Gga and gga derivatives compositions thereof and methods for treating neurodegenerative diseases including paralysis including them

A compound of Formula (I), (II), (III), (IV) or (V):

• or pharmaceutically acceptable salt thereof, wherein
• n1 is 1 or 2;
• n is 0, 1 or 2;
• m is 0 or 1;
• Q1 is —(C═O)—, —(C═S)—, or —S(O2)—;
• Q2 is hydrogen, R6, —O—R6, —NR7R8, or is a chiral moiety;
• Q3 is —OH, —NR22R23—X—CO—NR24R25, —X—CS—NR24R25, or —X—SO2—NR24R25;
• Q4 is selected from the group consisting of:
• Q5 is —C(═O)H, —CO2H or an ester or acyl halide thereof, wherein the ester is optionally substituted with —CO-phenyl;
• a 6-10 membered aryl or a 5-14 membered heteroaryl or heterocycle containing up to 6 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, and further wherein the aryl, heteroaryl, or heterocyclyl ring is optionally substituted with 1-3 substituents selected from the group consisting of:
• hydroxy, oxo, —N(R40)2, C1-C6 alkoxy group, and C1-C6 alkyl group, wherein the alkyl group is optionally substituted with 1-3 substituents selected from hydroxy, NH2, —CO2H or an ester or an amide thereof,
• a 5-9 membered heteroaryl containing up to 3 ring heteroatoms, wherein the heteroaryl is optionally substituted with 1-3 hydroxy, —N(R40)2, and C1-C6 alkyl group,
• benzyl, and phenyl optionally substituted with 1-3 substituents selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, hydroxy, and halo groups;
• and
• when Q5 is present:
• R5 and Q5 together with the intervening carbon atoms form a 6 membered aryl ring, or a 5-8 membered cycloalkenyl ring, or a 5-14 membered heteroaryl or heterocycle, wherein each aryl, cycloalkenyl, heteroaryl, or heterocycle, ring is optionally substituted with 1-2 substituents selected from the group consisting of halo, hydroxy, oxo, —N(R40)2, and C1-C6 alkyl;
• Q6 is selected from the group consisting of:
• X is —O—, —S—, —NR26—, or —CR27R28;
• when X1 is bonded via a single bond, X1 is —O—, —NR31—, or —CR32R33—, and when X1 is bonded via a double bond, X1 is —CR32—;
• when X2 is bonded via a single bond, X2 is —O—, —NR52—, or —CR53R54—, and when X2 is bonded via a double bond, X2 is —CR53—;
• Y1 is hydrogen, —OH or —O—R10,
• Y2 is —OH, —OR11 or —NHR12, or Y1 and Y2 are joined to form an oxo group (═O), an imine group (═NR13), a oxime group (═N—OR14), or a substituted or unsubstituted vinylidene (═CR16R17);
• Y11 is hydrogen, —OH or —OR55;
• Y22 is —OH, —OR56, —NHR57, or —O—CO—NR58R59, or Y11 and Y22 are joined to form an oxo group (═O), an imine group (═NR60), a oxime group (═N—OR61), or a substituted or unsubstituted vinylidene (═CR63R64);
• each R1 and R2 are independently C1-C6 alkyl, or R1 and R2 together with the carbon atom they are attached to form a C5-C7 cycloalkyl ring optionally substituted with 1-3 C1-C6 alkyl groups;
• each of R3, R4, and R5 independently are hydrogen or C1-C6 alkyl;
• R6 is:
• C1-C6 alkyl, optionally substituted with —CO2H or an ester thereof, C1-C6 alkoxy, oxo, —OH, —CR═CR2, —CCR, C3-C10 cycloalkyl, C3-C8 heterocyclyl, C6-C10aryl, C2-C10heteroaryl, wherein each R independently is hydrogen or C1-C6 alkyl;
• CO—C1-C6 alkyl;
• C3-C10 cycloalkyl;
• C3-C8 heterocyclyl;
• C6-C10 aryl;
• or
• C2-C10 heteroaryl;
• wherein each cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-3 alkyl groups;
• —CF3, 1-3 halo, preferably, chloro or fluoro, groups;
• 1-3 nitro groups;
• 1-3 C1-C6 alkoxy groups;
• —CO-phenyl;
• or —NR18R19;
• each R7 and R8 are independently hydrogen or defined as R6;
• R10 is C1-C6 alkyl;
• R11 and R12 are independently C1-C6 alkyl, C3-C10 cycloalkyl, —CO2R15, or —CON(R15)2, or R10 and R11 together with the intervening carbon atom and oxygen atoms form a heterocycle optionally substituted with 1-3 C1-C6 alkyl groups;
• R13 is C1-C6 alkyl or C3-C10cycloalkyl optionally substituted with 1-3 C1-C6 alkyl groups;
• R14 is hydrogen, C3-C8 heterocyclyl, or C1-C6 alkyl optionally substituted with a —CO2H or an ester thereof or a C6-C10 aryl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, or a C3-C8 heterocyclyl, wherein each cycloalkyl, heterocyclyl, or aryl, is optionally substituted with 1-3 alkyl groups;
• each R15 independently are hydrogen, C3-C10 cycloalkyl, C1-C6 alkyl optionally substituted with 1-3 substituents selected from the group consisting of —CO2H or an ester thereof, aryl, or C3-C8 heterocyclyl, or two R15 groups together with the nitrogen atom they are bonded to form a 5-7 membered heterocycle;
• R16 is hydrogen or C1-C6 alkyl;
• R17 is hydrogen, C1-C6 alkyl substituted with 1-3 hydroxy groups, —CHO, or is CO2H or an ester thereof;
• each R18 and R19 independently is hydrogen;
• C1-C6 alkyl, optionally substituted with —CO2H or an ester thereof, C1-C6 alkoxy, oxo, —CR═CR2, —CCR, C3-C10 preferably C3-C8 cycloalkyl, C3-C8 heterocyclyl, C6-C10 aryl, or C2-C10 heteroaryl, wherein each R independently is hydrogen or C1-C6 alkyl;
• C3-C10 cycloalkyl;
• C3-C8 heterocyclyl;
• C6-C10 aryl;
• or C2-C10 heteroaryl;
• wherein each cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-3 alkyl groups, optionally substituted with 1-3 halo, preferably, fluoro, groups, or where R18 and R19 together with the nitrogen atom they are attached to form a 5-7 membered heterocycle;
• each R22 and R23 independently is hydrogen;
• C1-C6 alkyl, optionally substituted with C1-C6 alkoxy;
• and C3-C10 cycloalkyl;
• each R24 and R25 independently is hydrogen;
• C1-C6 alkyl, optionally substituted with —CO2H or an ester thereof, C1-C6 alkoxy, oxo, —CR═CR2, —CCR, C3-C10 preferably C3-C8 cycloalkyl, C3-C8 heterocyclyl, C6-C10 aryl, or C2-C10 heteroaryl, wherein each R independently is hydrogen or C1-C6 alkyl;
• C3-C10 cycloalkyl;
• C3-C8 heterocyclyl;
• C6-C10 aryl;
• or C2-C10 heteroaryl;
• wherein each cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-3 alkyl groups, optionally substituted with 1-3 halo, preferably, fluoro, groups, or R24 and R25 together with the nitrogen atom they are attached to form a 5-7 membered heterocycle;
• R26 is hydrogen or together with R24 or R25 and the intervening atoms form a 5-7 membered heterocyclic ring optionally substituted with 1-3 C1-C6 alkyl groups;
• each R27 and R28 independently are hydrogen, C1-C6 alkyl, —COR81 or —CO2R81, or R27 together with R24 or R25 and the intervening atoms form a 5-7 membered heterocyclyl ring optionally substituted with 1-3 C1-C6 alkyl groups;
• R30 is C1-C6 alkyl optionally substituted with 1-3 alkoxy or 1-5 halo group, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C6-C10 aryl, C3-C8 heterocyclyl, or C2-C10 heteroaryl, wherein each cycloalkyl or heterocyclyl is optionally substituted with 1-3 C1-C6 alkyl groups, or wherein each aryl or heteroaryl is independently substituted with 1-3 C1-C6 alkyl or nitro groups, or R30 is —NR34R35;
• R31 is hydrogen or together with R30 and the intervening atoms form a 5-7 membered ring optionally substituted with 1-3 C1-C6 alkyl groups;
• each R32 and R33 independently are hydrogen, C1-C6 alkyl, —COR81 or —CO2R81, or R32 together with R30 and the intervening atoms form a 5-7 membered cycloalkyl or heterocyclyl ring optionally substituted with oxo or 1-3 C1-C6 alkyl groups;
• each R34 and R35 independently is hydrogen, C1-C6 alkyl, optionally substituted with —CO2H or an ester thereof, C3-C10 cycloalkyl, C3-C8 heterocyclyl, C6-C10 aryl, or C2-C10 heteroaryl, or is C3-C10 cycloalkyl, C3-C8 heterocyclyl, C6-C10 aryl, or C2-C10 heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-3 alkyl groups, or R34 and R35 together with the nitrogen atom they are attached to form a 5-7 membered heterocycle;
• each R40 independently is hydrogen or C1-C6 alkyl;
• R51 is C1-C6 alkyl, C1-C6 alkyl substituted with 1-3 alkoxy or 1-5 halo groups, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C3-C8 heterocyclyl, C6-C10 aryl, C2-C10 heteroaryl, or —NR65R66, wherein each cycloalkyl or heterocyclyl is optionally substituted with 1-3 Cr C6 alkyl groups, and wherein each aryl or heteroaryl is optionally substituted independently with 1-3 nitro and Cr C6 alkyl groups;
• R52 is hydrogen or together with R51 and the intervening atoms form a 5-7 membered ring optionally substituted with 1-3 C1-C6 alkyl groups;
• each R53 and R54 independently are hydrogen, C1-C6 alkyl, —COR81, —CO2R81, or —CONHR82, or R53 together with R51 and the intervening atoms form a 5-7 membered cycloalkyl or heterocyclyl ring optionally substituted with 1-3 C1-C6 alkyl groups;
• R55 is C1-C6 alkyl;
• each R56 and R57 independently are C1-C6 alkyl, C3-C10cycloalkyl, —CO2R62, or —CON(R62)2;
• or R55 and R56 together with the intervening carbon atom and oxygen atoms form a heterocycle optionally substituted with 1-3 C1-C6 alkyl groups;
• R58 is:
• C3-C10 cycloalkyl, C1-C6 alkyl optionally substituted with —OH, CO2H or an ester thereof, or C3-C10 cycloalkyl,
• R59 is hydrogen or C1-C6 alkyl;
• R60 is C1-C6 alkyl or C3-C10 cycloalkyl optionally substituted with 1-3 C1-C6 alkyl groups, or is:
• R61 is hydrogen, C3-C8 heterocyclyl, or C1-C6 alkyl optionally substituted with a —CO2H or an ester thereof or a C6-C10 aryl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10cycloalkyl, or a C3-C8 heterocyclyl, wherein each cycloalkyl, heterocyclyl, or aryl, is optionally substituted with 1-3 alkyl groups;
• each R62 independently are hydrogen, C3-C10 cycloalkyl, C1-C6 alkyl optionally substituted with 1-3 substituents selected from the group consisting of —CO2H or an ester thereof, aryl, C3-C8 heterocyclyl, or two R62 groups together with the nitrogen atom they are bonded to form a 5-7 membered heterocycle;
• R63 is hydrogen or C1-C6 alkyl;
• R64 is hydrogen, C1-C6 alkyl substituted with 1-3 hydroxy groups, —CHO, or is CO2H or an ester thereof;
• one or both of R65 and R66 independently are hydrogen, C1-C6 alkyl, optionally substituted with —CO2H or an ester thereof, C3-C10 cycloalkyl, C3-C8 heterocyclyl, C2-C10 aryl, or C2-C10 heteroaryl, or is C3-C10 cycloalkyl, C3-C8 heterocyclyl, C6-C10aryl, or C2-C10 heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-3 alkyl groups, or R65 and R66 gether with the nitrogen atom they are bonded to form a 5-7 membered heterocycle, and if only one of R65 and R66 are defined as above, then the other one is
• R81 is C1-C6 alkyl;
• and
• R82 is:
• provided that, when X2 is bonded via a single bond, and R53 or R54 is not CONHR82, Y11 and Y22 are joined to form an imine group (═NR60), and R60 is:
• or Y22 is —O—CO—NR58R59;
• or provided that, when Q6 is:
• and R53 is not —CONHR82, Y22 is —O—CO—NR58R59;
• or provided that, when Q6 is —O—CO—NR65R66, then at least one of R65 and R66 is: