Ecteinascidin compound and use thereof

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

[0001] This application claims the benefit of priority to Chinese Patent Application No. 2024101788699, filed on February 8, 2024; Chinese Patent Application No. 2024110452422, filed on July 31, 2024; Chinese Patent Application No. 2024113891578, filed on September 30, 2024; and Chinese Patent Application No. 2025101161329, filed on January 24, 2025. The entire contents of the aforementioned Chinese patent applications are incorporated herein by reference. Technical Field

[0002] The present invention belongs to the field of medical technology, and in particular relates to ecteinascidin compounds and applications thereof. Background Art

[0003] Cancer is a serious malignant disease that threatens human health, claiming over 5 million lives worldwide each year. In recent years, the incidence of tumors has been increasing, with mortality ranking first among all diseases. Chemotherapy is a commonly used and effective cancer treatment in clinical practice. However, due to the multidrug resistance of cancer cells and the severe side effects of existing anticancer drugs, new anticancer drugs with improved efficacy and minimal side effects are urgently needed.

[0004] Et-743 (Trabectedin) is a highly potent 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 tumors. Lubinectedin (PM01183), a structural analog of trabectedin, was approved in the US in 2020 for the treatment of small cell lung cancer. Lubinectedin exerts its anticancer effects through covalent modification of guanine in the minor groove of DNA, ultimately leading to DNA double-strand breaks, S-phase arrest, and apoptosis in cancer cells.

[0005] At present, there is still a need to continue to develop ectocystin compounds with better efficacy and lower toxicity to meet more clinical needs. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to overcome the deficiencies of existing drugs, thereby providing an ectoderma compound and its application. The ectoderma compound of the present invention has one or more effects selected from the following group: (1) having an inhibitory activity on the proliferation of tumor cells in vitro; (2) having an in vivo tumor-suppressing effect; (3) having an in vivo tumor-targeting ability; and (4) having good in vivo safety.

[0007] The present invention provides a compound as shown in formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof:

[0008] in,

[0009] R 1 For hydrogen, deuterium, halogen, -OH, -CN, -NH2, 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 Cycloalkyl, (4 to 12 membered heterocycloalkylene) or -N(R 1-1 )C(O)(4 to 12 membered heterocycloalkyl), said C 1-6 Alkyl, C 1-6 Alkylene, C 3-12 Cycloalkyl, C 3- 12Cycloalkylene, 4 to 12 membered heterocycloalkylene and 4 to 12 membered heterocycloalkyl are each optionally substituted by one or more radicals selected from halogen, -OH, -SH, -NH2, -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-NH2 substituent substitution;

[0010] R 2 For 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 、-NH2、-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 3-12 Cycloalkyl, C(O)(4- to 12-membered heterocycloalkyl), -N(C 1-6 alkyl)C(O)(4- to 12-membered heterocycloalkyl) or -NH-S(O)2-R 2-2 , the C 1-6 Alkyl, C 3-12 The cycloalkyl and 4 to 12 membered heterocycloalkyl groups are each optionally substituted with one or more radicals selected from halogen, -OH, -O-NHCH3, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Substitution of alkyl groups;

[0011] R 3 For hydrogen, deuterium, -C 1-6 Alkyl, -CH2-NHC 1-6 Alkyl, -CH2-NHC(O)C 1-6 Alkyl, -CH2-OC(O)-NR 3-1 R3-2 、-CH2-NR 3-1 C(O)NR 3-1 -R 3-2 、-CH2-NR 3-1 C(O)OR 3-2 、-CH2-NHC(O)C 3-12 Cycloalkyl, -CH2-NHC(O)(4 to 12 membered heterocycloalkyl), -CH2-N(C 1-6 alkyl)C(O)C 1-6 Alkyl, -CH2-N(C 1-6 alkyl)C(O)C 3-12 Cycloalkyl, -CH2-N(C 1-6 alkyl)C(O)(4- to 12-membered heterocycloalkyl), -CH2NH-S(O)2-R 3-2 、-CH2-S(O)2-R 3-2 or -C(O)R 3-2 , the C 1-6 Alkyl, C 3-12 Cycloalkyl and 4 to 12 membered heterocycloalkyl are each optionally substituted by one or more radicals selected from halogen, cyclopropyl, -OH, -O-NHCH3, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Substitution of alkyl groups;

[0012] R 4 For hydrogen, deuterium, -C 1-6 Alkyl, -C(O)C 1-6 Alkyl, -C(O)C 3-12 Cycloalkyl or -C(O)(4 to 12 membered heterocycloalkyl), the C 1-6 Alkyl, C 3-12 The cycloalkyl and 4 to 12 membered heterocycloalkyl groups are each optionally substituted with one or more radicals selected from halogen, -OH, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Substitution of alkyl groups;

[0013] or R 3 With R 4 The atoms to which it is attached together form a 5-12 membered heterocycloalkyl group; each of the 5-12 membered heterocycloalkyl groups is optionally substituted by one or more halogen, oxo, -OH, -CN, -NH2, -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 3-12Substitution with cycloalkylene-OH and -C(O)-(4- to 12-membered heterocycloalkylene)-OH substituents;

[0014] R 1-1 、R 2-1 、R 3-1 are independently hydrogen, deuterium, C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0015] R 1-2 、R 2-2 、R 3-2 Each independently 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 by one or more independently selected from halogen, -OH, -O-NHCH3, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Substitution of alkyl groups;

[0016] Y is -OH or -CN.

[0017] In some embodiments, the compound represented by formula (I) is not the following compound:

[0018] In some embodiments, in the compound represented by formula (I),

[0019] R 1 For hydrogen, deuterium, halogen, -OH, -CN, -NH2, 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 Cycloalkyl or -N(R 1- 1 )C(O)(4 to 12 membered heterocycloalkyl), said 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 radicals selected from halogen, -OH, -SH, -NH2, -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-NH2 substituent substitution;

[0020] R 2 For 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 、-NH2、-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 3-12Cycloalkyl, -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, -N(C 1- 6-membered alkyl)C(O)(4- to 12-membered heterocycloalkyl) or -NH-S(O)2-R 2-2 , the C 1-6 Alkyl, C 3-12 The cycloalkyl and 4 to 12 membered heterocycloalkyl groups are each optionally substituted with one or more radicals selected from halogen, -OH, -O-NHCH3, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Substitution of alkyl groups;

[0021] R 3 For hydrogen, deuterium, -C 1-6 Alkyl, -CH2-NHC 1-6 Alkyl, -CH2-NHC(O)C 1-6 Alkyl, -CH2-OC(O)-NR 3-1 R 3-2 、-CH2-NR 3-1 C(O)NR 3-1 -R 3-2 、-CH2-NR 3-1 C(O)OR 3-2 、-CH2-NHC(O)C 3-12 Cycloalkyl, -CH2-NHC(O)(4 to 12 membered heterocycloalkyl), -CH2-N(C 1-6 alkyl)C(O)C 1-6 Alkyl, -CH2-N(C 1-6 alkyl)C(O)C 3-12 Cycloalkyl, -CH2-N(C 1-6 alkyl)C(O)(4- to 12-membered heterocycloalkyl), -CH2-S(O)2-R 3-2 or -C(O)R 3-2 , the C 1-6 Alkyl, C 3-12 The cycloalkyl and 4 to 12 membered heterocycloalkyl groups are each optionally substituted with one or more radicals selected from halogen, -OH, -O-NHCH3, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Substitution of alkyl groups;

[0022] R 4 For hydrogen, deuterium, -C 1-6 Alkyl, -C(O)C 1-6 Alkyl, -C(O)C3-12 Cycloalkyl or -C(O)(4 to 12 membered heterocycloalkyl), the C 1-6 Alkyl, C 3-12 The cycloalkyl and 4 to 12 membered heterocycloalkyl groups are each optionally substituted with one or more radicals selected from halogen, -OH, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Substitution of alkyl groups;

[0023] or R 3 With R 4 The atoms to which it is attached together form a 5-12 membered heterocycloalkyl group; each of the 5-12 membered heterocycloalkyl groups is optionally substituted by one or more halogen, oxo, -OH, -CN, -NH2, -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 Substitution with cycloalkylene-OH and -C(O)-(4- to 12-membered heterocycloalkylene)-OH substituents;

[0024] R 1-1 、R 2-1 、R 3-1 are independently hydrogen, deuterium, C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0025] R 1-2 、R 2-2 、R 3-2 Each independently 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 by one or more independently selected from halogen, -OH, -O-NHCH3, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Substitution of alkyl groups;

[0026] Y is -OH or -CN.

[0027] In some embodiments,

[0028] in,

[0029] R 1 For hydrogen, deuterium, halogen, -OH, -CN, -NH2, C 1-6Alkyl, -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)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), said 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 radicals selected from halogen, -OH, -SH, -NH2, -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-NH2 substituent substitution;

[0030] R 1-1 For hydrogen, deuterium, C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0031] R 1-2 C 1-6 Alkyl, C 3-12Cycloalkyl 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 by one or more independently selected from halogen, -OH, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Substitution of alkyl groups;

[0032] R 2 For hydrogen, deuterium, halogen, -C 1-6 Alkyl, -OH, -NH2, -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), said C 1-6 Alkyl, C 3-12 The cycloalkyl and 4 to 12 membered heterocycloalkyl groups are each optionally substituted with one or more radicals selected from halogen, -OH, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Substitution of alkyl groups;

[0033] R 3 For hydrogen, deuterium, -C 1-6 Alkyl, -CH2-NHC 1-6 Alkyl, -CH2-NHC(O)C 1-6 Alkyl, -CH2-NHC(O)C 3-12 Cycloalkyl, -CH2-NHC(O)(4 to 12 membered heterocycloalkyl), -CH2-N(C 1-6 alkyl)C(O)C 1-6 Alkyl, -CH2-N(C 1-6 alkyl)C(O)C 3-12 Cycloalkyl or -CH2-N(C 1-6 alkyl)C(O)(4 to 12 membered heterocycloalkyl), said C 1-6 Alkyl, C 3-12 The cycloalkyl and 4 to 12 membered heterocycloalkyl groups are each optionally substituted with one or more radicals selected from halogen, -OH, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Substitution of alkyl groups;

[0034] R 4For hydrogen, deuterium, -C 1-6 Alkyl, -C(O)C 1-6 Alkyl, -C(O)C 3-12 Cycloalkyl or -C(O)(4 to 12 membered heterocycloalkyl), the C 1-6 Alkyl, C 3-12 The cycloalkyl and 4 to 12 membered heterocycloalkyl groups are each optionally substituted with one or more radicals selected from halogen, -OH, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Substitution of alkyl groups;

[0035] or R 3 With R 4 The atoms to which it is attached together form a 5-12 membered heterocycloalkyl group; each of the 5-12 membered heterocycloalkyl groups is optionally substituted by one or more halogen, oxo, -OH, -CN, -NH2, -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 Substitution with cycloalkylene-OH and -C(O)-(4- to 12-membered heterocycloalkylene)-OH substituents;

[0036] Y is -OH or -CN.

[0037] In some embodiments, certain groups in the compound of formula (I), or its pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotope labels, metabolites or prodrugs are defined as follows. The unmentioned groups are the same as those described in any embodiment of the present application (referred to as "in some embodiments"), which satisfies at least one of the following conditions:

[0038] (1)R 1 Deuterium, halogen, -OH, -CN, -NH2, 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(R1-1 )-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 Cycloalkyl, (4 to 12 membered heterocycloalkylene) or -N(R 1- 1 )C(O)(4 to 12 membered heterocycloalkyl), said 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 radicals selected from halogen, -OH, -SH, -NH2, -O-NHCH3, -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-NH2 substituent substitution;

[0039] (2)R 2 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 、-NH2、-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 3-12 Cycloalkyl, C(O)(4- to 12-membered heterocycloalkyl), -N(C 1-6 alkyl)C(O)(4- to 12-membered heterocycloalkyl) or -NH-S(O)2-R 2-2 , the C 1-6 Alkyl, C 3-12 The cycloalkyl and 4 to 12 membered heterocycloalkyl groups are each optionally substituted with one or more radicals selected from halogen, -OH, -O-NHCH3, -SH, -NH2, -NHC 1- 6-alkyl and -SC 1-6 Substitution of alkyl groups;

[0040] (3)R 3 -CH2-NHC 1-6 Alkyl, -CH2-NHC(O)C 1-6 Alkyl, -CH2-OC(O)-NR 3-1 R 3-2 、-CH2-NR 3-1 C(O)NR 3- 1 -R 3-2 、-CH2-NR 3-1 C(O)OR 3-2 、-CH2-NHC(O)C 3-12 Cycloalkyl, -CH2-NHC(O)(4 to 12 membered heterocycloalkyl), -CH2-NHC(O)C 3-12 Cycloalkyl, -CH2-N(C 1-6 alkyl)C(O)C 1-6 Alkyl, -CH2-N(C 1-6 alkyl)C(O)C 3-12 Cycloalkyl, -CH2-N(C 1- 6-membered alkyl)C(O)(4- to 12-membered heterocycloalkyl), -CH2NH-S(O)2-R 3-2 、-CH2-S(O)2-R 3-2 or -C(O)R 3-2 , the C 1-6 Alkyl, C 3-12Cycloalkyl and 4 to 12 membered heterocycloalkyl are each optionally substituted by one or more radicals selected from halogen, cyclopropyl, -OH, -O-NHCH3, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Substitution of alkyl groups;

[0041] (4)R 4 -C(O)C 1-6 Alkyl, -C(O)C 3-12 Cycloalkyl or -C(O)(4 to 12 membered heterocycloalkyl), the C 1-6 Alkyl, C 3- 12 The cycloalkyl and 4 to 12 membered heterocycloalkyl groups are each optionally substituted with one or more radicals selected from halogen, -OH, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Substitution of alkyl groups;

[0042] (5)R 3 With R 4 The atoms to which it is attached together form a 5-12 membered heterocycloalkyl group; each of the 5-12 membered heterocycloalkyl groups is optionally substituted by one or more halogen, oxo, -OH, -CN, -NH2, -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 The substituents are cycloalkylene-OH and -C(O)-(4- to 12-membered heterocycloalkylene)-OH.

[0043] In some embodiments, the compound represented by formula (I) satisfies at least one of the following conditions:

[0044] (1)R 1 Deuterium, halogen, -OH, -CN, -NH2, 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 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), said 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 radicals selected from halogen, -OH, -SH, -NH2, -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-NH2 substituent substitution;

[0045] (2)R 2 For deuterium, halogen, C 1-6 Alkyl, -OH, -NH2, -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), said C 1-6 Alkyl, C 3-12 The cycloalkyl and 4 to 12 membered heterocycloalkyl groups are each optionally substituted with one or more radicals selected from halogen, -OH, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Substitution of alkyl groups;

[0046] (3)R 3-CH2-NHC 1-6 Alkyl, -CH2-NHC(O)C 1-6 Alkyl, -CH2-NHC(O)C 3-12 Cycloalkyl, -CH2-NHC(O)(4 to 12 membered heterocycloalkyl), -CH2-N(C 1-6 alkyl)C(O)C 1-6 Alkyl, -CH2-N(C 1-6 alkyl)C(O)C 3-12 Cycloalkyl or -CH2-N(C 1-6 alkyl)C(O)(4 to 12 membered heterocycloalkyl), said C 1-6 Alkyl, C 3-12 The cycloalkyl and 4 to 12 membered heterocycloalkyl groups are each optionally substituted with one or more radicals selected from halogen, -OH, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Substitution of alkyl groups;

[0047] (4)R 4 C 1-6 Alkyl, -C(O)C 1-6 Alkyl, -C(O)C 3-12 Cycloalkyl or -C(O)(4 to 12 membered heterocycloalkyl), the C 1- 6 alkyl, C 3-12 The cycloalkyl and 4 to 12 membered heterocycloalkyl groups are each optionally substituted with one or more radicals selected from halogen, -OH, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Substitution of alkyl groups;

[0048] (5)R 3 With R 4 The atoms to which it is attached together form a 5-12 membered heterocycloalkyl group; each of the 5-12 membered heterocycloalkyl groups is optionally substituted by one or more halogen, oxo, -OH, -CN, -NH2, -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 The substituents are cycloalkylene-OH and -C(O)-(4- to 12-membered heterocycloalkylene)-OH.

[0049] In some embodiments, the number of heteroatoms in the 4- to 12-membered heterocycloalkylene and 4- to 12-membered heterocycloalkylene is one or more, and each heteroatom is independently selected from N, O, and S; preferably, the 4- to 12-membered heterocycloalkylene and 4- to 12-membered heterocycloalkylene are 4- to 6-membered heterocycloalkylene and 4- to 6-membered heterocycloalkylene; the number of heteroatoms is one or two, and the heteroatoms are independently selected from N; for example, N-heterocyclobutyl Piperidinyl Piperazinyl or a divalent group thereof.

[0050] In some embodiments, the compound represented by general formula (I) is a compound represented by formula (IA):

[0051] in,

[0052] R 1 For hydrogen, halogen, -OH, -OC 1-6 alkyl;

[0053] R 2 is hydrogen, deuterium; R 3 -CH2-NHC 1-6 Alkyl, -CH2-NHC(O)C 1-6 Alkyl, -CH2-OC(O)-NR 3-1 R 3-2 、-CH2-NR 3- 1 C(O)NR 3-1 -R 3-2 、-CH2-NR 3-1 C(O)OR 3-2 、-CH2-NHC(O)C 3-12 Cycloalkyl, -CH2-NHC(O)(4 to 12 membered heterocycloalkyl), -CH2-NHC(O)C 3-12 Cycloalkyl, -CH2-N(C 1-6 alkyl)C(O)C 1-6 Alkyl, -CH2-N(C 1-6 alkyl)C(O)C 3-12 Cycloalkyl, -CH2-N(C 1-6 alkyl)C(O)(4- to 12-membered heterocycloalkyl), -CH2NH-S(O)2-R 3-2 、-CH2-S(O)2-R 3-2 or -C(O)R 3-2 , the C 1-6 Alkyl, C 3-12Cycloalkyl and 4 to 12 membered heterocycloalkyl are each optionally substituted by one or more radicals selected from halogen, cyclopropyl, -OH, -O-NHCH3, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Alkyl substituents substituted; R 4 For hydrogen, C 1-6 alkyl;

[0054] Or, R 2 is hydrogen, deuterium; R 3 With R 4 Together with the atoms to which it is attached, it forms a 5-12 membered heterocycloalkyl group; each of the 5-12 membered heterocycloalkyl groups is optionally substituted with one or more selected from -C(O)C 1-6 Alkylene-OH;

[0055] Or, R 2 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 、-NH2、-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 3-12 Cycloalkyl, C(O)(4- to 12-membered heterocycloalkyl), -N(C 1-6 alkyl)C(O)(4- to 12-membered heterocycloalkyl) or -NH-S(O)2-R 2-2 , the C 1-6 Alkyl, C 3-12 The cycloalkyl and 4 to 12 membered heterocycloalkyl groups are each optionally substituted with one or more radicals selected from halogen, -OH, -O-NHCH3, -SH, -NH2, -NHC 1- 6-alkyl and -SC 1-6 Alkyl substituents substituted; R 3 is hydrogen, deuterium; R 4 For hydrogen, C 1-6 alkyl;

[0056] Y is -OH or -CN.

[0057] In some embodiments, the compound represented by general formula (I) is a compound represented by formula (Ia):

[0058] in,

[0059] R 1 For hydrogen, deuterium, halogen, -OH, -CN, -NH2, 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;

[0060] R 2 For hydrogen, deuterium, halogen, C 1-6 Alkyl, -OH, -NH2, -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), said C 1-6 Alkyl, C 3-12 Cycloalkyl or 4 to 12 membered heterocycloalkyl are each optionally substituted by one or more radicals selected from halogen, -OH, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Substitution of alkyl groups;

[0061] R 3 H or -CH2-NR 3a R 3b ;

[0062] R 3a is hydrogen or C 1-6 Alkyl; the C 1-6 The alkyl group is optionally substituted with one or more radicals selected from halogen, -OH, -SH, -NH2, -NHC 1- 6-alkyl and -SC 1-6 Substitution of alkyl groups;

[0063] R 3b-C(O)C 1-6 Alkyl, -C(O)C 3-12 Cycloalkyl or -C(O)(4 to 12 membered heterocycloalkyl), the C 1-6 Alkyl, C 3-12 Cycloalkyl or 4 to 12 membered heterocycloalkyl are each optionally substituted by one or more radicals selected from halogen, -OH, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1- 6 alkyl substituents are substituted;

[0064] R 4 For hydrogen, deuterium, C 1-6 Alkyl, -C(O)C 1-6 Alkyl, -C(O)C 3-12 Cycloalkyl or -C(O)(4 to 12 membered heterocycloalkyl), the C 1-6 Alkyl, C 3-12 Cycloalkyl or 4 to 12 membered heterocycloalkyl are each optionally substituted by one or more radicals selected from halogen, -OH, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Substitution of alkyl groups;

[0065] or R 3 With R 4 The atoms to which it is attached together form a 5-12 membered heterocycloalkyl group; each of the 5-12 membered heterocycloalkyl groups is optionally substituted by one or more halogen, oxo, -OH, -CN, -NH2, -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 Substitution with cycloalkylene-OH and -C(O)-(4- to 12-membered heterocycloalkylene)-OH substituents;

[0066] Y is selected from -OH or -CN;

[0067] The premise is that R 2 and R 3 Cannot be H at the same time.

[0068] In some embodiments, R 2 and R 3 One of them is H and the other is not H.

[0069] In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein: for or a combination thereof.

[0070] In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein: for or a combination thereof.

[0071] In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R 1 It is hydrogen, halogen, -OH, -CN, -NH2, -CH3, -OCH3 or -NHCH3.

[0072] In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R 1 It is hydrogen, deuterium, -F, -Cl, -OH, -CH3, -OCH3, -NH2 or -NHCH3.

[0073] In some embodiments, R 1 It is hydrogen, deuterium, halogen, -OH, -CN, -CH3 or -NHCH3.

[0074] In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R 1 For hydrogen.

[0075] In some embodiments, the compound of the structure shown in formula (I), wherein R 1 It is -OH.

[0076] In some embodiments, the compound of the structure shown in formula (I), wherein R 1 For-OC 1-6 Alkyl; preferably -OCH3.

[0077] In some embodiments, the compound of the structure shown in formula (I), wherein R 1 For F.

[0078] In some embodiments, the compound of the structure shown in formula (I), wherein R 2 For H.

[0079] 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.

[0080] In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R 2-1 For H, CH3.

[0081] In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R 2-2 C 1-6Alkyl, 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; for example, substituted with -OH.

[0082] In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R 2-2 is -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH2ONH(CH3),

[0083] In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R 2 -OH, -NH2, 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, the C 1-6 Alkyl, C 3-12 The cycloalkyl or 4- to 12-membered heterocycloalkyl groups are each optionally substituted with one or more substituents selected from -OH, -SH, -NH2, -NHCH3, and -SCH3.

[0084] In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R 2 -OH, -NH2, C 1-6 Alkyl, -NHC(O)C 1- 6-alkyl or -N(C 1-6 alkyl)C(O)C 1-6 Alkyl, the C 1-6 Each alkyl group is optionally substituted with one or more substituents selected from -OH, -SH, -NH2, -NHCH3 and -SCH3.

[0085] In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R 2 -OH, -NH2, -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.

[0086] In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R 2 -NHC(O)C 1-6 Alkylene-NH2 or -N(C 1- 6-alkyl)C(O)C 1-6 Alkylene-NH2.

[0087] In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R 2 -NHC(O)C 1-3 Alkylene-NH2 or -N(C 1- 6-alkyl)C(O)C 1-3 In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R 2 -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 .

[0088] In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R 2 NH2, 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 、-NH-S(O)2-R 2-2 .

[0089] In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R 2 NH2, OH, CH2OH,

[0090] In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R 2 for

[0091] In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R 2 for

[0092] In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R 2 -OH, -NH2, -NHCH3, -CH2OH,

[0093] In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R 2 for

[0094] In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R 2 -OH, -NH2, -NHCH3, -CH2OH,

[0095] In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R 2 -OH, -NH2, -CH2OH,

[0096] In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R 2 for

[0097] In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R 3 For H.

[0098] 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.

[0099] In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R 3-1 It is hydrogen or -CH3.

[0100] In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R 3-2 C 1-6 Alkyl; the C 1-6 The alkyl group is optionally substituted with one or more substituents independently selected from halogen, -OH; for example, -OH.

[0101] In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R 3-2 for

[0102] In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R 3-2 is -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH2O-NHCH3, -CH2ONH(CH3),

[0103] In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R 3-2 is -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH2ONH(CH3) or

[0104] In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R 3 -C(O)R 3-2 、-CH2-NHC(O)C 1-6 Alkyl, -CH2-N(C 1-6 alkyl)C(O)C 1-6 Alkyl, -CH2NH-S(O)2-R 3-2 、-CH2-NR 3-1 C(O)OR 3-2 、-CH2-OC(O)-NR 3-1 R 3- 2 、-CH2-NR 3-1 C(O)NR 3-1 -R 3-2 、-CH2-NHC(O)C 3-12 Cycloalkyl; the C 1-6 Alkyl, C 3-12The cycloalkyl and 4- to 12-membered heterocycloalkyl groups are each optionally substituted with one or more substituents selected from cyclopropyl, -OH, -O-NHCH3.

[0105] In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R 3 for

[0106] In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R 3a is hydrogen or C 1-3 alkyl.

[0107] In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R 3a It is hydrogen or -CH3.

[0108] In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein:

[0109] R 3b -C(O)C 1-6 Alkyl or -C(O)C 3-6 Cycloalkyl, the C 1-6 Alkyl or C 3-6 Each cycloalkyl group is optionally substituted with one or more substituents selected from -OH, -SH, -NH2, -NHCH3 and -SCH3.

[0110] In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein:

[0111] R 3b -C(O)C 1-6 Alkylene-OH.

[0112] In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R 3b for

[0113] In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R 3b for

[0114] In some embodiments, the compound of formula (I) or formula (Ia), wherein -CH2-NR 3a R 3b for

[0115] In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R 4 For hydrogen, deuterium, -C 1-6 Alkyl or -C(O)C 1-6 Alkylene-OH.

[0116] In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R 4 For hydrogen or

[0117] In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R 4 For hydrogen.

[0118] In some embodiments, the compound of the structure represented by formula (Ia), wherein R 3 With R 4 Together with the atoms to which it is attached, it forms a 5- to 6-membered heterocycloalkyl, wherein each of the 5- to 6-membered heterocycloalkyl groups is optionally substituted with one or more halogen, oxo, -OH, -CN, -NH2, -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 Substituted with cycloalkylene-OH, -C(O)-(4- to 12-membered heterocycloalkylene)-OH substituents.

[0119] In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R 3 With R 4 The atom to which it is attached together forms a piperazinyl group, wherein each of the piperazinyl groups is optionally substituted with one or more halogen, oxo, -OH, -CN, -NH2, -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 Substituted with cycloalkylene-OH, -C(O)-(4- to 12-membered heterocycloalkylene)-OH substituents.

[0120] In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R 3 With R 4 Together with the atoms it is connected to, it forms

[0121] In some embodiments, the compound represented by the structure of formula (I) or formula (Ia), wherein R 3 With R 4 Together with the atoms it is connected to, it forms

[0122] 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).

[0123] in,

[0124] R 1 For hydrogen, halogen, -OH, -OC 1-6 alkyl;

[0125] R 3 -CH2-NHC 1-6 Alkyl, -CH2-NHC(O)C 1-6 Alkyl, -CH2-OC(O)-NR 3-1 R 3-2 、-CH2-NR 3-1 C(O)NR 3-1 -R 3- 2 、-CH2-NR 3-1 C(O)OR 3-2 、-CH2-NHC(O)C 3-12 Cycloalkyl, -CH2-NHC(O)(4 to 12 membered heterocycloalkyl), -CH2-NHC(O)C 3-12 Cycloalkyl, -CH2-N(C 1-6 alkyl)C(O)C 1-6 Alkyl, -CH2-N(C 1-6 alkyl)C(O)C 3-12 Cycloalkyl, -CH2-N(C 1- 6-membered alkyl)C(O)(4- to 12-membered heterocycloalkyl), -CH2NH-S(O)2-R 3-2 、-CH2-S(O)2-R 3-2 or -C(O)R 3-2 , the C 1-6 Alkyl, C 3-12 Cycloalkyl and 4 to 12 membered heterocycloalkyl are each optionally substituted by one or more radicals selected from halogen, cyclopropyl, -OH, -O-NHCH3, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Substitution of alkyl groups;

[0126] R 4 For hydrogen, C 1-6 alkyl;

[0127] or R 3 With R 4 Together with the atoms to which it is attached, it forms a 5-12 membered heterocycloalkyl group; each of the 5-12 membered heterocycloalkyl groups is optionally substituted with one or more selected from -C(O)C 1-6 Alkylene-OH;

[0128] Y is -OH or -CN.

[0129] 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).

[0130] in,

[0131] Y, R 3a 、R 3b and R 4 The definitions are as described in any one of formula (I) and formula (Ia) of the present invention.

[0132] In some embodiments, the compound represented by the structure of Formula (I), Formula (Ia), or Formula (Ia-1), wherein:

[0133] R 3a is hydrogen or -CH3;

[0134] R 3b -C(O)C 1-6 Alkylene-OH;

[0135] R 4 is hydrogen;

[0136] or, for

[0137] Y is -OH or -CN.

[0138] In some embodiments, the compound represented by the structure of formula (I), formula (Ia), or formula (Ia-1), wherein R 3a is -CH3.

[0139] In some embodiments, the compound represented by the structure of formula (I), formula (Ia), or formula (Ia-1), wherein R 3b -C(O)C 1-3 Alkylene-OH.

[0140] In some embodiments, the compound represented by the structure of formula (I), formula (Ia), or formula (Ia-1), wherein R 3b for

[0141] In some embodiments, the compound represented by the structure of Formula (I), Formula (Ia), or Formula (Ia-1), wherein: for

[0142] In some embodiments, the compound represented by the structure of Formula (I), Formula (Ia), or Formula (Ia-1), wherein: for

[0143] In some embodiments, the compound represented by formula (I) is a compound represented by formula (IA-2):

[0144] in,

[0145] R 1 For hydrogen, halogen, -OH, -OC 1-6 alkyl;

[0146] R 2 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 、-NH2、-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 3-12 Cycloalkyl, C(O)(4- to 12-membered heterocycloalkyl), -N(C 1-6 alkyl)C(O)(4- to 12-membered heterocycloalkyl) or -NH-S(O)2-R 2-2 , the C 1-6 Alkyl, C 3-12 The cycloalkyl and 4 to 12 membered heterocycloalkyl groups are each optionally substituted with one or more radicals selected from halogen, -OH, -O-NHCH3, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Substitution of alkyl groups;

[0147] R 4 For hydrogen, C 1-6 alkyl;

[0148] Y is -OH or -CN.

[0149] In some embodiments, the compound represented by formula (I) or formula (Ia) is a compound represented by formula (Ia-2):

[0150] Among them, Y and R 2 The definitions are as described in any one of formula (Ia) of the present invention.

[0151] In some embodiments, the compound represented by the structure of formula (I), formula (Ia), or formula (Ia-2), wherein R 2 -OH, -NH2, -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.

[0152] In some embodiments, the compound represented by the structure of formula (I), formula (Ia), or formula (Ia-2), wherein R 2 -NHC(O)C 1-6 Alkylene-NH2 or -N(C 1-6 alkyl)C(O)C 1-6 Alkylene-NH2; preferably, R 2 -NHC(O)C 1-3 Alkylene-NH2 or -N(C 1-3 alkyl)C(O)C 1- 3Alkylene-NH2.

[0153] In some embodiments, the compound represented by the structure of formula (I), formula (Ia), or formula (Ia-2), wherein R 2 -OH, -NH2, -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.

[0154] In some embodiments, the compound represented by the structure of formula (I), formula (Ia), or formula (Ia-2), wherein R 2 -NH2, -CH2OH or

[0155] In some embodiments, the compound represented by the structure of formula (I), formula (Ia), or formula (Ia-2), wherein R 2 for

[0156] In some embodiments, the compound of formula (I) or formula (Ia) of the present invention is:

[0157] In some embodiments, the compound of formula (Ia) of the present invention is:

[0158] In some embodiments, the compound represented by general formula (I) is a compound represented by formula (IB):

[0159] in,

[0160] R 1 -OH, -CN, -NH2, 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 、-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)R1-2 、-(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), said 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 radicals selected from halogen, -OH, -SH, -NH2, -O-NHCH3, -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-NH2 substituent substitution;

[0161] R 4 For hydrogen, -C 1-6 alkyl;

[0162] Y is -OH or -CN.

[0163] In some embodiments, the compound represented by general formula (I) is a compound represented by formula (Ib):

[0164] in,

[0165] R 1 -NH2, -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)R1-2 、-(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), said C 1-6 Alkyl, C 1-6 Alkylene, C 3-12 Cycloalkyl, C 3-12 Cycloalkylene, 4 to 12 membered heterocycloalkylene or 4 to 12 membered heterocycloalkyl are each optionally substituted by one or more radicals selected from halogen, -OH, -SH, -NH2, -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-NH2 substituent substitution;

[0166] R 1-1 For hydrogen, deuterium, C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0167] R 1-2 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 are each optionally substituted by one or more radicals selected from halogen, -OH, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Substitution of alkyl groups;

[0168] Y is -OH or -CN.

[0169] In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein:

[0170] R 1 -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 、-OC3- 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- 12 Cycloalkyl or -N(R 1-1 )C(O)(4 to 12 membered heterocycloalkyl), said C 1-6 Alkyl, C 1-6 Alkylene, C 3-12 Cycloalkyl, C 3-12 Cycloalkylene, 4 to 12 membered heterocycloalkylene or 4 to 12 membered heterocycloalkyl are each optionally substituted by one or more radicals selected from halogen, -OH, -SH, -NH2, -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-NH2 substituent substitution;

[0171] R 1-1 For hydrogen, deuterium, C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0172] R 1-2 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 are each optionally substituted by one or more radicals selected from halogen, -OH, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Substitution of alkyl groups;

[0173] Y is -OH or -CN.

[0174] 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.

[0175] In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R 1-1 It is hydrogen, deuterium or -CH3.

[0176] In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R 1-2 C 1-6 Alkyl, C 3-6 Cycloalkyl or 4 to 6 membered heterocycloalkyl; the C 1-6 Alkyl, C 3-6 Cycloalkyl or 4 to 6 membered heterocycloalkyl are each optionally substituted by one or more radicals selected from halogen, -OH, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 The alkyl group is substituted with a substituent.

[0177] In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R 1-2 -C 1-6 Alkylene -OH or -C 3-6 Cycloalkylene-OH.

[0178] In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R 1-2 -CH2OH, -CH(CH3)OH,

[0179] In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R 1-2 -CH2OH, -CH(CH3)OH or

[0180] In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R 1-2 It is -CH2CH2OH, -CH2ONH(CH3).

[0181] In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R 1-2 is -CH2OH, -CH(CH3)OH, -CH2CH2OH, -CH2ONH(CH3),

[0182] In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R 1 -NH2, -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 3-6 Cycloalkyl or -N(R 1-1 )C(O)(4 to 6 membered heterocycloalkyl), said C 1-6 Alkylene, C 3-6 Cycloalkyl, C 3-6 Cycloalkylene, 4 to 6 membered heterocycloalkyl or 4 to 6 membered heterocycloalkylene are each optionally substituted by one or more radicals selected from halogen, -OH, -SH, -NH2, -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-NH2 substituent; R 1-1 As defined in any one of formula (Ib) of the present invention, R 1-2 As defined in any one of formula (Ib) of the present invention.

[0183] In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R 1 -NH2, -C 1-6 Alkylene-NH-C(O)R 1- 2 、-C 1-6 Alkylene-N(CH3)-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(CH3)-C(O)R 1-2 、-NH-(4 to 6 membered heterocycloalkylene)-C(O)R 1-2 、-N(CH3)-(4 to 6 membered heterocycloalkylene)-C(O)R 1-2 、-NHC(O)C 3-6 Cycloalkyl, -N(CH3)C(O)C 3-6 Cycloalkyl, -NHC(O)(4 to 6 membered heterocycloalkyl) or -N(CH3)C(O)(4 to 6 membered heterocycloalkyl), wherein the C 1-6 Alkylene, C 3-6 Cycloalkyl, C 3-6 Cycloalkylene, 4 to 6 membered heterocycloalkyl or 4 to 6 membered heterocycloalkylene are each optionally substituted by one or more radicals selected from halogen, -OH, -NH2, -NHCH3, -C 1-6 The substituent of the alkylene-OH group is substituted; R 1-1 As defined in any one of formula (Ib) of the present invention, R 1-2 As defined in any one of formula (Ib) of the present invention.

[0184] In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R 1 -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 3- 6-cycloalkyl or -N(R 1-1 )C(O)(4 to 6 membered heterocycloalkyl), said C 1-6 Alkylene, C 3-6 Cycloalkyl, C 3-6 Cycloalkylene, 4 to 6 membered heterocycloalkyl or 4 to 6 membered heterocycloalkylene are each optionally substituted by one or more radicals selected from halogen, -OH, -SH, -NH2, -NHC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6Alkylene-OH, -C 1-6 Alkylene -SH, -C 1-6 Alkylene-S(C 1-6 alkyl) and -C 1-6 Alkylene-NH2 substituent; R 1-1 As defined in any one of formula (Ib) of the present invention, R 1-2 As defined in any one of formula (Ib) of the present invention.

[0185] In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R 1 -C 1-6 Alkylene-NH-C(O)R 1-2 、-C 1- 6-alkylene-N(CH3)-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(CH3)-C(O)R 1-2 、-NH-(4 to 6 membered heterocycloalkylene)-C(O)R 1-2 、-N(CH3)-(4 to 6 membered heterocycloalkylene)-C(O)R 1-2 、-NHC(O)C 3-6 Cycloalkyl, -N(CH3)C(O)C 3-6 Cycloalkyl, -NHC(O)(4 to 6 membered heterocycloalkyl) or -N(CH3)C(O)(4 to 6 membered heterocycloalkyl), wherein the C 1-6 Alkylene, C 3-6 Cycloalkyl, C 3-6 Cycloalkylene, 4 to 6 membered heterocycloalkyl or 4 to 6 membered heterocycloalkylene are each optionally substituted by one or more radicals selected from halogen, -OH, -NH2, -NHCH3, -C 1-6 The substituent of the alkylene-OH group is substituted; R 1-1 As defined in any one of formula (Ib) of the present invention, R 1-2 As defined in any one of formula (Ib) of the present invention.

[0186] In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R 1 -NH2, -O-(4 to 6 membered heterocycloalkylene)-C(O)R 1-2 or -C 1-6 Alkylene-N(CH3)-C(O)R 1-2 ; R 1-2 As defined in any one of formula (Ib) of the present invention.

[0187] In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R 1 -O-(4- to 6-membered heterocycloalkylene)-C(O)R 1- 2 or -C 1-6 Alkylene-N(CH3)-C(O)R 1-2 ; R 1-2 As defined in any one of formula (Ib) of the present invention.

[0188] In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R 1 is (4 to 12 membered heterocycloalkylene).

[0189] In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R 1 -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 、-N(R 1-1 )-C(O)-OR 1-2 .

[0190] In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R 1 It is -OH.

[0191] In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R 1 for

[0192] In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R 1 NH2, -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-R1-2 、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).

[0193] In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R 1 NH2, -OH,

[0194] In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R 1 -NH2,

[0195] In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R 1 -NH2,

[0196] In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R 1 -NH2,

[0197] In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R 1 for

[0198] In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R 1 for

[0199] In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R 1 for

[0200] In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R 1 for

[0201] In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R1 for

[0202] In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein:

[0203] R 1 -NH2, -O-(4 to 6 membered heterocycloalkylene)-C(O)R 1-2 or -C 1-6 Alkylene-N(CH3)-C(O)R 1-2 ;

[0204] R 1-2 -C 1-6 Alkylene -OH or -C 3-6 Cycloalkylene-OH.

[0205] In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein:

[0206] R 1 -O-(4- to 6-membered heterocycloalkylene)-C(O)R 1-2 or -C 1-6 Alkylene-N(CH3)-C(O)R 1-2 ;

[0207] R 1-2 -C 1-6 Alkylene -OH or -C 3-6 Cycloalkylene-OH.

[0208] In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R 1-2 -NH2, -C 1-3 Alkylene -OH or -C 3- 4-cycloalkylene-OH.

[0209] In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R 1 -NH2,

[0210] In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R 1 for

[0211] In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R 1 -NH2,

[0212] In some embodiments, the compound represented by the structure of formula (I) or formula (Ib), wherein R 1 for

[0213] In some embodiments, the compound of formula (I) or formula (Ib) of the present invention is:

[0214] Those skilled in the art will appreciate 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 in one embodiment with the technical features or preferred technical features in another embodiment are also included within the scope of the present invention.

[0215] In another aspect, the present invention provides a compound (an intermediate for preparing a compound of formula (I)) having the structure shown below:

[0216] In another aspect, the present invention provides a pharmaceutical composition comprising (a prophylactically or therapeutically effective amount of) a compound as described herein or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopically labeled, metabolite or prodrug thereof, and one or more pharmaceutically acceptable carriers.

[0217] 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.

[0218] 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).

[0219] The pharmaceutical composition can be administered in any form, as long as it prevents, alleviates, prevents or cures the symptoms of a human or animal patient. For example, it can be prepared into various suitable dosage forms according to the route of administration.

[0220] In other embodiments, the administration of the compound or pharmaceutical composition of the present invention can be combined with another treatment method. The other treatment method can be selected from, but not limited to: radiation therapy, chemotherapy, immunotherapy, or a combination thereof.

[0221] The present invention also relates to a pharmaceutical preparation 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 preparation is in the form of a solid preparation, a semi-solid preparation, a liquid preparation, or a gaseous preparation.

[0222] A further object of the present invention is to provide an article of manufacture, for example, in the form of a kit. As used herein, an article of manufacture is intended to include, but is not limited to, a kit and a package. The article of manufacture 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, the first therapeutic agent comprising: a compound of the present invention or a pharmaceutically acceptable form thereof, or a mixture thereof; (c) an optional package insert indicating that the pharmaceutical composition can be used to treat a neoplastic condition (as defined below); and (d) a second container.

[0223] The first container is a container for holding a pharmaceutical composition. This container can be used for preparation, storage, transportation and / or individual / bulk sales. The first container is intended to encompass bottles, jars, vials, flasks, syringes, tubes (e.g., for cream products), or any other container for preparing, holding, storing, or dispensing pharmaceutical products.

[0224] The second container is a container for accommodating the first container and optional package insert. 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 package insert can be physically adhered to the outside of the first container via a cable tie, glue, staples, or other adhesion methods, or it can be placed inside the second container without any physical tool for adhering to the first container. Alternatively, the package insert is located outside the second container. When located outside the second container, it is preferred that the package insert is physically adhered via a cable tie, glue, staples, or other adhesion methods. Alternatively, it can abut or contact the outside of the second container without physical adhesion.

[0225] The package insert is a trademark, label, or indicia that lists information about the pharmaceutical composition within the first container. The information listed is typically determined by the regulatory agency (e.g., the U.S. Food and Drug Administration) that governs the region in which the product is to be sold. Preferably, the package insert specifically lists the indications for which the pharmaceutical composition is approved. The package insert can be made of any material from which the information contained therein or thereon can be read. Preferably, the package insert is 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).

[0226] In yet 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.

[0227] 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.

[0228] In another aspect, the present invention provides a method for preventing or treating tumors, comprising administering (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 to an individual in need thereof.

[0229] In another aspect, the present invention provides a compound as described herein or a pharmaceutically acceptable form thereof (in a prophylactically or therapeutically effective amount), or a pharmaceutical composition of the present invention, for use in preventing or treating tumors or cancer.

[0230] In another aspect, the present invention provides a method for preventing or treating tumors or cancer by combining (a prophylactically or therapeutically effective amount) 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.

[0231] 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.

[0232] In a further preferred embodiment, the compounds of the present invention can be used in combination with chemoradiotherapy or immunotherapy to prevent or treat tumors or cancers.

[0233] The dosage regimen can be adjusted to provide the optimal desired response. For example, when administered as an injectable, a single bolus, bolus, and / or continuous infusion can be administered, among others. For example, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of the therapeutic situation. It should be noted that dosage values ​​can vary depending on the type and severity of the condition to be alleviated and can include single or multiple doses. Generally, the dosage for treatment varies, 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 can be adjusted by the individual physician. It will be further understood that for any particular individual, the specific dosage 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 field. For example, the composition or compound of the present invention can be administered in divided doses from 4 times a day to once every 3 days, with the dosage amount being, for example, 0.01 to 1000 mg / dose. The required dose may be administered in one or more doses to achieve the desired result.The pharmaceutical composition according to the present invention may also be provided in unit dosage form.

[0234] General Terms and Definitions

[0235] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including variations of technology or substitutions of equivalent technology that would be apparent to those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

[0236] The terms "include," "comprising," "having," "containing," or "involving," and their variations herein, are inclusive or open-ended and do not exclude other unrecited elements or method steps. Those skilled in the art will understand that the above terms, such as "comprising," encompass the meaning of "consisting of."

[0237] The term "about" means within ±10%, preferably within ±5%, and more preferably within ±2% of the stated numerical value.

[0238] Unless otherwise indicated, concentrations are by weight and ratios (including percentages) are by molar amounts.

[0239] 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.

[0240] When the lower and upper limits 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, "approximately a to b," or equivalently, "about a b") should be understood to represent each value and range encompassed within the broader range.

[0241] For example, the statement "C 1-6 " should be understood to include any sub-ranges therein and each point value, such as C 2-5 、C 3-4 、C 1-2 、C 1-3 、C1-4、C 1-5 etc., as well as C1, C2, C3, C4, C5, C6, etc. For example, the expression “C 3-10 ” should also be understood in a similar manner, for example, any sub-ranges and point values ​​contained therein may be included, for example, 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. and C3, C4, C5, C6, C7, C8, C9, C 10 etc. For another example, the expression "3-10 yuan" should be understood to include any sub-ranges and point values ​​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 it can include any sub-ranges and point values ​​contained 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.

[0242] In this specification, groups and substituents thereof can be selected by those 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 obtained when the structural formula is written from right to left.

[0243] As used herein, the term "alkyl" refers to a saturated straight or branched chain hydrocarbon group, alone or in combination with other groups. 1-6 "Alkyl" refers to a saturated straight or branched chain hydrocarbon group having 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5 or 6 carbon atoms).1-6 "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 group in the present invention is optionally substituted with one or more substituents described in the present invention.

[0244] In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood to be a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl", it should be understood that the "alkyl" represents the linking alkylene group. For example, in some specific structures, when an alkyl group is clearly shown as a linking group, the alkyl group represents the linking alkylene group, for example, the group "halo-C 1-6 C in "alkyl" 1-6 Alkyl should be understood as C 1-6 Alkylene.

[0245] As used herein, the term "alkylene" refers to a saturated, linear or branched, divalent hydrocarbon group. 1-6 "Alkylene" refers to a saturated straight or branched divalent hydrocarbon group having 1 to 6 carbon atoms. 1-6 Examples of "alkylene" include, but are not limited to, methylene, ethylene, propylene, or butylene. The alkylene group in the present invention is optionally substituted by one or more substituents described in the present invention.

[0246] In this application, the term "cycloalkyl" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic) non-aromatic hydrocarbon group. For example, "C 3-12 "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.

[0247] In this application, the term "cycloalkylene" refers to a saturated or partially saturated, monocyclic or polycyclic (such as 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, bridged 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.

[0248] The term "heterocycloalkyl" refers to a saturated or partially saturated non-aromatic cyclic group containing at least one ring member selected from N, O, P and S, wherein the number of heteroatoms is preferably 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, a 3-8-membered, 3-6-membered, 4-12-membered, or 4-6-membered heterocycloalkyl. In addition, the heterocycloalkyl may contain 0, 1, 2 or 3 oxo groups. Specific examples include, but are not limited to, oxiranyl, oxocyclobutane, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, homopiperazinyl, pyrrolidonyl, and the like.

[0249] The term "heterocycloalkylene" refers to a saturated or partially saturated, non-aromatic divalent cyclic group containing at least one ring member selected from N, O, P and S, wherein the number of heteroatoms is preferably 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, a 3-8-membered, 3-6-membered, 4-12-membered, or 4-6-membered heterocycloalkylene group. In addition, the heterocycloalkylene group may contain 0, 1, 2 or 3 oxo groups. Specific examples include, but are not limited to, oxiranylene, oxocyclobutaneylene, pyrrolidinylene, tetrahydrofuranylene, piperidinylene, piperazinylene, tetrahydropyranylene, homopiperazinylene, and pyrrolidonylene.

[0250] In the present application, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0251] In this application, the term "hydroxyl" refers to -OH.

[0252] As used herein, the term "cyano" refers to -CN.

[0253] As used herein, the term "nitro" refers to -NO2.

[0254] As used herein, the term "amino" refers to -NH2.

[0255] In the present application, "oxo" refers to C(O), ie, carbonyl.

[0256] 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. 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 C atoms. Examples of haloalkyl include, for example, -CH2F, -CHF2, -CF3, -CCl3, -C2F5, -C2Cl5, -CH2CF3, -CH2Cl or -CH2CH2CF3. The haloalkyl groups of the present invention are optionally substituted with one or more substituents described herein.

[0257] In this application, the term "alkoxy" when used alone or in combination with other groups means an alkyl group as described above with an oxygen atom attached to the parent molecular moiety. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, n-butoxy, tert-butoxy, pentoxy, and the like.

[0258] The term "independently" as used in this application means that at least two groups (or fragments) with the same or similar value ranges in a structure may have the same or different meanings under specific circumstances. For example, substituent A and substituent B are each independently hydrogen, halogen, hydroxyl, cyano, alkyl or aryl. When substituent A is hydrogen, substituent B can be either hydrogen, or halogen, hydroxyl, cyano, alkyl or aryl. Similarly, when substituent B is hydrogen, substituent A can be either hydrogen, or halogen, hydroxyl, cyano, alkyl or aryl.

[0259] The term "substituted" as used in this application and its other variant forms in this article refer to that one or more (such as 1, 2, 3 or 4) atoms or atomic groups (such as hydrogen atoms) on the specified atom are replaced by other equivalents, provided that the normal valence of the specified atom or atomic group in the current situation is not exceeded and a stable compound can be formed. If a certain atom or atomic group is described as "optionally substituted by...", it can be substituted or unsubstituted. Unless otherwise indicated, the attachment site of a substituent herein can be from any suitable position of a substituent. When the connecting bond in a substituent is shown as a chemical bond between two atoms connected to each other in a ring system, it means that the substituent can be connected to any ring-forming atom in the ring system.

[0260] When any variable (such as R a) appears multiple times in the definition of a compound, the definition of each position of the variable is independent of the definition of the other positions, and their meanings are independent of each other and do not affect each other. Therefore, if a group is replaced by 1, 2 or 3 R a group substituted, that is, the group may be replaced by up to 3 R a Substitution, where a position R a Definition and other positions R a The definitions of are independent of each other. In addition, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. The term "optionally replaced by one or more R a "Replaced" means not replaced by R a substituted and replaced by one or more R a Replace the two situations. For example, "the C 1-6 The alkyl group is optionally replaced by one or more R a "Substitution" means C 1-6 Alkyl and (with one or more R a Replaced)C 1-6 alkyl.

[0261] When a group is listed without specifying that it has a substituent, such group is only meant to be unsubstituted. For example, when "C 1-6 When "alkyl" is not limited to "substituted or unsubstituted", it only refers to "C 1-6 Alkyl" itself or "unsubstituted C 1-6 alkyl".

[0262] 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 may 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.

[0263] The term "stereoisomer" includes conformational isomers and configurational isomers, wherein configurational isomers mainly include cis-trans isomers and optical isomers. The compounds described in the present invention may exist in the form of stereoisomers, and therefore encompass all possible stereoisomeric forms, including but not limited to cis-trans isomers, enantiomers, diastereomers, atropisomers, etc. The compounds described in the present invention may also exist in the form of any combination or any mixture of the aforementioned stereoisomers, such as meso-, racemic-, and equal mixtures of atropisomers, or single enantiomers, single diastereomers, or mixtures thereof, or single atropisomers or mixtures thereof.

[0264] The term "tautomer" refers to functional isomers that result from the rapid shift of an atom between two positions in a molecule.

[0265] In this application, solid lines (——), solid wedges or virtual wedge The carbon-carbon bonds of the compounds of the present invention are depicted. The use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.). The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the indicated stereoisomers exist. When present in a racemic mixture, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise indicated, the compounds of the present invention may exist as stereoisomers, which include 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 (e.g., racemic mixtures and diastereomeric pairs).

[0266] In this application, unless otherwise indicated, the structures described herein may also include compounds that differ only in the presence or absence of one or more isotopically enriched atoms. For example, compounds that are identical to the structures described herein except for the replacement of a hydrogen atom by deuterium or tritium, or a carbon atom by carbon-13 or carbon-14, are within the scope of this application.

[0267] The present invention also encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of more than one polymorph in any ratio.

[0268] Unless otherwise stated, "or" or "and" as used herein means "and / or".

[0269] Unless otherwise specified, the specific groups in this article Refers to the connection location; the two are interchangeable.

[0270] The term "pharmaceutically acceptable form" refers to, but is not limited to, pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotopically labeled, metabolites, or prodrugs thereof.

[0271] 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. In 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 a compound of the present invention or a metabolite thereof. Therefore, when reference is made herein to a "compound of the present invention," such various derivative forms of the compound are also intended to be encompassed.

[0272] 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 review 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.

[0273] As used herein, the term "ester" refers to esters derived from compounds described herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the invention in the free acid or alcohol form). The compounds of the invention may themselves also be esters.

[0274] 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 as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0275] Those skilled in the art will appreciate that, since nitrogen requires an available lone pair of electrons to be oxidized to oxides, not all nitrogen-containing heterocycles are capable of forming nitrogen oxides. Those skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming nitrogen oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming nitrogen oxides. Synthetic methods for preparing nitrogen oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidizing heterocycles and tertiary amines with peroxyacids such as Peracetic Acid and Metachloroperbenzoic Acid (mCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxirane such as dimethyldioxirane. 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 ESGWerstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392 (AR Katritzky and AJ Boulton, Eds., Academic Press).

[0276] Also included within the scope of the present invention are metabolites of the compounds of the present invention, i.e., substances formed in vivo upon administration of the compounds of the present invention. Metabolites of the compounds can be identified using 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, etc. of the administered compound. Thus, the present invention includes metabolites of the compounds of the present invention, including compounds produced by methods that contact the compounds of the present invention with a mammal for a period of time sufficient to produce their metabolites.

[0277] 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 and can be converted into compounds of the present invention having the desired activity by, for example, hydrolytic cleavage when administered to the body or thereon. Typically, such prodrugs will be functional group derivatives of the compounds that are readily converted into the desired therapeutically active compounds 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)).

[0278] 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 a chemically protected form of the compounds of the present invention. This can be achieved using conventional protecting groups, for example, those described in TW Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 2006, which references are incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.

[0279] The present invention also encompasses methods for preparing the compounds described herein. It should 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 reaction can be carried out in a solvent or solvent mixture that is appropriate for the reagents and materials used and suitable for the transformation to be achieved.

[0280] 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 disorder or condition.

[0281] As used herein, the term "effective amount" (e.g., "therapeutically effective amount" or "prophylactically effective amount") refers to an amount of active ingredient that, after administration, will achieve the desired effect to some extent, such as alleviating one or more symptoms of the condition being treated or preventing the appearance of the condition or its symptoms.

[0282] As used herein, unless otherwise indicated, the terms "treat," ...

[0283] As used herein, "subject" includes humans and non-human animals. Exemplary human subjects include human subjects suffering from diseases (e.g., the diseases described herein) (referred to as patients) or normal individuals. "Non-human animals" herein include all vertebrates, such as non-mammals (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.).

[0284] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0285] The reagents and raw materials used in the present invention are commercially available.

[0286] The positive progress of the present invention is 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 (such as solubility, physical and / or chemical stability); (3) excellent safety (lower toxicity and / or fewer side effects, wider therapeutic window), etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0287] FIG1 shows the body weight changes of SD rats in efficacy test example 2 after the first intravenous injection of 0.04 mg / kg and 9 days later after injection of 0.3 mg / kg of Compound 26, Compound 25 or Rubitidine.

[0288] FIG2 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 injection of 0.3 mg / kg of Compound 26, Compound 25 or Rubitidine.

[0289] FIG3 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 injection of 0.1 mg / kg of Compound 26, Compound 25 or Rubitidine. DETAILED DESCRIPTION

[0290] The present invention includes all combinations of the described specific embodiments. Further embodiments of the present invention and the full scope of applicability will become apparent from the detailed description provided below. However, it should be understood that although the detailed description and specific examples indicate preferred embodiments of the present invention, these descriptions and examples are provided by way of illustration only, because 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. For all purposes, all publications, patents and patent applications cited herein, including citations, will be incorporated herein by reference in their entirety. The present invention is further illustrated below by way of example, but the present invention is not limited to the scope of the described embodiments. The experimental methods for which specific conditions are not specified in the following examples are selected according to conventional methods and conditions, or according to the product specifications.

[0291] Mass spectrometry (MS) was measured using an Agilent (ESI) mass spectrometer, manufactured by Agilent, model: Agilent 6120B.

[0292] Preparative high performance liquid chromatography (HPLC) was performed using a Shimadzu LC-8A preparative liquid chromatograph (YMC, ODS, 250 × 20 mm column).

[0293] Thin layer chromatography purification was performed using GF 254 (0.4-0.5 nm) silica gel plates produced in Yantai.

[0294] The reaction is monitored by thin layer chromatography (TLC) or liquid chromatography-mass spectrometry (LC-MS). The developing solvent systems used include, but are not limited to, dichloromethane and methanol systems, n-hexane and ethyl acetate systems, and petroleum ether and ethyl acetate systems. The volume ratio of the solvents is adjusted according to the polarity of the compounds or by adding triethylamine.

[0295] Column chromatography generally uses Qingdao Ocean 200-300 mesh silica gel as the stationary phase. Eluent systems include, but are not limited to, dichloromethane and methanol systems and n-hexane and ethyl acetate systems. The volume ratio of the solvents is adjusted according to the polarity of the compound, and a small amount of triethylamine can also be added for adjustment.

[0296] Unless otherwise specified in the examples, the reaction temperature is room temperature (20°C to 30°C).

[0297] 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.

[0298] The above embodiments do not limit the solutions of the present application in any way. In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, journal articles, books and any other disclosures) is incorporated by reference in its entirety.

[0299] 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.

[0300] Synthesis of intermediates:

[0301] Intermediate Preparation Example 1: Preparation of Compound Int1

[0302] Step 1: Preparation of compound Int1-2

[0303] 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 mixture was allowed to react at room temperature for two hours. After completion of the reaction, as monitored by TLC, the tetrahydrofuran was removed by concentration under reduced pressure. Ethyl acetate and water 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 to afford crude product Int1-2 (3 g, 70% yield), which was used directly in the next step.

[0304] Step 2: Preparation of Compound Int1-3

[0305] 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 completion of the reaction, 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, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain Int1-3 (1.5 g, 63% yield).

[0306] Step 3: Preparation of Compound Int1-4

[0307] 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 completion of the reaction as monitored by LCMS, the reaction mixture was cooled to room temperature, ethyl acetate and water were added, stirred, and separated. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to afford Int1-4 (2.0 g, 89% yield).

[0308] Step 4: Preparation of Compound Int1-5

[0309] 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 replacement, the mixture was heated to 35°C and stirred overnight. After LCMS monitoring, the reaction mixture was cooled to room temperature and filtered. The filter cake was rinsed with methanol, and the organic phase was concentrated to afford Int1-5 (1.4 g, 93% yield), which was used directly in the next reaction.

[0310] Step 5: Preparation of Compound Int1-6

[0311] 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 completion of the reaction as monitored by LCMS, ethyl acetate and water were added to the reaction mixture, 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 column chromatography to afford Int1-6 (1.1 g, 63% yield).

[0312] Step 6: Preparation of Compound Int1 Hydrochloride

[0313] 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).

[0314] MS m / z(ESI):290.0[M+H] +

[0315] 1H NMR (400MHz, DMSO-d6) δ10.90(d,J=2.5Hz,1H),8.03(s,3H),7.31(dd,J=8.7,5.0Hz,1H),7.23(d,J=2.4Hz, 1H),6.97(d,J=2.4Hz,1H),6.73(dd,J=8.7,2.5Hz,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).

[0316] Intermediate Preparation Example 2: Preparation of Compound Int2

[0317] Step 1: Preparation of compound Int2-2

[0318] 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. After nitrogen displacement, the reaction mixture was cooled to 0°C and a solution of SO3.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 completion of the reaction as monitored by LCMS, ice water and ethyl acetate were added, 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 column chromatography to afford Int2-2 (3.8 g, 90% yield).

[0319] Step 2: Preparation of compound Int2-3

[0320] 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 allowed to react at room temperature for 2 h. NaCNBH3 (1.50 g, 0.024 mmol) was then added and stirred for 2 h. After TLC monitoring, the reaction solution was concentrated under reduced pressure. Saturated sodium bicarbonate and DCM 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 column chromatography to afford Int2-3 (1.9 g, 52.7% yield).

[0321] Step 3: Preparation of Compound Int2-4

[0322] Compound Int2-3 (1.2 g, 3.96 mmol), glycolic 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 allowed to react at room temperature for 2 h. After completion of the reaction as monitored by LCMS, saturated sodium bicarbonate and ethyl acetate were added to the reaction solution, stirred, and separated. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to afford Int2-4 (1.0 g, 71.4% yield).

[0323] Step 4: Preparation of compound Int2

[0324] 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 temperature was naturally raised to room temperature and the reaction was allowed to react for 2 h. LCMS monitored the reaction completion. The reaction solution was concentrated under reduced pressure to dryness to obtain the hydrochloride salt of compound Int2 (400 mg), which was used directly in the next step without purification.

[0325] MS m / z(ESI):261.9[M+H] +

[0326] 1 H NMR (400MHz, DMSO-d6) δ11.05(s,1H),7.97(s,3H),7.61(d,J=7.9Hz,1H),7.39(d,J=8.1Hz,1H),7.30(d,J=2.4Hz,1H),7.11(t,J=7.5Hz, 1H),7.03(t,J=7.5Hz,1H),4.06(s,2H),4.03(t,J=7.1Hz,1H),3.63–3.64(m,1H),3.39(d,J=10.0Hz,1H),3.11–2.92(m,2H),2.83(s,3H).

[0327] Intermediate Preparation Example 3: Preparation of Compound Int3

[0328] Step 1: Preparation of compound Int3-2

[0329] 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 the filtrate was 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 temperature was lowered to 0°C. With stirring, TMSCN (9.5 g, 0.096 mol) was slowly added dropwise. After addition, the mixture was allowed to warm to room temperature and allowed to react for 16 hours. The reaction was monitored for completion by LCMS. The reaction mixture was extracted with saturated sodium bicarbonate and DCM. After stirring, the layers were separated. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to yield Int3-2 (4 g, 63.4% yield).

[0330] Step 2: Preparation of compound Int3-3

[0331] 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)2O (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 and concentrated under reduced pressure. The residue was purified by column chromatography to afford Int3-3 (0.6 g, 10% yield).

[0332] Step 3: Preparation of compound Int3

[0333] 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 then increased to 1.5 MPa and the reaction was continued 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 afford Int3 (410 mg, 67.7%).

[0334] MS m / z(ESI):290.2[M+H] +

[0335] Intermediate Preparation Example 4: Preparation of Compound Int4

[0336] Compound Int4 was synthesized by a similar method to that of Intermediate Preparation Example 3.

[0337] MS m / z(ESI):276.4[M+H] +

[0338] 1H NMR (400MHz, CDCl3) δ8.32(s,1H),7.65(d,J=7.9Hz,1H),7.37(d,J=8.1Hz,1H),7.24–7.18(m ,1H),7.15–7.08(m,2H),5.09(s,1H),4.98(d,J=7.4Hz,1H),3.21–3.13(m,2H),1.45(s,9H).

[0339] Intermediate Preparation Example 5: Preparation of Compound Int5

[0340] Step 1: Preparation of compound Int5-1

[0341] 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 NaCNBH3 (1.6 g, 25.8 mmol) were added sequentially. The mixture was stirred at room temperature for 4 h, and the reaction was monitored for completion 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 layers were separated. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain Int5-1 (2.6 g, 91% yield).

[0342] Step 2: Preparation of compound Int5-2

[0343] 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. AllocCl (1.8 g, 15.61 mmol) was slowly added dropwise. After addition, the temperature was naturally raised to allow the reaction to proceed for 16 hours. LCMS monitored the reaction for completion. Saturated sodium bicarbonate and ethyl acetate were added to the reaction, 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 column chromatography to yield Int5-2 (1 g, 71% yield).

[0344] MS m / z(ESI):418.2[M+H] +

[0345] 1H NMR(400MHz, CDCl3)δ8.10(s,1H),7.60(d,J=7.9Hz,1H),7.38–7.36(s,1H),7.22–7.17(m,1H),7.16–7.04(m,2H),5.94–5.79(m,1 H),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).

[0346] Step 3: Preparation of compound Int5

[0347] 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 completion of the reaction as monitored by LCMS, the reaction solution was concentrated under reduced pressure to dryness to afford the trifluoroacetic acid salt of compound Int5 (0.33 g), which was used directly in the next reaction.

[0348] Intermediate Preparation Example 6: Preparation of Compound Int6

[0349] Step 1: Preparation of compound Int6-2

[0350] LiHMDS (1.12 mL, 6.06 mmol, 2N) was added to a reaction flask under nitrogen atmosphere. The temperature was lowered to -78°C, followed by the dropwise addition of a solution of Int6-1 (776.1 mg, 3.03 mmol) in tetrahydrofuran (5 mL). The reaction was allowed to react for 1.5 hours. Isobutyl chloroformate (0.32 mL, 3.64 mmol) in tetrahydrofuran (3 mL) was then added dropwise. The temperature was naturally raised to room temperature and the reaction was allowed to react for 2 hours. LCMS indicated the reaction was complete. The temperature was then lowered to 0°C, and a saturated NH4Cl solution and ethyl acetate were added to the reaction mixture. 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 column chromatography to afford Int6-2 (0.82 g, 76% yield).

[0351] Step 2: Preparation of compound Int6-3

[0352] 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 allowed to react at room temperature for 2 h. After completion, the reaction 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, and concentrated under reduced pressure. The residue was purified by Pre-TLC to afford Int6-3 (250 mg, 69% yield).

[0353] Step 3: Preparation of compound Int6

[0354] Compound Int6-3 (300 mg, 1.17 mmol) was dissolved in tetrahydrofuran (4 mL), cooled to 0°C, and a solution of lithium aluminum hydride (2.3 mL, 5.85 mmol) in tetrahydrofuran was added dropwise. The mixture was allowed to react at room temperature for 2 h. After completion of the reaction as determined by LCMS, water was added dropwise to quench the reaction. The mixture was filtered, washed with methanol, and concentrated. The residue was purified by preparative HPLC to afford compound Int6 (50 mg, 22% yield).

[0355] MS m / z(ESI):191.1[M+H] +

[0356] Intermediate Preparation Example 7: Preparation of Compound Int7

[0357] Compound Int7 was synthesized by a similar method to Intermediate Preparation Example 2.

[0358] Intermediate Preparation Example 8: Preparation of Compound Int8

[0359] Compound Int8 was synthesized by referring to the method of Intermediate Preparation Example 2.

[0360] Intermediate Preparation Example 9: Preparation of Compound Int9

[0361] Compound Int9 was synthesized by referring to the method of Intermediate Preparation Example 2.

[0362] Intermediate Preparation Example 10: Preparation of Compound Int10

[0363] Step 1: Preparation of compound Int10-2

[0364] Compound Int10-1 (2.0 g, 9.1 mmol) was dissolved in THF (40 mL), and 2N 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 was continued for 2 h. After completion of the reaction as monitored by LCMS, the reaction solution was concentrated under reduced pressure to remove the THF. The residue was added with ethyl acetate and the pH was adjusted to approximately 6 with saturated aqueous citric acid. The layers were separated, the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to afford Int10-2 (2.5 g, 86% yield).

[0365] Step 2: Preparation of compound Int10-3

[0366] Compound Int10-2 (2.50 g, 7.8 mmol) and ammonium chloride (0.54 g, 10.1 mmol) were dissolved in DMF (20 mL). 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 saturated aqueous ammonium chloride were added, 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 column chromatography to afford Int10-3 (2 g, 80% yield).

[0367] Step 3: Preparation of compound Int10

[0368] Compound Int10-3 (2 g, 6.26 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), cooled to 0 ° C, and borane tetrahydrofuran solution (1N, 50 mL) was slowly added. After the addition was complete, the temperature was naturally raised to room temperature and the reaction was continued for 4 hours. LCMS monitored the reaction completion, the reaction solution was cooled to 0 ° C, and anhydrous methanol was slowly added under temperature control until the borane was completely quenched. Subsequently, the temperature was continued to be controlled, and 2N hydrochloric acid aqueous solution was slowly added until the pH of the mixture was about 3. After the addition was complete, the temperature was naturally raised to room temperature and stirring was continued for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse column chromatography to obtain compound Int10 (0.83 g, yield 65%).

[0369] Intermediate Preparation Example 11: Preparation of Compound Int11

[0370] Compound Int11 was synthesized by referring to the method of Intermediate Preparation Example 10.

[0371] Intermediate Preparation Example 12: Preparation of Compound Int14

[0372] Step 1: Preparation of compound Int14-2

[0373] Ammonium acetate (13.50 g, 176.47 mmol) was dissolved in nitromethane (200 mL), and compound Int14-1 (10.00 g, 58.80 mmol) was added. The reaction mixture was heated to 105°C under nitrogen for 2 hours. After completion of the reaction, the temperature was lowered to room temperature and filtered. The filter cake was washed with H2O / MeOH (V / V = 1 / 1), and the solid was dried to afford compound Int14-2 (10.30 g, 82% yield).

[0374] Step 2: Preparation of compound Int14-3

[0375] Compound Int14-2 (5.00 g, 23.47 mmol) was dissolved in a mixture of MeOH (25 ml) and DMF (25 ml). Sodium borohydride (4.30 g, 117.30 mmol) was added at 0°C and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the pH was adjusted to 7 with 2N dilute hydrochloric acid. DCM was added, 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 column chromatography to afford compound Int14-3 (1.77 g, 35% yield).

[0376] Step 3: Preparation of compound Int14-4

[0377] 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 completion of the reaction as monitored by LCMS, the reaction mixture was cooled to room temperature, 1N NaOH solution was added to adjust the pH to 11, and DCM was added. The mixture was stirred and separated. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford compound Int14-4 (800 mg, 53% yield), which was used directly in the next step.

[0378] Step 4: Preparation of compound Int14-5

[0379] 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 the mixture was stirred at room temperature overnight. After LCMS monitoring, ethyl acetate was added, 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 column chromatography to afford compound Int14-5 (700 mg, 55% yield).

[0380] Step 5: Preparation of compound Int14-6

[0381] 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 Raney nickel (4 g) were added. The mixture was stirred at room temperature under nitrogen for 3 h. After completion of the reaction 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, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide compound Int14-6 (600 mg, 91% yield).

[0382] Step 6: Preparation of compound Int14-7

[0383] 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 monitoring the reaction by LCMS, water and DCM were added to the reaction solution, stirred, and the layers were separated. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to afford compound Int14-7 (240 mg, 38% yield).

[0384] Step 7: Preparation of compound Int14-8

[0385] Compound Int14-7 (220 mg, 0.65 mmol) was dissolved in DMF (2 mL), and glycolic 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 on a reverse-phase medium-pressure preparative column to afford compound Int14-8 (200 mg, 78% yield).

[0386] Step 7: Preparation of compound Int14

[0387] 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 mixture 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 the filtrate was concentrated under reduced pressure to afford compound Int14 (100 mg, 89% yield), which was used directly in the next reaction.

[0388] Referring to Intermediate Preparation Example 10, intermediates Int12 and Int13 were synthesized using corresponding starting materials, and their structures are as follows:

[0389] Referring to the method of intermediate preparation example 2, the corresponding raw materials were used to synthesize intermediate Int15

[0390] Example 1: Synthesis of Compound 3

[0391] 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 the reaction was complete as monitored by LCMS, the temperature was lowered to room temperature, and the reaction solution was concentrated under reduced pressure. Ethyl acetate and saturated aqueous sodium bicarbonate solution were added to the residue, stirred, and then the layers were 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 3 (65 mg, 45% yield).

[0392] MS m / z(ESI):893.4[M+H] +

[0393] 1 H NMR (400MHz, CDCl3) δ7.74(s,1H),7.17(d,J=8.8Hz,1H),6.66(d,J=8.7Hz,2H),6.59(d,J=2.4Hz,1H),6.22( s,1H),6.02(s,1H),5.81(s,1H),5.08(d,J=11.7Hz,1H),5.00(d,J=7.4Hz,1H),4.56(s,1H),4.48–4.36(m,2 H),4.33(s,1H),4.27(d,J=4.6Hz,1H),4.17–4.07(m,3H),4.00(s,2H),3.81(s,3H),3.42(d,J=9.9Hz,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).

[0394] Example 2: Synthesis of Compound 4

[0395] 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). The mixture was stirred at room temperature in the dark for 12 hours. After completion of the reaction as monitored by LCMS, 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, concentrated under reduced pressure, and the residue was purified by preparative HPLC to yield compound 26 (1.5 mg, 4% yield).

[0396] MS m / z(ESI):866.3[M-OH] +

[0397] 1 H NMR (400MHz, CDCl3) δ7.71(s,1H),7.19(d,J=8.7Hz,1H),6.68(d,J=8.7Hz,2H),6.61(s,1H) ,6.22(s,1H),6.01(s,1H),5.22(d,J=11.5Hz,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).

[0398] Example 3: Synthesis of Compound 25

[0399] 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 were 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 25 (20 mg, 43% yield).

[0400] MS m / z(ESI):865.3[M+H] +

[0401] 1H NMR(400MHz, CDCl3)δ7.78(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,1 H),6.59(d,J=8.0Hz,1H),6.25(d,J=4.4Hz,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=13.1Hz,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).

[0402] Example 4: Synthesis of Compound 26

[0403] Compound 25 (20 mg, 0.023 mmol) was dissolved in ACN (3 mL) and water (2 mL), and silver nitrate (98 mg, 0.577 mmol) was added. The mixture was stirred at room temperature in the dark for 12 hours. After completion of the reaction as monitored by LCMS, 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, concentrated under reduced pressure, and the residue was purified by preparative HPLC to yield compound 26 (3 mg, 15.6% yield).

[0404] MS m / z(ESI):838.3[M-OH] +

[0405] 1H NMR (400MHz, CDCl3) δ7.34(t,J=7.2Hz,1H),7.22(d,J=6.3Hz,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=1.7Hz,1H),5.22(d,J=11.8Hz,1H),4.90(s,1H),4.51(s,2H),4.26(dd,J=15.8,11.4Hz,2H),4.17(d,J=7.5Hz,2H),4.11(s,1H),3 .84(d,J=2.6Hz,1H),3.81(s,2H),3.56(s,1H),3.24(d,J=9.0Hz,1H),3.04(d,J=3.3Hz,2H),2.99(d,J=11.7Hz,1H),2.93(d,J=4.0Hz,2H),2. 86(d,J=9.1Hz,1H),2.64–2.46(m,3H),2.43–2.32(m,3H),2.30(d,J=3. 0Hz, 6H), 2.27–2.19 (m, 2H), 2.16 (d, J = 11.4Hz, 1H), 2.13-2.08 (m, 3H).

[0406] Example 5: Synthesis of Compound 17

[0407] Step 1: Preparation of compound 17-1

[0408] Compound 17-1 was synthesized by a method similar to Example 1.

[0409] MS m / z(ESI):893.6[M+H] +

[0410] Step 2: Preparation of compound 17-2

[0411] Compound 17-1 (48 mg, 2.1 mmol) was dissolved in DCM (2 mL) and added to TFA (0.5 mL). The mixture was allowed to react at room temperature for 2 h. LCMS monitored the reaction for completion. The reaction solution was concentrated to dryness under reduced pressure, adjusted to pH 8 with saturated sodium bicarbonate solution, and extracted three times with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford crude product 17-2 (40 mg), which was used directly in the next step.

[0412] Step 3: Preparation of compound 17

[0413] Compound 17-2 (23.8 mg, 0.030 mmol) was dissolved in DMF (1.5 mL), and glycolic 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 monitored for completion by LCMS. Ethyl acetate and saturated aqueous sodium bicarbonate solution were added, 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 afford compound 17 (16 mg, 62% yield).

[0414] MS m / z(ESI):851.5[M+H] +

[0415] 1 H NMR (400MHz, CDCl3) δ6.56(d,J=8.3Hz,1H),6.47–6.42(m,1H),6.05(d,J=5.0Hz,1H),5.98(s,1H),5.75(d,J=9.5Hz,1H), 5.49(d,J=9.8Hz,1H),5.35(s,1H),5.03–4.95(m,1H),4.59(s,1H),4.33(d,J=7.7Hz,1H),4.28–4.20(m,2H),4.16–4.09( m,3H),3.81–3.77(m,3H),3.74–3.70(m,1H),3.65(d,J=3.2Hz,3H),3.52–3.49(m,1H),3.43–3.39(m,1H),2.93–2.82(m,3 H),2.61–2.58(m,1H),2.48(s,1H),2.45(s,1H),2.31(dd,J=6.5,2.9Hz,4H),2.29–2.23(m,3H),2.21(s,3H),2.05(s,3H).

[0416] Example 6: Synthesis of Compound 18

[0417] Compound 18 was synthesized by a method similar to Example 2.

[0418] MS m / z(ESI):824.4[M-OH] +

[0419] 1H NMR (400MHz, CDCl3) δ7.27–7.21(m,2H),7.07(t,J=7.3Hz,1H),6.95(t,J=7.5Hz,1H),6.56(d,J=8.8Hz,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=7.9Hz,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=3.8Hz,2H),2.34–2.27(m,3H),2.27–2.22(m,3H),2.19(d,J=6.3Hz,2H),2.13(d,J=2.6Hz,2H),2.00(s,3H).

[0420] Example 7: Synthesis of Compounds 13, 13R, and 13S

[0421] Step 1: Preparation of compound 13-1

[0422] Compound 13-1 was synthesized by a method similar to Example 1.

[0423] Step 2: Preparation of compound 13

[0424] Crude compound 13 was synthesized by a similar method as described in step 2 of Example 5. Compound 13 was purified by Pre-TLC to obtain compound 13.

[0425] MS m / z(ESI):779.3[M+H] +

[0426] 1H NMR (400MHz, CDCl3) δ8.47(s,1H),7.82(s,1H),7.56(d,J=7.8Hz,1H),7.22(d,J=8.2Hz,1H),7.11(t,J=7.6Hz,1H) ,7.03(t,J=7.4Hz,1H),6.65(s,1H),6.25(d,J=1.4Hz,1H),6.03(d,J=1.4Hz,1H),5.10(d,J=11.8Hz,1H),4.53(s,1 H),4.35(s,1H),4.33–4.24(m,2H),4.17(s,2H),3.78(s,4H),3.43(d,J=4.7Hz,1H),3.39(s,1H),2.90(d,J=5.1Hz ,4H),2.78(d,J=11.9Hz,2H),2.46(d,J=16.0Hz,2H),2.37(s,3H),2.25(s,3H),2.21(d,J=3.3Hz,3H),2.04(s,3H).

[0427] The pure compound 13 was then purified by reverse medium pressure preparative column purification under the following conditions:

[0428] Column: Agela technologies C18, 20-35uM, 100A, 120g

[0429] Mobile phase: pure water (0.1% hydrochloric acid) / acetonitrile

[0430] Gradient: 100% pure water-100% acetonitrile, 50% acetonitrile out product

[0431] The retention times of Peak 1 and Peak 2 on LCMS were 1.415 min and 1.392 min, respectively.

[0432] The first peak (1.415 min) is characterized as follows: 13R or 13S:

[0433] MS m / z(ESI):779.3[M+H] +

[0434] 1H NMR (400MHz, DMSO-d6) δ10.81(s,1H),8.95(s,1H),7.93(s,3H),7.64(d,J=6.4Hz,1H),7.40(d,J=6.4Hz,1H),7.11(t,J=6. 4Hz,1H),7.02(t,J=6.4Hz,1H),6.53(s,1H),6.25(d,J=16.8Hz,2H),5.06(d,J=11.2Hz,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).

[0435] The second peak (1.392 min) was characterized as follows: 13R or 13S:

[0436] MS m / z(ESI):779.3[M+H] +

[0437] 1 H NMR (400MHz, DMSO) δ10.67(s,1H),9.02(s,1H),8.24(s,3H),7.74(d,J=6.4Hz,1H),7.42(d,J=6.4Hz,1H),7.12(t,J= 6.4Hz,1H),7.02(t,J=6.4Hz,1H),6.49(s,1H),6.25(d,J=16.8Hz,2H),5.15(d,J=11.2Hz,1H),4.68-4.57(m,1H),4.5 4-4.42(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).

[0438] Example 8: Synthesis of Compound 14

[0439] Compound 14 was synthesized by a method similar to Preparation Example 2.

[0440] MS m / z(ESI):770.9[M+H] +

[0441] 1 H NMR (400MHz, CDCl3) δ7.48(d,J=25.9Hz,1H),7.15(s,1H),7.08–6.94(m,1H),6.51(s,1H),6.16(d,J=11.4Hz,1H),5.92 (d,J=6.9Hz,1H),5.00(d,J=10.9Hz,1H),4.76(d,J=26.5Hz,1H),4.37(d,J=13.9Hz,1H),4.21(s,1H),4.14(s,1H),4.1 0(s,1H),4.01(d,J=11.2Hz,1H),3.74(d,J=5.5Hz,3H),3.62(d,J=18.1Hz,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=5.5Hz,3H),2.05(s,3H),1.96(s,2H).

[0442] Example 9: Synthesis of Compound 33

[0443] Step 1: Preparation of compound 33-1

[0444] Compound 33-1 was synthesized by a similar method to Preparation Example 1.

[0445] Step 2: Preparation of compound 33-2

[0446] 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. Ms2O (32.5 mg, 0.184 mmol) was then added, and the mixture was allowed to warm to room temperature for 2 h. Saturated sodium bicarbonate solution (3 mL) was added to quench the mixture, and the mixture was heated to 45°C overnight. Completion of the reaction was monitored by LCMS. The reaction solution was directly extracted with DCM. 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 33-2 (28 mg, 25% yield).

[0447] Step 3: Preparation of compound 33

[0448] Compound 33-2 (16 mg, 0.018 mmol), acetic acid (5.4 mg, 0.09 mmol), and Pd(PPh3)4 (2.0 mg, 0.002 mmol) were added to DCM (2 mL). Bu3SnH (52 mg, 0.18 mmol) was added under nitrogen and 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 solution, 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 preparative HPLC to afford compound 33 (8 mg, 50% yield).

[0449] MS m / z(ESI):819.4[M+H] +

[0450] H NMR(400MHz, CDCl3)δ7.36(d,J=7.9Hz,1H),7.19–6.99(m,4H),6.50(s,1H),6.33(s,1H),6.14( s,1H),5.03(d,J=11.2Hz,1H),4.48–4.41(m,2H),4.28(d,J=4.7Hz,1H),4.21–4.18(m,1H),4.05 –4.02(m,1H),3.84(s,3H),3.69(d,J=4.7Hz,1H),3.44(d,J=9.2Hz,1H),3.18(d,J=12.0Hz,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).

[0451] Example 10: Synthesis of Compound 34

[0452] Compound 34 was synthesized by a similar method to Example 2.

[0453] MS m / z(ESI):810.3[M+H] +

[0454] 1H NMR (400MHz, CDCl3) δ7.25(d,J=7.9Hz,1H),7.05(d,J=7.3Hz,2H),7.00(d,J=7.4Hz,2H),6.95–6.92(m,1H),6.40( s,1H),6.20(d,J=3.6Hz,1H),6.00(d,J=3.6Hz,1H),5.04–4.96(m,1H),4.29–4.23(m,1H),4.16–3.98(m,2H),3.87 –3.80(m,1H),3.75(s,3H),3.71(s,1H),3.65(d,J=4.9Hz,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).

[0455] Example 11: Synthesis of Compound 21

[0456] Compound 21 was synthesized by a method similar to Example 1.

[0457] MS m / z(ESI):794.3[M+H] +

[0458] 1 H-NMR (400MHz, DMSO-d6): δ10.07(s,1H),8.77(s,1H),7.42(d,J=7.9Hz,1H),7.33(d,J=8.1Hz,1H),7.00(t,J=7.5Hz, 1H),6.89(t,J=7.5Hz,1H),6.48(s,1H),6.23(d,J=19.4Hz,2H),5.11(d,J=11.6Hz,1H),4.69(s,1H),4.51–4.37(m,2H) ,4.20(d,J=4.6Hz,1H),4.14(d,J=11.7Hz,1H),4.09(s,1H),3.82(d,J=9.8Hz,2H),3.66(s,3H),2.98–2.92(m,1H),2.8 2–2.71(m,5H),2.67(s,1H),2.33(d,J=4.6Hz,1H),2.27(d,J=7.2Hz,6H),2.06(s,3H),2.00–1.98(m,1H),1.96(s,3H).

[0459] Example 12: Synthesis of Compound 22

[0460] Compound 22 was synthesized by a method similar to Example 2.

[0461] MS m / z(ESI):785.4[M+H] +

[0462] 1 H-NMR (400MHz, DMSO-d6): δ10.05(d,J=8.8Hz,1H),8.65(s,1H),7.56–7.19(m,2H),6.99–6.90(m,2 H),6.48(s,1H),6.23(d,J=7.0Hz,1H),6.13(s,1H),5.04(dd,J=22.9,11.4Hz,1H),4.68(d,J=13.7H z,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).

[0463] Example 13: Synthesis of Compound 1

[0464] Compound 1 was synthesized by a method similar to Example 1.

[0465] MS m / z(ESI):779.4[M+H] + ;

[0466] 1H NMR(400MHz, DMSO-d6)δ9.62(s,1H),8.80(s,1H),7.03(d,J=8.6Hz,1H),6.52–6.46(m,2H),6.42(d d,J=8.6,2.1Hz,1H),6.23(d,J=7.8Hz,2H),5.34(t,J=4.7Hz,1H),5.07(d,J=11.2Hz,1H),4.47(d,J =2.7Hz,2H),4.22–4.19(m,1H),4.10(s,1H),4.07(s,2H),3.67(s,3H),3.21–3.08(m,2H),2.85–2.6 9(m,6H),2.36–2.33(m,2H),2.30(s,3H),2.27(s,3H),2.06(s,3H),2.04–2.02(s,1H),1.99(s,3H).

[0467] Example 14: Synthesis of Compound 2

[0468] Compound 2 was synthesized by a method similar to Example 2.

[0469] MS m / z(ESI):770.4[M+H] + .

[0470] 1 H NMR (400MHz, CDCl3) δ7.03 (s, 1H), 6.68 (s, 2H), 6.56 (d, J = 8.8Hz, 1H), 6.19 (s ,1H),5.99(s,1H),5.34–5.28(m,2H),5.19(d,J=11.5Hz,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).

[0471] Example 15: Synthesis of Compounds 15, 15R, and 15S

[0472] Compound 13 (50 mg, 0.064 mmol) was dissolved in DMF (1.5 mL), and glycolic 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 monitored for completion by LCMS. Ethyl acetate and saturated aqueous sodium bicarbonate were added, 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 afford compound 15 (40 mg, 75% yield).

[0473] Compound 15:

[0474] MS m / z(ESI):837.2[M+H] +

[0475] Compound 15 was then purified by reverse medium pressure preparative column under the following conditions:

[0476] Column: Agela technologies C18, 20-35uM, 100A, 120g

[0477] Mobile phase: pure water (0.1% formic acid) / acetonitrile

[0478] Gradient: 100% pure water-100% acetonitrile, 50% acetonitrile out product

[0479] The retention times of Peak 1 and Peak 2 on LCMS were 1.651 min and 1.587 min, respectively.

[0480] The first peak (1.651 min) was characterized as follows: 15R or 15S (15 mg, yield 28%):

[0481] MS m / z(ESI):837.2[M+H] +

[0482] 1H NMR (400MHz, DMSO) δ10.49(s,1H),8.82(s,1H),7.43(d,J=6.4Hz,1H),7.34(d,J=6.4Hz,1H),7.29(d,J=8.8Hz,1H),7.04(t,J=6.4Hz,1H), 6.92(t,J=6.4Hz,1H),6.49(s,1H),6.24(d,J=16.8Hz,2H),5.43(t,J=5.6Hz,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),2.90-2.7 8(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).

[0483] The second peak (1.587 min) was characterized as follows: 15R or 15S (12 mg, yield 22.6%):

[0484] MS m / z(ESI):837.2[M+H] +

[0485] 1H NMR (400MHz, DMSO) δ10.39(s,1H),8.81(s,1H),7.50(d,J=6.4Hz,1H),7.36(d,J=6.4Hz,1H),7.30(d,J=8.8Hz,1H),7.04(t,J=6. 4Hz,1H),6.90(t,J=6.4Hz,1H),6.48(s,1H),6.24(d,J=16.8Hz,2H),5.39(t,J=5.6Hz,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).

[0486] Example 16: Synthesis of Compound 16

[0487] Compound 16 was synthesized by a method similar to Example 2.

[0488] MS m / z(ESI):828.7[M+H] +

[0489] 1 H NMR (400MHz, CDCl3) δ7.96 (d, J = 24.5Hz, 1H), 7.61-7.43 (m, 1H), 7.30 (s, 1H), 7.14 (t, J = 7. 7Hz,1H),7.09-6.97(m,1H),6.88(s,1H),6.64(s,1H),6.23(d,J=3.2Hz,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,2H),4.29-4.03(m,4H),3.9 2-3.79(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).

[0490] Example 17: Synthesis of Compound 23 and Compound 24

[0491] Step 1: Synthesis of compound 23

[0492] 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 solution was cooled to room temperature. Ethyl acetate and saturated aqueous sodium bicarbonate were added to the residue, stirred, and the layers were 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).

[0493] MS m / z(ESI):851.2[M+H] +

[0494] 1 H NMR(400MHz, DMSO-d6)δ9.92(s,1H),8.77(s,1H),7.74(t,J=5.6Hz,1H),7.36–7.25(m,2H),7.02(t,J=7.6Hz,1H),6 .91(t,J=7.4Hz,1H),6.47(s,1H),6.29–6.20(m,2H),5.58(t,J=5.7Hz,1H),5.17(d,J=10.8Hz,1H),4.60–4.43(m,2H ),4.30–4.18(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).

[0495] Step 2: Synthesis of compound 24

[0496] Compound 24 was synthesized by a method similar to Example 4.

[0497] MS m / z(ESI):842.2[M+H] +

[0498] Example 18: Synthesis of Compound 27 and Compound 28

[0499] Compound 27 and Compound 28 were synthesized by methods similar to those in Example 2 and Example 3, respectively.

[0500] Compound 27:

[0501] MS m / z(ESI):851.2[M+H] +

[0502] 1 H NMR (400MHz, DMSO-d6) δ10.16(s,1H),8.77(s,1H),7.60–7.50(m,1H),7.40–7.25(m,2H),7.03(t,J=7.6Hz,1H),6.91(t,J=7 .8Hz,1H),6.53(s,1H),6.25(d,J=11.4Hz,2H),5.55(t,J=5.5Hz,1H),5.08(d,J=11.0Hz,1H),4.60–4.43(m,2H),4.20(d,J=3 .9Hz,1H),4.15–4.04(m,2H),3.87(d,J=5.5Hz,2H),3.69–3.56(m,4H),3.46–3.40(m,1H),3.25–3.15(m,1H),3.05–2.93(m,1 H),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).

[0503] Compound 28:

[0504] MS m / z(ESI):842.2[M+H] +

[0505] 1H NMR(400MHz, CDCl3)δ12.52(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=11.5Hz,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).

[0506] Example 19: Synthesis of Compound 39

[0507] Step 1: Preparation of compound 39-1

[0508] To a solution of compound 13 (95 mg, 0.12 μmol) in DMF (2 mL) was added Boc-glycine (64 mg, 0.36 μmol), HATU (45.6 mg, 0.12 μmol), and HOAt (27.2 mg, 0.12 μmol). The mixture was stirred at room temperature, followed by the addition of TMP (43.6 mg, 0.36 μmol). The reaction mixture was stirred at room temperature for one hour. The reaction mixture was directly purified by reverse-phase preparative column chromatography and lyophilized to afford compound 39-1 (65 mg, 58.0% yield).

[0509] Step 2: Preparation of compound 39

[0510] To a solution of 39-1 (60 mg, 0.06 mmol) in MeNO₂ (1.0 mL) was added ZnBr₂ (40.53 mg, 0.18 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours and 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.

[0511] MS m / z(ESI):836.2[M+H] +

[0512] 1HNMR(400MHz,DMSO-d6)δ10.49–10.37(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=7.6Hz,1H),6.95–6.85(m,1H),6.48(d,J=5.0Hz,1H),6.36–6.17(m,2H),5.17–5.01(m,1H),4.94(s, 1H),4.48(s,2H),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).

[0513] Example 20: Synthesis of Compound 29

[0514] 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 overnight at 70°C. 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 were separated. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse HPLC to afford compound 29 (18 mg, 8.6% yield).

[0515] MS m / z(ESI):865.3[M+H] +

[0516] 1H NMR (400MHz, CDCl3) δ7.62(d,J=12.4Hz,1H),7.30(t,J=7.3Hz,1H),7.27–7.20(m,1H),7.10–7.01(m,1H),6.96(q,J=8.0Hz,1H),6.49(d,J=22.3Hz ,1H),6.17(dd,J=2.8,1.3Hz,1H),5.96(d,J=1.2Hz,1H),5.71(d,J=3.2H z,1H),4.96(d,J=11.7Hz,1H),4.57(s,1H),4.31(d,J=4.8Hz,1H),4.26–4 .18(m,2H),4.16(d,J=2.7Hz,2H),4.13–4.06(m,1H),3.74(d,J=1.0Hz,3 H),3.66–3.54(m,2H),3.44(s,1H),3.40(d,J=5.1Hz,3H),3.09(s,1H),3. 07–2.94(m,1H),2.93(s,3H),2.54(ddd,J=31.3,14.7,3.1Hz,1H),2.43–2 .33(m,1H),2.25(s,3H),2.19(s,3H),2.10(d,J=1.3Hz,5H),2.02(s,3H).

[0517] Example 21: Synthesis of Compound 124S

[0518] Step 1: Preparation of compound 124S-1

[0519] 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 afford compound 124S-1 (72 mg, 60% yield).

[0520] Step 2: Preparation of compound 124S

[0521] Compound 124-1 (27 mg, 0.033 mmol) was dissolved in DMF (1.5 mL), and glycolic 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 monitored for completion by LCMS. Ethyl acetate and saturated aqueous sodium bicarbonate were added, 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-phase HPLC to afford compound 124S (10 mg, 35% yield).

[0522] MS m / z(ESI):867.5[M+H] +

[0523] Example 22: Synthesis of Compound 125S

[0524] Compound 125S was synthesized according to the method of Example 21.

[0525] MS m / z(ESI):881.4[M+H] +

[0526] Example 23: Synthesis of Compound 124R

[0527] Compound 124R was synthesized according to the method of Example 21.

[0528] MS m / z(ESI):867.5[M+H] +

[0529] Example 24: Synthesis of Compound 125R

[0530] Compound 125R was synthesized according to the method of Example 21.

[0531] MS m / z(ESI):881.4[M+H] +

[0532] Example 25: Synthesis of Compound 7

[0533] 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 solution was subjected to reverse-phase HPLC and lyophilized to afford compound 7 (38.79 mg, 33% yield).

[0534] MS m / z(ESI):865.4[M+H] +

[0535] 1 H NMR (400MHz, CDCl3) δ10.19(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=12.4Hz,6H),2.06(s,4H),1.99(s,3H)

[0536] Example 26: Synthesis of Compound 126

[0537] Compound 126 was synthesized by a similar method to Example 3.

[0538] MS m / z(ESI):865.3[M+H] +

[0539] Effect test example 1: In vitro tumor cell proliferation inhibition test of the compound

[0540] Purpose of the test

[0541] In order to test the inhibitory activity of drug compounds on the proliferation of NCI-H82, SKOV-3, OVCAR-3, NCI-H1781, MKN-45, LS174T and BT474 tumor cells in vitro, cells were treated with different concentrations of compounds in vitro and cultured for 6 days. Luminescent Cell Viability Assay (Promega, Catalog No. G7558) was used to detect cell proliferation. 50 The in vitro activity of the compound was evaluated.

[0542] Experimental methods

[0543] The following uses the in vitro proliferation inhibition test method of NCI-H82 cells as an example to illustrate the method for testing the in vitro proliferation inhibition activity of the compounds of the present application on tumor cells. This method is also applicable to, but not limited to, testing the in vitro proliferation inhibition activity of other tumor cells.

[0544] 1. Cell culture: NCI-H82 cells were cultured in RPMI-1640 medium supplemented with 10% FBS.

[0545] 2. Cell preparation: Take NCI-H82 cells in the logarithmic growth phase, wash once with PBS, add 2-3 ml of trypsin to digest for 2-3 minutes, wait until the cells are completely digested, 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 make a single-cell suspension.

[0546] 3. Cell plating: Mix the NCI-H82 single cell suspension and adjust the viable cell density to 6x10 4 After adjusting the density, the cell suspension was mixed and added to a 96-well cell culture plate at 50 μl / well. The culture plate was cultured in an incubator for 18 hours (37°C, 5% CO2).

[0547] 4. Compound Preparation: Dissolve the compound in DMSO and prepare a stock solution with an initial concentration of 10 mM. For small molecule compounds, a total of 9 concentrations are prepared, with a maximum concentration of 1 uM, and 3-fold dilution.

[0548] 5. Sample addition: Add different concentrations of the test sample to the culture plate, with two replicates for each sample. Incubate the culture plate in an incubator for 6 days (37°C, 5% CO2).

[0549] 6. Color development: Take out the 96-well cell culture plate, add 50ul CTG reagent to each well, and incubate at room temperature for 10 minutes.

[0550] 7. Plate reading operation: Take out the 96-well cell culture plate, place it in a microplate reader, and measure the chemiluminescence using the microplate reader.

[0551] Data analysis: Microsoft Excel and Graphpad Prism 5 were used to process and analyze the data.

[0552] Table 1 IC values ​​of the compounds in this application for inhibition of cell proliferation in vitro 50 value

[0553] Conclusion: According to the results in Table 1, the compounds of the present application have better proliferation inhibitory activity against at least one of NCI-H82, SKOV-3, OVCAR-3, NCI-H1781, MKN-45, LS174T and BT474 tumor cells than the control compound rubitinine.

[0554] Effect Test Example 2: Toxicology Study of Different Compounds by Intravenous Injection in SD Rats

[0555] Purpose of the experiment

[0556] Sprague-Dawley rats were given a single intravenous injection of the three test articles to observe the acute toxic reactions of the three test articles in SD rats, so as to compare the toxic effects of the three test articles and provide data support for subsequent safety evaluation.

[0557] dose:

[0558] First dose, D1; second dose, D9

[0559] Symptoms: Sprague-Dawley (SD) rats showed no significant toxicity after the initial intravenous injection of 0.04 mg / kg and 0.1 mg / kg of Compound 26, Compound 25, or Rubitidine. Nine days later, 0.3 mg / kg of Compound 26, Compound 25, or Rubitidine was administered to Groups G1, G3, and G5, respectively, resulting in weight loss. While Compound 25 and Compound 26 groups gradually recovered from the second or third day after administration, the Rubitidine group experienced a further significant decline. Both male and female rats in the Rubitidine group exhibited perianal soiling due to loose stools. Female rats also exhibited piloerection, 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, the Rubitidine-treated group, died by day 18, while rats in the remaining groups survived. Clinical pathology results showed that both Compound 26 and rubitidine administration resulted in elevated serum ALT, AST, GGT, and DBIL, with rubitidine producing more significant changes. In routine blood tests, significant decreases in EO and PLT were observed in the rubitidine group, while no significant changes were observed with Compound 26. Following administration of Compound 25, no significant abnormalities were observed in serum or routine blood tests. Nine days later, groups G2, G4, and G6 were re-injected with 0.1 mg / kg of Compound 26, Compound 25, or rubitidine, respectively, without significant toxicity. The experimental results are shown in Figures 1-3.

[0560] Conclusion: Compounds 25 and 26 were well tolerated in SD rats at 0.3 mpk, and their toxicity was significantly better than that of rubitinine.

[0561] Effect Test Example 3: Toxicology Study of Different Compounds in SD Rats by Intravenous Injection

[0562] Purpose of the experiment

[0563] Seven test articles were administered as a single intravenous injection to Sprague-Dawley rats. The acute toxicity reactions of the seven test articles in SD rats were observed to compare the toxic effects of the seven test articles and provide data support for subsequent safety evaluation.

[0564] dose:

[0565] Symptoms: 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 soiling due to loose stools. Female rats also exhibited piloerection, 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. All animals in the remaining groups survived until the scheduled dissection date.

[0566] On Day 3, blood biochemical test indicators showed a significant increase in CK in the G4 group; a significant increase in CK, ALT and AST in the G5 group, which returned to normal on Day 7; and an increase in serum ALT, AST, GGT and DBIL in the G6 group, and a decrease in RET, WBC, LYMPH, MONO, EO and PLT in the blood routine test.

[0567] 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 rubitinine.

[0568] The above embodiments do not limit the solutions of the present application in any way. In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, journal articles, books and any other disclosures) is incorporated by reference in its entirety.

Claims

1. A compound represented by formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof: in, R 1 For hydrogen, deuterium, halogen, -OH, -CN, -NH2, 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 Cycloalkyl, (4 to 12 membered heterocycloalkylene) or -N(R 1-1 )C(O)(4 to 12 membered heterocycloalkyl), said 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 radicals selected from halogen, -OH, -SH, -NH2, -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-NH2 substituent substitution; R 2 For 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 、-NH2、-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 3-12 Cycloalkyl, C(O)(4- to 12-membered heterocycloalkyl), -N(C 1-6 alkyl)C(O)(4- to 12-membered heterocycloalkyl) or -NH-S(O)2-R 2-2 , the C 1-6 Alkyl, C 3-12 The cycloalkyl and 4 to 12 membered heterocycloalkyl groups are each optionally substituted with one or more radicals selected from halogen, -OH, -O-NHCH3, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Substitution of alkyl groups; R 3 For hydrogen, deuterium, -C 1-6 Alkyl, -CH2-NHC 1-6 Alkyl, -CH2-NHC(O)C 1-6 Alkyl, -CH2-OC(O)-NR 3-1 R 3-2 、-CH2-NR 3-1 C(O)NR 3-1 -R 3-2 、-CH2-NR 3-1 C(O)OR 3-2 、-CH2-NHC(O)C 3-12 Cycloalkyl, -CH2-NHC(O)(4 to 12 membered heterocycloalkyl), -CH2-N(C 1-6 alkyl)C(O)C 1-6 Alkyl, -CH2-N(C 1-6 alkyl)C(O)C 3-12 Cycloalkyl, -CH2-N(C 1-6 alkyl)C(O)(4- to 12-membered heterocycloalkyl), -CH2NH-S(O)2-R 3-2 、-CH2-S(O)2-R 3-2 or -C(O)R 3-2 , the C 1-6 Alkyl, C 3-12 Cycloalkyl and 4 to 12 membered heterocycloalkyl are each optionally substituted by one or more radicals selected from halogen, cyclopropyl, -OH, -O-NHCH3, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Substitution of alkyl groups; R 4 For hydrogen, deuterium, -C 1-6 Alkyl, -C(O)C 1-6 Alkyl, -C(O)C 3-12 Cycloalkyl or -C(O)(4 to 12 membered heterocycloalkyl), the C 1-6 Alkyl, C 3-12 The cycloalkyl and 4 to 12 membered heterocycloalkyl groups are each optionally substituted with one or more radicals selected from halogen, -OH, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Substitution of alkyl groups; or R 3 With R 4 The atoms to which it is attached together form a 5-12 membered heterocycloalkyl group; each of the 5-12 membered heterocycloalkyl groups is optionally substituted by one or more halogen, oxo, -OH, -CN, -NH2, -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 Substitution with cycloalkylene-OH and -C(O)-(4- to 12-membered heterocycloalkylene)-OH substituents; R 1-1 、R 2-1 、R 3-1 are independently hydrogen, deuterium, C 1-6 Alkyl or halogenated C 1-6 alkyl; R 1-2 、R 2-2 、R 3-2 Each independently 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 by one or more independently selected from halogen, -OH, -O-NHCH3, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Substitution of alkyl groups; Y is -OH or -CN.

2. The compound according to 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 Deuterium, halogen, -OH, -CN, -NH2, 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 、-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), said 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 radicals selected from halogen, -OH, -SH, -NH2, -O-NHCH3, -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-NH2 substituent substitution; (2)R 2 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 、-NH2、-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 3-12 Cycloalkyl, C(O)(4- to 12-membered heterocycloalkyl), -N(C 1-6 alkyl)C(O)(4- to 12-membered heterocycloalkyl) or -NH-S(O)2-R 2-2 , the C 1-6 Alkyl, C 3-12 The cycloalkyl and 4 to 12 membered heterocycloalkyl groups are each optionally substituted with one or more radicals selected from halogen, -OH, -O-NHCH3, -SH, -NH2, -NHC 1- 6-alkyl and -SC 1-6 Substitution of alkyl groups; (3)R 3 -CH2-NHC 1-6 Alkyl, -CH2-NHC(O)C 1-6 Alkyl, -CH2-OC(O)-NR 3-1 R 3-2 、-CH2-NR 3-1 C(O)NR 3- 1 -R 3-2 、-CH2-NR 3-1 C(O)OR 3-2 、-CH2-NHC(O)C 3-12 Cycloalkyl, -CH2-NHC(O)(4 to 12 membered heterocycloalkyl), -CH2-NHC(O)C 3-12 Cycloalkyl, -CH2-N(C 1-6 alkyl)C(O)C 1-6 Alkyl, -CH2-N(C 1-6 alkyl)C(O)C 3-12 Cycloalkyl, -CH2-N(C 1- 6-membered alkyl)C(O)(4- to 12-membered heterocycloalkyl), -CH2NH-S(O)2-R 3-2 、-CH2-S(O)2-R 3-2 or -C(O)R 3-2 , the C 1-6 Alkyl, C 3-12 Cycloalkyl and 4 to 12 membered heterocycloalkyl are each optionally substituted by one or more radicals selected from halogen, cyclopropyl, -OH, -O-NHCH3, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Substitution of alkyl groups; (4)R 4 C 1-6 Alkyl, -C(O)C 1-6 Alkyl, -C(O)C 3-12 Cycloalkyl or -C(O)(4 to 12 membered heterocycloalkyl), the C 1- 6 alkyl, C 3-12 The cycloalkyl and 4 to 12 membered heterocycloalkyl groups are each optionally substituted with one or more radicals selected from halogen, -OH, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Substitution of the alkyl group by a substituent; and (5)R 3 With R 4 The atoms to which it is attached together form a 5-12 membered heterocycloalkyl group; each of the 5-12 membered heterocycloalkyl groups is optionally substituted by one or more halogen, oxo, -OH, -CN, -NH2, -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 The substituents are cycloalkylene-OH and -C(O)-(4- to 12-membered heterocycloalkylene)-OH.

3. The compound according to claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof, wherein: The compound represented by formula (I) is a compound represented by formula (IA), (IB), (Ia), or (Ib): in, R 1 For hydrogen, halogen, -OH, -OC 1-6 alkyl; R 2 is hydrogen, deuterium; R 3 -CH2-NHC 1-6 Alkyl, -CH2-NHC(O)C 1-6 Alkyl, -CH2-OC(O)-NR 3-1 R 3-2 、-CH2-NR 3- 1 C(O)NR 3-1 -R 3-2 、-CH2-NR 3-1 C(O)OR 3-2 、-CH2-NHC(O)C 3-12 Cycloalkyl, -CH2-NHC(O)(4 to 12 membered heterocycloalkyl), -CH2-NHC(O)C 3-12 Cycloalkyl, -CH2-N(C 1-6 alkyl)C(O)C 1-6 Alkyl, -CH2-N(C 1-6 alkyl)C(O)C 3-12 Cycloalkyl, -CH2-N(C 1-6 alkyl)C(O)(4- to 12-membered heterocycloalkyl), -CH2NH-S(O)2-R 3-2 、-CH2-S(O)2-R 3-2 or -C(O)R 3-2 , the C 1-6 Alkyl, C 3-12 Cycloalkyl and 4 to 12 membered heterocycloalkyl are each optionally substituted by one or more radicals selected from halogen, cyclopropyl, -OH, -O-NHCH3, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Alkyl substituents substituted; R 4 For hydrogen, C 1-6 alkyl; Or, R 2 is hydrogen, deuterium; R 3 With R 4 Together with the atoms to which it is attached, it forms a 5-12 membered heterocycloalkyl group; each of the 5-12 membered heterocycloalkyl groups is optionally substituted with one or more selected from -C(O)C 1-6 Alkylene-OH; Or, R 2 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 、-NH2、-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 3-12 Cycloalkyl, C(O)(4- to 12-membered heterocycloalkyl), -N(C 1-6 alkyl)C(O)(4- to 12-membered heterocycloalkyl) or -NH-S(O)2-R 2-2 , the C 1-6 Alkyl, C 3-12 The cycloalkyl and 4 to 12 membered heterocycloalkyl groups are each optionally substituted with one or more radicals selected from halogen, -OH, -O-NHCH3, -SH, -NH2, -NHC 1- 6-alkyl and -SC 1-6 Alkyl substituents substituted; R 3 is hydrogen, deuterium; R 4 For hydrogen, C 1-6 alkyl; Y is -OH or -CN; in, R 1 -OH, -CN, -NH2, 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 、-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), said 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 radicals selected from halogen, -OH, -SH, -NH2, -O-NHCH3, -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-NH2 substituent substitution; R 4 For hydrogen, -C 1-6 alkyl; Y is -OH or -CN; in, R 1 For hydrogen, deuterium, halogen, -OH, -CN, -NH2, 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 For hydrogen, deuterium, halogen, C 1-6 Alkyl, -OH, -NH2, -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), said C 1-6 Alkyl, C 3-12 Cycloalkyl or 4 to 12 membered heterocycloalkyl are each optionally substituted by one or more radicals selected from halogen, -OH, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Substitution of alkyl groups; R 3 H or -CH2-NR 3a R 3b ; R 3a is hydrogen or C 1-6 Alkyl; the C 1-6 The alkyl group is optionally substituted with one or more radicals selected from halogen, -OH, -SH, -NH2, -NHC 1- 6-alkyl and -SC 1-6 Substitution of alkyl groups; R 3b -C(O)C 1-6 Alkyl, -C(O)C 3-12 Cycloalkyl or -C(O)(4 to 12 membered heterocycloalkyl), the C 1-6 Alkyl, C 3-12 Cycloalkyl or 4 to 12 membered heterocycloalkyl are each optionally substituted by one or more radicals selected from halogen, -OH, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1- 6 alkyl substituents are substituted; R 4 For hydrogen, deuterium, C 1-6 Alkyl, -C(O)C 1-6 Alkyl, -C(O)C 3-12 Cycloalkyl or -C(O)(4 to 12 membered heterocycloalkyl), the C 1-6 Alkyl, C 3-12 Cycloalkyl or 4 to 12 membered heterocycloalkyl are each optionally substituted by one or more radicals selected from halogen, -OH, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Substitution of alkyl groups; or R 3 With R 4 The atoms to which it is attached together form a 5-12 membered heterocycloalkyl group; each of the 5-12 membered heterocycloalkyl groups is optionally substituted by one or more halogen, oxo, -OH, -CN, -NH2, -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 Substitution with cycloalkylene-OH and -C(O)-(4- to 12-membered heterocycloalkylene)-OH substituents; Y is selected from -OH or -CN; The premise is that R 2 and R 3 Cannot be H at the same time; in, R 1 -NH2, -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 3-12 Cycloalkyl or -N(R 1-1 )C(O)(4 to 12 membered heterocycloalkyl), said C 1-6 Alkyl, C 1-6 Alkylene, C 3-12 Cycloalkyl, C 3-12 Cycloalkylene, 4 to 12 membered heterocycloalkylene or 4 to 12 membered heterocycloalkyl are each optionally substituted by one or more radicals selected from halogen, -OH, -SH, -NH2, -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-NH2 substituent substitution; R 1-1 For hydrogen, deuterium, C 1-6 Alkyl or halogenated C 1-6 alkyl; R 1-2 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 are each optionally substituted by one or more radicals selected from halogen, -OH, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Substitution of alkyl groups; Y is -OH or -CN.

4. 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, characterized in that: The compound represented by the structure of formula (I) is a compound represented by the structure of formula (IA-1), formula (IA-2), formula (Ia-1), and formula (Ia-2). in, R 1 For hydrogen, halogen, -OH, -OC 1-6 alkyl; R 3 -CH2-NHC 1-6 Alkyl, -CH2-NHC(O)C 1-6 Alkyl, -CH2-OC(O)-NR 3-1 R 3-2 、-CH2-NR 3-1 C(O)NR 3-1 -R 3- 2 、-CH2-NR 3-1 C(O)OR 3-2 、-CH2-NHC(O)C 3-12 Cycloalkyl, -CH2-NHC(O)(4 to 12 membered heterocycloalkyl), -CH2-NHC(O)C 3-12 Cycloalkyl, -CH2-N(C 1-6 alkyl)C(O)C 1-6 Alkyl, -CH2-N(C 1-6 alkyl)C(O)C 3-12 Cycloalkyl, -CH2-N(C 1- 6-membered alkyl)C(O)(4- to 12-membered heterocycloalkyl), -CH2NH-S(O)2-R 3-2 、-CH2-S(O)2-R 3-2 or -C(O)R 3-2 , the C 1-6 Alkyl, C 3-12 Cycloalkyl and 4 to 12 membered heterocycloalkyl are each optionally substituted by one or more radicals selected from halogen, cyclopropyl, -OH, -O-NHCH3, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Substitution of alkyl groups; R 4 For hydrogen, C 1-6 alkyl; or R 3 With R 4 Together with the atoms to which it is attached, it forms a 5-12 membered heterocycloalkyl group; each of the 5-12 membered heterocycloalkyl groups is optionally substituted with one or more selected from -C(O)C 1-6 Alkylene-OH; Y is -OH or -CN; in, R 1 For hydrogen, halogen, -OH, -OC 1-6 alkyl; R 2 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 、-NH2、-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 3-12 Cycloalkyl, C(O)(4- to 12-membered heterocycloalkyl), -N(C 1-6 alkyl)C(O)(4- to 12-membered heterocycloalkyl) or -NH-S(O)2-R 2-2 , the C 1-6 Alkyl, C 3-12 The cycloalkyl and 4 to 12 membered heterocycloalkyl groups are each optionally substituted with one or more radicals selected from halogen, -OH, -O-NHCH3, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Substitution of alkyl groups; R 4 For hydrogen, C 1-6 alkyl; Y is -OH or -CN; in, Y, R 2 、R 3a 、R 3b and R 4 As defined in any one of claims 1 to 3; Preferably, among the compounds represented by formula (Ia) and formula (Ia-1), R 3a is hydrogen or -CH3; R 3b -C(O)C 1-6 Alkylene-OH; R 4 is hydrogen; or, for Y is -OH or -CN.

5. 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, characterized in that: It meets 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 heterocycloalkyl 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 ...6-membered heterocycloalkylene group and the 4- to 6-membered heterocycloalkylene group are 4- to 6-membered heterocycloalkylene groups and 4- to 6-membered heterocycloalkyl groups; 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, -NH2, -CH3, -OCH3 or -NHCH3; Preferably, R 1 is hydrogen, deuterium, -F, -Cl, -OH, -CH3, -OCH3, -NH2 or -NHCH3; (3) In the compounds represented by formula (I), formula (Ia), and formula (Ia-2), R 2 -OH, -NH2, 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, 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, -NH2, -NHCH3 and -SCH3; preferably, R 2 -OH, -NH2, -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-NH2 or -N(C 1-6 alkyl)C(O)C 1-6 Alkylene-NH2; Preferably, R 2 -OH, -NH2, -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 -OH, -NH2, -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-NH2 or -N(C 1-6 alkyl)C(O)C 1-3 Alkylene-NH2; (4) In the compounds represented by formula (I) and formula (Ia), R 3a is hydrogen or C 1-3 alkyl; Preferably, R 3a is hydrogen or -CH3; (5) In the compounds represented by formula (I) and formula (Ia), R 3b -C(O)C 1-6 Alkyl or -C(O)C 3-6 Cycloalkyl, the C 1-6 Alkyl or C 3-6 Each cycloalkyl group is optionally substituted with one or more substituents selected from -OH, -SH, -NH2, -NHCH3 and -SCH3; Preferably, R 3b -C(O)C 1-6 Alkylene-OH; More preferably, R 3b -C(O)C 1-3 Alkylene-OH; (6) In the compounds represented by formula (I), formula (Ia), and formula (Ia-1), R 4 For hydrogen, deuterium, -C 1-6 Alkyl or -C(O)C 1-6 Alkylene-OH; (7) In the compounds represented by formula (I) and formula (Ia), R 3 With R 4 Together with the atoms to which it is attached, it forms a 5- to 6-membered heterocycloalkyl, wherein each of the 5- to 6-membered heterocycloalkyl groups is optionally substituted with one or more halogen, oxo, -OH, -CN, -NH2, -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 Substitution with cycloalkylene-OH, -C(O)-(4- to 12-membered heterocycloalkylene)-OH substituents; Preferably, R 3 With R 4 The atom to which it is attached forms a piperazinyl group, wherein the piperazinyl group is optionally substituted with one or more halogen, oxo, -OH, -CN, -NH2, -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 Substitution with cycloalkylene-OH, -C(O)-(4- to 12-membered heterocycloalkylene)-OH substituents; (8) In the compounds represented by formula (I) and formula (Ib), R 1-1 is hydrogen, deuterium or -C 1-6 alkyl; Preferably, R 1-1 is hydrogen, deuterium or -CH3; (9) In the compounds represented by formula (I) and formula (Ib), R 1-2 C 1-6 Alkyl, C 3-6 Cycloalkyl or 4 to 6 membered heterocycloalkyl; the C 1-6 Alkyl, C 3-6 Cycloalkyl or 4 to 6 membered heterocycloalkyl are each optionally substituted by one or more radicals selected from halogen, -OH, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Substitution of alkyl groups; Preferably, R 1-2 -C 1-6 Alkylene -OH or -C 3-6 Cycloalkylene-OH; More preferably, R 1-2 -NH2, -C 1-3 Alkylene -OH or -C 3-4 Cycloalkylene-OH; (10) Compounds represented by formula (I) and formula (Ib), wherein R 1 -NH2, -C 1-6 Alkylene-NH-C(O)R 1-2 、-C 1-6 Alkylene-N(CH3)-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(CH3)-C(O)R 1-2 、-NH-(4 to 6 membered heterocycloalkylene)-C(O)R 1-2 、-N(CH3)-(4 to 6 membered heterocycloalkylene)-C(O)R 1- 2 、-NHC(O)C 3-6 Cycloalkyl, -N(CH3)C(O)C 3-6 Cycloalkyl, -NHC(O)(4 to 6 membered heterocycloalkyl) or -N(CH3)C(O)(4 to 6 membered heterocycloalkyl), wherein the C 1-6 Alkylene, C 3-6 Cycloalkyl, C 3-6 Cycloalkylene, 4 to 6 membered heterocycloalkyl or 4 to 6 membered heterocycloalkylene are each optionally substituted by one or more radicals selected from halogen, -OH, -NH2, -NHCH3, -C 1-6 Substitution of the alkylene-OH group; Preferably, R 1 -NH2, -O-(4 to 6 membered heterocycloalkylene)-C(O)R 1-2 or -C 1-6 Alkylene-N(CH3)-C(O)R 1-2 ; (11) Compounds represented by formula (I) and formula (Ia), wherein R 2-1 is hydrogen or C 1-3 Alkyl; preferably H, CH3; (12) Compounds represented by formula (I) and formula (Ia), wherein R 2-2 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 by one or more substituents independently selected from halogen, -OH; preferably substituted with -OH; preferably, R 2-2 is -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH2ONH(CH3), (11) Compounds represented by formula (I) and formula (Ia), wherein R 3-1 is hydrogen or C 1-3 Alkyl; preferably hydrogen or -CH3; (12) Compounds represented by formula (I) and formula (Ia), wherein R 3-2 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 by one or more substituents independently selected from halogen, -OH; preferably substituted with -OH; preferably, R 3-2 is -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH2O-NHCH3, -CH2ONH(CH3), (13) Compounds represented by formula (I) and formula (Ia), wherein R 3 H, -C(O)R 3-2 、-CH2-NHC(O)C 1-6 Alkyl, -CH2-N(C 1-6 alkyl)C(O)C 1-6 Alkyl, -CH2-NR 3-1 C(O)OR 3-2 、-CH2-OC(O)-NR 3-1 R 3-2 、-CH2NH-S(O)2-R 3-2 、-CH2-NR 3-1 C(O)NR 3-1 -R 3-2 、-CH2-NHC(O)C 3-12 Cycloalkyl; the C 1-6 Alkyl, C 3-12 The cycloalkyl and 4- to 12-membered heterocycloalkyl groups are each optionally substituted with one or more substituents selected from cyclopropyl, -OH, -O-NHCH3.

6. The compound according to claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof, wherein: It meets at least one of the following conditions: (1) In the compounds represented by formula (I) and formula (Ia), R 1 is hydrogen, halogen, -OH, -CN, -NH2, -CH3, -OCH3 or -NHCH3, preferably hydrogen, F, -OH or -OCH3; more preferably hydrogen; (2) In the compounds represented by formula (I), formula (Ia), and formula (Ia-2), R 2 -OH, -NH2, -NHCH3, -CH2OH, Preferably, R 2 -OH, -NH2, -CH2OH, More preferably, R 2 -NH2, -CH2OH or (3) In the compounds represented by formula (I), formula (Ia), and formula (Ia-1), R 3a is -CH3; (4) In the compounds represented by formula (I), formula (Ia), and formula (Ia-1), R 3b for Preferably, R 3b for (5) In the compounds represented by formula (I), formula (Ia), and formula (Ia-1), -CH2-NR 3a R 3b for (6) In the compounds represented by formula (I), formula (Ia), and formula (Ia-1), R 4 For hydrogen or Preferably, R 4 is hydrogen; (7) In the compounds represented by formula (I), formula (Ia), and formula (Ia-1), R 3 With R 4 Together with the atoms it is connected to, it forms Preferably, (8) In the compounds represented by formula (I) and formula (Ib), R 1-2 is -CH2OH, -CH(CH3)OH, -CH2CH2OH, -CH2ONH(CH3), Preferably, R 1-2 -CH2OH, -CH(CH3)OH or (9) In the compounds represented by formula (I) and formula (Ib), R 1 -NH2, -OH, Preferably, R 1 -NH2, More preferably, R 1 -NH2, (10) Compounds having structures represented by formula (I) and formula (Ia), wherein for or a combination thereof; (11) Compounds having structures represented by formula (I) and formula (Ia), wherein for or a combination thereof; (12) Compounds represented by formula (I) and formula (Ia), wherein R 3 For H, 7. The compound according to claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof, wherein: The compound is any of the following structures:

8. A compound having the structure shown below:

9. A pharmaceutical composition, characterized in that It comprises the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite or prodrug thereof, and one or more pharmaceutically acceptable carriers.

10. Use of a substance A in the preparation of a medicament for preventing or treating tumors or cancers, characterized in that: The substance A is a compound according to 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 according to claim 9; The tumor or cancer is preferably 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 tissue 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 chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL) and chronic myeloid leukemia (CML).

Images