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1. WO2020229974 - MACROCYCLIC CHELATORS AND METHODS OF USE THEREOF

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

[ EN ]

CLAIMS

We claim:

1. A chelator of formula (I):


wherein:

each of ring A and ring B is independently a 6-10 membered aryl or a 5-10 membered heteroaryl, wherein each of ring A and ring B is optionally substituted with one or more substituents independently selected from the group consisting of halo, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, -OR13, -SR13, -(CH2)p COOR13, -OC(O)R13, -N(R13)2, -CON(R13)2, -NO2, -CN -OC(O)N(R13)2, and X;

each of Z1 and Z2 is independently -(C(R12)2)m- or -(CH2)n-C(R12)(X)-(CH2)n-; each X is independently -L1-R11;

each n is independently 0, 1, 2, 3, 4, or 5;

each m is independently 1, 2, 3, 4, or 5;

each p is independently 0 or 1 ;

L1 is absent or a linker;

R11 is a nucleophilic moiety or an electrophilic moiety, or R11 comprises a targeting ligand;

each R12 is independently hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl;

each R13 is independently hydrogen or alkyl;

each of Rn, R15, R16, and R17 is independently hydrogen, alkyl, or X,

or alternatively R14 and R15 and/or R16 and R17 are taken together with the carbon atoms to which they are attached to form a 5- or 6-membered cycloalkyl ring optionally substituted with X;

provided that the chelator comprises at least one X, and when X is present on ring A or ring B, L1 is a linker or at least one of R12 and R14-R17 is not hydrogen.

2. The chelator of claim 1, being a chelator of formula (II):

wherein:

A1 is N or CR1 or is absent;

A2 is N or CR2;

A3 is N or CR3;

A4 is N or CR4;

A5 is N or CR5;

A6 is N or CR6 or is absent;

A7 is N or CR7;

A8 is N or CR8;

A9 is N or CR9;

A10 is N or CR10;

provided that no more than three of A1, A2, A3, A4, and As are N, and no more than three of A6, A7, A8, A9, and A10 are N;

each of R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 is independently selected from the group consisting of hydrogen, halo, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, -OR13, -SR13, -(CH2)PCOOR13, -OC(O)R13, -N(R13)2, - CON(R13)2, -NO2, -CN, -OC(O)N(R13)2, and -X,

or, alternatively, any two directly adjacent R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are taken together with the atoms to which they are attached to form a five or six- membered substituted or unsubstituted carbocyclic or nitrogen-containing ring;

each of Z1 and Z2 is independently -(C(R12)2)m- or -(CH2)n-C(R12)(X)-(CH2)n-; each X is independently -L1-R11;

each n is independently 0, 1, 2, 3, 4, or 5;

each m is independently 1, 2, 3, 4, or 5;

each p is independently 0 or 1 ;

L1 is absent or a linker;

R11 is a nucleophilic moiety or an electrophilic moiety, or R11 comprises a targeting ligand;

each R12 is independently hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl;

each R13 is independently hydrogen or alkyl;

each of R14, R15, Rio, and R17 is independently hydrogen, alkyl, or X, or alternatively R14 and R15 and/or Rio and R17 are taken together with the carbon atoms to which they are attached to form a 5- or 6-membered cycloalkyl ring optionally substituted with X;

provided that the chelator comprises at least one X, and when any one of R1, R2, R3, R4, Rs, R6, R7, R8, R9, and R10 is X, then L1 is a linker or at least one of R12 and R14- R17 is not hydrogen.

3. The chelator of claim 1, being a chelator of formula (III):


wherein:

each A11 is independently O, S, NMe, or NH;

each of Z1 and Z2 is independently -(C(R12)2)m- or -(CH2)n-C(R12)(X)-(CH2)n-; each X is independently -L1-R11;

each n is independently 0, 1, 2, 3, 4, or 5;

each m is independently 1, 2, 3, 4, or 5;

each p is independently 0 or 1 ;

L1 is absent or a linker;

R11 is a nucleophilic moiety or an electrophilic moiety, or R11 comprises a targeting ligand;

each R12 is independently hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl;

each R13 is independently hydrogen or alkyl;

each of R14, R15, R16, and R17 is independently hydrogen, alkyl, or X, or alternatively R14 and R15 and/or R16 and R17 are taken together with the carbon atoms to which they are attached to form a 5- or 6-membered cycloalkyl ring optionally substituted with X;

each R15 is independently selected from the group consisting of hydrogen, halo, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, -OR13, -SR13, - (CH2)pCOOR13, -OC(O)R13, -N(R13)2, -CON(R13)2, -NO2, -CN -OC(O)N(R13)2, and -X, provided that the chelator comprises at least one X, and when R18 is X, then L1 is a linker or at least one of R12 and R14-R17 is not hydrogen.

4. The chelator of claim 1, wherein the chelator is selected from the group consisting of:

wherein:

L1 is absent or a linker;

R11 is a nucleophilic moiety or an electrophilic moiety, or R11 comprises a targeting ligand;

each R12 is independently hydrogen, -CH3, or -CH2CH3, provided at least one R12 is -CH3 or -CH2CH3.

5. The chelator of any one of claims 1 to 4, wherein R11 is -Nth, -NCS, -NCO, -N3, alkynyl, cycloalkynyl, -C(O)R13, -COOR13, -CON(R13)2, maleimido, acyl halide, tetrazine, or trans-cyclooctene.

6. The chelator of claim 5, wherein R11 is cyclooctynyl or a cyclooctynyl derivative selected from the group consisting of bicyclononynyl (BCN), difluorinated cyclooctynyl (DIFO), dibenzocyclooctynyl (DIBO), keto-DIBO, biarylazacyclooctynonyl (BARAC), dibenzoazacyclooctynyl (DIBAC, DBCO, ADIBO), dimethoxyazacyclooctynyl

(DIMAC), difluorobenzocyclooctynyl (DIFBO), monobenzocyclooctynyl (MOBO), and tetramethoxy dibenzocyclooctynyl (TMDIBO).

7. The chelator of claim 6, wherein R11 is DBCO or BCN.

8. The chelator of any one of claims 1 to 4, wherein R11 comprises a targeting ligand,

wherein the targeting ligand comprises an antibody or antigen binding fragment thereof, scaffold protein, small molecule, or aptamer.

9. The chelator of any one of claims 1-8, wherein LI is selected from the group consisting of:



wherein n is an integer of 0 to 10, preferably an integer of 1 to 4, and m is an integer of 0 to 12, preferably an integer of 0 to 6.

10. A chelator selected from the group consisting of:


11. The chelator of any one of claims 1 to 10, wherein the chelator comprises a radiometal ion bound to the chelator via coordinate bonding thereby forming a radiometal complex.

12. A radiometal complex comprising a chelator bound to an alpha-emitting radiometal ion via coordinate bonding, wherein the radiometal complex has the structure of formula (I- m):


(I-m)

wherein:

M is a radiometal ion, preferably an alpha-emitting radiometal ion, and more preferably actinium- 225 (225Ac);

each of ring A and ring B is independently a 6-10 membered aryl or a 5-10 membered heteroaryl, wherein each of ring A and ring B is optionally substituted with one or more substituents independently selected from the group consisting of halo, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, -OR13, -SR13, , - (CH2)PCOOR13, -OC(O)R13, -N(R13)2, -CON(R13)2, -N02, -CN -OC(O)N(R13)2, and X; each of Z1 and Z2 is independently -(C(R12)2)m- or -(CH2)n-C(R12)(X)-(CH2)n-; each X is independently -L1-R11;

each n is independently 0, 1, 2, 3, 4, or 5;

each m is independently 1, 2, 3, 4, or 5;

each p is independently 0 or 1 ;

L1 is absent or a linker;

R11 is a nucleophilic moiety or an electrophilic moiety, or R11 comprises a targeting ligand;

each RI2 is independently hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl;

each R13 is independently hydrogen or alkyl;

each of Rn, R15, R16, and R17 is independently hydrogen, alkyl, or X, or alternatively R14 and R15 and/or R16 and R17 are taken together with the carbon atoms to which they are attached to form a 5- or 6-membered cycloalkyl ring optionally substituted with X;

provided that the radiometal complex comprises at least one X, and when X is present on ring A or ring B, L1 is a linker or at least one of RI2 and R14-R17 is not hydrogen.

13. The radiometal complex of claim 12, being a radiometal complex of formula (Il-m):


(Il-m)

wherein:

M is a radiometal ion, preferably an alpha-emitting radiometal ion, and more preferably actinium- 225 (225Ac);

A1 is N or CR1 or is absent;

A2 is N or CR2;

A3 is N or CR3;

A4 is N or CR4;

As is N or CR5;

A6 is N or CR6 or is absent;

A7 is N or CR7;

A8 is N or C R8;

A9 is N or CR9;

A10 is N or CR10;

provided that no more than three of A1, A2, A3, A4, and As are N, and no more than three of A6, A7, AS, A9, and A10 are N;

each of R1, R2, R3, R4, Rs, R6, R7, R8, R9, and R10 is independently selected from the group consisting of hydrogen, halo, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, -OR13, -SR13, -(CH2)PCOOR13, -OC(O)R13, -N(R13)2, -CON(R13)2, -NO2, -CN -OC(O)N(R13)2, and -X,

or, alternatively, any two directly adjacent R1, R2, R3, R4, Rs, R6, R7, R8, R9, and R10 are taken together with the atoms to which they are attached to form a five or six-membered substituted or unsubstituted carbocyclic or nitrogen-containing ring;

each of Z1 and Z2 is independently -(C(R12)2)m- or -(CH2)n-C(R12)(X)-(CH2)n-; each X is independently -L1-R11;

each n is independently 0, 1, 2, 3, 4, or 5;

each m is independently 1, 2, 3, 4, or 5;

each p is independently 0 or 1 ;

L1 is absent or a linker;

R11 is a nucleophilic moiety or an electrophilic moiety, or R11 comprises a targeting ligand;

each R12 is independently hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl;

each R13 is independently hydrogen or alkyl;

each of R14, R15, Rio, and R17 is independently hydrogen, alkyl, or X, or alternatively R14 and R15 and/or Rio and R17 are taken together with the carbon atoms to which they are attached to form a 5- or 6-membered cycloalkyl ring optionally substituted with X;

provided that the radiometal complex comprises at least one X, and when any one of R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 is X, then L1 is a linker or at least one of R12 and R14-R17 is not hydrogen.

14. The radiometal complex of claim 12, being a radiometal complex of formula (Ill-m):


wherein:

M is a radiometal ion, preferably an alpha-emitting radiometal ion, and more preferably actinium- 225 (225Ac);

each An is independently O, S, NMe, or NH;

each of Z1 and Z2 is independently -(C(R12)2)m- or -(CH2)n-C(R12)(X)-(CH2)n-; each X is independently -L1-R11;

each n is independently 0, 1, 2, 3, 4, or 5;

each m is independently 1, 2, 3, 4, or 5;

each p is independently 0 or 1 ;

L1 is absent or a linker;

R11 is a nucleophilic moiety or an electrophilic moiety, or R11 comprises a targeting ligand;

each R12 is independently hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl;

each R13 is independently hydrogen or alkyl;

each of R14, R15, R16, and R17 is independently hydrogen, alkyl, or X, or alternatively R14 and R15 and/or R16 and R17 are taken together with the carbon atoms to which they are attached to form a 5- or 6-membered cycloalkyl ring optionally substituted with X; and

each R15 is independently selected from the group consisting of hydrogen, halo, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, -OR13, -SR13, , - (CH2)PCOOR13, -OC(O)R13, -N(R13)2, -CON(R13)2, -NO2, -CN -OC(O)N(R13)2, and -X, provided that the radiometal complex comprises at least one X, and when R15 is X, then L1 is a linker or at least one of RI2 and R14-R17 is not hydrogen.

15. The radiometal complex of any one of claims 12-14, wherein the radiometal complex is selected from the group consisting of:

wherein:

M is actinium- 225 (225Ac), L1 is absent or a linker; and

R11 is a nucleophilic moiety or an electrophilic moiety, or R11 comprises a targeting ligand; and

each R12 is independently hydrogen, -CH3 or -CH2CH3, provided at least one R12 is -CH3 or -CH2CH3.

16. A radioimmunoconjugate comprising the radiometal complex of any one of claims 12 to

15 conjugated to an antibody or antigen binding fragment thereof.

17. The radioimmunoconjugate of claim 16, wherein the antibody or antigen binding

fragment thereof is linked to R11 of the radiocomplex via a triazole moiety.

18. A radioimmunoconjugate having a structure selected from the group consisting of:


M is a radiometal ion, preferably an alpha-emitting radiometal ion, and more preferably actinium-225 (225Ac);

L1 is a linker;

mAb is an antibody or antigen binding fragment thereof;

each R12 is independently hydrogen, -CH3, or -CH2CH3, provided at least one R12 is -CH3 or -CH2CH3.

19. The radioimmunoconjugate of claim 18, wherein the radioimmunoconjugate is selected from the group consisting of:



wherein mAb is an antibody or antigen binding fragment thereof, preferably, the antibody or antigen binding fragment thereof that binds specifically to a tumor antigen, more preferably. the mAb is selected from PSMB127, Pertuzumab, Cetuximab, Panitumumab,

Herceptin, and HI 1B6.

20. A method of preparing a radioimmunoconjugate, the method comprising: contacting the chelator of claim 8 with a radiometal ion, thereby forming a radiometal complex bound to the targeting ligand.

21. The method of claim 20, wherein the targeting ligand is an antibody or antigen binding fragment thereof.

22. A method of preparing a radioimmunoconjugate, the method comprising:

(i) providing a modified polypeptide comprising the antibody or antigen binding fragment thereof covalently linked to an azido group;

(ii) providing a chelator complex comprising a chelator covalently linked to an alkynyl group or cycloalkynyl group;

(iii) contacting the modified polypeptide with the chelator complex under a condition to allow the azido group to react with the alkynyl group or cycloalkynyl group to thereby form an immunoconjugate; and

(iv) contacting the immunoconjugate with an alpha-emitting radiometal ion to thereby form the radioimmunoconjugate, the radioimmunoconjugate comprising a radiocomplex comprising the alpha-emitting radiometal ion bound to the chelator, wherein the radiocomplex has the structure of formula (I-m):


wherein:

M is a radiometal ion, preferably an alpha-emitting radiometal ion, and more preferably actinium- 225 (225Ac);

each of ring A and ring B is independently a 6-10 membered aryl or a 5-10 membered heteroaryl, wherein each of ring A and ring B is optionally substituted with one or more substituents independently selected from the group consisting of halo, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, -OR13, -SR13, , -(CH2)PCOOR13, -OC(O)R13, -N(R13)2, -CON(R13)2, -NO2, -CN -OC(O)N(R13)2, and X; each of Z1 and Z2 is independently -(C(R12)2)m- or -(CH2)n-C(R12)(X)-(CH2)n-; each X is independently -L1-R11;

each n is independently 0, 1, 2, 3, 4, or 5;

each m is independently 1, 2, 3, 4, or 5;

each p is independently 0 or 1 ;

L1 is absent or a linker;

R11 is an alkynyl or cycloalkynyl group;

each R12 is independently hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl;

each R13 is independently hydrogen or alkyl;

each of R14, R15, R16, and Riv is independently hydrogen, alkyl, or X, or alternatively R14 and R15 and/or R16 and Riv are taken together with the carbon atoms to which they are attached to form a 5- or 6-membered cycloalkyl ring optionally substituted with X;

provided that the radiometal complex comprises at least one X, and when X is present on ring A or ring B, L1 is a linker or at least one of R12 and R14-R17 is not hydrogen.

23. A method of preparing a radioimmunoconjugate, the method comprising:

(i) providing a modified antibody or antigen binding fragment thereof comprising the antibody or antigen binding fragment thereof covalently linked to an azido group;

(ii) providing a radiocomplex comprising an alpha-emitting radiometal ion bound to a chelator via coordinate bonding, wherein the chelator is covalently linked to an alkynyl group or cycloalkynyl group; and

(iii) contacting the modified antibody or antigen binding fragment thereof with the radiocomplex under a condition to allow the azido group to react with the alkynyl group or cycloalkynyl group to thereby prepare the radioimmunoconjugate, wherein the radiocomplex has the structure of formula (I-m):


wherein:

M is the alpha-emitting radiometal ion;

each of ring A and ring B is independently a 6-10 membered aryl or a 5-10 membered heteroaryl, wherein each of ring A and ring B is optionally substituted with one or more substituents independently selected from the group consisting of halo, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, -OR13, -SR13, , - (CH2)PCOOR13, -OC(O)R13, -N(R13)2, -CON(R13)2, -NO2, -CN -OC(O)N(R13)2, and X; each of Z1 and Z2 is independently -(C(R12)2)m- or -(CH2)n-C(R12)(X)-(CH2)n-; each X is independently -L1-R11;

each n is independently 0, 1, 2, 3, 4, or 5;

each m is independently 1, 2, 3, 4, or 5;

each p is independently 0 or 1 ;

L1 is absent or a linker;

R11 is an alkynyl or cycloalkynyl group;

each RI2 is independently hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl;

each R13 is independently hydrogen or alkyl;

each of Rn, R15, R16, and R17 is independently hydrogen, alkyl, or X, or alternatively R14 and R15 and/or R16 and R17 are taken together with the carbon atoms to which they are attached to form a 5- or 6-membered cycloalkyl ring optionally substituted with X;

provided that the radiometal complex comprises at least one X, and when X is present on ring A or ring B, L1 is a linker or at least one of RI2 and R14-R17 is not hydrogen.

24. The method of either of claims 22 or 23, wherein R11 is cyclooctynyl or a cyclooctynyl derivative selected from the group consisting of bicyclononynyl (BCN), difluorinated cyclooctynyl (DIFO), dibenzocyclooctynyl (DIBO), keto-DIBO, biarylazacyclooctynonyl (BARAC), dibenzoazacyclooctynyl (DIBAC, DBCO, ADIBO),

dimethoxyazacyclooctynyl (DIMAC), difluorobenzocyclooctynyl (DIFBO),

monobenzocyclooctynyl (MOBO), and tetramethoxy dibenzocyclooctynyl (TMDIBO).

25. A pharmaceutical composition comprising the radioimmunoconjugate of any one of claims 16-19, and a pharmaceutically acceptable carrier.

26. A method of selectively targeting neoplastic cells for radiotherapy in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 25.

27. A method of treating a neoplastic disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 25.

28. A method of treating cancer in a subject in need thereof, the method comprising

administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 25.