Pyrazolopyridazinone compound, and pharmaceutical composition and use thereof

A compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope labeled compound, stereoisomer or prodrug 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)NR a2Rb2, —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, —NRc2C(═O)NRa2Rb2, —NRe2C(═NRd2)NRa2Rb2, —NRa2S(═O)2Rc2, —NRe2S(═O)2NRa2Rb2, nitro, —PRc2Rf2, —P(═O)Rc2Rf2 and phosphonic acid group;
• 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 alicyclic 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, —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 Rc4 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 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, —NRc3C(═O)NRa3Rb3, —NRc3C(═NRc3)NRa3Rb3, —NRa3S(═O)2Rc3, —NRc3S(═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 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, C3-10 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, —NRc7C(═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:
• 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.