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EP-4739347-A1 - CONJUGATES OF DRUG UNITS AND TARGETING UNITS AND PRECURSOR COMPOUNDS THEREOF

EP4739347A1EP 4739347 A1EP4739347 A1EP 4739347A1EP-4739347-A1

Abstract

Provided herein is a Drug-Linker of Formula (I) or a pharmaceutically acceptable salt thereof, wherein D is a drug unit, K1 is selected from (i) a peptide unit, (ii) an oligosaccharide, and (iii) a polyether, and M1 is a group which can react with a ligand to form a connector unit. Such compounds can be useful as anti-cancer agents.

Inventors

  • LANNUTTI, BRIAN
  • WATKINS, JEFF
  • JESSEN, Katti

Assignees

  • Solve Therapeutics, Inc.

Dates

Publication Date
20260513
Application Date
20240705

Claims (20)

  1. CLAIMS WHAT IS CLAIMED IS: 1. A Drug-Linker of Formula (X): or a pharmaceutically acceptable salt thereof, wherein; D is a Drug unit; Y 1 is absent or selected from -O-T 1 and -NH-T 2 ; T 1 is a sugar cleavable unit; T 2 is a peptide cleavable unit; S 1 is selected from: (i) an optionally substituted C1-C30 alkylene wherein one or more alkylene units of the C 1 -C 30 alkylene are optionally and independently replaced by –N(R 20 )–, – N(R 20 )C(O)–, –C(O)N(R 20 )–, –N(R 20 )S(O) 2 –, – S(O) 2 N(R 20 )–, –O–, –C(O)–, –OC(O)–, – C(O)O–, –S–, –S(O)–, –S(O)2–, 5- to 6-membered heterocyclene, or –P(O)(R 20 )2–; (ii) optionally substituted C3-C30 alkenylene, wherein one or more alkenylene units of the C3- C 30 alkenylene are optionally and independently replaced by –N(R 20 )–, –N(R 20 )C(O)–, – C(O)N(R 20 )–, –N(R 20 )S(O)2–, – S(O)2N(R 20 )–, –O–, –C(O)–, –OC(O)–, –C(O)O–, –S–, –S(O)–, –S(O)2–, or –P(O)(R 20 )2; (iii) one or more amino acid(s); (iv) one or more N-substituted amino acid(s); (v) optionally substituted polyether; (vi) optionally substituted C 3 -C 10 carbocyclene; (vii) optionally substituted 5- to 10-membered heterocyclene; S 2 is selected from an optionally substituted C1-C30 alkylene wherein one or more alkylene units of the C 1 -C 30 alkylene are optionally and independently replaced by –N(R 20 )–, – N(R 20 )C(O)–, –C(O)N(R 20 )–, –N(R 20 )S(O) 2 –, – S(O) 2 N(R 20 )–, –O–, –C(O)–, –OC(O)–, – C(O)O–, –S–, –S(O)–, –S(O)2–, 5- to 6-membered heterocyclene, or –P(O)(R 20 )2–; S 3 is selected from a spacer, wherein S 3 is present or absent; wherein the optional substituents on M 1 , K 1 , S 1 , S 2 , and S 3 , are independently selected at each occurrence from: (i) halogen, -OR 30 , -N(R 30 )2, -SR 30 , -N(R 30 )2, -C(O)R 30 , -C(O)N(R 30 )2, - N(R 30 )C(O)R 30 , -C(O)OR 30 , -OC(O)R 30 , -S(O)R 30 , -S(O) 2 R 30 , -O- S(O) 2 OR 30 , -P(O)(OR 30 ) 2 , -OP(O)(OR 30 ) 2 , -NO 2 , =O, =S, =N(R 30 ), and -CN; (ii) C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 30 , - C(O)N(R 30 ) 2 , -N(R 30 )C(O)R 30 , -C(O)OR 30 , -OC(O)R 30 , -S(O)R 30 , -S(O) 2 R 30 , -O- S(O)2OR 30 , -P(O)(OR 30 )2, -OP(O)(OR 30 )2, -NO2, =O, =S, =N(R 30 ), -CN, C3-10 carbocycle and 3- to 10-membered heterocycle; and (iii) C 3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 30 , -SR 30 , - N(R 30 )2, -C(O)R 30 , -C(O)N(R 30 )2, -N(R 30 )C(O)R 30 , -C(O)OR 30 , -OC(O)R 30 , -S(O)R 30 , - S(O) 2 R 30 , -P(O)(OR 30 ) 2 , -OP(O)(OR 30 ) 2 , -NO 2 , =O, =S, =N(R 30 ), -CN, C 1-6 alkyl, C 2-6 alkenyl, and C2-6 alkynyl; M 1 is a group which can react with a ligand to form a connector unit; K 1 is selected from: (i) a peptide unit, (ii) an oligosaccharide; and (iii) a polyether; each R 20 is independently selected from hydrogen; and C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, - N(C 1-6 alkyl) 2 , C 1-10 alkyl, -C 1-10 haloalkyl, -O-C 1-10 alkyl, oxo, C 3-12 carbocycle, and 3- to 12- membered heterocycle; and each R 30 is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, - N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12- membered heterocycle.
  2. 2. The Drug-Linker or salt of claim 1, wherein Formula (X) is represented by o ua ( ) or a pharmaceutically acceptable salt thereof.
  3. 3. The Drug-Linker of claims 1 or 2, wherein the optionally substituted C1-C30 alkylene of S 1 is linear.
  4. 4. The Drug-Linker of any one of claims 1 to 3, wherein S 1 is selected from: (i) an optionally substituted C1-C30 alkylene wherein one or more alkylene units of the C1-C30 alkylene are optionally and independently replaced by –N(H)C(O)–.
  5. 5. The Drug-Linker of any one of claims 1 to 4, wherein S 1 is selected from -NH-C(O)-C1- C 6 alkylene-NH-C(O)-C 1- C 6 alkylene-NH-C(O)-C 1- C 6 alkylene-.
  6. 6. The Drug-Linker of any one of claims 1 to 5, wherein S 1 is selected from -NH-C(O)-C 1- C6 alkylene-NH-C(O)-C1-C6 alkylene-NH-C(O)-C1-C6 alkylene-, and wherein S 2 is bound to one of the alkylene.
  7. 7. The Drug-Linker of any one of claims 1 to 6, wherein S 1 -S 2 -K 1 is .
  8. 8. The Drug-Linker of any one of claims 1 to 7, wherein S 2 is selected from an optionally substituted C1-C30 alkylene wherein one or more alkylene units of the C1-C30 alkylene are optionally and independently replaced by –C(O)–.
  9. 9. The Drug-Linker of any one of claims 1 to 8, wherein S 2 is selected from an optionally substituted C1-C6 alkylene wherein one or more alkylene units of the C1-C6 alkylene are optionally and independently replaced by –C(O)–.
  10. 10. The Drug-Linker of any one of claims 1 to 9, wherein .
  11. 11. The Drug-Linker of any one of claims 1 to 10, wherein S 1 -S 2 -K 1 is .
  12. 12. The Drug-Linker of any one of claims 1 to 11, wherein Formula (X) or Formula (I) is represented by Formula (I-A) or a pharmaceutically acceptable salt thereof.
  13. 13. The Drug-Linker or salt of any one of claims 1 to 12, wherein the sugar cleavable unit of T 1 includes a sugar.
  14. 14. The Drug-Linker or salt of any one of claims 1 to 13, wherein the sugar is glucuronide.
  15. 15. The Drug-Linker or salt of any one of claims 1 to 14, wherein .
  16. 16. The Drug-Linker or salt of any one of claims 1 to 12, wherein the peptide unit of T 2 includes one or more amino acids selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, sarcosine, serine, threonine, tryptophan, tyrosine, valine, citrulline, and β-Alanine.
  17. 17. The Drug-Linker or salt of any one of claims 1 to 15, wherein the peptide unit of T 2 includes a dipeptide or tripeptide.
  18. 18. The Drug-Linker or salt of any one of claims 1 to 15, wherein the peptide unit of T 2 includes a dipeptide.
  19. 19. The Drug-Linker or salt of any one of claims 1 to 15, wherein the dipeptide is selected from Val-Cit, Val-Ala and Phe-Lys.
  20. 20. The Drug-Linker or salt of any one of claims 1 to 12 or 16 to 19, wherein the peptide unit of T 2 includes a capping moiety.

Description

CONUGATES OF DRUG UNITS AND TARGETING UNITS AND PRECURSOR COMPOUNDS THEREOF CROSS-REFERENCE [0001] This application claims the benefit of: U.S. Provisional Patent Application No. 63/512,428 filed on July 07, 2023; U.S. Provisional Patent Application No. 63/606,519 filed on December 05, 2023; U.S. Provisional Patent Application No. 63/558,540 filed on February 27, 2024; U.S. Provisional Patent Application No. 63/640,733 filed on April 30, 2024; and U.S. Provisional Patent Application No. 63/667,649 filed on July 3, 2024; the entire contents of each of which are incorporated herein by reference. BACKGROUND [0002] Currently, small cytotoxic molecules for antibody drug conjugates can include camptothecin derivatives, which have antitumor effects by inhibiting topoisomerase I. Camptothecin derivatives can be used in antibody drug conjugates (ADC). However, there is still a need for further development of camptothecin derivatives and ADC drugs with better efficacy and/or safety. SUMMARY OF THE INVENTION [0003] In an aspect, the present disclosure provides a Drug-Linker of Formula (X): or a pharmaceutically acceptable salt thereof, wherein; D is a Drug unit; Y1 is absent or selected from -O-T1 and -NH-T2; T1 is a sugar cleavable unit; T2 is a peptide cleavable unit; S1 is selected from: (i) an optionally substituted C1-C30 alkylene wherein one or more alkylene units of the C1-C30 alkylene are optionally and independently replaced by -N(R20)-, - N(R20)C(O)-, -C(O)N(R20)-, -N(R20)S(O)2-, - S(O)2N(R20)-, -O-, -C(O)-, -OC(O)-, - C(O)O-, -S-, — S(O)— , — S(O)2— , 5- to 6-membered heterocyclene, or -P(O)(R20)2-; (ii) optionally substituted C3-C30 alkenylene, wherein one or more alkenylene units of the C3- C30 alkenylene are optionally and independently replaced by -N(R20)-, -N(R20)C(O)-, - C(O)N(R20)-, -N(R20)S(O)2-, - S(O)2N(R20)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, –S(O)2–, or –P(O)(R20)2; (iii) one or more amino acid(s); (iv) one or more N-substituted amino acid(s); (v) optionally substituted polyether; (vi) optionally substituted C3-C10 carbocyclene; (vii) optionally substituted 5- to 10-membered heterocyclene; S2 is selected from an optionally substituted C1-C30 alkylene wherein one or more alkylene units of the C1-C30 alkylene are optionally and independently replaced by –N(R20)–, – N(R20)C(O)–, –C(O)N(R20)–, –N(R20)S(O)2–, – S(O)2N(R20)–, –O–, –C(O)–, –OC(O)–, – C(O)O–, –S–, –S(O)–, –S(O)2–, 5- to 6-membered heterocyclene, or –P(O)(R20)2–; S3 is selected from a spacer, wherein S3 is present or absent; wherein the optional substituents on M1, K1, S1, S2, and S3, are independently selected at each occurrence from: (i) halogen, -OR30, -N(R30)2, -SR30, -N(R30)2, -C(O)R30, -C(O)N(R30)2, - N(R30)C(O)R30, -C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -O- S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), and -CN; (ii) C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR30, -SR30, -N(R30)2, -C(O)R30, - C(O)N(R30)2, -N(R30)C(O)R30, -C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -O- S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), -CN, C3-10 carbocycle and 3- to 10-membered heterocycle; and (iii) C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from halogen, -OR30, -SR30, - N(R30)2, -C(O)R30, -C(O)N(R30)2, -N(R30)C(O)R30, -C(O)OR30, -OC(O)R30, -S(O)R30, - S(O)2R30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), -CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl; M1 is a group which can react with a ligand to form a connector unit; K1 is selected from: (i) a peptide unit, (ii) an oligosaccharide; and (iii) a polyether; each R20 is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, - N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12- membered heterocycle; and each R30 is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, - N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12- membered heterocycle. [0004] In an aspect, the present disclosure provides a conjugate of the Formula (XX): or a pharmaceutically acceptable salt thereof, wherein; D is a Drug unit; Y1 is absent or selected from -O-T1 and -NH-T2; T1 is a sugar cleavable unit; T2 is peptide cleavable unit; L is a Targeting Unit; S1 is selected from: (i) an optionally substituted C1-C30 alkylene wherein one or more alkylene units