Derivative of tricyclic structure, preparation method therefor, and use thereof

Abstract

The present invention relates to a derivative of a tricyclic structure, a preparation method therefor, and use thereof. The derivative of the tricyclic structure can be used as a sodium channel inhibitor, or be used for treating neuropsychiatric diseases such as epilepsy, Parkinson's disease, schizophrenia, or depression.

Description

Derivatives of fused tricyclic structures, their preparation methods and applications Technical Field

[0001] This invention belongs to the field of pharmaceuticals, specifically relating to derivatives with fused tricyclic structures, their preparation methods, and applications. Background Technology

[0002] Epilepsy is a common disorder caused by abnormal or excessive electrical activity (discharge) in the brain, characterized by recurrent seizures over a period of time. Patients with epilepsy have an increased risk of death compared to the general population. The pathophysiology of most forms of epilepsy is not well understood, but it is known that epileptic seizures are caused by the oversynchronization and sustained firing of a group of neurons. This sustained increase in neuronal excitability is common to all epilepsy syndromes. Treatment strategies for epilepsy involve reducing neuronal excitability through various mechanisms and pathways.

[0003] Sodium ions (Na) + The channel primarily opens transiently and deactivates rapidly, thereby generating rapid Na+. + The current initiates the action potential. Delayed or sustained sodium current (INaL) is a rapid Na+ release in cardiomyocytes and neurons. + The persistent component of electrical current. Many common neurological and cardiac symptoms are associated with abnormal INaL enhancement, which contributes to the pathogenesis of electrical and contractile dysfunction in mammals. Prior art WO2023049364A1, WO2023049369A2, WO2023049367A1, etc., disclose pyridine derivatives as voltage-gated sodium channel modulators for the treatment of epileptic seizures such as epilepsy.

[0004] A team led by Yan Ning from Tsinghua University / Shenzhen Academy of Medical Sciences published a review article titled "A structural atlas of druggable sites on Nav channels" online in Channels, describing nine subtypes of the human Navα subunit, namely Nav1.1-Nav1.9. Among them, Nav1.1-Nav1.3 and Nav1.6 are mainly expressed in the central nervous system, Nav1.4 and Nav1.5 are found in skeletal muscle and cardiac muscle, respectively, and Nav1.7-Nav1.9 mainly act on the peripheral nervous system.

[0005] The prior art WO2011014462A1 discloses a compound that has a strong inhibitory effect on Nav1.5, but it can cause significant cardiotoxicity and poor safety. The present invention aims to avoid the above-mentioned defects and further optimize or replace it. Developing a regulator that targets voltage-gated sodium channels is of great significance. Summary of the Invention

[0006] The tricyclic derivatives of this invention can be compounds of Formula I or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or stereoisomers thereof, wherein the structural formula of Formula I is as follows:

[0007] in,

[0008] X is independently selected from N or CR a ;

[0009] R1, R2, R a Each group is independently selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, cycloalkyl, heterocyclic, aryl, or heteroaryl, and optionally, may be further substituted by one or more substituents.

[0010] In some implementations, R1, R2, R a Each is independently selected from hydrogen, halogen, and C. 1-15 Alkyl, C 1-15 Haloalkyl, C 1-15 Alkoxy, C 1-15 Halogenated alkoxy groups, C 1-15 Alkylthio, C 1-15 The haloalkylthio, 3-10 membered cycloalkyl, 3-10 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, optionally, may be further substituted by one or more substituents;

[0011] In some implementations, R1, R2, R a Each is independently selected from hydrogen, halogen, and C. 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkoxy groups, C 1-10 Alkylthio, C 1-10 The haloalkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, optionally, may be further substituted by one or more substituents;

[0012] R0 is independently selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, cycloalkyl, heterocyclic, aryl or heteroaryl, and optionally may be further substituted by one or more substituents.

[0013] In some embodiments, R0 is selected from hydrogen, halogen, C 1-15Alkyl, C 1-15 Haloalkyl, C 1-15 Alkoxy, C 1-15 Halogenated alkoxy groups, C 1-15 Alkylthio, C 1-15 The haloalkylthio, 3-10 membered cycloalkyl, 3-10 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, optionally, may be further substituted by one or more substituents;

[0014] In some embodiments, R0 is selected from hydrogen, halogen, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkoxy groups, C 1-10 Alkylthio, C 1-10 The haloalkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, optionally, may be further substituted by one or more substituents;

[0015] In some embodiments, R0 is selected from hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, -CHF-OR b -OR b -SR b -N(R) b (R) c ), -N(R b )-C(O)-R c -CF2-R b -CF2-C(O)-OR b -CF2-C(O)-N(R) b )-S(=O)2-R c -CF2-tetrazolyl, -C(O)-N(R) b )-S(=O)2-R c -N(R) b )-C(O)-N(R b (R) c -C(O)-R b -C(O)-OR b -C(O)-N(R) b (R) c ), and -N(R b )-S(=O)2-R c -R b -, -S-CF3, -S-CHF2, -CHF-SR b , cycloalkyl, heterocyclic, aryl or heteroaryl, optionally, may be further substituted by one or more substituents;

[0016] R b R c The group is independently selected from the group consisting of hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, alkenyl, alkynyl, acylamino, ester, cycloalkyl, heterocyclic, aryl, or heteroaryl groups, and may be further substituted by one or more substituents selected from the group consisting of hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, cycloalkyl, heterocyclic, aryl, or heteroaryl groups;

[0017] In some implementations, R0 is selected from C 1-15 Alkyl, C 1-15 Haloalkyl, C 1-15 Alkoxy, C 1-15 Halogenated alkoxy groups, C 1-15 Alkylthio, C 1-15 Haloalkylthio groups, -C(O)-OR b -C(O)-N(R) b (R) c ), -N(R b )-S(=O)2-R c , 3-10 membered cycloalkyl, 3-10 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, optionally, may be further substituted by one or more substituents;

[0018] In some embodiments, R0 is selected from hydrogen, -F, -C(CH3)3, -CF3, -CF2OCH2CH3, -CHF2, -O-CF3, -OC(CH3)3, -C(CH2)2OH, -S(=O)2CH2CH3,

[0019] R d R e R f The group is independently selected from the group consisting of hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, alkenyl, alkynyl, acylamino, ester, cycloalkyl, heterocyclic, aryl, or heteroaryl groups, and may be further substituted by one or more substituents selected from the group consisting of hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, cycloalkyl, heterocyclic, aryl, or heteroaryl groups;

[0020] Ring A is independently selected from cycloalkyl, heterocyclic, aryl, or heteroaryl groups; the cycloalkyl, heterocyclic, aryl, or heteroaryl groups may be further substituted with R;

[0021] R is independently selected from the absence of, hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, and optionally, it may be further substituted by one or more substituents;

[0022] Optionally, the Rs in Formula I can be arbitrarily linked to each other to form a ring, and the ring can be further substituted by substituents; the ring can be independently selected from cycloalkyl, heterocyclic, aryl or heteroaryl, and is a fused ring, bridged ring or spiro ring; optionally, it can be further substituted by one or more substituents;

[0023] Optionally, R and R1 in Formula I can be arbitrarily connected to form a ring, and optionally, it can be further substituted by one or more substituents;

[0024] In some embodiments, R is independently selected from hydrogen, halogen, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkoxy groups, C 1-10 Alkylthio, C 1-10 The haloalkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, optionally, may be further substituted by one or more substituents;

[0025] In some embodiments, R is independently selected from the absence of, hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, and C. 1-4 Alkyl, C 1-3 Alkylthio, C 1-3 Alkoxy, C2-4 alkenyl, C2-4 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl, optionally, may be further substituted by one or more substituents;

[0026] In some embodiments, R is independently selected from absent, hydrogen, -F, methyl, -O-CF3, -OC(CH2)2CF3, -O-CH(CH2)CF3 or -O-CH2CF3;

[0027] In some implementations, R is independently selected from -SF5, -O-CF3, -O-CHF2, -C(O)-OR g -OR g -SR g-Si(CH3)3-O-CF3, -C(O)-R g -C(O)OH, -N(R) g (R) h ), -C(O)-N(R) g (R) h ), -N(R g )-C(O)-R h -N(R) g )-S(=O)2-R h -S(=O)2-R g -S(=O)2-N(R) g (R) h -NR g -C(O)-NR h ;

[0028] In some embodiments, R is independently selected from the absence of, hydrogen, -F, methyl, -CF3, -OCF3, -OCH2CF3,

[0029] n is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;

[0030] In some implementations, n is 1, 2, 3, 4, 5, or 6;

[0031] In some implementations, n is 1;

[0032] In some implementations, n is 2;

[0033] In some implementations, n is 3;

[0034] In some implementations, n is 4;

[0035] In some implementations, n is 5;

[0036] In some implementations, n is 6;

[0037] In some embodiments, ring A is selected from benzene rings;

[0038] In some embodiments, ring A is selected from imidazole rings;

[0039] In some embodiments, ring A is selected from a benzimidazole ring;

[0040] In some embodiments, ring A is selected from pyridine rings;

[0041] In some implementations, R aIt is independently selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, cycloalkyl, heterocyclic, aryl or heteroaryl, and optionally, it may be further substituted by one or more substituents.

[0042] In some implementations, R a Independently selected from hydrogen, halogen, C 1-15 Alkyl, C 1-15 Haloalkyl, C 1-15 Alkoxy, C 1-15 Halogenated alkoxy groups, C 1-15 Alkylthio, C 1-15 The haloalkylthio, 3-10 membered cycloalkyl, 3-10 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, optionally, may be further substituted by one or more substituents;

[0043] In some implementations, R a Each is independently selected from hydrogen, halogen, and C. 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkoxy groups, C 1-10 Alkylthio, C 1-10 The haloalkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, optionally, may be further substituted by one or more substituents;

[0044] In some embodiments, R2 is independently selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, cycloalkyl, heterocyclic, aryl, or heteroaryl, and optionally, it may be further substituted by one or more substituents.

[0045] In some embodiments, R2 is independently selected from hydrogen, halogen, C 1-15 Alkyl, C 1-15 Haloalkyl, C 1-15 Alkoxy, C 1-15 Halogenated alkoxy groups, C 1-15 Alkylthio, C 1-15 The haloalkylthio, 3-10 membered cycloalkyl, 3-10 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, optionally, may be further substituted by one or more substituents;

[0046] In some embodiments, R2 is independently selected from hydrogen, halogen, C, etc. 1-10 Alkyl, C1-10 Haloalkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkoxy groups, C 1-10 Alkylthio, C 1-10 The haloalkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, optionally, may be further substituted by one or more substituents;

[0047] In some embodiments, the hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be further substituted with one or more substituents selected from the hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, cycloalkyl, heterocyclic, aryl, or heteroaryl group;

[0048] This invention also provides a tricyclic derivative, which may be a compound of formula II-1, II-2, II-3, II-4, II-5 or II-6, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the structural formulas of formula II-1, II-2, II-3, II-4, II-5 or II-6 are as follows:

[0049] The definitions of X, R0, R1, and R2 are as described above;

[0050] R3, R4, R5, R6, R7, R8, and R9 are each independently selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, cycloalkyl, heterocyclic, aryl, or heteroaryl, and optionally, they may be further substituted by one or more substituents.

[0051] R 10 It is independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, cycloalkyl, heterocyclic, aryl or heteroaryl, and optionally may be further substituted by one or more substituents.

[0052] Optionally, R3, R4, R5, R6, and R7 in Formula II-1 can be arbitrarily linked together to form a ring, and the ring can be further substituted by substituents; the ring can be independently selected from cycloalkyl, heterocyclic, aryl, or heteroaryl, and is a fused ring, bridged ring, or spirocyclic ring; optionally, it can be further substituted by one or more substituents.

[0053] Optionally, R3, R4, R5, and R6 in Formula II-2 can be arbitrarily linked together to form a ring, and the ring can be further substituted by substituents; the ring can be independently selected from cycloalkyl, heterocyclic, aryl, or heteroaryl, and is a fused ring, bridged ring, or spirocyclic ring; optionally, it can be further substituted by one or more substituents.

[0054] Optionally, R3, R4, R6, and R7 in Formula II-3 can be arbitrarily linked together to form a ring, and the ring can be further substituted by substituents; the ring can be independently selected from cycloalkyl, heterocyclic, aryl, or heteroaryl, and is a fused ring, bridged ring, or spirocyclic ring; optionally, it can be further substituted by one or more substituents.

[0055] Optionally, R3, R5, R6, and R7 in Formula II-4 can be arbitrarily linked together to form a ring, and the ring can be further substituted by substituents; the ring can be independently selected from cycloalkyl, heterocyclic, aryl, or heteroaryl, and is a fused ring, bridged ring, or spirocyclic ring; optionally, it can be further substituted by one or more substituents.

[0056] Optionally, R4, R5, R6, and R7 in Formula II-5 can be arbitrarily linked together to form a ring, and the ring can be further substituted by substituents; the ring can be independently selected from cycloalkyl, heterocyclic, aryl, or heteroaryl, and is a fused ring, bridged ring, or spirocyclic ring; optionally, it can be further substituted by one or more substituents.

[0057] Optionally, R8, R9, and R in Equation II-6 10 They can be arbitrarily linked together to form rings, and can be further substituted by substituents after ring formation; the ring formation can be independently selected from cycloalkyl, heterocyclic, aryl or heteroaryl, and is a fused ring, bridged ring or spirocyclic ring; optionally, it can be further substituted by one or more substituents;

[0058] Optionally, the R6 and R7 substituents in Formula II-1, Formula II-3, Formula II-4 or Formula II-5 can be linked to form a ring, and optionally, they can be further substituted by one or more substituents.

[0059] Optionally, the R5 and R6 substituents in Formula II-1, Formula II-2, Formula II-4 or Formula II-5 can be linked to form a ring, and optionally, they can be further substituted by one or more substituents.

[0060] Optionally, the R1 and R7 substituents in Formula II-1, Formula II-3, Formula II-4 or Formula II-5 can be linked into a ring, and optionally, they can be further substituted by one or more substituents.

[0061] Optionally, the R8 and R9 substituents in Formula II-6 can be linked to form a ring, and optionally, they can be further substituted by one or more substituents;

[0062] Optionally, R1 and R in Equation II-6 10 The substituents can be linked into a ring, and optionally, they can be further substituted by one or more substituents;

[0063] In some embodiments, R3, R4, R5, R6, R7, R8, and R9 are each independently selected from hydrogen, halogen, and C. 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkoxy groups, C 1-10 Alkylthio, C 1-10 The haloalkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, optionally, may be further substituted by one or more substituents;

[0064] In some embodiments, R3, R4, R5, R6, R7, R8, and R9 are each independently selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, and C. 1-4 Alkyl, C 1-3 Alkylthio, C 1-3 Alkoxy, C 2-4 alkenyl, C 2-4 The alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, optionally, may be further substituted by one or more substituents;

[0065] In some embodiments, R3, R4, R5, R6, R7, R8, and R9 are each independently selected from hydrogen, -F, methyl, -O-CF3, -OC(CH2)2CF3, -O-CH(CH2)CF3, or -O-CH2CF3;

[0066] In some implementations, R3, R4, R5, R6, R7, R8, and R9 are independently selected from -SF5, -O-CF3, -O-CHF2, and -C(O)-OR, respectively. g -OR g -SR g -Si(CH3)3-O-CF3, -C(O)-R g -C(O)OH, -N(R) g (R)h ), -C(O)-N(R) g (R) h ), -N(R g )-C(O)-R h -N(R) g )-S(=O)2-R h -S(=O)2-R g -S(=O)2-N(R) g (R) h -NR g -C(O)-NR h ;

[0067] R g R h Each group is independently selected from hydrogen, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups, and may be further substituted by one or more substituents selected from hydrogen, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, cycloalkyl, heterocyclic, aryl, or heteroaryl groups;

[0068] In some embodiments, R3, R4, R5, R6, R7, R8, and R9 are each independently selected from hydrogen, -F, methyl, -CF3, -OCF3, -OCH2CF3, ...

[0069] In some embodiments, R3 is independently selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, cycloalkyl, heterocyclic, aryl, or heteroaryl, and optionally, it may be further substituted by one or more substituents.

[0070] In some embodiments, R3 is independently selected from hydrogen, halogen, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkoxy groups, C 1-10 Alkylthio, C 1-10 The haloalkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, optionally, may be further substituted by one or more substituents;

[0071] In some embodiments, R3 is independently selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, C1-4 alkyl, C2-4 alkyl, C3-4 alkyl, C4-4 alkyl, C3 ... 1-3 Alkylthio, C 1-3 Alkoxy, C 2-4 alkenyl, C 2-4 The alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, optionally, may be further substituted by one or more substituents;

[0072] In some embodiments, R3 is independently selected from hydrogen, -F, methyl, -O-CF3, -OC(CH2)2CF3, -O-CH(CH2)CF3 or -O-CH2CF3;

[0073] In some implementations, R3 is independently selected from -SF5, -O-CF3, -O-CHF2, and -C(O)-OR. g -OR g -SR g -Si(CH3)3-O-CF3, -C(O)-R g -C(O)OH, -N(R) g (R) h ), -C(O)-N(R) g (R) h ), -N(R g )-C(O)-R h -N(R) g )-S(=O)2-R h -S(=O)2-R g -S(=O)2-N(R) g (R) h -NR g -C(O)-NR h ;

[0074] In some embodiments, R4 is independently selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, cycloalkyl, heterocyclic, aryl, or heteroaryl, and optionally, it may be further substituted by one or more substituents.

[0075] In some embodiments, R4 is independently selected from hydrogen, halogen, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkoxy groups, C 1-10 Alkylthio, C 1-10The haloalkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, optionally, may be further substituted by one or more substituents;

[0076] In some embodiments, R4 is independently selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, C 1-4 Alkyl, C 1-3 Alkylthio, C 1-3 Alkoxy, C 2-4 alkenyl, C 2-4 The alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, optionally, may be further substituted by one or more substituents;

[0077] In some embodiments, R4 is independently selected from hydrogen, -F, methyl, -O-CF3, -OC(CH2)2CF3, -O-CH(CH2)CF3 or -O-CH2CF3;

[0078] In some implementations, R4 is independently selected from -SF5, -O-CF3, -O-CHF2, and -C(O)-OR. g -OR g -SR g -Si(CH3)3-O-CF3, -C(O)-R g -C(O)OH, -N(R) g (R) h ), -C(O)-N(R) g (R) h ), -N(R g )-C(O)-R h -N(R) g )-S(=O)2-R h -S(=O)2-R g -S(=O)2-N(R) g (R) h -NR g -C(O)-NR h ;

[0079] In some embodiments, R5 is independently selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, cycloalkyl, heterocyclic, aryl, or heteroaryl, and optionally, it may be further substituted by one or more substituents.

[0080] In some embodiments, R5 is independently selected from hydrogen, halogen, C 1-10 Alkyl, C1-10 Haloalkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkoxy groups, C 1-10 Alkylthio, C 1-10 The haloalkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, optionally, may be further substituted by one or more substituents;

[0081] In some embodiments, R5 is independently selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, C 1-4 Alkyl, C 1-3 Alkylthio, C 1-3 Alkoxy, C 2-4 alkenyl, C 2-4 The alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, optionally, may be further substituted by one or more substituents;

[0082] In some embodiments, R5 is independently selected from hydrogen, -F, methyl, -O-CF3, -OC(CH2)2CF3, -O-CH(CH2)CF3 or -O-CH2CF3;

[0083] In some implementations, R5 is independently selected from -SF5, -O-CF3, -O-CHF2, and -C(O)-OR. g -OR g -SR g -Si(CH3)3-O-CF3, -C(O)-R g -C(O)OH, -N(R) g (R) h ), -C(O)-N(R) g (R) h ), -N(R g )-C(O)-R h -N(R) g )-S(=O)2-R h -S(=O)2-R g -S(=O)2-N(R) g (R) h -NR g -C(O)-NR h ;

[0084] In some embodiments, R6 is independently selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, cycloalkyl, heterocyclic, aryl, or heteroaryl, and optionally, it may be further substituted by one or more substituents.

[0085] In some embodiments, R6 is independently selected from hydrogen, halogen, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkoxy groups, C 1-10 Alkylthio, C 1-10 The haloalkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, optionally, may be further substituted by one or more substituents;

[0086] In some embodiments, R6 is independently selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, C 1-4 Alkyl, C 1-3 Alkylthio, C 1-3 Alkoxy, C 2-4 alkenyl, C 2-4 The alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, optionally, may be further substituted by one or more substituents;

[0087] In some embodiments, R6 is independently selected from hydrogen, -F, methyl, -O-CF3, -OC(CH2)2CF3, -O-CH(CH2)CF3 or -O-CH2CF3;

[0088] In some implementations, R6 is independently selected from -SF5, -O-CF3, -O-CHF2, and -C(O)-OR. g -OR g -SR g -Si(CH3)3-O-CF3, -C(O)-R g -C(O)OH, -N(R) g (R) h ), -C(O)-N(R) g (R) h ), -N(R g )-C(O)-R h -N(R) g )-S(=O)2-R h -S(=O)2-R g -S(=O)2-N(R) g(R) h -NR g -C(O)-NR h ;

[0089] This invention also provides a tricyclic derivative that can be a compound of formula III-1, III-2, III-3, III-4, III-5, or III-6, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or a compound or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer, wherein the structural formulas of formula III-1, III-2, III-3, III-4, III-5, or III-6 are as follows:

[0090] The definitions of X, R0, R2, R3, R4, R5, R6, R8, and R9 are as described above;

[0091] Selected from single or double bonds;

[0092] R 11 The group is independently selected from hydrogen, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl groups, and may be further substituted by one or more substituents selected from hydrogen, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, cycloalkyl, heterocyclic, aryl or heteroaryl groups;

[0093] Optionally, R6, R in Formula III-1, Formula III-3, Formula III-4 or Formula III-5 11 The substituents can be linked into a ring, and optionally, they can be further substituted by one or more substituents;

[0094] Optionally, R9 and R in Equation III-6 11 The substituents can be linked into a ring, and optionally, they can be further substituted by one or more substituents;

[0095] k is selected from 0, 1, 2, 3, 4;

[0096] In some implementations, k is 0;

[0097] In some implementations, k is 1;

[0098] In some implementations, k is 2;

[0099] In some implementations, k is 3;

[0100] In some implementations, k is 4;

[0101] In some implementations, R 11 Independently selected from non-existent, hydrogen, halogen, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkoxy groups, C 1-10 Alkylthio, C 1-10 The haloalkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, optionally, may be further substituted by one or more substituents;

[0102] In some implementations, R 11 Independently selected from non-existent, hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, C 1-4 Alkyl, C 1-3 Alkylthio, C 1-3 Alkoxy, C 2-4 alkenyl, C 2-4 The alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, optionally, may be further substituted by one or more substituents;

[0103] This invention also provides a tricyclic derivative which may be a compound of formula IV-1, IV-2, IV-3, IV-4, IV-5 or IV-6, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, wherein formula IV-1, IV-2, IV-3, IV-4, IV-5 or IV-6 are as follows:

[0104] The definitions of X, R0, R2, R3, R4, R5, R6, R8, and R9 are as described above;

[0105] X 1 X 2 X 3 Selected independently from -CR m R n -NR m , -O-, -S-, -C(O)-, -S(O)2-, -C(O)-O-, -C(O)-N(R m )-;

[0106] m is selected from 0, 1, 2, and 3;

[0107] In some implementations, m is 0;

[0108] In some implementations, m is 1;

[0109] In some implementations, m is 2;

[0110] In some implementations, m is 3;

[0111] R m R n Each group is independently selected from hydrogen, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups, and may be further substituted by one or more substituents selected from hydrogen, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, cycloalkyl, heterocyclic, aryl, or heteroaryl groups;

[0112] In some implementations, when m is 1, (X 3 ) m It can be -O-;

[0113] In some implementations, when m is 2, (X 3 ) m It can be -CH2O-;

[0114] In some implementations, when m is 2, (X 3 ) m It can be -OCH2-;

[0115] In some implementations, when m is 3, (X 3 ) m It can be -CH2CH2O-;

[0116] In some implementations, when m is 3, (X 3 ) m It can be -CH2OCH2-;

[0117] In some implementations, when m is 3, (X 3 ) m It can be -OCH2CH2-;

[0118] Optionally, R6 and R in Formula IV-1, Formula IV-3, Formula IV-4 or Formula IV-5 m or R n The substituents can be linked into a ring, and optionally, they can be further substituted by one or more substituents;

[0119] Optionally, R9 and R in Equation IV-6 m or R n The substituents can be linked into a ring, and optionally, they can be further substituted by one or more substituents;

[0120] In some implementations, R m R n Each element is independently selected from non-existent, hydrogen, halogen, and C. 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkoxy groups, C 1-10 Alkylthio, C 1-10 The haloalkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, optionally, may be further substituted by one or more substituents;

[0121] In some implementations, R m R n Each is independently selected from non-existent, hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, and C. 1-4 Alkyl, C 1-3 Alkylthio, C 1-3 Alkoxy, C 2-4 alkenyl, C 2-4 The alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, optionally, may be further substituted by one or more substituents;

[0122] The present invention also provides a tricyclic derivative which may be a compound of formula V-1, V-2, V-3, V-4, V-5 or V-6, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the structural formulas of formula V-1, V-2, V-3, V-4, V-5 or V-6 are as follows:

[0123] Among them, R0, R2, R3, R4, R5, R6, R8, R9, R 11 R a k is defined as described above; Defined as described above;

[0124] The present invention also provides a tricyclic derivative which may be a compound of formula VI-1, formula VI-2, formula VI-3, formula VI-4, formula VI-5, formula VI-6 or formula VI-7, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the structural formulas of formula VI-1, formula VI-2, formula VI-3, formula VI-4, formula VI-5, formula VI-6 or formula VI-7 are as follows:

[0125] in,

[0126] R0, R2, R3, R4, R5, R6, R8, R9, X 1 X 2 X 3 R a The definitions of m and m are as described above;

[0127] R 12 The group is independently selected from hydrogen, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl groups, and may be further substituted by one or more substituents selected from hydrogen, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, cycloalkyl, heterocyclic, aryl or heteroaryl groups;

[0128] In some implementations, R 12 Independently selected from non-existent, hydrogen, halogen, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkoxy groups, C 1-10 Alkylthio, C 1-10 The haloalkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, optionally, may be further substituted by one or more substituents;

[0129] In some implementations, R 12 Independently selected from non-existent, hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, C 1-4 Alkyl, C 1-3 Alkylthio, C 1-3 Alkoxy, C 2-4 alkenyl, C 2-4 The alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, optionally, may be further substituted by one or more substituents;

[0130] In some implementations, R 12 Independently selected from non-existent, hydrogen, -F, methyl, -O-CF3, -OC(CH2)2CF3, -O-CH(CH2)CF3 or -O-CH2CF3;

[0131] This invention also provides a tricyclic derivative which may be a compound of formula VII-1 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the structural formula of formula VII-1 is as follows:

[0132] Among them, R0, R2, R3, R4, R5, R6, X 1 X 2 X 3 The definitions of m and m are as described above;

[0133] This invention also provides a tricyclic derivative which may be a compound of formula VIII-1, VIII-2, VIII-3, VIII-4 or VIII-5, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the structural formulas of compounds of formula VIII-1, VIII-2, VIII-3, VIII-4 or VIII-5 are as follows:

[0134] This invention also provides a tricyclic derivative which may be a compound of formula IX-1, formula IX-2, formula IX-3, formula IX-4 or formula IX-5, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the structural formulas of compounds of formula IX-1, formula IX-2, formula IX-3, formula IX-4 or formula IX-5 are as follows:

[0135] This invention also provides a tricyclic derivative which may be a compound of formula X-1, X-2, X-3, X-4 or X-5, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the structural formulas of compounds of formula X-1, X-2, X-3, X-4 or X-5 are as follows:

[0136] In some specific embodiments, the compound may further be:

[0137] In this invention, the substituents in "which may be further substituted by one or more substituents" are selected from hydrogen, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, cycloalkyl, heterocyclic, aryl, or heteroaryl, preferably hydrogen, halogen, nitro, hydroxy, mercapto, cyano, amino, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Hydroxyalkyl, C 1-10 Alkoxy, C 1-10 Hydroxyalkoxy, C 1-10 Halogenated alkoxy groups, C 1-10 Acyl group, C 1-10 sulfonyl, C 1-10 Acylamino, C 1-10Ester group, 3-10 membered cycloalkyl group, 3-10 membered heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group;

[0138] In this invention, cycloalkyl, heterocyclic, aryl, or heteroaryl groups optionally include monocyclic, fused, bridged, or spirocyclic groups;

[0139] In this invention, if the carbon atom optionally connected to the substituent is a chiral carbon, the chirality of the carbon atom can be R-type or S-type.

[0140] In this invention, the compound of formula I includes compounds of formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, and formula X;

[0141] In this invention, the compound of formula I includes compounds of formulas III, IV, V, VI, VII, VIII, IX, and X;

[0142] In this invention, the compounds of formula II include formulas II-1, II-2, II-3, II-4, II-5, and II-6;

[0143] In this invention, compounds of formula III include formulas III-1, III-2, III-3, III-4, III-5, and III-6;

[0144] In this invention, the compounds of formula IV include formulas IV-1, IV-2, IV-3, IV-4, IV-5, and IV-6;

[0145] In this invention, compounds of formula V include formulas V-1, V-2, V-3, V-4, V-5, and V-6;

[0146] In this invention, compounds of formula VI include formulas VI-1, VI-2, VI-3, VI-4, VI-5, VI-6, and VI-7;

[0147] In this invention, the compound of formula VII includes formula VII-1;

[0148] In this invention, compounds of formula VIII include formulas VIII-1, VIII-2, VIII-3, VIII-4, and VIII-5;

[0149] In this invention, compounds of formula IX include formulas IX-1, IX-2, IX-3, IX-4, and IX-5;

[0150] In this invention, compounds of formula X include formulas X-1, X-2, X-3, X-4, and X-5;

[0151] The present invention also relates to a pharmaceutical composition comprising the fused tricyclic derivative of the present invention;

[0152] The present invention also relates to a pharmaceutical composition comprising a compound of formula I or II of the present invention or a pharmaceutically acceptable salt thereof, a prodrug, a solvate, a hydrate, a tautomer, or a stereoisomer.

[0153] In some embodiments, the pharmaceutical composition may optionally also comprise a pharmaceutically acceptable carrier.

[0154] The present invention also relates to the use of a compound of formula I or II or a pharmaceutically acceptable salt thereof, a prodrug, a solvate, a hydrate, a tautomer, or a stereoisomer thereof for use as a voltage-gated sodium channel inhibitor / sodium channel blocker, or for use in the preparation of a drug that inhibits sodium channels.

[0155] The present invention also relates to the use of a compound of formula I or II or a pharmaceutically acceptable salt thereof, a prodrug, a solvate, a hydrate, a tautomer, or a stereoisomer thereof, for use as an inhibitor of Nav1.1, Nav1.2, Nav1.3, Nav1.6, or Nav1.8, or for use in the preparation of a medicament for inhibiting Nav1.1, Nav1.2, Nav1.3, Nav1.6, or Nav1.8;

[0156] The present invention also relates to the use of a compound of formula I or II or a pharmaceutically acceptable salt thereof, a prodrug, a solvate, a hydrate, a tautomer, or a stereoisomer thereof for the treatment of epilepsy, Parkinson's disease, depression, or schizophrenia, or for the preparation of a medicament for the treatment of epilepsy, Parkinson's disease, depression, or schizophrenia.

[0157] Detailed description of the invention

[0158] Before further describing the invention, it should be understood that the invention is not limited to the specific embodiments described, as they may, of course, vary. It should also be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to constitute limitation, as the scope of the invention is limited only by the appended claims.

[0159] Unless otherwise stated, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All patents, applications, publications, and other publications referenced herein are incorporated herein by reference in their entirety. If any definition in this section contradicts or is inconsistent with the definitions listed in the patents, applications, and other publications incorporated herein, the definition in this section shall prevail over the definition incorporated herein.

[0160] In this invention, "alkyl" refers to a saturated aliphatic hydrocarbon group, which can be C 1-20 Alkyl groups, preferably C 1-10 Alkyl groups, more preferably C 1-6 Alkyl groups, with C being the most preferred.1-3 Alkyl groups. 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 their various branched isomers, etc.

[0161] In this invention, "alkenyl" refers to a substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon group having at least one, typically one, two, or three, carbon-carbon double bonds. The main chain includes, but is not limited to, 2 to 10, 2 to 6, or 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, and 2-methyl-1-butenyl. Alkenes include 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, and 1,4-hexadiene, etc.; the alkenyl groups appearing in this article are defined in accordance with this definition. Alkenyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0162] In this invention, "alkynyl" refers to a substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon group having at least one, typically one, two, or three, carbon-carbon triple bonds, including but not limited to having 2 to 10 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms in the main chain. Examples of alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, etc. 1-Methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-hepynyl, 2-hepynyl, 3-hepynyl, 4-hepynyl, 1-octyynyl, 3-octyynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, etc.; the ynyl group can be monovalent, divalent, trivalent, or tetravalent.

[0163] In this invention, "cycloalkyl" refers to a saturated or partially unsaturated monocyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group or a polycyclic 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"), more 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, cyclohepttrienyl, cyclooctyl, etc.

[0164] In this invention, "heterocyclic" or "heterocyclic group" 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 a cycloalkyl ring. The heterocyclic group may contain 3 to 20 ring atoms ("3-20 membered heterocyclic group"), preferably 3 to 12 ring atoms ("3-12 membered heterocyclic group"), more preferably 3 to 10 ring atoms ("3-10 membered heterocyclic group"), more preferably 3 to 8 ring atoms ("3-8 membered heterocyclic group"), and most preferably 3 to 6 ring atoms ("3-6 membered heterocyclic group"). Non-limiting examples of heterocyclic groups include ethylene oxide, tetrahydrofuranyl, tetrahydropyrroleyl, tetrahydropyranyl, tetrahydrothiaranyl, piperidinyl, etc.; "heterocycle" or "heterocyclic group" can be monocyclic ("monocyclic heterocyclic group") or fused, bridged, or spirocyclic systems, such as bicyclic systems ("bicyclic heterocyclic group"), and can be saturated or partially unsaturated. A heterocyclic bicyclic system may include one or more heteroatoms in one or both rings.

[0165] In this invention, "aryl" or "aromatic ring" refers to a optionally substituted monocyclic, biaryl, or fused bicyclic or polycyclic ring system having well-known aromatic characteristics, wherein at least one ring contains a fully conjugated π-electron system. Typically, aryl groups contain 6-20 carbon atoms ("6-20-membered aryl") as ring members, preferably 6-14 carbon atoms ("6-14-membered aryl") or more preferably 6-10 carbon atoms ("6-10-membered aryl"). Fused aryl groups may include aryl rings fused to another aryl ring, or aryl rings fused to saturated or partially unsaturated carbon rings or heterocycles. The connection point to the base molecule on such a fused aryl ring system can be... The C atom of the aromatic portion of the ring system or the C or N atom of the non-aromatic portion. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracene, phenanthryl, indanyl, indenyl, benzo[d][1,3]dioxacyclopentene, and tetrahydronaphthyl; “aryl” or “aromatic ring” can be monocyclic (“monocyclic aromatic group”) or fused, bridged, or spirocyclic systems, such as bicyclic systems (“bicyclic heterocyclic group”), and can be saturated or partially unsaturated.

[0166] In this invention, "heteroaryl" or "heteroaryl ring" refers to a monocyclic, heteroaryl, or fused bicyclic or polycyclic ring system with well-known aromatic characteristics, containing a specified number of ring atoms and including at least one heteroatom selected from N, O, and S as a ring member in the aromatic ring. The inclusion of heteroatoms allows for the aromaticity of both 5-membered and 6-membered rings. Typically, heteroaryl contains 5-20 ring atoms ("5-20-membered heteroaryl"), preferably 5-14 ring atoms ("5-14-membered heteroaryl"), and more preferably 5-10 ring atoms ("5-10-membered heteroaryl"). The heteroaryl ring is linked to the base molecule through the ring atoms of the heteroaryl ring, thereby maintaining aromaticity. Thus, a 6-membered heteroaryl ring can be linked to the base molecule through a ring C atom, while a 5-membered heteroaryl ring can be linked to the base molecule through a ring C or N atom. Examples of unsubstituted heteroaryl groups often include, but are not limited to, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazolium, pyridine, pyridazine, pyrimidine, pyrazine, benzofuran, benzothiophene, indole, benzimidazole, indazole, quinoline, isoquinoline, purine, triazine, naphthidine, and carbazole; "heteroaryl" or "heteroary ring" can be monocyclic ("monocyclic") or fused, bridged, or spirocyclic systems, such as bicyclic systems ("bicyclic heterocyclic"), and can be saturated or partially unsaturated.

[0167] In this invention, "ester group" refers to a group formed by the esterification of a carboxyl group (-COOH) and a hydroxyl group (-OH), where the OH group is removed from the carboxyl group and the H group is removed from the hydroxyl group. For example, an ester group can be... Where R a1 R b1 It can be an alkyl group and can be selected from C. 1-20Ester group, preferably C 1-10 Ester group, further preferably C 2-8 Ester group, more preferably C 2-6 Ester group, C is the most preferred. 2-3 Ester group;

[0168] In this invention, "acyl" refers to the atomic group remaining after removing the hydroxyl group from an organic acid, with the general formula R. b1 -CO-, where R b1 As defined above, the acyl group can be selected from C 1-20 Acyl group, preferably C 1-10 Acyl group, further preferably C 1-8 Acyl group, more preferably C 1-6 Acyl group, C is the most preferred. 1-3 Acyl group;

[0169] In this invention, "sulfonyl group" refers to the functional group formed after the sulfonic acid loses its hydroxyl group. The sulfonyl group can be written as R. c1 -S(=O)2-, where there are two coordinate bonds between sulfur and oxygen. If the group -S(=O)2- is not attached to any carbon atom, it is called thioyl.

[0170] In this invention, "aldehyde group" refers to -C(O)H;

[0171] In this invention, "sulfur group" refers to -SH;

[0172] In this invention, "alkoxy" refers to alkyl-O-, wherein alkyl is as defined above; cycloalkyloxy, heterocyclic oxy, aryloxy, heteroaryloxy, etc. are defined similarly;

[0173] In this invention, "amide group" refers to Where R c1 It can be H or alkyl;

[0174] In this invention, "acylamine group" refers to Where R b1 R c1 As defined above;

[0175] In this invention, "amine group" refers to Where R c1 It can be H or alkyl, and at least one R c1 Not H; the alkyl-substituted amino group in this invention may be the above-mentioned amino group;

[0176] In this invention, "alkoxy" refers to a substituted or unsubstituted -O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy.

[0177] In this invention, "halogenated alkyl" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above;

[0178] In this invention, "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above;

[0179] In this invention, "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, wherein the alkyl group is as defined above;

[0180] In this invention, "hydroxyalkoxy" refers to an alkoxy group substituted with one or more hydroxyl groups, wherein the alkoxy group is as defined above;

[0181] In this invention, "hydroxyl group" refers to -OH;

[0182] In this invention, "halogen" refers to fluorine, chlorine, bromine, or iodine;

[0183] In this invention, "amino" refers to -NH2;

[0184] In this invention, "cyano" refers to -CN;

[0185] In this invention, "nitro" refers to -NO2;

[0186] In this invention, the groups defined above can be optionally substituted or unsubstituted, and when substituted, they can be replaced by one or more of the following groups:

[0187] Hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclic, aryl or heteroaryl; optionally, it may be further substituted.

[0188] In this invention, any isotopically labeled derivatives of the compounds of this invention or their pharmaceutically acceptable salts are covered by this invention. Atoms capable of being isotopically labeled include, but are not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine. 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 I, etc. are used instead. Unless otherwise stated, when a position is specifically designated as deuterium (D), the position shall be understood as having a deuterium abundance of at least 3,000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 45% deuterium incorporation).

[0189] In this invention, the term "multiple" can specifically refer to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0190] In this invention, the following abbreviations / terms are used:

[0191] Pd2(dba)3:tris(dibenzylacetone)dipalladium(0)

[0192] Pd(dppf)Cl2.CH2Cl2:[1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex Pd2(dba)3:tris(dibenzylacetone)dipalladium(0)

[0193] Dioxane: 1,4-Dioxane

[0194] KOAc: Potassium Acetate

[0195] Cs2CO3: Cesium carbonate

[0196] X-Phos: 2-Dicyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl

[0197] Grubbs second-generation catalyst: 1,3-bis(2,4,6-trimethylphenyl)-2-(imidazolidinedimethyl))(dichlorobenzylmethyl))(tricyclohexylphosphine)ruthenium

[0198] BINAP: 1,1'-binaphthyl-2,2'-bis(diphenylphosphine)

[0199] NaBH3CN: Sodium cyanoborohydride

[0200] TEA: Triethylamine

[0201] DIAD: Diisopropyl azodicarbonate

[0202] LiHMDS: Lithium bis(trimethylsilylamine)

[0203] NMP: N-methylpyrrolidone

[0204] NBS: N-bromosuccinimide

[0205] MeOH: Methanol

[0206] Boc2O: Ditert-butyl dicarbonate

[0207] POCl3: Phosphorus oxychloride

[0208] XantPhos: 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene

[0209] AgBF4: Silver tetrafluoroborate

[0210] XPhos Pd G3: Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)

[0211] TFAA: Trifluoroacetic anhydride

[0212] THF: Tetrahydrofuran

[0213] TMSCl: Trimethylchlorosilane

[0214] TBAB: Tetrabutylammonium bromide

[0215] NMP: N-methylpyrrolidone

[0216] NBS: N-bromosuccinimide

[0217] Boc2O: Ditert-butyl dicarbonate

[0218] POCl3: Phosphorus oxychloride

[0219] AgBF4: Silver tetrafluoroborate

[0220] PPh3: Triphenylphosphine

[0221] Pd(OAc)2: Palladium acetate

[0222] DMF: N,N-dimethylformamide

[0223] DCM: Dichloromethane

[0224] DMSO: Dimethyl sulfoxide

[0225] KOH: Potassium hydroxide

[0226] K3PO4: Potassium phosphate

[0227] t-BuOK: Potassium tert-butoxide

[0228] DIBAL-H: Diisobutylaluminum hydride

[0229] DIEA: N,N-Diisopropylethylamine

[0230] NaH: Sodium hydride

[0231] NaOH: Sodium hydroxide

[0232] NaBH4: Sodium borohydride

[0233] Na2CO3: Sodium carbonate

[0234] NaHCO3: Sodium bicarbonate

[0235] LiCl: Lithium chloride

[0236] NH4Cl: Ammonium chloride

[0237] EtOH: Ethanol

[0238] EA: Ethyl acetate

[0239] BBr3: Boron tribromide

[0240] BBr3: Boron tribromide

[0241] ACN: Acetonitrile

[0242] TMSI: Trimethyliodosilane Detailed Implementation

[0243] The present invention is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present invention.

[0244] Example 1

[0245] Step 1: Synthesis of compound 1c

[0246] Compound 1a (1500 mg, 4.652 mmol) was dissolved in dioxane (20 mL) / H₂O (5 mL), and 1b (1016.21 mg, 6.047 mmol), K₃PO₄ (1974.82 mg, 9.304 mmol) and Pd₂(dba)₃ (237.74 mg, 0.465 mmol) were added. The reaction mixture was heated to 100 °C and stirred for 3 hours under nitrogen protection. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to give compound 1c (1000 mg, yield: 90.85%).

[0247] Step 2: Synthesis of compound 1e

[0248] Compound 1c (1000 mg, 4.226 mmol) was dissolved in dioxane (15 mL), and 1d (1609.81 mg, 6.339 mmol), X-Phos (201.48 mg, 0.423 mmol), KOAc (829.52 mg, 8.452 mmol), and Pd2(dba)3 (193.50 mg, 0.211 mmol) were added. The reaction mixture was heated to 100 °C and stirred for 6 hours under nitrogen protection. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to give compound 1e (900 mg, yield: 64.90%).

[0249] Step 3: Synthesis of compound 1f

[0250] Reactant 1f-1 (1300 mg, 4.084 mmol) was dissolved in dioxane (10 mL) / water (3 mL), and compound 1f-2 (547.01 mg, 4.084 mmol), Cs₂CO₃ (3991.64 mg, 12.251 mmol), and Pd(dppf)Cl₂·CH₂Cl₂ (334.31 mg, 0.408 mmol) were added. The reaction mixture was heated to 100 °C and stirred for 6 hours under nitrogen protection. Purification by silica gel column chromatography yielded compound 1f (730 mg, yield: 81.82%).

[0251] MS m / z(ESI): 219.9 [M+H] +

[0252] Step 4: Synthesis of 1g of compound

[0253] Compound 1f (600 mg, 2.746 mmol) was dissolved in dioxane (10 mL) / water (3 mL), and compound 1e (901.16 mg, 2.746 mmol), potassium carbonate (1138.60 mg, 8.239 mmol), and Pd(dppf)Cl2·CH2Cl2 (224.82 mg, 0.275 mmol) were added. The reaction mixture was heated to 100 °C and stirred for 3 hours under nitrogen protection. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to give compound 1 g (610 mg, yield: 65.38%).

[0254] MS m / z(ESI): 339.9 [M+H] +

[0255] Step 5: Synthesis of compound 1h

[0256] 1 g (600 mg, 1.766 mmol) of the compound was dissolved in 20 mL of DCM, and 74.97 mg (0.088 mmol) of Grubbs II catalyst was added. The reaction mixture was stirred overnight at room temperature under nitrogen protection. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to give compound 1 h (500 mg, yield: 95.11%).

[0257] MS m / z(ESI): 298.0 [M+H] +

[0258] Step 6: Synthesis of Compound 1j

[0259] Compound 1h (300 mg, 1.008 mmol) was dissolved in dioxane (10 mL), and 1i (538.44 mg, 2.318 mmol), BINAP (188.27 mg, 0.302 mmol), cesium carbonate (985.14 mg, 3.024 mmol), and palladium acetate (22.63 mg, 0.101 mmol) were added. The reaction mixture was heated to 100 °C and stirred for 3 hours under nitrogen protection. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to give compound 1j (430 mg, yield: 86.46%).

[0260] MS m / z(ESI): 494.2 [M+H] +

[0261] Step 7: Synthesis of compound 1m

[0262] Compound 1j (430 mg, 0.871 mmol) was dissolved in 1k (5 mL). The reaction mixture was heated to 110 °C and stirred for 2 hours under nitrogen protection. After the reaction was completed, 10 mL of saturated Na2CO3 aqueous solution was added to the reaction solution to quench the reaction, and then extracted with ethyl acetate (20 mL * 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give compound 1m (210 mg, yield: 61.91%).

[0263] MS m / z(ESI): 390.1 [M+H] +

[0264] Step 8: Synthesis of Compound 1

[0265] Compound 1m (30 mg, 0.077 mmol) was dissolved in p-xylene (0.5 mL), and POCl3 (1 mL) was added. The mixture was heated in an oil bath at 150 °C and stirred for 3 hours. After the reaction solution cooled to room temperature, 10 mL of saturated Na2CO3 aqueous solution was added to quench the reaction. The mixture was then extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, purified by silica gel column chromatography, evaporated to dryness, and then lyophilized with water to give compound 1 (7.4 mg, yield: 25.86%).

[0266] MS m / z(ESI): 372.0 [M+H] + .

[0267] 1H NMR (400MHz, DMSO-d6) δ9.83 (s, 1H), 9.11 (d, J = 9.0Hz, 1H), 8.65 (d, J = 1.2Hz, 1H), 7.96 (dd, J = 2.6, 1.3Hz, 1H), 7.83 (s, 2H), 7.67 (dd, J = 8.6, 2.4Hz, 1H).

[0268] Example 2

[0269] Step 1: Synthesis of Compound 2

[0270] Compound 2a (30 mg, 0.081 mmol) was dissolved in MeOH (5 mL), and Pd / C (5%, 20 mg) was added. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 9 hours. The reaction solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography. After concentration, acetonitrile and water were added and lyophilized to give compound 2 (19.87 mg, yield: 65.88%).

[0271] MS m / z(ESI): 374.1 [M+H] +

[0272] 1 H NMR (400MHz, DMSO-d6) δ8.18(d,J=9.2Hz,1H),8.11-8.05(m,2H),7.69-7.59(m,2H),5.87(t,2H),4.54(t,J=3.1Hz,2H).

[0273] Example 3

[0274] Step 1: Synthesis of compound 3a-3

[0275] Compound 3a-2 (6220.05 mg, 18.145 mmol) was dissolved in THF (35 mL). After cooling to 0 °C, LiHMDS (18.145 mL, 18.145 mmol) was added dropwise. After the addition was complete, the mixture was kept at this temperature for 30 min. Then, a THF (20 mL) solution of 3a-1 (2000 mg, 9.072 mmol) was added dropwise. The mixture was stirred at 0 °C for 1 h and then allowed to react at room temperature for 2 h. The reaction was quenched directly with purified water (50 mL), and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 3a-3 (1610 mg, yield: 71.41%).

[0276] MS m / z(ESI): 248.0 [M+H] +

[0277] Step 2: Synthesis of compound 3a-6

[0278] Dioxane (70 mL) was added to compounds 3a-4 (3000 mg, 11.069 mmol), 3a-5 (4216.20 mg, 16.603 mmol), and KOAc (2172.58 mg, 22.138 mmol). Pd(dppf)Cl2.CH2Cl2 (453.07 mg, 0.553 mmol) was added under nitrogen protection, and the reaction was carried out overnight at 100 °C. The mixture was directly filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated and purified by column chromatography to give 3a-6 (3.04 g, yield: 86.34%).

[0279] MS m / z (ESI): 319.1 [M+H] +

[0280] Step 3: Synthesis of compound 3a-7

[0281] Compounds 3a-6 (1600 mg, 5.030 mmol), 3a-3 (1300 mg, 5.231 mmol), and K3PO4 (3202.93 mg, 15.090 mmol) were dissolved in dioxane (40 mL) and H2O (10 mL). Under nitrogen protection, Pd(dppf)Cl2·CH2Cl2 (205.89 mg, 0.251 mmol) was added, and the reaction was carried out at 100 °C for 1 h. The water was directly removed, the organic phase was concentrated, and purified by column chromatography to give 3a-7 (1558 mg, yield: 86.11%).

[0282] MS m / z(ESI): 360.1 [M+H] +

[0283] Step 4: Synthesis of compound 3a-8

[0284] Compound 3a-7 (1.558 g, 4.331 mmol) was dissolved in concentrated HCl (10 mL) and THF (20 mL), stirred at 60 °C for 2 h, and then extracted directly with purified water (20 mL) and ethyl acetate (20 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 3a-8 (1580 mg, yield: 84.42%, purity: 80%).

[0285] MS m / z(ESI): 346.0 [M+H] +

[0286] Step 5: Synthesis of compound 3a-9

[0287] Compound 3a-8 (1580 mg, 3.656 mmol) was dissolved in MeOH (15 mL), cooled to 0 °C, and then NaBH4 (276.64 mg, 7.313 mmol) was added. The reaction was allowed to proceed for 2 h. Purified water (10 mL) and ethyl acetate (10 mL * 3) were added directly to the reaction solution for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 3a-9 (1130 mg, yield: 88.88%).

[0288] MS m / z (ESI): 348.1 [M+H] +

[0289] Step 6: Synthesis of compound 3a-10

[0290] Compound 3a-9 (1130 mg, 3.250 mmol) was dissolved in DCM (10 mL), cooled to -60 °C, and boron tribromide (dichloromethane solution, approximately 1 mol / L) (16.249 mL, 16.249 mmol) was added dropwise. The mixture was kept at this temperature for 1 hour, then brought to room temperature and stirred overnight. The reaction solution was diluted directly with ethyl acetate (30 mL), and then washed successively with saturated sodium bicarbonate (20 mL) and saturated sodium chloride (20 mL). After drying with anhydrous sodium sulfate, the solution was filtered, concentrated, and purified by silica gel column chromatography to obtain 3a-10 (540 mg, yield: 49.80%).

[0291] MS m / z(ESI): 334.0 [M+H] +

[0292] Step 7: Synthesis of compound 3a

[0293] Compound 3a-10 (540 mg, 1.618 mmol) was dissolved in THF (20 mL), followed by the addition of PPh3 (848.91 mg, 3.237 mmol) and DIAD (654.46 mg, 3.237 mmol), and stirred at room temperature for 3 h. The reaction solution was diluted with ethyl acetate (30 mL), washed successively with water (20 mL) and saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography to obtain 3a (380 mg, yield: 74.39%).

[0294] MS m / z(ESI): 316.0 [M+H] +

[0295] Step 8: Synthesis of compound 3c

[0296] Compound 3a (110 mg, 0.348 mmol) was dissolved in 1,4-dioxane (5 mL), and 3b (186.16 mg, 0.801 mmol), BINAP (65.09 mg, 0.105 mmol), cesium carbonate (340.60 mg, 1.045 mmol), and palladium acetate (7.82 mg, 0.035 mmol) were added. The reaction mixture was heated to 100 °C and stirred for 5 hours under nitrogen protection. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to give compound 3c (150 mg, yield: 84.16%) as a white solid.

[0297] MS m / z(ESI): 412.1 [M+H-Boc] +

[0298] Step 9: Synthesis of compound 3e

[0299] Compound 3c (150 mg, 0.293 mmol) was dissolved in 3d (3 mL), and the reaction mixture was heated to 110 °C and stirred for 1.5 h under nitrogen protection. The reaction was quenched by adding saturated Na₂CO₃ aqueous solution (10 mL), and then extracted with ethyl acetate (20 mL * 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 3e (100 mg, yield: 83.73%).

[0300] MS m / z (ESI): 408.1 [M+H] +

[0301] Step 10: Synthesis of Compound 3

[0302] Compound 3e (90 mg, 0.221 mmol) was dissolved in p-xylene (1 mL), and POCl3 (2 mL) was added. The mixture was heated in an oil bath at 150 °C and stirred for 3 hours. The reaction was quenched by adding saturated Na2CO3 aqueous solution (10 mL), and then extracted with ethyl acetate (20 mL * 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography. After concentration, acetonitrile and water were added and lyophilized to give compound 3 (4.43 mg, yield: 5.15%).

[0303] MS m / z(ESI): 390.1 [M+H] +

[0304] 1H NMR (400MHz, DMSO-d6) δ8.64(s,1H),8.10(s,1H),7.78(d,J=8.5Hz,1H),7.42 -7.33(m,1H),7.31-7.21(m,1H),4.51(t,J=6.3Hz,2H),3.00(t,J=6.3Hz,2H).

[0305] Example 4

[0306] Step 1: Synthesis of compound 4b

[0307] Compound 4a (5000 mg, 22.681 mmol) was dissolved in methanol (100 mL), and methylamine hydrochloride (6125.29 mg, 90.724 mmol) was added. After stirring at room temperature for 30 min, NaBH3CN (5701.07 mg, 90.724 mmol) was added, and the mixture was stirred at room temperature for 14 h. The mixture was then concentrated, and water (60 mL) was added. The pH was adjusted to 7-8 with saturated sodium bicarbonate aqueous solution. The mixture was extracted with EA (40 mL * 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by silica gel column chromatography to obtain compound 4b (1.4 g, yield: 26.21%).

[0308] MS m / z(ESI): 237.0 [M+H] +

[0309] Step 2: Synthesis of compound 4d

[0310] Compound 4c (1000 mg, 2.625 mmol) and compound 4b (618.14 mg, 2.625 mmol) were dissolved in DCM (10 mL), and TEA (2318.71 mg, 23.15 mmol) was added. The mixture was stirred at room temperature for 2 h. Then, purified water (60 mL) was added, and the mixture was extracted with DCM (30 mL x 3). The mixture was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by silica gel column chromatography to obtain compound 4d (380 mg, yield: 31.93%).

[0311] MS m / z(ESI): 453.0 [M+H] +

[0312] Step 3: Synthesis of compound 4e

[0313] Compound 4d (380 mg, 0.838 mmol) was added to a sealed tube, followed by Pd(dppf)Cl2·CH2Cl2 (68.60 mg, 0.084 mmol), K3PO4 (355.76 mg, 1.676 mmol), dioxane (15 mL), and H2O (5 mL). After purging with nitrogen for 1 min, the tube was sealed and reacted at 90 °C for 2 h. Purified water (50 mL) was added, followed by extraction with EA (30 mL x 3), washing with saturated brine (20 mL), drying with anhydrous sodium sulfate, filtration, concentration, and silica gel column chromatography to obtain compound 4e (230 mg, yield: 83.49%).

[0314] MS m / z(ESI): 329.1 [M+H] +

[0315] Step 4: Synthesis of 4g of compound

[0316] Compound 4e (230 mg, 0.7 mmol) and compound 4f (195.03 mg, 0.84 mmol) were dissolved in dioxane (10 mL), and Cs2CO3 (455.94 mg, 1.399 mmol), Pd2(dba)3 (64.07 mg, 0.070 mmol), and X-Phos (80.97 mg, 0.140 mmol) were added. After purging with nitrogen for 1 min, the mixture was reacted at 100 °C for 6 h. The mixture was concentrated and then purified by silica gel column chromatography to give compound 4 g (299 mg, yield: 81.47%).

[0317] MS m / z (ESI): 425.2 [M+H] +

[0318] Step 5: Synthesis of Compound 4

[0319] Compound 4 g (300 mg, 0.572 mmol) was dissolved in TFA (10 mL) and reacted at 110 °C for 16 h in a sealed container. After concentration, saturated sodium carbonate aqueous solution (30 mL) was added, and the mixture was extracted with EA (20 mL * 3). After concentration of the organic phase, the crude product was obtained by silica gel column chromatography. The crude product was then used to prepare compound 4 (8.3 mg, yield: 3.61%).

[0320] MS m / z (ESI): 403.1 [M+H] +

[0321] 1 H NMR (400MHz, DMSO-d6) δ8.65(s,1H),8.14(s,1H),7.84-7.77(m,1H),7.52(d,J=6.8Hz,2H),3.47(s,2H),3.43(s,2H),2.35(s,3H).

[0322] Example 5

[0323] Synthesis of compound 5a (Step 1)

[0324] Compound 4a (5000 mg, 22.681 mmol) was dissolved in methanol (100 mL), and methylamine hydrochloride (6125.29 mg, 90.724 mmol) was added. After stirring at room temperature for 30 minutes, NaBH3CN (5701.07 mg, 90.724 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, diluted with water (60 mL), and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. The solution was extracted with ethyl acetate (40 mL * 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%-50%) to give compound 5a (3 g, yield 60%).

[0325] MS m / z(ESI): 222.0 [M+H] +

[0326] The second step involves the synthesis of compound 5b.

[0327] Compound 5a-1 (1000 mg, 2.625 mmol) and compound 5a (583.91 mg, 2.625 mmol) were dissolved in acetonitrile (10 mL), and Cs₂CO₃ (1026.21 mg, 3.150 mmol) was added. The mixture was stirred at room temperature for 16 hours. The solution was diluted with water (60 mL), extracted with ethyl acetate (30 mL x 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–15%) to give compound 5b (580 mg, yield 42%).

[0328] MS m / z(ESI): 522.0 [M+H] +

[0329] The third step involves the synthesis of compound 5c.

[0330] Compound 5b (580 mg, 1.110 mmol) was added to a sealed tube, followed by the sequential addition of Pd(dppf)Cl2.CH2Cl2 (90.87 mg, 0.111 mmol), K3PO4 (471.19 mg, 2.220 mmol), dioxane (15 mL), and H2O (5 mL). After purging the system with nitrogen, the tube was sealed and reacted at 100 °C for 2 hours. The mixture was diluted with water (50 mL), extracted with ethyl acetate (30 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–30%) to obtain compound 5c (300 mg, yield 86%).

[0331] MS m / z(ESI): 316.0 [M+H] +

[0332] Step 4: Synthesis of compound 5d

[0333] Compound 5c (380 mg, 1.204 mmol) and di-tert-butyl azide dicarboxylate (335.53 mg, 1.445 mmol) were dissolved in dioxane (10 mL). Pd2(dba)3 (110.23 mg, 0.120 mmol), XantPhos (139.31 mg, 0.241 mmol), and cesium carbonate (784.42 mg, 2.408 mmol) were added. The system was purged with nitrogen and the reaction was carried out at 100 °C for 6 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–30%) to give compound 5d (299 mg, yield 49%).

[0334] MS m / z(ESI): 412.1 [M-100+H] +

[0335] Step 5: Synthesis of compound 5e

[0336] Compound 5d (300 mg, 0.587 mmol) was dissolved in TFA (6 mL) and reacted at 110 °C for 16 hours. After the reaction solution was concentrated under reduced pressure, it was extracted with saturated sodium carbonate aqueous solution (30 mL) and ethyl acetate (20 mL * 3). The organic phase was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 0%-10%) to give compound 5e (80 mg, yield 33%).

[0337] MS m / z (ESI): 408.1 [M+H] +

[0338] Step 6: Synthesis of Compound 5

[0339] Compound 5e (80 mg, 0.196 mmol) was dissolved in p-xylene (3 mL), and POCl3 (1 mL) was added. The mixture was sealed and reacted at 150 °C for 4 hours. After the reaction solution was concentrated under reduced pressure, it was extracted with saturated sodium carbonate aqueous solution (20 mL), ethyl acetate (15 mL * 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%-100%) to obtain the crude product. The crude product was purified by HPLC (acetonitrile / water = 10%-80%) to obtain compound 5 (5.39 mg, yield 7%).

[0340] MS m / z(ESI): 390.1 [M+H] +

[0341] 1 H NMR (400MHz, DMSO-d6) δ8.75(s,1H),8.32(d,J=1.0Hz,1H),7.90(d,J=8.4Hz,1H) ,7.66(d,J=2.5Hz,1H),7.61(ddd,J=8.5,2.6,1.2Hz,1H),4.48(d,J=15.8Hz,4H).

[0342] Example 7

[0343] The first step is the synthesis of compound 7c.

[0344] Compound 7a (670 mg, 1.310 mmol) was dissolved in 7b (3 mL), and stirred at 110 °C for 2 hours. After the reaction cooled to room temperature, saturated sodium bicarbonate solution (30 mL) was added directly, followed by extraction with ethyl acetate (20 mL * 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 0%–10%) to obtain compound 7c (283 mg, yield 51%).

[0345] MS m / z(ESI): 424.0 [M+H] +

[0346] The second step involves the synthesis of compound 7d.

[0347] Compound 7c (270 mg, 0.637 mmol) was dissolved in POCl3 (4 mL) and xylene (2 mL) and reacted at 150 °C for 5 hours. The reaction solution was directly concentrated, and the crude product was extracted with saturated sodium bicarbonate solution (50 mL) and ethyl acetate (20 mL * 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–50%) to obtain compound 7d (100 mg, yield 39%).

[0348] MS m / z(ESI): 406.0 [M+H] +

[0349] Step 3: Synthesis of Compound 7

[0350] Compound 7d (70 mg, 0.173 mmol) and AgBF4 (168.22 mg, 0.863 mmol) were dissolved in ethanol (5 mL) and reacted at 85 °C for 5 hours. The reaction solution was directly extracted with saturated sodium bicarbonate solution (20 mL) and ethyl acetate (20 mL * 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–50%) to give compound 7 (37.78 mg, yield 52%).

[0351] MS m / z (ESI): 416.1 [M+H] +

[0352] 1 H NMR (400MHz, DMSO-d6) δ8.49(s,1H),8.01(d,J=0.9Hz,1H),7.71(d,J=8.4Hz,1H),7.47-7.32(m,1H),7.26(dd ,J=2.5,1.0Hz,1H),4.49(t,J=6.3Hz,2H),4.26(q,J=7.1Hz,2H),2.98(t,J=6.3Hz,2H),1.35(t,J=7.1Hz,3H).

[0353] Example 8

[0354] The first step is the synthesis of compound 8c.

[0355] Compound 8a (4000 mg, 26.499 mmol) and compound 8b (5000 mg, 31.208 mmol) were dissolved in toluene (50 mL) and reacted at 100 °C for 16 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0-30%) to give compound 8c (6.6 g, yield 88%).

[0356] MS m / z(ESI): 283.1 [M+H] +

[0357] The second step involves the synthesis of compound 8d.

[0358] Compound 8c (6600 mg, 23.309 mmol) was dissolved in EtOH (30 mL), and 50% hydrazine hydrate (23337 mg, 233.09 mmol) was added. The mixture was reacted at 80 °C for 16 hours. The reaction solution was concentrated under reduced pressure, diluted with water (50 mL), filtered, and the filter cake was dried to give compound 8d (5100 mg, yield 78%).

[0359] MS m / z(ESI): 279.1 [M+H] +

[0360] The third step involves the synthesis of compound 8e.

[0361] Compound 8d (5127 mg, 18.393 mmol) was dissolved in trifluoroacetic acid (20 mL), and triethylamine (3722 mg, 36.782 mmol) was added. The reaction mixture was reacted at 80 °C for 16 hours. The reaction solution was concentrated under reduced pressure and extracted with saturated sodium carbonate aqueous solution (50 mL), ethyl acetate (30 mL x 3), washed with saturated brine (20 mL), and the organic phase was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%-30%) to give compound 8e (4.7 g, yield 72%).

[0362] MS m / z (ESI): 357.1 [M+H] +

[0363] The fourth step involves the synthesis of 8g of compound.

[0364] Compounds 3a-6 (4949 mg, 15.558 mmol) and 8e (3700 mg, 10.372 mmol) were dissolved in dioxane (30 mL). Under nitrogen protection, K3PO4 (4403 mg, 20.743 mmol), di(tri-tert-butylphosphine)palladium (530 mg, 1.037 mmol), and H2O (10 mL) were added, and the mixture was sealed and reacted at 95 °C for 1 hour. The reaction solution was diluted with water (90 mL), extracted with ethyl acetate (50 mL * 3), washed with saturated brine (50 mL), and the organic phase was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%-60%) to give compound 8 g (3.7 g, yield 70%).

[0365] MS m / z (ESI): 513.1 [M+H] +

[0366] Step 5: Synthesis of compound 8h

[0367] 8 g (3400 mg, 6.635 mmol) of the compound was dissolved in methanol (50 mL), and 5% Pd / C (680 mg, 0.195 mmol) and trifluoroacetic acid (0.5 mL) were added. After purging the system with hydrogen, the system was heated to 50 °C and reacted for 16 hours under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give compound 8 h (2700 mg, yield 96%).

[0368] MS m / z(ESI): 423.1 [M+H] +

[0369] Step 6: Synthesis of compound 8i

[0370] Compound 8h (360 mg, 0.852 mmol) was dissolved in DCM (5 mL), cooled in an ice bath, and 2 M BBr3 / DCM (5 mL, 10 mmol) was added under nitrogen protection. The reaction mixture was reacted at room temperature for 40 hours. The reaction solution was slowly added to ice water, concentrated under reduced pressure, extracted with ethyl acetate (20 mL * 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 8i (350 mg, 100% yield).

[0371] MS m / z (ESI): 409.1 [M+H] +

[0372] Step 7: Synthesis of Compound 8

[0373] Compound 8i (300 mg, 0.735 mmol) was added to a three-necked flask, along with PPh3 (385.5 mg, 1.470 mmol) and THF (15 mL). The mixture was cooled in an ice bath, and under nitrogen protection, a THF solution of DIAD (742.9 mg, 3.674 mmol) (2.5 mL) was added. The reaction was carried out at room temperature for 3 hours. The reaction was quenched with saturated ammonium chloride aqueous solution (2 mL), diluted with water (50 mL), extracted with ethyl acetate (30 mL x 3), washed with saturated brine (30 mL), and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%-50%) to obtain the crude product. The crude product was then prepared by HPLC (acetonitrile / water = 20%-80%) to obtain compound 8 (97 mg, yield 34%).

[0374] MS m / z(ESI): 391.1 [M+H] +

[0375] 1 H NMR (400MHz, DMSO-d6) δ8.59(s,1H),7.85(d,J=8.6Hz,1H),7.43(ddd,J=8.6,2.5,1 .1Hz,1H),7.31(dd,J=2.4,1.1Hz,1H),4.55(t,J=6.1Hz,2H),3.09(t,J=6.1Hz,2H).

[0376] Example 10

[0377] Synthesis of compound 10b in step one

[0378] Compound 10a-1 (5097.1 mg, 14.869 mmol) was dissolved in THF (50 mL). Potassium tert-butoxide (1918.7 mg, 17.099 mmol) was added under ice bath conditions. After stirring at room temperature for 1 hour, a THF solution of compound 10a (2000 mg, 7.434 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated NH4Cl aqueous solution (100 mL), followed by the addition of EA (100 mL x 2). The mixture was separated. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to obtain an oily substance. This oil was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–5%) to give 10b (1900 mg, yield 86%).

[0379] MS m / z(ESI): 297.0 [M+H] +

[0380] The second step involves the synthesis of compound 10c.

[0381] Compound 10b (1900 mg, 6.396 mmol) was dissolved in dioxane (30 mL), and 10b-1 (2111.4 mg, 8.315 mmol), KOAc (1255.4 mg, 12.792 mmol), and Pd(dppf)Cl2.CH2Cl2 (523.6 mg, 0.640 mmol) were added. The reaction mixture was heated to 100 °C and stirred for 3 hours under nitrogen protection. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–5%) to give compound 10c (1800 mg, yield 82%).

[0382] The third step involves the synthesis of compound 10e.

[0383] Compound 10c (1800 mg, 5.230 mmol), compound 10d (1280.0 mg, 5.754 mmol), and K3PO4 (3330.7 mg, 15.691 mmol) were dissolved in a mixed solution of dioxane (30 mL) and H2O (10 mL). Pd(dppf)Cl was added under nitrogen protection. 2. CH2Cl2 (428.2 mg, 0.523 mmol) was reacted at 80 °C for 3 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%-10%) to give compound 10e (1500 mg, yield 83%).

[0384] MS m / z(ESI): 346.0 [M+H] +

[0385] Step 4: Synthesis of compound 10f

[0386] Compound 10e (1500 mg, 4.170 mmol) was dissolved in THF (20 mL), and concentrated hydrochloric acid (8 mL) was added. The mixture was reacted at 50 °C for 3 hours. After dilution with water (50 mL), extraction with ethyl acetate (30 mL x 3), washing with saturated brine (30 mL), drying over anhydrous sodium sulfate, filtering, and concentrating, compound 10f (1100 mg, 73% yield) was obtained.

[0387] MS m / z(ESI): 360.1 [M+H] +

[0388] Step 5: Synthesis of 10g of compound

[0389] Compound 10f (1100 mg, 3.182 mmol) was dissolved in methanol (20 mL). NaBH4 (601.9 mg, 15.910 mmol) was added in portions at 0 °C, and the mixture was stirred at room temperature for 2 hours. Purified water (50 mL) and ethyl acetate (50 mL x 3) were added directly to the reaction mixture for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 10 g of compound (1020 mg, 92% yield).

[0390] MS m / z(ESI): 348.0 [M+H] +

[0391] Step 6: Synthesis of compound 10i

[0392] 10 g (1020 mg, 2.933 mmol) of compound was dissolved in acetonitrile (15 mL), and sodium iodide (2198.4 mg, 14.667 mmol) and TMSCl (1.116 mL, 8.800 mmol) were added. The reaction mixture was heated to 100 °C and stirred for 6 hours under nitrogen protection. The reaction was quenched by adding saturated NaHCO3 aqueous solution (30 mL), extracted with ethyl acetate (50 mL * 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the intermediate. The intermediate was added to silica gel (10 g) and NaHCO3 (600 mg), and stirred overnight at 60 °C. The mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%-10%) to give compound 10i (660 mg, yield 71%).

[0393] MS m / z(ESI): 316.0 [M+H] +

[0394] Step 7: Synthesis of compound 10j

[0395] Compound 10i (630 mg, 1.996 mmol) was dissolved in 1,4-dioxane (15 mL), and compound 10i-1 (1066.2 mg, 4.590 mmol), BINAP (372.8 mg, 0.599 mmol), cesium carbonate (1950.7 mg, 5.987 mmol), and palladium acetate (44.8 mg, 0.200 mmol) were added. The reaction mixture was heated to 100 °C and stirred for 6 hours under nitrogen protection. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–25%) to give compound 10j (900 mg, yield 88%).

[0396] MS m / z (ESI): 512.2 [M+H] +

[0397] Step 8: Synthesis of compound 10k

[0398] Compound 10j (700 mg, 1.369 mmol) was dissolved in compound 10j-1 (1 mL). The reaction mixture was heated to 110 °C and stirred for 1.5 hours under nitrogen protection. The reaction mixture was concentrated, diluted with saturated Na2CO3 aqueous solution (10 mL), extracted with ethyl acetate (30 mL * 2), dried over anhydrous sodium sulfate, and concentrated to give the oily compound 10k (330 mg, yield 59%).

[0399] MS m / z (ESI): 408.1 [M+H] +

[0400] Step 9: Synthesis of Compound 10

[0401] Compound 10k (150 mg, 0.293 mmol) was dissolved in trifluoroacetic anhydride (2 mL), and the reaction mixture was stirred at 90 °C for 3 hours. After the reaction mixture was concentrated to dryness, it was diluted with saturated sodium carbonate aqueous solution (10 mL), extracted with ethyl acetate (30 mL * 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0% - 26%) to give compound 10 (81.3 mg, yield 71%).

[0402] MS m / z(ESI): 390.1 [M+H] +

[0403] 1 H NMR(400MHz, Methanol-d4)δ8.41(d,J=0.9Hz,1H),7.60-7.54(m,1H),7.50(d, J=0.8Hz,1H),7.31-7.25(m,2H),4.50(t,J=6.3Hz,2H),2.94(t,J=6.3Hz,2H).

[0404] Example 17

[0405] Synthesis of compound 17b (Step 1)

[0406] Compound 17a (10 g, 52.627 mmol) was dissolved in DMSO (80 mL), followed by the addition of paraformaldehyde (1.6 g, 52.627 mmol) and then potassium tert-butoxide (5.9 g, 52.627 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction was quenched by adding saturated ammonium chloride aqueous solution (200 mL), and then extracted with ethyl acetate (200 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–25%) to give compound 17b (1.3 g, yield 11%).

[0407] MS m / z(ESI): 222.0 [M+H] +

[0408] The second step involves the synthesis of compound 17d.

[0409] Compound 17b (1.3 g, 5.856 mmol) was dissolved in 25% NaOH aqueous solution (20 mL), and TBAB (190.5 mg, 0.591 mmol) and compound 17c (1.405 mL, 11.816 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding saturated ammonium chloride aqueous solution (50 mL), and then extracted with ethyl acetate (50 mL * 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–5%) to give compound 17d (1.6 g, yield 87%).

[0410] The third step involves the synthesis of compound 17e.

[0411] Compound 17d (1600 mg, 5.159 mmol) was dissolved in dioxane (20 mL), and then hydrazine hydrate (10 mL) was added. The reaction mixture was stirred at 100 °C for 3 hours. The reaction solution was diluted with saturated Na₂CO₃ aqueous solution, and then extracted with ethyl acetate (100 mL * 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 17e (1.65 g, 99% yield).

[0412] MS m / z(ESI): 324.1 [M+H] +

[0413] The fourth step: synthesis of compound 17f

[0414] Compound 17e (1000 mg, 3.104 mmol) was dissolved in trifluoroacetic anhydride (10 mL), and the reaction mixture was heated to 70 °C and stirred for 2 hours under nitrogen protection. The reaction was quenched at 0 °C with saturated Na₂CO₃ aqueous solution, followed by extraction with ethyl acetate (50 mL x 2). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–25%) to give compound 17f (500 mg, 40% yield).

[0415] MS m / z(ESI): 402.0 [M+H] +

[0416] Step 5: Synthesis of compound 17h

[0417] Compound 17g-1 (3.3g, 14.834mmol) was dissolved in DMF (50mL), and NaH (771.4mg, 19.284mmol) was added in portions at 0°C, followed by stirring for 0.5 hours. Then, compound 17h (3300mg, 14.834mmol) was added, and the reaction mixture was stirred overnight at 100°C. The reaction was quenched by adding saturated ammonium chloride aqueous solution (100mL), followed by extraction with ethyl acetate (150mL*2). The organic phases were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–5%) to give compound 17h (2.9g, yield 68%).

[0418] MS m / z(ESI): 288.0 [M+H] +

[0419] Step 6: Synthesis of compound 17i

[0420] Compound 17h (2800 mg, 9.789 mmol) was dissolved in dioxane (30 mL), and compound 7h-1 (4971.4 mg, 19.577 mmol), KOAc (1921.3 mg, 19.577 mmol), and Pd(dppf)Cl2.CH2Cl2 (801.3 mg, 0.979 mmol) were added. The reaction mixture was heated to 100 °C and stirred overnight under nitrogen protection. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–5%) to give compound 17i (2300 mg, yield 71%).

[0421] MS m / z(ESI): 334.2 [M+H] +

[0422] Step 7: Synthesis of compound 17j

[0423] Compound 17i (300 mg, 0.750 mmol) was dissolved in dioxane (8 mL) / water (2 mL), and compound 17f (749 mg, 2.248 mmol), Pd(dppf)Cl2.CH2Cl2 (61 mg, 0.075 mmol) and potassium phosphate (345 mg, 1.498 mmol) were added. The reaction mixture was heated to 110 °C and stirred for 3 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–30%) to give compound 17j (260 mg, yield 66%).

[0424] MS m / z (ESI): 527.2 [M+H] +

[0425] Step 8: Synthesis of compound 17k

[0426] Compound 17j (180 mg, 0.342 mmol) was dissolved in NMP (3 mL), and LiCl (145 mg, 3.421 mmol) and p-toluenesulfonic acid (589 mg, 3.420 mmol) were added. The reaction mixture was stirred at 180 °C for 1.5 hours. An aqueous solution (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined and concentrated to obtain an oily substance, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–40%) to give compound 17k (130 mg, 74% yield).

[0427] MS m / z (ESI): 513.2 [M+H] +

[0428] Step 9: Synthesis of compound 17l

[0429] Compound 17k (130 mg, 0.254 mmol) was dissolved in methanol (5 mL), and 5% Pd / C (30 mg, 0.282 mmol) was added. The reaction solution was stirred at room temperature for 6 hours under a hydrogen atmosphere. After filtration, the filtrate was concentrated to give compound 17l (100 mg, 93% yield).

[0430] MS m / z(ESI): 423.01 [M+H] +

[0431] Step 10: Synthesis of Compound 17

[0432] Under nitrogen protection, compound 17 (60 mg, 0.142 mmol) was dissolved in THF (3 mL), and triphenylphosphine (111.8 mg, 0.426 mmol) was added. DIAD (0.084 mL, 0.426 mmol) was slowly added dropwise at 0 °C, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with saturated ammonium chloride aqueous solution (5 mL), extracted with ethyl acetate (20 mL * 3), and the organic phases were combined. After concentration under reduced pressure, the mixture was purified by high performance liquid chromatography (C18, 0.1% ammonium bicarbonate aqueous solution / acetonitrile), and the concentrate yielded compound 17 (3.2 mg, yield 6%).

[0433] MS m / z (ESI): 405.1 [M+H] +

[0434] 1 H NMR (400MHz, Methanol-d4) δ8.45 (s, 1H), 8.22 (s, 1H), 7.81 (d, J = 1.0Hz, 1H), 6.5 8(s,1H),4.84(q,J=8.7Hz,2H),4.50(q,J=7.3,6.6Hz,2H),3.05(t,J=5.9Hz,2H).

[0435] Example 18

[0436] Synthesis of compound 18b (Step 1)

[0437] Compound 3a-3 (3000 mg, 12.072 mmol), compound 18a (2655.34 mg, 12.072 mmol), and K3PO4 (7687.36 mg, 36.217 mmol) were dissolved in a mixed solution of dioxane (50 mL) and H2O (10 mL). Under nitrogen protection, Pd(dppf)Cl2·CH2Cl2 (988.29 mg, 1.207 mmol) was added, and the reaction was carried out at 100 °C for 3 hours. The water phase was directly removed, the organic phase was concentrated, and purified by column chromatography to give compound 18b (3000 mg, 72% yield).

[0438] Compound 3a-3 was prepared according to the synthesis of 3a-3 in Example 3;

[0439] MS m / z(ESI): 344.1 [M+H] +

[0440] The third step involves the synthesis of compound 18c.

[0441] Compound 18b (3000 mg, 8.728 mmol) was dissolved in HCl (10 mL) and THF (40 mL) and stirred at 60 °C for 2 hours. The reaction solution was diluted directly with purified water (50 mL), extracted with ethyl acetate (50 mL * 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 18c (2300 mg, 80% yield).

[0442] MS m / z(ESI): 330.1 [M+H] +

[0443] The fourth step: synthesis of compound 18d

[0444] Compound 18c (2200 mg, 6.673 mmol) was dissolved in MeOH (30 mL), cooled to 0 °C, and then NaBH4 (2524.27 mg, 66.727 mmol) was added. The reaction mixture was reacted for 2 hours. The reaction solution was diluted with purified water (50 mL), extracted with ethyl acetate (50 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 18d (2100 mg, 95% yield).

[0445] MS m / z(ESI): 332.1 [M+H] +

[0446] Step 5: Synthesis of compound 18e

[0447] Compound 18d (2100 mg, 6.331 mmol) was dissolved in DCM (50 mL), cooled to 0 °C, and boron tribromide (1 M in DCM, 31.653 mL, 31.653 mmol) was added dropwise. The mixture was reacted at 0 °C for 1 hour, then heated to room temperature and stirred overnight. The reaction solution was quenched with methanol (10 mL), extracted with ethyl acetate (100 mL), and then washed successively with saturated sodium bicarbonate (50 mL) and saturated sodium chloride (20 mL). After drying with anhydrous sodium sulfate, the mixture was filtered and concentrated to give compound 18e (1800 mg, 90% yield).

[0448] MS m / z (ESI): 318.1 [M+H] +

[0449] Step 6: Synthesis of compound 18f

[0450] Compound 18e (1800 mg, 5.666 mmol) was dissolved in THF (30 mL), then PPh3 (2972.20 mg, 11.332 mmol) and DIAD (2.231 mL, 11.332 mmol) were added, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous solution of NH4Cl (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 2). The liquid was separated. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain an oily substance, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–10%) to give compound 18f (800 mg, yield 47%).

[0451] MS m / z(ESI): 300.1 [M+H] +

[0452] Step 7: Synthesis of compound 18g

[0453] Compound 18f (750 mg, 2.503 mmol) was dissolved in 1,4-dioxane (10 mL), and compound 3b (1337.05 mg, 5.756 mmol), BINAP (467.52 mg, 0.751 mmol), cesium carbonate (2446.28 mg, 7.508 mmol), and palladium acetate (56.19 mg, 0.250 mmol) were added. The reaction mixture was heated to 100 °C and stirred for 5 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–20%) to give compound 18 g (1100 mg, yield 89%).

[0454] MS m / z(ESI): 396.2 [M+H-100] +

[0455] Step 8: Synthesis of compound 18i

[0456] Compound 18 g (1050 mg, 2.119 mmol) was dissolved in compound 18 h (5 mL), and the reaction mixture was heated to 110 °C and stirred for 3 hours under nitrogen protection. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 0%-10%) to give compound 18i (950 mg, 99% yield).

[0457] MS m / z(ESI): 452.0 [M+H] +

[0458] Step 9: Synthesis of compound 18j

[0459] Compound 18i (900 mg, 1.990 mmol) was dissolved in p-xylene (3 mL), and phosphorus oxychloride (3 mL) was added. The mixture was heated in an oil bath at 140 °C and stirred for 3 hours. After quenching the reaction with saturated NaHCO3 aqueous solution (50 mL), the mixture was extracted with ethyl acetate (50 mL * 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain an oily substance. The oil was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–30%). The product was concentrated to give compound 18j (110 mg, yield 13%).

[0460] MS m / z(ESI): 436.0 [M+H] +

[0461] Step 10: Synthesis of Compound 18

[0462] Compound 18j (110 mg, 0.253 mmol) and AgBF4 (148.22 mg, 0.760 mmol) were dissolved in ethanol (5 mL) and reacted at 80 °C for 3 hours. The reaction was quenched with saturated sodium bicarbonate (20 mL), extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography to give a white solid, which was lyophilized to give compound 18 (33.9 mg, yield 34%).

[0463] MS m / z (ESI): 400.1 [M+H] +

[0464] 1 H NMR (400MHz, Methanol-d4) δ8.42(s,1H),7.78(d,J=1.0Hz,1H),7.64(d,J=8.0Hz,1H),7.58-7.52(m,1H),7.4 0(d,J=1.8Hz,1H),4.47(t,J=6.4Hz,2H),4.22(q,J=7.1Hz,2H),2.94(t,J=6.3Hz,2H),1.33(t,J=7.1Hz,3H).

[0465] Example 19

[0466] Synthesis of compound 19b (Step 1)

[0467] Compound 19a (4500 mg, 31.661 mmol) was dissolved in hexafluoroisopropanol (50 mL), cooled in an ice bath, and NBS (6762.09 mg, 37.994 mmol) was added in portions under nitrogen protection. The mixture was then stirred at room temperature for 1 hour. The reaction was quenched with saturated sodium bicarbonate aqueous solution (60 mL), extracted with ethyl acetate (40 mL x 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–3%) to obtain compound 19b (6 g, yield 43%, purity 50%).

[0468] The second step involves the synthesis of compound 19d.

[0469] Compound 19b (4841 mg, 21.902 mmol) was dissolved in DMF (30 mL), and K2CO3 (6053.84 mg, 43.805 mmol) and compound 9c (5568.11 mg, 21.902 mmol) were added. The mixture was heated to 110 °C and reacted for 16 hours. The solution was diluted with water (50 mL), extracted with ethyl acetate (30 mL x 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–10%) to obtain compound 19d (5 g, 75% yield).

[0470] The third step involves the synthesis of compound 19e.

[0471] Compound 19d (5000 mg, 16.556 mmol) and pinacol diboronate (5207 mg, 19.796 mmol) were dissolved in dioxane (60 mL). Pd(dppf)Cl2.CH2Cl2 (675 mg, 0.825 mmol) and KOAc (3238 mg, 32.994 mmol) were added. The system was purged with nitrogen and then sealed and reacted at 100 °C for 1 hour. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–20%) to give compound 19e (2.2 g, yield 38%).

[0472] MS m / z (ESI): 351.2 [M+H] +

[0473] The fourth step involves the synthesis of compound 19g.

[0474] Compound 3a-3 (1200 mg, 4.829 mmol) and compound 19e (1700 mg, 4.856 mmol) were dissolved in dioxane (36 mL), and Pd(dppf)Cl2.CH2Cl2 (197.66 mg, 0.241 mmol), K3PO4 (2049.96 mg, 9.658 mmol) and H2O (12 mL) were added. After purging the system with nitrogen, the mixture was sealed and reacted at 100 °C for 2 hours. The mixture was diluted with water (100 mL), extracted with ethyl acetate (50 mL * 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude compound 19 g (1.4 g, yield 74%).

[0475] MS m / z(ESI): 392.1 [M+H] +

[0476] Compound 3a-3 was prepared according to the synthesis of 3a-3 in Example 3;

[0477] Step 5: Synthesis of compound 19h

[0478] 19 g (1400 mg, 3.574 mmol) of compound was dissolved in THF (10 mL), and concentrated hydrochloric acid (5 mL) was added. The mixture was reacted at 60 °C for 3 hours. The solution was diluted with water (40 mL), extracted with ethyl acetate (30 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 19h (1.4 g), which was used directly in the next reaction.

[0479] MS m / z(ESI): 378.1 [M+H] +

[0480] Step 6: Synthesis of Compound 19i

[0481] Compound 19h (1300 mg, 3.442 mmol) was dissolved in MeOH (20 mL), and NaBH4 (260.40 mg, 6.883 mmol) was added in portions. The reaction was allowed to proceed at room temperature for 1 hour. The reaction was quenched with saturated ammonium chloride aqueous solution (0.5 mL), concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%-80%) to give compound 19i (1158 mg, yield 89%).

[0482] MS m / z(ESI): 380.1 [M+H] +

[0483] Step 7: Synthesis of compound 19j

[0484] Compound 19i (1158 mg, 3.049 mmol) was dissolved in DCM (10 mL), cooled in an ice bath, and 2 M BBr3 / DCM (7.5 mL, 15 mmol) was added under nitrogen protection. The mixture was stirred at room temperature for 16 hours. The reaction was quenched with methanol (1 mL), diluted with water (50 mL), extracted with dichloromethane (50 mL x 3), and the organic phase was concentrated under reduced pressure to give compound 19j (900 mg, 81% yield).

[0485] MS m / z(ESI): 366.1 [M+H] +

[0486] Step 8: Synthesis of compound 19k

[0487] Compound 19j (850 mg, 2.324 mmol) and PPh3 (731 mg, 2.787 mmol) were dissolved in THF (25 mL), cooled in an ice bath, and under nitrogen protection, a THF solution of DIAD (939 mg, 4.644 mmol) (2 mL) was added. The reaction was carried out at room temperature for 30 minutes. The mixture was diluted with water (50 mL), extracted with ethyl acetate (30 mL x 3), concentrated the organic phase, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%-70%) to give compound 19k (860 mg, yield 90%, purity 85%).

[0488] MS m / z(ESI): 348.0 [M+H] +

[0489] Step 9: Synthesis of compound 19l

[0490] Compound 19k (900 mg, 2.588 mmol) and di-tert-butyl azide dicarboxylate (1202 mg, 5.175 mmol), Pd2(dba)3 (237 mg, 0.259 mmol), XantPhos (300 mg, 0.518 mmol), and Cs2CO3 (1686 mg, 5.175 mmol) were dissolved in dioxane (10 mL). After purging the system with nitrogen, the mixture was sealed and reacted at 100 °C for 16 hours. The reaction solution was concentrated under reduced pressure and then purified directly by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–80%) to give compound 19l (350 mg, yield 25%).

[0491] MS m / z (ESI): 444.1 [M-100+H] +

[0492] Step 10: Synthesis of compound 19m

[0493] Compound 19l (340 mg, 0.626 mmol) was dissolved in monochlorodifluoroacetic acid (6 mL) and reacted at 100 °C for 16 hours. The pH was adjusted to 8 with saturated sodium carbonate aqueous solution, and then extracted with ethyl acetate (20 mL * 3). The extract was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound 19m (360 mg), which was used directly in the next step.

[0494] MS m / z(ESI): 456.0 [M+H] +

[0495] Step 11: Synthesis of compound 19n

[0496] Compound 19m (360 mg, 0.79 mmol) was dissolved in p-xylene (6 mL), and phosphorus oxychloride (2 mL) was added. The mixture was reacted at 150 °C for 3 hours. After concentration, the mixture was extracted with saturated sodium bicarbonate aqueous solution (40 mL), ethyl acetate (20 mL * 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%-50%) to give compound 19n (66 mg, yield 19%).

[0497] MS m / z(ESI): 438.0 [M+H] +

[0498] Step 12: Synthesis of Compound 19

[0499] Compound 19n (66 mg, 0.151 mmol) was dissolved in anhydrous ethanol (5 mL), and silver tetrafluoroborate (146.76 mg, 0.754 mmol) was added. After purging the system with nitrogen, the mixture was sealed and reacted at 85 °C for 4 hours. The mixture was then cooled to room temperature, quenched with saturated sodium carbonate aqueous solution (3 mL), filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%–50%) to give compound 19 (27.17 mg, yield 41%).

[0500] MS m / z(ESI): 438.0 [M+H] +

[0501] 1H NMR (400MHz, DMSO-d6) δ8.46(s,1H),8.00(s,1H),7.60(d,J=11.6Hz,1H),7.25(d,J=7.7Hz,1H),4.94(q, J=8.8Hz,2H),4.44(t,J=6.4Hz,2H),4.26(q,J=7.1Hz,2H),2.96(t,J=6.3Hz,2H),1.35(t,J=7.1Hz,3H).

[0502] Example 20

[0503] Synthesis of compound 20a-3 (Step 1)

[0504] Compound 20a-1 (10 g, 49.253 mmol), compound 20a-2 (15.0 g, 98.505 mmol), and cesium carbonate (48.1 g, 147.758 mmol) were dissolved in DMF (100 mL), purged three times with nitrogen, and then reacted overnight at 90 °C. The mixture was directly filtered, and the filter cake was washed with DCM (30 mL). Then, 10% LiCl aqueous solution (200 mL) was added to the solution, and the mixture was stirred briefly. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (30 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–10%) to obtain compound 20a-3 (6.11 g, yield 49%).

[0505] MS m / z (ESI): 254.9 [M+H] +

[0506] The second step involves the synthesis of compound 20a.

[0507] Compound 20a-3 (2000 mg, 7.904 mmol), compound 20a-4 (2609.2 mg, 10.275 mmol), and potassium acetate (2598.6 mg, 26.478 mmol) were added to isopropyl acetate (50 mL). Under nitrogen protection, X-Phos (75.4 mg, 0.158 mmol) and XPhos Pd G3 (401.4 mg, 0.474 mmol) were added, and the reaction was carried out overnight at 90 °C. After the reaction solution cooled to room temperature, it was diluted directly with purified water (30 mL), extracted with DCM (20 mL * 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–20%) to obtain compound 20a (1.73 g, yield 73%).

[0508] MS m / z (ESI): 301.2 [M+H] +

[0509] The third step involves the synthesis of compound 20b.

[0510] Compound 20a (1.73 g, 5.765 mmol), compound 3a-3 (1.3 g, 5.188 mmol), and K3PO4 (3.7 g, 17.294 mmol) were dissolved in dioxane (20 mL) and H2O (4 mL). Under nitrogen protection, Pd(dppf)Cl2.CH2Cl2 (0.5 g, 0.576 mmol) was added, and the reaction was carried out at 100 °C for 2 hours. After cooling to room temperature, the reaction solution was diluted directly with purified water (50 mL), extracted with ethyl acetate (30 mL x 3), and the organic phases were combined. The mixture was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–30%) to obtain compound 20b (1.51 g, 85% yield).

[0511] MS m / z(ESI): 342.1 [M+H] +

[0512] The preparation of compound 3a-3 was carried out in accordance with the synthesis of compound 3a-3 in Example 3.

[0513] Step 4: Synthesis of compound 20c

[0514] Compound 20b (2 g, 5.852 mmol) was dissolved in HCl (5 mL) and THF (10 mL) and stirred at 60 °C for 2 hours. After cooling to room temperature, ethyl acetate (50 mL) was added directly, followed by slow addition of saturated sodium bicarbonate (50 mL * 2) for washing. The organic phase was washed with saturated brine (30 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 20c (2.67 g).

[0515] MS m / z(ESI): 328.0 [M+H] +

[0516] Step 5: Synthesis of compound 20d

[0517] Compound 20c (3.0 g, 9.154 mmol) was dissolved in methanol (30 mL), cooled to 0 °C, and then NaBH4 (276.64 mg, 7.313 mmol) was added. The mixture was reacted at room temperature for 2 hours. Purified water (50 mL) and ethyl acetate (50 mL x 2) were added directly to the reaction solution for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 20d (2.7 g, 89% yield).

[0518] MS m / z(ESI): 330.3 [M+H]+

[0519] Step 6: Synthesis of compound 20e

[0520] Compound 20d (2.7 g, 8.189 mmol) was dissolved in DCM (20 mL), cooled to 0 °C, and boron tribromide (2 M in DCM, 20.471 mL, 40.943 mmol) was added dropwise. The mixture was allowed to rise naturally to room temperature and stirred overnight. The reaction solution was diluted with ethyl acetate (80 mL), and then washed successively with saturated sodium bicarbonate (30 mL * 2) and saturated sodium chloride (20 mL). After drying with anhydrous sodium sulfate, the solution was filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%-100%) to give compound 20e (0.87 g, yield 40%).

[0521] MS m / z(ESI): 266.0 [M+H] +

[0522] Step 7: Synthesis of compound 20f

[0523] Compound 20e (820 mg, 3.086 mmol) and PPh3 (810 mg, 3.088 mmol) were dissolved in THF (70 mL), and then a THF solution of DIAD (624 mg, 3.086 mmol) in THF (10 mL) was added. The mixture was purged with nitrogen three times and stirred overnight at room temperature. Since some reactants were not completely reacted, PPh3 (810 mg, 3.088 mmol) and DIAD (624 mg, 3.086 mmol) were added separately, and the mixture was purged with nitrogen again and reacted for another 5 hours. The mixture was then extracted directly with purified water (100 mL) and ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%-50%) to obtain crude compound 20f (1700 mg).

[0524] MS m / z(ESI): 248.1 [M+H] +

[0525] Step 8: Synthesis of compound 20h

[0526] Compound 20f (1.7 g, 6.864 mmol), compound 20g (3.1 g, 20.591 mmol), and Cs₂CO₃ (11.2 g, 34.319 mmol) were dissolved in N,N-dimethylformamide (50 mL) and H₂O (10 mL). The mixture was stirred overnight at 105 °C under nitrogen protection. After the reaction solution cooled to room temperature, it was diluted with ethyl acetate (100 mL), and then washed successively with purified water (20 mL x 3), saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–50%) to obtain compound 20h (200 mg, yield 10%).

[0527] MS m / z(ESI): 298.1 [M+H] +

[0528] Step 9: Synthesis of compound 20j

[0529] Compound 20h (180 mg, 0.605 mmol), compound 20i (323.0 mg, 1.391 mmol), Cs₂CO₃ (591.0 mg, 1.814 mmol), Pd(OAc)₂ (13.6 mg, 0.060 mmol), and BINAP (37.7 mg, 0.060 mmol) were dissolved in dioxane (10 mL) and stirred overnight at 100 °C under nitrogen protection. After the reaction solution cooled to room temperature, purified water (30 mL) was added directly to dilute the solution. The mixture was extracted with ethyl acetate (20 mL x 3), and the organic phases were combined. The mixture was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–50%) to obtain compound 20j (130 mg, yield 44%).

[0530] MS m / z(ESI): 394.2 [M-100+H] +

[0531] Step 10: Synthesis of compound 20k

[0532] Compound 20j (120 mg, 0.243 mmol) was dissolved in TFA (2 mL, 26.118 mmol) and reacted at 110 °C for 1 hour. After concentration, the crude product was diluted with ethyl acetate (30 mL), washed with saturated sodium bicarbonate (20 mL * 2), and the aqueous phases were combined and extracted with ethyl acetate (20 mL * 2). The organic phases were combined, washed with saturated brine (20 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 20k (90 mg).

[0533] MS m / z(ESI): 390.1 [M+H]+

[0534] Step 11: Synthesis of Compound 20

[0535] Compound 20k (80 mg, 0.206 mmol) was dissolved in TFAA (2 mL) and stirred at 90 °C for 1 hour. After the reaction solution cooled to room temperature, it was directly concentrated and then diluted with ethyl acetate (20 mL). The mixture was washed with saturated sodium bicarbonate (20 mL x 2), and the combined aqueous phases were extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%-50%) to give compound 20 (24.24 mg, yield 32%).

[0536] MS m / z(ESI): 372.1 [M+H] +

[0537] 1 H NMR (400MHz, DMSO-d6) δ8.62(s,1H),8.14(d,J=1.0Hz,1H),7.76(d,J=8.5Hz,1H),7.52(d,J=73. 7Hz,1H),7.28-7.18(m,1H),7.12(d,J=2.5Hz,1H),4.54(t,J=6.3Hz,2H),3.04(t,J=6.3Hz,2H).

[0538] Example 21

[0539] Synthesis of compound 21b in step one

[0540] Compound 21a (3000 mg, 14.632 mmol), pinacol diboronate (4459 mg, 17.559 mmol), Pd(dppf)Cl2.CH2Cl2 (599 mg, 0.732 mmol), and KOAc (2872 mg, 29.264 mmol) were dissolved in dioxane (100 mL). The system was purged with nitrogen and then sealed for reaction at 100 °C for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 21b (3000 mg, 81% yield), which was used directly in the next step.

[0541] The second step involves the synthesis of compound 21d.

[0542] Compound 21b (3000 mg, 11.9 mmol) and compound 21c (2700 mg, 10.865 mmol) were dissolved in dioxane (30 mL). Under nitrogen protection, Pd(dppf)Cl2.CH2Cl2 (487.1 mg, 0.595 mmol), K3PO4 (5052.0 mg, 23.801 mmol), and H2O (10 mL) were added. The mixture was sealed and reacted at 100 °C for 3 hours. After cooling to room temperature, the mixture was diluted with water (120 mL), extracted with ethyl acetate (50 mL * 3), washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%-50%) to obtain compound 21d (1300 mg, yield 41%).

[0543] MS m / z(ESI): 294.1 [M+H] +

[0544] The third step involves the synthesis of compound 21e.

[0545] Compound 21d (1290 mg, 4.392 mmol) was dissolved in THF (10 mL), and concentrated hydrochloric acid (5 mL) was added. The mixture was reacted at 60 °C for 3 hours. After dilution with water (50 mL), extraction with ethyl acetate (30 mL x 3), washing with saturated brine (20 mL), drying over anhydrous sodium sulfate, filtering, and concentration under reduced pressure, compound 21e (1228 mg, 100% yield) was obtained.

[0546] MS m / z (ESI): 280.1 [M+H] +

[0547] The fourth step is the synthesis of compound 21f.

[0548] Compound 21e (1228 mg, 4.39 mmol) was dissolved in methanol (15 mL), and NaBH4 (332.2 mg, 8.781 mmol) was added in portions. The mixture was stirred at room temperature for 1 hour. The reaction was quenched with saturated ammonium chloride solution (2 mL), and the solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%-100%) to give compound 21f (900 mg, yield 73%).

[0549] MS m / z(ESI): 282.1 [M+H] +

[0550] Step 5: Synthesis of compound 21g

[0551] Compound 21f (900 mg, 3.195 mmol) was dissolved in dichloromethane (10 mL), cooled in an ice bath, and 2 M BBr3 / DCM (8 mL, 16 mmol) was added under nitrogen protection. The mixture was stirred at room temperature for 16 hours. The reaction solution was added to ice water (30 mL), concentrated under reduced pressure, extracted with ethyl acetate (30 mL * 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 21 g (850 mg, 99% yield).

[0552] MS m / z(ESI): 268.1 [M+H] +

[0553] Step 6: Synthesis of compound 21h

[0554] 21 g (865 mg, 3.231 mmol) of compound was dissolved in THF (30 mL), and PPh3 (1695.1 mg, 6.463 mmol) was added. The mixture was cooled in an ice bath, and under nitrogen protection, a THF solution of DIAD (2613.7 mg, 12.926 mmol) was added dropwise (4 mL). The mixture was stirred at room temperature for 3 hours. The reaction was quenched with saturated ammonium chloride solution (5 mL), diluted with water (50 mL), extracted with ethyl acetate (20 mL * 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%-50%) to give compound 21h (620 mg, yield 77%).

[0555] MS m / z(ESI): 250.0 [M+H] +

[0556] Step 7: Synthesis of compound 21i

[0557] Compound 21h (600 mg, 2.403 mmol), 21h-1 (1674.6 mg, 7.210 mmol), palladium acetate (54.0 mg, 0.240 mmol), BINAP (448.9 mg, 0.721 mmol), and Cs₂CO₃ (2349.0 mg, 7.210 mmol) were dissolved in dioxane (13 mL). After purging the system with nitrogen, the mixture was sealed and reacted at 100 °C for 16 hours. The reaction solution was diluted with water (50 mL), extracted with ethyl acetate (25 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–50%) to give compound 21i (1300 mg, yield 97%, purity 80%).

[0558] MS m / z(ESI): 346.2 [M-100+H]+

[0559] Step 8: Synthesis of compound 21j

[0560] Compound 21i (400 mg, 0.898 mmol) was dissolved in TFA (6 mL) and reacted at 80 °C for 3 hours. After concentration under reduced pressure, it was extracted with saturated sodium bicarbonate aqueous solution (20 mL), ethyl acetate (20 mL * 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 21j (300 mg, 98% yield).

[0561] MS m / z(ESI): 342.2 [M+H] +

[0562] Step 9: Synthesis of Compound 21

[0563] Compound 21j (100 mg, 0.293 mmol) was dissolved in trifluoroacetic anhydride (3 mL) and reacted at 80 °C under sealed conditions for 3 hours. After concentration under reduced pressure, the solution was diluted with sodium bicarbonate aqueous solution (20 mL), extracted with ethyl acetate (15 mL * 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%-50%) to obtain compound 21 (20.57 mg, yield 22%).

[0564] MS m / z(ESI): 324.1 [M+H] +

[0565] 1 H NMR (400MHz, DMSO-d6) δ8.56(s,1H),8.08(d,J=1.0Hz,1H),7.70(dd,J=8.6,6.6Hz,1H),7.22( td,J=8.6,2.7Hz,1H),7.14(dd,J=9.7,2.7Hz,1H),4.48(t,J=6.3Hz,2H),2.98(t,J=6.3Hz,2H)

[0566] Example 22

[0567] Synthesis of compound 22a in step one

[0568] 18 g (600 mg, 1.211 mmol) of compound TFA was dissolved in 3 mL of compound TFA. The reaction mixture was heated to 110 °C and stirred for 1.5 h under nitrogen protection. The reaction mixture was concentrated, diluted with 10 mL of saturated Na₂CO₃ aqueous solution, extracted with ethyl acetate (30 mL * 2), and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate and concentrated to give compound 22a (400 mg, yield 84%).

[0569] MS m / z(ESI): 392.1 [M+H] +

[0570] The preparation of compound 18g was carried out in accordance with the synthesis and preparation of compound 18g in Example 18.

[0571] The second step involves the synthesis of compound 22.

[0572] Compound 22a (100 mg, 0.256 mmol) was dissolved in trifluoroacetic anhydride (2 mL), and the reaction mixture was heated to 90 °C and stirred for 3 hours under nitrogen protection. The reaction mixture was evaporated to dryness, and saturated Na₂CO₃ aqueous solution (10 mL) was added, followed by ethyl acetate (30 mL * 2). The mixture was separated. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain an oily substance, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0% - 26%) to give compound 22 (59.55 mg, yield 62%).

[0573] MS m / z(ESI): 374.1 [M+H] +

[0574] 1 H NMR (400MHz, Methanol-d4) δ8.46 (s, 1H), 7.85 (d, J = 1.0Hz, 1H), 7.75 -7.66(m,1H),7.59-7.53(m,1H),7.40(d,J=1.9Hz,1H),4.47(t,J=6.4Hz,2H),2.99-2.91(m,2H).

[0575] Example 23

[0576] Synthesis of compound 23b in step one

[0577] Compound 23a (4000 mg, 17.693 mmol), tetrabutylammonium bromide (285.2 mg, 0.885 mmol), and KOH (9927.8 mg, 176.934 mmol) were dissolved in toluene (80 mL) and H₂O (8 mL). Finally, 1,2-dibromoethane (166.2 mg, 0.885 mmol) was added, and the mixture was reacted at 100 °C for 1 hour. After concentration under reduced pressure, the mixture was diluted with water (50 mL), extracted with ethyl acetate (40 mL * 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–20%) to give compound 23b (4600 mg, yield 63%, purity 61%).

[0578] MS m / z(ESI): 252.0 [M+H] +

[0579] The second step involves the synthesis of compound 23c.

[0580] Compound 23b (5041.3 mg, 19.852 mmol) and pinacol diboronate (4550 mg, 18.048 mmol) were dissolved in dioxane (80 mL). Pd(dppf)Cl2.CH2Cl2 (738.7 mg, 0.902 mmol) and KOAc (5313.6 mg, 54.143 mmol) were added. The system was purged with nitrogen and then sealed and reacted at 100 °C for 5 hours. The mixture was diluted with water (200 mL), extracted with ethyl acetate (100 mL * 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–20%) to give compound 23c (2600 mg, yield 48%).

[0581] The third step involves the synthesis of compound 23e.

[0582] Compound 23c (2600 mg, 8.691 mmol) and compound 23d (2000 mg, 8.048 mmol) were added to a sealed tube, followed by Pd(dppf)Cl2.CH2Cl2 (355.7 mg, 0.435 mmol), K3PO4 (5533.9 mg, 26.072 mmol), dioxane (45 mL), and H2O (15 mL). After purging the system with nitrogen, the tube was sealed and reacted at 90 °C for 5 hours. The mixture was diluted with water (100 mL), extracted with ethyl acetate (50 mL x 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–50%) to obtain compound 23e (2300 mg, yield 84%).

[0583] MS m / z(ESI): 341.1 [M+H] +

[0584] The fourth step involves the synthesis of compound 23f.

[0585] Compound 23e (3200 mg, 9.389 mmol) was dissolved in THF (7 mL), and concentrated hydrochloric acid (14 mL) was added. The mixture was reacted at 60 °C for 3 hours. The solution was diluted with water (30 mL), the pH was adjusted to 7-8 with saturated sodium carbonate solution, extracted with ethyl acetate (30 mL x 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound 23f (3 g, yield 39%, purity 40%).

[0586] MS m / z (ESI): 327.1 [M+H] +

[0587] Step 5: Synthesis of compound 23g

[0588] Compound 23f (2950 mg, 9.027 mmol) was dissolved in methanol (30 mL), and NaBH4 (683.0 mg, 18.055 mmol) was added in portions. The reaction was carried out at room temperature for 1 hour. After concentration under reduced pressure, the solution was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%-80%) to give compound 23 g (380 mg, yield 13%).

[0589] MS m / z(ESI): 329.2 [M+H] +

[0590] Step 6: Synthesis of compound 23h

[0591] 23 g (340 mg, 1.034 mmol) of compound was dissolved in dichloromethane (10 mL), cooled in an ice bath, and 2 M BBr3 / DCM (2.5 mL, 5 mmol) was added under nitrogen protection. The mixture was stirred at room temperature for 16 hours. The reaction solution was slowly added to ice water (50 mL), concentrated under reduced pressure, extracted with ethyl acetate (30 mL x 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 23 h (420 mg), which was directly used in the next reaction.

[0592] MS m / z (ESI): 315.1 [M+H] +

[0593] Step 7: Synthesis of compound 23i

[0594] Compound 23h (400 mg, 1.271 mmol) was dissolved in THF (10 mL), and PPh3 (999.9 mg, 3.812 mmol) was added. The mixture was cooled in an ice bath, and under nitrogen protection, a THF solution of DIAD (1284.8 mg, 6.354 mmol) was added dropwise (2 mL). The reaction was carried out at room temperature for 3 hours. After quenching with saturated ammonium chloride solution (1 mL), the mixture was diluted with water (30 mL), extracted with ethyl acetate (20 mL * 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%-60%) to give compound 23i (350 mg, yield 93%).

[0595] MS m / z(ESI): 297.1 [M+H] +

[0596] Step 8: Synthesis of compound 23j

[0597] Di-tert-butyl azide dicarboxylate (1722.0 mg, 7.414 mmol), compound 23i (1100 mg, 3.707 mmol), palladium acetate (83.2 mg, 0.371 mmol), BINAP (692.5 mg, 1.112 mmol), and Cs₂CO₃ (2415.5 mg, 7.414 mmol) were sequentially added to a sealed tube. Dioxane (20 mL) was added, the system was purged with nitrogen, and the mixture was sealed and reacted overnight at 100 °C. The mixture was diluted with water (100 mL), extracted with ethyl acetate (30 mL x 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–80%) to give compound 23j (100 mg, 5% yield).

[0598] MS m / z (ESI): 437.2 [M-56+H] +

[0599] Step 9: Synthesis of compound 23k

[0600] Compound 23j (80 mg, 0.162 mmol) was added to a sealed tube, followed by 3 mL of trifluoroacetic acid. The tube was sealed and reacted at 80 °C for 3 hours. The reaction solution was concentrated under reduced pressure to obtain crude product 23k, which was then directly added to the next step.

[0601] MS m / z(ESI): 389.1 [M+H] +

[0602] Step 10: Synthesis of Compound 23

[0603] Compound 23k (60 mg, 0.154 mmol) from the previous step was dissolved in Boc2O (3 mL), and the mixture was sealed and reacted at 80 °C for 3 hours. After concentration under reduced pressure, the product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%-60%) to obtain the crude product. The crude product was then prepared by HPLC (acetonitrile / water = 20%-100%) to obtain compound 23 (11.1 mg, yield 19%).

[0604] MS m / z(ESI): 371.1 [M+H] +

[0605] 1 H NMR(600MHz,Chloroform-d)δ8.19(s,1H),7.83(s,1H),7.42(d,J=7.9Hz,1H),7.29-7.24(m,1H),7.1 3(d,J=2.0Hz,1H),4.54(t,J=6.3Hz,2H),2.98(t,J=6.3Hz,2H),1.86-1.81(m,2H),1.51-1.46(m,2H).

[0606] Example 24

[0607] Synthesis of compound 24a (Step 1)

[0608] Compound 10j (400 mg, 0.782 mmol) was dissolved in compound 24a-1 (5 mL). The reaction mixture was heated to 110 °C and stirred for 1.5 h under nitrogen protection. The reaction solution was concentrated under reduced pressure, the reaction was quenched with saturated sodium carbonate aqueous solution (10 mL), and extracted with ethyl acetate (20 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 24a (300 mg, 91% yield).

[0609] MS m / z(ESI): 424.0 [M+H] +

[0610] The preparation of compound 10j was carried out in accordance with the synthesis of compound 10j in Example 10.

[0611] The second step involves the synthesis of compound 24c.

[0612] Under nitrogen protection, compound 24a (280 mg, 0.661 mmol) was dissolved in compound 24b (3 mL), and the reaction mixture was stirred at 110 °C for 1 hour. The reaction was quenched with saturated sodium carbonate aqueous solution (10 mL), and extracted with ethyl acetate (20 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 24c (170 mg, 63% yield).

[0613] MS m / z(ESI): 406.0 [M+H] +

[0614] Step 3: Synthesis of Compound 24

[0615] Compound 24c (170 mg, 0.419 mmol) was dissolved in ethanol (5 mL), and silver tetrafluoroborate (326.3 mg, 1.676 mmol) was added. The reaction mixture was stirred at 90 °C for 3 hours. Saturated sodium bicarbonate aqueous solution (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined and concentrated to obtain an oil, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–38%). After concentration, compound 24 (88 mg, yield 51%) was obtained.

[0616] MS m / z (ESI): 416.1 [M+H] +

[0617] 1 H NMR (400MHz, Methanol-d4) δ8.38 (s, 1H), 7.55-7.50 (m, 1H), 7.42 (d, J = 0.8Hz, 1H), 7.31-7.25 (m ,2H),4.48(t,J=6.3Hz,2H),4.22(q,J=7.1Hz,2H),2.93(t,J=6.3Hz,2H),1.33(t,J=7.1Hz,3H).

[0618] Example 27

[0619] Synthesis of compound 27b (Step 1)

[0620] Compound 27a (5100 mg, 21.793 mmol) was added to a three-necked flask, followed by the addition of THF (100 mL). The mixture was cooled to -60°C in a dry ice-ethanol bath under nitrogen protection. DIBAL-H (46 mL, 46.00 mmol, 1 M in THF) was added dropwise, and the mixture was kept at this temperature for 1 hour. After heating to room temperature and stirring for 2 hours, LC-MS monitoring showed that the reaction proceeded completely. Methanol (5 mL) and saturated ammonium chloride (5 mL) were added, and the mixture was stirred overnight. The mixture was then filtered, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%-30%) to give compound 27b (4200 mg, 94% yield).

[0621] MS m / z(ESI): 206.0 [M+H] +

[0622] The second step involves the synthesis of compound 27c.

[0623] Compound 27b (3800 mg, 18.445 mmol) was added to a round-bottom flask and dissolved in 80 mL of ACN. 2-Iodobenzoic acid (10330.1 mg, 36.891 mmol) was added with stirring. The mixture was reacted at 80 °C for 2 hours, and the product was detected by LC-MS. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 27c (1700 mg, 45% yield).

[0624] MS m / z(ESI): 223.9 [M+20] +

[0625] The third step involves the synthesis of compound 27d.

[0626] (Methoxymethyl)triphenylphosphine chloride (10082.5 mg, 29.412 mmol) was dissolved in THF (60 mL), cooled in an ice-water bath, and potassium tert-butoxide (3465.3 mg, 30.883 mmol) was added in portions under nitrogen protection. The reaction mixture was stirred at 0 °C for 1 hour, then compound 27c (3000 mg, 14.706 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction was complete as determined by LC-MS. The reaction mixture was extracted with water (100 mL) and ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–30%) to give compound 27d (1750 mg, 51% yield).

[0627] MS m / z(ESI): 232.0 [M+H] +

[0628] The fourth step involves the synthesis of compound 27e.

[0629] 2,2,2-Trifluoroethanol (1.591 mL, 21.978 mmol) was dissolved in DMF (20 mL). The solution was cooled in an ice bath, and under nitrogen protection, 60% NaH (586.1 mg, 14.652 mmol) was added in portions. After stirring at room temperature for 15 minutes, a DMF solution of compound 27d (1700 mg, 7.326 mmol) was added. After stirring at room temperature for 2 hours, the product was detected by LC-MS. The solution was diluted with water (120 mL), extracted with ethyl acetate (50 mL x 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%-30%) to give compound 27e (1250 mg, yield 54%).

[0630] MS m / z(ESI): 314.0 [M+H] +

[0631] Step 5: Synthesis of compound 27f

[0632] Compound 27e (1230 mg, 3.941 mmol) was dissolved in 1,4-dioxane (40 mL), and pinacol diboronic acid ester (1201.0 mg, 4.729 mmol), KOAc (773.6 mg, 7.882 mmol), and Pd(dppf)Cl2.CH2Cl2 (161.3 mg, 0.197 mmol) were added. After purging the system with nitrogen, the reaction was carried out at 100 °C for 5 hours, and the reaction was complete as monitored by LCMS. The solution was diluted with water (50 mL), extracted with EA (30 mL x 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 27f (1415 mg, 100% yield).

[0633] MS m / z(ESI): 360.1 [M+H] +

[0634] Step 6: Synthesis of compound 27g

[0635] Compound 27f (1400 mg, 3.898 mmol) and compound 17g (867.2 mg, 3.898 mmol) were added to a round-bottom flask, along with Pd(dppf)Cl2.CH2Cl2 (319.1 mg, 0.390 mmol), K3PO4 (1654.8 mg, 7.796 mmol), dioxane (21 mL), and water (7 mL). After purging the system with nitrogen, the reaction was carried out at 80 °C for 2 hours, and the reaction was monitored by LCMS until complete. After cooling to room temperature, the mixture was diluted with water (80 mL), extracted with ethyl acetate (40 mL * 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–50%) to obtain compound 27g (676 mg, yield 46%).

[0636] MS m / z (ESI): 375.1 [M+H] +

[0637] Step 7: Synthesis of compound 27h

[0638] 27 g (656 mg, 1.751 mmol) of the compound was dissolved in 6 mL of THF, and 3 mL of concentrated hydrochloric acid (36%-38%) was added. The reaction was carried out at 60 °C for 3 hours, and the reaction was monitored by LCMS until it was complete. The solution was diluted with 50 mL of water, extracted with ethyl acetate (20 mL x 3), washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude compound 27 h (631 mg, 100% yield).

[0639] MS m / z(ESI): 361.0 [M+H] +

[0640] Step 8: Synthesis of compound 27i

[0641] Compound 27h (631 mg, 1.749 mmol) was dissolved in MeOH (15 mL), and NaBH4 (140 mg, 3.701 mmol) was added in portions. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until it was complete. After concentration under reduced pressure, the mixture was diluted with water (50 mL), extracted with ethyl acetate (25 mL * 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude compound 27i (1220 mg).

[0642] MS m / z(ESI): 363.1 [M+H] +

[0643] Step 9: Synthesis of compound 27j

[0644] Compound 27i (1200 mg, 3.308 mmol) was dissolved in THF (20 mL), cooled in an ice bath, and under nitrogen protection, tri-sec-butylborohydride (10 mL, 10.000 mmol, 1.0 M in THF) was added. The mixture was stirred at room temperature for 3 hours, and the reaction was monitored by LCMS until complete. The solution was diluted with water (60 mL), extracted with ethyl acetate (30 mL x 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%-100%) to give 27j (236 mg, yield 20%).

[0645] MS m / z (ESI): 349.1 [M+H] +

[0646] Step 10: Synthesis of compound 27k

[0647] Compound 27j (236 mg, 0.677 mmol) and PPh3 (355.0 mg, 1.354 mmol) were dissolved in tetrahydrofuran (11 mL). The mixture was cooled in an ice bath, and under nitrogen protection, DIAD (410.6 mg, 2.030 mmol) in tetrahydrofuran (1 mL) was added. After stirring at room temperature for 3 hours, the reaction was monitored by LCMS and found to be complete. The mixture was diluted with water (40 mL), extracted with ethyl acetate (20 mL * 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%-40%) to give crude compound 27k (234 mg).

[0648] MS m / z(ESI): 331.0 [M+H] +

[0649] Step 11: Synthesis of compound 27l

[0650] Compound 27l (214 mg, 0.647 mmol), di-tert-butyl hydrazine-1,2-dicarboxylate (375.8 mg, 1.618 mmol), palladium acetate (29.1 mg, 0.129 mmol), BINAP (120.9 mg, 0.194 mmol), cesium carbonate (632.5 mg, 1.941 mmol), and dioxane (10 mL) were added sequentially to a sealed tube. After purging the system with nitrogen, the tube was sealed and reacted at 100 °C for 16 hours. The reaction was monitored by LC-MS and found to be complete. The mixture was diluted with water (50 mL), extracted with ethyl acetate (30 mL x 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–50%) to obtain crude compound 27l (460 mg).

[0651] MS m / z(ESI): 427.1 [M+H] +

[0652] Step 12: Synthesis of compound 27m

[0653] Compound 27l (420 mg, 0.798 mmol) was added to a sealed tube, followed by 6 mL of trifluoroacetic acid. The tube was sealed and reacted overnight at 100 °C. The reaction was confirmed to be complete by LC-MS. After concentration, crude compound 27m (335 mg, 99% yield) was obtained.

[0654] MS m / z(ESI): 423.1 [M+H] +

[0655] Step 13: Synthesis of Compound 27

[0656] Compound 27m (330 mg, 0.781 mmol) was added to a sealed tube, followed by 6 mL of trifluoroacetic anhydride. The tube was sealed and reacted at 90 °C for 4 hours. The reaction was monitored by LCMS and found to be complete. After concentration under reduced pressure, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%-50%) to give compound 27 (115.73 mg, yield 37%).

[0657] MS m / z (ESI): 405.1 [M+H] +

[0658] 1H NMR (400MHz, DMSO-d6) δ8.74 (s, 1H), 8.38 (s, 1H), 7.78 (d, J = 0.7Hz, 1H), 7.1 2(s,1H),5.08(q,J=9.1Hz,2H),4.52(t,J=6.3Hz,2H),2.99(t,J=6.4Hz,2H).

[0659] Example 28

[0660] The first step is the synthesis of compound 28a.

[0661] Compound 10j (1.2 g, 2.346 mmol) was dissolved in 2,2-difluoroacetic acid (5 mL, 0.039 mmol), and the reaction mixture was sealed in a tube at 110 °C for 2 hours. After the reaction was complete, ethyl acetate (30 mL) was added directly to the reaction solution for dilution, followed by washing with saturated sodium bicarbonate (30 mL * 2). The aqueous phase was extracted with ethyl acetate (20 mL * 2), the organic phases were combined, washed with saturated brine (20 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 28a (650 mg).

[0662] MS m / z(ESI): 390.1 [M+H] +

[0663] The second step involves the synthesis of compound 28.

[0664] Compound 28a (260 mg, 0.668 mmol) was dissolved in 2,2-difluoroacetic anhydride (3 mL, 0.668 mmol) and stirred overnight at 95 °C. The reaction solution was directly concentrated, and then ethyl acetate (30 mL) was added. After washing with saturated sodium bicarbonate (30 mL * 2), the aqueous phase was extracted with ethyl acetate (30 mL * 2). The organic phases were combined, washed with saturated brine (20 mL * 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 0%-50%) to give compound 28 (83.94 mg, yield 34%).

[0665] MS m / z(ESI): 372.1 [M+H] +

[0666] 1 H NMR (400MHz, DMSO-d6) δ8.71(d,J=0.9Hz,1H),7.91-7.61(m,3H),7.52-7.43(m,2H),4.51(t,J=6.3Hz,2H),3.00(t,J=6.3Hz,2H).

[0667] Example 33

[0668] Synthesis of compound 33a (Step 1)

[0669] Compound 10f (2 g, 5.785 mmol) was dissolved in THF (30 mL), cooled to 0 °C, and then methylmagnesium bromide (1.4 g, 11.571 mmol) was added dropwise. The mixture was kept at this temperature for 1 hour, then heated to room temperature and stirred for 3 hours. LCMS analysis showed that the target product was predominant, and the reaction was terminated. The reaction was quenched by adding saturated ammonium chloride aqueous solution (50 mL), followed by the addition of ethyl acetate (50 mL x 3), and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain an oily substance. This oily substance was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–20%) to obtain compound 33a (1.3 g, yield 62%).

[0670] MS m / z(ESI): 362.0 [M+H] +

[0671] The second step involves the synthesis of compound 33b.

[0672] Compound 33a (1.3 g, 3.594 mmol) was dissolved in THF (20 mL), and tri-sec-butylborohydride (2.0 g, 10.781 mmol) was added. The reaction mixture was stirred at 70 °C for 3 hours. LC-MS analysis showed the disappearance of the starting material and the formation of the target product. The reaction was quenched by adding saturated ammonium chloride aqueous solution (50 mL), followed by the addition of ethyl acetate (50 mL x 3), and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 33b (2 g). The crude product was used directly in the next step.

[0673] MS m / z(ESI): 348.0 [M+H] +

[0674] The third step involves the synthesis of compound 33c.

[0675] Compound 33b (2 g, 5.752 mmol) and triphenylphosphine (3.0 g, 11.504 mmol) were dissolved in THF (30 mL). DIAD (2.265 mL, 11.504 mmol) was slowly added at 0 °C. The reaction mixture was stirred at room temperature for 3 hours under nitrogen protection. The reaction was confirmed by LCMS. Saturated ammonium chloride aqueous solution (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–10%) to obtain compound 33c (730 mg, yield 38%).

[0676] MS m / z(ESI): 330.0 [M+H] +

[0677] Step 4: Synthesis of compound 33d

[0678] Compound 33c (700 mg, 2.123 mmol) was dissolved in 1,4-dioxane (20 mL), and di-tert-butyl azide dicarboxylate (1134.3 mg, 4.883 mmol), BINAP (396.6 mg, 0.637 mmol), cesium carbonate (2075.3 mg, 6.369 mmol), and palladium acetate (47.7 mg, 0.212 mmol) were added. The reaction mixture was heated to 100 °C and stirred for 5 hours under nitrogen protection. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–25%) to obtain compound 33d (1.6 g). The crude product was used directly in the next step.

[0679] MS m / z(ESI): 526.2 [M+H] +

[0680] Step 5: Synthesis of compound 33e

[0681] Compound 33d (600 mg, 1.142 mmol) was dissolved in 2,2,2-trifluoroacetic acid (3 mL, 39.176 mmol). The reaction mixture was heated to 110 °C and stirred for 2 hours under nitrogen protection. LC-MS monitoring showed that the product was predominantly the target product. The reaction mixture was evaporated to dryness, and saturated sodium carbonate aqueous solution (20 mL) was added. Ethyl acetate (20 mL x 3) was added for extraction, and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 33e (230 mg, 48% yield).

[0682] MS m / z(ESI): 422.1 [M+H] +

[0683] Step 6: Synthesis of Compound 33

[0684] Compound 33e (200 mg, 0.475 mmol) was dissolved in trifluoroacetic anhydride (5 mL), and the reaction mixture was stirred at 90 °C for 4 hours. The reaction was confirmed to be complete by LC-MS. After the reaction mixture was evaporated to dryness, saturated sodium carbonate aqueous solution (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–23%) to obtain compound 33 (75.2 mg, yield 39%).

[0685] MS m / z (ESI): 404.1 [M+H] +

[0686] 1H NMR (400MHz, Methanol-d4) δ8.42(s,1H),7.57(d,J=8.2Hz,1H),7.45(d,J=0.8Hz,1H),7.31-7.21(m,2H ),4.81-4.75(m,1H),3.00(dd,J=14.6,5.0Hz,1H),2.67(dd,J=14.6,6.7Hz,1H),1.33(d,J=6.3Hz,3H).

[0687] Example 34

[0688] Synthesis of compound 34a (Step 1)

[0689] Under ice bath conditions, triethyl phosphoroacetate (5.0 g, 22.303 mmol) was added to a THF (80 mL) solution of NaH (1.0 g, 25.000 mmol). White foam appeared, and the reaction was allowed to proceed at room temperature for 0.5 h. The temperature was then lowered to 0 °C, and a THF (20 mL) solution of compound 10a (5 g, 18.586 mmol) was added. The reaction was allowed to proceed at room temperature for 1 h. Saturated ammonium chloride (30 mL) was added directly to the reaction solution, followed by extraction with ethyl acetate (50 mL). After shaking and separation, the organic phase was washed with purified water (20 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–20%) to obtain compound 34a (3030 mg, yield 48%).

[0690] MS m / z(ESI): 339.0 [M+H] +

[0691] The second step involves the synthesis of compound 34b.

[0692] Compound 34a (2700 mg, 7.962 mmol), pinacol diboronate (2628.5 mg, 10.351 mmol), KOAc (1562.8 mg, 15.924 mmol), and Pd(dppf)Cl2.CH2Cl2 (651.8 mg, 0.796 mmol) were dissolved in dioxane (30 mL), and the mixture was stirred at 100 °C for 3 hours under nitrogen protection. Ethyl acetate (80 mL) was added directly to the reaction mixture, and the mixture was washed with purified water (30 mL * 2). The combined aqueous phases were extracted with ethyl acetate (30 mL * 2), and the combined organic phases were washed with saturated brine (30 mL * 2). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 34b (4940 mg).

[0693] MS m / z (ESI): 387.1 [M+H] +

[0694] The third step involves the synthesis of compound 34c.

[0695] Compound 34b (5.2 g, 13.485 mmol), 5-bromo-2-chloro-4-methoxypyridine (2 g, 8.990 mmol), potassium phosphate (5.7 g, 26.970 mmol), and Pd(dppf)Cl2.CH2Cl2 (0.7 g, 0.899 mmol) were dissolved in dioxane (60 mL) and water (10 mL) under nitrogen protection and stirred at 100 °C for 4 hours. The reaction mixture was diluted directly with ethyl acetate (50 mL), followed by washing with purified water (30 mL x 2). The combined aqueous phases were extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–30%) to give compound 34c (1.95 g, 54% yield).

[0696] MS m / z (ESI): 402.1 [M+H] +

[0697] Step 4: Synthesis of compound 34d

[0698] Compound 34c (1 g, 2.489 mmol) was dissolved in THF (10 mL), cooled to -78 °C, and then triethyllithium borohydride solution (1 M in THF, 10 mL, 10.000 mmol) was added dropwise. After the addition was complete, the reaction was maintained at this temperature for 1 hour, and then allowed to proceed overnight at room temperature. Purified water (3 mL) was added to the reaction mixture, and the mixture was refluxed at 80 °C for 2 hours. After cooling to room temperature, 3 M sodium hydroxide solution (6 mL) was added, and the temperature was lowered to 0 °C. 30% hydrogen peroxide (6 mL) was added, and the mixture was stirred for 1 hour. Then, purified water (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 34d (1.17 g).

[0699] MS m / z(ESI): 360.0 [M+H] +

[0700] Step 5: Synthesis of compound 34e

[0701] Compound 34d (900 mg, 2.502 mmol) was dissolved in methanol (20 mL), and platinum dioxide (142.0 mg, 0.625 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The mixture was directly filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–20%) to give compound 34e (620 mg, yield 69%).

[0702] MS m / z(ESI): 362.0 [M+H] +

[0703] Step 6: Synthesis of compound 34f

[0704] Compound 34e (0.6 g, 1.714 mmol) was dissolved in ACN (10 mL), and trimethyliodosilane (1.7 g, 8.570 mmol) was added under nitrogen protection. The reaction mixture was heated to 80 °C and stirred overnight under nitrogen protection. Purified water (30 mL) was slowly added under ice bath, and the mixture was stirred briefly. Ethyl acetate (20 mL x 3) was added for extraction. The organic phases were combined and washed successively with saturated sodium bicarbonate (20 mL x 2) and saturated brine (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–50%) to give compound 34f (655 mg, yield 84%).

[0705] MS m / z(ESI): 458.0 [M+H] +

[0706] Step 7: Synthesis of compound 34g

[0707] Compound 34f (440 mg, 0.962 mmol) was dissolved in ACN (10 mL), and DIEA (372.8 mg, 2.885 mmol) was added. The mixture was stirred at 50 °C for 5 hours. The reaction solution was directly concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–20%) to give compound 34 g (230 mg, yield 73%).

[0708] MS m / z(ESI): 330.0 [M+H] +

[0709] Step 8: Synthesis of compound 34 hours

[0710] 34 g (70 mg, 0.212 mmol) of the compound was dissolved in EtOH (1 mL), and hydrazine hydrate (1.5 mL, 26.284 mmol) was added. The mixture was reacted overnight at 110 °C. Purified water (10 mL) was added directly, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude compound 34 h (115 mg).

[0711] MS m / z(ESI): 326.1 [M+H] +

[0712] Step 9: Synthesis of Compound 34

[0713] Compound 34h (110 mg, 0.338 mmol) was dissolved in 2,2,2-trifluoroacetic anhydride (3 mL, 0.015 mmol) and reacted at 90 °C for 4 hours. After the reaction was complete, ethyl acetate (30 mL) was added to dilute the reaction solution, and then saturated sodium bicarbonate aqueous solution (50 mL) was slowly added and stirred for a while. The aqueous phase was separated and extracted with ethyl acetate (20 mL * 2). The organic phases were combined, washed with saturated brine (20 mL * 2), dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%-50%) to obtain 40 mg of crude product. The crude product was purified by Prep-HPLC (acetonitrile / NH4HCO3 in H2O = 30%-100%) to obtain compound 34 (10.04 mg, yield 7%).

[0714] MS m / z (ESI): 404.1 [M+H] +

[0715] 1H NMR(600MHz,Chloroform-d)δ8.12(s,1H),7.54(s,1H),7.36(d,J=8.3Hz,1H),7.25-7.22(m,1H),7.20(d,J=2.5Hz,1H),4.8 0(dt,J=12.1,3.6Hz,1H),4.08(td,J=11.2,3.7Hz,1H),2.99-2.93(m,1H),2.45(dd,J=14.2,11.7Hz,1H),2.14-2.02(m,2H).

[0716] Example 35

[0717] Synthesis of compound 35b in step one

[0718] Compound 35a (10 g, 45.455 mmol) and iodomethane (5.533 mL, 68.183 mmol) were dissolved in DMF (50 mL). Potassium carbonate (12.6 g, 90.910 mmol) was added with stirring, and the mixture was stirred overnight at room temperature. The reaction was monitored by LCMS and found to be complete. The mixture was diluted with water (160 mL), extracted with ethyl acetate (80 mL x 3), washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–15%) to give compound 35b (8000 mg, 75% yield).

[0719] MS m / z(ESI): 234.0 [M+H] +

[0720] The second step involves the synthesis of compound 35c.

[0721] Compound 35b (8000 mg, 34.184 mmol) was added to a three-necked flask, followed by the addition of THF (80 mL). Under nitrogen protection, the mixture was cooled to -60°C in a dry ice-ethanol bath, and then DIBAL-H (102 mL, 102.000 mmol, 1 min THF) was added dropwise. After stirring at room temperature for 1 hour, the reaction was monitored by LC-MS and found to be complete. The reaction was quenched by adding methanol (50 mL) and stirring for 2 hours. After filtration through a diatomaceous earth filter, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%-10%) to give compound 35c (6276 mg, yield 89%).

[0722] MS m / z(ESI): 206.0 [M+H] +

[0723] The third step involves the synthesis of compound 35d.

[0724] Compound 35c (6276 mg, 30.464 mmol) was dissolved in ACN (62 mL), and 2-iodobenzoic acid (25591.5 mg, 91.392 mmol) was added. The reaction was carried out at 80 °C for 2 hours, and the reaction was monitored by LCMS until it was complete. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%-10%) to give crude compound 35d (7400 mg).

[0725] MS m / z(ESI): 203.9 [M+H] +

[0726] The fourth step is the synthesis of compound 35e.

[0727] (Methoxymethyl)triphenylphosphine chloride (24870.2 mg, 72.550 mmol) was dissolved in THF (80 mL). Under nitrogen protection and cooling in an ice-water bath, t-BuOK (8547.8 mg, 76.177 mmol) was added in portions. After incubation for 1 hour, compound 35d (7400 mg, 36.275 mmol) was added. After stirring at room temperature for 1 hour, the product was detected by LC-MS. The reaction was quenched with saturated ammonium chloride aqueous solution (5 mL), diluted with water (150 mL), extracted with ethyl acetate (60 mL * 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%-20%) to give compound 35e (4100 mg, yield 49%).

[0728] MS m / z(ESI): 232.0 [M+H] +

[0729] Step 5: Synthesis of compound 35f

[0730] 2,2,2-Trifluoroethanol (2.557 mL, 35.337 mmol) was dissolved in DMF (40 mL), cooled in an ice-water bath, and 60% NaH (1413.5 mg, 35.337 mmol) was added in portions under nitrogen protection. After stirring at room temperature for 15 minutes, compound 35e (4100 mg, 17.668 mmol) was added, and stirring was continued at room temperature for 2 hours. The target product was detected by LCMS. The solution was diluted with water (120 mL), extracted with ethyl acetate (60 mL * 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%-30%) to give compound 35f (3980 mg, yield 72%).

[0731] MS m / z(ESI): 312.0 [M+H] +

[0732] Step 6: Synthesis of compound 35g

[0733] Compound 35f (3980 mg, 12.753 mmol), pinacol diboronic acid ester (3886.2 mg, 15.303 mmol), Pd(dppf)Cl2.CH2Cl2 (522.0 mg, 0.638 mmol), KOAc (2503.1 mg, 25.506 mmol), and dioxane (60 mL) were added sequentially to a round-bottom flask. After purging the system with nitrogen, the reaction was carried out at 100 °C for 3 hours. The reaction was monitored by LC-MS and found to be complete. After filtration with diatomaceous earth, the filtrate was concentrated under reduced pressure to obtain 35 g (4580 mg, 100% yield) of crude compound.

[0734] MS m / z(ESI): 360.2 [M+H] +

[0735] Step 7: Synthesis of compound 35h

[0736] 35 g (4580 mg, 12.752 mmol) of compound, 5-bromo-2-chloro-4-methoxypyridine (2695.1 mg, 12.115 mmol), Pd(dppf)Cl2.CH2Cl2 (522.0 mg, 0.638 mmol), K3PO4 (5413.6 mg, 25.505 mmol), dioxane (45 mL), and water (10 mL) were added sequentially to a round-bottom flask. After purging the system with nitrogen, the reaction was carried out at 100 °C for 6 hours, and the reaction was monitored by LC-MS until complete. The mixture was diluted with water (100 mL), extracted with ethyl acetate (60 mL x 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–50%) to give compound 35 h (1900 mg, yield 42%).

[0737] MS m / z(ESI): 375.0 [M+H] +

[0738] Step 8: Synthesis of compound 35i

[0739] Compound 35h (1900 mg, 5.070 mmol) was dissolved in THF (21 mL), and concentrated hydrochloric acid (36%-38%, 7 mL) was added. The reaction was carried out at 70 °C for 3 hours, and the reaction was monitored by LCMS until it was complete. The solution was diluted with water (50 mL), extracted with ethyl acetate (30 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound 35i (3300 mg).

[0740] MS m / z(ESI): 361.0 [M+H] +

[0741] Step 9: Synthesis of compound 35j

[0742] Compound 35i (3300 mg, 9.148 mmol) was dissolved in MeOH (30 mL), and NaBH4 (361 mg, 9.543 mmol) was added in portions. After reacting at room temperature for 1 hour, the reaction was monitored by LCMS and found to be complete. The solution was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%-50%) to give compound 35j (500 mg, yield 15%).

[0743] MS m / z(ESI): 363.14 [M+H] +

[0744] Step 10: Synthesis of compound 35k

[0745] Compound 35j (500 mg, 1.378 mmol) was dissolved in acetonitrile (10 mL), and TMSI (966.69 mg, 6.892 mmol) was added. The reaction was carried out at 80 °C for 2 hours, and the reaction was monitored by LCMS until it was complete. After concentration, the solution was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%-100%) to give compound 35k (84 mg, yield 17%).

[0746] MS m / z(ESI): 349.0 [M+H] +

[0747] Step 11: Synthesis of Compound 35l

[0748] Compound 35k (84 mg, 0.241 mmol) and PPh3 (126.37 mg, 0.482 mmol) were added to a three-necked reaction flask. After adding THF (9 mL), the mixture was protected with nitrogen and cooled in an ice-water bath. Then, a THF (1 mL) solution of DIAD (487.10 mg, 2.409 mmol) was added dropwise. The mixture was stirred at room temperature for 3 hours, and the product was detected by LCMS. After quenching with saturated ammonium chloride (2 mL), the mixture was diluted with water (30 mL), extracted with ethyl acetate (20 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–50%) to give compound 35l (67 mg, yield 84%).

[0749] MS m / z(ESI): 331.1 [M+H] +

[0750] Step 12: Synthesis of compound 35m

[0751] Compound 35l (50 mg, 0.151 mmol), di-tert-butyl azide dicarboxylate (105.36 mg, 0.454 mmol), cesium carbonate (147.79 mg, 0.454 mmol), Pd2(dba)3 (13.85 mg, 0.015 mmol), Xantphos (17.50 mg, 0.030 mmol), and dioxane (3 mL) were added sequentially to a sealed tube. After purging the system with nitrogen, the tube was sealed and reacted at 100 °C for 16 hours. The product was detected by LCMS. The product was extracted with water (30 mL), ethyl acetate (20 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 35m (40 mg, 50% yield).

[0752] MS m / z(ESI): 427.2 [M-99] +

[0753] Step 13: Synthesis of Compound 35n

[0754] Compound 35m (40 mg, 0.076 mmol) was dissolved in difluoroacetic acid (3 mL) and reacted at 110 °C for 3 hours. The reaction was complete as monitored by LCMS. After concentration under reduced pressure, crude compound 35n (30 mg, 98% yield) was obtained.

[0755] MS m / z (ESI): 405.1 [M+H] +

[0756] Step Fourteen: Synthesis of Compound 35

[0757] Compound 35n (46 mg, 0.114 mmol) was dissolved in difluoroacetic anhydride (2 mL) and reacted at 110 °C for 3 hours. The reaction was complete as monitored by LCMS. Saturated sodium bicarbonate aqueous solution (30 mL) was added, followed by extraction with ethyl acetate (15 mL x 3). The organic phase was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0-50%) to obtain the crude product. The crude product was purified by Prep-HPLC (C18, acetonitrile / 0.05% ammonium formate aqueous solution = 20%-80%) to obtain compound 35 (4.65 mg, yield 11%).

[0758] MS m / z (ESI): 387.1 [M+H] +

[0759] 1 H NMR(600MHz,Chloroform-d)δ8.30(s,1H),7.73(d,J=8.4Hz,1H),7.56(s,1H),7.26(s,1H) ,6.96(d,J=8.3Hz,1H),4.86(q,J=8.5Hz,2H),4.66(t,J=6.4Hz,2H),3.09(t,J=6.4Hz,2H).

[0760] Example 36

[0761] The preparation of compound PRAX-628 was carried out in accordance with the specification of patent WO2019232209A1, Example 3: Synthesis of 3-[ethoxy(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine.

[0762] Experimental Example 1

[0763] 1. Reagents and consumables:

[0764] 1.1 Cell Culture

[0765] Table 1-1: CHO hNav1.6 cell culture

[0766] 1.2 Cell Solution

[0767] Table 1-2: Composition of physiological solutions, extracellular fluid and intracellular fluid

[0768] *200 nM ATXII was added to the extracellular fluid before the experiment to induce a sustained sodium current in hNav1.6.

[0769] 1.3NPC-384 Chip:

[0770] Table 1-3: NPC-384 Chip

[0771] 2. Instruments:

[0772] Instrument Name: SyncroPatch 384PE

[0773] Instrument Introduction: This instrument is a world-leading patch-clamp system capable of simultaneously recording 384 cells and providing high-quality data at the GΩ level. It is a fully automated drug screening environment tightly integrated with a Patch Engine (PE) module containing 384 independent amplifiers and a Biomek FXP 384-channel pipetting system. Both the hardware and software are industry-leading and have been fully tested to provide optimal real-world high-throughput ion channel screening performance.

[0774] 3. Experimental methods:

[0775] 3.1 Experimental Objective

[0776] This study used CHO cells stably expressing the hNav1.6 channel to investigate the effects of compounds at different concentrations on the sustained sodium current of hNav1.6 and their dose-response relationship using a fully automated patch-clamp method.

[0777] 3.2 Cell Culture

[0778] The CHO cell line stably expressing the hNav1.6 channel was obtained from Shanghai WuXi AppTec Co., Ltd. The gene information is as follows: Nav1.6 (NM_014191.4). The cells were cultured at 37°C in a 5% CO2 incubator; culture information is shown in Table 1-1.

[0779] 3.3.1 Cell Preparation

[0780] CHO cells used in the experiment should be cultured for at least two days and have a cell density of at least 75%. Before the experiment, the cells were digested with TrypLE until they became round, then gently pipetted and resuspended in physiological solution to collect the cells.

[0781] 3.3.2 Solution Preparation

[0782] The composition of the solutions required for the experiment is shown in Table 1-2. Physiological solutions and extracellular fluids should be prepared at least once a month. Intracellular fluids should be prepared every three months, and all solutions should be filtered and stored at 4°C.

[0783] 3.4 Preparation of the test compound

[0784] The test compound was dissolved in 100% DMSO to prepare a 10.00 mM stock solution. The stock solution was then further diluted in extracellular fluid to obtain final concentrations of 0.30, 1.00, 3.00, 10.00, and 30.00 μM. Each concentration was repeated at least twice per cell. The precipitate was visually inspected before testing. The final DMSO solution concentration of the test compound should not exceed 0.3%.

[0785] 3.5 SyncroPatch 384PE whole-cell patch-clamp recording

[0786] hNav1.6 SyncroPatch experiments were performed at room temperature. Different programs were created on the software, including basic information settings, chip loading, cell capture and sealing, amplifier settings, voltage pulse programs, and compound applications, to run the experiments.

[0787] Voltage pulse program: After establishing whole-cell recording mode, maintain the clamp potential at -120mV, apply a 0mV pulse voltage for 200ms, and then return to the clamp potential of -120mV to recover. During recording, the above voltage pulse program is repeated every 10 seconds until the detection ends.

[0788] Compound Application: After recording begins, add 40 μL of extracellular fluid and monitor the peak current for 300 seconds; this period serves as the baseline for subsequent analyses. Then, add 40 μL of each concentration of the test compound, incubating for at least 300 seconds for each concentration. Throughout the recording process, all QC indicators must meet the data analysis acceptance criteria. If the acceptance criteria are not met, the cell / well will not be included in the data analysis, and the corresponding concentration will be retested. The entire recording process is automated by the analysis software.

[0789] 4. Data Analysis:

[0790] For each cell / well, the mean of its last 5 current peaks during the monitoring period (without administration of the test compound) was used as the current peak for the blank control. Similarly, at each concentration assay, the mean of its last 5 current peaks was used as the current peak for that concentration for statistical data analysis. The percentage inhibition of persistent sodium current in hNav1.6 at each assay concentration was calculated using the following formula:

[0791] (1 - Peak tail current recorded after compound perfusion / Peak tail current recorded before compound perfusion) × 100%

[0792] The mean percentage of sustained sodium current inhibition of hNav1.6 recorded for all cells / wells at the same detection concentration was calculated, and the data are expressed as mean ± standard deviation.

[0793] Final half-maximal inhibitory concentration (IC50) 50 The value is obtained by fitting the Hill equation: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * HillSlope))

[0794] Where Y = inhibition%; Top = 100%; Bottom = 0%; X = compound concentration; IC50 = 100%; 50 = Half-maximal inhibitory concentration; HillSlope = slope.

[0795] Curve fitting and IC 50 All calculations were performed using GraphPad Prism 5.0 software. If the inhibition rate at the lowest concentration exceeds half-maximum inhibition or the inhibition rate at the highest concentration does not reach half-maximum inhibition, then the IC50 of the compound is determined. 50 The concentration is displayed as either less than the minimum concentration or greater than the maximum concentration.

[0796] Table 1-4: Compound IC 50 result

[0797] Table 1-5: Results of sustained sodium current suppression of compound hNav1.6

[0798] Experimental results show that the compound of the present invention has a strong inhibitory effect on the continuous sodium current of hNav1.6.

[0799] Experimental Example 2

[0800] 1. Reagents and consumables:

[0801] 1.1: Cell Culture

[0802] Table 2-1. CHO hNav1.6 cell culture

[0803] 1.2: Cell Solution

[0804] Table 2-2. Composition of physiological solutions, extracellular fluid and intracellular fluid

[0805] 1.3: NPC-384 Chip:

[0806] Table 2-3. NPC-384 Chip

[0807] 2. Instruments:

[0808] Instrument Name: SyncroPatch 384PE

[0809] 3. Experimental methods:

[0810] 3.1: Experimental Objective

[0811] This study used CHO cells stably expressing the hNav1.6 channel to investigate the effect of the patented compound at different concentrations on hNav1.6 sodium current and its dose-response relationship using a fully automated patch-clamp method.

[0812] 3.2: Cell Culture

[0813] The CHO cell line stably expressing the hNav1.6 channel was obtained from Shanghai WuXi AppTec Co., Ltd. Gene information is as follows: Na v 1.6 (NM_014191.4). The cells were cultured at 37°C in a 5% CO2 incubator. The culture information is shown in Table 2-1.

[0814] 3.3: Cell Preparation

[0815] CHO cells used in the experiment should be cultured for at least two days and have a cell density of at least 75%. Before the experiment, the cells were digested with TrypLE until they became round, then gently pipetted and resuspended in physiological solution to collect the cells.

[0816] 3.3: Solution Preparation

[0817] The composition of the solutions required for the experiment is shown in Table 2-2. Physiological solutions and extracellular fluids should be prepared at least once a month. Intracellular fluids should be prepared every three months, and all solutions should be filtered and stored at 4°C.

[0818] 3.4: Preparation of the test compound

[0819] The test compound of this patent was dissolved in 100% DMSO to prepare a 10.00 mM stock solution. The stock solution was then further diluted in extracellular fluid to obtain final concentrations of 0.10, 0.30, 1.00, 3.00, and 10.00 μM. Each concentration was repeated at least twice per cell. The precipitate was visually inspected before testing. The final DMSO solution concentration of the test compound was no greater than 0.3%.

[0820] 3.5: SyncroPatch 384PE whole-cell patch-clamp recording

[0821] hNav1.6 SyncroPatch experiments were performed at room temperature. Different programs were created on the software, including basic information settings, chip loading, cell capture and sealing, amplifier settings, voltage pulse programs, and compound applications, to run the experiments.

[0822] 3.5.1: hNav1.6-TB+VDB sodium current-voltage pulse program:

[0823] After establishing the whole-cell recording mode, a clamping potential of -120mV was maintained, followed by a 0mV pulse voltage for 20ms. Then, the voltage was returned to the clamping potential of -120mV for 2000ms, and a -50mV pulse voltage for 8000ms was applied to inactivate the channel. The voltage was then returned to the clamping potential of -120mV and held for 20ms. Next, the voltage was depolarized to 0mV for 20ms to activate the hNav1.6 channel. The peak currents generated during the two 0mV pulses were used for TB and VDB data analysis, respectively. Finally, the voltage was returned to the clamping potential of -120mV. During recording, the above voltage pulse program was repeated every 10 seconds until the detection was completed.

[0824] 3.5.2: hNav1.6-UDB Sodium Current-Voltage Pulse Program:

[0825] Voltage pulse program: After establishing the whole-cell recording mode, a clamping potential of -120mV was applied, followed by a 0mV pulse voltage for 20ms, then the clamping potential was returned to -120mV for recovery. This cycle was repeated 29 times. The peak currents generated at the 2nd, 6th, and 29th 0mV pulses were used for UDB data analysis. During recording, the above voltage pulse program was continuously applied 10 times until the end of the detection.

[0826] Compound Application: After recording begins, add 40 μL of extracellular fluid and monitor the peak current for 300 seconds; this period serves as the baseline for subsequent analyses. Then, add 40 μL of each concentration of the test compound, incubating for at least 300 seconds for each concentration. Throughout the recording process, all QC indicators must meet the data analysis acceptance criteria. If the acceptance criteria are not met, the cell / well will not be included in the data analysis, and the corresponding concentration will be retested. The entire recording process is automated by the analysis software.

[0827] 4. Data Analysis:

[0828] For each cell / well, the mean of the last 5 current peaks during the monitoring period (without administration of the test compound) was used as the current peak for the blank control. Similarly, at each concentration assay, the mean of the last 5 current peaks was used as the current peak for that concentration for statistical data analysis. The percentage inhibition of hNav1.6 sodium current at each assay concentration was calculated using the following formula:

[0829] (1 - Peak tail current recorded after compound perfusion / Peak tail current recorded before compound perfusion) × 100%

[0830] The mean percentage of inhibition of hNav1.6 sodium current by all recorded cells / wells at the same detection concentration was calculated, and the data are expressed as mean ± standard deviation.

[0831] Final half-maximal inhibitory concentration (IC50) 50 The value is obtained by fitting the Hill equation: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * HillSlope))

[0832] Where Y = inhibition%; Top = 100%; Bottom = 0%; X = compound concentration; IC50 = 100%; 50 = Half-maximal inhibitory concentration; HillSlope = slope.

[0833] Curve fitting and IC 50 All calculations were performed by software analysis. If the inhibition rate at the lowest concentration exceeds half-maximum inhibition or the inhibition rate at the highest concentration does not reach half-maximum inhibition, then the IC50 of the compound is determined. 50 The concentration is displayed as either less than the minimum concentration or greater than the maximum concentration.

[0834] Table 2-4: Sodium current detection results for compound hNav1.6-TB+VDB:

[0835] Experimental results show that the compound of the present invention has a strong inhibitory effect on the sodium current of hNav1.6-VDB and a weak inhibitory effect on the sodium current of hNav1.6-TB.

[0836] Experimental Example 3

[0837] 1. Experimental Objective

[0838] After a single oral gavage administration of the compound to ICR mice, blood samples were collected at different time points. Peripheral circulating blood and brain tissue were then collected from the animals. The concentration of the test substance was detected by LC-MS / MS and relevant parameters were calculated to investigate the pharmacokinetics, blood-brain permeability, and other properties of the test substance.

[0839] 2. Experimental Materials

[0840] ICR mice (male, 6-8 weeks old, weighing 25-30g)

[0841] 3. Experimental Procedure

[0842] The pharmacokinetic characteristics of the compound after oral administration in rodents were tested using a standard protocol. In this experiment, the candidate compound was prepared as a 0.5 mg / mL suspension and administered to mice via a single oral dose. The oral solvent was 5% DMSO + 5% Solutol + 90% physiological saline. Male ICR mice were used in this project, and the oral administration was performed at a dose of 5 mg / kg. Blood samples were collected from the orbital venous plexus and brain tissue at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration.

[0843] Plasma sample preparation: Take 30 μL of plasma sample and precipitate proteins with 300 μL of methanol containing 10 ng / mL internal standard. Vortex the mixture for 1 minute. Centrifuge the sample in the EP tube at 14000 rpm for 7 minutes, while centrifuge the sample for 96-well plate preparation at 4000 rpm for 10 minutes. Transfer 200 μL of supernatant to the 96-well plate. Take 2 μL of supernatant for liquid chromatography-mass spectrometry / mass spectrometry analysis.

[0844] Brain sample analysis: 50 μL of homogenized brain tissue sample (W:V = 1:5, brain: 50% methanol) was mixed with 300 μL of methanol containing 100 ng / mL internal standard for protein precipitation. The mixture was vortexed for 1 min. Then, the sample in the EP tube was centrifuged at 14000 rpm for 7 min, while the sample for 96-well plate treatment was centrifuged at 4000 rpm for 10 min. 200 μL of supernatant was transferred to a 96-well plate. 2 μL of the supernatant was analyzed by liquid chromatography-mass spectrometry / mass spectrometry (LC-MS / MS).

[0845] 4. Data Analysis

[0846] Blood drug concentrations were quantitatively analyzed using LC-MS / MS, and pharmacokinetic parameters were calculated, including peak plasma concentration (C). max Peak time (T) max The area under the drug-time curve (AUC) 0-t Eliminate half-life (T) 1 / 2 The brain plasma exposure ratio (Kp) and the brain plasma free drug concentration ratio (Kp,uu) were calculated based on the exposure amount.

[0847] Experimental results show that the compound of the present invention has good pharmacokinetic properties, and the blood drug exposure after oral administration to mice is better, with a brain-plasma exposure ratio and brain entry capacity superior to the control compound PRAX-628.

[0848] Experiment Example 4

[0849] 1. Experimental Objective

[0850] After a single oral gavage administration of the compound to SD rats, blood samples were collected at different time points. Peripheral circulating blood and brain tissue were then collected from the animals. The concentration of the test substance was detected by LC-MS / MS and relevant parameters were calculated to investigate the pharmacokinetics, blood-brain permeability, and other properties of the test substance.

[0851] 2. Experimental Materials

[0852] SD rats (male, 6-8 weeks old, weighing 175-200g)

[0853] 3. Experimental Procedure

[0854] The pharmacokinetic characteristics of the compound after oral administration in rodents were tested using a standard protocol. In the experiment, the candidate compound of this patent was prepared as a 0.1 mg / mL solution for intravenous injection and a 0.5 mg / mL suspension, and administered to rats via a single intravenous injection or oral administration. The solvent for both intravenous and oral administration was 5% DMSO + 5% Solutol + 90% physiological saline. Male SD rats were used in this project. For intravenous administration, the dose was 1 mg / kg, and blood was collected from the jugular vein at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h post-administration. For oral administration, the dose was 5 mg / kg. Peripheral circulating blood and brain tissue were collected at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h post-administration.

[0855] Plasma sample preparation: Take 30 μL of plasma sample and precipitate proteins with 300 μL of methanol containing 10 ng / mL internal standard. Vortex the mixture for 1 minute. Centrifuge the sample in the EP tube at 14000 rpm for 7 minutes, while centrifuge the sample for 96-well plate preparation at 4000 rpm for 10 minutes. Transfer 200 μL of supernatant to the 96-well plate. Take 2 μL of supernatant for liquid chromatography-mass spectrometry / mass spectrometry analysis.

[0856] Brain sample analysis: 50 μL of homogenized brain tissue sample (W:V = 1:5, brain: 50% methanol) was mixed with 300 μL of methanol containing 100 ng / mL internal standard for protein precipitation. The mixture was vortexed for 1 min. Then, the sample in the EP tube was centrifuged at 14000 rpm for 7 min, while the sample for 96-well plate treatment was centrifuged at 4000 rpm for 10 min. 200 μL of supernatant was transferred to a 96-well plate. 2 μL of the supernatant was analyzed by liquid chromatography-mass spectrometry / mass spectrometry (LC-MS / MS).

[0857] 4. Data Analysis

[0858] Blood drug concentrations were quantitatively analyzed using LC-MS / MS, and pharmacokinetic parameters, including clearance (CL), steady-state apparent volume of distribution (Vss), and peak plasma concentration (C), were calculated. max Peak time (T) max The area under the drug-time curve (AUC) 0-t Eliminate half-life (T) 1 / 2 The brain plasma exposure ratio (Kp) and the brain plasma free drug concentration ratio (Kp,uu) were calculated based on the exposure amount, as shown in Tables 4-1 and 4-2.

[0859] Table 4-1: Oral pharmacokinetic properties of compounds in rats

[0860] Table 4-2: PK properties of compounds administered intravenously to rats

[0861] Experimental results show that the compound of the present invention has good pharmacokinetic properties. After intravenous and oral administration to rats, the plasma clearance rate is lower, the blood drug exposure is better, and the peak concentration, brain plasma exposure ratio and brain penetration ability are superior to the control compound PRAX-628.

[0862] Experimental Example 5

[0863] 1. Experimental Objective

[0864] This project uses manual patch-clamp technique (the gold standard for hERG safety evaluation) to study the inhibitory effect of the patented compound on hERG potassium channels and to evaluate its risk of causing ventricular repolarization toxicity.

[0865] 2. Materials and Methods

[0866] 2.1. Information on Main Reagents and Instruments

[0867] 2.1.1. Main Reagent Information

[0868] Table 5-1 Main Reagent Information

[0869] 2.1.2. Main Instrument Information

[0870] Table 5-2 Patch Clamp Systems

[0871] 2.2. Compound Preparation

[0872] 2.2.1. Preparation of blank control standard

[0873] DMSO was used as the blank control stock solution. An appropriate amount of DMSO stock solution was added to the extracellular fluid to obtain an extracellular fluid containing 0.3% DMSO, which was used as the blank control working solution.

[0874] 2.2.2. Preparation of the test substance

[0875] The 30 mM test substance stock solution was sequentially diluted with DMSO to prepare intermediate dilutions of 10 mM, 3.33 mM, 1 mM, 0.33 mM, and 0.1 mM. Then, the test substance stock solution and intermediate dilutions were sequentially diluted with extracellular fluid to prepare working solutions of 30 μM, 10 μM, 3 μM, 1 μM, and 0.3 μM, with a DMSO concentration of 0.3%.

[0876] 2.3. Cell Culture

[0877] The HEK-293 cell line, stably expressing hERG potassium channels, was used. These hERG potassium channel cells were purchased from Creacell (catalog number: A-0320). The cell culture method is as follows:

[0878] Culture preparation: HEK-293 cell line was cultured in DMEM medium containing 10% fetal bovine serum and 0.8 mg / mL G418 at a temperature of 37°C and a carbon dioxide concentration of 5%.

[0879] Cell passage: Remove the old culture medium and wash once with PBS, then add 1 mL TrypLE TM Incubate with Express solution at 37°C for approximately 1 minute. Once cells detach from the bottom of the dish, add approximately 5 mL of preheated (37°C) complete culture medium. Gently pipette the cell suspension to separate any aggregated cells. Transfer the cell suspension to sterile centrifuge tubes and centrifuge at 1000 rpm for 5 minutes to collect the cells. For expansion or maintenance culture, seed cells into 6 cm cell culture dishes at a density of 2.5 × 10⁶ cells per dish. 5 100 cells (final volume: 5 mL). To maintain cell electrophysiological activity, cell confluence should not exceed 80%.

[0880] Before patch-clamp detection, cells were treated with TrypLE. TMExpress separation, 4×10 3 The cells were seeded onto a coverslip and cultured in a 24-well plate (final volume: 500 μL). After 18 hours, the cells were tested.

[0881] 2.4. Electrophysiological Recording

[0882] 2.4.1. Record the liquids used.

[0883] Extracellular fluid: 140mM NaCl, 3.5mM KCl, 1mM MgCl2·6H2O, 2mM CaCl2·2H2O, 10mM D-Glucose, 10mM HEPES, 1.25mM NaH2PO4·2H2O, pH adjusted to 7.4 with NaOH.

[0884] Intracellular fluid: 20mM KCl, 115mM K-Aspartic, 1mM MgCl2·6H2O, 5mM EGTA, 10mM HEPES, 2mM Na2-ATP, pH adjusted to 7.2 with KOH.

[0885] Extracellular fluid should be stored at 4°C for 2 weeks. Intracellular fluid should be prepared, aliquoted into 1 mL tubes, and stored at -20°C. Freshly thawed intracellular fluid should be used for each experiment. All intracellular fluid should be used within three months; otherwise, discard and prepare fresh.

[0886] 2.4.2. Patch clamp testing

[0887] The voltage stimulation protocol for whole-cell patch-clamp recording of hERG currents is as follows: After whole-cell sealing, the cell membrane voltage is clamped at -80 mV. The clamping voltage is depolarized from -80 mV to -50 mV and maintained for 0.5 s (as a leakage current detection), then stepped to 30 mV and maintained for 2.5 s, and then rapidly restored to -50 mV and maintained for 4 s to excite the tail current of the hERG channel. Data is collected every 10 s to observe the effect of the drug on the hERG tail current. The experimental data are acquired using an EPC 10 amplifier (HEKA) and stored in the software.

[0888] The patch-clamp procedure begins by using a microelectrode puller to draw a glass capillary into a recording electrode. The electrode, filled with intracellular fluid, is then placed into a microelectrode holder. A coverslip containing cells is placed in a recording bath under an inverted microscope. Under the microscope, the microelectrode manipulator is used to immerse the electrode in the extracellular fluid, and the electrode resistance (Rpip) is recorded. The electrode is then slowly brought into contact with the cell surface, and negative pressure is applied to create a GΩ high-resistance seal. Fast capacitance compensation is then applied, and negative pressure is continued to rupture the cell membrane, establishing a whole-cell recording mode. Finally, slow capacitance compensation is performed, and experimental parameters such as series resistance (Rs) are recorded. No leakage compensation is applied.

[0889] Once the current amplitude stabilized in the control extracellular solution, drug administration began. After each drug concentration reached equilibrium (approximately 5 minutes), the next concentration was measured. Blank control extracellular solution and working solution of the test compound were administered sequentially from low to high concentration through the recording bath using gravity perfusion, while a peristaltic pump was used for fluid replacement during recording. Each concentration was measured independently twice. All electrophysiological experiments were performed at room temperature.

[0890] 2.5. Data Analysis

[0891] First, the peak tail current after each drug concentration was applied was recorded. compound Peak tail current (and blank control) control Normalize, and then calculate the inhibition rate corresponding to each drug concentration, i.e. For each concentration inhibition rate, the mean, standard deviation (SD), and standard error (SE) were calculated, and the data are expressed as mean ± SE. Y = Bottom + (Top - Bottom) / (1 + 10^(LogIC)) 50 -X)*HillSlope))

[0892] Calculate the IC for each compound using the above equations. 50 The values ​​were calculated, and a nonlinear fit was performed on the concentration-effect curve, where IC50 was used. 50 This is the half-inhibitory concentration (IC50). 50 The calculations and curve fitting were performed using GraphPad Prism software.

[0893] 3. Test Results

[0894] 3.1. Results of the test substance

[0895] The inhibitory effect of the test substance on hERG channels was detected in two independent repeated experiments using manual patch-clamp technique, and the IC50 of the test substance on hERG channels was calculated by fitting concentration-response curves. 50 Values. Test results show that the patented compound has low cardiotoxicity, as shown in Table 5-3.

[0896] Table 5-3: Inhibitory activity of compounds on hERG channels

[0897] Experimental results show that the compound of the present invention has a weaker inhibitory effect on hERG channels compared with the control compound PRAX-628, suggesting that the compound of the present invention has a lower cardiac safety risk.

[0898] Experimental Example 6

[0899] Human liver microsomal CYP inhibition experiment

[0900] 1. Experimental Objective

[0901] The aim was to evaluate the inhibitory effect of the test sample on human liver microsomal cytochrome P450 isoenzymes (CYP2C19, CYP2D6 and CYP3A4) using a 5-in-1 probe substrate of CYP isoenzymes.

[0902] 2. Instruments and reagents

[0903] 2.1 Experimental Apparatus

[0904] Table 6-1: Main Experimental Instruments

[0905] 2.2 Experimental Reagents

[0906] Table 6-2: Main Experimental Reagents

[0907] 3. Experimental Methods

[0908] The test sample or positive control inhibitor containing human liver microsomes was aliquoted into 96-well plates at 30 μL per well, followed by 15 μL of substrate working solution. The plates and NADPH working solution were preheated at 37°C for 5 minutes. 15 μL of NADPH working solution was added to the plates to initiate the reaction, and the plates were incubated at 37°C and 100 rpm. The specific incubation system and incubation time are shown in Table 6-3 below.

[0909] Table 6-3

[0910] After the reaction time was reached, 180 μL of stop solution was added to terminate the reaction. The incubation plate was shaken at 600 rpm for 10 minutes and then centrifuged at 6000 rpm for 15 minutes. 100 μL of the supernatant was taken and added to 150 μL of ultrapure water. After mixing thoroughly, the metabolites of the probe substrate were analyzed by LC-MS / MS.

[0911] 4. Data Analysis

[0912] The percentage of residual enzyme activity at different concentrations was calculated by dividing the peak area ratio of metabolites (analyte peak area / internal standard peak area) of the sample with the test sample or positive control added by the peak area ratio of metabolites of the solvent control sample without the test sample or positive control. The IC50 was then calculated by curve fitting using a (non-linear) dose-response model in the software. 50 The value is calculated using the following formula: Y = Bottom + (Top - Bottom) / (1 + 10^(Log IC)) 50-X)×HillSlope))

[0913] Where X is the logarithm of the concentration, Y represents the percentage of enzyme activity at the corresponding concentration, Bottom and Top represent the percentage of enzyme activity at the bottom and top plateaus of the curve, respectively, and HillSlope represents the slope.

[0914] 5. Test Results

[0915] Experimental results show that the compounds of this invention have weak inhibitory effects on all four CYP isoenzymes and exhibit strong safety.

[0916] Experimental Example 7

[0917] Fully automated patch-clamp method for detecting hNav1.5 sodium current

[0918] 1. Experimental Objective

[0919] This study used HEK-293 cells stably expressing the hNav1.5 channel to investigate the effects of compounds at different concentrations on hNav1.5 sodium current and their dose-response relationship using a fully automated patch-clamp method.

[0920] 2. Instruments and reagents

[0921] 2.1 Cell Culture

[0922] The HEK-293hNav1.5 cell culture reagents are shown in Table 7-1;

[0923] Table 7-1

[0924] 2.2 Cell Solution

[0925] The composition of physiological solutions, extracellular fluid and intracellular fluid is shown in Table 7-2;

[0926] Table 7-2

[0927] 2.3 Instruments

[0928] Table 7-3

[0929] 3. Experimental Methods

[0930] 3.1 Cell Culture

[0931] The HEK-293 cell line, stably expressing the hNav1.5 channel, was used. Genotype Na v 1.5 (NM_198056.3)

[0932] 3.2 Cell Preparation

[0933] HEK-293 cells used in the experiment were cultured for at least two days and the cell density reached at least 75%. Before the experiment, the cells were digested with TrypLE until they became round, then gently pipetted and resuspended in physiological solution to collect the cells.

[0934] 3.3 SyncroPatch 384PE Whole-cell Patch Clamp Recording

[0935] The hNav1.5 SyncroPatch experiments were performed at room temperature. Various programs were created in the Biomek software (Nanion), including basic information settings, chip loading, cell capture formation sealing, amplifier settings, voltage pulse programs, and compound applications to run the experiments.

[0936] Voltage pulse program: After establishing whole-cell recording mode, maintain the clamp potential at -95mV, apply a -120mV pulse voltage for 200ms, then return to -15mV and maintain for 40ms to open the channel. Depolarize to 40mV for 200ms, then continuously decrease from 40mV to -95mV over 108s. During this process, the peak current generated under the -15mV pulse is recorded for data analysis. Finally, return to the clamp potential of -95mV. This voltage pulse program is repeated every 10 seconds during recording until the end of the detection.

[0937] Compound Application: After recording begins, add 40 μL of extracellular fluid and monitor the peak current for 300 seconds; this period serves as the baseline for subsequent analysis. Then, add 40 μL of each concentration of the test compound, incubating for at least 300 seconds for each concentration. Throughout the recording process, all QC indicators must meet the data analysis acceptance criteria. If the acceptance criteria are not met, the cell / well will not be included in the data analysis, and the corresponding concentration will be retested. The entire recording process is automated using PatchControl analysis software.

[0938] 4. Data Analysis

[0939] For each cell / well, the mean of the last 5 current peaks during the monitoring period (without administration of the test compound) was used as the current peak for the blank control. Similarly, at each concentration assay, the mean of the last 5 current peaks was used as the current peak for that concentration for data analysis. The percentage inhibition of hNav1.5 sodium current at each assay concentration was calculated using the following formula:

[0940] (1 - Peak tail current recorded after compound perfusion / Peak tail current recorded before compound perfusion) × 100%

[0941] The mean of the inhibition percentage of hNav1.5 sodium current for all recorded cells / wells at the same detection concentration was calculated, and the data were expressed as mean ± standard deviation.

[0942] The final half-inhibitory concentration IC 50 value was obtained by fitting with the Hill equation: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC 50 -X) * HillSlope))

[0943] where Y = inhibition%; Top = 100%; Bottom = 0%; X = compound concentration; IC 50 = half-inhibitory concentration; HillSlope = slope.

[0944] Curve fitting and the calculation of IC 50 were both completed by software analysis. If the inhibition rate at the lowest concentration exceeded half-inhibition or the inhibition rate at the highest concentration did not reach half-inhibition, the IC 50 of this compound was shown to be less than the lowest concentration or greater than the highest concentration.

[0945] 4. Detection Results

[0946] Table 7-4: Detection Results of Compound Inhibition of hNavl.5 Channel

[0947] The experimental results showed that the compound of the present invention had a weaker inhibitory effect on the hNav1.5 channel than the control compound PRAX-628, indicating that the compound of the present invention had a lower cardiac safety risk.

[0948] Experimental Example 8

[0949] 1. Test Purpose

[0950] Pharmacodynamic study of CD1 mice after single oral gavage of the compound in the maximal electroshock (MES) epilepsy model.

[0951] 2. Experimental Animals, Instruments and Reagents

[0952] 2.1 Experimental Animals

[0953] CD1 mice, male, 7-8 weeks old, 80 mice, SPF grade, purchased from Beijing Speywood Biotechnology Co., Ltd., experimental animal production license number: SCXK(Beijing)2024-0001. After all animals arrived at the animal facility, they entered a 3-5-day adaptation feeding period. At the end of the feeding period, animals that passed the health check were selected to enter the experiment and were recorded.

[0954] 2.2 Instruments

[0955] Table 8-1: Main Instruments

[0956] 2.3 Reagents

[0957] Table 8-2: Main Reagents

[0958] 3. Experimental Methods

[0959] Animals were randomly grouped according to their weight.

[0960] Pre-administration by gavage 30 minutes or at other time points (refer to compound T) max After (value), apply an appropriate amount of physiological saline to both ears of the animal, clip alligator clips to both ear wings of the animal, and induce maximal electroshock epileptic seizures by applying electrical stimulation (50Hz, 25mA, 500ms) through an electrical stimulator. Mice exhibit tonic-clonic seizures characterized by tonic flexion of the forelimbs, followed by tonic extension of the hindlimbs, and finally clonic seizures. Mouse behavioral seizure grades: Grade 1: running; Grade 2: forelimb rigidity; Grade 3: rigidity of both forelimbs and hindlimbs; Grade 4: animal death (Grade 4 animals are considered to have a duration of 60s). Detection indicators: animal seizure grade, seizure duration, mortality rate.

[0961] 4. Data Analysis

[0962] All data are expressed as mean ± SEM, and statistical analysis was performed using software. * indicates P < 0.05; ** indicates P < 0.01; ***P indicates P < 0.001.

[0963] 5. Test Results

[0964] Table 8-3: Seizure patterns in MES model mice Note: Data are expressed as Mean ± SEM. ***p<0.001.

[0965] Experimental results showed that 100% of the animals in the Model+Vehicle group experienced rigidity in their forelimbs and hindlimbs, indicating that the model was successful. Compared with the Vehicle group, the seizure severity and duration were significantly reduced in the treatment group at a dose of 3 mg / kg. Both showed a certain protective effect on MES animals, suggesting anti-epileptic activity. The anti-epileptic efficacy of the compound of this invention in the MES model is superior to that of the control compound PRAX-628.

[0966] Experimental Example 9

[0967] 1. Experimental Objective

[0968] A mouse model of acute epilepsy induced by pentylenetetrazole (PTZ) was constructed to verify the antiepileptic efficacy of the test drug in this model.

[0969] 2. Laboratory animals, instruments, and reagents

[0970] 2.1 Laboratory Animals

[0971] ICR mice (male, 6 weeks old) were purchased from Spifor (Beijing) Biotechnology Co., Ltd.

[0972] Mice were acclimatized in the animal facility for 5 days, with 5 mice per cage during the acclimatization period, and free access to food and water. The housing environment was maintained at room temperature of 23-26℃, with a 12 / 12-hour day-night light-dark cycle. The lights were on from 07:00 to 19:00 and off from 19:00 to 07:00 the next day.

[0973] 2.2 Reagents

[0974] Table 9-1 Main Reagents

[0975] 3. Experimental Methods

[0976] Animals were randomly grouped according to their weight.

[0977] Pre-administration by gavage 30 minutes or at other time points (refer to compound T) max Mice were induced to have acute seizures by intraperitoneal injection of PTZ solution (100 mg / kg). Mice were placed in transparent cages, and seizure activity was observed and recorded over 0–30 minutes. The seizure severity was rated using the modified Racine scale. Grade 2 seizures were characterized by involuntary head nodding, Grade 4 by bilateral forelimb clonic movements, and Grade 6 by tonicity or death. The highest seizure grade, latency of Grade 2, Grade 4, and Grade 6 seizures, and mortality rate were observed and recorded.

[0978] 4. Data Analysis

[0979] One-way ANOVA was performed using software, and a p-value < 0.05 was considered statistically significant.

[0980] 5. Test Results

[0981] Table 9-2: Seizure patterns in PTZ model mice Note: Data are expressed as Mean ± SEM. ***p<0.001.

[0982] Experimental results showed that, compared with the Vehicle group, the drug administration group at a dose of 3 mg / kg significantly reduced the highest seizure grade in mice, prolonged the latency of grade 6 seizures, and reduced mortality, demonstrating anti-epileptic activity. The anti-epileptic efficacy of the compound of this invention in the PTZ model was superior to that of the control compound PRAX-628.

[0983] Experimental Example 10

[0984] 1. Experimental Objective

[0985] After a single intravenous injection or oral gavage administration of the compound to SD rats, blood samples were collected at different time points. Peripheral circulating blood and brain tissue were then collected from the animals. The concentration of the test substance was detected by LC-MS / MS and relevant parameters were calculated to investigate the pharmacokinetics, blood-brain permeability, and other properties of the test substance.

[0986] 2. Experimental Materials

[0987] SD rats (male, 6-8 weeks old, weighing 175-200g)

[0988] 3. Experimental Procedure

[0989] The pharmacokinetic characteristics of the compound after intravenous or oral administration were tested in rodents using a standard protocol. In the experiment, the candidate compound of this patent was prepared as a 0.1 mg / mL solution for intravenous injection and a 0.5 mg / mL suspension for oral administration, administered to rats via a single intravenous or oral injection. The solvent for both intravenous and oral administration was 5% DMSO + 5% Solutol + 90% physiological saline. Male SD rats were used in this project. The intravenous injection dose was 1 mg / kg, and blood was collected from the jugular vein at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h post-administration. The oral administration dose was 5 mg / kg. Peripheral circulating blood and brain tissue were collected at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h post-administration.

[0990] Plasma sample preparation: Take 30 μL of plasma sample and precipitate proteins with 300 μL of methanol containing 10 ng / mL internal standard. Vortex the mixture for 1 minute. Centrifuge the sample in the EP tube at 14000 rpm for 7 minutes, while centrifuge the sample for 96-well plate preparation at 4000 rpm for 10 minutes. Transfer 200 μL of supernatant to the 96-well plate. Take 2 μL of supernatant for liquid chromatography-mass spectrometry / mass spectrometry analysis.

[0991] Brain sample analysis: 50 μL of homogenized brain tissue sample (W:V = 1:5, brain: 50% methanol) was mixed with 300 μL of methanol containing 100 ng / mL internal standard for protein precipitation. The mixture was vortexed for 1 min. Then, the sample in the EP tube was centrifuged at 14000 rpm for 7 min, while the sample for 96-well plate treatment was centrifuged at 4000 rpm for 10 min. 200 μL of supernatant was transferred to a 96-well plate. 2 μL of the supernatant was analyzed by liquid chromatography-mass spectrometry / mass spectrometry (LC-MS / MS).

[0992] 4. Data Analysis

[0993] Blood drug concentrations were quantitatively analyzed using LC-MS / MS, and pharmacokinetic parameters, including clearance (CL), steady-state apparent volume of distribution (Vss), and peak plasma concentration (C), were calculated. max Peak time (T) max The area under the drug-time curve (AUC) 0-t Eliminate half-life (T) 1 / 2 The brain plasma exposure ratio (Kp) and the brain plasma free drug concentration ratio (Kp,uu) were calculated based on the exposure amount, as shown in Tables 4-1 and 4-2.

[0994] Table 4-1: Oral pharmacokinetic properties of compounds in rats

[0995] Table 4-2: PK properties of compounds administered intravenously to rats

[0996] Experimental results show that the compound of the present invention has good pharmacokinetic properties. After intravenous and oral administration to rats, the plasma clearance rate is lower, the blood drug exposure is better, and the peak concentration, brain plasma exposure ratio and brain penetration ability are superior to the control compound PRAX-628.

Claims

1. A tricyclic derivative of Formula I or a pharmaceutically acceptable salt thereof, a prodrug, a solvate, a hydrate, a tautomer, or a stereoisomer thereof, wherein the structural formula of Formula I is as follows: in, X is independently selected from N or CR a ; R1, R2, R a Each group is independently selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, cycloalkyl, heterocyclic, aryl, or heteroaryl, and optionally, may be further substituted by one or more substituents. R0 is independently selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, cycloalkyl, heterocyclic, aryl or heteroaryl, and optionally may be further substituted by one or more substituents. Ring A is independently selected from cycloalkyl, heterocyclic, aryl, or heteroaryl groups; the cycloalkyl, heterocyclic, aryl, or heteroaryl groups may be further substituted with R; R is independently selected from the absence of, hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, and optionally, it may be further substituted by one or more substituents; n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9. In the aforementioned formula I, the R groups can be arbitrarily linked together to form a ring, and the ring can be further substituted by substituents; the ring can be independently selected from cycloalkyl, heterocyclic, aryl, or heteroaryl groups, and is a fused ring, bridged ring, or spirocyclic ring; optionally, it can be further substituted by one or more substituents. As described above, R and R1 in Formula I can be arbitrarily connected to form a ring, and optionally, they can be further substituted by one or more substituents.

2. The tricyclic derivative according to claim 1, or its pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer, characterized in that, The R1, R2, R a Each is independently selected from hydrogen, halogen, and C. 1-15 Alkyl, C 1-15 Haloalkyl, C 1-15 Alkoxy, C 1-15 Halogenated alkoxy groups, C 1-15 Alkylthio, C 1-15 The haloalkylthio, 3-10 membered cycloalkyl, 3-10 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, optionally, may be further substituted by one or more substituents; Preferably, R1, R2, R a Each is independently selected from hydrogen, halogen, and C. 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkoxy groups, C 1-10 Alkylthio, C 1-10 The alkyl thioyl group, 3-6 membered cycloalkyl group, 3-6 membered heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group, optionally, may be further substituted by one or more substituents.

3. The tricyclic derivative according to any one of claims 1-2, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, characterized in that, The R0 is selected from non-existent, hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, -CHF-OR b -OR b -SR b -N(R) b (R) c ), -N(R b )-C(O)-R c -CF2-R b -CF2-C(O)-OR b -CF2-C(O)-N(R) b )-S(=O)2-R c -CF2-tetrazolyl, -C(O)-N(R) b )-S(=O)2-R c -N(R) b )-C(O)-N(R b (R) c -C(O)-R b -C(O)-OR b -C(O)-N(R) b (R) c ), and -N(R b )-S(=O)2-R c -R b -, -S-CF3, -S-CHF2, -CHF-SR b , cycloalkyl, heterocyclic, aryl or heteroaryl, optionally, may be further substituted by one or more substituents; Preferably, R0 is selected from C 1-15 Alkyl, C 1-15 Haloalkyl, C 1-15 Alkoxy, C 1-15 Halogenated alkoxy groups, C 1-15 Alkylthio, C 1-15 Haloalkylthio groups, -C(O)-OR b -C(O)-N(R) b (R) c ), -N(R b )-S(=O)2-R c , 3-10 membered cycloalkyl, 3-10 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, optionally, may be further substituted by one or more substituents; More preferably, the R0 is selected from hydrogen, -F, -C(CH3)3, -CF3, -CF2OCH2CH3, -CHF2, -O-CF3, -OC(CH3)3, -C(CH2)2OH, -S(=O)2-, R b R c Each group is independently selected from the group consisting of hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, alkenyl, alkynyl, acylamino, ester, cycloalkyl, heterocyclic, aryl, or heteroaryl groups, and may be further substituted by one or more substituents selected from the group consisting of hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, cycloalkyl, heterocyclic, aryl, or heteroaryl groups.

4. The tricyclic derivative according to any one of claims 1-3, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, characterized in that, The R is independently selected from non-existent, hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, C 1-4 Alkyl, C 1-3 Alkylthio, C 1-3 Alkoxy, C 2-4 alkenyl, C 2-4 The alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, optionally, may be further substituted by one or more substituents; Preferably, R is independently selected from non-existent, hydrogen, -F, methyl, -O-CF3, -OC(CH2)2CF3, -O-CH(CH2)CF3 or -O-CH2CF3.

5. The tricyclic derivative according to any one of claims 1-4, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, characterized in that, The ring A is selected from one of the benzene ring, imidazole ring, and benzimidazole ring; preferably, the ring A is selected from the benzene ring.

6. A tricyclic derivative of formula II-1, II-2, II-3, II-4, II-5 or II-6, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, characterized in that, The structural formulas of Formula II-1, Formula II-2, Formula II-3, Formula II-4, Formula II-5, or Formula II-6 are as follows: The definitions of X, R0, R1, and R2 are as described above; R3, R4, R5, R6, R7, R8, R9, R 10 Each group is independently selected from the groups that are absent, hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, and optionally, may be further substituted by one or more substituents. As described above, R3, R4, R5, R6, and R7 in Formula II-1 can be arbitrarily linked to form a ring, and the ring can be further substituted by substituents; the ring can be independently selected from cycloalkyl, heterocyclic, aryl, or heteroaryl, and is a fused ring, bridged ring, or spirocyclic ring; optionally, it can be further substituted by one or more substituents; As described above, R3, R4, R5, and R6 in Formula II-2 can be arbitrarily linked together to form a ring, and the ring can be further substituted by substituents; the ring can be independently selected from cycloalkyl, heterocyclic, aryl, or heteroaryl, and is a fused ring, bridged ring, or spirocyclic ring; optionally, it can be further substituted by one or more substituents; As described above, R3, R4, R6, and R7 in Formula II-3 can be arbitrarily linked together to form a ring, and the ring can be further substituted by substituents; the ring can be independently selected from cycloalkyl, heterocyclic, aryl, or heteroaryl, and is a fused ring, bridged ring, or spirocyclic ring; optionally, it can be further substituted by one or more substituents; As described above, R3, R5, R6, and R7 in Formula II-4 can be arbitrarily linked together to form a ring, and the ring can be further substituted by substituents; the ring can be independently selected from cycloalkyl, heterocyclic, aryl, or heteroaryl, and is a fused ring, bridged ring, or spirocyclic ring; optionally, it can be further substituted by one or more substituents; As described above, R4, R5, R6, and R7 in Formula II-5 can be arbitrarily linked together to form a ring, and the ring can be further substituted by substituents; the ring can be independently selected from cycloalkyl, heterocyclic, aryl, or heteroaryl, and is a fused ring, bridged ring, or spirocyclic ring; optionally, it can be further substituted by one or more substituents. As mentioned above, R8, R9, and R in Formula II-6 10 They can be arbitrarily linked together to form rings, and can be further substituted by substituents after ring formation; the ring formation can be independently selected from cycloalkyl, heterocyclic, aryl or heteroaryl, and is a fused ring, bridged ring or spirocyclic ring; optionally, it can be further substituted by one or more substituents; The R6 and R7 substituents in Formula II-1, Formula II-3, Formula II-4 or Formula II-5 can be linked to form a ring, and optionally, they can be further substituted by one or more substituents. The R5 and R6 substituents in Formula II-1, Formula II-2, Formula II-4 or Formula II-5 can be linked to form a ring, and optionally, they can be further substituted by one or more substituents. The R1 and R7 substituents in Formula II-1, Formula II-3, Formula II-4 or Formula II-5 can be linked into a ring, and optionally, they can be further substituted by one or more substituents. As described above, the R8 and R9 substituents in Formula II-6 can be linked to form a ring, and optionally, they can be further substituted by one or more substituents; As mentioned above, R1 and R in Formula II-6 10 Substituents can be linked together to form a ring, and optionally, they can be further substituted by one or more substituents.

7. The tricyclic derivative of claim 6 or its pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer, characterized in that, The R3, R4, R5, R6, R7, R8, R9, R 10 Each element is independently selected from non-existent, hydrogen, halogen, and C. 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkoxy groups, C 1-10 Alkylthio, C 1-10 The haloalkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, optionally, may be further substituted by one or more substituents; Preferably, R3, R4, R5, R6, R7, R8, R9, R 10 Each is independently selected from non-existent, hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, and C. 1-4 Alkyl, C 1-3 Alkylthio, C 1-3 Alkoxy, C 2-4 alkenyl, C 2-4 The alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, optionally, may be further substituted by one or more substituents; More preferably, R3, R4, R5, R6, R7, R8, R9, R 10 Each is independently selected from non-existent, hydrogen, -F, methyl, -O-CF3, -OC(CH2)2CF3, -O-CH(CH2)CF3 or -O-CH2CF3; More preferably, R3, R4, R5, R6, R7, R8, R9, R 10 Each is independently selected from -SF5, -O-CF3, -O-CHF2, and -C(O)-OR. g -OR g -SR g -Si(CH3)3-O-CF3, -C(O)-R g -C(O)OH, -N(R) g (R) h ), -C(O)-N(R) g (R) h ), -N(R g )-C(O)-R h -N(R) g )-S(=O)2-R h -S(=O)2-R g -S(=O)2-N(R) g (R) h -NR g -C(O)-NR h ; Among them, R g R h The group is independently selected from hydrogen, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl groups and may be further substituted by one or more substituents selected from hydrogen, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, cycloalkyl, heterocyclic, aryl or heteroaryl groups.

8. A tricyclic derivative of formula III-1, III-2, III-3, III-4, III-5, or III-6, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, characterized in that, The structural formulas of Formula III-1, Formula III-2, Formula III-3, Formula III-4, Formula III-5, or Formula III-6 are as follows: The definitions of X, R0, R2, R3, R4, R5, R6, R8, and R9 are as described above; Selected from single or double bonds; R 11 The group is independently selected from hydrogen, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl groups and may be further substituted by one or more substituents selected from hydrogen, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, cycloalkyl, heterocyclic, aryl or heteroaryl groups; k is selected from 0, 1, 2, 3, and 4; In the aforementioned locations, R6, R in formula III-1, formula III-3, formula III-4, or formula III-5 11 The substituents can be linked into a ring, and optionally, they can be further substituted by one or more substituents; The land, R9, R in formula III-6 11 Substituents can be linked together to form a ring, and optionally, they can be further substituted by one or more substituents.

9. The tricyclic derivative of claim 8 or its pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer, characterized in that, The R mentioned 11 Independently selected from non-existent, hydrogen, halogen, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkoxy groups, C 1-10 Alkylthio, C 1-10 The haloalkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, optionally, may be further substituted by one or more substituents; Preferably, the R 11 Independently selected from non-existent, hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, C 1-4 Alkyl, C 1-3 Alkylthio, C 1-3 Alkoxy, C 2-4 alkenyl, C 2-4 The alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, optionally, may be further substituted by one or more substituents.

10. A tricyclic derivative of formula IV-1, IV-2, IV-3, IV-4, IV-5 or IV-6, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or stereoisomer thereof, wherein the structural formula of formula IV-1, IV-2, IV-3, IV-4, IV-5 or IV-6 is as follows: in, The definitions of X, R0, R2, R3, R4, R5, R6, R8, and R9 are as described above; X 1 X 2 X 3 Selected independently from -CR m R n -NR m , -O-, -S-, -C(O)-, -S(O)2-, -C(O)-O-, -C(O)-N(R m )-; m is selected from 0, 1, 2, and 3; R m R n The group is independently selected from hydrogen, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl groups and may be further substituted by one or more substituents selected from hydrogen, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, cycloalkyl, heterocyclic, aryl or heteroaryl groups; As described, R6 and R in Formula IV-1, Formula IV-3, Formula IV-4 or Formula IV-5 m or R n The substituents can be linked into a ring, and optionally, they can be further substituted by one or more substituents; As mentioned above, R9 and R in Formula IV-6 m or R n Substituents can be linked together to form a ring, and optionally, they can be further substituted by one or more substituents.

11. The tricyclic derivative of claim 10 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, characterized in that, The R mentioned m R n Each element is independently selected from non-existent, hydrogen, halogen, and C. 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkoxy groups, C 1-10 Alkylthio, C 1-10 The haloalkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, optionally, may be further substituted by one or more substituents; Preferably, the R m R n Each is independently selected from non-existent, hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, and C. 1-4 Alkyl, C 1-3 Alkylthio, C 1-3 Alkoxy, C 2-4 alkenyl, C 2-4 The alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, optionally, may be further substituted by one or more substituents.

12. A tricyclic derivative of formula V-1, V-2, V-3, V-4, V-5, or V-6, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, characterized in that, The structural formulas of Equations V-1, V-2, V-3, V-4, V-5, or V-6 are as follows: Among them, R0, R2, R3, R4, R5, R6, R8, R9, R 11 R a k is defined as described above; Defined as described above.

13. A tricyclic derivative of formula VI-1, VI-2, VI-3, VI-4, VI-5, VI-6, or VI-7, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, characterized in that, The structural formulas of Formula VI-1, Formula VI-2, Formula VI-3, Formula VI-4, Formula VI-5, Formula VI-6, or Formula VI-7 are as follows: Among them, R0, R2, R3, R4, R5, R6, R8, R9, R a X 1 X 2 X 3 The definitions of m and m are as described above; R 12 The group is independently selected from hydrogen, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl groups and may be further substituted by one or more substituents selected from hydrogen, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, cycloalkyl, heterocyclic, aryl or heteroaryl groups; Preferably, R 12 Independently selected from non-existent, hydrogen, halogen, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkoxy groups, C 1-10 Alkylthio, C 1-10 The haloalkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, optionally, may be further substituted by one or more substituents; More preferably, R 12 Independently selected from non-existent, hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, C 1-4 Alkyl, C 1-3 Alkylthio, C 1-3 Alkoxy, C 2-4 alkenyl, C 2-4 The alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, optionally, may be further substituted by one or more substituents; More preferably, R 12 It is independently selected from non-existent, hydrogen, -F, methyl, -O-CF3, -OC(CH2)2CF3, -O-CH(CH2)CF3 or -O-CH2CF3.

14. The tricyclic derivative according to any one of claims 1-13, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the compound may specifically be:

15. A pharmaceutical composition comprising a tricyclic derivative of any one of claims 1-14 or a pharmaceutically acceptable salt thereof, a prodrug, a solvate, a hydrate, a tautomer, or a stereoisomer.

16. Use of the tricyclic derivative of any one of claims 1-15 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, for use as a voltage-gated sodium channel inhibitor / sodium channel blocker, or for use in the preparation of a drug that inhibits sodium channels; Preferably, it is used as an inhibitor of Nav1.1, Nav1.2, Nav1.3, Nav1.6, and Nav1.8, or for the preparation of drugs that inhibit Nav1.1, Nav1.2, Nav1.3, Nav1.6, and Nav1.

8.

17. Use of the tricyclic derivative of any one of claims 1-16 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof for the treatment of epilepsy, Parkinson's disease, depression, or schizophrenia, or for the preparation of a medicament for the treatment of epilepsy, Parkinson's disease, depression, or schizophrenia.

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