Search

CN-121986089-A - Preparation method and application of pyridazinone compound as ubiquitin-specific protease 1 inhibitor and application of pyridazinone compound

CN121986089ACN 121986089 ACN121986089 ACN 121986089ACN-121986089-A

Abstract

The invention discloses a preparation method, application and application of a pyridazinone compound serving as an ubiquitin-specific protease 1 inhibitor, and in particular discloses a compound shown in a formula (I), an optical isomer, a tautomer or a pharmaceutically acceptable salt thereof and application of the pyridazinone compound serving as the ubiquitin-specific protease 1 inhibitor.

Inventors

  • ZHANG FEI
  • BIE PINGYAN
  • PENG JIANBIAO

Assignees

  • 上海济煜医药科技股份有限公司

Dates

Publication Date
20260505
Application Date
20240925
Priority Date
20230925

Claims (20)

  1. A compound of formula (I), an optical isomer, a tautomer or a pharmaceutically acceptable salt thereof, Wherein, the Selected from the group consisting of When (when) Selected from the group consisting of When X 1 is selected from N; When (when) Selected from the group consisting of When X 1 is selected from C; X 2 is selected from N and CR 2X ; X 3 is selected from N and CR 3X ; R 2X 、R 3X is each independently selected from H, OH, CN, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, -O-C (=O) -C 1-6 alkyl, -O-C 3-6 cycloalkyl, -C (=o) -C 1-6 alkyl, -C (=o) -O-C 1-6 alkyl, C 1-6 alkylthio, -S (O) 2 -C 1-6 alkyl, -S (O) -C 1-6 alkyl, -S (O) -N (H) -C 1-6 alkyl, NRxR Y 、-C(＝O)NRxR Y and-P (=o) RxR Y , said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, -O-C (=O) C 1-6 alkyl, -O-C 3-6 cycloalkyl, -C (=o) C 1-6 alkyl, -C (=o) O-C 1-6 alkyl, C 1-6 alkylthio, -S (O) 2 C 1-6 alkyl, -S (O) C 1-6 alkyl or-S (O) N (H) -C 1-6 alkyl optionally substituted with 1,2 or 3 OH, NH 2 , Halogen, CN, NO 2 , COOH substitution; r X 、R Y is each independently selected from H, OH, CN, halogen, CN, NO 2 、COOH、C 1-6 alkyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 cycloalkyl, and 3-9 membered heterocyclyl, said C 1-6 alkyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 cycloalkyl, or 3-9 membered heterocyclyl optionally substituted with 1, 2, or 3H, OH, CN, halogen, CN, NO 2 、COOH、C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, or C 1-6 alkylamino; Or, R X 、R Y together with the nitrogen atom to which it is attached to form a 3-9 membered heterocyclyl or a 5-9 membered heteroaryl, said 3-9 membered heterocyclyl, 5-9 membered heteroaryl optionally substituted with 1,2 or 3 OH, NH 2 , halogen, CN, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl or C 3-6 cycloalkyl-O-; r 2 is selected from phenyl, naphthyl, and 5-9 membered heteroaryl, said phenyl, naphthyl, or 5-9 membered heteroaryl optionally substituted with 1,2,3,4, or 5R'; R' is selected from H, OH, CN, halogen, CN, NO 2 、COOH、C 1-6 alkyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 cycloalkyl and 3-9 membered heterocyclyl, said C 1-6 alkyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 cycloalkyl or 3-9 membered heterocyclyl optionally being substituted with 1, 2 or 3H, OH, CN, halogen, CN, NO 2 、COOH、C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio or C 1-6 alkylamino; L is selected from CR 3 R 4 、NR 3 , O, S, S (=o) and S (=o) 2 ; each R 3 、R 4 is independently selected from H, OH, CN, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, and C 3-6 cycloalkyl, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, or C 3-6 cycloalkyl optionally substituted with 1, 2, or 3 OH, NH 2 , halogen, CN, NO 2 , COOH; Or, R 3 、R 4 taken together with the carbon atom to which it is attached, forms a C 3-6 cycloalkyl, 3-9 membered heterocyclyl, C 6-14 aryl, or 5-9 membered heteroaryl, said C 3-6 cycloalkyl, 3-9 membered heterocyclyl, C 6-14 aryl, or 5-9 membered heteroaryl being optionally substituted with 1, 2, or 3 OH, NH 2 , halogen, CN, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, or C 3-6 cycloalkyl-O-; Ring E is selected from 5-7 membered unsaturated heterocyclyl, C 6-14 aryl, 5-9 membered heteroaryl, said 5-7 membered unsaturated heterocyclyl, C 6-14 aryl, 5-9 membered heteroaryl optionally substituted with 1,2, 3, 4 or 5R'; Ring B is selected from C 6-14 aryl, C 3-9 cycloalkyl, C 5-15 bridged cycloalkyl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, said C 6-14 aryl, C 3-9 cycloalkyl, C 5-15 bridged cycloalkyl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl optionally substituted with 1, 2 or 3R 5 ; R 5 is selected from H, CN, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl, C 3-9 cycloalkyl-O-, C 6-14 aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl-O-, C 6-14 aryl-O-, and 5-9 membered heteroaryl-O-, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl, C 3-9 cycloalkyl-O- C 6-14 aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl-O-, C 6-14 aryl-O-, or 5-9 membered heteroaryl-O-, optionally substituted with 1,2 or 3 OH, CN, halogen, CN, NO 2 、COOH、C 1-6 alkyl, A C 1-6 alkoxy, C 1-6 alkylthio or C 1-6 alkylamino substitution; or, two optionally present R 5 on ring B together with the atoms to which they are attached are joined to form C 3-6 cycloalkyl, 3-9 membered heterocyclyl, C 6-14 aryl or 5-9 membered heteroaryl, said C 3-6 cycloalkyl, 3-9 membered heterocyclyl, C 6-14 aryl or 5-9 membered heteroaryl optionally substituted with 1, 2 or 3 OH, NH 2 , halogen, CN, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl or C 3-6 cycloalkyl-O-; Optionally, R 5 is selected from H, CN, halogen 、-C(＝O)R a 、-C(＝O)OR b 、-NR a R b 、-NR a C(＝O)R b 、-NR a C(＝O)NR a R b 、-S(O) 2 NR a R b 、-C(＝O)NR a R b 、-S(O) 2 R a 、-NR a S(O) 2 R b 、-C 1-6 alkyl-C (=o) NR a R b 、C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-9 cycloalkyl, C 3-9 cycloalkyl-O-, C 6-14 aryl, 5-9 membered heteroaryl, and 3-9 membered heterocyclyl; R a 、R b is each independently selected from H, CN, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl, C 3-9 cycloalkyl-O-, C 6-14 aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 aryl-O-, and 5-9 membered heteroaryl-O-, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl, C 3-9 cycloalkyl-O-, C 6-14 aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 aryl-O-, and 5-9 membered heteroaryl-O-, optionally substituted with 1,2, or 3 OH, NH 2 , halogen, CN, C 1-6 alkyl, C 1-6 heteroalkyl, c 3-6 cycloalkyl or C 3-6 cycloalkyl-O-substitution; The C 1-6 -heteroalkyl, 3-9 membered heterocyclyl, 5-6 membered heterocyclyl, 5-9 membered heteroaryl contains 1,2, 3 or 4 heteroatoms or heteroatomic groups independently selected from-O-, -NH-, -n=, -S-, -C (=o) O-, -S (O) 2 -, and N.
  2. The compound of claim 1, an optical isomer, tautomer or pharmaceutically acceptable salt thereof, having the structure shown below, Wherein, the Y 1 、Y 2 、Y 3 、Y 4 、Y 5 are each independently selected from N or C (R'); each R' is independently selected from H, OH, CN, halogen, CN, NO 2 、COOH、C 1-6 alkyl, C 1-6 heteroalkyl, -S (O) 2 C 1-6 alkyl, C 3-9 cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 cycloalkyl and 3-9 membered heterocyclyl, said C 1-6 alkyl, C 1-6 heteroalkyl, -S (O) 2 C 1-6 alkyl, C 3-9 cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 cycloalkyl or 3-9 membered heterocyclyl optionally being substituted with 1, 2 or 3D, OH, CN, halogen, CN, NO 2 、COOH、C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio or C 1-6 alkylamino.
  3. The compound of claim 1, an optical isomer, tautomer or pharmaceutically acceptable salt thereof, having the structure shown below, Wherein, the R 2A 、R 2B 、R 2C 、R 2D 、R 2E 、R 2F 、R 2G 、R 2H 、R 2I 、R 2J 、R 2K 、R 2L 、R 2M 、R 2N 、R 2O Each independently selected from H, OH, CN, halogen, CN, NO 2 、COOH、C 1-6 alkyl, C 1-6 heteroalkyl, -S (O) 2 C 1-6 alkyl, C 3-9 cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 cycloalkyl and 3-9 membered heterocyclyl, said C 1-6 alkyl, C 1-6 heteroalkyl, -S (O) 2 C 1-6 alkyl, C 3-9 cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 cycloalkyl or 3-9 membered heterocyclyl optionally being substituted with 1, 2 or 3D, OH, CN, halogen, CN, NO 2 、COOH、C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio or C 1-6 alkylamino.
  4. The compound of claim 1, an optical isomer, tautomer or pharmaceutically acceptable salt thereof, having the structure shown below, Wherein, the Each X 5 、X 6 、X 7 、X 8 is independently selected from N and CR B ; r B is selected from H, OH, CN, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, and C 3-6 cycloalkyl, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, or C 3-6 cycloalkyl being optionally substituted with 1, 2, or 3 OH, NH 2 , halogen, CN, NO 2 , COOH.
  5. The compound of claim 1, an optical isomer, tautomer or pharmaceutically acceptable salt thereof, having the structure shown below, Wherein, the R 5A 、R 5B 、R 5C 、R 5D 、R 5E 、R 5F 、R 5G 、R 5H 、R 5I 、R 5J 、R 5K 、R 5L 、R 5M 、R 5N 、R 5O 、R 5P Each independently selected from H, CN, halogen 、-C(＝O)R a 、-C(＝O)OR b 、-NR a R b 、-NR a C(＝O)R b 、-NR a C(＝O)NR a R b 、-S(O) 2 NR a R b 、-C(＝O)NR a R b 、-S(O) 2 R a 、-NR a S(O) 2 R b 、-C 1-6 alkyl-C (=O) NR a R b 、C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl, C 3-9 cycloalkyl-O-, C 6-14 aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl-O-, C 6-14 -aryl-O-, and 5-9 membered heteroaryl-O-, said -C(＝O)R a 、-C(＝O)OR b 、-NR a R b 、-NR a C(＝O)R b 、-NR a C(＝O)NR a R b 、-S(O) 2 NR a R b 、-C(＝O)NR a R b 、-S(O) 2 R a 、-NR a S(O) 2 R b 、-C 1-6 alkyl-C (=o) NR a R b 、C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl, C 3-9 cycloalkyl-O-, C 6-14 aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl-O-, C 6-14 aryl-O-, or 5-9 membered heteroaryl-O-, optionally substituted with 1,2, or 3D, OH, CN, halogen, CN, NO 2 、COOH、C 1-6 alkyl, C 1-6 alkoxy, A C 1-6 alkylthio or C 1-6 alkylamino substitution; R a 、R b is each independently selected from H, CN, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl, C 3-9 cycloalkyl-O-, C 6-14 aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 aryl-O-, and 5-9 membered heteroaryl-O-, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl, C 3-9 cycloalkyl-O-, C 6-14 aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 aryl-O-, and 5-9 membered heteroaryl-O-, optionally substituted with 1,2, or 3 OH, NH 2 , halogen, CN, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl or C 3-6 cycloalkyl-O-substitution.
  6. The compound of claim 1, an optical isomer, tautomer or pharmaceutically acceptable salt thereof, having the structure shown below, Wherein, the Each X 5 、X 6 、X 7 、T 1 、T 2 is independently selected from N and CR B ; R B is selected from H, OH, CN, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, and C 3-6 cycloalkyl, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, or C 3-6 cycloalkyl being optionally substituted with 1, 2, or 3 OH, NH 2 , halogen, CN, NO 2 , COOH; J. K, M are each independently selected from CR 7A R 7B 、NR 7A , C (=o), O, S, S (O), and S (O) 2 ; Each R 7A 、R 7B is independently selected from H, OH, CN, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, and C 3-6 cycloalkyl, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, or C 3-6 cycloalkyl optionally substituted with 1, 2, or 3 OH, NH 2 , halogen, CN, NO 2 , COOH; Ring a is selected from C 3-9 cycloalkyl, C 6-14 aryl, 5-9 membered heteroaryl, and 3-9 membered heterocyclyl, said C 3-9 cycloalkyl, C 6-14 aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl optionally substituted with 1, 2, or 3R 6 ; R 6 is selected from H, CN, halogen 、-C(＝O)R a 、-C(＝O)OR b 、-NR a R b 、-NR a C(＝O)R b 、-NR a C(＝O)NR a R b 、- S(O) 2 NR a R b 、-C(＝O)NR a R b 、-S(O) 2 R a 、-NR a S(O) 2 R b 、-C 1-6 Alkyl-C (=O) NR a R b 、C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl, C 3-9 cycloalkyl-O-, C 6-14 aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl-O-, C 6-14 aryl-O-, and 5-9 membered heteroaryl-O-, said -C(＝O)R a 、-C(＝O)OR b 、-NR a R b 、-NR a C(＝O)R b 、-NR a C(＝O)NR a R b 、-S(O) 2 NR a R b 、-C(＝O)NR a R b 、-S(O) 2 R a 、-NR a S(O) 2 R b 、-C 1-6 alkyl-C (=O) NR a R b 、C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl, C 3-9 cycloalkyl-O- C 6-14 aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl-O-, C 6-14 aryl-O-, or 5-9 membered heteroaryl-O-, optionally substituted with 1,2 or 3D, OH, CN, halogen, CN, NO 2 、COOH、C 1-6 alkyl, A C 1-6 alkoxy, C 1-6 alkylthio or C 1-6 alkylamino substitution; or, two optionally present R 6 on ring A taken together with the carbon atom to which they are attached form C 3-6 cycloalkyl, 3-9 membered heterocyclyl, C 6-14 aryl or 5-9 membered heteroaryl, said C 3-6 cycloalkyl, 3-9 membered heterocyclyl, C 6-14 aryl or 5-9 membered heteroaryl optionally substituted with 1, 2 or 3 OH, NH 2 , halogen, CN, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl or C 3-6 cycloalkyl-O-; R a 、R b is each independently selected from H, CN, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl, C 3-9 cycloalkyl-O-, C 6-14 aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 aryl-O-, and 5-9 membered heteroaryl-O-, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl, C 3-9 cycloalkyl-O-, C 6-14 aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 aryl-O-, and 5-9 membered heteroaryl-O-, optionally substituted with 1,2, or 3 OH, NH 2 , halogen, CN, C 1-6 alkyl, C 1-6 heteroalkyl, c 3-6 cycloalkyl or C 3-6 cycloalkyl-O-substitution; The C 1-6 -heteroalkyl, 3-9 membered heterocyclyl, 5-6 membered heteroaryl, 5-9 membered heteroaryl contains 1,2,3 or 4 heteroatoms or heteroatom groups independently selected from-O-, -NH-, -n=, -S-, -C (=o) O-, -S (O) 2 -, and N.
  7. The compound of claim 1, an optical isomer, tautomer or pharmaceutically acceptable salt thereof, having the structure shown below, Wherein, the R 5A 、R 5B 、R 5C 、R 5D 、R 5E 、R 5F 、R 5G 、R 5H 、R 5I 、R 5J 、R 5K 、R 5L 、R 5M 、R 5N 、R 5O 、R 5P Each independently selected from H, CN, halogen 、-C(＝O)R a 、-C(＝O)OR b 、-NR a R b 、-NR a C(＝O)R b 、-NR a C(＝O)NR a R b 、-S(O) 2 NR a R b 、-C(＝O)NR a R b 、-S(O) 2 R a 、-NR a S(O) 2 R b 、-C 1-6 alkyl-C (=O) NR a R b 、C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl, C 3-9 cycloalkyl-O-, C 6-14 aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl-O-, C 6-14 -aryl-O-, and 5-9 membered heteroaryl-O-, said -C(＝O)R a 、-C(＝O)OR b 、-NR a R b 、-NR a C(＝O)R b 、-NR a C(＝O)NR a R b 、-S(O) 2 NR a R b 、-C(＝O)NR a R b 、-S(O) 2 R a 、-NR a S(O) 2 R b 、-C 1-6 alkyl-C (=o) NR a R b 、C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl, C 3-9 cycloalkyl-O-, C 6-14 aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl-O-, C 6-14 aryl-O-, or 5-9 membered heteroaryl-O-, optionally substituted with 1,2, or 3D, OH, CN, halogen, CN, NO 2 、COOH、C 1-6 alkyl, C 1-6 alkoxy, A C 1-6 alkylthio or C 1-6 alkylamino substitution; R a 、R b is each independently selected from H, CN, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl, C 3-9 cycloalkyl-O-, C 6-14 aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 aryl-O-, and 5-9 membered heteroaryl-O-, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl, C 3-9 cycloalkyl, C 6-14 aryl, 5-to 9-membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 aryl-O-, and 5-9 membered heteroaryl-O-, optionally substituted with 1,2, or 3 OH, NH 2 , halogen, CN, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl or C 3-6 cycloalkyl-O-substitution.
  8. The compound of claim 1, an optical isomer, tautomer or pharmaceutically acceptable salt thereof, having the structure shown below, Wherein, the X 4A 、X 5A are each independently selected from N or C (R'); x 4B 、X 5B are each independently selected from O, S, N (R ') or CR ' R '; R ', R' are each independently selected from H, OH, CN, halogen, CN, NO 2 、COOH、C 1-6 alkyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 cycloalkyl and 3-9 membered heterocyclyl, said C 1-6 alkyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 cycloalkyl or 3-9 membered heterocyclyl optionally being substituted with 1, 2 or 3H, OH, CN, halogen, CN, NO 2 、COOH、C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio or C 1-6 alkylamino.
  9. The compound of claim 1, an optical isomer, tautomer or pharmaceutically acceptable salt thereof, having the structure shown below, Wherein, the X 4A 、X 5A 、X 6A are each independently selected from N or C (R'); X 4B 、X 5B 、X 6B are each independently selected from O, S, N (R ') or CR ' R '; R ', R' are each independently selected from H, OH, CN, halogen, CN, NO 2 、COOH、C 1-6 alkyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 cycloalkyl and 3-9 membered heterocyclyl, said C 1-6 alkyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 cycloalkyl or 3-9 membered heterocyclyl optionally being substituted with 1, 2 or 3H, OH, CN, halogen, CN, NO 2 、COOH、C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio or C 1-6 alkylamino.
  10. The compound of claim 1, an optical isomer, tautomer or pharmaceutically acceptable salt thereof, having the structure shown below, Wherein, the X 5B 、X 6B 、X 7B are each independently selected from O, S, N (R ') or CR ' R '; R ', R' are each independently selected from H, OH, CN, halogen, CN, NO 2 、COOH、C 1-6 alkyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 cycloalkyl and 3-9 membered heterocyclyl, said C 1-6 alkyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 cycloalkyl or 3-9 membered heterocyclyl optionally being substituted with 1, 2 or 3H, OH, CN, halogen, CN, NO 2 、COOH、C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio or C 1-6 alkylamino.
  11. The compound of claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from the group consisting of
  12. The compound of any one of claims 1,4, 5, 6, 7, 8, 9, or 10, an optical isomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2 is selected from phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrrolyl, and pyrazolyl, said phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrrolyl, or pyrazolyl being optionally substituted with 1,2,3, or 4R'; Optionally, each R' is independently selected from H, OH, CN, halogen, CN, NO 2 、COOH、C 1-6 alkyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 cycloalkyl and 3-9 membered heterocyclyl, said C 1-6 alkyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 cycloalkyl or 3-9 membered heterocyclyl optionally being substituted with 1, 2 or 3H, OH, CN, halogen, CN, NO 2 、COOH、C 1- 6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio or C 1-6 alkylamino; Optionally, each R' is independently selected from H, CN, methyl, ethyl, -OCH 3 、-OCH 2 CH 3 、-OCD 3 、-OCHF 2 、-OCH 3 、-SCH 3 , Optionally, R 2 is selected from R 2A 、R 2B 、R 2C 、R 2D 、R 2E 、R 2F 、R 2G 、R 2H 、R 2I 、R 2J 、R 2K 、R 2L 、R 2M 、R 2N 、R 2O Selected from the group consisting of H, OH, CN, halogen, CN, NO 2 、COOH、C 1-6 alkyl, C 1-6 heteroalkyl, -S (O) 2 C 1-6 alkyl, C 3-9 cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3- 9 cycloalkyl and 3-9 membered heterocyclyl, said C 1-6 alkyl, C 1-6 heteroalkyl, -S (O) 2 C 1-6 alkyl, C 3-9 cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 cycloalkyl or 3-9 membered heterocyclyl optionally being substituted with 1,2 or 3D, OH, CN, halogen, CN, NO 2 、COOH、C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio or C 1-6 alkylamino; Optionally, R 2 is selected from
  13. The compound of any one of claims 1-10, an optical isomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L is selected from N R 3 、CR 3 R 4 ; Each R 3 、R 4 is independently selected from H, OH, CN, halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 alkylamino, C 2-3 alkenyl, C 2-3 alkynyl, and C 3-6 cycloalkyl, said C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 alkylamino, C 2-3 alkenyl, C 2-3 alkynyl, or C 3-6 cycloalkyl being optionally substituted with 1,2, or 3 OH, NH 2 , halogen, CN, NO 2 , or COOH; optionally, each R 3 、R 4 is independently selected from H, OH, CN, halogen, methyl, ethyl, and propyl.
  14. The compound of any one of claims 1-4, 8-10, an optical isomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 5 is selected from H, CN, halogen 、-C(＝O)R a 、-C(＝O)OR b 、-NR a R b 、-NR a C(＝O)R b 、-NR a C(＝O)NR a R b 、-S(O) 2 NR a R b 、-C(＝O)NR a R b 、-S(O) 2 R a 、-NR a S(O) 2 R b 、-C 1-6 alkyl-C (=o) NR a R b 、C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, 5-6 membered heteroaryl, and 5-6 membered heteroaryl and 5-6 membered heterocyclyl, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, 5-6 membered heteroaryl, or 5-6 membered heteroaryl and 5-6 membered heterocyclyl optionally substituted with 1, 2, or 3D, OH, CN, halogen, CN, NO 2 、COOH、C 1- 6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, or C 1-6 alkylamino; Optionally, R 5 is selected from H, CN, halogen 、-C(＝O)R a 、-C(＝O)OR b 、-NR a R b 、-NR a C(＝O)R b 、-NR a C(＝O)NR a R b 、-S(O) 2 NR a R b 、-C(＝O)NR a R b 、-S(O) 2 R a 、-NR a S(O) 2 R b 、-C 1-6 alkyl-C (=O) NR a R b 、C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, R 5A 、R 5B 、R 5C 、R 5D 、R 5E 、R 5F 、R 5G 、R 5H 、R 5I 、R 5J 、R 5K 、R 5L 、R 5M 、R 5N 、R 5O 、R 5P Each independently selected from H, CN, halogen 、-C(＝O)R a 、-C(＝O)OR b 、-NR a R b 、-NR a C(＝O)R b 、-NR a C(＝O)NR a R b 、-S(O) 2 NR a R b 、-C(＝O)NR a R b 、-S(O) 2 R a 、-NR a S(O) 2 R b 、-C 1-6 alkyl-C (=O) NR a R b 、C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl, C 3-9 cycloalkyl-O-, C 6-14 aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl-O-, C 6-14 -aryl-O-, and 5-9 membered heteroaryl-O-, said -C(＝O)R a 、-C(＝O)OR b 、-NR a R b 、-NR a C(＝O)R b 、-NR a C(＝O)NR a R b 、-S(O) 2 NR a R b 、-C(＝O)NR a R b 、-S(O) 2 R a 、-NR a S(O) 2 R b 、-C 1-6 alkyl-C (=o) NR a R b 、C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl, C 3-9 cycloalkyl-O-, C 6-14 aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl-O-, C 6-14 aryl-O-, or 5-9 membered heteroaryl-O-, optionally substituted with 1,2, or 3D, OH, CN, halogen, CN, NO 2 、COOH、C 1-6 alkyl, C 1-6 alkoxy, A C 1-6 alkylthio or C 1-6 alkylamino substitution; R a 、R b is each independently selected from H, CN, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl, C 3- 9 cycloalkyl-O-, C 6-14 aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl-O-, C 6-14 -aryl-O-, and 5-9 membered heteroaryl-O-, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl, C 3-9 cycloalkyl-O-, C 6-14 aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 aryl-O-, and 5-9 membered heteroaryl-O-, optionally substituted with 1,2, or 3 OH, NH 2 , halogen, CN, C 1-6 alkyl, C 1-6 heteroalkyl, c 3-6 cycloalkyl or C 3-6 cycloalkyl-O-substitution; Optionally ,R 5A 、R 5B 、R 5C 、R 5D 、R 5E 、R 5F 、R 5G 、R 5H 、R 5I 、R 5J 、R 5K 、R 5L 、R 5M 、R 5N 、R 5O 、R 5P are each independently selected from H, CN, halogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl-O- 3-6 membered heterocyclyl-O-, C 3-6 cycloalkyl, 3-6 membered heterocyclyl and-C 1-6 alkyl-C (=o) N (C 1-6 alkyl) 2 , said C 1-6 alkyl, C 1-6 Heteroalkyl, C 3-6 cycloalkyl-O-, 3-6 membered heterocyclyl-O-, C 3-6 cycloalkyl, 3-6 membered heterocyclyl or-C 1-6 alkyl-C (=O) N (C 1-6 alkyl) 2 is optionally substituted with 1, 2 or 3D, OH, CN, halogen, CN, NO 2 、COOH、C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio or C 1-6 alkylamino substitutions; Optionally ,R 5A 、R 5B 、R 5C 、R 5D 、R 5E 、R 5F 、R 5G 、R 5H 、R 5I 、R 5J 、R 5K 、R 5L 、R 5M 、R 5N 、R 5O 、R 5P is each independently selected from H, CN, halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 alkylamino, C 3-6 cycloalkyl-O-, 3-6 membered heterocyclyl-O-, C 3-6 cycloalkyl, 3-6 membered heteroalkyl and-C 1-3 alkyl-C (=o) N (C 1-3 alkyl) 2 , said C 1-3 alkylthio, c 1-3 alkylamino, C 3-6 cycloalkyl-O-, 3-6 membered heterocyclyl-O-, C 3-6 cycloalkyl, 3-6 membered heterocyclyl or-C 1-3 alkyl-C (=O) N (C 1-3 alkyl) 2 is optionally substituted with 1, 2 or 3D, OH, CN, halogen, CN, NO 2 、COOH、C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio or C 1-6 alkylamino substitutions; Optionally ,R 5A 、R 5B 、R 5C 、R 5D 、R 5E 、R 5F 、R 5G 、R 5H 、R 5I 、R 5J 、R 5K 、R 5L 、R 5M 、R 5N 、R 5O 、R 5P are each independently selected from H, CN, halogen, OCH 3 、OCH 2 CH 3 、CF 3 、CHF 2 、CD 3 , methyl, ethyl, Optionally, R 5 is selected from
  15. The compound according to any one of claims 1 to 6, an optical isomer, a tautomer or a pharmaceutically acceptable salt thereof, having the structure shown below, Wherein, the R 6A 、R 6B 、R 6C 、R 6D 、R 6E 、R 6F 、R 6G is each independently selected from H, CN, halogen 、-C(＝O)R a 、-C(＝O)OR b 、-NR a R b 、-NR a C(＝O)R b 、-NR a C(＝O)NR a R b 、-S(O) 2 NR a R b 、-C(＝O)NR a R b 、-S(O) 2 R a 、-NR a S(O) 2 R b 、-C 1-6 alkyl-C (=O) NR a R b 、C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl, C 3-9 cycloalkyl-O-, C 6-14 aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl-O-, C 6-14 -aryl-O-, and 5-9 membered heteroaryl-O-, said -C(＝O)R a 、-C(＝O)OR b 、-NR a R b 、-NR a C(＝O)R b 、-NR a C(＝O)NR a R b 、-S(O) 2 NR a R b 、-C(＝O)NR a R b 、-S(O) 2 R a 、-NR a S(O) 2 R b 、-C 1-6 alkyl-C (=o) NR a R b 、C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl, C 3-9 cycloalkyl-O-, C 6-14 aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl-O-, C 6-14 aryl-O-, or 5-9 membered heteroaryl-O-, optionally substituted with 1,2, or 3D, OH, CN, halogen, CN, NO 2 、COOH、C 1-6 alkyl, C 1-6 alkoxy, A C 1-6 alkylthio or C 1-6 alkylamino substitution; R a 、R b is each independently selected from H, CN, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl, C 3- 9 cycloalkyl-O-, C 6-14 aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl-O-, C 6-14 -aryl-O-, and 5-9 membered heteroaryl-O-, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl, C 3-9 cycloalkyl-O-, C 6-14 aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 aryl-O-, and 5-9 membered heteroaryl-O-, optionally substituted with 1,2, or 3 OH, NH 2 , halogen, CN, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl or C 3-6 cycloalkyl-O-substitution.
  16. The compound of claim 6, an optical isomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the structural unit Selected from the group consisting of R 6A 、R 6B 、R 6C 、R 6D 、R 6E 、R 6F 、R 6G is each independently selected from H, CN, halogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl-O- 3-6 membered heterocyclyl-O-, C 3-6 cycloalkyl, 3-6 membered heterocyclyl and-C 1-6 alkyl-C (=o) N (C 1-6 alkyl) 2 , said C 1-6 alkyl, C 1- 6 heteroalkyl, C 3-6 cycloalkyl-O-, 3-6 membered heterocyclyl-O-, C 3-6 cycloalkyl, 3-6 membered heterocyclyl or-C 1-6 alkyl-C (=o) N (C 1-6 alkyl) 2 optionally substituted with 1, 2 or 3D, OH, CN, halogen, CN, NO 2 、COOH、C 1-6 alkyl, A C 1-6 alkoxy, C 1-6 alkylthio or C 1-6 alkylamino substitution; Optionally, R 6A 、R 6B 、R 6C 、R 6D 、R 6E 、R 6F 、R 6G is each independently selected from H, CN, halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 alkylamino, C 3-6 cycloalkyl-O-, 3-6 membered heterocyclyl-O-, C 3-6 cycloalkyl, 3-6 membered heteroalkyl and-C 1-3 alkyl-C (=o) N (C 1- 3 alkyl) 2 , said C 1-3 alkylthio, c 1-3 alkylamino, C 3-6 cycloalkyl-O-, 3-6 membered heterocyclyl-O-, C 3-6 cycloalkyl, 3-6 membered heterocyclyl or-C 1-3 alkyl-C (=O) N (C 1-3 alkyl) 2 is optionally substituted with 1, 2 or 3D, OH, CN, halogen, CN, NO 2 、COOH、C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio or C 1-6 alkylamino substitutions; Optionally, each R 6A 、R 6B 、R 6C 、R 6D 、R 6E 、R 6F 、R 6G is independently selected from H, CN, halogen, OCH 3 、OCH 2 CH 3 、CF 3 、CHF 2 、CD 3 , methyl, ethyl, Optionally, the composition may be used in combination with, Selected from the group consisting of
  17. The compound of claim 6, an optical isomer, tautomer or pharmaceutically acceptable salt thereof, wherein, J. K, M are each independently selected from NR 7A 、CR 7A R 7B , C (=o) and O; Each R 7A 、R 7B is independently selected from H, OH, CN, halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 alkylamino, C 2- 3 alkenyl, C 2-3 alkynyl, and C 3-6 cycloalkyl, said C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 alkylamino, C 2-3 alkenyl, C 2-3 alkynyl, or C 3-6 cycloalkyl being optionally substituted with 1,2, or 3 OH, NH 2 , halogen, CN, NO 2 , or COOH; Optionally, each R 7A 、R 7B is independently selected from H, OH, CN, halogen, methyl, ethyl, and propyl.
  18. The compound of claim 6, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from the group consisting of R 6A 、R 6B 、R 6C 、R 6D is each independently selected from H, CN, halogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl-O- 3-6 membered heterocyclyl-O-, C 3-6 cycloalkyl, 3-6 membered heterocyclyl and-C 1-6 alkyl-C (=o) N (C 1-6 alkyl) 2 , said C 1-6 alkyl, C 1-6 Heteroalkyl, C 3-6 cycloalkyl-O-, 3-6 membered heterocyclyl-O-, C 3-6 cycloalkyl, 3-6 membered heterocyclyl or-C 1-6 alkyl-C (=O) N (C 1-6 alkyl) 2 is optionally substituted with 1, 2 or 3D, OH, CN, halogen, CN, NO 2 、COOH、C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio or C 1-6 alkylamino substitutions; optionally, a structural unit Selected from the group consisting of
  19. A compound of the formula, an optical isomer, a tautomer or a pharmaceutically acceptable salt thereof, selected from:
  20. the use of a compound according to any one of claims 1-19, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of a disease associated with USP1 activity or expression level.

Description

Preparation method and application of pyridazinone compound as ubiquitin-specific protease 1 inhibitor and application of pyridazinone compound The present application claims the following priorities: CN202311252269.4, application day 2023, month 09, 25; CN202311534440.0, application day 2023, 11, 16; CN202410155795.7, application day 2024, 02; CN202410981590.4, application day 2024, month 07, 19. Technical Field The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method, application and application of a pyridazinone compound serving as an ubiquitin-specific protease 1 inhibitor. Background Ubiquitination is a reversible process involving the Deubiquitinase (DUB) family, which regulates a variety of cellular processes by the deconjugation of ubiquitin from a substrate. DUBs are encoded by approximately 100 human genes and are divided into 6 families, with the largest family being ubiquitin-specific proteases (USPs) with more than 50 members. DUBs and their substrate proteins are often deregulated in cancer, supporting the hypothesis that targeted specific DUB family members may lead to anti-tumor activity by enhancing ubiquitination and subsequent degradation of the activity of oncogenic substrates and other key proteins involved in tumor growth, survival, differentiation and maintenance of the tumor microenvironment. USP1 is a cysteine isopeptidase of the USP subfamily of DUBs. Full length human USP1 consists of 785 amino acids, including the catalytic triplet consisting of Cys90, his593 and Asp 751. USP1 de-ubiquitination is involved in a variety of cellular targets for different processes related to cancer. For example, USP1 deubiquitination cross-lesion synthesis (TLS) is a key protein PCNA (proliferating cell nuclear antigen) and Fancnia (FA) is a key protein FANCD2 (fancnia group complement D2) in the FA pathway. Inhibition of USP1 with small molecule inhibitors therefore has potential as a therapeutic approach for the treatment of cancer and other disorders. For the above reasons, there is a considerable unmet need for potent small molecule inhibitors of USP 1. Disclosure of Invention In one aspect of the present invention, the present invention provides a compound of formula (I), an optical isomer, a tautomer thereof or a pharmaceutically acceptable salt thereof, Wherein, the Selected from the group consisting of When (when)Selected from the group consisting ofWhen X 1 is selected from N; When (when) Selected from the group consisting ofWhen X 1 is selected from C; X 2 is selected from N and CR 2X; X 3 is selected from N and CR 3X; R 2X、R3X is each independently selected from H, OH, CN, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, c 3-6 cycloalkyl, C 1-6 alkoxy, -O-C (=O) -C 1-6 alkyl, C 3-6 cycloalkyl-O-), -C (=o) -C 1-6 alkyl, -C (=o) -O-C 1-6 alkyl, C 1-6 alkylthio, -S (O) 2-C1-6 alkyl, -S (O) -C 1-6 alkyl, -S (O) -N (H) -C 1-6 alkyl, NRxR Y、-C(＝O)NRxRY and-P (=o) RxR Y, The C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, -O-C (=o) C 1-6 alkyl, C 3-6 cycloalkyl-O-, -C (=o) C 1-6 alkyl, -C (=o) O-C 1-6 alkyl, C 1-6 alkylthio, -S (O) 2C1-6 alkyl, -S (O) C 1-6 alkyl or-S (O) N (H) -C 1-6 alkyl is optionally substituted by 1, 2 or 3 OH, NH 2, halogen, CN, NO 2, COOH substitutions; r X、RY is each independently selected from H, OH, CN, halogen, CN, NO 2、COOH、C1-6 alkyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 cycloalkyl, and 3-9 membered heterocyclyl, said C 1-6 alkyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 cycloalkyl, or 3-9 membered heterocyclyl optionally substituted with 1, 2, or 3H, OH, CN, halogen, CN, NO 2、COOH、C1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, or C 1-6 alkylamino; Or, R X、RY together with the nitrogen atom to which it is attached to form a 3-9 membered heterocyclyl or a 5-9 membered heteroaryl, said 3-9 membered heterocyclyl, 5-9 membered heteroaryl optionally substituted with 1,2 or 3 OH, NH 2, halogen, CN, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl or C 3-6 cycloalkyl-O-; r 2 is selected from phenyl, naphthyl, and 5-9 membered heteroaryl, said phenyl, naphthyl, or 5-9 membered heteroaryl optionally substituted with 1,2,3,4, or 5R'; R' is selected from H, OH, CN, halogen, CN, NO 2、COOH、C1-6 alkyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 cycloalkyl and 3-9 membered heterocyclyl, said C 1-6 alkyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 cycloalkyl or 3-9 membered heterocyclyl optionally being substituted with 1, 2 or 3H, OH, CN, halogen, CN, NO 2、COOH、C1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio or C 1-6 alkylamino; L is selected from CR 3R4、NR3, O, S, S (=o) and S (=o) 2; each R 3、R4 is independently selected from H, OH, CN, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, and C 3-6 cycloalkyl, said C 1-6 alkyl, C 2-6