TW202532075A - Echinacea compounds and their applications - Google Patents

Abstract

Disclosed are an ecteinascidin compound and a use thereof. The present invention provides a compound as shown in formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled compound, metabolite, or prodrug thereof. The compound provided by the present invention exhibits one or more effects selected from the following group: (1) having inhibitory activity on in vitro proliferation of tumor cells; (2) having in vivo antitumor effect; (3) having in vivo tumor-targeting ability; and (4) having good in vivo safety.

Description

Echinacea compounds and their applications

Field of Invention This application claims priority to Chinese Patent Application No. 2024101788699, filed on February 8, 2024; No. 2024110452422, filed on July 31, 2024; No. 2024113891578, filed on September 30, 2024; and No. 2025101161329, filed on January 24, 2025. This application incorporates the full text of the aforementioned Chinese patent applications.

The present invention belongs to the field of medical technology, and specifically relates to ecteinascidin compounds and their applications.

Background of the Invention Cancer is a serious malignancy that threatens human health, claiming over 5 million lives worldwide each year. In recent years, the incidence of tumors has been increasing annually, with the highest mortality rate among all diseases. Chemotherapy is currently a common and effective cancer treatment. However, due to the multidrug resistance of cancer cells and the severe side effects of existing anticancer drugs, there is an urgent need for new anticancer drugs with improved efficacy and minimal side effects.

Et-743 (Trabectedin) is a highly effective antitumor agent isolated from the marine tunicate Ecteinascidia turbinata. It has been approved in the EU and the US for the treatment of advanced soft tissue neoplasia. Lurbinectedin (PM01183), a structural analog of trabectedin, was approved in the US in 2020 for the treatment of small cell lung cancer. Lurbinectedin exerts its anticancer effects through covalent modification of guanine residues in the minor groove of DNA, ultimately leading to DNA double-strand breaks, S-phase arrest, and apoptosis in cancer cells. There is still a need to continue developing ectocystin compounds with better efficacy and lower toxicity to meet more clinical needs.

Summary of the Invention The technical problem to be solved by the present invention is to overcome the shortcomings of existing drugs, thereby providing an ectodermin compound and its application. The ectodermin compound of the present invention has one or more effects selected from the following group: (1) having inhibitory activity on the proliferation of tumor cells in vitro; (2) having an in vivo tumor-suppressing effect; (3) having in vivo tumor-targeting ability; and (4) having good in vivo safety.

The present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof: wherein R ¹ is hydrogen, deuterium, halogen, -OH, -CN, -NH ₂ , C _1-6 alkyl, -OC _1-6 alkyl, -NHC _1-6 alkyl, -NH-S(O) ₂ -R ^1-2 , -C(O)R ^1-2 , C(O)-N(R ^1-1 )R ^1-2 , -C _1-6 alkylene-N(R ^1-1 )-C(O)R ^1-2 , -OC _3-12 cycloalkyl, -O-(4- to 12-membered heterocycloalkylene)-C(O)R ^1-2 , -OC _3-12 cycloalkylene-N(R ^1-1 )-C(O)R ^1-2 , -OC(O)-N(R ^1-1 )R ^1-2 , -N(R ^1-1 )-C(O)R ^1-2 , -N(R ^1-1 )-C(O)-OR ^1-2 , -N(R ^1-1 )-(4- to 12-membered heterocycloalkylene)-C(O)R ^1-2 , -N(R ^1-1 )-C _{3-12cycloalkylene} -N(R ^1-3 )-C(O)R ^1-2 , -(4- to 12-membered heterocycloalkylene)-C(O)R ^1-2 , -(4- to 12-membered heterocycloalkylene)-N(R ^1-1 )-C(O)R ^1-2 , -N(R ^1-1 )C(O)C _{3-12cycloalkylene} , (4- to 12-membered heterocycloalkylene) or -N(R ^1-1 )C(O)(4 to 12-membered heterocycloalkyl), wherein the C _1-6 alkyl, C _1-6 alkylene, C _3-12 cycloalkyl, C _3-12 cycloalkylene, 4 to 12-membered heterocycloalkylene and 4 to 12-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halogen, -OH, -SH, -NH ₂ , -NHC _1-6 alkyl, -SC _1-6 alkyl, -C _1-6 alkylene-OH, -C _1-6 alkylene-SH, -C _1-6 alkylene-S(C _1-6 alkyl) and -C _1-6 alkylene-NH ₂ ; R ² is hydrogen, deuterium, halogen, -C _1-6 alkyl, -OH, -OC(O)-N(R ^2-1 )R ^2-2 , -C(O)R ^2-2 , C(O)-N( ^R2-1 ) ^R2-2 , _-NH2 , -NHC1-6alkyl, -NHC(O) _C1-6alkyl , -N( _R2-1 )-C(O) ^-OR2-2 , -N( ^R2-1 )-C(O)-N( ^R2-1 ) ^R2-2 , -NHC(O) _{C3-12cycloalkyl} , -NHC(O)(4- to 12-membered heterocycloalkyl), -N( _C1-6alkyl )C(O) _C1-6alkyl , -N( _C1-6alkyl )C(O)C3-12cycloalkyl, C(O) ⁽ _4- to 12-membered heterocycloalkyl), -N( _C1-6alkyl )C(O)(4- to 12-membered heterocycloalkyl), or -NH-S(O) ₂ -R ^2-2 , said C _1-6 alkyl, C _3-12 cycloalkyl and 4 to 12 membered heterocycloalkyl are each optionally substituted by one or more substituents selected from halogen, -OH, -O-NHCH ₃ , -SH, -NH ₂ , -NHC _1-6 alkyl and -SC _1-6 alkyl; R ³ is hydrogen, deuterium, -C _1-6 alkyl, -CH ₂ -NHC _1-6 alkyl, -CH ₂ -NHC(O)C _1-6 alkyl, -CH ₂ -OC(O)-NR ^3-1 R ^3-2 , -CH ₂ -NR ^3-1 C(O)NR ^3-1 -R ^3-2 , -CH ₂ -NR ^3-1 C(O)OR ^3-2 , -CH ₂ -NHC(O)C _3-12 cycloalkyl, -CH ₂ -NHC(O)(4- to 12-membered heterocycloalkyl), -CH ₂ -N(C _1-6 alkyl)C(O)C _1-6 alkyl, -CH ₂ -N(C _1-6 alkyl)C(O)C _3-12 cycloalkyl, -CH ₂ -N(C _1-6 alkyl)C(O)(4- to 12-membered heterocycloalkyl), -CH ₂ NH-S(O) ₂ -R ^3-2 , -CH ₂ -S(O) ₂ -R ^3-2 or -C(O)R ^3-2 , wherein the C _1-6 alkyl, C _3-12 cycloalkyl and 4- to 12-membered heterocycloalkyl are each optionally substituted by one or more groups selected from halogen, cyclopropyl, -OH, -O-NHCH ₃ , -SH, -NH ₂ , -NHC _1-6 alkyl and -SC ^R4 is hydrogen, deuterium, -C1-6 alkyl, -C(O) _C1-6 alkyl, -C(O) _{C3-12 cycloalkyl} or -C(O)(4 to 12 membered heterocycloalkyl), said _C1-6 alkyl, _C3-12 cycloalkyl and 4 to 12 membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halogen, -OH, -SH, _-NH2 , _-NHC1-6 alkyl and _-SC1-6 alkyl; or ^R3 and ^R4 together with the atoms to which they are attached form a _5-12 membered heterocycloalkyl; said 5-12 membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halogen, oxo, -OH, -CN, _-NH2 , _-NHC1-6 alkyl, -N(C R _1-1 , R _2-1 , and R 3-1 are each independently hydrogen, deuterium ^{, C 1-6 alkyl, or halogenated C 1-6 alkyl; R 1-2} _{, R} ^{2-2 , and R 3-2} _are ^each _{independently} ^C _1-6 alkyl, C ^3-12 _cycloalkyl , or 4 ^to ₁₂ membered heterocycloalkyl; _{the C 1-6 alkyl} , C _{The 3-12-} membered cycloalkyl and the 4-12-membered heterocycloalkyl are each optionally substituted with one or more substituents independently selected from halogen, -OH, -O-NHCH ₃ , -SH, -NH ₂ , -NHC _1-6 alkyl, and -SC _1-6 alkyl; Y is -OH or -CN. In some embodiments, the compound represented by formula (I) is not the following compound: .

In some embodiments, in the compound of formula (I), R ¹ is hydrogen, deuterium, halogen, -OH, -CN, -NH ₂ , C _1-6 alkyl, -OC _1-6 alkyl, -NHC _1-6 alkyl, -NH-S(O) ₂ -R ^1-2 , -C(O)R ^1-2 , C(O)-N(R ^1-1 )R ^1-2 , -C _1-6 alkylene-N(R ^1-1 )-C(O)R ^1-2 , -OC _3-12 cycloalkyl, -O-(4 to 12 membered heterocycloalkylene)-C(O)R ^1-2 , -OC _3-12 cycloalkylene-N(R ^1-1 )-C(O)R ^1-2 , -OC(O)-N(R ^1-1 )R ^1-2 , -N(R ^1-1 )-C(O)R ^1-2 , -N(R ^1-1 )-C(O)-OR ^1-2 , -N(R ^1-1 )-(4- to 12-membered heterocycloalkylene)-C(O)R ^1-2 , -N(R ^1-1 )-C _3-12 cycloalkylene-N(R ^1-3 )-C(O)R ^1-2 , -(4- to 12-membered heterocycloalkylene)-C(O)R ^1-2 , -(4- to 12-membered heterocycloalkylene)-N(R ^1-1 )-C(O)R ^1-2 , -N(R ^1-1 )C(O)C _3-12 cycloalkylene or -N(R ^1-1 )C(O)(4- to 12-membered heterocycloalkyl), wherein each of the C _1-6 alkyl, C _1-6 alkylene, C _3-12 cycloalkyl, C _3-12 cycloalkylene, 4- to 12-membered heterocycloalkylene, and 4- to 12-membered heterocycloalkyl is optionally substituted with one or more substituents selected from halogen, -OH, -SH, -NH ₂ , -NHC _1-6 alkyl, -SC _1-6 alkyl, -C _1-6 alkylene-OH, -C _1-6 alkylene-SH, -C _1-6 alkylene-S(C _1-6 alkyl), and -C _1-6 alkylene-NH ₂ ;

R ² is hydrogen, deuterium, halogen, -C _1-6 alkyl, -OH, -OC(O)-N(R ^2-1 )R ^2-2 , -C(O)R ^2-2 , C(O)-N(R ^2-1 )R ^2-2 , -NH ₂ , -NHC _1-6 alkyl, -NHC(O)C _1-6 alkyl, -N(R ^2-1 )-C(O)-OR ^2-2 , -N(R ^2-1 )-C(O)-N(R ^2-1 )R ^2-2 , -NHC(O)C _3-12 cycloalkyl, -NHC(O) (4 to 12 membered heterocycloalkyl), -N(C _1-6 alkyl)C(O)C _1-6 alkyl, -N(C _1-6 alkyl)C(O)C -N(C _1-6 alkyl)C(O)(4- to 12-membered heterocycloalkyl) or -NH-S(O) ₂ -R ^2-2 , wherein the _{C 1-6} alkyl, C _3-12 cycloalkyl and 4- to 12-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halogen, -OH, -O-NHCH ₃ , -SH, -NH ₂ , -NHC _1-6 alkyl and -SC _1-6 alkyl;

R ³ is hydrogen, deuterium, -C _1-6 alkyl, -CH ₂ -NHC _1-6 alkyl, -CH ₂ -NHC(O)C _1-6 alkyl, -CH ₂ -OC(O)-NR ^3-1 R ^3-2 , -CH ₂ -NR ^3-1 C(O)NR ^3-1 -R ^3-2 , -CH ₂ -NR ^3-1 C(O)OR ^3-2 , -CH ₂ -NHC(O)C _3-12 cycloalkyl, -CH ₂ -NHC(O) (4 to 12 membered heterocycloalkyl), -CH ₂ -N(C _1-6 alkyl)C(O)C _1-6 alkyl, -CH ₂ -N(C _1-6 alkyl)C(O)C _3-12 cycloalkyl, -CH ₂ -N(C _-C1-6 alkyl)C(O)(4- to 12-membered heterocycloalkyl), _-CH2 -S(O) ₂ - ^R3-2 or -C(O) ^R3-2 , wherein the _C1-6 alkyl, _C3-12 cycloalkyl and 4- to 12-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halogen, -OH, -O- _NHCH3 , -SH, _-NH2 , _-NHC1-6 alkyl and _-SC1-6 alkyl;

^R4 is hydrogen, deuterium, _-C1-6 alkyl, -C(O) _C1-6 alkyl, -C(O) _C3-12 cycloalkyl, or -C(O)(4- to 12-membered heterocycloalkyl), wherein each of the _C1-6 alkyl, _C3-12 cycloalkyl, and 4- to 12-membered heterocycloalkyl groups is optionally substituted with one or more substituents selected from halogen, -OH, -SH, _-NH2 , _-NHC1-6 alkyl, and _-SC1-6 alkyl;

or R ³ and R ⁴ together with the atoms to which they are attached form a 5-12 membered heterocycloalkyl group; each of the 5-12 membered heterocycloalkyl groups is optionally substituted with one or more substituents selected from halogen, oxo, -OH, -CN, -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , -C _1-6 alkyl, -C _1-6 alkylene-OH, -C(O)C _1-6 alkylene-OH, -C(O)-C _3-12 cycloalkylene-OH and -C(O)-(4 to 12 membered heterocycloalkylene)-OH; R ^1-1 , R ^2-1 and R ^3-1 are each independently hydrogen, deuterium, C _1-6 alkyl or halogenated C _1-6 alkyl; R ^1-2 , R ^2-2 and R ^3-2 are each independently C _1-6 alkyl, C _3-12 cycloalkyl or 4- to 12-membered heterocycloalkyl; the C _1-6 alkyl, C _3-12 cycloalkyl and 4- to 12-membered heterocycloalkyl are each optionally substituted with one or more substituents independently selected from halogen, -OH, -O-NHCH ₃ , -SH, -NH ₂ , -NHC _1-6 alkyl and -SC _1-6 alkyl; Y is -OH or -CN.

In some embodiments, in,

R ¹ is hydrogen, deuterium, halogen, -OH, -CN, -NH ₂ , C _1-6 alkyl, -OC _1-6 alkyl, -NHC _1-6 alkyl, -C _1-6 alkylene-N(R ^1-1 )-C(O)R ^1-2 , -OC _3-12 cycloalkyl, -O-(4- to 12-membered heterocycloalkylene)-C(O)R ^1-2 , -OC _3-12 cycloalkylene-N(R ^1-1 )-C(O)R ^1-2 , -N(R ^1-1 )-C(O)R ^1-2 , -N(R ^1-1 )-(4- to 12-membered heterocycloalkylene)-C(O)R ^1-2 , -N(R ^1-1 )-C _3-12 cycloalkylene-N(R ^1-3 )-C(O) ^R1-2 , -(4 to 12-membered heterocycloalkylene)-C(O) ^R1-2 , -(4 to 12-membered heterocycloalkylene)-N( ^R1-1 )-C(O) ^R1-2 , -N( ^R1-1 )C(O) _{C3-12cycloalkyl} or -N( ^R1-1 )C(O)(4 to 12-membered heterocycloalkyl), wherein the _C1-6alkyl , _C1-6alkylene , C3-12cycloalkyl, C3-12cycloalkylene, 4 to ₁₂ -membered heterocycloalkylene and 4 to ₁₂ -membered heterocycloalkyl are each optionally substituted by one or more groups selected from halogen, -OH, -SH, _-NH2 , _-NHC1-6alkyl , -SC _{-C 1-6} alkyl, -C _1-6 alkylene-OH, -C _1-6 alkylene-SH, -C _1-6 alkylene-S(C _1-6 alkyl) and -C _1-6 alkylene-NH ₂ ; R ^1-1 is hydrogen, deuterium, C _1-6 alkyl or halogenated C _1-6 alkyl; R ^1-2 is C _1-6 alkyl, C _3-12 cycloalkyl or 4 to 12 membered heterocycloalkyl; the C _1-6 alkyl, C _3-12 cycloalkyl and 4 to 12 membered heterocycloalkyl are each optionally substituted with one or more substituents independently selected from halogen, -OH, -SH, -NH ₂ , -NHC _1-6 alkyl and -SC _1-6 alkyl; R ² is hydrogen, deuterium, halogen, -C _-NH2 , -NHC1-6alkyl, -NHC( _O) C1-6alkyl, -NHC(O _{) C3-12cycloalkyl} , -NHC(O)( ₄ to 12-membered heterocycloalkyl), -N(C1-6alkyl)C(O)C1-6alkyl, -N( _C1-6alkyl )C(O) _{C3-12cycloalkyl} or -N( _C1-6alkyl )C(O)( ₄ to ₁₂ -membered heterocycloalkyl), wherein the _C1-6alkyl , _{C3-12cycloalkyl} and 4 to 12-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halogen, -OH, -SH, _-NH2 , _-NHC1-6alkyl and _-SC1-6alkyl ; ^R3 is hydrogen, deuterium, -C -CH ₂ -NHC _1-6 alkyl, -CH ₂ -NHC(O)C _1-6 alkyl, -CH ₂ -NHC(O ₎ C _3-12 cycloalkyl, -CH ₂ -NHC(O)(4 to 12 membered heterocycloalkyl), -CH ₂ -N(C _1-6 alkyl)C(O)C _1-6 alkyl, -CH ₂ -N(C _1-6 alkyl)C(O)C _3-12 cycloalkyl or -CH ₂ -N(C _1-6 alkyl)C(O)(4 to 12 membered heterocycloalkyl), wherein the C _1-6 alkyl, C _3-12 cycloalkyl and 4 to 12 membered heterocycloalkyl are each optionally substituted by one or more groups selected from halogen, -OH, -SH, -NH ₂ , -NHC _1-6 alkyl and -SC ^R4 is hydrogen, deuterium, -C1-6 alkyl, -C(O) _C1-6 alkyl, -C(O) _{C3-12 cycloalkyl} or -C(O)(4 to 12 membered heterocycloalkyl), said _C1-6 alkyl, _C3-12 cycloalkyl and 4 to 12 membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halogen, -OH, -SH, _-NH2 , _-NHC1-6 alkyl and _-SC1-6 alkyl; or ^R3 and ^R4 together with the atoms to which they are attached form a _5-12 membered heterocycloalkyl; said 5-12 membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halogen, oxo, -OH, -CN, _-NH2 , _-NHC1-6 alkyl, -N(C The group is substituted by a substituent selected from -C(O)-C _{( 1-6} )alkyl) ₂ , -C(O)-C _(1-6 )alkyl, -C(O)-C _{(1-6 )} alkylene-OH, -C(O)-C3-12cycloalkylene-OH and -C(O)-(4- to 12-membered heterocycloalkylene)-OH; and Y is -OH or -CN.

In some embodiments, certain groups in the compound of formula (I), or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotope-labeled substances, metabolites or prodrugs thereof are defined as follows. Groups not mentioned are the same as those described in any scheme of this application (referred to as "in some embodiments"), and they satisfy at least one of the following conditions: (1) R ¹ is deuterium, halogen, -OH, -CN, -NH ₂ , C _1-6 alkyl, -NH-S(O) ₂ -R ^1-2 , -C(O)R ^1-2 , C(O)-N(R ^1-1 )R ^1-2 , -C _1-6 alkylene-N(R ^1-1 )-C(O)R ^1-2 , -OC _3-12- membered cycloalkyl, -O-(4- to 12-membered heterocycloalkylene)-C(O)R ^1-2 , -OC _3-12- membered cycloalkylene-N(R ^1-1 )-C(O)R ^1-2 , -OC(O)-N(R ^1-1 )R ^1-2 , -N(R ^1-1 )-C(O)R ^1-2 , -N(R ^1-1 )-C(O)-OR ^1-2 , -N(R ^1-1 )-(4- to 12-membered heterocycloalkylene)-C(O)R ^1-2 , -N(R ^1-1 )-C _3-12 -membered cycloalkylene-N(R ^1-3 )-C(O)R ^1-2 , -(4- to 12-membered heterocycloalkylene)-C(O)R ^1-2 , -(4 to 12 membered heterocycloalkylene)-N( ^R1-1 )-C(O) ^R1-2 , -N( ^R1-1 )C(O) _{C3-12cycloalkyl} , (4 to 12 membered heterocycloalkylene) or -N( ^R1-1 )C(O)(4 to 12 membered heterocycloalkyl), wherein the _C1-6alkyl , _C1-6alkylene , _{C3-12cycloalkyl} , _{C3-12cycloalkylene} , 4 to 12 membered heterocycloalkylene and 4 to 12 membered heterocycloalkyl are each optionally substituted by one or more groups selected from halogen, -OH, -SH, _-NH2 , -O- _NHCH3 , _-NHC1-6alkyl , _-SC1-6alkyl , _{-C1-6alkylene} -OH, -C (2) R ² is halogen, -C _1-6 alkyl _, -OH, -OC(O) _-N (R _2-1 )R 2-2 , -C(O)R 2-2 , C(O)-N(R ^2-1 )R _2-2 , -NH ² , _{-NHC 1-6 alkyl, -NHC(O)C 1-6 alkyl} ^, -N(R ^2-1 )-C( _O )-OR ^2-2 , -N(R ^2-1 )-C(O)-N( ^{R 2-1} )R ^2-2 , -NHC(O)C ^3-12 _cycloalkyl , -NHC(O) (4 _to 12 membered heterocycloalkyl), -N(C -NH-S(O) 2 _{-R 2-2 , wherein the C 1-6 alkyl} , C _{3-12 cycloalkyl} and 4 to 12 membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halogen, -OH, -O-NHCH ₃ , -SH, -NH ₂ , -NHC _1-6 alkyl and -SC _1-6 alkyl; (3) R ³ is -CH ² -NHC _1-6 alkyl, -CH _{2 -NHC} (O)C _1-6 alkyl, -CH ₂ -NHC(O) ^C _1-6 alkyl, -CH ₂ -OC(O) _{-NR 3-1} R ^3-2 , -CH ₂ -NR ^3-1 C(O)NR ^3-1 -R ^3-2 , -CH ₂ -NR ^3-1 C(O)OR ^3-2 , -CH ₂ -NHC(O)C _3-12 cycloalkyl, -CH ₂ -NHC(O)(4- to 12-membered heterocycloalkyl), -CH ₂ -NHC(O)C _3-12 cycloalkyl, -CH ₂ -N(C _1-6 alkyl)C(O)C _1-6 alkyl, -CH ₂ -N(C _1-6 alkyl)C(O)C _3-12 cycloalkyl, -CH ₂ -N(C _1-6 alkyl)C(O)(4- to 12-membered heterocycloalkyl), -CH ₂ NH-S(O) ₂ -R ^3-2 , -CH ₂ -S(O) ₂ -R ^3-2 or -C(O)R ^3-2 , wherein the C _1-6 alkyl, C _3-12 cycloalkyl and 4 to 12 membered heterocycloalkyl are each optionally substituted by one or more substituents selected from halogen, cyclopropyl, -OH, -O-NHCH ₃ , -SH, -NH ₂ , -NHC _1-6 alkyl and -SC _1-6 alkyl; (4) R ⁴ is -C(O)C _1-6 alkyl, -C(O)C _3-12 cycloalkyl or -C(O)(4 to 12 membered heterocycloalkyl), wherein the C _1-6 alkyl, C _3-12 cycloalkyl and 4 to 12 membered heterocycloalkyl are each optionally substituted by one or more substituents selected from halogen, -OH, -SH, -NH ₂ , -NHC _1-6 alkyl and -SC (5) R ³ and R ⁴ together with the atoms to which they are attached form a _5-12 membered heterocycloalkyl group; each of the 5-12 membered heterocycloalkyl groups is optionally substituted by one or more substituents selected from halogen, oxo, -OH, -CN, -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , -C _1-6 alkyl, -C _1-6 alkylene-OH, -C(O)C _1-6 alkylene-OH, -C(O)-C _3-12 cycloalkylene-OH and -C(O)-(4 to 12 membered heterocycloalkylene)-OH.

In some embodiments, the compound represented by formula (I) satisfies at least one of the following conditions: (1) R ¹ is deuterium, halogen, -OH, -CN, -NH ₂ , C _1-6 alkyl, -C _1-6 alkylene-N(R ^1-1 )-C(O)R ^1-2 , -OC _3-12 cycloalkyl, -O-(4 to 12 membered heterocycloalkylene)-C(O)R ^1-2 , -OC _3-12 cycloalkylene-N(R ^1-1 )-C(O)R ^1-2 , -N(R ^1-1 )-C(O)R ^1-2 , -N(R ^1-1 )-(4 to 12 membered heterocycloalkylene)-C(O)R ^1-2 , -N(R ^1-1 )-C C _3-12 cycloalkylene-N(R ^1-3 )-C(O)R ^1-2 , -(4 to 12 membered heterocycloalkylene)-C(O)R ^1-2 , -(4 to 12 membered heterocycloalkylene)-N(R ^1-1 )-C(O)R ^1-2 , -N(R ^1-1 )C(O)C _3-12 cycloalkyl or -N(R ^1-1 )C(O)(4 to 12 membered heterocycloalkyl), wherein the C _1-6 alkyl, C _1-6 alkylene, C _3-12 cycloalkyl, C _3-12 cycloalkylene, 4 to 12 membered heterocycloalkylene and 4 to 12 membered heterocycloalkyl are each optionally substituted by one or more groups selected from halogen, -OH, -SH, -NH ₂ , -NHC _1-6 alkyl, -SC _1-6 alkyl, -C _1-6 alkylene-OH, -C _1-6 alkylene-SH, -C _1-6 alkylene-S(C _1-6 alkyl) and -C _1-6 alkylene-NH ₂ ; (2) R ² is deuterium, halogen, C _1-6 alkyl, -OH, -NH ₂ , -NHC _1-6 alkyl, -NHC(O)C _1-6 alkyl, -NHC(O)C _3-12 cycloalkyl, -NHC(O)(4 to 12 membered heterocycloalkyl), -N(C _1-6 alkyl)C(O)C _1-6 alkyl, -N(C _1-6 alkyl)C(O)C _3-12 cycloalkyl or -N(C _1-6 alkyl)C(O)(4 to 12 membered heterocycloalkyl), wherein the C -CH _{2 -NHC 1-6} alkyl, -CH 2 -NHC(O)C _1-6 alkyl, -CH ₂ -NHC(O)C 3-12 cycloalkyl, -CH ₂ -NHC(O)(4 to _{12 membered heterocycloalkyl), -CH 2 -N(C 1-6 alkyl} ⁾ _{C (} O)C _1-6 alkyl, -CH ₂ -N(C _1-6 alkyl)C(O)C _3-12 cycloalkyl _{or -CH 2 -N (} C _{1-6 alkyl} )C(O)C _{3-12 cycloalkyl} (4) R 4 is C _1-6 alkyl, -C(O)C _1-6 alkyl, -C(O)C _3-12 cycloalkyl or -C(O)(4 to 12 membered heterocycloalkyl), wherein the C 1-6 alkyl, C 3-12 cycloalkyl and 4 to 12 membered heterocycloalkyl are each optionally substituted by one or more substituents selected from halogen, -OH, -SH, -NH ₂ , -NHC _1-6 alkyl and -SC _1-6 alkyl; (5) R ⁴ is C _1-6 alkyl, -C(O)C _1-6 alkyl, -C(O)C _3-12 cycloalkyl or -C(O)(4 to 12 membered heterocycloalkyl), wherein the C _1-6 alkyl, C _3-12 cycloalkyl and 4 to 12 membered heterocycloalkyl are each optionally substituted by one or more substituents selected from halogen, -OH, -SH, -NH ₂ , -NHC _1-6 alkyl and -SC (5) R ³ and R ⁴ together with the atoms to which they are attached form a _5-12 membered heterocycloalkyl group; each of the 5-12 membered heterocycloalkyl groups is optionally substituted by one or more substituents selected from halogen, oxo, -OH, -CN, -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , C _1-6 alkyl, -C _1-6 alkylene-OH, -C(O)C _1-6 alkylene-OH, -C(O)-C _3-12 cycloalkylene-OH and -C(O)-(4 to 12 membered heterocycloalkylene)-OH.

In some embodiments, the number of heteroatoms in the 4- to 12-membered heterocycloalkylene group and the 4- to 12-membered heterocycloalkylene group is one or more, and each heteroatom is independently selected from N, O, and S; preferably, the 4- to 12-membered heterocycloalkylene group and the 4- to 12-membered heterocycloalkylene group are 4- to 6-membered heterocycloalkylene group and 4- to 6-membered heterocycloalkylene group; the number of heteroatoms is one or two, and the heteroatoms are independently selected from N; for example, N-heterocyclobutyl ( 、 ), piperidinyl ( 、 ), piperidine ( 、 ), or a divalent group thereof.

In some embodiments, the compound represented by general formula (I) is a compound represented by formula (IA): wherein R ¹ is hydrogen, halogen, -OH, or -OC _1-6 alkyl; R ² is hydrogen or deuterium; R ³ is -CH ₂ -NHC _1-6 alkyl, -CH ₂ -NHC(O)C _1-6 alkyl, -CH ₂ -OC(O)-NR ^3-1 R ^3-2 , -CH ₂ -NR ^3-1 C(O)NR ^3-1 -R ^3-2 , -CH ₂ -NR ^3-1 C(O)OR ^3-2 , -CH ₂ -NHC(O)C _3-12 cycloalkyl, -CH ₂ -NHC(O) (4 to 12 membered heterocycloalkyl), -CH ₂ -NHC(O)C _3-12 cycloalkyl, -CH ₂ -N(C _1-6 alkyl)C(O)C _1-6 alkyl, -CH ₂ -N(C -C _1-6 alkyl) C (O) C _3-12 cycloalkyl, -CH ₂ -N (C _1-6 alkyl) C (O) (4 to 12 membered heterocycloalkyl), -CH ₂ NH-S (O) ₂ -R ^3-2 , -CH ₂ -S (O) ₂ -R ^3-2 or -C (O) R ^3-2 , wherein the C _1-6 alkyl, C _3-12 cycloalkyl and 4 to 12 membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halogen, cyclopropyl, -OH, -O-NHCH ₃ , -SH, -NH ₂ , -NHC _1-6 alkyl and -SC _1-6 alkyl; R ⁴ is hydrogen or C _1-6 alkyl; or, R ² is hydrogen or deuterium; R ³ and R ⁴ together with the atoms to which it is attached form a 5-12 membered heterocycloalkyl group; the 5-12 membered heterocycloalkyl group is optionally replaced by one or more selected from -C(O)C _1-6 alkylene-OH; or, R ² is halogen, -C _1-6 alkyl, -OH, -OC(O)-N(R ^2-1 )R ^2-2 , -C(O)R ^2-2 , C(O)-N(R ^2-1 )R ^2-2 , -NH ₂ , -NHC _1-6 alkyl, -NHC(O)C _1-6 alkyl, -N(R ^2-1 )-C(O)-OR ^2-2 , -N(R ^2-1 )-C(O)-N(R ^2-1 )R ^2-2 , -NHC(O)C -NHC _1-6 alkyl, -NHC _1-6 alkyl and -SC 1-6 alkyl; R 3 is hydrogen, deuterium; R _2-2 is hydrogen, deuterium; R 3 is hydrogen, _deuterium ; R _2-2 is hydrogen, deuterium; R ₃ is hydrogen, deuterium; R ₃ is hydrogen, _deuterium ^{; R 3 is hydrogen, deuterium; R 3 is hydrogen, deuterium; R 3 is} _{hydrogen , deuterium ; R} ⁴ is hydrogen or C _1-6 alkyl; Y is -OH or -CN.

In some embodiments, the compound represented by general formula (I) is a compound represented by formula (Ia): wherein R ¹ is hydrogen, deuterium, halogen, -OH, -CN, -NH ₂ , C _1-6 alkyl, halogenated C _1-6 alkyl, -OC _1-6 alkyl, -O-halogenated C _1-6 alkyl, -NHC _1-6 alkyl, -O-halogenated C _1-6 alkyl, or -NH-halogenated C _1-6 alkyl; R ² is hydrogen, deuterium, halogen, C _1-6 alkyl, -OH, -NH ₂ , -NHC _1-6 alkyl, -NHC(O)C _1-6 alkyl, -NHC(O)C _3-12 cycloalkyl, -NHC(O) (4 to 12 membered heterocycloalkyl), -N(C _1-6 alkyl)C(O)C _1-6 alkyl, -N(C _1-6 alkyl)C(O)C C _1-6 alkyl, -N(C _1-6 alkyl)C(O)(4- to 12-membered heterocycloalkyl), wherein the C _1-6 alkyl, C _3-12 cycloalkyl or 4- to 12-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halogen, -OH, -SH, -NH ₂ , -NHC _1-6 alkyl and -SC _1-6 alkyl; R ³ is H or -CH ₂ -NR ^3a R ^3b ; R ^3a is hydrogen or C _1-6 alkyl; the C _1-6 alkyl is optionally substituted with one or more substituents selected from halogen, -OH, -SH, -NH ₂ , -NHC _1-6 alkyl and -SC _1-6 alkyl; R ^3b is -C(O)C _1-6 alkyl, -C(O)C _R4 is hydrogen, deuterium, C1-6 alkyl, -C(O) _C1-6 alkyl, -C(O)C3-12 cycloalkyl or -C(O)(4 to 12 membered heterocycloalkyl), wherein the _C1-6 alkyl, _C3-12 cycloalkyl or 4 to 12 membered heterocycloalkyl are each optionally substituted by one or more substituents selected from halogen, -OH, -SH, -NH2, _-NHC1-6 alkyl and _-SC1-6 alkyl; ^R4 is hydrogen, deuterium, _C1-6 alkyl, -C(O) _C1-6 alkyl, -C(O) _C3-12 cycloalkyl or -C(O)(4 to 12 membered heterocycloalkyl), wherein the _C1-6 alkyl, _C3-12 cycloalkyl or 4 to 12 membered heterocycloalkyl are each optionally substituted by one or more substituents selected from halogen, -OH, -SH, -NH2, _-NHC1-6 alkyl and -SC1-6 alkyl. or R ³ and R ⁴ together with the atoms to which they are attached form a 5-12 membered heterocycloalkyl group; said _5-12 membered heterocycloalkyl group is each optionally substituted with one or _{more substituents selected from halogen, oxo, -OH, -CN, -NH 2 ,} -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , -C _1-6 alkyl, -C _1-6 alkylene-OH, -C(O)C _1-6 alkylene-OH, -C(O)-C _3-12 cycloalkylene-OH and -C(O)-(4 to 12 membered heterocycloalkylene)-OH; Y is selected from -OH or -CN; provided that R ² and R ³ cannot be H at the same time.

In some embodiments, one of R ² and R ³ is H and the other is not H.

In some embodiments, the compound of the structure shown in formula (I) or formula (Ia), wherein, for 、 or a combination thereof.

In some embodiments, the compound of the structure shown in formula (I) or formula (Ia), wherein, for 、 or a combination thereof.

In some embodiments, in the compound represented by the structure of Formula (I) or Formula (Ia), R ¹ is hydrogen, halogen, -OH, -CN, -NH ₂ , -CH ₃ , -OCH ₃ or -NHCH ₃ .

In some embodiments, in the compound represented by the structure of Formula (I) or Formula (Ia), R ¹ is hydrogen, deuterium, -F, -Cl, -OH, -CH ₃ , -OCH ₃ , -NH ₂ or -NHCH ₃ .

In some embodiments, R ¹ is hydrogen, deuterium, halogen, -OH, -CN, -CH ₃ or -NHCH ₃ .

In some embodiments, the compound represented by the structure of Formula (I) or Formula (Ia), wherein R ¹ is hydrogen.

In some embodiments, the compound of the structure represented by formula (I), wherein R ¹ is -OH.

In some embodiments, in the compound represented by formula (I), R ¹ is -OC _1-6 alkyl; preferably -OCH ₃ .

In some embodiments, the compound of the structure represented by formula (I), wherein R ¹ is F.

In some embodiments, the compound of the structure shown in formula (I), wherein R ² is H.

In some embodiments, the compound represented by the structure of Formula (I) or Formula (Ia), wherein R ^2-1 is hydrogen or C _1-3 alkyl.

In some embodiments, in the compound represented by the structure of Formula (I) or Formula (Ia), R ^2-1 is H or CH ₃ .

In some embodiments, the compound represented by the structure of Formula (I) or Formula (Ia), wherein R ^2-2 is C _1-6 alkyl, C _3-12 cycloalkyl, or 4- to 12-membered heterocycloalkyl; the C _1-6 alkyl, C _3-12 cycloalkyl, or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more substituents independently selected from halogen and -OH; for example, -OH.

In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R ^2-2 is -CH ₂ OH, -CH ₂ CH ₂ OH, -CH(OH)CH ₃ , -CH ₂ ONH(CH ₃ ), or .

In some embodiments, the compounds represented by the structures of Formula (I) and Formula (Ia), wherein R ² is -OH, -NH ₂ , C _1-6 alkyl, -NHC _1-6 alkyl, -NHC(O)C _1-6 alkyl, -N(C _1-6 alkyl)C(O)C _1-6 alkyl, or -N(C _1-6 alkyl)C(O)C _3-12 cycloalkyl, and the C _1-6 alkyl, C _3-12 cycloalkyl, or 4- to 12-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from -OH, -SH, -NH ₂ , -NHCH ₃ , and -SCH ₃ .

In some embodiments, the compound represented by the structure of Formula (I) or Formula (Ia), wherein R ² is -OH, -NH ₂ , C _1-6 alkyl, -NHC(O)C _1-6 alkyl or -N(C _1-6 alkyl)C(O)C _1-6 alkyl, and each of the C _1-6 alkyl groups is optionally substituted with one or more substituents selected from -OH, -SH, -NH ₂ , -NHCH ₃ and -SCH ₃ .

In some embodiments, in the compound represented by the structure of Formula (I) or Formula (Ia), R ² is -OH, -NH ₂ , -C _1-6 alkylene-OH, -NHC(O)C _1-6 alkylene-OH, or -N(C _1-6 alkyl)C(O)C _1-6 alkylene-OH.

In some embodiments, in the compound represented by the structure of Formula (I) or Formula (Ia), R ² is -NHC(O)C _1-6 alkylene-NH ₂ or -N(C _1-6 alkyl)C(O)C _1-6 alkylene-NH ₂ .

In some embodiments, in the compound represented by the structure of Formula (I) or Formula (Ia), R ² is -NHC(O)C _1-3 alkylene-NH ₂ or -N(C _1-6 alkyl)C(O)C _1-3 alkylene-NH ₂ . In some embodiments, in the compound represented by the structure of Formula (I) or Formula (Ia), R ² is -OC(O)-N(R ^2-1 )R ^2-2 , -C(O)R ^2-2 , -NHC(O)C _3-12 cycloalkyl, C(O)(4- to 12-membered heterocycloalkyl), C(O)-N(R ^2-1 )R ^2-2 , -N(R ^2-1 )-C(O)-OR ^2-2 , -N(R ^2-1 )-C(O)-N(R ^2-1 )R ^2-2 , or -NH-S(O) ₂ -R ^2-2 .

In some embodiments, the compounds represented by the structures of formula (I) and formula (Ia), wherein R ² is NH ₂ , OH, -C _1-6 alkyl, -NHC(O)C _1-6 alkyl, -N(C _1-6 alkyl)C(O)C _1-6 alkyl, -N(R ^2-1 )-C(O)-OR ^2-2 , -OC(O)-N(R ^2-1 )R ^2-2 , -N(R ^2-1 )-C(O)-N(R ^2-1 )R ^2-2 , -NHC(O)C _3-12 cycloalkyl, C(O)(4- to 12-membered heterocycloalkyl), C(O)-N(R ^2-1 )R ^2-2 , or -NH-S(O) ₂ -R ^2-2 .

In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R ² is NH ₂ , OH, CH ₂ OH, 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 .

In some embodiments, the compound of the structure shown in formula (I) or formula (Ia), wherein R ² is 、 、 、 、 、 、 .

In some embodiments, the compound of the structure shown in formula (I) or formula (Ia), wherein R ² is 、 、 、 、 .

In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R ² is -OH, -NH ₂ , -NHCH ₃ , -CH ₂ OH, 、 、 、 、 、 、 or .

In some embodiments, the compound of the structure shown in formula (I) or formula (Ia), wherein R ² is 、 、 、 .

In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R ² is -OH, -NH ₂ , -NHCH ₃ , -CH ₂ OH, or .

In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R ² is -OH, -NH ₂ , -CH ₂ OH, or .

In some embodiments, the compound of the structure shown in formula (I) or formula (Ia), wherein R ² is or .

In some embodiments, the compound represented by the structure of Formula (I) or Formula (Ia), wherein R ³ is H.

In some embodiments, the compound represented by the structure of Formula (I) or Formula (Ia), wherein R ^3-1 is hydrogen or C _1-3 alkyl.

In some embodiments, in the compound represented by the structure of Formula (I) or Formula (Ia), R ^3-1 is hydrogen or -CH ₃ .

In some embodiments, the compound represented by the structure of Formula (I) or Formula (Ia), wherein R ^3-2 is a C _1-6 alkyl group; the C _1-6 alkyl group is optionally substituted with one or more substituents independently selected from halogen and -OH; for example, -OH.

In some embodiments, the compound of the structure shown in formula (I) or formula (Ia), wherein R ^3-2 is 、 .

In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R ^3-2 is -CH ₂ OH, -CH ₂ CH ₂ OH, -CH(OH)CH ₃ , -CH ₂ O-NHCH ₃ , -CH ₂ ONH(CH ₃ ), or .

In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R ^3-2 is -CH ₂ OH, -CH ₂ CH ₂ OH, -CH(OH)CH ₃ , -CH ₂ ONH(CH ₃ ) or .

In some embodiments, the compounds represented by the structures of formula (I) and formula (Ia), wherein R ³ is -C(O)R ^3-2 , -CH ₂ -NHC(O)C _1-6 alkyl, -CH ₂ -N(C _1-6 alkyl)C(O)C _1-6 alkyl, -CH ₂ NH-S(O) ₂ -R ^3-2 , -CH ₂ -NR ^3-1 C(O)OR ^3-2 , -CH ₂ -OC(O)-NR ^3-1 R ^3-2 , -CH ₂ -NR ^3-1 C(O)NR ^3-1 -R ^3-2 , -CH ₂ -NHC(O)C _3-12 cycloalkyl; the C _1-6 alkyl, C _{The 3-12-} membered cycloalkyl and the 4- to 12-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from cyclopropyl, -OH, and -O-NHCH ₃ .

In some embodiments, the compound of the structure shown in formula (I) or formula (Ia), wherein R ³ is 、 、 、 、 、 、 、 、 、 、 、 、 .

In some embodiments, in the compound represented by the structure of Formula (I) or Formula (Ia), R ^3a is hydrogen or C _1-3 alkyl.

In some embodiments, in the compound represented by the structure of Formula (I) or Formula (Ia), R ^3a is hydrogen or -CH ₃ .

In some embodiments, the compound represented by the structure of Formula (I) or Formula (Ia), wherein R ^3b is -C(O)C _1-6 alkyl or -C(O)C _3-6 cycloalkyl, wherein the C _1-6 alkyl or C _3-6 cycloalkyl is each optionally substituted with one or more substituents selected from -OH, -SH, -NH ₂ , -NHCH ₃ and -SCH ₃ .

In some embodiments, in the compound represented by the structure of Formula (I) or Formula (Ia), R ^3b is -C(O)C _1-6 alkylene-OH.

In some embodiments, the compound of the structure shown in formula (I) or formula (Ia), wherein R ^3b is 、 、 or .

In some embodiments, the compound of the structure shown in formula (I) or formula (Ia), wherein R ^3b is .

In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein -CH ₂ -NR ^3a R ^3b is 、 .

In some embodiments, in the compound represented by the structure of Formula (I) or Formula (Ia), R ⁴ is hydrogen, deuterium, -C _1-6 alkyl, or -C(O)C _1-6 alkylene-OH.

In some embodiments, the compound of the structure shown in formula (I) or formula (Ia), wherein R ⁴ is hydrogen or .

In some embodiments, the compound represented by the structure of Formula (I) or Formula (Ia), wherein R ⁴ is hydrogen.

In some embodiments, the compound of the structure represented by formula (Ia), wherein R ³ and R ⁴ together with the atoms to which they are attached form a 5- to 6-membered heterocycloalkyl group, and the 5- to 6-membered heterocycloalkyl group is each optionally substituted with one or more substituents selected from halogen, oxo, -OH, -CN, -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , -C _1-6 alkyl, -C _1-6 alkyl-OH, -C(O)C _1-6 alkylene-OH, -C(O)-C _3-12 cycloalkylene-OH, and -C(O)-(4- to 12-membered heterocycloalkylene)-OH.

In some embodiments, in the compounds represented by the structures of Formula (I) and Formula (Ia), R ³ and R ⁴ together with the atoms to which they are attached form a piperidine group, and each piperidine group is optionally substituted with one or more substituents selected from halogen, oxo, -OH, -CN, -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , -C _1-6 alkyl, -C _1-6 alkyl-OH, -C(O)C _1-6 alkylene-OH, -C(O)-C _3-12 cycloalkylene-OH, and -C(O)-(4- to 12-membered heterocycloalkylene)-OH.

In some embodiments, the compound of the structure shown in formula (I) or formula (Ia), wherein R ³ and R ⁴ together with the atoms to which they are attached form 、 、 、 or .

In some embodiments, the compound of the structure shown in formula (I) or formula (Ia), wherein R ³ and R ⁴ together with the atoms to which they are attached form or .

In some embodiments, the compound represented by the structure of formula (I) or formula (IA) is a compound represented by the structure of formula (IA-1). wherein R ¹ is hydrogen, halogen, -OH, or -OC _1-6 alkyl; R ³ is -CH ₂ -NHC _1-6 alkyl, -CH ₂ -NHC(O)C _1-6 alkyl, -CH ₂ -OC(O)-NR ^3-1 R ^3-2 , -CH ₂ -NR ^3-1 C(O)NR ^3-1 -R ^3-2 , -CH ₂ -NR ^3-1 C(O)OR ^3-2 , -CH ₂ -NHC(O)C _3-12 cycloalkyl, -CH ₂ -NHC(O) (4- to 12-membered heterocycloalkyl), -CH ₂ -NHC(O)C _3-12 cycloalkyl, -CH ₂ -N(C _1-6 alkyl)C(O)C _1-6 alkyl, -CH ₂ -N(C _1-6 alkyl)C(O)C _-3-12- membered cycloalkyl, -CH ₂ -N(C _1-6 alkyl)C(O)(4- to 12-membered heterocycloalkyl), -CH ₂ NH-S(O) ₂ -R ^3-2 , -CH ₂ -S(O) ₂ -R ^3-2 or -C(O)R ^3-2 , wherein the C _1-6 alkyl, C _3-12 cycloalkyl and 4- to 12-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halogen, cyclopropyl, -OH, -O-NHCH ₃ , -SH, -NH ₂ , -NHC _1-6 alkyl and -SC _1-6 alkyl; R ⁴ is hydrogen, C _1-6 alkyl; or R ³ and R ⁴ together with the atoms to which it is attached form a 5-12 membered heterocycloalkyl group; each of the 5-12 membered heterocycloalkyl groups is optionally substituted with one or more groups selected from -C(O)C _1-6 alkylene-OH; Y is -OH or -CN.

In some embodiments, the compound represented by the structure of formula (I) or formula (Ia) is a compound represented by the structure of formula (Ia-1). wherein Y, R ^3a , R ^3b and R ⁴ are as defined in any one of Formula (I) and Formula (Ia) of the present invention.

In some embodiments, the compound represented by the structure of Formula (I), Formula (Ia), or Formula (Ia-1), wherein: R ^3a is hydrogen or -CH ₃ ; R ^3b is -C(O)C _1-6 alkylene-OH; R ⁴ is hydrogen; or for or ; Y is -OH or -CN.

In some embodiments, in the compound represented by the structure of Formula (I), Formula (Ia), or Formula (Ia-1), R ^3a is -CH ₃ .

In some embodiments, in the compound represented by the structure of Formula (I), Formula (Ia), or Formula (Ia-1), R ^3b is -C(O)C _1-3 alkylene-OH.

In some embodiments, the compound represented by the structure of formula (I), formula (Ia), or formula (Ia-1), wherein R ^3b is .

In some embodiments, the compound of the structure shown in Formula (I), Formula (Ia), or Formula (Ia-1), wherein: for or .

In some embodiments, the compound of the structure shown in Formula (I), Formula (Ia), or Formula (Ia-1), wherein: for .

In some embodiments, the compound represented by formula (I) is a compound represented by formula (IA-2): wherein R ¹ is hydrogen, halogen, -OH, or -OC _1-6 alkyl; R ² is halogen, -C _1-6 alkyl, -OH, -OC(O)-N(R ^2-1 )R ^2-2 , -C(O)R ^2-2 , C(O)-N(R ^2-1 )R ^2-2 , -NH ₂ , -NHC _1-6 alkyl, -NHC(O)C _1-6 alkyl, -N(R ^2-1 )-C(O)-OR ^2-2 , -N(R ^2-1 )-C(O)-N(R ^2-1 )R ^2-2 , -NHC(O)C _3-12 cycloalkyl, -NHC(O) (4- to 12-membered heterocycloalkyl), -N(C _1-6 alkyl)C(O)C _1-6 alkyl, -N(C -R 2-2 , wherein the C _1-6 alkyl, C _3-12 cycloalkyl and 4 to 12 membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halogen, -OH, -O-NHCH ₃ , -SH, ^{-NH 2 , -NHC 1-6 alkyl and -SC 1-6 alkyl; R 4} _{is hydrogen , C 1-6 alkyl} ^; _{and Y} is -OH or -CN.

In some embodiments, the compound represented by formula (I) or formula (Ia) is a compound represented by formula (Ia-2): wherein Y and R ² are as defined in any one of formula (Ia) of the present invention.

In some embodiments, the compounds represented by the structures of Formula (I), Formula (Ia), and Formula (Ia-2), wherein R ² is -OH, -NH ₂ , -C _1-6 alkylene-OH, -NHC(O)C _1-6 alkylene-OH, or -N(C _1-6 alkyl)C(O)C _1-6 alkylene-OH.

In some embodiments, the compounds represented by the structures of Formula (I), Formula (Ia), and Formula (Ia-2), wherein R ² is -NHC(O)C _1-6 alkylene-NH ₂ or -N(C _1-6 alkyl)C(O)C _1-6 alkylene-NH ₂ ; preferably, R ² is -NHC(O)C _1-3 alkylene-NH ₂ or -N(C _1-3 alkyl)C(O)C _1-3 alkylene-NH ₂ .

In some embodiments, the compounds represented by the structures of Formula (I), Formula (Ia), and Formula (Ia-2), wherein R ² is -OH, -NH ₂ , -C _1-3 alkylene-OH, -NHC(O)C _1-3 alkylene-OH, or -N(C _1-3 alkyl)C(O)C _1-3 alkylene-OH.

In some embodiments, the compound represented by the structure of formula (I), formula (Ia), or formula (Ia-2), wherein R ² is -NH ₂ , -CH ₂ OH, or .

In some embodiments, the compound of formula (I), formula (Ia), or formula (Ia-2), wherein R ² is .

In some embodiments, the compound of formula (I) or formula (Ia) of the present invention is: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 or .

In some embodiments, the compound of formula (Ia) of the present invention is: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 or .

In some embodiments, the compound represented by general formula (I) is a compound represented by formula (IB): wherein R ¹ is -OH, -CN, -NH ₂ , C _1-6 alkyl, -NH-S(O) ₂ -R ^1-2 , -C(O)R ^1-2 , C(O)-N(R ^1-1 )R ^1-2 , -C _1-6 alkylene-N(R ^1-1 )-C(O)R ^1-2 , -OC _3-12 cycloalkyl, -O-(4- to 12-membered heterocycloalkylene)-C(O)R ^1-2 , -OC _3-12 cycloalkylene-N(R ^1-1 )-C(O)R ^1-2 , -OC(O)-N(R ^1-1 )R ^1-2 , -N(R ^1-1 )-C(O)R ^1-2 , or -N(R ^1-1 )-C(O)-OR ^1-2 , -N(R ^1-1 )-(4 to 12-membered heterocycloalkylene)-C(O)R ^1-2 , -N(R ^1-1 )-C _3-12 cycloalkylene-N(R ^1-3 )-C(O)R ^1-2 , -(4 to 12-membered heterocycloalkylene)-C(O)R ^1-2 , -(4 to 12-membered heterocycloalkylene)-N(R ^1-1 )-C(O)R ^1-2 , -N(R ^1-1 )C(O)C _3-12 cycloalkyl, (4 to 12-membered heterocycloalkylene) or -N(R ^1-1 )C(O)(4 to 12-membered heterocycloalkyl), wherein the C _1-6 alkyl, C _1-6 alkylene, C C _3-12 cycloalkyl, C _3-12 cycloalkylene, 4- to 12-membered heterocycloalkylene and 4- to 12-membered heterocycloalkylene are each optionally substituted with one or more substituents selected from halogen, -OH, -SH, -NH ₂ , -O-NHCH ₃ , -NHC _1-6 alkyl, -SC _1-6 alkyl, -C _1-6 alkylene-OH, -C _1-6 alkylene-SH, -C _1-6 alkylene-S(C _1-6 alkyl) and -C _1-6 alkylene-NH ₂ ; R ⁴ is hydrogen, -C _1-6 alkyl; Y is -OH or -CN.

In some embodiments, the compound represented by general formula (I) is a compound represented by formula (Ib): wherein R ¹ is -NH ₂ , -C _1-6 alkylene-N(R ^1-1 )-C(O)R ^1-2 , -OC _3-12 cycloalkyl, -O-(4- to 12-membered heterocycloalkylene)-C(O)R ^1-2 , -OC _3-12 cycloalkylene-N(R ^1-1 )-C(O)R ^1-2 , -N(R ^1-1 )-(4- to 12-membered heterocycloalkylene)-C(O)R ^1-2 , -N(R ^1-1 )-C _3-12 cycloalkylene-N(R ^1-3 )-C(O)R ^1-2 , or -(4- to 12-membered heterocycloalkylene)-C(O)R ^1-2 , -(4 to 12 membered heterocycloalkylene)-N(R ^1-1 )-C(O)R ^1-2 , -N(R ^1-1 )C(O)C _{3-12cycloalkyl} or -N(R ^1-1 )C(O)(4 to 12 membered heterocycloalkyl), wherein the C _1-6 alkyl, C _1-6 alkylene, C _{3-12cycloalkyl} , C _{3-12cycloalkylene} , 4 to 12 membered heterocycloalkylene or 4 to 12 membered heterocycloalkylene are each optionally substituted by one or more groups selected from halogen, -OH, -SH, -NH ₂ , -NHC _1-6 alkyl, -SC _1-6 alkyl, -C _1-6 alkylene-OH, -C _1-6 alkylene-SH, -C _1-6 alkylene-S(C R ^1-1 is hydrogen, deuterium, C _1-6 alkyl or halogenated _{C 1-6} alkyl; R ^1-2 is C _1-6 alkyl, C _3-12 cycloalkyl or 4- to 12-membered heterocycloalkyl; each of _the C _1-6 alkyl, C _3-12 cycloalkyl or _4- to 12-membered heterocycloalkyl groups is optionally substituted with one or more substituents selected from halogen, -OH, -SH, -NH ₂ , -NHC _1-6 alkyl and -SC _1-6 alkyl; and Y is -OH or -CN.

In some embodiments, the compounds represented by the structures of formula (I) and formula (Ib), wherein R ¹ is -C _1-6 alkylene-N(R ^1-1 )-C(O)R ^1-2 , -OC _3-12 cycloalkyl, -O-(4- to 12-membered heterocycloalkylene)-C(O)R ^1-2 , -OC _3-12 cycloalkylene-N(R ^1-1 )-C(O)R ^1-2 , -N(R ^1-1 )-(4- to 12-membered heterocycloalkylene)-C(O)R ^1-2 , -N(R ^1-1 )-C _3-12 cycloalkylene-N(R ^1-3 )-C(O)R ^1-2 , -(4- to 12-membered heterocycloalkylene)-C(O)R ^1-2 , -(4 to 12 membered heterocycloalkylene)-N(R ^1-1 )-C(O)R ^1-2 , -N(R ^1-1 )C(O)C _{3-12cycloalkyl} or -N(R ^1-1 )C(O)(4 to 12 membered heterocycloalkyl), wherein the C _1-6 alkyl, C _1-6 alkylene, C _{3-12cycloalkyl} , C _{3-12cycloalkylene} , 4 to 12 membered heterocycloalkylene or 4 to 12 membered heterocycloalkyl are each optionally substituted by one or more groups selected from halogen, -OH, -SH, -NH ₂ , -NHC _1-6 alkyl, -SC _1-6 alkyl, -C _1-6 alkylene-OH, -C _1-6 alkylene-SH, -C _1-6 alkylene-S(C R ^1-1 is hydrogen, deuterium, C _1-6 alkyl or halogenated _{C 1-6} alkyl; R ^1-2 is C _1-6 alkyl, C _3-12 cycloalkyl or 4- to 12-membered heterocycloalkyl; each of _the C _1-6 alkyl, C _3-12 cycloalkyl or _4- to 12-membered heterocycloalkyl groups is optionally substituted with one or more substituents selected from halogen, -OH, -SH, -NH ₂ , -NHC _1-6 alkyl and -SC _1-6 alkyl; and Y is -OH or -CN.

In some embodiments, the compound represented by the structure of Formula (I) or Formula (Ib), wherein R ^1-1 is hydrogen, deuterium or -C _1-6 alkyl.

In some embodiments, in the compound represented by the structure of Formula (I) or Formula (Ib), R ^1-1 is hydrogen, deuterium or -CH ₃ .

In some embodiments, in the compound represented by the structure of Formula (I) or Formula (Ib), R ^1-2 is C _1-6 alkyl, C _3-6 cycloalkyl, or 4- to 6-membered heterocycloalkyl; each of the C _1-6 alkyl, C _3-6 cycloalkyl, or 4- to 6-membered heterocycloalkyl groups is optionally substituted with one or more substituents selected from halogen, -OH, -SH, -NH ₂ , -NHC _1-6 alkyl, and -SC _1-6 alkyl.

In some embodiments, in the compound represented by the structure of Formula (I) or Formula (Ib), R ^1-2 is -C _1-6 alkylene-OH or -C _3-6 cycloalkylene-OH.

In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R ^1-2 is -CH ₂ OH, -CH(CH ₃ )OH, 、 or .

In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R ^1-2 is -CH ₂ OH, -CH(CH ₃ )OH or .

In some embodiments, in the compound represented by the structure of Formula (I) or Formula (Ib), R ^1-2 is -CH ₂ CH ₂ OH or -CH ₂ ONH(CH ₃ ).

In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R ^1-2 is -CH ₂ OH, -CH(CH ₃ )OH, -CH ₂ CH ₂ OH, -CH ₂ ONH(CH ₃ ), 、 or .

In some embodiments, the compounds represented by the structures of formula (I) and formula (Ib), wherein R ¹ is -NH ₂ , -C _1-6 alkylene-N(R ^1-1 )-C(O)R ^1-2 , -O-(4- to 6-membered heterocycloalkylene)-C(O)R ^1-2 , -OC _3-6 cycloalkylene-N(R ^1-1 )-C(O)R ^1-2 , -N(R ^1-1 )-(4- to 6-membered heterocycloalkylene)-C(O)R ^1-2 , -(4- to 6-membered heterocycloalkylene)-C(O)R ^1-2 , -(4- to 6-membered heterocycloalkylene)-N(R ^1-1 )-C(O)R ^1-2 or -N(R ^1-1 )C(O)C wherein the C _1-6 alkylene group, C ^3-6 cycloalkyl group, C _3-6 cycloalkylene group, 4 to 6-membered heterocycloalkyl group or 4 to 6-membered heterocycloalkylene group is optionally substituted with one or more substituents selected from halogen, -OH, -SH, -NH ₂ , -NHC _1-6 alkyl group, -SC _1-6 alkyl group, -C _1-6 alkylene-OH, -C _1-6 alkylene-SH, -C _1-6 alkylene-S _{(C 1-6 alkyl} ) and -C _1-6 alkylene- _{NH 2 ;} R ^1-1 is as defined in any one of formula (Ib) of the present invention, and R ^1-2 is as defined in any one of formula (Ib) of the present invention.

In some embodiments, the compounds represented by the structures of formula (I) and formula (Ib), wherein R ¹ is -NH ₂ , -C _1-6 alkylene-NH-C(O)R ^1-2 , -C _1-6 alkylene-N(CH ₃ )-C(O)R ^1-2 , -O-(4- to 6-membered heterocycloalkylene)-C(O)R ^1-2 , -OC _3-6 cycloalkylene-NH-C(O)R ^1-2 , -OC _3-6 cycloalkylene-N(CH ₃ )-C(O)R ^1-2 , -NH-(4- to 6-membered heterocycloalkylene)-C(O)R ^1-2 , -N(CH ₃ )-(4- to 6-membered heterocycloalkylene)-C(O)R ^1-2 , -NHC(O)C wherein the C _1-6 alkylene group, C _3-6 cycloalkyl group, C _3-6 cycloalkyl group, 4 to 6-membered heterocycloalkyl group or 4 to 6-membered heterocycloalkyl group is optionally substituted with one or more substituents selected from halogen, -OH _{, -NH 2 ,} -NHCH ₃ , _or -C _1-6 alkylene group-OH; R _1-1 is as defined in any one of formula (Ib) of the present invention, _and R ^1-2 is as defined in any one of formula (Ib) of the present invention ^.

In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R ¹ is -C _1-6 alkylene-N(R ^1-1 )-C(O)R ^1-2 , -O-(4- to 6-membered heterocycloalkylene)-C(O)R ^1-2 , -OC _3-6 cycloalkylene-N(R ^1-1 )-C(O)R ^1-2 , -N(R ^1-1 )-(4- to 6-membered heterocycloalkylene)-C(O)R ^1-2 , -(4- to 6-membered heterocycloalkylene)-C(O)R ^1-2 , -(4- to 6-membered heterocycloalkylene)-N(R ^1-1 )-C(O)R ^1-2 or -N(R ^1-1 )C(O)C wherein the C _1-6 alkylene group, C ^3-6 cycloalkyl group, C _3-6 cycloalkylene group, 4 to 6-membered heterocycloalkyl group or 4 to 6-membered heterocycloalkylene group is optionally substituted with one or more substituents selected from halogen, -OH, -SH, -NH ₂ , -NHC _1-6 alkyl group, -SC _1-6 alkyl group, -C _1-6 alkylene-OH, -C _1-6 alkylene-SH, -C _1-6 alkylene-S _{(C 1-6 alkyl} ) and -C _1-6 alkylene- _{NH 2 ;} R ^1-1 is as defined in any one of formula (Ib) of the present invention, and R ^1-2 is as defined in any one of formula (Ib) of the present invention.

In some embodiments, the compounds represented by the structures of formula (I) and formula (Ib), wherein R ¹ is -C _1-6 alkylene-NH-C(O)R ^1-2 , -C _1-6 alkylene-N(CH ₃ )-C(O)R ^1-2 , -O-(4- to 6-membered heterocycloalkylene)-C(O)R ^1-2 , -OC _3-6 cycloalkylene-NH-C(O)R ^1-2 , -OC _3-6 cycloalkylene-N(CH ₃ )-C(O)R ^1-2 , -NH-(4- to 6-membered heterocycloalkylene)-C(O)R ^1-2 , -N(CH ₃ )-(4- to 6-membered heterocycloalkylene)-C(O)R ^1-2 , -NHC(O)C wherein the C _1-6 alkylene group, C _3-6 cycloalkyl group, C _3-6 cycloalkylene group, 4 to 6-membered heterocycloalkyl group or 4 to 6-membered heterocycloalkylene group is optionally substituted with one or more substituents selected from halogen, -OH _{, -NH 2 ,} -NHCH ₃ , _or -C _1-6 alkylene group-OH; R _1-1 is as defined in any one of formula (Ib) of the present invention, _and R ^1-2 is as defined in any one of formula (Ib) of the present invention ^.

In some embodiments, the compounds represented by the structures of Formula (I) and Formula (Ib) are those in which R ¹ is -NH ₂ , -O-(4- to 6-membered heterocycloalkylene)-C(O)R ^1-2 , or -C _1-6 alkylene-N(CH ₃ )-C(O)R ^1-2 ; R ^1-2 is as defined in any one of Formula (Ib) of the present invention.

In some embodiments, the compounds represented by the structures of Formula (I) and Formula (Ib) are those in which R ¹ is -O-(4- to 6-membered heterocycloalkylene)-C(O)R ^1-2 or -C _1-6 alkylene-N(CH ₃ )-C(O)R ^1-2 ; R ^1-2 is as defined in any one of Formula (Ib) of the present invention.

In some embodiments, the compound represented by the structure of Formula (I) or Formula (Ib) is ^a (4- to 12-membered heterocycloalkylene).

In some embodiments, in the compound represented by the structure of Formula (I) or Formula (Ib), R ¹ is -NH-S(O) ₂ -R ^1-2 , -C(O)R ^1-2 , C(O)-N(R ^1-1 )R ^1-2 , -OC(O)-N(R ^1-1 )R ^1-2 , or -N(R ^1-1 )-C(O)-OR ^1-2 .

In some embodiments, the compound represented by the structure of Formula (I) or Formula (Ib) is wherein R ¹ is -OH.

In some embodiments, the compound of the structure shown in formula (I) or formula (Ib), wherein R ¹ is 、 、 、 、 、 、 .

In some embodiments, the compounds represented by the structures of formula (I) and formula (Ib), wherein R ¹ is NH ₂ , -OH, -O-(4- to 12-membered heterocycloalkylene)-C(O)R ^1-2 , -C _1-6 alkylene-N(R ^1-1 )-C(O)R ^1-2 , -OC(O)-N(R ^1-1 )R ^1-2 , -N(R ^1-1 )-C(O)-OR ^1-2 , -N(R ^1-1 )-C(O)R ^1-2 , -NH-S(O) ₂ -R ^1-2 , C(O)-N(R ^1-1 )R ^1-2 , -(4- to 12-membered heterocycloalkylene)-N(R ^1-1 )-C(O)R ^1-2 , -C(O)R ^1-2 , (4 to 12 membered heterocycloalkylene).

In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R ¹ is NH ₂ , -OH, 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 .

In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R ¹ is -NH ₂ , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 or .

In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R ¹ is -NH ₂ , 、 、 、 、 、 、 or .

In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R ¹ is -NH ₂ , 、 、 、 、 or .

In some embodiments, the compound of the structure shown in formula (I) or formula (Ib), wherein R ¹ is 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 or .

In some embodiments, the compound of the structure shown in formula (I) or formula (Ib), wherein R ¹ is 、 、 、 、 、 、 or .

In some embodiments, the compound of the structure shown in formula (I) or formula (Ib), wherein R ¹ is 、 、 、 、 or .

In some embodiments, the compound of the structure shown in formula (I) or formula (Ib), wherein R ¹ is 、 .

In some embodiments, the compound of the structure shown in formula (I) or formula (Ib), wherein R ¹ is .

In some embodiments, the compounds represented by the structures of Formula (I) and Formula (Ib) are those in which R ¹ is -NH ₂ , -O-(4- to 6-membered heterocycloalkylene)-C(O)R ^1-2 , or -C _1-6 alkylene-N(CH ₃ )-C(O)R ^1-2 ; and R ^1-2 is -C _1-6 alkylene-OH or -C _3-6 cycloalkylene-OH.

In some embodiments, the compounds represented by the structures of Formula (I) and Formula (Ib) are as follows: R ¹ is -O-(4- to 6-membered heterocycloalkylene)-C(O)R ^1-2 or -C _1-6 alkylene-N(CH ₃ )-C(O)R ^1-2 ; R ^1-2 is -C _1-6 alkylene-OH or -C _3-6 cycloalkylene-OH.

In some embodiments, in the compound represented by the structure of Formula (I) or Formula (Ib), R ^1-2 is -NH ₂ , -C _1-3 alkylene-OH, or -C _3-4 cycloalkylene-OH.

In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R ¹ is -NH ₂ , 、 、 、 or .

In some embodiments, the compound of the structure shown in formula (I) or formula (Ib), wherein R ¹ is 、 、 、 or .

In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R ¹ is -NH ₂ , or .

In some embodiments, the compound of the structure shown in formula (I) or formula (Ib), wherein R ¹ is or .

In some embodiments, the compound of formula (I) or formula (Ib) of the present invention is: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 or .

Those skilled in the art will understand that the present invention encompasses compounds obtained by any combination of the various embodiments. Embodiments obtained by combining the technical features or preferred technical features of one embodiment with the technical features or preferred technical features of another embodiment are also included in the scope of the present invention.

In another aspect, the present invention provides a compound having the structure shown below (an intermediate for preparing a compound represented by formula (I)): 、 、 、 or .

In another aspect, the present invention provides a pharmaceutical composition comprising (a prophylactically or therapeutically effective amount of) a compound described herein or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopically labeled substance, metabolite or prodrug thereof, and one or more pharmaceutically acceptable carriers.

A further object of the present invention is to provide a method for preparing the pharmaceutical composition of the present invention, which comprises combining the compound of the present invention or a pharmaceutically acceptable form thereof, or a mixture thereof, with one or more pharmaceutically acceptable carriers.

The pharmaceutically acceptable carrier that can be used in the pharmaceutical composition of the present invention is a pharmaceutically acceptable carrier. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (2005).

The pharmaceutical composition can be administered in any form as long as it prevents, alleviates, prevents or cures symptoms in human or animal patients. For example, it can be formulated into various suitable dosage forms depending on the route of administration.

In other embodiments, the compounds or pharmaceutical compositions of the present invention may be administered in combination with another treatment modality, which may be selected from, but not limited to, radiation therapy, chemotherapy, immunotherapy, or a combination thereof.

The present invention also relates to a pharmaceutical formulation comprising a compound of the present invention or a pharmaceutically acceptable form thereof, or a mixture thereof as an active ingredient, or a pharmaceutical composition of the present invention. In some embodiments, the formulation is in the form of a solid formulation, a semi-solid formulation, a liquid formulation, or a gaseous formulation.

A further object of the present invention is to provide a preparation, for example in the form of a kit. As used herein, the term "preparation" is intended to include, but is not limited to, a kit and packaging. The preparation of the present invention comprises: (a) a first container; (b) a pharmaceutical composition in the first container, wherein the composition comprises: a first therapeutic agent, wherein the first therapeutic agent comprises: a compound of the present invention or a pharmaceutically acceptable form thereof, or a mixture thereof; (c) optionally, a package insert indicating that the pharmaceutical composition can be used to treat a neoplastic condition (as defined below); and (d) a second container.

The first container is a container for holding a pharmaceutical composition. This container can be used for preparation, storage, transportation, and/or individual or bulk sales. The first container is intended to include bottles, jars, vials, flasks, syringes, tubes (e.g., for cream products), or any other container used to prepare, hold, store, or distribute pharmaceutical products.

The second container is a container for holding the first container and optional packaging instructions. Examples of the second container include, but are not limited to, boxes (e.g., paper or plastic boxes), boxes, cartons, bags (e.g., paper or plastic bags), pouches, and sacks. The packaging instructions may be physically attached to the outside of the first container via ties, glue, U-shaped nails, or other means of attachment, or they may be placed inside the second container without any physical means of attachment to the first container. Alternatively, the packaging instructions are located on the outside of the second container. When located on the outside of the second container, it is preferred that the packaging instructions are physically attached via ties, glue, U-shaped nails, or other means of attachment. Alternatively, they may be adjacent to or in contact with the outside of the second container without being physically attached.

The packaging instructions are a trademark, label, inscription, or the like that lists information related to the pharmaceutical composition located in the first container. The listed information is typically determined by the regulatory agency (e.g., the U.S. Food and Drug Administration) that has jurisdiction over the area in which the product is to be sold. Preferably, the packaging instructions specifically list the indications for which the pharmaceutical composition is approved. The packaging instructions can be made of any material from which the information contained therein or thereon can be read. Preferably, the packaging instructions are a printable material (e.g., paper, plastic, cardboard, foil, adhesive paper or plastic, etc.) onto which the desired information can be formed (e.g., printed or applied).

In another aspect, the present invention provides use of a compound described herein or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present invention in the preparation of a medicament.

In another aspect, the present invention provides use of a compound described herein or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present invention, in the preparation of a medicament for preventing or treating tumors or cancer.

In another aspect, the present invention provides a method for preventing or treating tumors, comprising administering to a subject in need thereof (a preventive or therapeutically effective amount of) a compound as described herein or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present invention.

In another aspect, the present invention provides a compound as described herein or a pharmaceutically acceptable form thereof (in a preventive or therapeutically effective amount), or a pharmaceutical composition of the present invention, for use in preventing or treating tumors or cancer.

In another aspect, the present invention provides a method for preventing or treating tumors or cancer by combining (a preventively or therapeutically effective amount of) a compound as described herein or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present invention with another treatment method, including but not limited to: radiation therapy, chemotherapy, immunotherapy, or a combination thereof.

In some embodiments, the tumor or cancer includes but is not limited to breast cancer, colorectal cancer, colon cancer, lung cancer and prostate cancer, as well as bile duct cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal tissue cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer and vulvar cancer, as well as leukemia (including chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL) and chronic myeloid leukemia (CML)), multiple myeloma and lymphoma.

In a further preferred embodiment, the compounds of the present invention can be used in combination with chemotherapy, radiotherapy or immunotherapy to prevent or treat tumors or cancer.

The dosing regimen can be adjusted to provide the optimal desired response. For example, when administered as an injectable, the drug may be administered as a single bolus, bolus, and/or continuous infusion, among others. For example, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It should be noted that dosage values may vary depending on the type and severity of the condition to be alleviated and may include single or multiple doses. In general, the dosage of treatment will vary, depending on considerations such as: the age, sex, and general health of the patient to be treated; the frequency of treatment and the nature of the desired effect; the extent of tissue damage; the duration of symptoms; and other variables that may be adjusted by the individual physician. It will be further understood that for any particular individual, the specific dosing regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the composition. The dosage and administration regimen of the pharmaceutical composition can be readily determined by one of ordinary skill in the clinical art. For example, the compositions or compounds of the present invention may be administered in divided doses from 4 times a day to once every 3 days, with dosages ranging from, for example, 0.01 to 1000 mg per dose. The required dosage may be administered in one or more doses to achieve the desired result. Pharmaceutical compositions according to the present invention may also be provided in unit dosage form. General Terms and Definitions

Unless otherwise defined below, all technical and scientific terms used herein have the same meanings as commonly understood by those skilled in the art. References to technical terms used herein refer to those commonly understood in the art, including variations or equivalents readily apparent to those skilled in the art. While the following terms are believed to be well understood by those skilled in the art, the following definitions are provided to better explain the present invention.

The terms "include," "comprising," "having," "containing," or "involving," and their variations herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps. Those skilled in the art will understand that the above terms, such as "comprising," encompass the meaning of "consisting of."

The term "about" means within ±10% of the stated value, preferably within ±5%, and more preferably within ±2%.

Unless otherwise stated, concentrations are by weight and ratios (including percentages) are by mole.

The term "one or more" or the similar expression "at least one" may mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more.

When the lower limit and upper limit of a numerical range are disclosed, any value and any included range falling within the range are specifically disclosed. In particular, each range of values disclosed herein (in the form "about a to b," or equivalently, "about a to b," or equivalently, "about a-b") should be understood to encompass each value and range in the broader range.

For example, _the expression " _C1-6 " should be understood to cover any subranges and each point _value therein, such as _C2-5 , _C3-4 , _C1-2 , _C1-3 , _C1-4 , _{C1-5 , etc.} , as well _{as C1} , _C2 , _C3 , _C4 , _C5 , _{C6 , etc.} For example, the expression "C ₃ - ₁₀ " should be understood in a similar manner, and for example, may cover any sub-ranges and point values contained therein, such as C ₃ - ₉ , C ₆ - ₉ , C ₆ - ₈ , C ₆ - ₇ , C ₇ - ₁₀ , C ₇ - ₉ , C ₇ - ₈ , C ₈ - ₉ , etc., as well as C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C _{8, C 9 ,} C ₁₀ , etc. For another example, the expression "3-10 yuan" should be understood to include any sub-ranges and every point value therein, such as 3-4 yuan, 3-5 yuan, 3-6 yuan, 3-7 yuan, 3-8 yuan, 3-9 yuan, 4-5 yuan, 4-6 yuan, 4-7 yuan, 4-8 yuan, 5-7 yuan, 5-8 yuan, 6-7 yuan, etc., as well as 3, 4, 5, 6, 7, 8, 9, 10 yuan, etc. For another example, the expression "5-10 yuan" should also be understood in a similar manner, such as to include any sub-ranges and point values therein, such as 5-6 yuan, 5-7 yuan, 5-8 yuan, 5-9 yuan, 5-10 yuan, 6-7 yuan, 6-8 yuan, 6-9 yuan, 6-10 yuan, 7-8 yuan, etc., as well as 5, 6, 7, 8, 9, 10 yuan, etc.

In this specification, groups and substituents thereof can be selected by one skilled in the art to provide stable structural moieties and compounds. When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents when the formula is written from right to left.

As used herein, the term "alkyl," when used alone or in combination with other groups, refers to a saturated straight or branched chain alkyl group. As used herein, the term "Ci _-6 alkyl" refers to a saturated straight or branched chain alkyl group having 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6 carbon atoms). "Ci _-6 alkyl" is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl. The alkyl groups herein are optionally substituted with one or more substituents described herein.

Throughout this disclosure, linking substituents are described. When a structure clearly requires a linking group, the Markush variable listed for that group should be understood to refer to the linking group. For example, if a structure requires a linking group and the Markush group definition for that variable lists "alkyl," it should be understood that "alkyl" refers to a linking alkylene group. For example, in some specific structures, when an alkyl group is clearly indicated as a linking group, it should be understood that the alkyl group refers to a linking alkylene group. For example, the C _1-6 alkyl in the group "halo-C _1-6 alkyl" should be understood to refer to a C _1-6 alkylene group.

As used herein, the term "alkylene," when used alone or in combination with other groups, refers to a saturated, linear, or branched, divalent hydrocarbon group. As used herein, the term "C _1-6 alkylene" refers to a saturated, linear, or branched, divalent hydrocarbon group having 1 to 6 carbon atoms. Examples of "C _1-6 alkylene" include, but are not limited to, methylene, ethylene, propylene, or butylene. The alkylene groups herein are optionally substituted with one or more substituents described herein.

In this application, the term "cycloalkyl" refers to a saturated or partially saturated, monocyclic or polycyclic (e.g., bicyclic) non-aromatic hydrocarbon group. For example, " _C3-12 cycloalkyl" or "3-12 membered cycloalkyl" refers to a cycloalkyl group having 3-12 ring carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12). Common cycloalkyl groups include, but are not limited to, monocyclic cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutene, cyclopentene, cyclohexene, etc.; or bicyclic cycloalkyl groups, including fused rings, bridged rings, or spiro rings, such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]nonyl, decahydronaphthyl, etc.

In this application, the term "cycloalkylene" refers to a saturated or partially saturated, monocyclic or polycyclic (e.g., bicyclic), non-aromatic, divalent cyclic group. For example, "C _3-12 cycloalkylene" or "3-12 membered cycloalkylene" refers to a cycloalkylene group having 3-12 ring carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12). Common cycloalkylene groups include, but are not limited to, monocyclic cycloalkylene groups, such as cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclobutene, cyclopentene, cyclohexene, etc.; or bicyclic cycloalkylene groups, including fused rings, bridged rings, or spiro rings, such as bicyclo[1.1.1]pentylene, bicyclo[2.2.1]heptylene, bicyclo[3.2.1]octylene, bicyclo[5.2.0]nonylene, decahydronaphthylene, etc.

The term "heterocycloalkyl" refers to a saturated or partially saturated non-aromatic cyclic group containing at least one ring member being a heteroatom selected from N, O, P, and S. Preferably, the number of heteroatoms is 1, 2, 3, or 4 (e.g., the number of heteroatoms is 1 or 2, and the heteroatoms are independently selected from N). Examples include 3-8-membered, 3-6-membered, 4-12-membered, and 4-6-membered heterocycloalkyl groups. In addition, the heterocycloalkyl group may contain 0, 1, 2, or 3 oxo groups. Specific examples include, but are not limited to, oxirane, oxocyclobutane, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperonyl, tetrahydropyranyl, homopiperidinyl, and pyrrolidonyl.

The term "heterocycloalkylene" refers to a non-aromatic divalent cyclic group containing at least one ring member which is a saturated or partially saturated heteroatom selected from N, O, P, and S. Preferably, the number of heteroatoms is 1, 2, 3, or 4 (e.g., the number of heteroatoms is 1 or 2, and the heteroatoms are independently selected from N). For example, 3-8-membered, 3-6-membered, 4-12-membered, or 4-6-membered heterocycloalkylene. In addition, the heterocycloalkylene may contain 0, 1, 2, or 3 oxo groups. Specific examples include, but are not limited to, oxiranediylene, oxocyclobutanediylene, pyrrolidinylene, tetrahydrofuranylene, piperidinylene, piperidinediylene, tetrahydropyranylene, homopiperidinylene, and pyrrolidonylene.

In this application, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

As used herein, the term "hydroxyl" refers to -OH.

In this application, the term "cyano" refers to -CN.

In this application, the term "nitro" refers to -NO ₂ .

In this application, the term "amino group" refers to -NH ₂ .

In this application, "oxo" refers to C(O), i.e., carbonyl.

In this application, the term "haloalkyl," when used alone or in combination with other groups, refers to an alkyl group as described above in which one or more hydrogen atoms are replaced by a halogen. For example, the term "C _1-6 haloalkyl" or "halogenated C _1-6 alkyl" refers to a C _1-6 alkyl group optionally substituted with one or more (e.g., 1-3) halogens. It will be understood by those skilled in the art that when there are more than one halogen substituent, the halogens may be the same or different and may be located on the same or different carbon atoms. Examples of haloalkyl groups include -CH ₂ F, -CHF ₂ , -CF ₃ , -CCl ₃ , -C ₂ F ₅ , -C ₂ Cl ₅ , -CH ₂ CF ₃ , -CH ₂ Cl, or -CH ₂ CH ₂ CF ₃ . The halogenated alkyl groups in the present invention are optionally substituted with one or more substituents described herein.

As used herein, the term "alkoxy," alone or in combination with other groups, refers to an alkyl group as described above attached to the parent molecular moiety through an oxygen atom. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, n-butoxy, tert-butoxy, pentoxy, and the like.

The term "each independently" as used in this application means that at least two groups (or fragments) present in a structure with the same or similar value ranges may have the same or different meanings in specific circumstances. For example, if substituent A and substituent B are each independently hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl, then when substituent A is hydrogen, substituent B may be hydrogen, or a halogen, hydroxyl, cyano, alkyl, or aryl group; similarly, when substituent B is hydrogen, substituent A may be hydrogen, or a halogen, hydroxyl, cyano, alkyl, or aryl group.

As used in this application, the term "substituted" and its variant forms herein refer to the replacement of one or more (such as 1, 2, 3 or 4) atoms or atomic groups (such as hydrogen atoms) on the designated atom by other equivalents, provided that the normal valence of the designated atom or atomic group in the current situation is not exceeded and a stable compound can be formed. If an atom or atomic group is described as "optionally substituted by...", it can be substituted or unsubstituted. Unless otherwise specified, the attachment point of a substituent herein can be from any suitable position of the substituent. When the connecting bond in a substituent is shown as passing through a chemical bond between two atoms connected to each other in a ring system, it means that the substituent can be attached to any ring-forming atom in the ring system.

When any variable (e.g., ^Ra ) appears multiple times in the definition of a compound, the definition of the variable at each position is independent of the definitions at the remaining positions; their meanings are independent of each other and do not affect each other. Therefore, if a group is substituted with one, two, or three ^Ra groups, that is, the group may be substituted with up to three ^Ras , wherein the definition of ^Ra at one position is independent of the definitions of ^Ra at the remaining positions. In addition, combinations of substituents and/or variables are allowed only if the combination results in a stable compound. The term "optionally substituted with one or more ^Ras " refers to both unsubstituted with ^Ra and substituted with one or more ^Ras . For example, "the _C1-6 alkyl group is optionally substituted with one or more ^Ras " refers to _C1-6 alkyl and _C1-6 alkyl (substituted with one or more ^Ras ).

When a group is listed without explicitly indicating that it has a substituent, such group simply means that it is unsubstituted. For example, when "C _1-6 alkyl" does not include the qualification of "substituted or unsubstituted", it simply means "C _1-6 alkyl" itself or "unsubstituted C _1-6 alkyl".

As used herein, the compounds of the present invention may contain one or more chiral centers and exist in different optically active forms. When a compound contains one chiral center, the compound comprises enantiomers. The present invention includes both isomers and mixtures of isomers, such as racemic mixtures. Enantiomers can be resolved by methods known in the art, such as crystallization and chiral chromatography. When the compound of Formula I contains more than one chiral center, diastereomers can exist. The present invention includes resolved optically pure specific isomers and mixtures of diastereomers. Diastereomers can be resolved by methods known in the art, such as crystallization and chiral chromatography.

The term "stereoisomer" includes conformational isomers and configurational isomers, wherein configurational isomers primarily include cis-trans isomers and optical isomers. The compounds described herein may exist as stereoisomers and therefore encompass all possible stereoisomeric forms, including but not limited to cis-trans isomers, enantiomers, diastereomers, atropisomers, and the like. The compounds described herein may also exist as any combination or mixture of the aforementioned stereoisomers, such as equal mixtures of meso-, racemic-, and atropisomers, or as single enantiomers, single diastereomers, or mixtures thereof, or as single atropisomers or mixtures thereof.

The term "tautomers" refers to functional group isomers that result from the rapid shift of an atom between two positions in a molecule.

In this application, you may use solid lines ( ), solid wedge( ) or virtual wedge ( ) depict carbon-carbon bonds of the compounds of the present invention. The use of a solid line to depict bonds to an asymmetric carbon atom is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., a specific enantiomer, a racemic mixture, etc.). The use of a solid or dashed wedge to depict bonds to an asymmetric carbon atom is intended to indicate the presence of the indicated stereoisomer. When present in a racemic mixture, the use of solid and dashed wedges defines relative stereochemistry, not absolute stereochemistry. Unless otherwise indicated, the compounds of the present invention may exist as stereoisomers, including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof, such as racemic mixtures and diastereomeric pairs.

Throughout this application, unless otherwise indicated, the structures depicted herein may also include compounds that differ only in the presence or absence of one or more isotopically enriched atoms. For example, compounds identical to the structures depicted herein except for the replacement of a hydrogen atom by deuterium or tritium, or the replacement of a carbon atom by carbon-13 or carbon-14, are encompassed by this application.

The present invention also encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.

Unless otherwise stated, "or" or "and" as used herein means "and/or".

Unless otherwise specified, the “ "or" ” refers to the connection location; the two are interchangeable.

The term "pharmaceutically acceptable form" includes but is not limited to pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotopically labeled substances, metabolites, or prodrugs thereof.

It should also be understood that certain compounds of the present invention may be used therapeutically in free form or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. For purposes of the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, or prodrugs that, upon administration to a patient in need thereof, are capable of directly or indirectly providing the compound of the present invention or its metabolite. Therefore, references herein to "compounds of the present invention" are intended to encompass the various derivative forms of the compounds described above.

Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof. Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. For a general description of suitable salts, see, for example, "Remington's Pharmaceutical Sciences ," Mack Publishing Company, Easton, Pa., (2005); and "Handbook of Pharmaceutical Salts: Properties , Selection, and Use," Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.

As used herein, the term "ester" refers to esters derived from the compounds described herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the present invention in the free acid or alcohol form). The compounds of the present invention themselves can also be esters.

The compounds of the present invention may exist in the form of solvates, preferably hydrates, wherein the compounds of the present invention contain a polar solvent, such as water, methanol or ethanol, as a structural element of the crystal lattice of the compound. The polar solvent, especially water, may be present in a stoichiometric or non-stoichiometric amount.

Those skilled in the art will appreciate that not all nitrogen-containing heterocycles can form nitroxides because nitrogen requires an available lone pair of electrons to oxidize to an oxide. Those skilled in the art will recognize nitrogen-containing heterocycles that can form nitroxides. Those skilled in the art will also recognize that tertiary amines can form nitroxides. Synthetic methods for preparing nitroxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidation of heterocycles and tertiary amines with peroxyacids such as peracetic acid and m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxirane such as dimethylbis(oxirane). These methods for preparing nitrogen oxides have been extensively described and reviewed in the literature, see, for example, TL Gilchrist, Comprehensive Organic Synthesis , vol. 7, pp 748-750 (AR Katritzky and AJ Boulton, Eds., Academic Press); and GWH Cheeseman and ESG Werstiuk, Advances in Heterocyclic Chemistry , vol. 22, pp 390-392 (AR Katritzky and AJ Boulton, Eds., Academic Press).

Also within the scope of the present invention are metabolites of the compounds of the present invention, i.e., substances formed in the body upon administration of the compounds of the present invention. Metabolites of the compounds can be identified by techniques known in the art, and their activity can be characterized by assays. Such products can be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, and the like of the administered compound. Thus, the present invention includes metabolites of the compounds of the present invention, including compounds produced by contacting the compounds of the present invention with a mammal for a period of time sufficient to produce metabolites thereof.

The present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity but, when administered to or on the body, are converted, for example, by hydrolytic cleavage, into the compounds of the present invention having the desired activity. Typically, such prodrugs will be functional group derivatives of the compounds that are readily converted into the desired therapeutically active compound in vivo. Further information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems," Volume 14, ACS Symposium Series (T. Higuchi and V. Stella). Prodrugs of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g., as described in "Design of Prodrugs," H. Bundgaard (Elsevier, 1985)).

The present invention also encompasses compounds of the present invention that contain protecting groups. During any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules involved, thereby forming chemically protected forms of the compounds of the present invention. This can be achieved using conventional protecting groups, for example, those described in T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 2006, which reference is incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.

The present invention also encompasses methods for preparing the compounds described herein. It will be understood that the compounds of the present invention can be synthesized using the methods described below, as well as synthetic methods known in the art of synthetic organic chemistry, or variations thereof known to those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions can be carried out in a solvent or solvent mixture appropriate to the reagents and materials used and to the transformation being achieved.

The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating one or more symptoms of a target disease or condition.

As used herein, the term "effective amount" (e.g., "therapeutically effective amount" or "prophylactically effective amount") refers to an amount of active ingredient that, when administered, will achieve the desired effect to some extent, such as alleviating one or more symptoms of the disorder being treated or preventing the appearance of the disorder or its symptoms.

As used herein, unless otherwise indicated, the term "treating" means to reverse, alleviate, inhibit the progression of, or prevent the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.

As used herein, "individual" includes humans and non-human animals. Exemplary human individuals include those suffering from a disease (e.g., a disease described herein) (referred to as a patient) or a normal individual. As used herein, "non-human animals" include all vertebrates, such as non-mammalian animals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

Without violating the common sense in the field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

The reagents and raw materials used in the present invention are commercially available.

The positive advances of the present invention are that the novel, highly active ecteinascidin derivatives provided by the present invention can achieve at least one of the following technical effects: (1) high inhibitory activity against tumor cells; (2) excellent physicochemical properties (e.g., solubility, physical and/or chemical stability); (3) excellent safety (lower toxicity and/or fewer side effects, wider therapeutic window), etc.

Detailed Description of Preferred Embodiments The present invention encompasses all combinations of the specific embodiments described. Further embodiments and the full scope of applicability of the present invention will become apparent from the detailed description provided below. However, it should be understood that while the detailed description and specific examples indicate preferred embodiments of the present invention, they are provided by way of illustration only, as various changes and modifications within the spirit and scope of the present invention will become apparent to those skilled in the art from this detailed description. All publications, patents, and patent applications cited herein, including citations, are hereby incorporated by reference in their entirety for all purposes. The present invention is further illustrated below by way of examples, but is not intended to limit the invention to the described embodiments. For experimental methods without specific conditions in the following examples, conventional methods and conditions should be followed, or selected according to the product instructions.

Mass spectrometry (MS) was performed using an Agilent (ESI) mass spectrometer, manufacturer: Agilent, model: Agilent 6120B.

Preparative high performance liquid chromatography (HPLC) was performed using a Shimadzu LC-8A preparative liquid chromatograph (YMC, ODS, 250 × 20 mm column).

Thin-layer chromatography purification was performed using GF 254 (0.4 ~ 0.5 nm) silica gel sheets produced in Yantai.

The reaction is monitored by thin layer chromatography (TLC) or liquid chromatography-mass spectrometry (LC-MS). Developing solvent systems include, but are not limited to, dichloromethane and methanol, n-hexane and ethyl acetate, and petroleum ether and ethyl acetate. The volume ratio of the solvents can be adjusted according to the polarity of the compound or by adding triethylamine.

Column chromatography typically uses Qingdao Ocean 200-300 mesh silica gel as the stationary phase. Eluent systems include, but are not limited to, dichloromethane and methanol and n-hexane and ethyl acetate. The volume ratio of the solvents is adjusted based on the polarity of the compound, and a small amount of triethylamine can also be added for adjustment.

Unless otherwise specified in the examples, the reaction temperature was room temperature (20°C-30°C).

Unless otherwise specified, the reagents used in the examples were purchased from Acros Organics, Aldrich Chemical Company, Nanjing Yaoshi Technology, Anaiji, or Shanghai Shuya Pharmaceutical Technology.

The above embodiments do not limit the scope of the present application in any way. Various modifications of the present invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended patent applications. Each reference cited in this application (including all patents, patent applications, journal articles, books, and any other publications) is incorporated by reference in its entirety.

In the conventional synthesis methods, preparation examples, examples, and intermediate synthesis examples, starting materials were commercially available and purchased from Shanghai Leyan, Shanghai Shaoyuan, Bid Biotech, Aladdin Reagents, and others. The key starting material M24 and the reference compound rubitidine were both purchased from Zhejiang Zhongke Chuangyue. The meanings of the abbreviations are shown in the table below. Abbreviation Meaning Abbreviation Meaning DMF N,N-dimethylformamide HOBT 1-Hydroxybenzotriazole DIEA Diisopropylethylamine LC-MS Liquid chromatography-mass spectrometry HPLC High-performance liquid chromatography TLC Thin-layer chromatography HATU O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate AcOH acetic acid Ethyl acetate EA DMSO Dimethylsulfoxide DIPEA N,N-Diisopropylethylamine EtOH ethanol Boc ₂ O Di-tert-butyl dicarbonate AllocCl Allyl chloroformate ACN Acetonitrile Pd(PPh ₃ ) ₄ Tetrakistriphenylphosphine palladium NaCNBH ₃ Sodium cyanoborohydride THF Tetrahydrofuran SO3.Py Pyridine Sulfur Trioxide p-TsOH p-Toluenesulfonic acid Pd/C Palladium/Carbon DCM dichloromethane TMP 2,2,6,6-Tetramethylpiperidine HOAT N-Hydroxy-7-nitrobenzotriazole

Synthesis of intermediates: Intermediate preparation example 1: Preparation of compound Int1 Step 1 : Preparation of compound Int1-2

Compound Int1-1 (2.00 g, 11.35 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), and _Boc2O (6.40 g, 29.5 mmol), triethylamine (2.50 g, 25 mmol), and DMAP (0.70 g, 5.7 mmol) were added. The reaction was allowed to proceed at room temperature for two hours. After the reaction was complete as monitored by TLC, the tetrahydrofuran was removed by evaporation under reduced pressure and concentration. Ethyl acetate and water were added to the residue, stirred, and the mixture was separated. The organic phase was separated and dried over anhydrous sodium sulfate. The crude product Int1-2 (3 g, 70% yield) was obtained by evaporation under reduced pressure and concentration, which was used directly in the next step. Step 2 : Preparation of Compound Int1-3

Lithium hydroxide (1.3 g, 54.27 mmol) was dissolved in a mixture of methanol (30 mL) and water (10 mL) and stirred to dissolve. Compound Int1-2 (3.0 g, 6.3 mmol) was then added and stirred at room temperature for 2 hours. After the reaction was complete as monitored by TLC, the pH was adjusted to 6-7 with 1 M dilute hydrochloric acid solution, ethyl acetate was added, and the mixture was stirred and separated. The organic phase was separated and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain Int1-3 (1.5 g, yield 63%). Step 3 : Preparation of Compound Int1-4

Compounds Int1-3 (1.5 g, 4.0 mmol, 1.0 eq) and Int1-7 (1.6 g, 4.38 mmol) were dissolved in DMF (30 mL), and cesium carbonate (2.60 g, 8.00 mmol) was added. The reaction mixture was heated to 65°C with stirring for 6 hours. After the reaction was complete as monitored by LCMS, the reaction mixture was cooled to room temperature, ethyl acetate and water were added to the reaction mixture, stirred, and separated. The organic phase was separated and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain Int1-4 (2.0 g, yield 89%). Step 4 : Preparation of Compound Int1-5

Compound Int1-4 (2.0 g, 3.54 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL) and 10% Pd/C (0.2 g) was added. After hydrogen substitution, the mixture was heated to 35°C and stirred overnight. After LCMS monitoring, the reaction mixture was cooled to room temperature and filtered directly. The filter cake was washed with methanol, and the organic phase was concentrated to obtain Int1-5 (1.4 g, 93% yield), which was used directly in the next reaction. Step 5 : Preparation of Compound Int1-6

Compound Int1-5 (1.1 g, 2.55 mmol) was dissolved in DMF (20 mL) with glycolic acid (0.21 g, 2.8 mmol), HATU (1.14 g, 3.01 mmol), and DIEA (0.98 g, 7.65 mmol). The mixture was stirred at room temperature for 2 h. After the reaction was complete as monitored by LCMS, ethyl acetate and water were added to the reaction mixture, stirred, and separated. The organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain Int1-6 (1.1 g, 63% yield). Step 6 : Preparation of Compound Int1 Hydrochloride

Compound Int1-6 (1.1 g, 2.24 mmol) was dissolved in 1,4-dioxane (3 mL). Hydrogen chloride/1,4-dioxane (3 mL, 10 mmol) was added and stirred at room temperature for 2 h. After LCMS monitoring, the reaction solution was concentrated under reduced pressure to provide the hydrochloride salt of Int1 (0.67 g, 92% yield). MS m/z (ESI): 290.0 [M+H] ⁺ 1H NMR (400 MHz, DMSO-d6) δ 10.90 (d, J = 2.5 Hz, 1H), 8.03 (s, 3H), 7.31 (dd, J = 8.7, 5.0 Hz, 1H), 7.23 (d, J = 2.4 Hz, 1H), 6.97 (d, J = 2.4 Hz, 1H), 6.73 (dd, J = 8.7, 2.5 Hz, 1H), 5.10 – 5.05 (m, 1H), 4.70 – 4.65 (m, 1H), 4.42 – 4.38 (m 1H), 4.18 – 4.14 (m, 1H), 3.96 (s, 2H), 3.83 – 3.80 (m, 1H), 3.10 – 2.97 (m, 4H). Intermediate Preparation Example 2: Preparation of Compound Int2 Step 1 : Preparation of compound Int2-2

Compound Int2-1 (4.0 g, 13.78 mmol) was dissolved in a mixed solvent of DMSO (20 mL) and DCM (10 mL). TEA (3.2 g, 31.4 mmol) was added. The reaction mixture was purged with nitrogen and cooled to 0°C. A solution of SO ₃ .Py (4.4 g, 27.56 mmol) in DMSO (20 mL) was slowly added dropwise. The reaction was maintained at 0°C for 2 h. After the reaction was complete as monitored by LCMS, ice water and ethyl acetate were added. The mixture was stirred and separated. The organic phase was separated and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography to obtain Int2-2 (3.8 g, 90% yield). Step 2 : Preparation of Compound Int2-3

Compound Int2-2 (3.50 g, 0.012 mol), NaOAc (4.92 g, 0.060 mol), and methylamine hydrochloride (3.96 g, 0.060 mol) were added to MeOH (40 mL) and reacted at room temperature for 2 h. NaCNBH ₃ (1.50 g, 0.024 mmol) was then added and the mixture was stirred for a further 2 h. After monitoring the reaction by TLC, the reaction solution was concentrated under reduced pressure. Saturated sodium bicarbonate and DCM were added to the residue, stirred, and separated. The organic phase was separated and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain Int2-3 (1.9 g, yield 52.7%). Step 3 : Preparation of compound Int2-4

Compound Int2-3 (1.2 g, 3.96 mmol), hydroxyacetic acid (0.34 g, 4.35 mmol), HATU (1.65 g, 4.35 mmol), and DIEA (0.78 g, 9.90 mmol) were dissolved in DMF (8 mL) and reacted at room temperature for 2 h. After the reaction was complete as monitored by LCMS, saturated sodium bicarbonate and ethyl acetate were added to the reaction solution, stirred, and separated. The organic phase was separated and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain Int2-4 (1.0 g, yield 71.4%). Step 4 : Preparation of Compound Int2

Compound Int2-4 (500 mg, 1.38 mmol) was dissolved in ethyl acetate (5 mL), cooled to 0°C, and added to hydrogen chloride/ethyl acetate (2N, 10 mL). After addition, the mixture was allowed to warm to room temperature and react for 2 h. LCMS confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure to dryness to afford the hydrochloride salt of compound Int2 (400 mg), which was used directly in the next step without purification. MS m/z (ESI): 261.9 [M+H] ^{+ 1} H NMR (400 MHz, DMSO- d ₆ ) δ 11.05 (s, 1H), 7.97 (s, 3H), 7.61 (d, J = 7.9 Hz, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 2.4 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H), 4.06 (s, 2H), 4.03 (t, J = 7.1 Hz, 1H), 3.63 – 3.64 (m, 1H), 3.39 (d, J = 10.0 Hz, 1H), 3.11 – 2.92 (m, 2H), 2.83 (s, 3H). Intermediate Preparation Example 3: Preparation of Compound Int3 Step 1 : Preparation of compound Int3-2

Compound Int3-1 (5.0 g, 0.034 mol) was dissolved in methanol (50 mL) and cooled to 0°C. Sodium acetate (14.0 g, 0.170 mol) and methylamine hydrochloride (11.0 g, 0.170 mol) were added sequentially. The reaction mixture was then heated to 45°C for 4 hours. The reaction was monitored for completion by LCMS. The reaction mixture was cooled, filtered, and concentrated to dryness under reduced pressure. The residue was dissolved in dichloromethane (60 mL), acetic acid (1.9 g, 0.032 mol) was added, and the mixture was cooled to 0°C. With stirring, TMSCN (9.5 g, 0.096 mol) was slowly added dropwise. After addition, the temperature was naturally raised to room temperature and the reaction was continued for 16 hours. LCMS monitored the reaction completion. The reaction mixture was extracted with saturated sodium bicarbonate and DCM. After stirring, the mixture was separated. The organic phase was separated and dried over anhydrous sodium sulfate. The product was concentrated under reduced pressure and purified by column chromatography to obtain Int3-2 (4 g, yield 63.4%). Step 2 : Preparation of compound Int3-3

Compound Int3-2 (4.0 g, 0.021 mol) was dissolved in THF (40 mL), and DIEA (5.4 g, 0.042 mol) and (Boc) ₂ O (5.5 g, 0.025 mol) were added. The mixture was stirred at 60°C for 16 h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain Int3-3 (0.6 g, 10% yield). Step 3 : Preparation of Compound Int3

Compound Int3-3 (600 mg, 2.1 mmol) was dissolved in a mixture of EtOH (40 mL) and aqueous ammonia (30%, 10 mL). RanyNi (100 mg) was added, and the atmosphere was replaced with hydrogen three times. The pressure was increased to 1.5 MPa and the reaction was allowed to proceed at 50°C for 16 h. LCMS monitored the reaction for completion. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography to yield Int3 (410 mg, 67.7%). MS m/z (ESI): 290.2 [M+H] ⁺ Intermediate Preparation Example 4: Preparation of Compound Int4

Compound Int4 was synthesized by a similar method as described in Intermediate Preparation Example 3. MS m/z (ESI): 276.4 [M+H] ^{+ 1} H NMR (400 MHz, CDCl ₃ ) δ 8.32 (s, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.24 – 7.18 (m, 1H), 7.15 – 7.08 (m, 2H), 5.09 (s, 1H), 4.98 (d, J = 7.4 Hz, 1H), 3.21 – 3.13 (m, 2H), 1.45 (s, 9H). Intermediate Preparation Example 5: Preparation of Compound Int5 Step 1 : Preparation of compound Int5-1

Compound Int2-2 (2.5 g, 8.6 mmol) was dissolved in EtOH (40 mL), and AcOH (1.0 g, 17.2 mmol), ethanolamine (1.1 g, 17.2 mol), and NaCNBH ₃ (1.6 g, 25.8 mmol) were added in sequence. The mixture was stirred at room temperature for 4 h, and the reaction was complete as monitored by TLC. The reaction solution was concentrated under reduced pressure, and the residue was added to the reaction solution. Saturated sodium bicarbonate and ethyl acetate were added, stirred, and the mixture was separated. The organic phase was separated and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain Int5-1 (2.6 g, yield 91%). Step 2 : Preparation of compound Int5-2

Compound Int5-1 (2.6 g, 7.80 mmol) and DIEA (2.0 g, 15.61 mmol) were dissolved in ACN (30 mL). Under nitrogen, the mixture was cooled to 0°C and AllocCl (1.8 g, 15.61 mmol) was slowly added dropwise. After addition, the mixture was allowed to warm to room temperature and react for 16 hours. Completion of the reaction was monitored by LCMS. Saturated sodium bicarbonate and ethyl acetate were added to the reaction mixture, stirred, and the layers separated. The organic phase was separated and dried over anhydrous sodium sulfate. The residue was concentrated under reduced pressure and purified by column chromatography to yield Int5-2 (1 g, 71% yield). MS m/z (ESI): 418.2 [M+H] ^{+ 1} H NMR (400 MHz, CDCl ₃ ) δ 8.10 (s, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.38 – 7.36 (s, 1H), 7.22 – 7.17(m, 1H), 7.16 – 7.04 (m, 2H), 5.94 – 5.79 (m, 1H), 5.25 – 5.12 (m, 2H), 4.60 – 4.45 (m, 2H), 4.37 – 4.25 (m, 1H), 3.79 – 3.56 (m, 4H), 3.28 – 2.97 (m, 2H), 2.99 – 2.88 (m, 2H), 1.40 (s, 9H). Step 3 : Preparation of compound Int5

Compound Int5-2 (0.5 g, 1.57 mmol) was dissolved in DCM (3 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 1 h. After the reaction was complete as monitored by LCMS, the reaction solution was concentrated to dryness to obtain the trifluoroacetic acid salt of compound Int5 (0.33 g), which was used directly in the next reaction. Intermediate Preparation Example 6: Preparation of Compound Int6 Step 1 : Preparation of compound Int6-2

LiHMDS (1.12 mL, 6.06 mmol, 2N) was added to the reaction flask. Under nitrogen, the temperature was lowered to -78°C. A solution of Int6-1 (776.1 mg, 3.03 mmol) in tetrahydrofuran (5 mL) was then added dropwise. The reaction was allowed to react for 1.5 h. A solution of isobutyl chloroformate (0.32 mL, 3.64 mmol) in tetrahydrofuran (3 mL) was then added dropwise. The temperature was then allowed to rise to room temperature and the reaction was allowed to react for 2 h. LCMS showed the reaction was complete. The temperature was lowered to 0°C, and a saturated NH ₄ Cl solution and ethyl acetate were added to the reaction mixture. After stirring, the mixture was separated. The organic phase was separated and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain Int6-2 (0.82 g, yield 76%). Step 2 : Preparation of compound Int6-3

Compound Int6-2 (500 mg, 1.40 mmol) was dissolved in a mixture of dichloromethane and trifluoroacetic acid (5 ml, dichloromethane/trifluoroacetic acid = 4/1) and reacted at room temperature for 2 h. After the reaction was complete, the mixture was concentrated under reduced pressure. Saturated sodium bicarbonate solution and DCM were added to the residue, stirred, and the layers separated. The organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by pre-TLC to obtain Int6-3 (250 mg, yield 69%). Step 3 : Preparation of Compound Int6

Compound Int6-3 (300 mg, 1.17 mmol) was dissolved in tetrahydrofuran (4 mL), cooled to 0°C, and a solution of lithium aluminum hydroxide (2.3 mL, 5.85 mmol) in tetrahydrofuran was added dropwise. The reaction was allowed to react at room temperature for 2 h. After completion of the reaction as determined by LCMS, the reaction was quenched by dropwise addition of water, filtered, washed with methanol, and concentrated. The residue was purified by preparative HPLC to afford compound Int6 (50 mg, 22% yield). MS m/z (ESI): 191.1 [M+H] ⁺ Intermediate Preparation Example 7 : Preparation of Compound Int7

Compound Int7 was synthesized by a similar method as in Intermediate Preparation Example 2. Intermediate Preparation Example 8: Preparation of Compound Int8

Compound Int8 was synthesized according to the method of Intermediate Preparation Example 2. Intermediate Preparation Example 9: Preparation of Compound Int9

Compound Int9 was synthesized according to the method of Intermediate Preparation Example 2. Intermediate Preparation Example 10 : Preparation of Compound Int10 Step 1 : Preparation of compound Int10-2

Compound Int10-1 (2.0 g, 9.1 mmol) was dissolved in THF (40 mL), and 2 N aqueous sodium bicarbonate (30 mL) was added. After stirring at room temperature, di-tert-butyl dicarbonate (2.4 g, 10.9 mmol) was added and the reaction continued for 2 h. After completion of the reaction as monitored by LCMS, the reaction mixture was concentrated under reduced pressure to remove the THF. Ethyl acetate was added to the residue, and the pH was adjusted to approximately 6 with saturated citric acid solution while stirring. The organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to yield Int10-2 (2.5 g, 86% yield). Step 2 : Preparation of compound Int10-3

Compound Int10-2 (2.50 g, 7.8 mmol) and ammonium chloride (0.54 g, 10.1 mmol) were dissolved in DMF (20 mL), and HATU (3.56 g, 9.36 mmol) and DIEA (2.6 g, 20.2 mmol) were added sequentially. The mixture was stirred at room temperature for 4 h, and the reaction was monitored for completion by LCMS. Ethyl acetate and a saturated aqueous ammonium chloride solution were added, stirred, and the mixture was separated. The organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain Int10-3 (2 g, 80% yield). Step 3 : Preparation of Compound Int10

Compound Int10-3 (2 g, 6.26 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), cooled to 0°C, and a 1N tetrahydrofuran solution of borane (50 mL) was slowly added. After addition, the mixture was allowed to warm to room temperature and the reaction continued for 4 h. Following completion of the reaction as monitored by LCMS, the reaction mixture was cooled to 0°C and anhydrous methanol was slowly added under temperature control until the borane was completely quenched. Subsequently, while maintaining temperature control, 2N aqueous hydrochloric acid was slowly added until the mixture reached a pH of approximately 3. After addition, the mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reversed-phase column chromatography to yield compound Int10 (0.83 g, 65% yield). Intermediate Preparation Example 11 : Preparation of Compound Int11

Compound Int11 was synthesized according to the method of Intermediate Preparation Example 10. Intermediate Preparation Example 12: Preparation of Compound Int14 Step 1 : Preparation of compound Int14-2

Dissolve ammonium acetate (13.50 g, 176.47 mmol) in nitromethane (200 mL), add compound Int14-1 (10.00 g, 58.80 mmol), and heat to 105°C under nitrogen for 2 hours. After completion of the reaction as monitored by TLC, cool to room temperature and filter. The filter cake is washed with _H2O /MeOH (V/V = 1/1), and the solid is dried to afford compound Int14-2 (10.30 g, 82% yield). Step 2 : Preparation of compound Int14-3

Compound Int14-2 (5.00 g, 23.47 mmol) was dissolved in a mixed solution of MeOH (25 ml) and DMF (25 ml). Sodium borohydride (4.30 g, 117.30 mmol) was added at 0°C and the reaction was stirred at room temperature for 2 hours. After the reaction was complete as monitored by TLC, the pH was adjusted to 7 with 2N dilute hydrochloric acid solution, DCM was added, and the mixture was stirred and separated. The organic phase was separated and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound Int14-3 (1.77 g, yield 35%). Step 3 : Preparation of compound Int14-4

Compound Int14-3 (1.77 g, 8.20 mmol) was dissolved in MeOH (20 mL), and a suspension of zinc powder (5.00 g, 82.00 mmol) in 2N HCl (20 mL) was added. The reaction mixture was heated to 85°C with stirring for 2 hours. After the reaction was complete as monitored by LCMS, the reaction mixture was cooled to room temperature, 1N NaOH solution was added to the reaction mixture, the pH was adjusted to 11, DCM was added, and the mixture was stirred and separated. After separation of the organic phase, the mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound Int14-4 (800 mg, yield 53%), which was used directly in the next step. Step 4 : Preparation of compound Int14-5

Compound Int14-4 (750 mg, 4.00 mmol) was dissolved in anhydrous tetrahydrofuran (2 mL), and a solution of _NaCO₃ (510 mg, 4.86 mmol) in water (6 mL) was added. After nitrogen substitution, benzyl chloroformate (884 mg, 5.20 mmol) was added at 0°C and stirred overnight at room temperature. The reaction was monitored by LCMS, and ethyl acetate was added. After stirring, the mixture was separated. The organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound Int14-5 (700 mg, 55% yield). Step 5 : Preparation of compound Int14-6

Compound Int14-5 (650 mg, 2.00 mmol) was dissolved in pyridine (8 mL), and acetic acid (4 mL), aqueous sodium hypophosphite solution (4 mL, 10 g/35 mL), and ranyl nickel (4 g) were added. The reaction was stirred at room temperature under nitrogen for 3 h. After the reaction was complete as monitored by LCMS, the reaction solution was filtered, and ethyl acetate and aqueous copper sulfate solution were added to the filtrate. After separation, the organic phase was washed with water. After separation, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound Int14-6 (600 mg, 91% yield). Step 6 : Preparation of compound Int14-7

Compound Int14-6 (550 mg, 1.71 mmol) was dissolved in MeOH (5 mL), and methylamine hydrochloride (572 mg, 8.54 mmol) and sodium acetate (700 mg, 8.54 mmol) were added. The mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride (211 mg, 3.41 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After LCMS monitoring, water and DCM were added to the reaction mixture, stirred, and the layers were separated. The organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound Int14-7 (240 mg, 38% yield). Step 7 : Preparation of compound Int14-8

Compound Int14-7 (220 mg, 0.65 mmol) was dissolved in DMF (2 mL), and hydroxyacetic acid (54 mg, 0.70 mmol), DMAP (39 mg, 0.32 mmol), HOAT (442 mg, 3.25 mmol), and EDCI (620 mg, 3.25 mmol) were added. The mixture was stirred at room temperature for 2 h. LCMS monitored the reaction completion. The reaction solution was purified by reverse phase medium pressure preparative column to obtain compound Int14-8 (200 mg, 78% yield). Step 7 : Preparation of compound Int14

Compound Int14-8 (170 mg, 0.43 mmol) was dissolved in trifluoroethanol (2 mL), and acetic acid (25 mg, 0.43 mmol) and Pd/C (85 mg, 10%) were added. The reaction was stirred at room temperature overnight under a hydrogen atmosphere. After completion of the reaction as monitored by LCMS, the reaction solution was filtered and concentrated under reduced pressure to afford compound Int14 (100 mg, 89% yield), which was used directly in the next reaction.

Referring to Intermediate Preparation Example 10, intermediates Int12 and Int13 were synthesized using the corresponding starting materials. The structures are as follows: 、 Referring to the method of intermediate preparation example 2, the corresponding raw materials were used to synthesize intermediate Int15 Example 1 : Synthesis of Compound 3

Compound M24 (100 mg, 0.16 mmol) and compound Int1 hydrochloride (260 mg, 0.80 mmol) were dissolved in anhydrous ethanol (5 mL). Sodium acetate (164 mg, 2.00 mmol) and acetic acid (120 mg, 2.00 mmol) were added, and the mixture was stirred at 60°C overnight. After completion of the reaction as monitored by LCMS, the temperature was lowered to room temperature, and the reaction solution was concentrated under reduced pressure. The residue was added with ethyl acetate and saturated aqueous sodium bicarbonate, stirred, and separated. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by pre-TLC to afford compound 3 (65 mg, 45% yield). MS m/z (ESI): 893.4 [M+H] ^{+ 1} H NMR (400 MHz, CDCl ₃ ) δ 7.74 (s, 1H), 7.17 (d, J = 8.8 Hz, 1H), 6.66 (d, J = 8.7 Hz, 2H), 6.59 (d, J = 2.4 Hz, 1H), 6.22 (s, 1H), 6.02 (s, 1H), 5.81 (s, 1H), 5.08 (d, J = 11.7 Hz, 1H), 5.00 (d, J = 7.4 Hz, 1H), 4.56 (s, 1H), 4.48 – 4.36 (m, 2H), 4.33 (s, 1H), 4.27 (d, J = 4.6 Hz, 1H), 4.17 – 4.07 (m, 3H), 4.00 (s, 2H), 3.81 (s, 3H), 3.42 (d, J = 9.9 Hz, 2H), 3.15 –3.05 (m, 2H), 2.97 – 2.75 (m, 3H), 2.58 – 2.52 (m, 4H), 2.37 (s, 3H), 2.26 (s, 3H), 2.22 (s, 3H), 2.06 (s, 3H). Example 2 : Synthesis of Compound 4

Compound 3 (30 mg, 0.034 mmol) was dissolved in ACN (3 mL) and water (2 mL), followed by the addition of silver nitrate (143 mg, 0.840 mmol) and stirring at room temperature in the dark for 12 hours. After completion of the reaction as monitored by LCMS, a saturated aqueous sodium bicarbonate solution was added, stirred, and the layers separated. The organic phase was retained, and the aqueous phase was extracted once with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC to yield compound 26 (1.5 mg, 4% yield). MS m/z (ESI): 866.3 [M-OH] ^{+ 1} H NMR (400 MHz, CDCl ₃ ) δ 7.71 (s, 1H), 7.19 (d, J = 8.7 Hz, 1H), 6.68 (d, J = 8.7 Hz, 2H), 6.61 (s, 1H), 6.22 (s, 1H), 6.01 (s, 1H), 5.22 (d, J = 11.5 Hz, 1H), 5.04 – 5.02 (m, 1H), 4.86 (s, 1H), 4.52 – 4.43 (m, 4H), 4.23 – 4.09 (m, 4H), 4.03 (s, 2H), 3.84 (s, 3H), 3.55 – 3.52 (m, 1H), 3.25 – 3.17 (m, 2H), 3.05 – 2.83 (m, 3H), 2.62 – 2.53 (m, 4H), 2.40 (s, 3H), 2.28 (s, 3H), 2.23 (s, 3H), 2.07 (s, 3H). Example 3 : Synthesis of Compound 25

Compound M24 (40 mg, 0.06 mmol) and compound Int2 hydrochloride (100 mg, 0.35 mmol) were dissolved in anhydrous ethanol (1 mL) and acetic acid (2 mL). Sodium acetate (7.38 mg, 0.09 mmol) was added, and the mixture was stirred at 60°C overnight. After completion of the reaction as monitored by LCMS, the reaction solution was cooled to room temperature. Ethyl acetate and saturated aqueous sodium bicarbonate were added to the residue, stirred, and the layers separated. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by Pre-TLC to provide compound 25 (20 mg, 43% yield). MS m/z (ESI): 865.3 [M+H] ^{+ 1} H NMR (400 MHz, CDCl ₃ ) δ 7.78 (s, 1H), 7.36 – 7.32 (m, 1H), 7.25 – 7.20 (m, 1H), 7.16 – 7.08 (m, 1H), 7.04 – 6.99(m, 1H), 6.59 (d, J = 8.0 Hz, 1H), 6.25 (d, J = 4.4 Hz, 1H), 6.04 (s, 1H), 5.82 (s, 1H), 5.15 – 5.09 (m, 1H), 4.63 – 4.58 (m, 1H), 4.43 – 4.15 (m, 5H), 4.11 – 4.05 (m, 1H), 3.83 (d, J = 13.1 Hz, 3H), 3.64 – 3.62 (m, 1H), 3.55 – 3.41 (m, 3H), 3.40 – 3.20 (m, 1H), 3.04 (s, 2H), 2.96 – 2.91 (m, 4H), 2.63 – 2.35 (m, 4H), 2.30 (s, 6H), 2.15 (s, 3H), 2.05 (s, 3H). Example 4 : Synthesis of Compound 26

Compound 25 (20 mg, 0.023 mmol) was dissolved in ACN (3 mL) and water (2 mL), followed by the addition of silver nitrate (98 mg, 0.577 mmol) and stirring at room temperature in the dark for 12 hours. After completion of the reaction as monitored by LCMS, a saturated aqueous sodium bicarbonate solution was added, stirred, and the layers separated. The organic phase was retained, and the aqueous phase was extracted once with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC to yield compound 26 (3 mg, 15.6% yield). MS m/z (ESI): 838.3 [M-OH] ⁺ 1H NMR (400 MHz, CDCl ₃ ) δ 7.34 (t, J = 7.2 Hz, 1H), 7.22 (d, J = 6.3 Hz, 1H), 7.13 – 7.06 (m, 1H), 7.06 – 6.94 (m, 1H), 6.65 – 6.54 (m, 1H), 6.24 – 6.18 (m, 1H), 6.01 (t, J = 1.7 Hz, 1H), 5.22 (d, J = 11.8 Hz, 1H), 4.90 (s, 1H), 4.51 (s, 2H), 4.26 (dd, J = 15.8, 11.4 Hz, 2H), 4.17 (d, J = 7.5 Hz, 2H), 4.11 (s, 1H), 3.84 (d, J = 2.6 Hz, 1H), 3.81 (s, 2H), 3.56 (s, 1H), 3.24 (d, J = 9.0 Hz, 1H), 3.04 (d, J = 3.3 Hz, 2H), 2.99 (d, J = 11.7 Hz, 1H), 2.93 (d, J = 4.0 Hz, 2H), 2.86 (d, J = 9.1 Hz, 1H), 2.64 – 2.46 (m, 3H), 2.43 – 2.32 (m, 3H), 2.30 (d, J = 3.0 Hz, 6H), 2.27 – 2.19 (m, 2H), 2.16 (d, J = 11.4 Hz, 1H), 2.13-2.08 (m, 3H). Example 5 : Synthesis of Compound 17 Step 1 : Preparation of compound 17-1

Compound 17-1 was synthesized by a similar method as in Example 1. MS m/z (ESI): 893.6 [M+H] ⁺ Step 2 : Preparation of Compound 17-2

Compound 17-1 (48 mg, 2.1 mmol) was dissolved in DCM (2 mL) and added to TFA (0.5 mL). The reaction was allowed to react at room temperature for 2 h. The reaction was complete as monitored by LCMS. The reaction solution was concentrated under reduced pressure and the pH was adjusted to 8 with saturated sodium bicarbonate solution. The product was extracted three times with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 17-2 (40 mg), which was directly used in the next step. Step 3 : Preparation of Compound 17

Compound 17-2 (23.8 mg, 0.030 mmol) was dissolved in DMF (1.5 mL), and hydroxyacetic acid (3.0 mg, 0.039 mol), HATU (14.9 mg, 0.039 mmol), and DIEA (11.6 mg, 0.090 mmol) were added sequentially. The mixture was stirred at room temperature for 2 h, and the reaction was complete as monitored by LCMS. Ethyl acetate and saturated aqueous sodium bicarbonate were added, and the mixture was stirred and separated. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by pre-TLC to afford compound 17 (16 mg, 62% yield). MS m/z (ESI): 851.5 [M+H] ^{+ 1} H NMR (400 MHz, CDCl ₃ ) δ 6.56 (d, J = 8.3 Hz, 1H), 6.47 – 6.42 (m, 1H), 6.05 (d, J = 5.0 Hz, 1H), 5.98 (s, 1H), 5.75 (d, J = 9.5 Hz, 1H), 5.49 (d, J = 9.8 Hz, 1H), 5.35 (s, 1H), 5.03 – 4.95 (m, 1H), 4.59 (s, 1H), 4.33 (d, J = 7.7 Hz, 1H), 4.28 – 4.20 (m, 2H), 4.16 – 4.09 δ 5.77 – 5.91 (m, 3H), 3.65 (d, J = 3.2 Hz, 3H), 3.52 – 3.49 (m, 1H), 3.43 – 3.39 (m, 1H), 2.93 – 2.82 (m, 3H), 2.61 – 2.58 (m, 1H), 2.48 (s, 1H), 2.45 (s, 1H), 2.31 (dd, J = 6.5, 2.9 Hz , 4H), 2.29 – 2.23 (m, 3H), 2.21 (s, 3H) , 2.05 (s, 3H) .

Compound 18 was synthesized by a similar method as described in Example 2 . MS m/z (ESI): 824.4 [M-OH] ^{+ 1} H NMR (400 MHz, CDCl ₃ ) δ 7.27 – 7.21 (m, 2H), 7.07 (t, J = 7.3 Hz, 1H), 6.95 (t, J = 7.5 Hz, 1H), 6.56 (d, J = 8.8 Hz, 1H), 6.15 (s, 1H), 5.93 (s, 1H), 5.73 – 5.68 (m, 1H), 5.10 – 5.05 (m, 1H), 4.79 – 4.74 (m, 1H), 4.44 – 4.37 (m, 2H), 4.26 – 4.22 (m, 1H), 4.12 – 4.01 (m, 3H), 3.77 – 3.70 (m, 3H), 3.62 – 3.59 (m, 1H), 3.43 (d, J = 7.9 Hz, 1H), 3.19 – 3.12 (m, 1H), 3.08 – 2.96 (m, 1H), 2.96 – 2.72 (m, 4H), 2.60 (d, J = 2.6 Hz, 2H), 2.48 (d, J = 3.8 Hz, 2H), 2.34 – 2.27 (m, 3H), 2.27 – 2.22 (m, 3H), 2.19 (d, J = 6.3 Hz, 2H), 2.13 (d, J = 2.6 Hz, 2H), 2.00 (s, 3H) Example 7 : Synthesis of Compounds 13 , 13R , and 13S Step 1 : Preparation of compound 13-1

Compound 13-1 was synthesized by a method similar to Example 1. Step 2 : Preparation of Compound 13 A crude compound 13 was synthesized by a method similar to Step 2 of Example 5 . Compound 13 was purified by Pre-TLC to give compound 13. MS m/z (ESI): 779.3[M+H] ^{+ 1} H NMR (400 MHz, CDCl ₃ ) δ 8.47 (s, 1H), 7.82 (s, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 8.2 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 7.03 (t, J = 7.4 Hz, 1H), 6.65 (s, 1H), 6.25 (d, J = 1.4 Hz, 1H), 6.03 (d, J = 1.4 Hz, 1H), 5.10 (d, J = 11.8 Hz, 1H), 4.53 (s, 1H), 4.35 (s, 1H), 4.33 – 4.24 (m, 2H), 4.17 (s, 2H), 3.78 (s, 4H), 3.43 (d, J = 4.7 Hz, 1H), 3.39 (s, 1H), 2.90 (d, J = 5.1 Hz, 4H), 2.78 (d, J = 11.9 Hz, 2H), 2.46 (d, J = 16.0 Hz, 2H), 2.37 (s, 3H), 2.25 (s, 3H), 2.21 (d, J = 3.3 Hz, 3H), 2.04 (s, 3H).

The purified compound 13 was then purified using a reverse medium-pressure column. The purification conditions were as follows: Chromatographic column: Agela Technologies C18, 20-35 μM, 100 Å, 120 g Mobile phase: Pure water (0.1% hydrochloric acid)/acetonitrile Gradient: 100% pure water-100% acetonitrile, 50% acetonitrile to product The retention times of Peak 1 and Peak 2 on the LCMS were 1.415 min and 1.392 min, respectively.

The first peak (1.415 min) was characterized as follows: 13R or 13S: MS m/z (ESI): 779.3[M+H] ^{+ 1} H NMR (400 MHz, DMSO- d ₆ ) δ 10.81 (s, 1H), 8.95 (s, 1H), 7.93 (s, 3H), 7.64 (d, J = 6.4 Hz, 1H), 7.40 (d, J = 6.4 Hz, 1H), 7.11 (t, J = 6.4 Hz, 1H), 7.02 (t, J = 6.4 Hz, 1H), 6.53 (s, 1H), 6.25 (d, J = 16.8 Hz, 2H), 5.06 (d, J = 11.2 Hz, 1H), 4.71-4.57 (m, 1H), 4.55-4.47 (m, 1H), 4.44-4.38 (m, 1H), 4.37-4.28 (m, 1H), 4.09 (s, 1H), 4.07-4.04 (m, 1H), 3.67 (s, 3H), 3.43-3.40 (m, 1H), 3.35-3.25 (m, 1H), 2.99-2.92 (m, 3H), 2.73 – 2.69 (m, 1H), 2.32 (s, 3H), 2.30 (s, 3H), 2.22-2.08 (m, 4H), 2.00 (s, 3H), 1.99-1.94 (m, 1H).

The second peak (1.392 min) was characterized as follows: 13R or 13S: MS m/z (ESI): 779.3[M+H] ^{+ 1} H NMR (400 MHz, DMSO) δ 10.67 (s, 1H), 9.02 (s, 1H), 8.24 (s, 3H), 7.74 (d, J = 6.4 Hz, 1H), 7.42 (d, J = 6.4 Hz, 1H), 7.12 (t, J = 6.4 Hz, 1H), 7.02 (t, J = 6.4 Hz, 1H), 6.49 (s, 1H), 6.25 (d, J = 16.8 Hz, 2H), 5.15 (d, J = 11.2 Hz, 1H), δ 4.68-4.57 (m, 1H), 4.54-4.42 (m, 1H), 4.38-4.26 (brs, 2H), 4.23-4.20 (m, 1H), 4.14 (s, 1H), 3.66 (s, 3H), 3.34-3.26 (m, 1H), 3.14-3.03 (m, 1H), 3.01-2.84 (m, 3H), 2.56 – 2.53 (m, 1H), 2.31 (s, 3H), 2.29 (s, 3H), 2.22-2.11 (m, 3H), 2.10-2.01 (m, 2H), 1.97 (s, 3H). Example 8 : Synthesis of Compound 14

Compound 14 was synthesized by a similar method as described in Preparation Example 2 . MS m/z (ESI): 770.9 [M+H] ^{+ 1} H NMR (400 MHz, CDCl ₃ ) δ 7.48 (d, J = 25.9 Hz, 1H), 7.15 (s, 1H), 7.08 – 6.94 (m, 1H), 6.51 (s, 1H), 6.16 (d, J = 11.4 Hz, 1H), 5.92 (d, J = 6.9 Hz, 1H), 5.00 (d, J = 10.9 Hz, 1H), 4.76 (d, J = 26.5 Hz, 1H), 4.37 (d, J = 13.9 Hz, 1H), 4.21 (s, 1H), 4.14 (s, 1H), 4.10 (s, 3H), 3.62 (d, J = 18.1 Hz, 1H), 3.42 (s , 1H), 3.23 (s, 1H), 3.13 (s, 1H), 2.99 – 2.69 (m, 7H), 2.34 (s, 2H), 2.32 (s, 2H), 2.28 (s, 2H), 2.21 (s, 2H), 2.13 (d, J = 5.5 Hz , 3H), 2.05 (s, 3H), 1.96 (s, 2H). Example 9 : Synthesis of Compound 33 Step 1 : Preparation of compound 33-1

Compound 33-1 was synthesized by a similar method as in Preparation Example 1. Step 2 : Preparation of Compound 33-2

Compound 33-1 (85 mg, 0.09 mmol) and TEA (27 mg, 0.27 mmol) were dissolved in anhydrous DCM (4 mL) and cooled to 0°C. Ms ₂ O (32.5 mg, 0.184 mmol) was then added and the temperature was naturally raised to room temperature for reaction for 2 h. Saturated sodium bicarbonate solution (3 ml) was added to quench the mixture and the mixture was heated to 45 degrees for reaction overnight. LCMS monitored the reaction to be complete. The reaction solution was directly extracted with DCM. After separation of the organic phase, it was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by Pre-TLC to obtain compound 33-2 (28 mg, yield 25%). Step 3 : Preparation of compound 33

Compound 33-2 ( 16 mg, 0.018 mmol), acetic acid (5.4 mg, 0.09 mmol), and Pd(PPh ₃ ) ₄ (2.0 mg, 0.002 mmol) were added to DCM (2 mL). Bu ₃ SnH 3 (52 mg, 0.18 mmol) was added under nitrogen and the mixture was allowed to react at room temperature for 2 h. LCMS monitored the reaction for completion. Saturated ammonium chloride and dichloromethane were added to the reaction mixture, stirred, and the layers separated. The organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue purified by preparative HPLC to afford compound 33 (8 mg, 50% yield). MS m/z (ESI): 819.4 [M+H] ⁺ H NMR (400 MHz, CDCl ₃ ) δ 7.36 (d, J = 7.9 Hz, 1H), 7.19 – 6.99 (m, 4H), 6.50 (s, 1H), 6.33 (s, 1H), 6.14 (s, 1H), 5.03 (d, J = 11.2 Hz, 1H), 4.48 – 4.41 (m, 2H), 4.28 (d, J = 4.7 Hz, 1H), 4.21 – 4.18 (m, 1H), 4.05 – 4.02 (m, 1H), 3.84 (s, 3H), 3.69 (d, J = 4.7 Hz, 1H), 3.44 (d, J = 9.2 Hz, 1H), 3.18 (d, J = 12.0 Hz, 1H), 3.00 – 2.69 (m, 7H), 2.61– 2.55 (m, 2H), 2.49 – 2.36 (m, 2H), 2.32 (s, 6H), 2.20 (s, 3H), 2.02 (s, 3H). Example 10 : Synthesis of Compound 34

Compound 34 was synthesized by a similar method as described in Example 2 . MS m/z (ESI): 810.3 [M+H] ^{+ 1} H NMR (400 MHz, CDCl ₃ ) δ 7.25 (d, J = 7.9 Hz, 1H), 7.05 (d, J = 7.3 Hz, 2H), 7.00 (d, J = 7.4 Hz, 2H), 6.95 – 6.92 (m, 1H), 6.40 (s, 1H), 6.20 (d, J = 3.6 Hz, 1H), 6.00 (d, J = 3.6 Hz, 1H), 5.04 – 4.96 (m, 1H), 4.29 – 4.23 (m, 1H), 4.16 – 3.98 (m, 2H), 3.87 – 3.80 (m, δ 5.75 (s, 3H), 3.71 (s, 1H), 3.65 (d, J = 4.9 Hz, 1H), 3.42 (s, 1H), 3.19 – 3.03 (m, 3H), 2.90 – 2.82 (m, 3H), 2.82 – 2.44 (m, 7H), 2.36 – 2.25 (m, 3H), 2.22 (s, 3H), 2.21 (s, 3H), 2.19 – 2.14 (m, 1H), 2.09 (s, 3H), 2.06 – 1.96 (m, 1H). Example 11 : Synthesis of Compound 21

Compound 21 was synthesized by a similar method as described in Example 1 . MS m/z (ESI): 794.3 [M+H] ^{+ 1} H-NMR (400 MHz, DMSO- d ₆ ): δ 10.07 (s, 1H), 8.77 (s, 1H), 7.42 (d, J = 7.9 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H), 6.89 (t, J = 7.5 Hz, 1H), 6.48 (s, 1H), 6.23 (d, J = 19.4 Hz, 2H), 5.11 (d, J = 11.6 Hz, 1H), 4.69 (s, 1H), 4.51 – 4.37 (m, 2H), 4.20 (d, J = 4.6 Hz, 1H), 4.14 (d, J = 11.7 Hz, 1H), 4.09 (s, 1H), 3.82 (d, J = 9.8 Hz, 2H), 3.66 (s, 3H), 2.98 – 2.92 (m, 1H), 2.82 – 2.71 (m, 5H), 2.67 (s, 1H), 2.33 (d, J = 4.6 Hz, 1H), 2.27 (d, J = 7.2 Hz, 6H), 2.06 (s, 3H), 2.00 – 1.98 (m, 1H), 1.96 (s, 3H). Example 12 : Synthesis of Compound 22

Compound 22 was synthesized by a similar method as described in Example 2 . MS m/z (ESI): 785.4 [M+H] ^{+ 1} H-NMR (400 MHz, DMSO- d ₆ ): δ 10.05 (d, J = 8.8 Hz, 1H), 8.65 (s, 1H), 7.56 – 7.19 (m, 2H), 6.99 – 6.90 (m, 2H), 6.48 (s, 1H), 6.23 (d, J = 7.0 Hz, 1H), 6.13 (s, 1H), 5.04 (dd, J = 22.9, 11.4 Hz, 1H), 4.68 (d, J = 13.7 Hz, 1H), 4.35 – 4.30 (m, 2H), 4.12 – 4.09 (m, 2H), 3.83 – 3.81 (m, 1H), 3.66 (s, 3H), 3.64 – 3.51 (m, 2H), 3.11 – 2.99 (m, 4H), 2.78 – 2.69 (m, 4H), 2.29 (s, 3H), 2.27 (s, 3H), 2.07 – 2.03 (m, 4H), 1.96 – 1.92 (m, 4H). Example 13 : Synthesis of Compound 1

Compound 1 was synthesized by a similar method as described in Example 1. MS m/z (ESI): 779.4 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.62 (s, 1H), 8.80 (s, 1H), 7.03 (d, J = 8.6 Hz, 1H), 6.52 – 6.46 (m, 2H), 6.42 (dd, J = 8.6, 2.1 Hz, 1H), 6.23 (d, J = 7.8 Hz, 2H), 5.34 (t, J = 4.7 Hz, 1H), 5.07 (d, J = 11.2 Hz, 1H), 4.47 (d, J = 2.7 Hz, 2H), 4.22 – 4.19 (m, 1H), 4.10 (s, δ 5.77 (s, 2H), 3.11 (s, 4H), 3.96 (s, 3H), 2.37 (s, 2H), 2.19 (s, 3H), 2.13 (s, 4H), 2.26 (s, 3H), 2.13 (s, 3H), 2.26 (s, 3H), 2.00 (s, 1H) , 1.91 ( s , 3H). Compound 2 was synthesized according to a similar method to Example 2. MS m/z (ESI): 770.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.03 (s, 1H), 6.68 (s, 2H), 6.56 (d, J = 8.8 Hz, 1H), 6.19 (s, 1H), 5.99 (s, 1H), 5.34 – 5.28 (m, 2H), 5.19 (d, J = 11.5 Hz, 1H), 4.89 – 4.84 (m, 1H), 4.52 – 4.50 (m, 2H), 4.22 – 4.08 (m, 2H), 3.82 (s, 3H), 3.23– 3.08 (m, 2H), 2.92 – 2.42 (m, 6H), 2.37 (s, 3H), 2.26 – 2.22 (m, 7H), 2.05 (s, 3H), 2.04 – 2.02 (m, 1H). Example 15 : Synthesis of Compounds 15 , 15R , and 15S

Compound 13 (50 mg, 0.064 mmol) was dissolved in DMF (1.5 mL), and hydroxyacetic acid (5.8 mg, 0.077 mol), HATU (29.4 mg, 0.077 mmol), and DIEA (16.5 mg, 0.128 mmol) were added sequentially. The mixture was stirred at room temperature for 2 h, and the reaction was complete as monitored by LCMS. Ethyl acetate and saturated aqueous sodium bicarbonate were added, and the mixture was stirred and separated. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by Pre-TLC to obtain compound 15 (40 mg, 75% yield). Compound 15: MS m/z (ESI): 837.2 [M+H] ⁺

Compound 15 was then purified using a reverse medium-pressure column. Purification conditions were as follows: Column: Agela Technologies C18, 20-35 μM, 100 Å, 120 g Mobile phase: Water (0.1% formic acid)/acetonitrile Gradient: 100% water - 100% acetonitrile, 50% acetonitrile to product

The retention times of Peak 1 and Peak 2 on LCMS were 1.651 min and 1.587 min, respectively. 4 (t, J = 6.4 Hz, ^1H ), 6.49 (s, 1H), 6.24 (d, J = 16.8 Hz, 2H), 5.43 (t, J = 6.4 Hz, 1H), 7.11 (d, J = 6.4 ^Hz , 1H), 7.76 (t, J = 6.4 Hz, 1H), 7.10 (d, J = 6.4 Hz, 1H), 7.57 (t, J = 6.4 Hz, 1H), 7.11 (d, J = 6.4 Hz, 1H), 7.12 (t, J = 6.4 Hz, 1H), 7.62 (t, J = 6.4 Hz, 1H), 7.63 (t, J = 6.4 Hz, 1H), 7.61 (t, J = 6.4 Hz, 1H), 7.63 (t, J = 6.4 Hz, 1H), 7.61 (t, J = 6.4 Hz, 1H), 7.63 (t, J = 6.4 Hz, 1H), 7.61 (t, J = 6.4 Hz, 1H ), = 5.6 Hz, 1H), 5.10-5.07 (m, 1H), 4.98-4.96 (m, 1H), 4.48-4.47 (m, 2H), 4.21-4.20 (m, 1H), 4.08-4.05 (m, 3H), 3.81-3.68 (m, 2H), 3.65 (s, 3H), 3.45-3.42 (m, 1H), 3.38-3.35 (m, 1H), 3.23-3.19 (m, 1H), 2.90-2.78 (m, 2H), 2.76-2.72 (m, 1H), 2.69-2.66 (m, 2H), 2.31 (s, 3H), 2.23 (s, 3H), 2.06 (s, 3H), 1.99 (s, 3H), 1.98-1.96 (m, 1H), 1.85-1.83 (m, 1H).

The second peak (1.587 min) was characterized as follows: 15R or 15S (12 mg, 22.6% yield): MS m/z (ESI): 837.2 [M+H] ^{+ 1} H NMR (400 MHz, DMSO) δ 10.39 (s, 1H), 8.81 (s, 1H), 7.50 (d, J = 6.4 Hz, 1H), 7.36 (d, J = 6.4 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 7.04 (t, J = 6.4 Hz, 1H), 6.90 (t, J = 6.4 Hz, 1H), 6.48 (s, 1H), 6.24 (d, J = 16.8 Hz, 2H), 5.39 (t, J = 5.6 Hz, 1H), 5.13-5.10 (m, 1H), 4.97-4.92 (m, 1H), 4.48-4.47 (m, 2H), 4.21-4.20 (m, 1H), 4.14-4.09 (m, 2H), 3.86-3.85 (m, 2H), 3.65 (s, 3H), 3.40-3.38 (m, 1H), 3.21-3.20 (m, 1H), 2.95-2.76 (m, 4H), 2.63-2.59 (m, 1H), 2.30 (s, 3H), 2.24 (s, 3H), 2.06 (s, 3H), 2.05-2.02 (m, 1H), 1.98 (s, 3H), 1.93-1.82 (m, 1H). Example 16 : Synthesis of Compound 16

Compound 16 was synthesized by a similar method as described in Example 2 . MS m/z (ESI): 828.7 [M+H] ^{+ 1} H NMR (400 MHz, CDCl ₃ ) δ 7.96 (d, J = 24.5 Hz, 1H), 7.61-7.43 (m, 1H), 7.30 (s, 1H), 7.14 (t, J = 7.7 Hz, 1H), 7.09-6.97 (m, 1H), 6.88 (s, 1H), 6.64 (s, 1H), 6.23 (d, J = 3.2 Hz, 1H), 6.01 (s, 1H), 5.97-5.64 (m, 1H), 5.46-5.08 (m, 3H), 4.94 (s, 1H), 4.70-4.44 (m, 4H), 3.92-3.79 (m, 5H), 3.53-3.40 (m, 2H), 2.94-2.67 (m, 4H), 2.58-2.16 (m, 9H), 2.18-1.94 (m, 5H). Example 17 : Synthesis of Compounds 23 and 24 Step 1 : Synthesis of compound 23

Compound M24 (50 mg, 0.08 mmol) and compound Int7 (40 mg, 0.16 mmol) were dissolved in anhydrous ethanol (1 mL) and acetic acid (2 mL). Sodium acetate (7.38 mg, 0.09 mmol) was added, and the mixture was stirred at 60°C overnight. After completion of the reaction as monitored by LCMS, the reaction mixture was cooled to room temperature. Ethyl acetate and saturated aqueous sodium bicarbonate were added to the residue, stirred, and the layers separated. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse preparative HPLC to afford compound 23 (37 mg, 55% yield). MS m/z (ESI): 851.2 [M+H] ^{+ 1} H NMR (400 MHz, DMSO- d ₆ ) δ 9.92 (s, 1H), 8.77 (s, 1H), 7.74 (t, J = 5.6 Hz, 1H), 7.36 – 7.25 (m, 2H), 7.02 (t, J = 7.6 Hz, 1H), 6.91 (t, J = 7.4 Hz, 1H), 6.47 (s, 1H), 6.29 – 6.20 (m, 2H), 5.58 (t, J = 5.7 Hz, 1H), 5.17 (d, J = 10.8 Hz, 1H), 4.60 – 4.43 (m, 2H), 4.30 – δ 4.18 (m, 2H), 4.15 (s, 1H), 3.90 – 3.84 (m, 2H), 3.69 (s, 3H), 3.46 – 3.39 (m, 2H), 3.26 – 3.19 (m, 2H), 3.00 – 2.88 (m, 1H), 2.85 – 2.70 (m, 3H), 2.42 – 2.34 (m, 1H), 2.29 (s, 3H), 2.24 – 2.14 (m, 5H), 2.01 (s, 3H), 1.95 (s, 3H), 1.86 (s, 1H). Step 2 : Synthesis of compound 24

Compound 24 was synthesized by a similar method as described in Example 4. MS m/z (ESI): 842.2 [M+H] ⁺ Example 18 : Synthesis of Compounds 27 and 28

Compound 27 and Compound 28 were synthesized by similar methods to those in Example 2 and Example 3, respectively. Compound 27 : MS m/z (ESI): 851.2 [M+H] ^{+ 1} H NMR (400 MHz, DMSO- d ₆ ) δ 10.16 (s, 1H), 8.77 (s, 1H), 7.60 – 7.50 (m, 1H), 7.40 – 7.25 (m, 2H), 7.03 (t, J = 7.6 Hz, 1H), 6.91 (t, J = 7.8 Hz, 1H), 6.53 (s, 1H), 6.25 (d, J = 11.4 Hz, 2H), 5.55 (t, J = 5.5 Hz, 1H), 5.08 (d, J = 11.0 Hz, 1H), 4.60 – 4.43 (m, 2H), 4.20 (d, J = 3.9 Hz, 1H), 4.15 – 4.04 (m, 2H), 3.87 (d, J = 5.5 Hz, 2H), 3.69 – 3.56 (m, 4H), 3.46 – 3.40 (m, 1H), 3.25 – 3.15 (m, 1H), 3.05 – 2.93 (m, 1H), 2.95 – 2.80 (m, 2H), 2.63 – 2.57 (m, 1H), 2.40 – 2.28 (m, 4H), 2.19 (s, 3H), 2.15 – 2.05 (m, 2H), 2.04 – 1.99 (m, 7H), 1.81 (s, 1H). Compound 28: MS m/z (ESI): 842.2 [M+H] ^{+ 1} H NMR (400 MHz, CDCl ₃ ) δ 12.52 (s, 1H), 7.66-7.52 (m, 1H), 7.35-7.26 (m, 2H), 7.18-6.97 (m, 2H), 6.75 (s, 2H), 6.25 (s, 1H), 6.07-6.01 (m, 2H), 5.15 (d, J = 11.5 Hz, 2H), 4.90-4.89 (m, 2H), 4.65 (s, 1H), 4.33 (s, 1H), 4.17-4.09 (m, 4H), 3.97-3.83 (m, 6H), 3.51-3.50 (m, 2H), 3.18-3.14 (m, 2H), 2.65-2.58 (m, 4H), 2.38-2.35 (m, 4H), 2.31-2.14 (m, 4H), 2.08 (s, 3H), 2.02 (m, 1H). Example 19 : Synthesis of Compound 39 Step 1 : Preparation of compound 39-1

To a solution of compound 13 (95 mg, 0.12 umol) in DMF (2 mL) were added Boc-glycine (64 mg, 0.36 umol), HATU (45.6 mg, 0.12 umol), and HOAt (27.2 mg, 0.12 umol), stirred at room temperature, and then TMP (43.6 mg, 0.36 umol) was added. The reaction mixture was stirred at room temperature for one hour. The reaction mixture was directly purified by reverse preparative column and lyophilized to obtain compound 39-1 (65 mg, 58.0% yield). Step 2 : Preparation of compound 39

To a solution of compound 39-1 (60 mg, 0.06 mmol) in _MeNO₂ (1.0 mL) at room temperature was added _ZnBr₂ (40.53 mg, 0.18 mmol). The reaction mixture was stirred at room temperature for 3 hours and then concentrated. The reaction mixture was purified by reverse-phase HPLC and lyophilized to afford compound 39 (45 mg, 84.9% yield) as a white solid. MS m/z (ESI): 836.2 [M+H] ^{+ 1} HNMR (400 MHz, DMSO- d ₆ ) δ 10.49 – 10.37 (m, 1H), 8.82 (s, 1H), 8.33 (s, 1H), 8.07 – 7.89 (m, 1H), 7.49 – 7.26 (m, 2H), 7.04 (t, J = 7.6 Hz, 1H), 6.95 – 6.85 (m, 1H), 6.48 (d, J = 5.0 Hz, 1H), 6.36 – 6.17 (m, 2H), 5.17 – 5.01 (m, 1H), 4.94 (s, 1H), 4.48 (s, 2H), δ 4.20 (s, 1H), 4.13 – 4.01 (m, 2H), 3.65 (s, 3H), 3.21 (s, 3H), 3.10 (s, 1H), 3.00 – 2.60 (m, 5H), 2.36 – 2.26 (m, 3H), 2.26 – 2.20 (m, 3H), 2.12 – 2.07 (m, 1H), 2.08 – 2.02 (m, 3H), 2.02 – 1.95 (m, 3H), 1.94 – 1.75 (m, 2H). Example 20 : Synthesis of Compound 29

Compound M24 (150 mg, 0.24 mmol) and compound Int9 (213 mg, 0.7 mmol) were dissolved in anhydrous ethanol (4 mL) and acetic acid (4 mL) and stirred at 70°C overnight. After completion of the reaction as monitored by LCMS, the reaction mixture was cooled to room temperature. Ethyl acetate and saturated aqueous sodium bicarbonate were added to the residue, stirred, and the mixture was separated. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC to afford compound 29 (18 mg, 8.6% yield). MS m/z (ESI): 865.3 [M+H] ^{+ 1} H NMR (400 MHz, CDCl ₃ ) δ 7.62 (d, J = 12.4 Hz, 1H), 7.30 (t, J = 7.3 Hz, 1H), 7.27 – 7.20 (m, 1H), 7.10 – 7.01 (m, 1H), 6.96 (q, J = 8.0 Hz, 1H), 6.49 (d, J = 22.3 Hz, 1H), 6.17 (dd, J = 2.8, 1.3 Hz, 1H), 5.96 (d, J = 1.2 Hz, 1H), 5.71 (d, J = 3.2 Hz, 1H), 4.96 (d, J = 11.7 Hz, 1H), 4.57 (s, 1H), 4.31 (d, J = 4.8 Hz, 1H), 4.26 – 4.18 (m, 2H), 4.16 (d, J = 2.7 Hz, 2H), 4.13 – 4.06 (m, 1H), 3.74 (d, J = 1.0 Hz, 3H), 3.66 – 3.54 (m, 2H), 3.44 (s, 1H), 3.40 (d, J = 5.1 Hz, 3H), 3.09 (s, 1H), 3.07 – 2.94 (m, 1H), 2.93 (s, 3H), 2.54 (ddd, J = 31.3, 14.7, 3.1 Hz, 1H), 2.43 – 2.33 (m, 1H), 2.25 (s, 3H), 2.19 (s, 3H), 2.10 (d, J = 1.3 Hz, 5H), 2.02 (s, 3H). Example 21 : Synthesis of Compound 124S Step 1 : Preparation of compound 124S-1

Compound M24 (100 mg, 0.16 mmol), compound Int10 (65 mg, 0.32 mmol), and sodium acetate (138 mg, 1.60 mmol) were dissolved in acetic acid (4 mL), and the reaction mixture was stirred at 65°C for 2 hours. The solution was concentrated, and the crude product was diluted with ethyl acetate and water, and the pH was adjusted to 9 with saturated sodium bicarbonate. The aqueous phase was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified on a silica gel column to obtain compound 124S-1 (72 mg, 60% yield). Step 2 : Preparation of compound 124S

Compound 124-1 (27 mg, 0.033 mmol) was dissolved in DMF (1.5 mL), and hydroxyacetic acid (3.0 mg, 0.039 mol), HATU (14.9 mg, 0.039 mmol), and DIEA (11.6 mg, 0.090 mmol) were added sequentially. The mixture was stirred at room temperature for 2 h, and the reaction was complete as monitored by LCMS. Ethyl acetate and saturated aqueous sodium bicarbonate were added, stirred, and the mixture was separated. The organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by reverse HPLC to obtain compound 124S (10 mg, yield 35%). MS m/z (ESI): 867.5 [M+H] ⁺ Example 22 : Synthesis of Compound 125S

Compound 125S was synthesized according to the method of Example 21. MS m/z (ESI): 881.4 [M+H] ⁺ Example 23 : Synthesis of Compound 124R

Compound 124R was synthesized according to the method of Example 21. MS m/z (ESI): 867.5 [M+H] ⁺ Example 24 : Synthesis of Compound 125R

Compound 125R was synthesized according to the method of Example 21. MS m/z (ESI): 881.4 [M+H] ⁺ Example 25 : Synthesis of Compound 7

Compound Int14 (180 mg, 0.43 mmol) was dissolved in trifluoroethanol (2 mL), and M24 (89 mg, 0.14 mmol) was added. The mixture was stirred at 60°C for 2 h. After completion of the reaction as monitored by LCMS, the reaction mixture was subjected to reverse-phase HPLC preparation, and the prepared solution was lyophilized to afford compound 7 (38.79 mg, 33% yield). MS m/z (ESI): 865.4 [M+H] ^{+ 1} H NMR (400 MHz, CDCl ₃ ) δ 10.19 (d, J =14.8Hz, 1H), 8.76 (s, 1H), 7.28 – 7.34 (m, 1H), 7.19 (d, J =15.6, 1H), 6.89-6.93 (m, 1H), 6.49 (s, 1H), 6.24 (d, J =15.2, 2H), 5.08 (d, J =10.8, 1H), 4.52 (s, 1H), 4.46 (d, J =12.8,3H), 4.17-4.21 (m, 2H), 4.08 (d, J =11.2Hz, 3H), 3.66 (s, 3H), 3.12-3.20 (m, 4H), 2.62-2.90 (m, 9H), 2.39-2.47 (m, 1H), 2.28 (d, J =12.4 Hz, 6H), 2.06 (s, 4H), 1.99 (s, 3H) Example 26 : Synthesis of Compound 126

Compound 126 was synthesized by a similar method as in Example 3. MS m/z (ESI): 865.3 [M+H] ⁺ Effect Test Example 1 : In vitro inhibition test of tumor cell proliferation by the compound Test Purpose

To test the inhibitory activity of drug compounds on the in vitro proliferation of NCI-H82, SKOV-3, OVCAR-3, NCI-H1781, MKN-45, LS174T, and BT474 tumor cells, cells were treated with various concentrations of the compound in vitro. After 6 days of culture, cell proliferation was assessed using the CTG (CellTiter-Glo® Luminescent Cell Viability Assay, Promega, Cat. No. G7558) reagent. The in vitro activity of the compound was evaluated based on the IC ₅₀ value.

The following uses an in vitro proliferation inhibition assay using NCI-H82 cells as an example to illustrate the in vitro proliferation inhibition assay for compounds described in this application. This method is also applicable, but not limited to, in vitro proliferation inhibition assays for other tumor cells. 1. Cell Culture: NCI-H82 cells were cultured in RPMI-1640 medium containing 10% FBS. 2. Cell Preparation: Take logarithmically growing NCI-H82 cells, wash once with PBS, and then add 2-3 ml of trypsin to digest for 2-3 minutes. After complete digestion, add 10-15 ml of cell culture medium to elute the digested cells. Centrifuge at 1000 rpm for 5 minutes, discard the supernatant, and then add 10-20 ml of cell culture medium to resuspend the cells to prepare a single-cell suspension. 3. Cell Plating: Mix the NCI-H82 single cell suspension and adjust the viable cell density to 6 x ¹⁰⁴ cells/ml using cell culture medium. Mix the adjusted cell suspension and add 50 μl/well to a 96-well cell culture plate. Incubate the plate in an incubator for 18 hours (37°C, 5% _CO2 ). 4. Compound Preparation: Dissolve the compound in DMSO to an initial concentration of 10 mM. For small molecule compounds, use 9 concentrations, with a maximum concentration of 1 μM, and dilute three-fold. 5. Sample Addition: Add the prepared test sample to the plate at different concentrations, in duplicate. Incubate the culture plate in an incubator for 6 days (37°C, 5% CO ₂ ). 6. Color development: Remove the 96-well cell culture plate, add 50 μl of CTG reagent to each well, and incubate at room temperature for 10 minutes. 7. Plate reading: Remove the 96-well cell culture plate, place it in an enzyme-labeled instrument, and measure chemiluminescence using the enzyme-labeled instrument.

Data analysis: Data were processed and analyzed using Microsoft Excel and Graphpad Prism 5. Table 1 IC ₅₀ values of the compounds in this application for inhibiting cell proliferation in vitro Compound number NCI-H82 SKOV-3 OVCAR-3 NCI-H1781 MKN-45 LS174T BT474 IC ₅₀ (nM) Lubitadine 0.19 1.01 0.68 0.38 0.63 0.72 2.81 Compound 1 0.12 0.55 0.24 / / / 1.08 Compound 2 0.21 0.85 0.38 0.36 0.46 0.77 / Compound 3 0.12 0.7 0.26 / / / / Compound 7 / / / / / / 1.00 Compound 15 / 0.62 / / / 0.49 1.12 Compound 15 R or 15S Peak 1 / 0.46 / / / 0.43 1.11 Compound 15 R or 15S Peak 2 / 0.64 / / / 0.51 1.15 Compound 17 / 0.93 / / / / / Compound 18 / 0.83 / / / / / Compound 23 / / / / / / 2.66 Compound 25 0.07 0.31 0.24 0.11 0.22 0.24 1.16 Compound 27 / 0.98 0.02 / 0.58 0.43 0.98 Compound 29 / / / / / / 0.30 Conclusion: Based on the results in Table 1, the compounds in this application have a better inhibitory activity against at least one of the tumor cell lines NCI-H82, SKOV-3, OVCAR-3, NCI-H1781, MKN - 45 , LS174T, and BT474 than the control compound rupitinimide .

Sprague-Dawley rats were given a single intravenous injection of the three test articles to observe the acute toxicity reactions of the three test articles in SD rats in order to compare the toxic effects of the three test articles and provide data support for subsequent safety evaluation. Dosage: Group Compound Test sample Number of animals First dose (mg/kg) First dose concentration (mg/mL) Second dose (mg/kg) Second dose concentration (mg/mL) Dosage volume (mL/kg) female male G1 Compound 26 0.04 0.008 0.3 0.06 5 3 3 G2 Compound 26 0.1 0.02 0.1 0.02 5 3 3 G3 Compound 25 0.04 0.008 0.3 0.06 5 3 3 G4 Compound 25 0.1 0.02 0.1 0.02 5 3 3 G5 Lubitadine 0.04 0.008 0.3 0.06 5 3 3 G6 Lubitadine 0.1 0.02 0.1 0.02 5 3 3 First dose, D1 ; second dose, D9

Symptoms: Sprague-Dawley (SD) rats did not exhibit significant toxicity after the initial intravenous injection of 0.04 mg/kg and 0.1 mg/kg of Compound 26, Compound 25, or Lubiquinolone. Nine days later, Groups G1, G3, and G5 were injected with 0.3 mg/kg of Compound 26, Compound 25, or Lubiquinolone, respectively, and all experienced weight loss. Rats in the Compound 25 and Compound 26 groups gradually recovered starting on day 2 or 3 after dosing, but the Lubiquinolone group experienced a further significant decrease. Both male and female rats in the Lubiquinolone group developed perianal soiling due to loose stools. Female rats also exhibited erect hair growth, arched backs, decreased activity, and red discharge around the eyes and nose. No significant clinical symptoms were observed in the other treatment groups. Furthermore, all female rats in group G5, which received rubitidin, died on day 18, while rats in the remaining groups survived. Clinical pathology revealed that both compound 26 and rubitidin administration resulted in elevated serum ALT, AST, GGT, and DBIL, with rubitidin demonstrating more significant changes. In terms of routine blood tests, compound 26 and rubitidin administration resulted in significant decreases in EO and PLT in the rubitidin group, while no significant changes were observed with compound 26. Following compound 25 administration, serum and routine blood tests showed no significant abnormalities. Nine days later, groups G2, G4, and G6 were re-injected with 0.1 mg/kg of compound 26, compound 25, or rubitidin, respectively, without significant toxicity. The experimental results are shown in Figures 1-3.

Conclusion: Compound 25 and Compound 26 were well tolerated in SD rats at 0.3 mpk and their toxicity was significantly better than that of rupidinine. Effect Test Example 3 : Toxicological study of different compounds in SD rats by intravenous injection Experimental purpose

Seven test articles were administered via single intravenous injection to Sprague-Dawley rats to observe their acute toxicity in vivo. This was done to compare the toxicity of the seven test articles and provide data support for subsequent safety evaluation. Group Compound Test sample Number of animals Dosage (mg/kg) Dosage concentration (mg/mL) Dosage volume (mL/kg) female male G1 Compound 1 2.4 0.48 5 3 3 G2 Compound 15R or 15S (peak 1) 2.4 0.48 5 3 3 G3 Compound 15R or 15S (peak 2) 2.4 0.48 5 3 3 G4 Compound 23 2.4 0.48 5 3 3 G5 Compound 27 2.4 0.48 5 3 3 G6 Lubitadine 0.3 0.06 5 3 3 .

Results: Sprague-Dawley (SD) rats received a single intravenous dose of Compound 1, Compound 15, Compound 23, Compound 27, and rubitidine. Both male and female rats in the G6 group developed perianal irritation due to loose stools. Female rats also exhibited erect hair growth, arched backs, decreased activity, and red discharge around the eyes and nose. No obvious clinical symptoms were observed in the other treatment groups. Furthermore, all female rats in the G6 group died on day 5, while one male rat died. Animals in the remaining groups survived until the scheduled dissection date.

On Day 3, blood biochemical tests showed a significant increase in CK in the G4 group; in the G5 group, a significant increase in CK, ALT, and AST was observed, which returned to normal on Day 7; in the G6 group, serum ALT, AST, GGT, and DBIL were observed to be elevated, and routine blood tests showed a decrease in RET, WBC, LYMPH, MONO, EO, and PLT.

Conclusion: At 2.4 mpk, compounds 1, 15R, 15S, 23, and 27 were well tolerated in SD rats and their toxicity was significantly better than that of rupinitine.

The above embodiments do not limit the scope of the present application in any way. Various modifications of the present invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended patent applications. Each reference cited in this application (including all patents, patent applications, journal articles, books, and any other publications) is incorporated by reference in its entirety.

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Figure 1 shows the changes in body weight of SD rats in Efficacy Test Example 2 after the first intravenous injection of 0.04 mg/kg and 9 days later, after the injection of 0.3 mg/kg of Compound 26, Compound 25, or Lubiquinone. Figure 2 shows the changes in food intake of SD rats in Efficacy Test Example 2 after the first intravenous injection of 0.04 mg/kg and 9 days later, after the injection of 0.3 mg/kg of Compound 26, Compound 25, or Lubiquinone. Figure 3 shows the changes in food intake of SD rats in Efficacy Test Example 2 after the first intravenous injection of 0.1 mg/kg and 9 days later, after the injection of 0.1 mg/kg of Compound 26, Compound 25, or Lubiquinone.

(without)

Claims (10)

A compound represented by formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof: wherein R ¹ is hydrogen, deuterium, halogen, -OH, -CN, -NH ₂ , C _1-6 alkyl, -OC _1-6 alkyl, -NHC _1-6 alkyl, -NH-S(O) ₂ -R ^1-2 , -C(O)R ^1-2 , C(O)-N(R ^1-1 )R ^1-2 , -C _1-6 alkylene-N(R ^1-1 )-C(O)R ^1-2 , -OC _3-12 cycloalkyl, -O-(4- to 12-membered heterocycloalkylene)-C(O)R ^1-2 , -OC _3-12 cycloalkylene-N(R ^1-1 )-C(O)R ^1-2 , -OC(O)-N(R ^1-1 )R ^1-2 , -N(R ^1-1 )-C(O)R ^1-2 , -N(R ^1-1 )-C(O)-OR ^1-2 , -N(R ^1-1 )-(4- to 12-membered heterocycloalkylene)-C(O)R ^1-2 , -N(R ^1-1 )-C _{3-12cycloalkylene} -N(R ^1-3 )-C(O)R ^1-2 , -(4- to 12-membered heterocycloalkylene)-C(O)R ^1-2 , -(4- to 12-membered heterocycloalkylene)-N(R ^1-1 )-C(O)R ^1-2 , -N(R ^1-1 )C(O)C _{3-12cycloalkylene} , (4- to 12-membered heterocycloalkylene) or -N(R ^1-1 )C(O)(4 to 12-membered heterocycloalkyl), wherein the C _1-6 alkyl, C _1-6 alkylene, C _3-12 cycloalkyl, C _3-12 cycloalkylene, 4 to 12-membered heterocycloalkylene and 4 to 12-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halogen, -OH, -SH, -NH ₂ , -NHC _1-6 alkyl, -SC _1-6 alkyl, -C _1-6 alkylene-OH, -C _1-6 alkylene-SH, -C _1-6 alkylene-S(C _1-6 alkyl) and -C _1-6 alkylene-NH ₂ ; R ² is hydrogen, deuterium, halogen, -C _1-6 alkyl, -OH, -OC(O)-N(R ^2-1 )R ^2-2 , -C(O)R ^2-2 , C(O)-N( ^R2-1 ) ^R2-2 , _-NH2 , -NHC1-6alkyl, -NHC(O) _C1-6alkyl , -N( _R2-1 )-C(O) ^-OR2-2 , -N( ^R2-1 )-C(O)-N( ^R2-1 ) ^R2-2 , -NHC(O) _{C3-12cycloalkyl} , -NHC(O)(4- to 12-membered heterocycloalkyl), -N( _C1-6alkyl )C(O) _C1-6alkyl , -N( _C1-6alkyl )C(O)C3-12cycloalkyl, C(O) ⁽ _4- to 12-membered heterocycloalkyl), -N( _C1-6alkyl )C(O)(4- to 12-membered heterocycloalkyl), or -NH-S(O) ₂ -R ^2-2 , said C _1-6 alkyl, C _3-12 cycloalkyl and 4 to 12 membered heterocycloalkyl are each optionally substituted by one or more substituents selected from halogen, -OH, -O-NHCH ₃ , -SH, -NH ₂ , -NHC _1-6 alkyl and -SC _1-6 alkyl; R ³ is hydrogen, deuterium, -C _1-6 alkyl, -CH ₂ -NHC _1-6 alkyl, -CH ₂ -NHC(O)C _1-6 alkyl, -CH ₂ -OC(O)-NR ^3-1 R ^3-2 , -CH ₂ -NR ^3-1 C(O)NR ^3-1 -R ^3-2 , -CH ₂ -NR ^3-1 C(O)OR ^3-2 , -CH ₂ -NHC(O)C _3-12 cycloalkyl, -CH ₂ -NHC(O)(4- to 12-membered heterocycloalkyl), -CH ₂ -N(C _1-6 alkyl)C(O)C _1-6 alkyl, -CH ₂ -N(C _1-6 alkyl)C(O)C _3-12 cycloalkyl, -CH ₂ -N(C _1-6 alkyl)C(O)(4- to 12-membered heterocycloalkyl), -CH ₂ NH-S(O) ₂ -R ^3-2 , -CH ₂ -S(O) ₂ -R ^3-2 or -C(O)R ^3-2 , wherein the C _1-6 alkyl, C _3-12 cycloalkyl and 4- to 12-membered heterocycloalkyl are each optionally substituted by one or more groups selected from halogen, cyclopropyl, -OH, -O-NHCH ₃ , -SH, -NH ₂ , -NHC _1-6 alkyl and -SC ^R4 is hydrogen, deuterium, -C1-6 alkyl, -C(O) _C1-6 alkyl, -C(O) _{C3-12 cycloalkyl} or -C(O)(4 to 12 membered heterocycloalkyl), said _C1-6 alkyl, _C3-12 cycloalkyl and 4 to 12 membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halogen, -OH, -SH, _-NH2 , _-NHC1-6 alkyl and _-SC1-6 alkyl; or ^R3 and ^R4 together with the atoms to which they are attached form a _5-12 membered heterocycloalkyl; said 5-12 membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halogen, oxo, -OH, -CN, _-NH2 , _-NHC1-6 alkyl, -N(C R _1-1 , R _2-1 , and R 3-1 are each independently hydrogen, deuterium ^{, C 1-6 alkyl, or halogenated C 1-6 alkyl; R 1-2} _{, R} ^{2-2 , and R 3-2} _are ^each _{independently} ^C _1-6 alkyl, C ^3-12 _cycloalkyl , or 4 ^to ₁₂ membered heterocycloalkyl; _{the C 1-6 alkyl} , C _{The 3-12-} membered cycloalkyl and the 4- to 12-membered heterocycloalkyl are each optionally substituted with one or more substituents independently selected from halogen, -OH, -O-NHCH ₃ , -SH, -NH ₂ , -NHC _1-6 alkyl, and -SC _1-6 alkyl; Y is -OH or -CN. The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof, wherein the compound satisfies at least one of the following conditions: (1) R ¹ is deuterium, halogen, -OH, -CN, -NH ₂ , C _1-6 alkyl, -NH-S(O) ₂ -R ^1-2 , -C(O)R 1-2 , C(O)-N(R ^1-1 )R ^{1-2 ,} -C _1-6 alkylene-N(R ^1-1 )-C(O)R ^1-2 , -OC _3-12 cycloalkyl, -O-(4 to 12 membered heterocycloalkylene)-C(O)R ^1-2 , -OC _3-12- membered cycloalkylene-N(R ^1-1 )-C(O)R ^1-2 , -OC(O)-N(R ^1-1 )R ^1-2 , -N(R ^1-1 )-C(O)R ^1-2 , -N(R ^1-1 )-C(O)-OR ^1-2 , -N(R ^1-1 )-(4- to 12-membered heterocycloalkylene)-C(O)R ^1-2 , -N(R ^1-1 )-C _3-12- membered cycloalkylene-N(R ^1-3 )-C(O)R ^1-2 , -(4- to 12-membered heterocycloalkylene)-C(O)R ^1-2 , -(4- to 12-membered heterocycloalkylene)-N(R ^1-1 )-C(O)R ^1-2 , -N(R ^1-1 )C(O)C _3-12 cycloalkyl, (4 to 12-membered heterocycloalkylene) or -N(R ^1-1 )C(O)(4 to 12-membered heterocycloalkyl), wherein the C _1-6 alkyl, C _1-6 alkylene, C _3-12 cycloalkyl, C _3-12 cycloalkylene, 4 to 12-membered heterocycloalkylene and 4 to 12-membered heterocycloalkyl are each optionally substituted by one or more groups selected from halogen, -OH, -SH, -NH ₂ , -O-NHCH ₃ , -NHC _1-6 alkyl, -SC _1-6 alkyl, -C _1-6 alkylene-OH, -C _1-6 alkylene-SH, -C _1-6 alkylene-S(C _1-6 alkyl) and -C _1-6 alkylene-NH (2) R 2 is substituted by a substituent of ₂ ; (2) R ² is halogen, -C _1-6 alkyl, -OH, -OC(O)-N(R ^2-1 )R ^2-2 , -C(O)R ^2-2 , C(O)-N(R ^2-1 )R ^2-2 , -NH ₂ , -NHC _1-6 alkyl, -NHC(O)C _1-6 alkyl, -N(R ^2-1 )-C(O)-OR ^2-2 , -N(R ^2-1 )-C(O)-N(R ^2-1 )R ^2-2 , -NHC(O)C _3-12 cycloalkyl, -NHC(O) (4 to 12 membered heterocycloalkyl), -N(C _1-6 alkyl)C(O)C _1-6 alkyl, -N(C _1-6 alkyl)C(O)C -N(C _1-6 alkyl)C(O)(4 to 12 membered heterocycloalkyl) or -NH-S(O) ₂ -R ^2-2 , wherein the C _1-6 alkyl, C _3-12 cycloalkyl and 4 to 12 membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halogen, -OH, -O-NHCH ₃ , -SH, -NH ₂ , -NHC 1-6 alkyl and -SC _1-6 alkyl; (3) R ³ is -CH ₂ -NHC _1-6 alkyl, -CH ₂ -NHC(O)C _1-6 alkyl, -CH ₂ -OC(O)-NR _3-1 R ^{3-2 ,} -CH _{2 -NR} ^3-1 C(O)NR ^3-1 -R ^3-2 , -CH ₂ -NR ^3-1 C(O)OR ^3-2 , -CH ₂ -NHC(O)C _3-12 cycloalkyl, -CH ₂ -NHC(O)(4 to 12-membered heterocycloalkyl), -CH ₂ -NHC(O)C _3-12 cycloalkyl, -CH ₂ -N(C _1-6 alkyl)C(O)C _1-6 alkyl, -CH ₂ -N(C _1-6 alkyl)C(O)C _3-12 cycloalkyl, -CH ₂ -N(C _1-6 alkyl)C(O)(4 to 12-membered heterocycloalkyl), -CH ₂ NH-S(O) ₂ -R ^3-2 , -CH ₂ -S(O) ₂ -R ^3-2 or -C(O)R ^3-2 , wherein the C _1-6 alkyl, C (4) R 4 is C _1-6 alkyl, -C(O) _{C 1-6} alkyl, -C(O ₎ C _3-12 cycloalkyl or -C(O)(4 to 12 membered heterocycloalkyl), wherein the C _1-6 alkyl, C _3-12 cycloalkyl and 4 to ₁₂ membered heterocycloalkyl are ^each optionally substituted by one or more substituents selected from halogen, -OH, -SH, -NH ₂ , -NHC _1-6 alkyl and -SC _1-6 alkyl _; and (5) R ³ and _R ⁴ together with the atoms to which it is attached form a 5-12 membered heterocycloalkyl group; each of the 5-12 membered heterocycloalkyl groups is optionally substituted with one or more substituents selected from halogen, oxo, -OH, -CN, _-NH2 , _-NHC1-6alkyl , -N( _C1-6alkyl ) ₂ , _C1-6alkyl , _{-C1-6alkylene} -OH, -C(O) _C1-6alkylene -OH, -C(O) _{-C3-12cycloalkylene} -OH and -C(O)-(4 to 12 membered heterocycloalkylene)-OH. The compound of claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled product, metabolite, or prodrug thereof, wherein the compound represented by formula (I) is a compound represented by formula (IA), (IB), (Ia), or (Ib): wherein R ¹ is hydrogen, halogen, -OH, or -OC _1-6 alkyl; R ² is hydrogen or deuterium; R ³ is -CH ₂ -NHC _1-6 alkyl, -CH ₂ -NHC(O)C _1-6 alkyl, -CH ₂ -OC(O)-NR ^3-1 R ^3-2 , -CH ₂ -NR ^3-1 C(O)NR ^3-1 -R ^3-2 , -CH ₂ -NR ^3-1 C(O)OR ^3-2 , -CH ₂ -NHC(O)C _3-12 cycloalkyl, -CH ₂ -NHC(O) (4 to 12 membered heterocycloalkyl), -CH ₂ -NHC(O)C _3-12 cycloalkyl, -CH ₂ -N(C _1-6 alkyl)C(O)C _1-6 alkyl, -CH ₂ -N(C -C _1-6 alkyl) C (O) C _3-12 cycloalkyl, -CH ₂ -N (C _1-6 alkyl) C (O) (4 to 12 membered heterocycloalkyl), -CH ₂ NH-S (O) ₂ -R ^3-2 , -CH ₂ -S (O) ₂ -R ^3-2 or -C (O) R ^3-2 , wherein the C _1-6 alkyl, C _3-12 cycloalkyl and 4 to 12 membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halogen, cyclopropyl, -OH, -O-NHCH ₃ , -SH, -NH ₂ , -NHC _1-6 alkyl and -SC _1-6 alkyl; R ⁴ is hydrogen or C _1-6 alkyl; or, R ² is hydrogen or deuterium; R ³ and R ⁴ together with the atoms to which it is attached form a 5-12 membered heterocycloalkyl group; the 5-12 membered heterocycloalkyl group is optionally replaced by one or more selected from -C(O)C _1-6 alkylene-OH; or, R ² is halogen, -C _1-6 alkyl, -OH, -OC(O)-N(R ^2-1 )R ^2-2 , -C(O)R ^2-2 , C(O)-N(R ^2-1 )R ^2-2 , -NH ₂ , -NHC _1-6 alkyl, -NHC(O)C _1-6 alkyl, -N(R ^2-1 )-C(O)-OR ^2-2 , -N(R ^2-1 )-C(O)-N(R ^2-1 )R ^2-2 , -NHC(O)C -NHC _1-6 alkyl, -NHC _1-6 alkyl and -SC 1-6 alkyl; R 3 is hydrogen, deuterium; R _2-2 is hydrogen, deuterium; R 3 is hydrogen, _deuterium ; R _2-2 is hydrogen, deuterium; R ₃ is hydrogen, deuterium; R ₃ is hydrogen, _deuterium ^{; R 3 is hydrogen, deuterium; R 3 is hydrogen, deuterium; R 3 is} _{hydrogen , deuterium ; R} ⁴ is hydrogen or C _1-6 alkyl; Y is -OH or -CN; wherein R ¹ is -OH, -CN, -NH ₂ , C _1-6 alkyl, -NH-S(O) ₂ -R ^1-2 , -C(O)R ^1-2 , C(O)-N(R ^1-1 )R ^1-2 , -C _1-6 alkylene-N(R ^1-1 )-C(O)R ^1-2 , -OC _3-12 cycloalkyl, -O-(4- to 12-membered heterocycloalkylene)-C(O)R ^1-2 , -OC _3-12 cycloalkylene-N(R ^1-1 )-C(O)R ^1-2 , -OC(O)-N(R ^1-1 )R ^1-2 , -N(R ^1-1 )-C(O)R ^1-2 , or -N(R ^1-1 )-C(O)-OR ^1-2 , -N(R ^1-1 )-(4 to 12-membered heterocycloalkylene)-C(O)R ^1-2 , -N(R ^1-1 )-C _3-12 cycloalkylene-N(R ^1-3 )-C(O)R ^1-2 , -(4 to 12-membered heterocycloalkylene)-C(O)R ^1-2 , -(4 to 12-membered heterocycloalkylene)-N(R ^1-1 )-C(O)R ^1-2 , -N(R ^1-1 )C(O)C _3-12 cycloalkyl, (4 to 12-membered heterocycloalkylene) or -N(R ^1-1 )C(O)(4 to 12-membered heterocycloalkyl), wherein the C _1-6 alkyl, C _1-6 alkylene, C C _3-12 cycloalkyl, C _3-12 cycloalkylene, 4- to 12-membered heterocycloalkylene and 4- to 12-membered heterocycloalkylene are each optionally substituted with one or more substituents selected from halogen, -OH, -SH, -NH ₂ , -O-NHCH ₃ , -NHC _1-6 alkyl, -SC _1-6 alkyl, -C _1-6 alkylene-OH, -C _1-6 alkylene-SH, -C _1-6 alkylene-S(C _1-6 alkyl) and -C _1-6 alkylene-NH ₂ ; R ⁴ is hydrogen, -C _1-6 alkyl; Y is -OH or -CN; wherein R ¹ is hydrogen, deuterium, halogen, -OH, -CN, -NH ₂ , C _1-6 alkyl, halogenated C _1-6 alkyl, -OC _1-6 alkyl, -O-halogenated C _1-6 alkyl, -NHC _1-6 alkyl, -O-halogenated C _1-6 alkyl, or -NH-halogenated C _1-6 alkyl; R ² is hydrogen, deuterium, halogen, C _1-6 alkyl, -OH, -NH ₂ , -NHC _1-6 alkyl, -NHC(O)C _1-6 alkyl, -NHC(O)C _3-12 cycloalkyl, -NHC(O) (4 to 12 membered heterocycloalkyl), -N(C _1-6 alkyl)C(O)C _1-6 alkyl, -N(C _1-6 alkyl)C(O)C C _1-6 alkyl, -N(C _1-6 alkyl)C(O)(4- to 12-membered heterocycloalkyl), wherein the C _1-6 alkyl, C _3-12 cycloalkyl or 4- to 12-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halogen, -OH, -SH, -NH ₂ , -NHC _1-6 alkyl and -SC _1-6 alkyl; R ³ is H or -CH ₂ -NR ^3a R ^3b ; R ^3a is hydrogen or C _1-6 alkyl; the C _1-6 alkyl is optionally substituted with one or more substituents selected from halogen, -OH, -SH, -NH ₂ , -NHC _1-6 alkyl and -SC _1-6 alkyl; R ^3b is -C(O)C _1-6 alkyl, -C(O)C _R4 is hydrogen, deuterium, C1-6 alkyl, -C(O) _C1-6 alkyl, -C(O)C3-12 cycloalkyl or -C(O)(4 to 12 membered heterocycloalkyl), wherein the _C1-6 alkyl, _C3-12 cycloalkyl or 4 to 12 membered heterocycloalkyl are each optionally substituted by one or more substituents selected from halogen, -OH, -SH, -NH2, _-NHC1-6 alkyl and _-SC1-6 alkyl; ^R4 is hydrogen, deuterium, _C1-6 alkyl, -C(O) _C1-6 alkyl, -C(O) _C3-12 cycloalkyl or -C(O)(4 to 12 membered heterocycloalkyl), wherein the _C1-6 alkyl, _C3-12 cycloalkyl or 4 to 12 membered heterocycloalkyl are each optionally substituted by one or more substituents selected from halogen, -OH, -SH, -NH2, _-NHC1-6 alkyl and -SC1-6 alkyl. or R ³ and R ⁴ together with the atoms to which they are attached form a 5-12 membered heterocycloalkyl group; said _5-12 membered heterocycloalkyl group is each optionally substituted with one or _{more substituents selected from halogen, oxo, -OH, -CN, -NH 2 ,} -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , -C _1-6 alkyl, -C _1-6 alkylene-OH, -C(O)C _1-6 alkylene-OH, -C(O)-C _3-12 cycloalkylene-OH and -C(O)-(4 to 12 membered heterocycloalkylene)-OH; Y is selected from -OH or -CN; provided that R ² and R ³ cannot be H at the same time; wherein R ¹ is -NH ₂ , -C _1-6 alkylene-N(R ^1-1 )-C(O)R ^1-2 , -OC _3-12 cycloalkyl, -O-(4- to 12-membered heterocycloalkylene)-C(O)R ^1-2 , -OC _3-12 cycloalkylene-N(R ^1-1 )-C(O)R ^1-2 , -N(R ^1-1 )-(4- to 12-membered heterocycloalkylene)-C(O)R ^1-2 , -N(R ^1-1 )-C _3-12 cycloalkylene-N(R ^1-3 )-C(O)R ^1-2 , or -(4- to 12-membered heterocycloalkylene)-C(O)R ^1-2 , -(4 to 12 membered heterocycloalkylene)-N(R ^1-1 )-C(O)R ^1-2 , -N(R ^1-1 )C(O)C _{3-12cycloalkyl} or -N(R ^1-1 )C(O)(4 to 12 membered heterocycloalkyl), wherein the C _1-6 alkyl, C _1-6 alkylene, C _{3-12cycloalkyl} , C _{3-12cycloalkylene} , 4 to 12 membered heterocycloalkylene or 4 to 12 membered heterocycloalkyl are each optionally substituted by one or more groups selected from halogen, -OH, -SH, -NH ₂ , -NHC _1-6 alkyl, -SC _1-6 alkyl, -C _1-6 alkylene-OH, -C _1-6 alkylene-SH, -C _1-6 alkylene-S(C R ^1-1 is hydrogen, deuterium, C _1-6 alkyl or halogenated _{C 1-6} alkyl; R ^1-2 is C _1-6 alkyl, C _3-12 cycloalkyl or 4- to 12-membered heterocycloalkyl; each of _the C _1-6 alkyl, C _3-12 cycloalkyl or _4- to 12-membered heterocycloalkyl groups is optionally substituted with one or more substituents selected from halogen, -OH, -SH, -NH ₂ , -NHC _1-6 alkyl and -SC _1-6 alkyl; and Y is -OH or -CN. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled product, metabolite, or prodrug thereof, wherein the compound of formula (I) is a compound of formula (IA-1), formula (IA-2), formula (Ia-1), or formula (Ia-2), wherein R ¹ is hydrogen, halogen, -OH, or -OC _1-6 alkyl; R ³ is -CH ₂ -NHC _1-6 alkyl, -CH ₂ -NHC(O)C _1-6 alkyl, -CH ₂ -OC(O)-NR ^3-1 R ^3-2 , -CH ₂ -NR ^3-1 C(O)NR ^3-1 -R ^3-2 , -CH ₂ -NR ^3-1 C(O)OR ^3-2 , -CH ₂ -NHC(O)C _3-12 cycloalkyl, -CH ₂ -NHC(O) (4- to 12-membered heterocycloalkyl), -CH ₂ -NHC(O)C _3-12 cycloalkyl, -CH ₂ -N(C _1-6 alkyl)C(O)C _1-6 alkyl, -CH ₂ -N(C _1-6 alkyl)C(O)C _-3-12- membered cycloalkyl, -CH ₂ -N(C _1-6 alkyl)C(O)(4- to 12-membered heterocycloalkyl), -CH ₂ NH-S(O) ₂ -R ^3-2 , -CH ₂ -S(O) ₂ -R ^3-2 or -C(O)R ^3-2 , wherein the C _1-6 alkyl, C _3-12 cycloalkyl and 4- to 12-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halogen, cyclopropyl, -OH, -O-NHCH ₃ , -SH, -NH ₂ , -NHC _1-6 alkyl and -SC _1-6 alkyl; R ⁴ is hydrogen, C _1-6 alkyl; or R ³ and R ⁴ together with the atoms to which it is attached form a 5-12 membered heterocycloalkyl group; each of the 5-12 membered heterocycloalkyl groups is optionally substituted by one or more groups selected from -C(O)C _1-6 alkylene-OH; Y is -OH or -CN; wherein R ¹ is hydrogen, halogen, -OH, or -OC _1-6 alkyl; R ² is halogen, -C _1-6 alkyl, -OH, -OC(O)-N(R ^2-1 )R ^2-2 , -C(O)R ^2-2 , C(O)-N(R ^2-1 )R ^2-2 , -NH ₂ , -NHC _1-6 alkyl, -NHC(O)C _1-6 alkyl, -N(R ^2-1 )-C(O)-OR ^2-2 , -N(R ^2-1 )-C(O)-N(R ^2-1 )R ^2-2 , -NHC(O)C _3-12 cycloalkyl, -NHC(O) (4- to 12-membered heterocycloalkyl), -N(C _1-6 alkyl)C(O)C _1-6 alkyl, -N(C -R 2-2 , wherein the C _1-6 alkyl, C _3-12 cycloalkyl and 4 to 12 membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halogen, -OH, -O-NHCH _{3 ,} -SH, -NH ₂ ^, _{-NHC 1-6 alkyl} and -SC _1-6 alkyl; _R ⁴ is hydrogen, C _1-6 alkyl; Y is -OH or -CN _; wherein Y, R ² , R ^3a , R ^3b and R ⁴ are as defined in any one of claims 1 to 3; preferably, in the compound represented by the structure of formula (Ia) or formula (Ia-1), R ^3a is hydrogen or -CH ₃ ; R ^3b is -C(O)C _1-6 alkylene-OH; R ⁴ is hydrogen; or for or ; Y is -OH or -CN. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof, is characterized in that it satisfies at least one of the following conditions: (1) the number of heteroatoms in the 4- to 12-membered heterocycloalkylene group and the 4- to 12-membered heterocycloalkylene group is one or more, and each heteroatom is independently selected from N, O and S; preferably, the 4- to 12-membered heterocycloalkylene group and the 4- to 12-membered heterocycloalkylene group are 4- to 6-membered heterocycloalkylene group and 4- to 6-membered heterocycloalkylene group; the number of heteroatoms is one or two, and the heteroatoms are independently selected from N; (2) In the compounds represented by formula (I) and formula (Ia), R ¹ is hydrogen, halogen, -OH, -CN, -NH ₂ , -CH ₃ , -OCH ₃ or -NHCH ₃ ; preferably, R ¹ is hydrogen, deuterium, -F, -Cl, -OH, -CH ₃ , -OCH ₃ , -NH ₂ or -NHCH ₃ ; (3) In the compounds represented by formula (I), formula (Ia) and formula (Ia-2), R ² is -OH, -NH ₂ , C _1-6 alkyl, -NHC _1-6 alkyl, -NHC(O)C _1-6 alkyl, -N(C _1-6 alkyl)C(O)C _1-6 alkyl or -N(C _1-6 alkyl)C(O)C _3-12 cycloalkyl, wherein the C _1-6 alkyl, C _3-12- membered cycloalkyl or 4- to 12-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from -OH, -SH, -NH ₂ , -NHCH ₃ and -SCH ₃ ; preferably, R ² is -OH, -NH ₂ , -C _1-6 alkylene-OH, -NHC(O)C _1-6 alkylene-OH, -N(C _1-6 alkyl)C(O)C _1-6 alkylene-OH, -NHC(O)C _1-6 alkylene-NH ₂ or -N(C _1-6 alkyl)C(O)C _1-6 alkylene-NH ₂ ; preferably, R ² is -OH, -NH ₂ , -C _1-6 alkylene-OH, -NHC(O)C _1-6 alkylene-OH or -N(C _1-6 alkyl)C(O)C _1-6 alkylene-OH; More preferably, R ² is -OH, -NH ₂ , -C _1-3 alkylene-OH, -NHC(O)C _1-3 alkylene-OH, -N(C _1-3 alkyl)C(O)C _1-3 alkylene-OH, -NHC(O)C _1-3 alkylene-NH ₂ or -N(C _1-6 alkyl)C(O)C _1-3 alkylene-NH ₂ ; (4) In the compounds represented by the structures of formula (I) and formula (Ia), R ^3a is hydrogen or C _1-3 alkyl; Preferably, R ^3a is hydrogen or -CH ₃ ; (5) In the compounds represented by the structures of formula (I) and formula (Ia), R ^3b is -C(O)C _1-6 alkyl or -C(O)C _3-6 cycloalkyl, and the C _1-6 alkyl or C _3-6 cycloalkyl groups are each optionally substituted by one or more substituents selected from -OH, -SH, -NH ₂ , -NHCH ₃ and -SCH ₃ ; preferably, R ^3b is -C(O)C _1-6 alkylene-OH; more preferably, R ^3b is -C(O)C _1-3 alkylene-OH; (6) In the compounds represented by the structures of formula (I), formula (Ia) and formula (Ia-1), R ⁴ is hydrogen, deuterium, -C _1-6 alkyl or -C(O)C _1-6 alkylene-OH; (7) In the compounds represented by the structures of formula (I) and formula (Ia), R ³ and R Preferably, R ^{3 and} R 4 together with the atoms to which they are attached form a 5- to 6-membered heterocycloalkyl group, wherein each of the 5- to 6-membered heterocycloalkyl groups is optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -OH, -CN, -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , -C _1-6 alkyl, -C _1-6 alkyl-OH, -C(O)C _1-6 alkylene-OH, -C(O)-C _3-12 cycloalkylene-OH, and -C(O)-(4 to 12-membered heterocycloalkylene)-OH; Preferably, R ³ and R ⁴ together with the atoms to which they are attached form a piperidine group, wherein each of the piperidine groups is optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -OH, -CN, -NH ₂ , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 _1-6 alkyl, -N(C _1-6 alkyl) ₂ , -C _1-6 alkyl, -C _1-6 alkyl-OH, -C(O)C _1-6 alkylene-OH, -C(O)-C _3-12 cycloalkylene-OH, -C(O)-(4 to 12 membered heterocycloalkylene)-OH substituents; (8) In the compounds represented by the structures of formula (I) and formula (Ib), R ^1-1 is hydrogen, deuterium or -C _1-6 alkyl; Preferably, R ^1-1 is hydrogen, deuterium or -CH ₃ ; (9) In the compounds represented by the structures of formula (I) and formula (Ib), R ^1-2 is C _1-6 alkyl, C _3-6 cycloalkyl or 4 to 6 membered heterocycloalkyl; the C _1-6 alkyl, C _3-6- membered cycloalkyl or 4- to 6-membered heterocycloalkyl, each optionally substituted by one or more substituents selected from halogen, -OH, -SH, -NH ₂ , -NHC _1-6 alkyl and -SC _1-6 alkyl; preferably, R ^1-2 is -C _1-6 alkylene-OH or -C _3-6 cycloalkylene-OH; more preferably, R ^1-2 is -NH ₂ , -C _1-3 alkylene-OH or -C _3-4 cycloalkylene-OH; (10) Compounds of the structures represented by formula (I) and formula (Ib), wherein R ¹ is -NH ₂ , -C _1-6 alkylene-NH-C(O)R ^1-2 , -C _1-6 alkylene-N(CH ₃ )-C(O)R ^1-2 , -O-(4 to 6-membered heterocycloalkylene)-C(O)R ^1-2 , -OC _{3-6cycloalkylene} -NH-C(O)R ^1-2 , -OC _{3-6cycloalkylene} -N(CH ₃ )-C(O)R ^1-2 , -NH-(4 to 6-membered heterocycloalkylene)-C(O)R ^1-2 , -N(CH ₃ )-(4 to 6-membered heterocycloalkylene)-C(O)R ^1-2 , -NHC(O)C _{3-6cycloalkyl} , -N(CH ₃ )C(O)C _{3-6cycloalkyl} , -NHC(O)(4 to 6-membered heterocycloalkyl) or -N(CH ₃ )C(O)(4 to 6-membered heterocycloalkyl), wherein the C _1-6 alkylene, C _3-6 membered cycloalkyl, C _3-6 membered cycloalkylene, 4 to 6 membered heterocycloalkyl or 4 to 6 membered heterocycloalkylene, each optionally substituted by one or more substituents selected from halogen, -OH, -NH ₂ , -NHCH ₃ , -C _1-6 alkylene-OH; preferably, R ¹ is -NH ₂ , -O-(4 to 6 membered heterocycloalkylene)-C(O)R ^1-2 or -C _1-6 alkylene-N(CH ₃ )-C(O)R ^1-2 ; (11) Compounds of the structures represented by formula (I) and formula (Ia), wherein R ^2-1 is hydrogen or C _1-3 alkyl; preferably H, CH ₃ ; (12) Compounds of the structures represented by formula (I) and formula (Ia), wherein R ^2-2 is C _{C 1-6} alkyl, C _3-12 cycloalkyl or 4 to 12 membered heterocycloalkyl; said C _1-6 alkyl, C _3-12 cycloalkyl, 4 to 12 membered heterocycloalkyl; optionally substituted with one or more substituents independently selected from halogen, -OH; preferably substituted with -OH; preferably, R ^2-2 is -CH ₂ OH, -CH ₂ CH ₂ OH, -CH(OH)CH ₃ , -CH ₂ ONH(CH ₃ ), or ; (11) Compounds of the structures represented by formula (I) and formula (Ia), wherein R ^3-1 is hydrogen or C _1-3 alkyl; preferably hydrogen or -CH ₃ ; (12) Compounds of the structures represented by formula (I) and formula (Ia), wherein R ^3-2 is C _1-6 alkyl, C _3-12 cycloalkyl or 4- to 12-membered heterocycloalkyl; the C _1-6 alkyl, C _3-12 cycloalkyl, 4- to 12-membered heterocycloalkyl; optionally substituted with one or more substituents independently selected from halogen, -OH; preferably substituted with -OH; preferably, R ^3-2 is -CH ₂ OH, -CH ₂ CH ₂ OH, -CH(OH)CH ₃ , -CH ₂ O-NHCH ₃ , -CH ₂ ONH(CH ₃ ), or (13) Compounds of the structure represented by formula (I) and formula (Ia), wherein R ³ is H, -C(O)R ^3-2 , -CH ₂ -NHC(O)C _1-6 alkyl, -CH ₂ -N(C _1-6 alkyl)C(O)C _1-6 alkyl, -CH ₂ -NR ^3-1 C(O)OR ^3-2 , -CH ₂ -OC(O)-NR ^3-1 R ^3-2 , -CH ₂ NH-S(O) ₂ -R ^3-2 , -CH ₂ -NR ^3-1 C(O)NR ^3-1 -R ^3-2 , -CH ₂ -NHC(O)C _3-12 cycloalkyl; the C _1-6 alkyl, C _{The 3-12-} membered cycloalkyl and the 4- to 12-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from cyclopropyl, -OH, and -O-NHCH ₃ . The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof is characterized in that it satisfies at least one of the following conditions: (1) In the compound of the structure represented by formula (I) or formula (Ia), R ¹ is hydrogen, halogen, -OH, -CN, -NH ₂ , -CH ₃ , -OCH ₃ or -NHCH ₃ , preferably hydrogen, F, -OH or -OCH ₃ ; more preferably hydrogen; (2) In the compound of the structure represented by formula (I), formula (Ia) or formula (Ia-2), R ² is -OH, -NH ₂ , -NHCH ₃ , -CH ₂ OH, 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 or ; Preferably, R ² is -OH, -NH ₂ , -CH ₂ OH, or More preferably, R ² is -NH ₂ , -CH ₂ OH or ; (3) In the compounds represented by formula (I), formula (Ia), and formula (Ia-1), R ^3a is -CH ₃ ; (4) In the compounds represented by formula (I), formula (Ia), and formula (Ia-1), R ^3b is 、 、 or ; Preferably, R ^3b is (5) In the compounds represented by the structures of formula (I), formula (Ia), and formula (Ia-1), -CH ₂ -NR ^3a R ^3b is 、 (6) In the compounds represented by formula (I), formula (Ia), and formula (Ia-1), R ⁴ is hydrogen or ; Preferably, R ⁴ is hydrogen; (7) In the compounds of formula (I), formula (Ia), and formula (Ia-1), R ³ and R ⁴ together with the atoms to which they are connected form 、 、 、 、 、 、 、 or ; Preferably, or (8) In the compounds represented by the structures of formula (I) and formula (Ib), R ^1-2 is -CH ₂ OH, -CH(CH ₃ )OH, -CH ₂ CH ₂ OH, -CH ₂ ONH(CH ₃ ), 、 or ; Preferably, R ^1-2 is -CH ₂ OH, -CH(CH ₃ )OH or ; (9) In the compounds represented by formula (I) and formula (Ib), R ¹ is -NH ₂ , -OH, 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 or ; Preferably, R ¹ is -NH ₂ , 、 、 、 、 or More preferably, R ¹ is -NH ₂ , or (10) Compounds having structures represented by formula (I) and formula (Ia), wherein: for 、 or a combination thereof; (11) a compound having a structure represented by formula (I) or formula (Ia), wherein: for 、 or a combination thereof; (12) a compound having a structure represented by formula (I) or formula (Ia), wherein R ³ is H, 、 、 、 、 、 、 、 、 、 、 、 、 . The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled product, metabolite, or prodrug thereof, wherein the compound has any of the following structures: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 or . A compound with the following structure: 、 、 、 or . A pharmaceutical composition comprising the compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite, or prodrug thereof, and one or more pharmaceutically acceptable carriers. Use of a substance A in the preparation of a drug for preventing or treating tumors or cancer, characterized in that the substance A is a compound as described in any one of claims 1 to 7, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof, or the pharmaceutical composition as described in claim 9; The tumor or cancer is preferably selected from breast cancer, colorectal cancer, colon cancer, lung cancer, prostate cancer, bile duct cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer, vulvar cancer, leukemia, multiple myeloma, and lymphoma; The leukemia is preferably selected from chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), and chronic myeloid leukemia (CML).