Fused heteroaryl derivative, preparation method therefor, and application thereof

Abstract

The present invention relates to a fused heteroaryl derivative, a preparation method therefor, and an application thereof. The fused heteroaryl derivative can be used in a sodium channel inhibitor, and / or in a GABA receptor agonist, or in treating neuropsychiatric disorders such as epilepsy, Parkinson's, schizophrenia, or depression.

Description

Fused heteroaryl derivatives, their preparation methods and applications Technical Field

[0001] This invention belongs to the field of pharmaceuticals, specifically relating to fused heteroaryl derivatives, 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.

[0004] Gamma-aminobutyric acid (GABA) has been identified as a major inhibitory neurotransmitter, and substances that regulate GABAergic neurotransmission are widely used to treat conditions such as epilepsy, anxiety, and depression. Two families of GABA receptors have been described, collectively known as GABAa. A and GABA B .

[0005] Existing technologies such as WO2023049364A, WO2023049369A, and WO2023049367A disclose pyridine derivatives for use as voltage-gated sodium channel modulators, used to treat epileptic seizures such as epilepsy; existing technologies such as WO2005014597A, WO2006136530A1, WO2008017710A, and WO2006084835A disclose pyrazole or imidazole derivatives for use in diseases regulated by GABA receptors.

[0006] Existing technologies disclose many compounds that target voltage-gated sodium channels or GABA receptors respectively, but there are still many shortcomings. In particular, no regulators that simultaneously target voltage-gated sodium channels and GABA receptors have been found. Therefore, further optimization or replacement is needed, or the development of regulators that can simultaneously target voltage-gated sodium channels and GABA receptors is of great significance. Summary of the Invention

[0007] The fused heteroaryl derivatives of this invention can be compounds of formula I or II, or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or stereoisomers thereof, wherein the structural formulas of formula I or II are as follows:

[0008] in,

[0009] X is independently selected from O, S, NRa, or CRaRa';

[0010] Y and K are independently selected from NRa or CRaRa', respectively;

[0011] E, J, G, and M are each independently selected from N or CRa;

[0012] E, J, G, and M are each independently selected from CRa;

[0013] E, J, G, and M are each independently connected to L by at least one of them;

[0014] L is selected from chemical bonds, alkyl, alkoxy, alkylthio, acyl, acylamino; wherein the alkyl, alkoxy, or alkylthio group is optionally further substituted by one or more groups selected from hydrogen, halogen, nitro, hydroxy, 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; preferably, L is selected from chemical bonds, -CH2-, -CH2CH2-, -CH(CH3)-, -CH2-O-, or -NH-; more preferably, L is selected from chemical bonds;

[0015] In some embodiments, L is connected to E;

[0016] In some embodiments, L and J are connected;

[0017] In some embodiments, L is connected to G;

[0018] In some embodiments, L is connected to M;

[0019] In some implementations, when L is selected from chemical bonds, R is directly connected to E;

[0020] In some implementations, when L is selected from chemical bonds, R is directly connected to J;

[0021] In some implementations, when L is selected from chemical bonds, R is directly connected to G;

[0022] In some implementations, when L is selected from chemical bonds, R is directly connected to M;

[0023] Ra and Ra' are each 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, cycloalkyl, heterocyclic, aryl, or heteroaryl groups, and optionally, they may be further substituted by one or more substituents;

[0024] In some embodiments, Ra and Ra' are independently selected from the absence of, alkyl, haloalkyl, alkoxy, haloalkoxy, -CHF-O-Rb, -O-Rb, -S-Rb, -N(Rb)(Rc), -N(Rb)-C(O)-Rc, -CF2-Rb, -CF2-C(O)-O-Rb, -CF2-C(O)-N(Rb)-S(=O)2-Rc, -CF2-tetrazole, -C(O)-N (Rb)-S(=O)2-Rc, -N(Rb)-C(O)-N(Rb)(Rc), -C(O)-Rb, -C(O)-O-Rb, -C(O)-N(Rb)(Rc), and -N(Rb)-S(=O)2-Rc, -Rb-, -S-CF3, -S-CHF2, -CHF2-S-Rb, cycloalkyl, heterocyclic, aryl or heteroaryl, optionally, may be further substituted by one or more substituents;

[0025] In some implementations, Ra and Ra' are independently selected from non-existent and C, respectively. 1-15 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, -C(O)-O-Rb, -C(O)-N(Rb)(Rc), -N(Rb)-S(=O)2-Rc, 3-10 membered cycloalkyl, 3-10 membered heterocyclic group, 6-10 membered aryl or 5-10 membered heteroaryl, may optionally be further substituted by one or more substituents;

[0026] In some implementations, Ra and Ra' are each independently selected from non-existent;

[0027] In some implementations, Ra and Ra' are each independently selected from hydrogen;

[0028] In some embodiments, Ra and Ra' are independently selected from -F, -C(CH3)3, -CF3, -CHF2, -O-CF3, -OC(CH3)3, -C(CH2)2OH, -S(=O)2-,

[0029] In some implementations, Ra and Ra' are independently selected from non-existent, -F, -C(CH3)3, -CF3, and -CF2OCH2CH3, respectively;

[0030] In some implementations, Ra and Ra' are each independently selected from -Cl;

[0031] In some implementations, Ra and Ra' are each independently selected from -CHF2;

[0032] In some embodiments, Ra is selected from -F, -C(CH3)3, -CF3, -CHF2, -O-CF3, -OC(CH3)3, -C(CH2)2OH, -S(=O)2-,

[0033] In some embodiments, Ra is independently selected from the absence of, -F, -C(CH3)3, -CF3, -CF2OCH2CH3; in some embodiments, Ra' is selected from -F, -C(CH3)3, -CF3, -CHF2, -O-CF3, -OC(CH3)3, -C(CH2)2OH, -S(=O)2-,

[0034] In some implementations, Ra' is independently selected from non-existent, -F, -C(CH3)3, -CF3, -CF2OCH2CH3;

[0035] In some implementations, at least one of E, J, G, and M is selected from CRa;

[0036] Rb, Rc, Rd, Re, and Rf are each independently selected from one or more of the following groups: non-existent, hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, alkenyl, alkynyl, acylamino, ester, cycloalkyl, heterocyclic, aryl, or heteroaryl. Rb, Rc, Rd, Re, and Rf are each independently selected from one or more of the following groups: hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, cycloalkyl, heterocyclic, aryl, or heteroaryl. Substituent substitution; 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 be further substituted with one or more substituents selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, cycloalkyl, heterocyclic, aryl or heteroaryl group;

[0037] R is selected from 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.

[0038] In some embodiments, the cycloalkyl, heterocyclic, aryl, or heteroaryl group is a fused ring, a bridged ring, or a spirocyclic ring; optionally, it may be further substituted with one or more substituents.

[0039] In some embodiments, R is selected from -C(CH3)3, -CHF2-O-Rb, -O-Rb, -S-Rb, -N(Rb)(Rc), -N(Rb)-C(O)-Rc, -CF2-Rb, -CF2-C(O)-O-Rb, -CF2-C(O)-N(Rb)-S(=O)2-Rc, -CF2-tetrazolyl, -C(O)-N(Rb)-S(=O)2-Rc, -N(Rb)-C(O)-N(Rb)(Rc), -C(O)-Rb, -C(O)-O-Rb, -C(O)-N(Rb)(Rc), -N(Rb)-S(=O)2-Rc,

[0040] In some implementations, R is selected from...

[0041] In some implementations, R is selected from...

[0042] Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, Rk, Rm, Rn, R k1 R k2 R k3 R k4 R k5、 R p R q R S 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, acylamino, ester, alkenyl, alkynyl, 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, acylamino, ester, cycloalkyl, heterocyclic, aryl, or heteroaryl groups.

[0043] R p R q R S 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, acylamino, ester, alkenyl, alkynyl, 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, acylamino, ester, cycloalkyl, heterocyclic, aryl, or heteroaryl groups.

[0044] 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 be further substituted with one or more substituents selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclic, aryl, or heteroaryl groups;

[0045] In some embodiments, the cycloalkyl, heterocyclic, aryl, or heteroaryl group is a fused ring, a bridged ring, or a spirocyclic ring; optionally, it may be further substituted with one or more substituents.

[0046] In some implementations, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, Rk, Rm, Rn, R k1 R k2 R k3 R k4 R k5、 R p R q R S Each of the following is independently selected from: non-existent, hydrogen, -CH3, -CF3, -CH(CH3)2, -CH2CH3, -SF5,

[0047] In some embodiments, Ri is 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, acylamino, ester, cycloalkyl, heterocyclic, aryl, or heteroaryl groups;

[0048] In some embodiments, Ri is selected from hydrogen, halogen, alkyl, haloalkyl, C 1-15 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkoxy groups, C 1-10 Alkylthio, C 1-10 The haloalkylthioyl, 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;

[0049] In some implementations, Ri is selected from -CF3;

[0050] In some embodiments, Rg, Rh, and Rj are each independently selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups. They may be further substituted with one or more substituents selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclic, aryl, or heteroaryl groups.

[0051] In some embodiments, Rg, Rh, and Rj are each independently selected from hydrogen, halogen, alkyl, haloalkyl, and C.1-15 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkoxy groups, C 1-10 Alkylthio, C 1-10 The haloalkylthioyl, 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;

[0052] In some implementations, Rg, Rh, and Rj are each independently selected from hydrogen;

[0053] In some implementations... Selected from The definitions of E, J, G, M, X, Y, and K are as described in this article;

[0054] In some implementations... Selected from

[0055] The definitions of E, J, G, M, Ra, and Ra' are as described in this article;

[0056] Ry' and Rk' are each 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;

[0057] In some implementations... Selected from The definitions of E, J, G, M, X, Y, K, Ra, and Ra' are as described in this article;

[0058] In some implementations... Selected from The definitions of E, J, G, M, Ra, Ry', and Rk' are as described in this article;

[0059] In some implementations... Selected from The definitions of E, J, G, M, X, Y, and K are as described in this article;

[0060] In some implementations... Selected from

[0061] The definitions of X, Y, and K are as described in this article;

[0062] Re', Rj', Rg', and Rm' are each 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. They 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.

[0063] In some embodiments, Re', Rj', Rg', and Rm' are each independently selected from hydrogen, halogen, alkyl, haloalkyl, and C. 1-15 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkoxy groups, C 1-10 Alkylthio, C 1-10 The haloalkylthioyl, 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;

[0064] In some implementations... Selected from The definitions of X, Y, K, Re', Rj', Rg', and Rm' are as described in this article;

[0065] In some implementations... Selected from The definitions of Ra, Re', Rj', Rg', and Rm' are as described in this article;

[0066] In some implementations... Selected from The definitions of Ra, Re', Rj', Rg', and Rm' are as described in this article;

[0067] The present invention also provides a fused heteroaryl derivative which may be a compound of formula I-1 or formula II-1 or a pharmaceutically acceptable salt thereof, a prodrug, a solvate, a hydrate, a tautomer, or a stereoisomer, wherein the structural formula of formula I-1 or formula II-1 is as follows:

[0068] in,

[0069] X is independently selected from O, S, NRa, or CRaRa';

[0070] Y and K are independently selected from NRa or CRaRa', respectively;

[0071] A, B, D, T, and Q are independently selected from O, S, N, -CR0, -C=O, or -S=O, respectively;

[0072] Z is selected from N or -CR0;

[0073] Selected independently

[0074] E, J, G, and M are each independently selected from N or CRa;

[0075] E, J, G, and M are each independently selected from CRa;

[0076] E, J, G, and M are each independently connected to L by at least one of them;

[0077] L is selected from chemical bonds, alkyl, alkoxy, alkylthio, acyl, acylamino; wherein the alkyl, alkoxy, or alkylthio group is optionally further substituted by one or more groups selected from hydrogen, halogen, nitro, hydroxy, 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; preferably, L is selected from chemical bonds, -CH2-, -CH2CH2-, -CH(CH3)-, -CH2-O-, or -NH-; more preferably, L is selected from chemical bonds;

[0078] In some embodiments, the substitution position of L in the fused ring can be independently selected from 5-position substitution or 6-position substitution;

[0079] In some embodiments, L is connected to E;

[0080] In some embodiments, L and J are connected;

[0081] In some embodiments, L is connected to G;

[0082] In some embodiments, L is connected to M;

[0083] In some implementations, when L is selected from chemical bonds, Z is directly connected to E;

[0084] In some implementations, when L is selected from chemical bonds, Z is directly connected to J;

[0085] In some implementations, when L is selected from chemical bonds, Z is directly connected to G;

[0086] In some implementations, when L is selected from chemical bonds, Z is directly connected to M;

[0087] Ra and Ra' are each 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, cycloalkyl, heterocyclic, aryl, or heteroaryl groups, and optionally, they may be further substituted by one or more substituents;

[0088] In some embodiments, Ra and Ra' are each independently selected from the absence of, hydrogen, halogen, alkyl, haloalkyl, and C. 1-15 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkoxy groups, C 1-10 Alkylthio, C 1-10 The haloalkylthioyl, 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;

[0089] In some embodiments, Ra and Ra' are independently selected from the absence of, alkyl, haloalkyl, alkoxy, haloalkoxy, -CHF2-O-Rb, -O-Rb, -S-Rb, -N(Rb)(Rc), -N(Rb)-C(O)-Rc, -CF2-Rb, -CF2-C(O)-O-Rb, -CF2-C(O)-N(Rb)-S(=O)2-Rc, -CF2-tetrazole, -C(O)- N(Rb)-S(=O)2-Rc, -N(Rb)-C(O)-N(Rb)(Rc), -C(O)-Rb, -C(O)-O-Rb, -C(O)-N(Rb)(Rc), -N(Rb)-S(=O)2-Rc, -Rb-, -S-CF3, -S-CHF2, -CHF2-S-Rb, cycloalkyl, heterocyclic, aryl or heteroaryl, optionally, may be further substituted by one or more substituents;

[0090] In some implementations, Ra and Ra' are independently selected from non-existent and C, respectively. 1-15 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, -C(O)-O-Rb, -C(O)-N(Rb)(Rc), -N(Rb)-S(=O)2-Rc, 3-10 membered cycloalkyl, 3-10 membered heterocyclic group, 6-10 membered aryl or 5-10 membered heteroaryl, may optionally be further substituted by one or more substituents;

[0091] In some implementations, Ra and Ra' are each independently selected from non-existent;

[0092] In some embodiments, Ra and Ra' are independently selected from -F, -C(CH3)3, -CF3, -CHF2, -O-CF3, -OC(CH3)3, -C(CH2)2OH, -S(=O)2-, In some embodiments, Ra and Ra' are independently selected from H, -F, -C(CH3)3, -CF3, -CHF2, -CF2OCH2CH3, -O-CF3, -OC(CH3)3, and -C(CH2)2OH, respectively;

[0093] In some embodiments, Ra is selected from -F, -C(CH3)3, -CF3, -CHF2, -O-CF3, -OC(CH3)3, -C(CH2)2OH, -S(=O)2-,

[0094] In some embodiments, Ra is selected from H, -F, -C(CH3)3, -CF3, -CHF2, -CF2OCH2CH3, -O-CF3, -OC(CH3)3, -C(CH2)2OH; in some embodiments, Ra' is selected from -F, -C(CH3)3, -CF3, -CHF2, -O-CF3, -OC(CH3)3, -C(CH2)2OH, -S(=O)2-,

[0095] In some embodiments, Ra' is selected from H, -F, -C(CH3)3, -CF3, -CHF2, -CF2OCH2CH3, -O-CF3, -OC(CH3)3, -C(CH2)2OH;

[0096] Rb, Rc, Rd, Re, and Rf are each independently selected from the absence 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. They may be further substituted by one or more substituents selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, cycloalkyl, heterocyclic, aryl, or heteroaryl groups.

[0097] In some embodiments, the hydrogen, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group may be further substituted with 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;

[0098] R0, R1, R2, R3, R4, and R5 are each 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, they may be further substituted by one or more substituents;

[0099] Optionally, R0, R1, R2, R3, R4, and R5 in Formula I-1 or 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;

[0100] In some implementations, R1 and R2 are connected to form a ring;

[0101] In some implementations, R2 and R3 are connected to form a loop;

[0102] In some implementations, R3 and R4 are connected to form a ring;

[0103] In some implementations, R4 and R5 are connected to form a ring;

[0104] In some implementations, R0 is selected as not existing;

[0105] In some embodiments, R0, R1, R2, R3, R4, and R5 are each independently selected from the following groups: non-existent, hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, -SF5, -O-CF3, -O-CHF2, -C(O)-O-R6, -O-R6, -S-R6, -Si(CH3)3-O-CF3, -C(O)-R6, -C(O)OH, -N(R6)(R7), -C(O)-N(R6)(R7), -N(R6)-C(O)-R7, -N(R6)-S(=O)2-R7, -S(=O)2-R6, -S(=O)2-N(R6)(R7), -NR6-C(O)-NR7, C 1-4 Alkyl, C 1-3 Alkylthio, C 1-3 Alkoxy, C 2-4 alkenyl, C 2-4 The alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups may optionally be further substituted by one or more substituents.

[0106] In some embodiments, R0, R1, R2, R3, R4, and R5 are each independently selected from the absence of hydrogen, hydrogen, -F, -OC(CH2)2CF3, -O-CH(CH2)CF3, or -O-CH2CF3; R6 and R7 are each independently selected from hydrogen, halogen, nitro, hydroxyl, 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, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, cycloalkyl, heterocyclic, aryl, or heteroaryl groups;

[0107] In some embodiments, the hydrogen, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group may be further substituted with 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;

[0108] In some embodiments, the cycloalkyl, heterocyclic, aryl, or heteroaryl group is a fused ring, a bridged ring, or a spirocyclic ring; optionally, it may be further substituted with one or more substituents.

[0109] 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 are preferably hydrogen, halogen, nitro, hydroxyl, 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, C1- 10 Ester group, 3-10 membered cycloalkyl group, 3-10 membered heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group;

[0110] In some embodiments, the hydrogen, halogen, nitro, hydroxyl, 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 1-10 The ester group, 3-10 membered cycloalkyl group, 3-10 membered heterocyclic group, 6-10 membered aryl group, or 5-10 membered heteroaryl group may be further selected from hydrogen, halogen, nitro, hydroxyl, 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, C1- 10 The ester group, 3-10 membered cycloalkyl group, 3-10 membered heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group are substituted with one or more substituents;

[0111] In some specific implementations... Selected from L, A, B, D, Q, T, Z, R1, R2, R3, R4, and R5 are defined as described above;

[0112] In some specific implementations... Selected from L, R1, R2, R3, R4, and R5 are defined as described above;

[0113] In some specific implementations... Selected from L, A, B, D, Q, T, Z, R1, R2, R3, R4, and R5 are defined as described above;

[0114] in,

[0115] The ring M is selected from cycloalkyl, heterocyclic, aryl or heteroaryl, and optionally, it may be substituted by one or more substituents;

[0116] In some embodiments, ring M is selected from cycloalkyl, heterocyclic, aryl, or heteroaryl groups, and the cycloalkyl, heterocyclic, aryl, or heteroaryl group is a spirocyclic, fused, or bridged ring, and optionally may be further substituted by one or more substituents;

[0117] In some embodiments, ring M is selected from 3-10-membered cycloalkyl, 3-10-membered heterocyclic, 6-10-membered aryl, or 5-10-membered heteroaryl, and the 3-10-membered cycloalkyl, 3-10-membered heterocyclic, 6-10-membered aryl, or 5-10-membered heteroaryl are spirocyclic, fused, or bridged rings, and optionally may be further substituted by one or more substituents;

[0118] In some specific implementations... Selected from L, R1, R2, and R3 are defined as described in this article;

[0119] In some specific implementations... Selected from L, R1, R2, and R5 are defined as described in this article;

[0120] In some specific implementations... Selected from L, R1, R4, and R5 are defined as described in this article;

[0121] In some specific implementations... Selected from The definitions of L, R3, R4, and R5 are as described in this article;

[0122] In some specific implementations... Selected from

[0123] in,

[0124] L, R1, R2, R3, R4, and R5 are defined as described above;

[0125] X9, X 12 Selected independently from N or CR 10 ;

[0126] X1, X2, X3, X4, X5, X6, X7, X8, X 10 X 11 X 13 Selected independently from -O-, -S-, -C(O)-, and -NR- respectively. 11 -、-CR 12 R 13 -or-S(=O)-;

[0127] n1, n2, n3, n4, n5, n6, n7, n8, n10, n11, and n13 are each independently selected from 0, 1, 2, 3, or 4;

[0128] R8, R9, R 10 R 11 R 12 R 13 Each group is independently selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, alkenyl, alkynyl, acylamino, ester, sulfonyl, cycloalkyl, heterocyclic, aryl or heteroaryl, and optionally may be further substituted by one or more substituents.

[0129] In some specific implementations... Selected from Among them, L, Z, R1, R2, R3, R4, R5, X9, X 12 ,X1,X2,X3,X4,X5,X6,X7,X8,X 10 X 11 X 13 ,n1,n2,n3,n4,n5,n6,n7,n8,n10,n11,n13,R8,R9,R 10R 11 R 12 R 13 The definition is as described in this article;

[0130] In some specific implementations... Selected from Among them, L, Z, R1, R2, R3, R4, R5, X9, X 12 ,X1,X2,X3,X4,X5,X6,X7,X8,X 10 X 11 X 13 ,n1,n2,n3,n4,n5,n6,n7,n8,n10,n11,n13,R8,R9,R 10 R 11 R 12 R 13 The definition is as described in this article;

[0131] In some specific implementations... Selected from Among them, L, Z, R1, R2, R3, R4, R5, X9, X 12 ,X1,X2,X3,X4,X5,X6,X7,X8,X 10 X 11 X 13 ,n1,n2,n3,n4,n5,n6,n7,n8,n10,n11,n13,R8,R9,R 10 R 11 R 12 R 13 The definition is as described in this article;

[0132] In some implementations, n1, n2, n3, n4, n5, n6, n7, n8, n10, n11, and n13 are 1;

[0133] In some implementations, n1, n2, n3, n4, and n5 are 1;

[0134] In some implementations, n6, n7, and n8 are all 1;

[0135] In some implementations, n10, n11, and n13 are all 1;

[0136] In some implementations, n1, n2, and n3 are all 1, and n4 and n5 are all 2;

[0137] In some implementations, n5 and n7 are 1, and n8 is 2;

[0138] In some implementations, n11 is 1, and n10 and n13 are both 2;

[0139] In some implementations, n1, n2, n3, n4, and n5 are all 2;

[0140] In some implementations, n6, n7, and n8 are all 2;

[0141] In some implementations, n10, n11, and n13 are all 2;

[0142] In some implementations, n11 is 1;

[0143] In some implementations, n11 is 2;

[0144] In some implementations, n11 is 3;

[0145] In some implementations, n5 is 2;

[0146] In some implementations, n5 is 3;

[0147] In some implementations, n10 is 1;

[0148] In some implementations, n10 is 2;

[0149] In some embodiments, n10 is 3; in some embodiments, if the carbon atom connected to the substitution is a chiral carbon, then the chirality of the carbon atom can be R-type or S-type.

[0150] In some specific implementations... Selected from

[0151] The definitions of L, Z, A, T, Q, R1, R2, and R5 are as described in this article; W1, W2, W3, W4, W5, W6, W7, W8, and W... 10 W 11 W 13 W 14 Selected independently from -O-, -S-, -C(O)-, and -NR- respectively. 17 -、-CR 18 R 19 -、-S(=O)-、-BR 18 R 19 -、-PR 17 R 18 R 19 -or-SiR 18 R 19 -;

[0152] Selected independently

[0153] R 14 R 15 R 16 R 17 R 18 R 19 Each group is independently selected from the groups that are absent, hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, alkenyl, alkynyl, acylamino, ester, cycloalkyl, heterocyclic, aryl, or heteroaryl, and optionally may be further substituted by one or more substituents.

[0154] In some specific implementations... Selected from

[0155] The definitions of L, A, T, Q, R1, R2, and R5 are as described in this article; R 20 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 R 29 R 30 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 39 R 71 R 72 R 73 R 74 R 75 R 76 R 77 R 78 R 79 R 80 R 81 R 82 R 83 R 84Each group is independently selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, alkenyl, alkynyl, acylamino, ester, cycloalkyl, heterocyclic, aryl or heteroaryl, and optionally may be further substituted by one or more substituents.

[0156] In some specific implementations... Selected from

[0157] in,

[0158] The definitions of L, A, T, Q, R1, R2, and R5 are as described in this article;

[0159] R 40 R 41 R 42 R 43 R 44 R 45 R 46 R 47 R 48 R 49 R 50 R 51 R 52 R 53 R 54 R 55 R 56 R 57 R 58 R 59 R 60 R 61 R 62 R 63 R 64 R 65 R 66 R 67 R 68 R 69 R 70 Each group is independently selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, alkenyl, alkynyl, acylamino, ester, cycloalkyl, heterocyclic, aryl or heteroaryl, and optionally may be further substituted by one or more substituents.

[0160] In some specific implementations... Selected from

[0161] in,

[0162] The definitions of L, A, T, Z, Q, R1, R2, and R5 are as described in this article;

[0163] R 85 R 86 R 87 R 88 R 89 R 90 R 91 R 92 R 93 R 94 R 95 R 96 R 97 R 98 R 99 R 100 R 101 Each group is independently selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, alkenyl, alkynyl, acylamino, ester, cycloalkyl, heterocyclic, aryl or heteroaryl, and optionally may be further substituted by one or more substituents.

[0164] Furthermore, the R 85 R 86 R 87 R 88 R 89 R 90 R 91 R 92 R 93 R 94 R 95 R 96 R 97 R 98 R 99 R 100 R 101 Each of the following is independently selected from hydrogen, -F, -CF3, -CH3, -SF5, and -CH2CH3;

[0165] In some specific implementations... Selected from

[0166] in,

[0167] R1, R2, R5, R 85 R 86 R 87 R 88 R 89 R 90 R 91 R92 R 93 R 94 R 95 R 96 R 97 R 98 R 99 R 100 R 101 The definition is as described in this article;

[0168] In some specific implementations... Selected from

[0169] R1, R2, R5, R 85 R 86 R 87 R 88 R 91 R 92 R 93 R 94 R 95 The definition is as described in this article;

[0170] Furthermore, R1, R2, R5, R 85 R 86 R 87 R 88 R 91 R 92 R 93 R 94 R 95 Each is independently selected from hydrogen, -CH3, -CF3, -CH(CH3)2, -CH2CH3, -SF5,

[0171] In some implementations, R1, R2, R5, R 85 R 86 R 87 R 88 R 89 R 90 R 91 R 92 R 93 R 94 R 95 R 96 R 97 R 98 R 99 R 100 R 101 Each is independently selected from hydrogen, -CH3, -CF3, -CH(CH3)2, -CH2CH3, -SF5,

[0172] In some specific implementations... Selected from and

[0173] in,

[0174] R3, R4, R5, R 92 R 93 R 94 R 95 The definitions are as described in this article; furthermore, R3, R4, R5, R 92 R 93 R 94 R 95 Each is independently selected from hydrogen, -CH3, -CF3, -CH(CH3)2, -CH2CH3, -SF5,

[0175] In some embodiments, the hydrogen, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, cycloalkyl, heterocyclic, aryl, or heteroaryl group may be further substituted with 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 group;

[0176] In some embodiments, the cycloalkyl, heterocyclic, aryl, or heteroaryl group is a fused ring, a bridged ring, or a spirocyclic ring; optionally, it may be further substituted with one or more substituents.

[0177] In some embodiments, the hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, cycloalkyl, heterocyclic, aryl, or heteroaryl are preferably hydrogen, halogen, nitro, hydroxyl, 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 1-10 Ester group, 3-10 membered cycloalkyl group, 3-10 membered heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group;

[0178] In some embodiments, the hydrogen, halogen, nitro, hydroxyl, 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 1-10 The ester group, 3-10 membered cycloalkyl group, 3-10 membered heterocyclic group, 6-10 membered aryl group, or 5-10 membered heteroaryl group may be further selected from hydrogen, halogen, nitro, hydroxyl, 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, C1- 10 The ester group, 3-10 membered cycloalkyl group, 3-10 membered heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group are substituted with one or more substituents;

[0179] In some specific embodiments, R0 is selected from absent, 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;

[0180] In some embodiments, R0 is selected from the absence of, hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, -SF5, -O-CF3, -O-CHF2, -C(O)-O-R6, -O-R6, -S-R6, -Si(CH3)3-O-CF3, -C(O)-R6, -C(O)OH, -N(R6)(R7), -C(O)-N(R6)(R7), -N(R6)-C(O)-R7, -N(R6)-S(=O)2-R7, -S(=O)2-R6, -S(=O)2-N(R6)(R7), -NR6-C(O)-NR7, C 1-4 Alkyl, C 1-3 Alkylthio, C 1-3 Alkoxy, C 2-4 alkenyl, C2-4 The alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be further substituted by one or more substituents; R6 and R7 are each independently selected from hydrogen, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, sulfonyl, 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;

[0181] In some specific embodiments, R1 is selected from absent, 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;

[0182] In some embodiments, R1 is selected from the absence of, hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, -SF5, -O-CF3, -O-CHF2, -C(O)-O-R6, -O-R6, -S-R6, -Si(CH3)3-O-CF3, -C(O)-R6, -C(O)OH, -N(R6)(R7), -C(O)-N(R6)(R7), -N(R6)-C(O)-R7, -N(R6)-S(=O)2-R7, -S(=O)2-R6, -S(=O)2-N(R6)(R7), -NR6-C(O)-NR7, C 1-4 Alkyl, C 1-3 Alkylthio, C 1-3 Alkoxy, C 2-4 alkenyl, C 2-4 The alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be further substituted by one or more substituents; R6 and R7 are each 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;

[0183] In some specific embodiments, R2 is selected from absent, 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;

[0184] In some embodiments, R2 is selected from the following: absent, hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, -SF5, -O-CF3, -O-CHF2, -C(O)-O-R6, -O-R6, -S-R6, -Si(CH3)3-O-CF3, -C(O)-R6, -C(O)OH, -N(R6)(R7), -C(O)-N(R6)(R7), -N(R6)-C(O)-R7, -N(R6)-S(=O)2-R7, -S(=O)2-R6, -S(=O)2-N(R6)(R7), -NR6-C(O)-NR7, C 1-4 Alkyl, C 1-3 Alkylthio, C 1-3 Alkoxy, C 2-4 alkenyl, C 2-4 The alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be further substituted by one or more substituents; R6 and R7 are each 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;

[0185] In some specific embodiments, R3 is selected from absent, 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;

[0186] In some embodiments, R3 is selected from the following: absent, hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, -SF5, -O-CF3, -O-CHF2, -C(O)-O-R6, -O-R6, -S-R6, -Si(CH3)3-O-CF3, -C(O)-R6, -C(O)OH, -N(R6)(R7), -C(O)-N(R6)(R7), -N(R6)-C(O)-R7, -N(R6)-S(=O)2-R7, -S(=O)2-R6, -S(=O)2-N(R6)(R7), -NR6-C(O)-NR7, C 1-4 Alkyl, C 1-3 Alkylthio, C 1-3 Alkoxy, C 2-4 alkenyl, C 2-4 The alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be further substituted by one or more substituents; R6 and R7 are each 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;

[0187] In some specific embodiments, R4 is selected from absent, 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;

[0188] In some embodiments, R4 is selected from the following: absent, hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, -SF5, -O-CF3, -O-CHF2, -C(O)-O-R6, -O-R6, -S-R6, -Si(CH3)3-O-CF3, -C(O)-R6, -C(O)OH, -N(R6)(R7), -C(O)-N(R6)(R7), -N(R6)-C(O)-R7, -N(R6)-S(=O)2-R7, -S(=O)2-R6, -S(=O)2-N(R6)(R7), -NR6-C(O)-NR7, C 1-4 Alkyl, C 1-3 Alkylthio, C 1-3 Alkoxy, C 2-4 alkenyl, C 2-4The alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be further substituted by one or more substituents; R6 and R7 are each 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;

[0189] In some specific embodiments, R5 is selected from absent, 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.

[0190] In some embodiments, R5 is selected from the following: absent, hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, -SF5, -O-CF3, -O-CHF2, -C(O)-O-R6, -O-R6, -S-R6, -Si(CH3)3-O-CF3, -C(O)-R6, -C(O)OH, -N(R6)(R7), -C(O)-N(R6)(R7), -N(R6)-C(O)-R7, -N(R6)-S(=O)2-R7, -S(=O)2-R6, -S(=O)2-N(R6)(R7), -NR6-C(O)-NR7, C 1-4 Alkyl, C 1-3 Alkylthio, C 1-3 Alkoxy, C 2-4 alkenyl, C 2-4 The alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be further substituted by one or more substituents; R6 and R7 are each 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;

[0191] In some embodiments, the hydrogen, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, cycloalkyl, heterocyclic, aryl, or heteroaryl group may be further substituted with 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 group;

[0192] In some embodiments, the cycloalkyl, heterocyclic, aryl, or heteroaryl group is a fused ring, a bridged ring, or a spirocyclic ring; optionally, it may be further substituted with one or more substituents.

[0193] In some embodiments, the hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, cycloalkyl, heterocyclic, aryl, or heteroaryl are preferably hydrogen, halogen, nitro, hydroxyl, 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 1-10 Ester group, 3-10 membered cycloalkyl group, 3-10 membered heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group;

[0194] In some embodiments, the hydrogen, halogen, nitro, hydroxyl, 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 Acylamino, C 1-10 The ester group, 3-10 membered cycloalkyl group, 3-10 membered heterocyclic group, 6-10 membered aryl group, or 5-10 membered heteroaryl group may be further selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Hydroxyalkyl, C 1-10 Alkoxy, C 1-10 Hydroxyalkoxy, C1-10 Halogenated alkoxy groups, C 1-10 Acyl group, C 1-10 sulfonyl, C 1-10 Acylamino, C 1-10 The ester group, 3-10 membered cycloalkyl group, 3-10 membered heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group are substituted with one or more substituents;

[0195] In some embodiments, the present invention also provides that if the carbon atom in the compound of formula I or formula II that is substituted is a chiral carbon, then the chirality of the carbon atom may be R-type or S-type.

[0196] In some embodiments, the present invention also provides compounds of formula I-2 or formula II-2, or pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, or stereoisomers, wherein the structural formula of formula I-2 or formula II-2 is as follows:

[0197] The definitions of E, J, G, M, L, A, B, D, T, Q, Z, R1, R2, R3, R4, R5, Ra, and Ra' are as described above;

[0198] In some embodiments, the present invention also provides compounds of formula I-3 or formula II-3, or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or stereoisomers thereof, wherein the structural formula of formula I-3 or formula II-3 is as follows:

[0199] The definitions of L, A, B, D, T, Q, R1, R2, R3, R4, R5, Ra, Ra', Re', Rg', and Rm' are as described above;

[0200] In some embodiments, the present invention also provides compounds of formula I-4 or formula II-4, or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or stereoisomers thereof, wherein the structural formula of formula I-4 or formula II-4 is as follows:

[0201] The definitions of L, A, B, D, T, Q, R1, R2, R3, R4, R5, Ra, Ra', Re', Rg', and Rm' are as described above.

[0202] In some embodiments, the present invention also provides compounds of formula III-4 or pharmaceutically acceptable salts thereof, prodrugs, solvates, hydrates, tautomers, or stereoisomers, wherein the structural formula of formula III-4 is as follows:

[0203] Among them, L, A, B, D, T, Q, R1, R2, R3, R4, R5, Ra, Ra', Re', and Rm' are defined as described above;

[0204] In some embodiments, the present invention also provides compounds of formula I-5 or formula II-5, or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or stereoisomers thereof, wherein the structural formula of formula I-5 or formula II-5 is as follows:

[0205] The definitions of L, R1, R2, R3, R4, R5, Ra, Ra', Re', Rg', and Rm' are as described above.

[0206] In some embodiments, the present invention also provides compounds of formula III-5 or formula IV-5, or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or stereoisomers thereof, wherein the structural formula of formula III-5 or formula IV-5 is as follows:

[0207] The definitions of L, R1, R2, R3, R4, R5, Ra, Ra', Re', Rg', and Rm' are as described above.

[0208] In some embodiments, the present invention also provides compounds of formula I-6 or II-6, or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or stereoisomers thereof, wherein the structural formula of formula I-6 or II-6 is as follows:

[0209] The definitions of L, R1, R2, R3, R4, R5, Ra, Ra', Re', Rg', and Rm' are as described above;

[0210] In some embodiments, the present invention also provides compounds of formula I-7 or formula II-7, or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or stereoisomers thereof, wherein the structural formula of formula I-7 or formula II-7 is as follows:

[0211] The definitions of L, R1, R2, R3, R4, R5, Ra, Ra', Re', Rg', and Rm' are as described above;

[0212] In some embodiments, the present invention also provides compounds of formula I-8, II-8, III-8, VI-8, V-8, or VI-8, or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or stereoisomers thereof, wherein the structural formulas of formula I-8, II-8, III-8, VI-8, V-8, or VI-8 are as follows:

[0213] Among them, L, R1, R2, R3, R5, R 92 R 93 R 94 R 95 The definitions of Ra, Ra', Re', Rg', and Rm' are as described above;

[0214] In some specific embodiments, the compound may further be:

[0215] In this invention, the substituents in "optionally 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 1-10 Ester group, 3-10 membered cycloalkyl group, 3-10 membered heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group;

[0216] In this invention, cycloalkyl, heterocyclic, aryl, or heteroaryl groups optionally include fused rings, bridged rings, or spirocyclic rings;

[0217] In this invention, if the carbon atom optionally substituted is a chiral carbon, then the chirality of the carbon atom can be R-type or S-type.

[0218] The present invention also relates to a pharmaceutical composition comprising the fused heteroaryl derivative of the present invention;

[0219] 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.

[0220] In some embodiments, the pharmaceutical composition may optionally also comprise a pharmaceutically acceptable carrier.

[0221] 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.

[0222] and / or

[0223] 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, as a GABAA receptor agonist, or for the preparation of a drug that agonizes the GABAA receptor.

[0224] 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, Nav1.4, Nav1.5, Nav1.6, or Nav1.8, or for use in the preparation of a medicament for inhibiting Nav1.1, Nav1.2, Nav1.3, Nav1.4, Nav1.5, Nav1.6, or Nav1.8;

[0225] and / or

[0226] 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, as an agonist of GABA-α1, GABA-α2, GABA-α3, or GABA-α5 receptors, or for the preparation of a medicament for agonizing GABA-α1, GABA-α2, GABA-α3, or GABA-α5 receptors.

[0227] 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.

[0228] Detailed description of the invention

[0229] 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.

[0230] 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.

[0231] 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.

[0232] 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.

[0233] 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.

[0234] 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.

[0235] 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.

[0236] 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... Ra1 and Rb1 can be alkyl groups and can be selected from C12. 1-20 Ester group, preferably C1-10 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;

[0237] In this invention, "acyl group" refers to the atomic group remaining after removing the hydroxyl group from an organic acid, with the general formula Rb1-CO-, where Rb1 is defined as described above, and the acyl group can be selected from C. 1-20 Acyl group, preferably C 1-10 Acyl group, further preferably C 1- 8 acyl, more preferably C 1-6 Acyl group, C is the most preferred. 1-3 Acyl group;

[0238] In this invention, "sulfonyl group" refers to the functional group of sulfonic acid after losing the hydroxyl group. The sulfonyl group can be written as Rc1-S(=O)2-, where there are two coordinate bonds between sulfur and oxygen. If the group -S(=O)2- is not connected to any carbon atom, it is called thioyl.

[0239] In this invention, "aldehyde group" refers to -C(O)H;

[0240] In this invention, "alkoxy" refers to alkyl-O-, wherein alkyl is as defined above; cycloalkyloxy, heterocyclic oxy, aryloxy, heteroaryloxy, etc. are defined similarly;

[0241] In this invention, "amide group" refers to Rc1 can be H or an alkyl group;

[0242] In this invention, "acylamine group" refers to Where Rb1 and Rc1 are defined as above;

[0243] In this invention, "amine group" refers to Rc1 can be H or alkyl, and at least one Rc1 is not H; the alkyl-substituted amino group in this invention can be the above-mentioned amino group;

[0244] In this invention, "halogenated alkyl" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above;

[0245] In this invention, "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above;

[0246] In this invention, "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, wherein the alkyl group is as defined above;

[0247] In this invention, "hydroxyalkoxy" refers to an alkoxy group substituted with one or more hydroxyl groups, wherein the alkoxy group is as defined above;

[0248] In this invention, "hydroxyl group" refers to -OH;

[0249] In this invention, "halogen" refers to fluorine, chlorine, bromine, or iodine;

[0250] In this invention, "amino" refers to -NH2;

[0251] In this invention, "cyano" refers to -CN;

[0252] In this invention, "nitro" refers to -NO2;

[0253] 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:

[0254] 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.

[0255] 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).

[0256] In this invention, the term "multiple" can specifically refer to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0257] In this invention, the following abbreviations / terms are used:

[0258] Dioxin: Dioxin

[0259] Pd(dppf)Cl2.CH2Cl2: [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride DCM complex

[0260] Et3N: Triethylamine

[0261] Xantphos: 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene

[0262] Pd2(dba)3:tris(dibenzylacetone)dipalladium(0)

[0263] Pd(dppf)Cl 2. CH2Cl2: [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride DCM complex

[0264] TBAB: Tetrabutylammonium bromide

[0265] Toluene

[0266] B2Pin2: Bis(pinacol)diboron

[0267] NCS: N-chlorosuccinimide

[0268] DMA: N,N-dimethylacetamide

[0269] DMAP: 4-Dimethylpyridine

[0270] Pd2(dba)3:tris(dibenzylacetone)dipalladium(0)

[0271] Dioxane: 1,4-Dioxane

[0272] Xylene: xylene

[0273] AgBF4: Silver tetrafluoroborate

[0274] TBAB: Tetrabutylammonium bromide

[0275] DIEA: N,N-Diisopropylethylamine

[0276] KOAc: Potassium Acetate

[0277] BAST: Bis(2-methoxyethyl)aminosulfuric acid

[0278] Mn2(TMHD)3: Tris(2,2,6,6-tetramethyl-3,5-heptanoic acid)manganese(III)

[0279] TEA: Triethylamine

[0280] borane tetrahydrofuran: tetrahydrofuran borane

[0281] RuPhosPdG3: Methanosyl(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II)

[0282] RuPhos: 2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl

[0283] TBAF: Tetrabutylammonium fluoride

[0284] XPhos PdG3: Mesylate (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)

[0285] m-CPBA: m-chloroperoxybenzoic acid

[0286] (1R,2R)-N,N'-Dimethyl-1,2-cyclohexanediamine: (1R,2R)-N,N'-Dimethyl-1,2-cyclohexanediamine

[0287] Boc2O: Ditert-butyl dicarbonate

[0288] DMAP: 4-Dimethylpyridine

[0289] X-Phos: 2-Dicyclohexylphospho-2′,4′,6′-triisopropylbiphenyl

[0290] EA: Ethyl acetate

[0291] PE: Petroleum ether

[0292] KOAc: Potassium acetate

[0293] LiAlH4: Lithium aluminum hydride

[0294] TFA: Trifluoroacetic acid Detailed Implementation

[0295] 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.

[0296] Example 1

[0297] Synthesis of compound 1c in step one

[0298] Compound 1a (1 g, 5.318 mmol) and compound 1b (0.66 g, 5.318 mmol) were mixed with 20 mL of EtOH, refluxed for 1 h, cooled to room temperature, diluted with 20 mL of EtOH, and then iodobenzene diacetate (1.72 g, 5.318 mmol) was added. The mixture was reacted overnight at room temperature. The reaction mixture was directly evaporated to dryness, and then a mixture of methanol and ethyl acetate (20 mL, V / V = 1 / 1) was added. The mixture was filtered, and the filtrate was evaporated to dryness to obtain the crude product. Ethyl acetate was added, and a solid remained insoluble. The mixture was thoroughly sonicated, filtered, and the filter cake was washed with ethyl acetate to obtain compound 1c (1.097 g, yield 70.6%).

[0299] MS M / Z(ESI):294.0,296.0[M+1] +

[0300] Step 2: Synthesis of Compound 1

[0301] Compound 1c (80 mg, 0.274 mmol), compound 1d (105.52 mg, 0.329 mmol), and K3PO4 (174.39 mg, 0.822 mmol) were mixed with dioxane (4 mL) and water (0.5 mL). Under nitrogen protection, Pd(dppf)Cl2·CH2Cl2 (22.42 mg, 0.027 mmol) was added, and the mixture was reacted in a microwave at 100 °C for 2 h. The mixture was then extracted directly with purified water (10 mL) and ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified to obtain compound 1 (73 mg, yield 65.6%).

[0302] MS M / Z (ESI): 407.0 [M+1] +

[0303] 1 H NMR (400MHz, DMSO-d6) δ8.63(s,1H),8.46(d,J=2.1Hz,1H),8.33(dd,J=11.6,2.1Hz,1H),8.04( d,J=9.6Hz,1H),7.93–7.83(m,2H),7.77–7.69(m,1H),7.58–7.43(m,2H),5.15(q,J=9.0Hz,2H).

[0304] Example 2

[0305] The first step is the synthesis of compound 2c.

[0306] Compound 2a (900 mg, 6.226 mmol) was added to a reaction flask, followed by dioxane (30 mL) and Et3N (692.99 mg, 6.848 mmol). The mixture was stirred and cooled to 0-5 °C in an ice bath. At this temperature, a dioxane solution of compound 2b (1085.88 mg, 6.848 mmol) in 10 mL was slowly added, and the mixture was stirred for 2 hours. The reaction mixture was then cooled to room temperature and the solvent was removed by vacuum distillation to obtain the crude product. POCl3 (30 mL) was added to the crude product, and the mixture was refluxed at 100 °C in an oil bath for 3 hours. The reaction mixture was cooled to room temperature, and the solvent was removed by vacuum distillation to obtain a black oily substance. Sodium bicarbonate solution (100 mL) was added, followed by extraction with EA (200 mL x 2). The organic phase was evaporated to dryness, and silica gel column chromatography was used to obtain compound 2c (682 mg, 44% yield).

[0307] MS M / Z (ESI): 249.0 [M+1] +

[0308] Step 2: Synthesis of Compound 2

[0309] Compound 2c (150 mg, 0.603 mmol) was added to a reaction flask, followed by dioxane (5 mL), compound 2d (232.43 mg, 0.724 mmol), Pd(dppf)Cl2 (44.14 mg, 0.060 mmol), K3PO4 (256.09 mg, 1.207 mmol), and water (0.5 mL). The mixture was stirred, purged with nitrogen for 2 min, and then heated in an oil bath for 3 h. The reaction mixture was cooled to room temperature, and purified with purified water (20 mL). Extraction was performed using EA (30 mL x 3), and the organic phase was evaporated to dryness. The purified compound was then purified by silica gel column chromatography to obtain compound 2 (2.06 mg, yield 0.84%).

[0310] MS m / z(ESI): 408.0 [M+1] +

[0311] 1 H NMR (400MHz, DMSO-d6) δ8.79(d,J=2.0Hz,1H),8.67(d,J=9.8Hz,1H),8.42(dd,J=11.1,2.0Hz,1H),8.13( d,J=9.8Hz,1H),8.05(td,J=7.4,1.8Hz,1H),7.78–7.70(m,1H),7.60–7.51(m,2H),5.22(q,J=8.9Hz,2H).

[0312] Example 3

[0313] The first step is the synthesis of compound 3c.

[0314] Compound 3a (260 mg, 1.383 mmol), compound 3b (504 mg, 2.075 mmol), and toluene (10 mL) were reacted overnight at 120 °C. The mixture was concentrated and purified by silica gel column chromatography to give compound 3c (170 mg, yield 43.52%). MS m / z (ESI): 281.9, 284.0 [M+1] +

[0315] The second step involves the synthesis of compound 3d.

[0316] 60% NaH (106.21 mg, 2.655 mmol) was dissolved in EtOH (5 mL) and added to an ethanol (5 mL) solution of compound 3c (150 mg, 0.531 mmol). The reaction was carried out at 80 °C for 3 h. After cooling to room temperature, the reaction was quenched with 5 mL of water, concentrated to remove ethanol, diluted with 20 mL of water, extracted with EA (20 mL * 3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain compound 3d (115 mg, yield 74.14%).

[0317] MS m / z(ESI): 292.0, 294.0 [M+1] +

[0318] Step 3: Synthesis of Compound 3

[0319] Compound 3e (138.15 mg, 0.719 mmol), compound 3d (105 mg, 0.359 mmol), Xantphos (83.20 mg, 0.144 mmol), Cs₂CO₃ (234.26 mg, 0.719 mmol), Pd₂(dba)₃ (32.92 mg, 0.036 mmol), and dioxane (10 mL) were reacted overnight at 100 °C under nitrogen protection. Water (50 mL) was added, and the mixture was extracted with EA (30 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the crude product. The crude product was then used to prepare compound 3 (16.41 mg, yield 11.32%).

[0320] MS m / z(ESI): 404.0 [M+1] +

[0321] 1H NMR (400MHz, DMSO-d6) δ8.46(s,1H),8.06(d,J=2.7Hz,1H),7.89(dd,J=9.8,0.9Hz,1H),7.80(t,J=1.4Hz,1H),7.68(dd,J=8.8,2 .8Hz,1H),7.39(dd,J=9.9,2.1Hz,1H),7.02(d,J=8.8Hz,1H),4.96(q,J=9.1Hz,2H),4.17(q,J=7.1Hz,2H),1.29(t,J=7.1Hz,3H).

[0322] Example 4

[0323] The first step is the synthesis of compound 4c.

[0324] Compound 4b (1000 mg, 9.996 mmol) was slowly added dropwise to a 5 mL solution of 60% NaH (240 mg, 5.998 mmol) in THF, and the mixture was stirred for 1 h. Then, compound 4a (1495 mg, 9.996 mmol) was added, and the mixture was stirred for 16 h. The reaction was quenched by adding 50 mL of saturated ammonium chloride aqueous solution to the reaction mixture, followed by extraction with ethyl acetate (50 mL x 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 4c (2000 mg, yield 87.16%).

[0325] MS m / z(ESI): 230[M+1] +

[0326] The second step involves the synthesis of compound 4d.

[0327] Compound 4c (1500 mg, 6.534 mmol), bipinnatrol borate (4978 mg, 19.603 mmol), palladium acetate (147 mg, 0.653 mmol), SPhos (805 mg, 1.960 mmol), and K3PO4 (2774 mg, 13.068 mmol) were dissolved in dioxane (60 mL), and then stirred in an oil bath at 85 °C for 16 h. The mixture was filtered through diatomaceous earth, concentrated under reduced pressure, and then dissolved in ethyl acetate (100 mL). The organic phase was washed successively with water (100 mL x 2) and saturated brine (100 mL). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 4d (1.3 g, yield 61.96%).

[0328] MS m / z(ESI): 322[M+1] +

[0329] The third step involves the synthesis of compound 4i.

[0330] Compound 4e (1000 mg, 5.318 mmol) was suspended in toluene (10 mL), and then compound 4f (982 mg, 5.318 mmol) was added dropwise. The mixture was stirred for 30 min, then heated in an oil bath to 120 °C and stirred for 36 h. The mixture was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 4i (500 mg, yield 29.55%). MS m / z (ESI): 318, 320 [M+1] +

[0331] Step 4: Synthesis of Compound 4

[0332] Compound 4i (100 mg, 0.314 mmol), compound 4d (121 mg, 0.377 mmol), potassium carbonate (87 mg, 0.629 mmol), and DPPF palladium dichloride methane complex (51 mg, 0.063 mmol) were dissolved in a mixed solvent of 1,4-dioxane (10 mL) and water (2 mL). The mixture was evacuated three times with argon gas, and then microwaved at 100 °C for 2 h. The reaction solution was extracted with water (50 mL) and ethyl acetate (50 mL x 2), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was used to prepare compound 4 (82.32 mg, yield 60.6%).

[0333] MS m / z(ESI): 433[M+1] +

[0334] 1 H NMR (400MHz, DMSO-d6) δ8.82(t,J=1.5Hz,1H),8.47(d,J=2.1Hz,1H),8.31(dd,J=11.5,2.1Hz,1H),7.93(dd,J=9.7 ,1.1Hz,1H),7.84(dd,J=9.6,1.7Hz,1H),7.40–7.21(m,5H),5.25–5.16(m,2H),5.15(d,J=3.3Hz,2H),4.63(s,2H).

[0335] Example 5

[0336] The first step is the synthesis of compound 5c.

[0337] Compound 5a (300 mg, 1.58 mmol) was dissolved in n-butanol (5 mL), and compound 5b (905 mg, 4.74 mmol) was added. The reaction was carried out at 150 °C for 2 h. After the reaction was completed, the reaction solution was diluted with water (30 mL), extracted with dichloromethane (15 mL * 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography to give compound 5c (90 mg, 20% yield).

[0338] MS m / z(ESI): 281.85 [M+1] +

[0339] Step 2: Synthesis of Compound 5

[0340] Compound 5c (90 mg, 0.32 mmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL). Compound 5e (111 mg, 0.48 mmol), potassium carbonate (132 mg, 0.96 mmol), and Pd(dppf)Cl2 (24 mg, 0.032 mmol) were added, and the mixture was reacted at 100 °C for 16 h. After the reaction was complete, the reaction solution was diluted with water (40 mL), extracted with ethyl acetate (20 mL * 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was prepared by reverse phase reaction to give compound 5 (12.6 mg, yield: 10.1%).

[0341] MS m / z(ESI): 388.90 [M+1] +

[0342] 1 H NMR (400MHz, DMSO-d6) δ8.98(s,1H),8.85(s,1H),8.12-8.05(m,2H),7.86(s,1H),7.38-7.20(m,2H).

[0343] Example 6

[0344] The first step is the synthesis of compound 6c.

[0345] Compound 6a (500 mg, 1.88 mmol) was dissolved in 1,4-dioxane (15 mL), and Pd(dppf)Cl2 (137 mg, 0.19 mmol), potassium acetate (370 mg, 3.76 mmol), and compound 6b (621 mg, 2.44 mmol) were added. The mixture was reacted at 90 °C for 16 h. After the reaction was complete, the reaction solution was filtered and washed with dichloromethane. The filtrate was concentrated to obtain compound 6c (500 mg crude product).

[0346] MS m / z(ESI): 231.90 [M+1]+

[0347] The second step involves the synthesis of compound 6e.

[0348] Compound 6d (20 g, 105.2 mmol) was dissolved in pyridine (120 mL), and p-toluenesulfonyl chloride (20 g, 115.8 mmol) was added. The reaction was carried out overnight at room temperature. After the reaction was completed, the reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, and washed with dilute hydrochloric acid. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give crude compound 6e (35 g, 97% yield).

[0349] 1 H NMR (400MHz, CDCl3) δ7.76-7.73(m,1H),7.68(d,J=8.0Hz,2H),7.25(d,J=8 .0Hz,2H),7.17-7.13(m,1H),6.86-6.81(m,1H),6.70(s,1H),2.39(s,3H).

[0350] The third step involves the synthesis of 6g of compound.

[0351] Compound 6d (10 g, 29.1 mmol) was dissolved in isopropanol (50 mL) and water (2.5 mL). Compound 6f (6.5 g, 58.2 mmol) and anhydrous sodium carbonate (4.6 g, 43.6 mmol) were added, and the mixture was reacted overnight at 80 °C in a sealed container. After the reaction was complete, water (100 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain crude product 6g (14 g).

[0352] MS m / z(ESI): 456.00 [M+1] + 458.00 [M+3] +

[0353] The fourth step is the synthesis of compound 6h.

[0354] 14 g of compound 6 g was dissolved in tetrahydrofuran (140 mL), and TBAB (986 mg, 3.1 mmol) and sodium hydroxide (4.9 g, 122.0 mmol) were added. The reaction mixture was reacted at 70 °C for 1 h. The reaction solution was diluted with water (500 mL), extracted with ethyl acetate (200 mL * 3), and the organic phase was washed three times with brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain crude product of compound 6 h (10 g).

[0355] Step 5: Synthesis of compound 6i

[0356] Compound 6h (10 g) was dissolved in methanol (100 mL), and magnesium filings (2.8 g, 114.6 mmol) were added at 0 °C. The reaction was carried out overnight at room temperature. The solid was filtered and washed with dichloromethane, and the filtrate was evaporated to dryness. The crude product was purified by column chromatography to give compound 6i (2 g, 24% yield in three steps).

[0357] MS m / z(ESI): 281.85 [M+1] +

[0358] 1 H NMR (400MHz, DMSO-d6) δ6.78 (s, 1H), 6.72 (d, J = 8.4Hz, 1H), 6.64-6.61 (m, 1H),6.28(s,1H),4.86-4.82(m,1H),3.50-3.47(m,1H),3.23-3.20(m,1H).

[0359] Step 5: Synthesis of Compound 6

[0360] Compound 6i (1.0 g, 3.55 mmol) was dissolved in 1,4-dioxane (10 mL) and water (2 mL). Compound 6c (818 mg, 3.55 mmol), Pd(dppf)Cl2 (260 mg, 0.35 mmol), and cesium carbonate (2.9 g, 8.86 mmol) were added, and the mixture was reacted at 100 °C for 4 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the crude product was purified to obtain compound 6 (112.7 mg, yield 8%).

[0361] MS m / z(ESI): 389.05 [M+1] +

[0362] 1 H NMR(400MHz,CD3OD)δ8.40(s,1H),7.98-7.95(m,1H),7.91-7.88(m,1H),7.00-6.99(m ,1H),6.95(d,J=1.2Hz,2H),4.70-4.65(m,1H),3.62-3.59(m,1H),3.40-3.35(m,1H).

[0363] Example 7

[0364] Synthesis of Compound 7 (Step 1)

[0365] Compound 7a (61 mg, 0.200 mmol) was added to a reaction flask, followed by 10 mL of DMF. The mixture was stirred until dissolved, then reactant 7b (50.90 mg, 0.400 mmol) and solid NaH (40 mg, 1.000 mmol) were added. The mixture was stirred overnight at room temperature. The reaction mixture was quenched with 10 mL of purified water to obtain compound 7 (6.53 mg, yield 8.25%).

[0366] MS m / z(ESI): 396.1 [M+1] +

[0367] 1 H NMR (400MHz, DMSO-d6) δ8.12(s,1H),7.97(s,1H),7.93(td,J=7.5,1.8Hz,1H),7.68(tdd,J=7.4,5.2, 1.8Hz,1H),7.52–7.41(m,2H),5.58(s,2H),4.12(q,J=7.2Hz,2H),1.37(s,9H),1.27(t,J=7.2Hz,3H).

[0368] Example 8

[0369] The first step is the synthesis of compound 8c.

[0370] Compound 8a (500 mg, 2.617 mmol), compound 8b (403.38 mg, 2.617 mmol), triethylamine hydrochloride (360.23 mg, 2.617 mmol), and 1,4-dioxane (5 mL) were weighed and reacted at 100 °C for 30 min. After cooling, the reaction solution was concentrated and purified by column chromatography to obtain compound 8c (730 mg, 96% yield).

[0371] Step 2: Synthesis of Compound 8

[0372] Compound 8c (100 mg, 0.344 mmol), compound 8d (110.44 mg, 0.344 mmol), Pd(dppf)Cl2.CH2Cl2 (28.16 mg, 0.034 mmol), potassium phosphate (237.62 mg, 1.032 mmol), 1,4-dioxane (4 mL), and water (0.4 mL) were weighed and degassed with nitrogen. The mixture was microwaved at 100 °C for 1 h. The reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL x 3), dried, concentrated, and then compound 8 (26.92 mg, 17.41% yield) was obtained.

[0373] 1H NMR(400MHz,Chloroform-d)δ8.13–7.96(m,2H),7.83(td,J=7.4,1.8Hz,1H),7.59–7.41(m, 2H),7.34–7.21(m,2H),4.83(q,J=8.3Hz,2H),3.04(p,J=6.8Hz,1H),1.21(d,J=6.8Hz,6H).

[0374] Example 9

[0375] The first step is the synthesis of compound 9c.

[0376] Toluene (10 mL) was added to compounds 9a (1 g, 6.918 mmol) and 9b (1.68 g, 6.918 mmol), and the mixture was reacted at 110 °C for 3 h. After concentration, the mixture was extracted with saturated sodium bicarbonate aqueous solution (20 mL) and ethyl acetate (20 mL * 3). The organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound 9c (1.115 g, yield 67.44%). MS m / z (ESI): 241.0 [M+1] +

[0377] The second step involves the synthesis of compound 9e.

[0378] Compound 9c (275 mg, 1.151 mmol) and compound 9d (260.88 mg, 1.358 mmol) were dissolved in DMF (10 mL), and then DIEA (446.14 mg, 3.452 mmol) was added. The reaction was carried out overnight at 80 °C. After cooling to room temperature, the mixture was diluted directly with purified water (20 mL), and then extracted with ethyl acetate (20 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound 9e (312 mg, yield 68.7%).

[0379] MS m / z(ESI): 395.0 [M+1] +

[0380] Step 3: Synthesis of Compound 9

[0381] Compound 9e (80 mg, 0.203 mmol) and silver trifluoromethanesulfonate (624.93 mg, 2.432 mmol) were dissolved in a mixed solvent of EtOH (2 mL) and DMF (2 mL) and stirred overnight at 90 °C. After cooling to room temperature, the solution was directly filtered, concentrated, and then extracted with ethyl acetate (20 mL * 3) and purified water (20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and purified to obtain compound 9 (20.41 mg, yield 24.87%). MS m / z (ESI): 405.1 [M+1] +

[0382] 1 H NMR (400MHz, Chloroform-d) δ8.01(d,J=10.1Hz,1H),7.04(d,J=10.1Hz,1H),4.90(s,2H),4.44(t,J=5.5Hz,2H),4.28–3.96(m,4H),1.37(t,J=7.1Hz,3H).

[0383] Examples 10 and 11

[0384] Synthesis of compound 10c in step one

[0385] Compound 10a (500 mg, 2.092 mmol) and compound 10b (292.59 mg, 2.301 mmol) were dissolved in DMF (7 mL), and then 60% NaH (92.05 mg, 2.301 mmol) was added. The mixture was stirred at room temperature for 30 min. Purified water (30 mL) and ethyl acetate (30 mL x 5) were added directly to the reaction solution for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 10c (470 mg, 68.14%).

[0386] MS m / z(ESI): 330.0 [M+1] +

[0387] The second step involves the synthesis of compounds 10 and 11.

[0388] Compound 10c (120 mg, 0.364 mmol) and silver trifluoromethanesulfonate (1122.17 mg, 4.368 mmol) were dissolved in a mixed solvent of EtOH (2 mL) and DMF (2 mL). The reaction was carried out at 90 °C over the weekend. Silver trifluoromethanesulfonate (280.57 mg, 1.092 mmol) was added, and the reaction was continued for another 4 h. After cooling to room temperature, the mixture was directly filtered. The filter cake was washed with methanol, and the filtrate was concentrated. The residue was extracted with purified water (20 mL) and ethyl acetate (20 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified to obtain compound 10 (4.86 mg, 4.21%) and compound 11 (19.31 mg, 15.64%).

[0389] Compound 10 MS m / z (ESI): 318.1 [M+1] +

[0390] 1 H NMR (400MHz, DMSO-d6) δ8.49(d,J=9.8Hz,1H),8.00(s,1H),7.34(d,J=9.8Hz,1H),6.05(s, 2H), 5.62 (s, 2H), 4.48 (q, J = 7.1Hz, 2H), 4.32 (q, J = 7.2Hz, 2H), 1.39 (td, J = 7.2, 5.9Hz, 6H).

[0391] Compound 11 MS m / z (ESI): 340.1 [M+1] +

[0392] 1 H NMR (400MHz, DMSO-d6) δ8.49(d,J=9.8Hz,1H),8.00(s,1H),7.34(d,J=9.8Hz,1H),6.05(s, 2H), 5.62 (s, 2H), 4.48 (q, J = 7.1Hz, 2H), 4.32 (q, J = 7.2Hz, 2H), 1.39 (td, J = 7.2, 5.9Hz, 6H).

[0393] Example 12

[0394] Synthesis of compound 12b in step one

[0395] Compound 12a (500 mg, 2.21 mmol) was dissolved in DMF (10 mL), and 60% NaH (106 mg, 2.65 mmol) was added at 0 °C. The mixture was stirred at 0 °C for 15 min, and then iodomethane (941 mg, 6.63 mmol) was added. The reaction was allowed to proceed at room temperature for 2 h. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride solution (40 mL), extracted with ethyl acetate (20 mL * 3), and the organic phase was washed three times with brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 12b (520 mg, yield: 98%).

[0396] 1 H NMR (400MHz, CDCl3) δ7.14-7.10(m,2H),7.03-7.00(m,1H),3.32(s,3H),2.86-2.83(m,2H),2.65-2.61(m,2H).

[0397] The second step involves the synthesis of compound 12c.

[0398] Compound 12b (550 mg, 2.29 mmol) was dissolved in 1,4-dioxane (20 mL), and B2Pin2 (756 mg, 2.98 mmol), Pd(dppf)Cl2 (168 mg, 0.23 mmol), and potassium acetate (562 mg, 5.73 mmol) were added. The mixture was reacted overnight at 90 °C. After the reaction was complete, the reaction solution was filtered and washed with dichloromethane. The filtrate was concentrated. The crude product was purified by column chromatography to give compound 12c (500 mg, 76% yield).

[0399] MS m / z(ESI): 288.20 [M+1] +

[0400] 1 H NMR (400MHz, DMSO-d6) δ7.32-7.20(m,3H),3.23(s,3H),2.87-2.83(m,2H),2.51-2.47(m,2H),1.27(s,12H).

[0401] Step 3: Compound 12

[0402] Compound 12c (200 mg, 0.70 mmol) was dissolved in 1,4-dioxane (10 mL) and water (2 mL). Compound 12d (266 mg, 0.91 mmol), Pd(dppf)Cl2 (50 mg, 0.07 mmol), and cesium carbonate (570 mg, 1.75 mmol) were added, and the mixture was reacted at 100 °C for 2 h. The reaction solution was cooled to room temperature and diluted with water (40 mL). Extraction was performed with DCM / MeOH = 10 / 1 (20 mL * 3), followed by washing with brine (15 mL * 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to give compound 12 (120.7 mg, yield 46%).

[0403] MS m / z(ESI): 373.05 [M+1] +

[0404] 1 H NMR (400MHz, DMSO-d6) δ8.56(s,1H),8.04(d,J=9.6Hz,1H),7.93(d,J=9.6Hz,1H),7.34-7.32(m ,3H),4.28-4.22(m,2H),3.33(s,3H),2.92-2.88(m,2H),2.57-2.53(m,2H),1.36-1.33(m,3H).

[0405] Example 13

[0406] Synthesis of compound 13b in step one

[0407] Compound 13a (500 mg, 2.525 mmol) and NCS (371 mg, 2.777 mmol) were dissolved in chloroform (20 mL), and then heated and stirred in an oil bath at 65 °C for 16 h. Dichloromethane (100 mL) was added to the reaction solution, followed by washing with saturated sodium bicarbonate aqueous solution (50 mL * 2), drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain crude compound 13b (630 mg), which was directly added to the next reaction.

[0408] MS m / z(ESI): 234[M+1] +

[0409] The second step involves the synthesis of compound 13d.

[0410] Compound 13b (580 mg, 2.495 mmol), phenol (0.444 mL, 4.990 mmol), and K₂CO₃ (689.60 mg, 4.990 mmol) were dissolved in DMA (15 mL), and then stirred in an oil bath at 125 °C for 12 h. The mixture was concentrated to dryness under reduced pressure. Water (50 mL) and ethyl acetate (50 mL) were added to the residue, and the mixture was shaken well. The aqueous layer was extracted with ethyl acetate (50 mL), and the organic phases were combined and washed successively with water (50 mL) and saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was passed through a silica gel column to obtain crude compound 13d (250 mg), which was used directly in the next reaction.

[0411] MS m / z(ESI): 292[M+1] +

[0412] Step 3: Synthesis of Compound 13

[0413] Compound 13d (50 mg, 0.172 mmol), compound 13e (66 mg, 0.207 mmol), K₂CO₃ (48 mg, 0.345 mmol), and DPPF palladium dichloride methane complex (28 mg, 0.034 mmol) were dissolved in a mixed solvent of 1,4-dioxane (2.5 mL) and water (0.5 mL). The mixture was evacuated three times with argon gas, and then microwaved at 90 °C for 1 h. The reaction solution was extracted with water (50 mL) and ethyl acetate (50 mL x 2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was used to prepare compound 13 (38.42 mg, yield 55.2%).

[0414] MS m / z(ESI): 405 [M+1] +

[0415] 1 H NMR(400MHz,DMSO-d6)δ8.73(s,1H),8.50(d,J=2.1Hz,1H),8.38(dd,J=11.7,2.0Hz,1H), 7.92–7.70(m,2H),7.59–7.42(m,4H),7.30(td,J=6.5,2.3Hz,1H),5.16(q,J=9.0Hz,2H).

[0416] Example 14

[0417] The first step is the synthesis of compound 14c.

[0418] Compound 14a (200 mg, 0.740 mmol), compound 14b (285 mg, 0.889 mmol), Na₂CO₃ (94 mg, 0.889 mmol), and DPPF palladium dichloride methane complex (121 mg, 0.148 mmol) were dissolved in a mixed solvent of toluene (13 mL), ethanol (3.2 mL), and water (0.2 mL). The mixture was evacuated three times with argon gas, and then reacted in an oil bath at 85 °C for 2 h (two parallel reactions were performed). The reaction solutions from the two reactions were combined, and water (50 mL) and ethyl acetate (50 mL x 2) were added for extraction. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 14c (500 mg, yield 87.9%).

[0419] MS m / z(ESI): 385[M+1] + .

[0420] The second step involves the synthesis of compound 14d.

[0421] Compound 14c (450 mg, 1.171 mmol) was dissolved in tetrahydrofuran (15 mL), then cooled to 0 °C in an ice-water bath. 1 M DIBAL-H tetrahydrofuran solution (4.684 mL, 4.684 mmol) was then added dropwise, and the mixture was stirred at 0 °C for 1 h. Water (2 mL) and 15% sodium hydroxide aqueous solution (2 mL) were added to the reaction mixture in an ice-water bath. The reaction was quenched with water (5 mL), and then dichloromethane (50 mL) was added. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. This crude product was then purified by silica gel column chromatography to obtain compound 14d (105 mg, yield 26.2%).

[0422] MS m / z(ESI): 343[M+1] +

[0423] Step 3: Synthesis of Compound 14

[0424] Compound 14d (90 mg, 0.263 mmol) and compound 14e (88 mg, 0.526 mmol) were dissolved in DMF (5 mL), then cooled to 0 °C in an ice-water bath. 60% NaH (53 mg, 1.315 mmol) was added, and the mixture was stirred for 2 h. A saturated ammonium chloride aqueous solution (10 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (20 mL x 2). The mixture was washed successively with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was used to prepare compound 14 (10.38 mg, 9% yield).

[0425] MS m / z(ESI): 437[M+1]+

[0426] 1 H NMR (400MHz, DMSO-d6) δ8.86(t,J=1.5Hz,1H),8.49(d,J=2.0Hz,1H),8.40(dd,J=11.7,2.1Hz,1H),7.91(d,J=9.6Hz,1H),7.84(d d,J=9.6,1.6Hz,1H),7.54(d,J=1.5Hz,1H),7.14(d,J=1.4Hz,1H),5.19(q,J=9.0Hz,2H),5.05(s,2H),4.48(s,2H),3.62(s,3H).

[0427] Example 15

[0428] Synthesis of Compound 15 (Step 1)

[0429] Compound 15a (100 mg, 0.344 mmol), compound 15b (132.10 mg, 0.378 mmol), potassium phosphate (237.62 mg, 1.032 mmol), 1,4-dioxane (5 mL), and water (0.5 mL) were added. Under nitrogen protection, di(tri-tert-butylphosphine)palladium (17.58 mg, 0.034 mmol) was added, and the mixture was microwaved at 85 °C for 2 h. The mixture was then extracted directly with purified water (20 mL) and ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified to obtain compound 15 (32.10 mg, yield 19.55%).

[0430] MS m / z(ESI): 478.1 [M+1] +

[0431] 1 H NMR(400MHz, DMSO-d6)δ8.50(s,1H),8.24(d,J=2.0Hz,1H),8.12(dd,J=10.6,2.0Hz,1H),7.90(td,J=7.4,1.8Hz,1H), 7.66(dddd,J=8.7,7.3,5.3,1.8Hz,1H),7.51–7.41(m,2H),2.91(q,J=6.7Hz,1H),1.83(s,6H),1.21(d,J=6.8Hz,6H).

[0432] Example 16

[0433] The first step is the synthesis of compound 16c.

[0434] Compound 16b (495.24 mg, 3.866 mmol) was dissolved in THF (10 mL). Under nitrogen protection, 60% NaH (309.31 mg, 7.733 mmol) was added in portions at 0 °C. After stirring at room temperature for 15 min, a mixed solution of compound 16a (500 mg, 2.578 mmol) and THF (2 mL) was added, and the mixture was refluxed at 80 °C for 4 h. Water (40 mL) was added, and the mixture was extracted with EA (30 mL * 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by silica gel column chromatography to obtain compound 16c (310 mg, yield 39.81%).

[0435] MS m / z(ESI): 302.0 [M+1] +

[0436] The second step involves the synthesis of compound 16e.

[0437] Compound 16c (300 mg, 0.993 mmol), compound 16d (302.64 mg, 1.192 mmol), Pd2(dba)3 (90.95 mg, 0.099 mmol), KOAc (116.96 mg, 1.192 mmol), tricyclohexylphosphine (55.70 mg, 0.199 mmol), and dioxane (10 mL) were reacted overnight at 100 °C under nitrogen protection. Water (60 mL) was added, and the mixture was extracted with EA (30 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 16e (300 mg, yield 86.52%).

[0438] MS m / z(ESI): 350.1 [M+1] +

[0439] The third step involves the synthesis of compound 16.

[0440] Compound 16e (281.94 mg, 0.808 mmol) and compound 16f (100 mg, 0.404 mmol) were dissolved in dioxane (9 mL), and potassium carbonate (111.60 mg, 0.808 mmol), Pd(dppf)Cl2.CH2Cl2 (33.06 mg, 0.040 mmol), and water (3 mL) were added. The mixture was reacted overnight at 100 °C under nitrogen protection. Water (50 mL) was added, and the mixture was extracted with EA (30 mL * 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the crude product. The crude product was then used to prepare compound 16 (77.2 mg, yield 44%).

[0441] MS m / z(ESI): 435.0 [M+1] +

[0442] 1 H NMR (400MHz, DMSO-d6) δ8.63(dt,J=2.8,1.4Hz,1H),8.45(d,J=2.2Hz,1H),8.29(dd,J=11.5,2.2Hz,1H),8.03(dd,J= 9.6,1.1Hz,1H),7.91–7.83(m,2H),7.73(dddd,J=8.6,7.3,5.4,1.8Hz,1H),7.56–7.46(m,2H),1.80(d,J=1.1Hz,6H).

[0443] Example 17

[0444] Synthesis of compound 17b (Step 1)

[0445] Reactant 17a (205 mg, 1.000 mmol) was added to a microwave-safe reaction flask, followed by THF (5 mL), hydrazine hydrate (294.36 mg, 4.998 mmol), and DIEA (142.12 mg, 1.100 mmol). The mixture was purged with nitrogen and stirred. The flask was then microwave-safe at 90 °C for 3 h. After cooling to room temperature, EA (30 mL) and purified water (10 mL) were added. The mixture was separated, and the organic phase was evaporated to dryness to give crude compound 17b (143 mg, yield 71.29%). MS m / z (ESI): 201.1 [M+1] +

[0446] The second step involves the synthesis of compound 17d.

[0447] Compound 17b (143 mg, 0.713 mmol) was added to a reaction flask, followed by dioxane (5 mL) and Et3N (79.32 mg, 0.784 mmol). The mixture was stirred and cooled to 0–5 °C in an ice bath. At this temperature, a solution of compound 17c (137.80 mg, 0.713 mmol) in dioxane (5 mL) was slowly added, and the mixture was stirred and kept at this temperature for 1 h. After the reaction system was brought to room temperature, the solvent was removed by rotary evaporation under reduced pressure to obtain compound 17d (160 mg, yield 62.79%).

[0448] MS m / z(ESI): 358.9 [M+1] +

[0449] The third step involves the synthesis of compound 17e.

[0450] Compound 17d (160 mg, 0.447 mmol) was added to a reaction flask, followed by Xylene (15 mL). The mixture was refluxed at 150 °C in an oil bath for 3 h. The reaction mixture was then cooled to room temperature, concentrated under reduced pressure to remove the solvent, and extracted with sodium bicarbonate solution (100 mL). The organic phase was concentrated and purified by silica gel column chromatography to obtain compound 17e (150 mg, 98.72% yield).

[0451] MS m / z(ESI): 338.3 [M+1] +

[0452] The fourth step: synthesis of compound 17f

[0453] Compound 17e (150 mg, 0.442 mmol) was added to a reaction flask, along with anhydrous ethanol (15 mL) and AgBF4 (171.99 mg, 0.883 mmol). The mixture was heated in an oil bath at 95 °C and refluxed with stirring for 2 h. The reaction mixture was then cooled to room temperature, quenched with saturated NaCl solution (10 mL), and extracted with EA (30 mL). The organic phase was purified by silica gel column chromatography to give compound 17f (108 mg, yield 80.23%).

[0454] MS m / z(ESI): 305.1 [M+1] +

[0455] Step 5: Synthesis of Compound 17

[0456] Compound 17 g (49.57 mg, 0.390 mmol) was added to a reaction flask, followed by the addition of THF (10 mL). The mixture was stirred until dissolved, then compound 17f (108 mg, 0.354 mmol) and 60% NaH (70.88 mg, 1.772 mmol) were added. The mixture was stirred at room temperature for 1 h. The reaction mixture was then quenched with purified water (10 mL) to obtain compound 17 (25.34 mg, yield 18.08%).

[0457] MS m / z(ESI): 396.2 [M+1] +

[0458] 1 H NMR (400MHz, DMSO-d6) δ8.14(s,1H),7.99(d,J=3.5Hz,1H),5.65(s,2H),4.31(q,J=7.2Hz, 2H), 4.16 (q, J = 7.1Hz, 2H), 1.42–1.38 (m, 3H), 1.36 (d, J = 5.4Hz, 9H), 1.31 (d, J = 7.1Hz, 3H).

[0459] Example 18

[0460] The first step is the synthesis of compound 18c.

[0461] Compound 18a (500 mg, 2.645 mmol) and compound 18b (407.69 mg, 2.645 mmol) were dissolved in xylene (10 mL), and triethylamine hydrochloride (364.08 mg, 2.645 mmol) was added. The mixture was reacted at 140 °C for 24 h. Water (200 mL) was added, and the mixture was extracted with DCM (50 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by silica gel column chromatography to give compound 18c (160 mg, yield 20.81%).

[0462] MS m / z(ESI): 289.1 [M+1] +

[0463] The second step involves the synthesis of compound 18.

[0464] Compound 18c (333.64 mg, 1.039 mmol) and compound 18d (150 mg, 0.520 mmol) were added to a sealed tube, along with potassium phosphate (358.93 mg, 1.559 mmol), bis(tert-butylphosphine)palladium (53.10 mg, 0.104 mmol), dioxane (9 mL), and water (3 mL). The mixture was microwaved at 100 °C for 6 h, then 40 mL of water was added. The mixture was extracted with EA (25 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by silica gel column chromatography to obtain the crude product. The crude product was then used to prepare compound 18 (22.73 mg, yield 9.8%).

[0465] MS m / z(ESI): 448.1 [M+1] +

[0466] 1 H NMR (400MHz, DMSO-d6) δ8.73(d,J=2.0Hz,1H),8.40(dd,J=11.3,2.0Hz,1H),7.99(td,J=7.4,1.8Hz,1H),7.73–7.65(m,2 H),7.57–7.45(m,2H),5.19(q,J=8.9Hz,2H),2.61(tt,J=8.3,5.1Hz,1H),1.60–1.54(m,2H),1.36(dt,J=8.4,3.4Hz,2H).

[0467] Example 19

[0468] The first step is the synthesis of compound 19c.

[0469] Compound 19a (500 mg, 1.773 mmol), compound 19b (540.18 mg, 2.127 mmol), Pd2(dba)3 (162.33 mg, 0.177 mmol), tricyclohexylphosphine (99.43 mg, 0.355 mmol), KOAc (347.94 mg, 3.545 mmol), and dioxane (10 mL) were reacted overnight at 100 °C under nitrogen protection. Water (60 mL) was added, and the mixture was extracted with EA (40 mL x 3), washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by silica gel column chromatography to give compound 19c (300 mg, yield 51.42%).

[0470] MS m / z(ESI): 330.1 [M+1] +

[0471] The second step involves the synthesis of compound 19f.

[0472] Compound 19e (82.25 mg, 1.416 mmol) was dissolved in DMF (5 mL). Under nitrogen protection, 60% NaH (84.96 mg, 2.124 mmol) was added at 0 °C. After stirring at room temperature for 10 min, compound 19d (200 mg, 0.708 mmol) was added, and the mixture was stirred at room temperature for 1 h. Water (30 mL) was added, and the mixture was extracted with EA (20 mL * 3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by silica gel column chromatography to obtain compound 19f (20 mg, yield 9.29%).

[0473] MS m / z(ESI): 304.0 [M+1] +

[0474] The third step involves the synthesis of compound 19.

[0475] Compound 19c (43.29 mg, 0.132 mmol) and compound 19f (20 mg, 0.066 mmol) were dissolved in dioxane (3 mL), and Pd(dppf)Cl2.CH2Cl2 (10.77 mg, 0.013 mmol), potassium carbonate (18.18 mg, 0.132 mmol), and water (1 mL) were added. The mixture was reacted overnight at 100 °C under nitrogen protection. Water (20 mL) was added, and the mixture was extracted with EA (15 mL * 3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to prepare compound 19 (9.71 mg, yield 34.51%).

[0476] MS m / z(ESI): 427.1 [M+1] +

[0477] 1 H NMR(400MHz, DMSO-d6)δ8.32(s,1H),8.03(dd,J=9.7,1.0Hz,1H),7.81(dd,J=9.6,1.7Hz,1H),7.03–6.90(m,3H),6.30(s,1H),4.96(td, J=6.8,3.0Hz,1H),4.17(td,J=6.3,3.1Hz,1H),3.58(d,J=12.5Hz,1H),3.37–3.34(m,1H),0.87(q,J=4.7,3.8Hz,2H),0.78–0.70(m,2H).

[0478] Example 20

[0479] Synthesis of compound 20c in step one

[0480] Compound 20a (652 mg, 4.000 mmol) was dissolved in xylene (10 mL), and compound 20b (616.56 mg, 4.000 mmol) and triethylamine hydrochloride (1101.20 mg, 8.000 mmol) were added. The mixture was reacted in a microwave oven at 140 °C for 18 h. After cooling to room temperature, the mixture was purified by silica gel column chromatography to give compound 20c (450 mg, yield 42.83%).

[0481] MS m / z(ESI): 263.0 [M+1] +

[0482] The second step involves the synthesis of compound 20.

[0483] Reactant 20c (132 mg, 0.503 mmol) was added to a reaction flask and dissolved in dioxane (10 mL). Reactant 20d (193.62 mg, 0.603 mmol), purified water (1 mL), di(tri-tert-butylphosphine)palladium (25.68 mg, 0.050 mmol), and K3PO4 (213.33 mg, 1.005 mmol) were added. The mixture was stirred overnight at 100 °C under nitrogen protection. After cooling to room temperature, purified water (15 mL) was added, followed by extraction with EA (35 mL x 2). The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to obtain an oily substance. This was dissolved in MeOH (15 mL) to prepare and purify compound 20 (27.91 mg, yield 13.17%).

[0484] MS m / z(ESI): 421.9 [M+1]+

[0485] 1 H NMR (400MHz, DMSO-d6) δ8.44(d,J=1.4Hz,1H),8.29(d,J=1.9Hz,1H),8.21(dd,J=10.9,2.0Hz,1H),7.94(td,J=7.4, 1.8Hz,1H),7.70–7.63(m,1H),7.46(dtd,J=15.1,8.1,7.6,1.1Hz,2H),5.17(q,J=8.9Hz,2H),2.38(d,J=1.3Hz,3H).

[0486] Example 21

[0487] Synthesis of compound 21c in step one

[0488] Compound 21a (652 mg, 4.000 mmol) was dissolved in xylene (10 mL), and reactant 21b (616.56 mg, 4.000 mmol) and triethylamine hydrochloride (1101.20 mg, 8.000 mmol) were added. The mixture was reacted in a microwave oven at 140 °C for 18 h. After cooling to room temperature, the mixture was purified by silica gel chromatography to give compound 21c (450 mg, yield 42.83%).

[0489] MS m / z(ESI): 263.0 [M+1] +

[0490] The second step involves the synthesis of compound 21.

[0491] Compound 21c (132 mg, 0.503 mmol) was added to a reaction flask, along with dioxane (10 mL), compound 21d (193.62 mg, 0.603 mmol), purified water (1 mL), di(tri-tert-butylphosphine)palladium (25.68 mg, 0.050 mmol), and K3PO4 (213.33 mg, 1.005 mmol). The mixture was stirred overnight at 100 °C under nitrogen protection. After cooling to room temperature, purified water (15 mL) was added, followed by extraction with EA (35 mL x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated. Compound 21 (21.72 mg, yield 10.2%) was obtained.

[0492] MS m / z(ESI): 421.9 [M+1] +

[0493] 1H NMR(400MHz,DMSO-d6)δ8.73(d,J=2.0Hz,1H),8.37(dd,J=11.2,2.0Hz,1H),8.03–7.98(m ,2H),7.75–7.68(m,1H),7.57–7.48(m,2H),5.19(q,J=8.9Hz,2H),2.76(d,J=1.2Hz,3H).

[0494] Example 22

[0495] Synthesis of compound 22c in step one

[0496] Compound 22a (500 mg, 2.824 mmol), compound 22b (478.88 mg, 3.107 mmol), and triethylamine hydrochloride (505.41 mg, 3.672 mmol) were dissolved in xylene (10 mL) and reacted in a microwave oven at 150 °C for 2 h. The reaction mixture was cooled to room temperature and purified by silica gel column chromatography to give compound 22c (180 mg, yield 23.04%). MS m / z (ESI): 277.1 [M+1] +

[0497] The second step involves the synthesis of compound 22.

[0498] Compound 22c (50 mg, 0.181 mmol) was dissolved in dioxane (3 mL) and water (1 mL), and compound 22d (92.3 mg, 0.18 mmol) was added. The reaction mixture was heated to 100 °C and stirred for 3 h under nitrogen protection. After returning to room temperature, purified water (10 mL) was added, and extracting was performed with EA (20 mL * 2). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified to obtain compound 22 (13.64 mg, yield 17.3%).

[0499] MS m / z(ESI): 435.9 [M+1] +

[0500] 1 H NMR(400MHz, DMSO-d6)δ8.75(d,J=2.0Hz,1H),8.41(dd,J=11.2,2.0Hz,1H),8.06–7.97(m,1H),7.93(s,1 H),7.76–7.67(m,1H),7.59–7.46(m,2H),5.19(q,J=8.9Hz,2H),3.24–3.06(m,2H),1.48(t,J=7.5Hz,3H).

[0501] Example 23

[0502] The synthesis method was as described in Example 22, yielding compound 23 (17.12 mg).

[0503] MS M / Z(ESI): 435.9 [M+1] +

[0504] 1 H NMR (400MHz, DMSO-d6) δ8.44–8.39(m,1H),8.30(d,J=1.9Hz,1H),8.22(dd,J=10.8,2.0Hz,1H),8.00–7.92(m ,1H),7.73–7.62(m,1H),7.54–7.42(m,2H),5.19(q,J=8.9Hz,2H),2.75–2.63(m,2H),1.18(t,J=7.4Hz,3H).

[0505] Example 24

[0506] The first step is the synthesis of compound 24c.

[0507] Compound 24a (370 mg, 2.4 mmol) was dissolved in N,N-dimethylformamide (10 mL), and compound 24b (1.08 g, 4.8 mmol) was added. The reaction was carried out at 100 °C for 16 h. After the reaction was completed, the reaction solution was filtered and evaporated to dryness. The crude product was subjected to silica gel column chromatography to give compound 24c (480 mg, yield 79%).

[0508] MS m / z(ESI): 250.90 [M+1] +

[0509] 1 H NMR (400MHz, CDCl3) δ7.93(d,J=8.8Hz,1H),7.48(d,J=8.8Hz,1H),4.90-4.87(m,2H),2.97-2.90(m,2H)

[0510] The second step involves the synthesis of compound 24.

[0511] Compound 24c (70 mg, 0.28 mmol) was dissolved in 1,2-dioxane (5 mL), and compound 24d (41 mg, 0.33 mmol), cesium carbonate (273 mg, 0.84 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (32 mg, 0.056 mmol) and tris(dibenzylacetone)dipalladium (25 mg, 0.028 mmol) were added. The reaction mixture was reacted at 80 °C for 16 h. After the reaction was complete, the reaction solution was filtered and evaporated to dryness. The crude product was used to prepare compound 24 (40 mg, 43% yield) using a reverse-phase reaction.

[0512] MS m / z(ESI): 338.00 [M+1] +

[0513] 1 H NMR(400MHz,DMSO-d6)δ9.48(s,1H),8.15(d,J=8.8Hz,1H),7.59(s,1H),7.387.33(m,1H),7.20-7.18(m,1H),7 .05(d,J=8.8Hz,1H),6.53-6.50(m,1H),4.88-4.76(m,2H),3.73(s,3H),3.07-2.98(m,2H),1.99-1.93(m,1H).

[0514] Example 25

[0515] Synthesis of compound 25b in step one

[0516] Compound 25a (3.0 g, 12.6 mmol) was dissolved in ethanol (30 mL) and water (6 mL), and iron powder (2.1 g, 37.8 mmol) and ammonium chloride (2.0 g, 37.8 mmol) were added. The mixture was reacted at 80 °C for 5 h. The solution was filtered and washed with ethyl acetate, and the filtrate was evaporated to dryness. The crude product was purified by silica gel column chromatography to give compound 25b (2.3 g, yield: 88%). 1 H NMR (400MHz, CDCl3) δ6.69-6.64(m,2H),3.88(s,2H).

[0517] The second step involves the synthesis of compound 25c.

[0518] Compound 25b (2.3 g, 11.1 mmol) was dissolved in pyridine (12 mL), and p-toluenesulfonyl chloride (2.3 g, 12.1 mmol) was added at 0 °C. The reaction was carried out at room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and extracted with ethyl acetate (20 mL * 3) and dilute hydrochloric acid (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 25c (4 g, 99% yield).

[0519] 1 H NMR (400MHz, DMSO-d6) δ10.66(s,1H),7.62-7.61(m,2H),7.59-7.52(m,1H),7.40-7.33(m,2H),7.19-7.17(m,1H),2.33(s,3H).

[0520] The third step involves the synthesis of compound 25e.

[0521] Compound 25c (4 g, 11.0 mmol) was dissolved in isopropanol (30 mL) and water (1.5 mL). Compound 25d (2.5 g, 22.1 mmol) and anhydrous sodium carbonate (1.8 g, 16.6 mmol) were added, and the mixture was reacted in a sealed container at 80 °C for 16 h. After the reaction was complete, 30 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL * 3). The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain compound 25e (6.5 g crude product).

[0522] MS m / z(ESI): 474.00 [M+1] +

[0523] The fourth step is the synthesis of compound 25f.

[0524] Compound 25e (6.5 g crude) was dissolved in tetrahydrofuran (70 mL), and TBAB (442 mg, 1.4 mmol) and sodium hydroxide (2.2 g, 54.8 mmol) were added. The reaction mixture was reacted at 70 °C for 1 h. The reaction solution was diluted with water (100 mL), extracted with ethyl acetate (50 mL * 3), and the organic phase was washed three times with brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by column chromatography to give compound 25f (2.7 g, two-step yield 53%).

[0525] 1 H NMR (400MHz, DMSO-d6) δ7.77-7.45(m,2H),7.47-7.42(m,4H),4.74-4.70(m,1H),4.33-4.28(m,1H),3.99-3.93(m,1H),2.37(s,3H).

[0526] Step 5: Synthesis of 25g of compound

[0527] Compound 25f (1.0 g, 2.2 mmol) was dissolved in methanol (100 mL), and magnesium filings (264 mg, 11.0 mmol) were added at 0 °C. The reaction was carried out at room temperature for 2 h. The mixture was filtered and washed with dichloromethane, and the filtrate was evaporated to dryness. The crude product was purified by silica gel column chromatography to give crude compound 25 g (360 mg).

[0528] MS m / z(ESI): 299.95 [M+1] +

[0529] Step 6: Synthesis of compound 25j

[0530] Compound 25h (500 mg, 1.7 mmol) was dissolved in 1,4-dioxane (15 mL), and Pd(dppf)Cl2 (125 mg, 0.17 mmol), potassium acetate (336 mg, 3.4 mmol), and compound 25i (565 mg, 2.2 mmol) were added. The reaction was carried out at 70 °C for 16 h. After the reaction was completed, the reaction solution was filtered and washed with dichloromethane. The filtrate was concentrated to obtain crude compound 25j (400 mg).

[0531] MS m / z(ESI): 257.75 [M+1] +

[0532] Step 7: Synthesis of Compound 25

[0533] Compound 25 g (360 mg) was dissolved in 1,4-dioxane (12 mL) and water (3 mL), and compound 25j (400 mg), Pd(dppf)Cl2 (88 mg, 0.12 mmol), and cesium carbonate (978 mg, 3.0 mmol) were added. The reaction was carried out at 100 °C for 2 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography. The crude product was then purified by slurrying with methanol to obtain compound 25 (300 mg, two-step yield: 32%).

[0534] MS m / z(ESI): 433.20 [M+1] +

[0535] 1H NMR(400MHz,DMSO-d6)δ8.40(s,1H),8.01-7.98(m,1H),7.79-7.76(m,1H),6.94-6.91(m,1H),6.79-6.78(m,1H ),6.58(s,1H),5.03-4.99(m,1H),4.26-4.21(m,2H),3.61-3.58(m,1H),3.40-3.32(m,1H),1.35-1.31(m,3H).

[0536] Example 26

[0537] Synthesis of compound 26c in step one

[0538] Compound 26a (1000 mg, 4.291 mmol) and compound 26b (737.21 mg, 8.582 mmol) were dissolved in dioxane (9 mL), and Pd(dppf)Cl2.CH2Cl2 (175.65 mg, 0.215 mmol), potassium carbonate (1186.06 mg, 8.582 mmol), and water (3 mL) were added. The mixture was reacted overnight at 100 °C under nitrogen protection. Water (60 mL) was added, and the mixture was extracted with EA (30 mL * 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by silica gel column chromatography to give compound 26c (697 mg, yield 83.64%).

[0539] MS m / z(ESI): 195.1 [M+1] +

[0540] The second step involves the synthesis of compound 26d.

[0541] Compound 26c (677 mg, 3.486 mmol) was dissolved in EtOH (15 mL), and NaOH (278.87 mg, 6.972 mmol) and water (3 mL) were added. The mixture was reacted at 65 °C for 1 h. After concentration, the solution was dissolved in water (20 mL), the pH was adjusted to 1-2 with 1 N HCl aqueous solution, extracted with EA (30 mL * 3), washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 26d (600 mg, yield 95.53%).

[0542] MS m / z(ESI): 181.1 [M+1] +

[0543] The third step involves the synthesis of compound 26f.

[0544] Compound 26d (200 mg, 1.064 mmol) and compound 26e (239.56 mg, 1.33 mmol) were dissolved in DMF (6 mL), and DIEA (412.43 mg, 3.191 mmol) and EA solution of 50% T3P (947.92 mg, 1.490 mmol) were added. The mixture was stirred at room temperature for 2 h. Water (30 mL) was added, and the mixture was extracted with EA (20 mL x 3). The extract was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain compound 26f (370 mg, 99.33% yield).

[0545] MS m / z(ESI): 350.0 [M+1] +

[0546] The fourth step involves the synthesis of compound 26g.

[0547] Compound 26f (370 mg, 1.057 mmol) was dissolved in ACN (10 mL), and phosphorus oxychloride (1 mL) was added. The mixture was reacted in a microwave at 150 °C for 30 min. After concentration, sodium bicarbonate aqueous solution (40 mL) was added, followed by extraction with EA (20 mL * 3), washing with saturated brine (20 mL), drying with anhydrous sodium sulfate, filtration, and concentration. The resulting product was then purified by silica gel column chromatography to obtain compound 26 g (100 mg, yield 28.48%).

[0548] MS m / z(ESI): 332.0 [M+1] +

[0549] Step 6: Synthesis of Compound 26

[0550] Compound 26 g (59.45 mg, 0.181 mmol), compound 26 h (40 mg, 0.120 mmol), Pd(dppf)Cl2.CH2Cl2 (9.86 mg, 0.012 mmol), potassium carbonate (33.28 mg, 0.241 mmol), dioxane (3 mL), and water (1 mL) were added sequentially to a sealed tube and reacted overnight at 100 °C under nitrogen protection. Water (30 mL) was added, and the mixture was extracted with EA (20 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 26 (20.2 mg, yield 37.04%).

[0551] MS m / z(ESI): 455.0 [M+1] +

[0552] 1H NMR (400MHz, DMSO-d6) δ8.20(t,J=2.1Hz,1H),7.98(d,J=9.5Hz,1H),7.82(dd,J=7.0,2.3Hz,1H),7.74(ddd,J=9.6,6.5,3.4Hz,2H),7.48(t,J=9.3Hz ,1H),7.00(s,1H),6.94(s,2H),6.56(d,J=15.7Hz,1H),6.47–6.37(m,1H), 6.20(s,1H),4.99–4.90(m,1H),3.57(d,J=12.3Hz,1H),1.93–1.77(m,4H).

[0553] Example 27

[0554] Synthesis of compound 27c in step one

[0555] Compound 27a (1000 mg, 4.404 mmol), compound 27b (1230 mg, 4.845 mmol), and KOAc (1297 mg, 13.212 mmol) were dissolved in 1,4-dioxane (15 mL), degassed for 15 min, and then Pd(dppf)Cl2.CH2Cl2 (180 mg, 0.220 mmol) was added, degassed for 5 min, and then stirred overnight in an oil bath at 95 °C. The mixture was filtered, concentrated under reduced pressure, and then water (100 mL) and ethyl acetate (100 mL) were added to the residue. The mixture was shaken well, separated into layers, and washed successively with water (100 mL) and saturated brine (100 mL). The residue was dried over anhydrous sodium sulfate, filtered through a silica gel filter, and concentrated under reduced pressure to obtain crude compound 27c (1300 mg), which was directly added to the next reaction. MS m / z (ESI): 275 [M+1] +

[0556] The second step involves the synthesis of compound 27e.

[0557] Compound 27c (200 mg, 0.752 mmol) and compound 27d (412 mg, 1.504 mmol) were dissolved in a mixed solvent of toluene (12 mL), ethanol (3 mL), and water (0.6 mL). Then, Na₂CO₃ (159 mg, 1.504 mmol) was added, and the mixture was evacuated three times with nitrogen. Next, Pd(dppf)Cl₂.CH₂Cl₂ (123 mg, 0.150 mmol) was added, and the mixture was evacuated for 5 min. The reaction was then carried out in an oil bath at 85 °C for 5 h. Ethyl acetate (50 mL) and water (50 mL) were added to the reaction mixture, and the mixture was shaken well. The layers were separated, and the aqueous layer was extracted with ethyl acetate (50 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain crude compound 27e (250 mg), which was directly added to the next reaction step.

[0558] MS m / z(ESI): 334[M+1] +

[0559] Step 3: Synthesis of Compound 27

[0560] Compound 27e (90 mg, 0.270 mmol) and BAST (717 mg, 3.241 mmol) were dissolved in DCM (2 mL) and stirred overnight in an oil bath at 50 °C. 1 mL of methanol was added to the reaction mixture, which was then poured into ice water (20 mL). The mixture was extracted with ethyl acetate (20 mL x 3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified to give compound 27 (18.81 mg, yield 19.6%).

[0561] MS m / z(ESI): 356[M+1] +

[0562] 1 H NMR(400MHz, DMSO-d6)δ8.73(s,1H),8.13(dd,J=9.6,1.1Hz,1H),8.04–7.97(m,2H),7.89(dd, J=8.8,2.4Hz,1H),7.14(d,J=8.7Hz,1H),4.48–4.36(m,2H),2.62(tq,J=13.0,6.6,5.7Hz,2H).

[0563] Example 28

[0564] Synthesis of Compound 28 (Step 1)

[0565] Compound 28a (80 mg, 0.275 mmol), compound 28b (95.12 mg, 0.330 mmol), potassium phosphate (190.10 mg, 0.826 mmol), 1,4-dioxane (5 mL), and water (0.5 mL) were added. Under nitrogen protection, di(tri-tert-butylphosphine)palladium (14.06 mg, 0.028 mmol) was added, and the reaction was carried out at 100 °C for 3 h. Purified water (30 mL) and ethyl acetate (30 mL x 3) were added directly to the reaction solution for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified to obtain compound 28 (22.14 mg, yield 19.32%).

[0566] MS m / z (ESI): 416.9 [M+1] +

[0567] 1 H NMR(400MHz, DMSO-d6)δ8.49(s,1H),7.89(td,J=7.4,1.8Hz,1H),7.73(d,J=8.6Hz,2H),7.69–7 .61(m,1H),7.58–7.52(m,2H),7.50–7.39(m,2H),2.90(p,J=6.8Hz,1H),2.50(q,J=1.9Hz,6H).

[0568] Example 29

[0569] Example 29 (8.24 mg, 8.83%) was obtained by following the synthesis method of Example 28.

[0570] MS m / z(ESI): 417.9 [M+1] +

[0571] 1 H NMR (400MHz, DMSO-d6) δ8.62 (d, J=2.4Hz, 1H), 8.53 (s, 1H), 8.30 (dd, J=8.5, 2.5Hz, 1H), 7.92 (td, J= 7.4,1.8Hz,1H),7.73–7.61(m,1H),7.55–7.37(m,3H),2.88(p,J=6.8Hz,1H),1.21(d,J=6.8Hz,6H).

[0572] Example 30

[0573] Synthesis of Compound 30 (Step 1)

[0574] Reactant 30a (132 mg, 0.503 mmol) was added to a reaction flask, followed by dioxane (10 mL), reactant 30b (193.62 mg, 0.603 mmol), purified water (1 mL), bis(tert-butylphosphine)palladium (25.68 mg, 0.050 mmol), and K3PO4 (213.33 mg, 1.005 mmol). The mixture was stirred overnight at 100 °C under nitrogen protection. After cooling to room temperature, purified water (15 mL) was added, followed by extraction with EA (35 mL x 2). The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to obtain the crude product. The crude product was dissolved in MeOH (15 mL) and purified to obtain compound 30 (23.13 mg, 10.2% yield).

[0575] MS m / z(ESI): 449.9 [M+1] +

[0576] 1 H NMR (400MHz, DMSO-d6) δ8.44(d,J=1.4Hz,1H),8.27(d,J=2.0Hz,1H),8.17(dd,J=10.9,2.0Hz,1H),7 .94(td,J=7.4,1.9Hz,1H),7.72–7.64(m,1H),7.53–7.42(m,2H),2.39(d,J=1.3Hz,3H),1.83(s,7H).

[0577] Example 31

[0578] The synthesis method is the same as in Example 30.

[0579] MS m / z(ESI): 449.9 [M+1] +

[0580] 1 H NMR (400MHz, DMSO-d6) δ8.72(d,J=2.1Hz,1H),8.34(dd,J=11.1,2.1Hz,1H),8.02–7. 97(m,2H),7.76–7.68(m,1H),7.59–7.48(m,2H),2.76(d,J=1.2Hz,3H),1.84(s,6H).

[0581] Example 32

[0582] Synthesis of compound 32c in step one

[0583] Compound 32a (200 mg, 0.712 mmol) was dissolved in dioxane (3 mL) and water (1 mL). Compound 32b (75.43 mg, 0.235 mmol), K3PO4 (453.08 mg, 2.135 mmol), and bis(tri-tert-butylphosphine)palladium (36.36 mg, 0.071 mmol) were added. The reaction mixture was heated to 110 °C and stirred for 3 h under nitrogen protection. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to give compound 32c (210 mg, yield 63.09%). MS m / z (ESI): 467.9 [M+1] +

[0584] The second step involves the synthesis of compound 32.

[0585] Compound 32c (180 mg, 0.385 mmol) was dissolved in ethanol (5 mL), and AgBF4 (224.72 mg, 1.154 mmol) was added. The mixture was heated in an oil bath at 80 °C and refluxed with stirring overnight. After cooling to room temperature, purified water (10 mL) was added, and extractive ester (EA) (20 mL x 2) was added. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to obtain an oily substance. Compound 32 (2.6 mg, yield 1.4%) was prepared and purified.

[0586] MS m / z(ESI): 477.9 [M+1] +

[0587] 1 H NMR (400MHz, Methanol-d4) δ8.19(s,1H),8.09(d,J=2.1Hz,1H),7.79(dd,J=10.3,2.1Hz,1H),4.12(q,J =7.1Hz,2H),3.02(p,J=6.8Hz,1H),1.81(d,J=1.2Hz,6H),1.26(t,J=7.1Hz,3H),1.17(d,J=6.8Hz,7H).

[0588] Example 33

[0589] Synthesis of Compound 33 (Step 1)

[0590] Compound 33a (40 mg, 0.120 mmol) was dissolved in dioxane (3 mL) and water (0.5 mL). Compound 33b (41.79 mg, 0.120 mmol), K₂CO₃ (49.62 mg, 0.359 mmol), and DPPF palladium dichloride methane complex (9.80 mg, 0.012 mmol) were added. The reaction mixture was heated to 100 °C and stirred for 3 h under nitrogen protection. After returning to room temperature, purified water (10 mL) was added, and extracting was performed with EA (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated. Compound 33 (16 mg, 28% yield) was obtained after purification.

[0591] MS m / z(ESI): 477.0 [M+1] +

[0592] 1 H NMR (400MHz, DMSO-d6) δ8.20(d,J=3.0,0.9Hz,1H),8.09(d,J=2.1Hz,1H),7.99(dd,J=10.9,2.0Hz,1H),7.90(s,1H ),7.86–7.80(m,1H),7.74–7.66(m,1H),7.53–7.44(m,2H),3.02–2.81(m,1H),1.83(s,6H),1.20(d,J=6.8Hz,6H).

[0593] Example 34

[0594] Synthesis of compound 34b (Step 1)

[0595] Compound 34a (3 g, 11.977 mmol) was added to a three-necked flask, followed by the addition of THF (50 mL). The mixture was cooled to below -10 °C under nitrogen protection, and a 1 M methyl magnesium bromide THF solution (35.931 mL, 35.931 mmol) was added dropwise. The mixture was then slowly heated to 0 °C and reacted for 2 h. The reaction was quenched with a saturated ammonium chloride aqueous solution, and water (50 mL) was added. The mixture was extracted with EA (20 mL * 3), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by silica gel column chromatography to give a white solid compound 34b (3 g, 99.98% yield).

[0596] MS m / z(ESI): 249.9 [M+1] +

[0597] The second step involves the synthesis of compound 34c.

[0598] Compound 34b (2 g, 7.983 mmol) was added to a sealed tube, followed by the addition of 55% HI (30 mL). The tube was sealed and reacted at 110 °C for 36 h. After quenching with sodium bisulfite aqueous solution (15 mL), the pH was adjusted to 9 with saturated sodium carbonate aqueous solution. Extraction was performed using EA (60 mL * 2), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by silica gel column chromatography to obtain compound 34c (1.5 g, yield 80.12%).

[0599] MS m / z(ESI): 233.9 [M+1] +

[0600] The third step involves the synthesis of compound 34d.

[0601] Compound 34c (1.5 g, 6.396 mmol) was dissolved in 85% hydrazine hydrate (30 mL), and the reaction was carried out overnight in a sealed tube. It was then diluted with water (20 mL), extracted with EA (25 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 34d (1.3 g, 88.33% yield).

[0602] MS m / z(ESI): 230.9 [M+1] +

[0603] The fourth step involves the synthesis of compound 34e.

[0604] Compound 34d (500 mg, 2.173 mmol) was dissolved in trimethyl orthoformate (6 mL) and formic acid (6 mL), and the mixture was sealed and reacted at 110 °C for 6 h. After concentration, silica gel column chromatography was used to obtain compound 34e (200 mg, yield 38.34%).

[0605] MS m / z(ESI): 239.9 [M+1] +

[0606] Step 5: Synthesis of compound 34g

[0607] Compound 34f (381.22 mg, 1.187 mmol) and compound 34e (190 mg, 0.791 mmol) were dissolved in dioxane (9 mL), and potassium carbonate (218.73 mg, 1.583 mmol), Pd(dppf)Cl2.CH2Cl2 (64.78 mg, 0.079 mmol), and water (3 mL) were added. The mixture was reacted overnight at 100 °C under nitrogen protection. Water (60 mL) was added, and the mixture was extracted with EA (30 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by silica gel column chromatography to give compound 34 g (210 mg, yield 74.93%).

[0608] MS m / z(ESI): 355.0 [M+1] +

[0609] Step 6: Synthesis of Compound 34

[0610] Compound 34f (210 mg, 0.593 mmol) was dissolved in chloroform (10 mL), and NCS (158.29 mg, 1.185 mmol) was added. The mixture was sealed and reacted overnight at 70 °C. The solution was washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by silica gel column chromatography to give compound 34 (215 mg, yield 93.91%).

[0611] MS m / z(ESI): 388.9 [M+1] +

[0612] 1 H NMR (400MHz, DMSO-d6) δ8.34(d,J=0.9Hz,1H),8.14(d,J=2.0Hz,1H),8.06(dd,J=11.0,2. 0Hz, 1H), 7.84 (s, 1H), 5.18 (q, J = 9.0Hz, 2H), 2.87 (h, J = 6.8Hz, 1H), 1.15 (d, J = 6.8Hz, 6H).

[0613] Example 35

[0614] Synthesis of compound 35c in the first step

[0615] Reactant 35a (2.0 g, 10.310 mmol) was added to a reaction flask, followed by THF (15 mL). The mixture was cooled to 0-5 °C, and then 60% NaH (0.49 g, 12.25 mmol) was added. Reactant 35b (1.18 g, 10.345 mmol) was added, and the mixture was brought back to room temperature. The mixture was then heated to 50 °C and stirred for 1 h. The system was cooled to 0 °C and quenched with purified water (20 mL). EA (100 mL x 3) was added, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography to obtain compound 35c (2.1 g, 70.7% yield).

[0616] MS m / z(ESI): 287.9 ​​[M+1] +

[0617] The second step involves the synthesis of compound 35e.

[0618] Reactant 35c (1.2 g, 4.166 mmol) was added to a reaction flask, followed by dioxane (30 mL), reactant 35d (1.27 g, 4.999 mmol), PdCl2(dppf).CH2Cl2 (0.34 g, 0.417 mmol), and KOAc (0.82 g, 8.332 mmol). The mixture was stirred overnight at 100 °C under nitrogen protection. After cooling to room temperature, the mixture was purified by silica gel column chromatography to give compound 35e (1.24 g, 88.82% yield).

[0619] MS m / z(ESI): 336.0 [M+1] +

[0620] The third step involves the synthesis of 35g of compound.

[0621] Reactant 35f (420 mg, 1.494 mmol) was added to a reaction flask, followed by dioxane (15 mL), reactant 35e (751.07 mg, 2.241 mmol), purified water (5 mL), di(tri-tert-butylphosphine)palladium (76.36 mg, 0.149 mmol), and K3PO4 (951.47 mg, 4.483 mmol). The mixture was stirred overnight at 100 °C under nitrogen protection. After cooling to room temperature, purified water (35 mL) was added, followed by extraction with EA (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated. Purification by silica gel column chromatography yielded 35 g (356 mg, yield 52.51%) of the compound.

[0622] MS m / z(ESI): 453.9 [M+1] +

[0623] Step 4: Synthesis of Compound 35

[0624] 35 g (60 mg, 0.132 mmol) of the reactant was added to a reaction flask, along with 15 mL of anhydrous ethanol and 128.70 mg (0.661 mmol) of AgBF4. The mixture was heated in an oil bath at 95 °C and stirred under reflux overnight. The reaction system was then cooled to room temperature, quenched with 10 mL of saturated NaCl solution, and 30 mL of EA was added. The mixture was separated and purified by silica gel column chromatography to obtain compound 35 (1.66 mg, yield 2.71%).

[0625] MS m / z(ESI): 464.1 [M+1] +

[0626] 1H NMR (400MHz, DMSO-d6) δ8.55(s,1H),8.29(d,J=2.0Hz,1H),8.18(dd,J=10.7,2.0Hz,1H),6.05(hept,J=6.6Hz,1H),4 .15(q,J=7.1Hz,2H),2.92(h,J=6.8Hz,1H),1.56(d,J=6.5Hz,3H),1.29(t,J=7.1Hz,3H),1.20(dd,J=6.7,1.7Hz,6H).

[0627] Example 36

[0628] Synthesis of compound 36c in step one

[0629] Reactant 36a (2.0 g, 10.310 mmol) was added to a reaction flask, followed by THF (15 mL). The mixture was cooled to 0-5 °C, and 60% NaH (0.49 g, 12.25 mmol) was added. Then, reactant 36b (1.18 g, 10.345 mmol) was added, and the mixture was allowed to return to room temperature. The mixture was then heated to 50 °C and stirred for 1 h. The mixture was cooled to 0 °C and quenched with purified water (20 mL). Extraction was performed using EA (100 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography to obtain compound 35c (2.4 g, yield 80.81%).

[0630] MS m / z(ESI): 287.9 ​​[M+1] +

[0631] The second step involves the synthesis of compound 36e.

[0632] Reactant 36c (1.2 g, 4.166 mmol) was added to a reaction flask, followed by dioxane (30 mL), reactant 36d (1.27 g, 4.999 mmol), PdCl2 (dppf).CH2Cl2 (0.34 g, 0.417 mmol), and KOAc (0.82 g, 8.332 mmol). The mixture was stirred overnight at 100 °C under nitrogen protection. After cooling to room temperature, the mixture was purified by silica gel column chromatography to give compound 35e (980 g, 70.2% yield). MS m / z (ESI): 336.0 [M+1] +

[0633] The third step involves the synthesis of compound 36g.

[0634] Reactant 3f (300 mg, 1.067 mmol) was added to a reaction flask, followed by dioxane (15 mL), reactant 36e (536.48 mg, 1.601 mmol), purified water (5 mL), di(tri-tert-butylphosphine)palladium (54.54 mg, 0.107 mmol), and K3PO4 (679.62 mg, 3.202 mmol). The mixture was stirred overnight at 100 °C under nitrogen protection. After cooling to room temperature, purified water (35 mL) was added, followed by extraction with EA (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated. Purification by silica gel column chromatography yielded compound 36 g (328 mg, yield 67.73%).

[0635] MS m / z(ESI): 453.9 [M+1] +

[0636] Step 4: Synthesis of Compound 36

[0637] 36 g (90 mg, 0.198 mmol) of the reactant was added to a reaction flask, followed by 15 mL of anhydrous ethanol and 193.05 mg (0.992 mmol) of AgBF4. The mixture was heated in an oil bath at 95 °C and refluxed with stirring overnight. The reaction mixture was then cooled to room temperature, quenched with 10 mL of saturated NaCl solution, and 30 mL of EA was added. The mixture was separated, and the organic phase was concentrated and purified to obtain compound 36 (4.78 mg, 5.20%).

[0638] MS m / z(ESI): 464.1 [M+1] +

[0639] 1 H NMR (400MHz, DMSO-d6) δ8.56(s,1H),8.29(d,J=2.0Hz,1H),8.18(dd,J=10.8,2.0Hz,1H),6.04(h,J=6.7Hz,1H),4.1 5(q,J=7.1Hz,2H),2.92(p,J=6.8Hz,1H),1.57(d,J=6.5Hz,3H),1.29(t,J=7.1Hz,3H),1.20(dd,J=6.8,1.7Hz,7H).

[0640] Example 37

[0641] Synthesis of Compound 37 (Step 1)

[0642] Compound 37a (45 mg, 0.163 mmol) was dissolved in dioxane (3 mL) and H₂O (1 mL). Compound 37b (54.50 mg, 0.163 mmol), K₃PO₄ (103.56 mg, 0.488 mmol), and di(tri-tert-butylphosphine)palladium (8.31 mg, 0.016 mmol) were added. The reaction mixture was heated to 100 °C and stirred for 2 h under nitrogen protection. After returning to room temperature, purified water (10 mL) was added, and the mixture was extracted with EA (20 mL * 2). The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to obtain an oil. Compound 37 (52.81 mg, yield 67.20%) was prepared and purified to obtain compound 37.

[0643] MS m / z (ESI): 449.9 [M+H] +

[0644] 1 H NMR(400MHz, DMSO-d6)δ8.74(d,J=2.0Hz,1H),8.40(dd,J=11.2,2.0Hz,1H),8.04–7.97(m,1H),7.92(s,1H),7.76– 7.66(m,1H),7.57–7.47(m,2H),6.15–5.92(m,1H),3.22–3.10(m,2H),1.54(d,J=6.6Hz,3H),1.48(t,J=7.5Hz,3H).

[0645] Example 38

[0646] Synthesis of compound 38c (Step 1)

[0647] Compound 38a (300 mg, 1.304 mmol) and compound 38b (147.16 mg, 1.043 mmol) were dissolved in DMF (10 mL). N-methylimidazole (1213.37 mg, 1.695 mmol) and N,N,N',N'-tetramethylchloromethamphexane hexafluorophosphate (365.80 mg, 1.304 mmol) were added under stirring, and the mixture was stirred at room temperature for 1 h. Water (60 mL) was added, and the mixture was extracted with EA (30 mL x 3). The mixture was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain compound 38c (360 mg, yield 78.18%).

[0648] MS m / z(ESI): 352.9 [M+1] +

[0649] The second step involves the synthesis of compound 38d.

[0650] Compound 38c (350 mg, 0.991 mmol) was dissolved in p-xylene (3 mL), and POCl3 (1.5 mL) was added. The mixture was sealed and reacted at 150 °C for 6 h. After concentration, water (30 mL) was added, and the mixture was extracted with EA (20 mL * 3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain compound 38d (77 mg, yield 23.18%).

[0651] MS m / z (ESI): 334.9, 336.9 [M+1] +

[0652] The third step involves the synthesis of compound 38.

[0653] Compound 38e (96.27 mg, 0.300 mmol) and compound 38d (67 mg, 0.200 mmol) were dissolved in dioxane (9 mL), and Pd(dppf)Cl2.CH2Cl2 (16.36 mg, 0.020 mmol), potassium carbonate (55.25 mg, 0.400 mmol), and water (3 mL) were added. The mixture was reacted overnight at 100 °C under nitrogen protection. Water (25 mL) was added, and the mixture was extracted with EA (15 mL * 3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified to obtain actual compound 38 (14.1 mg, yield 15.70%).

[0654] MS m / z(ESI): 449.9 [M+1] +

[0655] 1 H NMR(400MHz, DMSO-d6)δ9.19(d,J=0.9Hz,1H),8.63(dt,J=4.7,1.5Hz,1H),8.15(d,J=2.0Hz,1H),8.11–8.00(m,2 H),7.97(s,1H),7.65(dt,J=8.5,4.2Hz,1H),5.17(q,J=8.9Hz,2H),2.90(p,J=6.7Hz,1H),1.19(d,J=6.8Hz,6H).

[0656] Example 39

[0657] Synthesis of compound 39 in step one

[0658] Compound 39a (50 mg, 0.181 mmol) was dissolved in dioxane (3 mL) / H₂O (1 mL), and compound 39b (60.55 mg, 0.181 mmol), K₃PO₄ (115.07 mg, 0.542 mmol), and bis(tri-tert-butylphosphine)palladium (9.23 mg, 0.018 mmol) were added. The reaction mixture was heated to 100 °C and stirred for 2 h under nitrogen protection. After returning to room temperature, purified water (10 mL) was added, and extraction was performed with EA (20 mL * 2). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain an oil. Compound 39 (15.23 mg, yield 17.82%) was prepared and purified.

[0659] MS m / z (ESI): 449.9 [M+H] +

[0660] 1 H NMR(400MHz, DMSO-d6)δ8.75(d,J=2.0Hz,1H),8.41(dd,J=11.2,2.0Hz,1H),8.05–7.97(m,1H),7.93(s,1H),7.76– 7.68(m,1H),7.61–7.45(m,2H),6.10–5.95(m,1H),3.22–3.09(m,2H),1.55(d,J=6.5Hz,3H),1.49(t,J=7.5Hz,3H).

[0661] Example 40

[0662] Synthesis of compound 40c in step one

[0663] Compound 40a (750 mg, 3.259 mmol) was dissolved in DCM (10 mL), and TEA (50.13 mg, 0.495 mmol) was added. After cooling to 0-5 °C, a DCM solution of compound 40b (504.20 mg, 2.607 mmol) was added dropwise (2 mL). The mixture was then allowed to warm naturally to room temperature for 1 h. Saturated sodium bicarbonate aqueous solution (20 mL) was added directly, followed by extraction with DCM (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 40c (281 mg, yield 22.82%).

[0664] MS m / z (ESI): 387.7, 389.8 [M+1] +

[0665] The second step involves the synthesis of compound 40d.

[0666] Compound 40c (280 mg, 0.723 mmol) was reacted overnight in an oil bath at 150 °C with 3 mL xylene and 4.5 mL POCl3. After cooling to room temperature, the mixture was concentrated under reduced pressure to remove phosphorus oxychloride, 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, concentrated, and purified by column chromatography to obtain compound 40d (190 mg, yield 80.92%).

[0667] MS m / z (ESI): 323.8, 324.9 [M+1] +

[0668] The third step involves the synthesis of compound 40f.

[0669] Compound 40d (233 mg, 0.718 mmol), compound 40e (299.66 mg, 0.933 mmol), and K3PO4 (457.16 mg, 2.154 mmol) were added to a reaction flask, along with dioxane (10 mL) and purified water (1.0 mL). Under nitrogen protection, di(tri-tert-butylphosphine)palladium (36.69 mg, 0.072 mmol) was added, and the mixture was heated to 100 °C and stirred overnight. After returning to room temperature, purified water (20 mL) and ethyl acetate (20 mL x 3) were added directly to the reaction mixture for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 40f (266 mg, yield 84.45%).

[0670] MS m / z(ESI): 438.9 [M+1] +

[0671] Step 4: Synthesis of Compound 40

[0672] 40f (100 mg, 0.228 mmol) was added to a reaction flask, along with silver tetrafluoroborate (150 mg, 0.771 mmol) and EtOH (5 mL). The mixture was heated to 90 °C and stirred overnight. After cooling to room temperature, saturated sodium chloride solution (20 mL) was added to the reaction solution, followed by extraction with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by reverse phase reversal to obtain compound 40 (7.42 mg, yield 7.26%).

[0673] MS m / z(ESI): 448.9 [M+1] +

[0674] 1H NMR (400MHz, DMSO-d6) δ8.39(s,1H),8.16(d,J=2.0Hz,1H),8.10(dd,J=11.0,2.0Hz,1H),7.98(s,1H),5.19 (q,J=9.0Hz,2H),4.24(q,J=7.1Hz,2H),2.87(p,J=6.8Hz,1H),1.33(t,J=7.1Hz,3H),1.18(d,J=6.8Hz,6H).

[0675] Example 41

[0676] Synthesis of compound 41b in step one

[0677] Compound 41a (3000 mg, 9.424 mmol) was dissolved in dioxane (50 mL) and water (10 mL). Potassium isopropenyl trifluoroborate (1394.55 mg, 9.424 mmol), K2CO3 (3907.14 mg, 28.272 mmol), and DPPF palladium dichloride methane complex (771.49 mg, 0.942 mmol) were added. The reaction mixture was heated to 100 °C and stirred for 3 h under nitrogen protection. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 41b (1.5 g, yield 68.46%).

[0678] MS m / z(ESI): 233.9 [M+1] +

[0679] The second step involves the synthesis of compound 41d.

[0680] Compound 41c (828.59 mg, 2.581 mmol) was dissolved in dioxane (9 mL), and 41b (1000 mg, 4.301 mmol), Pd(dppf)Cl2.CH2Cl2 (352.11 mg, 0.430 mmol), potassium carbonate (1188.82 mg, 8.602 mmol), and water (3 mL) were added. The mixture was reacted at 100 °C for 3 h. Water (40 mL) was added, and the mixture was extracted with EA (30 mL * 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and then subjected to silica gel column chromatography (EA / PE = 0-50%) to give compound 41d (460 mg, yield 30.85%).

[0681] MS m / z(ESI): 347.0 [M+1] +

[0682] The third step involves the synthesis of compound 41e.

[0683] Compound 41d (460 mg, 1.327 mmol) was dissolved in ethanol (4.5 mL), and 85% hydrazine hydrate (4.5 mL) was added. The mixture was reacted overnight at 100 °C. After dilution with water (20 mL), the mixture was extracted with EA (15 mL * 3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 41e (360 mg, yield 79.27%).

[0684] MS m / z(ESI): 343.0 [M+1] +

[0685] The fourth step involves the synthesis of compound 41g.

[0686] Compound 41e (360 mg, 1.052 mmol) was dissolved in DCM (5 mL), and DIEA (271.87 mg, 2.103 mmol) was added. Compound 41f (88.70 mg, 0.631 mmol) in DCM solution (2 mL) was added at 0 °C. The mixture was stirred at room temperature for 10 min, and water (20 mL) was added. The mixture was extracted with DCM (15 mL * 3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 41 g (260 mg, yield 53.23%), which was used directly in the next step.

[0687] MS m / z(ESI): 464.9 [M+1] +

[0688] Step 5: Synthesis of compound 41h

[0689] Compound 41 g (350 mg, 0.754 mmol) was dissolved in p-xylene (5 mL), and phosphorus oxychloride (5 mL) was added. The mixture was reacted at 150 °C for 6 h. After concentration, the residual phosphorus oxychloride was neutralized with saturated sodium bicarbonate to pH 7-8. After dilution with water (30 mL), the mixture was extracted with EA (20 mL * 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain compound 41 h (130 mg, yield 38.64%).

[0690] MS m / z(ESI): 446.9 [M+1] +

[0691] Step 6: Synthesis of Compound 41

[0692] Compound 41h (100 mg, 0.224 mmol) was dissolved in DCM (4 mL) and isopropanol (4 mL). Mn2(TMHD)3 (13.55 mg, 0.022 mmol) and phenylsilane (4.85 mg, 0.045 mmol) were added at 0 °C, and the mixture was stirred at room temperature for 1.5 h. After concentration, water (30 mL) was added, and the mixture was extracted with EA (20 mL * 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 41 (7.7 mg, yield 7.4%).

[0693] MS m / z(ESI): 464.9 [M+1] +

[0694] 1 H NMR(400MHz, DMSO-d6)δ8.02(d,J=3.5Hz,3H),7.93–7.88(m,1H),7.81(t,J=7.4Hz,1H),7.67 (t,J=7.1Hz,1H),7.46(q,J=8.4,7.0Hz,2H),5.31(s,1H),5.13(q,J=9.0Hz,2H),1.37(s,6H).

[0695] Example 42

[0696] Synthesis of compound 42c in step one

[0697] Compound 42a (1000 mg, 5.234 mmol), compound 42b (847.10 mg, 5.496 mmol), and triethylamine hydrochloride (792.50 mg, 5.757 mmol) were dissolved in xylene (10 mL) and reacted in a microwave oven at 150 °C for 3 h. After cooling to room temperature, the mixture was directly loaded onto a wet plate and purified by silica gel column chromatography to give compound 42c (700 mg, yield 46.00%).

[0698] MS m / z(ESI): 291.0 [M+H] +

[0699] The second step involves the synthesis of compound 42c.

[0700] Compound 42c (100 mg, 0.344 mmol) was dissolved in dioxane (3 mL) and H₂O (1 mL). Compound 42d (126.79 mg, 0.378 mmol), K₃PO₄ (219.03 mg, 1.032 mmol), and bis(tri-tert-butylphosphine)palladium (17.58 mg, 0.034 mmol) were added. The reaction mixture was heated to 110 °C and stirred for 2 h under nitrogen protection. After returning to room temperature, purified water (10 mL) and EA (20 mL x 2) were added, and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain an oily substance. Compound 42 (55.78 mg, 35% yield) was obtained after purification.

[0701] MS m / z (ESI): 463.9 [M+H] +

[0702] 1 H NMR(400MHz, DMSO-d6)δ8.52(s,1H),8.27(d,J=1.9Hz,1H),8.16(dd,J=10.7,2.0Hz,1H),7.96–7.87(m,1H),7.72–7.6 2(m,1H),7.53–7.40(m,2H),6.10–5.93(m,1H),3.01–2.87(m,1H),1.54(d,J=6.5Hz,3H),1.22(dd,J=6.7,1.9Hz,6H).

[0703] Example 43

[0704] Synthesis of Compound 43 (Step 1)

[0705] Compound 43a (80 mg, 0.275 mmol) was dissolved in dioxane (3 mL) and H₂O (1 mL). Compound 43b (92.21 mg, 0.275 mmol), K₃PO₄ (175.22 mg, 0.826 mmol), and di(tri-tert-butylphosphine)palladium (14.06 mg, 0.028 mmol) were added. The reaction mixture was heated to 110 °C and stirred for 2 h under nitrogen protection. After returning to room temperature, purified water (10 mL) was added, and extraction was performed with EA (20 mL * 2). The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to obtain an oil. The purified compound 43 (33.8 mg, yield 26.51%) was obtained.

[0706] MS m / z (ESI): 463.9 [M+H] +

[0707] 1H NMR(400MHz, DMSO-d6)δ8.51(s,1H),8.27(d,J=1.9Hz,1H),8.16(dd,J=10.7,2.0Hz,1H),7.96–7.87(m,1H),7.72–7.6 2(m,1H),7.52–7.40(m,2H),6.10–5.93(m,1H),3.01–2.88(m,1H),1.55(d,J=6.5Hz,3H),1.22(dd,J=6.8,1.8Hz,6H).

[0708] Example 44

[0709] Synthesis of compound 44b (Step 1)

[0710] Compound 44a (2300 mg, 11.140 mmol) was dissolved in ethanol (5 mL), and hydrazine hydrate (5 mL) was added. The mixture was reacted overnight at 100 °C. After dilution with water (50 mL), the mixture was extracted with EA (30 mL * 3), washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 44b (2 g, yield 88.85%).

[0711] MS M / Z(ESI): 201.9 [M+1] +

[0712] The second step involves the synthesis of compound 44d.

[0713] Compound 44b (500 mg, 2.47 mmol) was dissolved in DCM (10 mL), and DIEA (638.5 mg, 4.94 mmol) and compound 44c (313.3 mg, 1.98 mmol) were added. The mixture was stirred at room temperature for 30 min. The solution was diluted with DCM (20 mL), washed once with water (10 mL), washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 44d (500 mg, yield 77.9%).

[0714] MS M / Z(ESI):323.9;325.9[M+1] +

[0715] The third step involves the synthesis of compound 44e.

[0716] Compound 44d (500 mg 1.542 mmol) was dissolved in p-xylene (6 mL), and phosphorus oxychloride (3 mL) was added. The mixture was reacted at 150 °C for 6 h. After concentration, the solution was purified by silica gel column chromatography to give compound 44e (190 mg, yield 40.24%). MS M / Z (ESI): 305.9; 307.9 [M+1] +

[0717] Step 4: Synthesis of Compound 44

[0718] Compound 44f (85.53 mg, 0.245 mmol) and compound 44e (50 mg, 0.163 mmol) were dissolved in dioxane (9 mL), and Pd(dppf)Cl2.CH2Cl2 (13.37 mg, 0.016 mmol), K2CO3 (45.14 mg, 0.327 mmol), and water (3 mL) were added. The mixture was reacted overnight at 100 °C under nitrogen protection. After dilution with water (30 mL), extraction with EA (20 mL * 3), washing with saturated brine (20 mL), drying with anhydrous sodium sulfate, filtering, and concentrating, compound 44 (55.3 mg, yield 75.51%) was obtained.

[0719] MS M / Z(ESI): 448.9 [M+1] +

[0720] 1 H NMR (400MHz, DMSO-d6) δ8.22(d,J=3.0Hz,1H),8.09(d,J=2.1Hz,1H),8.01(dd,J=11.1,2.1Hz,1H),7.88–7 .79(m,2H),7.69(dddd,J=8.9,7.3,5.4,1.8Hz,1H),7.52–7.43(m,2H),2.31(d,J=1.2Hz,3H),1.81(s,6H).

[0721] Example 45

[0722] Synthesis of Compound 45 (Step 1)

[0723] Compound 45a (80 mg, 0.289 mmol) was dissolved in dioxane (3 mL) and H₂O (1 mL). Compound 45b (111.04 mg, 0.318 mmol), K₃PO₄ (184.11 mg, 0.867 mmol), and di(tri-tert-butylphosphine)palladium (14.78 mg, 0.029 mmol) were added. The reaction mixture was heated to 110 °C and stirred for 2 h under nitrogen protection. After returning to room temperature, purified water (10 mL) was added, and extracting was performed with EA (20 mL * 2). The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to obtain an oily substance. The purified compound 45 (63.14 mg, yield 44.77%) was obtained.

[0724] MS M / Z(ESI): 464.0 [M+H] +

[0725] 1 H NMR (400MHz, DMSO-d6) δ8.74(d,J=2.1Hz,1H),8.37(dd,J=11.2,2.1Hz,1H),8.10–7.94(m,1H),7.92(d,J =1.2Hz,1H),7.78–7.63(m,1H),7.60–7.45(m,2H),3.21–3.07(m,2H),1.83(s,6H),1.48(t,J=7.5Hz,3H).

[0726] Example 46

[0727] Synthesis of compound 46c in step one

[0728] Compound 46a (500 mg, 2.604 mmol) and compound 46b (603 mg, 3.125 mmol) were dissolved in DMF (15 mL), and then K2CO3 (720 mg, 5.209 mmol) was added. The mixture was stirred in an oil bath at 100 °C for 16 h. Two reactions were carried out in parallel. The reaction mixtures were combined, and water (100 mL) and ethyl acetate (100 mL) were added. The mixtures were shaken well, and the layers were separated. The aqueous layer was extracted with ethyl acetate (50 mL). The organic phases were combined and washed successively with water (50 mL) and saturated brine (50 mL). The mixtures were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 46c (1200 mg, yield 81.11%).

[0729] MS M / Z(ESI): 284, 286 [M+1] +

[0730] The second step involves the synthesis of compound 46d.

[0731] Compound 46c (250 mg, 0.880 mmol), compound 46e (246 mg, 0.968 mmol), and KOAc (259 mg, 2.641 mmol) were dissolved in dioxane (5 mL), degassed for 5 minutes, and then Pd(dppf)Cl2.CH2Cl2 (72 mg, 0.088 mmol) was added, degassed for 5 minutes, and then stirred overnight in an oil bath at 80 °C. Water (50 mL) and ethyl acetate (50 mL) were added to the reaction solution, shaken well, and the layers were separated. The aqueous layer was extracted again with ethyl acetate (50 mL), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound 46d (460 mg), which was directly added to the next reaction.

[0732] MS M / Z(ESI): 332[M+1] +

[0733] The third step involves the synthesis of compound 46.

[0734] Compound 46e (60 mg, 0.204 mmol), compound 46d (165 mg, 0.274 mmol), Na₂CO₃ (26 mg, 0.245 mmol), and DPPF palladium dichloride methane complex (33 mg, 0.041 mmol) were dissolved in a mixed solvent of toluene (6 mL), ethanol (2 mL), and water (0.2 mL). The mixture was evacuated three times with argon gas, and then reacted in an oil bath at 85 °C for 3 h. Water (50 mL) and ethyl acetate (50 mL) were added to the reaction solution, and the mixture was shaken well. The layers were separated, and the aqueous layer was extracted with ethyl acetate (50 mL). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the crude product. The crude product was further purified to obtain compound 46 (34.56 mg, yield 40.5%).

[0735] MS M / Z(ESI): 419[M+1] +

[0736] 1 H NMR(400MHz,DMS M / Z(ESI)O-d6)δ8.48(s,1H),7.97(s,1H),7.94(d,J=2.1Hz,1H),7.65(d,J=2.1Hz,1H),5. 53(dq,J=7.4,3.8Hz,1H),4.65–4.42(m,2H),2.62(q,J=7.4Hz,2H),1.11(t,J=7.4Hz,3H).

[0737] Example 47

[0738] Synthesis of compound 47b (Step 1)

[0739] Compound 47a (900 mg, 4.359 mmol) was dissolved in hydrazine (4 mL) and ethanol (4 mL), and then stirred overnight in an oil bath at 110 °C. After cooling to room temperature, a large amount of solid precipitated. The solid was filtered, the filter cake was washed with a small amount of ethanol, and dried under vacuum to give compound 47b (450 mg, yield 51.09%).

[0740] MS M / Z(ESI): 204[M+1] +

[0741] The second step involves the synthesis of compound 47c.

[0742] Compound 47b (400 mg, 1.980 mmol) was suspended in toluene (10 mL), and then 2,2,2-trifluoroacetic anhydride (1247.33 mg, 5.939 mmol) was added dropwise under an ice-water bath. The mixture was then stirred in an oil bath at 130 °C for 72 h. Ethyl acetate (100 mL) and saturated sodium bicarbonate aqueous solution (100 mL) were added to the reaction solution, and the mixture was shaken well. The layers were separated, and the aqueous layer was extracted once again with ethyl acetate (100 mL). The organic layers were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 47c (420 mg, yield 75.76%).

[0743] MS M / Z(ESI): 282[M+1] +

[0744] Step 3: Synthesis of Compound 47

[0745] Compound 47c (110 mg, 0.393 mmol), compound 47d (250 mg, 0.755 mmol), Na₂CO₃ (50 mg, 0.471 mmol), and DPPF palladium dichloride methane complex (64 mg, 0.079 mmol) were dissolved in a mixed solvent of toluene (12 mL), ethanol (4 mL), and water (0.4 mL). The mixture was evacuated three times with argon gas, and then reacted in an oil bath at 85 °C for 3 h. Water (50 mL) and ethyl acetate (50 mL) were added to the reaction solution, and the mixture was shaken well. The layers were separated, and the aqueous layer was extracted with ethyl acetate (50 mL). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 47 (81.52 mg, yield 51.3%).

[0746] MS M / Z(ESI): 405[M+1] +

[0747] 1 H NMR(400MHz,DMS M / Z(ESI)O-d6)δ8.50(s,1H),8.06–7.99(m,1H),7.95(d,J=2.1Hz,1H),7.67(d,J= 2.1Hz,1H),5.54(dt,J=7.2,3.6Hz,1H),4.66–4.39(m,2H),2.32(d,J=1.2Hz,3H).

[0748] Example 48

[0749] Synthesis of compound 48b (Step 1)

[0750] Compound 48a (900 mg, 4.277 mmol) was dissolved in EtOH (15 mL) at room temperature, followed by the addition of hydrazine hydrate (5 mL, 103.076 mmol). The reaction mixture was stirred at room temperature for 3 h. A saturated aqueous sodium carbonate solution (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL x 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 48b (900 mg, 94.59% yield).

[0751] MS M / Z(ESI): 223.9 [M+1] +

[0752] The second step involves the synthesis of compound 48c.

[0753] Compound 48b (500 mg, 2.247 mmol) was dissolved in DCM (3 mL), and triethylamine (0.312 mL, 2.247 mmol) was added. Trifluoroacetic anhydride (472.04 mg, 2.247 mmol) was slowly added at 0 °C, and the mixture was stirred at this temperature for 2 h. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to give compound 48c (550 mg, yield 76.84%).

[0754] MS M / Z(ESI): 319.8 [M+1] +

[0755] The third step involves the synthesis of compound 48d.

[0756] Compound 48c (500 mg, 1.570 mmol) was dissolved in p-xylene (3 mL), and phosphorus oxychloride (3 mL, 0.397 mmol) was added. The mixture was heated in an oil bath at 150 °C and stirred for 5 h. The phosphorus oxychloride was evaporated to dryness, and the reaction was quenched by adding saturated NaHCO3 aqueous solution (30 mL). The mixture was then extracted with ethyl acetate (50 mL * 2), and the organic phases were combined. The mixture was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound 48d (300 mg, yield 63.60%).

[0757] MS M / Z(ESI): 301.80 [M+1] +

[0758] The fourth step was the synthesis of compound 48d.

[0759] Compound 48d (80 mg, 0.266 mmol) was dissolved in dioxane (3 mL) and water (0.5 mL). Compound 48e (93.95 mg, 0.293 mmol), K₂CO₃ (110.39 mg, 0.799 mmol), and DPPF palladium dichloride methane complex (21.80 mg, 0.027 mmol) were added. The reaction mixture was heated to 100 °C and stirred for 3 h under nitrogen protection. After returning to room temperature, purified water (10 mL) was added, and extracting was performed with EA (20 mL * 2). The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to obtain an oily substance. Compound 48d (30.48 mg, yield 27.6%) was obtained after preparative purification.

[0760] MS M / Z(ESI): 414.8 [M+1] +

[0761] 1 HNMR (400MHz, DMSO-d6) δ8.86(s,1H),8.56(d,J=0.8Hz,1H),8.18(d,J=2.0Hz,1H),8.09(dd,J=10.9,2.0Hz,1H),5.26–5.15(m,2H).

[0762] Example 49

[0763] Synthesis of compound 49c (Step 1)

[0764] Compound 49a (800 mg, 4.469 mmol), compound 49b (757.78 mg, 4.916 mmol), and triethylamine hydrochloride (676.72 mg, 4.916 mmol) were dissolved in xylene (10 mL) and reacted in a microwave oven at 150 °C for 3 h. After cooling to room temperature, the mixture was directly loaded onto a wet plate and purified by silica gel column chromatography to give compound 49c (53 mg, yield 4.26%).

[0765] MS M / Z(ESI): 278.9 [M+H] +

[0766] The second step involves the synthesis of compound 49.

[0767] Compound 49c (50 mg, 0.179 mmol) was dissolved in dioxane (2.5 mL) / H₂O (0.5 mL), and compound 49d (81.43 mg, 0.233 mmol), K₃PO₄ (114.25 mg, 0.538 mmol) and bis(tri-tert-butylphosphine)palladium (9.17 mg, 0.018 mmol) were added. The reaction mixture was heated to 110 °C and stirred for 1.5 h under nitrogen protection. The reaction mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give compound 49 (10.14 mg, yield 11.54%).

[0768] MS M / Z(ESI): 465.9 [M+H] +

[0769] 1 H NMR(400MHz, DMSO-d6)δ8.55(d,J=2.1Hz,1H),8.19(dd,J=11.3,2.1Hz,1H),8.13–8.0 2(m,1H),7.79–7.70(m,1H),7.61–7.47(m,2H),6.75(s,1H),4.48(s,3H),1.78(s,6H).

[0770] Example 50

[0771] Synthesis of Compound 50 (Step 1)

[0772] Compound 51a (80 mg 0.305 mmol) was added to a reaction flask, followed by dioxane (10 mL), compound 51b (122.48 mg 0.365 mmol), purified water (3 mL), di(tri-tert-butylphosphine)palladium (15.57 mg 0.030 mmol), and K3PO4 (129.29 mg 0.609 mmol). The mixture was stirred at 100 °C for 5 h under nitrogen protection. After cooling to room temperature, purified water (15 mL) was added, followed by extraction with EA (35 mL x 2). The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to obtain an oily substance. Compound 50 (42.51 mg, yield 32.06%) was prepared and purified to obtain compound 50.

[0773] MS m / z(ESI): 435.9 [M+1] +

[0774] 1H NMR (400MHz, DMSO-d6) δ8.44(d,J=1.4Hz,1H),8.30(d,J=1.9Hz,1H),8.21(dd,J=10.9,2.0Hz,1H),7.95(td,J=7.4,1.8Hz,1 H),7.67(tdd,J=7.4,5.3,1.8Hz,1H),7.53–7.42(m,2H),6.02(p,J=6.7Hz,1H),2.40(d,J=1.3Hz,3H),1.54(d,J=6.5Hz,3H).

[0775] Example 51

[0776] Synthesis of Compound 51 (Step 1)

[0777] Compound 51a (70 mg, 0.266 mmol) was added to a reaction flask, followed by dioxane (10 mL), compound 51b (107.17 mg, 0.320 mmol), purified water (3 mL), di(tri-tert-butylphosphine)palladium (13.62 mg, 0.027 mmol), and K3PO4 (113.13 mg, 0.533 mmol). The mixture was stirred overnight at 100 °C under nitrogen protection. After cooling to room temperature, purified water (15 mL) was added, followed by extraction with EA (35 mL x 2). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified to obtain compound 51 (13.98 mg, yield 12.05%).

[0778] MS m / z(ESI): 435.9 [M+1] +

[0779] 1 H NMR (400MHz, DMSO-d6) δ8.44(d,J=1.3Hz,1H),8.30(d,J=2.0Hz,1H),8.21(dd,J=10.9,1.9Hz,1H),7.95(td,J=7.4,1.8Hz,1H), 7.67(dddd,J=8.6,7.3,5.4,1.8Hz,1H),7.53–7.42(m,2H),6.02(p,J=6.6Hz,1H),2.40(d,J=1.2Hz,3H),1.54(d,J=6.5Hz,3H).

[0780] Example 52

[0781] Synthesis of Compound 52 (Step 1)

[0782] Compound 52b (95 mg, 0.314 mmol), compound 52a (75 mg, 0.286 mmol), and K3PO4 (181.82 mg, 0.857 mmol) were added to a microwave-safe flask. Then, dioxane (2 mL) and water (0.5 mL) were added, and the mixture was evacuated three times. Next, di(tri-tert-butylphosphine)palladium (29.18 mg, 0.057 mmol) was added, and the mixture was evacuated three times. The mixture was reacted in an oil bath at 100 °C for 3 h. Water (50 mL) and ethyl acetate (50 mL) were added to the reaction mixture, and the mixture was shaken well. The layers were separated, and the aqueous layer was extracted with ethyl acetate (30 mL). The organic layers were combined, washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the crude product. Then, compound 52 (89.64 mg, yield 77.9%) was obtained by preparative purification.

[0783] MS M / Z(ESI): 403[M+1] +

[0784] 1 H NMR(400MHz,Chloroform-d)δ8.02(d,J=1.6Hz,1H),7.87(td,J=7.3,1.8Hz,1H),7.5 0(tdd,J=7.5,5.1,1.8Hz,1H),7.33–7.12(m,5H),2.19(s,3H),2.17(d,J=1.3Hz,3H).

[0785] Example 53

[0786] The synthesis method is as described in Example 52.

[0787] MS M / Z(ESI): 402.9 [M+1] +

[0788] 1 H NMR(400MHz, DMSO-d6)δ7.90(td,J=7.4,1.8Hz,1H),7.67(ddd,J=8.7,5.4,1.8Hz,1H),7.63( d,J=8.4Hz,1H),7.53(t,J=1.3Hz,1H),7.51–7.30(m,4H),2.75(d,J=1.2Hz,3H),2.40(s,3H).

[0789] Example 54

[0790] Synthesis of Compound 54 (Step 1)

[0791] Compound 54a (249.27 mg, 2.264 mmol) was dissolved in DMF (6 mL), and 60% NaH (135.82 mg, 3.395 mmol) was added under ice bath conditions. After stirring at room temperature for 15 min, compound 54b (440 mg, 1.132 mmol) was added, and the mixture was stirred overnight at room temperature. Water (30 mL) was added, and the mixture was extracted with EA (20 mL x 3), washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the crude product. The crude product was then further purified to obtain compound 54 (8.70 mg, yield 1.66%).

[0792] MS M / Z(ESI): 463.2 [M+1] +

[0793] 1 H NMR(400MHz,Chloroform-d)δ8.82(d,J=4.9Hz,2H),7.90(s,1H),7.84(s,1H),7.79(s,1H),7.40(d,J=9.8Hz ,1H),7.33(t,J=5.0Hz,1H),5.78(s,2H),5.04(q,J=7.8Hz,2H),2.96(p,J=6.6Hz,1H),1.20(d,J=6.8Hz,6H).

[0794] Example 55

[0795] Synthesis of compound 55b in step one

[0796] Compound 55a (3000 mg, 16.946 mmol) was dissolved in THF (40 mL), and TEA (23.555 mL, 169.463 mmol) and 85% hydrazine hydrate (5.803 mL, 101.678 mmol) were added. The mixture was sealed and reacted overnight at 100 °C. After dilution with water (50 mL), the mixture was extracted with EA (30 mL * 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 55b (2.5 g, yield 85.46%).

[0797] MS M / Z(ESI): 172.1 [M+1] +

[0798] The second step involves the synthesis of compound 55d.

[0799] Compound 55b (250 mg, 1.448 mmol) was dissolved in DCM (15 mL), and TEA (439.65 mg, 4.345 mmol) was added. Compound 55c (230.12 mg, 1.303 mmol) in DCM solution (5 mL) was added under ice bath conditions, and the mixture was stirred at room temperature for 10 min. The solution was diluted with DCM (30 mL), washed once with water (20 mL), washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 55d (450 mg, yield 99.37%).

[0800] MS M / Z(ESI): 312.9 [M+1] +

[0801] The third step involves the synthesis of compound 55e.

[0802] Compound 55d (270 mg, 0.863 mmol) was dissolved in p-xylene (6 mL), and phosphorus oxychloride (3 mL) was added. The mixture was reacted at 150 °C for 3 h. After concentration, residual POCl3 was quenched with a small amount of sodium bicarbonate aqueous solution, diluted with water (30 mL), extracted with EA (20 mL * 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain compound 55e (214 mg, yield 84.10%).

[0803] MS M / Z(ESI): 294.9 [M+1] +

[0804] Step 4: Synthesis of Compound 55

[0805] Compound 55f (163.43 mg, 0.509 mmol) and compound 55e (100 mg, 0.339 mmol) were dissolved in dioxane (9 mL), and potassium phosphate (156.29 mg, 0.679 mmol), bis(tert-butylphosphine)palladium (17.34 mg, 0.034 mmol), and water (3 mL) were added. The mixture was reacted at 110 °C for 3 h under nitrogen protection. Water (30 mL) was added, and the mixture was extracted with EA (20 mL * 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to prepare compound 55 (38.9 mg, yield 25.29%).

[0806] MS M / Z(ESI): 453.9 [M+1] +

[0807] 1H NMR (400MHz, DMSO-d6) δ8.44(d,J=1.3Hz,1H),8.23(d,J=1.9Hz,1H),8.17(dd,J=10.8,1.9Hz,1H),7.77(tt,J=8 .5,6.6Hz,1H),7.41(t,J=8.3Hz,2H),5.16(q,J=8.9Hz,2H),2.67(qd,J=7.4,1.3Hz,2H),1.16(t,J=7.4Hz,3H).

[0808] Examples 56 and 57

[0809] Synthesis of compound 56c in the first step

[0810] Compound 56a (250 mg, 1.448 mmol) was dissolved in DCM (15 mL), and TEA (293.10 mg, 2.897 mmol) was added. After cooling in an ice bath, a DCM solution of compound 56b (302.05 mg, 1.448 mmol) in 3 mL was added, and the mixture was incubated for 10 min. The solution was diluted with DCM (30 mL), washed once with water (20 mL), washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 56c (450 mg, yield 90.14%). MS M / Z (ESI): 344.9 [M+1] +

[0811] The second step involves the synthesis of compound 56d.

[0812] Compound 55d (440 mg, 1.276 mmol) was dissolved in p-xylene (6 mL), and phosphorus oxychloride (3 mL) was added. The mixture was reacted at 150 °C for 3 h. After concentration, residual POCl3 was quenched with a small amount of sodium bicarbonate aqueous solution, diluted with water (30 mL), extracted with EA (20 mL * 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain compound 56d (250 mg, 60% yield).

[0813] MS M / Z(ESI): 327.0 [M+1] +

[0814] The third step involves the synthesis of compounds 56 and 57.

[0815] Compound 56e (147.42 mg, 0.459 mmol) and compound 56d (100 mg, 0.339 mmol) were dissolved in dioxane (9 mL), and K3PO4 (129.94 mg, 0.612 mmol), bis(tri-tert-butylphosphine)palladium (15.64 mg, 0.031 mmol), and water (3 mL) were added. The mixture was reacted at 110 °C for 3 h under nitrogen protection. The mixture was diluted with water (30 mL), extracted with EA (20 mL * 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and separated to obtain compound 56 (29.4 mg, yield 19.79%) and compound 57 (50 mg, 33.67 mg).

[0816] Compound 56: MS M / Z (ESI): 485.9 [M+1] +

[0817] 1 H NMR(400MHz,DMSO-d6)δ8.62(d,J=8.2Hz,2H),8.47–8.40(m,2H),8.31(dd,J=10.8,2.0Hz,1H), 8.00(d,J=8.3Hz,2H),5.23(q,J=8.9Hz,2H),2.73(qd,J=7.4,1.4Hz,2H),1.18(t,J=7.4Hz,3H)

[0818] Compound 57: MS M / Z (ESI): 485.9 [M+1] +

[0819] 1 H NMR (400MHz, DMSO-d6) δ8.93(d,J=2.0Hz,1H),8.73(d,J=8.2Hz,2H),8.64(dd,J=11.3,2.0Hz,1H),8.07 (d,J=8.3Hz,2H),7.99(d,J=1.3Hz,1H),5.25(q,J=8.9Hz,2H),3.22–3.14(m,2H),1.50(t,J=7.5Hz,3H).

[0820] Example 58

[0821] Synthesis of compound 58b (Step 1)

[0822] Compound 58a (300 mg, 1.165 mmol) was dissolved in DMF (10 mL), and sodium methanethiol (98.02 mg, 1.398 mmol) was added under ice bath conditions. The reaction was carried out at room temperature for 1 h. Purified water (20 mL) and ethyl acetate (20 mL * 3) were added directly for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 58b (286 mg, yield 85.95%).

[0823] The second step involves the synthesis of compound 58c.

[0824] Compound 58b (270 mg, 0.946 mmol) was dissolved in a mixed solvent of EtOH (8 mL) and hydrazine hydrate (8 mL) and reacted under electric heating at 115 °C for 2 h. Saturated sodium carbonate (20 mL) and ethyl acetate (20 mL x 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 crude compound 58c (517 mg), which was used directly in the next step.

[0825] MS M / Z(ESI): 281.8 [M+1] +

[0826] The third step involves the synthesis of compound 58e.

[0827] The crude compound 58c (497 mg, 1.238 mmol) was dissolved in TEA (250.46 mg, 2.475 mmol) in THF (8 mL). Compound 58d (367.92 mg, 1.856 mmol) in THF (2 mL) was added under ice bath conditions, and the reaction was brought to room temperature for 1 h. The reaction was quenched directly with purified water (30 mL), extracted with ethyl acetate (30 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude compound 58e (586 mg), which was directly used in the next reaction step.

[0828] MS M / Z(ESI): 403.8 [M+1] +

[0829] The fourth step: synthesis of compound 58f

[0830] The crude compound 58e (586 mg, 0.727 mmol, 50%) was dissolved in a mixed solvent of xylene (3 mL) and POCl3 (3 mL) and reacted at 150 °C for 3 h. After cooling to room temperature, the mixture was directly concentrated to remove phosphorus oxychloride. The reaction solution was then added dropwise to purified water (20 mL), and saturated sodium carbonate was added to adjust the pH to ~7. Ethyl acetate (20 mL) was then added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 58f (60 mg, yield 21.44%).

[0831] MS M / Z(ESI): 386.0 [M+1] +

[0832] Step 5: Synthesis of compound 58f

[0833] Compound 58f (40 mg, 0.104 mmol), compound 58g (50.01 mg, 0.156 mmol), and K3PO4 (66.12 mg, 0.312 mmol) were added to a reaction flask, along with dioxane (2.5 mL) and purified water (0.5 mL). Under nitrogen protection, Pd(dppf)Cl2.CH2Cl2 (8.50 mg, 0.010 mmol) was added, and the reaction was carried out in an oil bath at 100 °C for 2 h. After returning to room temperature, purified water (20 mL) and ethyl acetate (20 mL * 3) were added directly for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by reverse phase preparation to obtain compound 58f (22.29 mg, yield 45.08%).

[0834] MS M / Z(ESI): 452.9 [M+1] +

[0835] 1 H NMR (400MHz, DMSO-d6) δ8.24(d,J=3.0Hz,1H),8.10(d,J=1.9Hz,1H),8.00(dd,J=11.0,2.0Hz,1H),7.83(td ,J=7.5,1.8Hz,1H),7.73–7.66(m,1H),7.64(s,1H),7.51–7.43(m,2H),5.16(q,J=8.9Hz,2H),2.60(s,3H).

[0836] Example 59

[0837] Synthesis of compound 59c in the first step

[0838] Compound 59a (150 mg, 0.674 mmol) and TEA (136.45 mg, 1.348 mmol) were dissolved in THF (8 mL). Compound 59b (117.60 mg, 0.742 mmol) in THF (2 mL) was added under ice bath conditions, and the reaction was brought to room temperature for 1 h. The reaction was quenched directly with purified water (10 mL), and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound 59c (186 mg, yield 80.06%).

[0839] The second step involves the synthesis of compound 59d.

[0840] Compound 59c (160 mg, 0.464 mmol) was dissolved in a mixed solvent of POCl3 (4 mL) and p-xylene (4 mL) and reacted at 150 °C for 3 h. After cooling to room temperature, the mixture was concentrated to remove phosphorus oxychloride. The reaction solution was then added dropwise to purified water (50 mL), extracted with ethyl acetate (30 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound 59d (119 mg, yield 78.48%).

[0841] The third step involves the synthesis of compound 59f.

[0842] Compound 59d (90 mg, 0.276 mmol) and compound 59e (130.18 mg, 1.102 mmol) were dissolved in DMSO (5 mL) and reacted at 150 °C for 4 h. After cooling to room temperature, purified water (20 mL) was added directly to the reaction solution, followed by extraction with ethyl acetate (20 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 59f (60 mg, yield 58.81%).

[0843] MS M / Z (ESI): 369.8, 371.8 [M+1] +

[0844] The fourth step: synthesis of compound 59f

[0845] Compound 59f (50 mg, 0.135 mmol), compound 59g (65.05 mg, 0.203 mmol), and K3PO4 (86.00 mg, 0.405 mmol) were added to a reaction flask, along with dioxane (5 mL) and purified water (0.5 mL). Under nitrogen protection, Pd(dppf)Cl2.CH2Cl2 (11.06 mg, 0.014 mmol) was added, and the mixture was stirred in an oil bath at 100 °C for 2 h. After cooling to room temperature, purified water (10 mL) and ethyl acetate (10 mL * 3) were added directly for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by reverse phase reaction to obtain compound 59f (18.08 mg, yield 27.64%).

[0846] MS M / Z(ESI): 484.9 [M+1] +

[0847] 1H NMR (400MHz, DMSO-d6) δ8.63(d,J=0.9Hz,1H),8.52(dd,J=2.9,0.9Hz,1H),8.12(d,J=1.9Hz,1H),7.97(dd,J=11.0 ,2.0Hz,1H),7.86(td,J=7.4,1.8Hz,1H),7.77–7.69(m,1H),7.54–7.45(m,2H),5.16(q,J=9.0Hz,2H),3.14(s,3H).

[0848] Example 60

[0849] Synthesis of compound 60c in the first step

[0850] A tetrahydrofuran solution (30 mL) of compound 60b (3000 mg, 11.142 mmol) was slowly added dropwise to a 30 mL solution of 60% NaH (445.67 mg, 11.142 mmol) in THF, and the mixture was stirred for 1 h. Then, a tetrahydrofuran solution (20 mL) of compound 60a (2645 mg, 11.142 mmol) in tetrahydrofuran was added, and the mixture was stirred for 3 h. The reaction was quenched dropwise by adding a saturated ammonium chloride aqueous solution (100 mL) to the reaction mixture under ice water conditions. The mixture was then extracted with ethyl acetate (100 mL x 3). The organic phase was washed successively with water (100 mL) and saturated brine (100 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 60c (6500 mg), which was directly added to the next reaction step.

[0851] MS M / Z(ESI): 370 [M+1-100] +

[0852] The second step involves the synthesis of compound 60e.

[0853] A tetrahydrofuran solution (30 mL) of compound 60c (3000 mg, 11.142 mmol) was slowly added dropwise to a THF solution (30 mL) of NaH (445.67 mg, 11.142 mmol), and the mixture was stirred for 1 h. Then, a tetrahydrofuran solution (20 mL) of compound 60d (2645 mg, 11.142 mmol) was added, and the mixture was stirred for 3 h. The reaction was quenched by adding a saturated ammonium chloride aqueous solution (100 mL) dropwise to the reaction solution under ice water conditions. The solution was then extracted with ethyl acetate (100 mL x 3), and the organic phase was washed successively with water (100 mL) and saturated brine (100 mL). The solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 60e (6500 mg), which was directly added to the next reaction step.

[0854] MS M / Z(ESI): 370 [M+1-100] +

[0855] The third step involves the synthesis of compound 60f.

[0856] Compound 60e (5500 mg, 11.696 mmol) was dissolved in ethyl acetate (40 mL), and then 4 M HCl / EA solution (40 mL) was added. The mixture was stirred overnight at room temperature. After filtration, the filter cake was washed with a small amount of ethyl acetate and dried under vacuum to obtain a diluted compound 60f (4200 mg), which was directly added to the next reaction.

[0857] MS M / Z(ESI): 370[M+1] +

[0858] Step 4: Synthesis of 60g of compound

[0859] Compound 60f (4200 mg, 10.330 mmol), CuI (393 mg, 2.066 mmol), L-proline (951 mg, 8.264 mmol), and K2CO3 (5710 mg, 41.319 mmol) were suspended in DMSO (80 mL) and stirred at 90 °C for 3 h. A saturated ammonium chloride aqueous solution (150 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (150 mL x 2), washing with water (150 mL) and saturated brine (150 mL), drying over anhydrous sodium sulfate, filtering through a silica gel filter, concentrating under reduced pressure, and then precipitating the residue by silica gel column chromatography to give compound 60 g (800 mg, yield 20.9%).

[0860] MS M / Z(ESI): 290[M+1] +

[0861] Step 5: Synthesis of compound 60h

[0862] 60 g (700 mg, 2.420 mmol) of the compound was dissolved in EA (20 mL), then 5% Pd / C (500 mg, 4.698 mmol) was added. The mixture was evacuated three times with hydrogen, and then stirred at room temperature for 3 h. The mixture was filtered through diatomaceous earth, concentrated under reduced pressure, and dried under vacuum to obtain 60 h (630 mg) of compound, which was directly added to the next reaction.

[0863] MS M / Z(ESI): 260[M+1] +

[0864] Step 6: Synthesis of compound 60j

[0865] Copper bromide (1086 mg, 4.861 mmol) was added to a 20 mL solution of compound 60h (630 mg, 2.430 mmol) in acetonitrile. The mixture was then cooled to 0-5 °C in an ice-water bath. Compound 60i (376 mg, 3.645 mmol) was then added dropwise, and the mixture was stirred for 1 h. Water (100 mL) and ethyl acetate (100 mL) were added to the reaction mixture, and the mixture was shaken well. The aqueous layer was then extracted with ethyl acetate (50 mL). The organic phases were combined and washed successively with water (100 mL) and saturated brine (100 mL). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 60j (150 mg), which was directly added to the next reaction.

[0866] MS M / Z(ESI): 323\325[M+1] +

[0867] Step 7: Synthesis of compound 60k

[0868] Compound 60j (130 mg, 0.402 mmol), pinacol diboronate (112 mg, 0.443 mmol), and KOAc (118 mg, 1.207 mmol) were dissolved in dioxane (10 mL), degassed for 5 minutes, and then Pd(dppf)Cl2.CH2Cl2 (66 mg, 0.080 mmol) was added, degassed for 5 minutes, and then stirred in an oil bath at 95 °C for 3 hours. Water (50 mL) and ethyl acetate (50 mL) were added to the reaction solution, shaken well, and the layers were separated. The aqueous layer was extracted again with ethyl acetate (50 mL), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 60k (170 mg), which was directly added to the next reaction.

[0869] MS M / Z(ESI): 371[M+1] +

[0870] Step 8: Synthesis of Compound 60

[0871] Compound 60k (150 mg, 0.405 mmol), 60kl (108 mg, 0.405 mmol), Na2CO3 (86 mg, 0.810 mmol), and DPPF palladium dichloride methane complex (66 mg, 0.081 mmol) were dissolved in a mixed solvent of dioxane (4 mL) and water (1 mL). The mixture was evacuated three times with argon gas, and then reacted in an oil bath at 85 °C for 1 h. Water (50 mL) and ethyl acetate (50 mL) were added to the reaction solution, and the mixture was shaken well. The layers were separated, and the aqueous layer was extracted with ethyl acetate (50 mL). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography to obtain compound 60 (30.39 mg, yield 17.5%).

[0872] MS M / Z(ESI): 430[M+1] +

[0873] 1 H NMR (400MHz, DMS) M / Z(ESI)O-d6)δ8.68(s,1H),8.23(d,J=2.1Hz,1H),8.10(dd,J=9.6,1.1Hz,1 H),8.01(dd,J=9.7,1.6Hz,1H),7.77(d,J=2.1Hz,1H),5.41(td,J=8.4,4.4Hz ,1H),4.06(s,1H),3.71(td,J=8.4,4.3Hz,1H),3.50(dt,J=10.4,7.4Hz,1H), 2.28(dq,J=12.2,4.5Hz,1H),2.17–2.05(m,0H),1.94(dq,J=37.0,9.8Hz,1H).

[0874] Example 61

[0875] Synthesis of compound 61c in step one

[0876] Compound 61a (1000 mg, 4.672 mmol) was dissolved in DCM (15 mL), and TEA (1.948 mL, 14.015 mmol) was added. Compound 61b (1962.35 mg, 9.343 mmol) was slowly added at 0 °C, and the mixture was stirred at this temperature for 0.5 h. The reaction was then carried out at room temperature for 3 h. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to give compound 61c (1.4 g, 96.65% yield).

[0877] MS M / Z(ESI): 311.9 [M+H] +

[0878] The second step involves the synthesis of compound 61e.

[0879] Compound 61c (600 mg, 1.935 mmol) was dissolved in dioxane (3 mL), and compound 61d (737.08 mg, 2.903 mmol), KOAc (189.91 mg, 1.935 mmol), and DPPF palladium dichloride methane complex (158.41 mg, 0.194 mmol) were added. The reaction mixture was heated to 100 °C and stirred for 2 h under nitrogen protection. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography to give compound 61e (600 mg, yield 86.82%).

[0880] MS M / Z(ESI): 358.0 [M+H] +

[0881] The third step involves the synthesis of compound 61g.

[0882] Compound 61f (180 mg, 0.619 mmol) was dissolved in dioxane (6 mL) and H₂O (2 mL). Compound 61e (287.45 mg, 0.805 mmol), K₃PO₄ (394.25 mg, 1.857 mmol), and bis(tri-tert-butylphosphine)palladium (31.64 mg, 0.062 mmol) were added. The reaction mixture was heated to 110 °C and stirred for 1.5 h under nitrogen protection. The reaction mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give compound 61 g (230 mg, yield 95.41%). MS M / Z (ESI): 389.9 [M+H] +

[0883] Step 4: Synthesis of Compound 61

[0884] Compound 61 g (150 mg, 0.385 mmol) was dissolved in DCM (5 mL), and TEA (0.214 mL, 1.541 mmol) and DMAP (23.53 mg, 0.193 mmol) were added. Compound 61b (196 mg, 0.934 mmol) was slowly added at 0 °C and stirred at this temperature for 2 h. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to give compound 61 (43.26 mg, yield 21.98%).

[0885] MS M / Z(ESI): 485.9 [M+H] +

[0886] 1H NMR(400MHz,DMSO-d6)δ8.46(s,1H),8.10(s,1H),7.94–7.87(m,1H),7.71–7.60(m,1H),7.53–7.32(m,3H),7.1 3(d,J=8.5Hz,1H),4.50(t,J=5.3,3.7Hz,2H),4.05(t,J=4.4Hz,2H),3.17–3.02(m,1H),1.22(d,J=6.9Hz,6H).

[0887] Example 62

[0888] Synthesis of compound 62c in step one

[0889] Compound 62a (250 mg, 1.448 mmol) was dissolved in DCM (20 mL), and TEA (293.10 mg, 2.897 mmol) was added. Compound 62b (325.16 mg, 1.448 mmol) in DCM (5 mL) was added under ice bath conditions, and the mixture was stirred at room temperature for 10 min. The solution was diluted with DCM (30 mL), washed once with water, washed once with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 62c (450 mg, yield 86.15%).

[0890] MS M / Z(ESI): 360.9 [M+1] +

[0891] The second step involves the synthesis of compound 62d.

[0892] Compound 62c (440 mg, 1.220 mmol) was dissolved in p-xylene (6 mL) and POCl3 (3 mL), and the mixture was sealed and reacted at 150 °C for 3 h. After concentration, the residual POCl3 was neutralized with saturated sodium bicarbonate, diluted with water (30 mL), extracted with EA (20 mL * 3), washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 62d (240 mg, yield 57.41%).

[0893] MS M / Z(ESI): 342.9 [M+1] +

[0894] The third step involves the synthesis of compound 62.

[0895] Compound 62e (140.53 mg, 0.438 mmol) and compound 62d (100 mg, 0.292 mmol) were dissolved in dioxane (9 mL), and bis(tri-tert-butylphosphine)palladium (14.91 mg, 0.029 mmol), K3PO4 (123.87 mg, 0.584 mmol), and water (3 mL) were added. After bubbling under nitrogen for 1 min, the mixture was sealed and reacted at 110 °C for 5 h. After dilution with water (30 mL), the mixture was extracted with EA (20 mL * 3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified to obtain compound 62 (62.56 mg, yield 40.63%).

[0896] MS M / Z(ESI): 501.9 [M+1] +

[0897] 1 H NMR (400MHz, DMSO-d6) δ8.53–8.47(m,2H),8.40(d,J=1.8Hz,2H),8.29(dd,J=10.9,2.0Hz,1H) ,7.65–7.59(m,2H),5.21(q,J=8.9Hz,2H),2.70(qd,J=7.4,1.3Hz,2H),1.16(t,J=7.4Hz,3H).

[0898] Example 63

[0899] Synthesis of compound 63b (Step 1)

[0900] Compound 63a (800 mg, 2.580 mmol) was dissolved in THF (15 mL) at 0 °C, and borane tetrahydrofuran (554.33 mg, 6.450 mmol) was slowly added. The reaction mixture was then stirred overnight at 70 °C. The reaction was quenched by adding saturated NH4Cl aqueous solution (20 mL), and then extracted with ethyl acetate (50 mL * 2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give compound 63b (600 mg, 78.54% yield).

[0901] MS M / Z(ESI): 297.9 [M+1] +

[0902] The second step involves the synthesis of compound 63d.

[0903] Compound 63b (550 mg, 1.858 mmol) was dissolved in dioxane (3 mL), and compound 63c (707.56 mg, 2.786 mmol), KOAc (182.30 mg, 1.858 mmol), and DPPF palladium dichloride methane complex (152.07 mg, 0.186 mmol) were added. The reaction mixture was heated to 100 °C and stirred for 2 h under nitrogen protection. 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 to obtain compound 63d (610 mg, yield 95.70%).

[0904] MS M / Z(ESI): 344.0 [M+1] +

[0905] The third step involves the synthesis of compound 63.

[0906] Compound 63e (80 mg, 0.275 mmol) was dissolved in dioxane (3 mL) and H2O (1 mL). Compound 63d (122.75 mg, 0.358 mmol), K3PO4 (175.22 mg, 0.826 mmol), and di(tri-tert-butylphosphine)palladium (14.06 mg, 0.028 mmol) were added. The reaction mixture was heated to 110 °C and stirred for 1.5 h under nitrogen protection. After cooling to room temperature, purified water (10 mL) was added, and extraction was performed with EA (20 mL * 2). The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to obtain an oily substance. Compound 63 (20.09 mg, yield 15.5%) was obtained after purification.

[0907] MS M / Z(ESI): 471.9 [M+1] +

[0908] 1 H NMR (400MHz, DMSO-d6) δ8.43(s,1H),7.98–7.85(m,1H),7.71–7.60(m,1H),7.49–7.37(m,2H),7.08(s,1H),6.86(d,J=8. 1Hz,1H),6.77(dd,J=8.0,1.9Hz,1H),4.29–4.13(m,4H),3.52(t,J=4.3Hz,2H),3.11–2.99(m,1H),1.20(d,J=6.8Hz,6H).

[0909] Example 64

[0910] Synthesis of compound 64c (Step 1)

[0911] Compound 64a (1500 mg, 6.578 mmol) was dissolved in DMF (20 mL), and then 60% NaH (316 mg, 7.893 mmol) was added under an ice-water bath. The mixture was stirred for 30 min, and then compound 64b (2420 mg, 13.156 mmol) was added dropwise. The mixture was then heated to 120 °C and stirred for 48 h. Water (250 mL) and ethyl acetate (250 mL) were added to the reaction mixture, and the mixture was shaken to separate the layers. The aqueous phase was then extracted with ethyl acetate (100 mL), and the organic phases were combined. The organic layer was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 64c (1000 mg, yield 53.51%).

[0912] MS M / Z(ESI): 284, 286 [M+1] +

[0913] The second step involves the synthesis of compound 64d.

[0914] Compound 64c (130 mg, 0.458 mmol), pinacol diboronate (128 mg, 0.503 mmol), and KOAc (135 mg, 1.373 mmol) were dissolved in dioxane (5 mL), degassed for 5 minutes, and then Pd(dppf)Cl2.CH2Cl2 (75 mg, 0.092 mmol) was added, degassed for 5 minutes, and then stirred in an oil bath at 95 °C for 3 hours. Water (50 mL) and ethyl acetate (50 mL) were added to the reaction mixture, shaken well, and the layers were separated. The aqueous layer was extracted again with ethyl acetate (50 mL), and the organic layers were combined. The mixture was then washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound 64d (220 mg), which was directly added to the next reaction. MS M / Z (ESI): 332 [M+1] +

[0915] The third step involves the synthesis of compound 64.

[0916] Compound 64d (100 mg, 0.206 mmol), compound 64e (50 mg, 0.172 mmol), and K3PO4 (110 mg, 0.516 mmol) were added to a microwave-safe flask, followed by the addition of dioxane (4 mL) and water (1 mL). The mixture was evacuated three times, and then di(tri-tert-butylphosphine)palladium (18 mg, 0.034 mmol) was added. The mixture was evacuated three times, and the mixture was microwaved at 110 °C for 1.5 h. Water (50 mL) and ethyl acetate (50 mL) were added to the reaction mixture, and the mixture was shaken well. The layers were separated, and the aqueous layer was extracted with ethyl acetate (50 mL). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a crude product, which was then used to prepare compound 64 (18.37 mg, yield 23.24%).

[0917] MS M / Z(ESI): 460[M+1] +

[0918] 1 H NMR(400MHz, DMSO-d6)δ8.47(s,1H),7.92(td,J=7.4,1.8Hz,1H),7.71–7.59(m,1H),7.51–7.35(m,2H),7.22(d,J=1.4Hz,2H), 6.89 (s, 1H), 5.11 (q, J = 7.4Hz, 1H), 4.85 (t, J = 6.9Hz, 2H), 4.63 (t, J = 7.1Hz, 2H), 2.98 (p, J = 6.8Hz, 1H), 1.20 (d, J = 6.8Hz, 6H).

[0919] Example 65

[0920] Synthesis of compound 65b in step one

[0921] Compound 65a (440 mg, 2.499 mmol) was dissolved in ethanol (1 mL) and hydrazine hydrate (9 mL), and reacted overnight at 100 °C under sealed conditions. Water (20 mL) was added, and the mixture was extracted with EA (20 mL x 3). The organic phase was concentrated to give compound 65b (430 mg, 100% yield).

[0922] MS M / Z(ESI): 172.0 [M+1] +

[0923] The second step involves the synthesis of compound 65d.

[0924] Compound 65b (430 mg, 2.505 mmol) was dissolved in DCM (12 mL), and DIEA (647.64 mg, 5.011 mmol) was added. Compound 65c (486.91 mg, 2.004 mmol) was added under ice bath conditions, and the mixture was stirred at room temperature for 1 h. Water (20 mL) was added, and the mixture was extracted with DCM (20 mL x 3). The organic phase was concentrated to give compound 65d (450 mg, yield 63.22%).

[0925] MS M / Z (ESI): 283.9, 285.9 [M+1] +

[0926] The third step involves the synthesis of compound 65e.

[0927] Compound 65d (450 mg, 1.584 mmol) was dissolved in p-xylene (6 mL), and POCl3 (3 mL) was added. The mixture was reacted at 150 °C under sealed conditions for 3 h. After concentration, the residual POCl3 was neutralized with saturated sodium bicarbonate, diluted with water (20 mL), extracted with EA (20 mL * 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 65e (270 mg, yield 64.06%).

[0928] MS M / Z(ESI): 265.9 [M+1] +

[0929] The fourth step involves the synthesis of 65g of compound.

[0930] Compound 65e (100 mg, 0.376 mmol) was dissolved in EtOH (5 mL), and a 20% sodium ethoxide ethanol solution (2557.60 mg, 7.517 mmol) was added. The reaction was carried out at 80 °C for 3 h. The reaction was quenched with water, concentrated, and purified by silica gel column chromatography to give compound 65 g (96 mg, yield 92.65%).

[0931] MS M / Z(ESI): 276.0 [M+1] +

[0932] Step 5: Synthesis of Compound 65

[0933] Compound 65 (174.70 mg, 0.544 mmol) was dissolved in dioxane (9 mL), followed by the addition of di(tri-tert-butylphosphine)palladium (18.54 mg, 0.036 mmol), K3PO4 (153.99 mg, 0.725 mmol), and water (3 mL). The mixture was then purged with nitrogen for 1 min and sealed at 110 °C for 3 h. After adding 20 mL of dioxane, the mixture was extracted with EA (20 mL x 3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the crude product. The crude product was then used to prepare compound 65 (30.51 mg, yield 18.40%).

[0934] MS M / Z(ESI): 434.9 [M+1] +

[0935] 1 H NMR (400MHz, DMSO-d6) δ8.55(d,J=7.1Hz,1H),8.18(d,J=1.9Hz,1H),8.07(dd,J=11.0,1.9Hz,1H),7.30(d,J=7.2Hz, 1H), 5.22 (q, J = 9.0Hz, 2H), 4.28 (q, J = 7.1Hz, 2H), 2.62 (q, J = 7.5Hz, 2H), 1.39 (t, J = 7.1Hz, 3H), 1.17 (t, J = 7.5Hz, 3H).

[0936] Example 66

[0937] Synthesis of Compound 66 (Step 1)

[0938] Compound 66a (60 mg, 0.187 mmol) was added to a reaction flask, followed by dioxane (6 mL), water (2 mL), compound 66b (63.69 mg, 0.224 mmol), PdCl2 (dppf)·CH2Cl2 (15.29 mg, 0.019 mmol), and K2CO3 (51.64 mg, 0.374 mmol). The mixture was stirred at 100 °C for 3 h under nitrogen protection. After cooling to room temperature, purified water (15 mL) was added, followed by extraction with EA (35 mL x 2). The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to obtain an oily substance. Compound 66 (50.03 mg, 67.22%) was purified to obtain the final product.

[0939] MS m / z(ESI): 399.0 [M+1] +

[0940] 1H NMR (400MHz, DMSO-d6) δ8.37(d,J=1.3Hz,1H),7.92(td,J=7.4,1.8Hz,1H),7.72(d,J=1.7Hz,1H),7.70–7 .62(m,1H),7.58(d,J=8.3Hz,1H),7.51–7.38(m,3H),2.64(qd,J=7.4,1.2Hz,2H),1.13(t,J=7.4Hz,3H).

[0941] Example 67

[0942] Synthesis of compound 67c in step one

[0943] Compound 67a (1500 mg, 6.519 mmol) was dissolved in DCM (20 mL), and TEA (1319.24 mg, 13.037 mmol) was added. A DCM solution of compound 67b (1067.98 mg, 7.822 mmol) was added under ice bath conditions, and the mixture was stirred at room temperature for 0.5 h. After dilution with DCM (20 mL), the mixture was washed once with water (10 mL) and once with saturated brine (10 mL). The solution was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 67c (2000 mg). MS m / z (ESI): 330.0 [M+1] +

[0944] The second step involves the synthesis of compound 67d.

[0945] Compound 67c (2000 mg, 6.057 mmol) was dissolved in p-xylene (12 mL), and POCl3 (6 mL) was added. The mixture was sealed and reacted at 150 °C for 3 h. After concentration, the residual POCl3 was neutralized with saturated sodium bicarbonate, diluted with water (50 mL), extracted with EA (30 mL * 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 67d (460 mg, yield 24.33%).

[0946] MS m / z(ESI):311.9, 313.9[M+1] +

[0947] The third step involves the synthesis of compound 67e.

[0948] Compound 67d (430 mg, 1.377 mmol) was dissolved in ethanol (20 mL), and NaBH4 (440 mg, 11.631 mmol) was added in portions under ice bath conditions. The reaction was carried out at room temperature for 12 h. After quenching with saturated ammonium chloride, the ethanol was removed by concentration, diluted with water (30 mL), extracted with EA (20 mL * 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by silica gel column chromatography to obtain compound 67e (260 mg, yield 66.43%).

[0949] MS m / z(ESI):283.9, 285.9[M+1] +

[0950] The fourth step involves the synthesis of compound 67g.

[0951] Compound 67e (100 mg, 0.352 mmol), compound 67f (50.72 mg, 0.528 mmol), and PPh3 (138.46 mg, 0.528 mmol) were added to a three-necked flask, dissolved in THF (13 mL), and DCM (5 mL) was added. Under nitrogen protection, the mixture was cooled to 0°C in an ice bath, and then a THF (2 mL) solution of DIAD (142.32 mg, 0.704 mmol) was added dropwise. The reaction was allowed to proceed overnight at room temperature. After quenching with water (30 mL), the mixture was extracted with EA (20 mL * 3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by silica gel column chromatography to obtain compound 67 g (86 mg, yield 67.47%).

[0952] MS m / z(ESI): 361.9 [M+1] +

[0953] Step 5: Synthesis of Compound 67

[0954] Compound 67h (87.58 mg, 0.273 mmol) and compound 67g (76 mg, 0.210 mmol) were dissolved in dioxane (9 mL), and bis(tri-tert-butylphosphine)palladium (10.72 mg, 0.021 mmol), K3PO4 (89.07 mg, 0.420 mmol), and water (3 mL) were added. After purging with nitrogen for 1 min, the reaction was carried out at 110 °C for 3 h. Water (30 mL) was added, and the mixture was extracted with EA (20 mL * 3). The mixture was washed with saturated brine (10 mL). After drying with anhydrous sodium sulfate, the mixture was filtered, concentrated, and then purified by silica gel column chromatography to obtain the crude product. The crude product was further purified to obtain compound 67 (23.82 mg, yield 23.83%).

[0955] MS m / z(ESI): 476.9 [M+1] +

[0956] 1 H NMR (400MHz, DMSO-d6) δ8.57(d,J=4.8Hz,2H),8.51(d,J=0.9Hz,1H),8.16(d,J=1.9Hz,1H),8.08(dd,J=11.0,2.0Hz,1H),7.70(s,1H), 7.13(t,J=4.8Hz,1H),5.19(q,J=9.0Hz,2H),4.76(t,J=6.4Hz,2H),3.62(t,J=6.4Hz,2H),2.91(h,J=6.6Hz,1H),1.15(d,J=6.8Hz,6H).

[0957] Example 68

[0958] The first step is the synthesis of compound 68c.

[0959] Compound 68a (3.0 g, 9.424 mmol) was added to a reaction flask, along with dioxane (60 mL), compound 60b (1.39 g, 10.366 mmol), PdCl2 (dppf).CH2Cl2 (0.77 g, 0.942 mmol), and Cs2CO3 (9.21 g, 28.272 mmol). The mixture was stirred at 100 °C for 3 h under nitrogen protection. After cooling to room temperature, the mixture was purified by silica gel column chromatography to obtain crude product 68c (1500 mg, yield 72.85%).

[0960] MS m / z(ESI):217.48 / 219.48[M+1] +

[0961] The second step involves the synthesis of compound 68d.

[0962] Compound 68c (800 mg, 3.662 mmol) was dissolved in MeOH (15 mL), and PtO2 (34.13 mg, 0.150 mmol) was added. The mixture was purged three times with a hydrogen balloon, and the reaction was carried out at room temperature for 1.0 h under hydrogen atmosphere. The reaction mixture was filtered and evaporated to dryness to give compound 68d (352 mg, yield 43.60%).

[0963] MS m / z(ESI):219.49 / 221.49[M+1] +

[0964] The third step involves the synthesis of compound 68e.

[0965] Compound 68d (300 mg, 1.361 mmol) was added to a reaction flask, followed by 5 mL of EtOH and 5 mL of 85% hydrazine hydrate. The reaction mixture was reacted overnight at 100 °C. After the reaction was brought back to room temperature, the mixture was evaporated to dryness. The residue was added to 30 mL of DCM, followed by 20 mL of saturated NaHCO3 solution. The mixture was separated, dried, and evaporated to dryness to give compound 68e (269 mg, yield 91.50%).

[0966] MS m / z(ESI): 216.08 [M+1] +

[0967] The fourth step involves the synthesis of compound 68g.

[0968] Compound 68e (30 mg, 0.139 mmol) was added to a reaction flask, followed by 3 mL of DCM and Et3N (28.10 mg, 0.153 mmol). The mixture was stirred and cooled in an ice bath to 0-5 °C. At this temperature, compound 68f (37.10 mg, 0.153 mmol) was slowly added, and the mixture was stirred for 1 h. The solvent was removed by rotary evaporation under reduced pressure, and the mixture was purified by silica gel column chromatography to give compound 68 g (26 mg, yield 57.00%).

[0969] MS m / z(ESI): 328.54 [M+1] +

[0970] Step 5: Synthesis of compound 68h

[0971] Compound 68 g (20 mg, 0.061 mmol) was added to a reaction flask, along with POCl3 (1 mL) and p-xylene (1 mL). The mixture was refluxed at 150 °C overnight. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and a black oily substance was obtained. Sodium bicarbonate solution (100 mL) was added, followed by extraction with EA (200 mL * 2). The organic phase was evaporated to dryness and purified by silica gel column chromatography to obtain compound 68 h (15 mg, yield 79.35%).

[0972] MS m / z(ESI):309.53 / 311.53[M+1] +

[0973] Step 6: Synthesis of compound 68j

[0974] Compound 68h (15 mg, 0.048 mmol) was added to a reaction flask, followed by 3 mL of water (1 mL), compound 68i (31.02 mg, 0.097 mmol), PdCl2 (dppf).CH2Cl2 (7.91 mg, 0.010 mmol), and Na2CO3 (6.14 mg, 0.058 mmol). The mixture was heated to 100 °C under nitrogen protection for 3 h. After cooling to room temperature, the mixture was purified by silica gel column chromatography to obtain compound 68j (20 mg, yield 97.47%).

[0975] MS m / z(ESI): 424.73 [M+1] +

[0976] Step 7: Synthesis of Compound 68

[0977] Compound 68j (10 mg, 0.024 mmol) was added to a reaction flask, along with benzyl alcohol (5 mL) and AgBF4 (22.92 mg, 0.118 mmol). The mixture was heated to 100 °C and refluxed overnight. The reaction system was cooled to room temperature, quenched with saturated NaCl solution (10 mL), and EA (30 mL) was added. The mixture was separated, and the organic phase was evaporated to dryness. The mixture was then purified by reverse phase preparation to obtain compound 68 (1.4 mg, yield 11.98%).

[0978] MS m / z(ESI): 496.41 [M+1] +

[0979] 1 H NMR (400MHz, DMSO-d6) δ8.28(s,1H),8.08(d,J=2.0Hz,1H),8.02(dd,J=11.0,2.0Hz,1H),7.87(d,J=1.1Hz,1H),7.44( dt,J=7.0,2.7Hz,2H),7.38–7.32(m,3H),5.26(s,2H),5.19(q,J=9.0Hz,2H),2.62–2.55(m,2H),1.08(t,J=7.4Hz,3H).

[0980] Example 69

[0981] Synthesis of Compound 69 (Step 1)

[0982] Compound 69a (100 mg, 0.218 mmol) was dissolved in THF (10 mL), and then 1 M boranetetrahydrofuran solution (0.76 mL, 0.76 mmol) was added dropwise. The mixture was stirred at room temperature for 30 min, then heated to 80 °C and stirred for 2 h. The reaction was quenched by adding methanol dropwise, and then water (20 mL) and ethyl acetate (20 mL) were added to the mixture. The mixture was shaken well, and the layers were separated. The aqueous layer was extracted with ethyl acetate (20 mL), and the organic phase was washed with saturated brine (20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified to obtain compound 69 (2.49 mg, yield 2.57%).

[0983] MS m / z(ESI): 446[M+1] +

[0984] 1 H NMR(400MHz,DMSO-d6)δ8.38(s,1H),7.88(td,J=7.5,1.8Hz,1H),7.67–7.5 6(m,1H),7.47–7.33(m,2H),6.85–6.73(m,2H),6.45(d,J=1.9Hz,1H),4.73 (t,J=6.6Hz,2H),4.65(t,J=6.2Hz,2H),4.59(q,J=6.4Hz,1H),4.33(t,J=4 .5Hz,2H),3.27(t,J=4.4Hz,2H),3.04–2.96(m,1H),1.17(d,J=6.8Hz,6H).

[0985] Example 70

[0986] Synthesis of compound 70c in step one

[0987] Compound 70a (80 mg, 0.370 mmol) was added to a reaction flask, followed by DCM (5 mL) and Et3N (44.96 mg, 0.444 mmol). The mixture was stirred and cooled to 0–5 °C in an ice bath. At this temperature, compound 70b (91.45 mg, 0.407 mmol) was slowly added, and the mixture was stirred at room temperature for 1 h. After concentration, the mixture was purified by silica gel column chromatography to obtain compound 70c (120 mg, yield 80.19%).

[0988] MS m / z(ESI): 404.19 [M+1] +

[0989] The second step involves the synthesis of compound 70d.

[0990] Compound 70c (120 mg, 0.297 mmol) was added to a reaction flask, along with POCl3 (4 mL) and p-xylene (2 mL). The mixture was refluxed at 150 °C for 3 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and a black oily substance was obtained. Sodium bicarbonate solution (10 mL) was added, and the mixture was extracted with EA (20 mL * 2). After concentration of the organic phase, the mixture was purified by silica gel column chromatography to obtain compound 70d (75 mg, yield 65.42%).

[0991] MS m / z(ESI): 386.17 [M+1] +

[0992] Step 3: Synthesis of Compound 70

[0993] Compound 70d (50 mg, 0.129 mmol) was added to a reaction flask, along with dioxane (3 mL), water (1 mL), compound 70e (49.89 mg, 0.155 mmol), PdCl2 (dppf).CH2Cl2 (10.60 mg, 0.013 mmol), and K3PO4 (54.97 mg, 0.259 mmol). The mixture was stirred at 100 °C for 3 h. After cooling to room temperature, purified water (15 mL) was added, followed by extraction with EA (35 mL x 2). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain compound 70 (4.28 mg, yield 6.61%).

[0994] MS m / z(ESI): 500.38 [M+1] +

[0995] 1 H NMR(400MHz, DMSO-d6)δ8.48(s,1H),8.18–8.04(m,4H),7.80(s,1H),7.59(d,J= 8.3Hz, 2H), 5.17 (q, J = 8.9Hz, 2H), 2.62 (d, J = 7.3Hz, 2H), 1.10 (t, J = 7.4Hz, 3H).

[0996] Example 71

[0997] Synthesis of Compound 71 (Step 1)

[0998] Compound 71a (120 mg, 0.451 mmol) was dissolved in dioxane (3 mL) and H2O (1 mL). Compound 71b (140.95 mg, 0.496 mmol), K2CO3 (187.02 mg, 1.353 mmol), and DPPF palladium dichloride methane complex (36.93 mg, 0.045 mmol) were added. The reaction mixture was heated to 100 °C and stirred for 2 h under nitrogen protection. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to give compound 71 (113.81 mg, yield 69.84%).

[0999] MS m / z(ESI): 343.9 [M+H] +

[1000] 1 H NMR (400MHz, DMSO-d6) δ8.75(s,1H),8.17(dd,J=9.6,1.1Hz,1H),7.99(dd,J=9.6,1 .7Hz,1H),7.96(d,J=1.9Hz,1H),7.67(dd,J=8.4,1.9Hz,1H),7.58(d,J=8.4Hz,1H).

[1001] Example 72

[1002] Synthesis of compound 72b (Step 1)

[1003] Compound 72 (5000 mg, 21.009 mmol) was dissolved in a mixed solvent of ethanol (50 mL) and water (10 mL), then reduced iron powder (5866 mg, 105.047 mmol) and ammonium chloride (5619 mg, 105.047 mmol) were added, and the mixture was stirred in an oil bath at 90 °C for 3 h. The reaction mixture was filtered through diatomaceous earth, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 72b (3300 mg, yield 75.51%).

[1004] MS M / Z(ESI): 208[M+1] +

[1005] The second step involves the synthesis of compound 72c.

[1006] Compound 72b (2700 mg, 12.980 mmol) was dissolved in pyridine (15 mL), cooled to 0 °C in an ice-water bath, and then p-toluenesulfonyl chloride (2722 mg, 14.278 mmol) was added. The mixture was stirred at room temperature for 3 h. The solution was concentrated to dryness under reduced pressure. Then, 1 N hydrochloric acid aqueous solution (200 mL) and ethyl acetate (200 mL) were added to the reaction solution, shaken well, separated into layers, and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and dried under vacuum to obtain compound 72c (4900 mg), which was directly added to the next reaction.

[1007] The third step involves the synthesis of compound 72e.

[1008] Compound 72c (4900 mg, 13.529 mmol) was dissolved in a mixture of isopropanol (50 mL) and water (2.5 mL), followed by the addition of compound 72d (3032 mg, 27.058 mmol) and sodium carbonate (1434 mg, 13.529 mmol). The mixture was then sealed in an oil bath at 80 °C and reacted for 18 h. Water (200 mL) and ethyl acetate (200 mL) were added to the reaction mixture, and the mixture was shaken well. The organic phase was then washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 72e (6700 mg), which was directly added to the next reaction step.

[1009] MS M / Z(ESI): 474[M+1] +

[1010] The fourth step is the synthesis of compound 72f.

[1011] Compound 72e (6700 mg, 14.128 mmol) was dissolved in tetrahydrofuran (80 mL), followed by the addition of TBAB (455 mg, 1.413 mmol) and sodium hydroxide (2260 mg, 56.511 mmol). The mixture was stirred in an oil bath at 70 °C for 1 h. Water (200 mL) and ethyl acetate (200 mL) were added to the reaction mixture, and the mixture was shaken well. The layers were separated, and the organic layer was washed with saturated brine (200 mL x 3). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a brown oily substance. The oil was purified by silica gel column chromatography to obtain compound 72f (3400 mg, three-step yield 57.7%).

[1012] Step 5: Synthesis of compound 72g

[1013] Compound 72f (2000 mg, 4.403 mmol) was suspended in a mixed solvent of concentrated hydrochloric acid (36%-38%) (50 mL, 0.044 mmol), glacial acetic acid (50 mL, 873.439 mmol), and water (25 mL, 1383.185 mmol). The mixture was stirred in an oil bath at 95 °C for 18 h. The reaction solution was concentrated to dryness under reduced pressure. Then, saturated sodium bicarbonate aqueous solution (100 mL) and ethyl acetate (100 mL) were added to the residue, and the mixture was shaken well. The layers were separated, and the organic layer was washed with saturated brine (100 mL). The residue was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oily substance. The oil was purified by silica gel column chromatography to give 72 g (1100 mg, yield 83.26%) of colorless compound.

[1014] MS M / Z(ESI): 300[M+1] +

[1015] Step 6: Synthesis of Compound 72

[1016] Compound 72 g (26 mg, 0.087 mmol), compound 72 h (26 mg, 0.113 mmol), and sodium carbonate (18 mg, 0.167 mmol) were added to a microwave-safe flask. Then, toluene (2 mL), ethanol (0.5 mL), and water (0.1 mL) were added, and the mixture was evacuated three times. Next, Pd(dppf)Cl2.CH2Cl2 (7 mg, 0.009 mmol) was added, and the mixture was evacuated three times. The reaction was carried out in an oil bath at 85°C for 2 h. Water (20 mL) and ethyl acetate (20 mL) were added to the reaction mixture, and the mixture was shaken well. The layers were separated, and the aqueous layer was extracted again with ethyl acetate (20 mL). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 72 (26 mg, yield 73.6%).

[1017] MS M / Z(ESI): 407[M+1] +

[1018] 1 H NMR(400MHz,DMS M / Z(ESI)O-d6)δ8.56(s,1H),8.11(d,J=9.5Hz,1H),7.89(dd,J=9.7,1.6Hz,1H),7.0 4(dd,J=11.8,2.1Hz,1H),6.89(d,J=1.8Hz,1H),6.57(s,1H),5.12–4.98(m,1H),3.68 -3.58(m,1H),3.48 -3.30(m,1H).

[1019] Example 73

[1020] Synthesis of compound 73b (Step 1)

[1021] Compound 73a (70 mg, 0.233 mmol), CH3I (331 mg, 2.333 mmol), and Cs2CO3 (91 mg, 0.280 mmol) were suspended in DMF (3 mL) and reacted in an oil bath at 65 °C with stirring for 72 h. After filtration, water (50 mL) and ethyl acetate (50 mL) were added to the reaction solution, and the mixture was shaken well. The solution was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 73b (60 mg), which was directly added to the next reaction.

[1022] MS M / Z(ESI): 314[M+1] +

[1023] The second step involves the synthesis of compound 73.

[1024] Compound 73b (60 mg, 0.191 mmol), compound 73c (53 mg, 0.230 mmol), and Na₂CO₃ (50.62 mg, 0.478 mmol) were added to a microwave-safe flask. Then, Toluene (6 mL), EtOH (1.5 mL), and Water (0.3 mL) were added, and the mixture was evacuated three times. Next, Pd(dppf)Cl₂.CH₂Cl₂ (16 mg, 0.019 mmol) was added, and the mixture was evacuated three times. The reaction was carried out in an oil bath at 85 °C for 2.5 h. Water (50 mL) and ethyl acetate (50 mL) were added to the reaction mixture, and the mixture was shaken well. The layers were separated, and the aqueous layer was extracted with ethyl acetate (50 mL). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 50 mg of crude product, which was then further purified to obtain compound 73 (20.23 mg, yield 25.2%).

[1025] MS M / Z(ESI): 421[M+1] +

[1026] 1 H NMR(400MHz,DMS M / Z(ESI)O-d6)δ8.67(s,1H),8.13(dd,J=9.6,1.1Hz,1H),8.01(dd,J=9.6,1.6Hz,1H),7.17(dd,J=11.7,2.1Hz,1H ),6.98(t,J=1.7Hz,1H),5.24(td,J=6.7,3.2Hz,1H),3.66–3.58(m,1H),3.42(dd,J=12.6,6.4Hz,1H),3.04(s,3H).

[1027] Example 74

[1028] Synthesis of Compound 74 (Step 1)

[1029] Compound 74a (50 mg, 0.149 mmol) was added to a reaction flask, followed by dioxane (3 mL), H₂O (1 mL), compound 74b (50.85 mg, 0.179 mmol), PdCl₂ (dppf), CH₂Cl₂ (12.21 mg, 0.015 mmol), and K₃PO₄ (63.33 mg, 0.298 mmol). The mixture was stirred overnight at 100 °C under nitrogen protection. After cooling to room temperature, purified water (15 mL) was added, followed by extraction with EA (35 mL x 2). The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to obtain an oily substance. The purified compound 74 (13.08 mg, yield 22.9%) was obtained.

[1030] MS m / z(ESI): 412.37 [M+H] +

[1031] 1 H NMR (400MHz, DMSO-d6) δ8.49(s,1H),7.90(td,J=7.4,1.8Hz,1H),7.71(d,J=1.7Hz,1H),7.66(dddd,J=8.6,7.3 ,5.4,1.8Hz,1H),7.58(d,J=8.3Hz,1H),7.50–7.39(m,3H),2.91(dt,J=13.5,6.9Hz,1H),1.20(d,J=6.8Hz,6H).

[1032] Example 75

[1033] Synthesis of compound 75c in the first step

[1034] Compound 75a (300 mg, 1.321 mmol) was dissolved in dioxane (10 mL), and compound 75b (503.28 mg, 1.982 mmol), KOAc (259.34 mg, 2.643 mmol), and DPPF palladium dichloride methane complex (108.16 mg, 0.132 mmol) were added. The reaction mixture was heated to 100 °C and stirred for 2 h under nitrogen protection. The reaction solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound 75c (330 mg, yield 91.11%).

[1035] MS m / z(ESI): 275.0 [M+H] +

[1036] The second step involves the synthesis of compound 75e.

[1037] Compound 75d (250 mg, 0.940 mmol) was dissolved in dioxane (5 mL) / water (1 mL), and compound 75c (283.38 mg, 1.034 mmol), K2CO3 (389.63 mg, 2.819 mmol), and DPPF palladium dichloride methane complex (76.93 mg, 0.094 mmol) were added. The reaction mixture was heated to 100 °C and stirred for 2 h under nitrogen protection. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to give compound 75e (280 mg, yield 89.40%).

[1038] MS m / z(ESI): 333.9 [M+H] +

[1039] The third step involves the synthesis of compound 75.

[1040] Compound 75e (130 mg, 0.390 mmol) was dissolved in DCM (3 mL), and BAST (0.719 mL, 3.901 mmol) was added. The mixture was heated in an oil bath at 40 °C and stirred for 2 days. After returning to room temperature, the reaction was quenched by adding saturated Na₂CO₃ aqueous solution (20 mL), and then extracted with ethyl acetate (30 mL * 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, dissolved in acetonitrile (3 mL), and purified by reverse phase to give compound 75 (9.90 mg, yield 6.79%).

[1041] MS m / z (ESI): 355.9 [M+H] +

[1042] 1 H NMR (400MHz, DMSO-d6) δ8.75(s,1H),8.16(dd,J=9.6,1.1Hz,1H),8.00(dd,J=9.6,1.6Hz,1H),7.72( d,J=8.1Hz,1H),7.49(dd,J=8.1,1.8Hz,1H),7.43(d,J=1.6Hz,1H),4.41(t,2H),2.68–2.53(m,2H).

[1043] Example 76

[1044] Synthesis of compound 76c (Step 1)

[1045] Compound 76a (80 mg, 0.267 mmol) and compound 76b (371 mg, 2.666 mmol) were dissolved in acetonitrile (2 mL), followed by the addition of potassium iodide (44 mg, 0.267 mmol) and potassium carbonate (368 mg, 2.666 mmol). The mixture was stirred in an oil bath at 100 °C for 72 h. After filtration and concentration under reduced pressure, 50 mL of sodium bicarbonate aqueous solution and 50 mL of ethyl acetate were added to the residue. The mixture was shaken well, separated into layers, and the organic phase was washed with saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 76 (90 mg, 94.26% yield), which was directly added to the next reaction.

[1046] MS m / z (ESI): 358, 360 [M+1] +

[1047] The second step involves the synthesis of compound 76.

[1048] Compound 76d (87 mg, 0.377 mmol), compound 76c (90 mg, 0.251 mmol), and Na2CO3 (80 mg, 0.754 mmol) were added to a microwave-safe flask. Toluene (8 mL), EtOH (2 mL), and water (0.4 mL) were then added. The mixture was evacuated three times. Pd(dppf)Cl2.CH2Cl2 (21 mg, 0.025 mmol) was then added, and the mixture was evacuated three times. The reaction was carried out in an oil bath at 85°C for 2 hours. Water (50 mL) and ethyl acetate (50 mL) were added to the reaction mixture, and the mixture was shaken well. The layers were separated, and the aqueous layer was extracted with ethyl acetate (50 mL). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain a crude product, which was then further purified to obtain compound 76 (29.37 mg, yield 25.17%).

[1049] MS m / z(ESI): 465[M+1] +

[1050] 1 H NMR (400MHz, DMSO-d6) δ8.64(s,1H),8.14(dd,J=9.6,1.1Hz,1H),7.99(dd,J=9.6,1.6Hz,1H),7.11(dd,J=11.6,2.0Hz ,1H),7.03(t,J=1.6Hz,1H),5.10(td,J=6.6,2.9Hz,1H),3.74(td,J=11.1,5.2Hz,2H),3.69–3.48(m,4H),3.28(s,3H).

[1051] Example 77

[1052] Synthesis of Compound 77 (Step 1)

[1053] Compound 77a (30 mg, 0.166 mmol), compound 77b (35 mg, 0.199 mmol), potassium carbonate (46 mg, 0.332 mmol), Xantphos (19 mg, 0.033 mmol), and Pd2(dba)3 (15 mg, 0.017 mmol) were suspended in 1,4-dioxane (1 mL), and the mixture was evacuated three times with nitrogen and stirred overnight in an oil bath at 105 °C. A saturated ammonium chloride aqueous solution (30 mL) and ethyl acetate (30 mL) were added to the reaction mixture, and the mixture was shaken well. The layers were separated, and the aqueous layer was extracted with ethyl acetate (30 mL). The organic layers were combined, washed with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified to obtain compound 77 (37.33 mg, yield 70.19%).

[1054] MS:321[M+1] +

[1055] 1 H NMR (400MHz, DMSO-d6) δ8.59(s,1H),7.68(dd,J=8.7,2.5Hz,1H),7.61(d,J=8.7Hz,1H),7.55(d,J=2.5Hz,1H),6.98(d ,J=8.8Hz,1H),6.57(d,J=8.8Hz,1H),6.11(s,1H),3.62(s,3H),3.23(s,3H),2.82(dd,J=8.6,6.0Hz,2H),2.39(s,3H).

[1056] Example 78

[1057] Synthesis of Compound 78 (Step 1)

[1058] Compound 78a (46 mg, 0.260 mmol) was added to a reaction flask, followed by compound 78b (46.91 mg, 0.260 mmol), and 1,4-dioxane (5 mL). The mixture was stirred to dissolve, then K₂CO₃ (71.78 mg, 0.519 mmol), Pd₂(dba)₃ (23.78 mg, 0.026 mmol), and Xantphos (30.05 mg, 0.052 mmol). The mixture was purged with nitrogen for 2 min. The reaction was carried out in a sealed system at 100 °C for 3 h. After cooling to room temperature, purified water (15 mL) was added, followed by extraction with EA (35 mL x 2). The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to obtain an oily substance. Compound 78 (60.8 mg, 72.78%) was prepared and purified to obtain compound 78.

[1059] MS m / z(ESI): 322.1 [M+1] +

[1060] 1 H NMR(400MHz,DMSO-d6)δ8.92(s,1H),7.87–7.81(m,2H),7.66(dd,J=8.7,0.9Hz,1H),7.25–7 .18(m,2H),6.61(d,J=8.8Hz,1H),6.15(t,J=0.9Hz,1H),3.63(s,3H),2.40(d,J=0.8Hz,3H).

[1061] Example 79

[1062] Synthesis of compound 79c (Step 1)

[1063] 60% NaH (149.93 mg, 3.748 mmol) was dissolved in THF (3 mL). After cooling to 0 °C, a THF solution of compound 79b (343.27 mg, 3.436 mmol) (2 mL) was added dropwise. The reaction was carried out at 25 °C for 30 min. Then, a THF solution of compound 79a (500 mg, 3.123 mmol) (5 mL) was added, and the reaction was carried out overnight at room temperature. Saturated ammonium chloride (30 mL) and ethyl acetate (30 mL * 3) were added directly for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 79c (611 mg, yield 81.47%).

[1064] MS M / Z(ESI): 240.9 [M+1] +

[1065] The second step involves the synthesis of compound 79d.

[1066] Compound 79c (200 mg, 0.833 mmol) was dissolved in MeOH (10 mL), and then Pd / C 5% (100 mg, 0.940 mmol) was added. The mixture was reacted overnight at room temperature under hydrogen protection, filtered directly, concentrated, and then column chromatography was used to obtain compound 79d (114 mg, yield 65.13%).

[1067] MS M / Z(ESI): 211.0 [M+1] +

[1068] The third step involves the synthesis of compound 79g.

[1069] Compound 79e (200 mg, 1.200 mmol), compound 79f (154.67 mg, 1.801 mmol), copper acetate (654.09 mg, 3.601 mmol), pyridine (0.291 mL, 3.601 mmol), pyridine nitride (342.48 mg, 3.601 mmol), and 4A molecular sieve (200 mg, 0.060 mmol) were added to DMF (10 mL) and reacted overnight at 100 °C. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with ethyl acetate (10 mL). The filtrate was then added to purified water (30 mL), and extracted with ethyl acetate (30 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 79 g (113 mg, yield 45.55%).

[1070] MS M / Z(ESI): 207.0 [M+1] +

[1071] Step 4: Synthesis of Compound 79

[1072] Compound 79d (90 mg, 0.428 mmol), compound 79g (88.52 mg, 0.428 mmol), and Cs₂CO₃ (418.65 mg, 1.285 mmol) were added to a reaction flask, followed by 1,4-dioxane (10 mL). Then, under nitrogen protection, RuPhos (19.99 mg, 0.043 mmol) and RuPhos Pd G₃ (35.87 mg, 0.043 mmol) were added. The sealed system was heated in an oil bath at 110 °C for 3 h. After cooling to room temperature, purified water (30 mL) and ethyl acetate (30 mL x 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 a white solid compound 79 (11.79 mg, yield 7.24%).

[1073] MS M / Z(ESI): 381.0 [M+1] +

[1074] 1 H NMR (400MHz, DMSO-d6) δ9.07(d,J=1.4Hz,1H),8.66(dd,J=13.6,2.3Hz,1H),8.32(d,J=2.2Hz,1H),7.52(d,J=8.6Hz,1 H),6.55(d,J=8.6Hz,1H),6.01(dd,J=16.8,10.1Hz,1H),5.19–4.85(m,4H),3.44(dt,J=6.5,1.6Hz,2H),2.35(s,3H).

[1075] Example 80

[1076] Synthesis of compound 80c in step one

[1077] Compound 80a (2 g, 9.640 mmol), compound 80b (2.16 g, 19.281 mmol), TBAF (5.04 g, 19.281 mmol), bis(triphenylphosphine)palladium dichloride (0.34 g, 0.482 mmol), and CuI (0.55 g, 2.892 mmol) were reacted overnight at room temperature under nitrogen protection with 40 mL of THF added. 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, concentrated, and purified by column chromatography to obtain compound 80c (1.48 g, 92.14% yield).

[1078] MS M / Z(ESI): 167.0 [M+1] +

[1079] The second step involves the synthesis of compound 80d.

[1080] Compound 80c (1.0 g, 6.002 mmol) was dissolved in DMF (10 mL), and 60% NaH (0.48 g, 12.004 mmol) was added under nitrogen atmosphere. The reaction was carried out at room temperature for 2 h. The reaction was quenched by adding water (20 mL), and then extracted with ethyl acetate (20 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give a light compound 80d (320 mg, yield 32.00%).

[1081] MS M / Z(ESI): 167.0 [M+1] +

[1082] The third step involves the synthesis of compound 80e.

[1083] Compound 80d (300 mg, 1.801 mmol) was dissolved in DMF (10 mL). 60% NaH (144.05 mg, 3.601 mmol) was added in portions under ice bath conditions, and the reaction was maintained at this temperature for 0.5 h. Then, iodomethane (383.37 mg, 2.701 mmol) was added, and the reaction was carried out at room temperature for 2 h. The reaction was quenched directly with saturated ammonium chloride aqueous solution (30 mL), and 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 compound 80e (279 mg, yield: 87.75%).

[1084] MS M / Z(ESI): 181.1 [M+1] +

[1085] Step 4: Synthesis of 80g

[1086] Compound 80e (490 mg, 2.713 mmol), compound 80f (545.05 mg, 4.069 mmol), and Cs2CO3 (1767.72 mg, 5.425 mmol) were mixed with dioxane (30 mL) and water (9 mL). Under nitrogen protection, XPhos PdG3 (114.81 mg, 0.136 mmol) was added, and the mixture was microwaved at 100 °C for 1 h (Note: This reaction was performed in parallel batches, and the reaction solutions were combined after the reaction was completed). Purified water (30 mL) and ethyl acetate (30 mL * 3) were added directly for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 80 g (160 mg, yield 34.2%).

[1087] MS M / Z(ESI): 173.1 [M+1] +

[1088] Step 5: Synthesis of compound 80h

[1089] 80 g (350 mg, 2.032 mmol) of the compound was dissolved in 20 mL of MeOH, and palladium on carbon (5% palladium) (350 mg, 3.289 mmol) was added. The reaction was carried out at room temperature for 2 h under hydrogen protection. The solution was directly filtered and evaporated to dryness to give compound 80 h (326 mg, 92.06%).

[1090] MS M / Z(ESI): 175.1 [M+1] +

[1091] Step 6: Synthesis of compound 80i

[1092] Compound 80h (326 mg, 1.871 mmol) was dissolved in CHCl3 (10 mL), and m-CPBA (484.26 mg, 2.806 mmol) was added. The reaction mixture was allowed to react overnight at room temperature. A saturated sodium thiosulfate solution (40 mL) was added directly to the reaction mixture, and the mixture was stirred for approximately 20 min. Dichloromethane (30 mL x 3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound 80i (327 mg, yield 78.09%). MS M / Z (ESI): 191.1 [M+1] +

[1093] Step 7: Synthesis of compound 80j

[1094] Compound 80i (130 mg, 0.683 mmol) was dissolved in DMF (5 mL), cooled to 0 °C, and oxalyl chloride (173.45 mg, 1.367 mmol) was added dropwise. After the addition was complete, the mixture was allowed to rise to room temperature and reacted for 1 h. Purified water (20 mL) was added directly to the reaction solution, followed by extraction with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 80j (110 mg, yield 77.14%).

[1095] MS M / Z(ESI): 209.0 [M+1] +

[1096] Step 8: Synthesis of Compound 80

[1097] Compound 80j (55 mg, 0.264 mmol), compound 80k (126.93 mg, 0.395 mmol), and K3PO4 (167.82 mg, 0.791 mmol) were added to a reaction flask, along with dioxane (5 mL) and water (0.5 mL). Under nitrogen protection, di(tri-tert-butylphosphine)palladium (15.47 mg, 0.026 mmol) was added, and the mixture was reacted in a microwave oven at 100 °C for 1 h. After cooling to room temperature, the mixture was directly concentrated and purified by column chromatography to give compound 80 (21.35 mg, yield 22.05%).

[1098] MS M / Z(ESI): 368.0 [M+1] +

[1099] 1H NMR (400MHz, DMSO-d6) δ8.23(s,1H),8.09(d,J=1.9Hz,1H),8.04(dd,J=10.8,1.9Hz,1H),6.39(d,J=1.0Hz,1 H),5.18(qd,J=9.0,0.9Hz,2H),3.07(s,3H),2.45–2.38(m,2H),2.37(d,J=1.0Hz,3H),1.01(t,J=7.5Hz,3H).

[1100] Example 81

[1101] Synthesis of compound 81b in step one

[1102] Compound 81a (1000 mg, 6.098 mmol) was added to a sealed tube, followed by ethylamine (5 mL). The tube was sealed and reacted at 120 °C for 24 h. Water (50 mL) was added, and the mixture was extracted with EA (30 mL x 3). The organic phase was concentrated to obtain compound 81b (950 mg, yield 90.25%).

[1103] MS M / Z(ESI): 173.1 [M+1] +

[1104] The second step involves the synthesis of compound 81d.

[1105] Compound 81c (558.01 mg, 1.738 mmol) and compound 81b (200 mg, 1.159 mmol) were dissolved in dioxane (9 mL), and bis(tri-tert-butylphosphine)palladium (59.21 mg, 0.116 mmol), K3PO4 (491.85 mg, 2.317 mmol), and water (3 mL) were added. After purging with nitrogen for 1 min, the mixture was sealed and reacted at 110 °C for 3 h. The mixture was then concentrated and purified by silica gel column chromatography to obtain crude compound 81d (400 mg).

[1106] MS M / Z(ESI): 332.0 [M+1] +

[1107] The third step involves the synthesis of compound 81.

[1108] Compound 81c (400 mg, 1.207 mmol) was dissolved in DCM (10 mL), and TEA (366.55 mg, 3.622 mmol) and 2,2,2-trifluoroacetic anhydride (507.21 mg, 2.415 mmol) were added. The mixture was stirred overnight at room temperature. Water (20 mL) was added, and the mixture was extracted with DCM (20 mL x 3). The mixture was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by silica gel column chromatography to obtain the crude product. The crude product was further prepared to obtain compound 81 (29.36 mg, yield 5.94%).

[1109] MS M / Z(ESI): 409.9 [M+1] +

[1110] 1 H NMR(400MHz,DMSO-d6)δ9.84(s,1H),9.15(d,J=1.9Hz,1H),8.81(dd,J=11.5,2 .0Hz,1H),5.24(q,J=9.0Hz,2H),4.69(q,J=7.2Hz,2H),1.55(t,J=7.2Hz,3H).

[1111] Example 82

[1112] Synthesis of compound 82c in step one

[1113] Compound 82a (500 mg, 3.700 mmol) was dissolved in DMF (5 mL), followed by the addition of K2CO3 (1021.24 mg, 7.400 mmol) and compound 82b (759.45 mg, 4.440 mmol). The reaction was carried out at room temperature for 5 h. The mixture was then extracted directly with purified water (20 mL) and ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 82c (611 mg, 73.31%). MS M / Z (ESI): 226.1 [M+1] +

[1114] The second step involves the synthesis of compound 82e.

[1115] Compound 82c (250 mg, 1.110 mmol), compound 82d (364.94 mg, 1.332 mmol), and K3PO4 (706.75 mg, 3.330 mmol) were reacted with DMSO (15 mL) under N2 protection, followed by the addition of CuI (63.41 mg, 0.333 mmol) and (1R,2R)-N,N'-Dimethyl-1,2-cyclohexanediamine (47.36 mg, 0.333 mmol). The reaction was carried out in an oil bath at 150 °C for 2 h. After cooling to room temperature, purified water (50 mL) was added, followed by extraction with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give a brown solid compound 82e (163 mg, yield 35.11%).

[1116] MS M / Z(ESI): 419.1 [M+1] +

[1117] The third step involves the synthesis of 82g of compound.

[1118] Compound 82e (70 mg, 0.167 mmol) was reacted with 5% palladium on carbon (500 mg, 0.167 mmol) in 8 mL of THF at room temperature under hydrogen atmosphere overnight. The mixture was then filtered directly, and the filter cake was washed with ethyl acetate and dried to obtain compound 82 g (50 mg, yield 91.04%).

[1119] MS M / Z(ESI): 328.9 [M+1] +

[1120] Step 4: Synthesis of Compound 82

[1121] Compound 82 g (30 mg, 0.091 mmol), compound 82 h (15.35 mg, 0.110 mmol), anhydrous copper acetate (II) (33.45 mg, 0.274 mmol), pyridine (0.022 mL, 0.274 mmol), pyridine nitride (26.08 mg, 0.274 mmol), and 4A molecular sieve (30 mg, 0.091 mmol) were reacted with DMF (3 mL) at 100 °C overnight. The molecular sieve was removed by filtration, and the filter cake was washed with ethyl acetate. Then, purified water (30 mL) was added to the filtrate, and after separation, ethyl acetate (30 mL * 2) was added to the aqueous phase for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to prepare compound 82 (3.44 mg, yield 8.41%).

[1122] MS M / Z(ESI): 422.9 [M+1] +

[1123] 1 H NMR(400MHz,Chloroform-d)δ7.95(s,1H),7.90(d,J=2.2Hz,1H),7.54(dd,J=9.6,2.2Hz,1H),7.44–7 .37(m,2H),7.22(d,J=8.1Hz,2H),7.16(d,J=7.4Hz,1H),6.84(d,J=7.3Hz,1H),4.79(q,J=8.4Hz,2H).

[1124] Example 83

[1125] Compound 83 was obtained with reference to Example 82.

[1126] MS M / Z(ESI): 422.9 [M+1] +

[1127] 1 H NMR (400MHz, Chloroform-d) δ8.07 (d, J=1.7Hz, 1H), 7.99–7.86 (m, 2H), 7.52–7. 42(m,3H),7.37–7.29(m,2H),7.03(dd,J=5.6,1.6Hz,1H),4.78(q,J=8.4Hz,2H).

[1128] Example 84

[1129] Synthesis of compound 84c (Step 1)

[1130] Compound 84a (300 mg, 1.44 mmol) was dissolved in 1,4-dioxane (6 mL) and water (3 mL). Compound 84b (274 mg, 1.59 mmol), potassium carbonate (498 mg, 3.60 mmol), and 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (64 mg, 0.09 mmol) were added, and the mixture was reacted overnight at 100 °C. After the reaction was complete, the reaction solution was diluted with water (30 mL), extracted with DCM / MeOH = 20 / 1, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to give compound 84c (160 mg, 63% yield).

[1131] MS M / Z(ESI): 175.05 [M+1] +

[1132] 1H NMR (400MHz, DMSO-d6) δ8.27(d,J=2.4Hz,1H),7.68(d,J=8.8Hz,1H),7.60(d,J=2.0Hz,1H),6.47-6.40(m,2H),5.92(s,2H),3.78(s,3H).

[1133] The second step involves the synthesis of compound 84e.

[1134] Compound 84d (2 g, 10.15 mmol) was dissolved in tetrahydrofuran (30 mL), and compound Boc2O (3.3 g, 15.26 mmol), triethylamine (3.1 g, 30.45 mmol), and DMAP (124 mg, 1.02 mmol) were added. The reaction was carried out at room temperature for 2 h. After the reaction was completed, the reaction solution was diluted with water (100 mL), extracted with ethyl acetate (50 mL * 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to give compound 84e (1.6 g, yield: 53%).

[1135] MS M / Z(ESI): 298.70 [M+1] +

[1136] 1 H NMR (400MHz, DMSO-d6) δ8.36(s,1H),8.08-8.05(m,1H),7.59-7.57(m,1H),5.73-7.48(m,1H),1.62(s,9H).

[1137] The third step involves the synthesis of compound 84f.

[1138] Compound 84c (160 mg, 0.92 mmol) was dissolved in tert-butanol (10 mL), and compound 84e (273 mg, 0.92 mmol), Pd2(dba)3 (84 mg, 0.09 mmol), cesium carbonate (898 mg, 2.75 mmol), and X-Phos (132 mg, 0.28 mmol) were added. The mixture was reacted overnight at 100 °C. After the reaction was complete, the reaction solution was cooled to room temperature, filtered, and the filter cake was washed with dichloromethane. The filtrate was concentrated to obtain compound 84f (300 mg crude product).

[1139] MS M / Z(ESI): 391.15 [M+1] +

[1140] Step 4: Synthesis of Compound 84

[1141] Compound 84f (300 mg) was dissolved in 10 mL of 4 M hydrochloric acid / ethyl acetate solution and reacted at room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the crude product was purified to obtain compound 84 (85 mg, two-step yield 31%).

[1142] MS M / Z(ESI): 291.05 [M+1] +

[1143] 1 H NMR (400MHz, DMSO-d6) δ12.90(s,1H),9.12(s,1H),8.58(d,J=2.4Hz,1H),8.30(s,1H),7.97-7.8 6(m,2H),7.68(s,1H),7.22-7.18(m,1H),7.10-7.00(m,2H),6.61(d,J=2.4Hz,1H),3.83(s,3H).

[1144] Example 85

[1145] Synthesis of compound 85b in step one

[1146] Reactant 85a (8 g, 41.571 mmol) was added to a reaction flask, followed by EtOH (35 mL) and 85% hydrazine hydrate (10.41 g, 176.76 mmol). The mixture was heated to 90 °C and refluxed overnight. After returning to room temperature, the solvent in the reaction system was evaporated, and the residue was added to ice water (35 mL). A large amount of solid precipitated out. The mixture was filtered, washed with ice water, and dried to give a grayish-white solid compound 85b (6.7 g, yield: 85.72%).

[1147] MS M / Z(ESI): 188.1 [M+1] +

[1148] The second step involves the synthesis of compound 85c.

[1149] Reactant 85b (2.0 g, 10.637 mmol) was added to a reaction flask, followed by DCM (100 mL), Et3N (2.15 g, 21.273 mmol), and reactant 2-chloro-2,2-difluoroacetic anhydride (2.84 g, 11.700 mmol). The mixture was stirred at room temperature for 1 h. Then, purified water (15 mL) and DCM (35 mL x 2) were added, and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate, and the solution was evaporated to dryness to obtain an oil. The solution was purified by silica gel column chromatography (PE / EA 0-100%), and evaporated to dryness to obtain a black oily compound 85c (1800 mg, yield: 56.32%).

[1150] MS M / Z(ESI): 299.9 [M+1] +

[1151] The third step involves the synthesis of compound 85d.

[1152] The reactant 85c (1.8 g, 5.990 mmol) was added to a reaction flask, along with POCl3 (20 mL). The mixture was heated to 150 °C and refluxed for 5 h in an oil bath with p-xylene (10 mL). The reaction system was cooled to room temperature, and the solvent was removed by rotary evaporation under reduced pressure to obtain a black oily substance. Sodium bicarbonate solution (100 mL) was added, followed by EA (200 mL * 2). The mixture was separated, and the organic phase was evaporated to dryness. Silica gel was added and the mixture was purified by PE / EA from 0% to 100% to obtain the crude product 85d (800 mg, yield: 47.28%).

[1153] MS M / Z(ESI): 281.9 [M+1] +

[1154] The fourth step: synthesis of compound 85f

[1155] Add reactant 85d (300 mg, 1.062 mmol) to a reaction flask, add dioxane (12 mL) / H2O (4 mL), add reactant 85e (362.03 mg, 1.274 mmol), add PdCl2 (dppf)·CH2Cl2 (86.94 mg, 0.106 mmol), add K3PO4 (450.86 mg, 2.124 mmol), heat to 100 °C under nitrogen protection and stir overnight; return to room temperature, add purified water (15 mL), add EA (35 mL * 2), and separate the layers. Dry the organic phase with anhydrous sodium sulfate, evaporate to dryness, mix with silica gel, purify by silica gel column chromatography, PE / EA (0%-100%), evaporate to dryness to obtain a pale yellow solid crude product 85f (300 mg, yield 78.54%).

[1156] Step 5: Synthesis of Compound 85

[1157] Reactant 85f (80 mg, 0.222 mmol) was added to a reaction flask, along with sodium ethoxide (75.68 mg, 1.112 mmol) and ethanol (10 mL). The mixture was heated to 80 °C and stirred overnight. After returning to room temperature, silica gel was added and the mixture was purified by column chromatography (PE / EA 0-100%) to obtain the crude product. The crude product was dissolved in MeOH (15 mL), purified by reversed-phase prep-HPLC, and lyophilized to obtain compound 85 (4.66 mg, yield: 5.67%).

[1158] MS M / Z(ESI): 369.9 [M+1] +

[1159] 1 HNMR(400MHz,DMSO-d6)δ8.60(d,J=1.4Hz,1H),8.09(dd,J=9.6,1.1Hz,1H),7.9 6–7.87(m,2H),7.63–7.55(m,2H),4.29(q,J=7.1Hz,2H),1.37(t,J=7.1Hz,3H).

[1160] Example 86

[1161] Synthesis of compound 86b (first step)

[1162] Compound 86a (0.5 g, 2.538 mmol) was added to a three-necked flask and dissolved under nitrogen protection by adding 10 mL of THF. The mixture was cooled in an ice bath, and a solution of 3.4 M ethyl magnesium bromide in 2-methyltetrahydrofuran (12.682 mmol, 3.73 mL) was slowly added dropwise. After reacting in an ice bath for 2 h, the reaction was monitored by LCMS to indicate completion. The reaction was quenched by adding 0.5 mL of 6 M HCl and stirred for 2 h. Saturated sodium carbonate aqueous solution (30 mL) was added, and the mixture was extracted with EA (25 mL * 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 86b (560 mg, yield 96.75%).

[1163] MS M / Z(ESI): 228.0 [M+1] +

[1164] The second step involves the synthesis of compound 86c.

[1165] Compound 86b (560 mg, 2.455 mmol) was dissolved in DCM (10 mL), and TEA (0.683 mL, 4.910 mmol) was added. Trifluoroacetic anhydride (0.409 mL, 2.946 mmol) was added under ice bath conditions, and the reaction was carried out at room temperature for 3 min. The reaction was monitored by LC-MS. After concentration, silica gel column chromatography (EA / PE = 0-10%) was used to give compound 86c (600 mg, yield 75.40%).

[1166] MS M / Z(ESI): 324.0 [M+1] +

[1167] The third step involves the synthesis of compound 86d.

[1168] Compound 86c (500 mg, 1.543 mmol) was added to a microwave tube, followed by 10 mL of 3.4 M ammonia in isopropanol. The tube was sealed and reacted overnight at 80 °C. The reaction was monitored by LC-MS. After concentration, the mixture was purified by silica gel column chromatography (pure PE) to give compound 86d (340 mg, yield 72.23%).

[1169] MS M / Z(ESI): 305.0 [M+1] +

[1170] Step 4: Synthesis of Compound 86

[1171] Compound 86d (80 mg, 0.262 mmol) and compound 86e (121.11 mg, 0.524 mmol) were added to a sealed tube, followed by Pd(dppf)Cl2.CH2Cl2 (21.47 mg, 0.026 mmol), K3PO4 (111.31 mg, 0.524 mmol), dioxane (9 mL), and H2O (3 mL). The mixture was purged with nitrogen for 1 min, sealed, and reacted at 90 °C for 1 h, monitored by LC-MS. After cooling to room temperature, purified water (30 mL) was added, and the mixture was extracted with EA (30 mL x 2), washed with saturated brine (20 mL), concentrated, and then subjected to silica gel column chromatography (EA / PE = 0-50%) to obtain the crude product. The crude product was purified by preparative HPLC and lyophilized to obtain compound 86 (50 mg, yield 46.36%).

[1172] MS M / Z(ESI): 412.1 [M+1] +

[1173] 1H NMR (400MHz, DMSO-d6) δ9.03 (s, 1H), 8.82 (d, J = 2.1Hz, 1H), 8.60 (dd, J = 8.8, 2.0Hz, 1H) ,8.33(d,J=8.8Hz,1H),8.33–8.22(m,2H),3.60(q,J=7.4Hz,2H),1.43(t,J=7.4Hz,3H)

[1174] Example 87

[1175] Synthesis of compound 87b (Step 1)

[1176] 87a (50 mg, 0.189 mmol), bromoethane (103 mg, 0.945 mmol), and K2CO3 (130 mg, 0.941 mmol) were suspended in N,N-dimethylformamide (2 mL) and stirred overnight in an oil bath at 95 °C.

[1177] 87a (50 mg, 0.189 mmol), bromoethane (103 mg, 0.945 mmol), and K2CO3 (130 mg, 0.941 mmol) were suspended in acetonitrile (2 mL) and stirred overnight in an oil bath at 95 °C.

[1178] The two batches of reaction solutions were combined, and then ethyl acetate (50 mL) and water (50 mL) were added to the reaction solution. The mixture was shaken to separate into layers. The organic phase was washed successively with water (50 mL * 2) and saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a mixture of compounds 87b and 87c (110 mg, combined yield 99.47%), which was then directly added to the next reaction step.

[1179] MS M / Z(ESI): 293[M+1] +

[1180] Step 2: Synthesis of Compound 87

[1181] A mixture of compounds 87b and 87c (30 mg, 0.102 mmol), compound 87d (28 mg, 0.121 mmol), and sodium carbonate (32 mg, 0.302 mmol) were added to a reaction flask. Then, toluene (2 mL), ethanol (0.5 mL), and water (0.1 mL) were added. The mixture was evacuated three times. Then, Pd(dppf)Cl2.CH2Cl2 (8 mg, 0.010 mmol) was added. The mixture was evacuated three times. The reaction was carried out in an oil bath at 85 °C for 2 hours.

[1182] A mixture of compounds 87b and 87c (80 mg, 0.273 mmol), compound 87d (76 mg, 0.329 mmol), and sodium carbonate (87 mg, 0.819 mmol) were added to a reaction flask. Then, toluene (4 mL), ethanol (1 mL), and water (0.2 mL) were added, and the mixture was evacuated three times. Then, Pd(dppf)Cl2.CH2Cl2 (22 mg, 0.027 mmol) was added, and the mixture was evacuated three times. The mixture was reacted in an oil bath at 85 °C for 2 hours.

[1183] Combine the above reaction solutions, add water (50 mL) and ethyl acetate (50 mL), shake well, separate the layers, extract the aqueous layer with ethyl acetate (50 mL), combine the organic layers, wash with saturated brine (50 mL), dry to anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (developing solvent: petroleum ether: ethyl acetate = 0-50%), followed by preparative thin-layer chromatography (chromatographic solvent: petroleum ether: ethyl acetate = 3:1, 1% triethylamine) to give compound 87 (28.28 mg, yield 21.45%). MS M / Z (ESI): 400 [M+1] +

[1184] 1 H NMR (400MHz, DMSO-d6) δ8.79(s,1H),8.30(d,J=2.3Hz,1H),8.22(dd,J=9.5,1.1Hz,1H),8.15(dd,J=9.6,1 .6Hz,1H),7.98(d,J=8.5Hz,1H),7.83(dd,J=8.6,1.7Hz,1H),4.56(q,J=7.2Hz,2H),1.45(t,J=7.1Hz,3H).

[1185] Example 88

[1186] Synthesis of compound 88c (Step 1)

[1187] Compounds 88a (1000 mg, 5.236 mmol) and 88b (1010 mg, 5.236 mmol) were dissolved in N,N-dimethylformamide (15 mL), followed by the addition of potassium carbonate (1592 mg, 11.518 mmol). The mixture was stirred in an oil bath at 100 °C for 5 hours. Water (100 mL) and ethyl acetate (100 mL) were added to the reaction mixture, and the mixture was shaken well. The layers were separated, and the aqueous layer was extracted with ethyl acetate (50 mL). The organic phases were combined and washed successively with water (50 mL) and saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: PE:EA = 0-40%) to give compound 88c (1300 mg, yield 81.93%).

[1188] MS M / Z(ESI): 303[M+1] +

[1189] The second step involves the synthesis of compound 88e.

[1190] Compound 88c (300 mg, 0.990 mmol), compound 88d (274 mg, 1.188 mmol), and sodium carbonate (315 mg, 2.970 mmol) were added to a reaction flask, followed by toluene (12 mL), ethanol (3 mL), and water (0.3 mL). The mixture was evacuated three times, and then Pd(dppf)Cl2.CH2Cl2 (81 mg, 0.099 mmol) was added. The mixture was evacuated three times and then reacted in an oil bath at 80 °C for 2 hours. Add saturated ammonium chloride aqueous solution (50 mL) and ethyl acetate (50 mL) to the filtrate, shake well and separate into layers. Extract the aqueous layer once with ethyl acetate (30 mL). Combine the organic layers and wash successively with water (50 mL) and saturated brine (50 mL). Dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 0-80%) to give compound 88e (360 mg, yield 88.86%), which is directly added to the next reaction.

[1191] MS M / Z(ESI): 410[M+1] +

[1192] The third step involves the synthesis of compound 88.

[1193] Compound 88e (310 mg, 0.757 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of potassium carbonate (419 mg, 3.030 mmol). The mixture was stirred in an oil bath at 100 °C for 48 hours. A saturated aqueous solution of ammonium chloride (100 mL) and ethyl acetate (100 mL) were added to the reaction mixture, and the mixture was shaken well. The layers were separated, and the organic layer was washed successively with water (100 mL) and saturated brine (100 mL). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (eluent: acetonitrile:water = 20-80%) to give compound 88 (14.08 mg, yield 3.62%).

[1194] MS M / Z(ESI): 390[M+1] +

[1195] 1 H NMR(400MHz, DMSO-d6)δ8.69(s,1H),8.14(dd,J=9.6,1.1Hz,1H),7.98(dd,J=9.6,1.7Hz,1H),7 .63(d,J=1.9Hz,1H),7.42(dd,J=8.2,1.9Hz,1H),7.26(d,J=8.3Hz,1H),1.97(d,J=1.4Hz,3H).

[1196] Example 89

[1197] Synthesis of compound 89b (Step 1)

[1198] Reactant 89a (600 mg, 4.150 mmol) was added to a reaction flask, followed by Et3N (839.97 mg, 8.301 mmol) and TFA (10 mL). The mixture was refluxed in an oil bath at 110 °C with stirring overnight. After cooling to room temperature, purified water (15 mL) and EA (35 mL x 2) were added, and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, mixed with silica gel, and purified by silica gel column chromatography (PE / EA, 0%-100%). The purified phase was then evaporated to dryness to give compound 89b (672 mg, yield: 72.75%).

[1199] MS M / Z(ESI): 223.1 [M+1] +

[1200] The second step involves the synthesis of compound 89d.

[1201] Add reactant 89c (28.5 mg, 0.101 mmol) to a reaction flask, add dioxane (3 mL), add reactant pinacol diboronate (30.68 mg, 0.121 mmol), add PdCl2 (dppf)CH2Cl2 (8.24 mg, 0.010 mmol), add KOAc (19.76 mg, 0.201 mmol), and stir under nitrogen protection to 100 °C for 3 h. After the reaction system is cooled to room temperature, mixed with silica gel, purified by silica gel column chromatography (PE / EA, 0%-100%), and evaporated to dryness to obtain crude product 89d (30 mg, yield: 90.26%), which is a brownish-black viscous solid.

[1202] The third step involves the synthesis of compound 89.

[1203] Reactant 89b (18 mg, 0.081 mmol) was added to a reaction flask, followed by dioxane (3 mL) / H2O (1 mL), reactant 89d (29.37 mg, 0.089 mmol), PdCl2 (dppf).CH2Cl2 (6.62 mg, 0.008 mmol), and K3PO4 (34.33 mg, 0.162 mmol). The mixture was heated to 100 °C under nitrogen protection and stirred for 2 h. After cooling to room temperature, purified water (15 mL) and EA (35 mL * 2) were added, and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, mixed with silica gel, and purified by silica gel column chromatography (PE / EA, 0%-100%). The crude target compound was obtained by evaporation and dissolved in MeOH (15 mL). The mixture was then purified by reverse-phase preparative high-performance liquid chromatography and lyophilized to obtain compound 89 (6 mg, yield: 19.01%).

[1204] MS M / Z(ESI): 391.0 [M+1] +

[1205] 1H NMR (400MHz, DMSO-d6) δ8.78 (d, J=9.8Hz, 1H), 8.31 (dd, J=18.8, 9.2Hz, 3H), 8.22–8.14 (m, 2H).

[1206] Example 90

[1207] The first step involves the synthesis of compound 90b.

[1208] Add 90a (2g, 10.637mmol), toluene (20mL), and 2-chloro-2,2-difluoroacetic anhydride (3.88g, 15.955mmol) to the reaction flask, heat to 110℃ and react overnight; react for 48h; cool down, concentrate the system, add 50mL of water and 50mL of EA, stir for 10min to separate the layers, extract the aqueous phase with 50mL of EA, combine the organic phases, concentrate to dryness, and purify by column chromatography (PE / EA = 0-23%) to give compound 90b (1.7g, yield 56.58%).

[1209] MS M / Z(ESI): 281.9 [M+1] +

[1210] The second step involves the synthesis of compound 90c.

[1211] Add 60% sodium hydroxide (1.06 g, 26.551 mmol) to the reaction flask, slowly add ethanol (10 mL), dissolve, then add 90b (1.5 g, 5.310 mmol), react at 80 °C for 2-3 h; cool, slowly add 3 mL of water to quench, concentrate the system, add 20 mL of water and 20 mL of EA, stir to separate the layers, extract the aqueous phase once with 20 mL of EA, combine the organic phases, concentrate to dryness, and purify by column chromatography (EA / PE = 0-50%) to give compound 90c (product 200 mg, yield 12.9%).

[1212] MS M / Z(ESI): 292.0 [M+1] +

[1213] The third step involves the synthesis of compound 90d.

[1214] Add 90c (200 mg, 0.685 mmol), pinacol diboronate (182.58 mg, 0.719 mmol), potassium acetate (134.40 mg, 1.369 mmol), PdCl2 (dppf)·CH2Cl2 (56.06 mg, 0.068 mmol), and dioxane (2 mL) to a reaction flask. Heat to 90 °C and react for 3 h. Cool and filter (with diatomaceous earth lining) to obtain the mother liquor. Wash with 15 mL of EA, concentrate to dryness, and give compound 90d (300 mg, yield 129%).

[1215] MS M / Z(ESI): 258.1 [M+1] +

[1216] Step 4: Synthesis of Compound 90

[1217] Add 90e (100 mg, 0.355 mmol), 90d (144.28 mg, 0.425 mmol), potassium phosphate (163.27 mg, 0.709 mmol), PdCl2 (dppf), CH2Cl2 (29.02 mg, 0.035 mmol), dioxane and water in a 3:1 ratio (5 mL) to the reaction flask, stir and react at 100 °C for 2 h; cool to room temperature, add 5 mL of water and 5 mL of EA, stir for 10 min to separate the phases, wash the aqueous phase with 5 mL of EA, combine the organic phases, wash with 10 mL of brine, concentrate the organic phase to dryness, and purify by column chromatography, EA / PE = 0-50%, about 40% of the product yielded, giving 200 mg of crude product, which was then prepared and lyophilized to give compound 90 (37.09 mg, yield 25.25%).

[1218] MS M / Z(ESI): 415.1 [M+1] +

[1219] H NMR (400MHz, DMSO-d6) δ8.76 (s, 1H), 8.70 (d, 1H), 8.52-8.54 (d, J = 8Hz, 1H), 8.12-8. 15(dd,J=12Hz,1H),8.14–8.17(m,2H),4.21-4.33(m,2H),1.35-1.39(t,J=16Hz,3H).

[1220] Example 91

[1221] Synthesis of compound 91b (Step 1)

[1222] Compound 91a (600 mg, 2.643 mmol) was dissolved in isopropyl acetate (12 mL), and DIEA (683.1 mg, 5.285 mmol) was added. Then, thionyl chloride (1571.9 mg, 13.213 mmol) was added dropwise. After stirring at room temperature for 2 h, LCMS monitoring showed that the reaction proceeded completely. After concentration, saturated sodium bicarbonate aqueous solution (20 mL) was added, followed by extraction with EA (20 mL x 3), washing with saturated brine (20 mL), drying to anhydrous sodium sulfate, filtration, and concentration to obtain compound 91b (580 mg, yield 89.40%).

[1223] The second step involves the synthesis of compound 91c.

[1224] Chromium trichloride (596.67 mg, 3.768 mmol) was dissolved in THF (15 mL) under nitrogen protection. A 1 M LiAlH4 THF solution (9.344 mL, 9.344 mmol) was added dropwise under ice bath conditions. After stirring for 15 min, DMF (9 mL) and isopropanol (0.45 mL) were added. Finally, a DMF solution of compound 91b (370 mg, 1.507 mmol) (9 mL) was added, and the mixture was stirred at room temperature for 12 h, monitored by LC-MS. Water (30 mL) was added, and the mixture was extracted with EA (20 mL x 3). The organic phase was concentrated and then purified by silica gel column chromatography (PE:EA = 0-1%) to give compound 91c (240 mg, yield 75.45%).

[1225] The third step involves the synthesis of compound 91e.

[1226] Compound 91c (200 mg, 0.948 mmol) and compound 91d (437.68 mg, 1.895 mmol) were added to a sealed tube, followed by Pd(dppf)Cl2.CH2Cl2 (77.58 mg, 0.095 mmol), K3PO4 (402.28 mg, 1.895 mmol), dioxane (9 mL), and H2O (3 mL). The mixture was purged with nitrogen for 1 min, sealed, and reacted at 100 °C for 2 h, monitored by LC-MS. After concentration, the mixture was purified by silica gel column chromatography (PE:EA = 0-75%) to give compound 91e (240 mg, yield 79.83%).

[1227] MS M / Z(ESI): 318.1 [M+1] +

[1228] Step 4: Synthesis of Compound 91

[1229] Compound 91e (200 mg, 0.630 mmol) was dissolved in DCE (10 mL) under nitrogen protection. 1 M diethylzinc toluene solution (1.891 mL) and chloroiodomethane (555.93 mg, 3.152 mmol) were added in an ice bath. The mixture was stirred at room temperature for 1 h, then heated to 65 °C for 3 h, and monitored by LC-MS. The reaction was quenched with saturated ammonium chloride (30 mL), extracted with DCM (20 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by silica gel column chromatography (PE:EA = 0-25%) to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography to obtain compound 91 (8.02 mg, yield 3.84%).

[1230] MS M / Z(ESI): 332.1 [M+1] +

[1231] 1 H NMR (400MHz, DMSO-d6) δ8.59(s,1H),8.11(dd,J=9.6,1.1Hz,1H),7.96(dd,J=9.6,1.6Hz,1H),7.80(d,J=2.1Hz,1H),7.50(dd,J=8.3 ,2.1Hz,1H),6.95(d,J=8.3Hz,1H),2.64(dd,J=8.9,3.9Hz,1H),1.74(s,3H),1.22(dd,J=9.0,5.9Hz,1H),0.34(dd,J=5.9,3.9Hz,1H)

[1232] Example 92

[1233] The first step is the synthesis of compound 92c.

[1234] 60% NaH (304 mg, 7.591 mmol) was dissolved in tetrahydrofuran (10 mL), and the mixture was cooled in an ice-water bath. A tetrahydrofuran solution (10 mL) of compound 92b (1000 mg, 6.326 mmol) was added dropwise, and the mixture was stirred for 30 min. Then, a tetrahydrofuran solution (10 mL) of compound 92a (1670 mg, 7.591 mmol) was added dropwise, and the mixture was stirred overnight at room temperature. A saturated aqueous solution of ammonium chloride (100 mL) and ethyl acetate (100 mL) were added to the reaction mixture in an ice-water bath, and the mixture was shaken well. The layers were separated and washed successively with water (100 mL) and saturated brine (100 mL). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was passed through a silica gel column (eluent: petroleum ether: ethyl acetate = 0-60%) to give compound 92c (140 mg, yield 6.18%).

[1235] MS M / Z(ESI): 358[M+1]+

[1236] The second step involves the synthesis of compound 92d.

[1237] Compound 92c (140 mg, 0.391 mmol) was dissolved in AcOH (5 mL), and then iron (218 mg, 3.910 mmol) was added. The mixture was then heated in an oil bath at 60 °C with stirring for 4 hours. The solution was concentrated to dryness under reduced pressure. A saturated aqueous solution of sodium bicarbonate (50 mL) and ethyl acetate (50 mL) were added to the residue, and the mixture was shaken well. The layers were separated, and the aqueous layer was extracted with ethyl acetate (50 mL). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 92d (110 mg, 95.03% yield), which was directly added to the next reaction.

[1238] MS M / Z(ESI): 296[M+1] +

[1239] The third step involves the synthesis of compound 92e.

[1240] Dissolve 92d (60 mg, 0.203 mmol) in N,N-dimethylformamide (5 mL), cool in an ice-water bath, then add 60% NaH (12 mg, 0.304 mmol), stir for 30 min, then add iodoethane (190 mg, 1.216 mmol), and stir the reaction in an ice-water bath for 2 h. Add saturated ammonium chloride aqueous solution (30 mL) and ethyl acetate (30 mL) to the reaction solution, shake well, extract the aqueous phase with ethyl acetate (30 mL), combine the organic phases, wash successively with water (30 mL) and saturated brine (30 mL), dry to anhydrous sodium sulfate, filter, concentrate under reduced pressure to obtain crude product 92e (80 mg), and directly add to the next reaction.

[1241] MS M / Z(ESI): 324[M+1] +

[1242] Step 4: Synthesis of Compound 92

[1243] Compounds 92e (70 mg, 0.216 mmol) and 92f (55.51 mg, 0.216 mmol) were dissolved in a mixed solvent of toluene (8 mL), ethanol (2 mL), and water (0.5 mL). Then sodium carbonate (69 mg, 0.648 mmol) was added, and the mixture was evacuated and replaced with nitrogen three times. Then Pd(dppf)Cl2.CH2Cl2 (35 mg, 0.043 mmol) was added, and the mixture was evacuated for 5 min. Then the mixture was stirred in an oil bath at 85 °C for 3 h. Add water (50 mL) and ethyl acetate (50 mL) to the reaction solution, shake well, separate into layers, extract the aqueous phase with ethyl acetate (50 mL), combine the organic phases, wash once with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure to dryness, purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate = 0-60%), and then preparatively purify by high performance liquid chromatography (eluent: acetonitrile: water = 10-80%) to give compound 92 (44.06 mg, yield 44.70%).

[1244] MS M / Z(ESI): 457[M+1] +

[1245] 1 H NMR (400MHz, DMSO-d6) δ8.63(s,1H),8.10(d,J=9.6Hz,1H),7.98(dd,J=9.6,1.7Hz,1H),7.58(d,J=2.0Hz,1H),7.47(dd,J=8.3,2.0Hz,1H ),7.33(d,J=8.4Hz,1H),5.90(q,J=7.8Hz,1H),4.30(q,J=7.1Hz,2H),4.16(q,J=7.1Hz,2H),1.39(t,J=7.1Hz,3H),1.23(t,J=7.0Hz,3H).

[1246] Example 93

[1247] Synthesis of compound 93c in the first step

[1248] Compound 93a (500 mg, 1.887 mmol) was dissolved in DMF (10 mL), and Cs₂CO₃ (3073.4 mg, 9.433 mmol) and compound 93b (1160.2 mg, 9.433 mmol) were added. The mixture was reacted at 100 °C for 2 hours. Then, it was diluted with purified 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 (ethyl acetate / petroleum ether = 0-10%) to give compound 93c (550 mg, 95% yield).

[1249] MS m / z(ESI): 307.0 [M+1] +

[1250] The second step involves the synthesis of compound 93d.

[1251] Compound 93c (550 mg, 1.791 mmol) and pinacol diboronate (545.73 mg, 2.149 mmol) were dissolved in dioxane (10 mL), and Pd(dppf)Cl2.CH2Cl2 (146.61 mg, 0.179 mmol) and KOAc (351.51 mg, 3.582 mmol) were added. The system was purged with nitrogen and reacted at 100 °C for 3 hours. After filtration, the filtrate was concentrated to obtain crude compound 93b (900 mg, yield 71%, purity 50%).

[1252] MS m / z (ESI): 355.2 [M+1] +

[1253] The third step involves the synthesis of compound 93.

[1254] Compound 93d (363.78 mg, 1.027 mmol), compound 90c (200 mg, 0.685 mmol), Pd(dppf)Cl2.CH2Cl2 (56.06 mg, 0.068 mmol), K3PO4 (290.68 mg, 1.369 mmol), dioxane (9 mL), and H2O (3 mL) were sequentially added to a sealed tube. After purging the system with nitrogen, the tube was sealed and reacted at 90°C for 2 hours. 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 (ethyl acetate / petroleum ether = 0-80%) to obtain the crude product. The crude product was purified by HPLC (Boston Prime C18, 10% ammonium formate aqueous solution: acetonitrile = 50%-60%) to obtain compound 93 (32.87 mg, yield 11%).

[1255] Compound 90c was prepared according to the synthesis of compound 90c in Example 90.

[1256] MS m / z(ESI): 440.1 [M+1] +

[1257] 1H NMR (400MHz, DMSO-d6) δ8.66(s,1H),8.24(d,J=1.6Hz,1H),8.10(qd,J=9.6,1.4Hz,2H),8.01(d,J=8.5Hz,1H),7.7 3(dd,J=8.5,1.7Hz,1H),4.96(p,J=6.9Hz,1H),4.30(q,J=7.1Hz,2H),1.73(d,J=6.9Hz,6H),1.39(t,J=7.1Hz,3H).

[1258] Example 94

[1259] Synthesis of compound 94b (Step 1)

[1260] Compound 94a (5 g, 17.664 mmol) and pinacol diborate (5.38 g, 21.197 mmol) were added to a sealed tube, followed by Pd(dppf)Cl2.CH2Cl2 (0.72 g, 0.883 mmol), KOAc (3.47 g, 35.329 mmol), and dioxane (50 mL). After purging the system with nitrogen, the tube was sealed and reacted at 100 °C for 3 hours. The mixture was then extracted with water (100 mL) and 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) to obtain compound 94b (5200 mg, yield 89%, purity 80%).

[1261] The second step involves the synthesis of compound 94d.

[1262] Compound 94c (4800 mg, 18.675 mmol) was dissolved in p-xylene (24 mL), and phosphorus oxychloride (8 mL) was added. The mixture was sealed and reacted at 150 °C for 4 hours. After concentration, toluene (30 mL) and triethylamine (5 mL) were added, and the mixture was reacted at 120 °C for 2 hours. After filtration, the filtrate was concentrated under reduced pressure and then subjected to silica gel column chromatography (ethyl acetate / petroleum ether = 0-30%) to give compound 94d (796 mg, yield 18%, purity 85%).

[1263] MS m / z(ESI): 239.0 [M+1] +

[1264] The third step involves the synthesis of compound 94e.

[1265] Compound 94b (2199 mg, 6.661 mmol) and compound 94d (796 mg, 3.33 mmol) were dissolved in dioxane (12 mL), and Pd(dppf)Cl2.CH2Cl2 (136 mg, 0.166 mmol), K3PO4 (1414 mg, 6.662 mmol), and H2O (4 mL) were added. After purging the system with nitrogen, the mixture was sealed and reacted at 70 °C for 2 hours. 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 (ethyl acetate / petroleum ether = 0-80%) to give compound 94e (170 mg, yield 13%, purity 90%).

[1266] MS m / z(ESI): 407.0 [M+1] +

[1267] Step 4: Synthesis of Compound 94

[1268] Compound 94d (50 mg, 0.123 mmol) was dissolved in EtOH (10 mL), and silver tetrafluoroborate (120 mg, 0.616 mmol) was added. The mixture was sealed and reacted overnight at 95 °C under nitrogen protection. Saturated sodium bicarbonate aqueous solution (3 mL) was added, and the mixture was filtered. The filtrate was concentrated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-30%) to give compound 94 (16.95 mg, yield 33%, purity 95%).

[1269] MS m / z(ESI): 417.1 [M+1] +

[1270] 1 H NMR (400MHz, DMSO-d6) δ9.74(d,J=1.6Hz,1H),8.99(d,J=1.6Hz,1H),8.34(d, J=8.5Hz,2H),8.13-8.04(m,2H),4.32(q,J=7.1Hz,2H),1.40(t,J=7.1Hz,3H).

[1271] Example 95

[1272] Synthesis of compound 95b (Step 1)

[1273] Compound 95a (5 g, 32.862 mmol) and sodium perborate (25.28 g, 164.308 mmol) were added to acetic acid (60 mL) and reacted overnight at 60 °C. The reaction was quenched with water (100 mL), 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 purified by silica gel column chromatography to give compound 95b (1.7 g, 28% yield).

[1274] The second step involves the synthesis of compound 95c.

[1275] Compound 95b (1700 mg, 9.334 mmol), 1,1,1-trifluoroprop-2-one (4.177 mL, 46.669 mmol), TBAF (5613.13 mg, 21.468 mmol), and DIEA (2412.77 mg, 18.667 mmol) were dissolved in THF (30 mL) and stirred overnight in an oil bath at 80 °C. The reaction was quenched by adding saturated NH4Cl aqueous solution (50 mL), and extracted with EA (50 mL * 2). The mixture was separated. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to obtain an oily substance. Purification by silica gel column chromatography yielded compound 95c (830 mg, 36% yield).

[1276] MS m / z(ESI): 248.1 [M+1] +

[1277] The third step involves the synthesis of compound 95d.

[1278] Compound 95c (830 mg, 3.358 mmol) was dissolved in methanol (15 mL), and Pd / C 10% (50 mg, 0.470 mmol) was added. The mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction solution was filtered, evaporated to dryness to obtain an oil, and purified by silica gel column chromatography to give compound 95d (700 mg, 96% yield).

[1279] MS m / z(ESI): 218.1 [M+1] +

[1280] The fourth step is the synthesis of compound 95e.

[1281] To a 10 mL solution of acetonitrile containing compound 95d (330 mg, 1.519 mmol) cooled to 0 °C, a 1 mL solution of water containing sulfuric acid (0.422 mL, 3.798 mmol) was added. After stirring for 5 minutes, a 0.5 mL solution of water containing sodium nitrite (241.09 mg, 3.495 mmol) was added dropwise, and the reaction mixture was stirred for another 30 minutes at 0 °C. Then, a 1 mL solution of water containing potassium iodide (1084.55 mg, 6.533 mmol) was added, and the ice bath was removed. After heating to room temperature, the reaction mixture was stirred for another 1 hour. The mixture was diluted with water (50 mL), extracted with EA (50 mL x 2), separated, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain an oily substance. Purification by silica gel column chromatography yielded compound 95e (450 mg, 90% yield).

[1282] Step 5: Synthesis of Compound 95

[1283] Compound 95e (100 mg, 0.305 mmol) was dissolved in dioxane (3 mL) / H2O (0.6 mL), and compound 92f (180.18 mg, 0.701 mmol), K3PO4 (129.40 mg, 0.610 mmol) and Pd(dppf)Cl2.CH2Cl2 (24.95 mg, 0.030 mmol) were added. The reaction mixture was heated to 80 °C and stirred for 1 hour under nitrogen protection. The mixture was concentrated under reduced pressure, purified by silica gel column chromatography, concentrated, and then lyophilized with water to give compound 95 (50.38 mg, yield 40%).

[1284] Compound 92f was prepared according to the synthesis of compound 92f in Example 92.

[1285] MS m / z(ESI): 414.1 [M+1] +

[1286] 1 H NMR (400MHz, Methanol-d4) δ8.39(t,J=1.3Hz,1H),7.86-7.73(m,2H),7.47(d,J=1.8Hz,1H),7.40(dd,J=8.3,2.2Hz,1H ),6.87(d,J=8.3Hz,1H),4.23(q,J=7.1Hz,2H),3.53(d,J=16.7Hz,1H),3.24(s,1H),1.57(s,3H),1.34(t,J=7.1Hz,3H).

[1287] Example 96

[1288] Synthesis of Compound 96 (Step 1)

[1289] Compound 95e (110 mg, 0.335 mmol) was dissolved in dioxane (3 mL) / H2O (0.6 mL), and compound 6c (232.30 mg, 1.006 mmol), K3PO4 (142.34 mg, 0.671 mmol), and Pd(dppf)Cl2.CH2Cl2 (27.45 mg, 0.034 mmol) were added. The reaction mixture was heated to 80 °C and stirred for 1 hour under nitrogen protection. The mixture was concentrated under reduced pressure, purified by silica gel column chromatography, and the product was concentrated and lyophilized with water to give compound 96 (92.7 mg, yield 71%).

[1290] Compound 95e was prepared according to the synthesis of compound 95e in Example 95, and compound 6c was prepared according to the synthesis of compound 6c in Example 6.

[1291] MS m / z(ESI): 388.0 [M+1] +

[1292] 1 H NMR (400MHz, Methanol-d4) δ8.41(s,1H),7.90(dd,J=9.7,1.2Hz,1H),7.84(dd,J=9.6,1.6Hz,1H),7.51(d,J=1.7Hz ,1H),7.44(dd,J=8.4,2.3Hz,1H),6.87(d,J=8.4Hz,1H),3.53(d,J=16.7Hz,1H),3.23(d,J=8.6Hz,1H),1.57(s,3H).

[1293] Example 97

[1294] The first step is the synthesis of compound 97c.

[1295] Compound 97b (200 mg, 0.963 mmol) and bis(triphenylphosphine)palladium dichloride (70 mg, 0.100 mmol) were dissolved in THF (10 mL). Compound 97a (200 mg, 0.98 mmol) was added under nitrogen protection, and the reaction was carried out at 70 °C for 16 hours. After concentration, the mixture was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-5%) to give compound 97c (160 mg, yield 58%).

[1296] The second step involves the synthesis of compound 97.

[1297] Compound 97c (140 mg, 0.496 mmol), compound 25j (255 mg, 0.992 mmol), Pd(dppf)Cl2.CH2Cl2 (58 mg, 0.071 mmol), K3PO4 (210 mg, 0.989 mmol), dioxane (9 mL), and H2O (3 mL) were sequentially added to a sealed tube. After purging the system with nitrogen, the tube was sealed and reacted at 100 °C for 3 hours. Water (40 mL) was added, followed by extraction with ethyl acetate (20 mL * 3). The organic phase was concentrated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-60%) to obtain compound 97 (31.68 mg, yield 15%).

[1298] Compound 25j was prepared according to the synthesis of compound 25j in Example 25.

[1299] MS m / z(ESI): 415.0 [M+1] +

[1300] 1 H NMR (400MHz, DMSO-d6) δ8.81(d,J=1.8Hz,1H),8.74(t,J=1.4Hz,1H),8.42(d,J=8.6Hz,1H),8.13(dd d,J=19.7,9.1,1.5Hz,2H),8.03(dd,J=9.6,1.7Hz,1H),4.30(q,J=7.1Hz,2H),1.38(t,J=7.1Hz,3H).

[1301] Example 98

[1302] Synthesis of compound 98b (Step 1)

[1303] 98a (350 mg, 1.321 mmol), iodoethane (680 mg, 4.360 mmol), and cesium carbonate (1291 mg, 3.962 mmol) were dissolved in acetonitrile (10 mL) and stirred in an oil bath at 50 °C for 2 hours. A saturated aqueous solution of NH4Cl (50 mL) was added, followed by extraction with EA (50 mL x 2). The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to give compound 98b (350 mg, 90% yield).

[1304] MS m / z(ESI): 293.0 [M+1] +

[1305] The second step involves the synthesis of compound 98.

[1306] Compound 98b (110 mg, 0.375 mmol) was dissolved in dioxane (4 mL) / H2O (1 mL), and compound 6c (260.03 mg, 1.126 mmol), K3PO4 (159.33 mg, 0.751 mmol), and Pd(dppf)Cl2.CH2Cl2 (30.73 mg, 0.038 mmol) were added. The reaction mixture was heated to 80 °C and stirred for 2 hours under nitrogen protection. The mixture was concentrated under reduced pressure, purified by silica gel column chromatography, and the product was concentrated and lyophilized to give compound 98 (97.68 mg, yield 65%).

[1307] Compound 6c was prepared according to the synthesis of compound 6c in Example 6.

[1308] MS m / z(ESI): 400.0 [M+1] +

[1309] 1 H NMR (400MHz, Methanol-d4) δ8.67 (s, 1H), 8.03 (t, J = 1.2Hz, 1H), 8.02-7.96 (m, 2H), 7.89 -7.83(m,1H),7.58(dd,J=8.6,1.5Hz,1H),4.55(q,J=7.3Hz,2H),1.48(t,J=7.3Hz,3H).

[1310] Examples 99-100

[1311] The first step was the synthesis of compounds 99c and 99d.

[1312] Compound 99b (1680.75 mg, 6.229 mmol) was dissolved in a mixed solvent of MeOH (12 mL) and H2O (12 mL), heated to 98 °C, and reacted for 30 minutes. Then, compound 99a (500 mg, 2.673 mmol) was added, cooled to room temperature, stirred overnight, filtered directly, and the filter cake was washed with pure water and then dried to obtain a mixture of 99c and 99d (716 mg, yield 97%).

[1313] MS m / z(ESI): 277.0 [M+1] +

[1314] The second step involves the synthesis of compounds 99 and 100.

[1315] A mixture of compounds 99c and 99d (120 mg, 0.433 mmol), compound 6c (200 mg, 0.312 mmol), and K3PO4 (275.82 mg, 1.299 mmol) were dissolved in a mixed solution of dioxane (10 mL) and H2O (3 mL). Under nitrogen protection, Pd(dppf)Cl2.CH2Cl2 (35.46 mg, 0.043 mmol) was added, and the reaction was carried out at 100 °C for 3 hours. After separating the aqueous phase directly, the mixture was concentrated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-50%) to give a mixture of compound 99 and compound 100 (130 mg, yield 78.31%). The above mixture was then separated by preparation (C18, 10 mM NH4HCO3 / methanol) to give compound 99 (27.76 mg, yield 23%) and compound 100 (2.62 mg, 0.006 mmol, yield 2.2%).

[1316] Compound 6c was prepared according to the synthesis of compound 6c in Example 6.

[1317] MS m / z(ESI): 384.1 [M+1] +

[1318] Compound 99: 1 H NMR (400MHz, DMSO-d6) δ9.44(s,1H),9.00(s,1H),8.67(d,J=2.1Hz,1H),8.44(dd,J=8.9,2.1Hz,1H),8.34(d,J=8.8Hz,1H),8.22-8.12(m,2H).

[1319] Compound 100: 1 H NMR (400MHz, DMSO-d6) δ9.55(s,1H),9.14(s,1H),8.86(d,J=2.1Hz,1H),8.60(dd,J=8.9,2.2Hz,1H),8.46(d,J=8.8Hz,1H),8.30(qd,J=9.6,1.4Hz,2H).

[1320] Example 101

[1321] Synthesis of compound 101b in step one

[1322] Compound 101a (400 mg, 1.509 mmol), cyclopropylborate (298.2 mg, 3.471 mmol), and cesium carbonate (1106.4 mg, 3.396 mmol) were dissolved in DCE (10 mL). After stirring at room temperature for 10 minutes, copper(II) acetate (274.1 mg, 1.509 mmol) and pyridine (0.122 mL, 1.509 mmol) were added, and the mixture was stirred at 80 °C for 6 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography to give compound 101b (400 mg, 86% yield). MS m / z (ESI): 307.0 [M+1] +

[1323] The second step involves the synthesis of compound 101.

[1324] Compound 101b (100 mg, 0.328 mmol) was dissolved in dioxane (4 mL) / H2O (1 mL), and compound 6c (227.1 mg, 0.983 mmol), K3PO4 (139.1 mg, 0.656 mmol), and Pd(dppf)Cl2.CH2Cl2 (26.8 mg, 0.033 mmol) were added. The reaction mixture was heated to 80 °C and stirred for 2 hours under nitrogen protection. The mixture was concentrated under reduced pressure, purified by silica gel column chromatography, and the product was concentrated and lyophilized with water to give compound 101 (39.64 mg, yield 29%).

[1325] Compound 6c was prepared according to the synthesis of compound 6c in Example 6.

[1326] MS m / z(ESI): 412.1 [M+1] +

[1327] 1 H NMR(400MHz,Methanol-d4)δ8.67(s,1H),8.07(s,1H),8.04-7.95(m,2H),7.89- 7.82(m,1H),7.59(dd,J=8.6,1.5Hz,1H),3.90-3.77(m,1H),1.22-1.16(m,4H).

[1328] Example 102

[1329] Synthesis of compound 102b in step one

[1330] Compound 97c (130 mg, 0.461 mmol), pinacol diboronate (152 mg, 0.599 mmol), and KOAc (135.7 mg, 1.383 mmol) were dissolved in dioxane (5 mL), and then Pd(dppf)Cl2.CH2Cl2 (37.7 mg, 0.046 mmol) was added. The mixture was purged with nitrogen and stirred in an oil bath at 100 °C for 3 hours. The reaction solution was filtered through diatomaceous earth, washed with ethyl acetate, and 50 mL of ethyl acetate was added to the filtrate. The organic phase was washed successively with 50 mL of water and 50 mL of saturated brine. The solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound 102b, which was used directly in the next reaction.

[1331] Compound 97c was prepared according to the synthesis of compound 97c in Example 97.

[1332] MS m / z(ESI): 330.1 [M+1] +

[1333] The second step involves the synthesis of compound 102.

[1334] Take the crude product 102b (75 mg, 0.228 mmol), compound 89b (71.0 mg, 0.319 mmol), and potassium phosphate (145 mg, 0.683 mmol) obtained in the previous step and add them to the reaction flask. Then add dioxane (4 mL) and water (1 mL), purge with nitrogen, and then add di(tri-tert-butylphosphine)palladium (23 mg, 0.045 mmol). Purge with nitrogen again and react in an oil bath at 108 °C for 3 hours. Add ethyl acetate (50 mL) and water (50 mL) to the reaction solution, shake well, separate into layers, extract the aqueous phase with ethyl acetate (50 mL), combine the organic phases, wash the organic phase with saturated brine (50 mL), dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (ethyl acetate / petroleum ether = 0-80%) to obtain the crude product, which is then purified by high performance liquid chromatography (C18, 0.1% ammonium bicarbonate aqueous solution / acetonitrile) to obtain compound 102 (50.69 mg, yield 57%).

[1335] MS m / z(ESI): 390.1 [M+1] +

[1336] 1 H NMR (400MHz, DMSO-d6) δ9.19(d,J=1.8Hz,1H),8.79(d,J=9.9Hz,1H),8.50(d,J=8.7Hz,1H),8.43(dd,J=8.7,1.9Hz,1H),8.31(d,J=9.9Hz,1H).

[1337] Example 103

[1338] Synthesis of compound 103b in step one

[1339] 103a (5 g, 21.019 mmol), EtOH (20 mL), and hydrazine hydrate (85%, 5.998 mL, 105.094 mmol) were added to the reaction flask, and the mixture was heated to 90 °C and stirred under reflux for 3 hours. After the reaction solution cooled to room temperature, it was concentrated, and the residue was added to pure water (35 mL). A large amount of solid precipitated out. The solid was filtered, washed with pure water, and dried to give compound 103b (3.64 g, 92% yield).

[1340] MS m / z(ESI): 189.1 [M+1] +

[1341] The second step involves the synthesis of compound 103c.

[1342] Compound 103b (1.0 g, 5.29 mmol) was suspended in toluene (10 mL), and then 2,2,2-trifluoroacetic anhydride (1.67 g, 7.937 mmol) was added dropwise. The mixture was stirred in an oil bath at 130 °C for 48 hours. The crude product was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-30%) to give compound 103c (180 mg, yield 13%).

[1343] MS m / z(ESI): 267.0 [M+1] +

[1344] Step 4: Synthesis of Compound 103

[1345] Compound 103c (100 mg, 0.375 mmol), compound 102b (148 mg, 0.450 mmol), Pd(dppf)Cl2.CH2Cl2 (31 mg, 0.038 mmol), and K3PO4 (239 mg, 1.126 mmol) were dissolved in dioxane (5 mL) and H2O (1 mL), and reacted overnight at 80 °C under nitrogen protection. Pure water (20 mL) was added directly to the reaction solution, and the mixture was 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, concentrated, and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-50%) to obtain the crude product. The crude product was then lyophilized to give compound 103 (47.70 mg, yield 33%).

[1346] Compound 102b was prepared according to the synthesis of compound 102b in Example 102.

[1347] MS m / z(ESI): 390.0 [M+1] +

[1348] 1 H NMR (400MHz, DMSO-d6) δ9.83(d,J=1.6Hz,1H),9.20(t,J=1.7Hz,2H),8.54(dd,J=8.7,1.9Hz,1H),8.41(d,J=8.7Hz,1H).

[1349] Example 104

[1350] Synthesis of Compound 104 (Step 1)

[1351] Compound 97c (100 mg, 0.355 mmol) and compound 6c (164 mg, 0.71 mmol) were dissolved in dioxane (9 mL). Under nitrogen protection, K3PO4 (150 mg, 0.707 mmol), H2O (3 mL), and Pd(dppf)Cl2.CH2Cl2 (30 mg, 0.037 mmol) were added, and the mixture was heated to 100 °C and reacted for 3 hours. The mixture was diluted with water (30 mL), extracted with ethyl acetate (15 mL * 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then subjected to silica gel column chromatography (ethyl acetate / petroleum ether = 0-50%) to obtain the crude product. The crude product was then prepared by HPLC (acetonitrile / water = 30%-90%) to obtain compound 104 (3.31 mg, yield 2.4%, purity 95%).

[1352] Compound 97c was prepared according to the synthesis of compound 97c in Example 97;

[1353] Compound 6c was prepared according to the synthesis of compound 6c in Example 6.

[1354] MS m / z(ESI): 389.0 [M+1] +

[1355] 1 H NMR(400MHz,Chloroform-d)δ8.42(s,1H),8.37(d,J=8.5Hz,1H),8.22(s,1H),8.07(d,J=8.7Hz,1H),7.80(dd,J=18.4,8.4Hz,2H)

[1356] Example 115

[1357] Synthesis of compound 115b in step one

[1358] Compound 115a (5 g, 26.592 mmol) was added to a sealed tube, followed by difluoroacetic anhydride (11 mL). The tube was sealed and reacted at 110 °C for 6 hours. The reaction was monitored by LCMS and found to be complete. The pH was adjusted to 8 with saturated sodium carbonate aqueous solution, and the mixture was extracted with ethyl acetate (50 mL * 3). The extract was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0-50%) to give compound 115b (6500 mg, 99% yield).

[1359] MS m / z(ESI): 248.0 [M+1] + .

[1360] The second step involves the synthesis of compound 115.

[1361] Compound 102b (4777.3 mg, 14.514 mmol), compound 115b (3000 mg, 12.095 mmol), Pd(dppf)Cl2.CH2Cl2 (495.1 mg, 0.605 mmol), K3PO4 (5134.7 mg, 24.191 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 90 °C for 6 hours, and the reaction was monitored by LCMS until it was complete. The mixture 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 under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0-50%) to obtain compound 115 (2341.0 mg, 52%).

[1362] Compound 102b was prepared according to the synthesis of compound 102b in Example 102.

[1363] MS m / z(ESI): 371.1 [M+1] + .

[1364] 1 H NMR(600MHz,DMSO-d6)δ9.00(t,J=1.4Hz,1H),8.81(d,J=1.9Hz,1H),8.42(d,J=8 .6Hz,1H),8.16-8.11(m,2H),8.03(dd,J=9.6,1.7Hz,1H),7.84(t,J=51.7Hz,1H).

[1365] Example 116

[1366] 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.

[1367] Experimental Example 1

[1368] 1. Reagents and consumables:

[1369] 1.1 Cell Culture

[1370] Table 1-1: CHO hNav1.6 cell culture

[1371] 1.2 Cell Solution

[1372] Table 1-2: Composition of physiological solutions, extracellular fluid and intracellular fluid

[1373] *200 nM ATXII was added to the extracellular fluid before the experiment to induce a sustained sodium current in hNav1.6.

[1374] 1.3NPC-384 Chip:

[1375] Table 1-3: NPC-384 Chip

[1376] 2. Instruments:

[1377] Instrument Name: SyncroPatch 384PE

[1378] Instrument Description: 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 modular Patch Engine (PE) containing 384 independent amplifiers and a 384-channel Biomek FXP 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.

[1379] 3. Experimental methods:

[1380] 3.1 Experimental Objective

[1381] 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.

[1382] 3.2 Cell Culture

[1383] The CHO cell line stably expressing the hNav1.6 channel was obtained from Shanghai WuXi AppTec Co., Ltd., and the gene information is as follows: Nav1.6 (NM_014191.4). The cells were cultured in an incubator at 37℃ with 5% carbon dioxide, and the culture information is shown in Table 1-1.

[1384] 3.3.1 Cell Preparation

[1385] 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.

[1386] 3.3.2 Solution Preparation

[1387] 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.

[1388] 3.4 Preparation of the test compound

[1389] 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%.

[1390] 3.5 SyncroPatch 384PE whole-cell patch-clamp recording

[1391] The hNav1.6 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.

[1392] 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.

[1393] 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.

[1394] 4. Data Analysis:

[1395] 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:

[1396] (1 - peak tail current recorded after compound perfusion / peak tail current recorded before compound perfusion) × 100% is the mean of the percentage of sustained sodium current inhibition of hNav1.6 recorded for all cells / wells at the same detection concentration. All data are expressed as mean ± standard deviation.

[1397] Final half-maximal inhibitory concentration (IC50) 50 The value was obtained by fitting the Hill equation:

[1398] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[1399] Where Y = inhibition%; Top = 100%; Bottom = 0%; X = compound concentration; IC50 = 100%; 50 = Half-maximal inhibitory concentration; HillSlope = slope.

[1400] 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.

[1401] Experimental results show that the compound of the present invention has a strong inhibitory effect on the continuous sodium current of hNav1.6.

[1402] Experimental Example 2

[1403] 1. Experimental Objective

[1404] Manual patch-clamp technique was used to detect the regulatory activity of test substances on GABAA(α1β3γ2)&GABAA(α2β2γ2)&GABAA(α3β3γ2) receptors.

[1405] 2. Materials and Methods

[1406] 2.1 Reagents

[1407] 2.1.1 Reagent Information

[1408] Table 2-1 Reagent Information

[1409] 2.2 Instrument Information

[1410] Table 2-2 Patch Clamp Systems

[1411] 2.3 Compound Information

[1412] 2.3.1 Information on positive control

[1413] Table 2-3 Information on Positive Controls

[1414] 2.3.2 Solvent information

[1415] Table 2-4 Solvent Information

[1416] 2.3.3 Preparation of the test substance

[1417] Weigh an appropriate amount of the test sample. Calculate the required DMSO volume using the formula: DMSO volume = actual compound mass × purity / (molecular weight × theoretical concentration). Dissolve the test sample in the corresponding volume of DMSO. If solubility issues arise, the stock solution concentration will be adjusted.

[1418] The positive control stock solution and the test substance stock solution were taken out at -20°C and diluted in an appropriate amount of extracellular fluid to serve as working solutions.

[1419] The detection concentration of the test substance is obtained directly by diluting the stock solution concentration with extracellular fluid, or the stock solution needs to be further diluted with DMSO.

[1420] Table 2-5 Storage Conditions

[1421] 2.4 Cell Culture

[1422] Using instantaneous expression of GABA A HEK-293 cell line containing (α2β2γ2) receptor, GABA A (α2β2γ2) receptor cells were constructed in-house by the laboratory of Beijing Aisiyipu Biotechnology Co., Ltd., and their gene information is as follows:

[1423] GABA-α2: NM_000807; GABA-β2: NM_021911; GABA-γ2: NM_198904. Stable expression of GABA. A The HEK-293 cell line containing (α2β2γ2) receptors was cultured in DMEM medium containing 10% fetal bovine serum and 0.3 μg / mL puromycin, 200 μg / mL hygromycin, and 100 μg / mL bleomycin at 37°C and 5% carbon dioxide.

[1424] Cell passage: Remove the old culture medium and wash once with PBS, then add 1 mL of 0.25% Trypsin-EDTA solution and incubate at 37°C for about 1 min. When the cells detach from the bottom of the dish, add about 5 mL of preheated (37°C) complete culture medium. Gently pipette the cell suspension to separate aggregated cells. Transfer the cell suspension to sterile centrifuge tubes and centrifuge at 1000 rpm for 5 min to collect the cells. For expansion or maintenance culture, seed the cells in 6 cm cell culture dishes at a density of 2.5 × 10⁶ cells per dish. 5 100 cells (final volume: 5 mL).

[1425] To maintain the electrophysiological activity of cells, the cell density must not exceed 80%.

[1426] Prior to patch-clamp assay, cells were separated using 0.25% Trypsin-EDTA, and 8 × 10⁸ cells were collected. 3 One cell was seeded onto a coverslip, and 0.5 μg / mL LDOX was added for induction. The cells were then cultured in a 24-well plate (final volume: 500 μL) and tested after 24 hours.

[1427] 2.5 Electrophysiological Recording

[1428] 2.5.1 Record the liquids used

[1429] Extracellular fluid: GABA-001-1

[1430] 140mM NaCl, 5mM CsCl, 2mM CaCl2·2H2O, 1mM MgCl2·6H2O, 5mM HEPES, 10mM D-Glucose, and NaOH to adjust pH to 7.4.

[1431] Intracellular fluid: GABA-001-2

[1432] 130mM CsCl, 0.1mM CaCl2·2H2O, 2mM MgCl2·6H2O, 1.1mM EGTA, 5mM Na2-ATP, 10mM HEPES, CsOH adjust pH=7.2.

[1433] Extracellular fluid was stored at 4°C for 2 weeks. Intracellular fluid was prepared, aliquoted into 1 mL tubes, and stored at -20°C. Freshly thawed intracellular fluid was used daily for experiments. All intracellular fluid was used within three months. After three months, the old intracellular fluid was discarded and freshly prepared.

[1434] 2.5.2 Patch clamp testing

[1435] The voltage stimulation protocol for whole-cell patch-clamp recording of GABA receptor currents is as follows: After whole-cell sealing is achieved, the cell membrane voltage is clamped at -70mV, and recording is performed in gap-free mode by sequentially and rapidly administering GABA EC to the cell surface. X After pre-incubating each drug concentration for 30 seconds, the test substance and GABA EC were administered at increasingly higher concentrations. X The mixed working fluid, and the peak current after GABA saturation. For GABA... A The GABA concentration required for the effect of receptor positive allosteric modulators (PAMs) is generally selected to activate the GABA EC of that receptor subtype. 10 The following steps were performed: Each concentration of the test substance wa...

Claims

1. A fused heteroaryl derivative of formula I or formula II, 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 or formula II is as follows: in, X is independently selected from O, S, NRa, or CRaRa'; Y and K are independently selected from NRa or CRaRa', respectively; E, J, G, and M are each independently selected from N or CRa; E, J, G, and M are each independently selected from CRa; E, J, G, and M are each independently connected to L by at least one of them; L is selected from chemical bonds, alkyl, alkoxy, alkylthio, acyl, acylamino; wherein the alkyl, alkoxy, or alkylthio group is optionally further substituted by one or more groups selected from hydrogen, halogen, nitro, hydroxy, 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; preferably, L is selected from chemical bonds, -CH2-, -CH2CH2-, -CH(CH3)-, -CH2-O-, or -NH-; more preferably, L is selected from chemical bonds; Ra and Ra' are each 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, cycloalkyl, heterocyclic, aryl, or heteroaryl groups, and optionally, they may be further substituted by one or more substituents; R is selected from 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.

2. The fused heteroaryl derivative or its pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer according to claim 1, characterized in that, Ra and Ra' are independently selected from the following: non-existent, alkyl, haloalkyl, alkoxy, haloalkoxy, -CHF2-O-Rb, -O-Rb, -S-Rb, -N(Rb)(Rc), -N(Rb)-C(O)-Rc, -CF2-Rb, -CF2-C(O)-O-Rb, -CF2-C(O)-N(Rb)-S(=O)2-Rc, -CF2-tetrazole, -C(O)-N(Rb) -S(=O)2-Rc, -N(Rb)-C(O)-N(Rb)(Rc), -C(O)-Rb, -C(O)-O-Rb, -C(O)-N(Rb)(Rc), and -N(Rb)-S(=O)2-Rc, -Rb-, -S-CF3, -S-CHF2, -CHF2-S-Rb, cycloalkyl, heterocyclic, aryl or heteroaryl, optionally, may be further substituted by one or more substituents; Preferably, Ra and Ra' are independently selected from -F, -C(CH3)3, -CF3, -CHF2, -O-CF3, -OC(CH3)3, -C(CH2)2OH, -S(=O)2-, Rb, Rc, Rd, Re, and Rf are each independently selected from the group consisting of no presence, 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. Rb, Rc, Rd, Re, and Rf are each independently selected from the group consisting of one or more substituents selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, sulfonyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups.

3. The fused heteroaryl derivative according to any one of claims 1-2, or its pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer, characterized in that, Described R is selected from -C(CH3)3, -CHF2-O-Rb, -O-Rb, -S-Rb, -N(Rb)(Rc), -N(Rb)-C(O)-Rc, -CF2-Rb, -CF2-C(O)-O-Rb, -CF2-C(O)-N(Rb)-S(=O)2 -Rc, -CF2-tetrazolyl, -C(O)-N(Rb)-S(=O)2-Rc, -N(Rb)-C(O)-N(Rb)(Rc), -C(O)-Rb, -C(O)-O-Rb, -C(O)-N(Rb)(Rc), -N(Rb)-S(=O)2-Rc; Preferably, R is selected from Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, Rk, Rm, and Rn are each independently selected from the group that is absent, hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups. They may be further substituted by one or more substituents selected from the group that is absent, hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclic, aryl, or heteroaryl.

4. The fused heteroaryl derivative according to any one of claims 1-3, or its pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer, characterized in that, The aforementioned Selected from The definitions of E, J, G, M, Ra, and Ra' are as described above; Ry' and Rk' are each 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; The aforementioned Selected from The definitions of E, J, G, M, Ra, Ra', Ry', and Rk' are as described above.

5. The fused heteroaryl 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 aforementioned Selected from The definitions of E, J, G, M, X, Y, and K are as described above; Preferably, the Selected from The definitions of X, Y, and K are as described above; Re', Rj', Rg', and Rm' are each independently selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups. They may be further substituted by one or more substituents selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, acylamino, ester, cycloalkyl, heterocyclic, aryl, or heteroaryl groups.

6. The fused heteroaryl 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 aforementioned Selected from The definitions of X, Y, K, Re', Rj', Rg', and Rm' are as described above; Preferably, the ground Selected from The definitions of Ra, Re', Rj', Rg', and Rm' are as described above.

7. The fused heteroaryl 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 aforementioned Selected from The definitions of Ra, Ra', Re', Rj', Rg', and Rm' are as described above.

8. A fused heteroaryl derivative of formula I-1 or formula II-1, 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-1 or formula II-1 is as follows: in, The definitions of X, Y, K, E, J, G, M, and L are as described above; A, B, D, Q, and T are each independently selected from O, S, N, CR0, -C=O, or -S=O; Z is selected from N or CR0; Selected independently R0, R1, R2, R3, R4, and R5 are each 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, they may be further substituted by one or more substituents; R0, R1, R2, R3, R4, and R5 can optionally be linked together to form a ring, and can be further substituted by substituents after ring formation; the ring formation 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.

9. The fused heteroaryl derivative according to claim 8, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, characterized in that, R0, R1, R2, R3, R4, and R5 are each independently selected from the following groups: non-existent, hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, -SF5, -O-CF3, -O-CHF2, -C(O)-O-R6, -O-R6, -S-R6, -Si(CH3)3-O-CF3, -C(O)-R6, -C(O)OH, -N(R6)(R7), -C(O)-N(R6)(R7), -N(R6)-C(O)-R7, -N(R6)-S(=O)2-R7, -S(=O)2-R6, -S(=O)2-N(R6)(R7), -NR6-C(O)-NR7, C 1-4 Alkyl, C 1-3 Alkylthio, C 1-3 Alkoxy, C 2-4 alkenyl, C 2-4 The alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups may optionally be further substituted by one or more substituents. R6 and R7 are each 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.

10. The fused heteroaryl derivative or its pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer according to any one of claims 8-9, characterized in that, The aforementioned Selected from A, B, D, Q, T, Z, L, R1, R2, R3, R4, and R5 are defined as described above; Preferably, the ground Selected from L, R1, R2, R3, R4, and R5 are defined as described above.

10. The fused heteroaryl derivative or its pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer according to any one of claims 8-9, characterized in that... Selected from A, B, D, Q, T, Z, L, R1, R2, R3, R4, and R5 are defined as described above; in, The ring M is selected from cycloalkyl, heterocyclic, aryl or heteroaryl, and optionally, it may be substituted by one or more substituents; Preferably, ring M is selected from cycloalkyl, heterocyclic, aryl, or heteroaryl, and the cycloalkyl, heterocyclic, aryl, or heteroaryl is a spirocyclic, fused, or bridged ring, and optionally may be further substituted by one or more substituents; More preferably, ring M is selected from 3-10 membered cycloalkyl, 3-10 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl, and the 3-10 membered cycloalkyl, 3-10 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl is a spirocyclic, fused, or bridged ring, and optionally may be further substituted by one or more substituents.

11. The fused heteroaryl derivative according to claim 10, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, characterized in that, The aforementioned Selected from L, R1, R2, and R3 are defined as described above; The aforementioned Selected from L, R1, R2, and R5 are defined as described above; The aforementioned Selected from L, R1, R4, and R5 are defined as described above; The aforementioned Selected from L, R3, R4, and R5 are defined as described above.

12. The fused heteroaryl derivative or its pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer according to any one of claims 8-11, characterized in that, The aforementioned Selected from in, L, R1, R2, R3, R4, and R5 are defined as described above; X9, X 12 Selected independently from N or CR 10 ; X1, X2, X3, X4, X5, X6, X7, X8, X 10 X 11 X 13 Selected independently from -O-, -S-, -C(O)-, and -NR- respectively. 11 -、-CR 12 R 13 -or-S(=O)-; n1, n2, n3, n4, n5, n6, n7, n8, n10, n11, and n13 are each independently selected from 0, 1, 2, 3, or 4; R8, R9, R 10 R 11 R 12 R 13 Each group is independently selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, alkenyl, alkynyl, acylamino, ester, cycloalkyl, heterocyclic, aryl or heteroaryl, and optionally may be further substituted by one or more substituents. The aforementioned Selected from Among them, L, R1, R2, R3, R4, R5, X9, X 12 ,X1,X2,X3,X4,X5,X6,X7,X8,X 10 X 11 X 13 ,n1,n2,n3,n4,n5,n6,n7,n8,n10,n11,n13,R8,R9,R 10 R 11 R 12 R 13 The definition is as described above; The aforementioned Selected from Among them, L, R1, R2, R3, R4, R5, X9, X 12 ,X1,X2,X3,X4,X5,X6,X7,X8,X 10 X 11 X 13 ,n1,n2,n3,n4,n5,n6,n7,n8,n10,n11,n13,R8,R9,R 10 R 11 R 12 R 13 The definition is as described in this article; The aforementioned Selected from Among them, L, R1, R2, R3, R4, R5, X9, X 12 ,X1,X2,X3,X4,X5,X6,X7,X8,X 10 X 11 X 13 ,n1,n2,n3,n4,n5,n6,n7,n8,n10,n11,n13,R8,R9,R 10 R 11 R 12 R 13 The definition is as described in this article.

13. The fused heteroaryl derivative according to claim 12, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, characterized in that, The aforementioned Selected from in, The definitions of L, A, T, Q, Z, R1, R2, and R5 are as described in this article; W1, W2, W3, W4, W5, W6, W7, W8, W 10 W 11 W 13 W 14 Selected independently from -O-, -S-, -C(O)-, and -NR- respectively. 17 -、-CR 18 R 19 -、-S(=O)-、-BR 18 R 19 -、-PR 17 R 18 R 19 -or-SiR 18 R 19 -; Selected independently R 14 R 15 R 16 R 17 R 18 R 19 Each group is independently selected from the groups that are absent, hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, alkenyl, alkynyl, acylamino, ester, cycloalkyl, heterocyclic, aryl, or heteroaryl, and optionally may be further substituted by one or more substituents. Preferably, the Selected from The definitions of L, A, T, Q, R1, R2, and R5 are as described in this article; R 20 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 R 29 R 30 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 39 R 71 R 72 R 73 R 74 R 75 R 76 R 77 R 78 R 79 R 80 R 81 R 82 R 83 R 84 Each group is independently selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, alkenyl, alkynyl, acylamino, ester, cycloalkyl, heterocyclic, aryl or heteroaryl, and optionally may be further substituted by one or more substituents. More preferably, the Selected from in, The definitions of L, A, T, Q, R1, R2, and R5 are as described in this article; R 40 R 41 R 42 R 43 R 44 R 45 R 46 R 47 R 48 R 49 R 50 R 51 R 52 R 53 R 54 R 55 R 56 R 57 R 58 R 59 R 60 R 61 R 62 R 63 R 64 R 65 R 66 R 67 R 68 R 69 R 70 Each group is independently selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, sulfonyl, alkenyl, alkynyl, acylamino, ester, cycloalkyl, heterocyclic, aryl, or heteroaryl, and optionally may be further substituted by one or more substituents.

14. A fused heteroaryl derivative of formula I-2 or formula II-2, 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-2 or formula II-2 is as follows: in, The definitions of E, J, G, M, L, A, B, D, T, Q, Z, R1, R2, R3, R4, R5, Ra, and Ra' are as described above.

15. A fused heteroaryl derivative of formula I-3, II-3, I-4 or II-4, or a pharmaceutically acceptable salt thereof, a prodrug, a solvate, a hydrate, a tautomer, or a stereoisomer, wherein the structural formula of formula I-3, II-3, I-4 or II-4 is as follows: in, L, A, B, D, T, Q, R1, R2, R3, R4, R5, Ra, Ra', Re', Rg', and Rm' are defined as described above.

16. A fused heteroaryl derivative of formula I-5, II-5, I-6 or II-6, or a pharmaceutically acceptable salt thereof, a prodrug, a solvate, a hydrate, a tautomer, or a stereoisomer, wherein the structural formula of formula I-5, II-5, I-6 or II-6 is as follows: in, The definitions of L, R1, R2, R3, R4, R5, Ra, Ra', Re', Rg', and Rm' are as described above.

17. The fused heteroaryl 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:

18. A pharmaceutical composition comprising the fused heteroaryl derivative of any one of claims 1-17 or a pharmaceutically acceptable salt thereof, a prodrug, a solvate, a hydrate, a tautomer, or a stereoisomer.

19. Use of the fused heteroaryl derivatives according to any one of claims 1-17, or as 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; and / or It is used in GABAA receptor agonists, or in the preparation of drugs that agonize GABAA receptors; Preferably, it is used as an inhibitor of Nav1.1, Nav1.2, Nav1.3, Nav1.4, Nav1.5, Nav1.6, and Nav1.8, or for the preparation of drugs that inhibit Nav1.1, Nav1.2, Nav1.3, Nav1.4, Nav1.5, Nav1.6, and Nav1.8; and / or It is used as an agonist of GABA-α1, GABA-α2, GABA-α3, and GABA-α5 receptors, or for the preparation of drugs that agonize GABA-α1, GABA-α2, GABA-α3, and GABA-α5 receptors.

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

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