Ecdysteroid compounds and their use

Abstract

This invention discloses a sucrose-like compound and its applications. This invention provides a compound as shown in formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite, or prodrug thereof; the compound provided by this invention has one or more effects selected from the group consisting of: (1) inhibitory activity against the in vitro proliferation of tumor cells; (2) in vivo tumor-suppressive effect; (3) in vivo tumor-targeting ability; and (4) good in vivo safety.

Description

[0001] This application claims priority to Chinese Patent Application No. 2024101780235, filed on February 8, 2024; Chinese Patent Application No. 2024111028377, filed on August 12, 2024; Chinese Patent Application No. 2024113883016, filed on September 30, 2024; and Chinese Patent Application No. 2025101162270, filed on January 24, 2025. The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of pharmaceutical technology, specifically relating to sucrose compounds and their applications. Background Technology

[0003] Cancer is one of the most serious malignant diseases threatening human health, causing more than 5 million deaths worldwide each year. Moreover, the incidence of cancer has been rising annually in recent years, and its mortality rate ranks first among all diseases. Chemotherapy is currently a commonly used and effective treatment for cancer. However, due to the multidrug resistance of cancer cells and the serious toxic side effects of existing anticancer drugs, there is an urgent clinical need for new anticancer drugs with better efficacy and fewer side effects.

[0004] Et-743 (Trabectedin) is a highly effective antitumor agent isolated from the marine tunicate Ecteinascidiaturbinata, and has been approved by the European Union and the United States for the treatment of advanced soft tissue tumors.

[0005]

[0006] There is still a need to continue developing arachin compounds with better efficacy and lower toxicity to meet more clinical needs. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to overcome the shortcomings of existing drugs, thereby providing a sucrose compound and its application. The sucrose compound of the present invention has one or more effects selected from the group consisting of: (1) having inhibitory activity against the 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.

[0008] This invention provides a compound of formula (IA), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite, or prodrug thereof:

[0009]

[0010] in,

[0011] Q 1 For N or CH;

[0012] Q 2 For N or CR 11 ;

[0013] R 1 and R 11 Independently 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 1-6 Alkylene-N(R) 1-1 )-C(O)R 1-2 -OC 3-12 Cycloalkyl, -O- (4 to 12-membered heterocyclic alkyl), -O- (4 to 12-membered heterocyclic alkylene)-C(O)R 1-2 -OC 3-12 Cycloalkyl-N(R) 1-1 )-C(O)R 1-2 -N(R) 1-1 )-C 3-12 cycloalkyl, -N(R) 1-1 )-C(O)R 1-2 -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 -N(R) 1-1 )-C(O)-N(R 1-1 )R 1-2 -N(R) 1-1 )-(4 to 12-membered heterocyclic alkylene)-C(O)R 1-2 -N(R) 1-1 )-C 3-12 Cycloalkyl-N(R) 1 -3 )-C(O)R 1-2 -(4 to 12-membered heterocyclic alkylene)-C(O)R 1-2 -(4 to 12-membered heterocyclic alkylene)-N(R 1-1 )-C(O)R 1-2 -N(R) 1-1 )C(O)C 3-12 cycloalkyl, -N(R) 1-1)C(O)-C 1-6 Alkylene-R 1-2 or -N(R) 1-1 )C(O)(4 to 12-membered heterocyclic alkyl), wherein the C 1-6 Alkyl, C 1-6 Alkylene, C 3-12 cycloalkyl, C 3-12 Cycloalkylene, 4- to 12-membered heterocycloalkylene, and 4- to 12-membered heterocycloalkyl are each optionally separated by one or more elements 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 Substitution of alkylene-NH2;

[0014] Or, R 1 With R 11 Together with their respective attached atoms, they are conceived as 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl; each of the cycloalkyl or heterocycloalkyl is optionally bonded by one or more atoms selected from halogens, -C 1-6 Alkyl substituents;

[0015] R 2 Hydrogen, deuterium, halogen, -C 1-6 Alkyl, -OH, -NH2, -NHC 1-6 Alkyl group, -NHC(O)C 1-6 Alkyl group, -NHC(O)C 3-12 Cycloalkyl, -NHC(O) (4 to 12-membered heterocycloalkyl), -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)C(O)C 1-6 Alkyl, -OC(O)-NR 2-1 R 2-2 -NR 2-1 C(O)-OR 2-2 -NH-S(O)2-R 2-2 -N(R) 2-1 )C(O)-C 1-6 Alkylene-R 2-2 -NR 2-1 C(O)NR 2-1 -R 2-2 -N(C 1-6 Alkyl)C(O)C 3-12 cycloalkyl, -N(C) 1-6 Alkyl)C(O) (4 to 12-membered heterocyclic alkyl), -N(C1-6 Alkyl)C(O)C 1-6 Alkyl, -N(C) 1-6 Alkyl)C(O)C 3-12 cycloalkyl, -N(C) 1-6 Alkyl)C(O) (4 to 12-membered heterocyclic alkyl), -C(O)-R 2-2 or C(O)-NR 2-1 R 2-2 The C mentioned 1-6 Alkyl, C 3-12 The cycloalkyl group and the 4- to 12-membered heterocycloalkyl group are each optionally separated by one or more elements selected from halogen, -OH, -O-NH-CH3, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Alkyl substituents;

[0016] R 3 Hydrogen, deuterium, -C 1-6 Alkyl, NHC 1-6 Alkyl group, -CH2-NHC 1-6 Alkyl group, -CH2-NHC(O)C 1-6 Alkyl group, -CH2-OC(O)-NR 3-1 R 3-2 -CH2-NR 3-1 C(O)-OR 3-2 -CH2-NR 3-1 C(O)NR 3-1 -R 3-2 -CH2-NHC(O)C 3-12 Cycloalkyl, -CH2-NHC(O) (4 to 12-membered heterocyclic alkyl groups), -CH2-N(C 1-6 Alkyl)2、-CH2-N(C 1-6 Alkyl)C(O)C 1-6 Alkyl group, -CH2-N(C) 1-6 Alkyl)C(O)C 3-12 cycloalkyl, -CH2-N(C 1-6 Alkyl)C(O) (4 to 12-membered heterocyclic alkyl), -CH2-N(C 1-6 Alkyl)C(O)C 1-6 Alkyl, -CH2-N(R) 3-1 )C(O)-C 1-6 Alkylene-R 3-2 -CH2-N(C 1-6 Alkyl)C(O)C 3-12 cycloalkyl, -CH2-N(C 1-6 Alkyl)C(O) (4 to 12-membered heterocyclic alkyl) or -C(O)-R 3-2 The C mentioned1-6 Alkyl, C 3-12 The cycloalkyl group and the 4- to 12-membered heterocycloalkyl group are each optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -O-NH-CH3, -NHC 1-6 Alkyl and -SC 1-6 Alkyl substituents;

[0017] R 4 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), wherein the C 1-6 Alkyl, C 3-12 The cycloalkyl group and the 4- to 12-membered heterocycloalkyl group are each optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents;

[0018] Or R 3 With R 4 Together with the atoms attached thereto, they form 5-12 membered heterocyclic alkyl groups; each of the 5-12 membered heterocyclic alkyl groups is optionally bonded by one or more groups selected from halogen, oxo group, -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 Substituents of cyclohexene alkyl-OH and -C(O)-(4 to 12-membered heterocyclohexene alkyl)-OH;

[0019] R 1-1 R 2-1 R 3-1 Each is independently hydrogen, deuterium, and C. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0020] 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 heterocyclic alkyl; the C 1-6 Alkyl, C 3-12 The cycloalkyl group and the 4- to 12-membered heterocycloalkyl group are each optionally selected independently from one or more halogens, -OH, -SH, -NH2, -O-NH-CH3, -NHC 1-6Alkyl and -SC 1-6 Alkyl substituents;

[0021] Y is either -OH or -CN;

[0022] And the following conditions are met:

[0023] (1) When R 1 -OH or -OC 1-6 Alkyl, R 11 When it is -OCH3, R 2 R 3 and R 4 They are not both hydrogen;

[0024] (2) When R 1 -OH, R 11 -OCH3, R 2 and R 3 When it is hydrogen, R 4 Not methyl; and

[0025] (3) When R 1 -OH, R 11 -CH3, R 2 and R 4 When it is hydrogen, R 3 It is not ethyl.

[0026] In some implementation schemes,

[0027]

[0028] in,

[0029] Q 1 For N or CH;

[0030] Q 2 For N or CR 11 ;

[0031] R 1 and R 11 Independently 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 1-6 Alkylene-N(R) 1-1 )-C(O)R 1-2 -OC 3-12 Cycloalkyl, -O- (4 to 12-membered heterocyclic alkyl), -O- (4 to 12-membered heterocyclic alkylene)-C(O)R 1-2 -OC 3-12 Cycloalkyl-N(R)1-1 )-C(O)R 1-2 -N(R) 1-1 )-C(O)R 1-2 -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 -N(R) 1-1 )-C(O)-N(R 1-1 )R 1-2 -N(R) 1-1 )-(4 to 12-membered heterocyclic alkylene)-C(O)R 1-2 -N(R) 1-1 )-C 3-12 Cycloalkyl-N(R) 1-3 )-C(O)R 1-2 -(4 to 12-membered heterocyclic alkylene)-C(O)R 1-2 -(4 to 12-membered heterocyclic alkylene)-N(R 1-1 )-C(O)R 1-2 -N(R) 1-1 )C(O)C 3-12 cycloalkyl, -N(R) 1-1 )C(O)-C 1-6 Alkylene-R 1-2 or -N(R) 1-1 )C(O)(4 to 12-membered heterocyclic alkyl), wherein the C 1-6 Alkyl, C 1-6 Alkylene, C 3-12 cycloalkyl, C 3-12 Cycloalkylene, 4- to 12-membered heterocycloalkylene, and 4- to 12-membered heterocycloalkyl are each optionally separated by one or more elements 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 Substitution of alkylene-NH2;

[0032] Or, R 1 With R 11 Together with their respective attached atoms, they are conceived as 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl; each of the cycloalkyl or heterocycloalkyl is optionally bonded by one or more atoms selected from halogens, -C 1-6 Alkyl substituents;

[0033] R 2 Hydrogen, deuterium, halogen, -C 1-6 Alkyl, -OH, -NH2, -NHC 1-6 Alkyl group, -NHC(O)C 1-6 Alkyl group, -NHC(O)C 3-12 Cycloalkyl, -NHC(O) (4 to 12-membered heterocycloalkyl), -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)C(O)C 1-6 Alkyl, -OC(O)-NR 2-1 R 2-2 -NR 2-1 C(O)-OR 2-2 -NH-S(O)2-R 2-2 -N(R) 2-1 )C(O)-C 1-6 Alkylene-R 2-2 -NR 2-1 C(O)NR 2-1 -R 2-2 -N(C 1-6 Alkyl)C(O)C 3-12 cycloalkyl, -N(C) 1-6 Alkyl)C(O) (4 to 12-membered heterocyclic alkyl), -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 Alkyl)C(O) (4 to 12-membered heterocyclic alkyl), or -C(O)-R 2-2 The C mentioned 1-6 Alkyl, C 3-12 The cycloalkyl group and the 4- to 12-membered heterocycloalkyl group are each optionally separated by one or more elements selected from halogen, -OH, -O-NH-CH3, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Alkyl substituents;

[0034] R 3 Hydrogen, deuterium, -C 1-6 Alkyl group, -CH2-NHC 1-6 Alkyl group, -CH2-NHC(O)C 1-6 Alkyl group, -CH2-OC(O)-NR 3-1 R 3 -2 -CH2-NR 3-1 C(O)-OR 3-2 -CH2-NR3-1 C(O)NR 3-1 -R 3-2 -CH2-NHC(O)C 3-12 Cycloalkyl, -CH2-NHC(O) (4 to 12-membered heterocyclic alkyl groups), -CH2-N(C 1-6 Alkyl)2、-CH2-N(C 1-6 Alkyl)C(O)C 1-6 Alkyl group, -CH2-N(C) 1-6 Alkyl)C(O)C 3-12 cycloalkyl, -CH2-N(C 1-6 Alkyl)C(O) (4 to 12-membered heterocyclic alkyl), -CH2-N(C 1-6 Alkyl)C(O)C 1-6 Alkyl, -CH2-N(R) 3-1 )C(O)-C 1-6 Alkylene-R 3-2 -CH2-N(C 1-6 Alkyl)C(O)C 3-12 cycloalkyl, -CH2-N(C 1-6 Alkyl)C(O) (4 to 12-membered heterocyclic alkyl) or -C(O)-R 3-2 The C mentioned 1-6 Alkyl, C 3-12 The cycloalkyl group and the 4- to 12-membered heterocycloalkyl group are each optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -O-NH-CH3, -NHC 1-6 Alkyl and -SC 1-6 Alkyl substituents;

[0035] R 4 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), wherein the C 1-6 Alkyl, C 3-12 The cycloalkyl group and the 4- to 12-membered heterocycloalkyl group are each optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents;

[0036] Or R 3 With R 4 Together with the atoms attached thereto, they form 5-12 membered heterocyclic alkyl groups; each of the 5-12 membered heterocyclic alkyl groups is optionally bonded by one or more groups selected from halogen, oxo group, -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 Substituents of cyclohexene alkyl-OH and -C(O)-(4 to 12-membered heterocyclohexene alkyl)-OH;

[0037] R 1-1 R 2-1 R 3-1 Each is independently hydrogen, deuterium, and C. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0038] 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 heterocyclic alkyl; the C 1-6 Alkyl, C 3-12 The cycloalkyl group and the 4- to 12-membered heterocycloalkyl group are each optionally selected independently from one or more halogens, -OH, -SH, -NH2, -O-NH-CH3, -NHC 1-6 Alkyl and -SC 1-6 Alkyl substituents;

[0039] Y is either -OH or -CN;

[0040] And the following conditions are met:

[0041] (1) When R 1 -OH or -OC 1-6 Alkyl, R 11 When it is -OCH3, R 2 R 3 and R 4 They are not both hydrogen;

[0042] (2) When R 1 -OH, R 11 -OCH3, R 2 and R 3 When it is hydrogen, R 4 Not methyl; and

[0043] (3) When R 1 -OH, R 11 -CH3, R 2 and R 4 When it is hydrogen, R 3 It is not ethyl.

[0044] In some embodiments, the compound represented by formula (IA) is the same as the compound represented by formula (I):

[0045]

[0046] in,

[0047] R 1 and R 11 Independently hydrogen, deuterium, halogen, -OH, -CN, -NH2, C 1-6 Alkyl, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -C 1-6 Alkylene-N(R) 1-1 )-C(O)R 1-2 -OC 3-12 Cycloalkyl, -O-(4 to 12-membered heterocyclic alkylene)-C(O)R 1-2 -OC 3-12 Cycloalkyl-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 heterocyclic alkylene)-C(O)R 1-2 -N(R) 1-1 )-C 3-12 Cycloalkyl-N(R) 1-3 )-C(O)R 1-2 -(4 to 12-membered heterocyclic alkylene)-C(O)R 1-2 -(4 to 12-membered heterocyclic alkylene)-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 heterocyclic alkyl), wherein the C 1-6 Alkyl, C 1-6 Alkylene, C 3-12 cycloalkyl, C 3-12 Cycloalkylene, 4- to 12-membered heterocycloalkylene, and 4- to 12-membered heterocycloalkyl are each optionally separated by one or more elements 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 1-6Substitution of alkylene-NH2;

[0048] Or, R 1 With R 11 Together with their respective attached atoms, they are conceived as 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl; each of the cycloalkyl or heterocycloalkyl is optionally bonded by one or more atoms selected from halogens, -C 1-6 Alkyl substituents;

[0049] R 1-1 For hydrogen, deuterium, C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0050] R 1-2 C 1-6 Alkyl, C 3-12 Cycloalkyl or 4- to 12-membered heterocyclic alkyl; the C 1-6 Alkyl, C 3-12 The cycloalkyl group and the 4- to 12-membered heterocycloalkyl group are each optionally selected independently from one or more halogens, -OH, -SH, -NH2, -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents;

[0051] R 2 Hydrogen, deuterium, halogen, -C 1-6 Alkyl, -OH, -NH2, -NHC 1-6 Alkyl group, -NHC(O)C 1-6 Alkyl group, -NHC(O)C 3-12 Cycloalkyl, -NHC(O) (4 to 12-membered heterocycloalkyl), -N(C 1-6 Alkyl)2, -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 Alkyl)C(O) (4 to 12-membered heterocyclic alkyl), -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 heterocyclic alkyl), wherein the C 1-6 Alkyl, C 3-12 The cycloalkyl group and the 4- to 12-membered heterocycloalkyl group are each optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents;

[0052] R 3 Hydrogen, deuterium, -C 1-6 Alkyl group, -CH2-NHC 1-6 Alkyl group, -CH2-NHC(O)C 1-6 Alkyl group, -CH2-NHC(O)C 3-12 Cycloalkyl, -CH2-NHC(O) (4 to 12-membered heterocyclic alkyl groups), -CH2-N(C 1-6 Alkyl)2、-CH2-N(C 1-6 Alkyl)C(O)C 1-6 Alkyl group, -CH2-N(C) 1-6 Alkyl)C(O)C 3-12 cycloalkyl, -CH2-N(C 1-6 Alkyl)C(O) (4 to 12-membered heterocyclic alkyl), -CH2-N(C 1-6 Alkyl)C(O)C 1-6 Alkyl group, -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 heterocyclic alkyl), wherein the C 1-6 Alkyl, C 3-12 The cycloalkyl group and the 4- to 12-membered heterocycloalkyl group are each optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents;

[0053] R 4 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), wherein the C 1-6 Alkyl, C 3-12 The cycloalkyl group and the 4- to 12-membered heterocycloalkyl group are each optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents;

[0054] Or R 3 With R 4 Together with the atoms attached thereto, they form 5-12 membered heterocyclic alkyl groups; each of the 5-12 membered heterocyclic alkyl groups is optionally bonded by one or more groups selected from halogen, oxo group, -OH, -CN, -NH2, -NHC. 1-6 Alkyl, -N(C) 1-6 Alkyl)2, -C 1-6 Alkyl, -C1-6 Alkylene -OH, -C(O)C 1-6 Alkylene -OH, -C(O)-C 3-12 Substituents of cyclohexene alkyl-OH and -C(O)-(4 to 12-membered heterocyclohexene alkyl)-OH;

[0055] Y is either -OH or -CN;

[0056] And the following conditions are met:

[0057] (1) When R 1 -OH or -OC 1-6 Alkyl, R 11 When it is -OCH3, R 2 R 3 and R 4 They are not both hydrogen;

[0058] (2) When R 1 -OH, R 11 -OCH3, R 2 and R 3 When it is hydrogen, R 4 Not methyl; and

[0059] (3) When R 1 -OH, R 11 -CH3, R 2 and R 4 When it is hydrogen, R 3 It is not ethyl.

[0060] In some embodiments, certain groups in the compound of formula (I), or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite, or prodrug, are defined as follows, and groups not mentioned are as described in any embodiment of this application (hereinafter referred to as "in some embodiments").

[0061] In some embodiments, the compound shown in formula (I) is the same as the compound shown in formula (II):

[0062]

[0063] in,

[0064] R 1 Hydrogen, deuterium, halogen, -OH, -CN, -NH2, C 1-6 Alkyl, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -C 1-6 Alkylene-N(R) 1-1 )-C(O)R 1-2 -OC3-12 Cycloalkyl, -O-(4 to 12-membered heterocyclic alkylene)-C(O)R 1-2 -OC 3-12 Cycloalkyl-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 heterocyclic alkylene)-C(O)R 1-2 -N(R) 1-1 )-C 3-12 Cycloalkyl-N(R) 1-3 )-C(O)R 1-2 -(4 to 12-membered heterocyclic alkylene)-C(O)R 1-2 -(4 to 12-membered heterocyclic alkylene)-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 heterocyclic alkyl), wherein the C 1-6 Alkyl, C 1-6 Alkylene, C 3-12 cycloalkyl, C 3-12 Cycloalkylene, 4- to 12-membered heterocycloalkylene, and 4- to 12-membered heterocycloalkyl are each optionally separated by one or more elements 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 Substitution of alkylene-NH2;

[0065] R 1-1 For hydrogen, deuterium, C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0066] R 1-2 C 1-6 Alkyl, C 3-12 Cycloalkyl or 4- to 12-membered heterocyclic alkyl; the C 1-6 Alkyl, C 3-12 The cycloalkyl group and the 4- to 12-membered heterocycloalkyl group are each optionally selected independently from one or more halogens, -OH, -SH, -NH2, -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents;

[0067] R 2 Hydrogen, deuterium, halogen, -C 1-6 Alkyl, -OH, -NH2, -NHC 1-6 Alkyl group, -NHC(O)C 1-6 Alkyl group, -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 heterocyclic alkyl), wherein the C 1-6 Alkyl, C 3-12 The cycloalkyl group and the 4- to 12-membered heterocycloalkyl group are each optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents;

[0068] R 3 For hydrogen, deuterium, C 1-6 Alkyl group, -CH2-NHC 1-6 Alkyl group, -CH2-NHC(O)C 1-6 Alkyl group, -CH2-NHC(O)C 3-12 Cycloalkyl, -CH2-NHC(O) (4 to 12-membered heterocyclic alkyl groups), -CH2-N(C 1-6 Alkyl)C(O)C 1-6 Alkyl group, -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 heterocyclic alkyl), wherein the C 1-6 Alkyl, C 3-12 The cycloalkyl group and the 4- to 12-membered heterocycloalkyl group are each optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents;

[0069] 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), wherein the C 1-6 Alkyl, C 3-12The cycloalkyl group and the 4- to 12-membered heterocycloalkyl group are each optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents;

[0070] Or R 3 With R 4 Together with the atoms attached thereto, they form 5-12 membered heterocyclic alkyl groups; each of the 5-12 membered heterocyclic alkyl groups is optionally bonded by one or more groups selected from halogen, oxo group, -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 Substituents of cyclohexene alkyl-OH and -C(O)-(4 to 12-membered heterocyclohexene alkyl)-OH;

[0071] Y is either -OH or -CN;

[0072] And the following conditions are met:

[0073] When R 1 -OH or -OC 1-6 When alkyl, R 2 R 3 and R 4 They are not both hydrogen.

[0074] In some implementation schemes, at least one of the following conditions must be met:

[0075] (1)R 1 Hydrogen, deuterium, halogen, -CN, -NH2, C 1-6 Alkyl, -NHC 1-6 Alkyl, -NH-S(O)2-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 heterocyclic alkyl), -O- (4 to 12-membered heterocyclic alkylene)-C(O)R 1-2 -OC 3-12 Cycloalkyl-N(R) 1-1 )-C(O)R 1-2 -N(R) 1-1 )-C 3-12 cycloalkyl, -N(R) 1-1 )-C(O)R 1-2 -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 -N(R) 1-1 )-C(O)-N(R 1-1 )R 1-2 -N(R) 1-1 )-(4 to 12-membered heterocyclic alkylene)-C(O)R 1-2 -N(R) 1-1 )-C 3-12 Cycloalkyl-N(R) 1-3 )-C(O)R 1-2 -(4 to 12-membered heterocyclic alkylene)-C(O)R 1-2 -(4 to 12-membered heterocyclic alkylene)-N(R 1-1 )-C(O)R 1-2 -N(R) 1-1 )C(O)C 3-12 cycloalkyl, -N(R) 1-1 )C(O)-C 1-6 Alkylene-R 1-2 or -N(R) 1-1 )C(O)(4 to 12-membered heterocyclic alkyl), wherein the C 1-6 Alkyl, C 1-6 Alkylene, C 3-12 cycloalkyl, C 3-12 Cycloalkylene, 4- to 12-membered heterocycloalkylene, and 4- to 12-membered heterocycloalkyl are each optionally separated by one or more elements 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 Substitution of alkylene-NH2;

[0076] (2)R 11 Hydrogen, deuterium, halogen, -OH, -CN, -NH2, C 1-6 Alkyl, -NHC 1-6 Alkyl, -NH-S(O)2-R 1-2 -C 1-6 Alkylene-N(R) 1-1 )-C(O)R 1-2 -OC 3-12Cycloalkyl, -O- (4 to 12-membered heterocyclic alkyl), -O- (4 to 12-membered heterocyclic alkylene)-C(O)R 1-2 -OC 3-12 Cycloalkyl-N(R) 1-1 )-C(O)R 1-2 、N(R 1-1 )-C 3-12 cycloalkyl, -N(R) 1-1 )-C(O)R 1-2 -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 -N(R) 1-1 )-C(O)-N(R 1-1 )R 1-2 -N(R) 1 -1 )-(4 to 12-membered heterocyclic alkylene)-C(O)R 1-2 -N(R) 1-1 )-C 3-12 Cycloalkyl-N(R) 1-3 )-C(O)R 1-2 -(4 to 12-membered heterocyclic alkylene)-C(O)R 1-2 -(4 to 12-membered heterocyclic alkylene)-N(R 1-1 )-C(O)R 1-2 -N(R) 1-1 )C(O)C 3-12 cycloalkyl, -N(R) 1-1 )C(O)-C 1-6 Alkylene-R 1-2 or -N(R) 1-1 )C(O)(4 to 12-membered heterocyclic alkyl), wherein the C 1-6 Alkyl, C 1-6 Alkylene, C 3-12 cycloalkyl, C 3-12 Cycloalkylene, 4- to 12-membered heterocycloalkylene, and 4- to 12-membered heterocycloalkyl are each optionally separated by one or more elements 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 Substitution of alkylene-NH2;

[0077] (3)R 1 With R 11 Together with their respective attached atoms, they are conceived as 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl; each of the cycloalkyl or heterocycloalkyl is optionally bonded by one or more atoms selected from halogens, -C 1-6 Alkyl substituents;

[0078] (4)R 2 For deuterium, halogen, -C 1-6 Alkyl, -OH, -NH2, -NHC 1-6 Alkyl group, -NHC(O)C 1-6 Alkyl group, -NHC(O)C 3-12 Cycloalkyl, -NHC(O) (4 to 12-membered heterocycloalkyl), -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)C(O)C 1-6 Alkyl, -OC(O)-NR 2-1 R 2-2 -NR 2-1 C(O)-OR 2-2 -NH-S(O)2-R 2-2 -N(R) 2-1 )C(O)-C 1-6 Alkylene-R 2-2 -NR 2-1 C(O)NR 2-1 -R 2-2 -N(C 1-6 Alkyl)C(O)C 3-12 cycloalkyl, -N(C) 1-6 Alkyl)C(O) (4 to 12-membered heterocyclic alkyl), -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 Alkyl)C(O) (4 to 12-membered heterocyclic alkyl), -C(O)-R 2-2 or C(O)-N(R) 1-1 )R 1-2 The C mentioned 1-6 Alkyl, C 3-12 The cycloalkyl group and the 4- to 12-membered heterocycloalkyl group are each optionally separated by one or more elements selected from halogen, -OH, -O-NH-CH3, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Alkyl substituents;

[0079] (5)R 3 -C 1-6Alkyl, -NHC 1-6 Alkyl group, -CH2-NHC 1-6 Alkyl group, -CH2-NHC(O)C 1-6 Alkyl group, -CH2-OC(O)-NR 3-1 R 3-2 -CH2-NR 3-1 C(O)-OR 3-2 -CH2-NR 3-1 C(O)NR 3-1 -R 3-2 -CH2-NHC(O)C 3-12 Cycloalkyl, -CH2-NHC(O) (4 to 12-membered heterocyclic alkyl groups), -CH2-N(C 1-6 Alkyl)2、-CH2-N(C 1-6 Alkyl)C(O)C 1-6 Alkyl group, -CH2-N(C) 1-6 Alkyl)C(O)C 3-12 cycloalkyl, -CH2-N(C 1-6 Alkyl)C(O) (4 to 12-membered heterocyclic alkyl), -CH2-N(C 1-6 Alkyl)C(O)C 1-6 Alkyl, -CH2-N(R) 3-1 )C(O)-C 1-6 Alkylene-R 3-2 -CH2-N(C 1-6 Alkyl)C(O)C 3-12 cycloalkyl, -CH2-N(C 1-6 Alkyl)C(O) (4 to 12-membered heterocyclic alkyl) or -C(O)-R 3-2 The C mentioned 1-6 Alkyl, C 3-12 The cycloalkyl group and the 4- to 12-membered heterocycloalkyl group are each optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -O-NH-CH3, -NHC 1-6 Alkyl and -SC 1-6 Alkyl substituents;

[0080] Preferably, R 3 -NHC 1-6 Alkyl group, -CH2-NHC 1-6 Alkyl group, -CH2-NHC(O)C 1-6 Alkyl group, -CH2-OC(O)-NR 3 -1 R 3-2 -CH2-NR 3-1 C(O)-OR 3-2 -CH2-NR 3-1C(O)NR 3-1 -R 3-2 -CH2-NHC(O)C 3-12 Cycloalkyl, -CH2-NHC(O) (4 to 12-membered heterocyclic alkyl groups), -CH2-N(C 1-6 Alkyl)2、-CH2-N(C 1-6 Alkyl)C(O)C 1-6 Alkyl group, -CH2-N(C) 1-6 Alkyl)C(O)C 3-12 cycloalkyl, -CH2-N(C 1-6 Alkyl)C(O) (4 to 12-membered heterocyclic alkyl), -CH2-N(C 1-6 Alkyl)C(O)C 1-6 Alkyl, -CH2-N(R) 3-1 )C(O)-C 1-6 Alkylene-R 3-2 -CH2-N(C 1-6 Alkyl)C(O)C 3-12 cycloalkyl, -CH2-N(C 1-6 Alkyl)C(O) (4 to 12-membered heterocyclic alkyl) or -C(O)-R 3-2 The C mentioned 1-6 Alkyl, C 3-12 The cycloalkyl group and the 4- to 12-membered heterocycloalkyl group are each optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -O-NH-CH3, -NHC 1-6 Alkyl and -SC 1-6 Alkyl substituents;

[0081] (6)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), wherein the C 1-6 Alkyl, C 3-12 The cycloalkyl group and the 4- to 12-membered heterocycloalkyl group are each optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents; for example, -C(O)C 1-6 Alkyl, -C(O)C 3-12 Cycloalkyl or -C(O) (4 to 12-membered heterocycloalkyl), wherein the C 1-6 Alkyl, C 3-12 The cycloalkyl group and the 4- to 12-membered heterocycloalkyl group are each optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -NHC. 1-6 Alkyl and -SC1-6 Alkyl substituents;

[0082] (7)R 3 With R 4 Together with the atoms attached thereto, they form 5-12 membered heterocyclic alkyl groups; each of the 5-12 membered heterocyclic alkyl groups is optionally bonded by one or more groups selected from halogen, oxo group, -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 Substituents of cyclohexene alkyl-OH and -C(O)-(4 to 12-membered heterocyclohexene alkyl)-OH;

[0083] (8)Q 1 For N; and

[0084] (9)Q 2 Let N be the number of elements in the array.

[0085] In some embodiments, the compound represented by formula (I) satisfies at least one of the following conditions:

[0086] (1)R 1 Hydrogen, deuterium, halogen, -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 heterocyclic alkylene)-C(O)R 1-2 -OC 3-12 Cycloalkyl-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 heterocyclic alkylene)-C(O)R 1-2 -N(R) 1-1 )-C 3-12 Cycloalkyl-N(R) 1-3 )-C(O)R 1 -2 -(4 to 12-membered heterocyclic alkylene)-C(O)R 1-2 -(4 to 12-membered heterocyclic alkylene)-N(R 1-1 )-C(O)R 1-2 -N(R) 1-1 )C(O)C3-12 cycloalkyl or -N(R) 1-1 )C(O)(4 to 12-membered heterocyclic alkyl), wherein the C 1-6 Alkyl, C 1-6 Alkylene, C 3-12 cycloalkyl, C 3-12 Cycloalkylene, 4- to 12-membered heterocycloalkylene, and 4- to 12-membered heterocycloalkyl are each optionally separated by one or more elements 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 Substitution of alkylene-NH2;

[0087] (2)R 2 For deuterium, halogens, C 1-6 Alkyl, -OH, -NH2, -NHC 1-6 Alkyl group, -NHC(O)C 1-6 Alkyl group, -NHC(O)C 3-12 Cycloalkyl, -NHC(O) (4 to 12-membered heterocycloalkyl), -N(C 1-6 Alkyl)2, -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 Alkyl)C(O) (4 to 12-membered heterocyclic alkyl), -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 heterocyclic alkyl), wherein the C 1-6 Alkyl, C 3-12 The cycloalkyl group and the 4- to 12-membered heterocycloalkyl group are each optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents;

[0088] (3)R 3 -CH2-NHC 1-6 Alkyl group, -CH2-NHC(O)C 1-6 Alkyl group, -CH2-NHC(O)C 3-12Cycloalkyl, -CH2-NHC(O) (4 to 12-membered heterocyclic alkyl groups), -CH2-N(C 1-6 Alkyl)2、-CH2-N(C 1-6 Alkyl)C(O)C 1-6 Alkyl group, -CH2-N(C) 1-6 Alkyl)C(O)C 3-12 cycloalkyl, -CH2-N(C 1-6 Alkyl)C(O) (4 to 12-membered heterocyclic alkyl), -CH2-N(C 1-6 Alkyl)C(O)C 1-6 Alkyl group, -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 heterocyclic alkyl), wherein the C 1-6 Alkyl, C 3-12 The cycloalkyl group and the 4- to 12-membered heterocycloalkyl group are each optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents;

[0089] (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), wherein the C 1-6 Alkyl, C 3-12 The cycloalkyl group and the 4- to 12-membered heterocycloalkyl group are each optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents; for example, -C(O)C 1-6 Alkyl, -C(O)C 3-12 Cycloalkyl or -C(O) (4 to 12-membered heterocycloalkyl), wherein the C 1-6 Alkyl, C 3-12 The cycloalkyl group and the 4- to 12-membered heterocycloalkyl group are each optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents; and

[0090] (5)R 3 With R 4 Together with the atoms attached thereto, they form 5-12 membered heterocyclic alkyl groups; each of the 5-12 membered heterocyclic alkyl groups is optionally bonded by one or more groups selected from halogen, oxo group, -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 Substituents of cyclohexene alkyl-OH and -C(O)-(4 to 12-membered heterocyclohexene alkyl)-OH;

[0091] (6)R 11 Hydrogen, deuterium, halogen, -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 heterocyclic alkylene)-C(O)R 1-2 -OC 3-12 Cycloalkyl-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 heterocyclic alkylene)-C(O)R 1-2 -N(R) 1-1 )-C 3-12 Cycloalkyl-N(R) 1-3 )-C(O)R 1-2 -(4 to 12-membered heterocyclic alkylene)-C(O)R 1-2 -(4 to 12-membered heterocyclic alkylene)-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 heterocyclic alkyl), wherein the C 1-6 Alkyl, C 1-6 Alkylene, C 3-12 cycloalkyl, C 3-12 Cycloalkylene, 4- to 12-membered heterocycloalkylene, and 4- to 12-membered heterocycloalkyl are each optionally separated by one or more elements 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 1-6Substituents of alkylene-NH2.

[0092] In some embodiments, the compounds shown in formula (I) and formula (II) satisfy at least one of the following conditions:

[0093] (1)R 1 Hydrogen, deuterium, halogen, -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 heterocyclic alkylene)-C(O)R 1-2 -OC 3-12 Cycloalkyl-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 heterocyclic alkylene)-C(O)R 1-2 -N(R) 1-1 )-C 3-12 Cycloalkyl-N(R) 1-3 )-C(O)R 1 -2 -(4 to 12-membered heterocyclic alkylene)-C(O)R 1-2 -(4 to 12-membered heterocyclic alkylene)-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 heterocyclic alkyl), wherein the C 1-6 Alkyl, C 1-6 Alkylene, C 3-12 cycloalkyl, C 3-12 Cycloalkylene, 4- to 12-membered heterocycloalkylene, and 4- to 12-membered heterocycloalkyl are each optionally separated by one or more elements 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 Substitution of alkylene-NH2;

[0094] (2)R 2 For deuterium, halogens, C 1-6Alkyl, -OH, -NH2, -NHC 1-6 Alkyl group, -NHC(O)C 1-6 Alkyl group, -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 heterocyclic alkyl), wherein the C 1-6 Alkyl, C 3-12 The cycloalkyl group and the 4- to 12-membered heterocycloalkyl group are each optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents;

[0095] (3)R 3 -CH2-NHC 1-6 Alkyl group, -CH2-NHC(O)C 1-6 Alkyl group, -CH2-NHC(O)C 3-12 Cycloalkyl, -CH2-NHC(O) (4 to 12-membered heterocyclic alkyl groups), -CH2-N(C 1-6 Alkyl)C(O)C 1-6 Alkyl group, -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 heterocyclic alkyl), wherein the C 1-6 Alkyl, C 3-12 The cycloalkyl group and the 4- to 12-membered heterocycloalkyl group are each optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents;

[0096] (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), wherein the C 1-6 Alkyl, C 3-12 The cycloalkyl group and the 4- to 12-membered heterocycloalkyl group are each optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents; and

[0097] (5)R 3 With R 4 Together with the atoms attached thereto, they form 5-12 membered heterocyclic alkyl groups; each of the 5-12 membered heterocyclic alkyl groups is optionally bonded by one or more groups selected from halogen, oxo group, -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 Substituents of cycloalkyl-OH and -C(O)-(4 to 12-membered heteroalkyl-OH)-OH.

[0098] In some embodiments, the compound shown is not one of the following:

[0099]

[0100]

[0101] In some embodiments, the compound shown is not one of the following:

[0102]

[0103] In some implementations, in equation (I), when R 1 -OH, R 11 -OCH3, R 2 and R 3 When it is hydrogen, R 4 Not C 1-6 alkyl.

[0104] In some implementations, in equation (II), when R 1 -OH, R 2 and R 3 When it is hydrogen, R 4 Not C 1-6 alkyl.

[0105] In some implementations, in equation (I), when R 1 -OH, R 11 -CH3, R 2 and R 4 When it is hydrogen, R 3 Not C 1-6 alkyl.

[0106] In some implementations, when R 1 For -OH, R 2 R 3 and R4 When it is hydrogen, R 11 It is not -OCH2CH2NH2, -OCH2CH2NHCH3, -CH2N(CH3)-C(O)-CH(OH)CH3, or -CH2N(CH3)-C(O)-CH2(OH).

[0107] In some implementations, when R 1 For -OH, R 2 R 3 and R 4 When it is hydrogen, R 11 Not for -OC 1-6 Alkyl, -C 1-6 Alkylene-N(R) 1-1 )-C(O)R 1-2 Among them, C 1-6 Alkyl groups are substituted with -NH2, -NHC 1-6 Alkyl substitution, R 1-1 H or CH3, R 1-2 C 1-6 Alkyl, the C 1-6 The alkyl group is replaced by a substituent -OH.

[0108] In some embodiments, the number of heteroatoms in the 4- to 12-membered heterocyclic alkyl group and the 4- to 12-membered heterocyclic alkyl group is one or more, and each heteroatom is independently selected from N, O, and S; preferably, the 4- to 12-membered heterocyclic alkyl group and the 4- to 12-membered heterocyclic alkyl group are 4- to 6-membered heterocyclic alkyl groups and 4- to 6-membered heterocyclic alkyl groups; the number of heteroatoms is one or two, and the heteroatoms are independently selected from N; for example, N-heterocyclic butyl. Piperidinyl Piperazine Or its divalent group.

[0109] In some embodiments, the general formula (IA) is a compound as shown in the following formula:

[0110]

[0111] in,

[0112] Q 1 For N or CH;

[0113] Q 2 For N or CR 11 ;

[0114] R 1 -NHC 1-6 Alkyl, -NH-S(O)2-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 heterocyclic alkyl), -O- (4 to 12-membered heterocyclic alkylene)-C(O)R 1-2 -OC 3-12 Cycloalkyl-N(R) 1-1 )-C(O)R 1-2 -N(R) 1-1 )-C 3-12 cycloalkyl, -N(R) 1-1 )-C(O)R 1-2 -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 -N(R) 1-1 )-C(O)-N(R 1-1 )R 1-2 -N(R) 1-1 )-(4 to 12-membered heterocyclic alkylene)-C(O)R 1-2 -N(R) 1-1 )-C 3-12 Cycloalkyl-N(R) 1-3 )-C(O)R 1-2 -(4 to 12-membered heterocyclic alkylene)-C(O)R 1-2 -(4 to 12-membered heterocyclic alkylene)-N(R 1-1 )-C(O)R 1-2 -N(R) 1-1 )C(O)C 3-12 cycloalkyl, -N(R) 1-1 )C(O)-C 1-6 Alkylene-R 1-2 or -N(R) 1 -1 )C(O)(4 to 12-membered heterocyclic alkyl), wherein the C 1-6 Alkyl, C 1-6 Alkylene, C 3-12 cycloalkyl, C 3-12 Cycloalkylene, 4- to 12-membered heterocycloalkylene, and 4- to 12-membered heterocycloalkyl are each optionally separated by one or more elements 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(C1-6 alkyl) and -C 1-6 Substitution of alkylene-NH2;

[0115] R 11 Hydrogen, deuterium, halogen, -OH, -CN, -NH2, C 1-6 Alkyl, -OC 1-6 Alkyl, -NHC 1-6 alkyl;

[0116] R 1 With R 11 Together with their respective attached atoms, they are conceived as 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl; each of the cycloalkyl or heterocycloalkyl is optionally bonded by one or more atoms selected from halogens, -C 1-6 Alkyl substituents;

[0117] R 4 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), wherein the C 1-6 Alkyl, C 3-12 The cycloalkyl group and the 4- to 12-membered heterocycloalkyl group are each optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents.

[0118] In some embodiments, the general formula (IA) is a compound as shown in the following formula:

[0119]

[0120] in,

[0121] Q 1 For N or CH;

[0122] R 1 Hydrogen, deuterium, halogen, -OH, -CN, -NH2, C 1-6 Alkyl, -OC 1-6 Alkyl, -NHC 1-6 alkyl;

[0123] R 11 Independently for -NHC 1-6 Alkyl, -NH-S(O)2-R 1-2 -C 1-6 Alkylene-N(R) 1-1 )-C(O)R 1-2 -OC 3-12Cycloalkyl, -O- (4 to 12-membered heterocyclic alkyl), -O- (4 to 12-membered heterocyclic alkylene)-C(O)R 1-2 -OC 3-12 Cycloalkyl-N(R) 1-1 )-C(O)R 1-2 -N(R) 1-1 )-C 3-12 cycloalkyl, -N(R) 1-1 )-C(O)R 1-2 -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 -N(R) 1-1 )-C(O)-N(R 1-1 )R 1-2 -N(R) 1-1 )-(4 to 12-membered heterocyclic alkylene)-C(O)R 1-2 -N(R) 1-1 )-C 3-12 Cycloalkyl-N(R) 1-3 )-C(O)R 1-2 -(4 to 12-membered heterocyclic alkylene)-C(O)R 1-2 -(4 to 12-membered heterocyclic alkylene)-N(R 1-1 )-C(O)R 1-2 -N(R) 1-1 )C(O)C 3-12 cycloalkyl, -N(R) 1-1 )C(O)-C 1-6 Alkylene-R 1-2 or -N(R) 1-1 )C(O)(4 to 12-membered heterocyclic alkyl), wherein the C 1-6 Alkyl, C 1-6 Alkylene, C 3-12 cycloalkyl, C 3-12 Cycloalkylene, 4- to 12-membered heterocycloalkylene, and 4- to 12-membered heterocycloalkyl are each optionally separated by one or more elements 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 Substitution of alkylene-NH2;

[0124] R 4 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), wherein the C 1-6 Alkyl, C 3-12 The cycloalkyl group and the 4- to 12-membered heterocycloalkyl group are each optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents.

[0125] In some embodiments, the general formula (IA) is a compound as shown in the following formula:

[0126]

[0127] in,

[0128] Q 1 For N or CH;

[0129] Q 2 For N or CR 11 ;

[0130] R 1 Hydrogen, deuterium, halogen, -OH, -CN, -NH2, C 1-6 Alkyl, -OC 1-6 Alkyl, -NHC 1-6 alkyl;

[0131] R 11 Hydrogen, deuterium, halogen, -OH, -CN, -NH2, C 1-6 Alkyl, -OC 1-6 Alkyl, -NHC 1-6 alkyl;

[0132] R 1 With R 11 Together with their respective attached atoms, they are conceived as 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl; each of the cycloalkyl or heterocycloalkyl is optionally bonded by one or more atoms selected from halogens, -C 1-6 Alkyl substituents;

[0133] R 2 Halogen, -C 1-6 Alkyl, -OH, -NH2, -NHC 1-6 Alkyl group, -NHC(O)C 1-6 Alkyl group, -NHC(O)C 3-12 Cycloalkyl, -NHC(O) (4 to 12-membered heterocycloalkyl), -N(C 1-6Alkyl)2, -N(C 1-6 Alkyl)C(O)C 1-6 Alkyl, -OC(O)-NR 2-1 R 2 -2 -NR 2-1 C(O)-OR 2-2 -NH-S(O)2-R 2-2 -N(R) 2-1 )C(O)-C 1-6 Alkylene-R 2-2 -NR 2-1 C(O)NR 2-1 -R 2-2 -N(C 1-6 Alkyl)C(O)C 3-12 cycloalkyl, -N(C) 1-6 Alkyl)C(O) (4 to 12-membered heterocyclic alkyl), -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 Alkyl)C(O) (4 to 12-membered heterocyclic alkyl), -C(O)-R 2-2 or C(O)-NR 2-1 R 2-2 The C mentioned 1-6 Alkyl, C 3-12 The cycloalkyl group and the 4- to 12-membered heterocycloalkyl group are each optionally separated by one or more elements selected from halogen, -OH, -O-NH-CH3, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Alkyl substituents;

[0134] R 4 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), wherein the C 1-6 Alkyl, C 3-12 The cycloalkyl group and the 4- to 12-membered heterocycloalkyl group are each optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents.

[0135] In some embodiments, the general formula (IA) is a compound as shown in the following formula:

[0136]

[0137] in,

[0138] Q 1 For N or CH;

[0139] Q 2 For N or CR 11 ;

[0140] R 1 Hydrogen, deuterium, halogen, -OH, -CN, -NH2, C 1-6 Alkyl, -OC 1-6 Alkyl, -NHC 1-6 alkyl;

[0141] R 11 Hydrogen, deuterium, halogen, -OH, -CN, -NH2, C 1-6 Alkyl, -OC 1-6 Alkyl, -NHC 1-6 alkyl;

[0142] R 1 With R 11 Together with their respective attached atoms, they are conceived as 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl; each of the cycloalkyl or heterocycloalkyl is optionally bonded by one or more atoms selected from halogens, -C 1-6 Alkyl substituents;

[0143] R 3 -C 1-6 Alkyl, -NHC 1-6 Alkyl group, -CH2-NHC 1-6 Alkyl group, -CH2-NHC(O)C 1-6 Alkyl group, -CH2-OC(O)-NR 3-1 R 3-2 -CH2-NR 3-1 C(O)-OR 3-2 -CH2-NR 3-1 C(O)NR 3-1 -R 3-2 -CH2-NHC(O)C 3-12 Cycloalkyl, -CH2-NHC(O) (4 to 12-membered heterocyclic alkyl groups), -CH2-N(C 1-6 Alkyl)2、-CH2-N(C 1-6 Alkyl)C(O)C 1-6 Alkyl group, -CH2-N(C) 1-6 Alkyl)C(O)C 3-12 cycloalkyl, -CH2-N(C 1-6 Alkyl)C(O) (4 to 12-membered heterocyclic alkyl), -CH2-N(C 1-6 Alkyl)C(O)C1-6 Alkyl, -CH2-N(R) 3-1 )C(O)-C 1-6 Alkylene-R 3-2 -CH2-N(C 1-6 Alkyl)C(O)C 3-12 cycloalkyl, -CH2-N(C 1-6 Alkyl)C(O) (4 to 12-membered heterocyclic alkyl) or -C(O)-R 3-2 The C mentioned 1-6 Alkyl, C 3-12 The cycloalkyl group and the 4- to 12-membered heterocycloalkyl group are each optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -O-NH-CH3, -NHC 1-6 Alkyl and -SC 1-6 Alkyl substituents;

[0144] R 4 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), wherein the C 1-6 Alkyl, C 3-12 The cycloalkyl group and the 4- to 12-membered heterocycloalkyl group are each optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents;

[0145] Or R 3 With R 4 Together with the atoms attached thereto, they form 5-12 membered heterocyclic alkyl groups; each of the 5-12 membered heterocyclic alkyl groups is optionally bonded by one or more groups selected from halogen, oxo group, -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 Substituents of cycloalkyl-OH and -C(O)-(4 to 12-membered heteroalkyl-OH)-OH.

[0146] In some embodiments, the compounds represented by formula (IA) and general formula (I) are compounds with the structure shown in formula (Ia):

[0147]

[0148] in,

[0149] R 1 and R 11 Independently 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;

[0150] Or, R 1 With R 11 Together with their respective attached atoms, they are conceived as 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl; each of the cycloalkyl or heterocycloalkyl is optionally bonded by one or more atoms selected from halogens, -C 1-6 Alkyl substituents;

[0151] R 2 Hydrogen, deuterium, halogens, C 1-6 Alkyl, -OH, -NH2, -NHC 1-6 Alkyl group, -NHC(O)C 1-6 Alkyl group, -NHC(O)C 3-12 Cycloalkyl, -NHC(O) (4 to 12-membered heterocycloalkyl), -N(C 1-6 Alkyl)2, -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 Alkyl)C(O) (4 to 12-membered heterocyclic alkyl), -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 heterocyclic alkyl), wherein the C 1-6 Alkyl, C 3-12 The cycloalkyl group or 4- to 12-membered heterocycloalkyl group is optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents;

[0152] R 3 For H or -CH2-NR 3a R 3b ;

[0153] R3a It is hydrogen or C 1-6 Alkyl; the C 1-6 The alkyl group is optionally surrounded by one or more elements selected from halogens, -OH, -SH, -NH2, and -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents;

[0154] R 3b For hydrogen, C 1-6 Alkyl, -C(O)C 1-6 Alkyl, -C(O)C 3-12 Cycloalkyl or -C(O) (4 to 12-membered heterocycloalkyl), wherein the C 1-6 Alkyl, C 3-12 The cycloalkyl group or 4- to 12-membered heterocycloalkyl group is optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents;

[0155] R 4 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), wherein the C 1-6 Alkyl, C 3-12 The cycloalkyl group or 4- to 12-membered heterocycloalkyl group is optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents;

[0156] Or R 3 With R 4 Together with the atoms attached thereto, they form 5-12 membered heterocyclic alkyl groups; each of the 5-12 membered heterocyclic alkyl groups is optionally bonded by one or more groups selected from halogen, oxo group, -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 Substituents include -OH and -C(O)-(4 to 12-membered heterocyclic alkylene)-OH substituents;

[0157] Y is either -OH or -CN;

[0158] The premise is that R 2 and R 3 They cannot both be H.

[0159] In some embodiments, the compounds represented by formula (IA), general formula (I), formula (Ia), and formula (II) are compounds with the structure shown in formula (IIa):

[0160]

[0161] in,

[0162] R 1 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;

[0163] R 2 Hydrogen, deuterium, halogens, C 1-6 Alkyl, -OH, -NH2, -NHC 1-6 Alkyl group, -NHC(O)C 1-6 Alkyl group, -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 heterocyclic alkyl), wherein the C 1-6 Alkyl, C 3-12 The cycloalkyl group or 4- to 12-membered heterocycloalkyl group is optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents;

[0164] R 3 For H or -CH2-NR 3a R 3b ;

[0165] R 3a It is hydrogen or C 1-6 Alkyl; the C 1-6 The alkyl group is optionally surrounded by one or more elements selected from halogens, -OH, -SH, -NH2, and -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents;

[0166] R 3b For hydrogen, C 1-6 Alkyl, -C(O)C 1-6 Alkyl, -C(O)C 3-12 Cycloalkyl or -C(O) (4 to 12-membered heterocycloalkyl), wherein the C 1-6 Alkyl, C 3-12 The cycloalkyl group or 4- to 12-membered heterocycloalkyl group is optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents;

[0167] R 4 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), wherein the C 1-6 Alkyl, C 3-12 The cycloalkyl group or 4- to 12-membered heterocycloalkyl group is optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents;

[0168] Or R 3 With R 4 Together with the atoms attached thereto, they form 5-12 membered heterocyclic alkyl groups; each of the 5-12 membered heterocyclic alkyl groups is optionally bonded by one or more groups selected from halogen, oxo group, -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 Substituents include -OH and -C(O)-(4 to 12-membered heterocyclic alkylene)-OH substituents;

[0169] Y is either -OH or -CN;

[0170] The premise is that R 2 and R 3 They cannot both be H.

[0171] In some embodiments, compounds with the structures shown in formulas (IA), (IA-2), (IA-3), (IA-4), (I), (Ia), (II), and (IIa), wherein,

[0172] R 1It can be hydrogen, halogen, -OH, -CN, -NH2, -CH3, -OCH3 or -NHCH3.

[0173] In some embodiments, compounds with the structures shown in formulas (IA), (IA-2), (IA-3), (IA-4), (I), (Ia), (II), and (IIa), wherein,

[0174] R 1 It can be hydrogen, deuterium, -F, -Cl, -OH, -CH3, -OCH3, -NH2 or -NHCH3.

[0175] In some embodiments, compounds with the structures shown in formulas (IA), (IA-2), (IA-3), (IA-4), (I), (Ia), (II), and (IIa), wherein R 1 It can be H, -CH3, -OH or -OCH3; for example, H, -OH or -OCH3; or for example, -OH or -OCH3.

[0176] In some embodiments, compounds with the structures shown in formulas (IA), (IA-2), (IA-3), (IA-4), (I), (Ia), (II), and (IIa), wherein,

[0177] R 1 It can be hydrogen, halogen, -CN, -CH3, -OCH3 or -NHCH3; for example, H or -OCH3; and for example, -OCH3.

[0178] In some embodiments, compounds with the structures shown in formulas (IA), (IA-2), (IA-3), (IA-4), (I), (Ia), (II), and (IIa), wherein R 1 It is -OH.

[0179] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (IA-3), (IA-4), (I), and (Ia), wherein R 11 It can be hydrogen, halogen, -OH, -CN, -NH2, -CH3, -OCH3 or -NHCH3.

[0180] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (IA-3), (IA-4), (I), and (Ia), wherein R 11 It can be hydrogen, deuterium, -F, -Cl, -OH, -CH3, -OCH3, -NH2 or -NHCH3.

[0181] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (IA-3), (IA-4), (I), and (Ia), wherein R 11 It can be hydrogen, deuterium, or -OCH3.

[0182] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (IA-3), (IA-4), (I), and (Ia), R 1 With R 11 Connected, together with the linked carbons, form Side a is cyclically connected to the benzene ring shown.

[0183] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (IA-3), (IA-4), (I), and (Ia), wherein R 1 and R 11 Independently, it can be H, -OH, -CH3, -OCH3, or R. 1 With R 11 Connected, together with the linked carbons, form Side a is cyclically connected to the benzene ring shown.

[0184] In some embodiments, compounds with the structures shown in formula (IA), formula (IA-3), formula (I), and formula (Ia), wherein R 2 -OH, -NH2, -C 1-6 Alkyl, -NHC 1-6 Alkyl group, -NHC(O)C 1-6 Alkyl, -N(C) 1-6 Alkyl)2, -N(C 1-6 Alkyl)C(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 Each cycloalkyl group may optionally be substituted with one or more alkyl groups selected from -OH, -SH, -NH2, -NHCH3 and -SCH3.

[0185] In some embodiments, compounds with the structures shown in formulas (IA), (IA-3), (I), (Ia), (II), and (IIa), wherein R 2 -OH, -NH2, -C 1-6 Alkyl, -NHC 1-6 Alkyl group, -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 Each cycloalkyl group may optionally be substituted with one or more alkyl groups selected from -OH, -SH, -NH2, -NHCH3 and -SCH3.

[0186] In some embodiments, compounds with the structures shown in formulas (IA), (IA-3), (I), (Ia), (II), and (IIa), wherein R 2 -NH2, -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 may optionally be substituted by one or more substituents selected from -OH, -SH, -NH2, -NHCH3 and -SCH3.

[0187] In some embodiments, compounds with the structures shown in formulas (IA), (IA-3), (I), (Ia), (II), and (IIa), wherein R 2 -NH2 or -N(C) 1-6 Alkyl)C(O)C 1-6 Alkylene-OH.

[0188] In some embodiments, compounds with the structures shown in formulas (IA), (IA-3), (I), (Ia), (II), and (IIa), wherein R 2 -OC(O)-NR 2-1 R 2-2 -NR 2-1 C(O)-OR 2-2 -NH-S(O)2-R 2-2 -N(R) 2-1 )C(O)-C 1-6 Alkylene-R 2-2 -NR 2-1 C(O)NR 2-1 -R 2-2 -C(O)-R 2-2 .

[0189] In some embodiments, compounds with the structures shown in formulas (IA), (IA-3), (I), (Ia), (II), and (IIa), wherein R 2 -OH, -NH2, -NHCH3, -CH2OH

[0190] In some embodiments, compounds with the structures shown in formulas (IA), (IA-3), (I), (Ia), (II), and (IIa), wherein R 2 -OH, -NH2, -NHCH3, -CH2OH

[0191] In some embodiments, compounds with the structures shown in formulas (IA), (IA-3), (I), (Ia), (II), and (IIa), wherein R 2 -NH2 or

[0192] In some embodiments, compounds with structures shown in formulas (IA), (I), (Ia), (II), and (IIa), wherein R 2 For H.

[0193] In some embodiments, compounds with the structures shown in formulas (I), (Ia), (II), and (IIa), wherein R 3a It is hydrogen or -C 1-3 alkyl.

[0194] In some embodiments, compounds with the structures shown in formulas (I), (Ia), (II), and (IIa), wherein R 3a It is hydrogen or -CH3.

[0195] In some embodiments, compounds with the structures shown in formulas (I), (Ia), (II), and (IIa), wherein R 3b Hydrogen, -CH3, -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 by one or more substituents selected from -OH, -SH, -NH2, -NHCH3 and -SCH3.

[0196] In some embodiments, compounds with the structures shown in formulas (I), (Ia), (II), and (IIa), wherein R 3b -C(O)C 1-6 Alkylene-OH.

[0197] In some embodiments, compounds with the structures shown in formulas (I), (Ia), (II), and (IIa), wherein R 3b For hydrogen, -CH3,

[0198] In some embodiments, compounds with the structures shown in formulas (I), (Ia), (II), and (IIa), wherein R 3b for

[0199] In some embodiments, compounds with structures shown in formulas (IA), (I), (Ia), (II), and (IIa), wherein R 3 It is hydrogen.

[0200] In some embodiments, compounds with the structures shown in formula (IA), formula (IA-4), formula (I), formula (Ia), formula (II), and formula (IIa), wherein R 3 for

[0201] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (IA-2), (IA-3), (IA-4), (I), (Ia), (II), and (IIa), wherein R 4 It is hydrogen, deuterium or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally surrounded by one or more elements selected from halogens, -OH, -SH, -NH2, and -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents.

[0202] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (IA-2), (IA-3), (IA-4), (I), (Ia), (II), and (IIa), wherein R 4 For hydrogen, deuterium, C 1-6 Alkyl or -C(O)C 1-6 Alkylene-OH.

[0203] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (IA-2), (IA-3), (IA-4), (I), (Ia), (II), and (IIa), wherein R 4 It is hydrogen or -CH3.

[0204] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (IA-2), (IA-3), (IA-4), (I), (Ia), (II), and (IIa), wherein R 4 It is hydrogen.

[0205] In some embodiments, compounds with the structures shown in formula (IA), formula (IA-4), formula (I), formula (Ia), formula (II), and formula (IIa), wherein R 3 With R 4 Together with the atoms attached thereto, they form 5- to 6-membered heterocyclic alkyl groups, each of which is optionally bonded by one or more groups selected from halogens, oxo groups, -OH, -CN, -NH2, and -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 cycloalkyl-OH or -C(O)-(4 to 12-membered heteroalkyl-hemisyl)-OH substituents.

[0206] In some embodiments, compounds with the structures shown in formula (IA), formula (IA-4), formula (I), formula (Ia), formula (II), and formula (IIa), wherein R 3 With R 4 Together with the atoms attached thereto, a piperazine group is formed, each of which is optionally surrounded by one or more atoms selected from halogens, oxo groups, -OH, -CN, -NH2, and -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 cycloalkyl-OH or -C(O)-(4 to 12-membered heteroalkyl-hemisyl)-OH substituents.

[0207] In some embodiments, compounds with the structures shown in formula (IA), formula (IA-4), formula (I), formula (Ia), formula (II), and formula (IIa), wherein R 3 With R 4 It forms together with the atoms it is attached to.

[0208] In some embodiments, compounds with the structures shown in formula (IA), formula (IA-4), formula (I), formula (Ia), formula (II), and formula (IIa), wherein R 3 With R 4 It forms together with the atoms it is attached to.

[0209] In some embodiments, the compounds with structures shown in formulas (IA), (IA-3), (I), and (Ia) are compounds with structures shown in formula (Ia-1).

[0210]

[0211] Among them, R 1 R 11 R 2 R 4 Y is defined as described in any one of formulas (I), (Ia), (II), and (IIa) of this invention.

[0212] In some embodiments, the compounds with structures shown in formulas (IA), (IA-3), (I), (Ia), (Ia-1), (II), and (IIa) are compounds with structures shown in formulas (IIa-1), (IIa-4), and (IIa-5).

[0213]

[0214] Among them, Y and R 2 The definition is as described in any one of formulas (I), (Ia), (II), and (IIa) of this invention.

[0215] In some embodiments, compounds with the structures shown in formulas (IA), (IA-3), (I), (Ia), (Ia-1), (II), (IIa), (IIa-1), (IIa-4), and (IIa-5), wherein,

[0216] R 2 -NH2 or -N(C) 1-6 Alkyl)C(O)C 1-6 Alkylene-OH.

[0217] In some embodiments, compounds with the structures shown in formulas (IA), (IA-3), (I), (Ia), (Ia-1), (II), (IIa), (IIa-1), (IIa-4), and (IIa-5), wherein,

[0218] R 2 -NHC 1-6 alkyl.

[0219] In some embodiments, compounds with the structures shown in formulas (IA), (IA-3), (I), (Ia), (Ia-1), (II), (IIa), (IIa-1), (IIa-4), and (IIa-5), wherein,

[0220] R2 -NH2 or -N(C) 1-3 Alkyl)C(O)C 1-3 Alkylene-OH.

[0221] In some embodiments, compounds with the structures shown in formulas (IA), (IA-3), (I), (Ia), (Ia-1), (II), (IIa), (IIa-1), (IIa-4), and (IIa-5), wherein,

[0222] R 2 -NH2, -NHCH3,

[0223] In some embodiments, compounds with the structures shown in formulas (IA), (IA-3), (I), (Ia), (Ia-1), (II), (IIa), (IIa-1), (IIa-4), and (IIa-5), wherein,

[0224] R 2 -NH2 or

[0225] In some embodiments, compounds with the structures shown in formulas (IA), (IA-3), (I), (Ia), (Ia-1), (II), (IIa), (IIa-1), (IIa-4), and (IIa-5), wherein,

[0226] R 2 -NHC 1-3 Alkyl; preferably, R 2 It is -NHCH3.

[0227] In some embodiments, the compounds with structures shown in formulas (IA), (IA-3), (I), (Ia), (Ia-1), (II), and (IIa) are compounds with structures shown in formulas (IIa-1), (IIa-4), and (IIa-5).

[0228] R 2 For NH2, -NHC 1-6 Alkyl, -N(R) 1-1 )-C(O)R 1-2 -N(R) 1-1 )C(O)C 3-12 cycloalkyl, -N(R) 1-1 )C(O)-C 1-6 Alkylene-R 1-2 -N(R) 1-1 -C(O) (4 to 12-membered heterocyclic alkyl), -O- (4 to 12-membered heterocyclic alkylene)-C(O)R1-2 -N(R) 1-1 )-(4 to 12-membered heterocyclic alkylene)-C(O)R 1-2 -N(R) 1-1 )-C 3-12 cycloalkyl, -N(R) 1-1 )-C(O)-OR 1-2 -N(R) 1 -1 )-C(O)-N(R 1-1 )R 1-2 -NH-S(O)2-R 1-2 -OC(O)-N(R) 1-1 )R 1-2 -OC 1-6 alkyl.

[0229] In some embodiments, the compounds represented by formulas (IA), (IA-4), (I), and (Ia) are compounds with the structure shown in formula (Ia-2).

[0230]

[0231] Among them, Y and R 1 R 11 R 3a R 3b and R 4 The definitions are as described in any one of formulas (I) and (Ia) of this invention.

[0232] In some embodiments, the compounds represented by formulas (IA), (IA-4), (I), (Ia), (Ia-2), (II), and (IIa) are compounds with structures as shown in formulas (IIa-2) and (IIa-3).

[0233]

[0234] Among them, Y and R 3a R 3b and R 4 The definition is as described in any one of formulas (I), (Ia), (Ia-2), (II), and (IIa) of this invention.

[0235] In some embodiments, compounds with the structures shown in formulas (IA), (IA-4), (I), (Ia), (Ia-2), (II), (IIa), (IIa-2), and (IIa-3), wherein,

[0236] R 3a It is hydrogen or -CH3;

[0237] R3b -C(O)C 1-6 alkylene-OH;

[0238] R 4 It is hydrogen or -CH3;

[0239] or, for

[0240] Y can be either -OH or -CN.

[0241] In some embodiments, compounds with the structures shown in formulas (IA), (IA-4), (I), (Ia), (Ia-2), (II), (IIa), (IIa-2), and (IIa-3), wherein R 3b -C(O)C 1-3 Alkylene-OH.

[0242] In some embodiments, compounds with the structures shown in formulas (IA), (IA-4), (I), (Ia), (Ia-2), (II), (IIa), (IIa-2), and (IIa-3), wherein -CH2-NR 3a R 3b for

[0243] In some embodiments, the compounds with structures shown in formulas (IA), (IA-4), (I), (Ia), (Ia-1), (II), and (IIa) are compounds with structures shown in formulas (IIa-1), (IIa-4), and (IIa-5).

[0244] R 3 -CH2-N(C 1-6 Alkyl)C(O)C 1-6 Alkyl group, -CH2-NHC(O)C 1-6 Alkyl, NHC 1-6 Alkyl group, -CH2-NHC(O)C 3-12 cycloalkyl, -CH2-N(R) 3-1 )C(O)-C 1-6 Alkylene-R 3-2 -CH2-NHC(O)C 3-12 Cycloalkyl, -CH2-OC(O)-NR 3-1 R 3-2 -CH2-NR 3-1 C(O)NR 3-1 -R 3-2 C(O)-R 3-2 .

[0245] In some embodiments, the compounds with structures shown in formulas (IA), (IA-4), (I), (Ia), (Ia-1), (II), and (IIa) are compounds with structures shown in formulas (IIa-1), (IIa-4), and (IIa-5).

[0246] R 3 For NHCH3,

[0247] In some embodiments, the compounds with structures shown in formulas (IA), (IA-4), (I), (Ia), (Ia-1), (II), and (IIa) are compounds with structures shown in formulas (IIa-1), (IIa-4), and (IIa-5).

[0248] R 3 For NHCH3,

[0249] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (IA-2), (IA-3), (IA-4), (I), (Ia), (Ia-2), (II), (IIa), (IIa-2), and (IIa-3), wherein R 4 It is hydrogen.

[0250] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (IA-2), (IA-3), (IA-4), (I), (Ia), (Ia-2), (II), (IIa), and (IIa-1), wherein, for Or a combination thereof.

[0251] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (IA-2), (IA-3), (IA-4), (I), (Ia), (Ia-2), (II), (IIa), (IIa-2), and (IIa-3), wherein, for Or a combination thereof.

[0252] In some embodiments, the compounds of formulas (IA), (I), (II), (Ia), and (ⅠIa) of the present invention are:

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261] In some embodiments, the compounds shown in formula (IA) and formula (I) are compounds with the structure shown in formula (Ib).

[0262]

[0263] in,

[0264] R 1 -NH2, -NHC 1-6 Alkyl, -C 1-6 Alkylene-N(R) 1-1 )-C(O)R 1-2 -O-(4 to 12-membered heterocyclic alkylene)-C(O)R 1-2 -OC 3-12 Cycloalkyl-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 heterocyclic alkylene)-C(O)R 1-2 -N(R) 1-1 )-C 3-12 Cycloalkyl-N(R) 1-1 )-C(O)R 1-2 -(4 to 12-membered heterocyclic alkylene)-C(O)R 1 -2 -(4 to 12-membered heterocyclic alkylene)-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 heterocyclic alkyl), wherein the C 1-6 Alkyl, C 1-6 Alkylene, C 3-12 cycloalkyl, C 3-12Cycloalkylene, 4- to 12-membered heterocycloalkylene, or 4- to 12-membered heterocycloalkylene are each optionally separated from one or more elements 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 Substitution of alkylene-NH2;

[0265] R 11 Hydrogen, deuterium, halogen, -OH, -CN, -NH2, C 1-6 Alkyl, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -C 1-6 Alkylene-N(R) 1-1 )-C(O)R 1-2 -OC 3-12 Cycloalkyl, -O-(4 to 12-membered heterocyclic alkylene)-C(O)R 1-2 -OC 3-12 Cycloalkyl-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 heterocyclic alkylene)-C(O)R 1-2 -N(R) 1-1 )-C 3-12 Cycloalkyl-N(R) 1-3 )-C(O)R 1-2 -(4 to 12-membered heterocyclic alkylene)-C(O)R 1-2 -(4 to 12-membered heterocyclic alkylene)-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 heterocyclic alkyl), wherein the C 1-6 Alkyl, C 1-6 Alkylene, C 3-12 cycloalkyl, C 3-12 Cycloalkylene, 4- to 12-membered heterocycloalkylene, and 4- to 12-membered heterocycloalkyl are each optionally separated by one or more elements 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 Substitution of alkylene-NH2;

[0266] R 1-1 For hydrogen, deuterium, C 1-6 Alkyl, Halogenated C 1-6 alkyl;

[0267] R 1-2 C 1-6 Alkyl, C 3-12 Cycloalkyl or 4- to 12-membered heterocyclic alkyl; the C 1-6 Alkyl, C 3-12 The cycloalkyl group or 4- to 12-membered heterocycloalkyl group is optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents;

[0268] R 4 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), wherein the C 1-6 Alkyl, C 3-12 The cycloalkyl group or 4- to 12-membered heterocycloalkyl group is optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents;

[0269] Y can be either -OH or -CN.

[0270] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (IA-3), (IA-4), (I), and (Ib), wherein R 11 It can be hydrogen, halogen, -OH, -CN, -NH2, -CH3, -OCH3 or -NHCH3.

[0271] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (IA-3), (IA-4), (I), and (Ib), wherein R 11 It can be hydrogen, deuterium, -F, -Cl, -OH, -CH3, -OCH3, -NH2 or -NHCH3.

[0272] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (IA-3), (IA-4), (I), and (Ib), wherein R 11 It can be hydrogen, deuterium, or -OCH3.

[0273] In some embodiments, the compounds shown in formulas (IA), (IA-1), (I), (Ib), and (II) are compounds with the structure shown in formula (IIb).

[0274]

[0275] in,

[0276] R 1 -NH2, -C 1-6 Alkylene-N(R) 1-1 )-C(O)R 1-2 -O-(4 to 12-membered heterocyclic alkylene)-C(O)R 1-2 -OC 3-12 Cycloalkyl-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 heterocyclic alkylene)-C(O)R 1-2 -N(R) 1-1 )-C 3-12 Cycloalkyl-N(R) 1-1 )-C(O)R 1-2 -(4 to 12-membered heterocyclic alkylene)-C(O)R 1-2 -(4 to 12-membered heterocyclic alkylene)-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 heterocyclic alkyl), wherein the 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 heterocycloalkylene are each optionally separated from one or more elements 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 1-6alkyl) and -C 1-6 Substitution of alkylene-NH2;

[0277] R 1-1 For hydrogen, deuterium, C 1-6 Alkyl, Halogenated C 1-6 alkyl;

[0278] R 1-2 C 1-6 Alkyl, C 3-12 Cycloalkyl or 4- to 12-membered heterocyclic alkyl; the C 1-6 Alkyl, C 3-12 The cycloalkyl group or 4- to 12-membered heterocycloalkyl group is optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents;

[0279] Y can be either -OH or -CN.

[0280] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (I), (Ib), (II), and (IIb), wherein,

[0281] R 1 -NH2, -C 1-6 Alkylene-N(R) 1-1 )-C(O)R 1-2 -O-(4 to 12-membered heterocyclic alkylene)-C(O)R 1-2 -OC 3-12 Cycloalkyl-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 heterocyclic alkylene)-C(O)R 1-2 -N(R) 1-1 )-C 3-12 Cycloalkyl-N(R) 1-1 )-C(O)R 1-2 -(4 to 12-membered heterocyclic alkylene)-C(O)R 1-2 -(4 to 12-membered heterocyclic alkylene)-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 heterocyclic alkyl), wherein the C 1-6 Alkyl, C 1-6 Alkylene, C3-12 cycloalkyl, C 3-12 Cycloalkylene, 4- to 12-membered heterocycloalkylene, or 4- to 12-membered heterocycloalkylene are each optionally separated from one or more elements 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 Substitution of alkylene-NH2;

[0282] R 1-1 For hydrogen, deuterium, C 1-6 Alkyl, Halogenated C 1-6 alkyl;

[0283] R 1-2 C 1-6 Alkyl, C 3-12 Cycloalkyl or 4- to 12-membered heterocyclic alkyl; the C 1-6 Alkyl, C 3-12 The cycloalkyl group or 4- to 12-membered heterocycloalkyl group is optionally separated by one or more elements selected from halogen, -OH, -O-NHCH3, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Alkyl substituents;

[0284] Y can be either -OH or -CN.

[0285] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (IA-2), (I), (Ib), (II), and (IIb), wherein R 1-1 It is hydrogen, deuterium or C 1-6 alkyl.

[0286] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (IA-2), (I), (Ib), (II), and (IIb), wherein R 1-1 It can be hydrogen, deuterium, or -CH3.

[0287] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (IA-2), (I), (Ib), (II), and (IIb), wherein R 1-1 It is hydrogen or -CH3.

[0288] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (IA-2), (I), (Ib), (II), and (IIb), wherein R 1-1 It is -CH3.

[0289] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (IA-2), (I), (Ib), (II), and (IIb), wherein R 1-2 C 1-6 Alkyl, C 3-6 Cycloalkyl or 4- to 6-membered heterocyclic alkyl; the C 1-6 Alkyl, C 3-6 The cycloalkyl group or 4- to 6-membered heterocycloalkyl group is optionally surrounded by one or more elements selected from halogen, -OH, -SH, -NH2, -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents.

[0290] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (IA-2), (I), (Ib), (II), and (IIb), wherein R 1-2 C 1-6 Alkyl, C 3-6 Cycloalkyl or 4- to 6-membered heterocyclic alkyl; the C 1-6 Alkyl, C 3-6 The cycloalkyl group or 4- to 6-membered heterocycloalkyl group is optionally separated by one or more elements selected from halogen, -OH, -O-NHCH3, -SH, -NH2, -NHC 1-6 Alkyl and -SC 1-6 Alkyl substituents.

[0291] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (IA-2), (I), (Ib), (II), and (IIb), wherein R 1-2 -C 1-6 Alkylene-OH.

[0292] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (IA-2), (I), (Ib), (II), and (IIb), wherein R 1-2 -C 1-6 Alkylene-O-NHCH3.

[0293] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (IA-2), (I), (Ib), (II), and (IIb), wherein R1-2 -CH2OH, -CH(CH3)OH,

[0294] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (IA-2), (I), (Ib), (II), and (IIb), wherein R 1-2 It is -CH2-O-NHCH3.

[0295] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (IA-2), (I), (Ib), (II), and (IIb), wherein R 1-2 -C 1-3 Alkylene-OH.

[0296] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (IA-2), (I), (Ib), (II), and (IIb), wherein R 1-2 -C 1-3 Alkylene-O-NHCH3.

[0297] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (IA-2), (I), (Ib), (II), and (IIb), wherein R 1-2 It is -CH2OH or -CH(CH3)OH.

[0298] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (I), (Ib), (II), and (IIb), wherein R 1 -NH2, -C 1-6 Alkylene-N(R) 1-1 )-C(O)R 1-2 -O-(4 to 6-membered heterocyclic alkylene)-C(O)R 1 -2 -OC 3-6 Cycloalkyl-N(R) 1-1 )-C(O)R 1-2 -N(R) 1-1 )-(4 to 6-membered heterocyclic alkylene)-C(O)R 1-2 -(4 to 6-membered heterocyclic alkylene)-C(O)R 1-2 -(4 to 6-membered heterocyclic alkylene)-N(R 1-1 )-C(O)R 1-2 -N(R) 1-1 )-C(O)R 1-2 -N(R)1-1 )C(O)C 3-6 cycloalkyl or -N(R) 1-1 )C(O)(4 to 6-membered heterocyclic alkyl), wherein the C 1-6 Alkylene, C 3-6 cycloalkyl, C 3-6 Cycloalkylene, 4- to 6-membered heterocyclic alkylene, or 4- to 6-membered heterocyclic alkylene may each be optionally separated from one or more elements 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 Substituents of alkylene-NH2; R 1-1 As defined by any one of formulas (II) and (IIb) of this invention, R 1-2 As defined by any one of formulas (II) and (IIb) of this invention.

[0299] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (I), (Ib), (II), and (IIb), 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 heterocyclic alkylene)-C(O)R 1-2 -OC 3-6 Cycloalkyl-NH-C(O)R 1-2 -OC 3-6 Cycloalkylene-N(CH3)-C(O)R 1 -2 -NH-C(O)R 1-2 -N(CH3)-C(O)R 1-2 -NH-(4 to 6-membered heterocyclic alkylene)-C(O)R 1-2 -N(CH3)-(4 to 6-membered heterocyclic alkylene)-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 heterocyclic alkyl) or -N(CH3)C(O) (4- to 6-membered heterocyclic alkyl), wherein the C 1-6 Alkylene, C 3-6 cycloalkyl, C 3-6Cycloalkylene, 4- to 6-membered heterocyclic alkylene, or 4- to 6-membered heterocyclic alkylene may each be optionally separated from one or more elements selected from halogen, -OH, -NH2, -NHCH3, -C 1-6 alkylene-OH substitution; R 1-2 As defined in any of the present invention formula (IIb).

[0300] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (I), (Ib), (II), and (IIb), wherein R 1 -O-(4 to 6-membered heterocyclic alkylene)-C(O)R 1-2 -NH-C(O)R 1-2 or -N(CH3)-C(O)R 1-2 ;R 1-2 As defined in any of the present invention formula (IIb).

[0301] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (I), (Ib), (II), and (IIb), wherein R 1 -NH2, -NHC 1-6 Alkyl, -O-(4 to 6-membered heterocyclic alkylene)-C(O)R 1-2 -NH-C(O)R 1-2 or -N(CH3)-C(O)R 1-2 ;R 1-2 As defined in any of the present invention formula (IIb).

[0302] In some implementation schemes, R 1 and R 11 Independently for -N(R) 1-1 )-R 1-2 -NH-S(O)2-R 1-2 -N(R) 1-1 )-C(O)-OR 1-2 -N(R) 1-1 )-C(O)-N(R 1-1 )R 1-2 -OC(O)-N(R) 1-1 )R 1-2 .

[0303] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (I), (Ib), (II), and (IIb), wherein R 1 -NH-S(O)2-R 1-2 -O-(4 to 12-membered heterocyclic alkylene)-C(O)R 1-2 -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 -N(R) 1-1 )-C(O)-N(R 1-1 )R 1-2 -N(R) 1-1 )C(O)-C 1-6 Alkylene-R 1-2 .

[0304] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (I), (Ib), (II), and (IIb), wherein,

[0305] R 1 -O-(4 to 6-membered heterocyclic alkylene)-C(O)R 1-2 -NH-C(O)R 1-2 or -N(CH3)-C(O)R 1-2 ;

[0306] R 1-2 -C 1-6 alkylene-OH;

[0307] Y can be either -OH or -CN.

[0308] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (I), (Ib), (II), and (IIb), wherein,

[0309] R 1 -O-(4 to 6-membered heterocyclic alkylene)-C(O)R 1-2 or -N(CH3)-C(O)R 1-2 ;

[0310] R 1-2 -C 1-6 alkylene-OH;

[0311] Y can be either -OH or -CN.

[0312] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (I), (Ib), (II), and (IIb), wherein,

[0313] R 1 -NH-C(O)R 1-2 ;

[0314] R 1-2 -C1-6 Alkylene-O-NHCH3

[0315] Y can be either -OH or -CN.

[0316] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (IA-2), (I), (Ib), (II), and (IIb), wherein R 1 For NH2, NHCH3,

[0317] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (IA-2), (I), (Ib), (II), and (IIb), wherein R 11 For NH2, NHCH3,

[0318] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (I), (Ib), (II), and (IIb), wherein R 1 for

[0319] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (I), (Ib), (II), and (IIb), wherein R 1 for

[0320] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (I), (Ib), (II), and (IIb), wherein R 1 for

[0321] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (I), (Ib), (II), and (IIb), wherein R 1 for

[0322] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (I), (Ib), (II), and (IIb), wherein R 1 for

[0323] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (I), (Ib), (II), and (IIb), wherein R 1 for

[0324] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (I), (Ib), (II), and (IIb), wherein R 11 for

[0325] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (I), (Ib), (II), and (IIb), wherein R 11 For NH2, NHCH3,

[0326] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (IA-2), (IA-3), (IA-4), (I), and (Ib), wherein R 11 It can be hydrogen, halogen, -OH, -CN, -NH2, -CH3, -OCH3 or -NHCH3.

[0327] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (IA-2), (IA-3), (IA-4), (I), and (Ib), wherein R 11 It can be hydrogen, deuterium, -F, -Cl, -OH, -CH3, -OCH3, -NH2 or -NHCH3.

[0328] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (IA-2), (IA-3), (IA-4), (I), and (Ib), wherein R 11 It can be hydrogen, deuterium, or -OCH3.

[0329] In some embodiments, the compounds shown in formulas (IA), (IA-1), (I), (Ib), and (II) are compounds with the structure shown in formula (IIb).

[0330]

[0331] Among them, R 1 For NH2 or -NHC 1-6 alkyl;

[0332] Y can be either -OH or -CN.

[0333] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (IA-2), (IA-3), (IA-4), (I), (Ib), (II), and (IIb), wherein R 1 NH2 or NHC 1-3 Alkyl; more preferably, R 1 It is either NH2 or NHCH3.

[0334] In some embodiments, compounds with the structures shown in formulas (IA), (IA-1), (IA-2), (IA-3), (IA-4), (I), (Ib), (II), and (IIb), wherein R 1 For NHC 1-6 Alkyl; more preferably, R 1 For NHC 1-3 Alkyl; more preferably, R 1 It is NHCH3.

[0335] In some embodiments, the compounds of formulas (IA), (I), (Ib), (II), and (IIb) of the present invention are:

[0336]

[0337]

[0338]

[0339]

[0340] Those skilled in the art will understand that this invention covers compounds obtained by any combination of the various embodiments. Embodiments obtained by combining technical features or preferred technical features from one embodiment with technical features or preferred technical features from another embodiment are also included within the scope of this invention.

[0341] In another aspect, the present invention provides a compound with the following structure:

[0342]

[0343] In another aspect, the present invention provides a pharmaceutical composition comprising (a preventive or therapeutically effective amount) of the compound described herein or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite, or prodrug thereof, and one or more pharmaceutically acceptable carriers.

[0344] A further object of the present invention is to provide a method for preparing the pharmaceutical composition of the present invention, the method comprising combining the compound of the present invention or a pharmaceutically acceptable form thereof, or a mixture thereof, with one or more pharmaceutically acceptable carriers.

[0345] The pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention are pharmaceutically acceptable carriers, and examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (2005).

[0346] Pharmaceutical compositions can be administered in any form, as long as they achieve the purpose of preventing, alleviating, preventing, or curing symptoms in human or animal patients. For example, they can be formulated into various suitable dosage forms depending on the route of administration.

[0347] In other embodiments, the administration of the compounds or pharmaceutical compositions of the present invention may be combined with other treatment methods. These other treatment methods may be selected from, but are not limited to, radiotherapy, chemotherapy, immunotherapy, or combinations thereof.

[0348] This invention also relates to a pharmaceutical formulation comprising, as an active ingredient, a compound of the invention or a pharmaceutically acceptable form thereof, or a mixture thereof, a pharmaceutical composition of the invention. In some embodiments, the formulation is in the form of a solid dosage form, a semi-solid dosage form, a liquid dosage form, or a gaseous dosage form.

[0349] A further object of the present invention is to provide an article of manufacture, for example, in the form of a kit. The article of manufacture as used herein is intended to include, but is not limited to, medicine boxes and packaging. The article of manufacture of the present invention comprises: (a) a first container; (b) a pharmaceutical composition contained 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) optionally present packaging instructions stating that the pharmaceutical composition may be used to treat oncological conditions (as defined below); and (d) a second container.

[0350] The first container is a container for containing a pharmaceutical composition. This container may be used for the 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 the preparation, containment, storage, or dispensing of pharmaceutical products.

[0351] The second container is a container for holding the first container and optional instruction manuals. Examples of the second container include, but are not limited to, boxes (e.g., cardboard or plastic boxes), cartons, cartons, bags (e.g., paper or plastic bags), sachets, and cloth bags. The instruction manuals may be physically attached to the outside of the first container by cable ties, glue, U-staples, or other adhesive methods, or they may be placed inside the second container without any physical means of attachment to the first container. Alternatively, the instruction manuals may be located outside the second container. When located outside the second container, it is preferable that the instruction manuals be physically attached by cable ties, glue, U-staples, or other adhesive methods. Alternatively, they may be adjacent to or in contact with the outside of the second container without physical attachment.

[0352] The packaging instructions, such as trademarks, labels, or markings, list information relating to the pharmaceutical composition contained within the first container. The listed information is typically determined by the regulatory authority governing the region where the product is to be sold (e.g., the U.S. Food and Drug Administration). Preferably, the packaging instructions specifically list the approved indications for which the pharmaceutical composition is used. The packaging instructions can be made of any material from which information contained therein or on the material can be read. Preferably, the packaging instructions are made of a printable material (e.g., paper, plastic, cardboard, foil, adhesive paper, or plastic) on which the desired information can be formed (e.g., printed or coated).

[0353] In another aspect, the present invention provides the use of the compounds described herein or in a pharmaceutically acceptable form thereof, or the pharmaceutical compositions of the present invention, in the preparation of a medicament.

[0354] In another aspect, the present invention provides the use of the compounds described herein or in a pharmaceutically acceptable form thereof, or the pharmaceutical compositions of the present invention, in the preparation of a medicament for the prevention or treatment of tumors or cancer.

[0355] In another aspect, the present invention provides a method for preventing or treating tumors, the method comprising administering to an individual in need (a preventive or therapeutically effective amount) of a compound as described herein or in a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present invention.

[0356] On the other hand, the present invention provides (preventive or therapeutically effective amounts) of the compounds described herein or in a pharmaceutically acceptable form thereof, or pharmaceutical compositions of the present invention, for the prevention or treatment of tumors or cancer.

[0357] In another aspect, the present invention provides a method for preventing or treating tumors or cancer by combining (a preventive or therapeutically effective amount) of the compounds described herein or in a pharmaceutically acceptable form thereof, or by combining the pharmaceutical compositions of the present invention with other treatment methods, including but not limited to: radiotherapy, chemotherapy, immunotherapy, or combinations thereof.

[0358] In some implementations, the tumors or cancers mentioned include, but are 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 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 lymphoblastic leukemia (ALL), and chronic myeloid leukemia (CML)), multiple myeloma, and lymphoma.

[0359] In a further preferred embodiment, the compounds of the present invention can be used in combination with radiotherapy, chemotherapy, or immunotherapy to prevent or treat tumors or cancer.

[0360] Dosing regimens can be adjusted to provide the optimal required response. For example, when administered in injectable form, a single bolus, bolus, and / or continuous infusion can be given, etc. For example, several fractions can be administered over time, or the dose can be reduced or increased proportionally as indicated by the urgency of the treatment 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 of treatment is variable, 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 individual physicians. To further understand, for any particular individual, the specific dosing regimen should be adjusted over time based on individual needs and the professional judgment of the person administering the composition or supervising the administration of the composition. The dosage and administration regimen of the pharmaceutical composition can be readily determined by a person skilled in the clinical field. For example, the compositions or compounds of the present invention can be administered in fractions from four times daily to once every three days, with dosages ranging from, for example, 0.01 to 1000 mg per dose. The required dose can be administered once or multiple times to achieve the desired results. The pharmaceutical compositions according to the invention can also be provided in unit dose form.

[0361] General terms and definitions

[0362] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technical terms herein refer to techniques commonly understood in the art, including variations or equivalent substitutions of techniques that are obvious to one of ordinary skill in the art. While it is believed that the following terms will be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain the invention.

[0363] The terms “comprising,” “including,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other elements or method steps not listed. Those skilled in the art will understand that the foregoing term “comprising” encompasses the meaning of “consisting of.”

[0364] The term “about” means within ±10% of the stated value, preferably within ±5%, and more preferably within ±2%.

[0365] Unless otherwise stated, concentrations are by weight and proportions (including percentages) are by moles.

[0366] The term "one or more species" or similar expression "at least one species" can mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more species.

[0367] When the lower and upper limits of a numerical range are disclosed, any numerical value falling within that range and any included range are specifically disclosed. In particular, each range of values ​​disclosed herein (in the form of “about a to b”, or equivalently, “approximately a to b”, or equivalently, “about ab”) should be understood to represent each numerical value and range encompassed within a wider range.

[0368] For example, the expression "C" 1-6 "This should be understood as encompassing any subrange and each point value, such as C." 2-5 C 3-4 C 1-2 C 1-3 C1-4, C 1-5 And so on, as well as C1, C2, C3, C4, C5, C6, etc. For example, the expression "C 3-10 "It should also be understood in a similar way, for example, it can encompass any subrange and point value contained within it, such as C." 3-9 C 6-9 C 6-8 C 6-7 C 7-10 C 7-9 C 7-8 C 8-9 And C3, C4, C5, C6, C7, C8, C9, C 10For example, the expression "3-10 yuan" should be understood as encompassing any sub-range and each point value within it, 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. Similarly, the expression "5-10 yuan" should also be understood in a similar way, for example, it can encompass any sub-range and point value included within it, 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.

[0369] In this specification, groups and their substituents may be selected by those skilled in the art to provide stable structural moieties and compounds. When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left.

[0370] When used alone or in combination with other groups herein, the term "alkyl" refers to a saturated straight-chain or branched hydrocarbon group. As used herein, the term "C" refers to a saturated straight-chain or branched hydrocarbon group. 1-6 "Alkyl" refers to a saturated straight-chain or branched hydrocarbon group having 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6 carbon atoms). "C" 1-6 "alkyl" can be, 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 this invention may optionally be substituted with one or more substituents described herein.

[0371] Linking substituents are described in various parts of this invention. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl," then it should be understood that "alkyl" represents a linked alkylene group. For example, in some specific structures, when an alkyl group is clearly indicated as a linking group, then that alkyl group represents a linked alkylene group, for example, the group "halogenated-C". 1-6 C in "alkyl" 1-6 Alkyl should be understood as C 1-6 Alkylene.

[0372] When used alone or in combination with other groups herein, the term "alkylene" refers to a saturated straight-chain or branched divalent hydrocarbon group. As used herein, the term "C 1-6 "Alkylene" refers to a saturated, straight-chain or branched divalent hydrocarbon group having 1-6 carbon atoms. 1-6"alkylene" includes, but is not limited to, methylene, ethylene, propylene, or butylene. The alkylene groups in this invention may optionally be substituted with one or more substituents described in this invention.

[0373] 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 bicyclic [1.1.1]pentyl, bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl, bicyclic [5.2.0]nonyl, decahydronaphthyl, etc.

[0374] In this application, the term "cycloalkylene" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic) non-aromatic dicyclic group. For example, "C 3-12 "Cycloalkylene" or "3-12-membered cycloalkylene" refers to cycloalkylene compounds having 3-12 ring carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12). Common cycloalkylene compounds include (but are not limited to) monocyclic cycloalkylene compounds, such as cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclobutene, cyclopentene, cyclohexene, etc.; or bicyclic cycloalkylene compounds, including fused rings, bridged rings, or spirocyclic compounds, such as bicyclic[1.1.1]pentylene, bicyclic[2.2.1]heptylene, bicyclic[3.2.1]octylene, bicyclic[5.2.0]nonylene, decahydronaphthylene, etc.

[0375] The term "heterocyclic alkyl" refers to a saturated or partially saturated non-aromatic cyclic group containing at least one heteroatom selected from N, O, P, and S as a ring member. Preferably, the number of heteroatoms is 1, 2, 3, or 4 (e.g., 1 or 2 heteroatoms independently selected from N). Examples include 3-8-membered, 3-6-membered, 4-12-membered, and 4-6-membered heterocyclic alkyl groups. Furthermore, the heterocyclic alkyl group may contain 0, 1, 2, or 3 oxo groups. Specific examples include, but are not limited to, ethylene oxide, oxocyclobutane, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, homopiperazinyl, and pyrrolidone.

[0376] The term "heterocyclic alkylene" refers to a saturated or partially saturated, non-aromatic divalent cyclic group containing at least one heteroatom selected from N, O, P, and S as a ring member. Preferably, the number of heteroatoms is 1, 2, 3, or 4 (e.g., 1 or 2 heteroatoms independently selected from N). Examples include 3-8-membered, 3-6-membered, 4-12-membered, and 4-6-membered heterocyclic alkylene groups. Furthermore, the heterocyclic alkylene group may contain 0, 1, 2, or 3 oxo groups. Specific examples include, but are not limited to, ethylene oxide, cyclobutane, pyrrolidine, tetrahydrofuranyl, piperidinyl, piperazine, tetrahydropyranyl, homopiperazine, and pyrrolidone groups.

[0377] In this application, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0378] In this application, the term "hydroxyl" refers to -OH.

[0379] In this application, the term "cyano" refers to -CN.

[0380] In this application, the term "nitro" refers to -NO2.

[0381] In this application, the term "amino" refers to -NH2.

[0382] In this application, "oxo" refers to C(O), i.e., carbonyl group.

[0383] When used alone or in combination with other groups in this application, the term "haloalkyl" refers to the alkyl group described above, wherein one or more hydrogen atoms are replaced by a halogen. For example, the term "C 1-6 "Halogenated alkyl" or "halogenated C" 1-6 "Alkyl" refers to a C-aryl group that is optionally substituted with one or more (e.g., 1-3) halogens. 1-6 Alkyl groups. Those skilled in the art will understand that when there is more than one halogen substituent, the halogens can be the same or different, and can be located on the same or different C atoms. Examples of alkyl halogens include, for example, -CH2F, -CHF2, -CF3, -CCl3, -C2F5, -C2Cl5, -CH2CF3, -CH2Cl, or -CH2CH2CF3. The alkyl halogens in this invention are optionally substituted with one or more substituents described in this invention.

[0384] When used alone or in combination with other groups in this application, the term "alkoxy" means an alkyl group to which an oxygen atom is attached as described above to the parent molecule. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, n-butoxy, tert-butoxy, and pentoxy.

[0385] As used in this application, the term "each independently" means that at least two groups (or segments) in a structure with the same or similar value ranges can have the same or different meanings under specific circumstances. For example, if substituent A and substituent B are each independently hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl, then when substituent A is hydrogen, substituent B can be hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl; similarly, when substituent B is hydrogen, substituent A can be hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl.

[0386] As used herein, the term "substitution" and its other variations refer to the replacement of one or more (e.g., 1, 2, 3, or 4) atoms or groups of atoms (e.g., hydrogen atoms) on a specified atom with other equivalents, provided that the replacement does not exceed the normal valence of the specified atom or group of atoms in the present case and is capable of forming a stable compound. If an atom or group of atoms is described as "optionally substituted," it may or may not be substituted. Unless otherwise stated, the linking site of a substituent herein may be derived from any suitable position of the substituent. When the linking bond in a substituent is shown as a chemical bond passing through two atoms connected to each other in a ring system, it indicates that the substituent may be linked to any one of the cyclic atoms in the ring system.

[0387] When any variable (e.g., R) a When a variable appears multiple times in the definition of a compound, the definition at each position is independent of the definitions at the other positions; their meanings are independent and do not affect each other. Therefore, if a group is surrounded by one, two, or three R... a Group substitution, meaning that the group can be replaced by up to 3 R groups. a Replacement, where a certain position R a Definition and other positions R a The definitions are independent of each other. Furthermore, combinations of substituents and / or variables are only permitted if the combination produces a stable compound. The term "optionally substituents" is used in conjunction with one or more R... a "Replace" indicates that it was not replaced by R a Replaced and by one or more R a Replaces both scenarios. For example, "the C..." 1-6 Alkyl groups are optionally surrounded by one or more R a "Replace" means C 1-6 Alkyl and (by one or more R) a (replaced) C 1-6 alkyl.

[0388] When a listed group does not explicitly indicate that it has a substituent, the group refers only to the unsubstituted group. For example, when "C 1-6 When "alkyl" is not specified as "substituted or unsubstituted," it refers only to "C".1-6 "alkyl" itself or "unsubstituted C" 1-6 alkyl".

[0389] As used herein, the compounds of this 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. This 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 be present. This 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.

[0390] The term "stereoisomer" includes conformational isomers and configurational isomers, wherein configurational isomers mainly include cis-trans isomers and optical isomers. The compounds described in this invention can exist in stereoisomer form, and therefore encompass all possible stereoisomer forms, including but not limited to cis-trans isomers, enantiomers, diastereomers, and transisomers. The compounds described in this invention can also exist in any combination or mixture of the aforementioned stereoisomers, such as equal mixtures of meso, racemic, and transisomers, or, for example, a single enantiomer, a single diastereomer or a mixture of more than one, or a single transisomer or a mixture thereof.

[0391] The term "tautomer" refers to a functional group isomer that is produced by the rapid movement of an atom in two positions within a molecule.

[0392] Solid lines may be used in this application. solid wedge Or virtual wedge The carbon-carbon bonds of the compounds of the present invention are depicted. Solid lines are used to depict bonds to asymmetric carbon atoms to indicate all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) at that carbon atom. Solid or imaginary wedges are used to depict bonds to asymmetric carbon atoms to indicate the presence of the indicated stereoisomers. When present in racemic mixtures, solid and imaginary wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise specified, the compounds of the present invention may exist as stereoisomers (including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, trans-blocking isomers, and mixtures thereof). The compounds of the present invention may exhibit more than one type of isomerism and may consist of mixtures thereof (e.g., racemic mixtures and diastereomer pairs).

[0393] Wavy lines may be used in this application. The depiction of the bond connecting to the asymmetric carbon atom indicates that the bond at that carbon atom is a real wedge. Or virtual wedge The absolute configuration of one of the stereoisomers shown.

[0394] In this application, unless otherwise specified, 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 whose structures are identical to those of this application except that hydrogen atoms are replaced by deuterium or tritium, or carbon atoms are replaced by carbon-13 or carbon-14, are within the scope of this application.

[0395] This invention also covers all possible crystalline forms or polymorphs of the compounds of this invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.

[0396] Unless otherwise stated, the word “or” or “and” in this article refers to “and / or”.

[0397] Unless otherwise specified, the specific groups appearing in this article... This refers to the connection position; the two can be interchanged.

[0398] The term “pharmaceutically acceptable form” refers to, but is not limited to, its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite or prodrug.

[0399] It should also be understood that certain compounds of the present invention may exist in their free form for therapeutic purposes, or, where appropriate, in their pharmaceutically acceptable derivative forms. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, or prodrugs, which, upon administration to a patient in need, can directly or indirectly provide the compounds of the present invention or their metabolites. Therefore, when referring to "compounds of the present invention" herein, it is also intended to encompass the various derivative forms of the compounds described above.

[0400] Pharmaceutically acceptable salts of the compounds of the present invention include their acid addition salts and base addition salts. Suitable acid addition salts are formed by acids that form pharmaceutically acceptable salts. Suitable base addition salts are formed by bases that form pharmaceutically acceptable salts. A review of suitable salts can be found, for example, in “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.

[0401] As used herein, the term "ester" means an ester derived from the compounds described herein, including physiologically hydrolyzable esters (the compounds of the present invention that can be hydrolyzed under physiological conditions to release free acids or alcohols). The compounds of the present invention may themselves also be esters.

[0402] The compounds of the present invention can exist as solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, can be stoichiometric or non-stoichiometric.

[0403] Those skilled in the art will understand that not all nitrogen-containing heterocycles can form nitrogen oxides because nitrogen requires available lone pairs of electrons to be oxidized. Those skilled in the art will identify nitrogen-containing heterocycles capable of forming nitrogen oxides. They will also recognize that tertiary amines can form nitrogen oxides. Synthetic methods for preparing nitrogen oxides of heterocycles and tertiary amines are well known to those skilled in the art, including the oxidation of heterocycles and tertiary amines with peroxyacids such as peracetic acid and m-chloroperoxybenzoic acid (mCPBA), hydrogen peroxide, alkyl peroxides such as tert-butyl peroxide, sodium perborate, and dioxiranes such as dimethyldioxirane. These methods for preparing nitrogen oxides have been extensively described and reviewed in the literature, see, for example: T.L. Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp. 748-750 (AR. Katritzky and A.J. Boulton, Eds., Academic Press); and G.W. H. Heeseman and E.S. G. Wierstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp. 390-392 (AR. Katritzky and A.J. Boulton, Eds., Academic Press).

[0404] The scope of this invention also includes metabolites of the compounds of this invention, i.e., substances formed in the body upon administration of the compounds of this invention. Metabolites of the compounds can be identified using techniques known in the art, and their activity can be characterized by experimental methods. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc., of the administered compound. Therefore, this invention includes metabolites of the compounds of this invention, including compounds obtained by methods that expose the compounds of this invention to mammals for a time sufficient to produce their metabolites.

[0405] This invention further includes, within its scope, prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention that may themselves have little or no pharmacological activity, which, when administered to or onto the body, can be converted, for example, by hydrolysis and cleavage into the compounds of the invention having the desired activity. Typically, such prodrugs are functional group derivatives of the compounds that are readily converted in vivo into the compounds with the desired therapeutic activity. Further information regarding the use of prodrugs can be found in “Pro-drugs as Novel Delivery Systems,” Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella). The prodrugs of the invention can be prepared, for example, by replacing suitable functional groups present in the compounds of the invention with certain portions known to those skilled in the art as “pro-moiety” (e.g., as described in “Design of Prodrugs,” H. Bundgaard (Elsevier, 1985)).

[0406] This invention also covers compounds of the invention containing protecting groups. In any process of preparing the compounds of the invention, protection of sensitive or reactive groups on any relevant molecule may be necessary and / or desired, thereby forming a form of chemical protection for the compounds of the invention. This can be achieved by conventional protecting groups, for example, those described in TW Greene & P. ​​GMWuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 2006, which are incorporated herein by reference. Protecting groups can be removed at appropriate subsequent stages using methods known in the art.

[0407] This invention also covers methods for preparing the compounds described herein. It should be understood that the compounds of this invention can be synthesized using the methods described below, as well as synthetic methods known in the field of synthetic organic chemistry or variations thereof understood by 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 suitable for the reagents and materials used and suitable for achieving the conversion.

[0408] The terms “active ingredient,” “therapeutic agent,” “active substance,” or “active agent” refer to a chemical entity that can effectively treat one or more symptoms of a target condition or disease.

[0409] As used herein, the term "effective amount" (e.g., "therapeutic effective amount" or "preventive effective amount") refers to the amount of active ingredient that, when administered, will achieve the desired effect to a certain extent, such as relieving one or more symptoms of the treated condition or preventing the occurrence of the condition or its symptoms.

[0410] Unless otherwise stated, as used herein, the term “treatment” means to reverse, alleviate, or inhibit the progression of a disease or condition to which such term applies, or one or more symptoms of such a disease or condition, or to prevent such a disease or condition, or one or more symptoms of such a disease or condition.

[0411] As used herein, “individual” includes both human and non-human animals. Exemplary human individuals include human individuals suffering from a disease (such as the disease described herein) (referred to as patients) or normal individuals. In this invention, “non-human animals” includes 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.).

[0412] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0413] The reagents and raw materials used in this invention are all commercially available.

[0414] The positive and progressive effects of the present invention are as follows: the novel highly active seasedge derivative provided by the present invention can achieve at least one of the following technical effects: (1) high inhibitory activity against tumor cells; (2) excellent physicochemical properties (e.g., solubility, physical and / or chemical stability); (3) excellent safety (lower toxicity and / or fewer side effects, wider therapeutic window), etc. Detailed Implementation

[0415] This invention includes all combinations of the specific embodiments described. Further embodiments of the invention and the full scope of its applicability will become apparent from the detailed description provided below. However, it should be understood that although the detailed description and specific embodiments indicate preferred embodiments of the invention, these descriptions and embodiments are provided by way of illustration only, as various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. For all purposes, all disclosures, patents, and patent applications cited herein, including in quotation marks, are incorporated herein by reference in their entirety. The invention is further illustrated below by way of examples, but this does not limit the invention to the scope of the examples described. Experimental methods in the following examples, unless specific conditions are specified, are performed according to conventional methods and conditions, or as selected according to the trade specification.

[0416] Mass spectrometry (MS) measurements were performed using an Agilent (ESI) mass spectrometer, manufacturer: Agilent, model: Agilent 6120B.

[0417] The preparative high performance liquid chromatography (HPLC) method was performed using a Shimadzu LC-8A preparative liquid chromatograph (YMC, ODS, 250×20mm column).

[0418] Thin-layer chromatography purification was performed using GF 254 (0.4–0.5 nm) silica gel plates produced in Yantai.

[0419] The reaction was monitored using thin-layer chromatography (TLC) or liquid chromatography-mass spectrometry (LC-MS). The developing solvent systems used included, but were 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 solvent was adjusted according to the polarity of the compound, or by adding triethylamine, etc.

[0420] Column chromatography typically uses 200-300 mesh silica gel from Qingdao Ocean 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 solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine can also be added for adjustment.

[0421] Unless otherwise specified in the examples, the reaction temperature is room temperature (20℃~30℃).

[0422] 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, etc.

[0423] The above embodiments do not limit the scope of this application in any way. In addition to those described herein, various modifications to the 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. All references cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) are incorporated herein by reference in their entirety.

[0424] In the conventional synthesis methods, preparation examples, and intermediate synthesis examples, the starting materials were commercially feasible and purchased from Shanghai Leyan, Shanghai Shaoyuan, Bid Biotechnology, Aladdin Reagent, etc. The key starting material M24 and the control compound trabectedine were both purchased from Zhejiang Zhongke Chuangyue. The meanings of the abbreviations are shown in the table below.

[0425]

[0426]

[0427] Synthesis of intermediates:

[0428] Example 1: Preparation of intermediate 1: Preparation of compound Int7

[0429]

[0430] Step 1: Preparation of compound Int7-2

[0431] Compound Int7-1 (5.0 g, 32.7 mmol) was dissolved in anhydrous methanol (80 mL), and a 30% aqueous solution of methylamine (6.8 g, 65.4 mmol) was added. After stirring for 30 min, trimethylcyanosilane (4.9 g, 49.3 mmol) was added, and the mixture was stirred at room temperature for another 30 min. The reaction was monitored by LCMS until complete. The reaction solution was concentrated under reduced pressure, and the residue was extracted with saturated sodium bicarbonate and DCM. After stirring, the mixture was separated into liquid and liquid phases, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain Int7-2 (4.12 g, 64% yield).

[0432] Step 2: Preparation of compound Int7-3

[0433] Compound Int7-2 (1.36 g, 7.08 mmol) was dissolved in THF (40 mL), and DIEA (1.37 g, 10.62 mol) and (Boc)₂O (3.2 g, 17 mmol) were added. The reaction mixture was stirred at room temperature for 16 h, cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography to give Int7-3 (1.2 g, yield 58%).

[0434] MS m / z(ESI): 293.1 [M+H] +

[0435] 1 H NMR (400MHz, CDCl3) δ7.28 (dd, J=8.5, 2.4Hz, 1H), 7.15 (d, J=2.4Hz, 1H), 6.98 (d ,J=8.5Hz,1H),6.40(brs,1H),3.86(s,3H),2.73(s,3H),1.52(d,J=16.5Hz,9H).

[0436] Step 3: Preparation of compound Int7

[0437] Compound Int7-3 (0.5 g, 1.28 mmol) was dissolved in a mixed solution of EtOH (40 mL) and ammonia (30%, 10 mL), and RanyNi (100 mg) was added. After three hydrogen purgings, the pressure was increased to 1.5 MPa and the reaction was carried out at 50 °C for 16 h. The reaction was monitored by LC-MS to ensure complete reaction. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain Int7 (0.26 g, yield 69%).

[0438] Example 2 of intermediate preparation:

[0439]

[0440] Step 1: Preparation of compound Int1-2

[0441] Int1-1 (450.0 mg, 2.13 mmol) was dissolved in MeOH (10 mL), 10% Pd / C (50 mg) was added, and the mixture was purged with hydrogen and stirred at 20 °C under hydrogen for 2 hours. The resulting mixture was filtered through diatomaceous earth, concentrated, and dried to obtain a colorless oily substance, Int1-2 (385 mg crude), which was then used in the next reaction.

[0442] Step 2: Preparation of compound Int1-3

[0443] Int1-2 (385 mg, 2.13 mmol) was dissolved in THF (10 mL), followed by the addition of saturated NaHCO3 (3 mL) and Boc2O (928.68 mg, 4.26 mmol). The mixture was stirred overnight at 20 °C. The resulting mixture was adjusted to pH 5-6 with 1 N HCl, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound Int1-3 (280.0 mg, 47% yield).

[0444] Step 3: Preparation of compound Int1-4

[0445] Int1-3 (270.0 mg, 0.96 mmol) was dissolved in DCM (10 mL) and DMF (1 drop), cooled to 0 °C, and oxaloyl chloride (243.7 mg, 1.92 mmol) was added under nitrogen protection. After the addition was complete, the mixture was allowed to warm naturally to room temperature for 30 minutes. The mixed solution was cooled to 0 °C, and ammonia was slowly added to adjust the pH to approximately 8. The solution was then extracted with ethyl acetate, separated, and the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound Int1-4 (230.0 mg, yield 85.48%).

[0446] Step 4: Preparation of compound Int1

[0447] Int1-4 (230.0 mg, 0.82 mmol) was dissolved in THF (5 mL), followed by the addition of BH3 / THF (6 mL, 1N), and the mixture was heated to 70 °C and stirred for 2 hours. The reaction solution was then cooled to 0 °C, and the reaction was quenched by slow dropwise addition of methanol. HCl / MeOH solution was then added, and the mixture was heated to 70 °C and stirred for 2 hours. The reaction solution was cooled to 40 °C and concentrated under reduced pressure. The residue was purified by reversed-phase HPLC to give compound Int1 (70.0 mg, yield 51.33%).

[0448] Example 3: Preparation of intermediate 2

[0449]

[0450] The intermediate Int2 was synthesized by referring to steps 3 to 4 of Example 2 for intermediate preparation.

[0451] Example 4: Preparation of intermediate 3

[0452]

[0453] The intermediate Int3 was synthesized by referring to steps 3 to 4 of Example 2 for intermediate preparation.

[0454] Example 5: Preparation of intermediate: Int4

[0455]

[0456] The intermediate Int4 was synthesized by referring to steps 3 to 4 of Example 2 for intermediate preparation.

[0457] Example 6: Preparation of intermediate 5

[0458]

[0459] The intermediate Int5 was synthesized by referring to steps 3 to 4 of Example 2 for intermediate preparation.

[0460] Example 7: Preparation of intermediates: Preparation of compound Int6

[0461]

[0462] Step 1: Preparation of compound Int6-2

[0463] At 0 °C, zinc iodide (1.1 g, 3.3 mmol) and TMSCN (1.9 g, 19.8 mmol) were added to a DCM (30 mL) solution of compound Int6-1 (1.0 g, 6.6 mmol), and the mixture was stirred at 0 °C for 1 hour. The reaction was monitored by TLC plate until the starting material was completely reacted. The supernatant was concentrated, and the residue was purified by column chromatography to obtain compound Int6-2 (1.17 g, 99% yield).

[0464] Step 2: Preparation of compound Int6-3

[0465] At 0 °C, a boranetetrahydrofuran solution (20 mL, 20.00 mmol, 1 M) was added to a THF (10 mL) solution of compound Int6-2 (1.17 g, 6.57 mmol), and the reaction mixture was stirred at 70 °C for 2 hours. The mixture was then cooled to 0 °C, and methanol (100 mL) was slowly added to quench the reaction. The reaction mixture was concentrated, and the residue was purified by column chromatography to give compound Int6-3 (1.19 g, 99% yield).

[0466] Step 3: Preparation of compound Int6-4

[0467] At 25°C, saturated sodium bicarbonate aqueous solution (10 mL) and Boc₂O (2.85 g, 13.06 mmol) were added to a tetrahydrofuran solution (10 mL) of compound Int₆-3 (1.19 g, 6.53 mmol), and the mixture was stirred at 25°C for 10 minutes. The reaction solution was concentrated under reduced pressure to remove THF, followed by the addition of ethyl acetate and water. The mixture was separated, and the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography to give compound Int₆-4 (1.5 g, 81% yield).

[0468] Step 4: Preparation of compound Int6-5

[0469] Iron powder (2.6 g, 46.05 mmol) and ammonium chloride (2.5 g, 46.05 mmol) were added to a MeOH / H2O solution (40 mL / 8 mL) of compound Int6-4 (1.3 g, 4.61 mmol) at 25 °C, and the mixture was stirred at 80 °C for 4 hours. After the reaction was complete, the mixture was filtered, the filtrate was concentrated to dryness, and the residue was purified by column chromatography to give compound Int6-5 (1 g, yield 86%).

[0470] Step 5: Preparation of compound Int6

[0471] At 25°C, a solution of dichloromethane (3 mL) containing 900.00 mg (3.57 mmol) of compound Int6-5 was mixed with 3 mL of dioxane solution (3 mL, 12.00 mmol, 4 M) and stirred at 25°C for 1 hour. The reaction solution was concentrated and purified, and Int6 (300.0 mg, yield 55%) was obtained by reverse HPLC purification.

[0472] MS m / z (ESI): 152.9 [M+H] + .

[0473] Example 8: Preparation of intermediates: Preparation of compound Int7

[0474]

[0475] Step 1: Preparation of compound Int7-2

[0476] At 30°C, 10 drops of 37% formaldehyde aqueous solution and sodium cyanoborohydride (317.90 mg, 5.06 mmol) were added to a 6 mL ethanol solution of compound Int7-1 (600.00 mg, 2.53 mmol), and the mixture was stirred at 30°C for 30 minutes. After the reaction solution was concentrated to dryness, the residue was purified by reverse HPLC to obtain compound Int7-2 (150.0 mg, yield 23%).

[0477] Step 1: Preparation of compound Int7

[0478] At 30°C, a solution of dioxane in hydrochloric acid (1.5 mL, 6.00 mmol, 4 M) was added to a 2 mL solution of compound Int7-2 (150.00 mg, 0.60 mmol) in dichloromethane, and the mixture was stirred at 30°C for 60 minutes. After the reaction solution was concentrated to dryness, the residue was purified by reverse HPLC to obtain compound Int7 (80.0 mg, yield 88%).

[0479] Example 1: Synthesis of Compounds 53 and 45

[0480]

[0481] Step 1: Preparation of compound 53-1

[0482] Compound M24 (100 mg, 0.16 mmol) and compound Int7 (0.80 mmol) were dissolved in anhydrous ethanol (5 mL), and acetic acid (120 mg, 2.00 mmol) was added. The mixture was stirred overnight at 60 °C. After the reaction was monitored by LCMS until complete, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was added to ethyl acetate and saturated sodium bicarbonate aqueous solution, stirred, and separated. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by Pre-TLC to give compound 53-1 (112 mg, 78% yield).

[0483] Step 2: Preparation of Compound 53

[0484] Compound 53-1 (112 mg, 0.12 mmol) was dissolved in DCM (2 mL) and added to TFA (0.5 mL). The reaction was carried out at room temperature for 2 h, and the reaction was monitored for completeness by LCMS. The reaction solution was concentrated to dryness under reduced pressure, the pH was adjusted to 8 with saturated sodium bicarbonate solution, and then extracted three times with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 53 (90 mg, 93% yield). Further purification by reverse HPLC yielded compound 53 (70 mg, 72% yield).

[0485] MS m / z (ESI): 800.1 [M+H] +.

[0486] 1 H NMR(400MHz,DMSO-d6)δ9.38(s,1H),8.95–8.65(m,1H),8.50(s,1H),8.43–8.10(m,1H),6.85–6.65(m,1H) ,6.55–6.35(m,2H),6.23–6.11(m,2H),5.95–5.15(brs,4H),5.06(t,J=12.2Hz,1H),4.53(s,2H),4.30–4.0 5(m,3H),4.01–3.88(m,1H),3.68–3.60(m,3H),3.60–3.50(m,3H),3.50–3.24(m,2H),3.24–3.03(m,1H),3. 01–2.61(m,3H),2.43(t,J=5.3Hz,2H),2.29(s,2H),2.24(s,2H),2.14–2.05(m,3H),1.97(d,J=6.8Hz,3H).

[0487] Step 3: Preparation of Compound 45

[0488] Compound 53 (60.0 mg, 0.075 mmol) was dissolved in DMF (1.5 mL), and glycolic acid (5.7 mg, 0.075 mol), HATU (28.7 mg, 0.075 mmol), and DIEA (11.6 mg, 0.090 mmol) were added sequentially. The reaction was carried out at room temperature with stirring for 2 h, and the reaction was monitored for completeness by LCMS. Ethyl acetate and saturated sodium bicarbonate aqueous solution were added, and the mixture was stirred and separated. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative HPLC to give compound 45 (50 mg, yield 64%).

[0489] MS m / z (ESI): 858.3 [M+H] + .

[0490] The compounds were further purified by Pre-TLC using DCM:MeOH as the developing solvent (10:1) to yield two compounds. Peak 1 had a retention time of 1.557 min on LCMS, and peak 2 had a retention time of 1.543 min on LCMS. Characterization is as follows:

[0491] Peak 1:

[0492] MS m / z (ESI): 858.3 [M+H] + .

[0493] 1H NMR (400MHz, DMSO) δ9.21 (s, 1H), 8.75 (s, 1H), 6.51–6.29 (m, 3H), 6.16 (d, J = 9.1Hz, 2H) ,5.14(s,1H),5.04(d,J=11.6Hz,1H),4.54–4.42(m,3H),4.21–4.16(m,1H),4.13–4.08 (m,1H),4.07–4.01(m,2H),3.62(s,3H),3.52(s,3H),2.83–2.67(m,4H),2.47–2.30(m, 3H),2.36–2.29(m,3H),2.22–2.16(m,3H),2.04(s,3H),1.98(s,3H),1.28–1.20(m,6H).

[0494] Peak 2:

[0495] MS m / z (ESI): 858.3 [M+H] + .

[0496] 1 H NMR(400MHz,DMSO-d6)δ9.26(s,1H),8.79(s,1H),6.50–6.40(m,1H),6.40–6.23(m,2H),6.20– 6.10(m,2H),5.40–5.25(m,1H),5.10–5.00(m,1H),4.70–4.60(m,1H),4.53–4.43(m,1H),4.24 –4.19(m,2H),4.15–4.08(m,3H),3.63(s,3H),3.21–3.13(d,J=4.4Hz,3H),2.82–2.64(m,4H), 2.34–2.28(m,3H),2.25–2.16(m,3H),2.08–2.03(m,3H),2.01–1.96(m,3H),1.29–1.21(m,6H).

[0497] Example 2: Synthesis of Compound 46

[0498]

[0499] Compound 45 (30 mg, 0.034 mmol) was dissolved in ACN (3 mL) and water (2 mL), and then silver nitrate (143 mg, 0.840 mmol) was added. The mixture was stirred at room temperature in the dark for 12 hours. After the reaction was monitored by LCMS until complete, saturated sodium bicarbonate aqueous solution was added, and the mixture was stirred and separated. The organic phase was retained, and the aqueous phase was extracted once with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative HPLC to give compound 46 (5 mg, yield 17%).

[0500] MS m / z (ESI): 849.4 [M+H] + .

[0501] 1 H NMR (400MHz, CDCl3) δ6.67-6.29(m,3H),6.08-5.91(m,2H),5.84-5.80(m,1H),5.63-5.50(m ,1H),5.40-5.30(m,1H),5.20-5.04(m,1H),4.88-4.84(m,1H),4.60-4.45(m,2H),4.45-4.0 0(m,5H),3.79(d,J=3.6Hz,3H),3.75-3.70(m,1H),3.67-3.62(m,3H),3.58-3.15(m,3H),3. 00-2.78(m,3H),2.60-2.58(m,1H),2.49-2.45(m,2H),2.38-2.20(m,9H),2.10-2.00(m,4H).

[0502] Example 3: Synthesis of Compound 55

[0503]

[0504] At room temperature, compounds Int1 (50.0 mg, 0.29 mmol) and NaOAc (200 mg, 2.46 mmol) were added to a solution of compound M24 (90.0 mg, 0.14 mmol) in acetic acid (3.0 mL). The reaction mixture was heated to 65 °C and stirred for 3 h. The resulting mixture was then concentrated, and the residue was purified by reversed-phase HPLC to give compound 55 (75 mg, 69% yield).

[0505] MS m / z (ESI): 770.2 [M+H] + .

[0506] 1H NMR (400MHz, DMSO-d6) δ8.69(s,1H),6.43(s,1H),6.20(s,1H),6.17(s,1H),6.15(s,1H),6.14(s,1H),5.02(d,J=11.6H z,1H),4.61(s,2H),4.47(d,J=2.8Hz,2H),4.18(d,J=3.6Hz,1H),4.09(s,1H),4.00(dd,J=2.0,11.2Hz,1H),3.63(s,3H ),3.47(s,3H),3.38-3.34(m,1H),3.32-3.26(m,1H),2.99-2.93(m,1H),2.83-2.75(m,2H),2.71-2.67(m,1H),2.40-2. 32(m,2H),2.29(s,3H),2.24(s,1H),2.20(s,3H),2.10(d,J=14.4Hz,1H),2.04(s,3H),1.97(s,3H),1.79-1.68(m,1H).

[0507] Example 4: Synthesis of Compound 59

[0508]

[0509] Step 1: Preparation of compound 59-1

[0510] At room temperature, Cs₂CO₃ (57.9 mg, 0.18 mmol) and iodomethane (25.2 mg, 0.18 mmol) were added to a DMF (12 mL) solution of compound 53-1 (80.0 mg, 0.09 mmol). The reaction mixture was stirred at room temperature for 1 minute. Ethyl acetate and a saturated aqueous solution of sodium bicarbonate were added, and the mixture was stirred and separated. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give compound 59-1 (30.0 mg, 37% yield).

[0511] Step 2: Preparation of compound 59-2

[0512] At room temperature, HCl / dioxane (4 mmol, 1 mL, 4 M) was added to a DCM (1 mL) solution of compound 59-1 (30.0 mg, 0.03 mmol), and the reaction mixture was stirred at room temperature for half an hour. After concentration, the residue was purified by column chromatography to give compound 59-2 (20.0 mg, 74% yield).

[0513] Step 3: Preparation of compounds 59R and 59S

[0514] At room temperature, glycolic acid (13.1 mg, 0.17 mmol), HATU (31.9 mg, 0.08 mmol), HOAT (31.9 mg, 0.24 mmol), and TMP (38.3 mg, 0.32 mmol) were added to a DMF (4 mL) solution of compound 59-2 (20.0 mg, 0.03 mmol). The reaction solution was stirred at room temperature for 1 hour. The reaction was confirmed to be complete by LCMS. Ethyl acetate and saturated ammonium chloride aqueous solution were added, and the mixture was stirred and separated. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by Pre-TLC. Two compounds were obtained using DCM:MeOH = 10:1 as the developing solvent. Peak 1 had a retention time of 1.649 min on LCMS, and peak 2 had a retention time of 1.622 min on LCMS. Characterization is as follows:

[0515] Peak 1: 6 mg, yield 30%

[0516] MS m / z (ESI): 872.2 [M+H] +

[0517] 1 H NMR (400MHz, DMSO-d6) δ8.74 (s, 1H), 6.74-6.30 (m, 3H), 6.15 (d, J = 9.5Hz, 2H), 5.44-4.90 (m, 2H), 4.40-4.34 (m, 3H), 4.22-4.05 (m, 5H), 3.68-3. 57(m,6H),3.51(s,3H),3.28-3.27(m,3H),3.00-2.62(m,3H),2.42(d,J= 3.1Hz, 3H), 2.32 (d, J = 2.3Hz, 3H), 2.22-2.18 (m, 4H), 2.12-1.87 (m, 8H).

[0518] Peak 2: 6 mg, yield 30%

[0519] MS m / z (ESI): 872.2 [M+H] +

[0520] 1H NMR (400MHz, DMSO-d6) δ8.74 (d, J=6.3Hz, 1H), 6.49-6.29 (m, 3H), 6.14 (d, J= 4.1Hz,2H),5.40-5.27(m,1H),5.05(d,J=11.4Hz,1H),4.67-4.42(m,3H),4. 30-4.03(m,5H),3.63(t,J=2.4Hz,6H),3.49(s,3H),3.27(d,J=12.1Hz,3H), 2.86-2.65(m,3H),2.42-2.28(m,6H),2.22-2.18(m,4H),2.06-1.94(m,8H).

[0521] Example 5: Synthesis of Compound 61

[0522]

[0523] 37% formic acid (4 drops) and NaBH3CN (20.0 mg, 0.32 mmol) were added to a 1 mL ethanol solution of compound 45 (25.0 mg, 0.006 mmol) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse HPLC to give compound 51 (10.0 mg, 40% yield).

[0524] MS m / z (ESI): 872.8 [M+H] +

[0525] 1 H NMR(400MHz,DMSO-d6)δ9.15(d,J=14.0Hz,1H),8.71(d,J=10.2Hz,1H),6.4 5-6.19(m,3H),6.11(d,J=9.7Hz,2H),5.39-4.78(m,2H),4.68-4.43(m,2H), 4.36-3.98(m,4H),3.79-3.54(m,4H),3.52-3.34(m,4H),3.30-3.20(m,3H), 2.87-2.80(m,2H),2.40-2.28(m,7H),2.22-2.06(m,6H),2.01-1.98(m,8H).

[0526] Example 6: Synthesis of Compound 89

[0527]

[0528] Compound 89 was synthesized according to steps 2 to 3 of Example 1.

[0529] MS m / z (ESI): 858.2 [M+H] + .

[0530] Example 7: Synthesis of Compound 91

[0531]

[0532] Compound 91 was synthesized according to steps 2 and 3 of Example 1.

[0533] MS m / z (ESI): 858.2 [M+H] + .

[0534] Example 8: Synthesis of Compound 81

[0535]

[0536] Compound 81 was synthesized according to steps 2 to 3 of Example 1.

[0537] MS m / z (ESI): 828.2 [M+H] + .

[0538] 1 H NMR (400MHz, DMSO-d6) δ9.32(s,1H),8.73(s,1H),7.67(t,J=6.0Hz,1H),6.83(d,J=8.0Hz,1H),6.48-6.39(m,2H),6.34(d,J=2.4Hz,1H),6. 25(s,1H),6.16(s,1H),5.56(t,J=5.6Hz,1H),5.09(d,J=11.2Hz,1H),4.54-4.50(m,1H),4.43(d,J=2.4Hz,1H),4.19(d,J=4.0Hz,1H),4.14 -4.12(m,1H),4.08-4.05(m,1H),3.85(d,J=3.6Hz,2H),3.65-3.64(m,3H),3.40(d,J=10.4Hz,1H),3.22(d,J=4.4Hz,1H),3.15-3.08(m,1H) ,2.89-2.77(m,2H),2.72–2.64(m,1H),2.58-2.54(m,1H),2.38-2.33 (m,1H),2.29(s,3H),2.15(s,3H),1.97(d,J=6.4Hz,6H),1.80(s,1H).

[0539] Example 9: Synthesis of Compound 83

[0540]

[0541] Compound 83 was synthesized according to steps 2 to 3 of Example 1.

[0542] MS m / z (ESI): 828.2 [M+H] + .

[0543] 1 H NMR (400MHz, DMSO-d6) δ9.34(s,1H),8.73(s,1H),7.47(t,J=4.0Hz,1H),6.68(d,J=8.8Hz,1H),6.49(s,1H),6.45(dd,J=8.8,2.4Hz,1H),6 .34(d,J=2.4Hz,1H),6.26(s,1H),6.15(s,1H),5.54(t,J=5.6Hz,1H),5.05(d,J=11.2Hz,1H),4.55-4.51(m,1H),4.46(d,J=2.4Hz,1H),4.1 9(d,J=4.0Hz,1H),4.10(s,1H),4.04-3.94(m,1H),3.85(d,J=5.2Hz,2H),3.63(s,3H),3.50-3.45(m,1H),3.42-3.38(m,1H),3.21(d,J=4. 8Hz,1H),2.91-2.75(m,3H),2.39-2.28(m,3H),2.29(s,3H),2.22-2.14(m,4H),2.02(d,J=7.6Hz,6H),1.97(s,1H),1.70(d,J=14.4Hz,1H).

[0544] Example 9: Synthesis of Compound 93

[0545]

[0546] Step 1: Preparation of Compound 74

[0547] M24 (45.0 mg, 72.4 μmol) and compound 74-1 (45.0 mg, 330.4 μmol) were dissolved in acetic acid (2 mL), and NaOAc (80 mg, 975.3 μmol) was added. The mixture was stirred at 65 °C for 1 hour. The reaction was confirmed to be complete by LCMS. The mixture was concentrated under reduced pressure, and the residue was purified by reversed-phase HPLC to obtain compound 74 (39.8 mg, yield 74.25%).

[0548] MS m / z (ESI): 740.7 [M+H] + .

[0549] 1 H NMR(400MHz,DMSO-d6)δ8.73(s,1H),6.55(d,J=8.5Hz,1H),6.44(s,1H),6.25(s,1H),6.21(dd,J=8 .5,2.3Hz,1H),6.15-6.12(m,2H),5.04(d,J=11.3Hz,1H),4.91(s,2H),4.44(d,J=2.6Hz,2H),4.19 (d,J=3.6Hz,1H),4.05(s,1H),3.94(d,J=9.8Hz,1H),3.63(s,3H),3.24-3.06(m,2H),2.78(d,J=5. 0Hz,2H),2.69-2.57(m,1H),2.45-2.31(m,3H),2.28(s,3H),2.22(s,3H),2.03(s,3H),1.98(s,4H).

[0550] Step 2: Preparation of compound 93-1

[0551] Compound 74 (30.0 mg, 0.041 mmol) was dissolved in DMF (1 mL), and tert-butoxycarbonylaminooxyacetic acid (7.8 mg, 0.041 mol), HATU (15.7 mg, 0.041 mmol), and DIEA (11.6 mg, 0.090 mmol) were added sequentially. The reaction was carried out at room temperature with stirring for 2 h, and the reaction was monitored for completeness by LC-MS. Ethyl acetate and saturated sodium bicarbonate aqueous solution were added, and the mixture was stirred and separated. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give compound 93-1 (26.5 mg, 70% yield).

[0552] Step 3: Preparation of Compound 93

[0553] Compound 93-1 (26.5 mg, 0.028 mmol) was dissolved in DCM (2 mL) and added to TFA (0.5 mL). The reaction was carried out at room temperature for 2 h, and the reaction was monitored for completeness by LC-MS. The reaction solution was concentrated to dryness under reduced pressure, the pH was adjusted to 8 with saturated sodium bicarbonate solution, and then extracted three times with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Compound 93 (3.4 mg, yield 15%) was purified by reverse HPLC. MS m / z (ESI): 827.2 [M+H] + .

[0554] 1H NMR (400MHz, DMSO-d6) δ9.55(s,1H),8.76(s,1H),7.32(s,1H),7.27(d,J=8.7Hz,1H),6.90-6.80(m,2H),6.46(s,1H),6.27(s, 1H),6.17(s,1H),5.06(d,J=11.3Hz,1H),4.46(d,J=2.5Hz,1H),4.20(d,J=4.0Hz,1H),4.08(d,J=9.1Hz,3H),4.01(d,J=10.2H z,1H),3.63(s,3H),3.22(d,J=3.7Hz,1H),3.16-3.11(m,1H),2.79(d,J=4.7Hz,2H),2.69-2.65(m,1H),2.56(d,J=6.4Hz,4H), 2.43(d,J=14.8Hz,2H),2.36–2.31(m,1H),2.28(s,3H),2.23(s,3H),2.04(s,3H),1.99(s,3H),1.77-1.67(s,1H),1.23(s,4H).

[0555] Example 10: Synthesis of Compound 94

[0556]

[0557] Compound 94 was synthesized according to steps 2 to 3 of Example 9.

[0558] MS m / z (ESI): 857.2 [M+H] + .

[0559] 1 H NMR(400MHz,DMSO-d6)δ9.18(s,1H),8.91(s,1H),7.90(s,1H),6.52(s,1H),6.32(s,1H),6.22(s,1 H),6.19(s,1H),5.18(d,J=10.4Hz,1H),4.66-4.57(m,2H),4.25-4.19(m,6H),3.65(s,4H),3.62(s, 4H),3.46(d,J=8.0Hz,1H),3.35(d,J=4.8Hz,2H),3.14(s,1H),2.90-2.84(m,1H),2.76(s,1H),2.6 9-2.66(m,1H),2.62(s,3H),2.43-2.36(s,2H),2.31(s,3H),2.25(s,3H),2.01(s,3H),1.98(s,3H).

[0560] Example 11: Synthesis of Compounds 216 and 217

[0561]

[0562] Step 1: Preparation of Compound 216

[0563] Sodium acetate (98.96 mg, 1.21 mmol) was added to a 5 mL acetic acid solution of M24 (50.00 mg, 0.08 mmol) and compound Int6 (39.17 mg, 0.26 mmol) at 20 °C, and the mixture was stirred at 65 °C for 2 hours. The reaction solution was concentrated and purified by reverse HPLC to give compound 216 (27.0 mg, yield 45%).

[0564] MS m / z (ESI): 756.3 [M+H] + .

[0565] 1 H NMR (400MHz, DMSO-d6) δ8.74 (d, J = 5.6Hz, 1H), 6.71-6.38 (m, 3H), 6.32-6.22 (m, 2H), 6.15 (s, 1H), 5.13-4.57 (m, 4H), 4. 45-4.42(m,2H),4.19-3.93(m,4H),3.63(d,J=5.9Hz,3H),3.23-2.92(m,3H),2.85-2.60(m,3H),2.39-2.23(m,8H),2.09 -1.90(m,7H).

[0566] Step 2: Preparation of compound 217

[0567] Compound 217 was synthesized according to the method in step 3 of Example 9.

[0568] MS m / z (ESI): 814.3 [M+H] + .

[0569] 1H NMR (400MHz, DMSO-d6) δ9.58(d,J=4.2Hz,1H),8.77(d,J=5.2Hz,1H),7.71(d,J=37.1Hz,1H),7.35(d,J=8.6Hz,1H),7. 21(s,1H),6.83(dd,J=20.0,9.4Hz,1H),6.47(d,J=6.3Hz,1H),6.27(d,J=2.3Hz,1H),6.17(s,1H),5.68-5.52(m,1H),5 .39-5.20(m,1H),5.13-5.04(m,1H),4.46(d,J=9.7Hz,2H),4.27-4.18(m,2H),4.12-3.97(m,2H),3.93(d,J=5.9Hz,2H) ,3.64(d,J=6.5Hz,3H),3.09-2.97(m,2H),2.83-2.75(m,3H),2.70-2.65(m,1H),2.34-2.21(m,7H),2.07-1.94(m,8H).

[0570] Example 12: Synthesis of Compound 39

[0571]

[0572] Compound 39 was synthesized according to steps 2 to 3 of Example 9.

[0573] MS m / z(ESI): 812.0 [M+H] + .

[0574] 1 H NMR(400MHz,DMSO-d6)δ8.78(s,1H),7.11-6.84(m,3H),6.47(s,1H),6.25(s,1H), 6.16(s,1H),5.08(d,J=11.4Hz,1H),4.54(t,J=5.7Hz,1H),4.48(s,2H),4.21(d,J= 3.6Hz,1H),4.11-3.97(m,2H),3.80-3.63(m,5H),3.23-3.16(m,4H),3.07(s,3H), 2.79-2.67(m,4H),2.33-2.28(m,4H),2.23(s,3H),2.09-2.04(m,5H),2.00(s,3H).

[0575] Example 1: In vitro proliferation inhibition test of compounds on OVCAR-3, BT474 and LOVO tumor cells

[0576] Test objective

[0577] To detect the inhibitory activity of drug compounds on the in vitro proliferation of OVCAR-3, BT474, and LOVO tumor cells, cells were treated with different concentrations of the compounds in vitro and cultured for 6 days. CTG (Cellular Transmission Therapy) was then used to analyze the cell proliferation. The Luminescent Cell Viability Assay (Promega, catalog number: G7558) uses reagents to detect cell proliferation based on IC50. 50 The value is used to evaluate the in vitro activity of the compound.

[0578] Experimental methods (using OVCAR3 as an example)

[0579] 1. Cell culture: OVCAR-3 cells were cultured in 10% FBS RPMI-1640 medium.

[0580] 2. Cell preparation: Take OVCAR-3 cells in the logarithmic growth phase, wash them once with PBS, add 2-3 ml of trypsin to digest for 2-3 min. After the cells are completely digested, add 10-15 ml of cell culture medium to wash off the digested cells, centrifuge at 1000 rpm for 5 min, discard the supernatant, and then add 10-20 ml of cell culture medium to resuspend the cells to prepare a single-cell suspension.

[0581] 3. Cell plating: Mix the OVCAR-3 single-cell suspension thoroughly, and adjust the viable cell density to 6 x 10⁻⁶ cells / cells using cell culture medium. 4 Cells / ml: After adjusting the cell density, mix the cell suspension thoroughly and add 50 μL / well to a 96-well cell culture plate. Incubate the plate in an incubator for 18 hours (37°C, 5% CO2).

[0582] 4. Compound preparation: Dissolve the compound in DMSO to prepare a stock solution with an initial concentration of 10 mM. There are 9 concentrations of small molecule compounds, with the highest concentration being 1 μM, diluted 3 times.

[0583] 5. Sample addition procedure: Add the prepared test samples at different concentrations to the culture plate, with two replicates for each sample. Incubate the culture plate in an incubator for 6 days (37℃, 5% CO2).

[0584] 6. Color development procedure: Take out the 96-well cell culture plate, add 50 μL of CTG reagent to each well, and incubate at room temperature for 10 minutes.

[0585] 7. Plate reading procedure: Take out the 96-well cell culture plate, place it in the microplate reader, and use the microplate reader to measure the chemiluminescence.

[0586] Data analysis: The data was processed and analyzed using Microsoft Excel and Graphpad Prism 9.

[0587] Table 1 shows the IC50 values ​​of the compounds in this application for inhibiting the in vitro cell proliferation of the aforementioned cells. 50 value

[0588]

[0589]

[0590] Conclusion: The results show that the compound in this application has strong inhibitory activity against the proliferation of OVCAR-3, BT474, and LOVO cells, and its activity is not weaker than or better than that of the control compound trabectedin.

[0591] Example 2 of efficacy test: Toxicological study of different compounds administered intravenously to SD rats

[0592] Experimental Objective

[0593] Sprague-Dawley rats were given a single intravenous injection of three test products. The acute toxicity of the three test products in SD rats was observed to compare their toxic effects and provide data support for subsequent safety evaluation.

[0594] dose:

[0595]

[0596] Under the conditions of this experiment, SD rats were given single intravenous administrations of 0.3 mg / kg trabectin, 2.4 mg / kg compound 45, 2.4 mg / kg compound 55, and 1.2 mg / kg compound 55, respectively.

[0597] Phenomena: On the second day after administration, male rats in the G1 group showed perianal soiling due to loose stools, while female rats exhibited piloerection, arched backs, reduced activity, and reddish discharge around the eyes and nose. All animals in the G1 group died on the second day after administration. Clinical pathological results showed that the G1 group exhibited decreased levels of WBC, PLT, LYMP, MONO, and RET; elevated serum ALT, AST, GGT, DBIL, and TBIL; and decreased K and Cl. Autopsy revealed yellowing in multiple tissues (inner skin, thymus, gastrointestinal tract, and uterus). Female animals also showed hepatomegaly, indicating potential hepatotoxicity of trabectin. Autopsy revealed intestinal hemorrhage, perianal soiling, and thin stomach walls. Male animals also showed punctate protrusions on the intestinal surface; the thymus and spleen were smaller; female animals also showed pulmonary hemorrhages and patchy gray spots on the heart.

[0598] Following administration to group G3, decreased levels of WBC, PLT, LYMP, MONO, and RET were observed; elevated serum ALT, AST, GGT, DBIL, and TBIL were observed, while decreased levels of K and Cl were observed. Animal autopsies also revealed yellowing in multiple tissues (inner skin, thymus, gastrointestinal tract, and uterus). Enlarged livers were also observed in female animals, indicating that compound 55 may be hepatotoxic. Seven days after administration, animals were euthanized. Autopsies revealed intestinal hemorrhage, perianal soiling, and thin stomach walls. Male animals also showed punctate protrusions on the intestinal surface; the thymus and spleen were smaller; and female animals showed pulmonary hemorrhages and patchy gray spots on the heart.

[0599] The G2 and G4 treatment groups were well tolerated, with no significant changes in body weight or food intake.

[0600] Conclusion: At 0.3 MPk, trabectin was intolerable in both male and female SD rats. Compound 45 was well tolerated at 2.4 mg / kg, with significantly better toxicity than trabectin. Compound 55 was well tolerated at 1.2 mg / kg, with significantly better toxicity than trabectin.

[0601] The above embodiments do not limit the scope of this application in any way. In addition to those described herein, various modifications to the 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. All references cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) are incorporated herein by reference in their entirety.

Claims

1. A compound of formula (Ia), or a pharmaceutically acceptable salt thereof: ， in, R 1 is -OH, -CH3or -OCH3; R 11 It can be hydrogen, deuterium, halogen, -CH3, or -OCH3; R 2 for ; R 3 For H; R 4 It is hydrogen, deuterium or C 1-6 alkyl; Y can be either -OH or -CN.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, R 1 It is -OH or -OCH3.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, R 11 It can be hydrogen, deuterium, -F, -Cl, -CH3 or -OCH3.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, R 11 It can be hydrogen, deuterium, or -OCH3.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, R 4 It is hydrogen or -CH3.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, R 4 It is hydrogen.

7. The compound as described in claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, for , Or a combination thereof.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The compound has any of the following structures: , , , , , , , , , , , , , , , , , , , , or .

9. A pharmaceutical composition, characterized in that, It comprises the compound as described in any one of claims 1-8 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

10. The use of substance A in the preparation of a medicament for the prevention or treatment of tumors or cancer, characterized in that, Substance A is a compound as described in any one of claims 1-8 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 9; The tumors or cancers mentioned are breast cancer, colon cancer, and ovarian cancer.

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