;
• R11 is at each occurrence independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, C1-C6 haloalkyl, and C2-C6 alkynyl;
• R10a and R11 are taken together with the atoms to which they are bound to form an optionally substituted four to six membered ring containing one nitrogen atom, and R12 is not hydrogen;
• R10b and R11 are taken together with the atoms to which they are bound to form an optionally substituted four to six membered ring containing one nitrogen atom, and R12 is not hydrogen;
• R12 is at each occurrence independently selected from the group consisting of hydrogen, C1-C6 alkyl, COCR13aR13bNR15aR15b, COCR13aR13bOR14SO2CR13aR13bNR15aR15b, COCR13aR13bNHSO2R15a
• and (CR19aR19b)qNHR20, and when R12 is hydrogen, R11 cannot be hydrogen;
• R11 and R12 are taken together with the atom to which they are bound to form an optionally substituted four to six membered saturated heterocyclic ring containing a nitrogen atom and optionally containing an additional heteroatom from the group consisting of N and O;
• R13a and R13b are at each occurrence independently selected from the group consisting of hydrogen, CH3, CH2CH3, CH2CH2CH3, CH2CCH, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2OH, CH2OCH2Ph, CH2CH2OCH2Ph, CH(OH)CH3, CH2Ph, CH2(cyclohexyl), CH2(4-OH-Ph), (CH2)4NH2, (CH2)3NHC(NH2)NH, CH2(3-indole), CH2(5-imidazole), CH2CO2H, CH2CH2CO2H, CH2CONH2, and CH2CH2CONH2;
• R13a and R13b are taken together with the atom to which they are bound to form an optionally substituted three to six membered saturated carbocyclic ring;
• R13a and R13b are taken together with the atom to which they are bound to form an optionally substituted six membered saturated heterocyclic ring with one 0 atom within the ring;
• R13a and R14 are taken together with the atoms to which they are bound to form an optionally substituted four to six membered ring containing one nitrogen atom;
• R13a and Ru15a are taken together with the atoms to which they are bound to form an optionally substituted four to six membered ring containing one nitrogen atom;
• Y1 is at each occurrence independently selected from the group consisting of H2, O, and —H/—OCH2Ph;
• R14 is at each occurrence independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, and C2-C6 alkynyl;
• R15a and R15b are at each occurrence independently selected from the group consisting of H, C1-C6 alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl C1-C6 fluoroalkyl, COR21, CH2R21, SO2R22, an optionally substituted four to six membered saturated heterocyclic ring containing a heteroatom selected from the group consisting of NR24 and O, COCHR23NH2,
• R15a and R15b are taken together with the atom to which they are bound to form an optionally substituted three to six membered saturated heterocyclic ring consisting of two to five carbon atoms and a member selected from the group consisting of O, NR, S, and SO2;
• R16 is at each occurrence independently selected from the group consisting of CH2, O, C═O, and NH;
• R17 is at each occurrence independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, and C2-C6 alkynyl;
• R18 is at each occurrence independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, and C2-C6 alkynyl;
• R17 and R18 are taken together with the atoms to which they are bound to form an optionally substituted five or six membered ring containing two nitrogen atoms;
• R19a and R19b are at each occurrence independently selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 branched alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted C2-C6 alkenyl, and optionally substituted C2-C6 alkynyl;
• R19a and R19b are taken together with the atom to which they are bound to form an optionally substituted 3 to 6 membered carbocyclic ring;
• R20 is at each occurrence independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, and C2-C6 alkynyl;
• q is 1, or 2;
• R21 is at each occurrence independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 fluoroalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
• R22 is at each occurrence independently selected from the group consisting of C1-C6 alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl;
• R23 is selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH2CCH, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2OH, CH2OCH2Ph, CH2CH2OCH2Ph, CH(OH)CH3, CH2Ph, CH2(cyclohexyl), CH2(4-OH-Ph), (CH2)4NH2, (CH2)3NHC(NH2)NH, CH2(3-indole), CH2(5-imidazole), CH2CO2H, CH2CH2CO2H, CH2CONH2, and CH2CH2CONH2;
• R24 is at each occurrence independently selected from the group consisting of H, C1-C6 alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, COR25, and SO2—C1-6alkyl;
• R25 is at each occurrence independently selected from the group consisting of H, C1-C6 alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, C1-C6 alkoxy, and C1-C6 alkylamino.