Benzyl aniline derivative and application thereof

Abstract

The invention designs a compound with a novel structure, and provides a new direction for the development of PSD-95 inhibitors and butylphthalide drugs. Test results show that the compound can quickly release the PSD-95 inhibitor compound and butylphthalide, almost all of the compound are hydrolyzed into the PSD-95 inhibitor compound and butylphthalide, few other metabolites are generated, and the compound has good in-vivo pharmacokinetics and has patent medicine potential.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, in particular to compounds used as uncoupling agents, in particular to a class of benzylaniline derivatives and uses thereof. Background Art

[0002] Stroke is an acute cerebrovascular disease caused by sudden rupture or occlusion of a cerebral blood vessel, resulting in brain tissue damage. It is categorized as either ischemic or hemorrhagic stroke. Currently, the key to the treatment of acute ischemic stroke (AIS) is to promptly recanalize the blocked vessel and salvage the ischemic penumbra. Currently, proven effective treatments for early recanalization of acute ischemic stroke include rt-PA thrombolysis (ischemic time <6 hours), endovascular mechanical thrombectomy (ischemic time <24 hours >6 hours), and a combination of these two approaches as a bridging therapy. Neuroprotection / brain protection is currently the most effective treatment for salvaging the ischemic penumbra in ischemic stroke research. Excitotoxicity is a key upstream link in the ischemic cascade. The resulting generation of excessive nitric oxide (NO) exacerbates oxidative stress and neuroinflammatory responses downstream, promoting apoptosis of numerous neurons and leading to irreversible neurological damage.

[0003] PSD (postsynaptic density protein) is an electron-dense structure under the excitatory postsynaptic membrane, located at the tip of the dendritic spine. PSD-95 belongs to the DLG (Discs large) scaffold protein family. It is the protein with a molecular weight of 95KD and the highest abundance in PSD. It is the main component of PSD. PSD-95 is the key to maintaining the complex framework of interactions between the postsynaptic density proteins of excitatory neurons and is closely related to neuronal function and survival (neurotransmitter transmission and signal transduction). The structural domain of PSD-95: PSD-95 contains highly conserved domains including PDZ1, PDZ2, PDZ3, SH3 and GK (from N-terminus to C-terminus). The supermodule 1 formed by PZD1 and PZD-2 can form a complex with the NMDAR-GluN2B subunit and nNOS. Under excessive glutamate stimulation, the NMDA receptor is overactivated, and a large amount of Ca 2+ Influx of nNOS activates and produces large amounts of NO, leading to excitotoxicity. Supermodule 2, formed by PDZ3, SH3, and GK, transmits neuronal survival signals and is a target for calpain hydrolysis under excitotoxic stimulation.

[0004] Excitotoxicity refers to neuronal damage caused by excessive release of excitatory neurotransmitters (glutamate and aspartate), which leads to nerve and glial cell damage. It can occur in a variety of neurological diseases (stroke, brain trauma, AD and ALS, etc.). After ischemic stroke, energy metabolism disorders caused by vascular blockage lead to excessive glutamate release, which activates NMDA receptors, thereby triggering a large amount of Ca 2+ Influx of nNOS causes nNOS to move from the cytoplasm to the cell membrane and form a complex with NMDAR-PSD-95, leading to the massive production of NO and triggering ischemic cascade reactions such as oxidative stress and neuroinflammation. 2+ Calpain activation caused by influx interferes with the formation of NMDAR-PSD-95-nNOS complex, inhibits excitotoxicity, blocks ischemic cascade, reduces neuronal and glial cell damage, and improves neural function, becoming a research strategy for neuroprotective therapy targeting NMDAR-PSD-95-nNOS.

[0005] The nNOS-PSD-95 uncoupler 4-N-(2-hydroxy-3,5-dichlorobenzyl)aminosalicylic acid (ZL006) or its analogs can reduce the pathological release of NO mediated by NMDAR without affecting the physiological functions of NMDAR and nNOS. They show significant neuroprotective effects against glutamate-stimulated neuronal cell damage, improve neurological deficits in animals with middle cerebral artery occlusion (MCAO) reperfusion, and reduce infarct volume (Nature Medicine 2010, 16, 1439–1443). Invention patent CN103086908B discloses the 2-canol ester of ZL006 (ZL006-05), which has good anti-stroke (Stroke Vasc Neurol. 2023Apr25:svn-2022-002156) and neuropathic pain effects (Theranostics 2021;11(12):5970-5985). ZL006-05 has currently entered Phase 2 clinical trials for the treatment of stroke.

[0006] 3-n-Butylphthalide (NBP), also known as butylphthalide (trade name "ENBIPU"), chemically known as racemic RS-3-n-butyl-1(3H)-isobenzofuranone, is the first class I new drug independently developed and marketed in my country for the treatment of cerebrovascular disease with independent intellectual property rights. It was approved for marketing in November 2004 for the treatment of mild to moderate ischemic stroke. Clinical trials have shown that butylphthalide significantly improves central nervous system damage in patients with acute ischemic stroke and promotes functional recovery. Animal pharmacodynamic studies have shown that butylphthalide can block multiple pathological links of brain damage caused by ischemic stroke, and has good anti-cerebral ischemia and brain protection effects. In particular, it can significantly increase the levels of ATP and creatine phosphate in the brain of ischemic mice, significantly reduce the infarct area of ​​local cerebral ischemia in rats, reduce cerebral edema, improve brain energy metabolism and microcirculation and blood flow in the ischemic brain area, inhibit nerve cell apoptosis, and exhibit certain anti-cerebral thrombosis and anti-platelet aggregation effects (J. Neurol. Sci., 2007, 260, 106). Literature shows that butylphthalide can relieve microvascular spasm, inhibit platelet aggregation, inhibit the synthesis of thromboxane A2, scavenge free radicals, etc. by affecting the metabolism of arachidonic acid (AA) and selectively inhibiting various pathophysiological processes mediated by AA and its metabolites. It can thus block the pathophysiological development process caused by cerebral ischemia through multiple pathways and multiple links, protect neurons, and restore neural function (J. Cardiovasc. Pharmacol., 2004, 43, 876; Acta Pharmacol. Sin., 1998, 19, 117).

[0007] How to more effectively utilize different drugs in preventing and treating acute ischemic brain injury and stroke is a technical problem that needs to be solved urgently with existing technologies. Summary of the Invention

[0008] The present invention aims to provide a novel PSD-95 uncoupler compound, a method for preparing the compound, and its use in treating diseases mediated by PSD-95. The novel compound has good pharmacokinetic properties and low toxicological properties.

[0009] One of the objects of the present invention is to provide a compound represented by the following formula (A1), a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt of the compound:

[0010]

[0011] in,

[0012] R1 is hydroxy, C1-C6 alkoxy or -OC(O)R 11 ;

[0013] R2, R3, R5, R6, R9, or R 10 each independently hydrogen, halogen, or trifluoromethyl;

[0014] R4is halogen or trifluoromethyl;

[0015] R7is -C(O)R 12 , hydroxy, C1-C6alkoxy, -OCH2C(O)R 12 , -OC(O)R 11 , -OCH2C(O)B,

[0016]

[0017] R8is -C(O)R 12 , hydroxy, C 1-6 alkyl, -OCH2C(O)R 12 , -OC(O)R 11 , or -OCH2C(O)B;

[0018] X is hydrogen or C 1-6 alkyl;

[0019] Y is hydrogen, C 1-6 alkyl, -CH2C(O)R 13 , -C(O)R 13 ,

[0020] wherein at least one of R7, R8, and Y contains a B group;

[0021] when R7is -C(O)R 12 , hydroxy, C1-C6alkoxy, -OCH2C(O)R 12 , -OC(O)R 11 , -OCH2C(O)B, Y is

[0022] when R7is , Y is hydrogen, C 1-6 alkyl, -CH2C(O)R 13 , -C(O)R 13 ,

[0023] R 11 each occurrence is independently selected from C 1-6 alkyl or B;

[0024] R 12 each occurrence is independently selected from C 1-6 alkyl, hydroxy, C 1-6 alkoxy, or B;

[0025] R 13 C 1-6 Alkyl, C1-C6 alkoxy or B;

[0026] B is

[0027] L1 is a bond, -C(O)-(CH2) 1-10 -O-, -C(O)NH-(CH2) 1-6 -O-, -C(O)N(CH3)-(CH2) 1-6 -O-, -C(O)-(CH2) 1-6 -NH-, -C(O)-(CH2) 1-6 -N(CH3)-, -C(O)NH-(CH2) 1-6 -NH-, -C(O)NH-(CH2) 1-6 -N(CH3)-, -C(O)N(CH3)-(CH2) 1-6 -NH-, -C(O)N(CH3)-(CH2) 1-6 -N(CH3)-, -(CH2) 1-6 -O-, -C(O)-(CH2) 1-6 -C(O)O-(CH2) 1-10 -O-;

[0028] L2 is -C(O)-(CH2) 1-6 -C(O)-, -C(O)-(CH2) 1-6 -P(O)(OH)-, -P(O)(OH)-(CH2) 1-6 -C(O)-, -P(O)(OH)-(CH2) 1-6 -P(O)(OH)-、-(CH2) 1-6 -C(O)-, -(CH2) 0-6 -P(O)(OH)-, -C(O)-(CH2) 1-6 -OC(O)-、-P(O)(OH)-(CH2) 1-6 -OC(O)-、-(CH2) 1-6 -OC(O)-;-C(O)-;

[0029] L3 is a bond, -C(O)-(CH2) 1-6 -O-, -C(O)NH-(CH2) 1-6 -O-, -C(O)N(CH3)-(CH2) 1-6 -O-, -C(O)-(CH2) 1-6-NH-, -C(O)-(CH2) 1-6 -N(CH3)-, -C(O)NH-(CH2) 1-6 -NH-, -C(O)NH-(CH2) 1-6 -N(CH3)-, -C(O)N(CH3)-(CH2) 1-6 -NH-, -C(O)N(CH3)-(CH2) 1-6 -N(CH3)-, -(CH2) 1-6 -O-;

[0030] L4 is -C(O)-(CH2) 1-6 -C(O)-, -C(O)-(CH2) 1-6 -P(O)(OH)-, -P(O)(OH)-(CH2) 1-6 -C(O)-, -P(O)(OH)-(CH2) 1-6 -P(O)(OH)-、-(CH2) 0-6 -C(O)-, -(CH2) 0-6 -P(O)(OH)-、-(CH2) 1-6 -OC(O)-, -C(O)-(CH2) 1-6 -OC(O)-、-P(O)(OH)-(CH2) 1-6 -OC(O)-、-(CH2) 1-6 -OC(O)-;

[0031] R 15 and R 17 are independently hydrogen, -C(O)-C 1-10 Alkyl, -C(O)-C 0-10 Alkyl-C 3-10 Cycloalkyl, -C(O)-C 1-10 Alkyl-C(O)OC 3-10 Cycloalkyl, -C(O)-C 1-10 Alkyl-OC 3-10 Cycloalkyl, -C(O)-C 1-10 Alkyl-NH-C 3-10 Cycloalkyl, -C(O)-C 1-10 Alkyl-C(O)OH, -C(O)-C 1-10 Alkyl-NH2, -C(O)-C 1-10 Alkyl-NH(CH3), -C(O)-C 1-10 Alkyl-N(CH3)2, -C 1-10 Alkyl-OC(O)-C 1-10 Alkyl, -C1-10 Alkyl-OC(O)-OC 1-10 Alkyl, -C 1-10 Alkyl-OC(O)-C 3-10 Cycloalkyl, -C(O)OC 1-10 Alkyl-OC 1-10 Alkyl, -C(O)OC 1-10 Alkyl-OC 3-10 Cycloalkyl, -C(O)-C 1-10 Alkyl-N(C 1-3 Alkyl)2;

[0032] R 16 and R 18 are independently hydrogen, C 1-10 Alkyl, C 3-10 Cycloalkyl, The C 1-10 Alkyl, C 3-10 Cycloalkyl is optionally substituted by one or more alkyl radicals selected from halogen, oxo, -CN, -OH, -SH, -NO2, -NH2, C 1-3 The group is substituted by an alkyl group or a halogenated C1-3 alkyl group.

[0033] Preferably, the present invention provides a compound represented by the following formula (A), a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt of the compound:

[0034]

[0035] in,

[0036] R1 is hydroxy, C1-C6 alkoxy or -OC(O)R 11 ;

[0037] R2, R3, R5, R6, R9 or R 10 are each independently hydrogen, halogen or trifluoromethyl;

[0038] R4 is halogen or trifluoromethyl;

[0039] R7 is -C(O)R 12 , hydroxyl, C1-C6 alkoxy, -OCH2C(O)R 12 、-OC(O)R 11 、-OCH2C(O)B、

[0040]

[0041] R8 is -C(O)R 12 , hydroxyl, C1-6 alkyl, -CH2C(O)R 12 , -C(O)R 11 , -OCH2C(O)B;

[0042] X is hydrogen or C 1-6 alkyl;

[0043] Y is hydrogen, C 1-6 alkyl, -CH2C(O)R 13 , -C(O)R 13 ,

[0044] wherein at least one of R7, R8and Y contains a B group;

[0045] when R7is -C(O)R 12 , hydroxy, C1-C6alkoxy, -OCH2C(O)R 12 , -OC(O)R 11 , -OCH2C(O)B, Y is

[0046] when R7is , Y is hydrogen, C 1-6 alkyl, -CH2C(O)R 13 , -C(O)R 13 ,

[0047] R 11 is independently at each occurrence C 1-6 alkyl or B;

[0048] R 12 is independently at each occurrence C 1-6 alkyl, hydroxy, C 1-6 alkoxy or B;

[0049] R 13 is C 1-6 alkyl, C1-C6alkoxy or B;

[0050] B is

[0051] L1is a bond, -C(O)-(CH2) 1-10 -O-, -C(O)NH-(CH2) 1-6 -O-, -C(O)N(CH3)-(CH2) 1-6 -O-, -C(O)-(CH2) 1-6 -NH-, -C(O)-(CH2) 1-6 -N(CH3)-, -C(O)NH-(CH2)1-6 -NH-, -C(O)NH-(CH2) 1-6 -N(CH3)-, -C(O)N(CH3)-(CH2) 1-6 -NH-, -C(O)N(CH3)-(CH2) 1-6 -N(CH3)-, -(CH2) 1-6 -O-, -C(O)-(CH2) 1-6 -C(O)O-(CH2) 1-10 -O-;

[0052] L2is -C(O)-(CH2) 1-6 -C(O)-, -C(O)-(CH2) 1-6 -P(O)(OH)-, -P(O)(OH)-(CH2) 1-6 -C(O)-, -P(O)(OH)-(CH2) 1-6 -P(O)(OH)-, -(CH2) 1-6 -C(O)-, -(CH2) 0-6 -P(O)(OH)-, -C(O)-(CH2) 1-6 -O-C(O)-, -P(O)(OH)-(CH2) 1-6 -O-C(O)-, -(CH2) 1-6 -O-C(O)-; -C(O)-;

[0053] L3is a bond, -C(O)-(CH2) 1-6 -O-, -C(O)NH-(CH2) 1-6 -O-, -C(O)N(CH3)-(CH2) 1-6 -O-, -C(O)-(CH2) 1-6 -NH-, -C(O)-(CH2) 1-6 -N(CH3)-, -C(O)NH-(CH2) 1-6 -NH-, -C(O)NH-(CH2) 1-6 -N(CH3)-, -C(O)N(CH3)-(CH2) 1-6 -NH-, -C(O)N(CH3)-(CH2) 1-6 -N(CH3)-, -(CH2) 1-6 -O-;

[0054] L4is -C(O)-(CH2) 1-6 -C(O)-, -C(O)-(CH2) 1-6 -P(O)(OH)-, -P(O)(OH)-(CH2) 1-6-C(O)-, -P(O)(OH)-(CH2) 1-6 -P(O)(OH)-、-(CH2) 0-6 -C(O)-, -(CH2) 0-6 -P(O)(OH)-、-(CH2) 1-6 -OC(O)-, -C(O)-(CH2) 1-6 -OC(O)-、-P(O)(OH)-(CH2) 1-6 -OC(O)-、-(CH2) 1-6 -OC(O)-;

[0055] R 15 and R 17 are independently hydrogen, -C(O)-C 1-10 Alkyl, -C(O)-C 0-10 Alkyl-C 3-10 Cycloalkyl, -C(O)-C 1-10 Alkyl-C(O)OC 3-10 Cycloalkyl, -C(O)-C 1-10 Alkyl-OC 3-10 Cycloalkyl, -C(O)-C 1-10 Alkyl-NH-C 3-10 Cycloalkyl, -C(O)-C 1-10 Alkyl-C(O)OH, -C(O)-C 1-10 Alkyl-NH2, -C(O)-C 1-10 Alkyl-NH(CH3), -C(O)-C 1-10 Alkyl-N(CH3)2, -C 1-10 Alkyl-OC(O)-C 1-10 Alkyl, -C 1-10 Alkyl-OC(O)-OC 1-10 Alkyl, -C 1-10 Alkyl-OC(O)-C 3-10 Cycloalkyl, -C(O)OC 1-10 Alkyl-OC 1-10 Alkyl, -C(O)OC 1-10 Alkyl-OC 3-10 Cycloalkyl,

[0056] R 16 and R 18 are independently hydrogen, C 1-10 Alkyl, C 3-10 Cycloalkyl, The C 1-10alkyl, C 3-10 cycloalkyl is optionally substituted with one or more substituents selected from the group consisting of halo, oxo, -CN, -OH, -SH, -NO2, -NH2, C 1-3 alkyl, haloC1-3alkyl.

[0057] Preferably, the present application further provides a compound of the following formula (I), a stereoisomer, a tautomer or a mixture thereof of the compound, or a pharmaceutically acceptable salt of the compound:

[0058]

[0059] wherein,

[0060] R1is hydroxy, C1-C6alkoxy or -OC(O)R 11 ;

[0061] R2, R3, R5, R6, R9or R 10 are each independently hydrogen, halo or trifluoromethyl;

[0062] R4is halo or trifluoromethyl;

[0063] R7is -C(O)R 12 , hydroxy, C1-C6alkoxy, -OCH2C(O)R 12 , -OC(O)R 11 , -OCH2C(O)B,

[0064]

[0065] R8is -C(O)R 12 , hydroxy, C 1-6 alkoxy, -OCH2C(O)R 12 , -OC(O)R 11 or -OCH2C(O)B;

[0066] X is hydrogen or C 1-6 alkyl;

[0067] Y is hydrogen, C 1-6 alkyl, -CH2C(O)R 13 , -C(O)R 13 ,

[0068] wherein at least one of R7, R8and Y contains a B group;

[0069] when R7is -C(O)R 12 , hydroxy, C1-C6alkoxy, -OCH2C(O)R 12 , -OC(O)R11 、-OCH2C(O)B, Y is

[0070] When R7 is When Y is hydrogen, C 1-6 Alkyl, -CH2C(O)R 13 、-C(O)R 13 、

[0071] R 11 Each occurrence is independently selected from C 1-6 Alkyl or B;

[0072] R 12 Each occurrence is independently selected from C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy or B;

[0073] R 13 C 1-6 Alkyl, C1-C6 alkoxy or B;

[0074] B is

[0075] L1 is a bond, -C(O)-(CH2) 1-6 -O-, -C(O)NH-(CH2) 1-6 -O-, -C(O)N(CH3)-(CH2) 1-6 -O-, -C(O)-(CH2) 1-6 -NH-, -C(O)-(CH2) 1-6 -N(CH3)-, -C(O)NH-(CH2) 1-6 -NH-, -C(O)NH-(CH2) 1-6 -N(CH3)-, -C(O)N(CH3)-(CH2) 1-6 -NH-, -C(O)N(CH3)-(CH2) 1-6 -N(CH3)-;

[0076] L2 is -C(O)-(CH2) 1-6 -C(O)-, -C(O)-(CH2) 1-6 -P(O)(OH)-, -P(O)(OH)-(CH2) 1-6 -C(O)-, -P(O)(OH)-(CH2) 1-6 -P(O)(OH)-、-(CH2) 1-6 -C(O)-, -(CH2) 0-6-P(O)(OH)-, -C(O)-(CH2) 1-6 -OC(O)-、-P(O)(OH)-(CH2) 1-6 -OC(O)-、-(CH2) 1-6 -OC(O)-;

[0077] L3 is a bond, -C(O)-(CH2) 1-6 -O-, -C(O)NH-(CH2) 1-6 -O-, -C(O)N(CH3)-(CH2) 1-6 -O-, -C(O)-(CH2) 1-6 -NH-, -C(O)-(CH2) 1-6 -N(CH3)-, -C(O)NH-(CH2) 1-6 -NH-, -C(O)NH-(CH2) 1-6 -N(CH3)-, -C(O)N(CH3)-(CH2) 1-6 -NH-, -C(O)N(CH3)-(CH2) 1-6 -N(CH3)-, -(CH2) 1-6 -O-;

[0078] L4 is -C(O)-(CH2) 1-6 -C(O)-, -C(O)-(CH2) 1-6 -P(O)(OH)-, -P(O)(OH)-(CH2) 1-6 -C(O)-, -P(O)(OH)-(CH2) 1-6 -P(O)(OH)-、-(CH2) 0-6 -C(O)-, -(CH2) 0-6 -P(O)(OH)-、-(CH2) 1-6 -OC(O)-, -C(O)-(CH2) 1-6 -OC(O)-、-P(O)(OH)-(CH2) 1-6 -OC(O)-、-(CH2) 1-6 -OC(O)-;

[0079] R 15 and R 17 are independently hydrogen, -C(O)-C 1-10 Alkyl, -C(O)-C 0-10 Alkyl-C 3-10 Cycloalkyl, -C(O)-C 1-10 Alkyl-C(O)OC 3-10 Cycloalkyl, -C(O)-C 1-10Alkyl-OC 3-10 Cycloalkyl, -C(O)-C 1-10 Alkyl-NH-C 3-10 Cycloalkyl, -C(O)-C 1-10 Alkyl-C(O)OH, -C(O)-C 1-10 Alkyl-NH2, -C(O)-C 1-10 Alkyl-NH(CH3), -C(O)-C 1-10 Alkyl-N(CH3)2, -C 1-10 Alkyl-OC(O)-C 1-10 Alkyl, -C 1-10 Alkyl-OC(O)-OC 1-10 Alkyl, -C 1-10 Alkyl-OC(O)-C 3-10 Cycloalkyl, -C(O)OC 1-10 Alkyl-OC 1-10 Alkyl, -C(O)OC 1-10 Alkyl-OC 3-10 Cycloalkyl,

[0080] R 16 and R 18 are independently hydrogen, C 1-10 Alkyl, C 3-10 Cycloalkyl, The C 1-10 Alkyl, C 3-10 Cycloalkyl is optionally substituted by one or more alkyl radicals selected from halogen, oxo, -CN, -OH, -SH, -NO2, -NH2, C 1-3 The group is substituted by an alkyl group or a halogenated C1-3 alkyl group.

[0081] In a preferred embodiment of the present invention, R1 is hydroxyl or C1-C4 alkoxy; more preferably, R1 is hydroxyl.

[0082] In a preferred embodiment of the present invention, R1 is hydroxy, methoxy or -OCOCH3; more preferably, R1 is hydroxy.

[0083] In a preferred embodiment of the present invention, R2, R3, R5, R6, R9 or R 10 Each independently represents -H, -F, -Cl or -Br; more preferably, R2, R3, R5, R6, R9 or R 10 are each independently -H or -Cl.

[0084] In a preferred embodiment of the present invention, R4 is trifluoromethyl, -F, -Cl or -Br; more preferably, R4 is -Cl.

[0085] In a preferred embodiment of the present invention, X is hydrogen or C 1-4 More preferably, X is hydrogen or methyl; more preferably, X is hydrogen.

[0086] In a preferred embodiment of the present invention, R7 is -COB, -OH, -OCOR 11 、-COR 12 , C1-C6 alkoxy or -OCH2COR 12 , Y is More preferably, R7 is -COB, -OH, -OCOCH3, -OCOC3H7, -OCOC5H 11 , -COOCH3, -COOH, -COOC2H5, -OCH3, -OC4H9, -OCH2COOCH3, -OCH2COOC2H5 or -OCH2COB, Y is

[0087] In a preferred embodiment of the present invention, R8 is -COB, -OH, -OCOR 11 or-COR 12 ; More preferably, R8 is -COB, -OH, -OCOCH3, -COOCH3, -COOH or -COOC2H5; More preferably, R8 is -COB.

[0088] In a preferred embodiment of the present invention, R 11 C 1-6 Straight chain alkyl; R 12 For hydroxyl, C 1-4 Straight chain alkoxy or B.

[0089] In a preferred embodiment of the present invention, L3 is a bond, -C(O)-(CH2) 1-4 -O-, -C(O)NH-(CH2) 1-4 -O-, -C(O)N(CH3)-(CH2) 1-4 -O-, -C(O)-(CH2) 1-4 -NH-, -C(O)-(CH2) 1-4 -N(CH3)-, -C(O)NH-(CH2) 1-4 -NH-, -C(O)NH-(CH2) 1-4 -N(CH3)-, -C(O)N(CH3)-(CH2) 1-4-NH-, -C(O)N(CH3)-(CH2) 1-4 -N(CH3)-, -(CH2) 1-4 -O-; More preferably, L3 is a bond, -C(O)-(CH2) 1-3 -O-, -C(O)NH-(CH2) 1-3 -O-, -C(O)N(CH3)-(CH2) 1-3 -O-, -C(O)-(CH2) 1-3 -NH-, -C(O)-(CH2) 1-3 -N(CH3)-, -C(O)NH-(CH2) 1-3 -NH-, -C(O)NH-(CH2) 1-3 -N(CH3)-, -C(O)N(CH3)-(CH2) 1-3 -NH-, -C(O)N(CH3)-(CH2) 1-3 -N(CH3)-, -(CH2) 1-3 -O-; More preferably, L3 is a bond, -C(O)-(CH2) 1-3 -NH-, -C(O)-(CH2) 1-3 -N(CH3)-, -(CH2) 1-3 -O-; More preferably, L3 is a bond, -C(O)-(CH2) 2-3 -NH-, -C(O)-(CH2) 2-3 -N(CH3)-, -(CH2)-O-.

[0090] In a preferred embodiment of the present invention, L4 is -C(O)-(CH2) 1-4 -C(O)-, -C(O)-(CH2) 1-4 -P(O)(OH)-, -P(O)(OH)-(CH2) 1-4 -C(O)-, -P(O)(OH)-(CH2) 1-4 -P(O)(OH)-、-(CH2) 0-4 -C(O)-, -(CH2) 0-4 -P(O)(OH)-、-(CH2) 1-4 -OC(O)-, -C(O)-(CH2) 1-4 -OC(O)-、-P(O)(OH)-(CH2) 1-4 -OC(O)-、-(CH2) 1-4 -OC(O)-; More preferably, L4 is -C(O)-(CH2) 1-3 -C(O)-, -C(O)-(CH2) 1-3-P(O)(OH)-, -P(O)(OH)-(CH2) 1-3 -C(O)-, -P(O)(OH)-(CH2) 1-3 -P(O)(OH)-、-(CH2) 0-3 -C(O)-, -(CH2) 0-3 -P(O)(OH)-、-(CH2) 1-3 -OC(O)-, -C(O)-(CH2) 1-3 -OC(O)-、-P(O)(OH)-(CH2) 1-3 -OC(O)-、-(CH2) 1-3 -OC(O)-; More preferably, L4 is -C(O)-(CH2)2-C(O)-, -(CH2) 0-1 -C(O)-, -(CH2) 0-1 -P(O)(OH)-.

[0091] In a preferred embodiment of the present invention, R 17 is hydrogen, -C(O)-C 1-6 Alkyl, -C(O)-C 0-6 Alkyl-C 3-6 Cycloalkyl, -C(O)-C 1-6 Alkyl-COO-C 3-6 Cycloalkyl, -C(O)-C 1-6 Alkyl-OC 3-6 Cycloalkyl, -C(O)-C 1-6 Alkyl-NH-C 3-6 Cycloalkyl, -C(O)-C 1-6 Alkyl-COOH,

[0092] -C(O)-C 1-6 Alkyl-NH2, -C(O)-C 1-6 Alkyl-NH(CH3), -C(O)-C 1-6 Alkyl-N(CH3)2, -C 1-6 Alkyl-OC(O)-C 1-6 Alkyl, -C 1-6 Alkyl-OC(O)-OC 1-6 Alkyl, -C 1-6 Alkyl-OC(O)-C 3-6 Cycloalkyl, -COO-C 1-6 Alkyl-OC 1-6 Alkyl, -COO-C 1-6 Alkyl-OC 3-6 Cycloalkyl, More preferably, R 17 is hydrogen, -C(O)-C 1-6 Alkyl, -C(O)-C 0-6 Alkyl-C 3-6 Cycloalkyl, -C(O)-C 1-6 Alkyl-COOH, -C(O)-C 1-6 Alkyl-NH2, -C(O)-C 1-6 Alkyl-NH(CH3), -C(O)-C 1-6 Alkyl-N(CH3)2, Even more preferably, R 17 is hydrogen, -C(O)-CH3, -C(O)-CH2CH3, -C(O)-CH(CH3)2, -C(O)-cyclopropane, -C(O)-cyclobutane, -C(O)-cyclopentane, -C(O)-cyclohexane, -C(O)-CH2CH2-COOH, -C(O)-CH2-NH2, -C(O)-CH2-NH(CH3), -C(O)-CH2-N(CH3)2, Even more preferably, R 17 is hydrogen, -C(O)-CH3, -C(O)-CH2CH3, -C(O)-CH(CH3)2, -C(O)-cyclopropane, -C(O)-cyclobutane, -C(O)-CH2CH2-COOH, -C(O)-CH2-NH(CH3),

[0093]

[0094] In a preferred embodiment of the present invention, R 18 are independently hydrogen, C 1-8 Alkyl, C 3-6 Cycloalkyl, The C 1-8 Alkyl, C 3-6 Cycloalkyl is optionally substituted by one or more alkyl radicals selected from halogen, oxo, -CN, -OH, -SH, -NO2, -NH2, C 1-3 Alkyl, halogenated C 1-3 More preferably, R 18 are independently hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, The C 1-6 Alkyl, C 3-6 Cycloalkyl is optionally substituted by one or more alkyl radicals selected from halogen, C 1-3 Alkyl, halogenated C 1-3More preferably, R 18 are independently hydrogen, n-hexyl, cyclohexyl,

[0095] In a preferred embodiment of the present invention, R7 is Y is hydrogen, C 1-3 Alkyl, -CH2C(O)C 1-3 Alkyl, -C(O)C 1-3 alkyl,

[0096] In a preferred embodiment of the present invention, R7 is Y is hydrogen, methyl, ethyl, n-propyl, isopropyl, -CH2C(O)CH3, -C(O)CH3,

[0097] In a preferred embodiment of the present invention, L1 is a bond, -C(O)-(CH2) 1-4 -O-, -C(O)NH-(CH2) 1-4 -O-, -C(O)N(CH3)-(CH2) 1-4 -O-, -C(O)-(CH2) 1-4 -NH-, -C(O)-(CH2) 1-4 -N(CH3)-, -C(O)NH-(CH2) 1-4 -NH-, -C(O)NH-(CH2) 1-4 -N(CH3)-, -C(O)N(CH3)-(CH2) 1-4 -NH-, -C(O)N(CH3)-(CH2) 1-4 -N(CH3)-; More preferably, L1 is a bond, -C(O)-(CH2) 1-3 -O-, -C(O)NH-(CH2) 1-3 -O-, -C(O)N(CH3)-(CH2) 1-3 -O-, -C(O)-(CH2) 1-3 -NH-, -C(O)-(CH2) 1-3 -N(CH3)-, -C(O)NH-(CH2) 1-3 -NH-, -C(O)NH-(CH2) 1-3 -N(CH3)-, -C(O)N(CH3)-(CH2) 1-3 -NH-, -C(O)N(CH3)-(CH2) 1-3 -N(CH3)-; More preferably, L1 is a bond, -C(O)NH-(CH2) 1-3-NH-, -C(O)NH-(CH2) 1-3 -N(CH3)-; More preferably, L1 is a bond, -C(O)NH-(CH2) 2-3 -NH-, -C(O)NH-(CH2) 2-3 -N(CH3)-.

[0098] In a preferred embodiment of the present invention, L1 is a bond, -C(O)-(CH2) 1-10 -O-, -(CH2) 1-6 -O-, -C(O)-(CH2) 1-6 -C(O)O-(CH2) 1-10 -O-; preferably, L1 is a bond, -C(O)-(CH2) 1-8 -O-, -(CH2) 1-3 -O-, -C(O)-(CH2) 1-3 -C(O)O-(CH2) 1-8 -O-; More preferably, L1 is a bond, -C(O)-(CH2) 1-7 -O-, -(CH2) 1-2 -O-, -C(O)-(CH2) 1-2 -C(O)O-(CH2) 1-6 -O-; even more preferably, L1 is a bond, -C(O)-(CH2)7-O-, -CH2-O-, -C(O)-(CH2)2-C(O)O-(CH2)6-O-.

[0099] In a preferred embodiment of the present invention, L2 is -C(O)-(CH2) 1-6 -C(O)-, -C(O)-(CH2) 1-6 -P(O)(OH)-, -P(O)(OH)-(CH2) 1-6 -C(O)-, -P(O)(OH)-(CH2) 1-6 -P(O)(OH)-、-(CH2) 1-6 -C(O)-, -(CH2) 0-6 -P(O)(OH)-、-(CH2) 1-6 -OC(O)-, -C(O)-(CH2) 1-6 -OC(O)-、-P(O)(OH)-(CH2) 1-6 -OC(O)-、-(CH2) 1-6 -OC(O)-; More preferably, L2 is -C(O)-(CH2) 1-4 -C(O)-, -C(O)-(CH2) 1-4-P(O)(OH)-, -P(O)(OH)-(CH2) 1-4 -C(O)-, -P(O)(OH)-(CH2) 1-4 -P(O)(OH)-、-(CH2) 1-4 -C(O)-, -(CH2) 0-4 -P(O)(OH)-、-(CH2) 1-4 -OC(O)-, -C(O)-(CH2) 1-4 -OC(O)-、-P(O)(OH)-(CH2) 1-4 -OC(O)-、-(CH2) 1-4 -OC(O)-; More preferably, L2 is -C(O)-(CH2) 1-3 -C(O)-, -C(O)-(CH2) 1-3 -P(O)(OH)-, -P(O)(OH)-(CH2) 1-3 -C(O)-, -P(O)(OH)-(CH2) 1-3 -P(O)(OH)-、-(CH2) 1-3 -C(O)-, -(CH2) 0-3 -P(O)(OH)-、-(CH2) 1-3 -OC(O)-, -C(O)-(CH2) 1-3 -OC(O)-、-P(O)(OH)-(CH2) 1-3 -OC(O)-、-(CH2) 1-3 -OC(O)-; even more preferably, L2 is -C(O)-(CH2)2-C(O)-, -CH2-C(O)-, -P(O)(OH)-, -CH2-OC(O)-.

[0100] In a preferred embodiment of the present invention, L2 is -C(O)-, -C(O)-(CH2) 1-6 -C(O)-; More preferably, L2 is -C(O)-, -C(O)-(CH2) 1-3 -C(O)-; even more preferably, L2 is -C(O)-, -C(O)-(CH2)2-C(O)-.

[0101] In a preferred embodiment of the present invention, R 15 is hydrogen, -C(O)-C 1-6 Alkyl, -C(O)-C 0-6 Alkyl-C 3-6 Cycloalkyl, -C(O)-C 1-6 Alkyl-COO-C 3-6 Cycloalkyl, -C(O)-C1-6 Alkyl-OC 3-6 Cycloalkyl, -C(O)-C 1-6 Alkyl-NH-C 3-6 Cycloalkyl, -C(O)-C 1-6 Alkyl-COOH, -C(O)-C 1-6 Alkyl-NH2, -C(O)-C 1-6 Alkyl-NH(CH3), -C(O)-C 1-6 Alkyl-N(CH3)2, -C 1-6 Alkyl-OC(O)-C 1-6 Alkyl, -C 1-6 Alkyl-OC(O)-OC 1-6 Alkyl, -C 1-6 Alkyl-OC(O)-C 3-6 Cycloalkyl, -COO-C 1-6 Alkyl-OC 1-6 Alkyl, -COO-C 1-6 Alkyl-OC 3-6 Cycloalkyl, More preferably, R 15 is hydrogen, -C(O)-C 1-4 Alkyl, -C(O)-C 0-4 Alkyl-C 3-6 Cycloalkyl, -C(O)-C 1-4 Alkyl-COO-C 3-6 Cycloalkyl, -C(O)-C 1-4 Alkyl-OC 3-6 Cycloalkyl, -C(O)-C 1-4 Alkyl-NH-C 3-6 Cycloalkyl, -C(O)-C 1-4 Alkyl-COOH,

[0102]

[0103] -C(O)-C 1-4 Alkyl-NH2, -C(O)-C 1-4 Alkyl-NH(CH3), -C(O)-C 1-4 Alkyl-N(CH3)2, -C 1-4 Alkyl-OC(O)-C 1-4 Alkyl, -C 1-4 Alkyl-OC(O)-OC 1-4 Alkyl, -C 1-4 Alkyl-OC(O)-C 3-6 Cycloalkyl, -COO-C 1-4 Alkyl-OC 1-4 Alkyl, -COO-C 1-4 Alkyl-OC 3-6 Cycloalkyl, Even more preferably, R 15 is hydrogen, -C(O)-C 1-3 Alkyl, -C(O)-C 0-3 Alkyl-C 3-6 Cycloalkyl, -C(O)-C 1-3 Alkyl-COOH, -C(O)-C 1-3 Alkyl-NH(CH3), Even more preferably, R 15 is hydrogen, -C(O)-CH3, -C(O)-CH2CH3, -C(O)-CH(CH3)2, -C(O)-cyclopropyl, -C(O)-cyclobutyl, -C(O)-cyclopentyl, -C(O)-cyclohexyl, -C(O)-CH2CH2-COOH, -C(O)-CH2-NH(CH3), Even more preferably, R 15 is hydrogen, -C(O)-CH3, -C(O)-CH2CH3, -C(O)-CH(CH3)2, -C(O)-cyclopropyl, -C(O)-cyclobutyl, -C(O)-CH2CH2-COOH, -C(O)-CH2-NH(CH3),

[0104] In a preferred embodiment of the present invention, R 15 -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Alkyl-COOH, -C(O)-C 1-6 Alkyl-N(CH3)2; More preferably, R 15 -C(O)-C 1-3 Alkyl, -C(O)-C 1-3 Alkyl-COOH, -C(O)-C 1-3 Alkyl-N(CH3)2; even more preferably, R 15 -C(O)-C 1-2 Alkyl, -C(O)-C 1-2 Alkyl-COOH, -C(O)-C 1-2 Alkyl-N(CH3)2; even more preferably, R 15It is -C(O)-CH3, -C(O)-CH2CH2-COOH, -C(O)-CH2-N(CH3)2.

[0105] In a preferred embodiment of the present invention, R 15 It is -C(O)-CH2-N(C2H5)2.

[0106] In a preferred embodiment of the present invention, R 16 are independently hydrogen, C 1-8 Alkyl, C 3-6 Cycloalkyl, The C 1-8 Alkyl, C 3-6 Cycloalkyl is optionally substituted by one or more alkyl radicals selected from halogen, oxo, -CN, -OH, -SH, -NO2, -NH2, C 1-3 Alkyl, halogenated C 1-3 More preferably, R 16 are independently hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, The C 1-6 Alkyl, C 3-6 Cycloalkyl is optionally substituted by one or more alkyl radicals selected from halogen, C 1-3 Alkyl, halogenated C 1-3 More preferably, R 16 are independently hydrogen, n-hexyl, cyclohexyl,

[0107] In a preferred embodiment of the present invention, R 16 for

[0108] In a preferred embodiment of the present invention, R 16 For methyl and ethyl.

[0109] In a preferred embodiment of the present invention, L3 is a bond, -C(O)-(CH2) 1-4 -O-, -C(O)NH-(CH2) 1-4 -O-, -C(O)N(CH3)-(CH2) 1-4 -O-, -C(O)-(CH2) 1-4 -NH-, -C(O)-(CH2) 1-4 -N(CH3)-, -C(O)NH-(CH2) 1-4 -NH-, -C(O)NH-(CH2) 1-4 -N(CH3)-, -C(O)N(CH3)-(CH2) 1-4-NH-, -C(O)N(CH3)-(CH2) 1-4 -N(CH3)-, -(CH2) 1-4 -O-; More preferably, L3 is a bond, -C(O)-(CH2) 1-3 -O-, -C(O)NH-(CH2) 1-3 -O-, -C(O)N(CH3)-(CH2) 1-3 -O-, -C(O)-(CH2) 1-3 -NH-, -C(O)-(CH2) 1-3 -N(CH3)-, -C(O)NH-(CH2) 1-3 -NH-, -C(O)NH-(CH2) 1-3 -N(CH3)-, -C(O)N(CH3)-(CH2) 1-3 -NH-, -C(O)N(CH3)-(CH2) 1-3 -N(CH3)-, -(CH2) 1-3 -O-; More preferably, L3 is a bond, -C(O)-(CH2) 1-3 -NH-, -C(O)-(CH2) 1-3 -N(CH3)-, -(CH2) 1-3 -O-; More preferably, L3 is a bond, -C(O)-(CH2) 2-3 -NH-, -C(O)-(CH2) 2-3 -N(CH3)-, -(CH2)-O-.

[0110] In a preferred embodiment of the present invention, L4 is -C(O)-(CH2) 1-4 -C(O)-, -C(O)-(CH2) 1-4 -P(O)(OH)-, -P(O)(OH)-(CH2) 1-4 -C(O)-, -P(O)(OH)-(CH2) 1-4 -P(O)(OH)-、-(CH2) 0-4 -C(O)-, -(CH2) 0-4 -P(O)(OH)-、-(CH2) 1-4 -OC(O)-, -C(O)-(CH2) 1-4 -OC(O)-、-P(O)(OH)-(CH2) 1-4 -OC(O)-、-(CH2) 1-4 -OC(O)-; More preferably, L4 is -C(O)-(CH2) 1-3 -C(O)-, -C(O)-(CH2) 1-3-P(O)(OH)-, -P(O)(OH)-(CH2) 1-3 -C(O)-, -P(O)(OH)-(CH2) 1-3 -P(O)(OH)-、-(CH2) 0-3 -C(O)-, -(CH2) 0-3 -P(O)(OH)-、-(CH2) 1-3 -OC(O)-, -C(O)-(CH2) 1-3 -OC(O)-、-P(O)(OH)-(CH2) 1-3 -OC(O)-、-(CH2) 1-3 -OC(O)-; More preferably, L4 is -C(O)-(CH2)2-C(O)-, -(CH2) 0-1 -C(O)-, -(CH2) 0-1 -P(O)(OH)-.

[0111] In a preferred embodiment of the present invention, R 17 is hydrogen, -C(O)-C 1-6 Alkyl, -C(O)-C 0-6 Alkyl-C 3-6 Cycloalkyl, -C(O)-C 1-6 Alkyl-COO-C 3-6 Cycloalkyl, -C(O)-C 1-6 Alkyl-OC 3-6 Cycloalkyl, -C(O)-C 1-6 Alkyl-NH-C 3-6 Cycloalkyl, -C(O)-C 1-6 Alkyl-COOH,

[0112] -C(O)-C 1-6 Alkyl-NH2, -C(O)-C 1-6 Alkyl-NH(CH3), -C(O)-C 1-6 Alkyl-N(CH3)2, -C 1-6 Alkyl-OC(O)-C 1-6 Alkyl, -C 1-6 Alkyl-OC(O)-OC 1-6 Alkyl, -C 1-6 Alkyl-OC(O)-C 3-6 Cycloalkyl, -COO-C 1-6 Alkyl-OC 1-6 Alkyl, -COO-C 1-6 Alkyl-OC 3-6 Cycloalkyl, More preferably, R 17 is hydrogen, -C(O)-C 1-6 Alkyl, -C(O)-C 0-6 Alkyl-C 3-6 Cycloalkyl, -C(O)-C 1-6 Alkyl-COOH, -C(O)-C 1-6 Alkyl-NH2, -C(O)-C 1-6 Alkyl-NH(CH3), -C(O)-C 1-6 Alkyl-N(CH3)2, Even more preferably, R 17 is hydrogen, -C(O)-CH3, -C(O)-CH2CH3, -C(O)-CH(CH3)2, -C(O)-cyclopropane, -C(O)-cyclobutane, -C(O)-cyclopentane, -C(O)-cyclohexane, -C(O)-CH2CH2-COOH, -C(O)-CH2-NH2, -C(O)-CH2-NH(CH3), -C(O)-CH2-N(CH3)2, Even more preferably, R 17 is hydrogen, -C(O)-CH3, -C(O)-CH2CH3, -C(O)-CH(CH3)2, -C(O)-cyclopropane, -C(O)-cyclobutane, -C(O)-CH2CH2-COOH, -C(O)-CH2-NH(CH3),

[0113]

[0114] In a preferred embodiment of the present invention, R 18 are independently hydrogen, C 1-8 Alkyl, C 3-6 Cycloalkyl, The C 1-8 Alkyl, C 3-6 Cycloalkyl is optionally substituted by one or more alkyl radicals selected from halogen, oxo, -CN, -OH, -SH, -NO2, -NH2, C 1-3 Alkyl, halogenated C 1-3 More preferably, R 18 are independently hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, The C 1-6 Alkyl, C 3-6 Cycloalkyl is optionally substituted by one or more alkyl radicals selected from halogen, C 1-3 Alkyl, halogenated C 1-3More preferably, R 18 are independently hydrogen, n-hexyl, cyclohexyl,

[0115] In a preferred embodiment of the present invention, Y is H, methyl, In a preferred embodiment of the present invention, Y is

[0116]

[0117] In a preferred embodiment of the present invention, R7 is OH.

[0118] In a preferred embodiment of the present invention, R7 is

[0119]

[0120] In a preferred embodiment of the present invention, R7 is

[0121] In a preferred embodiment of the present invention, R7 is

[0122] In a preferred embodiment of the present invention, the compound of formula (A1), formula (A) or formula (I), the stereoisomers, tautomers or mixtures thereof, or the pharmaceutically acceptable salts of the compound are further represented by formula (II):

[0123]

[0124] Wherein, the substituents Y and R7 are as described in formula (A1), formula (A) or formula (I).

[0125] In a preferred embodiment of the present invention, the compound represented by formula (A1), formula (A) or formula (I), the stereoisomers, tautomers or mixtures thereof, or the pharmaceutically acceptable salts of the compound are further represented by formula (III):

[0126]

[0127] Wherein, the substituent Y is as described in formula (A1), formula (A) or formula (I).

[0128] In a preferred embodiment of the present invention, the compound represented by formula (I) of the present invention, the stereoisomers, tautomers or mixtures thereof, or the pharmaceutically acceptable salts of the compound, is further represented by formula (IV):

[0129]

[0130] Wherein, the substituent R7 is as described in formula (A1), formula (A) or formula (I).

[0131] The present invention also provides a compound represented by formula (B1), a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt of the compound.

[0132]

[0133] in,

[0134] R 1a For hydroxyl, C 1-6 alkoxy;

[0135] R 2a 、R 3a 、R 4a 、R 5a 、R 6a 、R 9a or R 10a are independently hydrogen, halogen, C 1-3 Alkyl or halogenated C 1-3 alkyl;

[0136] R 7a Hydroxyl, -OL 1a -O-Ba;

[0137] R 8a -C(O)R 12a , hydroxyl, -C(O)O-(CH2) 1-6 -C(O)O-Ba, -C(O)O-Ba;

[0138] Xa and Ya are each independently hydrogen or C 1-6 Alkyl, C(O)C 1-6 alkyl;

[0139] R 12a Each occurrence is independently selected from C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy or B;

[0140] B is

[0141] Bawei

[0142] L 1a -(CH2) 1-6 -OC(O)-, -C(O)-, -C(O)-(CH2) 1-6 -C(O)-.

[0143] Preferably, the present invention also provides a compound represented by formula (B), a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt of the compound,

[0144]

[0145] in,

[0146] R 1a For hydroxyl, C 1-6 alkoxy;

[0147] R 2a 、R 3a 、R 4a 、R 5a 、R 6a 、R 9a or R 10a are independently hydrogen, halogen, C 1-3 Alkyl or halogenated C 1-3 alkyl;

[0148] R 7a Hydroxyl, -OL 1a -O-Ba;

[0149] R 8a -C(O)R 12a , hydroxyl, -C(O)O-(CH2) 1-3 -C(O)O-Ba, -C(O)O-Ba;

[0150] Xa and Ya are each independently hydrogen or C 1-6 Alkyl, C(O)C 1-6 alkyl;

[0151] R 12a Each occurrence is independently selected from C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy or B;

[0152] B is

[0153] Bawei

[0154] L 1a -(CH2) 1-6 -OC(O)-, -C(O)-, -C(O)-(CH2)1-6 -C(O)-.

[0155] In a preferred embodiment of the present invention, R 1a It is a hydroxyl group.

[0156] In a preferred embodiment of the present invention, R 2a 、R 3a 、R 4a 、R 5a 、R 6a 、R 9a or R 10a are independently hydrogen or halogen.

[0157] In a preferred embodiment of the present invention, R 2a and R 4a Cl, R 3a 、R 5a 、R 6a 、R 9a and R 10a For hydrogen.

[0158] In a preferred embodiment of the present invention, Xa, Ya are each independently hydrogen.

[0159] In a preferred embodiment of the present invention, R 7a is hydroxyl; R 8a is -C(O)O-Ba.

[0160] In a preferred embodiment of the present invention, R 7a is hydroxyl group, R 8a -C(O)O-(CH2) 1-4 -C(O)O-Ba; preferably, R 7a is hydroxyl group, R 8a It is -C(O)O-(CH2)3-C(O)O-Ba or -C(O)O-(CH2)4-C(O)O-Ba.

[0161] In a preferred embodiment of the present invention, R 7a For-OL 1a -O-Ba;L 1a -(CH2) 1-3 -OC(O)-, -C(O)-, -C(O)-(CH2) 1-3 -C(O)-; more preferably, L 1a It is -CH2-OC(O)-, -C(O)-, -C(O)-(CH2)2-C(O)-.

[0162] On the basis of conforming to the common sense in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0163] The compound of the present invention has the following structure:

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176] , or a stereoisomer, tautomer or mixture thereof, or a pharmaceutically acceptable salt of the compound.

[0177] The present invention also aims to provide a method for preparing the compound represented by the above general formula, the stereoisomers, tautomers or mixtures thereof, or the pharmaceutically acceptable salts of the compound.

[0178] The compound of the general formula can be prepared by a variety of methods, including but not limited to the following methods:

[0179] Option 1:

[0180]

[0181] Compound a is subjected to an ester condensation reaction to obtain compound c, and then the nitro group of compound c is reduced to produce compound h; compound h undergoes a reductive amination reaction with f to obtain compound j, and the amine of compound j undergoes condensation or SN2 reaction to obtain compound III, and compound III further undergoes a phenolic hydroxyl esterification reaction to obtain compound II.

[0182] Option 2:

[0183]

[0184] Compound a is subjected to an ester condensation reaction to obtain c, and then the phenolic hydroxyl group of the compound is further esterified to obtain intermediate d, and the nitro group is reduced to generate compound e; compound e undergoes a reductive amination reaction with f to obtain the present compound IV.

[0185] The present invention also provides a pharmaceutical composition comprising the compound of the present invention, a stereoisomer, a tautomer, or a mixture thereof, or a pharmaceutically acceptable salt of the compound. Furthermore, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0186] The present invention also aims to provide the use of the compound of the present invention, the stereoisomers, tautomers or mixtures thereof, or pharmaceutically acceptable salts of the compound in the preparation of drugs for treating or preventing diseases mediated by PSD-95.

[0187] In some embodiments, the PSD-95-mediated disease is stroke, chronic pathological pain, or neurodegenerative disease.

[0188] The present invention also aims to provide the use of the compounds of the present invention, stereoisomers, tautomers or mixtures thereof, or pharmaceutically acceptable salts of the compounds in the preparation of drugs for treating or preventing stroke, chronic pathological pain or neurodegenerative diseases.

[0189] The present invention also aims to provide a method for preventing and / or treating diseases mediated by PSD-95, comprising administering to a patient a therapeutically effective dose of a compound of the present invention, a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt of the compound or the pharmaceutical composition of the present invention.

[0190] The present invention also aims to provide a method for preventing and / or treating stroke, chronic pathological pain or neurodegenerative diseases, which comprises administering to a patient a therapeutically effective dose of the compound of the present invention, a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt of the compound or the pharmaceutical composition of the present invention.

[0191] The compounds of the present invention, their stereoisomers, tautomers or mixtures thereof, or pharmaceutically acceptable salts thereof can be administered in combination with other drugs for treating or preventing related diseases (stroke, chronic pathological pain or neurodegenerative diseases).

[0192] definition

[0193] Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, a straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 10 carbon atoms (i.e., C 1-10 Alkyl), further preferably containing 1 to 8 carbon atoms (C 1-8 Alkyl), more preferably containing 1-6 carbon atoms (ie C 1-6 Alkyl), such as "C 1-6 "Alkyl" means that the group is an alkyl group and the number of carbon atoms in the carbon chain is between 1 and 6 (specifically 1, 2, 3, 4, 5 or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0194] Unless otherwise specified, the term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (eg, bicyclic and tricyclic) groups, including fused cycloalkyl groups, bridged cycloalkyl groups, or spirocycloalkyl groups.

[0195] For example, cycloalkyl can comprise 3 to 16 (such as 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5 or 3 to 4) carbon atoms.Even further for example, cycloalkyl can be selected from the monocyclic group comprising 3 to 12 (such as 3 to 10, further such as 3 to 8, 3 to 6) carbon atoms.The example of monocyclic cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl.Particularly, the example of saturated monocyclic cycloalkyl (for example, C3-8 cycloalkyl) includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.In preferred embodiments, cycloalkyl is the monocycle (abbreviated as C3-6 cycloalkyl) comprising 3 to 6 carbon atoms, and it includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples of bicyclic cycloalkyls include those having 5 to 12, further such as 7 to 12 or 5 to 10 ring atoms arranged as a fused bicyclic ring selected from [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems, or arranged as a bridged bicyclic ring selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane. Other examples of bicyclic cycloalkyls include rings arranged as bicyclic rings selected from [5,6] and [6,6] ring systems. The rings may be saturated or have at least one double bond (i.e., partially unsaturated), but are not fully conjugated and are not aromatic as aromatic is defined herein.

[0196] "Alkoxy" refers to an -O-alkyl group, wherein the alkyl group is as defined above, i.e., containing 1-20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-8 carbon atoms, and more preferably 1-6 carbon atoms (specifically 1, 2, 3, 4, 5, or 6). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, and the like.

[0197] Unless otherwise specified, the term "halogen" or "halo" refers to F, Cl, Br, I. The term "haloalkyl" refers to an alkyl group as defined above in which one, two or more hydrogen atoms or all of the hydrogen atoms are replaced by halogen. Representative examples of haloalkyl include CCl3, CF3, CHCl2, CH2Cl, CH2Br, CH2I, CH2CF3, CF2CF3, and the like.

[0198] Unless otherwise specified, the term "aryl" refers to a monocyclic, bicyclic, or tricyclic aromatic carbocyclic ring system containing 6 to 16 carbon atoms, or 6 to 14 carbon atoms, or 6 to 12 carbon atoms, or 6 to 10 carbon atoms, preferably 6 to 10 carbon atoms. The term "aryl" can be used interchangeably with the term "aromatic ring." Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, or pyrenyl.

[0199] The term "alkylene" refers to a divalent alkyl group as defined above. The term "alkenylene" refers to a divalent alkenyl group as defined above. The term "alkynylene" refers to a divalent alkynyl group as defined above. The term "cycloalkylene" refers to a divalent cycloalkyl group as defined above. The term "heterocyclylene" refers to a divalent heterocyclyl group as defined above. The term "arylene" refers to a divalent aryl group as defined above. The term "heteroarylene" refers to a divalent heteroaryl group as defined above.

[0200] Unless otherwise specified, the term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with mammalian tissues, particularly human tissues, without excessive toxicity, irritation, allergic response, etc., and is commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. For example, pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of the present invention, or separately by reacting the free base or free acid with a suitable reagent.

[0201] The compounds of the present invention also include their "isotopic derivatives". Unless otherwise specified, the term "isotopic derivative" means that the compounds of the present invention may exist in an isotopically labeled or enriched form, containing one or more atoms whose atomic mass or mass number is different from the atomic mass or mass number of the largest atom found in nature. Isotopes can be radioactive or non-radioactive isotopes. Isotopes commonly used as isotopic labels are: hydrogen isotopes, 2 H and 3 H; Carbon isotope: 13 C and 14 C; Chlorine isotope: 35 Cl and 37 Cl; Fluorine isotope: 18 F; Iodine isotope: 123 I and 125 I; Nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotopes 35 These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. 3 H and 13 C, because they are easy to label and detect, they are more widely used. Some heavy isotopes, such as deuterium ( 2 H) substitution can enhance metabolic stability and prolong half-life, thereby achieving the goal of reducing dosage and providing therapeutic advantages. Isotope-labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques similar to those used for synthesizing non-isotope-labeled compounds.

[0202] The compounds of the present invention also include solvates thereof. Unless otherwise specified, the terms "solvate" and "solvate" mean a physical association of a compound of the present invention with one or more solvent molecules (whether organic or inorganic). This physical association includes hydrogen bonding. In certain circumstances, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be capable of isolation. The solvent molecules in the solvate may exist in a regular and / or disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" encompasses both solution-phase and isolatable solvates. Solvation methods are well known in the art.

[0203] Unless otherwise specified, the term "stereoisomer" refers to compounds that have the same chemical constitution but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans) isomers, atropisomers, etc. Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on the differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0204] Unless otherwise specified, the term "tautomer" refers to structural isomers of different energies that are interconvertible through a low energy barrier. If tautomerism is possible (e.g., in solution), a chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions that occur via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions that occur via reorganization of some of the bonding electrons.

[0205] Unless otherwise specified, the term "optionally substituted" means that the hydrogen at the substitutable position of the group is not replaced, or is replaced by one or more substituents, preferably substituted by 1, 2 or 3 substituents, preferably selected from the group consisting of halogen, hydroxy, mercapto, cyano, nitro, amino, azido, oxo, carboxyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkylsulfonyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-10 membered heteroaromatic ring group, wherein the C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkylsulfonyl, 3-10 membered heterocycloalkyl, C 6-14 The aryl or 5-10 membered heteroaromatic ring group may be optionally selected from halogen, hydroxy, amino, cyano, C 1-6 Alkyl or C 1-6 The alkoxy group is substituted by one or more substituents, and the oxo group means that two H at the same substitution position are replaced by the same O to form a double bond.

[0206] The beneficial effects of the present invention are:

[0207] This invention designs a class of novel compounds, providing a new direction for the development of PSD-95 inhibitors and butylphthalide-based drugs. Experimental results demonstrate that the compounds rapidly release ZL006-05 and butylphthalide, are almost completely hydrolyzed into ZL006-05 and butylphthalide, and produce minimal other metabolites. They also exhibit favorable in vivo pharmacokinetics. In an excitotoxicity model, the compounds demonstrate excellent neuroprotective effects at varying concentrations, demonstrating potential for drug development. DETAILED DESCRIPTION

[0208] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. Experimental methods in the following examples where specific conditions are not specified are generally performed under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to professionals in the field. In addition, any methods and materials similar or equivalent to those described herein can be applied to the present invention. The preferred embodiments and materials shown herein are for demonstration purposes only.

[0209] The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS) and / or liquid chromatography (HPLC). NMR measurements were performed using a Bruker 400 MHz and / or Varian 400 MHz instrument; LC-MS measurements were performed using an Agilent 1260 Infinity II-6120 / 6125 MSD; and HPLC measurements were performed using a Waters UPCC (CA-352) instrument.

[0210] The starting materials in the examples of the present invention are known and can be purchased commercially, or can be synthesized using or according to methods known in the art.

[0211] The present invention provides a method for preparing the compound. The compound can be prepared by the following steps.

[0212] Example 1 (Compound 1)

[0213] Preparation of 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl-4-(2-(1-acetoxypentyl)-N-(3,5-dichloro-2-hydroxybenzyl)benzamido)-2-hydroxybenzoate:

[0214]

[0215] Step 1: Dissolve 3-butylisobenzofuran-1-(3H)-one (5.0 g) in methanol (30.0 mL). Add potassium hydroxide (1.4 g) and reflux at 70°C for 16 hours. The reaction mixture is spin-dried, slurried with methyl tert-butyl ether, and filtered to obtain the desired product (3.0 g).

[0216] Step 2: Potassium 2-(1-hydroxypentyl)benzoate (1.0 g) was dissolved in dichloromethane (10.0 mL). N,N-dimethylformamide (5.0 mL) was added to aid solubilization. The temperature was then cooled to -20°C, and acetyl chloride (1.0 mol / L in chloroform) (4.0 mL) was slowly added dropwise. The reaction was maintained at this temperature and continued for 2.0 hours. The reaction solution was adjusted to a pH of 2.0-3.0 using 1.0 mol of dilute hydrochloric acid. The solution was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. The reaction solution was then spin-dried to obtain the crude compound. The desired product (0.3 g) was isolated by column chromatography using a petroleum ether-ethyl acetate system (petroleum ether:ethyl acetate = 9:1).

[0217] Step 3: Dissolve 2-hydroxy-4-nitrobenzoic acid (10.0 g) in dichloromethane (100.0 mL), add 1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (8.4 g), and then add 4-dimethylaminopyridine (1.3 g). Stir for 5 minutes, then add N,N'-dicyclohexylcarbodiimide (22.5 g). The reaction mixture is allowed to react at 25°C for 4.0 hours. The solid is filtered, and water (100.0 mL) is added for extraction. The organic phase is dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product is then separated by column chromatography using a petroleum ether / ethyl acetate system (petroleum ether:ethyl acetate = 20:1) to obtain the desired product (12.0 g).

[0218] Step 4: Dissolve 1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl-2-hydroxy-4-nitrobenzoate (12.0 g) in methanol (120.0 mL), then add 10% palladium on carbon (4.0 g) and react at 25°C for 16.0 hours. The reaction mixture was filtered to remove the solid, and the organic phase was dried to give the crude desired product (9.0 g). LCMS (ESI) [M+H] + =290.3.

[0219] Step 5: Dissolve 1,7,7-trimethylbicyclo[2.2.1]hept-2-yl-4-amino-2-hydroxybenzoate (1.0 g) in ethanol (30.0 mL), then add 3,5-dichloro-2-hydroxybenzaldehyde (0.7 g). React at 25°C for 4 hours. Filter the reaction mixture to obtain the crude desired product (0.6 g).

[0220] Step 6: 1,7,7-Trimethylbicyclo[2.2.1]heptan-2-yl(E)-4-((3,5-dichloro-2-hydroxybenzylidene)amino)-2-hydroxybenzoate (1.0 g) was dissolved in ethanol (30.0 mL), followed by the addition of sodium borohydride (122.0 mg) and the reaction was allowed to proceed at 0°C for 2 hours. The reaction mixture was adjusted to pH with 1.0 mol of dilute hydrochloric acid, filtered, and the organic phase was dried to obtain a crude product. The crude product was then separated by column chromatography using a petroleum ether-ethyl acetate system (petroleum ether:ethyl acetate = 8:1) to obtain the desired product (0.8 g). LCMS (ESI) [M+H] + =464.3.

[0221] Step 7: 1,7,7-Trimethylbicyclo[2.2.1]heptane-2-yl-4-((3,5-dichloro-2-hydroxybenzyl)amino)-2-hydroxybenzoate (100.0 mg) was dissolved in dichloromethane (5.0 mL), 2-(1-acetoxypentyl)benzoic acid (53.0 mg) was added, dissolved in dichloromethane (10.0 mL), 4-dimethylaminopyridine (6.0 mg) was added, and then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (82.0 mg) was slowly added. The reaction was maintained at this temperature and continued for 4.0 hours. Water (20.0 mL) was added and the mixture was extracted with ethyl acetate (20.0*3 mL). The organic phase was dried over anhydrous sodium sulfate and the reaction solution was spin-dried to obtain a crude product. The compound of Example 1 (50.0 mg) was obtained by column separation using a petroleum ether-ethyl acetate system. LCMS (ESI) [M+H] + =696.5. 1H NMR (400MHz, DMSO-d6) δ10.86(s,1H),8.23(d,J=8.0Hz,1H),7.81(d,J=4.0Hz,1H),7.75(td,J=7.6,1.4Hz,1H),7.65(d,J=8. 0Hz,1H),7.58–7.50(m,2H),7.35(d,J=4Hz,1H),7.26(t,J=6.0Hz,1H),6.39(s,1H),6.21(dd,J=8.8,2.2Hz,1H),5.96(d,J=2. 0Hz,1H),4.99-4.95(m,1H),4.35(s,2H),2.40–2.29(m,1H),2.05(s,3H),2.02–1.97(m,1H),1.81–1.73(m,2H),1.71-1.69(m, 1H),1.43–1.32(m,2H),1.31–1.20(m,4H),1.07–1.00(m,1H),0.91(s,3H),0.88(s,3H),0.86-0.81(m,6H),0.80–0.75(m,1H).

[0222] Example 2 (Compound 2)

[0223] Preparation of 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 4-(N-(3,5-dichloro-2-hydroxybenzyl)-2-(1-(isobutyryloxy)pentyl)benzamido)-2-hydroxybenzoate:

[0224]

[0225] Step 1: Refer to the first step of Example 1 to obtain the target product (3.0 g).

[0226] Step 2: Potassium 2-(1-hydroxypentyl)benzoate (3.0 g) was dissolved in dichloromethane (30.0 mL). N,N-dimethylformamide (10.0 mL) was added for solubilization. Triethylamine (3 mL) was then added and the temperature was cooled to -20°C. Isobutyric anhydride (2.0 g) was slowly added with stirring and the reaction was maintained at this temperature for 2.0 hours. The reaction mixture was adjusted to a pH of 2.0-3.0 using 1.0 mol of dilute hydrochloric acid. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. The solvent was evaporated to dryness to obtain the crude compound. The desired product (0.6 g) was obtained by column separation using a petroleum ether-ethyl acetate system (petroleum ether:ethyl acetate = 5:1).

[0227] Step 3: 1,7,7-Trimethylbicyclo[2.2.1]heptane-2-yl-4-((3,5-dichloro-2-hydroxybenzyl)amino)-2-hydroxybenzoate (100.0 mg) was dissolved in dichloromethane (5.0 mL), 2-(1-(isobutyryloxy)pentyl)benzoic acid (60 mg) was added and dissolved in dichloromethane (10.0 mL). 4-Dimethylaminopyridine (6.0 mg) was added, and then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (82.0 mg) was slowly added. The reaction was continued at room temperature for 4.0 hours. Water (20.0 mL) was added, and the mixture was extracted with ethyl acetate (20.0*3 mL). The organic phase was dried over anhydrous sodium sulfate, and the reaction solution was spin-dried to obtain the crude product. The compound of Example 2 (85.0 mg) was obtained by preparative separation using a reverse system. LCMS (ESI) [M+H] + =724.49. 1 H NMR (400MHz, DMSO-d6) δ10.86(s,1H),8.24(d,J=8.0Hz,1H),7.80(d,J=2.5Hz,1H),7.76(td,J=7.8,1.4Hz, 1H),7.63(d,J=7.8Hz,1H),7.58–7.48(m,2H),7.38(d,J=2.4Hz,1H),7.25(t,J=6.0Hz,1H),6.40(s,1H),6. 22(dd,J=8.9,2.3Hz,1H),5.98(d,J=2.2Hz,1H),4.99–4.95(m,1H),4.36(s,2H),2.61–2.56(m,1H),2.39–2 .31(m,1H),2.04–1.97(m,1H),1.78–1.69(m,4H),1.39–1.23(m,6H),1.10–1.01(m,7H),0.93–0.79(m,12H).

[0228] Example 3 (Compound 3)

[0229] Preparation of 2-(1-((4-((,5-dichloro-2-hydroxybenzyl)(3-hydroxy-4-(((1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl)oxy)carbonyl)phenyl)amino)-4-oxobutanoyl)oxy)pentyl)benzoic acid:

[0230]

[0231] Step 1: Potassium 2-(1-hydroxypentyl)benzoate (3.0 g) was dissolved in dichloromethane (30.0 mL). N,N-dimethylformamide (10.0 mL) was added to aid dissolution. The temperature was then cooled to -20°C. Succinic anhydride (1.8 g) was slowly added with stirring, and the reaction was maintained at this temperature for 2.0 hours. The reaction solution was adjusted to a pH of 2.0-3.0 using 1.0 mol of dilute hydrochloric acid. The solution was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. The solvent was evaporated to afford the crude compound. The desired product (0.8 g) was obtained by column separation using a dichloromethane-methanol system (dichloromethane:methanol = 20:1).

[0232] Step 2: 1,7,7-Trimethylbicyclo[2.2.1]heptan-2-yl-4-((3,5-dichloro-2-hydroxybenzyl)amino)-2-hydroxybenzoate (100.0 mg) was dissolved in dichloromethane (5.0 mL). 2-(1-((3-carboxypropionyl)oxy)pentyl)benzoic acid (66.0 mg) was added and dissolved in dichloromethane (10.0 mL). 4-Dimethylaminopyridine (6.0 mg) was added, followed by the slow addition of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (82.0 mg). The reaction was continued at room temperature for 4.0 hours. Water (20.0 mL) was added, and the mixture was extracted with ethyl acetate (20.0 x 3 mL). The organic phase was dried over anhydrous sodium sulfate, and the reaction solution was spin-dried to obtain the crude product. A reverse (ammonia) system was used to preparatively isolate Example 3 (8.0 mg). LCMS (ESI) [M+H] + =754.49.

[0233] 1 H NMR (400MHz, DMSO-d6) δ11.06(s,1H),7.68(d,J=4.0Hz,1H)7.63(d,J=8.0Hz,1H),7.54(d,J=8.0Hz,1H),7.35(d ,J=8.0Hz,2H),7.24(d,J=2.6Hz,2H),7.17(d,J=8.0Hz,1H),6.74(s,1H),6.20(d,J=8.0Hz,1H),5.93(s,1H),4.9 7(d,J=8.0Hz,1H),4.18(s,2H),2.99(t,J=6.5Hz,2H),2.83–2.72(m,2H),2.34(s,2H),2.06–2.00(m,2H),1.81–1 .70(m,4H),1.37(d,J=12.0Hz,1H),1.27–1.20(m,3H),1.14–1.10(m,1H),1.07–1.03(m,1H),0.92–0.77(m,12H).

[0234] Example 4 (Compound 7)

[0235] Preparation of 1-(2-((3,5-dichloro-2-hydroxybenzyl)(3-hydroxy-4-(1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl)oxy)carbonyl)phenyl)carbamoyl)phenyl)pentyl(1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl)succinate:

[0236]

[0237] Step 1: Dissolve 2-(1-((3-carboxypropionyl)oxy)pentyl)benzoic acid (200.0 mg) in dichloromethane (10.0 mL). Add 1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (100.0 mg) in dichloromethane (10.0 mL). Add 4-dimethylaminopyridine (16.0 mg). Then slowly add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (124.0 mg). Continue the reaction at room temperature for 4.0 hours. Add water (20.0 mL) and extract with ethyl acetate (20.0 x 3 mL). Dry the organic phase with anhydrous sodium sulfate. The reaction solution is spun down to dryness to obtain the crude product. Use petroleum ether-ethyl acetate (petroleum ether:ethyl acetate = 8:1) to separate the desired product (180.0 mg).

[0238] Step 2: 1,7,7-Trimethylbicyclo[2.2.1]heptane-2-yl-4-((3,5-dichloro-2-hydroxybenzyl)amino)-2-hydroxybenzoate (180.0 mg) was dissolved in dichloromethane (5.0 mL). 2-(1-(4-oxo-4-(1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl)oxy)butanoyl)oxy)pentyl)benzoic acid (180.0 mg) was added and dissolved in dichloromethane (10.0 mL). 4-Dimethylaminopyridine (10.0 mg) was added, followed by the slow addition of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (80.0 mg). The reaction was continued at room temperature for 4.0 hours. Water (20.0 mL) was added, and the mixture was extracted with ethyl acetate (20.0*3 mL). The organic phase was dried over anhydrous sodium sulfate. The reaction solution was then spin-dried to obtain the crude product. Reverse preparative separation was used to obtain Example 4 compound (60.0 mg). LCMS (ESI) [M+H] + =890.64. 1H NMR (400MHz, DMSO-d6) δ10.86(s,1H),8.24(d,J=8.0Hz,1H),7.80(d,J=2.5Hz,1H),7.74(td,J=7.6,1.4Hz,1H),7.64(d,J=8.0Hz,1H),7.55 –7.50(m,2H),7.35(d,J=2.4Hz,1H),7.25(t,J=6.0Hz,1H),6.43(s,1H),6.20(dd,J=8.8,2.2Hz,1H),5.96(d,J=2.2Hz,1H),5.00–4.95(m,1H ),4.76–4.70(m,1H),4.34(s,2H),2.70–2.62(m,2H),2.60–2.54(m,2H ),2.39–2.31(m,1H),2.16(s,1H),2.05–1.96(m,1H),1.81–1.68(m,5H ),1.62–1.57(m,2H),1.39–1.13(m,8H),1.06–1.01(m,2H),0.91(s,3H ),0.87(s,3H),0.84(s,3H),0.83–0.77(m,9H),0.67(d,J=8.8Hz,3H).

[0239] Example 5 (Compound 8)

[0240] Preparation of 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl-2-((2-(1-acetoxypentyl)benzoyl)oxy)-4-((3,5-dichloro-2-hydroxybenzyl)amino)benzoate:

[0241]

[0242] Step 1: Dissolve 1,7,7-trimethylbicyclo[2.2.1]hept-2-yl-2-hydroxy-4-nitrobenzoate (200.0 mg) in dichloromethane (5.0 mL). Add 2-(1-acetoxypentyl)benzoic acid (156.0 mg) and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (120.0 mg). Then, add 4-dimethylaminopyridine (15.0 mg) and triethylamine (95.0 mg). The reaction mixture is allowed to react at 25°C for 4.0 hours. The reaction mixture is extracted with water (20.0 mL) and dichloromethane (20.0 mL). The organic phase is dried over anhydrous sodium sulfate, evaporated, and concentrated to obtain the crude product. The crude product is then separated by column chromatography using a petroleum ether / ethyl acetate system (petroleum ether:ethyl acetate = 10:1) to obtain the product as a colorless oil (120 mg). LCMS (ESI) [M+Na] + =574.34.

[0243] Step 2: Dissolve 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl-2-((2-(1-acetoxypentyl)benzoyl)oxy)-4-nitrobenzoate (120.0 mg) in anhydrous ethanol (8.0 mL), add iron powder (60.0 mg), and then add ammonium chloride (19.0 mg). Then, add water (4.0 mL), and the reaction mixture is reacted at 60°C for 16.0 hours. Add water (20.0 mL) and extract with dichloromethane (20.0 mL). The organic phase is dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product is separated by column chromatography using a petroleum ether and ethyl acetate system (petroleum ether:ethyl acetate = 6:1) to obtain the desired product (80.0 mg). LCMS (ESI) [M+Na] + =544.32.

[0244] Step 3: Dissolve 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl-2-((2-(1-acetoxypentyl)benzoyl)oxy)-4-aminobenzoate (80.0 mg) in anhydrous ethanol (8.0 mL), then add 3,5-dichloro-2-hydroxybenzaldehyde (30.0 mg). The reaction mixture was reacted at 25°C for 16.0 hours. The reaction mixture was filtered to obtain the crude product (80.0 mg).

[0245] Step 4: Dissolve 1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl-(E)-2-((2-(1-acetoxypentyl)benzoyl)oxy)-4-((3,5-dichloro-2-hydroxybenzylidene)amino)benzoate (80.0 mg) in anhydrous ethanol (5.0 mL), and then add sodium triacetylborohydride (30.0 mg). The reaction solution was reacted at 25°C for 2.0 hours. Water (20.0 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20.0 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was subjected to reverse preparative separation to obtain the target product (8.0 mg). LCMS (ESI) [M+Na] + =718.38. 1H NMR(400MHz, DMSO-d6)δ9.78(s,1H),8.14(dd,J=8.0,1.4Hz,1H),7.81(dd,J=8.8,3.6Hz,1H),7.71–7.64(m,1H), 7.59(dt,J=8.0,1.6Hz,1H),7.49(t,J=8.0Hz,1H),7.41(d,J=4.0Hz,1H),7.26(s,1H),7.15(d,J=4.0Hz,1H),6.6 0(dd,J=8.8,2.3Hz,1H),6.47-6.43(m,2H),4.91–4.83(m,1H),4.35(d,J=8.0Hz,2H),2.27-2.18(m,1H),2.06(s, 3H),1.96–1.90(m,1H),1.75–1.59(m,4H),1.32–1.21(m,5H),1.11(s,1H),0.94-0.88(m,1H),0.85-0.75(m,12H).

[0246] Example 6 (Compound 6)

[0247] Preparation of 4-((1-(2-((3,5-dichloro-2-hydroxybenzyl)(3-hydroxy-4-(((1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy)carbonyl)phenyl)carbamoyl)phenyl)pentyl)oxy)-4-oxobutanoic acid:

[0248]

[0249] Step 1: Dissolve 2-(1-((3-carboxypropionyl)oxy)pentyl)benzoic acid (300.0 mg) in methyltetrahydrofuran (10.0 mL), add O-tert-butyl-N,N'-diisopropylisourea (300.0 mg), and continue the reaction at 60°C for 16 hours. Add water (20.0 mL) and extract with ethyl acetate (20.0 x 3 mL). The organic phase is dried over anhydrous sodium sulfate and the reaction solution is spun down to dryness to obtain the crude product. The desired product (160.0 mg) is separated by column chromatography using petroleum ether-ethyl acetate (petroleum ether:ethyl acetate = 5:1). LCMS (ESI) [M+Na] + =331.24.

[0250] Step 2: Dissolve 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl-4-((3,5-dichloro-2-hydroxybenzyl)amino)-2-hydroxybenzoate (160.0 mg) in dichloromethane (5.0 mL). Add 2-(1-((4-(tert-butoxy)-4-oxobutanoyl)oxy)pentyl)benzoic acid (160.0 mg) and 4-dimethylaminopyridine (10.0 mg). Then, slowly add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (100.0 mg). Continue the reaction at room temperature for 4.0 hours. Add water (20.0 mL) and extract with ethyl acetate (20.0 x 3 mL). Dry the organic phase over anhydrous sodium sulfate and spin dry the reaction mixture to obtain the crude product. Petroleum ether-ethyl acetate (petroleum ether:ethyl acetate = 8:1) was used to obtain the target compound (120.0 mg). LCMS (ESI) [M+H] + =810.52.

[0251] Step 3: Tert-butyl (1-(2-((3,5-dichloro-2-hydroxybenzyl)(3-hydroxy-4-(((1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl)oxy)carbonyl)phenyl)carbamoyl)phenyl)pentyl)succinate (120.0 mg) was dissolved in dichloromethane (10.0 mL), trifluoroacetic acid (100.0 mg) was added, and the reaction was continued at 40°C for 16.0 hours. Water (20.0 mL) was added, and the mixture was extracted with ethyl acetate (20.0*3 mL). The organic phase was dried over anhydrous sodium sulfate, and the reaction solution was spin-dried to obtain a crude product. Reverse preparative separation was used to obtain Example 6 (8.0 mg). LCMS (ESI) [M+H] + =754.25. 1 H NMR(400MHz,DMSO-d6)δ13.07(s,1H),10.72(s,1H),9.84(s,1H),7.88–7.80(m,2H),7.57–7 .32(m,4H),7.12(d,J=4.0Hz,1H),6.98(d,J=4.0Hz,1H),6.91(dd,J=8.4,2.0Hz,1H),6.51–6 .48(m,1H),5.04(d,J=8.0,1H),4.96–4.77(m,2H),2.71–2.56(m,2H),2.44–2.33(m,1H),2.0 7–1.99(m,1H),1.81–1.65(m,4H),1.42–1.16(m,8H),1.14–1.09(m,1H),0.94–0.81(m,12H).

[0252] Example 7 (Compound 9)

[0253] Preparation of 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 4-((3,5-dichloro-2-hydroxybenzyl)amino)-2-((2-(1-(isobutyryloxy)pentyl)benzoyl)oxy)benzoate:

[0254]

[0255] Step 1: Dissolve 1,7,7-trimethylbicyclo[2.2.1]hept-2-yl-2-hydroxy-4-nitrobenzoate (300.0 mg) in dichloromethane (10.0 mL). Add 2-(1-acetoxypentyl)benzoic acid (260.0 mg) and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (200.0 mg). Then, add 4-dimethylaminopyridine (23.0 mg) and triethylamine (100.0 mg). The reaction mixture is incubated at 25°C for 4.0 hours. TLC indicates complete reaction of the starting material with product formation. Water (20.0 mL) was added to the reaction solution, and dichloromethane (20.0 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, evaporated, and concentrated to give a colorless oily crude product. The crude product was separated by column chromatography using a petroleum ether and ethyl acetate system (petroleum ether: ethyl acetate = 10:1) to give the product as a colorless oily liquid (360.0 mg).

[0256] Step 2: Dissolve 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 2-((2-(1-(isobutyryloxy)pentyl)benzoyl)oxy)-4-nitrobenzoate (360.0 mg) in anhydrous ethanol (10.0 mL). Add iron powder (100.0 mg) and ammonium chloride (80.0 mg). Then add water (5.0 mL), and the reaction mixture is allowed to react at 60°C for 16.0 hours. Add water (20.0 mL) and extract with dichloromethane (20.0 mL). The organic phase is dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product is then separated by column chromatography using a petroleum ether / ethyl acetate system (petroleum ether:ethyl acetate = 5:1) to obtain the desired product (260.0 mg). LCMS (ESI) [M+Na] + =572.38.

[0257] Step 3: Dissolve 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 2-((2-(1-(isobutyryloxy)pentyl)benzoyl)oxy)-4-nitrobenzoate (260.0 mg) in anhydrous ethanol (10.0 mL), and then add 3,5-dichloro-2-hydroxybenzaldehyde (50.0 mg). The reaction mixture is reacted at 25°C for 16.0 hours. The reaction mixture is evaporated to dryness to obtain a crude product (200.0 mg).

[0258] Step 4: Dissolve 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl(E)-4-((3,5-dichloro-2-hydroxybenzylidene)amino)-2-((2-(1-(isobutyryloxy)pentyl)benzoyl)oxy)benzoate (110.0 mg) in anhydrous ethanol (10.0 mL), and then add sodium triacetylborohydride (40.0 mg). The reaction solution was reacted at 25°C for 2.0 hours. Water (20.0 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20.0 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was subjected to reverse preparative separation to obtain the target product (50.0 mg). LCMS (ESI) [M+H] + =724.38. 1 H NMR(400MHz, DMSO-d6)δ9.78(s,1H),8.14(d,J=8.0,Hz,1H),7.83–7.81(m,1H),7.71–7.64(m,1H),7.58(d,J=8.0, Hz,1H),7.49(t,J=8.0Hz,1H),7.41(d,J=4.0Hz,1H),7.26(t,J=8.0,Hz,1H),7.15(d,J=4.0Hz,1H),6.60(dd,J=8. 8,2.4Hz,1H),6.47-6.43(m,2H),4.91–4.83(m,1H),4.35(d,J=8.0Hz,2H),2.64-2.57(m,1H),2.27-2.18(m,1H),1 .96–1.90(m,1H),1.75–1.59(m,4H),1.32–1.21(m,6H),1.15–1.07(m,6H),0.94-0.88(m,1H),0.85-0.75(m,12H).

[0259] Example 8 (Compound 10)

[0260] Preparation of 4-((1-(2-((3,5-dichloro-2-hydroxybenzyl)(3-hydroxy-4-(((1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy)carbonyl)phenyl)carbamoyl)phenyl)pentyl)oxy)-4-oxobutanoic acid:

[0261]

[0262] First step: 1,7,7-Trimethylbicyclo[2.2.1]heptan-2-yl 2-hydroxy-4-nitrobenzoate (280.0 mg) was dissolved in dichloromethane (20.0 mL), then 2-(1-((4-(tert-butoxy)-4-oxobutanoyl)oxy)pentyl)benzoic acid (300.0 mg) was added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (240.0 mg). Then 4-dimethylaminopyridine (30.0 mg), triethylamine (100.0 mg) were added, and the reaction solution was reacted at 25 °C for 4.0 hours. The reaction solution was added with water (50.0 mL), and dichloromethane (50.0 mL) was added for extraction. The organic phase was dried with anhydrous sodium sulfate, evaporated, and concentrated to obtain a colorless oily crude product. The crude product was separated by column chromatography using a petroleum ether / ethyl acetate system (petroleum ether: ethyl acetate = 10:1) to obtain the product (240.0 mg). LCMS (ESI) [M+Na] = 688.32. +

[0263] Second step: tert-Butyl (1-(2-((5-nitro-2-(((1,7,7-trimethylbicyclo[2.2.1]heptan-2- yl)oxy)carbonyl)phenoxy)carbonyl)phenyl)pentyl)succinate (240.0 mg) was dissolved in anhydrous ethanol (10.0 mL), then iron powder (50.0 mg) was added, followed by ammonium chloride (40.0 mg). Then water (5.0 mL) was added, and the reaction solution was reacted at 50 °C for 16.0 hours. The reaction solution was added with water (20.0 mL), and dichloromethane (20.0 mL) was added for extraction. The organic phase was dried with anhydrous sodium sulfate, concentrated to obtain a crude product. The crude product was separated by column chromatography using a petroleum ether / ethyl acetate system (petroleum ether: ethyl acetate = 5:1) to obtain the target product (110.0 mg). LCMS (ESI) [M+Na] = 658.32. +

[0264] Third step: tert-Butyl (1-(2-((5-amino-2-(((1,7,7-trimethylbicyclo[2.2.1]heptan-2- yl)oxy)carbonyl)phenoxy)carbonyl)phenyl)pentyl)succinate (110.0 mg) was dissolved in anhydrous ethanol (10.0 mL), then 3,5-dichloro-2-hydroxybenzaldehyde (30.0 mg) was added. The reaction solution was reacted at 25 °C for 16.0 hours. The reaction solution was evaporated to obtain a crude product (55.0 mg).

[0265] ​​Step 4: Dissolve (E)-tert-butyl (1-(2-((5-((3,5-dichloro-2-hydroxybenzylidene)amino)-2-(((1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl)oxy)carbonyl)phenoxy)carbonyl)phenyl)pentyl)succinate (55.0 mg) in anhydrous ethanol (10.0 mL), and then add sodium triacetylborohydride (45.0 mg). The reaction solution was reacted at 25°C for 2.0 hours. Water (20.0 mL) was added to the reaction solution, and dichloromethane (20.0 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated to give a crude product (45.0 mg). LCMS (ESI) [M+H] + =810.31.

[0266] Step 5: Dissolve tert-butyl (1-(2-((5-((3,5-dichloro-2-hydroxybenzyl)amino)-2-(((1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl)oxy)carbonyl)phenoxy)carbonyl)phenyl)pentyl)succinate (55.0 mg) in dichloromethane (10.0 mL), add trifluoroacetic acid (40.0 mg), and continue the reaction at 40°C for 16.0 hours. The reaction solution was dried to give a crude product. Reverse preparative separation was used to obtain the target compound (25.0 mg). LCMS (ESI) [M+H] + =754.25. 1 H NMR (400MHz, DMSO-d6) δ8.14(d,J=8.0,1H),7.81(dd,J=8.8,3.6Hz,1H),7.70–7.63(m,1H),7.59(d,J=8.0, 1H),7.48(t,J=8.0,1H),7.39(d,J=2.4Hz,1H),7.26(t,J=8.0,1H),7.15(d,J=4.0Hz,1H),6.60(d,J=8.0,1H ),6.48–6.45(m,2H),4.89–4.84(m,1H),4.34(d,J=4.0Hz,2H),2.61–2.52(m,2H),2.48–2.45(m,2H),2.24–2 .18(m,1H),2.00–1.91(m,1H),1.83–1.59(m,4H),1.27–1.11(m,6H),0.94–0.88(m,1H),0.87–0.71(m,12H).

[0267] Example 9 (Compound 11)

[0268] Preparation of 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 4-((3,5-dichloro-2-hydroxybenzyl)amino)-2-((2-(1-(isobutyryloxy)pentyl)benzoyl)oxy)benzoate:

[0269]

[0270] Step 1: 2-(1-((3-carboxypropionyl)oxy)pentyl)benzoic acid (800.0 mg) was dissolved in dichloromethane (20.0 mL). 1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (600.0 mg) was added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (600.0 mg). 4-Dimethylaminopyridine (60.0 mg) and triethylamine (200.0 mg) were then added, and the reaction mixture was allowed to react at 25°C for 4.0 hours. Water (40.0 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (40.0 mL). The organic phase was dried over anhydrous sodium sulfate, evaporated, and concentrated to yield a colorless oily crude product. The crude product was separated by column chromatography using a petroleum ether / ethyl acetate system (petroleum ether:ethyl acetate = 7:1) to yield the product (400.0 mg). LCMS (ESI) [M+H] + =445.31.

[0271] Step 2: Dissolve 1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl-2-hydroxy-4-nitrobenzoate (300.0 mg) in dichloromethane (20.0 mL), add 2-(1-((4-oxo-4-((1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl)oxy)butanoyl)oxy)pentyl)benzoic acid (400.0 mg), and then add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (200.0 mg). Then, add 4-dimethylaminopyridine (23.0 mg) and triethylamine (100.0 mg), and the reaction solution is reacted at 25°C for 4.0 hours. The reaction mixture was added with water (20.0 mL) and extracted with dichloromethane (20.0 mL). The organic phase was dried over anhydrous sodium sulfate, evaporated, and concentrated to give a colorless oily crude product. The crude product was separated by column chromatography using a petroleum ether and ethyl acetate system (petroleum ether:ethyl acetate = 10:1) to give the product as a colorless oily liquid (250.0 mg). LCMS (ESI) [M+Na] + =768.31.

[0272] Step 3: 1-(2-((5-nitro-2-(((1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy)carbonyl)phenoxy)carbonyl)phenyl)pentyl(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)succinate (250.0 mg) was dissolved in anhydrous ethanol (20.0 mL), and iron powder (100.0 mg) was added, followed by ammonium chloride (80.0 mg). Water (10.0 mL) was then added, and the reaction mixture was reacted at 60°C for 16.0 hours. Water (20.0 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (20.0 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was then separated by column chromatography using a petroleum ether / ethyl acetate system (petroleum ether:ethyl acetate = 5:1) to obtain the desired product (190.0 mg). LCMS (ESI) [M+Na] + =738.31.

[0273] Step 4: Dissolve 1-(2-((5-amino-2-(((1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy)carbonyl)phenoxy)carbonyl)phenyl)pentyl(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)succinate (190.0 mg) in anhydrous ethanol (10.0 mL), and then add 3,5-dichloro-2-hydroxybenzaldehyde (50.0 mg). The reaction mixture was reacted at 25°C for 16.0 hours. The reaction mixture was evaporated to dryness to obtain a crude product (80.0 mg).

[0274] Step 5: 1-(2-((5-((3,5-dichloro-2-hydroxybenzyl)amino)-2-(((1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl)oxy)carbonyl)phenoxy)carbonyl)phenyl)pentyl(1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl)succinate (80.0 mg) was dissolved in anhydrous ethanol (10.0 mL), and sodium triacetylborohydride (30.0 mg) was added. The reaction solution was reacted at 25°C for 2.0 hours. Water (20.0 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20.0 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was subjected to reverse preparative separation to obtain the target product (27.0 mg). LCMS (ESI) [M+H] + =890.37. 1H NMR (400MHz, DMSO-d6) δ9.77(s,1H),8.15(d,J=8.0,1H),7.82–7.79(m,1H),7.71–7.63(m,1H),7.62–7.57(m,1H),7.48(t,J=7.6 Hz,1H),7.40(d,J=2.6Hz,1H),7.24(s,1H),7.15(d,J=2.4Hz,1H),6.59(dd,J=8.8,2.4Hz,1H),6.54–6.48(m,1H),6.43(d,J=2.3H z,1H),4.85(d,J=6.3Hz,1H),4.76(td,J=8.8,7.4,5.2Hz,1H),4.34(d,J=4.7Hz,2H),2.68–2.64(m,2H),2.62–2.56(m,2H),2.27 –2.16(m,2H),1.99–1.96(m,1H),1.83–1.57(m,7H),1.35–1.03(m,9H),0.93–0.87(m,2H),0.86–0.80(m,12H),0.80–0.69(m,8H).

[0275] Example 10 (Compound 110)

[0276] Preparation of 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 4-((3,5-dichloro-2-hydroxybenzyl)amino)-2-((2-(1-(isobutyryloxy)pentyl)benzoyl)oxy)benzoate:

[0277]

[0278] Step 1: Dissolve 1,7,7-trimethylbicyclo[2.2.1]hept-2-yl-2-hydroxy-4-nitrobenzoate (300.0 mg) in dichloromethane (20.0 mL). Add 2-(1-((3-carboxypropionyl)oxy)pentyl)benzoic acid (300.0 mg) and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (240.0 mg). Then, add 4-dimethylaminopyridine (30.0 mg) and triethylamine (100.0 mg). The reaction mixture is allowed to react at 25°C for 4.0 hours. Water (50.0 mL) is added to the reaction mixture, which is then extracted with dichloromethane (50.0 mL). The organic phase is dried over anhydrous sodium sulfate, evaporated, and concentrated to yield a colorless oily crude product. The crude product is then separated by column chromatography using a petroleum ether / ethyl acetate system (petroleum ether:ethyl acetate = 10:1) to yield the product (170.0 mg). LCMS (ESI) [M+Na] + =632.27.

[0279] Second step: 2-(l-((4-(5-nitro-2-(((l,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)oxy)carbonyl)phenoxy)-4- oxobutanoyl)oxy)pentyl)benzoic acid (170.0 mg) was dissolved in absolute ethanol (10.0 mL), iron powder (40.0 mg) was added, then ammonium chloride (30.0 mg) was added. Then water (5.0 mL) was added, and the reaction solution was reacted at 50 °C for 16.0 hours. The reaction solution was added with water (20.0 mL), dichloromethane (20.0 mL) was added for extraction, the organic phase was dried with anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was separated by column with petroleum ether and ethyl acetate system (petroleum ether: ethyl acetate = 5: 1) to obtain the target product (110.0 mg). LCMS (ESI) [M+Na] + = 602.26.

[0280] Third step: 2-(l-((4-(5-amino-2-(((l,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)oxy)carbonyl)phenoxy)-4- oxobutanoyl)oxy)pentyl)benzoic acid (110.0 mg) was dissolved in absolute ethanol (10.0 mL), and then 3,5- dichloro-2-hydroxybenzaldehyde (40.0 mg) was added. The reaction solution was reacted at 25 °C for 16.0 hours. The reaction solution was evaporated to obtain the crude product (90.0 mg).

[0281] Fourth step: (E)-2-(l-((4-(5-((3,5-dichloro-2-hydroxybenzylidene)amino)-2-(((l,7,7-trimethylbicyclo[2.2.1]heptan-2- yl)oxy)carbonyl)phenoxy)-4-oxobutanoyl)oxy)pentyl)benzoic acid (90.0 mg) was dissolved in absolute ethanol (10.0 mL), and then sodium triacetylborohydride (45.0 mg) was added. The reaction solution was reacted at 25 °C for 2.0 hours. The reaction solution was added with water (20.0 mL), dichloromethane (20.0 mL) was added for extraction, the organic phase was dried with anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was separated by reverse phase preparation to obtain the target product (30.0 mg). LCMS (ESI) [M+H] + = 754.25. 1HNMR (400MHz, DMSO-d6) δ7.80(d,J=8.2Hz,1H),7.74(d,J=8.8Hz,1H),7.48(d,J=4.0Hz,2H),7.38(d,J=4.0Hz,1 H),7.36–7.30(m,1H),7.20(t,J=6.0Hz,1H),7.10(d,J=2.6Hz,1H),6.59–6.52(m,2H),6.24(d,J=2.0Hz,1H),4.8 8(d,J=12.0,1H),4.31(d,J=4.0Hz,2H),2.81–2.76(m,2H),2.74–2.70(m,2H),2.31–2.25(m,1H),2.02–1.95(m,1 H),1.77–1.66(m,4H),1.36–1.20(m,6H),0.96(d,J=4.0Hz,1H),0.89(s,3H),0.86(s,3H),0.80(t,J=4.0Hz,6H).

[0282] Example 11 (Compound 112)

[0283] Preparation of 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 2-(((2-(1-acetoxypentyl)benzoyl)oxy)methoxy)-4-((3,5-dichloro-2-hydroxybenzyl)amino)benzoate:

[0284]

[0285] Step 1: Refer to the second step of Example 1 to obtain the target product (0.3 g).

[0286] Step 2: 2-(1-acetoxypentyl)benzoic acid (0.32 g) was dissolved in dichloromethane (5.0 mL). Water (5.0 mL) was added, followed by the slow addition of sodium bicarbonate (0.45 g). After stirring for 15 minutes, tetrabutylammonium hydrogen sulfate (30 mg) was added. The temperature was lowered to 0°C, and chloromethyl chlorosulfonate (0.28 g) was slowly added dropwise. The temperature was then slowly raised to room temperature and the reaction was maintained at this temperature for 16 hours. The reaction solution was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and the reaction solution was spin-dried to obtain the crude compound. The desired product (0.19 g) was obtained by column separation using a petroleum ether-ethyl acetate system (petroleum ether:ethyl acetate = 8:1). LCMS (ESI) [M+Na] + =321.27

[0287] Step 3: Dissolve 1,7,7-trimethylbicyclo[2.2.1]hept-2-yl-2-hydroxy-4-nitrobenzoate (200.0 mg) in dichloromethane (10.0 mL), add chloromethyl 2-(1-acetoxypentyl)benzoate (190.0 mg), and then add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (180.0 mg). Then, add 4-dimethylaminopyridine (30.0 mg) and triethylamine (90.0 mg). The reaction mixture is allowed to react at 25°C for 4.0 hours. Water (20.0 mL) is added to the reaction mixture, and the mixture is extracted with dichloromethane (20.0 mL). The organic phase is dried over anhydrous sodium sulfate, evaporated, and concentrated to yield a colorless oily crude product. The crude product is then separated by column chromatography using a petroleum ether / ethyl acetate system (petroleum ether:ethyl acetate = 10:1) to yield the product (110 mg). LCMS (ESI) [M+Na] + =604.34.

[0288] Step 4: Dissolve 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 2-(((2-(1-acetoxypentyl)benzoyl)oxy)methoxy)-4-nitrobenzoate (110.0 mg) in anhydrous ethanol (8.0 mL), add iron powder (60.0 mg), and then add ammonium chloride (25.0 mg). Then, add water (4.0 mL), and the reaction solution is reacted at 60°C for 16.0 hours. Add water (20.0 mL) to the reaction solution, extract with dichloromethane (20.0 mL), dry the organic phase over anhydrous sodium sulfate, and concentrate to obtain a crude product. The crude product is separated by column chromatography using a petroleum ether and ethyl acetate system (petroleum ether:ethyl acetate = 6:1) to obtain the desired product (85.0 mg). LCMS (ESI) [M+Na] + =574.32.

[0289] Step 5: Dissolve 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 2-(((2-(1-acetoxypentyl)benzoyl)oxy)methoxy)-4-aminobenzoate (85.0 mg) in anhydrous ethanol (8.0 mL), then add 3,5-dichloro-2-hydroxybenzaldehyde (30.0 mg). The reaction mixture was incubated at 25°C for 16.0 hours. TLC analysis indicated that the reaction of the starting material was complete and product was formed. The reaction mixture was evaporated to dryness to obtain the crude product (60.0 mg).

[0290] Step 6: 1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl(E)-2-(((2-(1-acetoxypentyl)benzoyl)oxy)methoxy)-4-((3,5-dichloro-2-hydroxybenzylidene)amino)benzoate (60.0 mg) was dissolved in anhydrous ethanol (5.0 mL), and sodium triacetylborohydride (40.0 mg) was added. The reaction solution was reacted at 25°C for 2.0 hours. LCMS detection showed that the reaction of the raw material was complete and the product was generated. Water (20.0 mL) was added to the reaction solution, and dichloromethane (20.0 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was subjected to reverse preparative separation to obtain the target product (40.0 mg). LCMS (ESI) [M+H] + =726.42. 1 H NMR(400MHz,DMSO-d6)δ9.75(s,1H),7.78(d,J=8.0Hz,1H),7.68–7.59(m,2H),7.54(d,J=7.8Hz,1 H),7.45–7.31(m,2H),7.18–6.99(m,2H),6.47(d,J=4.0Hz,1H),6.41–6.29(m,2H),6.03(d,J=8.0H z,1H),5.91(d,J=6.6Hz,1H),4.88(d,J=8.0Hz,1H),4.32(s,2H),2.31–2.26(m,1H),2.16–2.06(m ,1H),2.04(s,3H),1.71–1.64(m,4H),1.37–1.15(m,6H),0.95(d,J=12.0,1H),0.89–0.64(m,12H).

[0291] Example 12 (Compound 113)

[0292] Preparation of 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 4-((3,5-dichloro-2-hydroxybenzyl)amino)-2-((2-(1-(((dimethylglycyl)oxy)pentyl)benzoyl)oxy)benzoate:

[0293]

[0294] Step 1: Add 2-(dimethylamino)acetic acid (1 g) to sulfonyl dichloride (5 ml). Stir the reaction mixture at 70°C for 1 hour. The reaction mixture is then dried under reduced pressure to give crude 2-(dimethylamino)acetyl chloride (1 g).

[0295] Step 2: Take 5 mL of a solution of 2-[(1S)-1-hydroxypentyl]benzoic acid (565.29 mg) in ethyl acetate, add 20 mL of dichloromethane, and at -10°C, add triethylamine (4.99 g) and N,N-dimethylpyridin-4-amine (602.96 mg). Then, slowly add a solution of 2-(dimethylamino)acetyl chloride (1 g) in dichloromethane dropwise. After reacting at -10°C for 2 hours, water is added to the reaction solution, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried. The crude product is separated on a silica gel column to obtain 2-(1-{[2-(dimethylamino)acetyl]oxy}pentyl)benzoic acid (151 mg).

[0296] Step 3: To a solution of 2-(1-{[2-(dimethylamino)acetyl]oxy}pentyl)benzoic acid (150 mg) in dichloromethane (3 mL) were added 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl-2-hydroxy-4-nitrobenzoate (163.29 mg), N,N'-dicyclohexylmethanediamine (211 mg), and N,N-dimethylpyridin-4-amine (74.96 mg). The reaction solution was stirred at room temperature for 2 hours. The reaction solution was treated with water, extracted with dichloromethane, and the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and dried under reduced pressure. The crude product was separated on a silica gel column to obtain 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 2-[2-(1-{[2-(dimethylamino)acetyl]oxy}pentyl)benzoyloxy]-4-nitrobenzoate (150 mg).

[0297] Step 4: Iron (84.51 mg) and ammonium chloride (48.57 mg) were added to a solution of 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 2-[2-(1-{[2-(dimethylamino)acetyl]oxy}pentyl)benzoyloxy]-4-nitrobenzoate (180 mg) in ethanol (2 mL) and water (2 mL). The reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was separated on a silica gel column to obtain 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 4-amino-2-[2-(1-{[2-(dimethylamino)acetyl]oxy}pentyl)benzoyloxy]benzoate (120 mg).

[0298] Step 5: To a solution of 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 4-amino-2-[2-(1-{[2-(dimethylamino)acetyl]oxy}pentyl)benzoyloxy]benzoate (100 mg) in 1,2-dichloroethane (2 mL) were added 3,5-dichloro-2-hydroxybenzaldehyde (51.57 mg) and acetic acid (0.1 mL). The reaction solution was stirred at room temperature for 16 hours, the reaction solution was diluted with water, extracted with dichloromethane, the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and dried under reduced pressure to give crude 1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl 4-[(E)-[(3,5-dichloro-2-hydroxyphenyl)methylene]amino]-2-[2-(1-{[2-(dimethylamino)acetyl]oxy}pentyl)benzoyloxy]benzoate (120 mg).

[0299] Step 6: To a solution of 1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl 4-[(E)-[(3,5-dichloro-2-hydroxyphenyl)methylene]amino]-2-[2-(1-{[2-(dimethylamino)acetyl]oxy}pentyl)benzoyloxy]benzoate (120 mg) in 1,2-dichloroethane (2.0 mL) was added sodium triacetoxyborane (68.62 mg). The reaction solution was stirred at room temperature for 3 hours. The reaction solution was quenched with saturated ammonium chloride, extracted with dichloromethane, the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and dried under reduced pressure. The crude product was separated from silicon to obtain the product (67 mg). LCMS (ESI) [M+H] + =739.51; 1H NMR (400MHz, DMSO-d6) δ8.14 (dd, J=7.8, 1.4Hz, 1H), 7.81 (dd, J=8.8, 3.5Hz, 1 H),7.72–7.64(m,1H),7.59(dt,J=7.9,1.7Hz,1H),7.53–7.45(m,1H),7.40(d, J=2.6Hz,1H),7.28(s,1H),7.15(d,J=2.6Hz,1H),6.60(dd,J=8.8,2.3Hz,1H), 6.54–6.47(m,1H),6.45(d,J=2.3Hz,1H),4.87(t,J=9.3Hz,1H),4.35(d,J=5.2 Hz,2H),3.31–3.17(m,2H),2.23(s,6H),1.95(dd,J=8.2,4.0Hz,1H),1.83–1. 70(m,2H),1.61(dd,J=10.2,4.5Hz,2H),1.32–1.20(m,1H),1.24(s,4H),1.14( dd,J=14.9,6.4Hz,1H),1.04(d,J=9.8Hz,1H),0.91(ddd,J=13.4,7.8,3.4Hz,1 H),,0.83(dd,J=9.3,1.7Hz,6H),0.79(t,J=7.0Hz,3H),0.76(d,J=4.7Hz,3H).

[0300] Example 13 (Compound 114)

[0301] Preparation of 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 4-((3,5-dichloro-2-hydroxybenzyl)amino)-2-(((1-(2-((1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)oxy)carbonyl)phenyl)pentyl)oxy)carbonyl)benzoate:

[0302]

[0303] Step 1: Refer to the first step of Example 1 to obtain the target product (3.0 g).

[0304] Step 2: Potassium 2-(1-hydroxypentyl)benzoate (3.5 g) was dissolved in dichloromethane (30.0 mL). N,N-dimethylformamide (10.0 mL) was added for solubilization. The temperature was then cooled to -20°C and chloromethyl chloroformate (2.0 g) was slowly added dropwise. The reaction was maintained at this temperature and continued for 16.0 hours. The reaction mixture was adjusted to a pH of 4.0-6.0 using 1.0 mol of dilute hydrochloric acid. Water (30.0 mL) was added and the mixture was extracted three times with dichloromethane (30.0 mL). The organic phase was dried over anhydrous sodium sulfate and the reaction mixture was spin-dried to obtain the crude compound. The desired product (0.8 g) was obtained by column separation using a petroleum ether-ethyl acetate system (petroleum ether:ethyl acetate = 8:1).

[0305] Step 3: 2-(1-((chloromethoxy)carbonyl)oxy)pentyl)benzoic acid (0.8 g) was dissolved in dichloromethane (10.0 mL). 4-Dimethylaminopyridine (65.0 mg) was added at 25°C, followed by the slow addition of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (760.0 mg). After stirring for 15 minutes, 1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (400.0 mg) was added and the reaction continued for 4 hours. Water (30.0 mL) was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and the reaction solution was evaporated to dryness to obtain the crude compound. The desired product (0.40 g) was obtained by column chromatography using a petroleum ether-ethyl acetate system (petroleum ether:ethyl acetate = 9:1). LCMS (ESI) [M+H] + =437.27

[0306] Step 4: Dissolve 1,7,7-trimethylbicyclo[2.2.1]hept-2-yl 2-hydroxy-4-nitrobenzoate (320 mg) in acetonitrile (10.0 mL), add chloromethyl 2-(1-acetoxypentyl)benzoate (400 mg), and then add potassium carbonate (400.0 mg). Stir for 4 hours. Add water (30.0 mL), then extract three times with ethyl acetate (30.0 mL). The organic phase is dried over anhydrous sodium sulfate and concentrated to obtain the crude product. Purify the crude product by column chromatography using a petroleum ether / ethyl acetate system (petroleum ether:ethyl acetate = 8:1) to obtain the desired product (120.0 mg). LCMS (ESI) [M+Na] + =712.13.

[0307] Step 5: 1,7,7-Trimethylbicyclo[2.2.1]hept-2-yl 4-nitro-2-((((1-(2-(((1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy)carbonyl)phenyl)pentyl)oxy)carbonyl)oxy)benzoate (120.0 mg) was dissolved in anhydrous ethanol (8.0 mL), iron powder (60.0 mg) and ammonium chloride (25.0 mg) were added. Water (4.0 mL) was then added, and the reaction mixture was reacted at 50°C for 3.0 hours. Water (20.0 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (3.0 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was separated by column chromatography using a petroleum ether and ethyl acetate system (petroleum ether:ethyl acetate = 5:1) to obtain the desired product (90.0 mg). LCMS (ESI) [M+H] + =660.39.

[0308] Step 6: 1,7,7-trimethylbicyclo[2.2.1]hept-2-yl 4-amino-2-((((1-(2-(((1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy)carbonyl)phenyl)pentyl)oxy)carbonyl)oxy)benzoate (90.0 mg) was dissolved in anhydrous ethanol (8.0 mL), and then 3,5-dichloro-2-hydroxybenzaldehyde (35.0 mg) was added. The reaction mixture was reacted at 25°C for 16.0 hours. The reaction mixture was evaporated to dryness to obtain a crude product (80.0 mg).

[0309] Step 7: 1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl(E)-4-((3,5-dichloro-2-hydroxybenzylidene)amino)-2-(((1-(2-(((1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl)oxy)carbonyl)phenyl)pentyl)oxy)carbonyl)benzoate (80.0 mg) was dissolved in anhydrous ethanol (8.0 mL), and sodium triacetylborohydride (50.0 mg) was added. The reaction solution was reacted at 25°C for 2.0 hours. Water (20.0 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20.0 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was subjected to reverse preparative separation to obtain the target product (40.0 mg). LCMS (ESI) [M+H] + =834.42.

[0310] 1H NMR(400MHz, DMSO-d6)δ9.85(s,1H),7.85(dd,J=8.0,1.2Hz,1H),7.71(dd,J=8.8,2.4Hz,1H),7.66–7.60(m,1H),7.5 9–7.53(m,1H),7.49–7.45(m,1H),7.39(d,J=2.6Hz,1H),7.20(s,1H),7.14–7.06(m,1H),6.54(dd,J=8.8,2.4Hz,1H), 6.40–6.37(m,1H),6.31(t,J=2.8Hz,1H),5.03(d,J=9.6Hz,1H),4.85(d,J=9.2Hz,1H),4.31(s,2H),2.42–2.39(m,1H ),2.29–2.16(m,1H),1.98–1.92(m,2H),1.86–1.60(m,6H),1.45–1.13(m,9H),1.12–1.00(m,1H),0.94–0.72(m,21H).

[0311] Example 14 (Compound 96)

[0312] Preparation of 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 4-((3,5-dichloro-2-hydroxybenzyl)amino)-2-(((((1-(2-(((1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)oxy)carbonyl)phenyl)pentyl)oxy)carbonyl)oxy)methoxy)benzoate:

[0313]

[0314] Step 1-3: Refer to Example 13 to obtain the target product (0.40 g). LCMS (ESI) [M+H] + =437.27

[0315] Step 4: Dissolve 1,7,7-trimethylbicyclo[2.2.1]hept-2-yl 2-hydroxy-4-nitrobenzoate (320 mg) in acetonitrile (10.0 mL), add chloromethyl 2-(1-acetoxypentyl)benzoate (400 mg), and then add potassium carbonate (400.0 mg). Stir for 4 hours. Add water (30.0 mL), then extract three times with ethyl acetate (30.0 mL). The organic phase is dried over anhydrous sodium sulfate and concentrated to obtain the crude product. Purify the crude product by column chromatography using a petroleum ether / ethyl acetate system (petroleum ether:ethyl acetate = 8:1) to obtain the desired product (140.0 mg). LCMS (ESI) [M+Na] + =742.13

[0316] Step 5: 1,7,7-Trimethylbicyclo[2.2.1]hept-2-yl 4-nitro-2-(((((1-(2-(((1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy)carbonyl)phenyl)pentyl)oxy)oxy)methoxy)benzoate (140.0 mg) was dissolved in anhydrous ethanol (8.0 mL), iron powder (60.0 mg) and ammonium chloride (25.0 mg) were added. Water (4.0 mL) was then added, and the reaction mixture was reacted at 50°C for 3.0 hours. Water (20.0 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (3.0 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was separated by column chromatography using a petroleum ether and ethyl acetate system (petroleum ether:ethyl acetate = 5:1) to obtain the desired product (110.0 mg). LCMS (ESI) [M+H] + =690.39.

[0317] Step 6: 1,7,7-trimethylbicyclo[2.2.1]hept-2-yl 4-amino-2-(((((1-(2-(((1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy)carbonyl)phenyl)pentyl)oxy)oxy)methoxy)benzoate (110.0 mg) was dissolved in anhydrous ethanol (8.0 mL), and then 3,5-dichloro-2-hydroxybenzaldehyde (45.0 mg) was added. The reaction solution was reacted at 25° C. for 16.0 hours. The reaction solution was evaporated to dryness to obtain a crude product (130.0 mg).

[0318] Step 7: 1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl(E)-4-((3,5-dichloro-2-hydroxybenzylidene)amino)-2-(((((1-(2-(((1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl)oxy)carbonyl)phenyl)pentyl)oxy)carbonyl)oxy)methoxy)benzoate (130.0 mg) was dissolved in anhydrous ethanol (8.0 mL), and sodium triacetylborohydride (60.0 mg) was added. The reaction solution was reacted at 25°C for 2.0 hours. Water (20.0 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20.0 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was subjected to reverse preparative separation to obtain the target product (55.0 mg). LCMS (ESI) [M+H] + =864.42.

[0319] 1H NMR(400MHz, DMSO-d6)δ9.82(s,1H),7.85(dt,J=7.9,1.6Hz,1H),7.63–7.56(m,2H),7.52–7.42( m,2H),7.39(d,J=4.0Hz,1H),7.13(d,J=2.6Hz,1H),7.08(s,1H),6.40–6.30(m,3H),5.74–5.61( m,2H),5.10–5.01(m,1H),4.88–4.84(m,1H),4.32(s,2H),2.45–2.38(m,1H),2.31–2.19(m,1H), 2.03–1.94(m,2H),1.86–1.58(m,6H),1.45–1.11(m,9H),1.09–1.03(m,1H),0.97–0.74(m,21H).

[0320] Example 15 (Compound 115)

[0321] Preparation of 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 4-((3,5-dichloro-2-hydroxybenzyl)amino)-2-((2-(1-(isobutyryloxy)pentyl)benzoyl)oxy)benzoate:

[0322]

[0323] Step 1-Step 3: The target product (12.0 g) was obtained by referring to the method of Example 1.

[0324] Step 4: Dissolve 1,7,7-trimethylbicyclo[2.2.1]hept-2-yl-2-hydroxy-4-nitrobenzoate (300.0 mg) in dichloromethane (20.0 mL), add 2-(1-((3-carboxypropionyl)oxy)pentyl)benzoic acid (300.0 mg), and then add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (240.0 mg). Then, add 4-dimethylaminopyridine (30.0 mg) and triethylamine (100.0 mg), and the reaction mixture is reacted at 25°C for 4.0 hours. The reaction solution was added with water (50.0 mL), extracted with dichloromethane (50.0 mL), and the organic phase was dried over anhydrous sodium sulfate, evaporated, and concentrated to give a colorless oily crude product. The crude product was separated by column chromatography using a petroleum ether and ethyl acetate system (petroleum ether: ethyl acetate = 10:1) to give the product (250.0 mg). LCMS (ESI) [M+Na] + =632.27.

[0325] Step 5: Dissolve 2-(1-((4-(5-nitro-2-(((1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl)oxy)carbonyl)phenoxy)-4-oxobutanoyl)oxy)pentyl)benzoic acid (250.0 mg) in dichloromethane (8.0 mL), add 1,7,7-trimethylbicyclo[2.2.1]heptane-2-ol (90 mg), and then add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (100.0 mg). Then, add 4-dimethylaminopyridine (20.0 mg) and triethylamine (150.0 mg), and the reaction solution is reacted at 25°C for 4.0 hours. The reaction solution was added with water (20.0 mL), extracted with dichloromethane (20.0 mL), and the organic phase was dried over anhydrous sodium sulfate, evaporated, and concentrated to give a crude product. The crude product was separated by column chromatography using a petroleum ether and ethyl acetate system (petroleum ether: ethyl acetate = 10:1) to give the product (260.0 mg). LCMS (ESI) [M+H] + =746.38.

[0326] Step 6: 5-Nitro-2-(((1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl)oxy)carbonyl)phenyl(1-(2-(((1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl)oxy)carbonyl)phenyl)pentyl)succinate (260.0 mg) was dissolved in anhydrous ethanol (15.0 mL), iron powder (40.0 mg) was added, and then ammonium chloride (30.0 mg) was added. Water (7.0 mL) was then added, and the reaction solution was reacted at 50°C for 16.0 hours. Water (20.0 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20.0 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was separated by column chromatography using a petroleum ether and ethyl acetate system (petroleum ether:ethyl acetate = 5:1) to obtain the desired product (220.0 mg). LCMS (ESI) [M+H] + =716.41.

[0327] Step 7: 5-amino-2-(((1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl)oxy)carbonyl)phenyl(1-(2-(((1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl)oxy)carbonyl)phenyl)pentyl)succinate (220.0 mg) was dissolved in anhydrous ethanol (10.0 mL), and then 3,5-dichloro-2-hydroxybenzaldehyde (90.0 mg) was added. The reaction mixture was reacted at 25°C for 16.0 hours. The reaction mixture was evaporated to dryness to obtain a crude product (190.0 mg).

[0328] Step 8: 5-((3,5-dichloro-2-hydroxybenzylidene)amino)-2-(((1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl)oxy)carbonyl)phenyl(1-(2-(((1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl)oxy)carbonyl)phenyl)pentyl)succinate (190.0 mg) was dissolved in anhydrous ethanol (15.0 mL), and sodium triacetylborohydride (90.0 mg) was added. The reaction solution was reacted at 25°C for 2.0 hours. Water (20.0 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20.0 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was subjected to reverse preparative separation to obtain the target product (30.0 mg).

[0329] LCMS (ESI) [M+H] + =890.31.

[0330] 1 H NMR(400MHz, DMSO-d6)δ9.79(s,1H),8.15(dd,J=8.0,1.6Hz,1H),7.82(dd,J=8.8,3.6Hz,1H),7.69–7.5 7(m,1H),7.62–7.56(m,1H),7.55–7.46(m,1H),7.40(d,J=4.0Hz,1H),7.27–7.24(m,1H),7.16(d,J=4.0 1H),6.61–6.58(m,1H),6.53–6.50(m,1H),6.44(d,J=2.4Hz,1H),4.89–4.84(m,1H),4.82–4.74(m,1H),4.35(d,J=5.4Hz,2H),2.72 –2.63(m,2H),2.62–2.56(m,2H),2.15–2.18(m,2H)),1.95–1.91(m,1H),1.85–1.57(m,7H),1.36–1.08(m,8H),0.92–0.71(m,23H).

[0331] Example 18 (Compound 118)

[0332] Preparation of 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 4-((3,5-dichloro-2-hydroxybenzyl)amino)-2-(((((4-(3-oxo-1,3-dihydroisobenzofuran-1-yl)butan-2-yl)oxy)carbonyl)oxy)methoxy)benzoate:

[0333]

[0334] Step 1: 3-(3-Hydroxybutyl)isobenzofuran-1(3H)-one (500.0 mg) was dissolved in dichloromethane (10.0 mL). Pyridine (640.0 mg) was added, and the temperature was then lowered to 0°C. Chloromethyl chloroformate (460.0 mg) was slowly added while stirring. The reaction was maintained at this temperature for 16.0 hours. The reaction solution was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. The solvent was evaporated to dryness to obtain the crude compound. The target product (410 mg) was obtained by column separation using a petroleum ether-ethyl acetate system (petroleum ether:ethyl acetate = 5:1). LCMS (ESI) [M+Na] + =301.13

[0335] Step 2: Dissolve 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 2-hydroxy-4-nitrobenzoate (650 mg) in acetonitrile (10.0 mL), add chloromethyl (4-(3-oxo-1,3-dihydroisobenzofuran-1-yl)butan-2-yl)carbonate (410 mg), and then add potassium carbonate (600.0 mg). Stir for 4 hours. Add water (30.0 mL) and then extract three times with ethyl acetate (30.0 mL). The organic phase is dried over anhydrous sodium sulfate and concentrated to obtain the crude product. Purify the crude product by column chromatography using a petroleum ether / ethyl acetate system (petroleum ether:ethyl acetate = 8:1) to obtain the desired product (330.0 mg). LCMS (ESI) [M+Na] + =604.21.

[0336] Step 3: 1,7,7-Trimethylbicyclo[2.2.1]heptan-2-yl 4-nitro-2-(((((4-(3-oxo-1,3-dihydroisobenzofuran-1-yl)butan-2-yl)oxy)carbonyl)oxy)methoxy)benzoate (330.0 mg) was dissolved in anhydrous ethanol (10.0 mL), and iron powder (50.0 mg) was added, followed by ammonium chloride (40.0 mg). Water (5.0 mL) was then added, and the reaction mixture was allowed to react at 50°C for 16.0 hours. Water (20.0 mL) was added to the reaction mixture, and the mixture was extracted three times with dichloromethane (20.0 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was then separated by column chromatography using a petroleum ether / ethyl acetate system (petroleum ether:ethyl acetate = 3:1) to obtain the desired product (160.0 mg). LCMS (ESI) [M+Na] + =574.23.

[0337] Step 4: Dissolve 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 4-amino-2-(((((4-(3-oxo-1,3-dihydroisobenzofuran-1-yl)butan-2-yl)oxy)carbonyl)oxy)methoxy)benzoate (160.0 mg) in anhydrous ethanol (10.0 mL), followed by the addition of 3,5-dichloro-2-hydroxybenzaldehyde (80.0 mg). The reaction mixture was incubated at 25°C for 16.0 hours. The reaction mixture was evaporated to dryness to yield the crude product (90.0 mg).

[0338] Step 5: 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl(E)-4-((3,5-dichloro-2-hydroxybenzylidene)amino)-2-(((((4-(3-oxo-1,3-dihydroisobenzofuran-1-yl)butan-2-yl)oxy)carbonyl)oxy)methoxy)benzoate (90.0 mg) was dissolved in anhydrous ethanol (10.0 mL), and sodium triacetylborohydride (50.0 mg) was added. The reaction solution was reacted at 25°C for 2.0 hours. Water (20.0 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20.0 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was subjected to reverse preparative separation to obtain the target product (65.0 mg). LCMS (ESI) [M+H] + =726.22.

[0339] 1 H NMR(400MHz, DMSO-d6)δ9.79(s,1H),7.83(d,J=7.6Hz,1H),7.78–7.74(m,1H),7.65–7.58(m,3H),7.37 –7.36(m,1H),7.14–7.02(m,2H),6.35–6.31(m,2H),5.75–5.66(m,2H),5.66–5.62(m,1H),4.90–4.87(m ,1H),4.78–4.63(m,1H),4.31(s,2H),2.36–2.23(m,1H),2.18–1.99(m,2H),1.74–1.64(m,3H),1.61–1 .51(m,1H),1.29(d,J=12.8Hz,1H),1.25–1.18(m,4H),0.96(dd,J=13.5,3.4Hz,1H),0.91–0.77(m,9H).

[0340] Example 19 (Compound 119)

[0341] Preparation of 1,7,7-trimethylbicyclo[2.2.1]hept-2-yl 4-((3,5-dichloro-2-hydroxybenzyl)amino)-2-((((4-(3-oxo-1,3-dihydroisobenzofuran-1-yl)butan-2-yl)oxy)carbonyl)oxy)benzoate:

[0342]

[0343] First step: Refer to the first step of Example 18 to obtain the target product (410 mg). LCMS (ESI) [M+Na] + =301.13

[0344] Step 2: Dissolve 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 2-hydroxy-4-nitrobenzoate (650 mg) in acetonitrile (10.0 mL), add chloromethyl (4-(3-oxo-1,3-dihydroisobenzofuran-1-yl)butan-2-yl)carbonate (410 mg), and then add potassium carbonate (600.0 mg). Stir for 4 hours. Add water (30.0 mL) and then extract three times with ethyl acetate (30.0 mL). The organic phase is dried over anhydrous sodium sulfate and concentrated to obtain the crude product. Purify the crude product by column chromatography using a petroleum ether / ethyl acetate system (petroleum ether:ethyl acetate = 8:1) to obtain the desired product (110.0 mg). LCMS (ESI) [M+Na] + =574.21.

[0345] Step 3: 1,7,7-Trimethylbicyclo[2.2.1]heptan-2-yl 4-nitro-2-((((4-(3-oxo-1,3-dihydroisobenzofuran-1-yl)butan-2-yl)oxy)carbonyl)oxy)benzoate (110.0 mg) was dissolved in anhydrous ethanol (10.0 mL), and iron powder (50.0 mg) was added, followed by ammonium chloride (40.0 mg). Water (5.0 mL) was then added, and the reaction mixture was allowed to react at 50°C for 16.0 hours. Water (20.0 mL) was added to the reaction mixture, and the mixture was extracted three times with dichloromethane (20.0 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was then separated by column chromatography using a petroleum ether / ethyl acetate system (petroleum ether:ethyl acetate = 3:1) to obtain the desired product (80.0 mg). LCMS (ESI) [M+Na] + =544.23.

[0346] Step 4: Dissolve 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 4-amino-2-((((4-(3-oxo-1,3-dihydroisobenzofuran-1-yl)butan-2-yl)oxy)carbonyl)oxy)benzoate (80.0 mg) in anhydrous ethanol (10.0 mL), followed by the addition of 3,5-dichloro-2-hydroxybenzaldehyde (40.0 mg). The reaction mixture was incubated at 25°C for 16.0 hours. The reaction mixture was evaporated to dryness to yield the crude product (80.0 mg).

[0347] Step 5: 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl(E)-4-((3,5-dichloro-2-hydroxybenzylidene)amino)-2-((((4-(3-oxo-1,3-dihydroisobenzofuran-1-yl)butan-2-yl)oxy)carbonyl)oxy)benzoate (80.0 mg) was dissolved in anhydrous ethanol (10.0 mL), and sodium triacetylborohydride (40.0 mg) was added. The reaction solution was reacted at 25°C for 2.0 hours. Water (20.0 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20.0 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was subjected to reverse preparative separation to obtain the target product (45.0 mg). LCMS (ESI) [M+H] + =696.21. 1 H NMR (400MHz, DMSO-d6) δ9.81 (s, 1H), 7.85–7.59 (m, 5H), 7.41 (d, J = 2.6Hz, 1H), 7.21 (s, 1 H),7.14(d,J=2.6Hz,1H),6.59–6.52(m,1H),6.39(d,J=2.4Hz,1H),5.67(p,J=3.9Hz,1H) ,4.91–4.69(m,2H),4.36–4.32(m,2H), ,2.29–2.12(m,2H),1.99–1.93(m,1H),1.87–1.5 6(m,5H),1.28(d,J=6.2Hz,4H),1.24–1.16(m,1H),0.96–0.87(m,1H),0.86–0.76(m,9H).

[0348] Example 20 (Compound 120)

[0349] Preparation of 5-((3,5-dichloro-2-hydroxybenzyl)amino)-2-(((1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl)oxy)carbonyl)phenyl(4-(3-oxo-1,3-dihydroisobenzofuran-1-yl)butan-2-yl)succinate:

[0350]

[0351] Step 1: 3-(3-Hydroxybutyl)isobenzofuran-1(3H)-one (300.0 mg) was dissolved in N,N-dimethylformamide (10.0 mL). Succinic anhydride (300.0 mg) was added, and the temperature was raised to 85°C. The reaction was maintained at this temperature for 16.0 hours. Extraction with dichloromethane was performed, and the organic phase was dried over anhydrous sodium sulfate. The solvent was evaporated to obtain a crude compound. The target product (140 mg) was obtained by column separation using a dichloromethane-methanol system (dichloromethane:methanol = 20:1). LCMS (ESI) [M+Na] + =329.26

[0352] Step 2: Dissolve 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 2-hydroxy-4-nitrobenzoate (210 mg) in dichloromethane (10.0 mL). Add 4-oxo-4-((4-(3-oxo-1,3-dihydroisobenzofuran-1-yl)butan-2-yl)oxy)butanoic acid (140 mg), followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (131.0 mg) and 4-dimethylaminopyridine (6.0 mg). Stir for 4 hours. Add water (30.0 mL) and then extract three times with ethyl acetate (30.0 mL). The organic phase is dried over anhydrous sodium sulfate and concentrated to obtain the crude product. Purify the crude product by column chromatography using a petroleum ether and ethyl acetate system (petroleum ether:ethyl acetate = 6:1) to obtain the desired product (120.0 mg).

[0353] LCMS (ESI) [M+Na] + =630.21.

[0354] Step 3: Dissolve 5-nitro-2-(((1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy)carbonyl)phenyl(4-(3-oxo-1,3-dihydroisobenzofuran-1-yl)butan-2-yl)succinate (120.0 mg) in anhydrous ethanol (10.0 mL). Add iron powder (30.0 mg) and ammonium chloride (20.0 mg). Then add water (5.0 mL), and the reaction mixture is allowed to react at 50°C for 16.0 hours. Add water (20.0 mL) and extract three times with dichloromethane (20.0 mL). The organic phase is dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product is then separated by column chromatography using a petroleum ether / ethyl acetate system (petroleum ether:ethyl acetate = 3:1) to obtain the desired product (80.0 mg). LCMS (ESI) [M+Na] + =600.23.

[0355] Step 4: Dissolve 5-amino-2-(((1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy)carbonyl)phenyl(4-(3-oxo-1,3-dihydroisobenzofuran-1-yl)butan-2-yl)succinate (80.0 mg) in anhydrous ethanol (10.0 mL), followed by the addition of 3,5-dichloro-2-hydroxybenzaldehyde (40.0 mg). The reaction mixture was incubated at 25°C for 16.0 hours. The reaction mixture was evaporated to dryness to yield the crude product (60.0 mg).

[0356] Step 5: (E)-5-((3,5-dichloro-2-hydroxybenzylidene)amino)-2-(((1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl)oxy)carbonyl)phenyl(4-(3-oxo-1,3-dihydroisobenzofuran-1-yl)butan-2-yl)succinate (60.0 mg) was dissolved in anhydrous ethanol (10.0 mL), and sodium triacetylborohydride (30.0 mg) was added. The reaction solution was reacted at 25°C for 2.0 hours. Water (20.0 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20.0 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was subjected to reverse preparative separation to obtain the target product (40.0 mg). LCMS (ESI) [M+H] + =752.31. 1 H NMR(400MHz, DMSO-d6)δ7.82(d,J=7.6Hz,1H),7.78–7.68(m,2H),7.63–7.55(m,2H),7.39(d,J=2.6Hz,1H),7. 20(s,1H),7.09(d,J=2.6Hz,1H),6.53(dd,J=8.8,2.4Hz,1H),6.27–6.25(m,1H),5.66–5.57(m,1H),4.94–4.7 9(m,2H),4.30(s,2H),2.80(t,J=6.8Hz,2H),2.64–2.60(m,2H),2.35–2.24(m,1H),2.16–1.93(m,2H),1.72–1 .63(m,4H),1.57–1.49(m,1H),1.34–1.22(m,2H),1.15(d,J=6.4Hz,3H),0.97–0.91(m,1H),0.89–0.77(m,9H).

[0357] Example 21 (Compound 121)

[0358] Preparation of 4-(3-oxo-1,3-dihydro-2-benzofuran-1-yl)butan-2-yl 4-(((3,5-dichloro-2-hydroxyphenyl)methyl)amino)-2-hydroxybenzoate:

[0359]

[0360] Step 1: Add N,N-dimethylpyridin-4-amine (624 mg) to a solution of 2-hydroxy-4-nitrobenzoic acid (720 mg) and 3-((3S)-3-hydroxybutyl)-3H-2-benzofuran-1-one (811 mg) in dichloromethane (10 mL). The mixture was allowed to react at room temperature for 10 minutes. N,N-dicyclohexylmethanediimide (1622 mg) was then added and allowed to react at room temperature for 16 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was isolated and purified by flash chromatography to yield the title compound (270 mg). LCMS (ESI) [M+Na] + =394.1.

[0361] 1 H NMR (400MHz, CDCl3) δ11.04(s,1H),7.99(dd,J=12.9,8.7Hz,1H),7.92(d,J=7.6Hz,1H),7.82(t,J=2.4Hz,1H),7.73–7.66(m,2H),7.56(t ,J=7.5Hz,1H),7.43(d,J=7.6Hz,1H),5.57–5.48(m,1H),3.52–3.44(m,1H),1.95–1.92(m,2H),1.72–1.67(m,2H),1.43(d,J=6.2Hz,3H).

[0362] Step 2: Add palladium on carbon (30 mg) to a solution of 4-(3-oxo-1,3-dihydro-2-benzofuran-1-yl)butan-2-yl 2-hydroxy-4-nitrobenzoate (270 mg) in methanol (10 mL). Under a hydrogen atmosphere, react at room temperature for 3 hours. The reaction mixture was filtered and the filtrate was concentrated to obtain the title compound (220 mg). LCMS (ESI) [M+Na] + =364.0

[0363] Step 3: Add 3,5-dichloro-2-hydroxybenzaldehyde (118 mg) to a solution of 4-(3-oxo-1,3-dihydro-2-benzofuran-1-yl)butan-2-yl-4-amino-2-hydroxybenzoate (190 mg) in ethanol (5 mL) and react at room temperature for 16 hours. The reaction mixture was concentrated to obtain the crude target compound (190 mg). LCMS (ESI) [M+H] + =513.9.

[0364] Step 4: Sodium borohydride (125 mg) was added to a solution of 4-(3-oxo-1,3-dihydro-2-benzofuran-1-yl)butan-2-yl 4-[(E)-[(3,5-dichloro-2-hydroxyphenyl)methylene]amino]-2-hydroxybenzoate (190 mg) in ethanol (5 mL). The mixture was allowed to react at room temperature for 2 hours. The reaction solution was concentrated, and the residue was analyzed by prep-HPLC (C18, 0.1% NH3.H2O in water / MeCN) to yield the title compound (41.77 mg). LCMS (ESI) [M+H] + =516.1. 1 H NMR (400MHz, DMSO-d6) δ10.89(d,J=2.0Hz,1H),9.80(s,1H),7.86–7.74(m,2H),7.69(d,J=7.6Hz, 1H),7.63–7.57(m,1H),7.49(t,J=9.0Hz,1H),7.41(d,J=2.5Hz,1H),7.16(t,J=6.0Hz,1H),7.12–7 .05(m,1H),6.22(d,J=8.9Hz,1H),5.93(d,J=1.6Hz,1H),5.73–5.64(m,1H),5.13–4.97(m,1H),4.3 0(d,J=5.8Hz,2H),2.26–2.12(m,1H),1.85–1.71(m,2H),1.69–1.55(m,1H),1.27(d,J=6.2Hz,3H).

[0365] Example 22 (Compound 122)

[0366] Preparation of 4-{[1-(2-{(5-{(3,5-dichloro-2-hydroxyphenyl)methyl]amino}-2-[(1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl}oxy]phenoxy)methoxy]carbonyl}phenyl)pentyl]oxy}-4-oxobutanoic acid:

[0367]

[0368] Step 1: Refer to the first step of Example 1 to obtain the target product (12.0 g).

[0369] Step 2: Refer to the first step of Example 3 to obtain the target product (4.5 g). LCMS (ESI) [M+Na] + =331.24.

[0370] Step 3: Dissolve {1-[(3-carboxypropyl)oxy]pentyl}benzoic acid (3 g) in 2-methyltetrahydrofuran (50 mL), add (Z)-N,N'-bis(propan-2-yl)(tert-butoxy)formamidine (2.92 g), protect with nitrogen, heat to 60°C, stir and react for 12 hours. Remove the solvent under low pressure, and separate the reaction solution by column chromatography using petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 3:1) to obtain the desired product (1.6 g). LCMS (ESI) [M+Na] + =387.34.

[0371] Step 4: [(1-{2-[(tert-Butoxy)carbonyl]phenyl}pentyl)oxy]-4-oxobutanoic acid (1.6 g) was dissolved in dichloromethane (20 mL) and water (22 mL), and sodium bicarbonate (1.84 g) and tetrabutylammonium hydrogen sulfate (149.07 mg) were added. After the addition was complete, chloromethylsulfonyl chloride (579.54 mg) was added dropwise in an ice bath. The mixture was slowly warmed to room temperature and stirred overnight. Dichloromethane was added to the reaction solution, which was then washed with saturated ammonium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 1-(1-{2-[(tert-Butoxy)carbonyl]phenyl}pentyl)4-chloromethylsuccinate (1.7 g). LCMS (ESI) [M+Na] + =435.3.

[0372] Step 5: 1-tert-Butyl 4-(1-{2-[(chloromethoxy)carbonyl]phenyl}pentyl)succinate (800 mg), 1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl 2-hydroxy-4-nitrobenzoate (619.54 mg), and potassium carbonate (804.38 mg) were added to acetonitrile (15 mL) and stirred at 50°C for 2 hours. The reaction solution was desolvated under low pressure and separated by column chromatography using a petroleum ether / ethyl acetate system (petroleum ether:ethyl acetate = 3:1) to obtain the desired product (290.0 mg). LCMS (ESI) [M+Na] + =718.57.

[0373] Step 6: 1-tert-Butyl 4-(1-{2-[({5-nitro-2-[({1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl}oxy)carbonyl]phenoxy}methoxy)carbonyl]phenyl}pentyl)succinate (290 mg) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (1 mL) was added and the mixture was stirred at room temperature for 2 hours. The solvent was removed under low pressure and the reaction solution was separated by column chromatography using a petroleum ether and ethyl acetate system (petroleum ether:ethyl acetate = 2:1) to obtain the desired product (170.0 mg). LCMS (ESI) [M+Na] + =662.49.

[0374] Step 7: Compound 2-(1-{[4-({5-nitro-2-[({1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl}oxy)carbonyl]phenoxy}methoxy)-4-oxobutanoyl]oxy}pentyl)benzoic acid (170 mg) was dissolved in ethanol (3 mL), and water (1 mL) was added. After the addition of iron powder (74.2 mg) and ammonium chloride (71.08 mg), the temperature was raised to 50° C. and stirred for 1 hour. The reaction solution was filtered through celite, and the filtrate was desolvated under low pressure. The target product (100 mg) was obtained by column separation using a petroleum ether and ethyl acetate system (petroleum ether:ethyl acetate = 1:1). LCMS (ESI) [M+Na] + =632.5.

[0375] Step 8: 4-[(1-{2-[({5-amino-2-[({1,7,7-trimethylbicyclo[2.2.1]hept-2-yl}oxy)carbonyl]phenoxy}methoxy)carbonyl]phenyl}pentyl)oxy]-4-oxobutanoic acid (80 mg) and 3,5-dichloro-2-hydroxybenzaldehyde (30.07 mg) were dissolved in 1,2-dichloroethane (2 mL). One drop of acetic acid was added as a catalyst, and the reaction was stirred at room temperature for 12 hours. The solvent was evaporated under low pressure to obtain the desired product (80 mg).

[0376] Step 9: 4-[(1-{2-[(5-[(Z)-[(3,5-dichloro-2-hydroxyphenyl)methylene]amino]-2-[(1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl}oxy]phenoxy}methoxy)carbonyl]phenyl}pentyl)oxy]-4-oxobutanoic acid (80 mg) was dissolved in 1,2-dichloroethane (2 mL), and sodium triacetoxyborohydride (64.68 mg) was added under ice-cooling. The reaction mixture was stirred at room temperature for 3 hours. The reaction solution was quenched with water and extracted with dichloromethane. The organic phase was washed with saturated brine, concentrated, dissolved in acetonitrile, filtered, and the filtrate was subjected to reverse phase preparation to obtain the title compound (16.6 mg). LCMS (ESI) [M+H] + =784.44.

[0377] 1H NMR (400MHz, DMSO-d6) δ7.77(d,J=7.9Hz,1H),7.62(dd,J=8.5,5.7Hz,2H),7.54(d,J=7.9Hz,1H),7. 43–7.30(m,2H),7.11(d,J=2.6Hz,2H),6.46(d,J=2.1Hz,1H),6.43–6.31(m,2H),5.96(dd,J=50.3,6. 6Hz,2H),4.96–4.82(m,1H),4.32(s,2H),2.55(d,J=6.8Hz,2H),2.44(t,J=6.4Hz,2H),2.29(d,J=3. 8Hz,1H),2.08(d,J=6.0Hz,1H),1.68(dt,J=10.6,5.4Hz,4H),1.40–1.09(m,7H),1.00–0.67(m,12H).

[0378] Example 23 (Compound 123)

[0379] Preparation of 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 2-[(8-{2-[1-(acetyloxy)pentyl]benzoyloxy}octanoyl)oxy]-4-{[(3,5-dichloro-2-hydroxyphenyl)methyl]amino}benzoate:

[0380]

[0381] Step 1: 8-Hydroxyoctanoic acid (3 g) was dissolved in dichloromethane (60 mL), and 1H-imidazole (1.4 g) was added. After stirring at room temperature for 20 minutes, tert-butyl(chloro)diphenylsilane (5.15 g) was added. After the addition, the mixture was stirred at room temperature overnight. The solvent was removed under low pressure, and the target product (1.6 g) was obtained by column separation using a petroleum ether-ethyl acetate system (petroleum ether:ethyl acetate = 10:1).

[0382] Step 2: Dissolve 2-(1-acetoxybenzoic acid)benzoic acid (1 g) in dichloromethane (30 mL), add N,N'-dicyclohexylmethanediimide (1.24 g) and N,N-dimethylpyridin-4-amine (146.43 mg). Stir the mixture at room temperature for 10 minutes, then add tert-butyldiphenylsilyl 8-hydroxyoctanoate (1.59 g). Continue stirring for 2 hours. The reaction mixture is quenched with water and extracted with dichloromethane. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography using a petroleum ether-ethyl acetate system (petroleum ether:ethyl acetate = 5:1) to obtain the desired product (1.8 g). LCMS (ESI) [M+Na] + =653.53.

[0383] Step 3: Dissolve tert-butyldiphenylsilyl 8-{2-[1-(acetyloxy)pentyl]benzoyloxy}octanoate (1.6 g) in tetrahydrofuran (30 mL) and add 1 M tetrabutylammonium fluoride (3.32 g). Stir and react overnight at room temperature. The reaction mixture is quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent removed under low pressure to obtain the desired product (1.4 g). LCMS (ESI) [M+Na] + =415.33.

[0384] Step 4: Dissolve 8-{2-[1-(acetyloxy)pentyl]benzoyloxy}octanoic acid (1.5 g) in dichloromethane (30 mL). Add N,N'-dicyclohexylmethanediimide (1.58 g) and N,N-dimethylpyridin-4-amine (140.07 mg) in an ice bath. Stir the mixture at room temperature for 10 minutes, then add 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 2-hydroxy-4-nitrobenzoate (1.22 g). Stir the mixture at room temperature for 2 hours. The reaction mixture is quenched with water and extracted with dichloromethane. The organic phase is collected, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography using petroleum ether-ethyl acetate (petroleum ether:ethyl acetate = 5:1) to obtain the desired product (600 mg). LCMS (ESI) [M+Na] + =716.6.

[0385] Step 5: Dissolve the compound 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 2-[(8-{2-[1-(acetyloxy)pentyl]benzoyloxyoctyl)oxy]-4-nitrobenzyl ester (600 mg) in ethanol (8 mL), and add water (3 mL), iron powder (241.45 mg), and ammonium chloride (231.28 mg). Heat to 50°C and stir for 1 hour. The reaction solution is filtered through celite, and the filtrate is desolvated under low pressure. The desired product (370 mg) is separated by column chromatography using a petroleum ether-ethyl acetate system (petroleum ether:ethyl acetate = 1:1). LCMS (ESI) [M+H] + =664.6.

[0386] Step 6: Compound 1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl 2-[(8-{2-[1-(acetyloxy)pentyl]benzoyloxy}octanoyl)oxy]-4-aminobenzoate (370 mg) and 3,5-dichloro-2-hydroxybenzaldehyde (117.11 mg) were dissolved in 1,2-dichloroethane (10 mL), and a drop of acetic acid was added as a catalyst. The reaction was stirred at room temperature overnight, and the reaction solution was dried to obtain the target product (300 mg).

[0387] Step 7: Compound 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 2-[(8-{2-[1-(acetyloxy)pentyl]benzoyloxy}octanoyl)oxy]-4-[(E)-[(3,5-dichloro-2-hydroxyphenyl)methylene]amino]benzoate (300 mg) was dissolved in 1,2-dichloroethane (8 mL). Sodium triacetoxyborohydride (226.85 mg) was added under ice-cooling conditions. After the addition, the mixture was warmed to room temperature and stirred for 4 hours. The reaction solution was quenched with water, extracted with dichloromethane, and the organic phase was concentrated, dissolved in acetonitrile, and filtered. The filtrate was used to obtain the target product (140 mg). LCMS (ESI) [M+H] + =838.58.

[0388] 1 H NMR (400MHz, DMSO-d6) δ7.80(dd,J=7.8,1.4Hz,1H),7.73(d,J=8.8Hz,1H),7.59(td,J=7.6,1.5Hz,1H),7.53(dd,J=8.0,1. 4Hz,1H),7.44–7.35(m,2H),7.16(s,1H),7.12(d,J=2.6Hz,1H),6.52(dd,J=8.8,2.4Hz,1H),6.35(t,J=6.4Hz,1H),6.25(d, J=2.3Hz,1H),4.92–4.84(m,1H),4.36–4.20(m,4H),2.53(d,J=7.3Hz,2H),2.28(dd,J=13.5,9.6Hz,1H),2.04(s,3H),1.97 (ddd,J=13.0,9.3,4.4Hz,1H),1.73(h,J=6.7Hz,5H),1.63(dt,J=14.4,5.9Hz,3H),1.48–1.12(m,12H),0.99–0.70(m,13H).

[0389] Example 25 (Compound 125)

[0390] Preparation of 1-(6-{2-[1-(acetyloxy)pentyl]benzoyloxy}hexyl)5-{[(3,5-dichloro-2-hydroxyphenyl)methyl]amino}-2-[({1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl}oxy)carbonyl]phenylsuccinate:

[0391]

[0392] First step: compound 2-(1-acetyloxy-pentyl)-benzoic acid (700 mg) was dissolved in dichloromethane (30 mL), N,N'-dicyclohexylmethane diimine (865.58 mg) and N,N-dimethylpyridin-4-amine (102.5 mg) were added under ice bath condition. After stirring for 15 minutes, 6-[tert-butyl(dimethyl)silyl]oxyhexan-1-ol (650.08 mg) was added. After the addition was completed, the reaction was stirred at room temperature for 2 hours. The reaction solution was quenched with water (20 mL), extracted with dichloromethane, washed with saturated brine, and concentrated. The target product (800 mg) was obtained by column separation with a petroleum ether / ethyl acetate system (petroleum ether: ethyl acetate = 20:1). LCMS (ESI) [M+Na] + = 487.42.

[0393] Second step: compound 6-[(tert-butyldimethylsilyl)oxy]hexyl 2-[1-(acetyloxy)pentyl]benzoate (800 mg) was dissolved in tetrahydrofuran (30 mL), and tetrabutylammonium fluoride (1.12 g) was added. The reaction was stirred at room temperature overnight. The reaction solution was quenched with water, extracted with ethyl acetate, and washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the target product (700 mg). LCMS (ESI) [M+Na] + = 373.31.

[0394] Third step: compound 6-hydroxyhexyl 2-[1-(acetyloxy)pentyl]benzoate (700 mL) was dissolved in N,N-dimethylformamide (15 mL), and oxolane-2,5-dione (199.88 mg) and N,N-dimethylpyridin-4-amine (244.03 mg) were added. The reaction was stirred at 70°C for 1 hour. The reaction solution was quenched with water, extracted with ethyl acetate, and the organic phase was collected, washed with water and saturated brine, dried over anhydrous sodium sulfate, and column separated with a petroleum ether / ethyl acetate system (petroleum ether: ethyl acetate = 4:1) to obtain the target product (350 mg). LCMS (ESI) [M+Na] + = 473.35.

[0395] Step 4: Compound 4-[(6-{2-[1-(acetyloxy)pentyl]benzoyloxy}hexyl)oxy]-4-oxobutanoic acid (300 mg) was dissolved in dichloromethane (10 mL). N,N'-dicyclohexylmethanediimide (206.09 mg) and N,N-dimethylpyridin-4-amine (24.41 mg) were added under ice-cooling conditions. After stirring at room temperature for 10 minutes, 1,7,7-trimethylbicyclo[2.2.1]heptane-2-acyl-2-hydroxy-4-nitrobenzoate (212.65 mg) was added. After the addition, the reaction was stirred at room temperature overnight. The reaction solution was quenched with water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography using a petroleum ether / ethyl acetate system (petroleum ether:ethyl acetate = 5:1) to obtain the desired product (80 mg). LCMS (ESI) [M+Na] + =774.54.

[0396] Step 5: Compound 1-(6-{2-[1-(acetyloxy)pentyl]benzoyloxy}hexyl)5-nitro-2-[(1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl}oxy)carbonyl]benzene succinate (70 mg) was dissolved in ethanol (1 mL). Water (0.5 mL), iron powder (25.99 mg), and ammonium chloride (24.9 mg) were added. The temperature was raised to 50°C and stirred for 0.5 hours. The reaction solution was filtered through celite and washed with ethyl acetate. The filtrate was concentrated and separated by column chromatography using a petroleum ether and ethyl acetate system (petroleum ether:ethyl acetate = 3:1) to obtain the desired product (30 mg). LCMS (ESI) [M+Na] + =744.56.

[0397] Step 6: Compound 1-(6-{2-[1-(acetyloxy)pentyl]benzoyloxy}hexyl)5-amino-2-[({1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl}oxy)carbonyl]phenylsuccinate (25 mg) and 3,5-dichloro-2-hydroxybenzaldehyde (7.94 mg) were dissolved in 1,2-dichloroethane (3 mL), and 1 drop of acetic acid was added as a catalyst. The reaction was stirred at room temperature overnight, and the reaction solution was dried to give the title compound (20 mg).

[0398] Step 7: Compound 1-(6-{2-[1-(acetyloxy)pentyl]benzoyloxy}hexyl)5-[(Z)-[(3,5-dichloro-2-hydroxyphenyl)methylene]amino]-2-[({1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl}oxy)carbonyl]phenylsuccinate (20 mg) was dissolved in 1,2-dichloroethane (3 mL). Sodium triacetoxyborohydride (18.86 mg) was added under ice-cooling conditions. After addition, the mixture was stirred at room temperature for 3 hours. The reaction solution was dried, dissolved in acetonitrile, and filtered to obtain the desired product (3 mg). LCMS (ESI) [M+H] + =896.6.

[0399] 1 H NMR(400MHz, DMSO-d6)δ7.84–7.70(m,2H),7.59(td,J=7.6,1.4Hz,1H),7.52(dd,J=7.9,1.4Hz,1H),7.3 9(ddd,J=15.1,7.5,2.0Hz,2H),7.21(s,2H),7.08(d,J=2.6Hz,1H),6.52(dd,J=8.8,2.3Hz,1H),6.35(t, J=6.4Hz,1H),6.25(d,J=2.3Hz,1H),4.93–4.81(m,1H),4.36–4.19(m,3H),4.03(t,J=6.5Hz,2H),2.85– 2.56(m,4H),2.34–2.22(m,1H),2.03(s,4H),1.81–1.52(m,7H),1.51–1.12(m,13H),0.99–0.74(m,11H).

[0400] Example 26 (Compound 126)

[0401] Preparation of 5-((3,5-dichloro-2-hydroxybenzyl)amino)-2-((((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl)oxy)carbonyl)phenyl(4-((S)-3-oxo-1,3-dihydroisobenzofuran-1-yl)butan-2-yl)succinic acid formate:

[0402]

[0403] Step 1: Dissolve 2-hydroxy-4-nitrobenzoic acid (500 mg) in dichloromethane (10 mL). Add (1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (842.34 mg), (3-{[(ethylimino)methyleneimino]amino}propyl)dimethylamine hydrochloride (785.14 mg), and N,N-dimethylpyridin-4-amine (166.79 mg). The reaction was allowed to react at room temperature for 16 hours. LCMS confirmed the reaction was complete. Dilute the reaction solution with water (5 mL) and extract with dichloromethane (10 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 20:1) to yield the title compound (500 mg). LCMS (ESI) [MH]- = 317.9. 1 H NMR (400MHz, CDCl3) δ11.14(s,1H),8.04(d,J=8.7Hz,1H),7.82(d,J=2.2Hz,1H),7.72(dd,J=8.7,2.2Hz,1H),5.24–5.08(m,1H),2.55–2.45(m,1 H),2.10–2.00(m,1H),1.90–1.76(m,2H),1.52–1.42(m,1H),1.38–1.29( m,1H),1.16(dd,J=14.0,3.4Hz,1H),0.98(s,3H),0.94(d,J=1.6Hz,6H).

[0404] Step 2: Dissolve 3-[(3S)-3-hydroxybutyl]-3H-2-benzofuran-1-one (20 g) in methanol (100 mL) and add 10% sodium hydroxide solution (20 mL) under stirring. The reaction is complete within 15 minutes. Heat the system to a homogeneous solution and continue the reaction at room temperature for 2 hours. Remove the methanol by distillation under reduced pressure, and dilute the residue with distilled water (20 mL). Cool the system to -10°C, adjust the pH to 3-4 with 5% hydrochloric acid solution under stirring, and extract with ether (45 mL x 3). Combine the ether extracts, cool the solution to -10°C, and slowly add (1S)-1-phenylethylether-1-amine (11.75 g) dropwise. Keep the system at -10°C and let it stand for 24 hours. Filter to collect the crystals, which are then recrystallized twice from ethyl acetate. The crystals were dissolved in water (40 mL), and 10% sodium hydroxide solution was added to adjust the solution to pH 13. (1S)-1-phenethylether-1-amine was recovered by extraction with diethyl ether (45 mL x 2). The aqueous phase was adjusted to pH 2 with 3M hydrochloric acid, extracted with diethyl ether (80 mL x 2), dried, and concentrated to yield the title compound (1.8 g). LCMS (ESI) [M+H-18]+ = 189.2.

[0405] Step 3: Dissolve (3S)-3-(3-hydroxybutyl)-1,3-dihydro-2-benzofuran-1-one (350 mg) in N,N-dimethylformamide (10 mL), add oxocycloalkane-2,5-dione (339.65 mg) and N,N-dimethylpyridin-4-amine (103.66 mg), and react at 85°C for 16 hours. LCMS analysis confirmed the reaction was complete. Dilute the reaction solution with water (10 mL), adjust the pH to 5 with 1N HCl, and extract with ethyl acetate (25 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether:tetrahydrofuran = 2:1) to yield the title compound (450 mg). LCMS (ESI) [M+H]+ = 307.0. 1 H NMR (400MHz, CDCl3) δ7.90(d,J=7.7Hz,1H),7.68(t,J=7.5Hz,1H),7.54(t,J=7.3Hz,1H),7.45(d,J=7.7Hz,1H),5.55– 5.45(m,1H),5.14–4.88(m,1H),2.96(s,2H),2.89(s,2H),2.70–2.65(m,2H),2.63–2.57(m,2H),1.23(t,J=6.4Hz,3H).

[0406] Step 4: Dissolve 4-oxo-4-({4-[(1S)-3-oxo-1,3-dihydro-2-benzofuran-1-yl]butan-2-yl}oxy)butanoic acid (350 mg) and (1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl 2-hydroxy-4-nitrobenzoate (364.9 mg) in dichloromethane (10 mL). Add (3-{[(ethylimino)methylene]amino}propyl)dimethylamine hydrochloride (328.56 mg) and N,N-dimethylpyridin-4-amine (69.8 mg). The reaction was stirred at room temperature for 16 hours. LCMS indicated the formation of product. The reaction mixture was diluted with water (5 mL) and extracted with dichloromethane (10 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain the title compound (300 mg). LCMS (ESI) [M+18]+ = 625.3.

[0407] Step 5: Dissolve 5-nitro-2-({[(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]oxycarbonyl)phenyl 1-{4-[(1S)-3-oxo-1,3-dihydro-2-benzofuran-1-yl]butan-2-yl}succinate (300 mg) in ethanol (10 mL) and water (5 mL). Add iron powder (137.84 mg) and ammonium chloride (132.04 mg). Stir at 50°C for 16 hours. LCMS analysis indicates the reaction is complete. Filter the reaction solution, dilute the filtrate with water (5 mL), and extract with ethyl acetate (10 mL x 2). The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to yield the title compound (220 mg). LCMS (ESI) [M+H] + = 578.3.

[0408] Step 6: 5-Amino-2-({[(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl]oxycarbonyl)phenyl 1-{4-[(1S)-3-oxo-1,3-dihydro-2-benzofuran-1-yl]butan-2-yl}succinate (300 mg) was dissolved in 1,2-dichloroethane (6 mL). 3,5-Dichloro-2-hydroxybenzaldehyde (496.63 mg) and glacial acetic acid (0.2 mL) were added at room temperature. The reaction was stirred at 40°C for 16 hours. LCMS confirmed the reaction was complete, and the reaction solution was concentrated to obtain the crude product, which was used directly in the next step. LCMS (ESI) [M+H]+ = 750.2.

[0409] Step 7: 5-[(E)-[(3,5-dichloro-2-hydroxyphenyl)methylimino]amino]-2-({[(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]oxy}carbonyl)phenyl 1-{4-[(1S)-3-oxo-1,3-dihydro-2-benzofuran-1-yl]butan-2-yl}succinate (300 mg) was dissolved in methanol (10 mL). Sodium borohydride (30.24 mg) was added and the reaction was stirred at room temperature for 1 hour. LCMS confirmed the reaction was complete, and the reaction solution was filtered. The filtrate was purified by pre-HPLC (0.1% FA in H2O / ACN) to yield the title compound (180 mg). LCMS (ESI) [M+H]+ = 752.2. 1H NMR(400MHz, DMSO-d6)δ8.47(s,2H),7.82(d,J=7.6Hz,1H),7.71(t,J=7.0Hz,2H),7.63–7.54(m,2H),7.22–7.15(m,1H),6.99– 6.91(m,1H),6.52(d,J=8.8Hz,1H),6.29–6.21(m,1H),5.66–5.57(m,1H),4.94–4.78(m,2H),4.25(s,2H),2.80(t,J=6.7Hz,2H) ,2.68–2.56(m,2H),2.34–2.23(m,1H),2.19–2.05(m,1H),2.03–1.93(m,1H),1.76–1.59(m,4H),1.58–1.48(m,1H),1.37–1.29 (m,1H),1.27–1.20(m,1H),1.16(d,J=6.2Hz,3H),0.96–0.90(m,1H),0.88(d,J=3.0Hz,3H),0.85(s,3H),0.79(d,J=1.8Hz,3H).

[0410] Example 27 (Compound 127)

[0411] Preparation of 4-((1S)-3-oxo-1,3-dihydro-2-benzofuran-1-yl)butan-2-yl 4-(((3,5-dichloro-2-hydroxyphenyl)methyl)amino)-2-hydroxybenzoate:

[0412]

[0413] Step 1: Add N,N-dimethylpyridin-4-amine (770 mg) to a solution of 2-hydroxy-4-nitrobenzoic acid (888 mg) and (3S)-3-(3-hydroxybutyl)-1,3-dihydro-2-benzofuran-1-one (1000 mg) in dichloromethane (10 mL). The mixture was allowed to react at room temperature for 10 minutes. N,N-dicyclohexylmethanediimide (2001 mg) was then added and allowed to react at room temperature for 16 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by flash chromatography (Silica gel, PE / THF = 4 / 1) to yield the title compound (500 mg). LCMS (ESI) [M+Na]+ = 394.0.

[0414] Step 2: Add palladium on carbon (50 mg) to a solution of 4-((1S)-3-oxo-1,3-dihydro-2-benzofuran-1-yl)butan-2-yl 2-hydroxy-4-nitrobenzoate (500 mg) in methanol (10 mL). The mixture was reacted at 25°C under a hydrogen atmosphere for 3 hours. LCMS analysis indicated that the reaction was complete. The reaction solution was filtered and the filtrate was concentrated to obtain the title compound (360 mg). LCMS (ESI) [M+H] + = 342.1

[0415] Step 3: Add 3,5-dichloro-2-hydroxybenzaldehyde (222 mg) to a solution of 4-((1S)-3-oxo-1,3-dihydro-2-benzofuran-1-yl)butan-2-yl 4-amino-2-hydroxybenzoate (360 mg) in ethanol (5 mL). The mixture was allowed to react at 25°C for 16 hours. LCMS confirmed the reaction was complete. The reaction mixture was concentrated to afford the crude title compound (650 mg). LCMS (ESI) [M+H]+ = 514.0.

[0416] Step 4: Sodium borohydride (96 mg) was added to a solution of 4-((1S)-3-oxo-1,3-dihydro-2-benzofuran-1-yl)butan-2-yl 4-((E)-((3,5-dichloro-2-hydroxyphenyl)methylene)amino)-2-hydroxybenzoate (650 mg) in ethanol (5 mL). The mixture was allowed to react at 25°C for 3 hours. LCMS confirmed the reaction was complete, and the reaction solution was concentrated. The residue was purified by prep-HPLC (C18, 0.1% FA in water / MeCN) to yield the title compound (22.62 mg). LCMS (ESI) (M+H)+ = 516.1. 1 HNMR(400MHz,DMSO-d6)δ10.89(d,J=2.0Hz,1H),9.80(s,1H),7.84(d,J=7.7Hz,1H),7.81–7.74 (m,1H),7.69(d,J=7.6Hz,1H),7.62–7.58(m,1H),7.49(t,J=9.0Hz,1H),7.40(d,J=2.0Hz,1H),7 .16(s,1H),7.09(t,J=2.6Hz,1H),6.21(d,J=8.9Hz,1H),5.93(d,1H),5.71–5.66(m,1H),5.10– 5.00(m,1H),4.30(d,J=4.6Hz,2H),2.24–2.12(m,1H),1.83–1.59(m,3H),1.27(d,J=6.2Hz,3H).

[0417] Example 28 (Compound 128)

[0418] Preparation of 5-oxo-5-((4-(3-oxo-1,3-dihydroisobenzofuran-1-yl)butan-2-yl)oxy)pentyl 4-(((3,5-dichloro-2-hydroxybenzyl)amino)-2-hydroxybenzoate:

[0419]

[0420] Step 1: 2H-tetrahydropyran-2-one (20 g) was added to a 250 mL single-necked flask, followed by methanol (100 mL) and sodium hydroxide (8.8 g). The reaction was continued at 60°C for 16 hours. TLC confirmed the complete reaction mixture. The solvent was evaporated and the reaction mixture was slurried with methyl tert-butyl ether to yield sodium 5-hydroxyvalerate (22 g), which was used directly in the next step.

[0421] Step 2: Sodium 5-hydroxyvalerate (5 g) was added to a 100 mL single-necked flask, followed by DCM (50 mL), followed by imidazole (7.3 g) and tert-butyldiphenylsilyl chloride (9.8 g). The reaction was continued at 0°C for 16 hours. LCMS confirmed the complete reaction of the starting materials, with product formation. The reaction mixture was added with water (50 mL) and extracted. The organic phase was spin-dried to dryness to obtain the crude compound. The crude product was then separated by column chromatography using petroleum ether and ethyl acetate (1:1) to afford 5-(tert-butyldiphenylsilyl)oxy)pentanoic acid (3.2 g). LCMS (ESI) [M+H]+ = 357.17.

[0422] Step 3: Dissolve 3-(3-hydroxybutyl)isobenzofuran-1(3H)-one (400 mg) in dichloromethane (10.0 mL), add 5-((tert-butyldiphenylsilyl)oxy)pentanoic acid (829.78 mg), then add N,N'-dicyclohexylmethanediamine (600.26 mg) and N,N-dimethylpyridin-4-amine (47.39 mg). The reaction mixture was allowed to react at 25°C for 4.0 hours. LCMS confirmed the complete reaction of the starting material and the formation of the product. The reaction mixture was filtered to remove the solid, and water (20.0 mL) was added. Extraction was then performed with dichloromethane (20.0 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was then separated by column chromatography using a petroleum ether / ethyl acetate system (petroleum ether:ethyl acetate = 6:1) to obtain the desired product (320 mg). LCMS (ESI) [M+H] + =545.31

[0423] Step 4: Dissolve 4-(3-oxo-1,3-dihydro-2-benzofuran-1-yl)butan-2-yl 5-[(tert-butyldiphenylsilyl)oxy]pentanoate (180 mg) in tetrahydrofuran (5 mL) and add tetrabutylammonium fluoride (0.66 mL, 1 M in tetrahydrofuran). The reaction mixture was incubated at 25°C for 2 hours. LCMS indicated that the reaction was complete, with product formed. Add 20 mL of water and extract with dichloromethane (20 mL). The organic phase was dried over anhydrous sodium sulfate, evaporated, and concentrated to yield the crude product. The crude product was then separated by column chromatography using petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 4:1) to yield 4-(3-oxo-1,3-dihydroisobenzofuran-1-yl)butan-2-yl-5-hydroxypentanoate (80 mg). LCMS (ESI) [M+H] + =307.19

[0424] Step 5: Dissolve 4-(3-oxo-1,3-dihydroisobenzofuran-1-yl)butan-2-yl-5-hydroxypentanoate (108 mg) in dichloromethane (5 mL), add 2-hydroxy-4-nitrobenzoic acid (64.56 mg), N,N'-dicyclohexylmethanediamine (108.32 mg), and then add N,N-dimethylpyridin-4-amine (8.55 mg). The reaction mixture was allowed to react at 25°C for 16 hours. LCMS showed that the reaction was complete, with product formed. 20 mL of water was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL). The organic phase was dried over anhydrous sodium sulfate, evaporated, and concentrated to obtain the crude product. The crude product was then separated by column chromatography using a petroleum ether / ethyl acetate system (petroleum ether:ethyl acetate = 6:1) to obtain the product (90 mg). LCMS (ESI) [M+H] + =472.15.

[0425] Step 6: 5-Oxo-5-((4-(3-oxo-1,3-dihydroisobenzofuran-1-yl)butan-2-yl)oxy)2-hydroxy-4-nitrobenzoic acid pentyl ester (90 mg) was dissolved in anhydrous ethanol (2 mL), iron powder (53.3 mg) was added, and then ammonium chloride (20.42 mg) was added. Water (1 mL) was then added, and the reaction solution was reacted at 50°C for 3 hours. LCMS showed that the raw material reaction was complete and product was generated. 10 mL of water was added to the reaction solution, and dichloromethane (10 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, evaporated, and concentrated to obtain the crude product. The crude product was separated by column chromatography using a petroleum ether and ethyl acetate system (petroleum ether:ethyl acetate = 3:1) to obtain the product (80 mg). LCMS (ESI) [M+H] + =442.25

[0426] Step 7: Dissolve pentyl 5-oxo-5-((4-(3-oxo-1,3-dihydroisobenzofuran-1-yl)butan-2-yl)oxy)2-hydroxy-4-aminobenzoate (60 mg) in anhydrous ethanol (5 mL), then add 3,5-dichloro-2-hydroxybenzaldehyde (28.56 mg). The reaction mixture was incubated at 25°C for 16 hours. TLC indicated that the reaction of the starting material was complete and product was formed. The solvent was evaporated to dryness to obtain the product (60 mg).

[0427] Step 8: 5-Oxo-5-((4-(3-oxo-1,3-dihydroisobenzofuran-1-yl)butan-2-yl)oxy)pentyl (E)-4-((3,5-dichloro-2-hydroxybenzylidene)amino)-2-hydroxybenzoate (80 mg) was dissolved in anhydrous ethanol (5 mL), followed by the addition of sodium triacetylborohydride (54.92 mg). The reaction mixture was incubated at 25°C for 16 hours. LCMS analysis confirmed complete reaction of the starting material with product formation. 20 mL of water was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL). The organic phase was dried over anhydrous sodium sulfate, evaporated, and concentrated to afford the crude product, which was then subjected to reverse preparative separation to afford the product (66 mg). LCMS (ESI) [M+Na]+ = 616.24. 1 H NMR (400MHz, DMSO-d6) δ10.86(s,1H),9.79(s,1H),7.83(d,J=7.7Hz,1H),7.76(t,J=7.6Hz,1H),7.68-7. 65(m,1H),7.58(t,J=7.5Hz,1H),7.49(d,J=8.8Hz,1H),7.40(d,J=2.6Hz,1H),7.16(s,1H),7.11(d,J=2. 7Hz,1H),6.22(d,J=8.5Hz,1H),5.95(d,J=2.2Hz,1H),5.66-5.62(m,1H),4.89-4.80(m,1H),4.31–4.2(m ,4H),2.39-2.31(m,2H),2.18-2.04(m,1H),1.86-1.57(m,6H),1.56-1.47(m,1H),1.16(d,J=6.2Hz,3H).

[0428] Example 29 (Compound 129)

[0429] Preparation of 4-oxo-4-((4-(3-oxo-1,3-dihydroisobenzofuran-1-yl)butan-2-yl)oxy)butyl 4-(((3,5-dichloro-2-hydroxybenzyl)amino)-2-hydroxybenzoate:

[0430]

[0431] Step 1: 4-Oxo-4-((4-(3-oxo-1,3-dihydroisobenzofuran-1-yl)but-2-yl)oxy)butanoic acid (800 mg) was added to a 100 mL single-necked flask, followed by tetrahydrofuran (15 mL) and then borane tetrahydrofuran solution (1.0 M) (6.7 mL). The reaction was continued at -10°C for 16 hours. LCMS analysis confirmed the complete reaction. The reaction mixture was then added with 20 mL of water and 20 mL of dichloromethane for extraction. The organic phase was dried and the solvent evaporated to afford the crude product, which was then purified by column chromatography using petroleum ether-ethyl acetate (2:1) to afford the product (430 mg). LCMS (ESI) [M+Na]+ = 293.16

[0432] Step 2: Dissolve 4-(3-oxo-1,3-dihydroisobenzofuran-1-yl)butan-2-yl-4-hydroxybutanoate (430 mg) in dichloromethane (10 mL), add 2-hydroxy-4-nitrobenzoic acid (296.29 mg), N,N'-dicyclohexylmethanediamine (607 mg), and then add N,N-dimethylpyridin-4-amine (35.94 mg). The reaction mixture was allowed to react at 25°C for 16 hours. LCMS analysis confirmed complete reaction of the starting material and the formation of the product. Add 20 mL of water to the reaction mixture and extract with dichloromethane (20 mL). The organic phase was dried over anhydrous sodium sulfate, evaporated, and concentrated to obtain the crude product. The crude product was then separated by column chromatography using a petroleum ether / ethyl acetate system (petroleum ether:ethyl acetate = 6:1) to obtain the product (280 mg). LCMS (ESI) [M+H] + =458.19

[0433] Step 3: Dissolve 4-oxo-4-((4-(3-oxo-1,3-dihydroisobenzofuran-1-yl)but-2-yl)oxy)butyl 2-hydroxy-4-nitrobenzoate (280 mg) in anhydrous ethanol (5 mL), add iron powder (102.54 mg), and then add ammonium chloride (65.48 mg). Then, add water (5 mL), and the reaction solution is reacted at 50°C for 4 hours. LCMS shows that the raw material is completely reacted and the product is produced. 20 mL of water is added to the reaction solution, and dichloromethane (20 mL) is added for extraction. The organic phase is dried over anhydrous sodium sulfate, evaporated, and concentrated to obtain the crude product. The crude product is separated by column chromatography using a petroleum ether and ethyl acetate system (petroleum ether:ethyl acetate = 3:1) to obtain the product (220 mg). LCMS (ESI) [M+H] + =428.26

[0434] Step 4: Dissolve butyl 4-oxo-4-((4-(3-oxo-1,3-dihydroisobenzofuran-1-yl)butan-2-yl)oxy)4-amino-2-hydroxybenzoate (220 mg) in anhydrous ethanol (5 mL), then add 3,5-dichloro-2-hydroxybenzaldehyde (108.14 mg). The reaction mixture was incubated at 25°C for 16 hours. TLC analysis indicated that the reaction of the starting material was complete and product was formed. The solvent in the reaction mixture was evaporated to dryness to obtain the product (240 mg).

[0435] Step 5: Dissolve 4-oxo-4-((4-(3-oxo-1,3-dihydroisobenzofuran-1-yl)but-2-yl)oxy)butyl(E)-4-((3,5-dichloro-2-hydroxybenzylidene)amino)-2-hydroxybenzoate (240 mg) in anhydrous ethanol (5 mL), and then add sodium triacetylborohydride (126.47 mg). The reaction solution was reacted at 25 ° C for 16 hours. LCMS detection showed that the raw material reaction was complete and the product was generated. 20 mL of water was added to the reaction solution, and dichloromethane (20 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, evaporated, and concentrated to obtain a crude product. The crude product was subjected to reverse preparative separation to obtain the target product (80 mg). LCMS (ESI) [M+Na] + = 602.23; 1 H NMR (400MHz, DMSO-d6) δ10.81(d,J=2.2Hz,1H),9.80(s,1H),7.83(d,J=7.6Hz,1H),7.76(td,J=7.5,1.1Hz,1H),7 .69–7.56(m,2H),7.50(dd,J=8.8,1.8Hz,1H),7.40(d,J=2.7Hz,1H),7.17(t,J=6.0Hz,1H),7.13–7.08(m,1H),6.2 2(dd,J=8.8,2.2Hz,1H),5.95(d,J=2.2Hz,1H),5.70–5.62(m,1H),4.97–4.76(m,1H),4.40–4.16(m,4H),2.48–2.3 8(m,2H),2.19–2.02(m,1H),1.98–1.90(m,2H),1.77–1.59(m,2H),1.56–1.47(m,1H),1.15(dd,J=6.3,1.7Hz,3H).

[0436] Example 30 (Compound 130)

[0437] Preparation of 5-((3,5-dichloro-2-hydroxybenzyl)amino)-2-((((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)oxy)carbonyl)phenyl(1-(2-((((1R,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)oxy)carbonyl)phenyl)pentyl)succinate:

[0438]

[0439] Step 1: The target product (3.0 g) was obtained by referring to the first step of Example 1.

[0440] Step 2: The target product (0.8 g) was obtained by referring to the first step of Example 3. LCMS (ESI) [M+H] + = 331.24.

[0441] Step 3: The target product (11.0 g) was obtained by referring to the third step of Example 1.

[0442] Step 4: (1R,2S,4R)-1,7,7-Trimethylbicyclo[2.2.1]hept-2-yl 2-hydroxy-4-nitrobenzoate (500.0 mg) was dissolved in dichloromethane (10.0 mL), and 2-(1-((3-carboxypropionyl)oxy)pentyl)benzoic acid (482 mg) was added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (484.57 mg). 4-Dimethylaminopyridine (95.64 mg) was then added, and the reaction mixture was reacted at 25°C for 4.0 hours. The reaction solution was added with water (20.0 mL), extracted with dichloromethane (20.0 mL), and the organic phase was dried over anhydrous sodium sulfate, evaporated, and concentrated to give a crude product. The crude product was separated by column chromatography using a petroleum ether-tetrahydrofuran system (petroleum ether:tetrahydrofuran = 4:1) to give the product (210.0 mg). LCMS (ESI) [M+Na] + = 632.27.

[0443] Step 5: Dissolve 2-(1-((4-(5-nitro-2-((((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl)oxy)carbonyl)phenoxy)-4-oxobutanoyl)oxy)pentyl)benzoic acid (200.0 mg) in dichloromethane (8.0 mL), add (1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-ol (75.9 mg), and then add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (94.0 mg). Then, add 4-dimethylaminopyridine (20.0 mg), and the reaction solution is reacted at 25°C for 4.0 hours. The reaction solution was added with water (20.0 mL), extracted with dichloromethane (20.0 mL), and the organic phase was dried over anhydrous sodium sulfate, evaporated, and concentrated to give a crude product. The crude product was separated by column chromatography using a petroleum ether and ethyl acetate system (petroleum ether:ethyl acetate=10:1) to give the product (200.0 mg). LCMS (ESI) [M+H]+=746.38.

[0444] Step 6: 5-nitro-2-((((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl)oxy)carbonyl)phenyl(1-(2-(((1R,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl)oxy)carbonyl)phenyl)pentyl)succinate (1000.0 mg) was dissolved in anhydrous ethanol (16.0 mL), iron powder (373 mg) was added, and then ammonium chloride (143.0 mg) was added. Water (4.0 mL) was then added, and the reaction solution was reacted at 50°C for 4.0 hours. The reaction mixture was added with water (20.0 mL) and extracted with dichloromethane (20.0 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to give a crude product. The crude product was then separated by column chromatography using a petroleum ether and ethyl acetate system (petroleum ether:ethyl acetate = 5:1) to afford the desired product (780.0 mg). LCMS (ESI) [M+H] + = 716.41.

[0445] Step 7: 5-amino-2-((((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl)oxy)carbonyl)phenyl(1-(2-(((1R,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl)oxy)carbonyl)phenyl)pentyl)succinate (780.0 mg) was dissolved in anhydrous ethanol (10.0 mL), and then 3,5-dichloro-2-hydroxybenzaldehyde (312.0 mg) was added. The reaction solution was reacted at 25° C. for 4.0 hours. The reaction solution was evaporated to dryness to obtain a crude product (710.0 mg).

[0446] Step 8: 5-(((E)-3,5-dichloro-2-hydroxybenzylidene)amino)-2-((((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)oxy)carbonyl)phenyl(1-(2-((((1R,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)oxy)carbonyl)phenyl)pentyl)succinate (710.0 mg) was dissolved in 1,2-dichloroethane (20.0 mL), and sodium triacetylborohydride (337.0 mg) was added. The reaction mixture was reacted at 25°C for 4.0 hours. The reaction mixture was added with water (30.0 mL) and extracted with dichloromethane (30.0 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to give a crude product, which was then subjected to reverse preparative separation to give the desired product (650.0 mg). LCMS (ESI) [M+H] + = 890.31.

[0447] 1 H NMR(400MHz, DMSO-d6)δ9.79(s,1H),8.15(dd,J=8.0,1.4Hz,1H),7.81(dd,J=8.8,3.6Hz,1H),7.69–7.64(m,1H),7.60 –7.57(m,1H),7.55–7.45(m,1H),7.40(d,J=2.6Hz,1H),7.25(s,1H),7.15(d,J=2.6Hz,1H),6.59(dd,J=8.8,2.3Hz,1H) ,6.51–6.49(m,1H),6.43(d,J=2.3Hz,1H),4.88–4.83(m,1H),4.80–4.73(m,1H),4.34(d,J=2.6Hz,2H),2.72–2.63(m,2 H),2.60–2.56(m,2H),2.22–2.17(m,2H),1.99–1.89(m,1H),1.87–1.57(m,7H),1.32–1.08(m,8H),0.92–0.68(m,22H).

[0448] Example 31 (Compound 131)

[0449] Preparation of pentyl 5-oxo-5-((4-((S)-3-oxo-1,3-dihydroisobenzofuran-1-yl)butan-2-yl)oxy)4-((3,5-dichloro-2-hydroxybenzyl)amino)-2-hydroxybenzoate:

[0450]

[0451] The target product (150 mg) was obtained by referring to the method of Example 28. LCMS (ESI) [M+H]+ = 616.24.

[0452] 1 H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 9.79 (s, 1H), 7.83 (d, J = 8.0, 1H), 7.78-7.74 (m, 1H), 7.68-7.65 (m, 1H), 7.58 (t, J = 7.4 Hz, 1H), 7.49 (dd, J = 8.9, 1.2 Hz, 1H), 7.40 (d, J = 2.6 Hz, 1H), 7.23 - 7.04 (m, 2H), 6.22 (dt, J = 8.9, 2.0 Hz, 1H), 5.94 (d, J = 2.3 Hz, 1H), 5.64 (dt, J = 7.0, 3.2 Hz, 1H), 4.89 - 4.80 (m, 1H), 4.43 - 4.14 (m, 4H), 2.39 - 2.30 (m, 2H), 2.17 - 2.04 (m, 1H), 1.78 - 1.58 (m, 6H), 1.56 - 1.45 (m, 1H), 1.15 (dd, J = 6.2, 1.4 Hz, 3H).

[0453] Example 32 (Compound 132)

[0454] Preparation of 4-oxo-4-((4-((S)-3-oxo-l,3-dihydroisobenzofuran-l-yl)butan-2-yl)oxy)butyl 4-(((3,5-dichloro-2-hydroxybenzyl)amino)-2-hydroxybenzoate:

[0455]

[0456] First step: The target product (420 mg) was obtained according to the first step of Reference Example 20. LCMS (ESI) [M+Na] + = 329.26

[0457] Second to sixth steps: The product (380 mg) was obtained according to the method of Reference Example 29. LCMS (ESI) [M+H] + = 602.23.

[0458] 1H NMR (400MHz, DMSO-d6) δ10.81(d,J=2.2Hz,1H),9.79(s,1H),7.83(d,J=7.6Hz,1H),7.79–7.73(m,1H),7.69–7.56 (m,2H),7.49(dd,J=8.9,1.8Hz,1H),7.40(d,J=2.6Hz,1H),7.16(t,J=6.1Hz,1H),7.10(dd,J=2.7,1.1Hz,1H),6.2 1(dd,J=8.8,2.3Hz,1H),5.94(d,J=2.2Hz,1H),5.70–5.62(m,1H),5.01–4.78(m,1H),4.45–4.18(m,4H),2.48–2.3 8(m,2H),2.20–2.02(m,1H),1.98–1.90(m,2H),1.81–1.59(m,2H),1.56–1.47(m,1H),1.15(dd,J=6.2,1.6Hz,3H).

[0459] Example 33 (Compound 133)

[0460] Preparation of 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 4-((3,5-dichloro-2-hydroxybenzyl)amino)-2-((2-(1-((dimethylglycyl)oxy)pentyl)benzoyl)oxy)benzoate hydrochloride:

[0461]

[0462] 1,7,7-Trimethylbicyclo[2.2.1]heptan-2-yl 4-((3,5-dichloro-2-hydroxybenzyl)amino)-2-((2-(1-((dimethylglycyl)oxy)pentyl)benzoyl)oxy)benzoate (20.0 mg) was dissolved in dichloromethane (2.0 mL), and hydrochloric acid / ethyl acetate (4.0 M) (0.1 mL) was added, followed by stirring for 2 hours. LCMS analysis indicated that the reaction was complete. The reaction solution was added with 10 mL of water and 5 mL of acetonitrile, and lyophilized to obtain the desired product (20 mg). LCMS (ESI) [M+H] + =739.39

[0463] 1H NMR (400MHz, DMSO-d6) δ10.43(s,1H),9.84(s,1H),8.19(d,J=7.8Hz,1H),7.82(dd,J=8.8,3.1H z,1H),7.73-7.66(m,2H),7.53(t,J=7.5Hz,1H),7.47–7.31(m,2H),7.16(d,J=2.7Hz,1H),6.75– 6.56(m,2H),6.47(s,1H),4.88–4.83(m,1H),4.45–4.22(m,4H),2.78(s,6H),2.31–2.16(m,1H), 1.99–1.58(m,5H),1.42–1.19(m,6H),1.17–1.05(m,1H),0.94–0.89(m,1H),0.87–0.74(m,12H).

[0464] Example 34 (Compound 134)

[0465] Preparation of (1R,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 4-((3,5-dichloro-2-hydroxybenzyl)amino)-2-((2-(1-((diethylglycyl)oxy)pentyl)benzoyl)oxy)benzoate:

[0466]

[0467] Step 1: Potassium 2-(1-hydroxypentyl)benzoate (2.0 g) was dissolved in dichloromethane (30.0 mL). Ethylbis(2-propyl)amine (3.7 g) was then added, followed by the slow addition of 2-bromoacetyl chloride (2.3 g). The reaction mixture was allowed to react at -20°C for 16 hours. LCMS confirmed the reaction was complete. The reaction mixture was added with 40 mL of water, and the pH was adjusted to ~7 with dilute hydrochloric acid. The organic phase was then extracted and dried. The solvent was evaporated to dryness, and the product (0.76 g) was obtained by column chromatography using dichloromethane:methanol (10:1).

[0468] Step 2: 2-(1-(2-Bromoacetoxy)pentyl)benzoic acid (650 mg) was dissolved in acetonitrile (10.0 mL), and ethylbis(2-propyl)amine (765.5 mg) and diethylamine (216.6 mg) were added. The reaction was continued at 25°C for 16.0 hours. LCMS confirmed the complete reaction. The reaction mixture was added with 20 mL of water and extracted with dichloromethane (20 mL). The organic phase was dried over anhydrous sodium sulfate and the solvent evaporated to afford the crude compound. The desired product (500 mg) was obtained by column chromatography using a dichloromethane-methanol system (dichloromethane:methanol = 5:1). LCMS (ESI) [M+H]+ = 322.25.

[0469] Step 3: Dissolve 2-(1-((diethylglycyl)oxy)pentyl)benzoic acid (500 mg) in dichloromethane (5.0 mL). Add tetrabutylammonium hydrogen sulfate (264.1 mg), followed by sodium bicarbonate (653.5 mg) and water (5.0 mL). Stir for 5 minutes, then slowly add chloromethylsulfonyl chloride (513.4 mg). The reaction mixture is incubated at 0°C for 16.0 hours. LCMS monitoring indicates complete reaction of the starting material with product formation. The reaction mixture is filtered to remove solids, and water (20.0 mL) is added. Extraction is then performed with 20 mL of dichloromethane. The organic phase is dried over anhydrous sodium sulfate and concentrated to yield the crude product. The desired product (210 mg) is then separated by column chromatography using a dichloromethane-methanol system (10:1). LCMS (ESI) [M+H]+ = 370.24.

[0470] Step 4: Dissolve chloromethyl 2-(1-((diethylglycyl)oxy)pentyl)benzoate (210.0 mg) in acetonitrile (10.0 mL), add (1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 2-hydroxy-4-nitrobenzoate (182.03 mg), and then add potassium carbonate (236.34 mg). The reaction mixture was reacted at 50°C for 16.0 hours. LCMS showed that the starting material was completely reacted and the product was formed. The reaction mixture was added with water (20.0 mL) and extracted with dichloromethane (20.0 mL). The organic phase was dried over anhydrous sodium sulfate, evaporated, and concentrated to obtain the crude product. The crude product was separated by column chromatography using a petroleum ether / ethyl acetate system (petroleum ether:ethyl acetate = 4:1) to obtain the product (110.0 mg). LCMS (ESI) [M+H]+ = 623.42.

[0471] Step 5: (1R,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 2-((2-(1-((diethylglycyl)oxy)pentyl)benzoyl)oxy)-4-nitrobenzoate (110.0 mg) was dissolved in anhydrous ethanol (5.0 mL), iron powder (29 mg) was added, and then ammonium chloride (28 mg) was added. Water (5.0 mL) was then added, and the reaction mixture was reacted at 50°C for 2.0 hours. Water (20.0 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (20.0 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was separated by column chromatography using a petroleum ether / ethyl acetate system (petroleum ether:ethyl acetate = 2:1) to obtain the desired product (90.0 mg). LCMS (ESI) [M+H]+ = 593.41.

[0472] Step 6: (1R,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 2-((2-(1- ((diethylglycyl)oxy)pentyl)benzoyl)oxy)-4-amino benzoate (90.0 mg) was dissolved in 1,2-dichloroethane (5.0 mL), then 3,5-dichloro-2-hydroxybenzaldehyde (42.98 mg) was added. The reaction was stirred at 25 °C for 16.0 h. TLC detection showed the starting material was consumed and the product was formed. The reaction was evaporated to dryness to give the crude product (90.0 mg).

[0473] Step 7: (1R,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 4-(((E)-3,5-dichloro- 2-hydroxybenzylidene)amino)-2-((2-(1-((diethylglycyl)oxy)pentyl)benzoyl)oxy)benzoate (90.0 mg) was dissolved in anhydrous ethanol (6.0 mL), then sodium triacetylborohydride (74.37 mg) was added. The reaction was stirred at 25 °C for 2.0 h. The reaction was added water (10.0 mL), extracted with dichloromethane (10.0 mL), the organic phase was dried over anhydrous sodium sulfate, concentrated to give the crude product, which was separated by reverse phase preparative HPLC to give the target product (70.0 mg). LCMS (ESI) [M+H]+=767.46.

[0474] 1 H NMR (400 MHz, DMSO-d6) δ 9.82 (s, 1H), 8.15 (dd, J = 7.9, 1.4 Hz, 1H), 7.83-7.80 (m, 1H), 7.76-7.64 (m, 1H), 7.61-7.58 (m, 1H), 7.49 (td, J = 7.6, 1.4 Hz, 1H), 7.41 (d, J = 2.6 Hz, 1H), 7.27 (d, J = 6.9 Hz, 1H), 7.16 (d, J = 2.6 Hz, 1H), 6.64-6.40 (m, 3H), 4.93-4.84 (m, 1H), 4.35 (d, J = 5.6 Hz, 2H), 3.37 (d, J = 1.9 Hz, 2H), 2.61-2.52 (m, 4H), 2.31-2.15 (m, 1H), 2.00-1.90 (m, 1H), 1.87-1.58 (m, 4H), 1.53-1.40 (m, 1H), 1.38-1.19 (m, 5H), 1.07-1.02 (m, 1H), 0.95 (t, J = 7.1 Hz, 6H), 0.86-0.72 (m, 12H).

[0475] Example 35 (Compound 135)

[0476] Preparation of (1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 4-((3,5-dichloro-2-hydroxybenzyl)amino)-2-(((2-(1-((diethylglycyl)oxy)pentyl)benzoyl)oxy)methoxy)benzoate:

[0477]

[0478] First step to third step: refer to Example 34, first step to third step to obtain the target product (210 mg). LCMS (ESI) [M+H] + = 370.24.

[0479] Step 4: Dissolve chloromethyl 2-(1-((diethylglycyl)oxy)pentyl)benzoate (210.0 mg) in acetonitrile (10.0 mL), add (1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 2-hydroxy-4-nitrobenzoate (182.03 mg), and then add potassium carbonate (236.34 mg). The reaction mixture was reacted at 50°C for 16.0 hours. LCMS showed that the starting material was completely reacted and the product was formed. The reaction mixture was added with water (20.0 mL) and extracted with dichloromethane (20.0 mL). The organic phase was dried over anhydrous sodium sulfate, evaporated, and concentrated to obtain the crude product. The crude product was separated by column chromatography using a petroleum ether / ethyl acetate system (petroleum ether:ethyl acetate = 4:1) to obtain the product (160.0 mg). LCMS (ESI) [M+H]+ = 653.42.

[0480] Step 5: (1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 2-(((2-(1-((diethylglycyl)oxy)pentyl)benzoyl)oxy)methoxy)-4-nitrobenzoate (160.0 mg) was dissolved in anhydrous ethanol (3.0 mL), iron powder (41 mg) was added, and then ammonium chloride (39 mg) was added. Water (3.0 mL) was then added, and the reaction mixture was reacted at 50°C for 2.0 hours. Water (20.0 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (20.0 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was separated by column chromatography using a petroleum ether / ethyl acetate system (petroleum ether:ethyl acetate = 2:1) to obtain the desired product (110.0 mg). LCMS (ESI) [M+H]+ = 623.41.

[0481] Step 6: (1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 2-(((2-(1-((diethylglycyl)oxy)pentyl)benzoyl)oxy)methoxy)-4-aminobenzoate (110.0 mg) was dissolved in 1,2-dichloroethane (5.0 mL), followed by the addition of 3,5-dichloro-2-hydroxybenzaldehyde (50.6 mg). The reaction mixture was incubated at 25°C for 16.0 hours. TLC analysis indicated that the reaction of the starting material was complete and product was produced. The reaction mixture was evaporated to dryness to obtain the crude product (120.0 mg).

[0482] Step 7: (1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 4-(((E)-3,5-dichloro-2-hydroxybenzylidene)amino)-2-(((2-(1-((diethylglycyl)oxy)pentyl)benzoyl)oxy)methoxy)benzoate (120.0 mg) was dissolved in anhydrous ethanol (5.0 mL), followed by the addition of sodium triacetylborohydride (97.1 mg). The reaction mixture was allowed to react at 25°C for 16.0 hours. Water (10.0 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (10.0 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was subjected to reverse preparative separation to obtain the desired product (110.0 mg). LCMS (ESI) [M+H]+ = 797.48.

[0483] 1 H NMR(400MHz, DMSO-d6)δ9.78(s,1H),7.78(dt,J=7.9,1.3Hz,1H),7.70–7.51(m,3H),7.49–7.35(m, 2H),7.15–7.02(m,2H),6.51–6.30(m,3H),6.03(d,J=6.6Hz,1H),5.93(d,J=6.6Hz,1H),4.90-4.87( m,1H),4.32(d,J=4.2Hz,2H),3.33(s,2H),2.54-2.49(m,4H),2.37-2.26(m,1H),2.18–2.04(m,1H) ,1.76–1.62(m,4H),1.37–1.16(m,6H),1.05(d,J=6.1Hz,1H),0.98-0.89(m,9H),0.85-0.77(m,9H).

[0484] Example 36 (Compound 136)

[0485] Preparation of 5-((3,5-dichloro-2-hydroxybenzyl)amino)-2-((((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl)oxy)carbonyl)phenyl(1-(2-(methoxycarbonyl)phenyl)pentyl)succinate:

[0486]

[0487] First step: The target product (3.0 g) was obtained by referring to the first step of Example.

[0488] Step 2: The target product (0.8 g) was obtained by referring to the first step of Example 3. LCMS (ESI) [M+H] + = 331.24.

[0489] Step 3: 'The target product (11.0 g) was obtained by referring to the third step of Example 1.

[0490] Step 4: The product (210.0 mg) was obtained by referring to the first step of Example 10. LCMS (ESI) [M+Na]+=632.27.

[0491] Step 5: Dissolve 2-(1-((4-(5-nitro-2-((((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy)carbonyl)phenoxy)-4-oxobutanoyl)oxy)pentyl)benzoic acid (350.0 mg) in acetonitrile (10.0 mL), add iodomethane (162.97 mg), and then add potassium carbonate (238.0 mg). The reaction mixture was stirred at 40°C for 6.0 hours. LCMS showed that the starting material was completely reacted and product was produced. The reaction solution was added with water (20.0 mL), extracted with dichloromethane (20.0 mL), and the organic phase was dried over anhydrous sodium sulfate, evaporated, and concentrated to give a crude product. The crude product was separated by column chromatography using a petroleum ether and ethyl acetate system (petroleum ether:ethyl acetate=4:1) to give the product (320.0 mg). LCMS (ESI) [M+Na]+=646.27.

[0492] Step 6: 1-(2-(Methoxycarbonyl)phenyl)pentyl(5-nitro-2-((((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxycarbonyl)phenylsuccinate (320.0 mg) was dissolved in anhydrous ethanol (10.0 mL), and iron powder (143.25 mg) and ammonium chloride (137.22 mg) were added. Water (10.0 mL) was then added, and the reaction mixture was reacted at 50°C for 2.0 hours. LCMS showed that the starting material had reacted completely and the product had formed. The reaction mixture was added with water (20.0 mL) and extracted with dichloromethane (20.0 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was separated by column chromatography using a petroleum ether / ethyl acetate system (petroleum ether:ethyl acetate = 3:1) to obtain the desired product (260.0 mg). LCMS (ESI) [M+Na]+ = 616.25.

[0493] Step 7: 1-(2-(Methoxycarbonyl)phenyl)pentyl(5-amino-2-((((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxycarbonyl)phenylsuccinate (260.0 mg) was dissolved in 1,2-dichloroethane (10.0 mL), and then 3,5-dichloro-2-hydroxybenzaldehyde (83.65 mg) was added. The reaction mixture was reacted at 25°C for 16.0 hours. The reaction mixture was evaporated to dryness to obtain a crude product (260.0 mg).

[0494] Step 8: 5-(((E)-3,5-dichloro-2-hydroxybenzylidene)amino)-2-((((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy)carbonyl)phenyl(1-(2-(methoxycarbonyl)phenyl)pentyl)succinate (260.0 mg) was dissolved in anhydrous ethanol (10.0 mL), and sodium triacetoxyborohydride (214.59 mg) was added. The reaction mixture was reacted at 25°C for 2.0 hours. LCMS analysis showed that the reaction of the starting material was complete and the product was formed. Water (30.0 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (30.0 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was subjected to reverse preparative separation to obtain the desired product (110.0 mg). LCMS (ESI) [M+H]+ = 768.39.

[0495] 1H NMR(400MHz, DMSO-d6)δ9.79(s,1H),7.79(dd,J=31.0,8.3Hz,2H),7.62–7.46(m,2H),7.40–7.37 (m,2H),7.29–7.06(m,2H),6.52(dd,J=8.8,2.3Hz,1H),6.39(t,J=6.3Hz,1H),6.25(d,J=2.4Hz,1 H),4.90–4.87(m,1H),4.31(d,J=5.2Hz,2H),3.85(s,3H),2.82(t,J=6.7Hz,2H),2.75–2.63(m,2H ),2.33–2.25(m,1H),2.02–1.95(m,1H)1.75–1.66(m,4H),1.43–1.18(m,6H),0.99–0.65(m,13H).

[0496] Example 37 (Compound 137)

[0497] Preparation of 5-((3,5-dichloro-2-hydroxybenzyl)amino)-2-((((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl)oxy)carbonyl)phenyl(1-(2-(ethoxycarbonyl)phenyl)pentyl)succinate:

[0498]

[0499] The target product (85.0 mg) was obtained by the method of Example 36. LCMS (ESI) [M+H] + = 782.39. 1 H NMR(400MHz, DMSO-d6)δ9.80(s,1H),7.85–7.79(m,1H),7.75(d,J=8.8Hz,1H),7.57–7.52(m,2H),7.44–7.3 5(m,2H),7.19(t,J=5.7Hz,1H),7.12(d,J=2.6Hz,1H),6.53(dd,J=8.8,2.3Hz,1H),6.40(t,J=6.3Hz,1H),6. 26(d,J=2.3Hz,1H),4.91–4.87(m,1H),4.36–4.28(m,4H),2.82(t,J=6.7Hz,2H),2.76–2.64(m,2H),2.33–2 .25(m,1H),2.02–1.95(m,1H),1.83–1.63(m,4H),1.31–1.19(m,9H),0.97–0.92(m,1H),0.91–0.77(m,12H).

[0500] Compounds 4-5, 12-95, 97-109, and 111 were synthesized with reference to the above examples:

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509] Biological test evaluation

[0510] Experimental Example 1: Pharmacokinetic Study of Compound Concentrations in Rats Using LC-MS / MS

[0511] Test principle: Use LC-MS / MS to determine the drug concentration of the target drug in plasma at different times and draw the pharmacokinetic curve of the target compound in the body.

[0512] 1.1 Preparation of compound solution

[0513] The compound of the present invention was weighed, DMSO was added, and vortexed to dissolve (ultrasound can be used to assist dissolution). PEG400 was then added and vortexed to mix thoroughly. 4% Tween 80 was then added and vortexed to mix thoroughly to obtain a solution with a concentration of 0.4 mg / mL.

[0514] 1.2 Experimental animals

[0515] SPF male SD rats were purchased from Shanghai Jihui Experimental Animal Breeding Co., Ltd. The animals weighed 185–202 g and were fasted for 12–14 h 1 day before administration. They were fed 4 h after administration and had free access to water during the experiment.

[0516] 1.3 Test method:

[0517] The compound (3 mg / kg) was injected through the tail vein. The plasma samples were collected at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h after intravenous injection. About 100 μL blood sample was collected at the designated time point into an anticoagulant tube containing EDTA-K2 anticoagulant, and the plasma was obtained by centrifugation within 30 min. The drug concentration was obtained by analyzing the plasma sample using the LC-MS / MS method, and the PK parameters were calculated.

[0518] 1.4 Sample processing and detection

[0519] The extraction process of the standard curve, quality control and blank sample: 15.0 μL of the prepared blank, standard curve and quality control sample was added to a 96-well plate, respectively, 150.0 μL of internal standard working solution was added, the 96-well plate was placed on a vortex mixer for 10 min (temperature was set to room temperature, and the rotation speed was set to 500 rpm), centrifuged for 10 min (temperature was set to 4℃, and the centrifugal force rotation speed was 4000 rpm), 100.0 μL of supernatant was taken to a 96-well plate pre-added with 100.0 μL of ultrapure water, and the 96-well plate was placed on a vortex mixer for 10 min (temperature was set to room temperature, and the rotation speed was 500 rpm).

[0520] The extraction process of the standard curve, quality control and blank sample: 15.0 μL of the prepared blank, standard curve and quality control sample was added to a 96-well plate, respectively, 150.0 μL of internal standard working solution was added, the 96-well plate was placed on a vortex mixer for 10 min (temperature was set to room temperature, and the rotation speed was set to 500 rpm), centrifuged for 10 min (temperature was set to 4℃, and the centrifugal force rotation speed was 4000 rpm), 100.0 μL of supernatant was taken to a 96-well plate pre-added with 100.0 μL of ultrapure water, and the 96-well plate was placed on a vortex mixer for 10 min (temperature was set to room temperature, and the rotation speed was 500 rpm).

[0521] 1.5 Data analysis method

[0522] The raw data of bioanalysis was collected and calculated by the mass spectrometer software Analyst 1.7.2 of AB Sciex Company. The data was processed by the computer program Microsoft Office Excel (Microsoft, USA), and the experimental data was represented by "mean ± standard deviation" (Mean ± SD, n≥3). 8.2 The processing software was used to fit and calculate the main pharmacokinetic parameters in a non-compartment model. The data was processed by the computer program Microsoft Office Excel (Microsoft, USA), and the experimental data was represented by "mean ± standard deviation" (Mean ± SD, n≥3).

[0523] 1.6 Test results

[0524] The test results show that the compound of the present application has good in vivo pharmacokinetics and drug potential.

[0525] Experimental Example 2: Determination of drug concentration of drug in rat plasma at different times by LC-MS / MS

[0526] Test principle: Use LC-MS / MS to determine the drug concentration of the target drug in plasma at different times and draw a change curve of the target compound in rat plasma.

[0527] 2.1 Preparation of compound solution

[0528] Appropriate amounts of the compound of the present invention and the internal standard compound (reference compound enalapril) were weighed separately, added with DMSO, and vortexed to dissolve.

[0529] 2.2 Test system

[0530] Frozen pooled plasma from SD rats (anticoagulant: sodium heparin or EDTA-K2) was stored in a refrigerator below -60°C before use.

[0531] Detailed information about plasma is shown in the table below:

[0532]

[0533] 2.3 Test method:

[0534] Thaw the frozen plasma in cold tap water for 10 to 20 minutes. After the plasma is completely thawed, centrifuge it at 3220×g for 5 minutes to remove any suspended matter and sediment.

[0535] The incubation was performed in a 96-well plate. Several 96-well incubation plates were prepared and named T0, T10, T30, T60, and T120.

[0536] Add 98 μL of rat blank plasma to the corresponding incubation plates, including T0, T10, T30, T60, and T120. Add 2 μL of the working solution of the test article or control compound to the corresponding incubation plate, preparing two parallel wells for each sample.

[0537] All samples were incubated in a water bath at 37° C. The final incubation concentration of the test article and the reference compound enalapril was 2 μM, and the final organic phase content was 2.0%.

[0538] Add 500 μL of methanol or acetonitrile solution containing 250 nM labetalol and tolbutamide to each corresponding sample well of the T0 incubation plate to precipitate proteins.

[0539] At the end of each incubation time point, the corresponding incubation plate was removed and 500 μL of a methanol or acetonitrile solution containing 250 nM labetalol and tolbutamide was added to each corresponding sample well to precipitate the protein. All sample plates were sealed and shaken, and then centrifuged at 3220 × g for 20 minutes. 150 μL of the supernatant from each sample was analyzed by LC-MS / MS.

[0540] 2.4 Sample analysis

[0541] The concentrations of the test and control compounds in the samples were semiquantitatively determined using liquid chromatography-tandem mass spectrometry (LC-MS / MS), excluding standard curves and quality control samples. The sample concentration was expressed as the ratio of the analyte peak area to the internal standard peak area. Retention times of the analytes and internal standards, chromatogram acquisition, and chromatogram integration were performed using Analyst software (Sciex, Framingham, Massachusetts, USA).

[0542] The CV of the internal standard peak area in each matrix should be within 20% for each analytical run.

[0543] 2.5 Data Analysis

[0544] The calculation formulas for the remaining amount (%) and half-life of the test and control compounds are as follows:

[0545] % Remaining amount = (peak area ratio of reference substance and internal standard at any time point / peak area ratio of reference substance and internal standard at 0 minutes) × 100%

[0546] 2.6 Test results

[0547] Results of rat plasma stability test of the compound of the present invention:

[0548]

[0549] The test results show that the compound of the present invention can quickly release ZL006-05 and butylphthalide, and the hydrolyzed compound is almost completely hydrolyzed into ZL006-05 and butylphthalide, with very little other metabolites produced, and has drug potential.

[0550] Experimental Example 3 Neuroprotective efficacy test of compounds

[0551] 3.1 Test Principle:

[0552] The excitotoxicity model of PC-12 cells (Company: Wuhan Pronocell Life Science Co., Ltd., Catalog No.: CL-0412) was used to determine the neuronal cell protective efficacy of the target drug at different concentrations.

[0553] 3.2 Preparation of compound solution

[0554] The compounds were prepared into 1 M stock solutions in DMSO before testing. The neuronal cell protection efficacy test was performed using compounds at a concentration of 1 μM. The solvents for the compound solutions were 1% DMSO and 99% PBS.

[0555] Weigh appropriate amounts of ZL006-05, butylphthalide (NBP), and the compound of the present invention, add 36 μl, 116 μl, and 17 μl of DMSO, respectively, and vortex to dissolve to obtain a 1 M compound stock solution a. Add 1 μl of compound stock solution a to 99 μl of DMSO to obtain a 100 mM compound stock solution b. Prior to testing, add 1 μl of compound stock solution b to 99 μl of PBS to obtain a 100 μM compound solution.

[0556] 3.3 PC-12 cell excitotoxicity model

[0557] After passage, PC-12 cells were seeded into 96-well plates (5000 cells / well) and incubated under standard culture conditions (37°C / 5% CO2 incubator, complete medium containing 85% RPMI-1640 + 10% fetal bovine serum and 5% horse serum) for 24 hours. The complete medium was replaced with serum-free medium containing 20 mM glutamate, and the cells were placed in a 37°C / 5% CO2 incubator and incubated for 24 hours. The serum-free medium containing glutamate was replaced with complete medium, and the test compound solution was added to the medium to obtain a final concentration of 1 μM test compound. The cells were again placed in a 37°C / 5% CO2 incubator and incubated for 24 hours. Cell viability was then measured using CTG.

[0558] When performing compound activity detection, the groups were set up as follows: 1) control group (sham group), after cell inoculation, the cells were incubated under conventional culture conditions for 72 hours, and then a CTG test was performed; 2) model group (Control group), 24 hours after cell inoculation, glutamate was used to incubate for 24 hours to induce excitotoxic damage, and when the conventional culture medium was replaced after damage, the same volume of solvent was added and incubated for 24 hours, and a CTG test was performed; 3) positive control group (ZL006-05 group, butylphthalide group), after excitotoxic damage, 1 μM compound solution was added and incubated for 24 hours, and a CTG test was performed; 4) test compound group, after excitotoxic damage, 1 μM solution of the compound of the present invention was added and incubated for 24 hours, and a CTG test was performed; 5) negative control group (Negative group), no cells were inoculated, the same liquid replacement operation was performed during the culture medium replacement process, and a CTG test was performed at the same time point.

[0559] 3.4 Cell viability assay

[0560] After incubation for 24 h with culture medium containing different concentrations of the test compound, 50 μl of culture medium was removed and 50 μl of CTG detection reagent was added according to the CTG assay instructions. The contents were mixed using a shaker for 2 minutes, and the plate was incubated at room temperature for 10 minutes. The luminescence signal was recorded using an Infinite 200 Pro microplate reader.

[0561] 3.5 Data Analysis Methods

[0562] Data processing and analysis were performed using the computer program Microsoft Office Excel (Microsoft, USA). The mean response signal of the sham group, control group, positive control group, test compound group, and negative control group was measured. Cell viability of the compound was calculated using the formula "Cell viability % = (mean value - negative control group) / (sham group mean value - negative control group mean value) × 100%." ​​The concentration and corresponding survival data were then imported into Prism software, and a graph of compound concentration and cell viability was plotted. Cell viability data were expressed as "mean ± standard deviation" (n ≥ 3).

[0563] 3.6 Test results

[0564] At a concentration of 1 μM, the cell protection test results in the excitotoxicity model are as follows:

[0565]

[0566]

Claims

1. A compound represented by the following formula (A1), a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt of the compound: in, R1 is hydroxy, C1-C6 alkoxy or -OC(O)R 11 ; R2, R3, R5, R6, R9 or R 10 are each independently hydrogen, halogen or trifluoromethyl; R4 is halogen or trifluoromethyl; R7 is -C(O)R 12 , hydroxyl, C1-C6 alkoxy, -OCH2C(O)R 12 、-OC(O)R 11 、-OCH2C(O)B、 R8 is -C(O)R 12 , hydroxyl, C 1-6 Alkoxy, -OCH2C(O)R 12 、-OC(O)R 11 or -OCH2C(O)B; X is hydrogen or C 1-6 alkyl; Y is hydrogen, C 1-6 Alkyl, -CH2C(O)R 13 、-C(O)R 13 、 wherein at least one of R7, R8 and Y contains a B group; When R7 is -C(O)R 12 , hydroxyl, C1-C6 alkoxy, -OCH2C(O)R 12 、-OC(O)R 11 、-OCH2C(O)B, Y is When R7 is When Y is hydrogen, C 1-6 Alkyl, -CH2C(O)R 13 、-C(O)R 13 、 R 11 Each occurrence is independently selected from C 1-6 Alkyl or B; R 12 Each occurrence is independently selected from C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy or B; R 13 C 1-6 Alkyl, C1-C6 alkoxy or B; B is L1 is a key, -C(O)-(CH2) 1-10 -O-, -C(O)NH-(CH2) 1-6 -O-, -C(O)N(CH3)-(CH2) 1-6 -O-, -C(O)-(CH2) 1-6 -NH-, -C(O)-(CH2) 1-6 -N(CH3)-, -C(O)NH-(CH2) 1-6 -NH-, -C(O)NH-(CH2) 1-6 -N(CH3)-, -C(O)N(CH3)-(CH2) 1-6 -NH-, -C(O)N(CH3)-(CH2) 1-6 -N(CH3)-, -(CH2) 1-6 -O-, -C(O)-(CH2) 1-6 -C(O)O-(CH2) 1-10 -O-; L2 is -C(O)-(CH2) 1-6 -C(O)-, -C(O)-(CH2) 1-6 -P(O)(OH)-, -P(O)(OH)-(CH2) 1-6 -C(O)-, -P(O)(OH)-(CH2) 1-6 -P(O)(OH)-, -(CH2) 1-6 -C(O)-, -(CH2) 0-6 -P(O)(OH)-, -C(O)-(CH2) 1-6 -O-C(O)-, -P(O)(OH)-(CH2) 1-6 -O-C(O)-, -(CH2) 1-6 -O-C(O)-; -C(O)-; L3 is a key, -C(O)-(CH2) 1-6 -O-, -C(O)NH-(CH2) 1-6 -O-, -C(O)N(CH3)-(CH2) 1-6 -O-, -C(O)-(CH2) 1-6 -NH-, -C(O)-(CH2) 1-6 -N(CH3)-, -C(O)NH-(CH2) 1-6 -NH-, -C(O)NH-(CH2) 1-6 -N(CH3)-, -C(O)N(CH3)-(CH2) 1-6 -NH-, -C(O)N(CH3)-(CH2) 1-6 -N(CH3)-, -(CH2) 1-6 -O-; L4 is -C(O)-(CH2) 1-6 -C(O)-, -C(O)-(CH2) 1-6 -P(O)(OH)-, -P(O)(OH)-(CH2) 1-6 -C(O)-, -P(O)(OH)-(CH2) 1-6 -P(O)(OH)-, -(CH2) 0-6 -C(O)-, -(CH2) 0-6 -P(O)(OH)-, -(CH2) 1-6 -O-C(O)-, -C(O)-(CH2) 1-6 -O-C(O)-, -P(O)(OH)-(CH2) 1-6 -O-C(O)-, -(CH2) 1-6 -O-C(O)-; R 15 and R 17 are independently hydrogen, -C(O)-C 1-10 Alkyl, -C(O)-C 0-10 Alkyl-C 3-10 Cycloalkyl, -C(O)-C 1-10 Alkyl-C(O)OC 3-10 Cycloalkyl, -C(O)-C 1-10 Alkyl-OC 3-10 Cycloalkyl, -C(O)-C 1-10 Alkyl-NH-C 3-10 Cycloalkyl, -C(O)-C 1-10 Alkyl-C(O)OH, -C(O)-C 1-10 Alkyl-NH2, -C(O)-C 1-10 Alkyl-NH(CH3), -C(O)-C 1-10 Alkyl-N(CH3)2, -C 1-10 Alkyl-OC(O)-C 1-10 Alkyl, -C 1-10 Alkyl-OC(O)-OC 1-10 Alkyl, -C 1-10 Alkyl-OC(O)-C 3-10 Cycloalkyl, -C(O)OC 1-10 Alkyl-OC 1-10 Alkyl, -C(O)OC 1-10 Alkyl-OC 3-10 Cycloalkyl, -C(O)-C 1-10 Alkyl-N(C 1-3 Alkyl)2; R 16 and R 18 are independently hydrogen, C 1-10 Alkyl, C 3-10 Cycloalkyl, The C 1-10 Alkyl, C 3-10 Cycloalkyl is optionally substituted by one or more alkyl radicals selected from halogen, oxo, -CN, -OH, -SH, -NO2, -NH2, C 1-3 Alkyl, halogenated C 1-3 substituted by an alkyl substituent.

2. A compound represented by the following formula (A), a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt of the compound: in, R1 is hydroxy, C1-C6 alkoxy or -OC(O)R 11 ; R2, R3, R5, R6, R9 or R 10 are each independently hydrogen, halogen or trifluoromethyl; R4 is halogen or trifluoromethyl; R7 is -C(O)R 12 , hydroxyl, C1-C6 alkoxy, -OCH2C(O)R 12 、-OC(O)R 11 、-OCH2C(O)B、 R8 is -C(O)R 12 , hydroxyl, C 1-6 Alkoxy, -OCH2C(O)R 12 、-OC(O)R 11 or -OCH2C(O)B; X is hydrogen or C 1-6 alkyl; Y is hydrogen, C 1-6 Alkyl, -CH2C(O)R 13 、-C(O)R 13 、 wherein at least one of R7, R8 and Y contains a B group; When R7 is -C(O)R 12 , hydroxyl, C1-C6 alkoxy, -OCH2C(O)R 12 、-OC(O)R 11 、-OCH2C(O)B, Y is When R7 is When Y is hydrogen, C 1-6 Alkyl, -CH2C(O)R 13 、-C(O)R 13 、 R 11 Each occurrence is independently selected from C 1-6 Alkyl or B; R 12 Each occurrence is independently selected from C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy or B; R 13 C 1-6 Alkyl, C1-C6 alkoxy or B; B is L1 is a key, -C(O)-(CH2) 1-10 -O-, -C(O)NH-(CH2) 1-6 -O-, -C(O)N(CH3)-(CH2) 1-6 -O-, -C(O)-(CH2) 1-6 -NH-, -C(O)-(CH2) 1-6 -N(CH3)-, -C(O)NH-(CH2) 1-6 -NH-, -C(O)NH-(CH2) 1-6 -N(CH3)-, -C(O)N(CH3)-(CH2) 1-6 -NH-, -C(O)N(CH3)-(CH2) 1-6 -N(CH3)-, -(CH2) 1-6 -O-, -C(O)-(CH2) 1-6 -C(O)O-(CH2) 1-10 -O-; L2 is -C(O)-(CH2) 1-6 -C(O)-, -C(O)-(CH2) 1-6 -P(O)(OH)-, -P(O)(OH)-(CH2) 1-6 -C(O)-, -P(O)(OH)-(CH2) 1-6 -P(O)(OH)-, -(CH2) 1-6 -C(O)-, -(CH2) 0-6 -P(O)(OH)-, -C(O)-(CH2) 1-6 -O-C(O)-, -P(O)(OH)-(CH2) 1-6 -O-C(O)-, -(CH2) 1-6 -O-C(O)-; -C(O)-; L3 is a key, -C(O)-(CH2) 1-6 -O-, -C(O)NH-(CH2) 1-6 -O-, -C(O)N(CH3)-(CH2) 1-6 -O-, -C(O)-(CH2) 1-6 -NH-, -C(O)-(CH2) 1-6 -N(CH3)-, -C(O)NH-(CH2) 1-6 -NH-, -C(O)NH-(CH2) 1-6 -N(CH3)-, -C(O)N(CH3)-(CH2) 1-6 -NH-, -C(O)N(CH3)-(CH2) 1-6 -N(CH3)-, -(CH2) 1-6 -O-; L4 is -C(O)-(CH2) 1-6 -C(O)-, -C(O)-(CH2) 1-6 -P(O)(OH)-, -P(O)(OH)-(CH2) 1-6 -C(O)-, -P(O)(OH)-(CH2) 1-6 -P(O)(OH)-, -(CH2) 0-6 -C(O)-, -(CH2) 0-6 -P(O)(OH)-, -(CH2) 1-6 -O-C(O)-, -C(O)-(CH2) 1-6 -O-C(O)-, -P(O)(OH)-(CH2)[[ID=十七]] 1-6 -O-C(O)-, -(CH2) 1-6 -O-C(O)-; R 15 and R 17 are independently hydrogen, -C(O)-C 1-10 Alkyl, -C(O)-C 0-10 Alkyl-C 3-10 Cycloalkyl, -C(O)-C 1-10 Alkyl-C(O)OC 3-10 Cycloalkyl, -C(O)-C 1-10 Alkyl-OC 3-10 Cycloalkyl, -C(O)-C 1-10 Alkyl-NH-C 3-10 Cycloalkyl, -C(O)-C 1-10 Alkyl-C(O)OH, -C(O)-C 1-10 Alkyl-NH2, -C(O)-C 1-10 Alkyl-NH(CH3), -C(O)-C 1-10 Alkyl-N(CH3)2, -C 1-10 Alkyl-OC(O)-C 1-10 Alkyl, -C 1-10 Alkyl-OC(O)-OC 1-10 Alkyl, -C 1-10 Alkyl-OC(O)-C 3-10 Cycloalkyl, -C(O)OC 1-10 Alkyl-OC 1-10 Alkyl, -C(O)OC 1-10 Alkyl-OC 3-10 Cycloalkyl, R 16 and R 18 are independently hydrogen, C 1-10 Alkyl, C 3-10 Cycloalkyl, The C 1-10 Alkyl, C 3-10 Cycloalkyl is optionally substituted by one or more alkyl radicals selected from halogen, oxo, -CN, -OH, -SH, -NO2, -NH2, C 1-3 Alkyl, halogenated C 1-3 substituted by an alkyl substituent.

3. A compound represented by the following formula (I), a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt of the compound: in, R1 is hydroxy, C1-C6 alkoxy or -OC(O)R 11 ; R2, R3, R5, R6, R9 or R 10 are each independently hydrogen, halogen or trifluoromethyl; R4 is halogen or trifluoromethyl; R7 is -C(O)R 12 , hydroxyl, C1-C6 alkoxy, -OCH2C(O)R 12 、-OC(O)R 11 、-OCH2C(O)B、 R8 is -C(O)R 12 , hydroxyl, C 1-6 Alkoxy, -OCH2C(O)R 12 、-OC(O)R 11 or -OCH2C(O)B; X is hydrogen or C 1-6 alkyl; Y is hydrogen, C 1-6 Alkyl, -CH2C(O)R 13 、-C(O)R 13 、 wherein at least one of R7, R8 and Y contains a B group; When R7 is -C(O)R 12 , hydroxyl, C1-C6 alkoxy, -OCH2C(O)R 12 、-OC(O)R 11 、-OCH2C(O)B, Y is When R7 is When Y is hydrogen, C 1-6 Alkyl, -CH2C(O)R 13 、-C(O)R 13 、 R 11 Each occurrence is independently selected from C 1-6 Alkyl or B; R 12 Each occurrence is independently selected from C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy or B; R 13 C 1-6 Alkyl, C1-C6 alkoxy or B; B is L1 is a key, -C(O)-(CH2) 1-6 -O-, -C(O)NH-(CH2) 1-6 -O-, -C(O)N(CH3)-(CH2) 1-6 -O-, -C(O)-(CH2) 1-6 -NH-, -C(O)-(CH2) 1-6 -N(CH3)-, -C(O)NH-(CH2) 1-6 -NH-, -C(O)NH-(CH2) 1-6 -N(CH3)-, -C(O)N(CH3)-(CH2) 1-6 -NH-, -C(O)N(CH3)-(CH2) 1-6 -N(CH3)-; L2 is -C(O)-(CH2) 1-6 -C(O)-, -C(O)-(CH2) 1-6 -P(O)(OH)-, -P(O)(OH)-(CH2) 1-6 -C(O)-, -P(O)(OH)-(CH2) 1-6 -P(O)(OH)-, -(CH2) 1-6 -C(O)-, -(CH2) 0-6 -P(O)(OH)-, -C(O)-(CH2) 1-6 -O-C(O)-, -P(O)(OH)-(CH2) 1-6 -O-C(O)-, -(CH2) 1-6 -O-C(O)-; L3 is a key, -C(O)-(CH2) 1-6 -O-, -C(O)NH-(CH2) 1-6 -O-, -C(O)N(CH3)-(CH2) 1-6 -O-, -C(O)-(CH2) 1-6 -NH-, -C(O)-(CH2) 1-6 -N(CH3)-, -C(O)NH-(CH2) 1-6 -NH-, -C(O)NH-(CH2) 1-6 -N(CH3)-, -C(O)N(CH3)-(CH2) 1-6 -NH-, -C(O)N(CH3)-(CH2) 1-6 -N(CH3)-, -(CH2) 1-6 -O-; L4 is -C(O)-(CH2) 1-6 -C(O)-, -C(O)-(CH2) 1-6 -P(O)(OH)-, -P(O)(OH)-(CH2) 1-6 -C(O)-, -P(O)(OH)-(CH2) 1-6 -P(O)(OH)-, -(CH2) 0-6 -C(O)-, -(CH2) 0-6 -P(O)(OH)-, -(CH2) 1-6 -O-C(O)-, -C(O)-(CH2) 1-6 -O-C(O)-, -P(O)(OH)-(CH2) 1-6 -O-C(O)-, -(CH2) 1-6 -O-C(O)-; R 15 and R 17 are independently hydrogen, -C(O)-C 1-10 Alkyl, -C(O)-C 0-10 Alkyl-C 3-10 Cycloalkyl, -C(O)-C 1-10 Alkyl-C(O)OC 3-10 Cycloalkyl, -C(O)-C 1-10 Alkyl-OC 3-10 Cycloalkyl, -C(O)-C 1-10 Alkyl-NH-C 3-10 Cycloalkyl, -C(O)-C 1-10 Alkyl-C(O)OH, -C(O)-C 1-10 Alkyl-NH2, -C(O)-C 1-10 Alkyl-NH(CH3), -C(O)-C 1-10 Alkyl-N(CH3)2, -C 1-10 Alkyl-OC(O)-C 1-10 Alkyl, -C 1-10 Alkyl-OC(O)-OC 1-10 Alkyl, -C 1-10 Alkyl-OC(O)-C 3-10 Cycloalkyl, -C(O)OC 1-10 Alkyl-OC 1-10 Alkyl, -C(O)OC 1-10 Alkyl-OC 3-10 Cycloalkyl, R 16 and R 18 are independently hydrogen, C 1-10 Alkyl, C 3-10 Cycloalkyl, The C 1-10 Alkyl, C 3-10 Cycloalkyl is optionally substituted by one or more alkyl radicals selected from halogen, oxo, -CN, -OH, -SH, -NO2, -NH2, C 1-3 Alkyl, halogenated C 1-3 substituted by an alkyl substituent.

4. The compound according to any one of claims 1 to 3, a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt of the compound, wherein Formula (A1), Formula (A) or Formula (I) is further represented by Formula (II): in, Substituents Y and R7 are as described in formula (A1), formula (A) or formula (I).

5. The compound according to any one of claims 1 to 3, a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt of the compound, wherein Formula (A1), Formula (A) or Formula (I) is further represented by Formula (III): in, The substituent Y is as described in formula (A1), formula (A) or formula (I).

6. The compound according to any one of claims 1 to 3, a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt of the compound, wherein Formula (A1), Formula (A) or Formula (I) is further represented by Formula (IV): in, The substituent R7 is as described in formula (A1), formula (A) or formula (I).

7. A compound represented by formula (B1), a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt of the compound, in, R 1a For hydroxyl, C 1-6 alkoxy; R 2a 、R 3a 、R 4a 、R 5a 、R 6a 、R 9a or R 10a are independently hydrogen, halogen, C 1-3 Alkyl or halogenated C 1-3 alkyl; R 7a Hydroxyl, -OL 1a -O-Ba; R 8a -C(O)R 12a , hydroxyl, -C(O)O-(CH2) 1-6 -C(O)O-Ba, -C(O)O-Ba; Xa and Ya are each independently hydrogen or C 1-6 Alkyl, C(O)C 1-6 alkyl; R 12a Each occurrence is independently selected from C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy or B; B is Ba Wei L 1a is -(CH2) 1-6 -O-C(O)-, -C(O)-, -C(O)-(CH2) 1-6 -C(O)-.

8. A compound represented by formula (B), a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt of the compound, in, R 1a For hydroxyl, C 1-6 alkoxy; R 2a 、R 3a 、R 4a 、R 5a 、R 6a 、R 9a or R 10a are independently hydrogen, halogen, C 1-3 Alkyl or halogenated C 1-3 alkyl; R 7a Hydroxyl, -OL 1a -O-Ba; R 8a -C(O)R 12a , hydroxyl, -C(O)O-(CH2) 1-3 -C(O)O-Ba, -C(O)O-Ba; Xa, Ya are each independently hydrogen or C 1-6 Alkyl, C(O)C 1-6 alkyl; R 12a Each occurrence is independently selected from C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy or B; B is Ba Wei L 1a is -(CH2) 1-6 -O-C(O)-, -C(O)-, -C(O)-(CH2) 1-6 -C(O)-.

9. A compound characterized in that Has the following structure: ， or its stereoisomers, tautomers or mixtures thereof, or pharmaceutically acceptable salts of the compound.

10. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the compound shown in any one of claims 1 to 9, a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt of the compound; further, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

11. Use of the compound according to any one of claims 1 to 9, a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt of the compound, or the pharmaceutical composition according to claim 10 in the preparation of a medicament for treating or preventing a disease mediated by PSD-95; preferably, the disease mediated by PSD-95 is stroke, chronic pathological pain or neurodegenerative disease.

12. Use of the compound according to any one of claims 1 to 9, its stereoisomers, tautomers or mixtures thereof, or its pharmaceutically acceptable salts, or the pharmaceutical composition according to claim 10 in the preparation of a medicament for treating or preventing stroke, chronic pathological pain or neurodegenerative disease.

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