WO2023226976A1 - Sik inhibitor and composition thereof, method for preparing same, and use thereof - Google Patents

Abstract

Disclosed are a compound represented by formula (I), and a racemate, a stereoisomer, a tautomer, an isotopic label, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof. The compound has a good SIK inhibition effect and can be used for treating diseases related to SIK.

Description

SIK inhibitors and compositions, preparation methods and uses thereof

The present invention requires the following:

The priority of the earlier application submitted to the State Intellectual Property Office of China on May 24, 2022, with the patent application number 202210587316.X and titled "SIK inhibitors and their compositions, preparation methods and uses";

The priority of the earlier application submitted to the State Intellectual Property Office of China on November 15, 2022, with patent application number 202211430083.9 and titled "SIK inhibitors and compositions, preparation methods and uses thereof";

The entire contents of the above-mentioned prior applications are incorporated into this application by reference.

Technical field

The invention belongs to the field of medicine, and specifically relates to SIK inhibitors and their compositions, preparation methods and uses.

Background technique

Protein kinases belong to a large family of structurally related enzymes responsible for controlling a variety of cellular signaling processes. In particular, it has been shown to be a key regulator of cellular functions including, for example, proliferation, metabolism and apoptosis. Thus, defects in the control of protein phosphorylation resulting in uncontrolled signaling are associated with a variety of diseases including, for example, inflammation, allergies, cancer, autoimmune diseases, CNS disorders, and angiogenesis.

In healthy individuals, inflammation is self-limiting and is resolved by the production of anti-inflammatory mediators and cytokines such as interleukin-10 (IL-10), known as "suppressive" or "regulatory" cells (which The release of ) is controlled as part of a negative feedback loop. Indeed, during the body's normal inflammatory process, an initial pro-inflammatory response is followed by a pro-resolution response that resolves the inflammation after the damage has resolved, resulting in a reduction of pro-inflammatory cytokines such as TNFα and IL-12 and an anti-inflammatory response. Levels of inflammatory cytokines such as IL-10 and TGF-β are increased, creating a so-called tolerogenic environment.

Adenosine monophosphate-activated protein kinase (AMPK) belongs to the protein kinase family, which includes salt-inducible kinases (SIK), a family of serine/threonine kinases that are widely expressed in the body and are particularly involved in cellular energy homeostasis. middle. Three SIK isoforms have been identified, named SIK1, SIK2 and SIK3.

SIK plays multiple roles in different cell types. They have been found to phosphorylate a variety of substrates including CREB-responsive transcription coactivator (CRTC) proteins and histone deacetylase (HDAC) proteins, thereby regulating the transcription of a variety of different genes. One of the roles of CRTC signaling involves the control of macrophage phenotype, specifically the polarization of macrophages via CRTC3 phosphorylation, such as through reduced secretion of the pro-inflammatory cytokine IL-12 and a concomitant increase in pro-resolving cytokines. as measured by IL-10 secretion.

Research shows that SIK1 is associated with skeletal muscle sensitivity in obese mice and could be an interesting target for preventing type II diabetes and diabetic nephropathy.

Regulation of ALK5 by SIK1 and the identification of the SIK2 gene as a risk locus for primary sclerosing cholangitis suggest a role for SIK proteins in fibrotic diseases.

Studies have shown that SIK2 and SIK3 play a role in inflammation by secreting high levels of anti-inflammatory cytokines, especially interleukin-10 (IL-10), and inhibiting pro-inflammatory cytokines such as TNF-α and IL-12.

The role of SIK2 in T helper (Th)1 cell differentiation by regulating IFNγ and IL-12 signaling suggests that SIK2 could be a target of interest in inflammatory diseases.

Recent studies have shown that small molecule SIK inhibitors cause reduced phosphorylation and increased nuclear translocation of HDAC4/5 and CRTC2. Treatment with the small molecule SIK inhibitor YKL-05-099 increased bone formation and bone mass in mice, confirming the relevance of SIK inhibition in the treatment of bone turnover diseases.

Furthermore, it was also demonstrated that inhibition of SIK2 enhances neuronal survival or promotes melanogenesis in melanoma cells after oxygen-glucose deprivation. In this context, due to the need for therapeutic strategies to modulate cellular responses to stress (e.g. during ischemia and after tissue reperfusion, during chronic phases of cardiac remodeling, in diabetes and neurodegenerative conditions), there is a need for The rapid activation or degradation of SIK protein after stress makes it an interesting target in inflammatory, cardiac or metabolic diseases, and neurodegenerative diseases. SIK inhibition may also have applications in cosmetology or pigmentation-related diseases to induce melanogenesis.

Regulation of ALK5 by SIK1 and the identification of the SIK2 gene as a risk locus for primary sclerosing cholangitis suggest a role for SIK proteins in fibrotic diseases.

In addition to its important function in cellular energy homeostasis, SIK proteins are also implicated in the regulation of the cell cycle. Higher SIK2 expression is significantly associated with poor survival in patients with high-grade serous ovarian cancer. In addition, SIK3 expression is elevated in ovarian cancer, especially in serous subtypes and advanced ovarian cancer. Therefore, SIK inhibition can be used to treat cancer.

There has been considerable progress in treating patients with autoimmune diseases based on antibodies that target pro-inflammatory cytokines, such as anti-TNFα, but a large proportion of patients do not respond to these therapies or experience serious adverse events such as opportunistic infections. Therefore, there remains a large unmet medical need for the treatment of these diseases, and new drugs for the prevention and/or treatment of these diseases are urgently needed.

Therefore, it is of great research significance to develop small molecule SIK inhibitors with good anti-inflammatory effects and few side effects.

Contents of the invention

In order to improve the above technical problems, the present invention provides a compound represented by formula I, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or its Prodrugs:

in,

X and Y are independently selected from N or C, Z is N or CH; at least one of X, Y and Z is N, and at most 2 are N, and X and Y are not N or C at the same time;

When T is selected from N or CR ² , R ² is selected from H, halogen, CN, OH, the following groups that are unsubstituted or optionally substituted by 1, 2 or more deuterium or halogen: C _1-6 alkane group, C _1-6 alkoxy group, C _3-8 cycloalkyloxy group and NHR ⁸ ; or when T is CR ² , R ² and R ⁵ can form a 5-8 membered ring with the atoms to which they are connected. structure;

J is selected from N or CR ³ ;

E is selected from N or CR ⁴ ;

A is selected from the following groups substituted by 1, 2 or more R ^a : C _1-6 alkyl, -O(CH ₂ ) _m R ⁶ , -S(CH ₂ ) _m R ⁶ , -S (O) _n (CH ₂ ) _m R ⁶ , -NR ⁶ R ⁷ , -NR ⁶ C(O)R ⁷ , -C(O)NR ⁶ R ⁷ , -SO ₂ NR ⁶ R ⁷ , -O(CH ₂ ) _m (CO)R ⁶ , -O(CH ₂ ) _m C(O)R ⁶ , -OCH(CH ₃ )(CH ₂ ) _m R ⁶ , -OCD ₂ (CH ₂ ) _m R ⁶ ; by 1 C _3-12 cycloalkyl substituted by 1, 2 or more R ^b ; 3-12 membered heterocyclyl substituted by 1, 2 or more R ^c ; substituted by 1, 2 or more R c C _6-14 aryl groups substituted by multiple R ^d and 5-14 membered heteroaryl groups substituted by 1, 2 or more R ^e ;

R ¹ is selected from H, halogen, CN, OH, C _1-6 alkyl and C _1-6 alkoxy;

R ³ and R ⁴ are the same or different, and are independently selected from H, halogen, CN, OH, C _1-6 alkyl, C _1-6 alkoxy and NHR ⁸ ;

R ⁵ is selected from H; C _1-6 alkyl substituted by 1, 2 or more R ^5a1 and the following groups substituted by 1, 2 or more R ^5a2 : C _3-10 ring Alkyl and 3-12 membered heterocyclyl;

Each R ^5a1 is the same or different, independently selected from H, halogen, CN, OH, C _1-6 alkyl, C _1-6 alkoxy, C _3-10 cycloalkyl and 4-10 membered heterocycle group, the alkyl group, alkoxy group, cycloalkyl group or heterocyclic group can be substituted by 1, 2 or more halogens;

Each R ^5a2 is the same or different, and is independently selected from H, halogen, CN, OH, C _1-6 alkyl and C _1-6 alkoxy;

R ⁶ and R ⁷ are the same or different, and are independently selected from H, halogen, CN, OH, NH ₂ ; the following groups substituted by 1, 2 or more R ^f : C _1-6 alkyl, C _1-6 alkoxy and NR ^8a R ^8b ; the following groups substituted by 1, 2 or more R ^g : C _3-10 cycloalkyl, 3-10 membered heterocyclyl and 5-14 metaheteroaryl;

R ⁸ is selected from H; C _1-6 alkyl substituted by 1, 2 or more R ^8a1 ; C _3-10 ring substituted by 1, 2 or more R ^8a2 Alkyl or 3-12 membered heterocyclyl;

R ^8a and R ^8b are the same or different, and are independently selected from H; C _1-6 alkyl substituted by 1, 2 or more R ^8a1 ; substituted by 1, 2 or more R ^8a2 The following groups: C _3-10 cycloalkyl or 3-12 membered heterocyclyl;

Each R ^8a1 is the same or different, independently selected from H, halogen, CN, OH, C _1-6 alkyl, C _1-6 alkoxy, C _3-10 cycloalkyl and 4-10 membered heterocycle group, the alkyl group, alkoxy group, cycloalkyl group or heterocyclic group can be substituted by 1, 2 or more halogens;

Each R ^8a2 is the same or different, and is independently selected from H, halogen, CN, OH, C _1-6 alkyl and C _1-6 alkoxy;

R ^a is selected from H, deuterium, halogen, CN, OH, NH ₂ , oxo; the following groups substituted by 1, 2 or more R ^a1 : C _1-6 alkyl, C _1-6 alkyl Oxygen, NR ^8a R ^8b and the following groups substituted by 1, 2 or more R ^a2 : C _3-10 cycloalkyl, 3-10 membered heterocyclyl and 5-14 membered heteroaryl;

Each R ^a1 is the same or different, and is independently selected from H, halogen, CN and OH;

Each R ^a2 is the same or different and independently selected from H, halogen, CN, OH, C _1-6 alkyl, C _1-6 alkoxy, NH C _1-6 alkyl and N(C _1-6 alkyl) ₂ ;

Each R ^b , R ^c , R ^d and ^Re are the same or different, and are independently selected from H, halogen, CN, OH, NH ₂ ; the following groups substituted by 1, 2 or more R ^b1 : C _1-6 alkyl, C _1-6 alkoxy, NH C _1-6 alkyl, N(C _1-6 alkyl) ₂ and the following substituted by 1, 2 or more R ^b2 Group: C _3-10 cycloalkyl, 4-12 membered heterocyclyl, 5-14 membered heteroaryl;

Each R ^b1 is the same or different, and is independently selected from H, halogen, CN and OH;

Each R ^b2 is the same or different, independently selected from H, halogen, CN, OH, C _1-6 alkyl, C _1-6 alkoxy, NH C _1-6 alkyl and N(C _{1- 6alkyl} ) ₂ ;

Each R ^f is the same or different and is independently selected from H, halogen, CN and OH;

Each ^Rg is the same or different, independently selected from H, halogen, CN, OH, C _1-6 alkyl, C _1-6 alkoxy, NHC _1-6 alkyl, N(C _1-6 alkyl base) ₂ and oxo;

m is selected from 0, 1, 2, 3, 4, 5, 6;

n is selected from 1,2.

According to an embodiment of the present invention, in the compound represented by formula I, A is selected from the following groups substituted by 1, 2 or more R ^a : C _1-6 alkyl, -O(CH ₂ ) _m R ⁶ , -S(CH ₂ ) _m R ⁶ , -S(O) _n (CH ₂ ) _m R ⁶ , -NR ⁶ R ⁷ , -NR ⁶ C(O)R ⁷ , -C(O)NR ⁶ R ⁷ , -SO ₂ NR ⁶ R ⁷ , -O(CH ₂ ) _m (CO)R ⁶ , -OCH(CH ₃ )(CH ₂ ) _m R ⁶ , -OCD ₂ (CH ₂ ) _m R ⁶ ; by 1 C _3-12 cycloalkyl substituted by 1, 2 or more R ^b ; 3-12 membered heterocyclyl substituted by 1, 2 or more R ^c ; substituted by 1, 2 or more R c C _6-14 aryl groups substituted by multiple R ^d and 5-14 membered heteroaryl groups substituted by 1, 2 or more R ^e .

According to an embodiment of the present invention, in the compound represented by formula I, T is selected from N or CR ² ; R ² is selected from H, halogen, CN, OH, unsubstituted or optionally substituted by 1, 2 or more deuterium Or the following groups substituted by halogen: C _1-6 alkyl, C _1-6 alkoxy and NHR ⁸ ; A is selected from the following groups substituted by 1, 2 or more ^Ra : C _{1- 6Alkyl} , -O(CH ₂ ) _m R ⁶ , -S(CH ₂ ) _m R ⁶ , -S(O) _n (CH ₂ ) _m R ⁶ , -NR ⁶ R ⁷ , -NR ⁶ C(O )R ⁷ , -C(O)NR ⁶ R ⁷ , -SO ₂ NR ⁶ R ⁷ ; C _3-12 cycloalkyl substituted by 1, 2 or more R ^b ; substituted by 1, 2 or more R ^c -substituted 3-12-membered heterocyclyl; C _6-14 aryl substituted by 1, 2 or more R ^d ; substituted by 1, 2 or more R ^e 5-14 membered ^heteroaryl ; R ⁶ , R ⁷ , R ⁸ , Ra , R ^b , R ^c , R ^d , ^Re , m and n are as defined in formula (I).

According to an embodiment of the present invention, in the compound represented by formula I, T is selected from N or CR ² ; when T is CR ² , R ² and R ⁵ form a 5-8 membered cyclic structure with the atoms to which they are connected respectively; A Selected from the following groups substituted by 1, 2 or more R ^a : C _1-6 alkyl, -O(CH ₂ ) _m R ⁶ , -S(CH ₂ ) _m R ⁶ , -S( O) _n (CH ₂ ) _m R ⁶ , -NR ⁶ R ⁷ , -NR ⁶ C(O)R ⁷ , -C(O)NR ⁶ R ⁷ , -SO ₂ NR ⁶ R ⁷ ; by 1, 2 C _3-12 cycloalkyl substituted by one or more R ^b ; 3-12 membered heterocyclyl substituted by 1, 2 or more R ^c ; substituted by 1, 2 or more R ^d -substituted C _6-14 aryl and 5-14-membered heteroaryl substituted by 1, 2 or more R ^e ; R ⁶ , R ⁷ , R ⁸ , R ^a , R ^b , R ^c , R ^d , ^Re , m and n are as defined in formula (I).

According to an embodiment of the present invention, in the compound represented by formula I, T is selected from N or CR ² ; when T is CR ² , R ² and R ⁵ form a 5-8 membered heterocyclic ring with the atoms to which they are connected respectively; A is selected from From the following groups substituted by 1, 2 or more R ^a : C _1-6 alkyl, -O(CH ₂ ) _m R ⁶ , -S(CH ₂ ) _m R ⁶ , -S(O ) _n (CH ₂ ) _m R ⁶ , -NR ⁶ R ⁷ , -NR ⁶ C(O)R ⁷ , -C(O)NR ⁶ R ⁷ , -SO ₂ NR ⁶ R ⁷ ; by 1, 2 C _3-12 cycloalkyl or more R ^b substituted; 3-12 membered heterocyclyl substituted by 1, 2 or more R ^c ; 1, 2 or more R ^d Substituted C _6-14 aryl and 5-14 membered heteroaryl substituted by 1, 2 or more R ^e ; R ⁶ , R ⁷ , R ⁸ , R ^a , R ^b , R ^c , R ^d , ^Re , m and n are as defined in formula (I).

According to an embodiment of the present invention, in the compound represented by formula I, J is CH.

According to an embodiment of the present invention, in the compound represented by formula I, E is selected from N or CH.

According to an embodiment of the present invention, in the compound represented by Formula I, T is selected from N or CR ² ; R ² is selected from H, methoxy, difluoromethoxy, trifluoromethoxy, CN, methyl, cyclo Propyloxy, deuterated methoxy (such as trideuterated methoxy); or when T is CR ² , R ² and R ⁵ can form a piperidine ring with their respective attached atoms.

According to an embodiment of the present invention, in the compound represented by formula I, J is CR ³ ; R ³ is halogen, preferably fluorine.

According to an embodiment of the present invention, in the compound represented by formula I, E is CR ⁴ ; R ⁴ is halogen, preferably fluorine.

According to an embodiment of the present invention, in the compound represented by formula I, R ¹ is selected from H, halogen or C _1-3 alkyl.

According to an embodiment of the present invention, in the compound represented by formula I, R ⁵ is selected from H, C _1-6 alkyl, halo C _1-6 alkyl, cyano C _1-6 alkyl, cyclopropylmethyl , cyclopropyl, cyclobutyl, cyclopentyl, the cyclopropyl, cyclobutyl, cyclopentyl are optionally substituted by 1, 2 or more fluorine or hydroxyl groups.

According to an embodiment of the present invention, in the compound represented by formula I, R ⁵ is selected from H, cyclopropyl, trifluoroethyl (such as ), cyclopropylmethyl, fluorocyclopropyl, difluorocyclopropyl, cyanomethyl, hydroxycyclobutyl, isopropyl, cyclobutyl, cyclopentyl, hydroxycyclopentyl; for example like

According to an embodiment of the present invention, in the compound represented by formula I, J is CH;

E is selected from N or CH;

T is selected from N or CR ² ; R ² is selected from H, methoxy, difluoromethoxy, trifluoromethoxy, CN, methyl, cyclopropyloxy, deuterated methoxy (such as trideuterium methoxy);

R ¹ is selected from H, halogen or C _1-3 alkyl;

R ⁵ is selected from H, cyclopropyl, trifluoroethyl (such as ), cyclopropylmethyl, fluorocyclopropyl, difluorocyclopropyl, cyanomethyl, hydroxycyclobutyl, isopropyl, cyclobutyl, cyclopentyl, hydroxycyclopentyl; for example

In some embodiments, the structure of the compound of Formula I is as shown in Formula IIa and IIb:

Wherein A, J, E, T, R ¹ and R ⁵ have the definitions mentioned above.

In some embodiments, the structure of the compound of Formula I is as shown in Formula IIIa and IIIb:

Wherein A, R ² and R ⁵ have the definitions mentioned above.

According to an embodiment of the present invention, for the compounds represented by Formula I, Formula IIa, IIb, Formula IIIa and IIIb, A is selected from -O(CH ₂ ) _m R ⁶ , -O(CH ₂ ) _m (CO)R ⁶ , -O(CH ₂ ) _m C(O)R ⁶ , -OCH(CH ₃ )(CH ₂ ) _m R ⁶ , -OCD ₂ (CH ₂ ) _m R ⁶ and 3-8 membered heterocyclyl, wherein said The 3-8 membered heterocyclic group is optionally substituted by 1, 2 or more R ^c ;

R ⁶ is selected from NR ^8a R ^8b , C _3-8 cycloalkyl, 3-8 membered heterocyclyl and 5-9 membered heteroaryl, wherein the C _3-8 cycloalkyl, 3-8 membered heteroaryl Ring groups and 5-9 membered heteroaryl groups are optionally substituted by 1, 2 or more ^Rg ;

R ^8a and R ^8b are the same or different, and are independently selected from H or C _1-6 alkyl;

Each ^Rg is the same or different, independently selected from H, halogen, CN, OH, C _1-6 alkyl, C _1-6 alkoxy, NHC _1-6 alkyl, N(C _1-6 alkyl (base) ₂ and oxo, wherein the C _1-6 alkyl and C _1-6 alkoxy groups may be optionally substituted by R ^a ;

R ^a is selected from H, halogen, CN, OH and NH ₂ ;

R ^c is selected from H, halogen, CN, OH, NH ₂ and C _1-6 alkyl, wherein the C _1-6 alkyl is optionally substituted by 1, 2 or more R ^b1 ; and

Each R ^b1 is the same or different, and is independently selected from H, halogen, CN and OH;

m is 0, 1 or 2.

According to an embodiment of the present invention, for the compounds represented by Formula I, Formula IIa, IIb, Formula IIIa and IIIb, A is selected from -O(CH ₂ ) _m R ⁶ , -O(CH ₂ ) _m (CO)R ⁶ , -OCH(CH ₃ )(CH ₂ ) _m R ⁶ , -OCD ₂ (CH ₂ ) _m R ⁶ and 3-8-membered heterocyclyl, wherein the 3-8-membered heterocyclyl is optionally replaced by 1, 2 or more R ^c substitutions;

R ⁶ is selected from NR ^8a R ^8b , C _3-8 cycloalkyl, 3-8 membered heterocyclyl and 5-9 membered heteroaryl, wherein the C _3-8 cycloalkyl, 3-8 membered heteroaryl Ring groups and 5-9 membered heteroaryl groups are optionally substituted by 1, 2 or more ^Rg ;

R ^8a and R ^8b are the same or different, and are independently selected from H or C _1-6 alkyl;

Each ^Rg is the same or different, independently selected from H, halogen, CN, OH, C _1-6 alkyl, C _1-6 alkoxy, NHC _1-6 alkyl, N(C _1-6 alkyl (base) ₂ and oxo, wherein the C _1-6 alkyl and C _1-6 alkoxy groups may be optionally substituted by R ^a ;

R ^a is selected from H, halogen, CN, OH and NH ₂ ;

R ^c is selected from H, halogen, CN, OH, NH ₂ and C _1-6 alkyl, wherein the C _1-6 alkyl is optionally substituted by 1, 2 or more R ^b1 ; and

Each R ^b1 is the same or different, and is independently selected from H, halogen, CN and OH;

m is 0, 1 or 2.

According to an embodiment of the present invention, in the compounds represented by Formula I, Formula IIa, IIb, Formula IIIa and IIIb, A is -O(CH ₂ ) _m R ⁶ , -OCH(CH ₃ )(CH ₂ ) _m R ⁶ or Substituted by 1, 2 or more R ^c 3-8 membered heterocyclyl substituted;

R ⁶ is selected from NR ^8a R ^8b , C _3-8 cycloalkyl, 3-8 membered heterocyclyl and 5-9 membered heteroaryl, wherein the C _3-8 cycloalkyl, 3-8 membered heteroaryl Ring groups and 5-9 membered heteroaryl groups are optionally substituted by 1, 2 or more ^Rg ;

R ^8a and R ^8b are the same or different, and are independently selected from H or C _1-6 alkyl;

Each ^Rg is the same or different, independently selected from H, halogen, CN, OH, C _1-6 alkyl, C _1-6 alkoxy, NHC _1-6 alkyl, N(C _1-6 alkyl (base) ₂ and oxo, wherein the C _1-6 alkyl and C _1-6 alkoxy groups may be optionally substituted by R ^a ;

R ^a is selected from H, halogen, CN, OH and NH ₂ ;

R ^c is selected from H, halogen, CN, OH, NH ₂ and C _1-6 alkyl, wherein the C _1-6 alkyl is optionally substituted by 1, 2 or more R ^b1 ; and

Each R ^b1 is the same or different and is independently selected from the group consisting of H, halogen, CN and OH.

According to an embodiment of the present invention, in the compounds represented by Formula I, Formula IIa, IIb, Formula IIIa and IIIb, R ⁶ is selected from NR ^8a R ^8b or is optionally substituted by 1, 2 or more R ^g following groups group:

R ^8a and R ^8b are the same or different, and are independently selected from H or C _1-6 alkyl;

^Rg are the same or different, independently selected from H, halogen, CN, OH, C _1-6 alkyl, C _1-6 alkoxy, NHC _1-6 alkyl, N(C _1-6 alkyl) ₂ and oxo, the C _1-6 alkyl and C _1-6 alkoxy groups may be optionally substituted by R ^a ;

R ^a is selected from H, halogen, CN, OH and NH ₂ .

According to an embodiment of the present invention, for the compounds represented by Formula I, Formula IIa, IIb, Formula IIIa and IIIb, A is selected from

In some embodiments, the structure of the compound represented by Formula I is represented by Formula IVa or IVb:

Wherein R ⁶ and m have the definitions mentioned above.

In some embodiments, the structure of the compound represented by Formula I is represented by Formula V:

Wherein X, Y, Z, J, E, T, R ⁵ and R ⁶ have the definitions described above.

In some embodiments, the structure of the compound represented by Formula I is represented by Formula VI:

wherein R ⁶ has the definition stated above.

In some embodiments, m is 1 or 2 for the compounds represented by Formula I, Formula IIa, IIb, Formula IIIa and IIIb.

In some embodiments, for the compounds represented by Formula I, Formula IIa, IIb, Formula IIIa and IIIb, ^R2 is selected from H, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 Alkoxy, deuterated C _1-6 alkoxy, C _3-8 cycloalkyloxy and cyano.

In some embodiments, for the compounds represented by Formula I, Formula IIa, IIb, Formula IIIa and IIIb, R ² is selected from halo C _1-6 alkoxy.

In some embodiments, for the compounds represented by Formula I, Formula IIa, IIb, Formula IIIa and IIIb, R ² is -OCHF ₂ .

In some embodiments, for the compounds represented by Formula I, Formula IIa, IIb, Formula IIIa and IIIb, ^R5 is selected from H, C _1-6 alkyl and C _3-6 cycloalkyl, and the C _1-6 The alkyl group is optionally substituted by 1, 2 or more halogens, CN and C _3-8 cycloalkyl, and the C _3-6 cycloalkyl group is optionally substituted by 1, 2 or more hydroxyl groups, halogen replaced.

In some embodiments, for the compounds represented by Formula I, Formula IIa, IIb, Formula IIIa and IIIb, ^R5 is selected from H, halo C _1-3 alkyl, -CH ₂ CN, -CH ₂ -cyclopropyl ,isopropyl,cyclobutyl,cyclopentyl,

In some embodiments, for the compounds represented by Formula I, Formula IIa, IIb, Formula IIIa and IIIb, A is selected from -O(CH ₂ ) _m R ⁶ ; R ² is selected from H, CN, C _1-6 alkyl , C _1-6 alkoxy, halogenated C _1-6 alkoxy, deuterated C _1-6 alkoxy and cyclopropyloxy, preferably, R ² is -OCHF ₂ ;

R ⁵ is selected from H, C _1-3 alkyl and C _3-6 cycloalkyl. The C _3-6 cycloalkyl is optionally substituted by 1, 2 or more hydroxyl groups or halogens, preferably fluorine Substituted cyclopropyl;

R ⁶ is selected from NR ^8a R ^8b , 3-8 membered heterocyclyl and 5-9 membered heteroaryl, wherein the C _3-8 cycloalkyl, 3-8 membered heterocyclyl and 5-9 membered heteroaryl Aryl is optionally substituted by 1, 2 or more ^Rg ;

Each ^Rg is the same or different, independently selected from H, halogen, CN, OH, C _1-6 alkyl, C _1-6 alkoxy, NHC _1-6 alkyl, N(C _1-6 alkyl (base) ₂ and oxo, wherein the C _1-6 alkyl and C _1-6 alkoxy groups may be optionally substituted by R ^a ;

R ^a is selected from H, halogen, CN, OH and NH ₂ ;

R ^c is selected from H, halogen, CN, OH, NH ₂ and C _1-6 alkyl, wherein the C _1-6 alkyl is optionally substituted by 1, 2 or more R ^b1 ; and

Each R ^b1 is the same or different and is independently selected from the group consisting of H, halogen, CN and OH.

In some embodiments, in the compound represented by Formula IVb, m is 0 or 1.

In some embodiments, for the compounds represented by formula IVa and formula IVb, R ⁶ is selected from 3-8 membered heterocyclyl, N(C _1-6 alkyl) ₂ and 5-6 membered heteroaryl, and the 3 -8-membered heterocyclyl or 5-6-membered heteroaryl is optionally substituted by 1, 2 or more selected from C _1-6 alkyl, halogen, cyano, hydroxyl, C _1-6 alkoxy, deuterium Substituted with C _1-6 alkoxy, halo C _1-6 alkyl, oxo (=O), cyano C _1-6 alkyl and 4-6 membered heterocyclyl groups.

In some embodiments, for the compounds represented by formula IVa and formula IVb, R ⁶ is selected from 3-6 membered heterocyclyl groups, and the 3-6 membered heterocyclyl groups are optionally selected from 1, 2 or more C _1-3 alkyl, fluorine, cyano, hydroxyl, C _1-3 alkoxy, deuterated C _1-3 alkoxy, fluoro C _1-3 alkyl, oxo (=O), cyano Substituted with C _1-3 alkyl and 4-6 membered heterocyclyl groups.

In some embodiments, for the compound represented by formula IVa, R ⁶ is selected from a 5-6-membered heteroaryl group, and the 5-6-membered heteroaryl group is optionally composed of 1, 2 or more members selected from C _{1- 3} alkyl, fluorine, cyano, hydroxyl, C _1-3 alkoxy groups are substituted as described above.

In some embodiments, compound R ⁶ represented by formula IVa and formula IVb is selected from -N(CH ₃ ) ₂ .

In some embodiments, in the compounds represented by Formula V and Formula VI, R ⁶ is selected from 3-8 membered heterocyclyl groups, preferably 3-6 membered heterocyclyl groups, for example

According to an embodiment of the invention, the compound of formula I is selected from the following structures:

The present invention provides a method for preparing a compound represented by formula I, which includes the following steps: compound a and compound b undergo a coupling reaction to obtain a compound represented by formula I. The reaction formula is as follows:

^{Wherein ,} A _,

According to an embodiment of the invention, the reaction is carried out in the presence of a catalyst and/or a base.

According to an embodiment of the present invention, the catalyst may be a palladium catalyst, such as Pa(dppf)Cl ₂ (1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride), Pa ₂ ( At least one of dba) ₃ (tris(dibenzylideneacetone)dipalladium) and Pd(OAc) ₂ (palladium acetate).

According to an embodiment of the present invention, the base may be selected from at least one of sodium carbonate, potassium carbonate, potassium acetate, triethylamine and pyridine.

The present invention also provides at least one of the compounds represented by formula (I), their racemates, stereoisomers, tautomers, isotope labels, solvates, pharmaceutically acceptable salts or their prodrug compounds. A use in preparing medicine; the medicine is preferably a SIK inhibitor, more preferably an SIK2 inhibitor.

According to embodiments of the present invention, the medicament may be used to treat and/or prevent inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases involving cartilage turnover damage, congenital diseases cartilage malformations, diseases involving bone turnover damage, diseases associated with excessive secretion of TNFα, interferon, IL-6, IL-12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases , dermatological diseases and/or diseases related to abnormal angiogenesis; also such as psoriasis, inflammatory bowel disease (IBD), rheumatoid arthritis (RA), primary Sjogren's syndrome, ankylosing spondylitis, cryopyridine Phospholine-associated periodic syndrome (CAPS).

According to embodiments of the present invention, the inflammatory disease may be selected from rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g. Asthma), chronic obstructive pulmonary disease (COPD), and inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis). More specifically, the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and inflammatory bowel diseases (eg, Crohn's disease, ulcerative colitis).

The present invention also provides a pharmaceutical composition, which contains a therapeutically effective amount of the compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutical at least one of an acceptable salt or prodrug compound thereof, and one or more pharmaceutically acceptable excipients.

According to embodiments of the present invention, the pharmaceutical composition may further contain one or more additional therapeutic agents.

In the composition of the present application, the active ingredients are usually mixed with excipients, and the composition can be in the following forms: tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, and emulsions. , solutions, syrups, aerosols (solid or dissolved in liquid vehicles), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

"Excipients" as used in this application refer to ingredients other than active ingredients, including, for example, diluents, fillers, absorbents, wetting agents, binders, disintegrants, lubricants, etc.

The pharmaceutical compositions of the present invention can be administered by a variety of routes, including oral, rectal, transdermal, subcutaneous, intraarticular, intravenous, intramuscular and intranasal. The compounds of the present invention are preferably formulated as injectable or oral compositions or either as ointments, lotions or patches for transdermal administration.

Compositions for oral administration may take the form of bulk liquid solutions or suspensions or bulk powders. However, compositions are more typically presented in unit dosage form to facilitate precise administration. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined amount of activity calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient, excipient, or carrier. Material. Typical unit dosage forms include prefilled, pre-measured ampoules or syringes for liquid compositions or pills, tablets, capsules and the like for solid compositions. In such compositions, the compound of the invention of formula I is generally a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight), with the remainder being various ingredients that contribute to the formation of the desired dosage form. Excipients or carriers and processing aids.

Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous excipients containing buffers, suspending and dispersing agents, coloring agents, flavoring agents and the like. Solid forms may include, for example, any of the following ingredients or compounds of the invention with similar properties: binder, such as microcrystalline cellulose, tragacanth, or gelatin; excipient, such as starch or lactose; disintegration agents, such as alginic acid or corn starch; lubricants, such as magnesium stearate; glidants, such as colloidal silicon dioxide; sweeteners, such as sucrose or saccharin; or flavoring agents, such as mint or orange flavoring agent.

Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline or other injectable vehicles known in the art. As mentioned before, the active compound of formula (I) in the composition is usually a minor component, often about 0.05 to 10% by weight, with the balance being the injectable carrier and the like.

Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient in an amount generally from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight. weight, more preferably about 0.5 to about 15% by weight. When formulated as an ointment, the active ingredients are usually combined with a paraffin or water-miscible ointment base. Alternatively, the active ingredient may be formulated into a cream using, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and often include additional ingredients to enhance skin penetration or stability of the active ingredient or formulation. All such known transdermal formulations and ingredients are included within the scope of the present invention.

The compounds of the present invention may also be administered via transdermal devices. Thus, transdermal administration may be achieved using depot or porous membrane type patches or solid matrix type patches.

The present invention also provides the compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or its prodrug compound for preventing and /or for use in the treatment of inflammatory diseases.

According to embodiments of the present invention, the inflammatory disease may be selected from the group consisting of rheumatoid arthritis, osteoarthritis, allergic airway diseases (eg, asthma), chronic obstructive pulmonary disease (COPD), and inflammatory bowel disease (eg, Crohn's disease). Rohn's disease, ulcerative colitis). More specifically, the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and inflammatory bowel diseases (eg, Crohn's disease, ulcerative colitis).

The present invention also provides a method for preventing and/or treating inflammatory diseases, which includes administering to the patient a preventive or therapeutically effective amount of the compound represented by formula (I), its racemate, stereoisomer, and tautomer. , at least one of an isotope label, a solvate, a pharmaceutically acceptable salt or a prodrug compound thereof, or administering to the patient a prophylactically or therapeutically effective amount of the above-mentioned pharmaceutical composition.

beneficial effects

The compound of the present invention has good SIK inhibitory effect, the IC ₅₀ of the SIK2 kinase activity is below 100 nM, and can be used to treat SIK. Related diseases, such as inflammation-related diseases, and medicaments prepared for such conditions or diseases.

Definitions and explanations of terms

Unless otherwise stated, the definitions of groups and terms recorded in the specification and claims of this application include their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples. etc., can be arbitrarily combined and combined with each other. Such combinations and combined group definitions and compound structures should be understood to be within the scope of the description and/or claims of this application.

The "cyclic structure" mentioned above refers to heterocyclic and heteroaromatic rings that are well known in the art.

The compounds of the present application may exist in specific geometric or stereoisomeric forms. For example, cis and trans isomers, (D) or (+) isomers ("(D)" or "(+)" means dextrorotatory), (L) or (-) isomers ("( L)" or "(-)" means levorotatory), (R)- and (S)-enantiomers, diastereomers, racemic mixtures and other mixtures, as well as enantiomeric or diastereomeric Enantiomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of this disclosure.

In the chemical structure of the compound of this application, the bond Indicates that the configuration is not specified, Represents the absolute configuration of a stereocenter, that is, if there are chiral isomers in the chemical structure, the bond can be or both Two configurations.

key Indicates unspecified configuration, including cis (E) or trans (Z) configuration.

In addition, the compounds and intermediates of the present application may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. "Tautomers" refer to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also called proton transfer tautomers) include tautomers via proton migration, such as keto-enol isomerization, imine-enamine isomerization, and lactam-lactam isomerization. Isomerization of imides. All tautomeric forms of the compounds in this disclosure are within the scope of this disclosure. The name of a compound named in a single way does not exclude any tautomers. For example If this is the case, it is understood that either the two tautomers alone or a mixture of the two tautomers are within the scope of the present disclosure.

Unless otherwise stated, the numerical ranges stated in the specification and claims are equivalent to recording at least each specific integer value therein. For example, the numerical range "1-20" is equivalent to recording each integer value in the numerical range "1-20", that is, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 ,13,14,15,16,17,18,19,20. In addition, when certain numerical ranges are defined as "numbers," it should be understood that both endpoints of the range, every integer within the range, and every decimal within the range are recited. For example, "numbers from 0 to 10" should be understood as not only recording every integer from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, but also recording at least one of the integers respectively. The sum of 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9.

It should be understood that when describing one, two or more, "more" shall refer to an integer greater than 2, such as greater than or equal to 3, such as 3, 4, 5, 6, 7, 8, 9 or 10 .

The term "halogen" means fluorine, chlorine, bromine and iodine.

The term "C _1-6 alkyl" refers to straight and branched chain alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-Methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl base, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc. or their isomers.

The term "alkoxy" refers to -O-(alkyl), where alkyl is as defined herein. Alkoxy groups (C _1-12 alkoxy) containing 1 to 12 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms are preferred, more Alkoxy groups containing 1 to 6 carbon atoms (C _1-6 alkoxy) are preferred. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy and butoxy. Alkoxy groups may be substituted or unsubstituted.

The term "C _3-12 cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic (such as bridged, spiro) hydrocarbon ring or tricycloalkane having 3, 4, 5, 6, 7, 8 , 9, 10, 11 or 12 carbon atoms. The C _3-12 cycloalkyl group may be a monocyclic hydrocarbon group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecanyl, or bicyclic Hydrocarbon groups such as bornyl, indolyl, hexahydroindolyl, tetrahydronaphthyl, Decalinyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl base, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonyl, 2, 6-diazaspiro[3,4]octyl, or tricyclic hydrocarbon group such as adamantyl.

The term "cycloalkyloxy" refers to -O-(cycloalkyl), where cycloalkyl is as defined herein. Preferred are cycloalkyloxy groups (C _1-12 cycloalkyloxy groups) containing 3 to 12 (for example, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, more Cycloalkyloxy groups containing 3 to 6 carbon atoms (C _3-6 cycloalkyloxy) are preferred. Non-limiting examples of cycloalkyloxy include: cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy. Cycloalkyloxy groups may be substituted or unsubstituted.

The term "3-12 membered heterocyclyl" means a saturated or unsaturated non-aromatic ring or ring system and containing at least one heteroatom selected from O, S and N, preferably "4-10 membered heterocyclic ring" base". The heterocyclyl group may be attached to the remainder of the molecule through any of the carbon atoms or a nitrogen atom, if present. The heterocyclyl group may include fused or bridged rings as well as spirocyclic rings. In particular, the heterocyclyl group may include but is not limited to: 3-membered rings, such as oxetanyl; 4-membered rings, such as azetidinyl, oxetanyl; 5-membered rings, such as tetrahydrofuran base, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiane base, thiomorpholinyl, piperazinyl or trithialkyl; or 7-membered ring, such as diazacycloheptyl. Optionally, the heterocyclyl group may be benzo-fused. The heterocyclyl group may be bicyclic, such as but not limited to a 5,5-membered ring, such as a hexahydrocyclopenta[c]pyrrole-2(1H)-yl ring, or a 5,6-membered bicyclic ring, such as a hexahydropyrrole And [1,2-a]pyrazine-2(1H)-yl ring. Heterocyclyl may be partially unsaturated, i.e. it may contain one or more double bonds, such as, but not limited to, dihydrofuryl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H- [1,3,4]thiadiazinyl, 1,2,3,5-tetrahydroxazinyl or 4H-[1,4]thiazinyl, alternatively it can be benzo-fused such as but Not limited to dihydroisoquinolyl. When the 3-12-membered heterocyclic group is connected to other groups to form the compound of the present invention, the carbon atom on the 3-12-membered heterocyclic group can be connected to other groups, or it can be a 3-12-membered heterocyclic group. The heterocyclic atoms on the ring are connected to other groups. For example, when the 3-12-membered heterocyclic group is selected from piperazinyl, the nitrogen atom on the piperazinyl may be connected to other groups. Or when the 3-12-membered heterocyclic group is selected from piperidinyl, the nitrogen atom on the piperidinyl ring and the carbon atom in the para position may be connected to other groups.

The term "C _6-14 aryl" is understood to preferably mean a monovalent aromatic or partially aromatic monocyclic, bicyclic (such as fused ring, bridged ring, spirocyclic ring) or tricyclic ring having 6 to 14 carbon atoms. Hydrocarbon ring, which may be a single aromatic ring or polyaromatic rings fused together, preferably "C _6-10 aryl". The term "C _6-10 aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9 or 10 carbon atoms, in particular having a ring of 6 carbon atoms ("C ₆ aryl"), such as phenyl; or biphenyl, or a ring of 9 carbon atoms ("C ₉ aryl"), such as indanyl or indenyl, Or a ring with 10 carbon atoms ("C ₁₀ aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl. The C _6-14 aryl group can also be a ring with 13 carbon atoms ("C ₁₃ aryl"), such as fluorenyl, or a ring with 14 carbon atoms ("C ₁₄ aryl"), such as anthracenyl . When the C _6-20 aryl group is substituted, it may be mono- or poly-substituted. Moreover, there is no restriction on the substitution position, for example, it may be ortho, para or meta substitution.

The term "5-14 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic (such as fused, bridged, spiro) or tricyclic aromatic ring systems having 5 to 14 ring atoms And contains 1, 2, 3, 4 or 5 heteroatoms independently selected from N, O and S, such as "5-10 membered heteroaryl". The term "5-10 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms and which contains 1 to 5, preferably 1 to 3 heteroatoms each independently selected from N, O and S and, in addition in each case may be benzo-fused .

The term "spirocycloalkyl" refers to a 5- to 20-membered polycyclic group with one carbon atom (called a spiro atom) shared between each single ring in the system, which may contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of shared spiro atoms between the rings, the spirocycloalkyl group is divided into a single spirocycloalkyl group, a double spirocycloalkyl group or a polyspirocycloalkyl group, and is preferably a single spirocycloalkyl group and a double spirocycloalkyl group. More preferably, it is a 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocyclic alkyl group. Non-limiting examples of spirocycloalkyl groups include:

The term "fused cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, one or more of which may contain one or more rings. Multiple double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl groups, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered , 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 1/5-membered and 6-membered/6-membered bicycloalkyl groups. Non-limiting examples of fused cycloalkyl groups include:

The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms that are not directly connected, and may contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

"Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance does or does not occur. For example, "heterocycloalkyl group optionally substituted by alkyl" means that alkyl groups may but need not be present, and this description includes the case where the heterocycloalkyl group is substituted by an alkyl group and the heterocycloalkyl group is not substituted by an alkyl group. replacement situation.

"Substituted" means that one or more H's in a given structure are substituted with a specified substituent. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art is able to determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. Further, when the group is substituted by more than one substituent, the substituents are independent of each other (that is, the one or more substituents may be different from each other or may be the same ).

The term "comprising" is a developmental limitation and is not closed-ended, that is, the contents specified in the present disclosure, but does not exclude other aspects.

Detailed ways

The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following examples are only illustrative and explain the present invention and should not be construed as limiting the scope of the present invention. All technologies implemented based on the above contents of the present invention are covered by the scope of protection intended by the present invention.

Experimental methods without specifying specific conditions in the following examples were carried out according to conventional methods and conditions, or according to product instructions.

The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts (δ) are given in units of 10 ^-6 (ppm). The NMR was measured using a Bruker Avance III 400MHz nuclear magnetic instrument. The measurement solvents were deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), and deuterated methanol (CD ₃ OD). The internal standard was tetramethylmethane. silane (TMS).

Mass spectrometry (MS) is measured by Waters 2767HPLC/Waters SQD, Waters H-class UPLC-SQD2, and Agilent HPLC/Waters liquid phase mass spectrometer.

Chiral HPLC analysis was performed using Shimadzu LC-20AD.

Thin layer chromatography silica gel plates are used in Cheng Chemical (Shanghai) Co., Ltd. GF254 silica gel plates. The specifications of silica gel plates used in thin layer chromatography (TLC) are 0.2~0.25mm. The specifications of silica gel plates used in thin layer chromatography separation and purification products are It is 0.4~0.5mm.

Column chromatography generally uses 100-200 mesh silica gel from Cheng Chemical (Shanghai) Co., Ltd. as the carrier.

High performance liquid chromatography was performed using Waters HPLC, Gilson HPLC and Biotage MPLC preparative chromatographs.

Gilson GX-281 preparative HPLC was used for chiral preparation.

In the following examples, unless otherwise specified, the reactions were all carried out under a nitrogen atmosphere. Nitrogen atmosphere refers to the reaction bottle connected to a nitrogen gas with a volume of about 1 liter. balloon.

The temperature range of room temperature is 20℃-30℃.

The reagent name corresponding to the English abbreviation of the reagent

Synthesis of intermediate A1

Compound A1-1 (100 mg, 0.44 mmol) was dissolved in dichloromethane (3 mL), and then A1-2 (50 mg, 0.87 mmol), 2-(7-azobenzotriazole)-N, were added in sequence, N,N',N'-tetramethylurea hexafluorophosphate (248 mg, 0.65 mmol) and N,N-diisopropylethylamine (169 mg, 1.31 mmol). Under nitrogen protection, the reaction solution was stirred at room temperature overnight. LCMS monitored the reaction to be complete. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated and purified through silica gel column (ethyl acetate: petroleum ether = 0-100%) to obtain intermediate A1 (70 mg).

MS m/z(ESI):270(M+H) ⁺ .

Synthesis of intermediate A2

Compound A2-1 (500 mg, 3.67 mmol) was added to DMF (10 ml) solvent, sodium hydrogen (529 mg, 8.00 mmol) was added in an ice bath, and after stirring for 30 minutes, compound A2-2 (2.90 g, 22.1 mmol) was added. ) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The organic phase was separated, dried, reduced pressure, and concentrated to obtain intermediate A2 (416 mg).

MS m/z(ESI):248.1(M+H) ⁺ .

Synthesis of intermediate A3

Compound A3-1 (272 mg, 3.68 mmol) was dissolved in dimethylformamide (5 mL), and sodium hydrogen (442 mg, 11.0 mmol, 60%) was slowly added under ice bath and nitrogen protection conditions. After the addition was completed, the ice bath was removed, and the reaction was continued to stir at room temperature for 1 hour, and then compound A2-1 (500 mg, 3.68 mmol) was slowly added. After the addition was completed, the reaction solution was slowly raised to room temperature and the reaction was stirred overnight. After the reaction was completed, the reaction solution was poured into ice water (30 mL), and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified through silica gel column (methanol: dichloromethane = 0-100%) to obtain intermediate A3 (320 mg).

MS m/z(ESI):206.1(M+H) ⁺ .

Synthesis of intermediate A4

Compound A1-1 (2.00g, 8.69mmol) was dissolved in dichloromethane (30mL), and then compound A4-1 (1.03g, 10.4mmol) and 2-(7-azobenzotriazole) were added successively -N,N,N',N'-tetramethylurea hexafluorophosphate (4.95g, 13.10mmol) and N,N-diisopropylethylamine (3.37g, 26.10mmol), stir at room temperature Reaction was allowed to take place overnight. LCMS monitored that the reaction was complete, and the reaction solution was concentrated under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (petroleum ether: ethyl acetate = 1:0-2:1) to obtain intermediate A4 (1.40g, yield 51.9%).

MS m/z(ESI):311.9(M+H) ⁺ .

Synthesis of intermediate A5

first step

Compound A3-1 (238 mg, 2.67 mmol), cesium carbonate (1.74 g, 5.34 mmol), allyl palladium (II) chloride dimer (65 mg, 0.18 mmol), 2-(di-tert-butyl) were added in sequence. Phosphorus)-3-methoxy-6-methyl-2'4'6'-triisopropyl-biphenyl (167 mg, 0.36 mmol) was added to anhydrous toluene (10 mL). Under nitrogen protection, the aforementioned reaction solution was placed in a 90°C oil bath and stirred for 10 minutes. Then, a 1 mL anhydrous toluene solution of compound A5-1 (350 mg, 1.78 mmol) was added. The reaction solution was continued to stir at 90°C overnight. LCMS monitored the reaction to be complete. The reaction mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (methanol: dichloromethane = 0-100%) to obtain intermediate A5-2 (180 mg).

MS m/z(ESI):206.1(M+H) ⁺ .

Step 2

Compound A5-2 (180 mg, 0.88 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL). Under ice bath and nitrogen protection, N-iodosuccinimide (198 mg, 0.88 mmol) was slowly added in batches. After the addition is complete, remove the ice bath and stir the reaction mixture at room temperature. Should stay overnight. LCMS monitored the reaction to be complete. The reaction solution was poured into ice water (30 mL), and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel plate (petroleum ether: ethyl acetate = 2:1) to obtain intermediate A5 (120 mg).

MS m/z(ESI):332.1(M+H) ⁺ .

Example 1 Synthesis of Compound 1

Intermediate A1 (100mg), intermediate A2 (92mg, 0.37mmol), trimethylacetic acid (38mg, 0.37mmol), potassium carbonate (155mg, 1.12mmol) and 1,1'-bis prepared in multiple batches were sequentially added. (Diphenylphosphino)ferrocenepalladium dichloride (31 mg, 0.037 mmol) was added to dry 1,4-dioxane (10 mL). Under nitrogen protection, the reaction solution was heated to 110°C and stirred overnight. LCMS monitored the reaction to be complete. The reaction mixture was cooled, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product. The crude product was first separated and purified by preparative plate (dichloromethane:methanol=10:1), and then separated and purified by reverse preparative chromatography to obtain compound 1 (35 mg).

¹ H NMR (400MHz, CD ₃ OD) δ8.46 (d, J = 7.6 Hz, 1H), 8.01 (d, J = 8.3 Hz, 1H), 7.65 (s, 1H), 7.30 (dt, J = 3.8 ,1.9Hz,2H),6.96(s,1H),6.75(dd,J＝7.6,2.5Hz,1H),4.25(t,J＝5.4Hz,2H),4.02(s,3H),3.78-3.69 (m,4H),2.93-2.84(m,3H),2.63(t,J＝4.7Hz,4H),0.85(td,J＝7.1,5.1Hz,2H),0.68–0.61(m,2H).

MS m/z(ESI):437.2(M+H) ⁺ .

Example 2 Synthesis of Compound 2

first step

Compound 2-1 (200mg, 1.02mmol), compound 2-2 (58mg, 1.02mmol), sodium tert-butoxide (295mg, 3.06mmol), 1,1'-binaphthyl-2,2'-bisbis Phenylphosphine (127 mg, 0.204 mmol) and tris(dibenzylideneacetone)dipalladium (94 mg, 0.102 mmol) were added to toluene (5 mL). Under nitrogen protection, the reaction mixture was heated to 100°C and stirred overnight. LCMS monitored that the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (dichloromethane: methanol = 1:0-10:1) to obtain compound 2-3 (130 mg, yield 44.8%).

MS m/z(ESI):285.1(M+H) ⁺ .

Step 2

Intermediate A1 (70mg, 0.26mmol), compound 2-3 (74mg, 0.26mmol), trimethylacetic acid (27mg, 0.26mmol), potassium carbonate (108mg, 0.78mmol) and 1,1'-bis( Diphenylphosphino)ferrocene palladium dichloride (21 mg, 0.026 mmol) was added to dry 1,4-dioxane (10 mL). Under nitrogen protection, the reaction solution was heated to 110°C and stirred overnight. LCMS monitored the reaction to be complete. Mix the reaction The material was cooled, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product. The crude product was separated and purified through a preparative plate (dichloromethane: methanol = 10:1), and then subjected to reverse preparative purification to obtain compound 2 (10 mg).

¹ H NMR (400MHz, CD ₃ OD) δ8.40 (d, J＝7.8Hz, 1H), 8.03-7.98 (m, 1H), 7.60 (s, 1H), 7.29 (d, J＝7.5Hz, 2H ),6.92(dd,J＝7.8,2.5Hz,1H),6.76(d,J＝2.4Hz,1H),4.01(s,3H),3.36(t,J＝5.1Hz,4H),3.16(q ,J＝9.8Hz,2H),2.92-2.81(m,5H),0.88-0.81(m,2H),0.67-0.61(m,2H).

MS m/z(ESI):474.2(M+H) ⁺ .

Example 3 Synthesis of Compound 3

Intermediate A4 (100mg, 0.32mmol), intermediate A2 (80mg, 0.32mmol), trimethylacetic acid (33mg, 0.32mmol), potassium carbonate (134mg, 0.97mmol) and 1,1'-bis(di Phenylphosphino)ferrocene palladium dichloride (27 mg, 0.032 mmol) was added to dry 1,4-dioxane (10 mL). Under nitrogen protection, the reaction mixture was heated to 110°C, and the reaction was stirred overnight. LCMS monitored that the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain crude product. The crude product was separated and purified through the preparation plate (dichloromethane: methanol = 10:1) to obtain the crude product, and then the crude product was separated and purified through reverse preparation to obtain compound 3 (64 mg, yield 41.4%).

¹ H NMR (400MHz, CD ₃ OD) δ8.47(d,J＝7.6Hz,1H),8.07(d,J＝8.0Hz,1H),7.67(s,1H),7.37-7.29(m,2H ),6.97(d,J＝2.5Hz,1H),6.76(dd,J＝7.6,2.5Hz,1H),4.25(t,J＝5.4Hz,2H),4.17(q,J＝9.3Hz,2H ), 4.07 (s, 3H), 3.77-3.70 (m, 4H), 2.88 (t, J = 5.4Hz, 2H), 2.68-2.58 (m, 4H).

MS m/z(ESI):479.1(M+H) ⁺ .

Example 4 Synthesis of Compound 4

Intermediate A4 (100mg, 0.32mmol), intermediate A3 (66mg, 0.32mmol), trimethylacetic acid (33mg, 0.32mmol), potassium carbonate (133mg, 0.97mmol) and 1,1'-bis(di Phenylphosphino)ferrocene palladium dichloride (26 mg, 0.032 mmol) was added to dry 1,4-dioxane (10 mL). Heat to 110°C under nitrogen protection and stir the reaction overnight. LCMS monitored that the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain crude product. The crude product was separated and purified through the preparation plate (dichloromethane: methanol = 10:1) to obtain the crude product, and then compound 4 (30 mg, yield 21.3%) was obtained through reverse preparative separation and purification.

¹ H NMR (400MHz, CD ₃ OD) δ8.43(d,J＝7.6Hz,1H),8.05(d,J＝8.1Hz,1H),7.64(s,1H),7.36-7.23(m,2H ),6.93(d,J＝2.5Hz,1H),6.73(dd,J＝7.6,2.5Hz,1H),4.24-4.12(m,4H),4.06(s,3H),2.83(t,J＝ 5.3Hz,2H),2.37(s,6H).

MS m/z(ESI):437.2(M+H) ⁺ .

Example 5 Synthesis of Compound 5

Intermediate A3 (100mg, 0.49mmol), intermediate A1 (131mg, 0.49mmol), trimethylacetic acid (50mg, 0.49mmol), potassium carbonate (202mg, 1.46mmol) and 1,1'-bis(di Phenylphosphino)ferrocene palladium dichloride (40 mg, 0.049 mmol) was added to dry 1,4-dioxane (10 mL). Under nitrogen protection, the reaction mixture was heated to 110°C, and the reaction was stirred overnight. LCMS monitored that the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain crude product. The crude product was separated and purified through a preparative plate (dichloromethane: methanol = 10:1), and then compound 5 (30 mg, yield 15.6%) was obtained by reverse preparative separation and purification.

¹ H NMR (400MHz, CD ₃ OD) δ8.44 (d, J＝7.6Hz, 1H), 8.00 (d, J＝8.4Hz, 1H), 7.63 (s, 1H), 7.28 (m, 2H), 6.95(d,J＝2.5Hz,1H),6.75(dd,J＝7.6,2.5Hz,1H),4.21(t,J＝5.3Hz,2H),4.01(s,3H),2.87(m,3H ),2.38(s,6H),0.84(m,2H),0.68-0.59(m,2H).

MS m/z(ESI):395.2(M+H) ⁺ .

Example 6 Synthesis of Compound 6

first step:

Compound A1-1 (500 mg, 2.17 mmol) was dissolved in dichloromethane (5 mL), and then compound 6-1 (154 mg, 2.17 mmol), O-(7-azabenzotriazol-1-yl) were added successively )-N,N,N,N'-tetramethylurea hexafluorophosphate (1.24g, 3.26mmol) and N,N-diisopropylethylamine (1.07mL, 6.51mmol). The reaction mixture was stirred at room temperature overnight. LCMS monitored the reaction to be complete. The reaction solution was poured into ice water (50 mL), and extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated brine (100 mLx1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (petroleum ether: ethyl acetate = 1:0-2:1) to obtain compound 6-2 (550 mg, yield 89.6%).

MS m/z(ESI):284.1(M+H) ⁺ .

Step 2

Compound 6-2 (100mg, 0.35mmol), intermediate A3 (72mg, 0.35mmol), trimethylacetic acid (36mg, 0.35mmol), potassium carbonate (146mg, 1.06mmol) and 1,1'-bis( Diphenylphosphino)ferrocene palladium dichloride (29 mg, 0.035 mmol) was added to dry 1,4-dioxane (10 mL). Under nitrogen protection, the reaction mixture was heated to 110°C and stirred overnight. LCMS monitored the reaction to be complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain crude product. The crude product was separated and purified through a preparation plate (dichloromethane: methanol = 10:1), and then separated and purified through reverse preparation to obtain compound 6 (50 mg, yield 34.5%).

¹ H NMR (400MHz, CD ₃ OD) δ8.47(d,J＝7.5Hz,1H),8.05(d,J＝7.9Hz,1H),7.65(s,1H),7.35-7.26(m,2H ),6.97(d,J＝2.5Hz,1H),6.77(dd,J＝7.5,2.5Hz,1H),4.23(t,J＝5.3Hz,2H),4.07(s,3H),3.33(q ,J=1.8 Hz, 2H), 2.86 (t, J = 5.3Hz, 2H), 2.39 (s, 6H), 1.19-1.08 (m, 1H), 0.62-0.52 (m, 2H), 0.33 (m, 2H).

MS m/z(ESI):409.2(M+H) ⁺ .

Example 7 Synthesis of Compound 7

first step

Compound A1-1 (400 mg, 1.74 mmol) was dissolved in dichloromethane (5 mL), and then compound 7-1 (430 mg, 1.74 mmol), O-(7-azabenzotriazol-1-yl) were added successively )-N,N,N′,N′-tetramethylurea hexafluorophosphate (992 mg, 2.61 mmol) and N,N-diisopropylethylamine (0.86 mL, 5.22 mmol). The resulting reaction solution was stirred at room temperature overnight. LCMS monitored the reaction to be complete. The reaction solution was poured into ice water (50 mL), and extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified through silica gel column (ethyl acetate: petroleum ether = 0-100%) to obtain compound 7-2 (450 mg).

MS m/z(ESI):288.1(M+H) ⁺ .

Step 2

Compound 7-2 (100mg, 0.35mmol), intermediate A2 (86mg, 0.35mmol), trimethylacetic acid (35mg, 0.35mmol), potassium carbonate (145mg, 1.05mmol) and 1,1'-bis( Diphenylphosphino)ferrocene palladium dichloride (29 mg, 0.035 mmol) was added to dry 1,4-dioxane (10 mL). Under nitrogen protection, the reaction solution was heated to 110°C and stirred overnight. LCMS monitored the reaction to be complete. The reaction mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure to obtain crude product. The crude product was separated and purified through a preparative plate (dichloromethane: methanol = 10:1) to obtain a crude product, and then compound 7 (60 mg) was obtained through reverse preparative separation and purification.

¹ H NMR (400MHz, CD ₃ OD) δ8.48(d,J＝7.6Hz,1H),8.11(d,J＝8.4Hz,1H),7.67(s,1H),7.37–7.24(m,2H ),6.98(d,J＝2.5Hz,1H),6.76(dd,J＝7.6,2.5Hz,1H),4.89–4.85(m,0.5H),4.75–4.69(m,0.5H),4.26( t,J＝5.4Hz,2H),4.04(s,3H),3.73(t,J＝4.7Hz,4H),3.02–2.94(m,1H),2.90(t,J＝5.4Hz,2H), 2.64(t,J＝4.7Hz,4H),1.30–1.17(m,1H),1.09–0.94(m,1H).

MS m/z(ESI):455.2(M+H) ⁺ .

Example 8 Synthesis of Compound 8

first step

Compound 7-2 (350 mg, 1.22 mmol) was added to anhydrous tetrahydrofuran (10 mL) solvent, and under nitrogen protection conditions, the temperature was controlled at -65°C to -60°C, and BCl ₃ solution (1.8 mL, 1.83mmol, 1M). After the addition was completed, slowly raised to room temperature and stirred for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was poured into ice water (30 mL), and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (50 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated and purified through silica gel column (ethyl acetate: petroleum ether = 0-100%) to obtain compound 8-1 (202 mg).

MS m/z(ESI):274.1(M+H) ⁺ .

Step 2

Compound 8-1 (202 mg, 0.74 mmol) was dissolved in acetonitrile (5 mL) and water (5 mL), and potassium hydroxide (415 mg, 7.40 mmol) was slowly added under ice bath conditions and nitrogen protection. After the addition is complete, remove the ice bath and continue stirring the reaction solution at room temperature for 1 hour. The reaction solution was then placed in an ice bath, and compound 8-2 (295 mg, 1.11 mmol) was slowly added. After the addition was completed, the reaction solution was slowly raised to room temperature and stirred for 4 hours. LCMS monitored the reaction to be complete. The reaction solution was poured into ice water (30 mL), and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (80 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified through silica gel column (ethyl acetate: petroleum ether = 0-100%) to obtain compound 8-3 (160 mg).

MS m/z(ESI):324.1(M+H) ⁺ .

third step

Compound 8-3 (160mg, 0.50mmol), intermediate A2 (122mg, 0.50mmol), trimethylacetic acid (50mg, 0.50mmol), potassium carbonate (205mg, 1.49mmol) and 1,1'-bis( Diphenylphosphino)ferrocene palladium dichloride (36 mg, 0.050 mmol) was added to anhydrous 1,4-dioxane (5 mL). Under nitrogen protection, the reaction solution was heated to 110°C and stirred overnight. LCMS monitored the reaction to be complete. The reaction mixture was cooled, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (methanol: dichloromethane = 0-100%), and then compound 8 (60 mg) was obtained by reverse preparative separation and purification.

¹ H NMR (400MHz, CD ₃ OD) δ8.55 (d, J＝7.7Hz, 1H), 7.95-7.80 (m, 2H), 7.63 (dd, J＝8.0, 1.6Hz, 1H), 7.53 (s ,1H),7.25(s,1H),7.03(dd,J＝7.6,1.9Hz,1H),7.00(s,1H),4.69(m,1H),4.54(t,J＝4.9Hz,2H) ,3.90(t,J＝4.8Hz,4H),3.51(t,J＝4.9Hz,2H),3.24(t,J＝4.8Hz,4H),2.94(m,1H),1.23(m,1H) ,1.07(m,1H).

MS m/z(ESI):491.2(M+H) ⁺ .

Example 9 Synthesis of Compound 9

first step

Compound 9-1 (1.00g, 3.52mmol) was dissolved in dichloromethane (20mL), and then compound 7-1 (880mg, 3.52mmol), O-(7-azabenzotriazole-1- base)-N,N,N′,N′-tetramethylurea hexafluorophosphate (2.01g, 5.28mmol) and N,N-diisopropylethylamine (1.75mL, 10.60mmol). The reaction mixture was stirred at room temperature overnight. LCMS monitored the reaction to be complete. The reaction solution was poured into ice water (100 mL), and extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated brine (200 mLx1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (petroleum ether: ethyl acetate = 1:0-2:1) to obtain compound 9-2 (1.10 g, yield 91.7%).

MS m/z(ESI):342.1(M+H) ⁺ .

Step 2

Compound 9-2 (100mg, 0.29mmol), intermediate A2 (72mg, 0.29mmol), trimethylacetic acid (30mg, 0.29mmol), potassium carbonate (121mg, 0.88mmol) and 1,1'-bis( Diphenylphosphino)ferrocene palladium dichloride (24 mg, 0.029 mmol) was added to dry 1,4-dioxane (10 mL). Under nitrogen protection, the reaction mixture was heated to 110°C and stirred overnight. LCMS monitored the reaction to be complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain crude product. After the crude product was separated and purified by the preparation plate (dichloromethane: methanol = 10:1), compound 9 (18.0 mg, yield 12.1%) was obtained by reverse preparation and separation and purification.

¹ H NMR (400MHz, CD ₃ OD) δ8.42(d,J＝7.6Hz,1H),7.80(d,J＝8.0Hz,1H),7.76-7.66(m,2H),7.63(h,J ＝1.4Hz,1H),7.02(d,J＝2.5Hz,1H),6.81(dd,J＝7.6,2.4Hz,1H),4.85-4.79(m,0.5H),4.70-4.61(m,0.5 H),4.29(t,J＝5.3Hz,2H),3.79-3.68(m,4H),3.00-2.84(m,3H),2.74-2.60(m,4H),1.30-1.17(m,1H) ,1.14-0.99(m,1H).

MS m/z(ESI):509.2(M+H) ⁺ .

Example 10 Synthesis of Compound 10

first step

Compound 10-1 (500 mg, 2.09 mmol) was dissolved in methanol (10 mL), and 3 mL of lithium hydroxide aqueous solution (2 mol/L) was added dropwise under ice bath conditions. After the dropwise addition, the reaction solution was slowly raised to room temperature and stirred for 2 hours. LCMS monitored the reaction to be complete. Pour the reaction solution into ice water (30 mL), adjust the pH to 4-5 with 1 mol/L dilute hydrochloric acid solution, and extract with ethyl acetate (50 mL × 3). Combine the organic phases and use Dry over sodium sulfate and filter. The filtrate was concentrated under reduced pressure to obtain crude product 10-2 (450 mg).

MS m/z(ESI):226.1(M+H) ⁺ .

Step 2

Compound 10-2 (450 mg, 2.00 mmol) was dissolved in dichloromethane (10 mL), and then compound A1-2 (114 mg, 2.00 mmol), O-(7-azabenzotriazol-1-yl) were added successively )-N,N,N′,N′-tetramethylurea hexafluorophosphate (1.14g, 3.00mmol) and N,N-diisopropylethylamine (0.99mL, 6.00mmol). The reaction mixture was stirred at room temperature overnight. LCMS monitored the reaction to be complete. The reaction solution was poured into ice water (50 mL), and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was separated and purified through silica gel column (ethyl acetate: petroleum ether = 0-100%) to obtain compound 10-3 (250 mg).

MS m/z(ESI):265.1(M+H) ⁺ .

third step

Intermediate A3 (100mg, 0.49mmol), compound 10-3 (129mg, 0.49mmol), trimethylacetic acid (50mg, 0.49mmol), potassium carbonate (202mg, 1.46mmol) and 1,1'-bis( Diphenylphosphino)ferrocene palladium dichloride (40 mg, 0.049 mmol) was added to anhydrous 1,4-dioxane (5 mL). Under nitrogen protection, the reaction solution was heated to 110°C and stirred overnight. LCMS monitored the reaction to be complete. The reaction mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column (methanol: dichloromethane = 0-100%), and then separated and purified by reverse preparation to obtain compound 10 (30 mg).

¹ HNMR (400MHz, CD ₃ OD) δ8.51 (dd, J＝7.7, 2.8Hz, 1H), 8.26 (d, J＝20.8Hz, 1H), 7.99-7.88 (m, 2H), 7.71 (d, J＝11.0Hz,1H),7.00(t,J＝3.1Hz,1H),6.80(m,1H),4.24(m,2H),2.86(t,J＝5.3Hz,2H),2.77-2.62( m, 1H), 2.38 (s, 6H), 1.03 (m, 2H), 0.91 (dd, J = 5.7, 2.7Hz, 2H).

MS m/z(ESI):390.2(M+H) ⁺ .

Example 11 Synthesis of Compound 11

first step

Compound 10-3 (100 mg, 0.38 mmol), pinacol diboronate 11-1 (125 mg, 0.49 mmol), potassium acetate (112 mg, 1.14 mmol), 1,1'-bis(diphenylphosphino) Ferrocene palladium dichloride (28 mg, 0.038 mmol) was added to anhydrous 1,4-dioxane (10 mL). Under nitrogen protection, the aforementioned reaction solution was heated to 100°C and stirred for 2 hours. LCMS monitored the reaction to be complete. The reaction mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (ethyl acetate: petroleum ether = 0-100%) to obtain crude compound 11-2 (100 mg).

MS m/z(ESI):231.1(M+H) ⁺ .

Step 2

Intermediate A5 (120 mg, 0.36 mmol), crude compound 11-2 (100 mg, 0.44 mmol), potassium carbonate (100 mg, 0.73 mmol), 1,1'-bis(diphenylphosphino)ferrocene dichloride were added in sequence. Palladium (27 mg, 0.036 mmol) was added to a mixed solvent of anhydrous 1,4-dioxane (10 mL) and water (1 mL). Under nitrogen protection, the aforementioned reaction solution was heated to 100°C and stirred overnight. LCMS monitored the reaction to be complete. The reaction mixture was cooled, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel plate (dichloromethane: methanol = 10:1), and then separated and purified by reverse preparation to obtain compound 11 (16 mg).

¹ H NMR (400MHz, CD ₃ OD) δ8.29(d,J＝2.2Hz,1H),8.24(d,J＝8.4Hz,2H),8.01-7.91(m,2H),7.78(d,J ＝7.9Hz,1H),7.24(dd,J＝9.8,2.2Hz,1H),4.18(t,J＝5.3Hz,2H),2.85(t,J＝5.3Hz,2H),2.66(s,1H ),2.39(s,6H),1.10(s,2H),0.93(s,2H).

MS m/z(ESI):390.2(M+H) ⁺ .

Example 12 Synthesis of Compound 12

first step

Compound A1-1 (300 mg, 1.31 mmol) was dissolved in dichloromethane (5 mL), and then 2-aminoacetonitrile (73 mg, 1.31 mmol), O-(7-azabenzotriazole-1-yl) were added successively )-N,N,N′,N′-tetramethylurea hexafluorophosphate (749 mg, 1.97 mmol) and N,N-diisopropylethylamine (0.65 mL, 3.93 mmol). The reaction mixture was stirred at room temperature overnight. LCMS monitored the reaction to be complete. The reaction solution was poured into ice water (50 mL), and extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated brine (100 mLx1), dried over anhydrous sodium sulfate, and the filtrate was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified through silica gel column (petroleum ether: ethyl acetate = 1:0-2:1) to obtain compound 12-2 (330 mg, yield 94.1%).

MS m/z(ESI):269.1(M+H) ⁺ .

Step 2

Compound 12-2 (100mg, 0.37mmol), intermediate A3 (76mg, 0.37mmol), trimethylacetic acid (38mg, 0.37mmol), potassium carbonate (155mg, 1.12mmol) and 1,1'-bis( Diphenylphosphino)ferrocene palladium dichloride (31 mg, 0.037 mmol) was added to dry 1,4-dioxane (10 mL). Under nitrogen protection, the reaction mixture was heated to 110°C and stirred overnight. LCMS monitored the reaction to be complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain crude product. The crude product was separated and purified through a preparation plate (dichloromethane: methanol = 10:1), and then separated and purified through reverse preparation to obtain compound 12 (30 mg, yield 20.4%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.83 (t, J = 5.7 Hz, 1H), 8.56 (d, J = 7.6 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.78 (s,1H),7.39-7.31(m,2H),7.09(d,J＝2.6Hz,1H),6.69(dd,J＝7.6,2.6Hz,1H),4.34-4.29(m,2H), 4.16(t,J＝5.7Hz,2H), 4.02(s,3H), 2.67(t,J＝5.6Hz,2H), 2.23(s,6H).

MS m/z(ESI):394.2(M+H) ⁺ .

Example 13 Synthesis of Compound 13

first step

Compound A1-1 (2.00g, 8.70mmol) was dissolved in N,N-dimethylformamide (20mL), and then ammonium chloride (922mg, 17.40mmol), 2-(7-azobenzo Triazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (4.95g, 13.10mmol) and N,N-diisopropylethylamine (4.30mL, 26.10mmol). After the addition is completed, the reaction solution is allowed to stir at room temperature overnight. LCMS monitored the reaction to be complete. The reaction solution was poured into ice water (50 mL), and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified through silica gel column (ethyl acetate: petroleum ether = 0-100%) to obtain compound 13-1 (1.40g).

MS m/z(ESI):230.1(M+H) ⁺ .

Step 2

Compound 13-1 (200mg, 0.87mmol), compound 11-1 (287mg, 1.13mmol), potassium acetate (257mg, 2.62mmol), 1,1'-bis(diphenylphosphino)ferrocene dichloride were added in sequence. Palladium (64 mg, 0.087 mmol) was added to anhydrous 1,4-dioxane (10 mL). Under nitrogen protection, the aforementioned reaction solution was heated to 100°C and stirred overnight. LCMS monitored the reaction to be complete. The reaction mixture was cooled and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified through silica gel column (ethyl acetate: petroleum ether = 0-100%) to obtain compound 13-2 (206 mg).

MS m/z(ESI):278.2(M+H) ⁺ .

third step

Compound 13-2 (96mg, 0.35mmol), compound 13-3 (149mg, 0.35mmol), potassium carbonate (144mg, 1.04mmol), 1,1'-bis(diphenylphosphino)ferrocene dichloride were added in sequence. Palladium (25 mg, 0.035 mmol) was added to a mixed solvent of anhydrous 1,4-dioxane (10 mL) and water (1 mL). Under nitrogen protection, the aforementioned reaction solution was heated to 100°C and stirred overnight. LCMS monitored the reaction to be complete. The reaction mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified on a silica gel plate (dichloromethane: methanol = 10:1) to obtain compound 13-4 (60 mg).

MS m/z(ESI):452.2(M+H) ⁺ .

the fourth step

Compound 13-4 (60 mg, 0.13 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (2 mL) was slowly added dropwise under ice bath conditions. After the dropwise addition was completed, the reaction solution was raised to room temperature and stirred for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was concentrated under reduced pressure to obtain crude product 13-5 (46 mg).

MS m/z(ESI):352.2(M+H) ⁺ .

the fifth step

Compound 13-5 (46 mg, 0.13 mmol) was dissolved in acetonitrile (2 mL), and N, N-diisopropylethylamine (51 mg, 0.39 mmol) and 2,2,2-trifluoroethyltrifluoro were added successively. Methanesulfonate (46 mg, 0.20 mmol). After the addition was completed, the reaction solution was stirred at room temperature for 2 hours. TLC monitored the reaction to be complete. The reaction solution was poured into water (10 mL), and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified through reverse preparation to obtain compound 13 (5 mg).

¹ H NMR (400MHz, CDCl ₃ ) δ8.27(d,J＝8.1Hz,1H),8.09(s,1H),8.00(d,J＝2.0Hz,1H),7.72(d,J＝9.6Hz ,2H),7.30(dd,J＝8.2,1.5Hz,1H),7.19-7.12(m,2H),5.81(s,1H),4.05(s,3H),3.16(dd,J＝6.3,3.5 Hz, 4H), 3.07 (q, J = 9.5 Hz, 2H), 2.90 (dd, J = 5.8, 3.8 Hz, 4H).

MS m/z(ESI):434.2(M+H) ⁺ .

Example 14 Synthesis of Compound 14

first step

Compound 8-3 (120mg, 0.37mmol), compound 11-1 (123mg, 0.48mmol), potassium acetate (110mg, 1.12mmol), 1,1'-bis(diphenylphosphino)ferrocene dichloride were added in sequence. Palladium (30 mg, 0.037 mmol) was added to anhydrous 1,4-dioxane (10 mL). Under nitrogen protection, the aforementioned reaction solution was heated to 100°C and stirred for 2 hours. LCMS monitored the reaction to be complete. The reaction mixture was cooled and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified through silica gel column (ethyl acetate: petroleum ether = 0-100%) to obtain compound 14-1 (100 mg).

MS m/z(ESI):372.2(M+H) ⁺ .

Step 2

Compound 14-1 (100mg, 0.27mmol), compound 14-2 (83mg, 0.22mmol), potassium carbonate (93mg, 0.67mmol), 1,1'-bis(diphenylphosphino)ferrocene dichloride were added in sequence. Palladium (18 mg, 0.022 mmol) was added to a solvent mixture of anhydrous 1,4-dioxane (10 mL) and water (1 mL). Under nitrogen protection, the aforementioned reaction solution was heated to 100°C and stirred overnight. LCMS monitored the reaction to be complete. The reaction mixture was cooled and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified through silica gel plate (dichloromethane: methanol = 10:1), and then separated and purified through reverse preparation to obtain compound 14 (20 mg).

¹ H NMR (400MHz, CDCl ₃ ) δ8.20 (d, J = 8.2Hz, 1H), 8.12 (d, J = 2.1Hz, 1H), 8.09 (s, 1H), 7.68 (d, J = 9.7Hz ,1H),7.53(dd,J＝8.2,1.7Hz,1H),7.32(d,J＝1.7Hz,2H),7.11(dd,J＝9.7,2.2Hz,1H),6.63(t,J＝ 72.8Hz,1H),4.88-4.66(m,1H),4.13(t,J＝5.5Hz,2H),3.75(t,4H),3.14-3.04(m,1H),2.86(t,J＝5.5 Hz, 2H), 2.60 (t, J = 4.7Hz, 4H), 1.28-1.22 (m, 1H), 1.09-0.94 (m, 1H).

MS m/z(ESI):491.2(M+H) ⁺ .

Example 15 Synthesis of Compound 15

first step

Compound 15-1 (300 mg, 1.13 mmol) was dissolved in dichloromethane (5 mL), and then compound A4-1 (135 mg, 1.36 mmol) and 2-(7-azobenzotriazole)-N were added successively ,N,N',N'-tetramethylurea hexafluorophosphate (642mg, 1.69mmol) and N,N-diisopropylethylamine (0.560mL, 3.39mmol). The reaction mixture was stirred at room temperature overnight. LCMS monitored the reaction to be complete. The reaction solution was poured into ice water (30 mL), and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified through silica gel column (petroleum ether: ethyl acetate = 1:0-2:1) to obtain compound 15-2 (200 mg, yield 51.0%). MS m/z(ESI):348.1(M+H) ⁺ .

Step 2

Compound 15-2 (200mg, 0.58mmol), pinacol diboronate 11-1 (190mg, 0.75mmol), potassium acetate (170mg, 1.73mmol), 1,1'-bis(diphenylphosphino) Ferrocene palladium dichloride (42 mg, 0.058 mmol) was added to dry 1,4-dioxane (10 mL). Under nitrogen protection, the reaction mixture was heated to 100°C and stirred overnight. LCMS monitored the reaction to be complete. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (petroleum ether: ethyl acetate = 1:0-2:1) to obtain compound 15-3 (160 mg, yield 70.3%).

MS m/z(ESI):396.1(M+H) ⁺ .

third step

Compound 15-3 (160mg, 0.41mmol), compound 14-2 (151mg, 0.41mmol), potassium carbonate (168mg, 1.22mmol), 1,1'-bis(diphenylphosphino)ferrocene dichloride were added in sequence. Palladium (30 mg, 0.041 mmol) was added to anhydrous 1,4-dioxane (10 mL) and water (1 mL). Under nitrogen protection, the reaction mixture was heated to 100°C and stirred overnight. LCMS monitored the reaction to be complete. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel plate (dichloromethane: methanol = 10:1), and then separated and purified by reverse preparation to obtain compound 15 (9 mg, yield 4.1%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.24 (d, J＝8.2Hz, 1H), 8.20-8.10 (m, 2H), 7.72 (d, J＝9.7Hz, 1H), 7.59 (dd, J＝ 8.2,1.7Hz,1H),7.40(t,J＝6.4Hz,1H),7.36(d,J＝1.4Hz,1H),7.17(d,J＝2.2Hz,1H),6.70(s,1H) ,4.20(m,4H),3.90-3.70(m,4H),2.92(s,2H),2.66(s,4H).

MS m/z(ESI):515.2(M+H) ⁺ .

Example 16 Synthesis of Compound 17

first step

Under nitrogen protection, N-bromosuccinimide (1.69g, 9.47mmol) was added to a solution of compound 13-3 (2.60g, 8.61mmol) in anhydrous N,N-dimethylformamide (20mL). ). After the addition was completed, the reaction solution was stirred at room temperature overnight. LCMS monitored the reaction to be complete. Pour the reaction solution into ice water (100mL), extract with ethyl acetate (80mLx3), combine the organic phases, wash with saturated brine (200mLx1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product is separated on a silica gel column. Purification (petroleum ether: ethyl acetate = 2:1) gave compound 17-1 (2.00 g, yield: 61%).

MS m/z(ESI):381.1(M+H) ⁺ .

Step 2

Under nitrogen protection, compound 7-2 (500mg, 1.74mmol), compound 11-1 (574mg, 2.26mmol), potassium acetate (512 mg, 5.22 mmol), a solution of 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (142 mg, 0.17 mmol) in anhydrous 1,4-dioxane (10 mL) was heated to 100°C and stir the reaction overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure. The crude product is separated and purified through silica gel column (petroleum ether: ethyl acetate = 1:0-2:1) to obtain compound 17-2 (400 mg, yield: 69%).

MS m/z(ESI):336.1(M+H) ⁺ .

third step

Under nitrogen protection, compound 17-1 (200 mg, 0.53 mmol), compound 17-2 (176 mg, 0.53 mmol), potassium carbonate (218 mg, 1.58 mmol), 1,1'-bis(diphenylphosphino)bis A mixed solution of ferrocene palladium dichloride (43 mg, 0.053 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was heated to 100°C and stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and the filtrate is concentrated under reduced pressure. The crude product is separated and purified through silica gel column (dichloromethane: methanol = 10:1) to obtain compound 17-3 (140 mg, yield: 52%).

MS m/z(ESI):510.2(M+H) ⁺ .

the fourth step

Under ice-water bath conditions, trifluoroacetic acid (2 mL) was slowly added dropwise to a solution of compound 17-3 (140 mg, 0.28 mmol) in dichloromethane (3 mL). After the dropwise addition was completed, the ice-water bath was removed, the reaction solution was raised to room temperature, and the reaction was stirred for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was concentrated under reduced pressure to obtain compound 17-4 (120 mg).

MS m/z(ESI):410.2(M+H) ⁺ .

the fifth step

Under nitrogen protection, N,N-diisopropylethylamine (114 mg, 0.88 mmol) and compound 13-6 (102 mg, 0.44 mmol). After the addition is completed, the reaction solution is placed at room temperature and stirred for 2 hours. TLC monitored the reaction to be complete. Pour the reaction solution into water (10mL), extract with ethyl acetate (30mLx3), combine the organic phases, wash with saturated brine (30mLx1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product is separated by reverse preparation. Purification gave compound 17 (26 mg, yield: 18%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.30(d,J＝8.0Hz,1H),8.21(d,J＝4.0Hz,1H),8.09(s,1H),8.01(s,1H),7.73 -7.70(m,1H),7.30(d,J＝8.0Hz,1H),7.18-7.10(m,2H),4.88-4.82(m,0.5H),4.71-4.65(m,0.5H),4.02 (s,3H),3.20-3.15(m,4H),3.14-3.03(m,3H),2.92-2.89(m,4H),1.28-1.18(m,1H),1.05-0.99(m,0.5H ),0.99-0.93(m,0.5H).

MS m/z(ESI):492.2(M+H) ⁺ .

Example 17 Synthesis of Compound 18

According to the synthesis methods of Example 7 and Example 16, starting from compound 18-1, compound 18 (18 mg) was obtained through a 5-step reaction.

¹ H NMR (400MHz, CDCl ₃ ) δ8.78(s,1H),8.26-7.99(m,5H),7.72-7.69(m,1H),7.20-7.17(m,1H),4.93-4.82(m ,0.5H),4.76-4.61(m,0.5H),3.22-3.14(m,4H),3.13-3.02(m,3H),2.95-2.85(m,4H),1.29-1.23(m,1H) ,1.15-1.09(m,0.5H),1.08-1.01(m,0.5H).

MS m/z(ESI):463.3(M+H) ⁺ .

Example 18 Synthesis of Compound 19

Under nitrogen protection, compound 19-1 (100 mg, 0.31 mmol), compound 19-2 (164 mg, 0.46 mmol), potassium carbonate (128 mg, 0.92 mmol), 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (25 mg, 0.031 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was heated to 100°C and stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column (dichloromethane: methanol = 10:1) and reverse preparative separation and purification to obtain compound 19 (19 mg, yield: 13%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.18-8.07(m,3H),7.73(d,J＝8.0Hz,1H),7.57(d,J＝8.0Hz,1H),7.39(s,1H) ,7.08(dd,J＝8.0,2.0Hz,1H),4.27-4.20(m,2H),4.14-4.11(m,2H),3.77-3.74(m,6H),3.12-3.09(m,2H) ,2.86-2.84(m,2H),2.642.54(m,4H).

MS m/z(ESI):475.3(M+H) ⁺ .

Example 19 Synthesis of Compound 32

first step

Under nitrogen protection, compound 14-1 (200 mg, 0.54 mmol), compound 17-1 (205 mg, 0.54 mmol), potassium carbonate (224 mg, 1.62 mmol) and 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (44 mg, 0.054 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was heated to 100°C and stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (dichloromethane: methanol = 10:1) to obtain compound 32-1 (100 mg, yield: 34%).

MS m/z(ESI):546.2(M+H) ⁺ .

Step 2

Under ice-water bath conditions, trifluoroacetic acid (2 mL) was slowly added dropwise to a solution of compound 32-1 (100 mg, 0.18 mmol) in dichloromethane (3 mL). After the dropwise addition was completed, the ice-water bath was removed, the reaction solution was raised to room temperature, and the reaction was stirred for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was concentrated under reduced pressure to obtain compound 32-2 (100 mg).

MS m/z(ESI):446.2(M+H) ⁺ .

third step

Under nitrogen protection, N,N-diisopropylethylamine (87 mg, 0.68 mmol) and compound 32-3 (40 mg, 0.34 mmol). After the addition was completed, the reaction solution was allowed to stir at room temperature overnight. TLC monitored the reaction to be complete. Pour the reaction solution into water (10mL), extract with ethyl acetate (30mLx3), combine the organic phases, wash with saturated brine (30mLx1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product is separated by reverse preparation. Purification gave compound 32 (21 mg, yield: 19%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.21 (d, J = 8.0Hz, 1H), 8.09 (s, 1H), 8.01 (s, 1H), 7.71-7.68 (m, 1H), 7.54 (d, J＝8.0Hz,1H),7.32(s,2H),7.19-7.16(m,1H),6.63(t,J＝72.0Hz,1H),4.87-4.83(m,0.5H),4.71-4.68( m,0.5H),3.61(s,2H),3.21-3.18(m,4H),3.13-3.07(m,1H),2.83-2.81(m,4H),1.08-0.97(m,1H),0.92 -0.83(m,1H).

MS m/z(ESI):485.3(M+H) ⁺ .

Example 20 Synthesis of Compound 35

first step

Under nitrogen protection, compound 17-1 (100 mg, 0.26 mmol), compound 19-2 (185 mg, 0.52 mmol), potassium carbonate (91 mg, 0.66 mmol), 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (22 mg, 0.026 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was heated to 100°C and stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (dichloromethane: methanol = 10:1) to obtain compound 35-1 (90 mg, yield: 65%).

MS m/z(ESI):530.2(M+H) ⁺ .

Step 2

Under ice-water bath conditions, trifluoroacetic acid (2 mL) was slowly added dropwise to a solution of compound 35-1 (90 mg, 0.17 mmol) in dichloromethane (3 mL). After the dropwise addition was completed, the ice-water bath was removed, the reaction solution was naturally raised to room temperature, and the reaction was stirred for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was concentrated under reduced pressure to obtain compound 35-2 (80 mg).

MS m/z(ESI):430.2(M+H) ⁺ .

third step

Under nitrogen protection, N,N-diisopropylethylamine (72 mg, 0.56 mmol) and compound 13-6 (65 mg, 0.28) were added sequentially to a solution of compound 35-2 (80 mg, 0.19 mmol) in acetonitrile (2 mL) mmol). After the addition was completed, the reaction solution was allowed to stir at room temperature overnight. TLC monitored the reaction to be complete. The reaction solution was poured into water (30 mL), extracted with ethyl acetate (30 mLx3), the organic phases were combined, washed with saturated brine (30 mLx1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by reverse preparation to obtain compound 35 (20 mg, two-step yield: 23%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.17-8.00(m,3H),7.79-7.72(m,1H),7.59-7.56(m,1H),7.40(s,1H),7.15-7.12(m ,1H),4.27-4.20(m,2H),3.77-3.74(m,2H),3.20-3.03(m,8H),2.91-2.88(m,4H).

MS m/z(ESI):512.3(M+H) ⁺ .

Example 21 Synthesis of Compound 36

first step

Under nitrogen protection, compound 19-1 (300mg, 0.92mmol), compound 11-1 (178mg, 1.39mmol), triethylamine (283mg, 2.77mmol), 1,1'-bis(diphenylphosphino) A solution of ferrocene palladium dichloride (76 mg, 0.092 mmol) in 1,4-dioxane (5 mL) was heated to 110°C and stirred for 6 hours. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (dichloromethane: methanol = 1:0-10:1) to obtain compound 36-1 (210 mg, yield: 61%).

MS m/z(ESI):374.2(M+H) ⁺ .

Step 2

According to the synthesis method of Example 17, compound 31 (17 mg) was obtained through a one-step reaction from compound 36-1 and compound 36-2.

¹ H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.67(brs,2H),8.54-8.47(m,2H),8.18(brs,1H),7.96-7.94(m,1H) ,7.31-7.28(m,1H),4.86(brs,0.5H),4.70(brs,0.5H),4.18(brs,2H),3.59(brs,4H),3.33(brs,4H),2.86(brs ,1H),2.73(brs,2H),1.17-1.14(m,2H).

MS m/z(ESI):426.2(M+H) ⁺ .

Example 22 Synthesis of Compound 37

According to the synthesis methods of Example 7 and Example 16, starting from compound 37-1, compound 37 (20 mg) was obtained through a 5-step reaction.

¹ H NMR (400MHz, CDCl ₃ ) δ8.04 (s, 1H), 7.98 (d, J = 2.0Hz, 1H), 7.68 (d, J = 8.0Hz, 1H), 7.47-7.39 (m, 3H) ,7.12-7.09(m,1H),6.04-6.03(m,1H),4.86-4.83(m,0.5H),4.70-4.67(m,0.5H),3.16-3.00(m,7H),2.93- 2.85 (m,4H),2.54(s,3H),1.33-1.21(m,1H),1.09-0.95(m,1H).

MS m/z(ESI):476.3(M+H) ⁺ .

Example 23 Synthesis of Compound 38

first step

Under nitrogen protection, compound 17-1 (350 mg, 0.92 mmol), compound 11-1 (177 mg, 1.38 mmol), triethylamine (282 mg, 2.76 mmol), 1,1'-bis(diphenylphosphino) A solution of ferrocene palladium dichloride (75 mg, 0.092 mmol) in 1,4-dioxane (5 mL) was heated to 110°C and stirred for 5 hours. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure. The crude product is separated and purified through silica gel column (petroleum ether: ethyl acetate = 1:0-4:1) to obtain compound 38-1 (360 mg, yield: 91%).

MS m/z(ESI):429.2(M+H) ⁺ .

Step 2

Under nitrogen protection, compound 38-1 (150 mg, 0.35 mmol), compound 38-2 (59 mg, 0.23 mmol), potassium carbonate (95 mg, 0.69 mmol), 1,1'-bis(diphenylphosphino)bis A mixed solution of ferrocene palladium dichloride (19 mg, 0.023 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was heated to 100°C and stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure. The crude product is separated and purified through silica gel column (petroleum ether: ethyl acetate = 1:0-0:1) to obtain compound 38-3 (38 mg, yield: 35%).

MS m/z(ESI):481.2(M+H) ⁺ .

third step

Under ice-water bath conditions, trifluoroacetic acid (1 mL) was slowly added dropwise to a solution of compound 38-3 (38 mg, 0.079 mmol) in dichloromethane (3 mL). After the dropwise addition was completed, the ice-water bath was removed, the reaction solution was raised to room temperature, and the reaction was stirred for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was concentrated under reduced pressure to obtain compound 38-4 (40 mg).

MS m/z(ESI):381.2(M+H) ⁺ .

the fourth step

Under nitrogen protection, N,N-diisopropylethylamine (41 mg, 0.32 mmol) and compound 13-6 (49 mg, 0.21) were added sequentially to a solution of compound 38-4 (40 mg, 0.11 mmol) in acetonitrile (2 mL). mmol). After the addition is completed, the reaction solution is stirred at room temperature for 16 hours. TLC monitored the reaction to be complete. Pour the reaction solution into water (10mL), extract with ethyl acetate (15mLx3), combine the organic phases, wash with saturated brine (10mLx1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product is separated by reverse preparation. Purification gave compound 38 (18 mg, yield: 37%).

¹ H NMR (400MHz, CDCl ₃ ) δ9.01 (s, 1H), 8.49 (d, J = 8.0Hz, 1H), 8.36 (s, 1H), 8.11 (d, J = 8.0Hz, 1H), 8.01 (s,1H),7.67(d,J＝8.0Hz,1H),7.25(d,J＝8.0Hz,1H),6.45(s,1H),4.88(brs,0.5H),4.73(brs,0.5 H), 3.20-3.18(m,4H),3.12-3.05(m,3H),2.92-2.90(m,4H),1.38-1.27(m,1H),1.14-1.06-5(m,1H).

MS m/z(ESI):463.2(M+H) ⁺ .

Example 24 Synthesis of Compound 39

first step

Under nitrogen protection, compound 39-1 (500mg, 2.22mmol), compound 11-1 (235mg, 734mmol), potassium acetate (653mg, 6.66mmol), 1,1'-bis(diphenylphosphino)diocene A solution of iron palladium dichloride (162 mg, 0.0222 mmol) in anhydrous 1,4-dioxane (10 mL) was heated to 100°C and stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure. The crude product is separated and purified through silica gel column (petroleum ether: ethyl acetate = 1:0-1:1) to obtain compound 39-2 (550 mg, yield: 91%).

MS m/z(ESI):274.1(M+H) ⁺ .

Step 2

Under nitrogen protection, compound 39-2 (202 mg, 0.74 mmol), compound 19-1 (200 mg, 0.62 mmol), potassium carbonate (212 mg, 1.54 mmol), 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (45 mg, 0.062 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was heated to 100°C and stirred for 3 hours. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (dichloromethane: methanol = 1:0-8:1) to obtain compound 39-3 (130 mg, yield: 61%).

MS m/z(ESI):393.2(M+H) ⁺ .

third step

Under nitrogen protection, compound 39-3 (130mg, 0.33mmol), compound 39-4 (171mg, 1.99mmol), triethylamine (0.4mL, 2.92mmol), pyridine (0.18mL, 1.46mmol), monohydrate A solution of copper acetate (199 mg, 1.00 mmol) in tetrahydrofuran (5 mL) was heated to 60°C and stirred for 24 hours. LCMS monitored the reaction to be complete. Cool, pour the reaction solution into water (30 mL), extract with ethyl acetate (20 mLx2), combine the organic phases, wash with saturated brine (30 mLx1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was separated and purified through silica gel plate (dichloromethane: methanol = 10:1) to obtain compound 39 (17 mg, yield: 12%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.09-8.01 (m, 3H), 7.65 (d, J = 8.0Hz, 1H), 7.46 (d, J = 8.0Hz, 1H), 7.18 (s, 1H) ,7.00-6.97(m,1H),4.04(brs,2H),3.68(brs,4H),3.52(brs,2H),2.92(brs,2H),2.78(brs,3H),2.52(brs,4H ),0.84(brs,2H),0.67(brs,2H).

MS m/z(ESI):433.5(M+H) ⁺ .

Example 25 Synthesis of Compound 40

first step

Under nitrogen protection, to a solution of compound 40-1 (2.00g, 8.70mmol) in N,N-dimethylformamide (30mL) was added cesium carbonate (4.25g, 13.10mmol) and 1-bromo-2- Ethyl chloride (1.24g, 10.40mmol). After the addition was completed, the resulting reaction solution was stirred and reacted at 65°C for 2 hours. TLC monitored the reaction to be complete. Cool, filter, pour the filtrate into ice water (100mL), extract with methyl tert-butyl ether (30mLx3), combine the organic phases, wash with saturated brine (100mLx1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain Compound 40-2 (1.42g, crude product).

MS m/z(ESI):293.1(M+H) ⁺ .

Step 2

Under nitrogen protection and ice bath conditions, a 1 mol/L potassium tert-butoxide tetrahydrofuran solution (7.24 mL, 7.24 mmol) was added dropwise to a solution of compound 40-2 (1.42 g, 4.83 mmol) in anhydrous tetrahydrofuran (20 mL). After the dropwise addition was completed, the reaction mixture was continued to stir for 1 hour in an ice bath. LCMS monitored the reaction to be complete. The reaction solution was poured into ice water (80 mL), and extracted with methyl tert-butyl ether (30 mLx2). The aqueous phase was adjusted to pH=4~5 with 1 mol/L dilute hydrochloric acid solution, extracted with ethyl acetate (30 mLx2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 40-3 (520 mg ,Crude).

MS m/z(ESI):243.1(M+H) ⁺ .

third step

Under nitrogen protection and ice bath conditions, potassium carbonate (593 mg, 4.30 mmol) and methyl iodide (0.20 mL, 3.23mmol). After the addition was completed, the ice bath was removed, the reaction solution was naturally raised to room temperature, and the reaction was stirred for 4 hours. LCMS monitored the reaction to be complete. The reaction solution was poured into ice water (40 mL), extracted with ethyl acetate (20 mLx3), the organic phases were combined, washed with saturated brine (50 mLx1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified through silica gel column (petroleum ether: ethyl acetate = 1:0-10:1) to obtain compound 40-4 (480 mg, total yield in three steps: 22%).

MS m/z(ESI):257.1(M+H) ⁺ .

the fourth step

Under nitrogen protection and ice bath conditions, trifluoroacetic acid (0.37 mL, 4.89 mmol) was slowly added dropwise to a solution of diethyl zinc (3.56 mL, 7.13 mmol, 2 M in hexane) in anhydrous dichloromethane (5 mL). After the dropwise addition was completed, the reaction solution was continued to stir for 10 minutes in an ice bath. Under ice bath conditions, diiodomethane (1.15 mL, 14.3 mmol) was added dropwise to the reaction solution. After the addition was completed, the reaction was continued to stir for 10 minutes under an ice bath, and then a solution of compound 40-4 (480 mg, 1.88 mmol) in anhydrous dichloromethane (5 mL) was added dropwise to the aforementioned reaction solution. After the addition was completed, the reaction solution was slowly raised to room temperature and the reaction was stirred overnight. LCMS monitored the reaction to be complete. Pour the reaction solution into saturated ice-water solution of ammonium chloride (50 mL). Extract with dichloromethane (30 mLx3), combine the organic phases, wash with saturated brine (50 mLx1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was separated and purified through silica gel column (petroleum ether: ethyl acetate = 1:0-10:1) to obtain compound 40-5 (272 mg, yield: 54%).

MS m/z(ESI):271.1(M+H) ⁺ .

the fifth step

Under ice bath conditions, aqueous NaOH solution (2 mL, 2N) was added dropwise to a solution of compound 40-5 (400 mg, 1.48 mmol) in methanol (5 mL). After the addition was completed, the reaction solution was slowly raised to room temperature and stirred for 2 hours. LCMS monitored the reaction to be complete. Pour the reaction solution into ice water (20 mL), adjust the pH = 4 to 5 with 1 mol/L dilute hydrochloric acid solution, extract with ethyl acetate (15 mLx3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and depressurize the filtrate Concentration gave compound 40-6 (350 mg).

MS m/z(ESI):257.1(M+H) ⁺ .

Step 6

Under nitrogen protection, compound 7-1 (124 mg, 1.65 mmol), HATU (798 g, 2.11 mmol) and N, N- were added sequentially to a solution of compound 40-6 (350 mg, 1.37 mmol) in dichloromethane (5 mL). Diisopropylethylamine (530 mg, 4.11 mmol). After the addition was completed, the reaction solution was allowed to stir at room temperature overnight. LCMS monitored the reaction to be complete. The reaction solution was poured into water (20 mL), extracted with ethyl acetate (30 mLx3), the organic phases were combined, washed with saturated brine (30 mLx1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified through silica gel column (petroleum ether: ethyl acetate = 1:0-2:1) to obtain compound 40-7 (280 mg, yield: 65%).

MS m/z(ESI):314.1(M+H) ⁺ .

Step 7

Under nitrogen protection, compound 40-7 (175 mg, 0.56 mmol), compound 11-1 (185 mg, 0.73 mmol), potassium acetate (165 mg, 1.68 mmol), 1,1'-bis(diphenylphosphino)bis A solution of palladium ferrocene dichloride (46 mg, 0.056 mmol) in anhydrous 1,4-dioxane (10 mL) was heated to 100°C and stirred for 2 hours. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (petroleum ether: ethyl acetate = 1:0-2:1) to obtain compound 40-8 (200 mg, yield: 99%).

MS m/z(ESI):362.2(M+H) ⁺ .

Step 8

Under nitrogen protection, compound 40-8 (100 mg, 0.28 mmol), compound 19-1 (75 mg, 0.23 mmol), potassium carbonate (96 mg, 0.69 mmol), 1,1'-bis(diphenylphosphino)bis A mixed solution of ferrocene palladium dichloride (19 mg, 0.023 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was heated to 100°C and stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column (dichloromethane: methanol = 10:1) and reverse preparation to obtain compound 40 (23 mg, yield: 21%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.28 (d, J = 8.0 Hz, 1H), 8.15-8.10 (m, 3H), 7.72 (d, J = 8.0 Hz, 1H), 7.51 (s, 1H) ,7.30(d,J＝8.0Hz,1H),7.09-7.06(m,1H),4.86-4.83(m,0.5H),4.70-4.67(m,0.5H),4.15-4.12(m,2H) ,3.97-3.93(m,1H),3.77-3.74(m,4H),3.15-3.09(m,1H),2.87-2.84(m,2H),2.61-2.59(m,4H),1.23-1.16( m,1H),1.0-0.89(m,5H).

MS m/z(ESI):481.2(M+H) ⁺ .

Example 26 Synthesis of Compound 41

first step

Under nitrogen protection, compound 14-1 (200 mg, 0.54 mmol), compound 17-1 (205 mg, 0.54 mmol), potassium carbonate (224 mg, 1.62 mmol) and 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (44 mg, 0.054 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was heated to 100°C and stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (dichloromethane: methanol = 10:1) to obtain compound 41-1 (100 mg, yield: 34%).

MS m/z(ESI):546.2(M+H) ⁺ .

Step 2

Under ice-water bath conditions, trifluoroacetic acid (2 mL) was slowly added dropwise to a solution of compound 41-1 (100 mg, 0.18 mmol) in dichloromethane (3 mL). After the dropwise addition was completed, the ice-water bath was removed, the reaction solution was raised to room temperature, and the reaction was stirred for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was concentrated under reduced pressure to obtain compound 41-2 (100 mg).

MS m/z(ESI):446.2(M+H) ⁺ .

third step

Under nitrogen protection, N,N-diisopropylethylamine (87 mg, 0.68 mmol) and compound 13-6 (79 mg, 0.34 mmol). The resulting reaction solution was stirred at room temperature for 2 hours. TLC monitored the reaction to be complete. Pour the reaction solution into water (30mL), extract with ethyl acetate (30mLx3), combine the organic phases, wash with saturated brine (30mLx1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product is separated by reverse preparation. Purification gave compound 41 (20 mg, two-step yield: 21%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.21(d,J＝8.0Hz,1H),8.09(s,1H),8.00(d,J＝2.0Hz,1H),7.70-7.67(m,1H) ,7.54(dd,J＝8.0,2.0Hz,1H),7.32(s,2H),7.17(dd,J＝8.0,2.0Hz,1H),6.63(t,J＝72.0Hz,1H),4.89- 4.82(m,0.5H),4.73-4.66(m,0.5H),3.17-3.03(m,7H),2.91-2.88(m,4H),1.27-1.24(m,1H),1.08-1.02(m ,0.5H),1.02-0.97(m,0.5H).

MS m/z(ESI):528.3(M+H) ⁺ .

Example 27 Synthesis of Compound 51

first step

Under nitrogen protection, compound 51-1 (147 mg, 1.58 mmol), HATU (753 mg, 1.98 mmol) and N, N- were added sequentially to a solution of compound 15-1 (350 mg, 1.32 mmol) in dichloromethane (5 mL). Diisopropylethylamine (0.65 mL, 3.96 mmol). After the addition was completed, the resulting reaction solution was stirred at room temperature overnight. LCMS monitored the reaction to be complete. Pour the reaction solution into water (50mL), extract with ethyl acetate (30mLx3), combine the organic phases, wash with saturated brine (30mLx1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product, which is separated on a silica gel column. Purification (petroleum ether: ethyl acetate = 1:0-2:1) gave compound 51-2 (210 mg, yield: 47%).

MS m/z(ESI):342.1(M+H) ⁺ .

Step 2

Under nitrogen protection, compound 51-2 (210 mg, 0.62 mmol), compound 11-1 (235 mg, 0.92 mmol), potassium acetate (182 mg, 1.85 mmol), 1,1'-bis(diphenylphosphino)bis A solution of palladium ferrocene dichloride (51 mg, 0.062 mmol) in anhydrous 1,4-dioxane (10 mL) was heated to 100°C and stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (petroleum ether: ethyl acetate = 1:0-2:1) to obtain compound 51-3 (210 mg, yield: 88%).

MS m/z(ESI):390.1(M+H) ⁺ .

third step

Under nitrogen protection, compound 51-3 (210 mg, 0.54 mmol), compound 19-1 (175 mg, 0.54 mmol), potassium carbonate (224 mg, 1.62 mmol), 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (44 mg, 0.054 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was heated to 100°C and stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (dichloromethane: methanol = 10:1) and reverse preparative separation and purification to obtain compound 51 (10 mg, yield: 4%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.20 (d, J = 8.0 Hz, 1H), 8.13 (s, 1H), 8.09 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.54 (d,J＝8.0Hz,1H),7.38(d,J＝4.0Hz,1H),7.31(s,1H),7.12(dd,J＝8.0,4.0Hz,1H),6.65(t,J＝ 72.0Hz,1H),4.15(t,J＝4.0Hz,2H),3.76(t,J＝4.0Hz,4H),3.66-3.54(m,1H),2.89(t,J＝5.4Hz,2H) ,2.63(t,J=4.0Hz,4H),1.96-1.84(m,1H),1.51-1.37(m,1H).

MS m/z(ESI):509.3(M+H) ⁺ .

Example 28 Synthesis of Compound 52

Under nitrogen protection, compound 52-1 (200 mg, 0.57 mmol), compound 19-1 (100 mg, 0.28 mmol), potassium carbonate (117 mg, 0.85 mmol), 1,1'-bis(diphenylphosphino)bis Ferrocene palladium dichloride (23 mg, 0.028 mmol) in 1,4-dioxane (5 mL) and water (1 mL) mixed solution was heated to 100°C and stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure. The crude product is separated and purified by silica gel column (dichloromethane: methanol = 10:1) and reverse preparation to obtain compound 52 (70 mg, yield: 52%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.18 (d, J=8.0Hz, 1H), 8.12 (s, 1H), 8.08 (s, 1H), 7.69-7.66 (m, 1H), 7.53 (d, J＝8.0Hz,1H),7.28(s,1H),7.15-7.07(m,2H),6.61(t,J＝72.0Hz,1H),4.15-4.12(m,2H),3.79-3.72(m ,4H),2.96(s,1H),2.87-2.84(m,2H),2.64-2.54(m,4H),0.92-0.86(m,2H),0.66-0.60(m,2H).

MS m/z(ESI):473.3(M+H) ⁺ .

Example 29 Synthesis of Compound 53

Under nitrogen protection, compound 53-1 (100 mg, 0.35 mmol), compound 14-1 (195 mg, 0.53 mmol), potassium carbonate (145 mg, 1.05 mmol), 1,1'-bis(diphenylphosphino)bis A mixed reaction solution of palladium ferrocene dichloride (29 mg, 0.035 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was heated to 100°C and stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column (dichloromethane: methanol = 10:1) and reverse preparation to obtain compound 53 (22 mg, yield: 14%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.20 (d, J = 8.0Hz, 1H), 8.12-8.08 (m, 2H), 7.69-7.66 (m, 1H), 7.53 (d, J = 8.0Hz, 1H),7.32(brs,2H),7.13(d,J＝8.0Hz,1H),6.64(t,J＝72.0Hz,1H),4.87-4.83(m,0.5H),4.71-4.67(m, 0.5H),4.12-4.09(m,2H),3.12-3.06(m,1H),2.86-2.84(m,2H),2.41(s,6H),1.28-1.22(m,1H),1.07-0.97 (m,1H).

MS m/z(ESI):449.2(M+H) ⁺ .

Example 30 Synthesis of Compound 54

first step

Under nitrogen protection, compound A5-1 (150mg, 0.77mmol), compound 54-1 (215mg, 1.15mmol), cesium carbonate (747 mg, 2.29mmol), 2-(di-tert-butylphosphonium)-3-methoxy-6-methyl-2'4'6'-triisopropyl-biphenyl (72mg, 0.15mmol), ene A solution of propylpalladium(II) chloride dimer (14 mg, 0.038 mmol) in toluene (50 mL) was heated to 100°C and stirred overnight. LCMS monitored the reaction to be complete. Cool and filter, and the filtrate is concentrated under reduced pressure to obtain a crude product, which is separated and purified through silica gel column (dichloromethane: methanol = 1:0-10:1) to obtain compound 54-2 (80 mg, yield: 35%).

MS m/z(ESI):304.1(M+H) ⁺ .

Step 2

To a solution of compound 54-2 (80 mg, 0.26 mmol) in anhydrous DMF (5 mL) was added NBS (52 mg, 0.29 mmol) under nitrogen protection and -40°C. After the addition was completed, the cold bath was removed and the mixture was allowed to warm to room temperature naturally and the reaction was continued to stir for 2 hours. LCMS monitored the reaction to be complete. Pour the reaction solution into ice water (10 mL) and extract with ethyl acetate (10 mL Column separation and purification (petroleum ether: ethyl acetate = 100%-0) gave compound 54-3 (70 mg, yield: 69%).

MS m/z(ESI):381.1(M+H) ⁺ .

third step

Under nitrogen protection, combine standard compound 54-3 (70 mg, 0.18 mmol), compound 14-1 (103 mg, 0.28 mmol), potassium carbonate (76 mg, 0.55 mmol), 1,1'-bis(diphenylphosphine) A mixed solution of ferrocene palladium dichloride (15 mg, 0.018 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was heated to 100°C and stirred for 2 hours. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (dichloromethane: methanol = 100%-0) to obtain compound 54-4 (80 mg, yield: 79%).

MS m/z(ESI):547.2(M+H) ⁺ .

the fourth step

To a solution of compound 54-4 (80 mg, 0.15 mmol) in dichloromethane (3 mL) was slowly added trifluoroacetic acid (1 mL) under ice bath conditions. After the dropwise addition was completed, the reaction solution was raised to room temperature and stirred for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was concentrated under reduced pressure to obtain crude compound 54-5 (87 mg).

MS m/z(ESI):447.2(M+H) ⁺ .

the fifth step

Under nitrogen protection and ice bath conditions, 30% formaldehyde aqueous solution (41 mg, 0.39 mmol) was added to a solution of crude compound 54-5 (87 mg, 0.20 mmol) in methanol (5 mL). After the addition was completed, the reaction solution was continued to stir for 20 minutes under these conditions, and then sodium cyanoborohydride (26 mg, 0.39 mmol) was slowly added. After the addition was completed, the reaction solution was naturally raised to room temperature and stirred for 2 hours. LCMS monitored the reaction to be complete. Pour the reaction solution into ice water (20 mL), extract with ethyl acetate (30 mLx3), combine the organic phases, wash with saturated brine (100 mLx1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was separated and purified by reverse preparation to obtain compound 54 (20 mg, yield 22%).

¹ H NMR (400MHz, CD ₃ OD) δ8.35 (s, 1H), 8.24 (s, 1H), 7.90 (d, J = 8.0Hz, 1H), 7.81 (d, J = 8.0Hz, 1H), 7.61(d,J＝8.0Hz,1H),7.47(s,1H),7.34(d,J＝8.0Hz,1H),7.00(t,J＝72.0Hz,1H),4.74-4.60(m,1H ),4.31-4.15(m,6H),3.34(brs,1H),2.96-2.91(m,4H),1.30-1.02(m,2H).

MS m/z(ESI):461.2(M+H) ⁺ .

Example 31 Synthesis of Compound 55

first step

Under nitrogen protection, compound A5-1 (350 mg, 1.78 mmol), compound 55-1 (210 mg, 1.78 mmol), cesium carbonate (1.74 g, 5.34 mmol), 2-(di-tert-butylphosphorus)-3 -Methoxy-6-methyl-2'4'6'-triisopropyl-biphenyl (167 mg, 0.36 mmol), allylpalladium(II) chloride dimer (65 mg, 0.18 mmol) The toluene (5 mL) solution was heated to 100°C and the reaction was stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure. The crude product is separated and purified through silica gel column (dichloromethane: methanol = 1:0-10:1) to obtain compound 55-2 (65 mg, yield: 16%).

MS m/z(ESI):235.1(M+H) ⁺ .

Step 2

Under ice-water bath conditions, N-bromosuccinimide (54 mg, 0.30 mmol) was slowly added to a solution of compound 55-2 (65 mg, 0.28 mmol) in anhydrous N,N-dimethylformamide (2 mL). ). After the addition is completed, remove the ice-water bath and place the reaction solution at room temperature for stirring overnight. LCMS monitored the reaction to be complete. Pour the reaction solution into water (30mL), extract with ethyl acetate (20mLx3), combine the organic phases, wash with saturated brine (30mLx1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product is separated and purified on a silica gel plate. (Petroleum ether: ethyl acetate = 2:1) Compound 55-3 (57 mg, yield: 66%) was obtained.

MS m/z(ESI):313.1(M+H) ⁺ .

third step

Under nitrogen protection, compound 55-3 (57 mg, 0.18 mmol), compound 14-1 (102 mg, 0.28 mmol), potassium carbonate (76 mg, 0.55 mmol), 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (15 mg, 0.018 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was heated to 100°C and stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel plate (dichloromethane: methanol = 10:1) and reverse preparation to obtain compound 55 (15 mg, yield: 17%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.21 (d, J＝8.0Hz, 1H), 8.13-8.09 (m, 2H), 7.68 (d, J＝8.0Hz, 1H), 7.54 (d, J＝ 8.0Hz,1H),7.32-7.30(m,2H),7.13(d,J＝8.0Hz,1H),6.63(t,J＝72.0Hz,1H),4.86-4.84(m,0.5H),4.70 -4.67(m,0.5H),4.06-3.56(m,9H),3.12-3.08(m,1H),1.25(brs,1H),1.08-0.97(m,1H).

MS m/z(ESI):478.2(M+H) ⁺ .

Example 32 Synthesis of Compound 56

first step

Under nitrogen protection, compound A5-1 (250 mg, 1.28 mmol), compound 56-1 (168 mg, 1.28 mmol), cesium carbonate (1.25 g, 3.84 mmol), 2-(di-tert-butylphosphorus)-3 -Methoxy-6-methyl-2'4'6'-triisopropyl-biphenyl (120 mg, 0.26 mmol), allylpalladium(II) chloride dimer (47 mg, 0.13 mmol) The toluene (5 mL) solution was heated to 100°C and the reaction was stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (dichloromethane: methanol = 1:0-10:1) to obtain compound 56-2 (140 mg, yield: 44%).

MS m/z(ESI):248.1(M+H) ⁺ .

Step 2

To a solution of compound 56-2 (140 mg, 0.57 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added N-bromosuccinimide (111 mg, 0.62 mmol) under ice-water bath conditions. . After the addition is completed, remove the ice-water bath, let the reaction solution naturally rise to room temperature, and stir the reaction overnight. LCMS monitored the reaction to be complete. The reaction solution was poured into water (50 mL), extracted with ethyl acetate (50 mLx3), the organic phases were combined, washed with saturated brine (30 mLx1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified through silica gel column (petroleum ether: ethyl acetate = 2:1) to obtain compound 56-3 (140 mg, yield: 76%).

MS m/z(ESI):326.1(M+H) ⁺ .

third step

Under nitrogen protection, compound 56-3 (140 mg, 0.43 mmol), compound 14-1 (240 mg, 0.65 mmol), potassium carbonate (178 mg, 1.29 mmol), 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (35 mg, 0.043 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was heated to 100°C and stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure. The crude product is separated and purified by silica gel column (dichloromethane: methanol = 10:1) and reverse preparation to obtain compound 56 (72 mg, yield: 34%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.19(d,J＝8.0Hz,1H),8.12-8.08(m,2H),7.67(d,J＝8.0Hz,1H),7.54-7.51(m, 1H),7.33-7.31(m,2H),7.15-7.11(m,1H),6.64(t,J＝72.0Hz,1H),4.85-4.83(m,0.5H),4.70-4.67(m,0.5 H),4.05-3.94(m,4H),3.79-3.73(m,1H),3.10-3.07(m,1H),2.87-2.84(m,1H),2.71-2.68(m,1H),2.34( s,3H),2.24-2.17(m,1H),2.10-2.05(m,1H),1.29-1.22(m,1H),1.07-0.98(m,1H).

MS m/z(ESI):491.2(M+H) ⁺ .

Example 33 Synthesis of Compound 57

first step

Under nitrogen protection, compound A5-1 (350 mg, 1.79 mmol), compound 57-1 (516 mg, 3.58 mmol), cesium carbonate (1.75 g, 5.37 mmol), 2-(di-tert-butylphosphorus)-3 -Methoxy-6-methyl-2'4'6'-triisopropyl-biphenyl (168 mg, 0.36 mmol), allylpalladium(II) chloride dimer (33 mg, 0.090 mmol) The toluene solution was heated to 100°C and the reaction was stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure. The crude product is separated and purified through silica gel column (dichloromethane: methanol = 1:0-10:1) to obtain compound 57-2 (100 mg, yield: 22%).

MS m/z(ESI):261.1(M+H) ⁺ .

Step 2

To a solution of compound 57-2 (100 mg, 0.39 mmol) in anhydrous DMF (5 mL) was added N-bromosuccinimide (76 mg, 0.42 mmol) under ice-water bath conditions. After the addition is completed, remove the ice-water bath, allow the reaction solution to naturally rise to room temperature, and stir the reaction overnight. LCMS monitored the reaction to be complete. Pour the reaction solution into water (10mL), extract with ethyl acetate (10mLx3), combine the organic phases, wash with saturated brine (15mLx1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product is separated and purified on a silica gel column. (Petroleum ether: ethyl acetate = 2:1) Compound 57-3 (80 mg, yield: 62%) was obtained.

MS m/z(ESI):339.1(M+H) ⁺ .

third step

Under nitrogen protection, compound 57-3 (80 mg, 0.24 mmol), compound 14-1 (132 mg, 0.36 mmol), potassium carbonate (98 mg, 0.71 mmol), 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (19 mg, 0.024 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was heated to 100°C and stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure. The crude product is separated and purified by silica gel column (dichloromethane: methanol = 10:1) and reverse preparation to obtain compound 57 (44 mg, yield: 37%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.22 (d, J＝8.0Hz, 1H), 8.12-8.10 (m, 2H), 7.69 (d, J＝8.0Hz, 1H), 7.54 (d, J＝ 8.0Hz,1H),7.32(s,2H),7.12-7.09(m,1H),6.63(t,J＝72.0Hz,1H),4.87-4.84(m,0.5H),4.71-4.68(m, 0.5H),4.14-4.11(m,2H),3.13-3.07(m,1H),2.93-2.79(m,10H),2.52(s,3H),1.25(brs,1H),1.08-0.97(m ,1H).

MS m/z(ESI):504.2(M+H) ⁺ .

Example 34 Synthesis of Compound 58

first step

Under nitrogen protection, compound 17-1 (200 mg, 0.53 mmol), compound 58-1 (190 mg, 0.53 mmol), potassium carbonate (218 mg, 1.58 mmol), 1,1'-bis(diphenylphosphino)bis A mixed solution of ferrocene palladium dichloride (43 mg, 0.053 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was heated to 100°C and stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (dichloromethane: methanol = 10:1) to obtain compound 58-2 (186 mg, yield: 66%).

MS m/z(ESI):534.2(M+H) ⁺ .

Step 2

Under ice-water bath conditions, trifluoroacetic acid (2 mL) was slowly added dropwise to a solution of compound 58-2 (186 mg, 0.35 mmol) in dichloromethane (3 mL). After the dropwise addition was completed, the ice-water bath was removed, the reaction solution was naturally raised to room temperature, and the reaction was stirred for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was concentrated under reduced pressure to obtain compound 58-3 (152 mg).

MS m/z(ESI):434.2(M+H) ⁺ .

third step

Under nitrogen protection, N,N-diisopropylethylamine (136 mg, 1.05 mmol) and compound 58-4 (63 mg, 0.26 mmol). After the addition is completed, the reaction solution is stirred at room temperature for 2 hours. TLC monitored the reaction to be complete. The reaction solution was poured into water (50 mL), extracted with ethyl acetate (30 mLx3), the organic phases were combined, washed with saturated brine (30 mLx1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified through reverse preparation to obtain compound 58 (15 mg, two-step yield: 9%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.28 (d, J = 8.0Hz, 1H), 8.24-8.21 (m, 1H), 8.10 (s, 1H), 8.02 (s, 1H), 7.74-7.71 ( m,1H),7.32(d,J＝8.0Hz,1H),7.17-7.14(m,2H),4.224.13(m,2H),4.08(s,3H),3.62(s,2H),3.21 -3.18(m,4H),2.83-2.81(m,4H).

MS m/z(ESI):473.3(M+H) ⁺ .

Example 35 Synthesis of Compound 59

Under nitrogen protection, N,N-diisopropylethylamine (57 mg, 0.44 mmol) and compound 58-4 (27 mg, 0.22 mmol). After the addition was completed, the reaction solution was allowed to stir at room temperature overnight. TLC monitored the reaction to be complete. Pour the reaction solution into water (10mL), extract with ethyl acetate (30mLx3), combine the organic phases, wash with saturated brine (30mLx1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product is separated by reverse preparation. Purification gave compound 59 (20 mg, yield: 30%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.30(d,J＝8.0Hz,1H),8.21(d,J＝8.0Hz,1H),8.09(s,1H),8.01(s,1H),7.74 -7.71(m,1H),7.32-7.29(m,1H),7.16-7.13(m,2H),4.87-4.83(m,0.5H),4.71-4.67(m,0.5H),4.02(s, 3H),3.61(s,2H),3.20-3.09(m,5H),2.83-2.81(m,4H),1.26-1.24(m,1H),1.04-0.94(m,1H).

MS m/z(ESI):449.3(M+H) ⁺ .

Example 36 Synthesis of Compound 60

first step

Under nitrogen protection and ice bath conditions, thionyl chloride (1 mL, 13.4 mmol) was added dropwise to a solution of compound 60-1 (500 mg, 4.46 mmol) in anhydrous dichloromethane (5 mL). After the dropwise addition was completed, the ice bath was removed, the reaction mixture was naturally raised to room temperature, and the stirring reaction was continued for 3 hours. LCMS monitored the reaction to be complete. The reaction solution was concentrated under reduced pressure to obtain crude compound 60-2 (760 mg).

MS m/z(ESI):131.1(M+H) ⁺ .

Step 2

Under nitrogen protection, cesium carbonate (1.46 g, 4.47 mmol) was added to a solution of crude compound 60-2 (293 mg, 2.24 mmol) and compound 60-3 (200 mg, 1.49 mmol) in acetonitrile (5 mL). The reaction solution was stirred at room temperature for 3 hours. The reaction is over. Filter, and the filtrate is concentrated under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (dichloromethane: methanol = 1:0-5:1) to obtain compound 60-4 (142 mg, yield: 42%).

MS m/z(ESI):229.1(M+H) ⁺ .

third step

To a solution of compound 60-4 (142 mg, 0.62 mmol) in anhydrous N,N-dimethylformamide (3 mL) under nitrogen protection and -40°C, N-bromosuccinimide ( 111 mg, 0.623 mmol). After the addition is completed, remove the cold bath, allow the reaction solution to naturally rise to room temperature, and continue to stir the reaction for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was poured into water (50 mL), extracted with ethyl acetate (20 mLx3), the organic phases were combined, washed with saturated brine (30 mLx1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified through silica gel column (dichloromethane: methanol = 1:0-10:1) to obtain compound 60-5 (156 mg, yield: 82%).

MS m/z(ESI):307.1(M+H) ⁺ .

the fourth step

Under nitrogen protection, compound 60-5 (80 mg, 0.26 mmol), compound 14-1 (116 mg, 0.31 mmol), potassium carbonate (90 mg, 0.65 mmol) and 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (19 mg, 0.026 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was heated to 100°C and stirred for 3 hours. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was sequentially separated and purified through silica gel column (dichloromethane: methanol = 1:0-10:1) and methanol pulping to obtain compound 60 (70 mg, yield: 57%).

¹ H NMR (400MHz, DMSO-d6) δ8.73 (s, 1H), 8.40-8.37 (m, 2H), 7.95 (d, J = 8.0Hz, 1H), 7.63 (brs, 2H), 7.46-7.11 (m,4H),6.91(s,1H),5.25(s,2H),4.86(brs,0.5H),4.70(brs,0.5H),3.72(s,3H),2.87(brs,1H), 1.23-0.99(m,2H).

MS m/z(ESI):472.6(M+H) ⁺ .

Example 37 Synthesis of Compound 61

According to the synthesis method of Example 36, compound 61 (20 mg) was obtained from compound 61-1 through a 4-step reaction.

¹ H NMR (400MHz, DMSO-d6) δ8.43(s,1H),8.23(s,1H),8.11(s,1H),8.05(d,J＝2.0Hz,1H),7.65(d,J ＝8.0Hz,1H),7.34-7.29(m,2H),7.17-6.80(m,3H),5.11(s,2H),4.54(brs,0.5H),4.38(m,0.5H),3.43( s,3H),2.56(brs,1H),0.84-0.68(m,2H).

MS m/z(ESI):473.4(M+H) ⁺ .

Example 38 Synthesis of Compound 62

According to the synthesis method of Example 30, compound 62 (11 mg) was obtained from compound A5-1 and compound 62-1 through a three-step reaction.

¹ H NMR (400MHz, CDCl ₃ ) δ8.20(d,J＝8.0Hz,1H),8.12(d,J＝2.2Hz,1H),8.08(s,1H),7.68(d,J＝8.0Hz ,1H),7.55-7.52(m,1H),7.33(brs,2H),7.15-7.12(m,1H),6.63(t,J＝72.0Hz,1H),4.87-4.83(m,0.5H) ,4.71-4.67(m,0.5H),4.14-4.11(m,2H),3.13-3.06(m,1H),2.97-2.94(m,2H),2.66-2.63(m,4H),1.85-1.81 (m,4H),1.31-1.19(m,1H),1.07-0.97(m,1H).

MS m/z(ESI):475.3(M+H) ⁺ .

Example 39 Synthesis of Compound 63

According to the synthesis method of Example 1, compound 63 (58 mg) was obtained through a one-step reaction from compound A2 and compound 13-1.

¹ H NMR (400MHz, CDCl ₃ ) δ8.82(d,J＝4.0Hz,1H),8.32(s,1H),8.00(d,J＝8.0Hz,1H),7.74(s,1H),7.70 (s,1H),7.50(s,1H),7.45(s,1H),8.37(d,J＝8.0Hz,1H),7.15-7.12(m,1H),4.64(t,J＝4.0Hz, 2H),3.99(s,3H),3.87(brs,4H),3.68(brs,2H),3.39(brs,4H).

MS m/z(ESI):480.3(M+H) ⁺ .

Example 42 Synthesis of Compound 66

first step

Under nitrogen protection, compound 38-1 (170 mg, 0.40 mmol), compound 66-1 (62 mg, 0.33 mmol), potassium carbonate (137 mg, 0.99 mmol), 1,1'-bis(diphenylphosphino)bis Ferrocene palladium dichloride (27 mg, 0.033 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) mixed solution was heated to 100°C and stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure. The crude product is separated and purified on a silica gel plate (dichloromethane: methanol = 10:1) to obtain compound 66-2 (55 mg, yield: 37%).

MS m/z(ESI):453.2(M+H) ⁺ .

Step 2

Under ice-water bath conditions, trifluoroacetic acid (1 mL) was slowly added dropwise to a solution of compound 66-2 (55 mg, 0.12 mmol) in dichloromethane (3 mL). After the dropwise addition was completed, the ice-water bath was removed, the reaction solution was raised to room temperature, and the reaction was stirred for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was concentrated under reduced pressure to obtain compound 66-3 (60 mg).

MS m/z(ESI):352.2(M+H) ⁺ .

third step

Under nitrogen protection, N,N-diisopropylethylamine (66 mg, 0.51 mmol) and compound 13-6 (79 mg, 0.34 mmol). After the addition is completed, the reaction solution is stirred at room temperature for 16 hours. TLC monitored the reaction to be complete. Pour the reaction solution into water (10mL), extract with ethyl acetate (15mLx3), combine the organic phases, wash with saturated brine (30mLx1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product is separated by reverse preparation. Purification gave compound 66 (21 mg, yield: 28%).

¹ H NMR (400MHz, DMSO-d6) δ8.81 (s, 1H), 8.71 (s, 1H), 8.44 (d, J = 8.0Hz, 1H), 8.16-8.13 (m, 1H), 7.58-7.45 (m,4H),4.04(s,3H),3.30-3.22(m,2H),3.16-3.13(m,4H),2.82-2.79(m,4H).

MS m/z(ESI):435.2(M+H) ⁺ .

Example 43 Synthesis of Compound 67

According to the synthesis methods of Example 7 and Example 51, compound 67 (22 mg) was obtained from compound 15-1 and compound 67-1 through a three-step reaction.

¹ H NMR (400MHz, CDCl ₃ ) δ8.17-8.07(m,3H),7.68-7.65(m,1H),7.52(d,J＝8.0Hz,1H),7.11(d,J＝8.0Hz, 1H),7.02(s,1H),6.61(d,J＝72.0Hz,1H),4.73(brs,0.5H),4.58(brs,0.5H),4.15(brs,2H),3.77(brs,4H ),3.28(brs,1H),2.88(brs,2H),2.68(brs,4H),1.54-1.48(m,1H),1.04(brs,1H).

MS m/z(ESI):491.3(M+H) ⁺ .

Example 44 Synthesis of Compound 68

According to the synthesis method of Example 68, compound 68 (18 mg) was obtained from compound A5-1 and compound 68-1 through a three-step reaction.

¹ H NMR (400MHz, CDCl ₃ ) δ8.15 (d, J = 8.0 Hz, 1H), 8.05-8.03 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8.0 Hz, 1H), 7.48 (d,J＝8.0Hz,1H),7.20(s,1H),7.07-7.04(m,1H),6.57(t,J＝72.0Hz,1H),4.79(brs,0.5H),4.63(brs ,0.5H),3.95-3.88(m,2H),3.08-3.04(m,2H),2.64(brs,1H),2.44(s,3H),2.31-2.25(m,1H),2.05-1.95( m,1H),1.82-1.70(m,3H),1.22-1.15(m,1H),0.99-0.92(m,1H).

MS m/z(ESI):475.4(M+H) ⁺ .

Example 45 Synthesis of Compound 69

first step

Under nitrogen protection, compound A5-1 (900mg, 4.59mmol), compound 69-1 (1.99g, 9.18mmol), cesium carbonate (4.5g, 13.8mmol), 2-(di-tert-butylphosphorus)- 3-Methoxy-6-methyl-2'4'6'-triisopropyl-biphenyl (431 mg, 0.92 mmol), allylpalladium(II) chloride dimer (86 mg, 0.23 mmol) A solution of toluene (10 mL) was heated to 100°C and the reaction was stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (dichloromethane: methanol = 1:0-10:1) to obtain compound 69-2 (650 mg, yield: 43%).

MS m/z(ESI):334.1(M+H) ⁺ .

Step 2

To the solvent of compound 69-2 (650 mg, 1.95 mmol) in anhydrous DMF (5 mL) was added NBS (383 mg, 2.15 mmol) under nitrogen protection and -40°C. After the addition was completed, the cold bath was removed, and the reaction solution was naturally raised to room temperature and stirred for 2 hours. LCMS monitored the reaction to be complete. Pour the reaction solution into water (20mL), extract with ethyl acetate (20mLx3), combine the organic phases, wash with saturated brine (15mLx1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product is separated and purified on a silica gel column. (Petroleum ether: ethyl acetate = 2:1) Compound 69-3 (550 mg, yield: 69%) was obtained.

MS m/z(ESI):412.1(M+H) ⁺ .

third step

Under nitrogen protection, compound 69-3 (550 mg, 1.34 mmol), compound 14-1 (746 mg, 2.01 mmol), potassium carbonate (555 mg, 4.02 mmol), 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (110 mg, 0.14 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was heated to 100°C and stirred for 2 hours. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (dichloromethane: methanol = 10:1) to obtain compound 69-4 (600 mg, yield: 78%).

MS m/z(ESI):577.2(M+H) ⁺ .

the fourth step

Under ice-water bath conditions, trifluoroacetic acid (1 mL) was slowly added dropwise to a solution of compound 69-4 (100 mg, 0.17 mmol) in dichloromethane (3 mL). After the dropwise addition was completed, the ice-water bath was removed, the reaction solution was raised to room temperature, and the reaction was stirred for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was concentrated under reduced pressure to obtain compound 69-5 (110 mg).

MS m/z(ESI):477.2(M+H) ⁺ .

the fifth step

Under nitrogen protection, to a solution of compound 69-5 (110 mg, 0.23 mmol) in acetonitrile (2 mL) was added cesium carbonate (226 mg, 0.69 mmol) and compound 58-4 (42 mg, 0.35 mmol) in sequence. After the addition is completed, the reaction solution is placed at room temperature and stirred for 2 hours. TLC monitored the reaction to be complete. Pour the reaction solution into water (30mL), extract with ethyl acetate (30mLx3), combine the organic phases, wash with saturated brine (30mLx1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product is separated by reverse preparation. Purification gave compound 69 (25 mg, yield: 21%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.21 (d, J＝8.0Hz, 1H), 8.14-8.10 (m, 2H), 7.69 (d, J＝8.0Hz, 1H), 7.54 (dd, J＝ 8.0,2.0Hz,1H),7.32-7.31(m,2H),7.13(dd,J＝8.0,2.0Hz,1H),6.63(t,J＝72.0Hz,1H),4.86-4.84(m,0.5 H),4.70-4.68(m,0.5H),4.11-3.97(m,4H),3.80-3.74(m,1H),3.58(s,2H),3.12-3.08(m,1H),2.88-2.84 (m,1H),2.70-2.57(m,2H),2.49-2.46(m,1H),1.29(brs,1H),1.08-0.97(m,1H).

MS m/z(ESI):516.2(M+H) ⁺ .

Example 46 Synthesis of Compound 70

Under nitrogen protection, DIEA (81 mg, 0.63 mmol) and compound 13-6 (97 mg, 0.42 mmol) were added sequentially to acetonitrile (2 mL) of compound 69-5 (100 mg, 0.21 mmol). After the addition is completed, the reaction solution is placed at room temperature and stirred for 2 hours. TLC monitored the reaction to be complete. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (30 mLx3), the organic phases were combined, washed with saturated brine (10 mLx1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified through reverse preparation to obtain compound 70 (50 mg, yield: 42%).

¹ H NMR (400MHz, CD ₃ OD) δ8.27 (d, J＝2.0Hz, 1H), 8.20 (s, 1H), 7.86-7.79 (m, 2H), 7.60 (dd, J＝8.0, 2.0Hz ,1H),7.45(s,1H),7.22(dd,J＝8.0,2.0Hz,1H),6.81(t,J＝72.0Hz,1H),4.85-4.80(m,0.5H),4.70-4.67 (m,0.5H),4.08-4.05(m,2H),3.99-3.90(m,2H),3.76-3.70(m,1H),3.16-2.83(m,5H),2.60-2.45(m,2H ),1.23-1.17(m,1H),1.10-1.01(m,1H).

MS m/z(ESI):559.2(M+H) ⁺ .

Example 47 Synthesis of Compound 71

Under nitrogen protection and ice-water bath conditions, 3-oxetanone (30 mg, 0.42 mmol) was added to a solution of compound 69-5 (100 mg, 0.21 mmol) in dichloromethane (5 mL). The reaction solution was kept in an ice bath and stirred for 20 minutes. Sodium cyanoborohydride (40 mg, 0.63 mmol) was added slowly. After the addition was completed, the ice-water bath was removed, the reaction solution was slowly raised to room temperature, and the reaction was stirred for 2 hours. LCMS monitored the reaction to be complete. Pour the reaction solution into water (20mL), extract with ethyl acetate (30mLx3), combine the organic phases, wash with saturated brine (30mLx1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product is separated by reverse preparation. Purification gave compound 71 (30 mg, yield: 27%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.21 (d, J = 8.0 Hz, 1H), 8.13 (s, 1H), 8.09 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.54 (d,J＝8.0Hz,1H),7.32(s,2H),7.15-7.13(m,1H),6.63(t,J＝72.0Hz,1H),4.85(brs,0.5H),4.71-4.68 (m,4.5H),4.10-4.00(m,4H),3.84(t,J＝12.0Hz,1H),3.63-3.61(m,1H),3.09(brs,1H),2.87-2.84(m, 1H),2.71-2.68(m,1H),2.24-2.09(m,2H),1.06-0.99(m,2H).

MS m/z(ESI):533.2(M+H) ⁺ .

Example 48 Synthesis of Compound 72

first step

Under nitrogen protection, compound A5-1 (250mg, 1.27mmol), compound 72-1 (552mg, 2.54mmol), cesium carbonate (1.24g, 3.81mmol), 2-(di-tert-butylphosphorus)-3 -Methoxy-6-methyl-2'4'6'-triisopropyl-biphenyl (119 mg, 0.25 mmol), allylpalladium(II) chloride dimer (23 mg, 0.064 mmol) The toluene (10 mL) solution was heated to 100°C and the reaction was stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure. The crude product is separated and purified through silica gel column (dichloromethane: methanol = 1:0-10:1) to obtain compound 72-2 (200 mg, yield: 47%).

MS m/z(ESI):334.1(M+H) ⁺ .

Step 2

Under nitrogen protection and -40°C, NBS was added to a solution of compound 72-2 (200 mg, 0.60 mmol) in anhydrous DMF (5 mL). (118mg,0.66mmol). After the addition was completed, the cold bath was removed, and the reaction solution was naturally raised to room temperature and stirred for 2 hours. LCMS monitored the reaction to be complete. Pour the reaction solution into water (20mL), extract with ethyl acetate (10mLx3), combine the organic phases, wash with saturated brine (15mLx1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product is separated and purified on a silica gel column. (Petroleum ether: ethyl acetate = 2:1) Compound 72-3 (240 mg, yield: 97%) was obtained.

MS m/z(ESI):412.1(M+H) ⁺ .

third step

Under nitrogen protection, compound 72-3 (240 mg, 0.58 mmol), compound 14-1 (325 mg, 0.88 mmol), potassium carbonate (242 mg, 1.75 mmol), 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (48 mg, 0.058 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was heated to 100°C and stirred for 2 hours. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (dichloromethane: methanol = 10:1) to obtain the target compound 72-4 (240 mg, yield: 71%).

MS m/z(ESI):577.2(M+H) ⁺ .

the fourth step

Under ice-water bath conditions, trifluoroacetic acid (1 mL) was slowly added dropwise to a solution of compound 72-4 (240 mg, 0.42 mmol) in dichloromethane (3 mL). After the dropwise addition was completed, the ice-water bath was removed, the reaction solution was raised to room temperature, and the reaction was stirred for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was concentrated under reduced pressure to obtain compound 72-5 (190 mg).

MS m/z(ESI):477.2(M+H) ⁺ .

the fifth step

Under nitrogen protection and ice-water bath conditions, 30% formaldehyde aqueous solution (42 mg, 0.42 mmol) was added to a solution of compound 72-5 (100 mg, 0.21 mmol) in methanol (5 mL). The reaction solution was kept under ice-water bath conditions and stirred for 20 minutes. Sodium cyanoborohydride (27 mg, 0.42 mmol) was slowly added to the reaction solution. After the addition was completed, the ice-water bath was removed, the reaction solution was slowly raised to room temperature, and the reaction was stirred for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was poured into water (20 mL), extracted with ethyl acetate (30 mLx3), the organic phases were combined, washed with saturated brine (30 mLx1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified through reverse preparation to obtain compound 72 (23 mg, yield: 22%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.20 (d, J = 8.0 Hz, 1H), 8.10 (s, 1H), 8.09 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.53 (dd,J＝8.0,2.0Hz,1H),7.13-7.10(m,2H),6.63(t,J＝72.0Hz,1H),4.86-4.84(m,0.5H),4.70-4.68(m, 0.5H),4.07-3.94(m,4H),3.86-3.82(m,1H),3.74-3.68(m,1H),3.62-3.57(m,1H),3.11-3.07(m,1H),2.79 -2.74(m,1H),2.63-2.60(m,1H),2.47-2.41(m,4H),1.30-1.26(m,1H),1.07-0.98(m,1H).

MS m/z(ESI):491.2(M+H) ⁺ .

Example 49 Synthesis of Compound 73

Under nitrogen protection, to a solution of compound 72-5 (95 mg, 0.20 mmol) in acetonitrile (2 mL) was added cesium carbonate (196 mg, 0.60 mmol) and compound 58-4 (48 mg, 0.40 mmol) in sequence. After the addition is completed, the reaction solution is placed at room temperature and stirred for 2 hours. TLC monitored the reaction to be complete. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (30 mLx3), the organic phases were combined, washed with saturated brine (10 mLx1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by reverse preparation to obtain compound 73 (19 mg, yield: 18%).

¹ H NMR (400MHz, DMSO-d6) δ8.55(d,J＝2.0Hz,1H),8.39-8.36(m,2H),7.94(d,J＝8.0Hz,1H),7.65-7.59(m ,2H),7.46-7.09(m,3H),4.86-4.85(m,0.5H),4.70-4.68(m,0.5H),4.19-3.78(m,6H),3.56-3.50(m,2H) ,2.88-2.83(m,1H),2.80-2.74(m,2H),2.56-2.52(m,1H),1.16-0.96(m,2H).

MS m/z(ESI):516.2(M+H) ⁺ .

Example 50 Synthesis of Compound 74

first step

Under nitrogen protection, compound 74-1 (64 mg, 0.90 mmol), HATU (429 mg, 1.13 mmol) and N, N- were added sequentially to a solution of compound 15-1 (200 mg, 0.75 mmol) in dichloromethane (5 mL). Diisopropylethylamine (292 mg, 2.26 mmol). After the addition was completed, the reaction solution was allowed to stir at room temperature overnight. LCMS monitored the reaction to be complete. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mLx3), the organic phases were combined, washed with saturated brine (20 mLx1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified through silica gel column (petroleum ether: ethyl acetate = 1:0-2:1) to obtain compound 74-2 (150 mg, yield: 63%).

MS m/z(ESI):320.1(M+H) ⁺ .

Step 2

Under nitrogen protection, compound 74-2 (150 mg, 0.47 mmol), compound 11-1 (155 mg, 0.61 mmol), potassium acetate (136 mg, 1.41 mmol), 1,1'-bis(diphenylphosphino)bis A solution of palladium ferrocene dichloride (39 mg, 0.047 mmol) in anhydrous 1,4-dioxane (10 mL) was heated to 100°C and stirred for 2 hours. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure. The crude product is separated and purified by silica gel column (petroleum ether: ethyl acetate = 1:0-2:1) to obtain compound 74-3 (170 mg, yield: 98%).

MS m/z(ESI):368.2(M+H) ⁺ .

the fourth step

Under nitrogen protection, compound 74-3 (170 mg, 0.46 mmol), compound 19-1 (101 mg, 0.31 mmol), potassium carbonate (128 mg, 0.93 mmol), 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (25 mg, 0.031 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was heated to 100°C and stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column (dichloromethane: methanol = 10:1) and reverse preparation to obtain compound 74 (20 mg, yield: 13%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.11(4-8.07(m,3H),7.67(d,J＝8.0Hz,1H),7.51(d,J＝8.0Hz,1H),7.29-7.09( m,3H),6.64(t,J＝72.0Hz,1H),4.59(brs,1H),4.12(brs,2H),3.75(brs,4H),2.85(brs,2H),2.60(brs,4H ),2.45(brs,2H),2.00-1.79(m,4H).

MS m/z(ESI):487.2(M+H) ⁺ .

Example 51 Synthesis of Compound 75

first step

Under nitrogen protection, compound 75-1 (116 mg, 1.36 mmol), HATU (646 mg, 1.70 mmol) and N, N- were added sequentially to a solution of compound 15-1 (300 mg, 1.13 mmol) in dichloromethane (5 mL). Diisopropylethylamine (437 mg, 3.39 mmol). After the addition was completed, the reaction solution was allowed to stir at room temperature overnight. LCMS monitored the reaction to be complete. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mLx3), the organic phases were combined, washed with saturated brine (20 mLx1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified through silica gel column (petroleum ether: ethyl acetate = 1:0-2:1) to obtain compound 75-2 (312 mg, yield: 83%).

MS m/z(ESI):334.1(M+H) ⁺ .

Step 2

Under nitrogen protection, compound 75-2 (312 mg, 0.94 mmol), compound 11-1 (358 mg, 1.41 mmol), potassium acetate (270 mg, 2.81 mmol), 1,1'-bis(diphenylphosphino)bis A solution of palladium ferrocene dichloride (77 mg, 0.0937 mmol) in anhydrous 1,4-dioxane (10 mL) was heated to 100°C and stirred for 2 hours. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (petroleum ether: ethyl acetate = 1:0-2:1) to obtain compound 75-3 (350 mg, yield: 98%).

MS m/z(ESI):382.2(M+H) ⁺ .

third step

Under nitrogen protection, compound 75-3 (170 mg, 0.45 mmol), compound 19-1 (97 mg, 0.30 mmol), potassium carbonate (125 mg, 0.90 mmol), 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (25 mg, 0.030 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was heated to 100°C and stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column (dichloromethane: methanol = 10:1) and reverse preparation to obtain compound 75 (20 mg, yield: 13%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.21-8.04(m,3H),7.68(d,J＝8.0Hz,1H),7.52(d,J＝8.0Hz,1H),7.28(s,1H) ,7.11(d,J＝8.0Hz,1H),7.02(d,J＝8.0Hz,1H),6.62(t,J＝72.0Hz,1H),4.48-4.41(m,1H),4.15-4.12( m,2H),3.77-3.74(m,4H),2.87-2.84(m,2H),2.64-2.56(m,4H),2.10-2.03(m,2H),1.78-1.65(m,4H), 1.58-1.52(m,2H).

MS m/z(ESI):501.2(M+H) ⁺ .

Example 52 Synthesis of Compound 76

first step

Under nitrogen protection, compound 76-1 (81 mg, 1.36 mmol), HATU (646 mg, 1.70 mmol) and N, N- were added sequentially to a solution of compound 15-1 (300 mg, 1.13 mmol) in dichloromethane (5 mL). Diisopropylethylamine (437 mg, 3.39 mmol). After the addition was completed, the reaction solution was allowed to stir at room temperature overnight. LCMS monitored the reaction to be complete. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mLx3), the organic phases were combined, washed with saturated brine (20 mLx1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified through silica gel column (petroleum ether: ethyl acetate = 1:0-2:1) to obtain compound 76-2 (262 mg, yield: 76%).

MS m/z(ESI):308.1(M+H) ⁺ .

Step 2

Under nitrogen protection, compound 76-2 (262 mg, 0.85 mmol), compound 11-1 (325 mg, 1.28 mmol), potassium acetate (245 mg, 2.55 mmol), 1,1'-bis(diphenylphosphino)bis A solution of palladium ferrocene dichloride (70 mg, 0.085 mmol) in anhydrous 1,4-dioxane (10 mL) was heated to 100°C and stirred for 2 hours. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (petroleum ether: ethyl acetate = 1:0-2:1) to obtain compound 76-3 (300 mg, yield: 99%).

MS m/z(ESI):356.2(M+H) ⁺ .

third step

Under nitrogen protection, compound 76-3 (170 mg, 0.48 mmol), compound 19-1 (104 mg, 0.32 mmol), potassium carbonate (133 mg, 0.96 mmol), 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (26 mg, 0.032 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was heated to 100°C and stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column (dichloromethane: methanol = 10:1) and reverse preparation to obtain compound 76 (20 mg, yield: 13%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.18-8.08(m,3H),7.68(d,J＝8.0Hz,1H),7.53(d,J＝8.0Hz,1H),7.29(s,1H) ,7.11(dd,J＝8.0,4.0Hz,1H),6.87(d,J＝4.0Hz,1H),6.61(t,J＝72.0Hz,1H),4.35-4.26(m,1H),4.15- 4.12(m,2H),3.77-3.74(m,4H),2.87-2.84(m,2H),2.60(t,J＝4.4Hz,4H),1.28(d,J＝7.6Hz,6H).

MS m/z(ESI):475.2(M+H) ⁺ .

Example 53 Synthesis of Compound 77

first step

Under nitrogen protection, compound 77-1 (200 mg, 0.60 mmol), compound 11-1 (227 mg, 0.90 mmol), potassium acetate (172 mg, 1.79 mmol), 1,1'-bis(diphenylphosphino)bis A solution of palladium ferrocene dichloride (49 mg, 0.060 mmol) in anhydrous 1,4-dioxane (10 mL) was heated to 100°C and stirred for 2 hours. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (petroleum ether: ethyl acetate = 1:0-2:1) to obtain compound 77-2 (120 mg, yield: 53%).

MS m/z(ESI):384.2(M+H) ⁺ .

Step 2

Under nitrogen protection, compound 77-2 (120 mg, 0.31 mmol), compound 19-1 (68 mg, 0.21 mmol), potassium carbonate (86 mg, 0.63 mmol), 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (17 mg, 0.021 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was heated to 100°C and stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column (dichloromethane: methanol = 10:1) and reverse preparative separation and purification to obtain compound 77 (20 mg, yield: 19%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.18-8.07 (m, 3H), 7.68 (d, J = 8.0Hz, 1H), 7.54 (dd, J = 8.0, 2.0Hz, 1H), 7.35 (s, 1H),7.29(s,1H),7.13(dd,J＝8.0,2.0Hz,1H),6.65(t,J＝72.0Hz,1H),4.15-4.07(m,4H),3.77-3.74(m ,4H),2.87-2.85(m,2H),2.60(brs,4H),2.26-2.16(m,2H),1.80-1.70(m,1H),1.54-1.46(m,1H).

MS m/z(ESI):503.2(M+H) ⁺ .

Example 54 Synthesis of Compound 78

first step

Under nitrogen protection, compound A5-1 (500mg, 2.54mmol), compound 78-1 (655mg, 5.07mmol), cesium carbonate (1.24g, 3.81mmol), 2-(di-tert-butylphosphorus)-3 -Methoxy-6-methyl-2'4'6'-triisopropyl-biphenyl (238 mg, 0.51 mmol), allylpalladium(II) chloride dimer (46 mg, 0.13 mmol) The toluene (10 mL) solution was heated to 100°C and the reaction was stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (dichloromethane: methanol = 1:0-10:1) to obtain compound 78-2. (200 mg, yield: 32%).

MS m/z(ESI):246.1(M+H) ⁺ .

Step 2

To a solution of compound 78-2 (200 mg, 0.82 mmol) in anhydrous DMF (5 mL) was added NBS (160 mg, 0.90 mmol) under nitrogen protection and -65°C. After the addition was completed, the cold bath was removed, the reaction solution was naturally raised to room temperature, and the reaction was stirred for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mLx3), the organic phases were combined, washed with saturated brine (15 mLx1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified through silica gel column (petroleum ether: ethyl acetate = 2:1) to obtain compound 78-3 (70 mg, yield: 27%).

MS m/z(ESI):324.1(M+H) ⁺ .

third step

Under nitrogen protection, compound 78-3 (70 mg, 0.22 mmol), compound 14-1 (121 mg, 0.33 mmol), potassium carbonate (91 mg, 0.65 mmol), 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (18 mg, 0.022 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was heated to 100°C and stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column (dichloromethane: methanol = 10:1) and reverse preparation to obtain compound 78 (20 mg, yield: 19%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.21(d,J＝8.0Hz,1H),8.11(d,J＝2.0Hz,1H),8.09(s,1H),7.68(d,J＝8.0Hz ,1H),7.54(dd,J＝8.0,1.6Hz,1H),7.32-7.31(m,2H),7.16(dd,J＝8.0,2.0Hz,1H),6.63(t,J＝72.0Hz, 1H),4.87-4.83(m,0.5H),4.71-4.67(m,0.5H),4.07-3.99(m,2H),3.13-3.07(m,1H),2.95-2.91(m,1H), 2.39(s,3H),2.33-2.30(m,1H),2.19-2.17(m,1H),1.84-1.78(m,2H),1.68-1.60(m,4H),1.30-1.20(m,1H ),1.07-0.97(m,1H).

MS m/z(ESI):489.2(M+H) ⁺ .

Example 55 Synthesis of Compound 79

first step

Under nitrogen protection, compound A5-1 (200mg, 1.02mmol), compound 79-1 (263mg, 2.04mmol), cesium carbonate (998mg, 3.06mmol), 2-(di-tert-butylphosphorus)-3- Methoxy-6-methyl-2'4'6'-triisopropyl-biphenyl (96 mg, 0.20 mmol), allylpalladium(II) chloride dimer (19 mg, 0.051 mmol) in toluene (5 mL) solution was heated to 100°C and the reaction was stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (dichloromethane: methanol = 1:0-10:1) to obtain compound 79-2 (100 mg, yield: 40%).

MS m/z(ESI):246.1(M+H) ⁺ .

Step 2

NBS (80 mg, 0.45 mmol) was added to the anhydrous DMF (5 mL) solution of compound 79-2 (100 mg, 0.41 mmol) under nitrogen protection and -40°C. After the addition is complete, remove the cold bath, allow the reaction solution to naturally rise to room temperature, and stir the reaction overnight. LCMS monitored the reaction to be complete. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mLx3), the organic phases were combined, washed with saturated brine (15 mLx1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified through silica gel column (petroleum ether: ethyl acetate = 2:1) to obtain compound 79-3 (70 mg, yield: 53%).

MS m/z(ESI):324.1(M+H) ⁺ .

third step

Under nitrogen protection, compound 79-3 (70 mg, 0.22 mmol), compound 14-1 (121 mg, 0.33 mmol), potassium carbonate (90 mg, 0.65 mmol), 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (18 mg, 0.022 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was heated to 100°C and stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column (dichloromethane: methanol = 10:1) and reverse preparative separation and purification to obtain compound 79 (20 mg, yield: 19%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.21(d,J＝8.0Hz,1H),8.13(s,1H),8.09(s,1H),7.68(dd,J＝8.0,2.0Hz,1H) ,7.54(d,J＝8.0Hz,1H),7.32(brs,2H),7.13(dd,J＝8.0,2.0Hz,1H),6.63(t,J＝72.0Hz,1H),4.85(brs, 0.5H),4.69(brs,0.5H),4.14(t,J＝5.6Hz,2H),3.10(t,J＝8.0Hz,1H),2.84(t,J＝5.6Hz,2H),2.55( brs,4H),1.65(brs,3H),1.48(brs,3H),1.28(brs,1H),1.06-0.97(s,1H).

MS m/z(ESI):489.2(M+H) ⁺ .

Example 56 Synthesis of Compound 80

first step

Under nitrogen protection, compound A5-1 (200mg, 1.02mmol), compound 80-1 (263mg, 2.04mmol), cesium carbonate (998mg, 3.06mmol), 2-(di-tert-butylphosphorus)-3- Methoxy-6-methyl-2'4'6'-triisopropyl-biphenyl (96 mg, 0.20 mmol), allylpalladium(II) chloride dimer (19 mg, 0.051 mmol) in toluene (5 mL) solution was heated to 100°C and the reaction was stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (dichloromethane: methanol = 1:0-10:1) to obtain compound 80-2 (100 mg, yield: 40%).

MS m/z(ESI):246.1(M+H) ⁺ .

Step 2

To a solution of compound 80-2 (100 mg, 0.41 mmol) in anhydrous DMF (5 mL) was added NBS (80 mg, 0.45 mmol) under nitrogen protection and -40°C. After the addition was completed, the cold bath was removed, the reaction solution was naturally raised to room temperature, and the reaction was stirred overnight. LCMS monitored the reaction to be complete. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mLx3), the organic phases were combined, washed with saturated brine (15 mLx1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified through silica gel column (petroleum ether: ethyl acetate = 2:1) to obtain compound 80-3 (50 mg, yield: 38%).

MS m/z(ESI):324.1(M+H) ⁺ .

third step

Under nitrogen protection, compound 80-3 (50 mg, 0.16 mmol), compound 14-1 (87 mg, 0.23 mmol), potassium carbonate (65 mg, 0.47 mmol), 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (13 mg, 0.016 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was heated to 100°C and stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column (dichloromethane: methanol = 10:1) and reverse preparative separation and purification to obtain compound 80 (6 mg, yield: 8%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.21(d,J＝8.0Hz,1H),8.11(s,1H),8.09(s,1H),7.68(d,J＝8.0Hz,1H),7.54 (dd,J＝8.0,2.0Hz,1H),7.32(brs,2H),7.09(d,J＝8.4Hz,1H),6.63(t,J＝72.0Hz,1H),4.85(brs,0.5H ),4.69(brs,0.5H),4.10-3.99(m,2H),3.14-3.10(m,2H),2.38(s,3H),2.33-2.18(m,4H),2.02(brs,1H) ,1.81(brs,1H),1.61(brs,1H),1.29(brs,1H),1.06-0.99(m,1H),0.87(brs,1H).

MS m/z(ESI):489.2(M+H) ⁺ .

Example 57 Synthesis of Compound 81

first step

Under nitrogen protection, compound A5-1 (1.00g, 5.08mmol), compound 81-1 (1.16g, 10.20mmol), cesium carbonate (4.97g, 15.20mmol), 2-(di-tert-butylphosphorus) -3-Methoxy-6-methyl-2'4'6'-triisopropyl-biphenyl (478mg, 1.02mmol), allylpalladium(II) chloride dimer (186mg, 0.51mmol) ) in toluene (15 mL) was heated to 90°C and the reaction was stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (dichloromethane: methanol = 1:0-10:1) to obtain compound 81-2 (370 mg, yield: 32%).

MS m/z(ESI):232.1(M+H) ⁺ .

Step 2

To a solution of compound 81-2 (370 mg, 1.60 mmol) in anhydrous DMF (5 mL) was added NBS (313 mg, 1.76 mmol) under nitrogen protection and -40°C. After the addition is completed, remove the cold bath, allow the reaction solution to naturally rise to room temperature, and continue to stir the reaction for 1 hour. LCMS monitored the reaction to be complete. Pour the reaction solution into water (10mL), extract with ethyl acetate (10mLx3), combine the organic phases, wash with saturated brine (15mLx1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product is separated and purified on a silica gel column. (Petroleum ether: ethyl acetate = 2:1) Compound 81-3 (310 mg, yield: 63%) was obtained.

MS m/z(ESI):310.1(M+H) ⁺ .

third step

Under nitrogen protection, compound 81-3 (310 mg, 1.00 mmol), compound 14-1 (557 mg, 1.50 mmol), potassium carbonate (414 mg, 3.00 mmol), 1,1'-bis(diphenylphosphino)bis A mixed reaction solution of palladium ferrocene dichloride (73 mg, 0.10 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was heated to 90°C and stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column (dichloromethane: methanol = 10:1) and reverse preparative separation and purification to obtain compound 81 (150 mg, yield: 32%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.21 (d, J＝8.0Hz, 1H), 8.12-8.08 (m, 2H), 7.67 (d, J＝8.0Hz, 1H), 7.53 (dd, J＝ 8.0,2.0Hz,1H),7.32(brs,2H),7.12(dd,J＝8.0,2.0Hz,1H),6.63(t,J＝72.0Hz,1H),4.86-4.83(m,0.5H) ,4.70-4.67(m,0.5H),4.03-3.92(m,2H),3.20-3.05(m,2H),2.76-2.72(m,1H),2.51(s,3H),2.38-2.32(m ,1H),2.11-1.76(m,4H),1.30-1.20(m,1H),1.07-0.97(m,1H).

MS m/z(ESI):475.2(M+H) ⁺ .

Example 58 Synthesis of Compound 82

first step

Under nitrogen protection, compound A5-1 (1.50g, 7.61mmol), compound 82-1 (1.75g, 15.20mmol), cesium carbonate (7.44g, 22.80mmol), 2-(di-tert-butylphosphorus) -3-Methoxy-6-methyl-2'4'6'-triisopropyl-biphenyl (713mg, 1.52mmol), allylpalladium(II) chloride dimer (139mg, 0.38mmol) ) in toluene (15 mL) was heated to 90°C and the reaction was stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure. The crude product is separated and purified through silica gel column (dichloromethane: methanol = 1:0-10:1) to obtain compound 82-2 (640 mg, yield: 36%).

MS m/z(ESI):232.1(M+H) ⁺ .

Step 2

To a solution of compound 82-2 (640 mg, 2.77 mmol) in anhydrous DMF (7 mL) was added NBS (543 mg, 3.05 mmol) under nitrogen protection and -40°C. After the addition is complete, remove the cold bath, allow the reaction solution to naturally rise to room temperature, and continue stirring for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mLx3), the organic phases were combined, washed with saturated brine (15 mLx1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified through silica gel column (petroleum ether: ethyl acetate = 2:1) to obtain compound 82-3 (430 mg, yield: 50%).

MS m/z(ESI):310.1(M+H) ⁺ .

third step

Under nitrogen protection, compound 82-3 (430 mg, 1.39 mmol), compound 14-1 (775 mg, 2.09 mmol), potassium carbonate (575 mg, 4.17 mmol) and 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (102 mg, 0.14 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was heated to 90°C and stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column (dichloromethane: methanol = 10:1) and reverse preparative separation and purification to obtain compound 82 (180 mg, yield: 27%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.19 (d, J＝8.0Hz, 1H), 8.12-8.08 (m, 2H), 7.67 (d, J＝8.0Hz, 1H), 7.53 (dd, J＝ 8.0,2.0Hz,1H),7.31(brs,2H),7.12(dd,J＝8.0,2.0Hz,1H),6.63(t,J＝72.0Hz,1H),4.85-4.83(m,0.5H) ,4.69-4.67(m,0.5H),4.05-3.93(m,2H),3.20-3.05(m,2H),2.78-2.74(m,1H),2.52(s,3H),2.40-2.33(m ,1H),2.10-1.76(m,4H),1.29-1.20(m,1H),1.05-0.97(m,1H).

MS m/z(ESI):475.2(M+H) ⁺ .

Example 59 Synthesis of Compound 83

first step

Under nitrogen protection and -78°C, DAST (6.78g, 0.042mol) was slowly added dropwise to the solvent of compound 83-1 (5.00g, 0.021mol) in anhydrous dichloromethane (50mL). After the dropwise addition was completed, the reaction solution was slowly raised to -20°C and stirred for 5 hours. LCMS monitored the reaction to be complete. The reaction solution was poured into ice water (100 mL), extracted with dichloromethane (100 mLx3), the organic phases were combined, washed with saturated brine (150 mLx1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 83-2 ( 5.10g).

MS m/z(ESI):266.1(M+H) ⁺ .

Step 2

Under nitrogen protection and ice-water bath conditions, LAH (2.20g, 0.057mol) was slowly added to the solvent of compound 83-2 (5.10g, 0.019mol) in anhydrous tetrahydrofuran (50mL). After the addition is completed, the temperature of the reaction solution is raised to 70°C and the stirring reaction is continued for 5 hours. LCMS monitored the reaction to be complete. The reaction solution was cooled to 0°C, sodium sulfate decahydrate was slowly added to quench the reaction, and ethyl acetate (100 mL) was added and stirred overnight. After filtration, the filtrate was concentrated under reduced pressure to obtain compound 83-3 (2.70 g).

MS m/z(ESI):152.1(M+H) ⁺ .

third step

Under nitrogen protection and ice-water bath conditions, SOCl ₂ (3 mL) was slowly added dropwise to a solution of compound 83-3 (300 mg, 1.99 mmol) in anhydrous dichloromethane (10 mL). After the addition is completed, remove the ice-water bath, raise the reaction solution to 70°C and stir for 5 hours. LCMS monitored the reaction to be complete. After cooling, the reaction solution was concentrated under reduced pressure to obtain compound 83-4 (334 mg).

MS m/z(ESI):170.1(M+H) ⁺ .

the fourth step

Under nitrogen protection, a solution of compound 83-4 (334 mg, 1.98 mmol), compound 60-3 (200 mg, 1.49 mmol), and potassium carbonate (617 mg, 4.47 mmol) in acetonitrile (5 mL) was heated to 75°C and stirred overnight. . LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (dichloromethane: methanol = 1:0-10:1) to obtain compound 83-5 (200 mg, yield: 50%).

MS m/z(ESI):268.2(M+H) ⁺ .

the fifth step

To a solution of compound 83-5 (200 mg, 0.75 mmol) in anhydrous DMF (5 mL) was added NBS (134 mg, 0.75 mmol) under nitrogen protection and -40°C. After the addition is complete, remove the cold bath, allow the reaction solution to naturally rise to room temperature, and stir the reaction overnight. LCMS monitored the reaction to be complete. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mLx3), the organic phases were combined, washed with saturated brine (15 mLx1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified through silica gel column (petroleum ether: ethyl acetate = 1:1) to obtain compound 83-6 (120 mg, yield: 46%).

MS m/z(ESI):346.1(M+H) ⁺ .

Step 6

Under nitrogen protection, compound 83-6 (120 mg, 0.35 mmol), compound 14-1 (171 mg, 0.35 mmol), potassium carbonate (145 mg, 1.05 mmol), 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (29 mg, 0.035 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was heated to 80°C and stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column (dichloromethane: methanol = 10:1) and reverse preparation to obtain compound 83 (37 mg, yield: 21%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.21 (d, J = 2.0Hz, 1H), 8.17 (d, J = 8.0Hz, 1H), 8.10 (s, 1H), 7.69 (d, J = 8.0Hz ,1H),7.51(dd,J＝8.0,2.0Hz,1H),7.30(brs,2H),7.10(dd,J＝8.0,2.0Hz,1H),6.64(t,J＝72.0Hz,1H) ,4.85-4.83(m,0.5H),4.69-4.66(m,0.5H),4.52-4.48(m,1H),3.11-3.01(m,2H),2.92-2.84(m,1H),2.57- 2.34(m,6H),2.07-1.98(m,1H),1.29-1.19(m,1H),1.06-0.97(m,1H).

MS m/z(ESI):511.2(M+H) ⁺ .

Example 60 Synthesis of Compound 84

first step

Under nitrogen protection and ice-water bath conditions, lithium bistrimethylsilylamide (43.66 mL, 43.66 mmol, 1 M) was added dropwise to a solution of compound 84-1 (5.00 g, 21.83 mmol) in tetrahydrofuran (50 mL). After the dropwise addition was completed, stirring was continued for 0.5 hours under this condition. Methyl iodide (4.65g, 32.75mmol) was added dropwise to the aforementioned reaction solution. The ice-water bath was removed, the reaction solution was naturally raised to room temperature, and the reaction was stirred for 12 hours. The reaction solution was poured into ice water (50 mL), extracted with ethyl acetate (50 mLx3), the organic phases were combined, washed with saturated brine (30 mLx1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 84-2 ( 5.00g, yield: 94%).

MS m/z(ESI):244.2(M+H) ⁺ .

Step 2

Under nitrogen protection and ice-water bath conditions, compound 84-2 (5.00g, 20.58mmol) was slowly added to a solution of lithium aluminum hydride (2.34g, 61.74mmol) in tetrahydrofuran (80mL). After the addition was completed, the ice-water bath was removed, and the reaction solution was heated to 75°C and stirred for 2 hours. LCMS monitored the reaction to be complete. Cool, lower the reaction solution to 0°C, quench with sodium sulfate decahydrate, slowly add ethyl acetate (10 mL) and stir for 1 hour, add sodium hydroxide, filter, and concentrate the filtrate under reduced pressure to obtain compound 84-3 (2.60 g , Yield: 98%).

MS m/z(ESI):130.1(M+H) ⁺ .

third step

Under nitrogen protection and ice-water bath conditions, thionyl chloride (5 mL) was added dropwise to a solution of compound 84-3 (1.00 g, 7.75 mmol) in 1,2-dichloroethane (10 mL). After the dropwise addition is completed, remove the ice-water bath, heat the reaction solution to 80°C and stir for 2 hours. LCMS monitored the reaction to be complete. After cooling, the reaction solution was concentrated under reduced pressure to obtain compound 84-4 (1.10 g, yield: 97%).

the fourth step

Under nitrogen protection, a solution of compound 60-3 (334 mg, 2.50 mmol), compound 84-4 (550 mg, 3.74 mmol), and potassium carbonate (1.04 g, 7.50 mmol) in acetonitrile (5 mL) was heated to 75°C and the reaction was stirred. overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (dichloromethane: methanol = 1:0-10:1) to obtain compound 84-5 (170 mg, yield: 28%).

MS m/z(ESI):246.2(M+H) ⁺ .

the fifth step

To a solution of compound 84-5 (170 mg, 0.69 mmol) in anhydrous DMF (5 mL) was added NBS (135 mg, 0.76 mmol) under nitrogen protection and -40°C. After the addition is completed, remove the cold bath, allow the reaction solution to naturally rise to room temperature, and continue to stir the reaction for 1 hour. LCMS monitored the reaction to be complete. Pour the reaction solution into water (10mL), extract with ethyl acetate (10mLx3), combine the organic phases, wash with saturated brine (15mLx1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product is separated and purified on a silica gel column. (Petroleum ether: ethyl acetate = 2:1) Compound 84-6 (140 mg, yield: 63%) was obtained.

MS m/z(ESI):324.1(M+H) ⁺ .

Step 6

Under nitrogen protection, compound 84-6 (140 mg, 0.43 mmol), compound 14-1 (241 mg, 0.65 mmol), potassium carbonate (178 mg, 1.29 mmol), 1,1'-bis(diphenylphosphino)bis A mixed solution of ferrocene palladium dichloride (31 mg, 0.043 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was heated to 80°C and stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column (dichloromethane: methanol = 10:1) and reverse preparative separation and purification to obtain compound 84 (51 mg, yield: 24%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.19 (d, J = 8.0Hz, 1H), 8.11 (d, J = 2.0Hz, 1H), 8.07 (s, 1H), 7.66 (d, J = 8.4Hz ,1H),7.53(dd,J＝8.0,2.0Hz,1H),7.31(brs,2H),7.12(dd,J＝8.4,2.0Hz,1H),6.63(t,J＝72.0Hz,1H) ,4.85-4.84(m,0.5H),4.69-4.67(m,0.5H),3.83-3.77(m,2H),3.11-2.97(m,2H),2.74-2.67(m,1H),2.40( s,3H),2.07-1.79(m,3H),1.73-1.68(m,1H),1.27-1.20(m,1H),1.15(s,3H),1.06-0.97(m,1H).

MS m/z(ESI):489.2(M+H) ⁺ .

Example 61 Synthesis of Compound 85

first step

Under nitrogen protection, a solution of compound 60-3 (125 mg, 0.93 mmol), compound 85-1 (297 mg, 1.40 mmol), and cesium carbonate (910 mg, 2.79 mmol) in acetonitrile (5 mL) was heated to 75°C and stirred overnight. . LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (dichloromethane: methanol = 1:0-10:1) to obtain compound 85-2 (90 mg, yield: 36%).

MS m/z(ESI):268.1(M+H) ⁺ .

Step 2

To a solution of compound 85-2 (90 mg, 0.34 mmol) in anhydrous DMF (5 mL) was added NBS (66 mg, 0.37 mmol) under nitrogen protection and -40°C. After the addition is completed, remove the cold bath, allow the reaction solution to naturally rise to room temperature, and continue to stir the reaction for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mLx3), the organic phases were combined, washed with saturated brine (15 mLx1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate = 1:1) Compound 85-3 was obtained (80 mg, yield: 86%).

MS m/z(ESI):346.1(M+H) ⁺ .

third step

Under nitrogen protection, compound 85-3 (80 mg, 0.23 mmol), compound 14-1 (128 mg, 0.35 mmol), potassium carbonate (95 mg, 0.69 mmol), 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (17 mg, 0.023 mmol) in 1,4-dioxane (1 mL) and water (0.1 mL) was heated to 90°C and stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column (dichloromethane: methanol = 10:1) and reverse preparation to obtain compound 85 (30 mg, yield: 27%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.21 (d, J＝8.0Hz, 1H), 8.12-8.10 (m, 2H), 7.69 (d, J＝8.0Hz, 1H), 7.54 (dd, J＝ 8.0,2.0Hz,1H),7.32(brs,2H),7.11(dd,J＝8.0,2.0Hz,1H),6.63(t,J＝72.0Hz,1H),4.87-4.83(m,0.5H) ,4.71-4.67(m,0.5H),4.13-4.10(m,2H),3.13-3.06(m,3H),3.03-2.95(m,2H),2.91-2.88(m,2H),2.36-2.25 (m,2H),1.30-1.25(m,1H),1.08-0.97(m,1H).

MS m/z(ESI):511.2(M+H) ⁺ .

Example 62 Synthesis of Compound 86

first step

Under nitrogen protection, a solution of compound 60-3 (1.60g, 11.93mmol), bromoethanol (2.98g, 23.86mmol) and cesium carbonate (11.66g, 35.80mmol) in DMF (6mL) was heated to 75°C and stirred overnight. . LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (dichloromethane: methanol = 1:0-10:1) to obtain compound 86-1 (1.90 g, yield: 89%).

MS m/z(ESI):179.1(M+H) ⁺ .

Step 2

Under nitrogen protection and ice-water bath conditions, triethylamine (0.5 mL, 3.37 mmol) and methylsulfonyl chloride (0.13 mL, 1.68mmol). After the dropwise addition is completed, the reaction solution is naturally raised to room temperature and stirred for 2 hours. LCMS monitored the reaction to be complete. Pour the reaction solution into ice water (10 mL), extract with ethyl acetate (10 mLx3), combine the organic phases, wash with saturated aqueous sodium chloride solution (15 mLx1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound 86- 2(400mg).

MS m/z(ESI):256.1(M+H) ⁺ .

third step

Under nitrogen protection, a solution of compound 86-2 (400 mg, 1.56 mmol), compound 86-3 (237 mg, 2.34 mmol) and potassium carbonate (1.08 g, 7.80 mmol) in acetonitrile (5 mL) was heated to 75°C and stirred overnight. . LCMS monitored the reaction to be complete. Cool, filter, and the filtrate is concentrated under reduced pressure. The crude product is separated and purified through silica gel column (dichloromethane: methanol = 1:0-10:1) to obtain compound 86-4 (195 mg, yield: 48%).

MS m/z(ESI):262.2(M+H) ⁺ .

the fourth step

To a solution of compound 86-4 (195 mg, 0.75 mmol) in anhydrous DMF (5 mL) was added NBS (147 mg, 0.83 mmol) under nitrogen protection and -40°C. After the addition is completed, remove the cold bath, allow the reaction solution to naturally rise to room temperature, and continue to stir the reaction for 1 hour. LCMS monitored the reaction to be complete. Pour the reaction solution into water (10mL), extract with ethyl acetate (10mLx3), combine the organic phases, wash with saturated brine (15mLx1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product is separated and purified on a silica gel column. (Petroleum ether: ethyl acetate = 2:1) Compound 86-5 (125 mg, yield 49.2%) was obtained. MS m/z(ESI):340.1(M+H) ⁺ .

the fifth step

Under nitrogen protection, compound 86-5 (125 mg, 0.37 mmol), compound 14-1 (206 mg, 0.56 mmol), potassium carbonate (153 mg, 1.11 mmol), 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (27 mg, 0.037 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was heated to 80°C and stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column (dichloromethane: methanol = 10:1) and reverse preparative separation and purification to obtain compound 86 (65 mg, yield: 35%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.20 (d, J＝8.0Hz, 1H), 8.11-8.08 (m, 2H), 7.67 (d, J＝8.0Hz, 1H), 7.53 (dd, J＝ 8.0,2.0Hz,1H),7.31(brs,2H),7.12(dd,J＝8.0,2.0Hz,1H),6.63(t,J＝72.0Hz,1H),4.86-4.83(m,0.5H) ,4.70-4.67(m,0.5H),4.13(t,J＝4.0Hz,2H),3.98-3.93(m,1H),3.30(s,3H),3.11-3.08(m,1H),2.98- 2.62(m,6H),2.13-2.06(m,1H),1.90-1.87(m,1H),1.30-1.20(m,1H),1.07-0.97(m,1H).

MS m/z(ESI):505.2(M+H) ⁺ .

Example 63 Synthesis of Compound 87

first step

Under nitrogen protection, a solution of compound 86-2 (300 mg, 1.17 mmol), compound 87-1 (150 mg, 1.4 mmol) and potassium carbonate (485 mg, 3.51 mmol) in acetonitrile (5 mL) was heated to 75°C and stirred overnight. . LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (dichloromethane: methanol = 1:0-10:1) to obtain compound 87-2 (120 mg, yield: 38%).

MS m/z(ESI):268.1(M+H) ⁺ .

Step 2

To a solution of compound 87-2 (120 mg, 0.45 mmol) in anhydrous DMF (5 mL) was added NBS (80 mg, 0.45 mmol) under nitrogen protection and -40°C. After the addition is complete, remove the cold bath, allow the reaction solution to naturally rise to room temperature, and stir the reaction overnight. LCMS monitored the reaction to be complete. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mLx3), the organic phases were combined, washed with saturated brine (15 mLx1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified through silica gel column (petroleum ether: ethyl acetate = 1:1) to obtain compound 87-3 (120 mg, yield: 77%).

MS m/z(ESI):346.1(M+H) ⁺ .

third step

Under nitrogen protection, compound 87-3 (120 mg, 0.35 mmol), compound 14-1 (171 mg, 0.46 mmol), potassium carbonate (145 mg, 1.05 mmol) and 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (29 mg, 0.035 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was heated to 90°C and stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column (dichloromethane: methanol = 10:1) and reverse preparative separation and purification to obtain compound 87 (100 mg, yield: 56%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.21 (d, J＝8.2Hz, 1H), 8.12-8.09 (m, 2H), 7.69 (d, J＝8.0Hz, 1H), 7.54 (dd, J＝ 8.0,2.0Hz,1H),7.32(brs,2H),7.11(dd,J＝8.0,2.0Hz,1H),6.63(t,J＝72.0Hz,1H),5.14-5.09(m,1H), 5.01-4.96(m,1H),4.87-4.82(m,0.5H),4.71-4.67(m,0.5H),4.12-4.09(m,2H),3.26-2.98(m,7H),1.30-1.20 (m,1H),1.08-0.96(m,1H).

MS m/z(ESI):511.1(M+H) ⁺ .

Example 64 Synthesis of Compound 88

first step

Under nitrogen protection, a solution of compound 86-2 (400 mg, 1.56 mmol), compound 88-1 (200 mg, 1.87 mmol) and potassium carbonate (646 mg, 4.68 mmol) in acetonitrile (5 mL) was heated to 75°C and stirred overnight. . LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (dichloromethane: methanol = 1:0-10:1) to obtain compound 88-2 (240 mg, yield: 58%).

MS m/z(ESI):268.1(M+H) ⁺ .

Step 2

To a solution of compound 88-2 (240 mg, 0.90 mmol) in anhydrous DMF (5 mL) was added NBS (160 mg, 0.90 mmol) under nitrogen protection and -40°C. After the addition is complete, remove the cold bath, allow the reaction solution to naturally rise to room temperature, and stir the reaction overnight. LCMS monitored the reaction to be complete. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mLx3), the organic phases were combined, washed with saturated brine (15 mLx1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified through silica gel column (petroleum ether: ethyl acetate = 1:1) to obtain compound 88-3 (270 mg, yield: 87%).

MS m/z(ESI):346.1(M+H) ⁺ .

third step

Under nitrogen protection, compound 88-3 (270 mg, 0.78 mmol), compound 14-1 (374 mg, 1.01 mmol), potassium carbonate (323 mg, 2.34 mmol) and 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (64 mg, 0.078 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was heated to 90°C and stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column (dichloromethane: methanol = 10:1) and reverse preparative separation and purification to obtain compound 88 (70 mg, yield: 18%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.20 (d, J＝8.0Hz, 1H), 8.11-8.09 (m, 2H), 7.68 (d, J＝8.0Hz, 1H), 7.53 (dd, J＝ 8.0,2.0Hz,1H),7.32-7.30(m,2H),7.10(dd,J＝8.0,2.0Hz,1H),6.63(t,J＝72.0Hz,1H),5.24-5.18(m,1H ),5.11-5.05(m,1H),4.86-4.84(m,0.5H),4.70-4.68(m,0.5H),4.14-4.11(m,2H),3.26-2.90(m,7H),1.30 -1.20(m,1H),1.07-0.96(m,1H).

MS m/z(ESI):511.1(M+H) ⁺ .

Example 65 Synthesis of Compound 89

first step

Under nitrogen protection and -78°C, DAST (6.78g, 0.042mol) was slowly added dropwise to a solution of compound 89-1 (5.00g, 0.021mol) in anhydrous dichloromethane (50mL). After the addition is completed, react at -78°C for 1 hour, remove the cold bath, slowly raise the reaction solution to room temperature naturally, and continue stirring for 5 hours. LCMS monitored the reaction to be complete. Pour the reaction solution into water (100mL), extract with dichloromethane (100mLx3), combine the organic phases, wash with saturated brine (150mLx1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound 89-2 (3.10 g).

MS m/z(ESI):248.1(M+H) ⁺ .

Step 2

Under nitrogen protection and 0°C, compound 89-2 (3.10g, 0.013mol) in anhydrous tetrahydrofuran (20mL) was added dropwise to a solution of lithium aluminum tetrahydrogen (1.50g, 0.039mol) in anhydrous tetrahydrofuran (50mL). solution. After the addition was completed, the reaction solution was raised to 70°C and stirred for 5 hours. LCMS monitored the reaction to be complete. The reaction solution was cooled to 0°C, sodium sulfate decahydrate was slowly added to quench the reaction, ethyl acetate (100 mL) was added and stirred overnight, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 89-3 (1.20 g).

MS m/z(ESI):134.1(M+H) ⁺ .

third step

To a solution of compound 89-3 (500 mg, 3.76 mmol) in 1,2-dichloroethane (10 mL) under nitrogen protection and 0°C, SOCl ₂ (3 mL) was slowly added. After the addition was completed, the reaction solution was raised to 70°C and stirred for 5 hours. LCMS monitored the reaction to be complete. The reaction solution was concentrated under reduced pressure to obtain compound 89-4 (550 mg).

MS m/z(ESI):152.1(M+H) ⁺ .

the fourth step

Under nitrogen protection, a solution of compound 60-3 (550 mg, 3.64 mmol), compound 89-4 (200 mg, 1.49 mmol) and potassium carbonate (617 mg, 4.47 mmol) in acetonitrile (5 mL) was heated to 75°C and stirred overnight. . LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (dichloromethane: methanol = 1:0-10:1) to obtain compound 89-5 (154 mg, yield: 42%).

MS m/z(ESI):250.2(M+H) ⁺ .

the fifth step

To a solution of compound 89-5 (154 mg, 0.62 mmol) in anhydrous DMF (5 mL) was added NBS (110 mg, 0.62 mmol) under nitrogen protection and -40°C. After the addition was completed, the cold bath was removed, the reaction solution was naturally raised to room temperature, and the reaction was stirred overnight. LCMS monitored the reaction to be complete. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mLx3), the organic phases were combined, washed with saturated brine (15 mLx1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified through silica gel column (petroleum ether: ethyl acetate = 1:1) to obtain compound 89-6 (150 mg, yield: 74%).

MS m/z(ESI):328.1(M+H) ⁺ .

Step 6

Under nitrogen protection, compound 89-6 (150 mg, 0.46 mmol), compound 14-1 (222 mg, 0.60 mmol), potassium carbonate (191 mg, 1.38 mmol) and 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (38 mg, 0.046 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was heated to 80°C and stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column (dichloromethane: methanol = 10:1) and reverse preparative separation and purification to obtain compound 89 (69 mg, yield: 31%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.20-8.05(m,3H),7.68-7.63(m,1H),7.49(dd,J＝8.0,2.0Hz,1H),7.32-7.29(m,2H ),7.12-7.07(m,1H),6.64(t,J＝72.0Hz,1H),5.22-4.61(m,2H),4.31-3.97(m,1H),3.42-2.77(m,3H), 2.53-2.33(m,5H),2.10-1.75(m,2H),1.27-1.16(m,1H),1.05–0.94(m,1H).

MS m/z(ESI):493.2(M+H) ⁺ .

Example 66 Synthesis of Compound 90

first step

Under nitrogen protection, a solution of compound 86-2 (450 mg, 1.76 mmol), compound 90-1 (151 mg, 2.64 mmol) and cesium carbonate (1.70 g, 5.28 mmol) in acetonitrile (5 mL) was heated to 75°C and the reaction was stirred. overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (dichloromethane: methanol = 1:0-10:1) to obtain compound 90-2 (70 mg, yield: 18%).

MS m/z(ESI):218.1(M+H) ⁺ .

Step 2

To a solution of compound 90-2 (70 mg, 0.32 mmol) in anhydrous DMF (5 mL) was added NBS (57 mg, 0.32 mmol) under nitrogen protection and -40°C. After the addition is complete, remove the cold bath, allow the reaction solution to naturally rise to room temperature, and stir the reaction overnight. LCMS monitored the reaction to be complete. Pour the reaction solution into water (10 mL), extract with ethyl acetate (10 mLx3), combine the organic phases, wash with saturated brine (15 mLx1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was separated and purified through silica gel column (petroleum ether: ethyl acetate = 1:1) to obtain compound 90-3 (70 mg, yield: 74%).

MS m/z(ESI):296.1(M+H) ⁺ .

third step

Under nitrogen protection, compound 90-3 (70 mg, 0.24 mmol), compound 14-1 (116 mg, 0.31 mmol), potassium carbonate (100 mg, 0.72 mmol) and 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (20 mg, 0.024 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was heated to 90°C and stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column (dichloromethane: methanol = 10:1) and reverse preparation to obtain compound 90 (26 mg, yield: 24%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.21 (d, J＝8.0Hz, 1H), 8.10-8.09 (m, 2H), 7.67 (d, J＝8.4Hz, 1H), 7.54 (dd, J＝ 8.0,2.0Hz,1H),7.31(brs,2H),7.12(dd,J＝8.4,2.0Hz,1H),6.63(t,J＝72.0Hz,1H),4.87-4.83(m,0.5H) ,4.71-4.67(m,0.5H),4.01(t,J＝4.8Hz,2H),3.43-4.40(m,4H),3.13-3.07(m,1H),2.92(t,J＝4.8Hz, 2H), 2.22-2.15(m,2H),1.30-1.19(m,1H),1.08-0.97(m,1H).

MS m/z(ESI):461.1(M+H) ⁺ .

Example 67 Synthesis of Compound 91

first step

Under nitrogen protection, a solution of compound 86-2 (600 mg, 2.34 mmol), compound 91-1 (327 mg, 3.51 mmol) and cesium carbonate (2.30 g, 7.02 mmol) in acetonitrile (5 mL) was heated to 75°C and the reaction was stirred. overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure. The crude product is separated and purified through silica gel column (dichloromethane: methanol = 1:0-10:1) to obtain compound 91-2 (200 mg, yield: 34%).

MS m/z(ESI):254.1(M+H) ⁺ .

Step 2

Under nitrogen protection and -40°C, NBS (140 mg, 0.79 mmol) was added to a solution of compound 91-2 (200 mg, 0.79 mmol) in anhydrous DMF (5 mL). After the addition was completed, the cold bath was removed and the reaction was The solution was naturally raised to room temperature and the reaction was stirred overnight. LCMS monitored the reaction to be complete. Pour the reaction solution into water (10mL), extract with ethyl acetate (10mLx3), combine the organic phases, wash with saturated brine (15mLx1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product is separated and purified on a silica gel column. (Petroleum ether: ethyl acetate = 1:1) Compound 91-3 (150 mg, yield: 57%) was obtained.

MS m/z(ESI):332.1(M+H) ⁺ .

third step

Under nitrogen protection, compound 91-3 (150 mg, 0.45 mmol), compound 14-1 (218 mg, 0.59 mmol), potassium carbonate (186 mg, 1.35 mmol) and 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (37 mg, 0.045 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was heated to 90°C and stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column (dichloromethane: methanol = 10:1) and reverse preparation to obtain compound 91 (47 mg, yield: 21%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.18 (d, J＝8.0Hz, 1H), 8.11-8.04 (m, 2H), 7.66 (d, J＝8.4Hz, 1H), 7.51 (d, J＝ 8.0Hz,1H),7.32-7.30(m,2H),7.07(dd,J＝8.4,2.0Hz,1H),6.64(t,J＝72.0Hz,1H),4.86-4.82(m,0.5H) ,4.70-4.66(m,0.5H),4.04(t,J＝5.2Hz,2H),3.74(t,J＝12.0Hz,4H),3.11-3.01(m,3H),1.30-1.19(m, 1H),1.08-0.96(m,1H).

MS m/z(ESI):497.1(M+H) ⁺ .

Example 68 Synthesis of Compound 92

first step

Under nitrogen protection, compound A5-1 (200mg, 1.02mmol), compound 92-1 (263mg, 2.04mmol), cesium carbonate (998mg, 3.06mmol), 2-(di-tert-butylphosphorus)-3- Methoxy-6-methyl-2'4'6'-triisopropyl-biphenyl (96 mg, 0.20 mmol) and allylpalladium(II) chloride dimer (37 mg, 0.10 mmol) in toluene (15 mL) solution was heated to 90°C and the reaction was stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure. The crude product is separated and purified through silica gel column (dichloromethane: methanol = 1:0-10:1) to obtain compound 92-2 (100 mg, yield: 40%).

MS m/z(ESI):246.1(M+H) ⁺ .

Step 2

To a solution of compound 92-2 (100 mg, 0.41 mmol) in anhydrous DMF (5 mL) was added NBS (80 mg, 0.45 mmol) under nitrogen protection and -40°C. After the addition is completed, remove the cold bath, allow the reaction solution to naturally rise to room temperature, and continue to stir the reaction for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mLx3), the organic phases were combined, washed with saturated brine (15 mLx1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified through silica gel column (petroleum ether: ethyl acetate = 2:1) to obtain compound 92-3 (85 mg, yield: 64%).

MS m/z(ESI):324.1(M+H) ⁺ .

third step

Under nitrogen protection, compound 92-3 (85 mg, 0.26 mmol), compound 14-1 (146 mg, 0.39 mmol), potassium carbonate (107 mg, 0.78 mmol) and 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (19 mg, 0.026 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was heated to 85°C and stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column (dichloromethane: methanol = 10:1) and reverse preparative separation and purification to obtain compound 92 (33 mg, yield: 26%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.21 (d, J＝8.0Hz, 1H), 8.11-8.10 (m, 2H), 7.69 (d, J＝8.4Hz, 1H), 7.54 (dd, J＝ 8.0,2.0Hz,1H),7.32-7.30(m,2H),7.08(dd,J＝8.4,2.0Hz,1H),6.63(t,J＝72.0Hz,1H),4.87-4.83(m,0.5 H),4.71-4.67(m,0.5H),4.14(t,J＝5.2Hz,2H),3.74(t,J＝5.2Hz,2H),3.59(t,J＝8.0Hz,2H),3.13 -3.07(m,1H),2.42(t,J＝8.0Hz,2H),2.11-2.03(m,2H),1.30-1.20(m,1H),1.08-0.96(m,1H).

MS m/z(ESI):489.2(M+H) ⁺ .

Example 69 Synthesis of Compound 93

first step

Under nitrogen protection, a solution of compound 60-3 (300 mg, 2.3 mmol), methyl 2-bromoacetate (420 mg, 2.76 mmol), and cesium carbonate (2.30 g, 6.90 mmol) in acetonitrile (5 mL) was heated to 55°C and Stir overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure. The crude product is separated and purified through silica gel column (dichloromethane: methanol = 1:0-10:1) to obtain compound 93-1 (312 mg, yield: 66%).

MS m/z(ESI):207.1(M+H) ⁺ .

Step 2

Under ice-water bath conditions, LiOH aqueous solution (1 mL, 2N) was added dropwise to a solution of compound 93-1 (312 mg, 1.52 mmol) in methanol (3 mL). After the addition was completed, the ice-water bath was removed, the reaction solution was naturally raised to room temperature, and the reaction was stirred for 2 hours. LCMS monitored the reaction to be complete. Pour the reaction solution into ice water (10 mL), adjust to pH=4~5 with 1 mol/L dilute hydrochloric acid solution, extract with ethyl acetate (20 mLx3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and reduce the filtrate to Concentrate under pressure to obtain compound 93-2 (350 mg).

MS m/z(ESI):193.1(M+H) ⁺ .

third step

Under nitrogen protection, to a solution of compound 93-2 (350 mg, 1.83 mmol) in dichloromethane (10 mL) were added pyrrolidine (156 mg, 2.20 mmol), HATU (1.05 g, 2.75 mmol) and N,N-bis Isopropylethylamine (0.90 mL, 5.49 mmol). After the addition was complete, the resulting reaction solution was stirred at room temperature overnight. LCMS monitored the reaction to be complete. The reaction solution was poured into ice water (20 mL), extracted with ethyl acetate (30 mLx3), the organic phases were combined, washed with saturated brine (50 mLx1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified through silica gel column (petroleum ether: ethyl acetate = 1:0-2:1) to obtain compound 93-3 (86 mg, yield: 19%).

MS m/z(ESI):246.1(M+H) ⁺ .

the fourth step

To a solution of compound 93-3 (86 mg, 0.35 mmol) in anhydrous DMF (3 mL) was added NBS (62 mg, 0.35 mmol) under nitrogen protection and -40°C. After the addition is complete, remove the cold bath, allow the reaction solution to naturally rise to room temperature, and stir the reaction overnight. LCMS monitored the reaction to be complete. Pour the reaction solution into water (10mL), extract with ethyl acetate (10mLx3), wash the combined organic phases with saturated brine (15mLx1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product is separated and purified on a silica gel column. (Petroleum ether: ethyl acetate = 2:1) Compound 93-4 (70 mg, yield: 62%) was obtained.

MS m/z(ESI):324.1(M+H) ⁺ .

the fifth step

Under nitrogen protection, compound 93-4 (70 mg, 0.22 mmol), compound 14-1 (108 mg, 0.29 mmol), potassium carbonate (91 mg, 0.66 mmol) and 1,1'-bis(diphenylphosphino)bis A mixed solution of ferrocene palladium dichloride (18 mg, 0.022 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was heated to 90°C and stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column (dichloromethane: methanol = 10:1) and reverse preparative separation and purification to obtain compound 93 (21 mg, yield: 20%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.20 (d, J = 8.0Hz, 1H), 8.16 (d, J = 2.0Hz, 1H), 8.09 (s, 1H), 7.70 (d, J = 8.4Hz ,1H),7.53(dd,J＝8.4,2.0Hz,1H),7.32-7.31(m,2H),7.21(dd,J＝8.4,2.0Hz,1H),6.64(t,J＝72.0Hz, 1H),4.87-4.83(m,0.5H),4.71-4.65(m,2.5H),3.57-3.48(m,4H),3.11-3.08(m,1H),2.06-1.99(m,2H), 1.93-1.86(m,2H),1.30-1.20(m,1H),1.07-0.96(m,1H).

MS m/z(ESI):489.1(M+H) ⁺ .

Example 70 Synthesis of Compound 94

first step

Under nitrogen protection, compound A5-1 (300 mg, 1.53 mmol), compound 94-1 (628 mg, 3.06 mmol), cesium carbonate (748 mg, 2.30 mmol), 2-(di-tert-butylphosphorus)-3- Methoxy-6-methyl-2'4'6'-triisopropyl-biphenyl (143 mg, 0.31 mmol) and allylpalladium(II) chloride dimer (55 mg, 0.15 mmol) in toluene (10 mL) solution was heated to 90°C and the reaction was stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (dichloromethane: methanol = 1:0-10:1) to obtain compound 94-2 (235 mg, yield: 48%).

MS m/z(ESI):322.2(M+H) ⁺ .

Step 2

To a solution of compound 94-2 (235 mg, 0.73 mmol) in anhydrous DMF (5 mL) was added NBS (143 mg, 0.81 mmol) under nitrogen protection and -40°C. After the addition is completed, remove the cold bath, allow the reaction solution to naturally rise to room temperature, and continue to stir the reaction for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mLx3), the organic phases were combined, washed with saturated brine (15 mLx1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified through silica gel column (petroleum ether: ethyl acetate = 2:1) to obtain compound 94-3 (180 mg, yield: 62%).

MS m/z(ESI):400.1(M+H) ⁺ .

third step

Under nitrogen protection, compound 94-3 (180 mg, 0.45 mmol), compound 14-1 (251 mg, 0.68 mmol), potassium carbonate (186 mg, 1.35 mmol) and 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (33 mg, 0.045 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was heated to 90°C and stirred overnight. LCMS monitored the reaction to be complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (dichloromethane: methanol = 10:1) to obtain compound 94-4 (180 mg, yield: 71%).

MS m/z(ESI):565.2(M+H) ⁺ .

the fourth step

Under ice-water bath conditions, trifluoroacetic acid (1 mL) was slowly added dropwise to a solution of compound 94-4 (180 mg, 0.32 mmol) in dichloromethane (3 mL). After the dropwise addition was completed, the ice-water bath was removed, the reaction solution was raised to room temperature, and the reaction was stirred for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was concentrated under reduced pressure to obtain compound 94-5 (148 mg).

MS m/z(ESI):465.2(M+H) ⁺ .

the fifth step

Under ice-water bath conditions, 30% formaldehyde solution (32 mg, 0.40mmol). After the addition was completed, the reaction solution was continued to stir for 0.5 hours. Under an ice-water bath, sodium cyanoborohydride (40 mg, 0.64 mmol) was added to the aforementioned reaction solution. After the addition was completed, the ice-water bath was removed, the reaction solution was naturally raised to room temperature, and the reaction was stirred for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (30 mLx3), the organic phases were combined, washed with saturated brine (10 mLx1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column (dichloromethane: methanol = 10:1) and reverse preparative separation and purification to obtain compound 94 (20 mg, yield: 27%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.25-8.20 (m, 2H), 8.13 (s, 1H), 7.73 (d, J = 8.4Hz, 1H), 7.57 (dd, J = 8.0, 1.6Hz, 1H),7.35-7.33(m,2H),7.18(dd,J＝8.4,2.0Hz,1H),6.66(t,J＝72.0Hz,1H),4.90-4.86(m,0.5H),4.74- 4.70(m,0.5H),4.34(d,J＝24.0Hz,2H),3.75-3.70(m,2H),3.31-3.23(m,2H),3.16-3.11(m,1H),2.49(s ,3H),1.33-1.24(m,1H),1.11-1.00(m,1H).

MS m/z(ESI):479.2(M+H) ⁺ .

Example 71 Synthesis of Compound 95

Under nitrogen protection, to a solution of compound 94-5 (70 mg, 0.15 mmol) in acetonitrile (2 mL) was added cesium carbonate (147 mg, 0.45 mmol) and compound 58-4 (36 mg, 0.30 mmol) in sequence. After the addition is completed, the reaction solution is stirred at room temperature for 2 hours. LCMS monitored the reaction to be complete. Pour the reaction solution into water (10mL), extract with ethyl acetate (30mLx3), combine the organic phases, wash with saturated brine (10mLx1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product, which is purified in reverse order Compound 95 (22 mg, yield: 29%) was obtained by preparation, isolation and purification.

¹ H NMR (400MHz, CDCl ₃ ) δ8.21(d,J＝8.0Hz,1H),8.17(d,J＝2.0Hz,1H),8.11(s,1H),7.71(d,J＝8.0Hz ,1H),7.54(dd,J＝8.0,1.6Hz,1H),7.33-7.30(m,2H),7.16(dd,J＝8.4,2.0Hz,1H),6.64(t,J＝72.0Hz, 1H),4.87-4.83(m,0.5H),4.71-4.67(m,0.5H),4.30(d,J＝24.0Hz,2H),3.75-3.59(m,6H),3.12-3.08(m, 1H),1.30-1.21(m,1H),1.08-0.98(m,1H).

MS m/z(ESI):504.2(M+H) ⁺ .

Example 72 Synthesis of Compound 96

Under nitrogen protection, N,N-diisopropylethylamine (1.30 mL, 0.78 mmol) and compound 13-6 (60 mg, 0.52mmol). After the addition was completed, the reaction solution was brought to room temperature and stirred overnight. LCMS monitored the reaction to be complete. The reaction solution was concentrated under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (dichloromethane: methanol = 1:0-10:1) to obtain compound 96 (27 mg, yield: 19%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.22 (d, J＝8.0Hz, 1H), 8.12-8.10 (m, 2H), 7.69 (d, J＝8.4Hz, 1H), 7.55 (dd, J＝ 8.4,2.0Hz,1H),7.33-7.31(m,2H),7.09(dd,J＝8.4,2.0Hz,1H),6.63(t,J＝72.0Hz,1H),4.87-4.84(m,0.5 H),4.71-4.68(m,0.5H),4.13(d,J＝6.4Hz,2H),3.63(t,J＝7.6Hz,2H),3.33(t,J＝7.6Hz,2H),3.13 -3.00(m,4H),1.31-1.21(m,1H),1.08-0.97(m,1H).

MS m/z(ESI):529.2(M+H) ⁺ .

Example 73 Synthesis of Compound 97

Under nitrogen protection, cesium carbonate (249 mg, 0.765 mmol) and bromoacetonitrile (61 mg, 0.51 mmol) were added sequentially to a solution of compound 54-5 (114 mg, 0.26 mmol) in acetonitrile (2 mL). After the addition was completed, the reaction solution was brought to room temperature and stirred for 2 hours. LCMS monitored the reaction to completion. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine (10 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified through reverse preparation to obtain compound 97 (3 mg, yield: 3%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.21 (d, J = 8.0Hz, 1H), 8.12 (d, J = 2.0Hz, 1H), 8.09 (s, 1H), 7.69 (d, J = 8.0Hz ,1H),7.54(dd,J＝8.0,2.0Hz,1H),7.33-7.31(m,2H),7.14(dd,J＝8.0,2.0Hz,1H),6.63(t,J＝72.0Hz, 1H),4.87-4.83(m,0.5H),4.71-4.67(m,0.5H),4.14(d,J＝8.0Hz,2H),3.61(t,J＝7.6Hz,2H),3.49(s ,2H),3.41-3.38(m,2H),3.13-3.06(m,1H),3.05-2.96(m,1H),1.08-1.03(m,1H),1.02-0.96(m,1H).

MS m/z(ESI):486.2(M+H) ⁺ .

Example 74 Synthesis of Compound 98

first step

Under nitrogen protection and ice-water bath conditions, lithium bistrimethylsilylamide (94 mL, 0.094 mol, 1 M in THF) was added dropwise to a solution of compound 98-1 (10.00 g, 0.047 mol) in anhydrous tetrahydrofuran (100 mL). ) solution. After the dropwise addition is completed, the reaction solution is continued to stir for 30 minutes. Then, methyl iodide (10.10g, 0.071mol) was added dropwise to the reaction solution. After the dropwise addition was completed, the cold bath was removed, the reaction solution was naturally raised to room temperature, and stirring was continued for 12 hours. The reaction is over. Pour the reaction solution into ice-saturated aqueous ammonium chloride solution (150 mL), remove most of the tetrahydrofuran under reduced pressure, extract with ethyl acetate (100 mL × 3), combine the organic phases, wash with saturated brine (150 mL × 1), and wash with anhydrous sulfuric acid. It was dried over sodium, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 98-2 (5.60 g, yield: 52%).

MS m/z(ESI):230.2(M+H) ⁺ .

Step 2

Under nitrogen protection and ice-water bath conditions, sodium borohydride (836 mg, 0.022 mol) was slowly added in batches to a mixed solution of compound 98-2 (2.50 g, 0.011 mol) in methanol (15 mL) and tetrahydrofuran (15 mL). After the addition is completed, remove the cold bath, allow the reaction solution to naturally rise to room temperature and stir for 2 hours. LCMS monitored the reaction to completion. Pour the reaction solution into ice-cold saturated aqueous ammonium chloride solution (100 mL), extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated brine (50 mL × 1), dry over anhydrous sodium sulfate, filter, and remove the filtrate Concentrate under reduced pressure to obtain the compound Product 98-3 (1.40g, yield: 64%).

MS m/z(ESI):202.1(M+H) ⁺ .

third step

Under nitrogen protection and ice-water bath conditions, triethylamine (0.70 mL, 4.50 mmol) and methylsulfonyl chloride (0.18 mL, 2.25mmol). After the addition is completed, remove the cold bath, allow the reaction solution to naturally rise to room temperature, and continue stirring for 2 hours. LCMS monitored the reaction to completion. Pour the reaction solution into saturated glacial ammonium chloride aqueous solution (20mL), extract with dichloromethane (10mL×3), combine the organic phases, wash with saturated brine (15mL×1), dry over anhydrous sodium sulfate, filter, and reduce the filtrate to Concentrate under pressure to obtain compound 98-4 (350 mg).

MS m/z(ESI):280.1(M+H) ⁺ .

the fourth step

Under nitrogen protection, a solution of compound 98-4 (350 mg, 1.25 mmol), compound 60-3 (120 mg, 0.90 mmol) and potassium carbonate (373 mg, 2.70 mmol) in acetonitrile (5 mL) was heated to 75°C and stirred overnight. LCMS monitored the reaction to completion. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (dichloromethane:methanol=1:0-10:1) to obtain compound 98-5 (210 mg, yield: 74%).

MS m/z(ESI):318.2(M+H) ⁺ .

the fifth step

To the solvent of compound 98-5 (210 mg, 0.66 mmol) in anhydrous DMF (5 mL) was added NBS (118 mg, 0.66 mmol) under nitrogen protection and -40°C. After the addition was completed, the reaction solution was continued to stir for 1 hour under these conditions. LCMS monitored the reaction to completion. Pour the reaction solution into ice water (10 mL), extract with ethyl acetate (10 mL × 3), combine the organic phases, wash with saturated brine (15 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain crude product . The crude product was separated and purified through silica gel column (petroleum ether: ethyl acetate = 1:0-0:1) to obtain compound 98-6 (185 mg, yield: 71%).

MS m/z(ESI):396.1(M+H) ⁺ .

Step 6

Under nitrogen protection, compound 98-6 (185 mg, 0.47 mmol), compound 14-1 (264 mg, 0.71 mmol), potassium carbonate (195 mg, 1.41 mmol), 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (39 mg, 0.047 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was heated to 80°C and stirred for 12 hours. LCMS monitored the reaction to completion. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (dichloromethane: methanol = 1:0-0:1) to obtain compound 98-7 (200 mg, yield: 76%).

MS m/z(ESI):561.2(M+H) ⁺ .

Step 7

Under ice-water bath conditions, trifluoroacetic acid (1 mL) was slowly added dropwise to a solution of compound 98-7 (200 mg, 0.36 mmol) in dichloromethane (3 mL). After the addition is completed, remove the cold bath, allow the reaction solution to naturally rise to room temperature and stir for 1 hour. LCMS monitored the reaction to completion. The reaction solution was concentrated under reduced pressure to obtain compound 98-8 (180 mg).

MS m/z(ESI):461.2(M+H) ⁺ .

Step 8

Under nitrogen protection, cesium carbonate (382 mg, 1.17 mmol) and bromoacetonitrile (71 mg, 0.59 mmol) were added sequentially to a solution of compound 98-8 (180 mg, 0.39 mmol) in acetonitrile (2 mL). After the addition was completed, the reaction solution was stirred at room temperature for 2 hours. LCMS monitored the reaction to completion. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified through reverse preparation to obtain compound 98 (30 mg, yield: 15%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.21 (d, J＝8.0Hz, 1H), 8.13-8.09 (m, 2H), 7.69 (d, J＝8.0Hz, 1H), 7.54 (dd, J＝ 8.0,2.0Hz,1H),7.33-7.30(m,2H),7.17(dd,J＝8.0,2.0Hz,1H),6.63(t,J＝72.0Hz,1H),4.87-4.83(m,0.5 H),4.71-4.67(m,0.5H),3.99(s,2H),3.50(t,J＝4.0Hz,4H),3.22(d,J＝7.2Hz,2H),3.13-3.07(m, 1H),1.43(s,3H),1.30-1.28(m,1H),1.23-0.97(m,1H).

MS m/z(ESI):500.2(M+H) ⁺ .

Example 75 Synthesis of Compound 99

first step

Under nitrogen protection, a solution of compound 86-2 (350 mg, 1.37 mmol), compound 99-1 (155 mg, 1.78 mmol) and potassium carbonate (567 mg, 4.11 mmol) in acetonitrile (5 mL) was heated to 75°C and stirred for 12 hours. . LCMS monitored the reaction to completion. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (dichloromethane:methanol=1:0-10:1) to obtain compound 99-2 (123 mg, yield: 36%).

MS m/z(ESI):248.1(M+H) ⁺ .

Step 2

Under nitrogen protection, NBS (89 mg, 0.50 mmol) was added to the solvent of compound 99-2 (123 mg, 0.50 mmol) in anhydrous DMF (5 mL). After the addition was completed, the reaction solution was stirred at room temperature for 12 hours. LCMS monitored the reaction to completion. Pour the reaction solution into ice water (10 mL), extract with ethyl acetate (10 mL × 3), combine the organic phases, wash with saturated brine (15 mL × 1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain crude product . The crude product was separated and purified through silica gel column (petroleum ether: ethyl acetate = 1:0-0:1) to obtain compound 99-3 (74 mg, yield: 46%).

MS m/z(ESI):326.1(M+H) ⁺ .

third step

Under nitrogen protection, compound 99-3 (74 mg, 0.23 mmol), compound 14-1 (111 mg, 0.30 mmol), potassium carbonate (95 mg, 0.69 mmol) and 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (19 mg, 0.023 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was heated to 90°C and stirred for 12 hours. LCMS monitored the reaction to completion. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column (dichloromethane: methanol = 1:0-10:1) and reverse preparative separation and purification to obtain compound 99 (20 mg, yield: 18%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.10-8.08 (m, 2H), 7.67 (d, J = 8.0Hz, 1H), 7.53 (dd, J = 8.0, 2.0Hz, 1H), 7.32 (brs, 2H),7.11(dd,J＝8.0,2.0Hz,1H),6.63(t,J＝72.0Hz,1H),4.87-4.83(m,0.5H),4.71-4.67(m,0.5H),4.14 -4.08(m,1H),4.02(t,J＝5.2Hz,2H),3.82-3.79(m,2H),3.28(s,3H),3.13-3.07(m,3H),2.97(t,J ＝5.2Hz,2H),1.30-1.20(m,1H),1.07-0.97(m,1H).

MS m/z(ESI):491.1(M+H) ⁺ .

Example 76 Synthesis of Compound 100

first step

Under nitrogen protection, compound 86-2 (500 mg, 1.95 mmol), compound 100-1 (192 mg, 2.34 mmol) and potassium carbonate (807 mg, 5.85 mmol) in acetonitrile (5 mL) was heated to 75°C and stirred for 12 hours. LCMS monitored the reaction to completion. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (dichloromethane: methanol = 1:0-10:1) to obtain compound 100-2 (130 mg, yield: 28%).

MS m/z(ESI):243.1(M+H) ⁺ .

Step 2

Under nitrogen protection, NBS (96 mg, 0.54 mmol) was added to the solvent of compound 100-2 (130 mg, 0.54 mmol) in anhydrous DMF (5 mL). After the addition was completed, the reaction solution was stirred at room temperature for 12 hours. LCMS monitored the reaction to completion. Pour the reaction solution into ice water (10 mL), extract with ethyl acetate (10 mL × 3), combine the organic phases, wash with saturated brine (15 mL × 1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain crude product . The crude product was separated and purified through silica gel column (petroleum ether: ethyl acetate = 1:0-0:1) to obtain compound 100-3 (160 mg, yield: 93%).

MS m/z(ESI):321.1(M+H) ⁺ .

third step

Under nitrogen protection, compound 100-3 (160 mg, 0.50 mmol), compound 14-1 (278 mg, 0.75 mmol), potassium carbonate (207 mg, 1.50 mmol) and 1,1'-bis(diphenylphosphino)bis A reaction mixture of palladium ferrocene dichloride (41 mg, 0.050 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was heated to 90°C and stirred for 12 hours. LCMS monitored the reaction to completion. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column (dichloromethane:methanol=1:0-10:1) and reverse preparative column to obtain compound 100 (59 mg, yield: 24%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.20 (d, J＝8.0Hz, 1H), 8.08-8.07 (m, 2H), 7.68 (d, J＝8.0Hz, 1H), 7.53 (dd, J＝ 8.0,2.0Hz,1H),7.32-7.30(m,2H),7.07(dd,J＝8.0,2.0Hz,1H),6.63(t,J＝72.0Hz,1H),4.87-4.83(m,0.5 H),4.71-4.67(m,0.5H),4.00(t,J＝5.2Hz,2H),3.77-3.73(m,2H),3.49-3.45(m,2H),3.37-3.31(m,1H ),3.11-3.07(m,1H),2.91(t,J＝5.2Hz,2H),1.28-1.20(m,1H),1.07-0.98(m,1H).

MS m/z(ESI):486.2(M+H) ⁺ .

Example 77 Synthesis of Compound 101

first step

Under nitrogen protection, a solution of compound 86-2 (500 mg, 1.95 mmol), compound 101-1 (293 mg, 2.34 mmol) and potassium carbonate (807 mg, 5.85 mmol) in acetonitrile (5 mL) was heated to 75°C and stirred for 12 hours. . LCMS monitored the reaction to completion. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (dichloromethane: methanol = 1:0-10:1) to obtain compound 101-2 (420 mg, yield: 76%).

MS m/z(ESI):286.1(M+H) ⁺ .

Step 2

Under nitrogen protection, NBS (262 mg, 1.47 mmol) was added to compound 101-2 (420 mg, 1.47 mmol) in anhydrous DMF (5 mL) solvent. After the addition was completed, the reaction solution was stirred at room temperature for 12 hours. LCMS monitored the reaction to completion. Pour the reaction solution into ice water (10 mL), extract with ethyl acetate (10 mL × 3), combine the organic phases, wash with saturated brine (15 mL × 1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain crude product . The crude product was separated and purified through silica gel column (petroleum ether: ethyl acetate = 1:0-0:1) to obtain compound 101-3 (520 mg, yield: 97%).

MS m/z(ESI):364.1(M+H) ⁺ .

third step

Under nitrogen protection, compound 101-3 (300 mg, 0.83 mmol), compound 14-1 (408 mg, 1.10 mmol), potassium carbonate (344 mg, 2.49 mmol) and 1,1'-bis(diphenylphosphino)bis A reaction mixture of palladium ferrocene dichloride (68 mg, 0.083 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was heated to 90°C and stirred for 12 hours. LCMS monitored the reaction to completion. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column (dichloromethane:methanol=1:0-10:1) and reverse preparative column to obtain compound 101 (42 mg, yield: 10%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.21 (d, J＝8.0Hz, 1H), 8.10-8.09 (m, 2H), 7.68 (d, J＝8.0Hz, 1H), 7.54 (dd, J＝ 8.0,2.0Hz,1H),7.31(dd,J＝8.0,2.4Hz,2H),7.10(dd,J＝8.0,2.0Hz,1H),6.63(t,J＝72.0Hz,1H),4.87- 4.83(m,0.5H),4.71-4.67(m,0.5H),4.00(t,J＝5.2Hz,2H),3.65(t,J＝8.0Hz,2H),3.36(t,J＝7.6Hz ,2H),3.26-3.20(m,1H),3.12-3.08(m,1H),2.92(t,J＝5.2Hz,2H),1.32-1.27(m,1H),1.08-0.97(m,1H ).

MS m/z(ESI):529.2(M+H) ⁺ .

Example 78 Synthesis of Compound 102

first step

Under nitrogen protection, a solution of compound 86-2 (500 mg, 1.95 mmol), compound 102-1 (204 mg, 2.34 mmol) and potassium carbonate (807 mg, 5.85 mmol) in acetonitrile (5 mL) was heated to 75°C and stirred for 12 hours. . LCMS monitored the reaction to completion. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (dichloromethane:methanol=1:0-10:1) to obtain compound 102-2 (410 mg, yield: 85%).

MS m/z(ESI):248.1(M+H) ⁺ .

Step 2

Under nitrogen protection and ice-water bath conditions, sodium hydride (80 mg, 3.32 mmol, 60%) was added to a solution of compound 102-2 (410 mg, 1.66 mmol) in anhydrous DMF (5 mL). The obtained reaction liquid was stirred under this condition for 0.5 hours, and then compound 102-3 (378 mg, 2.0 mmol) was added to the reaction liquid. The cold bath was removed, the reaction solution was naturally raised to room temperature, and stirring was continued for 12 hours. The reaction is over. Pour the reaction mixture into glacial ammonium chloride aqueous solution (30 mL), extract with ethyl acetate (30 mL × 3), combine the organic phases, wash with saturated brine (30 mL × 2), dry over anhydrous sodium sulfate, filter, and depressurize the filtrate Concentration gave compound 102-4 (220 mg, yield: 50%).

MS m/z(ESI):265.2(M+H) ⁺ .

third step

Under nitrogen protection, NBS (150 mg, 0.84 mmol) was added to a solution of compound 102-4 (220 mg, 0.84 mmol) in anhydrous N,N-dimethylformamide (5 mL). After the addition was completed, the resulting reaction solution was stirred at room temperature for 12 hours. LCMS monitored the reaction to completion. Pour the reaction solution into ice water (10 mL), extract with ethyl acetate (10 mL × 3), combine the organic phases, and wash with saturated brine (15 mL × 2). Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product is separated and purified by silica gel column (petroleum ether: ethyl acetate = 1:0-0:1) to obtain compound 102-5 (160 mg, yield: 56%) .

MS m/z(ESI):343.1(M+H) ⁺ .

the fourth step

Under nitrogen protection, compound 102-5 (160 mg, 0.47 mmol), compound 14-1 (263 mg, 0.71 mmol), potassium carbonate (195 mg, 1.41 mmol) and 1,1'-bis(diphenylphosphino)bis A reaction mixture of palladium ferrocene dichloride (39 mg, 0.047 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was heated to 90°C and stirred for 12 hours. LCMS monitored the reaction to completion. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column (dichloromethane:methanol=1:0-10:1) and reverse preparative column to obtain compound 102 (79 mg, yield: 33%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.23-8.11(m,3H),7.71-7.54(m,2H),7.35(brs,1H),7.35(s,2H),7.15-7.13(m,1H ),6.67(t,J＝72.0Hz,1H),4.88-4.72(m,1H),4.16-3.99(m,3H),3.13-2.66(m,7H),2.15-1.99(m,2H), 1.30-1.02(m,2H).

MS m/z(ESI):508.2(M+H) ⁺ .

Example 79 Synthesis of Compound 103

first step

Under nitrogen protection, a solution of compound 103-1 (5.00g, 0.049mol), methyl 2-bromoacetate (11.31g, 0.074mol) and potassium carbonate (20.71g, 0.15mol) in acetonitrile (50mL) was placed at room temperature. Stir for 12 hours. LCMS monitored the reaction to completion. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (petroleum ether: ethyl acetate = 1:0-0:1) to obtain compound 103-2 (3.91g, yield: 46%).

MS m/z(ESI):174.1(M+H) ⁺ .

Step 2

Under nitrogen protection and ice-water bath conditions, lithium deuterated aluminum hydride (1.50 g, 0.035 mol) was added in batches to a solution of compound 103-2 (3.91 g, 0.023 mol) in anhydrous tetrahydrofuran (50 mL). After the addition is completed, remove the cold bath, allow the reaction solution to naturally rise to room temperature, and continue stirring for 5 hours. LCMS monitored the reaction to completion. The reaction solution was placed in an ice-water bath, sodium sulfate decahydrate was slowly added to the reaction solution to quench the reaction, and ethyl acetate (100 mL) was added thereto, and the resulting mixture was stirred overnight. The reaction liquid was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 103-3 (2.81 g).

MS m/z(ESI):148.1(M+H) ⁺ .

third step

Under nitrogen protection and ice-water bath conditions, thionyl chloride (10 mL) was slowly added to a solution of compound 103-3 (2.81 g, 0.019 mol) in 1,2-dichloroethane (40 mL). After the addition was completed, the reaction solution was heated to 70°C and stirred for 5 hours. LCMS monitored the reaction to completion. After cooling, the reaction solution was concentrated under reduced pressure to obtain compound 103-4 (3.90 g).

MS m/z(ESI):166.1(M+H) ⁺ .

the fourth step

Under nitrogen protection, compound 103-4 (800mg, 4.85mmol), compound 60-3 (326mg, 2.43mmol) and potassium carbonate (1.10 g, 7.31 mmol) in acetonitrile (10 mL) was heated to 75°C and stirred for 12 hours. LCMS monitored the reaction to completion. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (dichloromethane:methanol=1:0-10:1) to obtain compound 103-5 (360 mg, yield: 56%).

MS m/z(ESI):264.2(M+H) ⁺ .

the fifth step

To a solvent of compound 103-5 (360 mg, 1.37 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added NBS (244 mg, 1.37 mmol) under nitrogen protection and -40°C. After the addition was completed, the reaction solution was continued to stir for 1 hour under these conditions. LCMS monitored the reaction to completion. Pour the reaction solution into ice water (10 mL), extract with ethyl acetate (10 mL × 3), combine the organic phases, wash with saturated brine (20 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain crude product . The crude product was separated and purified through silica gel column (petroleum ether: ethyl acetate = 1:0-0:1) to obtain compound 103-6 (340 mg, yield: 73%).

MS m/z(ESI):342.1(M+H) ⁺ .

Step 6

Under nitrogen protection, compound 103-6 (340 mg, 1.01 mmol), compound 14-1 (557 mg, 1.51 mmol), potassium carbonate (414 mg, 3.01 mmol) and 1,1'-bis(diphenylphosphino)bis A reaction mixture of palladium ferrocene dichloride (82 mg, 0.11 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was heated to 80°C and stirred for 12 hours. LCMS monitored the reaction to completion. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column (dichloromethane:methanol=1:0-10:1) and reverse preparative column to obtain compound 103 (171 mg, yield: 34%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.19-8.07(m,3H),7.68-7.51(m,2H),7.31-7.10(m,3H),7.31(s,2H),6.64(t,J ＝72.0Hz,1H),4.84-4.69(m,1H),4.11-3.95(m,2H),3.29(s,3H),3.10-2.63(m,6H),2.12-1.97(m,2H), 1.27-0.98(m,2H).

MS m/z(ESI):507.2(M+H) ⁺ .

Example 80 Synthesis of Compound 104

first step

Under nitrogen protection, a solution of compound 104-1 (5.00g, 0.057mol), methyl 2-bromoacetate (13.11g, 0.086mol), and potassium carbonate (23.50g, 0.17mol) in acetonitrile (50mL) was placed at room temperature. Stir for 12 hours. LCMS monitored the reaction to completion. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (petroleum ether: ethyl acetate = 1:0-0:1) to obtain compound 104-2 (5.91g, yield: 65%).

MS m/z(ESI):160.1(M+H) ⁺ .

Step 2

Under nitrogen protection and ice-water bath conditions, lithium aluminum deuterated hydride (2.40 g, 0.056 mol) was slowly added to a solution of compound 104-2 (5.91 g, 0.037 mol) in anhydrous tetrahydrofuran (50 mL). After the addition is completed, remove the cold bath, allow the reaction solution to naturally rise to room temperature, and continue stirring for 5 hours. LCMS monitored the reaction to completion. The reaction solution was placed in an ice-water bath, sodium sulfate decahydrate was slowly added to quench the reaction, ethyl acetate (100 mL) was added, and the resulting reaction solution was continued to stir at room temperature overnight. The reaction liquid was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 104-3 (5.20 g).

MS m/z(ESI):134.1(M+H) ⁺ .

third step

Under nitrogen protection and ice-water bath conditions, thionyl dichloride (15 mL) was slowly added to a solution of compound 104-3 (5.20 g, 0.039 mol) in 1,2-dichloroethane (70 mL). After the addition is complete, remove the cold bath, heat the reaction solution to 70°C and continue stirring for 5 hours. LCMS monitored the reaction to completion. After cooling, the reaction solution was concentrated under reduced pressure to obtain compound 104-4 (6.10 g).

MS m/z(ESI):152.1(M+H) ⁺ .

the fourth step

Under nitrogen protection, a solution of compound 104-4 (1.2g, 7.95mmol), compound 60-3 (533mg, 3.98mmol) and potassium carbonate (1.65g, 11.9mmol) in acetonitrile (6mL) was heated to 75°C and continued. Stir for 12 hours. LCMS monitored the reaction to completion. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (dichloromethane: methanol = 1:0-10:1) to obtain compound 104-5 (650 mg, yield: 66%).

MS m/z(ESI):250.2(M+H) ⁺ .

the fifth step

To a solution of compound 104-5 (650 mg, 2.61 mmol) in anhydrous DMF (10 mL) was added NBS (465 mg, 2.61 mmol) under nitrogen protection and -40°C. After the addition was completed, the reaction solution was continued to stir for 1 hour under this condition. LCMS monitored the reaction to completion. Pour the reaction solution into ice water (10 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated brine (20 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain crude product . The crude product was separated and purified through a silica gel column (petroleum ether: ethyl acetate = 1:0-0:1) to obtain compound 104-6 (535 mg, yield: 63%).

MS m/z(ESI):328.1(M+H) ⁺ .

Step 6

Under nitrogen protection, compound 104-6 (535 mg, 1.64 mmol), compound 14-1 (913 mg, 2.46 mmol), potassium carbonate (679 mg, 4.92 mmol) and 1,1'-bis(diphenylphosphino)bis A reaction mixture of palladium ferrocene dichloride (134 mg, 0.164 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was heated to 80°C and stirred for 12 hours. LCMS monitored the reaction to completion. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column (dichloromethane: methanol = 1:0-10:1) and reverse preparative column to obtain compound 104 (458 mg, yield: 57%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.20 (d, J＝8.0Hz, 1H), 8.12-8.09 (m, 2H), 7.68 (d, J＝8.0Hz, 1H), 7.53 (d, J＝ 8.4Hz,1H),7.32(brs,2H),7.11(d,J＝8.0Hz,1H),6.63(t,J＝72.0Hz,1H),4.86-4.83(m,0.5H),4.71-4.67 (m,0.5H),4.12(brs,1H),3.75(t,J＝4.8Hz,4H),3.11-3.08(m,1H),2.84(brs,1H),2.59(t,J＝4.8Hz ,4H),1.30-1.20(m,1H),1.07-0.97(m,1H).

MS m/z(ESI):493.2(M+H) ⁺ .

Example 81 Synthesis of Compound 108

first step

Under nitrogen protection and 0°C, triethylamine (1.76g, 17.31mmol) and compound 108-1 (1.08g) were added dropwise to a solution of compound 104-1 (500mg, 5.75mmol) in dichloromethane (5mL). ,6.90mmol). After the addition is completed, remove the cold bath, allow the reaction solution to naturally rise to room temperature, and continue stirring for 2 hours. The reaction is over. Pour the reaction solution into ice water (10 mL), extract with ethyl acetate (10 mL × 3), and combine the organic phase, washed with saturated brine (15 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 108-2 (800 mg).

MS m/z(ESI):208.1(M+H) ⁺ .

Step 2

Under nitrogen protection, a solution of compound 108-2 (800 mg, 3.86 mmol), compound 60-3 (259 mg, 1.93 mmol) and potassium carbonate (800 mg, 5.79 mmol) in acetonitrile (5 mL) was heated to 75°C and stirred overnight. The reaction is over. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (dichloromethane:methanol=1:0-10:1) to obtain compound 108-3 (145 mg, yield: 29%).

MS m/z(ESI):262.1(M+H) ⁺ .

third step

Under nitrogen protection, NBS (100 mg, 0.56 mmol) was added in portions to a solution of compound 108-3 (145 mg, 0.56 mmol) in anhydrous DMF (5 mL). After the addition was completed, the reaction solution was placed at room temperature and stirred for 2 hours. The reaction is over. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated brine (15 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified through a silica gel column (petroleum ether: ethyl acetate = 1:0-0:1) to obtain compound 108-4 (80 mg, yield: 42%).

MS m/z(ESI):340.1(M+H) ⁺ .

the fourth step

Under nitrogen protection, compound 108-4 (80 mg, 0.24 mmol), compound 14-1 (131 mg, 0.35 mmol), potassium carbonate (98 mg, 0.71 mmol) and 1,1'-bis(diphenylphosphino)bis Ferrocene palladium dichloride (20 mg, 0.024 mmol) was added to a mixed solution of 1,4-dioxane (5 mL) and water (0.5 mL), heated to 90°C and stirred overnight. The reaction is over. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column (dichloromethane:methanol=1:0-10:1) and reverse preparative column to obtain compound 108 (19 mg, yield: 16%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.23–8.20(m,2H),8.11(s,1H),7.72(d,J＝9.6Hz,1H),7.54(dd,J＝8.0,1.6Hz, 1H),7.32–7.30(m,2H),7.17(dd,J＝9.6,2.0Hz,1H),6.63(t,J＝72.0Hz,1H),4.87–4.84(m,0.5H),4.74( s,2H),4.71–4.68(m,0.5H),3.74–3.66(m,6H),3.58–3.56(m,2H),3.13–3.07(m,1H),1.29–1.21(m,1H) ,1.08–0.97(m,1H).

MS m/z(ESI):505.2(M+H) ⁺ .

Example 82 Synthesis of Compound 109

first step

Under nitrogen protection, a solution of compound 86-2 (300 mg, 1.17 mmol), compound 109-1 (178 mg, 1.76 mmol) and potassium carbonate (485 mg, 3.51 mmol) in acetonitrile (5 mL) was heated to 75°C and stirred overnight. The reaction is over. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through a silica gel column (dichloromethane:methanol=1:0-10:1) to obtain compound 109-2 (100 mg, yield: 33%).

MS m/z(ESI):262.1(M+H) ⁺ .

Step 2

Under nitrogen protection, NBS (68 mg, 0.38 mmol) was added in portions to a solution of compound 109-2 (100 mg, 0.38 mmol) in anhydrous DMF (5 mL). After the addition was completed, the reaction solution was brought to room temperature and stirred for 2 hours. The reaction is over. Pour the reaction solution into water (10mL), extract with ethyl acetate (10mL×3), combine the organic phases, wash with saturated brine (15mL×1), dry over anhydrous sodium sulfate, filter, and reduce the filtrate to Concentrate under pressure to obtain crude product. The crude product was separated and purified through a silica gel column (petroleum ether: ethyl acetate = 1:0-0:1) to obtain compound 109-3 (80 mg, yield: 61%).

MS m/z(ESI):340.1(M+H) ⁺ .

third step

Under nitrogen protection, compound 109-3 (80 mg, 0.24 mmol), compound 14-1 (158 mg, 0.43 mmol), potassium carbonate (98 mg, 0.71 mmol) and 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (20 mg, 0.024 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was heated to 90°C and stirred overnight. The reaction is over. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column (dichloromethane:methanol=1:0-10:1) and reverse preparative column to obtain compound 109 (43 mg, yield: 36%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.21 (d, J＝8.0Hz, 1H), 8.13–8.10 (m, 2H), 7.69 (d, J＝9.6Hz, 1H), 7.54 (d, J＝ 8.0Hz,1H),7.32–7.31(m,2H),7.07(dd,J＝9.6,2.0Hz,1H),6.64(t,J＝72.0Hz,1H),4.87-4.68(m,1H), 4.24–4.21(m,4H),3.93–3.84(m,4H),3.64–3.62(m,2H),3.12–3.08(m,1H),1.31–1.21(m,1H),1.07–0.97(m ,1H).

MS m/z(ESI):505.2(M+H) ⁺ .

Example 83 Synthesis of Compound 119

first step

Under nitrogen protection and 0°C, triethylamine (13.64g, 135.00mmol) and DMAP (550mg, 4.50 mol) and TBSCl (10.17g, 67.50mmol). After the addition is complete, remove the cold bath, allow the reaction solution to naturally rise to room temperature, and continue stirring overnight. The reaction is over. Pour the reaction solution into water (200 mL), extract with dichloromethane (100 mL × 2), combine the organic phases, wash with saturated brine (200 mL × 1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound 119 -2(8.01g).

MS m/z(ESI):227.1(M+H) ⁺ .

Step 2

To a solution of compound 119-2 (8.01 g, 35.40 mmol) in anhydrous tetrahydrofuran (100 mL) under nitrogen protection and 0°C, sodium hydride (2.83 g, 70.75 mmol, 60%) was slowly added in batches. After the addition was completed, the reaction solution was stirred at 0°C for 30 minutes, and then methyl iodide (7.50g, 53.10mmol) was slowly added dropwise to the reaction solution. After the dropwise addition was completed, the cold bath was removed, and the reaction solution was naturally raised to room temperature and stirred overnight. The reaction is over. Slowly pour the reaction solution into ice water (100 mL), extract with ethyl acetate (200 mL × 3), combine the organic phases, wash with saturated brine (300 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain Crude. The crude product was separated and purified through a silica gel column (petroleum ether: ethyl acetate = 1:0-0:1) to obtain compound 119-3 (2.80 g, two-step total yield: 26%).

MS m/z(ESI):241.1(M+H) ⁺ .

third step

To a solution of compound 119-3 (2.80 g, 11.65 mmol) in methanol (30 mL) at 0°C, hydrogen chloride/1,4-dioxane (10 mL, 4M) was slowly added dropwise. After the dropwise addition is completed, remove the cold bath, allow the reaction solution to naturally rise to room temperature, and continue stirring for 1 hour. The reaction is over. The reaction solution was directly concentrated under reduced pressure to obtain compound 119-4 (2.60 g).

MS m/z(ESI):127.1(M+H) ⁺ .

the fourth step

Under nitrogen protection and 0°C, SOCl ₂ (10 mL) was slowly added dropwise to a solution of compound 119-4 (2.60 g, 20.61 mmol) in 1,2-dichloroethane (30 mL). After the dropwise addition is completed, remove the cold bath, heat the reaction solution to 70°C and continue stirring for 5 hours. The reaction is over. After cooling, the reaction solution was directly concentrated under reduced pressure to obtain compound 119-5 (2.40g).

MS m/z(ESI):145.1(M+H) ⁺ .

the fifth step

Under nitrogen protection, a solution of compound 119-5 (500 mg, 3.47 mmol), compound 60-3 (233 mg, 1.74 mmol) and potassium carbonate (720 mg, 5.22 mmol) in acetonitrile (5 mL) was heated to 75°C and stirred overnight. The reaction is over. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through a silica gel column (dichloromethane: methanol = 1:0-10:1) to obtain compound 119-6 (200 mg, yield: 47%).

MS m/z(ESI):243.1(M+H) ⁺ .

Step 6

Under nitrogen protection, NBS (148 mg, 0.83 mmol) was added in portions to a solution of compound 119-6 (200 mg, 0.83 mmol) in anhydrous DMF (5 mL). After the addition was completed, the reaction solution was placed at room temperature and stirred for 2 hours. The reaction is over. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified through silica gel column (petroleum ether: ethyl acetate = 1:0-0:1) to obtain compound 119-7 (230 mg, yield: 86%).

MS m/z(ESI):321.1(M+H) ⁺ .

Step 7

Under nitrogen protection, compound 119-7 (230 mg, 0.72 mmol), compound 14-1 (482 mg, 1.31 mmol), potassium carbonate (304 mg, 2.21 mmol) and 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (53 mg, 0.072 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was heated to 90°C and stirred overnight. The reaction is over. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column (dichloromethane:methanol=1:0-10:1) and reverse preparative column to obtain compound 119 (150 mg, yield: 43%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.21 (d, J＝8.0Hz, 1H), 8.11–8.07 (m, 2H), 7.70 (d, J＝9.6Hz, 1H), 7.54 (dd, J＝ 8.0,1.6Hz,1H),7.43(s,1H),7.32(brs,3H),7.09(d,J＝9.6Hz,1H),6.63(t,J＝72.0Hz,1H),4.87–4.67( m,1H),4.11(t,J＝8.0Hz,2H),3.87(s,3H),3.13–3.07(m,1H),3.00(t,J＝8.0Hz,2H),1.30–1.21(m ,1H),1.08–0.97(m,1H).

MS m/z(ESI):486.2(M+H) ⁺ .

Example 84 Synthesis of Compound 122

first step

Under nitrogen protection and 0°C, a solution of compound 86-3 (500 mg, 4.95 mmol) in anhydrous dichloromethane (10 mL) was added successively. Triethylamine (1.52g, 14.90mmol) and compound 108-1 (927mg, 5.94mmol) were added. After the addition is completed, remove the cold bath, allow the reaction solution to naturally rise to room temperature, and continue stirring for 3 hours. The reaction is over. Pour the reaction solution into ice water (20 mL), extract with ethyl acetate (30 mL × 3), combine the organic phases, wash with saturated brine (30 mL × 1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the compound 122-1(660mg).

MS m/z(ESI):222.1(M+H) ⁺ .

Step 2

Under nitrogen protection, a solution of compound 122-1 (300 mg, 2.24 mmol), compound 60-3 (660 mg, 2.99 mmol) and potassium carbonate (927 mg, 6.72 mmol) in acetonitrile (10 mL) was heated to 75°C and stirred overnight. The reaction is over. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through a silica gel column (dichloromethane: methanol = 1:0-10:1) to obtain compound 122-2 (365 mg, two-step yield: 27%).

MS m/z(ESI):276.1(M+H) ⁺ .

third step

Under nitrogen protection and 0°C, NBS (237 mg, 1.33 mmol) was added in portions to a solution of compound 122-2 (365 mg, 1.33 mmol) in anhydrous DMF (5 mL). After the addition is completed, remove the cold bath, allow the reaction solution to naturally rise to room temperature, and continue stirring for 2 hours. The reaction is over. The reaction solution was poured into water (30 mL), extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine (30 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified through silica gel column (petroleum ether: ethyl acetate = 1:0-0:1) to obtain compound 122-3 (350 mg, yield: 74%).

MS m/z(ESI):354.1(M+H) ⁺ .

the fourth step

Under nitrogen protection, compound 122-3 (80 mg, 0.99 mmol), compound 14-1 (660 mg, 1.78 mmol), potassium carbonate (410 mg, 2.97 mmol) and 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (81 mg, 0.099 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was heated to 90°C and stirred overnight. The reaction is over. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column (dichloromethane:methanol=1:0-10:1) and reverse preparative column to obtain compound 122 (170 mg, yield: 33%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.18–8.10(m,3H),7.70(d,J＝9.6Hz,1H),7.50(d,J＝8.4Hz,1H),7.33–7.30(m, 2H),7.16(dd,J＝9.6,4.0Hz,1H),6.65(t,J＝72.0Hz,1H),4.86–4.62(m,3H),4.06–3.96(m,1H),3.79–3.48 (m,4H),3.35–3.32(m,3H),3.11–3.05(m,1H),2.08–1.86(m,2H),1.29–1.19(m,1H),1.07–0.97(m,1H) .

MS m/z(ESI):519.2(M+H) ⁺ .

Example 85 Synthesis of Compound 123

first step

To a solution of compound 123-1 (2.01 g, 8.55 mmol) in ethanol (20 mL) at room temperature, concentrated sulfuric acid (3 mL) was slowly added dropwise. The resulting reaction solution was heated to 80°C and stirred overnight. The reaction is over. Cool, slowly pour the reaction solution into ice water (50 mL), extract with ethyl acetate (50 mL × 3), combine the organic phases, and wash with saturated sodium bicarbonate (200 mL × 1) and saturated brine (200 mL × 1). , anhydrous sulfuric acid It was dried over sodium, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 123-2 (1.31 g).

MS m/z(ESI):263.1(M+H) ⁺ .

Step 2

To a mixed solution of compound 123-2 (1.31 g, 4.98 mmol) in acetonitrile (20 mL) and water (20 mL), potassium hydroxide (2.80 g, 5.00 mmol) was slowly added at 0°C. After the addition is complete, remove the cold bath, allow the reaction solution to naturally rise to room temperature, and continue stirring for 1 hour. Then diethyl (bromodifluoromethyl)phosphonate (1.98g, 7.44mmol) was slowly added to the reaction solution at 0°C. After the addition is completed, remove the cold bath, allow the reaction solution to naturally rise to room temperature, and continue stirring for 4 hours. The reaction is over. Pour the reaction solution into ice water (100 mL), extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated brine (100 mL × 1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain crude product . The crude product was separated and purified through a silica gel column (petroleum ether: ethyl acetate = 1:0-0:1) to obtain compound 123-3 (1.20 g, two-step yield: 45%).

MS m/z(ESI):313.1(M+H) ⁺ .

third step

To a solution of compound 123-3 (1.20 g, 3.85 mmol) in methanol (10 mL), aqueous sodium hydroxide solution (3 mL, 6.00 mmol, 2N) was added dropwise at 0°C. After the dropwise addition is completed, remove the cold bath, allow the reaction solution to naturally rise to room temperature, and continue stirring for 2 hours. The reaction is over. Pour the reaction solution into ice water (30 mL), adjust pH = 4 to 5 with dilute hydrochloric acid (1N), extract with ethyl acetate (50 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and depressurize the filtrate Concentration gave compound 123-4 (1.01 g).

MS m/z(ESI):285.1(M+H) ⁺ .

the fourth step

Under nitrogen protection and 0°C, N,N-diisopropylethylamine (1.79 mL, 10.56 mmol) was added to compound 123-4 (1.01 g, 3.54 mmol) in dichloromethane (15 mL). 7-1 (1.05g, 4.23mmol), HATU (2.00g, 5.28mmol). After the addition is completed, remove the cold bath, allow the reaction solution to naturally rise to room temperature and stir overnight. The reaction is over. Pour the reaction solution into ice water (50 mL), extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated brine (50 mL × 1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain crude product . The crude product was separated and purified through a silica gel column (petroleum ether: ethyl acetate = 1:0-0:1) to obtain compound 123-5 (860 mg, yield: 72%).

MS m/z(ESI):342.1(M+H) ⁺ .

the fifth step

Under nitrogen protection, compound 19-1 (300 mg, 0.92 mmol), pinacolborane (236 mg, 1.84 mmol), triethylamine (282 mg, 2.76 mmol) and 1,1'-bis(diphenylphosphine) ) A solution of ferrocene palladium dichloride (75 mg, 0.092 mmol) in anhydrous 1,4-dioxane (5 mL) was heated to 130°C and stirred for 2 hours. The reaction is over. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through a silica gel column (petroleum ether: ethyl acetate = 1:0-0:1) to obtain compound 123-6 (320 mg, yield: 93%).

MS m/z(ESI):374.1(M+H) ⁺ .

Step 6

Under nitrogen protection, compound 123-5 (195 mg, 0.57 mmol), compound 123-6 (320 mg, 0.86 mmol), potassium carbonate (237 mg, 1.72 mmol) and 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (47 mg, 0.057 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was heated to 90°C and stirred overnight. The reaction is over. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column (dichloromethane:methanol=1:0-10:1) and reverse preparative column to obtain compound 123 (169 mg, yield: 58%).

¹ H NMR (400MHz, CD ₃ OD) δ8.32 (d, J = 2.0 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 7.73 (dd, J = 9.6, 2.0 Hz, 1H), 7.64(dd,J＝8.0,7.6Hz,1H),7.52(dd,J＝8.4,1.6Hz,1H),7.22(dd,J＝9.6,2.0Hz,1H),6.90(t,J＝72.0Hz ,1H),4.85–4.66(m,1H),4.22(t,J＝8.0Hz,2H),3.75–3.72(m,4H),2.92–2.86(m,3H),2.65–2.62(m,4H ),1.27–1.17(m,1H),1.13–1.03(m,1H).

MS m/z(ESI):509.2(M+H) ⁺ .

Example 86 Synthesis of Compound 124

first step

To a solution of compound 124-1 (4.01 g, 16.10 mmol) in ethanol (40 mL) at 0°C, concentrated sulfuric acid (8 mL) was slowly added dropwise. After the addition is complete, remove the cold bath, heat the reaction solution to 80°C and stir overnight. The reaction is over. Cool, pour the reaction solution into ice water (50mL), extract with ethyl acetate (50mL×3), combine the organic phases, and wash with saturated sodium bicarbonate (100mL×1) and saturated brine (100mL×1) in sequence. Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound 124-2 (3.60 g).

MS m/z(ESI):277.1(M+H) ⁺ .

Step 2

Under nitrogen protection and -65°C, a solution of BCl ₃ in dichloromethane (14.30 mmol, 14.3 mL, 1M). After the dropwise addition was completed, the cold bath was removed, and the reaction solution was naturally raised to room temperature and stirred for 2 hours. The reaction is over. Pour the reaction solution into ice water (100 mL), extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated brine (100 mL × 1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain crude product . The crude product was separated and purified through a silica gel column (petroleum ether: ethyl acetate = 1:0-0:1) to obtain compound 124-3 (2.60g, two-step yield: 62%).

MS m/z(ESI):263.1(M+H) ⁺ .

third step

To a mixed solution of compound 124-3 (2.60 g, 9.88 mmol) in acetonitrile (30 mL) and water (30 mL), potassium hydroxide (5.60 g, 99.89 mmol) was slowly added at 0°C. After the addition is complete, remove the cold bath, allow the reaction solution to naturally rise to room temperature, and continue stirring for 1 hour. The reaction liquid was cooled to 0°C, and diethyl (bromodifluoromethyl)phosphonate (3.96 g, 14.88 mmol) was slowly added thereto. After the addition is completed, remove the cold bath, allow the reaction solution to naturally rise to room temperature, and continue stirring for 4 hours. The reaction is over. Pour the reaction solution into ice water (100 mL), extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated brine (100 mL × 1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain crude product . The crude product was separated and purified through a silica gel column (petroleum ether: ethyl acetate = 1:0-0:1) to obtain compound 124-4 (2.80 g, yield: 90%).

MS m/z(ESI):313.1(M+H) ⁺ .

the fourth step

To a solution of compound 124-4 (2.80 g, 8.94 mmol) in methanol (15 mL), sodium hydroxide solution (10 mL, 2N) was added dropwise at 0°C. After the addition was completed, the cold bath was removed, the reaction solution was slowly raised to room temperature and stirred for 2 hours. The reaction is over. Pour the reaction solution into ice water (50 mL), adjust pH = 4 to 5 with 1 mol/L dilute hydrochloric acid, extract with ethyl acetate (50 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and reduce the filtrate to Concentrate under pressure to obtain compound 124-5 (2.60g).

MS m/z(ESI):285.1(M+H) ⁺ .

the fifth step

Under nitrogen protection and 0°C, N,N-diisopropylethylamine (4.53 mL, 27.45 mmol) was added successively to a solution of compound 124-5 (2.60 g, 9.12 mmol) in anhydrous dichloromethane (30 mL). ), compound 7-1 (2.74g, 10.98mmol) and HATU (5.22g, 13.73mmol). After the addition is complete, remove the cold bath, allow the reaction solution to naturally rise to room temperature, and continue stirring overnight. The reaction is over. Pour the reaction solution into ice water (100 mL), extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated brine (50 mL × 1), dry over anhydrous sodium sulfate, filter, and obtain the filtrate Concentrate under reduced pressure to obtain crude product. The crude product was separated and purified through a silica gel column (petroleum ether: ethyl acetate = 1:0-0:1) to obtain compound 124-6 (2.60g, yield: 83%).

MS m/z(ESI):342.1(M+H) ⁺ .

Step 6

Under nitrogen protection, compound 124-6 (500 mg, 1.47 mmol), pinacol diborate (485 mg, 1.91 mmol), potassium acetate (433 mg, 4.41 mmol) and 1,1'-bis(diphenylphosphine) ) A solution of ferrocene palladium dichloride (121 mg, 0.15 mmol) in anhydrous 1,4-dioxane (5 mL) was heated to 130°C and stirred for 2 hours. The reaction is over. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through a silica gel column (petroleum ether: ethyl acetate = 1:0-0:1) to obtain compound 124-7 (400 mg, yield: 70%).

MS m/z(ESI):390.1(M+H) ⁺ .

Step 7

Under nitrogen protection, compound 124-7 (400 mg, 1.03 mmol), compound 19-1 (280 mg, 0.86 mmol), potassium carbonate (356 mg, 2.58 mmol) and 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (70 mg, 0.086 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was heated to 90°C and stirred overnight. The reaction is over. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column (dichloromethane:methanol=1:0-10:1) and reverse preparative column to obtain compound 124 (116 mg, yield: 27%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.20–7.96(m,3H),7.59–7.13(m,4H),6.78–6.39(m,1H),4.86–4.70(m,1H),4.15(brs ,2H),3.82–3.76(m,4H),3.10–2.61(m,7H),1.27(brs,1H),1.06–1.00(m,1H).

MS m/z(ESI):509.2(M+H) ⁺ .

Example 87 Synthesis of Compound 125

first step

Under nitrogen protection and 0°C, NBS (187 mg, 1.05 mmol) was added in portions to a solution of compound 102-2 (260 mg, 1.05 mmol) in anhydrous DMF (5 mL). After the addition is completed, remove the cold bath, allow the reaction solution to naturally rise to room temperature and stir overnight. The reaction is over. Pour the reaction solution into ice water (20 mL), extract with ethyl acetate (10 mL × 3), combine the organic phases, wash with saturated brine (15 mL × 1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain crude product . The crude product was separated and purified through a silica gel column (petroleum ether: ethyl acetate = 1:0-0:1) to obtain compound 125-1 (255 mg, yield: 75%).

MS m/z(ESI):326.1(M+H) ⁺ .

Step 2

Under nitrogen protection, compound 125-1 (255 mg, 0.785 mmol), compound 14-1 (438 mg, 1.18 mmol), potassium carbonate (326 mg, 2.36 mmol) and 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (57 mg, 0.0785 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was heated to 90°C and stirred overnight. The reaction is over. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column (dichloromethane:methanol=1:0-10:1) and reverse preparative column to obtain compound 125 (201 mg, yield: 52%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.22(d,J＝8.0Hz,1H),8.13(d,J＝2.0Hz,1H),8.10(s,1H),7.69(d,J＝8.0Hz ,1H),7.54(dd,J＝8.0,1.6Hz,1H),7.33–7.31(m,2H),7.13(dd,J＝8.0,2.0Hz,1H),6.63(t,J＝72.0Hz, 1H),4.87–4.68(m,1H),4.43–4.40(m,1H),4.15(t,J＝5.6Hz,2H),3.12–2.99(m,5H),2.86–2.75(m,2H) , 2.53–2.51(m,1H),2.27–2.22(m,1H),1.85–1.78(m,1H),1.29–1.23(m,1H),1.08–0.99(m,1H).

MS m/z(ESI):491.2(M+H) ⁺ .

Example 88 Synthesis of Compound 126

first step

Under nitrogen protection, a solution of compound 86-2 (400 mg, 1.56 mmol), compound 126-1 (236 mg, 2.34 mmol) and potassium carbonate (646 mg, 4.68 mmol) in anhydrous acetonitrile (5 mL) was heated to 75°C and stirred. Reaction was allowed to take place overnight. The reaction is over. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through a silica gel column (dichloromethane: methanol = 1:0-10:1) to obtain compound 126-2 (300 mg, yield: 74%).

MS m/z(ESI):262.1(M+H) ⁺ .

Step 2

Under nitrogen protection and 0°C, NBS (205 mg, 1.15 mmol) was added in portions to a solution of compound 126-2 (300 mg, 1.15 mmol) in anhydrous DMF (5 mL). After the addition is complete, remove the cold bath, allow the reaction solution to naturally rise to room temperature, and continue stirring overnight. The reaction is over. Pour the reaction solution into ice water (20 mL), extract with ethyl acetate (10 mL × 3), combine the organic phases, wash with saturated brine (15 mL × 1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain crude product . The crude product was separated and purified through a silica gel column (petroleum ether: ethyl acetate = 1:0-0:1) to obtain compound 126-3 (200 mg, yield: 51%).

MS m/z(ESI):340.1(M+H) ⁺ .

third step

Under nitrogen protection, compound 126-3 (200 mg, 0.59 mmol), compound 14-1 (329 mg, 0.89 mmol), potassium carbonate (244 mg, 1.77 mmol) and 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (43 mg, 0.059 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was heated to 90°C and stirred overnight. The reaction is over. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column (dichloromethane:methanol=1:0-10:1) and reverse preparative column to obtain compound 126 (176 mg, yield: 59%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.21 (d, J＝8.0Hz, 1H), 8.12–8.09 (m, 2H), 7.68 (d, J＝8.0Hz, 1H), 7.54 (dd, J＝ 8.0,1.6Hz,1H),7.33–7.31(m,2H),7.11(dd,J＝8.0,2.0Hz,1H),6.63(t,J＝72.0Hz,1H),4.87–4.67(m,1H ),4.14–4.11(m,2H),3.15–3.08(m,2H),2.99–2.96(m,2H),2.90–2.88(m,1H),2.53–2.41(m,2H),1.95–1.91 (m,2H),1.39(s,3H),1.30–1.21(m,1H),1.08–0.99(m,1H).

MS m/z(ESI):505.2(M+H) ⁺ .

Example 89 Synthesis of Compound 128

first step

Under nitrogen protection and 0°C, compound 128-1 (5.00g, 0.033mol) was slowly added to a solution of lithium aluminum tetrahydrogen (3.80g, 0.10mol) in anhydrous tetrahydrofuran (50mL). After the addition is completed, remove the cold bath, allow the reaction solution to naturally rise to room temperature, and continue stirring for 5 hours. The reaction is over. The reaction solution was cooled to 0°C, sodium sulfate decahydrate (41.20 g, 0.10 mol) was slowly added to the reaction solution to quench the reaction, and then ethyl acetate (200 mL) was added and stirring continued overnight. The reaction liquid was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 128-2 (3.50 g).

MS m/z(ESI):113.1(M+H) ⁺ .

Step 2

To a solution of compound 128-2 (3.50 g, 0.031 mol) in anhydrous dichloromethane (30 mL) under nitrogen protection and 0°C, thionyl dichloride (10 mL) was slowly added. After the addition is completed, remove the cold bath, allow the reaction solution to naturally rise to room temperature, and continue stirring for 3 hours. The reaction is over. The reaction liquid was concentrated under reduced pressure to obtain compound 128-3 (3.10 g).

MS m/z(ESI):131.1(M+H) ⁺ .

third step

Under nitrogen protection, a solution of compound 128-3 (500 mg, 3.85 mmol), compound 60-3 (260 mg, 1.93 mmol) and potassium carbonate (800 mg, 5.80 mmol) in acetonitrile (5 mL) was heated to 75°C and stirred overnight. The reaction is over. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (dichloromethane:methanol=1:0-10:1) to obtain compound 128-4 (90 mg, yield: 20%).

MS m/z(ESI):229.2(M+H) ⁺ .

the fourth step

Under nitrogen protection and 0°C, NBS (70 mg, 0.39 mmol) was added in portions to a solution of compound 128-4 (90 mg, 0.39 mmol) in anhydrous DMF (5 mL). After the addition is completed, remove the cold bath, allow the reaction solution to naturally rise to room temperature, and continue stirring for 2 hours. The reaction is over. Pour the reaction solution into ice water (20 mL), extract with ethyl acetate (10 mL × 3), combine the organic phases, wash with saturated brine (15 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain crude product . The crude product was separated and purified through a silica gel column (petroleum ether: ethyl acetate = 1:0-0:1) to obtain compound 128-5 (105 mg, yield: 87%).

MS m/z(ESI):307.1(M+H) ⁺ .

the fifth step

Under nitrogen protection, compound 128-5 (105 mg, 0.34 mmol), compound 14-1 (191 mg, 0.52 mmol), potassium carbonate (142 mg, 1.03 mmol) and 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (28 mg, 0.034 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was heated to 80°C and stirred overnight. The reaction is over. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column (dichloromethane:methanol=1:0-10:1) and reverse preparative column to obtain compound 128 (97 mg, yield: 60%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.25–8.20 (m, 2H), 8.13 (s, 1H), 7.72 (d, J = 8.0Hz, 1H), 7.61–7.52 (m, 3H), 7.35–7.34(m,2H),7.13(dd,J＝8.0,2.0Hz,1H),6.66(t,J＝72.0Hz,1H),5.01(s,2H),4.90–4.70(m,1H) ,3.95(s,3H),3.16–3.10(m,1H),1.33–1.24(m,1H),1.10–1.00(m,1H).

MS m/z(ESI):472.2(M+H) ⁺ .

Example 90 Synthesis of Compound 130

first step

Under nitrogen protection, compound 130-2 (5.40g, 22.57mmol) was added dropwise to a solution of compound 130-1 (1.50g, 15.13mmol) and cesium carbonate (14.70g, 45.12mmol) in acetonitrile (50mL). After the addition was completed, the reaction solution was raised to 80°C and stirred overnight. The reaction is over. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through a silica gel column (petroleum ether: ethyl acetate = 1:0-0:1) to obtain compound 130-3 (700 mg, yield: 18%).

MS m/z(ESI):258.1(M+H) ⁺ .

Step 2

To a solution of compound 130-3 (700 mg, 2.72 mmol) in methanol (5 mL), a hydrogen chloride/1,4-dioxane (5 mL, 4 M) solution was slowly added dropwise at 0°C. After the dropwise addition was completed, the cold bath was removed, and the reaction solution was naturally raised to room temperature and stirred for 1 hour. The reaction is over. The reaction solution was concentrated under reduced pressure to obtain compound 130-4 (350 mg).

MS m/z(ESI):144.1(M+H) ⁺ .

third step

To a solution of compound 130-4 (350 mg, 2.45 mmol) in 1,2-dichloroethane (5 mL) under nitrogen protection and 0°C, thionyl dichloride (2 mL) was slowly added. After the addition is completed, remove the cold bath, naturally raise the reaction solution to 70°C and continue stirring for 5 hours. The reaction is over. After cooling, the reaction solution was concentrated under reduced pressure to obtain compound 130-5 (400 mg).

MS m/z(ESI):162.1(M+H) ⁺ .

the fourth step

Under nitrogen protection, a solution of compound 130-5 (400 mg, 2.49 mmol), compound 60-3 (222 mg, 1.66 mmol) and potassium carbonate (687 mg, 4.98 mmol) in acetonitrile (5 mL) was heated to 75°C and stirred overnight. The reaction is over. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through silica gel column (dichloromethane:methanol=1:0-10:1) to obtain compound 130-6 (144 mg, yield: 33%).

MS m/z(ESI):260.1(M+H) ⁺ .

the fifth step

Under nitrogen protection and 0°C, NBS (100 mg, 0.56 mmol) was added in portions to a solution of compound 130-6 (144 mg, 0.56 mmol) in anhydrous DMF (5 mL). After the addition is completed, remove the cold bath, allow the reaction solution to naturally rise to room temperature, and continue stirring for 2 hours. The reaction is over. Pour the reaction solution into ice water (20 mL), extract with ethyl acetate (10 mL × 3), combine the organic phases, and wash with saturated brine (20 mL × 2). Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified through a silica gel column (petroleum ether: ethyl acetate = 1:0-0:1) to obtain compound 130-7 (154 mg, yield: 81%).

MS m/z(ESI):338.1(M+H) ⁺ .

Step 6

Under nitrogen protection, compound 130-7 (154 mg, 0.46 mmol), compound 14-1 (256 mg, 0.69 mmol), potassium carbonate (191 mg, 1.38 mmol) and 1,1'-bis(diphenylphosphino)bis A mixed solution of palladium ferrocene dichloride (38 mg, 0.046 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was heated to 90°C and stirred overnight. The reaction is over. Cool, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column (dichloromethane:methanol=1:0-10:1) and reverse preparative column to obtain compound 130 (81 mg, yield: 35%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.21 (d, J = 8.0Hz, 1H), 8.10 (brs, 2H), 7.69 (d, J = 8.0Hz, 1H), 7.54 (dd, J = 8.0, 1.6Hz,1H),7.32–7.30(m,2H),7.08–7.05(m,1H),6.63(t,J＝72.0Hz,1H),4.87–4.67(m,1H),4.13(t,J ＝5.2Hz,2H),3.98–3.86(m,2H),3.51–3.47(m,1H),3.12–3.08(m,1H),2.45–2.24(m,3H),1.67–1.65(m,1H) ),1.32–1.21(m,4H),1.08–0.97(m,1H).

MS m/z(ESI):503.2(M+H) ⁺ .

According to the method of the above example, the following compounds were prepared:

biological evaluation

Test Example 1 SIK2 Kinase Activity Test Experiment

Dissolve test compounds in DMSO to 10mM stock solution and store at -20°C until use. The starting concentration of the compound is 20μM, 1% DMSO, 5-fold dilution, 10 concentrations, duplicate wells; 25mM Tris pH 7.5, 5mM MgCl ₂ , 0.01% Triton X-100, 0.5mM EGTA, 2.5mM DTT as reaction The buffer is used to prepare 2.5x SIK2-AMARA mixture and 2.5x ATP working solution. The final 5μL reaction system is run in a 384-well plate (Corning, 4512), containing 0.0625ng/μL SIK2 (ThermoFisher Scientific, PV4792), 45μM AMARA (SignalCjem, A11-58), 5 μM ATP; the negative control well does not contain SIK2 protein and compounds, and the positive control well does not contain compounds. After reacting at room temperature for 2 hours, centrifuge briefly with 5 μL ADP-Glo Reagent (Promega, V912B). After incubating at room temperature for 40 minutes, add 10 μL Kinase Detection Reagent (Promega, V913B+V914B) to each well, centrifuge briefly, and incubate at room temperature for 30 minutes. Microplate reader detection (Luminescence). Use GraphPad Prism 8 software to fit the concentration-effect curve, and calculate the compound concentration with 50% inhibitory effect, that is, IC ₅₀ . The test results are shown in Table 1.

Table 1

The test results in Table 1 show that the compounds disclosed in the present invention have significant SIK2 kinase inhibitory effect.

Test Example 2 Evaluation of the Inhibitory Effect of Compounds on TNF-α Production in LPS-Stimulated Human Whole Blood

Fresh human whole blood (from healthy adult males, anticoagulated with sodium heparin) was plated in a 96-well plate (Corning, 3599) at a volume of 100 μL/well. The starting concentration of the compound to be tested was 50 μM, diluted 5 times. 8 concentrations, double wells, DMSO final concentration is 0.4%, add 25 μL/well into the 96-well culture plate; after pre-incubation at 37°C, 5% _CO2 for 30 minutes, add 25 μL LPS to each well to make it The final concentration is 100ng/mL (the medium used for dilution is RPMI-1640+10% FBS); no LPS and compounds are added to the blank control wells, and no compounds are added to the model control wells. After continuing to culture for 2 hours, centrifuge at 2000g for 5 minutes to collect the cells. Culture the supernatant and operate according to the Elisa kit (Beyotime, PI518) operation manual to detect the concentration of TNF-a. Use GraphPad Prism 8 software to fit the concentration-effect curve, and calculate the concentration at which the compound reaches 50% inhibitory effect, that is, IC ₅₀ . The test results are shown in Table 2 below.

Table 2

As can be seen from Table 2, the compounds disclosed in the present invention have significant TNF-α inhibitory effect.

Test Example 3 Evaluation of the Inhibitory Effect of Compounds on TNF-α Production by LPS-Stimulated Human PBMC Cells

Fresh human peripheral blood mononuclear cells (PBMC) (Sel Biotech) were plated in a 384-well plate (Greiner, 781074) at a quantity of 1*10 ^{^6} /mL, and 18 μL of RPMI-1640 (Gibco) containing the above cells was added to each well. #A1049101) + 10% FBS (Gibco, 10099141C); the starting concentration of the compound to be tested is 10 μM, 4 times diluted, 8 concentrations, double wells, DMSO final concentration is 0.4%, with a volume of 5 μL/well Add to the 384-well culture plate; after pre-incubation for 30 minutes at 37°C in 5% _CO2 , add 2 μL of LPS to each well to make the final concentration 100ng/mL (the medium used for dilution is RPMI-1640+10% FBS) ; No LPS and compounds were added to the blank control wells, and no compounds were added to the model control wells. After continuing to culture for 24 hours, centrifuge at 2000g for 5 minutes. Collect the cell culture supernatant and operate according to the Elisa kit (Beyotime, PI518) operation manual to detect TNF. -a concentration. Use GraphPad Prism 8 software to fit the concentration-effect curve, and calculate the concentration at which the compound reaches 50% inhibitory effect, that is, IC ₅₀ . The test results are shown in Table 3 below.

table 3

As can be seen from Table 3, the compounds disclosed in the present invention have significant TNF-α inhibitory effect.

The embodiments of the present invention have been described above. However, the present invention is not limited to the above-described embodiment. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included in the protection scope of the present invention.

Claims (15)

A compound represented by Formula I, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or prodrug thereof;
in, X and Y are independently selected from N or C, Z is N or CH; at least one of X, Y and Z is N, and at most 2 are N, and X and Y are not N or C at the same time; T is selected from N or CR ² ; When T is CR ² , R ² is selected from H, halogen, CN, OH, the following groups that are unsubstituted or optionally substituted by 1, 2 or more deuterium or halogen: C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyloxy and NHR ⁸ ; or R ² and R ⁵ can form a 5-8 membered cyclic structure with the atoms connected to each of them; J is selected from N or CR ³ ; E is selected from N or CR ⁴ ; A is selected from the following groups substituted by 1, 2 or more R ^a : C _1-6 alkyl, -O(CH ₂ ) _m R ⁶ , -S(CH ₂ ) _m R ⁶ , -S (O) _n (CH ₂ ) _m R ⁶ , -NR ⁶ R ⁷ , -NR ⁶ C(O)R ⁷ , -C(O)NR ⁶ R ⁷ , -SO ₂ NR ⁶ R ⁷ , -O(CH ₂ ) _m (CO)R ⁶ , -O(CH ₂ ) _m C(O)R ⁶ , -OCH(CH ₃ )(CH ₂ ) _m R ⁶ , -OCD ₂ (CH ₂ ) _m R ⁶ ; by 1 C _3-12 cycloalkyl substituted by 1, 2 or more R ^b ; 3-12 membered heterocyclyl substituted by 1, 2 or more R ^c ; substituted by 1, 2 or more R c C _6-14 aryl groups substituted by multiple R ^d and 5-14 membered heteroaryl groups substituted by 1, 2 or more R ^e ; R ¹ is selected from H, halogen, CN, OH, C _1-6 alkyl and C _1-6 alkoxy; R ³ and R ⁴ are the same or different, and are independently selected from H, halogen, CN, OH, C _1-6 alkyl, C _1-6 alkoxy and NHR ⁸ ; R ⁵ is selected from H; C _1-6 alkyl substituted by 1, 2 or more R ^5a1 and the following groups substituted by 1, 2 or more R ^5a2 : C _3-10 ring Alkyl and 3-12 membered heterocyclyl; Each R ^5a1 is the same or different, independently selected from H, halogen, CN, OH, C _1-6 alkyl, C _1-6 alkoxy, C _3-10 cycloalkyl and 4-10 membered heterocycle group, the alkyl group, alkoxy group, cycloalkyl group or heterocyclic group can be substituted by 1, 2 or more halogens; Each R ^5a2 is the same or different, and is independently selected from H, halogen, CN, OH, C _1-6 alkyl and C _1-6 alkoxy; R ⁶ and R ⁷ are the same or different, and are independently selected from H, halogen, CN, OH, NH ₂ ; the following groups substituted by 1, 2 or more R ^f : C _1-6 alkyl, C _1-6 alkoxy and NR ^8a R ^8b and the following groups substituted by 1, 2 or more R ^g : C _3-10 cycloalkyl, 3-10 membered heterocyclyl and 5-14 metaheteroaryl; R ⁸ is selected from H; C _1-6 alkyl substituted by 1, 2 or more R ^8a1 ; C _3-10 ring substituted by 1, 2 or more R ^8a2 Alkyl or 3-12 membered heterocyclyl; R ^8a and R ^8b are the same or different, and are independently selected from H; C _1-6 alkyl substituted by 1, 2 or more R ^8a1 ; substituted by 1, 2 or more R ^8a2 The following groups: C _3-10 cycloalkyl, 3-12 membered heterocyclyl; Each R ^8a1 is the same or different, independently selected from H, halogen, CN, OH, C _1-6 alkyl, C _1-6 alkoxy, C _3-10 cycloalkyl and 4-10 membered heterocycle group, the alkyl group, alkoxy group, cycloalkyl group or heterocyclic group can be substituted by 1, 2 or more halogens; Each R ^8a2 is the same or different, and is independently selected from H, halogen, CN, OH, C _1-6 alkyl and C _1-6 alkoxy; R ^a is selected from H, halogen, CN, OH, NH ₂ , oxo; the following groups substituted by 1, 2 or more R ^a1 : C _1-6 alkyl, C _1-6 alkoxy , NR ^8a R ^8b ; the following groups substituted by 1, 2 or more R ^a2 : C _3-10 cycloalkyl, 3-10 membered heterocyclyl, 5-14 membered heteroaryl; Each R ^a1 is the same or different, and is independently selected from H, halogen, CN and OH; Each R ^a2 is the same or different and is independently selected from H, halogen, CN, OH, C _1-6 alkyl, C _1-6 alkoxy, NH C _1-6 alkyl and N(C _1-6 alkyl) ₂ ; Each R ^b , R ^c , R ^d and ^Re are the same or different, and are independently selected from H, halogen, CN, OH, NH ₂ ; the following groups substituted by 1, 2 or more R ^b1 : C _1-6 alkyl, C _1-6 alkoxy, NH C _1-6 alkyl, N (C _1-6 alkyl) ₂ ; the following substituted by 1, 2 or more R ^b2 Group: C _3-10 cycloalkyl, 4-12 membered heterocyclyl, 5-14 membered heteroaryl; Each R ^b1 is the same or different, and is independently selected from H, halogen, CN and OH; Each R ^b2 is the same or different, independently selected from H, halogen, CN, OH, C _1-6 alkyl, C _1-6 alkoxy, NH C _1-6 alkyl and N(C _{1- 6alkyl} ) ₂ ; Each R ^f is the same or different and is independently selected from H, halogen, CN and OH; Each ^Rg is the same or different, independently selected from H, halogen, CN, OH, C _1-6 alkyl, C _1-6 alkoxy, NHC _1-6 alkyl, N(C _1-6 alkyl base) ₂ and oxo; m is selected from 0, 1, 2, 3, 4, 5, 6; n is selected from 1,2. The compound according to claim 1, its racemate, stereoisomer, tautomer, isotopic label, solvate, pharmaceutically acceptable salt or prodrug thereof, wherein T is selected from N or CR ² ; R ² is selected from the following groups: H, halogen, CN, OH, unsubstituted or optionally substituted by 1, 2 or more deuterium or halogen: C _1-6 alkyl, C _1-6 alkyl Oxygen and NHR ⁸ ; A is selected from the following groups substituted by 1, 2 or more R ^a : C _1-6 alkyl, -O(CH ₂ ) _m R ⁶ , -S(CH ₂ ) _m R ⁶ , -S (O) _n (CH ₂ ) _m R ⁶ , -NR ⁶ R ⁷ , -NR ⁶ C(O)R ⁷ , -C(O)NR ⁶ R ⁷ , -SO ₂ NR ⁶ R ⁷ ; by 1, C _3-12 cycloalkyl substituted by 2 or more R ^b ; 3-12 membered heterocyclyl substituted by 1, 2 or more R ^c ; substituted by 1, 2 or more C _6-14 aryl group substituted by R ^d ; 5-14 membered heteroaryl group substituted by 1, 2 or more R ^e ; R ⁶ , R ⁷ , R ⁸ , R ^a , R ^b , R ^c , R ^d , ^Re , n and m are as defined in claim 1 . The compound according to claim 1, its racemate, stereoisomer, tautomer, isotopic label, solvate, pharmaceutically acceptable salt or prodrug thereof, wherein T is selected from N or CR ² ; R ² and R ⁵ together with their respective connected atoms form a 5-8 membered cyclic structure. Preferably, R ² and R ⁵ together with their respective connected atoms form a 5-8 membered heterocyclic ring; A is selected from the group consisting of The following groups substituted by 1, 2 or more R ^a : C _1-6 alkyl, -O(CH ₂ ) _m R ⁶ , -S(CH ₂ ) _m R ⁶ , -S(O) _n (CH ₂ ) _m R ⁶ , -NR ⁶ R ⁷ , -NR ⁶ C(O)R ⁷ , -C(O)NR ⁶ R ⁷ , -SO ₂ NR ⁶ R ⁷ ; by 1, 2 or more C _3-12 cycloalkyl substituted by multiple R ^b ; 3-12 membered heterocyclyl substituted by 1, 2 or more R ^c ; substituted by 1, 2 or more R ^d C _6-14 aryl; 5-14 membered heteroaryl substituted by 1, 2 or more R ^e ; R ² , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ^a , R ^b , ^Rc , ^Rd , ^Re , n and m are as defined in claim 1. The compound according to any one of claims 1 to 3, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or prodrug thereof, wherein, J is CH; Preferably, J is CR ³ ; R ³ is halogen, preferably fluorine; Preferably, E is selected from N or CH; Preferably, E is CR ⁴ ; R ⁴ is halogen, preferably fluorine; Preferably, T is selected from N or CR ² ; R ² is selected from H, methoxy, difluoromethoxy, trifluoromethoxy, CN, methyl, cyclopropyloxy, deuterated methoxy ( Such as trideuterated methoxy); Preferably, R ¹ is selected from H, halogen or C _1-3 alkyl; Preferably, ^R5 is selected from H, cyclopropyl, trifluoroethyl (such as ), cyclopropylmethyl, fluorocyclopropyl, difluorocyclopropyl, cyanomethyl, hydroxycyclobutyl, isopropyl, cyclobutyl, cyclopentyl, hydroxycyclopentyl; for example like The compound according to claim 1, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or prodrug thereof, wherein the compound represented by formula I The structure is shown in formulas IIa and IIb:
Among them, A, J, E, T, R ¹ and R ⁵ have the definitions described in any one of claims 1 to 4; Preferably, the structure of the compound represented by formula I is as shown in formula IIIa and IIIb:
Wherein A, R ² and R ⁵ have the definitions described in any one of claims 1 to 4. The compound according to claim 1, its racemate, stereoisomer, tautomer, isotopic label, solvate, pharmaceutically acceptable salt or prodrug thereof, wherein A is selected from -O( CH ₂ ) _m R ⁶ , -O(CH ₂ ) _m (CO)R ⁶ , -O(CH ₂ ) _m C(O)R ⁶ , -OCH(CH ₃ )(CH ₂ ) _m R ⁶ , -OCD ₂ (CH ₂ ) _m R ⁶ and 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is optionally substituted by 1, 2 or more R ^c ; preferably, A is - O(CH ₂ ) _m R ⁶ or 3-8 membered heterocyclyl substituted by 1, 2 or more R ^c ; R ⁶ is selected from NR ^8a R ^8b , C _3-8 cycloalkyl, 3-8 membered heterocyclyl and 5-9 membered heteroaryl, wherein the C _3-8 cycloalkyl, 3-8 membered heteroaryl Ring groups and 5-9 membered heteroaryl groups are optionally substituted by 1, 2 or more ^Rg ; R ^8a and R ^8b are the same or different, and are independently selected from H or C _1-6 alkyl; each R ^g is the same or different, and is independently selected from H, halogen, CN, OH, C _1-6 alkyl. , C _1-6 alkoxy, NHC _1-6 alkyl, N(C _1-6 alkyl) ₂ and oxo, wherein the C _1-6 alkyl and C _1-6 alkoxy can be optional Selected to be replaced by R ^a ; R ^a is selected from H, halogen, CN, OH and NH ₂ ; R ^c is selected from H, halogen, CN, OH, NH ₂ and C _1-6 alkyl, wherein the C _1-6 alkyl is optionally substituted by 1, 2 or more R ^b1 ; Each R ^b1 is the same or different, and is independently selected from H, halogen, CN and OH; m is 0, 1 or 2; More preferably, A is selected from
The compound according to any one of claims 1 to 6, its racemate, stereoisomer, tautomer, isotope label, and solvent Compounds, pharmaceutically acceptable salts or prodrugs thereof, wherein R ² is selected from H, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, deuterated C _{1- 6} alkoxy, C _3-8 cycloalkyloxy and cyano; preferably, R ² is selected from halogenated C _1-6 alkoxy; more preferably, R ² is -OCHF ₂ . The compound according to any one of claims 1 to 7, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or prodrug thereof, wherein R ⁵ is selected from H, C _1-6 alkyl and C _3-6 cycloalkyl, the C _1-6 alkyl is optionally replaced by 1, 2 or more halogens, CN and C _3-8 cycloalkyl Substituted, C _3-6 cycloalkyl is optionally substituted by 1, 2 or more hydroxyl groups or halogens; Preferably, R ⁵ is selected from H, halogenated C _1-3 alkyl, -CH ₂ CN, -CH ₂ -cyclopropyl, isopropyl, cyclobutyl, cyclopentyl, The compound according to any one of claims 1 to 8, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or prodrug thereof, wherein A is selected From -O(CH ₂ ) _m R ⁶ ; R ² is selected from H, CN, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, deuterated C _1-6 Alkoxy and C _3-6 cycloalkyloxy, preferably, R ² is -OCHF ₂ ; R ⁵ is selected from H, C _1-3 alkyl and C _3-6 cycloalkyl, the C _{3- 6} cycloalkyl is optionally substituted by 1, 2 or more hydroxyl groups or halogens; R ⁶ is as defined in claim 6; m is 1 or 2. The compound according to any one of claims 1 to 9, its racemate, stereoisomer, tautomer, isotopic label, solvate, pharmaceutically acceptable salt or prodrug thereof, wherein m is 1 or 2. The compound according to any one of claims 1 to 10, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or prodrug thereof, wherein the formula Ⅰ Compounds are selected from the following structures:








The preparation method of the compound according to any one of claims 1 to 11, comprising the following steps: compound a and compound b undergo a coupling reaction to obtain the compound represented by formula I;
^Wherein , A ^, OH) ₂ , A pharmaceutical composition, which contains a therapeutically effective amount of the compound described in any one of claims 1-11, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutical at least one of an acceptable salt or prodrug compound thereof, and one or more pharmaceutically acceptable excipients. The compound of any one of claims 1 to 11, at least one of its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or its prodrug compound , or the use of the pharmaceutical composition according to claim 13 in the preparation of a drug; the drug is preferably an SIK inhibitor, and more preferably an SIK2 inhibitor. The use according to claim 14, characterized in that the medicine is used to treat and/or prevent inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, and cartilage turnover related Damaging diseases, congenital cartilage malformations, diseases involving bone turnover impairment, diseases associated with excessive secretion of TNFα, interferon, IL-6, IL-12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases diseases, cardiovascular diseases, dermatological diseases and/or diseases related to abnormal angiogenesis; also such as psoriasis, inflammatory bowel disease (IBD), rheumatoid arthritis (RA), primary Sjogren's syndrome, ankylosing Spondylitis, cryopyrin-associated periodic syndrome (CAPS); Preferably, the inflammatory disease is selected from rheumatoid arthritis, osteoarthritis, allergic airway diseases (eg asthma), chronic obstructive pulmonary disease (COPD) and inflammatory bowel disease (eg Crohn's disease, ulcers colitis).