WO2024208187A1 - Azaaryl compound and use thereof as lsd1 inhibitor - Google Patents

Abstract

The present invention relates to a compound as represented by formula I, a pharmaceutically acceptable salt, an isomer, or an isotope marker thereof. The compound can be used as an LSD1 inhibitor, and can also be used for preventing or treating tumors such as hematological neoplasms and small cell lung cancer.

Description

Azaaryl compounds and their use as LSD1 inhibitors Technical Field

The present application belongs to the field of medicine and relates to a compound of formula I and its use as a lysine-specific demethylase (LSD1) inhibitor.

Background Art

Lysine specific demethylase 1 (LSD1) is the first reported protein lysine demethylase. It widely participates in transcriptional regulation by regulating the methylation state of histone lysine, affecting many processes such as cell proliferation and differentiation, embryonic stem cell pluripotency, etc. After binding to different protein factors, LSD1 acts on different substrates and can play different regulatory roles on histone and gene expression: after binding to CoREST, LSD1 will preferentially act on histone H3K4, remove activation-related histone marks through demethylation, and inhibit gene transcription; after binding to androgen receptor protein, recombinant LSD1 will preferentially act on H3K9, and activate androgen receptor-related gene transcription through demethylation. Studies have found that the expression level of LSD1 is significantly increased in different tumor tissues. Such as neuroblastoma, breast cancer, hematological tumors, small cell lung cancer, etc. [Sehrawat,A.;Gao,L.;et al.,Proc.Nat.Acad.Sci.USA,2018,E4179-4188]

Summary of the invention

The present application provides a series of compounds which are LSD1 inhibitors and have preventive and therapeutic uses in the treatment of tumors such as leukemia, small cell lung cancer, etc.

According to one aspect of the present application, the present application provides 1, a compound of formula I, a pharmaceutically acceptable salt thereof, an isomer thereof or an isotope-labeled substance thereof,

In Formula I,

Choose one of T, V, and W to be N, and the others to be C;

U, X, Y, and Z are each independently N or CR ² ;

The two rings indicated by the dashed lines are fused bicyclic aromatic rings;

R ¹ is hydrogen, halogen, hydroxyl, cyano, C _2-6 alkynyl, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, -NR ⁵ R ⁶ ;

n is 0, 1, 2 or 3;

R ² is hydrogen, halogen, hydroxy, cyano, C _1-6 alkyl optionally substituted by hydroxy or halogen, C _1-6 alkoxy optionally substituted by halogen, C _2-6 alkynyl, -S(O) ₂ C _1-6 alkyl, -C(O)-C _1-6 alkyl, -NR ⁵ R ⁶ , -NHCOC _1-6 alkyl, -NHCOOC _1-6 alkyl;

L is a bond, O, S, -NH-, -CO-, or -CH ₂ O-;

Ring A is C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _3-10 cycloalkenyl, 3-10 membered heterocyclyl and 5-6 membered heteroaryl, C _6-10 aryl and C 3-10 cycloalkyl, C _6-10 aryl and 3-10 membered heterocyclyl, C _6-10 aryl and C _3-10 cycloalkenyl, 5-10 membered heteroaryl and C _3-10 cycloalkyl, _5-10 membered heteroaryl and 3-10 membered heterocyclyl, 5-10 membered heteroaryl and C _3-10 cycloalkenyl, the heteroaryl is optionally oxoed, and Ring A is optionally substituted with 0 to 4 ^Ra ;

^Ra is selected from halogen, -CN, hydroxy, C1-6 alkyl optionally substituted by a substituent selected from _-OH and halogen, _C1-6 alkoxy, _C1-6 alkoxy substituted by _C6-10 aryl, _-OC3-10 ^cycloalkyl , _C3-10 cycloalkyl, _C2-6 alkenyl, _C2-6 alkynyl, ^-NR5R6 , _-NHCOC1-6 alkyl, - NHCOOC _1-6 alkyl, -SO ₂ C _1-6 alkyl, -SO ₂ NR ⁵ R ⁶ , 5-6 membered heteroaryl (containing heteroatoms selected from nitrogen and oxygen) optionally substituted by substituents selected from -CN, -CHF ₂ and -CF ₃ , wherein the alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl is optionally substituted by halogen, hydroxy, acetylene or cyano;

When two ^Ra are on the same atom, the two ^Ra can be linked together to form =O, or =C(Raa) ₂ ;

or when two ^Ras are on the same atom, the two ^Ras may be linked together to form a _C3-12 cycloalkyl or a 3-12 membered heterocyclyl, wherein the _C3-12 cycloalkyl or the 3-12 membered heterocyclyl is optionally substituted by 1, 2, 3 or 4 ^Ras ;

or when two ^Ras are on different atoms, the two ^Ras may be linked together to form a _C3-12 cycloalkyl, a 3-12 membered heterocyclyl, a 5-12 membered heteroaryl or a _{C6-12 aryl} group, wherein the _C3-12 cycloalkyl, the 3-12 membered heterocyclyl, the 5-12 membered heteroaryl or the _C6-12 aryl group is optionally substituted by 1, 2, 3 or 4 ^Ras ;

^Raa is selected from halogen, -CN, hydroxy, _C1-6 alkyl, halogen-substituted _C1-6 alkyl, _C1-6 alkoxy, halogen-substituted _C1-6 alkoxy, _C6-10 aryl-substituted _C1-6 alkoxy, _-OC3-10 cycloalkyl, _C3-10 cycloalkyl, _C2-6 alkenyl, _C2-6 alkynyl;

Ring B is C _6-10 aryl, C _5-10 heteroaryl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, or C3-10 cycloalkenyl, which may be substituted by 0 to 4 R ^b ;

When L is -CO-, Ring B is a 3- to 10-membered heterocyclyl group, optionally substituted by 0 to 4 R ^b ;

R ^b is selected from halogen, -CN, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy substituted by C _6-10 aryl, -OC _3-10 cycloalkyl, C _3-10 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -NR ⁵ R ⁶ , -NHCOC _1-6 alkyl, -NHCOOC _1-6 alkyl, wherein the alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl is optionally substituted by halogen, acetylene or cyano;

When two R ^b are on the same atom, the two R ^b can be linked together to form =0, or =C(R _bb ) ₂ ;

or when two R ^b are on the same atom, the two R ^b may be linked together to form a C _3-12 cycloalkyl or a 3-12 membered heterocyclyl, wherein the C _3-12 cycloalkyl or the 3-12 membered heterocyclyl is optionally substituted by 1, 2, 3 or 4 R ^bb ;

or when two R ^b are on different atoms, the two R ^b may be linked together C _3-12 cycloalkyl, 3-12 membered heterocyclyl, 5-12 _{membered heteroaryl or C 6-12 aryl, wherein the C 3-12 cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl or C 6-12 aryl is optionally} substituted by 1, 2, 3 or 4 R ^bb ;

R ^bb is selected from halogen, -CN, hydroxy, C _1-6 alkyl, halogen-substituted C _1-6 alkyl, C _1-6 alkoxy, halogen-substituted C _1-6 alkoxy, C _6-10 aryl-substituted C _1-6 alkoxy, -OC _3-10 cycloalkyl, C _3-10 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl; and

R ⁵ and R ⁶ are each independently selected from hydrogen, C _1-6 alkyl optionally substituted by -OH, halogen, and 3-5 membered oxygen-containing heterocyclic group.

According to some embodiments, the present application provides a compound represented by Formula II or Formula III, a pharmaceutically acceptable salt thereof, an isomer thereof, or an isotope-labeled substance thereof,

In Formula II,

X, Y and Z are all selected from CR ⁷ ;

One of X, Y and Z is selected from N, and the others are selected from CR ⁸ ; or

X and Y are both selected from N, and Z is selected from CR ⁹ ;

R ⁷ , R ⁸ , and R ⁹ are each independently selected from hydrogen, halogen, hydroxy, cyano, C _2-6 alkynyl, C _1-6 alkyl optionally substituted by hydroxy or halogen, C _1-6 alkoxy optionally substituted by halogen, -NR ⁵ R ⁶ , -CONR ⁵ R ⁶ , COR ⁵ , C(O)OR ⁵ , -SO ₂ NR ⁵ R ⁶ , for example selected from hydrogen, halogen (such as fluorine), cyano or C _1-6 alkyl (such as methyl) optionally substituted by hydroxy or halogen (such as fluorine).

In formula III, one of W and V is selected from N, and the other is selected from CH;

R ¹⁰ and R ¹¹ are each independently selected from hydrogen, halogen (such as fluorine), hydroxyl, cyano, C _2-6 alkynyl, C _1-6 alkyl optionally substituted by hydroxyl or halogen, C _1-6 alkoxy optionally substituted by halogen, -NR ⁵ R ⁶ , -CONR ⁵ R ⁶ , COR ⁵ , C(O)OR ⁵ , -SO ₂ NR ⁵ R ⁶ , for example selected from hydrogen, C _1-6 alkyl optionally substituted by hydroxyl or halogen (such as fluorine).

According to some embodiments, in Formula I, Formula II or Formula III, R ¹ is selected from hydrogen, halogen (e.g. -F), hydroxyl, cyano, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, -NR ⁵ R ₆ , for example ^, selected from halogen (e.g. fluorine).

According to some embodiments, in Formula I, Formula II or Formula III, n=0 or 1, for example, n=1.

According to some embodiments, in Formula I, Formula II or Formula III, L is selected from a bond, -CO-, and -CH ₂ O-.

According to some embodiments, in Formula I, Formula II or Formula III, L is selected from a bond, -CO-.

According to some embodiments, in Formula I, Formula II or Formula III, Ring A can be selected from C _6-10 aryl (such as _{phenyl), C 3-10 cycloalkenyl (such as C 3-6 cycloalkenyl, specifically cyclohexenyl), C 3-10 cycloalkyl ( such} as C _3-6 cycloalkyl, specifically cyclohexyl), optionally oxo-substituted 5-10 membered heteroaryl (such as imidazolyl, pyridyl), 3-10 membered heterocyclyl (which can be a double bridged ring, a double spiro ring, or a monocyclic ring (such as 1-piperidinyl), 3-8 membered heterocyclyl and 5-6 membered heteroaryl (such as 3-6 membered heterocyclyl and 5-6 membered heteroaryl), C _6-10 aryl and C _3-6 cycloalkyl, phenyl and 3-6 membered heterocyclyl, phenyl and C _3-6 cycloalkenyl, 5-6 membered heteroaryl and C The invention further comprises _{a 3-6} -membered cycloalkyl, a 5-6-membered heteroaryl and a 3-6-membered heterocyclic group, a 5-6-membered heteroaryl and a C _3-6- cycloalkenyl group, wherein the heteroaryl group is optionally oxo-substituted, and the heteroaryl group and the heterocyclic group may contain a N heteroatom and an optional O heteroatom. If the N heteroatom is contained, the N heteroatom is connected to the fused bicyclic aromatic ring in formula I, formula II or formula III; Ring A is optionally substituted by 0 to 2, for example 1 or 2 ^Ra . The heteroatom of the 3-10-membered heterocyclic group may be, for example, a heteroatom selected from a N atom and an O atom.

According to some embodiments, in Formula I, Formula II or Formula III, ^Ra is selected from halogen (e.g., -F), -CN, hydroxyl, _C1-6 alkyl (optionally substituted with -OH, halogen (e.g., -F)), _C1-6 alkoxy, _-OC3-6 cycloalkyl, _C3-6 cycloalkyl, _C2-6 alkenyl, _C2-6 alkynyl, -NR5R6, _NHCOC1-6 alkyl, ^-NHCOOC1-6 alkyl; the alkyl, alkoxy, cycloalkyl, ^alkenyl , alkynyl are optionally substituted with halogen, acetylene or _cyano ; for example, ^Ra is selected from halogen (e.g., F), _C1-6 alkyl (e.g., methyl, trifluoromethyl) optionally substituted with halogen, acetylene, hydroxyl, _C1-6 alkoxy (e.g., methoxy), _-NHCOC1-6 alkyl (e.g., acetylamino), _-NHCOOC1-6 alkyl (e.g., methoxyformylamino).

According to some embodiments, in Formula I, Formula II or Formula III, ^Ra is selected from halogen, -CN, hydroxyl, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 alkoxy substituted with _{C6-10 aryl} , _-OC3-10 cycloalkyl, _C3-10 cycloalkyl, _C2-6 alkenyl, _C2-6 alkynyl, ^-NR5R6 _, -NHCOC1-6 alkyl, _-NHCOOC1-6 alkyl, _{-SO2C1-6 alkyl} , ^-SO2NR5R6 , ^and the ^alkyl , alkoxy, _cycloalkyl , alkenyl and alkynyl are optionally substituted with halogen, hydroxyl, acetylene or cyano.

According to some embodiments, in Formula I, Formula II or Formula III, ^Ra is selected from a 5-6 membered heteroaryl group (containing a heteroatom selected from nitrogen and oxygen) optionally substituted by a substituent selected from -CN, _-CHF2 and _-CF3 .

According to some embodiments, in Formula I, Formula II or Formula III, Ring B can be selected from C _6-10 aryl, C _5-6 heteroaryl, C _3-6 cycloalkyl, 3 to 10 membered heterocyclic group, the heteroatom of the heterocyclic group is selected from nitrogen atom and oxygen atom, it can be a double bridged ring, a double spiro ring, or a monocyclic ring (for example, a 5-6 membered heterocyclic group, specifically 1-piperidinyl, 1-pyrrolyl, or a nitrogen-containing double bridged ring, a nitrogen-containing double spiro ring), C _3-6 cycloalkenyl, the heteroaryl or heterocyclic group can contain an N heteroatom; if it contains an N heteroatom, the N heteroatom is connected to the fused bicyclic aromatic ring in Formula I, Formula II or Formula III; the above groups are optionally substituted by 0 to 4, for example 0 to 2 R ^b .

According to some embodiments, in Formula I, Formula II or Formula III, R ^b is selected from halogen (e.g., -F), -CN, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy, -OC _3-6 cycloalkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -NR ⁵ R ⁶ , for example, selected from amino, halogen (e.g., -F), C _1-6 alkoxy (e.g., methoxy), and the alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl is optionally substituted with halogen, acetylene or cyano.

According to some embodiments, in Formula I, Formula II or Formula III, R ⁵ and R ⁶ can each be independently selected from hydrogen (including deuterium), C _1-6 alkyl optionally substituted with -OH, 3-5 membered oxygen-containing heterocyclic group or C _1-6 alkoxy group.

According to some embodiments, in Formula I, Formula II or Formula III, R ⁵ and R ⁶ can each be independently selected from hydrogen, C _1-6 alkyl or C _1-6 alkoxy.

According to some embodiments, in Formula I, Formula II or Formula III, R ⁵ and R ⁶ are each independently selected from hydrogen, C _1-6 alkyl or halogenated C _1-6 alkyl.

According to some embodiments, the present application provides specific compounds in the following examples or pharmaceutically acceptable salts thereof, isomers thereof or isotope-labeled substances thereof.

Another aspect of the present application provides a pharmaceutical composition comprising the compound of the present application or a pharmaceutically acceptable salt thereof, an isomer thereof or an isotope-labeled substance thereof, and a pharmaceutically acceptable carrier.

Another aspect of the present application provides a compound of the present application or a pharmaceutically acceptable salt thereof, an isomer thereof or an isotope-labeled substance thereof, or the above-mentioned pharmaceutical composition, which is a LSD1 inhibitor.

Another aspect of the present application provides a compound of the present application or a pharmaceutically acceptable salt, an isomer or an isotope-labeled substance thereof, or the above-mentioned pharmaceutical composition, which is used for preventing or treating diseases mediated by LSD1.

Another aspect of the present application provides a compound of the present application or a pharmaceutically acceptable salt thereof, an isomer thereof or an isotope-labeled substance thereof, or the above-mentioned pharmaceutical composition, which is used for preventing or treating tumors.

Another aspect of the present application provides a use of the compound of the present application or a pharmaceutically acceptable salt thereof, an isomer thereof or an isotope-labeled substance thereof, or the above-mentioned pharmaceutical composition in the preparation of a drug for preventing or treating a disease mediated by LSD1.

Another aspect of the present application provides a use of a compound of the present application or a pharmaceutically acceptable salt thereof, an isomer thereof or an isotope-labeled substance thereof, or the above-mentioned pharmaceutical composition in the preparation of a drug for preventing or treating a disease, wherein the disease includes a tumor.

One aspect of the present application provides a method for inhibiting LSD1 activity, which comprises administering a compound of the present application or a pharmaceutically acceptable salt, an isomer or an isotope-labeled substance thereof to an individual.

One aspect of the present application provides a method for preventing or treating a disease or condition in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the present application or a pharmaceutically acceptable salt, an isomer or an isotope label thereof, wherein the disease is a LSD1-mediated disease.

One aspect of the present application provides a method for preventing or treating a disease or condition in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the present application or a pharmaceutically acceptable salt, an isomer or an isotope label thereof, wherein the disease is a tumor.

In some embodiments of the present application, LSD1-mediated diseases include diseases caused by high expression of LSD1.

In some embodiments of the present application, the tumor includes but is not limited to neuroblastoma, breast cancer, blood tumor (such as leukemia), small cell lung cancer and Ewing's sarcoma.

In some embodiments, the dosage of the compound can be in the range of about 0.001 mg/kg body weight/day to about 1000 mg/kg body weight/day. In other embodiments, dosage levels below the lower limit of the above range may be sufficient. In other embodiments, dosage levels higher than the upper limit of the above range may be required. In some embodiments, the compound is administered in a single dose, once a day. In other embodiments, the compound is administered in multiple doses, more than once a day. In some embodiments, the individual to whom the pharmaceutical composition is administered is a mammal. In some embodiments, the compound or pharmaceutical composition can be administered orally or parenterally. In some embodiments, the individual to whom the administration is administered can be a mammal, such as a primate, such as a human.

Definition of terms

Unless otherwise defined, all technical terms herein have the same meaning as commonly understood by those skilled in the art to which the subject matter of the claims belongs. Unless otherwise indicated, all patents, patent applications, and public materials cited in the entirety of this article are incorporated herein by reference in their entirety.

It should be understood that the above brief description and the following detailed description are exemplary and are only used for explanation, and do not limit the subject matter of the present application in any way. It should also be noted that unless otherwise specified, the use of "or" and "or" means "and/or". In addition, the use of the term "including" and other forms, such as "including", "containing" and "comprising" are all non-limiting descriptions.

Definitions of standard chemical terms can be found in the references, including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV/Vis spectroscopy and pharmacological methods, are used. Unless specific definitions are provided, the terms used herein in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and drugs and medicinal chemistry are known in the art. Standard techniques can be used in chemical syntheses, chemical analyses, drug preparation, formulation and delivery, and treatment of patients. For example, the manufacturer's instructions for the use of the kit can be used, or reactions and purifications can be carried out in a manner known in the art or as described in this application. The above techniques and methods can generally be carried out according to conventional methods well known in the art, as described in the various general and more specific references cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural parts and compounds.

When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents that would result if the formula were written from right to left. For example, _-CH2O- is equivalent to _-OCH2- .

Unless otherwise indicated, general chemical terms such as, but not limited to, "alkyl", "amine", and "aryl" are used to represent the same as their optional substituents. For example, "alkyl" as used herein includes optionally substituted alkyl.

The term "optional" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes the occurrence of the event or situation and the non-occurrence of the event or situation. For example, according to the definition below, "optionally substituted alkyl" refers to "unsubstituted alkyl" (alkyl not substituted by substituents) or "substituted alkyl" (alkyl substituted by substituents).

The term "substituted" means that one or more hydrogens on a specified atom are replaced with the specified radical and if the normal valency of the specified atom is not exceeded under existing conditions, the substitution results in a stable compound.

As used herein, C _1-n includes C _1-6 and C _3-10 . For example, the "C _1-6 " refers to a group having 1 to 6 carbon atoms.

The term "alkyl" as used herein, alone or in combination, refers to an optionally substituted straight chain or optionally substituted branched aliphatic hydrocarbon. "Alkyl" herein, for example, has 1-10 carbon atoms, has 1-8 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms. Examples of alkyl groups herein include, but are not limited to, methyl, ethyl, propyl, and the like. When a group as defined herein, such as "alkyl" appears in a numerical range, for example, "C _1-6 alkyl" refers to an alkyl group that can be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

The "alkyl" used in combination herein includes alkyl groups combined with other groups, for example, alkyl groups in alkoxy groups, alkyl groups in alkylthio groups, hydroxyalkyl groups, haloalkyl groups, cyanoalkyl groups, "alkyl" groups in alkylamino groups (such as monoalkylamino groups, dialkylamino groups), and the like.

The term "alkoxy" as used herein, alone or in combination, refers to an alkyl ether group (-O-alkyl). Non-limiting examples of alkoxy include methoxy, ethoxy, and the like.

The term "alkenyl" as used herein, alone or in combination, refers to an optionally substituted straight chain or optionally substituted branched monovalent hydrocarbon group having one or more C=C double bonds. The alkenyl group has, but is not limited to, 2-10 carbon atoms, or 2-8 carbon atoms, 2-6 carbon atoms, 2-4 carbon atoms. The double bonds in these groups can be in cis or trans configurations and should be understood to include the two isomers. Examples include, but are not limited to, vinyl (CH=CH2), 1-propenyl (CH2CH=CH2), isopropenyl (C(CH3)=CH2), butenyl, etc. When a numerical range appears in the alkenyl group defined herein, for example, "C _2-6 alkenyl" refers to an alkenyl group that can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

The term "halo" or "halogen substitution" used herein, alone or in combination, refers to an optionally substituted group (such as an alkyl) wherein one or more hydrogen atoms are replaced with fluorine, chlorine, bromine, iodine atoms or a combination thereof. In some embodiments, two or more hydrogen atoms are replaced with halogen atoms that are identical to each other (e.g., difluoromethyl, trifluoromethyl); in other embodiments, two or more hydrogen atoms are replaced with halogen atoms that are not identical to each other (e.g., 1-chloro-1-fluoro-1-iodoethyl).

The term aromatic ring as used herein, alone or in combination, includes aryl and heteroaryl groups.

The term "aryl" used herein alone or in combination refers to an optionally substituted aromatic hydrocarbon group having 6-20, such as 6-12 or 6-10 ring-forming carbon atoms. It can be a fused aromatic ring or a non-fused aromatic ring. The fused aromatic ring contains a ring of 2-4 aromatic rings fused together, and the other independent rings can be alicyclic (carbocyclic), heterocyclic, aromatic, aromatic heterocyclic (i.e., heteroaryl) or any combination thereof. The aryl herein includes monocyclic, bicyclic, tricyclic or more cyclic aromatic groups. Non-limiting examples of monocyclic aromatic groups include monocyclic aromatic groups of 6 to 12, 6 to 10 or 6 to 8 ring-forming carbon atoms, such as phenyl; fused ring aromatic groups include bicyclic, tricyclic or more cyclic aromatic groups, such as naphthyl, phenanthrenyl, anthracenyl; non-fused biaryl groups include biphenyl.

The term "heteroaryl" used herein alone or in combination refers to an arbitrarily substituted monovalent heteroaryl group, which contains about 5 to 20, such as 5 to 12 or 5 to 10 skeleton ring atoms, which contains at least one heteroatom (such as 1-4, 1-3, 1-2 heteroatoms) as a skeleton ring atom, and the heteroatom is independently selected from the heteroatoms in oxygen, nitrogen, and sulfur, but is not limited thereto. The ring of the group does not contain two adjacent O or S atoms. Heteroaryl includes monocyclic heteroaryl or polycyclic heteroaryl (e.g., bicyclic heteroaryl, tricyclic heteroaryl, etc.). In embodiments where two or more heteroatoms appear in the ring, the two or more heteroatoms may be the same as each other, or some or all of the two or more heteroatoms are different from each other. The term heteroaryl includes optionally substituted monovalent fused or non-fused heteroaryl groups having at least one heteroatom. In addition, the term heteroaryl also includes fused and non-fused heteroaryl containing 5 to about 12 skeleton ring atoms, and fused and non-fused heteroaryl containing 5 to about 10 skeleton ring atoms. Can be combined with heteroaryl by carbon atoms or heteroatoms. Thus, for example, imidazole can be connected to the parent molecule by its arbitrary carbon atom (imidazole-2-yl, imidazole-4-yl or imidazole-5-yl) or its nitrogen atom (imidazole-1-yl or imidazole-3-yl). Similarly, heteroaryl groups can be further substituted by any or all of its carbon atoms and/or any or all of its heteroatoms. The fused heteroaryl can include fused rings of 2-4 aromatic heterocycles, and other independent rings can be alicyclic, heterocyclic, aryl, heteroaryl or any combination thereof. Non-limiting examples of monocyclic heteroaryl groups include monocyclic heteroaryl groups with 5 to 12, 5 to 10, 5 to 7 or 6 backbone ring atoms. Examples of heteroaryl groups include, but are not limited to, pyridine, pyrimidine, pyrazine, and the like.

The term "heterocycle" or "heterocyclyl" used herein alone or in combination refers to a non-aromatic heterocycle, including heterocycloalkyl (saturated heterocyclyl) and heterocycloalkenyl (unsaturated heterocyclyl). It contains at least one heteroatom (such as 1-4, 1-3, 1-2 heteroatoms) as a skeleton ring atom, and the heteroatom is, for example, an oxygen, nitrogen or sulfur atom. The heterocyclyl may include a monocyclic heterocyclyl (a heterocyclyl has one ring) or a polycyclic heterocyclyl (for example, a bicyclic heterocyclyl (a heterocyclyl has two rings), a tricyclic heterocyclyl, etc.). The bicyclic heterocyclyl may be a spirocycle or a bridged ring. The heterocyclyl may have 3 to 20, such as 3-10, 3-8, 5-8 or 5-6 ring atoms. The heterocyclyl having one or more aromatic fusions may be connected to other groups through an aromatic ring or a non-aromatic ring portion. Other groups may be combined with the heterocycle through a heteroatom or a carbon atom (i.e., the heterocycle is connected to the parent molecule or further substituted).

The term "cycloalkyl" as used herein, alone or in combination, refers to a non-aromatic saturated carbocyclic ring. A cycloalkyl group may be a monocyclic cycloalkyl group or a polycyclic cycloalkyl group (e.g., having 2, 3 or 4 rings; such as a bicyclic cycloalkyl group), which may be a spirocyclic ring or a bridged ring. A cycloalkyl group may have 3-10 ring-forming carbon atoms, 3-8 or 3-6 ring-forming carbon atoms. A cycloalkyl group may also include a ring having one or more aromatic rings fused (i.e., having a common bond). A cycloalkyl group having one or more aromatic fusions may be connected to other groups through portions of aromatic or non-aromatic rings. Examples of cycloalkyl groups include cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term "cycloalkenyl" as used herein, alone or in combination, refers to a non-aromatic double-bonded carbocyclic ring. The cycloalkenyl group can be a monocyclic or polycyclic cycloalkenyl group (e.g., having 2, 3, or 4 rings), which can be a spirocyclic ring or a bridged ring. The cycloalkenyl group can have 3-10 ring-forming carbon atoms, 3-8, or 3-6 ring-forming carbon atoms.

"Halogen" refers to fluorine, chlorine, bromine and iodine, for example fluorine.

Cyano refers to "-CN".

Hydroxyl refers to "-OH".

Mercapto refers to "-SH".

Amino refers to " _-NH2 ".

The term "isomer" refers to an isomer produced by different spatial arrangements of atoms in a molecule. Unless otherwise specified, the compounds described herein include all isomers thereof. As some compounds have asymmetric carbon atoms (optical centers) or double bonds, the compounds of the present application include racemates, enantiomers, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., individual enantiomers) thereof. When stereochemical descriptions are performed, it is meant that there is an isomer therein and the compound is substantially free of another isomer. "Substantially free of" another isomer means that the ratio of the two isomers is at least 80/20, more preferably 90/10, or 95/5 or higher. In some embodiments, an isomer will be present in an amount of at least 99%.

The term "isotope label" refers to a compound of the present application in which one or more constituent atoms are replaced by their isotope atoms. The compound of the present application may contain an atomic isotope in a non-natural ratio on one or more atoms constituting the compound. For example, a radioactive isotope labelled compound may be used, such as deuterium ( ^2H ), tritium ( ^3H ), iodine 125 ( ^125I ) or C14 ( ^14C ). All isotopic composition changes of the compound of the present application, whether radioactive or not, are included in the scope of the present application. In some embodiments of the present application, H is deuterium or tritium.

The term "subject", "patient" or "individual" as used herein refers to an individual suffering from a disease, disorder or condition, etc., including mammals and non-mammals. In one embodiment provided herein, the mammal is a human.

As used herein, the term "treat" and other similar synonyms include alleviating, relieving or ameliorating symptoms of a disease or condition, inhibiting a disease or condition, such as preventing the development of a disease or condition, alleviating a disease or condition, making a disease or condition better, alleviating symptoms caused by a disease or condition, or stopping symptoms of a disease or condition, preventing other symptoms, improving or preventing the underlying metabolic causes of symptoms, and in addition, the term includes the purpose of prevention. The term also includes obtaining a therapeutic effect and/or a prophylactic effect. The therapeutic effect refers to the cure or improvement of the underlying disease being treated. In addition, the cure or improvement of one or more physiological symptoms associated with the underlying disease is also a therapeutic effect, for example, although the patient may still be affected by the underlying disease, the patient's condition is observed to improve. In terms of prophylactic effects, the composition can be administered to a patient at risk for a particular disease, or even if a disease diagnosis has not yet been made, the composition can be administered to a patient who has one or more physiological symptoms of the disease.

As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of at least one active substance (such as a compound of the present application) sufficient to relieve to some extent one or more symptoms of the disease or condition being treated. The result may be signs, symptoms or causes of The reduction and/or alleviation of a disease, or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant symptom alleviation effect. Techniques such as dose escalation trials can be used to determine the effective amount suitable for any individual case.

As used herein, the terms "administration" or "administration" refer to methods that enable a compound or composition to be delivered to the desired site for biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical and rectal administration. Those skilled in the art are familiar with administration techniques that can be used for the compounds and methods described herein, such as those discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

The term "acceptable" with respect to a formulation, composition or ingredient, as used herein, means having no long-term detrimental effect on the general health of the subject being treated.

The term "pharmaceutically acceptable" as used herein refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present application and is relatively non-toxic, that is, the substance can be administered to a subject without causing adverse biological reactions or interacting in an adverse manner with any components contained in the composition.

The term "pharmaceutical composition" as used herein refers to a mixture of the compound of the present application and at least one pharmaceutically acceptable substance. The pharmaceutically acceptable substance includes, but is not limited to, a carrier, a stabilizer, a diluent, a dispersant, a suspending agent, a thickener and/or an excipient.

As used herein, the term "carrier" refers to a relatively nontoxic substance that facilitates the introduction of a compound of the present application into cells or tissues.

The term "pharmaceutically acceptable salt" as used herein refers to a salt form in which the basic group in the parent compound is converted, which retains the biological effectiveness of the free base compound and has no adverse effects biologically or otherwise. Pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups such as amine (amino) groups.

DETAILED DESCRIPTION

Typical embodiments that embody the features and advantages of the present application will be described in detail in the following description. It should be understood that the present application can have various changes in different embodiments without departing from the scope of the present application, and the descriptions therein are essentially used for illustration rather than for limiting the present application.

synthesis

The compounds of the present application or salts, isomers or isotopically labeled thereof can be prepared using known organic synthesis techniques and can be prepared according to any of a number of possible synthetic routes, such as those described below.

Intermediate synthesis

Intermediate EX5-02

EX4-06 (1.60 g, 4.54 mmol) and EX1-01 (1.26 g, 5.45 mmol) were dissolved in a solution of dioxane (20 mL) and water (5 mL), and Pd(dppf)Cl ₂ (0.330 g, 0.454 mmol) and potassium carbonate (1.25 g, 9.08 mmol) were added. The reaction solution was heated to 90°C under a nitrogen atmosphere and stirred for 12 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL*3). The combined organic phases were washed with saturated brine (50 mL) and the mixture was stirred for 2 hours. mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 4/1) to give EX5-01 (1.20 g, yield 75.21%). LCMS: MS m/z (ESI) [M+H] ⁺ = 377.3.

Compound EX5-01 (800 mg, 2.12 mmol) and (4-cyano-3-fluorophenyl)boronic acid (700 mg, 4.24 mmol) were dissolved in dichloromethane (20 mL) solution, and copper acetate (771 mg, 4.24 mmol), pyridine (168 mg, 2.12 mmol) and 4A molecular sieves (500 mg) were added. The reaction solution was stirred at room temperature under an oxygen atmosphere for 16 hours. The reaction solution was filtered, the filter cake was washed with dichloromethane/methanol (10/1, 50 mL), the filtrate and the washing solution were combined and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 3/1) to obtain EX5-02 (550 mg, yield 52.2%). LCMS: MS m/z (ESI) [M+H] ⁺ = 496.2;

Intermediate EX9-01

Compound EX1-01 (3.50 g, 15.1 mmol) was dissolved in dichloromethane (40 mL), and 4-cyano-3-fluorophenylboronic acid (4.99 g, 30.2 mmol) and pyridine (3.65 mL, 45.4 mmol) were added. Molecular sieves (3.50 g) and copper acetate (5.49 g, 30.2 mmol). The reaction solution was stirred at 25°C for 16 hours under an oxygen atmosphere. The reaction solution was filtered and concentrated under reduced pressure. The crude product was chromatographed on a silica gel column (silica, petroleum ether/tetrahydrofuran = 100/0 to 1/1) to obtain the target product EX9-01 (3.00 g, yield 56.6%). LCMS: MS m/z (ESI) [M+H] ⁺ = 349.7;

Intermediate EX7-02

Compound EX7-01 (2.00 g, 10.1 mmol) was dissolved in acetonitrile (40 mL) and N-chlorosuccinimide (2.97 g, 22.2 mmol) was added. The reaction solution was stirred at 60 ° C for 4 hours. After the reaction solution was cooled to room temperature, ethyl acetate (50 mL) was added for dilution, and it was washed with 1M sodium hydroxide solution (20 mL) and saturated brine (10 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 5/1) to obtain EX7-02 (1.35 g, yield 57.5%). LCMS: MS m/z (ESI) [M+H] ⁺ =232.0; ¹ H NMR (400MHz, CDCl ₃ ) δ 10.11 (brs, 1H), 8.70 (d, J = 2.0Hz, 1H), 8.03 (d, J = 2.0Hz, 1H).

Intermediate EX4-06

Compound EX4-01 (2 g, 12.8 mmol) was dissolved in tetrahydrofuran (50 mL), replaced with nitrogen three times, and a tetrahydrofuran solution of methylmagnesium chloride (3 M, 6.40 mL) was slowly added dropwise at 0°C. The reaction solution was stirred at 0°C for 10 minutes. The reaction solution was quenched with saturated NH ₄ Cl aqueous solution (50 mL), and extracted with ethyl acetate (80 mL*3). The organic phases were combined, washed with saturated brine (50 mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 3/1) to obtain the target product EX4-02 (2.00 g, yield 90.7%). ¹ H NMR: (400MHz, CDCl ₃ ) δ4.05-3.85(m,4H), 1.96-1.85(m,2H), 1.79-1.65(m,4H), 1.65-1.57(m,2H), 1.28(s,3H).

Compound EX4-02 (500 mg, 2.90 mmol) was dissolved in dichloromethane (10 mL), 2,6-dimethylpyridine (933 mg, 8.71 mmol, 1.01 mL) was added, and tert-butyldimethylsilyl trifluoromethanesulfonate (1.15 g, 4.35 mmol, 1.00 mL) was added at 0 ° C under nitrogen protection. The reaction solution was stirred at 25 ° C for 16 hours. The reaction was quenched by adding water (20 mL) and extracted with dichloromethane (30 mL * 3). The organic phases were combined, washed with saturated brine (20 mL * 2) in turn, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was chromatographed on a silica gel column (silica, petroleum ether/ethyl acetate = 100/0 to 10/1) to obtain the target product EX4-03 (500 mg, yield 60.1%). ¹ H NMR: (400MHz, CDCl ₃ ) δ3.95–3.80(m,4H),1.92-1.77(m,2H),1.64-1.39(m,6H),1.17(s,3H)0.80(s,9H)0.00(s,6H).

Compound EX4-03 (500 mg, 2.90 mmol) was dissolved in acetic acid (4 mL) and water (1 mL). The reaction solution was heated to 65 °C and stirred for 2 hours. The reaction solution was concentrated under reduced pressure to remove most of the acetic acid, neutralized with saturated sodium bicarbonate solution (20 mL), and extracted with ethyl acetate (30 mL*3). The organic phases were combined, washed with saturated brine (20 mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target product EX4-04 (190.0 mg, yield 44.9%). ¹ H NMR: (400 MHz, CDCl ₃ )δ2.65–2.50 (m, 2H)2.12–1.98 (m, 2H)1.89-1.80 (m, 2H)1.68–1.52 (m, 2H)1.22 (s, 3H)0.77 (s, 9H)0.00 (s, 6H).

Compound EX4-04 (150 mg, 619 μmol) was dissolved in tetrahydrofuran (10 mL), and a tetrahydrofuran/n-heptane solution of lithium diisopropylamide (2M, 340 μL) was slowly added at -78°C, replaced with nitrogen three times, and stirred at -78°C for one hour. Phenylbis(trifluoromethanesulfonyl)imide (199 mg, 557 μmol) was added. The reaction solution was stirred at 25°C for 16 hours. The reaction solution was quenched with saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (30 mL*3). The organic phases were combined, washed with saturated brine (20 mL*2) in turn, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was chromatographed on a silica gel column (silica, petroleum ether/ethyl acetate = 100/0 to 97/3) to obtain the target product EX4-05 (110.0 mg, yield 47.8%). ¹ H NMR: (400MHz, CDCl ₃ ) δ5.67-5.59(m,1H),2.70-2.53(m,1H),2.36-2.18(m,3H)1.93-1.81(m,1H)1.76-1.60(m,1H)1.32(s,3H)0.87(s,9H)0.12,0.0 9(2s,6H).

Compound EX4-05 (110 mg, 294 μmol) was dissolved in dioxane (6 mL), and bis-naphthalene alcohol borate (89.5 mg, 352 μmol), Pd(dppf)Cl ₂ (10.8 mg, 14.7 μmol) and potassium acetate (86.5 mg, 881 μmol) were added. The reaction solution was heated to 90°C under nitrogen protection and stirred for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/0 to 97/3) to obtain the target product EX4-06 (100 mg, yield 70.9%).

Intermediate EX12-03a

EX12-01 (5.00 g, 32.6 mmol) was dissolved in (50 mL), N-iodosuccinimide (8.80 g, 39.1 mmol) was added, and the reaction solution was stirred at 100 ° C for 2 hours. After the reaction was completed, it was cooled to room temperature, diluted with water (100 mL), extracted with ethyl acetate (100 mL*3), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica, petroleum ether/ethyl acetate = 100/0-1/1) to obtain EX12-02a (9.00 g, yield 98.9%). LCMS: MS m/z (ESI) [M+1] ⁺ =279.9; ¹ H NMR (400MHz, CDCl ₃ ) δ7.82 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H).

EX12-02a (9.00 g, 32.2 mmol) was dissolved in DCM (150 mL), and 4-cyano-3-fluoro-phenylboronic acid (10.6 g, 64.4 mmol), pyridine (7.80 mL, 96.6 mmol) were added. Molecular sieves (28.4 g, 64.4 mmol) and copper acetate (11.7 g, 64.4 mmol), the reaction solution was stirred at room temperature under oxygen atmosphere for 18 hours. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with dichloromethane (200 mL), and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica, petroleum ether/dichloromethane = 100/0-1/1) to obtain EX12-03a (6.5 g, 16.307 mmol, 50.6%). LCMS: MS m/z (ESI) [M+1] ⁺ = 398.9; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.43-8.35 (m, 2H), 7.86 (d, J = 8.4 Hz, 1H), 7.80-7.74 (m, 1H), 7.37 (d, J = 8.4 Hz, 1H).

Intermediate EX12-03b

Compound EX12-01b (800 mg, 5.21 mmol) was dissolved in anhydrous DMF (5 mL), and NCS (834 mg, 6.25 mmol) was added. The reaction solution was reacted at 25°C for 16 hours. The reaction solution was poured into ice water (30 mL), solid precipitated, filtered, and the filter cake was washed with water (5 mL*3). The filter cake was vacuum dried to obtain the crude product EX12-02b (900 mg, yield 91.9%). LCMS: MS m/z (ESI) [M+H] ⁺ = 231.8.

Compound EX12-02b (1.00 g, 4.30 mmol) was dissolved in dichloromethane (20 mL), and 4-cyano-3-fluorophenylboronic acid (1.40 g, 8.60 mmol) and pyridine (1.04 mL, 12.9 mmol) were added. Molecular sieves (1.00 g) and copper acetate (1.60 g, 8.60 mmol). The reaction solution was stirred at 25°C for 16 hours under an oxygen atmosphere. The reaction solution was filtered and concentrated under reduced pressure. The crude product was chromatographed on a silica gel column (silica, petroleum ether/dichloromethane = 100/0 to 1/2) to obtain the target product EX12-03b (1.10 g, yield 72.7%). LCMS: MS m/z (ESI) [M+H] ⁺ = 350.9.

Intermediate EX14-01

Compound EX7-02 (1.00 g, 4.30 mmol) was dissolved in dichloromethane (30 mL), and 4-cyano-3-fluorophenylboronic acid (1.42 g, 8.60 mmol) was added. Molecular sieves (1.00 g, 8.60 mmol), pyridine (1.04 mL, 12.9 mmol) and copper acetate (1.56 g, 8.60 mmol). The reaction mixture was stirred at room temperature for 16 hours in an oxygen atmosphere. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/0 to 3/1) to obtain EX14-01 (550 mg, yield 36.4%). LCMS: MS m/z (ESI) [M+H] ⁺ = 351.0;

Intermediate EX21-03

Compound EX21-01 (2.00 g, 10.6 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), cooled to 0 ° C, NaH (0.64 g, 16.0 mmol, 60%) was added, stirred at 0 ° C for 15 minutes, and SEMCl (2.26 mL, 12.8 mmol) was slowly added dropwise. After the addition was complete, the reaction solution was reacted at room temperature for 2 hours. The reaction solution was quenched with saturated ammonium chloride (20 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 1/1 to 4/1) to obtain EX21-02 (600 mg, yield 17.7%). LCMS: MS m/z (ESI) [M+H] ⁺ = 318.1; ¹ HNMR: (400MHz, CDCl ₃ ) δ6.69 (s, 1H), 6.19 (s, 1H), 5.47 (s, 2H), 3.66 (t, J = 8.0Hz, 2H), 2.43 (s, 3H), 0.93 (t, J = 8.0Hz, 2H) ,0.00(s,9H).

Compound EX21-02 (630 mg, 1.98 mmol) was dissolved in 1,4-dioxane (10 mL), and bis-naphthalene borate (603 mg, 2.38 mmol), KOAc (583 mg, 5.94 mmol), and Pd(dppf)Cl ₂ (145 mg, 0.198 mmol) were added. The reaction solution was stirred at 90°C for 2 hours. After the reaction solution was cooled to room temperature, it was filtered, concentrated under reduced pressure, and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 4/1) to obtain EX21-03 (520 mg, yield 71.9%). LCMS: MS m/z (ESI) [M+H] ⁺ = 284.2; ¹ H NMR: (400MHz, CDCl ₃ ) δ 6.88 (s, 1H), 6.27 (s, 1H), 5.54 (s, 2H), 3.67 (t, J = 8.0Hz, 2H), 2.44 (s, 3H), 1.34 (s, 12H), 0.93 ( t,J＝8.0Hz,2H),0.01(s,9H).

Intermediate EX26-03

Compound EX26-01 (2.00 g, 7.84 mmol), 4-cyano-3-fluorophenylboronic acid (2.59 g, 15.682 mmol), Type molecular sieve (2.00 g, 7.84 mmol), pyridine (1.89 mL, 23.5 mmol) were dissolved in dichloromethane (30 mL) and copper acetate (2.85 g, 15.7 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours in an oxygen atmosphere. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain mixture EX26-02 (870 mg). LCMS: MS m/z (ESI) [M+H] ⁺ = 373.9; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.32 (s, 1H), 8.21-8.02 (m, 3H), 7.98-7.76 (m, 1H), 7.73-7.48 (m, 1H), 3.99, 3.89 (2s, 3H).

The mixture EX26-02 (820 mg, 2.19 mmol) was dissolved in dioxane (10 mL) and water (2 mL), and EX4-06 (927 mg, 2.63 mmol), potassium carbonate (606 mg, 4.38 mmol) and Pd(dppf)Cl ₂ (160.4 mg, 0.219 mmol) were added. The reaction solution was heated to 100°C under nitrogen protection and stirred for 3 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 4/1) to obtain

EX26-03(705mg). LCMS:MS m/z(ESI)[M+H] ⁺ =520.1;

The mixture EX26-03 (605 mg, 1.16 mmol) was dissolved in tetrahydrofuran (12 mL), methanol (6 mL) and water (3 mL), and lithium hydroxide (55.8 mg, 2.33 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction solution was adjusted to pH = 2 with 5% citric acid solution, diluted with water (15 mL), and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain EX26-04. LCMS: MS m/z (ESI) [M+H] ⁺ = 506.2.

Intermediate EX40-03

EX40-01a (5.0 g, 25.4 mmol) was dissolved in anhydrous N,N-dimethylformamide (50 mL), potassium hydroxide (5.0 g, 88.8 mmol) was added, and iodine (9.0 g, 35.5 mmol) was slowly added in an ice-water bath. The reaction solution was stirred at 25°C for 4 hours. After the reaction was completed, the reaction solution was poured into 1.5% ammonia water, filtered, and the filter cake was vacuum dried to obtain EX40-01 (7.0 g, yield 85.4%). LCMS: MS m/z (ESI) [M+H] ⁺ = 322.7; ¹ H NMR: (400MHz, DMSO-d ₆ ) δ7.81 (d, J = 1.2 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.32 (dd, J = 8.8, 1.2 Hz, 1H).

EX40-01 (3.00 g, 9.29 mmol) was dissolved in anhydrous dichloromethane (30 mL), and 4-cyano-3-fluorophenylboronic acid (3.10 g, 18.5 mmol) was added. Molecular sieves (3.00g), pyridine (2.25mL, 27.8mmol) and copper acetate (3.40g, 18.6mmol), the reaction solution was stirred at 25°C under an oxygen atmosphere for 16 hours. After the reaction was completed, the filtrate was filtered, diluted with water (30mL), and extracted with dichloromethane (50mL x 3). The organic phases were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/0 to 1/3), and the obtained solid was ground with ethyl acetate (8mL), filtered, and the filter cake was vacuum dried to obtain EX40-02 (3.00g, yield 73.1%). LCMS: MS m/z (ESI) [M+H] ⁺ = 441.9;

Compound EX40-02 (2.5 g, 5.65 mmol) was dissolved in dioxane (30 mL), and tert-butyl piperidine-4-carbamate (1.13 g, 5.66 mmol), cesium carbonate (7.37 g, 22.6 mmol), Xantphos (0.654 g, 1.13 mmol) and Pd ₂ (dba) ₃ (1.03 g, 1.13 mmol) were added. The reaction solution was heated to 100 ° C and stirred for 16 hours under nitrogen protection. After the reaction solution was cooled to room temperature, it was diluted with water (50 mL) and extracted with ethyl acetate (50 mL*3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 3/1) to obtain EX40-03. LCMS:MS m/z(ESI)[M+H] ⁺ =514.2;

Intermediate EX52-05a, EX52-05b

Potassium tert-butoxide (3.5 g, 31.1 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), and methyl triphenylphosphonium bromide (11.9 g, 33.3 mmol) was added in batches under an ice bath. The reaction solution was stirred for 15 minutes under a nitrogen atmosphere and then heated to 70 ° C and stirred for 45 minutes. After the reaction solution was cooled to room temperature, a solution of EX52-01 (5 g, 22.2 mmol) in anhydrous tetrahydrofuran (50 mL) was slowly added to the reaction solution, and the reaction was continued to stir for 1 hour. After the reaction was completed, the reaction solution was quenched with acetone (30 mL), filtered, and the filtrate was concentrated under reduced pressure. The residue was added with water (80 mL) and extracted with ethyl acetate (80 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 10/1) to give EX52-02 (3.98 g, yield 80.2%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.84 (t, J = 2.0 Hz, 2H), 4.23 (brs, 2H), 2.55–2.37 (m, 2H), 2.11–2.01 (m, 2H), 1.90-1.83 (m, 2H), 1.60-1.53 (m, 2H), 1.47 (s, 9H).

Compound EX52-02 (2.98 g, 13.3 mmol) was dissolved in anhydrous dichloromethane (50 mL) and m-CPBA (4.30 g, 21.2 mmol) was added. The reaction mixture was stirred at 25 ° C for 15 hours. The reaction solution was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 12/1) to obtain EX52-03a (969 mg, 4.049 mmol, yield 30.4%) and EX52-03b (828 mg, yield 26.0%).

EX52-03a:

1H NMR (400MHz, CDCl ₃ ) δ4.48-4.20(m,2H),2.75(s,2H),2.34-2.11(m,2H),2.08-1.94(m,2H),1.79-1.69(m, 2H),1.49(s,9H),1.29-1.24(m,2H).

EX52-03b:

¹ H NMR (400MHz, CDCl ₃ ) δ4.51-4.11(m,2H),2.44(s,2H),2.44-2.24(m,2H),2.12-1.93(m,4H),1.48(s,9H) ),1.24–1.15(m,2H).

EX52-03a (1.89 g, 7.89 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), and LiBHEt ₃ (8.68 mL, 8.68 mmol) was added in an ice bath under nitrogen atmosphere. The reaction solution was warmed to room temperature and stirred for 2 hours. The reaction was quenched with saturated ammonium chloride solution (30 mL) and extracted with ethyl acetate (40 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 7/1) to obtain EX52-04a (675 mg, yield 35.5%). ¹ H NMR (400MHz, DMSO-d ₆ ) δ4.39 (s, 1H), 4.10-3.94 (m, 2H), 1.91-1.73 (m, 4H), 1.70-1.55 (m, 4H), 1.40 (s, 9H), 1.33 (s, 3H).

EX52-04a (379 mg, 1.571 mmol) was dissolved in anhydrous dichloromethane (4 mL) and trifluoroacetic acid (0.8 mL, 0.186 mmol) was added. The reaction solution was stirred at 25°C for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the crude product EX52-05a (360 mg, 1.41 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.85-8.26 (m, 2H), 3.95 (brs, 2H), 2.11–2.00 (m, 2H), 1.97-1.83 (m, 4H), 1.79-1.70 (m, 2H), 1.33 (s, 3H).

EX52-03b (253 mg, 1.06 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), and LiBHEt ₃ (1.16 mL, 1.16 mmol) was added in an ice bath under nitrogen atmosphere. The reaction solution was warmed to room temperature and stirred for 2 hours. The reaction was quenched with saturated ammonium chloride solution (5 mL), and the tetrahydrofuran was removed by vacuum concentration, and then diluted with water (10 mL) and extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 7/1) to obtain EX52-04b (148 mg, yield 58.0%). ¹ H NMR (400MHz, DMSO-d ₆ ) δ4.20(s,1H),4.07–3.93(m,2H),2.16–2.04(m,2H),1.81-1.55(m,6H),1.38(s,9H),1.01(s,3H).

EX52-04b (148 mg, 0.613 mmol) was dissolved in anhydrous dichloromethane (3 mL) and TFA (0.6 mL, 0.613 mmol) was added. The reaction solution was stirred at 25°C for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the crude product EX52-05b. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.81-8.27 (m, 2H), 4.02–3.85 (m, 2H), 2.33–2.24 (m, 2H), 1.92-1.80 (m, 4H), 1.79-1.72 (m, 2H), 1.07 (s, 3H).

Intermediate EX53-03

Compound EX53-01 (1.50 g, 6.97 mmol) was dissolved in THF (20 mL), and 3 M MeMgCl solution (3.72 mL, 11.15 mmol) was slowly added at 0°C under nitrogen protection. The reaction solution was stirred at 0°C for 30 minutes. The reaction solution was quenched and diluted with water (50 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, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/(tetrahydrofuran + 0.1% ammonia water) = 100/0 to 55/45) to obtain the target product EX53-02 (1.90g, yield 91.7%). ¹ H NMR: (400MHz, CDCl ₃ ) δ7.41-7.34(m,2H),7.34-7.28(m,2H),7.26-7.16(m,1H),3.56(s,2H),2.75–2.64(m,2H),2.54–2.42(m,2H),1.83-1.77(m, 2H),1.73–1.62(m,4H),1.27(s,3H).

Compound EX53-02 (1.00 g, 4.32 mmol) was dissolved in MeOH (10 mL) and HCl (1 mL), and Pd/C (1.30 g, 12.2 mmol) was added. The reaction solution was stirred in a H ₂ (45 Psi) atmosphere for 16 h. After the reaction was completed, Pd/C was recovered by filtration, and the filtrate was concentrated under reduced pressure. Ethyl acetate (5 mL) was added to the crude product, and the mixture was ground and stirred for 5 minutes, then filtered. The filter cake was dried in vacuo to obtain the target product EX53-03 (443 mg, yield 72.5%).

Intermediate EX65-02

EX53-02 (200 mg, 0.865 mmol) was dissolved in tetrahydrofuran (5 mL), sodium hydrogen (173.0 mg, 4.33 mmol) was added at 0 ° C and stirred for 15 minutes, then iodomethane (0.220 mL, 3.46 mmol) was slowly added at 0 ° C, and the reaction solution was stirred at 25 ° C for 2 hours under nitrogen protection. The reaction solution was quenched with saturated ammonium chloride (10 mL) and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the reaction solution was concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/tetrahydrofuran = 100/0 to 1/3) to obtain EX65-01 (100 mg, yield 47.1%). LCMS: MS m/z (ESI) [M+H] ⁺ = 246.0.

EX65-01 (100 mg, 0.407 mmol) was dissolved in anhydrous methanol (1 mL), and wet palladium carbon (100 mg, 0.940 mmol) was added. The reaction solution was stirred at room temperature for 12 hours under a hydrogen atmosphere (45 psi). After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound EX65-02 (30.0 mg, yield 47.4%).

Intermediate EX69-03

EX69-01 (300 mg, 1.25 mmol) was dissolved in THF (3 mL), and 3 M methylmagnesium bromide solution (0.84 mL, 2.51 mmol) was slowly added dropwise under an ice-water bath. After the addition was completed, the reaction solution was stirred at room temperature for 2 hours. The reaction solution was quenched and diluted with water (10 mL), extracted with ethyl acetate (30 mL*3), the organic layers were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product EX69-02 (270 mg, yield 84.3%). ¹ H NMR (400MHz, DMSO-d ₆ ) δ4.51,4.37(2s,1H),3.94-3.60(m,2H),3.25-3.00(m,2H),2.21–2.00(m,2H),1.83-1.60(m,1H),1.60-1.43(m,3H),1.39( s,9H),1.36-1.28(m,2H),1.25(s,3H).

EX69-02 (300 mg, 1.175 mmol) was dissolved in 4M hydrochloric acid/dioxane (5 mL) and stirred at room temperature for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product EX69-03 (180 mg, yield 98.7%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.75-9.25 (m, 1H), 7.95-7.57 (m, 1H), 3.38-2.94 (m 1H), 2.21-1.73 (m, 3H), 1.72-1.36 (m, 5H), 1.27 (s, 3H).

Intermediate EX71-03

EX71-01 (300 mg, 1.24 mmol) was dissolved in tetrahydrofuran (3 mL), and 3 M methylmagnesium bromide (0.83 mL, 2.49 mmol) was added at 0°C, and the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride (5 mL), extracted with ethyl acetate (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain EX71-02 (300 mg, yield 93.8%). ¹ H NMR (400MHz, DMSO-d ₆ ) δ4.81-4.68(m,1H),4.16-3.70(m,5H),3.59-3.36(m,2H),3.29-3.09(m,1H),1.45-1.38(m,2H),1.38(s,9H),1.37-1.23(m,3 H).

EX71-02 (270 mg, 1.05 mmol) was dissolved in 4M hydrochloric acid/dioxane (3 mL) and stirred at room temperature for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure to obtain EX71-03 (200 mg, yield 98.4%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.76-9.16 (m, 1H), 8.03-7.48 (m, 1H), 5.23 (brs, 1H), 4.21-3.91 (m, 2H), 3.87-3.71 (m, 2H), 3.43-3.35 (m, 2H), 3.30-3.14 (m, 2H), 1.71-1.56 (m, 2H), 1.48-1.29 (m, 3H).

Intermediate EX73-02

EX53-01 (1.00 g, 4.65 mmol) was dissolved in methanol (30 mL), and sodium borohydride (280 mg, 6.50 mmol) was slowly added at 0 ° C. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, it was quenched and diluted with saturated aqueous ammonium chloride solution (50 ml) under an ice bath, and extracted with ethyl acetate (50 mL * 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain the crude product EX73-01a (1.10 g, yield 87.2%). LCMS: MS m/z (ESI) [M+H] ⁺ =217.9; ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.34-7.26 (m, 4H), 7.25-7.18 (m, 1H), 4.74 (d, J = 2.4Hz, 1H), 3.77-3.71 (m, 1H), 3.45 (s, 2H) ,2.67–2.56(m,2H),2.32–2.19(m,2H),1.88–1.75(m,2H),1.68-1.52(m,4H).

Compound EX73-01a (1.50 g, 6.90 mmol) was dissolved in dichloromethane (70 mL), and tert-butyldimethylsilyl chloride (1.20 g, 8.28 mmol) and imidazole (0.70 g, 10.4 mmol) were added. The reaction solution was stirred at 50 ° C for 16 hours. After the reaction was completed, it was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 10/1 to 10/3) to obtain EX73-01 (1.40 g, yield 61.2%). LCMS: MS m/z (ESI) [M+H] ⁺ = 332.2.

Compound EX73-01 (1.40 g, 4.22 mmol) was dissolved in methanol (20 mL), and 10% wet palladium carbon (1.40 g, 13.2 mmol) was added. The reaction solution was stirred under a hydrogen atmosphere (45 psi) for 16 hours. After the reaction, the reaction solution was filtered through diatomaceous earth, the filter cake was washed with methanol (30 ml), and the filtrate was combined and concentrated under reduced pressure and dried to obtain EX73-02 (800 mg, yield 78.5%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.95 (t, J = 4.8 Hz, 1H), 3.09 (d, J = 12.0 Hz, 2H), 2.21 (dd, J = 12.0, 2.0 Hz, 2H), 1.71-1.53 (m, 6H), 0.90 (s, 9H), 0.05 (s, 6H).

Intermediate EX74-03

EX73-01a (500 mg, 2.30 mmol) and pyridine (1.67 mL, 20.7 mmol) were dissolved in dichloromethane (15 mL), cooled to 0 ° C, trifluoromethanesulfonic anhydride (0.85 mL, 5.06 mmol) was slowly added under nitrogen protection and stirred for 0.5 hours. After the reaction was completed, the reaction solution was quenched and diluted with water (10 mL), and extracted with dichloromethane (30 mL * 3). After the organic phases were combined, they were washed with saturated brine (3A0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain compound EX74-01 (800 mg, yield 99.5%).

EX74-01 (804 mg, 2.30 mmol) and p-toluenesulfonic acid (594 mg, 3.45 mmol) were dissolved in water (2 ml), dimethyl sulfoxide (5 ml) and toluene (10 ml) at room temperature, and the temperature was raised to 100 ° C and stirred for 16 hours. After the reaction was completed, it was cooled to room temperature, the reaction solution was diluted with water (5 ml), and extracted with ethyl acetate (20 mL * 3). After the organic phases were combined, they were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 85/15) to obtain the target product EX74-02 (300 mg, yield 60.0%). LCMS: MS m/z (ESI) [M+H] ⁺ = 218.2.

EX74-02 (300 mg, 1.38 mmol) was dissolved in methanol (12 mL), and 10% wet palladium carbon (60 mg, 0.564 mmol) was added. The reaction solution was stirred at room temperature for 12 hours under a hydrogen atmosphere (45 psi). After the reaction was completed, the palladium carbon was recovered by filtration, and the filter cake was washed with methanol (30 mL). The filtrate was combined and concentrated under reduced pressure to dryness to obtain the target product EX74-03 (130 mg, yield 74.0%). ¹ H NMR (400MHz, CD ₃ OD) δ3.99-3.72(m,1H),2.81-2.74(m,2H),2.14–2.07(m,2H),2.06–2.01(m,1H),1.96-1.90(m,1H),1.84-1.78(m,1H),1.66-1.5 9(m,2H),1.56–1.50(m,1H).

Intermediate EX76-05

Potassium tert-butoxide (628 mg, 5.59 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL) under nitrogen protection, and then PPh ₃ MeBr (238 mg, 0.666 mmol) in tetrahydrofuran (10 mL) was slowly added at 0°C. After the addition, the reaction solution was heated to 80°C and stirred for 45 minutes. After cooling to room temperature, EX76-01 (900 mg, 3.99 mmol) was dissolved in tetrahydrofuran (8 mL) and added dropwise to the reaction solution. The reaction solution was stirred at 25°C for 12 hours. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride solution (10 mL), extracted with ethyl acetate (30 mL*3), the organic phases were combined, washed with saturated brine (20 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 95/5) to obtain the target product EX76-02 (289 mg, yield 32.4%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.72 (s, 2H), 4.00-3.75 (m, 2H), 2.95-2.68 (m, 2H), 2.52- 2.40(m,2H),1.62(d,J＝4.0Hz,2H),1.52-1.44(m,2H),1.40(s,9H).

At 0°C, compound EX76-02 (189 mg, 0.846 mmol) was dissolved in dichloromethane (2 mL), and then m-CPBA (161 mg, 0.931 mmol) was added. The reaction solution was stirred at 25°C for 15 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate (10 mL) solution and extracted with dichloromethane (10 mL*3). The organic phases were combined, washed with saturated brine (20 mL*2), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 87/13) to obtain the target product EX76-03 (110 mg, yield 54.3%). ¹ H NMR (400MHz, CDCl ₃ ) δ4.20-3.90(m,2H),3.18-2.95(m,4H),2.08–1.92(m,2H),1.75–1.60(m,4H),1.48(s,9H).

Compound EX76-03 (120 mg, 0.501 mmol) was dissolved in tetrahydrofuran (1.5 mL), and 1 M lithium triethylborohydride solution (0.55 mL, 0.552 mmol) was added at 0°C under nitrogen protection. The reaction solution was stirred at 0°C for 2 hours. The reaction solution was quenched with saturated NH ₄ Cl (5 mL) solution, then diluted with water (5 mL) and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated brine (10 mL*3), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was subjected to silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 72/28) to obtain EX76-04 (115 mg, yield 95.0%). ¹ H NMR (400MHz, DMSO-d ₆ ) δ4.41(s,1H),3.67-3.51(m,2H),3.08-2.87(m,2H),1.92–1.83(m,2H),1.75–1.65(m,2H),1.38(s,9H),1.30(s,3H),1.28-1. 20(m,2H).

Compound EX76-04 (95.0 mg, 0.394 mmol) was dissolved in dichloromethane (1.5 mL), and then trifluoroacetic acid (40.6 mg, 0.414 mmol) was added. The reaction solution was stirred at 25°C for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure and dried to obtain the crude product EX76-05 (90.0 mg, yield 95.6%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.73 (brs, 1H), 8.15 (brs, 1H), 3.17-3.05 (m, 2H), 3.05-2.94 (m, 2H), 2.06-1.98 (m, 2H), 1.92–1.82 (m, 2H), 1.60–1.50 (m, 2H), 1.37 (s, 3H).

Intermediate EX79-03

Compound EX79-01 (300 mg, 1.25 mmol) was dissolved in methanol (2 mL), sodium borohydride (150 mg, 3.97 mmol) was added at 0°C, and the reaction solution was stirred at 25°C for 2 hours. After the reaction was completed, the reaction solution was quenched with saturated aqueous ammonium chloride solution (10 mL), extracted with ethyl acetate (20 mL x 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 1/1) to give EX79-02 (300 mg, yield 99.2%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.30–4.17 (m, 2H), 3.44-3.34 (m, 1H), 2.21-2.01 (m, 3H), 1.48-1.36 (m, 5H), 1.38 (s, 9H), 1.29-1.18 (m, 2H).

EX79-02 (300 mg, 1.24 mmol) was dissolved in 4M hydrochloric acid/dioxane (3 mL) and stirred at room temperature for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure to obtain EX79-03 (hydrochloride) (220 mg, 99.6%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.91 (brs, 2H), 5.09 (s, 1H), 4.04-3.90 (m, 1H), 3.61-3.50 (m, 2H), 2.49-2.39 (m, 1H), 2.32-2.21 (m, 2H), 1.95-1.82 (m, 2H), 1.58-1.45 (m, 4H), 1.44-1.36 (m, 1H).

Intermediate EX88-06

EX88-01 (5.00 g, 34.22 mmol) was dissolved in ethyl acetate (5.0 mL), sodium ethoxide (11.7 g, 34.22 mmol) was added, and the reaction solution was stirred at 80°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain EX88-02 (6.6 g, yield 91.7%). ¹ H NMR (400 MHz, DMSO-d6) δ 5.07 (s, 1H), 4.06 (q, J = 7.2 Hz, 2H), 3.92 (q, J = 7.2 Hz, 2H), 1.20 (t, J = 7.2 Hz, 3H), 1.13 (t, J = 7.2 Hz, 3H).

EX88-02 (5.60 g, 26.6 mmol) was dissolved in water (50 mL), and a mixture of 3-aminopyrazole (2.20 g, 26.6 mmol) in water (50 mL) and acetic acid (39.7 mL, 693 mmol) was added. The reaction solution was stirred at 85°C for 16 hours. After cooling to room temperature, the reaction solution was filtered and the filter cake was dried under vacuum to obtain EX88-03 (1.42 g, yield 25.7%). ¹ H NMR (400 MHz, DMSO-d6) δ 13.35 (s, 1H), 12.12 (s, 1H), 8.17 (s, 1H), 6.64 (s, 1H), 4.37 (q, J = 6.8 Hz, 2H), 1.36 (t, J = 6.8 Hz, 3H).

EX88-03 (1.42 g, 6.85 mmol) was dissolved in toluene (24 mL), and DBU (1.23 mL, 8.22 mmol) was added. The reaction solution was stirred at 25 °C for 10 minutes, and then a toluene (12 mL) solution of phosphorus oxychloride (0.70 mL, 7.54 mmol) was added. The reaction solution was stirred at 110 °C for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was washed with petroleum ether/ethyl acetate (5/1, 5 mL), filtered, and the filter cake was removed under reduced pressure and dried to obtain EX88-04 (1.48 g, 95.7%). LCMS: MS m/z (ESI) [M+H] ⁺ = 226.1; ¹ H NMR (400 MHz, DMSO-d6) δ 14.21 (s, 1H), 8.38 (s, 1H), 7.62 (s, 1H), 4.44 (q, J = 7.2 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H).

EX88-04 (1.48 g, 6.56 mmol) was dissolved in N,N-dimethylformamide (10 mL), and N-iodosuccinimide (2.51 g, 11.2 mmol) was added. The reaction solution was stirred at room temperature for 16 hours. The reaction solution was diluted with water (30 mL), and the solid precipitated and filtered. The filter cake was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 5/1) to obtain EX88-05 (2.30 g, yield 99.7%). LCMS: MS m/z (ESI) [M+H] ⁺ = 351.9.

EX88-05 (2.30 g, 6.54 mmol) was dissolved in dichloromethane (200 mL), and 4-cyano-3-fluorophenylboronic acid (2.16 g, 13.1 mmol), copper acetate (2.38 g, 13.1 mmol), 4A molecular sieve (2.00 g) and pyridine (1.58 mL, 19.6 mmol) were added. The reaction solution was stirred at room temperature under an oxygen atmosphere for 48 hours. The reaction solution was concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/0 to 10/1) to obtain EX88-06 (2.70 g, yield 87.7%). LCMS: MS m/z (ESI) [M+H] ⁺ = 470.9.

Intermediate EX90-04

Compound EX90-01 (1.70 g, 12.7 mmol) was dissolved in anhydrous acetonitrile (70 mL), and TMSCl (3.52 mL, 27.9 mmol) and N-benzyl-1-methoxy-N-(methoxymethyl)methylamine (2.48 g, 12.7 mmol) were added. The reaction solution was stirred at 80 °C for 12 hours. The reaction solution was adjusted to pH ~ 8 by adding sodium bicarbonate aqueous solution (20 mL), extracted with ethyl acetate (50 mL*3), and the organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 9/1) to obtain EX90-02 (1.70 g, yield 43.1%). LCMS:MS m/z(ESI)[M+H2O+H] ⁺ =284.2; ¹ H NMR: (400MHz, CDCl3) δ7.40-7.36(m,4H),7.35-7.30(m,1H),3.66(s,2H),3.08-3.00(m,2H),2.78-2.68(m,1H),2 .65-2.59(m,1H),2.58-2.46(m,6H).

Compound EX90-02 (1.00 g, 3.77 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), cooled to -78 ° C, and methyl lithium (2.83 mL, 4.52 mmol) solution was slowly added. After the addition was complete, the reaction solution was stirred at -78 ° C for 2 hours under nitrogen protection. The reaction solution was quenched with saturated ammonium chloride (50 mL), extracted with ethyl acetate (50 mL*3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried to obtain EX90-03 (1.00 g, yield 94.3%). LCMS:MS m/z(ESI)[M+H] ⁺ =281.9; ¹ H NMR (400MHz, CDCl3) δ7.38-7.28(m,4H),7.27-7.20(m,1H),3.50(s,2H),2.84–2.70(m,2H),2.63–2.50(m,2H),2.47 -2.20(m,4H),1.85–1.74(m,2H),1.38(s,3H).

Compound EX90-03 (1.10 g, 3.91 mmol) was dissolved in methanol (20 mL), and Pd(OH) ₂ (0.55 g) and 10% Pd/C (0.55 g) were added. The reaction solution was stirred at room temperature for 16 hours under a hydrogen atmosphere (15 psi). The reaction solution was filtered, the filter cake was washed twice with methanol (2*10 ml), and the filtrate was concentrated under reduced pressure and dried to obtain EX90-04 (600 mg, yield 80.2%). ¹ H NMR (400 MHz, DMSO-d6) δ4.57 (s, 1H), 3.28-3.16 (m, 2H), 2.49-2.42 (m, 2H), 2.33-2.07 (m, 4H), 1.52–1.43 (m, 2H), 1.20 (s, 3H).

Intermediate EX101-05

EX101-01 (15.0 g, 90.3 mmol) was dissolved in acetic acid (100 mL) and water (100 mL), 1H-pyrazole-3-amine (7.50 g, 90.3 mmol) was added, and the reaction solution was stirred at 80°C for 8 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain EX101-02 (7.66 g, yield 45.8%). ¹ H NMR (400 MHz, DMSO-d6) δ 13.36 (s, 1H), 12.01 (s, 1H), 8.14 (s, 1H), 7.05 (t, J = 54.4 Hz, 1H), 6.33 (s, 1H).

EX101-02 (7.60 g, 41.1 mmol) was dissolved in phosphorus oxychloride (18.3 mL, 197 mmol), and the reaction solution was stirred at 85°C for 4 hours. After the reaction was completed, it was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 5/1) to obtain EX101-03 (3.50 g, yield 41.9%). LCMS: MS m/z (ESI) [M+H] ⁺ = 204.0; ¹ H NMR (400 MHz, DMSO-d6) δ 14.23 (s, 1H), 8.28 (s, 1H), 7.49 (s, 1H), 7.41 (t, J = 54.4 Hz, 1H).

EX101-03 (1.00 g, 4.91 mmol) was dissolved in dichloroethane (10 mL), and NIS (1.70 g, 9.82 mmol) was added. The reaction solution was stirred at 80°C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 EX101-04 (1.30 g, yield 80.3%) was obtained by purification (10/1). LCMS: MS m/z (ESI) [M+H] ⁺ = 329.9; ¹ H NMR (400 MHz, DMSO-d6) δ 14.62 (s, 1H), 7.68 (t, J = 54.4 Hz, 1H), 7.52 (s, 1H).

EX101-04 (1.30 g, 3.95 mmol) was dissolved in dichloromethane (20 mL), and 4-cyano-3-fluorophenylboronic acid (1.30 g, 7.89 mmol), pyridine (0.96 mL, 11.8 mmol), 4A molecular sieve (1.30 g) and copper acetate (1.43 g, 7.89 mmol) were added. The reaction solution was stirred at 25 ° C for 48 hours under an oxygen atmosphere. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 10/1) to obtain EX101-05 (1.70 g, yield 96.1%). LCMS: MS m/z (ESI) [M+H] ⁺ = 448.9; ¹ H NMR (400MHz, DMSO-d6) δ 8.28-8.12 (m, 3H), 7.78 (s, 1H), 7.70 (t, J = 53.6Hz, 1H).

Intermediate EX102-05

EX102-01 (2.0 g, 11.2 mmol) was dissolved in THF (30 mL). The reaction solution was cooled to -78 ° C under nitrogen protection and then 2.5 M n-butyl lithium n-hexane solution (4.95 mL, 12.4 mmol) was slowly added. The reaction solution was stirred at -78 ° C for 30 minutes, and DMF (1.58 mL, 1.50 mmol) was slowly added. The reaction solution was stirred at -78 ° C for 3 hours. After the reaction was completed, saturated ammonium chloride solution (30 mL) was added to quench and dilute, and the reaction solution was extracted with ethyl acetate (30 mL * 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product EX102-02 (2.0 g, yield 86.4%). ¹ H NMR (400MHz, CDCl ₃ ) δ10.40(s,1H),6.94(s,1H),4.02(s,3H).

EX102-02 (3.00 g, 14.6 mmol) was dissolved in n-butanol (35 mL), hydrazine hydrate (1.33 mL, 21.8 mmol) was added, and the reaction solution was stirred at 125°C for 12 hours. LCMS detected that the reaction was complete, and the reaction solution was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column (silica, petroleum ether/ethyl acetate = 100/0 to 3/1) to obtain EX102-03 (770 mg, yield 28.8%). LCMS: MS m/z (ESI) [M+H] ⁺ = 184.0; ¹ HNMR (400 MHz, DMSO-d6) δ 13.73 (s, 1H), 8.12 (s, 1H), 6.80 (s, 1H), 4.04 (s, 3H).

EX102-03 (720 mg, 3.92 mmol) was dissolved in dichloroethane (15 mL), and N-iodosuccinimide (1.36 g, 7.84 mmol) was added. The reaction solution was stirred at 80°C for 16 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 10/1) to obtain EX102-04 (600 mg, yield 49.4%). LCMS: MS m/z (ESI) [M+H] ⁺ = 309.9; ¹ H NMR (400 MHz, DMSO-d6) δ 14.03 (s, 1H), 6.82 (s, 1H), 4.02 (s, 3H).

EX102-04 (600 mg, 1.94 mmol) was dissolved in dichloromethane (2 mL), and 4-cyano-3-fluorophenylboronic acid (639 mg, 3.88 mmol), pyridine (0.470 mL, 5.82 mmol), 4A molecular sieve (600 mg) and copper acetate (704 mg, 3.88 mmol) were added. The reaction solution was stirred at 25 ° C for 48 hours under an oxygen atmosphere. The reaction solution was concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 10/1) to obtain EX102-05 (830 mg, yield 99.9%). LCMS: MS m/z (ESI) [M+H] ⁺ = 429.0.

Intermediate EX150-04

Compound EX150-01 (2.40 g, 11.0 mmol) and CbzCl (1.90 mL, 13.2 mmol) were dissolved in DCM (30 mL), and then DIPEA (3.60 mL, 22.0 mmol) was slowly added. The reaction solution was stirred at room temperature for 12 hours. The reaction solution was quenched with NaHCO ₃ aqueous solution (20 mL), and extracted with dichloromethane (20 mL*3). The organic phases were combined, washed with saturated brine (20 mL*2), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was subjected to silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 82/18) to obtain EX150-02 (3.80 g, yield 98.1%). LCMS:MS m/z(ESI)[M+Na] ⁺ =374.9; ¹ H NMR: (400MHz, DMSO-d ₆ )δ7.43-7.24(m,5H),5.12-5.01(m,2H),4.80-4.57(m,1H),4.30-4.14(m,1H),4.06-3.94(m, 1H),3.72-3.60(m,1H),3.24-2.82(m,2H),1.68-1.48(m,2H),1.39(s,9H).

At 0°C and _N2 atmosphere, compound EX150-02 (3.80 g, 10.8 mmol) was dissolved in DMF (40 mL), and then NaH (0.60 g, 14.0 mmol) was added. After half an hour, iodomethane (1.80 g, 12.9 mmol) was slowly added. The reaction solution was stirred at room temperature for 12 hours. The reaction solution was quenched with saturated aqueous ammonium chloride solution (30 mL), and extracted with ethyl acetate (30 mL*3). The organic phases were combined, washed with saturated brine (30 mL*2), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 87/13) to obtain EX150-03. LCMS:MS m/z(ESI)[M+Na] ⁺ =389.0; ¹ H NMR: (400MHz, DMSO-d ₆ )δ7.45-7.22(m,5H),5.08(s,2H),4.94-4.64(m,1H),4.35-4.20(m,1H),4.20-3.88(m,2H), 3.27-2.86(m,2H),2.75(s,3H),2.03-1.84(m,1H),1.63-1.47(m,1H),1.42(s,9H).

Compound EX150-03 (3.79 g, 10.3 mmol) was dissolved in EtOH (30 mL), and then 10% wet Pd/C (1.10 g, 10.3 mmol) was added. The reaction solution was stirred at room temperature for 2 hours under a pressure of 15 Psi in a H ₂ atmosphere. The reaction solution was filtered through diatomaceous earth, and the palladium catalyst was removed and concentrated under reduced pressure. After spin drying, EX150-04 was directly obtained. ¹ H NMR: (400 MHz, DMSO-d ₆ )δ4.74-4.43 (m, 1H), 4.17-3.74 (m, 1H), 3.09-2.94 (m, 2H), 2.76 (s, 3H), 2.72-2.51 (m, 2H), 1.94-1.78 (m, 1H), 1.40 (s, 9H), 1.48-1.32 (m, 1H).

Example EX1

Compound EX1-01 (1.50 g, 6.48 mmol) was dissolved in 1,4-dioxane (30 mL) and water (5 mL), and phenylboric acid (790 mg, 6.48 mmol), Pd(dppf)Cl ₂ (474 mg, 648.01 umol) and potassium carbonate (1.79 g, 13.0 mmol) were added. The reaction solution was heated to 100°C under nitrogen protection and stirred for 4 hours. Ethyl acetate (40 mL) and water (10 mL) were added to the reaction solution for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 20/1) to obtain EX1-02 (1.00 g, yield 67.5%). LCMS: MS m/z (ESI) [M+H] ⁺ = 229.0.

Compound EX1-02 (0.90 g, 3.94 mmol) and 4-(dihydroxyboryl)-2-fluorobenzene-1-carbonitrile (1.30 g, 7.87 mmol) were dissolved in anhydrous dichloromethane (40 mL), and pyridine (935 mg, 11.8 mmol, 953 uL) was added. Molecular sieves (1.00 g) and copper acetate (1.43 g, 7.87 mmol). The reaction solution was stirred at room temperature under an oxygen atmosphere for 16 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 20/1) to obtain EX1-03 (400 mg, yield 29.2%). LCMS: MS m/z (ESI) [M+H] ⁺ = 348.1; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.92 (s, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.83-7.78 (m, 1H), 7.77-7.71 (m, 2H), 7.67-7.60 (m, 3H), 7.56–7.49 (m, 2H), 7.49-7.43 (m, 1H).

Compound EX1-03 (200 mg, 575 umol) and tert-butyl N-(4-piperidinyl)carbamate (230 mg, 1.15 mmol) were dissolved in 1,4-dioxane (4 mL), and Pd ₂ (dba) ₃ (52.7 mg, 57.5 umol), Xantphos (66.6 mg, 115 umol) and cesium carbonate (562 mg, 1.73 mmol) were added. The reaction solution was heated to 100°C under nitrogen protection and stirred for 12 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 10/1 to 3/1) to obtain EX1-04 (100 mg). LCMS: MS m/z (ESI) [M+H] ⁺ = 512.3.

Compound EX1-04 (100 mg) was dissolved in 4M hydrochloric acid/1,4-dioxane (1 mL) and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: YMC-Triart Prep C18 150*40mm*7um; mobile phase: [water (formic acid)-acetonitrile]; B%: 23%-63%, 9 minutes) to obtain EX1. LCMS:MS m/z(ESI)[M+H] ⁺ =412.0; ¹ H NMR: (400MHz, DMSO-d ₆ )δ8.40(s,1H),8.11(s,1H),8.07(d,J＝8.4Hz,1H),8.04–7.99(m,1H),7.98-7.90(m,2H),7.85– 7.80(m,2H),7.58-7.49(m,3H),7.47-7.40(m,1H),4.15–4.05(m,2H),3.13-3.01(m,3H),2.00–1.90(m,2H),1.70-1.55(m,2H).

Example EX2

Example EX2 was prepared by using EX1-01 and (2-methylphenyl)boric acid as raw materials through the same synthesis route as EX1. LCMS: MS m/z (ESI) [M+H] ⁺ =426.2; ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.01 (d, J = 8.4Hz, 1H), 7.95 (t, J = 8.4Hz, 1H), 7.90–7.82 (m, 3H), 7.36–7.27 (m, 4H), 7.23 (dd, J = 8 .4,1.2Hz,1H),4.04(d,J＝12.8Hz,2H),3.12–3.02(m,2H),2.85-2.72(m,1H),2.26(s,3H),1.91–1.82(m,2H),1.46(td,J＝13.6,4.0Hz,2H).

Example EX3

2-(4,4-difluorocyclohex-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (580 mg, 2.4 mmol) and EX1-01 (500 mg, 2.2 mmol) were dissolved in a solution of dioxane (10 mL) and water (1 mL), and Pd(dppf)Cl ₂ (158 mg, 0.22 mmol) and potassium carbonate (896 mg, 6.5 mmol) were added. The reaction solution was heated to 100°C under a nitrogen atmosphere and stirred for 12 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL*3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 3/1 to 1/1) to obtain EX3-02 (325 mg, yield 56%). LCMS:m/z(ESI):269.2[M+H] ⁺ ;

Compound EX3-02 (305 mg, 1.1 mmol) and (4-cyano-3-fluorophenyl)boronic acid (374 mg, 2.3 mmol) were dissolved in dichloromethane (10 mL), and copper acetate (412 mg, 2.3 mmol), pyridine (0.27 mL, 3.4 mmol) and Molecular sieves (500 mg). The reaction solution was stirred at room temperature under an oxygen atmosphere for 18 hours. The reaction solution was filtered, and the filter cake was washed with dichloromethane/methanol (10/1, 50 mL). The filtrate and washing solution were combined and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 5/1 to 1/1) to obtain EX3-03 (264 mg, yield 60%). LCMS: MS m/z (ESI) [M+H] ⁺ = 388.0;

Compound EX3-03 (150 mg, 0.39 mmol) and tert-butyl piperidine-4-carbamate (155 mg, 0.77 mmol) were dissolved in a dioxane (4 mL) solution, and tris(dibenzylideneacetone)dipalladium (35.0 mg, 0.039 mmol), Xantphos (45.0 mg, 0.077 mmol) and cesium carbonate (378 mg, 1.2 mmol) were added. The reaction solution was heated to 100 ° C under a nitrogen atmosphere and stirred for 12 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL*3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 5/1 to 1/1) to obtain EX3-04 (83 mg, yield 23%). LCMS: MS m/z(ESI)[M+H] ⁺ =552.4.

Compound EX3-04 (110 mg, 167 umol) was dissolved in dichloromethane (1 mL), and hydrochloric acid/dioxane solution (0.32 mL, 1.27 mmol) was added, and the reaction solution was stirred at room temperature for 1 hour. After the reaction solution was concentrated under reduced pressure, it was purified by preparative HPLC (chromatographic column: Ultimate XB-C18, 50*250 mm, 10 um; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; B%: 20%-40%) to obtain EX3. LCMS:MS m/z(ESI)[M+H] ⁺ =452.2; ¹ HNMR (400MHz, CD ₃ OD): δ7.88–7.74(m,5H),7.37(d,J＝9.6Hz,1H),6.12(s,1H),4.22(d,J＝13.6Hz,2H),3.43–3.35(m,1H ),3.14(t,J＝11.6Hz,2H),2.85–2.70(m,4H),2.29–2.17(m,2H),2.13(d,J＝10.4Hz,2H),1.88(tt,J＝12.4,6.0Hz,2H).

Example EX5, EX6

Compound EX5-02 (550 mg, 1.10 mmol) and tert-butyl piperidine-4-carbamate (333 mg, 1.66 mmol) were dissolved in a dioxane (10 mL) solution, and tris(dibenzylideneacetone)dipalladium (102 mg, 111 umol,), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (128 mg, 222 umol) and cesium carbonate (722 mg, 2.21 mmol) were added. The reaction solution was heated to 100 ° C under a nitrogen atmosphere and stirred for 12 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL*3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 3/1) to obtain EX5-03 (110 mg, yield 15.00%). LCMS: MS m/z (ESI) [M+H] ⁺ = 660.6.

Compound EX5-03 (110 mg, 167 umol) was dissolved in methanol (5 mL) solution, p-toluenesulfonic acid (574 mg, 3.33 mmol) was added, and the reaction solution was stirred at room temperature for 16 hours. The reaction solution was purified by preparative HPLC (chromatographic column: Phenomenex C18 80*30 mm*5 um; mobile phase: [water (formic acid)-acetonitrile]; B%: 20%-40%, 10 minutes). Subsequently, EX5 and EX5 were separated and purified by preparative SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: [0.1% ammonia water. ethanol]; B%: 50%-50%). LCMS: MS m/z (ESI) [M+H] ⁺ = 446.3;

EX5: ¹ H NMR (400MHz, CD ₃ OD) δ7.83-7.67(m,5H),7.34(d,J＝9.6Hz,1H),6.19–6.13(m,1H),4.15–4.04(m, 2H),3.10–2.98(m,2H),2.95-2.84(m,1H),2.76-2.65(m,1H),2.57-2.45(m,1H),2.37–2.30(m,2H),2.04- 1.94(m,2H),1.92-1.84(m,1H),1.81-1.73(m,1H),1.69–1.55(m,2H),1.31(s,3H).

EX6: ¹ H NMR (400MHz, CD ₃ OD) δ7.83-7.67(m,5H),7.34(d,J＝9.6Hz,1H),6.19–6.13(m,1H),4.15–4.04(m, 2H),3.10–2.98(m,2H),2.95-2.84(m,1H),2.76-2.65(m,1H),2.57-2.45(m,1H),2.37–2.30(m,2H),2.04- 1.94(m,2H),1.92-1.84(m,1H),1.81-1.73(m,1H),1.69–1.55(m,2H),1.31(s,3H).

Example EX7

Compound EX7-02 (1.35 g, 5.81 mmol) was dissolved in 1,4-dioxane (25 mL) and water (4 mL), and phenylboric acid (743 mg, 6.10 mmol), potassium carbonate (1.61 g, 11.6 mmol) and Pd(dppf)Cl ₂ (425 mg, 0.581 mmol) were added. The reaction mixture was heated to 100 °C under nitrogen protection and stirred for 4 hours. The reaction solution was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (40 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was ground with (petroleum ether/ethyl acetate = 3/1, 10 mL) and filtered, and the filter cake was dried under vacuum to obtain EX7-03 (700 mg, yield 52.5%). LCMS: MS m/z (ESI) [M+H] ⁺ =229.9; ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.89 (s, 1H), 8.23 (s, 1H), 7.82 (d, J = 6.8Hz, 2H), 7.60-7.50 (m, 2H), 7.50-7.42 (m, 1H).

Compound EX7-03 (700 mg, 3.05 mmol) was dissolved in dichloromethane (30 mL), and 4-cyano-3-fluorophenylboronic acid (1.01 g, 6.10 mmol) was added. Type molecular sieve (1g), pyridine (723mg, 9.14mmol) and copper acetate (1.11g, 6.10mmol). The reaction mixture was stirred at room temperature for 16 hours in an oxygen atmosphere. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was slurried (petroleum ether/ethyl acetate = 3/1) to obtain EX7-04 (300mg, yield 28.22%). LCMS: MS m/z (ESI) [M+H] ⁺ = 349.0; ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.08 (s, 1H), 8.69 (s, 1H), 8.24-8.10 (m, 2H), 8.02 (br d, J = 8.0Hz, 1H), 7.93 (d, J = 7.2Hz, 2H), 7. 64-7.55(m,2H),7.55-7.46(m,1H).

Compound EX7-04 (200 mg, 0.575 mol) and tert-butyl piperidine-4-carbamate (230 mg, 1.15 mmol) were dissolved in 1,4-dioxane (5 mL), and Pd ₂ (dba) ₃ (52.7 mg, 57.5 umol), Xantphos (66.6 mg, 115 μmol) and cesium carbonate (562 mg, 1.73 mmol) were added. The reaction mixture was stirred at 100 ° C for 16 hours in a nitrogen atmosphere. After the reaction solution was cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/0 to 3/1) to obtain EX7-05 (38.0 mg, yield 12.9%). LCMS: MS m/z (ESI) [M+H] ⁺ = 513.3.

Compound EX7-05 (30 mg, 59.0 μmol) was dissolved in 4M hydrochloric acid/1,4-dioxane solution (3 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was subjected to preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 28%-48%, 9 minutes) to obtain EX7. LCMS: MS m/z (ESI) [M+H] ⁺ = 413.1; ¹ H NMR (400MHz, CD ₃ OD) δ8.79 (d, J = 2.0Hz, 1H), 8.55 (s, 1H), 8.41 (d, J = 2.0Hz, 1H), 7.89-7.82 (m, 3H), 7.79 (d, J = 7.2Hz, 2H ),7.59-7.52(m,2H),7.51-7.45(m,1H),5.00–4.90(m,2H),3.43-3.36(m,1H),3.24-3.11(m,2H),2.19–2.07(m,2H),1.89–1.74(m,2H).

Example EX8

Under nitrogen protection, Pd/C (7.7 mg, 10% wt., 55% H ₂ O) was added to a methanol solution of EX3-04 (40 mg, 0.073 mmol). The reaction solution was stirred at room temperature for 18 hours under a hydrogen atmosphere. The filtrate was filtered and concentrated under reduced pressure. The crude product was purified by reverse silica gel column chromatography to obtain EX8-01 (5 mg). LCMS: MS m/z (ESI) [M+H] ⁺ = 554.3;

Compound EX8-01 (5 mg, 0.009 mmol) was dissolved in 4M hydrochloric acid/1,4-dioxane solution (0.11 mL) and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was subjected to preparative HPLC (column: Xtimate C18, 50*250 mm, 10 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 30%-80%) to obtain EX8. LCMS:MS m/z(ESI)[M+H] ⁺ =454.2; ¹ H NMR (400MHz, CD ₃ OD): δ7.87–7.81(m,2H),7.80–7.73(m,3H),7.22–7.19(m,1H),4.13(d,J＝13.2Hz,2H),3.11–3.03(m ,2H),2.90(t,J＝12.4Hz,1H),2.21–2.15(m,2H),2.10–1.97(m,6H),1.95–1.83(m,3H),1.75–1.62(m,2H).

Example EX9

Compound EX9-01 (800 mg, 2.28 mmol) was dissolved in 1,4-dioxane (12 mL) and water (2 mL), and 1H-pyrazole-3-boric acid (255 mg, 2.282 mmol), Pd(dtbpf)Cl ₂ (134 mg, 0.205 mmol) and potassium carbonate (946 mg, 6.85 mmol) were added. The reaction solution was heated to 100°C and stirred for 2 hours under nitrogen protection. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography to obtain EX9-02 (500 mg, yield 64.9%). LCMS: MS m/z (ESI) [M+H] ⁺ = 337.9;

Compound EX9-02 (490 mg, 1.45 mmol) was dissolved in dichloromethane (10 mL), and diisopropylethylamine (0.719 mL, 4.35 mmol) and SEMCl (0.385 mL, 2.18 mmol) were added. The reaction solution was stirred at 25 °C for 12 hours. The reaction solution was quenched and diluted with water (10 mL), and extracted with dichloromethane (10 mL*3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/tetrahydrofuran = 100/0 to 4/1) to obtain EX9-03 (500 mg, yield 73.6%). LCMS: MS m/z (ESI) [M+H] ⁺ = 468.2;

Compound EX9-03 (250 mg, 0.534 mmol) was dissolved in dioxane (15 mL), and tert-butyl N-(4-piperidinyl)carbamate (267 mg, 1.34 mmol), cesium carbonate (522 mg, 1.60 mmol), sodium iodide (16.0 mg, 0.107 mmol) and RuPhos Pd G2 (41.5 mg, 0.053 mmol) were added. The reaction solution was heated to 100 ° C under nitrogen protection and stirred for 12 hours. After the reaction solution was cooled to room temperature, it was filtered, concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/tetrahydrofuran = 100/0 to 4/1) to obtain EX9-04 (100 mg, yield 29.6%). LCMS: MS m/z (ESI) [M+H] ⁺ = 632.3;

Compound EX9-04 (200 mg, 0.361 mmol) was dissolved in 4M hydrochloric acid/1,4-dioxane solution (3 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and dried by spin drying. The residue was subjected to preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 3%-43%, 13 minutes) to obtain EX9. LCMS: MS m/z (ESI) [M+H] ⁺ = 402.1; ¹ H NMR: (400MHz, DMSO-d ₆ ) δ8.39 (s, 1H), 8.30 (s, 1H), 8.09-7.99 (m, 2H), 7.94-7.86 (m, 2H), 7.84-7.77 (m, 1H), 7.77-7. 73(m,1H),6.96(d,J＝2.4Hz,1H),4.17-4.05(m,2H),3.10-3.04(m,3H),2.02-1.92(m,2H),1.71-1.58(m,2H).

Example EX10

Compound EX9-01 (1.10 g, 3.13 mmol) was dissolved in anhydrous 1,4-dioxane (20 mL), and 4-methylpiperidin-4-ol (0.300 g, 2.61 mmol), cesium carbonate (2.55 g, 7.81 mmol), Xantphos (0.30 g, 0.521 mmol) and Pd ₂ (dba) ₃ (0.24 g, 0.260 mmol) were added. The reaction solution was protected by nitrogen and heated to 100 ° C. and stirred for 12 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was dried by rotary evaporation. The residue was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 2/1) to obtain the target product EX10-01 (500 mg, 49.9%). LCMS: MS m/z (ESI) [M+H] ⁺ = 385.0;

EX10-01 (0.57 g, 1.47 mmol) was dissolved in 4M hydrochloric acid 1,4-dioxane solution (10 mL), and tert-butyl N-(4-piperidinyl)carbamate (0.740 g, 3.68 mmol), cesium carbonate (1.44 g, 4.42 mmol), sodium iodide (40.0 mg, 0.294 mmol) and RuPhos-Pd-G2 (110 mg, 0.147 mmol) were added. The reaction solution was heated to 100 ° C under nitrogen protection and stirred for 12 hours. The reaction solution was cooled to room temperature, diluted with water (3 mL), and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 2/1) to give EX10-02 (120 mg, yield 14.9%). LCMS: MS m/z (ESI) [M+H] ⁺ = 549.2;

Compound EX10-02 (50 mg, 91.0 umol) was dissolved in methanol (4 mL), TsOH (78.5 mg, 0.456 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and then spin-dried, and then subjected to preparative HPLC (column: Boston Prime C18 150*30 mm*5 um; mobile phase: [water (formic acid)-acetonitrile]; B%: 5-35%, 10 minutes) to obtain EX10. LCMS: MS m/z (ESI) [M+H] ⁺ = 449.1; ¹ H NMR: (400 MHz, CD ₃ OD)δ8.55(s,1H),7.85-7.77(m,1H),7.76-7.62(m,3H),7.17(d,J＝1.2Hz,1H),7.02(dd,J＝9.2,1.6Hz,1H),4.25–4.10(m,2H),3.55–3.43(m,2H),3.3 7–3.32(m,1H),3.31–3.24(m,2H),3.16–3.02(m,2H),2.17-2.03(m,2H),1.91-1.79(m,2H),1.78-1.70(m,4H),1.28(s,3H).

Example EX11

Compound EX7-02 (1.2 g, 3.61 mmol) was dissolved in dioxane (15 mL) and water (3 mL), and EX4-06 (1.27 g, 3.61 mmol), Pd(dppf)Cl ₂ (0.26 g, 0.361 mmol), and potassium carbonate (1.00 g, 7.23 mmol) were added. The reaction solution was heated to 100°C under nitrogen protection and stirred for 18 hours. The reaction solution was concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 4/1) to obtain EX11-01 (0.6 g, yield 43.9%). LCMS: MS m/z (ESI) [M+H] ⁺ = 378.2;

Compound EX11-01 (580 mg, 1.53 mmol) was dissolved in anhydrous dichloromethane (10 mL), and 4-cyano-3-fluorophenylboronic acid (506 mg, 3.07 mmol), copper acetate (557 mg, 3.07 mmol), molecular sieves (500 mg) and pyridine (0.370 mL, 4.60 mmol) were added. The reaction solution was stirred at room temperature under oxygen conditions for 16 hours. The reaction solution was filtered, and the filtrate was concentrated and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 14/1) to obtain EX11-02 (50 mg, yield 6.56%). LCMS: MS m/z (ESI) [M+H] ⁺ = 497.1;

Compound EX11-02 (40 mg, 80.0 umol) was dissolved in dioxane (2 mL), and tert-butyl piperidine-4-carbamate (40.1 mg, 0.200 mmol), RuPhos Pd G2 (1.55 mg, 2.00 umol), sodium iodide (0.60 mg, 4.00 umol) and cesium carbonate (13.0 mg, 40.0 umol) were added. The reaction solution was heated to 100 ° C and stirred for 18 hours under nitrogen protection. The reaction solution was filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/0 to 4/1) to obtain EX11-03 (30 mg, yield 56.4%). LCMS: MS m/z (ESI) [M+H] ⁺ = 661.3;

Compound EX11-03 (30 mg, 0.045 mmol) was dissolved in methanol (1 mL), p-toluenesulfonic acid monohydrate (39.1 mg, 0.227 mmol) was added, and stirred at room temperature for 12 hours. The reaction solution was separated and purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 13%-43%, 11 minutes) to obtain EX11. LCMS: MS m/z (ESI) [M+H] ⁺ = 447.1; ¹ H NMR (400 MHz, CD ₃ OD)δ8.64(d,J＝1.6Hz,1H),8.55(s,1H),8.17(d,J＝1.6Hz,1H),7.89-7.77(m,3H),6.30-6.23(m,1H),3.39-3.33(m,3H),3.19-3.08(m,2H),2.82-2.7 0(m,1H),2.62-2.51(m,1H),2.41–2.33(m,2H),2.15-2.05(m,2H),1.96-1.87(m,1H),1.85-1.71(m,3H),1.36-1.31(m,3H).

Example EX12

Compound EX12-03b (500 mg, 1.42 mmol) was dissolved in dioxane (10 mL) and water (2 mL), and EX4-06 (501 mg, 1.42 mmol), Pd(dppf)Cl ₂ (104 mg, 0.142 mmol) and potassium carbonate (393 mg, 2.84 mmol) were added. The reaction solution was heated to 100°C under nitrogen protection and stirred for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/dichloromethane = 100/0 to 3/2) to obtain EX12-04b (440 mg, yield 62.2%). LCMS: MS m/z (ESI) [M+H] ⁺ = 497.3; ¹ H NMR:(400MHz,DMSO)δ8.57(dd,J＝11.2,2.0Hz,1H),8.47(dd,J＝8.8,1.2Hz,1H),8.01(d,J＝8.4Hz,1H),7.75(J＝8,4,6.8Hz,1H),7.54(d,J＝8.4Hz,1H),6.77–6.71(m,1H),2.95–2.80(m,1H),2.75-2.60(m,2H),2.54-2.34(m,2H),2.01-1.90(m,1H),1.78–1.70(m,1H),1.27(s,3H),0.84(s,9H),0.15(s,3H),0.09(s,3H).

Compound EX12-04b (220 mg, 0.443 mmol) was dissolved in dioxane (10 mL), and tert-butyl piperidine-4-carbamate (222 mg, 1.11 mmol), cesium carbonate (433 mg, 1.33 mmol), NaI (13.3 mg, 89.0 umol), RuPhos Pd G2 (34.4 mg, 44.0 umol) were added. The reaction solution was heated to 100 ° C under nitrogen protection and stirred for 12 hours. After the reaction solution was cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/tetrahydrofuran = 100/0 to 4/1) to obtain EX12-05b (80 mg, yield 27.4%). LCMS: MS m/z (ESI) [M+H] ⁺ = 661.4; ¹ H NMR: (400 MHz, CDCl ₃ )δ8.47-8.28(m,2H),7.93(d,J＝8.4Hz,1H),7.57(dd,J＝8.4,7.2Hz,1H),7.24(d,J＝8.4Hz,1H),6.64-6.54(m,1H),4.52–4.35(m,1H),4.05-3.90(m,2H ),3.76-3.52(m,1H),3.16-3.02(m,2H),2.8 2-2.67(m,1H),2.61-2.48(m,1H),2.43-2.22(m,2H),2.10-1.95(m,2H),1.91-1.79(m,1H),1.71-1.61(m,1H),1.60-1.55(m,2H),1.38(s,9H),1 .27(s,3H),0.75(s,9H),0.05(s,3H),0.00(s,3H).

Compound EX12-05b (80.0 mg, 0.121 mmol) was dissolved in methanol (2 mL) and TsOH (153 mg, 0.886 mmol) was added. The mixture was stirred at 25°C for 12 hours. The reaction solution was subjected to preparative HPLC (column: Boston Prime C18 75*30 mm*5 um; mobile phase: [water (ammonia water)-acetonitrile]; B%: 50%-70%, 11 minutes) to obtain EX12. LCMS: MS m/z (ESI) [M+H] ⁺ = 447.0; ¹ H NMR: (400MHz, DMSO) δ8.49(dd,J＝12.0,1.6Hz,2H),8.45-8.33(m,2H),8.01(t,J＝8.0Hz,1H),7.55(d,J＝8.4Hz,1H),6.88–6.80(m,1H),4.42(s,1H),4.15–4. 02(m,2H) ,3.12–3.02(m,2H),2.90-2.81(m,1H),2.80-2.58(m,2H),2.36–2.27(m,2H),1.92–1.82(m,2H),1.82-1.74(m,1H),1.71-1.62(m,1H),1.49-1.3 4(m,2H),1.21(s,3H).

Example EX13

Compound EX9-01 (1.04 g, 2.97 mmol) was dissolved in dioxane (10 mL), and 4,4-difluoropiperidine (300 mg, 2.48 mmol), cesium carbonate (2.42 g, 7.43 mmol), Xantphos (290 mg, 0.495 mmol) and Pd ₂ (dba) ₃ (230 mg, 0.248 mmol) were added. The reaction solution was stirred at 100 ° C for 12 hours under nitrogen protection. LCMS detected the target product (petroleum ether: ethyl acetate = 3:1, Rf = 0.7). The reaction solution was filtered and concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 7/3) to obtain the target product EX13-01 (400 mg, yield 41.33%). LCMS: MS m/z (ESI) [M+H] ⁺ = 391.1.

Compound EX13-01 (380 mg, 0.972 mmol) and 4-Boc-aminopiperidine (487 mg, 2.43 mmol) were dissolved in dioxane (10 mL), and Cs ₂ CO ₃ (950 mg, 2.92 mmol), NaI (29.3 mg, 0.194 mmol), and RuPhos Pd G ₂ (75.5 mg, 97.0 umol) were added. The reaction solution was stirred at 100°C for 12 hours under nitrogen protection. After the reaction solution was cooled to room temperature, it was filtered, concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/tetrahydrofuran = 100/0 to 4/1) to obtain EX13-02 (200 mg, yield 37.1%). LCMS: MS m/z (ESI) [M+H] ⁺ = 555.3;

Compound EX13-02 (200 mg, 0.361 mmol) was dissolved in 4M hydrochloric acid/1,4-dioxane solution (3 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and dried by spin drying. The crude product was subjected to preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 16%-56%, 13 minutes) to obtain EX13. LCMS: MS m/z (ESI) [M+H] ⁺ = 455.1; ¹ H NMR: (400MHz, CD ₃ OD) δ8.55 (brs, 1H), 7.86-7.80 (m, 1H), 7.77-7.69 (m, 3H), 7.24 (d, J = 1.2Hz, 1H), 7.05 (dd, J = 9.2, 2.0 Hz,1H),4.24–4.11(m,2H),3.56-3.45(m,4H),3.39-3.33(m,1H),3.17-3.01(m,2H),2.19-2.06(m,6H),1.95–1.76(m,2H).

Example EX14

Example EX14 was prepared by the same route as EX13 using EX14-01 and 4,4-difluoropiperidine as raw materials. Preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 19%-59%, 9 minutes). LCMS:MS m/z(ESI)[M+H] ⁺ =456.0; ¹ H NMR (400MHz, CD ₃ OD) δ8.57(brs,1H),8.40(s,1H),7.85-7.79(m,1H),7.80–7.70(m,2H),7.56(s,1H),5.00-4.92(m,2 H),3.62–3.51(m,4H),3.32-3.22(m,1H),3.15–3.03(m,2H),2.24-2.11(m,4H),2.10–2.00(m,2H),1.82-1.69(m,2H).

Example EX15

Compound EX5-03 (100 mg, 152 umol) was dissolved in methanol (5 mL), Pd/C (50 mg, 10%) was added, and the reaction solution was stirred at room temperature for 16 hours under a hydrogen atmosphere (15 psi). The reaction solution was filtered to recover palladium carbon, and the filtrate was concentrated under reduced pressure to obtain a crude product EX15-01. LCMS: MS m/z (ESI) [M+H] ⁺ = 662.2;

Compound EX15-01 (40 mg, 60.0 umol) was dissolved in methanol (5 mL), p-toluenesulfonic acid (156 mg, 906 umol) was added, and the reaction solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The crude product was purified by preparative HPLC (chromatographic column: Phenomenex C18 80*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 20%-40%, 10 minutes) to obtain EX15. LCMS: MS m/z (ESI) [M+H] ⁺ = 448.1; ¹ H NMR (400MHz, CD ₃ OD) δ8.55 (s, 1H), 7.90-7.70 (m, 5H), 7.23 (d, J = 8.4Hz, 1H), 4.29–4.11 (m, 2H), 3.32–3.22 (m, 1H), 3. 18-3.04(m,2H),2.77-2.63(m,1H),2.16-2.06(m,2H),2.05-1.91(m,2H),1.90-1.76(m,4H),1.75-1.66(m,2H),1.64-1.52(m,2H),1.26(s,3H).

Example EX16

Example EX16 was prepared by the same route as EX11 using EX4-01 and MeMgBr as raw materials. Preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 47%-77%, 8 minutes). LCMS: MS m/z (ESI) [M+H] ⁺ = 461.1; ¹ H NMR (400MHz, CD ₃ OD)δ8.62(d,J＝1.6Hz,1H),8.14(d,J＝1.6Hz,1H),7.87-7.75(m,3H),6.30-6.22(m,1H),4.78-4.70(m,2H),3.15-3.03(m,2H),3.02-2.92(m,1H),2. 80-2.69(m,1H),2.59-2.49(m,1H),2.42-2.26(m,2H),2.05-1.94(m,2H),1.93-1.85(m,1H),1.84-1.75(m,1H),1.67-1.52(m,4H),1.01(t,J＝7.2 Hz,3H).

Example EX17

Example EX17 was prepared by the same route as EX13 using EX9-01 and 4-methoxy-4-methylpiperidine hydrochloride as raw materials. Preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 20%-60%, 9 minutes). LCMS: MS m/z (ESI) [M+H] ⁺ = 463.2; ¹ H NMR (400MHz, CD ₃ OD) δ7.82-7.75 (m, 1H), 7.71-7.63 (m, 3H), 7.14 (d, J＝1.6Hz,1H),6.99(dd,J＝9.2,2.0Hz,1H),4.13–4.02(m,2H),3.52–3.42(m,2H),3.25(s,3H),3.21-3.12(m,2H),3.07–2.97(m,2H),2.96–2.83(m,1H) ),2.02-1.87(m,4H),1.75-1.56(m,4H),1.23(s,3H).

Example EX18

EX9-01 (500 mg, 1.43 mmol) was dissolved in dioxane (5 mL), and tert-butyl piperidine-4-carbamate (286 mg, 1.43 mmol), Pd(dba) ₃ (115 mg, 0.143 mmol), Xantphos (165 mg, 0.285 mmol) and cesium carbonate (1.40 g, 4.28 mmol) were added. The reaction solution was heated to 100 ° C under nitrogen protection and stirred for 12 hours. The reaction solution was diluted with ethyl acetate (10 mL) and water (5 mL). The organic phase was washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/0 to 3/1) to obtain EX18-01 (291 mg, yield 43.4%). LCMS:MS m/z(ESI)[M+H] ⁺ =470.1;

EX18-01 (420 mg, 0.894 mmol) was dissolved in 4M hydrochloric acid 1,4-dioxane solution (10 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and dried to obtain EX18-02 (310 mg). LCMS: MS m/z (ESI) [M+H] ⁺ = 370.1.

EX18-02 (305 mg, 0.412 mmol) was dissolved in anhydrous dichloromethane (5 mL), triethylamine (0.287 mL, 2.062 mmol) was added, and then acetyl chloride (97.1 mg, 1.24 mmol, 88.0 uL) was slowly added at 0 ° C. The reaction solution was reacted at room temperature for 1 hour. The reaction solution was quenched with saturated sodium bicarbonate aqueous solution (5 mL), separated, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silica, dichloromethane/methanol = 100/0 to 30/1) to obtain EX18-03 (90 mg). LCMS: MS m/z (ESI) [M+H] ⁺ = 412.0;

EX18-03 (50 mg, 0.121 mmol) was dissolved in 1,4-dioxane (1 mL), and tert-butyl piperidine-4-carbamate (60.8 mg, 0.303 mmol), RuPhos Pd G2 (9.43 mg, 0.012 mmol), NaI (3.64 mg, 0.024 mmol) and cesium carbonate (119 mg, 0.364 mmol) were added. The reaction solution was heated to 100 ° C and stirred for 12 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 50/1) to obtain EX18-04. LCMS: MS m/z (ESI) [M+H] ⁺ = 576.3;

EX18-04 (30.0 mg, 0.052 mmol) was dissolved in 4M hydrochloric acid 1,4-dioxane solution (1 mL) and stirred at room temperature for 1 hour. The reaction solution was subjected to preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 7%-37%, 8 minutes) to obtain EX18. LCMS: MS m/z (ESI) [M+H] ⁺ = 476.1; ¹ H NMR (400 MHz, CD ₃ OD)δ8.53(s,1H),7.85-7.79(m,1H),7.76-7.67(m,3H),7.19(d,J＝1.6Hz,1H),7.02(dd,J＝9.2,2.0Hz,1H),4.25–4.11(m,2H),3.89-3.78(m,3H),3.4 2-3.34(m,1H),3.16-3.04(m,2H),3.01-2.89(m,2H),2.15-2.08(m,2H),2.06–1.96(m,2H),1.95(s,3H),1.94–1.77(m,2H),1.69-1.58(m,2H).

Example EX19

Example EX19 was prepared by the same route as EX18 using EX18-02, methyl chloroformate and piperidine-4-carbamic acid tert-butyl ester as raw materials. Preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 5%-32%, 8 minutes). LCMS: MS m/z (ESI) [M+H] ⁺ = 492.2; ¹ H NMR (400MHz, CD ₃ OD)δ8.54(s,1H),7.87-7.78(m,1H),7.78-7.62(m,3H),7.18(s,1H),7.01(dd,J＝9.2,1.6Hz,1H),4.98-4.90(m,1H),4.22–4.12(m,2H),3.85–3.76(m ,2H),3.64(s,3H),3.65-3.53(m,1H),3.15–3.02(m,2H),3.00–2.89(m,2H),2.16-1.96(m,4H),1.89–1.75(m,2H),1.69-1.57(m,2H).

Example EX20

Compound EX20-01 (1.00 g, 5.75 mmol) was dissolved in THF (30 mL), and 60% NaH (0.32 g, 8.05 mmol) was slowly added at 0°C and stirred for 30 minutes. Then SEMCl (1.22 mL, 6.89 mmol) was slowly added dropwise to the reaction solution, and the reaction solution was stirred at 25°C for 2 hours. After the reaction was completed, the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (100 mL*3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 2/1) to obtain EX20-02 (950 mg, yield 54.3%). ¹ H NMR (400 MHz, DMSO-d ₆ )δ7.67 (d,J＝7.2Hz,1H),6.75(d,J＝2.0Hz,1H),6.48(dd,J＝7.2,2.0Hz,1H),5.22(s,2H),3.55(t,J＝8.0Hz,2H),0.85(t,J＝8.0Hz,2H),-0.04(s,9H).

EX20-02 (0.96 g, 3.15 mmol) was dissolved in 1,4-dioxane (20 mL), and bis(boronic acid) pinacol ester (1.20 g, 3.15 mmol), potassium acetate (0.93 g, 9.46 mmol) and Pd(dppf)Cl ₂ (0.12 g, 0.320 mmol) were added. The reaction solution was heated to 100 °C and stirred for 3 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 2/1) to obtain EX20-03 (500 mg, yield 47.0%). ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.61 (d, J = 6.8 Hz, 1H), 6.63 (s, 1H), 6.29 (dd, J = 6.8, 1.2 Hz, 1H), 5.23 (s, 2H), 3.54 (t, J = 8.0 Hz, 2H), 1.28 (s, 12H), 0.85 (t, J = 8. 0Hz,2H),-0.04(s,9H).

EX20-03 (230 mg, 0.856 mmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL), and EX9-01 (300 mg, 0.87 mmol), potassium carbonate (237 mg, 1.71 mmol) and Pd(dppf)Cl ₂ (62.6 mg, 90.0 umol) were added. The reaction solution was heated to 100 °C and stirred for 3 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with water (6 mL), and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (6 mL), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 2/1) to obtain EX20-04 (240 mg, yield 56.7%). LCMS:MS m/z(ESI)[M+H] ⁺ =495.0;

EX20-04 (200 mg, 0.40 mmol) was dissolved in 1,4-dioxane (2 mL), and tert-butyl piperidine-4-carbamate (243 mg, 1.21 mmol), cesium carbonate (395 mg, 1.21 mmol), NaI (12.1 mg, 0.08 mmol) and RuPhos Pd G ₂ (31.4 mg, 40.0 mmol) were added. The reaction solution was heated to 100 ° C and stirred for 12 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with water (6 mL), and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (6 mL), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 2/1) to obtain EX20-05 (150 mg, yield 56.4%). LCMS:MS m/z(ESI)[M+H] ⁺ =659.1;

Compound EX20-05 (40 mg, 60.0 umol) was dissolved in MeOH (1 mL), p-toluenesulfonic acid (105 mg, 0.610 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction solution was concentrated under reduced pressure, the crude product was purified by preparative HPLC (column: Boston Prime C18 150*30 mm*5 um; mobile phase: [water (ammonia)-acetonitrile]; B%: 20%-60%, 9 minutes) to obtain EX20. LCMS: MS m/z (ESI) [M+H] ⁺ = 429.1; ¹ HNMR (400 MHz, DMSO-d ₆ )δ8.42(s,1H),8.12(s,1H),8.08(d,J＝8.4Hz,1H),8.05-8.00(m,1H),8.00-7.96(m,1H),7.95-7.90(m,1H),7.53(dd,J＝8.8,1.2Hz,1H),7.50(d,J＝7 .2Hz,1H),6.80(d,J＝1.6Hz,1H),6.65(dd,J＝7.2,1.6Hz,1H),4.14–4.03(m,2H),3.74-3.64(m,1H),3.13–3.00(m,2H),2.00–1.87(m,2H),1.68-1.52 (m,2H).

Example EX21

Example EX21 was prepared by the same route as EX20 using EX21-03, EX9-01 and piperidine-4-carbamic acid tert-butyl ester as raw materials. Preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 20%-40%, 11 minutes). LCMS: MS m/z (ESI) [M+H] ⁺ = 443.1; ¹ H NMR: (400MHz, DMSO-d ₆ ) δ8.41 (s, 1H), 8.12-7.88 (m, 5H), 7.51 (d, J = 8.4Hz, 1H), 6.59 (s, 1H), 6.48 (s, 1H), 4.15-4.04 ( m,2H),3.18-3.10(m,1H),3.08-3.00(m,2H),2.27(s,3H),2.05-1.92(m,2H),1.76-1.59(m,2H).

Example EX22

Example EX22 was prepared by the same route as EX20 using EX21-03, EX14-01 and piperidine-4-carbamic acid tert-butyl ester as raw materials. Preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 15%-35%, 11 min). LCMS: MS m/z (ESI) [M+H] ⁺ = 444.1; ¹ H NMR (400MHz, CD ₃ OD) δ8.78 (d, J = 1.6Hz, 1H), 8.55 (s, 1H), 8.47 (d, J = 1.6Hz, 1H), 7.96-7.78 (m, 3H), 6.73 (s, 1H), 6.69 ( s,1H),4.98-4.90(m,2H),3.28-3.23(m,1H),3.22-3.10(m,2H),2.41(s,3H),2.16-2.04(m,2H),1.85-1.67(m,2H).

Example EX23

Example EX23 was prepared by the same route as EX13 using EX14-01, 4,4-difluoropiperidine and (3S,4S)-4-tert-butylcarbamate-3-fluoropiperidine as raw materials. Preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 20%-50%, 8 minutes). LCMS:MS m/z(ESI)[M+H] ⁺ ＝474.1； ¹ H NMR(400MHz,CD ₃ OD)δ8.41(d,J＝2.4Hz,1H),7.84-7.76(m,1H),7.73(s,1H),7.71(s,1H),7.53(d,J＝2.4Hz,1H),5.05-4.93(m,1H),4.75–4.65(m,1H),4.51-4.30(m,1H),3.61-3.51(m,4H),3.12-2.98(m,3H),2.26-2.10(m,4H),2.09-1.98(m,1H),1.72-1.53(m,1H).

Example EX24

Compound EX9-01 (600 mg, 1.71 mmol) was dissolved in dioxane (6 mL) and water (1 mL), and tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)carbamate (553 mg, 1.71 mmol), Pd(dppf)Cl ₂ (125 mg, 0.171 mmol) and potassium carbonate (473 mg, 3.42 mmol) were added. The reaction solution was stirred at 100°C for 3 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (silica, petroleum ether/dichloromethane = 100/0 to 2/3) to obtain EX24-01 (570 mg, yield 71.3%). LCMS:MS m/z(ESI)[M+H] ⁺ =467.0; ¹ H NMR: (400MHz, DMSO-d ₆ )δ8.18–8.08(m,1H),8.01(dd,J＝ 10.8,2.0Hz,1H),7.94-7.86(m,2H),7.76(d,J＝8.4Hz,1H),7.57(d,J＝8.4Hz,1H),6.85(d,J＝6.8Hz,1H),6.34-6.24(m,1H),3.64-3.53(m,1H),2.65– 2.52(m,2H),2.46-2.42(m,1H),2.20-2.08(m,1H),2.02-1.91(m,1H),1.68-1.56(m,1H),1.41(s,9H).

Compound EX24-01 (560 mg, 1.20 mmol) was dissolved in 4M hydrochloric acid/1,4-dioxane solution (10 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain EX24-02 (400 mg). LCMS: MS m/z (ESI) [M+H] ⁺ = 367.1;

Compound EX24-02 (200 mg, 0.545 mmol) was dissolved in dichloromethane (4 mL), and triethylamine (0.380 mL, 2.73 mmol) and acetyl chloride (60.0 uL, 0.818 mmol) were added. Stir at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and dried, and the crude product was purified by silica gel column chromatography (silica, dichloromethane/methanol = 100/0 to 95/5) to obtain the target product EX24-03 (160 mg, yield 71.8%). LCMS: MS m/z (ESI) [M+H] ⁺ = 409.1;

Compound EX24-03 (160 mg, 0.391 mmol) and tert-butyl piperidine-4-carbamate (196 mg, 0.978 mmol) were dissolved in dioxane (3 mL), and Cs ₂ CO ₃ (383 mg, 1.17 mmol), NaI (11.7 mg, 0.078 mmol) and RuPhos Pd G2 (30.4 mg, 0.039 mmol) were added. The reaction solution was stirred at 100°C for 12 hours under nitrogen protection. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silica, dichloromethane/methanol = 100/0 to 98/2) to obtain EX24-04 (160 mg, yield 35.7%). LCMS: MS m/z (ESI) [M+H] ⁺ = 573.1;

Compound EX24-04 (150 mg, 0.262 mmol) was dissolved in 4M hydrochloric acid 1,4-dioxane solution (3 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and dried by spin drying. The crude product was subjected to preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 20%-40%, 11 minutes) to obtain EX24. LCMS: MS m/z (ESI) [M+H] ⁺ = 473.1; ¹ H NMR: (500 MHz, DMSO-d ₆ )δ8.39(s,1H),8.02(t,J＝8.0Hz,1H),7.94-7.83(m,5H),7.37(d,J＝8.8Hz,1H),6.28(brs,1H),4.13–4.04(m,2H),3.90-3.84(m,1H),3.09-3.00(m,3H ),2.64-2.57(m,2H),2.48-2.40(m,1H),2.15-2.07(m,1H),1.98–1.90(m,3H),1.83(s,3H),1.68-1.60(m,3H).

Example EX25

Example EX25 was prepared by the same route as EX24 using EX24-02, methyl chloroformate and tert-butyl piperidine-4-carbamate as raw materials. Preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 25%-45%, 11 minutes). LCMS: MS m/z (ESI) [M+H] ⁺ = 489.1; ¹ HNMR: (500MHz, DMSO-d ₆ ) δ8.38 (s, 1H), 8.01 (t, J = 8.0Hz, 1H), 7.94-7.78 (m, 4H), 7.35 (d, J = 8.8Hz, 1H), 7.22 (d, J = 6.0Hz, 1H),6.24(brs,1H),4.11–4.00(m,2H),3.68–3.56(m,1H),3.54(s,3H),3.09-3.01(m,3H),2.64–2.55(m,2H),2.48-2.40(m,1H),2.18-2.09(m, 1H),2.01-1.89(m,3H),1.69-1.52(m,3H).

Example EX26, EX27

The mixture EX26-04 (150 mg, 0.297 mmol) was dissolved in dichloromethane (3 mL), HATU (169 mg, 0.445 mmol), (R)-piperidin-3-ylcarbamic acid tert-butyl ester (89.1 mg, 0.445 mmol) were added, and N,N-diisopropylethylamine (70.0 μL, 0.445 mmol) was added after stirring at room temperature for 30 minutes, and stirring was continued for 12 hours. After the reaction was completed, it was concentrated under reduced pressure, diluted with water (15 mL), and extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and filtered. The crude product obtained by concentration under reduced pressure was chromatographed on a silica gel column (silica, petroleum ether/ethyl acetate = 100/0 to 3/1) to obtain EX26-05 (189 mg, yield 92.6%). LCMS:MS m/z(ESI)[M+H] ⁺ =688.4;

The mixture EX26-05 (202 mg, 0.294 mmol) was dissolved in methanol (4 mL) and p-toluenesulfonic acid (253 mg, 1.47 mmol) was added. The reaction solution was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the crude product was subjected to preparative HPLC (column: Boston Prime C18150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 18%-48%, 8 minutes) to obtain a mixture of EX26 and EX27. EX26 and EX27 were separated and purified by SFC (column: DAICEL CHIRALPAK AS (250mm*30mm, 10um); mobile phase: [0.1% ammonia/ethanol]; B%: 50%-50%, 45min).

EX26: Retention time: 1.05min; LCMS: MS m/z (ESI) [M+Na] ⁺ = 496.2; ¹ H NMR (400MHz, CD ₃ OD)δ8.05-7.81(m,5H),7.54(dd,J＝8.8,1.2Hz,1H),6.30–6.15(m,1H),4.68-4.30(m,2H),3.29-2.82(m ,3H),2.80-2.65(m,1H),2.61-2.46(m,1H),2.39–2.30(m,2H),2.12-2.01(m,1H),1.97-1.74(m,3H),1.73 -1.58(m,1H),1.55-1.40(m,1H),1.31(s,3H).

EX27: Retention time: 1.38min; LCMS: MS m/z (ESI) [M+Na] ⁺ = 496.2; ¹ H NMR (400MHz, CD ₃ OD)δ8.05-7.81(m,5H),7.54(dd,J＝8.8,1.2Hz,1H),6.30–6.15(m,1H),4.68-4.30(m,2H),3.29-2.82(m ,3H),2.80-2.65(m,1H),2.61-2.46(m,1H),2.39–2.30(m,2H),2.12-2.01(m,1H),1.97-1.74(m,3H),1.73 -1.58(m,1H),1.55-1.40(m,1H),1.31(s,3H).

Example EX28, EX29

Example EX28, EX29 was prepared by the same route as EX26 using (S)-piperidin-3-ylcarbamic acid tert-butyl ester as raw material. Preparative HPLC (column: C18-1 150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 19%-59%, 9 minutes). Preparative SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: [0.1% ammonia. n-Heptane-IPA]; B%: 55%-55%). EX28: Retention time: 2.84min; LCMS: MS m/z (ESI) [M+H] ⁺ = 474.2; ¹ H NMR (400MHz, CD ₃ OD)δ8.02-7.97(m,1H),7.96-7.85(m,4H),7.54(d,J＝8.8Hz,1H),6.21(brs,1H),4.60-4.31(m,2H),3.20-3.07(m,1H),3.06-2.82(m,2H),2.80-2.6 6(m,1H),2.61-2.47(m,1H),2.40–2.29(m,2H),2.13–2.01(m,1H),1.97-1.74(m,3H),1.73-1.59(m,1H),1.55-1.41(m,1H),1.31(s,3H).

EX29: Retention time: 3.38min; LCMS: MS m/z (ESI) [M+H] ⁺ = 474.2; ¹ H NMR (400MHz, CD ₃ OD)δ8.02-7.97(m,1H),7.96-7.85(m,4H),7.54(d,J＝8.8Hz,1H),6.21(brs,1H),4.60-4.31(m,2H), 3.20-3.07(m,1H),3.06-2.82(m,2H),2.80-2.66(m,1H),2.61-2.47(m,1H),2.40–2.29(m,2H),2.13–2.01(m ,1H),1.97-1.74(m,3H),1.73-1.59(m,1H),1.55-1.41(m,1H),1.31(s,3H).

Example EX30, EX31

Examples EX30 and EX31 were prepared by using (R)-3-(Boc-amino)pyrrolidine as raw material through the same route as EX26. Preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 18%-48%, 8 minutes). SFC (column: DAICEL CHIRALPAK AS (250mm*30mm, 10um); mobile phase: [0.1% ammonia/ethanol]; B%: 55%-55%, 45min).

EX30: Retention time: 1.58min; LCMS: MS m/z (ESI) [M+H] ⁺ = 460.2; ¹ H NMR (400MHz, CD ₃ OD)δ8.20(d,J＝8.8Hz,1H),8.02-7.95(m,1H),7.94-7.87(m,2H),7.84(s,1H),7.52(dd,J＝8.8,1.2 Hz,1H),6.25–6.14(m,1H),4.34-4.22(m,1H),4.21-3.82(m,2H),3.80-3.46(m,2H),2.81-2.62(m,1H), 2.62-2.44(m,1H),2.39-2.30(m,2H),2.29-2.13(m,1H),1.98-1.72(m,3H),1.31(s,3H).

EX31: Retention time: 2.29min; LCMS: MS m/z (ESI) [M+H] ⁺ = 460.2; ¹ H NMR (400MHz, CD ₃ OD)δ8.20(d,J＝8.8Hz,1H),8.02-7.95(m,1H),7.94-7.87(m,2H),7.84(s,1H),7.52(dd,J＝8.8,1.2 Hz,1H),6.25–6.14(m,1H),4.34-4.22(m,1H),4.21-3.82(m,2H),3.80-3.46(m,2H),2.81-2.62(m,1H), 2.62-2.44(m,1H),2.39-2.30(m,2H),2.29-2.13(m,1H),1.98-1.72(m,3H),1.31(s,3H).

Example EX32, EX33

Examples EX32 and EX33 were prepared by using (S)-3-(Boc-amino)pyrrolidine as raw material through the same route as EX26. Preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 25%-55%, 8 minutes). SFC (column: DAICEL CHIRALCEL OD (250mm*30mm, 10um); mobile phase: [0.1% ammonia.ethanol]; B%: 45%-45%).

EX32: Retention time: 1.63min; LCMS: MS m/z (ESI) [M+H] ⁺ = 460.2; ¹ H NMR (400MHz, CD ₃ OD)δ8.21(d,J＝8.4Hz,1H),8.04-7.96(m,1H),7.96-7.89(m,2H),7.86(s,1H),7.54(d,J＝8.4Hz, 1H),6.21(brs,1H),4.35-4.24(m,1H),4.20-3.85(m,2H),3.79-3.50(m,2H),2.81–2.66(m,1H),2.61–2.46( m,1H),2.40–2.30(m,2H),2.29-2.14(m,1H),2.00-1.74(m,3H),1.31(s,3H).

EX33: Retention time: 2.44min; LCMS: MS m/z (ESI) [M+H] ⁺ = 460.2; ¹ H NMR (400MHz, CD ₃ OD)δ8.21(d,J＝8.4Hz,1H),8.04-7.96(m,1H),7.96-7.89(m,2H),7.86(s,1H),7.54(d,J＝8.4Hz, 1H),6.21(brs,1H),4.35-4.24(m,1H),4.20-3.85(m,2H),3.79-3.50(m,2H),2.81–2.66(m,1H),2.61–2.46( m,1H),2.40–2.30(m,2H),2.29-2.14(m,1H),2.00-1.74(m,3H),1.31(s,3H).

Example EX34

EX34-01 (5 g, 43.8 mmol) was dissolved in DCM (100 mL), and diisopropylethylamine (13.2 g, 87.6 mmol) and tert-butyldimethylsilyl chloride (7.26 g, 48.2 mmol) were added. The reaction solution was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). After the organic phases were combined, they were washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 10/1) to obtain EX34-02 (9.2 g, yield 91.9%). ¹ H NMR: (400MHz, CDCl ₃ ) δ4.10–3.98(m,1H),2.64-2.52(m,2H),2.21-2.09(m,2H),1.92-1.74(m,4H),0.82(s,9H),0.00(s,6H).

EX34-02 (4.00 g, 17.5 mmol) was dissolved in tetrahydrofuran (50 mL), N-phenyl-trifluoromethanesulfonimide (9.40 g, 26.3 mmol) was added, and the mixture was cooled to -78 °C under nitrogen protection, and potassium bis(trimethylsilyl)amide solution (1 M, 24.5 mL, 24.5 mmol) was slowly added dropwise. After the addition was completed, the mixture was stirred at -78 °C for 2 hours. The reaction solution was quenched with saturated ammonium chloride solution (50 mL) at 0 °C, extracted with ethyl acetate (80 mL x 3), and the organic phases were combined, washed with saturated brine (50 mL), dried, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 20/1) to obtain the target product EX34-03 (5.50 g, yield 87.1%). ¹ HNMR (400MHz, CDCl ₃ ) δ5.67-5.57(m,1H),4.05–3.93(m,1H),2.59-2.45(m,1H),2.44-2.28(m,2H),2.24-2.11(m,1H),1.89-1.79(m,2H),0.89(s,9H ),0.07(d,J＝2.0Hz,6H).

EX34-03 (1.0 g, 2.77 mmol) was dissolved in 1,4-dioxane (50 mL), and bis-boronic acid pinacol ester (0.80 g, 3.33 mmol) and potassium acetate (0.50 g, 5.55 mmol) were added. The reaction solution was heated to 80 ° C under nitrogen protection and stirred for 12 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried. The crude product was chromatographed on a silica gel column (silicon dioxide, petroleum ether/ethyl acetate = 100/0 to 20/1) to obtain the target product EX34-04 (850 mg, yield 85.2%). ¹ H NMR (400MHz, CDCl ₃ ) δ6.50–6.35(m,1H),3.92-3.81(m,1H),2.41-2.27(m,2H),2.21-1.99(m,2H),1.88-1.75(m,1H),1.57-1.47(m,1H),1.26(s,1 2H),0.89(s,9H),0.06(s,6H).

EX34-04 (290 mg, 0.856 mmol) was dissolved in 1,4-dioxane (2.4 mL) and water (0.6 ml), and EX9-01 (300 mg, 0.856 mmol), Pd(dppf)Cl ₂ (62.6 mg, 0.086 mmol) and potassium carbonate (355 mg, 2.57 mmol) were added. The reaction solution was heated to 100°C under nitrogen protection and stirred for 12 hours. After the reaction was completed, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 10/1) to obtain the target product EX34-05 (320 mg, yield 77.6%). LCMS:MS m/z(ESI)[M+H] ⁺ =482.2;

EX34-05 (170 mg, 0.353 mmol) was dissolved in 1,4-dioxane (2 mL), and tert-butyl piperidine-4-carbamate (77.7 mg, 0.388 mmol), RuPhos Pd G2 (27.4 mg, 0.035 mmol), sodium iodide (26.4 mg, 0.176 mmol) and cesium carbonate (345 mg, 1.06 mmol) were added. The reaction solution was heated to 100 ° C under nitrogen protection and stirred for 12 hours. After the reaction was completed, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). After the organic phases were combined, they were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness. The crude product was chromatographed on a silica gel column (silica, petroleum ether/ethyl acetate = 100/0 to 5/1) to obtain EX34-06 (130 mg, yield 57.1%). LCMS:MS m/z(ESI)[M+H] ⁺ =646.4;

EX34-06 (130 mg, 0.201 mmol) was dissolved in methanol (0.5 mL), and p-toluenesulfonic acid (173 mg, 1.01 mmol) was added. The reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Phenomenex C1875*30mm*3um; mobile phase: [water (ammonia)-acetonitrile]; B%: 33%-73%, 9 minutes) to obtain EX34 (18.91 mg, yield 21.6%). LCMS: MS m/z (ESI) [M+H] ⁺ = 432.0; ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.03-7.95(m,1H),7.91-7.77(m,4H),7.33(d,J＝8.8Hz,1H),6.22(brs,1H),4.83-4.65(m,1H),4.23-3.90(m,4H),3.88-3.77(m,1H),3.06-2.96( m,2H),2.85-2.74(m,1H),2.65–2.52(m,2H),2.48–2.40(m,1H),2.17-2.03(m,1H),1.96-1.77(m,3H),1.72-1.56(m,1H),1.51-1.33(m,2H).

Example EX35

Compound EX5-02 (200 mg, 0.403 mmol) and (3S, 4S)-3-fluoropiperidin-4-yl)carbamic acid tert-butyl ester (132.0 mg, 0.605 mmol) were dissolved in dioxane (4 mL), and sodium iodide (30.2 mg, 0.202 mmol), cesium carbonate (263 mg, 0.806 mmol), and Ruphos Pd G2 (31.3 mg, 0.040 mmol) were added. The reaction solution was heated to 100 ° C under nitrogen protection and stirred for 12 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 3/1) to obtain EX35-01 (70 mg, 25.6%).

Compound EX35-01 (70 mg, 0.103 mmol) was dissolved in MeOH (0.8 mL), p-toluenesulfonic acid (88.7 mg, 0.515 mmol) was added, and the mixture was stirred at room temperature for 12 hours. After the reaction solution was concentrated under reduced pressure, EX35 was obtained by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 20%-60%, 9 minutes). LCMS: MS m/z (ESI) [M+H] ⁺ = 464.1;

Example EX36

Example EX36 was prepared by the same route as EX35 using EX5-02, (3S, 4R)-3-fluoropiperidin-4-yl)carbamic acid tert-butyl ester as raw material. Preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 20%-60%, 9 minutes). LCMS: MS m/z (ESI) [M+H] ⁺ = 464.2;

Example EX37

Example EX37 was prepared by the same route as EX35 using EX5-02, (3R, 4R)-3-fluoropiperidin-4-yl)carbamic acid tert-butyl ester as raw material. Preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 38%-68%, 9 minutes). LCMS: MS m/z (ESI) [M+H] ⁺ = 464.1;

Example EX38

Example EX38 was prepared by the same route as EX16 using EX9-01 and EX16-05 as raw materials. Preparative HPLC (column: phenomenex C18 (75 mm*30 mm, 3 um); mobile phase: [water (ammonia water)-acetonitrile]; B%: 43%-83%, 9 minutes). LCMS: MS m/z (ESI) [M+H] ⁺ = 460.2; ¹ H NMR (400MHz, CD ₃ OD) δ7.88-7.75 (m, 5H), 7.38 (d, J = 8.8Hz, 1H), 6.20 (brs, 1H), 4.20–4.09 (m, 2H), 3.15–3.03 (m, 2H), 3 .02-2.90(m,1H),2.82-2.65(m,1H),2.58-2.45(m,1H),2.42-2.25(m,2H ),2.06-1.96(m,2H),1.94-1.75(m,2H),1.74-1.55(m,4H),1.02(t,J＝7.6 Hz,3H).

Example EX39

Example EX39 was prepared by the same route as EX13 using EX9-01,4,5,6,7-tetrahydropyrazolo[1,5-A]pyrazine dihydrochloride as raw material. Preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 20%-40%, 11 minutes). LCMS: MS m/z (ESI) [M+H] ⁺ = 457.0; ¹ HNMR: (400MHz, DMSO-d ₆ )δ8.42(s,1H),8.05–7.95(m,1H),7.89-7.78(m,3H),7.46(d,J＝1.6Hz,1H),7.30(s,1H),7.12(dd,J＝8.8,1.6Hz,1H),6.18(d,J＝1.6Hz,1H),4.65(s,2 H),4.25(t,J＝5.2Hz,2H),4.10–4.00(m,2H),3.94(t,J＝5.2Hz,2H),3.11-3.06(m,1H),3.04-2.97(m,2H),2.00–1.88(m,2H),1.68-1.53(m,2H).

Example EX40

EX40-03 (100 mg, 0.194 mmol) and 2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (31.6 mg, 0.233 mmol) were dissolved in 1,4-dioxane (2 mL), and RuPhos Pd G2 (15.1 mg, 0.019 mmol), sodium iodide (14.6 mg, 0.097 mmol) and cesium carbonate (190 mg, 0.583 mmol) were added. The reaction solution was heated to 100 ° C under nitrogen protection and stirred for 12 h. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water (5 mL), and extracted with ethyl acetate (5 mL*3). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 3/1) to give EX40-04 (102 mg, yield 98.3%). LCMS: MS m/z (ESI) [M+H] ⁺ = 532.9;

Compound EX40-04 (102 mg, 0.191 mmol) was dissolved in MeOH (3 mL), and then p-toluenesulfonic acid (165 mg, 0.956 mmol) was added. The reaction solution was stirred at 25°C for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the crude product was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 45%-65%, 16 min) to obtain EX40. LCMS: MS m/z (ESI) [M+H] ⁺ = 433.1; ¹ H NMR: (400MHz, DMSO-d ₆ ) δ7.98–7.88 (m, 1H), 7.85–7.76 (m, 2H), 7.70 (d, J = 9.2Hz, 1H), 6.85 (s, 1H), 6.65 (d, J = 8.4Hz, 1H),4.81(s,1H),4.68(s,1H),3.99-3.91(m,2H),3.80(d, J＝7.6Hz,1H),3.69(d,J＝7.6Hz,1H),3.59(d,J＝9.2Hz,1H),3.14(d,J＝9.6Hz,1H),3.03-2.89(m,2H),2.81-2.72(m,1H),1.99-1.87(m,2H),1.87-1.77 (m,2H),1.48-1.33(m,2H).

Example EX41

Example EX41 was prepared by the same route as EX40 using EX40-03, 2-oxa-5-azabicyclo[2.2.2]octane hemioxalate as raw material. Preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 16%-46%, 8min). LCMS: MS m/z (ESI) [M+H] ⁺ = 446.8; ¹ H NMR: (400MHz, DMSO-d ₆ )δ8.31(s,1H),8.02-7.92(m,1H),7.84-7.77(m,2H),7.73(d,J＝9.2Hz,1H),6.86(s,1H),6.74(d,J＝9.2Hz,1H),4.25–4.17(m,1H),4.12–3.95(m,5H ),3.80–3.73(m,1H),3.48–3.41(m,1H),3.25–3.17(m,1H),3.07–2.95(m,2H),2.13-1.86(m,5H),1.77-1.60(m,3H).

Example EX42

Example EX42 was prepared by the same route as EX40 using EX40-03,6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride as raw material. Preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 61%-100%, 9 minutes). LCMS:MS m/z(ESI)[M+H] ⁺ =453.2; ¹ H NMR: (400MHz, CD ₃ OD) δ7.84-7.79(m,1H),7.77-7.66(m,3H),6.74(s,1H),6.64(d,J＝8.8Hz,1H),4.17–4.04(m,2H),3 .83-3.75(m,2H),3.75-3.69(m,2H),3.10-3.03(m,3H),2.65-2.55(m,2H),2.06–1.95(m,2H),1.74-1.58(m,2H).

Example EX43

EX43-01 (200 mg, 0.857 mmol) was dissolved in DCM (2 mL), and TFA (489 mg, 4.29 mmol) was added. The reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated and dried to give the crude product EX43-02 (200 mg, yield 94.4%). ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 8.92 (brs, 2H), 4.07 (t, J = 6.4 Hz, 4H), 2.86 (t, J = 12.4 Hz, 4H).

Example EX43 was prepared by the same route as EX40 using EX40-03 and EX43-02 as raw materials. Preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 30%-50%, 16 min). LCMS:MS m/z(ESI)[M+H] ⁺ =467.3[M+H] ⁺ ; ¹ H NMR: (400MHz, DMSO-d ₆ )δ8.05-7.92(m,1H),7.83-7.72(m,3H),6.71(s,1H),6.43(d,J＝8.8Hz,1H),4.06(s,4H ),4.10–3.95(m,2H),3.20–3.10(m,1H),3.05-2.96(m,2H),2.89(t,J＝12.4Hz,4H),2.02–1.89(m,2H),1.73-1.56(m,2H).

Example EX44

Compound EX44-01 (500 mg, 2.09 mmol) was dissolved in anhydrous dichloromethane (40 mL) and placed in an ice bath. DAST (1.38 mL, 10.4 mmol) was added dropwise to the reaction solution in a nitrogen atmosphere. After the addition was complete, the reaction solution was heated to room temperature and stirred for 20 h. The reaction solution was quenched with saturated sodium bicarbonate solution (40 mL) and extracted with dichloromethane (40 mL x 3). The organic phases were combined, washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain the crude product EX44-02 (520 mg, yield 95.2%). ¹ H NMR (400MHz, DMSO-d ₆ ) δ3.67-3.50(m,4H),2.27-2.19(m,1H),1.97-1.78(m,4H),1.77-1.70(m,3H),1.37(s,9H). Example EX44 was prepared by the same route as EX43 using EX40-03 and EX44-02 as raw materials. Preparative HPLC (column: C18-1150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 52%-92%, 9 minutes). LCMS: MS m/z (ESI) [M+H] ⁺ = 494.9. ¹ H NMR (400MHz, CD ₃ OD) δ 7.82-7.76 (m, 1H), 7.74-7.67 (m, 2H), 7.65 (d, J = 8.8Hz, 1H), 6.66 (d, J = 1.6Hz, 1H), 6.47 (dd, J = 8. 8,1.6Hz,1H),4.14–4.03(m,2H),3.75(s,4H),3.07-2.91(m,3H),2.02-1.92(m,10H),1.71-1.58(m,2H).

Example EX45

Example EX45 was prepared from EX40-03, 7-oxa-2-azaspiro[3.5]nonane hydrochloride by the same route as EX40. Preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 18%-58%, 9min). LCMS:MS m/z(ESI)[M+H] ⁺ =461.1; ¹ H NMR: (400MHz, DMSO-d ₆ )δ8.02-7.91(m,1H),7.85-7.70(m,3H),6.68(d,J＝1.2Hz,1H),6.42(dd,J＝8.2,1.2Hz,1H),4.10– 3.97(m,2H),3.74(s,4H),3.65–3.50(m,4H),3.20–3.10(m,1H),3.05-2.94(m,2H),2.00-1.89(m,2H),1.83–1.71(m,4H),1.70-1.56(m,2H).

Example EX46

Example EX46 was prepared from EX40-03, 2-oxa-7-azaspiro[3.5]nonane by the same route as EX40. Preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 40%-70%, 8 minutes). LCMS: MS m/z (ESI) [M+H] ⁺ = 460.7; ¹ H NMR: (400MHz, CD ₃ OD) δ7.84-7.75 (m, 1H), 7.74-7.63 (m, 3H), 7.15 (d, J = 0.8Hz, 1H), 6.99 (dd, J = 8.8, 1, 2Hz, 1H), 4.51 (s ,4H),4.16–4.01(m,2H),3.28-3.21(m,4H),3.09-2.95(m,3H),2.08-1.95(m,6H),1.75–1.60(m,2H).

Example EX47

Example EX47 was prepared by the same route as EX10 using EX9-01, 4-(trifluoromethyl)piperidin-4-ol as raw material. Preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 42%-72%, 8 minutes). LCMS: MS m/z (ESI)[M+H] ⁺ ＝503.0； ¹ H NMR:(400MHz,DMSO-d6)δ8.00-7.91(m,1H),7.83-7.77(m,2H),7.74(d,J＝8.8Hz,1H),7.21(d,J＝1.6Hz,1H),7.00(dd,J＝8.8,1.6Hz,1H),6.04(s,1H),4.02-3.91(m,2H),3.88–3.76(m,2H),3.12–3.03(m,2H),3.02-2.92(m,2H),2.82-2.71(m,1H),1.89-1.72(m,6H),1.48-1.35(m,2H).

Example EX48

Dissolve trimethylsilyl acetylene (2.2g, 22.1mmol) in anhydrous tetrahydrofuran (20mL), slowly add 2.5M n-butyl lithium (4.82mL, 12.0mmol) at -78℃, after the addition is complete, stir the reaction solution at -78℃ for 1 hour, then slowly add a tetrahydrofuran solution (10mL) of EX48-01 (2.00g, 10.0mmol). After the addition is complete, the reaction solution is naturally heated to 25℃ and reacted for 12 hours. The reaction solution is slowly quenched with saturated ammonium chloride (20mL) and extracted three times with ethyl acetate (30mL*3). Combine the organic phases, wash with saturated brine (100mL), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure and spin dry. The crude product is purified by silica gel column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 1/0 to 10/1) to obtain EX48-02 (2.00g, yield 67.0%). ¹ H NMR: (400MHz, CDCl ₃ ) δ3.88-3.74(m,2H),3.28-3.12(m,2H),1.95-1.81(m,2H),1.75-1.64(m,2H),1.46(s,9H),0.18(s,9H);

Compound EX48-02 (200 mg, 0.672 mmol) was dissolved in anhydrous dichloromethane (4 mL), trifluoroacetic acid (0.25 mL, 3.36 mmol) was added, and the reaction solution was stirred at 25°C for 12 hours. The reaction solution was concentrated under reduced pressure and dried, and the crude product was dissolved in methanol (15 mL), adjusted to pH 7-8 with saturated potassium carbonate, and water (15 mL) was added. The mixture was extracted three times with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product EX48-03 (130 mg, yield 98.0%). ¹ H NMR: (400MHz, CDCl ₃ )δ=3.16–3.05(m,2H),2.97–2.84(m,2H),2.01-1.92(m,2H),1.77–1.65(m,2H),0.18(s,9H);

Compound EX40-03 (300 mg, 0.583 mmol) was dissolved in dioxane (2 mL), and EX48-03 (230 mg, 1.17 mmol), cesium carbonate (570 mg, 1.75 mmol), sodium iodide (17.5 mg, 0.117 mmol) and RuPhos Pd G ₂ (45.3 mg, 58.0 mmol) were added. The reaction solution was heated to 100°C under nitrogen protection and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/tetrahydrofuran = 100/0 to 4/1) to obtain EX51-04 (100 mg, yield 27.2%). LCMS: MS m/z (ESI) [M+H] ⁺ = 631.1;

Compound EX48-04 (90.0 mg, 0.143 mmol) was dissolved in anhydrous methanol (1.2 mL) and water (0.2 mL), potassium carbonate (78.9 mg, 0.571 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction, the reaction solution was poured into ice water (20 mL), solid precipitated, filtered, and the filter cake was washed with a small amount of water (5 mL*3) and vacuum dried to obtain the crude product EX48-05. LCMS: MS m/z (ESI) [M+H] ⁺ = 559.1;

Compound EX48-05 (100 mg, 0.179 mmol) was dissolved in methanol (2 mL), TsOH (154 mg, 0.895 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was subjected to preparative HPLC (column: Boston Prime C18-1 150*30 mm*5 um; mobile phase: [water (formic acid)-acetonitrile]; B%: 22%-62%, 9 minutes) to obtain EX48. LCMS: MS m/z (ESI) [M+H] ⁺ = 459.2; ¹ H NMR: (400MHz, DMSO) δ8.00-7.92(m,1H),7.83-7.76(m,2H),7.73(d,J＝8.8Hz,1H),7.18(d,J＝1.6Hz,1H),6.99(dd,J＝8.8,1.6Hz,1H),5.65(s,1H),4.01-3.9 0(m,2H),3.63-3.52(m,2H),3.41(s,1H),3.24-3.16(m,2H),3.02-2.92(m,2H),2.83-2.73(m,1H),1.93-1.87(m,2H),1.86-1.75(m,4H),1.49-1. 33(m,2H).

Example EX49

Compound EX49-01 (4.00 g, 18.8 mmol) was dissolved in tetrahydrofuran (80 mL), and methyl lithium (23 mL, 37.5 mmol) was slowly added in an ice-water bath. After the addition was complete, the reaction solution was reacted at room temperature for 1 hour. The reaction solution was quenched with saturated aqueous ammonium chloride solution (40 mL) at 0°C and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 5/1) to obtain EX49-02 (1.5 g, yield 34.9%). ¹ H NMR (400MHz, CDCl ₃ ) δ4.42–4.28(m,1H),3.94-3.82(m,1H),3.27-3.14(m,1H),1.71(dd,J＝14.0,6.8Hz,1H),1.57-1.50(m,3H),1.46(s,9H),1.31(d ,J＝7.2Hz,3H),1.24(s,3H).

Compound EX49-02 (1.00 g, 4.36 mmol) was dissolved in anhydrous tetrahydrofuran (8 mL), and sodium hydrogen (349 mg, 8.72 mmol, 60%) was slowly added under an ice-water bath. After the reaction solution was stirred at 0°C for 30 minutes, iodomethane (0.54 mL, 8.72 mmol) was slowly added dropwise to the reaction solution. After the addition was complete, the reaction solution was stirred at room temperature for 16 hours. The reaction solution was quenched with saturated aqueous ammonium chloride solution (30 mL) at 0°C and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness. The crude product was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 10/1) to obtain EX49-03. ¹ H NMR (400MHz, CDCl ₃ ) δ4.34–4.22(m,1H),3.87-3.77(m,1H),3.19(s,3H),3.16–3.02(m,1H),1.82-1.74(m,2H),1.54-1.49(m,1H),1.46(s,9H),1.4 5–1.30(m,1H),1.26(d,J＝7.2Hz,3H),1.13(s,3H).

Compound EX49-03 (610 mg, 2.51 mmol) was dissolved in 4M hydrochloric acid/1,4-dioxane solution (8 mL) and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain crude product EX49-04 (450 mg). ¹ H NMR (400 MHz, CDCl ₃ ) δ9.84 (brs, 1H), 9.35 (brs, 1H), 3.49-3.39 (m, 1H), 3.38-3.28 (m, 1H), 3.23 (s, 3H), 3.03-2.88 (m, 1H), 2.14-2.02 (m, 1H), 1.94-1.81 (m, 3H), 1.57 (d, J = 5.6 Hz, 3H), 1.27 (s, 3H).

EX40-03 (120 mg, 0.233 mmol) was dissolved in dioxane (1 mL), and EX49-04 (50.0 mg, 0.278 mmol), RuPhos Pd G2 (16.3 mg, 21.0 umol), sodium iodide (6.30 mg, 42.0 umol) and cesium carbonate (205 mg, 0.628 mmol) were added. The reaction solution was heated to 100 ° C under nitrogen protection and stirred for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (silica, EX49-05 (40.0 mg, yield 29.7%) was purified by petroleum ether/ethyl acetate = 100/0 to 2/1). LCMS: MS m/z (ESI) [M+H] ⁺ = 577.1;

Compound EX49-05 (40.0 mg, 69.0 umol) was dissolved in 4M hydrochloric acid/1,4-dioxane solution (1 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and then spin-dried, and then HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia water)-acetonitrile]; B%: 53%-73%, 11 minutes) was used to obtain EX49. LCMS:MS m/z(ESI)[M+H] ⁺ =477.1; ¹ H NMR (400MHz, CDCl ₃ ) δ7.72-7.50(m,4H),7.07(s,1H),6.96-6.84(m,1H),4.15–3.96(m,3H),3.32-3.16(m,6H),3.10- 2.99(m,2H),2.23-2.10(m,2H),2.04-1.93(m,2H),1.92-1.86(m,2H),1.86–1.75(m,1H),1.74-1.60(m,1H),1.22(s,3H),1.18(d,J＝6.8Hz,3H).

Example EX50

EX50-01 (3.00 g, 13.6 mmol) was dissolved in tetrahydrofuran (30 mL), and hydrazine hydrate (6.60 mL, 135 mmol) was added. The reaction solution was heated to 90°C and stirred for 18 hours. The reaction solution was cooled to room temperature, diluted with water (200 mL), filtered, and the filter cake was vacuum dried to obtain the crude product EX50-02. LCMS: MS m/z (ESI) [M+H] ⁺ = 214.7.

Compound EX50-02 (3.00 g, 13.9 mmol) was dissolved in N, N-dimethylformamide (30 mL), potassium hydroxide (2.70 g, 48.8 mmol) was added, and iodine (5.00 g, 19.5 mmol) was slowly added under ice-water bath. Stir at room temperature for 4 hours. LCMS detected 44.5% of the target product. After the reaction solution was cooled to room temperature, it was diluted with water (50 mL) and extracted with ethyl acetate (50 mL*3). The organic phases were combined and saturated with salt. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 5/2) to obtain EX50-03 (1.50 g, yield 18.9%). LCMS: MS m/z (ESI) [M+H] ⁺ = 340.9.

Compound EX50-03 (1.40 g, 410 mmol) was dissolved in dichloromethane (70 mL), and 4-cyano-3-fluorophenylboronic acid (1.35 g, 8.21 mmol) and copper acetate (1.49 g, 8.21 mmol) were added. Molecular sieves (powder) (1.40 g) and pyridine (0.99 mL, 12.3 mmol). The reaction solution was stirred at room temperature for 18 hours under an oxygen atmosphere. After the reaction was completed, the filtrate was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 10/3) to obtain EX50-04 (500 mg, yield 26.5%). LCMS: MS m/z (ESI) [M+H] ⁺ = 459.8; ¹ HNMR (400 MHz, DMSO-d ₆ ) δ 8.18-8.11 (m, 1H), 8.01-7.95 (m, 1H), 7.81–7.73 (m, 1H), 7.65 (dd, J = 8.4, 5.6 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H).

Compound EX50-04 (500 mg, 1.09 mmol) was dissolved in 1,4-dioxane (20 mL), and tert-butyl piperidin-4-ylcarbamate (217 mg, 1.09 mmol), cesium carbonate (708 mg, 2.17 mmol), Xantphos (62.9 mg, 0.109 mmol) and Pd ₂ (dba) ₃ (99.5 mg, 0.109 mmol) were added. The reaction solution was heated to 100 ° C under a nitrogen atmosphere and stirred for 16 hours. After the reaction solution was cooled to room temperature, it was diluted with water (50 mL) and extracted with ethyl acetate (50 mL*3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 30%) to obtain EX50-05 (175 mg, yield 30.2%). LCMS:MS m/z(ESI)[M+H] ⁺ =532.0.

EX50-05 (150 mg, 0.282 mmol) was dissolved in 1,4-dioxane (2 mL), and 4-methoxy-4-methylpiperidine hydrochloride (56.1 mg, 0.338 mmol), RuPhos Pd G ₂ (21.9 mg, 0.028 mmol), cesium carbonate (184 mg, 0.563 mmol) and sodium iodide (8.40 mg, 0.056 mmol) were added. The reaction solution was heated to 100 ° C under nitrogen protection and stirred for 18 hours. The reaction solution was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 30%) to obtain EX50-06 (30.0 mg, yield 18.3%); LCMS: MS m/z (ESI) [M+H] ⁺ = 580.9.

Compound EX50-06 (30.0 mg, 52.0 umol) was dissolved in methanol solution (1 mL), p-toluenesulfonic acid (44.5 mg, 0.258 mmol) was added, and the mixture was stirred at room temperature for 18 hours. After the reaction, the reaction solution was subjected to preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia water)-acetonitrile]; B%: 55%-75%, 11 minutes) to obtain EX50. LCMS: MS m/z (ESI) [M+H] ⁺ = 481.3; ¹ H NMR (400MHz, CD ₃ OD) δ7.78 (t, J = 8.0 Hz, 1H), 7.60–7.47 (m, 3H), 7.04 (t, J = 8.0 Hz, 1H), 4.15–3.97 (m, 2H), 3.25 (s, 3H) ),3.19-3.02(m,7H),2.09-1.97(m,2H),1.94-1.88(m,2H),1.77-1.68(m,4H),1.23(s,3H).

Example EX51

EX51-01 (200 mg, 0.843 mmol) was dissolved in 1,4-dioxane (2 mL), and 4 M hydrochloric acid/dioxane solution (2 mL) was added. The reaction solution was stirred at 25°C for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain EX51-02 (130 mg, yield 88.3%).

Example EX51 was prepared by the same route as EX40 using EX51-02 and EX40-03 as raw materials. Preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 42%-72%, 8 minutes). LCMS: MS m/z (ESI) [M+H] ⁺ = 471.0; ¹ H NMR: (400MHz, CD ₃ OD) δ7.85-7.78 (m, 1H), 7.76-7.68 (m, 3H), 7.25 (s, 1H), 7.03 (dd, J=9.2, 2.0 Hz, 1H), 4.15–4.01 (m, 2H), 4.00–3.85 (m, 1H), 3.63–3.53 (m, 1H), 3.53–3.37 (m, 3H), 3.07–2.98 (m, 2H), 2.97–2.84 (m, 1H), 2.42–2.26 (m, 1H), 2.18–2.02 (m, 1H), 2.01–1.92 (m, 2H), 1.71–1.54 (m, 2H). Example EX52

Example EX52 was prepared by the same route as EX40 using EX52-05b and EX40-03 as raw materials. Preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 5%-45%, 9 minutes). LCMS: MS m/z (ESI) [M+H] ⁺ = 475.2; ¹ H NMR (400MHz, CD ₃ OD)δ8.54(s,1H),7.83-7.79(m,1H),7.75-7.62(m,3H),7.02(d,J＝1.6Hz,1H),6.85(dd,J＝8.8,1.6Hz,1H),4.37(brs,2H),4.26–4.06(m,2H),3.38-3. 30(m,1H),3.17-3.03(m,2H),2.45-2.32(m,2H),2.14-2.05(m,2H),2.05-1.93(m,4H),1.90-1.78(m,2H),1.72–1.61(m,2H),0.98(s,3H).

Example EX53

Example EX53 was prepared by the same route as EX40 using EX53-03 and EX40-03 as raw materials. Preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 18%-48%, 8min). LCMS: MS m/z (ESI) [M+H] ⁺ = 475.0; ¹ H NMR: (400MHz, DMSO-d ₆ )δ8.39(s,1H),7.97(t,J＝8.4Hz,1H),7.82-7.75(m,2H),7.71(d,J＝8.8Hz,1H),7.03(s,1H),6.92(d,J＝8.0Hz,1H),4.77(brs,1H),4.08-3.96(m,2H),3 .46-3.40(m,2H),3.24-3.16(m,1H),3.06-2.94(m,2H),2.48–2.38(m,2H),1.94-1.84(m,4H),1.80–1.70(m,2H),1.62-1.51(m,4H),1.25(s,3H).

Example EX54

Example EX54 was prepared from EX10-01, tert-butyl (R)-pyrrolidin-3-ylcarbamate, by the same route as EX10. Preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 33%-63%, 8 minutes). LCMS:MS m/z(ESI)[M+H] ⁺ ＝435.2； ¹ H NMR:(400MHz,DMSO-d ₆ )δ7.91(dd,J＝8.8,7.6Hz,1H),7.79-7.68(m,3H),7.14(d,J＝1.6Hz,1H),6.94(dd,J＝9.2,1.6Hz,1H),4.35(s,1H),3.80-3.70(m,2H),3.66-3.56(m,2H),3.51-3.44(m,2H),3.27–3.17(m,3H),2.13-2.01(m,1H),1.77–1.68(m,1H),1.64-1.52(m,4H),1.17(s,3H).

Example EX55

Example EX55 was prepared from EX5-02,2-methylpropane-2-yl{[(1R,5S)-8-azabicyclo[3.2.1]octan-3-yl]carbamate by the same route as EX5. Preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 50%-70%, 11 minutes). LCMS:MS m/z(ESI)[M+H] ⁺ =472.0; ¹ H NMR: (400MHz, DMSO-d ₆ )δ8.05–7.96(m,1H),7.95-7.79(m,4H),7.36(d,J＝8.4Hz,1H),6.23(brs,1H),4.67–4.55(m,2H) ,4.41(brs,1H),2.70–2.56(m,1H),2.28–2.18(m,2H),2.10–1.96(m,2H),1.84-1.57(m,9H),1.30-1.21(m,1H),1.20(s,3H).

Example EX56

Example EX56 was prepared from EX5-02,2-methylpropane-2-yl{[(1S,5R,8s)-3-azabicyclo[3.2.1]octan-8-yl]carbamate by the same route as EX5. Preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 53%-73%, 11 minutes). LCMS: MS m/z (ESI) [M+H] ⁺ = 472.3; ¹ H NMR: (400MHz, DMSO-d ₆ )δ8.03-7.91(m,2H),7.87-7.78(m,3H),7.34(d,J＝8.4Hz,1H),6.28–6.20(m,1H),4.40(s,1H),3.95–3.83(m,2H),3.18–3.09(m,2H),3.05(s,1H), 2.70-2.59(m,1H),2.48-2.41(m,1H),2.30–2.21(m,2H),2.15–2.05(m,2H),2.01-1.90(m,2H),1.80-1.71(m,1H),1.69-1.55(m,3H),1.21(s,3H) .

Example EX57

Example EX57 was prepared from EX5-02,2-methylpropane-2-yl{[(1S,5R,8r)-3-azabicyclo[3.2.1]octan-8-yl]carbamate by the same route as EX5. Preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 53%-73%, 11 minutes). LCMS:MS m/z(ESI)[M+H] ⁺ ＝471.8； ¹ H NMR:(400MHz,DMSO-d ₆ )δ8.07–7.95(m,2H),7.91-7.78(m,3H),7.34(d,J＝8.4Hz,1H),6.33–6.20(m,1H),4.40(s,1H),3.68-3.60(m,4H),3.20–3.07(m,1H),2.70–2.58(m,1H),2.50–2.40(m,1H),2.32–2.20(m,2H),2.12–2.00(m,2H),1.86-1.63(m,6H),1.21(s,3H).

Example EX59

EX59-01 (5.61 g, 24.2 mmol) was dissolved in N, N-dimethylformamide (100 mL), and N-iodosuccinimide (6.60 mL, 135 mmol) was added. The reaction solution was stirred at room temperature for 18 hours. After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate (200 mL), and washed with a mixed solution of sodium bicarbonate (50 mL) and sodium thiosulfate (50 mL), and saturated brine (50 mL) in sequence. Drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure and drying to obtain the crude product EX59-02 (8.00 g, yield 92.4%). LCMS: MS m/z (ESI) [M+H] ⁺ = 356.9.

Compound EX59-02 (2.00 g, 5.59 mmol) was dissolved in dichloromethane (70 mL), and 4-cyano-3-fluorophenylboronic acid (1.80 g, 11.2 mmol), copper acetate (2.00 g, 11.2 mmol), 4A molecular sieve powder (2.00 g, 9.29 mmol) and pyridine (1.36 mL, 16.8 mmol) were added. The reaction solution was stirred at room temperature under an oxygen atmosphere for 18 hours. After the reaction was completed, the reaction solution was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 10/1 to 10/3) to obtain EX59-03 (1.20 g, yield 45.0%). LCMS: MS m/z (ESI) [M+H] ⁺ = 475.8.

Compound EX59-03 (600 mg, 1.26 mmol) was dissolved in 1,4-dioxane (10 mL), and tert-butyl piperidin-4-ylcarbamate (252 mg, 1.26 mmol), cesium carbonate (820 mg, 2.52 mmol), Xantphos (72.9 mg, 0.126 mmol) and Pd ₂ (dba) ₃ (115 mg, 0.126mmol). The reaction solution was stirred at 100°C for 16 hours. After the reaction solution was cooled to room temperature, diluted with water (50mL), and extracted with ethyl acetate (50mL*3). The organic phases were combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/0-2/1) to obtain EX59-04 (300mg, yield 43.4%). LCMS: MS m/z (ESI) [M+H] ⁺ = 548.1.

Compound EX59-04 (300 mg, 0.547 mmol) was dissolved in N, N-dimethylformamide (5 mL), and zinc cyanide (38.5 mg, 0.328 mmol) and tetrakistriphenylphosphine palladium (126 mg, 0.109 mmol) were added. The reaction solution was heated to 90 ° C under nitrogen protection and stirred for 18 hours. After the reaction was completed, it was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 30%) to obtain EX59-05 (150 mg, yield 55.4%). LCMS: MS m/z (ESI) [M+H] ⁺ = 494.9.

EX59-05 (100 mg, 81.0 umol) was dissolved in 1,4-dioxane (1.5 mL) and water (0.3 mL), and EX4-06 (42.7 mg, 0.121 mmol), Pd(dppf)Cl ₂ (5.90 mg, 8.00 umol) and potassium carbonate (33.5 mg, 0.242 mmol) were added. The reaction solution was heated to 100 °C under nitrogen protection and stirred for 18 hours. After the reaction was completed, it was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was subjected to silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0–4/1) to obtain EX59-06 (35 mg, yield 63.2%). LCMS:MS m/z(ESI)[M+H] ⁺ =685.6.

Compound EX59-06 (40.0 mg, 58.0 umol) was dissolved in methanol solution (1 mL), p-toluenesulfonic acid (50.3 mg, 0.292 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction solution was purified by preparative HPLC (column: Boston Prime C18 75*30 mm*3 um; mobile phase: [water (ammonia hydroxide)-acetonitrile]; B%: 39%-79%, 9 minutes) to obtain EX59. LCMS: MS m/z (ESI) [M+H] ⁺ = 471.2; ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.59(s,1H),8.05(t,J＝8.0Hz,1H),7.90(dd,J＝11.2,2.0Hz,1H),7.83(dd,J＝8.4,2.0Hz,1H),7.80(s,1H),5.86(brs,1H),4.46(s,1H),4.09–3.96(m, 2H),3.0 9–2.98(m,2H),2.84-2.78(m,1H),2.60-2.55(m,1H),2.41-2.35(m,1H),2.25–2.17(m,2H),1.90–1.80(m,2H),1.77–1.58(m,2H),1.49-1.34(m, 2H),1.23(s,3H).

Example EX60

EX60-01 (3.00 g, 14.2 mmol) was dissolved in N,N-dimethylformamide (100 mL), and N-iodosuccinimide (4.80 g, 21.3 mmol) was added under ice-water bath, and the reaction solution was stirred at 25°C for 4 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dioxide EX60-02 (4.70 g, yield 98.1%) was obtained by HPLC-MS: MS m/z (ESI) [M+H] ⁺ = 337.0; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.55 (s, 1H), 7.65 (s, 1H), 7.07 (s, 1H), 2.74 (s, 3H).

EX60-02 (4.70 g, 14.0 mmol) was dissolved in dichloromethane (100 mL), and 4-cyano-3-fluorophenylboronic acid (4.60 g, 27.9 mmol) and copper acetate (5.10 g, 27.9 mmol) were added. Molecular sieves (4.50 g) and pyridine (3.38 mL, 41.8 mmol), the reaction solution was stirred at 25 ° C for 16 hours under an oxygen atmosphere. The reaction solution was concentrated under reduced pressure, and the crude product was chromatographed on a silica gel column (silica, petroleum ether/ethyl acetate = 100/0 to 10/1) to obtain EX60-03 (4.60 g, yield 72.3%). LCMS: MS m/z (ESI) [M+H] ⁺ = 455.9.

EX60-03 (4.60 g, 10.1 mmol) was dissolved in dioxane (300 mL), and tert-butyl N-(piperidin-4-yl)aminomethyl ester (2.02 mg, 10.1 mmol), Pd ₂ (dba) ₃ (923 mg, 1.01 mmol), Xantphos (1.17 g, 2.02 mmol) and cesium carbonate (6.57 g, 20.2 mmol) were added. The reaction solution was heated to 100°C under nitrogen atmosphere and stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 3/1) to obtain EX60-04 (1.40 g, yield 26.3%). LCMS: MS m/z (ESI) [M+H] ⁺ = 528.2.

EX60-04 (1.30 g, 2.46 mmol) was dissolved in water (5 mL) and dioxane (30 mL), and EX4-06 (1.30 g, 3.69 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (II) (180 mg, 0.246 mmol), and potassium carbonate (680 mg, 4.92 mmol) were added. The reaction solution was heated to 100 ° C under nitrogen atmosphere and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 3/1) to obtain EX60-05 (670 mg, yield 40.4%). LCMS: MS m/z (ESI) [M+H] ⁺ = 674.4.

EX60-05 (300 mg, 0.445 mmol) was dissolved in methanol (2 mL), 4-toluenesulfonic acid (383 mg, 2.23 mmol) was added, and the reaction solution was stirred at 25°C for 16 hours. LCMS detected that the reaction was complete, and the reaction solution was purified by preparative HPLC (column: Xtimate C18 150*40mm*5um; mobile phase: [water (ammonia water + ammonium bicarbonate)-acetonitrile]; B%: 30%-70%, 9 minutes) to obtain EX60. LCMS: MS m/z (ESI) [M+H] ⁺ = 460.3; ¹ H NMR (400MHz, DMSO-d ₆ )δ8.03(t,J＝8.0Hz,1H),7.91-7.79(m,2H),7.62(s,1H),7.18(s,1H),6.19(brs,1H),4.36(s,1H),3.55–3.42(m,2H),2.95–2.82(m,2H),2.81–2.72 (m,1H),2.68(s,3H),2.65–2.55(m,1H),2.45–2.35(m,1H),2.27–2.17(m,2H),1.93–1.80(m,2H),1.77-1.69(m,1H),1.67–1.57(m,1H),1.55-1. 40(m,2H),1.19(s,3H).

Example EX61

Compound EX61-01 (1 g, 4.05 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), cooled to 0°C, and 2.5 M lithium aluminum tetrahydride tetrahydrofuran solution (1.62 mL, 4.05 mmol) was slowly added. After the addition was complete, the reaction solution was stirred at 25°C for 2 hours. The reaction solution was quenched with sodium sulfate decahydrate until no gas was released, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried to obtain EX61-02 (700 mg, yield 78.9%). ¹ H NMR (400 MHz, CDCl ₃ ) δ7.36 (dd, J＝8.4, 0.8 Hz, 1H), 7.15 (t, J＝8.0 Hz, 1H), 4.72 (s, 2H), 2.36 (d, J＝2.4 Hz, 3H).

Compound EX61-02 (710 mg, 3.24 mmol) was dissolved in anhydrous dichloromethane (4 mL), cooled to 0°C, and then pyridinium chlorochromate (44.5 mg, 1.17 mmol) was added. The reaction solution was heated to room temperature and stirred for 12 hours. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with dichloromethane (10 mL), and the filtrate was concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 90/10) to obtain EX61-03 (600 mg, yield 85.3%). ¹ H NMR (400 MHz, CDCl ₃ ) δ10.34 (s, 1H), 7.64-7.55 (m, 1H), 7.49 (d, J = 8.4 Hz, 1H), 2.42 (d, J = 2.4 Hz, 3H).

Compound EX61-03 (1.2 g, 5.53 mmol) was dissolved in ethylene glycol dimethyl ether (20 mL), and potassium carbonate (2.6 g, 18.5 mmol) and MeONH ₂ (0.8 g, 10.18 mmol) were added. The reaction solution was stirred at 40°C for 3 hours. The reaction solution was filtered, the filter cake was washed with ethylene glycol dimethyl ether (10 mL), and the filtrate was concentrated under reduced pressure and dried to obtain a crude product EX61-04 (800 mg). ¹ H NMR (400 MHz, CDCl ₃ ) δ8.24 (s, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 3.98 (s, 3H), 2.34 (d, J = 2.4 Hz, 3H).

Compound EX61-04 (800 mg, 3.25 mmol) was dissolved in DMSO (5 mL), and hydrazine hydrate (8.87 mL, 183 mmol) was added. The reaction solution was stirred at 110 ° C for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature and diluted with water (20 mL). A large amount of white solid precipitated and filtered. The filter cake was washed with 5 mL 2.0 mol/L dilute hydrochloric acid and then washed with 10 mL water. The filter cake was vacuum dried to obtain the target product EX61-05 (500 mg, yield 72.9%). LCMS: MS m/z (ESI) [M+H] ⁺ =211.0; ¹ H NMR (400MHz, DMSO-d ₆ ) δ 13.33 (brs, 1H), 8.09 (s, 1H), 7.54 (d, J = 8.4Hz, 1H), 7.27 (d, J = 8.4Hz, 1H), 2.57 (s, 3H).

Compound EX61-05 (500 mg, 2.37 mmol) was dissolved in anhydrous DMF (4 mL), and NIS (492 mg, 2.84 mmol) was added. The reaction solution was reacted at 25°C for 4 hours. After the reaction was completed, the reaction solution was poured into ice water (30 mL), and a large amount of white solid precipitated. It was filtered and the filter cake was washed with a small amount of water (5 mL*3). Concentrated under reduced pressure and dried in vacuum to obtain the crude product EX61-06 (600 mg, yield 75.2%). LCMS: MS m/z (ESI)[M+H] ⁺ =336.5.

Compound EX61-06 (500 mg, 1.48 mmol) was dissolved in dichloromethane (10 mL), and 4-cyano-3-fluorophenylboronic acid (489 mg, 2.97 mmol) and pyridine (0.36 mL, 4.45 mmol) were added. Molecular sieves (500 mg, 1.48 mmol) and cupric acetate (539 mg, 2.97 mmol). The reaction solution was stirred at room temperature under an oxygen atmosphere for 48 hours. After the reaction was completed, the filtrate was filtered and concentrated under reduced pressure. The crude product was chromatographed on a silica gel column (silica, petroleum ether/dichloromethane = 100/0 to 5/1) to obtain the target product. The solid was ground and slurried with petroleum ether/ethyl acetate = 5/1 (10 mL) for 2 hours, filtered, and the filter cake was vacuum dried to obtain EX61-07 (400 mg, yield 59.1%). LCMS: MS m/z (ESI) [M+H] ⁺ = 455.8.

Compound EX61-07 (420 mg, 0.921 mmol) was dissolved in 1,4-dioxane (10 mL), and tert-butyl piperidin-4-ylcarbamate (184 mg, 0.921 mmol), Cs ₂ CO ₃ (900 mg, 2.76 mmol), Xantphos (107 mg, 0.184 mmol) and Pd ₂ (dba) ₃ (84.3 mg, 92.0 umol) were added. The reaction solution was heated to 100°C under nitrogen protection and stirred for 12 hours. After the reaction, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/tetrahydrofuran = 100/0 to 5/1) to obtain EX61-08 (200 mg, yield 41.1%). LCMS: MS m/z (ESI) [M+H] ⁺ = 528.2.

Compound EX61-08 (200 mg, 0.379 mmol) was dissolved in dioxane (3 mL) and water (0.5 mL), and EX4-06 (160 mg, 0.454 mmol), Pd(dppf)Cl ₂ (27.7 mg, 38.0 umol) and potassium carbonate (105 mg, 0.757 mmol) were added. The reaction solution was heated to 100°C under nitrogen protection and stirred for 3 hours. After the reaction, the reaction solution was filtered, concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/tetrahydrofuran = 100/0 to 4/1) to obtain EX61-09 (160 mg, yield 75.5%). LCMS: MS m/z (ESI) [M+H] ⁺ = 674.4.

Compound EX61-09 (160 mg, 0.237 mmol) was dissolved in methanol (2 mL), p-toluenesulfonic acid (204 mg, 1.19 mmol) was added, and the mixture was stirred at 25°C for 12 hours. After the reaction, the reaction solution was purified by preparative HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 35%-55%, 11 minutes) to obtain EX61. LCMS: MS m/z (ESI) [M+H] ⁺ = 460.2; ¹ H NMR: (400 MHz, DMSO-d ₆ )δ7.98(t,J＝8.0Hz,1H),7.69(d,J＝8.0Hz,1H),7.62(dd,J＝10.8,1.6Hz,1H),7.40(dd,J＝8.4,1.6Hz,1H),7.02(d,J＝8.0Hz,1H),5.52(brs,1H),4.38(s,1H ),3.94–3.80(m,2H),3 .00–2.89(m,2H),2.81-2.73(m,1H),2.65-2.55(m,1H),2.25-2.14(m,3H),2.04(s,3H),1.88-1.78(m,2H),1.76-1.67(m,1H),1.66-1.56(m,1H) ,1.50-1.37(m,2H),1.21(s,3H).

Example EX62

Example EX62 was prepared by the same route as EX10 using EX10-01, piperidin-3-ylcarbamic acid tert-butyl ester as raw material. Preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 33%-63%, 8 minutes). LCMS: MS m/z (ESI) [M+H] ⁺ = 449.1

Example EX63

Example EX63 was prepared from EX40-03, 8-oxo-3-azabicyclo[3.2.1]octane hydrochloride by the same route as EX40. Preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 20%-60%, 9 minutes). LCMS: MS m/z (ESI) [M+1] ⁺ = 447.1; ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.41 (s, 1H), 7.96 (t, J = 8.0Hz, 1H), 7.84-7.69 (m, 3H), 7.05 (s, 1H), 6.91 (d, J = 9.2Hz, 1H), 4.47 (brs,2H),4.07–3.96(m,2H),3.65–3.53(m,2H),3.13–3.05(m,1H),3.04–2.95(m,2H),2.95-2.88(m,2H),2.00-1.89(m,2H),1.86(brs,4H),1.71-1. 52(m,2H).

Example EX64

EX12-03a (1.00 g, 2.51 mmol) and EX53-03 (0.800 g, 2.83 mmol) were dissolved in 1-methyl-2-pyrrolidone (15.0 mL), and cesium carbonate (1.00 g, 7.53 mmol) was added. The reaction solution was heated to 100 ° C and stirred for 12 hours under nitrogen protection. After the reaction solution was cooled to room temperature, it was diluted with water (20 mL) and extracted with ethyl acetate (30 mL*3). The organic phases were combined, washed with water (15 mL x 3) and saturated brine (15 mL) in turn, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 2/1) to obtain EX64-01 (1.20 g, yield 71.4%). LCMS: MS m/z (ESI) [M+H] ⁺ =504.0; ¹ H NMR: (400MHz, DMSO-d6) δ8.41 (d, J = 12.0Hz, 1H), 8.33 (d, J = 8.4Hz, 1H), 8.05 (t, J = 8.0Hz, 1H), 7.63 (d, J = 9.2Hz, 1H), 6.93 ( d,J＝9.2Hz,1H),4.90(s,1H),3.95–3.75(m,2H),3.60-3.47(m,2H),1.95–1.85(m,2H),1.84-1.71(m,2H),1.57–1.40(m,2H),1.26(s,3H).

EX64-01 (300 mg, 0.596 mmol) and tert-butyl piperidin-4-ylcarbamate (179 mg, 0.894 mmol) were dissolved in 1,4-dioxane (4.0 mL), and potassium carbonate (583 mg, 1.79 mmol) and RuPhos Pd G2 (46.3 mg, 0.060 mmol) were added. The reaction solution was heated to 100 ° C and stirred for 12 hours under nitrogen protection. After the reaction solution was cooled to room temperature, it was diluted with water (10 mL) and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 2/1) to obtain EX64-02 (280 mg, yield 81.6%). LCMS:MS m/z(ESI)[M+H] ⁺ =576.1.

EX64-02 (280 mg, 0.486 mmol) was dissolved in methanol (2.0 mL), and p-toluenesulfonic acid (418 mg, 2.43 mmol) was added. The reaction solution was stirred at room temperature for 12 hours. After the reaction solution was concentrated under reduced pressure, it was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia water, ammonium bicarbonate)-acetonitrile]; B%: 60%-90%, 8 minutes) to obtain EX64. LCMS: MS m/z (ESI) [M+H] ⁺ = 476.1; ¹ H NMR: (400MHz, DMSO-d ₆ ) δ8.39 (dd, J = 12.8, 1.6 Hz, 1H), 8.30 (dd, J = 8.8, 2.0 Hz, 1H), 8.09 (d, J = 9.2 Hz, 1H), 7.99-7.88 (m, 1H),6.71(d,J＝9.2Hz,1H),4.86(s,1H),4.06–3.95(m,2H),3.85-3.72 (m,2H),3.55–3.45(m,2H),3.06-2.95(m,2H),2.85-2.72(m,1H),1.94-1.86(m,2H),1.85-1.73(m,4H),1.54-1.46(m,2H),1.44-1.31(m,2H),1.26 (s,3H).

Example EX65

Example EX65 was prepared by the same route as EX64 using EX12-03a and EX65-02 as raw materials. Preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 28%-58%, 8 minutes). LCMS: MS m/z (ESI) [M+H] ⁺ = 490.1; ¹ H NMR: (400MHz, CD ₃ OD)δ8.55(brs,1H),8.44–8.30(m,2H),7.97(d,J＝9.2Hz,1H),7.70(t,J＝8.0Hz,1H),6.69(d,J＝9.2Hz,1H),4.27–4.15(m,2H),3.94–3.80(m,2H),3.52– 3.42(m,2H ),3.39(s,3H),3.29-3.21(m,1H),3.14-3.03(m,2H),2.24–2.15(m,2H),2.13–2.02(m,2H),1.95-1.84(m,2H),1.83-1.71(m,2H),1.68-1.59(m,2 H),1.34(s,3H).

Example EX66

Compound EX66-01 (1.00 g, 6.47 mmol) was dissolved in N,N-dimethylformamide (5 mL), and N-iodosuccinimide (1.30 g, 7.76 mmol) was added. The reaction solution was heated to 100°C and stirred for 3 hours. After the reaction was completed, the reaction solution was poured into ice water (20 mL), and a large amount of white solid precipitated. Filter, wash the filter cake with water (5 mL*3), and vacuum dry the filter cake to obtain EX66-02 (1.2 g, yield 66.1%). LCMS: MS m/z (ESI) [M+H] ⁺ = 280.8.

EX66-02 (1.20 g, 4.28 mmol) was dissolved in dichloromethane (10 mL), and pyridine (1.04 mL, 12.8 mmol) was added. Molecular sieve (2.00 g), copper acetate (1.60 g, 8.56 mmol). The reaction was stirred at room temperature under an oxygen atmosphere for 16 hours. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/dichloromethane = 100/0 to 1/1) to obtain a yellow solid The solid was further slurried and purified (petroleum ether: ethyl acetate = 5:1 (20 mL)) to obtain EX66-03 (800 mg, yield 46.8%). LCMS: MS m/z (ESI) [M+H] ⁺ = 399.8.

EX66-03 (200 mg, 0.500 mmol) and EX66-03 (196 mg, 0.550 mmol) were dissolved in N-methylpyrrolidone (2 mL), potassium carbonate (208 mg, 1.50 mmol) was added, and the reaction solution was heated to 100 ° C and stirred for 12 hours. After the reaction was completed, water (5 mL) was added to the reaction solution, and ethyl acetate (4 mL*3) was extracted. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain EX66-04 (150.00 mg, yield 59.4%). LCMS: MS m/z (ESI) [M+H] ⁺ = 505.1.

EX66-04 (100 mg, 0.200 mmol) was dissolved in dioxane (2 mL), and 4-tert-butyloxycarbonyl-amino-piperidine (47.7 mg, 0.24 mmol), Xantphos (5.7 mg, 0.010 mmol), Pd ₂ (dba) ₃ (18.20 mg, 0.020 mmol) and cesium carbonate (129.2 mg, 0.397 mmol) were added. The reaction solution was heated to 100 ° C under nitrogen protection and stirred for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and dried, and the crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain EX66-05 (70.00 mg, yield 61.2%). LCMS: MS m/z (ESI) [M+H] ⁺ = 577.4.

Compound EX66-05 (70.0 mg, 0.120 mmol) was dissolved in dioxane hydrochloride (2 mL) and stirred at room temperature for 20 minutes. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure and purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (hydrochloric acid)-acetonitrile]; B%: 22%-62%, 9 minutes) to obtain EX66. LCMS: MS m/z (ESI) [M+H] ⁺ = 477.3; ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.08(s,1H),8.31-8.24(m,2H),8.16(brs,3H),8.00(t,J＝8.4Hz,1H),4.35–4.24(m,1H),4.21–4.10(m,2H),4.09–4.00(m,1H),3.65-3.55(m,2H) ,3.35–3.24(m,1H),3.15–3.03(m,2H),2.07–1.95(m,2H),1.91-1.80(m,2H),1.78-1.61(m,4H),1.47–1.37(m,2H),1.25(s,3H).

Example EX67

EX67-01 (3.78 g, 19.1 mmol) was dissolved in ethanol (56 mL), and 9% sodium hypochlorite solution (63.2 mL, 195 mmol) was slowly added under ice-water bath. The reaction solution was stirred at 25°C for 10 minutes. TLC showed a new spot was generated. The mixture was diluted with water (100 mL), extracted with ethyl acetate (100 mL*3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0-10/1) to obtain EX67-02 (6 g, yield 94.6%). ¹ H NMR (400 MHz, CDCl ₃ )δ8.85 (s, 1H), 7.63 (s, 1H).

EX67-02 (6 g, 25.8 mmol) was dissolved in anhydrous dichloromethane (150 mL), and pyridine (4.17 mL, 51.6 mmol) and cupric acetate were added. (14.1 g, 77.4 mmol), the reaction solution was stirred at room temperature under oxygen atmosphere for 16 hours. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/0 to 3/1) to obtain EX67-03 (1.9 g, yield 20.9%). LCMS: MS m/z (ESI) [M+H] ⁺ = 350.8; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.92 (d, J = 0.4 Hz, 1H), 7.90 (d, J = 0.8 Hz, 1H), 7.89-7.78 (m, 1H), 7.70-7.61 (m, 2H).

EX67-03 (400 mg, 1.138 mmol) was dissolved in 1,4-dioxane (2.5 ml) and water (0.5 mL), and EX4-06 (441.0 mg, 1.251 mmol), potassium carbonate (471.7 mg, 3.413 mmol) and Pd(dppf)Cl ₂ (83.2 mg, 0.114 mmol) were added, and the reaction solution was stirred at 100°C for 3 hours. After the reaction was completed, the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (20 mL*3), the organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (petroleum ether/ethyl acetate = 100/0 to 5/1) to obtain EX67-04 (500 mg, 1.006 mmol, 88.4%). LCMS: MS m/z (ESI) [M+1] ⁺ = 497.2; ¹ H NMR (400MHz, CDCl ₃ ) δ9.08 (s, 1H), 7.85 (dd, J = 8.8, 6.8Hz, 1H), 7.73-7.64 (m, 2H), 7.57 (s, 1H), 6.98–6.80 (m, 1H), 2.84 -2.67(m,1H),2.60-2.33(m,3H),1.98-1.89(m,1H),1.80-1.70(m,1H),1.35(s,3H),0.84(s,9H),0.13(s,3H),0.08(s,3H).

EX67-04 (250 mg, 0.503 mmol) was dissolved in anhydrous 1,4-dioxane (3 mL), and tert-butyl piperidin-4-ylcarbamate (110.8 mg, 0.553 mmol), RuPhos Pd G2 (39.1 mg, 0.050 mmol), sodium iodide (15.1 mg, 0.101 mmol) and cesium carbonate (491.6 mg, 1.509 mmol) were added. The reaction solution was heated to 100 ° C under nitrogen protection and stirred for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water (10 mL), extracted with ethyl acetate (15 mL*3), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 3/1) to obtain EX67-05 (130 mg, yield 39.1%). LCMS: MS m/z (ESI) [M+1] ⁺ = 661.3.

EX67-05 (130 mg, 0.197 mmol) was dissolved in methanol (1 mL), p-toluenesulfonic acid (187 mg, 0.984 mmol) was added, and the mixture was stirred at 25°C for 12 hours. After the reaction, the reaction solution was concentrated under reduced pressure and dried, and the crude product was purified by preparative HPLC (column: Boston Prime C18150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 20%-60%, 9 minutes) to obtain EX67. LCMS: MS m/z (ESI) [M+1] ⁺ = 447.2; ¹ H NMR (400 MHz, CD ₃ OD)δ9.04(s,1H),7.90-7.83(m,1H),7.81-7.74(m,2H),7.71(s,1H),6.73-6.62(m,1H),4.25–4.11(m,2H),3.20-3.07(m,2H),3.01-2.89(m,1H), 2.83-2.69(m,1H),2.67-2.55(m,1H),2.44–2.31(m,2H),2.06–1.95(m,2H),1.94-1.86(m,1H),1.84-1.70(m,1H),1.69–1.54(m,2H),1.31(s,3H) .

Example EX68

Example EX68 was prepared by the same route as EX64 using EX64-01, ((3S, 4R)-3-fluoropiperidin-4-yl)carbamic acid tert-butyl ester as raw material. Preparative HPLC (column: YMC Triart 30*150mm*7um; mobile phase: [water (ammonia)-acetonitrile]; B%: 60%-90%, 8 minutes). LCMS: MS m/z (ESI) [M+H] ⁺ = 494.1; ¹ H NMR: (400MHz, DMSO-d ₆ )δ8.39(d,J＝12.8Hz,1H),8.31(d,J＝8.8Hz,1H),8.10(d,J＝9.2Hz,1H),7.94(t,J＝8.4Hz,1H),6.72(d,J＝9.2Hz,1H),4.86(s,1H),4.81-4.61(m,1H),4. 30-4.15(m,1H),4.11–3. 98(m,1H),3.88-3.71(m,2H),3.56–3.44(m,2H),3.30-3.23(m,1H),3.13-3.01(m,1H),2.99-2.84(m,1H),1.95–1.85(m,2H),1.82-1.70(m,4H), 1.55–1.45(m,2H),1.26(s,3H).

Example EX69, EX70

Example EX69, EX70 was synthesized by the same route as EX64 using EX12-03a and EX69-03 as raw materials. Preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 20%-60%, 9 minutes). The mixture of EX69 and EX70 was further separated and purified by preparative SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: [0.1% ammonia.ethanol]; B%: 50%-50%) to obtain EX69 and EX70.

EX69: LCMS: MS m/z (ESI) [M+1] ⁺ = 490.3; ¹ H NMR (400MHz, CD ₃ OD) δ8.55 (s, 1H), 8.41 (d, J = 2.4Hz, 1H) ,8.38(s,1H),8.01(d,J＝9.2Hz,1H),7.72(t,J＝8.0Hz,1H),6.72(d,J＝9.2Hz,1H),4.31-4.13(m, 4H),3.65–3.50(m,2H),3. 40–3.30(m,1H),3.18–3.04(m,2H),2.36–2.23(m,2H),2.17-2.04(m,2H),1.97–1.88(m,2H),1.87-1.70(m ,3H),1.66-1.54(m,2H),1.46(s,3H),1.45–1.35(m,1H).

EX70:LCMS:MS m/z(ESI)[M+1] ⁺ =490.3; ¹ H NMR (400MHz, CD ₃ OD)δ8.44(d,J＝12.8Hz,1H),8.42-8.37(m,1H),7.98(d,J＝9.2Hz,1H),7.74(t,J＝8.0Hz,1H),6.73 (d,J＝9.2Hz,1H),4.28–4.16(m,2H),4.14-4.01(m,2H),3.79–3.66(m,2H),3.28-3.17(m,1H),3.14–3.01 (m,2H),2.11-2.02(m,2H),2.00-1.89(m,4H),1.88-1.68(m,5H),1.48(s,3H),1.38–1.28(m,1H).

Example EX71, EX72

EX71 and EX72 were prepared by using EX12-03a and EX71-03 as raw materials through the same route as EX64. Preparative HPLC (column: Boston Prime C18 150*30mm*5um; Condition: water (ammonia hydroxide v/v)-ACN; B%: 29%-69%, 9minute). The mixture of EX71 and EX72 was further separated and purified by preparative SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); Condition: [CO2-EtOH (0.1% NH3H2O)]; B%: 55%-55%, 45minute) to obtain EX71 and EX72.

EX71:LCMS:MS m/z(ESI)[M+H] ⁺ =492.1; ¹ H NMR (400MHz, DMSO-d ₆ )δ8.44-8.30(m,2H),8.11(d,J＝9.2Hz,1H),7.96-7.88(m,1H),6.65(d,J＝9.2Hz,1H),4.92(s,1H ),4.18–4.06(m,2H),4.05–3.93(m,2H),3.67–3.58(m,2H),3.57–3.48(m,2H),3.05–2.95(m,2H),2.83-2.72 (m,1H),2.64-2.53(m,2H),1.88–1.77(m,2H),1.75–1.65(m,2H),1.46-1.37(m,2H),1.36(s,3H).

EX72:LCMS:MS m/z(ESI)[M+H] ⁺ =492.1; ¹ H NMR (400MHz, DMSO-d ₆ )δ8.42(dd,J＝12.8,1.6Hz,1H),8.34(dd,J＝8.8,1.6Hz,1H),8.09(d,J＝9.2Hz,1H),7.94(t,J＝8.4 Hz,1H),6.67(d,J＝9.2Hz,1H),4.97(s,1H),4.07–3.97(m,2H),3.87-3.76(m,4H),3.72–3.65(m,2H) ,3.06–2.95(m,2H),2.87-2.78(m,1H),2.65-2.55(m,2H),1.87-1.75(m,4H),1.47(s,3H),1.45-1.34(m, 2H).

Example EX73

Example EX73 was prepared by the same route as EX64 using EX12-03a and EX73-02 as raw materials. Preparative HPLC (column: Boston Prime C18 75*30mm*3um; mobile phase: [water (ammonia hydroxide)-acetonitrile]; B%: 44%-84%, 9 minutes). LCMS: MS m/z (ESI) [M+H] ⁺ = 462.2; ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.36(d,J＝13.6Hz,1H),8.30(d,J＝8.8Hz,1H),8.08(d,J＝9.2Hz,1H),7.93(t,J＝8.4Hz,1H),6.72(d,J＝9.2Hz,1H),5.15(brs,1H),4.06-3.91(m,3H),3. 85–3.7 2(m,2H),3.50–3.35(m,2H),3.10–2.95(m,2H),2.83-2.73(m,1H),2.22–2.05(m,2H),1.90-1.77(m,2H),1.77-1.70(m,2H),1.58–1.45(m,2H),1 .43-1.31(m,2H).

Example EX74

Example EX74 was prepared by the same route as EX64 using EX12-03a and EX74-03 as raw materials. Preparative HPLC (column: Boston Prime C18 75*30mm*3um; mobile phase: [water (formic acid)-acetonitrile]; B%: 13%-53%, 9 minutes). LCMS: MS m/z (ESI) [M+H] ⁺ = 462.2; ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.38 (brs, 1H), 8.35–8.25 (m, 2H), 8.11 (d, J = 9.2Hz, 1H), 7.95 (t, J = 8.4Hz, 1H), 6.73 (d, J = 9.2Hz, 1H),4.13–4.01(m,4H),3.92(s,1H),3.12-2.94(m,4H),2.60-2.51(m,1H ),2.27–2.18(m,2H),2.00–1.80(m,4H),1.63-1.49(m,2H),1.45–1.34(m, 2H).

Example EX75

Example EX75 was prepared by the same route as EX64 using EX12-03a and EX52-05a as raw materials. Preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 36%-76%, 9 minutes) EX75. LCMS: MS m/z (ESI) [M+H] ⁺ = 476.1; ¹ H NMR (400MHz, CD ₃ OD)δ8.43(dd,J＝12.8,2.0Hz,1H),8.38(dd,J＝8.8,1.6Hz,1H),7.99(d,J＝9.2Hz,1H),7.78-7.68(m,1H),6.67(d,J＝9.2Hz,1H),4.77–4.61(m,2H),4.21– 4.05(m,2H),3.09-3.00(m,2H),3.00-2.91(m,1H),2.24-2.11(m,4H),2.06-1.94(m,4H),1.92–1.82(m,2H),1.68-1.58(m,2H),1.56(s,3H).

Example EX76

Example EX76 was prepared by the same route as EX64 using EX12-03a and EX76-05 as raw materials. Preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 48%-88%, 2 minutes). LCMS: MS m/z (ESI) [M+H] ⁺ = 476.3; ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.38–8.27(m,2H),8.11(d,J＝9.2Hz,1H),8.00-7.90(m,1H),6.68(d,J＝9.6Hz,1H),4.57(s,1H),4.07–3.97(m,2H),3.96–3.85(m,2H),3.35–3.22 (m,2H),3.09-2.91(m,2H),2.84-2.72(m,1H),2.09–1.95(m,4H),1.88–1.72(m,2H),1.48–1.39(m,4H),1.38(s,3H).

Example EX78

Example EX78 was prepared by the same route as EX64 using EX12-03a and piperidine-4-ol as raw materials. Preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 10%-40%, 9 minutes). LCMS: MS m/z (ESI) [M+1] ⁺ = 436.2; ¹ H NMR (400MHz, CD ₃ OD) δ8.54 (s, 1H), 8.33-8.24 (m, 2H), 7.96 (d, J = 9.2Hz, 1H), 7.66 (dd, J = 8.8, 7.6Hz, 1H), 6.75 (d, J = 9.2 Hz,1H),4.26-4.15(m,4H),3.98-3.85(m,1H),3.45-3.33(m,3H),3.15-3. 04(m,2H),2.18–2.08(m,2H),2.05-1.94(m,2H),1.89–1.75(m,2H),1.66– 1.50(m,2H).

Example EX79

EX79-03 (200 mg, 1.42 mmol) was dissolved in 1-methyl-2-pyrrolidone (3 mL), and EX12-03a (565 mg, 1.42 mmol) and potassium carbonate (392 mg, 2.83 mmol) were added, and the reaction solution was stirred at 100°C for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the crude product was chromatographed on a silica gel column (silica, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain EX79-04 (600 mg, yield 84.2%). LCMS: MS m/z (ESI) [M+H] ⁺ =504.1; ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.24-8.11 (m, 2H), 7.94 (t, J = 8.0Hz, 1H), 7.51 (d, J = 9.2Hz, 1H), 6.93 (d, J = 9.2Hz, 1H), 5.22-4.7 9(m,1H),4.70(d,J＝4.4Hz,1H),4.66-4.31(m,1H),3.53-3.42(m,1H),2.41-2.24(m,3H),1.68-1.53(m,4H),1.52-1.43(m,3H).

EX79-04 (150 mg, 0.298 mmol) was dissolved in 1,4-dioxane (2 mL), and tert-butyl piperidine-4-carbamate (89.5 mg, 0.447mmol), cesium carbonate (194mg, 0.596mmol) and Ruphos Pd G ₂ (23.1mg, 0.0300mmol). The reaction solution was heated to 100°C under nitrogen protection and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain EX79-05 (50.0mg, 29.2%). LCMS: MS m/z (ESI) [M+H] ⁺ = 574.3.

EX79-05 (50.0 mg, 0.087 mmol) was dissolved in methanol (1 mL), sodium borohydride (9.90 mg, 0.262 mmol) was added at 0°C, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride (2 mL), extracted with ethyl acetate (5 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product EX79-06 (25.0 mg, yield 49.9%). LCMS: MS m/z (ESI) [M+H] ⁺ = 576.2.

EX79-06 (25.0 mg, 0.043 mmol) was dissolved in methanol (1 mL), p-toluenesulfonic acid (37.4 mg, 0.217 mmol) was added, and the reaction solution was stirred at 25°C for 18 hours. After the reaction, the reaction solution was purified by HPLC (column: Boston Prime C18 150*30mm*5um; Condition: water (ammonia hydroxide v/v)-ACN; B%: 43%-83%, 9 minutes) to obtain a single isomer EX79. LCMS: MS m/z (ESI) [M+H] ⁺ = 476.2; ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.38-8.26 (m, 2H), 8.09 (d, J = 9.2Hz, 1H), 7.98 (t, J = 8.0Hz, 1H), 6.82 (d, J = 9.2Hz, 1H), 5.08-4.4 0(m,2H),4.07–3.94(m,2H),3.51–3.43(m,1H),3.06–2.92(m,2H),2.91–2.80(m,1H),2.38-2.23(m,3H),1.92–1.77(m,2H),1.74-1.38(m,9H).

Example EX80

EX64-01 (200 mg, 0.397 mmol) was dissolved in 1,4-dioxane (2 mL), and tert-butyl ((1R, 5S, 8S)-3-azabicyclo[3.2.1]octan-8-yl)carbamate (117 mg, 0.517 mmol), cesium carbonate (388 mg, 1.19 mmol) and Ruphos Pd G2 (30.9 mg, 40.0 umol) were added. The reaction solution was heated to 100 °C under nitrogen protection and stirred for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain EX80-01 (120 mg, yield 50.2%). LCMS: MS m/z (ESI) [M+H] ⁺ = 602.5; ¹ H NMR (400MHz, DMSO-d6) δ8.36(d,J＝12.8Hz,1H),8.27(dd,J＝8.8,2.0Hz,1H),8.08(d,J＝9.2Hz,1H),7.90(t,J＝8.4Hz,1H),6.68(d,J＝9.2Hz,1H),4.87(s,1H),3 .94-3.84 (m,2H),3.83-3.73(m,2H),3.58-3.45(m,3H),3.20-3.08(m,2H),2.36-2.27(m,2H),1.94-1.82(m,4H),1.80-1.70(m,2H),1.60-1.45(m,4H),1.4 2(s,9H),1.26(s,3H).

EX80-01 (120 mg, 0.199 mmol) was dissolved in methanol (1 mL), p-toluenesulfonic acid (171 mg, 0.995 mmol) was added, and the reaction solution was stirred at 25°C for 18 hours. After the reaction, the reaction solution was purified by HPLC (column: Boston Prime C18 150*40mm*5um; Condition: water (NH ₃ H ₂ O + NH ₄ HCO ₃ )-ACN; B%: 55%-95%, 9 minutes) to obtain a white solid EX80 (35.77 mg, yield 35.8%). LCMS: MS m/z (ESI) [M+H] ⁺ = 502.2; ¹ H NMR (400MHz, DMSO-d6) δ8.39(d,J＝12.8Hz,1H),8.30(dd,J＝8.8,2.0Hz,1H),8.10(d,J＝9.2Hz,1H),7.93(t,J＝8.4Hz,1H),6.69(d,J＝9.2Hz,1H),4.89(s,1H),3 .91-3.83 (m,2H),3.82-3.70(m,2H),3.55-3.45(m,2H),3.15-3.05(m,2H),3.03(s,1H),2.10-2.01(m,2H),1.98-1.86(m,4H),1.82-1.73(m,2H),1.56-1.46 (m,4H),1.26(s,3H).

Example EX81

EX81-01 (1.00 g, 2.85 mmol) was dissolved in tetrahydrofuran (20.0 mL), sodium hydride (0.1 g, 3.71 mmol) was slowly added at 0 ° C, and iodomethane (0.20 mL, 3.14 mmol) was added after stirring for 0.5 hours. The reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was quenched by adding saturated aqueous ammonium chloride solution (20 ml) under an ice-water bath, extracted with ethyl acetate (20 mL * 3), the organic layers were combined, washed with saturated aqueous salt solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 10/3) to obtain a pale yellow solid EX81-02 (900 mg, yield 86.5%). LCMS: MS m/z(ESI)[M+Na] ⁺ =387.0; ¹ H NMR (400MHz, DMSO-d6) δ7.43-7.25(m,5H),7.05-6.90(m,1H),5.07(s,2H),3.92-3.74(m,1H),3.70-3.54(m,1H),3. 51-3.37(m,1H),3.32(s,3H),3.20-2.90(m,3H),1.81-1.68(m,1H),1.38(s,9H),1.32-1.21(m,1H).

Compound EX81-02 (900 mg, 2.47 mmol) was dissolved in ethanol (20 mL), and 10% wet palladium carbon (736 mg, 6.92 mmol) was added. The reaction solution was stirred under a hydrogen atmosphere (50 psi) for 16 hours. After the reaction was completed, palladium carbon was recovered by filtration, and the filtrate was concentrated under reduced pressure and dried to obtain a crude product EX81-03 (500 mg, yield 87.9%). ¹ H NMR(400MHz,DMSO-d6)δ6.76(brs,1H),3.28(s,3H),3.23-3.08(m,2H),2.93-2.82(m,1H),2.80-2.71(m,1H),2.37-2.27(m,1H),2.17–2.05(m,1H), 1.75-1.62(m,1H),1.38(s,9H),1.28-1.16(m,1H).

Compounds EX64-01 (200 mg, 0.397 mmol) and EX81-03 (137 mg, 0.596 mmol) were dissolved in 1,4-dioxane (1.0 mL), and cesium carbonate (388 mg, 1.19 mmol) and RuPhos Pd G2 (30.8 mg, 0.040 mmol) were added. The reaction solution was heated to 100 ° C under nitrogen protection and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0-70/30) to obtain EX81-04 (100 mg, yield 41.5%). LCMS: MS m/z(ESI)[M+H] ⁺ =606.1.

Compound EX81-04 (100 mg, 0.165 mmol) was dissolved in dichloromethane (1.0 ml) and methanol (0.1 mL), p-toluenesulfonic acid (142 mg, 0.825 mmol) was added, and the mixture was stirred at room temperature for 12 hours. After the reaction, the reaction solution was purified by preparative HPLC (column: Boston Prime C18150*30 mm*5 um; mobile phase: [water (ammonia water + ammonium bicarbonate)-acetonitrile]; B%: 48%-78%, 8 minutes) to obtain EX81 (13.1 mg, yield 15.7%). LCMS: MS m/z (ESI) [M+H] ⁺ = 505.9; ¹ H NMR (400MHz, DMSO-d6) δ8.42(dd,J＝12.8,1.6Hz,1H),8.32(dd,J＝8.8,2.0Hz,1H),8.11(d,J＝9.2Hz,1H),7.96(t,J＝8.4Hz,1H),6.74(d,J＝9.2Hz,1H),4.87(s,1 H),4.31–4.18(m ,1H),4.01-3.90(m,1H),3.85–3.74(m,2H),3.55–3.47(m,2H),3.43(s,3H),3.09-2.95(m,2H),2.81–2.72(m,1H),2.71-2.61(m,1H),1.94–1.83( m,2H),1.82-1.72(m,2H),1.68– 1.58(m,1H),1.57-1.48(m,2H),1.48-1.39(m,1H),1.27(s,3H).

Example EX82

Compound EX52-05b (273 mg, 1.14 mmol) and compound EX12-03a (350 mg, 0.878 mmol) were dissolved in N-methylpyrrolidone (4 mL), and potassium carbonate (303 mg, 2.20 mmol) was added. The reaction solution was stirred at 100 ° C for 12 hours. After the reaction was completed, it was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (10 mL * 3). The organic phases were combined, washed with saturated brine (10 mL * 2), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/0 to 78/22) to obtain EX82-01 (425 mg, yield 96.2%). LCMS: MS m/z (ESI) [M+H] ⁺ =504.0; ¹ H NMR: (400MHz, DMSO-d6) δ8.35 (dd, J = 12.0, 2.0 Hz, 1H), 8.31 (dd, J = 8.8, 2.0 Hz, 1H), 8.02 (dd, J = 8.4, 7.6 Hz, 1H), 7.59 (d, J = 8. 8Hz,1H),6.83(d,J＝9.2Hz,1H),4.80-4.50(m,2H),4.36(s,1H),2.40-2.30(m,2H),1.94-1.85(m,2H),1.82-1.69(m,4H),0.92(s,3H).

Under nitrogen atmosphere, compound EX82-01 (150 mg, 0.298 mmol) and tert-butyl piperidine-4-carbamate (77.6 mg, 0.387 mmol) were dissolved in 1,4-dioxane (2 mL), and then RuPhos Pd G2 (23.1 mg, 0.030 mmol) and cesium carbonate (243 mg, 0.745 mmol) were added. The reaction solution was heated to 100 ° C under nitrogen protection and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, diluted with water (10 mL), extracted with ethyl acetate (10 mL * 3), and the organic phases were combined, washed with saturated brine (5 mL * 2), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was subjected to silica gel column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/0 to 75/25) to obtain EX82-02 (117 mg, yield 68%). LCMS: MS m/z(ESI)[M+H] ⁺ =576.2.

Compound EX82-02 (96.6 mg, 0.168 mmol) was dissolved in methanol (1 mL), and then p-toluenesulfonic acid (217 mg, 1.26 mmol) was added. The reaction was stirred at 25°C for 12 hours. After the reaction, the reaction solution was subjected to preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 56%-96%, 9 minutes) to obtain EX82 (7.42 mg, yield 9.3%). LCMS: MS m/z (ESI) [M+H] ⁺ = 476.4; ¹ H NMR: (400MHz, DMSO-d6) δ8.36-8.25(m,2H),8.04(d,J＝9.2Hz,1H),7.95-7.88(m,1H),6.61(d,J＝9.2Hz,1H),4.62-4.47(m,2H),4.30(s,1H),4.05-3.87(m, 2H),3.07-2.89(m,2H),2.80-2.70(m,1H),2.35-2.25(m,2H),1.95-1.85(m,2H),1.83-1.71(d,J＝12.0Hz,4H),1.70-1.60(m,2H),1.44-1.26(m,2 H),0.88(s,3H).

Example EX83

EX83-01 (13.0 g, 69.5 mmol) was dissolved in anhydrous dichloromethane (80 mL), and 1 M DIBALH toluene solution (69.5 mL, 69.5 mmol) was slowly added at -78 ° C, and the reaction solution was stirred at 25 ° C for 2 hours. LCMS detected the formation of the target product. The reaction solution was quenched with saturated ammonium chloride (160 mL) at 0 ° C, and the reaction solution was stirred at 0 ° C for 1 hour and then acidified with 1 M hydrochloric acid. The liquid was separated, and the aqueous phase was extracted with dichloromethane (120 mL x 3). The organic phases were combined, washed with saturated sodium bicarbonate solution (10 mL*3) and saturated brine (10 mL) in turn, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 2/1) to obtain a white solid EX83-02 (3.00 g, yield 22.7%).

LCMS: MS m/z (ESI) [M+H] ⁺ =189.8; ¹ H NMR (400MHz, CDCl ₃ ) δ10.55 (s, 1H), 7.22 (s, 1H), 2.63 (s, 3H).

EX83-02 (3.00 g, 15.8 mmol) was dissolved in n-butanol (30 mL), and 80% hydrazine hydrate (3.00 g, 47.4 mmol) was added dropwise at 25 °C. The reaction solution was stirred at 125 °C for 12 hours. LCMS detected the formation of the target product. After the reaction was completed, it was cooled to room temperature, diluted with water (50 mL), and extracted with dichloromethane (50 mL x 3). The organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silica, dichloromethane/methanol = 100/0 to 20/1) to obtain the target product EX83-03 (1.72 g, yield 65.0%). LCMS: MS m/z (ESI) [M+H] ⁺ = 167.7.

EX83-03 (1.72 g, 10.3 mmol) was dissolved in anhydrous N,N-dimethylformamide (20 mL), and N-iodosuccinimide (4.60 g, 20.5 mmol) was added. The reaction solution was stirred at 40°C for 12 hours. After the reaction was completed, saturated sodium thiosulfate solution (15 mL) and saturated sodium bicarbonate solution (15 mL) were added to the reaction solution, stirred for 10 minutes and filtered. The filter cake was washed with water (30 mL) and dried in vacuo to obtain the target product, light yellow solid EX83-04 (1.79 g, yield 59.4%). LCMS: MS m/z (ESI) [M+H] ⁺ = 293.7.

Compound EX83-04 (2.72 g, 9.27 mmol) was dissolved in dichloromethane (30 mL), and 4-cyano-3-fluorophenylboronic acid (3.80 g, 23.2 mmol), 4A molecular sieves (2.63 g, 0.170 mmol), anhydrous copper acetate (3.40 g, 18.5 mmol) and pyridine (2.24 mL, 27.8 mmol) were added at 25 °C. The reaction solution was stirred at 25 °C for 48 hours under an oxygen atmosphere. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/dichloromethane = 100/0 to 1/1) to obtain EX83-05 (3.40 g, yield 88.9%). LCMS: MS m/z (ESI) [M+H] ⁺ = 412.8.

EX83-05 (500 mg, 1.21 mmol) was dissolved in 1-methyl-2-pyrrolidone (10 mL), potassium carbonate (502 mg, 3.64 mmol) and EX53-03 (171 mg, 1.21 mmol) were added, and the reaction solution was stirred at 100°C for 12 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain yellow solid EX83-06 (300 mg, yield 47.9%). LCMS: MS m/z (ESI) [M+H] ⁺ = 518.0.

EX83-06 (300 mg, 0.580 mmol) was dissolved in dioxane (4 mL), and tert-butyl piperidine-4-carbamate (174 mg, 0.870 mmol), cesium carbonate (567 mg, 1.74 mmol) and Ruphos Pd G2 (45.0 mg, 0.0580 mmol) were added. The reaction solution was heated to 100 ° C and stirred for 12 hours under a nitrogen atmosphere. After the reaction was completed, it was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column (silica, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain EX83-07 (140 mg, yield 40.9%). LCMS: MS m/z (ESI) [M+H] ⁺ = 590.1.

EX83-07 (140 mg, 0.237 mmol) was dissolved in methanol (1 mL) and p-toluenesulfonic acid (204 mg, 1.19 mmol) was added. The reaction solution was stirred at 25°C for 12 hours. After the reaction, the reaction solution was purified by preparative HPLC (column: Xtimate C18 150*40mm*10um; Condition: water (ammonia water + ammonium bicarbonate)-acetonitrile; B%: 45%-85%, 9 minutes) to obtain EX83 (20.1 mg, yield 17.3%). LCMS: MS m/z (ESI) [M+H] ⁺ = 490.2; ¹ H NMR (400MHz, DMSO-d6) δ8.42(dd,J＝12.4,1.6Hz,1H),8.31(dd,J＝8.8,2.0Hz,1H),7.97(t,J＝8.0Hz,1H),6.61(s,1H),4.86(s,1H),3.86–3.70(m,2H),3.57-3 .43(m,4H),2.93–2.81(m,2H),2.81-2.70(m,1H),2.54(s,3H),1.94-1.81(m,4H),1.80–1.70(m,3H),1.52-1.39(m,4H),1.26(s,3H).

Example EX84 EX85

Compound EX71-03 (133 mg, 0.848 mmol) was dissolved in N-methylpyrrolidone (5 mL), and EX83-05 (350 mg, 0.848 mmol) and potassium carbonate (352 mg, 2.55 mmol) were added. The reaction solution was heated to 100 ° C under nitrogen protection and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (10 mL x 3). The organic phases were combined and washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was subjected to silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 3/4) to obtain the target product EX84-01 (220 mg, yield 48.6%). LCMS: MS m/z (ESI) [M+H] ⁺ = 533.9.

Compound EX84-01 (370 mg, 0.694 mmol) was dissolved in 1,4-dioxane (7 mL), and tert-butyl piperidine-4-carbamate (209 mg, 1.04 mmol), RuPhos Pd G2 (53.9 mg, 69.0 umol) and cesium carbonate (678 mg, 2.08 mmol) were added. The reaction solution was heated to 100 ° C under nitrogen protection and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, and the reaction solution was concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain a light yellow oil EX84-02 (240 mg, yield 36.6%). LCMS: MS m/z (ESI) [M+H] ⁺ = 606.1.

Compound EX84-02 (240 mg, 0.396 mmol) was dissolved in methanol (3 mL), p-toluenesulfonic acid monohydrate (341 mg, 1.98 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction, the reaction solution was purified by preparative HPLC (column: Xtimate C18 150*40mm*10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 8%-48%, 9 minutes) to obtain EX84-03 (40.0 mg, yield 20.0%). LCMS: MS m/z (ESI) [M+H] ⁺ = 506.0.

Compound ISME15-224 (40 mg, 0.079 mmol) was subjected to SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: [carbon dioxide (0.1% ammonia water)-ethanol]; B%: 40%-40%, 20 minutes) to give EX84 (7.50 mg, yield 18.8%) and EX85 (14.1 mg, yield 35.3%).

EX84:LCMS:MS m/z(ESI)[M+H] ⁺ =505.9; ¹ H NMR(400MHz, DMSO-d6)δ8.41-8.30(m,2H),7.95(t,J＝8.4Hz, 1H),6.54(s,1H),4.90(s,1H),4.25-4.05(m,4H),3.66-3.57(m,2H),3.56-3.45(m,4H),2.93- 2.80(m,2H),2.79-2.70(m,1H),2.55(s,3H),1.89-1.78(m,2H),1.74-1.66(m,2H),1.48-1.38(m,2H), 1.35(s,3H).

EX85:LCMS:MS m/z(ESI)[M+H] ⁺ =506.0; ¹ H NMR (400MHz, DMSO-d6) δ8.43(d,J＝12.8Hz,1H),8.33(d,J＝8.8Hz,1H),7.95(t,J＝8.0Hz,1H),6.55(s, 1H),4.95(s,1H),4.20-3.90(m,2H),3.86-3.74(m,4H),3.71-3.60(m,2H),3.56-3.44(m,2H),2.94-2.80( m,2H),2.79-2.69(m,1H),2.54(s,3H),1.89-1.80(m,2H),1.79-1.71(m,2H),1.46(s,3H),1.45-1.36( m,2H).

Example EX86 EX87

Compound EX71-01 (500 mg, 2.07 mmol) was dissolved in anhydrous methanol (10 mL), cooled to 0 ° C, sodium borohydride (118 mg, 3.11 mmol) was added, and stirred at 25 ° C for 2 hours under nitrogen protection. TLC detected the formation of new spots (petroleum ether: ethyl acetate = 3: 1, Rf = 0.5). After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (20 mL * 3), the organic phases were combined, washed with saturated brine (20 mL * 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried to obtain EX86-01 (450 mg, yield 89.3%). ¹ H NMR: (400MHz, DMSO-d6) δ5.15-5.08(m,1H),4.29-4.09(m,1H),3.99-3.74(m,4H),3.63-3.48(m,2H),3.32-2.80(m,2H),1.60-1.51(m,1H),1.50-1 .41(m,1H),1.38(s,9H).

Compound EX86-01 (200 mg, 0.822 mmol) was dissolved in anhydrous dioxane (1 mL), 4M hydrochloric acid/dioxane solution (1 mL) was added, and stirred at 25° C. for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure and dried to obtain a white solid EX86-02 (140 mg, yield 94.8%). ¹ H NMR (400MHz, DMSO-d6) δ9.45-8.78(m,1H),7.96-7.50(m,1H),5.70-5.32(m,1H),4.09-3.99(m,2H),3.97-3.86(m,1H),3.79-3.71(m,1H),3.70-3. 60(m,1H),3.54-3.39(m,2H),3.23-3.13(m,2H),1.83(brs,1H),1.74(brs,1H).

Compound EX12-03a (300 mg, 0.753 mmol) was dissolved in N-methylpyrrolidone (3 mL), and EX86-02 (203 mg, 1.13 mmol) and potassium carbonate (105 mg, 0.757 mmol) were added. The reaction solution was heated to 100 ° C and stirred for 12 hours under nitrogen protection. LCMS detected the target product (dichloromethane: methanol = 10: 1, Rf = 0.5). After the reaction was completed, it was cooled to room temperature, the reaction solution was diluted with water (10 mL), and extracted with ethyl acetate (20 mL x 3). The organic phases were combined and washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silica, dichloromethane/methanol = 100/0 to 95/5) to obtain EX86-03 (350 mg, yield 92.0%). LCMS: MS m/z(ESI)[M+H] ⁺ =506.0.

Compound EX86-03 (200 mg, 0.396 mmol) was dissolved in dioxane (3 mL), and tert-butyl piperidine-4-carbamate (119 mg, 0.594 mmol), cesium carbonate (322 mg, 0.990 mmol) and RuPhos Pd G2 (30.7 mg, 0.040 mmol) were added. The reaction solution was stirred at 100 ° C for 12 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, the reaction solution was filtered, and it was concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silica, dichloromethane/methanol = 100/0 to 95/5) to obtain EX86-04 (200 mg, yield 87.5%). LCMS: MS m/z (ESI) [M+H] ⁺ = 578.6.

Compound EX86-04 (200 mg, 0.346 mmol) was dissolved in dioxane (2 mL) and 4 M hydrochloric acid/dioxane solution (2 mL) was added, and the mixture was stirred at 25°C for 1 hour. After the reaction, the reaction solution was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 8%-38%, 9 minutes) to obtain EX86-05 (80.0 mg, yield 48.4%). LCMS: MS m/z (ESI) [M+H] ⁺ = 478.2.

EX86-05 (80.0 mg) was separated and purified by preparative SFC (column: DAICEL CHIRALPAK IC (250 mm*30 mm, 10 um); mobile phase: [0.1% ammonia water. ethanol]; B%: 50%-50%) to obtain EX86 (12.05 mg, yield 15.1%) and EX87 (6.27 mg, yield 7.8%).

EX86:LCMS:MS m/z(ESI)[M+H] ⁺ =478.0; ¹ H NMR(400MHz, DMSO-d6)δ8.43(s,1H),8.42-8.33(m,2H),8.10( d,J＝9.2Hz,1H),7.96(t,J＝8.4Hz,1H),6.73(d,J＝9.2Hz,1H),4.24-4.00(m,4H),3.99-3.88(m,4H ),3.62-3.49(m,5H),3.06-2.96(m,3H),1.99-1.87(m,4H),1.60-1.44(m,2H).

EX87:LCMS:MS m/z(ESI)[M+H] ⁺ =478.1; ¹ H NMR (400MHz, DMSO-d6) δ8.39-8.30(m,2H),8.08(d,J＝9.2Hz,1H),7.94(t,J＝8.4Hz,1H),6.75(d,J＝9.2 Hz,1H),5.26(d,J＝2.4Hz,1H),4.59-4.34(m,2H),4.07-3.96(m,5H),3.61(d,J＝11.2Hz,2H),3.39-3.30 (m,2H),3.05-2.92(m,2H),2.84-2.72(m,1H),1.86-1.72(m,4H),1.48-1.31(m,2H).

Example EX88

EX88-06 (2.70 g, 5.74 mmol) was dissolved in 1-methyl-2-pyrrolidone (30 mL), and EX53-03 (1.02 g, 5.74 mmol) and potassium carbonate (1.59 g, 11.5 mmol) were added. The reaction solution was stirred at 100 ° C for 12 hours. After cooling to room temperature, the reaction solution was diluted with EtOAc (80 mL) and water (50 mL), and the aqueous phase was extracted with EtOAc (50 mL x 3). The organic phases were combined, washed with water (50 mL x 2) and saturated brine (50 mL) in turn, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain EX88-07 (2.60 g, yield 78.8%). LCMS: MS m/z (ESI) [M+H] ⁺ =576.0; ¹ HNMR (400MHz, DMSO-d6) δ8.33 (dd, J = 12.0, 2.0Hz, 1H), 8.26 (dd, J = 8.4, 2.0Hz, 1H), 8.06-7.98 (m, 1H), 7.07 (s, 1H), 4.91 (s, 1H),4.44(q,J＝7.2Hz,2H),4.05-3.67(m,2H),3.61–3.48(m,2H),1.95–1. 85(m,2H),1.84-1.70(m,2H),1.57–1.45(m,2H),1.41(t,J＝7.2Hz,3H),1.2 6(s,3H).

EX88-07 (1.60 g, 2.78 mmol) was dissolved in dioxane (20 mL), and tert-butyl piperidine-4-carbamate (1.11 g, 5.56 mmol), cesium carbonate (1.81 g, 5.56 mmol) and Pd-PEPPSI-IHeptCl (271 mg, 0.278 mmol) were added. The reaction solution was stirred at 110 ° C for 12 hours under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain EX88-08 (900 mg, yield 50.0%). LCMS: MS m/z (ESI) [M+H] ⁺ = 648.6.

EX88-08 (850 mg, 1.31 mmol) was dissolved in tetrahydrofuran (5 mL). After the reaction solution was cooled to -15 °C, 1 M lithium triethylborohydride solution (2.62 mL, 2.62 mmol) was slowly added. The reaction solution was stirred at -15 °C for 10 minutes. The reaction solution was quenched with water (5 mL), extracted with ethyl acetate (10 mL x 3), the organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain EX88-09 (500 mg, yield 62.9%). LCMS: MS m/z (ESI) [M+H] ⁺ = 606.2.

EX88-09 (430 mg, 0.710 mmol) was dissolved in dichloromethane (5 mL), and pyridinium chlorochromate (459 mg, 2.13 mmol) was added. The reaction solution was stirred at 25°C for 12 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain yellow solid EX88-10 (70.0 mg, yield 16.3%). LCMS: MS m/z (ESI) [M+H] ⁺ = 604.3.

EX88-10 (40.0 mg, 66.0 mmol) was dissolved in methanol (1 mL), and potassium carbonate (18.3 mg, 0.133 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (15.3 mg, 0.0800 mmol) were added. The reaction solution was stirred at 25 ° C for 1 hour under a nitrogen atmosphere. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain EX88-11 (35.0 mg, yield 88.1%). LCMS: MS m/z (ESI) [M+H] ⁺ = 600.4.

EX88-11 (40.0 mg, 67.0 umol) was dissolved in methanol (0.5 mL), 4-toluenesulfonic acid (57.4 mg, 0.334 mmol) was added, and the reaction solution was stirred at 25°C for 16 hours. After the reaction was completed, the reaction was purified by HPLC (column: Phenomenex Gemini NX 150×30 mm, 5 μm; Condition: water (FA)-ACN; B%: 25%-65%, 9 minutes) to obtain EX88 (formate) (3.79 mg, yield 11.4%). LCMS: MS m/z (ESI) [M+H] ⁺ = 500.2; ¹ H NMR (400MHz, DMSO-d6) δ8.43(s,1H),8.34(dd,J＝12.4,1.6Hz,1H),8.27(dd,J＝8.8,1.6Hz,1H),7.97(t,J＝8.0Hz,1H),6.90(s,1H),4.95(s,1H),3.94–3.83(m ,2H),3.81-3.73 (m,2H),3.55–3.45(m,2H),3.16–3.05(m,1H),2.96–2.83(m,2H),2.02–1.92(m,2H),1.92–1.84(m,2H),1.82-1.74(m,2H),1.73–1.59(m,2H),1.5 3–1.44(m,2H),1.26(s,3H).

Example EX89

EX88-06 (2.00 g, 4.25 mmol) was dissolved in dioxane (10 mL), and 1 M sodium hydroxide aqueous solution (8.50 mL, 8.50 mmol) was added. The reaction solution was stirred at 25 ° C for 18 hours. After the reaction was completed, the reaction solution was adjusted to pH = 3 with 1 M hydrochloric acid to precipitate solids. Filter, and the filter cake was dried under reduced pressure to obtain EX89-01 (1.70 g, yield 90.4%). LCMS: MS m/z (ESI) [MH] ^- = 440.9.

EX89-01 (1.70 g, 3.61 mmol) was dissolved in dichloromethane (20 mL), and ammonium chloride (387 mg, 7.23 mmol), HATU (2.75 g, 7.23 mmol) and N,N-diisopropylethylamine (2.99 mL, 18.1 mmol) were added. The reaction solution was stirred at 25 ° C for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 2/1) to obtain EX89-02 (900 mg, yield 56.4%). ¹ H NMR (400 MHz, DMSO-d6) δ8.33 (s, 1H), 8.31-8.23 (m, 2H), 8.22-8.12 (m, 2H), 7.60 (s, 1H).

EX89-02 (800 mg, 1.81 mmol) was dissolved in dichloromethane (10 mL), triethylamine (1.00 mL, 7.25 mmol) and trifluoroacetic anhydride (1.14 mg, 5.44 mmol) were added, and the reaction solution was stirred at 25 ° C for 0.5 hours. After the reaction was completed, the reaction solution was quenched with water (10 mL), extracted with dichloromethane (20 mL x 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 2/1) to obtain EX89-03 (740 mg, yield 96.4%).

EX89-03 (300 mg, 0.708 mmol) was dissolved in 1-methyl-2-pyrrolidone (3 mL), EX53-03 (125 mg, 0.708 mmol) and potassium carbonate (196 mg, 1.42 mmol) were added, and the mixture was stirred at 100 °C for 12 hours. After the reaction, the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (15 mL x 3), and the organic phases were combined, washed with water (10 mL x 3) and saturated brine (10 mL) in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 2/1) to obtain yellow solid EX89-04 (200 mg, yield 53.5%). LCMS: MS m/z (ESI) [M+H] ⁺ = 529.1.

EX89-04 (200 mg, 0.379 mmol) was dissolved in dioxane (2 mL), and tert-butyl piperidine-4-carbamate (151.7 mg, 0.757 mmol), cesium carbonate (246.7 mg, 0.757 mmol) and Pd-PEPPSI-HeptCl (36.8 mg, 38.0 umol) were added. The reaction solution was heated to 110°C under nitrogen protection and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain EX89-05 (130 mg, yield 57.2%). LCMS: MS m/z (ESI) [M+H] ⁺ = 601.4.

EX89-05 (120 mg, 0.200 mmol) was dissolved in 4M hydrochloric acid/dioxane (0.5 mL), and the reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC (column: Boston Prime C18 150*30mm*5um; Condition: water(FA)-ACN; B%: 10%-40%, 9 minutes) to obtain EX89 (24.1 mg, 24.1%). LCMS:MS m/z(ESI)[M+H] ⁺ =501.3; ¹ H NMR (400MHz, DMSO-d6) δ8.39(s,1H),8.34-8.24(m,2H),8.08-7.98(m,1H),7.41(s,1H),3.90-3.70(m,4H),3.61–3.4 8(m,2H),3.07-2.92(m,3H),1.98-1.86(m,4H),1.82–1.73(m,2H),1.72–1.57(m,2H),1.51–1.42(m,2H),1.26(s,3H).

Example EX90

Compound EX83-05 (300 mg, 0.73 mmol) was dissolved in NMP (2 mL), and EX90-04 (250 mg, 1.31 mmol) and potassium carbonate (301 mg, 2.18 mmol) were added. The reaction solution was heated to 100 ° C and stirred for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was diluted with water (10 mL), the solid precipitated, filtered, and the filter cake was concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain EX90-05 (350 mg, yield 84.8%). LCMS:MS m/z(ESI)[M+H] ⁺ =568.0; 1H NMR (400MHz, DMSO-d6) δ8.42(dd,J＝12.0,2.0Hz,1H),8.34(dd,J＝8.4,2.0Hz,1H),8.07-7.99(m,1H),6.75(s,1H),5.03(s ,1H),4.11-3.92(m,2H),3.65-3.55(m,2H),2.67(s,3H),2.26-2.14(m,4H),2.07–1.98(m,2H),1.39(s,3H).

Compound EX90-05 (350 mg, 0.617 mmol) was dissolved in dioxane (6 mL), and 4-Boc-aminopiperidine (185 mg, 0.925 mmol), cesium carbonate (603 mg, 1.85 mmol) and RuPhos Pd G2 (24.0 mg, 0.031 mmol) were added. The reaction solution was stirred at room temperature to 100°C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was dried under reduced pressure, and the crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain EX90-06 (300 mg, yield 76.0%). LCMS: MS m/z (ESI) [M+H]+ = 640.4.

Compound EX90-06 (300 mg, 0.469 mmol) was dissolved in dioxane (2 mL), 4 M dioxane hydrochloride (3 mL) was added, and stirred at 25°C for 2 hours. The reaction solution was concentrated and dried, and the crude product was purified by preparative HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 28%-48%, 11 minutes) to obtain EX90 (formate) (52.8 mg, yield 19.2%). LCMS: MS m/z (ESI) [M+H] ⁺ =540.3; ¹ H NMR (400MHz, DMSO-d6) δ8.42 (s, 1H), (d, J = 12.4Hz, 1H), 8.34 (dd, J = 8.8, 1.6Hz, 1H), 7.98 (t, J = 8.4Hz, 1H), 6.60 (s, 1H), 4. 03-3.93(m,2H),3.62–3.50(m,4H),3.10–2.97(m,1H),2.96–2.84(m,2H) ,2.55(s,3H),2.40-2.17(m,4H),2.07-1.87(m,4H),1.70-1.53(m,2H),1. 39(s,3H).

Example EX91

The compound N-benzyl-1-methoxy-N-(methoxymethyl)methylamine (1.7 g, 12.7 mmol) was dissolved in anhydrous methanol (0.42 mL, 10.5 mmol) and MeCN (8 mL), and MeSiCl ₃ (1.33 g, 8.89 mmol) and EX91-01 (450 mg, 5.23 mmol) were added. The reaction solution was stirred at 25°C for 16 hours. The reaction solution was quenched with saturated sodium bicarbonate aqueous solution and adjusted to pH ~ 9, extracted with ethyl acetate (50 mL*3), the organic phases were combined, washed with saturated brine (50 mL*3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain EX91-02 (800 mg, yield 35.2%). LCMS:MS m/z(ESI)[M+H ₂ O+H] ⁺ =236.2; ¹ H NMR (400MHz, CDCl ₃ ) δ7.38-7.23(m,5H),4.54-4.20(m,1H),4.19-4.00(m,1H),3.88-3.50(m,3H),3.38-3.17(m ,1H),3.14-2.90(m,1H),2.75-2.39(m,3H).

Compound EX91-02 (1.50 g, 6.90 mmol) was dissolved in anhydrous methanol (20 mL), cooled to 0°C, and NaBH ₄ (391 mg, 10.4 mmol) was added, and stirred at 25°C for 2 hours under nitrogen protection. The reaction solution was quenched with saturated aqueous ammonium chloride solution (50 mL), extracted with ethyl acetate (50 mL*3), and the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography. (silica, dichloromethane/methanol = 100/0 to 92/8) to obtain EX91-03 (900 mg, yield 59.5%). LCMS: MS m/z (ESI) [M+H] ⁺ = 220.2; ¹ H NMR (400 MHz, CDCl3) δ 7.45-7.29 (m, 5H), 4.30 (t, J = 5.2 Hz, 1H), 4.26-4.16 (m, 1H), 4.05-3.92 (m, 2H), 3.76-3.68 (m, 1H), 3.67-3.57 (m, 1H), 2.93-2.81 (m, 2H), 2.80-2.72 (m, 1H), 2.70-2.57 (m, 1H), 2.36–2.27 (m, 1H).

Compound EX91-03 (900 mg, 4.10 mmol) was dissolved in methanol (10 mL), and Pd(OH) ₂ (0.55 g, 0.39 mmol) and Pd/C 10% (450 mg, 0.423 mmol) were added. The reaction solution was stirred at 25°C for 16 hours under hydrogen protection. The reaction solution was filtered to recover palladium carbon, and the filter cake was washed with methanol (10 mL*2). The filtrates were combined and concentrated under reduced pressure and dried to obtain EX91-04 (500 mg, yield 94.3%). ^1. 42-2.29(m,2H),2.01-1.91(m,1H).

Compound EX83-05 (400 mg, 0.969 mmol) was dissolved in NMP (10 mL), and EX91-04 (163 mg, 1.26 mmol) and potassium carbonate (402 mg, 2.91 mmol) were added. The reaction solution was heated to 100 ° C and stirred for 12 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature and poured into ice water (50 mL). A white solid was precipitated and filtered. The filter cake was washed with water (5 mL*3) and dried under reduced pressure to obtain a white solid EX91-05 (350 mg, yield 71.4%). LCMS: MS m/z (ESI) [M+H] ⁺ =506.0; ¹ H NMR (400MHz, DMSO-d6) δ8.41 (dd, J = 12.0, 1.6Hz, 1H), 8.33 (dd, J = 8.8, 1.6Hz, 1H), 8.07-7.98 (m, 1H), 6.73 (s, 1H), 5.65 (s, 1H),4.21-4.21(m,1H),4.15-4.05(m,1H),4.00-3.90(m,2H),3.85-3.76(m,1H),3.57-3.49(m,1H),3.32-3.23(m,2H),2.70(s,3H),2.00-1.82(m, 1H).

Compound EX91-05 (420 mg, 0.831 mmol) was dissolved in dioxane (10 mL), and 4-Boc-aminopiperidine (333 mg, 1.66 mmol), Cs ₂ CO ₃ (812 mg, 2.49 mmol) and RuPhos Pd G2 (32.3 mg, 0.042 mmol) were added. The reaction solution was stirred at 100°C for 12 hours under nitrogen protection. After the reaction was completed, the reaction solution was poured into ice water (50 mL), and a large amount of solid precipitated and filtered. The filter cake was washed with water (5 mL*3), dried under reduced pressure, and the crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain EX91-06 (300 mg, yield 28.1%). LCMS: MS m/z (ESI) [M+H] ⁺ = 578.2.

Compound EX91-06 (270 mg, 0.467 mmol) was dissolved in dioxane (3 mL), 4 M dioxane hydrochloride (3 mL) was added, and stirred at 25°C for 1 hour. The reaction solution was concentrated and dried, and the crude product was subjected to preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 20%-40%, 11 minutes) to obtain EX91 (4.89 mg, yield 2.2%). LCMS: MS m/z (ESI) [M+H] ⁺ = 478.2; ¹ H NMR (400MHz, DMSO-d6) δ8.42(dd,J＝13.2,1.6Hz,1H),8.35(dd,J＝9.2,1.6Hz,1H),7.98(t,J＝8.4Hz,1H),6.59(s,1H),5.64(s,1H),4.27-4.20(m,1H),4.14–4. 04(m,1H),3.98-3.75(m,4H),3.60-3.47(m,4H),3.01-2.78(m,3H),2.57(s,3H),2.42-2.31(m,1H),1.94–1.82(m,2H),1.61-1.42(m,2H).

Example EX92

Compound EX92-01 (15.0 g, 104 mmol) was dissolved in DMF (200 mL), and Zn(CN) ₂ (24.4 g, 208 mmol), Pd ₂ (dba) ₃ (4.70 g, 5.19 mmol) and dppf (5.90 g, 10.4 mmol) were added. The reaction solution was stirred at 100 °C for 5 hours under nitrogen protection. After the reaction, the reaction solution was diluted with water (100 mL), extracted with ethyl acetate (100 mL*3), and the organic phase was washed with saturated brine (100 mL*3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried, and the crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain EX92-02 (4.00 g, yield 28.5%). ¹ H NMR (400MHz, DMSO-d6) δ13.81(s,1H),6.93(s,1H),2.28(s,3H).

Compound EX92-02 (3.7 g, 27.4 mmol) was dissolved in methanol (40 mL), and HCl (9.13 mL, 54.8 mmol) and Pd/C 10% (3.70 g, 34.8 mmol) were added. The reaction solution was stirred at room temperature for 12 hours under a hydrogen atmosphere. The reaction solution was filtered, and the filter cake was washed twice with methanol (2*10 ml). The filtrates were combined and concentrated under reduced pressure and dried to obtain EX92-03 (4.00 g, yield 83.2%). 1H NMR (400 MHz, DMSO-d6) δ13.83 (s, 1H), 6.93 (s, 1H), 4.05 (s, 2H), 2.27 (s, 3H).

The compound 4-cyano-3-fluorobenzoic acid (4.1 g, 25.1 mmol) was dissolved in ethyl acetate (10 mL), and EX92-03 (4 g, 22.8 mmol), DIPEA (11.4 mL, 68.5 mmol) and n-butylphosphonic anhydride (50% ethyl acetate solution) (24.7 g, 34.3 mmol) were added. The reaction was stirred at 25 ° C for 16 hours. After the reaction was completed, the reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL*3), the organic phases were combined, washed with saturated brine (50 mL*3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried, and the crude product was purified by silica gel column chromatography (silica, dichloromethane/methanol = 100/0 to 95/5) to obtain EX92-04 (900 mg, yield 13.8%). LCMS: MS m/z (ESI) [M+H] ⁺ =287.1; ¹ HNMR (400MHz, DMSO-d6) δ12.79 (s, 1H), 9.16 (t, J = 5.2Hz, 1H), 8.12-8.05 (m, 1H), 7.98-7.86 (m, 2H), 6.71 (s, 1H), 4.45 (d ,J＝5.2Hz,2H),2.19(s,3H).

Compound EX92-04 (900 mg, 3.14 mmol) was dissolved in DCE (4 mL), and POCl ₃ (4 mL) was added. The reaction was stirred at 80°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was transferred to warm water for quenching (50 mL). Saturated sodium bicarbonate aqueous solution was slowly added dropwise to adjust the pH to 7. The aqueous phase was extracted with ethyl acetate (50 mL*3). The organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried, and the crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 3/2) to obtain EX92-05 (270 mg, yield 30.0%). LCMS: MS m/z(ESI)[M+H] ⁺ =287.1; ¹ H NMR (400MHz, DMSO-d6) δ8.47-8.35(m,2H),8.14-8.08(m,1H),8.02(s,1H),7.06(s,1H),2.58(s,3H).

Compound EX92-05 (240 mg, 0.837 mmol) was dissolved in anhydrous acetonitrile (4 mL), and NIS (188 mg, 1.09 mmol) was added. The reaction was stirred at 90°C for 12 hours. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (10 mL*3), and the organic phases were combined and washed with brine (10 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain EX92-06 (200 mg, 58%). LCMS: MS m/z (ESI) [M+H] ⁺ = 413.0.

Compound EX92-06 (200 mg, 0.485 mmol) was dissolved in NMP (4 mL), and EX53-03 (103 mg, 0.582 mmol) and potassium carbonate (201 mg, 1.45 mmol) were added. The reaction solution was heated to 100 ° C and stirred for 12 hours under nitrogen protection. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (10 mL*3), and the organic phase was washed with brine (10 mL*3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/tetrahydrofuran = 100/0 to 5/4) to obtain EX92-07 (160 mg, yield 63.8%). LCMS: MS m/z (ESI) [M+H] ⁺ =518.1; ¹ H NMR (400MHz, DMSO-d6) δ8.47 (d, J = 10.4Hz, 1H), 8.37 (d, J = 8.4Hz, 1H), 8.02-7.95 (m, 1H), 6.93 (s, 1H), 4.91 (s, 1H), 3. 72-3.62(m,2H),3.57-3.47(m,2H),2.69(s,3H),1.92-1.87(m,2H),1.81-1.76(m,2H),1.57-1.51(m,2H),1.26(s,3H).

Compound EX92-07 (150 mg, 0.290 mmol) was dissolved in dioxane (5 mL), and 4-Boc-aminopiperidine (87.1 mg, 0.435 mmol), Cs ₂ CO ₃ (236 mg, 0.725 mmol) and Pd-PEPPSI-IHeptCl (11.5 mg, 0.014 mmol) were added. The reaction solution was heated to 110°C and stirred for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was dried under reduced pressure, and the crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/tetrahydrofuran = 100/0 to 1/1) to obtain EX92-08 (100 mg, yield 58.5%). LCMS: MS m/z (ESI) [M+H] ⁺ = 590.3.

Compound EX92-08 (100 mg, 0.170 mmol) was dissolved in dioxane (1 mL), and 4 M dioxane hydrochloride (1 mL) was added, and stirred at 25°C for 2 hours. The reaction solution was concentrated and dried, and the crude product was subjected to preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 30%-50%, 11 minutes) to obtain EX92 (15.65 mg, yield 18.8%). LCMS: MS m/z (ESI) [M+H] ⁺ = 490.2; ¹ H NMR (400MHz, DMSO-d6) δ8.49 (d, J = 11.6Hz, 1H), 8.43 (s, 1H), 8.38 (d, J = 8.8Hz, 1H), 7.95 (t, J = 7.6Hz, 1H), 6.66 (s, 1H), 4. 90(s,1H),3.68-3.64(m,2H),3.55-3.45(m,4H),3.00-2.88(m,3H),2.57(s,3H),1.93-1.84(m,4H),1.82-1.74(m,2H),1.64-1.48(m,4H),1.26(s, 3H).

Example EX93

EX83-05 (400 mg, 0.969 mmol) and (R)-3-methylmorpholine (127 mg, 1.26 mmol) were dissolved in 1-methyl-2-pyrrolidone (5.0 mL), and potassium carbonate (401.9 mg, 2.91 mmol) was added. The reaction solution was heated to 100 °C and stirred for 18 hours. The reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (40 mL*3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 20%) to obtain EX93-01 (55 mg, yield 11.9%). LCMS: MS m/z (ESI) [M+H] ⁺ = 478.1.

EX93-01 (80.0 mg, 0.168 mmol) was dissolved in 1,4-dioxane (1.0 mL), and tert-butyl piperidine-4-carbamate (43.6 mg, 0.218 mmol), RuPhos Pd G2 (13.0 mg, 0.017 mmol) and cesium carbonate (109 mg, 0.335 mmol) were added. The reaction solution was heated to 100 ° C and stirred for 16 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 20%) to obtain EX93-02 (30 mg, yield 32.6%). LCMS:MS m/z(ESI)[M+H] ⁺ =550.4.

EX93-02 (30 mg, 0.055 mmol) was dissolved in 4M hydrochloric acid dioxane (1.0 mL), and the reaction solution was stirred at 25°C for 1 hour. After the reaction solution was filtered, it was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 25%-45%, 11 minutes) to obtain EX93 (formate) (3.25 mg, yield 13.2%). LCMS: MS m/z (ESI) [M+H] ⁺ = 450.2; ¹ H NMR (400 MHz, CD3OD)δ8.48(s,1H),8.45-8.35(m,2H),7.76(t,J＝8.0Hz,1H),6.59(s,1H),4.67-4.60(m,1H),4.50-4.40(m,1H),4.10-3.98(m,2H),3.90-3.83( m,1H),3.82-3.71(m,3H),3.70–3.58(m,1H),3.40–3.32(m,1H),3.10-2.98(m,2H),2.63(s,3H),2.22-2.11(m,2H),1.98-1.84(m,2H),1.31(d,J＝6 .8Hz,3H).

Example EX94 EX95

EX88-06 (3.00 g, 6.38 mmol) was dissolved in 1-methyl-2-pyrrolidone (30 mL), and EX71-03 (1.23 g, 6.38 mmol) and potassium carbonate (1.76 g, 12.8 mmol) were added. The reaction solution was stirred at 100 ° C for 12 hours. After the reaction was completed, it was cooled to room temperature, and the reaction solution was diluted with EtOAc (80 mL) and water (50 mL). The aqueous phase was extracted with EtOAc (50 mL x 3), and the organic phases were combined, washed with water (50 mL x 2) and saturated brine (50 mL) in turn, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 2/1) to obtain EX94-01 (3.70 g, yield 98.1%). LCMS:MS m/z(ESI)[M+H]+=592.2.

EX94-01 (3.60 g, 6.09 mmol) was dissolved in dioxane (50 mL), and tert-butyl piperidine-4-carbamate (2.44 g, 12.2 mmol), cesium carbonate (3.40 g, 12.2 mmol) and Pd-PEPPSI-IHeptCl (592 mg, 0.609 mmol) were added. The reaction mixture was heated to 110 °C under nitrogen protection and stirred for 12 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain yellow solid EX94-02 (2.50 g, yield 61.9%). LCMS: MS m/z (ESI) [M+H] ⁺ = 664.4.

EX94-02 (2.20 g, 3.31 mmol) was dissolved in tetrahydrofuran (100 mL), and lithium triethylborohydride (6.63 mL, 6.63 mmol) was added. The reaction solution was stirred at -15 ° C for 10 minutes. The reaction solution was quenched with water (5 mL), extracted with ethyl acetate (10 mL x 3), and the organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 1/3) to obtain EX94-03 (840 mg, yield 40.8%). LCMS: MS m/z (ESI) [M+H] ⁺ = 622.4.

EX94-03 (820 mg, 1.32 mmol) was dissolved in dichloromethane (4 mL), pyridinium chlorochromate (853 g, 3.96 mmol) was added, and the mixture was stirred at 25°C for 16 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain EX94-04 (370 mg, yield 45.3%). LCMS: MS m/z (ESI) [M+H] ⁺ = 620.2.

EX94-04 (350 mg, 0.565 mmol) was dissolved in methanol (1 mL), and dimethyl (1-diazo-2-oxopropyl)phosphonate (130 mg, 0.678 mmol) and potassium carbonate (156 mg, 1.13 mmol) were added, and the reaction solution was stirred at 25°C for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain EX94-05 (300 mg, yield 86.3%). LCMS:MS m/z(ESI)[M+H] ⁺ =616.3.

EX94-05 (280 mg, 0.455 mmol) was dissolved in 4M hydrochloric acid/dioxane (3 mL), and the reaction solution was stirred at 25°C for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure and purified by HPLC (column: ACSSH-CK C18 150×30 mm; Condition: water (FA)-ACN; B%: 8%-38%, 9 minutes) and then purified by SFC (column: DAICEL CHIRALPAK IC (250 mm*30 mm, 10 um); Condition: CO ₂ -MeOH (0.1% NH 3 H 2 O); B%: 60%-60%, 20 minutes) to obtain EX94 (1.61 mg, yield 0.7%) and EX95 (20.9 mg, yield 8.9%).

EX94: LCMS: MS m/z (ESI) [M+H] ⁺ = 516.2; ¹ H NMR (400MHz, DMSO-d6) δ8.38 (d, J = 12.4Hz, 1H), 8.32 (d, J = 8.4Hz,1H),7.98(t,J＝8.4Hz,1H),6.86(s,1H),4.97(s,1H),4.92(s,1H),4.35-3.91(m,2H),3.90- 3.74(m,6H),3.71-3.60(m,2H),2.95-2.72(m,3H),1.86-1.70(m,4H),1.55-1.40(m,2H),1.46(s,3H).

EX95:LCMS:MS m/z(ESI)[M+H] ⁺ =516.2; ¹ H NMR(400MHz, DMSO-d6)δ8.39-8.22(m,2H),7.96(t,J＝7.6Hz, 1H),6.84(s,1H),4.93(s,2H),4.36-4.00(m,4H),3.92-3.78(m,2H),3.71-3.48(m,4H),2.97-2.78(m, 3H),1.95-1.77(m,2H),1.75-1.62(m,2H),1.58-1.44(m,2H),1.36(s,3H).

Example EX96 EX97

Compound EX92-06 (200 mg, 0.485 mmol) was dissolved in NMP (4 mL), and EX71-03 (122 mg, 0.630 mmol) and potassium carbonate (201 mg, 1.45 mmol) were added. The reaction solution was heated to 100 ° C and stirred for 12 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (10 mL * 3), and the organic phase was washed with saturated brine (10 mL * 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/tetrahydrofuran = 100/0 to 1/1) to obtain EX96-01 (200 mg, yield 77.4%). LCMS: MS m/z (ESI) [M+H] ⁺ = 534.0.

Compound EX96-01 (200 mg, 0.375 mmol) was dissolved in dioxane (5 mL), and 4-Boc-aminopiperidine (150 mg, 0.750 mmol), cesium carbonate (367 mg, 1.13 mmol) and Pd-PEPPSI-IHeptCl (14.8 mg, 0.019 mmol) were added. The reaction solution was heated to 110°C under nitrogen protection and stirred for 16 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/tetrahydrofuran = 100/0 to 1/1) to obtain yellow solid EX96-02 (100 mg, yield 44.0%). LCMS: MS m/z (ESI) [M+H] ⁺ = 606.3.

Compound EX96-02 (100 mg, 0.165 mmol) was dissolved in dioxane (1 mL), and 4 M dioxane hydrochloride (1 mL) was added, and stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure and dried by spin drying. The crude product was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 20%-40%, 11 minutes), and then by preparative SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: [0.1% ammonia water. isopropanol]; B%: 45%-45%) was used for separation and purification to obtain EX96 (2.89mg, yield 1.9%) and EX97 (6.68mg, yield 4.5%).

EX96: LCMS: MS m/z (ESI) [M+H] ⁺ = 506.2; ¹ H NMR (400MHz, CD ₃ OD) δ8.55-8.36 (m, 2H), 7.74 (t, J = 7.6Hz, 1H),6.58(s,1H),4.39-4.29(m,2H),4.24-4.14(m,2H),4.3.82-3.72(m,2H),3.70-3.60(m,2H),3.40- 3.33(m,2H),3.15-3.05(m,3H),2.65(s,3H),2.08-1.98(m,2H),1.82-1.70(m,4H),1.48(s,3H).

EX97:LCMS:MS m/z(ESI)[M+H] ⁺ =506.1; ¹ H NMR (400MHz, CD ₃ OD)δ8.48(d,J＝12.0Hz,1H),8.43(d,J＝8.8Hz,1H),7.80-7.72(m,1H),6.56(s,1H),4.12-4.03(m, 2H),4.03-3.90(m,4H),3.85-3.75(m,2H),3.33-3.25(m,2H),3.15-3.04(m,2H),3.03-2.90(m,1H),2.65( s,3H),2.06-1.95(m,2H),1.87-1.79(m,2H),1.76-1.62(m,2H),1.60(s,3H).

Example EX98

EX98-01 (1.00 g, 3.53 mmol) was dissolved in 1,4-dioxane (0.5 mL), and 4 M hydrochloric acid/dioxane solution (2 mL) was added. The reaction solution was stirred at 25 °C for 1 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain EX98-02 (750 mg, yield 96.7%). ¹ H NMR (400 MHz, DMSO-d6) δ 9.68-9.20 (m, 2H), 6.43 (s, 1H), 3.49-3.36 (m, 1H), 3.26-3.16 (m, 1H), 3.02-2.90 (m, 1H), 2.20-1.67 (m, 4H), 1.38-1.26 (m, 3H).

EX98-02 (444 mg, 2.42 mmol) and EX83-05 (500 mg, 1.21 mmol) were dissolved in 1-methyl-2-pyrrolidone (5.0 mL), and potassium carbonate (502 mg, 3.64 mmol) was added. The reaction solution was heated to 100 ° C and stirred for 12 hours. The reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/tetrahydrofuran = 100/0 to 3/2) to obtain EX98-03 (200 mg, yield 29.5%). LCMS: MS m/z(ESI)[M+H] ⁺ =560.1; ¹ H NMR (400MHz, DMSO-d6) δ8.41-8.24(m,2H),8.09-7.99(m,1H),6.87(s,1H),6.12(s,1H),4.96-4.75(m,1H),4.45-4. 24(m,1H),3.43-3.33(m,1H),2.67(s,3H),2.21-2.13(m,1H),1.95-1.70(m,5H),1.36(d,J＝8.0Hz,3H).

EX98-03 (200 mg, 0.358 mmol) was dissolved in 1,4-dioxane (4.5 mL), and NaI (10.7 mg, 0.072 mmol), tert-butyl piperidin-4-ylcarbamate (86.0 mg, 0.429 mmol), Pd-PEPPSI-IHeptCl (34.8 mg, 0.036 mmol) and cesium carbonate (350 mg, 1.07 mmol) were added. The reaction solution was heated to 100 ° C and stirred for 12 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated and dried. Crude product The product was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 50%) to give EX98-04 (60.00 mg, yield 26.6%). LCMS: MS m/z (ESI) [M+H] ⁺ = 632.1; ¹ H NMR (400 MHz, CDCl ₃ )δ8.38(dd,J＝12.0,1.6Hz,1H),8.26(dd,J＝8.8,1.6Hz,1H),7.67-7.57(m,1H),6.38(s,1H),4.88-4.74(m,1H),4./65-4.50(m,1H),4.39-4.25(m,1H), 3.80-3.66(m,1H),3.60-3.42(m,3H),3.10-2.96(m,2H),2.58(s,3H),2.16-2.07(m,2H),1.98-1.83(m,4H),1.70-1.59(m,2H),1.48(s,9H),1.4 4(s,3H).

EX98-04 (40 mg, 0.063 mmol) was dissolved in 4M hydrochloric acid/1,4-dioxane solution (2 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 23%-53%, 8 minutes) to obtain EX98 (formate) (13.9 mg, yield 41.3%). LCMS: MS m/z (ESI) [M+H] ⁺ = 532.2; ¹ H NMR(400MHz, DMSO-d6)δ8.42(s,1H),8.32(dd,J＝12.4,1.6Hz,1H),8.27(dd,J＝8.8,1.6Hz,1H),7.96(t,J＝8.4Hz,1H),6.72(s,1H),4.88-4.75(m,1H),4.35-4 .22(m,1H),3.65-3.55(m,1H),3.40-3.25(m,2H),3.13-3.00(m,1H),2.96-2.84(m,2H),2.54(s,3H),1.99-1.60(m,8H),1.36(d,J＝7.2Hz,3H).

Example EX99, EX100

EX89-03 (400 mg, 0.944 mmol) was dissolved in 1-methyl-2-pyrrolidone (5 mL), and EX71-03 (183 mg, 0.944 mmol) and potassium carbonate (261 mg, 1.89 mmol) were added. The reaction solution was stirred at 100°C for 12 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 2/1) to obtain EX99-01 (400 mg, yield 77.8%). LCMS: MS m/z (ESI) [M+H] ⁺ = 545.2.

EX99-01 (400 mg, 0.735 mmol) was dissolved in dioxane (1 mL), and tert-butyl piperidin-4-ylcarbamate (294 mg, 1.47 mmol), Pd-PEPPSI-IHeptCl (71.5 mg, 73.0 umol) and cesium carbonate (479 mg, 1.47 mmol) were added. The reaction solution was heated to 110 ° C under nitrogen protection and stirred for 12 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain EX99-02 (70.0 mg, yield 15.4%). LCMS: MS m/z (ESI) [M+H] + = 617.4.

EX99-02 (100 mg, 0.162 mmol) was dissolved in 4M hydrochloric acid/dioxane (2 mL), and the reaction solution was stirred at 25°C for 1 hour. After the reaction, the reaction solution was dried under reduced pressure, and the crude product was purified by HPLC (column: ACSSH-CP C18 150×30 mm; Condition: water (FA)-ACN; B%: 0%-40%, 9 minutes), and then purified by SFC (column: DAICEL CHIRALPAK IC (250mm*30mm, 10um); Condition: CO ₂ -EtOH (0.1% NH ₃ H2O); B%: 60%-60%, 20 minutes) to obtain EX99 (9.83 mg, yield 11.8%) and EX100 (2.52 mg, yield 3.0%).

EX99:LCMS:MS m/z(ESI)[M+H] ⁺ =517.2; ¹ H NMR(400MHz, DMSO-d6)δ8.35-8.25(m,2H),8.03-7.94 (m,1H),7.34(s,1H),5.02(s,1H),4.34-4.16(m,1H),4.05-3.90(m,1H),3.89-3.63(m,8H),3.00-2.87 (m,2H),2.85-2.75(m,1H),1.92-1.82(m,2H),1.80-1.67(m,2H),1.58-1.48(m,2H),1.47(s,3H).

EX100:LCMS:MS m/z(ESI)[M+H] ⁺ =517.2; ¹ H NMR(400MHz, DMSO-d6)δ8.37-8.23(m,2H),8.00(t,J＝8.4Hz, 1H),7.34(s,1H),4.93(s,1H),4.47-4.00(m,4H),3.75-3.65(m,2H),3.64-3.50(m,4H),3.00-2.88(m, 2H),2.86-2.71(m,1H),1.93-1.80(m,2H),1.77-1.65(m,2H),1.58-1.46(m,2H),1.37(s,3H).

Example EX101

EX101-05 (2.37 g, 5.28 mmol) was dissolved in 1-methyl-2-pyrrolidone (20 mL), and EX53-03 (936 mg, 5.28 mmol) and potassium carbonate (1.46 g, 10.6 mmol) were added. The reaction solution was stirred at 100 ° C for 12 hours. After the reaction was completed, it was cooled to room temperature, and the reaction solution was diluted with water (50 mL) to precipitate solids. It was filtered under reduced pressure, and the filter cake was purified by silica gel column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain EX101-06 (2.40 g, yield 82.1%). LCMS: MS m/z (ESI) [M+H] ⁺ =554.2; ¹ H NMR (400MHz, DMSO-d6) δ8.29 (d, J = 12.0Hz, 1H), 8.21 (d, J = 8.8Hz, 1H), 7.97 (t, J = 8.0Hz, 1H), 7.48 (t, J = 54.0Hz, 1H), 7.09 ( s,1H),4.93(s,1H),4.01-3.67(m,2H),3.62-3.52(m,2H),1.96-1.87(m,2H),1.81-1.74(m,2H),1.58-1.45(m,2H),1.27(s,3H).

EX101-06 (500 mg, 0.904 mmol) was dissolved in dioxane (6 mL), and tert-butyl piperidine-4-carbamate (272 mg, 1.36 mmol), cesium carbonate (589 mg, 1.81 mmol) and Ruphos Pd G2 (70.2 mg, 90.0 umol) were added. The reaction solution was stirred at room temperature to 100 ° C under nitrogen atmosphere for 12 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain EX101-07 (500 mg, yield 88.4%). LCMS: MS m/z (ESI) [M+H] ⁺ = 626.3.

EX101-07 (400 mg, 0.639 mmol) was dissolved in 4M hydrochloric acid/dioxane (4 mL), and the reaction solution was stirred at 25°C for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC (column: ACSSH-CAC18 150×40 mm; Condition: water (FA)-ACN; B%: 23%-63%, 9 minutes) to obtain EX101 (formate) (81.55 mg, yield 24.3%). LCMS: MS m/z (ESI) [M+H] ⁺ = 526.2; 1H NMR (400MHz, DMSO-d6) δ8.39(s,1H),8.37(dd,J＝11.6,2.0Hz,1H),8.31(d,J＝8.0,2.0Hz,1H),8.02(t,J＝8.0Hz,1H),7.26(t,J＝54.4Hz,1H),6.99(s,1H),3.9 5-3.72(m,2H),3.60-3.50(m,4H),3.10-3.00(m,1H),2.98-2.85(m,2H),1.98-1.88(m,4H),1.83-1.74(m,2H),1.71-1.60(m,2H),1.53-1.44(m, 2H),1.26(s,3H).

Example EX102

EX102-05 (800 mg, 1.87 mmol) was dissolved in 1-methyl-2-pyrrolidone (10 mL), and EX53-03 (332 mg, 1.87 mmol) and potassium carbonate (516 mg, 3.73 mmol) were added. The reaction solution was stirred at 100 ° C for 12 hours under a nitrogen atmosphere. After the reaction was completed, it was cooled to room temperature, and the reaction solution was diluted with water (20 mL) to precipitate a solid. It was filtered under reduced pressure, and the filter cake was chromatographed on a silica gel column (silicon dioxide, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain EX102-06 (700 mg, yield 70.3%). LCMS: MS m/z (ESI) [M+H] ⁺ =534.1; ¹ H NMR (400MHz, DMSO-d6) δ8.37 (dd, J = 12.0, 1.6 Hz, 1H), 8.26 ( dd, J = 8.8, 1.6 Hz, 1H), 7.98 ( t, J = 8.4 Hz, 1H), 6.21 ( s, 1H), 4.87 ( s,1H),3.98(s,3H),3.90-3.75(m,2H),3.55-3.45(m,2H),2.22-2.14(m,2H),1.94-1.82(m,2H),1.80-1.70(m,2H),1.26(s,3H).

Compound EX102-06 (350 mg, 0.656 mmol) was dissolved in dioxane (0.5 mL), and tert-butyl piperidine-4-carbamate (263 mg, 1.31 mmol), cesium carbonate (428 mg, 1.31 mmol) and Pd-PEPPSI-Iheptcl (3.6 mg, 4.00 umol) were added. The reaction solution was heated to 110°C under a nitrogen atmosphere and stirred for 12 hours. After the reaction, the reaction solution was vacuum dried, and the crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 10/1 to 3/1) to obtain EX102-07 (300 mg, yield 75.5%). LCMS: MS m/z (ESI) [M+H] ⁺ = 606.1.

Compound EX102-07 (130 mg, 0.215 mmol) was dissolved in 4M dioxane hydrochloride (1 mL) and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and the crude product was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 42%-72%, 8 minutes) to obtain EX102 (10.59 mg, yield 9.8%). LCMS: MS m/z (ESI) [M+H] ⁺ =506.4; ¹ H NMR (400MHz, DMSO-d6) δ8.43 (d, J = 12.8Hz, 1H), 8.31 (d, J = 8.8Hz, 1H), 7.96 (t, J = 8.4Hz, 1H), 6.15 (s, 1H), 4.91 (s, 1H), 4. 00(s,3H),3.96-3.86(m,2H),3.85-3.75(m,2H),3.55-3.45(m,2H),2.94-2.78(m,3H),1.93-1.77(m,6H),1.57-1.40(m,4H),1.29(s,3H).

Example EX103 EX104

EX83-01 (600 mg, 1.13 mmol) was dissolved in dioxane (12 mL), and RuPhos Pd G2 (87.4 mg, 0.113 mmol), 4-dimethylaminopiperidine (173 mg, 1.35 mmol), and cesium carbonate (1.10 g, 3.38 mmol) were added. The reaction solution was stirred at 100 ° C for 12 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (silica, dichloromethane/methanol = 100/0-100/8) to obtain EX103-01 (220 mg, yield 36.6%). LCMS: MS m/z (ESI) [M+H] ⁺ = 534.4;

Compound EX103-01 (80 mg, 0.150 mmol) was separated and purified by preparative SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: [0.1% ammonia water.ethanol]; B%: 50%-50%, 20 minutes) to obtain EX103 (35.71 mg, yield 44.6%) and EX104 (18.27 mg, yield 22.8%).

EX103:LCMS:MS m/z(ESI)[M+H] ⁺ =534.3; ¹ H NMR(400MHz,DMSO-d6)δ8.43-8.34(m,2H),8.01-7.92(m,1H),6.55(s,1H),4.89(s,1H),4.25-4.07(m,4H) ,3.65-3.56(m,4H),3.56-3.50(m,2H),2.88-2.76(m,2H),2.56(s,3H),2.35-2.28(m,1H),2.22(s,6H) ,1.91-1.84(m,2H),1.72-1.67(m,2H),1.61-1.52(m,2H),1.35(s,3H).

EX104: LCMS: MS m/z (ESI) [M+H] ⁺ = 534.3; ¹ H NMR (400MHz, DMSO-d6) δ8.43 (dd, J = 12.4, 1.6Hz, 1H), 8.33 (dd, J＝8.8,1.6Hz,1H),7.95(t,J＝8.4Hz,1H),6.55(s,1H),4.94(s,1H),4.16-3.87(m,2H),3.85-3.75(m ,4H),3.70-3.55(m,4H),2.87-2.73(m,2H),2.54(s,3H),2.37-2.29(m,1H),2.24(s,6H),1.93- 1.84(m,2H),1.78-1.70(m,2H),1.63-1.52(m,2H),1.46(s,3H).

Example EX105

EX83-06 (300 mg, 0.580 mmol) was dissolved in 1,4-dioxane (10 mL), methyl (piperidin-4-yl) carbamic acid tert-butyl ester (149 mg, 0.696 mmol), cesium carbonate (567 mg, 1.74 mmol), RuPhos Pd G2 (45.0 mg, 58.0 umol) were added, and the reaction solution was stirred at 100 ° C for 12 hours under nitrogen protection. After the reaction solution was concentrated under reduced pressure, it was purified by column chromatography (petroleum ether/ethyl acetate = 100/0-10/1) to obtain EX105-01 (130 mg, yield 37.1%). LCMS: MS m/z (ESI) [M+H] ⁺ = 604.4.

EX105-01 (110 mg, 0.182 mmol) was dissolved in 4M hydrochloric acid/1,4-dioxane (5 mL), and the reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 20%-60%, 9 minutes) to obtain EX105 (formate) (23.20 mg, yield 25.3%). LCMS: MS m/z (ESI) [M+H] ⁺ = 504.3; ¹ H NMR (400MHz, CD3OD) δ8.55(s,1H),8.36(d,J＝12.4Hz,1H),8.32(d,J＝8.8Hz,1H),7.64(t,J＝8.4Hz,1H),6.51(s,1H),3.93-3.82(m,2H),3.79-3.70(m,2H), 3.61-3. 50(m,2H),3.22-3.12(m,1H),3.05-2.93(m,2H),2.71(s,3H),2.60(s,3H),2.25-2.14(m,2H),2.02-1.94(m,2H),1.91-1.77(m,4H),1.68-1.58( m,2H),1.36(s,3H).

Example EX106

Compound EX91-02 (800 mg, 3.68 mmol) was dissolved in tetrahydrofuran (5 mL), LaCl ₃ ·LiCl tetrahydrofuran solution (7.36 mL, 3.68 mmol) was added, stirred at 25°C for 1 hour under nitrogen protection, cooled to 0°C, 3M methylmagnesium bromide (1.35 mL, 4.05 mmol) was added, and stirred at 25°C for 4 hours under nitrogen protection. The reaction solution was slowly quenched with saturated ammonium chloride solution (30 mL), extracted with ethyl acetate (30 mL*3), the organic phase was washed with saturated brine (10 mL*3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silica, dichloromethane/methanol = 100/0 to 97/3) to obtain EX106-01 (520 mg, yield 60.5%). LCMS:MS m/z(ESI)[M+H] ⁺ =234.2; ¹ H NMR (400MHz, DMSO-d6) δ7.32-7.27(m,5H),4.92(s,1H),3.98-3.93(m,1H),3.74-3.70(m,1H),3.59-3.46(m,2H),3.4 3-3.38(m,1H),2.77-2.72(m,1H),2.64-2.59(m,1H),2.59-2.55(m, 1H),2.41-2.36(m,1H),1.84-1.79(m,1H),1.24(s,3H).

Compound EX106-01 (540 mg, 2.32 mmol) was dissolved in methanol (10 mL), and Pd(OH) ₂ (300 mg, 0.214 mmol) and Pd/C 10% (300 mg, 0.282 mmol) were added. The reaction solution was stirred at 25°C for 16 hours under a hydrogen atmosphere (15 psi). The reaction solution was filtered, and the filter cake was washed twice with methanol (2*10 ml). The filtrate was concentrated under reduced pressure and dried to obtain EX106-02 (300 mg, yield 90.5%). ¹ H NMR (400MHz, DMSO-d6) δ3.99-3.92(m,1H),3.78-3.72(m,1H),3.31-3.28(m,1H),3.15-3.11(m,1H),2.98-2.91(m,1H),2.41-2.30(m,2H),1.72-1. 65(m,1H),1.20(s,3H).

Compound EX83-05 (400 mg, 0.969 mmol) was dissolved in NMP (10 mL), and EX106-02 (208 mg, 1.45 mmol) and potassium carbonate (402 mg, 2.91 mmol) were added. The reaction solution was heated to 100 ° C and stirred for 12 hours under nitrogen protection. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (20 mL x 3), and the organic phases were combined, washed with water (20 mL*3) and saturated brine (10 mL) in turn, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/tetrahydrofuran = 100/0 to 1/1) to obtain EX106-03 (230 mg, yield 45.7%). LCMS: MS m/z (ESI) [M+H] ⁺ = 520.0.

Compound EX106-03 (200 mg, 0.39 mmol) was dissolved in dioxane (6 mL), and 4-Boc-aminopiperidine (154 mg, 0.77 mmol), Cs ₂ CO ₃ (376 mg, 1.16 mmol) and Pd-PEPPSI-IHeptCl (30.5 mg, 0.039 mmol) were added. The reaction solution was stirred at 100°C for 12 hours under nitrogen protection. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and dried, and the crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain yellow solid EX106-04 (120 mg, yield 52.7%). LCMS: MS m/z (ESI) [M+H] ⁺ = 592.3.

Compound EX106-04 (120 mg, 0.203 mmol) was dissolved in dioxane (2 mL) and 4 M hydrochloric acid dioxane solution (2 mL) was added, and stirred at 25°C for 1 hour. The reaction solution was concentrated and dried, and the crude product was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 20%-40%, 11 minutes) to obtain EX106 (27.87 mg, yield 28.0%, formate). LCMS: MS m/z (ESI) [M+H] ⁺ = 492.1; ¹ H NMR (400 MHz, CD ₃ OD)δ8.63-8.50(m,1H),8.49-8.38(m,2H),7.80-7.68(m,1H),6.54(s,1H),4.09-3.94(m,3H),3.94-3.90(m,1H),3.90-3.84(m,1H),3.79-3.69(m ,2H),3.68-3.60(m,1H),3.50-3.40(m,2H),3.10-2.98(m,2H),2.63(s,3H),2.35-2.25m,1H),2.18-2.06(m,2H),1.95-1.78(m,2H),1.49(s,3H).

Example EX107

EX83-05 (300 mg, 0.727 mmol) and (S)-2-methylmorpholine (95.6 mg, 0.945 mmol) were dissolved in 1-methyl-2-pyrrolidone (5.0 mL), and potassium carbonate (301 mg, 2.18 mmol) was added. The reaction solution was heated to 100°C and stirred for 18 hours. The reaction solution was cooled to room temperature and diluted with water (30 mL). Filtered, the filter cake was concentrated and dried under reduced pressure to obtain the crude product EX107-01 (130 mg, yield 30.3%). LCMS: MS m/z (ESI) [M+H] ⁺ = 478.1.

EX107-01 (300 mg, 0.629 mmol) was dissolved in 1,4-dioxane (5.0 mL), and tert-butyl piperidine-4-carbamate (164 mg, 0.817 mmol), RuPhos Pd G2 (97.6 mg, 0.126 mmol) and cesium carbonate (410 mg, 1.26 mmol) were added. The reaction solution was heated to 100 ° C and stirred for 16 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/tetrahydrofuran = 100/0-5/1) to give EX107-02 (130 mg, yield 37.6%). LCMS:MS m/z(ESI)[M+H] ⁺ =550.3; ¹ H NMR (400MHz, DMSO-d6) δ8.37-8.25(m,2H),7.98(t,J＝8.0Hz,1H),6.73(s,1H),4.25–4.15(m,2H),4.00-3.93(m,1H),3. 67-3.48(m,4H),3.05-2.95(m,2H),2.93-2.83(m,2H),2.70-2.64(m,1H) ,2.55(s,3H),1.92-1.84(m,2H),1.65-1.57(m,2H),1.41(s,9H),1.20(d, J＝6.4Hz,3H).

EX107-02 (100 mg, 0.182 mmol) was dissolved in 4 M dioxane hydrochloride (2.0 mL), and the reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure and dried by spin drying, and the crude product was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 21%-51%, 8 minutes) to obtain EX107 (formate) (37.9 mg, yield 46.4%). LCMS:MS m/z(ESI)[M+H] ⁺ =450.2; ¹ H NMR (400MHz, DMSO-d6) δ8.39(s,1H),8.35-8.26(m,2H),8.02-7.95(m,1H),6.74(s,1H),4.26–4.17(m,2H),4.01–3.94 (m,2H),3.65–3.54(m,4H),3.06-3.00(m,2H),2.94-2.87(m,2H),2.70-2. 65(m,1H),2.55(s,3H),1.99-1.91(m,2H),1.69-1.56(m,2H),1.20(d,J＝6 .0Hz,3H).

Example EX108

EX83-05 (300 mg, 0.727 mmol) and (R)-2-methylmorpholine (36.8 mg, 0.364 mmol) were dissolved in 1-methyl-2-pyrrolidone (4.0 mL), and K ₂ CO ₃ (302 mg, 2.18 mmol) was added. The reaction solution was heated to 100°C and stirred for 12 hours. The reaction solution was cooled to room temperature and diluted with water (30 mL). Filtered. The filter cake was concentrated and dried under reduced pressure to obtain EX108-01 (300 mg, yield 86.4%).

EX108-01 (300 mg, 0.629 mmol) was dissolved in 1,4-dioxane (3.0 mL), and tert-butyl piperidine-4-carbamate (151 mg, 0.754 mmol), RuPhos Pd G2 (48.8 mg, 0.063 mmol) and cesium carbonate (614 mg, 1.89 mmol) were added. The reaction solution was heated to 100 ° C and stirred for 12 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was subjected to silica gel column chromatography (silicon dioxide, petroleum ether/tetrahydrofuran = 30%) to obtain EX108-02 (200 mg, yield 57.8%). LCMS: MS m/z (ESI) [M+H] ⁺ =550.3; ¹ H NMR (400MHz, CDCl ₃ )δ8.39(dd,J＝12.0,2.0Hz,1H),8.27(dd,J＝8.8,2.0Hz,1H),7.70-7.55(m,1H),6.37(s,1H),4.17-4.01(m,4H),3.80-3.63(m,3H),3.60-3.46(m,2H), 3.10-3.00(m,2H),2.82-2.73(m,1H),2.59(s,3H),2.15-2.05(m,2H),1.70-1.58(m,2H),1.48(s,9H),1.32(d,J＝6.0Hz,3H).

EX108-02 (60.0 mg, 0.109 mmol) was dissolved in dioxane (0.5 mL), and 4 M dioxane hydrochloride (1.0 mL) was added. The reaction solution was stirred at 25°C for 1 h. The reaction solution was concentrated under reduced pressure and dried by spin drying. The crude product was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 19%-49%, 8 minutes) to obtain EX108 (14.6 mg, yield 29.7%). LCMS:MS m/z(ESI)[M+H] ⁺ =450.2; ¹ H NMR (400MHz, DMSO-d6) δ8.38(s,1H),8.35-8.26(m,2H),8.02-7.95(m,1H),6.74(s,1H),4.26-4.17(m,2H),4.01-3.94 (m,2H),3.65-3.54(m,4H),3.06-3.00(m,2H),2.94-2.87(m,2H),2.70-2. 65(m,1H),2.55(s,3H),1.99-1.91(m,2H),1.69-1.56(m,2H),1.20(d,J＝6 .0Hz,3H).

Example EX109

Compound EX109-01 (600 mg, 2.41 mmol) was dissolved in anhydrous THF (10 mL), and triphenylphosphine (884 mg, 3.37 mmol) and 4-nitrobenzoic acid (523 mg, 3.13 mmol) were added. The reaction solution was cooled to -15 °C, and diethyl azodicarboxylate (587 mg, 3.37 mmol) was slowly added dropwise. The reaction solution was stirred at 25 °C for 12 hours. The reaction solution was quenched and diluted with water (50 mL), extracted with ethyl acetate (50 mL*3), and the organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 3/2) to obtain a light yellow oil EX109-01 (800 mg, yield 83.4%). LCMS: MS m/z (ESI) [M+H] ⁺ =399.0; ¹ H NMR (400MHz, CDCl ₃ ) δ8.22 (d, J = 8.8 Hz, 2H), 8.08 (d, J = 8.8 Hz, 2H), 7.33-7.01 (m, 5H), 5.28-5.15 (m, 1H), 5.07 (s, 2H), 4 .75-4.58(m,1H),4.42(d,J＝14.8Hz,1H),3.26(dd,J＝14.8Hz,1H),2.22-1.93(m,3H),1.53-1.44(m,1H),1.28(d,J＝6.8Hz,3H).

Compound EX109-02 (770 mg, 1.93 mmol) was dissolved in anhydrous THF (7 mL) and methanol (1 mL), and 1N NaOH (2.90 mL, 2.90 mmol) was added. The reaction solution was stirred at 25 ° C for 12 hours. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (20 mL*3), and the organic phase was washed with saturated brine (20 mL*3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain a light yellow oil EX109-03 (400 mg, yield 80.4%). LCMS: MS m/z (ESI) [M+H] ⁺ = 250.2; ¹ H NMR (400MHz, CDCl3) δ7.41-7.29 (m, 5H), 5.20-5.08 (m, 2H), 4.61-4.44 (m, 1H), 4.08 (d, J = 14.4Hz, 1H), 3.95 (brs, 1H), 3. 10(dd,J＝14.4,1.6Hz,1H),2.17-2.05(m,1H),1.86-1.74(m,1H),1.74-1.61(m,1H),1.36-1.27(m,1H),1.17(d,J＝6.8Hz,3H).

Compound EX109-03 (420 mg, 1.69 mmol) was dissolved in ethanol (10 mL), and 10% Pd/C (400 mg, 0.376 mmol) was added. The reaction solution was stirred at 25°C for 12 hours under hydrogen protection. The reaction solution was filtered, and the filter cake was washed twice with ethanol (2*10 ml). The filtrate was concentrated under reduced pressure and dried to obtain a yellow solid EX109-04 (230 mg, yield 89%). ¹ H NMR (400MHz, CDCl ₃ ) δ3.71-3.55(m,1H),3.28-3.15(m,1H),2.65-2.54(m,1H),2.52-2.43(m,1H),2.10-1.98(m,1H),1.78-1.67(m,1H),1.39-1.2 5(m,1H),1.23-1.10(m,1H),1.07(d,J＝6.4Hz,3H).

Compound EX83-05 (800 mg, 1.94 mmol) was dissolved in NMP (10 mL), and EX109-04 (223 mg, 1.94 mmol) and potassium carbonate (804 mg, 5.82 mmol) were added. The reaction solution was heated to 100 ° C and stirred for 12 hours under nitrogen protection. The reaction solution was filtered, diluted with ethyl acetate (50 mL), and the organic phase was washed with water (20 mL * 3). Drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure and drying. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/tetrahydrofuran = 100/0 to 3/2) to obtain light yellow solid EX109-05 (300 mg, yield 31.5%). LCMS: MS m/z (ESI) [M+H] ⁺ = 492.0.

Compound EX109-05 (260 mg, 0.529 mmol) was dissolved in dioxane (3 mL), and 4-Boc-aminopiperidine (212 mg, 1.06 mmol), cesium carbonate (517 mg, 1.59 mmol) and RuPhos Pd G2 (0.8 mg, 0.001 mmol) were added. The reaction solution was stirred at 100 ° C for 12 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain EX109-06 (100 mg, yield 33.5%). LCMS: MS m/z (ESI) [M+H] ⁺ = 564.5.

Compound EX109-06 (80 mg, 0.142 mmol) was dissolved in dioxane (2 mL), dioxane hydrochloride (2 mL) was added, and stirred at 25°C for 1 hour. The reaction solution was concentrated and dried, and the crude product was subjected to preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 30%-50%, 11 minutes) to obtain EX109 (2.66 mg, yield 10.2%, formate). LCMS: MS m/z (ESI) [M+H] ⁺ = 464.3; ¹ H NMR (400MHz, DMSO-d6) δ8.42(dd,J＝12.8,2.0Hz,1H),8.40(s,1H),8.30(dd,J＝8.8,2.0Hz,1H),8.05-7.86(m,1H),6.65(s,1H),4.82-4.67(m,1H),4.20-4.11 (m,1H),3.98-3.90(m,1H),3 .60-3.52(m,2H),3.20-3.13(m,2H),3.05-2.95(m,1H),2.94-2.85(m,2H),2.54(s,3H),2.24-2.07(m,1H),1.99-1.81(m,3H),1.69-1.51(m,3H), 1.43-1.33(m,1H),1.18(d,J=6.8Hz,3H).

Example EX110

Compound EX110-01 (4.10 g, 19.2 mmol) was dissolved in methanol (40 mL), sodium diborohydride (1.09 g, 28.8 mmol) was added dropwise at 0°C, and the reaction solution was stirred at 0°C for one hour. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride (50 mL), extracted three times with ethyl acetate (50 mL*3), and the organic phases were combined and dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and spin-dried. Crude product EX110-02 (4.10 g, yield 99.1%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.59-3.77 (m, 3H), 3.31-2.83 (m, 1H), 1.98-1.47 (m, 4H), 1.47 (s, 9H), 1.36-1.12 (m, 3H).

EX110-02 (4.10 g, 19.04 mmol) was dissolved in dichloromethane (40 mL), triethylamine (10.56 mL, 76.2 mmol) was added, and then methanesulfonic anhydride (9.94 g, 57.1 mmol) was slowly added, and the reaction was allowed to react at 25°C for 1 hour. The reaction solution was quenched and diluted with water (50 mL), extracted with dichloromethane (40 mL*3), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product EX110-03 (6.10 g).

Pyrazole (1.95 g, 28.6 mmol) was dissolved in tetrahydrofuran (20 mL), sodium hydride (1.22 g, 30.5 mmol) was added, and the reaction solution was reacted at 0 ° C for 1 hour. Then EX110-03 (6.10 g, 21.0 mmol) was dissolved in tetrahydrofuran (40 mL) and slowly added dropwise to the reaction solution, and the reaction temperature was raised to 85 ° C for 12 hours. After cooling to room temperature, the reaction solution was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 10/1 to 1/1) to obtain EX110-04 (1.10 g, yield 21.7%). ¹ H NMR (400MHz, CDCl ₃ ) δ7.56-7.50(m,1H),7.47-7.39(m,1H),6.32-6.23(m,1H),4.63-4.49(m,1H),4.44-4.32(m,1H),4.25-4.03(m,1H),4.00-3.8 0(m,1H),2.20-1.87(m,4H),1.47(s,9H),1.30-1.20(m,3H).

EX110-04 (1.1 g, 4.15 mmol) was dissolved in 4 M dioxane hydrochloride (5 mL) and reacted at 25° C. for 2 hours. The reaction solution was concentrated under reduced pressure and dried to obtain EX110-05 (830 mg, crude product).

EX110-05 (1.3 g, 6.45 mmol) was dissolved in 1-methylpyrrolidone (15 mL), and potassium carbonate (1.78 g, 12.9 mmol) and EX88-06 (3.03 g, 6.45 mmol) were added. The reaction temperature was raised to 100 °C for 12 hours. The reaction solution was diluted with water (30 mL), and ethyl acetate (50 mL*3) was added for extraction. The organic phases were combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 10/1 to 3/1) to obtain EX110-06 (1.00 g, yield 25.9%). LCMS: MS m/z (ESI) [M+H] ⁺ = 600.2.

EX110-06 (400 mg, 0.667 mmol) was dissolved in dioxane (4 mL), 4-Boc-aminopiperidine (267.3 mg, 1.34 mmol), cesium carbonate (435 mg, 1.34 mmol) and Pd-PEPPSI-Iheptcl (64.9 mg, 0.067 mmol) were added, and the reaction was heated to 100 ° C under a nitrogen atmosphere for 12 hours. The reaction solution was diluted with water (5 mL), and ethyl acetate (5 mL*3) was added to extract three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and dried. The residue was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 10/1 to 3/1) to obtain EX110-07 (270 mg, yield 60.2%). LCMS: MS m/z (ESI) [M+H] ⁺ = 672.3.

EX110-07 (270 mg, 0.429 mmol) was dissolved in tetrahydrofuran (2 mL), and 1 M lithium triethylborohydride (1.33 mL, 1.33 mmol) solution was slowly added at -30 °C, followed by stirring at -30 °C for 10 minutes. The reaction solution was quenched with saturated ammonium chloride (5 mL), extracted with ethyl acetate (5 mL*3), and the organic phase was dried with anhydrous sodium sulfate, filtered, and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 10/1 to 1/1) to obtain EX110-08 (150 mg, yield 59.3%). LCMS: MS m/z (ESI) [M+H]+ = 630.2.

EX110-08 (130 mg, 0.206 mmol) was dissolved in dioxane hydrochloride (1 mL), and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and dried by spin drying, and then separated and purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 13%-53%, 9 minutes), and then by preparative SFC (column: DAICEL CHIRALPAK AS (250mm*30mm, 10um); mobile phase: [CO ₂ -isopropanol (0.1% ammonia water)]; B%: 40%-40%,) to obtain EX110 (10.05 mg, yield 38.7%). LCMS: MS m/z (ESI) [M+H] ⁺ = 530.1; ¹ H NMR (400MHz, CD3OD) δ8.47-8.31(m,2H),7.80-7.71(m,2H),7.52(d,J＝1.6Hz,1H),6.96(s,1H),6.31(t,J＝2.0Hz,1H),5.11-5.00(m,1H),4.96(s,2H),4.8 3-4.74(m,1H),4.60–4.50( m,1H),3.65-3.51(m,2H),3.43-3.34(m,1H),3.03-2.90(m,3H),2.34-2.23(m,2H),2.22-2.15(m,1H),2.14-2.06(m,1H),2.06-1.95(m,2H),1.76 -1.60(m,2H),1.42(d,J＝7.2Hz,3H).

Example EX111

EX110-06 (200 mg, 0.334 mmol) was dissolved in dioxane (1 mL), methyl (piperidin-4-yl) carbamic acid tert-butyl ester (71.5 mg, 0.668 mmol), cesium carbonate (217 mg, 0.667 mmol) and Pd-PEPPSI-Iheptcl (32.5 mg, 0.033 mmol) were added, and the reaction was heated to 100 ° C under a nitrogen atmosphere for 12 hours. After the reaction was completed, it was cooled to room temperature, the reaction solution was diluted with water (5 mL), and ethyl acetate (5 mL*3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 10/1 to 3/1) to obtain EX111-01 (90 mg, yield 39.3%). LCMS: MS m/z (ESI) [M+H] ⁺ = 686.3.

EX111-01 (90 mg, 0.131 mmol) was dissolved in tetrahydrofuran (1 mL), 1 M lithium triethylborohydride (0.4 mL, 0.433 mmol) solution was added at -30°C, and then stirred at -30°C for 10 minutes. The reaction solution was quenched with saturated ammonium chloride (2 mL), extracted with ethyl acetate (5 mL*3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product EX111-02 (90 mg, crude product). LCMS: MS m/z (ESI) [M+H] ⁺ = 644.3.

EX111-02 (70 mg, 0.109 mmol) was dissolved in dioxane hydrochloride (1 mL), and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and dried by spin drying, and then separated and purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 0%-40%, 15 minutes), and then by preparative SFC (column: DAICEL CHIRALPAK AS (250mm*30mm, 10um); mobile phase: [CO ₂ -isopropanol (0.1% ammonia water)]; B%: 40%-40%,) to obtain EX111 (3.75 mg, yield 6.1%). LCMS: MS m/z (ESI) [M+H] ⁺ = 544.4; ¹ H NMR (400MHz, CD ₃ OD)δ8.49-8.34(m,2H),7.85-7.70(m,2H),7.52(d,J＝1.6Hz,1H),6.97(s,1H),6.31(t,J＝2.0Hz,1H),5.13-5.02(m,1H),4.96(s,2H),4.82-4.74(m, 1H),4.61-4.50(m,1H),3.67-3. 58(m,2H),3.43-3.34(m,1H),3.04-2.92(m,2H),2.74-2.63(m,1H),2.48(s,3H),2.35-2.23(m,2H),2.21-2.15(m,1H),2.14-2.03(m,3H),1.70- 1.55(m,2H),1.42(d,J＝6.8Hz,3H).

Example EX112

Compound EX109-05 (310 mg, 0.631 mmol) was dissolved in dioxane (6 mL), and methyl (piperidin-4-yl) carbamic acid tert-butyl ester (270 mg, 1.26 mmol), Pd-PEPPSI-IHeptCl (50.0 mg, 0.0630 mmol) and cesium carbonate (617 mg, 1.89 mmol) were added. The reaction solution was heated to 100 ° C and stirred for 12 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure and dried, and the crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain EX112-01 (100 mg, yield 10.1%). LCMS: MS m/z (ESI) [M+H] ⁺ = 578.2.

Compound EX112-01 (90.0 mg, 0.156 mmol) was dissolved in 4M hydrochloric acid 1,4-dioxane solution (1 mL) and stirred at room temperature for 1 hour. The reaction solution was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 9%-49%, 9 minutes) to obtain white solid ISME15-298 (formate) (22.8 mg, yield 30.7%). LCMS: MS m/z (ESI) [M+H] ⁺ = 478.3; ¹ H NMR (400 MHz, CD ₃ OD)δ8.54(s,1H),8.45(dd,J＝12.4,2.0Hz,1H),8.41(dd,J＝8.8,2.0Hz,1H),7.80-7.74(m,1H),6.61(s,1H),4.40-4.28(m,1H),4.13-4.05(m,1H),3.82 -3.72(m,2H),3.29-3.25(m,2H) ,3.25-3.17(m,1H),3.09-2.96(m,2H),2.74(s,3H),2.60(s,3H),2.32-2.15(m,3H),2.10-1.96(m,1H),1.92-1.76(m,2H),1.76-1.67(m,1H),1. 56-1.46(m,1H),1.26(d,J=6.8Hz,3H).

Example EX113

EX83-05 (300 mg, 0.727 mmol) and 7-aza-2-oxaspiro[3.5]nonane (139 mg, 1.09 mmol) were dissolved in 1-methyl-2-pyrrolidone (4.0 mL), and K ₂ CO ₃ (302 mg, 2.18 mmol) was added. The reaction solution was heated to 100°C and stirred for 12 hours. The reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 40%) to obtain EX113-01 (130 mg, yield 35.5%). LCMS: MS m/z (ESI) [M+H] ⁺ = 504.0; ¹ H NMR (400MHz, CDCl3) δ8.42 (dd, J = 11.6, 2.0Hz, 1H), 8.31 (dd, J = 8.8, 2.0Hz, 1H), 7.69 (dd, J = 8.8, 7.2Hz, 1H), 6.50 (s, 1H), 4 .53(s,4H),3.72-3.60(m,4H),2.72(s,3H),2.07-1.94(m,3H).

EX113-01 (100 mg, 0.199 mmol) was dissolved in 1,4-dioxane (1.0 mL), and tert-butyl piperidine-4-carbamate (47.8 mg, 0.238 mmol), RuPhos Pd G2 (15.4 mg, 0.020 mmol) and cesium carbonate (194 mg, 0.596 mmol) were added. The reaction solution was heated to 100 ° C and stirred for 12 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/tetrahydrofuran = 30%) to obtain EX113-02 (60 mg, yield 52.5%). LCMS:MS m/z(ESI)[M+H] ⁺ =576.3.

EX113-02 (60 mg, 0.104 mmol) was dissolved in dichloromethane (1.0 mL), and trifluoroacetic acid (20.4 mg, 0.208 mmol) was added. The reaction solution was stirred at 25°C for 1 h. The reaction solution was concentrated under reduced pressure and then spin-dried. It was then purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 21%-51%, 8 minutes) to obtain a pale yellow solid EX113 (5.57 mg, yield 11.2%). LCMS: MS m/z (ESI) [M+H] ⁺ = 476.1; ¹ H NMR (400 MHz, CD ₃ OD)δ8.39(dd,J＝8.8,1.6Hz,1H),8.28(dd,J＝11.6,1.6Hz,1H),7.90(t,J＝8.0Hz,1H),7.64(s,1H),4.48-4.39(m,2H),4.12(s,2H),4.11-4.01(m,2H),3 .93(s,2H),3.85-3.74(m,2H),3.47-3.37(m,1H),3.20-3.08(m,2H),2.91(s,3H),2.54-2.38(m,2H),2.25-2.14(m,2H),2.13-2.06(m,2H),1.99- 1.88(m,2H).

Example EX114

Under _N2 atmosphere, compound EX114-01 (4.00 g, 55.5 mmol) and benzylamine (5.90 g, 55.5 mmol) were dissolved in MeCN (40 mL), and then _LiClO4 (14.8 g, 139 mmol) and TMSCl (1.40 mL, 11.1 mmol) were added. The reaction solution was stirred at 40°C for 12 hours. The reaction solution was quenched by adding saturated sodium carbonate solution (30 mL), and then extracted with ethyl acetate (30 mL*3). The organic phases were combined, washed with saturated brine (30 mL*2), dried over anhydrous sodium sulfate, filtered, concentrated and spin-dried to obtain EX114-02 (8.10 g, yield 81.4%). LCMS: MS m/z (ESI) [M+H] ⁺ = 180.2; ¹ H NMR (400MHz, DMSO-d6) δ7.35-7.27 (m, 5H), 3.79 (d, J = 13.2Hz, 1H), 3.60 (d, J = 13.2Hz, 1H), 3.44-3.37 (m, 1H), 2.43-2.3 4(m,1H),1.02(d,J＝6.4Hz,3H),0.92(d,J＝6.4Hz,3H).

Compound EX114-02 (8.10 g, 45.2 mmol) was dissolved in DCM (50 mL), triethylamine (18.8 mL, 136 mmol) was added, and chloroacetyl chloride (6.10 g, 54.2 mmol) was slowly added at 0°C. The reaction solution was stirred at 0°C for 1 hour. The reaction solution was quenched with water (30 mL) at 0°C, and then extracted with DCM (30 mL*3). The organic phases were combined, washed with saturated brine (30 mL*2), dried over anhydrous sodium sulfate, filtered, concentrated and dried to obtain a yellow solid EX114-03 (13.0 g, yield 90.0%). LCMS: MS m/z (ESI) [M+H] ⁺ = 256.1.

Compound EX114-03 (12.0 g, 46.9 mmol) was dissolved in THF (60 mL), and t-BuOK (10.5 g, 93.9 mmol) was added at 0°C. The reaction solution was stirred at 25°C for 3 hours. The reaction solution was diluted with water (60 mL) and extracted with ethyl acetate (50 mL*3). The organic phases were combined, washed with saturated brine (50 mL*2), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 72/28) to give EX114-04 (6.59 g, yield 64.0%). LCMS: MS m/z (ESI) [M+H] ⁺ = 220.1; ¹ H NMR (400 MHz, DMSO-d6) δ 7.37-7.30 (m, 2H), 7.28-7.24 (m, 3H), 5.01 (d, J = 15.6 Hz, 1H), 4.23 (d, J = 15.6 Hz, 1H), 4.14 (s, 2H), 3.67-3.55 (m, 1H), 3.14-3.03 (m, 1H), 1.11 (t, J = 6.8 Hz, 6H).

Compound EX114-04 (3.00 g, 13.7 mmol) was dissolved in THF (30 mL), cooled to 0 ° C under nitrogen protection, and 10 M borane dimethyl sulfide solution (3.01 mL, 30.1 mmol) was slowly added. The reaction solution was stirred at 25 ° C for 12 hours. The reaction solution was slowly quenched with methanol (30 mL), and after reflux at 80 ° C for 1 hour, dilute hydrochloric acid was added to acidify. The mixture was concentrated, and the residue was diluted with NaOH (1 M) aqueous solution and extracted with ethyl acetate (30 mL * 3). The organic phases were combined, washed with saturated brine (30 mL * 2), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was subjected to silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 92/8) to obtain a yellow solid EX114-05 (2.40 g, yield 85.5%). LCMS: MS m/z (ESI) [M+H] ⁺ = 206.1; ¹ H NMR (400MHz, DMSO-d6) δ7.40-7.09 (m, 5H), 4.06 (d, J = 13.6Hz, 1H), 3.68-3.57 (m, 1H), 3.43 (td, J = 11.2, 2.4Hz, 1H), 3. 23-3.12(m,1H),3.06(d,J＝13.6Hz,1H),2.47 (dt,J＝11.6,2.0Hz,1H),2.10(td,J＝11.6,3.2Hz,1H),2.02-1.92(m,1H),1.10(d,J＝6.4Hz,3H),1.07(d,J＝6.0Hz,3H).

Compound EX114-05 (1.00 g, 4.87 mmol) was dissolved in 1,2-dichloroethane (10 mL), and then 1-chloromethyl chloroformate (5.28 mL, 48.7 mmol) was added. The reaction solution was stirred at 80 ° C for 16 hours. The reaction solution was cooled to room temperature, methanol was added until no bubbles emerged, and heated to reflux for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and then n-heptane (20 mL) was added, and the solution was concentrated under reduced pressure again and dried. The residue was diluted with water (10 mL) and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated brine (5 mL*2), dried over anhydrous sodium sulfate, filtered, concentrated and dried to obtain EX114-06 (740 mg, yield 92.3%). ¹ H NMR (400MHz, DMSO-d6) δ9.85-9.41(m,2H),3.92-3.82(m,1H),3.80-3.70(m,1H),3.61-3.50(m,1H),3.20-3.07(m,1H),3.05-2.78(m,2H),1.19(d,J ＝6.48Hz,3H),1.11(d,J＝6.4Hz,3H).

Compounds EX83-05 (800 mg, 1.94 mmol) and EX114-06 (323 mg, 2.13 mmol) were dissolved in NMP (8 mL), and then K ₂ CO ₃ (804 mg, 5.82 mmol) was added. The reaction solution was stirred at 100°C for 12 hours. The reaction solution was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (5 mL*3). The organic phases were combined, washed with water (5 mL*2) and saturated brine (10 mL) in turn, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 72/28) to obtain EX114-07 (230 mg, yield 24.1%). LCMS: MS m/z (ESI) [M+H] ⁺ = 492.0.

Under _N2 atmosphere, compound EX114-07 (180 mg, 0.366 mmol) and 4-Boc-aminopiperidine (73.4 mg, 0.366 mmol) were dissolved in 1,4 _- dioxane (2.00 mL), and then RuPhos Pd G2 (28.5 mg, 0.037 mmol) and _Cs2CO3 (358 mg, 1.10 mmol) were added. The reaction solution was stirred at 110°C for 12 hours. The reaction solution was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 72/28) to obtain EX114-08 (70 mg, yield 33.9%). LCMS:MS m/z(ESI)[M+H] ⁺ =564.2.

Compound EX114-08 (20 mg, 0.035 mmol) was dissolved in 4M HCl/dioxane (1 mL). The reaction was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 22%-52%, 8 minutes) to obtain EX114 (formate) (5.28 mg, yield 32.1%). LCMS: MS m/z (ESI) [M+H] ⁺ = 464.3; ¹ H NMR(400MHz, DMSO-d6)δ8.42(s,1H),8.34(dd,J＝12.0,2.0Hz,1H),8.29(dd,J＝8.8,1.6Hz,1H),8.03-7.93(m,1H),6.68(s,1H),4.23-4.14(m,1H),4.10–4.0 0(m,1H),3.90-3.82(m,2H),3.7 4-3.68(m,1H),3.59-3.54(m,2H),3.25–3.20(m,1H),3.03-2.95(m,1H),2.94-2.86(m,2H),2.55(s,3H),1.99-1.85(m,2H),1.67-1.49(m,2H),1 .28(d,J＝6.4Hz,3H),1.25(d,J＝6.8Hz,3H).

Example EX115

Compound EX49-04 (360 mg, 2.51 mmol) was dissolved in N-methylpyrrolidone (10 mL), and EX88-06 (1.06 g, 2.26 mmol) and potassium carbonate (1.04 g, 7.54 mmol) were added. The reaction solution was heated to 100 °C and stirred for 12 hours under nitrogen protection. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL*3). The organic phases were combined and washed with saturated brine (5 mL*3), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was subjected to silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 9/1) to obtain the target product EX115-01 (540 mg, yield 37.2%). LCMS: MS m/z (ESI) [M+H] ⁺ = 578.1; ¹ H NMR (400 MHz, CDCl ₃ )δ8.42(dd,J＝11.2,2.0Hz,1H),8.30(dd,J＝8.8,1.6Hz,1H),7.71(dd,J＝8.8,7.2Hz,1H),6.98(s,1H),4.71-4.61(m,1H),4.53(q,J＝7.2Hz,2H),4.25-4.1 1(m,1H),3.51-3.41(m,1H),3.28(s,3H),2.08-1.97(m,2H),1.73–1.63(m,1H),1.60-1.51(m,1H),1.50(t,J＝7.2Hz,3H),1.43(d,J＝7.2Hz,3H),1.2 1(s,3H).

Compound EX115-01 (490 mg, 0.849 mmol) was dissolved in dioxane (10 mL), and 4-Boc-aminopiperidine (340 mg, 1.70 mmol), Pd-PEPPSI-IHeptCl (67.2 mg, 0.0850 mmol) and cesium carbonate (691 mg, 2.12 mmol) were added. The reaction solution was heated to 110 ° C and stirred for 12 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/tetrahydrofuran = 100/0 to 9/1) to obtain EX115-02 (290 mg, yield 52.6%). LCMS: MS m/z (ESI) [M+H] ⁺ = 650.3; ¹ H NMR (400 MHz, CDCl ₃ )δ8.39(dd,J＝12.0,1.6Hz,1H),8.29(d,J＝8.8Hz,1H),7.69-7.62(m,1H),6.84(s,1H),4.70-4.59(m,1H),4.59-4.51(m,1H),4.46(q,J＝7.2Hz,2H),4. 19-4.05(m,1H),3.78-3.63(m, 1H),3.62-3.52(m,2H),3.50-3.37(m,1H),3.29(s,3H),3.04-2.85(m,2H),2.10-1.96(m,4H),1.75-1.62(m,4H),1.48(s,9H),1.45(t,J＝7.2Hz,3H ),1.44-1.42(m,3H),1.21(s,3H).

EX115-02 (270 mg, 0.416 mmol) was dissolved in tetrahydrofuran (5 mL), and lithium triethylborohydride (2.50 mL, 2.50 mmol) was added dropwise at -78 °C. The reaction solution was stirred at -78 °C for 10 min. After the reaction was completed, it was quenched with saturated ammonium chloride (10 mL) and extracted with ethyl acetate (8 mL*3). The organic phases were combined and washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated and dried to obtain the target product EX115-03 (200 mg, yield 79.2%). LCMS: MS m/z (ESI) [M+H] ⁺ = 608.3.

Compound EX115-03 (200 mg, 0.329 mmol) was dissolved in 4M hydrochloric acid 1,4-dioxane solution (1 mL) and stirred at room temperature for 1 hour. The reaction solution was dried under reduced pressure and purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 20%-45%, 8 minutes) to obtain EX115 (11.5 mg, yield 6.4%). LCMS: MS m/z (ESI) [M+H] ⁺ =508.1; ¹ H NMR (400MHz, DMSO-d6) δ8.39 (s, 1H), 8.38 (dd, J = 12.0, 2.0, 2H), 8.29 (dd, J = 8.8, 2.0Hz, 1H), 7.99 (t, J = 8.0Hz, 1H), 6.89 (s,1H),4.80(s,2H),4.66-4.56(m,1H),4.17-4.10(m,1H),3.55-3.50(m,1H),3.28-3.21(m, 2H),3.18(s,3H),3.10-2.97(m,1H),2.93-2.82(m,2H),2.02-1.89(m,4H),1.69-1.47(m,4H),1.31(d,J＝6.8Hz,3H),1.13(s,3H).

Example EX116

Compound EX115-01 (510 mg, 0.883 mmol) was dissolved in dioxane (10 mL), and 4-N-Boc-4-N-methyl-aminopiperidine (379 mg, 1.77 mmol), Pd-PEPPSI-IHeptCl (69.9 mg, 0.088 mmol) and cesium carbonate (719 mg, 2.21 mmol) were added. The reaction solution was heated to 110°C and stirred for 12 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/tetrahydrofuran = 100/0 to 9/1) to obtain EX116-01 (290 mg, yield 52.8%). LCMS: MS m/z (ESI) [M+H] ⁺ = 664.2; ¹ H NMR (400 MHz, CDCl ₃ )δ(dd,J＝12.0,2.0Hz,1H),8.28(dd,J＝8.8,2.0Hz,1H),7.64(dd,J＝8.8,7.2Hz,1H),6.83(s,1H),4.68-4.61(m,1H),4.49-4.43(m,2H),4.27-3.98(m,2H ),3.72-3.62(m,2H),3.50-3 .37(m,1H),3.28(s,3H),2.96-2.85(m,2H),2.80(s,3H),2.07-1.97(m,3H),1.96-1.83(m,2H),1.76-1.65(m,3H),1.49(s,9H),1.45-1.44(m,3H ),1.41(d,J＝6.8Hz,3H),1.21(s,3H).

EX116-01 (240 mg, 0.362 mmol) was dissolved in tetrahydrofuran (5 mL), and 1 M lithium triethylborohydride tetrahydrofuran solution (1.81 mL, 1.81 mmol) was added dropwise at -78 °C. The reaction solution was stirred at -78 °C for 10 min. After the reaction was completed, it was quenched with saturated ammonium chloride (10 mL) and extracted with ethyl acetate (8 mL*3). The organic phases were combined and washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated and dried to obtain the target product EX116-02 (180 mg, yield 80.1%). LCMS: MS m/z (ESI) [M+H] ⁺ = 622.3.

Compound EX116-02 (150 mg, 0.241 mmol) was dissolved in 4M hydrochloric acid 1,4-dioxane solution (4 mL) and stirred at room temperature for 1 hour. The reaction solution was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 14%-39%, 8 minutes) to obtain EX116 (64.36 mg, yield 51.1%, formate). LCMS: MS m/z (ESI) [M+H] ⁺ = 522.2; ¹ H NMR (400MHz, DMSO-d6) δ8.38(dd,J＝12.4,1.6Hz,1H),8.34(s,1H),8.28(dd,J＝8.8,1.6Hz,1H),7.99(t,J＝8.0Hz,1H),6.89(s,1H),4.80(s,2H),4.66-4.55(m ,1H),4.18-4.09(m,1 H),3.60-3.50(m,2H),3.31-3.23(m,1H),3.18(s,3H),2.91-2.80(m,2H),2.80-2.71(m,1H),2.43(s,3H),2.06-1.87(m,4H),1.68-1.46(m,4H),1. 31(d,J＝6.8Hz,3H),1.13(s,3H).

Example EX117

Compound EX116-08 (600 mg, 0.926 mmol) was dissolved in ethanol (10 mL), and 5 M NaOH (1.48 mL, 7.41 mmol) was added. The reaction was stirred at 25 °C for 2 hours. The reaction solution was adjusted to pH 2-3 with 3 M HCl, diluted with water (20 mL), filtered, and the filter cake was concentrated under reduced pressure and dried. EX117-01 (500 mg, yield 87.1%) was obtained. LCMS: MS m/z (ESI) [M+H] ⁺ = 620.4.

Compound EX117-01 (230 mg, 0.371 mmol) was dissolved in anhydrous DCM (6 mL), dimethylamine hydrochloride (60.5 mg, 0.742 mmol) and HATU (282 mg, 0.742 mmol) were added, and finally DIPEA (0.31 mL, 1.86 mmol) was slowly added. The reaction was stirred at 25 ° C for 12 hours. Water (20 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL*3), and the organic phase was washed with saturated brine (20 mL*3). Drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure and drying. The crude product was purified by silica gel column chromatography (silica, dichloromethane/methanol = 100/0 to 95/5) to obtain EX117-02 (150 mg, yield 62.5%). LCMS: MS m/z (ESI) [M+H] ⁺ = 647.4.

Compound EX117-02 (150 mg, 0.232 mmol) was dissolved in dioxane (2 mL), dioxane hydrochloride (2 mL) was added, and stirred at 25°C for 2 hours. The reaction solution was concentrated and dried, and the crude product was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 28%-40%, 10 minutes) to obtain EX117 (47.95 mg, yield 37.8%, formate). LCMS: MS m/z (ESI) [M+H] ⁺ = 547.5; ¹ H NMR(400MHz,DMSO-d6)δ8.44(s,1H),8.41(dd,J＝12.8,1.6Hz,1H),8.33(dd,J＝8.8,1.6Hz,1H),8.01(t,J＝8.0Hz,1H),6.66(s,1H),3.92-3.72(m,2H),3.64-3.45(m,4H),3.08(s,3H),3.01-2.91(m,2H),2.79(s,3H),2.75-2.65(m,1H),1.98-1.83(m,4H),1.82-1.74(m,2H),1.58-1.43(m,4H),1.26(s,3H).

Example EX118

Compound EX117-01 (230 mg, 0.371 mmol) was dissolved in anhydrous DCM (6 mL), and ammonium chloride (39.7 mg, 0.742 mmol) and HATU (282 mg, 0.742 mmol) were added, and finally DIPEA (0.28 mL, 1.67 mmol) was slowly added. The reaction was stirred at 25 ° C for 12 hours. Water (20 mL) was added to the reaction solution, and ethyl acetate was extracted (20 mL*3), and the organic phase was washed with brine (20 mL*3). Drying over anhydrous sodium sulfate, filtering, and concentrating under reduced pressure was spin-dried. The crude product was purified by silica gel column chromatography (silica, dichloromethane/methanol = 100/0 to 95/5) to obtain EX118-01 (150 mg, yield 65.3%). LCMS: MS m/z (ESI) [M+H] ⁺ = 619.4.

Compound EX118-01 (100 mg, 0.162 mmol) was dissolved in dioxane (2 mL), dioxane hydrochloride (2 mL) was added, and stirred at 25°C for 2 hours. The reaction solution was concentrated and dried, and the crude product was purified by preparative HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 25%-45%, 11 minutes) to obtain EX118 (47.95 mg, yield 43.3%, formate). LCMS: MS m/z (ESI) [M+H] ⁺ =519.4; ¹ H NMR (400MHz, DMSO-d6) δ8.42 (dd, J = 12.4, 2.0 Hz, 1H), 8.40 (s, 1H), 8.34 (dd, J = 8.8, 2.0 Hz, 1H), 8.16 (s, 1H), 8.01 (dd, J = 8 .8,8.0Hz,1H),7.90(s,1H),6.84(s,1H),3.92-3.76(m,2H),3.70-3.60(m,2H),3.58 -3.50(m,2H),3.10-2.98(m,1H),2.94 -2.81(m,2H),1.96-1.85(m,4H),1.84-1.74(m,2H),1.72-1.56(m,2H),1.54-1.43(m,2H),1.27(s,3H).

Example EX119

Compound EX102-06 (150 mg, 0.281 mmol) was dissolved in dioxane (2 mL), and (3S, 4R)-N-Boc-4-amino-3-fluoropiperidine (122.8 mg, 0.563 mmol), cesium carbonate (183.3 mg, 0.563 mmol) and Pd-PEPPSI-Iheptcl (27.4 mg, 0.028 mmol) were added. The reaction solution was heated to 110°C and stirred for 12 hours under a nitrogen atmosphere. After the reaction was completed, the reaction solution was vacuum dried, and the crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 10/1 to 1/1) to obtain EX119-01 (160 mg, yield 91.2%). LCMS: MS m/z (ESI) [M+H] ⁺ = 624.4; ¹ H NMR (400MHz, DMSO-d6) δ8.41(dd,J＝12.8,1.6Hz,1H),8.29(dd,J＝8.8,2.0Hz,1H),7.95(t,J＝8.0Hz,1H),6.14(s,1H),4.84(s,1H),4.85-4.70(m,1H),4.29-4 .17(m,1H),4.06-3.99(m,1H),3 .98(s,3H),3.88-3.62(m,3H),3.56-3.44(m,2H),3.25-3.04(m,1H),3.00–2.85(m,1H),2.22-2.14(m,2H),1.95-1.84(m,3H),1.82-1.75(m,1H) ,1.54-1.46(m,2H),1.41(s,9H),1.35(s,3H).

Compound EX119-01 (160 mg, 0.257 mmol) was dissolved in dioxane hydrochloride (2 mL) and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure and dried by spin drying. EX119 (28.33 mg, yield 21.1%) was obtained by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 30%-70%, 9 minutes). LCMS: MS m/z (ESI) [M+H] ⁺ = 524.2; ¹ HNMR(400MHz, DMSO-d6)δ8.38(dd,J＝12.8,2.0Hz,1H),8.27(dd,J＝8.8,2.0Hz,1H),8.00-7.81(m,1H),6.12(s,1H),4.86(s,1H),4.77-4.56(m,1H),4.15-4.0 5(m,1 H),3.98(s,3H),3.94-3.85(m,1H),3.85-3.69(m,2H),3.55-3.43(m,2H),3.25-3.06(m,1H),2.99-2.81(m,2H),1.95-1.58(m,8H),1.56-1.42(m, 2H),1.26(s,3H).

Example EX120

EX120-01 (5.00 g, 23.4 mmol) was dissolved in tetrahydrofuran (100 mL), (trifluoromethyl) trimethylsilane (6.70 g, 46.9 mmol) and 1 M tetrabutylammonium fluoride tetrahydrofuran solution (46.9 mL, 46.9 mmol) were added at 0 ° C, and the reaction solution was stirred at 25 ° C for 2 hours. Saturated ammonium chloride solution (300 ml) was added to the reaction solution and stirred for 30 minutes. After concentrating under reduced pressure, dichloromethane (300 ml) was added for extraction, and then washed with water (300 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product ISME15-242-02. ¹ H NMR (400MHz, CDCl ₃ ) δ4.79-4.19(m,1H),4.08-3.78(m,1H),3.42-2.92(m,1H),2.01-1.88(m,1H),1.85-1.60(m,3H),1.46(s,9H),1.32(d,J＝7.2Hz ,2H),1.25(d,J＝7.2Hz,1H).

EX120-02 (440 mg, 1.553 mmol) was dissolved in tetrahydrofuran (5 mL), sodium hydride (55.9 mg, 2.33 mmol) was added under nitrogen protection at 0°C, stirred for 30 min, and then iodomethane (0.24 mL, 2.33 mmol) was added. The reaction solution was stirred at 25°C for 12 hours. The reaction solution was quenched by adding saturated ammonium chloride solution (20 ml), extracted with ethyl acetate (30 ml*3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative thin layer chromatography (petroleum ether/ethyl acetate = 0% to 2%) to obtain EX120-03. ¹ H NMR (400 MHz, CDCl ₃ ) δ4.60 –4.00(m,1H),3.99-3.72(m,1H),3.41,3.38(2s,3H),3.21-2.93(m,1H),2.11–1.74(m,3H),1.73-1.61(m,1H),1.47(s,9H),1.26,1.23(2d,3H).

EX120-03 (600 mg, 2.02 mmol) was dissolved in 4M dioxane hydrochloride (5.0 mL), and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain EX120-04. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.55-9.17 (m, 2H), 3.56 (s, 3H), 3.50–3.39 (m, 1H), 3.31-3.19 (m, 1H), 3.04-2.89 (m, 1H), 2.23-2.13 (m, 2H), 2.13-1.78 (m, 2H), 1.37-1.29 (m, 3H).

EX120-04 (650 mg, 2.78 mmol) and EX83-05 (956 mg, 2.32 mmol) were dissolved in 1-methyl-2-pyrrolidone (5.0 mL), and potassium carbonate (961 mg, 6.95 mmol) was added. The reaction solution was heated to 100 °C and stirred for 18 hours. The reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0–5/1) to obtain EX120-05. LCMS: MS m/z (ESI) [M+H] ⁺ =573.9; ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.35 (d, J = 12.8Hz, 1H), 8.28 (d, J = 8.4Hz, 1H), 8.03 (t, J = 8.4Hz, 1H), 6.86 (s, 1H), 4.87–4.71 (m, 1H),4.41-4.27(m,1H),3.44(s,3H),3.30–3.17(m,1H),2.67(s,3H),2.20 –2.05(m,2H),1.98-1.88(m,1H),1.85-1.74(m,1H),1.31(d,J＝6.8Hz,3H) .

EX120-05 (80.0 mg, 0.140 mmol) was dissolved in 1,4-dioxane (1.0 mL), and tert-butyl piperidine-4-carbamate (36.3 mg, 0.181 mmol), RuPhos Pd G2 (21.7 mg, 28.0 umol) and cesium carbonate (90.9 mg, 0.279 mmol) were added. The reaction solution was heated to 100 ° C and stirred for 18 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was subjected to silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0–10/1) to obtain EX120-06. LCMS:MS m/z(ESI)[M+H] ⁺ =646.5.

EX120-06 (100 mg, 0.155 mmol) was dissolved in 4 M dioxane hydrochloride (3.0 mL). The reaction solution was stirred at 25 °C for 1 hour. After the reaction solution was filtered, it was purified by preparative HPLC (column: Boston Prime C18 150*40 mm; mobile phase: [water (formic acid)-acetonitrile]; B%: 34%-74%, 8 minutes) to obtain a pale yellow solid EX120 (formate) (31.2 mg, yield 36.9%). LCMS: MS m/z (ESI) [M+H] ⁺ = 546.3; ¹ HNMR (400 MHz, DMSO-d ₆ )δ8.37-8.31(m,2H),8.29(dd,J＝8.8,2.0Hz,1H),8.01-7.93(m,1H),6.73(s,1H),4.84-4.74(m,1H),4.36–4.25(m,1H),3.65–3.53(m,2H),3.44(s, 3H),3.15-3.07(m,2H),2.97–2.87(m,2H),2.55(s,3H),2.18-2.04(m,2H),2.01-1.87(m,3H),1.83–1.72(m,1H),1.71-1.59(m,2H),1.31(d,J＝6 .8Hz,3H).

Example EX121

Compound EX121-01 (5 g, 24.1 mmol) was dissolved in anhydrous dichloromethane (50 mL) and placed in an ice bath. DAST (4.78 mL, 36.2 mmol) was added dropwise to the reaction solution. The reaction system was naturally warmed to room temperature and the reaction was continued for 1 hour. The reaction system was quenched with saturated sodium bicarbonate solution (50 mL), and the mixture was extracted with dichloromethane (3×50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 12/1) to obtain EX121-02. LCMS: MS m/z (ESI) [M+H] ⁺ = 210.1; ¹ H NMR (400MHz, CDCl3) δ = 7.39-7.27 (m, 5H), 4.78-4.46 (m, 2H), 4.02 (d, J = 13.6Hz, 1H), 3.85 (dd, J = 11.6, 3.2Hz, 1H), 3.76 -3.68(m,1H),3.66-3.54(m,2H),3.46(d,J＝13.6Hz,1H),2.88-2.65(m,2H),2.35–2.26(m,1H).

EX121-02 (3.48 g, 16.6 mmol) was dissolved in 1,2-dichloroethane (35 mL), and 1-chloroethyl chloroformate (18.0 mL, 166 mmol) was added. The reaction solution was heated to 80 ° C and stirred for 16 hours. After the reaction solution was cooled to room temperature, methanol was added until no bubbles were generated, and the reaction mixture was heated to reflux and stirred for 1 hour. Then it was cooled to room temperature, and n-heptane (2*35 mL) was added and concentrated. After washing with ethyl acetate, the crude product EX121-03 (1.15 g, yield 44.4%) was obtained. ¹ H NMR(400MHz, DMSO-d ₆ )δ10.43-9.81(m,2H),4.70(d,J＝46.4,4.0Hz,2H),3.76-3.67(m,1H),3.66-3.54(m,2H),3.54-3.45(m,1H),3.26-3.17(m,2H), 3.14-3.02(m,1H).

EX83-05 (1 g, 2.42 mmol) and EX121-03 (447 mg, 2.91 mmol) were dissolved in NMP (10 mL) and potassium carbonate (1005 mg, 7.27 mmol) was added. The reaction mixture was heated to 100 °C and stirred for 12 hours. The reaction solution was diluted with water (100 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, filtered, and concentrated under reduced pressure to obtain a crude product which was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 7/1) to obtain EX121-04 (508 mg, 1.03 mmol, yield 42.3%). LCMS: MS m/z (ESI) [M+H] ⁺ = 496.1; ¹ H NMR (400MHz, CDCl3) δ = 8.40 (dd, J = 11.6, 2.0Hz, 1H), 8.29 (dd, J = 8.8, 2.0Hz, 1H), 7.68 (dd, J = 8.8, 7.2Hz, 1H), 6.47 (s, 1H), 4. 35-4.20(m,1H),4.09-4.00(m,2H),3.93-3.87(m,2H),3.77-3.68(m,2H),3.51–3.41(m,1H),3.27–3.16(m,1H),2.74(s,3H).

EX121-04 (448 mg, 0.905 mmol), 4-Boc-aminopiperidine (272 mg, 1.36 mmol), cesium carbonate (884 mg, 2.71 mmol) were dissolved in 1,4-dioxane (5 mL) and Ruphos Pd G2 (70.3 mg, 9.0 μmol) was added. The reaction mixture was heated to 100 ° C under nitrogen protection and stirred for 12 hours. After the reaction solution was cooled to room temperature, it was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (silicon dioxide, petroleum ether/tetrahydrofuran = 100/0 to 1/1) to obtain a yellow solid EX121-05 (223 mg, 0.393 mmol, yield 43.4%). LCMS: MS m/z (ESI) [M+H] ⁺ =568.3; ¹ H NMR (400MHz, CDCl ₃ ) δ = 8.36 (dd, J = 12.0, 2.0Hz, 1H), 8.28 (dd, J = 8.8, 2.0Hz, 1H), 7.62 (dd, J = 8.8, 7.2Hz, 1H), 6.36 (s, 1H), 4 .06-4.02(m,2H),3.93-3.88(m,4H),3.73-3.66(m,2H),3.58-3.51(m,2H),3.50–3.41(m,1H),3.26–3.17(m,1H),3.09–2.96(m,2H),2.58(s,3H), 2.18–2.05(m,2H),1.68-1.55(m,2H),1.47(s,9H).

Compound EX121-05 (203 mg, 0.358 mmol) was dissolved in hydrochloric acid-dioxane (4M, 4 mL), and the reaction solution was stirred at room temperature for 1 hour. After the reaction solution was concentrated under reduced pressure, it was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia water + ammonium bicarbonate)-acetonitrile]; B%: 15%-45%, 8 minutes) to obtain EX121 (27.7 mg, yield 16.5%). LCMS: MS m/z (ESI) [M+H] ⁺ = 468.3; ¹ HNMR (400MHz, CD ₃ OD) δ8.36 (dd, J = 12.4, 2.0Hz, 1H), 8.32 (dd, J = 8.8, 2.0Hz, 1H), 7.72 (t, J = 8.0Hz, 1H), 6.58 (s, 1H), 5.19- 5.02(m,1H),4.44-4.28(m,1H),4.14-3.88(m,4H),3.87-3.56(m,5H),3.03-2.86(m,3H),2.61(s,3H),2.06-1.94(m,2H),1.75-1.56(m,2H).

Example EX122

EX88-07 (700 mg, 1.22 mmol) was dissolved in ethanol (7 mL), and 5 M NaOH (1.95 mL) was added to the solution. The reaction solution was stirred at room temperature for 2.5 h. The reaction solution was adjusted to pH 1 with 1 M HCl and solids were precipitated. The filter cake was concentrated under reduced pressure and dried to obtain EX122-01 (610 mg, yield 91.6%). LCMS: MS m/z(ESI)[M+H] ⁺ =548.0; ¹ H NMR (400MHz, DMSO-d ₆ ) δ13.98 (brs, 1H), 8.36 (d, J = 12Hz, 1H), 8.28 (d, J = 8.8Hz, 1H), 8.08–7.98 (m, 1H), 7.02 (s, 1H), 4 .91(brs,1H),3.40-3.14(m,4H),1.97-1.79(m,4H),1.55–1.45(m,2H),1.25(s,3H).

EX122-01 (510 mg, 0.932 mmol), triethylamine (0.65 mL, 4.66 mmol), DPPA (513 mg, 1.86 mmol) were dissolved in toluene (5 mL), stirred for 30 mins at 25 ° C in a nitrogen atmosphere, and then tert-butyl alcohol (5 mL, 54.7 mmol) was slowly added to the reaction system, and the reaction system was heated to 90 ° C and stirred for 12 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 5/1 to 1/1) to obtain EX122-02. LCMS: MS m/z (ESI) [M+H] ⁺ = 519.0.

EX122-02 (200 mg, 0.386 mmol), 4-Boc-aminopiperidine (116 mg, 0.579 mmol), cesium carbonate (251 mg, 0.772 mmol) were dissolved in 1,4-dioxane (2 mL) and Pd-PEPPSI-IHept-Cl (37.5 mg, 39.0 μmol) was added. The reaction mixture was heated to 100 ° C under nitrogen protection and stirred for 12 hours. After the reaction solution was cooled to room temperature, it was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 1/1) to obtain EX122-03. LCMS: MS m/z (ESI) [M+H] ⁺ = 591.3.

Compound EX122-03 (74 mg, 0.125 mmol) was dissolved in hydrochloric acid-dioxane (4 M, 2 mL), and the reaction solution was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-ethyl acetate] nitrile]; B%: 10%-40%, 8 minutes) to give EX122 (formate salt). LCMS: MS m/z (ESI) [M+H] ⁺ = 491.2; 1H NMR (400 MHz, CD ₃ OD)δ8.55(s,1H),8.48(dd,J＝12.8,1.6Hz,1H),8.39(dd,J＝8.8,1.6Hz,1H),7.76-7.70(m,1H),5.83(s,1H),3.84-3.72(m,4H),3.52–3.45(m,2H),3.2 1-3.14(m,1H),3.08-2.96(m,2H),2.09-2.02(m,2H),1.97-1.90(m,2H),1.90-1.78(m,4H),1.68-1.56(m,2H),1.35(s,3H).

Example EX123

EX102-05 (250 mg, 0.583 mmol) was dissolved in NMP (5 mL), EX73-02 (169 mg, 0.700 mmol) and potassium carbonate (242 mg, 1.75 mmol) were added, and the reaction solution was stirred at 100 ° C for 12 hours. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (20 mL x 2), and the organic phases were combined, washed with water (10 mL x 2) and saturated brine (10 mL) in turn, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0-10/1) to obtain EX123-01. LCMS: MS m/z (ESI) [M+1] ⁺ =634.1; ¹ H NMR (400MHz, CDCl ₃ ) δ8.46 (dd, J = 11.6, 2.0 Hz, 1H), 8.35 (dd, J = 8.8, 2.0 Hz, 1H), 7.68 (dd, J = 8.8, 7.2 Hz, 1H), 5.93 (s, 1H), 4. 07(t,J＝5.2Hz,1H),4.00(s,3H),3.87-3.76(m,2H),3.53(d,J＝11.2Hz,2H),2.20–2.11(m,2H),1.85-1.75(m,2H),1.65-1.59(m,2H),0.93(s,9H),0. 13(s,6H).

EX102-05 (50 mg, 0.079 mmol) was dissolved in dioxane (1 mL), and tert-butyl piperidine-4-carbamate (23.7 mg, 0.118 mmol), Pd-PEPPSI-HeptCl (7.7 mg, 0.008 mmol) and cesium carbonate (77.1 mg, 0.237 mmol) were added. The reaction solution was stirred at 110°C for 12 hours under nitrogen protection. After the reaction solution was concentrated under reduced pressure, it was purified by preparative thin layer chromatography (petroleum ether/ethyl acetate = 3/1) to obtain EX123-02. LCMS: MS m/z (ESI) [M+1] ⁺ = 706.4; ¹ H NMR (400 MHz, CDCl ₃ )δ8.41(dd,J＝12.0,2.0Hz,1H),8.33(dd,J＝8.8,2.0Hz,1H),7.62(dd,J＝8.8,7.2Hz,1H),5.86(s,1H),4.58-4.46(m,1H),4.12–4.02(m,1H),3.99(s,3H), 3.96-3.88(m,2H), 3.84-3.75(m,2H),3.55–3.44(m,2H),3.05-2.93(m,2H),2.20–2.12(m,2H),2.11-2.04(m,2H),1.81-1.75(m,2H),1.68-1.60(m,4H),1.47(s,9H ),0.93(s,9H),0.13(s,6H).

EX123-02 (40.0 mg, 0.057 mmol) was dissolved in hydrochloric acid-dioxane (4M, 1.0 mL), and the reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure and dried by spin drying. The crude product was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 20%-60%, 9 minutes) to obtain EX123. LCMS: MS m/z (ESI) [M+1] ⁺ = 492.3; ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.39(d,J＝12.8Hz,1H),8.30(d,J＝8.0Hz,1H),7.95(t,J＝8.0Hz,1H),6.15(s,1H),5.18(s,1H),3.98(s,3H),3.95-3.86(m,3H),3.85–3.75(m,2H), 3.66-3.55(m,2H),3.24-3.15(m,1H),2.90–2.75(m,2H),2.17–2.08(m,2H),1.86-1.71(m,4H),1.54-1.42(m,4H).

Example EX124

Compound EX90-05 (220 mg, 441 umol) was dissolved in anhydrous dioxane (5 mL), and 4-N-Boc-4-N-methyl-aminopiperidine was added. (113 mg, 529 umol), cesium carbonate (359 mg, 1.10 mmol) and Ruphos Pd G2 (34.2 mg, 44.0 umol). Under nitrogen protection, the temperature was raised to 110 ° C and stirred for 16 hours. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/tetrahydrofuran = 100/0 to 3/1) to obtain EX124-01 (108 mg, purity 55.22%, yield 20.60%). LCMS: 654.3 [M + H] ⁺ ;

Compound EX124-01 (100 mg, 153 umol) was dissolved in hydrochloric acid/dioxane (4 mL, concentration: 4 M) and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the crude product was purified by preparative HPLC (column: ACSSH-CAC18 150*40mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 20%-60%, 9 minutes) to obtain EX124 (16.80 mg, 29.0 umol, 96.72% yield). LCMS: MS m/z (ESI) [M+H] ⁺ = 554.2; ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.41(dd,J＝12.4,2.0Hz,1H),8.33(dd,J＝8.8,1.6Hz,2H),7.98(t,J＝8.4Hz,1H),6.59(s,1H),4.02-3.88(m,2H),3.63–3.51(m,4H),2.95–2.83(m,2H) ),2.82–2.69(m,1H),2.54(s,3H),2.42(s,3H),2.32-2.15(m,4H),2.05–1.94(m,4H),1.61–1.46(m,2H),1.38(s,3H).

Example EX125

Compound EX88-10 (200 mg, 0.331 mmol) was dissolved in anhydrous THF (5 mL), cooled to 0 °C, and 3 M MeMgBr (0.13 mL) was added. The reaction solution was heated to room temperature and stirred for 1 hour. The reaction solution was quenched with saturated aqueous ammonium chloride solution (20 mL), extracted with ethyl acetate (20 mL*3), and the organic phase was washed with brine (20 mL*3). Dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure and spin dry. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/tetrahydrofuran = 100/0 to 1/1) to obtain the crude product EX125-01. LCMS: MS m/z (ESI) [M+H] ⁺ = 620.4.

Compound EX125-01 (100 mg, 0.161 mmol) was dissolved in 4M dioxane hydrochloride (2 mL), and the reaction solution was stirred at 25°C for 2 hours. The reaction solution was concentrated and dried, and the crude product was purified by preparative HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 30%-50%, 11 minutes) to obtain EX125. LCMS: MS m/z (ESI) [M+H] ⁺ = 520.2; ¹ H NMR (400 MHz, CD ₃ OD)δ8.57(s,1H),8.53-8.43(m,2H),7.81(dd,J＝8.8,7.6Hz,1H),6.93(s,1H),5.34(q,J＝6.4Hz,1H),4.05-3.86(m,2H),3.75-3.51(m,4H),3.26-3.13 (m,2H),3.04-2.92(m,1H),2.21-2.08(m,2H),2.04-1.98(m,2H),1.96-1.84(m,4H),1.69-1.59(m,2H),1.58(d,J＝6.4Hz,3H),1.39(s,3H).

Example EX126

Under N2 atmosphere, compound EX88-07 (400 mg, 0.695 mmol) and 4-Boc-aminopiperidine (298 mg, 1.39 mmol) were dissolved in 1,4-dioxane (5.00 mL), and cesium carbonate (566 mg, 1.74 mmol) and Pd-PEPPSI-IheptCl (47.3 mg, 0.049 mmol) were added. The reaction solution was stirred at 110°C for 12 hours. The reaction solution was cooled to room temperature, then diluted with water (5 mL), and extracted with ethyl acetate (5 mL*3). The organic phases were combined, washed with saturated brine (10 mL*2), dried over anhydrous sodium sulfate, filtered, concentrated and spun dry. The crude product was chromatographed on a silica gel column (silica, petroleum ether/tetrahydrofuran = 100/0 to 68/32) to obtain EX126-01. LCMS: MS m/z (ESI) [M+H] ⁺ = 662.2; 1H NMR (400 MHz, DMSO-d ₆ )δ8.36(d,J＝12.8Hz,1H),8.29(d,J＝8.4Hz,2H),8.03-7.91(m,1H),6.95(s,1H),4.90(s,1H),4.39(q,J＝7.2Hz,2H),3.87-3.76(m,2H),3.75-3.64(m ,1H),3.62-3.49(m,4H),3.31(s,3H),2.92–2.78(m,2H),1.93–1.86(m,2H),1.83-1.72(m,4H),1.67–1.57(m,2H),1.53-1.45(m,2H),1.41(s,9H ),1.35(s,3H).

Compound EX126-01 (140 mg, 0.212 mmol) was dissolved in THF (2.00 mL), cooled to -78 °C under nitrogen protection, and LiBHEt ₃ (0.63 mL, 0.635 mmol) was slowly added. The reaction solution was stirred at -78 °C for 2 hours. The reaction solution was quenched with saturated ammonium chloride (5 mL) and extracted with tetrahydrofuran (5 mL*3). The organic phases were combined, washed with saturated brine (10 mL*2), dried over anhydrous sodium sulfate, filtered, concentrated and spin-dried to obtain the crude product EX126-02 as a yellow solid. LCMS: MS m/z (ESI) [M+H] ⁺ = 620.3.

Compound EX126-02 (130 mg, 0.210 mmol) was dissolved in 4M HCl/dioxane (2 mL). The reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure, spin-dried, and purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 0%-39%, 9 minutes) to obtain EX126. LCMS: MS m/z (ESI) [M+H] ⁺ = 520.1; ¹ H NMR (400 MHz, CD ₃ OD)δ8.54(s,1H),8.46(d,J＝12.4Hz,1H),8.41(dd,J＝8.8,2.0Hz,1H),7.80-7.71(m,1H),6.87(s,1H),4.94(s,2H),3.93(d,J＝10.4Hz,2H),3.74(d,J＝ 13.2Hz,2H),3.61(d,J＝10.8Hz,2H),3.29-3.16(m,1H),3.03(t,J＝12.0Hz,2H),2.75(s,3H),2.28-2.16(m,2H),2.05-1.95(m,2H),1.94 -1.80(m,4H),1.68-1.56(m,2H),1.37(s,3H).

Embodiment 127

EX109-05 (800 mg, 1.63 mmol) was dissolved in dioxane (10 mL), and 4-N-BOC-4-N-methyl-aminopiperidine (152 mg, 0.757 mmol), cesium carbonate (1.59 g, 4.89 mmol) and Pd-PEPPSI-HeptCl (64.5 mg, 0.081 mmol) were added. The reaction solution was heated to 100°C under nitrogen protection and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain EX127-01. LCMS: MS m/z (ESI) [M+H] ⁺ = 578.2.

EX127-01 (200 mg, 0.346 mmol) was dissolved in 4M hydrochloric acid/dioxane (10 mL), and the reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water(FA)-ACN]; B%: 30%-50%, 11 min) to obtain EX127. LCMS: MS m/z (ESI) [M+H] ⁺ = 478.1; ¹ H NMR (400 MHz, CD ₃ OD)δ8.55(s,1H),8.50-8.30(m,2H),7.85-7.69(m,1H),6.60(s,1H),4.40–4.25(m,1H),4.15–4.03(m,1H),3.83-3.66(m,2H),3.32–3.20(m,2H), 3.18-3.10(m,1H),3.05–2.93(m,2H),2.70(s,3H),2.60(s,3H),2.34-2.14(m,3H),2.09-1.96(m,1H),1.89-1.67(m,3H),1.60-1.47(m,1H),1.2 6(d,J＝6.4Hz,3H).

Embodiment 128

4-(Trifluoromethyl)-1H-pyrazole (1.70 g, 12.3 mmol) was dissolved in tetrahydrofuran (25.0 mL), sodium hydride (0.5 g, 12.3 mmol) was slowly added in batches at 0°C, and EX128-01 (3 g, 10.2 mmol) was added after stirring for 0.5 hours. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was cooled to 0°C and quenched by adding saturated ammonium chloride solution (30 ml) dropwise, extracted with ethyl acetate (40 ml*3), the organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 5/0 to 5/1) to obtain EX128-02. LCMS: MS m/z (ESI) [M+H] ^- = 334.2; ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.45 (s, 1H), 7.88 (s, 1H), 4.75-4.57 (m, 1H), 4.54-4.39 (m, 1H), 4.00-3.90 (m, 1H), 3.13-2 .90(m,1H),2.19-2.01(m,2H),1.98-1.87(m,2H),1.41(s,9H),1.19(d,J=6.8Hz,3H).

EX128-02 (1 g, 2.99 mmol) was dissolved in 4M hydrochloric acid/dioxane (5 mL), and the reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure and dried to give compound EX128-03. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.40-9.05 (m, 2H), 8.55 (s, 1H), 7.97 (s, 1H), 4.84-4.66 (m, 1H), 3.52-3.43 (m, 1H), 3.27-3.17 (m, 1H), 3.13-3.01 (m, 1H), 2.40-2.16 (m, 4H), 1.30 (d, J = 6.4 Hz, 3H).

EX128-03 (700 mg, 2.60 mmol) was dissolved in 1-methyl-2-pyrrolidone (10 mL), and EX88-06 (1.22 g, 2.60 mmol) and potassium carbonate (1.08 mg, 7.79 mmol) were added. The reaction solution was stirred at 80°C for 12 hours. After the reaction was completed, water (30 mL) was added to the reaction solution, and the precipitated solid was slurried with (petroleum ether/ethyl acetate = 5/1, 15 mL), filtered, and the filter cake was dried under reduced pressure to obtain EX128-04. LCMS: MS m/z (ESI) [M+H] ⁺ = 668.2; ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.50(s,1H),8.36-8.22(m,2H),8.12-8.06(m,1H),7.92(s,1H),7.26(s,1H),5.10-4.95(m,1H),4.93-4.77(m,1H),4.60-4.50(m,1H),4.45(q, J＝7.2Hz,2H),3.40-3.25(m,1H),2.24-2.11(m,3H),2.05-1.95(m,1H),1.42(t,J＝7.2Hz,3H),1.35(d,J＝6.8Hz,3H).

EX128-04 (800 mg, 1.20 mmol) was dissolved in dioxane (10 mL), and methyl (piperidin-4-yl) carbamic acid tert-butyl ester (385 mg, 1.80 mmol), cesium carbonate (1.17 g, 3.60 mmol) and Pd-PEPPSI-HeptCl (233 mg, 0.240 mmol) were added. The reaction solution was heated to 110 ° C and stirred for 12 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/tetrahydrofuran = 100/0 to 3/1) to obtain EX128-05. LCMS: MS m/z (ESI) [M+H] ⁺ = 754.5.

EX128-05 (250 mg, 0.332 mmol) was dissolved in tetrahydrofuran (2.0 mL), and LiBHEt ₃ was slowly added under nitrogen protection at -78 °C. (0.3mL, 0.332mmol), the reaction solution was stirred at -78°C for 10 minutes. The reaction solution was quenched by adding saturated aqueous ammonium chloride solution (10ml) at -70°C and then warmed to room temperature, extracted with ethyl acetate (20ml*3), the organic layers were combined, washed with saturated brine (10mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried to obtain compound EX128-06. LCMS: MS m/z (ESI) [M+H] ⁺ = 712.5.

EX128-06 (200 mg, 0.281 mmol) was dissolved in 4M hydrochloric acid/dioxane (5.0 mL), and the reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC (column: Boston Prime C18 150*40 mm; Condition: water (FA)-ACN; B%: 26%-66%, 9 minutes) to obtain EX128. LCMS: MS m/z (ESI) [M+H] ⁺ = 612.5; ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.51(s,1H),8.36(dd,J＝12.4,1.6Hz,1H),8.33(s,1H),8.30(dd,J＝8.8,1.6Hz,1H),8.00(t,J＝8.0Hz,1H),7.92(s,1H),6.98(s,1H),5.01-4.89(m,1 H),4.88-4.75(m,1H),4.82(s,2H),4.51-4.3 7(m,1H),3.60-3.50(m,2H),3.37-3.25(m,1H),2.95-2.85(m,2H),2.84-2.76(m,1H),2.44(s,3H),2.29-2.21(m,1H),2.19-2.09(m,2H),2.08-1 .93(m,3H),1.64-1.50(m,2H),1.33(d,J=6.8Hz,3H).

Embodiment 129

EX110-01 (304 mg, 0.947 mmol) was dissolved in toluene (5 mL) and (R)-N-Boc-3-hydroxymethyl-pyrrolidine (202 mg, 1.00 mmol), CuI (159 mg, 0.834 mmol), 1,10-phenanthroline (150 mg, 0.834 mmol) and cesium carbonate (815 mg, 2.50 mmol) were added. The reaction mixture was heated to 110°C under nitrogen protection and stirred for 12 hours. After the reaction solution was cooled to room temperature, it was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (silicon dioxide, petroleum ether/tetrahydrofuran = 100/0 to 1/1) to obtain EX129-01. LCMS: MS m/z (ESI) [M+H] ⁺ = 673.5.

EX129-01 (114 mg, 0.309 mmol) was dissolved in tetrahydrofuran (3 mL), and LiBHEt ₃ (0.71 mL, 0.713 mmol) was slowly added at -78 °C in a nitrogen atmosphere and stirred for 10 minutes. Saturated ammonium chloride solution (3 mL) was added to the reaction system in an ice bath for quenching. Dilute with water (3 mL) and extract with ethyl acetate (5 mL x 3). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 1/2) to give EX129-02 (100 mg, yield 66.7%). LCMS: MS m/z (ESI) [M+H] ⁺ = 631.4.

EX129-02 (90 mg, 0.143 mmol) was dissolved in hydrochloric acid-dioxane (2 M, 2 mL), and the reaction solution was stirred at room temperature for 1 hour. After the reaction solution was concentrated under reduced pressure, it was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 17%-47%, 8 minutes) to obtain EX-120. LCMS: MS m/z (ESI) [M+H] ⁺ = 531.1; ¹ H NMR (400 MHz, CD ₃ OD)δ8.55(s,1H),8.39-8.28(m,2H),7.79–7.70(m,2H),7.52(d,J＝1.6Hz,1H),6.94(s,1H),6.31(t,J＝2.0Hz,1H),5.12–5.00(m,1H),4.91(s,2H),4 .84–4.76(m,1H),4.63-4.50(m,2H),4.48 -4.41(m,1H),3.53–3.44(m,1H),3.42-3.34(m,2H),3.29-3.16(m,2H),3.00-2.89(m,1H),2.34-2.23(m,3H),2.22-2.15(m,1H),2.14-2.03(m,1H ),2.01-1.89(m,1H),1.42(d,J=7.2Hz,3H).

Embodiment 130

Compound EX110-01 (500 mg, 0.83 mmol) and tert-butyl 1,8-diazaspiro[4.5]decane-1-carboxylate (401 mg, 1.67 mmol) were dissolved in 1,4-dioxane (5 mL), and then Pd-PEPPSI-IheptCl (81.1 mg, 0.08 mmol) and cesium carbonate (815 mg, 2.50 mmol) were added. The reaction solution was heated to 110 ° C and stirred for 12 hours under nitrogen protection. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (5 mL*3). The organic phases were combined, washed with saturated brine (5 mL*2), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 77/23) to obtain EX130-01. LCMS:MS m/z(ESI)[M+H] ⁺ =712.8;

Compound EX130-01 (155 mg, 0.22 mmol) was dissolved in THF (2 mL), cooled to -78 °C under nitrogen protection, and then LiBHEt ₃ (0.40 mL, 0.44 mmol) was slowly added. The reaction solution was stirred at -78 °C for 1 hour. The reaction solution was quenched with saturated ammonium chloride solution (5 mL) and extracted with ethyl acetate (5 mL*3). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried to obtain the crude product EX130-02. LCMS: MS m/z (ESI) [M+H] ⁺ = 670.4.

Compound EX130-02 (150 mg, 0.22 mmol) was dissolved in 4M HCl/dioxane (2 mL), and the reaction was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure and then spin-dried, and then purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 19%-49%, 8 minutes) to obtain EX130. LCMS: MS m/z (ESI) [M+H] ⁺ = 570.5; ¹ H NMR: (400 MHz, CD ₃ OD)δ8.55(s,1H),8.46–8.35(m,2H),7.79(t,J＝8.0Hz,1H),7.74(d,J＝2.4Hz,1H),7.52(d,J＝1.6Hz,1H),6.98(s,1H),6.31(t,J＝2.0Hz,1H),5.14-5.02 (m,1H),4.96(s,2H),4 .92-4.89(m,1H),4.59-4.52(m,1H),3.53-3.45(m,2H),3.43-3.36(m,1H),3.29-3.19(m,4H),2.35-2.23(m,2H),2.22-2.15(m,1H),2.12-1.94(m ,9H),1.42(d,J＝6.8Hz,3H).

Embodiment 131

Compound EX110-01 (500 mg, 0.80 mmol) and (R)-(1-methylpiperidin-3-yl)methanol (216 mg, 1.67 mmol) were dissolved in anhydrous toluene (5 mL), and 1,10-phenoline (150 mg, 0.83 mmol), cesium carbonate (815 mg, 2.50 mmol) and cuprous iodide (159 mg, 0.83 mmol) were added. The reaction solution was stirred at 110°C for 12 hours. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (5 mL*3). The organic phases were combined, washed with saturated brine (5 mL*2), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 20/80) to obtain EX131-01. LCMS: MS m/z (ESI) [M+H] ⁺ = 601.1.

Compound EX131-01 (170 mg, 0.28 mmol) was dissolved in THF (2 mL), cooled to -78 °C under nitrogen protection, and then LiBHEt ₃ (0.80 mL, 0.85 mmol) was added. The reaction solution was stirred at -78 °C for 1 hour. The reaction solution was slowly quenched with NH 4 Cl (5 mL), and extracted with ethyl acetate (5 mL*3). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated and dried, and the crude product was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 25%-56%, 8 minutes) to obtain EX131. LCMS: MS m/z (ESI) [M+H] ⁺ =559.3; ¹ H NMR (400MHz, CD ₃ OD) δ8.42-8.35 (m, 2H), 7.82-7.75 (m, 2H), 7.54 (d, J = 1.2Hz, 1H), 6.98 (s, 1H), 6.33 (t, J = 2.0Hz, 1H), 5.17-5.06(m,2H),5.03-4.99(m,1H),4.96(s,2H),4.83–4.77(m,1H),4.62–4.55(m,1H),4.42-4.37(m,1H),4.34-4.28(m,1H), 3.47-3.40(m,1H),3.20-3.12(m,1H),3.03-2.92(m,1H),2.42(s,3H),2.36-2.26(m,3H),2.24-2.07(m,4H),1.99-1.82(m,2H),1.44(d,J＝6.8Hz,3 H).

Embodiment 132

EX110-01 (500 mg, 0.834 mmol) was dissolved in dioxane (10 mL), and tert-butyl octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (378 mg, 1.67 mmol), cesium carbonate (679 mg, 2.09 mmol) and Pd-PEPPSI-HeptCl (33.0 mg, 0.042 mmol) were added. The reaction solution was heated to 100°C under nitrogen protection and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain EX132-01. LCMS: MS m/z (ESI) [M+H] ⁺ = 698.3.

EX132-01 (130 mg, 0.037 mmol) was dissolved in tetrahydrofuran (5 mL), and lithium triethylborohydride (0.1 mL, 1 mol/L) was slowly added at -70 °C, and the reaction was stirred at -70 °C for 10 minutes. After the reaction was completed, the reaction solution was quenched with saturated aqueous ammonium chloride (10 mL), extracted with ethyl acetate (15 mL x 3), and the organic phases were combined, washed with water (10 mL x 3) and saturated brine (10 mL) in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain EX132-02. LCMS: MS m/z (ESI) [M+H] ⁺ = 656.3.

EX132-02 (100 mg, 0.030 mmol) was dissolved in 4M hydrochloric acid/dioxane (5 mL), and the reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC (column: Boston Prime C18 150*30mm*5um; Condition: water(FA)-ACN; B%: 33%-53%, 11 minutes) to obtain EX132 (3.29 mg, yield 19.4%). LCMS: MS m/z (ESI) [M+H] ⁺ = 556.1; ¹ H NMR (400 MHz, CD ₃ OD)δ8.50-8.35(m,2H),7.81(t,J＝8.0Hz,1H),7.76(s,1H),7.54(s,1H),7.01(s,1H),6.33(s,1H),5.13-5.06(m,1H),4.98(s,2H),4.82-4.75(m,1H ),4.65-4.53(m,1H),3.80-3.68(m,1H),3.56-3.39(m,5H),3.23-3.05(m,1H),2.73-2.55(m,1H),2.37-1.99(m,9H),1.44(d,J＝6.4Hz,3H).

Embodiment 133

Compound EX83-05 (500 mg, 1.21 mmol) and 3S-3-methyl-1,4-oxazinane (147 mg, 1.45 mmol) were dissolved in NMP (5 mL), and then K ₂ CO ₃ (502 mg, 3.64 mmol) was added. The reaction solution was stirred at 100°C for 12 hours. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (5 mL*3), and then the organic phase was washed with water (5 mL*3). The organic phases were combined, washed with saturated brine (10 mL*2), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 86/14) to obtain EX133-01. LCMS: MS m/z (ESI) [M+H] ⁺ = 478.0.

Under nitrogen atmosphere, compound EX133-01 (150 mg, 0.31 mmol) and tert-butyl piperidin-4-ylcarbamate (75.5 mg, 0.38 mmol) were dissolved in 1,4-dioxane (2 mL), and then RuPhos Pd G2 (24.4 mg, 0.03 mmol), cesium carbonate (307 mg, 0.94 mmol). The reaction solution was stirred at 100°C for 12 hours. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (5 mL*3). The organic phases were combined, washed with saturated brine (5 mL*2), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 65/35) to obtain EX133-02. LCMS: MS m/z (ESI) [M+H] ⁺ = 550.0.

Compound EX133-02 (50.0 mg, 0.091 mmol) was dissolved in 4M HCl/dioxane (1 mL). The reaction was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure, dried by spin drying, and purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 18%-48%, 16 minutes) to obtain EX-133. LCMS: MS m/z (ESI) [M+H] ⁺ = 450.2; ¹ H NMR (400MHz, DMSO-d ₆ )δ8.54(s,1H),8.43-8.36(m,2H),7.77(dd,J＝9.2,7.6Hz,1H),6.59(s,1H),4.50-4.42(m,1H),4.15-3.97(m,4H),3.90-3.83(m,1H),3.82-3.70(m, 3H),3.69-3.59(m,1H),3.08-2.99(m,2H),2.63(s,3H),2.16-2.07(m,2H),1.91-1.82(m,2H),1.31(d,J=5.6Hz,3H).

Embodiment 134

At 0°C, under _N2 atmosphere, compound benzyl alcohol (5.30 g, 49.0 mmol) was dissolved in THF (90 mL), and then NaH (2.20 g, 56.0 mmol) was added in batches. After half an hour, EX134-01 (9.00 g, 46.6 mmol) was added. The reaction solution was stirred at 0°C for half an hour. The reaction solution was quenched with saturated _NH4Cl (100 mL), and extracted with ethyl acetate (50 mL*3). The organic phases were combined, washed with saturated brine (50 mL*2), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 90/10) to obtain EX134-02. LCMS: MS m/z(ESI)[M+H] ⁺ =254.0; ¹ H NMR: (400MHz, CD ₃ COCD ₃ ) δ7.57-7.48(m,2H),7.47-7.35(m,3H),7.14(s,1H),5.33(s,2H).

At -78°C, under _N2 atmosphere, compound EX134-02 (12.2 g, 48.0 mmol) was dissolved in THF (180 mL), and then n-BuLi (23.0 mL, 57.6 mmol) was added. After half an hour, DMF (5.54 mL, 72.0 mmol) was slowly added. The reaction solution was stirred at -78°C for 1 hour. The reaction solution was quenched with saturated NH ₄ Cl (200 mL) and extracted with ethyl acetate (100 mL*3). The organic phases were combined, washed with saturated brine (100 mL*2), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 80/20) to obtain EX134-03. LCMS: MS m/z (ESI) [M+H] ⁺ = 281.9; ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 10.28 (s, 1H), 7.62 (s, 1H), 7.54-7.46 (m, 2H), 7.45-7.35 (m, 3H), 5.41 (s, 2H).

Compound EX134-03 (2.70 g, 9.57 mmol) and hydrazine hydrate (1.91 mL, 33.4 mmol) were dissolved in n-butanol (54 mL). The reaction solution was stirred at 120 ° C for 16 hours. The reaction solution was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (30 mL*3). The organic phases were combined, washed with water (30 mL*2) and saturated brine (30 mL) in turn, dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 90/10) to obtain EX134-04. LCMS: MS m/z (ESI) [M+H] ⁺ = 260.0.

Compound EX134-04 (1.26 g, 4.85 mmol) was dissolved in DCE (40 mL), and then NIS (2.20 g, 9.70 mmol) was added. The reaction solution was stirred at 80°C for 16 hours. The reaction solution was cooled to room temperature, washed with saturated NaHCO ₃ (30 mL) and saturated Na ₂ SO ₃ (30 mL), and extracted with ethyl acetate (80 mL*3). The organic phases were combined, washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 80/20) to obtain EX134-05. LCMS: MS m/z (ESI) [M+H] ⁺ = 386.0.

Under an O ₂ atmosphere, compound EX134-05 (1.33 g, 3.45 mmol) and (4-cyano-3-fluorophenyl) boronic acid (0.70 g, 4.14 mmol) were dissolved in dichloromethane (10 mL), and then copper acetate (1.30 g, 6.90 mmol), pyridine (0.84 mL, 10.3 mmol) and 4A molecular sieves (1.00 g) were added. The reaction solution was stirred at room temperature for 48 hours. After filtration, the filter cake was washed with ethyl acetate (50 mL), and the combined filtrate was dried by spin drying. The crude product was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 77/23) to obtain EX134-06. ¹ H NMR: (400MHz, DMSO-d ₆ )δ8.29-8.20(m,2H),8.11(dd,J＝8.8,7.6Hz,1H),7.62(d,J＝7.2Hz,2H),7.49-7.43(m,2H),7.42–7.34(m,1H),7.27(s,1H),5.49 (s,2H).

Compounds EX134-06 (1.00 g, 1.98 mmol) and EX53-03 (282 mg, 1.59 mmol) were dissolved in NMP (10 mL), and K ₂ CO ₃ (822 mg, 5.94 mmol) was then added. The reaction solution was stirred at 100°C for 12 hours. The reaction solution was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with water (10 mL*2) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated and spin-dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 75/25) to obtain EX134-07. LCMS: MS m/z (ESI) [M+H] ⁺ = 610.0; ¹ H NMR: (400MHz, DMSO-d ₆ ) δ8.38 (d, J = 12.0Hz, 1H), 8.26 (d, J = 8.8Hz, 1H), 7.97 (t, J = 8.0Hz, 1H), 7.62 (br d,J＝7.6Hz,2H),7.48-7.40(m,2H),7.39-7.33(m,1H),6.36(s,1H),5.38(s,2H),4.00-3.68(m,2H),3.57-3.42(m,2H),1.93-1.85(m,2H),1.82-1 .70(m,2H),1.56-1.43(m,2H),1.26(s,3H).

Compound EX134-07 (1.00 g, 1.64 mmol) and tert-butyl piperidine-4-carbamate (493 mg, 2.46 mmol) were dissolved in 1,4-dioxane (10 mL), and then Pd-PEPPSI-IHeptCl (160 mg, 0.16 mmol) and cesium carbonate (1.60 g, 4.92 mmol) were added. The reaction solution was heated to 110 ° C and stirred for 12 hours under N ₂ atmosphere. The reaction solution was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated brine (10 mL*2), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 70/30) to obtain EX134-08. LCMS:MS m/z(ESI)[M+H] ⁺ =682.3.

Compound EX134-08 (500 mg, 0.73 mmol) was dissolved in MeOH (5 mL), and then Pd/C 10% (101 mg, 0.95 mmol) and Pd(OH) ₂ (134 mg, 0.95 mmol) were added. The reaction solution was stirred at room temperature for 12 hours under H ₂ atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain the crude product EX134-09 (250 mg, yield 57.6%). LCMS: MS m/z (ESI) [M+H] ⁺ = 592.2.

Compound EX134-09 (120 mg, 0.20 mmol) was dissolved in acetonitrile (2 mL), and then sodium 2-chloro-2,2-difluoroacetate (31.0 mg, 0.20 mmol) and potassium carbonate (56.1 mg, 0.41 mmol) were added. The reaction solution was stirred at 60 ° C for 16 hours. The reaction solution was cooled to room temperature, diluted with water (5 mL), and extracted with ethyl acetate (5 mL * 3). The organic phases were combined, washed with water (5 mL * 2) and saturated brine (5 mL) in turn, dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was subjected to silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 65/35) to obtain EX134-10 (80 mg, yield 61.5%). LCMS: MS m/z (ESI) [M + H] ⁺ = 642.5.

Compound EX134-10 (80 mg, 0.13 mmol) was dissolved in 4M HCl/dioxane (1 mL), and the reaction was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure and then spin-dried, and then purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 24%-54%, 8 minutes) to give EX134. LCMS: MS m/z (ESI) [M+H] ⁺ = 542.3; ¹ H NMR: (400 MHz, DMSO-d ₆ )δ8.55(s,1H),8.48-8.29(m,2H),7.84-7.69(m,1H),7.30(t,J＝72.8Hz,1H),6.26(s,1H),4.05-3.97(m,2H),3.95-3.79(m,2H),3.65-3.56(m,2H) ,3.22-3.10(m,1H),3.03-2.93(m,2H),2.09-2.02(m,2H),2.01-1.96(m,2H),1.95-1.85(m,2H),1.83-1.71(m,2H),1.69-1.56(m,2H),1.37(s,3H ).

Embodiment 135

Under _N2 atmosphere, compound EX88-07 (400 mg, 0.70 mmol) and (3S, 4R)-3-fluoropiperidin-4-ylcarbamic acid tert-butyl ester (167 mg, 0.77 mmol) were dissolved in 1,4-dioxane (4 mL), and then Pd-PEPPSI-IHeptCl (67.6 mg, 0.07 mmol) and cesium carbonate (679 mg, 2.09 mmol) were added. The reaction solution was stirred at 110 ° C for 12 hours. The reaction solution was cooled to room temperature, diluted with water (5 mL), and extracted with ethyl acetate (5 mL * 3). The organic phases were combined, washed with saturated brine (10 mL * 2), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was subjected to silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 72/28) to obtain EX135-01. LCMS:MS m/z(ESI)[M+H] ⁺ =666.4.

Compound EX135-01 (260 mg, 0.15 mmol) was dissolved in THF (3 mL), cooled to -78°C under nitrogen protection, and then 1M LiBHEt ₃ (0.78 mL, 0.78 mmol) was added. The reaction solution was stirred at -78°C for 1 hour. The reaction solution was quenched with NH ₄ Cl (5 mL) and extracted with ethyl acetate (5 mL*3). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated and spin-dried to directly obtain EX135-02. LCMS: MS m/z (ESI) [M+H] ⁺ = 624.2.

Compound EX135-02 (90.0 mg, 0.14 mmol) was dissolved in DCM (2 mL), and then PCC (62.2 mg, 0.29 mmol) and diatomaceous earth (130 mg, 0.02 mmol) were added. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was diluted with water (5 mL) and extracted with dichloromethane (5 mL*3). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 74/26) to obtain EX135-03. LCMS: MS m/z (ESI) [M+H] ⁺ = 622.2.

Under _N2 atmosphere, compound EX135-03 (20.0 mg, 0.03 mmol) was dissolved in MeOH (1 mL), and then (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (7.40 mg, 0.04 mmol) and _K2CO3 (8.90 mg, 0.06 mmol ₎ were added. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (5 mL*3). The organic phases were combined, washed with saturated brine (5 mL*2), dried over anhydrous sodium sulfate, filtered, concentrated and spin-dried to directly obtain EX135-04. LCMS: MS m/z (ESI) [M+H] ⁺ = 618.3.

Compound EX135-04 (15 mg, 0.02 mmol) was dissolved in MeOH (1 mL), and then TsOH (20.9 mg, 0.12 mmol) was added, and the reaction was stirred at 25°C for 16 hours. The reaction solution was concentrated under reduced pressure and dried, and then purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 23%-53%, 8 minutes) to obtain EX135. LCMS: MS m/z (ESI) [M+H] ⁺ = 518.0; ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.39-8.32(m,1H),8.29(dd,J＝8.8,2.0Hz,1H),7.99(t,J＝8.4Hz,1H),6.90(s,1H),4.90-4.65(m,1H),4.01-3.64(m,2H),3.55- 3.46(m,2H),3.22-3.10(m,2H),3.09-3.01(m,1H),2.99-2.89(m,2H),2.03-1.95(m,1H),1.92-1.83(m,2H),1.80-1.63(m,3H),1.52-1.40(m,2H) ,1.25(s,3H).

Embodiment 136

EX102-06 (100 mg, 0.188 mmol) was dissolved in dioxane (1 mL), and methyl (piperidin-4-yl) carbamic acid tert-butyl ester (80.4 mg, 0.375 mmol), cesium carbonate (183.3 mg, 0.563 mmol) and Pd-PEPPSI-IHeptCl (18.2 mg, 0.019 mmol) were added. The reaction solution was stirred at 110°C for 12 hours under nitrogen protection. After the reaction solution was concentrated under reduced pressure, it was purified by preparative thin layer chromatography (petroleum ether/ethyl acetate = 10/1) to obtain EX136-01. LCMS: MS m/z (ESI) [M+1] ⁺ = 620.5; ¹ H NMR (400 MHz, CDCl ₃ )δ8.44(dd,J＝12.4,2.0Hz,1H),8.31(dd,J＝8.8,2.0Hz,1H),7.60(dd,J＝8.8,7.6Hz,1H),5.87(s,1H),4.12-4.02(m,2H),4.00(s,3H),3.88-3.79(m,2H) ,3.66-3.5 6(m,2H),2.95-2.85(m,2H),2.80(s,3H),2.79-2.68(m,1H),1.97-1.90(m,1H),1.89-1.81(m,2H),1.80-1.71(m,3H),1.70-1.57(m,4H),1.49(s ,9H),1.42(s,3H).

EX136-01 (220 mg, 0.142 mmol) was dissolved in 4M hydrochloric acid-dioxane (2 mL), and the reaction solution was stirred at 25°C for 1 hour. The reaction solution was spin-dried, and the crude product was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 20%-60%, 9 minutes) to obtain EX136. LCMS: MS m/z (ESI) [M+1] ⁺ = 520.4; ¹ H NMR (400MHz, DMSO-d ₆ )δ8.40(d,J＝12.0Hz,1H),8.38(s,1H),8.28(d,J＝8.8Hz,1H),7.94(t,J＝8.0Hz,1H),6.13(s,1H),3.98(s,3H),3.97-3.88(m,2H),3.84-3.74(m,2H), 3.60-3.50(m,2H),2.92-2.80(m,2H),2.79-2.70(m,1H),2.42(s,3H),2. 03-1.93(m,2H),1.92-1.83(m,2H),1.82-1.72(m,2H),1.59-1.46(m,4H), 1.26(s,3H).

Embodiment 137

EX102-05 (400 mg, 0.933 mmol) was dissolved in 1-methyl-2-pyrrolidone (2 mL), EX110-05 and potassium carbonate (258 mg, 1.87 mmol) were added, and the reaction solution was stirred at 100°C for 12 hours. After the reaction was completed, the reaction solution was diluted with water (10 mL), the solid precipitated, filtered, and the filter cake was concentrated under reduced pressure to obtain EX137-01. LCMS: MS m/z (ESI) [M+H] ⁺ = 558.0.

EX137-01 (300 mg, 0.538 mmol) was dissolved in dioxane (2 mL), and tert-butyl piperidine-4-carbamate (216 mg, 1.08 mmol), cesium carbonate (351 mg, 1.08 mmol) and Pd-PEPPSI-HeptCl (52.4 mg, 0.054 umol) were added. The reaction solution was heated to 110 ° C and stirred for 12 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain EX137-02 (90 mg, yield 26.6%). LCMS: MS m/z (ESI) [M+H] ⁺ = 629.8.

EX137-02 (90 mg, 0.143 mmol) was dissolved in 4 M hydrochloric acid/dioxane (1 mL), and the reaction solution was stirred at 25° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC (column: ACSSH-CP C18 150*30mm; Condition: water (FA)-ACN; B%: 1%-41%, 9 minutes) to obtain EX137. LCMS: MS m/z (ESI) [M+H] ⁺ = 530.4; ¹ H NMR (400MHz, CD ₃ OD) δ8.57 (s, 1H), 8.44-8.34 (m, 2H), 7.82-7.73 (m, 2H), 7.54 (d, J = 2.0 Hz, 1H), 6.33 (t, J = 2.0 Hz, 1H), 6.25 (s, 1H), 5.12–5.04 (m, 1H), 4.80-4.76 (m, 1H), 4.57-4.48 (m, 1H), 4.20-4. 10(m,2H),4.06(s,3H),3.44-3.37(m,1H),3.30-3.20(m,1H),3.04-2.92(m,2H),2.37-2.25(m,2H),2.23-2.15(m,1H),2.13-2.03(m,3H),1.88- 1.74(m,2H),1.43(d,J＝6.8Hz,3H).

Embodiment 138

EX110-06 (500 mg, 0.834 mmol) was dissolved in ethanol (5 mL), and 1 M sodium hydroxide aqueous solution (1.30 mL, 6.67 mmol) was added. The reaction solution was stirred at 25 ° C for 2 hours. After the reaction was completed, the reaction solution was adjusted to pH = 5 with 1 M hydrochloric acid to precipitate solids. Filter, and the filter cake was dried under reduced pressure to obtain EX138-01. LCMS: MS m/z (ESI) [M+H] ⁺ =571.7; ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.43-8.26 (m, 2H), 8.13-8.04 (m, 1H), 7.83 (d, J = 2.0Hz, 1H), 7.46 (d, J = 1.2Hz, 1H), 7.17 (s, 1H) . .8Hz,3H).

EX138-01 (300 mg, 0.525 mmol) was dissolved in toluene (3 mL), triethylamine (0.4 mL, 2.63 mmol) and diphenylphosphoryl azide (289 mg, 1.05 mmol) were added, and the reaction solution was stirred at 25 ° C for half an hour in a nitrogen atmosphere. Then tert-butyl alcohol (3 mL, 32.8 mmol) was added, and the reaction solution was stirred at 90 ° C for 12 hours in a nitrogen atmosphere. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 3/1) to obtain EX138-02. LCMS: MS m/z (ESI) [M+H] ⁺ = 643.3.

EX138-02 (150 mg, 0.233 mmol) was dissolved in dioxane hydrochloride (3 mL). The reaction solution was stirred at 25°C for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain EX138-03. LCMS: MS m/z (ESI) [M+H] ⁺ = 543.8.

EX138-03 (200 mg, 0.369 mmol) was dissolved in dioxane (2 mL), and tert-butyl piperidine-4-carbamate (158.0 mg, 0.737 mmol), Pd-PEPPSI-HeptCl (35.9 mg, 0.037 umol) and cesium carbonate (240 mg, 0.737 mmol) were added. The reaction solution was stirred at 100 ° C for 12 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain EX138-04. LCMS: MS m/z (ESI) [M+H] ⁺ = 629.2.

EX138-04 (50 mg, 0.080 mmol) was dissolved in 4M hydrochloric acid/dioxane (1 mL), and the reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC (column: ACSSH-CP C18 150*30 mm; Condition: water (FA)-ACN; B%: 11%-51%, 9 minutes) to obtain EX138. LCMS: MS m/z (ESI) [M+H] ⁺ = 529.1; ¹ H NMR (400 MHz, CD ₃ OD) δ 8.55(s,1H),8.47-8.34(m,2H),7.83-7.67(m,2H),7.51(d,J＝1.6Hz,1H),6.30(t,J＝2.0Hz,1H),5.94(s,1H),4.99-4.88(m,1H),4.80-4.68(m,1H) ,4.46-4.33(m,1H),3.85-3.76(m,2H),3.07-2.94(m,3H),2.63(s,3H),2.30-2.20(m,2H),2.18-2.00(m,4H),1.86-1.71(m,2H),1.36(d,J＝6.8Hz, 3H).

Embodiment 139

EX102-05 (400 mg, 0.933 mmol) was dissolved in 1-methyl-2-pyrrolidone (2 mL), EX110-05 and potassium carbonate (258 mg, 1.87 mmol) were added, and the reaction solution was stirred at 100°C for 12 hours. After the reaction was completed, the reaction solution was diluted with water (10 mL) to precipitate solids. The filter cake was filtered and concentrated under reduced pressure to obtain EX139-01 (280 mg, yield 53.8%). LCMS: MS m/z (ESI) [M+H] ⁺ = 558.2.

EX139-01 (280 mg, 0.502 mmol) was dissolved in dioxane (3 mL), and 4-N-Boc-4-N-methylaminopiperidine (216 mg, 1.01 mmol), cesium carbonate (327 mg, 1.01 mmol) and Pd-PEPPSI-HeptCl (48.9 mg, 0.050 umol) were added. The reaction solution was heated to 110°C under nitrogen protection and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain EX139-02 (60 mg, yield 18.6%). LCMS: MS m/z (ESI) [M+H] ⁺ = 644.5.

EX139-02 (60 mg, 0.093 mmol) was dissolved in 4M hydrochloric acid/dioxane (1.5 mL), and the reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC (column: ACSSH-CP C18 150*30 mm; Condition: water (FA)-ACN; B%: 13%-53%, 9 minutes) to obtain EX139. LCMS: MS m/z (ESI) [M+H] ⁺ = 544.3; ¹ H NMR (400 MHz, CD ₃ OD)δ8.55(s,1H),8.41-8.30(m,2H),7.78-7.69(m,2H),7.52(d,J＝1.6Hz,1H),6.31(t,J＝2.0Hz,1H),6.23(s,1H),5.06-5.00(m,1H),4.82-4.75(m, 1H),4.28-4.22(m,1H),4.12 -4.05(m,2H),4.04(s,3H),3.42-3.33(m,1H),3.10-3.01(m,1H),3.00-2.92(m,2H),2.68(s,3H),2.34-2.24(m,2H),2.21-2.02(m,4H),1.85-1.6 8(m,2H),1.41(d,J＝6.8Hz,3H).

Embodiment 140

Compound EX120-01 (4.10 g, 19.2 mmol) was dissolved in methanol (40 mL), sodium diborohydride (1.09 g, 28.8 mmol) was added dropwise at 0°C, and the reaction solution was stirred at 0°C for one hour. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride (50 mL), extracted three times with ethyl acetate (50 mL*3), and the organic phases were combined and dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and dried. The crude product was colorless oil EX140-01 (4.10 g, yield 99.1%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.59-3.77 (m, 3H), 3.31-2.83 (m, 1H), 1.98-1.47 (m, 4H), 1.47 (s, 9H), 1.36-1.12 (m, 3H).

EX140-01 (4.10 g, 19.04 mmol) was dissolved in dichloromethane (40 mL), triethylamine (10.56 mL, 76.2 mmol) was added, and then methanesulfonic anhydride (9.94 g, 57.1 mmol) was slowly added, and the reaction was allowed to react at 25°C for 1 hour. The reaction solution was quenched and diluted with water (50 mL), extracted with dichloromethane (40 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and dried to obtain the crude product EX140-02.

Pyrazole (1.95 g, 28.6 mmol) was dissolved in tetrahydrofuran (20 mL), sodium hydride (1.22 g, 30.5 mmol) was added, and the reaction solution was reacted at 0 ° C for 1 hour. Then EX140-02 (6.10 g, 21.0 mmol) was dissolved in tetrahydrofuran (40 mL) and slowly added dropwise to the reaction solution, and the reaction temperature was raised to 85 ° C for 12 hours. After cooling to room temperature, the reaction solution was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 10/1 to 1/1) to obtain EX140-03. ¹ H NMR (400MHz, CDCl ₃ ) δ7.56-7.50(m,1H),7.47-7.39(m,1H),6.32-6.23(m,1H),4.63-4.49(m,1H),4.44-4.32(m,1H),4.25-4.03(m,1H),4.00-3.8 0(m,1H),2.20-1.87(m,4H),1.47(s,9H),1.30-1.20(m,3H).

EX140-03 (1.1 g, 4.15 mmol) was dissolved in 4 M dioxane hydrochloride (5 mL) and reacted at 25° C. for 2 hours. The reaction solution was concentrated under reduced pressure and dried to obtain EX140-04.

Compounds EX140-04 (185 mg, 1.12 mmol) and EX83-05 (555 mg, 1.34 mmol) were dissolved in NMP (2 mL), and then K ₂ CO ₃ (464 mg, 3.36 mmol) was added. The reaction solution was stirred at 80°C for 12 hours. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (5 mL*3). The organic phases were combined, washed with saturated brine (5 mL*2), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 70/30) to obtain EX140-05. LCMS: MS m/z (ESI) [M+H] ⁺ = 542.2.

Compound EX140-05 (430 mg, 0.79 mmol) and tert-butyl piperidin-4-ylcarbamate (159 mg, 0.79 mmol) were dissolved in 1,4-dioxane (4 mL), and then RuPhos Pd G2 (61.7 mg, 0.08 mmol) and Cs ₂ CO ₃ (776 mg, 2.38 mmol) were added. The reaction solution was heated to 100°C and stirred for 12 hours under N ₂ atmosphere. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (5 mL*3). The organic phases were combined, washed with saturated brine (5 mL*2), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 72/28) to obtain EX140-06. LCMS: MS m/z (ESI) [M+H] ⁺ = 614.1.

Compound EX140-06 (80.0 mg, 0.13 mmol) was dissolved in 4M HCl/dioxane (1 mL), and the reaction was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure, spin-dried, and purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 21%-51%, 8 minutes) to obtain EX140. LCMS: MS m/z (ESI) [M+H] ⁺ = 514.1; ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.40-8.33(m,2H),8.33-8.28(m,1H),8.00(t,J＝8.4Hz,1H),7.82(d,J＝2.0Hz,1H),7.45(d,J＝1.2Hz,1H),6.78(s,1H),6.25(d,J＝2.0Hz,1H),5.04- 4.89(m,1H),4.83-4.68(m,1H),4.50-4.36(m,1H),3.60-3.56(m,2H),3.07-2.98(m,2H),2.95-2.85(m,2H),2.56(s,3H),2.20-2.15(m,2H),2.12 -2.02(m,1H),2.00 -1.85(m,3H),1.65-1.57(m,2H),1.32(d,J=6.8Hz,3H).

Embodiment 141

At 0°C and _N2 atmosphere, compound 3,5-dimethyl-1H-pyrazole (2.00 g, 20.5 mmol) was dissolved in THF (30 mL), and then NaH (800 mg, 20.5 mmol) was added in batches. After reacting for 1 hour, EX140-02 (4.00 g, 13.6 mmol) was added. The reaction solution was stirred at 85°C for 12 hours. The reaction solution was quenched with saturated _NH4Cl (20 mL) and extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated brine (20 mL*2), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was subjected to silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 82/18) to obtain EX141-01. LCMS: MS m/z(ESI)[M+H] ⁺ =293.9; ¹ H NMR (400MHz, CDCl ₃ ) δ5.78(s,1H),4.79-4.46(m,1H),4.37-4.06(m,2H),3.14-2.85(m,1H),2.25(s,3H),2.21(s,3 H),1.89-1.76(m,1H),1.73-1.63(m,3H),1.47(s,9H),1.25(d,J＝7.2Hz,3H).

Compound EX141-01 (1.30 g, 4.43 mmol) was dissolved in 4M HCl/dioxane (15 mL), and the reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure and dried to obtain a crude yellow solid EX141-02 (1.00 g, yield 98.2%). LCMS: MS m/z (ESI) [M+H] ⁺ = 193.9.

Compounds EX88-06 (1.80 g, 3.83 mmol) and EX141-02 (1.00 g, 4.21 mmol) were dissolved in NMP (20 mL), and potassium carbonate (1.60 g, 11.5 mmol) was then added. The reaction solution was stirred at 90°C for 12 hours. The reaction solution was cooled to room temperature, diluted with water (20 mL), and a solid was precipitated. The solid was slurried and washed with (petroleum ether/ethyl acetate = 3/1, 15 mL) to obtain EX141-03. LCMS: MS m/z (ESI) [M+H] ⁺ = 628.3; ¹ H NMR (400 MHz, CDCl ₃ ) δ8.38 (dd, J = 11.6, 2.0 Hz, 1H), 8.27 (dd, J = 8.8, 1.6 Hz, 1H), 7.69 (dd, J ＝8.4,7.2Hz,1H),7.03(s,1H),5.81(s,1H),5.08–4.90(m,1H),4.86-4.66(m,1H),4.55(q,J＝7.2Hz,2H),4.50-4.40(m,1H),3.40-3.30(m,1H),2.5 5–2.43(m,1H),2.31(s,3H),2.35–2.25(m,1H),2.20(s,3H),2.14–2.07(m,1H),1.98-1.91(m,1H),1.50(t,J＝7.2Hz,3H),1.41(d,J＝6.8Hz,3H).

Under _N2 atmosphere, compound EX141-03 (500 mg, 0.80 mmol) and tert-butyl piperidin-4-ylcarbamate (342 mg, 1.59 mmol) were dissolved in 1,4-dioxane (5 mL), and then Pd-PEPPSI-IheptCl (77.5 mg, 0.08 mmol) and cesium carbonate (779 mg, 2.39 mmol) were added. The reaction solution was stirred at 110°C for 12 hours. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (5 mL*3). The organic phases were combined, washed with saturated brine (5 mL*2), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 80/20) to obtain EX141-04. LCMS: MS m/z (ESI) [M+H] ⁺ = 714.4.

Compound EX141-04 (130 mg, 0.18 mmol) was dissolved in THF (2 mL), cooled to -78 °C under nitrogen protection, and then LiBHEt ₃ (0.50 mL, 0.55 mmol) was added. The reaction solution was stirred at -78 °C for 1 hour. The reaction solution was quenched with NH 4 Cl (5 mL) and extracted with ethyl acetate (5 mL*3). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated and spin-dried to obtain the crude product EX141-05. LCMS: MS m/z (ESI) [M+H] ⁺ = 672.7.

Compound EX141-05 (100 mg, 0.15 mmol) was dissolved in 4M HCl/dioxane (1 mL), and the reaction was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure and then spin-dried, and then purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 20%-45%, 8 minutes) to obtain EX141. LCMS: MS m/z (ESI) [M+H] ⁺ = 572.5; ¹ H NMR (400 MHz, CD ₃ OD)δ8.55(s,1H),8.45-8.36(m,2H),7.84-7.71(m,1H),6.98(s,1H),5.85(s,1H),5.09-5.03(m,1H),4.95(s,2H),4.68-4.60(m,1H),4.58-4.47(m ,1H),3.72(d,J＝12.0Hz,2H),3.43-3.37(m,1H), 3.15-3.07(m,1H),3.05-2.93(m,2H),2.68(s,3H),2.40-2.35(m,1H),2.34(s,3H),2.25-2.16(m,3H),2.15(s,3H),2.10-2.02(m,1H),1.98-1.8 8(m,1H),1.87-1.73(m,2H),1.43(d,J=7.2Hz,3H).

Embodiment 142

Under _N2 atmosphere, compound EX110-06 (500 mg, 0.80 mmol) and (R)-3-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (718 mg, 3.34 mmol) were dissolved in toluene (5 mL), and 1,10-phenanthroline (150 mg, 0.83 mmol), cesium carbonate (815 mg, 2.50 mmol) and CuI (159 mg, 0.83 mmol) were added. The reaction solution was stirred at 110 °C for 12 hours. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (5 mL*3). The organic phases were combined, washed with saturated brine (5 mL*2), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 20/80) to obtain EX142-01. LCMS:MS m/z(ESI)[M+H] ⁺ =687.5.

Compound EX142-01 (220 mg, 0.32 mmol) was dissolved in THF (3 mL), cooled to -78 °C under N ₂ protection, and LiBHEt ₃ (1.00 mL, 0.96 mmol) was slowly added. The reaction solution was stirred at -78 °C for 1 hour. The reaction solution was quenched with saturated ammonium chloride solution (5 mL) and extracted with ethyl acetate (5 mL*3). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated and spin-dried, and then directly Got EX142-02. LCMS:MS m/z(ESI)[M+H] ⁺ =645.2.

Compound EX142-02 (200 mg, 0.31 mmol) was dissolved in 4M HCl/dioxane (1 mL), and the reaction was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure, spin-dried, and purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 23%-53%, 8 minutes) to obtain EX142. LCMS: MS m/z (ESI) [M+H] ⁺ = 545.1; ¹ H NMR (400 MHz, CD ₃ OD)δ8.55(brs,1H),8.39-8.25(m,2H),7.80-7.68(m,2H),7.52(d,J＝1.6Hz,1H),6.95(s,1H),6.31(t,J＝2.0Hz,1H),5.12-5.03(m,1H),4.93(s,2H), 4.80-4.74(m,1H),4.61–4.50(m,1H),4.46-4.37(m ,1H),4.36-4.27(m,1H),3.54-3.44(m,1H),3.43-3.32(m,2H),2.94-2.75(m,2H),2.42-2.23(m,3H),2.23-2.15(m,1H),2.14-1.91(m,3H),1.84 -1.65(m,1H),1.58-1.46(m,1H),1.42(d,J＝6.8Hz,3H).

Embodiment 143

EX110-06 (200 mg, 0.334 mmol) was dissolved in dioxane (5 mL), and tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (160 mg, 0.667 mmol), cesium carbonate (326 mg, 1.00 mmol) and Pd-PEPPSI-Iheptcl (3.2 mg, 0.003 mmol) were added. The reaction solution was stirred at 90 ° C for 12 hours under nitrogen protection. After the reaction solution was concentrated under reduced pressure, it was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0-1/1) to obtain EX143-01. LCMS: MS m/z (ESI) [M+1] ⁺ = 712.3.

EX143-01 (190 mg, 0.107 mmol) was dissolved in tetrahydrofuran (3 mL), cooled to -78 °C under nitrogen protection, and lithium triethylborohydride (0.1 mL, 0.320 mmol) was slowly added. The reaction solution was stirred at -78 °C for half an hour. The reaction solution was quenched with saturated ammonium chloride solution (3 mL) and extracted with ethyl acetate (10 mL). After the organic phase was concentrated under reduced pressure, it was purified by preparative thin layer chromatography (petroleum ether/ethyl acetate = 1/1) to obtain EX143-02. LCMS: MS m/z (ESI) [M+1] ⁺ = 670.6.

EX143-02 (80 mg, 0.119 mmol) was dissolved in 2M hydrochloric acid/dioxane (1 mL), and the reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure and dried by spin drying, and purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 20%-60%, 9 minutes) to obtain EX143. LCMS: MS m/z (ESI) [M+1] ⁺ = 570.6; 1H NMR (400MHz, DMSO-d ₆ )δ8.42(s,1H),8.35(d,J＝12.8Hz,1H),8.31(d,J＝8.4Hz,1H),7.99(t,J＝8.0Hz,1H),7.82(d,J＝2.0Hz,1H),7.45(d,J＝1.2Hz,1H),6.97(s,1H),6.25(t, J＝2.0Hz,1H),5.00-4.89(m,1H) ,4.83(s,2H),4.80-4.70(m,1H),4.50-4.34(m,1H),3.25-3.12(m,5H),3.11-3.06(m,2H),2.90(s,2H),2.25-2.09(m,3H),2.00-1.90(m,1H),1. 83-1.63(m,6H),1.33(d,J=6.8Hz,3H).

Embodiment 144

EX110-06 (500 mg, 0.834 mmol) was dissolved in dioxane (5 mL), and tert-butyl N-(2-azabicyclo[2.2.1]heptyl-5-yl)carbamate (354.2 mg, 1.67 mmol), cesium carbonate (543.5 mg, 1.67 mmol) and Pd-PEPPSI-HeptCl (81.1 mg, 0.083 mmol) were added. The reaction solution was heated to 100°C under nitrogen protection and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain EX144-01. LCMS: MS m/z (ESI) [M+H] ⁺ = 684.3.

EX144-01 (70 mg, 0.102 mmol) was dissolved in tetrahydrofuran (1 mL), and lithium triethylborohydride (0.3 mL, 0.307 mmol) was added at -78 °C. The reaction solution was stirred at -78 °C for 1 hour under nitrogen protection. After the reaction was completed, it was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate (2 mL*3), and the organic phases were combined, washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product obtained EX144-02. LCMS: MS m/z (ESI) [M+H] ⁺ = 642.5.

EX144-02 (70 mg, 0.109 mmol) was dissolved in 2M hydrochloric acid/dioxane (1 mL), and the reaction solution was stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC (column: ACSSH-CG C18 150*30 mm; Condition: water (FA)-ACN; B%: 21%-51%, 8 minutes) to obtain EX144. LCMS: MS m/z (ESI) [M+H] ⁺ = 542.2; ¹ H NMR (400 MHz, CD ₃ OD)δ8.53-8.37(m,2H),7.82-7.76(m,2H),7.54(d,J＝1.6Hz,1H),6.99(s,1H),6.33(t,J＝2.0Hz,1H),4.98(s,2H),4.66-4.51(m,1H),4.19-4.10(m, 1H),3.83-3.74(m,1H),3.69-3.62(m,1H),3.59-3.4 8(m,1H),3.44-3.37(m,2H),2.73-2.66(m,1H),2.35-2.25(m,2H),2.24-2.15(m,2H),2.13-2.02(m,1H),2.01-1.93(m,1H),1.78-1.70(m,1H),1 .69-1.59(m,1H),1.48-1.38(m,3H),1.37-1.27(m,1H).

Embodiment 145

EX145-01 (5.0 g, 24.8 mmol) was dissolved in anhydrous DCM (100 mL) and DIEA (16.5 mL, 62.1 mmol) was added. The reaction solution was stirred at 25°C for 2 hours. H ₂ O (30 mL) was added to the reaction solution and extracted with dichloromethane (80 mL×3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product which was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 3/1) to obtain EX145-02. ¹ H NMR (400MHz, CDCl ₃ ) δ4.94-4.82(m,1H),3.76-3.63(m,2H),3.34-3.23(m,2H),3.03(s,3H),2.00-1.91(m,2H),1.85-1.75(m,2H),1.45(s,9H).

After 1H-pyrazole (3.2 g, 46.8 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), sodium hydrogen (1.0 g, 26.0 mmol) was slowly added under ice bath. After the reaction solution was stirred for 10 minutes, EX145-02 was dissolved in tetrahydrofuran (50 mL) and slowly added to the reaction solution. The reaction system was heated to 75 ° C and stirred for 12 h. After cooling to room temperature, the reaction solution was quenched with saturated ammonium chloride (100 mL) and extracted with ethyl acetate (80 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 5/1) to obtain EX145-03. LCMS: MS m/z (ESI) [M+H]+ = 252.2; ¹ H NMR (400MHz, CDCl3) δ7.52 (d, J = 1.6Hz, 1H), 7.42 (d, J = 2.4Hz, 1H), 6.27 (t, J = 2.0Hz, 1H), 4.35-4.17 (m, 3H), 2.97-2.81 ( m,2H),2.18-2.08(m,2H),1.99-1.88(m,2H),1.48(s,9H).

EX145-03 (700 mg, 2.79 mmol) was dissolved in hydrochloric acid-dioxane (2M, 8 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product EX145-04. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.72-9.10 (m, 2H), 7.75 (d, J = 2.0 Hz, 1H), 7.48 (d, J = 1.2 Hz, 1H), 6.26 (t, J = 2.0 Hz, 1H), 4.59-4.40 (m, 1H), 3.40-3.24 (m, 2H), 3.14-2.91 (m, 2H), 2.25-2.09 (m, 4H).

EX102-05 (400 mg, 0.933 mmol) and EX145-04 (193 mg, 1.03 mmol) were dissolved in NMP (5 mL) and potassium carbonate (387 mg, 2.80 mmol) was added. The reaction mixture was heated to 100°C and stirred for 12 hours. After cooling to room temperature, H ₂ O (20 mL) was added to the reaction solution to precipitate solids, which were filtered, washed with water, and concentrated to obtain EX145-05. LCMS: MS m/z (ESI) [M+H] ⁺ =544.2; ¹ HNMR (400MHz, DMSO-d ₆ ) δ8.35-8.18 (m, 2H), 7.98 (t, J = 8.0Hz, 1H), 7.80 (d, J = 2.0Hz, 1H), 7.44 (s, 1H), 6.37 (s, 1H), 6.24 (d,J＝2.0Hz,1H),4.60-4.47(m,1H),4.00(s,3H),3.34-3.27(m,2H),3.26-3.12(m,2H),2.20-2.08(m,2H),2.02-1.90(m,2H).

EX145-05 (370 mg, 0.681 mmol), 4-N-Boc-4-N-methyl-aminopiperidine (219 mg, 1.02 mmol), cesium carbonate (444 mg, 1.36 mmol) were dissolved in 1,4-dioxane (5 mL) and Pd-Peppsi-IHept-Cl (9.0 mg, 9 μmol) was added. The reaction mixture was heated to 100 ° C under nitrogen protection and stirred for 12 hours. After the reaction solution was cooled to room temperature, it was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure to obtain the crude product The product was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 2/1) to give EX145-06. LCMS: MS m/z (ESI) [M+H] ⁺ = 630.4; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.35-8.21 (m, 2H), 7.91 (t, J = 8.4 Hz, 1H), 7.80 (d, J = 2.4 Hz, 1H), 7.43 (d, J = 1.2 Hz, 1H), 6.31 (s, 1H), 6.23 (t, J = 2.0 Hz, 1H), 4.58-4.46 (m, 1H), 4.07-4.01 (m, 3H), 3.99 (s,3H),3.35-3.25(m,2H),3.23-3.14(m,2H),2.87-2.80(m,2H),2.71(s,3H),2.16-2.08(m,2H),1.96-1.88(m,2H),1.87-1.78(m,2H),1.70-1.58 (m,2H),1.41(s,9H).

To EX145-06 (320 mg, 0.508 mmol) was added hydrochloric acid-dioxane (2 M, 6 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and subjected to preparative HPLC (column: Boston Prime C18 150*30 mm*5 um; mobile phase: [water (formic acid)-acetonitrile]; B%: 12%-52%, 9 minutes) to obtain EX145. LCMS: MS m/z (ESI) [M+H] ⁺ = 530.3; ¹ H NMR (400 MHz, CD ₃ OD)δ8.70-8.46(m,1H),8.30-8.20(m,2H),7.71(d,J＝2.4Hz,1H),7.63(t,J＝8.0Hz,1H),7.50(d,J＝1.6Hz,1H),6.29(t,J＝2.0Hz,1H),6.22(s,1H),4.6 6-4.48(m,3H),4.25-4.13(m,2H),4.04(s,3H),3.27-3.09(m,3H),2.99-2.86(m,2H),2.73(s,3H),2.25-2.14(m,4H),2.14-2.02(m,2H),1.91-1. 73(m,2H).

Embodiment 146

Compound EX146-01 (500 mg, 2.50 mmol) was added to anhydrous toluene (10 mL), stirred under nitrogen atmosphere, and 3-bromo-1-methylpyrazole (442.0 mg, 2.75 mmol), XPHOS (142.8 mg, 0.300 mmol), sodium tert-butoxide (288 mg, 3.00 mmol) and Pd ₂ (dba) ₃ (229 mg, 0.250 mmol) were added. The reaction solution was stirred at 105° C. for 12 hours. The reaction solution was concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silicon dioxide, ethyl acetate/petroleum ether=67/33) to obtain EX146-02. LCMS: MS m/z (ESI) [M+H] ⁺ =281.3; ¹ HNMR (400MHz, DMSO-d ₆ ) δ7.42 (d, J = 2.0Hz, 1H), 5.67 (d, J = 2.4Hz, 1H), 4.22-4.12 (m, 1H), 3.79-3.69 (m, 1H), 3.64 (s, 3H) ,3.58-3.50(m,1H),3.42(d,J＝12.0Hz,1H),3.07(td,J＝12.8,3.2Hz,1H),2.64(dd,J＝12.0,4.0Hz,1H),2.49-2.39(m,1H),1.41(s,9H),1.16(d,J＝6.8Hz ,3H).

EX146-02 (550 mg, 1.961 mmol) was dissolved in hydrochloric acid-dioxane (4 M, 10 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and dried to obtain a yellow solid EX146-03 (330 mg, yield 93.3%). ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.51-8.82(m,2H),7.48(d,J＝2.0Hz,1H),5.75(d,J＝2.4Hz,1H),3.75-3.67(m,1H),3.66(s,3H),3.65-3.56(m,1H),3.35-3.2 4(m,2H),3.11-2.99(m,1H),2.97-2.87(m,1H),2.70(dd,J＝13.2,10.4Hz,1H),1.26(d,J＝6.4Hz,3H).

EX102-05 (650 mg, 0.758 mmol) was dissolved in N-methylpyrrolidone (10 mL), and EX146-03 (200 mg, 1.11 mmol) and potassium carbonate (628.8 mg, 4.55 mmol) were added. The reaction mixture was stirred at 100 °C for 12 hours. The reaction was cooled to room temperature, and water (20 mL) and ethyl acetate (20 mL*3) were added. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/28) to obtain EX146-04. LCMS: MS m/z (ESI) [M+H] ⁺ = 573.4.

EX146-04 (180 mg, 0.314 mmol) was dissolved in anhydrous dioxane (6 mL) and methyl (piperidinium) was added under nitrogen atmosphere. The reaction mixture was stirred at 110°C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (silica, ethyl acetate/petroleum ether = 23/100) to obtain EX146-05. LCMS: MS m/z (ESI) [M+H] ⁺ = 659.5.

EX146-05 (10 mg, 0.015 mmol) was dissolved in hydrochloric acid-dioxane (4 M, 2 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and subjected to preparative HPLC (column: Boston Green ODS150*30 mm*5 um; mobile phase: [water (formic acid)-acetonitrile]; B%: 11%-51%, 9 minutes) to obtain EX146. LCMS: MS m/z (ESI) [M+H] ⁺ = 559.5; ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.37(dd,J＝12.4,2.0Hz,1H),8.29(dd,J＝8.8,2.0Hz,1H),7.96(t,J＝8.0Hz,1H),7.47(d,J＝2.0Hz,1H),6.26(s,1H),5.79(d,J＝2.0Hz,1H),4.79-4.65( m,1H),4.31-4.18(m,1H),4.00(s,3H),3.9 5–3.85(m,2H),3.78-3.71(m,1H),3.67(s,3H),3.65-3.55(m,1H),2.92-2.83(m,3H),2.74-2.65(m,2H),2.35(s,3H),2.34-2.28(m,1H),1.96-1 .88(m,2H),1.50-1.37(m,2H),1.27(d,J＝6.4Hz,3H).

Embodiment 147

Compound EX83-06 (400 mg, 0.969 mmol) was dissolved in N-methylpyrrolidone (10 mL), and (3R, 5R)-5-methylpyrrolidin-3-ol hydrochloride (108 mg, 1.07 mmol) and potassium carbonate (402 mg, 2.91 mmol) were added. The reaction solution was heated to 100 °C and stirred for 12 hours under nitrogen protection. The reaction solution was diluted with water (20 mL) and extracted three times with ethyl acetate (15 mL). The organic phases were combined and washed three times with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 3/1) to obtain the target product EX147-01. LCMS: MS m/z (ESI) [M+H] ⁺ = 478.1.

Compound EX147-01 (390 mg, 0.817 mmol) was dissolved in dioxane (10 mL), and 4-N-Boc-4-N-methyl-aminopiperidine (263 mg, 1.23 mmol), Pd-PEPPSI-IHeptCl (79.5 mg, 0.0820 mmol) and cesium carbonate (799 mg, 2.45 mmol) were added. The reaction solution was heated to 100 ° C under nitrogen protection and stirred for 12 hours. The reaction solution was concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/tetrahydrofuran = 100/0 to 3/1) to obtain EX147-02. LCMS: MS m/z (ESI) [M+H] ⁺ = 564.4.

Compound EX147-02 (90.0 mg, 0.160 mmol) was dissolved in 4M hydrochloric acid 1,4-dioxane solution (1 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and dried by spin drying. The crude product was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; B%: 19%-59%, 9 minutes) to obtain EX147. LCMS: MS m/z (ESI) [M+H] ⁺ = 464.2; ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.51(dd,J＝10.8,1.6Hz,1H),8.50(brs,2H),8.31(dd,J＝8.8,1.6Hz,1H),7.99(t,J＝8.4Hz,1H),6.35(s,1H),5.06(d,J＝4.0Hz,1H),4.52-4.44(m,1H), 4.34-4.23(m,1H),3.77 -3.61(m,3H),3.43-3.35(m,1H),3.23-3.16(m,1H),2.98-2.87(m,2H),2.62(s,3H),2.55(s,3H),2.15-2.05(m,3H),1.93-1.85(m,1H),1.81-1.6 5(m,2H),1.29(d,J＝6.0Hz,3H).

Embodiment 148

Compound EX148-01 (300 mg, 1.39 mmol) was dissolved in HCl/MeOH (3 mL) and the reaction was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure and then dried to give EX148-02. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.50-9.10 (m, 2H), 4.47-4.36 (m, 1H), 3.45-3.33 (m, 1H), 3.05-2.92 (m, 1H), 2.00 (dd, J = 13.6, 6.4 Hz, 1H), 1.72 (dd, J = 13.6, 3.2 Hz, 1H), 1.44 (s, 3H), 1.33 (s, 3H).

Compounds EX148-02 (176 mg, 1.16 mmol) and EX83-05 (400 mg, 0.97 mmol) were dissolved in NMP (5 mL), and K ₂ CO ₃ (402 mg, 2.91 mmol) was then added. The reaction solution was stirred at 100°C for 12 hours. The reaction solution was cooled to room temperature, and water (10 mL) was added to precipitate a solid. The solid was slurried and washed with (petroleum ether/ethyl acetate = 3/1) to obtain EX148-03. LCMS: MS m/z (ESI) [M+H] ⁺ = 492.0.

Compound EX148-03 (90.0 mg, 0.18 mmol) and methyl (piperidin-4-yl) carbamic acid tert-butyl ester (78.5 mg, 0.37 mmol) were dissolved in 1,4-dioxane (1 mL), and then Pd-PEPPSI-IHeptCl (17.8 mg, 0.02 mmol) and Cs2CO3 (179 mg, 0.55 mmol) were added. The reaction solution was heated to 110 ° C and stirred for 12 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with water (5 mL), and extracted with ethyl acetate (5 mL*3). The organic phases were combined, washed with saturated brine (10 mL*2), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 71/29) to obtain EX148-04. LCMS:MS m/z(ESI)[M+H] ⁺ =578.5.

Compound EX148-04 (75.0 mg, 0.13 mmol) was dissolved in HCl/dioxane (1 mL). The reaction was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure and then dried by spin drying. It was then purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 9%-49%, 9 minutes) to obtain EX148. LCMS: MS m/z (ESI) [M+H] ⁺ = 478.3; ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.53(dd,J＝12.8,1.6Hz,1H),8.31(s,1H),8.23(dd,J＝8.8,2.0Hz,1H),8.02-7.94(m,1H),6.32(s,1H),4.44-4.28(m,1H),3.75–3.65(m,1H),3.60- 3.50(m,2H),3 .46-3.35(m,1H),2.92-2.83(m,2H),2.77-2.68(m,1H),2.53(s,3H),2.41(s,3H),2.15-2.07(m,1H),2.04-1.92(m,3H),1.71(s,3H),1.58(s,3H ),1.56-1.50(m,2H).

Embodiment 149

EX83-05 (200 mg, 0.485 mmol) was dissolved in 1-methyl-2-pyrrolidone (8 mL), 5-azaspiro [2.4] heptane-7-ol hydrochloride (60.4 mg, 0.533 mmol) and potassium carbonate (201 mg, 1.45 mmol) were added, and the reaction solution was stirred at 100 ° C for 12 hours. After the reaction was completed, the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (15 mL x 3), and the organic phases were combined, washed with water (10 mL x 3) and saturated brine (10 mL) in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 3/2) to obtain EX149-01. LCMS: MS m/z (ESI) [M+H] ⁺ = 490.0; ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.54-8.36 (m, 1H), 8.30 (d, J = 8.8Hz, 1H), 8.08-7.87 (m, 1H), 6.39 (s, 1H), 5.09 (s, 1H), 3.90-3 .83(m,1H),3.82-3.68(m,2H),3.65-3.40(m,2H),2.65(s,3H),1.00-0.85(m,1H),0.75-0.65(m,3H).

EX149-01 (1.00 g, 2.04 mmol) was dissolved in dioxane (20 mL), and 4-N-Boc-4-N-methylaminopiperidine (876 mg, 4.09 mmol), cesium carbonate (2.00 g, 6.13 mmol) and Pd-PEPPSI-IheptCl (80.9 mg, 0.102 mmol) were added. The reaction solution was heated to 110 ° C and stirred for 12 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain EX149-02. LCMS: MS m/z (ESI) [M+H] ⁺ = 576.5.

EX149-02 (300 mg, 0.521 mmol) was dissolved in 4M hydrochloric acid/dioxane (10 mL), and the reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC (column: Boston Prime C18 150*25mm*5um; Condition: water(FA)-ACN; B%: 23%-43%, 11 minutes) to obtain EX149. LCMS: MS m/z (ESI) [M+H] ⁺ = 476.2; ¹ H NMR (400 MHz, CD ₃ OD)δ8.56(brs,1H),8.51(d,J＝12.8Hz,1H),8.44(d,J＝8.8Hz,1H),7.75(t,J＝8.0Hz,1H),6.29(s,1H),3.98-3.82(m,3H),3.81-3.65(m,3H),3.30-3.1 1(m,2H),3.11-2.96(m,2H),2.76(s,3H),2.63(s,3H),2.28-2.15(m,2H),1.95-1.75(m,2H),1.10-0.95(m,1H),0.87-0.75(m,2H),0.73-0.61(m, 1H).

Embodiment 150

EX149-01 (200 mg, 0.409 mmol) was dissolved in dichloromethane (10 mL), 2,6-dimethylpyridine (438 mg, 4.09 mmol) and TBSOTf (540 mg, 2.04 mmol) were added, and the reaction solution was stirred at 25 ° C for 16 hours. After the reaction was completed, the reaction solution was quenched with water (10 mL), extracted with dichloromethane (10 mL x 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether/dichloromethane = 100/0 to 20/1) to obtain EX149-01a. LCMS: MS m/z (ESI) [M+H] ⁺ = 604.1; ¹ H NMR (400MHz, CDCl ₃ ) δ8.71-8.49 (m, 1H), 8.37 (dd, J = 8.8, 1.6Hz, 1H), 7.68 (dd, J = 8.8, 7.2Hz, 1H), 6.17 (s, 1H), 4.16-4.05 (m,1H),4.00-3.85(m,1H),3.76-3.65(m,1H),3.54-3.43(m,1H),2.73(s,3H),1.02-0.97(m,1H),0.92(s,9H),0.73-0.64(m,3H),0.12(s,6H).

ISME15-410-01a (180 mg, 0.298 mmol) was dissolved in dioxane (8 mL), and EX149-04a (151.7 mg, 0.757 mmol), cesium carbonate (243 mg, 0.746 mmol) and Pd-PEPPSI-HeptCl (11.8 mg, 0.015 mmol) were added. The reaction solution was heated to 110°C and stirred for 12 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 100/0 to 3/2) to obtain yellow solid EX150-05 (160 mg, yield 75.8%). LCMS: MS m/z (ESI) [M+H] ⁺ = 708.2; 1H NMR (400 MHz, CDCl ₃ )δ8.53(d,J＝11.6Hz,1H),8.33(d,J＝8.4Hz,1H),7.61(dd,J＝8.4,7.2Hz,1H),6.08(s,1H),5.10-4.85(m,1H),4.13-4.01(m,1H),3.98-3.84(m,2H),3. 81-3.65(m,2H),3.56-3.40(m,2H), 3.26-3.02(m,2H),2.96(s,3H),2.63(s,3H),2.55-2.41(m,1H),1.86-1.68(m,1H),1.51(s,9H),1.55-1.45(m,1H),0.99-0.95(m,1H),0.90(s,9H) ),0.69-0.62(m,3H),0.13-0.05(m,6H).

EX150-05 (150 mg, 0.212 mmol) was dissolved in 4M hydrochloric acid/dioxane (3 mL), and the reaction solution was stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC (column: Boston Prime C18 150*30mm*5um; Condition: water (FA)- ACN; B%: 17%-57%, 9 minutes) was purified to obtain EX150. LCMS: MS m/z (ESI) [M+H] ⁺ = 494.1

Embodiment 151

EX109-05 (270 mg, 0.550 mmol) was dissolved in dichloromethane (10 mL), and 2,6-dimethylpyridine (589 mg, 5.50 mmol) and TBSOTf (726 mg, 2.75 mmol) were added. The reaction solution was stirred at 25 ° C for 16 hours. After the reaction was completed, the reaction solution was quenched with water (10 mL), extracted with dichloromethane (20 mL x 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether/dichloromethane = 100/0 to 1/1) to obtain EX109-05a. LCMS: MS m/z (ESI) [M+H] ⁺ = 606.0; ¹ H NMR (400 MHz, CDCl ₃ )δ8.49(dd,J＝11.6,2.0Hz,1H),8.33(dd,J＝8.8,2.0Hz,1H),7.66(dd,J＝8.8,7.2Hz,1H),6.46(s,1H),4.84-4.62(m,1H),4.29(d,J＝14.0Hz,1H),4.10(brs, 1H),3.23(dd,J ＝14.0,2.0Hz,1H),2.69(s,3H),2.38-2.19(m,1H),12.00-1.85(m,1H),1.67-1.60(m,1H),1.48-1.39(m,1H),1.27(d,J＝6.8Hz,3H),0.78(s,9H),0 .05(s,3H),0.04(s,3H).

EX109-05a (140 mg, 0.231 mmol) was dissolved in dioxane (10 mL), and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (91.7 mg, 0.462 mmol), cesium carbonate (226 mg, 0.694 mmol) and Pd-PEPPSI-HeptCl (18.3 mg, 0.023 mmol) were added. The reaction solution was heated to 100°C under nitrogen protection and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 1/1) to obtain EX151-01. CMS: MS m/z (ESI) [M+H] ⁺ = 676.4.

EX151-01 (70 mg, 0.104 mmol) was dissolved in tetrahydrofuran (4 mL), and 1 M TBAF (0.4 mL, 0.414 mmol) tetrahydrofuran solution was added, and the reaction solution was stirred at 25 ° C for 2 hours. After the reaction was completed, the reaction solution was quenched with water (10 mL), extracted with ethyl acetate (10 mL x 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by Prep-TLC (silica, petroleum ether/ethyl acetate = 1/1) to obtain EX151-02. LCMS: MS m/z (ESI) [M+H] ⁺ = 562.3; ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.42(dd,J＝12.8,2.0Hz,1H),8.28(dd,J＝8.8,2.0Hz,1H),8.06-7.86(m,1H),6.63(s,1H),4.77-4.69(m,1H),4.64(d,J＝3.6Hz,1H),4.25(s,4H),4.1 7(d,J＝12.4Hz,1H),4.10-4.01(m,4H),3.97-3.90(m,1H),2.45(s,3H),2.19-2.10(m,1H),2.00-1.83(m,2H),1.60-1.52(m,1H),1.39(s,9H),1.1 7(d,J＝6.8Hz,3H).

EX151-02 (30 mg, 0.053 mmol) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (244 mg, 2.14 mmol) was added, and the reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC (column: C18 150×30 mm; mobile phase: [Water(NH ₃ H ₂ O)-MeCN-THF]; B%: 35%-65%, 8 min) to obtain EX151. LCMS:MS m/z(ESI)[M+H] ⁺ =462.1; ¹ H NMR (400MHz, CD ₃ OD) δ8.53-8.43(m,1H),8.43-8.34(m,1H),7.83-7.69(m,1H),6.58(s,1H),4.39-4.30(m,2H),4.28 -4.18(m,2H),4.15 -4.05(m,1H),3.83-3.77(m,2H),3.75 -3.65(m,1H),3.62 -3.52(m,4H),2.54(s,3H),2.34-2.27(m,2H),1.87 -1.80(m,2H),1.27( d,J＝6.8Hz,3H).

Embodiment 152

EX109-05 (400 mg, 0.814 mmol) was dissolved in dioxane (10 mL), and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (369 mg, 1.63 mmol), cesium carbonate (796 mg, 2.44 mmol) and Pd-PEPPSI-HeptCl (32.2 mg, 0.041 mmol) were added. The reaction solution was heated to 100°C under nitrogen protection and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain EX152-01. LCMS: MS m/z (ESI) [M+H] ⁺ = 590.5.

EX152-01 (100 mg, 0.170 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (967 mg, 8.78 mmol) was added. The reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC (column: Boston Prime C18 150*30mm*5um; Condition: water (FA)-ACN; B%: 21%-61%, 9 minutes) to obtain EX152. LCMS: MS m/z (ESI) [M+H] ⁺ = 490.2; ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.44(s,1H),8.41(dd,J＝12.4,1.6Hz,1H),8.29(dd,J＝8.8,1.6Hz,1H),7.98(t,J＝8.0Hz,1H),6.64(s,1H),4.76-4.66(m,1H),4.17(d,J＝13.6Hz,1H), 3.95(brs,1H),3.62(s,4H),3.24-3.02(m,5H),2.53(s,3H),2.24-2.08(m,1H),1.99-1.81(m,5H),1.64-1.51(m,1H),1.46-1.30(m,1H),1.18(d, J＝6.8Hz,3H).

Embodiment 153

Compound EX83-05 (500 mg, 1.21 mmol) and (3R)-tetrahydropyrrol-3-ol (127 mg, 1.45 mmol) were dissolved in NMP (5 mL), and K ₂ CO ₃ (502 mg, 3.64 mmol) was then added. The reaction solution was stirred at 100°C for 12 hours. The reaction solution was cooled to room temperature, and water (10 mL) was added to precipitate a yellow solid. The solid was slurried (petroleum ether/ethyl acetate = 3/1, 10 mL) and then filtered, and the filter cake was concentrated and dried under reduced pressure to obtain EX153-01. LCMS: MS m/z (ESI) [M+H] ⁺ = 464.1.

Under _N2 atmosphere, compound EX153-01 (410 mg, 0.89 mmol) and methyl (piperidin-4-yl) carbamic acid tert-butyl ester (341 mg, 1.59 mmol) were dissolved in 1,4-dioxane (5 mL), and then Pd-PEPPSI-IHeptCl (86.1 mg, 0.09 mmol) and cesium carbonate (865 mg, 2.66 mmol) were added. The reaction solution was stirred at 110 ° C for 12 hours. The reaction solution was cooled to room temperature, diluted with water (5 mL), and extracted with ethyl acetate (5 mL * 3). The organic phases were combined, washed with saturated brine (10 mL * 2), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 77/23) to obtain EX153-02. LCMS:MS m/z(ESI)[M+H] ⁺ =550.1.

Compound EX153-02 (120 mg, 0.22 mmol) was dissolved in 4M HCl/dioxane (2 mL). The reaction was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure and dried by spin drying. The crude product was subjected to preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 16%-46%, 10 minutes) to obtain EX153. LCMS: MS m/z (ESI) [M+H] ⁺ = 450.1; ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.51 (d, J = 12.8Hz, 1H), 8.33 (d, J = 8.4Hz, 2H), 7.96 (t, J = 8.4Hz, 1H), 6.32 (s, 1H), 5.10-4.96 (m ,1H),4.48-4.39(m,1H),3.63-3.51(m,6H),2.93-2.83(m,2H),2.65-2.55(m,1H),2.54(s,3H), 2.36(s,3H),2.13-2.02(m,1H),2.02-1.92(m,3H),1.54-1.42(m,2H).

Embodiment 154

Compound EX83-05 (500 mg, 1.21 mmol) was dissolved in N-methylpyrrolidone (10 mL), and 4,4-dimethylpyrrolidinobutan-3-ol hydrochloride (183.7 mg, 1.21 mmol) and potassium carbonate (502 mg, 3.64 mmol) were added. The reaction solution was heated to 100 ° C and stirred for 12 hours under nitrogen protection. After the reaction was completed, the reaction solution was diluted with water (20 mL) and extracted three times with ethyl acetate (15 mL). The organic phases were combined and washed three times with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The target product EX154-01 was obtained. LCMS: MS m/z (ESI) [M+H] ⁺ = 492.0; ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.49-8.33 (m, 1H), 8.25 (dd, J = 8.8, 2.0Hz, 1H), 7.96 (t, J = 8.0Hz, 1H), 6.37 (s, 1H), 5.35-5.07 (m ,1H),4.00-3.75(m,2H),3.48-3.39(m,1H),3.32–3.20(m,2H),2.62(s,3H),1.07,(s,3H),1.06(s,3H).

Compound EX154-01 (500 mg, 1.02 mmol) was dissolved in dioxane (10 mL), and 4-N-Boc-4-N-methyl-aminopiperidine (218 mg, 1.02 mmol), Pd-PEPPSI-IHeptCl (99.0 mg, 0.102 mmol) and cesium carbonate (995 mg, 3.05 mmol) were added. The reaction solution was heated to 110°C and stirred for 12 hours under nitrogen protection. The target product was detected by LCMS. The reaction solution was concentrated under reduced pressure and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 2/1) to obtain EX154-02. LCMS: MS m/z (ESI) [M+H] ⁺ = 578.4; ¹ H NMR (400MHz, CDCl3) δ8.49(d,J＝12.0Hz,1H),8.36(dd,J＝9.2,2.0Hz,1H),7.65-7.59(m,1H),6.08(s,1H),4.35-4.10(m,1H),4.10-4.01(m,1H),3.99-3.85( m,1H),3.72-3.61(m,2H) ,3.60-3.53(m,1H),3.52-3.44(m,1H),3.43-3.31(m,1H),3.05-2.91(m,2H),2.82(s,3H),2.59(s,3H),2.00-1.85(m,2H),1.83-1.75(m,2H),1. 50(s,9H),1.21(s,3H),1.13(s,3H).

Compound EX154-03 (52.0 mg, 0.0900 mmol) was dissolved in 4M hydrochloric acid 1,4-dioxane solution (2 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and dried by spin drying. The crude product was subjected to preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 13%-53%, 9 minutes) to obtain EX154. LCMS: MS m/z (ESI) [M+H] ⁺ = 478.1; ¹ H NMR (400 MHz, CD ₃ OD)δ8.55(s,1H),8.47(d,J＝12.8Hz,1H),8.38(d,J＝8.8Hz,1H),7.70(t,J＝8.0Hz,1H),6.23(s,1H),4.02-3.95(m,1H),3.95-3.82(m,1H),3.77-3.64 (m,2H),3.58-3.39(m,2H),3.37-3.30(m,1H),3.05-2.90(m,3H),2.62(s,3H),2.60(s,3H),2.21-2.09(m,2H),1.82-1.67(m,2H),1.17(s,3H),1 .12(s,3H).

The following compounds can be synthesized using the above-mentioned synthesis methods and corresponding raw materials.

Embodiment 174

Compound EX83-04 (1.00 g, 3.41 mmol) was dissolved in dichloromethane (30.0 mL), and 4-cyanophenylboronic acid (1.0 g, 6.81 mmol), copper acetate (1.20 g, 6.81 mmol), 4A molecular sieve (2.00 g) and pyridine (0.800 mL, 10.2 mmol) were added. The reaction solution was stirred at room temperature for 48 hours under an oxygen atmosphere. After the reaction solution was cooled to room temperature, the reaction solution was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 10/0 to 10/6) to obtain EX174-01. LCMS: MS m/z (ESI) [M+H] ⁺ = 395.0.

EX174-01 (700 mg, 1.77 mmol) was dissolved in 1-methyl-2-pyrrolidone (10 mL), 4,4-dimethylpyrrolidin-3-ol hydrochloride (269 mg, 1.77 mmol) and potassium carbonate (736 mg, 5.32 mmol) were added, and the reaction solution was stirred at 100°C for 12 hours. After the reaction was completed, the reaction solution was diluted with water (30 mL) to precipitate solids. Filter, and the filter cake was dried under reduced pressure to obtain EX174-02. LCMS: MS m/z (ESI) [M+H] ⁺ = 474.2.

Compound EX174-02 (550 mg, 1.16 mmol) was dissolved in dichloromethane (10.0 mL), and TBSOTf (1.58 g, 5.81 mmol) and 2,6-dimethylpyridine (1.87 g, 17.4 mmol) were added. The reaction solution was stirred at room temperature for 16 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 10/1) to obtain EX174-03. LCMS: MS m/z (ESI) [M+H] ⁺ = 588.2.

EX174-03 (200 mg, 0.340 mmol) was dissolved in 1,4-dioxane (6 mL), and 4-N-Boc-4-N-methyl-aminopiperidine (72.9 mg, 0.340 mmol), cesium carbonate (332.3 mg, 1.020 mmol) and RuPhos Pd G3 (28.5 mg, 0.034 mmol) were added. The reaction solution was heated to 110 ° C and stirred for 12 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (30 mL*3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was subjected to silica gel column chromatography (silica, petroleum ether = 40%) to obtain EX174-04. LCMS: MS m/z (ESI) [M+H] ⁺ = 674.5.

EX174-04 (100 mg, 0.148 mmol) was dissolved in 4M hydrochloric acid/dioxane (4.0 mL), and the reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was analyzed by HPLC (column: Boston Prime C18 150*40 mm; Condition: water (FA)-ACN; EX174 (31.31 mg, yield 45.9%) was obtained by ^purification of ^1H NMR (400 MHz, DMSO-d ₆ )δ8.54(d,J＝8.8Hz,2H),7.91(d,J＝8.8Hz,2H),6.26(s,1H),5.40-4.96(m,1H),3.91-3.84(m,1H),3.84-3.72(m,1H),3.60-3.50(m,2H),3.32-3.20( m,3H),2.93-2.80(m,2H),2.75-2.65(m,1H),2.53(s,3H),2.40(s,3H),2.08-1.91(m,2H),1.65-1.36(m,2H),1.05(s,3H),1.02(s,3H).

Embodiment 175

At 0°C, under _N2 atmosphere, compound EX175-01 (5.00 g, 18.3 mmol) was dissolved in THF (50 mL), and then MeMgBr (9.15 mL, 27.5 mmol) was added. The reaction solution was stirred at 25°C for 2 hours. The reaction solution was quenched with saturated _NH4Cl (50 mL), and extracted with ethyl acetate (50 mL*3). The organic phases were combined, washed with saturated brine (100 mL*2), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 89/11) to obtain EX175-02. LCMS:MS m/z(ESI)[M+H] ⁺ =252.8; ¹ H NMR (400MHz, DMSO-d ₆ )δ8.70-8.50(m,1H),6.01-5.80(m,1H),3.99-3.85(m,1H),3.84-3.61(m,1H),2.77(s,3H),2 .48-2.31(m,1H),2.10-1.67(m,3H),1.66-1.45(m,2H).

Compound EX175-02 (3.3 g, 13.06 mmol) was dissolved in 4M HCl/Dioxane (30 ml). The reaction solution was stirred at 50°C for 4 hours. The reaction solution was concentrated under reduced pressure and dried to obtain the crude product EX175-03. LCMS: MS m/z (ESI) [M+H] ⁺ = 168.7; ¹ H NMR (400 MHz, DMSO-d ₆₎ δ 8.50 (s, 1H), 2.76 (s, 3H).

At 0°C, under _N2 atmosphere, compound EX175-03 (2.10 g, 12.5 mmol) was dissolved in DMF (20 mL), and then NIS (3.23 g, 18.69 mmol) was added. The reaction solution was stirred at 80°C for 12 hours. The reaction solution was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (30 mL*3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was subjected to silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 88/12) to obtain EX175-04. LCMS: MS m/z (ESI) [M+H] ⁺ = 294.6; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.86 (s, 3H).

Compound EX175-04 (2.00 g, 6.79 mmol) and 4-cyano-3-fluorophenylboronic acid (1.34 g, 8.15 mmol) were dissolved in DCM (20 mL), and then Cu(OAc) ₂ (2.47 g, 13.6 mmol), pyridine (1.61 g, 20.4 mmol), and molecular sieves (2.00 g, 6.79 mmol) were added. The reaction solution was stirred at room temperature for 48 hours under an oxygen atmosphere. The insoluble solids in the reaction solution were removed by filtration through a pad of diatomaceous earth, and the solution was concentrated and dried. The crude product was subjected to silica gel column chromatography (silicon dioxide, petroleum ether/tetrahydrofuran = 100/0 to 88/12) to obtain EX175-05 (980 mg, yield 34.9%). ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.25-8.14 (m, 3H), 2.96 (s, 3H).

Compound EX175-05 (820 mg, 1.98 mmol) and 5-azaspiro[2.4]heptane-7-ol hydrochloride (311 mg, 2.08 mmol) were dissolved in NMP (8 mL), and then K ₂ CO ₃ (822 mg, 5.95 mmol) was added. The reaction solution was stirred at 100°C for 12 hours. The reaction solution was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with water (10 mL*2) and saturated brine (10 mL) in turn, dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 85/15) to obtain EX175-06 (970 mg, yield 100%). LCMS: MS m/z (ESI) [M+H] ⁺ = 490.9.

Compound EX175-06 (900 mg, 1.84 mmol) was dissolved in DCM (10 mL), and then 2,6-dimethylpyridine (0.54 ml, 4.59 mmol) and TBSOTf (776 mg, 2.94 mmol) were added. The reaction solution was stirred at room temperature for 16 hours. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with water (10 mL*2) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 96/4) to obtain EX175-07. LCMS: MS m/z (ESI) [M+H] ⁺ = 605.0.

Under _N2 atmosphere, compound EX175-07 (780 mg, 1.29 mmol) and methyl (piperidin-4-yl) carbamic acid tert-butyl ester (553 mg, 2.58 mmol) were dissolved in dioxane (8 mL), and then Pd-PEPPSI-IHeptCl (126 mg, 0.13 mmol) _{and Cs2CO3 (} 1.26 g, 3.87 mmol) were added. The reaction solution was stirred at 110°C for 12 hours. The reaction solution was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated brine (10 mL*2), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 89/11) to obtain EX175-08 (630 mg, yield 70.7%). LCMS:MS m/z(ESI)[M+H] ⁺ =691.3.

Compound EX175-08 (200 mg, 0.29 mmol) was dissolved in 2M HCl/dioxane (2 mL). The reaction was stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure and then spun dry. The crude product was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water(FA)-ACN]; B%: 15%-45%, 9 minutes) to obtain EX175 (20.7 mg, yield 15.0%). LCMS: MS m/z (ESI) [M+H] ⁺ = 477.2; ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.37(s,1H),8.29-8.06(m,2H),7.98-7.78(m,1H),4.00-3.80(m,3H),3.55-3.46(m,2H),3.45-3.25(m,2H),3.06-2.94(m,1H),2.93-2.80(m,2 H),2.55(d,J=9.6Hz,3H),2.50(s,3H),2.20-1.98(m,2H),1.76-1.55(m,2H),0.96–0.81(m,1H),0.75-0.50(m,3H).

The following compounds can be synthesized using the above-mentioned synthesis methods and corresponding raw materials.

Embodiment 186

Under nitrogen atmosphere, t-BuOK (11.8 g, 105 mmol) was added in batches to methoxymethyl triphenylphosphine chloride (36.2 g, 105 mmol) in THF (250 mL) under stirring. After stirring for one hour, a solution of EX186-01 (15 g, 70.3 mmol) in THF (100 mL) was slowly added to the reaction solution. During this period, the temperature of the reaction system was kept at no more than 10 ° C. The reaction mixture was stirred at 25 ° C for 12 hours under nitrogen atmosphere. The reaction was quenched with water (150 mL) and extracted with ethyl acetate (200 mL × 3). The organic phases were combined and washed with saturated brine (300 mL). The product was washed, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product which was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 9/1) to obtain EX186-02. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.08-5.69 (m, 1H), 4.54-4.34 (m, 1H), 4.11-3.86 (m, 1H), 3.57, 3.55 (2s, 3H), 2.90-2.75 (m, 1H), 2.68-2.47 (m, 1H), 2.34-1.91 (m, 2H), 1.89-1.73 (m, 1H), 1.46 (s, 9H), 1.06 (d, J = 6.8 Hz, 3H).

To EX186-02 (7.25 g, 30.0 mmol) was added hydrochloric acid-dioxane (2 M, 100 mL) dropwise and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product EX186-03 which was used directly in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.68-9.54 (m, 1H), 9.52-8.98 (m, 2H), 3.32-3.16 (m, 1H), 3.14-2.96 (m, 1H), 2.94-2.76 (m, 1H), 2.72-2.60 (m, 1H), 2.15-1.95 (m, 2H), 1.82-1.68 (m, 1H), 1.62-1.49 (m, 1H), 1.30-1.24 (m, 3H).

After EX186-04 (3.6 g, 28.3 mmol) was dissolved in anhydrous dichloromethane (60 mL), DIPEA (14.8 ml, 85 mmol) was slowly added under ice bath, and then CbzCl (4.85 ml, 34.0 mmol) was added. The reaction mixture was stirred at 25 ° C for 12 h, water (100 mL) was added, and it was extracted with dichloromethane (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product which was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 4/1) to obtain EX186-04 (1.8 g, yield 24.34%). LCMS: MS m/z (ESI) [M+H] ⁺ =262.1; ¹ H NMR (400MHz, CDCl ₃ ) δ = 9.86-9.61 (m, 1H), 7.40-7.31 (m, 5H), 5.14 (s, 2H), 4.75-4.60 (m, 1H), 4.27-4.11 (m, 1H), 3.05 -2.91(m,1H),2.66-2.55(m,1H),2.00-1.88(m,1H),1.85-1.76(m,1H),1.70-1.59(m,1H),1.49-1.37(m,1H),1.23-1.05(m,3H).

Compound EX186-04 (1.8 g, 6.89 mmol) was dissolved in MeOH (30 mL), and then ammonia water (7.24 g, 62.0 mmol) was added, followed by glyoxal (4.00 g, 27.6 mmol). The reaction mixture was stirred at 25 °C for 4 hours. Saturated brine (50 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (40 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 1/1) to obtain EX186-05 (1.82 g, yield 88%). LCMS: MS m/z (ESI) [M+H] ⁺ =300.2; ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.74 (brs, 1H), 7.48-7.28 (m, 5H), 6.86 (s, 2H), 5.18-5.00 (m, 2H), 4.53-4.40 (m, 1H), 4.04- 3.93(m,1H),3.15-2.89(m,2H),1.99-1.92(m,1H),1.92-1.83(m,2H),1.80-1.71(m,1H),1.19(d,J＝7.2Hz,3H).

EX186-05 (1.82 g, 6.08 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), and sodium hydrogen (0.365 g, 9.12 mmol) was slowly added in an ice bath. After the reaction solution was stirred for 10 minutes, SEMCl (1.62 mL, 9.12 mmol) was added, and the reaction mixture was stirred at 25 ° C for 12 h. The reaction was quenched with saturated ammonium chloride solution (10 mL), concentrated under reduced pressure to remove tetrahydrofuran, and water (50 mL) was added and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 3/1) to obtain EX186-06. LCMS:MS m/z(ESI)[M+H] ⁺ =430.3; ¹ H NMR (400MHz, DMSO-d ₆ )δ＝7.41-7.31(m,5H),7.15(d,J＝1.2Hz,1H),6.77(d,J＝1.2Hz,1H),5.37-5.27(m,2H),5.11-5.06(m,2H),4.49-4.41(m,1H),4.02–3.91(m,1H),3.4 7(t,J＝8.0Hz,2H),3.27-3.14(m,1H),3.13-2.94(m,1H),1.85-1.75(m,2H),1.71-1.49(m,2H),1.20(d,J＝7.2Hz,3H),0.84(t,J＝8.0Hz,2H),-0.04( s,9H).

Pd/C (0.594 g, 0.559 mmol) was added to a solution of EX186-06 (2.4 g, 5.59 mmol) in methanol (30 mL). The reaction mixture was stirred at 25 °C for 16 h in a hydrogen atmosphere (20 psi). After the reaction was complete, the mixture was filtered through celite and the filtrate was concentrated under reduced pressure to obtain the crude product EX186-07 which was used directly in the next step without further purification. LCMS: MS m/z (ESI) [M+H] ⁺ = 296.2.

EX186-07 (1 g, 2.13 mmol) and EX88-06 (0.753 g, 2.55 mmol) were dissolved in NMP (15 mL) and potassium carbonate (0.881 g, 6.37 mmol) was added. The reaction mixture was heated to 110°C under nitrogen protection and stirred for 12 hours. After the reaction solution was cooled to room temperature, H ₂ O (100 mL) was added and stirred for 10 minutes, filtered, and the filter cake was washed with water and concentrated under reduced pressure to obtain EX186-08. LCMS: MS m/z (ESI) [M+H] ⁺ = 730.3.

EX186-08 (1.3 g, 1.78 mmol), 4-N-Boc-4-N-methyl-aminopiperidine (0.573 g, 2.67 mmol), cesium carbonate (1.16 g, 3.56 mmol) were dissolved in 1,4-dioxane (20 mL) and Pd-PEPPSI-IheptCl (0.173 g, 0.178 mmol) was added. The reaction mixture was heated to 110°C under nitrogen protection and stirred for 16 hours. After the reaction solution was cooled to room temperature, it was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain EX186-09. LCMS: MS m/z (ESI) [M+H] ⁺ = 816.5.

EX189-09 (370 mg, 0.453 mmol) was dissolved in tetrahydrofuran (5 mL), and LiBHEt3 (1.36 mL, 1.36 mmol) was added at -78 ° C in a nitrogen atmosphere and stirred for 1 hour. Saturated ammonium chloride solution (5 mL) was added to the reaction system in an ice bath for quenching. After removing tetrahydrofuran by vacuum concentration, water (5 mL) was added for dilution and extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 2/1) to obtain EX186-10. LCMS: MS m/z (ESI) [M+H] ⁺ = 774.5.

To EX186-10 (200 mg, 0.258 mmol) was added hydrochloric acid-dioxane (2M, 5 mL) and stirred at 60°C for 12 hours. The reaction solution was concentrated under reduced pressure and purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 8%-38%, 9 minutes) to obtain EX186. LCMS: MS m/z (ESI) [M+H] ⁺ =544.4; ¹ H NMR (400MHz, CD ₃ OD) δ = 8.50-8.37 (m, 4H), 7.79 (dd, J = 8.8, 7.6Hz, 1H), 7.07 (s, 2H), 6.97 (s, 1H), 4.95 (s, 2H), 4.62-4. 41(m,1H),3.82-3.70(m,2H),3.50-3.32(m,4H),3.04(t,J＝12.0Hz,2H),2.77(s,3H),2.30-2.16(m,3H),2.12-2.04(m,2H),1.97-1.79(m,3H),1.39 (d,J＝7.2Hz,3H).

Embodiment 191

EX83-04 (500 mg, 1.70 mmol) was dissolved in DMF (10 ml), 2-chloro-4-fluorobenzonitrile (398 mg, 2.56 mmol) and potassium carbonate (706 mg, 5.11 mmol) were added, and the mixture was stirred at 100°C for 2 hours. After the reaction, the reaction solution was diluted with water (20 mL), a large amount of solid precipitated, filtered, the filter cake was washed with water (5 mL*3), concentrated under reduced pressure and dried to obtain EX191-01. LCMS: MS m/z (ESI) [M+H] ⁺ = 428.9; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.40 (s, 1H), 8.29 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.37 (s, 1H), 2.78 (s, 3H).

EX191-01 (600 mg, 1.40 mmol) was dissolved in NMP (10 ml), and EX154-05 (212 mg, 1.40 mmol) and potassium carbonate (580 mg, 4.20 mmol) were added, and the mixture was stirred at 100°C for 2 hours. After the reaction, the reaction solution was diluted with water (20 mL), and a large amount of solid precipitated, which was filtered, and the filter cake was washed with water (5 mL*3), concentrated under reduced pressure and dried to obtain EX191-02. LCMS: MS m/z (ESI) [M+H] ⁺ =507.8; ¹ HNMR (400MHz, DMSO-d ₆ ) δ8.84-8.67 (m, 1H), 8.44 (d, J = 9.6Hz, 1H), 8.07 (d, J = 8.8Hz, 1H), 6.43 (s, 1H), 5.26-5.15 (m, 1H) ,4.13-4.07(m,1H),3.94-3.78(m,2H),3.58-3.47(m,2H),2.65(s,3H),1.06(s,3H),1.03(s,3H).

EX191-02 (200 mg, 0.39 mmol) was dissolved in dichloromethane (10 mL), 2,6-dimethylpyridine (0.46 ml, 3.94 mmol) and TBSOTf (521 mg, 1.97 mmol) were added, and the reaction solution was stirred at 25 ° C for 12 hours. After the reaction was completed, the reaction solution was quenched with water (10 mL), extracted with dichloromethane (10 mL x 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether/dichloromethane = 100/0 to 7/3) to obtain EX191-03. LCMS: MS m/z (ESI) [M+H] ⁺ = 622.0; ¹ HNMR (400MHz, CDCl ₃ ) δ8.89 (s, 1H), 8.45 (d, J = 7.6Hz, 1H), 7.71 (d, J = 8.8Hz, 1H), 6.14 (s, 1H), 4.04-3.94 (m, 1H), 3.91 -3.66(m,1H),3.53-3.24(m,3H),2.70(s,3H),1.10(d,J＝4.0Hz,6H),0.91(s,9H),0.12 (s,6H).

EX191-03 (130 mg, 0.21 mmol) was dissolved in dioxane (10 mL), and (3S, 4R)-3-fluoropiperidin-4-ylcarbamic acid tert-butyl ester (45.6 mg, 0.209 mmol), cesium carbonate (170 mg, 0.52 mmol) and Pd-PEPPSI-HeptCl (10.16 mg, 10.45 μmol) were added. The reaction solution was heated to 100 ° C and stirred for 12 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether/ethyl acetate = 100/0 to 4/1) to obtain EX191-04. LCMS: MS m/z (ESI) [M+H] ⁺ = 712.3.

EX191-04 (30 mg, 0.042 mmol) was dissolved in 4M hydrochloric acid/dioxane (5 mL), and the reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water(FA)-ACN]; B%: 33%-53%, 11 min) to obtain EX191. LCMS: MS m/z (ESI) [M+H] ⁺ = 498.1; ¹ H NMR (400MHz, CD ₃ OD) δ 8.83 (s, 1H), 8.65-8.50 (m, 2H), 7.82 (d, J = 8.8Hz, 1H), 6.28 (s, 1H), 5.05-4.90 (m, 1H), 4.06-3. 87(m,3H),3.80-3.68(m,1H),3.61-3.37(m,4H),3.24-3.13(m,1H),3.12 -2.95(m,1H),2.65(s,3H),2.34-2.11(m,1H),2.07-1.86(m,1H),1.19(s, 3H),1.14(s,3H).

The following compounds can be synthesized using the above-mentioned synthesis methods and corresponding raw materials.

Embodiment 192

Under _N2 atmosphere, compound EX175-08 (70.0 mg, 0.10 mmol) was dissolved in dioxane (1 mL), and then _SeO2 (16.9 mg, 0.15 mmol) was added. The reaction solution was stirred at 100°C for 20 hours. The reaction solution was filtered to remove SeO2, and the solution was concentrated and dried to directly obtain EX192-01 (50.0 mg, yield 70.0%). LCMS: MS m/z (ESI) [M+H] ⁺ = 705.4.

At 0°C and _N2 atmosphere, compound EX192-01 (50.0 mg, 0.07 mmol) was dissolved in MeOH (1 mL) and THF (0.05 mL), and then _NaBH4 (4.03 mg, 0.11 mmol) was added. The reaction solution was stirred at 25°C for 15 min. The reaction solution was quenched by adding saturated _NH4Cl (5 mL), and then extracted with ethyl acetate (5 mL*3). The organic phases were combined, washed with saturated brine (5 mL*2), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The crude product was purified by silica gel column chromatography (silica, petroleum ether/tetrahydrofuran = 100/0 to 56/44) to obtain EX192-02 (50.0 mg, yield 100%). LCMS: MS m/z (ESI) [M+H] ⁺ = 707.6.

Compound EX192-02 (300 mg, 0.47 mmol) was dissolved in HCl/dioxane (3 mL). The reaction was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure, dried by spin drying, and purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 15%-45%, 8 minutes) to obtain EX192. LCMS: MS m/z (ESI) [M+H] ⁺ = 493.1; ¹ HNMR (400 MHz, DMSO-d ₆ )δ8.39-8.20(m,2H),8.10-7.90(m,1H),5.40-4.95(m,1H),4.72-4.60(m,1H),3.95-3.74(m,3H),3.70-3.60(m,1H),3.54-3.36(m,4H),3.15-3.0 0(m,1H),2.98-2.83(m,1H),2.40(s,3H),2.05-1.85(m,2H),1.60-1.37(m,2H),0.95-0.80(m,1H),0.75-0.50(m,3H).

The following compounds can be synthesized using the above-mentioned synthesis methods and corresponding raw materials.

Determination of biological activity

LSD1 enzymology experiments

The compound was prepared into a 100-fold highest final concentration solution and then transferred to a 384-well reaction plate. Both the negative control and positive control wells were transferred to 100% DMSO. The 1-fold reaction buffer contained 50mM Tris-HCl (pH 7.5), 0.005% Tween-20, 1mM DTT, and 0.005% BSA. LSD1 was added to the 1-fold reaction buffer to form a 2-fold enzyme solution (the final concentration of LSD1 was 0.5nM). The biotin-labeled peptide H3K4me2 was added to the 1-fold reaction buffer to form a 2-fold substrate solution (the final concentration of the peptide was 100nM). The 2-fold enzyme solution was added to the wells of the 384-well reaction plate. For the negative control wells, the enzyme solution was replaced with 1-fold reaction buffer. Centrifuge at 1000rpm for 1 minute and incubate at room temperature for 15 minutes. Add 2-fold substrate solution to each well of the 384-well reaction plate. Centrifuge at 1000rpm for 1 minute. React at room temperature for 40 minutes. Prepare 1x reaction termination buffer and add AlphaLISA Anti-unmodified Histone H3 Lysine 4(H3K4)Acceptor Beads, Alpha Donor beads were added to 1x reaction detection buffer to form 25/15x reaction detection solution. 25/15x reaction detection solution was added to each well of the 384-well reaction plate and centrifuged at 1000 rpm for 1 minute. Incubated at room temperature for 60 minutes and the fluorescence signal value was read using an ELISA reader (EX680/Em615).

Enzyme activity range: A≤5nM; 50nM>B>5nM; 1000nM>C≥50nM.

MV-4-11 and NCI-H1417 cell proliferation assay

Take MV-4-11 (ATCC, #CRL-9591) and NCI-H1417 (ATCC, #CRL-5869) cells in the logarithmic growth phase, digest and count, and then spread them into 384-well cell culture plates (Corning, #3764), with 125 cells per well of MV-4-11 and 2000 cells per well of NCI-H1417. The cell culture plates containing cells were cultured overnight in a cell culture incubator at 37°C and 5% _CO2 , and then 3-fold gradient dilutions of the test compound were added (maximum concentration of 10μM). MV4-11 cells containing the compound were cultured for another 7 days, and NCI-H1417 cells were cultured for another 10 days, and then an equal volume of CellTiter-Glo reagent (Promega, #7573) was added. After incubation at room temperature for 30 minutes, the chemiluminescence value was read using Envision 2105 (PerkinElmer). The cell proliferation inhibition rate (%) of the wells treated with each concentration of the compound was calculated, and then the IC ₅₀ of each compound to be tested was obtained by plotting the compound concentration as the abscissa and the cell proliferation inhibition rate (%) as the ordinate using Graphpad software.

Results of MV-4-11 and NCI-H1417 cell proliferation assay

Cell proliferation activity range: A≤50nM; 100nM>B>50nM;2000nM>C≥100nM. ND: Not detected.

Claims (10)

The compound according to claim 1, its pharmaceutically acceptable salt, its isomer or its isotope-labeled substance, characterized in that the compound is represented by Formula I,
Choose one of T, V, and W to be N, and the others to be C; U, X, Y, and Z are each independently N or CR ² ; The two rings indicated by the dashed lines are fused bicyclic aromatic rings; R ¹ is hydrogen, halogen, hydroxyl, cyano, C _2-6 alkynyl, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, -NR ⁵ R ⁶ ; n is 0, 1, 2 or 3; R ² is hydrogen, halogen, hydroxy, cyano, C _1-6 alkyl optionally substituted by hydroxy or halogen, C _1-6 alkoxy optionally substituted by halogen, C _2-6 alkynyl, -S(O) ₂ C _1-6 alkyl, -C(O)-C _1-6 alkyl, -NR ⁵ R ⁶ , -NHCOC _1-6 alkyl, -NHCOOC _1-6 alkyl; L is a bond, O, S, -NH-, -CO-, or -CH ₂ O-; Ring A is C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _3-10 cycloalkenyl, 3-10 membered heterocyclyl and 5-6 membered heteroaryl, C _6-10 aryl and C 3-10 cycloalkyl, C _6-10 aryl and 3-10 membered heterocyclyl, C _6-10 aryl and C _3-10 cycloalkenyl, 5-10 membered heteroaryl and C _3-10 cycloalkyl, _5-10 membered heteroaryl and 3-10 membered heterocyclyl, 5-10 membered heteroaryl and C _3-10 cycloalkenyl, the heteroaryl is optionally oxoed, and Ring A is optionally substituted with 0 to 4 ^Ra ; R ^a is selected from halogen, -CN, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, C _6-10 aryl substituted C _1-6 alkoxy, -OC _3-10 cycloalkyl, C _3-10 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -NR ⁵ R ⁶ , -NHCOC _1-6 alkyl, -NHCOOC _1-6 alkyl, -SO ₂ C _1-6 alkyl, -SO ₂ NR ⁵ R ⁶ , wherein the alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl is optionally substituted with halogen, _hydroxy , acetylene or cyano; When two ^Ra are on the same atom, the two ^Ra can be linked together to form =O, or =C(Raa) ₂ ; or when two ^Ras are on the same atom, the two ^Ras may be linked together to form a _C3-12 cycloalkyl or a 3-12 membered heterocyclyl, wherein the _C3-12 cycloalkyl or the 3-12 membered heterocyclyl is optionally substituted by 1, 2, 3 or 4 ^Ras ; or when two ^Ras are on different atoms, the two ^Ras may be linked together to form a _C3-12 cycloalkyl, a 3-12 membered heterocyclyl, a 5-12 membered heteroaryl or a _{C6-12 aryl} group, wherein the _C3-12 cycloalkyl, the 3-12 membered heterocyclyl, the 5-12 membered heteroaryl or the _C6-12 aryl group is optionally substituted by 1, 2, 3 or 4 ^Ras ; ^Raa is selected from halogen, -CN, hydroxy, _C1-6 alkyl, halogen-substituted _C1-6 alkyl, _C1-6 alkoxy, halogen-substituted _C1-6 alkoxy, _C6-10 aryl-substituted _C1-6 alkoxy, _-OC3-10 cycloalkyl, _C3-10 cycloalkyl, _C2-6 alkenyl, _C2-6 alkynyl; Ring B is C _6-10 aryl, C _5-10 heteroaryl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, or C3-10 cycloalkenyl, which may be substituted by 0 to 4 R ^b ; When L is -CO-, Ring B is a 3- to 10-membered heterocyclyl group, optionally substituted by 0 to 4 R ^b ; R ^b is selected from halogen, -CN, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy substituted by C _6-10 aryl, -OC _3-10 cycloalkyl, C _3-10 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -NR ⁵ R ⁶ , -NHCOC _1-6 alkyl, -NHCOOC _1-6 alkyl, wherein the alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl is optionally substituted by halogen, acetylene or cyano; When two R ^b are on the same atom, the two R ^b can be linked together to form =0, or =C(R _bb ) ₂ ; or when two R ^b are on the same atom, the two R ^b may be linked together to form a C _3-12 cycloalkyl or a 3-12 membered heterocyclyl, wherein the C _3-12 cycloalkyl or the 3-12 membered heterocyclyl is optionally substituted by 1, 2, 3 or 4 R ^bb ; or when two R ^b are on different atoms, the two R ^b may be linked together to _form a C _3-12 cycloalkyl, a 3-12 membered heterocyclyl, a 5-12 membered heteroaryl or a C _6-12 aryl, wherein the C _3-12 cycloalkyl, the 3-12 membered heterocyclyl, the 5-12 membered heteroaryl or the C _6-12 aryl is optionally substituted by 1, 2, 3 or 4 R ^bb ; R ^bb is selected from halogen, -CN, hydroxy, C _1-6 alkyl, halogen-substituted C _1-6 alkyl, C _1-6 alkoxy, halogen-substituted C _1-6 alkoxy, C _6-10 aryl-substituted C _1-6 alkoxy, -OC _3-10 cycloalkyl, C _3-10 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl; and R ⁵ and R ⁶ are each independently selected from hydrogen, C _1-6 alkyl optionally substituted by -OH, halogen, and 3-5 membered oxygen-containing heterocyclic group. The compound according to claim 1, its pharmaceutically acceptable salt, its isomer or its isotope-labeled substance, characterized in that the compound is represented by Formula II or Formula III,
In Formula II, X, Y and Z are all selected from CR ⁷ ; One of X, Y and Z is selected from N, and the others are selected from CR ⁸ ; or X and Y are both selected from N, and Z is selected from CR ⁹ ; In formula III, One of W and V is selected from N, and the other is selected from CH; In Formula II or Formula III, R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ are independently selected from hydrogen, halogen, _hydroxyl , cyano, C _2-6 alkynyl, C _1-6 alkyl optionally substituted by hydroxyl or halogen, C _1-6 alkoxy optionally substituted by halogen, -NR ⁵ R ⁶ , -CONR ⁵ R ⁶ , COR ⁵ , C(O)OR ⁵ , -SO ₂ NR ⁵ R ⁶ ; R ¹ is selected from hydrogen, halogen, hydroxyl, cyano, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, -NR ⁵ R ⁶ ; n = 0 or 1; L is selected from a bond, -CO-; Ring A is C _6-10 aryl, 5-10 membered heteroaryl optionally substituted with oxo, C _3-6 cycloalkyl, 3-10 membered heterocyclyl, C _3-6 cycloalkenyl, 3-10 membered heterocyclyl and 5-6 membered heteroaryl, C _6-10 aryl and C _3-6 cycloalkyl, C ₆ aryl and 3-6 membered heterocyclyl, C ₆ aryl and C _3-6 cycloalkenyl, 5-6 membered heteroaryl and C _3-6 cycloalkyl, 5-6 membered heteroaryl and 3-6 membered heterocyclyl, 5-6 membered heteroaryl and C _3-6 cycloalkenyl, the heteroaryl is optionally substituted with oxo, and Ring A is optionally substituted with 0 to 2 ^Ra ; R ^a is selected from halogen, -CN, hydroxyl, C _1-6 alkyl optionally substituted by a substituent selected from -OH and halogen, C _1-6 alkoxy, C _1-6 alkoxy substituted by C _6-10 aryl, -OC _3-10 cycloalkyl, C _3-10 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -NR ⁵ R ⁶ , -NHCOC _1-6 alkyl, -NHCOOC _1-6 alkyl, -SO ₂ C _1-6 alkyl, -SO ₂ NR ⁵ R ⁶ , 5-6 membered heteroaryl optionally substituted by a substituent selected from -CN, -CHF ₂ and -CF ₃ , the heteroatom of the 5-6 membered heteroaryl is selected from nitrogen and oxygen atoms, and the alkyl, alkoxy, cycloalkyl, alkenyl and alkynyl are optionally substituted by halogen, hydroxyl, acetylene or cyano; Ring B is C _6-10 aryl, C _5-6 heteroaryl, C3-6 cycloalkyl, 3- to 6-membered heterocyclic group, C3-6 cycloalkenyl, wherein the heteroaryl or heterocyclic group contains N heteroatom; the above groups are optionally substituted by 0 to 4 R ^b ; R ^b is selected from halogen, -CN, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, -OC _3-6 cycloalkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -NR ⁵ R ⁶ , wherein the alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl is optionally substituted with halogen, acetylene or cyano; and R ⁵ and R ⁶ are each independently selected from hydrogen, C _1-6 alkyl or C _1-6 alkoxy. The compound, pharmaceutically acceptable salt, isomer or isotope-labeled substance thereof according to claim 2, characterized in that, in Formula II, X is selected from N, and Z and Y are both selected from CR ⁸ . The compound according to claim 2 or 3, its pharmaceutically acceptable salt, its isomer or its isotope-labeled substance, characterized in that in the formula II or III, R ¹ is selected from halogen, cyano, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy; n＝1 L is selected from a bond, -CO-; Ring A is selected from C _6-10 aryl, C _3-10 cycloalkenyl, C _3-10 cycloalkyl, 5-10 membered heteroaryl optionally substituted with oxo, 3-10 membered heterocyclyl, 3-10 membered heterocyclyl and 5-6 membered heteroaryl, wherein the heteroaryl and heterocyclyl contain N heteroatom and optionally O heteroatom; ^Ra is selected from halogen, _C1-6 alkyl optionally substituted by halogen, acetylene, cyano, hydroxy, _C1-6 alkoxy, _-NHCOC1-6 alkyl, _-NHCOOC1-6 alkyl, Ring B is selected from a 5-10 membered heterocyclic group, wherein the heterocyclic group contains a N heteroatom; R ^b is selected from amino, -NR ⁵ R ⁶ , halogen, hydroxyl, C _1-6 alkoxy; R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ are each independently selected from hydrogen, halogen, hydroxy, cyano, C _2-6 alkynyl, C _1-6 alkyl optionally substituted by hydroxy or halogen, C _1-6 alkoxy optionally substituted by halogen, -NR ⁵ R ⁶ , -CONR ⁵ R ⁶ , COR ⁵ , C(O)OR ⁵ , -SO ₂ NR ⁵ R ⁶ ; and R ⁵ and R ⁶ are independently selected from hydrogen, C _1-6 alkyl or C _1-6 alkoxy. The compound according to any one of claims 2 to 4, its pharmaceutically acceptable salt, its isomer or its isotope-labeled substance, characterized in that in the formula II or III, ^R1 is selected from halogen; n = 1; L is selected from a bond, -CO-; Ring A is selected from _C6-10 aryl, _C3-6 cycloalkenyl, C3-6 cycloalkyl, _5-10 membered heteroaryl, 3-10 membered heterocyclyl, 3-10 membered heterocyclyl and 5-6 membered heteroaryl, wherein the heteroaryl and heterocyclyl contain N heteroatom and optional O heteroatom, wherein the N heteroatom is connected to the fused bicyclic aromatic ring of formula I, formula II or formula III; R ^a is selected from halogen, C _1-6 alkyl optionally substituted by halogen, acetylene, hydroxyl, C _1-6 alkoxy, -NHCOC _1-6 alkyl, -NHCOOC _1-6 alkyl; Ring B is selected from a 5-10 membered heterocyclic group containing a N heteroatom, and the N heteroatom is connected to a fused bicyclic aromatic ring in Formula I, Formula II or Formula III; R ^b is selected from amino, halogen, C _1-6 alkoxy; and R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently selected from hydrogen, halogen, cyano and C _1-6 alkyl. The compound according to claim 1, its pharmaceutically acceptable salt, its isomer or its isotope-labeled substance, characterized in that the compound is selected from the following compounds:














A pharmaceutical composition, characterized in that it comprises a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable Salts, isomers or isotope-labeled substances thereof, and pharmaceutically acceptable carriers. Use of the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, an isomer thereof or an isotope-labeled substance thereof in the preparation of a medicament for treating a disease mediated by LSD1. Use of the compound according to any one of claims 1 to 6 or its pharmaceutically acceptable salt, its isomer or its isotope-labeled substance in the preparation of a drug for treating tumors. The use according to claim 9, characterized in that the tumor is selected from neuroblastoma, breast cancer, hematological tumor, small cell lung cancer and Ewing's sarcoma.