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CN-121991095-A - Macrocyclic chelators, pharmaceutical compositions and biomedical applications

CN121991095ACN 121991095 ACN121991095 ACN 121991095ACN-121991095-A

Abstract

Provided herein are macrocyclic chelators and their conjugates with target-binding moieties, e.g., conjugates of compounds of formula (I). Also provided herein are pharmaceutical compositions comprising the conjugates and their diagnostic and/or therapeutic uses.

Inventors

  • CAO XIAODONG
  • Bai Chiyao
  • WANG XIAOLEI

Assignees

  • 成都纽瑞特医疗科技股份有限公司

Dates

Publication Date
20260508
Application Date
20251031
Priority Date
20241101

Claims (20)

  1. 1. A compound of formula (I): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein: Each R 1 、R 2 and R 3 is independently (i) hydrogen, deuterium, cyano, halo, or nitro, (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl ;(iii)–C(O)R 1a 、–C(O)OR 1a 、–C(O)NR 1b R 1c 、–C(O)SR 1a 、–C(NR 1a )NR 1b R 1c 、–C(S)R 1a 、–C(S)OR 1a 、–C(S)NR 1b R 1c 、–OR 1a 、–OC(O)R 1a 、–OC(O)OR 1a 、–OC(O)NR 1b R 1c 、–OC(O)SR 1a 、–OC(NR 1a )NR 1b R 1c 、–OC(S)R 1a 、–OC(S)OR 1a 、–OC(S)NR 1b R 1c 、–OS(O)R 1a 、–OS(O) 2 R 1a 、–OS(O)NR 1b R 1c 、–OS(O) 2 NR 1b R 1c 、–NR 1b R 1c 、–NR 1a C(O)R 1d 、–NR 1a C(O)OR 1d 、–NR 1a C(O)NR 1b R 1c 、–NR 1a C(O)SR 1d 、–NR 1a C(NR 1d )NR 1b R 1c 、–NR 1a C(S)R 1d 、–NR 1a C(S)OR 1d 、–NR 1a C(S)NR 1b R 1c 、–NR 1a S(O)R 1d 、–NR 1a S(O) 2 R 1d 、–NR 1a S(O)NR 1b R 1c 、–NR 1a S(O) 2 NR 1b R 1c 、–SR 1a 、–S(O)R 1a 、–S(O) 2 R 1a 、–S(O)NR 1b R 1c , or-S (O) 2 NR 1b R 1c , or (iv) Each R 4 、R 5 and R 6 is independently (i) hydrogen or deuterium, (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl ;(iii)–C(O)R 1a 、–C(O)OR 1a 、–C(O)NR 1b R 1c 、–C(NR 1a )NR 1b R 1c 、–OR 1a 、–OC(O)R 1a 、–OC(O)OR 1a 、–OC(O)NR 1b R 1c 、–OC(NR 1a )NR 1b R 1c 、–OS(O)R 1a 、–OS(O) 2 R 1a 、–OS(O)NR 1b R 1c 、–OS(O) 2 NR 1b R 1c 、–NR 1b R 1c 、–NR 1a C(O)R 1d 、–NR 1a C(O)OR 1d 、–NR 1a C(O)NR 1b R 1c 、–NR 1a C(NR 1d )NR 1b R 1c 、–NR 1a S(O)R 1d 、–NR 1a S(O) 2 R 1d 、–NR 1a S(O)NR 1b R 1c or-NR 1a S(O) 2 NR 1b R 1c , or (iv) Each R 7 is independently deuterium or Each R 4a 、R 5a and R 6a is independently (i) hydroxy, (ii) C 1-6 alkoxy or C 1-6 heteroalkoxy, (iii) -NR 1b R 1c , or (iv) R T is a target binding moiety; Each L is independently a linker; each X is independently a bond, O, or NR 1b ; Each R 1a 、R 1b 、R 1c and R 1d is independently hydrogen, deuterium, C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; Each m is independently an integer of 0 or 1, and N is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; Provided that no more than one of R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 4a 、R 5a and R 6a is Wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment 1,2,3, or 4 substituents Q, wherein each Q is independently selected from (a) deuterium, cyano, halo, imino, nitro, and oxo, (b) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment 1,2, 3 or 4 substituents Q a , and (c)–C(O)R a 、–C(O)OR a 、–C(O)NR b R c 、–C(O)SR a 、–C(NR a )NR b R c 、–C(S)R a 、–C(S)OR a 、–C(S)NR b R c 、–OR a 、–OC(O)R a 、–OC(O)OR a 、–OC(O)NR b R c 、–OC(O)SR a 、–OC(NR a )NR b R c 、–OC(S)R a 、–OC(S)OR a 、–OC(S)NR b R c 、–OS(O)R a 、–OS(O) 2 R a 、–OS(O)NR b R c 、–OS(O) 2 NR b R c 、–NR b R c 、–NR a C(O)R d 、–NR a C(O)OR d 、–NR a C(O)NR b R c 、–NR a C(O)SR d 、–NR a C(NR d )NR b R c 、–NR a C(S)R d 、–NR a C(S)OR d 、–NR a C(S)NR b R c 、–NR a S(O)R d 、–NR a S(O) 2 R d 、–NR a S(O)NR b R c 、–NR a S(O) 2 NR b R c 、–P(O)(R a )R d 、–SR a 、–S(O)R a 、–S(O) 2 R a 、–S(O)NR b R c and-S (O) 2 NR b R c , wherein each R a 、R b 、R c and R d is independently (i) hydrogen or deuterium, (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, c 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment 1, 2, 3, or 4 substituents Q a , or (iii) R b and R c together with the N atom to which they are attached form a ring which is optionally substituted with one or more, in one embodiment 1, 2. A heterocyclic group substituted with 3 or 4 substituents Q a ; Wherein each Q a is independently selected from (a) deuterium, cyano, halo, nitro, imino, and oxo, (b) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl and heterocyclyl, and (c)–C(O)R e 、–C(O)OR e 、–C(O)NR f Rg、–C(O)SR e 、–C(NR e )NR f Rg、–C(S)R e 、–C(S)OR e 、–C(S)NR f Rg、–OR e 、–OC(O)R e 、–OC(O)OR e 、–OC(O)NR f Rg、–OC(O)SR e 、–OC(NR e )NR f Rg、–OC(S)R e 、–OC(S)OR e 、–OC(S)NR f Rg、–OS(O)R e 、–OS(O) 2 R e 、–OS(O)NR f Rg、–OS(O) 2 NR f Rg、–NR f Rg、–NR e C(O)R h 、–NR e C(O)OR f 、–NR e C(O)NR f Rg、–NR e C(O)SR f 、–NR e C(NR h )NR f Rg、–NR e C(S)R h 、–NR e C(S)OR f 、–NR e C(S)NR f Rg、–NR e S(O)R h 、–NR e S(O) 2 R h 、–NR e S(O)NR f Rg、–NR e S(O) 2 NR f Rg、–P(O)(R e )Rg、–SR e 、–S(O)R e 、–S(O) 2 R e 、–S(O)NR f Rg and-S (O) 2 NR f Rg, wherein each R e 、R f , Rg and R h are independently (i) hydrogen or deuterium, (ii) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl, or (iii) R f and Rg together with the N atom to which they are attached form heterocyclyl.
  2. 2. The compound of claim 1, wherein R 4 is
  3. 3. The compound of claim 1, wherein R 5 is
  4. 4. The compound of claim 1, wherein R 2 is
  5. 5. The compound of claim 1, wherein R 3 is
  6. 6. The compound according to any one of claims 1 to 5, wherein X is a bond.
  7. 7. The compound according to any one of claims 1 to 5, wherein X is O.
  8. 8. The compound according to any one of claims 1 to 5, wherein X is N (R 1b ).
  9. 9. The compound according to any one of claims 1, 2 and 6, having a structure represented by formula (VI): Or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  10. 10. The compound according to any one of claims 1,3 and 6, which has a structure represented by formula (VII): Or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  11. 11. The compound according to any one of claims 1, 4 and 7, which has a structure represented by formula (VIII): Or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  12. 12. The compound according to any one of claims 1, 5 and 7, having a structure represented by formula (IX): Or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  13. 13. The compound according to any one of claims 1,4 and 8, which has a structure represented by formula (X): Or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  14. 14. The compound according to any one of claims 1, 5 and 8, having a structure represented by formula (XI): Or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  15. 15. The compound of any one of claims 8, 13 and 14, wherein R 1b is (i) hydrogen, or (ii) C 1-6 alkyl or C 1-6 heteroalkyl, each of which is optionally substituted with one or more substituents Q.
  16. 16. The compound according to any one of claims 8 and 13 to 15, wherein R 1b is hydrogen.
  17. 17. The compound of any one of claims 1,2, 4 to 9, and 11 to 16, wherein R 5 is C 1-6 alkyl or C 1-6 heteroalkyl, each of which is optionally substituted with one or more substituents Q.
  18. 18. The compound of any one of claims 1,2, 4 to 9 and 11 to 17 wherein R 5 is C 1-6 alkylene-C (O) OR a 、C 1-6 alkylene-NR b R c OR C 1-6 alkylene-NR a C(O)R d , and wherein each alkylene is optionally substituted with one OR more substituents Q.
  19. 19. The compound of any one of claims 1,2, 4 to 9 and 11 to 18, wherein R 5 is- (CH 2 ) p C(O)R 5b ), and wherein R 5b is (i) hydroxy, (ii) C 1-6 alkoxy or C 1-6 heteroalkoxy, each optionally substituted with one or more substituents Q, or (iii) -NR b R c , and p is an integer of 1,2, 3, 4, 5 or 6.
  20. 20. The compound of claim 19, having a structure of formula (XII): Or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein R 2a is (i) hydrogen, or (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q.

Description

Macrocyclic chelators, pharmaceutical compositions and biomedical applications Technical Field Provided herein are macrocyclic chelators and their conjugates with target-binding moieties. Also provided herein are pharmaceutical compositions comprising the conjugates and their diagnostic and/or therapeutic uses. Background Radiotherapy diagnostics combining molecular imaging with targeted radionuclide therapy is an emerging tumor targeted therapy. Sgouros et al, nat.Rev.drug discovery.2020, 19,589-608; bodei et al, nat.Rev.Clin.Oncol.2022,19,534-50; salih et al, molecules 2022,27,5231. One key aspect of radiation therapy diagnostics is the selection of patients for radiation targeted therapy based on imaging of the same target region, and thus imaging and therapeutic intervention are closely related. Herrmann et al, lancet Oncol.2020,21, e146-e156, song et al, theranostics2024,14,2464-88. Common radioconjugates for radiotherapy diagnostics are designed with alpha-, beta-or auger electron emitters to cancer by linking a target ligand, such as a small molecule, peptide or antibody, to a bifunctional chelator that complexes with radionuclides for systemic delivery. Caers et al, front. Immunol.2022,13,911080; song et al, theranostics, 2024,14,2464-88. Bifunctional chelators are essential components of metal-based radio-conjugates that are capable of forming a stable complex with a metal radionuclide and binding it to a target ligand. Sneddon and Cornelissen et al, curr.Opin.chem.biol.2021,63,152-62; shalgunov et al, nucl.Med.biol.2022,104,11-21.1,4,7, 10-tetraazacyclododecane-1, 4,7, 10-tetraacetic acid (DOTA) is currently a series of gold standard chelators of radiometals, but its chelation typically requires harsh conditions, which can be problematic when radiolabeled chelators are attached to biological target ligands, such as peptides or antibodies. Sneddon and Cornelissen et al, curr.Opin.chem.biol.2021,63,152-62. Ideal chelators would allow rapid radiolabeling under mild conditions (e.g., near neutral pH and low temperature) and be thermodynamically and kinetically stable. As above. Despite advances in cancer treatment, cancer remains a major global public health problem. It was estimated that in 2024, there would be 2,001,140 newly diagnosed cancer cases and 611,720 cancer death cases in the united states alone. CANCERFACTS & Figures 2024. Thus, the need for effective cancer therapies has not been met. Bodei et al, nat.Rev.Clin.Oncol.2022,19,534-50; ganguly et al, J.Nucl.Med.2023,64,639-44. Disclosure of Invention Provided herein are compounds of formula (I): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein: Each R 1、R2 and R 3 is independently (i) hydrogen, deuterium, cyano, halo, or nitro, (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl ;(iii)–C(O)R1a、–C(O)OR1a、–C(O)NR1bR1c、–C(O)SR1a、–C(NR1a)NR1bR1c、–C(S)R1a、–C(S)OR1a、–C(S)NR1bR1c、–OR1a、–OC(O)R1a、–OC(O)OR1a、–OC(O)NR1bR1c、–OC(O)SR1a、–OC(NR1a)NR1bR1c、–OC(S)R1a、–OC(S)OR1a、–OC(S)NR1bR1c、–OS(O)R1a、–OS(O)2R1a、–OS(O)NR1bR1c、–OS(O)2NR1bR1c、–NR1bR1c、–NR1aC(O)R1d、–NR1aC(O)OR1d、–NR1aC(O)NR1bR1c、–NR1aC(O)SR1d、–NR1aC(NR1d)NR1bR1c、–NR1aC(S)R1d、–NR1aC(S)OR1d、–NR1aC(S)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 (iv) Each R 4、R5 and R 6 is independently (i) hydrogen or deuterium, (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl ;(iii)–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 or-NR 1aS(O)2NR1bR1c, or (iv) Each R 7 is independently deuterium or Each R 4a、R5a and R 6a is independently (i) hydroxy, (ii) C 1-6 alkoxy or C 1-6 heteroalkoxy, (iii) -NR 1bR1c, or (iv) R T is a target binding moiety; Each L is independently a linker; each X is independently a bond, O, or NR 1b; Each R 1a、R1b、R1c and R 1d is independently hydrogen, deuterium, C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; Each m is independently an integer of 0 or 1, and N is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; Provided that no more than one of R 1、R2、R3、R4、R5、R6、R7、R4a、R5a and R 6a is Wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment 1,2,3, or 4 substituents Q, wherein each Q is independently selec