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CN-122005840-A - Antitumor compound and preparation method and application thereof

CN122005840ACN 122005840 ACN122005840 ACN 122005840ACN-122005840-A

Abstract

The application relates to an anti-tumor compound and a preparation method and application thereof, in particular to a compound or a tautomer, a meso form, a racemate form, an enantiomer, a diastereoisomer or a mixture form thereof or a pharmaceutically acceptable salt thereof, and a preparation method and application thereof.

Inventors

  • ZHANG YU
  • ZHU ZHONGYUAN
  • HUA HAIQING
  • LI BING
  • LI JIAN
  • Lin Shengchao
  • LI XI
  • SHEN HONGXIA

Assignees

  • 映恩生物制药（苏州）有限公司

Dates

Publication Date
20260512
Application Date
20210929
Priority Date
20200930

Claims (17)

  1. 1. Use of a compound, or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of breast cancer, said compound having the structure of formula (II-D x ): Wherein, the L is-L a -L b -L c -, wherein, the-L a -is selected from the group consisting of: , A kind of electronic device , Wherein W is- (C (R wa )(R wb )) wn -, Y is- (OCH 2 CH 2 ) yn -O yp -, Z is- (C (R za )(R zb )) zn ; wherein wn is selected from integers of at least 0, Wherein yn is selected from integers of at least 0 and yp is 0 or 1; wherein zn is selected from integers of at least 0, Wherein each R wa ,R wb ,R za and R zb is independently hydrogen, protium, deuterium, tritium, halogen 、-NO 2 、-CN、-OR r 、-SR r 、-N(R ra )(R rb )、-C(O)R r 、-CO 2 R r 、-C(O)C(O)R r 、-C(O)CH 2 C(O)R r 、-S(O)R r 、-S(O) 2 R r 、-C(O)N(R ra )(R rb )、-SO 2 N(R ra )(R rb )、-OC(O)R r 、-N(R)SO 2 R r 、, or a C 1-6 aliphatic group optionally substituted with R r ; 0 or at least 1 methylene units of W are each independently replaced by -Cyr-、-N(R wx )C(O)-、-C(O)N(R wx )-、-C(O)-、-OC(O)-、-C(O)O-、-NR wx -、-O-、-S-、-SO-、-SO 2 -、-P(R wx )-、-P(=O)(R wx )-、-N(R wx )SO 2 -、-SO 2 N(R wx )-、-C(＝S)-、-C(＝NR wx )-、-N＝N-、-C＝N-、-N＝C- or-C (=n 2 ) -; 0 or at least 1 methylene units of Z are each independently replaced by -Cyr-、-N(R zx )C(O)-、-C(O)N(R zx )-、-C(O)-、-OC(O)-、-C(O)O-、-NR zx -、-O-、-S-、-SO-、-SO 2 -、-P(R zx )-、-P(=O)(R zx )-、-N(R zx )SO 2 -、-SO 2 N(R zx )-、-C(＝S)-、-C(＝NR zx )-、-N＝N-、-C＝N-、-N＝C- or-C (=n 2 ) -; -Cyr-is selected from the group consisting of 6 to 10 membered arylene, 5 to 8 membered heteroarylene, 3 to 10 membered heterocyclylene, and 3 to 10 membered saturated or partially unsaturated carbocyclylene, wherein said-Cyr-is unsubstituted or independently substituted with at least 1 substituent R cx ; Wherein each R wx ,R zx ,R cx is independently hydrogen, protium, deuterium, tritium, halogen 、-NO 2 、-CN、-OR r 、-SR r 、-N(R ra )(R rb )、-C(O)R r 、-CO 2 R r 、-C(O)C(O)R r 、-C(O)CH 2 C(O)R r 、-S(O)R r 、-S(O) 2 R r 、-C(O)N(R ra )(R rb )、-SO 2 N(R ra )(R rb )、-OC(O)R r 、-N(R)SO 2 R r 、, or a C 1-6 aliphatic group optionally substituted with R r ; Wherein each R r ,R ra ,R rb is independently hydrogen, protium, deuterium, tritium, halogen 、-NO 2 、-CN、-OH、-SH、-NH 2 、-C(O)H、-CO 2 H、-C(O)C(O)H、-C(O)CH 2 C(O)H、-S(O)H、-S(O) 2 H、-C(O)NH 2 、-SO 2 NH 2 、-OC(O)H、-N(H)SO 2 H、, or a C 1-6 aliphatic group; said-L b -represents a peptide residue consisting of 2 to 7 amino acids; said-L c -is selected from the group consisting of: , , , , , A kind of electronic device ; Wherein each R L1 、R L2 is independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen 、-NO 2 、-CN、-OH、-SH、-NH 2 、-C(O)H、-CO 2 H、-C(O)C(O)H、-C(O)CH 2 C(O)H、-S(O)H、-S(O) 2 H、-C(O)NH 2 、-SO 2 NH 2 、-OC(O)H、-N(H)SO 2 H, and C 1-6 aliphatic; L 2 is-R 2 -L 3 -, said R 2 is used for direct or indirect attachment of a ligand; Wherein L 3 is- (C (R 3a )(R 3b )) m -wherein m is 0,1 or 2), Wherein when L 3 comprises a methylene unit, 0 or at least 1 methylene unit of said L 3 is each independently replaced by -N(R 4 )C(O)-、-C(O)N(R 4 )-、-C(O)-、-OC(O)-、-C(O)O-、-NR 4 -、-O-、-S-、-SO-、-SO 2 -、-P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 )SO 2 -、-SO 2 N(R 4 )-、-C(＝S)-、-C(＝NR 4 )-、-N＝N-、-C＝N-、-N＝C- or-C (=n 2 ) -; Wherein R 2 is selected from the group consisting of: -O-, - (R 2a ) N-, -S-and-P (=o) (R 2a ) -; ring A is selected from the group consisting of 3 to 10 membered saturated or partially unsaturated heterocyclyl and 3 to 10 membered saturated or partially unsaturated carbocyclyl; X 1 is saturated C, said X 1 is substituted with R n , and said L 2 is not R n ; L 1 is- (C (R 5a )(R 5b )) n -wherein n is 0 or 1), Wherein when L 1 comprises a methylene unit, 0 or at least 1 methylene unit of said L 1 is each independently replaced by -N(R 6 )C(O)-、-C(O)N(R 6 )-、-C(O)-、-OC(O)-、-C(O)O-、-NR 6 -、-O-、-S-、-SO-、-SO 2 -、-P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 )SO 2 -、-SO 2 N(R 6 )-、-C(＝S)-、-C(＝NR 6 )-、-N＝N-、-C＝N-、-N＝C- or-C (=n 2 ) -; Wherein each R 1a ,R 2a ,R 3a ,R 3b ,R 4 ,R 5a ,R 5b ,R 6 ,R n is independently hydrogen, protium, deuterium, tritium, halogen 、-NO 2 、-CN、-OR、-SR、-N(R a )(R b )、-C(O)R、-CO 2 R、-C(O)C(O)R、-C(O)CH 2 C(O)R、-S(O)R、-S(O) 2 R、-C(O)N(R a )(R b )、-SO 2 N(R a )(R b )、-OC(O)R、-N(R)SO 2 R、, or a C 1-6 aliphatic optionally substituted with R; Wherein each R, R a ,R b is independently hydrogen, protium, deuterium, tritium, halogen 、-NO 2 、-CN、-OH、-SH、-NH 2 、-C(O)H、-CO 2 H、-C(O)C(O)H、-C(O)CH 2 C(O)H、-S(O)H、-S(O) 2 H、-C(O)NH 2 、-SO 2 NH 2 、-OC(O)H、-N(H)SO 2 H、, or C 1-6 aliphatic; the Ab is a ligand targeting HER2 and the average number of linkages Na is a fraction or integer selected from 1 to 10.
  2. 2. The use according to claim 1, wherein the average number of linkages Na is a fraction or integer selected from 3 to 8.
  3. 3. Use according to claim 1 or 2, wherein The L a is , The L b is , , , , Or (b) , The L c is Wherein R L1 、R L2 is each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, -OH, and C 1-6 aliphatic groups.
  4. 4. The use according to any one of claims 1-3, wherein the L is 。
  5. 5. The use of any one of claims 1-4, wherein the a is a four to six membered saturated carbocyclyl.
  6. 6. The use according to any one of claims 1-5, wherein m is 0 and l 3 is a covalent bond.
  7. 7. The use according to any one of claims 1-6, wherein m is 1 and l 3 is-C (R 3a )(R 3b ) -.
  8. 8. The use according to any one of claims 1-7, wherein m is 2, l 3 is (C (R 3a )(R 3b )) 2 -.
  9. 9. The use according to any one of claims 1-8, wherein n is 1 and l 1 is-C (R 5a )(R 5b ) -.
  10. 10. The use of any one of claims 1-9, wherein each R 5a ,R 5b is independently hydrogen and 1 methylene unit of the L 1 is substituted with C (O) -.
  11. 11. The use of any one of claims 1-10, wherein each R 3a ,R 3b is independently hydrogen.
  12. 12. The use according to any one of claims 1-11, wherein R n is hydrogen.
  13. 13. The use according to any one of claims 1-12, the compound having the structure: , , , , , , , , A kind of electronic device , Wherein Ab is as defined in claim 1, The average linkage number Na is a fraction or integer selected from 1 to 10.
  14. 14. The use of any one of claims 1-13, wherein the Ab is an antibody or antigen-binding fragment thereof that targets HER2 and comprises an antibody light chain variable region (VL) and an antibody heavy chain variable region (VH), the amino acid sequence of VL is shown in SEQ ID No. 25, and the amino acid sequence of VH is shown in SEQ ID No. 29.
  15. 15. The use of any one of claims 1-14, wherein the Ab is an antibody or antigen-binding fragment thereof that targets HER2, and comprises an antibody light chain and an antibody heavy chain, wherein the amino acid sequence of the light chain is shown in SEQ ID No. 33 and the amino acid sequence of the heavy chain is shown in SEQ ID No. 37.
  16. 16. The use according to any one of claims 1-15, said compound having the structure: Or (b) , Wherein the average linkage number n is an integer or fraction selected from 3 to 8.
  17. 17. The use according to any one of claims 1-16, the medicament being prepared in a form suitable for oral, intravenous drip, intraperitoneal injection or topical administration.

Description

Antitumor compound and preparation method and application thereof The application relates to a Chinese patent application with application date of 2021, 09 and 29, application number of 202180018263.3 and the name of an anti-tumor compound, a preparation method and application thereof. Technical Field The application relates to the field of biological medicine, in particular to an anti-tumor compound and a preparation method and application thereof. Background Currently, the small cytotoxic molecule used for antibody drug conjugates may be a camptothecin derivative, which has an anti-tumor effect by inhibiting topoisomerase I. The camptothecin derivatives can be applied to antibody conjugated drugs (ADC). There is still a need to further develop camptothecin derivatives and ADC drugs that are better in therapeutic and/or safety. Disclosure of Invention The application provides a compound or a tautomer, a meso, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, which can have one or more effects selected from the group consisting of (1) inhibition activity on proliferation of tumor cells in vitro, (2) targeted inhibition, (3) plasma stability, (4) in vivo tumor inhibition effect, (5) bystander killing effect (Bystander Effect), (6) anti-transporter transport capability, (7) in vivo tumor targeting capability, and (8) good in vivo safety. In one aspect, the present application provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said compound comprises a structure according to formula (II-a): Wherein X 1 is saturated C, said X 1 being substituted with R n; Ring A is selected from the group consisting of 3 to 10 membered saturated or partially unsaturated heterocyclyl, and 3 to 10 membered saturated or partially unsaturated carbocyclyl, wherein said ring A is substituted with 0 or at least 1 substituents R 1a; When ring a is a 3 to 10 membered saturated or partially unsaturated carbocyclyl, the ring a is substituted with p L 2, the L 2 is not R n; Or when ring a is a 3 to 10 membered saturated or partially unsaturated heterocyclyl, said ring a is substituted with p L 2; L 2 is-R 2-L3 -, said R 2 is used for direct or indirect attachment of a ligand; L 3 is- (C (R 3a)(R3b))m -, wherein when L 3 comprises methylene units, 0 or at least 1 methylene units of said L 3 are each independently replaced by -N(R4)C(O)-、-C(O)N(R4)-、-C(O)-、-OC(O)-、-C(O)O-、-NR4-、-O-、-S-、-SO-、-SO2-、-P(R4)-、-P(=O)(R4)-、-N(R4)SO2-、-SO2N(R4)-、-C(＝S)-、-C(＝NR4)-、-N＝N-、-C＝N-、-N＝C- or-C (=n 2) -; R 2 is selected from the group consisting of: -O-, - (R 2a) N-, -S-, and-P (=o) (R 2a) -; L 1 is- (C (R 5a)(R5b))n -, wherein when L 1 comprises methylene units, 0 or at least 1 methylene units of said L 1 are each independently replaced by -N(R6)C(O)-、-C(O)N(R6)-、-C(O)-、-OC(O)-、-C(O)O-、-NR6-、-O-、-S-、-SO-、-SO2-、-P(R6)-、-P(=O)(R6)-、-N(R6)SO2-、-SO2N(R6)-、-C(＝S)-、-C(＝NR6)-、-N＝N-、-C＝N-、-N＝C- or-C (=n 2) -; Wherein each R 1a,R2a,R3a,R3b,R4,R5a,R5b,R6,Rn is independently hydrogen, protium, deuterium, tritium, halogen 、-NO2、-CN、-OR、-SR、-N(Ra)(Rb)、-C(O)R、-CO2R、-C(O)C(O)R、-C(O)CH2C(O)R、-S(O)R、-S(O)2R、-C(O)N(Ra)(Rb)、-SO2N(Ra)(Rb)、-OC(O)R、-N(R)SO2R、, or a C 1-6 aliphatic optionally substituted with R; Wherein each R, R a,Rb is independently hydrogen, protium, deuterium, tritium, halogen 、-NO2、-CN、-OH、-SH、-NH2、-C(O)H、-CO2H、-C(O)C(O)H、-C(O)CH2C(O)H、-S(O)H、-S(O)2H、-C(O)NH2、-SO2NH2、-OC(O)H、-N(H)SO2H、, or C 1-6 aliphatic; m, n are each independently selected from integers of at least 0, and p is an integer of at least 1. In one aspect, the present application provides a compound of formula (II-E x) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: , Wherein X 1 is saturated C, said X 1 being substituted with R n; Ring A is selected from the group consisting of 3 to 10 membered saturated or partially unsaturated heterocyclyl, and 3 to 10 membered saturated or partially unsaturated carbocyclyl, wherein said ring A is substituted with 0 or at least 1 substituents R 1a; When ring a is a 3 to 10 membered saturated or partially unsaturated carbocyclyl, the ring a is substituted with p L 2, the L 2 is not R n; Or when ring a is a 3 to 10 membered saturated or partially unsaturated heterocyclyl, said ring a is substituted with p L 2; L 2 is-R 2-L3 -, said R 2 is used for direct or indirect attachment of a ligand; L 3 is- (C (R 3a)(R3b))m -, wherein when L 3 comprises methylene units, 0 or at least 1 methylene units of said L 3 are each independently replaced by -N(R4)C(O)-、-C(O)N(R4)-、-C(O)-、-OC(O)-、-C(O)O-、-NR4-、-O-、-S-、-SO-、-SO2-、-P(R4)-、-P(=O)(R4)-、-N(R4)SO2-、-SO2N(R4)-、-C(＝S)-、-C(＝NR4)-、-N＝N-、-C＝N-、-N＝C- or-C (=n 2) -; R 2 is selected from the group consisting of: -O-, - (R 2a) N-, -S-, and-P (=o) (R 2a) -; L 1 is- (C (R 5a)(R5b))