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CN-122005841-A - Antitumor compound and preparation method and application thereof

CN122005841ACN 122005841 ACN122005841 ACN 122005841ACN-122005841-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 (20)

  1. 1. A compound of the general formula (II-E x ) or a tautomer, meso, 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 -L 3 -, said R 2 is used for direct or indirect attachment of a ligand; L 3 is- (C (R 3a )(R 3b )) 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(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 ) -; 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 )(R 5b )) 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(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; m, n are each independently selected from integers of at least 0, and p is an integer of at least 1.
  2. 2. A compound, or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising a structure represented by formula (II-D x ): , Wherein Ab is a ligand and the average linkage number N a is an integer or fraction from 1 to 10; L is-L a -L b -L c -; said-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, 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 ) -; 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, 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 wa ,R wb ,R za ,R zb ,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; 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 -L 3 -, said R 2 is used for direct or indirect attachment of a ligand; L 3 is- (C (R 3a )(R 3b )) 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(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 ) -; 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 )(R 5b )) 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(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; m, n are each independently selected from integers of at least 0, and p is an integer of at least 1.
  3. 3. A compound of the general formula (II-F x ) or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: , The L x is L ax -L b -L c -; The L ax -is selected from the group consisting of: , A kind of electronic device ; Wherein R hal is iodine or bromine; 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, 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 ) -; 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, 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 wa ,R wb ,R za ,R zb ,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; 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 -L 3 -, said R 2 is used for direct or indirect attachment of a ligand; L 3 is- (C (R 3a )(R 3b )) 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(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 ) -; 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 )(R 5b )) 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(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; m, n are each independently selected from integers of at least 0, and p is an integer of at least 1.
  4. 4. A compound according to any one of claims 1-3, or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of a 3-to 10-membered saturated heterocyclyl group, and a 3-to 10-membered saturated carbocyclyl group.
  5. 5. A compound according to any one of claims 1-3, or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring a is a 3-to 6-membered saturated carbocyclyl.
  6. 6. A compound according to any one of claims 1-3, or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring a is a 4-membered saturated carbocyclyl.
  7. 7. A compound of the general formula (III-E) or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: Wherein R 1 is selected from the group consisting of: -O-, - (R 2 )N-,-P(=O)(R 2 ) -, and-S-; X is-L 1 -CH 2 -C (O) -; L 1 is- (C (R 3a )(R 3b )) m ) -wherein 0 or at least 1 methylene units of L 1 are each independently replaced by-C (O) -, -C (=s) -, -C (=nr 4b ) -or-C (=n 2 ) -; Wherein each R 2 ,R 3a ,R 3b ,R 4b 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; m is selected from integers of at least 0 and n is selected from integers of at least 1; When R 1 is-O-or-HN-, at least 1 methylene unit of L 1 is each independently replaced by-C (O) -, -C (=s) -, -C (=nr 4b ) -or-C (=n 2 ) -or each R 3a ,R 3b is not simultaneously hydrogen.
  8. 8. A compound, or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising a structure represented by formula (III-D): Wherein Ab is a ligand and the average linkage number N a is an integer or fraction from 1 to 10; L is-L a -L b -L c -; said-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, 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 ) -; 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, 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 wa ,R wb ,R za ,R zb ,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; Wherein R 1 is selected from the group consisting of: -O-, - (R 2 )N-,-P(=O)(R 2 ) -, and-S-; X is-L 1 -CH 2 -C (O) -; L 1 is- (C (R 3a )(R 3b )) m ) -wherein 0 or at least 1 methylene units of L 1 are each independently replaced by-C (O) -, -C (=s) -, -C (=nr 4b ) -or-C (=n 2 ) -; Wherein each R 2 ,R 3a ,R 3b ,R 4b 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; m is selected from integers of at least 0 and n is selected from integers of at least 1; When R 1 is-O-or-HN-, at least 1 methylene unit of L 1 is each independently replaced by-C (O) -, -C (=s) -, -C (=nr 4b ) -or-C (=n 2 ) -or each R 3a ,R 3b is not simultaneously hydrogen.
  9. 9. A compound of the general formula (III-F) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: , The L x is L ax -L b -L c -; The L ax -is selected from the group consisting of: , A kind of electronic device ; Wherein R hal is iodine or bromine; 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, 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 ) -; 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, 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 wa ,R wb ,R za ,R zb ,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; Wherein R 1 is selected from the group consisting of: -O-, - (R 2 )N-,-P(=O)(R 2 ) -, and-S-; X is-L 1 -CH 2 -C (O) -; L 1 is- (C (R 3a )(R 3b )) m ) -wherein 0 or at least 1 methylene units of L 1 are each independently replaced by-C (O) -, -C (=s) -, -C (=nr 4b ) -or-C (=n 2 ) -; Wherein each R 2 ,R 3a ,R 3b ,R 4b 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; m is selected from integers of at least 0 and n is selected from integers of at least 1; When R 1 is-O-or-HN-, at least 1 methylene unit of L 1 is each independently replaced by-C (O) -, -C (=s) -, -C (=nr 4b ) -or-C (=n 2 ) -or each R 3a ,R 3b is not simultaneously hydrogen.
  10. 10. The compound according to any one of claims 7-9, or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein X is-L 1 -CH 2 -C(O)-,L 1 is- (C (R 3a )(R 3b )) m -, m is not 0, each R 3a ,R 3b is not simultaneously hydrogen).
  11. 11. The compound according to any one of claims 7-9, or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein m is 1, l 1 is-C (R 3a )(R 3b ) -.
  12. 12. The compound according to any one of claims 7-9, or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein 0 methylene units of L 1 are replaced by-C (O) -, -C (=s) -, -C (=nr 4b ) -or-C (=n 2 ) -.
  13. 13. The compound of any one of claims 7-9, or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 3a is a C 1-6 aliphatic group.
  14. 14. The compound according to any one of claims 7-9, or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 3b is hydrogen or a C 1-6 aliphatic group.
  15. 15. The compound according to any one of claims 7-9, or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is-O-or-HN-.
  16. 16. The compound according to any one of claims 7-9, or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen or methyl.
  17. 17. The compound according to any one of claims 7-9, or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R, R a ,R b is hydrogen.
  18. 18. The compound of claim 2 or 5, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Ab is an antibody or antigen-binding fragment thereof.
  19. 19. The compound of claim 18, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said ligand Ab targets the group consisting of HER2, HER3, B7H3, TROP2, claudin 18.2, CD30, CD33, CD70, and EGFR.
  20. 20. The compound according to claim 2 or 5, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein-L a -L b -L c -is selected from the group consisting of: 。

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))