Derivative containing fused ring or bridged ring structure as well as preparation method and application thereof

Abstract

The invention relates to a derivative containing a fused ring or bridged ring structure and a preparation method and application thereof, and the derivative containing the fused ring or bridged ring structure can be used for adjusting an NMDA receptor containing an NR1 / NR2B subunit and is used for treating NR1 / NR2B receptor mediated diseases.

Description

Technical Field

[0001] The invention belongs to the field of medicine and relates to a derivative containing a condensed ring or a bridged ring structure, a preparation method and an application thereof. Background Art

[0002] Depression is a common neuropsychiatric disease with significant and persistent low mood as the main clinical feature. It is estimated that 3.8% of the world's population is affected by depression. In severe cases, depression can lead to suicide, and more than 700,000 people die from suicide each year. According to the WHO report, depression is currently the fourth largest disease burden in the world, and it is expected that by 2030, depression may become the largest burden disease.

[0003] NMDA receptors are glutamate-gated ion channels composed of heterotetrameric assemblies consisting of a combination of two or more of the three subunit subtypes GluN1, GluN2 (A, B, C, and D) and GluN3 (A and B), and the NR1 subunit derived from a single gene is ubiquitously expressed in the brain and is common to all NMDA receptors.

[0004] Among NMDA receptor subtypes, NR2B receptor is an important target for antidepressant drugs. At present, patents such as WO2013170072A2 and WO2015048507A1 disclose compounds that negatively regulate NMDA receptors containing NR1 / NR2B subunits, which have certain effects, but still have some shortcomings. Therefore, it is still necessary to develop new negative regulators of NR1 / NR2B receptors. Summary of the invention

[0005] The present invention provides a derivative containing a fused ring or bridged ring structure of Formula I or Formula II, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the structural formula of Formula I or Formula II is as follows:

[0006]

[0007] in,

[0008] X1 and X2 are independently selected from N or CR1;

[0009] X5 is independently selected from C(R1)2;

[0010] Ar1 and Ar2 are independently selected from aryl or heteroaryl, which may be further substituted by one or more substituents;

[0011] L1 is selected from a bond, -O-, -C(O)-, -[C(R 1 )2] n -、-[OC(R 1 )2]n -, -[C(R 1 )2O] n -, -OC(O)-, -C(O)O-, -NR 1 -, -C(O)NR 1 - or -NR 1 C(O)-;

[0012] L2 is selected from a bond, -O-, -C(O)-, -[C(R 1 )2] n -, -[C(R 1 )2] n -O-, -O-[C(R 1 )2] n -, -[OC(R 1 )2] n -, -[C(R 1 )2O] n -, -OC(O)-, -C(O)O-, -C(O)NR 1 -, -NR 1 C(O)-, -C(O)C(O)NR 1 -, -OC(O)C(O)NR 1 -, -NR 1 C(O)C(O)-, -C(O)C(O)O-, -OC(O)C(O)-, -[C(R 1 )2] n C(O)NR 1 -, -C(O)NR 1 [C(R 1 )2] n -, -NR 1 C(O)[C(R 1 )2] n -, -[C(R 1 )2] n C(O)O-, -C(O)O[C(R 1 )2] n -, -OC(O)[C(R 1 )2] n -, -C(O)[C(R 1 )2] n NR 1 -, -NR 1 [C(R 1 )2] n C(O)-, -C(O)[C(R 1 )2] n -, -[C(R 1 )2] nC(O)-、-[C(R 1 )2] n S(O)-、-C(O)NR 1 C(O)-, cycloalkylene, heterocyclylene, arylene or heteroarylene;

[0013] m is 0 or 1;

[0014] n is 1, 2, 3, 4 or 5;

[0015] R1 is each independently selected from hydrogen, halogen, nitro, hydroxyl, thiol, cyano, amino, phosphate, phosphoryl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclyl, aryl or heteroaryl, which may be further substituted by one or more substituents;

[0016] R 1 are independently selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, phosphate, phosphoryl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclyl, aryl or heteroaryl, which may be further substituted with one or more substituents;

[0017] In the present invention, the hydrogen, halogen, nitro, hydroxyl, thiol, cyano, amino, phosphate, phosphoryl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclic, aryl, heteroaryl, arylene or heteroarylene may be further substituted with one or more substituents selected from hydrogen, halogen, nitro, hydroxyl, thiol, cyano, amino, phosphate, phosphoryl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclic, aryl or heteroarylene groups;

[0018] In some specific embodiments, the derivative containing a fused ring or a bridged ring structure of Formula I may be of Formula I-1:

[0019]

[0020] Wherein, the definitions of each substituent and linker are the same as those of Formula I;

[0021] In some specific embodiments, Ar1 may be a 6-20 membered aryl group, a 5-20 membered heteroaryl group, which may be further substituted with one or more substituents; preferably a 6-12 membered aryl group, a 5-10 membered heteroaryl group, which may be further substituted with one or more substituents;

[0022] The further substituted substituents may be selected from one or more substituents of hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, C1-10 acyl, C1-10 acylamino, C1-10 ester, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl groups;

[0023] In some embodiments, Ar1 may be

[0024] In some embodiments, Ar1 may be

[0025] Among them, R 2 are independently selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, phosphate, phosphoryl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclyl, aryl or heteroaryl, which may be further substituted with one or more substituents;

[0026] The hydrogen, halogen, nitro, hydroxyl, thiol, cyano, amino, phosphate, phosphoryl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclyl, aryl or heteroaryl group may be further substituted with one or more substituents selected from hydrogen, halogen, nitro, hydroxyl, thiol, cyano, amino, phosphate, phosphoryl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclyl, aryl or heteroaryl groups;

[0027] In some specific embodiments, R 2 Each of the following is independently selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, C1-10 acyl, C1-10 acylamino, C1-10 ester, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; preferably hydrogen, halogen, C1-10 haloalkyl; halogen and halo are preferably fluorine or fluoro;

[0028] The hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, C1-10 acyl, C1-10 acylamino, C1-10 ester, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl can be further selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, C1-10 acyl, C1-10 acylamino, C1-10 ester, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl. substituted with one or more substituents selected from halogen, nitro, hydroxy, mercapto, cyano, amino, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, C1-10 acyl, C1-10 acylamino, C1-10 ester, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;

[0029] In some embodiments, Ar1 may be Preferably

[0030] In some embodiments, L1 is selected from a bond, -O-, -C(O)-, -NR 1 -or-[C(R 1 )2] n -;

[0031] In some embodiments, L1 is selected from a bond, -O-, -C(O)-, -NR 1 -or-[C(R 1 )2]-;

[0032] In some embodiments, L1 is selected from a bond, -O-, -C(O)-, -NH-, or -[CH2]-;

[0033] In some embodiments, L2 is selected from -[C(R 1 )2] n -、-[C(R 1 )2] n -O-, -C(O)C(O)NR 1 -、-OC(O)C(O)NR 1 -、-C(O)C(O)O-、-[C(R 1 )2] n C(O)NR 1 -、-[C(R 1 )2] n C(O)O-、-C(O)O[C(R 1 )2] n -、-C(O)[C(R 1 )2]n NR 1 -、-C(O)NR 1 [C(R 1 )2] n -、-C(O)[C(R 1 )2] n -、-[C(R 1 )2] n C(O)-, -[C(R 1 )2] n S(O)-、-C(O)NR 1 C(O)-, 3-20-membered cycloalkylene, 3-20-membered heterocyclylene, 6-20-membered arylene or 5-20-membered heteroarylene; the 6-20-membered arylene or 5-20-membered heteroarylene may be further substituted with one or more substituents;

[0034] In some embodiments, L2 is selected from -[C(R 1 )2]-[C(R 1 )(OH)]-、-[C(R 1 )2]-[C(R 1 )(OH)]-[C(R 1 )2]-O-, -C(O)C(O)NR 1 -、-OC(O)C(O)NR 1 -、-C(O)C(O)O-、-[C(R 1 )2]C(O)NR 1 -、-[C(R 1 )2]C(O)O-、-C(O)O[C(R 1 )2]-、-C(O)[C(R 1 )2]NR 1 -、-C(O)NR 1 [C(R 1 )2]-、-C(O)[C(R 1 )OH][C(R 1 )2]-、-[C(R 1 )2]C(O)-、-[C(R 1 )2][C(R 1 )2]C(O)-、-[C(R 1 )2][C(R 1 )2]S(O)-、-C(O)NR 1 C(O)-, 3-10 membered cycloalkylene, 3-10 membered heterocyclylene, 6-10 membered arylene or 5-10 membered heteroarylene; the 6-10 membered arylene or 5-10 membered heteroarylene may be further substituted with one or more substituents;

[0035] Among them, R 1 are independently selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, C1-10 acyl, C1-10 acylamino, C1-10 ester, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;

[0036] The hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, C1-10 acyl, C1-10 acylamino, C1-10 ester, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl can be further selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, C1-10 acyl, C1-10 acylamino, C1-10 ester, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl. substituted with one or more substituents selected from halogen, nitro, hydroxy, mercapto, cyano, amino, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, C1-10 acyl, C1-10 acylamino, C1-10 ester, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;

[0037] In some embodiments, the 5-10 membered heteroarylene group can be

[0038] In some embodiments, the 3-10 membered heterocyclylene group can be

[0039] Among them, R 3 are independently selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, phosphate, phosphoryl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclyl, aryl or heteroaryl, which may be further substituted with one or more substituents;

[0040] The hydrogen, halogen, nitro, hydroxyl, thiol, cyano, amino, phosphate, phosphoryl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclyl, aryl or heteroaryl group may be further substituted with one or more substituents selected from hydrogen, halogen, nitro, hydroxyl, thiol, cyano, amino, phosphate, phosphoryl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclyl, aryl or heteroaryl groups;

[0041] In some specific embodiments, R 3 are independently selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, C1-10 acyl, C1-10 acylamino, C1-10 ester, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;

[0042] The hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, C1-10 acyl, C1-10 acylamino, C1-10 ester, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl can be further selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, C1-10 acyl, C1-10 acylamino, C1-10 ester, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl. substituted with one or more substituents selected from halogen, nitro, hydroxy, mercapto, cyano, amino, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, C1-10 acyl, C1-10 acylamino, C1-10 ester, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;

[0043] In some specific embodiments, L2 can be specifically

[0044] In the linker L2 of the present invention, if the carbon atom connected to -OH is a chiral carbon atom, it may be in R configuration or S configuration;

[0045] In some specific embodiments, L2 can be specifically

[0046] In some specific embodiments, in Formula I Can

[0047] In some specific embodiments, in Formula I-1 Can

[0048] In some specific embodiments, in Formula II Can

[0049] In some specific embodiments, Can

[0050] In some specific embodiments, in Formula I If the two fused carbon atoms are chiral carbon atoms, they can be independently in R configuration or S configuration, for example, both carbon atoms are in S configuration, both carbon atoms are in R configuration, or one carbon atom is in R configuration and the other atom is in S configuration;

[0051] In some specific embodiments, If the two fused carbon atoms are chiral carbon atoms, they can be independently in R configuration or S configuration, for example, both carbon atoms are in S configuration, both carbon atoms are in R configuration, or one carbon atom is in R configuration and the other atom is in S configuration;

[0052] In some specific embodiments, If the two fused carbon atoms are chiral carbon atoms, the chiral carbon atom connected to X2 can be in R configuration or S configuration, and the chiral carbon atom connected to X5 can be in R configuration or S configuration;

[0053] In some specific embodiments, X1 on the left or right side of the center X2 of can be independently CR1; if the carbon atom connected to R1 is a chiral carbon atom, it can be R configuration or S configuration;

[0054] In some specific embodiments, Can

[0055]

[0056] In some embodiments, R1 is independently selected from hydrogen, halogen, nitro, hydroxyl, thiol, cyano, amino, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, C1-10 acyl, C1-10 acylamino, C1-10 ester, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;

[0057] The hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, C1-10 acyl, C1-10 acylamino, C1-10 ester, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl can be further selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, C1-10 acyl, C1-10 acylamino, C1-10 ester, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl. substituted with one or more substituents selected from halogen, nitro, hydroxy, mercapto, cyano, amino, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, C1-10 acyl, C1-10 acylamino, C1-10 ester, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;

[0058] In some specific embodiments, in Formula I Can

[0059] In some specific embodiments, in Formula I Can

[0060] In some specific embodiments, in Formula II Can

[0061] In some specific embodiments, Ar2 may be a 6-20 membered aryl group, a 5-20 membered heteroaryl group, which may be further substituted with one or more substituents, preferably a 6-12 membered aryl group, a 5-10 membered heteroaryl group, which may be further substituted with one or more substituents;

[0062] The further substituted substituents may be selected from one or more substituents of hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, C1-10 acyl, C1-10 acylamino, C1-10 ester, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl groups;

[0063] In some embodiments, Ar2 may be

[0064] Wherein, X3 and X4 are independently selected from C(R 4 )2. NR 4 , O or S;

[0065] In some embodiments, Ar2 may be

[0066] In some embodiments, Ar2 may be

[0067]

[0068] Among them, R 4 are independently selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, phosphate, phosphoryl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclyl, aryl or heteroaryl, which may be further substituted with one or more substituents;

[0069] The hydrogen, halogen, nitro, hydroxyl, thiol, cyano, amino, phosphate, phosphoryl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclyl, aryl or heteroaryl group may be further substituted with one or more substituents selected from hydrogen, halogen, nitro, hydroxyl, thiol, cyano, amino, phosphate, phosphoryl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclyl, aryl or heteroaryl groups;

[0070] In some specific embodiments, R 4 are independently selected from hydrogen, halogen, nitro, hydroxyl, thiol, cyano, amino, phosphate, phosphoryl, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, C1-10 acyl, C1-10 acylamino, C1-10 ester, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;

[0071] The hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, phosphate, phosphoryl, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, C1-10 acyl, C1-10 acylamino, C1-10 ester, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl can be further selected from hydrogen, halogen, 1-2-4-6-10-15-18-17-19-17-16-18-19-16-18-19-16-18-19-16-18-18-19-16-18-18-19-16-18-18-19-16-18-18-19-16-18-18-19-18 ...8-19-18-18-18-19-18-18-18-19-18-18-18-18-19-18-18-18-19-18-18-18-18-19-18-18-18-18-19-18 substituted with one or more substituents selected from halogen, nitro, hydroxy, mercapto, cyano, amino, phosphate, phosphoryl, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, C1-10 acyl, C1-10 acylamino, C1-10 ester, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;

[0072] In some embodiments, Ar2 may be

[0073] In some specific embodiments, the formula I or formula I-1 may be:

[0074]

[0075]

[0076] in,

[0077] L1 is defined the same as L1 in Formula I or Formula I-1;

[0078] L2 is defined the same as L2 in Formula I or Formula I-1;

[0079] X 11 , X 12 The definitions of are the same as X1, X 11 , X 12 The chirality of is defined the same as that of X1;

[0080] R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 110 The definitions of are the same as R1;

[0081] R 21 , R 22 , R 23 , R24 , R 25 The definitions are respectively the same as R 2 same;

[0082] R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 The definitions are respectively the same as R 4 same;

[0083] The chirality of the two fused carbon atoms in The chirality of the two fused carbon atoms in is defined identically;

[0084] In some specific embodiments, the formula I or formula I-1 can further be:

[0085]

[0086]

[0087] in,

[0088] R 11 , R 12 The definitions are respectively the same as R 1 same;

[0089] L2 definition is the same as above;

[0090] R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 110 The definitions of are the same as R1;

[0091] R 22 , R 23 , R 24 , R 25 The definitions are respectively the same as R 2 same;

[0092] R 41 , R 46 , R 47 , R 48 The definitions are respectively the same as R 4 same;

[0093] In, with R 13 The carbon atom connected to the R- or S-configuration 18 The connected carbon atoms may be in R configuration or S configuration, and the carbon atom at position 4 of the fused ring may be in R configuration or S configuration;

[0094] In some specific embodiments, the formula I or formula I-1 can further be:

[0095]

[0096]

[0097] in,

[0098] The definitions of L1 and L2 are the same as above;

[0099] R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 110 The definitions of are the same as R1;

[0100] R 21 , R 22 , R 23 , R 24 , R 25 The definitions are respectively the same as R 2 same;

[0101] R 41 , R 46 , R 47 , R 48 The definitions are respectively the same as R 4 same;

[0102] In, with R 13 The carbon atom connected to the R- or S-configuration 18 The connected carbon atoms may be in R configuration or S configuration, and the carbon atom at position 4 of the fused ring may be in R configuration or S configuration;

[0103] In some specific embodiments, the formula I or formula I-1 can further be:

[0104]

[0105] in,

[0106] The definitions of L1 and L2 are the same as above;

[0107] R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 110 The definitions of are the same as R1;

[0108] R 22 , R 23 , R 24 , R 25 The definitions are respectively the same as R 2 same;

[0109] R 41 , R 46 , R 47 , R 48 The definitions are respectively the same as R 4 same;

[0110] In, with R 13 The carbon atom connected to the R- or S-configuration 18 The connected carbon atoms can be in R configuration or S configuration, and the carbon atom at position 4 of the fused ring can be in R configuration or S configuration.

[0111] In some specific embodiments, the formula I or formula I-1 can be further specifically:

[0112]

[0113]

[0114] The present invention also relates to a pharmaceutical composition, which comprises the derivative containing a fused ring or bridged ring structure of the present invention;

[0115] In some specific embodiments, the pharmaceutical composition comprises a derivative containing a fused ring or bridged ring structure of the above-mentioned Formula I or Formula II, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof;

[0116] In some embodiments, optionally, the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier.

[0117] The present invention also relates to the use of a derivative containing a fused ring or a bridged ring structure, which is used as a negative regulator of NR1 / NR2B receptors, or for preparing a drug for negatively regulating NR1 / NR2B receptors;

[0118] In some specific embodiments, the derivatives containing fused rings or bridged ring structures of the above formula I or formula II or their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or stereoisomers are used as negative modulators of NR1 / NR2B receptors, or for the preparation of drugs that negatively regulate NR1 / NR2B receptors;

[0119] The present invention also relates to the use of a derivative containing a fused ring or a bridged ring structure for preparing a drug for treating NR1 / NR2B receptor-mediated diseases;

[0120] In some specific embodiments, the derivatives containing fused rings or bridged ring structures of the above formula I or formula II or their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or stereoisomers are used to prepare drugs for diseases mediated by NR1 / NR2B receptors;

[0121] In the present invention, the disease mediated by NR1 / NR2B receptors may be depression or schizophrenia.

[0122] Detailed description of the invention

[0123] Before further describing the present invention, it should be understood that the present invention is not limited to the specific embodiments described, as they may of course vary. It should also be understood that the purpose of the terms used herein is only to describe specific embodiments and is not intended to be limiting, as the scope of the present invention is limited only by the appended claims.

[0124] Unless otherwise indicated, all scientific and technological terms used herein have the same ordinary meaning as understood by those of ordinary skill in the art to which the present invention belongs. All patents, applications, published applications and other publications cited herein are incorporated herein by reference in their entirety. If the definitions in this section are contrary to or inconsistent with the definitions listed in the patents, applications and other publications incorporated herein by reference, the definitions in this section will prevail over the definitions incorporated herein by reference.

[0125] In the present invention, "alkyl" refers to a saturated aliphatic hydrocarbon group, which may be a C1-20 alkyl group, preferably a C1-10 alkyl group, more preferably a C1-6 alkyl group, and most preferably a C1-3 alkyl group. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof;

[0126] In the present invention, "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. The cycloalkyl group may contain 3 to 20 ring carbon atoms ("3-20-membered cycloalkyl"), preferably 3 to 12 ring carbon atoms ("3-12-membered cycloalkyl"), further preferably 3 to 10 ring carbon atoms ("3-10-membered cycloalkyl"), more preferably 3 to 8 ring carbon atoms ("3-8-membered cycloalkyl"), and most preferably 3 to 6 ring carbon atoms ("3-6-membered cycloalkyl"). Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.;

[0127] In the present invention, "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing a specified number of ring atoms and including at least one heteroatom selected from N, O and S as a ring member of the cycloalkyl ring. The heterocyclyl may contain 3 to 20 ring atoms ("3-20 membered heterocyclyl"), preferably 3 to 12 ring atoms ("3-12 membered heterocyclyl"), further preferably 3 to 10 ring atoms ("3-10 membered heterocyclyl"), more preferably 3 to 8 ring atoms ("3-8 membered heterocyclyl"), and most preferably 3 to 6 ring atoms ("3-6 membered heterocyclyl"). Non-limiting examples of heterocyclyl include oxirane, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, etc.;

[0128] In the present invention, "aryl" refers to an optionally substituted monocyclic, biaryl or fused bicyclic or polycyclic ring system having the well-known aromatic characteristics, wherein at least one ring contains a completely conjugated π-electron system. Typically, aryl contains 6 to 20 carbon atoms ("6-20 membered aryl") as ring members, preferably 6 to 14 carbon atoms ("6-C membered aryl") or more preferably 6 to 12 carbon atoms ("6-10 membered aryl"). Fused aryl may include an aryl ring fused to another aryl ring, or to a saturated or partially unsaturated carbocyclic or heterocyclic ring. The point of attachment to the base molecule on such a fused aryl ring system may be a C atom of the aromatic portion of the ring system or a C or N atom of the non-aromatic portion. Examples of aryl include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, benzo[d][1,3]dioxole and tetrahydronaphthyl;

[0129] In the present invention, " heteroaryl " refers to monocyclic, heterobiaryl or fused bicyclic or polycyclic ring system with well-known aromaticity characteristics, which contains a specified number of ring atoms and includes at least one heteroatom selected from N, O and S as a ring member in the aromatic ring. The inclusion of heteroatoms allows the aromaticity of 5-ring and 6-ring. Usually, heteroaryl contains 5-20 ring atoms (" 5-20 yuan heteroaryl "), preferably 5-14 ring atoms (" 5-14 yuan heteroaryl "), and more preferably 5-10 ring atoms (" 5-10 yuan heteroaryl "). The heteroaryl ring is connected to the base molecule by the ring atoms of the heteroaromatic ring, thereby keeping aromaticity. Therefore, 6 yuan heteroaryl rings can be connected to the base molecule by ring C atoms, and 5 yuan heteroaryl rings can be connected to the base molecule by ring C or N atoms. Examples of unsubstituted heteroaryl groups often include, but are not limited to, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, benzofuran, benzothiophene, indole, benzimidazole, indazole, quinoline, isoquinoline, purine, triazine, naphthyridine, and carbazole;

[0130] In the present invention, "ester group" refers to a group formed by esterification of a carboxyl group (-COOH) and a hydroxyl group (-OH), with the OH group removed and the H group removed. For example, the ester group can be Wherein R6' and R8' may be alkyl groups, which may be selected from C1-20 ester groups, preferably C1-10 ester groups, further preferably C2-8 ester groups, more preferably C2-6 ester groups, and most preferably C2-3 ester groups;

[0131] In the present invention, the "thioester group" can be, for example Wherein R6' and R8' may be alkyl groups, which may be selected from C1-20 thioester groups, preferably C1-10 thioester groups, further preferably C2-8 thioester groups, more preferably C2-6 thioester groups, and most preferably C2-3 thioester groups;

[0132] In the present invention, "acyl" refers to the atomic group remaining after removing the hydroxyl group from an organic acid, and has the general formula R8'-CO-, wherein R8' is defined as above, and the acyl group can be selected from C1-20 acyl, preferably C1-10 acyl, further preferably C1-8 acyl, more preferably C1-6 acyl, and most preferably C1-3 acyl;

[0133] In the present invention, "aldehyde group" refers to -C(O)H;

[0134] In the present invention, "alkoxy" refers to alkyl-O-, wherein alkyl is as defined above; cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy are similarly defined;

[0135] In the present invention, "alkylthio" refers to alkyl-S-, wherein the alkyl group is as defined above; cycloalkylthio, heterocyclylthio, arylthio, and heteroarylthio are similarly defined;

[0136] In the present invention, "amide group" refers to Wherein R7' can be H or alkyl;

[0137] In the present invention, "acylamino group" refers to wherein R7' and R8' are as defined above;

[0138] In the present invention, "amino group" refers to wherein R7' is as defined above, and at least one R7' is not H;

[0139] In the present invention, "haloalkyl" refers to an alkyl group substituted by one or more halogens, wherein alkyl is as defined above;

[0140] In the present invention, "haloalkoxy" refers to an alkoxy group substituted by one or more halogens, wherein the alkoxy group is as defined above;

[0141] In the present invention, "haloalkylthio" refers to an alkylthio group substituted by one or more halogens, wherein the alkylthio group is as defined above;

[0142] As used herein, "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein the alkyl group is as defined above;

[0143] As used herein, "hydroxyalkoxy" refers to an alkoxy group substituted with one or more hydroxy groups, wherein the alkoxy group is as defined above;

[0144] In the present invention, "hydroxyl" refers to -OH;

[0145] In the present invention, "thiol" refers to -SH;

[0146] In the present invention, "halogen" refers to fluorine, chlorine, bromine or iodine;

[0147] In the present invention, "amino" refers to -NH2;

[0148] In the present invention, "cyano" refers to -CN;

[0149] In the present invention, "nitro" refers to -NO2;

[0150] In the present invention, "sulfonic acid group" refers to -SO3H;

[0151] In the present invention, "sulfonyl" refers to R8'-S(=O)2-, wherein R8' is as defined above, and the sulfonyl group can specifically be methanesulfonyl, benzenesulfonyl, p-toluenesulfonyl, etc.;

[0152] In the present invention, "phosphate group" refers to wherein R6' and R8' are as defined above;

[0153] In the present invention, "phosphoryl" refers to wherein R6' and R8' are as defined above;

[0154] In the present invention, the above-defined groups may be optionally substituted or unsubstituted, and when substituted, may be substituted by one or more of the following groups:

[0155] Hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, amine, sulfonic acid, sulfonyl, phosphate, phosphoryl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, thioester, ester, cycloalkyl, heterocyclic, aryl or heteroaryl; optionally, it may be further substituted.

[0156] In the present invention, the terms "GluN2B", "NR2B", "NR2B-containing NMDA receptor", "2B" and "NMDA receptor subunit GluN2B" are used interchangeably. Because the NR1 subunit derived from a single gene is ubiquitously expressed in the brain and is common to all NMDA receptors, in the present invention, "GluN2B", "NR2B", "NR2B-containing NMDA receptor", "2B" and "NMDA receptor subunit GluN2B" refer to a tetrameric NMDA complex comprising GluN1 and GluN2B, or a tetrameric NMDA complex comprising NR1 / NR2B, unless otherwise specified. In the present invention, GluN2A can be used interchangeably with NR2A, GluN2D with NR2D, GluN2C with NR2C, GluN3A with NR3A, GluN3B with NR3B and GluN1 with NR1.

[0157] In the present invention, any isotope-labeled derivatives of the compounds of the present invention or their pharmaceutically acceptable salts are covered by the present invention. Atoms that can be isotopically labeled include, but are not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, iodine, etc. They can be labeled with isotopes. 2 H(D), 3 H. 11 C. 13 C. 14 C. 15 N. 18 F. 31 P. 32 P. 35 S. 36 Cl and 125 Unless otherwise indicated, when a position is specifically designated as deuterium (D), the position is understood to have an abundance of deuterium (i.e., at least 45% deuterium incorporation) that is at least 3000 times greater than the natural abundance of deuterium, which is 0.015%.

[0158] In the present invention, the term “plurality” may specifically refer to 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0159] In the present invention, the following abbreviations / terms are used:

[0160] DEAD: Diethyl azodicarboxylate

[0161] Pd2(dba)3: tris(dibenzylideneacetone)dipalladium

[0162] BINAP: 1,1'-binaphthyl-2,2'-bis(diphenylphosphine)

[0163] LCMS: Liquid spectrometry and mass spectrometry

[0164] PE: Petroleum ether

[0165] EA: Ethyl acetate

[0166] DCM: dichloromethane

[0167] RuPhos: 2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl

[0168] TBSOTF: tert-Butyldimethylsilyl trifluoromethanesulfonate

[0169] DIAD: diisopropyl azodicarboxylate

[0170] DMF: N,N-dimethylformamide

[0171] NMI: N-methylimidazole

[0172] TEA: triethylamine

[0173] RuCl(p-cymene)[S,S-TsDPEN]:(S,S)-N-(p-Toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene) chloride

[0174] TMSCHN2: (trimethylsilyl)diazomethane

[0175] TCFH: N,N,N',N'-Tetramethylchloroformamidine hexafluorophosphate

[0176] ACN: Acetonitrile

[0177] TFA: trifluoroacetic acid

[0178] LiHMDS: Lithium bis(trimethylsilyl)amide

[0179] EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

[0180] HOBt: 1-Hydroxybenzotriazole

[0181] Davephos: 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl

[0182] Xylene: Xylene

[0183] Tri(o-tolyl)phosphine: Tri(o-methylphenyl)phosphine DETAILED DESCRIPTION

[0184] The present invention is further described below with reference to examples, but these examples are not intended to limit the scope of the present invention.

[0185] Example 1

[0186]

[0187] Step 1: Synthesis of Intermediate 3

[0188] Dissolve intermediate 1 (10.00 g, 61.282 mmol) and intermediate 2 (4.54 g, 61.282 mmol) in 150 mL of tetrahydrofuran, add triphenylphosphine (17.68 g, 67.410 mmol), stir under ice bath, and then slowly add DEAD (11.74 g, 67.410 mmol). After the addition is complete, warm to room temperature, stir, and react for 6 hours. TLC monitors the end of the reaction, add 100 mL of water to quench the reaction, extract with ethyl acetate three times, combine the organic layers, dry over anhydrous sodium sulfate, filter and concentrate, and purify by column chromatography to obtain intermediate 3 (8.05 g, yield: 60%).

[0189] Step 2: Synthesis of intermediate 6

[0190] Intermediate 4 (550.00 mg, 2.444 mmol), intermediate 5 (593.39 mg, 2.933 mmol) and sodium tert-butoxide (469.80 mg, 4.889 mmol) were added to toluene (15 mL), and then Pd2(dba)3 (223.83 mg, 0.244 mmol) and BINAP (152.20 mg, 0.244 mmol) were added, and nitrogen was replaced, and stirred at 100°C for 12 h. LCMS monitoring showed that the main peak was the product peak. After the reaction solution was cooled to room temperature, water (40 mL) and ethyl acetate (20 mL*3) were added for extraction. The organic phases were combined, washed with saturated NaCl solution (20 mL), dried over anhydrous sodium sulfate, filtered and dried, and the sample was passed through a column (PE / EA=6 / 1) to obtain Intermediate 6 (780 mg, yield: 92.13%) as a yellow solid.

[0191] MS m / z(ESI):347.2[M+H] + .

[0192] Step 3: Synthesis of intermediate 7

[0193] Intermediate 6 (240 mg, 0.693 mmol) was added to methanol (5 mL), and 20% Pd(OH)2 / C (243.65 mg, 0.347 mmol) was added at room temperature, replaced with hydrogen 3 times, and stirred at 50 ° C for 3 h. LCMS detected that the product peak was the main peak. Post-treatment: The reaction solution was filtered and dried, and passed through a column (DCM / MeOH=20 / 1) to obtain intermediate 7 (80 mg, yield: 45.1%), which was a yellow oil.

[0194] MS m / z(ESI):257.2[M+H] +.

[0195] Step 4: Synthesis of Compound 1

[0196] Intermediate 7 (50 mg, 0.195 mmol) and intermediate 3 (64.16 mg, 0.293 mmol) were added to ethanol (2 mL) and refluxed at 78 ° C for 3 h. LCMS monitored that the raw materials were completely reacted or a small amount remained, and the product was the main peak. Post-treatment: After the reaction solution was cooled, silica gel was added and the sample was passed through a column (MeOH / DCM=5 / 95), and the target product was spin-dried to dry the solvent and freeze-dried to obtain compound 1 (28.57 mg, yield: 29.37%).

[0197] MS m / z(ESI):476.3[M+H] + .

[0198] 1 H NMR(400MHz,DMSO-d6)δ9.88(s,1H),7.45(d,J=8.6Hz,2H),6.80–6.60(m,5H) ,4.84(d,J=4.4Hz,1H),3.92–3.82(m,2H),3.81–3.73(m,1H),3.49(t,J=8.5Hz ,2H),3.12(dt,J=9.8,3.9Hz,2H),2.90(d,J=6.5Hz,2H),2.75(t,J=7.5Hz,2H) ,2.70–2.52(m,5H),2.42(dd,J=12.4,6.0Hz,1H),2.36(dd,J=8.4,6.5Hz,2H).

[0199] Example 2

[0200]

[0201] Step 1: Synthesis of intermediate 9

[0202] Under argon protection, intermediate 8 (50 mg, 0.271 mmol), intermediate 4 (92 mg, 0.409 mmol), sodium tert-butoxide (78 mg, 0.812 mmol) were added to 1,4-dioxane (2 ml), and then Pd2(dba)3 (25 mg, 0.027 mmol) and RuPhos (25 mg, 0.054 mmol) were added. The argon was replaced three times, heated to 100 ° C, reacted for 2 h, cooled to room temperature, filtered, and concentrated under reduced pressure to obtain residue 1.

[0203] Under argon protection, intermediate 8 (200 mg, 1.086 mmol), intermediate 4 (366 mg, 1.627 mmol), sodium tert-butoxide (313 mg, 3.257 mmol) were added to 1,4-dioxane (8 mL), and then Pd2(dba)3 (50 mg, 0.062 mmol) and RuPhos (51 mg, 0.109 mmol) were added. The argon was replaced three times, heated to 100 ° C, reacted for 2 h, cooled to room temperature, filtered, and concentrated under reduced pressure to obtain residue 2.

[0204] Residue 1 and residue 2 were combined and purified by silica gel column (PE:EA=5:1) to obtain intermediate 9 (440 mg, yield: 98.88%) as a light yellow solid.

[0205] MS m / z(ESI):329.1[M+H] + ,273.1[M+H-56] + .

[0206] Step 2: Synthesis of intermediate 10

[0207] Intermediate 9 (410 mg, 1.249 mmol) was dissolved in dichloromethane (15 mL), cooled to 0°C in an ice-water bath, TBSOTF (660 mg, 2.497 mmol) was added dropwise, and the mixture was stirred for 1 h. LCMS showed that the reaction was complete, and the reaction solution was concentrated to dryness, dichloromethane (10 mL) was added, and the mixture was washed with saturated sodium bicarbonate (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a viscous solid intermediate 10 (284 mg, crude product), which was directly used for the next step.

[0208] MS m / z(ESI):229.1[M+H] + .

[0209] Step 3: Synthesis of Compound 2

[0210] Intermediate 10 (100 mg, 0.438 mmol) and intermediate 3 (101 mg, 0.461 mmol) were dissolved in ethanol (2 mL) and stirred at 80°C for 3 h. The mixture was concentrated to dryness under reduced pressure, and the residue was dissolved in DMF and purified by reverse phase chromatography (eluent: acetonitrile: water = 55:45) to obtain compound 2 (6.25 mg, yield: 2.89%).

[0211] MS m / z(ESI):448.3[M+H] + .

[0212] Example 3

[0213]

[0214] Step 1: Synthesis of intermediate 13

[0215] Intermediate 11 (0.49 g, 4.399 mmol), intermediate 12 (1 g, 4.399 mmol) and triphenylphosphine (1.38 g, 5.279 mmol) were dissolved in 20 mL of tetrahydrofuran, DIAD (1.07 g, 5.279 mmol) was added dropwise under ice bath, and the mixture was reacted at room temperature for 2 h. TLC monitoring showed that the raw material spot disappeared and new spots were generated. 30 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate three times. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography (PE:EA=0-50) to obtain intermediate 13 (1.1 g, yield: 77%).

[0216] MS m / z(ESI):266[M-56+H] + .

[0217] Step 2: Synthesis of intermediate 14

[0218] Intermediate 13 (1.1 g, 3.423 mmol) was added to 5 mL of 4 M hydrochloric acid ethyl acetate solution and stirred at room temperature for 1 h. TLC monitoring showed that the raw material spot disappeared and a new spot was generated. The reaction solution was concentrated in vacuo, washed with sodium bicarbonate aqueous solution, extracted with dichloromethane three times, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude intermediate 14 (0.8 g, 3.620 mmol).

[0219] MS m / z(ESI):222[M+H] + .

[0220] Step 3: Synthesis of compound 3

[0221] Intermediate 14 (100 mg, 0.452 mmol) and intermediate 3 (99 mg, 0.452 mmol) were added to 3 mL of anhydrous ethanol and refluxed at 80°C for 3 h. TLC detection showed that the raw material spot disappeared and a new spot was generated. The reaction solution was concentrated and subjected to preparative separation (acetonitrile / water) and freeze-dried to obtain compound 3 (32.62 mg, yield: 16%).

[0222] MS m / z(ESI):441[M+H] + .

[0223] 1H NMR(400MHz,Chloroform-d)δ9.94(s,1H),7.30–7.08(m,3H),6.96(td,J=7.6,4.2Hz,1H),6.84–6.70(m,3H),5.13(dt,J=5.0,2.6Hz,1H),4.18(dt,J= 9.3,4.5Hz,1H),3.89(ddt,J=15.7,9.9,5.3Hz,4H),3.32–3.12(m,2H),3.0 5–2.75(m,6H),2.40(t,J=7.5Hz,2H),2.36–2.17(m,1H),2.15–1.69(m,4H).

[0224] Example 4

[0225]

[0226] Step 1: Synthesis of intermediate 16

[0227] Intermediate 15 (299.01 mg, 1.582 mmol) and intermediate 5 (320 mg, 1.582 mmol) were added to a DMF solution (2 mL), and potassium carbonate (262.35 mg, 1.898 mmol) was added, and the mixture was stirred at room temperature for 1 h. LCMS monitored that the raw material reaction was complete, and the main peak was the product peak. Post-treatment: water (20 mL) was added to the reaction solution, and ethyl acetate (5 mL*4) was added for extraction. The organic phases were combined and dried over anhydrous sodium sulfate, filtered and dried, and the crude product was subjected to column chromatography (DCM / MeOH=20 / 1). The solution was dried to obtain intermediate 16 (410 mg, yield: 83.5%), which was a colorless oil.

[0228] MS m / z(ESI):311.2[M+H] + .

[0229] Step 2: Synthesis of intermediate 17

[0230] Intermediate 16 (250 mg, 0.805 mmol) was added to a methanol solution (2 mL), and then 20% palladium hydroxide on carbon (565.50 mg, 0.805 mmol) was added and stirred at room temperature overnight. LCMS monitored that the raw material reaction was complete, and the main peak was the product peak. Post-treatment: Filter to remove palladium hydroxide on carbon, spin-dry the solvent, and obtain the crude intermediate 17 (160 mg, yield: 90.2%), which is a colorless oil. The crude intermediate 17 was directly used in the next step reaction.

[0231] MS m / z(ESI):221.2[M+H] + .

[0232] Step 3: Synthesis of intermediate 19

[0233] Intermediate 17 (160 mg, 0.726 mmol), potassium carbonate (301.15 mg, 2.179 mmol) and intermediate 18 (156.19 mg, 0.726 mmol) were added to acetonitrile solution (2 mL) and stirred at room temperature for 0.5 h. LCMS monitored that a small amount of raw materials remained, and the main peak was the product peak. Post-treatment: water (6 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL*4), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was spin-dried to obtain a crude product. The crude product was added with silica gel and mixed with a sample column chromatography (DCM / MeOH=50 / 1) to obtain intermediate 19 (200 mg, yield: 77.7%), which was a yellow solid.

[0234] MS m / z(ESI):355.2[M+H] + .

[0235] Step 4: Synthesis of compound 4

[0236] Intermediate 19 (100 mg, 0.282 mmol) was dissolved in methanol solution (1 mL), sodium borohydride (47.68 mg, 1.410 mmol) was added in an ice-water bath, and stirred at room temperature for 1.5 h. LCMS monitoring showed that the raw material had not reacted completely, and sodium borohydride (28.59 mg, 0.846 mmol) was added in an ice bath to react overnight. LCMS monitoring showed that the raw material had reacted completely, and the product peak was the main peak. Post-treatment: saturated ammonium chloride solution (15 mL) was added to the reaction solution, and then extracted with ethyl acetate (20 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product, which was mixed and passed through a column (MeOH / DCM=3%) to obtain compound 4 (18.09 mg, yield: 18%).

[0237] MS m / z(ESI):357.2[M+H] + .

[0238] 1H NMR(400MHz,Chloroform-d)δ7.38(td,J=7.5,1.8Hz,1H),7.23(ddd,J=7.5,5.4,2.0Hz ,1H),7.18–7.13(m,2H),7.10(td,J=7.5,1.2Hz,1H),7.02(ddd,J=9.6,8.1,1.2Hz,1H) ,6.81–6.72(m,2H),4.71(dd,J=10.5,3.1Hz,1H),4.20(s,1H),3.70(d,J=1.4Hz,2H),2 .99(t,J=7.9Hz,1H),2.88–2.66(m,7H),2.58–2.50(m,2H),2.46(td,J=9.3,3.5Hz,2H).

[0239] Example 5

[0240]

[0241] Step 1: Synthesis of intermediate 21

[0242] Intermediate 20 (103.89 mg, 0.741 mmol) and intermediate 5 (150 mg, 0.741 mmol) were added to DMF (2 mL), and then N-methylimidazole (304.37 mg, 3.707 mmol) was added, and finally tetramethyl chlorouronium hexafluorophosphate (624.13 mg, 2.224 mmol) was added, and the reaction was stirred at room temperature for 1 h. LCMS monitoring showed that the product was generated and it was the main peak. Post-treatment: water (30 mL) was added to the reaction solution, and then ethyl acetate (10 mL*3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried by column chromatography. The solution was dried by drying to obtain intermediate 21 (170 mg, yield: 70.7%), which was a colorless oil.

[0243] MS m / z(ESI):325.2[M+H] + .

[0244] Step 2: Synthesis of intermediate 22

[0245] Intermediate 21 (150 mg, 0.462 mmol) and 20% palladium hydroxide on carbon (324.39 mg, 0.462 mmol) were added to methanol (2 mL), replaced with hydrogen three times, and stirred at 50 ° C for 2 h. LCMS monitoring showed that the product was generated (there was a product peak, and the largest peak had an impurity of m / z=307). Post-treatment: Filter to remove palladium hydroxide on carbon, spin dry the solvent to obtain a crude product, and the crude product was subjected to column chromatography to obtain intermediate 22 (50 mg, yield: 46.2%), which was a colorless oil.

[0246] MS m / z(ESI):235.2[M+H] + .

[0247] Step 3: Synthesis of intermediate 23

[0248] Intermediate 22 (50 mg, 0.213 mmol) and intermediate 18 (45.90 mg, 0.213 mmol) were added to acetonitrile solution (1 mL), and potassium carbonate (88.49 mg, 0.640 mmol) was added, and stirred at room temperature for 1 h. LCMS monitored the formation of the target product, which accounted for the main proportion, and the raw materials were almost completely reacted. Post-treatment: water (10 mL) was added to the reaction solution, and then ethyl acetate (10 mL*3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried by column chromatography. The solution was dried by drying to obtain intermediate 23 (40 mg, yield: 51.0%), which was a colorless oil.

[0249] MS m / z(ESI):369.2[M+H] + .

[0250] Step 4 Synthesis of Compound 5

[0251] Intermediate 23 (40 mg, 0.109 mmol) was dissolved in methanol (1 mL), sodium borohydride (18.35 mg, 0.543 mmol) was added under ice bath, stirred for 1 h, LCMS monitoring showed that the raw material had not reacted completely, sodium borohydride (18.35 mg, 0.543 mmol) was added under ice bath, stirred for 4 h, and LCMS monitoring showed that the raw material had reacted completely. Post-treatment: saturated NH4Cl solution was added to quench the excess sodium borohydride, then ethyl acetate (4 mL*3) was added for extraction, the organic phases were combined, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, filtered, and dried to obtain an oily substance, which was purified by preparative liquid phase (MeCN / H2O=4%) to obtain compound 5 (4.22 mg, yield: 10.5%).

[0252] MS m / z(ESI):371.2[M+H] + .

[0253] 1 H NMR(400MHz, Methanol-d4)δ7.49(d,J=21.5Hz,2H),7.34–7.16(m,4H),6.82–6.74(m,2H),4.90–4.92(m,1H) ,3.81(s,2H),3.67(dd,J=5.5,4.0Hz,2H),3.56(dd,J=5.5,4.0Hz,2H),3.40(t,J=13.5Hz,3H),3.21(s,3H).

[0254] Example 6

[0255]

[0256] Step 1: Synthesis of intermediate 13

[0257] Intermediate 12 (300 mg, 1.326 mmol), intermediate 11 (222.89 mg, 1.988 mmol), PPh3 (417.32 mg, 1.591 mmol) were dissolved in THF (6 mL) and added to a flask. DIAD (402.06 mg, 1.988 mmol) was added dropwise at 0°C under nitrogen protection, stirred, and naturally warmed to room temperature. The mixture was reacted at room temperature for 16 h. After the reaction was completed, LCMS detected that the product peak was the main peak. Water was added to quench the reaction, and then ethyl acetate was added for extraction and separation. The organic phase was dried over anhydrous sodium sulfate, filtered and spin-dried, and column chromatography (PE / EA=0-30%) was performed to obtain intermediate 13 (250 mg, yield: 58.84%), which was a light yellow oil.

[0258] MS m / z(ESI):266.2[M+H-56] + .

[0259] Step 2: Synthesis of intermediate 14

[0260] The intermediate 13 (250 mg, 0.778 mmol) was added to a flask, and 3 mL of 4M HCl / 1,4-dioxane solution was added, and stirred at room temperature for 1 h. The plate showed that the raw material was completely reacted, and after spin drying, the intermediate 14 (170 mg, yield: 98.76%) was obtained as a white solid, which was directly used in the next step reaction.

[0261] Step 3: Synthesis of intermediate 24

[0262] Intermediate 14 (170 mg, 0.769 mmol), intermediate 18 (298.03 mg, 1.153 mmol) and K2CO3 (318.37 mg, 2.306 mmol) were added to a flask, acetonitrile (5 mL) was added, and the mixture was stirred at room temperature for 3 h. After the reaction was completed, LCMS showed that the main peak was the product peak, and water was added to quench, and the mixture was separated by extraction with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and dried by spin drying, and column chromatography (MeOH / DCM=0-10%) was performed to obtain intermediate 24 (100 mg, yield: 32.77%) as a white solid.

[0263] MS m / z(ESI):356.2[M+H] + .

[0264] Step 4: Synthesis of compound 6

[0265] Compound 24 (80 mg, 0.225 mmol) was added to a flask, MeOH (2 mL) was added to dissolve, and the mixture was stirred at 0°C. NaBH4 (76.08 mg, 2.251 mmol) was added, and the mixture was naturally stirred and warmed to room temperature, and the reaction was continued for 3 h. LCMS showed that the main peak was the product peak, and water was added to quench the reaction, and then ethyl acetate was added to extract and separate, the organic phase was dried over anhydrous sodium sulfate, filtered and spin-dried, the crude product was dissolved in methanol, purified by preparative liquid phase, and freeze-dried to obtain compound 6 (52.35 mg, yield: 61.25%).

[0266] MS m / z(ESI):358.2[M+H] + .

[0267] 1 H NMR(400MHz,Chloroform-d)δ11.48(s,1H),7.23–7.21(d,J=4.00Hz,2H),7.15–7.10(m,J=1 0.00Hz,2H),7.03–6.94(dq,J=18.00Hz,2H),6.85–6.83(d,J=4.00Hz,2H),5.13(s,1H),5.0 6–5.04(d,J=8.00Hz,1H),4.08(m,1H),3.82–3.80(t,J=8.00Hz,1H),3.67–3.65(t,J=8.00H z,1H),3.26(s,2H),3.14–3.11(m,J=6.00Hz,2H),2.17–2.13(m,J=4.00Hz,4H),2.00(s,2H).

[0268] Example 7

[0269]

[0270] Step 1: Synthesis of intermediate 26

[0271] Intermediate 11 (224.0 mg, 2.000 mmol) was dissolved in THF (6 mL), and triphenylphosphine (629.5 mg, 2.400 mmol) and intermediate 25 (454.6 mg, 2.000 mmol) were added. DIAD (0.79 mL, 4.000 mmol) was added under ice bath conditions. After stirring at room temperature for 6 h, 3 mL of purified water was added to quench the reaction. The mixture was extracted twice with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. Silica gel column chromatography (EA / PE=0-40%) gave intermediate 26 (374.2 mg, yield: 58.3%).

[0272] MS m / z(ESI):266.4[M+H-56] + .

[0273] Step 2: Synthesis of intermediate 27

[0274] Intermediate 26 (374.2 mg, 1.166 mmol) was added to 2 mL of 4 M hydrochloric acid ethyl acetate solution and stirred at room temperature for 1 h. The reaction solution was concentrated in vacuo, dichloromethane was added and washed with saturated sodium bicarbonate aqueous solution, the aqueous phase was extracted three times with dichloromethane, the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude intermediate 27 (258.01 mg, yield: 99%).

[0275] MS m / z(ESI):222.3[M+H] + .

[0276] Step 3: Synthesis of Compound 7

[0277] Intermediate 27 (222.3 mg, 1.000 mmol) was dissolved in anhydrous ethanol (5 mL), and intermediate 3 (223.4 mg, 1.001 mmol) and potassium carbonate (276.5 mg, 2.000 mmol) were added, and stirred at 80 ° C for 3 h. After the reaction was completed, it was filtered and concentrated, and prepared by reverse phase (MeCN / H2O=0-40%) to obtain compound 7 (190.3 mg, yield: 43.2%).

[0278] MS m / z(ESI):441.5[M+H] + .

[0279] 1 H NMR(400MHz, DMSO-d6)δ9.96(s,1H),7.30–7.08(m,3H),6.95(ddd,J=7.8,4.7,1.6Hz,1H),6.84–6.72(m,3H),5.92(d,J=49.9Hz,1H),5.07(d, J=56.7Hz,1H),4.74–4.18(m,2H),3.89(dd,J=12.9,6.5Hz,3H),3.10–2.76(m,6H),2.43–2.32(m,2H),2.10(s,2H),1.95(s,2H),1.39(m,2H).

[0280] Example 8

[0281]

[0282] Step 1: Synthesis of intermediate 25

[0283] Intermediate 28 (4.00 g, 20.00 mmol) was added to a flask, followed by THF (20 mL), water (20 mL) and Et3N (6.07 g, 60 mmol). After stirring for 10 min, (Boc)2O (6.55 g, 30.00 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 2 h. The reaction was completed. LCMS showed that all products were present. The spot plate showed that the raw materials had reacted and new spots were generated. Water (20 mL) was added and the mixture was extracted and separated with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and dried by spin drying. Column chromatography (PE / EA=0-20%) gave intermediate 25 (4.55 g, 99.9%) as a light yellow oily liquid.

[0284] MS m / z(ESI):228.3[M+H] +

[0285] Step 2: Synthesis of intermediate 26

[0286] Intermediate 25 (4.55 g, 20.00 mmol), intermediate 11 (4.48 g, 40.00 mmol), PPh3 (6.29 g, 24.00 mmol) were dissolved in THF (50 mL), DIAD (6.07 g, 30.00 mmol) was added at 0°C under nitrogen protection, stirred, and naturally warmed to room temperature for 12 h. The spot plate showed that the raw material had reacted and new spots were generated. Water was added to quench, and the mixture was separated by extraction with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and dried by spin drying, and column chromatography (PE / EA=0-20%) was performed to obtain intermediate 26 (3.90 g, yield: 60.67%), which was a light yellow oil.

[0287] MS m / z(ESI):266.4[M+H-56] + .

[0288] Step 3: Synthesis of intermediate 27

[0289] The intermediate 26 (3.80 g, 11.824 mmol) was added to a flask, and then 24 mL of 4M HCl / 1,4-dioxane was added and stirred at room temperature for 1 h. The dot plate showed that all the raw materials had reacted, and solids were precipitated by rotary evaporation. The filter cake was washed three times with ethyl acetate and dried to obtain the intermediate 27 (2.5 g, yield: 95.55%) as a white solid.

[0290] Step 4: Synthesis of intermediate 29

[0291] The intermediate 27 (200 mg, 0.776 mmol) was added to a flask, and then acetonitrile (3 mL) and triethylamine (235.56 mg, 2.328 mmol) were added. The mixture was stirred at room temperature for 5 min, and 3 mL of acetonitrile solution of the intermediate 18 (166.88 mg, 0.776 mmol) was added. The mixture was reacted at room temperature for 30 min. After the reaction was completed, the solvent was dried, and silica gel was added and the mixture was purified by column (EA / PE=0-50%) to obtain the intermediate 29 (220 mg, yield: 9.77%) as a light yellow solid.

[0292] MS m / z(ESI):356.3[M+H] + .

[0293] Step 5: Synthesis of compound 8

[0294] Intermediate 29 (220 mg, 0.619 mmol) was added to a flask, and MeOH (5 mL) was added to dissolve it. After stirring at 0°C, NaBH4 (209.22 mg, 6.190 mmol) was added, and the mixture was naturally stirred and warmed to room temperature. The reaction was continued for 10 h. LCMS showed that the main peak was the product peak. Water was added to quench the reaction, and the mixture was separated by extraction with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and spun dry. The crude product was dissolved in methanol, purified by preparative liquid phase, and freeze-dried to obtain compound 8 (116.04 mg, yield: 52.45%).

[0295] MS m / z(ESI):358.2[M+H] + .

[0296] 1 H NMR (400MHz, Chloroform-d) δ9.48 (s, 1H), 7.24–7.18 (d, J = 6.00Hz, 4H), 7.15–7.11 (m, J = 8. 00Hz, 1H), 6.98–6.93 (t, J=10.00Hz, 1H), 6.78–6.76 (d, J=4.00Hz, 2H), 6.08 (s, 1H), 5.09–5. 01(d,J=32.00Hz,1H),4.84(s,1H),3.86–3.78(d,J=32.00Hz,1H),3.51–3.47(d,J=16.00Hz, 1H),3.27–3.21(s,J=12.00Hz,2H),3.08(s,1H),2.95(s,3H),2.14–1.83(t,J=31.00Hz,4H).

[0297] Example 9

[0298]

[0299] Compound 8 (100 mg, 0.280 mmol) was added to a flask, and then DMF (2 mL) was added. After stirring until dissolved, NaH (8.06 mg, 0.336 mmol) was added, and stirred at room temperature for 20 min. A DMF (2 mL) solution of methyl chlorophosphate (80.85 mg, 0.56 mmol) was added, and stirring was continued at room temperature for 2 h. After the reaction was completed, LCMS showed that the main peak was the product peak, and water was added to quench, and the dichloromethane was extracted and separated. The organic phase was washed three times with saturated brine, and then spin-dried and column chromatography (MeOH / DCM=0-5%) was performed, and then spin-dried and freeze-dried to obtain compound 9 (30.63 mg, yield: 23.08%).

[0300] 1 H NMR (400MHz, DMSO-d6) δ7.38(d,J=8.3Hz,2H),7.21–7.05(m,5H),6.96–6.88(m,1H),5.11(s,1H),4.86(t,J=4.5Hz,1H),4.64(s,1H),3.79(s,3 H),3.76(s,3H),3.30(s,1H),2.63(d,J=8.2Hz,3H),2.59–2.52(m,2H), 2.31(d,J=10.2Hz,2H),1.94(dd,J=13.1,7.7Hz,2H),1.73–1.60(m,2H).

[0301] Example 10

[0302]

[0303] Step 1: Synthesis of intermediate 31

[0304] The intermediate 30 (2.25 g, 10.00 mmol), potassium trifluorovinyl borate (1.34 g, 10.00 mmol) and potassium carbonate (2.76 g, 20.00 mmol) were added to a flask, and then 20 mL of 1,4-dioxane was added. After dissolution, nitrogen was degassed and the reaction was carried out at 100°C for 3 h. After the reaction was completed by TLC monitoring, 50 mL of water was added to quench the reaction, and ethyl acetate was extracted three times. The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography to obtain the intermediate 31 (1.51 g, yield: 86%).

[0305] MS m / z(ESI):174[M+H] + .

[0306] Step 2: Synthesis of intermediate 33

[0307] Intermediate 31 (200 mg, 1.155 mmol) was dissolved in 2 mL of tetrahydrofuran, and then 2 mL of purified water was added, and finally intermediate 32 (205 mg, 1.155 mmol) was added, and stirred at room temperature for 10 min. TLC monitored that the raw material point disappeared and a new point was generated, and the reaction was terminated, and 10 mL of water was added to quench the reaction, and ethyl acetate was extracted three times. The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography (PE:EA=0-100) to obtain intermediate 33 (80 mg, yield: 27%).

[0308] MS m / z(ESI):271[M+H] + .

[0309] Step 3: Synthesis of intermediate 26

[0310] Intermediate 25 (900 mg, 3.960 mmol), triphenylphosphine (1246.25 mg, 4.751 mmol), intermediate 11 (488.25 mg, 4.355 mmol) and THF 20 mL were added into a flask, DIAD (960.79 mg, 4.751 mmol) was added dropwise at 0°C within 2 min, and then the mixture was moved to room temperature for reaction for 3 h. TLC showed that the reaction was complete, silica gel was added, the sample was mixed and purified by column to obtain intermediate 26 (708.81 mg, yield: 55.70%).

[0311] MS m / z(ESI):322[M+H] + .

[0312] Step 4: Synthesis of intermediate 27

[0313] Add intermediate 26 (1.10 g, 3.423 mmol) to a flask, then add 5 mL of 4 M hydrochloric acid ethyl acetate solution and stir at room temperature for 1 h. TLC monitoring shows that the raw material spot disappears and a new spot is generated. After the reaction solution is concentrated in vacuo, it is washed with sodium bicarbonate aqueous solution and extracted with dichloromethane three times. The organic layers are combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude intermediate 27 (0.80 g, 3.620 mmol).

[0314] MS m / z(ESI):222[M+H] + .

[0315] Step 5: Synthesis of compound 10

[0316] Intermediate 27 (50 mg, 0.226 mmol) was added to a flask, 2 mL of acetonitrile was added to dissolve, triethylamine (69 mg, 0.678 mmol) was added, stirred for 5 min, and intermediate 33 (61 mg, 0.226 mmol) was added, and stirred at room temperature for 30 min. TLC monitoring showed that the raw material point disappeared and a new point was generated. Water was added to quench the reaction, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated, separated on a TLC plate, and freeze-dried to obtain compound 10 (7.62 mg, yield: 8.22%).

[0317] MS m / z(ESI):411[M+H] + .

[0318] 1 H NMR(400MHz,DMSO-d6)δ9.99(s,1H),7.19–7.04(m,5H),6.96–6.89(m,1H),6. 77(d,J=8.0Hz,1H),4.97(t,J=4.2Hz,1H),4.43(t,J=5.4Hz,1H),3.68(dt,J=1 0.7,5.3Hz,1H),3.50–3.45(m,1H),3.06(t,J=5.6Hz,1H),2.84(t,J=7.6Hz,2H ),2.72–2.54(m,4H),2.46–2.12(m,6H),2.05–1.92(m,2H),1.56-1.75(m,2H).

[0319] Embodiment 11

[0320]

[0321] Step 1: Synthesis of intermediate 83

[0322] Intermediate 81 (3 g, 14.0 mmol) and intermediate 82 (2.3 g, 16.1 mmol) were dissolved in 1,4-dioxane (150 mL), tri(o-methylphenyl)phosphine (638 mg, 2.1 mmol), palladium acetate (476 mg, 2.1 mmol) and triethylamine (5.7 g, 56.0 mmol) were added, and the mixture was reacted at 110°C for 12 h. After the reaction, the reaction solution was diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried. The crude product was purified by column chromatography (dichloromethane / methanol = 100 / 1-10 / 1) to obtain intermediate 83 (2.6 g, yield 67%) as a white solid.

[0323] LCMS m / z(ESI):277.05[M+1] + .

[0324] 1 H NMR (400MHz, DMSO-d6) δ11.86(s,1H),9.59(s,1H),7.60(s,1H),7.44(d,J=8.0Hz,1H),7.23(s,1H),7.12(d,J=8.0Hz,1H),3.70(s,3H),2.10(s,3H)

[0325] Step 2: Synthesis of Intermediate 84

[0326] Intermediate 83 (2.6 g, 9.4 mmol) was dissolved in 1,4-dioxane (30 mL), and then 4M HCl (15 mL) was added and reacted at 110°C for 5 h. After the reaction was completed, the reaction solution was spin-dried, diluted with water, and the solid was filtered. The solid was washed with water 3 times and dried to obtain intermediate 84 (950 mg, yield 45%), which was a light yellow solid.

[0327] LCMS m / z(ESI):221.85[M+1] + .

[0328] 1 H NMR (400MHz, DMSO-d6) δ11.69(s,1H),9.27(s,1H),7.76(s,1H),7.50(d,J=8.4Hz,1H),7.06(d,J=8.0Hz,1H),6.44(s,1H).

[0329] Step 3: Synthesis of Intermediate 85

[0330] Intermediate 84 (260 mg, 1.2 mmol) was dissolved in pyridine (10 mL), EDCI (449 mg, 2.4 mmol) and intermediate 27 (363 mg, 1.4 mmol) were added, and the mixture was reacted at 50 ° C for 2 h. After the reaction, the reaction solution was diluted with water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried. The crude product was purified by thin layer chromatography (dichloromethane / methanol = 10 / 1) to obtain intermediate 85 (90 mg, yield 18%) as a white solid.

[0331] Step 4: Synthesis of compound 11

[0332] Intermediate 85 (90 mg, 0.21 mmol) was dissolved in methanol (5 mL), sodium borohydride (16 mg, 0.42 mmol) was added, and the reaction was carried out at room temperature for 5 min. After the reaction was completed, the reaction solution was quenched by adding water, and the crude product was prepared by reverse phase (acetonitrile / water and 0.1% ammonia water = 20%-50%) to obtain compound 11 (35.1 mg, yield 38%).

[0333] LCMS m / z(ESI):427.15[M+1] + .

[0334] 1 H NMR(400MHz,DMSO-d6)δ7.21-7.03(m,4H),6.93(s,3H),4.96(s,1H),4.8 2(s,1H),4.31-4.27(m,1H),3.67-6.63(m,1H),3.50-3.40(m,2H),3.34- 3.29(m,1H),3.22-3.18(m,1H),3.02-2.99(m,1H),2.90-2.83(m,1H),2. 80-2.67(m,2H),2.05-1.86(m,2H),1.82-1.75(m,1H),1.62-1.50(m,1H).

[0335] Example 12

[0336]

[0337] Step 1: Synthesis of intermediate 26

[0338] Intermediate 25 (2000 mg, 8.799 mmol) was added to a three-necked reaction bottle, and intermediate 11 (1085 mg, 9.679 mmol) was added under nitrogen protection, THF (18 mL) and PPh3 (2538.63 mg, 9.679 mmol) were added, and the temperature was lowered to about 0°C under nitrogen protection, and a THF solution (2 mL) of DIAD (2135.08 mg, 10.559 mmol) was added, and the reaction was allowed to react at room temperature overnight. LCMS monitored that the raw material reaction was complete, and water was added to quench the reaction, and EA was added for extraction, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and chromatographed on a silica gel column (EA / PE = 0-10%) to obtain intermediate 26 (2500 mg, yield: 88.41%).

[0339] MS m / z(ESI):266.2[M+H-56] + .

[0340] Step 2: Synthesis of intermediate 27

[0341] Intermediate 26 (2.5 g, 7.779 mmol) was dissolved in DCM (24 mL), TFA (6 mL) was added, and the mixture was stirred at room temperature for 2 h. After concentration, the trifluoroacetate salt of intermediate 27 (2.6 g, yield: 99.68%) was obtained.

[0342] MS m / z(ESI):222.1[M+H] + .

[0343] Step 3: Synthesis of intermediate 38

[0344] The trifluoroacetate of intermediate 27 (2600 mg, 7.754 mmol) was dissolved in DCM (20 mL), TEA (3923.23 mg, 38.771 mmol) was added, ethyl oxalyl chloride (1.302 mL, 11.631 mmol) was added dropwise under ice bath, and the mixture was reacted at room temperature for 1 h. The mixture was diluted with DCM, washed once with water, once with saturated sodium bicarbonate aqueous solution, once with 0.5 M HCl aqueous solution, once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 38 (2490 mg, yield: 99.93%).

[0345] MS m / z(ESI):322.0[M+H] + .

[0346] Step 4: Synthesis of intermediate 39

[0347] Intermediate 38 (2490 mg, 7.749 mmol) was added to a reaction flask, THF (45 mL) and purified water (15 mL) were added, and then lithium hydroxide monohydrate solid (0.98 g, 23.246 mmol) was added, and the reaction was stirred at room temperature for 3 h. The reaction system was decompressed and the solvent was dried, diluted with water, washed once with EA (20 mL), and the aqueous phase was adjusted to pH 1-2 with 1M hydrochloric acid solution. Solids precipitated, extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 39 (1800 mg, yield: 79.21%).

[0348] MS m / z(ESI):294.0[M+H] + .

[0349] Step 5: Synthesis of compound 12

[0350] Add intermediate 39 (200 mg, 1.705 mmol) to a reaction bottle, add DMF (6 mL), stir, add NMI (419.94 mg, 5.115 mmol) and TCFH (717.58 mg, 2.558 mmol), stir for 20-30 min, add intermediate 40 (281.55 mg, 1.875 mmol), stir at room temperature for 2 h. Add purified water (30 mL) to the reaction solution to quench the reaction, then add EA (20 mL*2) to extract, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, spin dry the organic phase to obtain a crude product, and then purify by reverse phase HPLC (H2O / ACN: 5%-70%) to obtain compound 12 (106 mg, yield: 13.88%).

[0351] MS m / z(ESI):426.0[M+H] + .

[0352] 1 H NMR (400MHz, DMSO-d6) δ11.61(s,1H),10.72(s,1H),7.75(d,J=1.9Hz,1H),7.47(dd,J =8.5,2.0Hz,1H),7.24–7.04(m,4H),6.94(tdd,J=6.5,4.7,2.1Hz,1H),5.01(dq,J=5. 2,2.7Hz,1H),3.90(dd,J=12.0,7.6Hz,1H),3.69–3.58(m,2H),3.41(dd,J=12.8,4.2H z,1H),2.98–2.82(m,2H),2.06(td,J=14.8,7.8Hz,2H),1.87(dt,J=14.0,6.0Hz,2H).

[0353] Embodiment 13

[0354]

[0355] Step 1: Synthesis of intermediate 43

[0356] The intermediate 41 (3000 mg, 6.647 mmol) was added to a three-necked flask, 25 mL of THF was added to dissolve, the mixture was cooled to -60 °C under nitrogen protection, 1 M LiHMDS solution in THF (19.942 mL) was added dropwise, and the mixture was kept warm for 30 min. Then, the intermediate 42 (3000 mg, 13.316 mmol) solution in THF (5 mL) was added dropwise, and the mixture was kept warm for 30 min. The mixture was reacted at room temperature overnight. 9 mL of saturated aqueous ammonium chloride solution was added to quench the reaction, water was added, and the mixture was extracted with EA three times. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and chromatographed on a silica gel column (EA / PE = 0-15%) to obtain the intermediate 43 (220 mg, yield: 10.43%).

[0357] MS m / z(ESI):262.2[M+H-56] + .

[0358] Step 2: Synthesis of intermediate 44

[0359] Intermediate 43 (220 mg, 0.693 mmol) was dissolved in methanol (10 mL), 5% palladium carbon (22 mg) was added, the system was replaced with hydrogen three times, and the mixture was stirred at room temperature overnight. After LCMS monitoring showed that the reaction of the raw material was complete and the main peak was the product peak, diatomaceous earth was added for filtration, and the filtrate was concentrated to obtain intermediate 44 (210 mg, yield: 94.85%).

[0360] MS m / z(ESI):264.0[M+H-56] + .

[0361] Step 3: Synthesis of intermediate 45

[0362] Intermediate 44 (220 mg, 0.689 mmol) was dissolved in DCM (8 mL), TFA (2 mL) was added, and the mixture was stirred at room temperature for 2 h. TLC monitored that the raw material was completely reacted, and the mixture was concentrated to obtain the TFA salt of intermediate 45 (229.66 mg, yield: 100%) as a brown oil.

[0363] Step 4: Synthesis of intermediate 46

[0364] Intermediate 45 (141 mg, 0.643 mmol) was dissolved in DCM (6 mL), TEA (650.65 mg, 6.43 mmol) was added, ethyl oxalyl chloride (175.57 mg, 1.286 mmol) was added under stirring, and the mixture was stirred at room temperature for 30 min. LCMS monitored the completion of the reaction, water was added, DCM was extracted, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Intermediate 46 (205.35 mg, yield: 100%) as a white solid.

[0365] MS m / z(ESI):320.0[M+H] + .

[0366] Step 5: Synthesis of intermediate 47

[0367] Intermediate 46 (200 mg, 0.626 mmol) was dissolved in THF (9 mL), and water (3 ml) and lithium hydroxide monohydrate (78.83 mg, 1.879 mmol) were added, and stirred at room temperature for 3 h. LCMS monitored the completion of the reaction, and the reaction solution was concentrated under reduced pressure to remove the solvent, and water was added, and EA was washed once. The aqueous phase was adjusted to pH 1-2 with 1M HCl, and solids precipitated, which were filtered and dried to obtain Intermediate 47 (182.43 mg, yield: 100%).

[0368] MS m / z(ESI):292.0[M+H] + .

[0369] Step 6: Synthesis of compound 13

[0370] Add intermediate 47 (100 mg, 0.343 mmol) to a reaction bottle, add DMF (5 mL), stir, add NMI (33.82 mg, 0.412 mmol) and TCFH (115.58 mg, 0.412 mmol), stir for 20-30 min, then add intermediate 40 (56.69 mg, 0.378 mmol), stir at room temperature for 1 h. Add purified water (10 mL) to the reaction solution to quench the reaction, add EA (20 mL*2) to extract, and the organic phase is spin-dried to obtain a crude product, which is purified by preparative purification (H2O / ACN=5%-70%) to obtain compound 13 (23.64 mg, yield: 15.61%).

[0371] MS m / z(ESI):423.9[M+H] + .

[0372] 1H NMR (400MHz, DMSO-d6) δ11.60(s,1H),10.70(d,J=16.3Hz,1H),7.73(dd,J=9.8,1.9Hz,1H),7.45(dd,J=8.5,2 .0Hz,1H),7.32–7.25(m,1H),7.22(ddd,J=7.2,5.4,2.2Hz,1H),7.15–7.08(m,2H),7.05(dd,J=8.5,5.4Hz,1H ),3.90–3.71(m,1H),3.70–3.55(m,1H),3.51(dd,J=12.8,7.6Hz,1H),3.43(dd,J=12.8,3.7Hz,1H),2.64(dd, J=22.1,7.1Hz,4H),2.15(td,J=11.0,5.5Hz,1H),1.93(ddt,J=20.1,13.6,7.1Hz,2H),1.08(q,J=10.9Hz,2H).

[0373] Embodiment 14

[0374]

[0375] Step 1: Synthesis of intermediate 26

[0376] Intermediate 25 (909.20 mg, 4.00 mmol), intermediate 11 (672.60 mg, 6.00 mmol) and PPh3 (1258.99 mg, 4.80 mmol) were added to a flask, THF (15.00 mL) was added, and the mixture was stirred at 0°C for 10 min. DIAD (1213.26 mg, 6.000 mmol) was then added under nitrogen protection, and the reaction system was moved to room temperature and continued to stir for 3 h. LCMS monitored that the raw material reaction was complete, water (20 mL) was added to quench the reaction, and EA (20 mL*3) was added to extract, the organic phase was dried over anhydrous sodium sulfate, filtered and sprayed with EA three times, the filtrate was combined and spin-dried, and column chromatography (EA / PE=0-10%) was performed to obtain intermediate 26 (1200 mg, yield 88.68%), which was a light yellow oily liquid.

[0377] Step 2: Synthesis of intermediate 27

[0378] 4M HCl / 1,4-dioxane (10 mL) was added to a flask containing intermediate 26 (1200 mg, 3.734 mmol) and stirred at room temperature for 1 h. The plate showed that all the raw materials reacted and the reaction was completed. After spin drying, intermediate 27 (850 mg, yield: 97.74%) was obtained as a white solid.

[0379] Step 3: Synthesis of intermediate 38

[0380] Intermediate 27 (260 mg, 1.009 mmol) was added to a flask, DCM (6 mL) was added to dissolve, TEA (306.23 mg, 3.029 mmol) was added, and the mixture was stirred at room temperature for 10 min. Ethyl oxalyl chloride (206.59 mg, 1.513 mmol) was added, and stirring was continued at room temperature for 1 h. The spot plate monitoring showed that new spots were generated. After adding water (10 mL) to quench, ethyl acetate (15 mL*3) was added for extraction and separation. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filter cake was sprayed with ethyl acetate for three times. The filtrate was spin-dried and subjected to column chromatography (EA / PE=0-15%) to obtain Intermediate 38 (300 mg, yield: 87.92%) as a white solid.

[0381] Step 4: Synthesis of intermediate 39

[0382] Intermediate 38 (280 mg, 0.871 mmol) was added to a flask, THF (4 mL) and water (2 mL) were added, and then LiOH monohydrate (109.68 mg, 2.614 mmol) was added, and the reaction was stirred at room temperature for 2 h. The spot plate monitoring showed that all the raw materials reacted and new spots were generated. THF was removed by rotary evaporation, and 2M dilute hydrochloric acid was slowly added to the remaining aqueous phase to adjust the pH to below 3. A large amount of white solid precipitated, which was filtered and the filter cake was dried to obtain Intermediate 39 (250 mg, yield: 92.94%), which was a white solid.

[0383] Step 5: Synthesis of compound 14

[0384] Intermediate 39 (200 mg, 0.682 mmol), intermediate 48 (113.33 mg, 0.682 mmol), TCFH (287.00 mg, 1.023 mmol) and NMI (111.97 mg, 1.364 mmol) were added to a flask, and DMF (3 mL) was added and stirred at room temperature for 1 h. LCMS showed that the product was generated and all the raw materials reacted, deionized water (10 mL) was added to quench, and then extracted and separated with DCM (10 mL*3), the organic phase was merged and washed three times with saturated brine (20 mL), the organic phase was spin-dried and then subjected to column chromatography (MeOH / DCM=0-6%) to obtain 120 mg of crude product, which was purified by preparative liquid phase to obtain compound 14 (31.93 mg, yield: 10.41%).

[0385] 1H NMR (400MHz, DMSO-d6) δ11.87(s,1H),10.71(s,1H),7.95(d,J=2.1Hz,1H),7.56(m,J=8.7,2.1Hz,1H),7.27–7.05(m,4H),7.00–6.87(m,1H),5.01( s,1H),3.87(m,J=20.00Hz,1H),3.68–3.55(m,2H),3.40(m,J=36.00Hz,1 H),2.89(m,J=22.00Hz,2H),2.12–1.99(m,2H),1.86(dt,J=16.00Hz,2H).

[0386] Embodiment 15

[0387]

[0388] Step 1: Synthesis of intermediate 50

[0389] Intermediate 49 (600 mg, 2.663 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to 0°C in an ice-water bath, and a 1M tetrahydrofuran solution (5.3 mL) of intermediate 42 (5.3 mmol) was added dropwise, and then naturally warmed to room temperature and stirred for 3 h. Saturated ammonium chloride (100 mL) was added to the reaction solution under ice-water cooling, and extracted with ethyl acetate (80 mL*2). The organic phase was washed with water (100 mL) and saturated brine (100 mL) in turn, dried over anhydrous sodium sulfate for 1 hr, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (eluent: PE:EA = 0-20%) to obtain intermediate 50 (520 mg, yield: 60.75%) as a white solid.

[0390] MS m / z(ESI):248[M+1-56-18] + 、344[M+23] + .

[0391] Step 2: Synthesis of Intermediate 51

[0392] Intermediate 50 (400 mg, 1.245 mmol) was dissolved in methanol (10 mL), 5% Pd / C (400 mg) was added, hydrogen was replaced three times, and the mixture was stirred at room temperature for 2 h. The mixture was filtered, concentrated under reduced pressure, and dried in vacuo to obtain Intermediate 51 (380 mg, yield 99.98%) as a colorless oil.

[0393] MS m / z(ESI):250[M-56+1] + .

[0394] Step 3: Synthesis of Intermediate 52

[0395] Intermediate 51 (365 mg, 1.195 mmol) was dissolved in dichloromethane (15 mL), trifluoroacetic acid (3 mL) was added, and stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure and dried in vacuo to obtain the trifluoroacetate salt of Intermediate 52 (382 mg, yield 100.1%) as a white solid.

[0396] MS m / z(ESI):206[M+1] + .

[0397] Step 4: Synthesis of intermediate 54

[0398] Intermediate 52 (381 mg, 1.193 mmol) was dissolved in acetonitrile (5 mL), triethylamine (603 mg, 5.970 mmol) was added, and the mixture was stirred for 5 min, and then intermediate 53 (245 mg, 1.134 mmol) was added, and the mixture was stirred at room temperature for 20 min. 10% sodium dihydrogen phosphate aqueous solution (30 mL) was added to the reaction solution, and then dichloromethane (30 mL*4) was added for extraction, and the organic phase was washed with sodium chloride aqueous solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate 54 (400 mg, yield: 98.48%), which was a viscous solid and was directly used for the next step reaction.

[0399] MS m / z(ESI):341[M+1] + .

[0400] Step 5: Synthesis of compound 15

[0401] Intermediate 54 (400 mg, 1.175 mmol) was dissolved in methanol (10 mL), cooled to 0°C in an ice-water bath, sodium borohydride (238 mg, 7.041 mmol) was added, and stirred for 30 min. LCMS monitored that the raw material reaction was complete, saturated aqueous ammonium chloride solution (20 mL) was added to the reaction solution, and then dichloromethane (30 mL*4) was added for extraction, washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a light yellow solid (360 mg), which was prepared by reverse phase chromatography (preparation system: containing 0.075% trifluoroacetic acid aqueous solution and acetonitrile) to obtain the trifluoroacetate salt of compound 15 (210 mg, yield 39.16%).

[0402] MS m / z(ESI):343[M+1] + .

[0403] 1H NMR (400MHz, Methanol-d4) δ8.13(d,J=2.8Hz,1H),7.55(d,J=8.6Hz,1H),7.40(dd,J=8.6,2.8Hz,1H),7.37–7 .27(m,2H),7.10–6.96(m,2H),5.09(t,J=6.5Hz,1H),4.21–2.63(m,9H),2.48–2.34(m,2H),1.74–1.52(m,2H).

[0404] Example 16

[0405]

[0406] Step 1: Synthesis of intermediate 56

[0407] Intermediate 55 (500 mg, 3.375 mmol) was dissolved in dichloromethane (40 mL), pyridine (320 mg, 4.046 mmol) was added, the mixture was cooled to 0°C in an ice-water bath, ethyl oxalyl chloride (553 mg, 4.050 mmol) was added dropwise, and the mixture was stirred for 1 h. The raw material reaction was complete, 100 mL of ethyl acetate and 40 mL of 1M hydrochloric acid were added to the reaction solution, the mixture was shaken well, the layers were separated, the aqueous phase was extracted with ethyl acetate (100 mL*3), the organic phases were combined, washed with deionized water (150 mL) and saturated brine (150 mL) in turn, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was slurried with ethyl acetate (20 mL) to obtain intermediate 56 (520 mg, yield 62.07%), which was a light yellow solid.

[0408] MS m / z(ESI):249[M+1] + .

[0409] Step 2: Synthesis of intermediate 57

[0410] Intermediate 56 (510 mg, 2.054 mmol) was dissolved in methanol (10 mL), potassium hydroxide (138 mg, 2.459 mmol) was added, and the reaction was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure, and the residue was dissolved in water (30 mL), and the pH was adjusted to 3-4 with 1 M hydrochloric acid. A large amount of solid was precipitated, filtered, and the solid was washed with pure water to obtain Intermediate 57 (440 mg, yield: 97.27%), which was a yellow solid.

[0411] MS m / z(ESI):221[M+1] + .

[0412] Step 3: Synthesis of compound 16

[0413] Intermediate 57 (140 mg, 0.636 mmol) was suspended in DMF (5 mL), cooled to 0°C in an ice-water bath, EDCI (310 mg, 1.617 mmol), HOBt (220 mg, 1.628 mol) and triethylamine (771 mg, 7.619 mmol) were added, stirred for 10 min, and the hydrochloride salt of intermediate 27 (130 mg, 0.504 mmol) was added, and the temperature was naturally raised to room temperature and stirred for 16 h. Water (50 mL) was added to the reaction solution, and then extracted with ethyl acetate (100 mL). The mixture was shaken and separated into layers. The organic layer was washed with 1 M hydrochloric acid (50 mL), water (50 mL), saturated sodium bicarbonate (50 mL), water (50 mL) and saturated brine (50 mL) in sequence, dried over anhydrous sodium sulfate for 1 h, filtered, and concentrated under reduced pressure. The mixture was slurried with ethyl acetate (10 mL) for 2 h, filtered, and the filter cake was washed with ethyl acetate (10 mL). The filter cake was dissolved with methanol (20 mL) and dichloromethane (20 mL), filtered, and water (30 mL) was added. The mixture was concentrated under reduced pressure and the residue was freeze-dried to give compound 16 (78.27 mg, yield: 34.95%).

[0414] MS m / z(ESI):424[M+1] + .

[0415] 1 H NMR (400MHz, DMSO-d6) δ10.51(s,1H),10.34(s,1H),7.61(s,1H),7.48(dd,J=8. 4,2.1Hz,1H),7.29–7.04(m,3H),7.00–6.88(m,1H),6.77(d,J=8.3Hz,1H),5.05– 4.95(m,1H),3.86(dd,J=11.9,7.6Hz,1H),3.72–3.52(m,2H),3.48(s,2H),3.40( dd,J=12.7,4.2Hz,1H),2.98–2.78(m,2H),2.16–1.95(m,2H),1.94–1.78(m,2H).

[0416] Embodiment 17

[0417]

[0418] Step 1: Synthesis of intermediate 59

[0419] Intermediate 58 (300 mg, 1.850 mmol) was dissolved in dichloromethane (20 mL), pyridine (190 mg, 2.402 mmol) was added, the mixture was cooled to 0°C in an ice-water bath, ethyl oxalyl chloride (328 mg, 2.402 mmol) was added dropwise, and the mixture was stirred for 1 h. The raw materials reacted completely, dichloromethane (80 mL) and 1M hydrochloric acid (40 mL) were added to the reaction solution, the mixture was shaken well, the layers were separated, the aqueous phase was extracted with dichloromethane (50 mL*3), the organic phases were combined, washed with water (150 mL) and saturated brine (150 mL) in turn, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was slurried with dichloromethane (20 mL) to obtain intermediate 59 (420 mg, yield: 86.58%).

[0420] MS m / z(ESI):263[M+1] + .

[0421] Step 2: Synthesis of intermediate 60

[0422] Intermediate 59 (420 mg, 1.601 mmol) was suspended in methanol (10 mL), potassium hydroxide (117 mg, 2.085 mmol) was added, and the reaction was stirred at room temperature for 2 h. The raw material reaction was complete, and it was concentrated to dryness under reduced pressure. The residue was dissolved in water (30 mL), and then the pH was adjusted to 3-4 with 1M hydrochloric acid. A large amount of solid was precipitated, filtered, and the filter cake was washed with pure water to obtain Intermediate 60 (340 mg, yield: 90.65%), which was a white solid.

[0423] MS m / z(ESI):235[M+1] + .

[0424] Step 3: Synthesis of compound 17

[0425] Intermediate 60 (152 mg, 0.649 mmol) was suspended in DMF (5 mL), cooled to 0°C in an ice-water bath, EDCI (303 mg, 1.581 mmol), HOBt (214 mg, 1.584 mol) and triethylamine (384 mg, 3.795 mmol) were added, stirred for 10 min, and then the hydrochloride salt of intermediate 27 (140 mg, 0.633 mmol) was added, the temperature was naturally raised to room temperature, and stirred for 16 h. Water (100 mL) was added to the reaction solution to quench the reaction, and then extracted with dichloromethane (100 mL), shaken, and separated. The organic layer was washed with 1M hydrochloric acid (100 mL), water (100 mL), saturated sodium bicarbonate (100 mL), water (100 mL) and saturated brine (100 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was slurried with dichloromethane (10 mL), filtered, and the filter cake was washed with dichloromethane (10 mL), dissolved with methanol (30 mL) and dichloromethane (30 mL), filtered, and then water (30 mL) was added. It was concentrated under reduced pressure and the residue was freeze-dried to give compound 17 (50.35 mg, yield: 17.93%).

[0426] MS m / z(ESI):438[M+1] + .

[0427] 1 H NMR (400MHz, DMSO-d6) δ10.51 (s, 1H), 10.05 (s, 1H), 7.56 (d, J = 2.3Hz, 1H), 7.43 (dd, J=8.4,2.3Hz,1H),7.25–7.04(m,3H),6.99–6.86(m,1H),6.80(d,J=8.5Hz,1H),5.05 –4.95(m,1H),3.86(dd,J=11.9,7.6Hz,1H),3.72–3.49(m,2H),3.40(dd,J=12.9,4.2 Hz,1H),3.04–2.71(m,4H),2.46–2.39(m,2H),2.12–1.96(m,2H),1.96–1.76(m,2H).

[0428] Embodiment 18

[0429]

[0430] Step 1: Synthesis of intermediate 62

[0431] Intermediate 61 (300 mg, 2.306 mmol) was dissolved in THF (10 mL), and intermediate 25 (576.59 mg, 2.537 mmol) and PPh3 (725.84 mg, 2.767 mmol) were added under nitrogen protection, and the temperature was lowered to about 0°C. A THF solution (2 mL) of DIAD (559.58 mg, 2.767 mmol) was added dropwise under nitrogen protection, and the mixture was reacted at room temperature for 3 h. The mixture was quenched with water, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and chromatographed on a silica gel column (EA / PE = 0-10%) to obtain intermediate 62 (1000 mg, purity: 50%, yield: 63.89%).

[0432] MS m / z(ESI):284.0[M+H-56] + .

[0433] Step 2: Synthesis of intermediate 63

[0434] Intermediate 62 (1 g, 2.947 mmol, purity: 50%) was dissolved in DCM (16 mL), TFA (4 mL) was added, and the mixture was stirred at room temperature for 2 h. The reaction solution was concentrated to obtain a crude intermediate 63 (700 mg, purity: 50%, yield: 99.29%).

[0435] Step 3: Synthesis of intermediate 64

[0436] Intermediate 63 (700 mg, purity 50%, 1.463 mmol) was dissolved in DCM (10 mL), TEA (1480.19 mg, 14.628 mmol) was added, ethyl oxalyl chloride (299.57 mg, 2.194 mmol) was slowly added dropwise under ice bath, and stirred at room temperature for 30 min. Water was added to quench, washed with DCM, and the pH of the aqueous phase was adjusted to 1-2. Solids precipitated, filtered and dried after filter cake drying to obtain Intermediate 64 (540 mg, purity: 80%, yield: 87.03%).

[0437] MS m / z(ESI):340.0[M+H] + .

[0438] Step 4: Synthesis of intermediate 65

[0439] Intermediate 64 (540 mg, 1.591 mmol) was dissolved in THF (9 mL), and lithium hydroxide monohydrate (200 mg, 4.77 mmol) and water (3 mL) were added, and stirred at room temperature overnight. LCMS monitored that the raw material reaction was complete, concentrated, and quenched with water, washed once with EA, and the aqueous phase was adjusted to pH 1-2, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Intermediate 65 (400 mg, purity: 95%, yield: 80.76%).

[0440] MS m / z(ESI):312.0[M+H] + .

[0441] Step 5: Synthesis of compound 18

[0442] Intermediate 65 (134 mg, 0.430 mmol) was dissolved in DMF (1 mL), NMI (176.68 mg, 2.152 mmol) and TCFH (181.18 mg, 0.646 mmol) were added, stirred for 5 min, intermediate 48 (78.70 mg, 0.474 mmol) was added, and the mixture was reacted at room temperature for 30 min. Water was added to quench the reaction, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and prepared by reverse phase (ACN: 0.01% TFA aqueous solution = 10%-100%) to obtain compound 18 (13 mg, yield: 6.24%).

[0443] MS m / z(ESI):459.8[M+H] + .

[0444] 1 H NMR (400MHz, DMSO-d6) δ11.87 (s, 1H), 10.71 (s, 1H), 7.96 (d, J = 2.1Hz, 1H), 7. 56(dd,J=8.7,2.2Hz,1H),7.16–7.07(m,2H),7.04–6.94(m,2H),5.06(dt,J=5 .8,3.0Hz,1H),3.88(dd,J=12.0,7.6Hz,1H),3.67–3.57(m,2H),3.45–3.39(m ,1H),2.96–2.84(m,2H),2.13–2.02(m,2H),1.89(m,J=14.7,6.2,4.1Hz,2H).

[0445] Embodiment 19

[0446]

[0447] Synthesis of compound 19

[0448] Intermediate 39 (50 mg, 0.170 mmol) was dissolved in DMF (2 mL), and NMI (41.87 mg, 0.510 mmol) and TCFH (95.40 mg, 0.340 mmol) were added. After stirring at room temperature for 10 min, intermediate 66 (27.97 mg, 0.188 mmol) was added and stirred at room temperature for 1 h. Water was added to quench the reaction, and EA was added to extract, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and prepared by reverse phase (ACN / 0.01% TFA aqueous solution = 10%-80%), and lyophilized to obtain compound 19 (21.85 mg, yield: 29.29%).

[0449] MS m / z(ESI):425.0[M+H] + .

[0450] 1 H NMR (400MHz, DMSO-d6) δ10.63–10.47(m,3H),7.51(d,J=2.0Hz,1H),7.22–7.08(m,4 H),6.93(m,J=6.5,4.7,2.1Hz,1H),6.86(d,J=8.4Hz,1H),5.00(m,J=5.1,2.3Hz,1H ),3.86(dd,J=11.9,7.5Hz,1H),3.66–3.54(m,2H),3.40(dd,J=12.8,4.1Hz,1H),2. 88(m,J=23.0,7.7,4.8Hz,2H),2.11–2.00(m,2H),1.86(m,J=14.7,5.9,3.0Hz,2H).

[0451] Embodiment 20

[0452]

[0453] Step 1: Synthesis of intermediate 69

[0454] Intermediate 67 (0.132 mL, 1.198 mmol), intermediate 68 (212 mg, 0.999 mmol) and sodium tert-butoxide (575.81 mg, 5.992 mmol) were added to a 40 mL flask, 8 mL of xylene was added, nitrogen was introduced under stirring, Davephos (39.30 mg, 0.100 mmol) and Pd (dba) 2 (28.71 mg, 0.050 mmol) were added under nitrogen protection, and the reaction was stopped after 4 h at 135 ° C. LCMS showed that the raw material was completely reacted. After the solvent was dried, water (20 mL) and ethyl acetate (20 mL * 3) were added for extraction. After the organic phase was combined, it was dried over anhydrous sodium sulfate, filtered and dried, and intermediate 69 (190 mg, yield: 62.1%) was obtained by column chromatography as an off-white solid.

[0455] MS m / z(ESI):307[M+H] + ,251[M+H-56] + .

[0456] Step 2: Synthesis of Intermediate 70

[0457] Intermediate 69 (190 mg, 0.620 mmol) was added to DCM (4 mL), TFA (1 mL) was added, and the mixture was stirred at room temperature for 30 min. LCMS detection showed that the raw material was completely reacted, and the mixture was spin-dried to obtain intermediate 70 (412 mg, yield: 322%, the sample contained some trifluoroacetic acid) as a light brown oil, which was directly used in the next step.

[0458] MS m / z(ESI):207[M+H] + .

[0459] Step 3: Synthesis of Intermediate 72

[0460] Intermediate 70 (320 mg, 0.776 mmol) was dissolved in 1 mL of acetonitrile, TEA (0.431 mL, 3.103 mmol) was added, and after stirring, intermediate 71 (134.06 mg, 0.621 mmol) was added in an ice bath, and the mixture was reacted for 30 min in an ice bath. LCMS detection showed that the main peak was the product peak, and 5 mL of 10% NaH2SO4 was added to quench the reaction, and DCM (3 mL*3) was added to extract. The organic phases were combined and dried over anhydrous sodium sulfate, filtered and spin-dried to obtain intermediate 72 (150 mg, 56.64%, crude product), which was a brown oil and was directly used in the next step.

[0461] MS m / z(ESI):342[M+H] + .

[0462] Step 4: Synthesis of compound 20

[0463] Intermediate 72 (150 mg, 0.439 mmol) was dissolved in 5 mL of methanol, and NaBH4 (44.55 mg, 1.318 mmol) was added under ice bath, and the mixture was kept warm for 20 min. LCMS showed that the raw material was completely reacted, and the reaction was stopped. 10 mL of saturated ammonium chloride was added to quench the reaction, and dichloromethane (10 mL*3) was added for extraction. The organic phases were combined and dried over anhydrous sodium sulfate, filtered and spin-dried. The crude product was prepared by reverse phase chromatography (preparation system: containing 0.05% trifluoroacetic acid aqueous solution and acetonitrile) to obtain the trifluoroacetate salt of compound 20 (39.61 mg, yield: 18.74%).

[0464] MS m / z(ESI):344[M+H] + .

[0465] 1 H NMR (400MHz, DMSO-d6) δ10.08(s,1H),9.79(s,1H),8.05(d,J=2.8Hz,1H),7.38(d,J=8.5Hz,1H),7.25(dd,J=8.5,2.8Hz,1 H),7.16–6.99(m,2H),6.88–6.64(m,2H),6.27(s,1H),4.91(dd,J=9.7,3.4Hz,1H),3.78(s,2H),3.11(m,J=19.6Hz,10H).

[0466] Embodiment 21

[0467]

[0468] Step 1: Synthesis of intermediate 26

[0469] Intermediate 11 (3920 mg, 34.969 mmol), intermediate 25 (5300 mg, 23.317 mmol), PPh3 (15300 mg, 58.332 mmol) were dissolved in tetrahydrofuran (180 mL), cooled to 0 ° C, and then DIAD (11800 mg, 58.355 mmol) was slowly added dropwise, and the reaction was stirred at room temperature for 18 h. Water (200 mL) and ethyl acetate (250 mL) were added to the reaction solution, shaken, and allowed to stand for stratification, and then the organic phase was washed with water (200 mL) and brine (200 mL) in turn, dried over anhydrous sodium sulfate for 1 h, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (PE: EA = 0-10%) to obtain intermediate 26 (7000 mg, yield 93.41%), which was a colorless oil.

[0470] MS m / z(ESI):266[M+1-56] + .

[0471] Step 2: Synthesis of intermediate 27

[0472] Intermediate 26 (7000 mg, 21.780 mmol) was dissolved in ethyl acetate (30 mL), and 4 M hydrogen chloride ethyl acetate solution (100 mL) was added. The mixture was stirred at room temperature for 4 h. The reaction solution was concentrated under reduced pressure, and the residue was slurried with ether (50 mL) for 1 h, filtered, and dried in vacuo to obtain Intermediate 27 (5500 mg, yield 97.97%) as a white solid.

[0473] MS m / z(ESI):222[M+1] + .

[0474] Step 3: Synthesis of Intermediate 74

[0475] Dissolve intermediate 27 (100 mg, 0.388 mmol) in MeCN (2 mL), add K2CO3 (161 mg, 1.165 mmol), stir at room temperature for 10 min, then add intermediate 73 (105 mg, 0.580 mmol), and continue stirring at 80°C for 16 h. TLC detection shows that new spots are generated, and the raw materials are basically reacted. Filter, wash the filter cake with ethyl acetate, add water (30 mL) to the filtrate, shake well, wash the organic layer with saturated brine (30 mL) once, dry over anhydrous sodium sulfate for 1 h, filter, and concentrate under reduced pressure to obtain residue 1.

[0476] Dissolve intermediate 27 (300 mg, 1.164 mmol) in MeCN (8 mL), add K2CO3 (482 mg, 3.488 mmol), stir at room temperature for 10 min, then add intermediate 73 (337 mg, 1.862 mmol), and continue stirring at 80°C for 16 h. TLC detection shows that new spots are generated, and the raw materials are basically reacted. Filter, wash the filter cake with ethyl acetate (100 mL), then add water (60 mL) to the filtrate, shake well, wash the organic layer once with saturated brine (60 mL), dry over anhydrous sodium sulfate for 1 h, filter, and concentrate under reduced pressure to obtain residue 2.

[0477] Residue 1 and residue 2 were combined and purified by silica gel column chromatography (PE:EA=0-10%) to obtain intermediate 74 (300 mg, yield 60.2%) as a colorless oil.

[0478] MS m / z(ESI):322[M+1] + .

[0479] Step 4: Synthesis of Intermediate 75

[0480] Intermediate 74 (250 mg, 0.778 mmol) was dissolved in a mixed solvent of methanol (8 mL) and water (8 mL), and potassium hydroxide solid (131 mg, 2.335 mmol) was added. The mixture was heated to 85°C and stirred for 18 h. The reaction solution was concentrated under reduced pressure to remove the organic solvent (the water in it did not need to be completely concentrated). Water (20 mL) was then added to the residue, and the mixture was cooled to 0°C in an ice-water bath. The pH was adjusted to 3-4 with a 1 M aqueous hydrochloric acid solution, and freeze-dried. A mixed solvent of dichloromethane and methanol (10 mL, V 二氯甲烷 / V 甲醇 =20 / 1), stirred for 1 h, filtered, and washed with a mixed solvent of dichloromethane and methanol (30 mL, V 二氯甲烷 / V 甲醇 =20 / 1) to wash the filter cake, and the filtrate was concentrated under reduced pressure to obtain intermediate 75 (260 mg, yield: 108.74%) as a white solid, which was directly used in the next step reaction.

[0481] Step 5: Synthesis of compound 21

[0482] Intermediate 75 (260 mg, 0.846 mmol) was suspended in DMF (20 mL), cooled to 0°C in an ice-water bath, EDCI (406 mg, 2.118 mmol), HOBt (286 mg, 2.116 mol) and triethylamine (513 mg, 5.070 mmol) were added, stirred for 10 min, intermediate 40 (203 mg, 1.352 mmol) was added, the temperature was naturally raised to room temperature, and stirred for 48 h. LCMS detection showed that the target product was generated. Water (100 mL) and ethyl acetate (150 mL) were added to the reaction solution, shaken and separated. The organic layer was washed with saturated sodium bicarbonate (100 mL), water (100 mL), 10% sodium dihydrogen phosphate (100 mL), water (100 mL), and saturated brine (100 mL) in sequence, dried over anhydrous sodium sulfate for 1 h, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA=0-40%) to give compound 21 (100.8 mg, yield 26.70%).

[0483] MS m / z(ESI):440[M+1] + .

[0484] Embodiment 22

[0485]

[0486] Step 1: Synthesis of intermediate 76

[0487] Intermediate 27 (300 mg, 1.164 mmol) was dissolved in dichloromethane (10 mL), triethylamine (240 mg, 2.372 mmol) was added, the mixture was cooled to 0°C in an ice-water bath, and then chloroacetyl chloride (150 mg, 1.328 mmol) was added dropwise, the mixture was naturally warmed to room temperature, and the mixture was stirred for 2 h. 1M aqueous hydrochloric acid solution (30 mL) and dichloromethane (50 mL) were added to the reaction solution, the mixture was shaken, the liquid was separated, the aqueous phase was extracted with dichloromethane (50 mL), the organic phases were combined, the organic phases were washed with water (50 mL) and saturated brine (50 mL) in turn, the organic phases were dried over anhydrous sodium sulfate for 1 h, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (PE:EA=0-20%) to obtain intermediate 76 (300 mg, yield: 86.56%) as a colorless oil.

[0488] Step 2: Synthesis of compound 22

[0489] Intermediate 76 (290 mg, 0.974 mmol), intermediate 40 (234 mg, 1.559 mmol), NaBr (40 mg, 0.389 mmol), KI (130 mg, 0.783 mmol), potassium carbonate (180 mg, 1.302 mmol) were dissolved in DMF (10 mL) and stirred at 80 ° C for 16 h. Water (50 mL) and ethyl acetate (100 mL) were added to the reaction solution, shaken and layered, then washed with saturated brine (50 mL), dried over anhydrous sodium sulfate for 1 h, filtered, and concentrated under reduced pressure to obtain a khaki solid, which was then prepared by reverse phase chromatography (preparation system: containing 0.075% trifluoroacetic acid aqueous solution and acetonitrile to obtain trifluoroacetate of compound 22 (22.3 mg, yield 4.28%).

[0490] MS m / z(ESI):412[M+1] + .

[0491] Embodiment 23

[0492] Step 1: Synthesis of intermediate 78

[0493] Intermediate 77 (250 mg, 1.561 mmol) was dissolved in dichloromethane (20 mL), pyridine (160 mg, 2.023 mmol) was added, the mixture was cooled to 0°C in an ice-water bath, ethyl oxalyl chloride (277 mg, 2.029 mmol) was added dropwise, and the mixture was stirred for 1 h. The raw materials were basically reacted, dichloromethane (80 mL) and 1M aqueous hydrochloric acid solution (40 mL) were added to the reaction solution, the mixture was shaken well, the layers were separated, the aqueous phase was extracted with dichloromethane (50 mL*5), the organic phases were combined, and then washed with saturated brine (50 mL), dried over anhydrous sodium sulfate for 1 h, filtered, and concentrated under reduced pressure. The residue was slurried with dichloromethane (10 mL) to obtain intermediate 78 (370 mg, yield 91.09%), which was an off-white solid.

[0494] Step 2: Synthesis of intermediate 79

[0495] Intermediate 78 (370 mg, 1.422 mmol) was suspended in a mixed solvent of tetrahydrofuran (10 mL) and water (10 mL), potassium hydroxide (100 mg, 1.782 mmol) was added, and the reaction was stirred at room temperature for 2 h. It was extracted once with methyl tert-butyl ether (50 mL), and then the aqueous phase was adjusted to pH 3-4 with 1M hydrochloric acid aqueous solution, a large amount of solid was precipitated, filtered, the filter cake was washed with pure water, and then vacuum dried to obtain intermediate 79 (330 mg, yield 99.97%), which was an off-white solid.

[0496] MS m / z(ESI):233[M+1] + .

[0497] Step 3: Synthesis of compound 23

[0498] Intermediate 79 (150 mg, 0.646 mmol) was suspended in DMF (5 mL), cooled to 0°C in an ice-water bath, EDCI (310 mg, 1.617 mmol), HOBt (218 mg, 1.613 mol) and triethylamine (392 mg, 3.874 mmol) were added, and intermediate 26 (167 mg, 0.648 mmol) was added after stirring for 30 min. The mixture was naturally warmed to room temperature and stirred for 16 h. Water (50 mL) was added to the reaction solution, and then extracted with dichloromethane (100 mL), shaken, separated, and the organic layer was washed with saturated sodium bicarbonate (50 mL), water (50 mL), 1M hydrochloric acid aqueous solution (50 mL), water (50 mL) and saturated brine (50 mL) in sequence, dried over anhydrous sodium sulfate for 1 h, filtered, concentrated under reduced pressure, and then slurried with dichloromethane (10 mL) for 2 h, filtered, and the filter cake was washed with dichloromethane (10 mL), the filter cake was dissolved with methanol (30 mL) and dichloromethane (30 mL), filtered, and then water (30 mL) was added to the filtrate, concentrated under reduced pressure, and freeze-dried to obtain compound 23 (85.54 mg, yield 28.81%).

[0499] MS m / z(ESI):436[M+1] + .

[0500] Embodiment 24

[0501]

[0502] Step 1: Synthesis of Intermediate 80

[0503] Intermediate 40 (300 mg, 1.998 mmol) was dissolved in DCM (10 mL), TEA (606.57 mg, 5.994 mmol) and chloroacetyl chloride (338.48 mg, 2.997 mmol) were added, and the mixture was stirred at room temperature for 10 min. Water (20 mL) was added to quench the reaction, and EA was extracted (10 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and chromatographed on a silica gel column (EA / PE=0-20%) to obtain Intermediate 80 (228 mg, yield 50.35%).

[0504] MS m / z(ESI):227.0[M+H] + .

[0505] Step 2: Synthesis of compound 24

[0506] Intermediate 27 (115.29 mg, 0.447 mmol) was dissolved in acetonitrile (6 mL), TEA (452.63 mg, 4.473 mmol) and intermediate 80 (118.26 mg, 0.521 mmol) were added, and the temperature was raised to 80°C for 2 h. LCMS monitoring showed that the product was generated. The reaction produced impurity solids, and the filtrate was filtered and chromatographed on a silica gel column (EA / PE = 0-50%) to obtain a crude product, which was prepared by reverse phase (ACN / 0.01% TFA aqueous solution = 10%-90%) and lyophilized to obtain compound 24 (6.42 mg, yield: 2.59%).

[0507] MS m / z(ESI):412.0[M+H] + .

[0508] 1 H NMR (400MHz, DMSO-d6) δ11.65(s,1H),10.59(s,1H),10.28(s,1H),7.66(d,J=2.0Hz,1H),7.27–7.06(m,5H), 7.00–6.93(m,1H),5.07(s,1H),4.20(s,2H),3.82(s,1H),3.54(s,1H),2.97(s,3H),2.04(d,J=76.0Hz,4H).

[0509] Test Example 1

[0510] Reagent Information

[0511]

[0512] Instrument Information

[0513]

[0514] Experimental protocol

[0515] Cell culture:

[0516] HEK-293 cells stably expressing NR1 / NR2B (NM_007327, NM_000834) receptors were cultured in a 37°C, 5% CO2 cell culture dish. To maintain electrophysiological activity, the cell density did not exceed 80%. Before the patch clamp assay, the cells were detached with 0.25%-Trypsin-EDTA, plated on coverslips, and cultured in 24-well plates (final volume: 500 μL). NR2B expression was induced by 1 mM D-AP5 and tetracycline together, and the assay was performed 18 hours later under the same conditions. Patch clamp assay:

[0517] After the whole cell seal is formed, the cell membrane voltage is clamped at -70mV, and the cell surface agonist 10μM Glycine and 10μM L-Glutamate mixed working solution is recorded in the Gap-free mode. After the current is stable, 10μM Glycine, 10μM L-Glutamate and different concentrations of the test substance mixed working solution are given from low to high, and finally the agonist working solution and extracellular fluid are eluted to observe the effect of the drug on the steady-state current of NR1 / NR2B receptors. All experiments were performed at room temperature.

[0518] The test results of the compounds of the present invention are shown in the following table:

[0519]

[0520] Among them, "+++" means the inhibition rate is greater than 80.00%;

[0521] “++” indicates an inhibition rate of 50.00%-80.00%;

[0522] “+” indicates an inhibition rate of 10.00%-49.99%;

[0523] “ / ” means not tested.

[0524] The compounds of the present invention are effective in inhibiting NR1 / NR2B receptors.

Claims

1. A derivative containing a fused ring or bridged ring structure of Formula I or Formula II, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the structural formula of Formula I or Formula II is as follows: in, X1 and X2 are independently selected from N or CR1; X5 is independently selected from C(R1)2 or a bond; Ar1 and Ar2 are independently selected from aryl or heteroaryl, which may be further substituted by one or more substituents; L1 is selected from a bond, -O-, -C(O)-, -[C(R 1 )2] n -、-[OC(R 1 )2] n -、-[C(R 1 )2O] n -、-OC(O)-、-C(O)O-、-NR 1 -、-C(O)NR 1 -or-NR 1 C(O)-; L2 is selected from a bond, -O-, -C(O)-, -[C(R 1 )2] n -, -[C(R 1 )2] n -O-, -O-[C(R 1 )2] n -, -[OC(R 1 )2] n -, -[C(R 1 )2O] n -, -OC(O)-, -C(O)O-, -C(O)NR 1 -, -NR 1 C(O)-, -C(O)C(O)NR 1 -, -OC(O)C(O)NR 1 -, -NR 1 C(O)C(O)-, -C(O)C(O)O-, -C(O)[C(R 1 )2] n C(O)-、-OC(O)C(O)-、-[C(R 1 )2] n C(O)NR 1 -、-C(O)NR 1 [C(R 1 )2] n -、-NR 1 C(O)[C(R 1 )2] n -、-[C(R 1 )2] n C(O)O-、-C(O)O[C(R 1 )2] n -、-OC(O)[C(R 1 )2] n -、-C(O)[C(R 1 )2] n NR 1 -、-NR 1 [C(R 1 )2] n C(O)-、-C(O)[C(R 1 )2] n -、-[C(R 1 )2] n C(O)-, -[C(R 1 )2] n S(O)-、-C(O)NR 1 C(O)-, cycloalkylene, heterocyclylene, arylene or heteroarylene m is 0 or 1; n is 1, 2, 3, 4 or 5; R1 is each independently selected from hydrogen, halogen, nitro, hydroxyl, thiol, cyano, amino, phosphate, phosphoryl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclyl, aryl or heteroaryl, which may be further substituted by one or more substituents; R 1 Each is independently selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, phosphate, phosphoryl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclic, aryl or heteroaryl, which may be further substituted by one or more substituents.

2. The derivative containing a fused ring or bridged ring structure according to claim 1, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, in, Ar1 is Preferably, Ar1 is Among them, R 2 Each is independently selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, phosphate, phosphoryl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclic, aryl or heteroaryl, which may be further substituted by one or more substituents.

3. The derivative containing a fused ring or bridged ring structure according to claim 2, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, in, Ar1 is 4. The derivative containing a fused ring or bridged ring structure according to claim 1, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, in, L1 is selected from a bond, -O-, -C(O)-, -NR 1 -or-[C(R 1 )2] n -.

5. The derivative containing a fused ring or bridged ring structure according to claim 1, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, L2 is selected from -[C(R 1 )2] n -、-[C(R 1 )2] n -O-, -C(O)C(O)NR 1 -、-OC(O)C(O)NR 1 -、-C(O)C(O)O-、-[C(R 1 )2] n C(O)NR 1 -、-[C(R 1 )2] n C(O)O-、-C(O)O[C(R 1 )2] n -、-C(O)[C(R 1 )2] n NR 1 -、-C(O)NR 1 [C(R 1 )2] n -、-C(O)[C(R 1 )2] n -、-[C(R 1 )2] n C(O)-, -[C(R 1 )2] n S(O)-、-C(O)NR 1 C(O)-, 3-20-membered cycloalkylene, 3-20-membered heterocyclylene, 6-20-membered arylene or 5-20-membered heteroarylene; the 6-20-membered arylene or 5-20-membered heteroarylene may be further substituted with one or more substituents; Preferably, L2 is selected from -[C(R 1 )2]-[C(R 1 )(OH)]-、-[C(R 1 )2]-[C(R 1 )(OH)]-[C(R 1 )2]-O-, -C(O)C(O)NR 1 -、-OC(O)C(O)NR 1 -、-C(O)C(O)O-、-[C(R 1 )2]C(O)NR 1 -、-[C(R 1 )2]C(O)O-、-C(O)O[C(R 1 )2]-、-C(O)[C(R 1 )2]NR 1 -、-C(O)NR 1 [C(R 1 )2]-、-C(O)[C(R 1 )OH][C(R 1 )2]-、-[C(R 1 )2]C(O)-、-[C(R 1 )2][C(R 1 )2]C(O)-、-[C(R 1 )2][C(R 1 )2]S(O)-、-C(O)NR 1 C(O)-, 3-10 membered cycloalkylene, 3-10 membered heterocyclylene, 6-10 membered arylene or 5-10 membered heteroarylene; the 6-10 membered arylene or 5-10 membered heteroarylene may be further substituted with one or more substituents; in, R 1 are independently selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, C1-10 acyl, C1-10 acylamino, C1-10 ester, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; The hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, C1-10 acyl, C1-10 acylamino, C1-10 ester, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl can be further selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, C1-10 acyl, C1-10 acylamino, C1-10 ester, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl. The present invention is substituted with one or more substituents selected from halogen, nitro, hydroxy, mercapto, cyano, amino, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, C1-10 acyl, C1-10 acylamino, C1-10 ester, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl groups.

6. The derivative containing a fused ring or bridged ring structure according to claim 5, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, in, L2 is 7. The derivative containing a fused ring or bridged ring structure according to claim 1, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, in, In Formula I for In formula II for R1 is independently selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, C1-10 acyl, C1-10 acylamino, C1-10 ester, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; The hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, C1-10 acyl, C1-10 acylamino, C1-10 ester, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl can be further selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, C1-10 acyl, C1-10 acylamino, C1-10 ester, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl. substituted with one or more substituents selected from halogen, nitro, hydroxy, mercapto, cyano, amino, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, C1-10 acyl, C1-10 acylamino, C1-10 ester, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; Preferably, in Formula I for 8. The derivative containing a fused ring or bridged ring structure according to claim 1, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, in, Ar2 is a 6- to 20-membered aryl group or a 5- to 20-membered heteroaryl group, which may be further substituted by one or more substituents.

9. The derivative containing a fused ring or bridged ring structure according to claim 8, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, in, Ar2 is Wherein, X3 and X4 are independently selected from C(R 4 )2. NR 4 , O or S; Among them, R 4 Each is independently selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, phosphate, phosphoryl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclic, aryl or heteroaryl, which may be further substituted by one or more substituents.

10. The derivative containing a fused ring or bridged ring structure according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, in, The formula I or formula I-1 is: in, L1 is defined the same as L1 in Formula I or Formula I-1; L2 is defined the same as L2 in Formula I or Formula I-1; X 11 , X 12 The definitions of are the same as X1, X 11 , X 12 The chirality of is defined the same as that of X1; R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 110 The definitions of are the same as R1; R 21 , R 22 , R 23 , R 24 , R 25 The definitions are respectively the same as R 2 same; R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 The definitions are respectively the same as R 4 same.

11. The derivative containing a fused ring or bridged ring structure according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, in, The formula I is: in, R 11 , R 12 The definitions are respectively the same as R 1 same; L2 definition is the same as above; R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 110 The definitions of are the same as R1; R 22 , R 23 , R 24 , R 25 The definitions are respectively the same as R 2 same; R 41 , R 46 , R 47 , R 48 The definitions are respectively the same as R 4 same.

12. The derivative containing a fused ring or bridged ring structure according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, in, The formula I is: in, The definitions of L1 and L2 are the same as above; R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 110 The definitions of are the same as R1; R 21 , R 22 , R 23 , R 24 , R 25 The definitions are respectively the same as R 2 same; R 41 , R 46 , R 47 , R 48 The definitions are respectively the same as R 4 same.

13. The derivative containing a fused ring or bridged ring structure according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, in, The formula I is: in, The definitions of L1 and L2 are the same as above; R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 110 The definitions of are the same as R1; R 22 , R 23 , R 24 , R 25 The definitions are respectively the same as R 2 same; R 41 , R 46 , R 47 , R 48 The definitions are respectively the same as R 4 same.

14. The derivative containing a fused ring or bridged ring structure according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, in, The formula I is:

15. A pharmaceutical composition comprising the derivative containing a fused ring or bridged ring structure according to any one of claims 1 to 14 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof.

16. Use of the derivative containing a fused ring or bridged ring structure as described in any one of claims 1 to 14 or its pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer, or the composition as described in claim 15, which is used as a negative regulator of NR1 / NR2B receptors, or for preparing a drug that negatively regulates NR1 / NR2B receptors; or, it is used to prepare a drug for treating diseases mediated by NR1 / NR2B receptors.

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