Pyrazole-containing polycyclic derivative inhibitors, preparation methods therefor, and uses thereof

Abstract

Provided are pyrazole-containing polycyclic derivative inhibitors, preparation methods therefor, and uses thereof. In particular, provided are compounds represented by formula (I), preparation methods therefor, pharmaceutical compositions containing the compounds, and uses thereof as P2X3 inhibitors in the treatment of P2X3 receptor dysfunction, particularly in the treatment of neurological diseases, wherein the substituents in formula (I) are the same as those described in the definitions. TIFF2023506436000188.tif48169

Description

[Technical Field]

[0001] The present invention is in the field of pharmaceutical synthesis, and specifically relates to pyrazole-containing polycyclic derivative inhibitors, methods for preparing same and uses thereof. [Background technology]

[0002] P2X receptors, also known as P2X purinoreceptors, are a family of cation-permeable ATP ligand-gated ion channels that can bind extracellular ATP. P2X receptors have seven subunits and exist in homotrimeric or heterotrimeric forms. P2X receptors are primarily expressed in nerve terminals (presynaptic and postsynaptic) in the nervous system and regulate synaptic transmission. P2X3 receptors are members of the P2X family and are important sensory receptors for detecting upper airway stimuli and eliciting the cough reflex. P2X3 receptors play an important role in sensitizing certain sensory nerves and are thought to be involved in the perception of pain, cough, and bone cancer pain. Blocking P2X3 can suppress cough signaling.

[0003] Coughing is a protective neural reflex of the body, helping to remove respiratory secretions and harmful agents. However, frequent and severe coughing can seriously affect a patient's work, lifestyle, and social activities. Coughs are divided into acute, subacute, and chronic coughs. Chronic cough is defined as coughing for more than 8 weeks with cough as the primary or only symptom and no obvious lung lesions on chest imaging. Chronic cough has long been considered the result of various diseases, such as asthma / eosinophilic bronchitis, rhinitis, and acid reflux disease. However, recent evidence indicates that chronic cough is a clinical manifestation of neuroticism with unique intrinsic pathophysiological features. Chronic cough of unknown etiology, or idiopathic cough, is primarily manifested by a chronic, irritating, dry cough. It is highly sensitive to external stimuli and generally has high cough sensitivity. Cough hypersensitivity is its physiological and pathological mechanism. Cough-related afferent nerve abnormalities may be the cause of intractable or unexplained chronic cough. Chronic cough can lead to cardiovascular, gastrointestinal, neurological, urinary and musculoskeletal complications, such as urinary incontinence, fainting, insomnia and anxiety.

[0004] Considering the pathophysiology of cough hypersensitivity syndrome, treatment should aim to reduce cough sensitivity. Current treatment options are limited and include pharmacological and non-pharmacological approaches. Clinical research results have shown that the neuromodulator gabapentin is effective. Other drugs, such as amitriptyline, baclofen, carbamazepine, and pregabalin, can also be used. Severe coughs can be treated with appropriate antitussives. Antitussives are mainly divided into centrally acting antitussives and peripherally acting antitussives. Centrally acting antitussives are divided into addictive antitussives (morphine alkaloids and their derivatives) and non-additive antitussives (synthetic dextromethorphan and pentoverine). Addictive antitussives have side effects, such as addiction and numbness. Non-additive antitussives are widely used in clinical practice. Peripheral antitussives, also known as ending antitussives, act by inhibiting certain connections in the cough reflex arc and include local anesthetics (narcotine, benzonatate) and mucosal protectants (benproperine and moguisteine). Summary of the Invention [Problem to be solved by the invention]

[0005] Currently, there are no approved P2X3 receptor antagonist small molecule drugs on the market. P2X3 receptor antagonist drugs currently in clinical trials include MK-7264, developed by Merck & Co., which is used to treat diseases such as chronic cough, pain, and pulmonary fibrosis. It has low selectivity for P2X3 / P2X2 / 3 and a favorable safety profile, but suffers from side effects such as taste loss. It is currently undergoing Phase III clinical studies for the indication of chronic cough. BLU5937, developed by Bellus Health, has high selectivity and no side effects, such as the taste-related side effects seen in Phase I clinical trials. On July 6, 2020, Bellus Health announced the primary results of the Phase 2 RELIEF trial of BLU-5937 in patients with refractory chronic cough: In the Phase II clinical study, the RELIEF trial failed to achieve statistical significance at any dose for the primary endpoint of placebo-adjusted reduction in cough frequency. In addition, BAY-1817080 and BAY-1902607 developed by Bayer and S-600918 developed by Shionogi & Co., Ltd. are currently in clinical Phase I / II for the indication of chronic cough. Therefore, there is an urgent need to develop safe, non-addictive, non-narcotic and highly selective P2X3 receptor inhibitors for treating diseases such as chronic cough to meet the huge market demand. [Means for solving the problem]

[0006] An object of the present invention is to provide a compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the structure of the compound of formula (I) is shown as follows: [ka] [In the formula, L1 is a bond, -(CH2) n1 -, -(CH2) n1 C(O)(CR aa R bb ) n2 -, -(CH2) n1 C(O)NR aa (CH2) n2 -, -(CH2) n1 (CR aa R bb ) n2 -, -(CR aa R bb ) n1 O(CH2) n2 -, -(CH2) n1 O(CR aa R bb ) n2 -, -(CR aa R bb ) n1 S(CH2) n2 -, -(CH2) n1 S(CR aa R bb ) n2 -, -(CR aa R bb ) n1 (CH2) n2 NR cc -, -(CH2) n1 NR aa (CR bb R cc ) n2 -, -(CH2) n1 NR aa C(O)-, -(CH2) n1 P(O)R aa -, -(CH2) n1 S(O) n2 -, -(CH2) n1 S(O) n2 NR aa - and -(CH2) n1 NR aa S(O) n2 - selected from the group consisting of; R aa From R ccare each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, heteroaryl, and heteroaryloxy, wherein amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, heteroaryl, and heteroaryloxy are each optionally further substituted; Or, R aa From R cc any two of join to form a cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally further substituted; L2 is a bond, -(CH2) n3 -, -(CH2) n3 C(O)(CR dd R ee ) n4 -, -(CH2) n3 C(O)NR dd (CH2) n4 -, -(CH2) n3 (CR dd R ee ) n4 -, -(CR dd R ee ) n3 O(CH2) n4 -, -(CH2) n3 O(CR dd R ee ) n4 -, -(CR dd R ee ) n3 S(CH2) n4 -, -(CH2) n3 S(CR dd R ee ) n4 -, -(CR dd R ee )n3 (CH2) n4 NR ff -, -(CH2) n3 NR dd (CR ee R ff ) n4 -, -(CH2) n3 NR dd C(O)-, -(CH2) n3 P(O)R dd -, -(CH2) n3 S(O) n4 -, -(CH2) n3 S(O) n4 NR dd - and -(CH2) n3 NR dd S(O) n4 - selected from the group consisting of; R dd From R ff are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, heteroaryl, and heteroaryloxy, wherein amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, heteroaryl, and heteroaryloxy are each optionally further substituted; Or, R dd From R ff any two of join to form a cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally further substituted; Ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; R1 is selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, heteroaryl, and heteroaryloxy, wherein amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, heteroaryl, and heteroaryloxy are each optionally further substituted; Ring B is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; R2 is selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, heteroaryl, and heteroaryloxy, wherein amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, heteroaryl, and heteroaryloxy are each optionally further substituted; R3 is selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, heteroaryl, and heteroaryloxy, wherein amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally further substituted; R a is hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thioxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) n5 R gg , -(CH2) n5 OR gg , -(CH2) n5 C(O)OR gg , -(CH2) n5 SR gg , -(CH2) n5 NR gg C(O)(CH2) n6 R hh , -(CH2) n5 NR gg C(O)OR hh , -(CH2) n5 NR gg C(O)NR hh R ii , -(CH2) n5 NR gg R hh , -NR gg (CH2) n5 R hh , -(CH2) n5 C(O)NR gg (CH2) n6 R hh , -(CH2) n5 C(O)R gg , -OC(R gg R hh ) n5 (CH2) n6 R ii , -(CH2) n5 S(O) n6 R gg , -(CH2) n5 NR gg S(O) n6 R hh , -CH=CH(CH2) n5 R gg , -CH=CH(CH2) n5 NR gg R hh, -CH=CH(CH2) n5 NR gg C(O)R hh and -CH=CH(CH2) n5 NR gg C(O)NR hh R ii wherein amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally further substituted; R gg From R ii are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, heteroaryl, and heteroaryloxy, wherein amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, heteroaryl, and heteroaryloxy are each optionally further substituted; Or, R gg From R ii any two of join to form a cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally further substituted; x is an integer from 0 to 6; e is an integer from 0 to 6; n1, n3, and n5 each independently represent an integer from 0 to 3; n2, n4 and n6 are each independently an integer from 0 to 2.

[0007] In a further preferred embodiment of the present invention, the compounds of formula (I), their stereoisomers or pharmaceutically acceptable salts thereof, are those in which L1 is a bond, -(CH2) n1 -, -(CH2) n1 C(O)(CR aa R bb ) n2 -, -(CH2) n1 C(O)NR aa (CH2) n2 -, -(CH2) n1 (CR aa R bb ) n2 -, -(CR aa R bb ) n1 O(CH2) n2 -, -(CH2) n1 O(CR aa R bb ) n2 -, -(CR aa R bb ) n1 S(CH2) n2 -, -(CH2) n1 S(CR aa R bb ) n2 -, -(CR aa R bb ) n1 (CH2) n2 NR cc -, -(CH2) n1 NR aa (CR bb R cc ) n2 -, -(CH2) n1 C(O)(CR aa R bb ) n2 -, -(CH2) n1 NR aa C(O)-, -(CH2) n1 P(O)R aa -, -(CH2) n1 S(O) n2 -, -(CH2) n1 S(O) n2 NR aa - and -(CH2) n1 NR aa S(O) n2 - selected from the group consisting of; Preferably, a bond, —(CH) n1 -, -(CH2) n1 O(CR aa R bb ) n2 -, -(CH2) n1 S(CR aa R bb ) n2 -, -(CH2) n1 C(O)-, -(CH2) n1 NR aa -, -(CH2) n1 S(O) n2 -, -(CH2) n1 C(O)NR aa -, -C(O)NR aa (CH2) n2 - and -(CH2) n1 NR aa C(O)-; More preferably, it is selected from the group consisting of a bond, -NH-, -C(O)NHCH2- and -C(O)N(CH3)CH2-; R aa From R cc But hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, cyano-substituted C 1~6 Alkyl, C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, wherein: 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, deuterated C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6Hydroxyalkyl, cyano-substituted C 1~6 Alkyl, C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 Aryl and 5- to 14-membered heteroaryl are selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, deuterated C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, cyano-substituted C 1~6 Alkyl, C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 each optionally substituted with one or more substituents selected from the group consisting of aryl and 5- to 14-membered heteroaryl; Or, R aa From R cc Any two of these are combined to form C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 aryl or 5- to 14-membered heteroaryl, wherein C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 The aryl or 5- to 14-membered heteroaryl is selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, cyano-substituted C 1~6 Alkyl, C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 optionally substituted with one or more substituents selected from the group consisting of aryl and 5- to 14-membered heteroaryl; n1 is an integer from 0 to 3; n2 is an integer between 0 and 2 It is characterized by:

[0008] In a further preferred embodiment of the present invention, the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that L1 is selected from the group consisting of a bond and -C(O)-.

[0009] In a further preferred embodiment of the present invention, the compounds of formula (I), their stereoisomers or pharmaceutically acceptable salts thereof, are those in which L2 is a bond, -(CH2) n3 -, -(CH2) n3 C(O)(CR dd R ee ) n4 -, -(CH2) n3 C(O)NR dd (CH2) n4 -, -(CH2) n3 (CR dd R ee ) n4 -, -(CR dd R ee ) n3 O(CH2) n4 -, -(CH2) n3 O(CR dd R ee ) n4 -, -(CR dd R ee ) n3 S(CH2) n4 -, -(CH2) n3 S(CR dd R ee ) n4 -, -(CR dd R ee ) n3 (CH2) n4 NR ff -, -(CH2) n3 NR dd (CR ee R ff ) n4 -, -(CH2) n3 NR dd C(O)-, -(CH2) n3 P(O)Rdd -, -(CH2) n3 S(O) n4 -, -(CH2) n3 S(O) n4 NR dd - and -(CH2) n3 NR dd S(O) n4 - selected from the group consisting of; Preferably, -(CH2) n3 -, -(CH2) n3 O-, -(CH2) n3 S-, -(CH2) n3 NR dd -, -(CH2) n3 C(O)NR dd - and -(CH2) n3 NR dd C(O)-; More preferably, it is selected from: —CHC(O)NH—; R dd From R ff But hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, cyano-substituted C 1~6 Alkyl, C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, wherein: 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, cyano-substituted C 1~6 Alkyl, C 3~12Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 Aryl and 5- to 14-membered heteroaryl are selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, cyano-substituted C 1~6 Alkyl, C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 each optionally substituted with one or more substituents selected from the group consisting of aryl and 5- to 14-membered heteroaryl; Or, R dd From R ff Any two of these are combined to form C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 aryl or 5- to 14-membered heteroaryl, wherein C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 The aryl or 5- to 14-membered heteroaryl is selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, cyano-substituted C 1~6 Alkyl, C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 optionally substituted with one or more substituents selected from the group consisting of aryl and 5- to 14-membered heteroaryl; n3 is an integer between 0 and 3; n4 is an integer between 0 and 2 It is characterized by:

[0010] In a further preferred embodiment of the present invention, in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, ring A is C 3~8 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl; preferably C 6~10 It is selected from the group consisting of aryl and 5- to 10-membered heteroaryl; more preferably, it is selected from the group consisting of phenyl, oxadiazolyl, and pyridyl.

[0011] In a further preferred embodiment of the present invention, in the compounds of formula (I), their stereoisomers or pharmaceutically acceptable salts thereof, R is hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 Aryl, C 6~14 aryloxy, 5- to 14-membered heteroaryl, and 5- to 14-membered heteroaryloxy, wherein amino, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 Aryl, C 6~14Aryloxy, 5- to 14-membered heteroaryl and 5- to 14-membered heteroaryloxy are selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, cyano-substituted C 1~6 Alkyl, C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 Aryl, C 6~14 Aryloxy, 5- to 14-membered heteroaryl, 5- to 14-membered heteroaryloxy, -(CH2) m1 OR a , -(CH2) m1 SR a , -(CH2) m1 C(O)R a , -(CH2) m1 NR a R b , -(CH2) m1 C(O)NR a R b , -(CH2) m1 NR a C(O)R b and -(CH2) m1 S(O) m2 R a each optionally substituted with one or more substituents selected from the group consisting of: Preferably, hydrogen, halogen, amino, cyano, C 1~4 Alkyl, C 1~4 Alkoxy, C 2~4 Alkenyl, C 2~4 Alkynyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, 3- to 6-membered heterocyclyl, C 6~10 aryl and 5- to 8-membered heteroaryl, wherein C 2~4 Alkenyl, C 2~4 Alkynyl, C3~6 Cycloalkyl, 3- to 6-membered heterocyclyl, C 6~10 Aryl and 5- to 8-membered heteroaryl are selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thioxo, C 1~4 Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 1~4 Deuterated alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 1~4 Hydroxyalkyl, C 3~6 Cycloalkyl, 3- to 6-membered heterocyclyl, C 6~10 Aryl, 5- to 8-membered heteroaryl, -(CH2) m1 C(O)R a , -(CH2) m1 NR a R b , -(CH2) m1 C(O)NR a R b , -(CH2) m1 NR a C(O)R b and -(CH2) m1 S(O) m2 R a each optionally substituted with one or more substituents selected from the group consisting of: More preferably, hydrogen, halogen, amino, cyano, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocyclyl containing 1 to 2 nitrogen atoms, phenyl, and 5- to 7-membered heteroaryl containing 1 to 2 nitrogen atoms; and 1~4 Alkyl, C 1~4 Deuterated alkyl, C 1~4 Haloalkyl and C 1~4 optionally further substituted with one or more substituents selected from the group consisting of alkoxy; More preferred are hydrogen, methyl, ethyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl, fluorine, chlorine, bromine, amino, isopropenyl, cyclopropyl, cyclopentyl, cyclopentenyl, oxetanyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, phenyl, pyridyl, [ka] selected from the group consisting of: R a and R b is hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, cyano-substituted C 1~6 Alkyl, C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, wherein: 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, cyano-substituted C 1~6 Alkyl, C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 Aryl and 5- to 14-membered heteroaryl are selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, cyano-substituted C 1~6 Alkyl, C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 each optionally substituted with one or more substituents selected from the group consisting of aryl and 5- to 14-membered heteroaryl; Or, R a and R b combine to form C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 aryl or 5- to 14-membered heteroaryl, wherein C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 The aryl or 5- to 14-membered heteroaryl is selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, cyano-substituted C 1~6 Alkyl, C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 optionally substituted with one or more substituents selected from the group consisting of aryl and 5- to 14-membered heteroaryl; m1 is an integer from 0 to 3; m2 is an integer between 0 and 2.

[0012] In a further preferred embodiment of the present invention, in the compounds of formula (I), their stereoisomers or pharmaceutically acceptable salts thereof, R2 is hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 3~8 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 selected from the group consisting of aryl and 5- to 14-membered heteroaryl; Preferably, hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1~3 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, C 1~3 Deuterated alkyl, C 1~3 Haloalkyl, C 1~3 Hydroxyalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, C 3~6 Cycloalkyl, 3- to 10-membered heterocyclyl, C 6~12 selected from the group consisting of aryl and 5- to 12-membered heteroaryl; More preferably, hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1~3 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, C 1~3 Deuterated alkyl, C 1~3 Haloalkyl, C 1~3 Hydroxyalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, C 3~6 cycloalkyl, 3- to 8-membered heterocyclyl containing 1 to 3 atoms selected from the group consisting of N, O, and S; C 6~10 selected from the group consisting of aryl and 5-10 membered heteroaryl containing 1-3 atoms selected from the group consisting of N, O and S; More preferred are hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, oxo, thioxo, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, fluoromethyl, fluoroethyl, fluoropropyl, chloromethyl, chloroethyl, chloropropyl, bromomethyl, bromoethyl, bromopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy, and propoxy. , fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, epoxypropyl, epoxybutyl, epoxypentyl, epoxyhexyl, epoxyheptyl, aziridinyl, azetidinyl, azacyclopentyl, azacyclohexyl, azacycloheptyl, thienyl, pyrrolyl, pyridyl, pyranyl, piperazinyl, phenyl, and naphthyl.

[0013] In a further preferred embodiment of the present invention, in the compounds of formula (I), their stereoisomers or pharmaceutically acceptable salts thereof, R3 is hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 3~8 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 selected from the group consisting of aryl and 5- to 14-membered heteroaryl; Preferably, hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1~3 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, C 1~3 Deuterated alkyl, C 1~3Haloalkyl, C 1~3 Hydroxyalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, C 3~6 Cycloalkyl, 3- to 10-membered heterocyclyl, C 6~12 selected from the group consisting of aryl and 5- to 12-membered heteroaryl; More preferably, hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1~3 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, C 1~3 Deuterated alkyl, C 1~3 Haloalkyl, C 1~3 Hydroxyalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, C 3~6 cycloalkyl, 3- to 8-membered heterocyclyl containing 1 to 3 atoms selected from the group consisting of N, O, and S; C 6~10 selected from the group consisting of aryl and 5-10 membered heteroaryl containing 1-3 atoms selected from the group consisting of N, O and S; More preferred are hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, oxo, thioxo, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, fluoromethyl, fluoroethyl, fluoropropyl, chloromethyl, chloroethyl, chloropropyl, bromomethyl, bromoethyl, bromopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy, and propoxy. , fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, epoxypropyl, epoxybutyl, epoxypentyl, epoxyhexyl, epoxyheptyl, aziridinyl, azetidinyl, azacyclopentyl, azacyclohexyl, azacycloheptyl, thienyl, pyrrolyl, pyridyl, pyranyl, piperazinyl, phenyl, and naphthyl.

[0014] In a further preferred embodiment of the present invention, in the compounds of formula (I), their stereoisomers or pharmaceutically acceptable salts thereof, R a is hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 3~8 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 Aryl, 5- to 14-membered heteroaryl, -(CH2) n5 R gg , -(CH2) n5 OR gg , -(CH2) n5 C(O)OR gg , -(CH2) n5 SR gg , -(CH2) n5 NR gg C(O)(CH2) n6 R hh , -(CH2) n5 NR gg C(O)OR hh , -(CH2) n5 NR gg C(O)NR hh R ii , -(CH2) n5 NR gg R hh , -NR gg (CH2) n5 R hh , -(CH2) n5 C(O)NR gg (CH2) n6 R hh , -(CH2) n5 C(O)R gg and -OC(R gg R hh ) n5 (CH2) n6 R iiselected from the group consisting of: Preferably, hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1~3 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, C 1~3 Deuterated alkyl, C 1~3 Haloalkyl, C 1~3 Hydroxyalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, C 3~6 Cycloalkyl, 3- to 10-membered heterocyclyl, C 6~12 selected from the group consisting of aryl and 5- to 12-membered heteroaryl; More preferably, hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1~3 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, C 1~3 Deuterated alkyl, C 1~3 Haloalkyl, C 1~3 Hydroxyalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, C 3~6 cycloalkyl, 3- to 8-membered heterocyclyl containing 1 to 3 atoms selected from the group consisting of N, O, and S; C 6~10 selected from the group consisting of aryl and 5-10 membered heteroaryl containing 1-3 atoms selected from the group consisting of N, O and S; More preferred are hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, oxo, thioxo, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, fluoromethyl, fluoroethyl, fluoropropyl, chloromethyl, chloroethyl, chloropropyl, bromomethyl, bromoethyl, bromopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy, and propoxy. , fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, epoxypropyl, epoxybutyl, epoxypentyl, epoxyhexyl, epoxyheptyl, aziridinyl, azetidinyl, azacyclopentyl, azacyclohexyl, azacycloheptyl, thienyl, pyrrolyl, pyridyl, pyranyl, piperazinyl, phenyl, and naphthyl; R gg From R ii is hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, cyano-substituted C 1~6 Alkyl, C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, wherein: 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6Hydroxyalkyl, cyano-substituted C 1~6 Alkyl, C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 Aryl and 5- to 14-membered heteroaryl are selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, cyano-substituted C 1~6 Alkyl, C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 each optionally substituted with one or more substituents selected from the group consisting of aryl and 5- to 14-membered heteroaryl; Or, R gg From R ii Any two of these are combined to form C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 aryl or 5- to 14-membered heteroaryl, wherein C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 The aryl or 5- to 14-membered heteroaryl is selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, cyano-substituted C 1~6 Alkyl, C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 optionally substituted with one or more substituents selected from the group consisting of aryl and 5- to 14-membered heteroaryl; n5 is an integer from 0 to 3; n6 is an integer between 0 and 2.

[0015] In a further preferred embodiment of the present invention, in the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, ring B is represented as follows: [ka] [In the formula, M1, M2, M3 and M4 are CR A1 , C(O), N, CR A1 R A2 and NR A3 each independently selected from the group consisting of: R A1 From R A3 are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, heteroaryl, and heteroaryloxy, wherein amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, heteroaryl, and heteroaryloxy are each optionally further substituted; Preferably, hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 3~8 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14selected from the group consisting of aryl and 5- to 14-membered heteroaryl; More preferably, hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1~3 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, C 1~3 Deuterated alkyl, C 1~3 Haloalkyl, C 1~3 Hydroxyalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, C 3~6 Cycloalkyl, 3- to 10-membered heterocyclyl, C 6~12 aryl and 5- to 12-membered heteroaryl].

[0016] In a further preferred embodiment of the present invention, in the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof, M1, M2, M3 and M4 are each independently CR A1 and; R A1 is hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1~3 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, C 1~3 Deuterated alkyl, C 1~3 Haloalkyl, C 1~3 Hydroxyalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, C 3~6 cycloalkyl, 3- to 8-membered heterocyclyl containing 1 to 3 atoms selected from the group consisting of N, O, and S atoms; C 6~10 selected from the group consisting of aryl and 5-10 membered heteroaryl containing 1-3 atoms selected from the group consisting of N, O and S; More preferred are hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, oxo, thioxo, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, fluoromethyl, fluoroethyl, fluoropropyl, chloromethyl, chloroethyl, chloropropyl, bromomethyl, bromoethyl, bromopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy, and propoxy. , fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, epoxypropyl, epoxybutyl, epoxypentyl, epoxyhexyl, epoxyheptyl, aziridinyl, azetidinyl, azacyclopentyl, azacyclohexyl, azacycloheptyl, thienyl, pyrrolyl, pyridyl, pyranyl, piperazinyl, phenyl, and naphthyl.

[0017] In a further preferred embodiment of the present invention, in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, at least one of M1, M2, M3 and M4 is N; Preferably, M4 is N, and M1, M2 and M3 are each independently CR A1 Is it; Or, M1 is N, and M2, M3 and M4 are each independently CR A1 and; R A1 is hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1~3 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, C 1~3 Deuterated alkyl, C 1~3 Haloalkyl, C 1~3 Hydroxyalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, C 3~6cycloalkyl, 3- to 8-membered heterocyclyl containing 1 to 3 atoms selected from the group consisting of N, O, and S; C 6~10 selected from the group consisting of aryl and 5-10 membered heteroaryl containing 1-3 atoms selected from the group consisting of N, O and S; More preferred are hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, oxo, thioxo, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, fluoromethyl, fluoroethyl, fluoropropyl, chloromethyl, chloroethyl, chloropropyl, bromomethyl, bromoethyl, bromopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy, and propoxy. , fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, epoxypropyl, epoxybutyl, epoxypentyl, epoxyhexyl, epoxyheptyl, aziridinyl, azetidinyl, azacyclopentyl, azacyclohexyl, azacycloheptyl, thienyl, pyrrolyl, pyridyl, pyranyl, piperazinyl, phenyl, and naphthyl.

[0018] In a further preferred embodiment of the present invention, ring B is shown as follows: [ka] [In the formula, M6, M7 and M8 are CR A4 ,C(O),N,O,S,CR A4 R A5 and NR A6 each independently selected from the group consisting of: R A4 From R A6are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, heteroaryl, and heteroaryloxy, wherein amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, heteroaryl, and heteroaryloxy are each optionally further substituted; Preferably, hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 3~8 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 selected from the group consisting of aryl and 5- to 14-membered heteroaryl; More preferably, hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1~3 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, C 1~3 Deuterated alkyl, C 1~3 Haloalkyl, C 1~3 Hydroxyalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, C 3~6 Cycloalkyl, 3- to 10-membered heterocyclyl, C 6~12 aryl and 5- to 12-membered heteroaryl].

[0019] In a further preferred embodiment of the invention, ring B is [ka] is selected from the group consisting of:

[0020] In a further preferred embodiment of the present invention, the compounds of formula (I), their stereoisomers or pharmaceutically acceptable salts thereof, are those in which ring A is [ka] Selected from; M5 is selected from the group consisting of N and CR4; preferably selected from the group consisting of N and CH; R4 is hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, wherein amino, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 Aryl and 5- to 14-membered heteroaryl are selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, cyano-substituted C 1~6 Alkyl, C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~12 each optionally substituted with one or more substituents selected from the group consisting of aryl and 5- to 12-membered heteroaryl; Preferably, hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1~3 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, C 1~3 Deuterated alkyl, C 1~3 Haloalkyl, C 1~3 Hydroxyalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, C 3~6 Cycloalkyl, 3- to 10-membered heterocyclyl, C 6~12 selected from the group consisting of aryl and 5- to 12-membered heteroaryl; More preferably, hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1~3 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, C 1~3 Deuterated alkyl, C 1~3 Haloalkyl, C 1~3 Hydroxyalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, C 3~6 cycloalkyl, 3- to 8-membered heterocyclyl containing 1 to 3 atoms selected from the group consisting of N, O, and S; C 6~10 selected from the group consisting of aryl and 5-10 membered heteroaryl containing 1-3 atoms selected from the group consisting of N, O and S; More preferred are hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, oxo, thioxo, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, fluoromethyl, fluoroethyl, fluoropropyl, chloromethyl, chloroethyl, chloropropyl, bromomethyl, bromoethyl, bromopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy, and propoxy. , fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, epoxypropyl, epoxybutyl, epoxypentyl, epoxyhexyl, epoxyheptyl, aziridinyl, azetidinyl, azacyclopentyl, azacyclohexyl, azacycloheptyl, thienyl, pyrrolyl, pyridyl, pyranyl, piperazinyl, phenyl, and naphthyl It is characterized by:

[0021] In a further preferred embodiment of the present invention, formula (I) is further as shown in formula (II): [ka] [wherein e is an integer from 0 to 3].

[0022] In a further preferred embodiment of the present invention, formula (I) is further as shown in formula (III): [ka] [In the formula, R5 is hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6Alkoxy, C 1~6 Haloalkoxy, C 3~8 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 selected from the group consisting of aryl and 5- to 14-membered heteroaryl; Preferably, hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1~3 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, C 1~3 Deuterated alkyl, C 1~3 Haloalkyl, C 1~3 Hydroxyalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, C 3~6 Cycloalkyl, 3- to 10-membered heterocyclyl, C 6~12 selected from the group consisting of aryl and 5- to 12-membered heteroaryl; More preferably, hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1~3 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, C 1~3 Deuterated alkyl, C 1~3 Haloalkyl, C 1~3 Hydroxyalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, C 3~6 cycloalkyl, 3- to 8-membered heterocyclyl containing 1 to 3 atoms selected from the group consisting of N, O, and S; C 6~10 selected from the group consisting of aryl and 5-10 membered heteroaryl containing 1-3 atoms selected from the group consisting of N, O and S; More preferred are hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, oxo, thioxo, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, fluoromethyl, fluoroethyl, fluoropropyl, chloromethyl, chloroethyl, chloropropyl, bromomethyl, bromoethyl, bromopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy, and propoxy. , fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, epoxypropyl, epoxybutyl, epoxypentyl, epoxyhexyl, epoxyheptyl, aziridinyl, azetidinyl, azacyclopentyl, azacyclohexyl, azacycloheptyl, thienyl, pyrrolyl, pyridyl, pyranyl, piperazinyl, phenyl, and naphthyl; R b is hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 3~8 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 selected from the group consisting of aryl and 5- to 14-membered heteroaryl; Preferably, hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1~3 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, C 1~3 Deuterated alkyl, C 1~3 Haloalkyl, C 1~3 Hydroxyalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, C3~6 Cycloalkyl, 3- to 10-membered heterocyclyl, C 6~12 selected from the group consisting of aryl and 5- to 12-membered heteroaryl; More preferred are hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, oxo, thioxo, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, fluoromethyl, fluoroethyl, fluoropropyl, chloromethyl, chloroethyl, chloropropyl, bromomethyl, bromoethyl, bromopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy, and propoxy. , fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, epoxypropyl, epoxybutyl, epoxypentyl, epoxyhexyl, epoxyheptyl, aziridinyl, azetidinyl, azacyclopentyl, azacyclohexyl, azacycloheptyl, thienyl, pyrrolyl, pyridyl, pyranyl, piperazinyl, phenyl, and naphthyl; y is an integer between 0 and 3].

[0023] In a further preferred embodiment of the present invention, in the compound of formula (III), its stereoisomers or pharmaceutically acceptable salts thereof, L 1 is a bond or —C(O)—.

[0024] In a further preferred embodiment of the present invention, in the compound of formula (III), its stereoisomers or pharmaceutically acceptable salts thereof, R is hydrogen, halogen, amino, cyano, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Hydroxyalkyl, C 1~4 Haloalkyl, C 3~6cycloalkyl, 4- to 6-membered heterocyclyl containing 1 to 2 nitrogen atoms, phenyl, and 5- to 7-membered heteroaryl containing 1 to 2 nitrogen atoms; and 1~4 Alkyl, C 1~4 Deuterated alkyl, C 1~4 Haloalkyl and C 1~4 and optionally further substituted with one or more substituents selected from the group consisting of alkoxy.

[0025] In a further preferred embodiment of the present invention, formula (I) is further as shown in formula (IV): [ka] [In the formula, Ring C is C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 selected from the group consisting of aryl and 5- to 14-membered heteroaryl, or ring C is absent; Preferably, C 3~8 Cycloalkyl, 3- to 10-membered heterocyclyl, C 6~12 selected from the group consisting of aryl and 5- to 12-membered heteroaryl; More preferably, C 3~6 cycloalkyl, 3- to 8-membered heterocyclyl containing 1 to 3 atoms selected from the group consisting of N, O, and S; C 6~10 selected from the group consisting of aryl and 5-10 membered heteroaryl containing 1-3 atoms selected from the group consisting of N, O and S; More preferably, it is selected from the group consisting of cyclopropyl, cyclopentyl, cyclopentenyl, oxetanyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, phenyl and pyridyl; R c is hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 Aryl, C 6~14 Aryloxy, 5- to 14-membered heteroaryl, 5- to 14-membered heteroaryloxy, -(CH2) m3 OR c , -(CH2) m3 SR c , -(CH2) m3 C(O)R c , -(CH2) m3 NR c R d , -(CH2) m3 C(O)NR c R d , -(CH2) m3 NR c C(O)R d and -(CH2) m3 S(O) m4 R c wherein amino, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 Aryl, C 6~14 Aryloxy, 5- to 14-membered heteroaryl and 5- to 14-membered heteroaryloxy are selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6Haloalkoxy, C 1~6 Hydroxyalkyl, cyano-substituted C 1~6 Alkyl, C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 Aryl, C 6~14 each optionally substituted with one or more substituents selected from the group consisting of aryloxy, 5- to 14-membered heteroaryl, and 5- to 14-membered heteroaryloxy; Preferably, hydrogen, halogen, amino, cyano, C 1~4 Alkyl, C 1~4 Alkoxy, C 2~4 Alkenyl, C 2~4 Alkynyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, 3- to 6-membered heterocyclyl, C 6~10 Aryl, 5- to 8-membered heteroaryl, -(CH2) m3 OR c , -(CH2) m3 SR c , -(CH2) m3 C(O)R c , -(CH2) m3 NR c R d , -(CH2) m3 C(O)NR c R d and -(CH2) m3 NR c C(O)R d wherein amino, C 1~4 Alkyl, C 1~4 Alkoxy, C 2~4 Alkenyl, C 2~4 Alkynyl, C 3~6 Cycloalkyl, 3- to 6-membered heterocyclyl, C 6~10 Aryl and 5- to 8-membered heteroaryl are selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thioxo, C 1~4 Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 1~4 Deuterated alkyl, C 1~4 Haloalkyl, C 1~4Alkoxy, C 1~4 Haloalkoxy, C 1~4 Hydroxyalkyl, C 3~6 Cycloalkyl, 3- to 6-membered heterocyclyl, C 6~10 each optionally substituted with one or more substituents selected from the group consisting of aryl and 5- to 8-membered heteroaryl; More preferably, it is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl, fluorine, chlorine, bromine, amino, and —C(O)CHF2; R c and R d is hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, cyano-substituted C 1~6 Alkyl, C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, wherein: 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, cyano-substituted C 1~6 Alkyl, C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 Aryl and 5- to 14-membered heteroaryl are selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, cyano-substituted C 1~6 Alkyl, C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 each optionally substituted with one or more substituents selected from the group consisting of aryl and 5- to 14-membered heteroaryl; Or, R c and R d combine to form C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 aryl or 5- to 14-membered heteroaryl, wherein C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 The aryl or 5- to 14-membered heteroaryl is selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, cyano-substituted C 1~6 Alkyl, C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 optionally substituted with one or more substituents selected from the group consisting of aryl and 5- to 14-membered heteroaryl; m3 is an integer from 0 to 3; m4 is an integer between 0 and 2; z is an integer between 0 and 6].

[0026] In a further preferred embodiment of the present invention, formula (II) is further as shown in formula (V): [ka] [In the formula, R1 is hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, wherein amino, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 Aryl and 5- to 14-membered heteroaryl are selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, cyano-substituted C 1~6 Alkyl, C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~12 each optionally substituted with one or more substituents selected from the group consisting of aryl and 5- to 12-membered heteroaryl; R2 is hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, wherein amino, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 Aryl and 5- to 14-membered heteroaryl are selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, cyano-substituted C 1~6 Alkyl, C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~12 each optionally substituted with one or more substituents selected from the group consisting of aryl and 5- to 12-membered heteroaryl; R3 is hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C1~6 Haloalkoxy, C 3~8 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 selected from the group consisting of aryl and 5- to 14-membered heteroaryl; e is an integer between 0 and 3].

[0027] In a preferred embodiment of the present invention, R1 is hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 3~12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, wherein amino, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 3~8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6~10 Aryl and 5- to 10-membered heteroaryl are selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, C 1~3 Alkyl, C 2~3 Alkenyl, C 2~3 Alkynyl, C 1~3 Deuterated alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, C 1~3 Hydroxyalkyl, cyano-substituted C 1~3 Alkyl, C 3~8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6~10each optionally substituted with one or more substituents selected from the group consisting of aryl and 5- to 10-membered heteroaryl.

[0028] In a further preferred embodiment of the invention, R1 is -H, -NH2, -F, -Cl, -Br, -CH3, -CH2CH3, -CF3, [ka] is selected from the group consisting of:

[0029] In a preferred embodiment of the present invention, R2 is hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1~3 Alkyl, C 2~3 Alkenyl, C 2~3 Alkynyl, C 1~3 Deuterated alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, C 1~3 Hydroxyalkyl, C 3~8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6~10 It is selected from the group consisting of aryl and 5- to 10-membered heteroaryl.

[0030] In a further preferred embodiment of the invention, R2 is selected from the group consisting of hydrogen, amino, cyano, fluorine, chlorine, bromine, methyl, isopropyl, trifluoromethyl, methoxy, cyclopropyl and morpholinyl.

[0031] In a preferred embodiment of the present invention, R3 is hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1~3 Alkyl, C 2~3 Alkenyl, C 2~3 Alkynyl, C 1~3 Deuterated alkyl, C 1~3 Haloalkyl, C 1~3 Hydroxyalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, C 3~8Cycloalkyl, 3- to 8-membered heterocyclyl, C 6~10 From aryl and 5 10 and n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 39, 38, 39, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 7

[0032] In a further preferred embodiment of the invention, R3 is selected from the group consisting of hydrogen and cyano, e is an integer from 0 to 3.

[0033] In a preferred embodiment of the present invention, the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is [ka] [ka] [ka] [ka] [ka] is selected from the group consisting of:

[0034] The present invention further provides a process for preparing a compound of formula (III), its stereoisomer, or a pharmaceutically acceptable salt thereof, comprising the steps of: [ka] Reacting the compound of formula (III-2) with a compound of formula (III-3) to obtain the target compound of formula (III). Including, During the ceremony, X2 is a halogen, preferably chlorine or bromine The present invention relates to a method characterized in that

[0035] The present invention further provides a process for preparing a compound of formula (III), its stereoisomer, or a pharmaceutically acceptable salt thereof, comprising the steps of: [ka] condensing the compound of formula (III-1) to obtain a compound of formula (III-2), and reacting the compound of formula (III-2) with a compound of formula (III-3) to obtain the target compound of formula (III). Including, During the ceremony, X1 is a halogen, preferably chlorine or bromine; X2 is a halogen, preferably chlorine or bromine; Regarding the method.

[0036] The present invention further provides a process for preparing a compound of formula (IV), its stereoisomer or a pharmaceutically acceptable salt thereof, comprising the steps of: [ka] reacting the compound of formula (IV-2) with a compound of formula (III-3) to obtain the target compound of formula (IV). Including, During the ceremony, X2 is a halogen, preferably chlorine or bromine; Regarding the method.

[0037] The present invention further provides a process for preparing a compound of formula (IV), its stereoisomer or a pharmaceutically acceptable salt thereof, comprising the steps of: [ka] condensing the compound of formula (IV-1) to obtain a compound of formula (IV-2), and reacting the compound of formula (IV-2) with a compound of formula (III-3) to obtain the target compound of formula (IV). Including, During the ceremony, X2 is a halogen, preferably chlorine or bromine; X3 is a halogen, preferably chlorine or bromine; Regarding the method.

[0038] The present invention further provides a process for preparing a compound of formula (V), its stereoisomer, or a pharmaceutically acceptable salt thereof, comprising the steps of: [ka] reacting the compound of formula (V-2) with a compound of formula (V-3) to obtain the target compound of formula (V). Including, During the ceremony, X5 is a halogen, preferably chlorine or bromine The present invention relates to a method characterized in that

[0039] The present invention further provides a process for preparing a compound of formula (V), its stereoisomer, or a pharmaceutically acceptable salt thereof, comprising the steps of: [ka] condensing a compound of formula (V-1) to obtain a compound of formula (V-2), and reacting the compound of formula (V-2) with a compound of formula (V-3) to obtain the target compound of formula (V). Including, During the ceremony, X4 is a halogen, preferably chlorine or bromine; X5 is a halogen, preferably chlorine or bromine The present invention relates to a method characterized in that

[0040] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of any one of the compounds of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0041] The present invention further relates to the use of any one of the compounds of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, or a pharmaceutical composition in the preparation of a P2X3 receptor inhibitor.

[0042] The present invention further relates to the use of a compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating a neurological disorder, wherein the neurological disorder is selected from the group consisting of gynecological disorders, urinary tract conditions, respiratory disorders, pulmonary fibrosis, and pain-related diseases or conditions.

[0043] The present invention further relates to a method for treating neurological disorders with a compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0044] The present invention also relates to a method for preventing and / or treating a neurological disease, comprising the step of administering to a patient a therapeutically effective dose of a compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0045] The present invention also provides methods for treating a medical condition by using a compound or pharmaceutical composition according to the present invention, the medical condition including, but not limited to, a condition associated with P2X3 receptor dysfunction.

[0046] The present invention also relates to a method for treating a neurological disorder in a mammal, comprising the step of administering to the mammal a therapeutically effective amount of a compound according to the invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.

[0047] In some embodiments, the methods involve gynecological disorders, urinary tract conditions, respiratory disorders, and pain-related diseases or conditions.

[0048] In some embodiments, the methods involve the treatment of endometriosis, overactive bladder, pulmonary fibrosis, or chronic cough.

[0049] In some embodiments, the methods involve neuropathic pain and pain and discomfort associated with uterine fibroids.

[0050] Chronic cough and neuropathic pain are preferred.

[0051] Chronic cough is more preferable.

[0052] definition Unless otherwise stated, terms used in the specification and claims have the following meanings.

[0053] The term "alkyl" refers to a saturated aliphatic hydrocarbon group that is a straight-chain or branched-chain group containing from 1 to 20 carbon atoms, preferably an alkyl having from 1 to 8 carbon atoms, more preferably an alkyl having from 1 to 6 carbon atoms, and most preferably an alkyl having from 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 ,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof.More preferably, the alkyl group is a lower alkyl having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group can be substituted or unsubstituted. If substituted, the substituent may be substituted at any available point of attachment. The substituents are preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxy, and alkoxycarbonyl. The alkyl of the present invention is preferably selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl.

[0054] The term "alkylene" refers to an alkyl in which a hydrogen atom is further substituted, for example, "methylene" refers to -CH-, "ethylene" refers to -(CH)-, "propylene" refers to -(CH)-, "butylene" refers to -(CH)-, etc.

[0055] The term "alkenyl" refers to an alkyl, as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, etc. Alkenyl groups can be substituted or unsubstituted. If substituted, the substituents are preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocyclylthio.

[0056] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent having 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of polycyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like. Polycyclic cycloalkyls include cycloalkyls having spirocyclic, fused, or bridged rings. Cycloalkyls are preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0057] The term "spirocycloalkyl" refers to a 5- to 20-membered polycyclic group with individual rings connected via one shared carbon atom (called a spiro atom), where the rings may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. Spirocycloalkyls are preferably 6- to 14-membered spirocycloalkyls, more preferably 7- to 10-membered spirocycloalkyls. According to the number of spiro atoms shared between the rings, spirocycloalkyls can be divided into mono-spirocycloalkyls, dis-spirocycloalkyls, or poly-spirocycloalkyls, and spirocycloalkyls are preferably mono-spirocycloalkyls or dis-spirocycloalkyls, more preferably 3-membered / 6-membered, 3-membered / 5-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered mono-spirocycloalkyls. Non-limiting examples of spirocycloalkyls are: [ka] Including; Also included are spirocycloalkyls in which the cycloalkyl and heterocyclyl are connected via a spiro atom, non-limiting examples of which are: [ka] etc.

[0058] The term "fused cycloalkyl" refers to a 5- to 20-membered all-carbon polycyclic group, where each ring in the system shares an adjacent pair of carbon atoms with another ring, and one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. Fused cycloalkyls are preferably 6- to 14-membered fused cycloalkyls, more preferably 7- to 10-membered fused cycloalkyls. According to the number of membered rings, fused cycloalkyls can be divided into bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyls, and fused cycloalkyls are preferably bicyclic or tricyclic fused cycloalkyls, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused cycloalkyls. Non-limiting examples of fused cycloalkyls are: [ka] etc.

[0059] The term "bridged cycloalkyl" refers to a 5- to 20-membered all-carbon polycyclic group, where every two rings in the system share two unconnected carbon atoms, and the rings may have one or more double bonds, but none of the rings has a completely conjugated π-electron system. Bridged cycloalkyls are preferably 6- to 14-membered bridged cycloalkyls, more preferably 7- to 10-membered bridged cycloalkyls. According to the number of membered rings, bridged cycloalkyls can be divided into bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyls, and bridged cycloalkyls are preferably bicyclic, tricyclic, or tetracyclic bridged cycloalkyls, more preferably bicyclic or tricyclic bridged cycloalkyls. Non-limiting examples of bridged cycloalkyls are: [ka] Includes.

[0060] A cycloalkyl ring can be fused to an aryl, heteroaryl, or heterocyclyl ring, where the ring attached to the parent structure is a cycloalkyl. Non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like. A cycloalkyl can be optionally substituted or unsubstituted. If substituted, the substituents are preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxy, and alkoxycarbonyl.

[0061] The term "heterocyclyl" refers to a 3- to 20-membered saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group, in which one or more ring atoms are selected from nitrogen, oxygen, and S(O). m (wherein m is an integer of 0 to 2), except that the remaining ring atoms in the ring, except for -OO-, -OS-, or -SS-, are carbon atoms. Preferably, the heterocyclyl has 3 to 12 ring atoms, of which 1 to 4 atoms are heteroatoms; more preferably 3 to 8 ring atoms; most preferably 3 to 8 ring atoms; and even more preferably 3 to 8 ring atoms with 1 to 3 nitrogen atoms. Optionally, the heterocyclyl is substituted by 1 to 2 oxygen atoms, sulfur atoms, or oxo. Heterocyclyl includes nitrogen-containing monocyclic heterocyclyl, nitrogen-containing spiroheterocyclyl, and nitrogen-containing fused heterocyclyl.

[0062] Non-limiting examples of monocyclic heterocyclyls include oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azetyl, 1,4-diazacycloheptyl, pyranyl, tetrahydrothiapyran ...

[0033] Preferred examples of heterocyclyls include oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiapyranyl, tetrahydrothiapyranyl dioxide groups, pyrrolidinyl, morpholinyl, piperidinyl, azetyl, 1,4-diazacycloheptyl, and piperazinyl, and more preferably oxetanyl, piperidinyl, tetrahydropyranyl, and tetrahydrothiapyranyl. Polycyclic heterocyclyls include heterocyclyls having spiro rings, fused rings, or bridged rings. Heterocyclyls having spiro rings, fused rings, or bridged rings are optionally bonded to other groups via a single bond, or further bonded to other cycloalkyls, heterocyclyls, aryls, and heteroaryls via any two or more atoms on the ring.

[0063] The term "spiroheterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclyl group with individual rings joined via one common atom (called a spiroatom), where one or more ring atoms are selected from the group consisting of nitrogen, oxygen, and S(O). m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon atoms, and the ring may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. Spiroheterocyclyl is preferably a 6- to 14-membered spiroheterocyclyl, more preferably a 7- to 10-membered spiroheterocyclyl. According to the number of spiro atoms shared between the rings, spiroheterocyclyl can be divided into mono-spiroheterocyclyl, di-spiroheterocyclyl, or poly-spiroheterocyclyl, and spiroheterocyclyl is preferably a mono-spiroheterocyclyl or di-spiroheterocyclyl, more preferably a 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered mono-spiroheterocyclyl. Non-limiting examples of spiroheterocyclyl are: [ka] etc.

[0064] The term "fused heterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclyl group, in which each ring in the system shares adjacent pairs of atoms with another ring, one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system, and one or more ring atoms is selected from the group consisting of nitrogen, oxygen, and S(O). m(wherein m is an integer of 0 to 2), and the remaining ring atoms are carbon atoms. The fused heterocyclyl is preferably a 6- to 14-membered fused heterocyclyl, more preferably a 7- to 10-membered fused heterocyclyl. According to the number of membered rings, the fused heterocyclyl can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl, preferably bicyclic or tricyclic fused heterocyclyl, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclyl. Non-limiting examples of fused heterocyclyls are: [ka] etc.

[0065] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclyl group, where every two rings in the system share two unconnected atoms, where the rings may have one or more double bonds, but where none of the rings has a completely conjugated pi-electron system, and where one or more ring atoms are selected from the group consisting of nitrogen, oxygen, and S(O). m (wherein m is an integer of 0 to 2), and the remaining ring atoms are carbon atoms. The bridged heterocyclyl is preferably a 6- to 14-membered bridged heterocyclyl, more preferably a 7- to 10-membered bridged heterocyclyl. According to the number of membered rings, the bridged heterocyclyl can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl, and the bridged heterocyclyl is preferably a bicyclic, tricyclic or tetracyclic bridged heterocyclyl, more preferably a bicyclic or tricyclic bridged heterocyclyl. Non-limiting examples of bridged heterocyclyls are: [ka] etc.

[0066] The heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, where the ring attached to the parent structure is a heterocyclyl. Non-limiting examples include: [ka] etc.

[0067] A heterocyclyl may be optionally substituted or unsubstituted. If substituted, the substituents are preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxy, and alkoxycarbonyl.

[0068] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic ring or polycyclic fused ring (i.e., each ring in the system shares adjacent pairs of carbon atoms with another ring in the system) having a conjugated π-electron system, preferably a 6- to 12-membered aryl, such as phenyl and naphthyl. Aryl is more preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring. Aryl includes 5- to 10-membered benzo heteroaryl, 3- to 8-membered benzo cycloalkyl, and 3- to 8-membered benzo heterocyclyl, preferably 5- to 6-membered benzo heteroaryl, 3- to 6-membered benzo cycloalkyl, and 3- to 6-membered benzo heterocyclyl, where the heterocyclyl is a heterocyclyl containing 1 to 3 nitrogen, oxygen, or sulfur atoms. Aryl also includes 3-membered nitrogen-containing fused rings containing a benzene ring.

[0069] The ring connecting the parent structure is an aryl ring, non-limiting examples of which include: [ka] etc.

[0070] Aryl can be substituted or unsubstituted. If substituted, the substituents are preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy, and alkoxycarbonyl.

[0071] The term "heteroaryl" refers to a 5- to 14-membered heteroaromatic system having 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen. Heteroaryl is preferably a 5- to 12-membered heteroaryl, more preferably a 5- or 6-membered heteroaryl, such as imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, pyridazinyl, pyrazinyl, etc., preferably pyridyl, oxadiazolyl, triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl, furyl, thienyl, pyridazinyl, pyrazinyl, and thiazolyl, more preferably pyridyl, furyl, thienyl, pyrimidinyl, oxazolyl, oxadiazolyl, pyrazolyl, pyrrolyl, thiazolyl, pyridazinyl, pyrazinyl, and oxazolyl. A heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, where the ring attached to the parent structure is a heteroaryl ring. Non-limiting examples include: [ka] etc.

[0072] Heteroaryl may be optionally substituted or unsubstituted. If substituted, the substituents are preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy, and alkoxycarbonyl.

[0073] The term "alkoxy" refers to an -O-(alkyl) or -O-(unsubstituted cycloalkyl) group, where alkyl is as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. An alkoxy can be optionally substituted or unsubstituted. If substituted, the substituents are preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy, and alkoxycarbonyl.

[0074] The term "alkylthio" refers to the group -S-(alkyl) or -S-(unsubstituted cycloalkyl), where alkyl is as defined above. Non-limiting examples of alkylthio include methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy. Alkylthio can be optionally substituted or unsubstituted. If substituted, the substituents are preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy, and alkoxycarbonyl.

[0075] "Haloalkyl" refers to an alkyl group substituted with one or more halogens, where alkyl is defined above.

[0076] "Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, where alkoxy is defined above.

[0077] "Hydroxyalkyl" refers to an alkyl group substituted by hydroxy, where alkyl is as defined above.

[0078] "Alkenyl" refers to an olefin chain, also known as an alkene group. The alkenyl may be further substituted with other related groups such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy, or alkoxycarbonyl.

[0079] "Alkynyl" refers to (CH≡C-). Alkynyl may be further substituted with other related groups such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy, or alkoxycarbonyl.

[0080] The term "alkenylcarbonyl" refers to -C(O)-(alkenyl), where alkenyl is as defined above. Non-limiting examples of alkenylcarbonyl include vinylcarbonyl, propenylcarbonyl, and butenylcarbonyl. Alkenylcarbonyl can be optionally substituted or unsubstituted. If substituted, the substituents are preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy, and alkoxycarbonyl.

[0081] "Hydroxy" refers to the group --OH.

[0082] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0083] "Amino" refers to the group -NH2.

[0084] "Cyano" refers to the radical -CN.

[0085] "Nitro" refers to the -NO2 group.

[0086] "Carbonyl" refers to the group -C(O)-.

[0087] "Carboxy" refers to the group --C(O)OH.

[0088] "THF" refers to tetrahydrofuran.

[0089] "EtOAc" refers to ethyl acetate.

[0090] "MeOH" refers to methanol.

[0091] "DMF" refers to N,N-dimethylformamide.

[0092] "DIPEA" refers to diisopropylethylamine.

[0093] "TFA" refers to trifluoroacetic acid.

[0094] "MeCN" refers to acetonitrile.

[0095] "DMA" refers to N,N-dimethylacetamide.

[0096] "Et2O" refers to diethyl ether.

[0097] "DCE" refers to 1,2-dichloroethane.

[0098] "DIPEA" refers to N,N-diisopropylethylamine.

[0099] "NBS" refers to N-bromosuccinimide.

[0100] "NIS" refers to N-iodosuccinimide.

[0101] "Cbz-Cl" refers to benzyl chloroformate.

[0102] "Pd2(dba)3" refers to tris(dibenzylideneacetone)dipalladium.

[0103] "Dppf" refers to 1,1'-bisdiphenylphosphinoferrocene.

[0104] "HATU" refers to 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0105] "KHMDS" refers to potassium hexamethyldisilazide.

[0106] "LiHMDS" refers to lithium bis(trimethylsilyl)amide.

[0107] "MeLi" refers to methyllithium.

[0108] "n-BuLi" refers to n-butyllithium.

[0109] "NaBH(OAc)3" refers to sodium triacetoxyborohydride.

[0110] Different expressions such as "X is selected from the group consisting of A, B, or C," "X is selected from the group consisting of A, B, and C," "X is A, B, or C," and "X is A, B, and C" have the same meaning, i.e., X can be any one or more of A, B, and C.

[0111] A hydrogen atom of the present invention may be replaced by its deuterium isotope. Any of the hydrogen atoms in the example compounds of the present invention may be replaced by a deuterium atom.

[0112] "Optional" or "optionally" means that the subsequently described event or circumstance does not necessarily have to occur, but rather that such a statement includes situations in which the event or circumstance occurs or does not occur. For example, "heterocyclyl optionally substituted with alkyl" does not require that the alkyl group be present, and means that such a statement includes situations in which the heterocyclyl is substituted with alkyl and situations in which the heterocyclyl is not substituted with alkyl.

[0113] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3, independently substituted with a corresponding number of substituents. It goes without saying that the substituents are present only in their possible chemical positions. Those skilled in the art can determine whether a substitution is possible or impossible by experiment or theory without undue effort. For example, the combination of an amino or hydroxyl group having free hydrogen with a carbon atom having an unsaturated bond (such as an olefin) may be unstable.

[0114] A "pharmaceutical composition" refers to a mixture of one or more compounds according to the present invention or physiologically / pharmaceutically acceptable salts or prodrugs thereof with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism, thereby promoting the absorption of the active ingredient so that it exerts its biological activity.

[0115] "Pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that is safe and effective in mammals and that possesses the desired biological activity. DETAILED DESCRIPTION OF THE INVENTION

[0116] The present invention is further described with reference to the following examples, which should not be construed as limiting the scope of the invention. [Example]

[0117] The structure of the compounds of the present invention was identified by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR shifts (δ) are reported in parts per million (ppm). NMR was determined using a Bruker AVANCE-400 instrument. The solvents used for determination were deuterated dimethyl sulfoxide (DMSO-d), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3), and the internal standard was tetramethylsilane (TMS).

[0118] Liquid chromatography-mass spectrometry (LC-MS) was performed on an Agilent 1200 Infinity Series mass spectrometer. High performance liquid chromatography (HPLC) was performed on an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).

[0119] Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used as thin-layer silica gel chromatography (TLC) plates. The size of the silica gel plates used in TLC is 0.15 mm to 0.2 mm, and the size of the silica gel plates used in product purification is 0.4 mm to 0.5 mm. Yantai Huanghai 200-300 mesh silica gel is generally used as the support for column chromatography.

[0120] The raw materials used in the examples of the present invention are known and commercially available or can be synthesized by or according to methods known in the art.

[0121] Unless otherwise stated, all reactions of this invention are carried out under a dry nitrogen or argon atmosphere with continuous magnetic stirring, solvents are dry, and reaction temperatures are in degrees Celsius.

[0122] Example 1 2-(2-(Tert-butyl)-5-oxopyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0123] Step 1: Preparation of N-(3-(tert-butyl)-1H-pyrazol-5-yl)-2-chloronicotinamide [ka]

[0124] 3-(Tert-butyl)-1H-pyrazol-5-amine (2.77 g, 19.93 mmol), DIPEA (6.2 g, 49.8 mmol), and HATU (5.4 g, 0.144 mmol) were added successively to a solution of 2-chloronicotinic acid (1.57 g, 9.96 mmol) in DMF (30 mL) under ice bath conditions. The ice bath was removed, and the reaction solution was stirred for 1 hour. The mixture was worked up to give Example 1-1 (2.5 g, 90%). MS m / z (ESI): 279.7 [M+H] + .

[0125] Step 2: Preparation of 2-(tert-butyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-5(4H)-one [ka]

[0126] Potassium carbonate (1.61 g, 11.66 mmol) and 1,4-diazabicyclo[2.2.2]octane (DABCO) (150.9 mg, 1.35 mmol) were added to a solution of Example 1-1 (2.5 g, 8.97 mmol) in DMF (50 mL). The reaction solution was stirred at room temperature for 16 hours. The mixture was worked up to give Example 1-2 (2.1 g, 97%). MS m / z (ESI): 279.7 [M+H] + .

[0127] Step 3: Preparation of 2-(2-(tert-butyl)-5-oxopyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0128] Potassium carbonate (4.28 g, 30.96 mmol) and Example 1-3 (4.33 g, 18.57 mmol) were added to a solution of Example 1-2 (1.5 g, 6.19 mmol) in DMF (30 mL) at room temperature. The mixture was heated to 80° C. and stirred for 2 hours. The reaction solution was cooled, followed by the addition of water. The precipitate was filtered, washed with ethyl acetate, and purified to give Example 1 (656 mg, yield: 27%). MS m / z (ESI): 395.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.80 - 8.78 (m, 1H), 8.47 (d, J = 7.6 Hz, 1H), 8.30 (d, J = 2.8 Hz, 1H), 8.01 - 7.94 (m, 1H), 7.73 - 7.66 (m, 1H), 7.49 (dd, J = 8.0, 4.8 Hz, 1H), 6.34 (s, 1H), 4.87 (s, 2H), 1.26 (s, 9H).

[0129] Example 2 2-(2-Bromo-5-oxopyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0130] Example 2 was synthesized according to the method of Example 1. The target compound (500 mg, yield: 68%) was obtained by replacing 3-(tert-butyl)-1H-pyrazol-5-amine with 3-bromo-1H-pyrazol-5-amine. MS m / z (ESI): 418.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.32 (s, 1H), 9.85 (d, J = 7.6 Hz, 1H), 8.74 (d, J = 6.4 Hz, 1H), 8.40 (d, J = 2.8 Hz, 1H), 8.05 - 8.00 (m, 1H), 7.78 - 7.73 (m, 1H), 7.23 - 7.17 (m, 1H), 6.31 (s, 1H), 5.52 (s, 2H).

[0131] Example 3 N-(5-fluoropyridin-2-yl)-2-(2-methyl-5-oxopyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)acetamide [ka]

[0132] Example 3 was synthesized according to the method of Example 1. The target compound (20 mg, yield: 26%) was obtained by replacing 3-(tert-butyl)-1H-pyrazol-5-amine with 3-methyl-1H-pyrazol-5-amine. MS m / z (ESI): 353.3 [M+H] + .

[0133] Example 4 N-(5-fluoropyridin-2-yl)-2-(2-ethyl-5-oxopyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)acetamide [ka]

[0134] Example 4 was synthesized according to the method of Example 1. The target compound (15 mg, yield: 36%) was obtained by replacing 3-(tert-butyl)-1H-pyrazol-5-amine with 3-ethyl-1H-pyrazol-5-amine. MS m / z (ESI): 367.4 [M+H] + .

[0135] Example 5 N-(5-fluoropyridin-2-yl)-2-(2-isopropyl-5-oxopyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)acetamide [ka]

[0136] Example 5 was synthesized according to the method of Example 1. The target compound (15 mg, yield: 36%) was obtained by replacing 3-(tert-butyl)-1H-pyrazol-5-amine with 3-isopropyl-1H-pyrazol-5-amine. MS m / z (ESI): 381.4 [M+H] + .

[0137] Example 6 N-(5-fluoropyridin-2-yl)-2-(2-isopropenyl-5-oxopyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)acetamide [ka]

[0138] Example 2 (100 mg, 0.24 mmol), isopropenylboronic acid (41.2 mg, 0.48 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (19.2 mg, 0.024 mmol), and cesium carbonate (232.8 mg, 0.72 mmol) were stirred in dioxane (4 mL) and water (1 mL) under microwave irradiation at 100°C for 1 hour. The reaction solution was concentrated to dryness by rotary evaporation and purified by preparative high-performance liquid chromatography to give Example 6 (54 mg, yield: 60%). MS m / z (ESI): 379.4 [M+H] + .

[0139] Example 7 N-(5-fluoropyridin-2-yl)-2-(5-oxo-2-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)acetamide [ka]

[0140] Example 7 was synthesized according to the method of Example 1. The target compound (15 mg, yield: 36%) was obtained by replacing 3-(tert-butyl)-1H-pyrazol-5-amine with 3-trifluoromethyl-1H-pyrazol-5-amine. MS m / z (ESI): 407.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.96 (dd, J = 8.0, 1.6 Hz, 1H), 8.65 (dd, J = 8.0, 1.6 Hz, 1H), 8.37 (d, J = 3.2 Hz, 1H), 8.07 - 8.02 (m, 1H), 7.78 - 7.73 (m, 2H), 7.05 (s, 1H), 5.02 (s, 2H).

[0141] Example 8 2-(2-amino-5-oxopyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0142] Step 1: Preparation of methyl 5-oxo-4,5-dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-2-carboxylate [ka]

[0143] The synthesis method of Example 8-1 followed the synthesis method of Example 1-2. Example 8-1 (500 mg, 73%) was obtained by replacing 3-(tert-butyl)-1H-pyrazol-5-amine with methyl 5-amino-1H-pyrazole-3-carboxylate. MS: m / z (ESI): 245.2 [M+H] + .

[0144] Step 2: Preparation of methyl 4-(2-((5-fluoropyridin-2-yl)amino)-2-oxoethyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-2-carboxylate [ka]

[0145] The synthesis method of Example 8-2 followed the synthesis method of Example 1. The title compound, Example 8-2 (500 mg, 51%), was obtained by using Example 8-1 as the starting material. MS m / z (ESI): 397.3 [M+H] + .

[0146] Step 3: Preparation of 4-(2-((5-fluoropyridin-2-yl)amino)-2-oxoethyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-2-carboxylic acid [ka]

[0147] A solution of LiOH (519 mg, 12.36 mmol) in water (2 mL) was added to a solution of Example 8-2 (490 mg, 1.24 mmol) in tetrahydrofuran (10 mL) at room temperature. The mixture was stirred at room temperature for 3 hours, and then the pH was adjusted to about 3 with 1 M HCl. The solution was concentrated to dryness to give Example 8-3 (470 mg, 99%). MS m / z (ESI): 383.3 [M+H] + .

[0148] Step 4: Preparation of 2-(2-amino-5-oxopyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0149] Ammonia was added to a solution of Example 8-3 (450 mg, 1.2 mmol) in 1,4-dioxane (10 mL), EtN (33 μL, 0.24 mmol), and BOP reagent (598 mg, 1.35 mmol) and stirred at room temperature for 20 minutes. Sodium azide (160 mg, 2.46 mmol) and tetrabutylammonium bromide (786 mg, 2.46 mmol) were added, and the reaction solution was stirred for 1 hour. The reaction solution was diluted with 1,4-dioxane (12 mL), followed by the addition of 2M aqueous HSO (4 mL), and heated at 100 °C for 2 hours. The solvent was evaporated, and the residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The resulting residue was purified by column chromatography to give Example 8 (360 mg, 86%). MS m / z (ESI): 354.3 [M+H] + .

[0150] Example 9 2-(2-cyclopropyl-5-oxopyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0151] The synthesis method of Example 9 followed the synthesis method of Example 6. The title compound, Example 9 (8 mg, 51%), was obtained by replacing isopropenylboronic acid with cyclopropylboronic acid. MS m / z (ESI): 378.4 [M+H] + .

[0152] Example 10 2-(2-Cyclopentyl-5-oxopyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0153] The synthesis method of Example 10 followed the synthesis method of Example 1. The title compound, Example 10 (9 mg, 28%), was obtained by replacing 3-bromo-1H-pyrazol-5-amine with 3-cyclopentyl-1H-pyrazol-5-amine. MS m / z (ESI): 407.4 [M+H] + .

[0154] Example 11 2-(2-Cyclopentenyl-5-oxopyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0155] The synthesis method of Example 11 followed the synthesis method of Example 6. The title compound, Example 11 (15 mg, 81%), was obtained by replacing isopropenylboronic acid with cyclopentenylboronic acid. MS m / z (ESI): 405.4 [M+H] + .

[0156] Example 12 N-(5-fluoropyridin-2-yl)-2-(5-oxo-2-(tetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)acetamide [ka]

[0157] Step 1: Preparation of 2-(2-(3,6-dihydro-2H-thiopyran-4-yl)-5-oxopyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0158] The synthesis method of Example 12-1 followed the synthesis method of Example 6. The title compound, Example 12-1 (20 mg, 81%), was obtained by replacing isopropenylboronic acid with (3,6-dihydro-2H-thiopyran-4-yl)boronic acid. MS m / z (ESI): 437.5 [M+H] + .

[0159] Step 2: Preparation of N-(5-fluoropyridin-2-yl)-2-(5-oxo-2-(tetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)acetamide [ka]

[0160] Example 12-1 (20 mg, 0.045 mmol) was dissolved in methanol (1 mL). 10% wet palladium on carbon (2 mg) was added, and the reaction solution was heated to reflux under a hydrogen atmosphere. After completion of the reaction, the reaction solution was filtered through Celite and purified to give Example 12 (13 mg, 65%). MS m / z (ESI): 439.5 [M+H] + .

[0161] Example 13 2-(2-(2,2-difluoroacetyl)piperidin-4-yl)-5-oxopyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0162] The synthesis method of Example 13 was the same as that of Example 6. The title compound, Example 13 (6 mg, 11%), was obtained. MS m / z (ESI): 500.4 [M+H] + .

[0163] Example 14 N-(5-fluoropyridin-2-yl)-2-(2-(oxetan-3-ylamino)-5-oxopyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)acetamide [ka]

[0164] Example 9 (35.3 mg, 0.1 mmol) and oxetanone (7.1 mg, 0.1 mmol) were dissolved in methanol (1 mL). Sodium borohydride (3.8 mg, 0.1 mmol) and p-toluenesulfonic acid monohydrate (0.1 mmol) were added to the resulting mixture, and the reaction solution was heated to reflux for 3 hours. The reaction mixture was quenched with saturated aqueous NaHCO3 (10 mL) and extracted with dichloromethane (3 x 10 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified to give Example 14 (20 mg, 50%). MS m / z (ESI): 410.4 [M+H] + .

[0165] Example 15 2-(2-(cyclopentylamino)-5-oxopyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0166] The synthesis method of Example 15 was the same as that of Example 14. The title compound, Example 15 (7 mg, 13%), was obtained. MS m / z (ESI): 422.4 [M+H] + .

[0167] Example 16 N-(cyclopropylmethyl)-4-(2-((5-fluoropyridin-2-yl)amino)-2-oxoethyl)-N-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-2-carboxamide [ka]

[0168] Example 8-3 (36.7 mg, 0.096 mmol) was dissolved in DMF (1 mL) under ice bath conditions, followed by the successive addition of 1-cyclopropyl-N-methylformamide (16.4 mg, 0.192 mmol), DIPEA (62 mg, 0.48 mmol), and HATU (54 mg, 0.144 mmol). The ice bath was removed, and the reaction solution was stirred for 1 hour. The mixture was worked up to give Example 16 (22 mg, 50%). MS m / z (ESI): 450.5 [M+H] + .

[0169] Example 17 N-(cyclopropyl)-4-(2-((5-fluoropyridin-2-yl)amino)-2-oxoethyl)-N-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-2-carboxamide [ka]

[0170] The synthesis method of Example 17 was the same as that of Example 16. The title compound, Example 17 (20 mg, 50%), was obtained. MS m / z (ESI): 436.4 [M+H] + .

[0171] Example 18 N-(5-fluoropyridin-2-yl)-2-(5-oxo-2-phenylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)acetamide [ka]

[0172] The synthesis method of Example 18 was the same as that of Example 6. The title compound, Example 18 (6 mg, 54%), was obtained. MS m / z (ESI): 415.4 [M+H] + .

[0173] Example 19 N-(5-fluoropyridin-2-yl)-2-(2-(6-methylpyridin-3-yl)-5-oxopyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)acetamide [ka]

[0174] Example 19 was synthesized according to the synthesis method of Example 6. The title compound, Example 19 (9 mg, 50%), was obtained. MS m / z (ESI): 430.4 [M+H] + .

[0175] Example 20 N-(5-fluoropyridin-2-yl)-2-(2-(2-methylpyridin-4-yl)-5-oxopyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)acetamide [ka]

[0176] Example 20 was synthesized according to the synthesis method of Example 6. The title compound, Example 20 (13 mg, 50%), was obtained. MS m / z (ESI): 430.4 [M+H] + .

[0177] Example 21 2-(2,5-dimethylpyridin-4-yl)-5-oxopyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0178] Example 21 was synthesized according to the synthesis method of Example 6. The title compound, Example 21 (18 mg, 56%), was obtained. MS m / z (ESI): 444.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.21 (s, 1H), 8.90 - 8.86 (m, 1H), 8.84 - 8.81 (m, 1H), 8.76 - 8.74 (m, 1H), 8.38 (s, 1H), 8.30 (s, 1H), 8.06 - 7.98 (m, 1H), 7.78 - 7.70 (m, 1H), 7.53 - 7.47 (m, 1H), 7.35 (s, 1H), 5.44 (s, 2H), 2.78 (s, 3H), 2.74 (s, 3H).

[0179] Example 22 2-(2-(Tert-butyl)-8-chloro-5-oxopyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0180] Example 22 was synthesized according to the synthesis method of Example 1. The title compound, Example 22 (4 mg, 19%), was obtained. MS m / z (ESI): 429.8 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.52 (d, J = 8.4 Hz, 1H), 8.38 (d, J = 2.8 Hz, 1H), 8.08 - 8.03 (m, 1H), 7.79 - 7.74 (m, 1H), 7.62 (d, J = 8.4 Hz, 1H), 6.47 (s, 1H), 4.93 (s, 2H), 1.33 (s, 9H).

[0181] Example 23 2-(2-(Tert-butyl)-8-methyl-5-oxopyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0182] Example 23 was synthesized according to the synthesis method of Example 1. The title compound, Example 23 (8 mg, 19%), was obtained. MS m / z (ESI): 409.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.40 (d, J = 8.0 Hz, 1H), 8.37 (d, J = 3.2 Hz, 1H), 8.06 - 8.02 (m, 1H), 7.75 (td, J = 8.4, 2.8 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 6.38 (s, 1H), 4.93 (s, 2H), 2.68 (s, 3H), 1.33 (s, 9H).

[0183] Example 24 2-(2-(Tert-butyl)-7-methyl-5-oxopyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0184] Example 24 was synthesized according to the synthesis method of Example 1. The title compound, Example 24 (7 mg, 16%), was obtained. MS m / z (ESI): 409.4 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.70 (d, J = 2.3 Hz, 1H), 8.36 (dd, J = 8.7, 2.7 Hz, 2H), 8.04 (s, 1H), 7.76 (dt, J = 8.9, 4.5 Hz, 1H), 6.38 (s, 1H), 4.93 (s, 2H), 2.45 (s, 3H), 1.31 (s, 9H).

[0185] Example 25 2-(2-(Tert-butyl)-6-methyl-5-oxopyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0186] Example 25 was synthesized according to the synthesis method of Example 1. The title compound, Example 25 (5 mg, 16%), was obtained. MS m / z (ESI): 409.4 [M+H] + .

[0187] Example 26 2-(2-(Tert-butyl)-5-oxopyrazolo[1,5-a]quinazolin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0188] Example 26 was synthesized according to the synthesis method of Example 1. The title compound, Example 26 (6 mg, 16%), was obtained. MS m / z (ESI): 394.4 [M+H] + .

[0189] Example 27 2-(2-(Tert-butyl)-5-oxopyrazolo[1,5-a]pyrido[2,3-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0190] Example 27 was synthesized according to the synthesis method of Example 1. The title compound, Example 27 (6 mg, 16%), was obtained. MS m / z (ESI): 395.4 [M+H] + .

[0191] Example 28 2-(2-(Tert-butyl)-7-methyl-5-oxopyrazolo[1,5-a]pyrido[2,3-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0192] Example 28 was synthesized according to the synthesis method of Example 1. The title compound, Example 28 (9 mg, 21%), was obtained. MS m / z (ESI): 409.4 [M+H] + .

[0193] Example 29 2-(2-(Tert-butyl)-7-chloro-5-oxopyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0194] Example 29 was synthesized according to the synthesis method of Example 1. The title compound, Example 29 (15 mg, 32%), was obtained. MS m / z (ESI): 429.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.91 (d, J = 2.4 , 1H), 8.54 (d, J = 2.4 Hz, 1H), 8.38 (d, J = 2.8 Hz, 1H), 8.08 - 8.02 (m, 1H), 7.79 - 7.74 (m, 1H), 6.47 (s, 1H), 4.94 (s, 2H), 1.32 (s, 9H).

[0195] Example 30 2-(2-(Tert-butyl)-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0196] The synthesis method of Example 30 followed the synthesis method of Example 1. The title compound, Example 30 (25 mg, 46%), was obtained by using 2-chloro-6-trifluoromethylnicotinic acid as the starting material. MS m / z (ESI): 463.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 8.38 (d, J = 2.8 Hz, 1H), 8.09 - 8.04 (m, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.79 - 7.74 (m, 1H), 6.52 (s, 1H), 4.95 (s, 2H), 1.34 (s, 9H).

[0197] Example 31 2-(Tert-butyl)-4-(4-chlorobenzyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-5(4H)-one [ka]

[0198] Example 31 was synthesized according to the synthesis method of Example 1. The title compound, Example 31 (12 mg, 24%), was obtained. MS m / z (ESI): 367.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.83 (dd, J = 4.8, 1.6 Hz, 1H), 8.56 (dd, J = 8.0, 1.6 Hz, 1H), 7.55 (dd, J = 8.0, 4.8 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 6.31 (s, 1H), 5.25 (s, 2H), 1.30 (s, 9H).

[0199] Example 32 2-(2-(Tert-butyl)-7-isopropyl-5,8-dioxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrimidin-4-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0200] Step 1: Preparation of 4-hydroxy-1-isopropyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid [ka]

[0201] LiOH (0.23 g, 9.4 mmol) was added to a solution of Example 32-1 (2.0 g, 9.4 mmol) in CHOH (30 mL) under ice bath conditions. The ice bath was removed and the reaction solution was stirred for 1 hour. The reaction solution was adjusted to pH 5-6 with 1 mol / L aqueous hydrochloric acid solution and extracted with ethyl acetate (10 mL x 3). The organic phase was dried and concentrated to give Example 32-2 (1.5 g, 73%). MS m / z (ESI): 184.7 [MH] + .

[0202] Step 2: Preparation of N-(3-(tert-butyl)-1H-pyrazol-5-yl)-4-hydroxy-1-isopropyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxamide [ka]

[0203] The synthesis method of Example 32-3 followed the synthesis method of Example 1-1. The title compound, Example 32-3 (0.26 g, 44%), was obtained by using Example 32-2 as the starting material. MS m / z (ESI): 307.2 [M+H] + .

[0204] Step 3: Preparation of 2-(tert-butyl)-7-isopropyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrimidine-5,8-dione [ka]

[0205] The synthesis method of Example 32-4 followed the synthesis method of Example 1-2. The title compound, Example 32-4 (0.18 g, 78%), was obtained by using Example 32-3 as the starting material. MS m / z (ESI): 289.2 [M+H] + .

[0206] Step 4: Preparation of 2-(2-(tert-butyl)-7-isopropyl-5,8-dioxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrimidin-4-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0207] The synthesis method of Example 32-4 followed the synthesis method of Example 1. The title compound, Example 32-5 (0.12 g, 65%), was obtained by using Example 32-4 as the starting material. MS m / z (ESI): 441.2 [M+H] + .

[0208] Example 33 N-(5-fluoropyridin-2-yl)-2-(2-methyl-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)acetamide [ka]

[0209] Example 33 was synthesized according to the synthesis method of Example 2. The title compound, Example 33 (18 mg, 30%), was obtained. MS m / z (ESI): 421.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.80 (d, J = 8.0 Hz, 1H), 8.37 (s, 1H), 8.07 - 8.03 (m, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.79 - 7.73 (m, 1H), 6.28 (s, 1H), 4.95 (s, 2H), 2.33 (s, 3H).

[0210] Example 34 2-(2-ethyl-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0211] Step 1: Preparation of tert-butyl 5-amino-3-ethyl-1H-pyrazole-1-carboxylate [ka]

[0212] 3-Ethyl-1H-pyrazol-5-amine (2.0 g, 18.0 mmol) was dissolved in anhydrous dichloromethane (50 mL), followed by the addition of triethylamine (2.2 g, 21.6 mmol) and di-tert-butyl dicarbonate (4.7 g, 21.6 mmol). The reaction solution was reacted at room temperature for 16 hours. The reaction solution was washed successively with water (50 mL × 2) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (ethyl acetate / dichloromethane = 0 to 20%) to give the title product, Example 34-1 (3.4 g), yield: 89.5%. MS: m / z (ESI): 212.1 [M+H] + .

[0213] Step 2: Preparation of tert-butyl 5-amino-3-ethyl-1H-pyrazole-1-carboxylate [ka]

[0214] Example 34-1 (3.4 g, 16.1 mmol) was dissolved in anhydrous dichloromethane (60 mL), followed by the addition of triethylamine (5.4 g, 53.1 mmol). A solution (50 mL) of freshly prepared 2-chloro-6-(trifluoromethyl)nicotinoyl chloride (4.3 g, 17.7 mmol) in dichloromethane was added dropwise at 0 °C under a nitrogen atmosphere. After the addition was completed, the reaction solution was reacted at room temperature for 30 minutes. The reaction solution was washed successively with water (200 mL × 2) and saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0 to 20%) to give Example 34-2 (2.6 g), yield: 38.2%. MS: m / z (ESI): 319.1 [M-Boc+H] + .

[0215] Step 3: Preparation of N-(3-ethyl-1H-pyrazol-5-yl)-2-chloro-6-(trifluoromethyl)nicotinamide [ka]

[0216] Example 34-2 (2.6 g, 6.2 mmol) was dissolved in anhydrous dichloromethane (10 mL), followed by the addition of a solution of hydrochloric acid in dioxane (4 M, 20 mL). The reaction solution was reacted at room temperature for 4 hours. The reaction solution was directly concentrated to dryness by rotary evaporation to give Example 34-3 (1.9 g), yield: 96.0%. MS: m / z (ESI): 319.0 [M+H] + .

[0217] Step 4: 2-Ethyl-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-5(4H)-one [ka]

[0218] Example 34-3 (1.9 g, 6.0 mmol) was dissolved in N,N-dimethylformamide (20 mL), followed by the addition of potassium carbonate (2.5 g, 18.0 mmol). The reaction solution was heated to 120° C. and reacted for 2 hours. The reaction solution was cooled to room temperature and used directly in the next step. MS: m / z (ESI): 283.1[M+H] + .

[0219] Step 5: 2-(2-ethyl-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0220] Potassium carbonate (1.5 g, 10.6 mmol) and 2-bromo-N-(5-fluoropyridin-2-yl)acetamide (0.99 g, 4.2 mmol) were added to a reaction solution of Example 34-4 (1.0 g, 3.5 mmol) in N,N-dimethylformamide (20 mL) and reacted at 40 ° C. for 2 hours. The reaction solution was cooled to room temperature, poured into 300 mL of water, and extracted with ethyl acetate (200 mL × 3). The organic phases were combined, washed successively with water (200 mL × 2) and saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was recrystallized from ethyl acetate to obtain Example 34. 1 H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.79 (d, J = 7.6 Hz, 1H), 8.37 (s, 1H), 8.07 - 8.03 (m, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.79 - 7.72 (m, 1H), 6.36 (s, 1H), 4.96 (s, 2H), 2.70 (q, J = 7.6 Hz, 2H), 1.25 (t, J = 7.6 Hz, 3H). MS m / z (ESI): 435.1 [M+H] + .

[0221] Example 35 2-(2-cyclopropyl-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0222] Example 35 was synthesized according to the synthesis method of Example 1. The title compound, Example 35 (17 mg, 28%), was obtained. 1 H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.78 (d, J = 8.0 Hz, 1H), 8.37 (s, 1H), 8.08 - 8.02 (m, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.79 - 7.73 (m, 1H), 6.23 (s, 1H), 4.91 (s, 2H), 2.11 - 2.04 (m, 1H), 1.04 - 0.98 (m, 2H), 0.82 - 0.78 (m, 2H). MS m / z (ESI): 447.1 [M+H] + .

[0223] Example 36 N-(5-fluoropyridin-2-yl)-2-(2-isopropyl-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)acetamide [ka]

[0224] The synthesis method of Example 36 followed the synthesis method of Example 4. The title compound, Example 36 (10 mg, 22%), was obtained. MS m / z (ESI): 449.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.79 (d, J = 8.0 Hz, 1H), 8.37 (s, 1H), 8.09 - 8.03 (m, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.79 - 7.74 (m, 1H), 6.42 (s, 1H), 4.96 (s, 2H), 3.08 - 3.01 (m, 1H), 1.29 (s, 3H), 1.27 (s, 3H).

[0225] Example 37 2-(2-Cyclopentyl-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0226] Example 37 was synthesized according to the synthesis method of Example 1. The title compound, Example 37 (18 mg, 30%), was obtained. MS m / z (ESI): 475.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.07 (s, 1H), 8.79 (d, J = 8.0 Hz, 1H), 8.38 (s, 1H), 8.14 - 7.89 (m, 2H), 7.77 (s, 1H), 6.42 (s, 1H), 4.96 (s, 2H), 3.17 (s, 1H), 2.14 - 1.93 (m, 3H), 1.67 (m, 5H).

[0227] Example 38 2-(2-(4,4-difluorocyclohexyl)-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0228] Example 38 was synthesized according to the synthesis method of Example 1. The title compound, Example 38 (8 mg, 20%), was obtained. MS m / z (ESI): 525.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.79 (d, J = 8.2 Hz, 1H), 8.37 (d, J = 3.0 Hz, 1H), 8.01 (d, J = 8.0 Hz, 2H), 7.76 (t, J = 9.0 Hz, 1H), 6.49 (s, 1H), 4.95 (s, 2H), 2.95 (s, 1H), 2.05 (q, J = 19.1, 17.8 Hz, 6H), 1.74 (d, J = 13.1 Hz, 2H).

[0229] Example 39 N-(5-fluoropyridin-2-yl)-2-(2-(6-methylpyridin-3-yl)-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)acetamide [ka]

[0230] Example 39 was synthesized according to the synthesis method of Example 1. The title compound, Example 39 (15 mg, 28%), was obtained. MS m / z (ESI): 498.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.01 (s, 1H), 8.85 (d, J = 8.0 Hz, 1H), 8.37 (d, J = 2.8 Hz, 1H), 8.25 (dd, J = 8.0, 2.4 Hz, 1H), 8.13 - 8.03 (m, 2H), 7.79 - 7.74 (m, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.15 (s, 1H), 5.02 (s, 2H), 2.54 (s, 3H).

[0231] Example 40 2-(2,5-dimethylpyridin-4-yl)-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0232] Example 40 was synthesized according to the synthesis method of Example 1. The title compound, Example 40 (22 mg, 45%), was obtained. MS m / z (ESI): 512.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.86 (d, J = 8.4 Hz, 1H), 8.46 - 8.43 (m, 2H), 8.39 - 8.36 (m, 1H), 8.12 - 8.03 (m, 2H), 7.79 - 7.74 (m, 1H), 7.57 (s, 1H), 7.02 (s, 1H), 5.05 (s, 2H), 2.53 (s, 3H), 2.51 (s, 3H).

[0233] Example 41 2-(2-amino-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0234] Example 41 was synthesized according to the synthesis method of Example 1. The title compound, Example 41 (12 mg, 26%), was obtained. MS m / z (ESI): 422.1 [M+H] + .

[0235] Example 42 2-(2-(cyclopentylamino)-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0236] Example 42 was synthesized according to the synthesis method of Example 8. The title compound, Example 42 (9 mg, 19%), was obtained. MS m / z (ESI): 489.2 [M+H] + .

[0237] Example 43 N-(5-fluoropyridin-2-yl)-2-(2-(oxetan-3-ylamino)-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)acetamide [ka]

[0238] The synthesis method of Example 43 was the same as that of Example 14. The title compound, Example 43 (15 mg, 25%), was obtained. MS m / z (ESI): 478.1 [M+H] + .

[0239] Example 44 2-(8-amino-2-(tert-butyl)-5-oxopyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0240] Step 1: Preparation of 2-(8-amino-2-(tert-butyl)-5-oxopyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0241] Example 22 (100 mg, 0.234 mmol) and aqueous ammonia (5 mL) were added to a round-bottom flask at room temperature, and the mixture was stirred at 80° C. for 5 hours. After completion of the reaction, the reaction solution was purified by HPLC to give Example 44 (52 mg, 54%). MS m / z (ESI): 410.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.41 (s, 1H), 8.02 - 7.95 (m, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.68 (s, 1H), 7.45 (s, 2H), 6.43 (d, J = 8.7 Hz, 1H), 6.15 (s, 1H), 4.79 (s, 2H), 1.23 (s, 9H).

[0242] Example 45 2-(2-(Tert-butyl)-8-cyano-5-oxopyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0243] Step 1: Preparation of 2-(2-(tert-butyl)-8-cyano-5-oxopyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0244] Example 22 (80 mg, 0.187 mmol), CuCN (45 mg, 0.5 mmol), and DMF (2 mL) were added to a round-bottom flask at room temperature, and the mixture was stirred at 150° C. for 5 hours under a nitrogen atmosphere. After completion of the reaction, the reaction solution was purified by HPLC to give Example 45 (26 mg, 33%). MS m / z (ESI): 420.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.06 (s, 1H), 8.72 (d, J = 8.0 Hz, 1H), 8.37 (s, 1H), 8.17 - 7.98 (m, 2H), 7.77 (d, J = 8.3 Hz, 1H), 6.51 (s, 1H), 4.94 (s, 2H), 1.28 (s, 9H).

[0245] Example 46 2-(2-(Tert-butyl)-8-methoxy-5-oxopyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0246] Step 1: Preparation of 2-(2-(tert-butyl)-8-methoxy-5-oxopyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0247] Example 22 (80 mg, 0.187 mmol), MeONa (43 mg, 0.8 mmol), and DMF (2 mL) were added to a round-bottom flask at room temperature, and the mixture was stirred at 80° C. for 3 hours under a nitrogen atmosphere. After completion of the reaction, the reaction solution was purified by HPLC to give Example 46 (35 mg, 45%). MS m / z (ESI): 425.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 8.45 (d, J = 8.8 Hz, 1H), 8.37 (d, J = 3.2 Hz, 1H), 8.06 - 8.00 (m, 1H), 7.76 - 7.71 (m, 1H), 6.75 (d, J = 8.8 Hz, 1H), 6.55 (s, 1H), 5.24 (s, 2H), 3.88 (s, 3H), 1.33 (s, 9H).

[0248] Example 47 2-(2-(Tert-butyl)-5-oxo-7-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0249] Example 47 was synthesized according to the method of Example 1. Example 47 (36 mg, 52%) was obtained by replacing 2-chloronicotinic acid with 2-chloro-5-(trifluoromethyl)nicotinic acid. MS m / z (ESI): 463.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.24 (s, 1H), 8.73 (s, 1H), 8.36 (d, J = 3.1 Hz, 1H), 8.04 (s, 1H), 7.75 (td, J = 8.8, 3.2 Hz, 1H), 6.51 (d, J = 2.7 Hz, 1H), 4.96 (s, 2H), 1.33 (s, 9H).

[0250] Example 48 2-(2-(Tert-butyl)-6-chloro-5-oxopyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0251] Example 48 was synthesized according to the method of Example 1. Example 48 (52 mg, 46%) was obtained by replacing 2-chloronicotinic acid with 2,4-dichloronicotinic acid. MS m / z (ESI): 429.2 [M+H] + .

[0252] Example 49 2-(2-(Tert-butyl)-6-isopropyl-5-oxopyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0253] Step 1: Preparation of 2-(2-(tert-butyl)-6-isopropyl-5-oxopyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0254] Isopropylmagnesium bromide (1M, 1 mL) was added dropwise to a solution of Example 48 (100 mg, 0.233 mmol) in THF (5 mL) under a nitrogen atmosphere at −70° C., and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was purified by HPLC to give Example 49 (62 mg, 60%). MS m / z (ESI): 437.0 [M+H] + .

[0255] Example 50 2-(2-(Tert-butyl)-6-cyclopropyl-5-oxopyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0256] Example 50 was synthesized according to the method of Example 49. Example 50 (36 mg, 58%) was obtained by replacing isopropylmagnesium bromide with cyclopropylmagnesium bromide. MS m / z (ESI): 435.2 [M+H] + .

[0257] Example 51 2-(2-(Tert-butyl)-5-oxo-6-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0258] Example 51 was synthesized according to the method of Example 1. Example 51 (36 mg, 52%) was obtained by replacing 2-chloronicotinic acid with 2-chloro-4-(trifluoromethyl)nicotinic acid. MS m / z (ESI): 463.1 [M+H] + .

[0259] Example 52 2-(6-amino-2-(tert-butyl)-5-oxopyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0260] Example 52 was synthesized according to the method of Example 44. Example 52 (36 mg, 52%) was obtained by substituting Example 48 for Example 22. MS m / z (ESI): 410.2 [M+H] + .

[0261] Example 53 2-(7-(Tert-butyl)-4-oxopyrazolo[1,5-a]thiazolo[5,4-e]pyrimidin-5(4H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0262] Example 53 was synthesized according to the synthesis method of Example 1. The title compound (19 mg, 21%) was obtained. MS m / z (ESI): 401.4 [M+H] + .

[0263] Example 54 2-(7-(Tert-butyl)-3-isopropyl-4-oxo-3,4-dihydro-5H-pyrazolo[5,1-b]purin-5-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0264] Example 54 was synthesized according to the synthesis method of Example 1. The title compound (11 mg, 28%) was obtained. MS m / z (ESI): 426.5 [M+H] + .

[0265] Example 55 2-(2-(Tert-butyl)-6-ethyl-5-oxo-5,6-dihydro-4H-dipyrazolo[1,5-a:3',4'-e]pyrimidin-4-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0266] Example 55 was synthesized according to the synthesis method of Example 1. The title compound (26 mg, 28%) was obtained. MS m / z (ESI): 412.4 [M+H] + .

[0267] Example 56 2-(7-(Tert-butyl)-3-methyl-4-oxoisoxazolo[4,3-e]pyrazolo[1,5-a]pyrimidin-5(4H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0268] Example 56 was synthesized according to the synthesis method of Example 1. The title compound (23 mg, 25%) was obtained. MS m / z (ESI): 399.4 [M+H]+ .

[0269] Example 57 2-(7-(Tert-butyl)-3-methyl-4-oxoisothiazolo[4,3-e]pyrazolo[1,5-a]pyrimidin-5(4H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0270] Example 57 was synthesized according to the synthesis method of Example 1. The title compound (19 mg, 29%) was obtained. MS m / z (ESI): 415.5[M+H] + .

[0271] Example 58 2-(2-(Tert-butyl)-5-thioxopyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0272] Step 1: Preparation of 2-(2-(tert-butyl)-5-thioxopyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0273] Lawson's reagent (158 mg, 0.39 mmol) was added to a solution of Example 1 (50 mg, 0.13 mmol) in toluene (2 mL) at room temperature, and the reaction solution was heated at 115°C for 1 hour by microwave. LCMS showed the reaction was complete, and the reaction solution was purified by p-HPLC (HCOOH) to give Example 58 (5 mg, 10%). MS m / z (ESI): 411.13 [M+H] + .

[0274] Example 59 N-(5-fluoropyridin-2-yl)-2-(2-(1-methylcyclopropyl)-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)acetamide [ka]

[0275] Example 59 was synthesized according to the synthesis method of Example 1. The title compound, Example 59 (21 mg, 40%), was obtained. MS m / z (ESI): 461.4 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.04 (s, 1H), 8.78 (d, J = 7.6 Hz, 1H), 8.37 (s, 1H), 8.17 - 7.90 (m, 2H), 7.76 (t, J = 8.1 Hz, 1H), 6.35 (s, 1H), 4.93 (s, 2H), 1.47 (s, 3H), 1.03 (s, 2H), 0.85 (s, 2H).

[0276] Example 60 N-(5-fluoropyridin-2-yl)-2-(5-oxo-8-(trifluoromethyl)-2-(1-(trifluoromethyl)cyclopropyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)acetamide [ka]

[0277] Example 60 was synthesized according to the synthesis method of Example 1. The title compound, Example 60 (15 mg, 31%), was obtained. MS m / z (ESI): 515.4 [M+H] + .

[0278] Example 61 2-(2-(2,2-difluoroethyl)azetidin-3-yl)-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0279] Step 1: Preparation of tert-butyl 5-amino-3-bromo-1H-pyrazole-1-carboxylate [ka]

[0280] 3-Bromo-1H-pyrazol-5-amine (10.0 g, 61.7 mmol) was dissolved in anhydrous dichloromethane (100 mL), followed by the addition of triethylamine (7.48 g, 74.1 mmol) and di-tert-butyl dicarbonate (16.0 g, 74.1 mmol). The reaction solution was reacted at room temperature for 16 hours. The reaction solution was washed successively with water (50 mL × 2) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (ethyl acetate / dichloromethane = 0 to 20%) to obtain the title product, tert-butyl 5-amino-3-bromo-1H-pyrazole-1-carboxylate, Example 61-1 (14.5 g), yield: 89.5%. MS: m / z (ESI): 262.0 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 6.62 (s, 2H), 5.41 (s, 1H), 1.56 (s, 9H).

[0281] Step 2: Preparation of tert-butyl 5-amino-3-bromo-1H-pyrazole-1-carboxylate [ka]

[0282] Tert-butyl 5-amino-3-bromo-1H-pyrazole-1-carboxylate, Example 61-1 (14.5 g, 55.3 mmol), was dissolved in anhydrous dichloromethane (200 mL), followed by the addition of triethylamine (18.5 g, 183 mmol). A solution (50 mL) of freshly prepared 2-chloro-6-(trifluoromethyl)nicotinoyl chloride (13.0 g, 61.0 mmol) in dichloromethane was added dropwise at 0 °C under a nitrogen atmosphere. After the addition was complete, the reaction solution was allowed to react at room temperature for 30 minutes. The reaction solution was washed successively with water (200 mL × 2) and saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether=0 to 20%) to obtain tert-butyl 5-amino-3-bromo-1H-pyrazole-1-carboxylate Example 61-2 (9.5 g), yield: 38.2%. MS: m / z (ESI): 371.0 [M-Boc+H] + 1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.40 (d, J = 7.6 Hz, 1H), 8.14 (d, J = 7.6 Hz, 1H), 6.96 (s, 1H), 1.58 (s, 9H).

[0283] Step 3: Preparation of N-(3-bromo-1H-pyrazol-5-yl)-2-chloro-6-(trifluoromethyl)nicotinamide [ka]

[0284] Tert-butyl 5-amino-3-bromo-1H-pyrazole-1-carboxylate, Example 61-2 (8.0 g, 17.1 mmol), was dissolved in anhydrous dichloromethane (20 mL), followed by the addition of a solution of hydrochloric acid in dioxane (4 M, 40 mL). The reaction solution was reacted at room temperature for 4 hours. The reaction solution was directly concentrated to dryness by rotary evaporation to give N-(3-bromo-1H-pyrazol-5-yl)-2-chloro-6-(trifluoromethyl)nicotinamide, Example 61-3 (6.2 g), yield: 98.4%. MS: m / z (ESI): 368.9 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 11.50 (s, 1H), 8.39 (d, J = 7.6 Hz, 1H), 8.10 (d, J = 7.6 Hz, 1H), 6.53 (s, 1H).

[0285] Step 4: Preparation of 2-bromo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-5(4H)-one [ka]

[0286] N-(3-bromo-1H-pyrazol-5-yl)-2-chloro-6-(trifluoromethyl)nicotinamide (Example 61-3) (6.2 g, 16.8 mmol) was dissolved in N,N-dimethylformamide (80 mL), followed by the addition of potassium carbonate (6.96 g, 50.4 mmol). The reaction solution was heated to 120 ° C and reacted for 2 hours. The reaction solution was cooled to room temperature and used directly in the next step. MS: m / z (ESI): 333.0 [M+H] +

[0287] Step 5: Preparation of 2-(2-bromo-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0288] Potassium carbonate (6.96 g, 50.4 mmol) and 2-bromo-N-(5-fluoropyridin-2-yl)acetamide (4.7 g, 20.2 mmol) were added to a reaction solution of 2-bromo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-5(4H)-one (Example 61-4) (Na, 16.8 mmol) in N,N-dimethylformamide (80 mL) and reacted at 40 ° C. for 2 hours. The reaction solution was cooled to room temperature, poured into 300 mL of water, and extracted with ethyl acetate (200 mL × 3). The organic phases were combined, washed successively with water (200 mL × 2) and saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was recrystallized from ethyl acetate to give the title product, 2-(2-bromo-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide, Example 61-A. 1 H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.84 (d, J = 8.0 Hz, 1H), 8.37 (s, 1H), 8.09 (d, J = 8.0 Hz, 1H), 8.07 - 8.02 (m, 1H),7.80 - 7.73 (m, 1H), 6.78 (s, 1H), 4.96 (s, 2H). MS m / z (ESI): 486.2 [M+H] + .

[0289] Step 6: Preparation of tert-butyl 3-(4-(2-(((5-fluoropyridin-2-yl)amino)-2-oxoethyl)-5-oxo-8-(trifluoromethyl)-4,5-dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-2-yl)azetidine-1-carboxylate [ka]

[0290] Zinc dust (<10 μM, 20.3 g) was stirred with 1 M HCl (100 mL). After 2 h, the suspension was filtered, and the resulting solid was washed with water (×2), then ethanol (×2), and finally ether (×2). The solid was dried under vacuum and stored under a nitrogen atmosphere. Zinc dust (washed, 0.60 g, 9.16 mmol) was vigorously stirred in dimethylacetamide (4 mL) under a nitrogen atmosphere, and the resulting suspension was heated to 65 °C. Trimethylchlorosilane (0.12 g, 0.14 mL, 1.14 mmol) and 1,2-dibromoethane (0.098 mL, 1.14 mmol) were added, and the reaction solution was stirred for 40 min. A solution of tert-butyl 3-iodoazetidine-1-carboxylate (2.0 g, 7.06 mmol) in dimethylacetamide (4 mL) was added dropwise to the reaction mixture within 0.5 h. The resulting suspension was stirred at 65° C. for 0.5 hours and then cooled to room temperature. The reaction mixture was used in the next step without further treatment. A solution of Example 2 (200 mg, 0.41 mmol) and Pd(dppf)Cl (33 mg, 0.04 mmol) in DMA (3 mL) was added to the above solution, heated to 85° C., and reacted for 16 hours. The mixture was worked up to give Example 61-B (100 mg, 43%). MS m / z (ESI): 562.17 [M+H] + .

[0291] Step 7: Preparation of 2-(2-(azetidin-3-yl)-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0292] 4M / L HCl / methanol (6 mL) was added to a solution of Example 61-B (100 mg, 0.18 mmol) in DCM (2 mL). The reaction solution was stirred at room temperature for 2 hours. The reaction solution was directly concentrated to dryness by rotary evaporation to give Example 61-C (80 mg, 97%). MS m / z (ESI): 462.17 [M+H] + .

[0293] Step 8: Preparation of 2-(2-(1-(2,2-difluoroethyl)azetidin-3-yl)-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0294] Potassium carbonate (46 mg, 0.33 mmol) and difluoroiodoethane (42 mg, 0.22 mmol) were added to a solution of Example 61-C (50 mg, 0.11 mmol) in DMF (5 mL) at room temperature. The mixture was heated to 40° C. and stirred for 2 hours. The reaction solution was cooled, followed by the addition of water. The precipitate was filtered, washed with ethyl acetate, and purified to give Example 61 (26 mg, yield: 46%). MS m / z (ESI): 526.4 [M+H] + .

[0295] Example 62 2-(2-Cyclohexyl-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0296] Example 62 was synthesized according to the synthesis method of Example 4. The title compound, Example 62 (15 mg, 31%), was obtained. MS m / z (ESI): 489.5 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.74 (d, J = 8.0 Hz, 1H), 8.33 (s, 1H), 8.04 - 7.93 (m, 2H), 7.72 (t, J = 9.1 Hz, 1H), 6.36 (s, 1H), 4.91 (s, 2H), 2.69 (s, 1H), 1.90 (d, J = 12.5 Hz, 3H), 1.70 (dd, J = 34.4, 12.4 Hz, 3H), 1.40 (td, J = 24.5, 12.0 Hz, 4H).

[0297] Example 63 N-(5-fluoropyridin-2-yl)-2-(2-(3-methylpyridin-4-yl)-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)acetamide [ka]

[0298] Example 63 was synthesized according to the synthesis method of Example 1. The title compound, Example 63 (15 mg, 30%), was obtained. MS m / z (ESI): 498.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.95 - 8.74 (m, 3H), 8.38 (s, 1H), 8.27 - 8.00 (m, 3H), 7.76 (t, J = 9.0 Hz, 1H), 7.25 (s, 1H), 5.09 (s, 2H), 2.72 (s, 3H).

[0299] Example 64 N-(5-fluoropyridin-2-yl)-2-(2-(2-methylpyridin-3-yl)-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)acetamide [ka]

[0300] Example 64 was synthesized according to the synthesis method of Example 1. The title compound, Example 64 (15 mg, 30%), was obtained. MS m / z (ESI): 498.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.90 - 8.62 (m, 3H), 8.36 (s, 1H), 8.15 - 7.99 (m, 2H), 7.93 - 7.68 (m, 2H), 7.11 (s, 1H), 5.08 (s, 2H), 2.96 (s, 3H).

[0301] Example 65 2-(2,4-dimethylpyridin-3-yl)-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0302] Example 65 was synthesized according to the synthesis method of Example 1. The title compound, Example 65 (10 mg, 33%), was obtained. MS m / z (ESI): 512.4 [M+H] + .

[0303] Example 66 N-(5-fluoropyridin-2-yl)-2-(5-oxo-2,8-bis(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)acetamide [ka]

[0304] Example 66 was synthesized according to the synthesis method of Example 1. The title compound, Example 66 (10 mg, 33%), was obtained. MS m / z (ESI): 475.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.91 (d, J = 8.0 Hz, 1H), 8.37 (d, J = 3.1 Hz, 1H), 8.19 (d, J = 8.1 Hz, 1H), 8.14 - 7.98 (m, 1H), 7.76 (t, J = 8.8 Hz, 1H), 7.13 (s, 1H), 5.04 (s, 2H).

[0305] Example 68 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0306] Step 1: Preparation of 2-(2-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0307] Example 61-A (300 mg, 0.619 mmol), Zn(CN) (300 mg, 2.56 mmol), Pd(dba) (20 mg, 0.022 mmol), Pd(dppf)Cl (30 mg, 0.036 mmol), and Zn powder (10 mg, 0.154 mmol) were dissolved in DMA (10 mL) at room temperature and then purged with nitrogen for 2 minutes. The reaction solution was heated to 140 °C in a microwave oven and reacted for 8 hours. The reaction solution was cooled to room temperature and extracted with ethyl acetate (50 mL). The organic phase was washed twice with saturated brine. The organic phase was dried (NaSO), concentrated under reduced pressure, and purified by p-HPLC (FA) to give 100 mg of the title compound (yield: 38%). 1 H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.92 (d, J = 8.2 Hz, 1H), 8.37 (d, J = 3.1 Hz, 1H), 8.22 (d, J = 7.9 Hz, 1H), 8.05 (s, 1H), 7.77 (t, J = 8.6 Hz, 1H), 7.24 (s, 1H), 5.01 (s, 2H). MS m / z (ESI): 432.3 [M+H] + .

[0308] Example 69 N-(5-fluoropyridin-2-yl)-2-(2-(2-hydroxypropan-2-yl)-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)acetamide [ka]

[0309] Step 1: Preparation of N-(5-fluoropyridin-2-yl)-2-(2-(2-hydroxypropan-2-yl)-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)acetamide [ka]

[0310] Example 69-1 (100 mg, 0.22 mmol) (Example 69-1 was synthesized according to the procedure of Example 6) was dissolved in dimethoxyethane (2 ml) / MeOH (2 ml) at 25° C., followed by the sequential addition of cobalt(II) isotetraphenylporphyrin (1.3 mg, 0.002 mmol) and tetraethylammonium borohydride (80.2 mg, 0.55 mmol). The reaction mixture was stirred for 1.25 hours. The reaction was stopped and quenched with saturated aqueous ammonium chloride solution (50 mL). The mixture was extracted with ethyl acetate (3×40 mL). The combined organic phase was washed with saturated aqueous sodium chloride solution (1×80 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to remove the solvent. The crude product was purified to give the title compound (42 mg, yield: 42%). MS m / z (ESI): 465.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.07 (s, 1H), 8.81 (d, J = 7.9 Hz, 1H), 8.37 (s, 1H), 8.12 - 7.92 (m, 2H), 7.76 (s, 1H), 6.44 (s, 1H), 4.99 (s, 2H), 1.51 (s, 6H).

[0311] Example 70 N-(5-fluoropyridin-2-yl)-2-(2-isobutyl-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)acetamide [ka]

[0312] Example 70 was synthesized according to the method of Example 1. The target compound (26 mg, yield: 26%) was obtained by replacing 3-(tert-butyl)-1H-pyrazol-5-amine with 3-(isobutyl)-1H-pyrazol-5-amine. MS m / z (ESI): 463.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.79 (d, J = 8.0 Hz, 1H), 8.37 (s, 1H), 8.07 - 8.03 (m, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.78 - 7.73 (m, 1H), 6.33 (s, 1H), 4.96 (s, 2H), 2.55 (d, J = 8.2 Hz, 2H), 2.04 - 1.93 (m, 1H), 0.95 (d, J = 6.4 Hz, 6H).

[0313] Example 71 N-(5-fluoropyridin-2-yl)-2-(2-morpholino-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)acetamide [ka]

[0314] Example 71 was synthesized according to the method of Example 1. The target compound (14 mg, yield: 35%) was obtained by replacing 3-(tert-butyl)-1H-pyrazol-5-amine with 3-(morpholinyl)-1H-pyrazol-5-amine. MS m / z (ESI): 492.4 [M+H] + .

[0315] Example 74 2-(2-(azetidine-1-carbonyl)-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0316] Step 1: Preparation of 2-(2-(azetidine-1-carbonyl)-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0317] DIPEA (0.1 mL, 0.6 mmol) was added to a solution of Example 74-1 (100 mg, 0.22 mmol) (Example 74-1 was synthesized according to Example 8-3) and HATU (83.4 mg, 0.22 mmol) in DMF (2 mL). The mixture was stirred at room temperature for 30 minutes, followed by the addition of azetidine (12.5 mg, 0.22 mmol). The reaction solution was stirred at room temperature for 18 hours. Water (40 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (2 × 20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified to give Example 74 (56 mg, yield: 52%). MS m / z (ESI): 490.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.86 (d, J = 8.1 Hz, 1H), 8.37 (s, 1H), 8.15 - 8.08 (m, 1H), 8.04 (s, 1H), 7.75 (t, J = 9.4 Hz, 1H), 6.81 (s, 1H), 5.04 (s, 2H), 4.68 - 4.52 (m, 2H), 4.08 (t, J = 7.5 Hz, 2H), 2.34 (d, J = 9.1 Hz, 2H).

[0318] Example 78 N-(5-fluoropyridin-2-yl)-2-(5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)acetamide [ka]

[0319] Step 1: 2-chloro-N-(1H-pyrazol-5-yl)-6-(trifluoromethyl)nicotinamide Preparation of [ka]

[0320] 1H-Pyrazol-5-amine (1.66 g, 19.93 mmol), DIPEA (6.2 g, 49.8 mmol), and HATU (5.4 g, 0.144 mmol) were added successively to a solution of 2-chloronicotinic acid (1.57 g, 9.96 mmol) in DMF (30 mL) under ice bath conditions. The ice bath was removed, and the reaction solution was stirred for 1 hour. The mixture was worked up to give Example 78-1 (2.0 g, 90%). MS m / z (ESI): 291.0 [M+H] + .

[0321] Step 2: 8-(Trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-5(4H)-one Preparation of [ka]

[0322] Potassium carbonate (1.61 g, 11.66 mmol) and 1,4-diazabicyclo[2.2.2]octane (DABCO) (150.9 mg, 1.35 mmol) were added to a solution of Example 78-1 (2.0 g, 8.97 mmol) in DMF (50 mL). The reaction solution was stirred at room temperature for 16 hours. The mixture was worked up to give Example 78-2 (1.6 g, 97%). MS m / z (ESI): 255.0[M+H] + .

[0323] Step 3: N-(5-fluoropyridin-2-yl)-2-(5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)acetamide Preparation of [ka]

[0324] Potassium carbonate (2.23 g, 16.11 mmol) and Example 1-3 (2.25 g, 9.67 mmol) were added to a solution of Example 78-2 (1.5 g, 8.06 mmol) in DMF (30 mL) at room temperature. The mixture was heated to 80° C. and stirred for 2 hours. The reaction solution was cooled, followed by the addition of water. The precipitate was filtered, washed with ethyl acetate, and purified to give Example 78 (2.1 g, yield: 78%). 1 H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.83 (d, J = 8.0 Hz, 1H), 8.37 (d, J = 3.2 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 8.05 - 8.02 (m, 1H), 7.98 (d, J = 2.0 Hz, 1H), 7.78 - 7.73 (m, 1H), 6.46 (s, 1H), 5.00 (s, 2H). MS m / z (ESI): 407.3 [M+H] + .

[0325] Example 79 2-(2-chloro-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0326] Example 79 was synthesized according to the method of Example 1. The target compound (31 mg, yield: 26%) was obtained by replacing 3-(tert-butyl)-1H-pyrazol-5-amine with 3-chloro-1H-pyrazol-5-amine. 1 H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.84 (d, J = 8.1 Hz, 1H), 8.36 (s, 1H), 8.15 - 7.99 (m, 2H), 7.76 (t, J = 9.0 Hz, 1H), 6.73 (s, 1H), 4.96 (s, 2H). MS m / z (ESI): 441.7 [M+H] + .

[0327] Example 80 2-(3-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0328] Example 80 was synthesized according to the method of Example 1. The target compound was obtained by replacing 3-(tert-butyl)-1H-pyrazol-5-amine with 4-cyano-1H-pyrazol-5-amine.

[0329] Step 1: tert-Butyl 3 Preparation of 4-amino-4-cyano-1H-pyrazole-1-carboxylate [ka]

[0330] 5-Amino-1H-pyrazole-4-carbonitrile (2.0 g, 18.5 mmol) was dissolved in anhydrous dichloromethane (40 mL), followed by the addition of triethylamine (3.74 g, 37.0 mmol) and di-tert-butyl dicarbonate (4.44 g, 20.4 mmol). The reaction solution was reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and slurried in petroleum ether (50 mL) to give the title product, tert-butyl 3-amino-4-cyano-1H-pyrazole-1-carboxylate, Example 80-1 (3.5 g), yield: 90.9%. 1 H NMR (400 MHz, DMSO-d6) δ 7.77 (s, 1H), 7.63 (s, 2H), 1.56 (s, 9H).

[0331] Step 2: Preparation of tert-butyl 3-(2-chloro-6-(trifluoromethyl)nicotinamido)-4-cyano-1H-pyrazole-1-carboxylate [ka]

[0332] Tert-butyl 3-amino-4-cyano-1H-pyrazole-1-carboxylate, Example 80-1 (3.5 g, 16.8 mmol), was dissolved in anhydrous dichloromethane (50 mL), followed by the addition of triethylamine (5.35 g, 7.37 mmol). A solution of freshly prepared 2-chloro-6-(trifluoromethyl)nicotinoyl chloride (4.3 g, 17.6 mmol) in dichloromethane (50 mL) was added dropwise at 0 °C under a nitrogen atmosphere. After the addition was complete, the reaction solution was allowed to react at room temperature for 1 hour. The reaction solution was washed successively with water (50 mL × 2) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0 to 40%) to obtain tert-butyl 3-(2-chloro-6-(trifluoromethyl)nicotinamide)-4-cyano-1H-pyrazole-1-carboxylate Example 80-2 (2.8 g), yield: 38.2%. MS: m / z (ESI): 432.8 [M+NH4] + 1 H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 9.23 (s, 1H), 8.43 (d, J = 7.6 Hz, 1H), 8.13 (d, J = 7.6 Hz, 1H), 1.59 (s, 9H).

[0333] Step 3: Preparation of 2-chloro-N-(4-cyano-1H-pyrazol-5-yl)-6-(trifluoromethyl)nicotinamide [ka]

[0334] Tert-butyl 3-(2-chloro-6-(trifluoromethyl)nicotinamide)-4-cyano-1H-pyrazole-1-carboxylate, Example 80-2 (2.8 g, 6.73 mmol), was dissolved in anhydrous dichloromethane (10 mL), followed by the addition of a solution of hydrochloric acid in dioxane (4 M, 30 mL). The reaction solution was reacted at room temperature for 5 hours. The reaction solution was directly concentrated to dryness by rotary evaporation to give 2-chloro-N-(4-cyano-1H-pyrazol-5-yl)-6-(trifluoromethyl)nicotinamide, Example 80-3 (2.1 g), yield: 98.8%. MS: m / z (ESI): 315.8 [M+H] +

[0335] Step 4: Preparation of 5-oxo-8-(trifluoromethyl)-4,5-dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-3-carbonitrile [ka]

[0336] 2-Chloro-N-(4-cyano-1H-pyrazol-5-yl)-6-(trifluoromethyl)nicotinamide, Example 80-3 (2.1 g, 6.65 mmol), was dissolved in N,N-dimethylformamide (40 mL), followed by the addition of potassium carbonate (1.84 g, 13.3 mmol). The reaction solution was heated to 120 °C and reacted for 2 hours. The reaction solution was cooled to room temperature, adjusted to pH 5-6 with 1 M dilute hydrochloric acid, and extracted with ethyl acetate (100 mL × 2). The organic phases were combined, washed successively with water (100 mL × 2) and saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and slurried in ethyl acetate (15 mL) to give 5-oxo-8-(trifluoromethyl)-4,5-dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-3-carbonitrile Example 80-4 (1.3 g), yield: 69.9%. MS: m / z (ESI): 279.8 [M+H] +

[0337] Step 4: Preparation of 2-(3-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide [ka]

[0338] 5-Oxo-8-(trifluoromethyl)-4,5-dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-3-carbonitrile, Example 80-4 (500 mg, 1.79 mmol), was dissolved in N,N-dimethylformamide (20 mL), followed by the addition of potassium carbonate (371 mg, 2.69 mmol) and 2-bromo-N-(5-fluoropyridin-2-yl)acetamide (501 mg, 2.15 mmol). The reaction solution was reacted at 40 °C for 2 hours. The reaction solution was cooled to room temperature, poured into 100 mL of water, and extracted with ethyl acetate (50 mL × 2). The combined organic phase was washed successively with water (50 mL × 2) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was slurried in ethyl acetate. The resulting mother liquor was concentrated under reduced pressure and purified by reverse HPLC to give the title product 2-(3-cyano-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)-N-(5-fluoropyridin-2-yl)acetamide, Example 80. MS m / z (ESI): 432.3[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.2 (s, 1H), 8.93 (d, J = 8.0 Hz, 1H), 8.58 (s, 1H), 8.38 (d, J = 3.2 Hz, 1H), 8.20 (d, J = 8.0 Hz, 1H), 8.07 - 8.04 (m, 1H), 7.81 - 7.75 (m, 1H), 5.19 (s, 2H).

[0339] Example 81 4-(2-((5-fluoropyridin-2-yl)amino)-2-oxoethyl)-N-methyl-5-oxo-8-(trifluoromethyl)-4,5-dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-2-carboxamide [ka]

[0340] Example 81 was synthesized according to the method of Example 74. The target compound (48 mg, yield: 61%) was obtained by replacing azacyclobutylamine with methylamine. MS m / z (ESI): 464.1[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.88 (d, J = 8.0 Hz, 1H), 8.53 (d, J = 5.4 Hz, 1H), 8.37 (s, 1H), 8.13 (d, J = 8.1 Hz, 1H), 8.04 (s, 1H), 7.76 (t, J = 8.9 Hz, 1H), 6.84 (s, 1H), 5.05 (s, 2H), 2.80 (d, J = 4.6 Hz, 3H).

[0341] Example 82 N-(5-fluoropyridin-2-yl)-2-(2-(hydroxymethyl)-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)acetamide [ka]

[0342] Step 1: Preparation of N-(5-fluoropyridin-2-yl)-2-(2-(hydroxymethyl)-5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)acetamide [ka]

[0343] Diisobutylaluminum hydride (1 M in toluene, 0.66 mL, 0.66 mmol) was added to a solution of Example 82-1 (100 mg, 0.22 mmol) (Example 82-1 was synthesized according to Example 8-2) in THF (2 mL) at 0° C. The mixture was stirred at room temperature overnight. Rochelle's salt solution (1.0 M, 5 mL) was added, followed by ethyl acetate (5 mL). The resulting suspension was stirred at room temperature until a clear phase separation was achieved. The organic phase was separated, and the aqueous phase was extracted with EtOAc (3×40 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified to give the target compound (32 mg, yield: 34%). MS m / z (ESI): 437.1[M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.06 (s, 1H), 8.82 (d, J = 7.9 Hz, 1H), 8.37 (s, 1H), 8.02 (m, 2H), 7.76 (s, 1H), 6.40 (s, 1H), 5.44 (s, 1H), 5.00 (s, 2H), 4.56 (s, 2H).

[0344] Example 83 N-(5-chloropyridin-2-yl)-2-(5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)acetamide [ka]

[0345] Example 83 was synthesized according to the method of Example 78. The target compound (23 mg, yield: 54%) was obtained by replacing 5-fluoropyridin-2-amine with 5-chloropyridin-2-amine. MS m / z (ESI): 423.1[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 8.84 (d, J = 8.0 Hz, 1H), 8.42 (d, J = 2.6 Hz, 1H), 8.05 (t, J = 9.3 Hz, 2H), 7.99 - 7.89 (m, 2H), 6.47 (d, J = 2.0 Hz, 1H), 5.02 (s, 2H).

[0346] Example 84 N-(5-chloropyrimidin-2-yl)-2-(5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)acetamide [ka]

[0347] Example 84 was synthesized according to the method of Example 78. The target compound (21 mg, yield: 53%) was obtained by replacing 5-fluoropyridin-2-amine with 5-chloropyrimidin-2-amine. MS m / z (ESI): 424.1[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.29 (s, 1H), 8.95 - 8.72 (m, 3H), 8.06 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 2.0 Hz, 1H), 6.46 (d, J = 2.0 Hz, 1H), 5.16 (s, 2H).

[0348] Example 85 N-(3,5-difluoropyridin-2-yl)-2-(5-oxo-8-(trifluoromethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-4(5H)-yl)acetamide [ka]

[0349] Example 85 was synthesized according to the method of Example 78. The target compound (25 mg, yield: 46%) was obtained by replacing 5-fluoropyridin-2-amine with 3,5-difluoropyridine. MS m / z (ESI): 425.1[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.32 (s, 1H), 8.82 (d, J = 8.0 Hz, 1H), 8.56 (dd, J = 10.2, 2.2 Hz, 1H), 8.12 - 7.91 (m, 3H), 6.45 (d, J = 2.0 Hz, 1H), 5.01 (s, 2H).

[0350] Biological Assays and Evaluation The present invention is further illustrated below in conjunction with the following test examples, which are not intended to limit the scope of the invention.

[0351] Test Example 1. Determination of the effect of compounds of the present invention on calcium ion mobility in cells stably expressing 1321N1-hP2X3 receptors Objective of the experiment: To determine the inhibitory activity of compounds on 1321N1-hP2X3 receptors.

[0352] Experimental equipment: 384-well cell plate (Corning; 3712); 384-well compound plate (Corning; 3657); 384-well assay plate (LABCYTE; P-05525); FLIPR (Molecular Devices).

[0353] Experimental Reagents: DMEM (Gibco; 11965); FBS (Gibco; 10099-141); hygromycin B (Invitrogen, 10687010); Matrix (Thermo; 5416); DMSO (Sigma; D2650); HBSS (Invitrogen; 14025); HEPES (Invitrogen; 15630080); probenecid (Sigma; P8761); Versene (Gibco; 15040066); G418 (Sigma; G5013); FLIPR® Calcium 4 Assay Kit (Molecular Devices; R8141); α,β-meATP (Sigma; M6517); ATP hydrolase (Sigma; A7646); Stably transfected cell line: 1321N1-hP2X3 (supplied by Shanghai ChemPartner Chemical Research Co., Ltd.).

[0354] Experimental Method: 1. Reagent composition: Assay buffer: 1x HBSS + 20mM HEPES; Cell culture medium: DMEM + 10% FBS + 75 μg / mL hygromycin B + 300 μg / mL G418; Plating medium: DMEM+10%DPBS; 0.5x dye: 10x dye stock + 1.25 probenecid + 1x assay buffer + 0.5U / mL ATP hydrolase;

[0355] 2. Cells were grown in cell culture medium at 37°C and 5% CO2 to 70%-90% confluency. The medium was discarded, the cells were added with 2 mL of Versene, and the cells were placed in an incubator at 37°C for 2 to 5 minutes. Cells were harvested and counted by adding 10 mL of plating medium to each well. 4 Cells were seeded into 384-well assay plates by addition of 1000 μl of PBS (density of cells / well) and incubated for 16 to 24 hours (at least overnight).

[0356] 3. The medium was discarded and 30 μL of 1× dye was added. The cells were incubated at 37° C. in the dark for 60 minutes.

[0357] 4. Compound powder was dissolved in DMSO to give a 20 mM stock solution. 180x compounds with the required concentration were formulated and diluted in a gradient for 10 concentration points.

[0358] 5. Compound Plate Preparation: 500 nL of 180x compound was transferred to the compound plate (source plate for FLIPR) using ECHO. 30 μL of assay buffer was added to each well and the plate was gently shaken for 20-40 minutes.

[0359] 6. Determination: 15 μL of 3× compound was taken from each well and added to the cell plate. The FLIPR instrument added the sample and detected the calcium signal. After 15 minutes, 22.5 μL of 3× agonist (EC 80 (concentration) was added to each well, and calcium signals were detected.

[0360] How to process experimental data: Calcium signal values ​​were determined by FLIPR. The ratio of the 340 / 510 nm wavelength signal to the 380 / 510 nm wavelength signal was used as the calculated result for each sampling time point in the experiment. The maximum minus minimum calculation was derived from the ratio signal curve.

[0361] Using GraphPad Prism, the percent inhibition and 10-point concentration data were fitted to a parametric nonlinear logistic equation to obtain the IC values ​​of the compounds. 50 The value was calculated.

[0362] Test Results: The results of the compounds of the examples of the present invention in the 1321N1-hP2X3 receptor cell functional calcium ion mobility assay are shown in Table 1: [Table 1]

[0363] Testing Conclusion: The above data indicate that the compounds of the present invention exhibit good inhibitory effects in the 1321N1-hP2X3 receptor cell functional calcium ion mobility assay.

[0364] Test Example 2. Determination of the effect of compounds of the present invention on calcium ion mobility in cells stably expressing 1321N1-hP2X2 / 3 receptors Objective of the experiment: 1321N1-To determine the inhibitory activity of compounds on hP2X2 / 3 receptors.

[0365] Experimental equipment: 384-well cell plate (Corning; 3712); 384-well compound plate (Corning; 3657); 384-well assay plate (LABCYTE; P-05525); FLIPR (Molecular Devices).

[0366] Experimental Reagents: DMEM (Gibco; 11965); FBS (Gibco; 10099-141); hygromycin B (Invitrogen, 10687010); Matrix (Thermo; 5416); DMSO (Sigma; D2650); HBSS (Invitrogen; 14025); HEPES (Invitrogen; 15630080); probenecid (Sigma; P8761); Versene (Gibco; 15040066); G418 (Sigma; G5013); FLIPR® Calcium 4 Assay Kit (Molecular Devices; R8141); α,β-meATP (Sigma; M6517); ATP hydrolase (Sigma; A7646); Stably transfected cell line: 1321N1-hP2X2 / 3 (supplied by Shanghai ChemPartner Chemical Research Co., Ltd.).

[0367] Experimental Method: 1. Reagent composition: Assay buffer: 1x HBSS + 20mM HEPES; Cell culture medium: DMEM + 10% FBS + 75 μg / mL hygromycin B + 150 μg / mL G418; Plating medium: DMEM+10%DPBS; 0.5x dye: 10x dye stock + 1.25 probenecid + 1x assay buffer + 0.5U / mL ATP hydrolase;

[0368] 2. Cells were grown in cell culture medium at 37°C and 5% CO2 to 70%-90% confluency. The medium was discarded, the cells were added with 2 mL of Versene, and the cells were placed in an incubator at 37°C for 2 to 5 minutes. Cells were harvested and counted by adding 10 mL of plating medium to each well. 4 Cells were seeded into 384-well assay plates by addition of 1000 μl of PBS (density of cells / well) and incubated for 16 to 24 hours (at least overnight).

[0369] 3. The medium was discarded and 30 μL of 1× dye was added. The cells were incubated at 37° C. in the dark for 60 minutes.

[0370] 4. Compound powder was dissolved in DMSO to give a 20 mM stock solution. 180x compounds with the required concentration were formulated and diluted in a gradient for 10 concentration points.

[0371] 5. Compound Plate Preparation: 500 nL of 180x compound was transferred to the compound plate (source plate for FLIPR) using ECHO. 30 μL of assay buffer was added to each well and the plate was gently shaken for 20-40 minutes.

[0372] 6. Determination: 15 μL of 3× compound was taken from each well and added to the cell plate. The FLIPR instrument added the sample and detected the calcium signal. After 15 minutes, 22.5 μL of 3× agonist (EC 80 (concentration) was added to each well, and calcium signals were detected.

[0373] How to process experimental data: Calcium signal values ​​were determined by FLIPR. The ratio of the 340 / 510 nm wavelength signal to the 380 / 510 nm wavelength signal was used as the calculated result for each sampling time point in the experiment. Maximum minus minimum calculations were derived from the ratio signal curve.

[0374] Using GraphPad Prism, the percent inhibition and 10-point concentration data were fitted to a parametric nonlinear logistic equation to obtain the IC values ​​of the compounds. 50 The value was calculated.

[0375] Test Results: The results of the compounds of the examples of the present invention in the 1321N1-hP2X2 / 3 receptor cell functional calcium ion mobility assay are shown in Table 2: [Table 2]

[0376] Testing Conclusion: The above data indicate that the compounds of the present invention exhibit weak inhibitory effects in the 1321N1-h2X2 / 3 receptor cell functional calcium ion mobility assay.

[0377] Test Example 3. Pharmacokinetic assay in Balb / C mice 1. Research purpose: Balb / C mice were used as test animals. The pharmacokinetic behavior of the compounds of the examples was studied in mice (plasma) by oral administration at a dose of 5 mg / kg.

[0378] 2. Experimental Protocol 2.1 Test Compounds: Examples of compounds of the present invention prepared by the applicant.

[0379] 2.2 Test animals: Male Balb / C mice (6 mice per group) were purchased from Shanghai Jiesijie Laboratory Animal Co., LTD, certificate number: SCXK (Shanghai) 2013-0006 N0.311620400001794.

[0380] 2.3 Compound Formulation: 5 g of hydroxyethyl cellulose (HEC, CMC-Na, viscosity: 800-1200 Cps) was weighed and dissolved in 1000 mL of purified water, followed by the addition of 10 g of Tween 80. The mixture was thoroughly mixed to obtain a clear solution.

[0381] 2.4 Administration: After an overnight fast, male Balb / C mice were orally administered test compounds at a dose of 5 mg / kg in a volume of 10 mL / kg.

[0382] 2.5 Sample Collection: 0.04 mL of blood was drawn from the orbit of each mouse before administration and at 0, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. The samples were stored in EDTA-K2 tubes and centrifuged at 6000 rpm for 6 minutes at 4°C to separate the plasma. The plasma samples were stored at -80°C.

[0383] 2.6 Sample Process: 1) 160 μL of acetonitrile was added to 20 μL of plasma sample for precipitation, and then the mixture was centrifuged at 3500×g for 5 to 20 minutes.

[0384] 2) After the above process, 100 μL of the supernatant was taken and analyzed for the concentration of the test compound by LC / MS / MS.

[0385] 2.7 Liquid Chromatography Analysis Liquid chromatography conditions: Shimadzu Corporation LC-20AD pump · Mass spectrometry conditions: AB Sciex API4000 mass spectrometer Chromatography column: Phenomenex Gemiu 5um C18 50 x 4.6mm Mobile phase: Eluent A was 0.1% formic acid in water, and Eluent B was acetonitrile · Flow rate: 0.8mL / min Elution time: 0-4.0 min. Eluent: [Table 3]

[0386] 3. Experimental results and analysis The main pharmacokinetic parameters were calculated by WinNonlin 8.2. The results of the pharmacokinetic study in mice are shown in Table 3 below: [Table 4]

[0387] Testing Conclusion: From the results of the pharmacokinetic test in mice in the table, the compounds of the examples of the present invention exhibited good pharmacokinetic properties, and the exposure AUC and maximum plasma concentration C max It can be seen that both are good.

[0388] Test Example 4. Pharmacokinetic assay in rats 1. Research purpose: SD rats were used as test animals. The pharmacokinetic behavior of the compounds of the examples was studied in rats (plasma) by oral administration at a dose of 5 mg / kg.

[0389] 2. Experimental Protocol 2.1 Test Compounds: Examples of compounds of the present invention prepared by the applicant.

[0390] 2.2 Test animals: Male SD rats (3 rats per group) were purchased from Shanghai Jiesijie Laboratory Animal Co., LTD, certificate number: SCXK (Shanghai) 2013-0006 N0.311620400001794.

[0391] 2.3 Compound Formulation: 5 g of hydroxyethyl cellulose (HEC, CMC-Na, viscosity: 800-1200 Cps) was weighed and dissolved in 1000 mL of purified water, followed by the addition of 10 g of Tween 80. The mixture was thoroughly mixed to obtain a clear solution.

[0392] 2.4 Administration: After an overnight fast, male SD rats (3 rats per group) were orally administered the test compound at a dose of 5 mg / kg and a volume of 10 mL / kg.

[0393] 2.5 Sample Collection: 0.2 mL of blood was drawn from the jugular vein of each rat before administration and at 0, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. The samples were stored in EDTA-K2 tubes and centrifuged at 6000 rpm for 6 minutes at 4°C to separate the plasma. The plasma samples were stored at -80°C.

[0394] 2.6 Sample Process: 1) 160 μL of acetonitrile was added to 40 μL of plasma sample for precipitation, and then the mixture was centrifuged at 3500×g for 5 to 20 minutes.

[0395] 2) After the above process, 100 μL of the supernatant was taken and analyzed for the concentration of the test compound by LC / MS / MS.

[0396] 2.7 Liquid Chromatography Analysis Liquid chromatography conditions: Shimadzu Corporation LC-20AD pump · Mass spectrometry conditions: AB Sciex API4000 mass spectrometer Chromatography column: Phenomenex Gemiu 5um C18 50 x 4.6mm Mobile phase: Eluent A was 0.1% formic acid in water, and Eluent B was acetonitrile · Flow rate: 0.8mL / min Elution time: 0-4.0 min. Eluent: [Table 5]

[0397] 3. Experimental results and analysis The main pharmacokinetic parameters were calculated by WinNonlin 8.2. The results of the pharmacokinetic study in rats are shown in Table 4 below: [Table 6]

[0398] 4. Experimental conclusion: From the results of the pharmacokinetic test in rats in the table, the compounds of the examples of the present invention showed good pharmacokinetic properties at a dose of 5 mg / kg, and the exposure AUC and maximum plasma concentration C max It can be seen that both are good.

[0399] Test Example 5. Metabolic stability assay in liver microsomes 1. Experimental Objective: The purpose of the experiment was to determine the stability of example compounds in mouse, rat, dog and human liver microsomes.

[0400] 2. Experimental Procedure: 2.1 Formulation of compound working solutions Formulation of compound working solutions: Compound stock solutions were added to phosphate buffer to a final concentration of 20 μM.

[0401] 2.2 Formulation of liver microsome working solution Liver microsomes were diluted with 100 mM phosphate buffer to give a final concentration of 0.625 mg / mL.

[0402] 2.3 Combination of NADPH and UDPGA NADPH (reduced nicotinamide adenine dinucleotide phosphate) and UDPGA (uridine diphosphate glucuronic acid) were weighed out, and then 100 mM phosphate buffer was added to the mixture to a final concentration of 20 mM.

[0403] 2.4 Formulation of channel-forming reagents 1 mg of alamethicin was weighed out and 200 μL of DMSO was added to give a 5 mg / mL solution, which was then diluted with phosphate buffer to give a final concentration of 50 μg / mL.

[0404] 2.5 Composition of the reaction stop solution Stop solution: cold acetonitrile containing 100 ng / mL labetalol hydrochloride and 400 ng / mL tolbutamide as internal standards.

[0405] 2.6 Incubation Procedure 400 μL of prepared liver microsomes, 25 μL of compound working solution, and 25 μL of alamethicin were added sequentially to a 96-well plate, which was then pre-incubated at 37° C. for 10 minutes. 50 μL of prepared NADPH / UDPGA was added to start the reaction, and the plate was incubated at 37° C. The total volume of the reaction system was 500 μL. The final contents of the components were as follows: [Table 7]

[0406] 2.7 Sample analysis 2.7.1 Chromatographic conditions: Equipment: Shimadzu Corporation LC-30AD; Chromatographic column: XBridge® C18 (50 × 4.6 mm, particle size: 5 μm); Mobile phase: A: 0.1% formic acid solution, B: methanol Eluent gradient: 0.2-1.6 min 5% A to 95% A, 3.0-3.1 min 95% A to 5% A Run time: 4.0 minutes.

[0407] 2.7.2 Mass spectrometry conditions: Instruments: API5500 liquid chromatography-mass spectrometer, AB Sciex; Ion source: electrospray ionization source (ESI); Drying gas: N2, temperature: 500℃; Electrospray voltage: 5000V; Detection method: cation detection; Scanning mode: reaction monitoring mode (MRM).

[0408] 3. Experimental results: [Table 8]

[0409] 4. Experimental conclusion: The above data show that the compounds of the examples of the present invention have good metabolic stability in liver microsomes of mice, rats, dogs and humans.

[0410] Test Example 6. Assay of plasma protein binding rate 1. Experimental Objective: The purpose of the experiment is to determine the plasma protein binding of the example compounds in plasma.

[0411] 2. Experimental equipment and materials: Liquid chromatography-mass spectrometer, centrifuge, vortex mixer, pipette, repeating pipette, 96-well plate, tissue homogenizer (used for tissue sample analysis), 50% methanol in water, acetonitrile solution containing internal standard, blank medium (plasma, urine, or tissue homogenate, etc.)

[0412] 3. Experimental Procedure: 3.1 Formulation of Test Compound Stock Solution A The example compounds were formulated in 1 mM solution A with DMSO;

[0413] 3.2 Plasma Solution B Formulation Solution A was added to the plasma solution to obtain 5 μM solution B;

[0414] 3.3 Operation Procedure 1) Add 200 μL of solution B to the inside of the membrane; 2) Add 350 μL of PBS to the outside of the membrane; 3) incubation in a water bath at 37°C for 6 hours; 4) The samples were diluted and analyzed by mass spectrometry.

[0415] 4. Chromatographic conditions: Equipment: Shimadzu Corporation LC-20AD; Chromatographic column: Phenomenex Gemiu® C18 (50 × 4.6 mm, particle size: 5 μm); Mobile phase: A: acetonitrile, B: 0.1% formic acid solution; 0–0.5 min: 5% A → 90% A, 2.0–2.1 min: 90% A → 5% A; flow rate: 0.8 mL / min; run time: 5.0 min; injection volume: 5 μL.

[0416] 5.Mass spectrometry conditions: Instruments: API4000 liquid chromatography-mass spectrometer, AB Co., USA; The ion source is an electrospray ionization source (ESI); The temperature of the dry gas (N2) was 500°C; The electrospray voltage was 5500 V; The detection method is positive ion detection; The scan mode was reaction monitoring mode (MRM); the scan time was 0.1 s.

[0417] 6. Experimental results: [Table 9]

[0418] 7. Experimental conclusion: The above data demonstrate that the compounds of the examples of the present invention have high plasma protein binding rates with little inter-species variation.

[0419] Test Example 7. CYP enzyme single-point inhibition assay 1. Purpose of the experiment The inhibition of compounds on CYP450 enzyme isoforms was rapidly predicted by a single-point method using a human liver microsome incubation system.

[0420] 2. Experimental Procedure 2.1 Solution formulation 2.5 mM NADPH: 4.165 mg of NADPH (reduced nicotinamide adenine dinucleotide phosphate) was weighed out, followed by adding 100 mM phosphate buffer to a volume of 2 mL. 0.25 mg / mL microsome solution: 4 mL of 100 mM phosphate buffer was added to 50 μL of 20 mg / mL microsome solution and mixed thoroughly.

[0421] Test compound reaction solution formulation: Test compounds of the examples were weighed and diluted to 10 mM in DMSO and then to 100 μM in 100 mM phosphate buffer.

[0422] 2.2 Experimental Procedure: 1. 40 μL of liver microsomes, 10 μL of substrate and 10 μL of test compound were added to a 96-well plate and pre-incubated for 3 minutes.

[0423] 2. 40 μL of NADPH was added.

[0424] 3. 300 μL of acetonitrile stop solution containing internal standard was added at 20 minutes.

[0425] 4. The sample was centrifuged and injected.

[0426] 3. Experimental results: [Table 10]

[0427] 4. Experimental conclusion: The above data demonstrate that the compounds of the examples of the present invention do not have strong inhibition on CYP enzyme isoforms and have a low risk of DDI.

[0428] Test Example 8. hERG potassium channel inhibitory activity assay 1. Cell preparation 7.1.1 CHO-hERG cells were cultured at 175 cm 2 The cells were cultured in a culture flask. After the cell density reached 60-80%, the culture medium was removed. The cells were washed once with 7 mL of PBS and dissociated with 3 mL of Detachin.

[0429] 7.1.2 After dissociation was complete, the cells were neutralized with 7 mL of culture medium. The solution was centrifuged and the supernatant was removed. The cells were resuspended in 5 mL of culture medium. The cell indensity was 2–5 × 10 6 / mL.

[0430] 2. Solution formulation [Table 11]

[0431] 3. Electrophysiological Recording Process Single cell sealing impedance and whole cell mode were automatically performed by the Qpatch instrument. After the whole cell recording mode was obtained, the cell was clamped at -80 mV. The cell was first subjected to a pre-voltage of -50 mV for 50 ms, then a depolarizing stimulus of +40 mV for 5 seconds, then a repolarizing stimulus of -50 mV for 5 seconds, and then the voltage was returned to -80 mV. The cell was subjected to this voltage stimulus every 15 seconds. Data was recorded for 2 minutes, then extracellular solution was administered, and data was recorded for 5 minutes. The administration process was then started. The test compound concentrations were administered starting from the lowest concentration, and each test concentration was administered for 2.5 minutes. At least three cells (n≧3) were tested for each concentration.

[0432] 4.Compound formulation 4.1 The 20 mM stock solution of the compound was diluted with extracellular solution. 2495 μL of extracellular solution was added to 5 μL of the 20 mM stock solution of the compound to obtain a concentration of 40 μM (500-fold dilution). The solution was subjected to a 3-fold serial dilution with extracellular solution containing 0.2% DMSO to obtain the required final concentration.

[0433] 4.2 The highest test concentration was 40 μM. The six concentrations were 40, 13.33, 4.44, 1.48, 0.49, and 0.16 μM.

[0434] 4.3 The DMSO content in the final test concentration did not exceed 0.2%. This concentration of DMSO had no effect on the hERG potassium channel.

[0435] 5. Data Analysis The experimental data were analyzed by XLFit software.

[0436] 6.Quality control Environment: Humidity 20~50%, temperature 22~25℃ Reagents: The reagents used were purchased from Sigma and were greater than 98% pure. The experimental data in the report must meet the following criteria: Whole cell sealing impedance >100MΩ Tail current amplitude >400pA Pharmacological parameters: The inhibitory effect of multiple concentrations of cisapride on the hERG channel was used as a positive control.

[0437] 7. Experimental results: [Table 12]

[0438] 8. Experimental conclusion: Drug-induced inhibition of cardiac hERG potassium channel is the main cause of drug-induced long QT syndrome. Experimental results show that the compounds of the present invention have no obvious inhibitory effect on cardiac hERG potassium channel. Therefore, cardiotoxic effects at high doses can be avoided.

[0439] Test Example 9. Taste sensitivity assay in BALB / c mice 1. Experimental Objective: In this assay, compounds with low toxicity and side effects on animal taste were screened using quinine bitter solution experiments.

[0440] 2. Main experimental equipment and materials 2.1 Equipment: 1. Ultra-clean workbench (CJ-2F, Suzhou Fengshi Laboratory Animal Equipment Co., Ltd.); 2.Electronic balance (CPA2202D, Sartorius); 3.Electronic balance (BSA2202S-CW, Sartorius); 4. Pure water manufacturer (Pacific TII, Thermo). 2.2 Reagents: Quinine monohydrochloride dihydrate (6119-47-7, Adamas). 2.3 Animals: BALB / c mice, 6 to 8 weeks old, male, were purchased from Shanghai SIPPR-BK Laboratory Animal Co., Ltd.

[0441] 3. Experimental Procedure: 3.1 Animal screening The day before the experiment, all BALB / c mice were weighed and animals that were too overweight or too underweight were excluded.

[0442] 3.2 Grouping and water restriction BALB / c mice were randomly divided into groups according to body weight and were water-deprived but not fasted for 12 to 16 hours before administration.

[0443] 3.3 Quinine aqueous solution formulation An appropriate amount of quinine monohydrochloride dihydrate was weighed and mixed with ultrapure water in an aqueous quinine hydrochloride solution (concentration: 3 mmol / L) for later use.

[0444] 3.4 Test Compound Formulation Appropriate amounts of test compounds were weighed and formulated according to the experimental design to the target concentration with the corresponding solvent for later use.

[0445] 3.5 Animal Dosing and Quinine Solution Intake Assay Dosing and fasting: On the day of the experiment, animals were weighed, fasted, bedding changed, and compounds were administered according to the experimental design.

[0446] Quinine Solution Uptake Assay: 1. A corresponding clean mouse drinking bottle was rinsed 2 to 3 times with ultrapure water and a formulated 3 mmol / L aqueous solution of quinine hydrochloride, respectively. The bottle was filled and weighed, and the mass was recorded as Wi0.

[0447] 2. According to the experimental design, at a certain period after administration, the filled bottle was gently placed into the corresponding mouse cage and timing was started. After 30 minutes, the bottle was gently removed and weighed, and the mass was recorded as Wi 30 was recorded as.

[0448] 3. Calculation of solution consumption of animals in each group: ΔWW (g) = Wi 30 -Wi0; Calculation of solution consumption of a single mouse: ΔpWW (g) = ΔWW / N, where N is the number of animals in each group.

[0449] 4. Taste disorder rate = (ΔpWW of the group whose drinking water was an aqueous solution of quinine hydrochloride and was simultaneously administered with the test compound - ΔpWW of the group whose drinking water was an aqueous solution of quinine hydrochloride and was simultaneously administered with the solvent control) / (ΔpWW of the group whose drinking water was ultrapure water and was simultaneously administered with the solvent control - ΔpWW of the group whose drinking water was an aqueous solution of quinine hydrochloride and was simultaneously administered with the solvent control) × 100%. Data processing was performed using software such as Excel.

[0450] 5. Animals were euthanized after completion of the experiment.

[0451] 4. Experimental results: [Table 13]

[0452] 5. Experimental conclusion: The above results show that the compounds of the present application have low toxicity and side effects on the taste of mice.

[0453] Test Example 10. Pharmacodynamic study on citric acid-induced acute cough in guinea pigs 1. Purpose of the experiment The purpose of this experiment was to evaluate the efficacy of compounds in the citric acid-induced acute cough model in guinea pigs.

[0454] 2. Laboratory equipment and reagents 2.1 Critical Equipment [Table 14]

[0455] 2.2 Key Reagents [Table 15]

[0456] 3. Experimental procedures and data processing: 3.1 Animals Hartley guinea pigs, male, were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. 3.2 Experimental procedure The animals were adaptively fed. After they reached a standard weight (300 to 400 g), they were given serial numbers and randomly divided into groups according to their weight.

[0457] Cough induction method: Guinea pigs were placed in a whole-body plethysmography box and allowed to adapt for 3 to 5 minutes. ATP nebulization was performed for 2 minutes. After a 3-minute interval, citric acid nebulization was performed for 5 minutes. From the beginning of citric acid nebulization, the number of coughs and cough latency of the animals were recorded within 10 minutes.

[0458] 3.3 Dosage Regimen and Cough Indicator Monitoring The test compound was administered to the guinea pigs by gavage once 2 hours before citric acid nebulization. The guinea pigs were placed in the respiratory plethysmography chamber of a DSI Buxco whole body plethysmography (WBP) at the designated time and subjected to cough induction by citric acid nebulization. From the beginning of citric acid nebulization, the total number of coughs (CCnt) and cough latency (CIP) of the guinea pigs within 10 minutes were recorded by the WBP system.

[0459] 3.4 Data Processing All data were entered into an Excel file and expressed as mean ± standard error. Data from each group were analyzed and compared by one-way ANOVA. Statistical analysis results showed p<0.05, indicating significant differences. Pairwise comparisons were performed using the t-test to compare differences.

[0460] The results show that the compounds of the examples of the present invention can effectively improve the symptoms of cough in the citric acid-induced acute cough model in guinea pigs, with a reduction rate of more than 59% in the total number of coughs.

Claims

1. A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, said compound having the formula (II): 【Chemistry 1】 [In the formula, L 1 is a bond, -(CH 2 ) n1 -, -(CH 2 ) n1 C(O)(CR aa R bb ) n2 -, -(CH 2 ) n1 C(O)NR aa (CH 2 ) n2 -, -(CH 2 ) n1 (CR aa R bb ) n2 -, -(CR aa R bb ) n1 (CH 2 ) n2 NR cc -, -(CH 2 ) n1 NR aa (CR bb R cc ) n2 -, -(CH 2 ) n1 S(O) n2 - selected from the group consisting of; R aa From R cc is hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, cyano-substituted C 1～6 Alkyl, C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 aryl and 5- to 14-membered heteroaryl, wherein the amino, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, cyano-substituted C 1～6 Alkyl, C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 Aryl and 5- to 14-membered heteroaryl are selected from the group consisting of deuterium, halogen, amino, hydroxy, cyano, nitro, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, cyano-substituted C 1～6 Alkyl, C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 each optionally substituted with one or more substituents selected from the group consisting of aryl and 5- to 14-membered heteroaryl; Or, R aa From R cc Any two of these are combined to form C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 aryl or 5- to 14-membered heteroaryl, wherein said C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 The aryl or 5- to 14-membered heteroaryl is selected from the group consisting of deuterium, halogen, amino, hydroxy, cyano, nitro, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, cyano-substituted C 1～6 Alkyl, C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 optionally substituted with one or more substituents selected from the group consisting of aryl and 5- to 14-membered heteroaryl; L 2 is -(CH 2 ) n3 C(O)NR dd (CH 2 ) n4 - and; R dd is hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, cyano-substituted C 1～6 Alkyl, C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 aryl and 5- to 14-membered heteroaryl, wherein the amino, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, cyano-substituted C 1～6 Alkyl, C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 Aryl and 5- to 14-membered heteroaryl are selected from the group consisting of deuterium, halogen, amino, hydroxy, cyano, nitro, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, cyano-substituted C 1～6 Alkyl, C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 each optionally substituted with one or more substituents selected from the group consisting of aryl and 5- to 14-membered heteroaryl; Ring A is C 6～14 selected from the group consisting of aryl and 5- to 14-membered heteroaryl; R 1 is hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 Aryl, C 6～14 aryloxy, 5- to 14-membered heteroaryl, and 5- to 14-membered heteroaryloxy, wherein said amino, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 Aryl, C 6～14 Aryloxy, 5- to 14-membered heteroaryl and 5- to 14-membered heteroaryloxy are selected from the group consisting of deuterium, halogen, amino, hydroxy, cyano, nitro, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, cyano-substituted C 1～6 Alkyl, C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 Aryl, C 6～14 Aryloxy, 5- to 14-membered heteroaryl, 5- to 14-membered heteroaryloxy, -(CH 2 ) m1 OR1a, -(CH 2 ) m1 SR1a, -(CH 2 ) m1 C(O)R1a, -(CH 2 ) m1 NR1aR1b, -(CH 2 ) m1 C(O)NR1aR1b, -(CH 2 ) m1 NR1aC(O)R1b and -(CH 2 ) m1 S(O) m2 R1a, each optionally substituted with one or more substituents selected from the group consisting of: R1a and R1b are hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, cyano-substituted C 1～6 Alkyl, C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 aryl and 5- to 14-membered heteroaryl, wherein the amino, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, cyano-substituted C 1～6 Alkyl, C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 Aryl and 5- to 14-membered heteroaryl are selected from the group consisting of deuterium, halogen, amino, hydroxy, cyano, nitro, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, cyano-substituted C 1～6 Alkyl, C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 each optionally substituted with one or more substituents selected from the group consisting of aryl and 5- to 14-membered heteroaryl; Alternatively, R1a and R1b may be joined to form C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 aryl or 5- to 14-membered heteroaryl, wherein said C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 The aryl or 5- to 14-membered heteroaryl is selected from the group consisting of deuterium, halogen, amino, hydroxy, cyano, nitro, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, cyano-substituted C 1～6 Alkyl, C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 optionally substituted with one or more substituents selected from the group consisting of aryl and 5- to 14-membered heteroaryl; R 2 is hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 3～8 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 selected from the group consisting of aryl and 5- to 14-membered heteroaryl; R 3 is hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 3～8 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 selected from the group consisting of aryl and 5- to 14-membered heteroaryl; R a is hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 3～8 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 Aryl, 5- to 14-membered heteroaryl, -(CH 2 ) n5 R gg , -(CH 2 ) n5 OR gg , -(CH 2 ) n5 C(O)OR gg , -(CH 2 ) n5 SR gg , -(CH 2 ) n5 NR gg C(O)(CH 2 ) n6 R hh , -(CH 2 ) n5 NR gg C(O)OR hh , -(CH 2 ) n5 NR gg C(O)NR hh R ii , -(CH 2 ) n5 NR gg R hh , -NR gg (CH 2 ) n5 R hh , -(CH 2 ) n5 C(O)NR gg (CH 2 ) n6 R hh , -(CH 2 ) n5 C(O)R gg and -OC(R gg R hh ) n5 (CH 2 ) n6 R ii selected from the group consisting of: R gg From R ii is hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, cyano-substituted C 1～6 Alkyl, C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 aryl and 5- to 14-membered heteroaryl, wherein the amino, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, cyano-substituted C 1～6 Alkyl, C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 Aryl and 5- to 14-membered heteroaryl are selected from the group consisting of deuterium, halogen, amino, hydroxy, cyano, nitro, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, cyano-substituted C 1～6 Alkyl, C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 each optionally substituted with one or more substituents selected from the group consisting of aryl and 5- to 14-membered heteroaryl; Or, R gg From R ii Any two of these are combined to form C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 aryl or 5- to 14-membered heteroaryl, wherein said C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 The aryl or 5- to 14-membered heteroaryl is selected from the group consisting of deuterium, halogen, amino, hydroxy, cyano, nitro, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, cyano-substituted C 1～6 Alkyl, C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 optionally substituted with one or more substituents selected from the group consisting of aryl and 5- to 14-membered heteroaryl; x is an integer from 0 to 6; e is an integer from 0 to 3; n1, n3, and n5 are each independently an integer from 0 to 3; n2, n4, and n6 are each independently an integer from 0 to 2; m1 is an integer from 0 to 3; m2 is an integer between 0 and 2] 1. A compound, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that:

2. L 1 is a bond, -(CH 2 ) n1 -, -(CH 2 ) n1 C(O)-, -(CH 2 ) n1 NR aa -, -(CH 2 ) n1 S(O) n2 -, -(CH 2 ) n1 C(O)NR aa - and -C(O)NR aa (CH 2 ) n2 - selected from the group consisting of; L 2 But -(CH 2 ) n3 C(O)NR dd - and; Ring A is C 6～10 selected from the group consisting of aryl and 5- to 10-membered heteroaryl; R 1 But hydrogen, halogen, amino, cyano, C 1～4 Alkyl, C 1～4 Alkoxy, C 2～4 Alkenyl, C 2～4 Alkynyl, C 1～4 Haloalkyl, C 3～6 Cycloalkyl, 3- to 6-membered heterocyclyl, C 6～10 aryl, and 5- to 8-membered heteroaryl, wherein said C 2～4 Alkenyl, C 2～4 Alkynyl, C 3～6 Cycloalkyl, 3- to 6-membered heterocyclyl, C 6～10 Aryl and 5- to 8-membered heteroaryl are selected from the group consisting of deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thioxo, C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, C 1～4 Deuterated alkyl, C 1～4 Haloalkyl, C 1～4 Alkoxy, C 1～4 Haloalkoxy, C 1～4 Hydroxyalkyl, C 3～6 Cycloalkyl, 3- to 6-membered heterocyclyl, C 6～10 Aryl, 5- to 8-membered heteroaryl, -(CH 2 ) m1 C(O)R1a, -(CH 2 ) m1 NR1aR1b, -(CH 2 ) m1 C(O)NR1aR1b, -(CH 2 ) m1 NR1aC(O)R1b and -(CH 2 ) m1 S(O) m2 R1a, each optionally substituted with one or more substituents selected from the group consisting of: R 2 However, hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1～3 Alkyl, C 2～5 Alkenyl, C 2～5 Alkynyl, C 1～3 Deuterated alkyl, C 1～3 Haloalkyl, C 1～3 Hydroxyalkyl, C 1～3 Alkoxy, C 1～3 Haloalkoxy, C 3～6 Cycloalkyl, 3- to 10-membered heterocyclyl, C 6～12 selected from the group consisting of aryl and 5- to 12-membered heteroaryl; R 3 However, hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1～3 Alkyl, C 2～5 Alkenyl, C 2～5 Alkynyl, C 1～3 Deuterated alkyl, C 1～3 Haloalkyl, C 1～3 Hydroxyalkyl, C 1～3 Alkoxy, C 1～3 Haloalkoxy, C 3～6 Cycloalkyl, 3- to 10-membered heterocyclyl, C 6～12 selected from the group consisting of aryl and 5- to 12-membered heteroaryl; R a However, hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1～3 Alkyl, C 2～5 Alkenyl, C 2～5 Alkynyl, C 1～3 Deuterated alkyl, C 1～3 Haloalkyl, C 1～3 Hydroxyalkyl, C 1～3 Alkoxy, C 1～3 Haloalkoxy, C 3～6 Cycloalkyl, 3- to 10-membered heterocyclyl, C 6～12 selected from the group consisting of aryl and 5- to 12-membered heteroaryl 2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof.

3. L 1 is a bond, -NH-, -C(O)NHCH 2 - and -C(O)N(CH 3 )CH 2 - selected from the group consisting of; L 2 But -CH 2 C(O)NH-; Ring A is selected from the group consisting of phenyl, oxadiazolyl, and pyridyl; R 1 is hydrogen, methyl, ethyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl, fluorine, chlorine, bromine, amino, isopropenyl, cyclopropyl, cyclopentyl, cyclopentenyl, oxetanyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, phenyl, pyridyl, 【Chemistry 2】 selected from the group consisting of: R 2 However, hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1～3 Alkyl, C 2～5 Alkenyl, C 2～5 Alkynyl, C 1～3 Deuterated alkyl, C 1～3 Haloalkyl, C 1～3 Hydroxyalkyl, C 1～3 Alkoxy, C 1～3 Haloalkoxy, C 3～6 cycloalkyl, 3- to 8-membered heterocyclyl containing 1 to 3 atoms selected from the group consisting of N, O, and S; C 6～10 aryl and 5-10 membered heteroaryl containing 1-3 atoms selected from the group consisting of N, O and S; R 3 However, hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1～3 Alkyl, C 2～5 Alkenyl, C 2～5 Alkynyl, C 1～3 Deuterated alkyl, C 1～3 Haloalkyl, C 1～3 Hydroxyalkyl, C 1～3 Alkoxy, C 1～3 Haloalkoxy, C 3～6 cycloalkyl, 3- to 8-membered heterocyclyl containing 1 to 3 atoms selected from the group consisting of N, O, and S; C 6～10 aryl and 5-10 membered heteroaryl containing 1 to 3 atoms selected from the group consisting of N, O, and S atoms; R a However, hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1～3 Alkyl, C 2～5 Alkenyl, C 2～5 Alkynyl, C 1～3 Deuterated alkyl, C 1～3 Haloalkyl, C 1～3 Hydroxyalkyl, C 1～3 Alkoxy, C 1～3 Haloalkoxy, C 3～6 cycloalkyl, 3- to 8-membered heterocyclyl containing 1 to 3 atoms selected from the group consisting of N, O, and S; C 6～10 aryl and 5- to 10-membered heteroaryl containing 1 to 3 atoms selected from the group consisting of N, O, and S 2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof.

4. R 2 is hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, oxo, thioxo, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, fluoromethyl, fluoroethyl, fluoropropyl, chloromethyl, chloroethyl, chloropropyl, bromomethyl, bromoethyl, bromopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy, propoxy, fluoro fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, epoxypropyl, epoxybutyl, epoxypentyl, epoxyhexyl, epoxyheptyl, aziridinyl, azetidinyl, azacyclopentyl, azacyclohexyl, azacycloheptyl, thienyl, pyrrolyl, pyridyl, pyranyl, piperazinyl, phenyl, and naphthyl 2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof.

5. R 3 is hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, oxo, thioxo, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, fluoromethyl, fluoroethyl, fluoropropyl, chloromethyl, chloroethyl, chloropropyl, bromomethyl, bromoethyl, bromopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy, propoxy, fluoro fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, epoxypropyl, epoxybutyl, epoxypentyl, epoxyhexyl, epoxyheptyl, aziridinyl, azetidinyl, azacyclopentyl, azacyclohexyl, azacycloheptyl, thienyl, pyrrolyl, pyridyl, pyranyl, piperazinyl, phenyl, and naphthyl 2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof.

6. R a is hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, oxo, thioxo, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, fluoromethyl, fluoroethyl, fluoropropyl, chloromethyl, chloroethyl, chloropropyl, bromomethyl, bromoethyl, bromopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy, propoxy, fluoro fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, epoxypropyl, epoxybutyl, epoxypentyl, epoxyhexyl, epoxyheptyl, aziridinyl, azetidinyl, azacyclopentyl, azacyclohexyl, azacycloheptyl, thienyl, pyrrolyl, pyridyl, pyranyl, piperazinyl, phenyl, and naphthyl 2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof.

7. The compound may further comprise the formula (III): 【Transformation 3】 [In the formula, R 5 is hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 3～8 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 selected from the group consisting of aryl and 5- to 14-membered heteroaryl; R b is hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 3～8 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 selected from the group consisting of aryl and 5- to 14-membered heteroaryl; y is an integer between 0 and 3.

2. The compound according to claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that it is shown as:

8. R 5 However, hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1～3 Alkyl, C 2～5 Alkenyl, C 2～5 Alkynyl, C 1～3 Deuterated alkyl, C 1～3 Haloalkyl, C 1～3 Hydroxyalkyl, C 1～3 Alkoxy, C 1～3 Haloalkoxy, C 3～6 Cycloalkyl, 3- to 10-membered heterocyclyl, C 6～12 selected from the group consisting of aryl and 5- to 12-membered heteroaryl; R b However, hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1～3 Alkyl, C 2～5 Alkenyl, C 2～5 Alkynyl, C 1～3 Deuterated alkyl, C 1～3 Haloalkyl, C 1～3 Hydroxyalkyl, C 1～3 Alkoxy, C 1～3 Haloalkoxy, C 3～6 Cycloalkyl, 3- to 10-membered heterocyclyl, C 6～12 selected from the group consisting of aryl and 5- to 12-membered heteroaryl; 8. The compound according to claim 7, its stereoisomer or a pharmaceutically acceptable salt thereof.

9. R 5 However, hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1～3 Alkyl, C 2～5 Alkenyl, C 2～5 Alkynyl, C 1～3 Deuterated alkyl, C 1～3 Haloalkyl, C 1～3 Hydroxyalkyl, C 1～3 Alkoxy, C 1～3 Haloalkoxy, C 3～6 cycloalkyl, 3- to 8-membered heterocyclyl containing 1 to 3 atoms selected from the group consisting of N, O, and S; C 6～10 aryl and 5-10 membered heteroaryl containing 1 to 3 atoms selected from the group consisting of N, O and S; 8. The compound according to claim 7, its stereoisomer or a pharmaceutically acceptable salt thereof.

10. R 5 is hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, oxo, thioxo, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, fluoromethyl, fluoroethyl, fluoropropyl, chloromethyl, chloroethyl, chloropropyl, bromomethyl, bromoethyl, bromopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy, propoxy, fluoro selected from the group consisting of fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, epoxypropyl, epoxybutyl, epoxypentyl, epoxyhexyl, epoxyheptyl, aziridinyl, azetidinyl, azacyclopentyl, azacyclohexyl, azacycloheptyl, thienyl, pyrrolyl, pyridyl, pyranyl, piperazinyl, phenyl, and naphthyl; R b is hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, oxo, thioxo, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, fluoromethyl, fluoroethyl, fluoropropyl, chloromethyl, chloroethyl, chloropropyl, bromomethyl, bromoethyl, bromopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy, propoxy, fluoro selected from the group consisting of fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, epoxypropyl, epoxybutyl, epoxypentyl, epoxyhexyl, epoxyheptyl, aziridinyl, azetidinyl, azacyclopentyl, azacyclohexyl, azacycloheptyl, thienyl, pyrrolyl, pyridyl, pyranyl, piperazinyl, phenyl and naphthyl; 8. The compound according to claim 7, its stereoisomer or a pharmaceutically acceptable salt thereof.

11. The compound may further comprise the formula (IV): 【Chemistry 4】 [In the formula, Ring C is C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 selected from the group consisting of aryl and 5- to 14-membered heteroaryl, or ring C is absent; R c is hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 Aryl, C 6～14 Aryloxy, 5- to 14-membered heteroaryl, 5- to 14-membered heteroaryloxy, -(CH 2 ) m3 OR1c, -(CH 2 ) m3 SR1c, -(CH 2 ) m3 C(O)R1c, -(CH 2 ) m3 NR1cR d , -(CH 2 ) m3 C(O)NR1cR d , -(CH 2 ) m3 NR1cC(O)R d and -(CH 2 ) m3 S(O) m4 R1c, wherein said amino, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 Aryl, C 6～14 Aryloxy, 5- to 14-membered heteroaryl and 5- to 14-membered heteroaryloxy are substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, cyano-substituted C 1～6 Alkyl, C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 Aryl, C 6～14 each optionally substituted with one or more substituents selected from the group consisting of aryloxy, 5- to 14-membered heteroaryl, and 5- to 14-membered heteroaryloxy; R1c and R d is hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, cyano-substituted C 1～6 Alkyl, C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 aryl and 5- to 14-membered heteroaryl, wherein the amino, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, cyano-substituted C 1～6 Alkyl, C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 Aryl and 5- to 14-membered heteroaryl are substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, cyano-substituted C 1～6 Alkyl, C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 each optionally substituted with one or more substituents selected from the group consisting of aryl and 5- to 14-membered heteroaryl; Alternatively, R and R d combine to form C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 aryl or 5- to 14-membered heteroaryl, wherein said C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 The aryl or 5- to 14-membered heteroaryl may be substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, cyano-substituted C 1～6 Alkyl, C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 optionally substituted with one or more substituents selected from the group consisting of aryl and 5- to 14-membered heteroaryl; m3 is an integer from 0 to 3; m4 is an integer between 0 and 2; z is an integer between 0 and 6.

8. The compound according to claim 7, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that it is shown as:

12. Ring C is C 3～8 Cycloalkyl, 3- to 10-membered heterocyclyl, C 6～12 selected from the group consisting of aryl and 5- to 12-membered heteroaryl; R c But hydrogen, halogen, amino, cyano, C 1～4 Alkyl, C 1～4 Alkoxy, C 2～4 Alkenyl, C 2～4 Alkynyl, C 1～4 Haloalkyl, C 3～6 Cycloalkyl, 3- to 6-membered heterocyclyl, C 6～10 Aryl, 5- to 8-membered heteroaryl, -(CH 2 ) m3 OR1c, -(CH 2 ) m3 SR1c, -(CH 2 ) m3 C(O)R1c, -(CH 2 ) m3 NR1cR d , -(CH 2 ) m3 C(O)NR1cR d and -(CH 2 ) m3 NR1cC(O)R d wherein said amino, C 1～4 Alkyl, C 1～4 Alkoxy, C 2～4 Alkenyl, C 2～4 Alkynyl, C 3～6 Cycloalkyl, 3- to 6-membered heterocyclyl, C 6～10 Aryl and 5- to 8-membered heteroaryl are substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thioxo, C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, C 1～4 Deuterated alkyl, C 1～4 Haloalkyl, C 1～4 Alkoxy, C 1～4 Haloalkoxy, C 1～4 Hydroxyalkyl, C 3～6 Cycloalkyl, 3- to 6-membered heterocyclyl, C 6～10 each optionally substituted with one or more substituents selected from the group consisting of aryl and 5- to 8-membered heteroaryl; 12. The compound of claim 11, its stereoisomer or a pharmaceutically acceptable salt thereof.

13. Ring C is C 3～6 cycloalkyl, 3- to 8-membered heterocyclyl containing 1 to 3 atoms selected from the group consisting of N, O, and S; C 6～10 aryl and 5-10 membered heteroaryl containing 1 to 3 atoms selected from the group consisting of N, O and S; 12. The compound of claim 11, its stereoisomer or a pharmaceutically acceptable salt thereof.

14. Ring C is selected from the group consisting of cyclopropyl, cyclopentyl, cyclopentenyl, oxetanyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, phenyl, and pyridyl; R c is hydrogen, methyl, ethyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl, fluorine, chlorine, bromine, amino and -C(O)CHF 2 selected from the group consisting of:

12. The compound of claim 11, its stereoisomer or a pharmaceutically acceptable salt thereof.

15. The compound may further comprise the formula (V): 【Transformation 5】 [In the formula, R 1 is hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 aryl and 5- to 14-membered heteroaryl, wherein the amino, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 Aryl and 5- to 14-membered heteroaryl are substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, cyano-substituted C 1～6 Alkyl, C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～12 each optionally substituted with one or more substituents selected from the group consisting of aryl and 5- to 12-membered heteroaryl; R 2 is hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 aryl and 5- to 14-membered heteroaryl, wherein the amino, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 Aryl and 5- to 14-membered heteroaryl are substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, cyano-substituted C 1～6 Alkyl, C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～12 each optionally substituted with one or more substituents selected from the group consisting of aryl and 5- to 12-membered heteroaryl; R 3 is hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 3～8 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 selected from the group consisting of aryl and 5- to 14-membered heteroaryl; e is an integer between 0 and 3.

2. The compound according to claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that it is shown as:

16. R 1 But hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 3～12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6～14 aryl and 5- to 14-membered heteroaryl, wherein the amino, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～10 Aryl and 5- to 10-membered heteroaryl are selected from the group consisting of deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, C 1～3 Alkyl, C 2～3 Alkenyl, C 2～3 Alkynyl, C 1～3 Deuterated alkyl, C 1～3 Haloalkyl, C 1～3 Alkoxy, C 1～3 Haloalkoxy, C 1～3 Hydroxyalkyl, cyano-substituted C 1～3 Alkyl, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～10 each optionally substituted with one or more substituents selected from the group consisting of aryl and 5- to 10-membered heteroaryl; R 2 But hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1～3 Alkyl, C 2～3 Alkenyl, C 2～3 Alkynyl, C 1～3 Deuterated alkyl, C 1～3 Haloalkyl, C 1～3 Alkoxy, C 1～3 Haloalkoxy, C 1～3 Hydroxyalkyl, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～10 selected from the group consisting of aryl and 5- to 10-membered heteroaryl; R 3 However, hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1～3 Alkyl, C 2～3 Alkenyl, C 2～3 Alkynyl, C 1～3 Deuterated alkyl, C 1～3 Haloalkyl, C 1～3 Hydroxyalkyl, C 1～3 Alkoxy, C 1～3 Haloalkoxy, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～10 selected from the group consisting of aryl and 5- to 10-membered heteroaryl; e is an integer between 0 and 3 16. The compound according to claim 15, its stereoisomer or a pharmaceutically acceptable salt thereof.

17. R 1 が、-H、-NH 2 、-F、-Cl、-Br、-CH 3 、-CH 2 CH 3 、-CF 3 、 【Transformation 6】 selected from the group consisting of: R 2 is selected from the group consisting of hydrogen, amino, cyano, fluorine, chlorine, bromine, methyl, isopropyl, trifluoromethyl, methoxy, cyclopropyl, and morpholinyl; R 3 is selected from the group consisting of hydrogen and cyano 16. The compound according to claim 15, its stereoisomer or a pharmaceutically acceptable salt thereof.

18. The specific structure of the compound is as follows: 【Chemistry 7-1】 【Chemistry 7-2】 【Transformation 7-3】 【Chemistry 7-4】 18. The compound according to any one of claims 1 to 17, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that:

19. A process for preparing a compound of formula (III) according to claim 7, its stereoisomer or a pharmaceutically acceptable salt thereof, comprising the steps of: 【Transformation 8】 Reacting the compound of formula (III-2) with a compound of formula (III-3) to obtain the target compound of formula (III). Including, During the ceremony, X 2 is a halogen A method characterized by:

20. X 2 20. The method of claim 19, wherein is chlorine or bromine.

21. 16. A process for preparing a compound of formula (V) according to claim 15, its stereoisomer or a pharmaceutically acceptable salt thereof, comprising the steps of: 【Chemistry 9】 reacting the compound of formula (V-2) with a compound of formula (V-3) to obtain the target compound of formula (V). Including, During the ceremony, X 5 is a halogen A method characterized by:

22. X 2 22. The method of claim 21, wherein is chlorine or bromine.

23. 20. A pharmaceutical composition comprising a therapeutically effective dose of a compound according to any one of claims 1 to 18, its stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

24. 26. Use of a compound according to any one of claims 1 to 18, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 23 in the preparation of a P2X3 inhibitor.

25. 26. Use of a compound according to any one of claims 1 to 18, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 23 in the preparation of a medicament for the treatment of a neurological disease.

26. 26. The use according to claim 25, wherein the neurological disorder is selected from the group consisting of gynecological disorders, urinary tract conditions, respiratory disorders and pain-related diseases or conditions.

27. 26. The use according to claim 25, wherein the neurological disorder is selected from the group consisting of endometriosis, overactive bladder, pulmonary fibrosis and chronic cough.

28. 27. The use of claim 26, wherein the pain-related disease or condition is selected from the group consisting of neuropathic pain and pain and discomfort associated with uterine fibroids.

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