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CN-121991160-A - Targeted protein degradation agent, and pharmaceutical composition and application thereof

CN121991160ACN 121991160 ACN121991160 ACN 121991160ACN-121991160-A

Abstract

The invention discloses a targeted protein degradation agent, a pharmaceutical composition and application thereof. The novel targeted protein degradation agent prepared by the invention has remarkable target protein degradation activity. The novel targeted protein degradation agent is used as the effective load of the antibody coupling drug, realizes more effective and safer degradation of the target protein by utilizing the targeting property and antigen-mediated internalization of the antibody, is used for treating diseases (such as tumors) mediated by the target protein, and has wide application prospect and research and development value in the field of medicine.

Inventors

  • WANG ZHISONG
  • WANG JIE
  • ZHOU BO
  • WANG NINGNING
  • Rong Xuedi

Assignees

  • 北京森妙生物科技有限公司

Dates

Publication Date
20260508
Application Date
20251107
Priority Date
20241108

Claims (12)

  1. 1. A compound, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuteride thereof, wherein the compound has the structure: Wherein, the U is selected from C 0 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 4-10 membered heterocyclic group; V is selected from-O-, -S-, and, B is The C ring is a divalent group attached to the A ring, which is absent or selected from C 3 -C 10 cycloalkylene, C 6 -C 10 arylene, 4-10 membered heterocyclylene; X, Y, Z is independently selected from the group consisting of a single bond, C 1 -C 10 alkylene, - (C 0 -C 6 alkylene) -O-, - (C 0 -C 6 alkylene) -S-, - (C 0 -C 6 alkylene) -C (O) -, - (C 0 -C 6 alkylene) -C (S) -, - (C 0 -C 6 alkylene) -N (R B1 )-、-(C 0 -C 6 alkylene) -CON (R B1 )-、-(C 0 -C 6 alkylene) -N (R B1 )CO-、-(C 0 -C 6 alkylene) -SO 2 -、-(C 0 -C 6 alkylene) -SO-, - (C 0 -C 6 alkylene) - (C 3 -C 10 cycloalkylene) -, - (C 0 -C 6 alkylene) - (C 6 -C 10 arylene) -, - (C 0 -C 6 alkylene) - (4-10 membered heterocyclylene) -, wherein the C 0 -C 10 alkylene, C 3 -C 10 cycloalkylene, C 6 -C 10 arylene, H in the 4-10 membered heterocyclylene group may be optionally substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, - (C 0 -C 6 alkylene) - (C 3 -C 10 cycloalkyl), amino, or a mixture thereof, - (C 0 -C 6 alkylene) - (C 6 -C 10 aryl), - (C 0 -C 6 alkylene) - (4-10 membered heterocyclyl), C 1 -C 10 haloalkyl, C 1 -C 10 haloalkoxy, -N (C 0-10 alkyl) (C 0-10 alkyl), -N (C 0-10 alkyl) CO (C 0-10 alkyl), -N (C 0-10 alkyl) CON (C 0-10 alkyl), -N (C 0-10 alkyl) SO 2 (C 0-10 alkyl), -O (C 0-10 alkyl), -S (C 0-10 alkyl), -SO (C 0-10 alkyl), -SO 2 (C 0-10 alkyl), -SO 2 N(C 0-10 alkyl) (C 0-10 alkyl), -COO (C 0-10 alkyl), -OCO (C 0-10 alkyl), -CON (C 0-10 alkyl) (C 0-10 alkyl), -CO (C 0-10 alkyl); The A ring is selected from C 3 -C 10 cycloalkylene, C 6 -C 10 arylene, 4-10 membered heterocyclylene, wherein C 3 -C 10 cycloalkylene, C 6 -C 10 arylene, H in the 4-10 membered heterocyclylene group may be optionally substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, - (C 0 -C 6 alkylene) - (C 3 -C 10 cycloalkyl), amino, or a mixture thereof, - (C 0 -C 6 alkylene) - (C 6 -C 10 aryl), - (C 0 -C 6 alkylene) - (4-10 membered heterocyclyl), C 1 -C 10 haloalkyl, C 1 -C 10 haloalkoxy, - (C 0 -C 6 alkylene) -N (C 0-10 alkyl) (C 0-10 alkyl), - (C 0 -C 6 alkylene) -N (C 0-10 alkyl) CO (C 0-10 alkyl), - (C 0 -C 6 alkylene) -N (C 0-10 alkyl) CON (C 0-10 alkyl), - (C 0 -C 6 alkylene) -N (C 0-10 alkyl) SO 2 (C 0-10 alkyl), - (C 0 -C 6 alkylene) -O (C 0-10 alkyl), - (C 0 -C 6 alkylene) -S (C 0-10 alkyl), - (C 0 -C 6 alkylene) -SO (C 0-10 alkyl), - (C 0 -C 6 alkylene) -SO 2 (C 0-10 alkyl), - (C 0 -C 6 alkylene) -SO 2 N(C 0-10 alkyl) (C 0-10 alkyl), - (C 0 -C 6 alkylene) -COO (C 0-10 alkyl), - (C 0 -C 6 alkylene) -OCO (C 0-10 alkyl), - (C 0 -C 6 alkylene) -CON (C 0-10 alkyl) (C 0-10 alkyl), - (C 0 -C 6 alkylene) -CO (C 0-10 alkyl); D is L 1 、L 2 、L 3 is independently selected from a single bond, C 1 -C 10 alkylene, -O- (C 0 -C 6 alkylene) -, -S- (C 0 -C 6 alkylene) -, and, -N (R L0 )-(C 0 -C 6 alkylene) -, -N (R L0 )C(O)-(C 0 -C 6 alkylene) -, -N (R L0 )C(O)O-(C 0 -C 6 alkylene) -, -N (R L0 )C(O)N(R L0 )-(C 0 -C 6 alkylene) -, -C (O) - (C 0 -C 6 alkylene) -, -C (S) - (C 0 -C 6 alkylene) -, -C (O) O- (C 0 -C 6 alkylene) -, -OC (O) - (C 0 -C 6 alkylene) -, and, - (C 0 -C 6 alkylene) -OC (O) -, -CON (R L0 )-(C 0 -C 6 alkylene) -, -SO 2 -(C 0 -C 6 alkylene) -, -SO- (C 0 -C 6 alkylene) -, c 3 -C 10 Cycloalkylene, C 6 -C 10 arylene, 4-10 membered heterocyclylene, wherein the C 0 -C 10 alkylene, C 3 -C 10 cycloalkylene, H in the C 6 -C 10 arylene, 4-10 membered heterocyclylene may be optionally substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, - (C 0 -C 6 alkylene) - (C 3 -C 10 cycloalkyl), - (C 0 -C 6 alkylene) - (C 6 -C 10 aryl), - (C 0 -C 6 alkylene) - (4-10 membered heterocyclyl), C 1 -C 10 haloalkyl, C 1 -C 10 haloalkoxy, -N (C 0-10 alkyl) (C 0-10 alkyl), -N (C 0-10 alkyl) CO (C 0-10 alkyl), -N (C 0-10 alkyl) CON (C 0-10 alkyl), -N (C 0-10 alkyl) SO 2 (C 0-10 alkyl), -O (C 0-10 alkyl), -S (C 0-10 alkyl), -SO (C 0-10 alkyl), -SO 2 (C 0-10 alkyl), -SO 2 N(C 0-10 alkyl) (C 0-10 alkyl), -COO (C 0-10 alkyl), -OCO (C 0-10 alkyl), -CON (C 0-10 alkyl) (C 0-10 alkyl), -CO (C 0-10 alkyl); L is a linker precursor; R V1 、R V2 、R B1 、R L0 is independently selected from H, deuterium, halogen, cyano, nitro, azido, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, - (C 0 -C 6 alkylene) - (C 3 -C 10 cycloalkyl), - (C 0 -C 6 alkylene) - (C 6 -C 10 aryl), - (C 0 -C 6 alkylene) - (4-10 membered heterocyclyl), C 1 -C 10 haloalkyl, C 1 -C 10 haloalkoxy, -N (C 0-10 alkyl) (C 0-10 alkyl), -N (C 0-10 alkyl) CO (C 0-10 alkyl), -N (C 0-10 alkyl) CON (C 0-10 alkyl), -N (C 0-10 alkyl) SO 2 (C 0-10 alkyl), -O (C 0-10 alkyl), -S (C 0-10 alkyl), -SO (C 0-10 alkyl), -SO 2 (C 0-10 alkyl), -SO 2 N(C 0-10 alkyl) (C 0-10 alkyl), -COO (C 0-10 alkyl), -OCO (C 0-10 alkyl), -CON (C 0-10 alkyl) (C 0-10 alkyl), -CO (C 0-10 alkyl).
  2. 2. The compound of claim 1, wherein U is selected from the group consisting of C 0 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, Preferably, W is selected from the group consisting of-O-, -S-, Preferably V is Preferably, X is selected from the group consisting of C 1 -C 10 alkylene, - (C 0 -C 6 alkylene) -O-, - (C 0 -C 6 alkylene) -S-, - (C 0 -C 6 alkylene) -C (O) -, - (C 0 -C 6 alkylene) -C (S) -, - (C 0 -C 6 alkylene) -N (R X1 )-、-(C 0 -C 6 alkylene) -CON (R X1 )-、-(C 0 -C 6 alkylene) -N (R X1 )CO-、-(C 0 -C 6 alkylene) -SO 2 -、-(C 0 -C 6 alkylene) -SO-; Preferably, Y is selected from: - (C 0 -C 6 alkylene) -O-, - (C 0 -C 6 alkylene) -S-, - (C 0 -C 6 alkylene) -C (O) -, - (C 0 -C 6 alkylene) -C (S) -, - (C 0 -C 6 alkylene) -N (R Y1 )-、-(C 0 -C 6 alkylene) -CON (R Y1 )-、-(C 0 -C 6 alkylene) -N (R Y1 )CO-、-(C 0 -C 6 alkylene) -SO 2 -、-(C 0 -C 6 alkylene) -SO-, - (C 0 -C 6 alkylene) - (C 3 -C 10 cycloalkylene) -, - (C 0 -C 6 alkylene) - (C 6 -C 10 arylene) -, - (C 0 -C 6 alkylene) - (4-10 membered heterocyclylene) -, wherein the C 0 -C 6 alkylene, C 3 -C 10 cycloalkylene, C 6 -C 10 arylene, H in the 4-10 membered heterocyclylene group may be optionally substituted with one or more groups selected from: deuterium, halogen, cyano, nitro, azido, C 1 -C 10 alkyl, C 1 -C 10 haloalkyl, -N (C 0-10 alkyl) (C 0-10 alkyl), alkyl, -N (C 0-10 alkyl) CO (C 0-10 alkyl), -O (C 0-10 alkyl), -COO (C 0-10 alkyl), -OCO (C 0-10 alkyl), -CON (C 0-10 alkyl) (C 0-10 alkyl), -CO (C 0-10 alkyl); Preferably, Z is selected from: - (C 0 -C 6 alkylene) -O-, - (C 0 -C 6 alkylene) -S-, - (C 0 -C 6 alkylene) -C (O) -, - (C 0 -C 6 alkylene) -C (S) -, - (C 0 -C 6 alkylene) -N (R Z1 )-、-(C 0 -C 6 alkylene) -CON (R Z1 )-、-(C 0 -C 6 alkylene) -N (R Z1 )CO-、-(C 0 -C 6 alkylene) -SO 2 -、-(C 0 -C 6 alkylene) -SO-; Preferably, R W1 、R W2 、R X1 、R Y1 、R Z1 is independently selected from H, deuterium, halogen, cyano, nitro, azido, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, - (C 0 -C 6 alkylene) - (C 3 -C 10 cycloalkyl), - (C 0 -C 6 alkylene) - (C 6 -C 10 aryl), - (C 0 -C 6 alkylene) - (4-10 membered heterocyclyl), C 1 -C 10 haloalkyl, C 1 -C 10 haloalkoxy, -N (C 0-10 alkyl) (C 0-10 alkyl), -N (C 0-10 alkyl) CO (C 0-10 alkyl), -N (C 0-10 alkyl) CON (C 0-10 alkyl), -N (C 0-10 alkyl) SO 2 (C 0-10 alkyl), -O (C 0-10 alkyl), -S (C 0-10 alkyl), -SO (C 0-10 alkyl), -SO 2 (C 0-10 alkyl), -SO 2 N(C 0-10 alkyl) (C 0-10 alkyl), -COO (C 0-10 alkyl), -OCO (C 0-10 alkyl), -CON (C 0-10 alkyl) (C 0-10 alkyl), -CO (C 0-10 alkyl); Preferably, R V1 、R V2 、R W1 、R W2 、R X1 、R Y1 、R Z1 is independently selected from H, deuterium, halogen, cyano, nitro, azido, C 1 -C 10 alkyl, C 1 -C 10 haloalkyl, -N (C 0-10 alkyl) (C 0-10 alkyl), -N (C 0-10 alkyl) CO (C 0-10 alkyl), -O (C 0-10 alkyl), -COO (C 0-10 alkyl), -OCO (C 0-10 alkyl), -CON (C 0-10 alkyl) (C 0-10 alkyl), -CO (C 0-10 alkyl); Preferably, the a ring is selected from: Preferably, R L4 、R L5 is independently selected from deuterium, halogen, cyano, nitro, azido, C 1 -C 10 alkyl, - (C 0 -C 6 alkylene) - (C 3 -C 10 cycloalkyl), - (C 0 -C 6 alkylene) - (C 6 -C 10 aryl), - (C 0 -C 6 alkylene) - (4-10 membered heterocyclyl), - (C 0 -C 6 alkylene) -N (C 0-10 alkyl) (C 0-10 alkyl), - (C 0 -C 6 alkylene) -N (C 0-10 alkyl) CO (C 0-10 alkyl), - (C 0 -C 6 alkylene) -O (C 0-10 alkyl), - (C 0 -C 6 alkylene) -COO (C 0-10 alkyl), - (C 0 -C 6 alkylene) -OCO (C 0-10 alkyl), - (C 0 -C 6 alkylene) -CON (C 0-10 alkyl) (C 0-10 alkyl), - (C 0 -C 6 alkylene) -CO (C 0-10 alkyl).
  3. 3. A compound according to claim 2, wherein U is selected from the group consisting of H, Preferably, the C ring is absent or selected from: X is selected from: preferably Y is selected from the group consisting of-O- Z is selected from: -O-, Preferably, B is selected from: Preferably, the a ring is selected from:
  4. 4. the compound of claim 1, wherein the compound of formula I contains at least one deuterium atom; Preferably, one or more H atoms to which the carbon atoms in D are attached may be substituted with deuterium; Preferably, one or more H atoms to which the carbon atoms in L 1 、L 2 、L 3 are attached may be substituted with deuterium; L 1 is selected from the group consisting of a single bond, -O- (C 0 -C 6 alkylene) -, -S- (C 0 -C 6 alkylene) -, -N (R L1 )-(C 0 -C 6 alkylene) -, and, -N (R L1 )C(O)-(C 0 -C 6 alkylene) -, -N (R L1 )C(O)O-(C 0 -C 6 alkylene) -, -N (R L1 )C(O)N(R L1 )-(C 0 -C 6 alkylene) -, -C (O) - (C 0 -C 6 alkylene) -, -C (O) O- (C 0 -C 6 alkylene) -, -CON (R L1 )-(C 0 -C 6 alkylene) -, wherein R L1 is selected from H, deuterium, halogen, cyano, nitro, azido, C 1 -C 10 alkyl, C 1 -C 10 haloalkyl, -N (C 0-10 alkyl) (C 0-10 alkyl), -N (C 0-10 alkyl) CO (C 0-10 alkyl), and, -O (C 0-10 alkyl), -COO (C 0-10 alkyl), -OCO (C 0-10 alkyl), -CON (C 0-10 alkyl) (C 0-10 alkyl), -CO (C 0-10 alkyl); Preferably, L 1 is selected from the group consisting of a single bond, -O-, and, Preferably, L 2 is selected from the group consisting of a single bond, C 1 -C 10 alkylene, -O- (C 0 -C 6 alkylene) -, -S- (C 0 -C 6 alkylene) -, and, -N (R L2 )-(C 0 -C 6 alkylene) -, -N (R L2 )C(O)-(C 0 -C 6 alkylene) -, -C (O) - (C 0 -C 6 alkylene) -, -CON (R L2 )-(C 0 -C 6 alkylene) -, wherein H in the C 0 -C 10 alkylene group is optionally substituted with one or more groups selected from deuterium, Halogen, cyano, nitro, azido, C 1 -C 10 alkyl- (C 0 -C 6 alkylene) - (C 3 -C 10 cycloalkyl), - (C 0 -C 6 alkylene) - (C 6 -C 10 aryl), - (C 0 -C 6 alkylene) - (4-10 membered heterocyclyl), C 1 -C 10 haloalkyl, -N (C 0-10 alkyl) (C 0-10 alkyl), -N (C 0-10 alkyl) CO (C 0-10 alkyl), -O (C 0-10 alkyl), -COO (C 0-10 alkyl), -OCO (C 0-10 alkyl), -CON (C 0-10 alkyl) (C 0-10 alkyl), -CO (C 0-10 alkyl), wherein R L2 is selected from H, Deuterium, halogen, cyano, nitro, azido, C 1 -C 10 alkyl, - (C 0 -C 6 alkylene) - (C 3 -C 10 cycloalkyl), - (C 0 -C 6 alkylene) - (C 6 -C 10 aryl), - (C 0 -C 6 alkylene) - (4-10 membered heterocyclyl), C 1 -C 10 haloalkyl, -N (C 0-10 alkyl) (C 0-10 alkyl), -N (C 0-10 alkyl) CO (C 0-10 alkyl), -O (C 0-10 alkyl), -COO (C 0-10 alkyl), -OCO (C 0-10 alkyl), -CON (C 0-10 alkyl) (C 0-10 alkyl), -CO (C 0-10 alkyl); Preferably, L 2 is selected from the group consisting of a single bond, Preferably, L 3 is selected from the group consisting of a single bond, - (C 0 -C 6 alkylene) -OC (O) -, C 3 -C 10 cycloalkylene, C 6 -C 10 arylene, 4-10 membered heterocyclylene, wherein H in the C 0 -C 6 alkylene, C 3 -C 10 cycloalkylene, C 6 -C 10 arylene, 4-10 membered heterocyclylene may be optionally substituted with one or more groups selected from deuterium, halogen, cyano, Nitro, azido, C 1 -C 10 alkyl, C 1 -C 10 haloalkyl, -N (C 0-10 alkyl) (C 0-10 alkyl), and, -N (C 0-10 alkyl) CO (C 0-10 alkyl), -O (C 0-10 alkyl), -COO (C 0-10 alkyl), -OCO (C 0-10 alkyl), -CON (C 0-10 alkyl) (C 0-10 alkyl), -CO (C 0-10 alkyl); Preferably, L 3 is selected from the group consisting of a single bond, Preferably, D is selected from the group consisting of-NH-,
  5. 5. A compound according to claim 1, wherein L is L 4 is a divalent group attached to L 3 selected from the group consisting of a single bond, L 5 is a divalent radical selected from the group consisting of a single bond, C 1 -C 6 alkylene, -N (C 0 -C 10 alkyl) -, -CO-, -O-, and, Wherein s is an integer of 1-10, r is an integer of 1-10, P 1 、P 2 、P 3 、P 4 is independently absent or an amino acid residue, and at least one of P 1 、P 2 、P 3 、P 4 is an amino acid residue selected from the group consisting of glycine residue, alanine residue, valine residue, leucine residue, isoleucine residue, methionine residue, proline residue, tryptophan residue, serine residue, tyrosine residue, cysteine residue, phenylalanine residue, asparagine residue, glutamine residue, threonine residue, aspartic acid residue, glutamic acid residue, lysine residue, arginine residue, histidine residue, citrulline residue, ornithine residue, cystine residue, selenocysteine, hydroxyproline, hydroxylysine, theanine; Preferably, P 1 、P 2 、P 3 、P 4 is independently absent or selected from the group consisting of glycine residues, L-alanine residues, D-alanine residues, L-valine residues, D-valine residues, L-phenylalanine residues, D-phenylalanine residues, L-citrulline residues, D-citrulline residues, L-asparagine residues, D-asparagine residues; L 6 is selected from: wherein q is an integer from 1 to 10, R L3 、R L6 、R L7 is independently selected from H, C 1 -C 10 alkyl, - (C 0 -C 6 alkylene) - (C 6 -C 10 aryl); preferably, L is selected from: wherein q is an integer of 1 to 10; preferably L is
  6. 6. A compound according to any one of claims 1 to 5, wherein the compound has the structure:
  7. 7. A conjugate, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuteride thereof, the conjugate having the structure: Wherein, the U is selected from C 0 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 4-10 membered heterocyclic group; V is selected from-O-, -S-, and, B is The C ring is a divalent group attached to the A ring, which is absent or selected from C 3 -C 10 cycloalkylene, C 6 -C 10 arylene, 4-10 membered heterocyclylene; X, Y, Z is independently selected from the group consisting of a single bond, C 1 -C 10 alkylene, - (C 0 -C 6 alkylene) -O-, - (C 0 -C 6 alkylene) -S-, - (C 0 -C 6 alkylene) -C (O) -, - (C 0 -C 6 alkylene) -C (S) -, - (C 0 -C 6 alkylene) -N (R B1 )-、-(C 0 -C 6 alkylene) -CON (R B1 )-、-(C 0 -C 6 alkylene) -N (R B1 )CO-、-(C 0 -C 6 alkylene) -SO 2 -、-(C 0 -C 6 alkylene) -SO-, - (C 0 -C 6 alkylene) - (C 3 -C 10 cycloalkylene) -, - (C 0 -C 6 alkylene) - (C 6 -C 10 arylene) -, - (C 0 -C 6 alkylene) - (4-10 membered heterocyclylene) -, wherein the C 0 -C 10 alkylene, C 3 -C 10 cycloalkylene, C 6 -C 10 arylene, H in the 4-10 membered heterocyclylene group may be optionally substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, - (C 0 -C 6 alkylene) - (C 3 -C 10 cycloalkyl), amino, or a mixture thereof, - (C 0 -C 6 alkylene) - (C 6 -C 10 aryl), - (C 0 -C 6 alkylene) - (4-10 membered heterocyclyl), C 1 -C 10 haloalkyl, C 1 -C 10 haloalkoxy, -N (C 0-10 alkyl) (C 0-10 alkyl), -N (C 0-10 alkyl) CO (C 0-10 alkyl), -N (C 0-10 alkyl) CON (C 0-10 alkyl), -N (C 0-10 alkyl) SO 2 (C 0-10 alkyl), -O (C 0-10 alkyl), -S (C 0-10 alkyl), -SO (C 0-10 alkyl), -SO 2 (C 0-10 alkyl), -SO 2 N(C 0-10 alkyl) (C 0-10 alkyl), -COO (C 0-10 alkyl), -OCO (C 0-10 alkyl), -CON (C 0-10 alkyl) (C 0-10 alkyl), -CO (C 0-10 alkyl); The A ring is selected from C 3 -C 10 cycloalkylene, C 6 -C 10 arylene, 4-10 membered heterocyclylene, wherein C 3 -C 10 cycloalkylene, C 6 -C 10 arylene, H in the 4-10 membered heterocyclylene group may be optionally substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, - (C 0 -C 6 alkylene) - (C 3 -C 10 cycloalkyl), amino, or a mixture thereof, - (C 0 -C 6 alkylene) - (C 6 -C 10 aryl), - (C 0 -C 6 alkylene) - (4-10 membered heterocyclyl), C 1 -C 10 haloalkyl, C 1 -C 10 haloalkoxy, - (C 0 -C 6 alkylene) -N (C 0-10 alkyl) (C 0-10 alkyl), - (C 0 -C 6 alkylene) -N (C 0-10 alkyl) CO (C 0-10 alkyl), - (C 0 -C 6 alkylene) -N (C 0-10 alkyl) CON (C 0-10 alkyl), - (C 0 -C 6 alkylene) -N (C 0-10 alkyl) SO 2 (C 0-10 alkyl), - (C 0 -C 6 alkylene) -O (C 0-10 alkyl), - (C 0 -C 6 alkylene) -S (C 0-10 alkyl), - (C 0 -C 6 alkylene) -SO (C 0-10 alkyl), - (C 0 -C 6 alkylene) -SO 2 (C 0-10 alkyl), - (C 0 -C 6 alkylene) -SO 2 N(C 0-10 alkyl) (C 0-10 alkyl), - (C 0 -C 6 alkylene) -COO (C 0-10 alkyl), - (C 0 -C 6 alkylene) -OCO (C 0-10 alkyl), - (C 0 -C 6 alkylene) -CON (C 0-10 alkyl) (C 0-10 alkyl), - (C 0 -C 6 alkylene) -CO (C 0-10 alkyl); D is L 1 、L 2 、L 3 is independently selected from a single bond, C 1 -C 10 alkylene, -O- (C 0 -C 6 alkylene) -, -S- (C 0 -C 6 alkylene) -, and, -N (R L0 )-(C 0 -C 6 alkylene) -, -N (R L0 )C(O)-(C 0 -C 6 alkylene) -, -N (R L0 )C(O)O-(C 0 -C 6 alkylene) -, -N (R L0 )C(O)N(R L0 )-(C 0 -C 6 alkylene) -, -C (O) - (C 0 -C 6 alkylene) -, -C (S) - (C 0 -C 6 alkylene) -, -C (O) O- (C 0 -C 6 alkylene) -, -OC (O) - (C 0 -C 6 alkylene) -, and, - (C 0 -C 6 alkylene) -OC (O) -, -CON (R L0 )-(C 0 -C 6 alkylene) -, -SO 2 -(C 0 -C 6 alkylene) -, -SO- (C 0 -C 6 alkylene) -, c 3 -C 10 Cycloalkylene, C 6 -C 10 arylene, 4-10 membered heterocyclylene, wherein the C 0 -C 10 alkylene, C 3 -C 10 cycloalkylene, H in the C 6 -C 10 arylene, 4-10 membered heterocyclylene may be optionally substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, - (C 0 -C 6 alkylene) - (C 3 -C 10 cycloalkyl), - (C 0 -C 6 alkylene) - (C 6 -C 10 aryl), - (C 0 -C 6 alkylene) - (4-10 membered heterocyclyl), C 1 -C 10 haloalkyl, C 1 -C 10 haloalkoxy, -N (C 0-10 alkyl) (C 0-10 alkyl), -N (C 0-10 alkyl) CO (C 0-10 alkyl), -N (C 0-10 alkyl) CON (C 0-10 alkyl), -N (C 0-10 alkyl) SO 2 (C 0-10 alkyl), -O (C 0-10 alkyl), -S (C 0-10 alkyl), -SO (C 0-10 alkyl), -SO 2 (C 0-10 alkyl), -SO 2 N(C 0-10 alkyl) (C 0-10 alkyl), -COO (C 0-10 alkyl), -OCO (C 0-10 alkyl), -CON (C 0-10 alkyl) (C 0-10 alkyl), -CO (C 0-10 alkyl); R V1 、R V2 、R B1 、R L0 is independently selected from H, deuterium, halogen, cyano, nitro, azido, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, - (C 0 -C 6 alkylene) - (C 3 -C 10 cycloalkyl), - (C 0 -C 6 alkylene) - (C 6 -C 10 aryl), - (C 0 -C 6 alkylene) - (4-10 membered heterocyclyl), C 1 -C 10 haloalkyl, C 1 -C 10 haloalkoxy, -N (C 0-10 alkyl) (C 0-10 alkyl), -N (C 0-10 alkyl) CO (C 0-10 alkyl), -N (C 0-10 alkyl) CON (C 0-10 alkyl), -N (C 0-10 alkyl) SO 2 (C 0-10 alkyl), -O (C 0-10 alkyl), -S (C 0-10 alkyl), -SO (C 0-10 alkyl), -SO 2 (C 0-10 alkyl), -SO 2 N(C 0-10 alkyl) (C 0-10 alkyl), -COO (C 0-10 alkyl), -OCO (C 0-10 alkyl), -CON (C 0-10 alkyl) (C 0-10 alkyl), -CO (C 0-10 alkyl); n is an integer or fraction between 1 and 10; L' is a linker; bm is the binding moiety.
  8. 8. The conjugate of claim 7, wherein L' is L 4 is a divalent group attached to L 3 selected from the group consisting of a single bond, L 5 is a divalent radical selected from the group consisting of a single bond, C 1 -C 6 alkylene, -N (C 0 -C 10 alkyl) -, -CO-, -O-, and, Wherein s is an integer of 1-10, r is an integer of 1-10, P 1 、P 2 、P 3 、P 4 is independently absent or an amino acid residue, and at least one of P 1 、P 2 、P 3 、P 4 is an amino acid residue selected from the group consisting of glycine residue, alanine residue, valine residue, leucine residue, isoleucine residue, methionine residue, proline residue, tryptophan residue, serine residue, tyrosine residue, cysteine residue, phenylalanine residue, asparagine residue, glutamine residue, threonine residue, aspartic acid residue, glutamic acid residue, lysine residue, arginine residue, histidine residue, citrulline residue, ornithine residue, cystine residue, selenocysteine, hydroxyproline, hydroxylysine, theanine; l 6 ' is selected from: Wherein q is an integer from 1 to 10, R L3 is selected from H, C 1 -C 10 alkyl, - (C 0 -C 6 alkylene) - (C 6 -C 10 aryl); preferably, L is selected from: q is an integer of 1 to 10; preferably, the binding moiety is an antibody, antibody fragment or antigen binding fragment; Preferably, the protein bound by the binding moiety is a surface antigen; Preferably, the surface antigen is selected from the group consisting of 5T4, ACE, ADRB3, AKAP-4, ALK, androgen receptor, AOC3, APP, axin 1、AXL、B7H3、B7-H4、BCL2、BCMA、bcr-abl、BORIS、BST2、C242、C4.4a、CA 125、CA6、CA9、CAIX、CCL11、CCR5、CD123、CD133、CD138、CD142、CD15、CD15-3、CD171、CD179a、CD18、CD19、CD19-9、CD2、CD20、CD22、CD23、CD24、CD25、CD27L、CD28、CD3、CD30、CD31、CD300LF、CD33、CD352、CD37、CD38、CD4、CD40、CD41、CD44、CD44v6、CD5、CD51、CD52、CD54、CD56、CD62E、CD62P、CD62L、CD70、CD71、CD72、CD74、CD79a、CD79b、CD80、CD90、CD97、CD125、CD138、CD141、CD147、CD152、CD154、CD326、CEA、CEACAM5、CFTR、 clotting factor, cKit, clain 3, clain 18.2, CLDN6, CLEC12A, CLL-1, cll3, c-MET, crypto 1 growth factor, CS1, CTLA-4, CXCR2, CXORF, cyclin B1, CYP1B1, cadherin-3, cadherin-6, DLL3, E7, EDNRB, EFNA4, EGFR, EGFRvIII, ELF2M, EMR2, ENPP3, EPCAM, ephA2, ephrin A4, ephrin B2, EPHB4, ERBB2 (Her 2/neu), erbB3, ERG (TMPRSS 2ETS fusion gene), ETBR, ETV6-AML, FAP, FCAR, FCRL5, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, and pharmaceutical compositions containing them, Folic acid receptor alpha, folic acid receptor beta, foLR1, fos associated antigen 1, fucosyl GM1、GCC、GD2、GD3、GloboH、GM3、GPC1、GPC2、GPC3、gp1OO、GPNMB、GPR20、GPRC5D、GUCY2C、HAVCR1、HER2、HER3、HGF、HMI.24、HMWMAA、HPV E6、hTERT、 human telomerase reverse transcriptase, ICAM, ICOS-L, IFN-alpha, IFNgamma, IGF-I receptor, IGLL1, IL-2 receptor, IL-4 receptor, IL-13Ra2, IL-1R a, IL-1, IL-12, IL-23, IL13, IL-22, IL-4, IL-5, IL-6, interferon receptor, Integrins (including α 4 、α v β 3 、α v β 5 、α v β 6 、α 1 β 4 、α 4 β 1 、α 4 β 7 、α 5 β 1 、α 6 β 4 、α IIb β 3 integrins), integrins αV, enterocarboxylesterase, KIT, LAGE-1a, LAIR1, LAMP-1, LCK, legumain (Legumain), lewis Y, LFA-1 (CD 11 a), L-selectin (CD 62L), LILRA2, LIV-1, LMP2, LRRC15, LY6E, LY6K, LY, MAD-CT-1, MAD-CT-2, MAGE Al, melanA/MARTl, mesothelin, ML-IAP, MSLN, mucin, MUC1, MUC16, mut hsp70-2, MYCN, myostatin, NA17, naPi2b, NCA-90, NCAM, connexin (Nectin) -4, NGF, NOTCH1, NOTCH2, NOTCH3, NOTCH4, NY-BR-1, NY-ESO-1, O-acetyl-GD 2, OR51E2, OY-TES1, p53 mutant, PANX3, PAP, PAX3, PAX5, p-CAD, PCTA-1/galectin 8, PD-L1, PD-L2, PDGFR-beta, phosphatidylserine, PIK3CA, PLAC1, polysialic acid, prostases, prostate cancer cells, prostaglandins, P.aeruginosa, rabies, survivin and telomerase, PRSS21, PSCA, PSMA, PTK, RAGE-1, RANKL, ras mutants, respiratory syncytial virus, rhesus factor, rhoC, RON, ROR1, ROR2, RU1, RU2, Sarcoma translocation breakpoint, SART3, SLAMF7, SLC44A4, sLe, SLITRK6, sperm protein 17, sphingosine-1-phosphate, SSEA-4, SSX2, STEAP1, TAG72, TARP, TCR beta, TEM1/CD248, TEM7R, tenascin C, TF, TGF-1, TGF-beta 2, TNF-alpha, TGS5, tie 2, TIM-1, tn Ag, TRAC, TRAIL-R1, TRAIL-R2, TROP-2, TRP-2, TRPV1, TSHR, TRP-1, TSHR, Tumor antigen CTAA 16.88.88, tyrosinase, UPK2, VEGF, VEGFR1, VEGFR2, vimentin, WT1, XAGE1, B7H3, LAG-3 (CD 223), PD-1/PD-L1, BTLA, TIM-3, AA2R, CEACAM1, SIRPalpha, CD200R, c-met; More preferably, the surface antigen is selected from the group consisting of HER2, B7H3, CD20, CD38, CD33, BCMA, CD138, EGFR, FGFR4, GD2, PDGFR, TEM1/CD248, TROP-2, PD-L1, CD123, c-met; Preferably, the antibody is selected from rituximab, trastuzumab, gemtuzumab, pertuzumab, obitumumab, ofatuzumab, olatuzumab, antuximab, ib Sha Tuo ximab, sha Xituo bead mab, U3-1784, darimumab, STI-6129, OR000213, rituximab, huMy9-6, bei Lantan mab, infliximab, cetuximab, dituximab, anti-CD 38 A2 antibody, huAT/5 antibody, alemtuzumab, timomumab, tositumumab, bevacizumab, panitumumab, trabeclomab, cetuximab, ago Fu Shan antibody, valtuzumab, anti-B7-H3 antibody.
  9. 9. The conjugate according to claim 7 or 8, characterized in that the conjugate is selected from the following structures:
  10. 10. the conjugate of claim 9, wherein the conjugate has a structure represented by L-1, wherein the Bm moiety is Herceptin, n=5-6, or, The conjugate has a structure shown as L-4, wherein Bm part is Herceptin, n=3-4, 5-6,7-8,8-9, or, The conjugate has a structure represented by L-4, wherein the Bm moiety is Ifinatamab, n=3-4, 6-7, or, The conjugate has a structure shown as L-3, wherein Bm part is Herceptin, n=3-4, 4-5,7-8, or, The conjugate has a structure shown as L-5, wherein Bm part is Herceptin, n=2-3, or, The conjugate has a structure shown as L-6, wherein Bm part is Herceptin, n=1-3, or, The conjugate has a structure shown as L-52, wherein Bm part is Herceptin, n=3-4, or, The conjugate has a structure shown as L-53, wherein Bm part is Herceptin, n=3-4, or, The conjugate has a structure shown as L-54, wherein Bm part is Herceptin, n=3-4, or, The conjugate has a structure shown as L-55, wherein the Bm part is Herceptin, and n=2-3.
  11. 11. A pharmaceutical composition comprising a compound of any one of claims 1-6, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuteride thereof, or a conjugate of any one of claims 7-10, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuteride thereof, and one or more pharmaceutically acceptable excipients.
  12. 12. Use of a compound as defined in any one of claims 1 to 6 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuteride thereof, or a conjugate as defined in any one of claims 7 to 10 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuteride thereof, or a pharmaceutical composition as defined in claim 11, for the preparation of a medicament for the prophylaxis and/or treatment of a disease; Preferably, the disease is selected from the group consisting of tumors, cardiovascular and cerebrovascular diseases, and diseases associated with viral infections; Preferably, the tumour is selected from liver cancer, lung cancer, stomach cancer, breast cancer, colon cancer, bile duct cancer, bladder cancer, head and neck cancer, cervical cancer, ovarian cancer, prostate cancer, thyroid cancer, squamous cell carcinoma, lymphoma, sarcoma, acute myelogenous leukemia, chronic lymphocytic leukemia, multiple myeloma, myelodysplastic syndrome.

Description

Targeted protein degradation agent, and pharmaceutical composition and application thereof Technical Field The invention belongs to the technical field of biological medicines, and particularly relates to a targeted protein degradation agent, a pharmaceutical composition thereof and application thereof. Background Targeting protein degradation (Targeted Protein Degradation, TPD) is a completely new breakthrough drug development strategy that exploits the intracellular intrinsic protein degradation pathway to directly degrade pathogenic target proteins. The novel pharmaceutical forms include various types such as PROTAC, molecular gelatin, LYTAC, ATAC, abTAC, ATTEC, AUTAC, AUTOTAC, and the like. The protein degradation targeting chimeric molecule (Proteolysis TARGETING CHIMERAS, PROTAC) is a heterobifunctional small molecule compound consisting of three parts, including a ligand that binds to the target protein, a ligand that recruits the E3 ligase, and a linker that helps anchor the target protein to the E3 ubiquitin ligase to promote its ubiquitination and subsequent proteasome degradation. Molecular Glue (MG) is a small Molecular compound that differs from PROTAC in that it binds to the E3 ligase and alters the shape of the ligase surface so that the ligase can bind to the target protein, resulting in ubiquitination and degradation of the target. The Antibody-conjugated drug (ADC) is formed by coupling monoclonal antibodies targeting tumor specific antigens or tumor related antigens with different numbers of small molecular cytotoxins (or payloads) through linkers, has the dual advantages of high targeting of the monoclonal Antibody drug and high activity of the cytotoxic drug in tumor tissues, and is one of the fastest-developing drug classes in the tumor targeted therapy field in recent years. It has been found that the inherent disadvantages of the targeted protein degrading agents described above can be overcome by using the targeted protein degrading agents as ADC payloads. Therefore, the targeted protein degradation agent has important significance for drug development. Disclosure of Invention In order to overcome the defects in the prior art, the invention discloses a targeted protein degradation agent, a pharmaceutical composition and application thereof. The inventor creatively develops a novel ADC drug formed by coupling a target protein degradation agent with an antibody, and can realize cell-specific target protein degradation. In a first aspect of the invention there is provided a compound, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuteride thereof, said compound having the structure: Wherein, the U is selected from C 0-C10 alkyl, C 3-C10 cycloalkyl, C 6-C10 aryl, 4-10 membered heterocyclic group; V is selected from-O-, -S-, and, B is The C ring is a divalent group attached to the A ring, which is absent or selected from C 3-C10 cycloalkylene, C 6-C10 arylene, 4-10 membered heterocyclylene; X, Y, Z is independently selected from the group consisting of a single bond, C 1-C10 alkylene, - (C 0-C6 alkylene) -O-, - (C 0-C6 alkylene) -S-, - (C 0-C6 alkylene) -C (O) -, - (C 0-C6 alkylene) -C (S) -, - (C 0-C6 alkylene) -N (R B1)-、-(C0-C6 alkylene) -CON (R B1)-、-(C0-C6 alkylene) -N (R B1)CO-、-(C0-C6 alkylene) -SO 2-、-(C0-C6 alkylene) -SO-, - (C 0-C6 alkylene) - (C 3-C10 cycloalkylene) -, - (C 0-C6 alkylene) - (C 6-C10 arylene) -, - (C 0-C6 alkylene) - (4-10 membered heterocyclylene) -, wherein the C 0-C10 alkylene, C 3-C10 cycloalkylene, C 6-C10 arylene, H in the 4-10 membered heterocyclylene group may be optionally substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-C10 alkyl, C 2-C10 alkenyl, C 2-C10 alkynyl, - (C 0-C6 alkylene) - (C 3-C10 cycloalkyl), amino, or a mixture thereof, - (C 0-C6 alkylene) - (C 6-C10 aryl), - (C 0-C6 alkylene) - (4-10 membered heterocyclyl), C 1-C10 haloalkyl, C 1-C10 haloalkoxy, -N (C 0-10 alkyl) (C 0-10 alkyl), -N (C 0-10 alkyl) CO (C 0-10 alkyl), -N (C 0-10 alkyl) CON (C 0-10 alkyl), -N (C 0-10 alkyl) SO 2(C0-10 alkyl), -O (C 0-10 alkyl), -S (C 0-10 alkyl), -SO (C 0-10 alkyl), -SO 2(C0-10 alkyl), -SO 2N(C0-10 alkyl) (C 0-10 alkyl), -COO (C 0-10 alkyl), -OCO (C 0-10 alkyl), -CON (C 0-10 alkyl) (C 0-10 alkyl), -CO (C 0-10 alkyl); The A ring is selected from C 3-C10 cycloalkylene, C 6-C10 arylene, 4-10 membered heterocyclylene, wherein C 3-C10 cycloalkylene, C 6-C10 arylene, H in the 4-10 membered heterocyclylene group may be optionally substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-C10 alkyl, C 2-C10 alkenyl, C 2-C10 alkynyl, - (C 0-C6 alkylene) - (C 3-C10 cycloalkyl), amino, or a mixture thereof, - (C 0-C6 alkylene) - (C 6-C10 aryl), - (C 0-C6 alkylene) - (4-10 membered heterocyclyl), C 1-C10 haloalkyl, C 1-C10 haloalkoxy, - (C 0-C6 alkylene) -N (C 0-10 alkyl) (C 0-10 alkyl), - (C 0-C6 alkylene) -N (C 0-10 alkyl