Functionalized pegylated cyanine compounds, pharmaceutical compositions, and methods of use thereof

A compound of Formula I:

• or a tautomer or a mixture of two or more tautomers thereof;
• or a pharmaceutically acceptable solvate or hydrate thereof;
• wherein:
• A is an anion bearing a negative charge;
• L is
• wherein:
• each RL is independently (a) hydrogen, deuterium, azido, cyano, halo, nitro, oxo, sulfo, —OPO3H2, or PO3H2;
• (b) C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-15 cycloalkyl, C6-20 aryl, C7-20 aralkyl, heteroaryl, or heterocyclyl;
• or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1c, —C(NR1a)NR1bR1c, —OR1a, —OC(O)OR1a, —OC(O)NR1bR1c, —OC(═NR1a)NR1bR1c, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1c, —OS(O)2NR1bR1c, —NR1bR1c, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1c, —NR1aC(═NR1d)NR1bR1c, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1c, —NR1aS(O)2NR1bR1c, —SR1a, —S(O)R1a, —S(O)2R1d, —S(O)NR1bR1c, or —S(O)2NR1bR1c;
• Xa is (a) hydrogen, deuterium, azido, cyano, halo, nitro, oxo, sulfo, OPO3H2, or —PO3H2;
• (b) C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-15 cycloalkyl, C6-20 aryl, C7-20 aralkyl, heteroaryl, or heterocyclyl , each of which is optionally substituted with one or more substituents Q;
• (c) —C(R1aR1b), —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1c, —C(NR1a)NR1bR1c, —OR1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1c, —OC(═NR1a)NR1bR1c, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1c, —OS(O)2NR1bR1c, —NR1bR1c, —NR1a(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1c, —NR1aC(═NR1d)NR1bR1c, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1c, —NR1aS(O)2NR1bR1c, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1c, or —S(O)2NR1bR1c;
• (d) —(CH2CH2O)p-L1-Z1, —(CH2CH2O)p—COOH, —(CH2CH2O)p—N3, —(CH2CH2O)p —OH, —(CH2CH2O)p—alkyne, —(CH2CH2O)p-biotin, —(CH2CH2O)p-NHS ester, —(CH2CH2O)p-amine, —(CH2CH2O)p-DBCO, —(CH2CH2O)p-Fmoc, —(CH2CH2O)p-aldehyde, —(CH2CH2O)p-phosphonate, —(CH2CH2O)p-tosylate, —(CH2CH2O)p-FPF ester, —(CH2CH2O)p-Boc, —(CH2CH2O)p-aminooxy, —(CH2CH2O)p-bromo, —(CH2CH2O)p-mal, or -(CH2CH2O)p-propargyl;
• or (e) carboxycylic acid, amine, azide, DBCO, hydrazide, maleimide, NHS ester, TCO, tetrazine, or biotin;
• m is an integer of 1, 2, or 3;
• and
• n is an integer of 0, 1, 2, 3, 4, 5, 6, or 7;
• X and Y are each independently C(RXaRXb), O, S, or NRXc;
• wherein:
• RXa and RXb are each independently (a) hydrogen or deuterium;
• or (b) C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-15 cycloalkyl, C6-20 aryl, C7-20 aralkyl, heteroaryl, or heterocyclyl;
• and
• RXc is (a) hydrogen or deuterium;
• (b) C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-15 cycloalkyl, C6-20 aryl, C7-20 aralkyl, heteroaryl, or heterocyclyl;
• or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1c, —C(NR1a)NR1bR1c, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1c, or —S(O)2NR1bR1c;
• R1 is (a) hydrogen or deuterium;
• (b) C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-15 cycloalkyl, C6-20 aryl, C7-20 aralkyl, heteroaryl, or heterocyclyl;
• (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1c, —C(NR1a)NR1bR1c, —S(O)R1a, —S(O)2R1, —S(O)NR1bR1c, or —S(O)2NR1bR1c;
• or (d) —(CH2CH2O)p-L1 -Z1;
• wherein:
• L1 is C1-10 alkylene, C1-10 heteroalkylene, C2-10 alkenylene, C2-10 alkynylene, C3-15 cycloalkylene, —C1-10 heteroalkylene—C3-15 cycloalkylene, C6-20 arylene, C7-20 aralkylene, heteroarylene, or heterocyclylene;
• Z1 is (a) amino, azido, chloro, bromo, iodo, or thiol;
• (b) N-maleimido, N-3,4-dibromo-maleimido, C2-6 alkynyl, heterocyclyl containing a carbon-carbon triple, acrylyl, 3-sulfo-N-succinimidyloxycarbonyl, tetrafluorophenoxycarbonyl, pentofluorophenoxycarbonyl, C2-6 alkynyloxy, C3-15 cycloalkyloxy containing a carbon-carbon triple, C6-20 aryloxy containing a carbon-carbon triple, or heterocyclyloxy containing a carbon-carbon triple;
• (c) —OP(OR1a)(NR1bR1c), ——OP((NR1bR1c)2, —OS(O)2R1a, or —S—SR1a;
• or (d) Z6;
• and
• p is an integer of 1 to 50;
• R2, R3, R4, R5, R7, R8, R9, and R10 are each independently (a) hydrogen, deuterium, azido, cyano, halo, nitro, sulfo, —OPO3H2, or —PO3H2;
• (b) C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-15 cycloalkyl, C6-20 aryl, C7-20 aralkyl, heteroaryl, or heterocyclyl;
• (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1c, —C(NR1a)NR1bR1c, —OR1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1c, —OC(═NR1a)NR1bR1c, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1c, —OS(O)2NR1bR1c, —NR1bR1c, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1c, —NR1aC(═NR1d)NR1bR1c, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1c, —NR1aS(O)2NR1bR1c, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1c, or —S(O)2NR1bR1c, (d) R2 and R3, R4 and R5, R7 and R8, or R9 and R10, each pair together with the carbon atoms to which they are attached independently form C3-15 cycloalkyl, C6-20 aryl, heteroaryl, or heterocyclyl;
• (e) R3 and R4, or R8 and R9, each pair together with the carbon atoms to which they are attached independently form C3-15 cycloalkyl, C6-20 aryl, heteroaryl, or heterocyclyl;
• or (f) —O(CH2CH2O)r-Lr-Zr, with the proviso that when Rc is not —(CH2CH2O)p-L1—Z1, at least one of R1, R2, R3, R4, R5, R7, R8, R9, and R10 is —O(CH2CH2O)r—Lr-Zr;
• wherein:
• Lr is C1-10 alkylene, C1-10 heteroalkylene, C2-10 alkenylene, C2-10 alkynylene, C3-15 cycloalkylene, C1-10 heteroalkylene-C3-15 cycloalkylene, C6-20 arylene, C7-20 aralkylene, heteroarylene, or heterocyclylene;
• Zr is (a) hydrogen, deuterium, halo, cyano, nitro, sulfo, —OPO3H2, or —PO3H2;
• (b) C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-15 cycloalkyl, C6-20 aryl, C7-20 aralkyl, heteroaryl, or heterocyclyl;
• (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1c, —C(NR1a)NR1bR1c, —OR1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1c, —OC(═NR1a)NR1bR1c, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1c, —OS(O)2NR1bR1c, —NR1bR1c, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1c, —NR1aC(═NR1d)NR1bR1c, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1c, —NR1aS(O)2NR1bR1c, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1c, or —S(O)2NR1bR1c;
• or (d) Z1;
• and
• r is an integer of 1 to 50;
• R6 is (a) hydrogen or deuterium;
• (b) C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-15 cycloalkyl, C6-20 aryl, C7-20 aralkyl, heteroaryl, or heterocyclyl;
• (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1c, —C(NR1a)NR1bR1c, —S(O)R1a, —S(O)2R1a, —S(O)2NR1bR1c;
• or (d) —(CH2CH2O)q-L6-Z6;
• wherein:
• L6 is C1-10 alkylene, C1-10 heteroalkylene, C2-10 alkenylene, C2-10 alkynylene, C3-15 cycloalkylene, C6-20 arylene, C7-20 aralkylene, heteroarylene, or heterocyclylene;
• Z6 is (a) hydrogen, deuterium, halo, cyano, nitro, sulfo, —OPO3H2, or —PO3H2;
• (b) C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-15 cycloalkyl, C6-20 aryl, C7-20 aralkyl, heteroaryl, or heterocyclyl;
• (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1c, —C(NR1a)NR1bR1c, —OR1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1c, —OC(═NR1a)NR1bR1c, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1c, —OS(O)2NR1bR1c, —NR1bR1c, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1c, —NR1aC(═NR1d)NR1bR1c, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1c, —NR1aS(O)2NR1bR1c, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1c, or —S(O)2NR1bR1c;
• or (d) Z1;
• and
• q is an integer of 1 to 50;
• and
• each R1a, R1b R1c, and R1d is independently (a) hydrogen or deuterium;
• (b) C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-15 cycloalkyl, C6-20 aryl, C7-20 aralkyl, heteroaryl, or heterocyclyl;
• (c) R1a and R1c together with the C and N atoms to which they are attached form heterocyclyl;
• or (d) R1b and R1c together with the N atom to which they are attached form heteroaryl or heterocyclyl;
• wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, heterocyclylene, alkynyloxy, cycloalkyloxy, aryloxy, and heterocyclyloxy is optionally substituted with one or more substituents Q, where each Q is independently selected from (a) deuterium, azido, cyano, halo, nitro, oxo, sulfo, —OPO3H2, and —PO3H2;
• (b) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa;
• and (c) —C(O)Ra, —C(O)ORa, —C(O)NRbRc, —C(NRa)NRbRc, —ORa, —OC(O)Ra, —OC(O)ORa, —OC(O)NRbRc, —OC(═NRa)NRbRc, —OS(O)Ra, —OS(O)2Ra, —OS(O)NRbRc, —OS(O)2NRbRc, —NRbRc, —NRaC(O)Rd, —NRaC(O)ORd, —NRaC(O)NRbRc, —NRaC(═NRd)NRbRc, —NRaS(O)Rd, —NRaS(O)2Rd, —NRaS(O)NRbRc, —NRaS(O)2NRbRc, —SRa, —S(O)Ra, —S(O)2Ra, —S(O)NRbRc, and —S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium;
• (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa;
• or (iii) Rb and Rc together with the N atom to which they are attached form heteroaryl or heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa;
• wherein each Qa is independently selected from the group consisting of (a) deuterium, azido, cyano, halo, nitro, oxo, sulfo, —OPO3H2, and —PO3H2;
• (b) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl;
• and (c) —C(O)Re, —C(O)ORe, —C(O)NRfRg, —C(NRe)NRfRg, —ORe, —OC(O)Re, —OC(O)ORe, —OC(O)NRfRg, —OC(═NRe)NRfRg, —OS(O)Re, —OS(O)2Re, —OS(O)NRfRg, —OS(O)2NRfRg, NRfRg, —NReC(O)Rh, —NReC(O)ORf, —NReC(O)NRfRg, —NReC(═NRh)NRfRg, —NReS(O)Rh, —NReS(O)2Rh, —NReS(O)NRfRg, —NReS(O)2NRfRg, —SRe, —S(O)Re, —S(O)2Re, —S(O)NRfRg, and —S(O)2NRfRg;
• wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen or deuterium;
• (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
• or (iii) Rf and Rg together with the N atom to which they are attached form heteroaryl or heterocyclyl.