CN118715221A - Tricyclic compounds and their applications - Google Patents

Abstract

Relates to a tricyclic compound shown in a formula (O), a pharmaceutical composition containing the compound as an active ingredient and application thereof. The compounds are excellent TEAD inhibitors and are useful in the treatment of tumors.

Description

Tricyclic compounds and their applications

Citation of Related Applications

This application claims the priority of Chinese patent application No. 202210113616.4 filed on January 30, 2022, with invention name “TEAD inhibitors” and Chinese patent application No. 202211572946.6 filed on December 8, 2022, with invention name “Tricyclic compounds and their applications”, the entire contents of which are incorporated herein by reference in their entirety.

Technical Field

The invention belongs to the field of medicinal chemistry, and in particular relates to tricyclic compounds and applications thereof.

Background Art

The Hippo signaling pathway regulates many biological processes, including cell proliferation, survival, differentiation, organ size, and tissue homeostasis. The pathway consists of a complex cascade of serine/threonine protein kinases, including serine threonine kinase 3 (STK3) and STK4. These kinases form a complex with the adaptor protein salvador homolog 1 (SAV1) that phosphorylates and activates the effector protein LATS1/2. Activated LATS1/2 binds to MOB kinase activator 1A/B (MOB1A/B) and inhibits the transcriptional cofactor yes-associated protein (YAP1) and transcriptional coactivator with PDZ binding motif (TAZ or WWTR1). When the Hippo pathway is “off,” phosphorylated YAP/TAZ is retained in the cytoplasm and may undergo proteolytic degradation. When the Hippo pathway is “on,” unphosphorylated YAP/TAZ enters the nucleus and binds to the transcription factor TEA DNA binding protein (TEAD1-4). Dysregulation of the Hippo pathway leads to increased activity of YAP/TAZ, which is associated with tumorigenesis, hyperproliferation, cell invasion, metastasis, and chemoresistance.

The TEAD transcription factor family is the final effector of the Hippo pathway, which regulates the expression of target genes (Kras, Braf, Ctgf, Cyr6, Axl, Myc, etc.) by integrating and coordinating multiple signal transduction pathways (including Hippo, Wnt, TGFβ and EGFR), thereby mediating tumor growth, metastasis, and tissue homeostasis. Numerous clinical studies have found that TEAD is highly expressed in a variety of solid tumors, including prostate cancer, gastric cancer, breast cancer, germ cell tumors, head and neck squamous cell carcinoma, renal cell carcinoma, etc. Due to its high correlation with clinical pathological parameters of human malignant tumors, TEAD can be used as a prognostic biomarker for solid tumors. The Hippo pathway is an important anti-tumor target discovered in the past decade. Compared with the regulators upstream of the Hippo signaling pathway, inhibitors targeting TEAD-YAP may more effectively and directly correct the dysregulated Hippo signaling pathway, thereby achieving the purpose of tumor treatment.

There is a continuing need for new compounds that act as TEAD inhibitors.

Summary of the invention

One aspect of the present application relates to a class of compounds that can bind to TEAD and act as TEAD inhibitors. Another aspect of the present application relates to methods for preparing the compounds described herein. Another aspect of the present application relates to pharmaceutical compositions comprising the compounds of the present invention as active ingredients, and clinical applications of the compounds of the present invention or pharmaceutical compositions for tumor treatment.

In the first aspect, the present application relates to the compound represented by the following general formula O:

or a tautomer, a stereoisomer, a geometric isomer, an enantiomer, a diastereomer, a racemate, a prodrug, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a hydrate, an ester, an isotope, or a metabolite thereof, wherein:

The Ao ring is selected from a 5-6 membered heteroaryl, a 5-6 membered heterocyclic group, a phenyl group, and the Ao ring is optionally substituted by 1-3 substituents selected from Rx, Ry, Rz, and Rm; preferably, the Ao ring is selected from a 5-membered heteroaryl, a 5-membered unsaturated heterocyclic group, a 6-membered saturated heterocyclic group, a phenyl group, and a pyridyl group, and the Ao ring is optionally substituted by 1-3 substituents selected from Rx, Ry, Rz, and Rm; more preferably, the Ao ring is selected from a 5-membered heteroaryl, a 5-membered unsaturated heterocyclic group, a 6-membered saturated heterocyclic group Preferably, the Ao ring is selected from a 5-membered heteroaryl, a 5-membered unsaturated heterocyclic group, a thiomorpholinyl, a tetrahydrothiopyranyl, a phenyl, a pyridyl, the 5-membered heteroaryl contains 2-4 heteroatoms selected from N, O, and S, and the Ao ring is optionally substituted by 1-3 substituents selected from Rx, Ry, Rz, and Rm; further preferably, the Ao ring is selected from a 5-membered heteroaryl, a 5-membered unsaturated heterocyclic group, a thiomorpholinyl, a tetrahydrothiopyranyl, a phenyl, and a pyridyl, the 5-membered heteroaryl contains 2-4 heteroatoms selected from N, O, and S, and satisfies any one of the following conditions (1)-(3):

(1) When the Ao ring is selected from a 5-membered heteroaryl group, the Ao ring is optionally substituted by Rx,

(2) When the Ao ring is selected from a 5-membered unsaturated heterocyclic group, any one of the following conditions (2-1) to (2-5) is satisfied:

(2-1) The Ao ring is optionally substituted by Rm;

(2-2) The Ao ring is optionally substituted by Ry, Rz and Rm;

(2-3) The Ao ring is optionally substituted by Ry and Rm;

(2-4) The Ao ring is optionally substituted by 2 Rm;

(2-5) The Ao ring is optionally substituted by Rz;

(3) When the Ao ring is selected from thiomorpholinyl, tetrahydrothiopyranyl, phenyl, and pyridyl, the Ao ring is optionally substituted by 1-2 substituents selected from Rz and Rm;

Most preferably, the Ao ring is selected from a 5-membered heteroaryl, a 5-membered unsaturated heterocyclic group,

The 5-membered heteroaryl group is selected from The 5-membered unsaturated heterocyclic group is selected from And any one of the following conditions (1)-(3) is met:

(1) When the Ao ring is selected from a 5-membered heteroaryl group, the Ao ring is optionally substituted by Rx,

(2) When the Ao ring is selected from a 5-membered unsaturated heterocyclic group, any one of the following conditions (2-1) to (2-5) is satisfied:

(2-1) The Ao ring is optionally substituted by Rm;

(2-2) The Ao ring is optionally substituted by Ry, Rz and Rm;

(2-3) The Ao ring is optionally substituted by Ry and Rm;

(2-4) the Ao ring is optionally substituted by 2 Rm;

(2-5) The Ao ring is optionally substituted by Rz;

(3) When the Ao ring is selected from thiomorpholinyl, tetrahydrothiopyranyl, phenyl, and pyridyl, the Ao ring is optionally substituted by 1-2 substituents selected from Rz and Rm;

Wherein, Rx is selected from C1-C6 alkyl, 4-6 membered saturated heterocyclic group (preferably, the 4-6 membered saturated heterocyclic group contains 1 heteroatom selected from N, O, S), -C(＝O)NRaRb, -S(＝O) ₂ NRaRb, carboxyl (-COOH), ester group (-CO-O-C1-C6 alkyl), hydroxyl, -NRaC(＝O)Rc, and the Rx is optionally substituted by 1-2 substituents selected from Rn; preferably, Rx is selected from methyl, ethyl, oxetanyl, tetrahydropyrrolyl, tetrahydropyranyl, piperidinyl, -C(＝O)NRaRb, -NRaC(＝O)Rc, -S(＝O) ₂ NRaRb, carboxyl (-COOH), ester group (-CO-O-C1-C6 alkyl), hydroxyl;

Rn is selected from C1-C6 alkyl, -NRaRb, -C(=O)NRaRb, oxo, 5-6 membered saturated heterocyclic group (preferably, the 5-6 membered saturated heterocyclic group contains 2 heteroatoms selected from N, O, S), C1-C6 alkoxy, carboxyl, hydroxyl; preferably, Rn is selected from methyl, ethyl, -NRaRb, -C(=O)NRaRb, oxo, morpholinyl, methoxy, hydroxyl, carboxyl;

Ra, Rb, Rc are each independently selected from H, C1-C6 alkyl, cyano, C3-C6 cycloalkyl, or Ra, Rb and the carbon atom to which they are commonly attached together form azetidine, and the azetidine is optionally substituted with hydroxyl; preferably, Ra, Rb, Rc are each independently selected from H, methyl, cyano, cyclopropyl, or Ra, Rb and the carbon atom to which they are commonly attached together form azetidine, and the azetidine is optionally substituted with hydroxyl;

Most preferably, Rx is selected from hydroxy, methyl,

Ry is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxy, C1-C6 alkyl substituted by 1-6 halogens, C1-C6 alkyl substituted by 1-6 deuteriums, C1-C6 alkyl substituted by C3-C6 cycloalkyl, C1-C6 alkyl substituted by C6-C10 aryl, substituted C1-C6 alkyl, 4-6 membered saturated heterocyclic group; preferably, Ry is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxyl, C1-C6 alkyl substituted by 1-6 halogens, C1-C6 alkyl substituted by 1-6 deuteriums, C1-C6 alkyl substituted by C3-C6 cycloalkyl, C1-C6 alkyl substituted by C6-C10 aryl, More preferably, Ry is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxy, C1-C6 alkyl substituted by 1-3 halogens, C1-C6 alkyl substituted by 1-3 deuteriums, C1-C6 alkyl substituted by cyclopropyl, C1-C6 alkyl substituted by phenyl, A 5-6 membered saturated heterocyclic group containing 1 heteroatom; further preferably, Ry is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxy, C1-C6 alkyl substituted by 1-3 halogens, C1-C6 alkyl substituted by 1-3 deuteriums, C1-C6 alkyl substituted by cyclopropyl, C1-C6 alkyl substituted by phenyl, tetrahydropyrrolyl, piperidinyl; most preferably, Ry is selected from methyl, -CHF ₂ , -CF ₃ , -CD ₃ , -CH ₂ CH ₃ , -CH ₂ CHF ₂ , -CH ₂ CF ₃ ,

Rz is selected from C1-C6 alkyl, halogen, Preferably, Rz is selected from methyl, Br, Or, Ry, Rz and the carbon atoms to which they are commonly connected together form a 4-6-membered saturated carbocyclic ring or a 4-6-membered saturated heterocyclic ring; or preferably, Ry, Rz and the carbon atoms to which they are commonly connected together form a 4-6-membered saturated carbocyclic ring or a 4-6-membered saturated heterocyclic ring, wherein the 4-6-membered saturated heterocyclic ring contains 1 heteroatom; or more preferably, Ry, Rz and the carbon atoms to which they are commonly connected together form cyclobutane, cyclopentane, cyclohexane, piperidine or tetrahydropyran; or most preferably, Ry, Rz and the carbon atoms to which they are commonly connected together form Among them, the carbon atom 1' is the carbon atom connected to Ry and Rz; Rm is an oxo group;

Most preferably, the Ao ring and its optional substituents as a whole are selected from the following:

Bo ring is selected from: It is optionally substituted by 1-3 substituents selected from the group consisting of sulfur pentafluoride, -OH, C1-C6 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, C1-C6 alkyl substituted with 1-6 halogens, C1-C6 alkoxy substituted with 1-6 halogens, halogen, nitro, cyano, and amino;

Preferably, the above It is optionally substituted by 1-2 substituents selected from the group consisting of: sulfur pentafluoride, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, C1-C6 alkoxy substituted with 1-6 halogens, halogen; more preferably, the above Optionally substituted by 1-2 substituents selected from: pentafluorosulfur, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, C1-C6 alkoxy substituted with 1-6 halogens, halogen; or the above Optionally substituted with 1-2 substituents selected from: C1-C6 alkyl, C1-C6 alkyl substituted with 1-6 halogens, halogen;

More preferably, the above Optionally substituted by 1-2 substituents selected from: -CF ₃ , -Cl, -SF ₅ , -CH ₃ , -F, -OCH ₃ , -OCF ₃ ; or the above Optionally substituted by 1-2 substituents selected from: -CF ₃ , -CH ₃ , -F,

More preferably, the above The substitution positions of the substituents thereon are: 2-position monosubstitution, 3-position monosubstitution, 5-position monosubstitution, 4-, 5-position disubstitution, 5-, 6-position disubstitution, 2-, 5-position disubstitution, 3-, 5-position disubstitution; The substitution positions of the substituents thereon are 3-position monosubstitution and 5-position monosubstitution; The substitution position of the substituent thereon is 5-position monosubstitution; The substitution position of the substituent thereon is 6-monosubstitution; The substitution position of the substituent thereon is mono- or di-substituted at the 5- or 6-position; The substitution position of the substituent thereon is 5-position monosubstitution; The substitution position of the substituent thereon is 5-position monosubstitution; The substitution position of the substituent thereon is 5-position monosubstitution; The substitution position of the substituent thereon is 5-position monosubstitution; The substitution position of the substituent thereon is 5-position monosubstitution; The substitution positions of the substituents thereon are 4-position monosubstitution and 5-position monosubstitution; The substitution position of the substituent thereon is 3-position monosubstitution;

Most preferably, the Bo ring is selected from:

The Co ring is selected from 5-membered heteroaromatic ring, 6-membered partially unsaturated heterocyclic ring; preferably, the 5-membered heteroaromatic ring is selected from Preferably, the 6-membered partially unsaturated heterocyclic ring is

A ₁₀ , A ₂₀ , A ₃₀ , and A ₄₀ are independently selected from: N, CH, wherein at most 3 of them are N;

L ₀ is selected from a direct bond, NH, O, S; preferably, L ₀ is selected from a direct bond, NH;

Ro is selected from the group consisting of aminosulfonyl substituted by 1-2 C1-C6 alkyl groups on N, carbamoyl substituted by 1-2 C1-C6 alkyl groups on N, C1-C5 heteroaryl, C1-C6 alkoxy, C1-C6 alkoxy substituted by hydroxy, C1-C6 alkoxy substituted by 5-6 membered heteroaryl, C3-C5 Heterocyclyloxy, carboxyl (-COOH), ester (-CO-O-C1-C6 alkyl), hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, C1-C6 alkyl substituted with cyano, C1-C6 alkoxy substituted with 1-6 halogens, halogen, cyano, nitro, oxo, C2-C6 alkenyl, C1-C6 alkyl substituted with C6-C10 aryl, 5-6 membered heterocyclyl, C1-C6 alkyl substituted with amino; C3-C5 heterocyclyl The alkyl is arbitrarily substituted by C1-C3 alkyl, the C6-C10 aryl is arbitrarily substituted by 1-6 halogens, and the 5-6-membered heterocyclic group is arbitrarily substituted by C1-C3 alkyl or hydroxyl; or two Ro, together with the atoms to which they are connected, form a C6-C10 aromatic ring, a partially unsaturated C5-C6 carbocyclic ring, a partially unsaturated 5-6-membered heterocyclic ring or a 5-6-membered heteroaromatic ring, wherein the partially unsaturated C5-C6 carbocyclic ring, the partially unsaturated 5-6-membered heterocyclic ring or the 5-6-membered heteroaromatic ring are each optionally substituted by 1-6 groups selected from halogen and deuterium; more preferably, Ro is selected from: N aminosulfonyl substituted by 1-2 C1-C6 alkyl groups, carbamoyl substituted by 1-2 C1-C6 alkyl groups on N, pyridyl C1-C6 alkoxy, C1-C6 alkoxy substituted by hydroxy, C3 heterocyclyloxy, carboxyl (-COOH), ester group (-CO-O-C1-C6 alkyl), hydroxy, amino, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkyl substituted by 1-3 halogens, C1-C6 alkyl substituted by cyano, halogen, cyano, oxo, C2-C6 alkenyl, C1-C6 substituted by phenyl 1-C6 alkyl, C1-C6 alkyl substituted by amino, tetrahydropyrrolyl, piperazinyl, wherein C3 heterocyclyl is arbitrarily substituted by C1-C3 alkyl, tetrahydropyrrolyl is arbitrarily substituted by hydroxyl, piperazinyl is arbitrarily substituted by C1-C3 alkyl; or two Ro, together with the atoms to which they are connected, form a benzene ring, a partially unsaturated C5-C6 carbocycle, a partially unsaturated 5-6-membered heterocycle or a 5-membered heteroaromatic ring, wherein the partially unsaturated C5-C6 carbocycle and the partially unsaturated 5-6-membered heterocycle are each optionally substituted by 1-6 groups selected from halogen (preferably -F) and deuterium;

Most preferably, Ro is selected from: oxo, -OCH ₃ , -CH ₃ , -F, -Cl, -CN, -OH, -NH ₂ , -COOH, -COOCH ₃ , -CH ₂ CH ₃ , -CF ₃ , -CHF ₂ , Or two Ro together with the atoms they are attached to form:

In some embodiments of the present application, the Ao ring and its optional substituents as a whole are selected from Preferably, the Ao ring and its optional substituents as a whole are selected from Most preferably, the Ao ring and its optional substituents as a whole are

In some embodiments of the present application, the compound of formula O is the following formula Oc:

The Aoc ring and its optional substituents as a whole are selected from Preferably, the Aoc ring and its optional substituents as a whole are selected from Most preferably, the Aoc ring and its optional substituents as a whole are

The definition of the Co ring is the same as that of the Co ring in the above formula O; the definition of Ro is the same as that of Ro in the above formula O.

In some embodiments of the present application, the compound of formula Oc is the following formula Occ:

The Aocc ring and its optional substituents as a whole have the same definition as the Aoc ring and its optional substituents as a whole in the above formula Oc; _A10 , _A20 , _A30 , _A40 have the same definition as _A10 , _A20 , _A30 , _A40 in the above formula O; and Ro has the same definition as Ro in the above formula O.

In some embodiments of the present application, the compound of formula O is the following formula O-1:

or a tautomer, a stereoisomer, a geometric isomer, an enantiomer, a diastereomer, a racemate, a prodrug, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a hydrate, an ester, an isotope, or a metabolite thereof of the compound,

wherein: the definition of Ao ring is the same as the definition of Ao ring in the above formula O; the definition of Bo ring is the same as the definition of Bo ring in the above formula O; the definition of Co ring is the same as the definition of Co ring in the above formula O; the definition of _L0 is the same as the definition of _L0 in the above formula O; Ro ₁₁ , Ro ₁₂ and the atoms connected to them together form a C6-C10 aromatic ring, a partially unsaturated C5-C6 carbocyclic ring, a partially unsaturated 5-6-membered heterocyclic ring or a 5-6-membered heteroaromatic ring, wherein the partially unsaturated C5-C6 carbocyclic ring, the partially unsaturated 5-6-membered heterocyclic ring or the 5-6-membered heteroaromatic ring are each optionally substituted by 1 to 6 groups selected from halogen and deuterium; preferably, Ro ₁₁ , Ro Ro 11 , _{Ro 12} and the atoms to which they are connected together form a benzene ring, a partially unsaturated C5-C6 carbocycle, a partially unsaturated 5-6-membered heterocycle or a 5-membered heteroaromatic ring, wherein the partially unsaturated C5-C6 carbocycle and the partially unsaturated 5-6-membered heterocycle are each optionally substituted by 1-6 groups selected from halogen and deuterium; or preferably, Ro ₁₁ , Ro ₁₂ and the atoms to which they are connected together form a partially unsaturated C5-C6 carbocycle or a partially unsaturated 5-6-membered heterocycle, wherein the partially unsaturated C5-C6 carbocycle and the partially unsaturated 5-6-membered heterocycle are each optionally substituted by 1-6 groups selected from halogen and deuterium; more preferably, Ro ₁₁ , Ro ₁₂ and the atoms to which they are connected together form:

Most preferably, Ro ₁₁ , Ro ₁₂ and the atoms to which they are attached together form:

In some embodiments of the present application, the compound of formula O is the following formula I:

The definition of A1 ring is the same as that of Ao ring in the above formula O; the definition of B1 ring is the same as that of Bo ring in the above formula O; the definition of _L1 is the same as that of _L0 in the above formula O; _A1 , _A2 , _A3 , _A4 are independently selected from: N, CH, of which at most 3 are N; the definition of _R1 is the same as that of Ro in the above formula O.

In some embodiments of the present application, the compound of formula I is the following formula Ic:

The _A1c ring and its optional substituents as a whole are defined the same as the Aoc ring and its optional substituents as a whole in the above formula Oc; _A1 , _A2 , _A3 , _A4 are independently selected from: N, CH, of which at most 3 are N; _R1 is defined the same as _R1 in the above formula I.

In some embodiments of the present application, the compound of formula I is the following formula I-1:

A11 ring is selected from 5-membered heteroaryl, 5-membered unsaturated heterocyclic group, The 5-membered heteroaryl group is selected from The 5-membered unsaturated heterocyclic group is selected from And any one of the following conditions (1)-(2) is met:

(1) When the A11 ring is selected from a 5-membered heteroaryl group, the A11 ring is optionally substituted by Rx,

(2) When the A11 ring is selected from a 5-membered unsaturated heterocyclic group, the A11 ring is optionally substituted by Rm or Rz, or optionally substituted by Ry and Rm;

Wherein, Rx is selected from methyl,

Ry is methyl; Rz is selected from halogen (preferably Br); Rm is oxo;

Preferably, the A11 ring and its optional substituents as a whole are selected from the following:

The B11 ring is selected from: It is optionally substituted by 1-3 substituents selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, C1-C6 alkyl substituted with 1-6 halogens, C1-C6 alkoxy substituted with 1-6 halogens, halogen, and amino;

Preferably, the above Optionally substituted by 1-2 substituents selected from: C1-C6 alkyl substituted by 1-6 halogens, C3-C4 cycloalkyl, C1-C6 alkoxy substituted by 1-6 halogens, amino;

More preferably, the above Optionally substituted with 1-2 substituents selected from: -CF ₃ , -OCF ₃ ;

Most preferably, the B11 ring is selected from:

R ₁₁ is selected from the group consisting of aminosulfonyl substituted with 1-2 C1-C6 alkyl groups on N, carbamoyl substituted with 1-2 C1-C6 alkyl groups on N, C1-C6 alkyl, C1-C6 alkoxy, halogen, cyano, and nitro;

More preferably, R ₁₁ is selected from: aminosulfonyl substituted with 1-2 C1-C6 alkyl groups on N, carbamoyl substituted with 1-2 C1-C6 alkyl groups on N, C1-C6 alkyl, halogen, cyano; further preferably, R ₁₁ is selected from: -CH ₃ , -F, -Cl, -CN; More preferably, R ₁₁ is located in the ring The position on is selected from: 1-position, 2-position, 3-position, 4-position.

In some embodiments of the present application, the compound of formula I-1 is the following formula I-1c:

The A _11c ring and its optional substituents as a whole are selected from Preferably, the A _11c ring and its optional substituents as a whole are selected from More preferably, the A _11c ring and its optional substituents as a whole are R ₁₁ has the same definition as R ₁₁ in the above formula I-1.

In some embodiments of the present application, the compound of formula I is the following formula I-2:

A12 ring is selected from 5-membered heteroaryl, 5-membered unsaturated heterocyclic group, The 5-membered heteroaryl group is selected from The 5-membered unsaturated heterocyclic group is selected from And any one of the following conditions (1)-(3) is met:

(1) When the A12 ring is selected from a 5-membered heteroaryl group, the A12 ring is optionally substituted by Rx,

(2) When the A12 ring is selected from a 5-membered unsaturated heterocyclic group, any one of the following conditions (2-1) to (2-5) is satisfied:

(2-1) the A12 ring is optionally substituted by Rm;

(2-2) The A12 ring is optionally substituted by Ry, Rz and Rm;

(2-3) the A12 ring is optionally substituted by Ry and Rm;

(2-4) the A12 ring is optionally substituted by 2 Rm;

(2-5) the A12 ring is optionally substituted by Rz;

(3) Ring A12 is selected from When the A12 ring is optionally substituted by 1-2 substituents selected from Rz and Rm;

Wherein, Rx is selected from hydroxyl, Ry is selected from methyl, -CHF ₂ , -CF ₃ , -CH ₂ CH ₃ , -CH ₂ CHF ₂ , -CH ₂ CF ₃ , Rz is selected from methyl, Or, Ry, Rz and the carbon atoms to which they are connected together form Among them, carbon atom 1' is the carbon atom connected to Ry and Rz; Rm is an oxo group;

Most preferably, the A12 ring and its optional substituents as a whole are selected from the following:

The B12 ring is selected from: It is optionally substituted by 1-3 substituents selected from the group consisting of sulfur pentafluoride, -OH, C1-C6 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, C1-C6 alkyl substituted with 1-6 halogens, halogen, nitro, cyano, and amino;

Preferably, the above It is optionally substituted by 1-2 substituents selected from the group consisting of: pentafluorosulfur, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, and halogen;

More preferably, the above Optionally substituted by 1-2 substituents selected from: pentafluorosulfur, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-6 halogens, halogen; or the above Optionally substituted by 1-2 substituents selected from: C1-C6 alkyl, C1-C6 alkyl substituted with 1-6 halogens;

More preferably, the above Optionally substituted by 1-2 substituents selected from: -CF ₃ , -Cl, -SF ₅ , -CH ₃ , -F, -OCH ₃ ; or Optionally substituted by 1-2 substituents, the substituents are selected from: -CF ₃ , -CH ₃ ; further preferably, the above The substitution positions of the substituents thereon are: 2-position monosubstitution, 3-position monosubstitution, 5-position monosubstitution, 4-, 5-position disubstitution, 5-, 6-position disubstitution, 2-, 5-position disubstitution, 3-, 5-position disubstitution; The substitution positions of the substituents thereon are 3-position monosubstitution and 5-position monosubstitution; The substitution position of the substituent thereon is 5-monosubstitution; The substitution position of the substituent thereon is 6-monosubstitution; The substitution position of the substituent thereon is mono- or di-substituted at the 5- or 6-position; The substitution position of the substituent thereon is 5-position monosubstitution; The substitution position of the substituent thereon is 5-position monosubstitution; The substitution position of the substituent thereon is 5-position monosubstitution; The substitution position of the substituent thereon is 5-position monosubstitution; The substitution position of the substituent thereon is 5-position monosubstitution;

Most preferably, the B12 ring is selected from:

R ₁₂ is selected from the group consisting of aminosulfonyl substituted by 1-2 C1-C6 alkyl groups on N, carbamoyl substituted by 1-2 C1-C6 alkyl groups on N, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-6 halogens, C1-C6 alkyl substituted by amino, C1-C6 alkoxy substituted by 1-6 halogens, C1-C5 heteroaryl, C1-C6 alkoxy, C1-C6 alkoxy substituted by hydroxy, C1-C6 alkoxy substituted by 5-6 membered heteroaryl -C6 alkoxy, C3-C5 heterocyclyloxy, carboxyl (-COOH), ester (-CO-O-C1-C6 alkyl), hydroxyl, amino, halogen, cyano, C2-C6 alkenyl, C1-C6 alkyl substituted by C6-C10 aryl, 5-6 membered heterocyclyl; wherein C3-C5 heterocyclyl is arbitrarily substituted by C1-C3 alkyl, C6-C10 aryl is arbitrarily substituted by 1-6 halogens, 5-6 membered heterocyclyl is arbitrarily substituted by C1-C3 alkyl or hydroxyl; or two R ₁₂ , together with the atoms to which they are connected, form a C6-C10 aromatic ring, a partially unsaturated C5-C6 carbocyclic ring, a partially unsaturated 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring, wherein the partially unsaturated C5-C6 carbocyclic ring, the partially unsaturated 5-6 membered heterocyclic ring or the 5-6 membered heteroaromatic ring are each optionally substituted by 1-6 groups selected from halogen and deuterium; more preferably, R _{R 12} is selected from the group consisting of aminosulfonyl substituted by 1-2 C1-C6 alkyl groups on N, carbamoyl substituted by 1-2 C1-C6 alkyl groups on N, pyridyl C1-C6 alkoxy, C1-C6 alkoxy substituted by hydroxy, C3 heterocyclyloxy, carboxyl (-COOH), ester (-CO-O-C1-C6 alkyl), hydroxy, amino, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkyl substituted by 1-3 halogens, C1-C6 alkyl substituted by amino, halogen, cyano, C2-C6 alkenyl, C1-C6 alkyl substituted by phenyl, tetrahydropyrrolyl, piperazinyl, wherein C3 heterocyclyl is arbitrarily substituted by C1-C3 alkyl, tetrahydropyrrolyl is arbitrarily substituted by hydroxy, piperazinyl is arbitrarily substituted by C1-C3 alkyl; or two R ₁₂ , and the atoms to which they are connected together form a benzene ring, a partially unsaturated C5-C6 carbocycle, a partially unsaturated 5-6-membered heterocycle or a 5-membered heteroaromatic ring, wherein the partially unsaturated C5-C6 carbocycle and the partially unsaturated 5-6-membered heterocycle are each optionally substituted by 1 to 6 groups selected from halogen (preferably -F) and deuterium; further preferably, R ₁₂ is selected from: -OH, -NH ₂ , -COOH, -COOCH ₃ , -CH ₃ , -CH ₂ CH ₃ , -F, -Cl, -CN, -CHF ₂ , -CF ₃ , Or two R ₁₂ together with the atoms to which they are attached form: More preferably, the position of R ₁₂ on the ring is selected from: A ₁₂ -position, A ₃₂ -position, A ₂₂ -position; A ₁₂ , A ₂₂ , A ₃₂ , A ₄₂ are independently selected from: N, CH, and only one of them is N, and the others are CH.

In some embodiments of the present application, the compound of formula I-2 is the following formula I-2c:

The _A12c ring and its optional substituents as a whole are selected from:

Preferably, the _A12c ring and its optional substituents as a whole are selected from:

Most preferably, the _A12c ring and its optional substituents as a whole are selected from: A ₁₂ , A ₂₂ , A ₃₂ , A ₄₂ have the same definitions as A ₁₂ , A ₂₂ , A ₃₂ , A ₄₂ in the above formula I-2; R ₁₂ has the same definition as R ₁₂ in the above formula I-2.

In some embodiments of the present application, the compound of formula I is the following formula I-3:

wherein the A13 ring is selected from a 5-6 membered heteroaryl, a 5-6 membered heterocyclic group, a phenyl group, and the A13 ring is optionally substituted by 1-3 substituents selected from Rx, Ry, Rz, and Rm; preferably, the A13 ring is selected from a 5-membered heteroaryl, a 5-membered unsaturated heterocyclic group, a 6-membered saturated heterocyclic group, a phenyl group, a pyridine group, Ring A13 is optionally substituted by 1-3 substituents selected from Rx, Ry, Rz, and Rm; more preferably, ring A13 is selected from 5-membered heteroaryl, 5-membered unsaturated heterocyclic group, 6-membered saturated heterocyclic group, phenyl, and pyridyl, wherein the 5-membered heteroaryl contains 2-4 heteroatoms selected from N, O, and S, and ring A13 is optionally substituted by 1-3 substituents selected from Rx, Ry, Rz, and Rm; further preferably, ring A13 is selected from 5-membered heteroaryl, 5-membered unsaturated heterocyclic group, thiomorpholinyl, tetrahydrothiopyranyl, phenyl, and pyridyl, wherein the 5-membered heteroaryl contains 2-4 heteroatoms selected from N, O, and S, and satisfies any one of the following conditions (1)-(3):

(1) When the A13 ring is selected from a 5-membered heteroaryl group, the A13 ring is optionally substituted by Rx,

(2) When the A13 ring is selected from a 5-membered unsaturated heterocyclic group, any one of the following conditions (2-1) to (2-5) is satisfied:

(2-1) the A13 ring is optionally substituted by Rm;

(2-2) the A13 ring is optionally substituted by Ry, Rz and Rm;

(2-3) The A13 ring is optionally substituted by Ry and Rm;

(2-4) the A13 ring is optionally substituted by 2 Rm;

(2-5) the A13 ring is optionally substituted by Rz;

(3) When the A13 ring is selected from thiomorpholinyl, tetrahydrothiopyranyl, phenyl, and pyridyl, the A13 ring is optionally substituted by 1-2 substituents selected from Rz and Rm;

More preferably, the A13 ring is selected from a 5-membered heteroaryl, a 5-membered unsaturated heterocyclic group,

The 5-membered heteroaryl group is selected from The 5-membered unsaturated heterocyclic group is selected from And any one of the following conditions (1)-(3) is met:

(1) When the A13 ring is selected from a 5-membered heteroaryl group, the A13 ring is optionally substituted by Rx,

(2) When the A13 ring is selected from a 5-membered unsaturated heterocyclic group, any one of the following conditions (2-1) to (2-5) is satisfied:

(2-1) the A13 ring is optionally substituted by Rm;

(2-2) the A13 ring is optionally substituted by Ry, Rz and Rm;

(2-3) the A13 ring is optionally substituted by Ry and Rm;

(2-4) the A13 ring is optionally substituted by 2 Rm;

(2-5) the A13 ring is optionally substituted by Rz;

(3) When the A13 ring is selected from thiomorpholinyl, tetrahydrothiopyranyl, phenyl, and pyridyl, the A13 ring is optionally substituted by 1-2 substituents selected from Rz and Rm;

Wherein, Rx is selected from C1-C6 alkyl, 4-6 membered saturated heterocyclic group (preferably, the 4-6 membered saturated heterocyclic group contains 1 heteroatom selected from N, O, S), -C(＝O)NRaRb, -S(＝O) ₂ NRaRb, carboxyl (-COOH), ester group (-CO-O-C1-C6 alkyl), hydroxyl, -NRaC(＝O)Rc, and the Rx is optionally substituted by 1-2 substituents selected from Rn; preferably, Rx is selected from methyl, ethyl, oxetanyl, tetrahydropyrrolyl, tetrahydropyranyl, piperidinyl, -C(＝O)NRaRb, -NRaC(＝O)Rc, -S(＝O) ₂ NRaRb, carboxyl (-COOH), ester group (-CO-O-C1-C6 alkyl), hydroxyl;

Rn is selected from C1-C6 alkyl, -NRaRb, -C(=O)NRaRb, oxo, 5-6 membered saturated heterocyclic group (preferably, the 5-6 membered saturated heterocyclic group contains 2 heteroatoms selected from N, O, S), C1-C6 alkoxy, carboxyl, hydroxyl; preferably, Rn is selected from methyl, ethyl, -NRaRb, -C(=O)NRaRb, oxo, morpholinyl, methoxy, hydroxyl, carboxyl;

Ra, Rb, Rc are each independently selected from H, C1-C6 alkyl, cyano, C3-C6 cycloalkyl, or Ra, Rb and the carbon atoms to which they are commonly connected together form azetidine, and the azetidine is optionally substituted by hydroxyl; preferably, Ra, Rb, Rc are each independently selected from H, methyl, cyano, cyclopropyl, or Ra, Rb and the carbon atoms to which they are commonly connected together form azetidine, and the azetidine is optionally substituted by hydroxyl;

Most preferably, Rx is selected from hydroxy, methyl,

Ry is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxy, C1-C6 alkyl substituted by 1-6 halogens, C1-C6 alkyl substituted by 1-6 deuteriums, C1-C6 alkyl substituted by C3-C6 cycloalkyl, C1-C6 alkyl substituted by C6-C10 aryl, substituted C1-C6 alkyl, 4-6 membered saturated heterocyclic group; preferably, Ry is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxyl, C1-C6 alkyl substituted by 1-6 halogens, C1-C6 alkyl substituted by 1-6 deuteriums, C1-C6 alkyl substituted by C3-C6 cycloalkyl, C1-C6 alkyl substituted by C6-C10 aryl, More preferably, Ry is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxy, C1-C6 alkyl substituted by 1-3 halogens, C1-C6 alkyl substituted by 1-3 deuteriums, C1-C6 alkyl substituted by cyclopropyl, C1-C6 alkyl substituted by phenyl, A 5-6 membered saturated heterocyclic group containing 1 heteroatom; further preferably, Ry is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxy, C1-C6 alkyl substituted by 1-3 halogens, C1-C6 alkyl substituted by 1-3 deuteriums, C1-C6 alkyl substituted by cyclopropyl, C1-C6 alkyl substituted by phenyl, tetrahydropyrrolyl, piperidinyl; most preferably, Ry is selected from methyl, -CHF ₂ , -CF ₃ , -CH ₂ CH ₃ , -CH ₂ CHF ₂ , -CH ₂ CF ₃ ,

Rz is selected from C1-C6 alkyl, halogen, Preferably, Rz is selected from methyl, Br,

Or, Ry, Rz and the carbon atoms to which they are commonly connected together form a 4-6-membered saturated carbocyclic ring or a 4-6-membered saturated heterocyclic ring; or preferably, Ry, Rz and the carbon atoms to which they are commonly connected together form a 4-6-membered saturated carbocyclic ring or a 4-6-membered saturated heterocyclic ring, wherein the 4-6-membered saturated heterocyclic ring contains 1 heteroatom; or more preferably, Ry, Rz and the carbon atoms to which they are commonly connected together form cyclobutane, cyclopentane, cyclohexane, piperidine or tetrahydropyran;

Or most preferably, Ry, Rz and the carbon atoms to which they are commonly connected together form Among them, carbon atom 1' is the carbon atom that is connected to Ry and Rz;

Rm is an oxo group;

Still further preferably, the A13 ring and its optional substituents as a whole are selected from the following:

Still more preferably, the A13 ring is selected from: And the is optionally substituted by Rm, or optionally substituted by Ry and Rm; wherein Ry is selected from methyl, -CHF ₂ , -CF ₃ , -CH ₂ CH ₃ , -CH ₂ CHF ₂ , -CH ₂ CF ₃ ; Rm is an oxo group;

Most preferably, the A13 ring and its optional substituents as a whole are selected from the following:

The B13 ring is selected from: It is optionally substituted by 1-2 substituents selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, C1-C6 alkyl substituted with 1-6 halogens, halogen, and amino;

Preferably, the above Optionally substituted by 1-2 substituents selected from: C1-C6 alkyl, C1-C6 alkyl substituted with 1-6 halogens;

More preferably, the above Optionally substituted with 1 substituent selected from: -CF ₃ ,

Most preferably, the B13 ring is selected from:

L ₁₃ is selected from a direct bond, NH, O, S; preferably, L ₁₃ is selected from a direct bond, NH;

R ₁₃ is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-6 halogens, C1-C6 alkoxy substituted by 1-6 halogens, C1-C6 alkyl substituted by cyano, halogen, cyano, amino, C1-C6 alkyl substituted by amino, C2-C6 alkenyl, 5-6 membered saturated heterocyclic group substituted by C1-C3 alkyl (preferably 6 membered saturated heterocyclic group substituted by C1-C3 alkyl); or two R ₁₃ , together with the atoms to which they are attached, form a C6-C10 aromatic ring, a partially unsaturated C5-C6 carbocyclic ring, a partially unsaturated 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring, wherein the partially unsaturated C5-C6 carbocyclic ring, the partially unsaturated 5-6 membered heterocyclic ring or the 5-6 membered heteroaromatic ring are each optionally substituted by 1-6 groups selected from halogen and deuterium; more preferably, R ₁₃ is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-3 halogens, C1-C6 alkyl substituted by cyano, halogen, cyano, amino, C1-C6 alkyl substituted by amino, C2-C6 alkenyl, piperazinyl substituted by C1-C3 alkyl; or two R ₁₃ , together with the atoms to which they are attached, form a benzene ring, a partially unsaturated C5 carbocycle, a partially unsaturated 5-6-membered heterocycle or a 5-membered heteroaromatic ring, wherein the partially unsaturated C5 carbocycle and the partially unsaturated 5-6-membered heterocycle are each optionally substituted by 1-6 groups selected from the group consisting of halogen (preferably -F) and deuterium;

More preferably, R ₁₃ is selected from: -OCH ₃ , -CH ₃ , -CH ₂ CH ₃ , -F, -Cl, -CN, -CF ₃ , -CHF ₂ , -NH ₂ , Or two R ₁₃ together with the atoms to which they are attached form: More preferably, the position of R ₁₃ on the ring is selected from: A ₂₃ , A ₃₃ ;

A ₁₃ , A ₂₃ , A ₃₃ , and A ₄₃ are independently selected from: N, CH, and only two of them are N, and the rest are CH;

Preferably, A ₁₃ , A ₂₃ , A ₃₃ , A ₄₃ are selected from the following combinations:

1) A ₁₃ and A ₄₃ are both N, and A ₂₃ and A ₃₃ are both CH;

2) A ₃₃ and A ₄₃ are both N, and A ₁₃ and A ₂₃ are both CH;

3) A ₂₃ and A ₄₃ are both N, and A ₁₃ and A ₃₃ are both CH.

In some embodiments of the present application, the compound of formula I-3 is the following formula I-3c:

The _A13c ring and its optional substituents as a whole are selected from:

Preferably, the A _13c ring and its optional substituents as a whole are selected from:

Most preferably, the A _13c ring and its optional substituents as a whole are selected from:

A ₁₃ , A ₂₃ , A ₃₃ , A ₄₃ have the same definitions as A ₁₃ , A ₂₃ , A ₃₃ , A ₄₃ in the above formula I-3; R ₁₃ has the same definition as R ₁₃ in the above formula I-3.

In some embodiments of the present application, the compound of formula I is the following formula I-4:

in:

_Y14 is selected from N, CH; A14 ring is selected from 5-membered heteroaryl, 5-membered unsaturated heterocyclic group, the 5-membered heteroaryl is selected from The 5-membered unsaturated heterocyclic group is selected from And any one of the following conditions (1)-(2) is met:

(1) When the A14 ring is selected from a 5-membered heteroaryl group, the A14 ring is optionally substituted by Rx,

(2) When the A14 ring is selected from a 5-membered unsaturated heterocyclic group, any one of the following conditions (2-1) to (2-5) is satisfied:

(2-1) the A14 ring is optionally substituted by Rm;

(2-2) the A14 ring is optionally substituted by Ry, Rz and Rm;

(2-3) the A14 ring is optionally substituted by Ry and Rm;

(2-4) the A14 ring is optionally substituted by 2 Rm;

(2-5) the A14 ring is optionally substituted by Rz;

in,

Rx is selected from hydroxyl,

Ry is selected from methyl, -CHF ₂ , -CF ₃ , -CH ₂ CH ₃ , -CH ₂ CHF ₂ , -CH ₂ CF ₃ , Rz is selected from methyl,

Or, Ry, Rz and the carbon atoms to which they are connected together form Among them, carbon atom 1' is the carbon atom connected to Ry and Rz;

Rm is an oxo group;

Most preferably, the A14 ring and its optional substituents as a whole are selected from the following:

The B14 ring is selected from: It is optionally substituted by 1-3 substituents selected from the group consisting of: pentafluorosulfur, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, halogen, nitro, cyano, amino, C3-C4 cycloalkyl,;

Preferably, the above It is optionally substituted by 1-2 substituents selected from the group consisting of pentafluorosulfur, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, and halogen;

More preferably, the above Optionally substituted by 1-2 substituents selected from: pentafluorosulfur, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-6 halogens, halogen; or the above Optionally substituted by 1-2 substituents selected from: C1-C6 alkyl, C1-C6 alkyl substituted by 1-6 halogens;

More preferably, the above Optionally substituted by 1-2 substituents selected from: -CF ₃ , -Cl, -SF ₅ , -CH ₃ , -F, -OCH ₃ , or the above Optionally substituted by 1-2 substituents, the substituents are selected from: -CF ₃ , -CH ₃ ; further preferably, the above The substitution positions of the substituents thereon are: 2-position monosubstitution, 3-position monosubstitution, 5-position monosubstitution, 4-, 5-position disubstitution, 5-, 6-position disubstitution, 2-, 5-position disubstitution, 3-, 5-position disubstitution; The substitution positions of the substituents thereon are 3-position monosubstitution and 5-position monosubstitution; The substitution position of the substituent thereon is 5-position monosubstitution; The substitution position of the substituent thereon is 6-monosubstituted, The substitution position of the substituent thereon is mono- or di-substituted at the 5- or 6-position; The substitution position of the substituent thereon is 5-position monosubstitution; The substitution position of the substituent thereon is 5-monosubstitution; The substitution position of the substituent thereon is 5-position monosubstitution; The substitution position of the substituent thereon is 5-position monosubstitution; The substitution position of the substituent thereon is 5-position monosubstitution;

Most preferably, the B14 ring is selected from:

R ₁₄ is selected from the group consisting of aminosulfonyl substituted by 1-2 C1-C6 alkyl groups on N, carbamoyl substituted by 1-2 C1-C6 alkyl groups on N, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-6 halogens, C1-C6 alkyl substituted by amino, C1-C6 alkyl substituted by cyano, C1-C6 alkoxy substituted by 1-6 halogens, C1-C5 heteroaryl, C1-C6 alkoxy, C1-C6 alkoxy substituted by hydroxy, C1-C6 alkoxy substituted by 5-6 membered heteroaryl, C3-C5 heterocyclyloxy, carboxyl (-COOH), ester (-CO-O-C1-C6 alkoxy) R 14 , together with the atoms to which they are connected, form a C6-C10 aromatic ring, a partially unsaturated C5-C6 carbocyclic ring, a partially unsaturated 5-6-membered heterocyclic ring or a 5-6-membered heteroaromatic ring, wherein the partially unsaturated C5-C6 carbocyclic ring, the partially unsaturated 5-6-membered heterocyclic ring or the 5-6-membered heteroaromatic ring are each optionally substituted by 1 to 6 groups selected from halogen and _deuterium ;

More preferably, R ₁₄ is selected from: aminosulfonyl substituted by 1-2 C1-C6 alkyl groups on N, carbamoyl substituted by 1-2 C1-C6 alkyl groups on N, pyridyl C1-C6 alkoxy, C1-C6 alkoxy substituted by hydroxy, C3 heterocyclyloxy, carboxyl (-COOH), ester (-CO-O-C1-C6 alkyl), hydroxy, amino, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkyl substituted by 1-3 halogens, C1-C6 alkyl substituted by amino, C1-C6 alkyl substituted by cyano, halogen, cyano, C2-C6 alkenyl, C1-C6 alkyl substituted by phenyl, tetrahydropyrrolyl, piperazinyl, wherein C3 heterocyclyl is arbitrarily substituted by C1-C3 alkyl, tetrahydropyrrolyl is arbitrarily substituted by hydroxy, piperazinyl is arbitrarily substituted by C1-C3 alkyl; or two R ₁₄ , together with the atoms to which they are attached, form a benzene ring, a partially unsaturated C5-C6 carbocycle, a partially unsaturated 5-6-membered heterocycle or a 5-membered heteroaromatic ring, wherein the partially unsaturated C5-C6 carbocycle and the partially unsaturated 5-6-membered heterocycle are each optionally substituted by 1 to 6 groups selected from halogen (preferably -F) and deuterium;

More preferably, R ₁₄ is selected from: -OH, -NH ₂ , -COOH, -COOCH ₃ , -CH ₃ , -CH ₂ CH ₃ , -F, -Cl, -CN, -CHF ₂ , -CF ₃ , Or two R ₁₄ together with the atoms to which they are attached form:

In certain embodiments of the present application, the above formula I is

Wherein, the A111 ring is selected from a 5-membered heteroaryl group, a 5-membered unsaturated heterocyclic group, and the 5-membered heteroaryl group is selected from The 5-membered unsaturated heterocyclic group is selected from And any one of the following conditions (1)-(2) is met:

(1) When the A111 ring is selected from a 5-membered heteroaryl group, the A111 ring is optionally substituted by Rx,

(2) When the A111 ring is selected from a 5-membered unsaturated heterocyclic group, the A111 ring is optionally substituted by Rm or Rz, or optionally substituted by Rm and Ry;

in,

Rx is selected from methyl, Ry is selected from methyl, -CHF2, -CF3, -CH2CH3, -CH2CHF2, -CH2CF3, Rz is selected from halogen (preferably Br); Rm is oxo;

Preferably, the A111 ring and its optional substituents as a whole are selected from the following: More preferably, the A111 ring and its optional substituents as a whole are selected from Further preferably, the A111 ring and its optional substituents as a whole are selected from Most preferably, the A111 ring and its optional substituents as a whole are

The B111 ring is selected from: It is optionally substituted by 1-3 substituents selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, C1-C6 alkoxy substituted with 1-6 halogens, halogen; preferably, the above Optionally substituted by 1-2 substituents, the substituents are selected from: 1-6 halogen-substituted C1-C6 alkyl, 1-6 halogen-substituted C1-C6 alkoxy; More preferably, the above Optionally substituted with 1-2 substituents selected from: -CF ₃ , -OCF ₃ ;

Most preferably, the B111 ring is selected from: Preferably

In certain embodiments of the present application, the above formula I is

Wherein, the A112 ring is selected from a 5-membered heteroaryl, a 5-membered unsaturated heterocyclic group, The 5-membered heteroaryl group is selected from The 5-membered unsaturated heterocyclic group is selected from And any one of the following conditions (1)-(2) is met:

(1) When the A112 ring is selected from a 5-membered heteroaryl group, the A112 ring is optionally substituted by Rx,

(2) When the A112 ring is selected from a 5-membered unsaturated heterocyclic group, the A112 ring is optionally substituted by Rm or Rz, or optionally substituted by Ry and Rm;

Wherein, Rx is selected from methyl,

Ry is selected from methyl, -CHF ₂ , -CF ₃ , -CH ₂ CH ₃ , -CH ₂ CHF ₂ , -CH ₂ CF ₃ , Rz is selected from halogen (preferably Br), Rm is oxo;

Preferably, the A112 ring and its optional substituents as a whole are selected from the following:

The B112 ring is selected from: It is optionally substituted by 1-3 substituents selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, C1-C6 alkoxy substituted with 1-6 halogens, halogen; preferably, the above Optionally substituted by 1-2 substituents, the substituents are selected from: 1-6 halogen-substituted C1-C6 alkyl, 1-6 halogen-substituted C1-C6 alkoxy; More preferably, the above Optionally substituted by 1-2 substituents selected from: -CF ₃ , -OCF ₃ ; Most preferably, the B112 ring is:

R ₁₁₂ is selected from the group consisting of: aminosulfonyl substituted with 1-2 C1-C6 alkyl groups on N, carbamoyl substituted with 1-2 C1-C6 alkyl groups on N, C1-C6 alkyl groups, C1-C6 alkoxy groups, halogen, cyano, nitro, and amino groups; more preferably, R ₁₁₂ is selected from the group consisting of: aminosulfonyl substituted with 1-2 C1-C6 alkyl groups on N, carbamoyl substituted with 1-2 C1-C6 alkyl groups on N, C1-C6 alkyl groups, halogen, and cyano groups; further preferably, R ₁₁₂ is selected from the group consisting of: -CH ₃ , -CH ₂ CH ₃ , CF ₃ , -F, -Cl, -CN;

More preferably, R ₁₁₂ is located in the ring The position on is selected from: 1-position, 2-position, 3-position, 4-position.

In certain embodiments of the present application, the above formula I-1-2 is

Wherein, the A _112c ring and its optional substituents as a whole are selected from Preferably, the A _112c ring and its optional substituents as a whole are selected from

More preferably, the A _112c ring and its optional substituents as a whole are R ₁₁₂ has the same definition as R ₁₁₂ in the above formula I-1-2.

In certain embodiments of the present application, the above formula I is

Wherein, the A121 ring is selected from a 5-membered heteroaryl group, a 5-membered unsaturated heterocyclic group, and the 5-membered heteroaryl group is selected from The 5-membered unsaturated heterocyclic group is selected from And any one of the following conditions (1)-(2) is met:

(1) When the A121 ring is selected from a 5-membered heteroaryl group, the A121 ring is optionally substituted by Rx,

(2) When the A121 ring is selected from a 5-membered unsaturated heterocyclic group, any one of the following conditions (2-1) to (2-5) is satisfied:

(2-1) the A121 ring is optionally substituted by Rm;

(2-2) the A121 ring is optionally substituted by Ry, Rz and Rm;

(2-3) the A121 ring is optionally substituted by Ry and Rm;

(2-4) the A121 ring is optionally substituted by 2 Rm;

(2-5) the A121 ring is optionally substituted by Rz;

in,

Rx is selected from hydroxyl,

Ry is selected from methyl, -CHF ₂ , -CF ₃ , -CH ₂ CH ₃ , -CH ₂ CHF ₂ , -CH ₂ CF ₃ , Rz is selected from methyl,

Or, Ry, Rz and the carbon atoms to which they are connected together form Among them, carbon atom 1' is the carbon atom that is connected to Ry and Rz;

Rm is an oxo group;

Most preferably, the A121 ring and its optional substituents as a whole are selected from the following:

The B121 ring is selected from: It is optionally substituted by 1-3 substituents selected from the group consisting of sulfur pentafluoride, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, halogen, nitro, cyano, and amino;

Preferably, the above It is optionally substituted by 1-2 substituents selected from the group consisting of pentafluorosulfur, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, and halogen;

More preferably, the above Optionally substituted by 1-2 substituents selected from: pentafluorosulfur, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-6 halogens, halogen; or the above Optionally substituted by 1-2 substituents selected from: C1-C6 alkyl, C1-C6 alkyl substituted by 1-6 halogens;

More preferably, the above Optionally substituted by 1-2 substituents selected from: -CF ₃ , -Cl, -SF ₅ , -CH ₃ , -F, -OCH ₃ ; or Optionally substituted with 1-2 substituents selected from: -CF ₃ , -CH ₃ ;

More preferably, the above The substitution positions of the substituents thereon are: 2-position monosubstitution, 3-position monosubstitution, 5-position monosubstitution, 4-, 5-position disubstitution, 5-, 6-position disubstitution, 2-, 5-position disubstitution, 3-, 5-position disubstitution; The substitution positions of the substituents thereon are 3-position monosubstitution and 5-position monosubstitution; The substitution position of the substituent thereon is 5-position monosubstitution; The substitution position of the substituent thereon is 6-monosubstituted, The substitution position of the substituent thereon is 5-position or 6-position mono- or di-substitution; The substitution position of the substituent thereon is 5-position monosubstitution; The substitution position of the substituent thereon is 5-position monosubstitution; The substitution position of the substituent thereon is 5-position monosubstitution; The substitution position of the substituent thereon is 5-position monosubstitution; The substitution position of the substituent thereon is 5-position monosubstitution;

Most preferably, the B121 ring is selected from:

R ₁₂₁ is selected from the group consisting of aminosulfonyl substituted by 1-2 C1-C6 alkyl groups on N, carbamoyl substituted by 1-2 C1-C6 alkyl groups on N, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-6 halogens, C1-C6 alkyl substituted by amino, C1-C6 alkoxy substituted by 1-6 halogens, C1-C5 heteroaryl, C1-C6 alkoxy, C1-C6 alkoxy substituted by hydroxy, C1-C6 alkoxy substituted by 5-6 membered heteroaryl 1-C6 alkoxy, C3-C5 heterocyclyloxy, carboxyl (-COOH), ester (-CO-O-C1-C6 alkyl), hydroxyl, amino, halogen, cyano, C2-C6 alkenyl, C1-C6 alkyl substituted by C6-C10 aryl, 5-6 membered heterocyclyl; wherein C3-C5 heterocyclyl is arbitrarily substituted by C1-C3 alkyl, C6-C10 aryl is arbitrarily substituted by 1-6 halogens, 5-6 membered heterocyclyl is arbitrarily substituted by C1-C3 alkyl or hydroxyl; or two R ₁₂₁ , together with the atoms to which they are connected, form a C6-C10 aromatic ring, a partially unsaturated C5-C6 carbocyclic ring, a partially unsaturated 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring, wherein the partially unsaturated C5-C6 carbocyclic ring, the partially unsaturated 5-6 membered heterocyclic ring or the 5-6 membered heteroaromatic ring are each optionally substituted by 1-6 groups selected from halogen and deuterium;

More preferably, R ₁₂₁ is selected from the group consisting of aminosulfonyl substituted by 1-2 C1-C6 alkyl groups on N, carbamoyl substituted by 1-2 C1-C6 alkyl groups on N, pyridyl C1-C6 alkoxy, C1-C6 alkoxy substituted by hydroxy, C3 heterocyclyloxy, carboxyl (-COOH), ester (-CO-O-C1-C6 alkyl), hydroxy, amino, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkyl substituted by 1-3 halogens, C1-C6 alkyl substituted by amino, halogen, cyano, C2-C6 alkenyl, C1-C6 alkyl substituted by phenyl, tetrahydropyrrolyl, piperazinyl, wherein C3 heterocyclyl is arbitrarily substituted by C1-C3 alkyl, tetrahydropyrrolyl is arbitrarily substituted by hydroxy, and piperazinyl is arbitrarily substituted by C1-C3 alkyl; or two R ₁₂₁ , together with the atoms to which they are attached, form a benzene ring, a partially unsaturated C5-C6 carbocycle, a partially unsaturated 5-6-membered heterocycle or a 5-membered heteroaromatic ring, wherein the partially unsaturated C5-C6 carbocycle and the partially unsaturated 5-6-membered heterocycle are each optionally substituted by 1 to 6 groups selected from halogen (preferably -F) and deuterium;

More preferably, R ₁₂₁ is selected from: -OH, -NH ₂ , -COOH, -COOCH ₃ , -CH ₃ , -CH ₂ CH ₃ , -F, -Cl, -CN, -CHF ₂ , -CF ₃ , Or two R ₁₂₁ together with the atoms to which they are attached form:

More preferably, the position of R ₁₂₁ on the ring is selected from: 1-position, 3-position, 2-position, preferably 3-position and 2-position.

In certain embodiments of the present application, the above formula I-2-1 is

Wherein, the A _121c ring and its optional substituents as a whole are selected from: Preferably, the A _121c ring and its optional substituents as a whole are selected from: Most preferably, the A _121c ring and its optional substituents as a whole are:

R ₁₂₁ has the same definition as R ₁₂₁ in the above formula I-2-1.

In certain embodiments of the present application, the above formula I is

Among them, the A122 ring is selected from Preferably, the A122 ring is selected from

The B122 ring is selected from: It is optionally substituted by 1 substituent, the substituent is selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, halogen; preferably, the substituent is selected from: C1-C6 alkyl substituted with 1-6 halogens; more preferably, the substituent is selected from -CF ₃ ; further more preferably, the B122 ring is

In certain embodiments of the present application, the above formula I is

The A123 ring is selected from Preferably, the A123 ring is selected from

The B123 ring is selected from: It is optionally substituted by 1 substituent, the substituent is selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, halogen; preferably, the substituent is selected from: C1-C6 alkyl substituted with 1-6 halogens; more preferably, the substituent is selected from -CF ₃ ; further more preferably, the B123 ring is

In certain embodiments of the present application, the above formula I is

Wherein, the A124 ring is selected from: And the is optionally substituted by Rm or optionally substituted by Ry and Rm, Optionally substituted with 1-2 substituents selected from Rz and Rm;

Wherein Ry is methyl; Rz is selected from Rm is an oxo group;

Preferably, the A124 ring and its optional substituents as a whole are selected from the following: More preferably, the A124 ring and its optional substituents as a whole are selected from

The B124 ring is selected from: It is optionally substituted by 1 substituent, the substituent is selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, halogen; preferably, the substituent is selected from: C1-C6 alkyl substituted with 1-6 halogens; more preferably, the substituent is selected from -CF ₃ ; further more preferably, the B124 ring is

In certain embodiments of the present application, the above formula I is

Wherein, the definition of A125 ring is the same as the definition of A12 ring in the above formula I-2; A ₁₂₅ , A ₂₂₅ , A ₃₂₅ , A ₄₂₅ are independently selected from: N, CH, and only one of them is N, and the rest are CH; preferably, A ₁₂₅ , A ₂₂₅ , A ₃₂₅ are CH, and A ₄₂₅ is N; R ₁₂₅ is the same as the definition of R ₁₂ in the above formula I-2;

The B125 ring is selected from: It is optionally substituted by 1 substituent selected from the group consisting of: pentafluorosulfur, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, halogen; and the above The substitution positions of the substituents thereon are: 5-position monosubstitution;

Preferably, the B125 ring is selected from: It is optionally substituted by 1 substituent selected from: -CF ₃ , -Cl, -SF ₅ , -CH ₃ , -F, -OCH ₃ ; and The substitution positions of the substituents thereon are: 5-position monosubstitution;

More preferably, the B125 ring is selected from: Most preferably, the B125 ring is

In certain embodiments of the present application, the above formula I is

Wherein, the A131 ring is selected from: And the is optionally substituted by Rm, or is optionally substituted by Ry and Rm;

Wherein, Ry is selected from methyl, -CHF ₂ , -CF ₃ , -CH ₂ CH ₃ , -CH ₂ CHF ₂ , -CH ₂ CF _3, -CH ₂ CH ₂ OH; Rm is an oxo group;

Preferably, the A131 ring and its optional substituents as a whole are selected from the following:

More preferably, the A131 ring and its optional substituents as a whole are selected from the following: Most preferably, the A131 ring and its optional substituents as a whole are selected from:

The B131 ring is selected from: It is optionally substituted by a substituent selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, halogen; preferably, the substituent is selected from: C1-C6 alkyl, C1-C6 alkyl substituted with 1-6 halogens; more preferably, the substituent is selected from: -CF ₃ , More preferably, the B131 ring is

L ₁₃₁ is selected from a direct bond, NH, O, S; preferably, L ₁₃₁ is selected from a direct bond, NH; A ₁₃₁ , A ₂₃₁ , A ₃₃₁ , A ₄₃₁ are independently selected from: N, CH, and only 2 of them are N, and the rest are CH; preferably, A ₁₃₁ , A ₂₃₁ , A ₃₃₁ , A ₄₃₁ are selected from the following combinations:

1) A ₁₃₁ , A ₄₃₁ are both N, A ₂₃₁ , A ₃₃₁ are both CH;

2) A ₃₃₁ , A ₄₃₁ are both N, A ₁₃₁ , A ₂₃₁ are both CH;

3) A ₂₃₁ , A ₄₃₁ are both N, and A ₁₃₁ , A ₃₃₁ are both CH.

In certain embodiments of the present application, the above formula I-3-1 is

Wherein, the definition of A131c ring is the same as that of A131 ring in the above formula I-3-1;

A ₁₃₁ , A ₂₃₁ , A ₃₃₁ , and A ₄₃₁ have the same definitions as A ₁₃₁ , A ₂₃₁ , A ₃₃₁ , and A ₄₃₁ in the above formula I-3-1.

In certain embodiments of the present application, the above formula I is

Wherein, the A132 ring is selected from: And the is optionally substituted by Rm, or is optionally substituted by Ry and Rm; wherein Ry is selected from methyl, -CHF ₂ , -CF ₃ , -CD ₃ , -CH ₂ CH ₃ , -CH ₂ CHF ₂ , -CH ₂ CF _3, -CH ₂ CH ₂ OH; and Rm is oxo;

Preferably, the A132 ring and its optional substituents as a whole are selected from the following:

More preferably, the A132 ring and its optional substituents as a whole are selected from the following: Most preferably, the A132 ring and its optional substituents as a whole are selected from:

The B132 ring is selected from: It is optionally substituted by 1 substituent, the substituent is selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, halogen; preferably, the substituent is selected from: C1-C6 alkyl substituted with 1-6 halogens; more preferably, the substituent is selected from -CF ₃ ; further more preferably, the B132 ring is

R ₁₃₂ is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-6 halogens, C1-C6 alkoxy substituted by 1-6 halogens, C1-C6 alkyl substituted by cyano, halogen, cyano, amino, C1-C6 alkyl substituted by amino, C2-C6 alkenyl, 6-membered saturated heterocyclic group substituted by C1-C3 alkyl; or two R ₁₃₂ together with the atoms to which they are attached form a C6-C10 aromatic ring, a partially unsaturated C5-C6 carbocyclic ring, a partially unsaturated 5-6-membered heterocyclic ring or a 5-6-membered heteroaromatic ring, wherein the partially unsaturated C5-C6 carbocyclic ring, the partially unsaturated 5-6-membered heterocyclic ring or the 5-6-membered heteroaromatic ring are each optionally substituted by 1-6 groups selected from halogen and deuterium; more preferably, R ₁₃₂ is selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-3 halogens, C1-C6 alkyl substituted by cyano, halogen, cyano, amino, C1-C6 alkyl substituted by amino, C2-C6 alkenyl, piperazinyl substituted by C1-C3 alkyl; or two R ₁₃₂ together with the atoms to which they are attached form a benzene ring, a partially unsaturated C5 carbocycle, a partially unsaturated 5-6-membered heterocycle or a 5-membered heteroaromatic ring, wherein the partially unsaturated C5 carbocycle and the partially unsaturated 5-6-membered heterocycle are each optionally substituted by 1-6 groups selected from halogen (preferably -F) and deuterium;

More preferably, R ₁₃₂ is selected from: -OCH ₃ , -CH ₃ , -CH ₂ CH ₃ , -F, -Cl, -CN, -CF ₃ , -CHF ₂ , -NH ₂ , Or two R ₁₃₂ together with the atoms to which they are attached form:

More preferably, R ₁₃₂ is located on the ring at a position selected from: A ₂₃₂ , A ₃₃₂ ; A ₁₃₂ , A ₂₃₂ , A ₃₃₂ , A ₄₃₂ are independently selected from: N, CH, and only 2 of them are N and the rest are CH; preferably, A ₁₃₂ , A ₂₃₂ , A ₃₃₂ , A ₄₃₂ are selected from the following combination: A ₁₃₂ , A ₄₃₂ are both N, and A ₂₃₂ , A ₃₃₂ are both CH.

In certain embodiments of the present application, the above formula I-3-2 is

Wherein, the definition of A132c ring is the same as that of A132 ring in the above formula I-3-2; the definition of _R132 is the same as that of _R132 in the above formula I-3-2; the definitions of _A132 , _A232 , _A332 , and _A432 are the same as those of _A132 , _A232 , _A332 , and _A432 in the above formula I-3-2.

In certain embodiments of the present application, the above formula I is

Wherein, the definition of A133 ring is the same as that of A13 ring in the above formula I-3; the definition of B133 ring is the same as that of B13 ring in the above formula I-3; and the definition of R ₁₃₃ is the same as that of R ₁₃ in the above formula I-3.

In certain embodiments of the present application, the above formula I is

Wherein, the definition of A134 ring is the same as that of A13 ring in the above formula I-3; preferably, A134 ring and its optional substituents as a whole are selected from More preferably, the A134 ring and its optional substituents as a whole are selected from:

The definition of B134 ring is the same as that of B13 ring in the above formula I-3; preferably, B134 ring is selected from: It is optionally substituted by 1-2 substituents selected from: C1-C6 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, C1-C6 alkyl substituted by 1-6 halogens, halogen, amino; more preferably, the above Optionally substituted by 1-2 substituents, the substituents are selected from: C1-C6 alkyl, C1-C6 alkyl substituted by 1-6 halogens; further preferably, the above Optionally substituted with 1 substituent selected from: -CF ₃ , Still more preferably, the B134 ring is selected from: Most preferably, the B134 ring is

The definition of R ₁₃₄ is the same as that of R ₁₃ in the above formula I-3; preferably, two R ₁₃₄ and the atoms to which they are connected together form a 5-membered heteroaromatic ring; more preferably, two R ₁₃₄ and the atoms to which they are connected together form:

In certain embodiments of the present application, the above formula I is

Wherein, the definition of A135 ring is the same as that of A13 ring in the above formula I-3;

The B135 ring is selected from: It is optionally substituted by 1 substituent selected from: C1-C6 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, C1-C6 alkyl substituted with 1-6 halogens, halogen, amino; and the above The substitution positions of the substituents thereon are: 5-position monosubstitution;

Preferably, the above Optionally substituted by 1 substituent selected from: C1-C6 alkyl, C1-C6 alkyl substituted with 1-6 halogens; and The substitution position of the substituent thereon is: 5-position monosubstitution; more preferably, the B135 ring is selected from: Most preferably, the B135 ring is

The definition of R ₁₃₅ is the same as that of R ₁₃ in the above formula I-3; A ₁₃₅ , A ₂₃₅ , A ₃₃₅ , A ₄₃₅ are independently selected from: N, CH, and only 2 of them are N and the rest are CH; preferably, A ₁₃₅ , A ₂₃₅ , A ₃₃₅ , A ₄₃₅ are selected from the following combinations:

1) A ₁₃₅ and A ₄₃₅ are both N, and A ₂₃₅ and A ₃₃₅ are both CH;

2) A ₃₃₅ and A ₄₃₅ are both N, and A ₁₃₅ and A ₂₃₅ are both CH;

3) A ₂₃₅ and A ₄₃₅ are both N, and A ₁₃₅ and A ₃₃₅ are both CH.

In some embodiments of the present application, the compound of formula O is the following formula II:

Ring A2 is selected from: Preferably, the A2 ring is selected from More preferably, the A2 ring is selected from

R ₂ is selected from: C1-C6 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, C1-C6 alkyl substituted with 1-6 halogens, halogen, amino; preferably, R ₂ is selected from: C1-C6 alkyl substituted with 1-6 halogens; more preferably, R ₂ is -CF ₃ ; further more preferably, the position of R ₂ is: 5-position monosubstituted.

In some embodiments of the present application, the compound of formula O is the following formula III:

The A3 ring is selected from: Preferably, the A3 ring is selected from More preferably, the A3 ring is selected from

R ₃ is selected from: C1-C6 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, C1-C6 alkyl substituted with 1-6 halogens, halogen, amino; preferably, R ₃ is selected from: C1-C6 alkyl substituted with 1-6 halogens; more preferably, R ₃ is -CF ₃ ; further more preferably, the position of R ₃ is: 5-position monosubstituted.

In some embodiments of the present application, the compound of formula O is the following formula IV:

Ring A4 is selected from: And the is optionally substituted by Rm, or is optionally substituted by Ry and Rm;

wherein Ry is selected from methyl, -CHF ₂ , -CF ₃ , CD ₃ , -CH ₂ CH ₃ , -CH ₂ CHF ₂ , -CH ₂ CF ₃ , Rm is an oxo group;

Preferably, the A4 ring and its optional substituents as a whole are selected from: Preferably, the A4 ring and its optional substituents as a whole are selected from: Most preferably, the A4 ring and its optional substituents as a whole are selected from:

The B4 ring is selected from: It is optionally substituted by 1 substituent, the substituent being selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, halogen; preferably, the substituent is selected from: C1-C6 alkyl substituted with 1-6 halogens; more preferably, the substituent is -CF ₃ ; further more preferably, the B4 ring is

The C4 ring is selected from

R ₄ is selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-6 halogens, C1-C6 alkoxy substituted by 1-6 halogens, halogen, cyano, amino; or two R ₄ , together with the atoms to which they are connected, form a 5-6-membered heterocyclic ring or a 5-6-membered heteroaromatic ring; preferably, R ₄ is selected from: C1-C6 alkyl; or two R ₄ , together with the atoms to which they are connected, form a 5-6-membered heterocyclic ring or a 5-6-membered heteroaromatic ring; more preferably, two R ₄ , together with the atoms to which they are connected, form a 5-6-membered heterocyclic ring; most preferably, two R ₄ , together with the atoms to which they are connected, form:

In some embodiments of the present application, the compound of formula IV is the following formula IV-1:

The definition of A41 ring is the same as that of A4 ring in the above formula IV;

The B41 ring is selected from: It is optionally substituted by 1 substituent, the substituent being selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, halogen; preferably, the substituent is selected from: C1-C6 alkyl substituted with 1-6 halogens; more preferably, the substituent is -CF ₃ ; further more preferably, the B41 ring is A ₄₁ is selected from: O, S.

In some embodiments of the present application, the compound of formula IV is the following formula IV-2,

The definition of A42 ring is the same as that of A4 ring in the above formula IV;

The B42 ring is selected from: It is optionally substituted by 1 substituent, the substituent being selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, halogen; preferably, the substituent is selected from: C1-C6 alkyl substituted with 1-6 halogens; more preferably, the substituent is -CF ₃ ; further more preferably, the B42 ring is

R ₄₂₁ and R ₄₂₂ are each independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, C1-C6 alkoxy substituted with 1-6 halogens, halogen, cyano, and amino; or R ₄₂₁ and R ₄₂₂ , together with the atoms to which they are connected, form a 5-6-membered heterocyclic ring or a 5-6-membered heteroaromatic ring; preferably, R ₄₂₁ and R ₄₂₂ are each independently selected from the group consisting of C1-C6 alkyl; or R ₄₂₁ and R ₄₂₂ , together with the atoms to which they are connected, form a 5-6-membered heterocyclic ring or a 5-6-membered heteroaromatic ring; more preferably, R ₄₂₁ and R ₄₂₂ , together with the atoms to which they are connected, form a 5-6-membered heterocyclic ring; most preferably, R ₄₂₁ and R ₄₂₂ , together with the atoms to which they are connected, form:

In some embodiments of the present application, the compound of formula IV is the following formula IV-3,

The definition of A43 ring is the same as that of A4 ring in the above formula IV;

The B43 ring is selected from: It is optionally substituted by 1 substituent, the substituent being selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, halogen; preferably, the substituent is selected from: C1-C6 alkyl substituted with 1-6 halogens; more preferably, the substituent is -CF ₃ ; further more preferably, the B43 ring is R ₄₃₁ and R ₄₃₂ are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, C1-C6 alkoxy substituted with 1-6 halogens, halogen, cyano, and amino; or R ₄₃₁ and R ₄₃₂ , together with the atoms to which they are connected, form a 5-6-membered heterocyclic ring or a 5-6-membered heteroaromatic ring; preferably, R ₄₃₁ and R ₄₃₂ are each independently selected from the group consisting of hydrogen, C1-C6 alkyl; or R ₄₃₁ and R ₄₃₂ , together with the atoms to which they are connected, form a 5-6-membered heterocyclic ring or a 5-6-membered heteroaromatic ring; more preferably, R ₄₃₁ and R ₄₃₂ are hydrogen; or R ₄₃₁ and R ₄₃₂ , together with the atoms to which they are connected, form a 5-6-membered heterocyclic ring; most preferably, R ₄₃₁ and R ₄₃₂ are hydrogen; or R ₄₃₁ and R ₄₃₂ , together with the atoms to which they are attached, form:

In some embodiments of the present application, the compound of formula O is the following formula V:

The A5 ring is selected from: And the is optionally substituted by Rm, or is optionally substituted by Ry and Rm; wherein Ry is selected from methyl, -CHF ₂ , -CF ₃ , CD ₃ , -CH ₂ CH ₃ , -CH ₂ CHF ₂ , -CH ₂ CF ₃ , Rm is an oxo group; preferably, the A5 ring and its optional substituents as a whole are selected from: Preferably, the A5 ring and its optional substituents as a whole are selected from: Most preferably, the A5 ring and its optional substituents as a whole are selected from:

The B5 ring is selected from: It is optionally substituted by a substituent selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, halogen; preferably, the substituent is selected from: C1-C6 alkyl substituted with 1-6 halogens; more preferably, the substituent is -CF ₃ ; further more preferably, the B5 ring is R ₅ is selected from: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-6 halogens, C1-C6 alkoxy substituted by 1-6 halogens, halogen, cyano, amino; preferably, R ₅ is selected from C1-C6 alkyl; more preferably, R ₅ is -CH ₃ .

In some embodiments of the present application, the compound of formula O is the following formula VI:

wherein: R _6′ is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxy, C1-C6 alkyl substituted by 1-6 halogens, C1-C6 alkyl substituted by 1-6 deuteriums, C1-C6 alkyl substituted by C3-C6 cycloalkyl, C1-C6 alkyl substituted by C6-C10 aryl, substituted C1-C6 alkyl; preferably, R _6' is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxy, C1-C6 alkyl substituted by 1-3 halogens, C1-C6 alkyl substituted by 1-3 deuteriums, C1-C6 alkyl substituted by cyclopropyl, C1-C6 alkyl substituted by phenyl, More preferably, R _6' is selected from methyl, -CHF ₂ , -CF ₃ , -CH ₂ CH ₃ , -CH ₂ CHF ₂ , -CH ₂ CF ₃ , Most preferably, R _6' is methyl;

The definition of B6 ring is the same as that of Bo ring in the above formula O; or, the definition of B6 ring is the same as that of B11 ring in the above formula I-1; or, the definition of B6 ring is the same as that of B12 ring in the above formula I-2; or, the definition of B6 ring is the same as that of B13 ring in the above formula I-3; or, the definition of B6 ring is the same as that of B14 ring in the above formula I-4; or, the definition of B6 ring is the same as that of B4 ring in the above formula IV;

The definition of C6 ring is the same as that of Co ring in the above formula O; or, the definition of C6 ring is the same as that of C4 ring in the above formula IV;

The definition of _R6 is the same as the definition of Ro in the above formula O; or, the definition of _R6 is the same as the definition of _R11 in the above formula I-1; or, the definition of _R6 is the same as the definition of _R12 in the above formula I-2; or, the definition of _R6 is the same as the definition of _R13 in the above formula I-3; or, the definition of _R6 is the same as the definition of _R14 in the above formula I-4; or, the definition of _R6 is the same as the definition of _R4 in the above formula IV.

In some embodiments of the present application, the compound of formula O is the following formula Ox:

in:

The Aox ring is selected from: Preferably, the Aox ring is selected from: Most preferably, the Aox ring is Y is selected from CH, N; the definition of Rx is the same as that of R ₁₂₁ in the above formula I-2-1; or, the definition of Rx is the same as that of R ₁₃₂ in the above formula I-3-2; preferably, the position of Rx on the ring is selected from: 2-position monosubstitution, 3-position monosubstitution, or 2-, 3-position disubstitution.

In some embodiments of the present application, the above compound is selected from the following:

In a second aspect, the present application relates to a method for preparing the above-mentioned compound, or a tautomer, a stereoisomer, a geometric isomer, an enantiomer, a diastereomer, a racemate, a prodrug, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a hydrate, an ester, an isotope, or a metabolite thereof, comprising:

Wherein: the definition of Co ring is the same as that of Co ring in the above formula O; the definition of Ro is the same as that of Ro in the above formula O; X is selected from halogen, preferably -F, -Cl.

In some embodiments of the present application, step a: 1) nucleophilic substitution is carried out under alkaline conditions (such as cesium carbonate, sodium tert-butoxide, sodium hydrogen, potassium tert-butoxide, etc.); 2) the reaction can also be carried out under Buchwald coupling conditions (such as Pd2(dba)3 or Pd G3, Pd G2 and other palladium catalysts, BINAP, Xantphos as phosphorus ligands, Cs2CO3, or sodium tert-butoxide as alkaline).

In some embodiments of the present application, the solvent of step a is N,N-dimethylformamide or dimethyl sulfoxide, 1,4-dioxane, toluene, and the like.

In some embodiments of the present application, step b is in the presence of molecular sieves.

In some embodiments of the present application, the solvent of step b is methanol. In some embodiments of the present application, the solvent of step c is tetrahydrofuran.

In some embodiments of the present application, the present application relates to a method for preparing the above-mentioned compound, or a tautomer, a stereoisomer, a geometric isomer, an enantiomer, a diastereomer, a racemate, a prodrug, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a hydrate, an ester, an isotope, or a metabolite thereof, comprising:

Wherein: R ^1' is defined the same as Ro in the above formula O; R ^2' is selected from -CF ₃ , -Cl, -SF ₅ , -CH ₃ , -F, -OCH ₃ , -OCF ₃ ;

R ^3' is selected from H, -CH ₃ ; R ^4' is selected from -CN, LG ₁ is a leaving group, preferably a halogen, more preferably -F or -Cl; A ₁ , A ₂ , A ₃ and A ₄ are each independently selected from N and CH.

In some embodiments of the present application, As a whole, selected from:

In some embodiments of the present application, step m can be designed and synthesized using three different ideas. Scheme (1) In alkaline conditions such as cesium carbonate, sodium tert-butoxide, sodium hydrogen, potassium tert-butoxide, etc., with DMF or MeCN as solvent, heated to the reaction temperature, the substituted indole undergoes nucleophilic substitution on the C ring to introduce a substituted indole ring structure; Scheme (2) can use Buchwald coupling, such as Pd ₂ (dba) ₃ or Pd G ₃ , Pd G ₂ , Pd G ₄ and other palladium catalysts, in the presence of BINAP phosphorus ligands, Xantphos and other phosphorus ligands, with Cs ₂ CO ₃ , or sodium tert-butoxide as base, toluene or 1,4-dioxane as solvent, heated to the reaction temperature to carry out coupling reaction, which can introduce a substituted indole ring structure with a relatively high yield. Scheme (3) can use the Ullmann reaction, under CuI catalysis, L-poline, or trans-N,N'-dimethyl-1,2-cyclohexanediamine as a ligand, potassium phosphate as a base, toluene as a solvent, and heating to a certain temperature to produce a coupling reaction of indole substituted indole ring.

In some embodiments of the present application, step n can use hydroxylamine hydrochloride, under the conditions of organic base such as N, N-diethylisopropylamine, triethylamine, etc., methanol as solvent, add The molecular sieve bar is heated to 80 degrees, reacted for a certain period of time to obtain hydroxylamine added to the cyano functional group to obtain an amidine structure, and then reacted under dicarbonyl imidazole reagent conditions, DBU as an organic base, THF as a solvent, and TLC detection. The reaction is completed to obtain a dioxazolone structure. This structure can be further electrophilically substituted by an electrophilic alkyl halide structure to introduce an alkyl side chain, such as

In a third aspect, the present application relates to a pharmaceutical composition comprising the above-mentioned compound, or a tautomer, a stereoisomer, a geometric isomer, an enantiomer, a diastereomer, a racemate, a prodrug, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a hydrate, an ester, an isotope, or a metabolite thereof; optionally, further comprising a pharmaceutically acceptable excipient.

In a fourth aspect, the present application relates to a method for treating cancer in a patient, comprising administering to the patient the above-mentioned compound, or a tautomer of the compound, a stereoisomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a hydrate thereof, an ester thereof, an isotope thereof, or a metabolite thereof; or the above-mentioned pharmaceutical composition.

In some embodiments, the cancer is associated with TEAD overexpression.

In some embodiments, the cancer is associated with increased TEAD activity.

In a fifth aspect, the present application relates to a method for inhibiting the progression of cancer in a patient, which comprises administering to the patient the above-mentioned compound, or a tautomer of the compound, a stereoisomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a hydrate thereof, an ester thereof, an isotope thereof, or a metabolite thereof; or the above-mentioned pharmaceutical composition.

In some embodiments, the cancer is associated with TEAD overexpression.

In some embodiments, the cancer is associated with increased TEAD activity.

In some embodiments, the present application relates to a method for treating a patient suffering from a disease or condition associated with increased TEAD expression, comprising administering to the patient the above-mentioned compound, or a tautomer of the compound, a stereoisomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a hydrate thereof, an ester thereof, an isotope thereof, or a metabolite thereof; or the above-mentioned pharmaceutical composition.

In some embodiments, the present application relates to a method for treating a patient suffering from a disease or condition associated with increased TEAD activity, comprising administering to the patient the above-mentioned compound, or a tautomer of the compound, a stereoisomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a hydrate thereof, an ester thereof, an isotope thereof, or a metabolite thereof; or the above-mentioned pharmaceutical composition.

In some embodiments, the present application relates to a method for treating a disease or condition, wherein inhibiting TEAD activity will be beneficial to the disease or condition, comprising administering to the patient the above-mentioned compound, or a tautomer of the compound, a stereoisomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a hydrate thereof, an ester thereof, an isotope thereof, or a metabolite thereof; or the above-mentioned pharmaceutical composition.

In some embodiments, the present application relates to a method for treating a disease or condition in which inhibition of the Hippo pathway will be beneficial, comprising administering to the patient the above-mentioned compound, or a tautomer of the compound, a stereoisomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a hydrate thereof, an ester thereof, an isotope thereof, or a metabolite thereof; or the above-mentioned pharmaceutical composition.

In some embodiments, the disease or disorder is a cell proliferative disorder.

In some embodiments, the cell proliferative disorder is cancer.

In some embodiments, the cancer is one in which YAP is localized to the nucleus of the cancer.

In some embodiments, the TEAD overexpression or increased TEAD activity is TEAD1 overexpression or increased TEAD1 activity.

In some embodiments, the TEAD overexpression or increased TEAD activity is TEAD2 overexpression or increased TEAD2 activity.

In some embodiments, the TEAD overexpression or increased TEAD activity is TEAD3 overexpression or increased TEAD3 activity.

In some embodiments, the TEAD overexpression or increased TEAD activity is TEAD4 overexpression or increased TEAD4 activity.

In some embodiments, the TEAD overexpression or increased TEAD activity is TEAD1 overexpression or increased TEAD1 activity; TEAD2 overexpression or increased TEAD2 activity; TEAD3 overexpression or increased TEAD3 activity; or TEAD4 overexpression or increased TEAD4 activity; or any combination thereof.

In a sixth aspect, the present application relates to a compound as described above, or a tautomer of the compound, a stereoisomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a hydrate thereof, an ester thereof, an isotope thereof, or a metabolite thereof; or the use of the pharmaceutical composition as described above in the preparation of a drug for treating cancer.

In some embodiments, the cancer is associated with TEAD overexpression.

In some embodiments, the cancer is associated with increased TEAD activity.

In the seventh aspect, the present application relates to a compound as described above, or a tautomer of the compound, a stereoisomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a hydrate thereof, an ester thereof, an isotope thereof, or a metabolite thereof; or the use of the above-mentioned pharmaceutical composition in the preparation of a drug for inhibiting cancer progression.

In some embodiments, the cancer is associated with TEAD overexpression.

In some embodiments, the cancer is associated with increased TEAD activity.

In some embodiments, the present application relates to a compound as described above, or a tautomer of the compound, a stereoisomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a hydrate thereof, an ester thereof, an isotope thereof, or a metabolite thereof; or the use of the pharmaceutical composition as described above in the preparation of a medicament for treating a disease or condition associated with increased TEAD expression.

In some embodiments, the present application relates to a compound as described above, or a tautomer of the compound, a stereoisomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a hydrate thereof, an ester thereof, an isotope thereof, or a metabolite thereof; or the use of the pharmaceutical composition as described above in the preparation of a drug for treating a disease or condition associated with increased TEAD activity.

In some embodiments, the present application relates to a compound as described above, or a tautomer of the compound, a stereoisomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a hydrate thereof, an ester thereof, an isotope thereof, or a metabolite thereof; or the use of the above-mentioned pharmaceutical composition in the preparation of a drug for treating a disease or condition associated with TEAD activity; wherein, inhibiting TEAD activity will benefit the disease or condition.

In some embodiments, the present application relates to a compound described above, or a tautomer, a stereoisomer, a geometric isomer, an enantiomer, a diastereomer, a racemate, a prodrug, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a hydrate, an ester, an isotope, or a metabolite thereof, or a use of the pharmaceutical composition described above in the preparation of a medicament for treating a disease or condition associated with the Hippo pathway; wherein inhibition of the Hippo pathway will benefit the disease or condition.

In some embodiments, the disease or disorder is a cell proliferative disorder.

In some embodiments, the cell proliferative disorder is cancer.

In some embodiments, the cancer is one in which YAP is localized to the nucleus of the cancer.

In some embodiments, the TEAD overexpression or increased TEAD activity is TEAD1 overexpression or increased TEAD1 activity.

In some embodiments, the TEAD overexpression or increased TEAD activity is TEAD2 overexpression or increased TEAD2 activity.

In some embodiments, the TEAD overexpression or increased TEAD activity is TEAD3 overexpression or increased TEAD3 activity.

In some embodiments, the TEAD overexpression or increased TEAD activity is TEAD4 overexpression or increased TEAD4 activity.

In some embodiments, the TEAD overexpression or increased TEAD activity is TEAD1 overexpression or increased TEAD1 activity; TEAD2 overexpression or increased TEAD2 activity; TEAD3 overexpression or increased TEAD3 activity; or TEAD4 overexpression or increased TEAD4 activity; or any combination thereof.

In an eighth aspect, the present application relates to a compound as described above, or a tautomer of the compound, a stereoisomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a hydrate thereof, an ester thereof, an isotope thereof, or a metabolite thereof, or the use of the pharmaceutical composition as described above in the preparation of a drug having the activity of binding to TEAD and blocking the interaction between YAP/TEAD.

In the ninth aspect, the present application relates to a method for treating a disease or condition in a patient, comprising administering to the patient the above-mentioned compound, or a tautomer of the compound, a stereoisomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a hydrate thereof, an ester thereof, an isotope thereof, or a metabolite thereof; or the above-mentioned pharmaceutical composition; the disease or condition is related to a protein that interacts with TEAD.

In some embodiments, the disease or disorder associated with the TEAD-interacting protein includes, but is not limited to, cancer, metabolic disease, inflammatory disease, or neurodegenerative disease.

In some embodiments, the cancer is selected from breast cancer, central nervous system cancer, endometrial cancer, liver cancer, kidney cancer, colorectal cancer, lung cancer, esophageal cancer, tongue cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, mesothelioma, melanoma, fibrosarcoma, bladder cancer, rectal cancer, lymphoma, cervical cancer, head and neck cancer, brain cancer, upper aerodigestive tract cancer, colorectal cancer, urinary tract cancer or colon cancer; preferably, the cancer is selected from brain cancer, esophageal cancer, kidney cancer, mesothelioma, liver cancer, head and neck cancer, lung cancer, gastric cancer, breast cancer or prostate cancer; more preferably, each cancer is selected from Preferably, the cancer is selected from adenocarcinoma, squamous cell carcinoma, mixed adenosquamous carcinoma, and undifferentiated carcinoma; further preferably, the brain cancer includes but is not limited to glioma; head and neck cancer includes but is not limited to head and neck squamous cell carcinoma; lung cancer includes but is not limited to lung adenocarcinoma, lung adenosquamous carcinoma, squamous cell lung cancer, large cell lung cancer, small cell lung cancer, papillary lung adenocarcinoma or non-small cell lung cancer; gastric cancer includes but is not limited to gastric adenocarcinoma; breast cancer includes but is not limited to ductal breast cancer, breast cancer or HR+ breast cancer; prostate cancer includes but is not limited to prostate adenocarcinoma, prostate squamous cell carcinoma, or prostate adenosquamous carcinoma.

In the tenth aspect, the present application relates to a compound as described above, or a tautomer of the compound, a stereoisomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a hydrate thereof, an ester thereof, an isotope thereof, or a metabolite thereof; or the use of the above-mentioned pharmaceutical composition in the preparation of a drug for treating a disease or condition; the disease or condition is related to a protein that interacts with TEAD.

In some embodiments, the disease or disorder associated with the TEAD-interacting protein includes, but is not limited to, cancer, metabolic disease, inflammatory disease, or neurodegenerative disease.

In some embodiments, the cancer is selected from breast cancer, central nervous system cancer, endometrial cancer, liver cancer, kidney cancer, colorectal cancer, lung cancer, esophageal cancer, tongue cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, mesothelioma, melanoma, fibrosarcoma, bladder cancer, rectal cancer, lymphoma, cervical cancer, head and neck cancer, brain cancer, upper aerodigestive tract cancer, colorectal cancer, urinary tract cancer or colon cancer; preferably, the cancer is selected from brain cancer, esophageal cancer, kidney cancer, mesothelioma, liver cancer, head and neck cancer, lung cancer, gastric cancer, breast cancer or prostate cancer; more preferably, each cancer is independently selected from adenocarcinoma, squamous cell carcinoma, mixed adenosquamous carcinoma, undifferentiated carcinoma; further preferably, the brain cancer includes but is not limited to glioma; head and neck cancer includes but is not limited to head and neck squamous cell carcinoma; lung cancer includes but is not limited to lung adenocarcinoma, lung adenosquamous carcinoma, squamous cell lung cancer, large cell lung cancer, small cell lung cancer, lung papillary adenocarcinoma or non-small cell lung cancer; gastric cancer includes but is not limited to gastric adenocarcinoma; breast cancer includes but is not limited to ductal breast cancer, Breast cancer or HR+ breast cancer; prostate cancer includes but is not limited to prostate adenocarcinoma, prostate squamous cell carcinoma, or prostate adenosquamous carcinoma.

In the eleventh aspect, the present application relates to a compound as described above, or a tautomer of the compound, a stereoisomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a hydrate thereof, an ester thereof, an isotope thereof, or a metabolite thereof; or the use of the above-mentioned pharmaceutical composition in the treatment of a disease or condition; the disease or condition is related to a protein that interacts with TEAD.

In some embodiments, the disease or disorder associated with the TEAD-interacting protein includes, but is not limited to, cancer, metabolic disease, inflammatory disease, or neurodegenerative disease.

In some embodiments, the cancer is selected from breast cancer, central nervous system cancer, endometrial cancer, liver cancer, kidney cancer, colorectal cancer, lung cancer, esophageal cancer, tongue cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, mesothelioma, melanoma, fibrosarcoma, bladder cancer, rectal cancer, lymphoma, cervical cancer, head and neck cancer, brain cancer, upper aerodigestive tract cancer, colorectal cancer, urinary tract cancer or colon cancer; preferably, the cancer is selected from brain cancer, esophageal cancer, kidney cancer, mesothelioma, liver cancer, head and neck cancer, lung cancer, gastric cancer, breast cancer or prostate cancer; more preferably, each cancer is selected from Preferably, the cancer is selected from adenocarcinoma, squamous cell carcinoma, mixed adenosquamous carcinoma, and undifferentiated carcinoma; further preferably, the brain cancer includes but is not limited to glioma; head and neck cancer includes but is not limited to head and neck squamous cell carcinoma; lung cancer includes but is not limited to lung adenocarcinoma, lung adenosquamous carcinoma, squamous cell lung cancer, large cell lung cancer, small cell lung cancer, papillary lung adenocarcinoma or non-small cell lung cancer; gastric cancer includes but is not limited to gastric adenocarcinoma; breast cancer includes but is not limited to ductal breast cancer, breast cancer or HR+ breast cancer; prostate cancer includes but is not limited to prostate adenocarcinoma, prostate squamous cell carcinoma, or prostate adenosquamous carcinoma.

Definition of terms

In the present invention, unless explicitly stated otherwise, the description method "...are independently selected from" used throughout this article can mean that in different groups, the specific options expressed by the same or different symbols do not affect each other, and can also mean that in the same group, the specific options expressed by the same or different symbols do not affect each other.

The substituents of the compounds of the present invention are disclosed in terms of group types or ranges. It is particularly noted that the present invention includes each independent secondary combination of the individual members of these group types and ranges. For example, the term "C1-C6 alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl.

The term "alkyl" refers to a branched and straight chain saturated aliphatic hydrocarbon group including a specified number of carbon atoms. For example, "C1-C6 alkyl" refers to C1, C2, C3, C4, C5 and C6. In addition, for example, "C1-C6 alkyl" refers to an alkyl group having 1 to 6 carbon atoms, preferably "C1-C4 alkyl", and more preferably "C1-C3 alkyl". Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), etc.

The term "alkoxy" refers to an oxygen atom substituted by an alkyl group as defined herein. For example, the term "C1-C6 alkoxy" includes the group -O-C1-C6 alkyl, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentoxy, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, etc.

The term "cycloalkyl" refers to a cyclized alkyl group, including a monocyclic, bicyclic or polycyclic system, which does not contain unsaturated bonds such as double bonds, and does not contain any heteroatoms, such as C3-C8 cycloalkyl, C3-C7 cycloalkyl or C3-C6 cycloalkyl. C3-C6 cycloalkyl refers to C3, C4, C5 and C6 cycloalkyl. "3-6 membered cycloalkyl" and "C3-C6 cycloalkyl" can be used interchangeably. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

In the present invention, "Ra, Rb and the carbon atom to which they are commonly connected together form azetidine", which means that Ra, Rb and the carbon atom to which they are commonly connected together form The azetidine is optionally substituted with a hydroxyl group, for example, Other similar definitions can be understood by referring to the above content.

In the present invention, "two Ro and the atoms to which they are connected together form a benzene ring" means that the ring formed by two Ro and the atoms to which they are connected respectively is a benzene ring. Similarly, "two Ro, together with the atoms to which they are connected, form a partially unsaturated C5-C6 carbon ring", which means that the ring formed by the two Ro and the atoms to which they are respectively connected is a partially unsaturated C5-C6 carbon ring, such as Similarly, "two Ro, together with the atoms to which they are connected, form a partially unsaturated 5-6-membered heterocyclic ring", which means that the ring formed by two Ro and the atoms to which they are respectively connected is a partially unsaturated 5-6-membered heterocyclic ring, such as Similarly, "two Ro, together with the atoms to which they are connected, form a 5-membered heteroaromatic ring", which means that the ring formed by two Ro and the atoms to which they are respectively connected is a 5-membered heteroaromatic ring, such as The wavy line in the above structure The two sites shown represent the sites where the ring formed by the two Ro and the atoms to which they are respectively connected is fused with the Co ring. For example, if the ring formed by the two Ro and the atoms to which they are respectively connected is And the Co ring is (Those skilled in the art will understand that the wavy line on the Co ring The two sites shown are the connection sites for connecting with the Ao ring and the L ₀ /Bo ring respectively), then the structure formed after the two rings are fused can be, for example, For another example, if two Ro and the atoms connected to them form a ring And the Co ring is Then the structure formed after the two rings are fused can be, for example, For another example, if two Ro and the atoms connected to them form a ring And the Co ring is Then the structure formed after the two rings are fused can be, for example, For another example, if two Ro and the atoms connected to them form a ring And the Co ring is The structure formed after the two rings are fused can be, for example, Other similar definitions can be understood by referring to the above content.

The term "C1-C6 alkyl substituted by hydroxyl" means that one hydrogen atom in the aforementioned C1-C6 alkyl is replaced by a hydroxyl group, for example Wherein, the definition of alkyl is as described above. Similarly, "C1-C6 alkyl substituted by C6-C10 aryl" means that one hydrogen atom in the aforementioned C1-C6 alkyl is replaced by a C6-C10 aryl, for example, benzyl or Similarly, "C1-C6 alkyl substituted by amino group" means that one hydrogen atom in the aforementioned C1-C6 alkyl group is replaced by amino group, for example Similarly, "C1-C6 alkyl substituted by cyano" means that one hydrogen atom in the aforementioned C1-C6 alkyl is replaced by cyano, for example Similarly, "C1-C6 alkyl substituted by C3-C6 cycloalkyl" means that one hydrogen atom in the aforementioned C1-C6 alkyl is replaced by a C3-C6 cycloalkyl, for example Other similar definitions can be understood by referring to the above content.

In the present invention, "partially unsaturated C5-C6 carbocycle and partially unsaturated 5-6 membered heterocycle are each optionally substituted by 1-6 groups selected from halogen and deuterium", which means that "partially unsaturated C5-C6 carbocycle" and "partially unsaturated 5-6 membered heterocycle" may not be substituted, or may be substituted by 1-6 groups selected from halogen and deuterium, and the substituents of "partially unsaturated C5-C6 carbocycle" and "partially unsaturated 5-6 membered heterocycle" do not affect each other, and may be the same or different. At the same time, if "partially unsaturated C5-C6 carbocycle" or "partially unsaturated 5-6 membered heterocycle" is substituted by 2-6 groups selected from halogen and deuterium, the 2-6 substituents may be the same or different from each other. Other similar definitions can be understood with reference to the above content.

The term "substituted" means that any one or more hydrogens on the designated atom or group are replaced with the selection of designated groups, provided that the normal valence of the designated atom is not exceeded.

The "heteroatom" described in the present invention is N, O or S. The "halogen" described in the present invention is fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.

The "C1-C6 alkyl substituted with 1-6 halogens" and " _C1 - _C6 alkoxy substituted with 1-6 halogens" of the present invention refer to groups formed by replacing one or more hydrogen atoms in the alkyl and alkoxy groups with 1-6 halogen atoms, especially fluorine or _{chlorine atoms} . _{In some} embodiments, fluorine is _preferred , such as _-CF3 , -CHF2, _-CH2F , -CH2CH2F, _{-CH2CHF2 ,} -CH2CF3, _-OCF3 , _-OCHF2 , _{-OCH2F , -OCH2CH2F} , _-OCH2CHF2 or _-OCH2CF3 . Similarly, "C1-C6 alkyl substituted with 1-6 deuteriums" refers to groups formed by replacing _one or more hydrogen atoms in the alkyl groups with 1-6 deuterium atoms, _such as _-CD3 .

The term "alkenyl" refers to a group formed by one or more double bonds in the above-mentioned "alkyl", preferably a "C2-C6 alkenyl", and preferred examples are

The term "heteroaryl" refers to substituted and unsubstituted aromatic 5- or 6-membered monocyclic groups, 8-, 9- or 10-membered bicyclic groups and 11- to 14-membered tricyclic groups having at least one heteroatom (O, N or S) in at least one ring, the heteroatom-containing ring optionally further having 1, 2 or 3 heteroatoms selected from O, N or S. The heteroaryl is preferably a 5- or 6-membered monocyclic group (i.e., a "5-6 membered heteroaryl"). The heteroaryl may be attached on any available nitrogen or carbon atom of any ring. If the heteroaryl group is limited by the number of carbon atoms, such as "C1-C5 heteroaryl", it means that the heteroaryl group contains carbon atoms with the limited number of carbon atoms, and contains 1-5 heteroatoms in addition to carbon atoms; for example, "C1-C5 heteroaryl" means that the heteroaryl group contains 1-5 carbon atoms, and contains 1-5 heteroatoms in addition to carbon atoms, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, etc. Exemplary 5-6 membered heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, and the like.

The terms "heterocycle", "heterocyclic" or "heterocyclyl" are used interchangeably and refer to substituted and unsubstituted 3- to 7-membered monocyclic groups, 7- to 11-membered bicyclic groups and 10- to 15-membered tricyclic groups, which may contain one or more double bonds but do not constitute an aromatic ring; wherein at least one ring has at least one heteroatom (O, S or N). The heterocyclyl is preferably a 5- to 6-membered monocyclic group (i.e., a "5-6 membered heterocyclyl"). The heterocyclic group may be attached at any available nitrogen or carbon atom. Wherein, if the heterocyclyl does not contain one or more double bonds, it is referred to as a "saturated heterocyclyl". Similarly, if the heterocyclyl contains one or more double bonds and does not constitute an aromatic ring, it is referred to as an "unsaturated heterocyclyl". If the heterocyclic group is limited by carbon atoms, such as "C3-C5 heterocyclic group", it means that the heterocyclic group contains the specified number of carbon atoms and contains 1-2 heteroatoms in addition to carbon atoms; for example, "C3-C5 heterocyclic group" means that the heterocyclic group contains 3-5 carbon atoms and contains 1-2 heteroatoms in addition to carbon atoms, for example

Exemplary 5-6 membered heterocyclic groups include azetidinyl, oxetanyl, pyrrolidinyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepanyl, 1-pyridonyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, 1,3-dioxolanyl, and the like.

The term "oxo" or "oxo" are used interchangeably and refer to "=O". For example, a 5-membered unsaturated heterocyclic ring is substituted by oxo or oxo, the structural formula after substitution is Similarly, if the thiomorpholinyl When it is substituted by 2 oxo groups and the substitution site is S, the structural formula after substitution is Other similar definitions can be understood by referring to the above content.

In the present invention, a direct bond refers to the groups on both sides being directly connected. For example, If L ₀ is a direct bond, the structure of formula O will become Other similar definitions can be understood by referring to the above content.

In the present invention, a dotted bond -------- means that the bond exists or does not exist.

Formula O If Ro is 0, it means that Ro does not exist, that is, the structural formula of formula O becomes If Ro is 1, the structural formula of formula O becomes If Ro is 2, the structural formula of formula O becomes The definitions of the two Ro are independent of each other and can be the same or different. Other similar structural formulas or definitions can be understood by referring to the above content.

In the present invention, "treatment" generally refers to obtaining the desired pharmacological and/or physiological effect. The effect can be preventive, based on the complete or partial prevention of the disease or its symptoms; and/or can be therapeutic, based on the partial or complete stabilization or cure of the disease and/or side effects caused by the disease. As used herein, "treatment" covers any treatment of a patient's disease, including: (a) preventing the disease or symptoms from occurring in a patient who is susceptible to the disease or symptoms but has not yet been diagnosed with the disease; (b) inhibiting the symptoms of the disease, i.e., preventing its development; or (c) alleviating the symptoms of the disease, i.e., causing the disease or symptoms to regress.

In the present invention, "subject" refers to a vertebrate. In certain embodiments, a vertebrate refers to a mammal. Mammals include, but are not limited to, livestock (such as cattle), pets (such as cats, dogs, and horses), primates, mice, and rats. In certain embodiments, a mammal refers to a human.

In the present invention, "effective amount" refers to an amount that is effective at the required dose and time to achieve the desired therapeutic or preventive effect. The "therapeutically effective amount" of the substance/molecule of the present invention may vary according to factors such as the disease state, age, sex and weight of the individual and the ability of the substance/molecule to induce the desired response in the individual. The therapeutically effective amount also covers the amount of the substance/molecule in which the therapeutic beneficial effect outweighs any toxic or harmful consequences. "Preventively effective amount" refers to an amount that is effective at the required dose and time to achieve the desired preventive effect. Usually, but not necessarily, since the preventive dose is used for the subject before the onset of the disease or in the early stage of the disease, the preventive effective amount will be lower than the therapeutic effective amount. In the case of cancer, the therapeutically effective amount of the drug can reduce the number of cancer cells; reduce the size of the tumor; inhibit (i.e., slow down to a certain extent, preferably stop) the infiltration of cancer cells into surrounding organs; inhibit (i.e., slow down to a certain extent, preferably stop) tumor metastasis; inhibit tumor growth to a certain extent; and/or alleviate one or more symptoms associated with cancer to a certain extent.

The pharmaceutical composition of the present invention may contain pharmaceutically acceptable excipients, including but not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human albumin, buffer substances such as phosphates, glycerol, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, beeswax, lanolin, etc.

The pharmaceutical composition of the present invention can be prepared into various forms according to different administration routes. For example, the pharmaceutical composition can be administered in any of the following ways: oral administration, spray inhalation, rectal administration, nasal administration, buccal administration, vaginal administration, topical administration, parenteral administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or administration via an explanted reservoir. Among them, oral, intraperitoneal or intravenous administration is preferred.

As used herein, unless otherwise indicated, the term "prodrug" refers to a derivative that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide a compound of the present invention. Prodrugs become active compounds only under biological conditions through this reaction, or they are active in their unreactive form. Prodrugs can generally be prepared using known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E. Wolff, 5th edition).

When the stereoisomers in the compounds described herein are specifically designated as (R)- or (S)-isomers in the chemical name, it should be understood that the main configuration is the (R)-isomer or (S)-isomer, respectively. Any asymmetric carbon atom can exist in the (R)-, (S)- or (R, S)-configuration, preferably in the (R)- or (S)-configuration.

The tautomers in the compounds described herein refer to two isomers containing heteroatoms (such as nitrogen, oxygen or sulfur atoms), whose structural difference lies only in the migration of protons and corresponding double bonds, and these two isomers coexist in an equilibrium system and transform with each other at a relatively high rate. A typical example is the group can be converted into Thus, if the structural formula of the compound described herein is Those skilled in the art will understand that the structure and structure If similar groups exist in other compounds, they should be understood with reference to the above content.

The definition of "geometric isomers" described herein is that isomers caused by the inability of double bonds or single bonds of ring carbon atoms to rotate freely are called geometric isomers, also known as cis-trans isomers.

The definition of "enantiomers" described herein is that stereoisomers that are real objects and mirror images of each other and are not superimposable are called enantiomers.

The term "diastereomer" as used herein refers to a stereoisomer having two or more chiral centers and having a non-mirror-image relationship between the molecules.

The "racemate" described herein includes racemate and mesomer. A racemate refers to an equimolar mixture of an optically active chiral molecule and its enantiomer. A mesomer refers to a molecule with two or more asymmetric centers, but with other symmetry factors, such as the presence of a symmetry plane, which makes the entire molecule inactive and without enantiomers, and is usually represented by meso or i.

As used herein, "hydrate" refers to a compound that exists in combination with water molecules. The combination may include a stoichiometric amount of water, such as a monohydrate or a dihydrate, or may include any amount of water.

"Ester" as used herein refers to an ester formed by -COOH present in the compounds provided by the present invention and a suitable alcohol, or an ester formed by -OH present in the compounds provided by the present invention and a suitable acid (e.g., a carboxylic acid or an oxygen-containing inorganic acid). Suitable ester groups include, but are not limited to, formates, acetates, propionates, butyrates, acrylates, ethylsuccinates, stearic acid esters or palmitates. Esters can undergo hydrolysis in the presence of an acid or base to generate the corresponding acid or alcohol.

Different atoms of the same element with the same number of protons but different numbers of neutrons are called isotopes. The "isotopes of a compound" mentioned herein refer to the structure formed after one or more atoms in the compound provided by the present invention are replaced by their isotopes.

The "metabolites" described herein refer to the intermediate metabolites or final metabolites of the compounds provided by the present invention under certain metabolic conditions.

The "pharmaceutically acceptable salt" of the present invention refers to an acid addition salt obtained by reacting the compound of the present invention with a pharmaceutically acceptable acid, or a salt formed by reacting a compound having an acidic group with a basic compound. Among them, the acid is preferably selected from inorganic acids (such as hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid, etc.), and organic acids (such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, lysine, histidine, citric acid or benzoic acid, etc.); the basic compound is preferably selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate or potassium bicarbonate, etc. The above-mentioned pharmaceutically acceptable salts are easy to separate and can be purified by conventional separation methods, such as solvent extraction, dilution, recrystallization, column chromatography and preparative thin layer chromatography.

A "solvate" is a compound that exists in combination with some solvent molecules. The combination may include a stoichiometric amount of some solvent, such as a monohydrate or a dihydrate, or may include any amount of water; for example, methanol or ethanol may form an "alcoholate", which may also be stoichiometric or non-stoichiometric. The term "solvate" as used herein refers to a solid form, i.e., a compound in a solution of a solvent, although it may be solvated, it is not a solvate as the term is used herein.

The compounds of the present invention may be used in combination with one or more other active ingredients, and the dosage and ratio of each may be adjusted by those skilled in the art according to the specific symptoms and patient conditions and clinical needs.

The examples and preparations provided in the present invention further illustrate and illustrate the compounds and preparation methods of the present invention. It should be understood that the following preparations and examples do not limit the scope of the present invention in any way.

DETAILED DESCRIPTION

The compounds of the present invention can be synthesized from commercially available reagents using the synthetic methods and reaction schemes described herein. The examples and general schemes that outline specific synthetic routes are intended to provide guidance to the ordinary synthetic chemist, who will readily understand that solvents, concentrations, reagents, protecting groups, order of synthetic steps, times, temperatures, etc. can be modified as needed within the skill and judgment of the ordinary technician.

Example

The following examples are provided to better illustrate the present invention. Unless otherwise expressly stated, all parts and percentages are by weight, and all temperatures are in degrees Celsius. The following abbreviations are used in the examples: molecular sieve; CDI: N,N'-carbonyldiimidazole; DBU: 1,8-diazabicyclo[5.4.0]-7-undecene; HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; Pd/C: palladium on carbon; Pd(dppf)Cl ₂ : 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride; Pd(PPh ₃ ) ₄ : tetrakis(triphenylphosphine)palladium; DMF: N,N-dimethylformamide; EA: ethyl acetate; CH ₃ CN/ACN: acetonitrile; DCM: dichloromethane; NMP: N-methylpyrrolidone; THF: tetrahydrofuran; TEA: triethylamine; DIPEA: N,N-diisopropylethylamine; h/hrs: hours; min/mins: minutes; NCS: N-chlorosuccinimide; rt/rt/rt/room temperature: temperature range is 20-30°C; MW: microwave; Pd ₂ (dba) ₃ : tris(dibenzylideneacetone)dipalladium; XantPhos: 4,5-bis(diphenylphosphino-9,9-dimethylxanthene); Deoxo fluor: bis(2-methoxyethyl)aminosulfur trifluoride; BrettPhos Pd G3: methanesulfonate (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II); XPhos Pd G2: chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II); t-Buxphos Pd G4: (methanesulfonate (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II);

Example 1

Step 1: 5-(Trifluoromethyl)-1H-indole (1.53 g, 8.26 mmol) was added to a mixture of 3-fluoro-2-benzonitrile (1.0 g, 8.26 mmol), cesium carbonate (5.38 g, 16.52 mmol) and N,N-dimethylformamide (8 mL). The reaction mixture was stirred at 80 ° C for 3 hours, diluted with water (15 mL), and extracted with ethyl acetate (45 mL). The organic phase was washed with saturated sodium chloride solution, dried and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent gradient from petroleum ether: EtOAc = 20: 1 to 4: 1) to obtain compound 1-1 (2.10 g, 6.99 mmol, yield: 84.6%).

Step 2: To a solution of compound 1-1 (389 mg, 1.36 mmol) in MeOH (17 mL) were added hydroxylamine hydrochloride (1.89 g, 27.20 mmol), triethylamine (5.5 mL, 39.68 mmol) and Molecular sieves (400 mg). The reaction mixture was stirred at 78°C overnight, filtered, and the filtrate was concentrated. The concentrate was diluted with H ₂ O and extracted with EA. The organic layer was dried and concentrated, and the residue was purified by column chromatography to obtain compound 1-2 (110 mg, 0.34 mmol, yield: 25.0%). MS (ESI): m/z=320[M+H] ⁺ .

Step 3: At 0°C, CDI (135 mg, 0.83 mmol) was added to a solution of compound 1-2 (90 mg, 0.28 mmol) in THF (4 mL), and DBU (0.13 mL, 0.89 mmol) was added after stirring at room temperature overnight. The reaction mixture was stirred at room temperature for 3 hours and then concentrated. EA was added to the obtained concentrate to dilute the concentrate, and the pH was adjusted to neutral with hydrochloric acid (1 M). The organic layer was dried and concentrated, and the obtained residue was purified by silica gel column chromatography to obtain compound 1 (60 mg, 0.17 mmol, yield: 60.7%). MS (ESI): m/z=346[M+H] ⁺ .

¹ HNMR (400MHz, DMSO-d ₆ ) δ8.05 (d, J＝1.8Hz, 1H), 7.90 (dd, J＝7.7, 1.6Hz, 1H), 7.86 (td, J＝7.7, 1.6Hz, 1H ),7.76(td,J＝7.6,1.3Hz,1H),7.70(dd,J＝7.9,1.2Hz,1H),7.59(d,J＝3.3Hz,1H),7.44(dd,J＝8.8, 1.8Hz, 1H), 7.24 (d, J = 8.6Hz, 1H), 6.85 (d, J = 3.3Hz, 1H).

Example 2

Step 1: 5-(trifluoromethyl)-1H-indole (331.71 mg, 1.79 mmol) was added to a solution of 3-chloropyrazine-2-carbonitrile (250 mg, 1.79 mmol) and sodium tert-butoxide (172.17 mg, 1.79 mmol) in N,N-dimethylformamide (8 mL). The reaction mixture was stirred at 120°C for 3 hours, diluted with water (15 mL), and then extracted with ethyl acetate (45 mL). The organic phase was washed with a saturated sodium chloride solution, dried, and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent gradient from petroleum ether: EtOAc = 20:1 to 4:1) to obtain compound 2-1 (303 mg, 1.05 mmol, yield: 58.68%). MS (ESI): m/z = 289 [M+H] ⁺ .

Step 2: Add hydroxylamine hydrochloride (121.61 mg, 1.75 mmol) to a mixture of compound 2-1 (100 mg, 3.05 mmol), triethylamine (0.97 mL, 7.00 mmol), molecular sieves (100 mg), and methanol (4 mL). After stirring the reaction mixture at 80 ° C for 2 hours, filter and concentrate the filtrate. Add water (10 mL) to the concentrate and then extract with ethyl acetate (30 mL). The organic phase was washed with a saturated sodium chloride solution, dried and concentrated, and the residue was purified by silica gel column chromatography (eluent gradient from petroleum ether: EtOAc = 20: 1 to 4: 1) to obtain compound 2-2 (110 mg, 0.34 mmol, yield: 98.69%). MS (ESI): m/z = 322 [M+H] ⁺ .

Step 3: At 0°C, CDI (69.40 mg, 0.43 mmol) was added to a tetrahydrofuran (3 mL) solution of compound 2-2 (110 mg, 0.34 mmol), and DBU (76.66 μL, 0.51 mmol) was added after stirring at room temperature for 0.5 hours. The reaction mixture was stirred at room temperature for 1 hour, diluted with water (15 mL), and extracted with ethyl acetate (45 mL). The organic phase was washed with a saturated sodium chloride solution, dried and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent gradient from dichloromethane: methanol = 1:0 to 10:1) to obtain compound 2 (47 mg, 0.14 mmol, yield: 39.53%). MS (ESI): m/z = 348 [M+H] ⁺ .

¹ H NMR (CHLOROFORM-d) δ: 9.75 (br s, 1H), 8.80 (d, J = 2.3Hz, 1H), 8.75 (d, J = 2.3Hz, 1H), 7.99 (s, 1H), 7.49 -7.54(m,3H),6.88(d,J＝3.5Hz,1H).

Example 3

Step 1: At 0°C, sodium tert-butoxide (69 mg, 0.72 mmol) was added to a solution of 2-chloro-3-cyanopyridine (100 mg, 0.72 mmol) and 5-(trifluoromethyl)indole (134 mg, 0.72 mmol) in N,N-dimethylformamide (3 mL). The reaction mixture was heated to 120°C and stirred for 18 hours. Water (10 mL) was added to quench the mixture, and then extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with water, dried and concentrated, and the residue was purified by silica gel column chromatography to obtain compound 3-1 (155 mg). MS (ESI): m/z=288[M+H] ⁺ .

Step 2: Compound 3-1 (85 mg, 0.30 mmol), hydroxylamine hydrochloride (206 mg, 2.96 mmol), triethylamine (0.82 mL, 5.92 mmol) and Molecular sieves (100 mg) were added to methanol (5 mL). The reaction mixture was stirred at room temperature for 15 minutes, then heated to 75°C and stirred at this temperature for 5 hours, water (10 mL) was added to quench the reaction, and extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with water, dried, and concentrated, and the residue was purified by silica gel column chromatography to obtain compound 3-2 (70 mg). MS (ESI): m/z=321[M+H] ⁺ .

Step 3: At 0°C, CDI (111 mg, 0.68 mmol) was added to a tetrahydrofuran (10 mL) solution of compound 3-2 (182 mg, 0.57 mmol), and DBU (0.13 mL, 0.85 mmol) was added after reacting at 0°C for 30 minutes. The reaction mixture was reacted at room temperature for 30 minutes, quenched with water (10 mL), and extracted with EA (20 mL×3). The combined organic phase was washed with water, dried, and concentrated, and the residue was purified by high performance liquid chromatography (HPLC) to obtain compound 3 (86.15 mg, 0.25 mmol, yield: 43.6%). MS (ESI): m/z=347[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ ) δ: 12.79 (br s, 1H), 8.87 (dd, J＝4.8, 1.7Hz, 1H), 8.36 (dd, J＝7.8, 1.8Hz, 1H), 8.07 (s ,1H),7.75(dd,J＝7.8,4.8Hz,1H),7.70(d,J＝8.8Hz,1H),7.63(d,J＝3.4Hz,1H),7.51(dd,J＝8.8, 1.3Hz, 1H), 6.88 (d, J = 3.4Hz, 1H).

Example 4

Step 1: Add trimethylcyclotriboroxane (1.31 mL, 4.6 mmol, 3.5 M in THF), cesium fluoride (5.24 g, 34.39 mmol), pd(dppf)Cl ₂ (0.42 g, 0.57 mmol) to a toluene (10 mL) solution of 3,5-dichloropyrazine-2-carbonitrile (2.00 g, 11.50 mmol). The reaction mixture was heated to 90 °C under nitrogen protection and stirred overnight, then filtered. The filtrate was diluted with water (50 mL) and extracted with ethyl acetate (50 mL*3). The combined organic phases were concentrated, and the residue was purified by flash column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain compound 4-1 (200 mg).

Step 2: Add potassium tert-butoxide (336.35 mg, 3.50 mmol) to a solution of 5-(trifluoromethyl)-indole (432.02 mg, 2.33 mmol) in DMF (5 mL), stir at room temperature for 0.5 h, and then add compound 4-1 (430 mg, 2.80 mmol). Heat the reaction mixture to 120 ° C and stir for 5 h, then dilute with water (10 mL), and extract with ethyl acetate (5 mL*3). The combined organic phases were concentrated to obtain a residue, and the residue was purified by flash column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain compound 4-2 (60 mg). LCMS: m/z = 303.08 [M+H] ⁺ .

Step 3: Add hydroxylamine hydrochloride (68.97 mg, 0.99 mmol), TEA (0.55 mL, 3.97 mmol) and 4A molecular sieves (10 mg) to a methanol (1 mL) solution of compound 4-2 (60 mg, 0.20 mmol). After the reaction mixture was heated to 80°C and stirred for 2 hours, it was filtered and the filtrate was concentrated. The concentrate was diluted with water (3 mL) and extracted with ethyl acetate (3 mL*3). The combined organic phases were concentrated to obtain a crude product of compound 4-3 (66 mg). LCMS: m/z=336.10[M+H] ⁺ .

Step 4: At 0°C, CDI (0.03 mL, 0.25 mmol) was added to a tetrahydrofuran (1 mL) solution of N-hydroxy-5-methyl-3-(5-(trifluoromethyl)-1H-indol-1-yl)pyrazine-2-carboximidamide (66 mg, 0.20 mmol), stirred at 0°C for 0.5 hours, and then DBU (0.04 mL, 0.30 mmol) was added at 0°C. The reaction mixture was warmed to room temperature and stirred for 1 hour, then diluted with water (3 mL), and extracted with ethyl acetate (3 mL*3). The combined organic phases were concentrated, and the residue was purified by preparative high performance liquid chromatography HPLC to obtain compound 4 (5.92 mg, 0.02 mmol, yield 7.80%, purity 93.69%). MS (ESI): m/z=362[M+H] ⁺ . ¹ H NMR (400MHz, MeOH-d4) δ8.76(d,J＝0.6Hz,1H),7.98(s,1H),7.64(d,J＝2.9Hz,1H),7.55(d,J＝8.6Hz,1H),7.44(d,J＝8.4Hz,1H),6.85(d,J＝2.9Hz,1H),2. 71(s,3H).

Example 5

Step 1: Sodium methoxide (117.19 mg, 2.17 mmol) was added to a methanol solution (25 mL) of 3,5-dichloropyrazine-2-carbonitrile (1.0 g, 5.75 mmol) at 0°C. The reaction mixture was stirred at room temperature for 12 hours and then concentrated. Water (15 mL) was added to the obtained concentrate and extracted with ethyl acetate (45 mL). The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated, and the obtained residue was purified by silica gel column chromatography (eluent gradient transition from PE:EA=20:1 to 8:1) to obtain compound 5-1 (856 mg, 5.05 mmol, 87.79%). MS (ESI): m/z=170[M+H] ⁺ .

Step 2: Add 5-(trifluoromethyl)-1H-indole (109.19 mg, 0.59 mmol) to a solution of compound 5-1 (100 mg, 22.99 mmol) and sodium tert-butoxide (56.67 mg, 0.59 mmol) in N,N-dimethylformamide (5 mL). The reaction mixture was stirred at 120°C for 12 hours, diluted with water (10 mL), and then extracted with ethyl acetate (30 mL). The organic phase was washed with a saturated sodium chloride solution, dried and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent gradient transition from PE:EA=20:1 to 8:1) to obtain compound 5-2 (20 mg, 0.06 mmol, yield: 10.66%). MS (ESI): m/z=319[M+H] ⁺ .

Step 3: Compound 5-2 (20 mg, 0.06 mmol), triethylamine (0.17 mL, 1.26 mmol) and Hydroxylamine hydrochloride (21.83 mg, 0.31 mmol) was added to a solution of molecular sieves (20 mg) in methanol (2 mL). The reaction mixture was stirred and refluxed at 80°C for 3 hours and then concentrated to obtain a crude product of compound 5-3 (20 mg), which was directly used in the next step without purification. MS (ESI): m/z = 352 [M+H] ⁺ .

Step 4: Add N,N'-carbonyldiimidazole (11.54 mg, 0.07 mmol) to a tetrahydrofuran solution (2 mL) of compound 5-3 (20 mg, 0.06 mmol) at 0°C, stir at room temperature for 0.5 hours, and then add 1,8-diazabicyclo[5.4.0]-7-undecene (12.75 μL, 0.09 mmol). After stirring the reaction mixture for 1 hour, dilute with water (15 mL) and extract with ethyl acetate (45 mL). The organic phase was washed with saturated ammonium chloride solution and saturated sodium chloride solution in sequence, dried and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent gradient from DCM:MeOH=99:1 to 10:1) to obtain compound 5 (21 mg, 0.06 mmol, yield: 97.77%, purity: 94.55%). MS (ESI): m/z=378[M+H] ⁺ . ¹ H NMR(DMSO-d ₆ )δ:13.07(br s,1H),8.60(s,1H),8.06(s,1H),7.78-7.87(m,2H),7.51(dd,J＝8.6,1.4Hz,1H),6.87(d,J＝3.3Hz,1H),4.02-4.05(m,3H)。

Example 6

Step 1: 5-(trifluoromethyl)-1H-indole (4.26 g, 22.99 mmol) was added to a solution of 3,6-dichloropyrazine-2-carbonitrile (4.0 g, 22.99 mmol) and sodium tert-butoxide (2.65 g, 27.59 mmol) in N,N-dimethylformamide (45 mL). The reaction mixture was stirred at 120°C for 12 hours, diluted with water (60 mL), and then extracted with ethyl acetate (180 mL). The organic phase was washed with saturated sodium chloride solution, dried and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent gradient transition from PE:EA=20:1 to 4:1) to obtain compound 6-1 (2.9 g, 8.99 mmol, yield: 39.09%). MS (ESI): m/z=323[M+H] ⁺ .

Step 2: Sodium methoxide (117.19 mg, 2.17 mmol) was added to a methanol solution (25 mL) of compound 6-1 (700 mg, 2.17 mmol) at 0°C. The reaction mixture was stirred at room temperature for 12 hours and then concentrated, then diluted with water (15 mL) and extracted with ethyl acetate (45 mL). The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent gradient transition from PE:EA=20:1 to 4:1) to obtain compound 6-2 (373 mg, 1.06 mmol, yield: 49.07%). MS (ESI): m/z=351[M+H] ⁺ .

Step 3: Compound 6-2 (100 mg, 0.29 mmol), triethylamine (0.40 mL, 2.85 mmol) and Hydroxylamine hydrochloride (99.19 mg, 1.43 mmol) was added to an ethanol solution (4 mL) of molecular sieves (100 mg). The reaction mixture was stirred and refluxed at 80°C for 3 hours and then concentrated, and then water (15 mL) was added and extracted with ethyl acetate (45 mL). The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent gradient transition from PE:EA=20:1 to 0:1) to obtain compound 6-3 (273 mg, crude product). MS (ESI): m/z=352[M+H] ⁺ .

Step 4: N, N'-carbonyldiimidazole (155.78 mg, 0.96 mmol) was added to a tetrahydrofuran solution (10 mL) of compound 6-3 (273 mg, crude product, 0.77 mmol) at 0°C. After the mixture was stirred at room temperature for 0.5 hours, 1,8-diazabicyclo[5.4.0]-7-undecene (172.08 μL, 1.15 mmol) was added. The reaction mixture was stirred for 1 hour, diluted with water (15 mL), and extracted with ethyl acetate (45 mL). The organic phase was washed with saturated ammonium chloride solution and saturated sodium chloride solution in sequence, dried and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent gradient transition from DCM:MeOH=99:1 to 10:1) to obtain compound 6 (66 mg, 0.17 mmol, yield: 22.76%, purity: 99.14%). MS (ESI): m/z=378[M+H] ⁺ . ¹ H NMR (methanol-d ₄ ) δ: 8.43 (s, 1H), 7.96 (s, 1H), 7.52 (d, J = 3.4 Hz, 1H), 7.38-7.42 (m, 1H), 7.32-7.37 (m, 1H), 6.81 (d, J = 3.4 Hz, 1H), 4.17 (s, 3H).

Example 7

Step 1: Add trimethylcyclotriboroxane (0.14 mL, 0.50 mmol, 3.5 M in THF), potassium carbonate (513.95 mg, 3.72 mmol) and pd(dppf)Cl ₂ (45.35 mg, 0.06 mmol) to a solution of compound 6-1 (400 mg, 1.24 mmol) in dioxane (4 mL) and water (0.5 mL). The reaction mixture was heated to 100 ° C under nitrogen protection and stirred overnight, filtered, and the concentrate was diluted with water (10 mL) and extracted with ethyl acetate (10 mL*3). The combined organic phase was concentrated, and the residue was purified by flash column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain compound 7-1 (190 mg). ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.92(s,1H),8.12(d,J＝3.6Hz,2H),7.93(d,J＝8.6Hz,1H),7.59(d,J＝8.8,1.5Hz,1H),7.02(d,J＝3.5Hz,1H),2.68(s,3H).

Step 2: Add hydroxylamine hydrochloride (80.47 mg, 1.16 mmol), TEA (0.64 mL, 4.63 mmol) and 4A molecular sieves (10 mg) to a methanol (1 mL) solution of compound 7-1 (70 mg, 0.23 mmol). After the reaction mixture is heated to 80°C and stirred for 2 hours, it is filtered and the filtrate is concentrated. Dilute the obtained concentrate with water (3 mL) and extract with ethyl acetate (3 mL*3). The combined organic phases are concentrated to obtain the crude product of compound 7-2 (60 mg). LCMS: m/z=336[M+H] ⁺ .

Step 3: At 0°C, CDI (0.03 mL, 0.23 mmol) was added to a tetrahydrofuran (1 mL) solution of the crude product of compound 7-2 (60 mg), stirred at 0°C for 0.5 h, and then DBU (0.04 mL, 0.28 mmol) was added at 0°C. The reaction mixture was heated to room temperature and stirred for 1 h, then diluted with water (3 mL), and extracted with ethyl acetate (3 mL*3). The combined organic phase was concentrated, and the residue was purified by preparative high performance liquid chromatography (HPLC) to obtain compound 7 (19.69 mg, 0.05 mmol, yield 29.12%, purity 98.79%). MS (ESI): m/z=362[M+H] ⁺ . ¹ HNMR (400MHz, DMSO-d6) δ13.03–13.28(m,1H),8.84(s,1H),8.06(s,1H),7.80(d,J＝3.4Hz,1H),7.55–7.60(m,1H),7.47(dd,J＝8.8,1.6Hz,1H),6.86(d, J＝3.0Hz,1H),2.72(s,3H).

Example 8

Step 1: Add 5-trifluoromethylindole (330 mg, 1.78 mmol) and sodium tert-butoxide (171 mg, 1.78 mmol) to a solution of compound 2-chloro-4-methoxynicotinonitrile (300 mg, 1.78 mmol) in DMF (6 mL). After stirring the reaction mixture at 120°C for 2 hours, cool it to 25°C, add saturated ammonium chloride solution (10 mL) to quench it, and then extract it with EA (50 mL). The combined organic phases were washed with saturated brine (3 times), dried and concentrated. The residue was purified by silica gel column chromatography (eluted with PE:EA=20/1 to 5/1) to obtain compound 8-1 (413 mg, 1.30 mmol). MS (ESI): m/z=318[M+H] ⁺ .

Step 2: To a solution of compound 8-1 (200 mg, 0.63 mmol) in methanol (10 mL) were added hydroxylamine hydrochloride (440 mg, 6.3 mmol), Molecular sieves (200 mg) and triethylamine (5.0 mL, 37.8 mmol). The reaction mixture was stirred at 75 ° C overnight, cooled to 25 ° C and filtered. Saturated ammonium chloride solution (15 mL) was added to the filtrate to quench, and extracted with EA (100 mL). The combined organic phase was washed with saturated brine (3 times), dried and concentrated. The residue was purified by silica gel column chromatography (eluted with PE: EA = 5/1 to 1/1) to obtain compound 8-2 (101 mg, 0.29 mmol). MS (ESI): m/z = 351 [M + H] ⁺ .

Step 3: At 0°C, CDI (82.5 mg, 0.505 mmol) was added to a THF (3 mL) solution of compound 8-2 (101 mg, 0.29 mmol), warmed to room temperature and stirred for 30 minutes, then overnight, cooled to 0°C, DBU (63 μL, 0.42 mmol) was added, warmed to room temperature and stirred for 1 hour, and then concentrated. Saturated ammonium chloride solution (2 mL) was added to the concentrate to quench the reaction, and extracted with EA (20 mL). The combined organic phase was washed with saturated brine (3 times), dried, and concentrated. The residue was purified by silica gel column chromatography (eluted with PE:EA=5/1 to 1/1) and preparative high performance liquid chromatography (HPLC) to obtain compound 8 (29 mg, 0.21 mmol, yield: 72.4%, purity 99.54%). MS (ESI): m/z=377[M+H] ⁺ . ¹ HNMR (DMSO-d ₆ ) δ: 12.79 (br s, 1H), 8.76 (d, J = 5.9 Hz, 1H), 8.06 (s, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.47-7.52 (m, 3H), 6.85 (d, J = 3.4 Hz, 1H), 4.05 (s, 3H).

Embodiment 9

Step 1: Disperse tert-butyloxycarbonylsarcosine (143.04 mg, 0.76 mmol) and HATU (359.33 mg, 0.95 mmol) in dichloromethane (5 mL). After stirring at room temperature for 3 mins, add compound 9-1 (200 mg, 0.63 mmol) and N,N-diisopropylethylamine (0.21 mL, 1.26 mmol). After stirring the reaction mixture at room temperature for 3 hours, add saturated sodium bicarbonate (2 mL) to quench, and extract with ethyl acetate (30 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluted with ethyl acetate) to obtain compound 9-2 (216 mg, yield: 69.9%). MS (ESI): m/z=391[M-100+H] ⁺ .

Step 2: Compound 9-2 was dissolved in dichloromethane (4 mL), and p-toluenesulfonyl chloride (77.74 mg, 0.41 mmol) and triethylamine were added sequentially under stirring at room temperature. The reaction mixture was stirred at room temperature for 5 hours and then concentrated, diluted with water (10 ml), and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 1) to obtain compound 9-3 (139 mg, yield: 72.15%). MS (ESI): m/z = 471 [MH] ^- .

Step 3: At 0°C, trifluoroacetic acid (0.4 mL, 5.37 mmol) was added to a solution of compound 9-3 (130 mg, 0.28 mmol) in dichloromethane (2 mL). The reaction mixture was stirred at room temperature overnight and then concentrated to obtain a crude product of compound 9-4 (150 mg). MS (ESI): m/z = 373 [M+H] ⁺ .

Step 4: Under stirring at room temperature, cyanogen bromide (49.00 mg, 0.46 mmol) was added to a tetrahydrofuran (2 mL) solution containing compound 9-4 (150 mg, 0.31 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.93 mmol). After the reaction mixture was stirred at room temperature for 10 minutes, it was quenched by adding water (1 ml) and extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with saturated ammonium chloride solution (5 ml) and saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluted with petroleum ether: ethyl acetate = 1:1) to obtain compound 9 (50 mg, yield: 40.80%). MS (ESI): m/z = 398 [M-56+H] ⁺ . ¹ H NMR (CHLOROFORM-d) δ: 8.28 (dd, J = 7.8, 1.5 Hz, 1H), 8.02 (s, 1H), 7.79-7.84 (m, 1H), 7.69-7.75 (m, 1H), 7.61 (dd, J = 7.8, 1.1Hz, 1H), 7.32-7.38 (m, 2H), 7. 06(d,J＝8.6Hz,1H), 6.88(dd,J＝3.3,0.6Hz,1H), 4.06(s,2H), 2.38(s,3H).

Example 10

Step 1: According to the similar synthesis method of Step 1 in Example 2, ethyl 2-chloronicotinate and 5-(trifluoromethyl)-indole were used as reactants to prepare compound 10-1. LCMS: m/z=335 [M+H] ⁺ .

Step 2: According to the similar synthesis method of Step 2 in Example 2, compound 10-2 was prepared using compound 10-1 as a reactant. LCMS: m/z=321 [M+H] ⁺ .

Step 3-Step 6 : Using compound 10-2 as the starting reactant, the intermediate product compound 10-3, compound 10-4, compound 10-5, and finally compound 10 (9 mg, 0.022 mmol, yield 42.25%, purity 96.65%) were obtained in sequence according to the similar synthesis method of step 1, step 2, step 3 and step 4 of Example 9. MS (ESI): m/z=399[M-56+H] ⁺ . ¹ H NMR(DMSO-d6)δ:8.91(dd,J＝4.8,1.8Hz,1H),8.62(dd,J＝7.8,1.8Hz,1H),8.06(s,1H),7.82(dd,J＝7.9,4.8Hz,1H),7.70-7.77(m,1H),7.36-7.53(m,2H) ), 6.86 (d, J = 3.3Hz, 1H), 4.47 (s, 2H), 2.60 (s, 3H).

Embodiment 11

Step 1: According to the similar synthesis method of Step 1 in Example 9, compound 11-1 was prepared using compound 10-2 as a reactant. LCMS: m/z=506 [M+H] ⁺ .

Step 2: According to the similar synthesis method of Step 2 in Example 9, compound 11-2 was prepared using compound 11-1 as a reactant. LCMS: m/z = 488 [M+H] ⁺ .

Step 3: According to the similar synthesis method of Step 3 in Example 9, compound 11-3 was prepared using compound 11-2 as a reactant. LCMS: m/z = 388 [M+H] ⁺ .

Step 4: According to the similar synthesis method of Step 4 in Example 9, compound 11 (123 mg, 0.29 mmol, yield 68.33%, purity 97.87%) was prepared using compound 11-3 as a reactant. MS (ESI): m/z=413 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 8.91-8.88 (m, 1H), 8.65-8.61 (m, 1H), 8.10-8.06 (m, 1H), 7.84-7.78 (m, 1H), 7.68 (d, J = 3.4Hz, 1H), 7.51-7.41 (m, 2H), 6.9 0-6.84(m,1H),3.20-3.13(m,2H),3.08-3.00(m,2H),2.72(s,3H).

Example 12

Preparation of compound 12-2:

Step 1: A mixture of 5-trifluoromethylindole (5.00 g, 27.01 mmol), DMF (20 mL), ethyl 2-chloronicotinate (7.52 g, 40.51 mmol) and Cs ₂ CO ₃ (17.60 g, 17.60 mmol) was purged with N ₂ three times, stirred at 120°C for 3 hours, diluted with H ₂ O (200 mL), and extracted with EA (50 mL). The combined organic phases were washed with saturated brine (20 mL×3), dried over anhydrous Na ₂ SO ₄ , and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with DCM:PE=1/1) to obtain compound 12-1 (7.86 g, 23.51 mmol, yield: 87.06%). MS (ESI): m/z=335[M+H] ⁺ .

Step 2: A mixture of compound 12-1 (7.86 g, 23.51 mmol), MeOH (165 mL) and N ₂ H ₄ ·H ₂ O (18 mL, 370.36 mmol) was stirred at 80°C for 18 hours and then concentrated, H ₂ O (50 mL) was added, and extracted with EA (50 mL). The combined organic phase was washed with saturated brine (20 mL×3), dried over anhydrous Na ₂ SO _4, and concentrated to obtain a crude product of compound 12-2 (6.57 g). MS (ESI): m/z＝321[M+H] ⁺ .

Preparation of compound 12:

Step 1: In an ice bath and nitrogen atmosphere, slowly drop LDA/THF (2M, 4.8 mL, 4.78 mmol) into a THF (20 mL) solution of compound 12-3 (2.14 g, 8.32 mmol), and then drop MeI (1.36 g, 9.57 mmol) into the solution. Stir the reaction mixture for 2 hours under ice bath, then quench with saturated NH ₄ Cl (20 mL), and extract with EA (50 mL). The combined organic phase was washed with saturated brine (20 mL×3), dried with anhydrous Na ₂ SO ₄ , and concentrated to obtain a residue. The obtained residue was purified by silica gel column chromatography (eluted with EA:PE=1/2) to obtain compound 12-4 (1.42 g, 5.23 mmol, yield: 62.93%). MS (ESI): m/z=272[M+H] ⁺ .

Step 2: Under stirring conditions, an aqueous solution of LiOH (0.25 g, 10.47 mmol) dissolved in H ₂ O (4 mL) was added to a solution of compound 12-4 (1.42 g, 5.23 mmol) in THF (10 mL). The reaction mixture was stirred at room temperature for 1 hour to obtain a mixture containing compound 12-5 (MS (ESI): m/z=244 [M+H] ⁺ ) which was directly used in the next step without purification.

Step 3: HCl/1,4-Dioxane (4M, 13.05 mL, 52.21 mmol) was added to the mixture containing compound 12-5 obtained in step 2. The reaction mixture was stirred at room temperature for 3 hours and then concentrated to obtain a crude product (1.53 g) of compound 12-6 (MS (ESI): m/z=144 [M+H] ⁺ ).

Step 4: T3P/EA (50%, 5.44 g, 8.55 mmol) was added dropwise to a mixture of the crude product of compound 12-6 obtained in step 3 above, DMF (15 mL), compound 12-2 (0.68 g, 2.14 mmol) and DIPEA (1.42 mL, 8.55 mmol) under stirring. The reaction mixture was stirred at room temperature for 10 minutes, quenched by adding saturated NaHCO ₃ (20 mL), and extracted with EA (50 mL). The combined organic phase was washed with saturated brine (50 mL×3), dried over anhydrous Na ₂ SO ₄ , and concentrated to obtain a residue. The obtained residue was slurried in DCM for 12 hours, and then filtered to obtain compound 12-7 (346.6 mg, 0.78 mmol, yield: 36.45%). MS (ESI): m/z＝446[M+H] ⁺ .

Step 5: A mixture of compound 12-7 (296.6 mg, 0.67 mmol), 3 mL DMF, TsCl (127.73 mg, 0.67 mmol) and TEA (0.19 mL, 1.34 mmol) was stirred at room temperature for 6 hours, saturated NaHCO ₃ (aq) (10 mL) was added, and extracted with EA (20 mL). The combined organic phases were washed with saturated brine (50 mL×3), dried over anhydrous Na ₂ SO ₄ , and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with MeOH:DCM=1/30) to obtain compound 12 (140.0 mg, 0.33 mmol, yield: 48.05%). MS (ESI): m/z=428[M+H] ⁺ . ¹ HNMR (400 MHz, DMSO-d ₆ )δppm 1.18(s,3H)1.81-1.88(m,2H)2.83(dt,J＝9.63,6.88Hz,1H)3.09(dt,J＝9.60,6.64Hz,1H)6.88(d,J＝3.38Hz,1H)7.30-7.36(m,1H)7.38-7.42(m,1H)7 .76(d,J＝3.38Hz,1H)7.80(dd,J＝7.88,4.75Hz,1H)7.96(s,1H)8.08(s,1H)8.64(dd,J＝7.88,1.75Hz,1H)8.90(dd,J＝4.75,1.75Hz,1H).

Embodiment 14

Preparation of compound 14-2:

Under stirring conditions, an aqueous solution of LiOH (0.26 g, 10.80 mmol) dissolved in H ₂ O (4 mL) was added dropwise to a solution of compound 14-1 (1.00 g, 5.40 mmol) dissolved in THF (10 mL). After stirring at room temperature for 0.5 hours, the pH of the reaction mixture was adjusted to 2 with 1M HCl (aq), and then concentrated to obtain a crude product (1.87 g) of compound 14-2 (MS (ESI): m/z=158 [M+H] ⁺ ).

Preparation of compound 14:

Step 1: A mixture of the crude product of compound 14-2 obtained in the above step (1.87 g, 5.40 mmol) (45.4% by content), 5 mL of DMF, HATU (2.26 g, 5.94 mmol) and DIPEA (1.34 mL, 8.10 mmol) was stirred at room temperature for 10 min, and compound 14-3 (1.73 g, 5.40 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours and then concentrated, saturated NaHCO ₃ (aq) (50 mL) was added, and extracted with EA (30 mL). The combined organic phase was concentrated to obtain a residue. The obtained residue was purified by silica gel column chromatography (DCM: MeOH = 20/1) to obtain compound 14-4 (292.6 mg, 0.64 mmol, yield: 11.79%). MS (ESI): m/z = 460 [M+H] ⁺ .

Step 2: Compound 14-4 (292.6 mg, 1.27 mmol), 2 mL THF, 2 mL DCM, TsCl (242.8 mg, 1.27 mmol) and TEA (0.35 mL, 2.55 mmol) were added to a 25 mL flask in sequence. The reaction mixture was stirred at room temperature for 2 hours and then concentrated. Saturated NaHCO ₃ (aq) (10 mL) was added and extracted with EA (20 mL). The residue was concentrated to obtain a residue. The obtained residue was purified by preparative HPLC to obtain compound 14 (31.1 mg, 0.07 mmol, yield: 11.06%). MS (ESI): m/z=442[M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.13-1.21(m,1H)1.24(s,3H)1.26-1.32(m,1H)1.39-1.46(m,1H)1.47-1.53(m,1H)2.85-2.93(m,1H)3.07(br dd,J＝7.07, 4.94Hz,1H)6.90(d,J＝3.38Hz,1H)7.26(d,J＝8.63Hz,1H)7.38(dd,J＝8.76,1.38Hz,1H)7.69(br s,1H)7.78-7.80(m,1H)7.80-7.83(m,1H)8.08(s,1H)8.66(dd,J＝7.88,1.75Hz,1H)8.90(dd,J＝4.75,1.75Hz,1H).

Example 16

Step 1: At room temperature, compound 16-1 was dissolved in acetic acid (25 mL), purged with _N2 and maintained under _N2 atmosphere. The reaction mixture was stirred at 70°C overnight, quenched by adding saturated sodium bicarbonate solution, and extracted with ethyl acetate (100 mL×3). The combined organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a residue. The obtained residue was purified by silica gel column chromatography (eluted with petroleum ether) to obtain compound 16-2 (1.142 g, yield: 65.34%). MS (ESI): m/z=320[M+H] ⁺ .

Step 2: At room temperature and _N2 atmosphere, hydrazine hydrate (5.8 mL, 119.57 mmol) was slowly dripped into a methanol (30 mL) solution of compound 16-2 (1.0 g, 3.28 mmol). The reaction mixture was stirred at 80°C for 4 hours and concentrated to obtain a residue. The obtained residue was purified by silica gel column chromatography (eluted with petroleum ether: ethyl acetate = 2:1) to obtain compound 16-3 (916 mg, yield: 91.60%). MS (ESI): m/z = 320 [M+H] ⁺ .

Step 3: At 0°C and _N2 atmosphere, compound 16-3 (200 mg, 0.63 mmol) was slowly added to a dichloromethane (5 mL) solution in which ethyl oxalyl chloride (0.07 mL, 0.63 mmol) and triethylamine (0.26 mL, 1.88 mmol) were dissolved. Maintaining _N2 atmosphere, the reaction mixture was stirred at room temperature overnight, and p-toluenesulfonyl chloride (0.12 mL, 0.63 mmol) was added, followed by continued reaction at room temperature for 5 hours, quenched by addition of a saturated sodium bicarbonate solution, and extracted with ethyl acetate (50 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a residue. The residue was purified by preparative silica gel plate (eluted with petroleum ether: ethyl acetate = 1:1) to obtain compound 16-4 (183 mg, yield: 69.67%). MS (ESI): m/z = 420 [M+H] ⁺ .

Step ₄ : Tosyl chloride (83 mg, 0.44 mmol) and triethylamine (0.12 mL, 0.87 mmol) were added to a solution of compound 16-4 (183 mg, 0.44 mmol) dissolved in dichloromethane (2 mL) in sequence at room temperature and under _{N2 atmosphere. Maintaining N2} atmosphere, the reaction mixture was stirred at room temperature for 5 hours and then concentrated, water was added, and extracted with ethyl acetate (50 mL×3). The combined organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a residue. The obtained residue was purified by silica gel column chromatography (eluted with petroleum ether: ethyl acetate = 1:1) to obtain compound 16-5 (169 mg, yield: 96.49%). MS (ESI): m/z = 402 [M+H] ⁺ .

Step 5: At room temperature and _N2 atmosphere, in a dry 25mL sealed tube, add ammonia water (0.4mL, 10.39mmol) to methanol (2mL) in which compound 16-5 (173mg, 0.43mmol) is dissolved. After the reaction mixture is quickly sealed, slowly warm up to 60°C and stir for 4 hours, dilute with water after concentration, and extract with ethyl acetate (50mL×3). The combined organic phase is dried over anhydrous sodium sulfate and concentrated to obtain a residue. The obtained residue is purified by silica gel column chromatography (eluted with ethyl acetate) to obtain compound 16 (136mg, yield: 84.74%). MS (ESI): m/z＝373[M+H] ⁺ . ¹ H NMR(DMSO-d ₆ )δ:8.46(s,1H),8.24(dd,J＝7.8,1.5Hz,1H),8.17(s,1H),8.05(s,1H),7.88-7.93(m,1H),7.79-7.84(m,1H),7.74(dd,J＝7.9,0.9Hz, 1H), 7.65 (d, J = 3.4Hz, 1H), 7.37 (dd, J = 8.8, 1.5Hz, 1H), 7.18 (d, J = 8.6Hz, 1H), 6.83 (d, J = 3.3Hz, 1H).

Embodiment 17

Step 1: A solution of compound 16 (30 mg, 0.08 mmol) dissolved in DMF (2 mL) was purged with N ₂ at room temperature and maintained under N ₂ atmosphere, cooled to 0°C, and at this temperature, sodium hydride (9.67 mg, 0.24 mmol) was added, stirred for 30 minutes, and then iodomethane (11.04 uL, 0.18 mmol) was added. The reaction mixture was slowly warmed to room temperature, stirred for 30 minutes, quenched by adding saturated sodium thiosulfate solution, added with water, and extracted with ethyl acetate (100 mL×3). The combined organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a residue. The obtained residue was purified by silica gel column chromatography (eluted with ethyl acetate) to obtain compound 17 (27 mg, yield: 83.69%). MS (ESI): m/z=401[M+H] ⁺ . ¹ H NMR (METHANOL-d ₄ ) δ: 8.24 (dd, J = 7.8, 1.5 Hz, 1H), 7.96 (s, 1H), 7.86-7.91 (m, 1H), 7.77 (td, J = 7.7, 1.3 Hz, 1H), 7.68 (dd, J = 7.9, 0.9 Hz, 1H), 7.48 (d, J = 3 .4Hz,1H),7.32(dd,J＝8.6,1.5Hz,1H),7.09(d,J＝8.6Hz,1H),6.83(d,J＝3.4Hz,1H),3.01(s,3H),2.95(s,3H).

Embodiment 21

Step 1: According to the similar synthesis method of Step 1 in Example 9, compound 21-1 was prepared using compound 12-2 as a reactant. LCMS: m/z=421 [M+H] ⁺ .

Step 2: According to the similar synthesis method of step 4 in Example 9, compound 21 (10 mg, 0.024 mmol, yield: 35.33%, purity: 97.10%) was prepared using compound 21-1 as a reactant. MS (ESI): m/z=433 [M+H] ⁺ .

¹ H NMR(DMSO-d6)δ:8.91(dd,J＝4.8,1.7Hz,1H),8.65(dd,J＝7.9,1.8Hz,1H),8.07(s,1H),7.81(dd,J ＝7.9,4.9Hz,1H),7.74(d,J＝3.5Hz,1H),7.39-7.50(m,2H),7.03(s,1H),6.87(d,J＝3.4Hz,1H),4.52 (q,J=7.0Hz,4H).

Embodiment 24

Step 1: 5-Trifluoromethylindole (212 mg, 1.14 mmol) and Cs ₂ CO ₃ (745 mg, 2.28 mmol) were added to a DMSO (5 mL) solution of 1-bromo-2-fluorobenzene (200 mg, 1.14 mmol). The reaction mixture was stirred at 130° C. for 2 hours under microwave conditions, cooled to room temperature, diluted with H ₂ O and extracted with EA. The combined organic phases were dried and concentrated to obtain a residue. The residue was purified by silica gel column chromatography to obtain compound 24-1 (350 mg, 1.04 mmol). MS (ESI): m/z=340[M+H] ⁺ .

Step 2: Add compound 2-methyl-5-(tributyltin)-2H tetrazole (442 mg, 1.18 mmol), Pd(PPh ₃ ) ₄ (68 mg, 0.06 mmol) and CuI (12 mg, 0.06 mmol) to a solution of compound 24-1 (200 mg, 0.59 mmol) in DMF (6 mL). The reaction mixture was stirred at 120° C. overnight, cooled to room temperature, diluted with potassium fluoride solution (2 M) and extracted with EA. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography to obtain compound 24 (68 mg, 0.20 mmol, yield: 33.9%). MS (ESI): m/z=344[M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ: 8.11 (dd, J = 7.5, 1.6 Hz, 1H), 8.02 (s, 1H), 7.77 (ddd, J = 10.3, 7.5, 1.6 Hz, 2H), 7.66 (dd, J = 7.6, 1.3 Hz, 1H), 7.50 (d, J = 3.3 Hz, 1H), 7.33 ( dd,J＝8.7,1.3Hz,1H),7.08(d,J＝8.6Hz,1H),6.77(d,J＝3.1Hz,1H),4.17(s,3H).

Embodiment 26

Step 1: To a mixture of compound 26-1 (200 mg, 0.59 mmol), potassium carbonate (162.52 mg, 1.18 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (48.02 mg, 0.06 mmol) in dioxane (2.5 mL) and water (0.5 mL), tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (443.69 mg, 1.18 mmol) was added. The reaction mixture was purged with nitrogen and maintained under nitrogen atmosphere, stirred at 100°C for 3 hours, and then water (10 mL) was added and extracted with ethyl acetate (30 mL). The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated, and the residue was chromatographed on a silica gel column (eluent gradient from PE:EA=20:1 to 5:1) to obtain compound 26-2 (374 mg, crude product). MS (ESI): m/z=511 [M+H] ⁺ .

Step 2: At 0°C, a solution of compound 26-2 (168 mg, 0.33 mmol) in dioxane (1.5 mL) was added with a solution of hydrochloric acid in dioxane (1 mL, 4.0 mol/L). The reaction mixture was stirred at room temperature for 1 hour and then concentrated, and the concentrate was purified by preparative high performance liquid chromatography (HPLC) to obtain the hydrochloride of compound 26 (39.28 mg, 0.10 mmol, yield: 30.16%, purity: 99.57%). MS (ESI): m/z=411[M+H] ⁺ . ¹ H NMR(DMSO-d ₆ )δ:8.55-8.79(m,1H),8.42(br s,1H),8.07(s,1H),7.85(d,J＝7.5Hz,1H),7.57-7.63(m,2H),7.44-7.51(m,2H),7.33(dd,J＝8.7,1.6Hz ,1H),7.10(s,1H),7.00(d,J＝8.6Hz,1H),6.88(d,J＝2.9Hz,1H),6.81(s,1H),4.18-4.32(m,1H),3.27(br d,J＝12.0Hz,2H),2.97(br t,J＝11.1Hz,2H),1. 77-1.96(m,4H).

Embodiment 27

According to the similar synthesis method of step 1 in Example 26, compound 27 (45.85 mg, 0.11 mmol, yield: 37.84%, purity: 99.82%) was prepared using compound 26-1 as a reactant. MS (ESI): m/z=412 [M+H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ -d) δ7.99(s,1H),7.71(d,J＝6.9Hz,1H),7.50–7.61(m,1H),7.44(d,J＝3.8Hz,3H),7.30(d,J＝8.9Hz,1H),7.22(d,J＝2.9Hz,1H),7.00( d,J＝8.4Hz,1H),6.79(d,J＝2.6Hz,1H),6.12(s,1H),4.07–4.23(m,1H),3.94(d,J＝10.1Hz,2H),3.40(t,J＝11.4Hz,2H),1.40–1.77(m,4H).

Embodiment 29

Step 1: Compound 29-1 (203 mg, 0.66 mmol), Pd(dppf)Cl ₂ (36 mg, 0.044 mmol) and sodium carbonate (93 mg, 0.8 mmol) were added to a solution of compound 26-1 (150 mg, 0.44 mmol) in 1,4-dioxane/water (4 mL/0.8 mL) in sequence. The reaction mixture was reacted at 105° C. under a nitrogen atmosphere for 16 hours, quenched by adding a saturated ammonium chloride solution (4 mL), and extracted with EA (40 mL). The combined organic phases were washed with saturated brine, dried, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (gradient of eluent transition from PE:EA=1/1 to pure EA) and preparative high performance liquid chromatography (HPLC) to obtain compound 29 (60.5 mg, 0.14 mmol, purity 96.26%). MS (ESI): m/z=441[M+H] ⁺ . ¹ H NMR (CHLOROFORM-d) δ: 7.90 (s, 1H), 7.63 (d, J = 7.6Hz, 1H), 7.45 (t, J = 7.4Hz, 1H), 7.33 (q, J = 8.0Hz, 2H), 7.24 (d, J = 8.6Hz, 1H), 7.20 (s, 1H), 7.12 (d, J = 3. 1Hz,1H),6.98(d,J＝8.6Hz,1H),6.68(d,J＝3.1Hz,1H),6.35(s,1H),3.98(br s,2H),3.49-3.61(m,4H),2.50(br d,J＝17.8 Hz,2H),2.23-2.38(m,4H).

Embodiment 30

According to the similar synthesis method of step 1 in Example 26, compound 30 (21 mg, 0.05 mmol, yield 16.67%, purity 99.55%) was prepared using compound 26-1 and compound 30-1 as reactants. MS (ESI): m/z=399 [M+H] ⁺ . ¹ H NMR(CHLOROFORM-d)δ:7.89(s,1H),7.57(d,J＝7.3Hz,1H),7.47(td,J＝7.5,1.4Hz,1H),7.38(td,J＝7.5,1.3Hz,1H),7.32-7.35(m,1H),7.20-7.23(m,1H ),7.15(d,J＝8.7Hz,1H),7.01(s,1H),6.85(d,J＝8.6Hz,1H),6.70-6.74(m,2H),4.22-4.39(m,2H),3.24(br s,2H),2.41(s,6H).

Embodiment 31

Step 1: Compound 31-1 (166 mg, 0.66 mmol), Pd(dppf)Cl ₂ (36 mg, 0.044 mmol) and sodium carbonate (93 mg, 0.8 mmol) were added to a solution of compound 26-1 (150 mg, 0.44 mmol) in 1,4-dioxane/water (4 mL/0.8 mL) in sequence. The reaction mixture was stirred at 105° C. for 16 hours in a N ₂ atmosphere, cooled to room temperature, quenched by adding saturated ammonium chloride solution (4 mL), and extracted with EA (40 mL). The combined organic phases were washed with saturated brine, dried and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluent gradient transition from PE:EA=5/1 to 1/1) and preparative high performance liquid chromatography (HPLC) to obtain compound 31 (114.2 mg, 0.30 mmol, purity: 99.39%). MS (ESI): m/z=386[M+H] ⁺ . ¹ H NMR(CHLOROFORM-d)δ:7.90(s,1H),7.61-7.66(m,1H),7.44(td,J＝7.3,2.1Hz,1H),7.23-7.34(m,3H),7.19(d,J＝1.8Hz,1H),7.11(d,J＝3.3Hz,1H),6.99 (d,J＝8.6Hz,1H),6.68(d,J＝3.1Hz,1H),6.36(s,1H),3.94(br t,J＝4.7Hz,2H),3.37(br s,2H),3.05(s,3H).

Embodiment 39

Step 1: A mixture of DMSO (10 mL), 5-trifluoromethylindole (1.50 g, 8.10 mmol), 3-fluorobenzyl cyanide (0.98 g, 8.10 mmol) and Cs ₂ CO ₃ (5.28 g, 16.20 mmol) was purged with N ₂ and maintained under N ₂ atmosphere. The reaction mixture was stirred at 90° C. for 4 hours, diluted with H ₂ O (30 mL), and extracted with EA (50 mL). The combined organic phase was washed with saturated brine (10 mL×3), dried over anhydrous Na ₂ SO _4, and concentrated to obtain a residue. The obtained residue was purified by silica gel column chromatography (PE:EA＝2/1) to obtain compound 39-1 (1.88 g, 6.57 mmol, yield: 81.06%). MS (ESI): m/z＝287[M+H] ⁺ .

Step 2: MeOH (50 mL), compound 39-1 (1.00 g, 3.49 mmol), NH ₂ OH·HCl (2.43 g, 34.93 mmol), TEA (29 mL) and The reaction mixture was purged with _N2 and maintained under _N2 atmosphere, stirred at 80°C for 4 hours, filtered and the filtrate was concentrated. _H2O (20 mL) was added to the obtained concentrate, and extracted with EA (30 mL). The combined organic phases were _dried over anhydrous _Na2SO4 and concentrated to obtain a crude product (1.23 g) of compound 39-2 (MS (ESI): m/z = 320 [M+H] ⁺ ).

Step 3: Under ice bath conditions, CDI (380.9 mg, 2.35 mmol) was added to a solution of the crude product of compound 39-2 (500.0 mg) in THF (10 mL). After stirring at room temperature for 30 minutes, DBU (357.6 mg, 2.35 mmol) was added dropwise under ice bath conditions again. The reaction mixture was stirred under ice bath conditions for 1 h, H ₂ O (20 mL) was added, and extracted with EA (30 mL). The combined organic phase was concentrated to obtain a residue, and the obtained residue was purified by preparative high performance liquid chromatography (HPLC) to obtain compound 39 (360 mg, 1.04 mmol, yield: 66.58%). MS (ESI): m/z=346[M+H] ⁺ . ¹ HNMR(400MHz, DMSO-d ₆ )δ6.94(d,J＝3.25Hz,1H)7.53(dd,J＝8.75,1.63Hz,1H)7.82(t,J＝7.94Hz,2H)7.87–7.94(m,3H)8.03(t,J＝1.75Hz,1H)8.11(s,1H)13 .09(br s,1H).

Embodiment 40

Step 1: Add 5-trifluoromethylindole (1.5 g, 8.26 mmol) and cesium carbonate (5.4 g, 16.52 mmol) to a solution of compound 4-fluoro-cyanobenzene (1.0 g, 8.26 mmol) in DMSO (21 mL). The reaction mixture was stirred at 120°C for 2.5 hours under a nitrogen atmosphere, cooled to 25°C, quenched by adding a saturated ammonium chloride solution (20 mL), and extracted with EA (100 mL). The combined organic phase was washed with saturated brine (3 times), dried, and concentrated to obtain a residue. The obtained residue was purified by silica gel column chromatography (eluent gradient transition from PE:EA=20/1 to 5/1) to obtain compound 40-1 (1.09 g, 3.84 mmol).

Step 2: To a solution of compound 40-1 (200 mg, 0.70 mmol) in methanol (10 mL) were added hydroxylamine hydrochloride (490 mg, 7.0 mmol), Molecular sieves (200 mg) and triethylamine (5.4 mL, 47 mmol). The reaction mixture was stirred at 75 ° C for 3 hours, cooled to 25 ° C, and filtered. Saturated ammonium chloride solution (15 mL) was added to the filtrate to quench the reaction, and extracted with EA (100 mL). The combined organic phase was washed with saturated brine (3 times), dried and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluent gradient transition from PE: EA = 5/1 to 1/1) to obtain compound 40-2 (181 mg, 0.57 mmol). MS (ESI): m/z = 320 [M + H] ⁺ .

Step 3: CDI (57 mg, 0.35 mmol) was added to a THF (2 mL) solution of compound 40-2 (90 mg, 0.28 mmol) at 0°C, warmed to room temperature, stirred at room temperature for 30 minutes, cooled to 0°C, added DBU (63 μL, 0.42 mmol) at 0°C, warmed to room temperature again, stirred at room temperature for 1 hour, and concentrated. Saturated ammonium chloride solution (2 mL) was added to the concentrate to quench the reaction, and extracted with EA (20 mL). The combined organic phase was washed with saturated brine (3 times), dried, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluent gradient transition from PE: EA = 5/1 to 1/1) and preparative high performance liquid chromatography (HPLC) to obtain compound 40 (72 mg, 0.21 mmol, purity 99.3%). MS (ESI): m/z = 344 [MH] ^- . ¹ H NMR (DMSO-d ₆ ) δ: 8.10 (s, 1H), 8.02 (d, J = 7.9Hz, 2H), 7.95 (d, J = 3.3Hz, 1H), 7.88 (d, J = 8.8Hz, 2H), 7.82 (d, J = 8.8Hz, 1H), 7.52 (d, J = 8.2Hz, 1H), 6.94 (d, J＝3.3Hz,1H)).

Embodiment 41

Step 1: At room temperature, 2-fluorobenzonitrile (0.27 mL, 2.48 mmol), 5-trifluoromethoxyindole (498.27 mg, 2.48 mmol) and cesium carbonate (1614.17 mg, 4.95 mmol) were dissolved in DMSO (10 mL) in sequence. The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 120°C and stirred for 1 hour, diluted with water, and extracted with ethyl acetate (100 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluted with ethyl acetate: petroleum ether = 1:5) to obtain compound 41-1 (675 mg, yield: 90.15%). MS (ESI): m/z = 303 [M+H] ⁺ .

Step 2: At room temperature, hydroxylamine hydrochloride (1551.83 mg, 22.33 mmol), Molecular sieves (675 mg, 2.23 mmol) and TEA (18.57 mL, 133.99 mmol) were added to a methanol (30 mL) solution of compound 41-1 (675 mg, 2.23 mmol). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 75 ° C and stirred overnight, quenched by adding a saturated ammonium chloride solution, and extracted with ethyl acetate (100 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (eluted with petroleum ether: ethyl acetate = 1:1) to obtain compound 41-2 (644 mg, yield: 86.01%). MS (ESI): m/z = 336 [M + H] ⁺ .

Step 3: At 0°C, N,N'-carbonyldiimidazole (199.49 mg, 1.23 mmol) was added to a tetrahydrofuran (5 mL) solution of compound 41-2 (330 mg, 0.98 mmol). The reaction mixture was warmed to room temperature, stirred at room temperature for 30 minutes, cooled to 0°C, DBU (0.22 mL, 1.48 mmol) was added, warmed to room temperature again, stirred at room temperature for 1 hour, quenched with a saturated solution of ammonium chloride, and extracted with ethyl acetate (50 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative silica gel plate (eluted with ethyl acetate) to obtain compound 41 (153 mg, yield: 43.03%). MS (ESI): m/z=362[M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ: 12.66 (br s, 1H), 7.82-7.92 (m, 2H), 7.68-7.77 (m, 2H), 7.65 (s, 1H), 7.53 (d, J = 3.3Hz, 1H), 7.09-7.21 (m, 2H), 6.76 (d, J = 2.8Hz, 1H) .

Embodiment 42

Step 1: 5-trifluoromethylindole (359 mg, 1.90 mmol) and cesium carbonate (1.23 g, 3.8 mmol) were added to a DMSO (14 mL) solution of 3-bromo-4-fluoro-N-toluenesulfonamide (510 mg, 1.90 mmol). The reaction mixture was reacted under microwave conditions (130 W, 120 ° C) for 40 min, cooled to 25 ° C, quenched with saturated ammonium chloride solution, and extracted with EA (100 mL). The combined organic phase was washed with saturated brine (3 times), dried and concentrated. The resulting residue was purified by silica gel column chromatography (eluent gradient transition from PE: EA = 10: 1 to 2: 1) to obtain compound 42-1 (594 mg, 1.37 mmol). MS (ESI): m / z = 433 [M + H] ⁺ .

Step 2: To a solution of compound 42-1 (494 mg, 1.14 mmol) in 1.4-dioxane/water (10 mL/2 ml) were added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)-1H imidazole (474 mg, 2.28 mmol), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (114 mg, 0.14 mmol), and sodium carbonate (242 mg, 2.28 mmol). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, stirred at 80° C. for 7 hours, quenched with saturated ammonium chloride solution (10 mL), and extracted with EA (60 mL). The combined organic phases were washed with saturated brine (twice), dried, and concentrated. The residue was purified by silica gel column chromatography (gradient of eluent transitioned from PE:EA=5:1 to 1:1) and preparative high performance liquid chromatography (HPLC) to obtain compound 42 (53 mg, 0.12 mmol, purity 98.50%). MS (ESI): m/z=435 [M+H] ⁺ . ¹ HNMR(CHLOROFORM-d)δ:8.82(d,J＝1.8Hz,1H),8.02(s,1H),7.89(dd,J＝8.1,2.0Hz,1H),7.47(d,J＝7.9Hz,1H),7.36-7.40(m,2H),7.20(d,J＝3.1Hz,1H),7. 10(d,J＝8.5Hz,1H),6.84(d,J＝2.7Hz,1H),5.38(s,1H),4.69(br d,J＝5.2Hz,1H),3.40(s,3H),2.80(d,J＝5.2Hz,3H).

Embodiment 43

Step 1: At 0°C, a solution of compound 43-1 (5.0 g, 18.28 mmol) in tetrahydrofuran (15 mL) was added to a mixture of methylamine hydrochloride (2.5 g, 37.03 mmol), sodium bicarbonate (4.6 g, 54.70 mmol) and water (15 mL). The reaction mixture was stirred at room temperature for 3 hours and then extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was slurried with petroleum ether to obtain compound 43-2 (4.5 g, 16.78 mmol). MS (ESI): m/z=268,270 [M+H] ⁺ .

Step 2: 5-Trifluoromethylindole (898 mg, 4.85 mmol) and Cs ₂ CO ₃ (3.2 g, 9.70 mmol) were added to a DMSO (15 mL) solution of compound 43-2 (1.3 g, 4.85 mmol). The reaction mixture was microwaved at 120°C for 40 minutes, cooled to room temperature, diluted with H ₂ O, and extracted with EA. The combined organic phases were dried and concentrated. The residue was purified by silica gel column chromatography to give compound 43-3 (1.4 g, 3.24 mmol). MS (ESI): m/z=433,435 [M+H] ⁺ .

Step 3: Add compound 2-methyl-5-(tributyltin)-2H tetrazole (174 mg, 0.4630 mmol), Pd(PPh ₃ ) ₄ (27 mg, 0.0231 mmol) and CuI (5 mg, 0.0231 mmol) to a solution of compound 43-3 (100 mg, 0.2315 mmol) in DMF (4 mL). The reaction mixture was stirred at 120°C overnight, cooled to room temperature, diluted with H ₂ O, and extracted with EA. The combined organic phases were dried and concentrated. The residue was purified by silica gel column chromatography and preparative high performance liquid chromatography (Prep-HPLC) to obtain compound 43 (24 mg, 0.0531 mmol). MS (ESI): m/z=437[M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ: 8.50 (s, 1H), 8.14 (br d, J = 8.0Hz, 1H), 8.05 (s, 1H), 7.94 (br d, J = 8.3Hz, 1H), 7.85 (br s, 1H), 7.57 (br d, J = 2.5Hz, 1H), 7.36 (br d, J = 8. 6Hz, 1H), 7.20 (br d, J = 8.5Hz, 1H), 6.83 (br d, J = 2.3Hz, 1H), 4.22 (s, 3H), 2.53-2.59 (m, 3H).

Embodiment 44

Step 1: Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (120 mg, 0.15 mmol) and triethylamine (1.40 g, 13.84 mmol) were added to a mixed solution of compound 43-3 (600 mg, 1.38 mmol) in DMF (9 mL) and MeOH (3 mL). The reaction mixture was stirred at 90° C. under a CO atmosphere overnight, cooled to room temperature, diluted with H ₂ O, and extracted with EA. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography to obtain compound 44-1 (160 mg, 0.39 mmol). MS (ESI): m/z=413[M+H] ⁺ .

Step 2: Add 40% hydrazine hydrate (1 mL, 8.23 mmol) to a solution of compound 44-1 (100 mg, 0.39 mmol) in MeOH (6 mL). The reaction mixture was stirred at 80 °C overnight, cooled to room temperature and concentrated. The residue was dispersed in DCM and filtered. The filtrate was spin-dried to give a crude product. The crude product was slurried with PE/DCM (10/1) to give compound 44-2 (125 mg, 0.30 mmol). MS (ESI): m/z=413[M+H] ⁺ .

Step 3: A mixture of compound 44-2 (110 mg, 0.27 mmol) and trimethyl orthoformate (6 mg, 54.84 mmol) was stirred at 150°C overnight, cooled to room temperature, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography and preparative high performance liquid chromatography (Prep-HPLC) to obtain compound 44 (9 mg, 0.02 mmol). MS (ESI): m/z = 423 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ: 9.17 (s, 1H), 8.53 (d, J = 2.1Hz, 1H), 8.19 (dd, J = 8.3, 2.2Hz, 1H), 8.08 (s, 1H), 7.97 (d, J = 8.4Hz, 1H), 7.88 (br d, J = 4.1Hz, 1H), 7.70 (d, J =3.3Hz, 1H), 7.40 (dd, J = 8.7, 1.6Hz, 1H), 7.28 (d, J = 8.6Hz, 1H), 6.89 (d, J = 3.3Hz, 1H), 2.56 (d, J = 3.5Hz, 3H).

Embodiment 45

Compound 2-(tributyltin)oxazole (267 mg, 0.69 mmol), Pd(PPh ₃ ) ₄ (54 mg, 0.05 mmol) and CuI (9 mg, 0.05 mmol) were added to a DMF (5 mL) solution of compound 43-3 (200 mg, 0.46 mmol). The reaction mixture was stirred at 120° C. overnight, cooled to room temperature, diluted with potassium fluoride solution (2 M), and extracted with EA. The combined organic phase was washed with saturated brine (3×5 ml), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography and preparative high performance liquid chromatography (Prep-HPLC) to obtain compound 45 (70 mg, 0.17 mmol). MS (ESI): m/z=422[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ ) δ: 8.51 (d, J = 2.1 Hz, 1H), 8.08 (dd, J = 8.4, 2.1 Hz, 1H), 8.06 (s, 1H), 7.99 (s, 1H) ,7.87(d,J＝8.3Hz,1H),7.82(q,J＝4.9Hz,1H),7.68(d,J＝3.4Hz,1H),7.36(d,J＝8.8Hz,1H),7.26 (s,1H),7.21(d,J＝8.6Hz,1H),6.87(d,J＝3.4Hz,1H),2.55(d,J＝4.9Hz,3H).

Embodiment 46

Step 1: Compound 46-1 (180 mg, 0.9259 mmol), Pd(dppf)Cl _2· CH ₂ Cl ₂ (40 mg, 0.0463 mmol) and Na ₂ CO ₃ (100 mg, 0.9259 mmol) were added to a solution of compound 43-3 (200 mg, 0.4630 mmol) in DMSO (5 mL) and H ₂ O (1 mL). The reaction mixture was stirred at 100° C. overnight, diluted with H ₂ O, and extracted with EA. The combined organic phases were dried and concentrated to obtain a residue. The residue was purified by silica gel column chromatography to obtain compound 46 (40 mg, 0.0952 mmol). MS (ESI): m/z=421[M+H] ⁺ . ¹ H NMR (DMSO-d6) δ: 12.87 (br s, 1H), 8.17 (d, J = 1.9Hz, 1H), 8.09 (s, 1H), 7.81 (dd, J = 8.2, 1.9Hz, 1H), 7.71 (d, J = 8.1Hz, 1H), 7.66 (br d, J = 5.0Hz, 1H), 7.65 (d ,J＝3.3Hz,1H),7.35(d,J＝8.8Hz,1H),7.19(br s,1H),7.09(d,J＝8.5Hz,1H),6.92(d,J＝3.1Hz,1H),6.89(br s,1H),2.55(d,J＝4.9Hz,3H).

Embodiment 47

Step 1: Disperse 2-chloro-3-fluoropyridine (0.76 mL, 7.60 mmol), 5-(trifluoromethyl)indole (1.41 g, 7.60 mmol) and cesium carbonate (4.95 g, 15.21 mmol) in N,N-dimethylformamide (12 mL) at room temperature. Purge the reaction mixture with N ₂ and maintain the N ₂ atmosphere. Slowly heat to 120 ° C and stir for 1 hour. Dilute the reaction solution with water and extract with ethyl acetate (100 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:5) to obtain compound 47-3 (2.0781 g). MS (ESI): m/z = 297 [M+H] ⁺ .

Step 2: In a dry 50mL single-mouth bottle, at 0°C, dissolve methylamine hydrochloride (6.34g, 93.93mmol) in H ₂ O (20mL) and then add sodium bicarbonate (10.52g, 125.24mmol) (aq) dissolved in water (30ml). Finally, dissolve 3-bromobenzenesulfonyl chloride (4.52mL, 31.31mmol) in tetrahydrofuran (60mL) and add to the reaction system to replace N ₂ . The reaction system is slowly heated to room temperature and stirred for 2 hours. After the reaction is completed, extract with ethyl acetate (150mL×3), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (ethyl acetate: petroleum ether=1:5) to obtain intermediate compound 47-1 (7.7681g). MS (ESI): m/z=250, 252[M+H] ⁺ .

Step 3: In a dry 50 mL single-mouth bottle, compound 47-1 (1.1 g, 4.40 mmol), biboronic acid pinacol ester (1.12 g, 4.40 mmol), potassium acetate (1.08 g, 11.00 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (0.36 g, 0.44 mmol) were dissolved in dimethyl sulfoxide (13 mL) at room temperature, nitrogen was replaced, and the reaction system was slowly heated to 80 ° C and stirred for 6 hours. After the reaction was completed, it was diluted with water and extracted with ethyl acetate (150 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain intermediate compound 47-2 (1.36 g).

¹ H NMR (DMSO-d ₆ ) δ: 8.07 (s, 1H), 7.63 (t, J = 7.6Hz, 1H), 7.49 (q, J = 5.0Hz, 1H), 3.93 (s, 1H), 2.39 (d,J＝5.0Hz,3H),1.32(s,12H)

Step 4: At room temperature, compound 47-3 (100 mg, 0.34 mmol), compound 47-2 (100.17 mg, 0.34 mmol), sodium carbonate (392.16 mg, 3.70 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (392.16 mg, 3.70 mmol) were dispersed in 1,4-dioxane (5 mL)/water (1 mL). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 105°C and stirred overnight, then diluted with water and extracted with ethyl acetate (50 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by preparative silica gel plate (ethyl acetate: petroleum ether = 1:1) to obtain compound 47 (64 mg, yield: 8.02%, purity 96.04%). MS m/z(ESI):432[M+H] ⁺ . ¹ HNMR(DMSO-d ₆ )δ:8.90(dd,J＝4.8,1.5Hz,1H),8.11(dd,J＝8.0,1.5Hz,1H),7.98(s,1H),7.72(dd,J＝8.0,4.8Hz,1H),7.69(t,J＝1.6Hz,1H),7.68(d,J＝3.3Hz,1H),7.60(dt ,J＝7.9,1.3Hz,1H),7.40(d,J＝15.5Hz,1H),7.32(dt,J＝7.8,1.4Hz,1H),7.26-7.31(m,2H),7.12(d,J＝8.6Hz,1H),6.83(d,J＝3.3Hz,1H),2.03(d,J＝5.1 Hz,3H).

Embodiment 50

Step 1: Sodium methoxide (117.19 mg, 2.17 mmol) was added to a methanol solution (25 mL) of 3,5-dichloropyridine-2-carbonitrile (1.0 g, 5.75 mmol) at 0°C. The reaction mixture was stirred at room temperature for 12 hours and then concentrated. Water (15 mL) was added to the concentrate and extracted with ethyl acetate (45 mL). The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent gradient transition from PE:EA=20:1 to 8:1) to obtain compound 50-1 (856 mg). MS (ESI): m/z=169[M+H] ⁺ .

Step 2: According to the similar synthesis method of Step 1 in Example 2, Compound 50-2 was prepared using Compound 50-1 and 5-(trifluoromethyl)-1H-indole as reactants. LCMS: m/z=318 [M+H] ⁺ .

Step 3: According to the similar synthesis method of Step 2 in Example 2, Compound 50-3 was prepared using Compound 50-2 as a reactant. LCMS: m/z = 351 [M+H] ⁺ .

Step 4: According to the similar synthesis method of step 3 in example 2, compound 50 (50 mg, 0.13 mmol, yield: 58%, purity: 98.29%) was prepared using compound 50-3 as a reactant. MS (ESI): m/z = 377 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ: 8.55 (d, J = 2.9 Hz, 1H), 8.04 (s, 1H), 7.95 (d, J = 2.9 Hz, 1H), 7.59 (d, J = 3.3 Hz, 1H), 7.41-7.50 (m, 2H), 6.81 (d, J = 3.3 Hz, 1H), 3.99 (s, 3H), 3.35 (br s, 1H).

Embodiment 51

Step 1: At room temperature, compound 51-1 (46.42 mg, 0.38 mmol), pyridin-2-ylboronic acid (46.42 mg, 0.38 mmol), tetrakis(triphenylphosphine)palladium (29.09 mg, 0.03 mmol), sodium bicarbonate (53.37 mg, 0.50 mmol) were dispersed in a mixed solvent of dimethyl sulfoxide (5 mL)/water (1 mL). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 105°C and stirred overnight, diluted with water, and then extracted with ethyl acetate (50 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a residue. The residue was purified by preparative silica gel plate (eluted with ethyl acetate: petroleum ether = 1:1) to obtain compound 51 (10 mg, yield: 10.05%). MS (ESI): m/z = 396 [M+H] ⁺ . ¹ H NMR(CHLOROFORM-d)δ:8.58(br d,J＝3.6Hz,1H),8.23(s,1H),8.03(br d,J＝6.6Hz,1H),7.84(s,1H),7.53(d,J＝8.3Hz,1H),7.23-7.31(m,2H),7.13(br d,J＝ 8.4Hz, 2H), 6.99 (d, J = 3.1Hz, 1H), 6.59 (br d, J = 2.9Hz, 1H), 6.52 (br s, 1H), 6.46 (br d, J = 7.6Hz, 1H), 3.00 (d, J = 4.8Hz, 3H).

Embodiment 52

Step 1: Disperse methyl 3-bromo-4-fluorobenzoate (1.5 g, 6.44 mmol), 5-(trifluoromethyl)indole (1.19 g, 6.44 mmol) and cesium carbonate (4.19 g, 12.87 mmol) in N,N-dimethylformamide (20 mL) at room temperature. Purge the reaction mixture with N ₂ and maintain the atmosphere of N ₂ . Slowly heat to 120°C and stir for 1 hour, dilute with water, and extract with ethyl acetate (100 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with ethyl acetate: petroleum ether = 1:5) to obtain compound 52-1 (1.5 g, yield: 58.53%).

Step 2: At room temperature, lithium hydroxide (0.47 g, 11.30 mmol) was added to a solution of compound 52-1 (1.5 g, 3.77 mmol) in tetrahydrofuran (8 mL), water (4 mL), and methanol (2 mL). The reaction mixture was slowly heated to 60°C, stirred for 2 hours, concentrated, diluted with water, adjusted to pH below 4 with dilute hydrochloric acid (2N), and extracted with ethyl acetate (100 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluted with petroleum ether: ethyl acetate = 1:1) to obtain compound 52-2 (850 mg, yield: 58.69%).

Step 3: At room temperature, N,N-diisopropylethylamine (1.10 mL, 6.64 mmol) was added to a solution of compound 52-2 (850 mg, 2.21 mmol), methylamine hydrochloride (224.10 mg, 3.32 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1262.02 mg, 3.32 mmol) in N,N-dimethylformamide (15 mL). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, stirred overnight at room temperature, diluted with water, and extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative silica gel plate (eluted with ethyl acetate) to give compound 52-3 (861 mg, yield: 97.97%). MS (ESI): m/z=397, 399 [M+H] ⁺ .

Step 4: Disperse compound 52-3 (200 mg, 0.50 mmol), 1-methyl-4-(tributylstannyl)-1H-imidazole (279.75 mg, 0.75 mmol), tetrakis(triphenylphosphine)palladium (57.78 mg, 0.05 mmol) and cuprous iodide (10 mg, 0.05 mmol) in N,N-dimethylformamide (4 mL) at room temperature. Purge the reaction mixture with N ₂ and maintain the N ₂ atmosphere, slowly heat to 120 ° C and stir overnight, add potassium fluoride solution (2N) and stir at room temperature for 2 hours to quench the reaction solution, and then extract with ethyl acetate (100 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluted with ethyl acetate: petroleum ether = 1:1) to obtain compound 52 (97 mg, yield: 48.35%). MS (ESI): m/z=399[M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ: 8.69 (d, J = 1.4Hz, 1H), 8.66 (br d, J = 4.4Hz, 1H), 8.11 (s, 1H), 7.85 (dd, J = 8.1, 1.7Hz, 1H), 7.56-7.61 (m, 2H), 7.46 (d, J = 8.1Hz, 1H), 7.3 7(br d,J＝8.6Hz,1H),7.06(br d,J＝8.6Hz,1H),6.92(d,J＝2.9Hz,1H),5.50(s,1H),3.35(s,3H),2.84(br d,J＝4.3Hz,3H).

Embodiment 53

Step 1: 5-Chloro-1H-indole (1.09 g, 7.22 mmol) was added to a solution of 2-chloronicotinonitrile (1.0 g, 7.22 mmol) and sodium tert-butoxide (0.83 g, 8.66 mmol) in N,N-dimethylformamide (20 mL), and the reaction was stirred at 120 ° C for 12 hours. The mixture was diluted with water (30 mL), extracted with ethyl acetate (90 mL), and washed with saturated sodium chloride solution. The combined organic layer was dried, filtered and concentrated to obtain a crude product. The residue was purified by silica gel column chromatography (eluent gradient from PE:EA = 20:1 to 4:1) to obtain compound 53-1 (1.34 g). MS (ESI): m/z = 254 [M+H] ⁺ .

Step 2: Compound 53-1 (400 mg, 1.58 mmol), triethylamine (2.19 mL, 15.77 mmol) and To an ethanol solution (25 mL) of molecular sieves (200 mg) was added hydroxylamine hydrochloride (547.83 mg, 7.88 mmol). The mixture was stirred and refluxed at 80°C for 12 hours. The mixture was concentrated, then water (15 mL) was added, extracted with ethyl acetate (45 mL), and washed with a saturated sodium chloride solution. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The resulting residue was purified by silica gel column chromatography (eluent gradient transition from PE:EA=20:1 to 0:1) to obtain compound 53-2 (crude, 422 mg). MS (ESI): m/z=287[M+H] ⁺ .

Step 3: Compound 53-2 (420 mg, 1.46 mmol) and N,N'-carbonyldiimidazole (285 mg, 1.76 mmol) were dissolved in tetrahydrofuran (10 mL), reacted at 0°C for 30 minutes, and then 1,8-diazabicyclo[5.4.0]-7-undecene (0.33 mL, 2.20 mmol) was added and reacted at room temperature for 30 minutes. The reaction was quenched with water (10 mL), extracted with ethyl acetate (20 mL×3), the organic phase was washed with water, dried and concentrated, and purified by column chromatography to obtain compound 53 (26.54 mg, 0.08 mmol, yield: 5.79%, purity: 99.33%). MS (ESI): m/z=313[M+H] ⁺ . ¹ H NMR(DMSO-d ₆ )δ:12.76(br s,1H),8.84(dd,J＝4.8,1.8Hz,1H),8.32(dd,J＝7.8,1.9Hz,1H),7.69-7.72(m,2H),7.53-7.57(m,1H),7.49-7.53(m,1H), 7.22(dd,J=8.9,2.1Hz,1H), 6.71(d,J=3.5Hz,1H).

Embodiment 56

Step 1: At 0°C, N-iodosuccinimide (5.28 g, 23.45 mmol) was added to a solution of 3-fluoro-4-(trifluoromethyl)aniline (2.8 g, 15.63 mmol) in dichloromethane (40 mL). The reaction mixture was warmed to room temperature and stirred for 1 hour, diluted with water (30 mL), and extracted with ethyl acetate (20 mL*3). The combined organic phases were concentrated. The residue was purified by flash column chromatography (eluted with petroleum ether/ethyl acetate = 4/1) to obtain compound 56-1 (2.9 g, 9.51 mmol, yield: 60.82%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.77 (d, J = 8.1 Hz, 1H), 6.63 (d, J = 13.6 Hz, 1H), 6.24 (s, 2H).

Step 2: Add ethynyltrimethylsilane (1.62mL, 11.41mmol), triethylamine (1.32mL, 9.51mmol), cuprous iodide (0.09mg, 0.68mmol) and bis(triphenylphosphine)palladium chloride (0.33g, 0,48mml) to tetrahydrofuran (15mL) of compound 56-1 (2.9g, 9.51mmol). The reaction mixture was purged with _N2 and maintained under _N2 atmosphere, stirred at room temperature for 3 hours, diluted with water (30mL), and extracted with ethyl acetate (20mL*3). The combined organic phase was concentrated to obtain a crude product. The crude product was purified by flash column chromatography (eluted with petroleum ether/ethyl acetate = 4/1) to obtain compound 56-2 (2.45g, 8.90mmol, yield: 93.59%). ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.43 (d, J = 8.3, 1H), 6.64 (d, J = 13.5 Hz, 1H), 6.32 (s, 2H), 0.24 (s, 9H).

Step 3: Add cuprous iodide (1.42 g, 7.45 mmol) to DMF (20 mL) of compound 56-2 (2.405 g, 7.45 mmol). Heat the reaction mixture to 100 °C and stir for 1.5 hours, dilute with water (30 mL), and extract with ethyl acetate (20 mL*3). Concentrate the combined organic phase to obtain a crude product. Purify the crude product by flash column chromatography (eluted with petroleum ether/ethyl acetate = 4/1) to obtain compound 56-3 (830 mg, 4.09 mmol, yield: 54.87%). ¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.59 (s, 1H), 7.95 (d, J = 7.1 Hz, 1H), 7.48–7.56 (m, 1H), 7.43 (d, J = 12.0 Hz, 1H), 6.61 (t, J = 2.1 Hz, 1H).

Step 4: Add compound 56-3 (700 mg, 3.45 mmol) and sodium tert-butoxide (331.15 mg, 3.45 mmol) to a DMF (10 mL) solution of 2-chloronicotinonitrile (0.24 mL, 2.30 mmol). The reaction mixture was heated to 100°C and stirred for 2 hours, diluted with water (30 mL), and extracted with ethyl acetate (20 mL*3). The combined organic phase was concentrated to obtain a crude product. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain compound 56-4 (730 mg, 2.39 mmol). ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.91(d,J＝4.9,1.8Hz,1H),8.62(d,J＝7.9,1.8Hz,1H),8.15(d,J＝7.1Hz,1H),8.10(d,J＝3.5Hz,1H),7.85(d,J＝12.1Hz,1H),7.71 (d, J = 7.9, 4.9 Hz, 1H), 6.99 (d, J = 3.5 Hz, 1H).

Step 5: Add hydroxylamine hydrochloride (170.74 mg, 2.46 mmol) to a methanol solution (10 mL) of compound 56-4 (150 mg, 0.49 mmol), triethylamine (0.68 mL, 4.91 mmol) and molecular sieves (100 mg). The reaction mixture was stirred at 80°C for 12 hours and then concentrated, then water (15 mL) was added and extracted with ethyl acetate (45 mL). The combined organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent gradient transition from petroleum ether: ethyl acetate = 20:1 to 1:1) to obtain compound 56-5 (136 mg, 0.40 mmol, yield: 81.81%). MS (ESI): m/z = 339 [M+H] ⁺ .

Step 6: At 0°C, N,N'-carbonyldiimidazole (81.49 mg, 0.50 mmol) was added to a tetrahydrofuran solution (5 mL) of compound 56-5 (136 mg, 0.40 mmol). After the reaction mixture was stirred at room temperature for 30 minutes, 1,8-diazabicyclo[5.4.0]-7-undecene (90.01 μL, 0.60 mmol) was added and stirred for 1 hour, diluted with water (15 mL), and extracted with ethyl acetate (45 mL). The combined organic phase was washed with a saturated sodium chloride solution, dried, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent gradient from dichloromethane: methanol = 1:0 to 10:1) to obtain compound 56 (26 mg, 0.07 mmol, yield: 17.75%, purity: 98.74%). MS (ESI): m/z = 365 [M+H] ⁺ . ¹ HNMR(DMSO-d ₆ )δ:8.84(br d,J＝3.5Hz,1H),8.34(br d,J＝7.5Hz,1H),8.09(d,J＝7.1Hz,1H),7.73(dd,J＝7.6,4.9Hz,1H),7.57-7.65(m,2H),6.86(d,J＝3.3 Hz,1H).

Embodiment 59

Step 1: A mixture of compound 3-fluoro-4-trifluoromethylaniline (1 g, 5.5 mmol), NIS (1.8 g, 8 mmol), and AcOH (5 mL) was stirred at room temperature for 2 hours and then concentrated. NaHCO ₃ (20 mL) was slowly added to the concentrate under ice bath conditions, and extracted with EA (30 mL). The combined organic phases were washed with saturated brine (10 mL×3), dried over anhydrous Na ₂ SO ₄ , and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with EA:PE=1/10) to obtain compound 59-1 (580 mg, 1.8 mmol, yield: 34.4%). MS (ESI): m/z=306[M+H] ⁺ .

Step 2: A mixture of compound 59-1 (500 mg, 1.6 mmol), trimethylethynylsilane (240 mg, 2.4 mmol), Pd(PPh ₃ ) ₄ (184 mg, 0.16 mmol), CuI (30 mg, 0.16 mmol), DIPEA (412 mg, 3.2 mmol), and DMF (10 mL) was purged with N ₂ and maintained under N ₂ atmosphere, then stirred at 80° C. for 12 hours, added with H ₂ O (20 mL), and extracted with EA (30 mL). The combined organic phases were washed with saturated brine (10 mL×3), dried over anhydrous Na ₂ SO _4, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with EA:PE=1/5) to obtain compound 59-2 (220 mg, 0.79 mmol, yield: 49.8%). MS (ESI): m/z=276[M+H] ⁺ .

Step 3: TBAF (247 mg, 0.94 mmol) was slowly added to a solution of compound 59-2 (220 mg, 0.79 mmol) in THF (10 mL). The reaction mixture was reacted at room temperature for 1 hour, diluted with H ₂ O (50 mL), and extracted with EA (20 mL). The organic phase was washed with saturated brine (20 mL×3), dried over anhydrous Na ₂ SO _4, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with EA:PE=1/5) to obtain compound 59-3 (90 mg, 0.45 mmol, yield: 57.5%). MS (ESI): m/z=204[M+H] ⁺ .

Step 4: A mixture of compound 59-3 (380 mg, 1.8 mmol), potassium tert-butoxide (403 mg, 3.6 mmol) and NMP (5 mL) was purged with N ₂ and maintained under N ₂ atmosphere. After stirring at 80°C for 12 hours, the mixture was diluted with H ₂ O (50 mL) and extracted with EA (20 mL). The organic phase was washed with saturated brine (20 mL×3), dried over anhydrous Na ₂ SO ₄ and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with EA:PE=1/3) to obtain compound 59-4 (270 mg, 1.32 mmol, yield: 73.5%). MS (ESI): m/z=204[M+H] ⁺ .

Step 5: Add 2-chloronicotinonitrile (293 mg, 1.58 mmol) and cesium carbonate (855 mg, 2.64 mmol) to a solution of compound 59-4 (270 mg, 1.32 mmol) in DMF (20 mL). The reaction mixture was stirred at 120°C for 3 hours, diluted with H ₂ O (200 mL), and extracted with EA (50 mL). The organic phase was washed with saturated brine (20 mL×3), dried over anhydrous Na ₂ SO ₄ , and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with EA:PE=1/4) to obtain compound 59-5 (300 mg, 0.98 mmol, yield: 74.2%). MS (ESI): m/z=306[M+H] ⁺ .

Step 6: Compound 59-5 (300 mg, 0.9 mmol), NH ₂ OH·HCl (630 mg, 9 mmol), 10 mL MeOH, TEA (3 mL) and The mixture of molecular sieves (300 mg) was purged with N ₂ and maintained under N ₂ atmosphere, stirred at 80° C. for 3 hours, and filtered under reduced pressure. The filtrate was concentrated, H ₂ O (20 mL) was added, and extracted with EA (30 mL). The organic phase was washed with saturated brine (10 mL×3), dried over anhydrous Na ₂ SO _4, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with EA:PE=1/2) to obtain compound 59-6 (158 mg, 0.46 mmol, yield 51.7%). MS (ESI): m/z=339[M+H] ⁺ .

Step 7: Under ice bath, CDI (57.3 mg, 0.35 mmol) was added to a solution of compound 59-6 (100 mg, 0.29 mmol) in THF (10 mL). The reaction mixture was stirred at room temperature for 30 minutes, cooled with ice bath, and DBU (66 mg, 0.43 mmol) was added dropwise and continued to stir under ice bath for 2 h. An aqueous solution of HCl (20 mL, pH = 2) was added and extracted with EA (20 mL). The organic phase was washed with saturated brine (10 mL × 3), dried over anhydrous Na ₂ SO ₄ and concentrated to obtain a residue. The residue was purified by preparative high performance liquid chromatography to obtain compound 59 (63 mg, 0.17 mmol, yield: 59.5%). MS (ESI): m/z = 365 [M + H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ: 8.87 (dd, J = 4.9, 1.8 Hz, 1H), 8.36 ( dd, J = 7.8, 1.8 Hz, 1H), 8.11 ( d, J = 7.1 Hz, 1H), 7.76 ( dd, J = 7.8, 4.8 Hz, 1H), 7.58-7.64 ( m, 2H), 6.88 ( d, J =3.5Hz,1H).

Embodiment 60

Step 1: In an ice bath, N-iodosuccinimide (2.59 g, 11.50 mmol) was added to a solution of 3-chloro-4-(trifluoromethyl)aniline (1.5 g, 7.67 mmol) in acetic acid (20 mL). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly warmed to room temperature and stirred for one hour, quenched with saturated sodium bicarbonate, and extracted with ethyl acetate (100 mL×3). The combined organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with ethyl acetate: petroleum ether=1:5) to obtain compound 60-1 (1.993 g, yield: 80.83%). ¹ HNMR (DMSO-d ₆ )δ:7.84(s,1H),6.89(s,1H),6.22(br s,2H).

Step 2: At room temperature, DIPEA (2.01 mL, 12.13 mmol) and ethynyltrimethylsilane (1.30 mL, 9.10 mmol) were added to a mixture of compound 60-1 (1.95 g, 6.07 mmol), tetrakis(triphenylphosphine)palladium (0.70 g, 0.61 mmol), cuprous iodide (0.12 g, 0.61 mmol) and DMF (25 mL). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 80°C and stirred overnight, then diluted with water and extracted with ethyl acetate (100 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with petroleum ether: ethyl acetate = 5:1) to obtain compound 60-2 (1.08 g, yield: 61.02%). MS (ESI): m/z = 292 [M+H] ⁺ .

Step 3: At room temperature, tetrabutylammonium fluoride (3.77 mL, 3.77 mmol) was added to a tetrahydrofuran (10 mL) solution of compound 60-2 (1.0 g, 3.43 mmol). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, stirred at room temperature for 30 minutes, diluted with water, and extracted with ethyl acetate (50 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a residue. The residue was purified by preparative silica gel plate (petroleum ether: ethyl acetate = 5:1) to obtain compound 60-3 (1.056 g). MS (ESI): m/z = 218 [MH] ^- .

Step 4: Under ice bath conditions, sodium tert-butoxide (1.02 g, 9.11 mmol) was added to a solution of compound 60-3 (1.0 g, 4.55 mmol) in NMP (10 mL). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 80 ° C and stirred for 2 hours, diluted with water, and extracted with ethyl acetate (50 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a residue. The obtained residue was purified by preparative silica gel plate (eluted with petroleum ether: ethyl acetate = 5: 1) to obtain compound 60-4 (678 mg, yield: 67.80%). MS (ESI): m/z = 220 [M + H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ: 11.64 (br s, 1H), 8.09 (s, 1H), 7.68 (s, 1H), 7.57 (t, J = 2.8 Hz, 1H), 6.64 (t, J = 2.1 Hz, 1H).

Step 5: At room temperature, 2-chloronicotinonitrile (350 mg, 1.59 mmol) and Cs ₂ CO ₃ (1038.64 mg, 3.19 mmol) were added to a DMF (7 mL) solution of compound 60-4 (350 mg, 1.59 mmol) in sequence. The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 120°C and stirred for 1 hour, diluted with water, and extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue. The residue was purified by preparative silica gel plate (eluted with petroleum ether: ethyl acetate = 5:1) to obtain compound 60-5 (429 mg, yield: 83.67%). MS (ESI): m/z = 322 [M+H] ⁺ .

Step 6: At room temperature, hydroxylamine hydrochloride (907.26 mg, 13.06 mmol), Molecular sieves (420 mg, 1.31 mmol) and triethylamine (10.86 mL, 78.34 mmol) were added to a methanol (15 mL) solution of compound 60-5 (420 mg, 1.31 mmol). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere. The temperature was slowly raised to 80°C and stirred for 3 hours. The mixture was quenched with saturated ammonium chloride, filtered and extracted with ethyl acetate (50 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a residue. The residue was purified by preparative silica gel plate (eluted with ethyl acetate) to obtain compound 60-6 (459 mg, yield: 99.11%). MS (ESI): m/z=355[M+H] ⁺ .

Step 7: Under ice bath conditions, CDI (257.13 mg, 1.59 mmol) was added to a tetrahydrofuran (5 mL) solution of compound 60-6 (450 mg, 1.27 mmol), stirred at room temperature for 30 minutes, and then DBU (284.02 μL, 1.90 mmol) was added again under ice bath conditions. The reaction mixture was slowly warmed to room temperature and stirred for 1 hour, diluted with water, and extracted with ethyl acetate (50 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a residue. The residue was purified by preparative silica gel plate (eluted with ethyl acetate) to obtain compound 60 (205 mg, yield: 42.45%). MS (ESI): m/z=381[M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ: 8.80 (dd, J = 4.8, 1.8 Hz, 1H), 8.37 ( dd, J = 7.8, 1.7 Hz, 1H), 8.19 ( s, 1H), 7.74 ( s, 1H), 7.71 ( dd, J = 7.8, 4.8 Hz, 1H), 7.64 ( d, J = 3.4 Hz, 1H), 6.85(d,J＝3.3Hz,1H).

Embodiment 66

Step 1: According to a similar synthesis method to Step 1 in Example 3, 2-fluoro-3-methylbenzonitrile and 5-(trifluoromethyl)-1H-indole were used as reactants to prepare compound 66-1. LCMS: m/z=301 [M+H] ⁺ .

Step 2: According to the similar synthesis method of Step 2 in Example 3, compound 66-2 was prepared using compound 66-1 as a reactant. LCMS: m/z=334 [M+H] ⁺ .

Step 3: According to the similar synthesis method of Step 3 in Example 3, Compound 66 (58 mg, purity 98.5%) was prepared using Compound 66-2 as the reactant. MS (ESI): m/z = 360 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ: 12.64 (br s, 1H), 8.04 (s, 1H), 7.65-7.76 (m, 3H), 7.53 (d, J = 3.3 Hz, 1H), 7.39 (dd, J = 8.7, 1.6 Hz, 1H), 6.96 (d, J = 8.5 Hz, 1H), 6.83 (d, J = 3.1 Hz, 1H), 1.90 (s, 3H).

Embodiment 67

Step 1: 5-(trifluoromethyl)-1H-indole (664.69 mg, 3.59 mmol) was added to a solution of 2,3-difluorobenzene-1-carbonitrile (0.4 mL, 3.59 mmol) and sodium tert-butoxide (414 mg, 4.31 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at 120°C for 12 hours, diluted with water, and then extracted with ethyl acetate (60 mL). The organic phase was washed with a saturated sodium chloride solution, dried, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent gradient transition from petroleum ether: ethyl acetate = 20:1 to 4/1) to obtain compound 67-1 (1.02 g, 3.36 mmol, yield: 93.57%). MS (ESI): m/z = 305 [M+H] ⁺ .

Step 2: Hydroxylamine hydrochloride (342.60 mg, 4.93 mmol) was added to a mixture of compound 67-1 (300 mg, 0.99 mmol), triethylamine (1.37 mL, 9.86 mmol), molecular sieves (200 mg) and methanol (4 mL). The reaction mixture was stirred at 80 ° C for 12 hours and then concentrated. Water (15 mL) was added to the concentrate and extracted with ethyl acetate (45 mL). The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent gradient transition from petroleum ether: ethyl acetate = 20: 1 to 0: 1) to obtain compound 67-2 (309 mg, 0.92 mmol, yield: 92.91%). MS (ESI): m/z = 338 [M+H] ⁺ .

Step 3: At 0°C, N,N'-carbonyldiimidazole (70.66 mg, 0.44 mmol) was added to a tetrahydrofuran solution (5 mL) of compound 67-2 (112 mg, 0.35 mmol), and after stirring at room temperature for 30, 1,8-diazabicyclo[5.4.0]-7-undecene (78.05 μL, 0.52 mmol) was added. The reaction mixture was stirred for 1 hour, diluted with water (15 mL), and extracted with ethyl acetate (45 mL). The organic phase was washed with a saturated sodium chloride solution, dried, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluent gradient from dichloromethane: methanol = 1:0 to 10:1) to obtain compound 67 (151 mg, 0.42 mmol, yield: 45.37%, purity: 99.0%). MS (ESI): m/z = 364 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ: 12.86 (br s, 1H), 8.06 (s, 1H), 7.82-7.90 (m, 2H), 7.73-7.80 (m, 1H), 7.59 (d, J = 3.4Hz, 1H), 7.44 (dd, J = 8.7, 1.4Hz, 1H), 7.16 (d, J = 8 .5Hz, 1H), 6.87 (d, J = 3.3Hz, 1H).

Embodiment 68

Step 1: According to the similar synthesis method of Step 1 in Example 67, 3-chloro-2-fluorobenzonitrile and 5-(trifluoromethyl)-1H-indole were used as reactants to prepare compound 68-1. LCMS: m/z=321 [M+H] ⁺ .

Step 2: According to the similar synthesis method of Step 2 in Example 67, compound 68-2 was prepared using compound 68-1 as a reactant. LCMS: m/z=354 [M+H] ⁺ .

Step 3: According to the similar synthesis method of Step 3 in Example 67, compound 68 (83 mg, purity: 98.9%) was prepared using compound 68-2 as a reactant. MS (ESI): m/z = 380 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ: 12.83 (br s, 1H), 8.02-8.09 (m, 2H), 7.81-7.95 (m, 2H), 7.55 (d, J = 3.3 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 8.6 Hz, 1H), 6.86 (d, J = 3.3 Hz, 1H).

Embodiment 69

Step 1: According to the similar synthesis method of Step 1 in Example 67, 3-chloro-2-fluorobenzonitrile and 5-(trifluoromethyl)-1H-indole were used as reactants to prepare compound 69-1. MS (ESI): m/z=413 [M+H] ⁺ .

Step 2: Compound 69-2 was prepared by using compound 69-1 as a reactant according to a similar synthesis method to that of step 2 in Example 67. MS (ESI): m/z = 446 [M+H] ⁺ .

Step 3: According to the similar synthesis method of Step 3 in Example 67, compound 69-3 (83 mg, purity: 98.9%) was prepared using compound 69-2 as a reactant. MS (ESI): m/z = 472 [M+H] ⁺ .

Step 4: Add Zn(CN) ₂ (115 mg, 1.47 mmol) and Pd(PPh ₃ ) ₄ (60 mg, 1.96 mmol) to a DMF (5 mL) solution of compound 69-3 (100 mg, 0.98 mmol). The reaction mixture was stirred at 120°C overnight, water was added, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain a residue. The residue was purified by silica gel column chromatography to obtain compound 69 (43 mg, 0.65 mmol). MS (ESI): m/z=371[M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ6.91 (d, J = 3.25Hz, 1H) 7.17 (d, J = 8.50Hz, 1H) 7.45 (d, J = 8.63Hz, 1H) 7.69 (d, J = 3.25Hz, 1H) 8.00 (t, J = 7.82Hz, 1H) 8.08 (s, 1H) 8. 23(dd,J=7.94,1.19Hz,1H)8.37(dd,J=7.82,1.19Hz,1H). ¹³ C NMR (DMSO-d6) δ: 156.0, 139.0, 138.5, 137.5, 135.5, 132.3, 131.0, 128.4, 125.4, 122.0, 121.7, 119.4, 119.0, 115.6, 114.4, 111.2, 105.5.

Embodiment 70

Step 1: According to the similar synthesis method of Step 1 in Example 2, 3-chloro-4-nitrile-pyridazine and 5-(trifluoromethyl)-1H-indole were used as reactants to prepare compound 70-1. MS (ESI): m/z=289 [M+H] ⁺ .

Step 2: Compound 70-2 was prepared by using compound 70-1 as a reactant according to a similar synthesis method to step 2 in Example 2. MS (ESI): m/z = 322 [M+H] ⁺ .

Step 3: According to the similar synthesis method of Step 3 in Example 2, Compound 70 (86.17 mg, 0.25 mmol, yield 8.54%, purity: 99.6%) was prepared using Compound 70-2 as the reactant. MS (ESI): m/z=348 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ )δ: 9.65 (d, J=5.1 Hz, 1H), 8.25 (d, J=5.1 Hz, 1H), 8.10 (s, 1H), 7.73-7.79 (m, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.54 (dd, J=8.8, 1.5 Hz, 1H), 6.95 (d, J=3.4 Hz, 1H).

Embodiment 71

Step 1: 5-(trifluoromethyl)-1H-indole (1.33 g, 7.17 mmol) was added to a solution of 4-chloropyrimidine-5-carbonitrile (1.0 g, 7.17 mmol) and sodium tert-butoxide (0.83 g, 8.60 mmol) in N,N-dimethylformamide (20 mL), and the reaction was stirred at 120 ° C for 12 hours. The mixture was diluted with water (30 mL), extracted with ethyl acetate (90 mL), and washed with saturated sodium chloride solution. The combined organic layer was dried, filtered and concentrated to obtain a crude product. The residue was purified by silica gel column chromatography (eluent gradient from PE:EA = 20:1 to 4:1) to obtain compound 71-1 (755 mg, 2.62 mmol, 36.55%). MS (ESI): m/z = 289 [M+H] ⁺ .

Step 2: Compound 71-1 (380 mg, 1.32 mmol), triethylamine (1.83 mL, 13.18 mmol) and To a methanol solution (15 mL) of molecular sieves (380 mg) was added hydroxylamine hydrochloride (458.08 mg, 6.59 mmol). The mixture was stirred and refluxed at 80 ° C for 12 hours. After returning to room temperature, it was filtered, the filtrate was concentrated, and then water (15 mL) was added, extracted with ethyl acetate (45 mL), and washed with saturated sodium chloride solution. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The resulting residue was purified by silica gel column chromatography (eluent gradient transition from PE: EA = 20: 1 to 0: 1) to obtain compound 71-2 (112 mg, 0.35 mmol, 26.44%). MS (ESI): m/z = 322 [M + H] ⁺ .

Step 3: At 0°C, N,N'-carbonyldiimidazole (70.66 mg, 0.44 mmol) was added to a tetrahydrofuran solution (5 mL) of compound 71-2 (112 mg, 0.35 mmol), and the mixture was stirred at room temperature for 30 minutes. 1,8-diazabicyclo[5.4.0]-7-undecene (78.05 μL, 0.52 mmol) was added to the mixture and stirred for 1 hour. The mixture was diluted with water (15 mL), extracted with ethyl acetate (45 mL), and washed with saturated ammonium chloride solution and saturated sodium chloride solution. The combined organic layer was dried, filtered and concentrated to obtain a crude product. The residue was purified by silica gel column chromatography (eluent gradient from DCM:MeOH=99:1 to 10:1) to obtain compound 71 (30 mg, 0.09 mmol, yield: 24.78%, purity: 98.17%). MS (ESI): m/z=348[M+H] ⁺ . ¹ H NMR(DMSO-d ₆ )δ:9.26(s,1H),9.10(s,1H),8.06(s,1H),8.02-8.04(m,1H),7.65(d,J＝3.6Hz,1H),7.54(dd,J＝8.9,1.5Hz,1H),7.19(s,1H),6.85(d,J =3.5Hz,1H).

Embodiment 72

Step 1: According to the similar synthesis method of Step 1 in Example 2, 3-chloroisonicotinonitrile and 5-(trifluoromethyl)-1H-indole were used as reactants to prepare compound 72-1. MS (ESI): m/z=288[M+H] ⁺ .

Step 2: Compound 72-2 was prepared by using compound 72-1 as a reactant according to a similar synthesis method to step 2 in Example 2. MS (ESI): m/z = 321 [M+H] ⁺ .

Step 3: According to the similar synthesis method of Step 3 in Example 2, compound 72 (76.46 mg, 0.22 mmol, yield: 22.24%, purity 99.7%) was prepared using compound 72-2 as the reactant. MS (ESI): m/z=347 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ )δ: 8.99 (d, J=5.0 Hz, 1H), 8.95 (s, 1H), 8.07 (s, 1H), 7.93 (d, J=5.0 Hz, 1H), 7.69 (d, J=3.4 Hz, 1H), 7.45 (dd, J=8.8, 1.5 Hz, 1H), 7.27 (d, J=8.6 Hz, 1H), 6.89 (d, J=3.3 Hz, 1H).

Embodiment 75

Step 1: Add 5-(trifluoromethyl)indole (2.55 g, 13.80 mmol) and potassium tert-butoxide (3.10 g, 27.59 mmol) to a DMF (30 mL) solution of 5-bromo-2-chloronicotinonitrile (3.00 g, 13.80 mmol). The reaction mixture was heated to 120°C and stirred for 2 h, then diluted with water (50 mL) and extracted with ethyl acetate (50 mL*3). The combined organic phase was concentrated, and the residue was purified by flash column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain compound 75-1 (3.20 g). ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.06 (d, J = 2.5Hz, 1H), 9.01 (d, J = 2.5Hz, 1H), 8.11 (s, 1H), 8.08 (d, J = 3.5Hz, 1H), 7.94 (d, J = 8.5Hz, 1H), 7.58 (d, J = 8.8, 1.6Hz, 1H) ,6.99(d,J＝3.5Hz,1H).

Step 2: Trimethylcyclotriboroxane (0.12 mL, 0.44 mmol, 3.5 M in THF), potassium carbonate (452.94 mg, 3.28 mmol) and pd(dppf)Cl ₂ (39.97 mg, 0.05 mmol) were added to a mixed solution of compound 75-1 (400 mg, 1.09 mmol) in dioxane (4 mL) and water (0.5 mL). The reaction mixture was heated to 100 ° C under nitrogen protection, stirred overnight and filtered, and the filtrate was diluted with water (10 mL) and extracted with ethyl acetate (10 mL*3). The combined organic phase was concentrated, and the residue was purified by flash column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain compound 75-2 (140 mg). ¹ H NMR (400MHz, DMSO-d6) δ8.77(d,J＝1.6Hz,1H),8.48(d,J＝1.5Hz,1H),8.11(s,1H),8.05(d,J＝3.5Hz,1H),7.85(d,J＝8.6Hz,1H),7.55(d,J＝8.8,1.4Hz,1H ), 6.96 (d, J = 3.4Hz, 1H), 2.45 (s, 3H).

Step 3: Add hydroxylamine hydrochloride (80.73 mg, 1.16 mmol), TEA (0.64 mL, 4.65 mmol) and 4A molecular sieve (10 mg) to a methanol (1 mL) solution of compound 75-2 (70 mg, 0.23 mmol). Heat the reaction mixture to 80°C, stir for 2 h, filter, and concentrate the filtrate. Dilute the concentrate with water (3 mL) and extract with ethyl acetate (3 mL*3). Concentrate the organic phase to obtain a crude product of compound 75-3 (60 mg). MS m/z (ESI): = 335.1 [M+H] ⁺ .

Step 4: At 0°C, CDI (0.03 mL, 0.22 mmol) was added to a tetrahydrofuran (1 mL) solution of the crude product of compound 75-3 (60 mg), and after stirring at 0°C for 0.5 h, DBU (0.04 mL, 0.27 mmol) was added at 0°C. The reaction mixture was warmed to room temperature and stirred for 1 h, then diluted with water (3 mL), and extracted with ethyl acetate (3 mL*3). The combined organic phases were concentrated, and the residue was purified by preparative high performance liquid chromatography (HPLC) to obtain compound 75 (13.47 mg, 0.04 mmol, yield 20.44%). MS m/z (ESI): m/z＝361.1[M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d6) δ8.69(d,J＝1.6Hz,1H),8.19(d,J＝1.6Hz,1H),8.05(s,1H),7.58–7.64(m,2H),7.48(dd,J＝8.8,1 .6Hz,1H),6.85(d,J＝3.4Hz,1H),2.45–2.48(m,3H).

Embodiment 76

Step 1: Add 5-(trifluoromethyl)indoline (810.55 mg, 4.33 mmol) and sodium tert-butoxide (416.17 mg, 4.33 mmol) to a DMF (10 mL) solution of 2-chloronicotinonitrile (0.45 mL, 4.33 mmol). After the reaction mixture was heated to 80°C and stirred for 2 hours, it was diluted with water (30 mL) and extracted with ethyl acetate (20 mL*3). The combined organic phases were concentrated to obtain a residue. The residue was purified by flash column chromatography (eluted with petroleum ether: ethyl acetate = 3:1) to obtain compound 76-1 (1.00 g, 3.46 mmol, yield: 79.83%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.57 (d, J＝4.8, 2.0Hz, 1H), 8.28 (d, J＝7.8, 1.9Hz, 1H), 7.73 (d, J＝8.5Hz, 1H),7.59(s,1H),7.49(d,J＝8.5Hz,1H),7.19(d,J＝7.8,4.8Hz,1H),4.42(t,J＝8.5Hz,2H),3.27( t,J=8.4Hz,2H).

Step 2: Hydroxylamine hydrochloride (1020.99 mg, 14.69 mmol), TEA (8.15 mL, 58.77 mmol) and Molecular sieves (100 mg) were added to a methanol (10 mL) solution of compound 76-1 (850 mg, 2.94 mmol). The reaction mixture was heated to 80°C and stirred for 2 hours and then concentrated. Water (30 mL) was added to the concentrate and the mixture was extracted with ethyl acetate (30 mL*3). The combined organic phases were concentrated to obtain a crude product. The crude product was purified by flash column chromatography (eluted with dichloromethane: methanol = 10:1) to obtain compound 76-2 (190 mg, 0.59 mmol, yield: 20.06%). MS (ESI): m/z = 323 [M+H] ⁺ .

Step 3: At 0°C and maintaining this temperature, CDI (0.09 mL, 0.74 mmol) was added to a tetrahydrofuran (2 mL) solution of compound 76-2 (190 mg, 0.59 mmol), stirred for 0.5 hours, and then DBU (0.13 mL, 0.88 mmol) was added. The reaction mixture was warmed to room temperature, stirred for 1 hour, diluted with water (3 mL), and extracted with ethyl acetate (3 mL*3). The combined organic phases were concentrated to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography to obtain compound 76 (5.23 mg, yield: 13.68%). MS (ESI): m/z=349[M+H] ⁺ . ¹ H NMR (400MHz, MeOH-d ₄ ) δ8.56(d,J＝4.8,1.9Hz,1H),8.08(d,J＝7.7,1.9Hz,1H),7.52(s,1H),7.26–7.41(m,2H),6.88(d,J＝8.3Hz,1H),4.06(t,J＝8.4Hz ,2H),3.18(t,J=8.3Hz,2H).

Embodiment 79

Step 1: A mixture of 5-trifluoromethylindole (5.00 g, 27.01 mmol), compound 2-chloronicotinate ethyl ester (7.52 g, 40.51 mmol), Cs ₂ CO ₃ (17.60 g, 17.60 mmol) and DMF (20 mL) was purged with N ₂ and maintained under N ₂ atmosphere. After stirring at 120°C for 3 hours, water (200 mL) was added to dilute the mixture and the mixture was extracted with EA (50 mL). The organic phase was washed with saturated brine (20 mL×3), dried over anhydrous Na ₂ SO ₄ and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with DCM:PE=1:1) to obtain compound 79-1 (7.86 g, 23.51 mmol, yield: 87.06%). MS (ESI): m/z=335[M+H] ⁺ .

Step 2: A mixture of compound 79-1 (7.86 g, 23.51 mmol), N ₂ H ₄ ·H ₂ O (18 mL, 370.36 mmol) and MeOH (165 mL) was stirred at 80° C. for 18 hours and then concentrated. H ₂ O (50 mL) was added to the concentrate, and extracted with EA (50 mL). The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated to give a crude product (6.57 g) of compound 79-2 (MS (ESI): m/z=321 [M+H] ⁺ ).

Step 3: A mixture of the crude product of compound 79-2 (200 mg), CDI (405.0 mg, 2.50 mmol) and THF (20 mL) was purged with N ₂ and maintained under N ₂ atmosphere, stirred at 80° C. for 3 hours and then concentrated. H ₂ O (50 mL) was added to the concentrate, and extracted with EA (30 mL). The organic phase was concentrated to obtain a residue. The obtained residue was purified by preparative high performance liquid chromatography to obtain compound 79 (121.8 mg, 0.35 mmol, yield: 56.28%). MS (ESI): m/z=347[M+H] ⁺ . ¹ H NMR (400MHz, CHLOROFORM-d) δppm 6.80 (d, J = 3.13Hz, 1H) 7.39 (s, 1H) 7.42 (d, J = 1.50Hz, 1H) 7.44 (d, J = 3.38Hz, 1H) 7.54 (dd, J = 7.88Hz, 4.75Hz, 1H) 7.96 (s, 1H) 8.32 (dd, J = 7.88Hz, 1.75Hz, 1H) 8.67 (brd, J = 7.50Hz, 1H) 8.77 (dd, J = 4.75Hz, 1.75Hz, 1H).

Embodiment 80

Step 1: Add 2-amino-2-methylpropionic acid methyl ester hydrochloride (226 mg, 1.47 mmol), HATU (647 mg, 1.96 mmol), DIPEA (759 mg, 5.88 mmol) and DMAP (12 g, 0.10 mmol) to a DMF (5 mL) solution of compound 2-(5-trifluoromethyl)-1H-indol-1-ylnicotinic acid (300 mg, 0.98 mmol). The reaction mixture was stirred at room temperature overnight and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a residue. The obtained residue was purified by silica gel column chromatography to obtain compound 80-1 (263 mg, 0.65 mmol). MS (ESI): m/z=406[M+H] ⁺ . ¹ H NMR(DMSO-d ₆ )δ:8.97(s,1H),8.72(dd,J＝4.8,1.8Hz,1H),8.07(dd,J＝7.7,1.8Hz,1H),8.04(s,1H),7.83(d,J＝8.6Hz,1H),7.64(d,J＝3.5Hz,1H),7.59 (dd, J＝7.7, 4.8Hz, 1H), 7.49 (dd, J＝8.8, 1.5Hz, 1H), 6.85 (d, J＝3.4Hz, 1H), 3.54 (s, 3H), 1.25 (s, 6H).

Step 2: A solution of compound 80-1 (210 mg, 0.50 mmol) in amine methanol (7 M, 5 mL) was stirred at 80°C overnight, cooled to room temperature, diluted with H ₂ O and extracted with EA. The organic phase was dried and concentrated to obtain a residue. The residue was purified by column chromatography to obtain compound 80-2 (130 mg, 0.65 mmol). MS (ESI): m/z=391[M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ: 8.70 (dd, J = 4.8, 1.8 Hz, 1H), 8.47 (s, 1H), 8.27 (dd, J = 7.6, 1.9 Hz, 1H), 8.03 (s, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 3.4 Hz, 1H), 7.59 ( dd,J＝7.6,4.9Hz,1H),7.47(d,J＝8.8Hz,1H),7.09(br s,1H),6.90(br s,1H),6.81(d,J＝3.4Hz,1H),1.21(s,6H).

Step 3: Add NaOH solution (6N, 0.26 mL, 1.56 mmol) to a solution of compound 80-2 (120 mg, 0.31 mmol) in MeOH (4 mL). The reaction mixture was heated to reflux and stirred overnight, cooled to room temperature, adjusted to neutral pH with hydrochloric acid (2 M), diluted with H ₂ O and extracted with EA. The organic phase was dried and concentrated to obtain a residue. The residue was purified by silica gel column chromatography and preparative high performance liquid chromatography (Prep-HPLC) to obtain compound 80 (26 mg, 0.069 mmol, purity: 94.30%). MS (ESI): m/z=373[M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ: 11.06 (s, 1H), 8.80 (br d, J = 3.4Hz, 1H), 8.21-8.35 (m, 1H), 8.05 (s, 1H), 7.69 (dd, J = 7.8, 4.9Hz, 1H), 7.66 (d, J = 3.4Hz, 1H), 7.62 (d, J = 8.8Hz, 1H), 7.47 (br d, J = 8.8Hz, 1H), 6.85 (d, J = 3.4Hz, 1H), 0.99 (s, 6H).

Embodiment 81

Step 1: Compound 81-1 was prepared by a similar synthesis method to that of Step 1 in Example 80 using 2-(5-trifluoromethyl)-1H-indol-1-ylnicotinic acid and 1-aminocyclopentane-1-carboxylic acid methyl ester hydrochloride as reactants. MS (ESI): m/z=432 [M+H] ⁺ .

Step 2: Compound 81-2 was prepared by using compound 81-1 as a reactant according to a similar synthesis method to that of step 2 in Example 80. MS (ESI): m/z = 417 [M+H] ⁺ .

Step 3: According to the similar synthesis method of Step 3 in Example 2, Compound 81 (15 mg, 0.037 mmol, purity: 98.3%) was prepared using Compound 81-2 as a reactant. MS (ESI): m/z = 399 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ: 11.00 (br s, 1H), 8.80 (dd, J＝4.8, 1.8Hz, 1H), 8.29 (dd, J＝7.8, 1.8Hz, 1H), 8.04 (s, 1H), 7.63-7.70 (m, 2H), 7.59 (d, J＝8.6Hz, 1H), 7.4 6(dd,J＝8.8,1.5Hz,1H), 6.85(d,J＝3.4Hz,1H), 1.55-1.72(m,8H), 1.31-1.44(m,2H).

Embodiment 94

Step 1: Add 5-(trifluoromethyl)-1H-indole (1.07 g, 5.78 mmol) to a solution of 2,5-dichloronicotinonitrile (1.0 g, 5.78 mmol) and sodium tert-butoxide (666.59 mg, 6.94 mmol) in N,N-dimethylformamide (15 mL). After stirring the reaction mixture at 120°C for 12 hours, dilute it with water (30 mL) and then extract it with ethyl acetate (90 mL). The organic phase is washed with a saturated sodium chloride solution, dried and concentrated to obtain a crude product. The crude product is purified by silica gel column chromatography (eluent gradient transition from petroleum ether: ethyl acetate = 20:1 to 4:1) to obtain compound 94-1 (1.5 g, 4.66 mmol, yield: 80.67%).

Step 2: Hydroxylamine hydrochloride (540.04 mg, 7.77 mmol) was added to a mixture of compound 94-1 (500 mg, 1.55 mmol), triethylamine (2.15 mL, 15.54 mmol), molecular sieves (300 mg) and methanol (15 mL). The reaction mixture was stirred at 80 ° C for 12 hours and then concentrated. Water (15 mL) was added to the concentrate and extracted with ethyl acetate (45 mL). The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent gradient from petroleum ether: ethyl acetate = 20: 1 to 2: 1) to obtain compound 94-2 (497 mg, 1.40 mmol, yield: 90.14%). MS (ESI): m/z = 355 [M + H] ⁺ .

Step 3: At 0°C, N,N'-carbonyldiimidazole (142.85 mg, 0.88 mmol) was added to a tetrahydrofuran (8 mL) solution of compound 94-2 (250 mg, 0.70 mmol), and after stirring at room temperature for 30 minutes, 1,8-diazabicyclo[5.4.0]-7-undecene (157.79 μL, 1.06 mmol) was added. The reaction mixture was stirred for 1 hour, diluted with water (15 mL), and extracted with ethyl acetate (45 mL). The organic phase was washed with a saturated sodium chloride solution, dried, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent gradient from dichloromethane: methanol = 1:0 to 10:1) to obtain compound 94 (90 mg, yield: 33.54%). MS (ESI): m/z = 381 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ: 8.92 (d, J = 2.5Hz, 1H), 8.51 (d, J = 2.5Hz, 1H), 8.06 (s, 1H), 7.68 (d, J = 8.6Hz, 1H), 7.62 (d, J = 3.4Hz, 1H), 7.50 (dd, J = 8.8, 1.4Hz, 1H), 6 .86(d,J＝3.4Hz,1H).

Embodiment 95

Step 1: Add 5-trifluoromethylindole (2.2 g, 12 mmol), CuI (92 mg, 0.5 mmol), trans-(1R, 2R)-N, N'-dimethyl 1,2-cyclohexanediamine (284 mg, 2 mmol), potassium phosphate (4.2 g, 20 mmol) to a mixture of 2-chloroquinoline-3-carbonitrile (1.88 g, 10 mmol) and 1-4-dioxane (20 mL). The reaction mixture was purged with _N2 and maintained under _N2 atmosphere. After stirring at 110°C for 12 hours, _H2O (200 mL) was added for dilution and extracted with EA (50 mL). The organic phase was washed with saturated brine (20 mL×3), dried over anhydrous _{Na2SO4 ,} and concentrated to obtain a residue. The obtained residue was purified by silica gel column chromatography (eluted with EA:PE=1:4) to obtain compound 95-1 (1.3 g, 3.45 mmol, yield: 34.5%). MS (ESI): m/z=338 [M+H] ⁺ .

Step 2: Compound 95-1 (1.3 g, 4.26 mmol), 20 mL MeOH, NH ₂ OH·HCl (2.9 g, 42.6 mmol), TEA (10 mL) and The mixture of molecular sieves (1.3 g) was purged with N ₂ and maintained under N ₂ atmosphere, stirred at 80° C. for 3 hours, filtered under reduced pressure, and the filtrate was concentrated. H ₂ O (20 mL) was added to the phase concentrate, and extracted with EA (30 mL). The organic phase was washed with saturated brine (10 mL×3), dried over anhydrous Na ₂ SO _4, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with EA:PE=1:2) to obtain compound 95-2 (875 mg, 2.36 mmol, yield: 55.6%). MS (ESI): m/z=371[M+H] ⁺ .

Step 3: CDI (99.1 mg, 0.61 mmol) was added to a THF (10 mL) solution of compound 95-2 (200 mg, 0.51 mmol) under ice bath conditions, stirred at room temperature for 30 minutes and then cooled in an ice bath again, DBU (116 mg, 0.76 mmol) was added dropwise and stirred for 2 h under ice bath conditions, HCl (aq, 20 mL, pH = 2) was added, and extracted with EA (20 mL). The organic phase was washed with saturated brine (10 mL × 3), dried over anhydrous Na ₂ SO _4, and concentrated to obtain a residue. The residue was purified by preparative high performance chromatography to obtain compound 95 (58 mg, 0.14 mmol, yield: 27%). MS (ESI): m/z = 397 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ = 9.06 (s, 1H), 8.26 (d, J = 7.6Hz, 1H), 8.15-8.07 (m, 2H), 8.07-7.98 (m, 1H), 7.92-7.76 (m, 2H), 7.72 (d, J = 3.5Hz, 1H), 7.55 (dd, J = 1. 5,8.8Hz,1H),6.92(d,J＝3.3Hz,1H).

Embodiment 96

At 0°C, pyridine (54 mg, 0.69 mmol) was added to a DCM (4 mL) solution of compound N-hydroxy-5-methoxy-2-(5-trifluoromethyl)-1H-indol-1-yl) nicotinamide (117-2) (120 mg, 0.34 mmol), and after cooling to -50°C, a DCM (0.5 mL) solution of SOCl ₂ (49 mg, 0.41 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours and then concentrated. The concentrate was diluted with DCM and the pH was adjusted to neutral with hydrochloric acid (1 M). The organic phase was dried and concentrated to obtain a residue. The residue was purified by silica gel column chromatography to obtain compound 96 (7 mg, 0.02 mmol, yield: 5%, purity: 93.18%). MS (ESI): m/z=397[M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δppm4.00 (s, 3H) 6.78 (d, J = 3.13Hz, 1H) 7.45 (br d, J = 8.63Hz, 1H) 7.50 (d, J = 3.25Hz, 1H) 7.55 (d, J = 8.53Hz, 1H) 7.93 (d, J = 2.75Hz, 1H) 8.02(s,1H)8.57(d,J=2.75Hz,1H).

Embodiment 97

Step 1: Add 5-trifluoromethylindole (2.2 g, 12 mmol), CuI (92 mg, 0.5 mmol), trans-(1R, 2R)-N, N'-dimethyl 1,2-cyclohexanediamine (284 mg, 2 mmol), potassium phosphate (4.2 g, 20 mmol) to a mixture of 3-chloro-6,7-dihydro-5H-cyclopentane[c]pyridine-4-carbonitrile (1.78 g, 10 mmol) and 1-4Dioxane (20 mL). The reaction mixture was purged with _N2 and maintained under _N2 atmosphere. After stirring at 110°C for 12 hours, it was diluted with water (200 mL) and extracted with EA (50 mL). The organic phase was washed with saturated brine (20 mL×3), dried over anhydrous _{Na2SO4 ,} and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with EA:PE=1/4) to obtain compound 97-1 (1.3 g, 4.26 mmol, yield: 42.6%). MS (ESI): m/z=328 [M+H] ⁺ .

Step 2: Compound 97-1 (1.3 g, 4.26 mmol), 20 mL MeOH, NH ₂ OH·HCl (2.9 g, 42.6 mmol), TEA (10 mL) and The mixture of molecular sieves (1.3 g) was purged with N ₂ and maintained under N ₂ atmosphere, stirred at 80° C. for 3 hours, filtered under reduced pressure, and the filtrate was concentrated. H ₂ O (20 mL) was added to the concentrate, and extracted with EA (30 mL). The organic phase was washed with saturated brine (10 mL×3), dried over anhydrous Na ₂ SO _4, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with EA:PE=1:2) to obtain compound 97-2 (855 mg, 2.36 mmol, yield: 55.6%). MS (ESI): m/z=361[M+H] ⁺ .

Step 3: Under ice bath conditions, CDI (458 mg, 2.8 mmol) was added to a THF (10 mL) solution of compound 97-2 (855 mg, 2.36 mmol), stirred at room temperature for 30 min, and then cooled in an ice bath again. DBU (440 mg, 2.9 mmol) was added dropwise and stirred for 2 h under ice bath conditions, 20 mL of HCl (aq, pH = 2) was added, and extracted with EA (20 mL). The organic phase was washed with saturated brine (10 mL × 3), dried over anhydrous Na ₂ SO _4, and concentrated to obtain a residue. The obtained residue was purified by preparative high performance liquid chromatography to obtain compound 97 (58 mg, 0.14 mmol, yield: 6%). MS (ESI): m/z = 387 [M + H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ: 8.65 (s, 1H), 8.04 (s, 1H), 7.66 (d, J=8.7Hz, 1H), 7.44-7.55 (m, 2H), 6.84 (d, J=3.3Hz, 1H), 2.99-3.18 (m, 4H), 2.10-2.21 (m, 2H).

Embodiment 108

Step 1: Disperse 2-aminonicotinonitrile (500 mg, 4.20 mmol), 1-chloro-2-nitro-4-trifluoromethylbenzene (0.63 mL, 4.20 mmol) and cesium carbonate (2735.00 mg, 8.39 mmol) in DMF (10 mL). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 100 ° C and stirred for one hour, then diluted with water and extracted with ethyl acetate (100 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with ethyl acetate: petroleum ether = 1:5) to obtain compound 108-1 (880 mg, yield: 67.98%). MS (ESI): m/z = 309 [M + H] ⁺ .

Step 2: At room temperature, iron powder (956.57 mg 17.13 mmol) and ammonium chloride (916.32 mg, 17.13 mmol) were added to a solution of compound 108-1 (880 mg, 2.86 mmol) in ethanol (12 mL) and water (3 mL) in sequence. The reaction mixture was purged with N ₂ and maintained in an N ₂ atmosphere, slowly heated to 80 ° C and stirred for 2 hours and then filtered while hot. The filtrate was concentrated to obtain a residue, which was purified by silica gel column chromatography (eluted with petroleum ether: ethyl acetate = 5: 1) to obtain compound 108-2 (562 mg, yield: 70.74%). MS (ESI): m/z = 279 [M + H] ⁺ .

Step 3: A solution of compound 108-2 (560 mg, 2.01 mmol) in trimethyl orthoformate (5 mL) was microwaved (150 W, 140 ° C.) for 2.5 hours, cooled to room temperature, diluted with water, and extracted with ethyl acetate (50 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a residue. The obtained residue was purified by preparative silica gel plate (eluted with ethyl acetate: petroleum ether=1:2) to obtain compound 108-3 (510 mg, yield: 87.91%). MS (ESI): m/z=289[M+H] ⁺ .

Step 4: At room temperature, hydroxylamine hydrochloride (1205.46 mg, 17.35 mmol), Molecular sieves (500 mg, 2.23 mmol) and TEA (14.43 mL, 104.08 mmol) were added to a solution of compound 108-3 (500 mg, 1.73 mmol) in methanol (15 mL). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 75°C and stirred overnight, quenched by adding saturated aqueous ammonium chloride solution, filtered and extracted with ethyl acetate (50 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product (579 mg) of compound 108-4 (MS (ESI): m/z＝322[M+H] ⁺ ), which was used directly in the next step without further purification.

Step 5: At room temperature, the crude product of compound 108-4 was dispersed in tetrahydrofuran (8 mL), and CDI (365.30 mg, 2.25 mmol) was added under ice bath conditions. The mixture was slowly heated to room temperature and stirred for 30 minutes. DBU (403.50 μL, 2.70 mmol) was added under ice bath conditions. The reaction system was slowly heated to room temperature and stirred for 1 hour. After the reaction was complete, the reaction system was diluted with water and extracted with ethyl acetate (50 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a residue. The residue was purified by preparative silica gel plate (eluted with ethyl acetate) to obtain compound 108 (130 mg, yield: 20.77%). MS (ESI): m/z=348[M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ: 8.81 (dd, J = 4.6, 1.3 Hz, 1H), 8.63 (s, 1H), 8.42 (dd, J = 7.9, 1.4 Hz, 1H), 8.13 (s, 1H), 7.79 (dd, J = 7.8, 4.9 Hz, 1H), 7.62 (s, 2H).

Embodiment 111

Step 1: Add 5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (806 mg, 4.33 mmol) and sodium tert-butoxide (416.17 mg, 4.33 mmol) to DMF (10 mL) of 2-chloronicotinonitrile (0.45 mL, 4.33 mmol). After the reaction mixture was heated to 80°C and stirred for 2 hours, it was diluted with water (30 mL) and extracted with ethyl acetate (20 mL*3). The combined organic phase was concentrated to obtain a residue. The residue was purified by flash column chromatography (eluted with petroleum ether: ethyl acetate = 3:1) to obtain compound 111-1 (670 mg, 2.32 mmol, yield: 53.68%). ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.94 (d, J = 4.9, 1.8 Hz, 1H), 8.57–8.73 (m, 3H), 8.16 ( d, J = 3.8, 1H), 7.79 ( d, J = 7.9, 4.9 Hz, 1H), 7.01 ( d, J = 3.8 Hz, 1H).

Step 2: Hydroxylamine hydrochloride (807.66 mg, 11.62 mmol), TEA (6.44 mL, 46.49 mmol) and Molecular sieves (100 mg) were added to a methanol (10 mL) solution of compound 111-1 (670 mg, 2.32 mmol). The reaction mixture was heated to 80°C and stirred for 2 hours and then filtered. The filtrate was concentrated and diluted with water (30 mL) and extracted with ethyl acetate (30 mL*3). The combined organic phases were concentrated to obtain a residue. The residue was purified by flash column chromatography (eluted with dichloromethane: methanol = 10:1) to obtain compound 111-2 (270 mg, 0.84 mmol, yield: 36.16%). MS (ESI): m/z = 322 [M+H] ⁺ .

Step 3: At 0°C, CDI (0.13 mL, 1.05 mmol) was added to a tetrahydrofuran (2 mL) solution of compound 111-2 (270 mg, 0.84 mmol), and DBU (0.19 mL, 1.26 mmol) was added after stirring at 0°C for 0.5 hours. After heating to room temperature and stirring for 1 hour, water (3 mL) was added for dilution, and the mixture was extracted with ethyl acetate (3 mL*3). The combined organic phases were concentrated to obtain a residue. The residue was purified by preparative high performance liquid chromatography (HPLC) to obtain compound 111 (15.47 mg, 0.04 mmol, yield: 5.29%). MS (ESI): m/z=348[M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ12.25–13.58(m,1H),8.77–8.95(m,1H),8.43–8.59(m,2H),8.28–8.41(m,1H),8.12(d,J＝3.6Hz,1H),7.79(d,J＝7.7,4.8Hz, 1H), 6.93 (d, J = 3.6Hz, 1H).

Embodiment 113

Step 1: At room temperature, 2-iodo-4-trifluoromethylaniline (1.0 g, 3.48 mmol) was dissolved in propyne (8 mL) and DMF (1 mL), and cuprous iodide (0.07 g, 0.35 mmol), bistriphenylphosphine palladium dichloride (0.12 g, 0.17 mmol) and triethylamine (3 mL, 21.64 mmol) were added in sequence. The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 80°C and stirred for 16 hours, diluted with water, and extracted with ethyl acetate (100 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with petroleum ether) to obtain compound 113-1 (677 mg, yield: 97.56%). MS (ESI): m/z=200[M+H] ⁺ .

Step 2: At room temperature, potassium tert-butoxide (381.39 mg, 3.40 mmol) was added to a solution of compound 113-1 (677 mg, 3.40 mmol) in NMP (8 mL). The reaction mixture was slowly heated to 80°C and stirred for 2 hours, diluted with water, and extracted with ethyl acetate (100 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with petroleum ether) to obtain compound 113-2 (380 mg, yield: 56.13%).

Step 3: A mixture of compound 113-2 (320 mg, 1.61 mmol), 2-chloronicotinonitrile (222.59 mg, 1.61 mmol), potassium tert-butoxide (360.55 mg, 3.21 mmol) and DMF (8 mL) was slowly heated to 100 ° C and stirred for 1 hour, diluted with water, and extracted with ethyl acetate (100 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a residue. The obtained residue was purified by silica gel column chromatography (eluted with ethyl acetate: petroleum ether = 1:5) to obtain compound 113-3 (156 mg, yield: 32.23%). MS (ESI): m/z = 300 [M+H] ⁺ .

Step 4: At room temperature, hydroxylamine hydrochloride (359.82 mg, 5.18 mmol) Molecular sieves (160 mg, 2.23 mmol), and triethylamine (4.31 mL, 31.07 mmol) were added to a methanol (5 mL) solution of compound 113-3 (156 mg, 0.52 mmol) in sequence. The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 75 ° C and stirred overnight, quenched with saturated ammonium chloride and filtered. The filtrate was extracted with ethyl acetate (50 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with ethyl acetate: petroleum ether = 1:1) to obtain compound 113-4 (168 mg, yield: 97.05%). MS (ESI): m/z = 335 [M + H] ⁺ .

Step 5: Under ice bath conditions, CDI (101.86 mg, 0.63 mmol) was added to a tetrahydrofuran (3 mL) solution of compound 113-4 (168 mg, 0.50 mmol), slowly warmed to room temperature and stirred for 30 min, and then DBU (112.51 μL, 0.75 mmol) was added again under ice bath conditions. The reaction mixture was slowly warmed to room temperature and stirred for 1 hour, diluted with water, and extracted with ethyl acetate (50 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with ethyl acetate) to obtain compound 113 (19.7 mg, yield: 10.91%). MS (ESI): m/z=361[M+H] ⁺ . ¹ HNMR(DMSO-d ₆ )δ:12.74-13.24(m,1H),8.93(dd,J＝4.9,1.8Hz,1H),8.45(dd,J＝7.9,1.8Hz,1H),7.92(s,1H),7.89(dd,J＝7.9,4.8Hz,1H),7.31(dd,J＝8.6 ,1.4Hz,1H),6.99(d,J=8.5Hz,1H),6.62(s,1H),2.25(s,3H).

Embodiment 114

Step 1: According to the similar synthesis method of Step 1 in Example 67, 2-chloro-4-methylbenzonitrile and 5-(trifluoromethyl)-1H-indole were used as reactants to prepare compound 114-1. MS (ESI): m/z=301 [M+H] ⁺ .

Step 2: Compound 114-2 was prepared by using compound 114-1 as a reactant according to a similar synthetic method to that of step 2 in Example 67. MS (ESI): m/z = 334 [M+H] ⁺ .

Step 3: According to the similar synthesis method of Step 3 in Example 67, compound 114 (85 mg, purity: 99.6%) was prepared using compound 114-2 as a reactant. MS (ESI): m/z=358 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ=12.61 (br s, 1H), 8.05 (s, 1H), 7.78 (d, J=7.9 Hz, 1H), 7.59-7.54 (m, 2H), 7.53 (s, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.24 (d, J=8.6 Hz, 1H), 6.83 (d, J=3.1 Hz, 1H), 2.48-2.46 (m, 3H).

Embodiment 116

Step 1: At room temperature, 2-chloro-4-methylnicotinonitrile (200 mg, 1.31 mmol), 5-(trifluoromethyl)-1H-indole (242.69 mg, 1.31 mmol) and cesium carbonate (854.16 mg, 2.62 mmol) were dispersed in DMF (5 mL). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 100 ° C and stirred for 1 hour, diluted with water, and extracted with ethyl acetate (100 mL×3). The combined organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with ethyl acetate: petroleum ether = 1:5) to obtain compound 116-1 (166 mg, yield: 42.04%). MS (ESI): m/z = 302 [M+H] ⁺ .

Step 2: At room temperature, hydroxylamine hydrochloride (369.05 mg, 5.31 mmol), Molecular sieves (160 mg, 2.23 mmol) and triethylamine (4.42 mL, 31.87 mmol) were added to a methanol (8 mL) solution of compound 116-1 (160 mg, 0.53 mmol). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 75°C and stirred overnight, quenched by adding saturated ammonium chloride and filtered. The filtrate was extracted with ethyl acetate (50 mL×2), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with ethyl acetate) to obtain compound 116-2 (125 mg, yield: 70.41%). MS (ESI): m/z=335[M+H] ⁺ .

Step 3: Under ice bath conditions, CDI (75.79 mg, 0.47 mmol) was added to a tetrahydrofuran (3 mL) solution of compound 116-2 (125 mg, 0.37 mmol), stirred at room temperature for 30 min, and then DBU (83.71 μL, 0.56 mmol) was added again under ice bath conditions. The reaction mixture was slowly warmed to room temperature and stirred for 1 hour, diluted with water, and extracted with ethyl acetate (50 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a residue. The obtained residue was purified by preparative silica gel plate (ethyl acetate) to obtain compound 116 (40 mg, yield: 29.69%). MS (ESI): m/z=361[M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ: 12.59-12.87 (m, 1H), 8.72 (d, J = 5.0 Hz, 1H), 8.06 (s, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 5.1 Hz, 1H), 7.51-7.53 (m, 1H), 7.49-7. 51(m,1H),6.86(d,J=3.3Hz,1H).

Embodiment 117

Step 1: According to the similar synthesis method of Step 1 in Example 116, 2-chloro-5-methoxynicotinonitrile and 5-(trifluoromethyl)-1H-indole were used as reactants to prepare compound 117-1. MS (ESI): m/z=318 [M+H] ⁺ .

Step 2: Compound 117-2 was prepared by using compound 117-1 as a reactant according to a similar synthesis method to that of step 2 in Example 116. MS (ESI): m/z = 351 [M+H] ⁺ .

Step 3: According to the similar synthesis method of Step 3 in Example 116, compound 117 (50 mg, 0.13 mmol, yield: 58%, purity: 98.29%) was prepared using compound 117-2 as the reactant. MS (ESI): m/z=377 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ: 8.55 (d, J=2.9 Hz, 1H), 8.04 (s, 1H), 7.95 (d, J=2.9 Hz, 1H), 7.59 (d, J=3.3 Hz, 1H), 7.41-7.50 (m, 2H), 6.81 (d, J=3.3 Hz, 1H), 3.99 (s, 3H), 3.35 (br s, 1H).

Embodiment 118

Step 1: Disperse 2-chloro-5-fluoronicotinonitrile (250 mg, 1.60 mmol), 5-(trifluoromethyl)-1H-indole (296.24 mg, 1.60 mmol) and cesium carbonate (1042.62 mg, 3.20 mmol) in DMF (5 mL) at room temperature. Purge the reaction mixture with N ₂ and maintain the N ₂ atmosphere, slowly heat to 120 ° C and stir for 1 hour, dilute with water, and extract with ethyl acetate (100 mL×3). The combined organic phases are dried over anhydrous sodium sulfate and concentrated to obtain a residue. The residue is purified by silica gel column chromatography (eluted with ethyl acetate: petroleum ether = 1:5) to obtain compound 118-1 (90 mg, yield: 18.43%). MS (ESI): m/z = 306 [M+H] ⁺ .

Step 2: At room temperature, hydroxylamine hydrochloride (182.13 mg, 2.62 mmol), Molecular sieves (80 mg, 0.26 mmol) and triethylamine (2.18 mL, 15.73 mmol) were added to a methanol (3 mL) solution of compound 118-2 (80 mg, 0.26 mmol). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 80 ° C and stirred for 3 hours, and the reaction solution was quenched with saturated ammonium chloride and filtered. The filtrate was extracted with ethyl acetate (50 mL × 2), and the combined organic phase was dried over anhydrous sodium sulfate and concentrated to obtain 118-2. The residue was purified by silica gel column chromatography (eluted with petroleum ether: ethyl acetate = 1:1) to obtain compound 118-2 (87 mg, yield: 98.13%). MS (ESI): m/z = 339 [M + H] ⁺ .

Step 3: Under ice bath conditions, CDI (100.06 mg, 0.62 mmol) was added to a tetrahydrofuran (3 mL) solution of compound 118-2 (167 mg, 0.49 mmol), stirred at room temperature for 30 minutes, and then DBU (110.53 μL, 0.74 mmol) was added again under ice bath conditions. The reaction mixture was slowly warmed to room temperature and stirred for 1 hour, diluted with water, and extracted with ethyl acetate (50 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a residue. The obtained residue was purified by preparative silica gel plate (ethyl acetate) to obtain compound 118 (23 mg, yield: 12.79%). MS (ESI): m/z=363[MH] ^- . ¹ H NMR (DMSO-d ₆ ) δ: 8.80 (dd, J = 4.8, 1.8 Hz, 1H), 8.37 ( dd, J = 7.8, 1.7 Hz, 1H), 8.19 ( s, 1H), 7.74 ( s, 1H), 7.71 ( dd, J = 7.8, 4.8 Hz, 1H), 7.64 ( d, J = 3.4 Hz, 1H), 6.85(d,J=3.3Hz,1H).

Embodiment 119

Step 1: Ethylboric acid (80.72 mg, 1.09 mmol) was added to a mixed solution of 5-bromo-2-[5-(trifluoromethyl)indol-1-yl]pyridine-3-carbonitrile (400 mg, 1.09 mmol), potassium carbonate (301.96 mg, 2.18 mmol) and bis[5-(diphenylphosphino)cyclopenta-1,3-dienyl]-λ2-iron(II)palladium chloride (79.94 mg, 0.11 mmol) in 1,4-dioxane (10 mL) and water (2 mL). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, stirred at 90 ° C for 12 hours, added with water (15 mL), and extracted with ethyl acetate (45 mL). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography (gradient of eluent: ethyl acetate = 20:1 to 5:1) to obtain compound 119-1 (140 mg, 0.44 mmol, yield: 40.64%). MS (ESI): m/z = 316 [M+H] ⁺ .

Step 2: Hydroxylamine hydrochloride (104.69 mg, 2.14 mmol) was added to a mixture of compound 119-1 (135 mg, 0.43 mmol), triethylamine (0.42 mL, 4.28 mmol), molecular sieves (100 mg), and methanol (10 mL). The reaction mixture was stirred at 80 ° C for 3 hours and then concentrated. Water (15 mL) was added to the obtained concentrate, and extracted with ethyl acetate (45 mL). The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain a residue. The obtained residue was purified by silica gel column chromatography (eluent gradient transition from petroleum ether: ethyl acetate = 20: 1 to 1: 1) to obtain a crude product of compound 119-2 (123 mg). MS (ESI): m/z = 349 [M + H] ⁺ .

Step 3: The crude product of compound 119-2 (123 mg) and N,N'-carbonyldiimidazole (71.57 mg, 0.44 mmol) were dispersed in tetrahydrofuran (5 mL), reacted at 0°C for 30 minutes, and then 1,8-diazabicyclo[5.4.0]-7-undecene (79.06 μL, 0.53 mmol) was added. After the reaction mixture was reacted at room temperature for 1 hour, it was quenched with water (15 mL) and extracted with ethyl acetate (15 mL×3). The combined organic phase was washed with water and concentrated to obtain a residue. The obtained residue was purified by silica gel column chromatography (eluent gradient from dichloromethane: methanol = 1:0 to 10:1) to obtain compound 119 (30.2 mg, 0.08 mmol, purity: 99.87%). MS (ESI): m/z = 375 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ: 12.77 (br s, 1H), 8.74 (d, J = 2.1Hz, 1H), 8.23 (d, J = 2.3Hz, 1H), 8.06 (s, 1H), 7.59-7.65 (m, 2H), 7.49 (dd, J = 8.7, 1.4Hz, 1H), 6.85 (d, J=3.4Hz, 1H), 2.81 (q, J=7.5Hz, 2H), 1.30 (t, J=7.6Hz, 3H).

Embodiment 121

Step 1: A mixture of 5-bromo-2-chloronicotinonitrile (3.00 g, 13.80 mmol), sodium tert-butoxide (1.59 g, 16.56 mmol), 5-(trifluoromethyl)-1H-indole (2.55 g, 13.80 mmol), and N,N-dimethylformamide (30 mL) was stirred at 120 ° C for 3 hours, diluted with water (40 mL), and then extracted with ethyl acetate (120 mL). The organic phase was washed with saturated sodium chloride solution, dried, and concentrated to obtain a crude product. The crude product was purified by silica gel chromatography (eluent gradient from petroleum ether: ethyl acetate = 20: 1 to 5: 1) to obtain compound 121-1 (1.19 g, 3.25 mmol, yield 23.56%).

Step 2: Hydroxylamine hydrochloride (759.16 mg, 10.92 mmol) was added to a mixture of compound 121-1 (800 mg, 2.18 mmol), triethylamine (3.03 mL, 21.85 mmol), molecular sieves (500 mg), and methanol (30 mL). The reaction mixture was stirred at 80 ° C for 12 hours and then concentrated. Water (20 mL) was added to the resulting concentrate and extracted with ethyl acetate (60 mL). The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The resulting crude product was purified by silica gel column chromatography (eluent gradient transition from petroleum ether: ethyl acetate = 20: 1 to 1: 1) to obtain a crude product of compound 121-2 (820 mg). MS (ESI): m/z = 399, 401 [M+H] ⁺ .

Step 3: Compound 121-2 (820 mg, 2.05 mmol) and N,N'-carbonyldiimidazole (416.37 mg, 2.57 mmol) were dispersed in tetrahydrofuran (12 mL), reacted at 0°C for 30 minutes, and then 1,8-diazabicyclo[5.4.0]-7-undecene (459.91 μL, 3.08 mmol) was added. After the reaction mixture was reacted at room temperature for 1 hour, it was quenched with water (20 mL) and extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with water and concentrated to obtain a residue. The residue was purified by silica gel chromatography (eluent gradient from dichloromethane: methanol = 1:0 to 10:1) to obtain compound 121-3 (495 mg, 1.16 mmol, yield: 56.67%).

Step 4: Zinc cyanide (181.17 mg, 1.54 mmol) was added to a mixture of compound 121-3 (164 mg, 0.39 mmol) and tetrakis(triphenylphosphine)palladium (89.15 mg, 0.08 mmol) and N,N-dimethylformamide solution (1.9 mL). The reaction mixture was purged with _N2 and maintained under _N2 atmosphere, then stirred at 120°C for 12 hours, water (10 mL) was added, and extracted with ethyl acetate (30 mL). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain a residue. The resulting residue was purified by silica gel column chromatography (with petroleum ether: ethyl acetate = 10/1) to obtain compound 121 (18.56 mg, yield: 13.0%). MS (ESI): m/z = 372 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ ) δ: 9.23 (d, J = 2.1 Hz, 1H), 8.79 (d, J = 2.1 Hz, 1H), 8.06 (s, 1H), 7.87 (d, J = 8.6 Hz ,1H),7.61(d,J＝3.6Hz,1H),7.54(dd,J＝8.8,1.6Hz,1H),6.89(d,J＝3.5Hz,1H).

Embodiment 122

Step 1: Dissolve 5,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (1.16 g, 7.83 mmol) in phosphorus oxychloride (15 mL). Heat the reaction mixture to 110°C, stir for 12 hours and then concentrate. Add saturated sodium bicarbonate solution to dilute and quench the concentrate until no bubbles are generated, and extract with ethyl acetate (90 mL). Wash the organic phase with saturated sodium chloride solution, dry and concentrate to obtain a crude product of compound 122-1 (1.12 g). The crude product can be used directly in the next step without purification. MS (ESI): m/z=167[M+H] ⁺ .

Step 2: 5-(Trifluoromethyl)-1H-indole (1.19 g, 6.42 mmol) was added to a mixture of the crude product of compound 122-1 (1.07 g, 6.42 mmol), sodium tert-butoxide (0.8 g, 7.06 mmol) and N,N-dimethylformamide (15 mL). The reaction mixture was stirred at 120°C for 1.5 hours, diluted with water (30 mL), and then extracted with ethyl acetate (90 mL). The organic phase was washed with a saturated sodium chloride solution, dried, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent gradient from petroleum ether: ethyl acetate = 20:1 to 5:1) to obtain compound 122-2 (1.01 g, 3.21 mmol, yield: 49.98%).

Step 3: Hydroxylamine hydrochloride (550.98 mg, 7.93 mmol) was added to a mixture of compound 122-2 (500 mg, 1.59 mmol), triethylamine (2.2 mL, 15.86 mmol), molecular sieves (300 mg) and methanol (15 mL). After the reaction mixture was stirred at 80 ° C for 12 hours, water (15 mL) was added and extracted with ethyl acetate (45 mL). The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent gradient from petroleum ether: ethyl acetate = 20: 1 to 1: 1) to obtain compound 122-3 (344 mg, 0.99 mmol, yield: 62.28%). MS (ESI): m/z = 349 [M + H] ⁺ .

Step 4: Under ice bath conditions, N,N'-carbonyldiimidazole (200.17 mg, 1.23 mmol) was added to a tetrahydrofuran (10 mL) solution of compound 122-3 (344 mg, 0.99 mmol), and 1,8-diazabicyclo[5.4.0]-7-undecene (221.1 μL, 1.48 mmol) was added after reacting at 0°C for 30 minutes. The reaction mixture was reacted at room temperature for 1 hour, quenched with water (15 mL), and extracted with ethyl acetate (15 mL×3). The combined organic phase was washed with water, dried and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluent gradient from dichloromethane: methanol = 1/0 to 10/1) to obtain compound 122-4 (95 mg, yield: 25.70%). MS (ESI): m/z = 375 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ ) δ: 12.70 (br s, 1H), 8.09 (s, 1H), 8.05 (s, 1H), 7.56-7.64 (m, 2H), 7.48 (dd, J = 8.7, 1.4Hz, 1H), 6.84 (d, J = 3.4Hz, 1H), 2.57 (s, 3H), 2.42 (s, 3H).

Embodiment 123

Step 1: Add 5-trifluoromethylindole (2, 88 mg, 0.48 mmol) and sodium tert-butoxide (46 mg, 0.48 mmol) to a DMF (2 mL) solution of compound 2-chloro-6-trifluoromethylnicotinonitrile (100 mg, 0.48 mmol). After stirring the reaction mixture at 80 ° C for 3 hours under a nitrogen atmosphere, it was cooled to 25 ° C, quenched by adding saturated ammonium chloride solution (5 mL), and extracted with EA (50 mL). The organic phase was washed with saturated brine (3 times), dried and concentrated to obtain a residue. The obtained residue was purified by silica gel column chromatography (eluent gradient transition from PE: EA = 20: 1 to 5: 1) to obtain compound 123-1 (83 mg, 0.23 mmol).

Step 2: To a solution of compound 123-1 (83 mg, 0.23 mmol) in methanol (5 mL) were added hydroxylamine hydrochloride (162 mg, 2.3 mmol), Molecular sieves (83 mg) and triethylamine (1.9 mL, 14 mmol). The reaction mixture was stirred at 75 ° C for 8 hours, cooled to 25 ° C and filtered. Saturated ammonium chloride solution (5 mL) was added to the filtrate to quench the reaction and extracted with EA (50 mL). The organic phase was washed with saturated brine (3 times), dried and concentrated to obtain a residue. The obtained residue was purified by silica gel column chromatography (eluent gradient transition from PE: EA = 5: 1 to 1: 1) to obtain compound 123-2 (69 mg, 0.18 mmol).

Step 3: At 0°C, CDI (36.5 mg, 0.22 mmol) was added to a THF (2 mL) solution of compound 123-2 (83 mg, 0.28 mmol), and the mixture was stirred for 30 minutes after warming to room temperature. DBU (41 μL, 0.27 mmol) was added at 0°C. The reaction mixture was warmed to room temperature, stirred for 1 hour, and then concentrated. Saturated ammonium chloride solution (2 mL) was added to the resulting concentrate to quench the reaction, and extracted with EA (20 mL). The organic phase was washed with saturated brine (3 times), dried and concentrated to obtain a residue. The resulting residue was purified by silica gel column chromatography (first with PE:EA=1/1, then eluted with DCM) and preparative high performance liquid chromatography (HPLC) to obtain compound 123 (13 mg, 0.03 mmol, yield: 17%). MS (ESI): m/z=413[MH] ^- .

¹ H NMR (DMSO-d ₆ ) δ: 8.62 (d, J = 7.9 Hz, 1H), 8.22 (d, J = 8.0 Hz, 1H), 8.09 (s, 1H), 7.76 (d, J = 8.8 Hz ,1H),7.65(d,J＝3.5Hz,1H),7.55-7.63(m,1H),6.90(d,J＝3.5Hz,1H).

Embodiment 124

Step 1: At room temperature, 2-chloro-6-methylnicotinonitrile (300 mg, 1.97 mmol), 5-(trifluoromethyl)-1H-indole (364.04 mg, 1.97 mmol) and cesium carbonate (1281.24 mg, 3.93 mmol) were dispersed in DMF (8 mL) in sequence. The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 120 ° C and stirred for 1 hour, diluted with water, and extracted with ethyl acetate (100 mL×3). The combined organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with ethyl acetate: petroleum ether=1:5) to obtain compound 124-1 (570 mg, yield: 96.04%). MS (ESI): m/z=302[M+H] ⁺ .

Step 2: At room temperature, hydroxylamine hydrochloride (1314.74 mg, 18.92 mmol), Molecular sieves (675 mg, 2.23 mmol) and TEA (15.74 mL, 113.52 mmol) were added to a methanol (20 mL) solution of compound 124-1 (570 mg, 1.89 mmol). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 75 ° C and stirred overnight, quenched with saturated ammonium chloride and filtered. The filtrate was extracted with ethyl acetate (50 mL × 2), and the combined organic phase was dried over anhydrous sodium sulfate and concentrated. The concentrated residue was purified by silica gel column chromatography (eluted with petroleum ether: ethyl acetate = 5: 1) to obtain compound 124-2 (504 mg, yield: 79.68%). MS (ESI): m/z = 335 [M + H] ⁺ .

Step 3: Under ice bath conditions, CDI (121.26 mg, 0.75 mmol) was added to a tetrahydrofuran (5 mL) solution of compound 124-2 (200 mg, 0.60 mmol), stirred at room temperature for 30 min, and then DBU (0.13 mL, 0.90 mmol) was added again under ice bath conditions. The reaction mixture was slowly warmed to room temperature and stirred for 1 hour, diluted with water, and extracted with ethyl acetate (50 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a residue. The obtained residue was purified by preparative silica gel plate (eluted with ethyl acetate) to obtain compound 124 (91 mg, yield: 42.22%). MS (ESI): m/z=361[M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ: 12.99 (br d, J = 2.5 Hz, 1H), 8.27 (d, J = 8.0 Hz, 1H), 8.06 (s, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.63 (d, J = 3.5 Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7. 49(dd,J=8.8,1.3Hz,1H), 6.86(d,J=3.3Hz,1H), 2.63(s,3H).

Embodiment 125

Step 1: To a solution of 6-chloro-5-iodopyridin-2-amine (5.0 g, 19.65 mmol) in DMF (30 mL) was added Zn(CN) ₂ (2.31 g, 19.65 mmol) and Pd(PPh ₃ ) ₄ (2.27 g, 1.96 mmol). The reaction mixture was stirred at 65° C. overnight, cooled to room temperature, diluted with water, and extracted with EA. The organic phase was washed with saturated brine (3 times), dried and concentrated to obtain a residue. The residue was purified by silica gel column chromatography to obtain compound 125-1 (2.56 g, 16.73 mmol). MS (ESI): m/z=154[M+H] ⁺ .

Step 2: Compound 125-2 was prepared by using compound 125-1 as a reactant according to a synthetic method similar to that of step 1 in Example 67. MS (ESI): m/z = 303 [M+H] ⁺ .

Step 3: Compound 125-3 was prepared by using compound 125-2 as a reactant according to a similar synthetic method to step 2 in Example 67. MS (ESI): m/z = 336 [M+H] ⁺ .

Step 4: Compound 125-4 was prepared by using compound 125-3 as a reactant according to a similar synthetic method to step 3 in Example 67. MS (ESI): m/z = 362 [M+H] ⁺ .

Step 5: To a solution of compound 125-4 (200 mg, 0.55 mmol) in acetonitrile (10 mL) were added t-BuONO (90 mg, 0.87 mmol) and CuCl ₂ (140 mg, 1.04 mmol). The reaction mixture was stirred at 70°C overnight, filtered, and the filtrate was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a residue, which was purified by silica gel column chromatography to obtain compound 125 (30 mg, 0.08 mmol). MS (ESI): m/z=381[M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ: 12.85 (br s, 1H), 8.36-8.40 (m, J = 8.1Hz, 1H), 8.08 (s, 1H), 7.87-7.91 (m, J = 8.1Hz, 1H), 7.74 (d, J = 8.8Hz, 1H), 7.63 (d, J = 3.5Hz, 1H) ,7.56(dd,J＝8.8,1.6Hz,1H),6.90(d,J＝3.3Hz,1H).

Embodiment 126

Step 1: Disperse 5-bromo-2-chloronicotinonitrile (500 mg, 2.30 mmol), 5-trifluoromethylindole (425.73 mg, 2.30 mmol) and cesium carbonate (1498.37 mg, 4.60 mmol) in DMF (10 mL). Purge the reaction mixture with N ₂ and maintain the N ₂ atmosphere, slowly heat to 120 ° C and stir for 1 hour, dilute with water, and extract with ethyl acetate (100 mL × 3). The combined organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is purified by silica gel column chromatography (eluted with ethyl acetate: petroleum ether = 1:5) to obtain compound 126-1 (600 mg, yield: 71.27%).

Step 2: Compound 126-1 (1130 mg, 3.09 mmol), biboronic acid pinacol ester (1175.58 mg, 4.63 mmol), potassium acetate (605.77 mg, 6.17 mmol) and Pd(dppf)Cl ₂ (225.82 mg, 0.31 mmol) were dispersed in 1,4-dioxane (20 mL) at room temperature. The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 95°C and stirred overnight, diluted with water, and extracted with ethyl acetate (100 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluted with ethyl acetate: petroleum ether=1:5) to obtain compound 126-2 (1100 mg, yield: 86.26%). MS (ESI): m/z=414[M+H] ⁺ .

Step 3: Disperse compound 126-2 (1.1 g, 2.66 mmol), 2-fluorobromomethylbenzene (0.38 mL, 3.19 mmol), potassium carbonate (0.74 g, 5.32 mmol) and Pd(dppf)Cl ₂ (0.19 g, 0.27 mmol) in a mixed solvent of acetonitrile (20 mL) and water (4 mL) at room temperature. Purge the reaction mixture with N ₂ and maintain the N ₂ atmosphere, slowly heat to 80°C and stir overnight, dilute with water, and extract with ethyl acetate (100 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether=1:5) to obtain compound 126-3 (554 mg, yield: 52.64%). MS (ESI): m/z=396[M+H] ⁺ .

Step 4: At room temperature, hydroxylamine hydrochloride (790.94 mg, 11.38 mmol), Molecular sieves (450 mg, 2.23 mmol) and TEA (9.47 mL, 68.29 mmol) were added to a methanol (15 mL) solution of compound 126-3 (450 mg, 1.14 mmol). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 75°C and stirred overnight, quenched with saturated ammonium chloride, filtered and extracted with ethyl acetate (50 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate: petroleum ether = 2:1) to obtain compound 126-4 (316 mg, yield: 64.81%). MS (ESI): m/z = 429 [M+H] ⁺ .

Step 5: Under ice bath conditions, CDI (149.51 mg, 0.92 mmol) was added to a tetrahydrofuran (3 mL) solution of compound 126-4 (316 mg, 0.74 mmol), slowly warmed to room temperature and stirred for 30 min, and DBU (165.15 μL, 1.11 mmol, 1 mL) was added again under ice bath conditions. The reaction mixture was slowly warmed to room temperature and stirred for 1 hour, diluted with water, and then extracted with ethyl acetate (50 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by preparative silica gel plate (eluted with ethyl acetate) to obtain compound 126 (81 mg, yield: 24.17%). MS (ESI): m/z=453[MH] ^- . ¹ H NMR(DMSO-d ₆ )δ: 10.86(br dd,J＝7.8,3.8Hz,1H),8.77(br s,1H),8.16(br s,1H),8.05(br s,1H),7.66(br d,J＝8.5Hz,1H),7.59(br d,J＝2.4Hz,1H),7.49 (br d,J＝5.5Hz,2H),7.35(br d,J＝6.0Hz,1H),7.16-7.29(m,2H),6.85(br s,1H),4.20(br s,2H).

Embodiment 127

Step 1: Add 5-trifluoromethylindole (2.2 g, 12 mmol) and sodium tert-butoxide (1.9 g, 20 mmol) to a mixture of compound 5-bromo-2-chloronicotinonitrile (2.14 g, 10 mmol) in DMF (20 mL). The reaction mixture was stirred at 80°C for 3 hours, diluted with H ₂ O (200 mL), and extracted with EA (50 mL). The organic phase was washed with saturated brine (20 mL×3), dried over anhydrous Na ₂ SO _4, and concentrated to obtain a residue. The obtained residue was purified by silica gel column chromatography (EA:PE=1/4) to obtain compound 127-1 (3.09 g, 8.5 mmol, yield: 84.5%). MS (ESI): m/z=366,368[M+H] ⁺ .

Step 2: A mixture of compound 127-1 (1.8 g, 5 mmol), 3-hydroxypyrrolidine (560 mg, 6.5 mmol), Pd ₂ (dba) ₃ (450 mg, 0.5 mmol), XantPhos (570 mg, 1 mmol), and 1-4-dioxane (20 mL) was stirred at 80° C. for 12 hours and then concentrated. H ₂ O (100 mL) was added to the concentrate, and extracted with EA (50 mL). The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with EA:PE=1:4) to obtain compound 127-2 (1.01 g, 2.7 mmol, yield: 54.6%). MS (ESI): m/z=373[M+H] ⁺ .

Step 3: Compound 127-2 (1 g, 2.7 mmol), MeOH (20 mL), NH ₂ OH·HCl (1.8 g, 27 mmol), TEA (10 mL) and The mixture was purged with _N2 and maintained under _N2 atmosphere, stirred at 80°C for 3 hours, and filtered under reduced pressure. The filtrate was concentrated, _H2O (20 mL) was added, and extracted with EA (30 mL). The organic phase was washed with saturated brine (10 mL×3), dried over anhydrous _{Na2SO4 ,} and concentrated. The residue was purified by silica gel column chromatography (eluted with EA:PE=1:2) to obtain compound 127-3 (595 mg, 1.47 mmol, yield: 54.5%). MS (ESI): m/z=406[M+H] ⁺ .

Step 4: Under ice bath conditions, CDI (46 mg, 0.28 mmol) was added to a solution of compound 127-3 (100 mg, 0.24 mmol) in THF (10 mL), stirred at room temperature for 30 min, and then DBU (54.7 mg, 0.36 mmol) was added dropwise under ice bath conditions. The reaction mixture was stirred under ice bath conditions for 2 h, and then an aqueous HCl solution (pH = 2, 20 mL) was added and extracted with EA (20 mL). The organic phase was washed with saturated brine (10 mL × 3), dried over anhydrous Na ₂ SO ₄ and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with MeOH: DCM = 1:20) to obtain compound 127 (3 mg, 0.006 mmol, yield: 2.5%). MS (ESI): m/z = 432 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ ) δ: 12.72-12.90 (m, 1H), 8.12 (d, J = 2.9Hz, 1H), 8.02 (s, 1H), 7.52-7.56 (m, 1H), 7.40- 7.44(m,1H),7.32-7.38(m,2H),6.76-6.82(m,1H),4.48(br s,1H),3.52-3.62(m,1H),3.43-3.51(m,2H) ,3.22-3.30(m,2H),1.96-2.15(m,2H).

Embodiment 128

Step 1: Add ethoxymethylenemalononitrile (2.4 g, 20 mmol) to a mixture of compound 4-(cyclopent-1-en-1-yl)morpholine (3 g, 20 mmol) in MeOH (20 mL). The reaction mixture was stirred at room temperature overnight and filtered. The filtered solid was washed with MeOH and dried to give compound 128-1 (2.29 g, 11 mmol, yield: 55%). MS (ESI): m/z = 230 [M+H] ⁺ .

Step 2: A mixture of compound 128-1 (229 mg, 1 mmol) and NH ₃ methanol solution (2 mol/L, 1 mL, 2 mmol) was placed under microwave (120 W, 100°C) for 1 hour. The resulting reaction solution was cooled and concentrated, H ₂ O (100 mL) was added, and extracted with EA (50 mL). The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with EA:PE=1:2) to obtain compound 128-2 (92 mg, 0.58 mmol, yield: 58.6%). MS (ESI): m/z=160[M+H] ⁺ .

Step 3: Under ice bath conditions, NaNO ₂ (276 mg, 4 mmol) was slowly added to a mixture of compound 128-2 (318 mg, 2 mmol), AcOH (5 mL) and HCl (5 mL). After the reaction mixture was stirred at room temperature for 3 hours, saturated sodium bicarbonate was slowly added to adjust the pH to 7, followed by extraction with EA (30 mL). The obtained organic phase was washed with saturated brine (10 mL×3), dried over anhydrous Na ₂ SO ₄ and concentrated, and the obtained residue was purified by silica gel column chromatography (eluted with EA:PE=1:4) to obtain compound 128-3 (234 mg, 1.47 mmol, yield: 65.8%). MS (ESI): m/z=179[M+H] ⁺ .

Step 4: Add 5-trifluoromethylindole (407 mg, 2.20 mmol) and cesium carbonate (955 mg, 2.94 mmol) to a solution of compound 128-3 (234 mg, 1.47 mmol) in DMF (20 mL). The reaction mixture was stirred at 120°C for 3 hours, diluted with H ₂ O (200 mL), and extracted with EA (50 mL). The obtained organic phase was washed with saturated brine (20 mL×3), dried over anhydrous Na ₂ SO ₄ and concentrated. The obtained residue was purified by silica gel column chromatography (eluted with EA:PE=1:4) to obtain compound 128-4 (315 mg, 0.96 mmol, yield: 65.6%). MS (ESI): m/z=328[M+H] ⁺ .

Step 5: Compound 128-4 (315 mg, 0.96 mmol), MeOH (20 mL), NH ₂ OH·HCl (672 mg, 9.6 mmol), TEA (15 mL) and The mixture was purged with _N2 and maintained under _N2 atmosphere, stirred at 80°C for 3 hours and then filtered under reduced pressure. _H2O (20 mL) was added to the filtrate, and extracted with EA (30 mL). The organic phase was washed with saturated brine (10 mL×3), _dried over anhydrous _Na2SO4 and concentrated, and the residue was purified by silica gel column chromatography (eluted with EA:PE=1:2) to obtain compound 128-5 (158 mg, 0.43 mmol, yield: 45.8%). MS (ESI): m/z=361[M+H] ⁺ .

Step 6: Under ice bath conditions, CDI (83 mg, 0.51 mmol) was added to a solution of compound 128-5 (158 mg, 0.43 mol) in THF (10 mL), stirred at room temperature for 30 min, and then DBU (98 mg, 0.64 mmol) was added dropwise under ice bath conditions. The reaction mixture was stirred under ice bath conditions for 2 h, and then an aqueous HCl solution (2 mL, pH = 2) was added and extracted with EA (20 mL). The obtained organic phase was washed with saturated brine (10 mL × 3), dried over anhydrous Na ₂ SO _4, and concentrated. The obtained residue was purified by silica gel column chromatography (eluted with MeOH:DCM = 1:20) to obtain compound 128 (110 mg, 0.28 mmol, yield: 66.2%). MS (ESI): m/z = 387 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ: 12.61-12.82 (m, 1H), 8.13 (s, 1H), 8.06 (s, 1H), 7.56-7.61 (m, 2H), 7.48 (dd, J = 8.8, 1.7Hz, 1H), 6.85 (d, J = 3.4Hz, 1H), 3.07 (t, J = 7 .6Hz,4H),2.13-2.27(m,2H).

Embodiment 129

Step 1: At room temperature, a solution of tetrahydro-4H-pyran-4-one (0.93 mL, 9.99 mmol) in DMF-DMA (10 mL) was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 110° C. and stirred for 16 hours. The mixture was concentrated to obtain a crude product (1.75 g) of compound 129-1 (MS (ESI): m/z=156[M+H] ⁺ ) which could be used directly in the next step without purification.

Step 2: At room temperature, malononitrile (0.49 mL, 7.73 mmol) and ammonium acetate (0.06 g, 0.77 mmol) were added to a solution of compound 129-1 (1.2 g, 7.73 mmol) in acetonitrile (15 mL). The reaction mixture was slowly heated to 80°C, stirred for 5 hours, and concentrated to obtain a residue. The obtained residue was purified by silica gel column chromatography (eluted with ethyl acetate) to obtain a crude product (2.5 g) of compound 129-2 (MS (ESI): m/z=177[M+H] ⁺ ).

Step 3: At room temperature, compound 129-2 (1.5 g, 8.51 mmol) was dissolved in POCl ₃ (10 mL). The reaction mixture was slowly heated to 100°C, stirred for 3 hours, and then concentrated to remove most of the POCl ₃ . Saturated sodium bicarbonate was then added to quench the reaction, diluted with water, and extracted with ethyl acetate (100 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate: petroleum ether=1:5) to obtain compound 129-3 (578 mg, yield: 34.88%). MS (ESI): m/z=195[M+H] ⁺ .

Step 4: At room temperature, compound 129-3 (570 mg, 2.93 mmol), 5-trifluoromethylindole (542.26 mg, 2.93 mmol) and cesium carbonate (1908.51 mg, 5.86 mmol) were dispersed in DMF (10 mL). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 80 ° C and stirred for 1 hour, diluted with water, and extracted with ethyl acetate (100 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (eluted with ethyl acetate: petroleum ether = 1:5) to obtain compound 129-4 (752.7 mg, yield: 74.86%). MS (ESI): m/z = 344 [M + H] ⁺ .

Step 5: At room temperature, hydroxylamine hydrochloride (1522.14 mg, 21.90 mmol) Molecular sieves (760 mg, mmol), and triethylamine (18.22 mL, 131.43 mmol) were added to a methanol (20 mL) solution of compound 129-4 (752 mg, 2.19 mmol). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 80°C and stirred for 3 hours, quenched with saturated ammonium chloride and filtered. The filtrate was extracted with ethyl acetate (50 mL×2), and the combined organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with ethyl acetate: petroleum ether = 1:1) to obtain compound 129-5 (488 mg, yield: 59.20%). MS (ESI): m/z = 377 [M+H] ⁺ .

Step 6: Under ice bath conditions, CDI (262.82 mg, 1.62 mmol) was added to a tetrahydrofuran (8 mL) solution of compound 129-5 (488 mg, 1.30 mmol), slowly warmed to room temperature and stirred for 30 min, and then DBU (290.31 μL, 1.95 mmol) was added under ice bath conditions. The reaction mixture was slowly warmed to room temperature and stirred for 1 hour, diluted with water, and extracted with ethyl acetate (50 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain compound 129 (15 mg, yield: 2.87%). MS (ESI): m/z=403[M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ: 8.08 (br s, 1H), 8.07 (br s, 1H), 7.69 (d, J = 8.6Hz, 1H), 7.60 (d, J = 3.4Hz, 1H), 7.49 (d, J = 8.9Hz, 1H), 6.86 (d, J = 3.4Hz, 1H), 4.87 (s, 2 H), 4.08 (t, J = 5.7Hz, 2H), 3.03 (brt, J = 5.6Hz, 2H).

Embodiment 130

Step 1: At room temperature, malononitrile (0.12 mL, 1.97 mmol) and ammonium acetate (15.15 mg, 0.20 mmol) were added to a solution of (E)-tert-butyl 3-(dimethylamino)methylene)-4-oxopiperidine-1-carboxylate (500 mg, 1.97 mmol) in acetonitrile (6 mL). The reaction mixture was slowly heated to 80°C, stirred for 5 hours, and then concentrated to obtain a crude product (500 mg) of compound 130-1 (MS (ESI): m/z=276[M+H] ⁺ ) which could be directly used in the next step without purification.

Step 2: At room temperature, the crude product of compound 130-1 (500 mg) was dissolved in phosphorus oxychloride (3 mL). The reaction mixture was slowly heated to 110°C and stirred for 3 hours, concentrated to remove most of POCl ₃ , and then quenched with saturated sodium bicarbonate, diluted with water, and extracted with dichloromethane (50 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (eluted with ethyl acetate: petroleum ether=1:5) to obtain compound 130-2 (375 mg, yield: 106.64%). MS (ESI): m/z=194[M+H] ⁺ .

Step 3: At room temperature, di-tert-butyl dicarbonate (0.41 mL, 1.94 mmol) was added dropwise to a solution of compound 130-2 (375 mg, 1.94 mmol) in tetrahydrofuran (5 mL) and water (2.5 mL), followed by the addition of sodium carbonate (205.27 mg, 1.94 mmol). The reaction mixture was purged with _N2 and maintained under _N2 atmosphere, stirred at 28°C for 12 hours, concentrated, and extracted with dichloromethane (20 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (eluted with ethyl acetate: petroleum ether = 1:5) to obtain compound 130-3 (150 mg, yield: 26.37%). MS (ESI): m/z = 294 [M+H] ⁺ .

Step 4: At room temperature, 5-trifluoromethylindole (94.54 mg, 0.51 mmol) and cesium carbonate (166.38 mg, 0.51 mmol) were added to a DMF (2 mL) solution of compound 130-3 (150 mg, 0.51 mmol). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 80 ° C. and stirred for 1 hour, diluted with water, and extracted with ethyl acetate (20 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (eluted with ethyl acetate: petroleum ether = 1:10) to obtain compound 130-4 (85 mg, yield: 37.62%). MS (ESI): m/z = 443 [M + H] ⁺ .

Step 5: At room temperature, hydroxylamine hydrochloride (133.50 mg, 1.92 mmol), Molecular sieves (90 mg, mmol) and triethylamine (1.60 mL, 11.53 mmol) were added to a solution of compound 130-4 (85 mg, 0.19 mmol) in methanol (2 mL). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 75°C and stirred for 3 hours, saturated ammonium chloride was added to quench the reaction, filtered, and extracted with ethyl acetate (50 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (eluted with ethyl acetate) to obtain compound 130-5 (56 mg, yield: 61.31%). MS (ESI): m/z=476[M+H] ⁺ .

Step 6: Under ice bath conditions, CDI (23.87 mg, 0.15 mmol) was added to tetrahydrofuran (1 mL) of compound 130-5 (56 mg, 0.12 mmol), and the temperature was slowly raised to room temperature and stirred for 30 min. DBU (26.37 μL, 0.18 mmol) was added under ice bath conditions. The reaction mixture was slowly raised to room temperature and stirred for 1 hour, diluted with water, and extracted with ethyl acetate (50 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (eluted with ethyl acetate) to obtain compound 130-6 (33 mg, yield: 55.87%). MS (ESI): m/z = [M+H] ⁺ .

Step 7: At 0°C, a dioxane hydrochloride solution (3 mL, 0.07 mmol) was added dropwise to a dichloromethane (2 mL) solution of compound 130-6 (33 mg, 0.07 mmol). The reaction mixture was slowly heated to 34°C and stirred for 3 hours, concentrated to obtain a residue, and the residue was purified by preparative high performance liquid chromatography (Pre-HPLC) (eluted with TFA) to obtain compound 130 (8 mg, yield: 30.15%). MS (ESI): m/z=402[M+H] ⁺ . ¹ HNMR(DMSO-d ₆ )δ:8.19(s,1H),8.02(s,1H),7.54-7.59(m,2H),7.43(d,J＝8.6Hz,1H),6.77(d,J＝3.3Hz,1H),4.45(s,2H),3.55(br t,J＝6.3Hz,2H),3.1 5(brt,J=6.0Hz,2H).

Embodiment 131

Step 1: Add 5-trifluoromethylindole (2, 159 mg, 0.86 mmol) and sodium tert-butoxide (83 mg, 0.86 mmol) to a DMF (4 mL) solution of compound 3,6-dichloropyrazine-2-carbonitrile (150 g, 0.86 mmol). The reaction mixture was purged with N ₂ and maintained in a N ₂ atmosphere. After stirring at 80 ° C for 3 hours, it was cooled to 25 ° C, quenched with a saturated ammonium chloride solution (5 mL), and extracted with EA (40 mL). The organic phase was washed with saturated brine (3 times) and concentrated to obtain a residue, and the residue was purified by silica gel column chromatography (eluent gradient transition from PE: EA = 20: 1 to 5: 1) to obtain compound 131-1 (116.5 mg, 0.36 mmol).

Step 2: Hydroxylamine hydrochloride (236 mg, 3.4 mmol), Molecular sieves (110 mg) and triethylamine (2.8 mL, 20.5 mmol) were added to a methanol (5 mL) solution of compound 131-1 (110 mg, 0.34 mmol). The reaction mixture was stirred at 75 ° C for 8 hours, cooled to 25 ° C and filtered. Saturated ammonium chloride solution (5 mL) was added to the filtrate to quench the reaction, and extracted with EA (50 mL). The organic phase was washed with saturated brine (3 times), dried and concentrated. The resulting residue was purified by silica gel column chromatography (eluent gradient transition from PE: EA = 5: 1 to 1: 1) to obtain compound 131-2 (55 mg, 0.15 mmol).

Step 3: At 0°C, CDI (31 mg, 0.19 mmol) was added to a THF (2 mL) solution of compound 131-2 (55 mg, 0.15 mmol), and the mixture was heated to room temperature and stirred for 30 minutes. DBU (34 μL, 0.22 mmol) was added at 0°C. The reaction mixture was heated to room temperature and stirred for 1 hour, then concentrated, saturated ammonium chloride solution (2 mL) was added to quench the mixture, and extracted with EA (20 mL). The organic phase was washed with saturated brine (3 times), dried and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent gradient transition from PE:EA=5:1 to 1:1) and preparative high performance liquid chromatography (HPLC) to obtain compound 131 (25 mg, 0.06 mmol, yield: 40%). MS (ESI): m/z=380[M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ: 12.86-13.95 (s, 1H), 9.08 (s, 1H), 8.07 (s, 1H), 7.80 (d, J = 3.5Hz, 1H), 7.69 (d, J = 8.8Hz, 1H), 7.51 (dd, J = 8.8, 1.4Hz, 1H), 6.89 (d, J = 3 .5Hz,1H).

Embodiment 133

Step 1: A mixture of 5-trifluoromethylindole (1500 mg, 8.10 mmol), DMF (15 mL), and t-BuONa (778.6 mg, 8.10 mmol) was stirred at room temperature for 30 min, and then 3,6-dichloropyrazine-2-carbonitrile (1423.6 mg, 8.18 mmol) was added under ice bath conditions. The reaction mixture was slowly warmed to room temperature and stirred for 30 minutes, diluted with saturated NH ₄ Cl (aq) (50 mL), and extracted with EA (50 mL). The organic phase was washed with saturated brine (10 mL×3), dried over anhydrous Na ₂ SO _4, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with DCM:PE=1:3) to obtain compound 133-1 (872 mg, 2.70 mmol, yield: 33.36%).

Step 2: Compound 133-1 (461.7 mg, 1.43 mmol), MeOH (21 mL), NH ₂ OH·HCl (994.3 mg, 14.31 mmol), TEA (13 mL) and The mixture was purged with _N2 and maintained under _N2 atmosphere, stirred at 80°C for 2 hours, filtered under reduced pressure, and the filtrate was concentrated. _H2O (20 mL) was added to the concentrate, and then extracted with EA (30 mL). The organic phase was washed with saturated brine (10 mL×3), dried over anhydrous _{Na2SO4 ,} and concentrated. The residue was purified by silica gel column chromatography (eluted with EA:PE=1:5) to obtain compound 133-2 (358.5 mg, 1.01 mmol, yield: 70.44%). MS (ESI): m/z=356[M+H] ⁺ .

Step 3: Add dicarbonyl imidazole (204.0 mg, 1.26 mmol) to a solution of compound 133-2 (358 mg, 0.17 mmol) in THF (10 mL) under ice bath conditions, stir at room temperature for 30 minutes, and then add DBU (229.8 mg, 1.51 mmol) dropwise under ice bath conditions. After stirring the reaction mixture under ice bath conditions for 2 hours, add an aqueous solution of HCl (20 mL, pH = 2), and extract with EA (20 mL). The organic phase was washed with saturated brine (10 mL × 3), dried over anhydrous Na ₂ SO ₄ , and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with MeOH:DCM = 1:20) to obtain compound 133-3 (239.4 mg, 0.63 mmol, yield: 62.32%). MS (ESI): m/z = 382 [M+H] ⁺ .

Step 4: A solution of Na ₂ CO ₃ (41.7 mg, 323.40 mmol) in water (0.2 mL) was added to a mixture of compound 133-3 (75.0 mg, 0.20 mmol), 1,4-dioxane (1.2 mL), vinyl pinacol borate (45.4 mg, 0.29 mmol) and Pd(dppf)Cl ₂ (14.3 mg, 0.02 mmol). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, stirred at 100° C. for 12 hours, diluted with H ₂ O (2 mL), and extracted with EA (5 mL). The organic phase was washed with saturated brine (2 mL×3), dried over anhydrous Na ₂ SO ₄ and concentrated, and the residue was purified by silica gel column chromatography (eluted with MeOH:DCM=1:20) to obtain compound 133-4 (26.0 mg, 0.07 mmol, yield: 35.45%). MS (ESI): m/z=372[M+H] ⁺ .

Step 5: A mixture of compound 133-4 (26.0 mg, 0.07 mmol), MeOH (0.5 mL) and Pd/C (5%) (5.0 mg) was purged with H ₂ and maintained under H ₂ atmosphere. After stirring at room temperature for 18 hours, it was purged with N ₂ and maintained under N ₂ atmosphere, and filtered under reduced pressure. The filtrate obtained by filtration and the filtrate obtained by washing the filter cake with DCM, EA, and MeOH in sequence were combined, dried over anhydrous Na ₂ SO ₄ , and concentrated to obtain a residue. The obtained residue was purified by silica gel column chromatography (eluted with MeOH:DCM=1:20) to obtain compound 133 (9.0 mg, 0.02 mmol, yield: 32.65%). MS (ESI): m/z=376[M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.40 (t, J = 7.57Hz, 3H) 3.02 (q, J = 7.55Hz, 2H) 6.86 (d, J = 3.38Hz, 1H) 7.47 (dd, J = 8.76, 1.38Hz, 1H) 7.59 (d, J = 8.63Hz, 1H) 7.81 (d,J＝3.38Hz,1H)8.06(s,1H)8.86(s,1H)13.12(br s,1H).

Embodiment 134

Step 1: A solution of Na ₂ CO ₃ (38.3 mg, 0.36 mmol) in water (0.2 mL _{H 2} O) was added to a mixture of compound 133-3 (70.0 mg, 0.18 mmol), 1,4-dioxane (1.2 mL), 4,4,5,5-tetramethyl-2-propen-2-yl-1,3,2-dioxaborolane (60.7 mg, 0.36 mmol) and Pd(dppf)Cl ₂ (13.2 mg, 0.02 mmol). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, stirred at 100° C. for 12 hours, diluted with H ₂ O (2 mL), and extracted with EA (5 mL). The obtained organic phase was washed with saturated brine (2 mL×3), dried over anhydrous Na ₂ SO ₄ and concentrated, and the obtained residue was purified by silica gel column chromatography (eluted with MeOH:DCM=1:20) to obtain compound 134-1 (15.0 mg, 0.04 mmol, yield: 21.43%). MS (ESI): m/z=388[M+H] ⁺ .

Step 2: A mixture of compound 134-1 (15.0 mg, 0.04 mmol), THF (0.2 mL), MeOH (0.5 mL) and Pd/C (5%) (3.0 mg) was purged with H ₂ and maintained under H ₂ atmosphere. After stirring at room temperature for 4 hours, it was purged with N ₂ and maintained under N ₂ atmosphere, and filtered under reduced pressure. The filtrate obtained by filtration and the filtrate obtained by washing the filter cake with DCM, EA, and MeOH in sequence were combined, dried over anhydrous Na ₂ SO ₄ , and concentrated to obtain a residue. The obtained residue was purified by silica gel column chromatography (eluted with MeOH:DCM=1:20) to obtain compound 134 (3.5 mg, 0.01 mmol, yield: 22.76%). MS (ESI): m/z=390[M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.38 (dd, J = 6.88, 2.00Hz, 6H) 3.32 (dt, J = 13.79, 7.05Hz, 1H) 6.86 (d, J = 3.50Hz, 1H) 7.46 (d, J = 8.75Hz, 1H) 7.53-7.59 (m, 1H) 7.78(t,J=3.44Hz,1H)8.05(s,1H)8.85(d,J=3.00Hz,1H).

Embodiment 135

A mixture of compound 133-3 (100.0 mg, 0.26 mmol), DMAc (1.7 mL), P(t-Bu) ₃ (10% toluene solution) (106.0 mg, 0.36 mmol), Pd ₂ (dba) ₃ (27.1 mg, 0.03 mmol) and Zn(CN) ₂ (21.5 mg, 0.18 mmol) was purged with N ₂ and maintained under N ₂ atmosphere. After stirring at 95° C. for 12 hours, the mixture was diluted with H ₂ O (5 mL) and extracted with EA (5 mL). The organic phase was washed with saturated brine (2 mL×3), dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography (eluted with MeOH:DCM=1:100) to obtain compound 135 (1.7 mg, 4.5 μmol, yield: 1.70%). MS (ESI): m/z=371[M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 6.93 (d, J = 3.63 Hz, 1H) 7.58 (d, J = 8.63 Hz, 1H) 7.83-7.86 (m, 1H) 7.89 (br d, J = 9.13 Hz, 1H) 8.08 (s, 1H) 9.38-9.42 (m, 1H).

Embodiment 136

Step 1: 2,3-Butanedione (2.7 g, 32 mmol) was added to a mixture of 2-aminomalonamide hydrochloride (5 g, 32 mmol), aqueous NaOH solution (50%, 20 mL) and H ₂ O (10 mL). The reaction mixture was stirred at room temperature for 12 hours, diluted with H ₂ O, and the pH was adjusted to 6 with aqueous HCl solution (2N) to precipitate a solid. The solid was dried in vacuo to obtain compound 136-1 without further purification. (4.5 g, 26 mmol, yield: 83.7%). MS (ESI): m/z=168[M+H] ⁺ .

Step 2: A mixture of compound 136-1 (2 g, 11 mmol), phosphorus oxychloride (40 mL) and TEA (3.7 mL) was purged with N ₂ and maintained under N ₂ atmosphere. After stirring at 60°C for 3 hours, H ₂ O (20 mL) was slowly added in an ice bath and extracted with EA (30 mL). The organic phase was washed with saturated brine (10 mL×3), dried over anhydrous Na ₂ SO ₄ and concentrated, and the residue was purified by silica gel column chromatography (eluted with EA:PE=1:5) to obtain compound 136-2 (1.2 g, 7.1 mmol, yield: 64.5%). MS (ESI): m/z=168[M+H] ⁺ .

Step 3: NaH (48 mg, 1.2 mmol) was slowly added to a DMF (5 mL) solution of compound 136-2 (100 mg, 0.59 mmol). After reacting at room temperature for 1 hour, 5-trifluoromethylindole (130 mg, 0.7 mmol) was added. The reaction mixture was stirred at 120°C for 3 hours, diluted with H ₂ O (200 mL), and extracted with EA (50 mL). The organic phase was washed with saturated brine (20 mL×3), dried over anhydrous Na ₂ SO ₄ , and concentrated. The resulting residue was purified by silica gel column chromatography (eluted with EA:PE=1:4) to obtain compound 136-3 (76 mg, 0.23 mmol, yield: 43.5%). MS (ESI): m/z=317[M+H] ⁺ .

Step 4: Compound 136-3 (176 mg, 0.55 mmol), MeOH (20 mL), NH ₂ OH·HCl (388 mg, 5.5 mmol), TEA (10 mL) and The mixture was purged with _N2 and maintained under _N2 atmosphere, stirred at 80°C for 3 hours, and filtered under reduced pressure. The filtrate was concentrated, _H2O (20 mL) was added to the concentrate, and extracted with EA (30 mL). The organic phase was washed with saturated brine (10 mL×3), dried over anhydrous _{Na2SO4 ,} and concentrated, and the residue was purified by silica gel column chromatography (eluted with EA:PE=1:2) to obtain compound 136-4 (150 mg, 0.42 mmol, yield: 78.1%). MS (ESI): m/z=350[M+H] ⁺ .

Step 5: CDI (91.9 mg, 0.56 mmol) was added to a solution of compound 136-4 (150 mg, 0.47 mmol) in THF (10 mL) under ice bath conditions, stirred at room temperature for 30 minutes, and then DBU (107 mg, 0.70 mmol) was added dropwise under ice bath conditions. After the reaction mixture was stirred under ice bath conditions for 2 hours, HCl aqueous solution (20 mL, pH = 2) was added, and extracted with EA (20 mL). The organic phase was washed with saturated brine (10 mL × 3), dried over anhydrous Na ₂ SO ₄ , and concentrated, and the resulting residue was purified by preparative high performance liquid chromatography to obtain compound 136 (21 mg, 0.14 mmol, yield: 9.4%). MS (ESI): m/z = 376 [M + H] ⁺ . ¹ H NMR(DMSO-d ₆ )δ:8.06(s,1H),7.77(d,J＝3.4Hz,1H),7.56(d,J＝8.8Hz,1H),7.43-7.51(m,1H),6.85(d,J＝3.4Hz,1H),2.69(s,3H),2.63-2.67(m,3H)。

Embodiment 137

Step 1: Add 3,5-dichloropyrazine-2-carbonitrile (3.13 mL, 28.74 mmol) to a solution of NH ₃ in dioxane (2.15.54 mL, 86.22 mmol, 0.4 M). The reaction mixture was stirred at room temperature for 3 hours and then concentrated. Water (100 mL) was added to the concentrate and extracted with ethyl acetate (100 mL*3). The combined organic phases were concentrated and the residue was purified by flash column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain compound 137-1 (3.46 g, 22.39 mmol, yield: 77.89%). ¹ H NMR (400 MHz, DMSO-d6) δ8.12 (s, 2H), 7.87 (s, 1H).

Step 2: Add 5-(trifluoromethyl)-indole (4.14 g, 4.33 mmol) and sodium tert-butoxide (2.15 g, 22.39 mmol) to a DMF (40 mL) solution of compound 137-1 (3.46 g, 22.39 mmol). The reaction mixture was stirred at 80°C for 2 hours, diluted with water (100 mL), and extracted with ethyl acetate (100 mL*3). The combined organic phase was concentrated, and the residue was purified by flash column chromatography (eluted with petroleum ether/ethyl acetate = 1/1) to obtain compound 137-2 (3.36 g, 11.08 mmol, yield: 49.49%). ¹ H NMR (400MHz, DMSO-d6) δ8.07–8.17(m,2H),8.04(s,2H),8.00(d,J＝3.5Hz,1H),7.97(s,1H),7.56(d,J＝8.8,1.6Hz,1H),6.95(d,J＝3.5Hz,1H).

Step 3: Hydroxylamine hydrochloride (229.15 mg, 3.30 mmol), TEA (1.83 mL, 13.19 mmol) and Molecular sieves (30 mg) were added to a methanol (2 mL) solution of compound 137-2 (200 mg, 0.66 mmol). The reaction mixture was stirred at 80°C for 2 hours, filtered, and water (5 mL) was added to dilute the obtained concentrate, and extracted with ethyl acetate (5 mL*3). The combined organic phase was concentrated, and the obtained residue was purified by flash column chromatography (eluted with dichloromethane: methanol = 10: 1) to obtain compound 137-3 (190 mg, 0.57 mmol, yield: 85.67%). MS (ESI): m/z = 338 [M+H] ⁺ .

Step 4: At 0°C, CDI (114.52 mg, 0.71 mmol) was added to a tetrahydrofuran (2 mL) solution of compound 137-3 (190 mg, 0.57 mmol), and after stirring at room temperature for 0.5 hours, DBU (0.13 mL, 0.85 mmol) was added at 0°C. After the reaction mixture was stirred at room temperature for 1 hour, it was diluted with water (3 mL) and extracted with ethyl acetate (3 mL*3). The combined organic phase was concentrated, and the residue was purified by preparative high performance liquid chromatography (HPLC) to obtain compound 137-4. (45.47 mg, 0.12 mmol, yield: 21.31%, purity: 96.04%). ¹ HNMR (400MHz, DMSO-d6) δ12.59–12.85(m,1H),8.07(s,1H),8.02(s,1H),7.71(d,J＝3.5Hz,1H),7.68(s,2H),7.53–7.59(m,1H),7.45(d,J＝8.7,1.6Hz, 1H), 6.80 (d, J = 3.4Hz, 1H).

Step 5: At 0°C, copper chloride (38.97 mg, 0.29 mmol) and tert-butyl nitrite (0.03 mL, 0.29 mmol) were added to a solution of compound 137-4 (70 mg, 0.19 mmol) in acetonitrile (1 mL). The reaction mixture was stirred at 50°C for 16 hours, diluted with water (3 mL), and extracted with ethyl acetate (3 mL*3). The combined organic phases were concentrated, and the crude product was purified by preparative high performance liquid chromatography (HPLC) to obtain compound 137 (2.88 mg, 0.01 mmol, yield: 3.89%, purity: 99.65%). MS (ESI): m/z=380[M+H] ⁺ . ¹ HNMR (400MHz, DMSO-d6) δ13.16–13.53(m,1H),9.09(s,1H),7.81(s,1H),7.75(d,J＝8.6Hz,1H),7.54(d,J＝8.3Hz,1H),6.89(d,J＝3.0Hz,1H).

Embodiment 138

Step 1: According to the similar synthesis method of Step 1 in Example 118, 3-chloro-5-trifluoromethylpyrazine-2-carbonitrile and 5-trifluoromethyl-1H-indole were used as reactants to prepare compound 138-1. MS (ESI): m/z=357 [M+H] ⁺ .

Step 2: According to the similar synthesis method of Step 2 in Example 118, compound 138-2 was prepared using compound 138-1 as a reactant. MS (ESI): m/z = 390 [M+H] ⁺ .

Step 3: According to the similar synthesis method of Step 3 in Example 118, compound 138 (17 mg, purity: 97.7%) was prepared using compound 138-2 as a reactant. MS (ESI): m/z=416 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ: 9.43 (s, 1H), 8.09 (s, 1H), 7.88 (d, J=3.4 Hz, 1H), 7.76 (d, J=8.6 Hz, 1H), 7.57 (d, J=8.8 Hz, 1H), 6.92 (d, J=3.4 Hz, 1H).

Embodiment 140

Step 1: At room temperature, 5-bromo-3-(5-(trifluoromethyl)-1H-indol-1-yl)pyrazine-2-carbonitrile (50 mg, 0.14 mmol), ethylboric acid (50 mg, 0.68 mmol), potassium carbonate (56 mg, 0.41 mmol) and Pd(dppf)Cl ₂ (28 mg, 0.07 mmol) were dispersed in 1,4-dioxane (1 mL)/water (0.1 mL). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 80°C and stirred overnight, diluted with water, and extracted with ethyl acetate (10 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (eluted with ethyl acetate: petroleum ether=1:5) to obtain compound 140-2 (24 mg, yield: 57.1%). MS (ESI): m/z=317[M+H] ⁺ .

Step 2: At room temperature, hydroxylamine hydrochloride (49 mg, 0.76 mmol), triethylamine (0.21 mL, 1.51 mmol) and Molecular sieves (50 mg) were added to a MeOH (5 mL) solution of compound 140-2 (24 mg, 0.07 mmol). The reaction mixture was heated to 80°C and stirred overnight, quenched with water, and extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain compound 140-3 (26 mg, yield: 97.4%) which could be used directly in the next step without purification. MS (ESI): m/z=350[M+H] ⁺ .

Step 3: At 0°C, CDI (22 mg, 0.14 mmol) was added to a THF (2 mL) solution of compound 140-3 (26 mg, 0.07 mmol), slowly heated to room temperature and stirred for 1 hour, and then DBU (21 mg, 0.14 mmol) was added dropwise at 0°C. The reaction system was slowly heated to room temperature and stirred for 1 hour, quenched with water, and extracted with ethyl acetate (50 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (eluted with ethyl acetate: petroleum ether=1:1) to obtain compound 140 (11 mg, yield: 41.7%). MS (ESI): m/z=376[M+H] ⁺ . ¹ H NMR(DMSO-d6)δ:13.03-13.36(m,1H),8.78-9.04(m,1H),8.01-8.15(m,1H),7.78-7.92(m,1H),7.65-7.76(m,1H),7.44-7.56(m,1H),6.78-6.96 (m,1H),2.85-3.15(m,2H),1.29-1.42(m,3H).

Embodiment 144

Step 1: m-CPBA (6.0 g, 3.71 mmol) was added to a solution of compound 2-chloro-6,7-dihydro-5H-cyclopentane[b]pyridine-3-carbonitrile (4.0 g, 24.54 mmol) in DCE (40 mL). The reaction mixture was stirred at 50°C overnight, diluted with H ₂ O, and extracted with EA. The organic layer was washed three times with saturated sodium thiosulfate solution, dried, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography to obtain compound 144-1 (4.5 g, 18.60 mmol). MS (ESI): m/z=242[M+H]+.

Step 2: A solution of compound 144-1 (2.5 g, 10.38 mmol) in acetic anhydride (30 mL) was stirred at 110°C overnight, cooled to room temperature, diluted with H ₂ O, and extracted with EA. The organic layer was washed with saturated brine (3 times), dried and concentrated, and the residue was purified by column chromatography to obtain compound 144-2 (429 mg, 2.28 mmol). MS (ESI): m/z=189[M+H]+.

Step 3: Add potassium carbonate (832.14 mg, 6.02 mmol) to a solution of compound 144-2 (570 mg, 2.41 mmol) in methanol (6 mL) and water (1.5 mL). Stir the reaction mixture at room temperature for 2 hours, dilute with H ₂ O and extract with EA. Wash the organic phase with saturated brine, dry and concentrate to obtain a crude product of compound 144-3 (380 mg). MS (ESI): m/z=195[M+H]+.

Step 4: Dess-Martin oxidant (1076.59 mg, 2.54 mmol) was slowly added to a solution of the crude product of compound 144-3 (380 mg) in DCM (12 mL) at 0°C. The reaction mixture was stirred at room temperature for 2 hours, quenched with a saturated sodium bicarbonate solution, and extracted with DCM. The organic phase was washed with a saturated sodium bicarbonate solution (2 times), washed with saturated brine (1 time), dried, and concentrated to obtain the crude product of compound 144-4 (290 mg). MS (ESI): m/z = 193 [M+H] +.

Step 5: At 0°C, bis(2-methoxyethyl)aminosulfur trifluoride (600 μL, 3.25 mmol) was slowly added to a solution of compound 144-4 (100 mg, 0.53 mmol) in DCM (6 mL). The reaction mixture was stirred at room temperature for 2 days, quenched by adding saturated sodium bicarbonate solution, and extracted with DCM. The organic layer was washed with saturated sodium bicarbonate solution (2 times), washed with saturated brine (1 time), dried and concentrated to give compound 144-5 (70 mg, 0.33 mmol, yield: 69.80%). MS (ESI): m/z=215[M+H]+.

Step 6: Under nitrogen atmosphere, cuprous iodide (100 mg, 0.53 mmol) was added to a toluene (6 mL) solution of compound 144-5 (100 mg, 0.56 mmol), 5-trifluoromethyl-1H-indole (123.32 mg, 0.67 mmol), trans-N-dimethylcyclohexane-1,2-diamine (165 mg, 1.16 mmol) and potassium phosphate (117.82 mg, 0.56 mmol). The reaction mixture was stirred at 110°C overnight, diluted with H ₂ O, and extracted with EA. The organic layer was washed with saturated brine, dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 144-6 (78 mg, 0.21 mmol, yield: 38.68%). MS (ESI): m/z=364[M+H]+.

Step 7: To a solution of compound 144-6 in methanol (4 mL) were added hydroxylamine hydrochloride (137.72 mg, 1.98 mmol), triethylamine (549.44 μL, 3.96 mmol) and Molecular sieves (160 mg). The reaction mixture was stirred at 80°C for 4 hours, cooled to room temperature and filtered. The filtrate was concentrated, diluted with H ₂ O and extracted with EA. The organic phase was washed with saturated brine, dried and concentrated to obtain a crude product of compound 144-7 (80 mg). MS (ESI): m/z=397[M+H]+.

Step 8: CDI (58.92 mg, 0.36 mmol) was added to a solution of compound 144-7 (72 mg, 0.18 mmol) in THF (4 mL) at 0°C. After stirring at room temperature for 1 hour, DBU (54.23 μL, 0.36 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 1.5 hours, cooled to 0°C, adjusted to pH 6 with hydrochloric acid (2 M), diluted with water, and extracted with EA. The organic phase was washed with saturated brine, dried, concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 144 (16 mg, 0.04 mmol, yield: 20.86%). MS (ESI): m/z = 423 [M+H] +. ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 12.85 (br s, 1H), 8.48 (s, 1H), 8.09 (s, 1H), 7.66 (d, J = 8.8Hz, 1H), 7.62 (d, J = 3.5Hz, 1H), 7.56 (dd, J = 1.3, 8.8Hz, 1H), 6.90 (d, J = 3.4Hz,1H),3.21(br s,2H),2.87-2.74(m,2H).

Embodiment 146

Step 1: NCS (1.34 g, 10.05 mmol) was added to a solution of 6-bromo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (2 g, 10.05 mmol) in acetonitrile (40 mL). The reaction mixture was stirred at 90°C for 18 hours and then filtered. The filtrate was concentrated and the residue was placed in a silicone column (eluted with PE:EA=1:1) for distillation to obtain compound 146-1 (1.14 g, yield: 48.59%). MS (ESI): m/z=233[M+H] ⁺ .

Step 2: Add cuprous cyanide (3.07 g, 34.26 mmol) to a solution of compound 146-1 (800 mg, 3.42 mmol) in NMP (16 mL). After stirring the reaction mixture at 180°C for 2.5 hours, pour it into water (12 mL) and extract it with ethyl acetate (20 mL x 3). The combined organic phases were washed with a saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was placed in a silicone column (eluted with PE:EA=2:1) for distillation to obtain compound 146-2. MS (ESI): m/z=180[M+H] ⁺ .

Step 3: Add 5-(trifluoromethyl)-1H-indole (132.36 mg, 0.71 mmol), BrettPhos Pd G3 (54.01 mg, 0.06 mmol) and sodium tert-butoxide (85.88 mg, 0.89 mmol) to a toluene (2 mL) solution of compound 146-2 (107 mg, 0.60 mmol). Stir the reaction mixture at 100 °C for 18 hours. Pour into water (3 mL) and extract with ethyl acetate (5 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate and concentrated, and the residue was placed in a silicone column (eluted with PE:EA=1:1) for distillation to obtain compound 146-3 (34 mg, yield: 17.38%). MS (ESI): m/z=329[M+H] ⁺ .

Step 4: To a solution of compound 146-3 (28 mg, 0.09 mmol) in methanol (1 mL) were added hydroxylamine hydrochloride (59.27 mg, 0.85 mmol), triethylamine (0.36 mL, 2.56 mmol) and Molecular sieves (100 mg). After the reaction mixture was stirred at 80°C for 6 hours, it was poured into water (1 mL) and extracted with dichloromethane (2 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (2 mL), dried over anhydrous sodium sulfate and concentrated to obtain a crude product of compound 146-4 (35 mg). MS (ESI): m/z = 362 [M+H] ⁺ .

Step 5: At 0°C, CDI (11.23 mg, 0.07 mmol) was added to a solution of the crude product of compound 146-4 (35 mg) in tetrahydrofuran (6 mL), and after stirring at 0°C for 1 hour, DBU (14.11 μL, 0.09 mmol) was added. The reaction mixture was stirred at 0°C for 1 hour, poured into water (6 mL), and extracted with ethyl acetate (6 mL x 3). The combined organic phase was washed with hydrochloric acid (1 M), dried over anhydrous sodium sulfate, and concentrated, and the residue was purified by high performance liquid chromatography to obtain compound 146 (3.16 mg, yield: 11.93%). MS (ESI): m/z = 388 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ: 12.60 (br s, 1H), 8.00 (s, 1H), 7.50 (d, J = 3.3Hz, 1H), 7.38-7.44 (m, 1H), 7.31-7.38 (m, 1H), 7.05 (s, 1H), 6.76 (d, J = 3.3Hz, 1H), 6.5 7(s,1H),3.68(t,J＝8.8Hz,2H),3.05-3.23(m,2H).

Embodiment 147

Step 1: Sodium hydride (5.05 g, 126.35 mmol) was added in batches to a DMF (150 mL) solution of dimethyl malonate (13.91 g, 105.29 mmol) under ice bath conditions. After reacting at room temperature for half an hour, 5-bromo-2-chloro-3-nitropyridine (25 g, 105.29 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours, diluted with water, and extracted with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography to obtain compound 147-1 (22.7 g, yield: 64.73%). MS (ESI): m/z = 335 [M+H] ⁺ .

Step 2: Sodium hydride (3.27 g, 81.78 mmol) was added in batches to a DMF (200 mL) solution of compound 147-1 (22.7 g, 68.15 mmol) under ice bath conditions. After reacting at room temperature for half an hour, ethyl bromoacetate (11.38 g, 68.15 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours, water was added, and extracted with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography to obtain compound 147-2 (23 g, yield: 48.31%). MS (ESI): m/z = 420 [M+H] ⁺ .

Step 3: A solution of compound 147-2 (21.8 g, 52.01 mmol) in concentrated hydrochloric acid (150 mL) was purged with N ₂ and maintained under N ₂ atmosphere. After stirring at 90°C for 12 hours, water (50 mL) was added to dilute the mixture and filtered. The resulting residue was washed with water and dried to obtain compound 147-3 (12 g, yield: 83.89%). MS (ESI): m/z=277[M+H] ⁺ .

Step 4: Compound 147-3 (12.1 g, 43.99 mmol), iron powder (7.37 g, 131.97 mmol), ammonium chloride (7.06 g, 131.97 mmol) were dispersed in a mixed solvent of tetrahydrofuran (150 mL), methanol (75 mL) and water (75 mL). The reaction mixture was purged with N ₂ and maintained in a N ₂ atmosphere, stirred at 60°C for 12 hours, concentrated, added with water, and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the residue was chromatographed on a silica gel column to obtain compound 147-4 (8 g, yield: 74.20%). MS (ESI): m/z=247[M+H] ⁺ .

Step 5: Add T ₃ P (20.77 g, 65.28 mmol) and DIEA (16.88 g, 130.57 mmol) to a DMF (100 mL) solution of compound 147-4 (8 g, 32.64 mmol). After stirring the reaction mixture at room temperature for 12 hours, water was added and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography to obtain compound 147-5 (7.4 g, yield: 99.84%). MS (ESI): m/z=229[M+H] ⁺ .

Step 6: A solution of compound 147-5 (7.8 g, 34.35 mmol) and NCS (9.17 g, 68.70 mmol) in acetonitrile (80 mL) was stirred at 90°C for 12 hours and then filtered. The resulting filter cake was rinsed with acetonitrile to obtain compound 147-6 (8.5 g, yield: 94.62%). MS (ESI): m/z = 262 [M1] ⁺ .

Step 7: Add a tetrahydrofuran solution of borane (1M, 53.54 mL) to a tetrahydrofuran solution (300 mL) of compound 147-6 (4 g, 15.30 mmol). After the reaction mixture was stirred at 70°C for 2 hours, water was added dropwise under ice bath conditions to quench the reaction, diluted with water, and extracted with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was chromatographed on a silica gel column to obtain compound 147-7 (3.7 g, yield: 97.72%). MS (ESI): m/z=249[M+H] ⁺ .

Step 8: Compound 147-7 (3.6 g, 14.54 mmol) and cuprous cyanide were dispersed in NMP (80 mL). The reaction mixture was purged with N ₂ and maintained in a N ₂ atmosphere. After stirring at 180°C for 3 hours, water was added and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain compound 147-8 (2.4 g, yield: 85.22%). MS (ESI): m/z=194[M+H] ⁺ .

Step 9: Compound 147-8 (1 g, 5.16 mmol), 5-(trifluoromethyl)-1H-indole (1.15 g, 6.20 mmol), and Breetphos G3 (468.17 mg, 0.52 mmol) were dispersed in toluene (20 mL). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere. After stirring at 100° C. for 12 hours, water was added and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography to obtain compound 147-9 (389 mg, yield: 22%). MS (ESI): m/z=343[M+H] ⁺ .

Step 10: Add triethylamine (5.12 g, 50.65 mmol) to compound 147-9 (289 mg, 0.84 mmol), hydroxylamine hydrochloride (586.64 mg, 8.44 mmol), and The reaction mixture was purged with _N2 and maintained under _N2 atmosphere. After stirring at 75°C for 12 hours, a saturated aqueous solution of ammonium chloride was added and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain compound 147-10 (126 mg, yield: 39.76%). MS (ESI): m/z = 317 [M+H] ⁺ .

Step 11: Under ice bath conditions, CDI (68.04 mg, 0.42 mmol) was added to a solution of compound 147-10 (126 mg, 0.34 mmol) in THF (2 mL), and DBU (76.66 mg, 0.5 mmol) was added after stirring for half an hour. The reaction mixture was stirred at room temperature for half an hour, water was added, and extracted with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography to obtain compound 147 (19.8 mg, yield: 14.70%). MS (ESI): m/z=402[M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ: 8.00 (s, 1H), 7.50 (d, J = 3.3Hz, 1H), 7.35-7.43 (m, 2H), 7.20 (s, 1H), 6.75 (d, J = 3.3Hz, 1H), 6.64 (s, 1H), 3.26-3.30 (m, 2H), 2.86 ( t,J＝6.3Hz,2H),1.96(br d,J＝5.4Hz,2H).

Embodiment 149

Step 1: Add 2-(ethoxymethylene)malononitrile (2.19 g, 17.94 mmol) to a methanol (35 mL) solution of 4-(cyclohex-1-en-1-yl)morpholine (3.0 g, 17.94 mmol). The reaction mixture was stirred at 28°C for 4 hours to precipitate a solid, and then filtered. The resulting filter cake was washed with 0°C methanol (3 mL*3) and dried to obtain compound 149-1 (1.86 g, 7.64 mmol, yield: 42.62%). MS (ESI): m/z = 243 [M+H] ⁺ .

Step 2: A mixture of compound 149-1 (1.86 g, 7.64 mmol) and NH ₃ methanol solution (7M, 20 mL) was reacted under microwave conditions (130w, 110°C) for 40 minutes, and a solid was precipitated after cooling to room temperature, and then filtered. The resulting filter cake was washed with 0°C methanol (3 mL*3) to obtain compound 149-2 (1130 mg, 6.52 mmol, yield: 88%). MS (ESI): m/z=174[M+H] ⁺ .

Step 3: At 0°C, sodium nitrite (1.55 mL, 28.99 mmol) was slowly added to a solution of compound 149-2 (1.0 g, 5.77 mmol) in acetic acid (6 mL) and concentrated hydrochloric acid (6 mL). After the reaction mixture was stirred at 0°C for 1 hour, water was slowly added at 0°C to quench the mixture, and the solid was precipitated and then filtered. The filter cake was washed with water (5 mL*3) and methanol at 0°C (3 mL*3) in turn and dried to obtain compound 149-3 (640 mg, 3.32 mmol, yield: 57.55%). MS (ESI): m/z=193[M+H] ⁺ .

Step 4: 5-Trifluoromethyl-1H-indole (563.47 mg, 3.04 mmol) and cesium carbonate (1352.16 mg, 4.15 mmol) were added to a DMF (8 mL) solution of compound 149-3 (533 mg, 2.77 mmol). The reaction mixture was stirred at 120°C for 1 hour, cooled to room temperature, diluted with H ₂ O, and extracted with EA. The obtained organic phase was washed with saturated brine (3 times), dried and concentrated, and the obtained residue was purified by silica gel column chromatography to obtain compound 149-4 (336 mg, 0.98 mmol, yield: 35.58%). MS (ESI): m/z=342[M+H] ⁺ .

Step 5: Hydroxylamine hydrochloride (684.03 mg, 9.84 mmol), triethylamine (2.72 mL, 19.69 mmol) and Molecular sieves (600 mg) were added to a methanol (12 mL) solution of compound 149-4 (336 mg, 0.98 mmol). The reaction mixture was stirred at 80°C for 4 hours, cooled to room temperature, filtered, and the filtrate was concentrated. H ₂ O was added to the concentrate to dilute it, and it was extracted with EA. The organic phase was washed with saturated brine, dried, and concentrated. The residue was purified by silica gel column chromatography to obtain compound 149-5 (230 mg, 0.61 mmol, yield: 62.41%). MS (ESI): m/z=375[M+H] ⁺ .

Step 6: CDI (150 mg, 0.92 mmol) was added to a solution of compound 149-5 (230 mg, 0.61 mmol) in THF (8 mL) at 0°C. After stirring at room temperature for 0.5 hours, DBU (0.14 mL, 0.92 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 1.5 hours, the pH was adjusted to 6 with hydrochloric acid (2 M) at 0°C, diluted with water, and extracted with EA. The organic layer was washed with saturated brine, dried and concentrated, and the resulting residue was purified by column chromatography to obtain compound 149 (160 mg, 0.40 mmol, yield: 65.51%). MS (ESI): m/z=401[M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ: 8.05 (s, 2H), 7.63 (d, J = 8.6Hz, 1H), 7.59 (d, J = 3.4Hz, 1H), 7.48 (dd, J = 8.8, 1.3Hz, 1H), 6.84 (d, J = 3.4Hz, 1H), 2.83-3.02 (m, 4H), 1.76- 1.96(m,4H).

Embodiment 150

Step 1: Dissolve compound 1,4-dioxacyclo[4.5]decan-8-one (10.0 g, 62.75 mmol) in DMF-DMA (100 mL, 724.49 mmol). Stir the reaction mixture at 110° C. overnight and then concentrate to obtain compound 150-1 (14.02 g, 66.36 mmol). MS (ESI): m/z=207[M+H] ⁺ .

Step 2: Add malononitrile (1804.01 μL, 28.40 mmol) and ammonium acetate (182.43 mg, 2.37 mmol) to a solution of compound 150-1 (5000 mg, 23.67 mmol) in acetonitrile (60 mL). Stir the reaction mixture at 70°C overnight, cool to room temperature, dilute with H ₂ O, and extract with EA. Wash the organic phase with saturated brine (3 times), dry and concentrate to obtain a crude product of compound 150-2 (2.56 g, 16.73 mmol). MS (ESI): m/z=233[M+H] ⁺ .

Step 3: The crude product of compound 150-2 (1.84 g, 7.92 mmol) was dissolved in phosphorus oxychloride (25 mL). The reaction mixture was stirred at 100°C for 2 hours and then concentrated. The concentrate was slowly dripped into a saturated sodium carbonate solution and extracted with EA. The organic phase was washed with saturated brine (3 times), dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 150-3 (750 mg, 3.63 mmol, yield: 45.81%). MS (ESI): m/z = 207 [M+H] ⁺ .

Step 4: At 0°C, bis(2-methoxyethyl)aminosulfur trifluoride (1381.14 μL, 10.45 mmol) was slowly added to a solution of compound 150-3 (720 mg, 3.48 mmol) in DCM (12 mL). The reaction mixture was stirred at room temperature for 2 days, quenched with saturated sodium bicarbonate solution, and extracted with DCM. The organic phase was washed with saturated sodium bicarbonate solution (2 times), washed with saturated brine (1 time), dried and concentrated to give compound 150-4 (425 mg, 1.86 mmol, yield: 53.35%). MS (ESI): m/z=229[M+H] ⁺ .

Step 5: 5-trifluoromethyl-1H-indole (344.98 mg, 1.86 mmol), cuprous iodide (202.83 mg, 1.06 mmol), trans-N,N-dimethylcyclohexane-1,2-diamine (66.85 mg, 0.47 mmol) and potassium phosphate (329.58 mg, 1.55 mmol) were added to a toluene (10 mL) solution of compound 150-4 (355 mg, 1.55 mmol). The reaction mixture was stirred at 110°C overnight, cooled to room temperature, diluted with H ₂ O, and extracted with EA. The organic phase was washed with saturated brine (3 times), dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 150-5 (280 mg, 0.74 mmol, yield: 47.79%). MS (ESI): m/z=378[M+H] ⁺ .

Step 6: To a solution of compound 150-5 (250 mg, 0.66 mmol) in methanol (8 mL) were added hydroxylamine hydrochloride (460.42 mg, 6.63 mmol), triethylamine (1.84 mL, 13.25 mmol) and Molecular sieves (250 mg). The reaction mixture was stirred at 80°C for 4 hours, cooled to room temperature and filtered, and the filtrate was concentrated. H ₂ O was added to the concentrate to dilute it, and it was extracted with EA. The organic phase was washed with saturated brine, dried and concentrated, and the residue was purified by silica gel column chromatography to obtain compound 150-6 (300 mg, 0.42 mmol, yield: 62.90%). MS (ESI): m/z=411[M+H] ⁺ .

Step 7: At 0°C, CDI (148.18 mg, 0.91 mmol) was added to a THF (8 mL) solution of compound 150-6 (230 mg, 0.61 mmol), and after stirring at room temperature for 0.5 hours, DBU (163.68 μL, 1.10 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 1.5 hours, cooled to 0°C, adjusted to pH 6 with hydrochloric acid (2 M), diluted with water, and extracted with EA. The organic phase was washed with saturated brine, dried, and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 150 (57 mg, 0.13 mmol, yield: 21.44%). MS (ESI): m/z = 437 [M+H] ⁺ . ¹ HNMR (DMSO-d ₆ ) δ: 8.17 (s, 1H), 8.07 (s, 1H), 7.72 (d, J = 8.8Hz, 1H), 7.60 (d, J = 3.5Hz, 1H), 7.51 (d, J = 8.8Hz, 1H), 6.87 (d, J = 3.5Hz, 1H), 3.48-3.60 (m, 2H),3.16-3.24(m,2H),2.38-2.49(m,2H).

Embodiment 155

Step 1: At room temperature, tert-butyl carbamate (740.69 mg, 6.32 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (997.75 mg, 1.72 mmol), cesium carbonate (3745.49 mg, 11.50 mmol) and palladium acetate (129.04 mg, 0.57 mmol) were added to a solution of 3,6-dichloropyrazine-2-carbonitrile (0.63 mL, 5.75 mmol) in 1,4-dioxane (25 mL). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 80°C and stirred for 6 hours, diluted with water, and extracted with ethyl acetate (100 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (eluted with ethyl acetate:petroleum ether=1:5) to obtain compound 155-1 (600 mg, yield: 40.99%). MS (ESI): m/z=199[M-56+H] ⁺ .

Step 2: Disperse compound 155-1 (600 mg, 2.36 mmol), 5-trifluoromethyl-1H-indole (436.21 mg, 2.36 mmol), and cesium carbonate (1535.26 mg, 4.71 mmol) in DMF (10 mL) at room temperature. Purge the reaction mixture with N ₂ and maintain the N ₂ atmosphere, slowly heat to 120°C and stir for 8 hours, then dilute with water and extract with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (eluted with ethyl acetate: petroleum ether = 1:5) to obtain compound 155-2 (390 mg, yield: 41.04%). MS (ESI): m/z = 348 [M-56+H] ⁺ .

Step 3: At 0°C, a solution of dioxane hydrochloride (4 mL) was added dropwise to a solution of compound 155-2 (200 mg, 0.50 mmol) in dichloromethane (1 mL). The reaction mixture was slowly heated to 34°C and stirred for 8 hours, then quenched with saturated sodium bicarbonate, diluted with water, and extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether=1:2) to obtain compound 155-3 (31 mg, yield: 20.62%). MS (ESI): m/z=304[M+H] ⁺ .

Step 4: At room temperature, hydroxylamine hydrochloride (71.04 mg, 1.02 mmol), Molecular sieves (270 mg, 0.66 mmol) and triethylamine (0.85 mL, 6.13 mmol) were added to a methanol (2 mL) solution of compound 155-3 (31 mg, 0.10 mmol). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 80 ° C and stirred for 3 hours, quenched with saturated ammonium chloride, and filtered. The filtrate was extracted with ethyl acetate (20 mL × 2), and the combined organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluted with ethyl acetate) to obtain compound 155-4 (32 mg, yield: 93.09%). MS (ESI): m/z = 337 [M + H] ⁺ .

Step 5: Under ice bath conditions, CDI (19.29 mg, 0.12 mmol) was added to tetrahydrofuran (1 mL) of compound 155-4 (32 mg, 0.10 mmol), and the temperature was slowly raised to room temperature and stirred for 30 minutes, and then DBU (21.30 μL, 0.14 mmol) was added under ice bath conditions. After the reaction mixture was slowly raised to room temperature and stirred for 1 hour, it was diluted with water and extracted with ethyl acetate (20 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by preparative silica gel plate to obtain compound 155 (20 mg, yield: 54.35%). MS (ESI): m/z=363[M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ: 7.95 (d, J = 9.6 Hz, 2H), 7.48 (d, J = 3.3 Hz, 1H), 7.34 (br d, J = 4.5 Hz, 2H), 7.00 (br s, 2H), 6.68 (d, J = 3.3 Hz, 1H).

Embodiment 159

Step 1: To a solution of compound 160-3 (50 mg, 0.14 mmol) in methanol (4 mL) was added a methanol solution of sodium methoxide (5.4 M, 125.22 μL, 0.68 mmol). The reaction mixture was stirred at 70°C for 2 hours, diluted with H ₂ O, and extracted with EA. The organic phase was washed with saturated brine (3 times), dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 159-2 (48 mg, 0.13 mmol, yield: 97.16%). MS (ESI): m/z=366[M+H] ⁺ .

Step 2: At 0°C, CDI (42.61 mg, 0.26 mmol) was added to a THF (5 mL) solution of compound 159-2 (48 mg, 0.13 mmol), and after stirring at room temperature for 0.5 hours, DBU (39.22 μL, 0.26 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 1.5 hours, and the pH was adjusted to 6 with hydrochloric acid (2 M) at 0°C, diluted with water, and extracted with EA. The organic phase was washed with saturated brine, dried, and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 159 (34 mg, 0.09 mmol, yield: 66.13%). MS (ESI): m/z = 392 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ: 13.03 (br s, 1H), 8.04 (s, 1H), 7.70 (d, J = 3.4Hz, 1H), 7.44 (s, 2H), 6.83 (d, J = 3.4Hz, 1H), 4.16 (s, 3H), 2.52-2.54 (m, 3H).

Embodiment 160

Step 1: At 0°C, 3,6-dichloropyrazine-2-carbonitrile (2000 mg, 11.50 mmol) was added to a DMF (30 mL) solution of compound 5-trifluoromethyl-1H-indole (2149.69 mg, 11.61 mmol) and sodium tert-butoxide (1115.77 mg, 11.61 mmol). After the reaction mixture was stirred at room temperature for 2 hours, it was quenched by adding water (40 mL) under ice bath conditions and extracted with EA (50 mL). The organic phase was washed with saturated sodium chloride solution (30 mL*3), dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 160-1 (1700 mg, 5.27 mmol, yield: 45.83%). MS (ESI): m/z=323[M+H] ⁺ .

Step 2: Compound 160-1 (460 mg, 2.11 mmol) and ammonium persulfate (1300 mg, 5.70 mmol) were added to a mixed solvent of acetonitrile (10 mL) and water (5 mL) to form a solution, and a solution of silver nitrate (2421 mg, 14.26 mmol) and acetic acid (815.29 μL, 14.26 mmol) in acetonitrile (4 mL) and water (2 mL) was added at 70°C. The reaction mixture was stirred at 70°C for 10 minutes, cooled to room temperature, quenched by adding water (20 mL), and extracted with EA (20 mL). The organic phase was washed with water (10 mL*2), dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 160-2 (91 mg, 0.27 mmol, yield: 18.96%). MS (ESI): m/z=337[M+H] ⁺ .

Step 3: To a solution of compound 160-2 (30 mg, 0.09 mmol) in methanol (4 mL) were added hydroxylamine hydrochloride (61.92 mg, 0.89 mmol), triethylamine (247.01 μL, 1.78 mmol) and Molecular sieves (60 mg). The reaction mixture was stirred at 80°C for 3 hours, cooled to room temperature and filtered, and the filtrate was concentrated. The concentrate was diluted with H ₂ O and extracted with EA. The organic phase was washed with saturated brine, dried and concentrated, and the residue was purified by silica gel column chromatography to obtain compound 160-3 (32 mg, 0.09 mmol, yield: 97.15%). MS (ESI): m/z=370[M+H] ⁺ .

Step 4: At 0°C, CDI (28.07 mg, 0.17 mmol) was added to a THF (4 mL) solution of compound 160-3 (32 mg, 0.09 mmol), and after stirring at room temperature for 1 hour, DBU (25.84 μL, 0.17 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 1.5 hours, cooled to 0°C, adjusted to pH 6 with hydrochloric acid (2 M), diluted with water, and extracted with EA. The organic phase was washed with saturated brine, dried, concentrated, and the resulting residue was purified by column chromatography to obtain compound 160 (25 mg, 0.06 mmol, yield: 72.99%). MS (ESI): m/z = 396 [M + H] ⁺ . ¹ HNMR (DMSO-d ₆ ) δ: 8.07 (s, 1H), 7.80 (d, J = 3.5 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.51 (d, J = 8.3 Hz, 1H), 6.88 (d, J = 3.4 Hz, 1H), 2.74 (s, 3H).

Embodiment 161

Step 1: A mixture of 3,5-dichloropyrazine-2-carbonitrile (10 g, 58 mmol) and a solution of NH ₃ in 1,4-dioxane (150 mL, 0.4 mol/L) was stirred at room temperature overnight and then concentrated. H ₂ O (100 mL) was added to the obtained concentrate, and extracted with EA (100 mL). The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated, and the obtained residue was purified by silica gel column chromatography (eluted with EA:PE=1:10) to obtain compound 161-1 (5.5 g, 35 mmol, yield: 61.5%). MS (ESI): m/z=155[M+H] ⁺ .

Step 2: Under ice bath conditions, NBS (6.8 g, 38 mmol) was added to a DMF (30 mL) solution of compound 161-1 (5.5 g, 35 mmol), stirred at room temperature overnight, and then H ₂ O (50 mL) was added, and extracted with EA (100 mL). The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with EA:PE=1:10) to obtain compound 161-2 (5.4 g, 23 mmol, yield: 65.9%). MS (ESI): m/z=234,235[M+H] ⁺ .

Step 3: Compound 161-2 (5.4 g, 23 mmol), trimethylcyclotriboroxane (5.7 g, 46 mmol), Pd(dppf)Cl ₂ (1.4 g, 2 mmol), potassium carbonate (6.3 g, 46 mmol), cesium fluoride (6.9 g, 46 mmol) were dispersed in a mixed solvent of 1,4-dioxane (50 mL) and H ₂ O (10 mL). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, stirred at 100° C. overnight and concentrated, H ₂ O (50 mL) was added to the obtained concentrate, and extracted with EA (100 mL). The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated, and the obtained residue was purified by silica gel column chromatography (eluted with EA:PE=1:4) to obtain compound 161-3 (2.3 g, 13 mmol, yield: 39.1%). MS (ESI): m/z=169[M+H] ⁺ .

Step 4: A mixture of compound 161-3 (2.3 g, 13 mmol), 5-trifluoromethylindole (2.8 g, 15 mmol) and cesium carbonate (8.4 g, 26 mmol) was stirred at 120°C for 3 hours, diluted with H ₂ O (200 mL), and extracted with EA (50 mL). The organic phase was washed with saturated brine (20 mL×3), dried over anhydrous Na ₂ SO ₄ and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with EA:PE=1:4) to obtain compound 161-4 (2.4 g, 7.5 mmol, yield: 58.2%). MS (ESI): m/z=318[M+H] ⁺ .

Step 5: A mixture of compound 161-4 (2.4 g, 7.5 mmol), cuprous iodide (118 g, 0.7 mmol), diiodomethane (1.2 mL, 15 mmol), tert-butyl nitrite (1.7 mL, 15 mmol) and THF (20 mL) was stirred at 60°C overnight and concentrated. H ₂ O (50 mL) was added to the concentrate and extracted with EA (30 mL). The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated, and the residue was purified by silica gel column chromatography (eluted with EA:PE=1:4) to obtain compound 161-5 (740 mg, 1.7 mmol, yield: 22.6%). MS (ESI): m/z=429[M+H] ⁺ .

Step 6: A mixture of compound 161-5 (740 mg, 1.7 mmol), methyl fluorosulfonyl difluoroacetate (489 mg, 2.5 mmol), cuprous iodide (19 mg, 0.1 mmol) and DMF (10 mL) was stirred at 100°C overnight, H ₂ O (20 mL) was added, and the mixture was extracted with EA (30 mL). The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated, and the resulting residue was purified by silica gel column chromatography (eluted with EA:PE=1:4) to obtain compound 161-6 (360 mg, 0.9 mmol, yield: 57.1%). MS (ESI): m/z=371[M+H] ⁺ .

Step 7: Compound 161-6 (360 mg, 0.9 mmol), hydroxylamine hydrochloride (672 mg, 9.0 mmol), triethylamine (15 mL), The mixture was purged with _N2 and maintained under _N2 atmosphere, stirred at 80°C for 3 hours, filtered under reduced pressure, and the filtrate was concentrated. ₂₀ mL of H2O was added to the concentrate, and extracted with EA (30 mL). The organic phase was washed with saturated brine (10 mL×3), dried over anhydrous _Na2SO4 , and concentrated. The residue was purified by silica gel column chromatography (eluted with EA:PE=1: ₂ ) to obtain compound 161-7 (240 mg, 0.59 mmol, yield: 66.1%). MS (ESI): m/z=404[M+H] ⁺ .

Step 8: Under ice bath conditions, CDI (115 mg, 0.71 mmol) was added to a THF (10 mL) solution of compound 161-7 (240 mg, 0.59 mmol), stirred at room temperature for 30 min, and then DBU (134 mg, 0.88 mmol) was added dropwise under ice bath conditions. The reaction mixture was stirred under ice bath conditions for 2 hours, and the pH was adjusted to 6 with hydrochloric acid (2M, 2 mL), and extracted with EA (20 mL). The organic phase was washed with saturated brine (10 mL×3), dried over anhydrous Na ₂ SO ₄ , and concentrated, and the resulting residue was purified by high performance liquid chromatography to obtain compound 161 (14 mg, 0.03 mmol, yield: 5.5%). MS (ESI): m/z＝430[M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ: 8.08 (s, 1H), 7.85 (d, J = 3.5 Hz, 1H), 7.73 (d, J = 8.6 Hz, 1H), 7.51-7.59 (m, 1H), 6.90 (d, J = 3.4 Hz, 1H), 2.86 (d, J = 1.6 Hz, 3H).

Embodiment 162

Step 1: Disperse compound 161-2 (1 g, 4.3 mmol), 5-trifluoromethyl-1-H-indole (1.6 g, 8.6 mmol), and cesium carbonate (4.1 g, 12.9 mmol) in DMF (30 mL). Stir the reaction mixture at 120°C for 3 hours, dilute with H ₂ O (50 mL), and extract with EA (30 mL). Wash the organic phase with saturated brine (20 mL×3), dry with anhydrous Na ₂ SO ₄ , and concentrate. Purify the residue by silica gel column chromatography (eluted with EA:PE=1:4) to obtain compound 162-1 (250 mg, 0.6 mmol, 15.2%). MS (ESI): m/z=382[M+H] ⁺ .

Step 2: Compound 162-1 (250 mg, 0.6 mmol), trimethylcyclotriboroxane (150 mg, 1.2 mmol), Pd(dppf)Cl ₂ (43 mg, 0.06 mmol), potassium carbonate (165 mg, 1.2 mmol), cesium fluoride (181 mg, 1.2 mmol) were dispersed in a mixed solvent of 1,4-dioxane (10 mL) and H ₂ O (2 mL). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, stirred at 100° C. overnight, concentrated, and H ₂ O (50 mL) was added to the obtained concentrate, and then extracted with EA (100 mL). The organic phase was dried over anhydrous Na ₂ SO ₄ , concentrated after drying, and the obtained residue was purified by silica gel column chromatography (EA:PE=1:4) to obtain compound 162-2 (50 mg, 0.15 mmol, yield: 13%). MS (ESI): m/z=318[M+H] ⁺ .

Step 3: Compound 162-2 (50 mg, 0.15 mmol), hydroxylamine hydrochloride (15 mg, 1.5 mmol), triethylamine (2 mL), The mixture of _1,4 - _dihydro -1,4-dihydro _{- 2} -thiazolinone ( ₂ ^...

Step 4: CDI (22 mg, 0.14 mmol) was added to a solution of compound 162-3 (45 mg, 0.12 mmol) in THF (10 mL) under ice bath conditions, stirred at room temperature for 30 min, and then DBU (27 mg, 0.18 mmol) was added dropwise under ice bath conditions. After the reaction mixture was stirred under ice bath conditions for 2 hours, HCl aqueous solution (1 mL) was added to adjust the pH to 2, and then extracted with EA (20 mL). The organic phase was washed with saturated brine (10 mL×3), dried over anhydrous Na ₂ SO _4, and concentrated, and the resulting residue was purified by preparative high performance liquid chromatography to obtain compound 162 (9 mg, 0.02 mmol, yield: 19.8%). MS (ESI): m/z＝377[M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ: 8.02 (s, 1H), 7.67 (d, J = 3.4 Hz, 1H), 7.50 (br d, J = 8.8 Hz, 2H), 7.39-7.53 (m, 2H), 6.79 (d, J = 3.3 Hz, 1H), 2.43 (s, 3H).

Embodiment 163

Step 1: Compound 133-1 (400 mg, 1.24 mmol) and ammonium persulfate (848 mg, 3.72 mmol) were dissolved in a mixed solvent of acetonitrile (10 mL) and water (5 mL) to form solution A, silver nitrate (2105 mg, 12.40 mmol) and propionic acid (1785.35 μL, 9.92 mmol) were dissolved in a mixed solvent of acetonitrile (4 mL) and water (2 mL) to form solution B, and solution B was added to solution A at 70°C. The reaction mixture was stirred at 70°C for 10 minutes, cooled to room temperature, quenched with water (20 mL), and extracted with EA (20 mL). The organic phase was washed with water (10 mL*2), dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 163-1 (287 mg, 0.73 mmol, yield: 58.75%). MS (ESI): m/z=351[M+H] ⁺ .

Step 2: Under nitrogen atmosphere, Pd(dppf)Cl 2 ·CH 2 Cl 2 (46.57 mg, 0.06 mmol) was added to a mixture of compound 163-1 (100 mg, 0.29 mmol), 2-trimethylcyclotriboroxane (244.39 μL, 0.86 mmol), potassium carbonate (78.81 mg, 0.57 mmol), cesium fluoride (86.62 mg, 0.57 mmol), 1,4-dioxane ( ₅ mL ₎ and _water (0.5 mL). The reaction mixture was stirred at 100° C. overnight, cooled to room temperature, dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 163-2 (78 mg, 0.24 mmol, yield: 82.82%). MS (ESI): m/z=331[M+H] ⁺ .

Step 3: To a solution of compound 163-2 (78 mg, 0.24 mmol) in methanol (4 mL) were added hydroxylamine hydrochloride (164.09 mg, 2.36 mmol), triethylamine (654.66 μL, 4.72 mmol) and Molecular sieves (60 mg). The reaction mixture was stirred at 80°C for 3 hours, cooled to room temperature and filtered, and the filtrate was concentrated. The concentrated solution was diluted with water and extracted with EA. The organic phase was washed with saturated brine, dried and concentrated, and the residue was purified by silica gel column chromatography to obtain compound 163-3 (82 mg, 0.23 mmol, yield: 95.57%). MS (ESI): m/z = 364 [M+H] ⁺ .

Step 4: CDI (73.19 mg, 0.45 mmol) was added to a THF (4 mL) solution of compound 163-3 (82 mg, 0.23 mmol) at 0°C, and after stirring at room temperature for 1 hour, DBU (67.37 μL, 0.45 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 1.5 hours, and then the pH was adjusted to 6 with hydrochloric acid (2 M) at 0°C, diluted with water, and extracted with EA. The organic phase was washed with saturated brine, dried, and concentrated, and the resulting residue was purified by column chromatography to obtain compound 163 (32 mg, 0.08 mmol, yield: 35.73%). MS (ESI): m/z=390[M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ: 13.06 (br s, 1H), 8.06 (s, 1H), 7.79 (d, J = 3.5Hz, 1H), 7.64 (d, J = 8.5Hz, 1H), 7.49 (d, J = 8.8Hz, 1H), 6.85 (d, J = 3.4Hz, 1H), 2.99 (q, J = 7 .4Hz,2H),2.70(s,3H),1.28(t,J=7.4Hz,3H).

Embodiment 165

Step 1: Sodium hydroxide (2.05 g, 51.20 mmol) aqueous solution (3 mL) was added to a solution of 2-aminomalonamide (5 g, 42.69 mmol) and hexane-3,4-dione (4.87 g, 42.67 mmol) in water (7 mL). The reaction mixture was stirred at room temperature overnight (12 hours) and then filtered. The resulting filter cake was dried to give compound 165-1 (6.29 g, yield: 75.52%). MS (ESI): m/z = 196 [M+H] ⁺ .

Step 2: Add phosphorus oxychloride (18.85 g, 122.94 mmol) to a solution of compound 165-1 (6 g, 30.73 mmol) in chlorobenzene (40 mL), stir at 60°C for 20 minutes, and dropwise add DIPEA (11.92 g, 92.20 mmol). The reaction mixture was heated to 90°C, stirred overnight (12 h), quenched with ice water, and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to obtain compound 165-2 (6 g, yield: 99.78%). MS (ESI): m/z = 196 [M+H] ⁺ .

Step 3: Under ice bath conditions, NaH (53.16 mg, 1.33 mmol) was added to a DMF (3 mL) solution of compound 165-2 (200 mg, 1.02 mmol) and 5-(trifluoromethyl)-1H-indole (189.27 mg, 1.02 mmol). After the reaction mixture was stirred at room temperature for 1.5 hours, a saturated aqueous solution of ammonium chloride was added to quench the reaction and extracted with dichloromethane. The combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography to obtain compound 165-3 (65 mg, yield: 18.47%). MS (ESI): m/z=345[M+H] ⁺ .

Step 4: Compound 165-3 (65 mg, 0.19 mmol), hydroxylamine hydrochloride (131.17 mg, 1.89 mmol), Molecular sieves (65 mg) were dispersed in methanol (4 mL), followed by the addition of triethylamine (1.15 g, 11.33 mmol). The reaction mixture was heated to 75 °C and stirred overnight (12 h), then quenched with saturated aqueous ammonium chloride solution and extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography to obtain compound 165-4 (34 mg, yield: 47.73%). MS (ESI): m/z = 378 [M+H] ⁺ .

Step 5: Under ice bath conditions, CDI (18.26 mg, 0.11 mmol) was added to a tetrahydrofuran (1 mL) solution of compound 165-4 (34 mg, 0.09 mmol), and DBU (20.57 mg, 0.14 mmol) was added after stirring for 30 minutes under ice bath conditions. The reaction mixture was slowly warmed to room temperature and continued to stir at room temperature for 30 minutes, water was added, and extracted with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography to obtain compound 165 (10 mg, yield: 27.52%). MS (ESI): m/z=404[M+H] ⁺ . ¹ H NMR (CHLOROFORM-d) δ: 7.98 (s, 1H), 7.49 (t, J = 3.9 Hz, 3H), 6.84 (d, J = 3.4 Hz, 1H), 3.03 (qd, J = 7.4, 3.1 Hz, 4H), 1.41 (dt, J = 17.7, 7.5 Hz, 6H).

Embodiment 167

Step 1: To a solution of compound 163-1 (80 mg, 0.23 mmol) in methanol (6 mL) were added hydroxylamine hydrochloride (158.50 mg, 2.28 mmol), triethylamine (632.36 μL, 4.56 mmol) and Molecular sieves (100 mg). The reaction mixture was stirred at 80°C for 4 hours, cooled to room temperature and filtered, and the filtrate was concentrated. H ₂ O was added to the concentrated solution and extracted with EA. The organic phase was washed with saturated brine, dried and concentrated, and the residue was purified by silica gel column chromatography to obtain compound 167-1 (85 mg, 0.22 mmol, yield: 97.11%). MS (ESI): m/z=384[M+H]+.

Step 2: CDI (84.51 mg, 0.52 mmol) was added to a solution of compound 167-1 (85 mg, 0.22 mmol, 97.11%) in THF (5 mL) at 0°C. After stirring at room temperature for 0.5 hours, DBU (77.79 μL, 0.52 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 1.5 hours, cooled to 0°C, adjusted to pH 6 with hydrochloric acid (2 M), diluted with water, and extracted with EA. The organic phase was washed with saturated brine, dried, concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 167 (56 mg, 0.13 mmol, yield: 62.68%). MS (ESI): m/z = 410 [M+H] +. ¹ H NMR (DMSO-d ₆ ) δ = 8.07 (s, 1H), 7.81 (d, J = 3.4Hz, 1H), 7.76 (d, J = 8.6Hz, 1H), 7.53 (d, J = 8.8Hz, 1H), 6.88 (d, J = 3.4Hz, 1H), 3.07 (q, J = 7.4Hz, 2H), 1.31 (t, J=7.4Hz,3H).

Embodiment 168

Step 1: At 0°C, N-bromosuccinimide (NBS) (2.98 g, 16.77 mmol) was added to a solution of 3-cyano-6-methyl-pyridone (1.5 g, 11.18 mmol) in N,N-dimethylformamide (30 mL). The reaction mixture was purged with N2 and maintained in an N2 atmosphere, slowly heated to 30°C and stirred for 18 hours, diluted with water, and extracted with ethyl acetate (100 mL×3). The combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain compound 168-1 (2.24 g, yield: 94.03%). MS (ESI): m/z = 213, 215 [M+H] ⁺ .

Step 2: At room temperature, compound 168-1 (2.24 g, 10.51 mmol) was dissolved in phosphorus oxychloride (20 mL). The reaction mixture was slowly heated to 80°C and stirred for 3 hours, then ice water (50 mL) was slowly added dropwise to quench the reaction, and extracted with ethyl acetate (100 mL×3). The combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (eluted with petroleum ether: ethyl acetate = 1:3) to obtain compound 168-2 (1.0496 g, yield: 48.12%). MS (ESI): m/z = 231, 233 [M+H] ⁺ .

Step 3: At room temperature, compound 168-2 (1 g, 4.32 mmol), 5-(trifluoromethyl)-1H-indole (0.80 g, 4.32 mmol) and cesium carbonate (2.82 g, 8.64 mmol) were dispersed in N,N-dimethylformamide (15 mL). The reaction mixture was slowly heated to 100 ° C and stirred for 1 hour, diluted with water, and extracted with ethyl acetate (100 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by preparative silica gel plate (eluted with ethyl acetate: petroleum ether = 1:5) to obtain compound 168-3 (358 mg, yield: 21.8%).

Step 4: At room temperature, (methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-methylamino-1,1'-biphenyl-2-yl) palladium (II) (55.29 mg, 0.07 mmol), sodium tert-butoxide (92.01 mg, 0.96 mmol) and methanol (0.14 mL, 3.42 mmol) were added sequentially to a solution of compound 168-3 (260 mg, 0.68 mmol) in 1,4-dioxane (5 mL). The reaction mixture was purged with _N2 and maintained at N ₂ atmosphere, slowly heated to 50°C and stirred for 16 hours, diluted with water (5 mL), and extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether=1:5) to obtain compound 168-4 (55 mg, yield: 25.27%). MS (ESI): m/z=332[M+H] ⁺ .

Step 5: At room temperature, hydroxylamine hydrochloride (83.90 mg, 1.21 mmol), Molecular sieves (40 mg, 0.33 mmol), and triethylamine (1.00 mL, 7.24 mmol) were added to a methanol (2 mL) solution of compound 168-4 (40 mg, 0.12 mmol) in sequence. The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 75 ° C and stirred for 3 hours, quenched with saturated ammonium chloride and filtered. The filtrate was extracted with ethyl acetate (50 mL × 2), dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (eluted with ethyl acetate) to obtain compound 168-5 (21 mg, yield: 47.74%). MS (ESI): m/z = 365 [M + H] ⁺ .

Step 6: Under ice bath conditions, N,N'-carbonyldiimidazole (11.68 mg, 0.07 mmol) was added to a tetrahydrofuran (3 mL) solution of compound 168-5 (21 mg, 0.06 mmol), slowly heated to room temperature and stirred for 30 minutes, and then DBU (12.90 μL, 0.09 mmol) was added under ice bath conditions. The reaction mixture was slowly heated to 30°C and stirred for 1 hour, diluted with water, and extracted with ethyl acetate (20 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by high performance liquid chromatography (HPLC) to obtain compound 168 (3 mg, yield: 13.33%). MS (ESI): m/z=391[M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ: 8.04 (s, 1H), 7.88 (s, 1H), 7.59 (d, J = 3.4 Hz, 1H), 7.46 (s, 2H), 6.82 (d, J = 3.3 Hz, 1H), 3.99 (s, 3H), 2.49-2.49 (m, 3H).

Embodiment 174

Step 1: At room temperature, potassium ethylene trifluoroborate (0.45 g, 3.39 mmol), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.25 mg, 0.34 mmol) and potassium carbonate (0.47 mg, 3.39 mmol) were added to a solution of compound 176-3 (1.45 g, 3.39 mmol) in 1,4-dioxane (25 mL) and water (5 mL). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 80 ° C and stirred for 16 hours, diluted with water (5 mL), and extracted with ethyl acetate (100 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (eluted with ethyl acetate: petroleum ether = 1:3) to obtain compound 174-2 (712 mg, yield: 63.65%). MS (ESI): m/z=329[M+H] ⁺ .

Step 2: At room temperature, a solution of compound 174-2 (580 mg, 0.12 mmol) in methanol (25 mL) was purged with N ₂ and maintained under N ₂ atmosphere, and Pd/C 10% (60 mg, 0.56 mmol) was added. The reaction mixture was purged with H ₂ and maintained under H ₂ atmosphere, stirred at 30° C. for 16 hours and then filtered. The filtrate was concentrated to obtain a crude product of compound 174-3 (560.9 mg, yield: 96.12%). MS (ESI): m/z=331[M+H] ⁺ .

Step 3: At room temperature, cuprous iodide (422.06 mg, 2.22 mmol), diiodomethane (0.74 mL, 9.23 mmol) and tert-butyl nitrite (0.80 mL, 6.65 mmol) were added to a solution of the crude product of compound 174-3 (610 mg, 1.85 mmol) in tetrahydrofuran (10 mL) in sequence. The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 68 ° C and stirred for 1 hour, quenched with a saturated sodium bicarbonate solution, diluted with water (5 mL), and extracted with ethyl acetate (50 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (eluted with ethyl acetate: petroleum ether = 1:3) to obtain compound 174-4 (737 mg, yield: 90.45%).

Step 4: Trimethylcyclotriboroxane (0.29 mL, 1.02 mmol), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (49.75 mg, 0.07 mmol), potassium carbonate (187.94 mg, 1.36 mmol) and cesium fluoride (206.57 mg, 1.36 mmol) were added to a solution of compound 174-4 (300 mg, 0.68 mmol) in 1,4-dioxane (7.5 mL) and water (1.5 mL) at room temperature. The reaction mixture was purged with _N2 and maintained under _N2 atmosphere, slowly heated to 80°C and stirred for 16 hours, diluted with water (3 mL), and extracted with ethyl acetate (100 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:5) to obtain compound 174-5 (187 mg, yield: 83.91%). MS (ESI): m/z=330 [M+H] ⁺ .

Step 5: At room temperature, hydroxylamine hydrochloride (394.58 mg, 5.68 mmol), Molecular sieves (190 mg, 0.33 mmol) and triethylamine (4.72 mL, 34.07 mmol) were added to a methanol (5 mL) solution of compound 174-5 (187 mg, 0.57 mmol). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 75 ° C and stirred for 3 hours, then saturated ammonium chloride was added to quench the reaction, filtered, and the filtrate was extracted with ethyl acetate (50 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (eluent gradient from ethyl acetate: petroleum ether = 1:3 to ethyl acetate) to obtain compound 174-6 (100 mg, yield: 69.38%). MS (ESI): m/z = 363 [M + H] ⁺ .

Step 6: Under ice bath conditions, CDI (77.75 mg, 0.48 mmol) was added to a tetrahydrofuran (3 mL) solution of compound 174-6 (139 mg, 0.38 mmol), slowly heated to 30 ° C and stirred for 30 minutes, and then DBU (85.88 μL, 0.58 mmol) was added under ice bath conditions. The reaction mixture was slowly heated to 30 ° C and stirred for 1 hour, diluted with water (2 mL), and then extracted with ethyl acetate (50 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by preparative high performance liquid chromatography (HPLC) to obtain compound 174 (45 mg, yield: 28.86%). MS (ESI): m/z＝389[M+H] ⁺ . ¹ H NMR(DMSO-d ₆ )δ:12.65-12.93(m,1H),8.08(s,1H),8.05(s,1H),7.57-7.64(m,2H),7.48(d,J＝8.9Hz,1H),6.83(d,J＝3.4Hz,1H),2.78(q,J＝7.6Hz,2H ), 2.60 (s, 3H), 1.28 (t, J = 7.5Hz, 3H).

Embodiment 175

Step 1: At room temperature, trimethylcyclotriboroxane (1.80 mL, 6.31 mmol), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.31 g, 0.42 mmol), potassium carbonate (1.16 g, 8.41 mmol) and cesium fluoride (1.28 g, 8.41 mmol) were added to a solution of compound 176-3 (1.8 g, 4.20 mmol) in 1,4-dioxane (30 mL) and water (6 mL). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 80 ° C and stirred for 16 hours, then diluted with water (3 mL) and extracted with ethyl acetate (100 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:5) to obtain compound 175-1 (590 mg, yield: 44.37%). MS (ESI): m/z = 315 [MH] ^- .

Step 2: At room temperature, cuprous iodide (216.77 mg, 1.14 mmol), diiodomethane (382.60 μL, 4.74 mmol) and tert-butyl nitrite (409.43 μL, 3.41 mmol) were added to a tetrahydrofuran (8 mL) solution of compound 175-1 (300 mg, 0.95 mmol). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 68 ° C and stirred for 1 hour, quenched with a saturated sodium bicarbonate solution, diluted with water (3 mL), and extracted with ethyl acetate (50 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (eluted with ethyl acetate: petroleum ether = 1:5) to obtain compound 175-2 (355 mg, yield: 87.62%). MS (ESI): m/z = 428 [M+H] ⁺ .

Step 3: At room temperature, potassium trifluoroborate (31.29 mg, 0.23 mmol), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (30.40 mg, 0.04 mmol) and potassium carbonate (114.85 mg, 0.83 mmol) were added to a solution of compound 175-2 (355 mg, 0.83 mmol) in 1,4-dioxane (10 mL) and water (2 mL) in sequence. The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 80 ° C and stirred for 16 hours, diluted with water (5 mL), and extracted with ethyl acetate (100 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:3) to obtain compound 175-3 (136 mg, yield: 50.00%). MS (ESI): m/z=328[M+H] ⁺ .

Step 4: At room temperature, a solution of compound 175-3 (136 mg, 0.42 mmol) in methanol (10 mL) was purged with N ₂ and maintained under N ₂ atmosphere, and 10% palladium on carbon (15 mg, 0.14 mmol) was added. The reaction mixture was purged with H ₂ and maintained under H ₂ atmosphere, stirred at 30° C. for 16 hours, and then filtered. The filtrate was concentrated to obtain a crude product of compound 175-4 (131 mg). MS (ESI): m/z=330[M+H] ⁺ .

Step 5: At room temperature, hydroxylamine hydrochloride (276.42 mg, 3.98 mmol), Molecular sieves (155 mg, 0.33 mmol) and triethylamine (3.31 mL, 23.87 mmol) were added to a methanol (5 mL) solution of compound 175-4 (131 mg, 0.40 mmol) in sequence. The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 75 ° C and stirred for 3 hours, the reaction was quenched with saturated ammonium chloride and filtered, and the filtrate was extracted with ethyl acetate (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (eluent gradient from ethyl acetate: petroleum ether = 1:1 to ethyl acetate) to obtain compound 175-5 (100 mg, yield: 69.38%). MS (ESI): m/z = 363 [M + H] ⁺ .

Step 6: Under ice bath conditions, CDI (55.94 mg, 0.34 mmol) was added to a tetrahydrofuran (5 mL) solution of compound 175-5 (100 mg, 0.28 mmol), and the temperature was slowly raised to 30°C and stirred for 30 minutes. DBU (61.78 μL, 0.41 mmol) (1 mL) was added under ice bath conditions. The reaction mixture was slowly heated to 30°C and stirred for 1 hour, diluted with water (2 mL), and extracted with ethyl acetate (50 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by preparative high performance liquid chromatography (HPLC) to obtain compound 175 (22 mg, yield: 20.26%). MS (ESI): m/z=389[M+H] ⁺ .

¹ H NMR (DMSO-d6) δ: 12.69 (br s, 1H), 8.08-8.10 (m, 1H), 8.06 (s, 1H), 7.70 (d, J = 8.8Hz, 1H), 7.58 (d, J＝3.4Hz,1H),7.49-7.53(m,1H),6.85(d,J＝3.3Hz,1H),2.90(q,J＝7.5Hz,2H),2.44(s,3H),1.27( t,J=7.5Hz,3H).

Embodiment 176

Step 1: At room temperature, 6-chloro-5-iodopyridin-2-amine (10 g, 39.30 mmol), Pd(PPh ₃ ) ₄ (2.27 g, 1.96 mmol) and zinc dicyanide (4.61 g, 39.30 mmol) were dispersed in DMF (100 mL). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 80°C and stirred for 16 hours and filtered. The filtrate was diluted with water (300 mL) and extracted with ethyl acetate (800 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (eluted with ethyl acetate: petroleum ether=1:5) to obtain compound 176-1 (7 g, yield: 115.99%). MS (ESI): m/z=154[M+H] ⁺ .

Step 2: At 0°C, (N-iodosuccinimide) (5.49 g, 24.42 mmol) and trifluoroacetic acid (1.21 mL, 16.28 mmol) were added to a solution of compound 176-1 (2.5 g, 16.28 mmol) in acetonitrile (40 mL). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly warmed to room temperature and stirred for 16 hours, quenched with a saturated sodium bicarbonate solution, diluted with water, and extracted with ethyl acetate (250 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (eluted with ethyl acetate: petroleum ether = 1:3) to obtain compound 176-2 (4.3 g, yield: 94.51%). MS (ESI): m/z = 280 [M+H] ⁺ .

Step 3: At room temperature, compound 176-2 (1.5 g, 5.37 mmol), 5-(trifluoromethyl)-1H-indole (0.99 g, 5.37 mmol) and cesium carbonate (3.50 g, 10.73 mmol) were dispersed in a DMF (30 mL) solution. The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 120°C and stirred for 1 hour, diluted with water (50 mL), and extracted with ethyl acetate (300 mL×3). The combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:5) to obtain compound 176-3 (1.95 g, yield: 84.85%). MS (ESI): m/z = 429 [M+H] ⁺ .

Step 4: Ethylboronic acid (245.92 mg, 3.33 mmol), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (81.18 mg, 0.11 mmol), potassium carbonate (306.80 mg, 2.22 mmol) and cesium fluoride (674.07 mg, 4.44 mmol) were added to a solution of compound 176-3 (950 mg, 2.22 mmol) in 1,4-dioxane (15 mL) and water (3 mL) at room temperature. The reaction mixture was purged with _N2 and maintained under _N2 atmosphere, slowly heated to 80°C and stirred for 16 hours, diluted with water (5 mL), and extracted with ethyl acetate (100 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (eluted with ethyl acetate:petroleum ether=1:3) to obtain compound 176-4 (109 mg, yield: 14.87%). MS (ESI): m/z=331 [M+H] ⁺ .

Step 5: At room temperature, hydroxylamine hydrochloride (229.31 mg, 3.30 mmol), Molecular sieves (110 mg, 0.33 mmol) and triethylamine (2.74 mL, 19.80 mmol) were added to a methanol (5 mL) solution of compound 176-4 (109 mg, 0.33 mmol). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 80 ° C and stirred for 3 hours, and the reaction solution was quenched with saturated ammonium chloride and filtered. The filtrate was extracted with ethyl acetate (50 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (eluent gradient from ethyl acetate: petroleum ether = 1:1 to ethyl acetate) to obtain compound 176-5 (47 mg, yield: 39.20%). MS (ESI): m/z = 364 [M + H] ⁺ .

Step 6: Under ice bath conditions, CDI (26.22 mg, 0.16 mmol) was added to a tetrahydrofuran (1 mL) solution of compound 176-5 (47 mg, 0.13 mmol), and the temperature was slowly raised to 30°C and stirred for 30 minutes, and then DBU (28.96 μL, 0.19 mmol) was added under ice bath conditions. The reaction mixture was slowly heated to room temperature and stirred for 1 hour, then diluted with water (2 mL), and then extracted with ethyl acetate (20 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by preparative high performance liquid chromatography (HPLC) to obtain compound 176 (7.6 mg, yield: 14.95%). MS (ESI): m/z=390[M+H] ⁺ . ¹ H NMR(DMSO-d ₆ )δ:8.02(s,1H),7.68(s,1H),7.53-7.59(m,2H),7.44(dd,J＝8.8,1.6Hz,1H),6.89(s,2H),6.78(d,J＝3.4Hz,1H),2.52-2.57(m,2H),1 .23(t,J=7.4Hz,3H).

Embodiment 187

Step 1: Add iodomethane (20 μL, 0.32 mmol) and potassium carbonate (79.59 mg, 0.58 mmol) to a DMF (4 mL) solution of compound 2 (100 mg, 0.29 mmol) at room temperature, and stir the reaction mixture at room temperature for 2 hours. Add water (5 mL) to dilute, and extract with EA (5 mL x 3). Wash the organic phase with saturated brine, dry and concentrate, and the resulting residue is purified by column chromatography and pre-HPLC to obtain compound 187 (94 mg, 0.26 mmol, yield 89.72%). MS (ESI): m/z = 362.1 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 9.02 (s, 2H), 8.10-8.04 (m, 1H), 7.86 (br d, J = 8.5Hz, 1H), 7.78 (br d, J = 3.0Hz, 1H), 7.55 (br d, J = 8.6Hz, 1H), 6.90 (br d, J = 2.9Hz, 1H),3.32(br s,3H).

Embodiment 209

Step 1: At room temperature, ethylboronic acid (75.36 mg, 1.02 mmol), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (49.75 mg, 0.07 mmol), potassium carbonate (187.94 mg, 1.36 mmol) and cesium fluoride (206.57 mg, 1.36 mmol) were added to a solution of compound 209-1 (300 mg, 0.68 mmol) in 1,4-dioxane (7.5 mL) and water (1.5 mL). The reaction mixture was slowly heated to 80°C and stirred for 16 hours, diluted with water (5 mL), and extracted with ethyl acetate (100 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (washed with ethyl acetate: petroleum ether = 1:5) to obtain compound 209-2 (193 mg, yield: 82.67%). MS (ESI): m/z=344[M+H] ⁺ .

Step 2: Hydroxylamine hydrochloride (390.61 mg, 5.62 mmol), Molecular sieves (190 mg, 0.33 mmol) and triethylamine (4.68 mL, 33.73 mmol) were added to a methanol (5 mL) solution of compound 209-2 (193 mg, 0.56 mmol). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 75 ° C and stirred for 3 hours, and the reaction solution was quenched with saturated ammonium chloride and filtered. The filtrate obtained by filtration was extracted with ethyl acetate (50 mL × 2), dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (eluent gradient from ethyl acetate: petroleum ether = 1:1 to ethyl acetate) to obtain compound 209-3 (135 mg, yield: 63.81%). MS (ESI): m/z = 377 [M + H] ⁺ .

Step 3: Under ice bath conditions, CDI (72.70 mg, 0.45 mmol) was added to a tetrahydrofuran (5 mL) solution of compound 209-3 (135 mg, 0.36 mmol), and the temperature was slowly raised to 30°C and stirred for 30 min. DBU (80.30 μL, 0.54 mmol) was added under ice bath conditions. The reaction mixture was slowly raised to room temperature and stirred for 1 hour, diluted with water (2 mL), and extracted with ethyl acetate (50 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by preparative high performance liquid chromatography (HPLC) to obtain compound 209 (2 mg, yield: 1.38%). MS (ESI): m/z=403[M+H] ⁺ . ¹ H NMR(DMSO-d ₆ )δ:8.03(s,2H),7.67(br d,J＝8.5Hz,1H),7.56(br s,1H),7.47(br d,J＝8.1Hz,1H),6.79(s,1H),2.90(d,J＝7.5Hz,2H),2.75-2.83(m,2H) ,1.28(br t,J=7.4Hz,6H).

Embodiment 210

Step 1: At 0°C, NIS (3.35 g, 14.91 mmol) was added to a DMF (22 mL) solution of 6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (2.0 g, 14.91 mmol). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to room temperature and stirred overnight, diluted with water (5 mL), and extracted with ethyl acetate (100 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (eluted with ethyl acetate: petroleum ether=1:1) to obtain compound 210-1 (3.14 g, yield: 80.99%). MS (ESI): m/z=261[M+H] ⁺ .

Step 2: At room temperature, compound 210-1 (2.14 g, 8.23 mmol) was dissolved in phosphorus oxychloride (15 mL). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 80°C and stirred for 5 hours, then slowly quenched with ice water and extracted with ethyl acetate (100 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (eluted with ethyl acetate: petroleum ether=1:1) to obtain compound 210-2 (1.4685 g, yield: 64.08%). MS (ESI): m/z=279[M+H] ⁺ .

Step 3: At room temperature, cuprous iodide (410.33 mg, 2.15 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.46 mL, 3.59 mmol) were added to a DMF (6 mL) solution of compound 210-2 (500 mg, 1.80 mmol). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 100 ° C. and stirred for 3 hours, diluted with water, and extracted with ethyl acetate (100 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (eluted with petroleum ether) to obtain compound 210-3 (300 mg, yield: 75.75%). ¹ H NMR (DMSO-d6) δ: 8.88 (s, 1H), 2.70 (d, J＝1.5 Hz, 3H). ¹⁹ F NMR (DMSO-d6) δ: -60.93 (s, 3F).

Step 4: Disperse compound 210-3 (140 mg, 0.63 mmol), 5-trifluoromethylindole (117.51 mg, 0.63 mmol) and potassium carbonate (104.48 mg, 0.76 mmol) in DMF (3 mL) at room temperature. Purge the reaction mixture with N ₂ and maintain the N ₂ atmosphere, stir at room temperature for 1 hour, dilute with water, and extract with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (eluted with ethyl acetate: petroleum ether = 1:5) to obtain compound 210-4 (30 mg, yield: 12.80%). ¹ H NMR (DMSO-d ₆ ) δ: 9.01 (s, 1H), 8.13 (s, 1H), 8.11-8.18 (m, 2H), 7.62 (d, J = 8.9 Hz, 1H), 7.04 (d, J = 3.5 Hz, 1H), 2.79 (s, 3H).

Step 5: At room temperature, hydroxylamine hydrochloride (56.45 mg, 0.81 mmol), Molecular sieves (40 mg, mmol), and triethylamine (0.68 mL, 4.87 mmol) were added to a methanol (3 mL) solution of compound 210-4 (30 mg, 0.08 mmol). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, slowly heated to 75°C and stirred for 3 hours, then saturated aqueous ammonium chloride solution was added to quench the reaction and filtered. The filtrate was extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (eluted with ethyl acetate) to obtain compound 210-5 (15.7 mg, yield: 48.04%). MS (ESI): m/z=403[M+H] ⁺ .

Step 6: Under ice bath conditions, CDI (7.56 mg, 0.05 mmol) was added to a tetrahydrofuran (1 mL) solution of compound 210-5 (15 mg, 0.04 mmol), and the temperature was slowly raised to room temperature and stirred for 30 minutes. DBU (8.35 μL, 0.06 mmol) was added under ice bath conditions. The reaction mixture was slowly raised to room temperature and stirred for 1 hour, diluted with water, and extracted with ethyl acetate (50 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (eluted with ethyl acetate) to obtain compound 210 (6 mg, yield: 37.57%). MS (ESI): m/z=429[M+H] ⁺ . ¹ HNMR(DMSO-d ₆ )δ:8.62(s,1H),8.08(s,1H),7.91(d,J＝8.6Hz,1H),7.66(d,J＝3.5Hz,1H),7.55(dd,J＝8.8,1.4Hz,1H),6.91(d,J＝3.4Hz,1H),2.78(d,J＝1 .0Hz,3H).

Embodiment 211

Step 1: To a solution of compound 3-bromo-2-chloro-5-methylpyridine (1000 mg, 4.84 mmol) in DMA (10 mL) were added Na ₂ CO ₃ (513.34 mg, 4.84 mmol), potassium ferrocyanide (II) trihydrate (0.24 mL, 1.07 mmol) and Pd(OAc) ₂ (54.37 mg, 0.24 mmol). The reaction mixture was stirred at 120° C. overnight, diluted with H ₂ O, and extracted with EA. The organic layer was washed with saturated brine (3 times), dried and concentrated, and the resulting residue was purified by column chromatography to obtain compound 211-1 (265 mg, 1.74 mmol, 35.86%). MS (ESI): m/z=153[M+H] ⁺ .

Step 2: At room temperature, silver nitrate (184.27 μL, 4.72 mmol) and trifluoroacetic acid (150 μL, 2.01 mmol) were added to a solution of compound 211-1 (240 mg, 1.57 mmol) and (benzyloxy)carbonyl)glycine (510.17 μL, 3.15 mmol) in water (5 mL). After slowly heating to 70°C, a solution of ammonium persulfate (725.11 μL, 6.29 mmol) in water (2 mL) was added. The reaction mixture was stirred at 70°C for 30 minutes, cooled to room temperature, quenched with water (20 mL), and extracted with EA (20 mL). The organic phase was washed with water (10 mL*2), dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 211-2 (145 mg, 0.46 mmol, 29.19%). MS (ESI): m/z=316[M+H] ⁺ .

Step 3: To a solution of compound 211-2 (90 mg, 0.29 mmol) in toluene (5 mL) were added 5-trifluoromethylindole (63.33 mg, 0.34 mmol), sodium tert-butoxide (32.87 mg, 0.34 mmol), XPhos Pd G2 (49.34 mg, 0.06 mmol) and Molecular sieves (25 mg). The reaction mixture was stirred at 90°C overnight, cooled to room temperature, diluted with H ₂ O and extracted with EA. The organic layer was washed with saturated brine (3 times), dried and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 211-3 (76 mg, 0.16 mmol, 57.41%). MS (ESI): m/z=465[M+H] ⁺ .

Step 4: To a solution of compound 211-3 (70 mg, 0.16 mmol) in methanol (6 mL) were added hydroxylamine hydrochloride (104.73 mg, 1.51 mmol), triethylamine (417.83 μL, 3.01 mmol) and Molecular sieves (150 mg). The reaction mixture was stirred at 80°C for 4 hours, cooled to room temperature and filtered, and the filtrate was concentrated. The concentrate was diluted with H ₂ O and extracted with EA. The organic phase was washed with saturated brine, dried and concentrated, and the residue was purified by silica gel column chromatography to obtain compound 211-4 (70 mg, 0.14 mmol, 93.36%). MS (ESI): m/z=498[M+H] ⁺ .

Step 5: At 0°C, CDI (45.63 mg, 0.28 mmol) was added to a THF (4 mL) solution of compound 211-4 (70 mg, 0.14 mmol), stirred at room temperature for 0.5 hours, cooled to 0°C, and DBU (42.00 μL, 0.28 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 hours, cooled to 0°C, adjusted to pH 6 with hydrochloric acid (2 M), diluted with water and extracted with EA. The organic phase was washed with saturated brine, dried and concentrated to obtain a crude product (72 mg) of compound 211-5 (MS (ESI): m/z=524[M+H] ⁺ ).

Step 6: At room temperature, 10% Pd/C (22 mg, 0.21 mmol) was added to a solution of compound 211-5 (50 mg, 0.10 mmol) in methanol (4 mL). The reaction mixture was stirred at room temperature for 2 hours and then filtered. The filtrate was concentrated and the residue was purified by preparative high performance liquid chromatography (HPLC) to obtain compound 211 (1.33 mg, 3.58%). MS (ESI): m/z = 390 [M+H] ⁺ .

Embodiment 214

Step 1: Add 5-trifluoromethylindole (331.71 mg, 1.79 mmol) and sodium tert-butoxide (172.17 mg, 1.79 mmol) to a DMF (8 mL) solution of compound 214-12-chloro-3-cyanopyrazine (250 mg, 1.79 mmol). The reaction mixture was stirred at 120°C for 3 hours. After cooling to room temperature, saturated ammonium chloride solution (10 mL) was added to quench, and extracted with EA (8 mL x 3). The organic phase was washed with saturated brine, dried and concentrated, and the resulting residue was purified by column chromatography to obtain compound 214-2 (429 mg, 1.49 mmol, yield 83.15%). MS (ESI): m/z=289.3[M+H] ⁺ .

Step 2: To a solution of compound 214-2 (200 mg, 0.69 mmol) in methanol (5 mL) were added N-methylhydroxylamine hydrochloride (579.54 mg, 6.94 mmol), triethylamine (5.77 mL, 41.63 mmol) and Molecular sieves (200 mg). The reaction mixture was stirred at 80 ° C for 2 hours under a nitrogen atmosphere. After cooling to room temperature, it was filtered and the filtrate was concentrated. The concentrate was diluted with water (5 mL) and extracted with EA (5 mL x 3). The organic phase was washed with saturated brine, dried and concentrated, and the residue was purified by column chromatography to obtain compound 214-3 (65.3 mg, 0.19 mmol, yield 28.07%). MS (ESI): m/z=336.0[M+H] ⁺ .

Step 3: CDI (39.47 mg, 0.24 mmol) was added to a solution of compound 214-3 (65.3 mg, 0.19 mmol) in THF (3 mL) at 0°C and stirred at 0°C for 1 hour. DBU (0.04 mL, 0.29 mmol) was then added at 0°C and the reaction mixture was stirred at room temperature for 1.5 hours. Saturated ammonium chloride solution (5 mL) was added to quench and extracted with EA (5 mL x 3). The organic phase was washed with saturated brine, dried and concentrated, and the resulting residue was purified by column chromatography and pre-HPLC to obtain trifluoroacetate salt of compound 214 (28 mg, 0.08 mmol, yield 39.77%). ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 10.50 (br s, 1H), 8.79 (br d, J = 4.5Hz, 2H), 8.22-7.90 (m, 2H), 7.74-7.48 (m, 2H), 6.95 (br s, 1H), 3.17 (br s, 3H).

Embodiment 215

Step 1: Potassium carbonate (36.82 mg, 0.27 mmol) and iodomethane (10.78 μL, 0.17 mmol) were added to a DMF (2 mL) solution of compound 136 (50 mg, 0.13 mmol). The reaction mixture was stirred at 25°C for 1.5 hours, cooled to 0°C and water was added, solid precipitated, warmed to room temperature and filtered, the filter cake was washed with water and dried, dissolved in dichloromethane and the filtrate was concentrated to obtain compound 215 (47 mg, 0.12 mmol, yield: 90.61%). MS (ESI): m/z = 390.0 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ: 8.07 (s, 1H), 7.81-7.67 (m, 2H), 7.52 (d, J = 8.8Hz, 1H), 6.87 (d, J = 3.4Hz, 1H), 3.28 (s, 3H), 2.69 (s, 6H).

Embodiment 216

Step 1: Potassium carbonate (28.40 mg, 0.21 mmol) and iodomethane (8.31 μL, 0.13 mmol) were added to a DMF (2 mL) solution of compound 163 (40 mg, 0.10 mmol). The reaction mixture was stirred at 25°C for 1.5 hours, cooled to 0°C and water was added, solid precipitated, warmed to room temperature and filtered, the filter cake was washed with water and dried, dissolved in dichloromethane and the filtrate was concentrated to give compound 216 (35 mg, 0.09 mmol, yield: 84.46%). MS (ESI): m/z=404.0[M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ: 8.07 (s, 1H), 7.83 (d, J = 8.6 Hz, 1H), 7.74 (d, J = 3.4 Hz, 1H), 7.54 (dd, J = 1.5, 8.8 Hz, 1H), 6.87 (d, J = 3.4 Hz, 1H), 3.28 (s, 3H), 3.04 (q, J ＝7.3Hz,2H),2.71(s,3H),1.33(t,J＝7.4Hz,3H).

Embodiment 217

Step 1: Potassium carbonate (27.94 mg, 0.20 mmol) and iodomethane (8.18 μL, 0.13 mmol) were added to a DMF (2 mL) solution of compound 160 (40 mg, 0.10 mmol). The reaction mixture was stirred at 25°C for 1.5 hours, cooled to 0°C and water was added, solid precipitated, warmed to room temperature and filtered, the filter cake was washed with water and dried, dissolved in dichloromethane and the filtrate was concentrated to give compound 217 (35 mg, 0.09 mmol, yield: 84.50%). MS (ESI): m/z = 409.9 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ) δ: 8.08 (s, 1H), 7.87 (d, 1H, J = 8.6Hz), 7.73 (d, 1H, J = 3.4Hz), 7.56 (d, 1H, J = 8.9Hz), 6.90 (d, 1H, J = 3.4Hz), 3.23 (s, 3H), 2.77 (s, 3H).

Embodiment 258

Step 1: Sodium difluorochloroacetate (17.56 mg, 0.12 mmol) and cesium carbonate (37.53 mg, 0.12 mmol) were added to a solution of compound 2 (20 mg, 0.06 mmol) in DMF (4 mL), and the reaction mixture was stirred at room temperature for 3 hours. Saturated ammonium chloride solution (5 mL) was added to quench, and extracted with EA (5 mL x 3). The organic phase was washed with saturated brine, dried and concentrated, and the resulting residue was purified by column chromatography and pre-HPLC to obtain compound 258 (8 mg, 0.02 mmol, yield 34.96%). MS (ESI): m/z = 398.0 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d6) δ = 9.02 (dd, J = 2.1, 19.0Hz, 2H), 8.09 (s, 1H), 7.92-7.81 (m, 2H), 7.55 (br d, J = 8.9Hz, 1H), 6.92 (d, J = 3.3Hz, 1H).

Embodiment 259

Step 1: Deuterated iodomethane (0.01 mL, 0.17 mmol) and potassium carbonate (47.76 mg, 0.35 mmol) were added to a solution of compound 2 (60 mg, 0.17 mmol) in DMF (3 mL), and the reaction mixture was stirred at room temperature for 2 hours. Saturated ammonium chloride solution (5 mL) was added to quench, and extracted with EA (5 mL x 3). The organic phase was washed with saturated brine, dried and concentrated, and the resulting residue was purified by column chromatography and pre-HPLC to obtain compound 259 (31 mg, 0.08 mmol, yield 48.49%). MS (ESI): m/z = 365.1 [M+H] ⁺ .

¹ HNMR (400MHz, DMSO-d6) δ = 9.02 (s, 2H), 8.08 (s, 1H), 7.86 (d, J = 8.8Hz, 1H), 7.78 (d, J = 3.5Hz, 1H), 7.55 (br d,J=8.0Hz,1H), 6.90 (d,J=3.4Hz,1H).

Embodiment 260

Step 1: Add iodoethane (0.01 mL, 0.12 mmol) and potassium carbonate (23.88 mg, 0.17 mmol) to a solution of compound 2 (40 mg, 0.12 mmol) in DMF (4 mL), and stir the reaction mixture at room temperature for 3 hours. Add saturated ammonium chloride solution (5 mL) to quench, and extract with EA (5 mL x 3). The organic phase is washed with saturated brine, dried and concentrated, and the resulting residue is purified by column chromatography and pre-HPLC to obtain compound 260 (24.5 mg, 0.07 mmol, yield 56.67%). MS (ESI): m/z = 376.0 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 9.03 (br s, 2H), 8.08 (br s, 1H), 7.84 (br d, J = 7.4Hz, 1H), 7.70 (br s, 1H), 7.63-7.46 (m, 1H), 6.90 (br s, 1H), 3.92-3.74 (m, 2H) ,1.26(br s,4H).

Embodiment 303

Step 1: To a solution of compound 2 (40 mg, 0.12 mmol) in DMF (2 mL) were added bromopropane (0.01 mL, 0.12 mmol) and potassium carbonate (31.84 mg, 0.23 mmol), and the reaction mixture was stirred at room temperature for 3 hours. Saturated ammonium chloride solution (3 mL) was added to quench, and the mixture was extracted with EA (3 mL x 3). The organic phase was washed with saturated brine, dried and concentrated, and the resulting residue was purified by column chromatography and pre-HPLC to give compound 303 (1.8 mg, 0.005 mmol, yield 4.01%). MS (ESI): m/z = 390.0 [M+H] ⁺ . ¹ 1H NMR (400MHz, METHANOL-d ₄ ) δ = 8.94-8.87 (m, 2H), 7.99 (s, 1H), 7.77 (d, J = 8.8Hz, 1H), 7.54 (d, J = 3.5Hz, 1H), 7.49 (d, J = 8.8Hz, 1H), 6.88 (d, J = 3.5Hz, 1H) ), 3.72-3.66 (m, 2H), 1.69-1.62 (m, 2H), 0.84 (t, J = 7.4Hz, 3H).

Preparation of control compounds

Synthesis of 3-(3-(4-(trifluoromethylphenyl)aminopyrazin-2-yl)-1,2,4-oxadiazol-5(4H)one

Step 1: 3-((4-(Trifluoromethyl)phenyl)amino)pyrazine-2-carbonitrile

3-Chloropyrazine-2-carbonitrile (1.3 g, 10 mmol), p-trifluoromethylaniline (1.9 g, 12 mmol), Pd ₂ (dba) ₃ (91 mg, 1 mmol), XantPhos (121 mg, 2 mmol), and cesium carbonate (8.1 g, 25 mmol) were dispersed in 1,4-dioxane (30 ml). The reaction mixture was purged with N ₂ and maintained under N ₂ atmosphere, stirred at 80°C overnight, diluted with H ₂ O (100 mL) and extracted with EA (50 mL). The organic phase was washed with saturated brine (20 mL×3), dried over anhydrous Na ₂ SO ₄ and concentrated, and the residue was purified by silica gel column chromatography (eluted with EA:PE=1:4) to obtain compound 3-((4-(trifluoromethyl)phenyl)amino)pyrazine-2-carbonitrile (2.1 g, 7.9 mmol, 79.5%). MS (ESI): m/z=265[M+H] ⁺ .

Step 2: N-Hydroxy-3-((4-(trifluoromethyl)phenyl)amino)pyrazine-2-carboximidamide

3-((4-(trifluoromethyl)phenyl)amino)pyrazine-2-carbonitrile (2.1 g, 7.9 mmol), MeOH (20 mL), NH ₂ OH·HCl (5.4 g, 79 mmol), TEA (15 mL) and The mixture was purged with _N2 and maintained under _N2 atmosphere, stirred at 80°C for 3 hours, filtered, and the filtrate was concentrated. _H2O (20 mL) was added to the concentrate, and extracted with EA (30 mL). The organic phase was washed with saturated brine (10 mL×3), dried over anhydrous _{Na2SO4 ,} and concentrated, and the residue was purified by silica gel column chromatography (eluted with EA:PE=1:2) to obtain the compound N-hydroxy-3-((4-(trifluoromethyl)phenyl)amino)pyrazine-2-carboximidamide (1.8 g, 6.1 mmol, 77.2%). MS (ESI): m/z=298[M+H] ⁺ .

Step 3: 3-(3-(4-(trifluoromethylphenyl)aminopyrazin-2-yl)-1,2,4-oxadiazol-5(4H)one

Under ice bath conditions, CDI (1.1 g, 7.3 mmol) was added to a solution of N-hydroxy-3-((4-(trifluoromethyl)phenyl)amino)pyrazine-2-carboximidamide (1.8 g, 6.1 mmol,) in THF (20 mL), stirred at room temperature for 30 minutes, and DBU (1.3 g, 9.1 mmol) was added dropwise under ice bath conditions. The reaction mixture was stirred under ice bath conditions for 1 hour, and HCl aqueous solution was added to adjust the pH to 2 (2 mL), and extracted with EA (20 mL). The organic phase was washed with saturated brine (10 mL×3), dried over anhydrous Na ₂ SO ₄ and concentrated, and the residue was purified by preparative high performance liquid chromatography to give compound 3-(3-(4-(trifluoromethylphenyl)aminopyrazin-2-yl)-1,2,4-oxadiazol-5(4H)-one (458 mg, 1.4 mmol, 23.2%). MS (ESI): m/z=323 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ , 400 MHz) δ13.40 (br s, 1H), 9.20 (s, 1H), 8.49 (d, 1H, J=2.5 Hz), 8.31 (d, 1H, J=2.3 Hz), 7.90 (d, 1H, J=8.5 Hz), 7.70 (d, 1H, J=8.5 Hz).

Other compounds of the present invention can be prepared by methods similar to those described in the above examples (with appropriate modifications, if necessary).

Biological evaluation

Test Example 1.TEAD reporter gene experiment-HEK293T

Cells: HEK293T cells stably transfected with 8X GTIIC luciferase reporter gene.

Cell culture: All cells were cultured according to the guidelines recommended by ATCC.

Cell seeding: After removing all the culture medium, rinse the cells gently with PBS, then add TrypLE, incubate at room temperature for one minute, add culture medium and gently resuspend the cells in the culture medium until the clumps completely disappear. Centrifuge the cells, rinse twice with PBS, remove PBS, dilute the cells with culture medium, and seed them into 384-well plates at a density of 10,000 cells/well. Incubate the cells in an incubator (37°C, 5% CO ₂ ).

Compound treatment: 30 μM as the starting concentration, 10 points were added in triplicate to a 384-well plate by Echo at a dilution of 1:3. The plate was placed in an incubator (37° C., 5% CO ₂ ) and incubated for 24 hours.

Detection: Add 25 μl of luciferase detection reagent to each well and detect the luminescence value using Envision microplate reader.

The results are shown in Table 1 below, and the HEK293 IC ₅₀ values of the compounds are as follows:

A: _IC50 ≤100nM

B: 100nM<IC ₅₀ ≤300nM

C: 300nM< _IC50 ≤3μM

D: IC ₅₀ >3 μM

Table 1

The experimental results show that the compounds of the present application have TEAD inhibitory activity, and the TEAD inhibitory activity _IC50 values of most compounds are less than 3 μM; the _IC50 values of many compounds are less than 300 nM; and even quite a few compounds have _IC50 values less than 100 nM.

Test Example 2.TEAD reporter gene experiment-MCF7

Cells: Hippo Pathway/TEAD Luciferase Reporter MCF7 cells (BPS Bioscience, 60618).

1. Before the experiment, preheat the growth medium (BPS Bioscience, 79531) in a 37°C water bath.

2. MCF7 cells (BPS Bioscience, 60618) were taken out from the 37°C constant temperature incubator and washed once with PBS.

3. Add 2 mL of trypsin into the T75 cell culture flask and digest for 3 minutes in a 37°C _CO2 incubator.

Add 4.5 mL of culture medium to terminate digestion, collect cells in a 50 mL centrifuge tube, centrifuge at 1000 rpm for 5 min, discard the supernatant, and resuspend the cells in 10 mL of fresh culture medium.

5. Mix 30 μL of cell suspension with 30 μL of trypan blue and count using a cell counter.

6. The cell density was adjusted to 2.5 x 10 ⁵ /mL, and 40 μL of cells were inoculated into each well of a white transparent bottom 384-well microplate (Corning, 3765).

7. Incubate the cells in a 37°C, _CO2 incubator overnight.

8. Add 40 nL of compound to 384-well microplate using Ehco 650. The final concentration of DMSO in the assay medium is 0.1%.

9. Incubate the cells in a 37°C, CO ₂ incubator for 24 hours.

10. Add 20 μL of ONE-Step ^™ Luciferase Assay System (BPS, 60690) reagent to each well and stabilize at room temperature for 5 minutes. Use EnVision Xcite Multilabel Reader (PerkinElmer, 2105-0020) to measure the luminescence value.

11. Data processing:

%Inhibition＝100(Signalcompound-SignalAve_PC)/(SignalAve_VC-SignalAve_PC)*100

IC ₅₀ (nM) calculation: curve fit(Prism 9,non-liner inhibitor,4parameter)

The results are shown in Table 2 below, and the _MCF7IC50 values of the compounds are ranked as follows:

A: _IC50 ≤30nM

B: 30nM<IC ₅₀ ≤100nM

C: 100nM<IC ₅₀ ≤300nM

D: IC ₅₀ >300nM

Table 2

The experimental results show that the compounds of the present application have the ability to inhibit TEAD reporter gene activity. Most compounds have IC ₅₀ values less than 300 nM; many compounds have IC ₅₀ values that satisfy 30 nM < IC ₅₀ ≤ 100 nM; and many compounds have IC ₅₀ values less than 30 nM.

Test case 3. Chemiluminescence assay to detect the effect of TEAD inhibitors on NCI-H226 and NCI-H2452 cell viability

1. Preparation before experiment: Corning Well black clear bottom cell plate, Corning, catalog number: #3603; Detection kit: Promega, catalog number: G7570; Model ELISA reader

2. NCI-H226 cell culture: NCI-H226 cells from ATCC catalog number: CRL-5826 were cultured in 89% RPMI-1640 + 10% FBS + 1% double antibody and placed in a 37°C constant temperature incubator containing 5% _CO2 .

NCI-H2452 cell culture: from ATCC catalog number: CRL-5946, culture method is the same as NCI-H226

Day 1: When the cell confluence rate reaches 90%, remove the culture medium, add 3 mL PBS to wash the residual culture medium, add 1 mL Trypsin and incubate in the incubator for 5 min. After most of the cells fall off, add 2 ^mL culture medium to stop digestion. Dilute the cell concentration to 5X103/mL and place in Corning 500 cells/well were plated in a black transparent bottom cell plate, i.e. 100 μL was added to each well.

3. Administration on the second day: Take out the 10mM TEAD inhibitor storage solution and thaw it at room temperature, and prepare the following working solutions: 0.0015μM, 0.0046μM, 0.0137μM, 0.0412μM, 0.1235μM, 0.3704μM, 1.1111μM, 3.3333μM, 10μM. 0.6mL complete medium + 1.2μL 10mM storage solution to prepare a 20μM working solution; take 0.2mL of the above solution and add it to 0.4mL complete medium to prepare a 6.6666μM working solution, and then dilute it 3 times to prepare other concentrations. Add 100μL of working solution to the 96-well plate with cells.

4. Replace the solution with fresh one on the third day after adding the medicine.

5. On the 6th day of administration Kit detection: Select the CellTiter-Glo detection program on the microplate reader and read the luminescence value.

6. Data processing: Cell viability value = 100*(luminescence value of drug-added well - luminescence value of blank well)/(luminescence value of solvent well - luminescence value of blank well), _IC50 calculation: The cell viability value and the corresponding drug concentration value were calculated using the (log(inhibitor) vs.normalized response--Variable slope algorithm in Curve fit of Prism 8 software.

The selectivity results are shown in Table 3 below, and the IC ₅₀ value rankings of compound H226 are: A: IC ₅₀ ≤300nM; B: 300nM<IC ₅₀ ≤1000nM; C: IC ₅₀ >1000nM; and the IC ₅₀ value rankings of compound H2452 are: A: IC ₅₀ ≤1μM; B: 1μM<IC ₅₀ ≤10μM; C: IC ₅₀ >10μM.

Table 3

The experimental results show that the compounds of the present application can effectively inhibit the proliferation of target-sensitive tumor cells H226, but do not inhibit the proliferation of target-insensitive tumor cells H2452. It can be seen that the compounds of the present application have good target selectivity. However, the control compound has almost no selectivity (the control compound is the compound in WO2021018869A1 ).

Test Example 4. Real-time fluorescence quantitative nucleic acid amplification detection system (qPCR) to detect the effect of TEAD inhibitors on YAP/TEAD transcriptional activity in NCI-H226 cells

1. Reagents and cells

NCI-H226 cell culture: NCI-H226 from ATCC catalog number: CRL-5826 was cultured in 89% RPMI-1640 + 10% FBS + 1% double antibody, and placed in a 37°C constant temperature incubator containing 5% CO _2. RNA extraction kit (Tiangen, DP430, placed at room temperature). SYBR dye (Kangwei Century, CW0957M, placed at -20°C).

2. RNA extraction steps

2.1 After the cells were treated with 0.5 μM or 1 μM drugs for 24 hours, the cells were collected (the cell amount should not exceed 1×10 ⁷ ), the cell culture medium supernatant was removed, the cells were washed once with PBS, the PBS was removed, and the second lysis step was immediately performed.

2.2 Cell lysis

Prepare lysis buffer: add β-mercaptoethanol to RL to a final concentration of 1%, for example, add 10 μL β-mercaptoethanol to 1 mL RL; Lysis: add an appropriate amount of lysis buffer RL, transfer the cell lysate to a centrifuge tube, and vortex to mix. The conditions are shown in Table 4.

Table 4

2.3 Transfer all the solutions to the filter column CS (the filter column CS is placed in the collection tube), centrifuge at 12000 rpm (~13400×g) for 2 min, and collect the filtrate.

2.4 Add 1 volume of 70% ethanol (usually 350 μL or 600 μL) to the filtrate, mix well, transfer the obtained solution and precipitate into the adsorption column CR3, centrifuge at 12000 rpm (～13400×g) for 30-60 seconds, pour out the waste liquid in the collection tube, and put the adsorption column CR3 back into the collection tube.

2.5 Add 350 μL of deproteinized solution RW1 to the adsorption column CR3, centrifuge at 12000 rpm (13400×g) for 30-60 seconds, pour out the waste liquid in the collection tube, and put the adsorption column CR3 back into the collection tube.

2.6 Preparation of DNase I working solution: Take 10 μL of DNase I stock solution and put it into a new RNase-Free centrifuge tube, add 70 μL of RDD buffer and mix gently.

2.7 Add 80 μL of DNase I working solution to the center of adsorption column CR3 and leave at room temperature for 15 minutes.

2.8 Add 350 μL of deproteinized solution RW1 to the adsorption column CR3, centrifuge at 12000 rpm (～13400×g) for 30-60 seconds, pour out the waste liquid in the collection tube, and put the adsorption column CR3 back into the collection tube.

2.9 Add 500 μL of rinsing solution RW to the adsorption column CR3, let it stand at room temperature for 2 min, centrifuge at 12000 rpm (～13400×g) for 30-60 sec, pour out the waste liquid in the collection tube, and put the adsorption column CR3 back into the collection tube.

2.10 Repeat step 9.

2.11 Centrifuge at 12000rpm (~13400×g) for 2min and discard the waste liquid. Place the adsorption column CR3 at room temperature for 3-5 minutes to completely dry the residual rinse liquid in the adsorption material.

2.12 Transfer the adsorption column CR3 into a new RNase-Free centrifuge tube, add 30-100 μL RNase-Free ddH2O and let stand at room temperature for 2 min. Centrifuge at 12000 rpm (～13400×g) for 2 min to obtain RNA solution.

2.13 Use Nanodrop to detect the concentration of the extracted RNA.

3. Reverse transcription steps

3.1 Place the RNA sample to be reverse transcribed and the reagents of the reverse transcription kit (thermo, 4368814, -20°C) on ice to completely dissolve.

3.2 Prepare 2×RT master mix according to the kit instructions

3.3 Mix the prepared 2×RT mastermix by flicking the bottom of the tube, shake it lightly with a handheld centrifuge, and place it on ice for later use.

3.4 First calculate the volume required to absorb 500ng RNA for each sample based on the extracted RNA concentration, and then calculate the volume of RNase-free H ₂ O that needs to be added according to the 10μL system. Number the PCR 8 tubes of RNase, add RNase-free H 2 O according to the number, then add the corresponding volume of 500ng RNA, pipette and beat several times to mix, add 10uL of 2×RT master mix, flick the bottom of the tube to mix evenly, shake it lightly with a handheld centrifuge, and place it on ice.

3.5 Place the PCR tube into the PCR instrument, tighten the lid and set the PCR program according to the following conditions. The reaction volume is 20ul.

3.6 Store the reversed cDNA at -20℃ for later use.

4 qPCR steps

4.1 Dissolve the forward and reverse primers of the detected genes 36B4, CTGF and CYR61, sample cDNA and SYBR green completely on ice and mix well.

4.2 Primer dilution

Dissolve the synthesized forward primer and reverse primer in ddH ₂ O according to the volume on the tube (generally the concentration is 100μM). Take 2.5μL of 100uM primer stock and add it to the EP tube containing 47.5μL ddH ₂ O to dilute it to 5μM. Then mix the 5μM forward primer and reverse primer in equal volumes to form a 2.5μM F/R primer mixture.

4.3 Dilution of cDNA

After the reverse transcribed cDNA is completely dissolved on ice, mix it evenly. According to each experiment, add 4 μL cDNA to each well of the 384QPCR plate, repeat 3 times, calculate the required sample volume, take out the PCR8 tube, dilute the cDNA 20 times with ddH ₂ O, flick the bottom of the tube to mix evenly, shake it on a handheld centrifuge, and place it on ice for later use.

4.4 Prepare the mixture of SYBR and primers in a 1.5 mL centrifuge tube, flick the bottom of the tube to mix evenly, spin it in a handheld centrifuge, and place it on ice for later use.

4.5 Add samples. After adding samples to all wells, use a spray gun to aspirate 6 μL of the SYBR and 2.5 μM F/R primer mixture of the corresponding gene. After adding, apply the sealing film and press the four sides tightly. Centrifuge for 5 minutes before loading to ensure that the liquid is at the bottom of the plate. Set the QPCR reaction program. The pre-denaturation reaction of Kangwei Century SYBR dye must be completed at 95℃ for 10 minutes, the reaction system is 20ul, and 40 cycles. Save the data for analysis.

The experimental results show that the compounds of the present application have a significant inhibitory effect on the YAP/TEAD transcriptional activity of NCI-H226 cells.

Test Example 5. In vivo PK test

1. Experimental Animals

Six SD rats/ICR mice (male/female) were divided into two groups: oral administration and intravenous administration, with three mice in each group. The mice were fasted for 10-14 hours before administration and had free access to water.

2. Preparation of drug delivery preparations

The compound to be tested is weighed according to the dosage, and prepared into a dosage preparation of appropriate concentration with a solvent (usually 5% DMSO + 10% Solutol + 85% saline) (the intravenous and oral administration for mice and rats is 5 mL/kg and 10 mL/kg, respectively). The intravenous injection is a clear solution, and the oral dosage is a clear solution or a uniform suspension.

3. Animal medication and blood sample collection

Animals were dosed by intravenous injection and oral gavage, and blood samples were collected at 0.033h, 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h and 24h after intravenous injection and 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h and 24h after oral administration. Whole blood was centrifuged at 4°C, 6800g for 6min, and the upper plasma was stored in a -80°C refrigerator for analysis.

4. Plasma sample testing

Take the DMSO stock solution of the test substance and dilute it with methanol or acetonitrile solution to form a series of working solutions, add it to the blank plasma matrix, and prepare the standard curve and quality control samples. Take an appropriate volume of plasma sample, and add an appropriate amount of methanol or acetonitrile containing internal standard according to the response for protein precipitation. Centrifuge all samples at 4℃, 18000g for 10 minutes, and take an appropriate amount of supernatant for LC-MS/MS injection analysis.

5. Parameter calculation

The blood drug concentration-time curve was drawn according to the test concentration, and the pharmacokinetic parameters including half-life (T1/2), area under the drug-time curve (AUC0-t), clearance (CL), steady-state distribution volume (Vss), bioavailability (F) were calculated by WinNonlin software according to the non-compartmental model. The results are shown in Table 5.

Table 5

The experimental results show that the compounds of the present application have excellent pharmacokinetic properties.

Test Example 6. Detection of TEAD inhibitors inhibiting YAP/TEAD transcriptional activity in vivo in the NCI-H226 nude mouse transplant tumor model

1. Establishment of NCI-H226 CDX nude mouse model

NCI-H226 from ATCC catalog number: CRL-5826 was cultured in 89% RPMI-1640 + 10% FBS + 1% penicillin-streptomycin and placed in a 37°C constant temperature incubator containing 5% CO _2. In a 15 cm culture dish, when the cell confluence rate reaches 90%, the culture medium is aspirated, 5 mL PBS is added to wash the residual culture medium, 3 mL Trypsin is added and placed in an incubator for 5 min. After most of the cells fall off, 6 mL of culture medium is added to stop digestion. Collect NCI-H226 cells, wash twice with 50 mL PBS, dilute the concentration with PBS to 2*10 ⁸ cells/mL, add 1 volume of Matrigel (Corning) and mix well. 100 μL of cell suspension, i.e. 1*10 ⁷ cells, is injected subcutaneously into the right anterior armpit of nude mice.

2. Drug administration

Drug preparation: Solvent: 8.5 mL of saline + 1 mL of Solutol, the drug is dissolved in DMSO to 20 mg/mL for storage. Drug working solution: 35 μL of drug storage solution is added to 665 μL of solvent to prepare 10 mg/kg of TEAD inhibitor.

When the volume of the transplanted tumor reached 100 mm ³ , 10 mg/kg of TEAD inhibitor and corresponding solvent were given by intragastric administration once a day for 3 consecutive days. On the morning of the fourth day, the transplanted tumor was removed and quickly frozen in liquid nitrogen.

3. Total RNA Extraction from Transplanted Tumors

3.1 Put the module, cover, and grinding tube of the tissue grinder in a -80 refrigerator for pre-cooling, and soak the module in liquid nitrogen before use. Put the tumor tissue that has been quick-frozen in liquid nitrogen into the grinder, run at 60HZ for 30s, interrupt for 30s, run 5 times, and take it out and soak it in liquid nitrogen for 30s each time to ensure low temperature;

3.2 After grinding, place on ice and add 600 μL lysis buffer (thermos, purelink) to each tube. mini kit, 12183025), shake to dissolve, let stand on ice for 5 min, transfer the supernatant to an enzyme-free EP tube, centrifuge at 12000 rpm at 4°C for 10 min, transfer the supernatant to a new enzyme-free EP tube, add an equal volume of 70% ethanol, and mix by shaking.

3.3 Transfer the mixed liquid to the adsorption column and centrifuge at 12000rpm for 1min at room temperature. Pour away the waste liquid. A maximum of 700ul can be transferred and the remaining liquid can be added to the centrifuge repeatedly.

3.4 Add 350 μL wash buffer I to the adsorption column, centrifuge at 12000 rpm for 1 min at room temperature, and discard the waste liquid.

3.5 DNase I digestion: Take 10 μL of DNase I storage solution and put it into a new RNase-Free centrifuge tube, add 70 μL of RDD buffer, and mix gently. Add 80 μL of DNase I working solution to the center of each sample adsorption column and place it at room temperature for 15 minutes.

3.6 After digestion, add 350 μL wash buffer I to the adsorption column, centrifuge at 12000 rpm for 1 min at room temperature, and discard the waste liquid.

3.7 Add 500 μL wash buffer II to the adsorption column, centrifuge at 12000 rpm for 1 min at room temperature, discard the waste liquid, and repeat once.

3.8 Place the adsorption column in a centrifuge and centrifuge at 12000rpm for 2 minutes at room temperature. Place the adsorption column at room temperature for 5 minutes to completely dry the residual rinse solution in the adsorption material.

3.9 Transfer the adsorption column into a new RNase-Free centrifuge tube, add 30-100 μL RNase-Free ddH2O and place at room temperature for 2 min. Centrifuge at 12000 rpm (～13400×g) for 2 min to obtain RNA solution.

3.10 Use Nanodrop to detect the concentration of the extracted RNA.

4. The reverse transcription and QPCR steps are consistent with step 4qPCR operation of test example 4.

The experimental results show that the compound of the present application has good TEAD/YAP transcriptional activity inhibition ability in the NCI-H226 nude mouse transplant tumor model.

Test Example 7. Long-term efficacy experiment on nude mouse transplanted tumors

1. NCI-H226 cell culture: NCI-H226 from ATCC catalog number: CRL-5826 was cultured in 89% RPMI-1640 + 10% FBS + 1% penicillin-streptomycin and placed in a 37°C constant temperature incubator containing 5% CO _2. In a 15 cm culture dish, when the cell confluence rate reaches 90%, the culture medium is aspirated, 5 mL PBS is added to wash the residual culture medium, 3 mL Trypsin is added and placed in an incubator for 5 min. After most of the cells fall off, 6 mL of culture medium is added to stop digestion. Collect NCI-H226 cells, wash twice with 50 mL PBS, dilute the concentration with PBS to 2*10 ⁸ cells/mL, add 1 volume of Matrigel (Corning) and mix well. 100 uL of cell suspension, i.e. 1*10 ⁷ cells, is injected subcutaneously into the right anterior armpit of nude mice.

2. About one and a half months later, when the transplanted tumor grows to about 100mm3, divide the mice into 5 groups and record the body weight, length and width of the transplanted tumor. Drug configuration: 85% saline + 10% Solutol + 5% DMSO dissolved drug storage solution, each nude mouse is gavaged with 200μL per day. Record the body weight, length and width of the transplanted tumor every week.

3. When the transplanted tumor grows to the appropriate size, the nude mice are anesthetized with 4% chloral hydrate and blood is collected from the heart. The nude mice are killed with CO ₂ and the following materials are collected: transplanted tumor, lung, heart, kidney, pancreas, spleen, stomach, liver, duodenum, jejunum, cecum, ileum, rectum, and colon. The transplanted tumor is quickly frozen in liquid nitrogen, and the remaining tissues are fixed in 4% paraformaldehyde.

The experimental results show that the compounds of the present application can effectively inhibit tumor growth in the NCI-H226 transplanted tumor model.

Test Example 8. Effect of TEAD inhibitors on TEAD1/2/3/4 palmitoylation at the cellular level

1. Cell plating: 293T cells were plated in a 10 cm cell culture dish (1 min 5), and the cell density reached about 40% on the second day;

2. Cell transfection: 1 dish of cells was not transfected as a blank control, and 4 dishes of cells were transfected with TEAD-myc-flag plasmid (8 μg plasmid was transfected into 1 dish). The transfection steps were based on the lipo2000 transfection protocol, and the medium was changed 6 hours after transfection.

3. Acylation reaction: 24 hours after transfection, Palmitic Acid Alkyne (working concentration 100 μM) and TEAD inhibitor were added to the cells overnight. The experimental groups were set as follows: blank control; negative group (DMSO+TEAD+PAA-); control group (DMSO+TEAD+PAA+); positive control (Yangshen drug+TEAD+PAA+); negative control group (Yinshen drug+TEAD+PAA+); drug-added group (test drug+TEAD+PAA+);

4. Protein collection: Lyse cells 48 hours after transfection to collect proteins (1 dish of cells, 1 mL RIPA lysis buffer), sonicate (20% power for 4 s, 9 s on, 5 times), centrifuge at maximum speed for 10 min, take 90 μL as input sample, and perform IP on the rest.

5.IP and elution of proteins: IP was performed using FLAG tag antibody magnetic beads. The magnetic beads were washed with RIPA before incubation. The cell lysate was pre-washed with agarose beads and incubated at room temperature for 20 minutes. The amount of magnetic beads was 40 μL per tube (refer to the dosage in the manual). The cell lysate and magnetic beads were incubated at room temperature for 1 hour (thermo Beads) or 2 hours (Biyuntian Beads). After IP, the magnetic beads were eluted with 200 μL 3xFLAG peptide (150 μg/ml) at 4°C for 2 hours;

6. Click chemistry: The protein sample eluted after IP in step 5 was subjected to the second reaction. First, the SDS concentration of the protein sample was adjusted to 1%, and then Tris-(benzyltriazolylmethyl)amine (100μM), CuSO4 (1mM), Tris-carboxyethylphosphine (1mM), and azidobiotin (100μM) were added. The reaction was carried out at 37℃ for 30min, and then 10 times the volume of acetone was added to terminate the reaction. The sample was placed in -20℃ for more than 1h to precipitate the protein, and 40μL 2x loading buffer was added to boil the sample.

7. Detect samples using conventional Western Blot procedures, and finally use Streptavidin-HRP for chemiluminescence detection of palmitoylation levels.

The experimental results show that the compounds of the present application have an inhibitory effect on TEAD1/2/3/4 palmitoylation at the cellular level.

Test Example 9. Immunoprecipitation (IP) to detect the effect of TEAD inhibitors on YAP/TEAD4 interaction

1.1 10cm 293T, spread the required number of 6-well plates at a ratio of 1/3 cells to 4 6-well plates, and do transfection the next day. Take the amount of transfection solution for 8 wells as an example: in 800μL serum-free DMEM+4ug YAP-Flag+4μg TEAD4, another tube in 800μL serum-free DMEM+8μL Lipo 2000. Add 800μL serum-free DMEM+4ug YAP-Flag+4μg TEAD4 to 800μL serum-free DMEM+8μL Lipo 2000, mix immediately, and leave at room temperature for 20 minutes. Take 200μL of the mixed cocktail and add it to one well.

2. 24 hours after transfection, the experimental groups were set as follows: blank control; negative group (DMSO); control group (DMSO + YAP-Flag / TEAD4); positive control (Yangshen drug + YAP-Flag / TEAD4); negative control group (Yinshen drug + YAP-Flag / TEAD4); drug-added group (test drug + YAP-Flag / TEAD4);

3. Protein collection: 24 hours after drug addition, cells were lysed and proteins were collected (1 dish of cells, 1 ml RIPA lysis buffer), ultrasonicated (20% power, 4 s, 9 s, 5 times), centrifuged at maximum speed for 10 min, 90 μl of which was used as input sample, and the rest was used for IP.

4.IP and elution of protein: IP was performed using FLAG tag antibody magnetic beads. The magnetic beads were washed with RIPA before incubation. The cell lysate was pre-washed with agarose beads and incubated at room temperature for 20 minutes. The amount of magnetic beads was 40μl per tube (refer to the dosage in the manual). The cell lysate and magnetic beads were incubated at room temperature for 1h (thermo Beads) or 2h (Biyuntian Beads). After IP, the magnetic beads were eluted with 200μl 3xFLAG peptide (150μg/ml) at 4℃ for 2h; the eluted protein supernatant was obtained by centrifugation, and the relative amount of TEAD4 protein was detected by subsequent Western blotting experiments.

All compounds described in the present invention, including the compounds of the present invention and reference molecules, are based on chemical structural formulas.

Claims (34)

The compound represented by the following general formula O or the tautomer, stereoisomer, geometric isomer, enantiomer, diastereomer, racemate, prodrug, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, ester, isotope, or metabolite thereof: in: The Ao ring is selected from a 5-6 membered heteroaryl, a 5-6 membered heterocyclic group, a phenyl group, and the Ao ring is optionally substituted by 1-3 substituents selected from Rx, Ry, Rz, and Rm; preferably, the Ao ring is selected from a 5-membered heteroaryl, a 5-membered unsaturated heterocyclic group, a 6-membered saturated heterocyclic group, a phenyl group, and a pyridyl group, and the Ao ring is optionally substituted by 1-3 substituents selected from Rx, Ry, Rz, and Rm; more preferably, the Ao ring is selected from a 5-membered heteroaryl, a 5-membered unsaturated heterocyclic group, a 6-membered saturated heterocyclic group Preferably, the Ao ring is selected from a 5-membered heteroaryl, a 5-membered unsaturated heterocyclic group, a thiomorpholinyl, a tetrahydrothiopyranyl, a phenyl, a pyridyl, the 5-membered heteroaryl contains 2-4 heteroatoms selected from N, O, and S, and the Ao ring is optionally substituted by 1-3 substituents selected from Rx, Ry, Rz, and Rm; further preferably, the Ao ring is selected from a 5-membered heteroaryl, a 5-membered unsaturated heterocyclic group, a thiomorpholinyl, a tetrahydrothiopyranyl, a phenyl, and a pyridyl, the 5-membered heteroaryl contains 2-4 heteroatoms selected from N, O, and S, and satisfies any one of the following conditions (1)-(3): (1) When the Ao ring is selected from a 5-membered heteroaryl group, the Ao ring is optionally substituted by Rx, (2) When the Ao ring is selected from a 5-membered unsaturated heterocyclic group, any one of the following conditions (2-1) to (2-5) is satisfied: (2-1) The Ao ring is optionally substituted by Rm; (2-2) The Ao ring is optionally substituted by Ry, Rz and Rm; (2-3) The Ao ring is optionally substituted by Ry and Rm; (2-4) The Ao ring is optionally substituted by 2 Rm; (2-5) The Ao ring is optionally substituted by Rz; (3) When the Ao ring is selected from thiomorpholinyl, tetrahydrothiopyranyl, phenyl, and pyridyl, the Ao ring is optionally substituted by 1-2 substituents selected from Rz and Rm; Most preferably, the Ao ring is selected from a 5-membered heteroaryl, a 5-membered unsaturated heterocyclic group, The 5-membered heteroaryl group is selected from The 5-membered unsaturated heterocyclic group And any one of the following conditions (1)-(3) is met: (1) When the Ao ring is selected from a 5-membered heteroaryl group, the Ao ring is optionally substituted by Rx, (2) When the Ao ring is selected from a 5-membered unsaturated heterocyclic group, any one of the following conditions (2-1) to (2-5) is satisfied: (2-1) The Ao ring is optionally substituted by Rm; (2-2) The Ao ring is optionally substituted by Ry, Rz and Rm; (2-3) The Ao ring is optionally substituted by Ry and Rm; (2-4) The Ao ring is optionally substituted by 2 Rm; (2-5) The Ao ring is optionally substituted by Rz; (3) When the Ao ring is selected from thiomorpholinyl, tetrahydrothiopyranyl, phenyl, and pyridyl, the Ao ring is optionally substituted by 1-2 substituents selected from Rz and Rm; Wherein, Rx is selected from C1-C6 alkyl, 4-6 membered saturated heterocyclic group (preferably, the 4-6 membered saturated heterocyclic group contains 1 heteroatom selected from N, O, S), -C(＝O)NRaRb, -S(＝O) ₂ NRaRb, carboxyl (-COOH), ester group (-CO-O-C1-C6 alkyl), hydroxyl, -NRaC(＝O)Rc, and the Rx is optionally substituted by 1-2 substituents selected from Rn; preferably, Rx is selected from methyl, ethyl, oxetanyl, tetrahydropyrrolyl, tetrahydropyranyl, piperidinyl, -C(＝O)NRaRb, -NRaC(＝O)Rc, -S(＝O) ₂ NRaRb, carboxyl (-COOH), ester group (-CO-O-C1-C6 alkyl), hydroxyl; Rn is selected from C1-C6 alkyl, -NRaRb, -C(=O)NRaRb, oxo, 5-6 membered saturated heterocyclic group (preferably, the 5-6 membered saturated heterocyclic group contains 2 heteroatoms selected from N, O, S), C1-C6 alkoxy, carboxyl, hydroxyl; preferably, Rn is selected from methyl, ethyl, -NRaRb, -C(=O)NRaRb, oxo, morpholino, methoxy, hydroxyl, carboxyl; Ra, Rb, Rc are each independently selected from H, C1-C6 alkyl, cyano, C3-C6 cycloalkyl, or Ra, Rb and the carbon atom to which they are commonly attached together form azetidine, and the azetidine is optionally substituted with hydroxyl; preferably, Ra, Rb, Rc are each independently selected from H, methyl, cyano, cyclopropyl, or Ra, Rb and the carbon atom to which they are commonly attached together form azetidine, and the azetidine is optionally substituted with hydroxyl; Most preferably, Rx is selected from hydroxy, methyl, Ry is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxy, C1-C6 alkyl substituted by 1-6 halogens, C1-C6 alkyl substituted by 1-6 deuteriums, C1-C6 alkyl substituted by C3-C6 cycloalkyl, C1-C6 alkyl substituted by C6-C10 aryl, substituted C1-C6 alkyl, 4-6 membered saturated heterocyclic group; preferably, Ry is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxyl, C1-C6 alkyl substituted by 1-6 halogens, C1-C6 alkyl substituted by 1-6 deuteriums, C1-C6 alkyl substituted by C3-C6 cycloalkyl, C1-C6 alkyl substituted by C6-C10 aryl, More preferably, Ry is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxy, C1-C6 alkyl substituted by 1-3 halogens, C1-C6 alkyl substituted by 1-3 deuteriums, C1-C6 alkyl substituted by cyclopropyl, C1-C6 alkyl substituted by phenyl, A 5-6 membered saturated heterocyclic group containing 1 heteroatom; further preferably, Ry is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxy, C1-C6 alkyl substituted by 1-3 halogens, C1-C6 alkyl substituted by 1-3 deuteriums, C1-C6 alkyl substituted by cyclopropyl, C1-C6 alkyl substituted by phenyl, Tetrahydropyrrolyl, piperidinyl; Most preferably, Ry is selected from methyl _{, -CHF2 ,} -CF3, _{-CD3 , -CH2CH3 , -CH2CHF2} , _-CH2CF3 , Rz is selected from C1-C6 alkyl, halogen, Preferably, Rz is selected from methyl, Br, Or, Ry, Rz and the carbon atoms to which they are commonly connected together form a 4-6-membered saturated carbocyclic ring or a 4-6-membered saturated heterocyclic ring; or preferably, Ry, Rz and the carbon atoms to which they are commonly connected together form a 4-6-membered saturated carbocyclic ring or a 4-6-membered saturated heterocyclic ring, wherein the 4-6-membered saturated heterocyclic ring contains 1 heteroatom; or more preferably, Ry, Rz and the carbon atoms to which they are commonly connected together form cyclobutane, cyclopentane, cyclohexane, piperidine or tetrahydropyran; or most preferably, Ry, Rz and the carbon atoms to which they are commonly connected together form Among them, carbon atom 1' is the carbon atom that is connected to Ry and Rz; Rm is an oxo group; Most preferably, the Ao ring and its optional substituents as a whole are selected from the following: Bo ring is selected from: It is optionally substituted by 1-3 substituents selected from the group consisting of sulfur pentafluoride, -OH, C1-C6 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, C1-C6 alkyl substituted with 1-6 halogens, C1-C6 alkoxy substituted with 1-6 halogens, halogen, nitro, cyano, and amino; Preferably, the above It is optionally substituted by 1-2 substituents selected from the group consisting of sulfur pentafluoride, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, C1-C6 alkoxy substituted with 1-6 halogens, halogen; More preferably, the above Optionally substituted by 1-2 substituents selected from: pentafluorosulfur, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, C1-C6 alkoxy substituted with 1-6 halogens, halogen; or the above Optionally substituted with 1-2 substituents selected from: C1-C6 alkyl, C1-C6 alkyl substituted with 1-6 halogens, halogen; More preferably, the above Optionally substituted by 1-2 substituents selected from: -CF ₃ , -Cl, -SF ₅ , -CH ₃ , -F, -OCH ₃ , -OCF ₃ ; or the above Optionally substituted by 1-2 substituents selected from: -CF ₃ , -CH ₃ , -F, More preferably, the above The substitution positions of the substituents thereon are: 2-position monosubstitution, 3-position monosubstitution, 5-position monosubstitution, 4-, 5-position disubstitution, 5-, 6-position disubstitution, 2-, 5-position disubstitution, 3-, 5-position disubstitution; The substitution positions of the substituents thereon are 3-position monosubstitution and 5-position monosubstitution; The substitution position of the substituent thereon is 5-position monosubstitution; The substitution position of the substituent thereon is 6-position monosubstitution; The substitution position of the substituent thereon is mono- or di-substituted at the 5- or 6-position; The substitution position of the substituent thereon is 5-position monosubstitution; The substitution position of the substituent thereon is 5-position monosubstitution; The substitution position of the substituent thereon is 5-position monosubstitution; The substitution position of the substituent thereon is 5-position monosubstitution; The substitution position of the substituent thereon is 5-position monosubstitution; The substitution positions of the substituents thereon are 4-position monosubstitution and 5-position monosubstitution; The substitution position of the substituent thereon is 3-position monosubstitution; Most preferably, the Bo ring is selected from: The Co ring is selected from 5-membered heteroaromatic ring, 6-membered partially unsaturated heterocyclic ring; preferably, the 5-membered heteroaromatic ring is selected from Preferably, the 6-membered partially unsaturated heterocyclic ring is A ₁₀ , A ₂₀ , A ₃₀ , and A ₄₀ are independently selected from: N, CH, wherein at most 3 of them are N; L ₀ is selected from a direct bond, NH, O, S; preferably, L ₀ is selected from a direct bond, NH; Ro is selected from: aminosulfonyl substituted by 1-2 C1-C6 alkyl groups on N, carbamoyl substituted by 1-2 C1-C6 alkyl groups on N, C1-C5 heteroaryl, C1-C6 alkoxy, C1-C6 alkoxy substituted by hydroxy, C1-C6 alkoxy substituted by 5-6 heteroaryl, C3-C5 heterocyclyloxy, carboxyl (-COOH), ester group (-CO-O-C1-C6 alkyl), hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-6 halogens, C1-C6 alkyl substituted by cyano, C1-C6 alkoxy substituted by 1-6 halogens, halogen, cyano, nitro, oxo, C2-C6 alkenyl, C1-C6 alkyl substituted by C6-C10 aryl, 5-6 membered heterocyclic group, C1-C6 alkyl substituted by amino; wherein C3-C5 heterocyclic group is arbitrarily substituted by C1-C3 alkyl, C6-C10 aryl is arbitrarily substituted by 1-6 halogens, 5-6 membered heterocyclic group is C1-C3 alkyl or hydroxyl are substituted arbitrarily; or two Ro, together with the atoms to which they are connected, form a C6-C10 aromatic ring, a partially unsaturated C5-C6 carbocyclic ring, a partially unsaturated 5-6-membered heterocyclic ring or a 5-6-membered heteroaromatic ring, wherein the partially unsaturated C5-C6 carbocyclic ring, the partially unsaturated 5-6-membered heterocyclic ring or the 5-6-membered heteroaromatic ring are each optionally substituted by 1-6 groups selected from halogen and deuterium; more preferably, Ro is selected from: aminosulfonyl substituted by 1-2 C1-C6 alkyl on N, carbamoyl substituted by 1-2 C1-C6 alkyl on N, pyridyl C1-C6 alkoxy, C1-C6 alkoxy substituted by hydroxy, C3 heterocyclyloxy, carboxyl (-COOH), ester group (-CO-O-C1-C6 alkyl), hydroxyl, amino, C1-C6 alkoxy Oxy, C1-C6 alkyl, C1-C6 alkyl substituted by 1-3 halogens, C1-C6 alkyl substituted by cyano, halogen, cyano, oxo, C2-C6 alkenyl, C1-C6 alkyl substituted by phenyl, C1-C6 alkyl substituted by amino, tetrahydropyrrolyl, piperazinyl, wherein C3 heterocyclyl is arbitrarily substituted by C1-C3 alkyl, tetrahydropyrrolyl is arbitrarily substituted by hydroxyl, piperazinyl is arbitrarily substituted by C1-C3 alkyl; or two Ro, together with the atoms to which they are connected, form a benzene ring, a partially unsaturated C5-C6 carbocycle, a partially unsaturated 5-6-membered heterocycle or a 5-membered heteroaromatic ring, wherein the partially unsaturated C5-C6 carbocycle and the partially unsaturated 5-6-membered heterocycle are each optionally substituted by 1-6 groups selected from halogen and deuterium; most preferably, Ro is selected from: oxo, -OCH ₃ , -CH ₃ , -F, -Cl, -CN, -OH, -NH ₂ , -COOH, -COOCH ₃ , -CH ₂ CH ₃ , -CF ₃ , -CHF ₂ , Or two Ro together with the atoms they are attached to form: The compound according to claim 1, or its tautomer, stereoisomer, geometric isomer, enantiomer, diastereomer, racemate, prodrug, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, ester, isotope, or metabolite, wherein the compound is of the following formula O-1: in: The definition of Ao ring is the same as that of Ao ring in claim 1; the definition of Bo ring is the same as that of Bo ring in claim 1; the definition of Co ring is the same as that of Co ring in claim 1; the definition of _L0 is the same as that of _L0 in claim 1; Ro ₁₁ , Ro ₁₂ and the atoms to which they are attached together form a C6-C10 aromatic ring, a partially unsaturated C5-C6 carbocyclic ring, a partially unsaturated 5-6-membered heterocyclic ring or a 5-6-membered heteroaromatic ring, wherein the partially unsaturated C5-C6 carbocyclic ring, the partially unsaturated 5-6-membered heterocyclic ring or the 5-6-membered heteroaromatic ring are each optionally substituted with 1-6 groups selected from halogen and deuterium; preferably, Ro ₁₁ , Ro ₁₂ and the atoms to which they are attached together form a benzene ring, a partially unsaturated C5-C6 carbocyclic ring, a partially unsaturated 5-6-membered heterocyclic ring or a 5-membered heteroaromatic ring, wherein the partially unsaturated C5-C6 carbocyclic ring and the partially unsaturated 5-6-membered heterocyclic ring are each optionally substituted with 1-6 groups selected from halogen and deuterium; or preferably, Ro ₁₁ , Ro Ro 11 , _{Ro 12} and the atoms to which they are attached together form a partially unsaturated C5-C6 carbocycle or a partially unsaturated 5-6-membered heterocycle, wherein the partially unsaturated C5-C6 carbocycle and the partially unsaturated 5-6-membered heterocycle are each optionally substituted by 1 to 6 groups selected from halogen and deuterium; more preferably, Ro ₁₁ , Ro ₁₂ and the atoms to which they are attached together form: Most preferably, Ro ₁₁ , Ro ₁₂ and the atoms to which they are attached together form: Or the compound of formula O is the following formula Oc: In formula Oc, the Aoc ring and its optional substituents as a whole are selected from Preferably, the Aoc ring and its optional substituents as a whole are selected from Most preferably, the Aoc ring and its optional substituents as a whole are The definition of Co ring is the same as that of Co ring in the formula O; the definition of Ro is the same as that of Ro in the formula O; Preferably, the compound of formula Oc is the following formula Occ: The Aocc ring and its optional substituents as a whole have the same definition as the Aoc ring and its optional substituents as a whole in the formula Oc; _A10 , _A20 , _A30 , _A40 have the same definition as _A10 , _A20 , _A30 , _A40 in the formula O; and Ro has the same definition as Ro in the formula O. The compound according to claim 1, or its tautomer, stereoisomer, geometric isomer, enantiomer, diastereomer, racemate, prodrug, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, ester, isotope, or metabolite, wherein the compound is the following formula I: The definition of A1 ring is the same as that of Ao ring in claim 1; the definition of B1 ring is the same as that of Bo ring in claim 1; the definition of _L1 is the same as that of _L0 in claim 1; _A1 , _A2 , _A3 , _A4 are independently selected from: N, CH, of which at most 3 are N; the definition of _R1 is the same as that of Ro in claim 1. The compound according to claim 3, or its tautomer, stereoisomer, geometric isomer, enantiomer, diastereomer, racemate, prodrug, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, ester, isotope, or metabolite, wherein the compound of formula I is the following formula Ic: The _A1c ring and its optional substituents as a whole are defined the same as the Aoc ring and its optional substituents as a whole in the above formula Oc; _A1 , _A2 , _A3 , _A4 are independently selected from: N, CH, of which at most 3 are N; _R1 is defined the same as _R1 in the above formula I; Alternatively, the compound is of the following formula I-1: A11 ring is selected from 5-membered heteroaryl, 5-membered unsaturated heterocyclic group, The 5-membered heteroaryl group is selected from The 5-membered unsaturated heterocyclic group is selected from And any one of the following conditions (1)-(2) is met: (1) When the A11 ring is selected from a 5-membered heteroaryl group, the A11 ring is optionally substituted by Rx, (2) When the A11 ring is selected from a 5-membered unsaturated heterocyclic group, the A11 ring is optionally substituted by Rm or Rz, or optionally substituted by Ry and Rm; Wherein, Rx is selected from methyl, Ry is methyl; Rz is selected from halogen (preferably Br); Rm is oxo; Preferably, the A11 ring and its optional substituents as a whole are selected from the following: The B11 ring is selected from: It is optionally substituted by 1-3 substituents selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, C1-C6 alkyl substituted with 1-6 halogens, C1-C6 alkoxy substituted with 1-6 halogens, halogen, and amino; Preferably, the above Optionally substituted by 1-2 substituents, the substituents are selected from: C1-C6 alkyl substituted by 1-6 halogens, C3-C4 cycloalkyl, C1-C6 alkoxy substituted by 1-6 halogens, amino; More preferably, the above Optionally substituted by 1-2 substituents selected from: -CF ₃ , -OCF ₃ ; Most preferably, the B11 ring is selected from: R ₁₁ is selected from the group consisting of: aminosulfonyl substituted by 1-2 C1-C6 alkyl groups on N, carbamoyl substituted by 1-2 C1-C6 alkyl groups on N, C1-C6 alkyl groups, C1-C6 alkoxy groups, halogen, cyano and nitro groups; more preferably, R ₁₁ is selected from the group consisting of: aminosulfonyl substituted by 1-2 C1-C6 alkyl groups on N, carbamoyl substituted by 1-2 C1-C6 alkyl groups on N, C1-C6 alkyl groups, halogen and cyano groups; further preferably, R ₁₁ is selected from the group consisting of: -CH ₃ , -F, -Cl, -CN; More preferably, R ₁₁ is located in the ring The position on is selected from: 1-position, 2-position, 3-position, 4-position; Preferably, the compound of formula I-1 is the following formula I-1c: The A _11c ring and its optional substituents as a whole are selected from Preferably, the A _11c ring and its optional substituents as a whole are selected from More preferably, the A _11c ring and its optional substituents as a whole are R ₁₁ has the same definition as R ₁₁ in the above formula I-1. The compound according to claim 3, or its tautomer, stereoisomer, geometric isomer, enantiomer, diastereomer, racemate, prodrug, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, ester, isotope, or metabolite, wherein the compound is the following formula I-2: A12 ring is selected from 5-membered heteroaryl, 5-membered unsaturated heterocyclic group, The 5-membered heteroaryl group is selected from The 5-membered unsaturated heterocyclic group is selected from And any one of the following conditions (1)-(3) is met: (1) When the A12 ring is selected from a 5-membered heteroaryl group, the A12 ring is optionally substituted by Rx, (2) When the A12 ring is selected from a 5-membered unsaturated heterocyclic group, any one of the following conditions (2-1) to (2-5) is satisfied: (2-1) the A12 ring is optionally substituted by Rm; (2-2) The A12 ring is optionally substituted by Ry, Rz and Rm; (2-3) The A12 ring is optionally substituted by Ry and Rm; (2-4) the A12 ring is optionally substituted by 2 Rm; (2-5) the A12 ring is optionally substituted by Rz; (3) Ring A12 is selected from When the A12 ring is optionally substituted by 1-2 substituents selected from Rz and Rm; Wherein, Rx is selected from hydroxyl, Ry is selected from methyl, -CHF ₂ , -CF ₃ , -CD ₃ , -CH ₂ CH ₃ , -CH ₂ CHF ₂ , -CH ₂ CF ₃ , Rz is selected from methyl, Or, Ry, Rz and the carbon atoms to which they are connected together form Wherein, carbon atom 1' is the carbon atom connected to Ry and Rz; Rm is an oxo group; most preferably, the A12 ring and its optional substituents as a whole are selected from the following: The B12 ring is selected from: It is optionally substituted by 1-3 substituents selected from the group consisting of sulfur pentafluoride, -OH, C1-C6 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, C1-C6 alkyl substituted with 1-6 halogens, halogen, nitro, cyano, and amino. Preferably, It is optionally substituted by 1-2 substituents selected from the group consisting of pentafluorosulfur, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, and halogen; More preferably, the above Optionally substituted by 1-2 substituents selected from: pentafluorosulfur, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-6 halogens, halogen; or the above Optionally substituted by 1-2 substituents, the substituents are selected from: C1-C6 alkyl, C1-C6 alkyl substituted by 1-6 halogens; More preferably, the above Optionally substituted by 1-2 substituents selected from: -CF ₃ , -Cl, -SF ₅ , -CH ₃ , -F, -OCH ₃ ; or Optionally substituted by 1-2 substituents, the substituents are selected from: -CF ₃ , -CH ₃ ; further preferably, the above The substitution positions of the substituents thereon are: 2-position monosubstitution, 3-position monosubstitution, 5-position monosubstitution, 4-, 5-position disubstitution, 5-, 6-position disubstitution, 2-, 5-position disubstitution, 3-, 5-position disubstitution; The substitution positions of the substituents thereon are 3-position monosubstitution and 5-position monosubstitution; The substitution position of the substituent thereon is 5-position monosubstitution; The substitution position of the substituent thereon is 6-position monosubstitution; The substitution position of the substituent thereon is mono- or di-substituted at the 5- or 6-position; The substitution position of the substituent thereon is 5-position monosubstitution; The substitution position of the substituent thereon is 5-position monosubstitution; The substitution position of the substituent thereon is 5-position monosubstitution; The substitution position of the substituent thereon is 5-position monosubstitution; The substitution position of the substituent thereon is 5-position monosubstitution; most preferably, the B12 ring is selected from: R ₁₂ is selected from the group consisting of aminosulfonyl substituted by 1-2 C1-C6 alkyl groups on N, carbamoyl substituted by 1-2 C1-C6 alkyl groups on N, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-6 halogens, C1-C6 alkyl substituted by amino, C1-C6 alkoxy substituted by 1-6 halogens, C1-C5 heteroaryl, C1-C6 alkoxy, C1-C6 alkoxy substituted by hydroxy, C1-C6 alkoxy substituted by 5-6 membered heteroaryl -C6 alkoxy, C3-C5 heterocyclyloxy, carboxyl (-COOH), ester (-CO-O-C1-C6 alkyl), hydroxyl, amino, halogen, cyano, C2-C6 alkenyl, C1-C6 alkyl substituted by C6-C10 aryl, 5-6 membered heterocyclyl; wherein C3-C5 heterocyclyl is arbitrarily substituted by C1-C3 alkyl, C6-C10 aryl is arbitrarily substituted by 1-6 halogens, 5-6 membered heterocyclyl is arbitrarily substituted by C1-C3 alkyl or hydroxyl; or two R ₁₂ , together with the atoms to which they are connected, form a C6-C10 aromatic ring, a partially unsaturated C5-C6 carbocyclic ring, a partially unsaturated 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring, wherein the partially unsaturated C5-C6 carbocyclic ring, the partially unsaturated 5-6 membered heterocyclic ring or the 5-6 membered heteroaromatic ring are each optionally substituted by 1-6 groups selected from halogen and deuterium; more preferably, R _{R 12} is selected from the group consisting of aminosulfonyl substituted by 1-2 C1-C6 alkyl groups on N, carbamoyl substituted by 1-2 C1-C6 alkyl groups on N, pyridyl C1-C6 alkoxy, C1-C6 alkoxy substituted by hydroxy, C3 heterocyclyloxy, carboxyl (-COOH), ester (-CO-O-C1-C6 alkyl), hydroxy, amino, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkyl substituted by 1-3 halogens, C1-C6 alkyl substituted by amino, halogen, cyano, C2-C6 alkenyl, C1-C6 alkyl substituted by phenyl, tetrahydropyrrolyl, piperazinyl, wherein C3 heterocyclyl is arbitrarily substituted by C1-C3 alkyl, tetrahydropyrrolyl is arbitrarily substituted by hydroxy, piperazinyl is arbitrarily substituted by C1-C3 alkyl; or two R ₁₂ , and the atoms to which they are connected together form a benzene ring, a partially unsaturated C5-C6 carbocycle, a partially unsaturated 5-6-membered heterocycle or a 5-membered heteroaromatic ring, wherein the partially unsaturated C5-C6 carbocycle and the partially unsaturated 5-6-membered heterocycle are each optionally substituted by 1 to 6 groups selected from halogen and deuterium; further preferably, R ₁₂ is selected from: -OH, -NH ₂ , -COOH, -COOCH ₃ , -CH ₃ , -CH ₂ CH ₃ , -F, -Cl, -CN, -CHF ₂ , Or two R ₁₂ together with the atoms to which they are attached form: More preferably, the position of R ₁₂ on the ring is selected from: A ₁₂ -position, A ₃₂ -position, A ₂₂ -position; A ₁₂ , A ₂₂ , A ₃₂ , A ₄₂ are independently selected from: N, CH, and only one of them is N, and the rest are CH; Preferably, the compound of formula I-2 is the following formula I-2c: The _A12c ring and its optional substituents as a whole are selected from: Preferably, the _A12c ring and its optional substituents as a whole are selected from: Most preferably, the _A12c ring and its optional substituents as a whole are selected from: A ₁₂ , A ₂₂ , A ₃₂ , A ₄₂ have the same definitions as A ₁₂ , A ₂₂ , A ₃₂ , A ₄₂ in the above formula I-2; R ₁₂ has the same definition as R ₁₂ in the above formula I-2. The compound according to any one of claims 1 to 5, or the tautomer, stereoisomer, geometric isomer, enantiomer, diastereomer, racemate, prodrug, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, ester, isotope, or metabolite thereof, wherein the compound is of formula I-1-1: Wherein, the A111 ring is selected from a 5-membered heteroaryl group, a 5-membered unsaturated heterocyclic group, and the 5-membered heteroaryl group is selected from The 5-membered unsaturated heterocyclic group is selected from And any one of the following conditions (1)-(2) is met: (1) When the A111 ring is selected from a 5-membered heteroaryl group, the A111 ring is optionally substituted by Rx, (2) When the A111 ring is selected from a 5-membered unsaturated heterocyclic group, the A111 ring is optionally substituted by Rm or Rz, or optionally substituted by Rm and Ry; in, Rx is selected from methyl, Ry is selected from methyl, -CHF2, -CF3, -CH2CH3, -CH2CHF2, -CH2CF3, Rz is selected from halogen (preferably Br); Rm is oxo; Preferably, the A111 ring and its optional substituents as a whole are selected from the following: More preferably, the A111 ring and its optional substituents as a whole are selected from Further preferably, the A111 ring and its optional substituents as a whole are selected from Most preferably, the A111 ring and its optional substituents as a whole are The B111 ring is selected from: It is optionally substituted by 1-3 substituents selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, C1-C6 alkoxy substituted with 1-6 halogens, halogen; preferably, the above Optionally substituted by 1-2 substituents, the substituents are selected from: 1-6 halogen-substituted C1-C6 alkyl, 1-6 halogen-substituted C1-C6 alkoxy; More preferably, the above Optionally substituted with 1-2 substituents selected from: -CF ₃ , -OCF ₃ ; Most preferably, the B111 ring is selected from: Preferably The compound according to any one of claims 1 to 6, or the tautomer, stereoisomer, geometric isomer, enantiomer, diastereomer, racemate, prodrug, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, ester, isotope, or metabolite thereof, wherein the compound is of formula I-1-2: Wherein, the A112 ring is selected from a 5-membered heteroaryl, a 5-membered unsaturated heterocyclic group, The 5-membered heteroaryl group is selected from The 5-membered unsaturated heterocyclic group is selected from And satisfy any one of the following conditions (1)-(2): (1) When the A112 ring is selected from a 5-membered heteroaryl group, the A112 ring is optionally substituted by Rx, (2) When the A112 ring is selected from a 5-membered unsaturated heterocyclic group, the A112 ring is optionally substituted by Rm or Rz, or optionally substituted by Ry and Rm; Wherein, Rx is selected from methyl, Ry is selected from methyl, -CHF ₂ , -CF ₃ , -CH ₂ CH ₃ , -CH ₂ CHF ₂ , -CH ₂ CF ₃ , Rz is selected from halogen (preferably Br), Rm is oxo; Preferably, the A112 ring and its optional substituents as a whole are selected from the following: The B112 ring is selected from: It is optionally substituted by 1-3 substituents selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, C1-C6 alkoxy substituted with 1-6 halogens, halogen; preferably, the above Optionally substituted by 1-2 substituents, the substituents are selected from: 1-6 halogen-substituted C1-C6 alkyl, 1-6 halogen-substituted C1-C6 alkoxy; More preferably, the above Optionally substituted by 1-2 substituents selected from: -CF ₃ , -OCF ₃ ; Most preferably, the B112 ring is: R ₁₁₂ is selected from the group consisting of: aminosulfonyl substituted with 1-2 C1-C6 alkyl groups on N, carbamoyl substituted with 1-2 C1-C6 alkyl groups on N, C1-C6 alkyl groups, C1-C6 alkoxy groups, halogen, cyano, nitro, and amino groups; more preferably, R ₁₁₂ is selected from the group consisting of: aminosulfonyl substituted with 1-2 C1-C6 alkyl groups on N, carbamoyl substituted with 1-2 C1-C6 alkyl groups on N, C1-C6 alkyl groups, halogen, and cyano groups; further preferably, R ₁₁₂ is selected from the group consisting of: -CH ₃ , -CH ₂ CH ₃ , CF ₃ , -F, -Cl, -CN; More preferably, R ₁₁₂ is located in the ring The position on is selected from: 1-position, 2-position, 3-position, 4-position; Preferably, the above formula I-1-2 is Wherein, the A _112c ring and its optional substituents as a whole are selected from Preferably, the A _112c ring and its optional substituents as a whole are selected from More preferably, the A _112c ring and its optional substituents as a whole are R ₁₁₂ has the same definition as R ₁₁₂ in the above formula I-1-2; Alternatively, the compound is of the following formula I-2-1: in: The A121 ring is selected from a 5-membered heteroaryl group and a 5-membered unsaturated heterocyclic group, wherein the 5-membered heteroaryl group is selected from The 5-membered unsaturated heterocyclic group is selected from And any one of the following conditions (1)-(2) is met: (1) When the A121 ring is selected from a 5-membered heteroaryl group, the A121 ring is optionally substituted by Rx, (2) When the A121 ring is selected from a 5-membered unsaturated heterocyclic group, any one of the following conditions (2-1) to (2-5) is satisfied: (2-1) the A121 ring is optionally substituted by Rm; (2-2) the A121 ring is optionally substituted by Ry, Rz and Rm; (2-3) the A121 ring is optionally substituted by Ry and Rm; (2-4) the A121 ring is optionally substituted by 2 Rm; (2-5) the A121 ring is optionally substituted by Rz; in, Rx is selected from hydroxyl, Ry is selected from methyl, -CHF ₂ , -CF ₃ , -CD ₃ , -CH ₂ CH ₃ , -CH ₂ CHF ₂ , -CH ₂ CF ₃ , Rz is selected from methyl, Or, Ry, Rz and the carbon atoms to which they are connected together form Among them, carbon atom 1' is the carbon atom connected to Ry and Rz; Rm is an oxo group; Most preferably, the A121 ring and its optional substituents as a whole are selected from the following: The B121 ring is selected from: It is optionally substituted by 1-3 substituents selected from the group consisting of sulfur pentafluoride, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, halogen, nitro, cyano, and amino. Preferably, It is optionally substituted by 1-2 substituents selected from the group consisting of sulfur pentafluoride, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, and halogen; More preferably, the above Optionally substituted by 1-2 substituents selected from: pentafluorosulfur, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-6 halogens, halogen; or the above Optionally substituted by 1-2 substituents, the substituents are selected from: C1-C6 alkyl, C1-C6 alkyl substituted by 1-6 halogens; More preferably, the above Optionally substituted by 1-2 substituents, the substituents are selected from: -CF ₃ , -Cl, -SF ₅ , -CH ₃ , -F, -OCH ₃ ; or the above Optionally substituted by 1-2 substituents, the substituents are selected from: -CF ₃ , -CH ₃ ; further preferably, the above The substitution positions of the substituents thereon are: 2-position monosubstitution, 3-position monosubstitution, 5-position monosubstitution, 4-, 5-position disubstitution, 5-, 6-position disubstitution, 2-, 5-position disubstitution, 3-, 5-position disubstitution; The substitution positions of the substituents thereon are 3-position monosubstitution and 5-position monosubstitution; The substitution position of the substituent thereon is 5-position monosubstitution; The substitution position of the substituent thereon is 6-monosubstituted, The substitution position of the substituent thereon is 5-position or 6-position mono- or di-substitution; The substitution position of the substituent thereon is 5-position monosubstitution; The substitution position of the substituent thereon is 5-monosubstitution; The substitution position of the substituent thereon is 5-position monosubstitution; The substitution position of the substituent thereon is 5-position monosubstitution; The substitution position of the substituent thereon is 5-position monosubstitution; Most preferably, the B121 ring is selected from: R ₁₂₁ is selected from the group consisting of aminosulfonyl substituted by 1-2 C1-C6 alkyl groups on N, carbamoyl substituted by 1-2 C1-C6 alkyl groups on N, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-6 halogens, C1-C6 alkyl substituted by amino, C1-C6 alkoxy substituted by 1-6 halogens, C1-C5 heteroaryl, C1-C6 alkoxy, C1-C6 alkoxy substituted by hydroxy, C1-C6 alkoxy substituted by 5-6 membered heteroaryl 1-C6 alkoxy, C3-C5 heterocyclyloxy, carboxyl (-COOH), ester (-CO-O-C1-C6 alkyl), hydroxyl, amino, halogen, cyano, C2-C6 alkenyl, C1-C6 alkyl substituted by C6-C10 aryl, 5-6 membered heterocyclyl; wherein C3-C5 heterocyclyl is arbitrarily substituted by C1-C3 alkyl, C6-C10 aryl is arbitrarily substituted by 1-6 halogens, 5-6 membered heterocyclyl is arbitrarily substituted by C1-C3 alkyl or hydroxyl; or two R ₁₂₁ , and the atoms to which they are connected together form a C6-C10 aromatic ring, a partially unsaturated C5-C6 carbocyclic ring, a partially unsaturated 5-6-membered heterocyclic ring or a 5-6-membered heteroaromatic ring, wherein the partially unsaturated C5-C6 carbocyclic ring, the partially unsaturated 5-6-membered heterocyclic ring or the 5-6-membered heteroaromatic ring are each optionally substituted by 1 to 6 groups selected from halogen and deuterium; more preferably, R _{R 121} is selected from the group consisting of aminosulfonyl substituted by 1-2 C1-C6 alkyl groups on N, carbamoyl substituted by 1-2 C1-C6 alkyl groups on N, pyridyl C1-C6 alkoxy, C1-C6 alkoxy substituted by hydroxy, C3 heterocyclyloxy, carboxyl (-COOH), ester (-CO-O-C1-C6 alkyl), hydroxy, amino, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkyl substituted by 1-3 halogens, C1-C6 alkyl substituted by amino, halogen, cyano, C2-C6 alkenyl, C1-C6 alkyl substituted by phenyl, tetrahydropyrrolyl, piperazinyl, wherein C3 heterocyclyl is arbitrarily substituted by C1-C3 alkyl, tetrahydropyrrolyl is arbitrarily substituted by hydroxy, piperazinyl is arbitrarily substituted by C1-C3 alkyl; or two R ₁₂₁ , and the atoms to which they are connected together form a benzene ring, a partially unsaturated C5-C6 carbocycle, a partially unsaturated 5-6-membered heterocycle or a 5-membered heteroaromatic ring, wherein the partially unsaturated C5-C6 carbocycle and the partially unsaturated 5-6-membered heterocycle are each optionally substituted by 1 to 6 groups selected from halogen (preferably -F) and deuterium; further preferably, R ₁₂₁ is selected from: -OH, -NH ₂ , -COOH, -COOCH ₃ , -CH ₃ , -CH ₂ CH ₃ , -F, -Cl, -CN, -CHF ₂ , -CF ₃ , Or two R ₁₂₁ together with the atoms to which they are attached form: More preferably, the position of R ₁₂₁ on the ring is selected from: 1-position, 3-position, 2-position, preferably 3-position, 2-position; Preferably, the compound is of the following formula I-1-2c: Wherein, the A _112c ring and its optional substituents as a whole are selected from Preferably, the A _112c ring and its optional substituents as a whole are selected from More preferably, the A _112c ring and its optional substituents as a whole are R ₁₁₂ has the same definition as R ₁₁₂ in the above formula I-1-2. A compound according to any one of claims 1 to 7, or a tautomer, a stereoisomer, a geometric isomer, an enantiomer, a diastereomer, a racemate, a prodrug, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a hydrate, an ester, an isotope, or a metabolite thereof, wherein the compound is of the following formula I-2-2, formula I-2-3, formula I-2-4 or formula I-2-5: Among them, the A122 ring is selected from Preferably, the A122 ring is selected from The B122 ring is selected from: It is optionally substituted by 1 substituent, the substituent is selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, halogen; preferably, the substituent is selected from: C1-C6 alkyl substituted with 1-6 halogens; more preferably, the substituent is selected from -CF ₃ ; further more preferably, the B122 ring is The A123 ring is selected from Preferably, the A123 ring is selected from The B123 ring is selected from: It is optionally substituted by 1 substituent, the substituent is selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, halogen; preferably, the substituent is selected from: C1-C6 alkyl substituted with 1-6 halogens; more preferably, the substituent is selected from -CF ₃ ; further more preferably, the B123 ring is Wherein, the A124 ring is selected from: And the is optionally substituted by Rm or optionally substituted by Ry and Rm, Optionally substituted with 1-2 substituents selected from Rz and Rm; Wherein Ry is methyl; Rz is selected from Rm is an oxo group; Preferably, the A124 ring and its optional substituents as a whole are selected from the following: More preferably, the A124 ring and its optional substituents as a whole are selected from B124 ring is selected from It is optionally substituted by 1 substituent selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, halogen; preferably, the substituent is selected from: C1-C6 alkyl substituted with 1-6 halogens; More preferably, the substituent is selected from -CF ₃ ; further more preferably, the B124 ring is wherein: the definition of A125 ring is the same as the definition of A12 ring in claim 5; A ₁₂₅ , A ₂₂₅ , A ₃₂₅ , A ₄₂₅ are independently selected from: N, CH, and only one of them is N, and the rest are CH; preferably, A ₁₂₅ , A ₂₂₅ , A ₃₂₅ are CH, and A ₄₂₅ is N; the definition of R ₁₂₅ is the same as the definition of R ₁₂ in claim 5; The B125 ring is selected from: It is optionally substituted by 1 substituent selected from the group consisting of: pentafluorosulfur, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, halogen; and the above The substitution position of the substituent thereon is: 5-position monosubstitution; preferably, the B125 ring is selected from: It is optionally substituted by 1 substituent selected from: -CF ₃ , -Cl, -SF ₅ , -CH ₃ , -F, -OCH ₃ ; and The substitution position of the substituent thereon is: 5-position monosubstitution; more preferably, the B125 ring is selected from: Most preferably, the B125 ring is The compound according to any one of claims 1 to 8, or a tautomer, a stereoisomer, a geometric isomer, an enantiomer, a diastereomer, a racemate, a prodrug, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a hydrate, an ester, an isotope, or a metabolite thereof, wherein the compound is of the following formula I-3: in, The A13 ring is selected from a 5-6 membered heteroaryl, a 5-6 membered heterocyclic group, and a phenyl group, and the A13 ring is optionally substituted by 1-3 substituents selected from Rx, Ry, Rz, and Rm; preferably, the A13 ring is selected from a 5-membered heteroaryl, a 5-membered unsaturated heterocyclic group, a 6-membered saturated heterocyclic group, a phenyl group, and a pyridyl group, and the A13 ring is optionally substituted by 1-3 substituents selected from Rx, Ry, Rz, and Rm; more preferably, the A13 ring is selected from a 5-membered heteroaryl, a 5-membered unsaturated heterocyclic group, a 6-membered saturated Heterocyclic group, phenyl, pyridyl, the 5-membered heteroaryl group contains 2-4 heteroatoms selected from N, O, and S, and the A13 ring is optionally substituted by 1-3 substituents selected from Rx, Ry, Rz, and Rm; further preferably, the A13 ring is selected from a 5-membered heteroaryl group, a 5-membered unsaturated heterocyclic group, a thiomorpholinyl group, a tetrahydrothiopyranyl group, a phenyl group, and a pyridyl group, the 5-membered heteroaryl group contains 2-4 heteroatoms selected from N, O, and S, and satisfies any one of the following conditions (1)-(3): (1) When the A13 ring is selected from a 5-membered heteroaryl group, the A13 ring is optionally substituted by Rx, (2) When the A13 ring is selected from a 5-membered unsaturated heterocyclic group, any one of the following conditions (2-1) to (2-5) is satisfied: (2-1) the A13 ring is optionally substituted by Rm; (2-2) the A13 ring is optionally substituted by Ry, Rz and Rm; (2-3) The A13 ring is optionally substituted by Ry and Rm; (2-4) the A13 ring is optionally substituted by 2 Rm; (2-5) the A13 ring is optionally substituted by Rz; (3) When the A13 ring is selected from thiomorpholinyl, tetrahydrothiopyranyl, phenyl, and pyridyl, the A13 ring is optionally substituted by 1-2 substituents selected from Rz and Rm; More preferably, the A13 ring is selected from a 5-membered heteroaryl, a 5-membered unsaturated heterocyclic group, The 5-membered heteroaryl group is selected from The 5-membered unsaturated heterocyclic group is selected from And any one of the following conditions (1)-(3) is met: (1) When the A13 ring is selected from a 5-membered heteroaryl group, the A13 ring is optionally substituted by Rx, (2) When the A13 ring is selected from a 5-membered unsaturated heterocyclic group, any one of the following conditions (2-1) to (2-5) is satisfied: (2-1) the A13 ring is optionally substituted by Rm; (2-2) the A13 ring is optionally substituted by Ry, Rz and Rm; (2-3) The A13 ring is optionally substituted by Ry and Rm; (2-4) the A13 ring is optionally substituted by 2 Rm; (2-5) the A13 ring is optionally substituted by Rz; (3) When the A13 ring is selected from thiomorpholinyl, tetrahydrothiopyranyl, phenyl, and pyridyl, the A13 ring is optionally substituted by 1-2 substituents selected from Rz and Rm; Wherein, Rx is selected from C1-C6 alkyl, 4-6 membered saturated heterocyclic group (preferably, the 4-6 membered saturated heterocyclic group contains 1 heteroatom selected from N, O, S), -C(＝O)NRaRb, -S(＝O) ₂ NRaRb, carboxyl (-COOH), ester group (-CO-O-C1-C6 alkyl), hydroxyl, -NRaC(＝O)Rc, and the Rx is optionally substituted by 1-2 substituents selected from Rn; preferably, Rx is selected from methyl, ethyl, oxetanyl, tetrahydropyrrolyl, tetrahydropyranyl, piperidinyl, -C(＝O)NRaRb, -NRaC(＝O)Rc, -S(＝O) ₂ NRaRb, carboxyl (-COOH), ester group (-CO-O-C1-C6 alkyl), hydroxyl; Rn is selected from C1-C6 alkyl, -NRaRb, -C(=O)NRaRb, oxo, 5-6 membered saturated heterocyclic group (preferably, the 5-6 membered saturated heterocyclic group contains 2 heteroatoms selected from N, O, S), C1-C6 alkoxy, carboxyl, hydroxyl; preferably, Rn is selected from methyl, ethyl, -NRaRb, -C(=O)NRaRb, oxo, morpholino, methoxy, hydroxyl, carboxyl; Ra, Rb, Rc are each independently selected from H, C1-C6 alkyl, cyano, C3-C6 cycloalkyl, or Ra, Rb and the carbon atom to which they are commonly attached together form azetidine, and the azetidine is optionally substituted with hydroxyl; preferably, Ra, Rb, Rc are each independently selected from H, methyl, cyano, cyclopropyl, or Ra, Rb and the carbon atom to which they are commonly attached together form azetidine, and the azetidine is optionally substituted with hydroxyl; Most preferably, Rx is selected from hydroxy, methyl, Ry is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxy, C1-C6 alkyl substituted by 1-6 halogens, C1-C6 alkyl substituted by 1-6 deuteriums, C1-C6 alkyl substituted by C3-C6 cycloalkyl, C1-C6 alkyl substituted by C6-C10 aryl, substituted C1-C6 alkyl, 4-6 membered saturated heterocyclic group; preferably, Ry is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxyl, C1-C6 alkyl substituted by 1-6 halogens, C1-C6 alkyl substituted by 1-6 deuteriums, C1-C6 alkyl substituted by C3-C6 cycloalkyl, C1-C6 alkyl substituted by C6-C10 aryl, More preferably, Ry is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxy, C1-C6 alkyl substituted by 1-3 halogens, C1-C6 alkyl substituted by 1-3 deuteriums, C1-C6 alkyl substituted by cyclopropyl, C1-C6 alkyl substituted by phenyl, A 5-6 membered saturated heterocyclic group containing 1 heteroatom; further preferably, Ry is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxy, C1-C6 alkyl substituted by 1-3 halogens, C1-C6 alkyl substituted by 1-3 deuteriums, C1-C6 alkyl substituted by cyclopropyl, C1-C6 alkyl substituted by phenyl, tetrahydropyrrolyl, piperidinyl; most preferably, Ry is selected from methyl, -CHF ₂ , -CF ₃ , -CD ₃ , -CH ₂ CH ₃ , -CH ₂ CHF ₂ , -CH ₂ CF ₃ , Rz is selected from C1-C6 alkyl, halogen, Preferably, Rz is selected from methyl, Br, Or, Ry, Rz and the carbon atoms to which they are commonly connected together form a 4-6-membered saturated carbocyclic ring or a 4-6-membered saturated heterocyclic ring; or preferably, Ry, Rz and the carbon atoms to which they are commonly connected together form a 4-6-membered saturated carbocyclic ring or a 4-6-membered saturated heterocyclic ring, wherein the 4-6-membered saturated heterocyclic ring contains 1 heteroatom; or more preferably, Ry, Rz and the carbon atoms to which they are commonly connected together form cyclobutane, cyclopentane, cyclohexane, piperidine or tetrahydropyran; or most preferably, Ry, Rz and the carbon atoms to which they are commonly connected together form Among them, carbon atom 1' is the carbon atom connected to Ry and Rz; Rm is an oxo group; Still further preferably, the A13 ring and its optional substituents as a whole are selected from the following: Still more preferably, the A13 ring is selected from: And the is optionally substituted by Rm, or optionally substituted by Ry and Rm; wherein Ry is selected from methyl, -CHF ₂ , -CF ₃ , -CH ₂ CH ₃ , -CH ₂ CHF ₂ , -CH ₂ CF ₃ ; Rm is an oxo group; Most preferably, the A13 ring and its optional substituents as a whole are selected from the following: Preferably, the _A13 ring and its optional substituents as a whole are selected from More preferably, the _A13 ring and its optional substituents as a whole are The B13 ring is selected from: It is optionally substituted by 1-2 substituents selected from: C1-C6 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, C1-C6 alkyl substituted by 1-6 halogens, halogen, amino; preferably, the above Optionally substituted by 1-2 substituents, the substituents are selected from: C1-C6 alkyl, C1-C6 alkyl substituted by 1-6 halogens; More preferably, the above Optionally substituted with 1 substituent selected from: -CF ₃ , Most preferably, the B13 ring is selected from: L ₁₃ is selected from a direct bond, NH, O, S; preferably, L ₁₃ is selected from a direct bond, NH; R ₁₃ is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-6 halogens, C1-C6 alkoxy substituted by 1-6 halogens, C1-C6 alkyl substituted by cyano, halogen, cyano, amino, C1-C6 alkyl substituted by amino, C2-C6 alkenyl, 5-6 membered saturated heterocyclic group substituted by C1-C3 alkyl (preferably 6 membered saturated heterocyclic group substituted by C1-C3 alkyl); or two R ₁₃ , together with the atoms to which they are attached, form a C6-C10 aromatic ring, a partially unsaturated C5-C6 carbocyclic ring, a partially unsaturated 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring, wherein the partially unsaturated C5-C6 carbocyclic ring, the partially unsaturated 5-6 membered heterocyclic ring or the 5-6 membered heteroaromatic ring are each optionally substituted by 1-6 groups selected from halogen and deuterium; more preferably, R ₁₃ is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-3 halogens, C1-C6 alkyl substituted by cyano, halogen, cyano, amino, C1-C6 alkyl substituted by amino, C2-C6 alkenyl, piperazinyl substituted by C1-C3 alkyl; or two R ₁₃ , together with the atoms to which they are attached, form a benzene ring, a partially unsaturated C5 carbocycle, a partially unsaturated 5-6-membered heterocycle or a 5-membered heteroaromatic ring, wherein the partially unsaturated C5 carbocycle and the partially unsaturated 5-6-membered heterocycle are each optionally substituted by 1-6 groups selected from halogen and deuterium; More preferably, R ₁₃ is selected from: -OCH ₃ , -CH ₃ , -CH ₂ CH ₃ , -F, -Cl, -CN, -CF ₃ , -CHF ₂ , -NH ₂ , Or two R ₁₃ together with the atoms to which they are attached form: More preferably, the position of R ₁₃ on the ring is selected from: A ₂₃ , A ₃₃ ; A ₁₃ , A ₂₃ , A ₃₃ , A ₄₃ are independently selected from: N, CH, and only two of them are N, and the rest are CH; preferably, A ₁₃ , A ₂₃ , A ₃₃ , A ₄₃ are selected from the following combinations: 1) A ₁₃ and A ₄₃ are both N, and A ₂₃ and A ₃₃ are both CH; 2) A ₃₃ and A ₄₃ are both N, and A ₁₃ and A ₂₃ are both CH; 3) A ₂₃ and A ₄₃ are both N, and A ₁₃ and A ₃₃ are both CH. A compound according to any one of claims 1 to 9, or a tautomer, a stereoisomer, a geometric isomer, an enantiomer, a diastereomer, a racemate, a prodrug, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a hydrate, an ester, an isotope, or a metabolite thereof, wherein the compound is of the following formula I-3-1, formula I-3-2 or formula I-3-3: Wherein, the A131 ring is selected from: And the is optionally substituted by Rm, or is optionally substituted by Ry and Rm; Wherein, Ry is selected from methyl, -CHF ₂ , -CF ₃ , -CH ₂ CH ₃ , -CH ₂ CHF ₂ , -CH ₂ CF _3, -CH ₂ CH ₂ OH; Rm is an oxo group; Preferably, the A131 ring and its optional substituents as a whole are selected from the following: More preferably, the A131 ring and its optional substituents as a whole are selected from the following: Most preferably, the A131 ring and its optional substituents as a whole are selected from: The B131 ring is selected from: It is optionally substituted by 1 substituent, the substituent is selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, halogen; preferably, the substituent is selected from: C1-C6 alkyl, C1-C6 alkyl substituted with 1-6 halogens; more preferably, the substituent is selected from: -CF ₃ , More preferably, the B131 ring is L ₁₃₁ is selected from a direct bond, NH, O, S; preferably, L ₁₃₁ is selected from a direct bond, NH; A ₁₃₁ , A ₂₃₁ , A ₃₃₁ , A ₄₃₁ are independently selected from: N, CH, and only 2 of them are N, and the rest are CH; preferably, A ₁₃₁ , A ₂₃₁ , A ₃₃₁ , A ₄₃₁ are selected from the following combinations: 1) A ₁₃₁ , A ₄₃₁ are both N, A ₂₃₁ , A ₃₃₁ are both CH; 2) A ₃₃₁ , A ₄₃₁ are both N, A ₁₃₁ , A ₂₃₁ are both CH; 3) A ₂₃₁ and A ₄₃₁ are both N, and A ₁₃₁ and A ₃₃₁ are both CH; Wherein, the definition of A131c ring is the same as that of A131 ring in the above formula I-3-1; A ₁₃₁ , A ₂₃₁ , A ₃₃₁ , and A ₄₃₁ are defined the same as A ₁₃₁ , A ₂₃₁ , A ₃₃₁ , and A ₄₃₁ in the above formula I-3-1; Wherein, the A132 ring is selected from: And the is optionally substituted by Rm, or is optionally substituted by Ry and Rm; wherein Ry is selected from methyl, -CHF ₂ , -CF ₃ , -CD ₃ , -CH ₂ CH ₃ , -CH ₂ CHF ₂ , -CH ₂ CF _3, -CH ₂ CH ₂ OH; and Rm is oxo; Preferably, the A132 ring and its optional substituents as a whole are selected from the following: More preferably, the A132 ring and its optional substituents as a whole are selected from the following: Most preferably, the A132 ring and its optional substituents as a whole are selected from: The B132 ring is selected from: It is optionally substituted by 1 substituent, the substituent is selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, halogen; preferably, the substituent is selected from: C1-C6 alkyl substituted with 1-6 halogens; more preferably, the substituent is selected from -CF ₃ ; further more preferably, the B132 ring is R ₁₃₂ is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-6 halogens, C1-C6 alkoxy substituted by 1-6 halogens, C1-C6 alkyl substituted by cyano, halogen, cyano, amino, C1-C6 alkyl substituted by amino, C2-C6 alkenyl, 6-membered saturated heterocyclic group substituted by C1-C3 alkyl; or two R ₁₃₂ together with the atoms to which they are attached form a C6-C10 aromatic ring, a partially unsaturated C5-C6 carbocyclic ring, a partially unsaturated 5-6-membered heterocyclic ring or a 5-6-membered heteroaromatic ring, wherein the partially unsaturated C5-C6 carbocyclic ring, the partially unsaturated 5-6-membered heterocyclic ring or the 5-6-membered heteroaromatic ring are each optionally substituted by 1-6 groups selected from halogen and deuterium; more preferably, R ₁₃₂ is selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-3 halogens, C1-C6 alkyl substituted by cyano, halogen, cyano, amino, C1-C6 alkyl substituted by amino, C2-C6 alkenyl, piperazinyl substituted by C1-C3 alkyl; or two R ₁₃₂ together with the atoms to which they are attached form a benzene ring, a partially unsaturated C5 carbocycle, a partially unsaturated 5-6-membered heterocycle or a 5-membered heteroaromatic ring, wherein the partially unsaturated C5 carbocycle and the partially unsaturated 5-6-membered heterocycle are each optionally substituted by 1-6 groups selected from halogen (preferably -F) and deuterium; More preferably, R ₁₃₂ is selected from: -OCH ₃ , -CH ₃ , -CH ₂ CH ₃ , -F, -Cl, -CN, -CF ₃ , -CHF ₂ , -NH ₂ , Or two R ₁₃₂ together with the atoms to which they are attached form: More preferably, the position of R ₁₃₂ on the ring is selected from: A ₂₃₂ , A ₃₃₂ ; A ₁₃₂ , A ₂₃₂ , A ₃₃₂ , A ₄₃₂ are independently selected from: N, CH, and only 2 of them are N, and the rest are CH; preferably, A ₁₃₂ , A ₂₃₂ , A ₃₃₂ , A ₄₃₂ are selected from the following combination: A ₁₃₂ , A ₄₃₂ are both N, A ₂₃₂ , A ₃₃₂ are both CH; Preferably, the formula I-3-2 is Formula I-3-2c, wherein the definition of A132c ring is the same as the definition of A132 ring in the above formula I-3-2; the definition of _R132 is the same as the definition of _R132 in the above formula I-3-2; the definitions of _A132 , _A232 , _A332 , _A432 are the same as the definitions of _A132 , _A232 , _A332 , _A432 in the above formula I-3-2; Wherein: the definition of A133 ring is the same as the definition of A13 ring in claim 9; the definition of B133 ring is the same as the definition of B13 ring in claim 9; the definition of R ₁₃₃ is the same as the definition of R ₁₃ in claim 9; or, the compound is the following formula I-3-4: in: The definition of A134 ring is the same as that of A13 ring in claim 9; preferably, A134 ring and its optional substituents as a whole are selected from More preferably, the A134 ring and its optional substituents as a whole are selected from: The definition of B134 ring is the same as that of B13 ring in claim 9; preferably, B134 ring is selected from: It is optionally substituted by 1-2 substituents selected from: C1-C6 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, C1-C6 alkyl substituted by 1-6 halogens, halogen, amino; more preferably, the above Optionally substituted by 1-2 substituents, the substituents are selected from: C1-C6 alkyl, C1-C6 alkyl substituted by 1-6 halogens; further preferably, the above Optionally substituted with 1 substituent selected from: -CF ₃ , Still more preferably, the B134 ring is selected from: Most preferably, the B134 ring is The definition of R ₁₃₄ is the same as that of R ₁₃ in claim 9; preferably, two R ₁₃₄ , together with the atoms to which they are connected, form a 5-membered heteroaromatic ring; More preferably, or two R ₁₃₄ together with the atom to which they are attached form: Alternatively, the compound is of the following formula I-3-5: in: The definition of A135 ring is the same as that of A13 ring in claim 9; The B135 ring is selected from: It is optionally substituted by 1 substituent selected from: C1-C6 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, C1-C6 alkyl substituted with 1-6 halogens, halogen, amino; and the above The substitution position of the substituent thereon is: 5-position monosubstitution; preferably, the above Optionally substituted by 1 substituent selected from: C1-C6 alkyl, C1-C6 alkyl substituted with 1-6 halogens; and The substitution position of the substituent thereon is: 5-position monosubstitution; more preferably, the B135 ring is selected from: Most preferably, the B135 ring is R ₁₃₅ has the same definition as R ₁₃ in claim 9; A ₁₃₅ , A ₂₃₅ , A ₃₃₅ , A ₄₃₅ are independently selected from: N, CH, and only two of them are N, and the rest are CH; preferably, A ₁₃₅ , A ₂₃₅ , A ₃₃₅ , A ₄₃₅ are selected from the following combinations: 1) A ₁₃₅ and A ₄₃₅ are both N, and A ₂₃₅ and A ₃₃₅ are both CH; 2) A ₃₃₅ and A ₄₃₅ are both N, and A ₁₃₅ and A ₂₃₅ are both CH; 3) A ₂₃₅ and A ₄₃₅ are both N, and A ₁₃₅ and A ₃₃₅ are both CH; Alternatively, the compound is of the following formula I-4: in: Y ₁₄ is selected from N, CH; The A14 ring is selected from a 5-membered heteroaryl group, a 5-membered unsaturated heterocyclic group, and the 5-membered heteroaryl group is selected from The 5-membered unsaturated heterocyclic group is selected from And any one of the following conditions (1)-(2) is met: (1) When the A14 ring is selected from a 5-membered heteroaryl group, the A14 ring is optionally substituted by Rx, (2) When the A14 ring is selected from a 5-membered unsaturated heterocyclic group, any one of the following conditions (2-1) to (2-5) is satisfied: (2-1) the A14 ring is optionally substituted by Rm; (2-2) the A14 ring is optionally substituted by Ry, Rz and Rm; (2-3) the A14 ring is optionally substituted by Ry and Rm; (2-4) the A14 ring is optionally substituted by 2 Rm; (2-5) the A14 ring is optionally substituted by Rz; in, Rx is selected from hydroxyl, Ry is selected from methyl, -CHF ₂ , -CF ₃ , D ₃ , -CH ₂ CH ₃ , -CH ₂ CHF ₂ , -CH ₂ CF ₃ , Rz is selected from methyl, Or, Ry, Rz and the carbon atoms to which they are connected together form Among them, carbon atom 1' is the carbon atom connected to Ry and Rz; Rm is an oxo group; Most preferably, the A14 ring and its optional substituents as a whole are selected from the following: The B14 ring is selected from: It is optionally substituted by 1-3 substituents selected from the group consisting of: pentafluorosulfur, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, halogen, nitro, cyano, amino, C3-C4 cycloalkyl,; Preferably, the above It is optionally substituted by 1-2 substituents selected from the group consisting of pentafluorosulfur, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, and halogen; More preferably, the above Optionally substituted by 1-2 substituents selected from: pentafluorosulfur, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-6 halogens, halogen; or the above Optionally substituted by 1-2 substituents selected from: C1-C6 alkyl, C1-C6 alkyl substituted by 1-6 halogens; More preferably, the above Optionally substituted by 1-2 substituents selected from: -CF ₃ , -Cl, -SF ₅ , -CH ₃ , -F, -OCH ₃ , or the above Optionally substituted by 1-2 substituents, the substituents are selected from: -CF ₃ , -CH ₃ ; further preferably, the above The substitution positions of the substituents thereon are: 2-position monosubstitution, 3-position monosubstitution, 5-position monosubstitution, 4-, 5-position disubstitution, 5-, 6-position disubstitution, 2-, 5-position disubstitution, 3-, 5-position disubstitution; The substitution positions of the substituents thereon are 3-position monosubstitution and 5-position monosubstitution; The substitution position of the substituent thereon is 5-position monosubstitution; The substitution position of the substituent thereon is 6-monosubstituted, The substitution position of the substituent thereon is mono- or di-substituted at the 5- or 6-position; The substitution position of the substituent thereon is 5-position monosubstitution; The substitution position of the substituent thereon is 5-monosubstitution; The substitution position of the substituent thereon is 5-position monosubstitution; The substitution position of the substituent thereon is 5-position monosubstitution; The substitution position of the substituent thereon is 5-position monosubstitution; Most preferably, the B14 ring is selected from: R ₁₄ is selected from the group consisting of aminosulfonyl substituted by 1-2 C1-C6 alkyl groups on N, carbamoyl substituted by 1-2 C1-C6 alkyl groups on N, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-6 halogens, C1-C6 alkyl substituted by amino, C1-C6 alkyl substituted by cyano, C1-C6 alkoxy substituted by 1-6 halogens, C1-C5 heteroaryl, C1-C6 alkoxy, C1-C6 alkoxy substituted by hydroxy, C1-C6 alkoxy substituted by 5-6 membered heteroaryl, C1-C6 alkoxy substituted with aryl, C3-C5 heterocyclyloxy, carboxyl (-COOH), ester (-CO-O-C1-C6 alkyl), hydroxyl, amino, halogen, cyano, C2-C6 alkenyl, C1-C6 alkyl substituted with C6-C10 aryl, 5-6 membered heterocyclyl; wherein C3-C5 heterocyclyl is arbitrarily substituted with C1-C3 alkyl, C6-C10 aryl is arbitrarily substituted with 1-6 halogens, 5-6 membered heterocyclyl is arbitrarily substituted with C1-C3 alkyl or hydroxyl; or two R ₁₄ , and the atoms to which they are connected together form a C6-C10 aromatic ring, a partially unsaturated C5-C6 carbocyclic ring, a partially unsaturated 5-6-membered heterocyclic ring or a 5-6-membered heteroaromatic ring, wherein the partially unsaturated C5-C6 carbocyclic ring, the partially unsaturated 5-6-membered heterocyclic ring or the 5-6-membered heteroaromatic ring are each optionally substituted by 1 to 6 groups selected from halogen and deuterium; more preferably, R _{R 14} is selected from the group consisting of aminosulfonyl substituted by 1-2 C1-C6 alkyl groups on N, carbamoyl substituted by 1-2 C1-C6 alkyl groups on N, pyridyl C1-C6 alkoxy, C1-C6 alkoxy substituted by hydroxy, C3 heterocyclyloxy, carboxyl (-COOH), ester (-CO-O-C1-C6 alkyl), hydroxy, amino, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkyl substituted by 1-3 halogens, C1-C6 alkyl substituted by amino, C1-C6 alkyl substituted by cyano, halogen, cyano, C2-C6 alkenyl, C1-C6 alkyl substituted by phenyl, tetrahydropyrrolyl, piperazinyl, wherein C3 heterocyclyl is arbitrarily substituted by C1-C3 alkyl, tetrahydropyrrolyl is arbitrarily substituted by hydroxy, piperazinyl is arbitrarily substituted by C1-C3 alkyl; or two R ₁₄ , and the atoms to which they are connected together form a benzene ring, a partially unsaturated C5-C6 carbocycle, a partially unsaturated 5-6-membered heterocycle or a 5-membered heteroaromatic ring, wherein the partially unsaturated C5-C6 carbocycle and the partially unsaturated 5-6-membered heterocycle are each optionally substituted by 1 to 6 groups selected from halogen (preferably -F) and deuterium; further preferably, R ₁₄ is selected from: -OH, -NH ₂ , -COOH, -COOCH ₃ , -CH ₃ , -CH ₂ CH ₃ , -F, -Cl, -CN, -CHF ₂ , -CF ₃ , Or two R ₁₄ together with the atoms to which they are attached form: The compound according to claim 1, or its tautomer, stereoisomer, geometric isomer, enantiomer, diastereomer, racemate, prodrug, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, ester, isotope, or metabolite, wherein the compound is the following formula II: Ring A2 is selected from: Preferably, the A2 ring is selected from More preferably, the A2 ring is selected from R ₂ is selected from: C1-C6 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, C1-C6 alkyl substituted with 1-6 halogens, halogen, amino; preferably, R ₂ is selected from: C1-C6 alkyl substituted with 1-6 halogens; more preferably, R ₂ is -CF ₃ ; More preferably, _R2 is located at: 5-position monosubstituted; Alternatively, the compound is of the following formula III: The A3 ring is selected from: Preferably, the A3 ring is selected from More preferably, the A3 ring is selected from R ₃ is selected from: C1-C6 alkyl, C1-C6 alkoxy, C3-C4 cycloalkyl, C1-C6 alkyl substituted with 1-6 halogens, halogen, amino; preferably, R ₃ is selected from: C1-C6 alkyl substituted with 1-6 halogens; more preferably, R ₃ is -CF ₃ ; further more preferably, the position of R ₃ is: 5-position monosubstituted. The compound according to claim 1, or a tautomer, a stereoisomer, a geometric isomer, an enantiomer, a diastereomer, a racemate, a prodrug, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a hydrate, an ester, an isotope, or a metabolite thereof, wherein the compound is of the following formula IV: Ring A4 is selected from: And the is optionally substituted by Rm, or is optionally substituted by Ry and Rm; wherein Ry is selected from methyl, -CHF ₂ , -CF ₃ , CD ₃ , -CH ₂ CH ₃ , -CH ₂ CHF ₂ , -CH ₂ CF ₃ , Rm is an oxo group; Preferably, the A4 ring and its optional substituents as a whole are selected from: Preferably, the A4 ring and its optional substituents as a whole are selected from: Most preferably, the A4 ring and its optional substituents as a whole are selected from: The B4 ring is selected from: It is optionally substituted by a substituent selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, halogen; preferably, the substituent is selected from: C1-C6 alkyl substituted with 1-6 halogens; more preferably, the substituent is -CF ₃ ; further more preferably, the B4 ring is The C4 ring is selected from R ₄ is selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-6 halogens, C1-C6 alkoxy substituted by 1-6 halogens, halogen, cyano, amino; or two R ₄ , together with the atoms to which they are connected, form a 5-6-membered heterocyclic ring or a 5-6-membered heteroaromatic ring; preferably, R ₄ is selected from: C1-C6 alkyl; or two R ₄ , together with the atoms to which they are connected, form a 5-6-membered heterocyclic ring or a 5-6-membered heteroaromatic ring; more preferably, two R ₄ , together with the atoms to which they are connected, form a 5-6-membered heterocyclic ring; most preferably, two R ₄ , together with the atoms to which they are connected, form: The compound according to claim 10, or its tautomer, stereoisomer, geometric isomer, enantiomer, diastereomer, racemate, prodrug, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, ester, isotope, or metabolite, wherein the compound is of the following formula IV-1: The A41 ring is selected from: And the is optionally substituted by Rm, or is optionally substituted by Ry and Rm; wherein Ry is selected from methyl, -CHF ₂ , -CF ₃ , CD ₃ , -CH ₂ CH ₃ , -CH ₂ CHF ₂ , -CH ₂ CF ₃ , Rm is an oxo group; Preferably, the A41 ring and its optional substituents as a whole are selected from: Preferably, the A41 ring and its optional substituents as a whole are selected from: Most preferably, the A41 ring and its optional substituents as a whole are selected from: The B41 ring is selected from: It is optionally substituted by 1 substituent, the substituent being selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, halogen; preferably, the substituent is selected from: C1-C6 alkyl substituted with 1-6 halogens; more preferably, the substituent is -CF ₃ ; further more preferably, the B41 ring is A ₄₁ is selected from: O, S; Alternatively, the compound is of the following formula IV-2, The A42 ring is selected from: And the is optionally substituted by Rm, or is optionally substituted by Ry and Rm; wherein Ry is selected from methyl, -CHF ₂ , -CF ₃ , CD ₃ , -CH ₂ CH ₃ , -CH ₂ CHF ₂ , -CH ₂ CF ₃ , Rm is an oxo group; Preferably, the A42 ring and its optional substituents as a whole are selected from: Preferably, the A42 ring and its optional substituents as a whole are selected from: Most preferably, the A42 ring and its optional substituents as a whole are selected from: The B42 ring is selected from: It is optionally substituted by 1 substituent, the substituent being selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, halogen; preferably, the substituent is selected from: C1-C6 alkyl substituted with 1-6 halogens; more preferably, the substituent is -CF ₃ ; further more preferably, the B42 ring is R ₄₂₁ and R ₄₂₂ are each independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, C1-C6 alkoxy substituted with 1-6 halogens, halogen, cyano, and amino; or R ₄₂₁ and R ₄₂₂ , together with the atoms to which they are attached, form a 5-6-membered heterocyclic ring or a 5-6-membered heteroaromatic ring; preferably, R ₄₂₁ and R ₄₂₂ are each independently selected from the group consisting of C1-C6 alkyl; or R ₄₂₁ and R ₄₂₂ , together with the atoms to which they are attached, form a 5-6-membered heterocyclic ring or a 5-6-membered heteroaromatic ring; more preferably, R ₄₂₁ and R ₄₂₂ , together with the atoms to which they are attached, form a 5-6-membered heterocyclic ring; most preferably, R ₄₂₁ and R ₄₂₂ , together with the atoms to which they are attached, form: Alternatively, the compound is of the following formula IV-3, The A43 ring is selected from: And the is optionally substituted by Rm, or is optionally substituted by Ry and Rm; wherein Ry is selected from methyl, -CHF ₂ , -CF ₃ , CD ₃ , -CH ₂ CH ₃ , -CH ₂ CHF ₂ , -CH ₂ CF ₃ , Rm is an oxo group; Preferably, the A43 ring and its optional substituents as a whole are selected from: Preferably, the A43 ring and its optional substituents as a whole are selected from: Most preferably, the A43 ring and its optional substituents as a whole are selected from: The B43 ring is selected from: It is optionally substituted by 1 substituent, the substituent being selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, halogen; preferably, the substituent is selected from: C1-C6 alkyl substituted with 1-6 halogens; more preferably, the substituent is -CF ₃ ; further more preferably, the B43 ring is R ₄₃₁ and R ₄₃₂ are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, C1-C6 alkoxy substituted with 1-6 halogens, halogen, cyano, and amino; or R ₄₃₁ and R ₄₃₂ , together with the atoms to which they are connected, form a 5-6-membered heterocyclic ring or a 5-6-membered heteroaromatic ring; preferably, R ₄₃₁ and R ₄₃₂ are each independently selected from the group consisting of hydrogen, C1-C6 alkyl; or R ₄₃₁ and R ₄₃₂ , together with the atoms to which they are connected, form a 5-6-membered heterocyclic ring or a 5-6-membered heteroaromatic ring; more preferably, R ₄₃₁ and R ₄₃₂ are hydrogen; or R ₄₃₁ and R ₄₃₂ , together with the atoms to which they are connected, form a 5-6-membered heterocyclic ring; most preferably, R ₄₃₁ and R ₄₃₂ are hydrogen; or R ₄₃₁ and R ₄₃₂ , together with the atoms to which they are attached, form: The compound according to claim 1, or its tautomer, stereoisomer, geometric isomer, enantiomer, diastereomer, racemate, prodrug, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, ester, isotope, or metabolite, wherein the compound is of the following formula V: The A5 ring is selected from: And the is optionally substituted by Rm, or is optionally substituted by Ry and Rm; wherein Ry is selected from methyl, -CHF ₂ , -CF ₃ , CD ₃ , -CH ₂ CH ₃ , -CH ₂ CHF ₂ , -CH ₂ CF ₃ , Rm is an oxo group; Preferably, the A5 ring and its optional substituents as a whole are selected from: Preferably, the A5 ring and its optional substituents as a whole are selected from: Most preferably, the A5 ring and its optional substituents as a whole are selected from: The B5 ring is selected from: It is optionally substituted by 1 substituent, the substituent being selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-6 halogens, halogen; preferably, the substituent is selected from: C1-C6 alkyl substituted with 1-6 halogens; more preferably, the substituent is -CF ₃ ; further more preferably, the B5 ring is R ₅ is selected from: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1-6 halogens, C1-C6 alkoxy substituted by 1-6 halogens, halogen, cyano, amino; preferably, R ₅ is selected from C1-C6 alkyl; more preferably, R ₅ is -CH ₃ . The compound according to claim 1, or its tautomer, stereoisomer, geometric isomer, enantiomer, diastereomer, racemate, prodrug, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, ester, isotope, or metabolite, wherein the compound is of the following formula VI: in: R _6′ is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxy, C1-C6 alkyl substituted by 1-6 halogens, C1-C6 alkyl substituted by 1-6 deuteriums, C1-C6 alkyl substituted by C3-C6 cycloalkyl, C1-C6 alkyl substituted by C6-C10 aryl, substituted C1-C6 alkyl; preferably, R _6' is selected from C1-C6 alkyl, C1-C6 alkyl substituted by hydroxy, C1-C6 alkyl substituted by 1-3 halogens, C1-C6 alkyl substituted by 1-3 deuteriums, C1-C6 alkyl substituted by cyclopropyl, C1-C6 alkyl substituted by phenyl, More preferably, R _6' is selected from methyl, -CHF ₂ , -CF ₃ , -CH ₂ CH ₃ , -CH ₂ CHF ₂ , -CH ₂ CF ₃ , Most preferably, R _6' is methyl; The definition of B6 ring is the same as that of Bo ring in claim 1; or, the definition of B6 ring is the same as that of B11 ring in claim 4; or, the definition of B6 ring is the same as that of B12 ring in claim 5; or, the definition of B6 ring is the same as that of B13 ring in claim 9; or, the definition of B6 ring is the same as that of B14 ring in claim 10; or, the definition of B6 ring is the same as that of B4 ring in claim 12; The definition of C6 ring is the same as the definition of Co ring in claim 1; or, the definition of C6 ring is the same as the definition of C4 ring in claim 15; _R6 has the same definition as Ro in claim 1; or, _R6 has the same definition as _R11 in claim 4; or, _R6 has the same definition as _R12 in claim 5; or, _R6 has the same definition as _R13 in claim 9; or, _R6 has the same definition as _R14 in claim 10; or, _R6 has the same definition as _R4 in claim 12; Or the compound is of the following formula Ox: in: The Aox ring is selected from: Preferably, the Aox ring is selected from: Most preferably, the Aox ring is Y is selected from CH, N; the definition of Rx is the same as that of R ₁₂₁ in the above formula I-2-1; or, the definition of Rx is the same as that of R ₁₃₂ in the above formula I-3-2; preferably, the position of Rx on the ring is selected from: 2-position monosubstitution, 3-position monosubstitution, or 2-, 3-position disubstitution. The compound according to any one of claims 1 to 15, or a tautomer, a stereoisomer, a geometric isomer, an enantiomer, a diastereomer, a racemate, a prodrug, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a hydrate, an ester, an isotope, or a metabolite thereof, wherein the compound is selected from the following: A pharmaceutical composition comprising the compound according to any one of claims 1 to 16, or a tautomer, a stereoisomer, a geometric isomer, an enantiomer, a diastereomer, a racemate, a prodrug, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a hydrate, an ester, an isotope, or a metabolite thereof; optionally, further comprising a pharmaceutically acceptable excipient. A method for treating cancer in a patient, comprising administering to the patient a compound according to any one of claims 1 to 16, or a tautomer, a stereoisomer, a geometric isomer, an enantiomer, a diastereomer, a racemate, a prodrug, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a hydrate, an ester, an isotope, or a metabolite thereof; or a pharmaceutical composition according to claim 17. A method for inhibiting the progression of cancer in a patient, comprising administering to the patient a compound according to any one of claims 1 to 16, or a tautomer, a stereoisomer, a geometric isomer, an enantiomer, a diastereomer, a racemate, a prodrug, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a hydrate, an ester, an isotope, or a metabolite thereof; or a pharmaceutical composition according to claim 17. The method according to claim 18 or 19, wherein the cancer is associated with TEAD overexpression; or associated with increased TEAD activity. A method for treating a patient suffering from a disease or condition associated with increased TEAD expression, comprising administering to the patient a compound according to any one of claims 1 to 16, or a tautomer of the compound, a stereoisomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a hydrate thereof, an ester thereof, an isotope thereof, or a metabolite thereof; or a pharmaceutical composition according to claim 17. A method for treating a patient suffering from a disease or condition associated with increased TEAD activity, comprising administering to the patient a compound according to any one of claims 1 to 16, or a tautomer of the compound, a stereoisomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a hydrate thereof, an ester thereof, an isotope thereof, or a metabolite thereof; or a pharmaceutical composition according to claim 17. A method for treating a disease or condition, wherein inhibition of TEAD activity will be beneficial to the disease or condition, comprising administering to the patient a compound according to any one of claims 1 to 16, or a tautomer of the compound, a stereoisomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a hydrate thereof, an ester thereof, an isotope thereof, or a metabolite thereof; or a pharmaceutical composition according to claim 17. A method for treating a disease or condition in which inhibition of the Hippo pathway would be beneficial, comprising administering to the patient a compound according to any one of claims 1 to 16, or a tautomer, a stereoisomer, a geometric isomer, an enantiomer, a diastereomer, a racemate, a prodrug, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a hydrate, an ester, an isotope, or a metabolite thereof; or a pharmaceutical composition according to claim 17. The method of any one of claims 18-24, wherein the disease or disorder is a cell proliferative disorder; preferably, the cell proliferative disorder is cancer; preferably, the cancer is a cancer in which YAP is localized in the nucleus of the cancer cell. The method according to any one of claims 18 to 25, wherein the TEAD overexpression or increased TEAD activity is TEAD1 overexpression or increased TEAD1 activity; TEAD2 overexpression or increased TEAD2 activity; TEAD3 overexpression or increased TEAD3 activity; or TEAD4 overexpression or increased TEAD4 activity; or any combination thereof. A compound according to any one of claims 1 to 16, or a tautomer, a stereoisomer, a geometric isomer, an enantiomer, a diastereomer, a racemate, a prodrug, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a hydrate, an ester, an isotope, or a metabolite thereof; or a pharmaceutical composition according to claim 17 for the preparation of a drug for treating cancer, inhibiting cancer progression, treating a disease or condition associated with increased TEAD expression, treating a disease or condition associated with increased TEAD activity, treating a disease or condition associated with the Hippo pathway, and having the activity of binding to TEAD and blocking the interaction between YAP/TEAD, wherein the inhibition of the Hippo pathway will be beneficial to the disease or condition. The use according to claim 27, wherein the cancer is associated with TEAD overexpression or increased TEAD activity, and/or the disease or disorder is a cell proliferative disorder, preferably, the cell proliferative disorder is cancer, more preferably, the cancer is a cancer in which YAP is localized in the nucleus of the cancer cell; preferably, the cancer is selected from breast cancer, central nervous system cancer, endometrial cancer, liver cancer, kidney cancer, colorectal cancer, lung cancer, esophageal cancer, tongue cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, mesothelioma, melanoma, fibrosarcoma, bladder cancer, rectal cancer, lymphoma, cervical cancer, head and neck cancer, brain cancer, upper aerodigestive tract cancer, colorectal cancer, urinary tract cancer or colon cancer; preferably, the cancer is selected from brain cancer, esophageal cancer, kidney cancer, mesothelioma, liver cancer, , head and neck cancer, lung cancer, gastric cancer, breast cancer or prostate cancer; more preferably, each cancer is independently selected from adenocarcinoma, squamous cell carcinoma, mixed adenosquamous carcinoma, undifferentiated carcinoma; further preferably, the brain cancer includes but is not limited to glioma; head and neck cancer includes but is not limited to head and neck squamous cell carcinoma; lung cancer includes but is not limited to lung adenocarcinoma, lung adenosquamous carcinoma, squamous cell lung cancer, large cell lung cancer, small cell lung cancer, lung papillary adenocarcinoma or non-small cell lung cancer; gastric cancer includes but is not limited to gastric adenocarcinoma; breast cancer includes but is not limited to ductal breast cancer, breast cancer or HR+ breast cancer; prostate cancer includes but is not limited to prostate adenocarcinoma, prostate squamous cell carcinoma, or prostate adenosquamous carcinoma; And/or the TEAD overexpression or increased TEAD activity is TEAD1 overexpression or increased TEAD1 activity; TEAD2 overexpression or increased TEAD2 activity; TEAD3 overexpression or increased TEAD3 activity; or TEAD4 overexpression or increased TEAD4 activity; or any combination thereof. A method for treating a disease or condition in a patient, comprising administering to the patient a compound according to any one of claims 1 to 16, or a tautomer, a stereoisomer, a geometric isomer, an enantiomer, a diastereomer, a racemate, a prodrug, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a hydrate, an ester, an isotope, or a metabolite thereof; or a pharmaceutical composition according to claim 17; wherein the disease or condition is associated with a protein that interacts with TEAD. The method according to claim 29, wherein the disease or condition associated with the protein interacting with TEAD includes but is not limited to cancer, metabolic disease, inflammatory disease, or neurodegenerative disease; Preferably, the cancer is selected from breast cancer, central nervous system cancer, endometrial cancer, liver cancer, kidney cancer, colorectal cancer, lung cancer, esophageal cancer, tongue cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, mesothelioma, melanoma, fibrosarcoma, bladder cancer, rectal cancer, lymphoma, cervical cancer, head and neck cancer, brain cancer, upper aerodigestive tract cancer, colorectal cancer, urinary tract cancer or colon cancer; preferably, the cancer is selected from brain cancer, esophageal cancer, kidney cancer, mesothelioma, liver cancer, head and neck cancer, lung cancer, gastric cancer, breast cancer or prostate cancer; more preferably, each cancer is independently selected Preferably, the brain cancer includes but is not limited to glioma; the head and neck cancer includes but is not limited to head and neck squamous cell carcinoma; the lung cancer includes but is not limited to lung adenocarcinoma, lung adenosquamous carcinoma, squamous cell lung cancer, large cell lung cancer, small cell lung cancer, papillary lung adenocarcinoma or non-small cell lung cancer; the gastric cancer includes but is not limited to gastric adenocarcinoma; the breast cancer includes but is not limited to ductal breast cancer, breast cancer or HR+ breast cancer; the prostate cancer includes but is not limited to prostate adenocarcinoma, prostate squamous cell carcinoma, or prostate adenosquamous carcinoma. A compound according to any one of claims 1 to 16, or a tautomer of the compound, a stereoisomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a hydrate thereof, an ester thereof, an isotope thereof, or a metabolite thereof; or use of the pharmaceutical composition according to claim 17 in the preparation of a medicament for treating a disease or condition; the disease or condition is related to a protein that interacts with TEAD. The method according to claim 31, wherein the disease or disorder associated with the protein interacting with TEAD is selected from cancer, metabolic disease, inflammatory disease, or neurodegenerative disease; Preferably, the cancer is selected from breast cancer, central nervous system cancer, endometrial cancer, liver cancer, kidney cancer, colorectal cancer, lung cancer, esophageal cancer, tongue cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, mesothelioma, melanoma, fibrosarcoma, bladder cancer, rectal cancer, lymphoma, cervical cancer, head and neck cancer, brain cancer, upper aerodigestive tract cancer, colorectal cancer, urinary tract cancer or colon cancer; preferably, the cancer is selected from brain cancer, esophageal cancer, kidney cancer, mesothelioma, liver cancer, head and neck cancer, lung cancer, gastric cancer, breast cancer or prostate cancer; more preferably, each cancer is independently selected Preferably, the brain cancer includes but is not limited to glioma; the head and neck cancer includes but is not limited to head and neck squamous cell carcinoma; the lung cancer includes but is not limited to lung adenocarcinoma, lung adenosquamous carcinoma, squamous cell lung cancer, large cell lung cancer, small cell lung cancer, papillary lung adenocarcinoma or non-small cell lung cancer; the gastric cancer includes but is not limited to gastric adenocarcinoma; the breast cancer includes but is not limited to ductal breast cancer, breast cancer or HR+ breast cancer; the prostate cancer includes but is not limited to prostate adenocarcinoma, prostate squamous cell carcinoma, or prostate adenosquamous carcinoma. A compound according to any one of claims 1 to 16, or a tautomer of the compound, a stereoisomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a hydrate thereof, an ester thereof, an isotope thereof, or a metabolite thereof; or use of the pharmaceutical composition according to claim 17 in treating a disease or condition; the disease or condition is related to a protein that interacts with TEAD. The method according to claim 33, wherein the disease or disorder associated with the protein interacting with TEAD is selected from cancer, metabolic disease, inflammatory disease, or neurodegenerative disease; Preferably, the cancer is selected from breast cancer, central nervous system cancer, endometrial cancer, liver cancer, kidney cancer, colorectal cancer, lung cancer, esophageal cancer, tongue cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, mesothelioma, melanoma, fibrosarcoma, bladder cancer, rectal cancer, lymphoma, cervical cancer, head and neck cancer, brain cancer, upper aerodigestive tract cancer, colorectal cancer, urinary tract cancer or colon cancer; preferably, the cancer is selected from brain .... Cancer, renal cancer, mesothelioma, liver cancer, head and neck cancer, lung cancer, gastric cancer, breast cancer or prostate cancer; more preferably, each cancer is independently selected from adenocarcinoma, squamous cell carcinoma, mixed adenosquamous carcinoma, undifferentiated carcinoma; further preferably, the brain cancer includes but is not limited to glioma; head and neck cancer includes but is not limited to head and neck squamous cell carcinoma; lung cancer includes but is not limited to lung adenocarcinoma, lung adenosquamous carcinoma, squamous cell lung cancer, large cell lung cancer, small cell lung cancer, lung papillary adenocarcinoma or non-small cell lung cancer; gastric cancer includes but is not limited to gastric adenocarcinoma; breast cancer includes but is not limited to ductal breast cancer, breast cancer or HR+ breast cancer; prostate cancer includes but is not limited to prostate adenocarcinoma, prostate squamous cell carcinoma, or prostate adenosquamous carcinoma.