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CA-3191362-C - PYRAZOLOPYRIDAZINONE COMPOUND, AND PHARMACEUTICAL COMPOSITION AND USE THEREOF

CA3191362CCA 3191362 CCA3191362 CCA 3191362CCA-3191362-C

Abstract

Provided in the present application are a compound represented by formula (I), a pharmaceutical composition containing the compound, and the use thereof. The compound represented by formula (I) of the present application has a good effect in terms of inhibiting the activity of HPK1.

Inventors

  • Gongping Duan
  • Xingmin Zhang
  • Zhihua WANG
  • Xianglong Wei
  • Min Li

Assignees

  • BROADENBIO CO., LTD.

Dates

Publication Date
20260505
Application Date
20211103
Priority Date
20201103

Claims (18)

  1. 107 Claims 1. A compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, isotope labeled compound, or isomer thereof, wherein, R1 is selected from the group consisting of: 1) hydrogen, halogen, cyano, -C(=O)NRaRb, -ORa and -NRaRb; 2) C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-8 cycloalkyl and 3- to 8-membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3 or 4 substituents independently selected from R11; Ra and Rb are each independently selected from the group consisting of: 1) hydrogen; 2) C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 monocyclic cycloalkyl, and 3- to 6-membered aliphatic monocyclic heterocyclyl, unsubstituted or optionally substituted with 1, 2, or 3 substituents independently selected from R11; or Ra and Rb attached to the same nitrogen atom, together with the nitrogen atom, form a 3-6 membered aliphatic monocyclic heterocyclyl, unsubstituted or optionally substituted with 1, 2 or 3 substituents independently selected from R11; R11 is selected from the group consisting of fluorine, chlorine, cyano, C1-3 alkyl and hydroxyl; CyA is selected from 6- to 10-membered aryl or 5- to 10-membered heteroaryl, unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R12; R12 is selected from the group consisting of: 1) oxo, halogen, cyano, -C(=O)Ra2, -C(=O)ORa2, -C(=O)NRa2Rb2, -C(=NRd2)NRa2Rb2, - ORa2, -OC(=O)Ra2, -OC(=O)ORc2, -OC(=O)NRa2Rb2, -SRa2, -S(=O)Rc2, -S(=O)2Rc2, sulfonic acid group, -S(=O)NRa2Rb2, -S(=O)2NRa2Rb2, -S(=O)(=NRd2)Rc2, -NRa2Rb2, -NRa2C(=O)Rb2, - NRa2C(=O)ORc2, -NRe2C(=O)NRa2Rb2, -NRe2C(=NRd2)NRa2Rb2, -NRa2S(=O)2Rc2, - NRe2S(=O)2NRa2Rb2, nitro, -PRc2Rf2, -P(=O)Rc2Rf2 and phosphonic acid group; 108 2) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C3-12 cycloalkyl and 3- to 12-membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3, 4, 5 or 6 substituents independently selected from R22; 3) the two R12 substituents attached to two adjacent ring-forming atoms on the aryl or heteroaryl group of CyA, respectively, together with the two said ring-forming atoms, form a C5- 12 alicyclyl or a 5- to 12-membered aliphatic heterocyclyl, unsubstituted or optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R22; Ra2, Rb2 and Re2 are each independently selected from the group consisting of: 1) hydrogen; 2) C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, 5-6 membered heteroaryl, C3-12 cycloalkyl and 3-12 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3, 4, 5 or 6 substituents independently selected from R22; or, Ra2 and Rb2 attached to the same nitrogen atom, together with the nitrogen, form a 3-12 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R22; Rc2 and Rf2 are each independently selected from the group consisting of C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, 5-6 membered heteroaryl, C3-12 cycloalkyl and 3-12 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R22; or, Rc2 and Rf2 attached to the same phosphorous atom, together with the phosphorous, form a 3-12 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R22; Rd2 is selected from the group consisting of: 1) hydrogen, cyano, nitro and -S(=O)2RG; 2) C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, 5-6 membered heteroaryl, C3-12 cycloalkyl and 3-12 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R22; R22 is selected from the group consisting of: 1) oxo, halogen, cyano, -C(=O)Ra4, -C(=O)ORa4, -C(=O)NRa4Rb4, -C(=NRd4)NRa4Rb4, - ORa4, -OC(=O)Ra4, -OC(=O)ORc4, -OC(=O)NRa4Rb4, -SRa4, -S(=O)Rc4, -S(=O)2Rc4, sulphonic acid group, -S(=O)NRa4Rb4, -S(=O)2NRa4Rb4, -S(=O)(=NRd4)Rc4, -NRa4Rb4, -NRa4C(=O)Rb4, - NRa4C(=O)ORc4, -NRe4C(=O)NRa4Rb4, -NRe4C(=NRd4)NRa4Rb4, -NRa4S(=O)2Rc4, - 109 NRe4S(=O)2NRa4Rb4, nitro, -PRc4Rf4, -P(=O)Rc4Rf4, phosphonic acid group, and =N-Rd4; 2) C1-6 alkyl, C1-6 alkylene, C2-6 alkenyl, C2-6 alkynyl, phenyl, 5-6 membered heteroaryl, C3- 10 cycloalkyl and 3-10 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R32; Ra4, Rb4 and Re4 are each independently selected from the group consisting of: 1) hydrogen; 2) C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, 5-6 membered heteroaryl, C3-10 cycloalkyl and 3-10 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R32; or, Ra4 and Rb4 attached to the same nitrogen atom, together with the nitrogen, form a 3-10 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R32; Rc4 and Rf4 are each independently selected from the group consisting of C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, 5-6 membered heteroaryl, C3-10 cycloalkyl and 3-10 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R32; or, Rc4 and Rf4 attached to the same phosphorous atom, together with the phosphorous, form a 3-10 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R32; Rd4 is selected from the group consisting of: 1) hydrogen, cyano, nitro, and -S(=O)2RG; 2) C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, 5-6 membered heteroaryl, C3-10 cycloalkyl and 3-10 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R32; R32 is selected from the group consisting of: 1) oxo, halogen, cyano, -C(=O)Ra6, -C(=O)ORa6, -C(=O)NRa6Rb6, -C(=NRd6)NRa6Rb6, - ORa6, -OC(=O)Ra6, -OC(=O)ORc6, -OC(=O)NRa6Rb6, -SRa6, -S(=O)Rc6, -S(=O)2Rc6, sulphonic acid group, -S(=O)NRa6Rb6, -S(=O)2NRa6Rb6, -S(=O)(=NRd6)Rc6, -NRa6Rb6, -NRa6C(=O)Rb6, - NRa6C(=O)ORc6, -NRe6C(=O)NRa6Rb6, -NRe6C(=NRd6)NRa6Rb6, -NRa6S(=O)2Rc6, - NRe6S(=O)2NRa6Rb6, nitro, -PRc6Rf6, -P(=O)Rc6Rf6, phosphonic acid group, and =N-Rd6; 2) C1-4 alkyl, C1-4 alkylene, C2-4 alkenyl, C2-4 alkynyl, phenyl, 5-6 membered heteroaryl, C3- 8 cycloalkyl, and 3-8 membered aliphatic heterocyclyl, unsubstituted or optionally substituted 110 with 1, 2, 3 or 4 substituents independently selected from RG; Ra6, Rb6 and Re6 are each independently selected from the group consisting of: 1) hydrogen; 2) C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, 5-6 membered heteroaryl, C3-8 cycloalkyl, and 3-8 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3 or 4 substituents independently selected from RG; or, Ra6 and Rb6 attached to the same nitrogen atom, together with the nitrogen, form a 3-8 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3 or 4 substituents independently selected from RG; Rc6 and Rf6 are each independently selected from the group consisting of C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, 5-6 membered heteroaryl, C3-8 cycloalkyl, and 3-8 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3 or 4 substituents independently selected from RG; or, Rc6 and Rf6 attached to the same phosphorous atom, together with the phosphorous, form a 3-8 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3 or 4 substituents independently selected from RG; Rd6 is selected from the group consisting of: 1) hydrogen, cyano, nitro, and -S(=O)2RG; 2) C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, 5-6 membered heteroaryl, C3-8 cycloalkyl, and 3-8 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3 or 4 substituents independently selected from RG; CyB is selected from the group consisting of 6-10 membered aryl and 5-10 membered heteroaryl, unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R13; R13 is selected from the group consisting of: 1) oxo, halogen, cyano, -C(=O)Ra3, -C(=O)ORa3, -C(=O)NRa3Rb3, -C(=NRd3)NRa3Rb3, - ORa3, -OC(=O)Ra3, -OC(=O)ORc3, -OC(=O)NRa3Rb3, -SRa3, -S(=O)Rc3, -S(=O)2Rc3, sulphonic acid group, -S(=O)NRa3Rb3, -S(=O)2NRa3Rb3, -S(=O)(=NRd3)Rc3, -NRa3Rb3, -NRa3C(=O)Rb3, - NRa3C(=O)ORc3, -NRe3C(=O)NRa3Rb3, -NRe3C(=NRd3)NRa3Rb3, -NRa3S(=O)2Rc3, - NRe3S(=O)2NRa3Rb3, nitro, -PRc3Rf3, -P(=O)Rc3Rf3, and phosphonic acid group ; 2) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 6-10 membered aryl, 5-10 membered heteroaryl, C3- 12 cycloalkyl, and 3-12 membered aliphatic heterocyclyl, unsubstituted or optionally substituted 111 with 1, 2, 3, 4, 5 or 6 substituents independently selected from R23; 3) two R13 substituents attached to two adjacent ring-forming atoms of the aryl or heteroaryl of CyB respectively, together with the two said ring-forming atoms, form a C5-12 aliphatic cyclyl or a 5-12 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R23; Ra3, Rb3 and Re3 are each independently selected from the group consisting of: 1) hydrogen; 2) C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, 5-6 membered heteroaryl, C3-12 cycloalkyl, and 3-12 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3, 4, 5 or 6 substituents independently selected from R23; or, Ra3 and Rb3 attached to the same nitrogen atom, together with the nitrogen, form a 3-12 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R23; Rc3 and Rf3 are each independently selected from the group consisting of C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, 5-6 membered heteroaryl, C3-12 cycloalkyl, and 3-12 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R23; or, Rc3 and Rf3 attached to the same phosphorous atom, together with the phosphorous atom, form a 3-12 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R23; Rd3 is selected from the group consisting of: 1) hydrogen, cyano, nitro, and S(=O)2RG; 2) C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, 5-6 membered heteroaryl, C3-12 cycloalkyl, and 3-12 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R23; R23 is selected from the group consisting of: 1) oxo, halogen, cyano, -C(=O)Ra5, -C(=O)ORa5, -C(=O)NRa5Rb5, -C(=NRd5)NRa5Rb5, - ORa5, -OC(=O)Ra5, -OC(=O)ORc5, -OC(=O)NRa5Rb5, -SRa5, -S(=O)Rc5, -S(=O)2Rc5, sulphonic acid group, -S(=O)NRa5Rb5, -S(=O)2NRa5Rb5, -S(=O)(=NRd5)Rc5, -NRa5Rb5, -NRa5C(=O)Rb5, - NRa5C(=O)ORc5, -NRe5C(=O)NRa5Rb5, -NRe5C(=NRd5)NRa5Rb5, -NRa5S(=O)2Rc5, - NRe5S(=O)2NRa5Rb5, nitro, -PRc5Rf5, -P(=O)Rc5Rf5, phosphonic acid group, and =N-Rd5; 2) C1-6 alkyl, C1-6 alkylene, C2-6 alkenyl, C2-6 alkynyl, phenyl, 5-6 membered heteroaryl, C3- 112 10 cycloalkyl, and 3-10 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R33; Ra5, Rb5 and Re5 are each independently selected from the group consisting of: 1) hydrogen; 2) C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, 5-6 membered heteroaryl, C3-10 cycloalkyl, and 3-10 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R33; or, Ra5 and Rb5 attached to the same nitrogen atom, together with the nitrogen atom, form a 3- 10 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R33; Rc5 and Rf5 are each independently selected from the group consisting of C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, 5-6 membered heteroaryl, C3-10 cycloalkyl, and 3-10 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R33; or, Rc5 and Rf5 attached to the same phosphorous atom, together with the phosphorous atom, form a 3-10 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R33; Rd5 is selected from the group consisting of: 1) hydrogen, cyano, nitro, and -S(=O)2RG; 2) C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, 5-6 membered heteroaryl, C3-10 cycloalkyl, and 3-10 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R33; R33 is selected from the group consisting of: 1) oxo, halogen, cyano, -C(=O)Ra7, -C(=O)ORa7, -C(=O)NRa7Rb7, -C(=NRd7)NRa7Rb7, - ORa7, -OC(=O)Ra7, -OC(=O)ORc7, -OC(=O)NRa7Rb7, -SRa7, -S(=O)Rc7, -S(=O)2Rc7, sulphonic acid group, -S(=O)NRa7Rb7, -S(=O)2NRa7Rb7, -S(=O)(=NRd7)Rc7, -NRa7Rb7, -NRa7C(=O)Rb7, - NRa7C(=O)ORc7, -NRe7C(=O)NRa7Rb7, -NRe7C(=NRd7)NRa7Rb7, -NRa7S(=O)2Rc7, - NRe7S(=O)2NRa7Rb7, nitro, -PRc7Rf7, -P(=O)Rc7Rf7, phosphonic acid group, and =N-Rd7; 2) C1-4 alkyl, C1-4 alkylene, C2-4 alkenyl, C2-4 alkynyl, phenyl, 5-6 membered heteroaryl, C3- 8 cycloalkyl, and 3-8 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3 or 4 substituents independently selected from RG; Ra7, Rb7 and Re7 are each independently selected from the group consisting of: 113 1) hydrogen; 2) C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, 5-6 membered heteroaryl, C3-8 cycloalkyl, and 3-8 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3 or 4 substituents independently selected from RG; or, Ra7 and Rb7 attached to the same nitrogen atom, together with the nitrogen atom, form a 3-8 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3 or 4 substituents independently selected from RG; Rc7 and Rf7 are each independently selected from the group consisting of C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, 5-6 membered heteroaryl, C3-8 cycloalkyl, and 3-8 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3 or 4 substituents independently selected from RG; or, Rc7 and Rf7 attached to the same phosphorous atom, together with the phosphorous atom, form a 3-8 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3 or 4 substituents independently selected from RG; Rd7 is selected from the group consisting of: 1) hydrogen, cyano, nitro, and -S(=O)2RG; 2) C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, 5-6 membered heteroaryl, C3-8 cycloalkyl, and 3-8 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3 or 4 substituents independently selected from RG; RG is selected from the group consisting of: 1) halogen, oxo, cyano, carboxyl, hydroxyl, C1-4 alkoxy, amino, C1-4 alkylamino, nitro, C1-4 alkylthio, sulphonic acid group, C1-4 alkyl sulfinyl, C1-4 alkyl sulfonyl, C1-4 alkylaminosulfinyl, and C1-4 alkylaminosulfonyl; 2) C1-4 alkyl, C1-4 alkylene, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl and 3-8 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of oxo, halogen, hydroxyl, hydroxymethyl, carboxyl, cyano, C1-3 alkoxy, amino, C1-4 alkylamino, nitro, and sulphonic acid group.
  2. 2. The compound according to claim 1, wherein, R1 is selected from the group consisting of hydrogen, fluorine, cyano, methyl, ethyl, 1- propyl, isopropyl, cyclopropyl, methoxy, ethoxy and cyclopropyloxy; CyA is selected from the group consisting of phenyl, naphthyl and 5-10 membered heteroaryl, 114 unsubstituted or optionally substituted with 1, 2, 3 or 4 substituents independently selected from R12; wherein 5-10 membered heteroaryl contains at least two ring-forming carbon atoms and 1, 2, or 3 ring-forming heteroatoms independently selected from the group consisting of N, O and S; R12 is selected from the group consisting of: 1) oxo, halogen, cyano, -C(=O)Ra2, -C(=O)ORa2, -C(=O)NRa2Rb2, -C(=NRd2)NRa2Rb2, - ORa2, -NRa2Rb2, -NRa2C(=O)Rb2, -NRa2C(=O)ORc2, -NRe2C(=O)NRa2Rb2, - NRe2C(=NRd2)NRa2Rb2, -NRa2S(=O)2Rc2 and -NRe2S(=O)2NRa2Rb2; 2) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 6-10 membered aryl, 5-10 membered heteroaryl, C3- 10 cycloalkyl, 3-10 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3 or 4 substituents independently selected from R22; 3) two R12, together with two adjacent ring-forming atoms of the aryl or heteroaryl in CyA to which they are attached respectively, form a C4-8 aliphatic cyclyl or 4-8 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2 or 3 substituens independently selected from R22; Ra2, Rb2 and Re2 are each independently selected from the group consisting of: 1) hydrogen; 2) C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, 5-6 membered heteroaryl, C3-6 cycloalkyl and 3-6 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2 or 3 subsituents independently selected from R22; or, Ra2 and Rb2, together with the same N atom to which they are attached, form a 3-8 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2 or 3 substituents independently selected from R22; Rc2 is selected from the group consisting of C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, 5- 6 membered heteroaryl, C3-6 cycloalkyl and 3-6 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2 or 3 substituents independently selected from R22; Rd2 is selected from the group consisting of: 1) hydrogen, cyano, nitro, and -S(=O)2RG; 2) C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, and 3-6 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2 or 3 substituents independently selected from R22; R22 is selected from the group consisting of: 1) oxo, halogen, cyano, carboxyl, -C(=O)Ra4, -C(=O)ORa4, -C(=O)NRa4Rb4, - 115 C(=NRd4)NRa4Rb4, -ORa4, -S(=O)2Rc4, sulphonic acid group, -S(=O)2NRa4Rb4, - S(=O)(=NRd4)Rc4, -NRa4Rb4, -NRa4C(=O)Rb4, -NRe4C(=O)NRa4Rb4, -NRe4C(=NRd4)NRa4Rb4, - NRa4S(=O)2Rc4, -NRe4S(=O)2NRa4Rb4 and =N-Rd4; 2) C1-4 alkyl, C1-4 alkylene, phenyl, 5-6 membered heteroaryl, C3-7 cycloalkyl and 3-7 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2 or 3 substituents independently selected from R32; Ra4, Rb4 and Re4 are each independently selected from the group consisting of: 1) hydrogen; 2) C1-4 alkyl, phenyl, 5-6 membered heteraryl, C3-6 cycloalkyl, and 3-6 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2 or 3 substituents independently selected from R32; or, Ra4 and Rb4, together with the same N atom to which they are attached, form a 3-6 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2 or 3 substituents independently selected from R32; Rc4 is selected from the group consisting of C1-4 alkyl, phenyl, 5-6 membered heteroaryl, C3- 6 cycloalkyl, and 3-6 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2 or 3 substituents independently selected from R32; Rd4 is selected from the group consisting of: 1) hydrogen, cyano, nitro, and -S(=O)2RG; 2) C1-4 alkyl, phenyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, and 3-6 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2 or 3 substituents independently selected from R32; R32 is selected from the group consisting of: 1) oxo, halogen, cyano, -C(=O)Ra6, -C(=O)ORa6, C(=O)NRa6Rb6, -C(=NRd6)NRa6Rb6, -ORa6, -S(=O)2Rc6, -S(=O)2NRa6Rb6, -S(=O)(=NRd6)Rc6, -NRa6Rb6, -NRa6C(=O)Rb6, - NRe6C(=O)NRa6Rb6, -NRe6C(=NRd6)NRa6Rb6, -NRa6S(=O)2Rc6, -NRe6S(=O)2NRa6Rb6, and =NRd6； 2) C1-4 alkyl, C1-4 alkylene, phenyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, and 3-6 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3 or 4 substituents independently selected from RG; Ra6, Rb6 and Re6 are each independently selected from the group consisting of: 1) hydrogen; 116 2) C1-4 alkyl, phenyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, and 3-6 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, or 3 substituents independently selected from RG; or, Ra6 and Rb6 attached to the same nitrogen atom, together with the nitrogen, form a 3-6 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, or 3 substituents independently selected from RG; Rc6 is independently selected from the group consisting of C1-4 alkyl, phenyl, 5-6 membered heteroaryl, C3-6 cycloalkyl and 3-6 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, or 3 substituents independently selected from RG; Rd6 is selected from the group consisting of: 1) hydrogen, cyano, nitro, and -S(=O)2RG; 2) C1-4 alkyl, phenyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, and 3-6 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2 or 3 substituents independently selected from RG; CyB is selected from the group consisting of phenyl, naphthyl and 5-10 membered heteroaryl, unsubstituted or optionally substituted with 1, 2, 3 or 4 substituents independently selected from R12; wherein the 5-10 membered heteroaryl contains at least one ring-forming carbon atom and 1, 2, or 3 ring-forming heteroatoms independently selected from the group consisting of N, O and S; R13 is selected from the group consisting of: 1) oxo, halogen, cyano, -C(=O)Ra3, -C(=O)ORa3, -C(=O)NRa3Rb3, -C(=NRd3)NRa3Rb3, - ORa3, -NRa3Rb3, -NRa3C(=O)Rb3, -NRe3C(=O)NRa3Rb3, -NRe3C(=NRd3)NRa3Rb3, - NRa3S(=O)2Rc3 and -NRe3S(=O)2NRa3Rb3; 2) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 6-10 membered aryl, 5-10 membered heteroaryl, C3- 10 cycloalkyl, and 3-10 membered aliphatic heterocyclyl; 3) two R13, together with two adjacent ring-forming atoms of the aryl or heteroaryl of CyB to which they are attached respectively, form a C4-8 aliphatic cyclyl or 4-8 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2 or 3 substituents independently selected from R23; Ra3, Rb3 and Re3 are each independently selected from the group consisting of: 1) hydrogen; 2) C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, 5-6 membered heteroaryl, C3-6 cycloalkyl and 3-6 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2 or 3 117 substituents independently selected from R23; or, Ra3 and Rb3 together with the same N atom to which they are attached form a 3-8 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2 or 3 substituents independently selected from R23; Rc3 is selected from the group consisting of C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, 5- 6 membered heteroaryl, C3-6 cycloalkyl and 3-6 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2 or 3 substituents independently selected from R23; Rd3 is selected from the group consisting of: 1) hydrogen, cyano, nitro and -S(=O)2RG; 2) C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, 5-6 membered heteroaryl, C3-6 cycloalkyl and 3-6 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2 or 3 substituents independently selected from R23; R23 is selected from the group consisting of: 1) oxo, halogen, cyano, carboxyl, -C(=O)Ra5, -C(=O)ORa5, -C(=O)NRa5Rb5, - C(=NRd5)NRa5Rb5, -ORa5, -S(=O)2Rc5, sulphonic acid group, -S(=O)2NRa5Rb5, - S(=O)(=NRd5)Rc5, -NRa5Rb5, -NRa5C(=O)Rb5, -NRe5C(=O)NRa5Rb5, -NRe5C(=NRd5)NRa5Rb5, - NRa5S(=O)2Rc5, -NRe5S(=O)2NRa5Rb5 and =N-Rd5; 2) C1-6 alkyl, C1-6 alkylene, phenyl, 5-6 membered heteroaryl, C3-7 cycloalkyl and 3-7 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2 or 3 substituens independently selected from R33; Ra5, Rb5 and Re5 are each independently selected from the group consisting of: 1) hydrogen; 2) C1-4 alkyl, phenyl, 5-6 membered heteroaryl, C3-6 cycloalkyl and 3-6 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2 or 3 substituents independently selected from R33; or, Ra5 and Rb5 together with the same N atom to which they are linked form a 3-6 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2 or 3 substitents independently selected from R33; Rc5 is selected from the group consisting of C1-4 alkyl, phenyl, 5-6 membered heteroaryl, C3- 6 cycloalkyl and 3-6 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2 or 3 substituents independently selected from R33; Rd5 is selected from the group consisting of: 118 1) hydrogen, cyano, nitro and -S(=O)2RG; 2) C1-4 alkyl, phenyl, 5-6 membered heteroaryl, C3-6 cycloalkyl and 3-6 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2 or 3 substituents independently selected from R33; R33 is selected from the group consisting of: 1) oxo, halogen, cyano, -C(=O)Ra7, -C(=O)ORa7, -C(=O)NRa7Rb7, -C(=NRd7)NRa7Rb7, - ORa7, -S(=O)2Rc7, -S(=O)2NRa7Rb7, -S(=O)(=NRd7)Rc7, -NRa7Rb7, -NRa7C(=O)Rb7, - NRe7C(=O)NRa7Rb7, -NRe7C(=NRd7)NRa7Rb7, -NRa7S(=O)2Rc7, -NRe7S(=O)2NRa7Rb7 and =NRd7; 2) C1-4 alkyl, C1-4 alkylene, phenyl, 5-6 membered heteroaryl, C3-6 cycloalkyl and 3-6 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2 or 3 substituents independently selected from RG; Ra7, Rb7 and Re7 are each independently selected from the group consisting of: 1) hydrogen; 2) C1-4 alkyl, phenyl, 5-6 membered heteroaryl, C3-6 cycloalkyl and 3-6 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2 or 3 substituents independently selected from RG; or, Ra7 and Rb7 together with the same N atom to which they are attahced form a 3-6 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2 or 3 substituents independently selected from RG; Rc7 is selected from the group consisting of C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, 5- 6 membered heteroaryl, C3-6 cycloalkyl and 3-6 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2 or 3 substituents independently selected from RG; Rd7 is selected from the group consisting of: 1) hydrogen, cyano, nitro and -S(=O)2RG; 2) C1-4 alkyl, phenyl, 5-6 membered heteroaryl, C3-6 cycloalkyl and 3-6 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2 or 3 substituents independently selected from RG; RG is selected from the group consisting of: 1) halogen, oxo, cyano, carboxyl, hydroxyl, C1-4 alkoxy, amino, C1-4 alkylamino, sulfonic acid group, C1-4 alkylsulfonyl and C1-4 alkylaminosulfonyl; 2) C1-4 alkyl, C1-4 alkylene, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl and 3-8 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, or 3 substituents 119 independently selected from the group consisting of oxo, halogen, hydroxyl, hydroxymethyl, carboxyl, cyano, C1-3 alkoxy, amino, and C1-3 alkylamino; or a pharmaceutically acceptable salt, hydrate, solvate, isotope labeled compound, or isomer thereof.
  3. 3. The compound according to claim 2, wherein, R1 is selected from the group consisting of hydrogen, fluorine, cyano, methyl and methoxy; CyA is selected from phenyl and 5 or 6 membered heteroaryl, unsubstituted or optionally substituted with 1 or 2, or 3 substituents independently selected from R12; wherein 5 or 6 membered heteroaryl contains 1 or 2 heteroatom(s) independently selected from the group consisting of N and S; CyB is selected from phenyl and 5 or 6 membered heteroaryl, unsubstituted or optionally substituted with 1, 2, 3 or 4 substituents independently selected from R13; wherein the 5 or 6 membered heteroaryl contains 1, 2, or 3 ring-forming heteroatoms independently selected from the group consisting of N and S; R12 is selected from the group consisting of: 1) oxo, halogen, cyano, -C(=O)Ra2, -C(=O)NRa2Rb2, -C(=NRd2)NRa2Rb2, -ORa2, -NRa2Rb2, - NRa2C(=O)Rb2, -NRa2C(=O)ORc2, -NRe2C(=O)NRa2Rb2, -NRe2C(=NRd2)NRa2Rb2, - NRa2S(=O)2Rc2, and -NRe2S(=O)2NRa2Rb2; 2) C1-6 alkyl, phenyl, 5-6 membered heteroaryl, C3-10 cycloalkyl and 3-10 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3 or 4 substituents independently selected from R22; 3) two R12, together with two adjacent ring-forming atoms of the aryl or heteroaryl of CyA to which they are connected respectively, form a C5, C6, C7 aliphatic monocyclyl or 5-, 6-, 7- membered aliphatic monoheterocyclyl, unsubstituted or optionally substituted with 1, 2 or 3 substituens independently selected from R22; R13 is selected from the group consisting of: 1) oxo, halogen, cyano, -C(=O)Ra3, -C(=O)NRa3Rb3, -C(=NRd3)NRa3Rb3, -ORa3, -NRa3Rb3, - NRa3C(=O)Rb3, -NRe3C(=O)NRa3Rb3, -NRe3C(=NRd3)NRa3Rb3, -NRa3S(=O)2Rc3, and - NRe3S(=O)2NRa3Rb3; 2) C1-6 alkyl, phenyl, 5-6 membered heteroaryl, C3-10 cycloalkyl and 3-10 membered aliphatic heterocyclyl, unsubstituted or optionally substituted with 1, 2, 3 or 4 substituents independently selected from R23; 3) two R13, together with two adjacent ring-forming atoms of the aryl or heteroaryl of CyB 120 to which they are connected respectively, form a C5, C6, C7 aliphatic monocyclyl or 5-, 6-, 7- membered aliphatic monoheterocyclyl, unsubstituted or optionally substituted with 1, 2 or 3 substituens independently selected from R23; or a pharmaceutically acceptable salt, hydrate, solvate, isotope labeled compound, or isomer thereof.
  4. 4. The compound according to claim 2, wherein, R1 is selected from the group consisting of hydrogen, fluorine, cyano, methyl and methoxy; CyA is selected from the group consisting of: 1) the following structures, wherein the “ ” at the end of the chemical bond in each structure means that the structures is connected to the rest of formula (I) through the bond: ; 2) phenyl, pyridyl, pyrimidyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, or isoxazolyl, unsubstituted or optionally substituted with 1, 2 or 3 substituents independently selected from R12; wherein, (a) each R12 is independently selected from the group consisting of fluorine and chlorine; non-hydrogen RG1, and ORG1; or, (b) CyA contains one R12, and the R12 is selected from one of the following structures, wherein the “ ” at the end of the chemical bond in each structure means that the structure is connected to the rest of formula (I) through the bond: 121 , or, CyA contains two or three R12, wherein one of R12 is selected from the group consisting of the above structures and the others of R12are each independently selected from the group consisting of fluorine, chlorine, non-hydrogen RG1, and -ORG1; wherein X is selected from the group consisting of CH and N; Y is selected from the group consisting of -CH2-, NH and O; E1 and E2 are each independently selected from the group consisting of -CH2- and carbonyl, 122 provided that E1 and E2 are not carbonyl simultaneously; RG2 is selected from the group consisting of hydrogen, -ORG1 and -N(RG1)2; each RG1 is independently selected from the group consisting of: 1) hydrogen, methyl, ethyl, isopropyl, cyclopropyl, 3-oxetanyl and 3-methyl-3-azetidinyl; 2) two RG1 attached to the same atom, together with said atom, form a C3-6 monocyclyl or 3-6 membered aliphatic monoheterocyclyl; 3) two RG1 attached to two different ring-forming atoms of the same monocycle are connected to form a ring structure together with part of the ring-forming atoms of said monocycle, wherein the two connected RG1 form a C2, C3 or C4 alkylene; CyB is phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, thienyl, optionally substituted with 1, 2 or 3 substituents independently selected from R13; R13 is selected from the group consisting of: 1) oxo, halogen, cyano, -C(=O)Ra3, -C(=O)NRa3Rb3, -C(=NRd3)NRa3Rb3, -ORa3, -NRa3Rb3, - NRa3C(=O)Rb3, -NRe3C(=O)NRa3Rb3, -NRe3C(=NRd3)NRa3Rb3, -NRa3S(=O)2Rc3, and - NRe3S(=O)2NRa3Rb3; 2) C1-6 alkyl, phenyl, 5-6 membered heteroaryl, C3-6 monocyclic cycloalkyl and 3-6 membered aliphatic monoheterocyclyl, unsubstituted or optionally substituted with 1, 2, 3 or 4 substituents independently selected from R23; 3) two R13, together with two adjacent ring-forming atoms of the aryl or heteroaryl of CyB to which they are connected respectively, form a C5, C6, C7 aliphatic monocyclyl or 5-, 6-, 7- membered aliphatic monocyclic heterocyclyl, unsubstituted or optionally substituted with 1, 2 or 3 substituens independently selected from R23; or a pharmaceutically acceptable salt, hydrate, solvate, isotope labeled compound, or isomer thereof.
  5. 5. The compound according to claim 1, wherein, R1 is selected from the group consisting of hydrogen, fluorine, cyano, methyl and methoxy; CyA is phenyl, pyridyl, pyrimidyl, pyrazolyl, imidazolyl, thiazolyl or isothiazolyl, unsubstituted or optionally substituted with 1, 2 or 3 substituents independently selected from R12, wherein 1) each R12 is independently selected from the group consisting of: fluorine, chlorine; nonhydrogen RG1, and ORG1; or, 2) CyA contains one R12, and the R12 is selected from one of the following strucutres: 123 , or, CyA contains two or three R12, wherein one of R12 is selected from the group consisting of the above structures and others of R12 are each independently selected from the group consisting of fluorine, chlorine, non-hydrogen RG1, and -ORG1; each RG1 is independently selected from the group consisting of: 1) hydrogen, 2) methyl, ethyl, isopropyl, cyclopropyl, 3-oxetanyl and 3-methyl-3-azetidinyl; optionally substituted with hydroxyl, C1-6 alkoxy or amino; CyB is selected from one of the following structures: ; Ra3 and Rb3 are each independently selected from the group consisting of hydrogen, C1-6 alkyl and C1-6 cycloalkyl, or, two Ra3 and Rb3 attached to two adjacent ring-forming atoms 124 respectively, together with said two ring-forming atoms form unsubstituted 5-6 membered aliphatic cyclyl or unsubstituted 5-6 membered aliphatic heterocyclyl; or a pharmaceutically acceptable salt, hydrate, solvate, isotope labeled compound, or isomer thereof.
  6. 6. The compound according to claim 1, wherein, R1 is selected from the group consisting of hydrogen, fluorine, cyano, methyl and methoxy; CyA is phenyl, pyridyl, pyrimidyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl or a bicyclyl represented by Z R o where a phenyl is fused with a 5-7 membered saturated aliphatic heterocyclyl, or a bicyclyl represented by where a pyridyl is fused with a 5-7 membered saturated aliphatic heterocyclyl; wherein Z represents 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen; when Z=N, N is optionally linked to Ry; Ro is selected from the group consisting of oxo, F, amino, and optionally substituted C1-3 alkyl; wherein said aliphatic heterocyclyl may be fused with another 5-6 membered nitrogen-containing saturated aliphatic heterocyclyl to form a fused ring; said phenyl, pyridyl, pyrimidyl, pyrazolyl, imidazolyl, thiazolyl, and isothiazolyl is unsubstituted or optionally substituted with 1, 2 or 3 substituents independently selected from R12, wherein, 1) when CyA contains one R12, the R12 is selected from one of the following: 125 , wherein Rx is selected from the group consisting of -OH, C1-6 alkyl, C1-6 alkoxy, -NH2, C1- 6 alkylamino, , and ; 2) when CyA contains more than one R12, the others of R12 are each independently selected from the group consisting of fluorine, C1-6 alkyl, C1-6 alkoxy, and (C1-6 alkylamino)methyl; CyB is selected from one of the following structures: 126 ; Ra3 and Rb3 are each independently selected from the group consisting of hydrogen, C1-6 alkyl and C3-6 cycloalkyl, or Ra3 and Rb3 together with N atom to which they are attached form a 4-6 membered saturated aliphatic heterocyclyl; said C1-6 alkyl, C3-6 cycloalkyl, and 4-6 membered saturated aliphatic heterocyclyl is unsubstituted or optionally substituted with substituent(s) selected from the group consisting of fluorine, hydroxyl, C1-6 alkyl, and fluoro-substituted C1-6 alkyl; Ry is selected from the group consisting of H, C1-6 alkyl, C1-6 alkyl substituted with a substituent selected from the group consisting of hydroxyl and halogen, C3-6 cycloalkyl, nitrogencontaining 4-6 membered saturated aliphatic heterocyclyl, oxygen-containing 5-6 membered saturated aliphatic heterocyclyl, and -C(=O)Rs; Rs is selected from C1-6 alkyl optionally substituted with substituents selected from the group consisting of hydroxyl, amino, and nitrogencontaining aliphatic heterocyclyl; or a pharmaceutically acceptable salt, hydrate, solvate, isotope labeled compound, or isomer thereof.
  7. 7. The compound according to any of claims 1-6, wherein, CyA is phenyl, pyridyl, pyrimidyl, thiazolyl or a bicyclyl represented by Z R o where a phenyl is fused with a 5-7 membered saturated aliphatic heterocyclyl, or a bicyclyl represented by where a pyridyl is fused with a 5-7 membered saturated aliphatic heterocyclyl, wherein Z represents 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen; when Z=N, N is optionally linked to Ry; Ro is selected from the group consisting of oxo, F, amino, optionally substituted C1-3 alkyl; wherein said saturated aliphatic heterocyclyl may be fused with another 5-6 membered nitrogen-containing saturated aliphatic heterocyclyl form a fused ring, wherein, Ry is selected from the group consisting of H, C1-6 alkyl, C1-6 alkyl substituted with the 127 substituent consisting of hydroxyl and halogen, C3-6 cycloalkyl, 4-6 membered N-containing saturated aliphatic heterocyclyl, 5-6 membered O-containing saturated aliphatic heterocyclyl, and -C(=O)Rs, Rs is selected from C1-6 alkyl optionally substituted with the group consisting of hydroxyl, amino, and N-containing aliphatic heterocyclyl; when CyA is selected from the group consisting of phenyl, pyridyl, pyrimidyl, and thiazolyl, R12 is selected from the group consisting of , , , , , and , wherein Rz is selected from the group consisting of hydrogen, optionally substituted C1-6 alkyl, 4-6 membered O-containing aliphatic heterocyclyl, and -S(=O)2-C1-6 alkyl; Rp, single or multiple substituent(s), are each optionally selected from the group consisting of hydrogen, and optionally substituted C1-6 alkyl; Rq is selected from the group consisting of hydroxyl, amino, optionally substituted C1-3 alkyl, spiro heterocyclyl composed of two 4-5 membered nitrogen- and/or oxygen-containing rings, and 5-6 membered aliphatic heterocyclyl containing one or two heteroatoms selected from the group consisting of nitrogen and oxygen, said aliphatic heterocyclyl is optionally substituted with F, and C1-3 alkyl; or a pharmaceutically acceptable salt, hydrate, solvate, isotope labeled compound, or isomer thereof.
  8. 8. The compound according to claim 7, wherein, CyA is selected from phenyl, R12 is selected from the group consisting of , , , , , and , wherein Rz is selected from the group consisting of hydrogen, optionally substituted C1-6 alkyl, 4-6 membered O-containing aliphatic heterocyclyl, and -S(=O)2-C1-6 alkyl; Rp, single or multiple substituent(s), are each optionally selected from the group consisting of hydrogen, and optionally substituted C1-6 alkyl; Rq is selected from the group consisting of hydroxyl, amino, optionally substituted C1-3 alkyl, spiro heterocyclyl composed of two 4-5 128 membered nitrogen and/or oxygen containing rings, and 5-6 membered aliphatic heterocyclyl containing one or two heteroatoms selected from the group consisting of nitrogen and oxygen, said aliphatic heterocyclyl is optionally substituted with F, and C1-3 alkyl; or a pharmaceutically acceptable salt, hydrate, solvate, isotope labeled compound, or isomer thereof.
  9. 9. The compound according to any of claims 1-8, wherein, CyA is selected from the group consisting of: , wherein, W1 is selected from CH2 or oxygen; RT is selected from hydrogen or methyl; RV is selected from fluorine or methyl, the number of RV is 0, 1 or 2; or a pharmaceutically acceptable salt, hydrate, solvate, isotope labeled compound, or isomer thereof.
  10. 10. The compound according to any of claims 1-9, wherein, CyB is selected from phenyl optionally substituted with a group selected from the group consisting of H, F, -CN, optionally substituted C1-3 alkyl, optionally substituted C1-3 alkoxy, optionally substituted C3-6 cycloalkoxy and C(=O)NRa3Rb3, wherein Ra3 and Rb3 are each independently selected from the group consisting of hydrogen, C1-6 alkyl and optionally substituted C3-6 cycloalkyl, or Ra3 and Rb3 together with the N atom to which whihch they attached form an optionally substituted 4-5 membered alicyclic heterocyclyl; or a pharmaceutically acceptable salt, hydrate, solvate, isotope labeled compound, or isomer thereof.
  11. 11. The compound according to any of claims 1-10, wherein, CyB is selected from the group 129 consisting of: .
  12. 12. The compound according to claim 1, wherein, R1 is H; CyA is selected from the group consisting of: 1) phenyl, pyridyl, and pyrimidyl, unsubstituted or optionally substituted with 1, 2 or 3 substituents independently selected from R12; each R12 is independently selected from the group consisting of fluorine, chlorine, non-hydrogen RG1, and ORG1; 2) phenyl, pyridyl, and pyrimidyl, optionally substituted with 1, 2 or 3 substituents independently selected from R12; one of R12 is selected from the group consisting of: , and other R12 are each independently selected from the group consisting of: fluorine, chlorine; non-hydrogen RG1, and ORG1; 3) the following structure: , wherein the phenyl or pyridyl is unsubstituted or optionally substituted with 1 or 2 substituents independently selected from R12; CyB is selected from 130 wherein Ra3 is selected from the group consisting of methyl, ethyl, difluoromethyl, trifluoromethyl, isopropyl and cyclopropyl; E1 is independently selected from the group consisting of -CH2- and oxygen; RG1 is selected from the group consisting of hydrogen, oxo, methyl, ethyl, isopropyl, cyclopropyl, 3-oxetanyl and 3-methyl-3-azetidinyl; R13 is selected from the group consisting of hydrogen, fluorine, cyano and -C(=O)-N(RG3)2; each RG3 is independently selected from the group consisting of: 1) hydrogen, methyl, ethyl, isopropyl, cyclopropyl, oxetanyl, oxacyclopentyl, azetidinyl, and azacyclopentyl; 2) two RG3 connected to the same atom, together with said atom, form a C3-6 monocyclyl or a 3-6 membered aliphatic monoheterocyclyl; 3) two RG3 respectively connected to two different ring-forming atoms on the same single ring are connected to form a ring structure together with part of the ring-forming atoms of said single ring, and the two connected RG3 form a C2, C3 or C4 alkylene, or a 2-, 3- or 4-membered oxaalkylene, or a 2-, 3- or 4-membered azaalkylene; and, when RG3 is not hydrogen, RG3 is unsubstituted or independently substituted with 1, 2 or 3 substituents optionally selected from the group consisting of oxo, fluorine, hydroxyl, methoxy, amino, methylamino, dimethylamino, methyl, ethyl, and cyano; or a pharmaceutically acceptable salt, hydrate, solvate, isotope labeled compound, or isomer thereof.
  13. 13. The compound according to any of claims 1-12, wherein, when CyA is phenyl, and R12 is heterocyclyl, R12 is attached to para- or meta- position of the phenyl; or a pharmaceutically acceptable salt, hydrate, solvate, isotope labeled compound, or isomer thereof.
  14. 14. The compound according to claim 1, wherein the compound is selected from: 131 Compound Structural Formula Name of Compound Compound 1 5-(2-fluoro-6-methylphenyl)-3-(4-(4- methylpiperazin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 2 5-(2-methoxy-6-methylphenyl)-3-(4-(4- methylpiperazin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 3 5-(2-methoxyphenyl)-3-(4-(4-methylpiperazin- 1-yl)phenyl)-1H-pyrazolo[4,3-c]pyridazin- 6(5H)-one Compound 4 5-(2,4-dimethoxyphenyl)-3-(4-(1-methyl- 1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 5 5-(2-methylphenyl)-3-(4-(4-methylpiperazin- 1-yl)phenyl)-1H-pyrazolo[4,3-c]pyridazin- 6(5H)-one Compound 6 5-(2-fluorophenyl)-3-(4-(4-methylpiperazin-1- yl)phenyl)-1H-pyrazolo[4,3-c]pyridazin- 6(5H)-one Compound 7 5-(2-chlorophenyl)-3-(4-(4-methylpiperazin-1- yl)phenyl)-1H-pyrazolo[4,3-c]pyridazin- 6(5H)-one Compound 8 5-(2-ethyl-6-fluorophenyl)-3-(4-(4- methylpiperazin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 9 5-(2-fluoro-6-methoxyphenyl)-3-(4-(4- methylpiperazin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 10 5-(2-fluoro-6-methoxyphenyl)-3-(6-(4- methylpiperazin-1-yl)pyrid-3-yl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one 132 Compound 11 5-(2-fluoro-6-methylphenyl)-3-(6-(4- methylpiperazin-1-yl)pyrid-3-yl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 12 5-(2-fluoro-6-methylphenyl)-3-(4-(4-methyl-2- oxopiperazin-1-yl)phenyl)-1H-pyrazolo[4,3- c]pyridazin-6(5H)-one Compound 13 3-(3,5-dimethyl-4-(4-methylpiperazin-1- yl)phenyl)-5-(2-fluoro-6-methylphenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 14 5-(2-fluoro-6-methylphenyl)-3-(3-methoxy-4- (4-methylpiperazin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 15 5-(2-fluoro-6-methylphenyl)-3-(4-((4-methyl- 2-oxo-piperazin-1-yl)methyl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 16 5-(2-fluoro-6-methylphenyl)-3-(2-methoxy-4- (4-methylpiperazin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 17 5-(2-fluoro-6-methylphenyl)-3-(1-methyl-1Hpyrazol- 4-yl)-1H-pyrazolo[4,3-c]pyridazin- 6(5H)-one Compound 18 5-(2-fluoro-6-methylphenyl)-3-(1-methyl-1Hpyrazol- 3-yl)-1H-pyrazolo[4,3-c]pyridazin- 6(5H)-one Compound 19 5-(2-fluoro-6-methylphenyl)-3-(1-(1- methylpiperidin-4-yl)-1H-pyrazol-4-yl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 20 5-(2-fluoro-6-methoxyphenyl)-3-(1-(1- methylpiperidin-4-yl)-1H-pyrazol-4-yl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one 133 Compound 21 5-(2-fluoro-6-methoxyphenyl)-3-(1-methyl- 1H-pyrazol-4-yl)-1H-pyrazolo[4,3- c]pyridazin-6(5H)-one Compound 22 5-(2-fluoro-6-methoxyphenyl)-3-(1-methyl- 1H-pyrazol-3-yl)-1H-pyrazolo[4,3- c]pyridazin-6(5H)-one Compound 23 5-(2-fluoro-6-methoxyphenyl)-3-(4-(1-methyl- 1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 24 5-(2-fluoro-6-methoxyphenyl)-3-(4-(1- methylpiperidin-4-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 25 5-(2,4-dimethoxyphenyl)-3-(4-(4- methylpiperazin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 26 5-(2,4-dimethoxyphenyl)-3-(4-(1- methylpiperidin-4-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 27 5-(2-fluoro-6-methoxyphenyl)-3-(6- morpholinopyrid-3-yl)-1H-pyrazolo[4,3- c]pyridazin-6(5H)-one Compound 28 5-(2-fluoro-6-methoxyphenyl)-3-(2-(4- methylpiperazin-1-yl)pyrimidin-5-yl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 29 5-(2-fluoro-6-isopropylphenyl)-3-(4-(4- methylpiperazin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 30 3-(4-(4-methylpiperazin-1-yl)phenyl)-5- phenyl-1H-pyrazolo[4,3-c]pyridazin-6(5H)- one 134 Compound 31 5-(2-fluoro-6-methylphenyl)-3-(2-(4- methylpiperazin-1-yl)pyrimidin-5-yl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 32 5-(2-fluoro-6-methylphenyl)-3-(2-morpholinyl pyrimidin-5-yl)-1H-pyrazolo[4,3-c]pyridazin- 6(5H)-one Compound 33 5-(2-fluoro-6-methoxyphenyl)-3-(4-(4-methyl- 3-oxopiperazin-1-yl)phenyl)-1H-pyrazolo[4,3- c]pyridazin-6(5H)-one Compound 34 5-(2-cyclopropyl-6-fluorophenyl)-3-(4-(4- methylpiperazin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 35 5-(2-fluoro-6-(trifluoromethyl)phenyl)-3-(4- (4-methylpiperazin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 36 5-(2-cyclopropoxy-6-fluorophenyl)-3-(4-(4- methylpiperazin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 37 5-(2-(difluoromethoxy)-6-fluorophenyl)-3-(4- (4-methylpiperazin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 38 5-(5-fluoro-2,3-dihydro-1H-indan-4-yl)-3-(4- (4-methylpiperazin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 39 5-(6-fluoro-2,3-dihydrobenzofuran-7-yl)-3-(4- (4-methylpiperazin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 40 5-(5-fluoro-2-methylisoindolin-4-yl)-3-(4-(4- methylpiperazin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one 135 Compound 41 5-(5-fluoro-2-(2-morpholinoacetyl)isoindolin- 4-yl)-3-(4-(4-methylpiperazin-1-yl)phenyl)- 1H-pyrazolo[4,3-c]pyridazin-6(5H)-one Compound 42 N N N NH O N N F N 3-fluoro-5-methyl-4-(3-(4-(4-methylpiperazin- 1-yl)phenyl)-6-oxo-1H-pyrazolo[4,3- c]pyridazin-5(6H)-yl)benzonitrile Compound 43 5-(2-fluoro-6-methyl-4- ((methylamino)methyl)phenyl)-3-(4-(4- methylpiperazin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 44 3-fluoro-N,5-dimethyl-4-(3-(4-(4- methylpiperazin-1-yl)phenyl)-6-oxo-1Hpyrazolo[ 4,3-c]pyridazin-5(6H)-yl)benzamide Compound 45 5-(2-fluoro-4-(3-hydroxyl-3-methylazetidine- 1-carbonyl)-6-methylphenyl)-3-(4-(4- methylpiperazin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 46 N-(2-(dimethylamino)ethyl)-3-fluoro-5- methyl-4-(3-(4-(4-methylpiperazin-1- yl)phenyl)-6-oxo-1H-pyrazolo[4,3- c]pyridazin-5(6H)-yl)benzamide Compound 47 3-(4-(4-methylpiperazin-1-yl)phenyl)-5-(4- methylpyrid-3-yl)-1H-pyrazolo[4,3- c]pyridazin-6(5H)-one Compound 48 5-(4-methoxypyrid-3-yl)-3-(4-(4- methylpiperazin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 49 5-(5-amino-4-methylpyrid-3-yl)-3-(4-(4- methylpiperazin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one 136 Compound 50 N N N NH O N N N HN O 5-(8-methyl-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazin-7-yl)-3-(4-(4-methylpiperazin-1- yl)phenyl)-1H-pyrazolo[4,3-c]pyridazin- 6(5H)-one Compound 51 3-(4-(4-methylpiperazin-1-yl)phenyl)-5-(4- methylpyrimidin-5-yl)-1H-pyrazolo[4,3- c]pyridazin-6(5H)-one Compound 52 5-(7-methyl-3H-imidazolo[4,5-b]pyrid-6-yl)- 3-(4-(4-methylpiperazin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 53 5-(5-isopropyl-1H-pyrazol-4-yl)-3-(4-(4- methylpiperazin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 54 5-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3- yl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 55 5-(2-fluoro-6-methylphenyl)-7-methyl-3-(4-(4- methylpiperazin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 56 5-(2-fluoro-6-methylphenyl)-7-methoxy-3-(4- (4-methylpiperazin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 57 5-(2-fluoro-6-methylphenyl)-3-(4-(4- methylpiperazin-1-yl)phenyl)-6-oxo-5,6- dihydro-1H-pyrazolo[4,3-c]pyridazin-7- carbonitrile Compound 58 3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)-5- (2-fluoro-6-methylphenyl)-1H-pyrazolo[4,3- c]pyridazin-6(5H)-one Compound 59 5-(2-fluoro-6-methylphenyl)-3-(4-(4-(oxetan- 3-yl)piperazin-1-yl)phenyl)-1H-pyrazolo[4,3- c]pyridazin-6(5H)-one 137 Compound 60 5-(2-fluoro-6-methylphenyl)-3-(4-(4- oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)- yl)phenyl)-1H-pyrazolo[4,3-c]pyridazin- 6(5H)-one Compound 61 5-(2-fluoro-6-methylphenyl)-3-(4-(8-methyl- 3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 62 3-(4-(4-(2-oxa-6-azaspiro[3.3]heptan-6- yl)piperidin-1-yl)phenyl)-5-(2-fluoro-6- methylphenyl)-1H-pyrazolo[4,3-c]pyridazin- 6(5H)-one Compound 63 3-(4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)- 5-(2-fluoro-6-methylphenyl)-1H-pyrazolo[4,3- c]pyridazin-6(5H)-one Compound 64 5-(2-fluoro-6-methylphenyl)-3-(4-(2- (hydroxymethyl)morpholino)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 65 3-(4-(1-(2-(dimethylamino)ethyl)-1H-pyrazol- 4-yl)phenyl)-5-(2-fluoro-6-methoxyphenyl)- 1H-pyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 66 5-(2-fluoro-6-methoxyphenyl)-3-(2-(4- methylpiperazin-1-yl)thiazol-5-yl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 67 2-(4-(5-(2-fluoro-6-methoxyphenyl)-6-oxo- 5,6-dihydro-1H-pyrazolo[4,3-c]pyridazin-3- yl)-1H-pyrazol-1-yl)propionitrile Compound 68 2-(5-(2-fluoro-6-methoxyphenyl)-6-oxo-5,6- dihydro-1H-pyrazolo[4,3-c]pyridazin-3-yl)-6- methyl-5,6-dihydro-4H-pyrazolo[1,5- d][1,4]diazepin-7(8H)-one Compound 69 3-(1-(2-hydroxyl-2-methylpropyl)-1H-pyrazol- 4-yl)-5-(4-methylpyrid-3-yl)-1H-pyrazolo[4,3- c]pyridazin-6(5H)-one 138 Compound 70 4-(4-(5-(2-fluoro-6-methylphenyl)-6-oxo-5,6- dihydro-1H-pyrazolo[4,3-c]pyridazin-3- yl)phenyl)piperazinyl-1-carbonamide Compound 71 N-(4-(5-(2-fluoro-6-methylphenyl)-6-oxo-5,6- dihydro-1H-pyrazolo[4,3-c]pyridazin-3- yl)phenyl)-N-methyl-2-(4-methylpiperazin-1- yl)acetamide Compound 72 5-(2-fluoro-6-methoxyphenyl)-3-(2-methyl- 1,2,3,4-tetrahydroisoquinolin-6-yl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 73 5-(2-fluoro-6-methoxyphenyl)-3-(2-methyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 74 3-fluoro-5-methoxy-4-(3-(4-(4- methylpiperazin-1-yl)phenyl)-6-oxo-1Hpyrazolo[ 4,3-c]pyridazin-5(6H)-yl)benzonitrile Compound 75 5-(1,3-dihydroisobenzofuran-4-yl)-3-(4-(4- methylpiperazin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 76 5-(benzo[d][1,3]dioxacyclopent-4-yl)-3-(4-(4- methylpiperazin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 77 5-(2,4-difluoro-6-methoxyphenyl)-3-(4-(4- methylpiperazin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 78 5-(4-chloro-2-fluoro-6-methylphenyl)-3-(4-(4- methylpiperazin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one 139 Compound 79 3-fluoro-5-methoxy-N-methyl-4-(3-(4-(4- methylpiperazin-1-yl)phenyl)-6-oxo-1Hpyrazolo[ 4,3-c]pyridazin-5(6H)-yl)benzamide Compound 80 3-fluoro-5-methoxy-N,N-dimethyl-4-(3-(4-(4- methylpiperazin-1-yl)phenyl)-6-oxo-1Hpyrazolo[ 4,3-c]pyridazin-5(6H)-yl)benzamide Compound 81 5-(2-fluoro-6-methylphenyl)-3-(4-(4-(methyld3) piperazin-1-yl)phenyl)-1H-pyrazolo[4,3- c]pyridazin-6(5H)-one Compound 82 (S)-4-(3-(4-(4-(2-aminopropionyl)piperazin-1- yl)phenyl)-6-oxo-1H-pyrazolo[4,3- c]pyridazin-5(6H)-yl)-3-fluoro-5- methylbenzonitrile hydrochloride Compound 83 4-(3-(4-(4-(2-hydroxylpropionyl)piperazin-1- yl)phenyl)-6-oxo-1H-pyrazolo[4,3- c]pyridazin-5(6H)-yl)-3-fluoro-5- methylbenzonitrile Compound 84 3-(4-(4-(2,2-difluoroethyl)piperazin-1- yl)phenyl)-5-(2-fluoro-6-methylphenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 85 3-fluoro-5-methyl-4-(6-oxo-3-(4-(4- (tetrahydrofuran-3-yl)piperazin-1-yl)phenyl)- 1H-pyrazolo[4,3-c]pyridazin-5(6H)- yl)benzonitrile Compound 86 3-fluoro-5-methoxy-4-(3-(4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)-6-oxo-1Hpyrazolo[ 4,3-c]pyridazin-5(6H)-yl)benzonitrile 140 Compound 87 5-(2-fluoro-6-methylphenyl)-3-(4-((1S,4S)-5- methyl-2,5-diazabicyclo[2.2.1]heptan-2- yl)phenyl)-1H-pyrazolo[4,3-c]pyridazin- 6(5H)-one Compound 88 5-(2-fluoro-6-methylphenyl)-3-(4-((1R,4R)-5- methyl-2,5-diazabicyclo[2.2.1]heptan-2- yl)phenyl)-1H-pyrazolo[4,3-c]pyridazin- 6(5H)-one Compound 89 5-(2-fluoro-6-methylphenyl)-3-(4-(3,3,4- trimethylpiperazin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 90 5-(2-fluoro-6-methylphenyl)-3-(4-((3S,5R)- 3,4,5-trimethylpiperazin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 91 5-(2-fluoro-6-methylphenyl)-3-(4-(6-methyl- 3,6-diazabicyclo[3.1.1]heptan-3-yl)phenyl)- 1H-pyrazolo[4,3-c]pyridazin-6(5H)-one Compound 92 5-(2-fluoro-6-methoxyphenyl)-3-(4- morpholinophenyl)-1H-pyrazolo[4,3- c]pyridazin-6(5H)-one Compound 93 5-(2-fluoro-6-methylphenyl)-3-(4-(piperazin- 2-ylmethoxy)phenyl)-1H-pyrazolo[4,3- c]pyridazin-6(5H)-one Compound 94 3-(3-fluoro-4-(4-methylpiperazin-1- yl)phenyl)-5-(2-fluoro-6-methylphenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 95 3-(3-((dimethylamino)methyl)-4-(4- methylpiperazin-1-yl)phenyl)-5-(2-fluoro-6- methylphenyl)-1H-pyrazolo[4,3-c]pyridazin- 6(5H)-one 141 Compound 96 3-(3-((methylamino)methyl)-4-(4- methylpiperazin-1-yl)phenyl)-5-(2-fluoro-6- methylphenyl)-1H-pyrazolo[4,3-c]pyridazin- 6(5H)-one Compound 97 5-(2-methoxy-6-methylphenyl)-3-(6-(4- methylpiperazin-1-yl)pyrid-3-yl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 98 5-(2-ethyl-6-fluorophenyl)-3-(6-(4- methylpiperazin-1-yl)pyrid-3-yl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 99 3-fluoro-5-methyl-4-(3-(6-(4-methylpiperazin- 1-yl)pyrid-3-yl)-6-oxo-1H-pyrazolo[4,3- c]pyridazin-5(6H)-yl)benzonitrile Compound 100 5-(2-fluoro-6-hydroxylphenyl)-3-(6-(4- methylpiperazin-1-yl)pyrid-3-yl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one hydrobromide Compound 101 3-(6-(4-ethylpiperazin-1-yl)pyrid-3-yl)-5-(2- fluoro-6-methylphenyl)-1H-pyrazolo[4,3- c]pyridazin-6(5H)-one Compound 102 3-(6-(4-acetylpiperazin-1-yl)pyrid-3-yl)-5-(2- fluoro-6-methylphenyl)-1H-pyrazolo[4,3- c]pyridazin-6(5H)-one Compound 103 5-(2-fluoro-6-methylphenyl)-3-(6-(4-(oxetan- 3-yl))piperazin-1-yl)pyrid-3-yl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 104 3-(6-(1,1-dioxidothiomorpholino)pyrid-3-yl)- 5-(2-fluoro-6-methylphenyl)-1H-pyrazolo[4,3- c]pyridazin-6(5H)-one Compound 105 3-(6-(4-(ethylsulfonyl)piperazin-1-yl)pyrid-3- yl)-5-(2-fluoro-6-methylphenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one 142 Compound 106 5-(2-fluoro-6-methylphenyl)-3-(6-(4- (tetrahydrofuran-3-yl)piperazin-1-yl)pyrid-3- yl)-1H-pyrazolo[4,3-c] pyridazin-6(5H)-one Compound 107 5-(2-chloro-6-fluorophenyl)-3-(6-(4- methylpiperazin-1-yl)pyrid-3-yl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 108 5-(4-chloro-2-fluoro-6-methylphenyl)-3-(4-(4- methylpiperazin-1-yl)pyrid-3-yl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 109 5-(2-fluoro-6-methylphenyl)-3-(6-(8-methyl- 3,8-diazabicyclo[3.2.1]octan-3-yl)pyrid-3-yl)- 1H-pyrazolo[4,3-c]pyridazin-6(5H)-one Compound 110 5-(2-ethyl-6-fluorophenyl)-3-(2-(4- methylpiperazin-1-yl)pyrimidin-5-yl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 111 5-(2-fluoro-6-methoxyphenyl)-3-(2- morpholinyl-pyrimidin-5-yl)-1H-pyrazolo[4,3- c]pyridazin-6(5H)-one Compound 112 5-(2-ethyl-6-fluorophenyl)-3-(4-(4-(2- hydroxyethyl)piperazin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 113 5-(2-fluoro-6-methoxyphenyl)-3-(4-(4-(2- hydroxyethyl)piperazin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)–one Compound 114 3-fluoro-4-(3-(4-(4-(2-hydroxyethyl)piperazin- 1-yl)phenyl)-6-oxo-1H-pyrazolo[4,3- c]pyridazin-5(6H)-yl)-5-methoxybenzonitrile Compound 115 5-(2-fluoro-6-methoxyphenyl)-3-(4-(4-(2- hydroxyl-2-methylpropyl)piperazin-1- yl)phenyl)-1H-pyrazolo[4,3-c]pyridazin- 6(5H)-one 143 Compound 116 5-(2-ethyl-6-fluorophenyl)-3-(4-(4-(2- hydroxyl-2-methylpropyl)piperazin-1- yl)phenyl)-1H-pyrazolo[4,3-c]pyridazin- 6(5H)-one Compound 117 5-(2-fluoro-6-methylphenyl)-3-(4-(8-(2- hydroxyethyl)-3,8-diazabicyclo[3.2.1]octan-3- yl)phenyl)-1H-pyrazolo[4,3-c]pyridazin- 6(5H)-one Compound 118 5-(2-fluoro-6-methylphenyl)-3-(6-(4-(2- hydroxyethyl)piperazin-1-yl)pyrid-3-yl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 119 5-(2-fluoro-6-methylphenyl)-3-(6-(4-(2- methoxyethyl)piperazin-1-yl)pyrid-3-yl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 120 5-(2-fluoro-6-methylphenyl)-3-(4-(3- (hydroxymethyl)-4-methylpiperazin-1- yl)phenyl)-1H-pyrazolo[4,3-c]pyridazin- 6(5H)-one Compound 121 5-(2-fluoro-6-methoxyphenyl)-3-(4-(3- (hydroxymethyl)-4-methylpiperazin-1- yl)phenyl)-1H-pyrazolo[4,3-c]pyridazin- 6(5H)-one Compound 122 7-(4-(5-(2-fluoro-6-methylphenyl)-6-oxo-5,6- dihydro-1H-pyrazolo[4,3-c]pyridazin-3- yl)phenyl)tetrahydro-1H-oxazolo[3,4- a]pyrazin-3(5H)-one Compound 123 7-(4-(5-(2-fluoro-6-methoxyphenyl)-6-oxo- 5,6-dihydro-1H-pyrazolo[4,3-c]pyridazin-3- yl)phenyl)tetrahydro-1H-oxazolo[3,4- a]pyrazin-3(5H)-one Compound 124 3-fluoro-5-methoxy-4-(6-oxo-3-(4-(3- oxotetrahydro-1H-oxazolo[3,4-a]pyrazin- 7(3H)-yl)phenyl)-1H-pyrazolo[4,3- c]pyridazin-5(6H)-yl)benzonitrile Compound 125 5-(2-fluoro-6-methylphenyl)-3-(4-(3-(2- hydroxylprop-2-yl)-4-methylpiperazin-1- yl)phenyl)-1H-pyrazolo[4,3-c]pyridazin- 6(5H)-one 144 Compound 126 5-(2-fluoro-6-methoxyphenyl)-3-(4-(3-(2- hydroxylprop-2-yl)-4-methylpiperazin-1- yl)phenyl)-1H-pyrazolo[4,3-c]pyridazin- 6(5H)-one Compound 127 5-(2-fluoro-6-methoxyphenyl)-3-(4-(3-(2- methoxyprop-2-yl)-4-methylpiperazin-1- yl)phenyl)-1H-pyrazolo[4,3-c]pyridazin- 6(5H)-one Compound 128 5-(2-fluoro-6-methylphenyl)-3-(6-(3- (hydroxymethyl)-4-methylpiperazin-1- yl)pyrid-3-yl)-1H-pyrazolo[4,3-c]pyridazin- 6(5H)-one Compound 129 7-(5-(5-(2-fluoro-6-methylphenyl)-6-oxo-5,6- dihydro-1H-pyrazolo[4,3-c]pyridazin-3- yl)pyridin-2-yl)tetrahydro-1H-oxazolo[3,4- a]pyrazin-3(5H)-one Compound 130 5-(2-fluoro-6-methylphenyl)-3-(4-(2- (hydroxymethyl)-4-methylpiperazin-1- yl)phenyl)-1H-pyrazolo[4,3-c]pyridazin- 6(5H)-one Compound 131 4-(4-(5-(2-fluoro-6-methylphenyl)-6-oxo-5,6- dihydro-1H-pyrazolo[4,3-c]pyridazin-3- yl)phenyl)-1-methylpiperazin-2-carboxylic acid Compound 132 8-(4-(5-(2-fluoro-6-methoxyphenyl)-6-oxo- 5,6-dihydro-1H-pyrazolo[4,3-c]pyridazin-3- yl)phenyl)-2-methylhexahydro-1Hpyrazino[ 1,2-a]pyrazin-4(6H)-one Compound 133 (S)-5-(2-fluoro-6-methylphenyl)-3-(4- (hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)- yl)phenyl)-1H-pyrazolo[4,3-c]pyridazin- 6(5H)-one Compound 134 (R)-5-(2-fluoro-6-methylphenyl)-3-(4- (hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)- yl)phenyl)-1H-pyrazolo[4,3-c]pyridazin- 6(5H)-one Compound 135 (S)-5-(2-fluoro-6-methoxyphenyl)-3-(4- (hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)- yl)phenyl)-1H-pyrazolo[4,3-c]pyridazin- 6(5H)-one 145 Compound 136 (R)-5-(2-fluoro-6-methoxyphenyl)-3-(4- (hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)- yl)phenyl)-1H-pyrazolo[4,3-c]pyridazin- 6(5H)-one Compound 137 3-(4-(5,6-dihydroimidazolo[1,2-a]pyrazin- 7(8H)-yl)phenyl)-5-(2-fluoro-6- methylphenyl)-1H-pyrazolo[4,3-c]pyridazin- 6(5H)-one Compound 138 5-(2-fluoro-6-methylphenyl)-3-(4-(4- hydroxylpiperidin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 139 5-(2-fluoro-6-methoxyphenyl)-3-(4-(4- hydroxylpiperidin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 140 5-(2-fluoro-6-methoxyphenyl)-3-(4-(4- hydroxyl-4-methylpiperidin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 141 5-(2-fluoro-6-methoxyphenyl)-3-(4-(4- methoxy-4-methylpiperidin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 142 5-(2-fluoro-6-methylphenyl)-3-(4-(4- morpholinopiperidin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 143 5-(2-fluoro-6-methylphenyl)-3-(4-(4-(4- methylpiperazin-1-yl)piperidin-1-yl)phenyl)- 1H-pyrazolo[4,3-c]pyridazin-6(5H)-one Compound 144 5-(2-fluoro-6-methoxyphenyl)-3-(4-(4- morpholinopiperidin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 145 5-(2-fluoro-6-methoxyphenyl)-3-(4-(4-(4- methylpiperazin-1-yl)piperidin-1-yl)phenyl)- 1H-pyrazolo[4,3-c]pyridazin-6(5H)-one Compound 146 3-(4-(4-amino-4-methylpiperidin-1-yl)phenyl)- 5-(2-fluoro-6-methoxyphenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one 146 Compound 147 3-(4-(4-(dimethylamino)-4-methylpiperidin-1- yl)phenyl)-5-(2-fluoro-6-methoxyphenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 148 N N N NH OF O S N N O 5-(2-fluoro-6-methoxyphenyl)-3-(2- morpholinothiazol-5-yl)-1H-pyrazolo[4,3- c]pyridazin-6(5H)-one Compound 149 5-(6-methoxy-4-methylpyrid-3-yl)-3-(4-(4- methylpiperazin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 150 3-(4-(1-methyl-1,2,3,6-tetrahydropyridin-4- yl)phenyl)-5-(4-methylpyrid-3-yl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 151 5-(4-methoxypyrid-3-yl)-3-(4-(1-methyl- 1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 152 5-(4-methoxypyrid-3-yl)-3-(4-(1-methyl-1Hpyrazol- 4-yl)phenyl)-1H-pyrazolo[4,3- c]pyridazin-6(5H)-one Compound 153 5-(3-methoxypyrid-4-yl)-3-(4-(4- methylpiperazin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 154 5-(2-fluoro-6-methoxyphenyl)-7-methyl-3-(4- (4-methylpiperazin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 155 5-(2-fluoro-6-methoxyphenyl)-7-methyl-3-(4- morpholinophenyl)-1H-pyrazolo[4,3- c]pyridazin-6(5H)-one 147 Compound 156 5-(2-fluoro-6-methylphenyl)-3-(2-methyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 157 5-(2-fluoro-6-methylphenyl)-3-(2-(methyl-d3) - 1,2,3,4-tetrahydroisoquinolin-7-yl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 158 5-(2,4-difluoro-6-methoxyphenyl)-3-(2- methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)- 1H-pyrazolo[4,3-c]pyridazin-6(5H)-one Compound 159 3-fluoro-5-methoxy-4-(3-(2-methyl-1,2,3,4- tetrahydroisoquinolin-7-yl)-6-oxo-1Hpyrazolo[ 4,3-c]pyridazin-5(6H)-yl)benzonitrile Compound 160 5-(2-ethyl-6-fluorophenyl)-3-(2-methyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 161 5-(2-fluoro-6-methylphenyl)-3-(1,2,3,4- tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3- c]pyridazin-6(5H)-one hydrochloride Compound 162 5-(2-fluoro-6-methylphenyl)-3-(2-(2- hydroxyethyl)-1,2,3,4-tetrahydroisoquinolin-7- yl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one Compound 163 3-(2-(3-aminocyclobutyl)-1,2,3,4- tetrahydroisoquinolin-7-yl)-5-(2-fluoro-6- methylphenyl)-1H-pyrazolo[4,3-c]pyridazin- 6(5H)-one hydrochloride 148 Compound 164 3-(2-(azetidin-3-yl)-1,2,3,4- tetrahydroisoquinolin-7-yl)-5-(2-fluoro-6- methylphenyl)-1H-pyrazolo[4,3-c]pyridazin- 6(5H)-one hydrochloride Compound 165 5-(2-fluoro-6-methylphenyl)-3-(2-(1- hydroxylprop-2-yl)-1,2,3,4- tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3- c]pyridazin-6(5H)-one Compound 166 3-(2-(2,2-difluoroethyl)-1,2,3,4- tetrahydroisoquinolin-7-yl)-5-(2-fluoro-6- methoxyphenyl)-1H-pyrazolo[4,3-c]pyridazin- 6(5H)-one Compound 167 5-(2-fluoro-6-methylphenyl)-3-(2-(tetrahydro- 2H-pyran-4-yl)-1,2,3,4-tetrahydroisoquinolin- 7-yl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one Compound 168 5-(2-fluoro-6-methylphenyl)-3-(2-(1- methylpiperidin-4-yl)-1,2,3,4- tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3- c]pyridazin-6(5H)-one Compound 169 5-(2-fluoro-6-methylphenyl)-3-(2-(2- morpholinoacetyl)-1,2,3,4- tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3- c]pyridazin-6(5H)-one Compound 170 3-fluoro-5-methyl-4-(3-(2-methyl-1,2,3,4- tetrahydroisoquinolin-7-yl)-6-oxo-1Hpyrazolo[ 4,3-c]pyridazin-5(6H)-yl)benzonitrile 149 Compound 171 3-fluoro-5-methyl-4-(3-(1,2,3,4- tetrahydroisoquinolin-7-yl)-6-oxo-1Hpyrazolo[ 4,3-c]pyridazin-5(6H)-yl)benzonitrile Compound 172 3-fluoro-4-(3-(2-(2-hydroxylacetyl)-1,2,3,4- tetrahydroisoquinolin-7-yl)-6-oxo-1Hpyrazolo[ 4,3-c]pyridazin-5(6H)-yl)-5- methylbenzonitrile Compound 173 3-fluoro-4-(3-(2-(2-hydroxylpropionyl)- 1,2,3,4-tetrahydroisoquinolin-7-yl)-6-oxo-1Hpyrazolo[ 4,3-c]pyridazin-5(6H)-yl)-5- methylbenzonitrile Compound 174 3-fluoro-4-(3-(2-(2-aminoacetyl)-1,2,3,4- tetrahydroisoquinolin-7-yl)-6-oxo-1Hpyrazolo[ 4,3-c]pyridazin-5(6H)-yl)-5- methylbenzonitrile hydrochloride Compound 175 (S)-3-fluoro-4-(3-(2-(2-aminopropionyl)- 1,2,3,4-tetrahydroisoquinolin-7-yl)-6-oxo-1Hpyrazolo[ 4,3-c]pyridazin-5(6H)-yl)-5- methylbenzonitrile hydrochloride Compound 176 (S)-5-(2-fluoro-6-methylphenyl)-3-(3- (hydroxymethyl)-2-methyl-1,2,3,4- tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3- c]pyridazin-6(5H)-one Compound 177 (S)-7-(5-(2-fluoro-6-methylphenyl)-6-oxo-5,6- dihydro-1H-pyrazolo[4,3-c]pyridazin-3-yl)- 10,10a-dihydro-1H-oxazolo[3,4-b]isoquinolin- 3(5H)-one 150 Compound 178 5-(2-fluoro-6-methylphenyl)-3-(2,3,3- trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)- 1H-pyrazolo[4,3-c]pyridazin-6(5H)-one Compound 179 (R)-5-(2-fluoro-6-methylphenyl)-3-(3- (hydroxymethyl)-2-methyl-1,2,3,4- tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3- c]pyridazin-6(5H)-one Compound 180 (S)-5-(2-fluoro-6-methylphenyl)-3-(3- (methoxymethyl)-2-methyl-1,2,3,4- tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3- c]pyridazin-6(5H)-one Compound 181 (S)-5-(2-fluoro-6-methylphenyl)-3- (1,3,4,6,11,11a-hexahydro-[1,4]oxazino[4,3- b]isoquinolin-8-yl)-1H-pyrazolo[4,3- c]pyridazin-6(5H)-one Compound 182 7-(5-(2-fluoro-6-methylphenyl)-6-oxo-5,6- dihydro-1H-pyrazolo[4,3-c]pyridazin-3-yl)-2- methyl-1,2-dihydroisoquinolin-3(4H)-one Compound 183 7-(5-(2-fluoro-6-methylphenyl)-6-oxo-5,6- dihydro-1H-pyrazolo[4,3-c]pyridazin-3-yl)-2- methyl-3,4-dihydroisoquinolin-1(2H)-one Compound 184 5-(2-fluoro-6-methylphenyl)-3-(1- (hydroxymethyl)-2-methyl-1,2,3,4- tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3- c] pyridazin-6(5H)-one Compound 185 9-(5-(2-fluoro-6-methylphenyl)-6-oxo-5,6- dihydro-1H-pyrazolo[4,3-c]pyridazin-3-yl)- 5,6-dihydro-1H-oxazolo[4,3-a]isoquinolin- 3(10bH)-one 151 Compound 186 3-(1-(aminomethyl)-2-methyl-1,2,3,4- tetrahydroisoquinolin-7-yl)-5-(2-fluoro-6- methylphenyl)-1H-pyrazolo[4,3-c]pyridazin- 6(5H)-one hydrochloride Compound 187 5-(2-fluoro-6-methylphenyl)-3-(6-methyl- 5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 188 3-(8-fluoro-2-methyl-1,2,3,4- tetrahydroisoquinolin-7-yl)-5-(2-fluoro-6- methylphenyl)-1H-pyrazolo[4,3-c]pyridazin- 6(5H)-one Compound 189 3-(6-fluoro-2-methyl-1,2,3,4- tetrahydroisoquinolin-7-yl)-5-(2-fluoro-6- methylphenyl)-1H-pyrazolo[4,3-c]pyridazin- 6(5H)-one Compound 190 3-(8-fluoro-2-methyl-1,2,3,4- tetrahydroisoquinolin-7-yl)-5-(2-fluoro-6- methoxyphenyl)-1H-pyrazolo[4,3-c]pyridazin- 6(5H)-one Compound 191 3-(6-fluoro-2-methyl-1,2,3,4- tetrahydroisoquinolin-7-yl)-5-(2-fluoro-6- methoxyphenyl)-1H-pyrazolo[4,3-c]pyridazin- 6(5H)-one Compound 193 3-(2-(azetidin-3-yl)-1,2,3,4- tetrahydroisoquinolin-6-yl)-5-(2-fluoro-6- methylphenyl)-1H-pyrazolo[4,3-c] pyridazin- 6(5H)-one hydrochloride Compound 194 5-(2-fluoro-6-methylphenyl)-3-(2-(1- methylazetidin-3-yl)-1,2,3,4- tetrahydroisoquinolin-6-yl)-1H-pyrazolo[4,3- c]pyridazin-6(5H)-one 152 Compound 195 5-(2-fluoro-6-methylphenyl)-3-(2-(tetrahydro- 2H-pyran-4-yl)-1,2,3,4-tetrahydroisoquinolin- 6-yl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one Compound 196 5-(2-fluoro-6-methylphenyl)-3-(2-(1- methylpiperidin-4-yl)-1,2,3,4- tetrahydroisoquinolin-6-yl)-1H-pyrazolo[4,3- c]pyridazin-6(5H)-one hydrochloride Compound 197 5-(2-fluoro-6-methylphenyl)-3-(2- methylisoindolin-5-yl)-1H-pyrazolo[4,3- c]pyridazin-6(5H)-one Compound 198 5-(2-fluoro-6-methylphenyl)-3-(3-(4- methylpiperazin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 199 5-(2-fluoro-6-methoxyphenyl)-3-(3-(4- methylpiperazin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 200 5-(2-ethyl-6-fluorophenyl)-3-(3-(4- methylpiperazin-1-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 201 5-(2-fluoro-6-methylphenyl)-3-(3-(8-methyl- 3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)-1Hpyrazolo[ 4,3-c ]pyridazin-6(5H)-one Compound 202 5-(2-fluoro-6-methoxyphenyl)-3-(3-(8-methyl- 3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 203 3-fluoro-5-methoxy-4-(3-(3-(8-methyl-3,8- diazabicyclo[3.2.1]octan-3-yl)phenyl)-6-oxo- 1H-pyrazolo[4,3-c]pyridazin-5(6H)- yl)benzonitrile 153 Compound 204 3-(3-(3-aminopiperidin-1-yl)phenyl)-5-(2- fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3- c]pyridazin-6(5H)-one hydrochloride Compound 205 3-(3-(4-aminopiperidin-1-yl)phenyl)-5-(2- fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3- c]pyridazin-6(5H)-one Compound 206 3-(3-(4-hydroxylpiperidin-1-yl)phenyl)-5-(2- fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3- c]pyridazin-6(5H)-one Compound 207 3-(2-fluoro-3-(4-methylpiperazin-1- yl)phenyl)-5-(2-fluoro-6-methylphenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 208 3-(2-fluoro-5-(4-methylpiperazin-1- yl)phenyl)-5-(2-fluoro-6-methylphenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 209 3-(2-fluoro-3-(4-methylpiperazin-1- yl)phenyl)-5-(2-fluoro-6-methoxyphenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one Compound 210 3-(2-fluoro-5-(4-methylpiperazin-1- yl)phenyl)-5-(2-fluoro-6-methoxyphenyl)-1Hpyrazolo[ 4,3-c]pyridazin-6(5H)-one
  15. 15. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt, hydrate, solvate, isotope labeled compound, or isomer thereof according to any of claims 1-14 and a pharmaceutically acceptable carrier.
  16. 16. Use of the compound or a pharmaceutically acceptable salt, hydrate, solvate, isotope labeled compound, or isomer thereof, or a pharmaceutical composition thereof according to any of claims 1-14, or the pharmaceutical composition of claim 15 in the preparation of a medicament 154 for the prevention or treatment of a disease mediated with HPK1, wherein the disease is selected from the group consisting of benign or malignant tumors, myelodysplastic syndromes and diseases caused by a virus.
  17. 17. The use according to claim 16, wherein the benign or malignant tumor is selected from the group consisting of leukemia, lymphoma, multiple myeloma, lung cancer, hepatocellular carcinoma, cholangiocarcinoma, gallbladder cancer, gastric cancer, colorectal cancer, intestinal leiomyosarcoma, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, vaginal cancer, malignant teratoma, pancreatic cancer, pancreatic ductal adenocarcinoma, nasopharyngeal cancer, oral cancer, laryngeal cancer, esophageal squamous cell carcinoma, thyroid cancer, kidney cancer, bladder cancer, malignant brain tumor, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, osteofibrosarcoma, malignant thymoma, malignant peripheral nerve sheath tumor, prostate cancer, testicular cancer, penile cancer and other malignant tumors, and benign and malignant tumors of the skin.
  18. 18. The use according to claim 16, wherein the virus is selected from the group consisting of hepatitis virus, human immunodeficiency virus, human papillomavirus, herpes simplex virus, measles virus, norovirus, Boca virus, Coxsackie virus, Ebola virus, enterovirus, lymphocytic meningitis virus, influenza virus, SARS virus, and COVID-19 virus.

Description

CA 03191362 2023-3-1 Pyrazolopyridazinone Compound, and Pharmaceutical Composition and Use Thereof TECHNICAL FIELD The present application relates to a pyrazolopyridazinone compound, particularly a pyrazolopyridazinone derivative with HPKl inhibitory activity. BACKGROUND ART Hematopoietic progenitor kinase 1 (HPKl), belonging to the mitogen-activated protein kinase kinase kinase kinase-4 (MAP4K) family, is a serine/threonine kinase originally cloned from hematopoietic progenitor cells (Hu, M. C. et al., Genes Dev. 1996; 10: 2251-2264; Keifer, F. et al, The EMBO Journal 1996; 15: 7013-7025). HPKl is mainly distributed in lymphoid organs and lymphoid tissues, such as bone marrow, lymph nodes, thymus, etc., and is expressed predominantly in immune cells (T cells, B cells, dendritic cells, macrophages, etc.) (Hu, M.C. et al., Genes Dev. 1996; 10:2251-2264). This has drawn attention to the immunomodulatory role of HPKl. Studies have shown that HPKl is a negative regulator of the T cell receptor (TCR) signaling pathway. TCR signaling causes the activation of HPKl, and subsequently binding to SLP-76 protein (Lasserre, R. et al., J Cell Biol. 2011; 195: 839-853; Shui, J. et al., Nature Immuno. 2007; 8: 84-91). Activated HPKl phosphorylates the Ser376 residue of SLP-76, promoting the binding of SLP-76 to 14-3-3 protein (Di Bartolo, V. et al., J. Exp. Med. 2007; 204: 681-691; Shui, J. et al, Nature Immuno. 2007; 8: 84-91). The SLP- 76/14-3-3 interaction downregulates ERK signaling and calcium flux, and triggers the ubiquitination of SLP-76. The degradation of the SLP-76 complex blocks the TCR activation pathway consequently, thereby inhibiting T cell function (Lasserre, R. et al, J. Cell Biol. 2011; 195: 839-853). In in vivo experiments, HPKl knockout mice showed enhanced T cell function under antigen stimulation and produced more cytokines, such as IL-2 and IFN-y (Shui, J. et al., Nature Immuno. 2007; 8: 84- 91; Alzabin, S. et al, J. Immunol. 2009; 182: 6187-6194; Alzabin, S. et al, Cancer Immunol. Immunother. 2010; 59: 419-429). Further studies demonstrated that the kinase activity ofHPKl plays a key role in the negative regulation of immune cells. Compared with wild-type mice, mice with blockade of the kinase activity 1 CA 03191362 2023-3-1 of HPKl showed enhanced CDS+ T cell function, faster clearance of chronic lymphocytic meningitis virus, and better inhibition of tumor growth (Hernandez, S. et al., Cell Reports 2018; 25: 80-94). In Lewis lung cancer (LLC) model, mice transfected with HPK1-1- T cells exhibited stronger antitumor immune responses than wild-type (Sawasdikosol, S. et al., Immunol. Res. 2012; 54: 262-265). Similar studies revealed that the immunosuppressive effects ofHPKl on B cells (Sauer, K. et al., J. Biol. Chem. 2001; 276: 45207-45216; Tsuji, S. et al., J. Exp. Med. 2001; 194: 529-539; Wang, X. et al, J. Biol. Chem. 2012; 287: 34091-34100; Konigsberger, S. et al, PLos One, 2010; 5: e12468), dendritic cells (Alzabin, S. et al, J. Immunol. 2009; 182: 6187-6194), NK cells and Treg cells are also derived from its kinase activity(Liu, J. et al., PLos One, 2019; 14: e0212670). Clinical studies have found that, comparing with health controls, the HPKl levels were significantly downregulated in tissues from patients of systemic lupus erythematosus (Zhang, Q. et al, J. Autoimmun., 2011; 37: 180-189) and psoriatic arthritis (Stoeckman, A. K. et al, Genes Immun 2006; 7: 583-591; Baltiwalla, F. M. et al., Mol. Med. 2005; 11: 21- 29), suggesting that HPKl downregulation contributes to the enhancement of autoimmune responses. On the other hand, upregulation of HPKl levels has been observed in various cancers, such as acute myeloid leukemia (Chen-Deutsch, X. et al., Leuk. Res. 2012; 36: 884-888; Chen-Deutsch, X. et al., Cell Cycle 2012; 11: 1364-1373), bladder urothelial carcinoma (Wang. Y et al, Mol. Med. Rep. 2012; 5: 260-265), extramammary Paget's disease (Qian, Yet al, Am J. Dermatopathol. 2011; 33: 681-686) and colon cancer (Yang, H.S. et al., Mol. Cell Biol. 2006; 26: 1297-1306). Therefore, HPKl is a potential target for the treatment of tumors and viral diseases. The development of small-molecule inhibitors of HPKl kinase holds important clinical promise. Although some patent applications for small molecule HPKl inhibitors have been published, such as WO2018049191, WO2018049200, WO2018102366, WO2018183964, WO2019090198, WO2019206049, WO2019238067 and WO2020092528, no drug targeting HPKl has been approved yet. Therefore, the development of novel smallmolecule HPKl inhibitors with good activity is still an urgent need. SUMMARY A main purpose of this application is to provide a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope labeled compound, isomer or prodrug thereof, 2 CA 03191362 2023-3-1 (I) wherein, R 1 is selected from: 1) hydrogen, halogen, cyano, -C(=O)NRaRh, -ORa and-NRaRb; 2) Ct-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-s cycl