TW202604902A - Compound as voltage-gated sodium channel inhibitor and application thereof - Google Patents

Abstract

The present application relates to selective inhibitor of the voltage-gated sodium channel NaV1.8 and the use in the preparation of relevant pharmaceutical composition. The described pharmaceutical is intended for the treatment of diseases responsive to inhibition of the voltage-gated sodium channel NaV1.8, such as chronic pain, visceral pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, internal organ pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, pathological cough, or cardiac arrhythmias. Specifically, the application pertains to compound represented by Formula (X), as well as the isomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug.

Description

Compounds as voltage gate sodium channel inhibitors and their applications

This application relates to the field of chemical pharmaceutical technology, and specifically to a compound and its application as a voltage-gated sodium channel inhibitor.

Pain plays an indispensable protective role in the body's normal life activities. As a warning signal, it reminds the body to pay attention to potential dangers. However, pain is also a common clinical symptom. After the external stimulus that caused the pain disappears, severe or persistent pain can cause physiological dysfunction and seriously affect the quality of life of living organisms.

Pain originates from nociceptors in the peripheral nervous system, which are free nerve endings widely distributed throughout the skin, muscles, joints, and internal organs. These receptors convert perceived thermal, mechanical, or chemical stimuli into nerve impulses (action potentials), which are then transmitted via afferent nerve fibers to the cell bodies of the dorsal root ganglia (DRGs), ultimately reaching higher nerve centers and causing the sensation of pain. The generation and conduction of action potentials in neurons depend on voltage-gated sodium ion channels (NaVs) on the cell membrane. When the cell membrane depolarizes, sodium ion channels activate, opening and causing an influx of sodium ions, further depolarizing the cell membrane and generating action potentials. Therefore, inhibiting abnormal sodium ion channel activity can help treat and relieve pain.

NaV1.8 is primarily expressed in sensory ganglia of the peripheral nervous system, such as dorsal root ganglia (DRGs). Small DRG neurons expressing NaV1.8 include pain receptors involved in pain signal transmission. NaV1.8 mediates large-amplitude action potentials in small neurons of the dorsal root ganglion, which are essential for rapid repetitive action potentials in pain receptors and spontaneous activity in damaged neurons. Knockdown of NaV1.8 in rats has been achieved using antisense DNA or small interfering RNA and has almost completely reversed neuropathic pain in spinal cord ligation and chronic compression injury models. Therefore, the NaV1.8 channel is considered a promising target for analgesics, with the potential to play a role in indications where pain exceeds its usefulness, such as neuropathic pain, inflammatory pain, and postoperative/spontaneous pain. Furthermore, since NaV1.8 is mainly confined to neurons that sense pain, selective NaV1.8 inhibitors may avoid the adverse events commonly seen with non-selective NaV blockers.

Besides pain, NaV1.8 channels are also believed to be associated with multiple sclerosis (MS), arrhythmias, cough, and itching. MS is an inflammatory demyelinating disease of the central nervous system, and its exact pathogenesis remains to be elucidated. Normal Purkinje fibers in the cerebellum do not express NaV1.8 channels, but their expression is upregulated in the cerebellum of MS patients. In the cardiovascular system, NaV1.8 has been shown to be expressed in cardiac nerves such as Purkinje fibers and is considered a potential therapeutic target for cardiovascular diseases such as arrhythmias. NaV1.8 is expressed in the vagus nerve plexus associated with cough; its phosphorylation level and expression increase during pathological coughing, and it participates in the cough reflex. In the itching sensation of mammals, itching factors such as histamine released by lymphocytes and mast cells can activate the NaV1.8 channel. Knocking out NaV1.8 in mice can effectively relieve histamine and endothelin-induced itching behavior.

Currently, selective inhibitors of NaV1.8, such as VERTEX's VX-150 and Suzetrigine, have shown positive effects in clinical trials for patients with acute pain and diabetic peripheral neuropathy. However, there are currently no marketed products targeting this target. Developing highly selective voltage-gated sodium channel NaV1.8 inhibitors is of great clinical significance.

This application provides a compound, or a pharmaceutical composition thereof, which can act as a selective inhibitor of NaV1.8. This application further relates to the use of said compound or a pharmaceutical composition thereof in the preparation of a drug that treats diseases and/or conditions by inhibiting NaV1.8 through said compound. This application further describes a method for synthesizing said compound. The compound of this application exhibits excellent biological activity and pharmacokinetic properties.

On the one hand, this application provides a compound that is a compound represented by formula (X), or a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvent, metabolite, pharmaceutically acceptable salt, or prodrug of a compound represented by formula (X). (X); where: ring A is phenyl, 5-10 membered heteroaryl, or 5-10 membered heterocycloyl; each ^Re is independently D, F, Cl, Br, I, CN, hydroxyl, nitro, -N( ^Ra ) ₂ , -( _C1-6 alkylene)N( ^Ra ) ₂ , -S(O)(=NH) _C1-6 alkyl, -C(O) ^ORa , -C(O)N( ^Ra ) ₂ , -( _C1-6 alkylene)C(O)N( ^Ra ) ₂ , -C(O) ^Ra , -S( ^O ) _2NRa , The _C1-6 alkyl, _C1-6 alkoxy, _C1-6 hydroxyalkyl, _C1-6 halogenated alkyl, _C1-6 halogenated alkoxy, _C1-6 alkylamino, _C1-6 alkylthio, _C3-6 cycloalkyl, or 3-6 membered heterocyclic group may optionally be 1, ₂ , _or 3 selected from D, F, _C1 , Br, _I , _CN , _hydroxyl , amino, nitro, oxo, hydroxyl, _{C1-3 alkyl} , _C1-3 alkylamino, _{C1-6 alkylyl} ... The _1-3 halogenated alkyl, _C1-3 hydroxyalkyl, and _C1-3 alkoxy substituents are substituted; each ^Ra is independently H, D, hydroxyl, _C1-6 alkyl, _C1-6 alkoxy, _C3-6 cycloalkyl, and 3-6 membered heterocyclic group, wherein the _C1-6 alkyl, _C1-6 alkoxy, C3-6 cycloalkyl, and _3-6 membered heterocyclic group may optionally be substituted by 1, 2, or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxyl, amino, nitro, oxo, and _C1-3 alkyl; ^R1 , ^R2 , ^R3 , ^R4 , and ^R5 are each independently H, D, F, Cl, Br, I, CN, hydroxyl, nitro, amino, _C1-6 alkyl, C1-6 alkoxy, C1-3 alkyl, C1-6 alkoxy, _C1-3 alkyl, C1-6 alkyl ... _1-6 alkylthio, _C2-6 alkenyl, _C2-6 alkynyl, _C3-6 cycloalkyl, or 3-6 membered heterocyclic group, wherein the _C1-6 alkyl, C1-6 alkoxy, _C1-6 alkylthio, _C2-6 alkenyl, _C2-6 alkynyl, _C3-6 cycloalkyl, and _3-6 membered heterocyclic group may optionally be substituted by 1, 2, or 3 substituents selected from D, F, Cl, Br, I, CN, nitro, amino, hydroxyl, _C1-3 alkyl, _C1-3 halogenated alkyl, _C1-3 hydroxyalkyl, and _C1-3 alkoxy; or ^R3 and ^R5 together with the adjacent carbon atom form a _C3-6 cycloalkyl group; ^R6 is CN, -S(O) _C1-6 alkyl, -S(O) _{2C 1-6} alkyl, -CH=NOC _1-6 alkyl, C _2-6 ynyl, C _1-6 alkylthio, or -L1 _{- L2-} ^Rc , wherein the C _1-6 alkyl, C _2-6 ynyl, and C _1-6 alkylthio can be independently and optionally substituted by 1, 2, or 3 substituents selected from D, F, Cl, Br, I, oxo, and hydroxyl; _L1 is a bond, O, or S; _L2 is a bond, C _1-6 alkylene, or -(C _1-6 alkylene)-C _1-6 alkoxy, wherein the C _1-6 alkylene and C _1-6 alkoxy can be independently and optionally substituted by 1 or 3 substituents selected from D, F, Cl, Br, I, oxo, and hydroxyl; ^Rc is -ON=, -P(O)(C _1-6 alkyl) ₂ , C _2-6 alkynyl or -O- (3-8 membered heterocyclic group), wherein the _C1-6 alkyl, _C2-6 alkynyl, and 3-8 membered heterocyclic group may be independently and optionally substituted by 1, 2, 3, 4, 5, or 6 substituents selected from D, F, Cl, Br, I, hydroxyl, oxo, nitro, amino, alkylamino, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 alkylthio, C3-6 cycloalkyl, and 3-6 membered heterocyclic group; ^R7 and ^R8 are each independently H, D, F, Cl, Br, I, CN, hydroxyl, amino, nitro, C1-6 alkyl, _C1-6 alkoxy, C3-6 cycloalkyl, and 3-6 membered heterocyclic group, wherein the C1-6 alkyl, _C1-6 alkoxy, _C3-6 cycloalkyl, and 3-6 membered heterocyclic group may be substituted by 1, _2, 3, 4, 5, or 6 substituents selected from D, F, Cl, Br, I, CN, hydroxyl, amino, nitro, C1-6 alkyl, _C1-6 alkoxy, _C3-6 cycloalkyl, and 3-6 membered heterocyclic group. _{The 3-6} cycloalkyl group and the 3-6 heterocyclic group may be optionally substituted with 1, 2, or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxyl, amino, nitro, and _C1-3 alkoxy groups. n is 0, 1, 2, or 3. Ring A may be phenyl, dazine, pyrazine, pyridine, or pyrimidine.

In some embodiments, it is a compound represented by formula (I), (II), or (III), or a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvent, metabolite, pharmaceutically acceptable salt, or prodrug of a compound represented by formula (I), (II), or (III). (I) (II) (III) Wherein: X is CR ¹⁰ or N; Y is CR ¹³ or N; R ⁹ and R ¹⁰ are each independently H, D, F, Cl, Br, I, CN, amino, nitro, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 halogenated alkyl or C _1-6 halogenated alkoxy; R ¹¹ , R ¹² and R ¹³ are each independently H, D, F, Cl, Br, I, CN, hydroxyl, nitro, -N( ^Ra ) ₂ , -(C _1-6 alkylene)N( ^Ra ) _{2 ,} -S(O)(=NH)C _1-6 alkyl, -C(O) ^ORa , -C(O)N( ^Ra ) ₂ , -(C _1-6 alkylene)C(O)N( ^Ra ) ₂ , -C(O) ^Ra , -S(O) ₂ NR ^a 、 The _C1-6 alkyl, _C1-6 alkoxy, _C1-6 hydroxyalkyl, _C1-6 halogenated alkyl, _C1-6 halogenated alkoxy, _C1-6 alkylamino, _C1-6 alkylthio, _C3-6 cycloalkyl, or 3-6 membered heterocyclic group may optionally be 1, ₂ , _or 3 selected from D, F, _C1 , Br, _I , _CN , _hydroxyl , amino, nitro, oxo, hydroxyl, _{C1-3 alkyl} , _C1-3 alkylamino, _{C1-6 alkylyl} ... The _1-3 halogenated alkyl, _C1-3 hydroxyalkyl, and _C1-3 alkoxy substituents are substituted; each ^Ra is independently H, D, hydroxyl, _C1-6 alkyl, _C1-6 alkoxy, _C3-6 cycloalkyl, or 3-6 membered heterocyclic group, wherein the _C1-6 alkyl, _C1-6 alkoxy, _C3-6 cycloalkyl, and 3-6 membered heterocyclic group may optionally be substituted by 1, 2, or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxyl, amino, nitro, oxo, and _C1-3 alkyl. In some implementation schemes, ^R1 , ^R2 , ^R3 , ^R4 and ^R5 are each independently H, D, F, Cl, _Br , I, hydroxyl, methyl, ethyl, _CH2F , _CHF2 , _CF3 , _-CH2OCH3 or _-CH2OH . In some embodiments, ^R9 , ^R10 , and ^R11 are each independently H, D, F, Cl, Br, I, CN, amino, nitro, methyl, ethyl, methoxy, trifluoromethyl, or trifluoromethoxy; ^R12 and ^R13 are each independently H, D, F, Cl, Br, I, CN, hydroxyl, amino, nitro, methyl, ethyl, _CH2F , _{CHF2 , -OCH3} , _-OCH2CH3 , _-C (O) _NH2 , -C(O)NHOH, -C(O)NHOCH3, _-CH2OH , _-CH (OH) _CH2OH , -C(O) _NHCH3 , -CH(OH)( _CH3 ) ₂ , -S(O)(=NH) _{CH3 ,} -S(O) _{2NH2 .} , , , , or .

In some implementations, ^R7 and ^R8 are each independently H, D, F, Cl, Br, I, hydroxyl, methyl, ethyl, _CH2F , _CHF2 , or _CF3 .

In some embodiments, ^R6 is CN, -S(O) _C1-3alkyl , -S(O) _2C1-3alkyl -CH= _NOC1-3alkyl , _-C2-6 ynyl, _C1-3 alkylthio, or -L1- _{L2 -} ^Rc , wherein the _C1-3 alkyl, _C1-3 alkylthio, and _C2-6 ynyl can be independently and optionally substituted by 1, 2, or 3 substituents selected from D, _F , Cl, Br, I, oxo, and hydroxyl; _L1 is bond, O, or S; _L2 is bond, _C1-3 alkylene, or -( _C1-3 alkylene) _-C1-3 alkoxy; ^Rc is -ON=, -P(O)( _CH3 ) ₂ , _C2-6 ynyl, or -O-(3-8 membered heterocyclic group); wherein the C _{The 2-6} ynyl and 3-8 heterocyclic groups can be independently and optionally substituted by 1 _{, 2, 3, 4, 5 or 6 substituents selected from D, F, Cl, Br, I, hydroxyl, oxo, nitro, amino, C1-3 alkyl} , _C1-3 alkoxy, C1-3 alkylthio, _C3-6 cycloalkyl and 3-6 heterocyclic groups.

In some implementation schemes, ^R6 is CN, -S(O) _CH3 , -S(O) _{2CH3 ,} -P ₍ O)( _CH3 ) ₂ , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

In some embodiments, the compounds disclosed in this application have the structure shown in formula (IV) or (V): (IV) (V) wherein ^Rc is _{a C2-6} ynyl group, which may be independently and optionally substituted by 1, 2, 3, 4, 5 or 6 substituents selected from D, F, Cl, Br, I, hydroxyl, nitro, amino, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 alkylthio, _C3-6 cycloalkyl and 3-6 heterocyclic groups.

In some embodiments, it is a compound having one of the following structures or a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvent, metabolite, pharmaceutically acceptable salt, or prodrug having one of the following structures: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

On the one hand, this application provides a pharmaceutical composition comprising the compound of formula (I) of this application, or its stereoisomers, geometric isomers, tautomers, nitrides, hydrates, solvents, metabolites, pharmaceutically acceptable salts or their prodrugs, and their pharmaceutically acceptable carriers, excipients, diluents, coenzymes, mediators or combinations thereof.

On one hand, this application provides the use of the aforementioned compound and pharmaceutical composition in the preparation of a drug for treating diseases in which the voltage-gated sodium channel NaV1.8 is responsive. These diseases include chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, Shaco-Malley-Duss disease, incontinence, pathological cough, or arrhythmia.

The foregoing description only outlines certain aspects of this application, but is not limited to them. These and other aspects will be described in more detail below.

Definitions and general terms

This application will list in detail the relevant literature for each specific content, and the embodiments are accompanied by structural and chemical diagrams. This application is intended to cover all alternatives, variations, and equivalents that may be included in the existing application field as defined in the claims. Those skilled in the art will recognize many similar or equivalent methods and substances described herein that can be applied to the practices described herein. This application is by no means limited to the description of methods and substances. Many documents and similar substances differ from or conflict with this application, including, but not limited to, the definitions of terms, usage of terms, described techniques, or the scope controlled by this application.

This application will apply the following definitions unless otherwise stated. For the purposes of this application, chemical elements are defined according to the periodic table, CAS version, and the Chemical Handbook, 75th Ed, 1994. Additionally, general principles of organic chemistry are found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007; therefore, all content incorporates the references.

The term "includes" is used in an open-ended sense, meaning it includes the contents specified in this application but does not exclude other contents.

Compounds as described herein can be optionally substituted with one or more substituents, such as those of the general formula in this application, or as specific examples, subclasses, and a class of compounds included in this application, as described in the embodiments. It should be understood that the term "optionally substituted" is used interchangeably with "substituted or unsubstituted." Generally, the term "optionally," whether or not it precedes the term "substituted," indicates that one or more hydrogen atoms in the given structure are substituted by specific substituents. Unless otherwise indicated, an optional substituent group may have one substituent substituted at each substituted position of the group. When more than one position in the given structure can be substituted by one or more substituents selected from a specific group, the substituents may be substituted at the same or different positions. The substituents described herein may be, but are not limited to, hydrogen, F, Cl, Br, I, nitro, cyano, oxo(=O), hydroxyl, alkyl, hydroxyalkyl, alkylamino, aminoalkyl, halogenated alkoxy, cycloalkyl, amino, aryl, heterocyclic, heteroaryl, alkenyl, alkynyl, cycloalkyloxy, alkoxy, alkoxyalkyl, halogenated alkyl, -COOH, -alkylene-C(=O)O-alkyl, -alkylene-S(=O)2-alkyl, -alkylene-S(=O) ₂ -amino, -S(=O) ₂ -alkyl, -S(=O) ₂ -amino, -S(=O) _2OH , -O-alkylene-C(=O) _O -alkyl, -O-alkylene-S(=O) ₂ -alkyl, -O-alkylene-S(=O) _2-alkyl -amino, -O-alkylene-S(=O) _2OH , -C(=O) _NH2 , -C(=O)NH-alkyl, -C(=O)N(alkyl)-alkyl, -C(=O)NHS(=O) ₂ -alkyl, -C(=O)NHS(=O) ₂ -amino, -C(=O)NHS(=O) _2OH , -N(halogenated alkyl)-alkyl, -N(alkyl)-S(=O) ₂ -alkyl, -NHS(=O) ₂ -alkyl, -NHS(=O) ₂ -halogenated alkyl, -N(alkyl)S(=O) ₂ -halogenated alkyl, -N(alkyl)S(=O) ₂ -alkylamino, -NHC(=O)-alkyl, -NHC(=O)-halogenatedalkyl, -N(alkyl)C(=O)-halogenatedalkyl, -N(alkyl)C(=O)-alkylamino, -N(alkyl)C(=O)O-alkyl, -NHC(=O)O-alkyl, -NHC(=O)O-halogenatedalkyl, -N(alkyl)C(=O)O-halogenatedalkyl, -N(alkyl)C(=O)O-aminoalkyl, -NHC(=O)-NH ₂ -NHC(=O)NH- (alkyl), -NHC(=O)NH (halogenated alkyl), -NHC(=O)N (alkyl)-alkyl, -OC(=O)-alkyl, -OC(=O)-amino, -OC(=O)-alkylamino, -OC(=O)-aminoalkyl, -OC(=O)-alkoxy, -C(=O)N(alkyl)S(=O) ₂ -alkyl, -C(=O)N(alkyl)S(=O) ₂ -amino, -C(=O)NH-S(=O) _2OH , -C(=NH) _NH2 , -C(=NH)NH-alkyl, -C(=NH)N(alkyl)-alkyl, -C(=N-alkyl) _-NH2 , -C(=O)NH-alkylene-S(=O) ₂ OH, -C(=O)NHC(=O)OH, -C(=O)NHC(=O)O-alkyl, -C(=O)N(alkyl)C(=O)O-alkyl, -C(=O)NH-alkylene-C(=O)OH and -C(=O)NH-alkylene-C(=O)O-alkyl, etc.

As used in this application, the term "alkyl" includes a monovalent hydrocarbon saturated with 1-20 carbon atoms, or 1-10 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, or 1-2 carbon atoms, wherein the alkyl group may be independently and optionally substituted by one or more substituents described in this application. Further examples of alkyl groups include, but are not limited to _, methyl (Me, _-CH3 ), ethyl (Et, _-CH2CH3 ), n-propyl (n-Pr, _-CH2CH2CH3 ), isopropyl (i-Pr, _-CH ( _CH3 ) _{2 )} , n-butyl (n-Bu, _{-CH2CH2CH2CH3} ), isobutyl (i-Bu _{, -CH2CH} ( _CH3 ) ₂ ), sec-butyl (s-Bu, _-CH ( _CH3 ) _CH2CH3 ), tert-butyl (t-Bu, -C( _{CH3 ) 3} ), _n - _pentyl ( _{-CH2CH2CH2CH2CH3} ) _, 2-pentyl ( _{-CH ( CH3} ) _CH2CH2CH3 ), and _{3 -} pentyl (-CH( _CH2CH3 ) ₂ ) _. ), 2-methyl- ₂ -butyl (-C( _CH3 ) _2CH2CH3 ), 3-methyl-2-butyl (-CH( _CH3 )CH( _CH3 ) _{2 )} , 3-methyl-1 _- butyl (-CH2CH2CH( _CH3 ) ₂ ), ₂ -methyl-1 _- butyl ( _{-CH2CH ( CH3} ) _CH2CH3 ), _n - _hexyl (-CH2CH2CH2CH2CH2CH3) _{, 2 -} hexyl _{( -CH} ( _CH3 ) _CH2CH2CH2CH3 ), ₃ -hexyl (-CH( _CH2CH3 )( _CH2CH2CH3 )), 2-methyl-2-pentyl ( _{-C ( CH3} ) _2CH2CH2CH3 ), 3-methyl-2-pentyl ₍ -CH( _CH3 ) _CH ( _{CH3 ) )} )CH ₂ CH ₃ ), 4-methyl-2-pentyl (-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C(CH ₃ )(CH ₂ CH ₃ ) ₂ ), 2-methyl-3-pentyl (-CH(CH ₂ CH ₃ )CH(CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl (-C(CH ₃ ) ₂ CH(CH ₃ ) ₂ ), 3,3-dimethyl-2-butyl (-CH(CH ₃ )C(CH ₃ ) ₃ ), n-heptyl and n-octyl, etc. The term "alkyl" and its initial "alkane" are used here, both including straight-chain and branched saturated carbon chains.

The term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated straight-chain or branched hydrocarbon group. Unless otherwise specified, alkylene groups contain 1-12 carbon atoms. In some embodiments, alkylene groups contain 1-6 carbon atoms; in others, 1-4 carbon atoms; in still others, 1-3 carbon atoms; and in still others, 1-2 carbon atoms. Such examples include methylene ( _-CH₂- ), _ethylene ( _-CH₂CH₂- ), isopropylene (-CH( _CH₃ ) _CH₂- ), etc.

The term "alkenyl" refers to a monovalent hydrocarbon of 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, either linear or branched, wherein at least one position is unsaturated, i.e., one C C is an sp ² double bond. The alkenyl group may be independently and optionally substituted by one or more substituents described in this application, including groups with "trans", "cis", or "E" or "Z" orientations. Specific examples of alkenyl include, but are not limited to, vinyl (-CH=CH ₂ ), allyl (-CH ₂ CH=CH ₂ ), etc.

The term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon with 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one position is unsaturated, i.e., one C C is an sp triple bond. The alkynyl group may be independently and optionally substituted by one or more substituents described in this application. Specific examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), propynyl ( _-CH₂C≡CH ), etc.

The term "heteroatom" refers to one or more O, S, N, P, and Si, including C, N, S, and P in any oxidation state; primary, secondary, tertiary amines, and quaternary ammonium salts; or a form in which the hydrogen atom on the nitrogen atom in the heterocycle is substituted, for example, N (like N in 3,4-dihydro-2H-pyrrole), NH (like NH in pyrrolidinyl), or NR (like NR in N-substituted pyrrolidinyl); or -CH _2- in the heterocycle is oxidized to form -C(=O)-.

The term "halogen" refers to F, Cl, Br, or I.

The term "氘" refers to deuterium, D.

The term "unsaturated" as used in this application indicates that the part contains one or more degrees of unsaturation.

The term "alkoxy" or "alkyloxy" as used in this application refers to an alkyl group, as defined in this application, that is attached to another part of the compound molecule via an oxygen atom. In some embodiments, the alkoxy group is a _C1-4 alkoxy group; such examples include, but are not limited to, methoxy, ethoxy, propoxy, and butoxy groups. Furthermore, the alkoxy group may be independently unsubstituted or substituted by one or more substituents described in this application.

The terms "alkathio" or "alkylthio" as used in this application refer to an alkyl group, as defined in this application, which is attached to other parts of a compound molecule via a sulfur atom. In some embodiments, the alkathio group is a _C1-4 alkathio group; such examples include, but are not limited to, methylthio, ethylthio, propylthio, and butylthio. Furthermore, the alkathio group may be independently unsubstituted or substituted by one or more substituents described in this application.

The term "alkylamino" as used in this application refers to an alkyl group, as defined in this application, which is attached to other parts of the compound molecule via an N atom. In some embodiments, the alkylamino group is a _C1-4 alkylamino group; such examples include, but are not limited to, methylamino, ethylamino, propylamino, and butylamino. Furthermore, the alkylamino group may be independently unsubstituted or substituted by one or more substituents described in this application.

The term "cycloalkyl" or "cycloalkane" refers to a monovalent or polyvalent monocyclic, bicyclic, or tricyclic carbocyclic system containing 3 to 12 carbon atoms, which is a saturated ring or a ring containing one or more unsaturated bonds, but does not include aromatic rings. "Cycloalkyl" or "cycloalkane" can also refer to bridged and spirocyclic rings. In one embodiment, the cycloalkyl group contains 3 to 10 carbon atoms; in another embodiment, it contains 3 to 8 carbon atoms; and in yet another embodiment, it contains 3 to 6 carbon atoms. Such examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl. The cycloalkyl group may be independently unsubstituted or substituted by one or more substituents described in this application.

The terms "heterocyclic group" and "heterocyclic" are used interchangeably here, both referring to saturated or partially unsaturated monocyclic, bicyclic, or tricyclic rings containing 3 to 12 ring atoms, excluding aromatic rings, wherein at least one ring atom is a heteroatom. "Heterocyclic group" or "heterocyclic" can also refer to bridged heterocyclic rings and spirocyclic heterocyclic rings. In one embodiment, the "heterocyclic group" or "heterocycle" comprises 3-10 ring atoms; in another embodiment, the "heterocyclic group" or "heterocycle" comprises 3-8 ring atoms; in yet another embodiment, the "heterocyclic group" or "heterocycle" comprises 5-8 ring atoms; in yet another embodiment, the "heterocyclic group" or "heterocycle" comprises 3-6 ring atoms; in yet another embodiment, the "heterocyclic group" or "heterocycle" comprises 5-6 ring atoms; and in yet another embodiment, the "heterocyclic group" or "heterocycle" comprises 4-6 ring atoms; unless otherwise stated, the heterocyclic group may be carbon-based or nitrogen-based, and the heteroatom has the meaning as described in this application. Examples of heterocyclic groups include, but are not limited to: ethylene oxide, azirmonobutyl, oxocyclobutyl, thiocyclobutyl, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolylyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H- Pyranyl, tetrahydrothiaranyl, piridyl, morpholinyl, thiomorpholinyl, piridinyl, dioxane, dithiaranyl, thiaranyl, hyperpiridinyl, hyperpiridinyl, oxocycloheptyl, thiocycloheptyl, oxonitrileyl, diazatrileyl, thioazatrileyl, 2-oxo-5-azabicyclo[2.2.1]hept-5-yl, 2-oxonitrilebicyclo[2.1.1]hexane, and 1,2,3,6-tetrahydropyridinyl. Examples of heterocyclic groups where the _-CH2- group is substituted with -C(=O)- include, but are not limited to: 2-oxopyrrolyl, oxo-1,3-thiazolyl, 2-piperidinone, 3,5-dioxopyridin, pyrimidinedione, and 5,6-dihydropyridine-2(1H)-keto. Examples of heterocyclic groups where the sulfur atom is oxidized include, but are not limited to, cyclobutanol and 1,1-dioxothiomorpholino. The heterocyclic group may optionally be substituted with one or more of the substituents described in this application.

The term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic system containing 6-14, 6-12, or 6-10 ring atoms, wherein at least one ring is aromatic, and each ring comprises a ring of 3-7 atoms and has one or more attachment sites connected to the remainder of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring." Examples of aryl groups may include phenyl, naphthyl, and anthracene. The aryl group may be independently and optionally substituted by one or more substituents described in this application.

The term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic system containing 5-12, 5-10, or 5-6 ring atoms, wherein at least one ring system is an aromatic ring, and at least one ring system contains one or more heteroatoms, wherein each ring comprises a ring consisting of 5-7 atoms, and has one or more attachment sites connected to the remainder of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound." The heteroaryl group is optionally substituted by one or more substituents described in this application. In one embodiment, the heteroaryl group consisting of 5-10 atoms comprises 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, wherein the nitrogen atom may be further oxidized.

Examples of heteroaryl groups include, but are not limited to: furanyl, imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl, oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrrolyl (e.g., N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl, pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), darazinyl, thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), tetrazolyl (e.g., 5-tetrazolyl) The group includes, but is not limited to, the following bicyclic groups: benzimidazolyl, benzofuranyl, benzothiophenyl, indoleyl (e.g., 2-thiophenyl, 3-thiophenyl), pyrazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl; and also includes, but is not limited to, the following bicyclic groups: benzimidazolyl, benzofuranyl, benzothiophenyl, indoleyl (e.g., benzo[i]... 2-Indolyl), purine, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), 1,2,3,4-tetrahydroisoquinolinyl, 1,3-benzodioxonyl, indololinyl, isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl), imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyrazinyl, [1,2,4]triazolo[4,3-b]pyrazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl and [1,2,4]triazolo[1,5-a]pyridyl, etc.

The terms "halogenated alkyl" or "halogenated alkoxy" indicate that an alkyl or alkoxy group is replaced by one or more halogen atoms. Examples of such substitution include, but are not limited to, trifluoromethyl, trifluoromethoxy, etc.

The term "halogenated cycloalkyl" means that the cycloalkyl group is replaced by one or more halogen atoms. Examples of such halogenation include, but are not limited to, 1,1-difluorocyclopropane, 1-chloro-2-fluorocyclopropane, etc.

As described in this application, a substituent drawn as a bond to a ring system represents that the substituent can be substituted at any substituted position on the ring. For example, formula (a) represents that the substituent R can be monosubstituted or polysubstituted at any substituted position on the pyridine ring. (a)

As described in this application, wavy lines intersecting with bonds in a chemical structure represent the points in the chemical structure where the wavy bond connects to the atoms and the remainder of the molecule or to a segment of the molecule.

Additionally, it should be noted that, unless otherwise explicitly stated, the descriptive phrases “each and each is independent,” “…and each is independent,” and “…and each is independent” used throughout this document are interchangeable and should be interpreted broadly. They can mean either that the specific options expressed by the same symbols in different foundations do not affect each other, or that the specific options expressed by the same symbols in the same foundation do not affect each other.

Unless otherwise indicated, the structural formulas described in this application include all isomers (such as enantiomers, diastereomers, geometric isomers, or conformational isomers): for example, R and S configurations containing asymmetric centers, (Z) and (E) isomers with double bonds, and (Z) and (E) conformational isomers. Therefore, any single stereochemical isomer of the compound of this application, or a mixture of its enantiomers, diastereomers, geometric isomers, or conformational isomers, is within the scope of this application.

Unless otherwise stated, the structural formulas and compounds described in this application include all isomers (e.g., enantiomers, diastereomers, geometric isomers, or conformational isomers), nitrides, hydrates, solvents, metabolites, pharmaceutically acceptable salts, and prodrugs. Therefore, individual stereochemical isomers, enantiomers, diastereomers, geometric isomers, conformational isomers, nitrides, hydrates, solvents, metabolites, pharmaceutically acceptable salts, and prodrugs of the compounds described in this application are also within the scope of this application. Furthermore, unless otherwise stated, the structural formulas of the compounds described in this application include enriched isotopes of one or more distinct atoms.

"Metabolic products" refers to products obtained in vivo by the metabolism of the specific compound described in this application or its pharmaceutically acceptable salts, analogues, or derivatives, which exhibit similar activity to the compound of formula (I) in vivo or externally. The metabolic products of a compound can be identified using techniques known in the art, and their activity can be characterized by experimental methods as described in this application. Such products can be obtained by administering a drug-treated compound through oxidation, reduction, hydrolysis, acetylation, deacetylation, esterification, defatting, or enzymatic cleavage, etc. Accordingly, this application includes metabolic products of compounds, including metabolic products produced by prolonged exposure of the compound of this application to mammals.

The definition and customary use of stereochemistry in this application generally refer to the following documents: S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of this application may contain asymmetric or chiral centers, and therefore exist in various stereoisomers. All stereoisomers of the compounds of this application, including, but not limited to, diastereomers, enantiomers, transisomers, and mixtures thereof, such as racemic mixtures, constitute a part of this application. Many organic compounds exist in optically active forms, meaning they are capable of rotating the plane of plane-polarized light. In describing optically active compounds, the initials D, L, or R, S are used to indicate the absolute configuration of the chiral center of the molecule. The initials d, l, or (+), (-) are used to name the symbol for the rotation of the compound in plane polarized light; (-) or l indicates the compound is levorotatory, and (+) or d indicates the compound is dextrorotatory. These stereoisomers have the same chemical structure but different stereostructures. Specific stereoisomers can be enantiomers, and mixtures of isomers are usually called enantiomer mixtures. A 50:50 enantiomer mixture is called a racemic mixture or racemate, which may result in a lack of stereoselectivity or stereoorientation during chemical reactions. The terms "racemic mixture" and "racemate" refer to a mixture of two equal moles of enantiomers that lack optical activity.

The terms "tautomerism" or "forms of tautomerism" refer to isomers of different energies that can interconvert through low-energy barriers. For example, proton tautomerism (i.e., proton-transfer tautomerism) includes isomerism via proton transfer, such as keto-enol and imine-enamine isomerization. Valence tautomerism includes isomerism involving recombination to form bonded electrons.

As used in this application, "pharmaceutically acceptable salts" refers to both organic and inorganic salts of the compounds in this application. Pharmaceutically acceptable salts are well-known in the field, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19, 1977. Pharmaceutically acceptable, non-toxic acid-derived salts include, but are not limited to: inorganic acids formed by reactions with amino groups, such as hydrochlorides, hydrobromides, phosphates, sulfates, and perchlorates; organic acids, such as acetates, oxalates, maleates, tartrates, citrates, succinates, and malonates; or salts obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipic acid salts, malic acid salts, 2-hydroxypropionate salts, alginate salts, ascorbic acid salts, aspartate salts, benzenesulfonate salts, benzoate salts, bisulfate salts, borate salts, butyrate salts, camphorate salts, camphorsulfonate salts, cyclopentylpropionate salts, digluconate salts, dodecyl sulfate salts, ethanesulfonate salts, formate salts, trans-butenedioic acid salts, gluconate salts, glycerophosphate salts, gluconate salts, and hemisulfate salts. Heptanoates, hexanoates, hydroiodates, 2-hydroxy-ethanesulfonates, lacturonic acid salts, lactates, laurates, lauryl sulfates, malates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitic acid salts, picrates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalate salts, propionates, stearates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, etc. Salts obtained through suitable alkalis include salts of alkali metals, alkaline earth metals, ammonium, and N+( _C1-4 alkyl) ₄ . This application also contemplates quaternary ammonium salts formed from any compound containing an N-group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metals or alkaline earth metals that can form salts include sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts, and amine cations that resist the formation of equilibrium ions, such as halides, hydroxides, carboxylates, sulfates, phosphorylates, nitrates, _C1-8 sulfonates, and aromatic sulfonates.

In this application, "hydrate" refers to a compound in which the solvent molecules are water.

The term "solvent" in this application refers to a compound formed by one or more solvent molecules and the compound of this application. Solvents that form solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.

The term "ester" in this application refers to an in vivo hydrolyzable ester containing a hydroxyl group and belonging to formula (I). Such an ester is, for example, a pharmaceutically acceptable ester that, upon hydrolysis in a human or animal body, produces a parent alcohol. The groups of an in vivo hydrolyzable ester containing a hydroxyl group and belonging to formula (I) include, but are not limited to: phosphate, acetoxymethoxy, 2,2-dimethylpropoxymethoxy, alkoxy, benzoyl, phenacetin, alkoxycarbonyl, dialkylaminomethoxy, and N-(dialkylaminoethyl)-N-alkylaminomethoxy, etc.

The term "nitrogen oxide" in this application refers to an N-oxide formed by oxidizing one or more nitrogen atoms when the compound contains several amine functional groups. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides containing nitrogen atoms in a nitrogen heterocyclic ring. The corresponding amines can be treated with oxidizing agents such as hydrogen peroxide or peracids (e.g., peroxycarboxylic acids) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared using L.W. Deady's method (Syn.Comm. 1977, 7, 509-514), for example, by reacting an amine compound with m-chloroperoxybenzoic acid (MCPBA) in an inert solvent (e.g., dichloromethane).

As used in this application, the term "prodrug" refers to the transformation of a compound into the compound represented by formula (I) in vivo. Such transformation is influenced by the hydrolysis of the prodrug in the blood or its enzymatic conversion in the blood or tissues to the parent structure. The prodrug compounds of this application can be esters. In existing applications, esters that can serve as prodrugs include phenyl esters, aliphatic ( _C1-24 ) esters, acetylated methyl esters, carbonates, carbamates, and amino acid esters. For example, a compound in this application containing a hydroxyl group can be acylated to obtain the prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent compound. For a complete discussion of prodrugs, please refer to the following literature: T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series; Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270; and SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

Unless otherwise stated herein or the context clearly implies otherwise, the terms “an,” “a,” “the,” and “the,” as used herein, and similar terms used in the context of this application (especially in the context of the claims), may be interpreted as including both the singular and the plural.

Examples are listed below to describe this application. However, it should be understood that this application is not limited to these examples, but merely provides methods for practicing this application.

Generally, the compounds of this application can be prepared by the methods described in this application, unless otherwise specified, wherein the substituents are defined as described in this application. The following reaction schemes and embodiments are used to further illustrate the contents of this application.

Those skilled in the art will recognize that the chemical reactions described in this application can be suitably used to prepare other compounds of this application, and other methods for preparing the compounds of this application are considered to be within the scope of this application. For example, the synthesis of those non-exemplary compounds according to this application can be successfully accomplished by those skilled in the art through modification methods, such as appropriate protection of interfering groups, by using other known reagents other than those described in this application, or by making some conventional modifications to the reaction conditions. In addition, the reactions disclosed in this application or the known reaction conditions are also generally accepted to be applicable to the preparation of other compounds of this application.

Unless otherwise specified, the raw materials and reagents used in the following embodiments are all derived from commercially available or known synthetic routes.

The equipment and testing conditions are described below: ¹H NMR spectra were recorded using a Bruker 500 MHz NMR spectrometer. ^¹H NMR spectra were recorded using _CDCl₃ , DMSO- _d₆ , _CD₃OD , or acetone- _d₆ as solvents (in ppm), with TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiplets are observed, the following abbreviations will be used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), brs (broadened singlet), dd (doublet of doublets), dt (doublet of triplets). The coupling constant J is denoted by Hertz (Hz).

The determination conditions for low-resolution mass spectrometry (MS) data were as follows: Agilent G6125C quadrupole HPLC-MS (column type: XBridge BEH C18, 4.6 x 50 mm, 2.5 μm, 6 min, flow rate: 1 mL/min; mobile phase: 0% - 95% ( _CH3CN ) in a ratio of _H2O containing 0.1% formic acid: _CH3CN = 90:10), using electrospray ionization (ESI) at 210 nm/254 nm, and detection by DAD.

Compounds are named according to conventional naming principles in this field or using software naming; commercially available compounds use supplier catalog names.

Implementation Example 1

Preparation of compounds 1-2

Under nitrogen atmosphere, compound 1-1 (40 g, 253 mmol) was dissolved in THF (200 mL). Methyllithium lithium bromide diethyl ether solution (506 mL, 759 mmol) was slowly added dropwise at 0°C. After the addition was complete, the temperature was slowly raised to room temperature and stirred for 16 hours. After the reaction was complete, the reaction solution was cooled to 0°C, and water (200 mL) was added dropwise to quench the reaction. After stirring for 1 hour, the solution was extracted with dichloromethane (200 mL × 5). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and distilled at 60-100°C until no more precipitate was collected. The residue in the flask was the THF solution of compound 1-2.

¹ H NMR (400 MHz, CDCl ₃ ): δ 2.36 (s, 3H), 1.52 (s, 3H).

Preparation of compounds 1-3

The preparation routes for compounds 1-3 are as follows:

Compounds 1-4 (33.2 mL, 299.40 mmol), compounds 1-5 (61.90 g, 329.34 mmol), potassium carbonate (140.68 g, 1017.96 mmol), and copper oxide (1.30 g, 8.98 mmol) were added sequentially to toluene (1000 mL). Tetraphenylphosphine palladium (10.38 g, 8.98 mmol) was added under nitrogen atmosphere, and the mixture was stirred at 25 °C for 16 hours. The reaction solution was concentrated, water (500 mL) was added, and the mixture was extracted with ethyl acetate (500 mL × 3). The combined organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to obtain compounds 1-6.

Compounds 1-6 (29 g, 126 mmol) were dissolved in THF (250 mL), and an aqueous lithium hydroxide solution (144.9 mL, 289.74 mmol, 2 mol/L) was added. The reaction mixture was heated to 50 °C and stirred for 1 hour. After the reaction was complete, the mixture was cooled to room temperature and washed with dichloromethane (200 mL × 1). The aqueous phase was adjusted to pH=1 with dilute hydrochloric acid (1 mol/L) and extracted with dichloromethane (100 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compounds 1-3.

Preparation of compounds 1-7

Compounds 1-3 (7.72 g, 38.2 mmol) were dissolved in acetonitrile (80 mL) under nitrogen atmosphere. Carbonyl diimidazole (6.50 g, 40.08 mmol) was added at 0 °C. After stirring the mixture for 1 hour, potassium carbonate (6.59 g, 47.7 mmol) and compound 1-2 (26.6 g, 38.2 mmol, 22.4% purity) were added sequentially. The reaction solution was heated to 35 °C and stirred for 10 hours. After the reaction was complete, the solid was removed by filtration. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compounds 1-7.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.00 - 6.87 (m, 2H), 3.92 (d, J = 2.1 Hz, 3H), 2.05 (s, 3H), 1.76 (s, 3H).

Preparation of compounds 1-8

Under nitrogen atmosphere, palladium-carbon (3 g, 10% purity) was added to 17.5 mL of isopropanol, and compounds 1-7 (3 g, 9.31 mmol) were added with stirring at room temperature. The reaction mixture was stirred at 30°C for 30 hours under hydrogen atmosphere (225 psi). The reaction mixture was filtered with diatomaceous earth, and the filter cake was washed successively with 100 mL of isopropanol and 20 mL of dichloromethane. After reduced pressure concentration, it was dried twice with 50 mL of toluene to obtain compounds 1-8.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.00 - 6.93 (m, 1H), 6.92 - 6.84 (m, 1H), 4.49 (d, J = 9.0 Hz, 1H), 4.04 (d, J = 2.9 Hz, 3H), 2.96 - 2.83 (m, 1H), 1.72 (s, 3H), 0.81 (dd, J = 2.1, 4.9 Hz, 3H);

m/z (ESI): [M + H] ⁺ = 325.1.

Preparation of compounds 1-9

Under nitrogen atmosphere, diisobutylaluminum hydroxide (13.0 mL, 13.0 mmol, 1 mol/L toluene solution) was slowly added dropwise to a 30 mL toluene solution of compounds 1-8 (2.8 g, 8.64 mmol) at -30 °C. After the addition was complete, the reaction mixture was stirred at -30 °C for 1.5 hours. After the reaction was complete, 100 mL of ethyl acetate was added to dilute the solution, the temperature was raised to 0 °C, and the reaction was quenched by adding saturated ammonium chloride aqueous solution. The mixture was stirred for 0.5 hours, filtered with diatomaceous earth, and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compounds 1-9.

¹ H NMR (400 MHz, CDCl ₃ ): δ 6.95 - 6.89 (m, 1H), 6.89 - 6.80 (m, 1H), 5.80 (t, J = 3.5 Hz, 1H), 4.00 (d, J = 2.6 Hz, 3H), 3.88 - 3.78 (m, 1H), 2.99 - 2.84 (m, 2H), 1.65 (s, 3H), 0.90 - 0.77 (m, 3H).

Preparation of compounds 1-10

Compounds 1-9 (2.4 g, 7.36 mmol), 4-dimethylaminopyridine (1.35 g, 11.03 mmol), and acetic anhydride (1.0 mL, 11.0 mmol) were added sequentially to 40 mL of dichloromethane under stirring at room temperature. The reaction mixture was stirred at 20 °C for 1 hour. After the reaction was complete, the reaction mixture was slowly poured into 100 mL of 30% ammonium chloride aqueous solution for quenching. The organic phase was washed with 100 mL of 10% sodium carbonate aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compounds 1-10.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.00 - 6.91 (m, 1H), 6.91 - 6.81 (m, 1H), 6.56 (d, J = 2.3 Hz, 1H), 4.01 - 3.99 (m, 3H), 3.96 (dd, J = 2.0, 8.9 Hz, 1H), 2.96 - 2.86 (m, 1H), 2.11 (s, 3H), 1.62 (s, 3H), 0.87 (dd, J = 1.9, 7.6 Hz, 3H).

Preparation of compounds 1-11

Compound 1-10 (2.6 g, 7.06 mmol) was added to 40 mL of dichloromethane under a nitrogen atmosphere. After cooling to -30 °C, silicon trimethylcyanide (2.8 mL, 21.2 mmol) was slowly added to the reaction solution. After stirring for 5 minutes, boron trifluoride diethyl ether (7.8 mL, 28.2 mmol) was added dropwise. The reaction solution was stirred at -30 to 0 °C for 2 hours. After the reaction was complete, potassium hydroxide aqueous solution (2 mol/L, 100 mL) was slowly added dropwise. The mixture was extracted with dichloromethane (50 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 1-11.

¹ H NMR (400 MHz, CDCl ₃ ): δ 6.93 - 6.85 (m, 1H), 6.78 - 6.76 (m, 1H), 5.08 - 5.01 (m, 1H), 4.26 - 4.21 (m, 1H), 4.08 - 4.05 (m, 3H), 2.89 -2.81 (m, 1H), 1.64 (s, 3H), 0.83 - 0.79 (m, 3H).

Preparation of compounds 1-12

Compound 1-11 (2.4 g, 7.16 mmol) was added to 20 mL of ethanol, and potassium hydroxide aqueous solution (20 mL, 2 mol/L) was added dropwise while stirring. The reaction solution was heated to 75 °C and stirred for 16 hours. After the reaction was completed and cooled, 100 mL of water was added to dilute the solution, and the ethanol was removed by depressurization concentration. 50 mL of ethyl acetate was added to the concentrate for separation. The aqueous phase was adjusted to pH = 5 with 6 M hydrochloric acid and extracted with ethyl acetate (50 mL × 2). The combined organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reversed-phase column chromatography (mobile phase A: water (0.1% formic acid) - B: acetonitrile; elution gradient: B: 70%-80%; elution for 15 min) to obtain compounds 1-12.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.13 - 12.80 (m, 1H), 7.22 - 7.16 (m, 1H), 7.16 - 7.09 (m, 1H), 4.98 (d, J = 10.4 Hz, 1H), 4.08 (dd, J = 7.9, 10.8 Hz, 1H), 3.93 (d, J = 2.1 Hz, 3H), 2.73 - 2.60 (m, 1H), 1.53 (s, 3H), 0.74 - 0.64 (m, 3H).

m/z (ESI): [MH] ^- = 353.2.

Preparation of compounds 1-13

Compound 1-12 (2.1 g, 5.93 mmol) was added to 4 mL of toluene, stirred and heated to 60 °C, and then 4 mL of toluene containing R-phenylethylamine (0.86 g, 7.11 mmol) was slowly added dropwise. After the addition was complete, the reaction temperature was lowered to 50 °C and stirred for 1 hour. The reaction temperature was then slowly lowered to 20 °C and stirred at 20 °C for 8 hours. The mixture was filtered, and the filter cake was washed with 5 mL of toluene and dried to obtain compound 1-13.

¹ H NMR (400 MHz, MeOD): δ 7.50 - 7.41 (m, 5H), 7.13 (ddd, J = 2.1, 6.0, 8.6 Hz, 1H), 6.96 - 6.87 (m, 1H), 4.73 (d, J = 10.4 Hz, 1H), 4.48 - 4.38 (m, 1H), 4.09 (dd, J = 8.3, 10.1 Hz, 1H), 3.96 (d, J = 2.1 Hz, 3H), 2.58 - 2.48 (m, 1H), 1.65 - 1.57 (m, 6H), 0.78 - 0.70 (m, 3H).

Preparation of compounds 1-14

Compound 1-13 (2.25 g, 4.73 mmol) was added to a mixed solution of 20 mL isopropanol and 40 mL n-heptane. While stirring, 40 mL dichloromethane and 40 mL hydrochloric acid aqueous solution (2 mol/L) were added sequentially. The reaction solution was stirred for half an hour, and the low-boiling solvent was removed by depressurization concentration. 50 mL ethyl acetate was added to the residue, and the mixture was extracted and separated. The organic phase was washed with 20 mL of water, dried over anhydrous sodium sulfate, and concentrated under depressurization to obtain an oily substance (1.76 g). Quinine (1.56 g, 4.80 mmol) was added to a 4 mL solution of dichloromethane containing the above oily substance. After adding 4 mL of isopropanol, the temperature was raised to 70 °C (to remove low-boiling-point dichloromethane). After the temperature of the reaction solution dropped to 65 °C, 12 mL of n-heptane was slowly added. The mixture was stirred at 65 °C for 1 hour, and then the temperature of the reaction solution was slowly lowered to 20 °C. After stirring at 20 °C for 2 hours, the mixture was filtered. The filter cake was washed with isopropanol/n-heptane = 1/3 (3 mL) and dried under reduced pressure to obtain compounds 1-14.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.68 (d, J = 4.5 Hz, 1H), 7.84 (d, J = 9.1 Hz, 1H), 7.60 (d, J = 4.4 Hz, 1H), 7.18 (dd, J = 2.6, 9.3 Hz, 1H), 7.10 (ddd, J = 1.8, 6.1, 8.4 Hz, 1H), 6.84 - 6.75 (m, 2H), 6.16 (s, 1H), 5.52 (ddd, J = 6.7, 10.4, 17.2 Hz, 1H), 5.06 - 4.92 (m, 2H), 4.85 (d, J = 10.1 Hz, 1H), 4.37 - 4.23 (m, 1H), 4.17 - 4.07 (m, 1H), 3.93 (d, J = 2.5 Hz, 3H), 3.70 (s, 3H), 3.39 - 3.24 (m, 2H), 3.07 - 2.91 (m, 2H), 2.60 - 2.48 (m, 1H), 2.58 (d, J = 1.5 Hz, 1H), 2.15 - 2.04 (m, 1H), 2.03 - 1.93 (m, 2H), 1.80 - 1.68 (m, 1H), 1.65 (s, 3H), 1.27 - 1.10 (m, 1H), 0.78 (dd, J = 1.8, 7.3 Hz, 3H).

Preparation of compounds 1-15

20 mL of dilute hydrochloric acid (2.5 mol/L) was added dropwise to a 20 mL dichloromethane solution of compound 1-14 (1.6 g, 2.36 mmol). The mixture was stirred at 20 °C for half an hour and then allowed to stand before separation. 30 mL of dilute hydrochloric acid (2.5 mol/L) was added to the organic phase again, and the mixture was separated. The combined aqueous phase was extracted with dichloromethane (20 mL × 2). The combined organic phase was washed with 20 mL of water, dried over anhydrous sodium sulfate, and concentrated to give a white solid (600 mg). Under nitrogen atmosphere and at 0°C, DMF (0.1 mL, 0.34 mmol) and oxalic acid (0.3 mL, 3.39 mmol) were added dropwise to 10 mL of dichloromethane solution containing the above white solid (600 mg, 1.69 mmol). The reaction solution was heated to room temperature, stirred for 2 hours, and concentrated under reduced pressure to obtain compound 1-15.

Preparation of compounds 1-16

Under a nitrogen atmosphere at 0°C, compound 1-15 (200 mg, 0.54 mmol) was slowly added to 4 mL of dichloromethane containing methyl 4-amino-2-pyridinecarboxylate (163.3 mg, 1.07 mmol) and triethylamine (0.2 mL, 1.61 mmol). The mixture was then heated to 20°C and stirred for 2 hours. After the reaction was complete, 20 mL of water was added dropwise to quench the reaction, and the mixture was extracted with dichloromethane (10 mL × 2). The combined organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by reversed-phase column chromatography (mobile phase A: water (0.1% ammonia) - B: acetonitrile; elution gradient: B: 70%-80%; elution for 15 minutes) to obtain compounds 1-16.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.64 (d, J = 5.4 Hz, 1H), 8.58 (s, 1H), 8.09 (d, J = 2.1 Hz, 1H), 7.94 (dd, J = 2.3, 5.5 Hz, 1H), 7.12 - 7.05 (m, 1H), 6.97 - 6.88 (m, 1H), 5.04 (d, J = 11.1 Hz, 1H), 4.21 - 4.06 (m, 2H), 2.84 - 2.70 (m, 1H), 1.70 (s, 3H), 1.56 (s, 4H), 0.86 - 0.75 (m, 3H);

m/z (ESI): [M+ H] ⁺ = 489.2.

Preparation of compounds 1-17

Compound 1-16 (210 mg, 0.43 mmol) was added to a 7 mol/L ammonia/methanol solution (6.1 mL, 43.00 mmol), and the reaction solution was reacted in a PTFE-sealed container at 40°C for 24 hours. After the reaction was complete, the crude product was concentrated and purified by preparative high-performance liquid chromatography (Phenomenex luna C18 150*25mm*10um; mobile phase: [A: water (0.1% formic acid)-B: acetonitrile; elution gradient: B%: 40%-70% elution for 10 min) to obtain compound 1-17.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.74 (s, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H), 8.07 (br d, J = 2.1 Hz, 1H), 7.83 (dd, J = 2.1, 5.5 Hz, 1H), 7.63 (s, 1H), 7.22 - 7.12 (m, 2H), 5.10 (d, J = 10.3 Hz, 1H), 4.25 (dd, J = 7.9, 10.1 Hz, 1H), 3.94 (d, J = 2.0 Hz, 3H), 2.83 - 2.71 (m, 1H), 1.61 (s, 3H), 0.73 (d, J = 6.5 Hz, 3H);

m/z (ESI): [M+ H] ⁺ = 474.4.

Preparation of compounds 1-18

Under a nitrogen atmosphere at 0°C, boron tribromide (0.30 mL, 0.32 mmol) was slowly added dropwise to a 2 mL solution of dichloromethane containing compound 1-17 (100 mg, 0.21 mmol). After the addition was complete, the mixture was stirred at 0°C for 2 hours. After the reaction was complete, the reaction solution was quenched in 50 mL of saturated sodium bicarbonate aqueous solution. The aqueous phase was extracted with ethyl acetate (20 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer silica gel (dichloromethane/methanol = 10:1) to obtain compound 1-18.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.74 (s, 1H), 10.53 - 10.41 (m, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.27 (s, 1H), 8.06 (s, 1H), 7.83 (dd, J = 2.1, 5.5 Hz, 1H), 7.62 (br s, 1H), 7.03 (t, J = 7.1 Hz, 1H), 6.86 (q, J = 8.9 Hz, 1H), 5.10 (d, J = 10.3 Hz, 1H), 4.30 - 4.20 (m, 1H), 2.90 - 2.78 (m 1H), 2.54 (d, J = 1.0 Hz, 2H), 1.60 (s, 3H), 0.71 (d, J = 6.3 Hz, 3H);

m/z (ESI): [M+ H] ⁺ = 460.2.

Preparation of Example 1

Under nitrogen atmosphere, bromopropyne (2.38 mg, 0.02 mmol) was slowly added dropwise to a 1 mL DMF solution of compound 1-18 (10 mg, 0.02 mmol) and potassium carbonate (13.8 mg, 0.02 mmol). After the addition was complete, the temperature was raised to 60 °C and the reaction was carried out for 2 hours. The reaction solution was cooled and filtered. The filtrate was purified by preparative high performance liquid chromatography (column type: Waters Xbridge 150*25 mm*5 μm; mobile phase A: water (ammonia)-B: acetonitrile; elution gradient: B%: 42%-72%; elution for 11 minutes) to obtain Example 1.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.68 (s, 1H), 8.46 (d, J = 5.6 Hz, 1H), 8.16 (dd, J = 2.2, 5.6 Hz, 1H), 7.94 (d, J = 2.1 Hz, 1H), 7.84 (s, 1H), 7.19 - 7.11 (m, 1H), 7.05 - 6.94 (m, 1H), 5.67 - 5.56 (m, 1H), 5.02 (d, J = 11.4 Hz, 1H), 4.93 - 4.74 (m, 2H), 4.26 (dd, J = 7.8, 11.3 Hz, 1H), 2.90 - 2.79 (m, 1H), 2.38 (t, J = 2.4 Hz, 1H), 1.72 (s, 3H), 0.86 - 0.77 (m, 3H);

m/z (ESI): [M+ H] ⁺ = 498.2.

Implementation Example 2

Under nitrogen atmosphere, 1-bromo-2-butyne (14.5 mg, 0.11 mmol) was slowly added dropwise to 1 mL of DMF solution containing compound 1-18 (50 mg, 0.11 mmol) and potassium carbonate (75.2 mg, 0.54 mmol). The reaction solution was heated to 60 °C and reacted for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature, filtered, and the filtrate was purified by preparative high-performance liquid chromatography (column type: Waters Xbridge 150*25 mm*5 μm; mobile phase A: water (ammonium bicarbonate)-B: acetonitrile; elution gradient: B%: 50%-80% elution for 9 minutes) to obtain Example 2.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.72 (s, 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H), 8.10 - 8.02 (m, 1H), 7.84 (dd, J = 2.0, 5.6 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.28 - 7.14 (m, 2H), 5.12 (d, J = 10.4 Hz, 1H), 4.93 - 4.78 (m, 2H), 4.37 (dd, J = 7.6, 10.3 Hz, 1H), 2.90 - 2.70 (m, 1H), 1.75 (t, J = 2.4 Hz, 3H), 1.62 (s, 3H), 0.73 (d, J = 6.4 Hz, 3H);

m/z (ESI): [M + H] ⁺ = 512.2.

Implementation Example 3

Preparation of compound 3-1

Under nitrogen atmosphere, compound 1-18 (200 mg, 0.04 mmol) and triethylamine (0.1 mL, 0.65 mmol) were dissolved in 3 mL of dichloromethane solution. The mixture was stirred at 0°C for 10 minutes, and trifluoromethanesulfonic anhydride (72.3 μL, 0.44 mmol) was added dropwise. After the addition was complete, the reaction was continued at 0°C for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 3-1.

m/z (ESI): [M + H] ⁺ = 592.1.

Preparation of compound 3-2

Under a nitrogen atmosphere, 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (6.19 mg, 0.01 mmol), copper iodide (3.22 mg, 0.02 mmol), and triethylamine (25.66 mg, 0.25 mmol) were added sequentially to 0.5 mL of DMF solvent containing compound 3-1 (50 mg, 0.08 mmol) and triisopropylsilylacetylene (0.1 mL, 0.25 mmol). The reaction solution was heated to 100 °C and stirred for 6 hours. After the reaction was completed, the reaction solution was cooled to room temperature and filtered through short silica gel (washed with ethyl acetate). The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by reversed-phase column chromatography (0.1% formic acid system) to obtain compound 3-2.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.61 (s, 1H), 8.47 (d, J = 5.6 Hz, 1H), 8.18 (dd, J = 2.1, 5.4 Hz, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.86 (d, J = 4.5 Hz, 1H), 7.18 (d, J = 5.7 Hz, 2H), 5.59 (d, J = 2.9 Hz, 1H), 5.03 (d, J = 11.2 Hz, 1H), 4.32 (dd, J = 8.2, 11.0 Hz, 2H), 2.97 (t, J = 7.6 Hz, 1H), 2.37 (s, 1H), 2.03 (d, J = 6.6 Hz, 1H), 1.68 (s, 3H), 1.10 (s, 18H), 0.87 - 0.81 (m, 3H);

m/z (ESI): [M + H] ⁺ = 624.2.

Preparation of Example 3

Under a nitrogen atmosphere, cesium fluoride (30.38 mg, 0.20 mmol) was added to 0.5 mL of DMF solution containing compound 3-2 (13 mg, 0.02 mmol), and the reaction solution was stirred at 25°C for 1 hour. After the reaction was complete, the solution was filtered, and the filtrate was purified by preparative high-performance liquid chromatography (Waters Xbridge 150*25mm*5um; mobile phase A: water (ammonium bicarbonate)-B: acetonitrile; elution gradient: B%: 45% - 75%; elution for 9 minutes) to obtain Example 3.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.67 (s, 1H), 8.48 (d, J = 5.5 Hz, 1H), 8.17 (dd, J = 2.0, 5.4 Hz, 1H), 7.94 (d, J = 1.6 Hz, 1H), 7.87 (s, 1H), 7.26 - 7.17 (m, 2H), 5.61 (d, J = 2.3 Hz, 1H), 5.06 (d, J = 11.0 Hz, 1H), 4.27 (dd, J = 7.9, 11.2 Hz, 1H), 3.64 (s, 1H), 2.97 (t, J = 7.6 Hz, 1H), 1.71 (s, 3H), 0.88 - 0.74 (m, 3H);

m/z (ESI): [M + H] ⁺ = 468.2.

Implementation Example 4

Preparation of compound 4-2

The synthetic route for compound 4-2 is as follows:

Under nitrogen atmosphere, compound 4-1 (3.00 g, 18.4 mmol) was added dropwise to 50 mL of DMF solution containing 1,2-dibromoethane (14.5 g, 77.2 mmol) and triethylamine (5.60 mL, 40.5 mmol). The mixture was stirred at 20 °C for 16 hours. After the reaction was complete, the reaction solution was poured into 100 mL of water, and the mixture was extracted with ethyl acetate (50 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluting with petroleum ether) to obtain compound 4-2.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.87 (s, 4H), 4.45 (t, J = 6.0 Hz, 2H), 3.77 - 3.77 (m, 1H), 3.75 (t, J = 6.0 Hz, 1H).

Preparation of compound 4-3

Under nitrogen atmosphere, compound 4-2 (58.8 mg, 0.22 mmol) was added to 2 mL of DMF solution containing compound 1-18 (100 mg, 0.22 mmol) and potassium carbonate (150 mg, 1.09 mmol). The reaction solution was heated to 60 °C and stirred for 6.5 hours. After the reaction was complete, the reaction solution was cooled to room temperature, filtered, and the filtrate was purified by reversed-phase column chromatography (0.1% formic acid system) to give compound 4-3.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.75 (s, 1H), 8.35 (d, J = 5.6 Hz, 1H), 8.23 (dd, J = 2.4, 5.6 Hz, 1H), 7.80 (d, J = 2.0 Hz, 2H), 7.70 (s, 4H), 7.25 - 7.17 (m, 1H), 7.02 - 6.92 (m, 1H), 5.82 - 5.71 (m, 1H), 5.00 (d, J = 11.6 Hz, 1H), 4.74 - 4.62 (m, 2H), 4.51 (dd, J = 8.0, 10.4 Hz, 1H), 4.44 - 4.25 (m, 2H), 3.07 - 2.97 (m, 1H), 1.78 (s, 3H), 0.80 (dd, J = 2.0, 5.6 Hz, 3H);

m/z (ESI): [M+ H] ⁺ = 649.2.

Preparation of compound 4-4

Under nitrogen atmosphere, hydrazine hydrate (14.2 mg, 0.28 mmol) was added to 3 mL of ethanol solution containing compound 4-3 (90.0 mg, 0.14 mmol). The reaction solution was heated to 65°C and stirred for 1 hour. After the reaction was complete, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated to obtain compound 4-4.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.70 - 8.64 (m, 1H), 8.47 (d, J = 5.6 Hz, 1H), 8.13 (dd, J = 2.4, 5.6 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.87 - 7.80 (m, 1H), 7.13 - 7.06 (m, 1H), 6.99 (d, J = 2.4 Hz, 1H), 5.62 - 5.56 (m, 1H), 5.02 (d, J = 11.2 Hz, 1H), 4.49 - 4.40 (m, 1H), 4.38 - 4.23 (m, 2H), 3.96 - 3.88 (m, 1H), 3.86 - 3.79 (m, 1H), 2.88 - 2.74 (m, 1H), 1.29 - 1.23 (m, 3H), 0.83 - 0.77 (m, 3H).

Preparation of Example 4

Under nitrogen atmosphere, pyridine p-toluenesulfonate (0.27 mg) and paraformaldehyde (6.37 mg, 0.21 mmol) were added sequentially to 3 mL of dichloromethane solution containing compound 4-4 (55 mg, 0.11 mmol), and the reaction solution was heated to 40 °C and stirred for 4 hours. After the reaction was complete, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 2). The combined organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative high-performance liquid chromatography (column type: Waters Xbridge 150*25 mm*5 μm; mobile phase A: water (ammonium bicarbonate)-B: acetonitrile; gradient: B: 48%-78% elution for 10 min) to obtain Example 4.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.69 (s, 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H), 8.07 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 2.4, 5.6 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.20 - 7.13 (m, 2H), 7.05 (d, J = 7.6 Hz, 1H), 6.58 (d, J = 7.6 Hz, 1H), 5.12 (d, J = 10.6 Hz, 1H), 4.43 (dd, J = 4.8, 6.8 Hz, 1H), 4.37 - 4.23 (m, 4H), 2.88 - 2.76 (m, 1H), 1.60 (s, 3H), 0.70 (d, J = 6.0 Hz, 3H);

m/z (ESI): [M+ H] ⁺ = 531.2.

Implementation Example 5

Preparation of compound 5-2

The synthetic route for compound 5-2 is as follows:

Under nitrogen atmosphere, tert-butyldimethylchlorosilane (865 mg, 5.74 mmol) was added to 5 mL of DMF solution containing compound 5-1 (300 mg, 2.87 mmol) and imidazole (586 mg, 8.61 mmol). The reaction solution was stirred at 20 °C for 3 hours. After the reaction was complete, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (25 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluting with petroleum ether) to obtain compound 5-2.

¹ H NMR (400 MHz, CDCl ₃ ): δ 4.37 (t, J = 2.0 Hz, 2H), 4.18 (t, J = 2.0 Hz, 2H), 0.92 (s, 9H), 0.13 (s, 6H).

Preparation of compound 5-3

Under nitrogen atmosphere, a DMF solution (1 mL) of compound 5-2 (28.6 mg, 0.13 mmol) was slowly added to a DMF suspension (1 mL) of compound 1-18 (60 mg, 0.13 mmol) and potassium carbonate (90.3 mg, 0.65 mmol). The reaction mixture was heated to 60 °C and stirred for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and filtered. The filtrate was purified by reverse-phase separation (mobile phase A: water (0.1% ammonia) - B: acetonitrile; elution gradient: B: 100%; elution for 3 minutes) to obtain compound 5-3.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.73 (s, 1H), 8.48 (d, J = 5.6 Hz, 1H), 8.27 (d, J = 2.0 Hz, 1H), 8.05 (d, J = 2.4 Hz, 1H), 7.95 (s, 4H), 7.84 (dd, J = 2.4, 5.6 Hz, 1H), 7.61 (d, J = 2.4 Hz, 1H), 7.26 - 7.17 (m, 2H), 5.12 (d, J = 10.4 Hz, 1H), 5.04 - 4.92 (m, 2H), 4.33 (dd, J = 7.6, 10.2 Hz, 1H), 4.28 - 4.22 (m, 2H), 1.61 (s, 3H), 0.77 (s, 9H), -0.06 (s, 6H);

m/z (ESI): [M+ H] ⁺ = 642.3.

Preparation of Example 5

Compound 5-3 (25 mg, 0.04 mmol) was dissolved in a methanol solution of hydrogen chloride (2 mL, 2 mol/L) and stirred at 25 °C for 0.5 hours. After the reaction was complete, the solution was concentrated, diluted with 2 mL of methanol, and adjusted to pH = 8 with ammonia. The solution was then purified by preparative high-performance liquid chromatography (column type: Waters Xbridge 150*25 mm*5 μm; mobile phase A: water (ammonium bicarbonate)-B: acetonitrile; elution gradient: B: 38%-68%; elution for 9 min) to obtain Example 5.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.73 (s, 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.26 (d, J = 2.0 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 2.0, 5.6 Hz, 1H), 7.63 (br d, J = 1.6 Hz, 1H), 7.28 - 7.14 (m, 2H), 5.21 (t, J = 6.0 Hz, 1H), 5.11 (d, J = 10.4 Hz, 1H), 4.94 (d, J = 1.6 Hz, 2H), 4.34 (dd, J = 7.6, 10.4 Hz, 1H), 4.10 - 4.03 (m, 2H), 2.90 - 2.79 (m, 1H), 1.62 (s, 3H), 0.74 (d, J = 6.4 Hz, 3H);

m/z (ESI): [M+ H] ⁺ = 528.2.

Implementation Example 6

Preparation of compound 6-2

Under a nitrogen atmosphere, at -78°C, methyllithium (5.3 mL, 8.41 mmol) was slowly added dropwise to 15 mL of tetrahydrofuran containing compound 6-1 (1.0 g, 8.41 mmol). After stirring the reaction solution at -78°C for 5 minutes, acetone (6.2 mL, 84.06 mmol) was slowly added dropwise. After the addition was complete, the reaction solution was stirred at -78°C for another 10 minutes. After the reaction was complete, 30 mL of saturated ammonium chloride aqueous solution was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with 50 mL of saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified and separated by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain compound 6-2.

¹ H NMR (400 MHz, CDCl ₃ ): δ 3.94 (s, 2H), 1.53 (s, 6H).

Preparation of Example 6

Under nitrogen atmosphere, potassium carbonate (63.18 mg, 0.46 mmol) and compound 6-2 (16.29 mg, 0.09 mmol) were added to 1 mL of DMF solution containing compound 1-18 (50 mg, 0.09 mmol). The reaction mixture was stirred at 60°C for 2 hours. After the reaction was complete, the mixture was filtered, and the filtrate was purified and separated by preparative high performance liquid chromatography (column type: Waters Xbridge 150* 25mm *5um; mobile phase A: water (ammonium bicarbonate)-B: acetonitrile; elution gradient: B: 35%~65%; elution for 10 min) to obtain Example 6.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.74 (s, 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.27 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 2.0, 5.6 Hz, 1H), 7.61 (d, J = 1.6 Hz, 1H), 7.24 - 7.15 (m, 2H), 5.31 (s, 1H), 5.12 (d, J = 10.6 Hz, 1H), 4.94 (s, 2H), 4.28 (dd, J = 7.2, 10.2 Hz, 1H), 2.85 (t, J = 7.2 Hz, 1H), 1.63 (s, 3H), 1.27 (s, 3H), 1.24 (s, 3H), 0.74 (d, J = 5.6 Hz, 3H);

m/z (ESI): [M + H] ⁺ = 556.3.

Implementation Example 7

Under a nitrogen atmosphere, 2-methyl-3-butyn-2-ol (0.1 mL, 0.89 mmol) and _K₂CO₃ ( _451.27 mg, 3.27 mmol) were added sequentially to a DMF (6 mL) solution containing compound 1-18 (300 mg, 0.65 mmol). The reaction was carried out at 100 °C for 2 hours. Then, compound 2 (0.1 mL, 0.89 mmol) was added to the reaction solution, and the reaction was continued at 100 °C for 2 hours. After the reaction was completed _, the reaction liquid was cooled to room temperature and filtered. The filtrate was purified by reverse phase preparation (Waters Xbridge 150 × 25 mm × 5 μm, water (water( _NH4HCO3 )-ACN, 52% - 82%, 16 min) to obtain Example 7.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.76 (br s, 1H), 8.48 (d, J = 5.52 Hz, 1H), 8.25 (d, J = 1.88 Hz, 1H), 8.08 (d, J = 2.00 Hz, 1H), 7.82 (dd, J = 5.40, 1.88 Hz, 1H), 7.63 (br s, 1H), 7.16 - 7.29 (m, 2H), 5.09 (d, J = 10.52 Hz, 1H), 4.43 (dd, J = 10.32, 7.60 Hz, 1H), 3.54 (s, 1H), 2.80 (t, J = 7.20 Hz, 1H), 1.70 (s, 3H), 1.67 (s, 3H), 1.61 (s, 3H), 0.70 (br d, J = 5.12 Hz, 3H);

m/z (ESI): [M+ H] ⁺ = 526.1.

Implementation Example 8

Preparation of compound 8-2

Under nitrogen atmosphere, methanesulfonic anhydride (0.80 mL, 6.42 mmol) was slowly added to a 5 mL solution of dichloromethane containing compound 8-1 (300 mg, 4.28 mmol) and triethylamine (1.8 mL, 12.8 mmol). The reaction mixture was stirred at 20 °C for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, diluted with 50 mL of water, and extracted with ethyl acetate (25 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 8-2.

¹ H NMR (400 MHz, CDCl ₃ ): δ 5.30 (dq, J = 2.0, 6.8 Hz, 1H), 3.13 (s, 3H), 2.71 (d, J = 2.0 Hz, 1H), 1.67 (d, J = 6.8 Hz, 3H).

Preparation of Example 8

Under nitrogen atmosphere, a DMF (0.5 mL) solution of compound 8-2 (6.45 mg, 0.04 mmol) was slowly added to a DMF (0.5 mL) solution of compound 1-18 (100 mg, 0.22 mmol) and potassium carbonate (150 mg, 1.09 mmol). The reaction mixture was stirred at 60°C for 16 hours. After the reaction was complete, the reaction mixture was filtered, and the filtrate was purified by reverse-phase preparation (column: Waters Xbridge 150 × 25 mm × 5 _μm , water ( _NH₄HCO₃ )-ACN, 40%-70%, 15 min) to obtain Example 8.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.70 (s, 1H), 8.48 (d, J = 5.6 Hz, 1H), 8.25 (d, J = 2.0 Hz, 1H), 8.07 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 2.0, 5.6 Hz, 1H), 7.62 (br d, J = 2.0 Hz, 1H), 7.27 - 7.14 (m, 2H), 5.25 (dq, J = 2.0, 6.4 Hz, 1H), 5.10 (d, J = 10.8 Hz, 1H), 4.31 (dd, J = 7.6, 10.8 Hz, 1H), 3.67 (d, J = 2.0 Hz, 1H), 2.85 - 2.73 (m, 1H), 1.66 - 1.57 (m, 6H), 0.77 (br d, J = 6.0 Hz, 3H);

m/z (ESI): [M+ H] ⁺ =512.2.

Implementation Example 9

Under a nitrogen atmosphere, cyanomethylene tri-n-butylphosphine (132.4 mg, 0.55 mmol) and (S)-(-)-3-butyn-2-ol (38.45 mg, 0.55 mmol) were added to a 2 mL solution of 1,4-dioxane containing compound 1-18 (60 mg, 0.11 mmol). The reaction mixture was stirred at 40 °C for 16 hours. After the reaction was complete, the mixture was quenched with water (40 mL), extracted with ethyl acetate (30 mL × 2), and the combined organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse phase preparation (Column: Waters Xbridge 150 × 25 mm × ₅ μm; Condition: water ( _NH4HCO3 )-ACN; Begin B: 43, End B: 73; Gradient Time (min): 10; 100%B Hold Time (min): 4, Flow Rate (ml/min): 25) and separated to obtain Example 9.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.72 (s, 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.26 (d, J = 2.0 Hz, 1H), 8.07 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 2.0, 5.6 Hz, 1H), 7.63 (br s, 1H), 7.30 - 7.15 (m, 2H), 5.16 - 5.06 (m, 2H), 4.45 (dd, J = 7.2, 10.2 Hz, 1H), 3.41 (d, J = 2.0 Hz, 1H), 2.91 - 2.79 (m, 1H), 1.66 - 1.59 (m, 6H), 0.70 (d, J = 6.0 Hz, 3H);

m/z (ESI): [M + H] ⁺ = 512.1.

Implementation Example 10

Preparation of compound 10-2

Under nitrogen atmosphere, tert-butyldimethylchlorosilane (1.92 g, 12.80 mmol) was added to a DMF (10 mL) solution of compound 10-1 (0.50 mL, 6.40 mmol) and imidazole (1.31 g, 19.2 mmol). The reaction mixture was stirred at 20 °C for 16 hours. After the reaction was complete, the reaction mixture was quenched with water (100 mL), extracted with ethyl acetate (50 mL × 2), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (eluting with petroleum ether) to obtain compound 10-2.

¹ H NMR (400 MHz, CDCl ₃ ): δ 3.74 (t, J = 6.4 Hz, 2H), 2.68 - 2.59 (m, 2H), 1.57 (s, 1H), 0.93 - 0.90 (m, 9H), 0.10 - 0.07 (m, 6H).

Preparation of compound 10-3

Under a nitrogen atmosphere, tris(dibenzylacetone)dipalladium (31.0 mg, 0.03 mmol) and 4,5-bis(diphenylphosphine-9,9-dimethyloxoanthracene) (39.1 mg, 0.07 mmol) were added to a 1,4-dioxane (4 mL) solution of compound 3-1 (200 mg, 0.34 mmol), compound 10-2 (130 mg, 0.68 mmol), and N,N-diisopropylethylamine (0.3 mL, 2.03 mmol). The reaction mixture was stirred at 100 °C for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, quenched with water (50 mL), extracted with ethyl acetate (20 mL × 2), and the combined organic phase was washed with brine (20 mL) and separated. The mixture was then dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate = 10/1 to 2/1) to obtain compound 10⁻³.

¹ H NMR (400 MHz, CDCl ₃ ): δ= 8.71 (s, 1H), 8.46 (d, J = 5.6 Hz, 1H), 8.16 (dd, J = 2.0, 5.6 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.85 (d, J = 4.0 Hz, 1H), 7.24 - 7.16 (m, 2H), 5.66 (d, J = 3.6 Hz, 1H), 5.06 (d, J = 11.2 Hz, 1H), 4.54 (dd, J = 8.0, 11.2 Hz, 1H), 3.73 - 3.65 (m, 2H), 3.15 (dq, J = 4.8, 7.2 Hz, 3H), 3.04 - 2.95 (m, 2H), 2.83 (m, 1H), 0.81 (s, 9H), 0.78 - 0.73 (m, 3H), 0.04 (d, J = 10.0 Hz, 6H);

m/z(ESI): [M+ H] ⁺ = 634.1.

Preparation of Example 10

Under nitrogen atmosphere, compound 10⁻³ (95 mg, 0.15 mmol) was added to a methanol hydrochloride (2N, 5 mL) solution, and the reaction solution was reacted at 17°C for 0.5 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was diluted with methanol (2 mL). After adjusting the _pH to 8 with ammonia, it was purified by reverse-phase preparation (column: Waters Xbridge 150*25mm*5um, water ( _NH₄HCO₃ )-ACN, 38%-68%, 15 min) to obtain Example 10.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.68 (s, 1H), 8.48 (d, J = 5.6 Hz, 1H), 8.26 (d, J = 2.0 Hz, 1H), 8.09 - 8.03 (m, 1H), 7.83 (dd, J = 2.4, 5.6 Hz, 1H), 7.62 (br d, J = 2.0 Hz, 1H), 7.55 - 7.43 (m, 1H), 7.29 (dd, J = 5.2, 8.0 Hz, 1H), 5.17 (d, J = 10.4 Hz, 1H), 4.84 (t, J = 5.6 Hz, 1H), 4.69 (dd, J = 7.6, 10.4 Hz, 1H), 3.51 - 3.39 (m, 2H), 2.96 - 2.89 (m, 2H), 2.84 (t, J = 7.2 Hz, 1H), 1.64 (s, 3H), 0.70 (br d, J = 6.0 Hz, 3H);

m/z (ESI): [M+ H] ⁺ = 520.2.

Implementation Example 11

Preparation of compound 11-2

Under nitrogen atmosphere, triethylamine (223.8 μL, 1.61 mmol) and 11-1 (81.67 mg, 0.54 mmol) were sequentially added to 4 mL of dichloromethane containing compound 1-15 (200 mg, 0.54 mmol). The reaction mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the crude product was concentrated and purified by reverse reaction (0.1% FA) to obtain compound 11-2.

m/z (ESI): [M + H] ⁺ = 489.1.

Preparation of compound 11-3

Under a nitrogen atmosphere at 0°C, boron tribromide (0.1 mL, 0.24 mmol) was slowly added dropwise to 2 mL of dichloromethane containing compound 11-2 (80 mg, 0.16 mmol). The reaction mixture was stirred at 25°C for 1.5 hours. After the reaction was complete, 3 mL of dichloromethane was added for dilution, and the mixture was quenched dropwise with 4 mL of saturated sodium bicarbonate aqueous solution. The mixture was extracted with dichloromethane (5 mL × 3). The combined organic phase was washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified and separated by reverse reaction (0.1% FA) to obtain 11-3.

LC-MS (ESI): [M + H] ⁺ =475.1.

Preparation of Example 11

Under a nitrogen atmosphere, 3-bromopropyne (12.54 mg, 0.11 mmol) was added to 1 mL of N,N-dimethylformamide solution containing compound _11-3 (50 mg, 0.11 mmol) and _K₂CO₃ (72.82 mg, 0.53 mmol). The reaction solution was reacted at 60 °C for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature and filtered. The filtrate was purified by reverse-phase preparation (Waters Xbridge 150 × 25 mm × ₅ μm, water (water( _NH₄HCO₃ )-ACN, 45% - 75% over 10 min) to obtain Example 11.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.54 (s, 1H), 8.34 (d, J = 5.52 Hz, 1H), 7.86 (d, J = 1.88 Hz, 1H), 7.49 (dd, J = 5.52, 2.12 Hz, 1H), 7.11 - 7.28 (m, 2H), 5.18 (s, 1H), 5.09 (d, J = 10.52 Hz, 1H), 4.86 - 4.99 (m, 2H), 4.33 (dd, J = 10.36, 7.52 Hz, 1H), 3.65 (t, J = 2.36 Hz, 1H), 2.84 (t, J = 7.44 Hz, 1H), 1.60 (s, 3H), 1.39 (s, 6H), 0.73 (d, J = 6.36 Hz, 3H);

m/z (ESI): [M+ H] ⁺ = 513.1.

Implementation Example 12

Preparation of compound 12-2

Under nitrogen atmosphere, deuterated aluminum lithium hydroxide (2.6 mL, 5.12 mmol, 2 M THF solution) was slowly added dropwise to 40 mL of tetrahydrofuran solution containing compound 12-1 (1 g, 6.40 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the solution was quenched with 1 mL of deuterium water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound 12-2.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.67 (s, 1H), 0.20 - 0.17 (m, 9H).

Preparation of compound 12-3

Under nitrogen atmosphere, tributyl cyanimide phosphate (176.54 mg, 0.77 mmol) and compound 12-2 (95.28 mg, 0.73 mmol) were sequentially added to a 2 mL solution of dioxane containing compound 1-18 (80 mg, 0.15 mmol). The reaction mixture was stirred at 40 °C for 16 hours. After the reaction was complete, the mixture was quenched with 10 mL of water, extracted with ethyl acetate (10 mL × 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound 12-3.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.71 - 8.67 (m, 1H), 8.47 (d, J = 5.6 Hz, 1H), 8.18 (dd, J = 2.0, 5.6 Hz, 1H), 7.92 (d, J = 2.0 Hz, 1H), 7.88 (br d, J = 2.0 Hz, 1H), 7.17 - 7.11 (m, 1H), 6.99 - 6.93 (m, 1H), 5.62 - 5.56 (m, 1H), 5.04 (d, J = 11.2 Hz, 1H), 4.18 (dd, J = 6.8, 10.8 Hz, 1H), 2.91 (t, J = 7.6 Hz, 1H), 1.72 (s, 3H), 0.84 - 0.80 (m, 3H), 0.09 (s, 9H);

m/z (ESI): [M + H] ⁺ = 572.2.

Preparation of Example 12

Under a nitrogen atmosphere, tetrabutylammonium fluoride (235 μL, 0.23 mmol, 1 M THF solution) was added to 2 mL of tetrahydrofuran solution containing compound 12-3 (60 mg, 0.08 mmol), and the reaction solution was stirred at 22.5 °C for 1.5 hours. After the reaction was complete, the mixture was quenched with 40 mL of water, extracted with ethyl acetate (20 mL × 3), and the combined organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse-phase preparation (Column: Waters Xbridge 150 × 25 mm × ₅ μm; Condition: water ( _NH₄HCO₃ )-ACN; Begin B: 43, End B: 73; Gradient Time (min): 10; 100%B Hold Time (min): 4, Flow Rate (ml/min): 25) and separated to obtain Example 12.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.71 (br s, 1H), 8.48 (d, J = 5.6 Hz, 1H), 8.26 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7.83 (dd, J = 2.0, 5.6 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.28 - 7.15 (m, 2H), 5.11 (d, J = 10.2 Hz, 1H), 4.33 (dd, J = 7.2, 10.2 Hz, 1H), 3.63 (s, 1H), 2.90 - 2.78 (m, 1H), 1.62 (s, 3H), 0.74 (d, J = 6.8 Hz, 3H);

m/z (ESI): [M + H] ⁺ = 500.1.

Implementation Example 13

Under nitrogen atmosphere, 4-bromobutyne (193.81 mg, 1.46 mmol) and potassium carbonate (225.64 mg, 1.63 mmol) were added sequentially to 3 mL of DMF solution containing compound 1-18 (150 mg, 0.33 mmol). The reaction solution was reacted at 80 °C for 16 hours. After the reaction was complete, the reaction solution was cooled to room temperature and filtered. The filtrate was purified by reverse-phase preparation (Waters Xbridge 150 × 25 mm × 5 _μm , water (water( _NH4HCO3 )-ACN, 48% - 78%, 25 min) to obtain Example 13.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.69 (s, 1H) , 8.49 (d, J = 5.52 Hz, 1H), 8.28 (d, J = 2.00 Hz, 1H), 8.06 (s, 1H), 7.84 (dd, J = 5.56, 2.20 Hz, 1H), 7.62 (d, J = 2.24 Hz, 1H), 7.23 - 7.13 (m, 2H), 5.12 (d, J = 10.52 Hz, 1H), 4.35 (dd, J = 10.28, 7.64 Hz, 1H), 4.30 - 4.23 (m, 1H), 4.20 - 4.13 (m, 1H), 2.89 - 2.87 (m, 1H), 2.69 - 2.65 (m, 2H), 2.47 - 2.43 (m, 1H), 1.63 (s, 3H), 0.72 (d, J = 6.76Hz, 3H);

m/z (ESI): [M+ H]+ =512.1.

Implementation Example 14

Preparation of compound 14-2

Under nitrogen protection at 0°C, sodium hydroxide (14.5 mg, 0.36 mmol) was slowly added to 5 mL of DMF solution containing compound 14-1 (0.4 mL, 8.06 mmol). After stirring the reaction solution at 0°C for half an hour, bromopropyne (642 mg, 5.40 mmol) was added dropwise. After the addition was complete, the reaction solution was heated to 50°C and stirred for 16 hours. After the reaction was complete, the reaction solution was added dropwise to ice-saturated ammonium chloride (0.0 mL) for quenching, and extracted with ethyl acetate (20 mL × 2). The combined organic phase was dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain crude product, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2/1) to obtain compound 14-2.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 4.65 (t, J = 5.4 Hz, 1H), 4.13 (d, J = 2.4 Hz, 2H), 3.53 - 3.47 (m, 2H), 3.47 - 3.43 (m, 2H), 3.41 (t, J = 2.4 Hz, 1H).

Preparation of Example 14

Under a nitrogen atmosphere, tributyl cyanimide phosphate (131 mg, 0.54 mmol) was added to a 2 mL solution of dioxane containing compound 1-18 (50.0 mg, 0.11 mmol) and compound 14-2 (54.5 mg, 0.54 mmol). The reaction solution was heated to 40 °C and reacted for 2 hours. After the reaction was completed, the reaction solution was quenched with 50 mL of water and extracted with ethyl acetate (20 mL * 2). The combined organic phase was washed with brine (20 mL) and separated. The aqueous phase was extracted again with ethyl acetate (20 mL). The combined organic phase was dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by reverse-phase preparation (column: Waters Xbridge 150 × 25 mm × 5 μm, water _{( NH4HCO3} )-ACN, 40%-70%, 15 min) to obtain Example 14.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.70 (s, 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.27 (d, J = 2.0 Hz, 1H), 8.07 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 2.0, 5.6 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.22 - 7.12 (m, 2H), 5.11 (d, J = 10.8 Hz, 1H), 4.36 - 4.27 (m, 2H), 4.27 - 4.21 (m, 1H), 4.19 (t, J = 2.4 Hz, 2H), 3.75 (td, J = 2.8, 5.2 Hz, 2H), 3.44 (t, J = 2.4 Hz, 1H), 2.91 - 2.80 (m, 1H), 1.62 (s, 3H), 0.71 (d, J = 6.0 Hz, 3H);

m/z (ESI): [M+ H] ⁺ = 542.2.

Implementation Example 15

Preparation of compound 15-2

Under nitrogen atmosphere, n-butyllithium (6.8 mL, 17.12 mmol, 2.5 M) was slowly added dropwise to a tetrahydrofuran (10 mL) solution containing compound 15-1 (1 g, 14.27 mmol) at -78 °C. The reaction solution was stirred at -78 °C for 1 hour, then paraformaldehyde (2.06 g, 22.83 mmol) was added, and the reaction solution was slowly heated to 25 °C and stirred for 16 hours. After the reaction was completed, the reaction solution was cooled to 0°C and quenched with saturated ammonium chloride aqueous solution (50 mL). It was then extracted with ethyl acetate (50 mL × 3). The combined organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2/1) to separate compound 15-2.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 5.19 (t, J = 5.2 Hz, 1H), 4.12 - 4.08 (m, 4H), 3.25 (s, 3H).

Preparation of Example 15

Under a nitrogen atmosphere, tributyl cyanimide (116.90 mg, 0.48 mmol) and compound 15-2 (48.49 mg, 0.48 mmol) were added sequentially to a solution of dioxane (2 mL) containing compound 1-18 (50 mg, 0.10 mmol). The reaction mixture was stirred at 40°C for 12 hours. After the reaction was complete, the mixture was quenched with water (40 mL), extracted with ethyl acetate (20 mL × 2), and the combined organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse-phase preparation (Column: Waters Xbridge 150 × 25 mm × ₅ μm; water ( _NH4HCO3 )-ACN; Begin B: 40, End B: 70; Gradient Time (min): 10; 100%B Hold Time (min): 4, Flow Rate (ml/min): 25) and separated to obtain Example 15.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.72 (s, 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H), 8.07 (d, J = 2.4 Hz, 1H), 7.84 (dd, J = 2.0, 5.6 Hz, 1H), 7.62 (d, J = 2.4 Hz, 1H), 7.28 - 7.15 (m, 2H), 5.12 (d, J = 10.4 Hz, 1H), 5.06 - 4.93 (m, 2H), 4.34 (dd, J = 7.2, 10.4 Hz, 1H), 4.12 - 4.01 (m, 2H), 3.13 (s, 3H), 2.88 - 2.80 (m, 1H), 1.61 (s, 3H), 0.73 (d, J = 6.0 Hz, 3H);

m/z (ESI): [M+ H] ⁺ = 542.2.

Implementation Example 16

Preparation of compound 16-2

Under a nitrogen atmosphere at 0°C, tert-butyldiphenylchlorosilane (21.57 g, 78.47 mmol) was added to a solution of dichloromethane (50 mL) containing compound 16-1 (5 g, 71.34 mmol), 4-dimethylaminopyridine (0.87 g, 7.13 mmol), and triethylamine (19.8 mL, 142.67 mmol). The reaction mixture was heated to 25°C and stirred for 12 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride aqueous solution (50 mL), the aqueous phase was extracted with dichloromethane (50 mL × 3), the combined organic phase was dried with anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure to obtain crude product, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain compound 16-2.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.77 (td, J = 1.3, 7.9 Hz, 2H), 7.70 (td, J = 1.3, 7.9 Hz, 2H), 7.51 - 7.37 (m, 6H), 4.53 - 4.42 (m, 1H), 2.35 (dd, J = 0.6, 2.0 Hz, 1H), 1.41 (dd, J = 0.9, 6.4 Hz, 3H), 1.10 (d, J = 1.0 Hz, 9H).

Preparation of compound 16-3

Under nitrogen atmosphere, a methyl lithium ether solution (15.2 mL, 24.31 mmol, 1.6 M) was slowly added dropwise to a tetrahydrofuran (100 mL) solution containing compound 16-2 (5 g, 16.21 mmol). After stirring the reaction solution at -70°C for 1 hour, paraformaldehyde (0.73 g, 24.31 mmol) was added to the reaction solution in portions. The mixture was then heated to 22°C and stirred for 12 hours. After the reaction was completed, the reaction solution was cooled to 0°C and quenched by adding saturated ammonium chloride aqueous solution (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain compound 16-3.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.76 (d, J = 6.6 Hz, 2H), 7.70 (d, J = 6.5 Hz, 2H), 7.48 - 7.35 (m, 6H), 4.54 (q, J = 6.4 Hz, 1H), 4.10 - 4.06 (m, 2H), 1.42 (d, J = 6.5 Hz, 3H), 1.21 - 1.14 (m, 1H), 1.08 (s, 9H).

Preparation of compound 16-4

Under nitrogen atmosphere, tributyl cyanimide (236.44 mg, 0.98 mmol) was added to a 1,4-dioxane (1.5 mL) solution containing 1-18 (150 mg, 0.33 mmol) and compound 16-3 (1105.38 mg, 3.27 mmol). The reaction mixture was stirred at 25 °C for 12 hours. After the reaction was complete, the reaction mixture was filtered, and the filtrate was purified by passing it through a reverse-phase column (0.1% formic acid system) to obtain compound 16-4.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.69 (s, 1H), 8.42 (d, J = 5.6 Hz, 1H), 8.14 (dd, J = 2.1, 5.5 Hz, 1H), 7.92 (d, J = 2.0 Hz, 1H), 7.89 - 7.84 (m, 1H), 7.68 (dd, J = 1.5, 7.9 Hz, 2H), 7.61 (dd, J = 1.3, 7.9 Hz, 2H), 7.45 - 7.32 (m, 7H), 7.15 - 7.08 (m, 1H), 7.00 - 6.90 (m, 1H), 5.65 (d, J = 4.1 Hz, 1H), 5.01 (d, J = 11.3 Hz, 1H), 4.76 (q, J = 15.1 Hz, 2H), 4.42 (q, J = 6.5 Hz, 1H), 2.89 - 2.78 (m, 1H), 1.64 (s, 3H), 1.29 - 1.27 (m, 3H), 1.01 (s, 9H), 0.82 - 0.77 (m, 3H);

m/z (ESI): [M + H] ⁺ = 780.2.

Preparation of Example 16

Under a nitrogen atmosphere, ammonium fluoride (189.98 mg, 5.13 mmol) was added to a methanol (4 mL) solution containing compound 16-4 (200 mg, 0.26 mmol). The reaction mixture was stirred at 25°C for 12 hours. After the reaction was complete, the reaction mixture was filtered, and the filtrate was purified by reverse-phase preparation (Phenomenex luna C18 150 × 40 mm × 15 μm; mobile phase: water (FA)-ACN; B%: 42% - 72%, 15 min) to obtain Example 16.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.72 (s, 1H), 8.49 (d, J = 5.4 Hz, 1H), 8.27 (d, J = 1.9 Hz, 1H), 8.07 (d, J = 2.1 Hz, 1H), 7.84 (dd, J = 2.2, 5.6 Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H), 7.27 - 7.14 (m, 2H), 5.32 (d, J = 5.4 Hz, 1H), 5.12 (d, J = 10.5 Hz, 1H), 4.93 (s, 2H), 4.40 - 4.22 (m, 2H), 2.90 - 2.81 (m, 1H), 1.62 (s, 3H), 1.20 (d, J = 6.5 Hz, 3H), 0.74 (d, J = 6.6 Hz, 3H);

m/z (ESI): [M + H] ⁺ = 542.2.

Implementation Example 17

Preparation of compound 17-2

Under a nitrogen atmosphere at 0°C, tert-butyldiphenylchlorosilane (8.63 g, 31.39 mmol) was added to a solution of dichloromethane (20 mL) containing compound 17-1 (2 g, 28.53 mmol), 4-dimethylaminopyridine (0.35 g, 2.85 mmol), and triethylamine (7.9 mL, 57.07 mmol). The reaction mixture was stirred at 25°C for 12 hours. After the reaction was complete, a saturated ammonium chloride aqueous solution (20 mL) was added to quench the reaction. The aqueous phase was extracted with dichloromethane (15 mL × 3). The combined organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain compound 17-2.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.77 (dd, J = 1.3, 7.8 Hz, 2H), 7.73 - 7.68 (m, 2H), 7.48 - 7.36 (m, 6H), 4.47 (dq, J = 2.0, 6.5 Hz, 1H), 2.35 (d, J = 2.1 Hz, 1H), 1.41 (d, J = 6.5 Hz, 3H), 1.10 (s, 9H).

Preparation of compound 17-3

Under nitrogen atmosphere, a methyl lithium ether solution (4.9 mL, 7.78 mmol, 1.6 M) was slowly added dropwise to a tetrahydrofuran (30 mL) solution containing compound 17-2 (1.6 g, 5.19 mmol). After stirring the reaction solution at -70°C for 1 hour, paraformaldehyde (0.47 g, 15.56 mmol) was added in portions to the reaction solution. The mixture was then heated to 27°C and stirred for 12 hours. After the reaction was completed, the reaction solution was cooled to 0°C, and the reaction was quenched by adding saturated ammonium chloride aqueous solution (15 mL). The aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain compound 17-3.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.77 (dd, J = 1.1, 7.6 Hz, 2H), 7.73 - 7.68 (m, 2H), 7.49 - 7.35 (m, 6H), 4.60 - 4.50 (m, 1H), 4.09 (d, J = 1.4 Hz, 2H), 1.42 (d, J = 6.5 Hz, 3H), 1.08 (s, 9H).

Preparation of compound 17-4

Under nitrogen atmosphere, tributyl cyanomethylene phosphate (157.62 mg, 0.65 mmol) was added to a 1,4-dioxane (1 mL) solution containing 1-18 (100 mg, 0.22 mmol) and compound 17-3 (736.92 mg, 2.18 mmol). The reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was filtered, and the filtrate was purified by reversed-phase column chromatography (0.1% formic acid system) to give compound 17-4.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.61 (s, 1H), 8.36 (d, J = 5.6 Hz, 1H), 8.08 (dd, J = 2.2, 5.6 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.84 - 7.79 (m, 1H), 7.61 (dd, J = 1.3, 7.9 Hz, 2H), 7.58 - 7.52 (m, 2H), 7.39 - 7.23 (m, 7H), 7.09 - 7.02 (m, 1H), 6.94 - 6.83 (m, 1H), 5.56 (br d, J = 3.5 Hz, 1H), 4.94 (d, J = 11.3 Hz, 1H), 4.80 - 4.58 (m, 2H), 4.35 (q, J = 6.5 Hz, 1H), 2.79 - 2.67 (m, 1H), 1.55 (s, 3H), 1.20 (s, 3H), 0.95 (s, 9H), 0.70 (dd, J = 1.9, 5.3 Hz, 3H);

m/z (ESI): [M + H] ⁺ = 780.3.

Preparation of Example 17

Under nitrogen atmosphere, ammonium fluoride (132.98 mg, 3.59 mmol) was added to a methanol (3 mL) solution containing compound 17-4 (140 mg, 0.18 mmol), and the reaction solution was stirred at 25°C for 12 hours. After the reaction was complete, the reaction solution was filtered, and the filtrate was purified by reverse-phase preparation (Phenomenex luna C18 150*25mm* 10um; mobile phase: water (FA)-ACN; B%: 42% - 72%, 15 min) to obtain Example 17.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.73 (s, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.27 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 2.1 Hz, 1H), 7.84 (dd, J = 2.1, 5.5 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.28 - 7.15 (m, 2H), 5.32 (d, J = 5.4 Hz, 1H), 5.12 (d, J = 10.5 Hz, 1H), 4.94 (s, 2H), 4.40 - 4.23 (m, 2H), 2.90 - 2.79 (m, 1H), 1.63 (s, 3H), 1.15 (d, J = 6.6 Hz, 3H), 0.74 (d, J = 6.1 Hz, 3H);

m/z (ESI): [M + H] ⁺ = 542.1.

Implementation Example 18

Preparation of compound 18-2

Under nitrogen atmosphere, deuterated aluminum lithium hydroxide (0.34 g, 8.15 mmol) was slowly added in portions to a solution of compound 18-1 (1 g, 10.19 mmol) in ether (15 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was quenched with deuterium water (1 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain compound 18-2.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.85 (s, 3H).

Preparation of Example 18

Under a nitrogen atmosphere, tributyl cyanimide phosphate (231.18 mg, 0.96 mmol) and compound 18-2 (138.12 mg, 1.92 mmol) were added to a solution of dioxane (1 mL) containing compound 1-18 (100 mg, 0.19 mmol), and the reaction solution was heated to 40°C and stirred for 16 hours. After the reaction was complete, water (30 mL) was added to quench the reaction, and ethyl acetate (30 mL × 2) was used for extraction. The combined organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse phase preparation (Column: Waters Xbridge 150 × _25mm × 5um; Condition: water ( _NH4HCO3 )-ACN; Begin B: 43, End B: 73; Gradient Time (min): 15; 100%B Hold Time (min): 4, Flow Rate (ml/min): 25) and separated to obtain Example 18.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.72 (s, 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 2.0, 5.6 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.28 - 7.14 (m, 2H), 5.12 (d, J = 10.8 Hz, 1H), 4.37 (dd, J = 7.2, 10.8 Hz, 1H), 2.90 - 2.79 (m, 1H), 1.75 (s, 3H), 1.62 (s, 3H), 0.73 (d, J = 6.0 Hz, 3H);

m/z (ESI): [M + H] ⁺ = 514.1.

Implementation Example 19

Preparation of compound 19-2

Under nitrogen atmosphere, n-butyllithium (14.1 mL, 35.2 mmol, 2.5 M) was slowly added dropwise to a tetrahydrofuran (150 mL) solution containing compound 19-1 (5.00 g, 29.4 mmol). After stirring the reaction solution at -40°C for 0.5 hours, chloroformate (3.3 mL, 43.2 mmol) was added dropwise, and the mixture was stirred at -40°C for another 2 hours. The reaction solution was slowly added dropwise to a saturated ammonium chloride aqueous solution (50 mL) pre-cooled to 0 °C. The aqueous phase was extracted with ethyl acetate (150 mL × 2). The combined organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 50/1) to obtain compound 19-2.

¹ H NMR (400 MHz, CDCl ₃ ): δ 4.44 (s, 2H), 3.79 (s, 3H), 0.92 (s, 9H), 0.14 (s, 6H).

Preparation of compound 19-3

Under nitrogen atmosphere, deuterated aluminum lithium hydroxide (0.29 g, 7.01 mmol) was slowly added in portions to a 100 mL solution of tetrahydrofuran containing compound 19-2 (2.00 g, 8.76 mmol). The mixture was stirred at -70 °C for 2 hours, then heated to 0 °C, and quenched by slowly adding 1 mL of deuterium water. After stirring for 10 minutes, the mixture was heated to 25 °C, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product. Compound 19-3 was obtained by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1).

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 5.12 (s, 1H), 4.32 (s, 2H), 0.87 (s, 9H), 0.08 (s, 6H).

Preparation of compound 19-4

Under nitrogen atmosphere, methanesulfonic anhydride (194 mg, 1.11 mmol) was slowly added to a solution of compound 19-3 (300 mg, 1.48 mmol) and triethylamine (0.6 mL, 4.45 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at 25 °C for 2 hours. After the reaction was complete, 20 mL of water was added to quench the reaction. The aqueous phase was extracted with dichloromethane (10 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 19-4.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 4.40 (s, 2H), 3.23 (s, 3H), 0.87 (s, 10H), 0.09 (s, 6H).

Preparation of compound 19-5

Under nitrogen atmosphere, compound 19-4 (183 mg, 0.65 mmol) was added to a solution of compound 1-18 (100 mg, 0.22 mmol) and potassium carbonate (150 mg, 1.09 mmol) in N-N, dimethylformamide (2 mL). The reaction mixture was stirred at 60 °C for 12 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and diluted with 20 mL of water. The aqueous phase was extracted with ethyl acetate (10 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product. This crude product was purified by reverse-phase reaction (0.1% FA/ACN, 80% to 90% over 10 min) to obtain compound 19-5.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.66 (s, 1H), 8.46 (d, J = 5.6 Hz, 1H), 8.16 (dd, J = 2.4, 5.6 Hz, 1H), 7.92 (d, J = 2.0 Hz, 1H), 7.88 - 7.81 (m, 1H), 7.16 - 7.10 (m, 1H), 7.03 - 6.91 (m, 1H), 5.58 (br s, 1H), 5.02 (d, J = 11.2 Hz, 1H), 4.21 (d, J = 1.6 Hz, 2H), 2.93 - 2.84 (m, 1H), 1.71 (s, 3H), 0.85 (s, 9H), 0.83 - 0.78 (m, 3H), 0.02 (s, 6H);

m/z (ESI): [M+ H] ⁺ = 644.3.

Preparation of Example 19

Under nitrogen atmosphere, a 3 mL hydrochloric acid/methanol (2 M) solution containing compound 19-5 (60.0 mg, 0.09 mmol) was stirred at 25°C for 0.5 hours. After the reaction was complete, the solution was concentrated under reduced pressure to obtain a crude product, which was then purified by reverse phase separation (column: Waters Xbridge 150 × 25 mm × 5 μm, 30% to 60% over 10 min) to obtain Example 19.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.72 (s, 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.26 (d, J = 2.0 Hz, 1H), 8.07 (d, J = 2.4 Hz, 1H), 7.84 (dd, J = 2.4, 5.6 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.26 - 7.14 (m, 2H), 5.19 (t, J = 6.0 Hz, 1H), 5.11 (d, J = 10.4 Hz, 1H), 4.34 (dd, J = 7.6, 10.4 Hz, 1H), 4.06 (d, J = 4.0 Hz, 2H), 2.92 - 2.80 (m, 1H), 1.62 (s, 3H), 0.74 (d, J = 6.0 Hz, 3H);

m/z (ESI): [M+ H] ⁺ =530.1.

Implementation Example 20

Preparation of Example 20

Under a nitrogen atmosphere, deuterium water (0.2 mL, 9.30 mmol) and potassium carbonate (15.42 mg, 0.11 mmol) were added to 1 mL of acetonitrile solution containing Example 12 (50 mg, 0.09 mmol). The reaction solution was stirred at 24°C for 12 hours. After the reaction was complete, the reaction solution was filtered, and the filtrate was purified by reverse-phase separation (column: Phenomenex 150 × 25 mm × 10 μm, Condition: water(FA)-CAN; Begin B: 48, End B: 78, Gradient Time (min): 11, 100%B Hold Time (min): 4, Flow Rate (ml/min): 2) to obtain Example 20.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.71 (s, 1H), 8.49 (d, J = 5.4 Hz, 1H), 8.27 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 2.4 Hz, 1H), 7.83 (dd, J = 2.4, 5.4 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.28 - 7.14 (m, 2H), 5.12 (d, J = 10.2 Hz, 1H), 4.33 (dd, J = 7.6, 10.2 Hz, 1H), 2.90 - 2.78 (m, 1H), 1.62 (s, 3H), 0.74 (d, J = 6.0 Hz, 3H);

m/z (ESI): [M+ H] ⁺ = 501.1.

Implementation Example 21

Preparation of compound 21-1

Under nitrogen atmosphere, compound 1-15 (200 mg, 0.54 mmol) was added to methanol (2 mL), and the mixture was stirred at 25°C for 2 hours. The reaction solution was concentrated to dryness to give compound 21-1.

m/z (ESI): [M+ H] ⁺ = 369.0.

Preparation of compound 21-2

Under nitrogen atmosphere, boron tribromide (2.04 g, 8.15 mmol) was added dropwise to dichloromethane (40 mL) containing compound 21-1 (2.00 g, 5.43 mmol) at 0°C, and the mixture was stirred at 25°C for 1.5 hours. Saturated sodium bicarbonate aqueous solution (20 mL) was slowly added dropwise to the reaction solution, and the mixture was extracted with dichloromethane (30 mL × 3). The combined organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain compound 21-2.

m/z (ESI): [M+ H] ⁺ = 355.1.

Preparation of compound 21-3

Proprynne bromide (0.34 g, 2.82 mmol) was added to a DMF (10 mL) suspension of compound 21-2 (1.00 g, 2.82 mmol) and potassium carbonate (1.95 g, 14.11). The mixture was stirred at 60°C for 2 hours. The reaction solution was filtered, and the filtrate was purified by reversed-phase column chromatography (0.1% formic acid system) to give compound 21-3.

m/z (ESI): [M+ H] ⁺ = 393.1.

Preparation of compound 21-4

Lithium hydroxide (497.33 mg, 11.85 mmol) was added to a solution of compound 21-3 (930 mg, 2.37 mmol) in THF (12 mL), methanol (4 mL), and water (4 mL). The mixture was stirred at 25°C for 1 hour. The reaction solution was diluted with water (30 mL), the pH was adjusted to 4 with dilute hydrochloric acid (1 mol/L), and the mixture was extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 21-4.

m/z (ESI): [MH] ^- = 377.0.

Preparation of compound 21-5

To a DCM (2 mL) solution of compound 21-4 (70 mg, 0.19 mmol), DMF (2.9 μL, 0.04 mmol) and xylazine (31.8 μL, 0.37 mmol) were added. The mixture was stirred at 25°C for 1 hour. The mixture was concentrated to give compound 21-5.

Preparation of compound 21-6

Preparation of compound 21-8

Under nitrogen atmosphere, di-tert-butyl dicarbonate (2.8 mL, 13.1 mmol) and triethylamine (1.8 mL, 13.1 mmol) were added to 10 mL of dichloromethane solution containing compound 21-7 (1.00 g, 6.57 mmol) and 4-dimethylaminopyridine (0.40 g, 3.29 mmol). The reaction mixture was stirred at 26°C for 16 hours. Di-tert-butyl dicarbonate (2.8 mL, 13.1 mmol) was then added, and the reaction mixture was heated to 40°C and stirred for another 16 hours. After the reaction was complete, the solution was diluted with 200 mL of water, separated, and the aqueous phase was extracted with ethyl acetate (100 mL × 2). The combined organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1 - 5/1) to obtain compound 21-8.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.57 (d, J = 5.6 Hz, 1H), 8.03 (d, J = 2.4 Hz, 1H), 7.71 (dd, J = 2.0, 5.6 Hz, 1H), 7.00 (s, 1H), 4.00 (s, 3H), 1.54 (s, 9H);

m/z (ESI): [M+ H] ⁺ =253.0.

Preparation of Compound 21-9

At 0°C, m-chloroperoxybenzoic acid (965.69 mg, 4.76 mmol, 85% purity) was slowly added in portions to 10 mL of dichloromethane solution containing compound 21-8 (600 mg, 2.38 mmol). The reaction solution was heated to 26°C and stirred for 16 hours. After the reaction was complete, the reaction solution was filtered, and the filtrate was slowly added dropwise to 50 mL of saturated sodium sulfite aqueous solution for quenching. After the test with potassium iodide-starch test paper showed a negative result, the aqueous phase was extracted with dichloromethane (20 mL × 2). The combined organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was then obtained by silica gel column chromatography (eluting with petroleum ether/ethyl acetate = 10/1 to 100% methanol) to give compound 21-9.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.13 (d, J = 7.2 Hz, 1H), 7.86 (s, 1H), 7.53 (d, J = 4.8 Hz, 1H), 3.96 (s, 3H), 1.51 (s, 9H);

m/z (ESI): [M+ H] ⁺ =269.0.

Preparation of compound 21-6

Under nitrogen atmosphere, trifluoroacetic acid (2.00 mL, 26.9 mmol) was slowly added dropwise to a 2 mL dichloromethane solution containing compound 21-9 (170 mg, 0.63 mmol). The mixture was stirred at 25°C for 2 hours and then concentrated. The residue was adjusted to pH 10 with triethylamine and purified by reverse-phase preparation (0.1% FA/ACN, 100% water over 3 min) to obtain compound 21-6.

Preparation of compound 21-10

Under nitrogen atmosphere, compound 21-5 (70.0 mg, 0.18 mmol) was added to a 0.5 mL dichloromethane solution containing compound 21-6 (148 mg, 0.88 mmol) and triethylamine (0.1 mL, 0.88 mmol). The reaction mixture was stirred at 25°C for 1.5 hours. After the reaction was complete, the reaction mixture was quenched with 20 mL of water. The aqueous phase was extracted with dichloromethane (10 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. This crude product was purified by reverse-phase reaction (0.1% FA/ACN, 50% to 60% over 5 min) to obtain compound 21-10.

m/z (ESI): [M+ H] ⁺ =529.2.

Preparation of Example 21

Under a nitrogen atmosphere, compound 21-10 (70.0 mg, 0.13 mmol) was added to 10 mL of ammonia-methanol (7 M). The reaction solution was stirred at 25°C for 16 hours and then concentrated to obtain a crude product. The crude product was then purified by reverse phase preparation (column: Waters Xbridge 150 × 25 mm × 5 μm, 32% to 62% over 11 min) to obtain Example 21.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 10.78 (s, 1H), 10.59 (d, J = 4.4 Hz, 1H), 8.52 (d, J = 3.2 Hz, 1H), 8.31 (d, J = 7.2 Hz, 1H), 8.23 (d, J = 4.4 Hz, 1H), 7.88 (dd, J = 3.2, 7.2 Hz, 1H), 7.26 - 7.16 (m, 2H), 5.10 (d, J = 10.4 Hz, 1H), 4.98 - 4.85 (m, 2H), 4.32 (dd, J = 7.6, 10.4 Hz, 1H), 3.63 (t, J = 2.4 Hz, 1H), 2.88 - 2.66 (m, 1H), 1.62 (s, 3H), 0.73 (d, J = 6.0 Hz, 3H);

m/z (ESI): [M+ H] ⁺ =514.1.

Implementation Examples 22 and 23

Preparation of compound 22-2

Under a nitrogen atmosphere, cesium carbonate (20.55 g, 63.08 mmol) and [1,1-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride (1.29 g, 1.58 mmol) were added to a mixed solution of 150 mL of 2-methyltetrahydrofuran and 15 mL of water containing compound 22-1 (5 g, 31.54 mmol) and potassium trifluoroborate (5.07 g, 37.85 mmol). The reaction solution was heated to 90°C and stirred for 4 hours. After the reaction was complete, the reaction solution was added and cooled to room temperature. The mixture was concentrated, and 50 mL of water was added to the residue for dilution. The residue was extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with 100 mL of saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by reverse-phase preparation (0.1% FA system) and silica gel column chromatography (petroleum ether/ethyl acetate = 5/1 ~ 2/1) to obtain compound 22-2.

¹ H NMR (400 MHz, CDCl ₃ ): δ 9.39 (d, J = 2.4 Hz, 1H), 8.44 (dd, J = 2.4, 8.4 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 6.91 (dd, J = 10.8, 17.6 Hz, 1H), 6.46 (d, J = 17.6 Hz, 1H), 5.75 (d, J = 10.8 Hz, 1H).

Preparation of compound 22-3

Under nitrogen atmosphere, 4.3 mL of aqueous solution of titanium tetroxide (63.55 mg, 0.25 mmol) was slowly added dropwise to a mixed solution of 4.3 mL of water and 16 mL of acetone containing N-methylmorpholine oxide (4353.92 mg, 37.17 mmol) and compound 22-2 (1860.00 mg, 12.39 mmol). After the addition was complete, the reaction solution was stirred at 25 °C for 3 hours. After the reaction was completed, the reaction solution was cooled to zero degrees Celsius, quenched with 50 mL of saturated sodium sulfite aqueous solution, stirred for 15 minutes, and the aqueous phase was extracted with ethyl acetate (50 mL × 15). The combined organic layer was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified and separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1~0/1) to obtain compound 22-3.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.29 (d, J = 2.4 Hz, 1H), 8.58 (dd, J = 2.8, 8.8 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 5.76 (d, J = 5.2 Hz, 1H), 4.79 (t, J = 6.0 Hz, 1H), 4.72 (q, J = 5.2 Hz, 1H), 3.78 - 3.69 (m, 1H), 3.62 - 3.53 (m, 1H).

Preparation of compound 22-4

Under nitrogen atmosphere, p-toluenesulfonic acid (120 mg, 0.67 mmol) and 2,2-dimethoxypropane (2.1 mL, 16.70 mmol) were added to a mixed solution of 20 mL of 2-methyltetrahydrofuran and 20 mL of acetone containing compound 22-3 (1230.00 mg, 6.68 mmol). The reaction mixture was stirred at 25°C for 16 hours. After the reaction was complete, 10 mL of saturated sodium bicarbonate aqueous solution was added for quenching, and 50 mL of water was added for dilution. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with 100 mL of saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain compound 22-4.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.32 (d, J = 2.4 Hz, 1H), 8.63 (dd, J = 2.4, 8.4 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 5.27 (t, J = 6.4 Hz, 1H), 4.45 (dd, J = 7.2, 8.4 Hz, 1H), 3.91 (dd, J = 6.0, 8.4 Hz, 1H), 1.46 (s, 3H), 1.43 (s, 3H);

m/z (ESI): [M+ H] ⁺ = 224.9.

Preparation of compound 22-5

Under argon atmosphere, 10% palladium-carbon catalyst (wet) (100 mg) was added to 28 mL of ethyl acetate solution containing compound 22-4 (700 mg, 3.12 mmol). After three hydrogen purgings, the reaction solution was stirred at 25°C for 6 hours under hydrogen (15 psi). After the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain compound 22-5.

Preparation of compound 22-6

Under a nitrogen atmosphere, triethylamine (559.4 μL, 4.02 mmol) was added to 10 mL of dichloromethane solution containing compound 1-15 (500 mg, 1.34 mmol) and compound 22-5 (260.56 mg, 1.34 mmol). The reaction solution was reacted at 25 degrees Celsius for 1 hour. After the reaction was complete, 10 mL of water was added to the reaction solution to dilute it. The aqueous phase was extracted with dichloromethane (15 mL × 3). The combined organic phase was washed with 30 mL of saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1~2/1) to obtain compound 22-6.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.44 (s, 1H), 8.70 (dd, J = 2.4, 5.2 Hz, 1H), 8.05 (ddd, J = 2.4, 5.2, 8.4 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.22 - 7.10 (m, 2H), 5.17 - 4.99 (m, 2H), 4.32 (dd, J = 6.8, 8.0 Hz, 1H), 4.23 (dd, J = 7.6, 10.4 Hz, 1H), 3.94 (d, J = 2.0 Hz, 3H), 3.81 (dd, J = 6.8, 8.0 Hz, 1H), 2.79 - 2.72 (m, 1H), 1.60 (s, 3H), 1.41 (s, 3H), 1.38 (s, 3H), 0.73 (d, J = 6.0 Hz, 3H);

m/z (ESI): [M+ H] ⁺ = 531.2.

Preparation of compound 22-7

Under a nitrogen atmosphere at 0°C, boron tribromide (0.8 mL, 1.67 mmol) was slowly added to 12 mL of dichloromethane containing compound 22-6 (590 mg, 1.11 mmol), and the reaction mixture was heated to 25°C and stirred for 1.5 hours. After the reaction was complete, 10 mL of saturated sodium bicarbonate solution was added to quench the reaction. The aqueous phase was extracted with dichloromethane (20 mL × 3). The combined organic phase was washed with 40 mL of saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) and reversed-phase column chromatography (0.1% formic acid system) to obtain compound 22-7.

¹ H NMR (400 MHz, DMSO-d6): δ 10.49 (br s, 1H), 8.66 (dd, J = 2.4, 9.2 Hz, 1H), 8.35 (s, 1H), 7.99 (dt, J = 2.4, 8.8 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.01 (t, J = 6.8 Hz, 1H), 6.80 (q, J = 8.8 Hz, 1H), 5.57 - 5.20 (m, 1H), 5.10 (d, J = 10.4 Hz, 1H), 4.89 - 4.59 (m, 1H), 4.53 (dd, J = 4.4, 6.8 Hz, 1H), 4.22 (dd, J = 7.6, 10.0 Hz, 1H), 3.62 (dd, J = 4.0, 10.8 Hz, 2H), 2.83 (t, J = 7.2 Hz, 1H), 1.58 (s, 3H), 0.70 (d, J = 6.0 Hz, 3H);

m/z (ESI): [M + H] ⁺ = 477.2.

Preparation of Examples 22 and 23

Under nitrogen atmosphere, bromopropyne (32.6 μL, 0.38 mmol) was slowly added to 1.5 mL of NN,dimethylformamide solution containing compound 22-7 (90 mg, 0.19 mmol) and potassium carbonate (130.54 mg, 0.94 mmol). The reaction solution was heated to 60°C and stirred for 2 hours. After the reaction was completed _, the reaction solution was cooled to room temperature and filtered. The filtrate was purified by reverse-phase preparation (Waters Xbridge 150 × 25mm × 5um; mobile phase: water ( _NH4HCO3 )-ACN; B%: 40% - 60%, 25 min) to obtain a mixture of Example 22 and Example 23. The mixture was separated by SFC (Column: DAICEL CHIRALCEL OX (250mm × 30mm × _10um ); Condition: CO2 _- EtOH (0.1% _NH3H2O ); B%: 15-15; Gradient Time (min): 6.2; 100% B Hold Time (min): 0; FlowRate (ml/min): 150) to obtain two single isomers.

Example 22 (Retention time = 1.505 minutes):

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.36 (s, 1H), 8.63 (d, J = 2.4 Hz, 1H), 7.99 (dd, J = 2.4, 8.4 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.27 - 7.15 (m, 2H), 5.33 (d, J = 4.4 Hz, 1H), 5.10 (d, J = 10.4 Hz, 1H), 4.92 (dd, J = 2.4, 4.0 Hz, 2H), 4.64 (t, J = 5.6 Hz, 1H), 4.53 (td, J = 4.4, 6.8 Hz, 1H), 4.31 (dd, J = 7.6, 10.4 Hz, 1H), 3.66 (t, J = 2.4 Hz, 1H), 3.62 (ddd, J = 4.4, 6.0, 10.8 Hz, 1H), 3.43 (td, J = 6.4, 11.2 Hz, 1H), 2.83 (t, J = 7.6 Hz, 1H), 1.60 (s, 3H), 0.74 (d, J = 6.0 Hz, 3H);

m/z (ESI): [M + H] ⁺ = 515.3.

Example 23 (Retention time = 1.649 minutes):

¹ H NMR (400 MHz, DMSO-d6) δ = 10.35 (s, 1H), 8.66 (d, J = 2.4 Hz, 1H), 7.97 (dd, J = 2.4, 8.4 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.26 - 7.15 (m, 2H), 5.33 (d, J = 4.8 Hz, 1H), 5.10 (d, J = 10.4 Hz, 1H), 4.97 - 4.86 (m, 2H), 4.64 (t, J = 5.6 Hz, 1H), 4.53 (td, J = 4.4, 6.8 Hz, 1H), 4.31 (dd, J = 7.6, 10.4 Hz, 1H), 3.66 (t, J = 2.4 Hz, 1H), 3.62 (ddd, J = 4.4, 6.4, 10.7 Hz, 1H), 3.43 (td, J = 6.4, 10.8 Hz, 1H), 2.89 - 2.77 (m, 1H), 1.61 (s, 3H), 0.74 (d, J = 5.8 Hz, 3H);

m/z (ESI): [M + H] ⁺ = 515.2.

Implementation Examples 24 and 25

Preparation of compound 24-1

Under nitrogen atmosphere, cyanomethylenetri-n-butylphosphine (7.15 g, 29.64 mmol) was added to 80 mL of a dioxane solution containing compound 21-2 (2.10 g, 5.93 mmol) and compound 12-2 (3.86 g, 29.64 mmol). The reaction mixture was heated to 40°C and stirred for 16 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and quenched with 100 mL of water. The aqueous phase was extracted with ethyl acetate (50 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 50/1 - 30/1) to obtain compound 24-1.

¹ H NMR (400 MHz, CDCl ₃ ): δ 6.98 - 6.92 (m, 1H), 6.92 - 6.86 (m, 1H), 4.92 (d, J = 10.4 Hz, 1H), 4.28 - 4.19 (m, 1H), 3.71 (s, 3H), 2.91 - 2.69 (m, 1H), 1.65 (s, 3H), 0.81 - 0.74 (m, 3H), 0.15 (s, 9H).

Preparation of compound 24-2

Under a nitrogen atmosphere, 8 mL of an aqueous solution of lithium hydroxide (1.01 g, 24.1 mmol) was added dropwise to a solution of 24 mL of tetrahydrofuran and 8 mL of methanol containing compound 24-1 (2.25 g, 4.82 mmol). The reaction mixture was stirred at 26°C for 1 hour. After the reaction was completed, the low-boiling solvent was removed by depressurization concentration. The pH of the residue was adjusted to 5 with 2 M dilute hydrochloric acid. The aqueous phase was extracted with ethyl acetate (20 mL × 2). The combined organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated by depressurization to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1 ~ ethyl acetate/methanol = 5/1) to obtain compound 24-2.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.24 - 7.08 (m, 2H), 4.76 (d, J = 10.4 Hz, 1H), 4.16 - 4.05 (m, 1H), 3.64 (s, 1H), 2.74 - 2.66 (m, 1H), 1.51 (s, 3H), 0.67 (d, J = 6.0 Hz, 3H);

m/z (ESI): [M-H] ^- =379.1.

Preparation of compound 24-3

Under nitrogen atmosphere, oxadiazine (67.7 μL, 0.79 mmol) was slowly added dropwise to 2 mL of dichloromethane solution containing compound 24-2 (100 mg, 0.26 mmol) and N,N-dimethylformamide (2.0 μL, 0.03 mmol). The reaction mixture was reacted at 26°C for 2 hours. After the reaction was complete, the solution was concentrated under reduced pressure to give compound 24-3.

Preparation of compound 24-5

Under nitrogen atmosphere, 1 mL of dichloromethane solution containing compound 24-3 (100 mg, 0.25 mmol) was added dropwise to 1 mL of dichloromethane solution containing compound 24-4 (70.3 mg, 0.5 mmol) and triethylamine (0.1 mL, 0.75 mmol). The reaction mixture was stirred at 26°C for 1 hour. After the reaction was complete, 50 mL of water was added for dilution, and the aqueous phase was extracted with dichloromethane (20 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Compound 24-5 was obtained by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1 ~ 5/1).

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.39 - 8.28 (m, 2H), 7.52 (d, J = 2.0 Hz, 1H), 7.16 - 7.11 (m, 1H), 7.09 (dd, J = 2.0, 5.6 Hz, 1H), 7.03 - 6.95 (m, 1H), 4.99 (d, J = 11.2 Hz, 1H), 4.20 (s, 1H), 2.88 - 2.76 (m, 1H), 2.54 (s, 3H), 2.37 (s, 1H), 1.70 (s, 3H), 0.84 - 0.76 (m, 3H);

m/z (ESI): [M+ H] ⁺ = 503.2.

Preparation of Examples 24 and 25

Under nitrogen atmosphere, iodobenzene diacetate (216.7 mg, 0.67 mmol) was added to 4 mL of methanol solution containing compound 24-5 (160 mg, 0.32 mmol) and ammonium acetate (39.27 mg, 0.51 mmol). The reaction solution was stirred at 26°C for 1 hour. After the reaction was complete, 20 mL of water was added for dilution, and the low-boiling solvent was removed by depressurization concentration. The aqueous phase was extracted with ethyl acetate (10 mL × 2). The combined organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated by depressurization to obtain the crude product. The crude product was purified by reverse phase preparation (0.1% _NH4OH , 40% to 50% over 10 min), and then separated into two single isomers by SFC (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm), CO2 _- EtOH (0.1% _NH3 • _H2O ), 25% over 4.1 min, flow rate: 60 mL/min).

Example 24 (Retention time = 1.265 minutes):

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.87 (s, 1H), 8.57 (d, J = 5.6 Hz, 1H), 8.35 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 2.0, 5.6 Hz, 1H), 7.30 - 7.13 (m, 2H), 5.13 (d, J = 10.4 Hz, 1H), 4.39 - 4.27 (m, 2H), 3.63 (s, 1H), 3.11 (s, 3H), 2.89 - 2.78 (m, 1H), 1.61 (s, 3H), 0.74 (d, J = 6.4 Hz, 3H);

m/z (ESI): [M+ H] ⁺ =534.1.

Example 25 (Retention time = 1.412 minutes):

¹ H NMR (400 MHz, DMSO-d6): δ 10.87 (s, 1H), 8.57 (d, J = 5.6 Hz, 1H), 8.35 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 2.0, 5.6 Hz, 1H), 7.29 - 7.14 (m, 2H), 5.13 (d, J = 10.4 Hz, 1H), 4.39 - 4.28 (m, 2H), 3.63 (s, 1H), 3.11 (d, J = 1.2 Hz, 3H), 2.90 - 2.78 (m, 1H), 1.61 (s, 3H), 0.74 (d, J = 6.0 Hz, 3H);

m/z (ESI): [M+ H] ⁺ =534.1.

Implementation Example 26

Preparation of compound 26-2

Compound 26-1 (380 mg, 2.55 mmol) was added to 10 mL of ammonia-methanol solution (6 M) under nitrogen atmosphere, and the reaction solution was stirred at 25°C for 20 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1 ~ 1/1, dichloromethane/methanol = 20/1 ~ 10/1) to obtain compound 26-2.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.83 (brs, 1H), 7.32 (brs, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H), 6.58 (dd, J = 2.4, 8.0 Hz, 1H), 5.16 (s, 2H), 5.07 (t, J = 5.6 Hz, 1H), 4.36 (d, J = 5.6 Hz, 2H).

Preparation of compound 26-3

Under nitrogen atmosphere, imidazole (40.97 mg, 0.60 mmol) and tert-butyldimethylchlorosilane (68.02 mg, 0.45 mmol) were added to 1 mL of N,N-dimethylformamide solution containing compound 26-2 (50.0 mg, 0.30 mmol), and the reaction was carried out at 25°C for 12 hours. After the reaction was complete, 20 mL of water was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (20 mL × 2). The combined organic phase was washed with 20 mL of saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1 ~ 0/1) to obtain compound 26-3.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.61 (brs, 1H), 7.21 (brs, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.67 (d, J = 2.4 Hz, 1H), 6.58 (dd, J = 2.4, 8.0 Hz, 1H), 5.14 (s, 2H), 4.65 (s, 2H), 0.86 (s, 9H), 0.04 (s, 6H).

Preparation of compound 26-4

Under nitrogen atmosphere, compound 26-3 (53.97 mg, 0.19 mmol) and triethylamine (87.1 μL, 0.63 mmol) were added to 2 mL of dichloromethane solution containing compound 24-3 (50.0 mg, 0.13 mmol). The reaction was carried out at 25°C for 1 hour. After the reaction was complete, 20 mL of water was added to quench the reaction. The aqueous phase was extracted with dichloromethane (20 mL × 2). The combined organic phase was washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1 ~ 1/1) to obtain compound 26-4.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.47 (s, 1H), 8.03 - 7.93 (m, 2H), 7.75 (d, J = 2.4 Hz, 1H), 7.29 (s, 1H), 7.20 - 7.15 (m, 1H), 7.02 - 6.94 (m, 1H), 5.68 (brs, 1H), 5.00 (d, J = 11.2 Hz, 1H), 4.78 (s, 2H), 4.25 (dd, J = 7.6, 11.2 Hz, 1H), 2.88 - 2.75 (m, 1H), 2.38 (s, 1H), 1.71 (s, 3H), 0.88 (s, 9H), 0.83 - 0.78 (m, 3H), 0.10 (s, 6H);

m/z (ESI): [M + H] ⁺ = 643.3.

Preparation of Example 26

Under a nitrogen atmosphere, a tetrabutylammonium fluoride tetrahydrofuran solution (133.4 μL, 0.13 mmol, 1 M) was added to a 1 mL tetrahydrofuran solution containing compound 26-4 (60.0 mg, 0.09 mmol), and the reaction was carried out at 25°C for 0.5 hours. After the reaction was completed, the crude product was concentrated and then purified by reverse phase preparation (Phenomenex luna C18 150 × 25mm × _10um ; mobile phase: water(FA)-ACN; B%: 45% - 75%, 25 min) and secondary reverse phase preparation (Waters Xbridge 150 × 25mm × 5um; mobile phase: water( _NH4HCO3 )-ACN; B%: 42% - 72%, 25 min) to obtain Example 26.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.29 (s, 1H), 7.86 (brs, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.65 (dd, J = 2.0, 8.0 Hz, 1H), 7.48 - 7.37 (m, 3.64 (s, 1H), 2.83 (t, J = 7.2 Hz, 1H), 1.60 (s, 3H), 0.73 (d, J = 6.0 Hz, 3H);

m/z (ESI): [M -17] ⁺ = 511.1.

Implementation Example 27

Preparation of compound 27-1

Under a nitrogen atmosphere, triethylamine (365.5 μL, 2.63 mmol) was added to a 1 mL solution of compound 24-3 (103.67 mg, 0.26 mmol) in dichloromethane, followed by the dropwise addition of a 0.5 mL solution of methyl 4-aminopyridine-2-carboxylate (80.01 mg, 0.53 mmol) in dichloromethane. The reaction mixture was stirred at 26°C for 2 hours. After the reaction was complete, the solution was diluted with 30 mL of water. The aqueous phase was extracted with dichloromethane (10 mL × 3). The combined organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain compound 27-1.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.63 (d, J = 5.6 Hz, 1H), 8.58 (s, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.93 (dd, J = 5.6, 2.0 Hz, 1H), 7.05 - 7.19 (m, 1H), 6.93 - 7.05 (m, 1H), 5.03 (d, J = 11.2 Hz, 1H), 4.21 - 4.32 (m, 1H), 4.01 (s, 3H), 2.73 - 2.94 (m, 1H), 2.38 (s, 1H), 1.72 (s, 3H), 0.76 - 0.87 (m, 3H);

m/z (ESI): [M - H] ^- = 513.2.

Preparation of Example 27

Under nitrogen atmosphere, potassium cyanide (2 mg, 0.03 mmol) and aqueous hydroxylamine (0.5 mL, 8.16 mmol, 50% aqueous solution) were added sequentially to a mixed solution of 0.5 mL methanol and 0.5 mL tetrahydrofuran containing compound 27-1 (30 mg, 0.06 mmol). The reaction mixture was stirred at 26°C for 12 hours. After the reaction was completed, the reaction solution was quenched in 20 mL of saturated sodium bicarbonate aqueous solution, and extracted with dichloromethane (10 mL x 3). The combined organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product. The crude product was purified by reverse phase preparation (Column Phenomenex luna C18 150*25mm* 10um; mobile phase: water(TFA)-ACN; B%: 28% - 58%, 14 min) to obtain Example 27.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.38 (s, 1H), 10.70 (s, 1H), 8.45 (d, J = 5.6 Hz, 1H), 8.22 (d, J = 2.0 Hz, 1H), 7.81 (dd, J = 5.6, 2.0 Hz, 1H), 7.07 - 7.38 (m, 2H), 5.11 (d, J = 10.4 Hz, 1H). 4.10 - 4.45 (m, 1H), 3.63 (s, 2H), 2.84 (s, 1H), 1.62 (s, 3H), 0.74 (d, J = 6.0 Hz, 3H);

m/z (ESI): [M + H] ⁺ = 516.1.

Implementation Example 28

Preparation of compound 28-1

Under nitrogen atmosphere, triethylamine (348.6 μL, 2.51 mmol) and 4-aminopyridine-2-carboxynitrile (59.75 mg, 0.50 mmol) were sequentially added to a 1 mL dichloromethane solution containing compound 24-3 (100 mg, 0.25 mmol). The reaction mixture was stirred at 26°C for 2 hours. After the reaction was complete, 10 mL of water was added for dilution, followed by dichloromethane extraction (10 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. This crude product was purified by thin-layer silica gel preparation (petroleum ether/ethyl acetate = 1/1) to obtain compound 28-1.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.67 - 8.53 (m, 2H), 8.08 - 7.99 (m, 1H), 7.70 - 7.60 (m, 1H), 7.16 - 7.07 (m, 1H), 7.06 - 6.91 (m, 1H), 5.13 - 4.94 (m, 1H), 4.31 - 4.18 (m, 1H), 2.91 - 2.78 (m, 1H), 2.44 - 2.36 (m, 1H), 1.75 - 1.67 (m, 3H), 0.86 - 0.76 (m, 3H);

m/z (ESI): [M + H] ⁺ = 482.1.

Preparation of Example 28

Under a nitrogen atmosphere, hydroxylamine hydrochloride (7.69 mg, 0.11 mmol) and sodium carbonate (23.47 mg, 0.22 mmol) were sequentially added to a 2 mL ethanol solution containing compound 28-1 (41 mg, 0.09 mmol). The reaction mixture was stirred at 25°C for 1 hour. After the reaction was complete, the mixture was filtered, and the pH of the filtrate was adjusted to 5 with 2N hydrochloric acid. The filtrate was then purified by reverse-phase preparation (Column Phenomenex luna C18 150*25mm* 10um Condition water(FA)-CAN Begin B 43 End B 73 Gradient Time(min) 11 100%B Hold Time(min) 4 FlowRate(ml/min) 25) to obtain Example 28.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.74 - 10.50 (m, 1H), 9.93 - 9.75 (m, 1H), 8.47 - 8.37 (m, 1H), 8.22 - 8.08 (m, 1H), 7.69 - 7.56 (m, 1H), 7.32 - 7.06 (m, 2H), 5.93 - 5.65 (m, 2H), 5.22 - 4.91 (m, 1H), 4.48 - 4.15 (m, 1H), 3.67 - 3.58 (m, 1H), 2.89 - 2.78 (m, 1H), 1.70 - 1.53 (m, 3H), 0.87 - 0.59 (m, 3H);

m/z (ESI): [M + H] ⁺ = 515.2.

Implementation Example 29

Preparation of Example 29

Under a nitrogen atmosphere, triethylamine (139.4 μL, 1.00 mmol) was added to 0.5 mL of dichloromethane containing compound 24-3 (100 mg, 0.25 mmol), followed by the addition of 4-aminopyridine-2-sulfonamide (45.17 mg, 0.26 mmol). The mixture was stirred at 26°C for 2 hours. After the reaction was complete, 20 mL of water was added to quench the precipitate, and the mixture was extracted with dichloromethane (10 mL × 3). The combined organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was then purified by reverse-phase preparation (Column Waters Xbridge 150*25mm* _5um ; mobile phase: water( _NH3H2O )-ACN; B%: 38% - 68%, 12 min) to obtain Example 29.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.52 (s, 1H), 8.09 - 8.31 (m, 1H), 7.75 (dt, J = 7.6, 2.0 Hz, 1H), 7.44 - 7.61 (m, 2H), 7.36 (s, 2H), 7.08 - 7.28 (m, 2H), 5.10 (d, J = 10.4 Hz, 1H), 4.34 (dd, J = 10.32, 7.44 Hz, 1H), 3.64 (s, 1H), 2.85 (s, 1H), 1.62 (s, 3H), 0.63 - 0.83 (m, 3H);

m/z (ESI): [M + H] ⁺ = 535.2.

Implementation Examples 30 and 31

Preparation of compound 30-1

Under nitrogen atmosphere, 2 mL of dichloromethane solution containing compound 24-3 (300 mg, 0.75 mmol) was added dropwise to 2 mL of dichloromethane solution containing 3-(methylthio)aniline (35.16 mg, 0.25 mmol) and triethylamine (0.3 mL, 2.26 mmol). The reaction mixture was stirred at 26°C for 2 hours. After the reaction was complete, 50 mL of water was added for dilution. The aqueous phase was extracted with dichloromethane (20 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 20/1 ~ 5/1) to obtain compound 30-1.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.30 (s, 1H), 7.57 - 7.51 (m, 1H), 7.26 - 7.20 (m, 2H), 7.20 - 7.14 (m, 1H), 7.03 - 6.94 (m, 2H), 5.00 (d, J = 11.2 Hz, 1H), 4.28 (dd, J = 7.6, 11.2 Hz, 1H), 2.88 - 2.76 (m, 1H), 2.47 (s, 3H), 2.37 (s, 1H), 1.70 (s, 3H), 0.84 - 0.76 (m, 3H);

m/z (ESI): [M+ H] ⁺ =502.1.

Preparation of Examples 30 and 31

Under a nitrogen atmosphere, 407 mg, 1.26 mmol of bis(ethoxyiodobenzene) was added to 5 mL of methanol solution containing compound 30-1 (300 mg, 0.60 mmol) and ammonium acetate (73.8 mg, 0.96 mmol). The reaction mixture was stirred at 26°C for 1 hour. After the reaction was completed, the low-boiling solvent was removed by depressurization concentration to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1 ~ 0/1) and reverse-phase preparation (0.1% FA/ACN, 50% to 60% over 5 min) to obtain a mixture of Example 30 and Example 31. The mixture was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm), CO2 _- EtOH (0.1% _{NH3 H2O} ), 30% to 30% over 2.7 min, 60 mL/min) to obtain two single isomers.

Example 30 (Retention time = 0.915 minutes):

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.53 (s, 1H), 8.24 (s, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.58 - 7.49 (m, 1H), 7.27 - 7.14 (m, 2H), 5.09 (d, J = 10.4 Hz, 1H), 4.33 (dd, J = 7.6, 10.4 Hz, 1H), 4.22 - 4.15 (m, 1H), 3.64 (s, 1H), 3.02 (s, 3H), 2.92 - 2.77 (m, 1H), 1.61 (s, 3H), 0.74 (d, J = 6.0 Hz, 3H);

m/z (ESI): [M+ H] ⁺ =533.3.

Implementation Example 31 (Retention Time = 1.165 minutes):

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.54 (s, 1H), 8.24 (t, J = 1.8 Hz, 1H), 7.88 - 7.82 (m, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.58 - 7.49 (m, 1H), 7.30 - 7.11 (m, 2H), 5.09 (d, J = 10.4 Hz, 1H), 4.33 (dd, J = 7.6, 10.4 Hz, 1H), 4.19 (s, 1H), 3.64 (s, 1H), 3.02 (d, J = 0.8 Hz, 3H), 2.90 - 2.77 (m, 1H), 1.61 (s, 3H), 0.74 (d, J = 6.0 Hz, 3H);

m/z (ESI): [M+ H] ⁺ =533.2.

Implementation Example 32

Preparation of compound 32-2

Under nitrogen atmosphere, tert-butyldimethylchlorosilane (865 mg, 5.74 mmol) was added to 5 mL of N,N-dimethylformamide solution containing compound 32-1 (300 mg, 2.87 mmol) and imidazole (586 mg, 8.61 mmol). The reaction mixture was reacted at 20°C for 3 hours. After the reaction was complete, the mixture was quenched with 50 mL of water, extracted with ethyl acetate (25 mL × 2), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (eluting with petroleum ether) to obtain compound 32-2.

¹ H NMR (400 MHz, CDCl ₃ ): δ 4.37 (t, J = 2.0 Hz, 2H), 4.18 (t, J = 2.0 Hz, 2H), 0.92 (s, 9H), 0.13 (s, 6H).

Preparation of compound 32-3

Under nitrogen atmosphere, a 1 mL solution of N,N-dimethylformamide containing compound 32-2 (28.6 mg, 0.13 mmol) was slowly added to a 1 mL solution of N,N-dimethylformamide containing compound 1-18 (60 mg, 0.13 mmol) and potassium carbonate (90.3 mg, 0.65 mmol). The reaction mixture was heated to 60°C and stirred for 2 hours. After the reaction was complete, the reaction mixture was cooled and filtered. The filtrate was then separated by reverse-phase chromatography to obtain compound 32-3.

Preparation of Example 32

Compound 32-3 (25 mg, 0.04 mmol) was dissolved in methanol hydrochloride (2 mL, 2 M) and stirred at 25°C for 0.5 hours. After the reaction was complete, the solution was concentrated, diluted with 2 mL of methanol, and adjusted to pH 8 with ammonia. The solution was then purified by reverse-phase separation (column: Waters Xbridge 150 × 25 mm × ₅ μm, water ( _NH₄HCO₃ )-ACN, 38%-68% over 9 min) to obtain Example 32.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.73 (s, 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.26 (d, J = 2.0 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 2.0, 5.6 Hz, 1H), 7.63 (d, J = 1.6 Hz, 1H), 7.28 - 7.14 (m, 2H), 5.21 (t, J = 6.0 Hz, 1H), 5.11 (d, J = 10.4 Hz, 1H), 4.94 (d, J = 1.6 Hz, 2H), 4.34 (dd, J = 7.6, 10.4 Hz, 1H), 4.10 - 4.03 (m, 2H), 2.91 - 2.79 (m, 1H), 1.62 (s, 3H), 0.74 (d, J = 6.4 Hz, 3H);

m/z (ESI): [M+ H] ⁺ = 528.2.

Implementation Example 33

Preparation of Example 33

Under a nitrogen atmosphere, [1,1-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride (13.81 mg, 0.02 mmol), copper iodide (6.48 mg, 0.03 mmol), triethylamine (117.5 μL, 0.85 mmol), and compound 33-1 (142.23 mg, 1.69 mmol) were added to a 2 mL solution of N,N-dimethylformamide containing compound 3-1 (100 mg, 0.17 mmol). The reaction mixture was stirred at 100°C for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with 40 mL of water, extracted with ethyl acetate (30 mL × 3), and the combined organic phase was washed with 50 mL of saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude product. The crude product was purified by reverse phase preparation (Column: Waters Xbridge 150 × 25 mm × 5 μm; Condition: water ( _NH₄HCO₃ )-ACN; Begin B: 38, End B: 68; Gradient Time (min): 10; 100%B Hold Time ( _min ): 4, Flow Rate (ml/min): 25) and separated to obtain Example 33.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.75 (s, 1H), 8.49 (d, J = 5.4 Hz, 1H), 8.29 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 1.6 Hz, 1H), 7.84 (dd, J = 2.0, 5.4 Hz, 1H), 7.62 (d, J = 1.6 Hz, 1H), 7.53 - 7.45 (m, 1H), 7.28 (dd, J = 4.0, 8.8 Hz, 1H), 5.69 (s, 1H), 5.22 (d, J = 10.2 Hz, 1H), 4.36 (dd, J = 7.6, 10.2 Hz, 1H), 2.96 (t, J = 7.6 Hz, 1H), 1.64 (s, 3H), 1.51 (s, 6H), 0.75 - 0.68 (m, 3H);

m/z (ESI): [M - 17] ⁺ = 508.2.

Implementation Example 34

Preparation of compound 34-2

Under nitrogen atmosphere, benzoyl chloride (322.7 μL, 2.78 mmol) and triethylamine (478.0 μL, 3.44 mmol) were added to 10 mL of dichloromethane solution containing compound 34-1 (500 mg, 2.65 mmol). The reaction mixture was stirred at 25°C for 12 hours. After the reaction was complete, the mixture was quenched with 30 mL of sodium hydroxide aqueous solution (1N). The aqueous phase was extracted with dichloromethane (20 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain compound 34-2.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.79 (s, 2H), 8.14 (dd, J = 1.2, 8.0 Hz, 2H), 7.63 - 7.56 (m, 1H), 7.50 - 7.44 (m, 2H), 5.53 (s, 2H);

m/z (ESI): [M + H] ⁺ = 294.4.

Preparation of compound 34-3

Under nitrogen atmosphere, cesium carbonate (607.20 mg, 1.86 mmol), (±)-2,2-bis(diphenylphosphino)-1,1-binaphthyl (178.53 mg, 0.29 mmol), palladium acetate (32.18 mg, 0.14 mmol), and benzophenone imine (312 mg, 1.72 mmol) were added to a 10 mL toluene solution containing compound 34-2 (440 mg, 1.43 mmol). The reaction mixture was stirred at 120°C for 12 hours. After the reaction was complete, the reaction solution was cooled to room temperature, quenched with 60 mL of water, extracted with ethyl acetate (30 mL × 3), and the combined organic phase was washed with 50 mL of saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was then separated by column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain compound 34-3.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.18 (s, 2H), 8.14 - 8.10 (m, 2H), 7.81 - 7.74 (m, 2H), 7.58 - 7.55 (m, 1H), 7.52 (d, J = 7.2 Hz, 1H), 7.48 - 7.42 (m, 4H), 7.38 - 7.32 (m, 3H), 7.13 (dd, J = 2.0, 7.2 Hz, 2H), 5.47 (s, 2H);

m/z (ESI): [M + H] ⁺ = 394.1.

Preparation of compound 34-4

Under nitrogen atmosphere, hydroxylamine hydrochloride (250.83 mg, 3.61 mmol) and sodium acetate (434.27 mg, 5.29 mmol) were added to 10 mL of methanol solution containing compound 34-3 (600 mg, 1.20 mmol). The reaction mixture was stirred at 25°C for 7 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain the crude product, which was separated into compound 34-4 by column chromatography (petroleum ether/ethyl acetate = 5/1 to 1/1).

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.22 (s, 2H), 8.12 (d, J = 7.2 Hz, 2H), 7.60 - 7.54 (m, 1H), 7.48 - 7.41 (m, 2H), 5.47 (s, 2H);

m/z (ESI): [M + 23] ⁺ = 252.1.

Preparation of compound 34-5

Under a nitrogen atmosphere, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (120.62 mg, 0.32 mmol), N,N-diisopropylethylamine (69.9 μL, 0.42 mmol), and compound 34-4 (64.93 mg, 0.25 mmol) were added to a 2 mL solution of N,N-dimethylformamide containing compound 21-4 (80 mg, 0.21 mmol). The reaction mixture was stirred at 25°C for 16 hours. After the reaction was complete, the mixture was quenched with 40 mL of water, extracted with ethyl acetate (30 mL × 3), and the combined organic phase was dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain the crude product, which was then separated by column chromatography (petroleum ether/ethyl acetate = 5/1~3/1) to obtain compound 34-5.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.97 (s, 2H), 8.38 (s, 1H), 8.16 - 8.09 (m, 2H), 7.63 - 7.55 (m, 1H), 7.50 - 7.41 (m, 2H), 7.17 - 7.09 (m, 1H), 7.04 - 6.94 (m, 1H), 5.53 (s, 2H), 5.04 (d, J = 11.2 Hz, 1H), 4.93 - 4.87 (m, 1H), 4.83 - 4.78 (m, 1H), 4.26 (dd, J = 7.6, 11.2 Hz, 1H), 2.89 - 2.81 (m, 1H), 2.44 (t, J = 2.4 Hz, 1H), 1.70 (s, 3H), 0.84 - 0.79 (m, 3H);

m/z (ESI): [M + H] ⁺ = 590.2.

Preparation of Example 34

Under a nitrogen atmosphere, lithium hydroxide (38.05 mg, 0.91 mmol) was added to 3 mL of methanol solution containing compound 34-5 (110 mg, 0.18 mmol). The reaction mixture was stirred at 25°C for 1 hour. After the reaction was complete, the crude product was concentrated under reduced pressure and purified by reverse-phase preparation (Column: Waters Xbridge 150 × 25 mm × 5 μm; Condition: water ( _NH₄HCO₃ )-ACN; Begin B: 23, End B: 53; Gradient Time (min): 10; 100%B Hold Time (min ₎ : 4, Flow Rate (ml/min): 25) to obtain Example 34.

1H NMR (400 MHz, DMSO-d ₆ ): δ 10.46 (s, 1H), 8.98 (s, 2H), 7.27 - 7.16 (m, 2H), 5.26 (t, J = 6.0 Hz, 1H), 5.15 (d, J = 10.4 Hz, 1H), 4.98 - 4.85 (m, 2H), 4.55 (d, J = 6.0 Hz, 2H), 4.32 (dd, J = 7.2, 10.2 Hz, 1H), 3.67 (t, J = 2.0 Hz, 1H), 2.89 - 2.78 (m, 1H), 1.62 (s, 3H), 0.74 (d, J = 6.0 Hz, 3H);

m/z (ESI): [M + H] ⁺ = 486.1.

Implementation Example 35

Preparation of compound 35-2

Under nitrogen atmosphere, triethylamine (94.1 mg, 0.93 mmol), tert-butyldimethyl(2-propynoxy)silane (317 mg, 1.86 mmol), (diphenylphosphine)ferrocene palladium chloride (13.6 mg, 0.02 mmol), and copper iodide (7.08 mg, 0.04 mmol) were sequentially added to 2 mL of N,N-dimethylformamide solution containing compound 3-1 (110 mg, 0.19 mmol). The reaction mixture was stirred at 80°C for 48 hours. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with 30 mL of water, and extracted with ethyl acetate (15 mL × 3). The combined organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by reverse-phase preparation (0.1% FA/ACN, 80% to 90% over 5 min) to obtain compound 35-2.

m/z (ESI): [M - H] ⁺ = 612.2

Preparation of Example 35

Compound 35-2 (14 mg, 0.02 mmol) was added to a 2 M methanol hydrochloride (2 mL) solution under nitrogen atmosphere, and the reaction solution was stirred at 25°C for 0.5 hours. After the reaction was complete, the reaction solution was concentrated to dryness to obtain a crude product, which was then purified by reverse phase preparation (column: Phenomenex luna C18 150 × 25 mm × 10 μm, 35% to 65% over 9 min) and (column: Waters Xbridge 150 × 25 mm × 5 μm, 35% to 65% over 11 min) to obtain Example 35.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.78 (br s, 1H), 8.47 (d, J = 5.2 Hz, 1H), 8.27 (s, 1H), 8.08 - 8.03 (m, 1H), 7.83 (d, J = 3.6 Hz, 1H), 7.60 (s, 1H), 7.52 - 7.45 (m, 1H), 7.30 (dd, J = 4.4, 8.5 Hz, 1H), 5.67 - 5.45 (m, 1H), 5.20 (d, J = 10.4 Hz, 1H), 4.42 (s, 2H), 4.36 (dd, J = 7.6, 10.3 Hz, 1H), 3.04 - 2.92 (m, 1H), 1.62 (s, 3H), 0.71 (d, J = 6.4 Hz, 3H);

m/z (ESI): [M+ H] ⁺ =498.2.

Implementation Examples 36 and 37

Preparation of compound 36-2

Under nitrogen atmosphere, compound 36-1 (35.34 mg, 0.25 mmol) was added to 2 mL of dichloromethane solution containing compound 21-5 (100 mg, 0.25 mmol) and triethylamine (105.1 μL, 0.76 mmol). The reaction mixture was reacted at 25°C for 1 hour. After the reaction was complete, 3 mL of water was added to dilute and extract the reaction. The aqueous phase was extracted with dichloromethane (10 mL × 3). The combined organic phase was washed with 5 mL of saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was then purified by reverse-phase preparation (0.1% formic acid system) to obtain compound 36-2.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.38 - 8.29 (m, 2H), 7.51 (d, J = 1.6 Hz, 1H), 7.09 (dd, J = 1.6, 5.6 Hz, 1H), 7.03 - 6.96 (m, 1H), 4.99 (d, J = 11.2 Hz, 1H), 4.92 - 4.86 (m, 1H), 4.83 - 4.77 (m, 1H), 4.25 (dd, J = 7.8, 11.2 Hz, 1H), 2.88 - 2.77 (m, 1H), 2.54 (s, 3H), 2.38 (t, J = 2.4 Hz, 1H), 1.70 (s, 3H), 0.80 (dd, J = 1.6, 7.4 Hz, 3H);

m/z (ESI): [M + H] ⁺ = 501.1.

Preparation of Examples 36 and 37

Under nitrogen atmosphere, iodobenzene diacetate (40.80 mg, 0.13 mmol) and ammonium acetate (7.39 mg, 0.10 mmol) were added sequentially to 1 mL of methanol solution containing compound 36-2 (30 mg, 0.06 mmol), and the reaction solution was reacted at 25°C for 18 hours. After the reaction was completed _, the reaction solution was concentrated to obtain a crude product, which was then purified by reverse phase preparation (Waters Xbridge 150 × 25mm × 5um; mobile phase: water( _NH4HCO3 )-ACN; B%: 43% - 63%, 25 min) to obtain a mixture of Examples 36 and 37; the mixture was then separated by SFC (Column DAICEL CHIRALPAK AD (250 × 50 mm × 10um); Condition: CO2 _- EtOH (0.1% _NH3H2O ); B%: 20-20; Gradient Time (min): 3.6; 100% B Hold Time ( _min ): 0; FlowRate (ml/min): 120) to obtain two single isomers.

Example 36 (Retention time = 1.273 minutes):

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.88 (s, 1H), 8.57 (d, J = 5.6 Hz, 1H), 8.36 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 2.0, 5.6 Hz, 1H), 7.27 - 7.17 (m, 2H), 5.13 (d, J = 10.4 Hz, 1H), 4.95 - 4.89 (m, 2H), 4.37 - 4.30 (m, 2H), 3.64 (t, J = 2.4 Hz, 1H), 3.11 (d, J = 0.8 Hz, 3H), 2.84 (t, J = 7.2 Hz, 1H), 1.61 (s, 3H), 0.74 (d, J = 6.4 Hz, 3H);

m/z (ESI): [M + H] ⁺ = 532.1.

Example 37 (Retention time = 1.420 minutes):

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.89 (s, 1H), 8.57 (d, J = 5.6 Hz, 1H), 8.35 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 2.0, 5.6 Hz, 1H), 7.27 - 7.16 (m, 2H), 5.13 (d, J = 10.4 Hz, 1H), 4.92 (t, J = 2.8 Hz, 2H), 4.39 - 4.29 (m, 2H), 3.64 (t, J = 2.4 Hz, 1H), 3.11 (d, J = 0.8 Hz, 3H), 2.87 - 2.80 (m, 1H), 1.61 (s, 3H), 0.74 (d, J = 5.6 Hz, 3H);

m/z (ESI): [M + H] ⁺ = 532.2.

Implementation Example 38

Preparation of Example 38

Under nitrogen atmosphere, tris(dibenzylacetone)dipalladium (7.74 mg, 0.01 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanethium) (4.89 mg, 0.01 mmol), and N,N-diisopropylethylamine (41.9 μL, 0.25 mmol) were sequentially added to 2 mL of dioxane solvent containing compound 3-1 (50 mg, 0.08 mmol) and dimethylphosphorus oxide (13.20 mg, 0.17 mmol). The reaction solution was heated to 100 °C and stirred for 15 hours. After the reaction was completed, the reaction solution was cooled to room temperature and filtered through a short silicone column (washed with ethyl acetate). The filtrate was concentrated by reduced pressure to obtain a crude product, which was then purified by reverse phase preparation (Waters Xbridge 150 × _25mm × 5um; mobile phase: water( _NH4HCO3 )-ACN; B%: 23% - 53%, 25 min) to obtain Example 38.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.60 (s, 1H), 8.48 (d, J = 5.5 Hz, 1H), 8.28 (d, J = 2.1 Hz, 1H), 8.06 (d, J = 2.1 Hz, 1H), 7.83 (dd, J = 2.2, 5.6 Hz, 1H), 7.72 - 7.59 (m, 2H), 7.46 - 7.39 (m, 1H), 5.48 (dd, J = 7.1, 10.8 Hz, 1H), 5.15 (d, J = 10.8 Hz, 1H), 2.90 (t, J = 7.4 Hz, 1H), 1.85 - 1.76 (m, 6H), 1.58 (s, 3H), 0.76 (d, J = 6.5 Hz, 3H);

m/z (ESI): [M + H] ⁺ = 520.2.

Implementation Example 39

Preparation of Example 39

Under a nitrogen atmosphere, triethylamine (139.4 μL, 1.00 mmol) was added to 0.5 mL of dichloromethane containing compound 24-3 (100 mg, 0.25 mmol), followed by the addition of 4-aminopyridine-2-sulfonamide (45.17 mg, 0.26 mmol). The mixture was stirred at 26°C for 2 hours. After the reaction was complete, 20 mL of water was added to quench the precipitate, and the mixture was extracted with dichloromethane (10 mL × 3). The combined organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was then purified by reverse-phase preparation (Column Waters Xbridge 150*25mm* _5um ; mobile phase: water( _NH3H2O )-ACN; B%: 38% - 68%, 12 min) to obtain Example 39.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.52 (s, 1H), 8.09 - 8.31 (m, 1H), 7.75 (dt, J = 7.6, 2.0 Hz, 1H), 7.44 - 7.61 (m, 2H), 7.36 (s, 2H), 7.08 - 7.28 (m, 2H), 5.10 (d, J = 10.4 Hz, 1H), 4.34 (dd, J = 10.32, 7.44 Hz, 1H), 3.64 (s, 1H), 2.85 (s, 1H), 1.62 (s, 3H), 0.63 - 0.83 (m, 3H);

m/z (ESI): [M+H] ⁺ = 535.2.

Implementation Example 40

Preparation of compound 40-2

Under nitrogen atmosphere, triethylamine (57.5 μL, 0.41 mmol) and compound 40-1 (43.28 mg, 0.21 mmol) were added to a 1 mL dichloromethane solution of compound 24-3 (55.0 mg, 0.14 mmol). The reaction mixture was reacted at 25°C for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain compound 40-2.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.51 (s, 1H), 7.82 - 7.77 (m, 3H), 7.20 - 7.12 (m, 1H), 7.03 - 6.94 (m, 1H), 5.02 (d, J = 11.2 Hz, 1H), 4.26 (dd, J = 7.6, 11.2 Hz, 1H), 3.90 (s, 3H), 3.89 (s, 3H), 2.90 - 2.78 (m, 1H), 2.37 (s, 1H), 1.71 (s, 3H), 0.85 - 0.78 (m, 3H);

m/z (ESI): [M+H] ⁺ = 572.2.

Preparation of Example 40

Compound 40-2 (50.0 mg, 0.08 mmol) was dissolved in 5 mL of ammonia-methanol (7M) solution under nitrogen atmosphere, and the reaction solution was reacted at 60°C for 17 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain crude product, which was then purified by reverse phase preparation (Column Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: water(FA)-ACN; B%: 43% - 73%, 11 min) to obtain Example 40.

¹ H NMR (400 MHz, METHANOL-d ₄ ): δ 8.54 (s, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.73 (dd, J = 2.0, 8.4 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.23 - 7.13 (m, 1H), 7.09 - 6.99 (m, 1H), 5.08 (d, J = 10.8 Hz, 1H), 4.43 (dd, J = 8.0, 10.2 Hz, 1H), 2.93 (s, 1H), 2.90 - 2.84 (m, 1H), 1.68 (s, 3H), 0.83 (d, J = 5.6 Hz, 3H);

m/z (ESI): [M+H] ⁺ =542.2.

Implementation Example 41

Preparation of Example 41

Under nitrogen atmosphere, m-chloroperoxybenzoic acid (55.0 mg, 0.32 mmol) was added to 3 mL of dichloromethane solution containing compound 24-5 (80 mg, 0.16 mmol) at 0°C, and the reaction solution was stirred at 0°C for 2 hours. After the reaction was complete, the reaction solution was slowly added to 50 mL of saturated sodium sulfite aqueous solution for quenching. After the aqueous phase showed a negative result when measured with potassium iodide starch test paper, it was extracted with dichloromethane (20 mL × 2). The combined organic phase was washed with 20 mL of saturated sodium bicarbonate, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was then separated and purified by reverse phase preparation (column: Waters Xbridge C18 150*25mm*5um; mobile phase: [A: H ₂ O (10mM NH ₄ HCO ₃ ); B: ACN]; B%: 48.00%-78.00%, 15.00min; flow rate: 25.00 ml/min) to obtain Example 41.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.90 (s, 1H), 8.63 (d, J = 5.6 Hz, 1H), 8.36 (d, J = 2.0 Hz, 1H), 7.91 (dd, J = 2.0, 5.6 Hz, 1H), 7.30 - 7.15 (m, 2H), 5.14 (d, J = 10.4 Hz, 1H), 4.33 (dd, J = 7.6, 10.4 Hz, 1H), 3.62 (s, 1H), 3.24 (s, 3H), 2.90 - 2.77 (m, 1H), 1.62 (s, 3H), 0.74 (d, J = 6.4 Hz, 3H);

m/z (ESI): [M+ H] ⁺ = 535.2.

Implementation Example 42

Preparation of compound 42-2

Under a nitrogen atmosphere, compounds dimethylphosphine oxide (676.69 mg, 8.67 mmol), potassium phosphate (3.07 g, 14.45 mmol), tris(dibenzylacetone)dipalladium (317.58 mg, 0.35 mmol), and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanethium (401.34 mg, 0.69 mmol) were added to a 20 mL solution of N,N-dimethylformamide containing compound 42-1 (1.0 g, 5.78 mmol). The reaction mixture was heated to 140°C and reacted for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filter cake was washed twice with 10 mL of ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (dichloromethane/methanol = 10:1) to separate compound 42-2.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.09 (d, J = 5.6 Hz, 1H), 7.10 (dd, J = 2.4, 7.2 Hz, 1H), 6.52 (td, J = 2.0, 5.6 Hz, 1H), 6.34 (s, 2H), 1.56 (s, 3H), 1.53 (s, 3H);

m/z (ESI): [M + H] ⁺ = 171.2.

Preparation of Example 42

Under nitrogen atmosphere, compound 42-2 (42.93 mg, 0.21 mmol) and triethylamine (57.5 μL, 0.41 mmol) were added sequentially to a 1 mL dichloromethane solution containing compound 24-3 (55 mg, 0.14 mmol). The reaction was carried out at 25°C for 1 hour. After the reaction was complete _, the crude product was concentrated under reduced pressure and purified by reverse phase chromatography (Waters Xbridge C18 column 150 × 25 mm × 5 μm, aqueous phase-organic phase _H₂O (10 mM _NH₄HCO₃ )-ACN, B%: 33% - 63%, 15 min) to obtain Example 42.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.74 (s, 1H), 8.61 (d, J = 5.6 Hz, 1H), 8.21 (dd, J = 2.0, 6.4 Hz, 1H), 7.77 (td, J = 2.0, 5.6 Hz, 1H), 7.27 - 7.13 (m, 2H), 5.12 (d, J = 10.6 Hz, 1H), 4.33 (dd, J = 7.2, 10.2 Hz, 1H), 3.65 (s, 1H), 2.91 - 2.77 (m, 1H), 1.70 - 1.51 (m, 9H), 0.74 (d, J = 6.0 Hz, 3H);

m/z (ESI): [M + H] ⁺ = 533.2.

Implementation Example 43

Preparation of compound 43-3

Under nitrogen atmosphere, compound 43-2 (2.69 g, 20.34 mmol), triphenylphosphine (5.34 g, 20.34 mmol), and diisopropyl azodicarbonate (4.0 mL, 20.34 mmol) were added to 30 mL of toluene solution containing compound 43-1 (1.9 g, 13.56 mmol). The reaction solution was heated to 80°C and reacted for 3 hours. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain the crude product, which was separated into compound 43-3 by column chromatography (petroleum ether/ethyl acetate = 10:1).

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.39 (d, J = 5.6 Hz, 1H), 7.61 (dd, J = 2.0, 5.6 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 4.57 - 4.39 (m, 3H), 4.17 (dd, J = 6.4, 8.4 Hz, 1H), 3.88 (dd, J = 6.0, 8.4 Hz, 1H), 1.47 (s, 3H), 1.41 (s, 3H).

Preparation of compound 43-4

Under nitrogen atmosphere, iron powder (2.42 g, 43.42 mmol) and ammonium chloride (2.32 g, 43.42 mmol) were added to 20 mL of ethanol and 4 mL of aqueous solution containing compound 43-3 (2.3 g, 8.68 mmol). The reaction solution was heated to 80°C and reacted for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with 40 mL of ethyl acetate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Compound 43-4 was separated by column chromatography (petroleum ether/ethyl acetate = 10/1~1/1).

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.59 (d, J = 6.0 Hz, 1H), 6.17 (dd, J = 2.0, 6.0 Hz, 1H), 5.93 (s, 2H), 5.81 (d, J = 1.6 Hz, 1H), 4.37 - 4.29 (m, 1H), 4.20 - 4.09 (m, 2H), 4.03 (dd, J = 6.4, 8.0 Hz, 1H), 3.69 (dd, J = 6.4, 8.0 Hz, 1H), 1.33 (s, 3H), 1.28 (s, 3H);

m/z (ESI): [M + H] ⁺ = 225.2.

Preparation of compound 43-5

Under nitrogen atmosphere, compound 43-5 (86.97 mg, 0.38 mmol) and triethylamine (104.6 μL, 0.75 mmol) were added to 1 mL of dichloromethane solution containing compound 24-3 (100 mg, 0.25 mmol). The reaction mixture was reacted at 25°C for 1 hour. After the reaction was complete, the mixture was quenched with 20 mL of water and extracted with dichloromethane (20 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was then separated by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1~3/1) to obtain compound 43-5.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.37 (s, 1H), 8.03 (d, J = 6.4 Hz, 1H), 7.17 - 7.10 (m, 1H), 7.06 - 6.95 (m, 3H), 4.98 (d, J = 11.2 Hz, 1H), 4.49 - 4.42 (m, 1H), 4.37 - 4.30 (m, 2H), 4.25 (dd, J = 8.0, 11.3 Hz, 1H), 4.12 (dd, J = 6.0, 8.4 Hz, 1H), 3.85 (dd, J = 6.0, 8.4 Hz, 1H), 2.89 - 2.77 (m, 1H), 2.37 (s, 1H), 1.69 (s, 3H), 1.45 (s, 3H), 1.39 (s, 3H), 0.83 - 0.78 (m, 3H);

m/z (ESI): [M + H] ⁺ = 587.2.

Preparation of Example 43

Under a nitrogen atmosphere, trifluoroacetic acid (0.2 mL, 2.69 mmol) was added to a 2 mL dichloromethane solution containing compound 43-5 (50 mg, 0.08 mmol). The reaction mixture was reacted at 26°C for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was then purified by reverse phase preparation (column: Waters Xbridge C18 150*25mm _* 5um; mobile phase: [A: _H₂O (10mM _NH₄HCO₃ ); B: ACN]; B%: 40.00%-70.00%, 15.00min; flow rate: 25.00 ml/min) to obtain Example 43.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.49 (s, 1H), 8.01 (d, J = 5.6 Hz, 1H), 7.26 - 7.19 (m, 1H), 7.17 - 7.10 (m, 3H), 5.08 (d, J = 10.4 Hz, 1H), 4.87 (d, J = 5.2 Hz, 1H), 4.60 (t, J = 5.6 Hz, 1H), 4.32 (dd, J = 7.6, 10.0 Hz, 1H), 4.22 (dd, J = 4.4, 10.8 Hz, 1H), 4.09 (dd, J = 6.0, 10.8 Hz, 1H), 3.75 (qd, J = 5.6, 10.8 Hz, 1H), 3.63 (s, 1H), 3.40 (t, J = 5.6 Hz, 2H), 2.90 - 2.77 (m, 1H), 1.59 (s, 3H), 0.73 (d, J = 6.0 Hz, 3H);

m/z (ESI): [M + H] ⁺ = 547.2.

Implementation Example 44

Preparation of Example 44

Under nitrogen atmosphere, compound 24-3 (424 mg, 1.06 mmol) was dissolved in dichloromethane (6 mL), triethylamine (0.5 mL, 3.6 mmol) was added, followed by compound 44-1 (127 mg, 1.06 mmol), and the reaction solution was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was quenched with 20 mL of saturated sodium bicarbonate aqueous solution. The aqueous phase was extracted with dichloromethane (3 × 20 mL). The combined organic phase was washed with saturated brine (1 × 30 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether/ethyl acetate = 10/1~1/1) to obtain Example 44.

LC-MS (ESI): [M + H] ⁺ = 482.1.

Implementation Example 45

Preparation of Example 45

Compound 45-1 (17.95 mg, 0.16 mmol) and triethylamine (87.1 μL, 0.63 mmol) were dissolved in DMF (1 mL). After stirring at room temperature for 5 minutes, a DMF solution of compound 24-3 (50 mg, 0.13 mmol) (1 mL) was slowly added dropwise to the mixture, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was washed with saturated sodium chloride aqueous solution (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer silicone preparation (dichloromethane: methanol = 10:1) and reverse-phase preparation (Phenomenex luna C18 150×25mm × 10um); flow rate: 25 mL/min; gradient: 47% - 67% B over 10 min; mobile phase A: 0.225% aqueous methanoic acid, mobile phase B: acetonitrile) to obtain Example 45.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.42 - 8.27 (m, 1H), 7.15 - 6.94 (m, 3H), 6.75 - 6.62 (m, 2H), 5.06 - 4.93 (m, 1H), 4.36 - 4.20 (m, 1H), 2.88 - 2.78 (m, 1H), 2.47 - 2.40 (m, 1H), 1.36 - 1.18 (m, 3H), 0.80 (d, J = 5.2 Hz, 3H);

m/z (ESI): [M + H] ⁺ = 473.1.

Implementation Example 46

Preparation of Example 46

Under nitrogen atmosphere, a sodium methoxide-methanol solution (0.01 mL, 0.05 mmol) was added to a 5 mL methanol solution containing Example 44 (100 mg, 0.21 mmol). The reaction mixture was stirred at room temperature for 2 hours, followed by the addition of ammonium chloride (23 mg, 0.42 mmol), and the temperature was raised to 40°C with continued stirring for 12 hours. The reaction mixture was concentrated, and the crude product was purified by reverse reaction (Phenomenex luna C18 150×25mm × 10µm; flow rate: 25 mL/min; gradient: 23% - 53% B over 10 min; mobile phase A: 0.225% aqueous methanoic acid, mobile phase B: acetonitrile) to obtain Example 46.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.61 (d, J = 5.6 Hz, 1H), 8.47 - 8.44 (m, 2H), 7.89 - 7.87 (m, 1H), 7.23 - 7.21 (m, 2H), 5.19 (d, J = 10.8 Hz, 1H), 4.38 - 4.33 (m, 1H), 3.66 (s, 1H), 2.89 - 2.81 (m, 1H), 1.62 (s, 3H), 0.75 (d, J = 6.0 Hz, 3H);

m/z (ESI): [M + H] ⁺ = 499.1.

Implementation Example 47

Preparation of Example 47

Under nitrogen atmosphere, Example 44 (100 mg, 0.21 mmol) was dissolved in 2 mL of 1,4-dioxane, and triethylamine (0.058 mL, 0.42 mmol) and dimethylamine hydrochloride (33.87 mg, 0.42 mmol) were added sequentially. The reaction solution was heated to 90°C and stirred for 16 hours. The reaction solution was concentrated, and the crude product was purified by reverse reaction (Phenomenex luna C18 150×25mm × 10um; flow rate: 25 mL/min; gradient: 24% - 54% B over 10 min; mobile phase A: 0.225% aqueous methanoic acid, mobile phase B: acetonitrile) to obtain Example 47.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.55 - 11.48 (m, 1H), 8.57 (d, J = 5.6 Hz, 1H), 8.44 (s, 1H), 8.04 (d, J = 1.6 Hz, 1H), 7.78 - 7.76 (m, 1H), 7.30 - 7.26 (m, 1H), 7.23 - 7.17 (m, 1H), 5.26 (d, J = 10.4 Hz, 1H), 4.37 - 4.33 (m, 1H), 3.66 (s, 1H), 3.02 (s, 6H), 2.87 - 2.78 (m, 1H), 1.61 (s, 3H), 0.75 (d, J = 6.4 Hz, 3H);

m/z (ESI): [M + H] ⁺ = 527.2.

Implementation Example 48

Preparation of compound 48-1

Compound 12-2 (500 mg, 3.85 mmol), imidazole (800 mg, 11.76 mmol), and tert-butyldiphenylchlorosilane (2.4 g, 8.73 mmol) were dissolved in anhydrous DCM (30 mL) and stirred at room temperature for 12 hours. The reaction was also concentrated to give a crude product, which was purified by silica gel column chromatography (eluting with petroleum ether) to give compound 48-1.

Preparation of compound 48-2

Compound 48-1 (900 mg, 2.44 mmol) and potassium carbonate (1.1 g, 7.96 mmol) were dissolved in DMF (12 mL) and stirred at room temperature for 24 hours. The reaction mixture was then added to ethyl acetate (100 mL), washed once with water (30 mL), washed once with saturated brine (30 mL), and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and purified by silica gel column chromatography to obtain compound 48-2.

¹ H NMR (400 MHz, CDCl3): δ 7.56 - 7.59 (m, 1H), 7.26 - 7.50 (m, 1H), 2.24 (s, 1H), 1.12 - 1.34 (m, 9H).

Preparation of compound 48-3

Under nitrogen atmosphere, compound 48-2 (370 mg, 1.25 mmol) was dissolved in THF (1 mL) at -50°C, and a solution of n-butyllithium hexane (1.0 mL, 2.50 mmol) was slowly added and stirred for 0.5 hours. A solution of deuterated iodomethane (370 mg, 2.55 mmol) in THF (1 mL) was added and stirred for 1 hour. The reaction mixture was quenched in an aqueous solution of saturated ammonium chloride (100 mL), and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phase was washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain compound 48-3.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.77 - 7.79 (m, 1H), 7.44 - 7.50 (m, 1H), 1.12 - 1.34 (m, 9H).

Preparation of compound 48-4

Compound 48-3 (370 mg, 1.18 mmol) was dissolved in a tetrabutylammonium fluoride tetrahydrofuran solution (5 mL, 5.00 mmol) and stirred at room temperature for 0.5 hours. The reaction solution was diluted with ethyl acetate (100 mL), washed once with water (100 mL), and once with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give compound 48-4.

Preparation of Example 48

Under nitrogen atmosphere, triphenylphosphine (70 mg, 0.11 mmol), compound 1-18 (50 mg, 0.11 mmol) and compound 48-4 (10 mg, 0.13 mmol) were dissolved in THF (1.5 mL), and diisopropyl azodicarbonate (30 mg, 0.15 mmol) was added under ice-water bath. The mixture was stirred overnight at room temperature. Ethyl acetate (20 mL) was added to the reaction solution, the mixture was washed with water (10 mL × 2), washed once with saturated brine (10 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to obtain a crude product, which was purified by reverse reaction (Phenomenex luna C18 150×25mm × 10um); flow rate: 25 mL/min; gradient: 48% - 78% B over 10 min; mobile phase A: 0.225% aqueous methanoic acid, mobile phase B: acetonitrile) to obtain Example 48.

m/z (ESI): [M + H] ⁺ = 517.1.

Implementation Example 49

Preparation of Example 49

Example 24 (50 mg, 0.09 mmol) was placed in a 50 mL single-necked flask, and DCM (3 mL) was added at room temperature. After replacing the argon gas, trimethyloxonium tetrafluoroboric acid (7 mg, 0.05 mmol) was added to the solution, and the mixture was stirred at room temperature for 6 hours. The reaction solution was evaporated to dryness to obtain a crude product, which was purified by thin-layer silica gel chromatography (petroleum ether: ethyl acetate = 1:1) to obtain Example 49.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.91 (s, 1H), 8.62 (d, J = 5.5 Hz, 1H), 8.32 (d, J = 1.9 Hz, 1H), 7.86 (dd, J = 5.5, 2.1 Hz, 1H), 7.32 – 7.12 (m, 2H), 5.14 (d, J = 10.4 Hz, 1H), 4.34 (dd, J = 10.4, 7.5 Hz, 1H), 3.63 (s, 1H), 3.16 (s, 3H), 2.93 – 2.76 (m, 1H), 2.45 (s, 3H), 1.62 (s, 3H), 0.74 (d, J = 6.2 Hz, 3H);

m/z (ESI): [M + H] ⁺ = 548.4.

Implementation Example 50

Preparation of compound 50-1

Under nitrogen atmosphere, a boron tribromide dichloromethane solution (12.7 mL, 25.4 mmol) was slowly added dropwise at 0°C to a 60 mL dichloromethane solution containing compound 1-12 (4.5 g, 12.7 mmol). The reaction mixture was heated to 25°C and stirred for 1 hour. After the reaction was complete, the reaction mixture was poured into 100 mL of saturated sodium bicarbonate aqueous solution, extracted once with 50 mL of dichloromethane, and the organic phase was discarded. The pH of the aqueous phase was adjusted to 3-4 with (30 mL, 3M) dilute hydrochloric acid, and the aqueous phase was extracted with dichloromethane (50 mL × 3). The combined organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 50-1.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.11 - 6.96 (m, 1H), 6.92 - 6.70 (m, 1H), 4.97 (d, J = 10.4 Hz, 1H), 4.09 (dd, J = 10.4, 7.6 Hz, 1H), 2.73 (s, 1H), 1.52 (s, 3H), 0.67 (d, J = 6.0 Hz, 3H).

Preparation of compound 50-2

Under nitrogen atmosphere, 10.82 g (49.52 mmol) of 2,2,2-trichloro-1-[(2-methylprop-2-yl)oxy]ethane-1-imine was added to 35 mL of dichloromethane solution containing compound 50-1 (3.37 g, 9.90 mmol). The reaction mixture was stirred at 25 °C for 1 hour. After the reaction was complete, 20 mL of water was added to quench the reaction mixture, and the mixture was extracted with dichloromethane (50 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1 - 5/1) to obtain compound 50-2.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.04 (t, J = 6.8 Hz, 1H), 6.91 - 6.74 (m, 1H), 4.90 (d, J = 10.4 Hz, 1H), 4.04 (dd, J = 10.8, 7.2 Hz, 1H), 2.70 (t, J = 7.6 Hz, 1H), 1.52 (d, J = 2.0 Hz, 5H), 1.27 (s, 9H), 0.70 (d, J = 5.6 Hz, 3H).

Preparation of compound 50-3

Under nitrogen atmosphere, trifluoromethanesulfonic anhydride (4.409 g, 15.63 mmol) was added to 40 mL of dichloromethane solution containing triethylamine (3.163 g, 31.26 mmol) and compound 50-2 (4.130 g, 10.42 mmol). The reaction mixture was reacted at 0°C for 2 hours. After the reaction was complete, the reaction mixture was poured into 100 mL of water, and the aqueous phase was extracted with dichloromethane (50 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1 - 2/1) to obtain compound 50-3.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.35 - 7.13 (m, 2H), 4.79 (d, J = 9.6 Hz, 1H), 4.23 - 4.03 (m, 1H), 2.78 (t, J = 7.6 Hz, 1H), 1.63 (s, 3H), 1.35 (s, 9H), 1.23 - 1.30 (m, 2H), 0.90 - 0.78 (m, 3H).

Preparation of compound 50-4

Under nitrogen atmosphere, potassium vinyl fluoroborate (2.23 g, 16.65 mmol), cesium carbonate (5.426 g, 16.65 mmol), and RuPhos Pd G3 (696 mg, 0.83 mmol) were added sequentially to a solution of 9 mL water and 45 mL toluene containing compound 50-3 (4.4 g, 8.33 mmol). The reaction solution was heated to 85°C and reacted for 5 hours. After the reaction was completed, the reaction solution was cooled to room temperature and diluted with 50 mL of water. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 20/1 - 5/1) to obtain compound 50-4.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.15 - 6.98 (m, 2H), 6.56 (dd, J = 17.6, 11.6 Hz, 1H), 5.84 - 5.46 (m, 2H), 4.89 - 4.75 (m, 2H), 4.06 - 3.94 (m, 1H), 2.58 (s, 1H), 1.56 (s, 3H), 1.31 (s, 9H), 1.29 - 1.27 (m, 1H). 0.81 - 0.72 (m, 3H).

Preparation of compound 50-5

Ozone was passed into 50 mL of dichloromethane solution containing compound 50-4 (3.287 g, 8.09 mmol). After the reaction solution turned blue, nitrogen gas was passed through and the solution was purged until it returned to yellow. Triphenylphosphine (3.18 g, 12.13 mmol) was added, and the reaction solution was slowly heated to 25 °C and reacted for 12 hours. After the reaction was complete, the reaction solution was evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 20/1 - 10/1) to obtain compound 50-5.

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.52 (s, 1H), 7.47 - 7.38 (m, 1H), 7.27 (s, 2H), 4.88 (d, J = 10.6 Hz, 1H), 4.76 - 4.63 (m, 1H), 2.87 (s, 1H), 1.68 (s, 3H), 1.32 (s, 9H), 0.78 - 0.69 (m, 3H).

Preparation of compound 50-6

Under nitrogen atmosphere, sodium borohydride (92.64 mg, 2.45 mmol) was slowly added at 0 °C to 6 mL of tetrahydrofuran solution containing compound 50-5 (0.5 g, 1.22 mmol). The reaction mixture was heated to 25 °C and stirred for 1 hour. After the reaction was complete, 10 mL of saturated ammonium chloride aqueous solution was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (10 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1 - 5/1) to obtain compound 50-6.

Preparation of compound 50-7

Under nitrogen atmosphere, sodium hydroxide (102 mg, 2.56 mmol, 60% purity) was slowly added to 6 mL of tetrahydrofuran solution containing compound 50-6 (350 mg, 0.85 mmol) at 0°C. After stirring for 10 minutes, (3-bromoprop-1-ynyl)trimethylsilane (244 mg, 1.28 mmol) was added, and the reaction solution was heated to 25°C and stirred for 6 hours. After the reaction was complete, 5 mL of saturated ammonium chloride aqueous solution was added to quench the reaction. The pH was adjusted to 3-4 with 0.5 M hydrochloric acid. The aqueous phase was extracted with dichloromethane (10 mL × 3). The combined organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1 - 1/1) to obtain compound 50-7.

Preparation of compound 50-8

Under a nitrogen atmosphere, N,N-dimethylformamide (2.3 μL, 0.03 mmol) and oxaloyl chloride (114.52 mg, 0.90 mmol) were added sequentially to 4 mL of dichloromethane solvent containing compound 50-7 (118 mg, 0.30 mmol). The reaction solution was reacted at 25°C for 1 hour to obtain a solution containing compound 50-8, which was directly used for the next reaction.

Preparation of compound 50-9

Under nitrogen atmosphere, triethylamine (416.2 μL, 2.99 mmol) was added to the reaction solution from the previous step (pH > 8), followed by methyl 4-aminopyridine-2-carboxylate (136.68 mg, 0.90 mmol). The reaction solution was stirred at 25°C for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1 - 1/2) to obtain compound 50-9.

Preparation of Example 50

Compound 50-9 (74 mg, 0.14 mmol) was added to 7.0 M ammonia-methanol solution (3 mL, 21 mmol) under nitrogen atmosphere, and the reaction solution was reacted at 25°C for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain crude product, which was purified by reverse phase preparation (column: Boston Green ODS 150*30mm*5um; mobile phase: [A: _H₂O (0.225% FA); B: ACN]; B%: 48.00%-78.00%, 11.00 min; flow rate: 25.00 mL/min) to obtain Example 50.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.62 (s, 1H), 8.48 (d, J = 5.6 Hz, 1H), 8.27 (d, J = 2.0 Hz, 1H), 8.05 (s, 1H), 7.81 (dd, J = 5.6, 2.0 Hz, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.51 - 7.37 (m, 1H), 7.35 - 7.23 (m, 1H), 5.16 (d, J = 10.8 Hz, 1H), 4.65 (d, J = 2.0 Hz, 2H), 4.40 - 4.30 (m, 1H), 4.24 (dd, J = 4.4, 2.4 Hz, 2H), 3.55 (s, 1H), 3.52 - 3.49 (m, 1H), 2.82 (s, 1H), 1.64 (s, 3H), 0.83 - 0.64 (m, 3H);

m/z (ESI): [M + H] ⁺ = 512.1.

Implementation Example 51

Preparation of Example 51

Compound 1-18 (200 mg, 0.44 mmol) was dissolved in DMF (2 mL), and potassium carbonate (180.50 mg, 1.31 mmol), chloromethyl sulfide (126.13 mg, 1.31 mmol), and potassium iodide (72.27 mg, 0.44 mmol) were added. The reaction was carried out at 25°C for 1 hour. The reaction solution was added to 20 mL of aqueous solution, extracted with dichloromethane, separated, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by reverse phase preparation (Phenomenex luna C18 150×25mm × 10um); flow rate: 25 mL/min; gradient: 52% - 72% B over 10 min; mobile phase A: 0.225% aqueous methanoic acid, mobile phase B: acetonitrile) to obtain Example 51.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.71 (s, 1H), 8.49 (d, J = 6.0 Hz, 1H), 8.27 (d, J = 2.4 Hz, 1H), 8.07 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 2.0, 5.6 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.21 (d, J = 6.4 Hz, 2H), 5.48 - 5.38 (m, 1H), 5.37 - 5.31 (m, 1H), 5.12 (d, J = 10.4 Hz, 1H), 4.38 (dd, J = 7.6, 10.0 Hz, 1H), 2.83 (t, J = 7.6 Hz, 1H), 2.22 (s, 3H), 1.62 (s, 3H), 0.73 (d, J = 6.0 Hz, 3H);

m/z (ESI): [M + H] ⁺ = 520.1.

Implementation Example 52

Preparation of Example 52

Compound 52-1 (70 mg, 0.26 mmol), compound 1-18 (120 mg, 0.26 mmol), potassium carbonate (110 mg, 0.80 mmol), and sodium iodide (50 mg, 0.33 mmol) were dissolved in DMF (5 mL) and stirred at room temperature for 12 hours. The reaction mixture was quenched in water (100 mL) and then extracted with ethyl acetate (100 mL x 2). The organic phase was then washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by reverse preparation (Phenomenex luna C18 150×25mm × 10um); flow rate: 25 mL/min; gradient: 45% - 75% B over 15 min; mobile phase A: 0.225% aqueous methanoic acid, mobile phase B: acetonitrile) to obtain Example 52.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.72 (s, 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.26 (d, J = 2.0 Hz, 1H), 8.08 (s, 1H), 7.84 (dd, J = 2.0, 5.6 Hz, 1H), 7.64 (s, 1H), 7.61 - 7.52 (m, 1H), 7.43 - 7.35 (m, 1H), 5.17 (d, J = 10.2 Hz, 1H), 4.79 - 4.71 (m, 1H), 4.26 - 4.18 (m, 1H), 2.73 - 4.64 (m, 1H), 1.60 (s, 3H), 0.78 – 0.70 (m, 3H);

m/z (ESI): [M + H] ⁺ = 534.0.

Implementation Examples 53 and 54

Preparation of compound 53-1

A solution of magnesium ethynyl bromide in tetrahydrofuran (1.9 mL, 0.96 mmol, 0.5 M) was slowly added dropwise to a 10 mL solution of THF (300 mg, 0.73 mmol) at 0°C. The reaction mixture was naturally heated from 0°C to 25°C and stirred for 2 hours. After the reaction was complete, an ammonium chloride aqueous solution (3 mL) was slowly added dropwise to quench the reaction at 0°C. The mixture was diluted with water (10 mL), and extracted with ethyl acetate (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1-3:1) to give compound 53-1.

Preparation of compound 53-2

Diethylaminosulfur trifluoride (0.1 mL, 607.73 μmol) was slowly added dropwise to a DCM (5 mL) solution of 53-1 (220 mg, 506.45 μmol) at -20°C. The reaction solution was naturally heated from 0°C to 25°C and reacted for 2 hours. The reaction solution was then slowly added dropwise to saturated sodium bicarbonate for quenching. The mixture was extracted with dichloromethane (5 mL × 3), and the organic phase was dried and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1~3:1) to obtain compound 53-2.

Preparation of compound 53-3

Compound 53-2 (195 mg, 0.45 mmol) was dissolved in DCM (5 mL), and trifluoroacetic acid (1 mL) was added. The reaction was carried out at 25°C for 1 hour. The reaction solution was directly concentrated to give compound 53-3.

Preparation of compound 53-4

Compound 53-3 (150 mg, 0.39 mmol) and DMF (3.1 μL, 0.04 mmol) were dissolved in DCM (5 mL), and oxaliplatin (169.4 μL, 1.97 mmol) was slowly added under ice bath conditions. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was then concentrated to give compound 53-4.

Preparation of compound 53-5

Compound 53-4 (140 mg, 0.35 mmol) was dissolved in DCM (0.5 mL), and triethylamine (0.2 mL, 1.76 mmol) and methyl 4-aminopyridine-2-carboxylate (53.42 mg, 0.35 mmol) were slowly added under ice bath conditions, with stirring at room temperature for 3 hours. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to give compound 53-5.

Preparation of Examples 53 and 54

Compound 53-5 (20 mg, 0.04 mmol) and ammonia-methanol (16.55 mg, 0.97 mmol) were dissolved in MeOH (0.5 mL), and the reaction solution was stirred at 25°C for 3 hours. The reaction solution was concentrated, and the crude product was purified by reverse-phase preparation (Phenomenex luna C18 150 × 2 5 mm × 10 μm; flow rate: 25 mL/min; gradient: 49% – 69% B over 10 min; mobile phase A: 0.225% aqueous methanoic acid, mobile phase B: acetonitrile) to give two isomers.

Implementation Example 53 (Shorter Retention Time):

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.56 (s, 1H), 8.48 (d, J = 5.6 Hz, 1H), 8.26 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 2.4 Hz, 1H), 7.82 (dd, J = 2.0, 5.2 Hz, 1H), 7.67 - 7.56 (m, 2H), 7.40 - 7.35 (m, 1H), 6.85 - 6.69 (m, 1H), 5.16 (d, J = 10.0 Hz, 1H), 4.46 (t, J= 9.2 Hz, 1H), 4.28 (dd, J = 2.0, 5.0 Hz, 1H), 2.94 - 2.85 (m, 1H), 1.66 (s, 3H), 0.76 (d, J = 7.2 Hz, 3H);

m/z (ESI): [M + H] ⁺ = 500.2.

Implementation Example 54 (Larger Retention Time):

¹ H NMR: (400 MHz, DMSO-d ₆ ): δ 10.58 (s, 1H), 8.48 (d, J = 5.2Hz, 1H), 8.27 (d, J =2.0 Hz, 1H), 8.06 (d, J = 1.2 Hz, 1H), 7.86 (dd, J = 2.2, 5.6 Hz, 1H), 7.65 - 7.56 (m, 2H), 7.40 (dd, J = 4.2, 8.8 Hz, 1H), 6.93 - 6.77 (m, 1H), 5.23 (d, J = 10.0 Hz, 1H), 4.63 (t, J = 9.2 Hz, 1H), 4.09 (dd, J = 2.2, 5.0 Hz, 1H), 2.67 - 2.61 (m, 1H), 1.67 (s, 3H), 0.69 (d, J = 6.4 Hz, 3H);

m/z (ESI): [M + H] ⁺ = 500.2.

Implementation Example 55

Preparation of compound 52-1

Under nitrogen atmosphere, a solution of n-butyllithium hexane (33 mL, 82.50 mmol) was slowly added dropwise to a THF (80 mL) solution of compound 55-1 (13.3 mL, 71.28 mmol). After stirring for 1 hour, compound 55-2 (23 g, 109.62 mmol) was slowly added dropwise to the reaction system. The temperature was restored to 20°C, and stirring was continued for 15 hours. The reaction mixture was poured into an ice-cold aqueous solution of ammonium chloride (100 mL), and the mixture was extracted with petroleum ether (200 mL × 2). After the organic phases were combined, the mixture was washed once with water and once with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was dissolved in 50 ml of petroleum ether, filtered through silicone powder (10 cm thick), and the filtrate was concentrated to obtain compound 52-1.

Preparation of compound 55-3

Compound 52-1 (10 g, 37.15 mmol) was dissolved in tetrahydrofuran (10 mL) and water (40 mL). Indium powder (6 g, 52.26 mmol) was added, and the mixture was sonicated for 8 hours. Formaldehyde aqueous solution (16 g, 197.14 mmol) was added to the reaction solution, and the mixture was stirred for another 32 hours. The reaction solution was diluted with ethyl acetate (300 mL), filtered, and the filtrate was allowed to stand for separation. The upper ethyl acetate phase was separated and washed once with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the product. Purification by silica gel column chromatography yielded compound 55-3.

Preparation of compound 55-4

Compound 55-3 (500 mg, 2.27 mmol) and pyridine (0.5 mL, 6.18 mmol) were dissolved in DCM (10 mL). Trifluoromethanesulfonic acid anhydride (0.5 mL, 3.01 mmol) was slowly added under ice bath conditions, and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate (200 mL), washed successively with water (100 mL × 2) and saturated brine (100 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain compound 55-4.

Preparation of Example 55

Compound 55-4 (130 mg, 0.37 mmol) and compound 1-18 (170 mg, 0.37 mmol) were dissolved in DMF (5 mL), potassium carbonate (180 mg, 1.30 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was poured into water (100 mL), and the mixture was extracted with ethyl acetate (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product, which was purified by reverse reaction (Phenomenex luna C18 150×25 mm × 10 μm; flow rate: 25 mL/min; gradient: 42% - 72% B over 15 min; mobile phase A: 0.225% aqueous methanoic acid, mobile phase B: acetonitrile) to obtain Example 55.

m/z (ESI): [M + H] ⁺ = 548.1.

Implementation Examples 56 and 57

Preparation of compound 56-1

Under nitrogen atmosphere, triethylamine (1.1 mL, 7.87 mmol) was added to 3 mL of dichloromethane containing 24-3 (314 mg, 0.79 mmol), followed by 3 mL of DCM solution containing compound 22-5 (198.83 mg, 1.02 mmol). The mixture was stirred at 26°C for 2 hours. After the reaction was complete, the mixture was quenched with 10 mL of water and extracted with dichloromethane (10 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain compound 56-1.

Preparation of Examples 56 and 57

Under a nitrogen atmosphere, trifluoroacetic acid (800.8 μL, 10.78 mmol) was added to a 9 mL dichloromethane solution containing compound 56-1 (300 mg, 0.54 mmol), and the reaction was carried out at 25 degrees Celsius for 2 hours. After the reaction was complete, the reaction solution was concentrated to obtain a crude product, _which was then purified by reverse-phase preparation (Waters Xbridge 150 × 25 mm × 5 μm, water (water( _NH₄HCO₃ )-ACN, 38% - 68% over 12 min) to obtain a mixture of Examples 56 and 57. The mixture was then separated by SFC (column: DAICEL CHIRALCEL OX (250 mm * 30 mm, 10 μm); mobile phase: [A: _CO₂ ; B: EtOH (0.1 _{% NH₃H₂O} )]; B%: 15.00%-15.00%, 60.00 min; flow rate: 150.00 g/min) to obtain two single isomers.

Example 56 (Retention time = 1.497 minutes)

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.36 (s, 1H), 8.71 - 8.56 (m, 1H), 8.09 - 7.88 (m, 1H), 7.50 - 7.37 (m, 1H), 7.29 - 7.08 (m, 2H), 5.44 - 5.29 (m, 1H), 5.16 - 5.04 (m, 1H), 4.70 - 4.60 (m, 1H), 4.57 - 4.48 (m, 1H), 4.40 - 4.26 (m, 1H), 3.70 - 3.57 (m, 2H), 3.49 - 3.39 (m, 1H), 2.91 - 2.75 (m, 1H), 1.61 (s, 3H), 0.81 - 0.63 (m, 3H);

m/z (ESI): [M+ H] ⁺ =517.3.

Example 57 (Retention time = 1.655 minutes)

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.37 (s, 1H), 8.72 - 8.59 (m, 1H), 7.97 (dd, J = 2.4, 8.6 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.29 - 7.10 (m, 2H), 5.34 (d, J = 4.8 Hz, 1H), 5.10 (d, J = 10.5 Hz, 1H), 4.64 (br t, J = 5.8 Hz, 1H), 4.59 - 4.47 (m, 1H), 4.31 (dd, J = 7.5, 10.3 Hz, 1H), 3.71 - 3.57 (m, 2H), 3.44 (td, J = 5.9, 11.4 Hz, 1H), 2.83 (t, J = 7.3 Hz, 1H), 1.61 (s, 3H), 0.74 (d, J = 6.0 Hz, 3H);

m/z: [M+ H] ⁺ = 517.1.

Implementation Examples 58 and 59

Preparation of compound 58-1

DMF (10 mg, 0.15 mmol) and oxalic acid (0.4 mL, 4.41 mmol) were added to a DCM (5 mL) solution of compound 50-1 (500 mg, 1.47 mmol). The mixture was stirred at 25°C for 1 hour. The mixture was then concentrated, and under nitrogen atmosphere, triethylamine (0.6 mL, 4.35 mmol) and the above concentrate were added sequentially to a 10 mL dichloromethane solution of compound 56-5 (337.89 mg, 1.74 mmol). The reaction mixture was stirred at 26°C for 16 hours. After the reaction was complete, 30 mL of water was added for dilution, and the mixture was extracted with ethyl acetate (30 mL × 2). The combined organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1 ~ 1/1) to obtain compound 58-1.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 8.56 (d, J = 2.4 Hz, 1H), 8.41 (s, 1H), 8.13 (dd, J = 2.4, 8.4 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.09 (t, J = 6.8 Hz, 1H), 6.83 - 6.72 (m, 1H), 6.31 (s, 1H), 5.18 (t, J = 6.8 Hz, 1H), 5.14 - 5.03 (m, 1H), 4.44 (t, J = 7.6 Hz, 1H), 3.91 (t, J = 7.6 Hz, 1H), 2.92 - 2.79 (m, 1H), 1.70 (s, 3H), 1.51 (d, J = 14.4 Hz, 6H), 0.87 - 0.78 (m, 3H);

m/z (ESI): [M+ H] ⁺ =517.2.

Preparation of compound 58-2

Under nitrogen atmosphere, trifluoromethanesulfonic anhydride (83.5 μL, 0.50 mmol) was added to 4 mL of dichloromethane solution containing compound 58-1 (280 mg, 0.61 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours. After the reaction was complete, 20 mL of water was added to quench the reaction mixture, and the mixture was extracted with dichloromethane (30 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1 ~ 2/1) to obtain compound 58-2.

Preparation of compound 58-3

Under a nitrogen atmosphere, acetylenyl[tris(prop-2-yl)]silane (0.2 mL, 0.77 mmol), copper iodide (3.0 mg, 0.02 mmol), triethylamine (23.4 mg, 0.23 mmol), and 1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (8.46 mg, 0.01 mmol) were sequentially added to a 1.5 mL solution of N,N-dimethylformamide containing compound 58-2 (50 mg, 0.08 mmol). The reaction mixture was heated to 100 degrees Celsius and stirred for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with 20 mL of water and 20 mL of ethyl acetate, filtered, and the filtrate was extracted with ethyl acetate (10 mL × 2). The combined organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by thin-layer silica gel preparation (petroleum ether/ethyl acetate = 3/1) to obtain compound 58-3.

Preparation of compound 58-4

Under nitrogen atmosphere, trifluoroacetic acid (262 μL, 3.53 mmol) was added to 2 mL of dichloromethane solution containing compound 58-3 (120 mg, 0.18 mmol), and the reaction mixture was stirred at 25°C for 0.5 hours. After the reaction was complete, saturated sodium bicarbonate was slowly added dropwise to the reaction mixture to adjust the pH to 7. The aqueous phase was extracted with dichloromethane (20 mL × 2), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 58-4.

Preparation of Examples 58 and 59

Under a nitrogen atmosphere, cesium fluoride (284 mg, 1.87 mmol) was added to 2 mL of N,N-dimethylformamide solution containing compound 58-4 (120 mg, 0.19 mmol). The reaction mixture was stirred at 25°C for 0.5 hours. After the reaction was complete, the reaction mixture was filtered, and the filtrate was purified by reverse-phase preparation (0.1% FA/ACN, 55%-65% over 5 min) to obtain a mixture of Examples 58 and 59. SFC separation (column: DAICEL CHIRALCEL OX (250 mm * 30 mm, 10 μm); mobile phase: [A: _CO₂ ; B: EtOH (0.1% _{NH₃ H₂O} )]; B%: 20.00%-20.00%, 4.00 min; flow rate: 150.00 g/min) yielded two monomeric isomers:

Example 58 (Retention time = 1.587 minutes)

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.39 (s, 1H), 8.64 (d, J = 2.4 Hz, 1H), 7.99 (dd, J = 2.4, 8.6 Hz, 1H), 7.61 - 7.50 (m, 1H), 7.42 (d, J = 8.6 Hz, 1H), 7.30 (dd, J = 4.4, 8.4 Hz, 1H), 5.34 (d, J = 4.8 Hz, 1H), 5.18 (d, J = 10.0 Hz, 1H), 5.03 (s, 1H), 4.64 (t, J = 6.0 Hz, 1H), 4.53 (td, J = 4.0, 6.8 Hz, 1H), 4.38 (dd, J = 7.8, 10.0 Hz, 1H), 3.68 - 3.58 (m, 1H), 3.43 (td, J = 6.0, 11.6 Hz, 1H), 2.97 - 2.84 (m, 1H), 1.60 (s, 3H), 0.73 (br d, J = 6.0 Hz, 3H);

m/z (ESI): [M+ H] ⁺ = 485.2.

Example 59 (Retention time = 1.726 minutes)

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.45 (s, 1H), 8.70 - 8.65 (m, 1H), 8.02 - 7.95 (m, 1H), 7.61 - 7.49 (m, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.32 (dd, J = 4.4, 8.4 Hz, 1H), 5.35 (d, J = 4.8 Hz, 1H), 5.20 (d, J = 10.0 Hz, 1H), 5.02 (s, 1H), 4.65 (t, J = 6.0 Hz, 1H), 4.58 - 4.49 (m, 1H), 4.39 (dd, J = 7.8, 9.8 Hz, 1H), 3.68 - 3.59 (m, 1H), 3.48 - 3.41 (m, 1H), 2.96 - 2.82 (m, 1H), 1.60 (s, 3H), 0.73 (br d, J = 6.0 Hz, 3H);

m/z: [M+ H] ⁺ = 485.1.

Implementation Example 60

Preparation of compound 60-2

Under nitrogen atmosphere, an acetonitrile solution of compound 60-1 (0.64 g, 5.60 mmol) was added dropwise to a 5 mL acetonitrile solution containing copper iodide (0.1 g, 0.51 mmol) and ethynyltrimethylsilane (0.7 mL, 5.09 mmol). The reaction mixture was reacted at 25°C for 16 hours. After the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain compound 60-2.

Preparation of compound 60-3

Under nitrogen atmosphere, deuterated aluminum hydroxide (0.13 g, 3.04 mmol) was slowly added in portions to 20 mL of THF solution containing compound 60-2 (0.7 g, 3.80 mmol) at 0 °C. The reaction mixture was reacted at 0 °C for 1 hour. After the reaction was complete, 1.5 mL of deuterium water was slowly added dropwise at 0 °C to quench the reaction. After stirring for 10 minutes, the temperature was raised to 26 °C, anhydrous sodium sulfate was added for drying, and the mixture was filtered. The filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain compound 60-3.

Preparation of compound 60-4

Under nitrogen atmosphere, cyanomethylene-tributylphosphine (210.17 mg, 0.87 mmol) was added to 2 mL of dioxane solution containing compound 1-18 (80 mg, 0.17 mmol) and compound 60-3 (170 mg, 1.39 mmol). The reaction solution was heated to 40°C and stirred for 16 hours. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with 10 mL of water, and extracted three times with ethyl acetate (5 mL × 3). The combined organic phase was washed with 10 mL of saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1~1/1) to obtain compound 60-4.

Preparation of Example 60

Under a nitrogen atmosphere, a tetrabutylammonium fluoride tetrahydrofuran solution (0.17 mL, 0.17 mmol) was added to a 1 mL THF solution containing compound 60-4 (50 mg, 0.09 mmol), and the reaction was carried out at 25 degrees Celsius for 1 hour. After the reaction was complete, 10 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (5 mL × 3). The combined organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was then purified by reverse-phase preparation (Phenomenex luna C18 150 × 25 mm × 10 μm); flow rate: 25 mL/min; gradient: 42% - 72% B over 10 min; mobile phase A: 0.225% aqueous methanoic acid, mobile phase B: acetonitrile) to obtain Example 60.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.81 - 10.60 (m, 1H), 8.55 - 8.46 (m, 1H), 8.33 - 8.26 (m, 1H), 8.11 - 8.01 (m, 1H), 7.90 - 7.80 (m, 1H), 7.69 - 7.58 (m, 1H), 7.27 - 7.07 (m, 2H), 5.19 - 5.05 (m, 1H), 4.44 - 4.26 (m, 1H), 2.92 - 2.79 (m, 2H), 2.70 - 2.60 (m, 2H), 1.72 - 1.57 (m, 3H), 0.79 - 0.64 (m, 3H);

m/z (ESI): [M + H] ⁺ = 514.0.

Implementation Example 61

Preparation of compound 61-1

Iodine (396.70 mg, 2.45 mmol) and ammonia (2.5 mL, 30% concentration) were added to a tetrahydrofuran (5 mL) solution of compound 50-5 (500 mg, 1.22 mmol). The reaction mixture was stirred at 30 °C for 10 hours. The reaction mixture was quenched with 30 mL of water and extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed successively with saturated sodium sulfite aqueous solution (30 mL × 2) and saturated sodium chloride aqueous solution (30 mL × 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 61-1.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.45 (q, J = 9.0 Hz, 1H), 7.24 (dd, J = 4.3, 8.8 Hz, 1H), 4.82 (d, J = 9.2 Hz, 1H), 4.15 - 4.12 (m, 1H), 2.94 - 2.89 (m, 1H), 1.66 (s, 3H), 1.39 (s, 9H), 0.88 - 0.79 (m, 3H).

Preparation of compound 61-2

Trifluoroacetic acid (2.00 mL) was added to a DCM (10 mL) solution of compound 61-1 (300 mg, 0.74 mmol), and the mixture was stirred at 20 °C for 5 hours. After the reaction was complete, the reaction solution was directly concentrated under reduced pressure to obtain compound 61-2.

m/z (ESI): [MH] ^- = 348.0.

Preparation of compound 61-3

Compound 61-2 (260 mg, 0.74 mmol) and methyl 4-aminopyridine-2-carboxylate (169.90 mg, 1.12 mmol) were dissolved in acetonitrile (5 mL), and N,N,N',N'-tetramethylchloromethanesulfonium hexafluorophosphate (313.31 mg, 1.12 mmol) was added. The reaction mixture was reacted at 20 °C for 16 hours. 30 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate = 3/7) to obtain compound 61-3.

m/z (ESI): [M + H] ⁺ = 484.2.

Preparation of Example 61

Compound 61-3 (100 mg, 0.21 mmol) was added to an ammonia-methanol solution (2 mL, 6 M) and reacted at 20 °C for 16 hours. After the reaction was complete, the reaction solution was directly concentrated under reduced pressure, and the crude product was purified by reverse-phase preparation (Phenomenex luna C18 150×25mm × 10um; flow rate: 25 mL/min; gradient: 42% - 62% B over 10 min; mobile phase A: 0.225% aqueous methanoic acid, mobile phase B: acetonitrile) to obtain Example 61.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.68 (s, 1H), 8.50 (d, J = 5.6 Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.95 - 7.87 (m, 1H), 7.85 (dd, J = 2.0, 5.6 Hz, 1H), 7.62 (br s, 1H), 7.49 (dd, J = 4.4, 8.8 Hz, 1H), 5.26 (d, J = 9.2 Hz, 1H), 4.31 (t, J = 8.8 Hz, 1H), 2.91 (t, J = 7.6 Hz, 1H), 1.62 (s, 3H), 0.79 (d, J = 6.4 Hz, 3H);

m/z (ESI): [M + H] ⁺ = 469.0.

Experimental Example 1: Manual Patch Clamp Method for Detecting the Inhibitory Activity of the Compound Applied for this Application on the Voltage-Gated Sodium Channel NaV1.8

Cell Culture and Passaging: CHO cells stably expressing human NaV1.8 were cultured in Ham's F-12 medium containing 10% fetal bovine serum and 10 μg/mL blasticidin, 200 μg/mL Hygromycin B, and 100 μg/mL Zeocin. The cell culture temperature was 37°C and the carbon dioxide concentration was 5%. During cell passaging, the old medium was removed, and the cells were washed once with PBS, followed by incubation at 37°C with 0.25% Trypsin-EDTA solution. When cells were observed to detach from the bottom of the dish, an appropriate amount of preheated 37°C complete medium was added. After agitating the cells from the bottom of the dish, transfer them to a sterile centrifuge tube and centrifuge at 1000 rpm for 5 min to collect the cells. Then, seed the cells into 6 cm cell culture dishes (2.5 × ^10⁵ cells/dish, 5 mL of medium) for proliferation or maintenance culture. To maintain the electrophysiological activity of the cells, the cell density should not be lower than 80%.

Before patch clamp testing, 0.25% Trypsin-EDTA solution was added to CHO cells stably expressing human NaV1.8 to isolate and count the cells. 6.5 × ^10³ cells were attached to coverslips and cultured in 24-well plates (final volume 500 μL). Testing was performed 18 hours later.

Preparation of compound samples: The test compound was prepared into a 100 mM stock solution using dimethyl sulfoxide (DMSO), and then diluted to different concentrations of working solution with extracellular fluid containing 100 nM tetrodotoxin (TTX) (140 mM NaCl, _3.5 mM KCl, ₁ mM _MgCl₂ • 6H₂O, 2 mM CaCl₂ • _2H₂O , 10 mM D-Glucose, ₁₀ mM HEPES, 1.25 mM _NaH₂PO₄ • _2H₂O , pH adjusted to 7.4 with NaOH). The concentration of DMSO in each working solution was 0.1%. The working solutions of the test compound were sonicated for 20 min before testing.

Patch clamp testing: During patch clamp operation, a microelectrode puller is first used to pull the capillary glass tube into a recording electrode. Then, the electrode filled with intracellular fluid (50 mM CsCl, 10 mM NaCl, 10 mM HEPES, 60 mM CsF, 20 mM EGTA, pH adjusted to 7.2 with CsOH) is inserted into the microelectrode holder. Under an inverted microscope, the microelectrode manipulator is manipulated to bring the recording electrode into contact with the cell, and negative pressure is applied to aspirate and form a GΩ seal. At this point, fast capacitance compensation is performed, and then negative pressure is continued to rupture the cell membrane, forming a whole-cell recording mode. Finally, slow capacitance compensation is performed and relevant parameters are recorded. No leakage compensation is provided.

Once the sodium current recorded in whole-cell imaging stabilized, drug administration began. Each drug concentration was administered for 5 minutes (or until the current stabilized) before measuring the next concentration. A coverslip containing cells was placed in a recording bath under an inverted microscope. Blank control solution and working solution of the test compound were sequentially administered to the cells via gravity perfusion, from low to high concentration, with fluid exchange performed using a peristaltic pump during recording. The current measured in the compound-free solution for each cell served as its control. Each concentration was measured independently twice. All electrophysiological experiments were performed at room temperature. Specifically, two concentrations (for initial screening) or five concentrations (for calculating the _IC50 value) were set for each test compound. The inhibitory activity of the test compound on the NaV1.8 sodium channel was determined by calculating the relative percentage of the peak current generated after the test compound was used to treat the cells to the peak current generated by the control cells.

The voltage stimulation protocol for recording sodium current in NaV1.8 using whole-cell patch clamps was as follows: After whole-cell sealing, the cell voltage was clamped at -120 mV. The voltage was first stepped from -130 mV to -10 mV in 10 mV increments and held for 5 s, followed by a 0 mV depolarization pulse to obtain the half-inactivated voltage (Vhalf). The resting state and half-inactivated state of sodium current were detected using a two-pulse mode. A first depolarization pulse (TP1) to 0 mV was applied for 50 ms to detect sodium current in the resting state. The voltage was then adjusted to Vhalf and maintained for 5 seconds. Next, the voltage was restored to -120 mV and maintained for 20 ms. A second depolarization pulse (TP2) was then applied to 0 mV for 50 ms to detect the semi-inactivated sodium current. Finally, the voltage was restored to the clamping voltage of -120 mV. Data was collected every 20 ms to observe the effect of the drug on the peak sodium current under the two different conditions.

The inhibitory activity of the example compounds against the _NaV 1.8 channel was determined by the above-mentioned experiments. The inhibition rate and _IC50 at 1 nM concentration are shown in Tables 1 and 2.

Table 1. Inhibitory activity (inhibition rate) of the exemplary compounds against NaV1.8 channels Implementation Examples 1 nM concentration inhibition rate /% Resting state Semi-inactivated state 1 97.03 97.53 2 97.41 96.79 3 63.16 62.49 5 99.25 99.92 15 91.57 89.51 16 89.55 89.07 17 91.12 92.09 18 98.24 97.76 19 94.69 94.96 20 96.75 95.88 twenty four 92.26 93.60 25 84.00 88.38 29 96.35 97.29 30 92.95 93.06 31 88.10 87.43 32 99.25 99.92 39 96.35 97.29 40 88.04 85.84 41 91.61 89.62 44 87.91 85.75 45 87.44 90.25 46 86.07 81.93 48 96.31 96.63 51 88.34 90.09 55 85.07 81.21

Table 2. Inhibitory activity of the exemplary compounds against NaV1.8 channels ( _IC50 ) Implementation Examples IC ₅₀ /nM Resting state Semi-inactivated state 1 0.022 0.027 12 0.019 0.029 twenty four 0.033 0.048 61 0.78 0.89

Experimental results show that the compounds in this application have good inhibitory effects on NaV1.8.

Experimental Example 2: In vivo pharmacokinetic studies were conducted on rats via single intravenous injection or oral gavage administration.

Experimental Methods: Six male SD rats (200-300 g) were divided into two groups: one group received a single oral dose of 5 mg/kg, and the other group received a single intravenous dose of 1 mg/kg. The animals administered the oral dose were fasted overnight and resumed eating 4 hours after administration, while the animals administered the intravenous dose had free access to food. Blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h post-administration. After pretreatment, plasma samples were analyzed by LC/MS/MS in MRM mode. A suitable standard curve was established to quantify the target compound in the plasma samples to obtain the drug concentration-time curve. Pharmacokinetic parameters were calculated using the non-atrioventricular membrane type of WinNonlin software. The experimental results are shown in the table below.

Table 3. Pharmacokinetic parameters of the compounds in this application in rats. Rat PK parameters Implementation Example 3 Implementation Example 12 Implementation Example 24 Implementation Example 61 Intravenous injection Dosage (mg/kg) 1 1 1 1 Scavenging rate CL (mL/min/kg) 5.19 8.9 24.1 3.97 Apparent distribution volume Vss (L/kg) 1.13 1.26 1.06 1.53 Exposure AUC _0-last (h*ng/mL) 3032 1858 707 4494 Half-life T _{_1/2} (h) 3.51 2.17 0.771 5.32 oral Dosage (mg/kg) 5 5 30 5 Maximum plasma drug concentration C _max (ng/mL) 696 718 5023 1181 Peak time _Tmax (h) 4.67 6 7.33 6.67 Exposure AUC _0-last (h*ng/mL) 8920 9600 69366 17898 Half-life T _{_1/2} (h) 4.46 2.81 2.4 6.24 Oral bioavailability F (%) 56 98 - 83

Experimental results show that the compound of this application has high blood concentration, high exposure, and low clearance in rats, exhibiting significant pharmacokinetic advantages.

Experimental Example 3: In vivo pharmacokinetic studies were conducted on mice by single intravenous injection or oral administration via gavage.

Experimental Methods: Six male C57BL/6 mice (20–30 g each) were divided into two groups. One group received a single intravenous dose of 5 mg/kg via tail vein, while the other group received a single oral dose of 1 mg/kg. Both groups had free access to food. Blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h post-administration. After pretreatment, plasma samples were analyzed by LC/MS/MS in MRM mode. A suitable standard curve was established to quantify the target compound in the plasma samples, obtaining the drug concentration-time curve. Pharmacokinetic parameters were calculated using a non-compartmental model in WinNonlin software. The experimental results are shown in the table below.

Table 4. Pharmacokinetic parameters of the compounds in this application in mice Mouse PK parameters Implementation Example 3 Implementation Example 12 Implementation Example 24 Implementation Example 61 Intravenous injection Dosage (mg/kg) 1 1 1 1 Scavenging rate CL (mL/min/kg) 3.35 14.8 18.7 5.84 Apparent distribution volume Vss (L/kg) 0.892 1.22 1.07 1.75 Exposure AUC _0-last (h*ng/mL) 4998 1129 904 2807 Half-life T _{_1/2} (h) 2.33 1.22 0.89 4.62 oral Dosage (mg/kg) 30 30 30 30 Maximum plasma drug concentration C _max (ng/mL) 5145 5590 9563 5520 Peak time _Tmax (h) 1.25 2 2 1.67 Exposure AUC _0-last (h*ng/mL) 76666 71639 84854 53267 Half-life T _{_1/2} (h) 10.2 2.17 3.1 4.26

Experimental results show that the compound of this embodiment has high blood drug concentration and high exposure in mice, and has pharmacokinetic advantages.

Experimental Example 4: In vivo pharmacokinetic studies of dogs via single intravenous injection or oral gavage.

Experimental method: Six male beagle dogs weighing 9-11 kg were divided into two groups. One group received a single intravenous injection of 0.5 mg/kg via the tail vein, while the other group received a single oral injection of 1 mg/kg. Animals in the intravenous injection group were allowed free access to food, while animals in the oral injection group were fasted overnight and allowed to resume eating 4 hours after administration. Blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, 24, and 48 h post-administration in the intravenous injection group, and at the same times in the oral administration group. After pretreatment, plasma samples were analyzed by LC/MS/MS in MRM mode. A suitable standard curve was established to quantify the target compound in the plasma samples, obtaining the drug concentration-time curve. Pharmacokinetic parameters were calculated using a non-compartmental model in WinNonlin software. The experimental results are shown in the table below.

Table 5. Pharmacokinetic parameters of the compounds in this application (canine version) Dog PK Parameters Implementation Example 3 Implementation Example 12 Implementation Example 24 Intravenous injection Dosage (mg/kg) 0.5 0.5 0.5 Scavenging rate CL (mL/min/kg) 0.202 1.96 1.61 Apparent distribution volume Vss (L/kg) 0.835 0.866 0.587 Exposure AUC _0-last (h*ng/mL) 21416 4612 5171 Half-life T _{_1/2} (h) 48.3 6.37 4.34 oral Dosage (mg/kg) 1 1 1 Maximum plasma drug concentration C _max (ng/mL) 1126 490 721 Peak time _Tmax (h) 2 2 2 Exposure AUC _0-last (h*ng/mL) 42706 8650 9695 Half-life T _{_1/2} (h) 101 8.5 4.7 Oral bioavailability F (%) >100 95.4 92.0

Experimental results show that the compound of this embodiment has low clearance in dogs, high exposure, high oral bioavailability, and pharmacokinetic advantages.

Experimental Example 5: In vivo pharmacokinetic studies were conducted on monkeys via single intravenous injection or oral gavage administration.

Six male cynomolgus macaques weighing 3.0–3.3 kg were divided into two groups: one group received a single intravenous dose of 1 mg/kg, and the other group received a single oral dose of 2 mg/kg. Animals in the intravenous dose group were allowed free access to food, while animals in the oral dose group were fasted overnight and resumed eating 4 hours after administration. Blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, 24, and 48 h post-administration in the intravenous injection group, and at the same times in the oral administration group. After pretreatment, plasma samples were analyzed by LC/MS/MS in MRM mode. A suitable standard curve was established to quantify the target compound in the plasma samples, obtaining the drug concentration-time curve. Pharmacokinetic parameters were calculated using a non-compartmental model in WinNonlin software. The experimental results are shown in the table below.

Table 6. Drug pharmacokinetic parameters of the compounds in this application (monkey drug). Monkey vs. Parameters Implementation Example 24 Implementation Example 61 Intravenous injection Dosage (mg/kg) 1 1 Scavenging rate CL (mL/min/kg) 8.88 5.45 Apparent distribution volume Vss (L/kg) 1.50 1.74 Exposure AUC _0-last (h*ng/mL) 1876 3128 Half-life T _{_1/2} (h) 2.98 6.10 oral Dosage (mg/kg) 2 2 Maximum plasma drug concentration C _max (ng/mL) 279 307 Peak time _Tmax (h) 3.33 4.00 Exposure AUC _0-last (h*ng/mL) 2364 3717 Half-life T _{_1/2} (h) 3.57 5.21 Oral bioavailability F (%) 63.6 59.4

Experimental results show that the compound of this embodiment has low clearance rate, high exposure, and high oral bioavailability in dogs, demonstrating pharmacokinetic advantages.

Experimental Example 6: Solubility of the compound in this application.

Experimental Method: 15 μL of 10 mM DMSO stock solution was added to 96-well plates (n=2) containing 485 μL of phosphate buffer (PBS pH 7.4), simulated post-fasting intestinal fluid (FaSSIF pH 6.5), simulated post-feeding intestinal fluid (FeSSIF pH 5.0), and simulated post-fasting gastric fluid (FaSSGF pH 1.6), respectively. The final concentration was 300 μM (containing 3% DMSO). After adding a stirring rod to each well, the plates were sealed and shaken at 25°C and 1100 rpm for 2 h in a thermostatic shaker. After shaking, the samples were filtered through a vacuum filter in a filter plate. Take 5 μL of filtrate, add 5 μL of DMSO, then add an appropriate amount of a 1:1 mixture of ultrapure water and acetonitrile containing internal standard to dilute by the corresponding factor. Mix well and then perform LC-MS/MS analysis. Take 5 μL of 300 μM DMSO standard solution, add 5 μL of different buffers, then add an appropriate amount of a 1:1 mixture of ultrapure water and acetonitrile containing internal standard to dilute by the corresponding factor. Mix well and perform LC-MS/MS analysis together with the sample. The experimental results are shown in the table below.

The solubility values of the test sample and the standard reference are calculated according to the following formula:

Table 7. Solubility of the compounds in this application Implementation Examples Kinetic solubility (μM) in different systems FaSSIF FeSSIF FaSSGF Implementation Example 3 33.4 293 32 Implementation Example 12 49.22 300 10.54 Implementation Example 24 284 315 106 Implementation Example 61 19.89 72.33 48.32

Experimental results show that the compound of this embodiment has good solubility in FaSSIF, FESSIF and FaSSGF solutions.

Experimental Example 7: CYP inhibition of the compound in this application.

Experimental Methods: Specific probe substrates of CYP450 isoenzymes were co-incubated with human liver microsomes and compounds of varying concentrations. The reaction was initiated with reduced nicotinamide adenine dinucleotide phosphate (NADPH). After the reaction, the samples were processed, and the concentrations of metabolites produced by the probe substrate were quantitatively detected using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The _IC50 values were then calculated. The experimental results are shown in the table below.

Table 8. Effects of the compounds of this application on the activity of human liver microsomal cytochrome P450. Implementation Examples Inhibitory activity _IC50 /μM CYP1A2 CYP2B6 CYP2C8 CYP2C9 CYP2C19 CYP2D6 CYP3A-M CYP3A-T Implementation Example 3 >30 28.4 9.2 12.7 6.25 12.6 >30 24.9 Implementation Example 24 >30 >30 21.3 28.5 27 >30 24.7 16.4 Implementation Example 61 >30 >30 11.6 7.3 15.8 >30 >30 20.0

Experimental results show that the compound of this application embodiment has weak inhibition of cytochrome P450 isoenzymes and low drug-drug interaction risk.

Experimental Example 8: Metabolic stability of the compound in liver microsomes.

Experimental method: In a 100 mM pH 7.4 phosphate buffer system, appropriate volumes of human, monkey, dog, rat, or mouse liver microsomes (final protein concentration 0.5 mg/mL) and reduced nicotinamide adenine dinucleotide phosphate (NADPH, final concentration 1 mM) were mixed and pre-incubated at 37°C with shaking for 10 min. Then, an appropriate volume of the target compound (final concentration 1 μM) was added to initiate the reaction, with the organic solvent not exceeding 1%. After 0.5, 5, 15, 30, and 60 min of reaction, the same volume of incubation solution was taken and an appropriate amount of ice-cold acetonitrile solution containing internal standard was added to terminate the reaction. After centrifugation at 3220 g for 40 min, the supernatant was diluted with ultrapure water and quantitatively analyzed by LC/MS/MS. The peak area ratio of the target compound to the internal standard at 0.5 min was taken as 100%, and the relative percentage of the target compound remaining at other time points was calculated. The natural logarithm of the percentage of the target compound remaining at each time point was linearly regressed against the incubation time to obtain the slope (k), and the half-life was calculated using the formula t _{_1/2} = -0.693/k. The experimental results are shown in the table below:

Table 9. Metabolic stability of the compounds in this application on liver microsomes Implementation Examples Metabolic half-life T1 _/2 (minutes) of various species people monkey dog rats mice Implementation Example 3 >184 29 >184 73.4 58.9 Implementation Example 24 111 47.5 113 90 102 Implementation Example 61 176 26.8 >184 >184 >184

Experimental results show that the compound of this embodiment is relatively stable in liver microsomes of various species.

Experimental Example 9: Hepatic cell metabolic stability of the compound in this application.

Experimental Methods: Human, monkey, dog, rat, or mouse hepatocytes (cell density 0.5 × ^10⁶ cells/mL) and the target compound (final concentration 1 μM) were mixed and incubated at 37°C with shaking for 120 min, with organic solvent not exceeding 1%. After 0.5, 15, 30, 60, 90, and 120 min of reaction, the same volume of incubation solution was collected, and an appropriate amount of ice-cold acetonitrile solution containing internal standard was added to terminate the reaction. The sample was centrifuged at 3220 g for 45 min, and the supernatant was diluted with ultrapure water. Quantitative analysis was performed using LC/MS/MS. The peak area ratio of the target compound to the internal standard at 0.5 min was taken as 100%, and the relative percentage of the target compound remaining at other time points was calculated. Linear regression analysis was performed on the natural logarithm of the remaining percentage of the target compound at each time point and the incubation time to obtain the slope (k). The half-life was calculated using the formula t _{_1/2} = -0.693/k. The experimental results are shown in the table below:

Table 10. Hepatic cell metabolic stability of the compounds in this application embodiment Implementation Examples Metabolic half-life T1 _/2 (minutes) of various species people monkey dog rats mice Implementation Example 3 107 96 ∞ 97 57 Implementation Example 24 463 121 286 72 77 Implementation Example 61 ∞ 91 >573 56 53

Experimental results show that the compound of this embodiment is relatively stable in various types of hepatocytes.

Experimental Example 10: Plasma protein binding rate of the compound in this application.

Experimental method: Take 10 mM DMSO stock solution and dilute it with DMSO into 1 mM working solution. Take 3 μL of the working solution of the test substance, add it to 597 μL of pre-incubated plasma, and mix thoroughly. The final concentration of test substance in plasma is 5 μM. The final organic solvent content of the incubation system was 0.5%. After mixing, immediately transfer 50 μL of the incubation system to a new 96-well plate as a 0-point sample. The treatment method is the same as that of the incubated sample.

After assembling the dialysis plate and dialysis membrane, add 120 μL of the test plasma sample and pH 7.4 phosphate buffer to the air pockets on both sides of the dialysis membrane, seal the membrane, and incubate on a vortex oscillator at 37°C, 5% CO2, and 300 rpm for 6 h. After incubation, remove the membrane and transfer 50 μL of sample from each well to a new 96-well plate. The remaining incubation system is incubated under the same conditions for the corresponding time for the stability test of the test substance. After incubation, transfer 50 μL of the incubation system for processing, in the same manner as the dialysis-incubated plasma sample.

Add 50 μL of blank plasma to the retrieved buffer sample, and add an equal volume of blank buffer to the retrieved plasma sample. Vortex for 2 minutes to mix thoroughly, then add 400 μL of quencher (acetonitrile containing 0.5 μM tolbutamide) to precipitate proteins. Vortex all samples for 10 minutes, then centrifuge at 3000 g, 4°C for 30 minutes. Transfer 100 μL of the supernatant to a new 96-well plate and centrifuge again at 3000 g, 4°C for 30 minutes. Transfer 150 μL of the supernatant to a new 96-well plate, add an equal volume of pure water, mix thoroughly, and proceed with LC-MS/MS analysis.

All data were calculated using Microsoft Excel. Peak areas were determined using extracted ion chromatograms. The percentage of free and bound molecules was calculated as the ratio of the test analyte peak area to the internal standard peak area, using the following formula:

The bound percentage (%) = 100 – free percentage. The experimental results are shown in the table below:

Table 11. Plasma protein binding rates of the compounds in this application Implementation Examples Human plasma protein binding rate / % Implementation Example 24 97.38 Implementation Example 61 96.93

Experiment 11: Efficacy Tests of Examples 3, 12, and 24 1. Experimental Objective: Male SD rats and male C57 BL/6J mice were used to establish a plantar incision pain model. The analgesic effect of the disclosed compound was evaluated by measuring changes in the mechanical pain threshold of the animals. 2. Experimental Drugs: Examples 3, 12, and 24. 5% DMSO, 10% solubilol, and 85% saline were added sequentially and vortexed until clear. 3. Experimental Materials and Methods: 3.1 Experimental Animals: Species, strains, ages, and sexes: Male SD rats, 6-8 weeks old; Male C57 BL/6J mice, 6-8 weeks old. 3.2 Experimental Animal Grouping: After acclimatization, the SD rats were grouped as follows: Group Number Dosage (mg/kg) Dosage volume (mL/kg) Dosage concentration (mg/mL) Frequency of drug administration Method of drug administration Solvent control 8 / 5 / single Gavage Implementation Example 3 8 30 5 6 single Gavage Implementation Example 12 8 15 5 3 single Gavage Implementation Example 12 8 30 5 6 single Gavage Implementation Example 24 8 30 5 6 single Gavage After acclimatization, C57 BL/6J mice were divided into the following groups: Group Number Dosage (mg/kg) Dosage volume (mL/kg) Dosage concentration (mg/mL) Frequency of drug administration Method of drug administration Solvent comparison 8 / 10 / single Gavage Implementation Example 3 8 60 10 6 single Gavage Implementation Example 12 8 60 10 6 single Gavage Implementation Example 24 8 30 10 3 single Gavage Implementation Example 24 8 15 10 1.5 single Gavage

3.3 Experimental Methods

Foot incision pain modeling: The experimental animal was anesthetized and fixed in a prone position on the operating table. The lateral hind limb was abducted with the foot facing upwards and secured with surgical tape, and the area was disinfected. A longitudinal incision was made in the skin fascia at the heel of the foot, extending towards the toes, using a sterile scalpel. One end of a bent tweezer was inserted below the lateral edge of the flexor digitorum brevis muscle and pushed into the medial side of the muscle to elevate the flexor digitorum brevis. A longitudinal incision was made in the muscle with a scalpel, ensuring that the muscle belly was cut in half to expose the skin. The incision was closed with 7-0 sutures and the area was disinfected. The animal was returned to its original position, and the animal remained in recovery overnight. Medication was administered orally via gavage, and mechanical pain assessment was performed 3 hours after administration.

Ascending test (mechanical pain assessment): Place the experimental animal on a mechanical pain metal mesh frame and let it remain still for 30-60 minutes until it stops looking around and exploring and becomes relatively quiet before starting the test. After the experimental animal is quiet, slowly and gently stimulate the sole of the hind limb of the test animal with Von-Frey fibers to bend the fibers, and observe the animal's foot withdrawal response for 2-3 seconds. Stimulate the test animal one by one according to the fiber weight in ascending order, with each fiber weight being stimulated 5 times consecutively, with an interval of at least 10 seconds between each stimulation. If fewer than 3 positive responses occur, repeat the above procedure using a larger fiber. When 3 or more positive responses occur on the first test, that fiber is taken as the animal's pain threshold (test each animal twice and take the average). If the experimental animal exhibits a foot-lifting, avoidance, or foot-licking response to the stimulus, it is marked as positive (×). Foot-withdrawing responses caused by body movement are not counted. If none of the above behaviors are observed, it is marked as negative (○).

Fiber count: Rats 0.6, 1.0, 1.4, 2.0, 4.0, 6.0, 8.0, 10.0, 15.0 (g), with a cut value of 15.0 g; Mice 0.16, 0.40, 0.60, 1.00, 1.40, 2.00 (g), with a cut value of 2.00 g.

3.4 Data Analysis

After data aggregation and statistics, SPSS statistical software (version R26.0.0.0) was used to perform mean and standard error analysis. Based on the SPSS statistical results, graphs were drawn using Graph Pad (version 8.0.2) software, and one-way ANOVA and t-test were used to test the data.

The percentage increase in threshold (%) = [( _Gt - _G0 )/ _G0 ] × 100 (%), where _Gt is the plantar pain threshold of the drug-treated group and _G0 is the plantar pain threshold of the solvent-treated group.

4. Results

The analgesic effects of Examples 3, 12, and 24 in a rat paw incision pain model are shown in Table 12. The analgesic effects of Examples 3, 12, and 24 in a mouse paw incision pain model are shown in Table 13.

Table 12 Analgesic efficacy of the disclosed compound in a rat model of plantar incision pain. Group Dosage (mg/kg) Pain threshold (g) Percentage increase in threshold (%) p(vs solvent comparison) Method of drug administration Number Solvent control / 3.6±0.3 / / Gavage 8 Implementation Example 3 30 7.1±0.2 97.2 <0.0001 Gavage 8 Implementation Example 12 15 7.0±0.3 94.4 <0.0001 Gavage 8 Implementation Example 12 30 7.5±0.2 108.3 <0.0001 Gavage 8 Implementation Example 24 30 8.1±0.3 125.0 <0.0001 Gavage 8

Table 13. Analgesic efficacy of the disclosed compound in a mouse model of plantar incision pain. Group Dosage (mg/kg) Pain threshold (g) Percentage increase in threshold (%) p(vs solvent comparison) Method of drug administration Number Solvent control / 0.36±0.02 / / Gavage 8 Implementation Example 3 60 0.70±0.05 94.4 0.0031 Gavage 8 Implementation Example 12 60 0.78±0.06 116.7 0.0002 Gavage 8 Implementation Example 24 30 0.74±0.08 105.6 0.0009 Gavage 8 Implementation Example 24 15 0.54±0.04 50.0 0.2468 Gavage 8

5. Conclusion

The baseline pain thresholds in rats before surgery were as follows: After surgery, 3 hours after drug administration, the pain threshold of compound 3 at 30 mg/kg was 7.1 ± 0.2 g, which was significantly higher than that of the solvent control group by 97.2% (p < 0.0001); the pain thresholds of compound 12 at 15 and 30 mg/kg were 7.0 ± 0.3 g and 7.5 ± 0.2 g, respectively, which were significantly higher than that of the solvent control group by 94.4% (p < 0.0001) and 108.3% (p < 0.0001), respectively. The pain threshold of compound 12 at 30 mg/kg was slightly higher than that at 15 mg/kg, and its analgesic effect was close to saturation. The pain threshold of compound 24 at 30 mg/kg was 8.1 ± 0.3 g, which was significantly higher than that of the solvent control group by 125% (p < 0.0001), and its analgesic effect was significantly higher than that of compound 3 at 30 mg/kg (p < 0.05).

The baseline pain thresholds in mice before surgery were as follows: Three hours after surgery, the pain threshold of compound 3 at 60 mg/kg was 0.70 ± 0.05 g, significantly higher than the solvent control group by 94.4% (p < 0.01); the pain threshold of compound 12 at 60 mg/kg was 0.78 ± 0.06 g, significantly higher than the solvent control group by 116.7% (p < 0.001); and the pain thresholds of compound 24 at 30 and 15 mg/kg were 0.74 ± 0.08 g and 0.54 ± 0.04 g, respectively, significantly higher than the solvent control group by 105.6% (p < 0.001) and 50.0% (p < 0.001), respectively. Compound 24 of Example 24 had a significantly higher pain threshold at 30 mg/kg than at 15 mg/kg (p < 0.05), indicating that its analgesic effect was significantly dose-dependent.

Example 12: Pharmacodynamic Test of Example 61 1. Experimental Objective: To evaluate the efficacy of the compound in a mouse paw incision pain model using a mechanical hypersensitivity test. 2. Experimental Drug: Compound of Example 61. 5% DMSO, 10% solubilizer, and 85% saline were added sequentially, and the mixture was vortexed until clear. 3. Experimental Materials and Methods: 3.1 Experimental Animals: Species, strain, age, and sex: C57 BL/6 mice, 6-8 weeks old, male. 3.2 Experimental Animal Grouping: After acclimatization, the C57 BL/6 mice were grouped as follows: Group Number Dosage (mg/kg) Dosage volume (mL/kg) Dosage concentration (mg/mL) Frequency of drug administration Method of drug administration Naïve vs. 10 / 10 / single Gavage Solvent control 10 / 10 / single Gavage Implementation Example 61 10 30 10 3 single Gavage Implementation Example 61 10 60 10 6 single Gavage

3.3 Experimental Methods

Inducing foot incision pain model: Animals were anesthetized with isoflurane, and the toes were squeezed to confirm complete anesthesia before surgery. Ophthalmic ointment was applied to the animals' eyes to prevent corneal dryness. The left foot was disinfected three times with povidone-iodine and 70% ethanol, and surgery began after the skin was dry. A longitudinal incision of approximately 5 mm was made, starting 2 mm from the heel and moving towards the toes. After cutting the skin, the flexor digitorum brevis muscle was lifted, creating a longitudinal blunt injury. The wound was sutured and disinfected. After the animals were fully awake (able to move freely), they were returned to their cages. Ten animals that did not undergo incision pain surgery in mice served as Naïve's control.

Mechanical hypersensitivity test (up-down method): One day after modeling, mechanical hypersensitivity tests were performed on the left hind paw of all model mice at 1 hour, 3 hours, and 6 hours after drug administration. Mice were placed individually in plexiglass boxes with a mesh bottom to ensure the mouse's paw was accessible for testing. Mice were allowed 15 minutes to acclimatize before testing. After acclimatization, test fibers were used to test the central area of the sole of the mouse's left hind paw. The test fibers included eight test intensities: 2.36 (0.02 g), 2.44 (0.04 g), 2.83 (0.07 g), 3.22 (0.16 g), 3.61 (0.4 g), 3.84 (0.6 g), 4.08 (1 g), and 4.17 (1.4 g). During testing, the test fiber is pressed vertically against the skin, applying force to bend the fiber for 6-8 seconds, with a 5-second interval between each test. A rapid withdrawal of the animal's leg during the test is recorded as a pain response. A leg withdrawal as the test fiber leaves the animal's skin is also recorded as a pain response. If the animal moves or walks, no pain response is recorded, and the test should be repeated. The test begins with 3.22 (0.16 g). If the animal shows a pain response, a lower-strength test fiber is used for the next test; if the animal does not show a pain response, a higher-strength test fiber is used for the next test. The maximum strength of the test fiber is 4.17 (1.4 g). Test results are recorded in the table below: X for a pain response, O for no pain response.

Mechanical pain hypersensitivity is expressed as the withdrawal threshold (PWT) in the behavioral test of mice, and is calculated according to the following formula: 50% response threshold (g) = (10 ^(Xf+kδ) )/10,000 Xf = the final test fiber value used in the test k = the table value (refer to the literature Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods. 1994 Jul;53(1):55-63.) δ = mean difference 3.4 Data analysis After the data were aggregated and statistically analyzed, Prism (Graph pad software, Inc.) software was used to analyze the data, and one-way ANOVA was used to test the data.

4. Results

The analgesic efficacy of Example 61 in a mouse plantar incision pain model is shown in Table 14.

Table 14. Analgesic efficacy of the disclosed compound in a mouse model of plantar incision pain. Group Dosage (mg/kg) 50% reaction threshold (g) Method of drug administration Number 1 h 3 h 6 h Naïve vs. / 1.28±0.05 ^**** 1.25±0.05 ^**** 1.15±0.05 ^**** Gavage 10 Solvent control / 0.32±0.02 0.32±0.04 0.32±0.04 Gavage 10 Implementation Example 61 30 0.58±0.07 ^** 0.79±0.08 ^**** 0.60±0.08 ^* Gavage 10 Implementation Example 61 60 0.87±0.07 ^**** 1.07±0.09 ^**** 0.70±0.09 ^*** Gavage 10

Note: Data represent Mean ± SEM, * vs solvent control, * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.0001.

5. Conclusion

At different time points after administration, compound 61 of Example 61 showed significant analgesic effects in a mouse model of plantar incision pain, and these effects were clearly dose-dependent.

In the description of this specification, the terms "an embodiment," "some embodiments," "example," "specific example," or "some examples," etc., refer to specific features, structures, materials, or characteristics described in connection with that embodiment or example, which are included in at least one embodiment or example of this application. In this specification, the illustrative expressions of the above terms need not refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

This application asserts the following priorities:

CN202410483482.4, application date: April 19, 2024; CN202411125232.X, application date: August 15, 2024.

without

without

Claims (13)

A compound that is a compound represented by formula (X), or a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvent, metabolite, pharmaceutically acceptable salt, or prodrug of a compound represented by formula (X). (X); where: ring A is phenyl, 5-10 membered heteroaryl, or 5-10 membered heterocycloyl; each ^Re is independently H, D, F, Cl, Br, I, CN, hydroxyl, nitro, -N( ^Ra ) ₂ , -( _C1-6 alkylene)N( ^Ra ) _{2 ,} -S(O)(=NH) _C1-6 alkyl, -C(O) ^ORa , -C(O)N( ^Ra ) ₂ , -( _C1-6 alkylene)C(O)N( ^Ra ) ₂ , -C(O) ^Ra , _-S (O) ^2NRa , The _C1-6 alkyl, _C1-6 alkoxy, _C1-6 hydroxyalkyl, _C1-6 halogenated alkyl, _C1-6 halogenated alkoxy, _C1-6 alkylamino, _C1-6 alkylthio, _C3-6 cycloalkyl, or 3-6 membered heterocyclic group may optionally be 1, ₂ , _or 3 selected from D, F, _C1 , Br, _I , _CN , _hydroxyl , amino, nitro, oxo, hydroxyl, _{C1-3 alkyl} , _C1-3 alkylamino, _{C1-6 alkylyl} ... The _1-3 halogenated alkyl, _C1-3 hydroxyalkyl, and _C1-3 alkoxy substituents are substituted; each ^Ra is independently H, D, hydroxyl, _C1-6 alkyl, _C1-6 alkoxy, _C3-6 cycloalkyl, and 3-6 membered heterocyclic group, wherein the _C1-6 alkyl, _C1-6 alkoxy, C3-6 cycloalkyl, and _3-6 membered heterocyclic group may optionally be substituted by 1, 2, or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxyl, amino, nitro, oxo, and _C1-3 alkyl; ^R1 , ^R2 , ^R3 , ^R4 , and ^R5 are each independently H, D, F, Cl, Br, I, CN, hydroxyl, nitro, amino, _C1-6 alkyl, C1-6 alkoxy, C1-3 alkyl, C1-6 alkoxy, _C1-3 alkyl, C1-6 alkyl ... _1-6 alkylthio, _C2-6 alkenyl, _C2-6 alkynyl, _C3-6 cycloalkyl, or 3-6 membered heterocyclic group, wherein the _C1-6 alkyl, C1-6 alkoxy, _C1-6 alkylthio, _C2-6 alkenyl, _C2-6 alkynyl, _C3-6 cycloalkyl, and _3-6 membered heterocyclic group may optionally be substituted by 1, 2, or 3 substituents selected from D, F, Cl, Br, I, CN, nitro, amino, hydroxyl, _C1-3 alkyl, _C1-3 halogenated alkyl, _C1-3 hydroxyalkyl, and _C1-3 alkoxy; or ^R3 and ^R5 together with the adjacent carbon atom form a _C3-6 cycloalkyl group; ^R6 is CN, -S(O) _C1-6 alkyl, -S(O) _{2C 1-6} alkyl, -CH=NOC _1-6 alkyl, C _2-6 ynyl, C _1-6 alkylthio, or -L1 _{- L2-} ^Rc , wherein the C _1-6 alkyl, C _2-6 ynyl, and C _1-6 alkylthio can be independently and optionally substituted by 1, 2, or 3 substituents selected from D, F, Cl, Br, I, oxo, and hydroxyl; _L1 is a bond, O, or S; _L2 is a bond, C _1-6 alkylene, or -(C _1-6 alkylene)-C _1-6 alkoxy, wherein the C _1-6 alkylene and C _1-6 alkoxy can be independently and optionally substituted by 1 or 3 substituents selected from D, F, Cl, Br, I, oxo, and hydroxyl; ^Rc is -ON=, -P(O)(C _1-6 alkyl) ₂ , C _2-6 alkynyl or -O- (3-8 membered heterocyclic group), wherein the _C1-6 alkyl, _C2-6 alkynyl, and 3-8 membered heterocyclic group may be independently and optionally substituted by 1, 2, 3, 4, 5, or 6 substituents selected from D, F, Cl, Br, I, hydroxyl, oxo, nitro, amino, alkylamino, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 alkylthio, C3-6 cycloalkyl, and 3-6 membered heterocyclic group; ^R7 and ^R8 are each independently H, D, F, Cl, Br, I, CN, hydroxyl, amino, nitro, C1-6 alkyl, _C1-6 alkoxy, C3-6 cycloalkyl, or 3-6 membered heterocyclic group, wherein the C1-6 alkyl, _C1-6 alkoxy, _{C3-6 cycloalkyl, or 3-6 membered heterocyclic group may be substituted by 1, 2} , 3, 4, 5, or 6 substituents selected from D, F, Cl, Br, I, CN, hydroxyl, amino, nitro, _C1-6 alkyl, _C1-6 alkoxy, _C3-6 cycloalkyl, or 3-6 membered heterocyclic group. _{The 3-6} cycloalkyl and 3-6 heterocyclic groups may be optionally substituted by 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxyl, amino, nitro and _C1-3 alkoxy; n is 1, 2 or 3. The compound according to claim 1, wherein ring A is phenyl, darazine, pyrazine, pyridine, or pyrimidine. The compound according to claim 1 is a compound represented by formula (I), (II) or (III), or a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvent, metabolite, pharmaceutically acceptable salt or prodrug of a compound represented by formula (I), (II) or (III). (I) (II) (III) Wherein: X is CR ¹⁰ or N; Y is CR ¹³ or N; R ⁹ and R ¹⁰ are each independently H, D, F, Cl, Br, I, CN, amino, nitro, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 halogenated alkyl or C _1-6 halogenated alkoxy; R ¹¹ , R ¹² and R ¹³ are each independently H, D, F, Cl, Br, I, CN, hydroxyl, nitro, -N( ^Ra ) ₂ , -(C _1-6 alkylene)N( ^Ra ) _{2 ,} -S(O)(=NH)C _1-6 alkyl, -C(O) ^ORa , -C(O)N( ^Ra ) ₂ , -(C _1-6 alkylene)C(O)N( ^Ra ) ₂ , -C(O) ^Ra , -S(O) ₂ NR ^a 、 The _C1-6 alkyl, _C1-6 alkoxy, _C1-6 hydroxyalkyl, _C1-6 halogenated alkyl, _C1-6 halogenated alkoxy, _C1-6 alkylamino, _C1-6 alkylthio, _C3-6 cycloalkyl, or 3-6 membered heterocyclic group may optionally be 1, ₂ , _or 3 selected from D, F, _C1 , Br, _I , _CN , _hydroxyl , amino, nitro, oxo, hydroxyl, _{C1-3 alkyl} , _C1-3 alkylamino, _{C1-6 alkylyl} ... The _1-3 halogenated alkyl, _C1-3 hydroxyalkyl, and _C1-3 alkoxy substituents are substituted; each ^Ra is independently H, D, hydroxyl, _C1-6 alkyl, _C1-6 alkoxy, _C3-6 cycloalkyl, or 3-6 membered heterocyclic group, wherein the _C1-6 alkyl, _C1-6 alkoxy, _C3-6 cycloalkyl, and 3-6 membered heterocyclic group may optionally be substituted by 1, 2, or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxyl, amino, nitro, oxo, and _C1-3 alkyl. The compound according to any one of claims 1-3, wherein ^R1 , ^R2 , ^R3 , ^R4 and ^R5 are each independently H, D, F, Cl, _Br , I, hydroxyl, methyl, ethyl, _CH2F , _CHF2 , _CF3 , _-CH2OCH3 or _-CH2OH . The compound according to any one of claims 1-4, wherein ^R9 , ^R10 and ^R11 are each independently H, D, F, Cl, Br, I, CN, amino, nitro, methyl, ethyl, methoxy, trifluoromethyl or trifluoromethoxy; and ^R12 and ^R13 are each independently H, D, F, Cl, Br, I, CN, hydroxyl, amino, nitro, methyl, ethyl, _CH2F , _{CHF2 , -OCH3} , _-OCH2CH3 , -C(O) _NH2 , -C(O)NHOH, -C(O _{) NHOCH3} , -CH2OH, -CH(OH) _CH2OH , -C(O)NHCH3, -CH _{( OH} )( _{CH3)2 ,} -S(O)(=NH) _{CH3 ,} -S(O) _{2NH2 .} , , , , or . The compound according to any one of claims 1-5, wherein ^R7 and ^R8 are each independently H, D, F, Cl, Br, I, hydroxyl, methyl, ethyl, _CH2F , _CHF2 or _CF3 . The compound according to any one of claims 1-6, wherein ^R6 is CN, -S(O) _C1-3alkyl , -S(O) _{2C1-3alkyl -} CH= _NOC1-3alkyl , -C2-6 ynyl, _C1-3 alkylthio, or -L1- _L2 - ^Rc , wherein the _C1-3 alkyl, _C1-3 alkylthio, and _C2-6 ynyl can be independently and optionally substituted by ₁ , 2, or 3 substituents selected from D, F, Cl, Br, I, oxo, and hydroxyl _{; L1} is bond, O, or S; _L2 is bond, _C1-3 alkylene, or -( _C1-3 alkylene) _-C1-3 alkoxy; ^Rc is -ON=, -P(O)( _CH3 ) ₂ , _C2-6 ynyl, or -O-(3-8 membered heterocyclic group); wherein the C _{The 2-6} ynyl and 3-8 heterocyclic groups can be independently and optionally substituted by 1 _{, 2, 3, 4, 5 or 6 substituents selected from D, F, Cl, Br, I, hydroxyl, oxo, nitro, amino, C1-3 alkyl} , _C1-3 alkoxy, C1-3 alkylthio, _C3-6 cycloalkyl and 3-6 heterocyclic groups. The compound according to any one of claims 1-7, wherein ^R6 is CN, -S(O) _CH3 , -S(O) _{2CH3 ,} -P ₍ O)( _CH3 ) ₂ , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or . The compounds according to claims 1-8 have the structure shown in formula (IV) or (V): (IV) (V) wherein ^Rc is _{a C2-6} ynyl group, which may be independently and optionally substituted by 1, 2, 3, 4, 5 or 6 substituents selected from D, F, Cl, Br, I, hydroxyl, nitro, amino, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 alkylthio, _C3-6 cycloalkyl and 3-6 heterocyclic groups. A compound that is a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvent, metabolite, pharmaceutically acceptable salt, or prodrug having one of the following structures: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or . A pharmaceutical composition comprising the compound described in any one of claims 1-10; wherein the pharmaceutical composition optionally further comprises a pharmaceutically acceptable adjuvant, carrier, adjuvant, or any combination thereof. Use of a compound according to any one of claims 1-10 or a pharmaceutical composition according to claim 11 in the preparation of a pharmaceutical, wherein the pharmaceutical is used to treat a disease in which a voltage-gated sodium channel NaV1.8 is responsive. According to the use described in claim 12, the disease is chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, Shaco-Malley-Duss disease, incontinence, pathological cough, or arrhythmia.