主权项 |
1. A compound having the structure of Formula (I):or a salt or isomer thereof,
wherein:
n is an integer from 2-35;G5 is halogen, OH, alkoxy, OSO2(alkyl), OSO2(aryl), or each B is an independently selected base pair moiety;each Y is independently O or NR10;each W is independently S or O;Z5 is -(L11)-(R15), -(L11)-(L15)-(R16), or -(L11)-(L12)-(R17);L11 is selected from:or k) —C(R23)2O—;wherein L13 is selected from: L12 is a linker cleaveable under biological conditions selected from: a) —(C1-C10 alkylene)-OC(O)O—CH2O—; b) —C(O)—(C1-C10 alkylene)-OC(O)O—CH2O—; c) —C(O)—(CH═CH)—C(O)O—CH2O—; d) —(C1-C10 alkylene)-S—S—CH2CH2O—; or e) —C(O)—(C1-C10 alkylene)-S—S—CH2CH2O—; L15 is divalent radical selected from C1-C30 alkylene, C3-C8 cycloalkylene, C6-C30 arylene, —(C6-C30 arylene)-(C1-C30 alkylene)-, —(C1-C30 alkylene)-C(═O)—, —(C2-C30 alkoxy)-C(═O)—, -(3-18 membered heteroalkylene)-C(═O)—, —(C3-C8 cycloalkylene)-C(═O)—, —(C3-C8 cycloalkylene)-(C1-C30 alkylene)-C(═O)—, —(C1-C30 alkylene) (C3-C8 cycloalkylene)-C(═O)—, —(C6-C30 arylene)-C(═O)—, —(C6-C30 arylene)-(C1-C30 alkylene)-C(═O)—, —(C1-C30 alkylene)-(C6-C30 arylene)-C(═O)—, —(C1-C30 alkylene)-O—C(═O)—, —(C3-C8 cycloalkylene)-O—C(═O)—, —(C7-C30 arylene)-O—C(═O)—, —(C6-C30 arylene)-(C1-C30 alkylene)-O—C(═O)—, —(C6-C30 arylene)-(C1-C30 alkylene)-O—C(═O)—, —C(═O)OR21, or —P(═O)(R22)2; R12 is an electron pair, with the provision that if R13 is C1-C30 alkyl, then R12 is an electron pair, an N-oxide, or C1-C6 alkyl; each R10 and R13 is independently selected from hydrogen, a cell-penetrating peptide, a natural or non-natural amino acid, guanidinyl, amidinyl, heterocyclyl, C1-C30 alkyl, C3-C8 cycloalkyl; C6-C30 aryl, C7-C30 aralkyl, C1-C30 alkylcarbonyl, C3-C8 cycloalkylcarbonyl, C3-C8 cycloalkylalkylcarbonyl, C6-C30 arylcarbonyl, C7-C30 aralkylcarbonyl, C1-C30 alkyloxycarbonyl, C3-C8 cycloalkyloxycarbonyl, C7-C30 aryloxycarbonyl, C8-C30 aralkyloxycarbonyl, —C(═O)OR21, —C(═O)NHR21, or —P(═O)(R22)2; R15 is independently selected from a cell-penetrating peptide, a natural or non-natural amino acid, guanidinyl, amidinyl, heterocyclyl, C1-C30 alkyl, C3-C8 cycloalkyl; C6-C30 aryl, C7-C30 aralkyl, C1-C30 alkylcarbonyl, C3-C8 cycloalkylcarbonyl, C3-C8 cycloalkylalkylcarbonyl, C6-C30 arylcarbonyl, C7-C30 aralkylcarbonyl, C2-C30 alkyloxycarbonyl, C3-C8 cycloalkyloxycarbonyl, C7-C30 aryloxycarbonyl, C8-C30 aralkyloxycarbonyl, 3-18 membered alkoxyalkylcarbonyl, —SO2R21, —C(═O)OR21, —P(═O)(OH)2 or —P(═O)(R22)2; R16 is a solid support matrix suitable for solid phase synthesis of oligonucleotides; R17 is a drug, protein or toxin; each R21 is independently C1-C30 alkyl, or a 3-18 membered alkoxyalkyl group; each R22 is independently an C6-C12 aryloxy; each R23 is independently H or C1-C6 alkyl; or optionally two R23 groups join to form a 3- to 8-membered ring; R24 is a C1-C6 alkylene; Q is independently selected from X1, X2, X3, X4, X5, X6, X7, or X8; each X is independently selected from X1, X2, X3, X4, X5, X6, X7, or X8 with wherein at least two instances of X are selected from X2, X3, X4, X5, X6, X7, or X8; wherein X1 is N(CH3)2; X2 is selected from:
a) —O-alkylene-CO2H;b) —O-alkylene-CHN4;c) —N(R1)-alkylene-CO2H;d) —N(R1)-alkylene-CHN4;e) -L1-CO-alkylene-CO2H;f) -L1-CO-alkylene-CHN4;g) -L1-CO-alkenylene-CO2H;h) -L1-CO-alkenylene-CHN4;i) -L1-CO-arylene-CO2H;j) -L1-CO-arylene-CHN4;k) -L1-CONH-alkylene-CO2H;l) -L1-CONH-alkylene-CHN4;m) -L1-CONH-arylene-CO2H;n) -L1-CONH-arylene-CHN4;o) -L1-SO2-alkylene-CO2H;p) -L1-SO2-alkylene-CHN4;q) -L1-SO2-arylene-CO2H;r) -L1-SO2-arylene-CHN4;s) -L1-alkylene-CO2H;t) -L1-alkylene-CHN4;u) -L1-arylene-CO2H;v) -L1-arylene-CHN4; andw) a protected form of any of the above X2 groups; X3 is selected from:
a) -L-alkyl;b) -L1-heterocyclyl;c) —O-alkylene-CNH—NH2;d) —N(R1)-alkylene-CNH—NH2;e) -L1-CNH—NH2;f) -L1-alkylene-CNH—NH2;g) -L1-arylene-CNH—NH2;h) -L1-CO-alkylene-CNH—NH2;i) -L1-CO-alkenylene-CNH—NH2;j) -L1-CO-arylene-CNH—NH2;k) -L1-CONH-alkylene-CNH—NH2;l) -L1-CONH-arylene-CNH—NH2;m) -L1-SO2-alkylene-CNH—NH2;n) -L1-SO2-arylene-CNH—NH2;o) —O-alkylene-N(R1)2;p) —N(R1)-alkylene-N(R1)2;q) -L1-N(R1)2;r) -L1-alkylene-N(R1)2;s) -L1-arylene-N(R1)2;t) -L1-CO-alkylene-N(R1)2;u) -L1-CO-alkenylene-N(R1)2;v) -L1-CO-arylene-N(R1)2;w) -L1-CONH-alkylene-N(R1)2;x) -L1-CONH-arylene-N(R1)2;y) -L1-SO2-alkylene-N(R1)2;z) —O-alkylene-N(R2)3;aa) —N(R1)-alkylene-N(R2)3;bb) -L1-N(R2)3;cc) -L1-alkylene-N(R2)3;dd) -L1-arylene-N(R2)3;ee) -L1-CO-alkylene-N(R2)3;ff) -L1-CO-alkenylene-N(R2)3;gg) -L1-CO-arylene-N(R2)3;hh) -L1-CONH-alkylene-N(R2)3;ii) -L1-CONH-arylene-N(R2)3;jj) -L1-SO2-alkylene-N(R2)3;kk) —O-alkylene-heterocyclyl;ll) —N(R1)-alkylene-heterocyclyl;mm) -L1-alkylene-heterocyclyl;nn) -L1-arylene-heterocyclyl;oo) -L1-CO-alkylene-heterocyclyl;pp) -L1-CO-alkenylene-heterocyclyl;qq) -L1-CO-arylene-heterocyclyl;rr) -L1-CONH-alkylene-heterocyclyl;ss) -L1-CONH-arylene-heterocyclyl;tt) -L1-SO2-alkylene-heterocyclyl;uu) —O-alkylene-N(O)(R2)2;vv) —N(R1)-alkylene-N(O)(R2)2;ww) -L-N(O)(R2)2;xx) -L-alkylene-N(O)(R2)2;yy) -L-arylene-N(O)(R2)2;zz) -L1-CO-alkylene-N(O)(R2)2;aaa) -L1-CO-alkenylene-N(O)(R2)23;bbb) -L1-CO-arylene-N(O)(R2)2;ccc) -L1-CONH-alkylene-N(O)(R2)2;ddd) -L1-CONH-arylene-N(O)(R2)2;eee) -L1-SO2-alkylene-N(O)(R2)2;fff) —O-alkylene-NH—CNH—NH2;ggg) —N(R1)-alkylene-NH—CNH—NH2;hhh) -L1-NH—CNH—NH2;iii) -L-alkylene-NH—CNH—NH2;jjj) -L-arylene-NH—CNH—NH2;kkk) -L1-CO-alkylene-NH—CNH—NH2;lll) -L1-CO-alkenylene-NH—CNH—NH2;mmm) -L1-CO-arylene-NH—CNH—NH2;nnn) -L1-CONH-alkylene-NH—CNH—NH2;ooo) -L1-CONH-arylene-NH—CNH—NH2;ppp) -L1-SO2-alkylene-NH—CNH—NH2;qqq) -L1-SO2-arylene-NH—CNH—NH2; andrrr) a protected form of any of the above X3 groups; X4 is selected from:
a) —O-alkylene-aryl;b) —N(R1)-aryl;c) —N(R1)-alkylene-aryl;d) -L1-CO-alkylene-aryl;e) -L1-CO-alkenylene-aryl;f) -L1-CO-arylene-aryl;g) -L1-CONH-alkylene-aryl;h) -L1-CONH-arylene-aryl;i) -L1-SO2-alkylene-aryl;j) -L1-SO2-arylene-aryl;k) -L-alkylene-aryl;l) -L-arylene-aryl;m) —N(R1)-alkylene-N(R1)-aryl;n) —N(R1)-alkylene-N(R1)CO-aryl;o) —N(R1)-alkylene-N(R1)SO2-aryl;p) —N(R1)-alkylene-N(R1)CH2-aryl;q) -L-aryl;r) -L1-CO-aryl;s) -L1-SO2-aryl;t) -L1-alkylene-P(aryl)3;u) -L1-CO-alkylene-P(aryl)3;v) -L1-SO2-alkylene-P(aryl)3; andw) a protected form of any of the above X4 groups; X5 is selected from:
a) —O-alkylene-heteroaryl;b) —N(R1)-alkylene-heteroaryl;c) -L1-CO-alkylene-heteroaryl;d) -L1-CO-alkenylene-heteroaryl;e) -L1-CO-arylene-heteroaryl;f) -L1-CONH-alkylene-heteroaryl;g) -L1-CONH-arylene-heteroaryl;h) -L1-SO2-alkylene-heteroaryl;i) -L1-S O2-arylene-heteroaryl;j) -L1-alkylene-heteroaryl;k) -L1-arylene-heteroaryl;l) —N(R1)-alkylene-N(R1)-hereroaryl;m) —N(R1)-alkylene-N(R1)CO-hereroaryl;n) —N(R1)-alkylene-N(R1)SO2-hereroaryl;o) —N(R1)-alkylene-N(R1)CH2-hereroaryl;p) -L-heteroaryl; andq) a protected form of any of the above X5 groups; X6 is selected from:
a) —O-alkylene-(OCH2CH2)mOH;b) —O-alkylene-(OCH2CH2)mOCH3;c) —N(R1)-alkylene-(OCH2CH2)mOH;d) —N(R1)-alkylene-(OCH2CH2)mOCH3;e) —N(R1)-arylene-(OCH2CH2)mOH;f) —N(R1)-arylene-(OCH2CH2)mOCH3;g) -L-alkylene-(OCH2CH2)mOH;h) -L1-CO-alkylene-(OCH2CH2)mOH;i) -L1-CO-alkylene-(OCH2CH2)mOCH3;j) -L1-SO2-alkylene-(OCH2CH2)mOH;k) -L1-SO2-alkylene-(OCH2CH2)mOCH3;l) -L1-CO-arylene-(OCH2CH2)mOH;m) -L1-CO-arylene-(OCH2CH2)mOCH3;n) -L1-SO2-arylene-(OCH2CH2)mOH;o) -L1-SO2-arylene-(OCH2CH2)mOCH3;p) -L1-CO—(OCH2CH2)mOH;q) -L1-CO—(OCH2CH2)mOCH3;r) —N(R1)-(dibenzo-18-crown-6);s) an aza-crown ether; andt) a protected form of any of the above X6 groups; X7 is selected from:
a) -heterocyclyl;b) —N(R1)(R3)c) -L1-hydrogen;d) -L-alkyl;e) -L1-CO-alkyl;f) -L1-CONH-alkyl;g) -L1-CON(alkyl)-alkyl;h) -L1-SO2-alkyl; andi) a protected form of any of the above X7 groups; X8 is selected from:
a) -L1-CA;b) -L1-dCA;c) -L1-COCH2(R4)d) -L1-COCH(R4)NHCO2-alkyl;e) —OR5;f) a protected form of any of the above X8 groups;each R1 is independently hydrogen, alkyl, or a cell-penetrating peptide;each R2 is independently C1-C12 alkyl or optionally when two R2 are C1-C12 alkyl, two R2 are joined to form a heterocyclic ring;each R3 is independently C2-C18 alkyl, alkenyl, or alkynyl;each R4 is independently hydrogen, alkyl, hydroxyalkyl, sulfhydrylalkyl, or arylalkyl;each R5 is independently C1-C12 alkyl;each R6 is independently hydrogen or C1-C12 alkyl; L1 is selected from: wherein
each Q1 and Q2 are each selected from a bond, —O— or —N(R6)—;each E1 is independently selected from optionally substituted aryl or optionally substituted heteroaryl;each E2 is independently an optionally substituted nitrogen containing heteroaryl;each L4 and L5 are each independently a bond, optionally substituted C1-C6 alkyl, or optionally substituted heteroalkyl; andm, p, q, s, and t are each independently 1-4. |